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] (In the formula, A and B each independently represent one or more R 1 L is cycloalkyl, heterocyclyl, aryl, or heteroaryl optionally substituted with -C-C alkylene, -C-C heteroalkylene, -O-, -C(O)-, -N(R 3)-, -S(O) x -, -N(R 3 )C(O)- or -C(O)N(R 3 )-, and 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 ), the bond between X and Y may be a single or double bond, when valences permit, and both X and Y are C(R 5a )(R 5b ) is not necessarily; each R 1 are independently hydrogen, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 heteroalkyl, C1-C6 haloalkyl, cycloalkyl, heterocyclyl, aryl, C1-C6 alkylene-aryl, C1-C6 alkenylene-aryl, C1-C6 alkylene-heteroaryl, heteroaryl, halo, cyano, oxo, -OR A , -NR B R C , -NR B C(O)R D , -NO2, -C(O)NR B R C , -C(O)R D , -C(O)OR D , -SR E or -S(O) x R D and each alkyl, alkylene, alkenyl, alkenylene, alkynyl, heteroalkyl, haloalkyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl may be selected from 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, and each cycloalkyl, heterocyclyl, aryl, and heteroaryl may be joined by one or more R 8 and each R2 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, C1-C6 heteroalkyl, C1-C6 haloalkyl, cycloalkyl, or heterocyclyl; each alkyl, heteroalkyl, haloalkyl, cycloalkyl, and heterocyclyl may be joined by one or more R 12 and 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)R D , -C(O)NR B R C , -C(O)R D or -SR E and alkyl, alkenyl, alkynyl, heteroalkyl, and haloalkyl are each independently selected from the group consisting of 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, and each cycloalkyl, heterocyclyl, aryl, and heteroaryl may be joined by one or more R 9 optionally substituted with 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 and each R A are independently hydrogen, C1-C6 alkyl, C1-C6 haloalkyl, aryl, heteroaryl, C1-C6 alkylene-aryl, C1-C6 alkylene-heteroaryl, -C(O)R D or -S(O) x R D and;R B and R C each independently represents hydrogen, C1-C6 alkyl, C1-C6 heteroalkyl, cycloalkyl, heterocyclyl, -OR A or 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 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 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 each R 12 are independently deuterium, 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] The terms "alkylene," "alkenylene," "alkynylene," "haloalkylene," "heteroalkylene," "cycloalkylene," or "heterocyclylene," by themselves or as part of another substituent, unless otherwise stated, are divalent radicals derived from alkyl, alkenyl, alkynyl, haloalkylene, heteroalkylene, cycloalkyl, or heterocyclyl, respectively. For example, the term "alkenylene," by itself or as part of another substituent, means, unless otherwise stated, a divalent group derived from an alkene. An alkylene, alkenylene, alkynylene, haloalkylene, heteroalkylene, cycloalkylene, or heterocyclylene group may be described, for example, as C-C-membered alkylene, C-C-membered alkenylene, C-C-membered alkynylene, C-C-membered haloalkylene, C-C-membered heteroalkylene, C-C-membered cycloalkylene, or C-C-membered heterocyclylene, where the term "membered" refers to a non-hydrogen atom within the moiety. For heteroalkylene and heterocyclylene groups, heteroatoms can also occupy either or both of the chain termini (e.g., alkyleneoxy, alkylenedioxy, alkyleneamino, alkylenediamino, etc.). Furthermore, no orientation of the linking group is implied by the direction in which the formula of the linking group is written. For example, the formula -C(O)R'- can represent both -C(O)R'- and -R'C(O)-.

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

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

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

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

[0035] As used herein, the term "nucleobase" refers to a nitrogen-containing biological compound found linked to a sugar in a nucleoside, which is a basic building block of deoxyribonucleic acid (DNA) and ribonucleic acid (RNA). The major or naturally occurring nucleobases are cytosine (DNA and RNA), guanine (DNA and RNA), adenine (DNA and RNA), thymine (DNA), and uracil (RNA), abbreviated as C, G, A, T, and U, respectively. Because A, G, C, and T occur in DNA, these molecules are referred to as DNA bases. A, G, C, and U are referred to as RNA bases. Adenine and guanine belong to a bicyclic class of molecules called purines (abbreviated as R). Cytosine, thymine, and uracil are all pyrimidines. Other nucleobases that do not function as a normal part of the genetic code are referred to as non-naturally occurring. In one embodiment, the nucleobase can be chemically modified, for example, with alkyl (e.g., methyl), halo, -O-alkyl, or other modifications.

[0036] As used herein, the term "nucleic acid" refers to deoxyribonucleic acid (DNA) or ribonucleic acid (RNA) and polymers thereof in single- or double-stranded form. The term "nucleic acid" includes genes, cDNAs, pre-mRNAs, or mRNAs. In one embodiment, a nucleic acid molecule is synthetic (e.g., chemically synthesized) or recombinant. Unless otherwise limited, the term encompasses nucleic acids containing analogs or derivatives of natural nucleotides that have similar binding properties as the reference nucleic acid and are metabolized in a manner similar to natural nucleotides. Unless otherwise indicated, a particular nucleic acid sequence implicitly encompasses not only the sequence explicitly indicated, but also conservatively modified variants thereof (e.g., degenerate codon substitutions), alleles, orthologs, SNPs, and complementary sequences.

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

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

[0039] 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.

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

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

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

[0043] As used herein, a pure enantiomer compound is substantially free of other enantiomers or stereoisomers of the compound (i.e., 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.

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

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

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

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

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

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

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

[0051] The term "solvate" refers to a form of a compound associated with a solvent, usually through solvolysis. This physical association may include hydrogen bonding. Conventional solvents include water, methanol, ethanol, acetic acid, DMSO, THF, diethyl ether, etc. The compound of formula (I) may be prepared, for example, in crystalline form, and may be solvated. Suitable solvates include pharmaceutically acceptable solvates, and further include both stoichiometric and non-stoichiometric solvates. In certain instances, a solvate may be isolated, for example, when one or more solvent molecules are incorporated into the crystal lattice of a crystalline solid. "Solvate" encompasses both solution-phase and isolatable solvates. Representative solvates include hydrates, ethanolates, and methanolates.

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

[0053] The term "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.

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

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

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

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

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

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

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

[0061] A "therapeutically effective amount" of a compound of Formula (I) is an amount sufficient to provide a therapeutic benefit in the treatment of a condition or to delay or minimize one or more symptoms associated with the condition. In some embodiments, a therapeutically effective amount is an amount sufficient to provide a therapeutic benefit in the treatment of a condition or to minimize one or more symptoms associated with the condition. A therapeutically effective amount of a compound refers to an amount of a therapeutic agent, alone or in combination with other therapies, that provides a therapeutic benefit in the treatment of a condition. The term "therapeutically effective amount" 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.

[0062] The terms "peptide," "polypeptide," and "protein" are used interchangeably and refer to compounds composed of amino acid residues covalently linked by peptide bonds. A protein or peptide must contain at least two amino acids, and there is no limit to the maximum number of amino acids it may contain. A polypeptide includes any peptide or protein containing two or more amino acids joined to each other by peptide bonds. As used herein, the term refers to both short chains, e.g., also commonly referred to in the art as peptides, oligopeptides, and oligomers, and longer chains, of which there are many varieties, commonly referred to in the art as proteins.

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

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

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

[0066] "Proliferative disease" refers to a disease caused by 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.

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

[0068] compound The present disclosure provides a compound of formula (I): [ka] (In the formula, A and B each independently represent one or more R 1 L is cycloalkyl, heterocyclyl, aryl, or heteroaryl optionally substituted with -C-C alkylene, -C-C heteroalkylene, -O-, -C(O)-, -N(R 3 )-, -S(O) x -, -N(R 3 )C(O)- or -C(O)N(R 3)-, and 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 ), the bond between X and Y may be a single or double bond, when valences permit, and both X and Y are C(R 5a )(R 5b ) or C(R 5a ) is not necessarily; each R 1 are independently hydrogen, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 heteroalkyl, C1-C6 haloalkyl, cycloalkyl, heterocyclyl, aryl, C1-C6 alkylene-aryl, C1-C6 alkenylene-aryl, C1-C6 alkylene-heteroaryl, heteroaryl, halo, cyano, oxo, -OR A , -NR B R C , -NR B C(O)R D , -NO2, -C(O)NR B R C , -C(O)R D , -C(O)OR D , -SR E or -S(O) x R D and each alkyl, alkylene, alkenyl, alkenylene, alkynyl, heteroalkyl, haloalkyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl may be selected from 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, and each cycloalkyl, heterocyclyl, aryl, and heteroaryl may be joined by one or more R 8 and each R 2are independently hydrogen, halo, cyano, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, or -OR A and each R 4 are independently hydrogen, C1-C6 alkyl, C1-C6 heteroalkyl, C1-C6 haloalkyl, cycloalkyl, or heterocyclyl, and each alkyl, heteroalkyl, haloalkyl, cycloalkyl, and heterocyclyl is selected from the group consisting of one or more R 12 and 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 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 and alkyl, alkenyl, alkynyl, heteroalkyl, and haloalkyl are each independently selected from the group consisting of one or more R 9or 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, and each cycloalkyl, heterocyclyl, aryl, and heteroaryl may be joined by one or more R 9 optionally substituted with 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 and each R A are independently hydrogen, C1-C6 alkyl, C1-C6 haloalkyl, aryl, heteroaryl, C1-C6 alkylene-aryl, C1-C6 alkylene-heteroaryl, -C(O)R D or -S(O) x R D and;R B and R C each independently represents hydrogen, C1-C6 alkyl, C1-C6 heteroalkyl, cycloalkyl, heterocyclyl, -OR A or 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 withD 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, 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 and each R 12 are independently deuterium, halo, cyano, -OR A , -NR B R C , -NR B C(O)R D , -C(O)NR B R C , -C(O)R D , -C(O)OR D or -C(O)R D 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.

[0069] In another aspect, the present disclosure provides a compound of formula (Ia): [ka] (In the formula, A and B each independently represent one or more R 1 L is cycloalkyl, heterocyclyl, aryl, or heteroaryl optionally substituted with -C-C alkylene, -C-C heteroalkylene, -O-, -C(O)-, -N(R 3 )-, -S(O) x -, -N(R3 )C(O)- or -C(O)N(R 3 )-, and 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 ), the bond between X and Y may be a single or double bond, when valences permit, and both X and Y are C(R 5a )(R 5b ) is not necessarily; each R 1 are independently hydrogen, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 heteroalkyl, C1-C6 haloalkyl, cycloalkyl, heterocyclyl, aryl, C1-C6 alkylene-aryl, C1-C6 alkenylene-aryl, C1-C6 alkylene-heteroaryl, heteroaryl, halo, cyano, oxo, -OR A , -NR B R C , -NR B C(O)R D , -NO2, -C(O)NR B R C , -C(O)R D , -C(O)OR D , -SR E or -S(O) x R D and each alkyl, alkylene, alkenyl, alkenylene, alkynyl, heteroalkyl, haloalkyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl may be selected from 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, and each cycloalkyl, heterocyclyl, aryl, and heteroaryl may be joined by one or more R 8 and each R 2are 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 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 and alkyl, alkenyl, alkynyl, heteroalkyl, and haloalkyl are each independently selected from the group consisting of 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, and each cycloalkyl, heterocyclyl, aryl, and heteroaryl may be joined by one or more R 9 optionally substituted with 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 and each R A are independently hydrogen, C1-C6 alkyl, C1-C6 haloalkyl, aryl, heteroaryl, C1-C6 alkylene-aryl, C1-C6 alkylene-heteroaryl, -C(O)R D or -S(O) x R D and;R B and R C each independently represents hydrogen, C1-C6 alkyl, C1-C6 heteroalkyl, cycloalkyl, heterocyclyl, -OR A or 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 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.

[0070] 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

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

[0072] In some embodiments, A or B is independently a bicyclic ring, such as a bicyclic cycloalkyl, bicyclic heterocyclyl, bicyclic aryl, or bicyclic heteroaryl. The bicyclic ring 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, A or B independently selects one or more R 1 is a bicyclic ring optionally substituted with

[0073] In some embodiments, A or B is independently a tricyclic ring, such as a tricyclic cycloalkyl, tricyclic heterocyclyl, tricyclic aryl, or tricyclic heteroaryl. The tricyclic ring can be saturated, partially unsaturated, or fully unsaturated (e.g., aromatic). In some embodiments, A or B is independently a tricyclic ring comprising a fused, bridged, or spiro ring system, or a combination thereof. In some embodiments, A or B is independently a tricyclic ring comprising 6 to 24 ring atoms (e.g., 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, or 24 ring atoms). In some embodiments, A is an 8-membered tricyclic ring. In some embodiments, B is an 8-membered tricyclic ring. In some embodiments, A is a 9-membered tricyclic ring. In some embodiments, B is a 9-membered tricyclic ring. In some embodiments, A is a 10-membered tricyclic ring. In some embodiments, B is a 10-membered tricyclic ring. In some embodiments, A or B independently comprises one or more R 1 is a tricyclic ring optionally substituted with

[0074] 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.

[0075] 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 is replaced by .

[0076] In some embodiments, A or B is independently a nitrogen-containing heteroaryl, for example, a heteroaryl containing one or more nitrogen atoms. The one or more nitrogen atoms of the nitrogen-containing heteroaryl 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 .

[0077] 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.

[0078] 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.

[0079] 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.

[0080] 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.

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

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

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

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

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

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

[0088] 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, 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.

[0089] 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

[0090] 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).

[0091] 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

[0092] 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 )-.

[0093] In some embodiments, L is oxygen. In some embodiments, L is nitrogen and R3 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-.

[0094] 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-.

[0095] 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).

[0096] In some embodiments, [ka] teeth, [ka] (In the formula, R 2 is as defined above) In some embodiments, R 2 is hydrogen.

[0097] 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 ) is not necessarily the case.

[0098] 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.

[0099] In some embodiments, X and Y are each independently R 7 In some embodiments, two R 7 The groups, taken together with the atoms to which they are attached, form a cycloalkyl, heterocyclyl, aryl, or heteroaryl. In some embodiments, X and Y are each independently R 7 C substituted with two R 7 The group, taken together with X and Y, forms a cycloalkyl, heterocyclyl, aryl, or heteroaryl (e.g., a 3- to 7-membered cycloalkyl, heterocyclyl, aryl, or heteroaryl). In some embodiments, R 7 The group, taken together with X and Y, forms a 4- to 7-membered heterocyclyl. In some embodiments, R 7 The group, taken together with X and Y, forms a 4- to 7-membered heteroaryl. In some embodiments, R 7 The group, taken together with X and Y, forms a 5-membered heterocyclyl. In some embodiments, R 7 The group, taken together with X and Y, forms a 5-membered heteroaryl. The cycloalkyl, heterocyclyl, aryl, or heteroaryl may be joined by one or more R 9 may be substituted with

[0100] In some embodiments, [ka] teeth, [ka] (In the formula, D, E, F, G, and H each independently represent C, C(R 5d ), C(R 5d )(R 5e ), N, N(R 5f ), S or O; R 5d , R 5e and R 5f are each independently hydrogen, halo, or C1-C6 alkyl, or R 5d and R 5e together form an oxo group; R 7 is as defined herein; and n is an integer of 0, 1, or 2. is selected from.

[0101] In some embodiments, one of D, E, F, G, and H is N(R 5f ) or N, and the others of D, E, F, G and H are each independently C(R 5d In some embodiments, two of D, E, F, G, and H are each independently N(R 5f ) or N, and the others of D, E, F, G and H are each independently C(R 5d In some embodiments, three of D, E, F, G, and H are each independently N(R 5f ) or N, and the others of D, E, F, G and H are each independently C(R 5d In some embodiments, one of D, E, F, G, and H is N(R 5f ), and the others of D, E, F, G, and H are each independently C(R 5d )(R 5e In some embodiments, two of D, E, F, G, and H are each independently N(R 5f), and the others of D, E, F, G and H are each independently C(R 5d )(R 5e In some embodiments, three of D, E, F, G, and H are each independently N(R 5f ), and the others of D, E, F, G and H are each independently C(R 5d )(R 5e )

[0102] In some embodiments, one of D, E, F, G, and H is N(R 5f ), and the others of D, E, F, G and H are independently O or C(R 5d )(R 5e In some embodiments, one of D, E, F, G, and H is S, and the others of D, E, F, G, and H are each independently N or C(R 5d ) (e.g., CH). In some embodiments, one of D, E, F, G, and H is S and the others of D, E, F, G, and H are each independently C(R 5d ) (e.g., CH).

[0103] In some embodiments, one of D, E, and F is N(R 5f ), and the others of D, E and F are each independently C(R 5d In some embodiments, two of D, E, and F are each independently N(R 5f ) or N, and the others of D, E and F are C(R 5d In some embodiments, three of D, E, and F are each independently N(R 5f ) or N. In some embodiments, D is N(R 5f ), and E and F are each independently C(R 5d In some embodiments, D is N(R 5f ) and E is C(R 5d ) and F is N. In some embodiments, D is N(R 5f) and E and F are each independently N. In some embodiments, one of D, E, and F is NH and the other of D, E, and F is independently CH or N.

[0104] In some embodiments, one of D, E, and F is N(R 5f ) (e.g., NH), and the others of D, E, and F are independently O or C(R 5d )(R 5e ) (e.g., C(O)). In some embodiments, D is N(R 5f ) (e.g., CH), and E is C(R 5d )(R 5e ) (e.g., C(O)) and F is O. In some embodiments, D is O and E is C(R 5d )(R 5e ) (e.g., C(O)), and F is N(R 5f ) (e.g., NH). In some embodiments, D is NH, E is C(O), and F is O. In some embodiments, D is O, E is C(O), and F is NH.

[0105] In some embodiments, one of D, E, and F is S and the others of D, E, and F are each independently N or C(R 5d ) (e.g., CH). In some embodiments, one of D, E, and F is S and the others of D, E, and F are each independently C(R 5d ) (e.g., CH). In some embodiments, D is S, and E and F are each independently N or C(R 5d ) (e.g., CH). In some embodiments, D is S and E is C(R 5d ) (e.g., CH) and F is N. In some embodiments, D is S and E and F are each independently C(R 5d ) (e.g., CH). In some embodiments, D is S, E is CH, and F is N. In some embodiments, D is S, and E and F are each independently CH.

[0106] In some embodiments, one of D, E, and F is N(R 5f ), and the others of D, E and F are each independently C(R 5d )(R 5e In some embodiments, two of D, E, and F are each independently N(R 5f ), and the others of D, E and F are C(R 5d )(R 5e In some embodiments, D is N(R 5f ), and E and F are each independently C(R 5d )(R 5e In some embodiments, E is N(R 5f ), and D and F are each independently C(R 5d )(R 5e In some embodiments, F is N(R 5f ), and D and E are each independently C(R 5d )(R 5e ). In some embodiments, D is NH, E is C(O), and F is CH. In some embodiments, D is CH, E is NH, and F is C(O). In some embodiments, D is NH, E is CH, and F is C(O).

[0107] In some embodiments, [ka] teeth, [ka] (In the formula, R 7 and n is as defined above). or a tautomer thereof.

[0108] In some embodiments, [ka] teeth, [ka] is selected from.

[0109] In some embodiments, [ka] teeth, [ka] In some embodiments, [ka] teeth, [ka] is.

[0110] In some embodiments, R 1 is hydrogen. In some embodiments, R 1 is C1-C6 alkyl. In some embodiments, R 1 is C2-C6 alkenyl. In some embodiments, R 1 is C2-C6 alkynyl. In some embodiments, R 1 is C1-C6 heteroalkyl. In some embodiments, R 1 is C1-C6 haloalkyl (e.g., —CF3). In some embodiments, R 1 is C alkyl (e.g., methyl). In some embodiments, R 1is 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.

[0111] 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 1 is C1-C6 alkylene-heteroaryl. In some embodiments, R 1 is heteroaryl. In some embodiments, R 1 is unsubstituted cycloalkyl, unsubstituted heterocyclyl, unsubstituted aryl, unsubstituted C1-C6 alkylene-aryl, unsubstituted C1-C6 alkenylene-aryl, unsubstituted C1-C6 alkylene-heteroaryl, or unsubstituted heteroaryl. In some embodiments, R 1 is one or more R8 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

[0112] In some embodiments, R 1 -OR A In some embodiments, R 1 is -NR B R C (e.g., NH or NMe). In some embodiments, R 1 is -NR B C(O)R D In some embodiments, R 1 is -C(O)NR B R C In some embodiments, R 1 is -C(O)R D In some embodiments, R 1 is -C(O)OR D In some embodiments, R 1 -SR E In some embodiments, R 1 is -S(O) x R D In some embodiments, R 1is 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.

[0113] 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

[0114] 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 2 is 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.

[0115] 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. In some embodiments, R 3 is one or more R 12 In some embodiments, R 12 is deuterium. In some embodiments, R 3 is CD3.

[0116] 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.

[0117] In some embodiments, R 5a and R 5b are each independently hydrogen or C1-C6 alkyl. In some embodiments, R 5a is hydrogen. In some embodiments, R5b 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).

[0118] 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.

[0119] In some embodiments, R 7 is C1-C6 alkyl. In some embodiments, R 7 is C2-C6 alkenyl. In some embodiments, R 7 is 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 7is 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.

[0120] In some embodiments, 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. In some embodiments, two R 7The groups, together with the atom to which they are attached (e.g., X or Y), form a 4- to 7-membered heterocyclyl. In some embodiments, two R 7 The groups, together with the atom to which they are attached (e.g., X or Y), form a 5- or 6-membered aryl. In some embodiments, two R 7 The groups, together with the atom to which they are attached (e.g., X or Y), form a 5- or 6-membered heteroaryl. In some embodiments, two R 7 The groups, together with the atom to which they are attached (e.g., X or Y), form a 5-membered heterocyclyl. In some embodiments, two R 7 The groups, together with the atom to which they are attached (e.g., X or Y), form a 5-membered heteroaryl. A cycloalkyl, heterocyclyl, aryl, or heteroaryl can be formed by one or more R 9 may be substituted with

[0121] In some embodiments, R 8 is 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 R11 In some embodiments, R 8 is one or more R 11 is a C1-C6 heteroalkyl substituted with

[0122] 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 11 In 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

[0123] 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 8is —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.

[0124] 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 9 is 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

[0125] 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 11 and heteroaryl substituted with

[0126] 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 DIn 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.

[0127] In some embodiments, R 10 is C1-C6 alkyl. In some embodiments, R 10 is halo (e.g., fluoro, chloro, bromo, or iodo).

[0128] In some embodiments, R 11 is C1-C6 alkyl. In some embodiments, R 11 is C1-C6 heteroalkyl. In some embodiments, R 11 is C1-C6 haloalkyl (e.g., —CF3). In some embodiments, R 11 is cycloalkyl. In some embodiments, R 11 is heterocyclyl. In some embodiments, R 11 is aryl. In some embodiments, R 11 is heteroaryl. In some embodiments, R 11 is halo. In some embodiments, R 11 is cyano. In some embodiments, R 11 is oxo. In some embodiments, R 11 -OR A is.

[0129] 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 Ais 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.

[0130] 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 C Each of R is independently hydrogen. B and R C Each of is independently C1-C6 alkyl. In some embodiments, R B and R C is hydrogen and R B and R C and the other is C1-C6 alkyl. In some embodiments, R B and R C are one or more R's along with the atoms to which they are attached. 10 (e.g., one, two, or three R 10 ) to form a 3- to 7-membered heterocyclyl ring optionally substituted with

[0131] In some embodiments, R D , R Eor 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, R E is C1-C6 haloalkyl. In some embodiments, R D is cycloalkyl. In some embodiments, R E is cycloalkyl. In some embodiments, R D is heterocyclyl. In some embodiments, R E is heterocyclyl. In some embodiments, R D is aryl. In some embodiments, R E is aryl. In some embodiments, R D is heteroaryl. In some embodiments, R E is heteroaryl. In some embodiments, R D is C1-C6 alkylene-aryl (e.g., benzyl). In some embodiments, RE 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.

[0132] 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.

[0133] In some embodiments, the compound has formula (Ib): [ka] (In the formula, A and B each independently represent one or more R 1 L is cycloalkyl, heterocyclyl, aryl, or heteroaryl optionally substituted with -C-C alkylene, -C-C heteroalkylene, -O-, -C(O)-, -N(R 3 )-, -S(O) x -, -N(R 3 )C(O)- or -C(O)N(R 3 )-, and 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(R5a ), C(R 5a )(R 5b ), N or N(R 5c ), the bond between X and Y may be a single or double bond, when valences permit, and both X and Y are C(R 5a )(R 5b ) is not necessarily; each R 1 are independently hydrogen, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 heteroalkyl, C1-C6 haloalkyl, cycloalkyl, heterocyclyl, aryl, C1-C6 alkylene-aryl, C1-C6 alkenylene-aryl, C1-C6 alkylene-heteroaryl, heteroaryl, halo, cyano, oxo, -OR A , -NR B R C , -NR B C(O)R D , -NO2, -C(O)NR B R C , -C(O)R D , -C(O)OR D , -SR E or -S(O) x R D and each alkyl, alkylene, alkenyl, alkenylene, alkynyl, heteroalkyl, haloalkyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl may be selected from 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, and each cycloalkyl, heterocyclyl, aryl, and heteroaryl may be joined by one or more R 8 and 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 4is 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 and alkyl, alkenyl, alkynyl, heteroalkyl, and haloalkyl are each independently selected from the group consisting of 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, and each cycloalkyl, heterocyclyl, aryl, and heteroaryl may be joined by one or more R 9 optionally substituted with 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)RD , -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 and each R A are independently hydrogen, C1-C6 alkyl, C1-C6 haloalkyl, aryl, heteroaryl, C1-C6 alkylene-aryl, C1-C6 alkylene-heteroaryl, -C(O)R D or -S(O) x R D and;R B and R C each independently represents hydrogen, C1-C6 alkyl, C1-C6 heteroalkyl, cycloalkyl, heterocyclyl, -OR A or 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 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 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.

[0134] In some embodiments, the present disclosure provides a compound of formula (Ic): [ka] (In the formula, A and B each independently represent one or more R 1 L is cycloalkyl, heterocyclyl, aryl, or heteroaryl optionally substituted with -C-C alkylene, -C-C 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 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 ), the bond between X and Y may be a single or double bond, when valences permit, and both X and Y are C(R 5a )(R 5b ) is not necessarily; 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)ORD , -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 or two R 1 The groups, together with the atom to which they are attached, form a 3- to 7-membered cycloalkyl, heterocyclyl, aryl, or heteroaryl, and each cycloalkyl, heterocyclyl, aryl, and heteroaryl may be joined by one or more R 8 and 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)R D , -C(O)NR B R C , -C(O)RD or -SR E and alkyl, alkenyl, alkynyl, heteroalkyl, and haloalkyl are each independently selected from the group consisting of 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, and each cycloalkyl, heterocyclyl, aryl, and heteroaryl may be joined by one or more R 9 optionally substituted with 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 and each R A are independently hydrogen, C1-C6 alkyl, C1-C6 haloalkyl, aryl, heteroaryl, C1-C6 alkylene-aryl, C1-C6 alkylene-heteroaryl, -C(O)R D or -S(O) x R D and;R B and R C each independently represents hydrogen, C1-C6 alkyl, C1-C6 heteroalkyl, cycloalkyl, heterocyclyl, -OR A or R B and RC 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 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 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.

[0135] In some embodiments, the compound of Formula (I) has the formula (Id): [ka] (In the formula, A and B each independently represent one or more R 1 cycloalkyl, heterocyclyl, aryl, or heteroaryl optionally substituted with; L 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; M and P each independently represent C(R 2) or N; D, E, and F each independently represent C(R 5d ), C(R 5d )(R 5e ), N, N(R 5f ), S or O, and the bonds between atoms in the rings, including D, E and F, can be single or double bonds, when valences permit; Each R 1 are independently hydrogen, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 heteroalkyl, C1-C6 haloalkyl, cycloalkyl, heterocyclyl, aryl, C1-C6 alkylene-aryl, C1-C6 alkenylene-aryl, C1-C6 alkylene-heteroaryl, heteroaryl, halo, cyano, oxo, -OR A , -NR B R C , -NR B C(O)R D , -NO2, -C(O)NR B R C , -C(O)R D , -C(O)OR D , -SR E or -S(O) x R D and each alkyl, alkylene, alkenyl, 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 3are independently hydrogen, C1-C6 alkyl, C1-C6 heteroalkyl, C1-C6 haloalkyl, cycloalkyl, or heterocyclyl, and each alkyl, heteroalkyl, haloalkyl, cycloalkyl, and heterocyclyl is selected from the group consisting of one or more R 12 is optionally replaced by; 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 5d and R 5e are each independently hydrogen, halo, or C1-C6 alkyl; or R 5d and R 5e together form an oxo group; R 5f is hydrogen, halo, or C1-C6 alkyl; 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 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 9are 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 A or 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 Eare independently hydrogen, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 heteroalkyl, C1-C6 haloalkyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, C1-C6 alkylene-aryl, or C1-C6 alkylene-heteroaryl; Each R 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; Each R 12 are independently deuterium, 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.

[0136] In some embodiments, A is [ka] (In the formula, R 1 is as defined herein) is selected from.

[0137] In some embodiments, A is [ka] is selected from.

[0138] In some embodiments, A is [ka] is selected from.

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

[0140] 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.

[0141] 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.

[0142] In some embodiments, one of D, E, and F is N(R 5f ), and the others of D, E and F are each independently C(R 5d In some embodiments, two of D, E, and F are each independently N(R 5f ) or N, and the others of D, E and F are C(R 5d In some embodiments, three of D, E, and F are each independently N(R 5f ) or N. In some embodiments, D is N(R 5f ), and E and F are each independently C(R 5d In some embodiments, D is N(R 5f ) and E is C(R 5d ) and F is N. In some embodiments, D is N(R 5f ) and E and F are each independently N. In some embodiments, one of D, E, and F is NH and the other of D, E, and F is independently CH or N.

[0143] In some embodiments, one of D, E, and F is N(R 5f ) (e.g., NH), and the others of D, E, and F are independently O or C(R 5d )(R 5e ) (e.g., C(O)). In some embodiments, D is N(R 5f ) (e.g., CH), and E is C(R 5d )(R 5e ) (e.g., C(O)) and F is O. In some embodiments, D is O and E is C(R 5d )(R 5e ) (e.g., C(O)), and F is N(R 5f ) (e.g., NH). In some embodiments, D is NH, E is C(O), and F is O. In some embodiments, D is O, E is C(O), and F is NH.

[0144] In some embodiments, one of D, E, and F is S and the others of D, E, and F are each independently N or C(R 5d ) (e.g., CH). In some embodiments, one of D, E, and F is S and the others of D, E, and F are each independently C(R 5d ) (e.g., CH). In some embodiments, D is S, and E and F are each independently N or C(R 5d ) (e.g., CH). In some embodiments, D is S and E is C(R 5d ) (e.g., CH) and F is N. In some embodiments, D is S and E and F are each independently C(R 5d ) (e.g., CH). In some embodiments, D is S, E is CH, and F is N. In some embodiments, D is S, and E and F are each independently CH.

[0145] In some embodiments, one of D, E, and F is N(R 5f ), and the others of D, E and F are each independently C(R 5d )(R5e In some embodiments, two of D, E, and F are each independently N(R 5f ), and the others of D, E and F are C(R 5d )(R 5e In some embodiments, D is N(R 5f ), and E and F are each independently C(R 5d )(R 5e In some embodiments, E is N(R 5f ), and D and F are each independently C(R 5d )(R 5e In some embodiments, F is N(R 5f ), and D and E are each independently C(R 5d )(R 5e ). In some embodiments, D is NH, E is C(O), and F is CH. In some embodiments, D is CH, E is NH, and F is C(O). In some embodiments, D is NH, E is CH, and F is C(O).

[0146] In some embodiments, [ka] teeth, [ka] (In the formula, R 7 and n is as defined above). or a tautomer thereof.

[0147] In some embodiments, [ka] teeth, [ka] is selected from.

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

[0149] In some embodiments, the compound of Formula (I) has the formula (Ie): [ka] (In the formula, A and B each independently represent one or more R 1 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; D, E, and F each independently represent C(R 5d ), C(R 5d )(R 5e ), N, N(R 5f), S or O, and the bonds between atoms in the rings, including D, E and F, can be single or double bonds, when valences permit; Each R 1 are independently hydrogen, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 heteroalkyl, C1-C6 haloalkyl, cycloalkyl, heterocyclyl, aryl, C1-C6 alkylene-aryl, C1-C6 alkenylene-aryl, C1-C6 alkylene-heteroaryl, heteroaryl, halo, cyano, oxo, -OR A , -NR B R C , -NR B C(O)R D , -NO2, -C(O)NR B R C , -C(O)R D , -C(O)OR D , -SR E or -S(O) x R D and each alkyl, alkylene, alkenyl, 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, C1-C6 heteroalkyl, C1-C6 haloalkyl, cycloalkyl, or heterocyclyl; each alkyl, heteroalkyl, haloalkyl, cycloalkyl, and heterocyclyl may be joined by one or more R 12 is optionally replaced by; 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 5d and R 5e are each independently hydrogen, halo, or C1-C6 alkyl; or R 5d and R 5e together form an oxo group; R 5f is hydrogen, halo, or C1-C6 alkyl; 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 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 RC , -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 A or 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 11are independently C1-C6 alkyl, C1-C6 heteroalkyl, C1-C6 haloalkyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, halo, cyano, oxo, or -OR A and; Each R 12 are independently deuterium, 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.

[0150] In some embodiments, A is [ka] (In the formula, R 1 is as defined herein) is selected from.

[0151] In some embodiments, A is [ka] is selected from.

[0152] In some embodiments, A is [ka] is selected from.

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

[0154] 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.

[0155] 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.

[0156] In some embodiments, one of D, E, and F is N(R 5f ), and the others of D, E and F are each independently C(R 5d In some embodiments, two of D, E, and F are each independently N(R 5f ) or N, and the others of D, E and F are C(R 5d In some embodiments, three of D, E, and F are each independently N(R 5f ) or N. In some embodiments, D is N(R 5f ), and E and F are each independently C(R 5d In some embodiments, D is N(R 5f ) and E is C(R 5d ) and F is N. In some embodiments, D is N(R 5f ) and E and F are each independently N. In some embodiments, one of D, E, and F is NH and the other of D, E, and F is independently CH or N.

[0157] In some embodiments, one of D, E, and F is N(R 5f ) (e.g., NH), and the others of D, E, and F are independently O or C(R 5d )(R 5e ) (e.g., C(O)). In some embodiments, D is N(R 5f ) (e.g., CH), and E is C(R 5d)(R 5e ) (e.g., C(O)) and F is O. In some embodiments, D is O and E is C(R 5d )(R 5e ) (e.g., C(O)), and F is N(R 5f ) (e.g., NH). In some embodiments, D is NH, E is C(O), and F is O. In some embodiments, D is O, E is C(O), and F is NH.

[0158] In some embodiments, one of D, E, and F is S and the others of D, E, and F are each independently N or C(R 5d ) (e.g., CH). In some embodiments, one of D, E, and F is S and the others of D, E, and F are each independently C(R 5d ) (e.g., CH). In some embodiments, D is S, and E and F are each independently N or C(R 5d ) (e.g., CH). In some embodiments, D is S and E is C(R 5d ) (e.g., CH) and F is N. In some embodiments, D is S and E and F are each independently C(R 5d ) (e.g., CH). In some embodiments, D is S, E is CH, and F is N. In some embodiments, D is S, and E and F are each independently CH.

[0159] In some embodiments, one of D, E, and F is N(R 5f ), and the others of D, E and F are each independently C(R 5d )(R 5e In some embodiments, two of D, E, and F are each independently N(R 5f ), and the others of D, E and F are C(R 5d )(R 5e In some embodiments, D is N(R 5f ), and E and F are each independently C(R 5d)(R 5e In some embodiments, E is N(R 5f ), and D and F are each independently C(R 5d )(R 5e In some embodiments, F is N(R 5f ), and D and E are each independently C(R 5d )(R 5e ). In some embodiments, D is NH, E is C(O), and F is CH. In some embodiments, D is CH, E is NH, and F is C(O). In some embodiments, D is NH, E is CH, and F is C(O).

[0160] In some embodiments, [ka] teeth, [ka] (In the formula, R 7 and n is as defined above). or a tautomer thereof.

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

[0162] In some embodiments, [ka] teeth, [ka] In some embodiments, [ka] teeth, [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, the compound of Formula (I) has the formula (If): [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 each one or more 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 R4 is optionally replaced by; M and P each independently represent C(R 2 ) or N; D, E, and F each independently represent C, C(R 5d ), C(R 5d )(R 5e ), N, N(R 5f ), S or O; Each R 1 are independently hydrogen, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 heteroalkyl, C1-C6 haloalkyl, cycloalkyl, heterocyclyl, aryl, C1-C6 alkylene-aryl, C1-C6 alkenylene-aryl, C1-C6 alkylene-heteroaryl, heteroaryl, halo, cyano, oxo, -OR A , -NR B R C , -NR B C(O)R D , -NO2, -C(O)NR B R C , -C(O)R D , -C(O)OR D , -SR E or -S(O) x R D and each alkyl, alkylene, alkenyl, 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 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 5d and R 5e are each independently hydrogen, halo, or C1-C6 alkyl; or R 5d and R 5e together form an oxo group; R 5f is hydrogen, halo, or C1-C6 alkyl; 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 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 9are 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 A or 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 Eare independently hydrogen, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 heteroalkyl, C1-C6 haloalkyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, C1-C6 alkylene-aryl, or C1-C6 alkylene-heteroaryl; Each R 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.

[0165] In some embodiments, A is [ka] (In the formula, R 1 is as defined herein) is selected from.

[0166] In some embodiments, A is [ka] is selected from.

[0167] In some embodiments, A is [ka] is selected from.

[0168] In some embodiments, A is [ka] is selected from.

[0169] 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.

[0170] 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.

[0171] In some embodiments, one of D, E, and F is N(R 5f ), and the others of D, E and F are each independently C(R 5d In some embodiments, two of D, E, and F are each independently N(R 5f ) or N, and the others of D, E and F are C(R 5d In some embodiments, three of D, E, and F are each independently N(R 5f ) or N. In some embodiments, D is N(R 5f ), and E and F are each independently C(R 5d In some embodiments, D is N(R 5f ) and E is C(R 5d ) and F is N. In some embodiments, D is N(R 5f ) and E and F are each independently N. In some embodiments, one of D, E, and F is NH and the other of D, E, and F is independently CH or N.

[0172] In some embodiments, one of D, E, and F is N(R 5f ) (e.g., NH), and the others of D, E, and F are independently O or C(R 5d )(R 5e) (e.g., C(O)). In some embodiments, D is N(R 5f ) (e.g., CH), and E is C(R 5d )(R 5e ) (e.g., C(O)) and F is O. In some embodiments, D is O and E is C(R 5d )(R 5e ) (e.g., C(O)), and F is N(R 5f ) (e.g., NH). In some embodiments, D is NH, E is C(O), and F is O. In some embodiments, D is O, E is C(O), and F is NH.

[0173] In some embodiments, one of D, E, and F is S and the others of D, E, and F are each independently N or C(R 5d ) (e.g., CH). In some embodiments, one of D, E, and F is S and the others of D, E, and F are each independently C(R 5d ) (e.g., CH). In some embodiments, D is S, and E and F are each independently N or C(R 5d ) (e.g., CH). In some embodiments, D is S and E is C(R 5d ) (e.g., CH) and F is N. In some embodiments, D is S and E and F are each independently C(R 5d ) (e.g., CH). In some embodiments, D is S, E is CH, and F is N. In some embodiments, D is S, and E and F are each independently CH.

[0174] In some embodiments, one of D, E, and F is N(R 5f ), and the others of D, E and F are each independently C(R 5d )(R 5e In some embodiments, two of D, E, and F are each independently N(R 5f ), and the others of D, E and F are C(R 5d )(R5e In some embodiments, D is N(R 5f ), and E and F are each independently C(R 5d )(R 5e In some embodiments, E is N(R 5f ), and D and F are each independently C(R 5d )(R 5e In some embodiments, F is N(R 5f ), and D and E are each independently C(R 5d )(R 5e ). In some embodiments, D is NH, E is C(O), and F is CH. In some embodiments, D is CH, E is NH, and F is C(O). In some embodiments, D is NH, E is CH, and F is C(O).

[0175] In some embodiments, [ka] teeth, [ka] (In the formula, R 7 and n is as defined above). or a tautomer thereof.

[0176] In some embodiments, [ka] teeth, [ka] is selected from.

[0177] In some embodiments, [ka] teeth, [ka] In some embodiments, [ka] teeth, [ka] is.

[0178] 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-.

[0179] In some embodiments, the compound of Formula (I) has the formula (Ig): [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 each one or more 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(R3 )-, -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; D, E, and F each independently represent C, C(R 5d ), C(R 5d )(R 5e ), N, N(R 5f ), S or O; Each R 1 are independently hydrogen, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 heteroalkyl, C1-C6 haloalkyl, cycloalkyl, heterocyclyl, aryl, C1-C6 alkylene-aryl, C1-C6 alkenylene-aryl, C1-C6 alkylene-heteroaryl, heteroaryl, halo, cyano, oxo, -OR A , -NR B R C , -NR B C(O)R D , -NO2, -C(O)NR B R C , -C(O)R D , -C(O)OR D , -SR E or -S(O) x R D and each alkyl, alkylene, alkenyl, 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 Aand; 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 5d and R 5e are each independently hydrogen, halo, or C1-C6 alkyl; or R 5d and R 5e together form an oxo group; R 5f is hydrogen, halo, or C1-C6 alkyl; 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 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 9are 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 A or 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 Eare independently hydrogen, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 heteroalkyl, C1-C6 haloalkyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, C1-C6 alkylene-aryl, or C1-C6 alkylene-heteroaryl; Each R 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.

[0180] In some embodiments, A 1 is one or more R 1 In some embodiments, A is a 6-membered heterocyclyl optionally substituted with 1 is a 6-membered nitrogen-containing heterocyclyl. 1 is optionally substituted piperidinyl. In some embodiments, A 1 teeth, [ka] In some embodiments, A 1 teeth, [ka] In some embodiments, A 1 teeth, [ka] In some embodiments, A 1 teeth, [ka] In some embodiments, A 1 teeth, [ka] In some embodiments, A1 is [ka] In some embodiments, A1 is [ka] In some embodiments, A1 is [ka] In some embodiments, A1 is [ka] is.

[0181] In some embodiments, L is R 3 In some embodiments, L is -N(CH3)-. In some embodiments, L is -NH-. In some embodiments, B 1 is one or more R 1 In some embodiments, B is a 5-membered heteroaryl optionally substituted with 1 is a 5-membered nitrogen-containing heteroaryl. In some embodiments, B 1 is an optionally substituted pyrazolyl. In some embodiments, B1 is [ka] In some embodiments, B1 is [ka] In some embodiments, B1 is [ka] In some embodiments, B1 is [ka] In some embodiments, B1 is [ka] In some embodiments, B1 is [ka] In some embodiments, B1 is [ka] In some embodiments, B1 is [ka] In some embodiments, B1 is [ka] In some embodiments, B1 is [ka] In some embodiments, B1 is [ka] In some embodiments, B1 is [ka] In some embodiments, B1 is [ka] is.

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

[0183] In some embodiments, [ka] teeth, [ka] In some embodiments, [ka] teeth, [ka] is.

[0184] In some embodiments, the compound of Formula (I) has the formula (Ih): [ka] (In the formula, A and B each independently represent one or more R 1 cycloalkyl, heterocyclyl, aryl, or heteroaryl optionally substituted with; M and P each independently represent C(R 2 ) or N; D, E, and F each independently represent C(R 5d ), C(R 5d )(R 5e ), N, N(R 5f ), S or O, and the bonds between atoms in the rings, including D, E and F, can be single or double bonds, when valences permit; Each R 1 are independently hydrogen, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 heteroalkyl, C1-C6 haloalkyl, cycloalkyl, heterocyclyl, aryl, C1-C6 alkylene-aryl, C1-C6 alkenylene-aryl, C1-C6 alkylene-heteroaryl, heteroaryl, halo, cyano, oxo, -OR A , -NR B R C , -NR B C(O)R D , -NO2, -C(O)NR B R C , -C(O)R D , -C(O)OR D , -SR E or -S(O) x R D and each alkyl, alkylene, alkenyl, 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 8is 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, C1-C6 heteroalkyl, C1-C6 haloalkyl, cycloalkyl, or heterocyclyl; each alkyl, heteroalkyl, haloalkyl, cycloalkyl, and heterocyclyl may be joined by one or more R 12 is optionally replaced by; R 5d and R 5e are each independently hydrogen, halo, or C1-C6 alkyl; or R 5d and R 5e together form an oxo group; R 5f is hydrogen, halo, or C1-C6 alkyl; 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 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 9are 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 A or 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 Eare independently hydrogen, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 heteroalkyl, C1-C6 haloalkyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, C1-C6 alkylene-aryl, or C1-C6 alkylene-heteroaryl; Each R 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; Each R 12 are independently deuterium, 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.

[0185] In some embodiments, the compound of Formula (I) has the formula (Ii): [ka] (In the formula, A and B each independently represent one or more R 1 cycloalkyl, heterocyclyl, aryl, or heteroaryl optionally substituted with; M and P each independently represent C(R 2 ) or N; D, E, and F each independently represent C(R 5d ), C(R 5d )(R 5e ), N, N(R 5f), S or O, and the bonds between atoms in the rings, including D, E and F, can be single or double bonds, when valences permit; Each R 1 are independently hydrogen, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 heteroalkyl, C1-C6 haloalkyl, cycloalkyl, heterocyclyl, aryl, C1-C6 alkylene-aryl, C1-C6 alkenylene-aryl, C1-C6 alkylene-heteroaryl, heteroaryl, halo, cyano, oxo, -OR A , -NR B R C , -NR B C(O)R D , -NO2, -C(O)NR B R C , -C(O)R D , -C(O)OR D , -SR E or -S(O) x R D and each alkyl, alkylene, alkenyl, 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; R 5d and R 5e are each independently hydrogen, halo, or C1-C6 alkyl; or R 5d and R 5e together form an oxo group; R 5fis hydrogen, halo, or C1-C6 alkyl; 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 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 Aare 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 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.

[0186] In some embodiments, the compound of Formula (I) has the formula (Ij): [ka] (In the formula, A and B each independently represent one or more R 1 cycloalkyl, heterocyclyl, aryl, or heteroaryl optionally substituted with; M and P each independently represent C(R 2 ) or N; D, E, and F each independently represent C(R 5d ), C(R 5d )(R 5e ), N, N(R 5f ), S or O, and the bonds between atoms in the rings, including D, E and F, can be single or double bonds, when valences permit; Each R 1 are independently hydrogen, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 heteroalkyl, C1-C6 haloalkyl, cycloalkyl, heterocyclyl, aryl, C1-C6 alkylene-aryl, C1-C6 alkenylene-aryl, C1-C6 alkylene-heteroaryl, heteroaryl, halo, cyano, oxo, -OR A , -NR B R C , -NR B C(O)R D , -NO2, -C(O)NR B R C , -C(O)R D , -C(O)OR D , -SR E or -S(O) x R D and each alkyl, alkylene, alkenyl, 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 8is optionally replaced by; Each R 2 are independently hydrogen, halo, cyano, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, or -OR A and; R 5d and R 5e are each independently hydrogen, halo, or C1-C6 alkyl; or R 5d and R 5e together form an oxo group; R 5f is hydrogen, halo, or C1-C6 alkyl; 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 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)NRB 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 A or 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.

[0187] In some embodiments, the compound of Formula (I) has the formula (Ik): [ka] (In the formula, A and B each independently represent one or more R 1 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; M and P each independently represent C(R 2 ) or N; F is C(R 5d ) or N; 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)ORD , -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, C1-C6 heteroalkyl, C1-C6 haloalkyl, cycloalkyl, or heterocyclyl; each alkyl, heteroalkyl, haloalkyl, cycloalkyl, and heterocyclyl may be joined by one or more R 12 is optionally replaced by; 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 5d is hydrogen, halo, or C1-C6 alkyl; R 5f is hydrogen, halo, or C1-C6 alkyl; 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 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 RC each independently represents hydrogen, C1-C6 alkyl, C1-C6 heteroalkyl, cycloalkyl, heterocyclyl, -OR A or 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; Each R 12 are independently deuterium, 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.

[0188] In some embodiments, the compound of Formula (I) has the formula (II): [ka] (In the formula, A and B each independently represent one or more R 1 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; F is C(R 5d ) or N; Each R 1 are independently hydrogen, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 heteroalkyl, C1-C6 haloalkyl, cycloalkyl, heterocyclyl, aryl, C1-C6 alkylene-aryl, C1-C6 alkenylene-aryl, C1-C6 alkylene-heteroaryl, heteroaryl, halo, cyano, oxo, -OR A , -NR B R C , -NR B C(O)R D , -NO2, -C(O)NR B R C , -C(O)R D , -C(O)OR D , -SR E or -S(O) x R D and each alkyl, alkylene, alkenyl, 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, C1-C6 heteroalkyl, C1-C6 haloalkyl, cycloalkyl, or heterocyclyl; each alkyl, heteroalkyl, haloalkyl, cycloalkyl, and heterocyclyl may be joined by one or more R 12 is optionally replaced by; 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 5d is hydrogen, halo, or C1-C6 alkyl; R 5f is hydrogen, halo, or C1-C6 alkyl; 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 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 A or 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 Eare independently hydrogen, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 heteroalkyl, C1-C6 haloalkyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, C1-C6 alkylene-aryl, or C1-C6 alkylene-heteroaryl; Each R 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; Each R 12 are independently deuterium, 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.

[0189] In some embodiments, the compound of formula (I) has the formula (Im): [ka] (In the formula, A and B each independently represent one or more R 1 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 R4 is optionally replaced by; M and P each independently represent C(R 2 ) or N; F is C(R 5d ) or N; Each R 1 are independently hydrogen, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 heteroalkyl, C1-C6 haloalkyl, cycloalkyl, heterocyclyl, aryl, C1-C6 alkylene-aryl, C1-C6 alkenylene-aryl, C1-C6 alkylene-heteroaryl, heteroaryl, halo, cyano, oxo, -OR A , -NR B R C , -NR B C(O)R D , -NO2, -C(O)NR B R C , -C(O)R D , -C(O)OR D , -SR E or -S(O) x R D and each alkyl, alkylene, alkenyl, 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 3are independently hydrogen, C1-C6 alkyl, C1-C6 heteroalkyl, C1-C6 haloalkyl, cycloalkyl, or heterocyclyl; each alkyl, heteroalkyl, haloalkyl, cycloalkyl, and heterocyclyl may be joined by one or more R 12 is optionally replaced by; 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 5d is hydrogen, halo, or C1-C6 alkyl; R 5f is hydrogen, halo, or C1-C6 alkyl; 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 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 9are 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 A or 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 Eare independently hydrogen, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 heteroalkyl, C1-C6 haloalkyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, C1-C6 alkylene-aryl, or C1-C6 alkylene-heteroaryl; Each R 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; Each R 12 are independently deuterium, 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.

[0190] In some embodiments, the compound of formula (I) has the formula (In): [ka] (In the formula, A and B each independently represent one or more R 1 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 R4 is optionally replaced by; M and P each independently represent C(R 2 ) or N; F is C(R 5d ) or N; Each R 1 are independently hydrogen, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 heteroalkyl, C1-C6 haloalkyl, cycloalkyl, heterocyclyl, aryl, C1-C6 alkylene-aryl, C1-C6 alkenylene-aryl, C1-C6 alkylene-heteroaryl, heteroaryl, halo, cyano, oxo, -OR A , -NR B R C , -NR B C(O)R D , -NO2, -C(O)NR B R C , -C(O)R D , -C(O)OR D , -SR E or -S(O) x R D and each alkyl, alkylene, alkenyl, 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 3are independently hydrogen, C1-C6 alkyl, C1-C6 heteroalkyl, C1-C6 haloalkyl, cycloalkyl, or heterocyclyl; each alkyl, heteroalkyl, haloalkyl, cycloalkyl, and heterocyclyl may be joined by one or more R 12 is optionally replaced by; 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 5d is hydrogen, halo, or C1-C6 alkyl; 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 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 RC , -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 A or 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 11are independently C1-C6 alkyl, C1-C6 heteroalkyl, C1-C6 haloalkyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, halo, cyano, oxo, or -OR A and; Each R 12 are independently deuterium, 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.

[0191] In some embodiments, the compound of formula (I) is selected from the compounds in Table 1 or a pharmaceutically acceptable salt thereof.

[0192] [Table 1]

[0193] [Table 2]

[0194] [Table 3]

[0195] [Table 4]

[0196] [Table 5]

[0197] [Table 6]

[0198] Table 7

[0199] Table 8

[0200] Table 9

[0201] Table 10

[0202] Table 11

[0203] Table 12

[0204] Table 13

[0205] Table 14

[0206] Table 15

[0207] Table 16

[0208] [Table 17]

[0209] [Table 18]

[0210] [Table 19]

[0211] [Table 20]

[0212] [Table 21]

[0213] [Table 22]

[0214] 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.

[0215] 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.

[0216] 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.

[0217] 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.

[0218] 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.

[0219] 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.

[0220] 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.

[0221] 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.

[0222] 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.

[0223] For use in the eye, provided pharmaceutically acceptable compositions may be formulated as a micronized suspension or in an ointment such as petrolatum.

[0224] 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.

[0225] 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.

[0226] 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.

[0227] 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.

[0228] 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.

[0229] 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.

[0230] 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.

[0231] 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.

[0232] 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.

[0233] 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.

[0234] 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.

[0235]

[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.

[0236] 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.

[0237] 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).

[0238] 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).

[0239] 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.

[0240] 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 、HMOX2、HNRNPC、HNRNPD、HNRNPH1、HNRNPH3、HNRNPR、HOMER3、HOPX、HOXA3、HOXB3、HOXB3、HOXB4、HOXC4、HOXD3、HOXD3、HOXD4、HPCAL1、HPS4、HPS5、HRH1、HS3ST3A1、HSH2D、HSP90AA1、HSPD1、HTT、HUWE1、HYOU1、IAH1、ICA1L、ICAM2、ICE2、ICK、IDH2、IDH3G、IDS、IFI27、IFI44、IFT20、IFT22、IFT88、IGF2、INS-IGF2、IGF2BP3、IGFBP6、IKBKAP、IKBKB、IL11、IL18BP、IL18RAP、IL1RAP、IL1RL1、IL18R1、IL1RN、IL32、IL4I1,NUP62,AC011452.1、IL4I1,NUP62,CTC-326K19.6、IL6ST、ILVBL、IMMP1L、IMPDH1、INCA1、ING1、INIP、INPP1、INPP5J、INPP5K、INSIG2、INTS11、INTS12、INTS14、IP6K2、IP6K3、IPO11、LRRC70、IQCE、IQGAP3、IRAK4、IRF3、IRF5、IRF6、ISG20、IST1、ISYNA1、ITFG2、ITGB1BP1、ITGB7、ITIH4、RP5-966M1.6、ITPRIPL1、JADE1、JAK2、JARID2、JDP2、KANK1、KANK1,RP11-31F19.1、KANK2、KANSL1L、KAT6A、KBTBD2、KBTBD3、KCNAB2、KCNE3、KCNG1、KCNJ16、KCNJ9、KCNMB2,AC117457.1,LINC01014、KCTD20、KCTD7,RABGEF1、KDM1B、KDM4A,AL451062.3、KHNYN、KIAA0040、KIAA0125、KIAA0196、KIAA0226L、PPP 1R2P4、KIAA0391、KIAA0391、AL121594.1、KIAA0391、PSMA6、KIAA0753 、KIAA0895、KIAA0895L、KIAA1191、KIAA1407、KIAA1841、C2orf74、KI 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 FAT5、NFE2、NFE2L2、AC019080.1、NFRKB、NFYA、NFYC、NIF3L1、NIPA2、NKIRAS1、NKX2-1、NLRC3、NME1、NME1-NME2、NME2、NME1-NME2、 NME2、NME4、NME6、NME9、NOD1、NOL10、NOL8、NONO、NPAS1、NPIPA8、RP11-1212A22.1、NPIPB3、NPIPB4、NPIPB9、NPL、NPM1、NPPA、NQO2 、NR1H3、NR2C2、NR2F2、NR4A1、NRDC、NREP、NRF1、NRG4、NRIP1、NSD2、NSDHL、NSG1、NSMCE2、NSRP1、NT5C2、NTF4、NTMT1、NTNG2、NUBP2、 NUCB2、NUDT1、NUDT2、NUDT4、NUF2、NUMBL、NUP50、NUP54、NUP85、NVL、NXF1、NXPE1、NXPE3、OARD1、OAT、OAZ2、OCIAD1、OCLN、ODF2、OG DHL、OGFOD2、AC026362.1、OGFOD2、RP11-197N18.2、OLA1、OPRL1、OPTN、OR2H1、ORAI2、ORMDL1、ORMDL2、ORMDL3、OSBPL2、OSBPL3、OSB PL5、OSBPL9、OSER1、OSGIN1、OSR2、P2RX4、P2RY2、P2RY6、P4HA2、PABPC1、PACRGL、PACSIN3、PADI1、PAIP2、PAK1、PAK3、PAK4、PAK7、P 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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.

[0241] In some embodiments, the gene encoding the target sequence comprises the HTT gene.

[0242] 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.

[0243] 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, AAAguaugu, 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, 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ccgg、CAGguaccuc、CAGguaccug、CAGguaccuu、CAGguacgag、CAGguacgca、CAGguacgcc、CAGguacggu、CAGguacgua、CAGguacgug、CAGguacuaa、CAGguacuag、CAGguacuau、CAGguacucc、CAGguacucu、CAGguacuga、CAGguacugc、CAGguacugu、CAGguacuua、CAGguacuuu、CAGguagaaa、CAGguagaac、CAGguagaag、CAGguagaca、CAGguagacc、CAGguagaga、CAGguagauu、CAGguagcaa、CAGguagcac、CAGguagc、CAGguagca、CAGguagccu、CAGguagc ug、CAGguaggcuu、CAGguaggaa、CAGguaggac、CAGguaggag、CAGguaggca、CAGguaggga、CAGguagggc、CAGguagggg、CAGguagggu、CAGguaggua、CAGguagguc、CAGguaggug、CAGguagguu、CAGguaguaa、CAGguaguau、CAGguaguca、CAGguagucc、CAGguaguga、CAGguaguc、CAGguaguu、CAGguagu auaag, CAGguauaca, CAGguauaga, CAGguauauc, CAGguauaug, CAGguauauu, CAGguaucag, CAGguaucau, CAGguauccu, CAGguaucga, CAGguaucgc, CAGguaucua, CAGguaucug, CAGguaucuu, CAGguaugaa, CAGguaugac, CAGguaugag, CAGguaugau, CAGguaugca, CAGguaugcc, CAGguaugcg, CAGguaugcu, CAGguaugg, CAGguaugggu, CAGguaugua, CAGguauguc, CAGguaugug, CAGguauguu, CAGguauuau, CAGguauuca, CAGguauucu, CAGguauuga, CAGguauugg, CAGguauugu, CAGguauuua, CAGguauuuc, CAGguauuug, CAGguauuuu, CAGgucaaca, CAGgucaaug, CAGgucacgu, CAGgucagaa, CAGgucagac, CAGgucagca, CAGgucagcc,CAGgucagcg, CAGgucagga, CAGgucagua, 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、UGGgugagug、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.

[0244] 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, AAGguggugg, 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, CGGgugggga, 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, GAGgcaggca, 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 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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 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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.,

[0245] 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, AGUguggguu, 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, AA...

Claims

1. Formula (I-d): 【Chemistry 417】 (In the formula, A is one or more R １ is a nitrogen-containing heterocyclyl optionally substituted with B is a nitrogen-containing heterocyclyl or heteroaryl, each optionally substituted with one or more R 1 ; L is absent, —O—, or —N(R ３ )- and; M and P each independently represent C(R ２ ) or N; M and P are not both N; D, E, and F each independently represent C(R ５ｄ ), C(R ５ｄ ) (R ５ｅ ), N, N(R ５ｆ ), S or O, and the bonds between atoms in the ring, including D, E and F, can be single or double bonds, when valences allow; 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 and 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 replaced by; 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, and each cycloalkyl, heterocyclyl, aryl, and heteroaryl may be joined by 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, C １ ~C ６ Heteroalkyl, C １ ~C ６ haloalkyl, cycloalkyl, or heterocyclyl; each alkyl, heteroalkyl, haloalkyl, cycloalkyl, and heterocyclyl may be one or more R １２ optionally substituted with; R ５ｄ and R ５ｅ are each independently hydrogen, halo, or C １ ~C ６ is alkyl; or R ５ｄ and R ５ｅ together form an oxo group; R ５ｆ is hydrogen, halo or C １ ~C ６ is alkyl; Each R ７ are independently 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 and alkyl, alkenyl, alkynyl, heteroalkyl, and haloalkyl are each independently 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 and 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, 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 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; Each R １０ are independently １ ~C ６ alkyl or halo; Each R １１ are independently 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 Each R １２ are independently deuterium, 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; and 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. A is, 【Chemistry 418】 The compound according to any one of claims 1 to 2, selected from:

4. A is, 【Chemistry 419】 The compound according to any one of claims 1 to 3, selected from:

5. A is, 【Chemistry 420】 The compound according to any one of claims 1 to 4, selected from:

6. B is, 【Chemistry 421】 The compound according to any one of claims 1 to 5, selected from:

7. B is, 【Chemistry 422】 The compound according to any one of claims 1 to 6, selected from:

8. B is, 【Chemistry 423】 The compound according to any one of claims 1 to 7, selected from:

9. L is —O— or —N(R ３ 9. The compound according to claim 1, wherein

10. L is -N(R ３ )- and R ３ is hydrogen, C １ ~C ６ alkyl or cycloalkyl, and each alkyl and cycloalkyl is selected from one or more R １２ 10. The compound of any one of claims 1 to 9, wherein each of the following is optionally substituted:

11. L is -N(CH ３ 11. The compound according to claim 1, wherein the aryl group is —N(H)— or —N(H)—.

12. L is -N(CH ３ 12. The compound according to claim 1, wherein:

13. 【Catalog 424】 teeth, 【Chemistry 425】 The compound according to any one of claims 1 to 12, selected from:

14. 【Catalogue 426】 teeth, 【Chemical 427】 The compound according to any one of claims 1 to 13,

15. Each of M and P is independently C(R ２ 15. The compound according to any one of claims 1 to 14, wherein

16. One of M and P is independently C(R ２ ) and the other of M and P is independently N.

17. 13. The compound of any one of claims 1 to 12, wherein M is CH and P is N.

18. One of D, E, and F is independently N or N(R ５ｆ 18. The compound according to any one of claims 1 to 17, wherein

19. Two of D, E, and F are independently N or N(R ５ｆ 19. The compound according to any one of claims 1 to 18, wherein

20. D is N, N(R ５ｆ 20. The compound according to any one of claims 1 to 19, wherein R is 1 or S.

21. D is N or N(R ５ｆ 21. The compound according to any one of claims 1 to 20, wherein

22. Each of D and E is independently N or N(R ５ｆ 22. The compound according to any one of claims 1 to 21, wherein

23. F is C(R ５ｄ ) or C(R ５ｄ ) (R ５ｅ 23. The compound according to any one of claims 1 to 22, wherein 【Request 24】 【Chemical No. 428】 teeth, 【Chemical 429】 The compound according to any one of claims 1 to 17, selected from:

25. [Catalog 430] teeth, 【Chemistry 431】 25. The compound of claim 24, selected from:

26. 【Catalogue 432】 teeth, 【Chemistry 433】 26. The compound of claim 25, wherein:

27. Formula (I-e): 【Chemical 434】 (In the formula, A, B, L, D, E, F, R ２ , R ７ , m, n and their subvariables are as defined in claim 1) or a pharmaceutically acceptable salt, solvate, hydrate, tautomer or stereoisomer thereof.

28. Formula (If): 【Chemistry 435】 (In the formula, A １ is one or more R １ is a 6-membered heterocyclyl optionally substituted with B １ Each of these is one or more R １ is a 5-membered heterocyclyl or heteroaryl optionally substituted with L, M, P, D, E, F, R １ , R ７ , n and its subvariables are as defined in claim 1) 28. The compound of any one of claims 1 to 27, which is a compound of the formula: or a pharmaceutically acceptable salt, solvate, hydrate, tautomer or stereoisomer thereof.

29. Formula (Ig): 【Chemistry 436】 (In the formula, A １ is one or more R １ is a 6-membered heterocyclyl optionally substituted with B １ Each of these is one or more R １ is a 5-membered heterocyclyl or heteroaryl optionally substituted with L, D, E, F, R １ , R ２ , R ７ , m, n and their subvariables are as defined in claim 1) or a pharmaceutically acceptable salt, solvate, hydrate, tautomer or stereoisomer thereof.

30. Formula (Ih): 【Chemistry 437】 (In the formula, A, B, M, P, D, E, F, R ３ , R ７ , n and its subvariables are as defined in claim 1) or a pharmaceutically acceptable salt, solvate, hydrate, tautomer or stereoisomer thereof.

31. Formula (Ik): 【Chemistry 438】 (In the formula, A, B, M, P, L, F, R ５ｆ , R ７ , n and its subvariables are as defined in claim 1) or a pharmaceutically acceptable salt, solvate, hydrate, tautomer or stereoisomer thereof.

32. Formula (In): 【Chemistry 439】 (In the formula, A, B, M, P, L, F, R ５ｄ , R ７ , n and its subvariables are as defined in claim 1) or a pharmaceutically acceptable salt, solvate, hydrate, tautomer or stereoisomer thereof.

33. A is monocyclic, bicyclic, or tricyclic heterocyclyl; B is monocyclic heterocyclyl or heteroaryl; L is absent, -N(R ３ )- or -O-; M is CH; P is CH or N; D is N(R ５ｆ ), C(R ５ｄ ) or S; E and F each independently represent N, NH, C(R ５ｄ ), C(R ５ｄ ) (R ５ｅ ) and R ７ is a halo; and 2. The compound of claim 1, wherein m is 0 or 1. 【Request 34】 【Chemical 440】 【Chemical 441】 【Chemical 442】 【Chemical 443】 【Chemical 444】 【Chemical 445】 【Chemical 446】 【Chemical 447】 【Chemical 448】 【Chemical 449】 【Chemical 450】 【Chemistry 451】 【Chemistry 452】 【Chemistry 453】 【Chemistry 454】 【Chemistry 455】 【Chemistry 456】 【Chemistry 457】 【Chemistry 458】 【Chemistry 459】 【Chemistry 460】 【Chemistry 461】 【Chemical 462】 【Chemistry 463】 or a pharmaceutically acceptable salt, solvate, hydrate, tautomer or stereoisomer thereof.

35. A pharmaceutical composition comprising a compound according to any one of claims 1 to 34 and a pharmaceutically acceptable excipient.

36. 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 34 or a pharmaceutical composition according to claim 35.

37. The compound is (i) increasing 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 within ±10% of said value; or (ii) reducing 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 within ±10% of said value; A compound according to any one of claims 1 to 34 or a pharmaceutical composition according to claim 35.

38. 35. A method for forming a complex comprising a spliceosome component, a nucleic acid and a compound of formula (I-d) according to any one of claims 1 to 34, said method comprising contacting said nucleic acid with a compound of formula (I-d).

39. 39. The method of claim 38, wherein the spliceosome component is recruited to the nucleic acid in the presence of the compound of formula (Id).

40. A method for modifying the conformation of a nucleic acid, the method comprising contacting the nucleic acid with a compound of formula (I-d) according to any one of claims 1 to 34 or a pharmaceutical composition according to claim 35.

41. 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 41. The method of claim 40, comprising:

42. A composition for use in treating a disease or disorder in a subject, the composition comprising a compound of formula (Id) according to any one of claims 1 to 34.

43. 43. The composition for use of claim 42, wherein the disease or disorder comprises a proliferative disease.

44. 43. The composition for use of claim 42, 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.

45. 43. The composition for use according to claim 42, wherein the disease or disorder comprises a neurological disease or disorder.

46. 43. The composition for use of claim 42, wherein the disease or disorder comprises Huntington's disease.

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