Heterocyclic amides and their use for modulating splicing

Abstract

To provide heterocyclic amides and their use for modulating splicing.SOLUTION: The present disclosure features compounds of Formula (I-a) and related compositions that, inter alia, modulate nucleic acid splicing, e.g., splicing of a pre-mRNA, as well as methods of use thereof.SELECTED DRAWING: None

Description

[Technical Field]

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

[0002] Alternative splicing is a major source of protein diversity in higher eukaryotes and is frequently regulated in tissue- or developmental stage-specific manners. Disease-associated alternative splicing patterns in pre-mRNAs are often mapped to alterations in splice site signals or sequence motifs and regulatory splicing factors (Faustino and Cooper (2003), Genes Dev 17(4):419-37). Current therapeutic approaches to modulate RNA expression include oligonucleotide targeting and gene therapy; however, these modalities each present their own unique challenges. Therefore, new technologies for modulating 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 Summary of the Invention [Means for solving the problem]

[0004] The present disclosure features, inter alia, compounds and related compositions that modulate nucleic acid splicing, e.g., pre-mRNA splicing, and methods of their use. In one embodiment, the compounds described herein are compounds of Formula (I) (e.g., Formula (Ia), (Ib), (Ic), (Id), (Ie), (If), or (Ig)), and pharmaceutically acceptable salts, solvates, hydrates, tautomers, or stereoisomers thereof. The present disclosure further provides methods of using the compounds of the invention (e.g., compounds of Formula (I), (Ia), (Ib), (Ic), (Id), (Ie), (If), (Ig), or (Ih) and pharmaceutically acceptable salts, solvates, hydrates, tautomers, stereoisomers thereof) and compositions thereof, e.g., to target, and in embodiments, bind to or complex with, a nucleic acid (e.g., a pre-mRNA or a small nuclear ribonucleoprotein (snRNP) or a nucleic acid component of the spliceosome), a protein (e.g., a protein component of a snRNP or spliceosome, e.g., a member of the splicing machinery, e.g., one or more of U1, U2, U4, U5, U6, U11, U12, U4atac, U6atac snRNP), or a combination thereof. In another aspect, the compounds described herein can be used to alter the composition or structure of a nucleic acid (e.g., a pre-mRNA or an mRNA (e.g., a pre-mRNA and an mRNA resulting from the pre-mRNA), for example, by increasing or decreasing splicing at a splice junction. In some embodiments, increasing or decreasing splicing modulates the level of a gene product (e.g., RNA or protein) produced. In another aspect, the compounds described herein are useful in treating a disease, disorder, or condition, such as splicin. In some embodiments, the compounds described herein (e.g., compounds of Formula (I), (Ia), (Ib), (Ic), (Id), (Ie), (If), (Ig), or (Ih) and pharmaceutically acceptable salts, solvates, hydrates, tautomers, and stereoisomers thereof) and compositions thereof are used to prevent and / or treat a proliferative disease, disorder, or condition in a subject (e.g., a disease, disorder, or condition characterized by unwanted cell proliferation, such as cancer or a benign neoplasm). In some embodiments, the compounds described herein (e.g., compounds of Formula (I), (Ia), (Ib), (Ic), (Id), (Ie), (If), (Ig), or (Ih) and pharmaceutically acceptable salts, solvates, hydrates, tautomers, stereoisomers thereof) and compositions thereof are used to prevent and / or treat a non-proliferative disease, disorder, or condition. In some embodiments, the compounds described herein (e.g., compounds of Formula (I), (Ia), (Ib), (Ic), (Id), (Ie), (If), (Ig), or (Ih) and pharmaceutically acceptable salts, solvates, hydrates, tautomers, stereoisomers thereof) and compositions thereof are used to prevent and / or treat a neurological disease or disorder, an autoimmune disease or disorder, an immunodeficiency disease or disorder, a lysosomal storage disease or disorder, a cardiovascular disease or disorder, a metabolic disease or disorder, a respiratory disease or disorder, a renal disease or disorder, or an infectious disease in a subject.

[0005] In another aspect, the present disclosure provides a compound of formula (Ia): [ka] (In the formula, A and B each independently represent one or more R 1 X, Y, and Z are each independently cycloalkyl, heterocyclyl, aryl, or heteroaryl optionally substituted with C(R 3a ), C(R 3a )(R 3b ), N, N(R 3c) or O, and at least one of X, Y and Z is N, N(R 3c ) or O, and the bond within the ring containing X, Y and Z may be a single or double bond, when valences permit; L 1 and L 2 each independently represents absent, C1-C6 alkylene, C1-C6 heteroalkylene, —O—, —C(O)—, —N(R 4 )-, -N(R 4 )C(O)- or -C(O)N(R 4 )-, and each alkylene and heteroalkylene is selected from one or more R 5 and each R 1 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 and each alkyl, alkylene, alkenyl, alkynyl, heteroalkyl, haloalkyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl may be selected from one or more R 6 or two R 1 The groups, together with the atom to which they are attached, form a 3- to 7-membered cycloalkyl, heterocyclyl, aryl, or heteroaryl, and each cycloalkyl, heterocyclyl, aryl, and heteroaryl may be joined by one or more R 6 and each R 2are 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 3 b are each independently 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 or R 3a and R 3b each of which, together with the carbon atom to which they are attached, form an oxo group; R 3c is hydrogen or C1-C6 alkyl; each R 4 are independently hydrogen, C1-C6 alkyl, or C1-C6 haloalkyl; each R 5 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 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 Dand each alkyl, alkenyl, alkynyl, heteroalkyl, haloalkyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl may be selected from one or more R 11 and each R 7 is C1-C6 alkyl, halo, cyano, oxo or -OR A1 and each R 11 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 are independently hydrogen, C1-C6 alkyl, C1-C6 haloalkyl, 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 independently represents hydrogen, C1-C6 alkyl, C1-C6 heteroalkyl, cycloalkyl, heterocyclyl, or -OR A or R B and R C are one or more R's along with the atoms to which they are attached. 7 forming a 3- to 7-membered heterocyclyl ring optionally substituted with D and R E 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 C1-C6 alkyl; m is 0, 1, or 2; and x is 0, 1, or 2. or a pharmaceutically acceptable salt, solvate, hydrate, tautomer or stereoisomer thereof.

[0006] In another aspect, the present invention provides pharmaceutical compositions comprising a compound of Formula (I) (e.g., a compound of Formula (Ia), (Ib), (Ic), (Id), (Ie), (If), (Ig), (Ih), or (Ii)) or a pharmaceutically acceptable salt, solvate, hydrate, tautomer, or stereoisomer thereof, and optionally a pharmaceutically acceptable excipient. In one embodiment, the pharmaceutical compositions described herein comprise 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), (If), (Ig), or (Ih)) or a pharmaceutically acceptable salt, solvate, hydrate, tautomer, or stereoisomer thereof.

[0007] In another aspect, the disclosure provides a method of modulating splicing, e.g., splicing of nucleic acids (e.g., DNA or RNA, e.g., pre-mRNA), with a compound of Formula (I) (e.g., a compound of Formula (I), (Ia), (Ib), (Ic), (Id), (Ie), (If), (Ig), or (Ih)) or a pharmaceutically acceptable salt, solvate, hydrate, tautomer, or stereoisomer thereof. In another aspect, the disclosure provides a method of modulating splicing, e.g., splicing of nucleic acids (e.g., DNA or RNA, e.g., pre-mRNA), with a compound of Formula (I) (e.g., a compound of Formula (I), (Ia), (Ib), (Ic), (Id), (Ie), (If), (Ig), or (Ih)) or a pharmaceutically acceptable salt, solvate, hydrate, tautomer, or stereoisomer thereof. The present invention provides compositions for use in modulating splicing. Modulating splicing can include affecting any step involved in splicing and can include events upstream or downstream of the splicing event. For example, in some embodiments, a compound of formula (I) binds to a target, e.g., a target nucleic acid (e.g., DNA or RNA, e.g., precursor RNA, e.g., pre-mRNA), a target protein, or a combination thereof (e.g., snRNP and pre-mRNA). The target can include a splice site in a pre-mRNA or a component of the splicing machinery, such as Ul snRNP. In some embodiments, a compound of formula (I) modifies a target nucleic acid (e.g., DNA or RNA, e.g., precursor RNA, e.g., pre-mRNA), a target protein, or a combination thereof. In some embodiments, a compound of Formula (I) increases or decreases splicing at a splice site on a target nucleic acid (e.g., an RNA, e.g., a precursor RNA, e.g., a pre-mRNA) by about 0.5% or more (e.g., about 1%, 2%, 3%, 4%, 5%, 10%, 20%, 30%, 40%, 50%, 75%, 90%, 95% or more), relative to a reference (e.g., the absence of a compound of Formula (I), e.g., a healthy or diseased cell or tissue). In some embodiments, the presence of a compound of Formula (I) results in an increase or decrease in transcription of the target nucleic acid (e.g., an RNA) by about 0.5% or more (e.g., about 1%, 2%, 3%, 4%, 5%, 10%, 20%, 30%, 40%, 50%, 75%, 90%, 95% or more), relative to a reference (e.g., the absence of a compound of Formula (I), e.g., a healthy or diseased cell or tissue).

[0008] In another aspect, the disclosure provides methods for preventing and / or treating a disease, disorder, or condition in a subject by administering a compound of Formula (I) (e.g., a compound of Formula (I), (Ia), (Ib), (Ic), (Id), (Ie), (If), (Ig), or (Ih)) or a pharmaceutically acceptable salt, solvate, hydrate, tautomer, or stereoisomer thereof, or a related composition. In some embodiments, the disease or disorder involves undesired or aberrant splicing. In some embodiments, the disease or disorder is a proliferative disease, disorder, or condition. Exemplary proliferative diseases include cancer, benign neoplasm, or angiogenesis. In other embodiments, the disclosure provides methods for treating and / or preventing a non-proliferative disease, disorder, or condition. In yet other embodiments, the present disclosure provides methods of treating and / or preventing a neurological disease or disorder, an autoimmune disease or disorder, an immunodeficiency disease or disorder, a lysosomal storage disease or disorder, a cardiovascular disease or disorder, a metabolic disease or disorder, a respiratory disease or disorder, a renal disease or disorder, or an infectious disease.

[0009] In another aspect, the disclosure provides a method of down-regulating the expression (e.g., level or rate of production) of a target protein in a biological sample or a subject with a compound of Formula (I) (e.g., a compound of Formula (I), (Ia), (Ib), (Ic), (Id), (Ie), (If), (Ig), or (Ih)) or a pharmaceutically acceptable salt, solvate, hydrate, tautomer, or stereoisomer thereof. In another aspect, the disclosure provides a method of up-regulating the expression (e.g., level or rate of production) of a target protein in a biological sample or a subject with a compound of Formula (I) (e.g., a compound of Formula (I), (Ia), (Ib), (Ic), (Id), (Ie), (If), (Ig), or (Ih)) or a pharmaceutically acceptable salt, solvate, hydrate, tautomer, or stereoisomer thereof. In another aspect, the present disclosure provides methods for modifying a target protein isoform in a biological sample or a subject with a compound of Formula (I) (e.g., a compound of Formula (I), (Ia), (Ib), (Ic), (Id), (Ie), (If), (Ig), or (Ih)) or a pharmaceutically acceptable salt, solvate, hydrate, tautomer, or stereoisomer thereof. Another aspect of the present disclosure relates to methods for inhibiting the activity of a target protein in a biological sample or a subject. In some embodiments, administering a compound of Formula (I) to a biological sample, cell, or subject comprises inhibiting cell growth or inducing cell death.

[0010] In another aspect, the present disclosure provides compounds of formula (I) (e.g., formula (I), (Ia), (I- In some embodiments, the disease or disorder involves undesired or aberrant splicing. In some embodiments, the disease or disorder is a proliferative disease, disorder, or condition. Exemplary proliferative diseases 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 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 infectious diseases.

[0011] In another aspect, the disclosure provides compositions for use in down-regulating the expression (e.g., level or rate of production) of a target protein in a biological sample or a subject with a compound of Formula (I) (e.g., a compound of Formula (I), (Ia), (Ib), (Ic), (Id), (Ie), (If), (Ig), or (Ih)) or a pharmaceutically acceptable salt, solvate, hydrate, tautomer, or stereoisomer thereof. In another aspect, the disclosure provides compositions for use in up-regulating the expression (e.g., level or rate of production) of a target protein in a biological sample or a subject with a compound of Formula (I) (e.g., a compound of Formula (I), (Ia), (Ib), (Ic), (Id), (Ie), (If), (Ig), or (Ih)) or a pharmaceutically acceptable salt, solvate, hydrate, tautomer, or stereoisomer thereof. In another aspect, the disclosure provides compositions for use in modifying a target protein isoform in a biological sample or a subject with a compound of Formula (I) (e.g., a compound of Formula (I), (Ia), (Ib), (Ic), (Id), (Ie), (If), (Ig), or (Ih)) or a pharmaceutically acceptable salt, solvate, hydrate, tautomer, or stereoisomer thereof. Another aspect of the disclosure relates to compositions for use in inhibiting the activity of a target protein in a biological sample or a subject. In some embodiments, administering a compound of Formula (I) to a biological sample, cell, or subject comprises inhibiting cell growth or inducing cell death.

[0012] In another aspect, the disclosure features a kit that includes a container having a compound of Formula (I) (e.g., a compound of Formula (I), (Ia), (Ib), (Ic), (Id), (Ie), (If), (Ig), or (Ih)) or a pharmaceutically acceptable salt, solvate, hydrate, tautomer, stereoisomer, or pharmaceutical composition thereof. In certain embodiments, the kits described herein further include instructions for administering the compound of Formula (I) or a pharmaceutically acceptable salt, solvate, hydrate, tautomer, stereoisomer, or pharmaceutical composition thereof.

[0013] In any aspect of the disclosure, in some embodiments, the compounds described herein, target nucleic acids (e.g., DNA, RNA, e.g., pre-mRNA), or target proteins can be prepared using methods described in U.S. Pat. No. 8,729,263, U.S. Patent Application Publication No. 2015 / 0005289, WO 2014 / 028459, WO 2016 / 128343, WO 2016 / 196386, WO 2017 / 100726, In some embodiments, the target nucleic acid (e.g., DNA, RNA, e.g., pre-mRNA) or target protein is a compound other than a compound described herein, a target nucleic acid (e.g., DNA, RNA, e.g., pre-mRNA), or a target protein, as described in one of WO 2018 / 232039, WO 2018 / 098446, WO 2019 / 028440, WO 2019 / 060917, and WO 2019 / 199972. The target nucleic acid (e.g., DNA, RNA, e.g., pre-mRNA) or target protein is a compound, target nucleic acid (e.g., DNA, RNA, e.g., pre-mRNA) or target protein described in one of U.S. Pat. No. 8,729,263, U.S. Patent Application Publication No. 2015 / 0005289, WO 2014 / 028459, WO 2016 / 128343, WO 2016 / 196386, WO 2017 / 100726, WO 2018 / 232039, WO 2018 / 098446, WO 2019 / 028440, WO 2019 / 060917, and WO 2019 / 199972, each of which is incorporated herein by reference in its entirety.

[0014] The details of one or more embodiments of the invention are set forth herein. Other features, objects, and advantages of the invention will become apparent from the detailed description, examples, and claims. DETAILED DESCRIPTION OF THE INVENTION

[0015] Selected Chemical Definitions Definitions of specific functional groups and chemical terms are explained in more detail below. Chemical elements are listed in the Periodic Table of the Elements, CAS version, Handbook of Chemistry and Physics, 75 th Ed., inside cover, and specific functional groups are generally defined as described therein. Further, general principles of organic chemistry and specific functional moieties and reactivities 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 Edition, Cambridge University Press, Cambridge, 1987.

[0016] The abbreviations used herein have their conventional meaning within the chemical and biological arts. The chemical structures and formulae set forth herein are constructed according to the standard rules of chemical valency known in the chemical arts.

[0017] When a range of values ​​is listed, it is intended to encompass each value and subrange within the 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 indicated below to aid in understanding the description and intended scope of the present invention.

[0019] As used herein, "alkyl" refers to a straight-chain or branched saturated hydrocarbon group having 1 to 24 carbon atoms ("C1-C 24 In some embodiments, an alkyl group has 1 to 12 carbon atoms ("C1-C 12 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-C8 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 instance of an alkyl group can independently be optionally substituted, i.e., unsubstituted (an "unsubstituted alkyl") or substituted with one or more substituents, e.g., 1 to 5 substituents, 1 to 3 substituents, or 1 substituent (a "substituted alkyl"). In certain embodiments, an alkyl group can be an unsubstituted C1-C 10 Alkyl (e.g., -CH3). In certain embodiments, the alkyl group is a substituted C1-C6 alkyl.

[0020] As used herein, "alkenyl" refers to the radical of a straight-chain 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 In some embodiments, an alkenyl group has 2 to 10 carbon atoms (“C-C 10In some embodiments, an alkenyl group has 2 to 8 carbon atoms ("C2-C8 alkenyl"). In some embodiments, an alkenyl group has 2 to 6 carbon atoms ("C2-C6 alkenyl"). In some embodiments, an alkenyl group has 2 carbon atoms ("C2 alkenyl"). The one or more carbon-carbon double bonds can be internal (such as 2-butenyl) or terminal (such as 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), and the like. Examples of C2-C6 alkenyl groups include the aforementioned C 2~4 Alkenyl groups include pentenyl (C5), pentadienyl (C5), hexenyl (C6), and the like. Further examples of alkenyl include heptenyl (C7), octenyl (C8), octatrienyl (C8), and the like. Each instance of an alkenyl group can independently be optionally substituted, i.e., unsubstituted (an "unsubstituted alkenyl") or substituted with one or more substituents, e.g., 1 to 5 substituents, 1 to 3 substituents, or 1 substituent (a "substituted alkenyl"). In certain embodiments, an alkenyl group is an unsubstituted C1-C 10 alkenyl. In certain embodiments, the alkenyl group is a 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 In some embodiments, an alkynyl group has 2 to 10 carbon atoms (“C-C 10In some embodiments, an alkynyl group has 2 to 8 carbon atoms ("C2-C8 alkynyl"). In some embodiments, an alkynyl group has 2 to 6 carbon atoms ("C2-C6 alkynyl"). In some embodiments, an alkynyl group has 2 carbon atoms ("C2 alkynyl"). The 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), and the like. Each instance of an alkynyl group can independently be optionally substituted, i.e., unsubstituted ("unsubstituted alkynyl") or substituted with one or more substituents, e.g., 1 to 5 substituents, 1 to 3 substituents, or 1 substituent ("substituted alkynyl"). In certain embodiments, an alkynyl group is an unsubstituted C 2~10 In certain embodiments, the alkynyl group is a substituted C 2~6 It is alkynyl.

[0022] As used herein, the term "haloalkyl" refers to an acyclic, stable, straight or branched chain, or combination thereof, containing at least one carbon atom and at least one halogen selected from the group consisting of F, Cl, Br, and I. The halogens F, Cl, Br, and I can be placed at any position of the haloalkyl group. Exemplary haloalkyl groups include, but are not limited to, -CF, -CCl, -CH-CF, -CH-CCl, -CH-CBr, -CH-CI, -CH-CH-CH(CF)-CH, -CH-CH-CH(Br)-CH, and -CH-CH=CH-CH-CF. Each instance of a haloalkyl group can independently be optionally substituted, i.e., unsubstituted (an "unsubstituted haloalkyl") or substituted with one or more substituents, e.g., 1 to 5 substituents, 1 to 3 substituents, or 1 substituent (a "substituted haloalkyl").

[0023] As used herein, the term "heteroalkyl" refers to an acyclic, stable, straight or branched chain, or combination thereof, containing 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 can be optionally oxidized, and the nitrogen heteroatom can be optionally quaternized. The heteroatoms O, N, P, S, and Si can be placed at any position of the heteroalkyl group. Exemplary heteroalkyl groups 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)-CH3, -CH=CH-O-CH3, -Si(CH3)3, -CH2-CH=N-OCH3, -CH=CH-N(CH3)-CH3, -O-CH3, and -O-CH2-CH3. Up to two or three heteroatoms may be consecutive, such as, for example, -CH2-NH-OCH3 and -CH2-O-Si(CH3)3. When "heteroalkyl" is referred to, it can be followed by -CHO, -NR C R D When a specific heteroalkyl group such as -CH2O or -NR2 is recited, the heteroalkyl and -CH2O or -NR2 are used interchangeably. C R D It will be understood that the terms "heteroalkyl" and "heteroalkyl-" are not redundant or mutually exclusive. Rather, specific heteroalkyl groups are recited to add clarity. Thus, the term "heteroalkyl" is used herein to refer to specific heteroalkyl groups, such as -CHO, -NR C R D etc. Each example of a heteroalkyl group can independently be optionally substituted, i.e., unsubstituted (an "unsubstituted heteroalkyl") or substituted with one or more substituents, e.g., 1 to 5 substituents, 1 to 3 substituents, or 1 substituent (a "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 (e.g., having 6, 10, or 14 pi electrons shared in a cyclic array) having 6 to 14 ring carbon atoms and no heteroatoms provided in the aromatic ring system ("C6-C 14 In some embodiments, an aryl group has 6 ring carbon atoms ("C 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, the aryl group has 14 ring carbon atoms ("C 14 Aryl"; e.g., anthracyl). The aryl group is, for example, C6-C 10 and may be described as a 1-membered aryl, where the term "membered" refers to a non-hydrogen ring atom within the moiety. Aryl groups include phenyl, naphthyl, indenyl, and tetrahydronaphthyl. Each instance of an aryl group can independently be optionally substituted, i.e., unsubstituted ("unsubstituted aryl") or substituted with one or more substituents ("substituted aryl"). In certain embodiments, an aryl group is an unsubstituted C6-C 14 In certain embodiments, the aryl group is a substituted C-C 14 It is aryl.

[0025] As used herein, "heteroaryl" refers to a radical of a 5- to 10-membered monocyclic or bicyclic 4n+2 aromatic ring system (e.g., having 6 or 10 π electrons shared by the cyclic array) having ring carbon atoms and 1 to 4 ring heteroatoms provided in the aromatic ring system, where each heteroatom is independently selected from nitrogen, oxygen, and sulfur ("5- to 10-membered heteroaryl"). In heteroaryl groups containing one or more nitrogen atoms, the point of attachment can be a carbon or nitrogen atom, when valence permits. Heteroaryl bicyclic ring systems can contain one or more heteroatoms in one or both rings. "Heteroaryl" also includes ring systems in which a heteroaryl ring, as defined above, is fused to one or more aryl groups, the point of attachment being on the aryl or heteroaryl ring; in such cases, the number of ring members designates the number of ring members in the fused (aryl / heteroaryl) ring system. In bicyclic heteroaryl groups in which one ring does not contain heteroatoms (e.g., indolyl, quinolinyl, carbazolyl, etc.), the point of attachment can be on either ring, i.e., the ring containing the heteroatom (e.g., 2-indolyl) or the ring containing no heteroatoms (e.g., 5-indolyl). Heteroaryl groups can be described, for example, as 6- to 10-membered heteroaryl, where the term "member" refers to a non-hydrogen ring atom within the moiety. Each instance of a heteroaryl group can independently be optionally substituted, 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 5-membered heteroaryl groups containing one heteroatom include, but are not limited to, pyrrolyl, furanyl, and thiophenyl. Exemplary 5-membered heteroaryl groups containing two heteroatoms include, but are not limited to, imidazolyl, pyrazolyl, oxazolyl, isoxazolyl, thiazolyl, and isothiazolyl. Exemplary 5-membered heteroaryl groups containing three heteroatoms include, but are not limited to, triazolyl, oxadiazolyl, and thiadiazolyl. Exemplary 5-membered heteroaryl groups containing four heteroatoms include, but are not limited to, tetrazolyl. Exemplary 6-membered heteroaryl groups containing one heteroatom include, but are not limited to, pyridinyl. Exemplary 6-membered heteroaryl groups containing two heteroatoms include, but are not limited to, pyridazinyl, pyrimidinyl, and pyrazinyl. Exemplary 6-membered heteroaryl groups containing three or four heteroatoms include, but are not limited to, triazinyl and tetrazinyl, respectively. Exemplary 7-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, benzofuranyl, benzisofuranyl, benzimidazolyl, benzoxazolyl, benzisoxazolyl, benzoxadiazolyl, benzthiazolyl, benzisothiazolyl, benzthiadiadiazolyl, indolizinyl, and purinyl. Exemplary 6,6-bicyclic heteroaryl groups include, but are not limited to, naphthyridinyl, pteridinyl, quinolinyl, isoquinolinyl, cinnolinyl, quinoxalinyl, phthalazinyl, and quinazolinyl. Other exemplary heteroaryl groups include heme and heme derivatives.

[0027] As used herein, "cycloalkyl" refers to a group having 3 to 10 ring carbon atoms ("C3-C 10"Cycloalkyl" refers to the radical of a non-aromatic cyclic hydrocarbon group having from 3 to 8 ring carbon atoms ("C3-C8 cycloalkyl"). In some embodiments, a cycloalkyl group has from 3 to 6 ring carbon atoms ("C3-C6 cycloalkyl"). In some embodiments, a cycloalkyl group has from 3 to 6 ring carbon atoms ("C3-C6 cycloalkyl"). In some embodiments, a cycloalkyl group has from 5 to 10 ring carbon atoms ("C5-C6 cycloalkyl"). 10 Cycloalkyl groups include, for example, For example, it may be described as a C4-C7 membered cycloalkyl, where the term "membered" refers to a non-hydrogen ring atom within the moiety. 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), cyclohexadienyl (C6), and the like. Exemplary C3-C8 cycloalkyl groups include, but are not limited to, the aforementioned C3-C6 cycloalkyl groups as well as cycloheptyl (C7), cycloheptenyl (C7), cycloheptadienyl (C7), cycloheptatrienyl (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), bicyclo[3.1.1]heptanyl (C7), and the like. 10 The cycloalkyl group includes the above-mentioned C3 to C8 cycloalkyl groups as well as cyclononyl (C9), cyclononenyl (C9), cyclodecyl (C 10 ), cyclodecenyl (C 10 ), octahydro-1H-indenyl (C9), decahydronaphthalenyl (C 10 ), spiro[4.5]decanyl (C 10), and the like. As the foregoing examples illustrate, in certain embodiments, cycloalkyl groups are monocyclic ("monocyclic cycloalkyl") or contain fused, bridged, or spiro ring systems, such as bicyclic ring systems ("bicyclic cycloalkyl"), and can be saturated or partially unsaturated. "Cycloalkyl" also includes ring systems in which a cycloalkyl ring, as defined above, is fused to one or more aryl groups whose points of attachment are on the cycloalkyl ring; in such cases, the number of carbons continues to designate the number of carbons in the cycloalkyl ring system. Each instance of a cycloalkyl group can independently be optionally substituted, i.e., unsubstituted ("unsubstituted cycloalkyl") or substituted with one or more substituents ("substituted cycloalkyl"). In certain embodiments, a cycloalkyl group is an unsubstituted C3-C6 10 In certain embodiments, the cycloalkyl group is a substituted C-C 10 It is cycloalkyl.

[0028] As used herein, "heterocyclyl" refers to the radical of a 3- to 10-membered non-aromatic ring system having ring carbon atoms 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 point of attachment can be a carbon or nitrogen atom, when valence permits. Heterocyclyl groups can be either monocyclic ("monocyclic heterocyclyl") or fused, bridged, or spiro ring systems, such as bicyclic ring systems ("bicyclic heterocyclyl"), and can be saturated or partially unsaturated. Heterocyclyl bicyclic ring systems can contain one or more heteroatoms in one or both rings. "Heterocyclyl" also includes ring systems in which a heterocyclyl ring, as defined above, is fused to one or more cycloalkyl groups, the points of attachment of which are on the cycloalkyl or heterocyclyl ring, or to one or more aryl or heteroaryl groups, the points of attachment of which are on the heterocyclyl ring; in such cases, the number of ring members continues to designate 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, where the term "member" refers to the non-hydrogen ring atoms within the moiety, i.e., carbon, nitrogen, oxygen, sulfur, boron, phosphorus, and silicon. Each instance of heterocyclyl may independently be 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 3-10 membered heterocyclyl.

[0029] Exemplary 3-membered heterocyclyl groups containing one heteroatom include, but are not limited to, aziridinyl, oxiranyl, and thiorenyl. Exemplary 4-membered heterocyclyl groups containing one heteroatom include, but are not limited to, azetidinyl, oxetanyl, and thietanyl. Exemplary 5-membered heterocyclyl groups containing one heteroatom include, but are not limited to, Examples of 5-membered heterocyclyl groups containing two heteroatoms include, but are not limited to, tetrahydrofuranyl, dihydrofuranyl, tetrahydrothiophenyl, dihydrothiophenyl, pyrrolidinyl, dihydropyrrolyl, and pyrrolyl-2,5-dione. Examples of 5-membered heterocyclyl groups containing two heteroatoms include, but are not limited to, dioxolanyl, oxasulfuranyl, disulfuranyl, and oxazolidin-2-one. Exemplary 5-membered heterocyclyl groups containing three heteroatoms include, but are not limited to, triazolinyl, oxadiazolinyl, and thiadiazolinyl. Exemplary 6-membered heterocyclyl groups containing one heteroatom include, but are not limited to, piperidinyl (e.g., 2,2,6,6-tetramethylpiperidinyl), tetrahydropyranyl, dihydropyridinyl, pyridinonyl (e.g., 1-methylpyridin-2-onyl), and thianyl. Exemplary 6-membered heterocyclyl groups containing two heteroatoms include, but are not limited to, piperazinyl, morpholinyl, pyridazinonyl (2-methylpyridazin-3-onyl), pyrimidinonyl (e.g., 1-methylpyrimidin-2-onyl, 3-methylpyrimidin-4-onyl), dithianyl, and dioxanyl. Exemplary 6-membered heterocyclyl groups containing two heteroatoms include, but are not limited to, triazinanyl. Exemplary 7-membered heterocyclyl groups containing one heteroatom include, but are not limited to, azepanyl, oxepanyl, and thiepanyl. Exemplary 8-membered heterocyclyl groups containing one heteroatom include, but are not limited to, azocanyl, oxecanyl, and thiocanyl. Exemplary 5-membered heterocyclyl groups (also referred to herein as 5,6-bicyclic heterocyclyl rings) fused to a C6 aryl ring include, but are not limited to, indolinyl, isoindolinyl, dihydrobenzofuranyl, dihydrobenzothienyl, benzoxazolinonyl, etc. Exemplary 5-membered heterocyclyl groups (also referred to herein as 5,5-bicyclic heterocyclyl rings) fused to a heterocyclyl ring include, but are not limited to, octahydropyrrolopyrrolyl (e.g., octahydropyrrolo[3,4-c]pyrrolyl), etc.Exemplary 6-membered heterocyclyl groups (also referred to herein as 4,6-membered heterocyclyl rings) fused to a heterocyclyl ring include, but are not limited to, diazaspirononanyl (e.g., 2,7-diazaspiro[3.5]nonanyl). Exemplary 6-membered heterocyclyl groups (also referred to herein as 6,6-bicyclic heterocyclyl rings) fused to an aryl ring include, but are not limited to, tetrahydroquinolinyl, tetrahydroisoquinolinyl, and the like. Exemplary 6-membered heterocyclyl groups (also referred to herein as 6,7-bicyclic heterocyclyl rings) fused to a cycloalkyl ring include, but are not limited to, azabicyclooctanyl (e.g., (1,5)-8-azabicyclo[3.2.1]octanyl). Exemplary 6-membered heterocyclyl groups (also referred to herein as 6,8-bicyclic heterocyclyl rings) fused to a cycloalkyl ring 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," by themselves or as part of another substituent, unless otherwise stated, are divalent radicals derived from alkyl, alkenyl, alkynyl, haloalkylene, heteroalkylene, cycloalkyl, or heterocyclyl, respectively. For example, the term "alkenylene," by itself or as part of another substituent, means, unless otherwise stated, a divalent group derived from an alkene. An alkylene, alkenylene, alkynylene, haloalkylene, heteroalkylene, cycloalkylene, or heterocyclylene group may be described, for example, as C1-C6-membered alkylene, C2-C6-membered alkenylene, C2-C6-membered alkynylene, C1-C6-membered haloalkylene, C1-C6-membered heteroalkylene, C3-C8-membered cycloalkylene, or C3-C8-membered heterocyclylene, where the term "membered" refers to a non-hydrogen atom within the moiety. For heteroalkylene and heterocyclylene groups, heteroatoms can also occupy either or both of the chain termini (e.g., alkyleneoxy, alkylenedioxy, alkyleneamino, alkylenediamino, etc.). Furthermore, the orientation of the linking group's formula may determine the orientation of the linking group. No preference is implied. For example, the formula -C(O)R'- can represent both -C(O)R'- and -R'C(O)-.

[0031] As used herein, the term "cyano" or "-CN" refers to a substituent having a carbon atom attached to a nitrogen atom by a triple bond, e.g., C≡N.

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

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

[0034] As used herein, the term "nitro" refers to a substituent having two oxygen atoms attached to a nitrogen atom, e.g., --NO.sub.2.

[0035] As used herein, the term "nucleobase" refers to a nitrogen-containing biological compound found linked to a sugar in a nucleoside, which is a basic building block of deoxyribonucleic acid (DNA) and ribonucleic acid (RNA). The major or naturally occurring nucleobases 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. Because A, G, C, and T occur in DNA, these molecules are referred to as DNA bases. A, G, C, and U are referred to as 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 nucleobases that do not function as a normal part of the genetic code are referred to as non-naturally occurring. In one embodiment, the nucleobase can 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 polymers thereof in single- or double-stranded form. The term "nucleic acid" includes genes, cDNAs, pre-mRNAs, or mRNAs. In one embodiment, a nucleic acid molecule is synthetic (e.g., chemically synthesized) or recombinant. Unless otherwise limited, the term encompasses nucleic acids containing analogs or derivatives of natural nucleotides that have similar binding properties as the reference nucleic acid and are metabolized in a manner similar to natural nucleotides. Unless otherwise indicated, a particular nucleic acid sequence implicitly encompasses not only the sequence explicitly indicated, but also conservatively modified variants thereof (e.g., degenerate codon substitutions), alleles, orthologs, SNPs, and complementary sequences.

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

[0038] Symbols used herein for compounds of formula (I) [ka] refers to the point of attachment to another moiety or functional group within a compound.

[0039] Alkyl, alkenyl, alkynyl, haloalkyl, heteroalkyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl groups as defined herein are optionally substituted. In general, the term "substituted," whether preceded by the term "optionally," refers to a group in which at least one hydrogen atom present on the group (e.g., a carbon or nitrogen atom) has been replaced with an acceptable substituent, e.g., a compound that is stable upon substitution, e.g., rearrangement. "Substituted" means substituted with a substituent that results in a compound that does not undergo spontaneous transformation, such as by cyclization, elimination, or other reaction. Unless otherwise specified, a "substituted" group has a substituent at one or more substitutable positions of the group, and when more than one position in a given structure is substituted, the substituents are the same or different at each position. The term "substituted" is intended to include substitution with all permissible substituents of organic compounds, including any of the substituents described herein, that result in the formation of stable compounds. The present disclosure contemplates any and all such combinations in order to arrive at stable compounds. For purposes of this invention, heteroatoms such as nitrogen may have hydrogen substituents and / or any suitable substituents described herein that satisfy the valence of the heteroatom and result in the formation of a stable moiety.

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

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

[0042] The compounds described herein may contain one or more asymmetric 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 may be in the form of mixtures of stereoisomers, including racemic mixtures and mixtures enriched in one or more stereoisomers. In one embodiment, the stereochemistry depicted in a compound is relative rather than absolute. Isomers can be isolated from mixtures 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 (EL Eliel, Ed., Univ. of Notre Dame Press, Notre Dame, IN 1972). The present disclosure further encompasses the compounds described herein as individual isomers substantially free of other isomers and alternatively as mixtures of various isomers.

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

[0044] In the compositions provided herein, the enantiomerically pure compound may be present together with other active or inactive ingredients. For example, a pharmaceutical composition containing an enantiomerically pure R compound may contain, for example, about 90% excipients and about 10% enantiomerically pure R compound. In certain embodiments, the enantiomerically pure R compound in such a composition may contain, 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 contain, for example, about 90% excipients and about 10% of the enantiomerically pure S compound. In certain embodiments, the enantiomerically pure S compound in such a composition may contain, 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 can be present together with other active or inactive ingredients. For example, a pharmaceutical composition comprising a diastereomerically pure exo compound can contain, for example, about 90% excipients and about 10% diastereomerically pure exo compound. In certain embodiments, the diastereomerically pure exo compound in such a composition can contain, for example, at least about 95% by weight of the exo compound and up to about 5% by weight of the endo compound, relative to the total weight of the compound. For example, a pharmaceutical composition comprising a diastereomerically pure endo compound can contain, for example, about 90% excipients and about 10% by weight of the diastereomerically pure endo compound. In certain embodiments, the diastereomerically pure endo compound in such a composition can contain, for example, at least about 95% by weight of the endo compound and up to about 5% by weight of the exo compound, relative to the total weight of the compound.

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

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

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

[0049] The term "pharmaceutically acceptable salts" is intended to include salts of active compounds prepared using relatively non-toxic acids or bases, depending on the particular substituents found on the compounds described herein. When a compound of the present disclosure contains a relatively acidic functional group, a base addition salt can be obtained by contacting the neutral form of such a compound with a sufficient amount of the desired base, either neat 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. When a compound of the present invention contains a relatively basic functional group, an acid addition salt can be obtained by contacting the neutral form of such a compound with a sufficient amount of the desired acid, either neat or in a suitable inert solvent. Examples of pharmaceutically acceptable acid addition salts include those derived from inorganic acids such as hydrochloric acid, hydrobromic acid, nitric acid, carbonic acid, monohydrogencarbonic acid, phosphoric acid, monohydrogenphosphate, dihydrogenphosphate, sulfuric acid, monohydrogensulfuric acid, hydroiodic acid, or phosphorous acid, as well as those 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 arginate and salts of organic acids such as glucuronic acid or galacturonic acid (see, e.g., Berge et al., Journal of Pharmaceutical Science 66:1-19 (1977)). Certain compounds of the present invention contain both basic and acidic functionalities that allow the compounds to be converted into either base or acid addition salts. These salts can be prepared by methods known to those skilled in the art. Other pharmaceutically acceptable carriers known to those of ordinary skill in the art are suitable for the present invention.

[0050] In addition to salt forms, the present disclosure provides compounds in prodrug form. 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, prodrugs 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" refers to a form of a compound associated with a solvent, usually through solvolysis. This physical association may include hydrogen bonding. Conventional solvents include water, methanol, ethanol, acetic acid, DMSO, THF, diethyl ether, etc. The compound of formula (I) may be prepared, for example, in crystalline form, and may be solvated. Suitable solvates include pharmaceutically acceptable solvates, and further include both stoichiometric and non-stoichiometric solvates. In certain instances, a solvate may be isolated, for example, when one or more solvent molecules are incorporated into the crystal lattice of a crystalline solid. "Solvate" encompasses both solution-phase and isolatable solvates. Representative solvates include hydrates, ethanolates, and methanolates.

[0052] The term "hydrate" refers to a compound associated with water. Typically, the number of water molecules contained in a hydrate of a compound is in a fixed ratio to the number of compound molecules in the hydrate. Thus, a hydrate of a compound 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 may form more than one type of hydrate, including, for example, a monohydrate (x is 1), a lower hydrate (x is a number greater than 0 and less than 1, e.g., a hemihydrate (R·0.5H2O)), and a polyhydrate (x is a number greater than 1, e.g., a dihydrate (R·2H2O) and a hexahydrate (R·6H2O)).

[0053] The term "tautomers" refers to interchangeable forms of a particular compound structure, which differ in the replacement of hydrogen atoms and electrons. Thus, two structures can be in equilibrium by the shifting of π electrons and atoms (usually H). For example, enols and ketones can be converted to tautomers by treatment with acid or base. They are tautomers because they are rapidly interconverted by treatment with an acid or base. Another example of tautomerism is the acid and nitro forms of phenylnitromethane, which are similarly formed by treatment with an acid or base. Tautomers may be relevant to achieving optimal chemical reactivity and biological activity of a compound of interest.

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

[0055] The articles "a" and "an" refer to one or to more than one (e.g., at least one) of the grammatical object of the article. By way of example, "an element" means one element or more than one element. The term "and / or" means either "and" or "or" unless otherwise indicated.

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

[0057] As used herein, "obtain" or "obtaining" refers to obtaining a value, e.g., a numerical value, 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 (e.g., implementing an analytical method or protocol) to obtain a value or physical entity. "Indirectly obtaining" refers to receiving a 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 includes obtaining a sample from a human subject. Directly obtaining a value includes performing a process that obtains mass spectrometry data using a machine or device, e.g., a mass spectrometer.

[0058] As used herein, the terms "administer," "administering," or "administration" refer to implanting, absorbing, ingesting, injecting, inhaling, or otherwise introducing a compound of the invention or a pharmaceutical composition thereof.

[0059] As used herein, the terms "condition," "disease," and "disorder" are used interchangeably.

[0060] The "effective amount" 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 amount of a compound of formula (I) can vary depending on factors such as the desired biological endpoint, the pharmacokinetics of the compound, the condition to be treated, the mode of administration, and the age and health of the subject. An effective amount encompasses therapeutic and prophylactic treatments. For example, in the treatment of cancer, an effective amount of a compound of the present invention can reduce tumor burden or stop tumor growth or spread.

[0061] A "therapeutically effective amount" 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, a therapeutically effective amount 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. A therapeutically effective amount of a compound refers to an amount of a therapeutic agent, alone or in combination with other therapies, that provides a therapeutic benefit in the treatment of a condition. The term "therapeutically effective amount" does not necessarily mean an amount that improves overall treatment. The term "therapeutic agent" can encompass an amount that 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 joined to each other by peptide bonds. As used herein, the term refers to both short chains, e.g., also commonly referred to in the art as peptides, oligopeptides, and oligomers, and longer chains, of which there are many varieties, commonly referred to in the art as proteins.

[0063] As used herein, "prevention," "prevent" and "preventing" refer to treatment that involves administering a therapy, e.g., administering a compound described herein (e.g., a compound of Formula (I)) prior to the onset of a disease, disorder or condition to eliminate the physical signs of the disease, disorder or condition. In some embodiments, "prevention," "prevent" and "preventing" require that no signs or symptoms of the disease, disorder or condition have yet occurred or are yet to be observed. In some embodiments, treatment includes prevention, while in other embodiments, it does not include prevention.

[0064] "Subjects" to which administration is intended include, but are not limited to, humans (i.e., male or female of any age, e.g., a pediatric subject (e.g., infant, child, adolescent) or an adult subject (e.g., young adult, middle-aged adult, or elderly adult)) and / or other non-human animals, such as mammals (e.g., primates (e.g., cynomolgus monkeys, rhesus monkeys); commercially relevant mammals such as cows, 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 can be male or female and at any stage of development. The non-human animal can be a transgenic animal.

[0065] As used herein, the terms "treatment," "treat," and "treating" refer to reversing, alleviating, delaying the onset, or inhibiting the progression of one or more symptoms, signs, or underlying causes of a disease, disorder, or condition (e.g., described herein), e.g., by administering a therapy, e.g., by administering a compound described herein (e.g., a compound of Formula (I)). In one embodiment, treatment includes alleviating, reversing, alleviating, delaying the onset, or inhibiting the progression of a symptom of a disease, disorder, or condition. In one embodiment, treatment includes alleviating, reversing, alleviating, delaying the onset, or inhibiting the progression of the manifestation of a disease, disorder, or condition. In one embodiment, treatment includes alleviating, reversing, alleviating, reducing, or delaying the onset of an underlying cause of a disease, disorder, or condition. In some embodiments, "treatment," "treat," and "treating" require that a sign or symptom of a disease, disorder, or condition has occurred or been observed. In other embodiments, treatment may be administered in the absence of signs or symptoms of a disease or condition, e.g., in prophylactic treatment. For example, treatment may be administered to a susceptible individual prior to the onset of symptoms (e.g., in light of a history of symptoms and / or in light of genetic or other susceptibility factors). Treatment may be continued after symptoms have resolved, e.g., to delay or prevent recurrence. Treatment may be continued after symptoms have resolved, e.g., to delay or prevent recurrence. In some embodiments, treatment includes prevention, and in other embodiments, it does not include prevention.

[0066] "Proliferative disease" refers to a disease caused by abnormal cell proliferation (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., tumor cell metastasis); 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 neoplastic cells. Exemplary proliferative disorders include cancer (i.e., "malignant neoplasms"), benign neoplasms, and angiogenesis.

[0067] A "non-proliferative disease" refers to a disease that does not spread primarily by abnormal proliferation of cells. A non-proliferative disease can be associated with any cell or tissue type in a subject. Exemplary non-proliferative diseases include neurological diseases or disorders (e.g., recurrent expansion diseases); autoimmune diseases or disorders; immunodeficiency diseases or disorders; lysosomal storage diseases or disorders; inflammatory diseases or disorders; cardiovascular conditions, diseases or disorders; metabolic diseases or disorders; respiratory conditions, diseases or disorders; renal diseases or disorders; and infectious diseases.

[0068] compound The present disclosure provides a compound of formula (I): [ka] (In the formula, A and B each independently represent one or more R 1 cycloalkyl, heterocyclyl, aryl, or heteroaryl optionally substituted with; 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, and the bond within the ring containing X, Y and Z may be a single or double bond, when valences permit; L 1 and L 2 each independently represents absent, C1-C6 alkylene, C1-C6 heteroalkylene, —O—, —C(O)—, —N(R 4 )-, -N(R 4 )C(O)- or -C(O)N(R 4 )-, and each alkylene and heteroalkylene is selected from one or more R 5 and each R 1 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 and each alkyl, alkylene, alkenyl, alkynyl, heteroalkyl, haloalkyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl may be selected from one or more R 6 or two R 1 The groups, together with the atom to which they are attached, form a 3- to 7-membered cycloalkyl, heterocyclyl, aryl, or heteroaryl, and each cycloalkyl, heterocyclyl, aryl, and heteroaryl may be joined by one or more R 6 and each R 2 are independently hydrogen, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 heteroalkyl, C1-C6 haloalkyl, halo, cyano, or -ORA and;R 3a and R 3b are each independently 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 or R 3a and R 3b Each of these, together with the carbon atom to which they are attached, forms an oxo group. Accomplishment;R 3c is hydrogen or C1-C6 alkyl; each R 4 are independently hydrogen, C1-C6 alkyl, or C1-C6 haloalkyl; each R 5 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 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 and each alkyl, alkenyl, alkynyl, heteroalkyl, haloalkyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl may be selected from one or more R 11 and each R 7is C1-C6 alkyl, halo, cyano, oxo or -OR A1 and each R 11 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 are independently hydrogen, C1-C6 alkyl, C1-C6 haloalkyl, 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 independently represents hydrogen, C1-C6 alkyl, C1-C6 heteroalkyl, cycloalkyl, heterocyclyl, or -OR A or R B and R C are one or more R's along with the atoms to which they are attached. 7 forming a 3- to 7-membered heterocyclyl ring optionally substituted with D and R E 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 C1-C6 alkyl; m is 0, 1, or 2; x is 0, 1, or 2; and y is 0 or 1. or a pharmaceutically acceptable salt, solvate, hydrate, tautomer or stereoisomer thereof.

[0069] As generally described herein, A and B each independently represent one or more R 1 is a cycloalkyl, heterocyclyl, aryl or heteroaryl optionally substituted with

[0070] In some embodiments, A and B are each independently a monocyclic ring, such as a monocyclic cycloalkyl, a monocyclic heterocyclyl, a monocyclic aryl, or a monocyclic heteroaryl. The monocyclic ring can be saturated, partially unsaturated, or fully unsaturated (e.g., aromatic). In some embodiments, A or B are independently a monocyclic ring 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 is a monocyclic ring optionally substituted with

[0071] In some embodiments, A or B is independently a bicyclic ring, such as a bicyclic cycloalkyl, a bicyclic heterocyclyl, a bicyclic aryl, or a bicyclic heteroaryl. The bicyclic ring can be saturated, partially unsaturated, or fully unsaturated (e.g., aromatic). In some embodiments, A or B is independently a bicyclic ring, including a fused, bridged, or spiro ring 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 bicyclic ring. In some embodiments, A is a 9-membered bicyclic ring. In some embodiments, B is a 9-membered bicyclic ring. In some embodiments, A is a 10-membered bicyclic ring. In some embodiments, B is a 10-membered bicyclic ring. In some embodiments, A is an 11-membered bicyclic ring. In some embodiments, B is an 11-membered bicyclic ring. In some embodiments, A is a 12-membered bicyclic ring. In some embodiments, B is a 12-membered bicyclic ring. In some embodiments, A or B independently selects one or more R 1 is a bicyclic ring optionally substituted with

[0072] 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 fused, bridged, or spiro ring 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 independently comprises one or more R 1 is a tricyclic ring optionally substituted with

[0073] In some embodiments, A or B is independently a monocyclic cycloalkyl, a monocyclic heterocyclyl, a monocyclic aryl, or a monocyclic heteroaryl. In some embodiments, A or B is independently a bicyclic cycloalkyl, a bicyclic heterocyclyl, a bicyclic aryl, or a bicyclic heteroaryl. In some embodiments, A or B is independently a tricyclic cycloalkyl, a tricyclic heterocyclyl, a tricyclic aryl, or a tricyclic heteroaryl. In some embodiments, A is a monocyclic heterocyclyl. In some embodiments, B is a monocyclic heterocyclyl. In some embodiments, A is a bicyclic heterocyclyl. In some embodiments, B is a bicyclic heterocyclyl. 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.

[0074] In some embodiments, A or B is independently a nitrogen-containing heterocyclyl, for example, a heterocyclyl containing one or more nitrogen atoms. The one or more nitrogen atoms of the nitrogen-containing heterocyclyl can be located at any position on the ring. In some embodiments, the nitrogen-containing heterocyclyl is monocyclic, bicyclic, or tricyclic. In some embodiments, A or B is independently a heterocyclyl containing at least 1, at least 2, at least 3, at least 4, at least 5, or at least 6 nitrogen atoms. In some embodiments, A is a heterocyclyl containing one nitrogen atom. In some embodiments, B is a heterocyclyl containing one nitrogen atom. In some embodiments, A is a heterocyclyl containing two nitrogen atoms. In some embodiments, B is a heterocyclyl containing two nitrogen atoms. In some embodiments, A is a heterocyclyl containing three nitrogen atoms. In some embodiments, B is a heterocyclyl containing three nitrogen atoms. In some embodiments, A is a heterocyclyl containing four nitrogen atoms. In some embodiments, B is a heterocyclyl containing four nitrogen atoms. In some embodiments, A or B is independently a nitrogen-containing heterocyclyl containing one or more additional heteroatoms, such as one or more oxygen, sulfur, boron, silicon, or phosphorus. In some embodiments, one or more nitrogens of the nitrogen-containing heterocyclyl can be, for example, R 1 is replaced by .

[0075] 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 can be present at any position on 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 1, at least 2, at least 3, at least 4, at least 5, or at least 6 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 containing one or more additional heteroatoms, such as one or more of oxygen, sulfur, boron, silicon, or phosphorus. In some embodiments, one or more nitrogens in the nitrogen-containing heteroaryl can be, for example, R 1 is replaced by .

[0076] In some embodiments, A is a 6-membered nitrogen-containing heterocyclyl, for example, a 6-membered heterocyclyl containing one or more nitrogen atoms. In some embodiments, A is a 6-membered heterocyclyl containing one nitrogen atom. In some embodiments, A is a 6-membered heterocyclyl containing two nitrogen atoms. In some embodiments, A is a 6-membered heterocyclyl containing three nitrogen atoms. In some embodiments, A is a 6-membered heterocyclyl containing four nitrogen atoms. The one or more nitrogen atoms of the 6-membered nitrogen-containing heterocyclyl can be located at any position on the ring. In some embodiments, A is a 6-membered heterocyclyl containing one or more R 1In some embodiments, one or more nitrogens of the 6-membered nitrogen-containing heterocyclyl are optionally substituted with, for example, R 1 In some embodiments, A is a 6-membered nitrogen-containing heterocyclyl containing one or more additional heteroatoms, such as one or more oxygen, sulfur, boron, silicon, or phosphorus.

[0077] In some embodiments, B is a 5-membered nitrogen-containing heterocyclyl or heteroaryl, for example, a 5-membered heterocyclyl or heteroaryl containing one or more nitrogen atoms. In some embodiments, B is a 5-membered heterocyclyl containing one nitrogen atom. In some embodiments, B is a 5-membered heteroaryl containing one nitrogen atom. In some embodiments, B is a 5-membered heterocyclyl containing two nitrogen atoms. In some embodiments, B is a 5-membered heteroaryl containing two nitrogen atoms. In some embodiments, B is a 5-membered heterocyclyl containing three nitrogen atoms. In some embodiments, B is a 5-membered heteroaryl containing three nitrogen atoms. The one or more nitrogen atoms of the 5-membered nitrogen-containing heterocyclyl or heteroaryl can be located at any position on the ring. In some embodiments, B is selected from the group consisting of one or more R 1 In some embodiments, B is a 5-membered nitrogen-containing heterocyclyl optionally substituted with one or more R 1 optionally replaced with In some embodiments, one or more nitrogens of a 5-membered nitrogen-containing heterocyclyl or heteroaryl can be, for example, R 1 In some embodiments, B is a 5-membered nitrogen-containing heterocyclyl or heteroaryl containing one or more additional heteroatoms, such as one or more oxygen, sulfur, boron, silicon, or phosphorus.

[0078] In some embodiments, B is one or more R 1In some embodiments, B is a nitrogen-containing bicyclic heteroaryl (e.g., a 9-membered nitrogen-containing bicyclic heteroaryl) optionally substituted with one or more R. In some embodiments, B is a 9-membered bicyclic heteroaryl containing one nitrogen atom. In some embodiments, B is a 9-membered bicyclic heteroaryl containing two nitrogen atoms. In some embodiments, B is a 9-membered bicyclic heteroaryl containing three nitrogen atoms. In some embodiments, B is a 9-membered bicyclic heteroaryl containing four nitrogen atoms. The one or more nitrogen atoms of the 9-membered bicyclic heteroaryl can be at any position on the ring. In some embodiments, B is a 9-membered bicyclic heteroaryl containing one or more R 1 is a 9-membered bicyclic heteroaryl substituted with

[0079] In some embodiments, A and B are [ka] [ka] [ka] [ka] [ka] [ka] [ka] [ka] [ka] (In the formula, each R1 is as defined herein) In one embodiment, A and B are each independently selected from the following: In one embodiment, A and B are each independently a saturated, partially saturated, or unsaturated (e.g., aromatic) derivative of one of the above rings In one embodiment, A and B are each independently a stereoisomer of one of the above rings.

[0080] In some embodiments, A and B are [ka] [ka] [ka] (In the formula, each R 1 is as defined herein) In one embodiment, A and B are each independently selected from the following: In one embodiment, A and B are each independently a saturated, partially saturated, or unsaturated (e.g., aromatic) derivative of one of the above rings In one embodiment, A and B are each independently a stereoisomer of one of the above rings.

[0081] In some embodiments, A is [ka] (In the formula, R 1 is as defined herein) is selected from.

[0082] In some embodiments, A is [ka] is selected from.

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

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

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

[0086] 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] is.

[0087] In some embodiments, B is [ka] (In the formula, R 1 is as defined herein) In some embodiments, B is selected from: [ka] is selected from.

[0088] In some embodiments, B is [ka] is selected from.

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

[0090] 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, the selected 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] is.

[0091] In some embodiments, B is a group represented by formula (A) or formula (B): [ka] wherein each of J, K, and M is selected from N and C(R'); R 1 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; at least one of J, K, and M is N; and the bond within the ring containing J, K, and M can be a single or double bond, when valences permit. The structure is as follows.

[0092] 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.

[0093] In some embodiments, B is [ka] In some embodiments, B is selected from: [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] is.

[0094] As generally described herein, L 1 and L 2 are each independently absent or 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 )-refers to the group and each alkylene and heteroalkylene may be one or more R 5 is optionally replaced by

[0095] In some embodiments, L 1 is absent. In some embodiments, L 1 is C1-C6 alkylene (e.g., C1 alkylene, C2 alkylene, C3 alkylene, C4 alkylene, C5 alkylene, or C6 alkylene). 1 is unsubstituted C1-C6 alkylene. In some embodiments, L 1 is a substituted C1-C6 alkylene, for example, one or more R 5 In some embodiments, L is a C1-C6 alkylene substituted with 1 is one R 5 In some embodiments, L is a C alkylene substituted with 1 is —CH— (or methylene). In some embodiments, L 1 is —C(O)— (or carbonyl).

[0096] In some embodiments, L 1 is absent, C1-C6 alkylene, C1-C6 heteroalkylene, -N(R 4 )C(O)- or -C(O)N(R 4 )-, and each alkylene and heteroalkylene is selected from one or more R 5 is optionally replaced by

[0097] In some embodiments, L 1is C1-C6 heteroalkylene (e.g., C1 heteroalkylene, C2 heteroalkylene, C3 heteroalkylene, C4 heteroalkylene, C5 heteroalkylene, or C6 heteroalkylene). 1 is unsubstituted C1-C6 heteroalkylene. In some embodiments, L 1 is a substituted heteroalkylene, e.g., one or more R 5 In some embodiments, the heteroalkylene includes one or more heteroatoms. In some embodiments, the heteroalkylene includes one or more of oxygen, sulfur, nitrogen, boron, silicon, or phosphorus. In some embodiments, L 1 is -N(R 4 )C(O)—. In some embodiments, L 1 is -C(O)N(R 4 In some embodiments, L 1 is -C(O)N(H)-.

[0098] In some embodiments, L 1 is oxygen. In some embodiments, L 1 is R 4 In some embodiments, L 1 is R 4 In some embodiments, L 1 is -N(R 4 )-, for example -N(CH3)-. In some embodiments, L 1 is —NH—. In some embodiments, L 1 is -O-.

[0099] In some embodiments, L 2 is absent, C1-C6 alkylene, C1-C6 heteroalkylene, -N(R 4 )C(O)- or -C(O)N(R 4 )-, and each alkylene and heteroalkylene is selected from one or more R 5 In some embodiments, L2 is unsubstituted C1-C6 heteroalkylene. In some embodiments, L 2 is a substituted heteroalkylene, e.g., one or more R 5 In some embodiments, the heteroalkylene includes one or more heteroatoms. In some embodiments, the heteroalkylene includes 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 is -C(O)N(R 4 In some embodiments, L 2 is -C(O)N(H)-.

[0100] In some embodiments, L 2 is R 4 In some embodiments, L 2 is R 4 In some embodiments, L 2 is -N(R 4 )-, for example -N(CH3)-. In some embodiments, L 2 is -NH-.

[0101] As generally described herein, X, Y, and Z are each independently C(R 3 a ), C(R 3a )(R 3b ), N or N(R 3c ) or O, and W refers to C(R 3a ), C(R 3a ), C(R 3b ), N or N(R 3c In some embodiments, at least one of X, Y, and Z is N or N(R 3c In some embodiments, at least one of X, Y, and Z is O. In some embodiments, at least two of X, Y, and Z are N or N(R3c ). In some embodiments, X is N. In some embodiments, X is N(R 3c In some embodiments, X is O. In some embodiments, X is C(R 3a ) (e.g., 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 ) (e.g., CH). In some embodiments, Y is C(R 3a )C(R 3b ). In some embodiments, Z is N. In some embodiments, Z is N(R 3c In some embodiments, Z is C(R 3a ) (e.g., CH). In some embodiments, Z is C(R 3a )C(R 3b In some embodiments, two of X, Y, and Z are N and the other of X, Y, and Z is C(R 3a ) (e.g., CH). In some embodiments, one of X, Y, and Z is C(R 3a ) (e.g., CH), and the others 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 ) (e.g., CH). In some embodiments, X is C(R 3a ) (e.g., CH), and Y and Z are each independently N.

[0102] In some embodiments, X, Y, and Z are each independently N or C(R 3a ) wherein at least one of X, Y and Z is N, and the bond in the ring containing X, Y and Z can be a single or double bond, when valences permit.

[0103] 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 ), Z is O, and y is 0. In some embodiments, X is C(R 3a ) and Y is C(R 3a ), 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 ), Z is O, and the bond between Y and Z is a single bond.

[0104] In some embodiments, y is 0.

[0105] In some embodiments, R 1 is hydrogen. In some embodiments, R 1 is C1-C6 alkyl. In some embodiments, R 1 is C2-C6 alkenyl. In some embodiments, R 1 is C2-C6 alkynyl. In some embodiments, R 1 is C1-C6 heteroalkyl. In some embodiments, R 1 is C1-C6 haloalkyl (e.g., —CF3). In some embodiments, R 1 is C alkyl (e.g., methyl). In some embodiments, R 1 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. 1 is one or more R 6 In some embodiments, R 1 is one or more R 6 In some embodiments, R 1 is one or more R 6In some embodiments, R 1 is one or more R 6 In some embodiments, R 1 is one or more R 6 In some embodiments, R 1 is methyl.

[0106] In some embodiments, R 1 is a cycloalkyl (e.g., 3- to 7-membered cycloalkyl In some embodiments, R 1 is heterocyclyl (e.g., 3- to 7-membered heterocyclyl). In some embodiments, R 1 is aryl. In some embodiments, R 1 is C1-C6 alkylene-aryl (e.g., benzyl). In some embodiments, R 1 is C1-C6 alkenylene-aryl. In some embodiments, R 1 is C1-C6 alkylene-heteroaryl. In some embodiments, R 1 is heteroaryl. In some embodiments, R 1 is 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 In some embodiments, R 1 is one or more R 6 In some embodiments, R is a heterocyclyl substituted with 1 is one or more R 6 In some embodiments, R 1 is one or more R 6 In some embodiments, R1 is one or more R 6 In some embodiments, R 1 is one or more R 6 In some embodiments, R 1 is one or more R 6 and heteroaryl substituted with

[0107] In some embodiments, R 1 -OR A In some embodiments, R 1 is -NR B R C (e.g., NH or NMe). In some embodiments, R 1 is -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 halo, such as fluoro, chloro, bromo, or iodo. In some embodiments, R 1 is cyano. In some embodiments, R 1 is nitro (—NO). In some embodiments, R 1 is oxo.

[0108] In some embodiments, two R 1 The groups, together with the atom to which they are attached, form a 3- to 7-membered cycloalkyl. In some embodiments, two R1 The groups, together with the atom to which they are attached, form a 3- to 7-membered heterocyclyl. In some embodiments, two R 1 The groups, together with the atom to which they are attached, form a 5- or 6-membered aryl. In some embodiments, two R 1 The groups, together with the atom to which they are attached, form a 5- or 6-membered heteroaryl. A cycloalkyl, heterocyclyl, aryl, or heteroaryl can be formed by one or more R 6 may be substituted with

[0109] In some embodiments, R 2 is hydrogen. In some embodiments, R 2 is halo (e.g., fluoro, chloro, bromo, or iodo). In some embodiments, R 2 is cyano. In some embodiments, R 2 is C1-C6 alkyl. In some embodiments, R 2 is C2-C6 alkenyl. In some embodiments, R 2 is C2-C6 alkynyl. In some embodiments, R 2 -OR A (e.g., —OH).

[0110] In some embodiments, R 3a , R 3b or both are independently 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 are each independently hydrogen or C1-C6 alkyl. In some embodiments, R 3a is hydrogen. In some embodiments, R 3b is hydrogen. In some embodiments, R 3ais C1-C6 alkyl (e.g., methyl). In some embodiments, R 3b is C1-C6 alkyl (e.g., methyl) In some embodiments, R 3a is halo (e.g., fluoro, chloro, bromo, or iodo). In some embodiments, R 3b is halo (e.g., fluoro, chloro, bromo, or iodo). In some embodiments, R 3a is cyano. In some embodiments, R 3b is cyano. In some embodiments, R 3a -OR A (e.g., —OH). In some embodiments, R 3b -OR A (e.g., —OH). In some embodiments, R 3a is -NR B R C In some embodiments, R 3b is -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 together with the carbon atom to which they are attached form an oxo group.

[0111] In some embodiments, R 3c is hydrogen. In some embodiments, R 3c is C1-C6 alkyl. In some embodiments, R 3c is methyl.

[0112] In some embodiments, R4 is hydrogen. In some embodiments, R 4 is C1-C6 alkyl. In some embodiments, R 4 is C1-C6 haloalkyl (e.g., —CF3 or —CHF2). In some embodiments, R 4 is methyl.

[0113] In some embodiments, R 5 is hydrogen. In some embodiments, R 5 is C1-C6 alkyl. In some embodiments, R 5 is C1-C6 heteroalkyl. In some embodiments, R 5 is C1-C6 haloalkyl. In some embodiments, R 5 is C1-C6 cycloalkyl. In some embodiments, R 5 is halo (e.g., fluoro, chloro, bromo, or iodo). In some embodiments, R 5 is cyano. In some embodiments, R 5 is oxo. In some embodiments, R 5 -OR A In some embodiments, R 5 is -NR B R C In some embodiments, R 5 is -C(O)R D or -C(O)OR D is.

[0114] In some embodiments, R 6 is C1-C6 alkyl. In some embodiments, R 6 is C2-C6 alkenyl. In some embodiments, R 6 is C2-C6 alkynyl. In some embodiments, R 6 is C1-C6 heteroalkyl. In some embodiments, R 6 is C1-C6 haloalkyl. In some embodiments, R 6is 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. 6 is one or more R 11 In some embodiments, R 6 is one or more R 11 In some embodiments, R 6 is one or more R 11 In some embodiments, R 6 is one or more R 11 In some embodiments, R 6 is one or more R 11 is a C1-C6 heteroalkyl substituted with

[0115] In some embodiments, R 6 is cycloalkyl. In some embodiments, R 6 is heterocyclyl. In some embodiments, R 6 is aryl. In some embodiments, R 6 is heteroaryl. In some embodiments, R 6 is unsubstituted cycloalkyl, unsubstituted heterocyclyl, unsubstituted aryl, or unsubstituted heteroaryl. In some embodiments, R 6 is one or more R 11 In some embodiments, R 6 is one or more R 11 In some embodiments, R is a heterocyclyl substituted with 6 is one or more R 11 A replaced with In some embodiments, R 6 is one or more R 11 and heteroaryl substituted with

[0116] In some embodiments, R6 is halo (e.g., fluoro, chloro, bromo, or iodo). In some embodiments, R 6 is cyano. In some embodiments, R 6 is oxo. In some embodiments, R 6 -OR A In some embodiments, R 6 is -NR B R C In some embodiments, R 6 is -NR B C(O)R D In some embodiments, R 6 is —NO. 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 is.

[0117] In some embodiments, R 7 is C1-C6 alkyl. In some embodiments, R 7 is halo (e.g., fluoro, chloro, bromo, or iodo). In some embodiments, R 7 is cyano. In some embodiments, R 7 is oxo. In some embodiments, R 7 -OR A1 (e.g., —OH).

[0118] In some embodiments, R 11 is C1-C6 alkyl. In some embodiments, R 11is C1-C6 heteroalkyl. In some embodiments, R 11 is C1-C6 haloalkyl (e.g., —CF3). In some embodiments, R 11 is cycloalkyl. In some embodiments, R 11 is heterocyclyl. In some embodiments, R 11 is aryl. In some embodiments, R 11 is heteroaryl. In some embodiments, R 11 is halo. In some embodiments, R 11 is cyano. In some embodiments, R 11 is oxo. In some embodiments, R 11 -OR A is.

[0119] In some embodiments, R A is hydrogen. In some embodiments, R A is C1-C6 alkyl (e.g., methyl). In some embodiments, R A is C1-C6 haloalkyl. In some embodiments, R A is aryl. In some embodiments, R A is heteroaryl. In some embodiments, R A is C1-C6 alkylene-aryl (e.g., benzyl). In some embodiments, R A is 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 is.

[0120] In some embodiments, R B , R C or both are independently hydrogen, C1-C6 alkyl, C1-C6 heteroalkyl, cycloalkyl, heterocyclyl, or -OR AIn some embodiments, R B and R C Each of R is independently hydrogen. B and R C Each of is independently C1-C6 alkyl. In some embodiments, R B and R C is hydrogen and R B and R C and the other is C1-C6 alkyl. In some embodiments, R B and R C are one or more R's along with the atoms to which they are attached. 7 forming a 3- to 7-membered heterocyclyl ring optionally substituted with

[0121] 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. D and R E are each independently hydrogen In some embodiments, R D and R E are each independently C1-C6 alkyl. In some embodiments, R D is hydrogen. In some embodiments, R E is hydrogen. In some embodiments, R D is C1-C6 alkyl (e.g., methyl). In some embodiments, R E is C1-C6 alkyl (e.g., methyl). In some embodiments, R D is C1-C6 heteroalkyl. In some embodiments, R E is C1-C6 heteroalkyl. In some embodiments, R Dis C1-C6 haloalkyl. In some embodiments, R E is C1-C6 haloalkyl. In some embodiments, R D is cycloalkyl. In some embodiments, R E is cycloalkyl. In some embodiments, R D is heterocyclyl. In some embodiments, R E is heterocyclyl. In some embodiments, R D is aryl. In some embodiments, R E is aryl. In some embodiments, R D is heteroaryl. In some embodiments, R E is heteroaryl. In some embodiments, R D is C1-C6 alkylene-aryl (e.g., benzyl). In some embodiments, R E is C1-C6 alkylene-aryl (e.g., benzyl). In some embodiments, R D is C1-C6 alkylene-heteroaryl. In some embodiments, R E is a C1-C6 alkylene-heteroaryl.

[0122] In some embodiments, R A1 is hydrogen. In some embodiments, R A1 is C1-C6 alkyl (for example, methyl).

[0123] 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.

[0124] In some embodiments, the compound of Formula (I) has the formula (Ia): [ka] (In the formula, A and B each independently represent one or more R 1 cycloalkyl, heterocyclyl, aryl, or heteroaryl optionally substituted with; X, Y, and Z each independently represent C(R 3a ), C(R 3a )(R 3b ), N, N(R 3c ) or O, and at least one of X, Y and Z is N, N(R 3c ) or O, and the bond within the ring containing X, Y and Z can be a single or double bond, when valences allow; L 1 and L 2 each independently represents absent, C1-C6 alkylene, C1-C6 heteroalkylene, —O—, —C(O)—, —N(R 4 )-, -N(R 4 )C(O)- or -C(O)N(R 4 )-, and each alkylene and heteroalkylene is selected from one or more R 5 is optionally replaced by; Each R 1 are independently hydrogen, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 a 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 and each alkyl, alkylene, alkenyl, alkynyl, heteroalkyl, haloalkyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl may be selected from one or more R 6 optionally replaced by; or The Two R's 1 The groups, together with the atom to which they are attached, form a 3- to 7-membered cycloalkyl, heterocyclyl, aryl, or heteroaryl, and each cycloalkyl, heterocyclyl, aryl, and heteroaryl may be joined by one or more R 6 is optionally replaced by; Each R 2 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 are each independently 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 or R 3a and R 3b each of which, together with the carbon atom to which they are attached, form an oxo group; R 3c is hydrogen or C1-C6 alkyl; Each R 4 are independently hydrogen, C1-C6 alkyl, or C1-C6 haloalkyl; Each R 5 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 R6 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 and each alkyl, alkenyl, alkynyl, heteroalkyl, haloalkyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl may be selected from one or more R 11 is optionally replaced by; Each R 7 is C1-C6 alkyl, halo, cyano, oxo or -OR A1 and; Each R 11 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 are independently hydrogen, C1-C6 alkyl, C1-C6 haloalkyl, 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 independently represents hydrogen, C1-C6 alkyl, C1-C6 heteroalkyl, cycloalkyl, heterocyclyl, or -OR A or R B and R C are one or more R's along with the atoms to which they are attached. 7forming a 3- to 7-membered heterocyclyl ring optionally substituted with Each R D and R E 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 C1-C6 alkyl; m is 0, 1 or 2; and x is 0, 1 or 2) or a pharmaceutically acceptable salt, solvate, hydrate, tautomer or stereoisomer thereof It is a sexual body.

[0125] In some embodiments, A is [ka] (In the formula, R 1 is as defined herein) is selected from.

[0126] In some embodiments, A is [ka] is selected from.

[0127] In some embodiments, A is [ka] is selected from.

[0128] In some embodiments, A is [ka] is selected from.

[0129] 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] is.

[0130] In some embodiments, B is [ka] In some embodiments, B is selected from: [ka] is selected from.

[0131] In some embodiments, B is [ka] is selected from.

[0132] In some embodiments, B is [ka] In some embodiments, the selected B is selected from: [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] is.

[0133] In some embodiments, X is N. In some embodiments, X is O. In some embodiments, X is C(R 3a In some embodiments, Y is N. In some embodiments, Y is C(R 3a In some embodiments, Z is C(R 3a ) (e.g., CH). In some embodiments, Z is N. In some embodiments, Z is O. In some embodiments, X and Y are each independently N or N(R 3c ), and Z is C(R 3a ) (e.g., CH). In some embodiments, Y and Z are each independently N or N(R 3c ), and X is C(R 3a ) (e.g., CH). In some embodiments, X is C(R 3a ) and Y is C(R 3a ) and Z is O. In some embodiments, Y is C(R 3a ), and Z is C(R 3a ) and X is O.

[0134] In some embodiments, [ka] teeth, [ka] In some embodiments, [ka] teeth, [ka] In some embodiments, [ka] teeth, [ka] is.

[0135] In some embodiments, L 1 and L 2 are each independently absent, -O-, -N(R 4 )-, -N(R 4 )C(O)- or -C(O)N(R 4 In some embodiments, L 1 and L 2 are each independently absent. In some embodiments, L 1 is absent or -N(R 4 In some embodiments, L 2 is absent, -N(R 4 )C(O)- or -C(O)N(R 4 In some embodiments, L 2 is -C(O)N(R 4 )-.

[0136] In some embodiments, the compound of Formula (I) has the formula (Ib): [ka] (In the formula, A and B each independently represent one or more R 1cycloalkyl, heterocyclyl, aryl, or heteroaryl optionally substituted with; X, Y, and Z each independently represent C(R 3a ), C(R 3a )(R 3b ), N, N(R 3c ) or O, and at least one of X, Y and Z is N, N(R 3c ) or O, and the bond within the ring containing X, Y and Z can be a single or double bond, when valences allow; L 2 represents absence, C1-C6 alkylene, C1-C6 heteroalkylene, -O-, -C(O)-, -N(R 4 )-, -N(R 4 )C(O)- or -C(O)N(R 4 )-, and each alkylene and heteroalkylene is selected from one or more R 5 is optionally replaced by; Each R 1 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 and each alkyl, alkylene, alkenyl, alkynyl, heteroalkyl, haloalkyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl may be selected from one or more R 6 optionally replaced by; or The Two R's 1The groups, together with the atom to which they are attached, form a 3- to 7-membered cycloalkyl, heterocyclyl, aryl, or heteroaryl, and each cycloalkyl, heterocyclyl, aryl, and heteroaryl may be joined by one or more R 6 is optionally replaced by; Each R 2 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 are each independently 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 or R 3a and R 3b each of which, together with the carbon atom to which they are attached, form an oxo group; R 3c is hydrogen or C1-C6 alkyl; Each R 4 are independently hydrogen, C1-C6 alkyl, or C1-C6 haloalkyl; Each R 5 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 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 , -NRB 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 and each alkyl, alkenyl, alkynyl, hexyl, Tetraalkyl, haloalkyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl are each independently one or more R 11 is optionally replaced by; Each R 7 is C1-C6 alkyl, halo, cyano, oxo or -OR A1 and; Each R 11 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 are independently hydrogen, C1-C6 alkyl, C1-C6 haloalkyl, 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 independently represents hydrogen, C1-C6 alkyl, C1-C6 heteroalkyl, cycloalkyl, heterocyclyl, or -OR A or R B and R C are one or more R's along with the atoms to which they are attached. 7 forming a 3- to 7-membered heterocyclyl ring optionally substituted with Each R D and R Eare 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 C1-C6 alkyl; m is 0, 1 or 2; and x is 0, 1 or 2) or a pharmaceutically acceptable salt, solvate, hydrate, tautomer or stereoisomer thereof.

[0137] In some embodiments, A is one or more R 1 In some embodiments, A is a heterocyclyl optionally substituted with. In some embodiments, A is a bicyclic heterocyclyl. In some embodiments, A is a monocyclic nitrogen-containing heterocyclyl. In some embodiments, A is a bicyclic nitrogen-containing heterocyclyl. In some embodiments, A is an optionally substituted piperidinyl. In some embodiments, A is an optionally substituted piperazinyl. In some embodiments, A is [ka] (In the formula, each R 1 are independently hydrogen or C1-C6 alkyl. In some embodiments, A is [ka] In some embodiments, A is [ka] is.

[0138] In some embodiments, L 2 is absent. In some embodiments, L 2 is one or more R 5In some embodiments, L is a C1-C6 heteroalkylene optionally substituted with 2 is -C(O)N(R 4 In some embodiments, L 2 is -C(O)N(H)-.

[0139] In some embodiments, X is N. In some embodiments, X is O. In some embodiments, X is C(R 3a In some embodiments, Y is N. In some embodiments, Y is C(R 3a In some embodiments, Z is C(R 3a ) (e.g., CH). In some embodiments, Z is N. In some embodiments, Z is O. In some embodiments, X and Y are each independently N or N(R 3c ), and Z is C(R 3a ) (e.g., CH). In some embodiments, Y and Z are each independently N or N(R 3c ), and X is C(R 3a ) (e.g., CH). In some embodiments, X is C(R 3a ) and Y is C(R 3a ) and Z is O. In some embodiments, Y is C(R 3a ), and Z is C(R 3a ) and X is O.

[0140] In some embodiments, A is [ka] (In the formula, R 1 is as defined herein) is selected from.

[0141] In some embodiments, A is [ka] is selected from.

[0142] In some embodiments, A is [ka] is selected from.

[0143] In some embodiments, A is [ka] is selected from.

[0144] 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] is.

[0145] In some embodiments, B is [ka] In some embodiments, B is selected from: [ka] is selected from.

[0146] In some embodiments, B is [ka] is selected from.

[0147] In some embodiments, B is [ka] In some embodiments, the selected B is selected from: [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] is.

[0148] In some embodiments, [ka] teeth, [ka] In some embodiments, [ka] teeth, [ka] In some embodiments, [ka] teeth, [ka] is.

[0149] In some embodiments, the compound of Formula (I) has the formula (I-hc): [ka] (In the formula, A and B each independently represent one or more R 1 cycloalkyl, heterocyclyl, aryl, or heteroaryl optionally substituted with; L 2 represents absence, C1-C6 alkylene, C1-C6 heteroalkylene, -O-, -C(O)-, -N(R 4 )-, -N(R 4 )C(O)- or -C(O)N(R 4 )-, and each alkylene and heteroalkylene is selected from one or more R 5 is optionally replaced by; Each R 1 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 Dand each alkyl, alkylene, alkenyl, alkynyl, heteroalkyl, haloalkyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl may be selected from one or more R 6 optionally replaced by; or The Two R's 1 The groups, together with the atom to which they are attached, form a 3- to 7-membered cycloalkyl, heterocyclyl, aryl, or heteroaryl, and each cycloalkyl, heterocyclyl, aryl, and heteroaryl may be joined by one or more R 6 is optionally replaced by; Each R 2 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 3a are independently 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 and; Each R 4 are independently hydrogen, C1-C6 alkyl, or C1-C6 haloalkyl; Each R 5 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 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 , -NRB 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 and each alkyl, alkenyl, alkynyl, heteroalkyl, haloalkyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl may be selected from one or more R 11 is optionally replaced by; Each R 7 is C1-C6 alkyl, halo, cyano, oxo or -OR A1 and; Each R 11 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 are independently hydrogen, C1-C6 alkyl, C1-C6 haloalkyl, 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 independently represents hydrogen, C1-C6 alkyl, C1-C6 heteroalkyl, cycloalkyl, heterocyclyl, or -OR A or R B and R C are one or more R's along with the atoms to which they are attached. 7 forming a 3- to 7-membered heterocyclyl ring optionally substituted with Each R D and R Eare 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 C1-C6 alkyl; m is 0, 1 or 2; and x is 0, 1 or 2) or a pharmaceutically acceptable salt, solvate, hydrate, tautomer or stereoisomer thereof.

[0150] In some embodiments, A is one or more R 1 In some embodiments, A is a bicyclic heterocyclyl. In some embodiments, A is a monocyclic nitrogen-containing heterocyclyl. In some embodiments, A is a bicyclic nitrogen-containing heterocyclyl. In some embodiments, A is an optionally substituted piperidinyl. In some embodiments, A is an optionally substituted In some embodiments, A is piperazinyl substituted by [ka] (In the formula, each R 1 are independently hydrogen or C1-C6 alkyl. In some embodiments, A is [ka] In some embodiments, A is [ka] is.

[0151] In some embodiments, L 2 is absent. In some embodiments, L 2 is one or more R5 In some embodiments, L is a C1-C6 heteroalkylene optionally substituted with 2 is -C(O)N(R 4 In some embodiments, L 2 is -C(O)N(H)-.

[0152] In some embodiments, each R 3a is independently hydrogen or C1-C6 alkyl (e.g., CH3). In some embodiments, each R 3a is independently hydrogen. In some embodiments, each R 3a is independently C1-C6 alkyl (e.g., CH3).

[0153] In some embodiments, B is one or more R 1 In some embodiments, B is a heteroaryl optionally substituted with [ka] (In the formula, each R 1 is as defined above) In some embodiments, B is selected from: [ka] In some embodiments, B is [ka] is.

[0154] In some embodiments, R 2is C1-C6 alkyl. In some embodiments, R 2 is halo (e.g., fluoro). In some embodiments, R 2 -OR A (e.g., —OH). In some embodiments, R 3a In some embodiments, m is 0.

[0155] In some embodiments, A is [ka] (In the formula, R 1 is as defined herein) is selected from.

[0156] In some embodiments, A is [ka] is selected from.

[0157] In some embodiments, A is [ka] is selected from.

[0158] In some embodiments, A is [ka] is selected from.

[0159] 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] is.

[0160] In some embodiments, B is [ka] In some embodiments, B is selected from: [ka] is selected from.

[0161] In some embodiments, B is [ka] is selected from.

[0162] In some embodiments, B is [ka] In some embodiments, the selected B is selected from: [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] is.

[0163] In some embodiments, the compound of Formula (I) has the formula (Id): [ka] (In the formula, A and B each independently represent one or more R 1 cycloalkyl, heterocyclyl, aryl, or heteroaryl optionally substituted with; L 2 represents absence, C1-C6 alkylene, C1-C6 heteroalkylene, -O-, -C(O)-, -N(R 4 )-, -N(R 4 )C(O)- or -C(O)N(R 4 )-, and each alkylene and heteroalkylene is selected from one or more R 5 is optionally replaced by; Each R 1 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 and each alkyl, alkylene, alkenyl, alkynyl, heteroalkyl, haloalkyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl may be selected from one or more R 6optionally replaced by; or The Two R's 1 The groups, together with the atom to which they are attached, form a 3- to 7-membered cycloalkyl, heterocyclyl, aryl, or heteroaryl, and each cycloalkyl, heterocyclyl, aryl, and heteroaryl may be joined by one or more R 6 is optionally replaced by; Each R 2 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 is 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 and; R 3c is hydrogen, C1-C6 alkyl, C1-C6 heteroalkyl, C1-C6 haloalkyl, halo, cyano, or —C(O)R D and; Each R 4 are independently hydrogen, C1-C6 alkyl, or C1-C6 haloalkyl; Each R 5 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 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 , -NRB 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 and each alkyl, alkenyl, alkynyl, heteroalkyl, haloalkyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl may be selected from one or more R 11 is optionally replaced by; Each R 7 is C1-C6 alkyl, halo, cyano, oxo or -OR A1 and; Each R 11 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 are independently hydrogen, C1-C6 alkyl, C1-C6 haloalkyl, 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 independently represents hydrogen, C1-C6 alkyl, C1-C6 heteroalkyl, cycloalkyl, heterocyclyl, or -OR A or R B and R C are one or more R's along with the atoms to which they are attached. 7 forming a 3- to 7-membered heterocyclyl ring optionally substituted with Each R D and R Eare 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 C1-C6 alkyl; m is 0, 1 or 2; and x is 0, 1 or 2) or a pharmaceutically acceptable salt, solvate, hydrate, tautomer or stereoisomer thereof.

[0164] In some embodiments, A is one or more R 1 In some embodiments, A is a heterocyclyl optionally substituted with. In some embodiments, A is a bicyclic heterocyclyl. In some embodiments, A is a monocyclic nitrogen-containing heterocyclyl. In some embodiments, A is a bicyclic nitrogen-containing heterocyclyl. In some embodiments, A is an optionally substituted piperidinyl. In some embodiments, A is an optionally substituted piperazinyl. In some embodiments, A is [ka] (In the formula, each R 1 are independently hydrogen or C1-C6 alkyl. In some embodiments, A is [ka] In some embodiments, A is [ka] is.

[0165] In some embodiments, L 2 is absent. In some embodiments, L 2 is one or more R 5In some embodiments, L is a C1-C6 heteroalkylene optionally substituted with 2 is -C(O)N(R 4 In some embodiments, L 2 is -C(O)N(H)-.

[0166] In some embodiments, R 3a is independently hydrogen or C1-C6 alkyl (e.g., CH3). In some embodiments, R 3a are independently hydrogen. In some embodiments, R 3a is independently C1-C6 alkyl (e.g., CH3).

[0167] In some embodiments, R 3c is independently hydrogen or C1-C6 alkyl (e.g., CH3). In some embodiments, R 3c are independently hydrogen. In some embodiments, R 3c is independently C1-C6 alkyl (e.g., CH3).

[0168] In some embodiments, B is one or more R 1 In some embodiments, B is a heteroaryl optionally substituted with [ka] (In the formula, each R 1 is as defined above) In some embodiments, B is selected from: [ka] In some embodiments, B is [ka] is.

[0169] In some embodiments, A is [ka] (In the formula, R 1 is as defined herein) is selected from.

[0170] In some embodiments, A is [ka] is selected from.

[0171] In some embodiments, A is [ka] is selected from.

[0172] In some embodiments, A is [ka] is selected from.

[0173] 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] is.

[0174] In some embodiments, B is [ka] In some embodiments, B is selected from: [ka] is selected from.

[0175] In some embodiments, B is [ka] is selected from.

[0176] In some embodiments, B is [ka] In some embodiments, the selected B is selected from: [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] is.

[0177] In some embodiments, R 2 is C1-C6 alkyl. In some embodiments, R 2 is halo (e.g., fluoro). In some embodiments, R 2 -OR A (e.g., —OH). In some embodiments, R 3a is hydrogen. In some embodiments, R 3c In some embodiments, m is 0.

[0178] In some embodiments, the compound of Formula (I) has the formula (Ie): [ka] (In the formula, A and B each independently represent one or more R 1 cycloalkyl, heterocyclyl, aryl, or heteroaryl optionally substituted with; X, Y, and Z each independently represent C(R 3a ), C(R 3a )(R 3b ), N, N(R 3c ) or O, and at least one of X, Y and Z is N, N(R 3c ) or O, and the bond within the ring containing X, Y and Z can be a single or double bond, when valences allow; Each R 1 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 and each alkyl, alkylene, alkenyl, alkynyl, heteroalkyl, haloalkyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl may be selected from one or more R 6 optionally replaced by; or The Two R's 1 The groups, together with the atom to which they are attached, form a 3- to 7-membered cycloalkyl, heterocyclyl, aryl, or heteroaryl, and each cycloalkyl, heterocyclyl, aryl, and heteroaryl may be joined by one or more R 6 is optionally replaced by; Each R 2 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 are each independently 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 or R 3a and R 3b each of which, together with the carbon atom to which they are attached, form an oxo group; R 3c is hydrogen or C1-C6 alkyl; Each R 4 are independently hydrogen, C1-C6 alkyl, or C1-C6 haloalkyl; Each R 6 are independently C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 heteroalkyl, C1-C6 haloalkyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, halo, cyano, oxo, -ORA , -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 and each alkyl, alkenyl, alkynyl, heteroalkyl, haloalkyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl may be selected from one or more R 11 is optionally replaced by; Each R 7 is C1-C6 alkyl, halo, cyano, oxo or -OR A1 and; Each R 11 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 are independently hydrogen, C1-C6 alkyl, C1-C6 haloalkyl, 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 independently represents hydrogen, C1-C6 alkyl, C1-C6 heteroalkyl, cycloalkyl, heterocyclyl, or -OR A or R B and R C are one or more R's along with the atoms to which they are attached. 7 forming a 3- to 7-membered heterocyclyl ring optionally substituted with Each R D and R Eare 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 C1-C6 alkyl; m is 0, 1 or 2; and x is 0, 1 or 2) or a pharmaceutically acceptable salt, solvate, hydrate, tautomer or stereoisomer thereof.

[0179] In some embodiments, A is [ka] (In the formula, R 1 is as defined herein) is selected from.

[0180] In some embodiments, A is [ka] is selected from.

[0181] In some embodiments, A is [ka] is selected from.

[0182] In some embodiments, A is [ka] is selected from.

[0183] 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] is.

[0184] In some embodiments, X is N. In some embodiments, X is O. In some embodiments, X is C(R 3a In some embodiments, Y is N. In some embodiments, Y is C(R 3a In some embodiments, Z is C(R 3a ) (e.g., CH). In some embodiments, Z is N. In some embodiments, Z is O. In some embodiments, X and Y are each independently N or N(R 3c ), and Z is C(R 3a ) (e.g., CH). In some embodiments, Y and Z are each independently N or N(R 3c ), and X is C(R 3a ) (e.g., CH). In some embodiments, X is C(R 3a ) and Y is C(R 3a ) and Z is O. In some embodiments, Y is C(R 3a ), and Z is C(R 3a ) and X is O.

[0185] In some embodiments, B is [ka] In some embodiments, B is selected from: [ka] is selected from.

[0186] In some embodiments, B is [ka] is selected from.

[0187] In some embodiments, B is [ka] In some embodiments, the selected B is selected from: [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] is.

[0188] In some embodiments, the compound of Formula (I) has the formula (If): [ka] (In the formula, A and B each independently represent one or more R 1 cycloalkyl, heterocyclyl, aryl, or heteroaryl optionally substituted with; X, Y, and Z each independently represent C(R 3a ), C(R 3a )(R 3b ), N, N(R 3c ) or O, and at least one of X, Y and Z is N, N(R 3c ) or O, and the bond within the ring containing X, Y and Z can be a single or double bond, when valences allow; L 2 represents absence, C1-C6 alkylene, C1-C6 heteroalkylene, -O-, -C(O)-, -N(R 4 )-, -N(R 4 )C(O)- or -C(O)N(R 4 )-, and each alkylene and heteroalkylene is selected from one or more R 5 is optionally replaced by; D, E, J, K, M, and W are each independently N and C(R'), and at least one of D, E, J, K, M, and W is N; the bond within the ring containing D, E, J, K, M, and W can be a single bond or a double bond, when valences permit; Each R 1 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 and each alkyl, alkylene, alkenyl, alkynyl, heteroalkyl, haloalkyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl may be selected from one or more R 6optionally replaced by; or The Two R's 1 The groups, together with the atom to which they are attached, form a 3- to 7-membered cycloalkyl, heterocyclyl, aryl, or heteroaryl, and each cycloalkyl, heterocyclyl, aryl, and heteroaryl may be joined by one or more R 6 is optionally replaced by; R ’ is hydrogen, C1-C6 alkyl or halo; Each R 2 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 are each independently hydrogen, C1-C6 alkyl, C1-C6 hetero Alkyl, C1-C6 haloalkyl, halo, cyano, -OR A , -NR B R C , -C(O)R D or -C(O)OR D or R 3a and R 3b each of which, together with the carbon atom to which they are attached, form an oxo group; R 3c is hydrogen or C1-C6 alkyl; Each R 4 are independently hydrogen, C1-C6 alkyl, or C1-C6 haloalkyl; Each R 5 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 6are 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 and each alkyl, alkenyl, alkynyl, heteroalkyl, haloalkyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl may be selected from one or more R 11 is optionally replaced by; Each R 7 is C1-C6 alkyl, halo, cyano, oxo or -OR A1 and; Each R 11 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 are independently hydrogen, C1-C6 alkyl, C1-C6 haloalkyl, 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 independently represents hydrogen, C1-C6 alkyl, C1-C6 heteroalkyl, cycloalkyl, heterocyclyl, or -OR A or R B and R C are one or more R's along with the atoms to which they are attached. 7forming a 3- to 7-membered heterocyclyl ring optionally substituted with Each R D and R E 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 C1-C6 alkyl; m is 0, 1 or 2; p is 0, 1, 2, 3 or 4; and x is 0, 1 or 2) or a pharmaceutically acceptable salt, solvate, hydrate, tautomer or stereoisomer thereof.

[0189] In some embodiments, the compound of Formula (I) has the formula (Ig): [ka] (In the formula, A and B each independently represent one or more R 1 is optionally replaced by cycloalkyl, heterocyclyl, aryl, or heteroaryl; X, Y, and Z each independently represent C(R 3a ), C(R 3a )(R 3b ), N, N(R 3c ) or O, and at least one of X, Y and Z is N, N(R 3c ) or O, and the bond within the ring containing X, Y and Z can be a single or double bond, when valences allow; L 2 represents absence, C1-C6 alkylene, C1-C6 heteroalkylene, -O-, -C(O)-, -N(R 4 )-, -N(R 4 )C(O)- or -C(O)N(R 4)-, and each alkylene and heteroalkylene is selected from one or more R 5 is optionally replaced by; D, J, K, and M are each independently N and C(R'), and at least one of D, J, K, and M is N; the bonds within the ring containing D, E, J, K, M, and W can be single or double bonds, when valences permit; Each R 1 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 and each alkyl, alkylene, alkenyl, alkynyl, heteroalkyl, haloalkyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl may be selected from one or more R 6 optionally replaced by; or The Two R's 1 The groups, together with the atom to which they are attached, form a 3- to 7-membered cycloalkyl, heterocyclyl, aryl, or heteroaryl, and each cycloalkyl, heterocyclyl, aryl, and heteroaryl may be joined by one or more R 6 is optionally replaced by; R ’ is hydrogen, C1-C6 alkyl or halo; Each R 2 are independently hydrogen, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 heteroalkyl, C1-C6 haloalkyl, halo, cyano, or -ORA and; R 3a and R 3b are each independently 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 or R 3a and R 3b each of which, together with the carbon atom to which they are attached, form an oxo group; R 3c is hydrogen or C1-C6 alkyl; Each R 4 are independently hydrogen, C1-C6 alkyl, or C1-C6 haloalkyl; Each R 5 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 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 Dand each alkyl, alkenyl, alkynyl, heteroalkyl, haloalkyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl may be selected from one or more R 11 is optionally replaced by; Each R 7 is C1-C6 alkyl, halo, cyano, oxo or -OR A1 and; Each R 11 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 are independently hydrogen, C1-C6 alkyl, C1-C6 haloalkyl, 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 independently represents hydrogen, C1-C6 alkyl, C1-C6 heteroalkyl, cycloalkyl, heterocyclyl, or -OR A or R B and R C are one or more R's along with the atoms to which they are attached. 7 forming a 3- to 7-membered heterocyclyl ring optionally substituted with Each R D and R E 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 C1-C6 alkyl; m is 0, 1 or 2; p is 0, 1, 2, 3 or 4; and x is 0, 1 or 2) or a pharmaceutically acceptable salt, solvate, hydrate, tautomer or stereoisomer thereof.

[0190] In some embodiments, the compound of Formula (I) has the formula (Ih): [ka] (In the formula, A and B each independently represent one or more R 1 cycloalkyl, heterocyclyl, aryl, or heteroaryl optionally substituted with; Each R 1 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 and each alkyl, alkylene, alkenyl, alkynyl, heteroalkyl, haloalkyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl may be selected from one or more R 6 optionally replaced by; or The Two R's 1 The groups, together with the atom to which they are attached, form a 3- to 7-membered cycloalkyl, heterocyclyl, aryl, or heteroaryl, and each cycloalkyl, heterocyclyl, aryl, and heteroaryl may be joined by one or more R 6is optionally replaced by; Each R 2 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 3a are independently 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 and; Each R 4 are independently hydrogen, C1-C6 alkyl, or C1-C6 haloalkyl; Each R 6 are independently C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 heteroalkyl, C1-C6 haloalkyl, cycloalkyl, heterocycloalkyl, Aryl, 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 and each alkyl, alkenyl, alkynyl, heteroalkyl, haloalkyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl may be selected from one or more R 11 is optionally replaced by; Each R 7 is C1-C6 alkyl, halo, cyano, oxo or -OR A1 and; Each R 11are independently C1-C6 alkyl, C1-C6 heteroalkyl, C1-C6 haloalkyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, halo, cyano, oxo, or -OR A and; Each R A are independently hydrogen, C1-C6 alkyl, C1-C6 haloalkyl, 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 independently represents hydrogen, C1-C6 alkyl, C1-C6 heteroalkyl, cycloalkyl, heterocyclyl, or -OR A or R B and R C are one or more R's along with the atoms to which they are attached. 7 forming a 3- to 7-membered heterocyclyl ring optionally substituted with Each R D and R E 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 C1-C6 alkyl; m is 0, 1 or 2; and x is 0, 1 or 2) or a pharmaceutically acceptable salt, solvate, hydrate, tautomer or stereoisomer thereof.

[0191] In some embodiments, A is one or more R 1In some embodiments, A is a heterocyclyl optionally substituted with. In some embodiments, A is a bicyclic heterocyclyl. In some embodiments, A is a monocyclic nitrogen-containing heterocyclyl. In some embodiments, A is a bicyclic nitrogen-containing heterocyclyl. In some embodiments, A is an optionally substituted piperidinyl. In some embodiments, A is an optionally substituted piperazinyl. In some embodiments, A is [ka] (In the formula, each R 1 are independently hydrogen or C1-C6 alkyl. In some embodiments, A is [ka] In some embodiments, A is [ka] is.

[0192] In some embodiments, each R 3a is independently hydrogen or C1-C6 alkyl (e.g., CH3). In some embodiments, each R 3a is independently hydrogen. In some embodiments, each R 3a is independently C1-C6 alkyl (e.g., CH3).

[0193] In some embodiments, B is one or more R 1 In some embodiments, B is a heteroaryl optionally substituted with [ka] (In the formula, each R 1 is as defined above) In some embodiments, B is selected from: [ka] In some embodiments, B is [ka] is.

[0194] In some embodiments, A is [ka] (In the formula, R 1 is as defined herein) is selected from.

[0195] In some embodiments, A is [ka] is selected from.

[0196] In some embodiments, A is [ka] is selected from.

[0197] In some embodiments, A is [ka] is selected from.

[0198] 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] is.

[0199] In some embodiments, B is [ka] In some embodiments, B is selected from: [ka] is selected from.

[0200] In some embodiments, B is [ka] is selected from.

[0201] In some embodiments, B is [ka] In some embodiments, the selected B is selected from: [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] is.

[0202] In some embodiments, the compound of Formula (I) is selected from the compounds of Table 1 or a pharmaceutically acceptable salt, solvate, hydrate, tautomer, or stereoisomer thereof.

[0203] [Table 1]

[0204] [Table 2]

[0205] [Table 3]

[0206] [Table 4]

[0207] [Table 5]

[0208] [Table 6]

[0209] [Table 7]

[0210] [Table 8]

[0211] [Table 9]

[0212] [Table 10]

[0213] [Table 11]

[0214] [Table 12]

[0215] [Table 13]

[0216] [Table 14]

[0217] [Table 15]

[0218] [Table 16]

[0219] In some embodiments, for Formula (I), A is a monocyclic heterocyclyl (e.g., piperidinyl); B is a bicyclic heteroaryl (e.g., imidazo[1,2-b]pyridazinyl); L 2 is -C(O)N(R 4)—(e.g., —C(O)N(H)—); X is C(R 3a ) (e.g., CH); Y is C(R 3a ) (e.g., C(CH3)); Z is O; y is 0; and m is 0. In some embodiments, the compound of Formula (I), (Id), (Ie), and (If) is Compound 118, or a pharmaceutically acceptable salt, solvate, hydrate, tautomer, or stereoisomer thereof.

[0220] In some embodiments, for Formula (I), A is a monocyclic heterocyclyl (e.g., piperidinyl); B is a bicyclic heteroaryl (e.g., imidazo[1,2-b]pyridazinyl); L 2 is -C(O)N(R 4 )—(e.g., —C(O)N(H)—); X and Y are each independently C(R 3a ) (e.g., CH); Z is O; y is 0; and m is 0. In some embodiments, the compound of Formula (I), (Id), (Ie), and (If) is compound 119, or a pharmaceutically acceptable salt, solvate, hydrate, tautomer, or stereoisomer thereof. In some embodiments, the compound of Formula (I), (Ia), (Ie), and (II-f) is one of compounds 140-150.

[0221] In some embodiments, for Formula (I), A is a monocyclic heterocyclyl (e.g., piperidinyl); B is a bicyclic heteroaryl (e.g., imidazo[1,2-b]pyridazinyl); L 1 is absent or -N(R 4 )-and;L 2 is absent or -C(O)N(R 4 )—(e.g., —C(O)N(H)—). In some embodiments, for Formula (I), the compound is selected from compounds 118, 141, 228, 229, 242, 243, 269, and 277.

[0222] Pharmaceutical Compositions, Kits and Administration The present invention provides pharmaceutical compositions comprising a compound of Formula (I), e.g., 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 compositions described herein comprise 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, solvate, hydrate, tautomer, or stereoisomer thereof is provided in an effective amount in the pharmaceutical composition. In certain embodiments, the effective amount is a therapeutically effective amount. In certain embodiments, the effective amount is a prophylactically effective amount.

[0223] The pharmaceutical compositions described herein may be prepared by any method known in the art of pharmacology. In general, such preparative methods include the step of bringing into association a compound of formula (I) (the "active ingredient") with the carrier and / or one or more other accessory ingredients, and then, if necessary and / or desired, shaping and / or packaging the product into the desired single or multi-dosage unit.

[0224] Pharmaceutical compositions can be prepared, packaged, and / or sold in bulk as a single unit dose and / or as a plurality of single unit doses. As used herein, a "unit dose" is a discrete amount of pharmaceutical composition containing a predetermined amount of active ingredient. The amount of active ingredient is generally equal to the dosage of the active ingredient that would be administered to a subject and / or a convenient fraction of such a dosage, for example, half or one-third of such a dosage.

[0225] The relative amounts of active ingredient, pharmaceutically acceptable excipient, and / or any additional ingredients in a pharmaceutical composition of the invention will vary depending on the identity, size, and / or condition of the subject being treated, as well as the route by which the composition is administered. By way of example, the composition may contain from 0.1% to 100% (w / w) active ingredient.

[0226] The term "pharmaceutically acceptable excipient" refers to a non-toxic carrier, adjuvant, diluent, or vehicle that does not destroy the pharmacological activity of the compound being formulated. Pharmaceutically acceptable excipients useful for preparing the pharmaceutical compositions of the present invention are any well-known in the art of pharmaceutical formulation, and include inert diluents, dispersing and / or granulating agents, surfactants and / or emulsifying agents, disintegrating agents, binders, preservatives, buffers, lubricants, and / or oils. Pharmaceutically acceptable excipients useful in the preparation of pharmaceutical compositions of the present invention include, but are not limited to, ion exchangers, alumina, aluminum stearate, lecithin, serum proteins such as human serum albumin, buffer substances such as phosphates, glycine, sorbic acid, potassium sorbate, partial glyceride mixtures of saturated vegetable fatty acids, water, protamine sulfate salts or electrolytes, disodium hydrogen phosphate, potassium hydrogen phosphate, sodium chloride, zinc salts, colloidal silica, magnesium trisilicate, polyvinylpyrrolidone, cellulose-based substances, polyethylene glycol, sodium carboxymethylcellulose, polyacrylates, waxes, polyethylene-polyoxypropylene-block polymers, polyethylene glycol, and wool fat.

[0227] The compositions of the present invention can be administered orally, parenterally (including subcutaneously, intramuscularly, intravenously, and intradermally), by inhalation spray, or by any other route. They can be administered intravenously, topically, rectally, nasally, orally, vaginally or via an implanted reservoir. In some embodiments, provided compounds or compositions can be administered intravenously and / or orally.

[0228] The term "parenteral" as used herein includes subcutaneous, intravenous, intramuscular, intraocular, intravitreal, intra-articular, intrasynovial, intrasternal, intrathecal, intrahepatic, intraperitoneal, intralesional, and intracranial injection or infusion techniques. Preferably, the compositions are administered orally, subcutaneously, intraperitoneally, or intravenously. 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 suitable dispersing or wetting agents and suspending agents. Sterile injectable preparations may also be sterile injectable solutions or suspensions in non-toxic parenterally acceptable diluents or solvents, such as solutions in 1,3-butanediol. Acceptable vehicles and solvents that may be used include water, Ringer's solution, and isotonic sodium chloride solution. Additionally, sterile, fixed oils are conventionally used as solvents or suspending media.

[0229] The pharmaceutically acceptable compositions of the present invention can be orally administered in any orally acceptable dosage form, including, but not limited to, capsules, tablets, aqueous suspensions, or solutions. For oral tablets, commonly used carriers include lactose and cornstarch. Lubricants such as magnesium stearate are also typically added. For oral administration in capsule form, useful diluents include lactose and dried cornstarch. When an aqueous suspension is required for oral administration, the active ingredient is combined with an emulsifying and suspending agent. If necessary, certain sweeteners, flavorings, or colorings may be added. In some embodiments, the provided oral formulations are formulated for immediate release or sustained / delayed release. In some embodiments, the compositions are suitable for buccal or sublingual administration and include tablets, lozenges, and pastilles. The provided compounds may be in microencapsulated form.

[0230] Alternatively, the pharmaceutically acceptable compositions of the present invention can be administered in the form of suppositories for rectal administration. The pharmaceutically acceptable compositions of the present invention can be administered topically, particularly when the target of treatment includes areas or organs that are easily accessible by topical application, including diseases of the eye, skin, or lower intestinal tract. For each of these areas or organs, suitable topical formulations are readily prepared.

[0231] For use in the eye, provided pharmaceutically acceptable compositions may be formulated as a micronized suspension or in an ointment such as petrolatum.

[0232] In order to prolong the effect of a drug, it is often desirable to delay the absorption of the drug from subcutaneous or intramuscular injection.This can be achieved by using a liquid suspension of crystalline or amorphous material with poor water solubility.The absorption rate of the drug then depends on its dissolution rate, which may also depend on crystal size and crystalline form.Alternatively, delayed absorption of a parenterally administered drug dosage form can be achieved by dissolving or suspending the drug in an oil vehicle.

[0233] While the description of pharmaceutical compositions provided herein is primarily directed to pharmaceutical compositions suitable for administration to humans, it will be understood by those skilled in the art that such compositions are generally suitable for administration to any type of animal. The modification of pharmaceutical compositions suitable for administration to humans to make them suitable for administration to a variety of animals is well understood, and a veterinary pharmacologist of ordinary skill can design and / or perform such modifications with routine experimentation.

[0234] The compounds provided herein are typically formulated in dosage unit form, for example, single unit dosage form, for ease of administration and uniformity of dosage.However, it will be understood that the total daily usage amount of the compositions of the present invention will be determined by the attending physician within the scope of sound medical judgment.The specific therapeutically effective dose level for any specific subject or organism will be determined by the amount of the compound to be treated. It will depend on a variety of factors, including the severity of the disease or disorder; the activity of the specific active ingredient used; the specific composition used; the age, weight, general health, sex and diet of the subject; the time of administration, route of administration and rate of excretion of the specific active ingredient used; the duration of treatment; drugs used in combination or concomitantly with the specific active ingredient used; and similar factors well known in the medical field.

[0235] The exact amount of compound required to achieve an effective dose will vary from subject to subject, depending, for example, on the species, age, and general condition of the subject, the severity of the side effect or disorder, the identity of the particular compound, the mode of administration, etc. The desired dose can be delivered three times a day, twice a day, once a day, every other day, every third day, weekly, every two weeks, every three weeks, or every four weeks. In certain embodiments, multiple administrations (e.g., 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, or more administrations) can be used to deliver the desired dose.

[0236] In certain embodiments, an effective amount of a compound for administration to a 70 kg adult human one or more times per day may include from about 0.0001 mg to about 3000 mg, from about 0.0001 mg to about 2000 mg, from about 0.0001 mg to about 1000 mg, from about 0.001 mg to about 1000 mg, from about 0.01 mg to about 1000 mg, from about 0.1 mg to about 1000 mg, from about 1 mg to about 1000 mg, from about 1 mg to about 100 mg, from about 10 mg to about 1000 mg, or from about 100 mg to about 1000 mg of the compound per unit dosage form.

[0237] In certain embodiments, the compound of formula (I) may be administered at a dosage level sufficient to deliver from about 0.001 mg / kg to about 100 mg / kg, about 0.01 mg / kg to about 50 mg / kg, preferably from about 0.1 mg / kg to about 40 mg / kg, preferably from 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 from about 1 mg / kg to about 25 mg / kg of body weight of the subject per day, one or more times per day, to obtain the desired therapeutic effect.

[0238] It will be understood that the dosage ranges described herein provide guidance for administering the provided pharmaceutical compositions to adults. For example, the amount administered to a child or adolescent can be determined by a physician or person skilled in the art and may be lower than or the same as the amount administered to an adult.

[0239] It will also be understood that the compounds or compositions described herein can be administered in combination with one or more additional drugs. The compounds or compositions can be administered in combination with additional drugs that improve their bioavailability, reduce and / or alter their metabolism, inhibit their excretion, and / or alter their biodistribution. It will also be understood that the treatments employed can achieve desired effects and / or different effects for the same disorder.

[0240] The compound or composition can be administered simultaneously with, before, or after one or more additional agents that may be useful, e.g., as a combination therapy. Agents include therapeutically active agents. Agents also include prophylactically active agents. Each additional agent can be administered at a dose and / or time schedule determined for that agent. The additional agents can be administered together and / or with the compounds or compositions described herein in a single dose, or can be administered separately in different doses. The particular combination used in the regimen will take into account compatibility of the compound of the present invention with the additional agent and / or the desired therapeutic and / or prophylactic effect to be achieved. In general, it is expected that additional agents used in combination will be used at levels that do not exceed the levels at which they are used individually. In some embodiments, the levels used in combination will be lower than the levels at which they are used individually.

[0241] Exemplary additional agents include antiproliferative agents, anticancer agents, antidiabetic agents, anti-inflammatory agents, immunosuppressants, and Drugs include, but are not limited to, drug compounds (e.g., compounds approved by the U.S. Food and Drug Administration as described in the Code of Federal Regulations (CFR)), small organic molecules such as 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 cells.

[0242] Kits (e.g., pharmaceutical packs) are also encompassed by the present invention. The kits of the present invention can be useful, for example, for preventing and / or treating proliferative or non-proliferative diseases, as described herein. The provided kits can include a pharmaceutical composition or compound of the present invention and a container (e.g., a vial, an ampoule, a bottle, a syringe and / or a dispenser package or other suitable container). In some embodiments, the provided kits can optionally further include a second container containing a pharmaceutical excipient for diluting or suspending the pharmaceutical composition or compound of the present invention. In some embodiments, the combination of the container and the pharmaceutical composition or compound of the present invention provided in the second container forms a single-unit dosage form.

[0243]

[0013] Accordingly, in one aspect, a kit is provided that includes a first container comprising a compound described herein, or a pharmaceutically acceptable salt, solvate, hydrate, tautomer, or stereoisomer thereof, or a pharmaceutical composition thereof. In certain embodiments, the kit of the present disclosure includes a first container comprising a compound described herein, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof. In certain embodiments, the kit is useful for preventing and / or treating a disease, disorder, or condition described herein (e.g., a proliferative disease or a non-proliferative disease) in a subject. In certain embodiments, the kit further includes instructions for administering the compound, or a pharmaceutically acceptable salt, solvate, hydrate, tautomer, or stereoisomer thereof, or a pharmaceutical composition thereof to a subject to prevent and / or treat a proliferative disease or a non-proliferative disease.

[0244] How to use Compounds useful for modulating splicing are described herein. In some embodiments, compounds of Formula (I) can be used to alter the amount, structure, or composition of a nucleic acid (e.g., a precursor RNA, such as a pre-mRNA or a resulting mRNA) by increasing or decreasing splicing at a splice site. In some embodiments, increasing or decreasing splicing modulates the level or structure of a produced gene product (e.g., RNA or protein). In some embodiments, compounds of Formula (I) can modulate a component of the splicing machinery, for example, by modulating the interaction of the component with another entity (e.g., a nucleic acid, a protein, or a combination thereof). The splicing machinery referred to herein includes one or more spliceosome components. Spliceosome components can include, for example, major spliceosome members (U1, U2, U4, U5, U6 snRNP) or minor spliceosome members (U11, U12, U4atac, U6atacsnRNP) and one or more of their auxiliary splicing factors.

[0245] In another aspect, the disclosure features a method of modifying a target (e.g., a precursor RNA, e.g., a pre-mRNA) by including a splice site in the target, the method including providing a compound of Formula (I). In some embodiments, the inclusion of a splice site in the target (e.g., a precursor RNA, e.g., a pre-mRNA or a resulting mRNA) results in the addition or deletion of one or more nucleic acids to the target (e.g., a new exon, e.g., a skipped exon). The addition or deletion of one or more nucleic acids to the target can result in an increased level of a gene product (e.g., an RNA, e.g., an mRNA or a protein).

[0246] In another aspect, the disclosure features a method of modifying a target (e.g., a precursor RNA, e.g., a pre-mRNA or a resulting mRNA) by eliminating a splice site in the target, the method including providing a compound of Formula (I). In some embodiments, elimination of a splice site in the target (e.g., a precursor RNA, e.g., a pre-mRNA) results in the deletion or addition of one or more nucleic acids from the target (e.g., a skipped exon, e.g., a new exon). The deletion or addition of one or more nucleic acids to the target can result in a decrease in the level of a gene product (e.g., an RNA, e.g., an mRNA or a protein). In other embodiments, the method of modifying a target (e.g., a precursor RNA, such as a pre-mRNA or a resulting mRNA) includes suppressing splicing at a splice site or enhancing splicing at a splice site (e.g., by 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), for example, as compared to a reference (e.g., the absence of a compound of Formula (I) or a healthy or diseased cell or tissue).

[0247] The methods described herein can be used, for example, to regulate splicing of nucleic acids containing a particular sequence (e.g., a target sequence). Exemplary genes encoding a target sequence (e.g., a target sequence comprising DNA or RNA, e.g., a pre-mRNA) include, among others, 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、CAPN3、CAPN9、CAPSL、CARD 11、CARKD、CASZ1、CAT、CBLB、CBX1、CBX3、CCDC102B、CCDC11、CCDC15、CCDC18、CCDC5、CCDC81、CCDC131、CCDC146、CD4、CD、 274、CD1B、CDC14A、CDC16、CDC2L5、CDC42BPB、CDCA8、CDH10、CDH11、CDH24、 CDH8、CDH9、CDK5RAP2、CDK6、CDK8、CDK11B、CD33、CD46、CDH1、CDH23、CDK6、C DK11B、CDK13、CEBPZ、CEL、CELSR3、CENPA、CENPI、CENPT、CENTB2、CENTG2、C EP110、CEP170、CEP192、CETP、CFB、CFTR、CFH、CGN、CGNL1、CHAF1A、CHD9、CHI C2、CHL1、CHN1、CHM、CLEC16A、CL1C2、CLCN1、CLINT1、CLK1、CLPB、CLPTM1、C MIP、CMYA5、CNGA3、CNOT1、CNOT7、CNTN6、COG3、COL11A1、COL11A2、COL12A1、 COL14A1、COL15A1、COL17A1、COL19A1、COL1A1、COL1A2、COL2A1、COL3A1、CO L4A1、COL4A2、COL4A5、COL4A6、COL5A2、COL6A1、COL7A1、COL9A1、COL9A2、CO L22A1、COL24A1、COL25A1、COL29A1、COLQ、COMTD1、COPA、COPB2、COPS7B、CO PZ2、CPSF2、CPXM2、CR1、CRBN、CRYZ、CREBBP、CRKRS、CSE1L、CSTB、CSTF3、CT4 5-6、CTNNB1、CUBN、CUL4B、CUL5、CXorf41、CXXC1、CYBB、CYFIP2、CYP3A4、CY P3A43、CYP3A5、CYP4F2、CYP4F3、CYP17、CYP19、CYP24A1、CYP27A1、DAB1、DAZ 2、DCBLD1、DCC、DCTN3、DCUN1D4、DDA1、DDEF1、DDX1、DDX24、DDX4、DENND2D、 DEPDC2、DES、DGAT2、DHFR、DHRS7、DHRS9、DHX8、DIP2A、DMD、DMTF1、DNAH3、DN AH8、DNAI1、DNAJA4、DNAJC13、DNAJC7、DNMT1、DNTTIP2、DOCK4、DOCK5、DOCK1 0、DOCK11、DOT1L、DPP3、DPP4、DPY19L2P2、DR1、DSCC1、DVL3、DUX4、DYNC1H1、DYSF、E2F1、E2F3、E2F8、E4F1、EBF1、EBF3、ECM2、EDEM3、EFCAB3、EFCAB4B、E FNA4、EFTUD2、EGFR、EIF3A、ELA1、ELA2A、ELF2、ELF3、ELF4、EMCN、EMD、EML5、 ENO3、ENPP3、EP300、EPAS1、EPB41L5、EPHA3、EPHA4、EPHB1、EPHB2、EPHB3、E PS15、ERBB4、ERCC1、ERCC8、ERGIC3、ERMN、ERMP1、ERN1、ERN2、ESR1、ESRRG、E TS2, ETV3, ETV4, ETV5, ETV6, EVC2, EWSR1, EXO1, EXOC4, F3, F11, F13A1, F5, F7, F8, FAH, FAM13A1, FAM13B1, FAM13C1, FAM134A, FAM161A, FAM176B, FAM18 4A, 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, GJA1 、GLA、GLT8D1、GNA11、GNAQ、GNAS、GNB5、GOLGB1、GOLT1A、GOLT1B、GPATCH1、 GPR158、GPR160、GPX4、GRAMD3、GRHL1、GRHL2、GRHPR、GRIA1、GRIA3、GRIA4、G RIN2B、GRM3、GRM4、GRN、GSDMB、GSTCD、GSTO2、GTF2I、GTPBP4、HADHA、HAND2 、HBA2、HBB、HCK、HDAC3、HDAC5、HDX、HEPACAM2、HERC1、HES7、HEXA、HEXB、HH、EX、HIPK3、HLA-DPB1、HLA-G、HLCS、HLTF、HMBS、HMGA1、HMGCL、HNF1A、HNF1B 、HNF4A、HNF4G、HNRNPH1、HOXC10、HP1BP3、HPGD、HPRT1、HPRT2、HSF1、HSF4、 HSF2BP、HSPA9、HSPG2、HTT、HXA、ICA1、IDH1、IDS、IFI44L、IKBKAP、IKZF1、I KZF3、IL1R2、IL5RA、IL7RA、IMMT、INPP5D、INSR、INTS3、INTU、IP04、IP08、IQ GAP2, IRF2, IRF4, IRF8, IRF3, ISL1, ISL2, ITFG1, ITFGA6, ITFAL, ITFGB1, ITFGB2, ITFGB3, ITFGB4, ITFH1, ITFPR2, IWS1, JAK1, JAK2, JAG1, JMJD1C, JPH3, KAL RN、KAT6A、KATNAL2、KCNN2、KCNT2、KDM2A、KIAA0256、KIAA0528、KIAA0564、 KIAA0586、KIAA1033、KIAA1166、KIAA1219、KIAA1409、KIAA1622、KIAA1787、 KIF3B, KIF15, KIF16B, KIF5A, KIF5B, KIF9, KIN, KIR2DL5B, KIR3DL2, KIR3DL3, KIT, KLF3, KLF5, KLF7, KLF10, KLF12, KLF16, KLHL20, KLK12, KLKB1, KMT 2A, KMT2B, KPNA5, KRAS, KREMEN1, KRIT1, KRT5, KRTCAP2, KYNU, L1CAM, L3MBTL, L3MBTL2, LACE1, LAMA1, LAMA2, LAMA3, LAMB1, LARP7, LDLR, LEF1, LENG1 LGALS3、LGMN、LHCGR、LHX3、LHX6、LIMCH1、LIMK2、LIN28B、LIN54、LMBRD1、L MBRD2、LMLN、LMNA、LMO2、LMO7、LOC389634、LOC390110、LPA、LPCAT2、LPL、L RP4、LRPPRC、LRRK2、LRRC19、LRRC42、LRWD1、LUM、LVRN、LYN、LYST、MADD、MA GI1、MAGT1、MALT1、MAP2K1、MAP4K4、MAPK8IP3、MAPK9、MAPT、MARC1、MARCH5、MATN2, MBD3, MCF2L2, MCM6, MDGA2, MDM4, ASXL1, FUS, SPR54, MECOM, MEF2C, MEF2D, MEGF10, MEGF11, MEMO1, MET, 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, MYB, MYBL2, MYC, MYCBP2, MYH2, MYRF, MYT1, MY019, MY03A, MY09B, MYOM2, MYO M3、NAG、NARG1、NARG2、NCOA1、NDC80、NDFIP2、NEB、NEDD4、NEK1、NEK5、ΝΕΚ11、NF1、NF2、NFATC2、NFE2L2、NFIA 、NFIB、NFIX、NFKB1、NFKB2、NFKBIL2、NFRKB、NFYA、NFYB、NIPA2、NKAIN2、NKAP、NLRC3、NLRC5、NLRP3、NLRP7、NL RP8, 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、PD 1A3、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、SAAL1、SAE1、SALL4、SAT1、SATB2、SBCAD、SCN1A、SCN2A、SCN3A、SCN4A、SCN5A、SCN8A、SCNA、SCN11A、SCO1、SCYL3、SDC1、SDK1、SDK2、SEC24A、SEC24 D、SEC31A、SEL1L、SENP3、SENP6、SENP7、SERPINA1、SETD3、SETD4、SETDB1、SE Z6、SFRS12、SGCE、SGOL2、SGPL1、SH2D1A、SH3BGRL2、SH3PXD2A、SH3PXD2B、S H3RF2、SH3TC2、SHOC2、SIPA1L2、SIPA1L3、SIVA1、SKAP1、SKIV2L2、SLC6A11、 SLC6A13、SLC6A6、SLC7A2、SLC12A3、SLC13A1、SLC22A17、SLC25A14、SLC28A 3、SLC33A1、SLC35F6、SLC38A1、SLC38A4、SLC39A10、SLC4A2、SLC6A8、SMARCA 1、SMARCA2、SMARCA5、SMARCC2、SMC5、SMN2、SMOX、SMS、SMTN、SNCAIP、SNORD 86、SNRK、SNRP70、SNX5、SNX6、SOD1、SOD10、SOS、SOS2、SOX5、SOX6、SOX8、SP1 、SP2、SP3、SP110、SPAG9、SPATA13、SPATA4、SPATS1、SPECC1L、SPDEF、SPI1、 SPINK5、SPP2、SPTA1、SRF、SRM、SRP72、SSX3、SSX5、SSX9、STAG1、STAG2、STAM BPLI、STARD6、STAT1、STAT3、STAT5A、STAT5B、STAT6、STK17B、STX3、STXBP1 、SUCLG2、SULF2、SUPT6H、SUPT16H、SV2C、SYCP2、SYT6、SYCPI、SYTL3、SYTL5、 TAF2、TARDBP、TBC1D3G、TBC1D8B、TBC1D26、TBC1D29、TBCEL、TBK1、TBP、TBP L1、TBR1、TBX、TCEB3、TCF3、TCF4、TCF7L2、TCFL5、TCF12、TCP11L2、TDRD3、TE AD1, TEAD3, TEAD4, TECTB, TEK, TERF1, TERF2, TET2, TFAP2A, TFAP2B, TFAP2C, TFAP4, TFDP1, TFRC, TG, TGM7, TGS1, THAP7, THAP12, THOC2, TIAL1, TIAM2T, IMM50, 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-PRAP1, ZNF519, ZNF521, ZNF592, ZNF618, ZNF763, and ZWINT are included.

[0248] Additional exemplary genes encoding target sequences (e.g., target sequences comprising DNA or RNA, e.g., pre-mRNA) 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, AC007780.1, PRKAR1A, AC007998.2, INO80C, AC009070.1, CMC2, AC009879.2, AC009879.3, ADHFE1, AC010487.3, ZNF816 -ZNF321P, ZNF816, AC010328.3, AC010522.1, ZNF587B, AC010547.4, ZNF19, AC012313.3, ZNF497, AC012651.1, CAPN3, AC013489.1, DE T1, AC016747.4, C2orf74, AC020907.6, FXYD3, AC021087.5, PDCD6, AHRR, AC022137.3, ZNF761, AC025283.3, NAA60, AC027644.4, RAB GEF1, AC055811.2, FLCN, AC069368.3, ANKDD1A, AC073610.3, ARF3, AC074091.1, GPN1, AC079447.1, LIPT1, AC092587.1, AC079594.2, TRIM59, AC091060.1, C18orf21, AC092143.3, MC1R, AC093227.2, ZNF607, AC093512.2, ALDOA, AC098588.1, ANAPC10, AC107871.1, CAL ML4, 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、A. HDC1、AHI1、AHNAK、AIFM1、AIFM3、AIMP2、AK4、AKAP1、AKNAD1、CLCC1、 AKR1A1、AKT1、AKT1S1、AKT2、AL139011.2、PEX19、AL157935.2、ST6GAL NAC6、AL358113.1,TJP2、AL441992.2、KYAT1、AL449266.1,CLCC1、AL5 90556.3、LINC00339、CDC42、ALAS1、ALB、ALDH16A1、ALDH1B1、ALDH3A1 、ALDH3B2、ALDOA、ALKBH2、ALPL、AMD1、AMICA1、AMN1、AMOTL2、AMY1B、A MY2B、ANAPC10、ANAPC11、ANAPC15、ANG、RNASE4、AL163636.2、ANGEL2、 ANGPTL1、ANKMY1、ANKRD11、ANKRD28、ANKRD46、ANKRD9、ANKS3、ANKS3, RP11-127I20.7、ANKS6、ANKZF1、ANPEP、ANXA11、ANXA2、ANXA8L2、AL60 3965.1、AOC3、AP000304.12、CRYZL1、AP000311.1、CRYZL1、AP000893. 2,RAB30、AP001267.5、ATP5MG、AP002495.2、AP003175.1、OR2AT4、AP0 03419.1, CLCF1, AP005263.1, ANKRD12, AP006621.5, AP006621.1, AP1G1, AP3M1, AP3M2, APBA2, APBB1, APLP2, APOA2, APOL1, APOL3, APTX, AR AP1,STARD10、ARF4、ARFIP1、ARFIP2、ARFRP1、ARHGAP11A、ARHGAP33、ARHGAP4、ARHGEF10、ARHGEF3、ARHGEF35、OR2A1-AS1、ARHGEF35、OR2A1- AS1、ARHGEF34P、ARID1B、ARHGEF35、OR2A20P、OR2A1-AS1、ARHGEF9、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、ART 3、ASB3,GPR75-ASB3、ASCC2、ASNS、ASNS、AC079781.5、ASPSCR1、ASS1、ASUN、ATE1、ATF1、ATF7IP2、ATG13、ATG4D、ATG4 ATM、ATOX1、ATP1B3、ATP2C1、ATP5F1A、ATP5G2、ATP5J、ATP5MD、ATP5PF、ATP6AP2、ATP6V0B、ATP6V1C1XD7B、ATP6V ATXN1L,IST1、ATXN3、ATXN7L1、AURKA、AURKB、AXDND1、B3GALNT1、B3GALT5,AF064860.1、B3GALT5,AF064860.5G3、B3、B. T3、B4GALT4、B9D1、BACH1、BAIAP2、BANF1、BANF2、BAX、BAZ2A、BBIP1、BCHE、BCL2L14、BCL6、BCL9L、BDH5L,3BCS1L 102.2、BEST1、BEST3、BEX4、BHLHB9、BID、BIN3、BIRC2、BIVM、BIVM-ERCC5、BIVM、BLCAP、BLK、BLK1S1、RP11.10F644 6、AC090527.2、BLOCK1S6、RP11-96O20.4、BLVRA、BMF、BALL1、BORCS8-MEF2B、BORCS8、BRCA1、BRD1、BROXBRDT、BT1BRINP3 、BTBD3、BTBD9、BTD、BTF3L4、BTNL9、BUB1B-PAK6、PAK6、BUB3、C10orf68、C11orf1、C11orf48、C1015,14CAP54、2、C11orf57、C11orf63、C11orf82、C12orf23、C12orf4、C12orf65、C12orf79、C14orf159、C14orf93、C17orf62、C18orf21、C19orf12、C19orf40、C19orf47、C19orf48、C19orf54、C1D、C1GALT1、C1QB、C1QTNF1、C1S、C1orf101、C1orf112、C1orf116、C1orf159、C1orf63、C2、C2,CFB、C20orf27、C21. orf58、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、C YP2R1、CYP4B1、CYP4F22、DAG1、DAGLB,KDELR2、DARS、DBNL、DCAF11、DCAF8,PEX19、DCLRE1C、DCTD、DCTN1、DCTN4、DCUN1D2、DDR1、D DX11, DDX19B, AC012184.2, 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, FANK1, FAR2, FAXC, F AXDC2、FBF1、FBH1、FBXL4、FBXO18、FBXO22、FBXO31、FBXO41、FBXO44、F BXO45、FBXW9、FCHO1、FCHSD2、FDFT1、FDPS、FER、FETUB、FGD4、FGF1、FGF R1、FGFRL1、FGL1、FHL2、FIBCD1、FIGNL1、FIGNL1,DDC、FKBP5、FKRP、FL RT2、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, GABA RAPL1、GABPB1、GABRA5、GAL3ST1、GALE、GALNT11、GALNT14、GALNT6、GA PVD1、GARNL3、GAS2L3、GAS8、GATA1、GATA2、GATA4、GBA、GCNT1、GDPD2、G DPD5、GEMIN7,MARK4、GEMIN8、GGA3、GGACT、AL356966.1、GGPS1、GHRL、G ID8、GIGYF2、GIMAP8、GIPC1、GJB1、GJB6、GLB1L、GLI1、GLT8D1、GMFG、GM PR2、GNAI2、GNAQ、GNB1、GNB2、GNE、GNG2、GNGT2、GNPDA1、GNPDA2、GOLG A3,CHFR、GOLGA4、GOLPH3L、GOLT1B、GPBP1L1、GPER1、GPR116、GPR141,E PDR1、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、G YPC、GYS1、GZF1、HAGH、HAO2、HAPLN3、HAVCR1、HAX1、HBG2、AC104389.4、HBG 2、AC104389.4、HBE1、HBG2、AC104389.4、HBE1,OR51B5、HBG2,HBE1、AC104 389.28、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、HNRNPH 1、HNRNPH3、HNRNPR、HOMER3、HOPX、HOXA3、HOXB3、HOXB3,HOXB4、HOXC4、HOX D3、HOXD3,HOXD4、HPCAL1、HPS4、HPS5、HRH1、HS3ST3A1、HSH2D、HSP90AA1、H SPD1、HTT、HUWE1、HYOU1、IAH1、ICA1L、ICAM2、ICE2、ICK、IDH2、IDH3G、IDS 、IFI27、IFI44、IFT20、IFT22、IFT88、IGF2、INS-IGF2、IGF2BP3、IGFBP6、IK BKAP、IKBKB、IL11、IL18BP、IL18RAP、IL1RAP、IL1RL1、IL18R1、IL1RN、IL32 、IL4I1,NUP62,AC011452.1、IL4I1,NUP62,CTC-326K19.6、IL6ST、ILVBL、I MMP1L、IMPDH1、INCA1、ING1、INIP、INPP1、INPP5J、INPP5K、INSIG2、INTS1 1、INTS12、INTS14、IP6K2、IP6K3、IPO11、LRRC70、IQCE、IQGAP3、IRAK4、IRF 3、IRF5、IRF6、ISG20、IST1、ISYNA1、ITFG2、ITGB1BP1、ITGB7、ITIH4、RP5-9 66M1.6、ITPRIPL1、JADE1、JAK2、JARID2、JDP2、KANK1、KANK1,RP11-31F19.1. KANK2, KANSL1L, KAT6A, KBTBD2, KBTBD3, KCNAB2, KCNE3, KCNG1, K CNJ16, KCNJ9, KCNMB2, AC117457.1, LINC01014, KCTD20, KCTD7, RAB GEF1, KDM1B, KDM4A, AL451062.3, KHNYN, KIAA0040, KIAA0125, KIAA 0196, KIAA0226L, PPP1R2P4, KIAA0391, KIAA0391, AL121594.1, KIA A0391, PSMA6, KIAA0753, KIAA0895, KIAA0895L, KIAA1191, KIAA140 7. KIAA1841, C2orf74, KIF12, KIF14, KIF27, KIF9, KIFC3, KIN, KIRR EL1, KITLG, KLC1, APOPT1, AL139300.1, KLC4, KLHDC4, KLHDC8A, KLH L13, KLHL18, KLHL2, KLHL24, KLHL7, KLK11, KLK2, KLK5, KLK6, KLK7, K NOP1、KRBA2、AC135178.2、KRBA2、RP11-849F2.7、KRIT1、KRT15、KRT 8. KTN1, KXD1, KYAT3, RBMXL1, KYNU, L3MBTL1, LACC1, LARGE, LARP4. LARP7, LAT2, LBHD1, LCA5, LCA5L, LCTL, LEPROTL1, LGALS8, LGALS9C LGMN, LHFPL2, LIG4, LIMCH1, LIMK2, LIMS2, LINC00921, ZNF263, LIP F LLGL2 LMAN2L LMCD1 LMF1 RP11-161M6.2 LMO1 LMO3 LOXHD1 LPAR1, LPAR2, LPAR4, LPAR5, LPAR6, LPHN1, LPIN2, LPIN3, LPP, LRFN 5. LRIF1, LRMP, LRRC14, LRRC20, LRRC24, C8orf82, LRRC39, LRRC42, LRRC48, LRRC4C, LRRC8A, LRRC8B, LRRD1, LRTOMT, LRTOMT, AP000812.5、LSM7、LTB4R、LTBP3、LUC7L2、FMC1-LUC7L2、LUC7L3、LUZP1、LYG1、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、MAP3K8、MAP7、MAP9、MAPK6、MAPK7、MAPK8、MAPKAP1、10-Mar、7-Mar、8-Mar、MARK2、MASP1、MATK、MATR3、MATR3,SNHG 4, MB, MBD5, MBNL1, MBOAT7, MCC, MCFD2, 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、MID1、MINA、MINOS1-NBL1,MINOS1、MIOS、MIPOL1、MIS12、M KLN1、MKNK1、MKNK1,MOB3C、MLF2、MLH1、MMP17、MOBP、MOCS1、MOGS、MOK、MORF4L1、MPC1、MPC2、MPG、MPI、MPP1、MPP2、MPPE1、MPST 、MRAS、MRO、MROH1、MROH7-TTC4、MROH7、MRPL14、MRPL24、MRPL33,BABAM2、MRPL33、BRE、MRPL47、MRPL48、MRPL55、MRRF、MRTFA、M RTFB、MRVI1、MS4A1、MS4A15、MS4A3、MS4A6E、MS4A7、MS4A14、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、NIPA2、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、N UP54、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、ORMDL2、ORMDL3、OSBPL2、OSBPL3、OSBPL5、OSBPL9、OSER 1、OSGIN1、OSR2、P2RX4、P2RY2、P2RY6、P4HA2、PABPC1、PACRGL、PACSIN3、PADI1、PAIP2、PAK1、PAK3、PAK4、PAK7、PAL B2、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、RNF13、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、R P11-164J13.1,CAPN3, RP11-21J18.1, ANKRD12, RP11-322E11.6, INO80C. RP11-337C18.10,CHD1L、RP11-432B6.3、TRIM59、RP11-468E2.4,IRF9、RP 11-484M3.5,UPK1B、RP11-517H2.6、CCR6、RP11-613M10.9、SLC25A51、RP1 1-659G9.3、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 RP5-1021I2 0.4, ZNF410, RP6-109B7.3, FLJ27365, RPE, RPH3AL, RPL15, RPL17, RPL17- C18orf32, RPL17, RPL23A, RPL36, HSD11B1L, RPP38, RPS20, RPS27A, RPS3 A、RPS6KA3、RPS6KC1、RPS6KL1、RPUSD1、RRAGD、RRAS2、RRBP1、RSL1D1、RSR C2, RSRP1, RUBCNL, RUNX1T1, RUVBL2, RWDD1, RWDD4, S100A13,AL162258.1 S100A13,RP1-178F15.5,S100A16,S100A4,S100A3,S100A6,S100PBPSA A1, SACM1L, SAMD4B, SAR1A, SARAF, SARNP,RP11-762I7.5, SCAMP5, SCAP,S CAPER, SCFD1, SCGB3A2, SCIN, SCML1, SCNN1D, SCO2, SCOC, SCRN1, SDC2, SD C4, SEC13, SEC14L1, SEC14L2, SEC22C, SEC23B, SEC24C, SEC61G, SEMA4A,S EMA4C, SEMA4D, SEMA6C, SENP7, SEPP1, 11-Sep, 2-Sep, SERGEF, AC055860.1、SERP1、SERPINA1、SERPINA5、SERPINB6、SERPING1、SERPINH1、SERTAD3、SETD5、SFMBT1、AC096887.1、SFTPA1、SF TPA2、SFXN2、SGCD、SGCE、SGK3、SGK3,C8orf44、SH2B1、SH2D6、SH3BP1,Z83844.3、SH3BP2、SH3BP5、SH3D19、SH3YL1、 SHC1、SHISA5、SHMT1、SHMT2、SHOC2、SHROOM1、SIGLEC5,SIGLEC14、SIL1、SIN3A、SIRT2、SIRT6、SKP1、STAT4、AC1041 09.3、SLAIN1、SLC10A3、SLC12A9、SLC14A1、SLC16A6、SLC1A2、SLC1A6、SLC20A2、SLC25A18、SLC25A19、SLC25A22、SL C25A25, SLC25A29, SLC25A30, SLC25A32, SLC25A39, SLC25A44, SLC25A45, SLC25A53, SLC26A11, SLC26A4, SLC28A1, SLC29A1, SLC2A14, SLC2A5, SLC2A8, SLC35B2, SLC35B3, SLC35C2, SLC37A1, SLC38A1, SLC38A11, SLC39A13, SLC39A 14、SLC41A3、SLC44A3、SLC4A7、SLC4A8、SLC5A10、SLC5A11、SLC6A1、SLC6A12、SLC6A9、SLC7A2、SLC7A6、SLC7A7、SLC O1A2、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、SPR R2E、SPRR2B、SPRR2F、SPRR2D、SPRR3、SPRY1、SPRY4、SPTBN2、SRC、SRGAP1、SRP68、SRSF11、SSX1、SSX2IP、ST3G AL4、ST3GAL6、ST5、ST6GALNAC6、ST7L、STAC3、STAG1、STAG2、STAMBP、STAMBPL1、STARD3NL、STAT6、STAU1、STA U2、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、TMEM9 8、TMEM9B、TMPRSS11D、TMPRSS5、TMSB15B、TMTC4、TMUB2、TMX2-CTNND1、RP11-691N7.6、CTNND1、TNFAIP 2、TNFAIP8L2、SCNM1、TNFRSF10C、TNFRSF19、TNFRSF8、TNFSF12-TNFSF13、TNFSF12、TNFSF13、TNFSF12-TNFSF13、TNFSF13、TNIP1、TNK2、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, TRMT2B-AS1, TRNT1, TRO, TROVE2, TRPS1, TRPT1, TSC2, TSGA10, TSPAN14, TSPAN3, TSPAN4, TSPAN5, TSPAN6, TSPAN9, TSPO, TTC12, TTC23, TTC3, TTC39. A, TTC39C, TTLL1, TTLL7, TTPAL, TUBD1, TWNK, TXNL4A, TXNL4B, TXNRD1, TYK2, U2AF1, UBA2, UBA52, UBAP2, UBE2D2, UBE2D3, UBE2E3, UBE2I, UBE2J2, UBE 3A, UBL7, UBXN11, UBXN7, UGDH, UGGT1, UGP2, UMAD1, AC007161.3, UNC45A, UQCC1, URGCP-MRPS24, URGCP, USMG5, USP16, USP21, USP28, USP3, USP33, USP 35、USP54、USP9Y、USPL1、UTP15、VARS2、VASH2、VAV3、VDAC1、VDAC2、VDR、VE ZT、VGF、VIL1、VILL、VIPR1、VPS29、VPS37C、VPS8、VPS9D1、VRK2、VWA1、VWA5 A、WARS、WASF1、WASHC5、WBP5、WDHD1、WDPCP、WDR37、WDR53、WDR6、WDR72、WD R74、WDR81、WDR86、WDYHV1、WFDC3、WHSC1、WIPF1、WSCD2、WWP2、XAGE1A、XAGE 1B、XKR9、XPNPEP1、XRCC3、XRN2、XXYLT1、YIF1A、YIF1B、YIPF1、YIPF5、YPEL 5、YWHAB、YWHAZ、YY1AP1、ZBTB1、ZBTB14、ZBTB18、ZBTB20、ZBTB21、ZBTB25、 ZBTB33, ZBTB34, ZBTB38, ZBTB43, ZBTB49, ZBTB7B, ZBTB7C, ZBTB8OS, ZC3H11A, ZBED6, ZC3H13, ZCCHC17, ZCCHC7, ZDHHC11, ZDHHC13, ZEB2, ZFAND5, ZFAN D6、ZFP1、ZFP62、ZFX、ZFYVE16、ZFYVE19、ZFYVE20、ZFYVE27、ZHX2、AC01640 5.1、ZHX3、ZIK1、ZIM2,PEG3、ZKSCAN1、ZKSCAN3、ZKSCAN8、ZMAT3、ZMAT5、ZM IZ2、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, ZNF2 83, ZNF287, ZNF3, ZNF320, ZNF322, ZNF324B, ZNF331, ZNF334, ZNF34, ZNF350, ZNF385A, ZNF395, FBXO16, ZNF415, ZNF418, ZNF43, ZNF4 33-AS1, AC008770.4, ZNF438, ZNF444, ZNF445, ZNF467, ZNF480, ZNF493, ZNF493, CTD-2561J22.3, ZNF502, ZNF507, ZNF512, AC07409 1.1, ZNF512,RP11-158I13.2, ZNF512B, ZNF512B, SAMD10, ZNF521, ZNF532, ZNF544, AC020915.5, ZNF544, CTD-3138B18.4, ZNF559,ZN F177, ZNF562, ZNF567, ZNF569, ZNF570, ZNF571-AS1, ZNF540, ZNF577, ZNF580, ZNF581, ZNF580, ZNF581, CCDC106, ZNF600, ZNF611, Z NF613, ZNF615, ZNF619, ZNF620, ZNF639, ZNF652, ZNF665, ZNF667, ZNF668, ZNF671, ZNF682, ZNF687, ZNF691, ZNF696, ZNF701, ZNF706 These genes include ZNF707, ZNF714, ZNF717, ZNF718, ZNF720, ZNF721, ZNF730, ZNF763, ZNF780B, AC005614.5, ZNF782, ZNF786, ZNF79, ZNF791, ZNF81, ZNF83, ZNF837, ZNF839, ZNF84, ZNF845, ZNF846, ZNF865, ZNF91, ZNF92, ZNHIT3, ZSCAN21, ZSCAN25, ZSCAN30, and ZSCAN32.

[0249] In some embodiments, the gene encoding the target sequence comprises the HTT gene.

[0250] Exemplary genes that may be modulated by the compounds of Formula (I) described herein include, among others, 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.

[0251] The compounds described herein can further be used to modulate sequences containing specific splice site sequences, such as RNA sequences (e.g., pre-mRNA sequences). In some embodiments, the splice site sequence comprises a 5' splice site sequence. In some embodiments, the splice site sequence comprises a 3' splice site sequence. Exemplary 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, AAAguaacugg, AAAguacuuc, AAAguacuug, AAAguagcuu, AAAguaggag, AAAguaggau, AAAguacaaa, AAAguaccgg, AAAguacuag, AAAguaacugg, AAAguacuuc, AAAguacuug, AAAguagcuu, AAAguaggag, AAAguaggau, AAAguaccaa, AAAguaccgg, AAAguacuag ... 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, AAGgcaagga, AAGgcaaggg, AAGgcaaggu, AAGgcaaggu, AAGgcaaggu, AAGgcaaguu, AAGgcacagcu, AAGgcagaaa, AAGgcaggau, AAGgcaggca, AAGgcaggga, AAGgcagggg, AAGgcaggua, AAGgcaggug, AAGgcaucuc, AAGgcaugcu, AAGgcaugga, AAGgcauguu, AAGgcauuau, AAGgcgagcu, AAGgcgaguc, AAGgcgaguu, AAGgcuagcc, AAGguaaaaa, AAGguaaaac, AAGguaaaag, AAGguaaaau, AAGguaaaca, AAGguaaacc, AAGguaaacu, AAGguaaaga, AAGguaaagc, AAGguaaagg, AAGguaaagu, AAGguaaaua, AAGguaaauc, AAGguaaug, AAGguaaauu, AAGguaacaa, AAGguaacau, AAGguaaccc, AAGguaacua, AAGguaacuc, AAGguaacug, AAGguaacuu, AAGguaagaa, AAGguaagac, AAGguaagag, AAGguaagau, AAGguaagca, AAGguaagcc, AAGguaagcg, AAGguaagcu, AAGguaagga, AAGguaaggc, AAGguaaggg, AAGguaaggu, AAGguaagua, AAGguaaguc, AAGguaagug, AAGguaaguu, AAGguaauaa, AAGguaauac, AAGguaauag, AAGguaauau, AAGguaauca, AAGguaaucc, AAGguaaucu, AAGguaauga, AAGguaaugc, AAGguaaugg, AAGguaaugu, AAGguaauua, AAGguaauuc, AAGguaauug, AAGguaauuu, AAGguacaaa, AAGguacaaa, AAGguacaag, AAGguacaau, AAGguacacc, AAGguacacu, AAGguacagg, AAGgu acagu, AAGguacaua, AAGguacaug, AAGguacauu, AAGguaccaa, AAGguaccag, AAGguaccca, AAGguacccu, AAGguaccuc, AAGguaccug, AAGguaccuu, AAGguacgaa, AAGguacggg, AAGguacggu, AAGguacguc, AAGguacguu, AAGguacuaa, AAGguacuau, AAGguacucu, AAGguacuga, AAGguacugc, AAGguacugu, AAGguacuuc, AAGguacuug, AAGguacuuu, AAGguagaaa, AAGguagaac, AAGguagaca, AAGguagacc, AAGguagacu, AAGguagagu, AAGguagaua, AAGguagcaa, AAGguagcag, AAGguagcca, AAGguagccu, AAGguagcua, AAGguagcuu, AAGguaggga,AAGguagggc, AAGguagggg, AAGguagggu, AAGguaggua, AAGguagguc, AAGguaggug, AAGguagguu, AAGguaguaa, AAGguaguag, AAGguagucu, AAGguagugc, AAGguagugg, AAGguaguuc, AAGguaguuu, AAGguauaaa, AAGguauaau, AAGguauca, AAGguauacu, AAGguauaua, AAGguauauc, AAGguauaug, AAGguauauu, AAGguaucac, AAGguaucag, AAGguauccc, AAGguauccu, AAGguaucuc, AAGguaucug, AAGguaucuu, AAGguaugaa, AAGguaugac, AAGguaugag, AAGguaugau, AAGguaugca, AAGguaugcc, AAGguaugcu, AAGguaugga, AAGguauggc, AAGguauggg, AAGguaugu, AAGguauguc, AAGguauguu, AAGguauuaa, AAGguauuac, AAGgu auuag, AAGguauuau, AAGguauucc, AAGguauuga, AAGguauugu, AAGguauuua, AAGguauuuc, AAGguauuug, AAGguauuuu, AAGgucaaau, AAGgucaaga, AAGgucaagu, AAGgucacag, AAGgucagaa, AAGgucagac, AAGgucagag, AAGgucagca, AAGgucagcc, AAGgucagcg, AAGgucagcu, AAGgucagga, AAGgucaggc, AAGgucaggu, AAGgucagua, AAGgucagucuA AGgaagu、AAGgugaaua、AAGgugaaug、AAGgagaaau、AAGgagacaa、AAGgagacag、AAGgugacau、AAGgagacug、AAGgugacau、AAGgagagaa、AAGgagagac、AAGg ugagag、AAGgugagau、AAGgugagca、AAGgugagcc、AAGgugagcg、AAGgugagcu、AAGgugagga、AAGgugaggc、AAGgugaggg、AAGgugaggu、AAGgugagua、AAGgugaguc、AAGgugagug、AAGgugaguu、AAGgugauaa、AAGgugauca、AAGgugaucc、AAGgugauga、AAGgugaugc、AAGgugaugu ,AAGgugcaca, AAGgugcauc, AAGgugcccu, AAGgugccug, AAGgugcgug, AAGgugcgug, AAGgugcguu, AAGgugcucc, AAGgugcuga, AAGgugcugc, AAGgugcugg, AAGgugcuua, AAGgugcuuu, AAGguggaua, AAGguggcua, AAGguggcug, AAGguggcuu, AAGgugggaa, AAGgugggag, AAGgugggau, AAGgugggca, AAGgugggcc, AAGguggcg, AAGgu gggga、AAGgugggu、AAGgugggua、AAGgugggug、AAGgugguu、AAGgugguaa、AAGgugguac、AAGgugguau、AAGguggugg、AAGguggua、AAGgugguua、AAGgugguuc、AAGgugguu、AAGguguaag、AAGgugucaa、AAGgugucag、AAGgugucug、AAGgugugaa、AAGgugugag、AAGgugugca、AAGgugugga、AAGguguggu、AAGgugugua、AAGgugugcu、AAGgugugug, AAGguguguu, AAGguguucu, AAGguguugc, AAGguguugg, AAGguguuug, AAGguuaaaa, AAGguuaaca, AAGguuaagc, AAGguuaauu, AAGguuacau, AAGguuagaa, AAGguuagau, AAGguuagca, AAGguuagcc, AAGguuagga, AAGguuaggc, AAGguuagua, AAGguuaguc, AAGguuagug, AAGguuaguu, AAGguuauag, AAGguuauga, AAGguucaaa, AAGguucaag, AAGguuccuu, AAGguuccgg, AAGguucgu, AAGguucuaa, AAGguucuga, AAGgucuua, AAGguugaau, AAGguugacu, AAGguugagg, AAGguugagu, AAGguugaua, AAGguugcac, AAGguugcac, AAGguuggga, AAGguuggg, AAGguuggua, AAGguuggu, AAGguugguc, AAGgu, uggug, AAGguugguu, AAGguuguaa, AAGguugucc, AAGguugugc, AAGguuguua, AAGguuuacc, AAGguuuaua, AAGguuuauu, AAGguuuccu, AAGguuucgu, AAGguuugag, AAGguuugca, AAGguuugcc, AAGguuugcu, AAGguuugga, AAGguuugga, AAGguuuggu, AAGguuugua, AAGguuuguc, AAGguuugug, AAGguuuuaa, AAGguuuuca, AAG guuuucg、AAGguuuugc、AAGguuuugu、AAGguuuuu、AAUgcaagua、AAUgcaaguc、AAUguaaaca、AAUguaaaua、AAUguaaauc、AAUguaaaug、AAUguaaaau、AA Uguaacua、AAUguaagaa、AAUguaagag、AAUguaagau、AAUguaagcc、AAUguaagcu、AAUguaagga、AAUguaagua、AAUguaaguc、AAUguaagug、AAUguaaguu、A AUguaauca、AAUguaauga、AAUguaaugu、AAUguacauc、AAUguacaug、AAUguacgau、AAUguacgua、AAUguacguc、AAUguacgug、AAUguacucu、AAUguaggca、AAUguagguu、AAUguaucua、AAUguaugaa、AAUguauguga、AAUguauguga、AAUguaugug、AAUguauguu、AAUgucagag、AAUgucagau、AAUgucagcu、AAUgucagua、AAUgucaguc、AAUgucagu g、AAUgucaguu、AAUgucggua、AAUgucuguu、AAUgugagaa、AAUgugagca、AAUgugagcc、AAUgugagga、AAUgugagua、AAUgugaguc、AAUgugagug、AAUgugaguu、AAUgugauau、AAUgugcaua、AAUgugcgua、AAUgugcguc、AAUgugggac、AAUguggguc、AAUguggguc、AAUguggguc、AAUgugggug、AAUgugguu、AAUgugugua、AAUguuaagu、AAUguuagaa、AAUguu agau、AAUguuagua、AAUguuggug、ACAgcaagua、ACAguaaaua、ACAguaaaug、ACAguaagaa、ACAguaagca、ACAguaagua、ACAguaaguc、ACAguaagug、ACAguaaguu 、ACAguacgua、ACAguaggug、ACAguauaac、ACAguaugua、ACAgucaguu、ACAgugagaa、ACAgugagcc、ACAgugagcu、ACAgugagga、ACAgugaggu、ACAgugagua、ACA gugaguc, ACAgugagug, ACAgugaguu, ACAgugggua, ACAguggguu, ACAguguaaa, ACAguuaagc, ACAguuaagu, ACAguuaugu, ACAguugagu, ACAguuguga, ACCguaagua, ACCgugagaa, ACCgugagca, ACCgugaguu, ACCgugggug, ACGguaaaac, ACGguaacua, ACGguaagua, ACGguaagug, ACGguaaguu, ACGguaauua, ACGguaauuu,ACGguacaau、ACGguacagu、ACGguaccag、ACGguacggu、ACGguacgua、ACGguaggaa、ACGguaggag、ACGguaggug、ACGguaguaa、ACGguauaau、ACGguaugac、ACGguaugcg、ACGguaugua、ACGguauguc、ACGgugaaac、ACGgugaagu、ACGgugaauc、ACGgugacag、ACGgugacca、ACGgugagaa、ACGgugagau、ACGgugagcc、ACGgugagua、ACGgugagug、ACGgugaguu、ACGgugcgug、ACGguggcac、ACGguggggc、ACGgugggug、ACGguguagu、ACGgugucac、ACGgugugua、ACGguguguu、ACGguuagug、ACGguuaguu、ACGguucaau、ACUguaaaua、ACUguaagaa、ACUguaagac、ACUguaagca、ACUguaagcu、ACUguaagua、ACUguaaguc、ACUguaaguu、ACUguacguu、ACUguacugc、ACUguaggcu、ACUguaggua、ACUguauauu、ACUguaugaa、ACUguaugcu、ACUguaugug、ACUguauucc、ACUgucagcu、ACUgucagug、ACUgugaacg、ACUgugagca、ACUgugagcg、ACUgugagcu、ACUgugagua、ACUgugaguc、ACUgugagug、ACUgugaguu、ACUgugggua、ACUgugugug、ACUguuaagu、AGAgcaagua、AGAguaaaac、AGAguaaacg、AGAguaaaga、AGAguaaagu、AGAguaaauc、AGAguaaaug、AGAguaacau、AGAguaacua、AGAguaagaa、AGAguaagac、AGAguaagag、AGAguaagau、AGAguaagca、AGAguaagcu、AGAguaagga、AGAguaaggc、AGAguaaggg、AGAguaaggu、AGAguaaguc、AGAguaagug、AGAguaaguu、AGAguaauaa、AGAguaaugu、AGAguaauuc、、AGAguaauuu、AGAguacacc、AGAguaccug、AGAguacgug、AGAguacucu、AGAguacuuu、AGAguacug、AGAguagga、AGAguaggga、AGAguagggu、A GAguagguc、AGAguaggug、AGAguagguu、AGAguauaua、AGAguauauu、AGAguaugaa、AGAguaugac、AGAguaugau、AGAguauguc、AGAguaugug、AGAguauguu、AGAg uauuaa、AGAguauuau、AGAgucagug、AGAgugagac、AGAgugagag、AGAgugagau、AGAgugagca、Agagugagua、Agagugaguc、Agagugagug、Agagugaguu、Agagugc guc、AGAgugggga、AGAgugggug、AGAgugugug、AGAguguuuc、AGAguuagua、AGAguugaga、AGAguugagu、AGAguuuguu、AGCguaagcu、AGCguaagug AGCgugagcc、AGCgugagug、AGCguuguuc、AGGgcagagu、AGGgcagccu、AGGgcuagua、AGGguaaaga、AGGguaaaua、AGGguaaauc、AGGguaaauu、AGGguaacca、AG Gguaacug、AGGguaacuu、AGGguaagaa、AGGguaagag、AGGguaagau、AGGguaagca、AGGguaagga、AGGguaaggc、AGGguaaggg、AGGguaagua、AGGguaaguc、AGGgu aagug、AGGguaaguu、AGGguaauac、AGGguaauga、AGGguaauua、AGGguaauuu、AGGguacacc、AGGguacagu、AGGguacggu、AGGguaggac、AGGguaggag、AGGguagg ca、AGGguaggcc、AGGguaggga、AGGguagggu、AGGguagguc、AGGguaggug、AGGguauguu、AGGguauaua、AGGguaugac、AGGguaugau、AGGguaugau、AGGguaugca、AGGguaugcu、AGGguauggg、AGGguauggu、AGGguaugua、AGGguauguc、AGGguaugug、AGGguauuac、AGGguauucu、AGGguauuuc、AGGGucagag、AGGgucagca、AGGg ucagga、AGGgucagg、AGGgucagug、AGGgucaguu、AGGguccccu、AGGgucggga、AGGgucugca、AGGguguu、AGGgugaaga、AGGgugacua、AGGgugagaa、AGGgugag ac、AGGGugagag、AGGGugagca、AGGGugagcc、AGGGugagcu、AGGGugagga、AGGGugaggg、AGGGugaggu、AGGGugagua、AGGGugaguc、AGGGugagag、AGGGugaguu、A GGguggga、AGGGugggu、AGGGugggua、AGGGuggug、AGGGugugua、AGGGugug、AGGguuaaug、AGGGuuagaa、AGGGuuaguu、AGGGuggug、AGGGuuugug、AGGgu uuguu, AGUguaaaag, AGUguaaaua, AGUguaaauu, AGUguaagaa, AGUguaagag, AGUguaagau, AGUguaagca, AGUguaagcc, AGUguaagua, AGUguaagug, AGUguaaguu, AGUguaauug, AGUguaggac, AGUguagguc, AGUguaugag, AGUguauguu, AGUguauguu, AGUguauugu, AGUguauuua, AGUgucaguc, AGUgugagag, AGUgugagag, AGUgugagca, AG Ugugagcc、AGUgugagcu、AGUgagua、AGUgugaguc、AGUgugagug、AGUgugaguu、AGUgugggua、AGUguggug、AGUgugugua、AGUguuccua、AGUguuggg、AGUguu ucag、AUAguaaaua、AUAguaagac、AUAguaagau、AUAguaagca、AUAguaagua、AUAguaagug、AUAguaaguu、AUAguaggua、AUAguauguu、AUAgucucac、AUAgugagac、AUAgugag、 ag、AUAgugagau、AUAgugagcc、AUAgugaggc、AUAgugagua、AUAgugaguc、AUAgugagug、AUAgugcguc、 AUAgugugua、AUAguucagu、AUCguaagcc、AUCguaaguu、AUCguauucc、AUCgugagua、AUGgcaagcg、AUG gcaagga、AUGgcaaguu、AUGgcaggua、AUGgcaugug、AUGgcgccau、AUGgcuugug、AUGguaaaac、AUGgua aaau、AUGguaaacc、AUGguaaaga、AUGguaaaua、AUGguaaaug、AUGguaaau、AUGguaacag、AUGguaaca u、AUGguaacua、AUGguaacuc、AUGguaacuu、AUGguaagaa、AUGguaagac、AUGguaagag、AUGguaagau、A UGguaagca、AUGguaagcc、AUGguaagcu、AUGguaagga、AUGguaaggg、AUGguaagua、AUGguaaguc、AUGg uaagug、AUGguaaguu、AUGguaauaa、AUGguaauau、AUGguaauga、AUGguaaugg、AUGguaauug、AUGguaa uuu、AUGguacagc、AUGguacauc、AUGguaccag、AUGguaccug、AUGguacgag、AUGguacggu、AUGguagauc、 AUGguagcag、AUGguagcug、AUGguaggaa、AUGguaggau、AUGguaggca、AUGguaggcu、AUGguagggg、AUGguagggu、AUGguaggua、AUGguaggug、AUGguaguuu、AUGguauagu、AUGguauaua、AUGguaucag、AUGguaucuu、AUGguaugau、AUGguaugca、AUGguaugcc、AUGguaugcg、AUGguaugcu、AUGguaugga、AUGguauggc、AUGguaugug、AUGguauguu、AUGguauuau、AUGguauuga、AUGguauuug、AUGgucaggg、AUGgucaguc、AUGgucagug、AUGgucauuu、AUGgugaaaa、AUGgugaaac、AUGgugaaau、AUGgugaacu、AUGgugaaga、AUGgugacgu、AUGgugagaa、AUGgugagac、AUGgugagag、AUGgugagca、AUGgugagcc、AUGgugagcg、AUGgugagcu、AUGgugaggc、AUGgugaggg、AUGgugagua、AUGgugaguc、AUGgugagug、AUGgugaguu、AUGgugauuu、AUGgugcgau、AUGgugcgug、AUGgugggua、AUGgugggug、AUGguggguu、AUGgugguua、AUGguguaag、AUGgugugaa、AUGgugugua、AUGgugugug、AUGguuacuc、AUGguuagca、AUGguuaguc、AUGguuagug、AUGguuaguu、AUGguucagu、AUGguucguc、AUGguuggua、AUGguugguc、AUGguugguu、AUGguuguuu、AUGguuugca、AUGguuugua、AUUgcaagua、AUUguaaaua、AUUguaagau、AUUguaagca、AUUguaagga、AUUguaaggc、AUUguaagua、AUUguaaguc、AUUguaaguu、AUUguaauua、AUUguaauuu、AUUguacaaa、AUUguaccuc、AUUguacgug、AUUguacuug、AUUguaggua、AUUguaugag、AUUguaugua、AUUgucuguu、AUUgugagcu、AUUgugagua、AUUgugaguc、AUUgugaguu、AUUgugcgug、AUUgugggug、AUUguuagug、CAAguaaaaa、CAAguaaaua、CAAguaaauc、CAAguaaaug、CAAguaaccc、CAAguaacua、CAAguaacug、CAAguaagaa、CAAguaagac、CAAguaagau、CAAguaaggu、CAAguaagua、CAAguaaguc、CAAguaagug、CAAguaaguu、CAAguaaucc、CAAguaaucu、CAAguaauua、CAAguaauuc、CAAguaauug、 CAAguaauuu、CAAguacaca、CAAguacguu、CAAguacuuu、CAAguagcug、CAAguaggau、CAAguaggua、CAAguagguc、CAAguaggug、CAAguagguu、CAAguaguuu、CAAguauaac、CAAguauaug、CAAguaucuu、CAAguaugag、CAAguaugua、CAAguauguc、CAAguaugug、CAAguauguu、CAAguauuga、CAAguauuuc、CAAgucagac、CAAgucagua、CAAgucuaua、CAAgucugau、CAAgugacuu、CAAgugagaa、CAAgugagac、CAAgugagca、CAAgugaggc、CAAgugaggg、CAAgugagua、CAAgugaguc、CAAgugagug、CAAgugaucc、CAAgugaucu、CAAgugauuc、CAAgugauug、CAAgugauuu、CAAgugccuu、CAAgugggua、CAAguggguc、CAAgugggug、CAAgugugag、CAAguuaaaa、CAAguuaagu、CAAguuaauc、CAAguuagaa、CAAguuaguu、CAAguucaag、CAAguuccgu、CAAguuggua、CAAguuuagu、CAAguuucca、CAAguuuguu、CACguaagag、CACguaagca、CACguaauug、CACguaggac、CACguaucga、CACgucaguu、CACgugagcu、CACgugaguc、CACgugagug、CAGgcaagaa、CAGgcaagac、CAGgcaagag、CAGgcaagga、CAGgcaagua、CAGgcaagug、CAGgcaaguu、CAGgcacgca、CAGgcagagg、CAGgcaggug、CAGgcaucau、CAGgcaugaa、CAGgcaugag、CAGgcaugca、CAGgcaugcg、CAGgcaugug、CAGgcgagag、CAGgcgccug、CAGgcgugug、CAGguaaaaa、CAGguaaaag、CAGguaaaca、CAGguaaacc、CAGguaaaga、CAGguaaagc、CAGguaaagu、CAGguaaaua、CAGguaaauc, CAGguaaaug, CAGguaaauu, CAGguaacag, CAGguaacau, CAGguaacca, CAGguaaccg, CAGguaacgu, CAGguaacua, CAGguaacuc, CAGguaacug, CAGguaacuu, CAGguaagaa, CAGguaagac, CAGguaagag, CAGguaagau, CAGguaagcc, CAGguaagga, CAGguaaggc, CAGguaaggg, CAGguaaggu, CAGguaagua, CAGguaagug, CAGguaaguu, CAGguaauaa, CAGguaauau, CAGguaaucc, CAGguaaugc, CAGguaaugg, CAGguaaugu, CAGguaauua, CAGguaauuc, CAGguaauug, CAGguaauuu, CAGguacaaa, CAGguacaag, CAGguacaauau, CAGguacaca, CAGguacacag, CAGguacaga, CAGguacagg, CAGguagu, CAGguacaua, CAGguacaug, CAGguacauu, CAGgu accac、CAGguaccca、CAGguacccg、CAGguacccu、CAGguaccgc、CAGguaccgg、CAGguaccuc、CAGguaccug、CAGguaccuu、CAGguacgag、CAGguacgca、CAGguacgcc、CAGguacggu、CAGguacgua、CAGguacgug、CAGguacua、CAGguacuag、CAGguacuau、CAGguacucc、CAGguacuc、CAGguacgu、CA Gguacuua、CAGguacuuu、CAGguagaaa、CAGguagaac、CAGguagaag、CAGguagaca、CAGguagacc、CAGguagaga、CAGguagauu、CAGguagcaa、CAGguagcac、CAGguagcag、CAGguagcca、CAGguagcgu、CAGguagcua、CAGguagcuc、CAGguagcug、CAGguaggac、CAGguaggca、CAGguaggca、CAGguaggcaa、CAGguaggggc、CAGguagggg、CAGguagggu、CAGguaggua、CAGguagguc、CAGguaggug、CAGguagguu、CAGguaguaa、CAGguaguau、CAGguaguca、CAGguagucc、C AGguaguga、CAGguaugugu、CAGguaguuc、CAGguaguug、CAGguaguuu、CAGguauaag、CAGguauaca、CAGguauaga、CAGguauauc、CAGguauaug、CAGguauauu、CAGg uaucag、CAGguaucau、CAGguauccu、CAGguaucga、CAGguaucgc、CAGguaucua、CAGguaucug、CAGguaucuu、CAGguaugaa、CAGguaugac、CAGguaugag、CAGguau gau、CAGguaugca、CAGguaugcc、CAGguaugcg、CAGguaugcu、CAGguaugga、CAGguauggg、CAGguaugu、CAGguaugua、CAGguauguc、CAGguaugug、CAGguauguu 、CAGguauuau、CAGguauuca、CAGguauucu、CAGguauuga、CAGguauugg、CAGguauugu、CAGguauuua、CAGguauuuc、CAGguauuug、CAGguauuuu、CAGgucaaca、CA Ggucaaug、CAGgucacgu、CAGgucagaa、CAGgucagac、CAGgucagca、CAGgucagcc、CAGgucagcg、CAGgucagga、CAGgucagua、CAGgucaguc、CAGgucagug、CAGgu caguu、CAGgucaucc、CAGgucauc、CAGgucauua、CAGgucauuu、CAGguccacc、CAGguccacu、CAGguccagu、CAGguccauc、CAGguccauu、CAGguccag、CAGgucccc ug、CAGguccuga、CAGguccugc、CAGguccugg、CAGgucggcc、CAGgucggug、CAGgucguug、CAGgucucuc、CAGgucucuu、CAGgucugag、CAGgucugcc、CAGgucugc、CAGgucugcCAGgucugga、CAGgucuggu、CAGgucugua、CAGgucuguc、CAGgucugug、CAGgucuguu、CAGgucuucc、CAGgucuuuc、CAGgugaaag、CAGgugaaau、CAGgugaaca、CAGgugaaga、CAGgugaagg、CAGgugaaua、CAGgugaauc、CAGgugaauu、CAGgugacaa、CAGgugacau、CAGgugacca、CAGgugaccc、CAGgugaccg、CAGgugaccu、CAGgugacgg、CAGgugacua、CAGgugacuc、CAGgugacug、CAGgugagaa、CAGgugagac、CAGgugagag、CAGgugagau、CAGgugagca、CAGgugagcc、CAGgugagcg、CAGgugagcu、CAGgugagga、CAGgugaggc、CAGgugaggg、CAGgugaggu、CAGgugagua、CAGgugaguc、CAGgugagug、CAGgugaguu、CAGgugauaa、CAGgugaucc、CAGgugaucu、CAGgugaugc、CAGgugaugg、CAGgugaugu、CAGgugauua、CAGgugauuc、CAGgugauug、CAGgugauuu、CAGgugcaaa、CAGgugcaag、CAGgugcaca、CAGgugcacg、CAGgugcaga、CAGgugcagg、CAGgugcaua、CAGgugcauc、CAGgugcaug、CAGgugccaa、CAGgugccca、CAGgugcccc、CAGgugcccg、CAGgugccua、CAGgugccug、CAGgugcgaa、CAGgugcgca、CAGgugcgcc、CAGgugcgcg、CAGgugcgga、CAGgugcggu、CAGgug、 cgua、CAGgugcguc、CAGgugcgug、CAGgugcuag、CAGgugcuau、CAGgugcuca、CAGgugcucc、CAGgugcucg、CAGgugcugc、CAGgugcugg、CAGgugcuua、CAGgugcuuc、CAGgugcuug、CAGguggaac、CAGguggaag、C AGguggaau, CAGguggaga, CAGguggagu, CAGguggauu, CAGguggcca, CAGguggcuc, CAGguggcug, CAGgugggaa, CAGgugggac, CAGgugggag, CAGgugggau, CAGgugggca, CAGguggcc, CAGgugggcu, CAGguggga, CAGgugggc, CAGgugggg, CAGgugggu, CAGgugggua, CAGgugguc, CAGgugggug, CAGguggguu, CAGguggucu, CAGguggug, CAGguguug, CAGguguaca, CAGguguagg, CAGguguauc, CAGgugucac, CAGgugucac, CAGgugucag, CAGgugucca, CAGguguccu, CAGgugucua, CAGgugucuc, CAGgugucua, CAGgugucuc, CAGgugucua, CAGgugucuc, CAGgugucug, CAGgugugaa, CAGgugugac, CAGgugugag, CAGgugugau, CAGgugugca, CAGgugugcc, CAGgugugcg, CAGgugugcu, CAGgugugga, CAGgugugc, CAGgugug ugua、CAGguguguc、CAGguguguc、CAGgugugu、CAGguguuua、CAGguuaaa、CAGguuaaua、CAGguuaauc、CAGguaccu、CAGguuagaa、CAGguuagag、CAGguuaagau 、CAGguuagcc、CAGguuagg、CAGguuaggu、CAGguuagua、CAGguuagc、CAGguuagc、CAGguuagu、CAGguuauca、CAGguuaugu、CAGguuauua、CAGguauug、CAGguuagu guucaaa, CAGguucaac, CAGguucaag, CAGguucaca, CAGguucacg, CAGguucagg, CAGguucaug, CAGguuccag, CAGguuccca, CAGguucccg, CAGguucgaa, CAGguucgag, CAGgucuau, CAGguucugc, CAGgucuua, CAGgucuuc, CAGguucuuu, CAGguugaac, CAGguugaag, CAGguugagu, CAGguugaua, CAGguuggag, CAGguuggca,CAGguuggcc, CAGguugguc, CAGguuggug, CAGguugguu, CAGguuguaa, CAGguuguac, CAGguuguau, CAGguuguca, CAGguuguga, CAGguuguug, CAGguuuaag, CAGguuuacc, CAGguuuagc, CAGguuuagu, CAGguuucu, CAGguuugaa, CAGguuugag, CAGguuugau, CAGguuugcc, CAGguuugcu, CAGguuuggg, CAGguuuggu, CAGguuug C AUguaagau、CAUguaagcc、CAUguaagua、CAUguaagug、CAUguaaugu、CAUguaauua、CAUguacaua、CAUguaccac、CAUguacgu、CAUguaggua、CAUguaggug、CAUgu agguu、CAUguaugaa、CAUguaugua、CAUguaugug、CAUguauguu、CAUgugagaa、CAUgugagca、CAUgugagcu、CAUgugagua、CAUgugaguc、CAUgugagug、CAUgugagu u、CAUgugcgua、CAUgugggaa、CAUguggguu、CAUguguguku、CAUguguguu、CAUguuaaua、CAUguuagcc、CCAguaagau、CCAguaagca、CCAguaagcc、CCAguaagcu、CC Aguaagga、CCAguaagua、CCAguaaguc、CCAguaagug、CCAguaaguu、CCAguaauug、CCAguacggg、CCAguagguc、CCAguauugu、CCAgugaggc、CCAgugagua、CCAgug agug、CCAguggguc、CCAguuagu、CCAguugagu、CCCguaagau、CCCguauguc、CCCguauguu、CCCguccugc、CCCgugagug、CCGguaaaga、CCGguaagau、CCGguaagcc、,CCGguaagga,CCGguaaggc,CCGguaaugg,CCGguacagu,CCGguacuga,CCGguauucc,CCGgucagug,CCGgugaaaa,CCGgugagaa,CCGgugaggg,CCGgugagug,CCGgugaguu,CCGgugcgcg,CCGguggcg,CCGguugguc,CCUguaaug,CCUguaaauu,CCUguaagaa,CCUguaagac,CCUguaagag,CCUguaagca,CCUguaagcg,CCUg uaagga、CCUguaaguu、CCUguaggua、CCUguaggug、CCUguaucuu、CCUguauggu、CCUguaugug、CCUgugagaa、CCUgugagca、CCUgugaggg、CCUgugaguc、CCUgugagug、CCUgugaguu、CCUguggcuc、CCUgugggua、CCUgugugua、CCUguuagaa、CGAguaaggg、CGAguaaggu、CGAguagcug、CGAguaggug、CGAguagguu、CGAgugagca ,CGCguaagag,CGGgcaggca,CGGguaagcc,CGGguaagcu,CGGguaaguu,CGGguaauuc,CGGguaauuu,CGGguacagu,CGGguacggg,CGGguaggag,CGGguaggcc,CGGguaggug,CGGguauuua,CGGgucugag,CGGgugaccg,CGGgugacuc,CGGgugagaa,CGGgugaggg,CGGgugagagu,CGGgugaggu,CGGgugagua,CGGgugagug,CGGgugaguu,CGGgu gauuu、CGGgugccuu、CGGgugggag、CGGguggug、CGGgugguu、CGGguguguc、CGGgugugug、CGGguguguu、CGGguucaag、CGGguucaug、CGGguuugcu、CGUguagggu、CGUguaugca、CGUguaugua、CGUgucugua、CGUgugagug、CGUguuucu、CUAguaaaug、CUAguaagcg、CUAguaagcu、CUAguaagua、CUAguaaguc、CUAguaagug、CUAguaaguu, CUAguaauuu, CUAguaggua, CUAguagguu, CUAguauguua, CUAguauguu, CUAgugagua, CUCguaagca, CUCguaagug, CUCguaaguu, CUCguaucug, CUCgucugug, CUCgugaaua, CUCgugagua, CUCgugauua, CUGguaaaaa, CUGguaaaau, CUGguaaacc, CUGguaaacg, CUGguaaagc, CUGguaaaua, CUGguaaauc, CUGguaaa C UGguaagcc、CUGguaagcu、CUGguaagga、CUGguaaggc、CUGguaaggg、CUGguaaggu、CUGguaagua、CUGguaaggu、CUGguaaguu、CUGguaauga、CUGguaaugc、CUGgu aauuc、CUGguaauuu、CUGguaac、CUGguacaau、CUGguacaga、CUGguacaua、CUGguacau、CUGguaccau、CUGguacguu、CUGguacuaa、CUGguacuug、CUGguacuu u、CUGguagaga、CUGguagaua、CUGguagcgu、CUGguaggau、CUGguaggca、CUGguaggua、CUGguagguc、CUGguaggug、CUGguaucaa、CUGguagau、CUGguaggc、CU Gguauggu, CUGguaugua, CUGguaugug, CUGguauguu, CUGguauuga, CUGguauuuc, CUGguauuuu, CUGgucaaca, CUGgucagag, CUGgucccgc, CUGgucggua, CUGgucuggg, CUGgugaagu, CUGgugaaua, CUGgugaauu, CUGgugacua, CUGgugagaa, CUGgugagac, CUGgugagca, CUGgugagcu, CUGgugagag, CUGgugaggc, CUGgugaggg,CUGgugag、 gu、CUGgugagua、CUGgugaguc、CUGgugagug、CUGgugaguu、CUGgugauua、CUGgugauuu、CUGgugcaga、CUGgugcgcu、CUGgugcgug、CUGgugcugg、CUGgugcugg、CUGgugcugg. gag、CUGgugggga、CUGgugggua、CUGguggguc、CUGgugggug、CUGguggguo、CUGgugugaa、CUGgugca、CUGgugugcu、CUGgugug、CUGgugugug、CUGgug、CUGgug uguu、CUGguuagcu、CUGguuagug、CUGguucgug、CUGguuggcu、CUGguuguuu、CUGguuugua、CUGguuuguc、CUGguuugug、CUUguaaaug、CUUguaUagcu、CUUguaUagcu no. ugagua. guaaauu、GAAguaagaa、GAAguaagcc、GAAguaagcu、GAAguaagua、GAAguaagua、GAAguaugc、GAAguaugc、GAAguaauua Aguaauuu、GAAguaccau、GAAguacgua、GAAguagguc、GAAguaggca、GAAguaugcu、GAAguaugcu、GAAguauguu、GAAguauua AAgucagug、GAAgugagcg、GAAgugaggu、GAAgugaguc、GAAgugagug、GAAgugaguu、GAAgugauaa、GAAgugauuc、GAAgugcgug、GAgugg、GAgugg AAguguguc、GAAguuggug、GACguaaagu、GACguaagcu、GACguaagua、GACguaaugg、GACguaugcc、GACguauguu、GACgugagcc、GACgugagug、GAGgcaaaug、GAGgcaagag、GAGgcaagua、GAGgcaagug、GAGgcaaguu、GAGgcacgag、GAGgcaggga、GAGgcaugug、GAGgcgaagg、GAGguaaaaa、GAGguaaaac、GAGguaaaag、GAGguaaaau、GAGguaaacc、GAGguaaaga、GAGguaaagc、GAGguaaagu、GAGguaaaua、GAGguaaauc、GAGguaaaug、GAGguaaauu、GAGguaacaa、GAGguaacag、GAGguaacca、GAGguaaccu、GAGguaacuu、GAGguaagaa、GAGguaagag、GAGguaagau、GAGguaagca、GAGguaagcc、GAGguaagcg、GAGguaagcu、GAGguaagga、GAGguaaggc、GAGguaaggg、GAGguaaggu、GAGguaagua、GAGguaaguc、GAGguaauaa、GAGguaauac、GAGguaauau、GAGguaauca、GAGguaaucu、GAGguaaugg、GAGguaaugu、GAGguaauug、GAGguaauuu、GAGguacaaa、GAGguacaac、GAGguacaga、GAGguacagc、GAGguacagu、GAGguacaua、GAGguacauu、GAGguaccag、GAGguaccga、GAGguaccug、GAGguaccuu、GAGguacuag、GAGguacuau、GAGguacucc、GAGguacugc、GAGguacugg、GAGguacugu、GAGguacuug、GAGguacuuu、GAGguagaag、GAGguagaga、GAGguagagg、GAGguagagu、GAGguagauc、GAGguagcua、GAGguagcug、GAGguaggaa、GAGguaggag、GAGguaggca、GAGguaggcu、GAGguaggga、GAGguagggc、GAGguagggg、。GAGguaggua、GAGguaggug、GAGguagguu、GAGguaguaa、GAGguaguag、GAGguaguau、GAGguagucu、GAGguagugc、GAGguagugg、GAGguaguua、GAGguagug、GAGguauaag、GAGguauacu、GAGguauagc、GAGguauaug、GAGguauau、GAGguacau、GAGguaucug、GAGguaucuu、GAGguaugaa、GAGguaugac、GAGguaugag、GAGguaug cc、GAGguaugcg、GAGguaugcu、GAGguaugga、GAGguauggg、GAGguauggu、GAGguaugua、GAGguauguc、GAGguaugug、GAGguauguu、GAGguauucc、GAGguauuga、GAGguauugu、GAGguauuua、GAGguauuuc、GAGguauuug、GAGguauuuu、GAGgucaaca、GAGgucaagg、GAGgucaaug、GAGgucag、GAGgucagaa、GAGgucagag、GAGgu cagcu、GAGgucagga、GAGgucaggc、GAGgucagg、GAGgucaggu、GAGgucagua、GAGgucauau、GAGgucaugu、GAGgucauuu、GAGguccaua、GAGguccauc、GAGguccgg g. Ggugaaca、GAGgugaagg、GAGgugaaua、GAGgugaauu、GAGgugacau、GAGgugacca、GAGgugaccu、GAGgugacua、GAGgugacuu、GAGgugagaa、GAGgugagac、GAGgugagag、GAGgugagau、GAGgugagca、GAGgugagcc、GAGgugagcg、GAGgugagcu、GAGgugagga、GAGgugaggc、GAGgugaggg、GAGgugaggg、GAGgugaggua、GAGgugagu、GAGgugaguu、GAGgugauau, GAGgugaucc, GAGgugaucu, GAGgugauga, GAGgugaugg, GAGgugaugu, GAGgugauuc, GAGgugcaca, GAGgugcaga, GAGgugcagc, GAGgugcagg, GAGgugccag, GAGgugccca, GAGgugccuu, GAGgugcggg, GAGgugcgug, GAGgugcucc, GAGgugcugg, GAGgugcuua, GAGgugcuug, GAGguggaaa, GAGguggaau, GAGgugga cc、GAGguggacg、GAGguggagg、GAGguggcug、GAGgugggaa、GAGguggag、GAGgugggau、GAGguggca、GAGgugggcg、GAGgugggcu、GAGguggga、GAGgugggc、GAGgugggg、GAGgugggua、GAGgugguc、GAGguggug、GAGgugguu、GAGguguau、GAGgugguuc、GAGgugucau、GAGgugugga、GAGgugugca、GAGgu gugcu、GAGGugguga、GAGGuggugg、GAGGugguggu、GAGGugugua、GAGGuggugu、GAGGuuaaau、GAGGuuaga、GAGGuuaaua、GAGGuuaccg、GAGGuuagaa、GAGGuuaga c. Gguugaag, GAGguugcag, GAGguugcug, GAGguuggaa, GAGguuggag, GAGguuggau, GAGguuggua, GAGguugguc, GAGguugguu, GAGguuguag, GAGguuucug, GAGguuugag, GAGguuugga, GAGguuugua, GAGguuuguu, GAGguuugga, GAGguuuuggg, GAGguuuuca, GAGguuuuga, GAGguuuugg, GAGguuuuuua, GAGguuuuc, GAUguaaaau, GAUguaagc,a、GAUguaagcc、GAUguaaggu、GAUguaagua、GAUguaagug、GAUguaaguu、GAUguacauc、GAUguaggua、GAUguauggc、GAUguaugua、GAUguauguu、GAUgucagug、GAUgugagag、GAUgugagcc、GAUgugagcu、GAUgugagga、GAUgugaguc、GAUgugagug、GAUgugaguu、GAUgugggua、GAUgugggug、GAUguguguu、GAUguuagcu、GAUguucagu、GAUguucgug、GAUguuuguu、GCAguaaagg、GCAguaagaa、GCAguaagga、GCAguaagua、GCAguaaguc、GCAguaaguu、GCAguagaug、GCAguaggua、GCAguaugug、GCAguauguu、GCAgucagua、GCAgucagug、GCAguccggu、GCAgugacuu、GCAgugagcc、GCAgugagcg、GCAgugagcu、GCAgugagua、GCAgugagug、GCAgugaguu、GCAgugggua、GCAguuaagu、GCAguugagu、GCCguaaguc、GCCgugagua、GCGguaaagc、GCGguaaaua、GCGguaagcu、GCGguaaggg、GCGguaagug、GCGguaauca、GCGguacgua、GCGguacuug、GCGguagggu、GCGguagugu、GCGgugagca、GCGgugagcu、GCGgugaguu、GCGguggcuc、GCGgugugca、GCGguguguu、GCGguuaagu、GCGguuugca、GCUgcuguaa、GCUguaaaua、GCUguaagac、GCUguaagag、GCUguaagca、GCUguaagga、GCUguaagua、GCUguaaguc、GCUguaagug、GCUguaaguu、GCUguaggug、GCUguauggu、GCUgucagug、GCUguccuug、GCUgugagaa、GCUgugagcc、GCUgugagga、GCUgugagua、GCUgugaguc、GCUgugagug、GCUgugaguu、GCUguggguu、GGAguaagag、GGAguaagca、GGAguaagcc、GGAguaagcu、GGAguaagga、GGAguaagug、GGAguaaguu、GGAguaauuu、GGAguacugu、GGAguaggaa、GGAguaggua、GGAguagguu、GGAguaguau、GGAguaugac、GGAguauggu、GGAgucaagu、GGAgugaggg、GGAgugagua、GGAgugaguc、GGAgugagug、GGAgugaguu、GGAgugcuuu、GGAguggg ca、GGAguggug、GGAguuaagg、GGAguugaga、GGCguaagcc、GGCguaggua、GGCguaggug、GGCgugagcc、GGCgugaguc、GGGguaaaca、GGGguaaacc、GGGguaaacu、G GGguaagaa、GGGguaagag、GGGguaagau、GGGguaagca、GGGguaagcc、GGGguaagcu、GGGguaagga、GGGguaaggg、GGGguaagua、GGGguaagug、GGGguaaguu、GGGgu agaca、GGGguaggag、GGGguaggcc、GGGguaggga、GGGguaggua、GGGguaggug、GGGguagguu、GGGguagugc、GGGguaucug、GGGguaugac、GGGguaugga、GGGguaugua、GGGguauguc、GGGguaugug、GGGguauguu、GGGgucagua、GGGguccgug、GGGgucggag、GGGgucugug、GGGGugaaca、GGGGugaaga、GGGGugagaa、GGGGugagau、GG Ggugagcc、GGGgugagcg、GGGgugagcu、GGGgugagga、GGGgugaggc、GGGgugagg、GGGgugaguc、GGGgugagug、GGGgugaguu、GGGgugcgua、GGGguggggu、GGGgug ggua、GGGguggug、GGGguggguu、GGGgugugcg、GGGgugugua、GGGguguguc、GGGgugug、GGGguuacag、GGGguuggac、GGGguuggga、GGGguuugcc、GGGguuugua、GGUguaa, gaa、GGUguaagau、GGUguaagca、GGUguaagcc、GGUguaagcg、GGUguaaguc、GGUguaagug、GGUguagguc、GGUguaggug、GGUguagguu、GGUguccgua、GGUguga gag、GGUgugagcc、GGUgugagcu、GGUgugagua、GGUgugaguc、GGUgugcuuc、GGUguggcug、GGUgugug、GGUgugcug、GGUgugaaa、GGUguugcug、GUAGUAGUA 、GUAGUAGUAGUA、GUAGUAGUAGUA、GUAGUAGUAGUAGUA、GUAGUAGUAGUAGUA、GUAGUAGUAGUA、GUAGUAGUAGUAUM、GUAGUAGUAGUAUM、GUAGUAAUGUG、GUGUGUGUU Cgugaguu、GUGgcaagua、GUGguaaaau、GUGguaaaau、GUGguaaaau、GUGguaaacau、GUGguaaaacau、GUGguaagaa、GUGguaagac、GUGGAG、GUGgua aagau、GUGguaagca、GUGguaagcg、GUGguaagcu、GUGguaaggc、GUGguaagc、GUGguaagua、GUGguaaguc、GUGguaagug、GUGguaagua、GUGGUAAU、GUGGUAGUAAUGA 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, UAAguauaaa, UAAguacuag, UAAguaguuu, UAAguauaaa, UAAguauaca, UAAguaugua, UAAguauuuau, UAAguauuuu, UAAguguugac, UAAgugagag, UAAgugaggg, UAAgugagua, UAAgugaguc, UAAgu gagug, UAAgugaguu, UAAgugaucc, UAAgugauuc, UAAgugcgug, UAAguuaagu, UAAguuccag, UAAguucuu, 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, UAGgugag cc、UAGgugagcu、UAGgugagga、UAGgugaggc、UAGgugaggu、UAGgugagua、UAGgugaguc、UAGgugagu、UAGgugauca、UAGgugauuc、UAGgugauuu、UAGgugcaua、U AGgugcauc、UAGgugccgu、UAGgugccug、UAGgugcgca、UAGgugcgua、UAGgugcgug、UAGgugcuga、UAGguggaua、UAGgugggaa、UAGgugggac、UAGgugggag、UAGgu gggau、UAGgugggcc、UAGgugggcu、UAGguggguu、UAGguggugu、UAGguguaaa、UAGgugugaa、UAGgugug、UAGgugugca、UAGgugugcc、UAGgugugcg、UAGgugg u、UAGgugugua、UAGgugug、UAGguguugg、UAGguuaagc、UAGguuagac、UAGguuagcc、UAGguuaggc、UAGguuagua、UAGguuaguc、UAGguuag、UAGguuccc、UA Gguucuac、UAGguuggua、UAGguugguu、UAGguugucc、UAGguuuauuu、UAGguuugcc、UAGguuugua、UAGguuuguc、UAGguuugug、UAGguuuguu、UAGguuuuuc、UAGguu uuug、UAUguaagaa、UAUguaagau、UAUguaagca、UAUguaagcc、UAUguaagua、UAUguaaguc、UAUguaagug、UAUguaaguu、UAUguacgug、UAUguacguu、UAUguagguc、UAUguagg、 uu, UAUguauccu, UAUguaucuc, UAUguaugua, UAUguauguc, UAUguaugug, UAUguauuau, UAUgucagaa, UAUgucugua, UAUguguaaua, UAUgugacag, UAUgugagua, UAUgugagug, UAUgugagug, UAUgugaguu, UAUgugggca, UAUgugugua, UAUguguuua, UAUguuuugu, UCAgcgacau, UCAguaaaau, UCAguaaaua, UCAguaacug, UCAguaagaa, UCAguaagag, UCAguaagag, UCAguaagau, UCAguaagca, UCAguaagcc, UCAguaagcu, UCAguaaggg, UCAguaagua, UCAguaaguc, UCAguaagug, UCAguaaguu, UCAguaucuu, UCAguaugga, UCAguauggu, UCAgucccca, UCAgugagca, UCAgugagcu, UCAgugagua, UCAgugagug, UCAgugaguu, UCAgugauug, UCAgugggug, UCAguugagc, UCAguugau u、UCAguuuagu、UCCguaagca、UCCguaagcu、UCCguaaguc、UCCguaagug、UCCguaauag、UCCguacuua、UCCguaugua、UCCguauguu、UCCgugagau、UCCgugaguc、UCCguaaauu、UCGguaagag、UCGguaagcu、UCGguacauc、UCGguacucc、UCGguagacc、UCGguagguu、UCGguaguaa、UCGguaugug、UCGguauguu、UCGguauuga、UCGg ucagua, UCGgucuuag, UCGugaagu, UCGugagaa, UCGugagagca, UCGugaggc, UCGugagua, UCGgugcgcu, UCGgugcuuu, UCGgugguu, UCGguuagcu, UCUguaaaag, UCUguaagaa, UCUguaagau, UCUguaagca, UCUguaagcu, UCUguaagua, UCUguaaguc, UCUguaagug, UCUguaaguu, UCUguaauaa, UCUguaauga, UCUguaaugu,UCUguaggua, UCUguagguu, UCUguauaua, UCUguaugac, UCUguaugua, UCUguccucg, UCUgugagag, UCUgugagcu, UCUgugagga, UCUgugagua, UCUgugaguc, UCUgugagug, UCUgugaguu, UCUgugcgua, UCUgugugag, UGAguaacuu, UGAguaagau, UGAguaagca, UGAguaagcu, UGAguaaggc, UGAguaaggu, UGAguaaguagua, UGAguaaguc, UGAguaagug, UGAguaaguu, UGAguaaucc, UG, Aguaauua、UGAguacagu、UGAguacgua、UGAguacguu、UGAguacugu、UGAguagcug、UGAguaggua、UGAguauaa、UGAguaugcu、UGAguaugga、UGAguaugua、UGAguauguc、UGAguauguu、UGAgucagag、UGAgucuacg、UGAguga aua、UGAGugaauu、UGAGugagaa、UGAGugagau、UGAGugagca、UGAGugagcc、UGAGugagga、UGAGugagua、UGAGugagug、UGAGugaguu、UGAGugggaa、UGAguuaaga、UGAguuaaug、UGAGuuacgg、UGAGuuaggu、UGAGuucuau、U GAguugguu、UGAguuguag、UGAguuuauc、UGCguaaguc、UGCguaagug、UGCguacggc、UGCguacggg、UGCguaugua、UGGgcaaguc、UGGgcaagug、UGGcacauc、UGGgccacgu、UGGgccccgg、UGGguaaau、UGGguaaaagc、UGGgua aagg、UGGguaaagu、UGGguaaaua、UGGguaaaug、UGGguaaauu、UGGguaacag、UGGguaacau、UGGguaacua、UGGguaacuu、UGGguaagaa、UGGguaagac、UGGguaaga、UGGguaagau、UGGguaagca、UGGguaagcc、UGGguaagcu、 UGGguaaggg、UGGguaaggu、UGGguaagua、UGGguaaguc、UGGguaagug、UGGguaaguu、UGGguaaugu、UGGguaauua、UGGguaauuu、UGGguacaaa、UGGguacagu、UGGguacuac、UGGguaggga、UGGguagguc、UGGguaggug、UGGguagguu、UGGguaguua、UGGguauagu、UGGguaugaa、UGGguaugac、UGGguaugag、UGGguaugua、UGGguaug Ug GGgugaggc、UGGgugaggg、UGGgugagua、UGGgugaguc、UGGgugagug、UGGgugaguu、UGGggcgug、UGGguggagg、UGGguggcuu、UGGgugggg、UGGgugggua、UGGgu ggguc、UGGgugggug、UGGguggguu、UGGgugguga、UGGguguguc、UGGguggugu、UGGguguu、UGGguguuua、UGGguuaaug、UGGguuaguc、UGGguuag、UGGguuagu u、UGGguuaag、UGGguuacgua、UGGguuggug、UGGguuaag、UGGguuugua、UGUgucaagua、UGUguaaaua、UGUguaaga、UGUguaagc、UGUguaaggu、UGUguaaggu、UG Uguaagua、UGUguaguc、UGUguagu、UGUguaguc、UGUguaggcg、UGUguaggua、UGUguaguu、UGUguaugu、UGUguagua、UGUgucugu、UGUguguc、UGUguug acc.UGUuguuaga、UUaguaaaua、UUaguaagaa、UUaguaagua、UUaguaagug、UUaguaaugu、UUaguaggug、UUAgugagca、UUAgugaguu、UUAguuaagu、UUCguaaguc、UUCg uaauu、UUCguaauua、UUCgugagua、UUCguugauu、UUGgcaagug、UUGgccgagu、UUGguaaaaa、UUGguaaaau、UUGguaaaga、UUGguaaagg、UUGguaaagu、UUGguaaa uc, UUGguaaug, UUGguaaauu, UUGguaacug, UUGguaacuu, UUGguaagaa, UUGguaagag, UUGguaagcu, UUGguaagga, UUGguaaggg, UUGguaagua, UUGguaagug, UUGguaaguu, UUGguaauac, UUGguaauca, UUGguaaugc, UUGguaaugu, UUGguaauug, UUGguaauuu, UUGguacaua, UUGguacgug, UUGguagagg, UUGguaggac, UUGgu aggcg、UUGguaggcu、UUGguaggga、UUGguaggua、UUGguagguc、UUGguaggug、UUGguauaaa、UUGguauaca、UUGguauauu、UUGguaucua、UUGguaucuc、UUGguaugca、UUGguaugua、UUGguaugug、UUGguauguu、UUGguauugu、UUGguauuua、UUGguauuuu、UUGgucagaa、UUGgucagua、UUGgucucug、UUGgucugca、UUGgugaaaa、UU Ggugacug、UUGgugagac、UUGgugagau、UGGugagca、UGGugagga、UGGugaggg、UUGgagua、UUGgugaguc、UUGgugagu、UUGgugagu、UUGgugaugg、UUGgug auua、UUGgugauug、UUGgugcaca、UUGggggaa、UUGgugggc、UUGgugggua、UUGgugguc、UUGguggug、UUGguggguu、UUGgugggu、UUGgugguc、UUGgugu、 g, UUGguguguu, UUGguuaagu, UUGguuagca, UUGguuagug, UUGguuaguu, UUGguugga, UUGguugguu, UUGguuugua, UUGgu uuguc, UUUgcaagug, UUUguaaaua, UUUguaaaug, UUUguaagaa, UUUguaagac, UUUguaagag, UUUguaagca, UUUguaaggu, UU These include Uguaagua, UUUguaaguc, UUUguaagug, UUUguaaguu, UUUguaauuu, UUUguacagg, UUUguacgug, UUUguacuag, UUUguacugu, UUUguagguu, UUUguauccu, UUUguauguu, UUUgugagca, UUUgugagug, UUUgugcguc, UUUguguguc and uGGguaccug.

[0252] Additional 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、UGUguacgug、UAGguaaaga、CUAguaggca、UCUgugaguc、UCUguaaggc、CAGguuugug、GAGguagggc、AAGguaacca、ACUgugaguu、UAGguaauag、AAAguaagcu、AUGgugag、 ug, UAGguuugug, AACguaggac, GUAgcaggua, GAGgucagac, AGGguaugaa, GAGguuagug, CAGgcacgug, GGGgcaagac, CAGguguguc, CAGguauuga, CAGguauguc, AAGgcaaggu, UUGgugagaa, AAGguaaaau, GGGguaagua, AAGguaucuu, GACgugaguc, UAUguaugcu, AAGguacugu, CAGgugaacu, CACguaaug, AAGgugugau, GAAguauuug, AAGgucugug, AAGguggagg, AAGguauaug, CAGgucuua, AGGguaacca, CAGgugucac, AAAguucugu, UUGgugaguu, CAAgugaguc, UAGguagguc, GCGgugagcu, AUUgugagga, CAGgugcaca, CAGguuggaa, CUGgucacuu, GGAguaagug, GAGguggcu, AAGguacuug, AAGGguaggau, AAUguguguu, ACAguuaagu, GAGgugug g、AAGgcgggcu、AUAgcaagua、AAGguuguua、CAAgcaaggc、GUGguaauua、UCUguucagu、AGGguaggcc、AAGguacau、UAGguaccuu、AAGguaugac、GGaguaggua、U AAguuggca、AGUgugaggc、GAGguuugug、UGGgucugcu、CAGgugaucc、CAGgucagug、AAGguaaggg、CAGgugcagu、GAGgugguc、GCUgugugag、AAGguggagu、GGGg ucaguu、AGCguaagug、AGAguaugaa、GGGguagggu、AAGgccagca、CGAguaugcc、GUGgugagcg、AAUguaaauu、CAGgugcgca、GGUguaugaa、CUUgugaguu、AAGguau cuc、AGAguaagga、UAGguaagac、GAGGugagug、CAGguguguu、UUGgugagua、AGGgcgaguu、CAGguuuugc、UUUgugagugu、AGGguaagca、GAGguccucu、CCAgcaggua、GAGguucgcg, CAGgugaucu, ACUguaagua, AAGguaaauc, CAGgcaaaua, GUGguaagca, CAGguuaaau, UUGguaauaa, UAUguaggua, CAGguaguau, AAGgugugcc, UGGg uaagag、CAGgcaagca、UUGguaaggg、AAGgcaggug、ACGguaaaug、GCUgugagca、AUGguacaca、GUAguguguu、ACUguaagag、CCCgcagguc、GAGgugagcc、GAGgugcu gu、UAAguaugcu、GAGgccaucu、UCAgugagug、CAGgugcuac、AAUgugggug、GAGgugugaa、CUGguagguc、GUGgcgcgcg、CAGgugcaaa、UAAguggagg、CAUgugggua、G AGguagggu, AAAgugaguu, AGGguucuag, UGUgugagcu, AGGgugaauc, CAGgucaggg, AAGgucccug, CUGguagagu, UAGgucaguu, AAAguaaggg, CAAguaugug, CAGgu gcuuu, AAGguaauuc, GGGgugcacg, ACUgugcuac, CAGguaccua, CAGguagcuu, UGGgugaggc, CUGguacauu, AGGguaaucu, CAGguacaag, CAGguaauuc, AGGgcacuu g、UAGgugagaa、GAGguaaugc、CCAgugaguu、AAAguaugug、CUGgugaauc、UAUguaugua、CCUgcaggug、CAGguaucug、GAGgugaggu、CUGguaaaac、UGUgugugcu CA Gguuaagu、CAGguaaucc、UAGguauuug、UGGguagguc、CAGguaacag、AGCgugcgug、AAGgucagga、GGUgugagcc、CUGguaagua、GGGgugggca、AAGgugggaa、CAGgug agug、CUGguuguua、CAGguaauag、UAGgugaguu、AGAguaaguu、UAGguaaucc、CCGgugacug、GUCgugauua、CUUguaagug、UAGguaguca、CUGguaaguc、AGGgugagcg、CAGgua、 ugga. c、GGGgugggag、GCAgcguaugua、GAGguaaga、GAGguaugua、AAGgugagac、AAGguacau、CUGguaugag、AACguaaaau、GUGguaggga、CUGguaugua、ca、ca AGguaggga、AUUguaagcc、AUGguaagcu、CAGgugaauu、UAGgugaaua、CAGuaugga、AUGguauggc、GAGgucaugc、CAGguacccu、ACAgugagac、CAGGAcugau、 uugggu、CUGgugcgug、CAGguacgag、ACAgugagcc、AAGguaagua、GGAguaaggc、GAGgugugua、AAGgucauuu、CAGguagucu、AUGguacug、AAGGAGAGUAacu ug. UUGguaaaac、GAGguaagua、CAGguucaag、UGGguaagua、GAGgugaguu、ACGguaaaac、GAUguaacca、CCGguacgug、GAUgugagagaa、CAGgggaa、GU uauuag、GAGguuggga、AAGgcuagua、AAGgugggcg、CAGgcaggga、AAUguaguu、GAGguaaagg、CAGgugugcu、CUGguaugau、AUGguuaguc、gCAGgugagacc、g gcg、CAGgugacug、AAAguaaggu、UAAguacuug、AAGguaaagc、UCGguagggg、CAGguaggaa、AGUguaggca、CCCgugagau、GUGguagguu、CAGguuugggcc、UAAguaagug、GAGguaagac、GAUguagguc、CAAguaggug、AUAguaaaua、GAGguugggg、GAGgcgagua、CAGguagugu、GUGguaggug、CAAgugagug、AAGgugacaa、CCAgcguaau、ACGgugaggu、GGGguauauu、CAGgugagua、AAGgugcgug、UAUguaaauu、CAGgucagua、ACGguacuua、GAGgucagca、UAAguaugua、GGGgucagac、AAUgugugag、UCCgucagua、CAGgugcuuc、CCAguuagug、CCGgugggcg、AGGgugcaug、GGGguaggau、UAGgugggcc、GAGguguucg、UUGgcaagaa、UCCguaagua、CAGguguaag、CUCgugagua、GAGguguuuu、GAGgugagca、GAGguaaagu、AAGguacguu、CAGguccagu、AUGgugaaac、GUAgugagcu、CAGgugaaaa、AGGguacagg、AAGguaacgc、AAGguauacc、CCUgugagau、GGGguacgug、GAGguauggu、UAGguauuau、GAAguaggag、UCGgu、 aaggg、CCGguaagcg、GAAguaauua、CAGgugaguc、AAGgucaaga、AUGguaaguc、CAGgugagcu、CCAguuuuug、CAGgugggag、AAGguauuau、AAGguaaaua、AAGgugcugu、AAAguacacc、CUGguucgug、UCAguaaguc、GAAguacgug、CAGgugacaa、UGGguaagaa、UGUguagggg、GAGguaggca、UUGgugaggc、AUGgugugua、CAGguccucc、UUGguaaaug、GCUgugaguu、AUGgucugua、CAUgcaggug、CUGguacacc、CAGguccuua、CAAguaaucu、AUGgcagccu、AAGgucagaa、AACgugaggc、CAGgcacgca、ACGguccagg、UCUguacaua、GAGgugauu a、ACGguaaaua、AUGguaacug、CAGgcgcguu、CAGguauaga、AAGguuuguu、CAGguaugaa、UAGguuggua、CUGgugagac、CAGguuagga、AUGgugacug、UUGguauccc、C UUguaggac, AAAguguguu, CAGguuucuu, GGGguauggc, GGGguaggac, ACUguaaguc, AUCguaagcu, UAGguucccc, GGUgagca, CUGguuggua, GGGguuaggg, UGAg uaagaa、GAGguauucc、UGGguuaguc、CAGgcucgug、UAGguagagu、UAGgugcccu、AAAgugagua、GAGguucaua、UUGguaagag、ACCgugugua、UAUguaguau、UGGguaa uag、CAGgucugaa、AAAguauaaa、GUGgugaguc、AGUgugauua、UUGgugugug、CAGgugaugg、GCUgugagua、CAGguacaug、AAGguacagu、GAAguuguag、CAGgugauua UAGgugaauu、GGUguuaaua、CAGguauuua、CAAguacucg、CAAguaagaa、AAGguaccuu、ACGgugaggg、UGAgcaggca、GGGgugaccg、GAGguaaaug、CGGguuugug、AA Ggugagcg、GUGguaugga、CUGguaagga、GAGguaccag、CCGgugagug、AAGguuagaa、GAGguacuug、AGAguaaaac、UCUgugagua、AAGgcgggaa、CAGguaugcg、AGGgu aaaac、AAGgugacug、AGGguauguu、AAGguaugua、CAGgucucuc、CAGgcaugua、CUGguaggua、AAGgucaugc、CAGguacaca、GAUguacguu、ACAguacgug、ACGguacc ca、CAGguagugc、ACAguaagag、GGUgcacacc、GAGguguaac、AAGgugugua、UAGguacuua、GCGguacugc、UGGguaaguc、CAUguaggua、CAGguaggau、CAGgucuggc、GUGguuuuaa、CAGgugggaa、UGGgugagua、CGAgugagcc、AAGguauggc、AGUguuguca、CAGgugauuu、UAGguaucuc、UAAguauguu、AAGguugagc、AGAguaaaga、GGUg uaagua、GGGgugagcu、CAGguauaau、GAGguacaaa、AUGguaccaa、UAGguagggg、UGAgucagaa、AAGgcaauua、UUGguaagau、CAGguacaga、AGAguuagag、CAGgugcg uc、GAGguauuac、ACGguacaga、CAGgucuucc、AAGguaaggu、GAGguaauuu、AGUguaggcu、AAAguaagcg、CCUguaagcc、AGGgugauuu、UGUguaugaa、CUGguacaca、A GGguagaga, AUAguaagca, AGAguaugua, UUGgucagca, CAGgcaaguu, AAGguauaua, AAGgucugga, CAGguacgca, AGGgugcggg, AUGguaagug, AAAgugauga, UGCgu There are many ways to get the best results from your search u、ACAgcaagua、GAGguaggag、UGGgugaguu、GCGgugagau、CCUguagguu、CAGgugugua、CUGguaagcc、AAGgugauuc、CAGguagcua、GUUguaagug、AUGguaagca、AU Aguaggga, GGGguucgcu, CCGgucagag, GUAguaugag, CGUguaagau, UGAguaggca, UCAguaugua, GAGguaucug, AGAguauuuu, AAGguuguag, AGUguaaguu, CGGgua aguu, UCGgugcgga, UAGguaagua, GAAguuagau, GCUgugagac, CAGgcaggua, CAGguagggg, UAAguuaaga, AUGguggguu, UAGguaaguu, CUGguaaauu, CCGguaagga.GAGgcag、 gca, CAUguaagug, AAGgugccua, UUGguaggga, AAGguaaaca, CGGgugugag, GGGgugugag, UCCguggguc, ACGguaaauc, UCAguaggua, CAGgucagcc, CAGgcggugg CGAguaagcu, CCCgugagca, AAAguaauga, CUGguaagcu, CGGguaacca, CAGgucgcac, GGguaggcc, UAGgugagcc, UAGguaggca, GCGgugcgug, AUGgugagua, GG Ggugaggg、GAGgucacac、CAGguaggcc、CAAgugcuga、GUCgucuuca、CAUguaagaa、GUAguaagga、UAGguuugua、CAAguuagag、AAGguagagu、AAGgugagau、AAAgu aggua、ACAgugaauc、CAGgugugcg、CAGgucggcc、AAGguaguau、ACUgucaguc、UCUgcagccu、CGAguaagug、AGAguaauua、AGUgugagug、CCGgugagcg、AAGguaacc u, AAGguugugg, AAGgcauggg, AAGgucagag, ACGguaaggu, GGGgugagca, GG GGguaagga, CCGguaacgc, CAGgucagaa, AAGguacuga, GGgugacca, GGGgugagcc, AAGguacagg, AUGguaauua, CAGgugagag, AAGgugacuc, AUAguaagua, GGg uaaacc、CAGgugggau、CAGgugagaa、AGGguaaaaa、GAGgugugac、CACguaagcu、CAGgucccccc、CAGgucaggu、CGGguaaguc、ACGguauggg、GAUguaaguu、CAAguaa uau、CAGguugggg、CCUgugcugg、AAGguaugau、AGGguagagg、AAGguggguu、CAGgugugaa、UUGguaugug、UUGguaucuc、GGGgugagug、CUGgugugug、AGGguagggc、GUGgugagua、CAGguaugua、AAGguacauu、UUAguaagua、AAUguauauc、CAGguaagua、CAGguaagua、AGGgugaggcGug、CAGguau ucugga、GGGgugugcu、UAGgugagug、AAUguaaccu、UAAgugaguc、CAGgugcacu、ACGguaagua、GAGguauccu、UCUguaaguc、CAGguauuca、UGUguaagugca、ag gc、GAGgugaagg、AAUguggggu、UCGgugcgug、UUGguaaggc、GAGguaagug、AAguaagau、UAGgucuuuu、GAGgucugau、CCAguuagag、GAUG、guGaaaa AGguaauug、CAGgccgguc、CCGguaagag、GAGgugagcu、CUGguaagac、CAGgugagau、CUGguuuguu、UGGguaggua、CAGguuagug、CAGguguucg、CGGguagguc acaua、AAGguacuaa、GAUgugagua、UGUguaagac、GAGguagccg、UAGgugaucu、CAGguacgug、CUUgucaguc、GAGguaugac、GAGguaugaa、AAGCAGguacac c. Gguaggug、AAAAguaaguc、CGGgugcagu、GGUgugugca、UGAgugagagu、CACguguguaag、GUGgugugua、GCAgccuuga、CGAgugugugau、CAGguauaua、UAUCCguaugug、UAUCCugugug、 was、AUGguaagac、GAGgugugugga、AGUguauccu、UGAguguguc、UGGguaaucu、AUGgcagguu、GAGguaagau、UCAgcagcgu、AAGgugggau、CGGgugcguggu、CAThe AGC, gguaa, AAUgugaaug, UCGgugagac, UAGguaaagc, CUGguaaaag, CCGgugcgga, CAGguacuca, CAGguagcaa, GAAguugagu, GAGguggagg, AGGguaugag, UAGguaugcu, UAGgugagac, CAGguaauua, CGUguaagcc, CUUguaaguu, AAGguaacuu, UCGgcaaggc, GAGgucucg, GAGguggcg, AAGgcaugug, CUGguauguu, UAAgucauuu, CAUguaauua, AAUguaaaga, UAGgugcuca, AAGguaaugg, GAGguacuga, UGGguaagua, UGGguaaaaa, AAGgugagcu, UACgugaguu, AGGgugagcc, CG Ggugagga、UGGgugagag、GGUguaagcu、CGGgugguu、CCAgcuaagu、AAGguuuguc、GAGguuagac、GAGguaccuc、UUUguaaguu、GAGguuagga、CAGguaggga、AGGguaauac、UGCgugugua、CCAguaacca、AGGgucuguc、UGGguaugua、GUGguaagcu、CAGguaaccu、AAGgugaguu、UAGguucgug、AAAguuagua、UGGgcaaguc、AAGgcacagu、GUUguaaguc、AAGguuugcc、CUUgcauggg、GCGgugagua、GGGguaagcg、GCCguaagaa、GAGgucggga、UUGguauugu、AGUgugagac、CUGguggga、 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、ACCguaugua、GUAguaagug、UUGgugggua、CGGguacuuu、UGGguaaaua、AGAgugagua、AAGguagguu、AAGguaugcg、CCUguaggcu、ACAguagaaa、CCGguuagua、CGGguagg、 cg, GCAgugagug, GAGgugaguc, CUGguagccu, CAUguaugua, GAAguaacuu, GAAguaagau, AAGguaauca, AAUguaugua, UGAguaagau, AGAgugagca. GUAguucuau、GAGguaauca、UAGguaugga、UAGgugggac、GAGguacaug、UGGguaaggc、CAGguacgcc、CCAguuacgc、ACUgugguga、GAGguaaguc、AUUguaggug、ACC gucagug、AAUgugaggg、ACUgugagug、UGGguguggu、AAGguuggga、AAGguuugga、UCCgugagug、CGGgugagug、AGAguaagcu、CAGgcaagcu、UAGguauauu、AAAgua gcag、GAGguaaccu、AAGgugggca、AGGgugagua、UGGguaaggu、CUUgucagug、UAGgugcgcu、GAGgcaaauu、AGGguaccuc、CAAgugcgua、AGAguaagac、GUGguaaau a、GAUguaagcg、GAGguaaagc、UAGgugagua、CAGguaacau、CCUguacggc、UAGguauguc、UAGguccaua、GAGgugaaaa、AAAguacuga、UUGguaagcg、CAGgcaagcg、U UUgcagguu、CAGguuuaua、CUGguaaagc、AUGgugagcu、CAGgugguug、GUAguaaguu、CAGguaauac、CAGgcaaggc、AAGguaauuu、UUUguccgug、GAGguagguu、ACCg ugagug、CAAguaagcu、ACAgugagua、UUGgugagau、AAGguagucu、CAGguaaagg、GGGguaugga、UUUguaagug、GUGguaagag、AGUgugaguu、AAGgcaagcg、UAAguga gua, 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、UUGguacuau、CAGgucggug、CAGgcauggg、AUGguaucuu、AAGguaacua、CAGgugggcg、CACgugagga、AAGgugguuc、UGGgcauucu、AUGguaagcc、AGGgucagug、AGAgua、 cgua、AAGguaggca、AAGguauuca、CAGguagauu、GAGguauuua、GAGgucuaca、GUUguagguc、CAGguacucg、GUCguauguu、AAGguacuuu、AGAgugagau、AGUguuggua、AAUgugagug、AAGguagauu、AUGguuugua、GAGgccccag、AUGgucaguu、UCUguaagga、CAGgucgggc、CAGguaagcc、UAGgucagug、AGAguaggaa、CUGguacuuc、CUCguaagca、CAGguaacua、CAGguggcug、UGGguccgua、GAGguugugc、CAGgugcgcg、AAAguauggc、UGAguacgua、CUGguacgga、CAAgugaccu、AAGgugaugu、AAGgucugca、AAAguuugua、AAGgugagca、GAUguaagcc、CAAguaauuu、CAGgugugug、UGGgugaggg、AAGgugaccu、UAGgugugag、CAGgcagguc、UCAguaaguu、UCAgcaguga、AAGguaccac、UAAguaggug、AAGgucagcc、CAGguaacuc、AAAguaagag、AAGguagaua、AAGgcaaggg、CAGgugucgg、CAGguggcua、GAGguugcca、CAGgccgugg、UUGguauaug、GAGguugagu、GAGguagguc、GUGguaagac、UAGguccuuc、GAGgcaaguc、GAGguaacau、CAGguauauc、UCGguugguu、CAGgugaacc、CAGgucuuuu、CAGgcauggc、AAAguacuug、CAGgugauuc、UUGguagguu、UAUgugagca、CAGgugagcg、AAUguaauaa、AAAguaaggc、UAGguuuguc、UAGgugggag、GAGguaaguu、AAGguagccg、CAGguggugc、UGAgucaguu、CUGguaggcc、CAAguaagga、CGGguaaggc、AAGgcgagga、CAGguaguuc、CAGguaagga、CCUgugagug、AAGguaaaug、CCGguaauua、CAGguaaguu, AAGgugguca, CAGguaaccuc, AUCguaagua, CCGguacaua, GCGgugagug, GAGgugguau, CUGgugugga, GGguaauuc, CAAguacgua, UCUguaagug、AAUguaagug、AGGgucuguu、GAGguacugc、AGGguaaggc、AAGgcaagag、CAGguggguu、UAGguuagga、UGAguaagcu、AGAguaagag、A UGgcaggug, UAGgcaagua, AUGguaggua, GCAgcccgca, ACGguaaacu, AGGgugaguu, GUAguagucu, GUGgcugaaa, CAGguuaguc, CUGgugagca, UC Aguaagug、AAAgugauug、UAGgucugga、GAGguguuuc、AAGguaaauu、CAUguacauc、AAGguuugaa、CCAgcaagug、UAGguaauaa、GAGgcaagug、CAA gugauuc, CAGgucgugg, GAAguaugcc, UCGgugcccu, GAGgucaguc, CAGgugagac, UUUgucugua, CAGguagaua, UGGguaucag, UAGgugggcu, AUGg ugagau、CAGguaacac、CCGguauccu、UAGguaagcu、UCAguacauc、UAGguuugcc、AUGguaagaa、UUGguaagac、CCGguuaguc、GAGguaagaa、UGGgu aaguu、CCGgugagaa、CCUgugaggg、ACGguaggag、ACAguauguc、CAGguauuaa、CAGguggauc、AGAgugcgua、AAGgugaccg、AGAguaggug、ACUgua ugua, UAGgucaauu, AGUguguaag, CGGguaccuu, CUAgugaguu, CUAguaagug, CAGguacaac, UAGgugugug, CAUguacggc, AUGgugugag, AGGgug. gaag、CAGgugcgag、UAGgugcucc、AAGguggugg、AAGgucuguu、CAGgugggcc、AAGgucaguc、CAGguuuuu a、AACgugaggu、CGGguaagag、UUUgucggua、UAGguaaagu、GUGguaagaa、CAGguauugg、GCUguaaguu、CUAguaagua、UCGguaaaua、CAGguaacuu、CCUgugagua、C AGguuauau、CUGgugaaca、AAGguauaaa、GAGguaagca、AAGgugaagc、CAGgugaguu、UUUgugagua、CUUguacgcc、AGAguaagug、UGGguaggug、UGAgcccugc、UGUg uaugua、AAGguagagg、GAGguggggg、UAGguaauuc、AAGgcauggu、AGAguaagca、AAGguaggaa、CAAguaagua、ACUguaauug、CAGgucugug、UCGguaccga、CUGguga gag、AAGguuugcu、AUGguaccac、UAAguuaguu、CAGguaggac、AGAgugaggc、CGAgucagua、CAGgucugag、GAGguggugg、ACGguauugg、GCUgcgagua、CUGguaagug GUGgugagau、GGGguuugau、UCUgugagug、CUUgucagua、GAGguaaaac、UCUguaagau、CCAguaaguu、CAGguaaagu、GCGgugagca、UAAguaagag、CUGgcaggug、GA Gguaaggg, UGAguaaguu, GAGgugagac, GCUgucuguu, AAGguaacaa, GAGguaacgg, CUGguauucu, CAAguaacug, AAGguggggu, UAGguauggc, CAGguauuuu, GUGgu aaacu、GAGgucugag、CUGguaaggu、CAAguaaguu、AAGguagacc、GAGgcgagcg、CUGguaaaua、UGUguaagcg、CAGguuaggg、GGGgugagga、ACAguaugug、CCGguggg ga、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、AAUguacgca、CCGgugggua、UGGgugaggu、AAGguauguu、CAGguauguu、CAGguuugcu、UUGguaaguu、CAGguaguug、CCUgugaaua、GCUgugugug、CAAguaauuc、AGGguaa, ugu、GCUgugaguc、ACCguaaguu、CGUguaagua、GGGguaaguc、AAUguaugau、AAUgugauua、UCAguaagaa、CAGguccguc、GAAguauuga、UUGguaagga、CAGgucgguu UAGguuagug, ACGguaaaac, AAGguagguc, UACgugagua, UUGguaagca, GCGgugaguc, GAAguaaggg, CGCgugaguu, CAGguacccc, UCUguaagac, GAGgugggca, AA Uguaagac, CAGgcaaggg, CAAguaacua, AAAguuuguc, CAGguacugu, AAGgucccuc, UCGguaaguc, UGGgugagug, CUUgugagau, AGAgugagcu, UAAgugggga, UAGgu aggga、CAGguuagcc、AGGguaauca、AAGguucagc、UGGgugggug、CAGguuguga、AAGguaagug、CAUgugcgua、CCGguauauu、ACCguaugug、CAGguauagu、CAGguauua c、CAGgugcagg、GUGgugagcu、AAGguaacau、CUGgugaugg、AUGguaaaug、CCGgugagca、AAGguaaacc、AAGguacugg、GCGgucagga、CUGgucaggg、AAAguacguu、A GAguagguu、AGGguaagcu、AUUgugagua、CCGgccacca、GAGguaacuu、GAGguaugaa、CAGgucagac、UAGgcgugug、AGGguaaguu、CAGgcaugag、CAGguaacgu、CAGg cgagca, UAGguauggu, AGAguaggau, CUGguuucaa, GAGguaaacu, CAGgcaugca, UUGguaaucu, AGGgcagaau, AUGguaaaac, GCUgcaggug, GAAgcacgug, CAUguaa aca, UGGguaagau, AGGguagcua, AGGguggggu, CCUguaaguu, UGAgugaguu, GGAguaugua, CAGgugaccu, AAAguacgga, GGguacaga, 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、AGGguaaaug、AAGguaugca、GCUgugcgug、GAGguucgcc、AAGgcuugca、CAGgcaagug、AUAguaaguc、UUGguaggua、GCAgcaggua、AAGguauauc、AGCguaagcc、CUGgu, ucgaa、ACGgugggug、CUGgucauug、CAGgucagga、CAAgugagac、GAGguacugg、GAGguguagu、GAGguguccu、CAGgugcgua、AGUgcccuga、AUGgugaguc、UGUgugug ua、CAGguaugcu、CUGguacagu、UUGguacgua、UCUguacgua、UAAguaauuc、CACguaugug、CAGgcaagua、UCGgugagug、GGUgugaguc、UCUguaagcu、AAGguucaga、A GGguacuuc、GCGgcagguu、GAGgcccgug、CAGguauaaa、AUGgucaagu、AAGgugagua、GUGguuuguu、AGAgugagga、GAGguaugac、UAGgcgugag、AAGguacucc、UGAg ugagga、GAGguaugau、GGGgucggua、ACGguaugca、CAGguaccac、UAAguaccug、AGGgugggcu、CUGgucuguu、UAGgucagag、AAGguguguu、CUGgucagug、AAGguggg ac、GUGguaguag、CUAguuuagg、CCCgccccau、GCUguacugc、GAGguaauau、UAGguuggug、AAGguccaac、UAGgugagga、GUGguaaguu、AGUgugagag、AAUguacaug、 UUGgcaggug, UAGguuauug, CAGguacuga, GCGguggguc, UGUguaagau, GAGgugagua, GCAgccccgg, CAGgugcuaa, AGUguaagag, CAGguacauc, CAGgugggac, AGGg uaaaua、UAAguaauua、CAGguaaccg、AAGguuugca、UAGgugguuu、CAGgugaccg、UGUguaagcu、GGAgugaguc、AGGguaggag、AGGgugggug、AAGgucugag、GAUguaa uau、GGGguaauua、UAGguaggua、GAGgcaagua、GAGguaagga、UAGguacuac、UCGgugggug、AAGgugugga、CAGgucugcc、UAAgugagcc、GAAguaaguu、GAAguaagcc、UAGgugcgac, GGguauggc, GCAguaagaa, CAGgugugga, U. UGguaacgu, GCUguaaaaa, UUGguuagua, AUAguaaggg, UUGguacuag, CGGgcagccg, CAGgugcugg, UAUgugaguu, CAGgucuggg, UAAguaagaa, AAGguu auua、AGAguaaagc、AGAgugugag、UAGgugcgag、CAAguaaacg、AAGguacgua、CUGgugagua、CCAguaugua、UUGgugagug、UGAguaagua、GAGguuagca、 GUGguaagcc, CUGguauggc, AAAguaacac, CAGguacuaa, UCUguaaguu, GAGgugaggg, ACUgugggua, GAUguuugug, CAGgugucaa, CAGgucacca, CCGgu gagua、UUGguaaaua、CAGguggggg、ACUgcaggug、UAGguauguu、GGAgcaagug、UCGgugccuc、CAAguaacuu、GAGguaacca、CAGguaauau、GGAguaagaa CCCg uaggcu、ACAguaugua、GACgugugua、GCGgugagga、CAGgugaccc、UAAguuuagu、ACAguugagu、CGGgugaggg、CAGguggauu、CGGguagagg、UAGgugcgu g、GGGguaagaa、GAGguggggu、CACguggguu、ACGguaauug、AGAgugaguc、UUGgcuccaa、AAGgugaugc、AAGguugguc、AGCguaaguu、AUUguaugua、UCA guuaagu、CAAguacgug、CAGgugcgug、CAGguaggua、AUGguggggu、AUGgugaguu、CAGguaauca、AAGguagggu、CAGgccaagg、GUGgugagag、AAGguugg ug. GCGguacaca、AGAguaugcu、UUUguaagua、UCUgugcgg、AAGgucagug、GAGguaggaa、GCGguuagca、AGGgugaggg、GAgugagua、CAGgugacag、GAAGua、guAAGga gccagcc、GAGguaagua、UAGguauuac、CAUguaagag、CUGguaggc、GAguaagua、CGGguaagug、CAGguaagua、GUGguaggua、CAGguaugua、AAAGgccagug、AAAGgccagug、AAAGgccagug、 aauc、ACGguaggaa、AUGguaggaa、CGGgugagac、GAGguaggaa、UGGgugagcc、CCAgugagua、CUAguacgag、CAGguaugac、GCUgugaggu、CUGguaugaac、GGUGAGA c. UGguaaggc、GUGguaaagca、UAAguaagca、GAGguuccaa、CUGguaugca、GGGgugggua、CAGguuuccc、CAGgucucug、GAGgugagga、CUUguggguu、AUGguCAGgagac ugaagg、GCCGguagggg、GUUguuuccc、AAAgcaucca、GUGguagguu、AAGgugugaa、CAGguaaug、AAGguaccaa、UUGguaauug、AAGgugcuca、uAAGguucaac、uAAGguucaac、 aca、GCUguaagug、AGGguauguc、GAGgucgggg、AAGgugccug、AAGguaaaaa、GUGgugaguu、UAGguaagaa、AGGguauccu、GUGguaauau、UCUGaguaugua、GaguaUgga、AUGguaugga、GACgugagcc、CUGguuuggc、AUGguauauc、AAAguaaacu、AGCgugagug、CUGguauaga、CAGgugggga、AGAguauguu、UAGguacuug、GCAguaggug、AGUguauguc、AAGguuaagc、CUGguggccu、GAAgugaguc、UUGguguaag、CAGguaagaa、CGGgucucgg、GAGgugcaca、CUCguuaguu、AAGgugauca、UAUguaagaa、GAGgugcuug、CAGgugguca、ACGguaaguc、ACAguaaugu、CCUguaaggu、GAGguuaagu、UCGguaugug、UGGguauguu、AAGguauuac、CAGgugaggg、UUGguaaaca、AAGguagugu、GAGguguggc、CAGguacgga、AAGgucauca、CAAguaggca、CAGgugaaac、CAGguacugc、AAUgcaagug、CAUguaauuc、AAGguaugcu、CUGgugaguu、CAGgugguuu、UGUgugagua、AAGgucggug、AUGguaaauu、AGGguauuac、AGUguaugga、AACguaagau、GUGguaaggu、ACUguuagua、CAGguaucag、AAGguuaguu、CUGgugagcu、UUGgugagcu、UGUguacgua、GAGgucagcc、GAGguagaau、AAGguaugag、UAGguauuuc、UGUguaacac、AGUguaaggc、GAGgucugcu、AAGguuagca、CAGguaaaug、AACguaagcu、CAGgucugca、CAGguauugu、GUGguaauuc、GAGguauaug、GCCgugagcc、GAGguaagag、UGAguaugua、CAGguaaggg、GAGguaaauu、CAGgcaacuu、UGUguaaguc、CAGgugcgcu、CGGguaaacc、CCGgucaguc、UAGgugggcg、GCGgucaguu、GGGguggguc、AGCguaauag、ACGgugaguc、CUGguacuug、CAGguuggua、AGAguaugug、CUGgugggua、GAGgug, gcuu、AUAguauuga、UGAgucgucc、CAGgugcucu、UACguaauau、GCUguccuga、CAGgcugcac、CUGgugcgcu、GCGguaagaa、UAAguuacuu、GAAgugagug、UAGgcaagu c、UAAguaaaua、ACGgugagug、CAGguagguu、GGGguauaac、GUUgugaguu、CAUgugagua、GAGgugcauu、AAGguuugua、UCGguaaugu、CGAguaaggg、GAGgcacgga、A GGgugugga、CAGguauggu、AAGguagaaa、CAGgugccug、UGGguauaug、UGAgugagac、UGGguaauuu、AUGguaaaua、AAGgcaaagg、AGUguuuguu、AUGguauugg、CUGg ugaggc, UUGguaaaau, ACAgugaguu, CAGgugcugu, GAGguuaaga, AGAguaagaa, GAGguccgcg, GUGgugagga, CAGgugagcc, CAGgugacau, AUGgcaagcu, UCGguaau au、CAGgcaacaa、GGGguaggga、CUGgucucgc、UAGguaacga、CGGguaaggu、UAGguaaugc、CAGgcaagaa、ACAguaggua、CAAguaugag、GCUguucgaa、AAGguuaugc、 GAUgugaguu, CAGguggaga, AGAguuaguu, UGAgugugcg, GAGguacagc, CAGguaagac, CAUgugcuuu, AGGguguguu, ACAguuaagg, ACAgugaggg, GAUguauacc, UUAg uaagcu、CAGguaagau、AGAgcugcgu、GAGgcaaguu、GAAguaagug、AAGgugaaaa、AAGguaccua、GAGguaucag、AUGguaugua、AAGguaugaa、UUGgugagcc、AAGguua gga、AGGguaugua、CAGguaccga、AGAguaaacu、AAGgugcaua、AAGguaaugu、CCGgugugug、AGGguaaauu、GGGguuuggc、CAGguacacg、UUGguaacca、GAGgucaggu、UCUguuggua、CAGguuaguu、UUGguauguc、AAGgugcguc、AGGguaagaa、UUUguaagcc、AAGgucaggu、CUGguaaacu、UCGguaauuu、CUGguaggcu、GAGgucugua、GAGg uacuuu, CUGguaaagg, CGGgugugug, CAGguguggu, UCGguacguc, CAGgugccag, GGGgugagaa, ACAgcuagua, AAGguauagc, CUGguaggag, GCUguacgua, AAGguaaa gg、CAAgcacgag、CUAguaagac、CCCguaagcg、CAAgugugag、AUGguaaggg、AAGgugaggg、CAAguaggua、GGUguugcug、GAGguacugu、UAGguaagau、CAGgugcgaa、G AGguccagg, UUGguauaca, GGAgugagua, GAGgugagau, AAGguggggc, CAGguaaacg, UCGguaacuu, CAGguaaauu, GGgugcgca, ACUgugagua, ACGgugugac, GUGgu aaguc, CAGguaggca, CAGgucagca, GUGguaugug, AAAguaucug, CGGguaugua, AAGguaauaa, GAGgugggga, GCUguaggug, GAAgugaguu, AAAguauuua, UAUguaagu a、ACGguaugag、CUGgugagug、AGAguaaaau、GCUguauggc、AUGguaaacc、GCAguauaaa、UAAguauuua、AAUgucagug、AUUgcaggag、CCGguaagaa、AAGgcaaguu、GA Gguuuguc, AAGguaacug, AAAguaugag, GAUguuagua, CAGguggguc, AAGguaccga, CCAguaauua, GUGguaugcg, AUGgugcgcu, CAGgucuaug, AAGguauuua, CUAgua agau, AGAguaauuu, GAGguaacgu, AAGguagcca, CUGgucccgg, GAGguccuuc, ACGgucaccc, AAGguaauac, CAGgugcaug, AUGguaauag, UUUguaacac, UGGguaugau.CAGg、 cccccc、AGAguaguaa、AGUguaagaa、GAAguauguu、CAGgugugca、UUGgugaggg、UGGguugguu、CAGguacgua、GAGgugcggc、UCUguacggg、CGGgugcgug、UACguaagug、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、ACGguaagag、AUGguacggu、GAGgccaguu、GAGguaugcg、UCGgugggag、AAGguggaua、CCAguguggc、AGGguaagug、UCUguagguc、CAGgcaagga、CGGguaauuu、AUUguga、 guc, CAGguaaacc, AAGgucaauu, AAGgugaaua, GUCguaagaa, GCGguaaguc, CUGguagagc, GGgucgguc, CAGguaaaca, AAGgcaagga, CAGgucgucu, GGGguagggc CUGguacuaa, GAGguagcug, CUUgucagcu, UAGguaaggc, CUGguauuac, UAAguacguc, AAGguaagcc, ACGgugaaag, CCAgccaaua, CAGguuuguc, AAGguauaau, AA Ggucuuag、AGGgugagcu、AAGguuaggg、CGGguaaauu、CAGguaacgg、AGAgugugua、ACAguaaguu、GAUguaauuu、GAGguaggga、UUGgcaagug、AAAgugagga、AAGgu agugc, AGAguaauuc, GGAguaaaua, GUGguaccca, CAGguauugc, GAUgugaggg, CAAguaaauc, CAGgugucuc, AAGguaacag, UUGguaaaag, CAGguaucau, ACGgugaga c、CUGguaugac、CAGguucacu、GAGgugauca、AGUguaaguc、AACguaagua、AAAgugagug、GAGguacagg、CAAguaauga、GAUguaagga、UCAguucccc、GCGguaagga、U AGguacuaa、AAGgugaaag、ACUguaagug、UGGguaugug、AUGguaacag、CAGguagggu、ACAguaagug、AAGgugcucc、AAGgugugcu、AAGgugguga、ACGgugcgcc、AAGg uauugc、GGGguaugug、CAGgugggcu、GAGguauguu、AACgugaaua、CAGguaaugg、UAGguaugau、CAGgcaggug、GGGguugguc、AAGguauggg、UAAgugaggc、CAAguga ucg、AAAguacggg、AGAgcuacag、GAGgugggaa、CAGguacuuu、GAGgugagag、CAGguagguc、UGGguacagc、AAGgugucag、AAGgcaagaa、GAGguaaaca、AAGguaaagu、AAGguaguca、CUGguauguc、GAGguauggg、AAGguauugu、CUGguacuga、GAGguaagcu、UGGgugggua、CAGguucgug、AAGguauggu、CAGgugagca、UGGguaaauu、UGUguaggug、UGUgugagcc、CUGguaauau、AAAguauguu、UGUguaagaa、CUAgugagaa、AGGguagguc、AAGgugggug、UCGguaagug、AGUguaaaua、GAUguaagug、AAGguuagug、UAGguaagca、CAAgugagaa、AGUguaagua、CAGgugaauc、UGGgugagac、AAGguagggc、CUGguuugug、GCGguagggc、GAGguaaucc、AUUguaauaa、CUGgugaaua、AAGguuuaaa、CCUguacugu、GCGgugagcg、AAGguaaucc、UAUgugagua、CCCgugagug、CAGgugcaga、CAGgucaguu、CAGguaggcu、AAAguaagug、UAGguugguc、CAGguugccu、AAGguaugga、GGUguggacg、AAAgugagaa、AGGgugagag、GAUguggcau、UCGguaaggu、GAGgugcguc、CGGgugaguc、AAGguacggg、GAGguucuug、AAGgugcuug、UAGguaugua、AUGgucagca、CGGguacuca、AGGgugagga、AUCgugagua、UCAguaagua、UAGguaaaua、AAGguaauug、GAAgucagug、CAGguacaaa、AAAguuaauc、AGCgugagcg、CCGgcuggug、AGUguaauuu、UGAgccacuc、GGGgucugua、AUGgcauguc、CGGguaaaga、AGGguagcau、CGGguaggag、GAGguucgug、UAAguuauuc、UAUguaagau、AAGguaguuu、CAGgugguau、GUGguaauga、AAGgugauuu、CAGgugaagu、GUAguaauua、AUGguuggug、CCAguaagug、UAGgugagag、AUGgugaggc、AAAguuagug、The AAG, gccuu、UAGguaugag、CAGgugugac、CUGguggguu、AUGguaagga、UCUguaagaa、UCCgugaguu、AAAgcaggua、UAUgugagug、CAGguggagg、CAGguuagac、AUAguaag ac、AAGguguugu、GAGgucugug、AAGguaagau、CAUguaaguu、CUGguaauua、CAGguaggcg、AGAguaaguc、UGGgugagga、AAUguaggua、UAGguuagca、GGGguaggua、G AGguauugc、AUUguacaca、GAAguaggua、GGAguaagcu、UAGguaugug、GAGgugaaua、GAGgugggau、AAGguaaucu、GGUgugaguu、AACgugaguu、GAGguaaccg、UAGg uaagga、AUUguaagaa、UGGgugagca、AAGguaaggc、CCAguaucgu、CCGgugggug、GAGguagugu、ACGgugggaa、GAGgugaccu、CACguaugua、AGGgugggga、AAUguaag uc、AAAguuaagu、CAUgugagug、AGAguauguc、GCGguaugac、CGGgugaguu、CCGguauuuu、GAGguagaac、UAGguaugaa、CAGgcgcgug、CAAguaaguc、AGUguaagau、 AAGguucuac, CCAguaagua, GAGguagcag, CAGgucuguu, CAGguacaau, CCGguaaaga, UAAgugcugu, AGGgugagaa, CUCguaaggu, CAGgucagcu, CAGguaaggc, AGGg ugcagg, GAGgugaaac, AGGguaagua, AAUguaugcc, AAGguaagca, ACGguacggu, AAGguaauga, UCUgcucaau, ACGguaaugu, AAGguaguug, ACGguaagug, CAGguga uga、GAGguaacac、GAGguaggua、CAGguaccuu、CAGguaauaa、UUGgugggug、CUGguaauga、UAGguaaguc、AGGgugugac、GAGgcaauaa、GUGguaaagc、CUGguggggcg、These include GAUguauguu, AGGgugagac, UCGgucagca, AUGgugauua, CGAgugugua, CAGguuggug, AGCgcaagua, UGGguacguu, GAGguauuug, AGUguacaua, AUGguaagua, ACAguagguu, AAGgugagag, UUGgugaagu, AAAguaugua, UGGguaagga, UAGgugccuu and CCUgugggug.

[0253] 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, UGUgu aacaa, AGGguauuag, UGAguauauc, AGAguuugug, GAGgucgcug, GAGgucaucg, ACGguaaagc, UGAguacuug, CGAgucgccg, C UGguacguc, AGGguauugc, GAAgugaaug, CAGaugaguc, UGGguauugg, UGAguaaaga, GUGguuccug, UGAgcaagua, UAUguaag ag. AAGgucuccc、UGGgugcguu、UGUguagguu、GAAgugagca、GGUguaauuu、CUGgugaaau、AUCguaaguc、AGAguaaucc、GGAguagguc、GAGguaccaa、CUUguaggug、AAGg uauaag, AGAguuggua, AUGguuugug, UGGgucagau, AGAguaggac, AGAguagugu, AGAguaggag, CAGgucucua, AAGguggaug, UGGguaucaa, GAUguaugga, AAGguguu uc、GCAguguaaa、UUAguaugua、UCUguaugca、AAUguaaaau、AGAguaaauu、GGGguacuuu、GAAguuugau、AAAguagauu、UGUguagagu、UGGguaagcg、CGGguucagg、A GGguacgac, UCGguaagaa, AGGguuggca, AAAguacagu, UAAguuaagg, AUGguaaugu, GUGguuuuac, AGAguaacaa, AAGguagccc, GCGgugaggc, AUGguucagc, AAGgu acuua、AAGguccgug、UAGguaagcg、AUGguaccuu、GCCguggugg、CUGgugcguc、CAGguggaaa、AAAgucugua、GAGguaaccc、AGAguauggg、UAUgccccug、AAGgugcca g、ACGgugcggc、AGGguacuga、AGAguaagcg、CUGgcaaggg、CCAgugugug、GAGguagacg、CGGgugcggg、GAUguaagcu、AUUguauuua、UGCgugagug、CUGgucuaua、GA Ggugcuag, GAGgugccau, CAGguacguc, GAGguucagc, AACguaagaa, AGAguaguac, AAGguaacgg, UAGgugugac, CCGguaauag, CAGguaccag, UUUguaauug, AAUgua cgaa、CAGguaauga、AUCgucaagg、CUGguagaug、GGGgugcagu、AGUgugagaa、GGGguuuuau、CCUguccccu、AUUgugaagu、AAGguaaacg、UACgucgugg、AAGgugccau、GGGgucccag, UAUguauggu, CGGguaauua, CGGguacucc, CAGgugacuu, AGUguggguu, AGAguauggc, AAGgccaaca, AAAgcaagua, UCAguagguc, GUGguggcgg, CAUg uauccu、UCGgugagcc、AUAguugggu、AAUguuagcu、AUGgugaaug、CGGguaaugu、UCUguaggug、CCGgugaggc、UGAguccacu、CUAguaagag、CGGguggggc、CGAguaag ca、UGUgccaauu、UCGguaagcc、UAUguaggug、UUGgugggcc、GAGgcugggc、AGAguaacuu、ACGguagguc、CAGgcccaga、CCGguggguu、AAGgugacgg、GGGguacagc、C AUguaaguc, AUUgugagaa, UGUguaagga, UUUguaagau, AGGgucauuu, UGGguuuguu, CGAguaagcc, GUGgugugua, AUGguauaac, UGGguacgua, AAAguagagu, UCGgu aacug、AGAguaauga、AUGguggguc、AGAguaauau、CAGguacugg、UAagucaguu、GCGguagaga、AAGgugaugg、ACAguauguu、GAUguacguc、UAGguuucuc、GAGgcaugg g、AUAgcuaagu、GUAgucugua、AAGgugaacg、GUGguggucg、GAGguugauc、UGAguggguu、ACUguacgug、CUGgugacug、CAAguuaagc、GAGguaccca、AACguaacuu、CA There are many ways to get the best results from your search aucu, UCGguagcug, AAAguaguag, CAGguucguc, CGUguaugaa, AGUguaaaaa, AAGgucucac, UAGguggagc, UGAguaggug, AGAguaugcc, GAGguugcau, CAAguaaga.g, UCUgugugcc, GAGgugaugc, GGGgugauaa, CCCgugagcc, AGAguaacug, GCGguaagua, AGAguacauc, UCGgucuggg, UAAguaucuc, GGCguagguu, AGAguacgcc, G AUgucuucu, AGGgcaaggu, CGAguaugau, AUGguagagu, CAAguacgag, UCGguaugau, CCGguguguu, AGGgucugug, GGAguaggcu, AAGgucuaug, GCAgugcgug, UGGg ugagaa、AGGguaaagu、GAGguaggac、CUAguaagca、UUAguaggcu、CUGgugggau、CUGguuagua、AAGguacgug、CGGgugagau、AAGgugcaug、AAUgugggcu、CAGguug acu, CAGguuacag, GCGguaacau, AUUgucaguc, CAAguauaca, GAUguccgcc, AAGgugcgga, AACguaagag, UGGguuggua, CAAguguaag, GUGguaacgu, CUGgugauca AGGguggggc, UCGguaaaga, CAGguacacc, CGGguaaggg, CAAguuugcu, ACAgugcgug, UUGguauggg, GAGgcucauc, CUGguaauag, AUGguggaua, UCAgugaauu, AA There are many ways to get the best results from your search uagua, UGAguaaagu, GAGgugaccg, GGguauauc, CAGgugccau, AGAgugguga, GUUguaagaa, AGAguaaaua, AGGgugaagg, CUGguagauu, GGguucagg, AGGgucuu ca, CUGguaaccu, ACAguacuga, AGAguggguc, AUGguaugag, AAGguuauau, AGAguauagu, AAAguaugaa, UAGguggcua, ACCguauggg, AAAguauaau, UUUguauggc.GGGgucgcgu、GUGgugguuu、CAGguuugac、GGAguaggcg、GAGguacccu、AUGgugugca、GUGguuggug、AAAguaugcu、UAAguacau、ACAguaugag、GGAguauguu、UUUg ugagaa、AAUgugcguu、CAGguaguuu、ACUguacaga、CCGguugu ga、UGGgucagug、GUAguaagaa、GACguacuuu、AGAgucaguc、UAGguuaguu、AGGgcagcag、AAGguccuac、AAUguaauug、CAGgugcggg、CUGguaaugg、CAAguagccc、G AAgucaguu, ACAguaauug, UUAguuagua, CCUguauuuu, AUCguaagaa, CCAgugagca, GAAguaaggc, UGAgugggua, UCAgugguag, UCUguacagg, CGAgugagug, UCCgu augug、CAUgccguuu、AAAgugacuu、AGAguaggca、GAAguaagag、CAGgcagguu、UUGguagagc、AAGguggaaa、GAGgcagguc、AUGguacgac、AGGguaggaa、AGGguaggu a、UUGguaaggu、AUGguacaga、CAGguagagc、UAGguaaggu、GGGguuagag、AAGguaucaa、GAGguagccc、CAGgugccuc、GCAguaagag、ACGguagagu、UGGguaaugg、CU Ggucaguu, GUGguacauu, AAAguagguu, AAGgccaaga, CGGgugggca, ACGguccggg, CGAguaugag, CUGguaugcc, GGguggaug, CAGgccuuuc, AAAguacauc, AAAgua auca, GAGguaacug, CUGguaaaga, CGUguaagca, UGGgcaagua, GCGguggcga, GGguggccg, AUUgcaugca, ACGgugacug, CAGgucagau, AGAguaacuc, UGAguaacag.AAGguac、 ccg、AGGguaggcu、GGGgcaggac、CCUguaagug、AUUguaagug、ACUguacgag、GUAguagugu、AGAguaugag、UCAgugugg g、UGGguauaua、UAGguagcua、GGGguaaaga、AGGguuacuu、CAUguaaaug、GGAguaguaa、CAGgucaauc、CGGguuagug、 UAGguacaug, UAGguaaaga, UGGguaccuu, CGGguggaca, CAGgucuuac, AAGguggagc, AUGguaacca, UCGguaaguu, UA Uguacaaa, 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, GGgucgagc, UUGguauaua, A AAgucaagg, AAGgucuagg, CGAguagguc, AGGguucguu, GAGgcaggcc, CUAguauuac, ACGguaugug, UAGgugguuc, AGAguauaac, UUGgugcguc, ACCguuaucu, CCAg ugauga, GAAguaugca, GAAguauggc, CCGguaggac, AAUguaagca, AGAguaauug, AGGguugguu, GUGguaggag, AAGgcaguuu, CAAguaagcc, CUGgcaagua, CAGgcau gau、AGGguaauug、GGGguaaccu、AAAguaacua、UAGgucugcc、ACGguaugaa、AGUguauggg、UGGguuggca、UAGguaaacu、AGAgugggua、AGAguauuug、AGUguaggaa 、CUUguacgua、GAUgugagau、CAGgcagcca、AAGgucacug、AAGgucugac、UAGguuccuu、CUGgugcuuu、UGAguuggug、UUGgugggau、UGAguagggu、UCGgugaggu、AA Aguaaaga、AAGgcaaguc、CGGguaaagc、AAAguuaguu、UUAguaagca、GAGgucacau、UAagugguau、UAGgugcuuu、GGAguaggca、UGAguaagga、CAGguggagc、GAUgu agaag、AAUgccugcc、AUGguaaggc、UGGguaauau、CUGguaccuc、CACgugagcc、UGAguuugug、CCGguagugu、AAAgugacaa、GAAguggguu、CAGgugcagc、GAGguggg cc, UAUgugcguc, GGGguacugg, CUGguagguu, UUGgcauguu, AAUguaauac, UAGgccggug, AGAgucagua, UAAguaaauc, CAGguuccuc, UAGguacgau, AGAguuagug.GCAguaagug、AGGgugguag、GGAguaaugu、GAUguaaguc、CCAguuucgu、AAGguucggg、AUGguggagu、AAGguaccgg、GAAgugcgaa、UGGgucaguu、AAGguguaga、UGGg uaggcc、CCAgugaguc、AAGgucacuu、AGCgugaggc、UCCgugguaa、AGAguacuua、GGGgucagau、AAGguggacc、AGAgugagcg、AGAgucagau、UAAguauuac、AGAguauac uc、AGAguucagc、AUGgugaagu、UAGgugaucc、GGAguaagau、UAGguaccaa、AGAguugguc、GAAgugagac、AUCguagguu、GAGguacgcu、ACGguaaggg、CAGgcauguc、CAGU UAguaagau、UGAguagguu、AGGguacgaa、ACGguauguu、AGGguacugu、UUGguaugga、UAAguaacug、GCGgucagcc、UUUgugaguc、GUGgucagug、CUGgucugua、GAGgu ucuua、AUGguacuga、AAUgugcuuu、AGGguggcgu、CCGgcaggaa、CAUgugggguc、UUGguuuguu、CAGguucugu、ACGguaagcg、CUGgucagua、UCAguaggcu、UGAguagga c、CAGguuuuaa、GAGguguccc、AGGguggguu、GUGgugagac、CACguaggga、GUGguauuuu、GAGauauccu、AAGgugaaca、UAAguagggc、CUGgugcggg、CUGgucaaua、AGgucau Aguaaaaa、AAGgugcagu、CGGguaagca、AAAgugagcc、AUGguaauca、GCAguacgug、AUGguacaug、AAGguuaaga、CGGguaaaug、GAGguucgca、GAGgcucugg、AUGgugg ggac、AACgugguag、AAGgugauag、GGGguuugca、CAUguaaggg、UCAguugagu、AAAgugcggc、AGAgugagcc、AUGgcaagaa、ACAguaaggu、AAGgucucuaa、GUGguaaaaaaaAAAguagg、 ug、UAGgugcacu、GUCgugguau、CAGguauagg、UGAgugagag、ACUgugagcc、AUCguuaguu、UUUguaccaa、UGGgugagau、AGAgugagaa、AGAguagggg、AGGgcaagua、 CGGgucagua、UUGguaugcc、CGGguuagau、GGGgugaagu、CCCgugugaa、GCAguuugga、UGCguaagac、AGAgucugua、CACgugagca、AGGguaaaag、CAGgcugaggu、GAAgggu gucuuca、AAGgcaaaaa、GUAguaaaua、CUAgugagag、GAAguuucug、CCUguacgua、GAGgugcgcg、AAGguguaaa、CCAguauguu、CCGgucagcu、AUGguuccug CAAguu aaau、AGAguaggcu、AUGgugggca、GGAguaagac、AGGgucacga、UAGgugauau、GAAguaaguc、CGGguaagau、CAAguagcua、UGAguaaaau、GUCguacgug、AUGgucguc a、CAGgucucgg、GAGgcauguc、AGAgugggau、GUGguuagag、UGGgugguga、AAGguuaaac、CUUguuagcu、AAAguaggaa、UAGguuguau、AGGgugcgcc、AAGgugggg、Ucu AAguaucug、AAGguaacgu、AUGguggggc、CAAguacacg、GGCguaagug、AUAguaggac、AGAgugaggu、UUUguaaaaa、GAAguuugua、CUAguaaucu、AAGguuuuua、GAGuuguua ugcguu、UAGgcgagua、ACCgugagua、CAGgucccga、AUGguacugg、UGAguucagu、AAUguguggu、UCCguugguu、CAGgucagag、CAGgucccua、UAGguagacu、CAAguua agg、GAGguugugcg、GAAgcugccc、CGAguacgug、CGGguaggua、UUGguauuga、AUUguaugau、UUGguaugaa、GAGgugguca、GCUguaugaa、CAGguguugc、CAGguaa、acAUAguaaggu、CUGguuagag、AGCgugugag、AAGguuaucu、CACgugagua、AGGgucagua、GAGguauaau、CAGguuauuu、AGGguggacu、AUUguaaouc、UUUguggguu、AUGgugagu AAGguguucc、CAGgugacgc、GAGguacuaa、ACAguucagu、GAGgucacgg、CAAguaaggc、AAGguuuggg、AAAguggggcu、GCGguucuug、GAGguggagc、UGAgucagug、CAGcagug AGUguaagcu、GAGgcagaaa、AAGgucacac、GAAguagguu、GUCguaaguu、AGAguaugca、CCUgugcaaa、ACGgugaaaa、CAGguacgaa、CAUgugagga、AGCgugagua、Gguagugu AACgugagcu、GAGgugaacu、AGAguucagu、AACgugugua、CAGguugugg、AAGguacuag、UCAgugaaaa、AAUgucuggu、ACGguaaaau、CUGguguaag、GAGgugcgaa、AGGguuuc CAGguagccc、AUUguauugg、AUGguacuua、GAGgcccgac、UCGguaagac、CGGgcuguag、UAUgugugug、UAGguagaaa、GUGgucauua、UAGgugaaag、 ACUguaauuc、GCAguacagg、UCGgugaguc、UAUguaggga、AUGguauguc、GUGgugugug、CUGgugaccu、AAUgugaaua、UAGgucucac、GAGguuauug、 UGAguaggcu、CGGgcacgua、GCAguaaaua、CCGgugagag、UAAguugguc、CCGgugagcc、AAGguuguca、CUGguauuau、GGGguauggg、AAAgucagua、 UUUguaugua、UAAguacugc、CAGguaccaa、GAAguucaga、AUGgugcggu、GUGgugaggu、UGAguaagcc、UAUguaaggg、GUGguggaaa、GAGgugauug、 These include GGAguuugua, AAGgucacga, GUGguagagg, UAAguauauc, AAGgugucca, UAUgugguau, GAGguacaau, AAGguggggg, GGAguaggug and UAGgugacuu.

[0254] In some embodiments, the splice site sequence (e.g., the 5' splice site sequence) comprises AGA. In some embodiments, the splice site sequence (e.g., the 5' splice site sequence) comprises AAA. In some embodiments, the splice site sequence (e.g., the 5' splice site sequence) comprises AAC. In some embodiments, the splice site sequence (e.g., the 5' splice site sequence) comprises AAU. In some embodiments, the splice site sequence (e.g., the 5' splice site sequence) comprises AAG. In some embodiments, the splice site sequence (e.g., the 5' splice site sequence) comprises ACA. In some embodiments, the splice site sequence (e.g., the 5' splice site sequence) comprises AUA. In some embodiments, the splice site sequence (e.g., the 5' splice site sequence) comprises AUU. In some embodiments, the splice site sequence (e.g., the 5' splice site sequence) comprises AUG. In some embodiments, the splice site sequence (e.g., the 5' splice site sequence) comprises AUC. In some embodiments, the splice site sequence (e.g., the 5' splice site sequence) comprises CAA. In some embodiments, the splice site sequence (e.g., the 5' splice site sequence) comprises CAU. In some embodiments, the splice site sequence (e.g., the 5' splice site sequence) comprises CAC. In some embodiments, the splice site sequence (e.g., the 5' splice site sequence) comprises CAG. In some embodiments, the splice site sequence (e.g., the 5' splice site sequence) comprises GAA. In some embodiments, the splice site sequence (e.g., the 5' splice site sequence) comprises GAC. In some embodiments, the splice site sequence (e.g., the 5' splice site sequence) comprises GAU. In some embodiments, the splice site sequence (e.g., the 5' splice site sequence) comprises GAG. In some embodiments, the splice site sequence (e.g., the 5' splice site sequence) comprises GGA. In some embodiments, the splice site sequence (e.g., the 5' splice site sequence) comprises GCA. In some embodiments, the splice site sequence (e.g., the 5' splice site sequence) comprises GGG.In some embodiments, the splice site sequence (e.g., the 5' splice site sequence) comprises GGC. In some embodiments, the splice site sequence (e.g., the 5' splice site sequence) comprises GUU. In some embodiments, the splice site sequence (e.g., the 5' splice site sequence) comprises GGU. In some embodiments, the splice site sequence (e.g., the 5' splice site sequence) comprises GUC. In some embodiments, the splice site sequence (e.g., the 5' splice site sequence) comprises GUA. In some embodiments, the splice site sequence (e.g., the 5' splice site sequence) comprises GUG. In some embodiments, the splice site sequence (e.g., the 5' splice site sequence) comprises UCU. In some embodiments, the splice site sequence (e.g., the 5' splice site sequence) comprises UCC. In some embodiments, the splice site sequence (e.g., the 5' splice site sequence) comprises UCA. In some embodiments, the splice site sequence (e.g., the 5' splice site sequence) comprises UCG. In some embodiments, the splice site sequence (e.g., the 5' splice site sequence) comprises UUU. In some embodiments, the splice site sequence (e.g., the 5' splice site sequence) comprises UUC. In some embodiments, the splice site sequence (e.g., the 5' splice site sequence) comprises UUA. In some embodiments, the splice site sequence (e.g., the 5' splice site sequence) comprises UUG. In some embodiments, the splice site sequence (e.g., the 5' splice site sequence) comprises UGU. In some embodiments, the splice site sequence (e.g., the 5' splice site sequence) comprises UAU. In some embodiments, the splice site sequence (e.g., the 5' splice site sequence) comprises GGA. In some embodiments, the splice site sequence (e.g., the 5' splice site sequence) comprises CUU. In embodiments, the splice site sequence (e.g., the 5' splice site sequence) comprises CUC. In some embodiments, the splice site sequence (e.g., the 5' splice site sequence) comprises CUA. In some embodiments, the splice site sequence (e.g., the 5' splice site sequence) comprises CUG. In some embodiments, the splice site sequence (e.g., the 5' splice site sequence) comprises CCU. In some embodiments, the splice site sequence (e.g., the 5' splice site sequence) comprises CCC. In some embodiments, the splice site sequence (e.g., the 5' splice site sequence) comprises CCA. In some embodiments, the splice site sequence (e.g., the 5' splice site sequence) comprises CCG. In some embodiments, the splice site sequence (e.g., the 5' splice site sequence) comprises ACU. In some embodiments, the splice site sequence (e.g., the 5' splice site sequence) comprises ACC. In some embodiments, the splice site sequence (e.g., the 5' splice site sequence) comprises ACG. In some embodiments, the splice site sequence (e.g., the 5' splice site sequence) comprises AGC. In some embodiments, the splice site sequence (e.g., the 5' splice site sequence) comprises AGU. In some embodiments, the splice site sequence (e.g., the 5' splice site sequence) comprises AGG. In some embodiments, the splice site sequence (e.g., the 5' splice site sequence) comprises CGU. In some embodiments, the splice site sequence (e.g., the 5' splice site sequence) comprises UAC. In some embodiments, the splice site sequence (e.g., the 5' splice site sequence) comprises UAA. In some embodiments, the splice site sequence (e.g., the 5' splice site sequence) comprises UAG. In some embodiments, the splice site sequence (e.g., the 5' splice site sequence) comprises CGC. In some embodiments, the splice site sequence (e.g., the 5' splice site sequence) comprises CGA. In some embodiments, the splice site sequence (e.g., the 5' splice site sequence) comprises CGG. In some embodiments, the splice site sequence comprises AGAguaaggg.

[0255] In one embodiment, the gene sequences or splice site sequences provided herein are associated with a proliferative disease, disorder, or condition (e.g., cancer, benign neoplasm, or inflammatory disease). In one embodiment, the gene sequences or splice site sequences provided herein are associated with a non-proliferative disease, disorder, or condition. In one embodiment, the gene sequences or splice site sequences provided herein are associated with a neurological disease or disorder; an autoimmune disease or disorder; an immunodeficiency disease or disorder; a lysosomal storage disease or disorder; a cardiovascular condition, disease, or disorder; a metabolic disease or disorder; a respiratory condition, disease, or disorder; a renal disease or disorder; or an infectious disease in a subject. In one embodiment, the gene sequences or splice site sequences provided herein are associated with a neurological disease or disorder (e.g., Huntington's disease). In one embodiment, the gene sequences or splice site sequences provided herein are associated with an immunodeficiency disease or disorder. In one embodiment, the gene sequences or splice site sequences provided herein are associated with a lysosomal storage disease or disorder. In one embodiment, the gene sequences or splice site sequences provided herein are associated with a cardiovascular condition, disease, or disorder. In one embodiment, the gene sequences or splice site sequences provided herein are associated with a metabolic disease or disorder. In one embodiment, the gene sequences or splice site sequences provided herein are associated with a respiratory condition, disease or disorder. In one embodiment, the gene sequences or splice site sequences provided herein are associated with a renal disease or disorder. In one embodiment, the gene sequences or splice site sequences provided herein are associated with an infectious disease.

[0256] In one embodiment, the gene sequences or splice site sequences provided herein are associated with a mental retardation disorder. In one embodiment, the gene sequences or splice site sequences provided herein are associated with a mutation in the SETD5 gene. In one embodiment, the gene sequences or splice site sequences provided herein are associated with an immunodeficiency disorder. In one embodiment, the gene sequences and splice site sequences provided herein are associated with a mutation in the GATA2 gene. do.

[0257] In some embodiments, compounds of Formula (I) described herein interact with (e.g., bind to) a splicing complex component (e.g., a nucleic acid (e.g., RNA) or a protein). In some embodiments, the splicing complex component is 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, muscleblind-like (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 snRNP, U2AF1-RS2, U2AF35, U2AF65, U4 snRNP, U5 snRNP, U6 snRNP, Urp and YB1.

[0258] In some embodiments, the splicing complex component comprises RNA (e.g., snRNA). In some embodiments, the compounds described herein bind to splicing complex components that comprise snRNA. The snRNA can be selected from, for example, U1 snRNA, U2 snRNA, U4 snRNA, U5 snRNA, U6 snRNA, U11 snRNA, U12 snRNA, U4 aca snRNA, and any combination thereof.

[0259] In some embodiments, the splicing complex component comprises a protein, e.g., a snRNA-associated protein. In some embodiments, the protein comprises SC35, SRp55, SRp40, SRm300, SFRS10, TASR-1, TASR-2, SF2 / ASF, 9G8, SRp75, SRp30c, SRp20, and P54 / SFRS11. In some embodiments, the splicing complex component comprises a U2 snRNA auxiliary factor (e.g., U2AF65, U2AF35), Urp / U2AF1-RS2, SF1 / BBP, CBP80, CBP20, SF1, or PTB / hnRNP1. In some embodiments, the splicing complex component comprises a heterogeneous ribonucleoprotein particle (hnRNP), e.g., an hnRNP protein. In some embodiments, the hnRNP protein comprises A1, A2 / B1, L, M, K, U, F, H, G, R, I, or C1 / C2. Human genes encoding hnRNPs include HNRNPA0, HNRNPA1, HNRNPA1L1, HNRNPA1L2, HNRNPA3, HNRNPA2B1, HNRNPAB, HNRNPB1, HNRNPC, HNRNPCL1, HNRNPD, HNRPDL, HNRNPF, HNRNPH1, HNRNPH2, HNRNPH3, HNRNPK, HNRNPL, HNRPLL, HNRNPM, HNRNPR, HNRNPU, HNRNPUL1, HNRNPUL2, HNRNPUL3, and FMR1.

[0260] In one embodiment, compounds of formula (I) and pharmaceutically acceptable salts, solvates, hydrates, and derivatives thereof are provided. The variants, stereoisomers, and compositions may modulate (e.g., increase or decrease) a splicing event of a target nucleic acid sequence (e.g., DNA, RNA, or pre-mRNA), such as a nucleic acid encoding a gene described herein or a nucleic acid encoding a protein described herein, or a nucleic acid comprising a splice site described herein. In one embodiment, the splicing event is an alternative splicing event.

[0261] In one embodiment, the compounds of Formula (I) or pharmaceutically acceptable salts, solvates, hydrates, tautomers, stereoisomers, and compositions thereof increase splicing at a splice site on a target nucleic acid (e.g., RNA, e.g., pre-mRNA) 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, for example, by methods known in the art, such as qPCR. In one embodiment, the compounds of Formula (I) or pharmaceutically acceptable salts, solvates, hydrates, tautomers, stereoisomers, and compositions thereof reduce splicing at a splice site on a target nucleic acid (e.g., RNA, e.g., pre-mRNA) 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, for example, by methods known in the art, such as qPCR.

[0262] In another aspect, the disclosure features a method of forming a complex comprising a spliceosome component (e.g., a major spliceosome component or a minor spliceosome component), a nucleic acid (e.g., DNA, RNA, e.g., pre-mRNA), and a compound of Formula (I) or a pharmaceutically acceptable salt, solvate, hydrate, tautomer, stereoisomer, or composition thereof, the method comprising contacting the nucleic acid (e.g., DNA, RNA, e.g., pre-mRNA) with the compound of Formula (I). In one embodiment, the spliceosome component is selected from U1, U2, U4, U5, U6, U11, U12, U4atac, U6atac small nuclear ribonucleoproteins (snRNPs) 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.

[0263] In another aspect, the disclosure features a method of modifying the conformation of a nucleic acid (e.g., DNA, RNA, e.g., pre-mRNA), the method including 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 a bulge or kink in the nucleic acid. In one embodiment, the modification includes reducing a 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 a nucleobase, ribose, or phosphate moiety of the nucleic acid (e.g., DNA, RNA, e.g., pre-mRNA).

[0264] The present disclosure also provides methods for the treatment or prevention of a disease, disorder, or condition. In one embodiment, the disease, disorder, or condition is associated with (e.g., caused by) a splicing event, such as an undesired, aberrant, or alternative splicing event. In one embodiment, the disease, disorder, or condition comprises a proliferative disease (e.g., cancer, benign neoplasm, or inflammatory disease) or a non-proliferative disease. In one embodiment, the disease, disorder, or condition comprises a neurological disease, an autoimmune disorder, an immunodeficiency disorder, a cardiovascular condition, a metabolic disorder, a lysosomal storage disease, a respiratory condition, a renal disease, or an infectious disease in a subject. In another embodiment, the disease, disorder, or condition comprises a haploinsufficient disease, an autosomal recessive disease (e.g., with residual function), or a paralog activation disorder. In another embodiment, the disease, disorder, or condition comprises an autosomal dominant disorder (e.g., with residual function). Such methods comprise administering to a subject in need thereof an effective amount of a compound of Formula (I) or a pharmaceutically acceptable salt, solvate, hydrate, tautomer, stereoisomer thereof, or a pharmaceutical composition thereof. In certain embodiments, the methods described herein comprise administering to a subject an effective amount of a compound of Formula (I) or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof.

[0265] In certain embodiments, the subject to be treated is a mammal. In certain embodiments, the subject is a human. In certain embodiments, the subject is a livestock animal, such as a dog, cat, cow, pig, horse, sheep, or goat. In certain embodiments, the subject is a companion animal, such as a dog or cat. In certain embodiments, the subject is a livestock animal, such as a cow, pig, horse, sheep, or goat. 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 a transgenic pig.

[0266] Proliferative diseases, disorders, or conditions may also be associated with the inhibition of apoptosis of cells in a biological sample or subject. All types of biological samples described herein or known in the art are contemplated as being 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 diseases, disorders, or conditions.

[0267] In certain embodiments, the proliferative disease treated or prevented using the compounds 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 carcinoma; anal carcinoma; ductal sarcoma (e.g., lymphangiosarcoma, lymphangioendothelial cell sarcoma, angiosarcoma); appendix cancer; benign monoclonal gammopathy; biliary tract cancer (e.g., cholangiocarcinoma); bladder cancer; breast cancer (e.g., breast adenocarcinoma, papillary carcinoma, breast carcinoma, medullary carcinoma); brain cancer (e.g., meningioma, glioblastoma, glioma (e.g., astrocytoma, oligodendroglioma), medulloblastoma); bronchial carcinoma; carcinoid tumor; cervical cancer (such as cervical adenocarcinoma); choriocarcinoma; chordoma; craniopharyngioma; colorectal cancer (e.g., colon carcinoma, rectal carcinoma, colorectal adenocarcinoma); connective tissue cancer; epithelial carcinoma; ependymoma; endothelial sarcoma (e.g., Kaposi's sarcoma, multiple idiopathic hemorrhagic sarcoma); endometrial cancer (e.g., uterine carcinoma, uterine sarcoma); Esophageal cancer (e.g., esophageal adenocarcinoma, Barrett's adenocarcinoma); Ewing's sarcoma; eye cancer (e.g., intraocular melanoma, retinoblastoma, etc.); familial eosinophilia; gallbladder cancer; gastric cancer (e.g., gastric adenocarcinoma); gastrointestinal stromal tumor (GIST); germ cell cancer; 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 lymphocytic 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 CLL, T-cell CLL); Hodgkin's lymphoma (HL) (e.g., B-cell HL, T-cell HL) and non-Hodgkin's lymphoma (NHL) (e.g., B-cell NHL such as diffuse large cell lymphoma (DLCL) (e.g., diffuse large B-cell lymphoma), 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 (MALT) lymphoma, nodal marginal zone B-cell lymphoma, splenic marginal zone B-cell lymphoma), primary mediastinal B-cell lymphoma, Burkitt's lymphoma, lymphoplasmacytic lymphoma (i.e., Waldenstrom's macroglobulinemia), hairy cell leukemia (HCL), immunoblastic large cell leukemia. lymphomas, such as precursor B-lymphoblastic lymphoma, precursor B-lymphoblastic lymphoma, and primary central nervous system (CNS) lymphoma; and T-cell NHL, such as precursor T-lymphoblastic lymphoma / leukemia, peripheral T-cell lymphoma (PTCL) (e.g., cutaneous T-cell lymphoma (CTCL) (e.g., mycosis fungoides, Sézary syndrome), 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); mixtures of one or more of the above leukemias / lymphomas; and multiple myeloma (MM), heavy chain disease ( e.g., alpha chain disease, gamma chain disease, mu chain disease); hemangioblastoma; hypopharyngeal carcinoma; inflammatory myofibroblastic tumor; immune cell amyloidosis; kidney 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 carcinoma; myelodysplastic syndrome (MDS); mesothelioma; myeloproliferative disorders (MPDs) (e.g., polycythemia vera (P V), essential thrombocytosis (ET), primary myelofibrosis (AMM) also known as myelofibrosis (MF), chronic idiopathic myelofibrosis, chronic myeloid leukemia (CML), chronic neutrophilic leukemia (CNL), hypereosinophilic syndrome (HES)); neuroblastoma; neurofibroma (e.g., neurofibromatosis (NF) type 1 or 2, schwannomatosis); neuroendocrine carcinoma (e.g., gastroenteropancreatic neuroendocrine tumor (GEP-NET), carcinoid tumor); osteosarcoma (e.g., bone carcinoma); ovarian cancer (e.g., cystadenocarcinoma, ovarian embryonal carcinoma, ovarian adenocarcinoma); papillary adenocarcinoma; pancreatic cancer (e.g., pancreatic adenocarcinoma, intraductal papillary mucinous tumor) (IPMN), pancreatic islet cell tumors); penile cancer (e.g., Paget's disease of the penis and scrotum); pinealoma; primitive neuroectodermal tumor (PNT); plasma cell neoplasms; paraneoplastic syndromes; intraepithelial neoplasia; prostate cancer (e.g., prostatic adenocarcinoma); rectal cancer; rhabdomyosarcoma; salivary gland cancer; skin cancer (e.g., squamous cell carcinoma (SCC), keratoacanthoma (KA), melanoma, basal cell carcinoma (BCC)); small intestine cancer (appendix cancer, etc.); soft tissue sarcomas (e.g., malignant fibrous histiocytoma (MFH), liposarcoma, malignant peripheral nerve sheath tumor (MPNST), chondrosarcoma, fibrosarcoma, myxosarcoma); sebaceous gland carcinoma; small intestine cancer; sweat gland carcinoma; synovium;These include, but are not limited to, testicular cancer (e.g., seminoma, testicular embryonal carcinoma); thyroid cancer (e.g., papillary thyroid carcinoma, papillary thyroid carcinoma (PTC), medullary thyroid carcinoma); urethral cancer; vaginal cancer; and vulvar cancer (e.g., Paget's disease of the vulva).

[0268] In some embodiments, the proliferative disorder is associated with a benign neoplasm. For example, benign neoplasms can include adenoma, fibroma, hemangioma, tuberous sclerosis, and lipoma. All types of benign neoplasms disclosed herein or known in the art are contemplated as being within the scope of the present disclosure.

[0269] In some embodiments, the proliferative disorder is associated with angiogenesis. All types of angiogenesis disclosed herein or known in the art are contemplated as being within the scope of the present disclosure.

[0270] In some 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 non-proliferative disease. Exemplary non-proliferative diseases include neurological diseases, autoimmune diseases, immunodeficiency diseases, lysosomal storage diseases, cardiovascular conditions, metabolic diseases, respiratory conditions, inflammatory diseases, renal diseases, or infectious diseases.

[0271] In certain embodiments, the non-proliferative disease is a neurological disease. 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 neurological disease, disorder, or condition. The neurological disease, disorder, or condition may include a neurodegenerative disease, a psychiatric condition, or a musculoskeletal disease. The neurological disease may further include a repeat expansion disease, which may be characterized, for example, by an expansion of a nucleic acid sequence in the genome. For example, a repeat expansion disease includes myotonic dystrophy. Neurological diseases, disorders, and conditions include ataxia, amyotrophic lateral sclerosis, Huntington's disease, trinucleotide repeat disorders, or polyglutamine disorders (e.g., ataxia, fragile X syndrome). In some embodiments, the neurological disease comprises a repeat proliferation disease, such as Huntington's disease. Additional neurological diseases, disorders, and conditions include Alzheimer's disease, Huntington's chorea, prion diseases (e.g., Creutzfeldt-Jakob disease, bovine spongiform encephalopathy, kuru, or scrapie), mental retardation disorders (e.g., disorders caused by SETD5 gene mutations, such as intellectual disability-facial dysmorphism syndrome, autism spectrum disorder), Lewy body disease, diffuse Lewy body disease (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's syndrome, multiple system atrophy, spinal muscular atrophy (SMA), progressive spinal and bulbar muscular atrophy (e.g., Kennedy's disease), post-polio syndrome (PPS), spinocerebellar ataxia, pantothenate kinase-associated neurodegeneration (PANK), spinal degenerative disease / motor neuron degenerative disease, upper motor neuron Neuronal disorders, lower motor neuron disorders, Hallervorden-Spatz syndrome, cerebral infarction, cerebral trauma, chronic traumatic encephalopathy, transient ischemic attack, Ritsch-Bodig disease (amyotrophic lateral sclerosis-parkinsonism dementia), Guam-parkinsonism dementia, hippocampal sclerosis, corticobasal degeneration, Alexander disease, Appler's disease, Krabbe disease, neuroborreliosis, neurosyphilis, Sandhoff disease, Tay-Sachs disease, Schilder's disease, Batten disease, Cockayne's disease In some embodiments, the neurological disorder includes Friedreich's ataxia or Sturge-Weber syndrome. In some embodiments, the neurological disorder includes Huntington's disease. 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 contemplated as being within the scope of this disclosure.

[0272] In certain embodiments, the non-proliferative disease is an autoimmune disease or an immunodeficiency disease. 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 an autoimmune disease, disorder or condition or an immunodeficiency disease, disorder or condition. 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's syndrome, Graves' disease, Guillain-Barré syndrome (GBS), Hashimoto's disease, hidradenitis suppurativa, Kawasaki disease, ankylosing spondylitis, IgA nephropathy, idiopathic thrombocytopenic purpura, inflammatory...

Claims

[Claim 1] The invention described in the specification.

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