Pyridazine derivatives for modulating nucleic acid splicing

Abstract

The present disclosure features, among other things, compounds and related compositions that modulate nucleic acid splicing, eg, pre-mRNA splicing, and methods of their use.

Description

[Technical Field]

[0001] Priority claims This application claims priority to U.S. Patent Application No. 62 / 983,537, filed February 28, 2020; U.S. Patent Application No. 63 / 007,134, filed April 8, 2020; U.S. Patent Application No. 63 / 040,474, filed June 17, 2020; U.S. Patent Application No. 63 / 072,781, filed August 31, 2020; and U.S. Patent Application No. 63 / 126,491, 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), (Ig), or (Ih)), 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 can be used to prevent and / or treat a disease, disorder, or condition, e.g., a disease, disorder, or condition associated with splicing, e.g., alternative splicing. 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, e.g., 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 one aspect, the present disclosure provides a compound of formula (I): [ka] wherein A and B are each independently cycloalkyl, heterocyclyl, aryl, or heteroaryl, each of which is selected from the group consisting of one or more R 1 L is optionally substituted with: -C1-C6 alkylene, -C1-C6 heteroalkylene, -O-, -C(O)-, -N(R 3 )-, -S(O)x -, -N(R 3 )C(O)- or -C(O)N(R 3 )-, where each alkylene and heteroalkylene is selected from one or more R 4 M and P are each independently C(R 2 ) or N; X and Y are each independently C, C(R 5a ), C(R 5a )(R 5b ), N, or N(R 5c ), where the bond between X and Y may be a single or double bond, if valences allow, and where X and Y are both C(R 5a )(R 5b ) or C(R 5a ) 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 wherein each alkyl, alkylene, alkenyl, alkenylene, alkynyl, heteroalkyl, haloalkyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl is selected from the group consisting of one or more R 8 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, where each cycloalkyl, heterocyclyl, aryl, and heteroaryl is selected from one or more R 8each R 2 are independently hydrogen, halo, cyano, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, or -OR A and each R 3 are independently hydrogen, C1-C6 alkyl, or C1-C6 haloalkyl; each R 4 is 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;R 5a is hydrogen, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 heteroalkyl, C1-C6 haloalkyl, halo, -NR B R C , or -OR F and;R 5b is hydrogen or C1-C6 alkyl; or R 5a and R 5b together with the carbon atom to which they are attached form an oxo group; each R 5c is hydrogen, C1-C6 alkyl, C1-C6 haloalkyl, or C(O)R D and each R 7 are independently C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 heteroalkyl, C1-C6 haloalkyl, halo, oxo, cyano, -OR A , -NR B R C , N.R. B C(O)R D , -C(O)NR B R C , -C(O)R D , or -SR E wherein alkyl, alkenyl, alkynyl, heteroalkyl, and haloalkyl are selected from one or more R 9 or two R 7The groups, together with the atom to which they are attached (e.g., X or Y), form a 4- to 7-membered cycloalkyl, heterocyclyl, aryl, or heteroaryl, where each cycloalkyl, heterocyclyl, aryl, and heteroaryl is selected from the group consisting of one or more R 9 optionally substituted with ;R 8 and R 9 each independently represents 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 wherein each of alkyl, alkenyl, alkynyl, heteroalkyl, haloalkyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl is selected from one or more R 11 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 A or R B and R C together with the atoms to which they are attached, one or more R 10 form a 3- to 7-membered heterocyclyl ring optionally substituted with 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; R F is hydrogen, C1-C6 alkyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl; R 10 is C1-C6 alkyl or halo; each R 11 are independently C1-C6 alkyl, C1-C6 heteroalkyl, C1-C6 haloalkyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, halo, cyano, oxo, or -OR A n 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.

[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), or (Ih)) 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 methods 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 compositions for use in 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. Modulation of splicing can include affecting any step involved in splicing, including events upstream or downstream of the splicing event. For example, in some embodiments, a compound of formula (I) binds to a target, such as 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). A 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), e.g., 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 a target nucleic acid (e.g., RNA) relative to a reference (e.g., the absence of a compound of Formula (I), e.g., a healthy or diseased cell or tissue) of about 0.5% or more (e.g., about 1%, 2%, 3%, 4%, 5%, 10%, 20%, 30%, 40%, 50%, 75%, 90%, 95% or more).

[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 disclosure provides compositions for use in the prevention and / or treatment of 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 neoplasms, or angiogenesis. In other embodiments, the disclosure provides methods of treating and / or preventing non-proliferative diseases, disorders, or conditions. In still other embodiments, the present disclosure provides compositions for use in the treatment and / or prevention of 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.

[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, , a compound other than a target nucleic acid (e.g., DNA, RNA, e.g., pre-mRNA) or a target protein described in one of WO 2018 / 232039, WO 2018 / 098446, WO 2019 / 028440, WO 2019 / 060917 and WO 2019 / 199972, a target nucleic acid (e.g., DNA, RNA, e.g., pre-mRNA) or a target protein. In some embodiments, the compounds described herein, target nucleic acids (e.g., DNA, RNA, e.g., pre-mRNA), or target proteins are 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, a compound, target nucleic acid (e.g., DNA, RNA, e.g., pre-mRNA), or target protein described in one of 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, an alkyl group has 1 to 8 carbon atoms ("C1-C8 alkyl"). In some embodiments, an alkyl group has 1 to 6 carbon atoms ("C1-C6 alkyl"). In some embodiments, an alkyl group has 2 to 6 carbon atoms ("C2-C6 alkyl"). In some embodiments, an 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), etc. Each example 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 is an unsubstituted C1 to C810 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 10 In 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-C24 In some embodiments, an alkynyl group has 2 to 10 carbon atoms (“C-C 10 In 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 may be described, for example, as C4-C7 membered cycloalkyl, where the term "member" 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, 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, and the like.Exemplary 5-membered heterocyclyl groups fused to a heterocyclyl ring (also referred to herein as 5,5-bicyclic heterocyclyl rings) include, but are not limited to, octahydropyrrolopyrrolyl (e.g., octahydropyrrolo[3,4-c]pyrrolyl), and the like. 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 fused to an aryl ring (also referred to herein as 6,6-bicyclic heterocyclyl rings) 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] 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.

[0031] As used herein, the term "halogen" or "halo" refers to fluorine, chlorine, bromine or iodine.

[0032] As used herein, the term "hydroxy" refers to --OH.

[0033] As used herein, the term "nitro" refers to a substituent having two oxygen atoms attached to a nitrogen atom, e.g., --NO.sub.2.

[0034] 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.

[0035] 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.

[0036] As used herein, "oxo" refers to carbonyl, i.e., --C(O)--.

[0037] Symbols used herein for compounds of formula (I) [ka] refers to a point of attachment to another moiety or functional group within a compound.

[0038] Alkyl, alkenyl, alkynyl, haloalkyl, heteroalkyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl groups defined herein are optionally substituted. In general, the term "substituted," whether preceded by the term "optionally," means that at least one hydrogen atom present on the group (e.g., a carbon or nitrogen atom) is replaced with a permissible substituent, e.g., a substituent whose substitution results in a stable compound, e.g., a compound that does not undergo spontaneous transformation, such as by rearrangement, cyclization, elimination, or other reaction. Unless otherwise specified, a "substituted" group has a substituent at one or more substitutable positions of the group; 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 a stable compound. The present disclosure contemplates any and all such combinations in order to arrive at a stable compound. For purposes of this invention, heteroatoms, such as nitrogen, can 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.

[0039] 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.

[0040] 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").

[0041] 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.

[0042] As used herein, a pure enantiomer compound is substantially free of other enantiomers or stereoisomers of the compound (i.e., in enantiomeric excess). In other words, the "S" form of a compound is substantially free of the "R" form of the compound and is thus in enantiomeric excess of the "R" form. The terms "enantiomerically pure" or "pure enantiomer" refer to a compound that contains more than 75%, more than 80%, more than 85%, more than 90%, more than 91%, more than 92%, more than 93%, more than 94%, more than 95%, more than 96%, more than 97%, more than 98%, more than 99%, more than 99.5%, or more than 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.

[0043] 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.

[0044] 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.

[0045] 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.

[0046] In certain embodiments, the active ingredient can be formulated with few or no excipients or carriers.

[0047] 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.

[0048] 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.

[0049] 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.

[0050] 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.

[0051] 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)).

[0052] The term "tautomer" refers to interchangeable forms of a particular compound structure, differing in the replacement of hydrogen atoms and electrons. Thus, two structures can be in equilibrium through the shifting of π electrons and atoms (usually H). For example, enols and ketones are tautomers because they are rapidly interconverted by treatment with acid or base. Another example of tautomerism is the acid and nitro forms of phenylnitromethane, which are similarly formed by treatment with acid or base. Tautomers can be relevant to achieving optimal chemical reactivity and biological activity of a compound of interest.

[0053] Other definitions The following definitions are of more general terms used throughout this disclosure.

[0054] 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.

[0055] 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.

[0056] 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.

[0057] 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.

[0058] As used herein, the terms "condition," "disease," and "disorder" are used interchangeably.

[0059] 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.

[0060] 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" can encompass an amount that improves overall treatment, reduces or avoids the cause of a symptom or condition, or enhances the therapeutic effect of another therapeutic agent.

[0061] 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.

[0062] 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.

[0063] "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.

[0064] 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.

[0065] "Proliferative disease" refers to a disease caused by the abnormal expansion of cells through proliferation (Walker, Cambridge Dictionary of Biology; Cambridge University Press: Cambridge, UK, 1990). Proliferative diseases can be associated with: 1) pathological proliferation of normal quiescent cells; 2) pathological migration of cells from their normal location (e.g., metastasis of tumor cells); 3) pathological expression of proteolytic enzymes such as matrix metalloproteinases (e.g., collagenase, gelatinase, elastase); 4) pathological angiogenesis, such as proliferative retinopathy and tumor metastasis; or 5) evasion of host immune surveillance and elimination of neoplastic cells. Exemplary proliferative diseases include cancer (i.e., "malignant neoplasms"), benign neoplasms, and angiogenesis.

[0066] 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.

[0067] compound The present disclosure provides a compound of formula (I): [ka] wherein A and B are each independently cycloalkyl, heterocyclyl, aryl, or heteroaryl, each of which is selected from the group consisting of one or more R 1 L is optionally substituted with: -C1-C6 alkylene, -C1-C6 heteroalkylene, -O-, -C(O)-, -N(R 3 )-, -S(O) x -, -N(R 3 )C(O)- or -C(O)N(R 3)-, where each alkylene and heteroalkylene is selected from one or more R 4 M and P are each independently C(R 2 ) or N; X and Y are each independently C, C(R 5a ), C(R 5a )(R 5b ), N, or N(R 5c ), where the bond between X and Y may be a single or double bond, if valences allow, and where X and Y are both C(R 5a )(R 5b ) 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 wherein each alkyl, alkylene, alkenyl, alkenylene, alkynyl, heteroalkyl, haloalkyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl is selected from the group consisting of one or more R 8 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, where each cycloalkyl, heterocyclyl, aryl, and heteroaryl is selected from one or more R 8 each R 2 are independently hydrogen, halo, cyano, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, or -ORA and each R 3 are independently hydrogen, C1-C6 alkyl, or C1-C6 haloalkyl; each R 4 is 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;R 5a is hydrogen, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 heteroalkyl, C1-C6 haloalkyl, halo, -NR B R C , or -OR F and;R 5b is hydrogen or C1-C6 alkyl; or R 5a and R 5b together with the carbon atom to which they are attached form an oxo group; each R 5c is hydrogen, C1-C6 alkyl, C1-C6 haloalkyl, or C(O)R D and each R 7 are independently C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 heteroalkyl, C1-C6 haloalkyl, halo, oxo, cyano, -OR A , -NR B R C , N.R. B C(O)R D , -C(O)NR B R C , -C(O)R D , or -SR E wherein alkyl, alkenyl, alkynyl, heteroalkyl, and haloalkyl are selected from one or more R 9 or two R 7 The groups, together with the atom to which they are attached (e.g., X or Y), form a 4- to 7-membered cycloalkyl, heterocyclyl, aryl, or heteroaryl, where each cycloalkyl, heterocyclyl, aryl, and heteroaryl is selected from the group consisting of one or more R 9 optionally substituted with ;R8 and R 9 each independently represents 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 wherein each of alkyl, alkenyl, alkynyl, heteroalkyl, haloalkyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl is selected from one or more R 11 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 A or R B and R C together with the atoms to which they are attached, one or more R 10 form 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; R Fis hydrogen, C1-C6 alkyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl; R 10 is C1-C6 alkyl or halo; each R 11 are independently C1-C6 alkyl, C1-C6 heteroalkyl, C1-C6 haloalkyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, halo, cyano, oxo, or -OR A n 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.

[0068] As generally described herein, A or B may each independently be one or more R 1 is a cycloalkyl, heterocyclyl, aryl or heteroaryl optionally substituted with

[0069] 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, either A or B independently contains one or more R 1 is a monocyclic ring optionally substituted with

[0070] In some embodiments, A or B is independently a bicyclic ring, such as a bicyclic cycloalkyl, bicyclic heterocyclyl, bicyclic aryl, or bicyclic heteroaryl. The bicyclic ring can be saturated, partially unsaturated, or fully unsaturated (e.g., aromatic). In some embodiments, A or B is independently a bicyclic ring comprising a fused, bridged, or spiro ring system. In some embodiments, A or B is independently a bicyclic ring comprising 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, either A or B independently selects one or more R 1 is a bicyclic ring optionally substituted with

[0071] 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, either A or B independently contains one or more R 1 is a tricyclic ring optionally substituted with

[0072] 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. In some embodiments, A is monocyclic heterocyclyl and B is monocyclic heteroaryl or monocyclic heterocyclyl.

[0073] 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 a monocyclic, bicyclic, or tricyclic ring. 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 in the nitrogen-containing heterocyclyl can be, for example, R 1 In some embodiments, A is a nitrogen-containing heterocyclyl containing 1 nitrogen atom and B is a nitrogen-containing heteroaryl or nitrogen-containing heterocyclyl containing 1, 2, or 3 nitrogen atoms.

[0074] 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 .

[0075] 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.

[0076] 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 In some embodiments, one or more nitrogens of the 5-membered nitrogen-containing heterocyclyl or heteroaryl may be optionally substituted, for example, by 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.

[0077] In some embodiments, A and B are [ka] [ka] [ka] [ka] [ka] [ka] [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.

[0078] In some embodiments, A and B are [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.

[0079] In some embodiments, A is [ka] (In the formula, R 1 is as defined herein) is selected from.

[0080] In some embodiments, A is [ka] is selected from.

[0081] In some embodiments, A is [ka] is selected from.

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

[0083] 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.

[0084] In some embodiments, B is [ka] (In the formula, R 1 is as defined herein) In some embodiments, B is selected from: [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] is.

[0085] In some embodiments, B is [ka] (In the formula, R 1 is as defined herein) is.

[0086] In some embodiments, B is [ka] (In the formula, R 1 is as defined herein) In some embodiments, B is selected from: [ka] In some embodiments, B is selected from: [ka] (In the formula, R1 is as defined herein) 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] is.

[0087] As generally described herein, L is absent or is selected from C1-C6 alkylene, C1-C6 heteroalkylene, -O-, -C(O)-, -N(R 3 )-, -S(O) x , -N(R 3)C(O)- or -C(O)N(R 3 )-group, and each alkylene and heteroalkylene may be one or more R 4 In some embodiments, L is absent or is selected from C1-C6 alkylene, C1-C6 heteroalkylene, —O—, —C(O)—, —N(R 3 )-, -N(R 3 )C(O)- or -C(O)N(R 3 )-group, and each alkylene and heteroalkylene may be one or more R 4 is optionally replaced by

[0088] In some embodiments, L is absent. In some embodiments, L is C1-C6 alkylene (e.g., C1 alkylene, C2 alkylene, C3 alkylene, C4 alkylene, C5 alkylene, or C6 alkylene). In some embodiments, L is unsubstituted C1-C6 alkylene. In some embodiments, L is substituted C1-C6 alkylene, such as one or more R 4 In some embodiments, L is a C1-C6 alkylene substituted with one R 4 In some embodiments, L is -CH- (or methylene). In some embodiments, L is -C(O)- (or carbonyl).

[0089] In some embodiments, L is absent, C1-C6 alkylene, C1-C6 heteroalkylene, —N(R 3 )C(O)- or -C(O)N(R 3 )-, and each alkylene and heteroalkylene is selected from one or more R 4 is optionally replaced by

[0090] In some embodiments, L is C1-C6 heteroalkylene (e.g., C1 heteroalkylene, C2 heteroalkylene, C3 heteroalkylene, C4 heteroalkylene, C5 heteroalkylene, or C6 heteroalkylene). In some embodiments, L is unsubstituted C1-C6 heteroalkylene. In some embodiments, L is selected from the group consisting of one or more R 4 In some embodiments, L is a C1-C6 heteroalkylene substituted with -N(R). In some embodiments, the heteroalkylene comprises one or more heteroatoms. In some embodiments, the heteroalkylene comprises one or more of oxygen, sulfur, nitrogen, boron, silicon, or phosphorus. In some embodiments, L is -N(R 3 )C(O)—. In some embodiments, L is —C(O)N(R 3 )-.

[0091] In some embodiments, L is oxygen. In some embodiments, L is nitrogen and R 3 In some embodiments, L can be substituted with one R 3 In some embodiments, L is a nitrogen substituted with -N(R 3 )-. In some embodiments, L is -N(CH3)-. In some embodiments, L is -NH-. In some embodiments, L is -O-.

[0092] In some embodiments, L is -S(O) x In some embodiments, x is 0, 1, or 2. In some embodiments, L is -S- or -S(O)2-. In some embodiments, L is -S-.

[0093] As generally described herein, M and P are each independently C(R 2 ) or N. In some embodiments, M and P each independently represent C(R 2 ) or N. In some embodiments, M and P are each independently C(R 2), e.g., CH. In some embodiments, one of M and P is C(R 2 ) and the other of M and P is N. In some embodiments, M is C(R 2 In some embodiments, M is N. In some embodiments, P is C(R 2 In some embodiments, P is N. In some embodiments, M is C(R 2 ) (e.g., CH) and P is N. In some embodiments, M is N and P is C(R 2 ) (e.g., CH).

[0094] In some embodiments, [ka] teeth, [ka] (In the formula, R 2 is as defined above) In some embodiments, R 2 is hydrogen.

[0095] As generally described herein, X and Y are each independently C, C(R 5a ), C(R 5a )(R 5b ), N or N(R 5c In some embodiments, X and Y are each independently C. In some embodiments, X and Y are each C(R 5a In some embodiments, X and Y are both C(R 5a In some embodiments, one of X and Y is not necessarily C(R 5a )(R 5b ), and the other of X and Y is N(R 5c In some embodiments, X is N(R 5c ) and Y is C(R 5a )(R 5bIn some embodiments, X is N(R 5c ) and Y is C(R 5a )(R 5b ), where R 5a and R 5b together with the carbon atom to which they are attached form an oxo group. In some embodiments, one of X and Y is C(R 5a ) and the other of X and Y is N. In some embodiments, Y is N and X is C(R 5a ) (e.g., CH or COCH). In some embodiments, X is N and Y is C(R 5a ) (e.g., CH or COCH3). In some embodiments, one of X and Y is C(O) and the other of X and Y is NH. In some embodiments, X is NH and Y is C(O). In some embodiments, the bond between X and Y is a single bond. In some embodiments, the bond between X and Y is a double bond.

[0096] In some embodiments, Y is N and X is C(R 5a ) (e.g., CH), L is -N(R 3 )—(e.g., —N(CH3)—). In some embodiments, when Y is N and X is CH, L is not —N(R 3 )—(e.g., —N(CH3)—). In some embodiments, Y is N and X is C(R 5a ) (e.g., CH), then L is not -N(CH3)-. In some embodiments, when Y is N and X is CH, then L is not -N(CH3)-. In some embodiments, when Y is N and L is -N(R 3 ), then R 3 is not C1-C6 alkylene. In some embodiments, Y is N and L is -N(R 3 ), then R 3 is not CH3. In some embodiments, when Y is N, X is also N. In some embodiments, X is C(R 5a) (e.g., CH), then Y is not N. In some embodiments, when Y comprises N, the bond between X and Y is not a double bond. In some embodiments, when Y comprises N, the bond between X and Y is a single bond. In some embodiments, when Y is N, B is not aryl or heteroaryl. In some embodiments, when Y is N, B is not aryl. In some embodiments, when Y is N, B is not heteroaryl. In some embodiments, when Y is N, B is cycloalkyl or heterocyclyl. In some embodiments, when Y is N, B is cycloalkyl. In some embodiments, when Y is N, B is heterocyclyl.

[0097] In some embodiments, [ka] but, [ka] wherein R 5a , R 5b , R 5c , R 7 and n are each as defined herein.

[0098] In some embodiments, [ka] but, [ka] wherein R 7 and n are each as defined herein.

[0099] In some embodiments, R 1 is hydrogen. In some embodiments, R 1 is C1-C6 alkyl. In some embodiments, R 1is 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 8 In some embodiments, R 1 is one or more R 8 In some embodiments, R 1 is one or more R 8 In some embodiments, R 1 is one or more R 8 In some embodiments, R 1 is one or more R 8 In some embodiments, R 1 is methyl.

[0100] In some embodiments, R 1 is 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 1is 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 8 In some embodiments, R 1 is one or more R 8 In some embodiments, R is a heterocyclyl substituted with 1 is one or more R 8 In some embodiments, R 1 is one or more R 8 In some embodiments, R 1 is one or more R 8 In some embodiments, R 1 is one or more R 8 In some embodiments, R 1 is one or more R 8 and heteroaryl substituted with

[0101] 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)RD 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.

[0102] 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 R 1 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 8 may be substituted with

[0103] In some embodiments, R 2 is hydrogen. 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 is C alkyl (e.g., methyl). In some embodiments, R 2is methyl. In some embodiments, R 2 -OR A In some embodiments, R 2 is halo (e.g., fluoro, chloro, bromo, or iodo). In some embodiments, R 2 is fluoro. In some embodiments, R 2 is cyano.

[0104] In some embodiments, R 3 is hydrogen. In some embodiments, R 3 is C1-C6 alkyl. In some embodiments, R 3 is C1-C6 haloalkyl. In some embodiments, R 3 is C alkyl (e.g., methyl). In some embodiments, R 3 is methyl.

[0105] In some embodiments, R 4 is C1-C6 alkyl. In some embodiments, R 4 is C1-C6 heteroalkyl. In some embodiments, R 4 is C1-C6 haloalkyl. In some embodiments, R 4 is cycloalkyl. In some embodiments, R 4 is halo (e.g., fluoro, chloro, bromo, or iodo). In some embodiments, R 4 is cyano. In some embodiments, R 4 is oxo. In some embodiments, R 4 -OR A In some embodiments, R 4 is -NR B R C In some embodiments, R 4 is -C(O)R D or -C(O)OR D is.

[0106] In some embodiments, R5a and R 5b are each independently hydrogen or C1-C6 alkyl. In some embodiments, R 5a is hydrogen. In some embodiments, R 5b is hydrogen. In some embodiments, R 5a and R 5b taken together form an oxo group. In some embodiments, R 5c is hydrogen. In some embodiments, R 5c is C1-C6 alkyl. In some embodiments, R 5c is C1-C6 haloalkyl (e.g., —CF3 or —CHF2). In some embodiments, R 5c is -CF3. In some embodiments, R 5c is -CHF. In some embodiments, R 5c is -C(O)R D (e.g., —C(O)CH). In some embodiments, R 5c is -C(O)CH3).

[0107] In some embodiments, R 5d , R 5e and R 5f are each independently hydrogen, C1-C6 alkyl, halo, or R 5d , R 5e taken together form an oxo group. In some embodiments, R 5d is hydrogen. In some embodiments, R 5e is hydrogen. In some embodiments, R 5f is hydrogen. In some embodiments, R 5e and R 5f together form an oxo group.

[0108] In some embodiments, R 7 is C1-C6 alkyl. In some embodiments, R 7 is C2-C6 alkenyl. In some embodiments, R 7is C2-C6 alkynyl. In some embodiments, R 7 is C1-C6 heteroalkyl. In some embodiments, R 7 is C1-C6 haloalkyl. In some embodiments, R 7 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. 7 is one or more R 9 In some embodiments, R 7 is one or more R 9 In some embodiments, R 7 is one or more R 9 In some embodiments, R 7 is one or more R 9 In some embodiments, R 7 is one or more R 9 In some embodiments, R 7 is halo, such as fluoro, chloro, bromo, or iodo. In some embodiments, R 7 is fluoro. In some embodiments, R 7 is cyano. In some embodiments, R 7 is oxo. In some embodiments, R 7 is -NR B C(O)R D In some embodiments, R 7 is -C(O)NR B R C In some embodiments, R 7 is -C(O)R D In some embodiments, R 7 -SR E is.

[0109] In some embodiments, R 8is C1-C6 alkyl. In some embodiments, R 8 is C2-C6 alkenyl. In some embodiments, R 8 is C2-C6 alkynyl. In some embodiments, R 8 is C1-C6 heteroalkyl. In some embodiments, R 8 is C1-C6 haloalkyl. In some embodiments, R 8 is an unsubstituted C1-C6 alkyl, an unsubstituted C2-C6 alkenyl, an unsubstituted C2-C6 alkynyl, an unsubstituted C1-C6 haloalkyl, or an unsubstituted C1-C6 heteroalkyl. 8 is one or more R 11 In some embodiments, R 8 is one or more R 11 In some embodiments, R 8 is one or more R 11 In some embodiments, R 8 is one or more R 11 In some embodiments, R 8 is one or more R 11 is a C1-C6 heteroalkyl substituted with

[0110] In some embodiments, R 8 is cycloalkyl. In some embodiments, R 8 is heterocyclyl. In some embodiments, R 8 is aryl. In some embodiments, R 8 is heteroaryl. In some embodiments, R 8 is unsubstituted cycloalkyl, unsubstituted heterocyclyl, unsubstituted aryl, or unsubstituted heteroaryl. In some embodiments, R 8 is one or more R 11 In some embodiments, R 8 is one or more R 11In some embodiments, R is a heterocyclyl substituted with 8 is one or more R 11 In some embodiments, R 8 is one or more R 11 and heteroaryl substituted with

[0111] In some embodiments, R 8 is halo (e.g., fluoro, chloro, bromo, or iodo). In some embodiments, R 8 is cyano. In some embodiments, R 8 is oxo. In some embodiments, R 8 -OR A In some embodiments, R 8 is -NR B R C In some embodiments, R 8 is -NR B C(O)R D In some embodiments, R 8 is —NO. In some embodiments, R 8 is -C(O)NR B R C In some embodiments, R 8 is -C(O)R D In some embodiments, R 8 is -C(O)OR D In some embodiments, R 8 -SR E In some embodiments, R 8 is -S(O) x R D is.

[0112] In some embodiments, R 9 is C1-C6 alkyl. In some embodiments, R 9 is C2-C6 alkenyl. In some embodiments, R 9 is C2-C6 alkynyl. In some embodiments, R 9is C1-C6 heteroalkyl. In some embodiments, R 9 is C1-C6 haloalkyl. In some embodiments, R 9 is an unsubstituted C1-C6 alkyl, an unsubstituted C2-C6 alkenyl, an unsubstituted C2-C6 alkynyl, an unsubstituted C1-C6 haloalkyl, or an unsubstituted C1-C6 heteroalkyl. 9 is one or more R 11 In some embodiments, R 9 is one or more R 11 In some embodiments, R 9 is one or more R 11 In some embodiments, R 9 is one or more R 11 In some embodiments, R 9 is one or more R 11 is a C1-C6 heteroalkyl substituted with

[0113] In some embodiments, R 9 is cycloalkyl. In some embodiments, R 9 is heterocyclyl. In some embodiments, R 9 is aryl. In some embodiments, R 9 is heteroaryl. In some embodiments, R 9 is unsubstituted cycloalkyl, unsubstituted heterocyclyl, unsubstituted aryl, or unsubstituted heteroaryl. In some embodiments, R 9 is one or more R 11 In some embodiments, R 9 is one or more R 11 In some embodiments, R is a heterocyclyl substituted with 9 is one or more R 11 In some embodiments, R 9 is one or more R 11and heteroaryl substituted with

[0114] In some embodiments, R 9 is halo (e.g., fluoro, chloro, bromo, or iodo). In some embodiments, R 9 is cyano. In some embodiments, R 9 is oxo. In some embodiments, R 9 -OR A In some embodiments, R 9 is -NR B R C In some embodiments, R 9 is -NR B C(O)R D In some embodiments, R 9 is —NO. In some embodiments, R 9 is -C(O)NR B R C In some embodiments, R 9 is -C(O)R D In some embodiments, R 9 is -C(O)OR D In some embodiments, R 9 -SR E In some embodiments, R 9 is -S(O) x R D is.

[0115] In some embodiments, R 10 is C1-C6 alkyl. In some embodiments, R 10 is halo (e.g., fluoro, chloro, bromo, or iodo).

[0116] In some embodiments, R 11 is C1-C6 alkyl. In some embodiments, R 11 is C1-C6 heteroalkyl. In some embodiments, R 11is 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.

[0117] 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.

[0118] In some embodiments, R B , R C or both are each independently hydrogen, C1-C6 alkyl, C1-C6 heteroalkyl, cycloalkyl, heterocyclyl, or -OR A In some embodiments, R B and R CEach 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. 10 (e.g., one, two, or three R 10 ) to form a 3- to 7-membered heterocyclyl ring optionally substituted with

[0119] In some embodiments, R D , R E or both are each 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 D is C1-C6 haloalkyl. In some embodiments, RE 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.

[0120] In some embodiments, m is an integer from 0 to 2 (e.g., 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, n is an integer from 0 to 4 (e.g., 0, 1, 2, 3, or 4). In some embodiments, n is 0. In some embodiments, n is 1. In some embodiments, n is 2. In some embodiments, n is 3. In some embodiments, n is 4. In some embodiments, x is an integer from 0 to 2 (e.g., 0, 1, or 2). In some embodiments, x is 0. In some embodiments, x is 1. In some embodiments, x is 2.

[0121] In some embodiments, the present disclosure provides a compound of formula (Ia): [ka] (In the formula, A and B are each independently cycloalkyl, heterocyclyl, aryl, or heteroaryl, each of which is selected from the group consisting of one or more R 1 optionally replaced by; L is absent, C1-C6 alkylene, C1-C6 heteroalkylene, -O-, -C(O)-, -N(R 3 )-, -N(R 3 )C(O)- or -C(O)N(R 3 )-, where each alkylene and heteroalkylene is selected from one or more R 4 optionally replaced by; M and P are each independently C(R 2 ) or N; X and Y are each independently C, C(R 5a ), C(R 5a )(R 5b ), N, or N(R 5c ), where the bond between X and Y may be a single or double bond, if valences allow, and where X and Y are both C(R 5a )(R 5b ) but not; 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 Dwherein each alkyl, alkylene, alkenyl, alkenylene, alkynyl, heteroalkyl, haloalkyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl is selected from the group consisting of one or more R 8 optionally substituted with; 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, where each cycloalkyl, heterocyclyl, aryl, and heteroaryl is selected from one or more R 8 optionally replaced by; Each R 2 are independently hydrogen, halo, cyano, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, or -OR A and; Each R 3 are independently hydrogen, C1-C6 alkyl, or C1-C6 haloalkyl; Each R 4 is 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; R 5a is hydrogen, C1-C6 alkyl, or -OR F and; R 5b is hydrogen or C1-C6 alkyl; or R 5a and R 5b together with the carbon atom to which they are attached form an oxo group; Each R 5c is hydrogen, C1-C6 alkyl, C1-C6 haloalkyl, or C(O)R D and; Each R 7 are independently C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 heteroalkyl, C1-C6 haloalkyl, halo, oxo, cyano, NR B C(O)RD , -C(O)NR B R C , -C(O)R D , or -SR E wherein alkyl, alkenyl, alkynyl, heteroalkyl, and haloalkyl are selected from one or more R 9 optionally substituted with; or The Two R's 7 The groups, together with the atom to which they are attached (e.g., X or Y), form a 4- to 7-membered cycloalkyl, heterocyclyl, aryl, or heteroaryl, where each cycloalkyl, heterocyclyl, aryl, and heteroaryl is selected from the group consisting of one or more R 9 optionally replaced by; R 8 and R 9 each independently represents 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 wherein each of alkyl, alkenyl, alkynyl, heteroalkyl, haloalkyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl is selected from one or more R 11 optionally replaced by; 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 Ceach independently represents hydrogen, C1-C6 alkyl, C1-C6 heteroalkyl, cycloalkyl, heterocyclyl, -OR A is; or R B and R C together with the atoms to which they are attached, one or more R 10 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; R F is hydrogen or C1-C6 alkyl; R 10 is C1-C6 alkyl or halo; 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; n is 0, 1, 2, 3, or 4; x is 0, 1, or 2) or a pharmaceutically acceptable salt, solvate, hydrate, tautomer, or stereoisomer thereof.

[0122] In some embodiments, the present disclosure provides a compound of formula (Ib): [ka] (In the formula, A and B are each independently cycloalkyl, heterocyclyl, aryl, or heteroaryl, each of which is selected from the group consisting of one or more R 1 optionally replaced by; L is absent, C1-C6 alkylene, C1-C6 heteroalkylene, -O-, -C(O)-, -N(R 3 )-, -N(R 3 )C(O)- or -C(O)N(R 3 )-, where each alkylene and heteroalkylene is selected from one or more R 4 optionally replaced by; M and P are each independently C(R 2 ) or N; X and Y are each independently C(R 5a ), C(R 5a )(R 5b ), N, or N(R 5c ), where the bond between X and Y may be a single or double bond, if valences allow, and where X and Y are both C(R 5a )(R 5b ) or C(R 5a ) but not; 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 wherein each alkyl, alkylene, alkenyl, alkenylene, alkynyl, heteroalkyl, haloalkyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl is selected from the group consisting of one or more R 8 optionally substituted with; 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, where each cycloalkyl, heterocyclyl, aryl, and heteroaryl is selected from one or more R 8 optionally replaced by; Each R 2 are independently hydrogen, halo, cyano, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, or -OR A and; Each R 3 are independently hydrogen, C1-C6 alkyl, or C1-C6 haloalkyl; Each R 4 is 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; R 5a and R 5b each of which is hydrogen, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, 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; R 5a and R 5b together with the carbon atom to which they are attached form an oxo group; Each R 5c is hydrogen, C1-C6 alkyl, C1-C6 haloalkyl, or C(O)R D and; Each R 7 are independently C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 heteroalkyl, C1-C6 haloalkyl, halo, oxo, cyano, NR B C(O)R D , -C(O)NR B RC , -C(O)R D , or -SR E wherein alkyl, alkenyl, alkynyl, heteroalkyl, and haloalkyl are selected from one or more R 9 optionally replaced by; R 8 and R 9 each independently represents 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 wherein each of alkyl, alkenyl, alkynyl, heteroalkyl, haloalkyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl is selected from one or more R 11 optionally replaced by; Each R A are independently hydrogen, C1-C6 alkyl, C1-C6 haloalkyl, cycloalkyl, heterocyclyl, 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 A is; or R B and R C together with the atoms to which they are attached, one or more R 10 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; R 10 is C1-C6 alkyl or halo; 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; n is 0, 1, 2, 3, or 4; x is 0, 1, or 2) or a pharmaceutically acceptable salt, solvate, hydrate, tautomer, or stereoisomer thereof.

[0123] 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 azabicyclo[3.2.1]octanyl.

[0124] In some embodiments, A is [ka] wherein R 1 is as defined herein.

[0125] In some embodiments, A is [ka] 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] where each R 1 is independently hydrogen or C1-C6 alkyl. In some embodiments, A is [ka] where each R 1 is independently hydrogen or C1-C6 alkyl. In some embodiments, A is [ka] where each R 1 is independently hydrogen or C1-C6 alkyl. In some embodiments, A is [ka] where each R 1 is independently hydrogen or C1-C6 alkyl. 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.

[0129] In some embodiments, L is absent. In some embodiments, L is oxygen. In some embodiments, L is R 3 In some embodiments, L is nitrogen optionally substituted with R 3 In some embodiments, R 3 is C1-C6 alkyl. In some embodiments, L is -N(CH3)-. In some embodiments, L is -NH-.

[0130] In some embodiments, B is one or more R 1 In some embodiments, B is a heteroaryl optionally substituted with [ka] wherein R 1 is as defined herein. 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] is.

[0131] In some embodiments, B is [ka] where R 1 is as defined herein.

[0132] In some embodiments, B is [ka] where each R 1 is independently hydrogen or C1-C6 alkyl. In some embodiments, B is [ka] where each R 1 is independently hydrogen or C1-C6 alkyl. In some embodiments, B is [ka] where each R 1 is independently hydrogen or C1-C6 alkyl. In some embodiments, B is [ka] where each R 1 is independently hydrogen or C1-C6 alkyl. In some embodiments, B is [ka] where each R 1 is independently hydrogen or C1-C6 alkyl. In some embodiments, B is [ka] where each R 1 is independently hydrogen or C1-C6 alkyl. 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] is.

[0133] As generally described herein, each of X and Y is independently C, C(R 5a ), C(R 5a )(R 5b ), N, or N(R 5c In some embodiments, each of X and Y is independently C. In some embodiments, each of X and Y is C(R 5a In some embodiments, one of X and Y is C(R 5a )(R 5b ), and the other of X and Y is N(R 5c In some embodiments, X is N(R 5c ) and Y is C(R 5a )(R 5b In some embodiments, X is N(R 5c ) and Y is C(R 5a )(R 5b ), where R 5a and R 5b together with the carbon atom to which they are attached form an oxo group. In some embodiments, one of X and Y is C(R 5a ) and the other of X and Y is N. In some embodiments, Y is N and X is C(R 5a ) (e.g., CH or COCH). In some embodiments, X is N and Y is C(R 5a ) (e.g., CH or COCH3). In some embodiments, one of X and Y is C(O) and the other of X and Y is NH. In some embodiments, X is NH and Y is C(O). In some embodiments, the bond between X and Y is a single bond. In some embodiments, the bond between X and Y is a double bond.

[0134] In some embodiments, Y is N and X is C(R 5a ) (e.g., CH), L is -N(R 3 )—(e.g., —N(CH)—). In some embodiments, when Y is N and X is CH, L is not —N(R 3 )—(e.g., —N(CH3)—). In some embodiments, Y is N and X is C(R 5a ) (e.g., CH), then L is not -N(CH3)-. In some embodiments, when Y is N and X is CH, then L is not -N(CH3)-. In some embodiments, when Y is N and L is -N(R 3 ), then R 3 is not C1-C6 alkylene. In some embodiments, Y is N and L is -N(R 3 ), then R 3 is not CH3. In some embodiments, when Y is N, X is also N. In some embodiments, X is C(R 5a ) (e.g., CH), then Y is not N. In some embodiments, when Y comprises N, the bond between X and Y is not a double bond. In some embodiments, when Y comprises N, the bond between X and Y is a single bond. In some embodiments, when Y is N, B is not aryl or heteroaryl. In some embodiments, when Y is N, B is not aryl. In some embodiments, when Y is N, B is not heteroaryl. In some embodiments, when Y is N, B is cycloalkyl or heterocyclyl. In some embodiments, when Y is N, B is cycloalkyl. In some embodiments, when Y is N, B is heterocyclyl.

[0135] In some embodiments, [ka] but, [ka] wherein R5a , R 5b , R 5c , R 7 and n are each as defined herein.

[0136] In some embodiments, [ka] but, [ka] wherein R 7 and n are each as defined herein.

[0137] In some embodiments, [ka] but, [ka] wherein R 2 is as defined above. In some embodiments, R 2 is hydrogen.

[0138] In some embodiments, the compound of Formula (I) has the formula (Ic): [ka] (In the formula, A and B are each independently cycloalkyl, heterocyclyl, aryl, or heteroaryl, each of which is selected from the group consisting of one or more R 1 optionally replaced by; L is absent, C1-C6 alkylene, C1-C6 heteroalkylene, -O-, -C(O)-, -N(R 3 )-, -N(R 3 )C(O)- or -C(O)N(R 3 )-, where each alkylene and heteroalkylene is selected from one or more R 4optionally 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 wherein each alkyl, alkylene, alkenyl, alkenylene, alkynyl, heteroalkyl, haloalkyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl is selected from the group consisting of one or more R 8 optionally substituted with; 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, where each cycloalkyl, heterocyclyl, aryl, and heteroaryl is selected from one or more R 8 optionally replaced by; Each R 2 are independently hydrogen, halo, cyano, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, or -OR A and; Each R 3 are independently hydrogen, C1-C6 alkyl, or C1-C6 haloalkyl; Each R 4 is 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; R 5c is hydrogen, C1-C6 alkyl, C1-C6 haloalkyl, or C(O)R D and; Each R 7 are independently C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 heteroalkyl, C1-C6 haloalkyl, halo, oxo, cyano, NR B C(O)R D , -C(O)NR B R C , -C(O)R D , or -SR E wherein alkyl, alkenyl, alkynyl, heteroalkyl, and haloalkyl are selected from one or more R 9 optionally substituted with; or The Two R's 7 The groups, together with the atom to which they are attached (e.g., X or Y), form a 4- to 7-membered cycloalkyl, heterocyclyl, aryl, or heteroaryl, where each cycloalkyl, heterocyclyl, aryl, and heteroaryl is selected from the group consisting of one or more R 9 optionally replaced by; R 8 and R 9 each independently represents 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 wherein each of alkyl, alkenyl, alkynyl, heteroalkyl, haloalkyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl is selected from one or more R11 optionally replaced by; 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 A is; or R B and R C together with the atoms to which they are attached, one or more R 10 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 10 are independently C1-C6 alkyl or halo; 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; m is 0, 1, or 2; n is 0, 1, 2, 3, or 4; x is 0, 1, or 2) or a pharmaceutically acceptable salt, solvate, hydrate, tautomer, or stereoisomer thereof.

[0139] 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 azabicyclo[3.2.1]octanyl. In some embodiments, A is [ka] where each R 1 is independently hydrogen or C1-C6 alkyl. In some embodiments, A is [ka] where each R 1 is independently hydrogen or C1-C6 alkyl. In some embodiments, A is [ka] where each R 1 is independently hydrogen or C1-C6 alkyl. In some embodiments, A is [ka] where each R 1 is independently hydrogen or C1-C6 alkyl. 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.

[0140] In some embodiments, L is oxygen. In some embodiments, L is R 3 In some embodiments, L is nitrogen optionally substituted with R 3In some embodiments, L is -N(CH3)-. In some embodiments, L is -NH-.

[0141] In some embodiments, B is one or more R 1 In some embodiments, B is a heteroaryl optionally substituted with [ka] where each R 1 is independently hydrogen or C1-C6 alkyl. In some embodiments, B is [ka] where each R 1 is independently hydrogen or C1-C6 alkyl. In some embodiments, B is [ka] where each R 1 is independently hydrogen or C1-C6 alkyl. In some embodiments, B is [ka] where each R 1 is independently hydrogen or C1-C6 alkyl. In some embodiments, B is [ka] where each R 1 is independently hydrogen or C1-C6 alkyl. In some embodiments, B is [ka] where each R 1are independently hydrogen or C1-C6 alkyl.

[0142] 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.

[0143] In some embodiments, R 1 is C1-C6 alkyl (e.g., methyl). In some embodiments, R 1 is methyl. In some embodiments, R 2 is hydrogen. In some embodiments, R 7 is hydrogen. In some embodiments, m and n are each 0. In some embodiments, R 5cis hydrogen.

[0144] In some embodiments, R 5c is hydrogen, C1-C6 alkyl. In some embodiments, R 5c is hydrogen. In some embodiments, R 5c is C1-C6 alkyl (for example, CH3).

[0145] In some embodiments, the compound of Formula (I) has the formula (Id): [ka] (In the formula, A 1 are each one or more R 1 is a 6-membered cycloalkyl, heterocyclyl, aryl, or heteroaryl optionally substituted with; B 1 are R 1 is a 5-membered cycloalkyl, heterocyclyl, aryl or heteroaryl optionally substituted with L is absent, C1-C6 alkylene, C1-C6 heteroalkylene, -O-, -C(O)-, -N(R 3 )-, -N(R 3 )C(O)- or -C(O)N(R 3 )-, and each alkylene and heteroalkylene is selected from one or more R 4 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 RC , -C(O)R D , -C(O)OR D , -SR E or -S(O) x R D and each alkyl, alkylene, alkenyl, alkenylene, alkynyl, heteroalkyl, haloalkyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl may be selected from one or more R 8 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 8 is optionally replaced by; Each R 2 are independently hydrogen, halo, cyano, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, or -OR A and; Each R 3 are independently hydrogen, C1-C6 alkyl, or C1-C6 haloalkyl; Each R 4 is 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; R 5C is hydrogen, C1-C6 alkyl, C1-C6 haloalkyl or -C(O)R D and; Each R 7 are independently C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 heteroalkyl, C1-C6 haloalkyl, halo, oxo, cyano, NR B C(O)R D , -C(O)NR B R C , -C(O)R D or -SRE and alkyl, alkenyl, alkynyl, heteroalkyl, and haloalkyl are each independently selected from the group consisting of one or more R 9 optionally replaced by; or The Two R's 7 The groups, together with the atom to which they are attached (e.g., X or Y), form a 4- to 7-membered cycloalkyl, heterocyclyl, aryl, or heteroaryl, and each cycloalkyl, heterocyclyl, aryl, and heteroaryl may be joined by one or more R 9 is optionally replaced by; R 8 and R 9 are each 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 of alkyl, alkenyl, alkynyl, heteroalkyl, haloalkyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl is selected from one or more R 11 is optionally replaced by; 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 Aor R B and R C are one or more R's along with the atoms to which they are attached. 10 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 10 are independently C1-C6 alkyl or halo; 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; m is 0, 1 or 2; n 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.

[0146] 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 azabicyclo[3.2.1]octanyl.

[0147] In some embodiments, A is [ka] wherein R 1 is as defined herein.

[0148] In some embodiments, A is [ka] is selected from.

[0149] In some embodiments, A is [ka] is selected from.

[0150] In some embodiments, A is [ka] is selected from.

[0151] In some embodiments, A is [ka] where each R 1 is independently hydrogen or C1-C6 alkyl. In some embodiments, A is [ka] where each R 1 is independently hydrogen or C1-C6 alkyl. In some embodiments, A is [ka] where each R 1 is independently hydrogen or C1-C6 alkyl. In some embodiments, A is [ka] where each R 1is independently hydrogen or C1-C6 alkyl. 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.

[0152] In some embodiments, L is absent. In some embodiments, L is oxygen. In some embodiments, L is R 3 In some embodiments, L is nitrogen optionally substituted with R 3 In some embodiments, R 3 is C1-C6 alkyl. In some embodiments, L is -N(CH3)-. In some embodiments, L is -NH-.

[0153] In some embodiments, B is one or more R 1 In some embodiments, B is a heteroaryl optionally substituted with [ka] wherein R 1 is as defined herein. 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] is.

[0154] In some embodiments, B is [ka] In some embodiments, B is [ka] where each R 1 is independently hydrogen or C1-C6 alkyl. In some embodiments, B is [ka] where each R 1 is independently hydrogen or C1-C6 alkyl. In some embodiments, B is [ka] where each R 1 is independently hydrogen or C1-C6 alkyl. In some embodiments, B is [ka] where each R 1is independently hydrogen or C1-C6 alkyl. In some embodiments, B is [ka] where each R 1 is independently hydrogen or C1-C6 alkyl. In some embodiments, B is [ka] where each R 1 is independently hydrogen or C1-C6 alkyl. In some embodiments, B is [ka] In some embodiments, B is [ka] is.

[0155] In some embodiments, R 1 is C1-C6 alkyl (e.g., methyl). In some embodiments, R 1 is methyl. In some embodiments, R 2 is hydrogen. In some embodiments, R 7 is hydrogen. In some embodiments, m and n are each 0. In some embodiments, R 5c is hydrogen.

[0156] In some embodiments, the compound of Formula (I) has the formula (Ie): [ka] (In the formula, A and B are each independently cycloalkyl, heterocyclyl, aryl, or heteroaryl, each of which is selected from the group consisting of one or more R 1 optionally replaced by; L is absent, C1-C6 alkylene, C1-C6 heteroalkylene, -O-, -C(O)-, -N(R 3 )-, -N(R 3 )C(O)- or -C(O)N(R 3 )-, where each alkylene and heteroalkylene is selected from one or more R 4 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 wherein each alkyl, alkylene, alkenyl, alkenylene, alkynyl, heteroalkyl, haloalkyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl is selected from the group consisting of one or more R 8 optionally substituted with; 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, where each cycloalkyl, heterocyclyl, aryl, and heteroaryl is selected from one or more R 8 optionally replaced by; Each R 2 are independently hydrogen, halo, cyano, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, or -OR A and; Each R 3are independently hydrogen, C1-C6 alkyl, or C1-C6 haloalkyl; Each R 4 is 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; R 5a is hydrogen, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, 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 7 are independently C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 heteroalkyl, C1-C6 haloalkyl, halo, oxo, cyano, NR B C(O)R D , -C(O)NR B R C , -C(O)R D , or -SR E wherein alkyl, alkenyl, alkynyl, heteroalkyl, and haloalkyl are selected from one or more R 9 optionally replaced by; R 8 and R 9 each independently represents 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)ORD , -SR E , or -S(O) x R D wherein each of alkyl, alkenyl, alkynyl, heteroalkyl, haloalkyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl is selected from one or more R 11 optionally replaced by; 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 A is; or R B and R C together with the atoms to which they are attached, one or more R 10 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; R F is hydrogen or C1-C6 alkyl; Each R 10 are independently C1-C6 alkyl or halo; 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; m is 0, 1, or 2; n is 0, 1, 2, 3, or 4; x is 0, 1, or 2) or a pharmaceutically acceptable salt, solvate, hydrate, tautomer, or stereoisomer thereof.

[0157] 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 azabicyclo[3.2.1]octanyl.

[0158] In some embodiments, A is [ka] wherein R 1 is as defined herein.

[0159] In some embodiments, A is [ka] is selected from.

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

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

[0162] In some embodiments, A is [ka] where each R 1 is independently hydrogen or C1-C6 alkyl. In some embodiments, A is [ka] where each R 1 is independently hydrogen or C1-C6 alkyl. In some embodiments, A is [ka] where each R 1 is independently hydrogen or C1-C6 alkyl. In some embodiments, A is [ka] where each R 1 is independently hydrogen or C1-C6 alkyl. 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.

[0163] In some embodiments, L is absent. In some embodiments, L is oxygen. In some embodiments, L is R 3 In some embodiments, L is nitrogen optionally substituted with R 3 In some embodiments, R 3 is C1-C6 alkyl. In some embodiments, L is -N(CH3)-. In some embodiments, L is -NH-.

[0164] In some embodiments, B is one or more R 1 In some embodiments, B is a heteroaryl optionally substituted with [ka] wherein R1 is as defined herein. 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] is.

[0165] In some embodiments, B is [ka] where R 1 is as defined herein.

[0166] In some embodiments, B is [ka] where each R 1 is independently hydrogen or C1-C6 alkyl. In some embodiments, B is [ka] where each R 1 is independently hydrogen or C1-C6 alkyl. In some embodiments, B is [ka] where each R 1 is independently hydrogen or C1-C6 alkyl. In some embodiments, B is [ka] where each R 1 is independently hydrogen or C1-C6 alkyl. In some embodiments, B is [ka] where each R 1 is independently hydrogen or C1-C6 alkyl. In some embodiments, B is [ka] where each R 1 is independently hydrogen or C1-C6 alkyl. In some embodiments, B is [ka] In some embodiments, B is [ka] is.

[0167] In some embodiments, R 1 is C1-C6 alkyl (e.g., methyl). In some embodiments, R 1 is methyl. In some embodiments, R 2 is hydrogen. In some embodiments, R 7 is hydrogen. In some embodiments, m and n are each 0. In some embodiments, R 5c is hydrogen.

[0168] In some embodiments, R 5a is hydrogen, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 heteroalkyl, C1-C6 haloalkyl, cycloalkyl, halo, cyano, -OR A , -NR B R C , -C(O)R D , or -C(O)OR D In some embodiments, R 5a is hydrogen. In some embodiments, R 5a is C1-C6 alkyl. In some embodiments, R 5a is C1-C6 heteroalkyl. In some embodiments, R 5a is C1-C6 haloalkyl. In some embodiments, R 5a is cycloalkyl. In some embodiments, R 5a is halo. In some embodiments, R 5a is cyano. In some embodiments, R 5a -OR A is.

[0169] In some embodiments, the compound of Formula (I) has the formula (If): [ka] (In the formula, A and B are each independently cycloalkyl, heterocyclyl, aryl, or heteroaryl, each of which is selected from the group consisting of one or more R 1optionally replaced by; X and Y are each independently C, C(R 5a ), C(R 5a )(R 5b ), N, or N(R 5c ), where the bond between X and Y may be a single or double bond, if valences allow, and where X and Y are both C(R 5a )(R 5b ) but not; 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 wherein each alkyl, alkylene, alkenyl, alkenylene, alkynyl, heteroalkyl, haloalkyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl is selected from the group consisting of one or more R 8 optionally substituted with; 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, where each cycloalkyl, heterocyclyl, aryl, and heteroaryl is selected from one or more R 8 optionally replaced by; Each R 2 are independently hydrogen, halo, cyano, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, or -OR A and; Each R3 are independently hydrogen, C1-C6 alkyl, or C1-C6 haloalkyl; Each R 4 is 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; R 5a is hydrogen, C1-C6 alkyl, or -OR F and; R 5b is hydrogen or C1-C6 alkyl; or R 5a and R 5b together with the carbon atom to which they are attached form an oxo group; Each R 5c is hydrogen, C1-C6 alkyl, C1-C6 haloalkyl, or C(O)R D and; Each R 7 are independently C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 heteroalkyl, C1-C6 haloalkyl, halo, oxo, cyano, NR B C(O)R D , -C(O)NR B R C , -C(O)R D , or -SR E wherein alkyl, alkenyl, alkynyl, heteroalkyl, and haloalkyl are selected from one or more R 9 optionally substituted with; or The Two R's 7 The groups, together with the atom to which they are attached (e.g., X or Y), form a 4- to 7-membered cycloalkyl, heterocyclyl, aryl, or heteroaryl, where each cycloalkyl, heterocyclyl, aryl, and heteroaryl is selected from the group consisting of one or more R 9 optionally replaced by; R 8 and R 9each independently represents 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 wherein each of alkyl, alkenyl, alkynyl, heteroalkyl, haloalkyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl is selected from one or more R 11 optionally replaced by; 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 A is; or R B and R C together with the atoms to which they are attached, one or more R 10 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; R F is hydrogen or C1-C6 alkyl; R 10 is C1-C6 alkyl or halo; 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; n 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.

[0170] In some embodiments, the compound of Formula (I) has the formula (Ig): [ka] (In the formula, A and B are each independently cycloalkyl, heterocyclyl, aryl, or heteroaryl, each of which is selected from the group consisting of one or more R 1 optionally replaced by; L is absent, C1-C6 alkylene, C1-C6 heteroalkylene, -O-, -C(O)-, -N(R 3 )-, -N(R 3 )C(O)- or -C(O)N(R 3 )-, where each alkylene and heteroalkylene is selected from one or more R 4 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 BC(O)R D , -NO2, -C(O)NR B R C , -C(O)R D , -C(O)OR D , -SR E , or -S(O) x R D wherein each alkyl, alkylene, alkenyl, alkenylene, alkynyl, heteroalkyl, haloalkyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl is selected from the group consisting of one or more R 8 optionally substituted with; 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, where each cycloalkyl, heterocyclyl, aryl, and heteroaryl is selected from one or more R 8 optionally replaced by; Each R 2 are independently hydrogen, halo, cyano, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, or -OR A and; Each R 3 are independently hydrogen, C1-C6 alkyl, or C1-C6 haloalkyl; Each R 4 is 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; R' is hydrogen, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 heteroalkyl, C1-C6 haloalkyl, cycloalkyl, heterocyclyl, -C(O)R D , or -C(O)OR D and; Each R 7are independently C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 heteroalkyl, C1-C6 haloalkyl, halo, oxo, cyano, NR B C(O)R D , -C(O)NR B R C , -C(O)R D , or -SR E wherein alkyl, alkenyl, alkynyl, heteroalkyl, and haloalkyl are selected from one or more R 9 optionally replaced by; R 8 and R 9 each independently represents 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 wherein each of alkyl, alkenyl, alkynyl, heteroalkyl, haloalkyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl is selected from one or more R 11 optionally replaced by; 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 Ais; or R B and R C together with the atoms to which they are attached, one or more R 10 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 10 are independently C1-C6 alkyl or halo; 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; m is 0, 1, or 2; n is 0, 1, 2, 3, or 4; x is 0, 1, or 2) or a pharmaceutically acceptable salt, solvate, hydrate, tautomer, or stereoisomer thereof.

[0171] In some embodiments, R' is C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 heteroalkyl, C1-C6 haloalkyl, cycloalkyl, or heterocyclyl. In some embodiments, R' is C1-C6 alkyl, C1-C6 heteroalkyl, C1-C6 haloalkyl, cycloalkyl, or heterocyclyl. In some embodiments, R' is C1-C6 alkyl, C1-C6 haloalkyl, or cycloalkyl. In some embodiments, R' is C1-C6 alkyl. In some embodiments, R' is C1-C6 haloalkyl. In some embodiments, R' is cycloalkyl. In some embodiments, R' is hydrogen.

[0172] In some embodiments, the compound of Formula (I) has the formula (Ih): [ka] (In the formula, A and B are each independently cycloalkyl, heterocyclyl, aryl, or heteroaryl, each of which is selected from the group consisting of one or more R 1 optionally replaced by; L is absent, C1-C6 alkylene, C1-C6 heteroalkylene, -O-, -C(O)-, -N(R 3 )-, -N(R 3 )C(O)- or -C(O)N(R 3 )-, where each alkylene and heteroalkylene is selected from one or more R 4 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 wherein each alkyl, alkylene, alkenyl, alkenylene, alkynyl, heteroalkyl, haloalkyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl is selected from the group consisting of one or more R 8 optionally substituted with; 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, where each cycloalkyl, heterocyclyl, aryl, and heteroaryl is selected from one or more R 8 optionally replaced by; Each R 2 are independently hydrogen, halo, cyano, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, or -OR A and; Each R 3 are independently hydrogen, C1-C6 alkyl, or C1-C6 haloalkyl; Each R 4 is 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; R 5a is hydrogen, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, 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 7 are independently C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 heteroalkyl, C1-C6 haloalkyl, halo, oxo, cyano, NR B C(O)R D , -C(O)NR B R C , -C(O)R D , or -SR E wherein alkyl, alkenyl, alkynyl, heteroalkyl, and haloalkyl are selected from one or more R 9 optionally replaced by; R 8 and R 9each independently represents 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 wherein each of alkyl, alkenyl, alkynyl, heteroalkyl, haloalkyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl is selected from one or more R 11 optionally replaced by; 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 A is; or R B and R C together with the atoms to which they are attached, one or more R 10 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 10 are independently C1-C6 alkyl or halo; 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; m is 0, 1, or 2; n is 0, 1, 2, 3, or 4; x is 0, 1, or 2) or a pharmaceutically acceptable salt, solvate, hydrate, tautomer, or stereoisomer thereof.

[0173] In some embodiments, R 5a is hydrogen, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 heteroalkyl, C1-C6 haloalkyl, cycloalkyl, halo, cyano, -OR A , -NR B R C , -C(O)R D In some embodiments, R 5a is hydrogen, C1-C6 alkyl, C1-C6 heteroalkyl, C1-C6 haloalkyl, cycloalkyl, halo, cyano, oxo, -OR A , -NR B R C , -C(O)R D In some embodiments, R 5a is hydrogen, C1-C6 alkyl, C1-C6 heteroalkyl, C1-C6 haloalkyl, cycloalkyl, halo, -OR A , -NR B R C , -C(O)R D In some embodiments, R 5a is hydrogen. In some embodiments, R 5a is halo. In some embodiments, R 5a is C1-C6 haloalkyl. In some embodiments, R 5ais C1-C6 alkyl. In some embodiments, R 5a -OR A is.

[0174] In some embodiments, the compound of formula (I) is selected from the compounds in Table 1, or a pharmaceutically acceptable salt thereof.

[0175] [Table 1]

[0176] [Table 2]

[0177] [Table 3]

[0178] [Table 4]

[0179] [Table 5]

[0180] [Table 6]

[0181] [Table 7]

[0182] [Table 8]

[0183] [Table 9]

[0184] In some embodiments, for Formula (I), A is monocyclic heterocyclyl (e.g., piperidinyl); B is monocyclic heteroaryl (e.g., pyrazolyl); and L is -N(R 3 )—(e.g., NMe); M and P are each independently C(R 2 ) (e.g., CH); X is N(R 5c ) (e.g., NH); Y is C(R 5a )(R 5b ) (e.g., —C(O)—); and n is 0. In some embodiments, the compound of Formula (I), (Ia), (Ib), (Ie), (If), and (Ih) is Compound 125, or a pharmaceutically acceptable salt, solvate, hydrate, tautomer, or stereoisomer thereof.

[0185] In some embodiments, for Formula (I), A is monocyclic heterocyclyl (e.g., piperidinyl); B is monocyclic heteroaryl (e.g., pyrazolyl); and L is -N(R 3 )—(e.g., NMe); M and P are each independently C(R 2 ) (e.g., CH); X is N(R 5c ) (e.g., NH); Y is C(R 5a )(R 5b ) (e.g., —C(O)—); and n is 0. In some embodiments, the compound of Formula (I), (Ia), (Id), (Ie), and (Ih) is Compound 126, or a pharmaceutically acceptable salt, solvate, hydrate, tautomer, or stereoisomer thereof.

[0186] In some embodiments, for Formula (I), A is monocyclic heterocyclyl (e.g., piperidinyl); B is monocyclic heteroaryl (e.g., pyrazolyl); and L is -N(R 3 )—(e.g., NMe); M and P are each independently C(R 2 ) (e.g., CH); X is N(R 5c) (e.g., NH); Y is C(R 5a )(R 5b ) (e.g., —C(O)—); and n is 0. In some embodiments, the compound of Formula (I), (Ia), (Ib), (Ie), (If), and (Ih) is Compound 127, or a pharmaceutically acceptable salt, solvate, hydrate, tautomer, or stereoisomer thereof.

[0187] In some embodiments, for Formula (I), A is monocyclic heterocyclyl (e.g., piperidinyl); B is monocyclic heteroaryl (e.g., pyrazolyl); and L is -N(R 3 )—(e.g., NMe); M and P are each independently C(R 2 ) (e.g., CH); X is N(R 5c ) (e.g., NH); Y is C(R 5a )(R 5b ) (e.g., —C(O)—); and n is 0. In some embodiments, the compound of Formula (I), (Ia), (Ib), (Ie), (If), and (Ih) is Compound 128, or a pharmaceutically acceptable salt, solvate, hydrate, tautomer, or stereoisomer thereof.

[0188] In some embodiments, for Formula (I), A is a bicyclic heterocyclyl (e.g., azabicyclo[3.2.1]octanyl); B is a monocyclic heteroaryl (e.g., pyrazolyl); and L is -N(R 3 )—(e.g., NMe); M and P are each independently C(R 2 ) (e.g., CH); X is N(R 5c ) (e.g., NH); Y is C(R 5a )(R 5b ) (e.g., —C(O)—); and n is 0. In some embodiments, the compound of Formula (I), (Ia), (Ib), (Ie), and (Ih) is Compound 129, or a pharmaceutically acceptable salt, solvate, hydrate, tautomer, or stereoisomer thereof.

[0189] In some embodiments, for Formula (I), A is a bicyclic heterocyclyl (e.g., azabicyclo[3.2.1]octanyl); B is a monocyclic heteroaryl (e.g., pyrazolyl); and L is -N(R 3 )—(e.g., NMe); M and P are each independently C(R 2 ) (e.g., CH); X is N(R 5c ) (e.g., NH); Y is C(R 5a )(R 5b ) (e.g., —C(O)—); and n is 0. In some embodiments, the compound of Formula (I), (Ia), (Ib), (Ie), and (Ih) is Compound 130, or a pharmaceutically acceptable salt, solvate, hydrate, tautomer, or stereoisomer thereof.

[0190] In some embodiments, for Formula (I), A is a bicyclic heterocyclyl (e.g., azabicyclo[3.2.1]octanyl); B is a monocyclic heteroaryl (e.g., pyrazolyl); and L is -N(R 3 )—(e.g., NMe); M and P are each independently C(R 2 ) (e.g., CH); X is N; Y is C(R 5a ) (e.g., —C(OMe)—); and n is 0. In some embodiments, the compound of Formula (I), (Ig), and (Ih) is Compound 133, or a pharmaceutically acceptable salt, solvate, hydrate, tautomer, or stereoisomer thereof.

[0191] In some embodiments, for Formula (I), A is a bicyclic heterocyclyl (e.g., azabicyclo[3.2.1]octanyl); B is a monocyclic heteroaryl (e.g., pyrazolyl); and L is -N(R 3 )—(e.g., NMe); M and P are each independently C(R 2 ) (e.g., CH); X is N; Y is C(R 5a) (e.g., —C(OMe)—); and n is 0. In some embodiments, the compound of Formula (I), (Ig), and (Ih) is Compound 134, or a pharmaceutically acceptable salt, solvate, hydrate, tautomer, or stereoisomer thereof.

[0192] In some embodiments, for Formula (I), A is monocyclic heterocyclyl (e.g., piperidinyl); B is monocyclic heteroaryl (e.g., pyrazolyl); and L is -N(R 3 )—(e.g., NMe); M and P are each independently C(R 2 ) (e.g., CH); X is N; Y is C(R 5a ) (e.g., —C(OMe)—); and n is 0. In some embodiments, the compound of Formula (I), (Ig), and (Ih) is Compound 135, or a pharmaceutically acceptable salt, solvate, hydrate, tautomer, or stereoisomer thereof.

[0193] In some embodiments, for Formula (I), A is monocyclic heterocyclyl (e.g., piperidinyl); B is monocyclic heteroaryl (e.g., pyrazolyl); and L is -N(R 3 )—(e.g., NMe); M and P are each independently C(R 2 ) (e.g., CH); X is N; Y is C(R 5a ) (e.g., —C(OMe)—); and n is 0. In some embodiments, the compound of Formula (I), (Ig), and (Ih) is Compound 136, or a pharmaceutically acceptable salt, solvate, hydrate, tautomer, or stereoisomer thereof.

[0194] In some embodiments, for Formula (I), A is monocyclic heterocyclyl (e.g., piperidinyl); B is monocyclic heteroaryl (e.g., pyrazolyl); and L is -N(R 3 )—(e.g., NMe); M and P are each independently C(R 2 ) (e.g., CH); X is N or N(R 5c) (e.g., NH); Y is C(R 5a ) (e.g., -C(OMe)-) or C(R 5a )(R 5b ) (e.g., —C(O)—); and n is 0. In some embodiments, the compound of Formula (I), (If), and (Ig) is compound 161, or a pharmaceutically acceptable salt, solvate, hydrate, tautomer, or stereoisomer thereof. In some embodiments, the compound of Formula (I), (Ia), (Ie), (If), (Ig), (Ih) is compound 162, or a pharmaceutically acceptable salt, solvate, hydrate, tautomer, or stereoisomer thereof.

[0195] In some embodiments, for Formula (I), A is monocyclic heterocyclyl (e.g., piperidinyl); B is monocyclic heteroaryl (e.g., pyrazolyl); and L is -N(R 3 )—(e.g., NMe); M and P are each independently C(R 2 ) (e.g., CH) or N; X is N or N(R 5c ) (e.g., NH); Y is C(R 5a ) (e.g., —C(CH), —C(OMe)—, C(CN), N(CH), C(O-cycloalkyl)) or C(R 5a )(R 5b ) (e.g., —C(O)—); and n is 0. In some embodiments, the compound of Formula (I), (If), and (Ig) is a compound selected from any one of compounds 171, 217, 236, 244-305, or a pharmaceutically acceptable salt, solvate, hydrate, tautomer, or stereoisomer thereof.

[0196] In some embodiments, the compound of Formula (I) is selected from any one of compounds 133, 134, 245, 246, 247, 249, 250, 260, 261, 262, 268, 269, 272, 284, and 286. In some embodiments, the compound of Formula (I) is selected from any one of compounds 249, 250, 260, 261, 268, 269, 284, and 286. In some embodiments, the compound of Formula (I) is not compound 207 or 208.

[0197] 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.

[0198] 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.

[0199] 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.

[0200] 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.

[0201] 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.

[0202] Compositions of the present invention can be administered orally, parenterally (including subcutaneously, intramuscularly, intravenously, and intradermally), by inhalation spray, topically, rectally, nasally, buccally, vaginally, or via an implanted reservoir. In some embodiments, provided compounds or compositions can be administered intravenously and / or orally.

[0203] 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.

[0204] 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.

[0205] 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.

[0206] For use in the eye, provided pharmaceutically acceptable compositions may be formulated as a micronized suspension or in an ointment such as petrolatum.

[0207] 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.

[0208] 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.

[0209] The compound provided herein is typically formulated in dosage unit form, for example, single unit dosage form, for the purpose of easy administration and uniformity of dosage.However, it will be understood that the total daily use amount of the composition of the present invention will be determined by attending physician within the scope of sound medical judgment.The specific therapeutically effective dose level for any specific subject or organism depends on various factors, including the severity of the disease and disorder being treated; the activity of the specific active ingredient used; the specific composition used; the age, weight, general health condition, sex and diet of the subject; the administration time, administration route and excretion rate of the specific active ingredient used; treatment duration; the drug used in combination with or simultaneously with the specific active ingredient used; and similar factors well known in the medical field.

[0210] 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.

[0211] 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.

[0212] 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.

[0213] 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.

[0214] 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.

[0215] The compounds or compositions 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 compounds of the present invention with the additional agents 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.

[0216] Exemplary additional agents include, but are not limited to, antiproliferative agents, anticancer agents, antidiabetic agents, anti-inflammatory agents, immunosuppressants, and analgesics. Agents include small organic molecules such as drug compounds (e.g., compounds approved by the U.S. Food and Drug Administration as described in the Code of Federal Regulations (CFR)), 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.

[0217] 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.

[0218]

[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.

[0219] 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.

[0220] 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).

[0221] 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).

[0222] 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、C ALCA、CALCOCO2、CAMK1D、CAMKK1、CAPN3、CAPN9、CAPSL、CARD11、CARKD、CAS Z1、CAT、CBLB、CBX1、CBX3、CCDC102B、CCDC11、CCDC15、CCDC18、CCDC5、CCDC 81、CCDC131、CCDC146、CD4、CD274、CD1B、CDC14A、CDC16、CDC2L5、CDC42BPB 、CDCA8、CDH10、CDH11、CDH24、CDH8、CDH9、CDK5RAP2、CDK6、CDK8、CDK11B、CD 33、CD46、CDH1、CDH23、CDK6、CDK11B、CDK13、CEBPZ、CEL、CELSR3、CENPA、CE NPI、CENPT、CENTB2、CENTG2、CEP110、CEP170、CEP192、CETP、CFB、CFTR、CFH 、CGN、CGNL1、CHAF1A、CHD9、CHIC2、CHL1、CHN1、CHM、CLEC16A、CL1C2、CLCN1 、CLINT1、CLK1、CLPB、CLPTM1、CMIP、CMYA5、CNGA3、CNOT1、CNOT7、CNTN6、COG 3、COL11A1、COL11A2、COL12A1、COL14A1、COL15A1、COL17A1、COL19A1、COL1 A1、COL1A2、COL2A1、COL3A1、COL4A1、COL4A2、COL4A5、COL4A6、COL5A2、COL6 A1、COL7A1、COL9A1、COL9A2、COL22A1、COL24A1、COL25A1、COL29A1、COLQ、C OMTD1、COPA、COPB2、COPS7B、COPZ2、CPSF2、CPXM2、CR1、CRBN、CRYZ、CREBBP、CRKRS、CSE1L、CSTB、CSTF3、CT45-6、CTNNB1、CUBN、CUL4B、CUL5、CXorf41、C XXC1、CYBB、CYFIP2、CYP3A4、CYP3A43、CYP3A5、CYP4F2、CYP4F3、CYP17、CYP 19, CYP24A1, CYP27A1, DAB1, DAZ2, DCBLD1, DCC, DCTN3, DCUN1D4, DDA1, DDEF1, DDX1, DDX24, DDX4, DENND2D, DEPDC2, DES, DGAT2, DHFR, DHRS7, DHRS9, DH X8, DIP2A, DMD, DMTF1, DNAH3, DNAH8, DNAI1, DNAJA4, DNAJC13, DNAJC7, DNM T1、DNTTIP2、DOCK4、DOCK5、DOCK10、DOCK11、DOT1L、DPP3、DPP4、DPY19L2P2、 DR1、DSCC1、DVL3、DUX4、DYNC1H1、DYSF、E2F1、E2F3、E2F8、E4F1、EBF1、EBF3 、ECM2、EDEM3、EFCAB3、EFCAB4B、EFNA4、EFTUD2、EGFR、EIF3A、ELA1、ELA2A、E LF2、ELF3、ELF4、EMCN、EMD、EML5、ENO3、ENPP3、EP300、EPAS1、EPB41L5、EPH A3、EPHA4、EPHB1、EPHB2、EPHB3、EPS15、ERBB4、ERCC1、ERCC8、ERGIC3、ERMN、 ERMP1, ERN1, ERN2, ESR1, ESRRG, ETS2, ETV3, ETV4, ETV5, ETV6, EVC2, EWSR1, EXO1, EXOC4, F3, F11, F13A1, F5, F7, F8, FAH, FAM13A1, FAM13B1, FAM13C1, F AM134A, FAM161A, FAM176B, FAM184A, FAM19A1, FAM20A, FAM23B, FAM65C, FANCA, FANCC, FANCG, FANCM, FANK1, FAR2, FBN1, FBXO15, FBXO18, FBXO38, FCGB P、FECH、FEZ2、FGA、FGD6、FGFR2、FGFR1OP、FGFR1OP2、FGFR2、FGG、FGR、FIX、 FKBP3、FLI1、FLJ35848、FLJ36070、FLNA、FN1、FNBP1L、FOLH1、FOSL1、FOSL2、FOXK1, FOXM1, FOXO1, FOXP4, FRAS1, FUT9, FXN, FZD3, FZD6, GAB1, GABPA, GALC, GALNT3, GAPDH, GART, GAS2L3, GATA3, GATAD2A, GBA, GBGT1, GCG, GCGR, G CK、GFI1、GFM1、GH1、GHR、GHV、GJA1、GLA、GLT8D1、GNA11、GNAQ、GNAS、GNB5、 GOLGB1、GOLT1A、GOLT1B、GPATCH1、GPR158、GPR160、GPX4、GRAMD3、GRHL1、GR HL2, GRHPR, GRIA1, GRIA3, GRIA4, GRIN2B, GRM3, GRM4, GRN, GSDMB, GSTCD, GSTO2, GTF2I, GTPBP4, HADHA, HAND2, HBA2, HBB, HKK, HDAC3, HDAC5, HDX, HEP ACAM2、HERC1、HES7、HEXA、HEXB、HHEX、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、ID H1、IDS、IFI44L、IKBKAP、IKZF1、IKZF3、IL1R2、IL5RA、IL7RA、IMMT、INPP5D 、INSR、INTS3、INTU、IP04、IP08、IQGAP2、IRF2、IRF4、IRF8、IRX3、ISL1、ISL 2、ITFG1、ITGA6、ITGAL、ITGB1、ITGB2、1TGB3、ITGB4、ITIH1、ITPR2、IWS1、JA K1、JAK2、JAG1、JMJD1C、JPH3、KALRN、KAT6A、KATNAL2、KCNN2、KCNT2、KDM2A 、KIAA0256、KIAA0528、KIAA0564、KIAA0586、KIAA1033、KIAA1166、KIAA121 9, KIAA1409, KIAA1622, KIAA1787, KIF3B, KIF15, KIF16B, KIF5A, KIF5B, KIF9, KIN, KIR2DL5B, KIR3DL2, KIR3DL3, KIT, KLF3, KLF5, KLF7, KLF10, KLF12KLF16、KLHL20、KLK12、KLKB1、KMT2A、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、LMBRD2、LMLN、LMNA、LMO2、LMO7、LOC389634 、LOC390110、LPA、LPCAT2、LPL、LRP4、LRPPRC、LRRK2、LRRC19、LRRC42、LRWD 1、LUM、LVRN、LYN、LYST、MADD、MAGI1、MAGT1、MALT1、MAP2K1、MAP4K4、MAPK8I P3、MAPK9、MAPT、MARC1、MARCH5、MATN2、MBD3、MCF2L2、MCM6、MDGA2、MDM4、A SXL1、FUS、SPR54、MECOM、MEF2C、MEF2D、MEGF10、MEGF11、MEMO1、MET、MGA、MG AM、MGAT4A、MGAT5、MGC16169、MGC34774、MKKS、MIB1、MIER2、MITF、MKL2、ML ANA、MLH1、MLL5、MLX、MME、MPDZ、MPI、MRAP2、MRPL11、MRPL39、MRPS28、MRPS3 5、MS4A13、MSH2、MSH3、MSMB、MST1R、MTDH、MTERF3、MTF1、MTF2、MTIF2、MTHF R、MUC2、MUT、MVK、MYB、MYBL2、MYC、MYCBP2、MYH2、MYRF、MYT1、MY019、MY03A、 MY09B、MYOM2、MYOM3、NAG、NARG1、NARG2、NCOA1、NDC80、NDFIP2、NEB、NEDD4 、NEK1、NEK5、ΝΕΚ11、NF1、NF2、NFATC2、NFE2L2、NFIA、NFIB、NFIX、NFKB1、NFK B2, NFKBIL2, NFRKB, NFYA, NFYB, NIPA2, NKAIN2, NKAP, NLRC3, NLRC5, NLRP3, NLRP7, NLRP8, NLRP13, NME1, NME1-NME2, NME2, NME7, NOL10, NOP561, NOS1NOS2A, 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、PAN2 PAOX、PAPOLG、PARD3、PARP1、PARVB、PAWR、PAX3、PAX8、PBGD、PBRM1、PBX2、PCBP4、PCCA、PCGF2、PCNX、PCOTH、PDCD4、PDE4D、PDE8B、PDE10A、PD1A3、PDH1、 PDLIM5、PDXK、PDZRN3、PELI2、PDK4、PDS5A、PDS5B、PGK1、PGM2、PHACTR4、PHEX、PHKB、PHLDB2、PHOX2B、PHTF1、PIAS1、PIEZO1、PIGF、PIGN、PIGT、PIK3C2 G、PIK3CA、PIK3CD、PIK3CG、PIK3RI、PIP5K1A、PITRM1、PIWIL3、PKD1、PKHD1L1、PKD2、PKIB、PKLR、PKM1、PKM2、PLAGL2、PLCB1、PLCB4、PLCG1、PLD1、PLEKH A5, 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, PRRG 2、PRUNE2、PSD3、PSEN1、PSMAL、PTCH1、PTEN、PTK2、PTK2B、PTPN2、PTPN3、PTPN4、PTPN11、PTPN22、PTPRD、PTPRK、PTPRM、PTPRN2、PTPRT、PUS10、PVRL2、PY GM、QRSL1、RAB11FIP2、RAB23、RAF1、RALBP1、RALGDS、RB1CC1、RBL2、RBM39、RBM45、RBPJ、RBSN、REC8、RELB、RFC4、RFT1、RFTN1、RHOA、RHPN2、RIF1、RIT1RLN3、RMND5B、RNF11、RNF32、RNFT1、RNGTT、ROCK1、ROCK2、RORA、RP1、RP6KA3、RP11-265F1、RP13-36C9、RPAP3、RPN1、RPGR、RPL22、RPL22L1、RP6KA6、R REB1、RRM1、RRP1B、RSK2、RTEL1、RTF1、RUFY1、RUNX1、RUNX2、RXRA、RYR3、SAAL1、SAE1、SALL4、SAT1、SATB2、SBCAD、SCN1A、SCN2A、SCN3A、SCN4A、SCN5A、S CN8A, SCNA, SCN11A, SCO1, SCYL3, SDC1, SDK1, SDK2, SEC24A, SEC24D, SEC31A, SEL1L, SENP3, SENP6, SENP7, SERPINA1, SETD3, SETD4, SETDB1, SEZ6, SFRS12, SGCE, SGOL2, SGPL1, SH2D1A, SH3BGRL2, SH3PXD2A, SH3PXD2B, SH3RF2, SH3TC2, SHOC2, SIPA1L2, SIPA1L3, SIVA1, SKAP1, SKIV2L2, SLC6A11, SLC6A1 3、SLC6A6、SLC7A2、SLC12A3、SLC13A1、SLC22A17、SLC25A14、SLC28A3、SLC33A1、SLC35F6、SLC38A1、SLC38A4、SLC39A10、SLC4A2、SLC6A8、SMARCA1、SMA RCA2、SMARCA5、SMARCC2、SMC5、SMN2、SMOX、SMS、SMTN、SNCAIP、SNORD86、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、STAMBPLI、 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、TBPL1、TB R1、TBX、TCEB3、TCF3、TCF4、TCF7L2、TCFL5、TCF12、TCP11L2、TDRD3、TEAD1、T EAD3, TEAD4, TECTB, TEK, TERF1, TERF2, TET2, TFAP2A, TFAP2B, TFAP2C, TFAP4, TFDP1, TFRC, TG, TGM7, TGS1, THAP7, THAP12, THOC2, TIAL1, TIAM2, TIMM5 0、TLK2、TM4SF20、TM6SF1、TMEM27、TMEM77、TMEM156、TMEM194A、TMF1、TMPR SS6、TNFRSF10A、TNFRSF10B、TNFRSF8、TNK2、TNKS、TNKS2、TOM1L1、TOM1L2、T OP2B、TP53、TP53INP1、TP53BP2、TP53I3、TP63、TRAF3IP3、TRAPPC2、TRIM44 、TRIM65、TRIML1、TRIML2、TRPM3、TRPM5、TRPM7、TRPS1、TSC1、TSC2、TSHB、TS PAN7、TTC17、TTF1、TTLL5、TTLL9、TTN、TTPAL、TTR、TUSC3、TXNDC10、UBE3A、 UCK1、UGT1A1、UHRF1BP1、UNC45B、UNC5C、USH2A、USF2、USP1、USP6、USP18、US P38、USP39、UTP20、UTP15、UTP18、UTRN、UTX、UTY、UVRAG、UXT、VAPA、VEGFA、 VPS29、VPS35、VPS39、VT11A、VT11B、VWA3B、WDFY2、WDR16、WDR17、WDR26、WDR 44, WDR67, WDTC1, WRN, WRNIP1, WT1, WWC3, XBP1, XRN1, XRN2, XX-FW88277, YAP1, YARS, YBX1, YGM, YY1, ZBTB18, ZBTB20, ZC3HAV1, ZC3HC1, ZC3H7A, ZDHHC 19、ZEB1、ZEB2、ZFPM1、ZFYVE1、ZFX、ZIC2、ZNF37A、ZNF91、ZNF114、ZNF155、 ZNF169、ZNF205、ZNF236、ZNF317、ZNF320、ZNF326、ZNF335、ZNF365、ZNF367、These include ZNF407, ZNF468, ZNF506, ZNF511, ZNF511-PRAP1, ZNF519, ZNF521, ZNF592, ZNF618, ZNF763 and ZWINT.

[0223] 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、AHDC1、AHI1、AH NAK、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、AL590556.3、LINC00339、CDC42、ALAS1、ALB、ALDH16A1、ALD H1B1、ALDH3A1、ALDH3B2、ALDOA、ALKBH2、ALPL、AMD1、AMICA1、AMN1、AMOTL2、AMY1B、AMY2B、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、AL603965.1、AOC3、AP000304.12、CRYZL1、AP000311.1、CRYZL1、AP000893.2、RAB30 、AP001267.5、ATP5MG、AP002495.2、AP003175.1、OR2AT4、AP003419.1、CLCF1、AP005263.1、ANKRD12、AP006621.5、AP006621.1, AP1G1, AP3M1, AP3M2, APBA2, APBB1, APLP2, APOA2, APOL1, APOL3, APTX, ARAP1, STARD10, ARF4, ARFIP1, ARFIP2, ARFRP1, AHRGAP11A, AHRGAP33, AHRGAP4, AHRGEF10, AHRGEF3, AHRGEF35, OR2A1-AS1, AHRGEF35, OR2A1-AS1, AHRGEF34P, ARID1B, AHRGEF35, OR2A20P, OR2A1-AS1, AHRGEF9, AR L1, ARL13B, ARL16, ARL6, ARMC6, ARMC8, ARMCX2, ARMCX5, RP4-769N13.6, ARMCX5-GPRASP2, BHLHB9, ARMCX5-GPRASP2, GPRASP1, ARMCX5-GPRASP2, GPRASP2, ARMCX6, ARNT2, ARPP19, ARRB2, ARSA, ART3, ASB3, GPR75-ASB3, ASCC2, ASNS, AC079781.5, ASPSCRI1, ASS1, ASUN, ATE1, ATF1, ATF 7IP2、ATG13、ATG4D、ATG7、ATG9A、ATM、ATOX1、ATP1B3、ATP2C1、ATP5F1A 、ATP5G2、ATP5J、ATP5MD、ATP5PF、ATP6AP2、ATP6V0B、ATP6V1C1、ATP6V1D 、ATP7B、ATXN1、ATXN1L,IST1、ATXN3、ATXN7L1、AURKA、AURKB、AXDND1、B 3GALNT1、B3GALT5,AF064860.1、B3GALT5,AF064860.5、B3GNT5、B4GALT3 、B4GALT4、B9D1、BACH1、BAIAP2、BANF1、BANF2、BAX、BAZ2A、BBIP1、BCHE 、BCL2L14、BCL6、BCL9L、BCS1L、BDH1、BDKRB2,AL355102.2、BEST1、BEST3 、BEX4、BHLHB9、BID、BIN3、BIRC2、BIVM、BIVM-ERCC5、BIVM、BLCAP、BLK、 BLOC1S1、RP11-644F5.10、BLOC1S6、AC090527.2、BLOC1S6、RP11-96O20.4、BLVRA、BMF、BOLA1、BORCS8-MEF2B、BORCS8、BRCA1、BRD1、BRDT、BRINP3、BROX、BTBD10、BTBD3、BTBD9、BTD、BTF3L4、BTNL9、BUB1B-PAK6、PAK6、BUB3、C10orf68、C11orf1、C11orf48、C11orf54、C11orf54,AP001273.2、C11orf5 7、C11orf63、C11orf82、C12orf23、C12orf4、C12orf65、C12orf79、C14orf159、C14orf93、C17orf62、C18orf21、 C19orf12、C19orf40、C19orf47、C19orf48、C19orf54、C1D、C1GALT1、C1QB、C1QTNF1、C1S、C1orf101、C1orf112、C 1orf116、C1orf159、C1orf63、C2、C2,CFB、C20orf27、C21orf58、C2CD4D、C2orf15、LIPT1、MRPL30、C2orf80、C2o rf81、C3orf14、C3orf17、C3orf18、C3orf22、C3orf33、AC104472.3、C4orf33、C5orf28、C5orf34、C6orf118、C6orf f203、C6orf211、C6orf48、C7orf50、C7orf55、C7orf55-LUC7L2、LUC7L2、C8orf44-SGK3、C8orf44、C8orf59、C9,D AB2、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、R P11-977G19.10、CSAD、CSDE1、CSF2RA、CSGALNACT1、CSK、CSNK2A1、CSRNP2、CT45A4、CT45A4、CT45A5、CT45A6、CT BP2、CTCFL、CTD-2116N17.1、KIAA0101、CTD-2349B8.1、SYT17、CTD-2528L19.4、ZNF607、CTD-2619J13.8、ZNF49 7、CTNNA1、CTNNBIP1、CTNND1、CTPS2、CTSB、CTSL、CTTN、CUL2、CUL9、CWC15、CXorf40B、CYB561A3、CYBC1、CYLD、CY P11A1、CYP2R1、CYP4B1、CYP4F22、DAG1、DAGLB,KDELR2、DARS、DBNL、DCAF11、DCAF8,PEX19、DCLRE1C、DCTD、DCTN 1、DCTN4、DCUN1D2、DDR1、DDX11、DDX19B、AC012184.2、DDX19B、RP11-529K1.3、DDX25、DDX39B、ATP6V1G2-DDX39 B, 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 SP18、DUSP22、DYDC1、DYDC2、DYNLL1、DYNLT1、DYRK1A、DYRK2、DYRK4、RP11-500M8.7、DZIP1L、E2F6 、ECHDC1、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, ENC1, ENDOV, ENO1, ENPP5, ENTHD2, ENTPD6, EP400NL, EPB41L1, EPDR1, NME8, EPHX1, EPM2A, EPN1, EPN2, EPN3, EPS8L2, ERBB3, ERC1, ERCC1, ERG, ERI2, ERI2, DCUN1D3, ERLIN2, ERMARD, ERRFI1, ESR2,RP11-544I20.2、ESRRA、ESRRB、ESRRG、ETFA、ETFRF1、ETV1、ETV4、ETV7 、EVA1A、EVC2、EVX1、EXD2、EXO5、EXOC1、EXOC2、FAAP24、FABP6、FADS1、 FADS2、FAHD2B、FAM107B、FAM111A、FAM111B、FAM114A1、FAM114A2、FAM 115C、FAM115C、FAM115D、FAM120B、FAM133B、FAM135A、FAM153A、FAM15 3B、FAM154B、FAM156A、FAM156B、FAM168B、FAM172A、FAM182B、FAM192A 、FAM19A2、FAM200B、FAM220A、FAM220A、AC009412.1、FAM222B、FAM227 B, FAM234A, AC004754.1, FAM3C, FAM45A, FAM49B, FAM60A, FAM63A, FAM81A, FAM86B1, FAM86B2, FANCI, FANK1, FAR2, FAXC, FAXDC2, FBF1, FBH1 FBXL4、FBXO18、FBXO22、FBXO31、FBXO41、FBXO44、FBXO45、FBXW9、FCHO 1、FCHSD2、FDFT1、FDPS、FER、FETUB、FGD4、FGF1、FGFR1、FGFRL1、FGL1、 FHL2、FIBCD1、FIGNL1、FIGNL1,DDC、FKBP5、FKRP、FLRT2、FLRT3、FMC1、 LUC7L2、FMC1-LUC7L2、FNDC3B、FOLH1、FOLR1、FOXP1、FOXK1、FOXM1、FO XO1, FOXP4, AC097634.4, FOXRED1, FPR1, FPR2, FRG1B, FRS2, FTO, FTSJ 1、FUK、FUT10、FUT3、FUT6、FXYD3、FZD3、G2E3、GAA、GABARAPL1、GABPB1 、GABRA5、GAL3ST1、GALE、GALNT11、GALNT14、GALNT6、GAPVD1、GARNL3、 GAS2L3、GAS8、GATA1、GATA2、GATA4、GBA、GCNT1、GDPD2、GDPD5、GEMIN7,MARK4、GEMIN8、GGA3、GGACT、AL356966.1、GGPS1、GHRL、GID8、GIGYF2、GIMAP8、GIPC1、GJB1、GJB6、GLB1L、GLI1、GLT8D 1、GMFG、GMPR2、GNAI2、GNAQ、GNB1、GNB2、GNE、GNG2、GNGT2、GNPDA1、GNPDA2、GOLGA3、CHFR、GOLGA4、GOLPH3L、GOLT1B、G PBP1L1、GPER1、GPR116、GPR141、EPDR1、GPR155、GPR161、GPR56、GPR63、GPR75-ASB3、ASB3、GPR85、GPSM2、GRAMD1B、GR B10、GRB7、GREM2、GRIA2、GSDMB、GSE1、GSN、GSTA4、GSTZ1、GTDC1、GTF2H1、GTF2H4、VARS2、GTF3C2、GUCY1A3、GUCY1B3、G UK1, GULP1, GYPC, GYS1, GZF1, HAGH, HAO2, HAPLN3, HAVCR1, HAX1, HBG2, AC104389.4, HBG2, AC104389.4, HBE1, HBG2, AC104389.4, HBE1, OR51B5, HBG2, HBE1, AC104389.28, HBS1L, HCFC1R1, HCK, HDAC2, HDAC6, HDAC7, HDLBP, HEATR4, HECTD 4、HEXIM2、HHAT、HHATL、CCDC13、HINFP、HIRA、C22orf39、HIVEP3、HJV、HKR1、HLF、HMBOX1、HMGA1、HMGB3、HMGCR、HMGN4 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F12、KIF14、KIF27、KIF9、KIFC3、KIN、KIRREL1、KITLG、KLC1、APOPT1、A L139300.1、KLC4、KLHDC4、KLHDC8A、KLHL13、KLHL18、KLHL2、KLHL24、 KLHL7、KLK11、KLK2、KLK5、KLK6、KLK7、KNOP1、KRBA2、AC135178.2、KRB A2, RP11-849F2.7, KRIT1, KRT15, ​​KRT8, KTN1, KXD1, KYAT3, RBMXL1, KYNU, L3MBTL1, LACC1, LARGE, LARP4, LARP7, LAT2, LBHD1, LCA5, LCA5L, L CTL、LEPROTL1、LGALS8、LGALS9C、LGMN、LHFPL2、LIG4、LIMCH1、LIMK2 、LIMS2、LINC00921、ZNF263、LIPF、LLGL2、LMAN2L、LMCD1、LMF1、RP11- 161M6.2、LMO1、LMO3、LOXHD1、LPAR1、LPAR2、LPAR4、LPAR5、LPAR6、LP HN1、LPIN2、LPIN3、LPP、LRFN5、LRIF1、LRMP、LRRC14、LRRC20、LRRC24、 C8orf82、LRRC39、LRRC42、LRRC48、LRRC4C、LRRC8A、LRRC8B、LRRD1、LRTOMT、LRTOMT、AP000812.5、LSM7、LTB4R、LTBP3、LUC7L2、FMC1-LUC7L 2、LUC7L3、LUZP1、LYG1、LYL1、LYPD4、LYPD6B、LYRM1、LYRM5、LYSMD4、M ACC1、MAD1L1、MAD1L1、AC069288.1、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, SNHG4, MB, MBD5, MBNL1, MBOAT7, MCC, M CFD2、MCM9、MCOLN3、MCRS1、MDC1、MDGA2、MDH2、MDM2、ME1、MEAK7、MECR、MED4、MEF2A、MEF2B,BORCS8-MEF2B、MEF2BNB-MEF 2B、MEF2B、MEF2BNB、MEF2C、MEF2D、MEGF10、MEI1、MEIS2、MELK、MET、METTL13、METTL23、MFF、MFN2、MFSD2A、MGST3、MIB2、MI CAL1、MICAL3、MICOS10、NBL1,MICOS10-NBL1、MID1、MINA、MINOS1-NBL1,MINOS1、MIOS、MIPOL1、MIS12、MKLN1、MKNK1、MKN MRO MROH1、MROH7-TTC4、MROH7、MRPL14、MRPL24、MRPL33,BABAM2、MRPL33、BRE、MRPL47、MRPL48、MRPL55、MRRF、MRTFA、MRTFB、 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、N 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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. 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TON1-GTF2A1L、STRAP、STRBP、STRC、AC011330.5、STRC、CATSPER2、STRC、CATSPER2、AC011330.5、STRC、STRCP1、STT3A、STX16-NPEPL1、NPEP L1、STX5、STX6、STX8、STXBP6、STYK1、SULT1A1、SULT1A2、SUMF2、SUN1、 SUN2、SUN2、DNAL4、SUOX、SUPT6H、SUV39H2、SV2B、SYBU、SYNCRIP、SYNJ 2、SYT1、SYTL4、TAB2、TACC1、TADA2B、TAF1C、TAF6,AC073842.2、TAF6 、RP11-506M12.1、TAF9、TAGLN、TANK、TAPSAR1,PSMB9、TAPT1、TATDN1、 TAZ、TBC1D1、TBC1D12、HELLS、TBC1D15、TBC1D3H、TBC1D3G、TBC1D5、TB C1D5,SATB1、TBCA、TBCEL、TBCEL、AP000646.1、TBL1XR1、TBP、TBX5、TB XAS1、TCAF1、TCEA2、TCEAL4、TCEAL8、TCEAL9、TCEANC、TCEB1"TCF19、 TCF25、TCF4、TCP1、TCP10L、AP000275.65、TCP11、TCP11L2、TCTN1、TDG 、TDP1、TDRD7、TEAD2、TECR、TENC1、TENT4A、TEX264、TEX30、TEX37、TFD P1、TFDP2、TFEB、TFG、TFP1,TF、TFPI、TGIF1、THAP6、THBS3、THOC5、THR AP3、THUMPD3、TIAL1、TIMM9、TIMP1、TIRAP、TJAP1、TJP2、TK2、TLDC1、T LE3、TLE6、TLN1、TLR10、TM9SF1、TMBIM1、TMBIM4、TMBIM6、TMC6、TMCC1 、TMCO4、TMEM126A、TMEM139、TMEM150B、TMEM155、TMEM161B、TMEM164、TMEM168、TMEM169、TMEM175、TMEM176B、TMEM182、TMEM199,CTB-96E2.3、TMEM216、TMEM218、TMEM230、TMEM263、TMEM45A、TMEM45B、TMEM62、TMEM63B、TMEM66、TMEM68、TMEM98、TMEM9B、TMPRSS11D、TMP RSS5、TMSB15B、TMTC4、TMUB2、TMX2-CTNND1、RP11-691N7.6,CTNND1、TNFAIP2、TNFAIP8L2、SCNM1、TNFRSF10C、TNFRSF19、TNFRSF 8、TNFSF12-TNFSF13、TNFSF12、TNFSF13、TNFSF12-TNFSF13、TNFSF13、TNIP1、TNK2、TNNT1、TNRC18、TNS3、TOB2、TOM1L1、TOP1MT、 TRAP PC3、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、TSPA N6、TSPAN9、TSPO、TTC12、TTC23、TTC3、TTC39A、TTC39C、TTLL1、TTLL7、TTPAL、TUBD1、TWNK、TXNL4A、TXNL4B、TXNRD1、TYK2、U2AF1 、UBA2、UBA52、UBAP2、UBE2D2、UBE2D3、UBE2E3、UBE2I、UBE2J2、U BE3A、UBL7、UBXN11、UBXN7、UGDH、UGGT1、UGP2、UMAD1,AC007161.3、UNC45A、UQCC1、URGCP-MRPS24,URGCP、USMG5、USP16、USP21、USP 28、USP3、USP33、USP35、USP54、USP9Y、USPL1、UTP15、VARS2、VASH2、 VAV3、VDAC1、VDAC2、VDR、VEZT、VGF、VIL1、VILL、VIPR1、VPS29、VPS 37C、VPS8、VPS9D1、VRK2、VWA1、VWA5A、WARS、WASF1、WASHC5、WBP5、W DHD1、WDPCP、WDR37、WDR53、WDR6、WDR72、WDR74、WDR81、WDR86、WDY HV1、WFDC3、WHSC1、WIPF1、WSCD2、WWP2、XAGE1A、XAGE1B、XKR9、XPNP EP1、XRCC3、XRN2、XXYLT1、YIF1A、YIF1B、YIPF1、YIPF5、YPEL5、YWH AB、YWHAZ、YY1AP1、ZBTB1、ZBTB14、ZBTB18、ZBTB20、ZBTB21、ZBTB25 、ZBTB33、ZBTB34、ZBTB38、ZBTB43、ZBTB49、ZBTB7B、ZBTB7C、ZBTB8 OS、ZC3H11A、ZBED6、ZC3H13、ZCCHC17、ZCCHC7、ZDHHC11、ZDHHC13、Z EB2、ZFAND5、ZFAND6、ZFP1、ZFP62、ZFX、ZFYVE16、ZFYVE19、ZFYVE2 0、ZFYVE27、ZHX2、AC016405.1、ZHX3、ZIK1、ZIM2,PEG3、ZKSCAN1、ZK SCAN3、ZKSCAN8、ZMAT3、ZMAT5、ZMIZ2、ZMYM6、ZMYND11、ZNF10,AC0 26786.1、ZNF133、ZNF146、ZNF16、ZNF177、ZNF18、ZNF200、ZNF202、Z NF211、ZNF219、ZNF226、ZNF227、ZNF23、AC010547.4、ZNF23、AC010 547.9、ZNF239、ZNF248、ZNF25、ZNF253、ZNF254、ZNF254、AC092279.1, ZNF263, ZNF274, ZNF275, ZNF28, ZNF468, ZNF283, ZNF287, ZNF3, ZNF320, ZNF322, ZNF324B, ZNF331, ZNF334, ZNF34, ZNF 350, ZNF385A, ZNF395, FBXO16, ZNF415, ZNF418, ZNF43, ZNF433-AS1, AC008770.4, ZNF438, ZNF444, ZNF445, ZNF467, ZNF48 0, ZNF493, ZNF493, CTD-2561J22.3, ZNF502, ZNF507, ZNF512, AC074091.1, ZNF512, RP11-158I13.2, ZNF512B, ZNF512B, SA MD10, ZNF521, ZNF532, ZNF544, AC020915.5, ZNF544, CTD-3138B18.4, ZNF559, ZNF177, ZNF562, ZNF567, ZNF569, ZNF570, Z NF571-AS1,ZNF540,ZNF577,ZNF580,ZNF581,ZNF580,ZNF581,CCDC106,ZNF600,ZNF611,ZNF613,ZNF615,ZNF619,ZNF620 , ZNF639, ZNF652, ZNF665, ZNF667, ZNF668, ZNF671, ZNF682, ZNF687, ZNF691, ZNF696, ZNF701, ZNF706, ZNF707, ZNF714, ZN These genes include F717, 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.

[0224] In some embodiments, the gene encoding the target sequence comprises the HTT gene.

[0225] 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.

[0226] 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、AACgugguguu、AACguuggua、AAGgcaaauu、AAGgcaagag、AAGgcaagau、AAGgcaag cc、AAGgcaagga、AAGgcaaggg、AAGgcaagug、AAGgcaaguu、AAGgcacugc、AAGgcagaaa、AAGgcaggau、AAGgcaggca、AAGgcaggga、AAGgcagggg、AAGgcaggua、AAGgcaggug、AAGgcaucuc、AAGgcaugcu、AAGgcaugga、AAGgcauguu、AAGgcauuau、AAGgcgagcu、AAGgcgaguu、AAGgcuagcc、AAGguaaaaa、AAGgu aaaac, AAGguaaaag, AAGguaaaau, AAGguaaaca, AAGguaaacc, AAGguaaacu, AAGguaaaga, AAGguaaagc, AAGguaaagg, AAGguaaagu, AAGguaaaua, AAGguaaauc, AAGguaaaug, 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, AAGguaauagc,AAGguaaugg, AAGguaaugu, AAGguaauua, AAGguaauuc, AAGguaauug, AAGguaauuu, AAGguacaaa, AAGguacaag, AAGguacaau, AAGguacacc, AAGguacacu, AAGguacagg, AAGguacagu, 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, AAGguagca, AAGguagacuu, AAGguagagu, AAGguagaua, AAGguagca, AAGguagacuu, AAGguagaaa, AAGguagaac, AAGguagaca, AAGguagacc, AAGguagacu, AAGguagagu, AAGguagaua, AAGguagca, AAGguagacuu, AAGguagagu, AAGguagacaa, AAGguagca, AAGguagagu, AAGguagacaa, AAGguagca, AAGguagagu, AAGguagaguaga, AAGguagaca, AAGguagacu, AAGguagagu, AAGguagagua agcag, AAGguagcca, AAGguagccu, AAGguagcua, AAGguagcug, AAGguagcuu, AAGguaggaa, AAGguaggag, AAGguaggau, AAGguaggca, AAGguaggcc, AAGguaggcu, AAGguaggga, AAGguagggc, AAGguagggg, AAGguagggu, AAGguaggua, AAGguagguc, AAGguaggug, AAGguagguu, AAGguaguaa, AAGguaguag, AAGguagucu, AAGguagugc, AAGguagugg, AAGguaguuc, AAGguaguuu, AAGguauaaa, AAGguauaau, AAGguauaca, AAGguauacu, AAGguauaua, AAGguauauc, AAGguauaug, AAGguauauu, AAGguaucac, AAGguaucag, AAGguauccc, AAGguauccu, AAGguaucuc, AAGguaucug, AAGguaucuu, AAGguaugaa, AAGguaugac, AAGguaugauga, AAGguaugau,AAGguaugca, AAGguaugcc, AAGguaugcu, AAGguaugga, AAGguauggc, AAGguauggg, AAGguaugua, AAGguauguc, AAGguaugug, AAGguauguu, AAGguauuaa, AAGguauuac, AAGguauuag, AAGguauuau, AAGguauucc, AAGguauuga, AAGguauugu, AAGguauuua, AAGguauuuc, AAGguauuug, AAGguauuuu, AAGgucaaau, AAGgucaaga, AAGgucaagu, AAGgucacag, AAGgucagaa, AAGgucagac, AAGgucagag, AAGgucagca, AAGgucagcc, AAGgucagcg, AAGgucagcu, AAGgucagga, AAGgucaggc, AAGgucaggu, AAGgucagua, AAGgucagu cccag, AAGgucccuc, AAGguccuuc, AAGgucgagg, AAGgucuaau, AAGgucuacc, AAGgucuaua, AAGgucucucu, AAGgucucug, AAGgucucuu, AAGgucugaa, AAGgucugag, AAGgucugga, AAGgucugga, AAGgucuggg, AAGgucugua, AAGgucuguu, AAGgucuucu, AAGgucuuuu, AAGgugaaac, AAGgugaaag, AAGgugaaau, AAGgugaacu, AAGgugaagc, AA Ggugaagg、AAGgugaagu、AAGgugaaua、AAGgugaaug、AAGgugaauu、AAGgugacaa、AAGgugacag、AAGgugacau、AAGgugacug、AAGgugacuu、AAGgugagaa、AAGgugagac、AAGgugagag、AAGgugagau、AAGgugagca、AAGgugagcc、AAGgugagcg、AAGgugagcu、AAGgugaga、AAGgugaggc、AAGgugaggg、AAGgugaggu、AAGgugagua、AAGgugaguc、AAGgugagug、AAGgugaguu、AAGgugauaa、AAGgugauca、AAGgugaucc、AAGgugauga、AAGgugaugc、AAGgugaugu、AAGgugauua、AAGgugauug、AAGgugauuu、AAGgugcaca、AAGgugcauc、AAGgugcccu、AAGgugccug、AAGgugcgug、AAGgugcguu、AAGgugcucc、AAGgugcuga、AAGgugcugcugg、AAGgugcu ua、AAGgugcuuu、AAGguggaua、AAGguggcua、AAGguggcug、AAGguggcuu、AAGgugggaa、AAGgugggag、AAGgugggau、AAGgugggca、AAGguggcc、AAGguggcg、AAGguggga、AAGgugggu、AAGgugggua、AAGgugggug、AAGgugguu、AAGguggguaa、AAGguguc、AAGguguu、AAGgugguggugg、AAGguguua、AAGguguuuc、AAGgu gguuu, AAGguguaag, AAGgugucaa, AAGgugucag, AAGgugucug, AAGgugugaa, AAGgugugag, AAGgugugca, AAGgugugga, AAGguguggu, AAGgugugua, AAGguguguc, AAGgugugugu, AAGguguucu, AAGguguugc, AAGguguugg, AAGguguuug, AAGguuaaaa, AAGguuaaca, AAGguuaagc, AAGguuaauu, AAGguuacau, AAGguuaagaa, AAGguuagau, AAGguuagca, AAGguuagcc, AAGguuagga, AAGguuaggc, AAGguuagua, AAGguuaguc, AAGguuagug, AAGguuaguu, AAGguuauaag, AAGguuauga, AAGguucaaa, AAGguucaag, AAGguuccuu, AAGguucgg, AAGguucguu, AAGguucuaa, AAGguucuga, AAGguucuua, AAGguugaau, AAGguugacu, AAGguugagg,AAGguugagu、AAGguugaua、AAGguugcac、AAGguugcug、AAGguuggaa、AAGguuggca、AAGguuggga、AAGguuggg、AAGguuggua、AAGguugguc、AAGgu、 uggug、AAGguugguu、AAGguugua、AAGguugucc、AAGguugugc、AAGguuguua、AAGguuuacc、AAGguuuaua、AAGguuuauu、AAGguuuccu、AAGguuucgu、AAGguuug A AGguuuugc、AAGguuuugu、AAGguuuuu、AAUgcaagua、AAUgcaaguc、AAUguaaaca、AAUguaaaua、AAUguaaauc、AAUguaaaug、AAUguaaaau、AAUguaacua、AAUg uaagaa、AAUguaagag、AAUguaagau、AAUguaagcc、AAUguaagcu、AAUguaagga、AAUguaagua、AAUguaaguc、AAUguaagug、AAUguaaguu、AAUguaauca、AAUguaau 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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, CAGguaacgu, CAGguaacua, CAGguaacuc, CAGguaacug, CAGguaacuu, CAGguaagaa, CAGguaagac, CAGguaaga, CAGguaagau, CAGgu aagcc、CAGguaagga、CAGguaaggc、CAGguaaggg、CAGguaaggu、CAGguaagua、CAGguaag、CAGguaaugu、CAGguaauaa、CAGguaauo、CAGguaaucc、CAGguaaugc、CAGguaaugg、CAGguaaugu、CAGguaauua、CAGguaauuc、CAGguaauug、CAGguaauuu、CAGguaaaa、CAGguacaag、CAGguacaau、CAGguacaca、CAGguacacg、CA Gguacaga、CAGguacagg、CAGguacagu、CAGguacaua、CAGguacaug、CAGguacauu、CAGguaccac、CAGguaccca、CAGguacccg、CAGguacccu、CAGguaccgc、CAGgua 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CAGguauuuc, CAGguauuug, CAGguauuuu, CAGgucaaca, CAGgucaaug, CAGgucacgu, CAGgucagaa, CAGgucagac, CAGgucagca, CAGgucagcc,CAGgucagcg, CAGgucagga, CAGgucagua, CAGgucaguc, CAGgucagug, CAGgucaguu, CAGgucaucc, CAGgucaugc, CAGgucauua, CAGgucauuu, CAGguccacc, CAGguccacu, CAGguccagu, CAGguccauc, CAGguccauu, CAGgucccag, CAGguccug, CAGguccuga, CAGguccugc, CAGguccugg, CAGgucggcc, CAGgucggug, CAGgucu C AGgucuucc、CAGguuuc、CAGgugaaau、CAGgugaaau、CAGgugaa、CAGgugaa、CAGgugaagg、CAGgugaaua、CAGgugaauc、CAGgugaaau、CAGgugaaaa、CAGgu gacau、CAGgugacca、CAGgugaccc、CAGgugaccg、CAGgugaccu、CAGgugacgg、CAGgugacua、CAGgacuc、CAGgugac、CAGgagagaa、CAGgugagac、CAGgugaga g、CAGgugagau、CAGgugagca、CAGgugagcc、CAGgugagcg、CAGgugagcu、CAGgugagga、CAGgugaggc、CAGgugaggg、CAGgugaggu、CAGgugagua、CAGgugaguc、CA Ggugagug, 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、CAGgugcgc、CAGgugcgga、CAGgugcggu、CAGgugcggu、CAGgug、 cgua、CAGgugcguc、CAGgugcgug、CAGgugcuag、CAGgugcuau、CAGgugcuca、CAGgugcucc、CAGgugcucg、CAGgugcugc、CAGgugcugg、CAGgugcuua、CAGgugcuu C AGgugggac, CAGgugggag, CAGgugggau, CAGgugggaca, CAGguggcc, CAGgugggcu, CAGguggga, CAGguggggc, CAGgugggggg, CAGgugggu, CAGgugggua, CAGgugguc, CAGguggug, CAGguggguu, CAGguggucu, CAGguggugg, CAGguguug, CAGguguaca, CAGguguagg, CAGguguauc, CAGgugucac, CAGgugucag, CAGguguc ca、CAGguguccu、CAGgugucua、CAGguguguc、CAGguguguc、CAGgugugaa、CAGgugugac、CAGgugugaa、CAGgugugau、CAGgugugca、CAGgugugcc、CAGgugugcg、CAGgugugcu、CAGgugugga、CAGgugugc、CAGgugugua、CAGgugugua、CAGgugugc、CAGgugugua、CAGguguua、CAGguuaaa、CAGguuaaua、CAGguuaauc、CAGg uuaccu、CAGguuagaa、CAGguuagag、CAGguuagau、CAGguuagcc、CAGguuagg、CAGguuaggu、CAGguuagua、CAGguuagc、CAGguuag、CAGguuagu、CAGguuag UcaCAGguuccca, CAGguucccg, CAGguucgaa, CAGguucgag, CAGguucuau, CAGguucugc, CAGguucuua, CAGguucuuc, CAGguucuuu, CAGguugaac, CAGguugaag, CAGguugagu, CAGguugaua, CAGguuggag, CAGguuggca, CAGguuggcc, CAGguugguc, CAGguuggug, CAGguugguu, CAGguuguaa, CAGguuguac, CAGguuguau, CAGguugu C AGuuugcu、CAGguuuugg、CAGguuugu、CAGguuugua、CAGguuugu、CAGguuugu、CAGguuuucu、CAGguuuugg、CAGguuuuuc、CAGguuuuuuu、CAUgcaggugu、CAUgu aaaac、CAUguaacua、CAUguaagaa、CAUguaagag、CAUguaagau、CAUguaagcc、CAUguaagua、CAUguaagug、CAUguaaguu、CAUguaauua、CAUguacaua、CAUguacca c. Ugugagua、CAUgugaguc、CAUgugagug、CAUgugaguu、CAUgugcgua、CAUgugggaa、CAUguggguu、CAUgugugugu、CAUguguguu、CAUguuaaua、CAUguuagcc、CCAgua agau、CCAguaagca、CCAguaagcc、CCAguaagcu、CCAguaagga、CCAguaagua、CCAguaaguc、CCAguaagug、CCAguaaguu、CCAguaauug、CCAguacggg、CCAguagguc、CCAguauugu, CCAGugaggc, CCAGugagua, CCAGugagug, CCAGuggguc, CCAGuguu, CCAguugagu, CCCguaagau, CCCguauguc, CCCguauguu, CCCguccugc, CCCgugagug, CCGguaaaga, CCGguaagau, CCGguaagcc, CCGguaagga, CCGguaaggc, CCGguaaugg, CCGguacagu, CCGguacuga, CCGguauucc, CCGgucagug, CCGgugaa aa、CCGgugagaa、CCGgugaggg、CCGgugagug、CCGgugaguu、CCGgugcgcg、CCGgugggcg、CCGguugguc、CCUguaaaug、CCUguaaauu、CCUguaagaa、CCUguaagac、C CCUguaagg、CCUguaagca、CCUguaagcg、CCUguaagga、CCUguaagu gagca, CCUgugaggg, CCUgugaguc, CCUgugagug, CCUgugaguu, CCUguggcuc, CCUgugggua, CCUgugugua, CCUguuagaa, CGAguaaggg, CGAguaaggu, CGAguagcug, CGAguaggug, CGAguagguu, CGAgugagca, CGCguaagag, CGGgcaggca, CGGguaagcc, CGGguaagcu, CGGguaaguu, CGGguaauuc, CGGguaauuu, CGGguacagu, CG Gguacggg、CGGguaggag、CGGguaggcc、CGGguaggug、CGGguauuua、CGGgucugag、CGGgugaccg、CGGgugacuc、CGGgugagaa、CGGgugaggg、CGGgugaggu、CGGgugagua、CGGgugagug、CGGgugaguu、CGGgugauuu、CGGgugccuu、CGGguggag、CGGguggug、CGGgugguu、CGGguguguc、CGGgugugug、CGGguguguu、CGGguucaag、CGGguucaug、CGGguuugcu、CGUguagggu、CGUguaugca、CGUguaugua、CGUgucugua、CGUgugagug、CGUguuuucu、CUAguaaaug、CUAguaagcg、CUAguaagcu、CUAg uaagua、CUAguaaguc、CUAguaagug、CUAguaaguu、CUAguaauuu、CUAguaggua、CUAguagguu、CUAguaugua、CUAguauguu、CUAgugagua、CUCguaagca、CUCguaag ug、CUCguaaguu、CUCguaucug、CUCgucugug、CUCgugaaua、CUCgugagua、CUCgugauua、CUGguaaaaa、CUGguaaaau、CUGguaaacc、CUGguaaacg、CUGguaaagc、C UGguaaaua、CUGguaaauc、CUGguaaaug、CUGguaaauu、CUGguaacc、CUGguaacag、CUGguaaccc、CUGguaaccg、CUGguaacug、CUGguaacuu、CUGguaagaa、CUGgu aagag、CUGguaagau、CUGguaagca、CUGguaagcc、CUGguaagcu、CUGguaagga、CUGguaaggc、CUGguaaggg、CUGguaaggu、CUGguaagua、CUGguaagg、CUGguaagu CU Gguacuaa, CUGguacuug, CUGguacuuu, CUGguagaga, CUGguagaua, CUGguagcgu, CUGguaggau, CUGguaggca, CUGguaggua, CUGguagguc, CUGguaggug, CUGguaucaa, CUGguaugau, CUGguauggc, CUGguauggu, CUGguaugua, CUGguaugug, CUGguauguu, CUGguauuga, CUGguauuuc, CUGguauuuu, CUGgucaaca, CUGgucagag,CUGgucccgc、CUGgucggua、CUGgucuggg、CUGgugaagu、CUGgugaaua、CUGgugaauu、CUGgugacua、CUGgugagaa、CUGgugagac、CUGgugagca、CUGgugagcu、CUGgugaga、CUGgugaggc、CUGgugaggg、CUGgugagaggu、CUGgugagua、CUGgugaguc、CUGgugagug、CUGgugaguu、CUGgugauua、CUGgugauuu、CUGgugcaga、CUGgugcg C UGgugggu、CUGguggugu、CUGguggugu、CUGguagcu、CUGguuggu、CUGguguggu、CUGguuggcu、CUGguugguuu、CUGguuugua、CUGguuugcu、CUGguuugu、CUUgu aaaug, CUUguaagcu, CUUguaagga, CUUguaaggc, CUUguaagua, CUUguaagug, CUUguaaguu, CUUguacguc, CUUguacgug, CUUguaggua, CUUguagugc, CUUguauagg, CUUgucugua, CUUgugagua, CUUgugaguc, CUUgugaguu, CUUgugguguu, CUUgugugua, CUUguuagug, CUUguuugag, GAAguaaaac, GAAguaaagc, GAAguaaagu, GA Aguaaaua、GAAguaaauu、GAAguaagaa、GAAguaagcc、GAAguaagcu、GAAguaagga、GAAguaagua、GAAguaagug、GAAguaaguu、GAAguaauo、GAAguaaugc、GAAguaauua、GAAaguaauuu、GAAguaccau、GAAguacgua、GAAguacguc、GAAguaggca、GAAguagguc、GAAaguaaaa、GAAguaugcu、GAAguaugug、GAAguauguu、GAAguauaua、GAAgucagug、GAAgugagag、GAAgugagcg、GAAgugaggu、GAAgugaguc、GAAgugagug、GAAgugaguu、GAAgugauaa、GAAgugauuc、GAAgugcgug、GAAguguggg、G、 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、GAGguu ugag、GAGguuugga、GAGguuuggg、GAGguuugua、GAGguuuguu、GAGguuuuca、GAGguuuuga、GAGguuuugg、GAGguuuuuua、GAGguuuuuc、GAUguaaau、GAUguaagca、GAUguaagcc、GAUguaaggu、GAUguaagua、GAUguaagug、GAUguaaguu、GAUguacauc、GAUguaggua、GAUguauggc、GAUguaugua、GAUguauguu、GAUgucagug、GAUg ugagag、GAUgugagcc、GAUgugagcu、GAUgugagga、GAUgugaguc、GAUgugagug、GAUgugaguu、GAUgugggua、GAUguggug、GAUguguguu、GAUguuagcu、GAUguuca gu, GAUguucgug, GAUguuuguu, GCAguaaagg, GCAguaagaa, GCAguaagga, GCAguaagua, GCAguaaguc, GCAguaaguu, GCAguagaug, GCAguaggua, GCAguaugug, GCAguauguu, GCAgucagua, GCAgucagug, GCAguccggu, GCAgugacuu, GCAgugagcc, GCAgugagcg, GCAgugagcu, GCAgugagua, GCAgugagug, GCAgugaguu, GCAgu gggua、GCAguuaagu、GCAguugagu、GCCguaaguc、GCCgugagua、GCGguaaagc、GCGguaaaua、GCGguaagcu、GCGguaaggg、GCGguaagug、GCGguaauca、GCGguacgu a. Ugcuguaa、GCUguaaaua、GCUguaagac、GCUguaagag、GCUguaagca、GCUguaagga、GCUguaagua、GCUguaaguc、GCUguaagug、GCUguaaguu、GCUguaggug、GCUguauggu、GCUgucagug、GCUguccuug、GCUgugagaa、GCUgugagcc、GCUgugagga、GCUgugagua、GCUgugaguc、GCUgugaguu、GCUgugguu、GGAguaagag、GGAguaagca、GGAguaagcc、GGAguaagcu、GGAguaagga、GGAguaagug、GGAguaaguu、GGAguaauuu、GGAguacugu、GGAguaggaa、GGAguaggua、GGAguagguu、GGAguaguau、GGAguaugac、GGAguauggu、GGAgucaagu、GGAgugaggg、GGAgugagua、GGAgugaguc、GGAgugagug、GGAgugaguu、GGAgugcuuu、GGAgugggca、GGAguggg ug、GGAguuaagg、GGAguugaga、GGCguaagcc、GGCguaggua、GGCguaggug、GGCgugagcc、GGCgugaguc、GGGguaaaca、GGGguaaacc、GGGguaaacu、GGGguaagaa、GGGguaagag、GGGguaagau、GGGguaagca、GGGguaagcc、GGGguaagcu、GGGguaagga、GGGguaaggg、GGGguaagua、GGGguaagug、GGGguaaguu、GGGguagaca、GGGgu aggag、GGGguaggcc、GGGguaggga、GGGguaggua、GGGguaggug、GGGguagguu、GGGguagugc、GGGguaucug、GGGguaugac、GGGguaugga、GGGguaugua、GGGguauguc、GGGguaugug、GGGguauguu、GGGgucagua、GGGguccgug、GGGgucggag、GGGgucugug、GGGgugaaca、GGGgugaaga、GGGgugagaa、GGGgugagau、GGGgugagcc、GGGgugagcg、GGGgugagcu、GGGgugagga、GGGgugaggc、GGGgugaggg、GGGgugaguc、GGGgugaguc、GGGgugaguc、GGGgugaguc、GGGgugagucgua、GGGgugggu、GGGgugggua、GGGguggug、GGGgugguu、GGGgugugcg、GGGgugugua、GGGgugugc、GGGguguuga、GGGguucag、GGGguuggac、GGGguugga、GGGguuugcc、GGGguuugua、GGUguaagaa、GGUguaagau, GGUguaagca, GGUguaagcc, GGUguaagcg, GGUguaaguc, GGUguaagug, GGUguagguc, GGUguaggug, GGUguagguu, GGUguccgua, GGUguga, gag、GGUgugagcc、GGUgugagcu、GGUgugagua、GGUgugaguc、GGUgugcuuc、GGUguggcug、GGUguggcug、GGUgugugcug、GGUgugaaa、GGUguugcug、GUUGUUAG 、GUAGUAGUAGUA、GUAGUAGUAGUA、GUAGUAGUAGUAGUA、GUAGUAGUAGUAGUA、GUAGUAGUAGUA、GUAGUAGUAGUAUM、GUAGUAGUAGUAUM、GUAGUAAUGUG、GUGUGAGU、GUAGUGA Cgugaguu、GUGgcaagua、GUGguaaaau、GUGguaaaau、GUGguaaaau、GUGguaaacau、GUGguaaaacau、GUGguaagaa、GUGguaagac、GUGGAG、GUGgua aagau、GUGguaagca、GUGguaagcg、GUGguaagcu、GUGguaaggc、GUGguaagc、GUGguaagua、GUGguaaguc、GUGguaagug、GUGguaagua、GUGGUAGUAAU、GUGGUAAUGAUS c. UGguauaaa、GUGguaucuc、GUGguaugaa、GUGguaugau、GUGguaugca、GUGguaugua、GUGguaugua、GUGguccgug、GUGgucuggc、GUGgugaaac、GUGgugagaa、GUGgugagaa ugagau、GUGgugagca、GUGgugagcu、GUGgugagga、GUGgugaggc、GUGgugagug、GUGgugaguu、GUGgugauua、GUGgugauuc、GUGgugcgau、GUGGGUGGUGUUA gaa、GUGgugggua、GUGguggguc、GUGguguccg、GUGguuagca、GUGguuaggu、GUGguuagug、GUGguuugca、GUGguuugua、GUUguaaggua、GUUguaagua、GUUagua、GUGUUguaaguu, GUUguaccac, GUUguagcgu, GUUguaugug, GUUguauguu, GUUgucugug, GUUgugagcu, GUUgugagug, GUUgugaguu, GUUgugggua, GUUguggguu, UAAguaaaug, UAAguaacua, UAAguaagaa, UAAguaagag, UAAguaagau, UAAguaagca, UAAguaagcu, UAAguaagga, UAAguaaggu, UAAguaagua, UAAguaaguc, UAAguaag ug、UAAguaaguu、UAAguaauaa、UAAguacuag、UAAguaguuu、UAAguauaaa、UAAguauaca、UAAguaugua、UAAguauuau、UAAguauuuu、UAAgucuuuuu、UAAgugagac、U AAgugagga、UAAgugagg、UAAgugagua、UAAgugaguc、UAAgugagug、UAAgugaguu、UAAgugaucc、UAAgugauuc、UAAgugcgug、UAAguuaagu、UAAguuccag、UAAgu ucuuu, UAAguuguaa, UAAguuguau, UAAguuuguu, UACguaacug, UACguaagaa, UACguaagau, UACguaagua, UACguaagug, UACguauccu, UACgucuggc, UACgugacca, UAGgcaagac, UAGgcaaguc, UAGgcagguc, UAGgcgugug, UAGguaaaaa, UAGguaaaac, UAGguaaaag, UAGguaaaau, UAGguaaaca, UAGguaaaga, UAGguaaaua, UAGguaaauc, UAGguaaaug, UAGguaaauu, UAGguaacac, UAGguaacag, UAGguaacau, UAGguaacca, UAGguaacgg, UAGguaacua, UAGguaacuc, UAGguaacug, UAGguaacuu, UAGguaagac, UAGguaagag, UAGguaagau, UAGguaagca, UAGguaagcc, UAGguaagcu, UAGguaagga, UAGguaaggc, UAGguaaggg, UAGguaagua, UAGguaaguc,UAGguaagug、UAGguaaguu、UAGguaauag、UAGguaauau、UAGguaaucu、UAGguaauga、UAGguaaugg、UAGguaaugu、UAGguaauua、UAGguaauuc、UAGguaauuu、UAGguacagc、UAGguacagu、UAGguacauu、UAGguaccag、UAGguaccua、UAGguaccuu、UAGguacgag、UAGguacgua、UAGguacguu、UAGguacuau、UAGguacuga、UAGguacugg、UAGguacuuc、UAGguacuuu、UAGguagcgg、UAGguaggaa、UAGguaggac、UAGguaggau、UAGguaggga、UAGguagggg、UAGguaggua、UAGguagguc、UAGguaggug、UAGguagguu、UAGguaguaa、UAGguagucu、UAGguagugg、UAGguagugu、UAGguaguuu、UAGguauaaa、UAGguauaac、UAGguauaag、UAGguauaau、UAGguauaca、UAGguauacu、UAGguauaua、UAGguauauc、UAGguauauu、UAGguaucag、UAGguaucua、UAGguaucuc、UAGguaugaa、UAGguaugag、UAGguaugca、UAGguaugga、UAGguauggc、UAGguauggu、UAGguaugua、UAGguauguc、UAGguaugug、UAGguauguu、UAGguauuaa、UAGguauuac、UAGguauuau、UAGguauuca、UAGguauucc、UAGguauucu、UAGguauuga、UAGguauuua、UAGguauuuc、UAGguauuuu、UAGgucacuc、UAGgucagcu、UAGgucaggu、UAGgucagua、UAGgucagug、UAGgucaguu、UAGgucaucu、UAGgucauug、UAGguccaau、UAGguccugu、UAGgucucaa、UAGgucucgc、UAGgucuggc、UAGgucuguc、UAGgucugug、UAGgugaagu、UAGgugaaua、UAGgugaaug、UAGgugaauu、UAGgugacau, UAGgugacca, UAGgugacua, UAGgugagaa, UAGgugagac, UAGgugagag, UAGgugagau, UAGgugagcc, UAGgugagcu, UAGgugagga, UAGgugaggc, UAGgugaggu, UAGgugagua, UAGgugaguc, UAGgugagug, UAGgugauca, UAGgugauuc, UAGgugauuu, UAGgugacaua, UAGgugcauc, UAGgugccgu, UAGgugccug, UAGgugcgca, UAGgugcgua, UAGgugcgug, UAGgugcuga, UAGgugaua, UAGgugggaa, UAGguggac, UAGguggag, UAGgugggau, UAGguggcc, UAGguggcu, UAGgugguu, UAGguguaa, UAGgugugaa, UAGgugugag, UAGguguga, UAGgugugca, UAGgugugcc, UAGgugugcg, UAGgugug, UAGgugugua, UAGgugug, UAGguguugg, UAGguguugg, UAGgu uaagc、UAGguuagac、UAGguuagcc、UAGguuaggc、UAGguuagua、UAGguuaguc、UAGguuagug、UAGguuccc、UAGguucuac、UAGguuggua、UAGguuggu、UAGguuguc c. Uguaagcc、UAUguaagua、UAUguaaguc、UAUguaagug、UAUguaaguu、UAUguacgug、UAUguacgu、UAUguagguc、UAUguagguu、UAUguauccu、UAUguaucuc、UAUgua ugua、UAUguauguc、UAUguaugug、UAUguauuau、UAUgucagaa、UAUgugugua、UAUgugaaua、UAUgugacag、UAUgugagua、UAUgugagug、UAUgugagu、UAUgugggca、UAUgugugua, UAUguguuua, UAUguuuugu, UCAgcgacau, UCAguaaaau, UCAguaaaua, UCAguaacug, UCAguaagaa, UCAguaagag, UCAguaagau, UCAguaagca, UCAguaagcc, UCAguaagcu, UCAguaaggg, UCAguaagua, UCAguaaguc, UCAguaagug, UCAguaaguu, UCAguaucuu, UCAguaugga, UCAguauggu, UCAgucccca, UCAgugagca, UCAgugagcu, UCAgugagua, UCAgugagug, UCAgugaguu, UCAgugauug, UCAgugggug, UCAguugagc, UCAguugauu, UCAguuuagu, UCCguaagca, UCCguaagcu, UCCguaaguc, UCCguaagug, UCCguaauag, UCCguacuua, UCCguauguu, UCCgugagau, UCCguaguaguc, UCCguaguaguc, UCCguaagag, UCCguaaguc, UCCguaguaguc, UCCguaguaguc, UCCguaguaguaguc, UCCguaguaguag, UCCguacuua, UCCguaugua, UCCguauguu, UCCgugagau, UCCgugaguc, UCCguaaauu, UCCguaagag, UCCguaagcu, UCCgu acauc、UCGguacucc、UCGguagacc、UCGguagguu、UCGguaguaa、UCGguaugug、UCGguauguu、UCGguauuga、UCGgucagua、UCGgucuuag、UCGguagau、UCGgugaga a. Uguaagcu、UCUguaagua、UCUguaaguc、UCUguaagug、UCUguaaguu、UCUguaauaa、UCUguaauga、UCUguaaugu、UCUguaggua、UCUguagguu、UCUguauaua、UCUguaugac、UCUguaugua、UCUguccucg、UCUgugagag、UCUgugagcu、UCUgugagag、UCUgugagua、UCUgugaguc、UCUgugagug、UCUgugaguu、UCUgugcgua、UCUgugugag、UGAguaacuu, UGAguaagau, UGAguaagca, UGAguaagcu, UGAguaaggc, UGAguaaggu, UGAguaagua, UGAguaaguc, UGAguaagug, UGAguaaguu, UGAguaaucc, UG, Aguaauua、UGAguacagu、UGAguacgua、UGAguacguu、UGAguacugu、UGAguagcug、UGAguaggua、UGAguauaa、UGAguagcu、UGAguauggu、UGAguaugua、UGAguauguc、UGAguauguu、UGAgucagag、UGAgucuacg、UGAguagaaua、UGAgugaagca、UGAgugagaa a. Cguaaguc、UGCguaagug、UGCguacggc、UGCguacggg、UGCguaugua、UGGcaaguc、UGGgcaagug、UGGcacauc、UGGgccacgu、UGGgccccgg、UGGguaaau、UGGgua aagc、UGGguaaagg、UGGguaaagu、UGGguaaaua、UGGguaaaug、UGGguaaauu、UGGguaacag、UGGguaacau、UGGguaacua、UGGguaacuu、UGGguaagaa、UGGguaagac、UGGguaagag、UGGguaagau、UGGguaagca、UGGguaagcc、UGGguaagcu、UGGguaaggg、UGGguaaggu、UGGguaagua、UGGguaaguc、UGGguaagug、UGGguaaguu、UGG guaaugu, UGGguaauua, UGGguaauuu, UGGguacaaa, UGGguacagu, UGGguacuac, UGGguaggga, UGGguagguc, UGGguaggug, UGGguagguu, UGGguaguua, UGGguauagu, UGGguaugaa, UGGguaugac, UGGguaugag, UGGguaugua, UGGguauguc, UGGguaugug, UGGguauguu, UGGguauuug, UGGgucuuug, UGGgugaccu, UGGgugacua,UGGgugagac、UGGgugagag、UGGgugagca、UGGgugagcc、UGGugagga、UGGgugaggc、UGGgugaggg、UGGgugagua、UGGgugaguc、UGGgugagu、UGGgugagu、UGGg ugcgug、UGGguggagg、UGGguggcuu、UGGgugggg、UGGgugggua、UGGgugguc、UGGguggug、UGGguggguu、UGGguggga、UGGgugguc、UGGguggug、UGGgugg uu, UGGguguuua, UGGguuaaug, UGGguuaguc, UGGguuagug, UGGguuaguu, UGGguucaag, UGGguucgua, UGGguuggug, UGGguuuaag, UGGguuugua, UGUgcaagua, UGUguaaaua, UGUguaagaa, UGUguaagac, UGUguaagag, UGUguaaggu, UGUguaagua, UGUguaaguc, UGUguaaguu, UGUguacuuc, UGUguaggcg, UGUguaggua, UGUgu aguua, UGUguaugug, UGUgucagua, UGUgucugua, UGUgucuguc, UGUgugaccc, UGUgugagau, UGUgugagca, UGUgugagagcc, UGUgugagua, UGUgugaguc, UGUgugagug, UGUgugugcgug, UGUgugggug, UGUgugguguu, UGUgugugag, UGUguguucu, UGUguuuaga, UUAguaaaua, UUAguaagaa, UUAguaagua, UUAguaagug, UUAguaaguu, UU Aguaggug, UUAgugagca, UUAgugaguu, UUAguuaagu, UUCguaaguc, UUCguaaguu, UUCguaauua, UUCgugagua, UUCgugaguu, UUGgcaagug, UUGgccgagu, UUGguaaaaa, UUGguaaaau, UUGguaaaga, UUGguaaagg, UUGguaaagu, UUGguaaauc, UUGguaaaug, UUGguaaauu, UUGguaacug, UUGguaacuu, UUGguaagaa, UUGguaagag,UUGguaagcu, UUGguaagga, UUGguaaggg, UUGguaagua, UUGguaagug, UUGguaaguu, UUGguaauac, UUGguaauca, UUGguaaugc, UUGguaaugu, UUGguaauug, UUGguaauuu, UUGguacaua, UUGguacgug, UUGguagagg, UUGguaggac, UUGguaggcg, UUGguaggcu, UUGguaggga, UUGguagua, UUGguagguc, UUGguaggug, UUGguaua aa、UUGguauaca、UUGguauauu、UUGguaucua、UUGguaucucuc、UUGguaugca、UUGguauguga、UUGguaugug、UUGguauguu、UUGguauugu、UUGguauuua、UUGguauuuu、UUGgucagaa、UUGgucagua、UUGgucucug、UUGgucugca、UUGgugaaaa、UUGgugacug、UUGgugagac、UUGgugagau、UUGgugagca、UUGgugagag、UUGgugaggg、UUGgu gagua、UUGgugaguc、UUGgugagug、UUGgugaguu、UUGgugaugg、UUGgugauua、UUGgugauug、UUGgugcaca、UUGgugggaa、UUGguggggaa、UUGguggggc、UUGgugggua、UUGgugguc、UUGgugggug、UUGgugguu、UUGguguggu、UUGguguguc、UUGgugug、UUGgugugug、UUGgugugug、UUGgugugug、UUGguguguu、UUGguuaagu、UUGguuagca、UUGguuagug、UUGguuaguu、UUGguuggga、UU Gguugguu, UUGguuugua, UUGguuuguc, UUUgcaagug, UUUguaaaua, UUUguaaug, UUUguaagaa, UUUguaagac, UUUguaagag, UUUguaagca, UUUguaaggu, UUUguaagua, UUUguaaguc, UUUguaagug, UUUguaaguu, UUUguaauuu, UUUguacagg, UUUguacgug, UUUguacuag, UUUguacugu, UUUguagguu, UUUguauccu, UUUguauguu,These include UUUgugagca, UUUgugagug, UUUgugcguc, UUUguguguc, and uGGguaccug.

[0227] 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、AUGgugagug、UAGguuugug、AACguaggac、GUAgcaggua、GAGgucagac、AGGguaugaa、GAGguuagug、CAGgcacgug、GGGgcaagac、CAGguguguc、CAGguauuga、CAGguauguc、AAGgcaaggu、UUGgugagaa、AAGguaaaau、GGGguaagua、AAGguaucuu、GACgugaguc、UAUguaugcu、AAGguacugu、CAGgugaacu、CACguaaaug、AAGgugugau、GAAguauuug、AAGgucugug、AAGguggagg、AAGguauaug、CAGguucuua、AGGguaacca、CAGgugucac、AAAguucugu、UUGgugaguu、CAAgugaguc、UAGguagguc、GCGgugagcu、AUUgugagga、CAGgugcaca、CAGguuggaa、CUGgucacuu、GGAguaagug、GAGgugggcu、AAGguacuug、AGGguaggau、AAUguguguu、ACAguuaagu、GAGgugugug、AAGgcgggcu、AUAgcaagua、AAGguuguua、CAAgcaaggc、GUGguaauua、UCUguucagu、AGGguaggcc、AAGguaucau、UAGguaccuu、AAGguaugac、GGAguaggua、UAAguuggca、AGUgugaggc、GAGguuugug、UGGgucugcu、CAGgugaucc、CAGgucagug、AAGguaaggg、CAGgugcagu、GAGguggguc、GCUgugagug、AAGguggagu、GGGgucaguu、AGCguaagug、AGAguaugaa、GGGguagggu、AAGgccagca、CGAguaugcc、GUGgugagcg、AAUguaaauu、CAGgugcgca、GGUguaugaa、CUUgugaguu、AAGguaucuc、AGAguaagga、UAGguaagac、GAGgugagug、CAGguguguu、UUGgugagua、AGGgcgaguu、CAGguuuugc、UUUgugaguu、AGGguaagca、GAGguccucu、CCAgcaggua、GAGguucgcg、CAGgugaucu、ACUguaagua、AAGguaaauc、CAGgcaaaua、GUGguaagca、CAGguuaaau、UUGguaauaa、UAUguaggua、CAGguaguau、AAGgugugcc、UGGguaagag、CAGgcaagca、UUGguaaggg、AAGgcaggug、ACGguaaaug、GCUgugagca、AUGguacaca、GUAguguguu、ACUguaagag、CCCgcagguc、GAGgugagcc、GAGgugcugu、UAAguaugcu、GAGgccaucu、UCAgugagug、CAGgugcuac、AAUgugggug、GAGgugugaa、CUGguagguc、GUGgcgcgcg、CAGgugcaaa、UAAguggagg、CAUgugggua、GAGguagggu、AAAgugaguu、AGGguucuag、UGUgugagcu、AGGgugaauc、CAGgucaggg、AAGgucccug、CUGguagagu、UAGgucaguu、AAAguaaggg、CAAguaugug、CAGgugcuuu、AAGguaauuc、GGGgugcacg、ACUgugcuac、CAGguaccua、CAGguagcuu、UGGgugaggc、CUGguacauu、AGGguaaucu、CAGguacaag、CAGguaauuc、AGGgcacuug、UAGgugagaa、GAGguaaugc、CCAgugaguu、AAAguaugug、CUGgugaauc、UAUguaugua、CCUgcaggug、CAGguaucug、GAGgugaggu、CUGguaaaac、UGUgugugcu、CAGguuaagu、CAGguaaucc、UAGguauuug、UGGguagguc、CAGguaacag、AGCgugcgug、AAGgucagga、GGUgugagcc、CUGguaagua、GGGgugggca、AAGgugggaa、CAGgugagug、CUGguuguua、CAGguaauag、UAGgugaguu、AGAguaaguu、UAGguaaucc、CCGgugacug、GUCgugauua、CUUguaagug、UAGguaguca、CUGguaaguc、AGGgugagcg、CAGguaugga、AUUgugacca、GUUgugggua、AAGguacaag、CUAgcaagug、CUGgugagau、CAGgugggca、AUGgcucgag、CUGguacguu、UUGgugugua、GAGgugucug、GAGgugggac、GGGgugggag、GCAgcgugag、GAGguaaaga、GAGguaugua、AAGgugagac、AAGguacaau、CUGguaugag、AACguaaaau、GUGguaggga、CUGguaugug、CUUguaagca、AAGguaggga、AUUguaagcc、AUGguaagcu、CAGgugaauu、UAGgugaaua、CAAguaugga、AUGguauggc、GAGgucaugc、CAGguacccu、ACAgugagac、CAGgucugau、GAAguugggu、CUGgugcgug、CAGguacgag、ACAgugagcc、AAGguaagua、GGAguaaggc、GAGgugugua、AAGgucauuu, CAGguagucu, AUGguaucug, AAGguaaacu, GAGguaggug, CUGguaagca, AGGguaagag, AAAguaaagc, CAGguuugag, GAGgcgggua, CGAguacgau, CAGg uuguug、AAAguauggg、UAGgcugguc、AAGguaagga、AAGguuuccu、UUGguaaaac、GAGguaagua、CAGguucaag、UGGguuaugu、GAGgugaguu、ACGgugaaac、GAUguaac ca、AAGguggcggg、CCGguacgug、GAUgugagaa、GUGgcgguga、CAGguauuag、GAGguuggga、AAGgcuagua、AAGgugggcg、CAGgcaggga、AAUguuaguu、GAGguaaagg、C AGgugugcu、CUGguaugau、AUGguuaguc、CUGgugagaa、CAGgccggcg、CAGgugacug、AAAguaaggu、UAAguacuug、AAGguaaagc、UCGguagggg、CAGguaggaa、AGUgu aagca、CCCgugagau、GUGguuguuu、CAGguuugcc、AGGguauggg、UAAguaagug、GAGguaagac、GAUguagguc、CAAguaggug、AUAguaaaua、GAGguugggg、GAGgcgagu a、CAGguagugu、GUGguaggug、CAAgugagug、AAGgugacaa、CCAgcguaau、ACGgugaggu、GGGguauauu、CAGgugagua、AAGgugcgug、UAUguaaauu、CAGgucagua、AC Gguacuua, GGgucagca, UAAguaugua, GGGgucagac, AAUgugugag, UCCgucagua, CAGgugcuuc, CCAguuagug, CCGgugggcg, AGGgugcaug, GGGguaggau, UAGgug ggcc、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、GAGgugauua、ACGguaaaua、AUGguaacug、CAGgcgcguu、CAGguauaga、AAGguuuguu、CAGguaugaa、UAGguuggua、CUGgugagac、CAGguuagga、AUGgugacug、UUGguauccc、CUUguaggac、AAAguguguu、CAGguuucuu、GGGguauggc、GGGguaggac、ACUguaaguc、AUCguaagcu、UAGguucccc、GGUgugagca、CUGguuggua、GGGguuaggg、UGAguaagaa、GAGguauucc、UGGguuaguc、CAGgcucgug、UAGguagagu、UAGgugcccu、AAAgugagua、GAGguucaua、UUGguaagag、ACCgugugua、UAUguaguau、UGGguaauag、CAGgucugaa、AAAguauaaa、GUGgugaguc、AGUgugauua、UUGgugugug、CAGgugaugg、GCUgugagua、CAGguacaug、AAGguacagu、GAAguuguag、CAGgugauua、UAGgugaauu、GGUguuaaua、CAGguauuua、CAAguacucg、CAAguaagaa、AAGguaccuu、ACGgugaggg、UGAgcaggca、GGGgugaccg、GAGguaaaug、CGGguuugug、AAGgugagcg、GUGguaugga、CUGguaagga、GAGguaccag、CCGgugagug、AAGguuagaa、GAGguaacuug、AGAguaaaac、UCUgugagua、AAGg cgggaa, CAGguaugcg, AGGguaaaac, AAGgugacug, AGGguauguu, AAGguaugua, CAGgucucuc, CAGgcaugua, CUGguaggua, AAGgucaugc, CAGguacaca, GAUguacg uu、ACAguacgug、ACGguaccca、CAGguagugc、ACAguaagag、GGUgcacacc、GAGguguaac、AAGgugugua、UAGguacuua、GCGguacugc、UGGguaaguc、CAUguagguaC AGguaggau, CAGgucuggc, GUGguuuuaa, CAGgugggaa, UGGgugagua, CGAgugagcc, AAGguauggc, AGUguuguca, CAGgugauuu, UAGguaucuc, UAAguauguu, AAGgu ugagc、AGAguaaaga、GGUguaagua、GGGgugagcu、CAGguauaau、GAGguacaaa、AUGguaccaa、UAGguagggg、UGAgucagaa、AAGgcaauua、UUGguaagau、CAGguacag a、AGAguuagag、CAGgugcguc、GAGguauuac、ACGguacaga、CAGgucuucc、AAGguaaggu、GAGguaauuu、AGUguaggcu、AAAguaagcg、CCUguaagcc、AGGgugauuu、UG There are many different types of characters in the film agug、AAAgugauga、UGCgugagua、AGAguaggga、UGUguaggua、UAGguaggau、UAAgugagug、GCUguaagua、GAAguaagaa、UCGgugaggc、UAGguauuuu、AAGguacaca、AAGguaggua, UGGguagguu, ACAgcaagua, GAGguaggag, UGGgugaguu, GCGgugagau, CCUguagguu, CAGgugugua, CUGguaagcc, AAGgugauuc, CAGguagcua, GUUg uaagug、AUGguaagca、AUAguaggga、GGGguucgcu、CCGgucagag、GUAguaugag、CGUguaagau、UGAguaggca、UCAguaugua、GAGguaucug、AGAguauuuu、AAGguugu ag、AGUguaaguu、CGGguaaguu、UCGgugcgga、UAGguaagua、GAAguuagau、GCUgugagac、CAGgcaggua、CAGguagggg、UAAguuaaga、AUGguggguu、UAGguaaguu、C UGguaaauu, CCGguaagga, GGgcaggca, CAUguaagug, AAGgugccua, UUGguaaggga, AAGguaaaca, CGGgugugag, GGGgugugag, UCCguggguc, ACGguaaauc, UCAgu aggua、CAGgucagcc、CAGgcggugg、CGAguaagcu、CCCgugagca、AAAguaauga、CUGguaagcu、CGGguaacca、CAGgucgcac、GAGguaggcc、UAGgugagcc、UAGguaggc a、GCGgugcgug、AUGgugagua、GGGgugaggg、GAGgucacac、CAGguaggcc、CAAgugcuga、GUCgucuuca、CAUguaagaa、GUAguaagga、UAGguuugua、CAAguuagag、AA Gguagagu, AAGgugagau, AAAguaggua, ACAgugaauc, CAGgugugcg, CAGgucggcc, AAGguaguau, ACUgucaguc, UCUgcagccu, CGAguaagug, AGAguaauua, AGUgug agug、CCGgugagcg、AAGguaaccu、AAGguugugg、AAGgcauggg、AAGgucagag、ACGguaaggu、GGGgugagca、GAGguugcuu、AAGguaucgc、CCGguaaagg、AAAguuaaug、UAGguacgag、ACCguaauua、GGGguaagga、CCGguaacgc、CAGgucagaa、AAGguacuga、GAGgugacca、GGGgugagcc、AAGguacagg、AUGguaauua、CAGgugagag、AAGgugacuc、AUAguaagua、GAGguaaacc、CAGgugggau、CAGgugagaa、AGGguaaaaa、GAGgugugac、CACguaagcu、CAGguccccc、CAGgucaggu、CGGguaaguc、ACGguauggg、GAUguaaguu、CAAguaauau、CAGguugggg、CCUgugcugg、AAGguaugau、AGGguagagg、AAGguggguu、CAGgugugaa、UUGguaugug、UUGguaucuc、GGGgugagug、CUGgugugug、AGGguagggc、GUGgugagua、CAGguaugua、AAGguacauu、UUAguaagug、AAUguauauc、CUUguaagua、GAGguuagua、CAGguaaggu、CAGguaaugu、AGGgugaggc、CAGguauuuc、CAGgucugga、GGGgugugcu、UAGgugagug、AAUguaaccu、UAAgugaguc、CAGgugcacu、ACGguaagua、GAGguauccu、UCUguaaguc、CAGguauuca、UGUguaagug、CCAgcaaggc、GAGgugaagg、AAUguggggu、UCGgugcgug、UUGguaaggc、GAGguaagug、AAAguaagau、UAGgucuuuu、GAGgucugau、CCAguuagag、UGGgugaaaa、AGAguaagau、CAGguaauug、CAGgccgguc、CCGguaagag、GAGgugagcu、CUGguaagac、CAGgugagau、CUGguuuguu、UGGguaggua、CAGguuagug、CAGguguucg、CGGguagguc、GUGguacaua、AAGguacuaa、GAUgugagua、UGUguaagac、GAGguagccg、UAGgugaucu、CAGguacgug、CUUgucaguc、GAGguaucac、GAGguaauga、AAGguaacac, CAGguaaagc, AAGgcaagua, CGCgugagcc, AGUgugcguu, GAUguaagca, AAGguaauag, GGAgcaguug, AGCguaagau, AAGgucaggc, GGguauuca, AAUg uaaagu, CAGguaacaa, UCGguaggug, AAAguaaguc, CGGgugcagu, GGUgugugca, UGAgugagaa, CACguguaag, GCAgccuuga, CGAgugugau, CAGguaua ua、UAUguaugug、CCCgugguca、AUGguaagac、GAGgugugga、AGUguauccu、UGAguguguc、UGGguaaucu、AUGgcagguu、GAGguaagau、UCAgcagcgu、AAGgugggau、C GGgugcgcu、CAGgugucug、AGCgugguaa、AAUgugaaug、UCGgugagac、UAGguaaagc、CUGguaaaag、CCGgugcgga、CAGguacuca、CAGguagcaa、GAAguugagu、GAGgu ggagg、AGGguaugag、UAGguaugcu、UAGgugagac、CAGguaauua、CGUguaagcc、CUUguaaguu、AAGguaacuu、UCGgcaaggc、GAGguucucg、GAGgugggcg、AAGgcaugu g、CUGguauguu、UAAgucauuu、CAUguaauua、AAUguaaaga、UAGgugcuca、AAGguaaugg、GAGguacuga、UGGguaagua、UGGguaaaaa、AAGgugagcu、UACgugaguu、AG Ggugagcc、CGGgugagga、UGGgugagag、GGUguaagcu、CGGguggguu、CCAgcuaagu、AAGguuuguc、GAGguuagac、GAGguaccuc、UUUguaaguu、GAGguuagga、CAGgua ggga、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、GUAg uaagug、UUGgugggua、CGGguacuuu、UGGguaaaua、AGAgugagua、AAGguagguu、AAGguaugcg、CCUguaggcu、ACAguagaaa、CCGguaagua、CGGguaggcg、GCAgugag ug、GAGgugaguc、CUGguagccu、CAUguaugua、GAAguaacuu、GAAguaagau、AAGguuagau、AAGguaauca、AAUguaugua、UGAguaagau、AGAgugagca、GUAguucuau、G AGguaauca, UAGguaugga, UAGgugggac, GGguacaug, UGGguaaggc, CAGguacgcc, CCAguuacgc, ACUgugguga, GAGguaaguc, AUUguaggug, ACCgucagug, AAUgu gaggg、ACUgugagug、UGGguguggu、AAGguuggga、AAGguuugga、UCCgugagug、CGGgugagug、AGAguaagcu、CAGgcaagcu、UAGguauauu、AAAguagcag、GAGguaacc u、AAGgugggca、AGGgugagua、UGGguaaggu、CUUgucagug、UAGgugcgcu、GAGgcaaauu、AGGguaccuc、CAAgugcgua、AGAguaagac、GUGguaaaua、GAUguaagcg、GA Gguaaagc, UAGgugagua, CAGguaacau, CCUguacggc, UAGguauguc, UAGguccaua, GGgugaaaa, AAAguacuga, UUGguaagcg, CAGgcaagcg, UUUgcagguu, CAGguu uaua、CUGguaaagc、AUGgugagcu、CAGgugguug、GUAguaaguu、CAGguaauac、CAGgcaaggc、AAGguaauuu、UUUguccgug、GAGguagguu、ACCgugagug、CAAguaagcu、ACAgugagua、UUGgugagau、AAGguagucu、CAGguaaagg、GGGguaugga、UUUguaagug、GUGguaagag、AGUgugaguu、AAGgcaagcg、UAAgugagua、AGGgugagug、AGUguacgug、AGGgugcgua、GGCgugagcc、CGAguuauga、CAGguaaaga、UUGgugaaga、AGGguaaugg、AAGguccaga、AGUgugaguc、CAGguaauuu、CAGguaacgc、CUGguacacu、CUGguuagug、CAGguacuug、CACguaagua、GUGgugcggc、GAGgucaguu、AUGguaugcc、AAGgugugug、CUGguggguc、CAGgugaggc、AAGguuaguc、AAGguagcug、GAGgucagga、GUUguaggua、UGGguacaag、AUGguaggug、GAGguaagcc、AUGgcaagua、AAGguauauu、GCGgugagag、AAGgugcuuc、UAGguacauc、ACUgugguaa、GAGguaggcu、GAGguaugca、AGGguaguuc、CAGguauccu、AGGguaaguc、AGGgucaguu、CAGguuggga、CAGguggaua、GGAguagguu、GAGguaggau、GGGguuugug、UAGguaauug、AAGguaaccc、ACGguaagaa、GAGguagggg、CGAguaggug、UCCguaagug、UCGguacagg、CAAguaagcg、AAGguccgcg、AAUgugagua、CAGgugaaug、GUGguaaggc、AGAgugagug、UCUguauguc、UGGgugaguc、UCGguuagua、GAUguaugca、GAGguuggug、GAGguggggc、UGGgucaguc、GCAgugagua、CAGguugcuu、AGGguagagu、UAGgucaggu、CGCguaugua、GAGguauuaa、CAGguaaacu、AAAguaaguu、GGGgucuggc、GCUguggggu、UUGguaaguc、AAGguagaag、AAUgugaguc、AAGgucagcu、AAGguaagag、AUGgugagga、AAGguacuuc、AAGguaagaa、CCGguacagc、GCGgugcgga、CAGguacaua、CUGgugagga、CUGguaggug、AACguagguu、AUGgugugug、UUGguacuau、CAGgucggug、CAGgcauggg、AUGguaucuu、AAGguaacua、CAGgugggcg、CACgugagga、AAGgugguuc、UGGgcauucu、AUGguaagcc、AGGgucagug、AGAguacgua、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 ucaguu、CUGguaggcc、CAAguaagga、CGGguaaggc、AAGgcgagga、CAGguaguuc、CAGguaagga、CCUgugagug、AAGguaaaug、CCGguaauua、CAGguaaguu、AAGguggu ca、CAGguaccuc、AUCguaagua、CCGguacaua、GCGgugagug、GAGgugguau、CUGgugugga、GAGguaauuc、CAAguacgua、UCUguaagug、AAUguaagug、AGGgucuguuG AGguacugc, AGGguaaggc, AAGgcaagag, CAGguggguu, UAGguuagga, UGAguaagcu, AGAguaagag, AUGgcaggug, UAGgcaagua, AUGguaggua, GCAgcccgca, ACGgu aaacu、AGGgugaguu、GUAguagucu、GUGgcugaaa、CAGguuaguc、CUGgugagca、UCAguaagug、AAAgugauug、UAGgucugga、GAGguguuuc、AAGguaaauu、CAUguacau c、AAGguuugaa、CCAgcaagug、UAGguaauaa、GAGgcaagug、CAAgugauuc、CAGgucgugg、GAAguaugcc、UCGgugcccu、GAGgucaguc、CAGgugagac、UUUgucugua、CA Gguagaua, UGGguaucag, UAGgugggcu, AUGgugagau, CAGguaacac, CCGguauccu, UAGguaagcu, UCAguacauc, UAGguuugcc, AUGguaagaa, UUGguaagac, CCGguu aguc、GAGguaagaa、UGGguaaguu、CCGgugagaa、CCUgugaggg、ACGguaggag、ACAguauguc、CAGguauuaa、CAGguggauc、AGAgugcgua、AAGgugaccg、AGAguaggug、ACUguaugua、UAGgucaauu、AGUguguaag、CGGguaccuu、CUAgugaguu、CUAguaagug、CAGguacaac、UAGgugugug、CAUguacggc、AUGgugugag、AGGgug、 gaag、CAGgugcgag、UAGgugcucc、AAGguggugg、AAGgucuguu、CAGgugggcc、AAGgucaguc、CAGguuuuua、AACgugaggu、CGGguaagag、UUUgucggua、UAGguuaag u、GUGguaagaa、CAGguauugg、GCUguaaguu、CUAguaagua、UCGguaaaua、CAGguaacuu、CCUgugagua、CAGguuauau、CUGgugaaca、AAGguauaaa、GAGguaagca、A AGgugaagc、CAGgugaguu、UUUgugagua、CUUguacgcc、AGAguaagug、UGGguaggug、UGAgcccugc、UGUguaugua、AAGguagagg、GAGguggggg、UAGguaauuc、AAGg cauggu、AGAguaagca、AAGguaggaa、CAAguaagua、ACUguaauug、CAGgucugug、UCGguaccga、CUGgugagag、AAGguuugcu、AUGguaccac、UAAguuaguu、CAGguagg ac、AGAgugaggc、CGAgucagua、CAGgucugag、GAGguggugg、ACGguauugg、GCUgcgagua、CUGguaagug、GUGgugagau、GGGguuugau、UCUgugagug、CUUgucagua、 GAGguaaaac, UCUguaagau, CCAguaaguu, CAGguaaagu, GCGgugagca, UAAguaagag, CUGgcaggug, GAGguaaggg, UGAguaaguu, GAGgugagac, GCUgucuguu, AAGg uaacaa、GAGguaacgg、CUGguauucu、CAAguaacug、AAGguggggu、UAGguauggc、CAGguauuuu、GUGguaaacu、GAGgucugag、CUGguaaggu、CAAguaaguu、AAGguag acc、GAGgcgagcg、CUGguaaaua、UGUguaagcg、CAGguuaggg、GGGgugagga、ACAguaugug、CCGgugggga、GAGgucagug、AGGguaaggu、ACAguaagua、GGUguaaggu、GAGguaauaa、CAGguauucc、CUGguauaaa、CCGgucugug、CAGguaacug、GCAguaagua、AAGguagggg、CAAguccacc、CAAguuggug、CAGgugcggu、CAGguaaaau、ACGguaagga、UGGguaauaa、UAGguaagug、CCGguagguu、AGAguaugga、CUCgugaguc、AAAgccggug、UUGguaauuu、GAGguaaaag、CCUgugugag、AAAguaagga、UGAgugagug、AAGguacaug、CCGguaaaug、CAGgugaagc、CAGguacccg、GAGguaaggc、UUUguauguu、CAGgugcucc、UCGguagguc、CGGgugaggc、AAGguaauua、ACUgugaguc、AAGgucagca、GUGgugagug、CAUguccacc、AAGgugaccc、CGGguuagua、GCGguaguaa、GCUguaggua、CCUguugagu、UAGgucuggc、GAUgugagcc、CUUgugagua、CUGguguguu、GAGgcaugug、CAGgcaagag、UUGguaagaa、GAGguguggg、GAGguauuuu、CAGguaguaa、AGGguaagac、UUUguaggca、AGGgugagau、GAGguuugua、AAGgugagug、GAGgugggag、AAGgugagaa、CUGguaagag、AUAguaaaga、GAUgugaguc、AAGgugcagg、CAGgucuguc、GAGgugauuu、CAGguuggcu、CGGguauggg、AUGguccauc、CCGguuggug、GGAguaaguc、AAUguaagga、CAGguuuguu、UAGgugugua、UAUgucuuug、ACGguacuuc、AAGgcacgcg、CUGguaaacc、CUUgugggua、UGAguaaguc、CUGgugggug、GAGguggaga、GUGguggcug、GUGguaagug、AACgugagua、GAAgcuguaa、CGGguaucuu、CAGgugucag、AAUguacgca、CCGgugggua、UGGgugaggu、AAGguauguu、CAGguauguu, CAGguuugcu, UUGguaaguu, CAGguaguug, CCUgugaaua, GCUgugugug, CAAguaauuc, AGGguaaugu, GCUgugaguc, ACCguaaguu, CGUguaagua, GGGg uaaguc、AAUguaugau、AAUgugauua、UCAguaagaa、CAGguccguc、GAAguauuga、UUGguaagga、CAGgucgguu、UAGguuagug、ACGguaaaac、AAGguagguc、UACgugag ua, UUGguaagca, GCGgugaguc, GAAguaaggg, CGCgugaguu, CAGguacccc, UCUguaagac, GAGgugggca, AAUguaagac, CAGgcaaggg, CAAguaacua, AAAguuuguc AGguacugu, AAGgucccuc, UCGguaaguc, UGGgugagug, CUUgugagau, AGAgugagcu, UAAgugggga, UAGguaggga, CAGguuagcc, AGGguaauca, AAGguucagc, UGGgu gggug、CAGguuguga、AAGguaagug、CAUgugcgua、CCGguauauu、ACCguaugug、CAGguauagu、CAGguauuac、CAGgugcagg、GUGgugagcu、AAGguaacau、CUGgugaug g、AUGguaaaug、CCGgugagca、AAGguaaacc、AAGguacugg、GCGgucagga、CUGgucaggg、AAAguacguu、AGAguagguu、AGGguaagcu、AUUgugagua、CCGgccacca、GA Gguaacuu、GAGguaugaa、CAGgucagac、UAGgcgugug、AGGguaaguu、CAGgcaugag、CAGguaacgu、CAGgcgagca、UAGguauggu、AGAguaggau、CUGguuucaa、GAGgua aacu, CAGgcaugca, UUGguaaucu, AGGgcagaau, AUGguaaaac, GCUgcaggug, GAAgcacgug, CAUguaaaca, UGGguaagau, AGGguagcua, AGGguggggu, CCUguaaguu.UGAgugaguu、GGAguaugua、CAGgugaccu、AAAguacgga、GAGguacaga、GAUguaggua、GGGguaauug、UAGguggguu、GUGguacgua、AAGguacagc、GAGgugaaga、GGGguaagca、UGAguagguc、GGGguaaguu、AUUgugaguu、UCAguaagac、AGUgugagcu、AAGgcaaaac、CUGgugaguc、AAGgucucug、GAGgcugugc、AGAgugagac、GAGgugaugu、AGAguauggu、UGGguggguc、GCUgcugagc、CAGguagcug、UAGgucagaa、CCGguaggug、GCAguaugau、CAGguuucag、GAGguuugcc、GGGguggggg、AAGguacaua、UGGguguguu、AGAguaaggc、GCGguuagug、AAGgugacuu、AUGguaagau、AUGguaguug、CAUguaagac、CUGguaugua、UUCguaagga、GAAguaugac、CGGguaauuc、UGGguaacuu、CAGgugccua、CAUguagggc、ACCgucagga、CGUguucgau、GAGgcaggac、UAGguaauau、UCGguauacu、UAGguugugc、CCGgugaguc、CAGgugccaa、CAGgugaugc、AAGgugagga、GUGgugaggg、UGGgucagua、GAGgucaggg、UAGguacgua、GAGgcaagag、CCUguuggua、GAGguaucca、UAAguaagcu、AAGgucaguu、AAAguuaaag、GAGgugcuau、ACGguaaguu、CUGgugaggg、GAGguuaugu、CUUgugugca、UGAgcugggg、AAGguauagu、UAGguaaaac、GGGgugaggu、GAGgcaagca、GGAguaacgu、AGAguaagua、AAAguaagua、GAGgcaacca、UGUguaaguu、UAGgugaggc、ACAguaagaa、UGAguaagug、CAAgucagua、AGGguaaaug、AAGguaugca、GCUgugcgug、GAGguucgcc、AAGgcuugca, CAGgcaagug, AUAguaaguc, UUGguaggua, GCAgcaggua, AAGguauauc, AGCguaagcc, CUGguucgaa, ACGgugggug, CUGgucauug, CAGgucagga, CAAg ugagac、GAGguacugg、GAGguguagu、GAGguguccu、CAGgugcgua、AGUgcccuga、AUGgugaguc、UGUgugugua、CAGguaugcu、CUGguacagu、UUGguacgua、UCUguacg ua、UAAguaauuc、CACguaugug、CAGgcaagua、UCGgugagug、GGUgugaguc、UCUguaagcu、AAGguucaga、AGGguacuuc、GCGgcagguu、GAGgcccgug、CAGguauaaa、A UGgucaagu、AAGgugagua、GUGguuuguu、AGAgugagga、GAGguaugac、UAGgcgugag、AAGguacucc、UGAgugagga、GAGguaugau、GGGgucggua、ACGguaugca、CAGgu accac、UAAguaccug、AGGgugggcu、CUGgucuguu、UAGgucagag、AAGguguguu、CUGgucagug、AAGgugggac、GUGguaguag、CUAguuuagg、CCCgccccau、GCUguacug c、GAGguaauau、UAGguuggug、AAGguccaac、UAGgugagga、GUGguaaguu、AGUgugagag、AAUguacaug、UUGgcaggug、UAGguuauug、CAGguacuga、GCGguggguc、UG There are many ways to get the best results from your search guuu、CAGgugaccg、UGUguaagcu、GGAgugaguc、AGGguaggag、AGGgugggug、AAGgucugag、GAUguaauau、GGGguaauua、UAGguaggua、GAGgcaagua、GAGguaagga、UAGguacuac、UCGguggug、AAGgugga、CAGgucugcc、UAAgugagcc、GAAguaaguu、GAAguaagcc、UAGgugcgac、GAGguauggc、GCAguaagaa、CAGgugugga、U、 UGguaacgu、GCUguaaaaa、UUGguuagua、AUAguaaggg、UUGguacuag、CGGgcagccg、CAGgugcugg、UAUgugaguu、CAGgucuggg、UAAguaagaa、AAGguuauua、AGAguaaagc、AGAgugugag、UAGgugcgag、CAAguaaacg、AAGguacgua、CUGgugagua、CCAguaugua、UUGgugagug、UGAguaagua、GAGguuagca、GUGguaagcc、CUGguauggc、AAAguaacac、CAGguacuaa、UCUguaaguu、GAGgugaggg、ACUgugggua、GAUguuugug、CAGgugucaa、CAGgucacca、CCGgugagua、UUGguaaaua、CAGguggggg、ACUgcaggug、UAGguauguu、GGAgcaagug、UCGgugccuc、CAAguaacuu、GAGguaacca、CAGguaauau、GGAguaagaa、GAGguaccuu、AGGguaagga、CCUgugaguc、GAGguaaugg、AUGguguguc、GGGgugagua、AGGgucaggu、UGGguaaggg、AGGguagguu、AUAgugaguu、CCCguaggcu、ACAguaugua、GACgugugua、GCGgugagga、CAGgugaccc、UAAguuuagu、ACAguugagu、CGGgugaggg、CAGguggauu、CGGguagagg、UAGgugcgug、GGGguaagaa、GAGguggggu、CACguggguu、ACGguaauug、AGAgugaguc、UUGgcuccaa、AAGgugaugc、AAGguugguc、AGCguaaguu、AUUguaugua、UCAguuaagu、CAAguacgug、CAGgugcgug、CAGguaggua、AUGguggggu、AUGgugaguu、CAGguaauca、AAGguagggu、CAGgccaagg、GUGgugagag、AAGguuggug、CAGguacucu、UAGgcaugug、UUGguaccuu、CUGgugugcc、ACAguugcca、UUGguaauau、GAGgugcaug、UUGguuugua、UUGguaagua、UGUgugugug、GUGguaugcu、GCGguacaca、UUUguaugcu、UCUgugcggg、AAGgucagug、GAGguaggaaaggauGggca、gGGca ugaggg、GAAgugagua、CAGgugacag、AAGgugauua、GAGgccagcc、GAGgucuccu、UAGguauuac、CAUaguaagag、CUGguagggc、GAAguaagua、CGGguaguagua、CAGaguagua、 cu、GUGguaggua、CAGgugggua、AAGgccagug、AAAgugaauc、ACGguuacgu、AUGguaggaa、CGGgugagac、GAGguaggaa、UGGgugagcc、CCAgugagua、gA、CU AGguaugac、GCUgugaggu、CUGguaugaa、GGUguacgac、CUUgugagug、GUGgugagca、CUGguaacuu、CAGguacuau、AGGguaaggg、UUGguuaguuG、Gguuaagca、GUGUAagca gagga. g. Gguaauug、AAGgugcuca、AAGguucaac、CAGguuuaca、GCUguaagug、AGGguauguc、GAGgucgggg、AAGgugccug、AAGguaaaaa、GUGgugaguuAGGaa、UAGgua uccu.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、GAGguggcuu、AUAguauuga、UGAgucgucc、CAGgugcucu、UACguaauau、GCUguccuga、CAGgcugcac、CUGgugcgcu、GCGguaagaa、UAAguuacuu、GAAgugagug、UAGgcaaguc、UAAguaaaua、ACGgugagug、CAGguagguu、GGGguauaac、GUUgugaguu、CAUgugagua、GAGgugcauu、AAGg uuugua、UCGguaaugu、CGAguaaggg、GAGgcacgga、AGGgugugga、CAGguauggu、AAGguagaaa、CAGgugccug、UGGguauaug、UGAgugagac、UGGguaauuu、AUGguaaa ua、AAGgcaaagg、AGUguuuguu、AUGguauugg、CUGgugaggc、UUGguaaaau、ACAgugaguu、CAGgugcugu、GAGguuaaga、AGAguaagaa、GAGguccgcg、GUGgugagga、C AGgugagcc, CAGgugacau, AUGgcaagcu, UCGguaauau, CAGgcaacaa, GGGguaggga, CUGgucucgc, UAGguaacga, CGGguaaggu, UAGguaaugc, CAGgcaagaa, ACAgu aggua、CAAguaugag、GCUguucgaa、AAGguuaugc、GAUgugaguu、CAGguggaga、AGAguuaguu、UGAgugugcg、GAGguacagc、CAGguaagac、CAUgugcuuu、AGGgugugu u、ACAguuaagg、ACAgugaggg、GAUguauacc、UUAguaagcu、CAGguaagau、AGAgcugcgu、GAGgcaaguu、GAAguaagug、AAGgugaaaa、AAGguaccua、GAGguaucag、AU There are many ways to get the best results from your search results uggc, CAGguacacg, UUGguaacca, GAGgucaggu, UCUguuggua, CAGguauguu, UUGguauguc, AAGgugcguc, AGGguaagaa, UUUguaagcc, AAGgucaggu, CUGguaaacu.UCGguaauuu, CUGguaggcu, GGgucugua, GGguacuuu, CUGguaaagg, CGGgugugug, CAGguguggu, UCGguacguc, CAGgugccag, GGGgugagaa, ACAgcuagua, AAGg uauagc、CUGguaggag、GCUguacgua、AAGguaaagg、CAAgcacgag、CUAguaagac、CCCguaagcg、CAAgugugag、AUGguaaggg、AAGgugaggg、CAAguaggua、GGUguugc ug、GAGguacugu、UAGguaagau、CAGgugcgaa、GAGguccagg、UUGguauaca、GGAgugagua、GAGgugagau、AAGguggggc、CAGguaaacg、UCGguaacuu、CAGguaaauu、G AGgugcgca, ACUgugagua, ACGgugugac, GUGguaaguc, CAGguaggca, CAGgucagca, GUGguaugug, AAAguaucug, CGGguaugua, AAGguauaaa, GAGgugggga, GCUgu aggug、GAAgugaguu、AAAguauuua、UAUguaagua、ACGguaugag、CUGgugagug、AGAguaaaau、GCUguauggc、AUGguaaacc、GCAguaauaa、UAAguauuua、AAUgucagu g、AUUgcaggag、CCGguaagaa、AAGgcaaguu、GAGguuuguc、AAGguaacug、AAAguaugag、GAUguuagua、CAGguggguc、AAGguaccga、CCAguaauua、GUGguaugcg、AU Ggugcgcu, CAGgucuaug, AAGguauuua, CUAguaagau, AGAguaauuu, GGguaacgu, AAGguagcca, CUGgucccgg, GGguccuuc, ACGgucaccc, AAGguaauac, CAGgug caug.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、AUUgugaguc、CAGguaaacc、AAGgucaauu、AAGgugaaua、GUCguaagaa、GCGguaaguc、CUGguagagc、GAGgucgguc、CAGguaaaca、AAGgcaagga、CAGgucgucu、GGGguagggc、CUGguacuaa、GAGguagcug、CUUgucagcu、UAGguaaggc、CUGguauuac、UAAguacguc、AAGguaagcc、ACGgugaaag、CCAgccaaua、CAGguuuguc、AAGguauaau、AAGgucuuag、AGGgugagcu、AAGguuaggg、CGGguaaauu、CAGguaacgg、AGAgugugua、ACAguaaguu、GAUguaauuu、GAGguaggga、UUGgcaagug、AAAgugagga、AAGguagugc、AGAguaauuc、GGAguaaaua、GUGguaccca、CAGguauugc、GAUgugaggg、CAAguaaauc、CAGgugucuc、AAGguaacag、UUGguaaaag、CAGguaucau、ACGgugagac、CUGguaugac、CAGguucacu、GAGgugauca、AGUguaaguc、AACguaagua、AAAgugagug、GAGguacagg、CAAguaauga、GAUguaagga、UCAguucccc、GCGguaagga、UAGguacuaa、AAGgugaaag、ACUguaagug、UGGguaugug、AUGguaacag、CAGguagggu、ACAguaagug、AAGgugcucc、AAGgugugcu、AAGgugguga、ACGgugcgcc、AAGguauugc、GGGguaugug、CAGgugggcu、GAGguauguu、AACgugaaua、CAGguaaugg、UAGguaugau、CAGgcaggug、GGGguugguc、AAGguauggg、UAAgugaggc、CAAgugaucg、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、AUUguauaaa、CUGg ugaaua, AAGguuuaaa, CCUguacugu, GCGgugagcg, AAGguaaucc, UAUgugagua, CCCgugagug, CAGgugcaga, CAGgucaguu, CAGguaggcu, AAAguaagug, UAGguugg uc、CAGguugccu、AAGguaugga、GGUguggacg、AAAgugagaa、AGGgugagag、GAUguggcau、UCGguaaggu、GAGgugcguc、CGGgugaguc、AAGguacggg、GAGguucuug、A AGgugcuug, UAGguaugua, AUGgucagca, CGGguacuca, AGGgugagga, AUCgugagua, UCAguaagua, UAGguaaaua, AAGguaauug, GAAgucagug, CAGguacaaa, AAAgu uaauc、AGCgugagcg、CCGgcuggug、AGUguaauuu、UGAgccacuc、GGGgucugua、AUGgcauguc、CGGguaaaga、AGGguagcau、CGGguaggag、GAGguucgug、UAAguauu c、UAUguaagau、AAGguaguuu、CAGgugguau、GUGguaauga、AAGgugauuu、CAGgugaagu、GUAguaauua、AUGguuggug、CCAguaagug、UAGgugagag、AUGgugaggc、AA Aguuagug、AAGgugccuu、UAGguaugag、CAGgugugac、CUGguggguu、AUGguaagga、UCUguaagaa、UCCgugaguu、AAAgcaggua、UAUgugagug、CAGguggagg、CAGguu agac, AUAguaagac, AAGguguugu, GAGgucugug, AAGguaagau, CAUguaaguu, CUGguaauua, CAGguaggcg, AGAguaaguc, UGGgugagga, AAUguaggua, UAGguuagca.GGGguaggua, GAGguauugc, AUUguacaca, GAAguaggua, GGAguaagcu, UAGguaugug, GAGgugaaua, GAGgugggau, AAGguaaucu, GGUgugaguu, AACgugaguu, GAGguaaccg, UAGguaagga, AUUguaagaa, UGGgugagca, AAGguaaggc, CCAguaucgu, CCGgugggug, GAGguagugu, ACGgugggaa, GAGgugaccu, CACguaugua, AGGgugggga, AAUguaaguc, AAAguuaagu, CAUgugagug, AGAguauguc, GCGguaugac, CGGgugaguu, CCGguauuuu, GAGguagaac, UAGguaugaa, CAGgcgcgug, CAAguaaguc, AGUguaagau, AAGguucuac, CCAguaagua, GAGguagcag, CAGgucuguu, CAGguacaau, CCGguaaaga, UAAgugcugu, AGGgugagaa, CUCguaaggu, CAGgucagcu, CAGguaaggc, AGGgugcagg, GAGgugaaac, AGGguaagua, AAUguaugcc, AAGguaagca, ACGguacggu, AAGguaauga, UCUgcucaau, ACGguaaugu, AAGguaguug, ACGguaagug, CAGgugauga, GAGguaacac, GAGguaggua, CAGguaccuu, CAGguaauaa, UUGgugggug, CUGguaauga, UAGguaaguc, AGGgugugac, GAGgcaauaa, GUGguaaagc, CUGgugggcg, GAUguauguu, AGGgugagac, UCGgucagca, AUGgugauua, CGAgugugua, CAGguuggug, AGCgcaagua, UGGguacguu, GAGguauuug, AGUguacaua, AUGguaagua, ACAguagguu, AAGgugagag, UUGgugaagu, AAAguaugua, UGGguaagga, UAGgugccuu and CCUgugggug are included.,

[0228] Additional 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, UGUguaacaa, AGGguauuag, UGAguauauc, AGAguuugug, GAGgucgcug, GAGgucaucg, ACGguaaagc, UGAguacuug, CGAgucccg, CUGguacguc, AGGguauugc, GAAgugaaug, CAGaugaguc, UGGguauugg, UGAguaaaga, GUGguuccug, UGAgcaagua, UAUguaagag, AAGgucuugc, AAAgcaugug, AGAguacagu, GUGguaaucc, CAGguagagg, AAGguacaac, UGGgcagcau, CCGgucauca, CCGguuugua, UGAguaaggg, GAAguaugua, GGGguagcuc, GCUguacaua, CUGgucucuu, GUGguaaaug, AUCguaagug, GAGgcaugua, AAGgucuccc, UGGgugcguu, UGUguagguu, GAAgugagca, GGUguaauuu, CUGgugaaau, AUCguaaguc, AGAguaaucc, GGAguagguc, GAGguaccaa, CUUguaggug, AAGguauaag, AGAguuggua, AUGguuugug, UGGgucagau, AGAguaggac, AGAguagugu, AGAguaggag, CAGgucucua, AAGguggaug, UGGguaucaa, GAUguaugga,AAGguguuuc、GCAguguaaa、UUAguaugua、UCUguaugca、AAUguaaaau、AGAguaaauu、GGGguacuuu、GAAguuugau、AAAguagauu、UGUguagagu、UGGguaagcg、CGGg uucagg, AGGguacgac, UCGguaagaa, AGGguuggca, AAAguacagu, UAAguuaagg, AUGguaaugu, GUGguuuuac, AGAguaacaa, AAGguagccc, GCGgugaggc, AUGguuca gc、AAGguacuua、AAGguccgug、UAGguaagcg、AUGguaccuu、GCCguggugg、CUGgugcguc、CAGguggaaa、AAAgucugua、GAGguaaccc、AGAguauggg、UAUgccccug、A AGgugccag, ACGgugcggc, AGGguacuga, AGAguaagcg, CUGgcaaggg, CCAgugugug, GAGguagacg, CGGgugcggg, GAUguaagcu, AUUguauuua, UGCgugagug, CUGgu cuaua, GAGgugcuag, GAGgugccau, CAGguacguc, GAGguucagc, AACguaagaa, AGAguaguac, AAGguaacgg, UAGgugugac, CCGguaauag, CAGguaccag, UUUguaauu g、AAUguacgaa、CAGguaauga、AUCgucaagg、CUGguagaug、GGGgugcagu、AGUgugagaa、GGGguuuuau、CCUguccccu、AUUgugaagu、AAGguaaacg、UACgucgugg、AA Ggugccau, GGGgucccag, UAUguauggu, CGGguaauua, CGGguacucc, CAGgugacuu, AGUggguu, AGAguauggc, AAGgccaaca, AAAgcaagua, UCAguagguc, GUGgug gcgg, CAUguauccu, UCGgugagcc, AUAguugggu, AAUguuagcu, AUGgugaaug, CGGguaaugu, UCUguaggug, CCGgugaggc, UGAguccacu, CUAguaagag, CGGguggggc,CGAguaagca、UGUgccaauu、UCGguaagcc、UAUguaggug、UUGgugggcc、GAGgcugggc、AGAguaacuu、ACGguagguc、CAGgcccaga、CCGguggguu、AAGgugacgg、GGGg uacagc, CAUguaaguc, AUUgugagaa, UGUguaagga, UUUguaagau, AGGgucauuu, UGGguuuguu, CGAguaagcc, GUGgugugua, AUGguauaac, UGGguacgua, AAAguaga gu、UCGguaacug、AGAguaauga、AUGguggguc、AGAguaauau、CAGguacugg、UAAgucaguu、GCGguagaga、AAGgugaugg、ACAguauguu、GAUguacguc、UAGguuucuc、G AGgcauggg、AUAgcuaagu、GUAgucugua、AAGgugaacg、GUGguggucg、GAGguugauc、UGAguggguu、ACUguacgug、CUGgugacug、CAAguuaagc、GAGguaccca、AACgu aacuu、CAGguuacua、AGAguuaguc、UGGgcacguc、AGUguauggu、AAGguugcaa、CAGguuguua、AAGgcauccc、GAUguaaggc、AGGguacggg、GAGgucaaag、CAAgugagc g、AGAguaaucu、UCGguagcug、AAAguaguag、CAGguucguc、CGUguaugaa、AGUguaaaaa、AAGgucucac、UAGguggagc、UGAguaggug、AGAguaugcc、GAGguugcau、CA Aguaagag, UCUgugugcc, GAGgugaugc, GGGgugauaa, CCCgugagcc, AGAguaacug, GCGguaagua, AGAguacauc, UCGgucuggg, UAAguaucuc, GGCguagguu, AGAgua cgcc, GAUgucuucu, AGGgcaaggu, CGAguaugau, AUGguagagu, CAAguacgag, UCGguaugau, CCGguguguu, AGGgucugug, GGAguaggcu, AAGgucuaug, GCAgugcgug.UGGgugagaa、AGGguaaagu、GAGguaggac、CUAguaagca、UUAguaggcu、CUGgugggau、CUGguuagua、AAGguacgug、CGGgugagau、AAGgugcaug、AAUguggggcu、CAGggcu uugacu、CAGguuacag、GCGguaacau、AUUgucaguc、CAAguauaca、GAUguccgcc、AAGgugcgga、AACguaagag、UGGguuggua、CAAguguaag、GUGguaacgu、CUGgugau ca、AGGguggggc、UCGguaaaga、CAGguacacc、CGGguaaggg、CAAguuugcu、ACAgugcgug、UUGguauggg、GAGgcucauc、CUGguaauag、AUGguggaua、UCAgugaauu AUguaauua、GCAgucuaaa、AAGguauucu、GAGgucauca、UGGguccaug、AGAguuugua、AGGguagacu、AAGguaggac、UGUguguuga、UCAguacgug、AUGgucucuc、UGAgugu uagua、UGAguaaagu、GAGgugaccg、GAGguauauc、CAGgugccau、AGAgugguga、GUUguaagaa、AGAguaaaua、AGGgugaagg、CUGguagauu、GAGguucagg、AGGgucuuc a、CUGguaaccu、ACAguacuga、AGAguggguc、AUGguaugag、AAGguuauau、AGAguauagu、AAAguaugaa、UAGguggcua、ACCguauggg、AAAguauaau、UUUguauggc、GGG Ggucgcgu、GUGgugguuu、CAGguugac、GGAguaggcg、GAGguacccu、AUGgugugca、GUGguuggug、AAAguaugcu、UAAguuacau、ACAguaugag、GGAguauguu、UUUUGUG agaa、AAUgugcguu、CAGguagagu、AUGguguuaa、CAUgugcguc、AUAguuggau、GAGguacgua、GUUgugagaa、CAAguacauc、GAGguaguuu、ACUguacaga、CCGguugugaUGGgucagug、GUAguaagaa、GACguacuuu、AGAgucaguc、UAGguuaguu、AGGgcagcag、AAGguccuac、AAUguaauug、CAGgugcggg、CUGguaaugg、CAAguagccc、GAAg ucaguu, ACAguaauug, UUAguuagua, CCUguauuuu, AUCguaagaa, CCAgugagca, GAAguaaggc, UGAgugggua, UCAgugguag, UCUguacagg, CGAgugagug, UCCguaug ug、CAUgccguuu、AAAgugacuu、AGAguaggca、GAAguaagag、CAGgcagguu、UUGguagagc、AAGguggaaa、GAGgcagguc、AUGguacgac、AGGguaggaa、AGGguaggua、U UGguaaggu, AUGguacaga, CAGguagagc, UAGguaaggu, GGGguuagag, AAGguaucaa, GGguagccc, CAGgugccuc, GCAguaagag, ACGguagagu, UGGguaaugg, CUGgu caguu, GUGguacauu, AAAguagguu, AAGgccaaga, CGGgugggca, ACGguccggg, CGAguaugag, CUGguaugcc, GAGguggaug, CAGgccuuuc, AAAguacauc, AAAguaauc a、GAGguaacug、CUGguaaaga、CGUguaagca、UGGgcaagua、GCGguggcga、GAGguggccg、AUUgcaugca、ACGgugacug、CAGgucagau、AGAguaacuc、UGAguaacag、AA Gguacccg, AGGguaggcu, GGGgcaggac, CCUguaagug, AUUguaagug, ACUguacgag, GGGgua aaga, AGGguuacuu, CAUguaaaug, GGAguaguaa, CAGgucaauc, CGGguuagug, UAGguacaug, UAGguuaaga, UGGguaccuu, CGGguggaca, CAGgucuuac, AAGguggagc.AUGguaacca, UCGguaaguu, UAUguacaaa, AAUguagauu, GUAgcuagua, AAGguauugg, GAGgucuuug, GAAguucagg, UGGguaucac, AGAguacugg, CAGgu. uaaug、AGGguacgug、AGGgcacagg、CUGguuaguu、UUGguacgag、ACGgugauca、CCUgugagag、GAGgugaagu、AAGguacauc、UCUguaugug、UUGguggaag、UGGgcagguu、GAAguggagc、ACAguaagac、CGGguaccaa、CAAguacguc、AGAgugaggg、CGGguaagaa、AAUguaggug、AUCgugugcu、UAGgucaugg、CAGguuuuga、AAGgcaugca、GAGgugcugc、AAGguuaaua、CAGguucauc、GCGguaggug、GACgugagua、CAGgucuacu、UUGguaugag、AGCgugggca、AUGguaaggu、AUGguaccuc、UUGguauggu、UAUguaugaa、UGGguauggg、GAUguaaaua、CCGguaaguu、GAGgucugaa、GAGgugcgag、CUGgucagcc、CAGguuuugu、CGGguggugu、UAAguuagua、UUUgugugug、CAGguuaacc、UUGguacuuu、GCUguaaggc、AGGguggcug、GAUguaaaaa、AAGgucaaaa、CAGguagcgc、CAGguuuggc、GAGgugguuu、CGGguaaaua、CUGguucggu、GGAgugagcc、AAGgugcgcg、GAAguacauc、AGUgucugua、CCCgugagcu、GAGguucaca、CUAgugggua、GAGguaacua、UCGguauguc、UAAguauuug、CAGguaagcg、GAGgugguaa、CGAguaagag、CCGguaagcu、GAGgucuugu、AAGguggguc、CACguaagug、AGUguaauga、AAAgugugua、GGAgugccaa、CACgugaguu、AAGguuggau、UAUguaaaua、CUGguaggaa、UAUguaaacu、AAUguauuuu、CUGgcaagug、UGUgugguau、UAUguauguu、UUGgugacuc、GGAguaaggu、AAGguagaug、UGGguagggu、AAUguaauuc、GUGguauggc、GGAguggguu、AGGguaccac、UAGgugacag、ACAguaggca、AUGguuugaa、GCAguaacua、CCGguaggua、AGAguaggcc、AAGguugaca、CUGgugugua、GAAgucuguc、UGGgcucgga、CAGguagccu、AGAguaggua、UAAguauguc、CUGguauauc、GAGguguguu、AUGgugcaug、AAGguacgcc、UGAguaacua、GAGgugacag、GUUguccugu、UUGgugucuu、AAUgugaagg、UUGguggaua、UAGguguguu、CUGgcaaguu、GCAguaagau、GCGguggaaa、UGCguccagc、AAAguggagu、CGUgugagcc、AGAguacugu、CAGguauagc、UACguaagga、AAGgucuuua、AAGguggucu、GGGguaaauu、UCAgugagga、AGAguacguu、GAGgucguca、UAGguuugau、CAUguaaacc、AAGguggcac、CAGguagaug、AACguaaaag、UAGgucucug、AUAguaggug、UAGgcaagag、UAGgcacggc、AAGgucuuca、CCAguaugcu、CAAgugaguu、CAGgucucaa、CAGguuacau、GGAgugagca、AGAguacgca、CUGguguugg、AAGguacuca、CUAguaaggg、AGAguaaaag、AAGguaacga、CUGguccccg、UAAguauggg、GAGgucgagc、UUGguauaua、AAAgucaagg、AAGgucuagg、CGAguagguc、AGGguucguu、GAGgcaggcc、CUAguauuac、ACGguaugug、UAGgugguuc、AGAguauaac、UUGgugcguc、ACCguuaucu、CCAgugauga、GAAguaugca、GAAguauggc、CCGguaggac、AAUguaagca、AGAguaauug、AGGguugguu、GUGguaggag、AAGgcaguuu、CAAguaagcc、CUGgcaagua、CAGgcaugau、AGGguaauug、GGGguaaccu、AAAguaacua、UAGgucugcc、ACGguaugaa、AGUguauggg、UGGguuggca、UAGguaaacu、AGAgugggua、AGAguauuug、AGUguaggaa、CUUguacgua、GAUgugagau、CAGg cagcca、AAGgucacug、AAGgucugac、UAGguuccuu、CUGgugcuuu、UGAguuggug、UUGgugggau、UGAguagggu、UCGgugaggu、AAAguaaaga、AAGgcaaguc、CGGguaa gc、AAAguuaguu、UUAguaagca、GAGgucacau、UAAgugguau、UAGgugcuuu、GGAguaggca、UGAguaagga、CAGguggagc、GAUguagaag、UAAUgccugcc、AUGguaaggc、UAGguaggc GGguaauau、CUGguaccuc、CACgugagcc、UGAguuugug、CCGguagugu、AAAgugacaa、GAAguggguu、CAGgugcagc、GAGgugggcc、UAUgugcguc、GGGguacugg、CUGgugg agguu、UUGgcauguu、AAUguaauac、UAGgccggug、AGAgucagua、UAAguaaauc、CAGguuccuc、UAGguacgau、AGAguuagug、GCAguaagug、AGGgugguag、GGAguaug u、GAUguaaguc、CCAguuucgu、AAGguucggg、AUGguggagu、AAGguaccgg、GAAgugcgaa、UGGgucaguu、AAGguguaga、UGGguaggcc、CCAgugaguc、AAGgucau、AAGguca Cgugaggc、UCCgugguaa、AGAguacuua、GGGgucagau、AAGguggacc、AGAgugagcg、AGAgucagau、UAAguauuac、AGAguauuuc、AGAguucagc、AUGgugagug、UAGug aucc、GGAguaagau、UAGguaccaa、AGAguugguc、GAAgugagac、AUCguagguu、GAGguacgcu、ACGguaaggg、CAGgcauguc、UUAguaagau、UGAguagguu、AGGguacgaa、ACGguauguu、AGGguacugu、UUGguaugga、UAAguaacug、GCGgucagcc、UUUgugaguc、GUGgucagug、CUGgucugua、GAGguucuua、AUGguacuga、AAUgugcuuu、AGGg uggcgu、CCGgcaggaa、CAUguggguc、UUGguuuguu、CAGguucugu、ACGguaagcg、CUGgucagua、UCAguaggcu、UGAguaggac、CAGguuuuaa、GAGguguccc、AGGguggg uu、GUGgugagac、CACguaggga、GUGguauuuu、GAGauauccu、AAGgugaaca、UAAguagggc、CUGgugcggg、CUGgucaaua、AGAguaaaaa、AAGgugcagu、CGGguaagca、A AAgugagcc, AUGguaauca, GCAguacgug, AUGguacaug, AAGguuaaga, CGGguaaaug, GGguucgca, GAGgcucugg, AUGgugggac, AACgugguag, AAGgugauag, GGGgu uugca, CAUguaaggg, UCAguugagu, AAAgugcggc, AGAgugagcc, AUGgcaagaa, ACAguaaggu, AAGgucucua, GUGguaaaaa, AAAguaggug, UAGgugcacu, GUCguggua u、CAGguauagg、UGAgugagag、ACUgugagcc、AUCguuaguu、UUUguaccaa、UGGgugagau、AGAgugagaa、AGAguagggg、AGGgcaagua、CGGgucagua、UUGguaugcc、CG Gguuagau, GGGgugaagu, CCCgugugaa, GCAguuugga, UGCguaagac, AGAgucugua, CACgugagca, AGGguaaaag, CAGgcugggu, GAAgucuuca, AAGgcaaaaa, GUAgua aaua, CUAgugagag, GAAguuucug, CCUguacgua, GAGgugcgcg, AAGguguaaa, CCAguauguu, CCGgucagcu, AUGguuccug, CAAguuaaau, AGAguaggcu, AUGgugggca.GGAguaagac、AGGgucacga、UAGgugauau、GAAguaaguc、CGGguaagau、CAAguagcua、UGAguaaaau、GUCguacgug、AUGguacgua、CAGgucucgg、GAGgcauguc、AGAg ugggau、GUGguuagag、UGGgugguga、AAGguuaaac、CUUguuagcu、AAAguaggaa、UAGguuguau、AGGgugcgcc、AAGgugggcu、UAAguaucug、AAGguaacgu、AUGgugg gc、CAAguacacg、GGCguaagug、AUAguaggac、AGAgugaggu、UUUguaaaaa、GAAguuugua、CUAguaaucu、AAGguuuuua、GAGgugcguu、UAGgcgaguagua、ACCgugagua、ACCgugagua AGgucccga、AUGguacugg、UGAguucagu、AAUguguggu、UCCguugguu、CAGgucagag、CAGgucccua、UAGguagacu、CAAguuaagg、GAGgugugcg、GAAgcugccc、CGAgu acgug、CGGguaggua、UUGguauuga、AUUguaugau、UUGguaugaa、GAGgugguca、GCUguaugaa、CAGguguugc、CAGguaaaac、AUAguaaggu、CUGguuagaggga、AGCgugugu g、AAGguuaucu、CACgugagua、AGGgucagua、GAGguauau、CAGguuauuu、AGGguggacu、AUUguaauuc、UUUguggguu、AUGguacgug、AAGguguucc、cGgugacGGA Gguacuaa、ACAguucagu、GAGgucacgg、CAAguaaggc、AAGguuuggg、AAAguggggcu、GCGguucuug、GAGguggagc、UGAgucagug、CAGgucaagg、AGUguaagcu、GAGgca gaaa、AAGgucacac、GAAguagguu、GUCguaaguu、AGAguaugca、CCUgugcaaa、ACGgugaaaa、CAGguacgaa、CAUgugagga、AGCgugagua、GGUguguagg、AACgugag、cuGAGgugaacu, AGAguucagu, AACgugugua, CAGguugugg, AAGguacuag, UCAgugaaaa, AAUgucuggu, ACGguaaaau, CUGguguaag, GAGgugcgaa, AGGguuucuc, 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, GGAguuugua, AAGgucacga, GUGguagagg, UAAguauauc, AAGgugucca, UAUgugguau, GAGguacaau, AAGguggggg, GGAguaggug and UAGgugacuu are included.

[0229] 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 some 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.

[0230] 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.

[0231] 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.

[0232] 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 selected from the group consisting of 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 hnRNP, H hnRNP, hnRNP1, hnRNP3, hnRNP C, hnRNP G, hnRNP K, hnRNP M, hnRNP U, Hu, HUR, I hnRNP, K hnRNP, KH-type splicing regulatory protein (KSRP), L hnRNP, LUC7L, M hnRNP, mBBP, muscle blind-like (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.

[0233] 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.

[0234] 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.

[0235] In one aspect, compounds of Formula (I) and pharmaceutically acceptable salts, solvates, hydrates, tautomers, stereoisomers, and compositions thereof can modulate (e.g., increase or decrease) splicing events of target nucleic acid sequences (e.g., DNA, RNA, or pre-mRNA), such as nucleic acids encoding genes described herein or encoding proteins described herein, or nucleic acids comprising splice sites described herein. In one embodiment, the splicing event is an alternative splicing event.

[0236] 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.

[0237] 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.

[0238] In another aspect, the disclosure features a method of modifying the structure or 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 (e.g., DNA, RNA, e.g., pre-mRNA). In one embodiment, the modification includes stabilizing a bulge or kink in the nucleic acid (e.g., DNA, RNA, e.g., pre-mRNA). In one embodiment, the modification includes reducing a bulge or kink in the nucleic acid (e.g., DNA, RNA, e.g., pre-mRNA). In one embodiment, the nucleic acid (e.g., DNA, RNA, e.g., pre-mRNA) 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).

[0239] 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 haploinsufficiency 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.

[0240] 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.

[0241] 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.

[0242] 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 Lymphomas such as lymphoma (i.e., Waldenstrom's macroglobulinemia), hairy cell leukemia (HCL), immunoblastic large cell lymphoma, precursor B-lymphoblastic lymphoma, and primary central nervous system (CNS) lymphoma; and precursor T-lymphoblastic lymphoma / leukemia, peripheral T-cell lymphomas (PTCL) (e.g., cutaneous T-cell lymphoma (CTCL) (e.g., mycosis fungoides, Sézary syndrome), angioimmunoblastic T-cell lymphoma, extranodal natural killer T-cell lymphoma, enteropathic T-cell lymphoma, subcutaneous panniculitis-like T-cell lymphoma, and anaplastic large cell lymphoma). T-cell NHL, such as leukemia / lymphoma; mixtures of one or more of the above leukemias / lymphomas; as well as multiple myeloma (MM), heavy chain diseases (e.g., alpha chain diseases, gamma chain diseases, mu chain diseases); 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., generalized obesity) myelodysplastic syndromes (MDS); mesothelioma; myeloproliferative disorders (MPDs) (e.g., polycythemia vera (PV), essential thrombocytosis (ET), primary myelofibrosis (AMM) also known as myelofibrosis (MF), chronic idiopathic myelofibrosis, chronic myeloid leukemia (CML), chronic neutrophilic leukemia (CNL), hypereosinophilic syndrome (HES)); neuroblastoma; neurofibromas (e.g., neurofibromatosis (NF) type 1 or 2, schwannomatosis); neuroendocrine carcinomas (e.g., gastroenteropancreatic neuroendocrine tumors (GEP-NETs), carcinoid tumors); osteosarcomas (e.g., bone cancer);Ovarian cancer (e.g., cystadenocarcinoma, ovarian embryonal carcinoma, ovarian adenocarcinoma); papillary adenocarcinoma; pancreatic cancer (e.g., pancreatic adenocarcinoma, intraductal papillary mucinous neoplasm (IPMN), pancreatic islet cell tumor); penile cancer (e.g., Paget's disease of the penis and scrotum); pinealoma; primitive neuroectodermal tumor (PNT); plasma cell neoplasm; 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...

Claims

1. Formula (Ib): 【Chemical 334】 (In the formula, A is a nitrogen-containing heterocyclyl optionally substituted with one or more R 1 ; B is a nitrogen-containing heteroaryl optionally substituted with one or more R 1 ; L is -O-, -N(R ３ ) -, -N(R ３ )C(O)-, or -C(O)N(R ３ )- and; M and P are each independently C(R ２ ) or N, and M and P cannot both be N; X is N or N(R 5c ) and Y is C(R ５ａ ) wherein the bond between X and Y, if valences allow, can be a single or double bond; Each R １ are independently hydrogen, C １ ~C ６ Alkyl, C ２ ~C ６ Alkenyl, C ２ ~C ６ Alkynyl, C １ ~C ６ Heteroalkyl, C １ ~C ６ Haloalkyl, cycloalkyl, heterocyclyl, aryl, C １ ~C ６ Alkylene-aryl, C １ ~C ６ Alkenylene-aryl, C １ ~C ６ Alkylene-heteroaryl, heteroaryl, halo, cyano, oxo, -OR Ａ , -NR Ｂ R Ｃ , -NR Ｂ C(O)R Ｄ , -NO ２ , —C(O)NR Ｂ R Ｃ , -C(O)R Ｄ , -C(O)OR Ｄ , -SR Ｅ , or -S(O) ｘ R Ｄ wherein each alkyl, alkylene, alkenyl, alkenylene, alkynyl, heteroalkyl, haloalkyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl is selected from one or more R ８ optionally substituted with; or Two R's １ The groups, together with the atoms to which they are attached, form a 3- to 7-membered cycloalkyl, heterocyclyl, aryl, or heteroaryl, where each cycloalkyl, heterocyclyl, aryl, and heteroaryl is selected from one or more R ８ optionally substituted with; Each R ２ are independently hydrogen, halo, cyano, C １ ~C ６ Alkyl, C ２ ~C ６ Alkenyl, C ２ ~C ６ Alkynyl, or -OR Ａ and Each R ３ are independently hydrogen, C １ ~C ６ Alkyl, or C １ ~C ６ haloalkyl; R ５ａ But hydrogen, C １ ~C ６ Alkyl, C ２ ~C ６ Alkenyl, C ２ ~C ６ Alkynyl, C １ ~C ６ Heteroalkyl, C １ ~C ６ Haloalkyl, cycloalkyl, halo, cyano, oxo, -OR Ａ , -NR Ｂ R Ｃ , -C(O)R Ｄ , or —C(O)OR Ｄ and Each R ５ｃ But hydrogen, C １ ~C ６ Alkyl, C １ ~C ６ Haloalkyl, or C(O)R Ｄ and Each R ７ But independently, C １ ~C ６ Alkyl, C ２ ~C ６ Alkenyl, C ２ ~C ６ Alkynyl, C １ ~C ６ Heteroalkyl, C １ ~C ６ Haloalkyl, halo, oxo, cyano, NR Ｂ C(O)R Ｄ , —C(O)NR Ｂ R Ｃ , -C(O)R Ｄ , or -SR Ｅ wherein alkyl, alkenyl, alkynyl, heteroalkyl, and haloalkyl are selected from one or more R ９ optionally substituted with; R ８ and R ９ are each independently, C １ ~C ６ Alkyl, C ２ ~C ６ Alkenyl, C ２ ~C ６ Alkynyl, C １ ~C ６ Heteroalkyl, C １ ~C ６ Haloalkyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, halo, cyano, oxo, -OR Ａ , -NR Ｂ R Ｃ , -NR Ｂ C(O)R Ｄ , -NO ２ , —C(O)NR Ｂ R Ｃ , -C(O)R Ｄ , -C(O)OR Ｄ , -SR Ｅ , or -S(O) ｘ R Ｄ wherein each of alkyl, alkenyl, alkynyl, heteroalkyl, haloalkyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl is selected from one or more R １１ optionally substituted with; Each R Ａ are independently hydrogen, C １ ~C ６ Alkyl, C １ ~C ６ Haloalkyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, C １ ~C ６ Alkylene-aryl, C １ ~C ６ Alkylene-heteroaryl, —C(O)R Ｄ , or -S(O) ｘ R Ｄ and R Ｂ and R Ｃ each independently represents hydrogen, C １ ~C ６ Alkyl, C １ ~C ６ Heteroalkyl, cycloalkyl, heterocyclyl, -OR Ａ or R Ｂ and R Ｃ together with the atoms to which they are attached, may be one or more R １０ forming a 3- to 7-membered heterocyclyl ring optionally substituted with Each R Ｄ and R Ｅ are independently hydrogen, C １ ~C ６ Alkyl, C ２ ~C ６ Alkenyl, C ２ ~C ６ Alkynyl, C １ ~C ６ Heteroalkyl, C １ ~C ６ Haloalkyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, C １ ~C ６ Alkylene-aryl, or C １ ~C ６ alkylene-heteroaryl; R １０ But C １ ~C ６ alkyl or halo; Each R １１ But independently, C １ ~C ６ Alkyl, C １ ~C ６ Heteroalkyl, C １ ~C ６ haloalkyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, halo, cyano, oxo, or -OR Ａ and n is 0, 1, 2, 3, or 4; x is 0, 1, or 2. or a pharmaceutically acceptable salt, solvate, hydrate, tautomer, or stereoisomer thereof.

2. 2. The compound of claim 1, wherein A is a monocyclic or bicyclic heterocyclyl.

3. 3. The compound of claim 1 or 2, wherein A is monocyclic heterocyclyl.

4. A is, 【Chemical 335】 The compound according to any one of claims 1 to 3, selected from:

5. A is, 【Chemical 336】 The compound according to any one of claims 1 to 4, selected from:

6. A is, 【Chemical 337】 The compound according to any one of claims 1 to 5, selected from:

7. B, 【Chemical 338】 The compound according to any one of claims 1 to 6, selected from:

8. B, 【Chemical 339】 The compound according to any one of claims 1 to 7, selected from:

9. B, 【Hua340】 The compound according to any one of claims 1 to 8, selected from:

10. L is —O— or —N(R ３ 10. The compound according to claim 1, wherein

11. L is -N(R ３ 11. The compound according to claim 1, wherein

12. 【341】 but, 【Chemical 342】 The compound according to any one of claims 1 to 11, selected from:

13. Each of M and P is independently C(R ２ 13. The compound according to any one of claims 1 to 12, wherein

14. The compound has the formula (I-c): 【Chemical 345】 (In the formula, A, B, L, R ２ , R ５ｃ , R ７ , m, n, and their subvariables are as defined in claim 1. or a pharmaceutically acceptable salt, solvate, hydrate, tautomer, or stereoisomer thereof.

15. The compound has the formula (I-e): 【Chemical 347】 (In the formula, A, B, L, R ２ , R ５ａ , R ７ , n, and their subvariables are as defined in claim 1, and m is 2. or a pharmaceutically acceptable salt, solvate, hydrate, tautomer, or stereoisomer thereof.

16. The compound has the formula (If): 【Chemical 348】 (In the formula, A, B, X, Y, R ３ , R ７ , n, and their subvariables are as defined in claim 1. or a pharmaceutically acceptable salt, solvate, hydrate, tautomer, or stereoisomer thereof.

17. The compound has the formula (I-g): 【Chemical 349】 (In the formula, A, B, L, R', R ２ , R ７ , n, and their subvariables are as defined in claim 1, and R' is hydrogen, C １ ~C ６ Alkyl, C １ ~C ６ Haloalkyl, cycloalkyl, or —C(O)R Ｄ and m is 2 or a pharmaceutically acceptable salt, solvate, hydrate, tautomer, or stereoisomer thereof.

18. The compound represented by formula (Ih): 【Hua350】 (In the formula, A is a 6-membered heterocyclyl or heteroaryl, each of which is selected from the group consisting of one or more R １ optionally substituted with; B is a 5-membered heterocyclyl or heteroaryl, each of which is selected from the group consisting of one or more R １ optionally substituted with; L, R ５ａ , R ２ , R ７ , n, and their subvariables are as defined in claim 1, and m is 2. or a pharmaceutically acceptable salt, solvate, hydrate, tautomer, or stereoisomer thereof.

19. The following table 【Chemistry 351】 【Chemical 352】 【Chemical 353】 【Chemical 354】 【Chemical 355】 【Chemical 356】 【Chemical 357】 【Chemical 358】 【Chemical 359】 【Hua360】 or a pharmaceutically acceptable salt, solvate, hydrate, tautomer or stereoisomer thereof.

20. A pharmaceutical composition comprising a compound according to any one of claims 1 to 19 and a pharmaceutically acceptable excipient.

21. The compound is (i) modifying a target nucleic acid; (ii) binds to a target nucleic acid; and / or (iii) stabilize the target nucleic acid; A compound according to any one of claims 1 to 19 or a pharmaceutical composition according to claim 20.

22. The compound is (i) increases splicing at a splice site on a target nucleic acid 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, where the term "about" means ±10% of the value; and / or (ii) reduces splicing at a splice site on a target nucleic acid 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, wherein the term "about" means ±10% of the value; A compound according to any one of claims 1 to 19 or a pharmaceutical composition according to claim 20.

23. 20. A method for forming a complex comprising a spliceosome component, a nucleic acid, and a compound of formula (I-b) according to any one of claims 1 to 19, the method comprising contacting the nucleic acid with the compound of formula (I-b).

24. 24. The method of claim 23, wherein the spliceosome components are recruited to the nucleic acid in the presence of the compound of formula (Ib).

25. A method for modifying the three-dimensional structure of a nucleic acid, the method comprising contacting the nucleic acid with a compound of formula (Ib) according to any one of claims 1 to 19 or the pharmaceutical composition according to claim 20.

26. The modification is (i) forming a bulge in the nucleic acid; (ii) stabilizing the bulge of the nucleic acid; and / or (iii) reducing the bulge of the nucleic acid; 26. The method of claim 25, comprising:

27. A composition for use in treating a disease or disorder in a subject, the composition comprising a compound of formula (Ib) according to any one of claims 1 to 19.

28. 28. The composition for use of claim 27, wherein the disease or disorder comprises a proliferative disease.

29. 28. The composition for use of claim 27, wherein the disease or disorder comprises 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.

30. 28. The composition for use according to claim 27, wherein the disease or disorder comprises a neurological disease or disorder.

31. 28. The composition for use of claim 27, wherein the disease or disorder comprises Huntington's disease.

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