Heterocyclic amides and their use for modulating splicing

Abstract

The present disclosure relates to, inter alia, compounds of formula (Ia) that modulate nucleic acid splicing, e.g., pre-mRNA splicing. TIFF2023515621000552.tif33170 and related compositions and methods of their use.

Description

Technical field

[0001] priority claim This application is filed February 28, 2020, U.S. Patent Application Serial No. 62 / 983,541; U.S. patent application Ser. No. 63 / 040,484 filed Aug. 17; U.S. patent application Ser. Priority is claimed to patent application Ser. No. 63 / 126,492. The disclosure of each of the aforementioned applications is incorporated herein by reference in its entirety. [Background technology]

[0002] Alternative splicing is a major source of protein diversity in higher eukaryotes and is frequently controlled in tissue- or developmental stage-specific ways. Disease-associated alternative splicing patterns in pre-mRNAs are often mapped to changes in splice site signals or sequence motifs and regulatory splicing factors (Faustino and Cooper (2003), Genes Dev 17(4):419 -37). Current therapies to modulate RNA expression include oligonucleotide targeting and gene therapy, but each of these modalities presents unique challenges as currently presented. Therefore, new techniques to modulate RNA expression are needed, including the development of small molecules that target splicing. [Prior art documents] [Non-Patent Literature]

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

[0004] This disclosure features, inter alia, compounds and related compositions that modulate nucleic acid splicing, eg, pre-mRNA splicing, and methods of their use. In one embodiment, the compounds described herein are compounds of formula (I) (e.g., formulas (I-a), (I-b), (I-c), (I-d), (I-e), (I-f) or (I-g )) and pharmaceutically acceptable salts, solvates, hydrates, tautomers or stereoisomers thereof. The present disclosure provides compounds of the invention (e.g. compounds of formula (I), (I-a), (I-b), (I-c), (I-d), (I-e), (I-f), (I-g) or (I-h) and Further provided are methods of using the pharmaceutically acceptable salts, solvates, hydrates, tautomers, stereoisomers thereof) and compositions thereof, e.g., to target, in embodiments nucleic acids ( e.g., pre-mRNA or small nuclear ribonucleoprotein (snRNP) or spliceosome nucleic acid component), protein (e.g., snRNP or spliceosome protein component, e.g. members of the splicing machinery, e.g. U1, U2, U4, U5, U6, one or more of U11, U12, U4atac, U6atac snRNPs) or combinations thereof. In another aspect, the compounds described herein are used to increase or decrease splicing at splice junctions, e.g. In some embodiments, increasing or decreasing splicing modulates the level of gene product (eg, RNA or protein) produced. In another aspect, the compounds described herein may be used for the prevention and / or treatment of diseases, disorders or conditions, such as diseases, disorders or conditions associated with splicing, eg alternative splicing. In some embodiments, a compound described herein (e.g., Formula (I), (I-a), (I-b), (I-c), (I-d), (I-e), (I-f), (I-g) or Compounds of (I-h) and pharmaceutically acceptable salts, solvates, hydrates, tautomers, stereoisomers thereof) and compositions thereof may be used to treat a proliferative disease, disorder or condition in a subject (e.g., It is used for the prevention and / or treatment of diseases, disorders or conditions characterized by unwanted cell proliferation, such as cancer or benign neoplasms. In some embodiments, a compound described herein (e.g., Formula (I), (I-a), (I-b), (I-c), (I-d), (I-e), (I-f), (I-g) or (I-h) and pharmaceutically acceptable salts, solvates, hydrates, tautomers, stereoisomers thereof) and compositions thereof for the prophylaxis and / or or used for treatment. In some embodiments, a compound described herein (e.g., Formula (I), (I-a), (I-b), (I-c), (I-d), (I-e), (I-f), (I-g) or Compounds (I-h) and pharmaceutically acceptable salts, solvates, hydrates, tautomers, stereoisomers thereof) and compositions thereof are used to treat neurological diseases or disorders, autoimmune diseases in a subject. or for the prevention and / or treatment of a 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 .

[0005] In another aspect, the disclosure provides a compound of Formula (I-a): [formation] (Wherein, A and B are each independently one or more R 1 is cycloalkyl, heterocyclyl, aryl or heteroaryl optionally substituted with; X, Y and Z are each independently C(R 3a ), C(R 3a )(R 3b ), N, N(R 3c ) or O, and at least one of X, Y and Z is N, N(R 3c ) or O, and the bonds in the ring containing X, Y and Z can be single or double bonds when valences permit; 1 and L 2 Each of the independently, absent, C 1 ~C 6 Alkylene, C 1 ~C 6 heteroalkylene, -O-, -C(O)-, -N(R 4 )-, -N(R 4 )C(O)- or -C(O)N(R 4 )- and each alkylene and heteroalkylene is one or more R 5 is optionally replaced with; 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, alkynyl, heteroalkyl, haloalkyl, cycloalkyl, heterocyclyl, aryl and heteroaryl is one or more R 6 optionally substituted with; or two R 1 The groups, together with the atoms to which they are attached, form a 3- to 7-membered cycloalkyl, heterocyclyl, aryl or heteroaryl, each cycloalkyl, heterocyclyl, aryl and heteroaryl being represented by one or more R 6 is optionally replaced with; each R 2 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, halo, cyano or -OR A is; R 3a and R 3b are each independently hydrogen, C 1 ~C 6 Alkyl, C 1 ~C 6 heteroalkyl, C 1 ~C 6 haloalkyl, halo, cyano, -OR A , -NR B R. C , -C(O)R D or -C(O)OR D or R 3a and R 3beach, together with the carbon atom to which they are attached, form an oxo group; R 3c is hydrogen or C 1 ~C 6 is alkyl; each R 4 are independently hydrogen, C 1 ~C 6 alkyl or C 1 ~C 6 is haloalkyl; each R 5 are independently hydrogen, C 1 ~C 6 Alkyl, C 1 ~C 6 heteroalkyl, C 1 ~C 6 haloalkyl, cycloalkyl, halo, cyano, oxo, -OR A , -NR B R. C , -C(O)R D or -C(O)OR D is; each R 6 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 alkyl, alkenyl, alkynyl, heteroalkyl, haloalkyl, cycloalkyl, heterocyclyl, aryl and heteroaryl is one or more R 11 is optionally replaced with; each R 7 is C 1 ~C 6 alkyl, halo, cyano, oxo or -OR A1 is; each R 11 independently, C 1 ~C 6 Alkyl, C 1 ~C 6 heteroalkyl, C 1 ~C 6 haloalkyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, halo, cyano, oxo or -OR A is; 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 is; R B and R C are independently hydrogen, C 1 ~C 6 Alkyl, C 1 ~C 6 heteroalkyl, cycloalkyl, heterocyclyl or -OR A or R B and R C together with the atoms to which they are attached, one or more R 7 forming a 3- to 7-membered heterocyclyl ring optionally substituted with; 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 is alkylene-heteroaryl; each R A1 is hydrogen or C 1 ~C 6 is alkyl; m is 0, 1 or 2; and x is 0, 1 or 2) or a pharmaceutically acceptable salt, solvate, hydrate, tautomer or stereoisomer thereof.

[0006] In another aspect, the present invention provides compounds of formula (I) (e.g. formulas (I-a), (I-b), (I-c), (I-d), (I-e), (I-f), (I-g), (I-h) or a compound of (I-i)) or a pharmaceutically acceptable salt, solvate, hydrate, tautomer or stereoisomer thereof and optionally a pharmaceutically acceptable excipient. offer things. 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., formula (I), (I-a), (I-b), (I-c) ), (I-d), (I-e), (I-f), (I-g) or (I-h)) or a pharmaceutically acceptable salt, solvate, hydrate, tautomer or stereoisomer thereof including.

[0007] In another aspect, the present disclosure provides compounds of Formula (I) (e.g., Formulas (I), (I-a), (I-b), (I-c), (I-d), (I-e), (I-f), (I-g) or compounds of (I-h)) or pharmaceutically acceptable salts, solvates, hydrates, tautomers or stereoisomers thereof, by splicing, e.g., nucleic acids (e.g., DNA or RNA, e.g., pre-mRNA) provide a method for modulating the splicing of In another aspect, the present disclosure provides compounds of Formula (I) (e.g., Formulas (I), (I-a), (I-b), (I-c), (I-d), (I-e), (I-f), (I-g) or compounds of (I-h)) or pharmaceutically acceptable salts, solvates, hydrates, tautomers or stereoisomers thereof, splicing, e.g., nucleic acids (e.g., DNA or RNA, e.g., pre-mRNA) Compositions are provided for use in modulating the splicing of . Modulation of splicing can include affecting any step involved in splicing and can include events upstream or downstream of the splicing event. For example, in some embodiments, a compound of Formula (I) is a target, such as a target nucleic acid (e.g., DNA or RNA, such as precursor RNA, such as pre-mRNA), a target protein, or a combination thereof (e.g., snRNP and Binds to pre-mRNA). Targets may include splice sites in the pre-mRNA or components of the splicing machinery such as U1snRNP. In some embodiments, compounds of Formula (I) modify target nucleic acids (eg, DNA or RNA, eg, precursor RNA, eg, pre-mRNA), target proteins, or combinations thereof. In some embodiments, compounds of formula (I) inhibit splicing at a splice site on a target nucleic acid (e.g., RNA, e.g., precursor RNA, e.g., pre-mRNA), e.g., see (e.g., formula (I) About 0.5% or more (e.g., about 1%, 2%, 3%, 4%, 5%, 10%, 20%, 30%, 40%, 50%, 75%, 90%, 95% or more) increase or decrease. In some embodiments, the presence of a compound of formula (I) is a reference to the transcription of a target nucleic acid (e.g., RNA) (e.g., the absence of a compound of formula (I), e.g., a healthy or diseased cell or tissue). ) (e.g., about 1%, 2%, 3%, 4%, 5%, 10%, 20%, 30%, 40%, 50%, 75%, 90%, 95% ) resulting in an increase or decrease in

[0008] In another aspect, the present disclosure provides compounds of Formula (I) (e.g., Formulas (I), (I-a), (I-b), (I-c), (I-d), (I-e), (I-f), (I-g) or a compound of (I-h)) or a pharmaceutically acceptable salt, solvate, hydrate, tautomer or stereoisomer thereof or a related composition to treat a disease, disorder or Methods are provided for preventing and / or treating conditions. In some embodiments, the disease or disorder involves unwanted 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 present disclosure provides methods of treating and / or preventing non-proliferative diseases, disorders or conditions. In still other embodiments, the present disclosure provides neurological diseases or disorders, autoimmune diseases or disorders, immunodeficiency diseases or disorders, lysosomal storage diseases or disorders, cardiovascular diseases or disorders, metabolic diseases or disorders, respiratory diseases or disorders. Methods of treating and / or preventing diseases or disorders, renal diseases or disorders, or infectious diseases are provided.

[0009] In another aspect, the present disclosure provides compounds of Formula (I) (e.g., Formulas (I), (I-a), (I-b), (I-c), (I-d), (I-e), (I-f), (I-g) or compounds of (I-h)), or a pharmaceutically acceptable salt, solvate, hydrate, tautomer or stereoisomer thereof, to reduce the expression of a target protein in a biological sample or subject (e.g., the level of production or speed). In another aspect, the present disclosure provides compounds of Formula (I) (e.g., Formulas (I), (I-a), (I-b), (I-c), (I-d), (I-e), (I-f), (I-g) or compounds of (I-h)), or a pharmaceutically acceptable salt, solvate, hydrate, tautomer or stereoisomer thereof, to reduce the expression of a target protein in a biological sample or subject (e.g., the level of production or speed). In another aspect, the present disclosure provides compounds of Formula (I) (e.g., Formulas (I), (I-a), (I-b), (I-c), (I-d), (I-e), (I-f), (I-g) or a compound of (I-h)) or a pharmaceutically acceptable salt, solvate, hydrate, tautomer or stereoisomer thereof to modify the isoform of a target protein in a biological sample or subject. offer. Another aspect of the present disclosure relates to methods of inhibiting target protein activity in a biological sample or subject. In some embodiments, administration of a compound of formula (I) to a biological sample, cell or subject comprises inhibition of cell growth or induction of cell death.

[0010] In another aspect, the present disclosure provides compounds of Formula (I) (e.g., Formulas (I), (I-a), (I-b), (I-c), (I-d), (I-e), (I-f), (I-g) or a compound of (I-h)) or a pharmaceutically acceptable salt, solvate, hydrate, tautomer or stereoisomer thereof, or a related composition, in a subject, Compositions are provided for use in the prevention and / or treatment of conditions. In some embodiments, the disease or disorder involves unwanted 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 present disclosure provides methods of treating and / or preventing non-proliferative diseases, disorders or conditions. In still other embodiments, the present disclosure provides neurological diseases or disorders, autoimmune diseases or disorders, immunodeficiency diseases or disorders, lysosomal storage diseases or disorders, cardiovascular diseases or disorders, metabolic diseases or disorders, respiratory diseases or disorders. Methods of treating and / or preventing diseases or disorders, renal diseases or disorders, or infectious diseases are provided.

[0011] In another aspect, the present disclosure provides compounds of Formula (I) (e.g., Formulas (I), (I-a), (I-b), (I-c), (I-d), (I-e), (I-f), (I-g) or a compound of (I-h)) or a pharmaceutically acceptable salt, solvate, hydrate, tautomer or stereoisomer thereof, of the target protein in a biological sample or subject (e.g., the level of production or rate). In another aspect, the present disclosure provides compounds of Formula (I) (e.g., Formulas (I), (I-a), (I-b), (I-c), (I-d), (I-e), (I-f), (I-g) or a compound of (I-h)) or a pharmaceutically acceptable salt, solvate, hydrate, tautomer or stereoisomer thereof, of the target protein in a biological sample or subject (e.g., the level of production or rate). In another aspect, the present disclosure provides compounds of Formula (I) (e.g., Formulas (I), (I-a), (I-b), (I-c), (I-d), (I-e), (I-f), (I-g) or compounds of (I-h)) or a pharmaceutically acceptable salt, solvate, hydrate, tautomer or stereoisomer thereof for use in modifying isoforms of a target protein in a biological sample or subject. provide a composition for Another aspect of the disclosure relates to compositions for use in inhibiting target protein activity in a biological sample or subject. In some embodiments, administration of a compound of formula (I) to a biological sample, cell or subject comprises inhibition of cell growth or induction of cell death.

[0012] In another aspect, the present disclosure provides compounds of Formula (I) (e.g., Formulas (I), (I-a), (I-b), (I-c), (I-d), (I-e), (I-f), (I-g) or compounds of (I-h)) or a pharmaceutically acceptable salt, solvate, hydrate, tautomer, stereoisomer thereof, or a pharmaceutical composition thereof. In certain embodiments, the kits described herein comprise a compound of Formula (I) or a pharmaceutically acceptable salt, solvate, hydrate, tautomer, stereoisomer or pharmaceutical thereof. Further comprising instructions for administering the composition.

[0013] In any aspect of this disclosure, in some embodiments, the compounds, target nucleic acids (e.g., DNA, RNA, e.g., pre-mRNA), or target proteins described herein are Application Publication No. 2015 / 0005289, International Publication No. 2014 / 028459, International Publication No. 2016 / 128343, International Publication No. 2016 / 196386, International Publication No. 2017 / 100726, International Publication No. 2018 / 232039, WO2018 / 098446, WO2019 / 028440, WO2019 / 060917 and one of WO2019 / 199972 compounds, target A compound other than a nucleic acid (eg, DNA, RNA, eg, pre-mRNA) or target protein, a target nucleic acid (eg, DNA, RNA, eg, pre-mRNA), or a target protein. In some embodiments, the compounds, target nucleic acids (e.g., DNA, RNA, e.g., pre-mRNA), or target proteins described herein are Specification, International Publication No. 2014 / 028459 Pamphlet, International Publication No. 2016 / 128343 Pamphlet, International Publication No. 2016 / 196386 Pamphlet, International Publication No. 2017 / 100726 Pamphlet, International Publication No. 2018 / 232039 Pamphlet, International Publication compounds described in one of WO 2018 / 098446, WO 2019 / 028440, WO 2019 / 060917 and WO 2019 / 199972; , eg, pre-mRNA) or target protein, each of which is hereby incorporated by reference in its entirety.

[0014] The details of one or more embodiments of the invention are set forth in this specification. Other features, objects and advantages of the present invention will become apparent from the detailed description, examples and claims. [Mode for carrying out the invention]

[0015] Selected chemical definition Definitions of specific functional groups and chemical terms are described in more detail below. Chemical elements can be found 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 can be found 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 in the fields of chemistry and biology. The chemical structures and formulas described herein are constructed according to standard rules of chemical valence known in the chemical arts.

[0017] When ranges of values ​​are recited, it is intended to include each value and subranges within the range. For example, "C 1 ~C 6 Alkyl” is C 1 , C 2 , C 3 , C 4 , C 5 , C 6 , C 1 ~C 6 , C 1 ~C 5 , C 1 ~C 4 , C 1 ~C 3 , C 1 ~C 2 , C 2 ~C 6 , C 2 ~C 5 , C 2 ~C 4 , C 2 ~C 3 , C 3 ~C 6 , C 3 ~C 5 , C 3 ~C4 , C 4 ~C 6 , C 4 ~C 5 and C 5 ~C 6 It is intended to include alkyl.

[0018] The following terms are intended to have the meanings indicated below and are helpful in understanding the description and intended scope of the invention.

[0019] As used herein, "alkyl" refers to a straight or branched chain saturated hydrocarbon group having 1 to 24 carbon atoms ("C 1 ~C 24 Alkyl”) radicals. In some embodiments, alkyl groups have 1-12 carbon atoms (“C 1 ~C 12 alkyl”). In some embodiments, alkyl groups have 1-8 carbon atoms (“C 1 ~C 8 alkyl”). In some embodiments, alkyl groups have 1-6 carbon atoms (“C 1 ~C 6 alkyl”). In some embodiments, alkyl groups have 2-6 carbon atoms (“C 2 ~C 6 alkyl”). In some embodiments, alkyl groups have 1 carbon atom (“C 1 alkyl”). C. 1 ~C 6 Examples of alkyl groups include methyl (C 1 ), ethyl (C 2 ), n-propyl (C 3 ), isopropyl (C 3 ), n-butyl (C 4 ), tert-butyl (C 4 ), sec-butyl (C 4 ), isobutyl (C 4 ), n-pentyl (C 5 ), 3-pentanyl (C 5 ), amyl (C 5 ), neopentyl (C 5 ), 3-methyl-2-butanyl (C 5 ), tertiary amyl (C 5 ) and n-hexyl (C 6 ) is included. Further examples of alkyl groups include n-heptyl (C 7 ), n-octyl (C 8 ), etc. Each instance of an alkyl group can independently be optionally substituted, i.e., unsubstituted (“unsubstituted alkyl”), or have one or more substituents, such as 1-5 substituents, 1-3 It can be substituted (“substituted alkyl”) with one substituent or one substituent. In certain embodiments, the alkyl group is an unsubstituted C 1 ~C 10 Alkyl (e.g., -CH 3 ). In certain embodiments, the alkyl group is substituted C 1 ~C 6 is alkyl.

[0020] As used herein, "alkenyl" refers to a straight or branched hydrocarbon group of 2 to 24 carbon atoms, having one or more carbon-carbon double bonds and no triple bonds. radical (“C 2に ~C 24 alkenyl”). In some embodiments, alkenyl groups have 2-10 carbon atoms ("C 2 ~C 10 alkenyl”). In some embodiments, alkenyl groups have 2-8 carbon atoms ("C 2 ~C 8 alkenyl”). In some embodiments, alkenyl groups have 2-6 carbon atoms ("C 2 ~C 6 alkenyl”). In some embodiments, an alkenyl group has 2 carbon atoms (“C 2 alkenyl”). The one or more carbon-carbon double bonds can be internal (such as 2-butenyl) or terminal (such as 1-butenyl). C. 2 ~C 4 Examples of alkenyl groups include ethenyl (C 2 ), 1-propenyl (C 3 ), 2-propenyl (C 3 ), 1-butenyl (C 4 ), 2-butenyl (C 4 ), butadienyl (C 4 ), etc. C. 2 ~C 6 Examples of alkenyl groups include the C 2~4 alkenyl groups and pentenyl (C 5 ), pentadienyl (C 5 ), hexenyl (C 6 ), etc. Further examples of alkenyl include heptenyl (C 7 ), octenyl (C 8 ), octatrienyl (C 8 ), etc. Each instance of an alkenyl group can independently be optionally substituted, i.e., unsubstituted (“unsubstituted alkenyl”), or have one or more substituents, such as 1-5 substituents, 1-3 It can be substituted (“substituted alkenyl”) with one substituent or one substituent. In certain embodiments, the alkenyl group is an unsubstituted C 1 ~C 10 It is alkenyl. In certain embodiments, the alkenyl group is substituted C 2 ~C 6 It is alkenyl.

[0021] As used herein, the term "alkynyl" refers to the radical of a straight or branched hydrocarbon group of 2 to 24 carbon atoms, having one or more carbon-carbon triple bonds ("C 2 ~C 24 alkenyl”). In some embodiments, alkynyl groups have 2-10 carbon atoms ("C 2 ~C 10 alkynyl”). In some embodiments, alkynyl groups have 2-8 carbon atoms (“C 2 ~C 8 alkynyl”). In some embodiments, alkynyl groups have 2-6 carbon atoms ("C 2 ~C 6 alkynyl”). In some embodiments, an alkynyl group has 2 carbon atoms ("C 2 alkynyl”). The one or more carbon-carbon triple bonds can be internal (such as 2-butynyl) or terminal (such as 1-butynyl). C. 2 ~C 4 Examples of alkynyl groups include ethynyl (C 2 ), 1-propynyl (C 3 ), 2-propynyl (C 3 ), 1-butynyl (C 4 ), 2-butynyl (C 4 ), etc. Each instance of an alkynyl group can independently be optionally substituted, i.e., unsubstituted (“unsubstituted alkynyl”), or have one or more substituents, such as 1-5 substituents, 1-3 It can be substituted (“substituted alkynyl”) with one substituent or one substituent. In certain embodiments, an alkynyl group is an unsubstituted C 2~10 is alkynyl. In certain embodiments, alkynyl groups are substituted C 2~6 is alkynyl.

[0022] As used herein, the term "haloalkyl" refers to an acyclic stable linear chain containing at least one carbon atom and at least one halogen selected from the group consisting of F, Cl, Br and I. or branched chains or combinations thereof. Halogens F, Cl, Br and I can be placed at any position of the haloalkyl group. Exemplary haloalkyl groups include -CF 3 , -CCl 3 , -CH 2 -CF 3 , -CH 2 -CCl 3 , -CH 2 -CBr 3 , -CH 2 -CI 3 , -CH 2 -CH 2 -CH(CF 3 )-CH 3 , -CH 2 -CH 2 -CH(Br)-CH 3 and -CH 2 -CH=CH-CH 2 -CF 3 including but not limited to. Each instance of a haloalkyl group can independently be optionally substituted, i.e., unsubstituted (“unsubstituted haloalkyl”), or have one or more substituents, such as 1-5 substituents, 1-3 It can be substituted (“substituted haloalkyl”) with one substituent or one substituent.

[0023] As used herein, the term "heteroalkyl" refers to an acyclic heteroatom containing at least one carbon atom and at least one heteroatom selected from the group consisting of O, N, P, Si and S. Refers to stable straight or branched chains or combinations thereof, the nitrogen and sulfur atoms may be optionally oxidized, and the nitrogen heteroatoms may 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 -CH 2 -CH 2 -O-CH 3 , -CH 2 -CH 2 -NH-CH 3 , -CH 2 -CH 2 -N(CH 3 )-CH 3 , -CH 2 -S-CH 2 -CH 3 , -CH2 -CH 2 , -S(O)-CH 3 , -CH 2 -CH 2 -S(O) 2 -CH 3 , -CH=CH-O-CH 3 , -Si(CH 3 ) 3 , -CH 2 -CH=N-OCH 3 , -CH=CH-N(CH 3 )-CH 3 , -O-CH 3 and -O-CH 2 -CH 3 including but not limited to. For example, -CH 2 -NH-OCH 3 and -CH 2 -O-Si(CH 3 ) 3 Up to 2 or 3 heteroatoms may be consecutive, such as "Heteroalkyl" is quoted followed by -CH 2 O, -NR C R. D Where specific heteroalkyl groups are cited such as heteroalkyl and -CH 2 O or -NR C R. D It will be understood that the terms are neither redundant nor mutually exclusive. Rather, specific heteroalkyl groups are recited for added clarity. Accordingly, the term "heteroalkyl," as used herein, refers to certain heteroalkyl groups, such as -CH 2 O, -NR C R. D etc. should not be construed to exclude Each instance of a heteroalkyl group can independently be optionally substituted, i.e., unsubstituted (“unsubstituted heteroalkyl”), or have one or more substituents, such as from 1 to 5 substituents, 1 It can be substituted (“substituted heteroalkyl”) with ˜3 substituents or 1 substituent.

[0024] As used herein, "aryl" is a monocyclic or polycyclic ring having 6 to 14 ring carbon atoms and no heteroatoms provided in the aromatic ring system (e.g., bicyclic or tricyclic) refers to radicals of 4n+2 aromatic ring systems (e.g., with 6, 10 or 14 π electrons shared in a cyclic array) (“C 6 ~C 14 aryl”). In some embodiments, an aryl group has 6 ring carbon atoms (“C 6 aryl"; e.g. phenyl). In some embodiments, an aryl group has 10 ring carbon atoms (“C 10 aryl"; naphthyl, such as 1-naphthyl and 2-naphthyl). In some embodiments, an aryl group has 14 ring carbon atoms (“C 14 aryl"; e.g. anthracyl). Aryl groups are, for example, C 6 ~C 10 It may be described as a membered aryl, where the term "member" 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, ie, unsubstituted (“unsubstituted aryl”) or substituted with one or more substituents (“substituted aryl”). In certain embodiments, the aryl group is an unsubstituted C 6 ~C 14 is aryl. In certain embodiments, the aryl group is substituted C 6 ~C 14 is aryl.

[0025] As used herein, "heteroaryl" is a 5- to 10-membered monocyclic or bicyclic ring having ring carbon atoms provided in the aromatic ring system and 1 to 4 ring heteroatoms. refers to a radical of a 4n+2 aromatic ring system (e.g., having 6 or 10 pi-electrons shared in a cyclic array) of where each heteroatom is independently selected from nitrogen, oxygen and sulfur (“5- to 10-membered heteroaryl”). In heteroaryl groups containing more than one nitrogen atom, the point of attachment can be a carbon or nitrogen atom, when valences permit. Heteroaryl bicyclic ring systems can include 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 whose points of attachment are on the aryl or heteroaryl ring; The number of members specifies the number of ring members in a fused (aryl / heteroaryl) ring system. In bicyclic heteroaryl groups where one ring does not contain a heteroatom (e.g., indolyl, quinolinyl, carbazolyl, etc.), the point of attachment may be in either ring, i.e. the ring containing a heteroatom (e.g., 2-indolyl) or the heteroatom. It can be present on any ring of rings that do not contain atoms (eg, 5-indolyl). A heteroaryl group can be described as, for example, a 6- to 10-membered heteroaryl, wherein the term "member" refers to non-hydrogen ring atoms within the moiety. Each instance of a heteroaryl group may independently be optionally substituted, i.e., unsubstituted (“unsubstituted heteroaryl”), or have one or more substituents, such as from 1 to 5 substituents, 1 It can be substituted (“substituted heteroaryl”) with up to 3 substituents or 1 substituent.

[0026] Exemplary 5-membered heteroaryl groups containing one heteroatom include, without limitation, pyrrolyl, furanyl and thiophenyl. Exemplary 5-membered heteroaryl groups containing two heteroatoms include, without limitation, imidazolyl, pyrazolyl, oxazolyl, isoxazolyl, thiazolyl and isothiazolyl. Exemplary 5-membered heteroaryl groups containing 3 heteroatoms include, without limitation, triazolyl, oxadiazolyl and thiadiazolyl. Exemplary 5-membered heteroaryl groups containing 4 heteroatoms include, without limitation, tetrazolyl. Exemplary 6-membered heteroaryl groups containing one heteroatom include, without limitation, pyridinyl. Exemplary 6-membered heteroaryl groups containing two heteroatoms include, without limitation, pyridazinyl, pyrimidinyl and pyrazinyl. Exemplary 6-membered heteroaryl groups containing 3 or 4 heteroatoms include, without limitation, triazinyl and tetrazinyl, respectively. Exemplary 7-membered heteroaryl groups containing one heteroatom include, without limitation, azepinyl, oxepinyl and thiepinyl. Examples of 5,6-bicyclic heteroaryl groups include indolyl, isoindolyl, indazolyl, benzotriazolyl, benzothiophenyl, isobenzothiophenyl, benzofuranyl, benzisofuranyl, benzimidazolyl, benzoxazolyl, benz Including, but not limited to isoxazolyl, benzoxadiazolyl, benzthiazolyl, benzisothiazolyl, benzthiadiadiazolyl, indolizinyl and purinyl. Exemplary 6,6-bicyclic heteroaryl groups include, without limitation, napthyridinyl, pteridinyl, quinolinyl, isoquinolinyl, cinnolinyl, quinoxalinyl, phthalazinyl and quinazolinyl. Other exemplary heteroaryl groups include heme and heme derivatives.

[0027] As used herein, "cycloalkyl" means 3 to 10 ring carbon atoms ("C 3 ~C 10 cycloalkyl") and refers to the radical of a non-aromatic cyclic hydrocarbon group having no heteroatoms in the non-aromatic ring system. In some embodiments, cycloalkyl groups have 3-8 ring carbon atoms (“C 3 ~C 8 cycloalkyl"). In some embodiments, cycloalkyl groups have 3-6 ring carbon atoms (“C 3 ~C 6 cycloalkyl"). In some embodiments, cycloalkyl groups have 3-6 ring carbon atoms (“C 3 ~C 6 cycloalkyl"). In some embodiments, cycloalkyl groups have 5-10 ring carbon atoms (“C 5 ~C 10 cycloalkyl"). Cycloalkyl groups are, for example, C 4 ~C 7 It can be described as a membered cycloalkyl, where the term "member" refers to a non-hydrogen ring atom within the moiety. Exemplary C 3 ~C 6 Cycloalkyl groups include cyclopropyl (C 3 ), cyclopropenyl (C 3 ), cyclobutyl (C 4 ), cyclobutenyl (C 4 ), cyclopentyl (C 5 ), cyclopentenyl (C 5 ), cyclohexyl (C 6 ), cyclohexenyl (C 6 ), cyclohexadienyl (C 6 ), etc., including but not limited to: Exemplary C 3 ~C 8 Cycloalkyl groups include the C 3 ~C 6 Cycloalkyl groups and cycloheptyl (C 7 ), cycloheptenyl (C 7 ), cycloheptadienyl (C 7 ), cycloheptatrienyl (C 7 ), cyclooctyl (C 8 ), cyclooctenyl (C 8 ), cubanyl (C 8 ), bicyclo[1.1.1]pentanyl (C 5 ), bicyclo[2.2.2]octanyl (C 8 ), bicyclo[2.1.1]hexanyl (C 6 ), bicyclo[3.1.1]heptanyl (C 7 ), etc., including but not limited to: Exemplary C 3 ~C10 Cycloalkyl groups include the C 3 ~C 8 Cycloalkyl and cyclononyl (C 9 ), cyclononenyl (C 9 ), cyclodecyl (C 10 ), cyclodecenyl (C 10 ), octahydro-1H-indenyl (C 9 ), decahydronaphthalenyl (C 10 ), spiro[4.5]decanyl (C 10 ), etc., including but not limited to: As the preceding examples demonstrate, in certain embodiments, a cycloalkyl group is monocyclic (“monocyclic cycloalkyl”) or a fused, bridged or spiro ring system such as a bicyclic ring system ( “bicyclic cycloalkyl”), which may 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; continues to specify 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, the cycloalkyl group is an unsubstituted C 3 ~C 10 is cycloalkyl. In certain embodiments, the cycloalkyl group is substituted C 3 ~C 10 is cycloalkyl.

[0028] As used herein, “heterocyclyl” refers to a radical of a 3-10 membered non-aromatic ring system having ring carbon atoms and 1-4 ring heteroatoms, wherein each heteroatom is , independently selected from nitrogen, oxygen, sulfur, boron, phosphorus and silicon (“3-10 membered heterocyclyl”). In heterocyclyl groups containing more than one nitrogen atom, the point of attachment can be a carbon or nitrogen atom, when valences permit. A heterocyclyl group can be either monocyclic (“monocyclic heterocyclyl”) or a fused, bridged or spiro ring system such as a bicyclic ring system (“bicyclic heterocyclyl”), saturated or partially unsaturated. obtain. Heterocyclyl bicyclic ring systems can include one or more heteroatoms in one or both rings. "Heterocyclyl" includes a ring system in which a heterocyclyl ring, as defined above, is fused to one or more cycloalkyl groups on which the point of attachment is cycloalkyl or on the heterocyclyl ring or a heterocyclyl ring, as defined above, is Also included are ring systems in which is fused to one or more aryl or heteroaryl groups on the heterocyclyl ring; in such cases, the number of ring members continues to designate the number of ring members in the heterocyclyl ring system. A heterocyclyl group can 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, namely carbon, nitrogen, oxygen, sulfur, boron, phosphorus and silicon. Each instance of heterocyclyl can independently be optionally substituted, that is, unsubstituted (“unsubstituted heterocyclyl”) or substituted with one or more substituents (“substituted heterocyclyl”). In certain embodiments, the heterocyclyl group is unsubstituted 3-10 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, without limitation, aziridinyl, oxiranyl, thiorenyl. Exemplary 4-membered heterocyclyl groups containing one heteroatom include, without limitation, azetidinyl, oxetanyl and thietanyl. Exemplary 5-membered heterocyclyl groups containing one heteroatom include tetrahydrofuranyl, dihydrofuranyl, tetrahydrothiophenyl, dihydrothiophenyl, pyrrolidinyl, dihydropyrrolyl and pyrrolyl-2,5-dione, It is not limited to these. 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 3 heteroatoms include, without limitation, triazolinyl, oxadiazolinyl and thiadiazolinyl. Exemplary 6-membered heterocyclyl groups containing one heteroatom include 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 piperazinyl, morpholinyl, pyridazinonyl (2-methylpyridazin-3-onyl), pyrimidinonyl (e.g., 1-methylpyrimidin-2-onyl, 3-methylpyrimidine- 4-onyl), dithianyl, dioxanyl, but are not limited to these. Exemplary 6-membered heterocyclyl groups containing two heteroatoms include, without limitation, triazinanyl. Exemplary 7-membered heterocyclyl groups containing one heteroatom include, without limitation, azepanyl, oxepanyl and thiepanyl. Exemplary 8-membered heterocyclyl groups containing one heteroatom include, without limitation, azocanyl, oxecanyl and thiocanyl. C. 6 Exemplary 5-membered heterocyclyl groups fused to an aryl ring (also referred to herein as a 5,6-bicyclic heterocyclyl ring) include indolinyl, isoindolinyl, dihydrobenzofuranyl, dihydrobenzothienyl, benzoxazolinonyl, and the like. including but not limited to. Exemplary 5-membered heterocyclyl groups fused to a heterocyclyl ring (also referred to herein as a 5,5-bicyclic heterocyclyl ring) include octahydropyrrolopyrrolyl (e.g., octahydropyrrolo[3,4-c] pyrrolyl) and the like, but are not limited to these. Exemplary 6-membered heterocyclyl groups fused to a heterocyclyl ring (also called 4-, 6-membered heterocyclyl rings) include diazaspirononanyl (e.g., 2,7-diazaspiro[3.5]nonanyl), but these include Not limited. Exemplary 6-membered heterocyclyl groups fused to an aryl ring (also referred to herein as a 6,6-bicyclic heterocyclyl ring) include, but are not limited to, tetrahydroquinolinyl, tetrahydroisoquinolinyl, and the like. Not limited. Exemplary 6-membered heterocyclyl groups fused to a cycloalkyl ring (also referred to herein as a 6,7-bicyclic heterocyclyl ring) include azabicyclooctanyl (e.g., (1,5)-8-azabicyclo[ 3.2.1]octanyl), including but not limited to). Exemplary 6-membered heterocyclyl groups fused to a cycloalkyl ring (also referred to herein as a 6,8-bicyclic heterocyclyl ring) include azabicyclononanyl (e.g., 9-azabicyclo[3.3.1]nonanyl) including but not limited to.

[0030] The terms "alkylene", "alkenylene", "alkynylene", "haloalkylene", "heteroalkylene", "cycloalkylene" or "heterocyclylene", alone or as part of another substituent, are expressly Unless otherwise specified, each is a divalent radical derived from an alkyl, alkenyl, alkynyl, haloalkylene, heteroalkylene, cycloalkyl or heterocyclyl. For example, the term "alkenylene," by itself or as part of another substituent, means a divalent radical derived from alkenes, unless otherwise specified. Alkylene, alkenylene, alkynylene, haloalkylene, heteroalkylene, cycloalkylene or heterocyclylene groups are, for example, C 1 ~C 6 member alkylene, C 2 ~C 6 member alkenylene, C 2 ~C 6 member alkynylene, C 1 ~C 6 membered haloalkylene, C 1 ~C 6 membered heteroalkylene, C 3 ~C 8 membered cycloalkylene or C 3 ~C 8 It can be described as a membered heterocyclylene, where the term "member" 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 (eg, alkyleneoxy, alkylenedioxy, alkyleneamino, alkylenediamino, and the like). Furthermore, the direction in which the formula of the linking group is written does not imply any orientation of the linking group. For example, the formula -C(O) 2 R'- is -C(O) 2 R'- and -R'C(O) 2 can represent both - and

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

[0032] As used herein, the terms "halogen" or "halo" refer 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 group having two oxygen atoms attached to a nitrogen atom, such as -NO 2 point to

[0035] As used herein, the term "nucleobase" is a nitrogen-containing biological compound found linked to sugars within nucleosides and is the basis of deoxyribonucleic acid (DNA) and ribonucleic acid (RNA). It is a component. The major or natural nucleobases are cytosine (DNA and RNA), guanine (DNA and RNA), adenine (DNA and RNA), thymine (DNA) and uracil (RNA), respectively C, G, A, T and abbreviated U. A, G, C and T are called DNA bases because they occur in DNA. A, G, C and U are called RNA bases. Adenine and guanine belong to the bicyclic class of molecules called purines (abbreviated R). Cytosine, thymine, and uracil are all pyrimidines. Other nucleobases that do not function as a normal part of the genetic code are called non-natural. In one embodiment, nucleobases can be chemically modified, eg, with alkyl (eg, 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 either single- or double-stranded form. The term "nucleic acid" includes genes, cDNAs, pre-mRNAs or mRNAs. In one embodiment, the nucleic acid molecule is synthetic (eg, chemically synthesized) or recombinant. Unless specifically 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 includes not only the explicitly indicated sequence, but also conservatively modified variants (e.g., degenerate codon substitutions), alleles, orthologs, SNPs and complementary sequences thereof. is also implicitly included.

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

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

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

[0040] Two or more substituents may optionally be joined 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, 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, 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, ring-forming substituents are attached to non-adjacent members of the base structure.

[0041] The compounds provided herein may have one or more specific geometric isomers, optical isomers, enantiomers, diastereomers, epimers, stereoisomers, tautomers, stereoisomers or anomeric forms. cis and trans forms; E and Z forms; endo and exo forms; R, S and meso forms; D and L forms; Syncline and Anticline; Alpha and β; Axial and Equatorial; Boat, Chair, Twist, Envelope and Half-Chair; and combinations thereof. , hereinafter collectively referred to as "isomers" (or "isomeric forms").

[0042] Compounds described herein may contain one or more asymmetric centers and therefore can exist in different isomeric forms, eg enantiomers and / or diastereomers. For example, the compounds described herein can be in the form of individual enantiomers, diastereomers or geometric isomers, or stereoisomers, including racemic mixtures and mixtures enriched in one or more stereoisomers. It can be in the form of a mixture of isomers. In one embodiment, the stereochemistry shown in the compounds 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 formation and crystallization of chiral salts; or preferred isomers are prepared by asymmetric synthesis. can do. 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 (E.L. Eliel, Ed., Univ. of Notre Dame Press, Notre Dame, IN 1972). This disclosure further includes the compounds described herein as individual isomers substantially free of other isomers and alternatively as mixtures of various isomers.

[0043] As used herein, an enantiomerically pure compound is substantially free of other enantiomers or stereoisomers of the compound (ie, enantiomeric excess). In other words, the 'S' form of the compound is substantially free of the 'R' form of the compound and is therefore in enantiomeric excess of the 'R' form. The term "enantiomerically pure" or "pure enantiomers" means that a compound contains greater than 75%, greater than 80%, greater than 85%, greater than 90%, greater than 91%, 92% by weight, greater than 93%, greater than 94%, greater than 95%, greater than 96%, greater than 97%, greater than 98%, greater than 99%, greater than 99.5% or greater than 99.9% by weight of mirror image Refers to a compound that contains isomers. In certain embodiments, weights are based on the total weight of all enantiomers or stereoisomers of the compound.

[0044] In the compositions provided herein, enantiomerically pure compounds can be present with other active or inactive ingredients. For example, a pharmaceutical composition comprising enantiomerically pure R compound can comprise, for example, about 90% excipient and about 10% enantiomerically pure R compound. In certain embodiments, the enantiomerically pure R compounds in such compositions are, for example, at least about 95% by weight of the R compound and up to about 5% by weight of the total weight of the compounds. May contain S compounds. For example, a pharmaceutical composition comprising enantiomerically pure S compound can comprise, for example, about 90% excipient and about 10% enantiomerically pure S compound. In certain embodiments, the enantiomerically pure S compound in such compositions is, for example, at least about 95% by weight S compound and up to about 5% by weight May contain R compounds.

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

[0046] In some embodiments, isomerically pure compounds may be present with other active or inactive ingredients. For example, a pharmaceutical composition comprising an isomerically pure exo compound can comprise, for example, about 90% excipient and about 10% isomerically pure exo compound. In certain embodiments, the isomerically pure exo compound in such compositions is, for example, at least about 95% by weight exo compound and up to about 5% by weight endo compound, based on the total weight of the compound. compound. For example, a pharmaceutical composition comprising isomerically pure Endo Compound can comprise, for example, about 90% excipient and about 10% isomerically pure Endo Compound. In certain embodiments, the isomerically pure endo compounds in such compositions are, for example, at least about 95% by weight of the endo compound and up to about 5% by weight of the exo compound, based on the total weight of the compounds. compound.

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

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

[0049] The term "pharmaceutically acceptable salt" refers to salts of active compounds prepared with relatively non-toxic acids or bases, depending on the particular substituents found in the compounds described herein. means to contain When the compounds of this disclosure contain relatively acidic functional groups, base addition salts are prepared by contacting the neutral form of such compounds with a sufficient amount of the desired base, either neat or in a suitable inert solvent. can be obtained by Examples of pharmaceutically acceptable base addition salts include sodium, potassium, calcium, ammonium, organic amino or magnesium salts or similar salts. When the compounds of the invention contain relatively basic functional groups, acid addition salts are formed by contacting the neutral form of such compounds with a sufficient amount of the desired acid, either neat or in a suitable inert solvent. can be obtained by Examples of pharmaceutically acceptable acid addition salts include hydrochloric acid, hydrobromic acid, nitric acid, carbonic acid, monohydrogencarbonic acid, phosphoric acid, monohydrogenphosphate, dihydrogenphosphate, sulfuric acid, monohydrogensulphate, iodide those derived from inorganic acids such as hydrogen acid or phosphorous acid, as well 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, Included are salts derived from organic acids such as benzenesulfonic acid, p-tolylsulfonic acid, citric acid, tartaric acid, methanesulfonic acid, and the like. Also included are salts of amino acids such as alginate and salts of organic acids such as glucuronic acid or galacturonic acid (see, eg, Berge et al, Journal of Pharmaceutical Sciences 66:1-19 (1977)). Certain specific 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 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 those compounds that readily undergo chemical changes under physiological conditions to provide the compounds of the present invention. Additionally, 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 forms of the compound that are associated with a solvent, usually by a solvolysis reaction. This physical association may include hydrogen bonding. Conventional solvents include water, methanol, ethanol, acetic acid, DMSO, THF, diethyl ether, and the like. The compounds of formula (I) may, for example, be prepared in crystalline form and may be solvated. Suitable solvates include pharmaceutically acceptable solvates and also include both stoichiometric and non-stoichiometric solvates. In certain instances the solvate will be capable of isolation, for example when one or more solvent molecules are incorporated in the crystal lattice of the 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, hydrates of compounds can be represented, for example, by the general formula R xH 2 It can be represented by O, where R is a compound and x is a number greater than zero. A given compound is, 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 0.5H 2 O))) and polyhydrates (where x is a number greater than 1, e.g. dihydrates (R 2H 2 O) and hexahydrate (R 6H 2 O)) can form more than one type of hydrate.

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

[0054] other definitions The following definitions are for the more general terms used throughout this disclosure.

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

[0056] The term "about" is used herein to mean within the typical tolerances in the art. For example, "about" can be understood as about 2 standard deviations from the mean. In certain embodiments, about means +10%. In certain embodiments, about means +5%. When a series or range is preceded by about, it is understood that "about" can modify each number in the series or range.

[0057] As used herein, "obtaining" or "obtaining" means "directly obtaining" a value, such as a value, image or physical entity (e.g., a sample), or It refers to acquiring by “obtaining indirectly”. "Directly obtaining" means performing a process (eg, performing 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 (eg, a third-party laboratory that directly obtained the physical entity or value). Obtaining a value or physical entity directly includes performing a process involving physical alteration of physical matter or use of a machine or device. Examples of obtaining values ​​directly include obtaining samples from human subjects. Obtaining values ​​directly involves using a machine or device, such as a mass spectrometer, to perform the process of obtaining mass spectrometry data.

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

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

[0060] An "effective amount" of a compound of Formula (I) refers to an amount sufficient to elicit the desired biological response, ie treat the condition. As will be appreciated by those skilled in the art, the effective amount of a compound of formula (I) will vary depending on factors such as the desired biological endpoint, the pharmacokinetics of the compound, the condition being treated, the mode of administration and the age and health of the subject. can vary depending on Effective amounts include therapeutic and prophylactic treatments. For example, in treating cancer, an effective amount of a compound of the invention may reduce tumor burden or arrest tumor growth or spread.

[0061] A "therapeutically effective amount" of a compound of formula (I) is an amount sufficient to provide therapeutic benefit in treating the condition or to delay or minimize one or more symptoms associated with the condition. is. In some embodiments, a therapeutically effective amount is an amount sufficient to provide therapeutic benefit in treating the condition or to minimize one or more symptoms associated with the condition. A therapeutically effective amount of a compound means that amount of therapeutic agent, alone or in combination with other therapies, that provides a therapeutic benefit in treating the condition. The term "therapeutically effective amount" can include an amount that ameliorates overall treatment, alleviates or avoids the cause of the symptoms or condition, or enhances the therapeutic efficacy of another therapeutic agent.

[0062] The terms "peptide", "polypeptide" and "protein" are used interchangeably and refer to a compound made up 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 can contain. A polypeptide includes any peptide or protein comprising two or more amino acids joined together 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 long chains, commonly referred to in the art as proteins, and many There are types.

[0063] As used herein, "prevention", "prevent" and "preventing" refer to administering treatment, e.g. Refers to treatment comprising administering a compound described herein (eg, a compound of formula (I)) prior to onset of symptoms. In some embodiments, "prevention", "prevent" and "preventing" require that signs or symptoms of a disease, disorder or condition have not yet occurred or have not yet been observed . In some embodiments, treatment includes prophylaxis, in other embodiments it does not.

[0064] "Subjects" intended for administration include humans (i.e., male or female of any age group, e.g., pediatric subjects (e.g., infants, children, adolescents) or adult subjects (e.g., young adults, middle-aged adults, or elderly adults). ))) and / or other non-human animals such as mammals (e.g. primates (e.g. cynomolgus monkeys, rhesus monkeys); commercially relevant mammals such as bovine, porcine, equine, ovine, goat, feline and / or canine). animals) and birds (eg, commercially relevant birds such as chickens, ducks, geese and / or turkeys). In certain embodiments, the animal is a mammal. Animals can be male or female and can be at any stage of development. A non-human animal can be a transgenic animal.

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

[0066] "Proliferative disease" refers to a disease caused by abnormal expansion due to cell proliferation (Walker, Cambridge Dictionary of Biology; Cambridge University Press: Cambridge, UK, 1990). Proliferative disorders include: 1) pathological proliferation of normal quiescent cells; 2) pathological migration of cells from their normal location (e.g. metastasis of tumor cells); 3) matrix metalloproteinases (e.g. collagenase, gelatinase, elastase), etc. 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 (ie, "malignant neoplasms"), benign neoplasms and angiogenesis.

[0067] "Non-proliferative disease" refers to a disease that is not spread primarily by abnormal cell proliferation. Non-proliferative diseases can be associated with any cell or tissue type of the subject. Exemplary nonproliferative 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; metabolic diseases or disorders; respiratory conditions, diseases or disorders; renal diseases or disorders; and infectious diseases.

[0068] Compound The present disclosure provides formula (I): [formation] (Wherein, A and B are each independently one or more R 1 is cycloalkyl, heterocyclyl, aryl or heteroaryl optionally substituted with; W is N, C or C(R 3a ); X, Y and Z are each independently C(R 3a ), C(R 3a )(R 3b ), N, N(R 3c ) or O, and the bonds in the ring containing X, Y and Z can be single or double bonds when valences permit; 1 and L 2 Each of the independently, absent, C 1 ~C 6 Alkylene, C 1 ~C 6 heteroalkylene, -O-, -C(O)-, -N(R 4 )-, -N(R 4 )C(O)- or -C(O)N(R 4 )- and each alkylene and heteroalkylene is one or more R 5 is optionally replaced with; 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, alkynyl, heteroalkyl, haloalkyl, cycloalkyl, heterocyclyl, aryl and heteroaryl is one or more R 6 optionally substituted with; or two R 1 The groups, together with the atoms to which they are attached, form a 3- to 7-membered cycloalkyl, heterocyclyl, aryl or heteroaryl, each cycloalkyl, heterocyclyl, aryl and heteroaryl being represented by one or more R 6 is optionally replaced with; each R 2 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, halo, cyano or -OR A is; R 3a and R 3b are each independently hydrogen, C 1 ~C 6 Alkyl, C 1 ~C 6 heteroalkyl, C 1 ~C 6 haloalkyl, halo, cyano, -OR A , -NR B R.C , -C(O)R D or -C(O)OR D or R 3a and R 3b each, together with the carbon atom to which they are attached, form an oxo group; R 3c is hydrogen or C 1 ~C 6 is alkyl; each R 4 are independently hydrogen, C 1 ~C 6 alkyl or C 1 ~C 6 is haloalkyl; each R 5 are independently hydrogen, C 1 ~C 6 Alkyl, C 1 ~C 6 heteroalkyl, C 1 ~C 6 haloalkyl, cycloalkyl, halo, cyano, oxo, -OR A , -NR B R. C , -C(O)R D or -C(O)OR D is; each R 6 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 alkyl, alkenyl, alkynyl, heteroalkyl, haloalkyl, cycloalkyl, heterocyclyl, aryl and heteroaryl is one or more R 11 is optionally replaced with; each R 7 is C 1 ~C 6 alkyl, halo, cyano, oxo or -OR A1 is; each R 11 independently, C 1 ~C 6 Alkyl, C 1 ~C 6 heteroalkyl, C 1 ~C 6 haloalkyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, halo, cyano, oxo or -OR A is; 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 is; R B and R C are independently hydrogen, C 1 ~C 6 Alkyl, C 1 ~C 6 heteroalkyl, cycloalkyl, heterocyclyl or -OR A or R B and R C together with the atoms to which they are attached, one or more R 7 forming a 3- to 7-membered heterocyclyl ring optionally substituted with; 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 is alkylene-heteroaryl; each R A1 is hydrogen or C 1 ~C 6 is alkyl; m is 0, 1 or 2; x is 0, 1 or 2; and y is 0 or 1) or a pharmaceutically acceptable salt, solvate, hydrate, tautomer or stereoisomer thereof.

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

[0070] In some embodiments, A and B are each independently a monocyclic ring, such as monocyclic cycloalkyl, monocyclic heterocyclyl, monocyclic aryl or monocyclic heteroaryl. Monocyclic rings may be saturated, partially unsaturated, or fully unsaturated (eg, aromatic). In some embodiments, A or B is independently a monocyclic ring containing 3-10 ring atoms (eg, 3, 4, 5, 6, 7, 8, 9, or 10 ring atoms) It is a ring. 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 is independently one or more R 1 is a monocyclic ring optionally substituted with .

[0071] In some embodiments, A or B is independently a bicyclic ring, such as bicyclic cycloalkyl, bicyclic heterocyclyl, bicyclic aryl or bicyclic heteroaryl. Bicyclic rings can be saturated, partially unsaturated, or fully unsaturated (eg, aromatic). In some embodiments, A or B is independently a bicyclic ring, including fused, bridged, or spiro ring systems. In some embodiments, A or B is independently 4 to 18 ring atoms (e.g., 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, It is a bicyclic ring containing 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 is independently one or more R 1 is a bicyclic ring optionally substituted with .

[0072] In some embodiments, A or B is independently a tricyclic ring, such as tricyclic cycloalkyl, tricyclic heterocyclyl, tricyclic aryl or tricyclic heteroaryl. Tricyclic rings can be saturated, partially unsaturated, or fully unsaturated (eg, aromatic). In some embodiments, A or B is independently a tricyclic ring comprising fused, bridged or spiro ring systems or combinations thereof. In some embodiments, A or B independently has 6 to 24 ring atoms (e.g., 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23 or 24 ring atoms). In some embodiments, A is an 8-membered tricyclic ring. In some embodiments, B is an 8-membered tricyclic ring. In some embodiments, A is a 9-membered tricyclic ring. In some embodiments, B is a 9-membered tricyclic ring. In some embodiments, A is a 10-membered tricyclic ring. In some embodiments, B is a 10-membered tricyclic ring. In some embodiments, A or B is independently one or more R 1 is a tricyclic ring optionally substituted with .

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

[0074] In some embodiments, A or B is independently nitrogen-containing heterocyclyl, eg, heterocyclyl containing one or more nitrogen atoms. One or more nitrogen atoms of the nitrogen-containing heterocyclyl can be present at any position in the ring. In some embodiments, the nitrogen-containing heterocyclyl is monocyclic, bicyclic, or tricyclic. In some embodiments, A or B is independently 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 heterocyclyl containing 1 nitrogen atom. In some embodiments, B is heterocyclyl containing 1 nitrogen atom. In some embodiments, A is heterocyclyl containing 2 nitrogen atoms. In some embodiments, B is heterocyclyl containing 2 nitrogen atoms. In some embodiments, A is heterocyclyl containing 3 nitrogen atoms. In some embodiments, B is heterocyclyl containing 3 nitrogen atoms. In some embodiments, A is heterocyclyl containing 4 nitrogen atoms. In some embodiments, B is heterocyclyl containing 4 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 of oxygen, sulfur, boron, silicon or phosphorus. In some embodiments, one or more nitrogens of the nitrogen-containing heterocyclyl are, for example, R 1 is replaced by

[0075] In some embodiments, A or B is independently nitrogen-containing heteroaryl, such as heteroaryl containing one or more nitrogen atoms. One or more nitrogen atoms of a nitrogen-containing heteroaryl can be present at any position in the ring. In some embodiments, the nitrogen-containing heteroaryl is monocyclic, bicyclic, or tricyclic. In some embodiments, A or B is independently 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 heteroaryl containing 1 nitrogen atom. In some embodiments, B is heteroaryl containing 1 nitrogen atom. In some embodiments, A is heteroaryl containing 2 nitrogen atoms. In some embodiments, B is heteroaryl containing 2 nitrogen atoms. In some embodiments, A is heteroaryl containing 3 nitrogen atoms. In some embodiments, B is heteroaryl containing 3 nitrogen atoms. In some embodiments, A is heteroaryl containing 4 nitrogen atoms. In some embodiments, B is heteroaryl containing 4 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 of the nitrogen-containing heteroaryl are, for example, R 1 is replaced by

[0076] In some embodiments, A is a 6-membered nitrogen-containing heterocyclyl, such as a 6-membered heterocyclyl containing one or more nitrogens. In some embodiments, A is a 6-membered heterocyclyl containing 1 nitrogen atom. In some embodiments, A is a 6-membered heterocyclyl containing 2 nitrogen atoms. In some embodiments, A is a 6-membered heterocyclyl containing 3 nitrogen atoms. In some embodiments, A is a 6-membered heterocyclyl containing 4 nitrogen atoms. One or more nitrogen atoms of the 6-membered nitrogen-containing heterocyclyl may be present at any position in the ring. In some embodiments, A is one or more R 1 is a 6-membered nitrogen-containing heterocyclyl optionally substituted with . In some embodiments, one or more nitrogens of the 6-membered nitrogen-containing heterocyclyl are, for example, R 1 is replaced by In some embodiments, A is a 6-membered nitrogen-containing heterocyclyl containing one or more additional heteroatoms, such as one or more of oxygen, sulfur, boron, silicon or phosphorus.

[0077] In some embodiments, B is a 5-membered nitrogen-containing heterocyclyl or heteroaryl, such as a 5-membered heterocyclyl or heteroaryl containing one or more nitrogens. In some embodiments, B is a 5-membered heterocyclyl containing 1 nitrogen atom. In some embodiments, B is a 5-membered heteroaryl containing 1 nitrogen atom. In some embodiments, B is a 5-membered heterocyclyl containing 2 nitrogen atoms. In some embodiments, B is a 5-membered heteroaryl containing 2 nitrogen atoms. In some embodiments, B is a 5-membered heterocyclyl containing 3 nitrogen atoms. In some embodiments, B is a 5-membered heteroaryl containing 3 nitrogen atoms. One or more nitrogen atoms of a 5-membered nitrogen-containing heterocyclyl or heteroaryl can be present at any position in the ring. In some embodiments, B is one or more R 1 is a 5-membered nitrogen-containing heterocyclyl optionally substituted with . In some embodiments, B is one or more R 1 is a 5-membered nitrogen-containing heteroaryl optionally substituted with . In some embodiments, one or more nitrogens of a 5-membered nitrogen-containing heterocyclyl or heteroaryl is, for example, R 1 is replaced by In some embodiments, B is a 5-membered nitrogen-containing heterocyclyl or heteroaryl containing one or more additional heteroatoms, such as one or more of oxygen, sulfur, boron, silicon or phosphorus.

[0078] In some embodiments, B is one or more R 1 is a nitrogen-containing bicyclic heteroaryl (eg, a 9-membered nitrogen-containing bicyclic heteroaryl) optionally substituted with . In some embodiments, B is a 9-membered bicyclic heteroaryl containing 1 nitrogen atom. In some embodiments, B is a 9-membered bicyclic heteroaryl containing 2 nitrogen atoms. In some embodiments, B is a 9-membered bicyclic heteroaryl containing 3 nitrogen atoms. In some embodiments, B is a 9-membered bicyclic heteroaryl containing 4 nitrogen atoms. One or more nitrogen atoms of a 9-membered bicyclic heteroaryl can be at any position on the ring. In some embodiments, B is one or more R 1 is a 9-membered bicyclic heteroaryl substituted with

[0079] In some embodiments, A and B are [formation] [formation] [formation] [formation] [formation] [formation] [formation] [formation] [formation] (In the formula, each R 1 is as defined herein) are each independently selected from In one embodiment, A and B are each independently a saturated, partially saturated or unsaturated (eg, 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 [formation] [formation] [formation] (In the formula, each R 1 is as defined herein) are each independently selected from In one embodiment, A and B are each independently a saturated, partially saturated or unsaturated (eg, 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 [formation] (In the formula, R 1 is as defined herein) is selected from

[0082] In some embodiments, A is [formation] is selected from

[0083] In some embodiments, A is [formation] is selected from

[0084] In some embodiments, A is [formation] is selected from

[0085] In some embodiments, A is [formation] is selected from

[0086] In some embodiments, A is [formation] is. In some embodiments, A is [formation] is. In some embodiments, A is [formation] is. In some embodiments, A is [formation] is. In some embodiments, A is [formation] is. In some embodiments, A is [formation] is. In some embodiments, A is [formation] is. In some embodiments, A is [formation] is. In some embodiments, A is [formation] is. In some embodiments, A is [formation] is. In some embodiments, A is [formation] is. In some embodiments, A is [formation] is. In some embodiments, A is [formation] is. In some embodiments, A is [formation] is. In some embodiments, A is [formation] is. In some embodiments, A is [formation] is. In some embodiments, A is [formation] is. In some embodiments, A is [formation] is. In some embodiments, A is [formation] is. In some embodiments, A is [formation] is. In some embodiments, A is [formation] is. In some embodiments, A is [formation] is. In some embodiments, A is [formation] is. In some embodiments, A is [formation] is. In some embodiments, A is [formation] is. In some embodiments, A is [formation] is. In some embodiments, A is [formation] is. In some embodiments, A is [formation] is. In some embodiments, A is [formation] is.

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

[0088] In some embodiments, B is [formation] is selected from

[0089] In some embodiments, B is [formation] is selected from

[0090] In some embodiments, B is [formation] is. In some embodiments, B is [formation] is. In some embodiments, B is [formation] is. In some embodiments, B is [formation] is. In some embodiments, B is [formation] is. In some embodiments, B is [formation] is. In some embodiments, B is [formation] is. In some embodiments, B is [formation] is. In some embodiments, B is [formation] is. In some embodiments, B is [formation] is. In some embodiments, B is [formation] is. In some embodiments, B is [formation] is. In some embodiments, B is [formation] is. In some embodiments, B is [formation] is. In some embodiments, B is [formation] is. In some embodiments, the selected B is [formation] is. In some embodiments, B is [formation] is. In some embodiments, B is [formation] is. In some embodiments, B is [formation] is. In some embodiments, B is [formation] is.

[0091] In some embodiments, B is Formula (A) or Formula (B): [formation] (wherein each of J, K and M is selected from N and C(R'); R 1 is as defined above; R ’ is hydrogen, halo (e.g. fluoro) or C 1 ~C 6 is alkyl (e.g. methyl); p is 0, 1, 2, 3 or 4; at least one of J, K and M is N; can be a single or double bond when valence permits) is the structure of

[0092] In some embodiments, J, K and M are each independently N. In some embodiments, J is C(R') and K and M are each independently M. In some embodiments, p is 0. In some embodiments, p is 1. In some embodiments, p is two. In some embodiments, p is three. In some embodiments, p is four.

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

[0094] As generally described herein, L 1 and L 2 are each independently absent or C 1 ~C 6 Alkylene, C 1 ~C 6 heteroalkylene, -O-, -C(O)-, -N(R 4 )-, -N(R 4 )C(O)- or -C(O)N(R 4 )- group, where each alkylene and heteroalkylene may refer to one or more R 5 is optionally replaced by

[0095] In some embodiments, L 1 is absent. In some embodiments, L 1 is C 1 ~C 6Alkylene (e.g. C 1 Alkylene, C 2 Alkylene, C 3 Alkylene, C 4 Alkylene, C 5 Alkylene or C 6 alkylene). In some embodiments, L 1 is the unsubstituted C 1 ~C 6 is alkylene. In some embodiments, L 1 is the permutation C 1 ~C 6 Alkylene, such as one or more R 5 C replaced by 1 ~C 6 is alkylene. In some embodiments, L 1 is one R 5 C replaced by 1 is alkylene. In some embodiments, L 1 is -CH 2 - (or methylene). In some embodiments, L 1 is -C(O)- (or carbonyl).

[0096] In some embodiments, L 1 is absent, C 1 ~C 6 Alkylene, C 1 ~C 6 heteroalkylene, -N(R 4 )C(O)- or -C(O)N(R 4 )- and each alkylene and heteroalkylene is one or more R 5 is optionally replaced by

[0097] In some embodiments, L 1 is C 1 ~C 6 heteroalkylene (e.g. C 1 heteroalkylene, C 2 heteroalkylene, C 3 heteroalkylene, C 4 heteroalkylene, C 5 heteroalkylene or C 6 heteroalkylene). In some embodiments, L 1 is the unsubstituted C 1 ~C 6 It is heteroalkylene. In some embodiments, L 1 is a substituted heteroalkylene, such as one or more R 5 C replaced by 1 ~C 6 It is heteroalkylene. In some embodiments, the heteroalkylene contains one or more heteroatoms. In some embodiments, heteroalkylene includes one or more of oxygen, sulfur, nitrogen, boron, silicon or phosphorous. In some embodiments, L 1 is -N(R 4 )C(O)-. In some embodiments, L 1 is -C(O)N(R 4 )-. In some embodiments, L 1 is -C(O)N(H)-.

[0098] In some embodiments, L 1 is oxygen. In some embodiments, L 1 is R 4 is nitrogen optionally substituted with . In some embodiments, L 1 is R 4 is nitrogen substituted with In some embodiments, L 1 is -N(R 4 )-, such as -N(CH 3 )-. In some embodiments, L 1 is -NH-. In some embodiments, L 1 is -O-.

[0099] In some embodiments, L 2 is absent, C 1 ~C 6 Alkylene, C 1 ~C 6 heteroalkylene, -N(R 4 )C(O)- or -C(O)N(R 4 )- and each alkylene and heteroalkylene is one or more R 5 is optionally replaced by In some embodiments, L 2 is the unsubstituted C 1 ~C 6 It is heteroalkylene. In some embodiments, L 2 is a substituted heteroalkylene, such as one or more R 5 C replaced by 1 ~C 6 It is heteroalkylene. In some embodiments, the heteroalkylene contains one or more heteroatoms. In some embodiments, heteroalkylene includes one or more of oxygen, sulfur, nitrogen, boron, silicon or phosphorous. In some embodiments, L 2 is -N(R 4 )C(O)-. In some embodiments, L 2 is -C(O)N(R 4 )-. In some embodiments, L 2 is -C(O)N(H)-.

[0100] In some embodiments, L 2 is R 4 is nitrogen optionally substituted with . In some embodiments, L 2 is R 4 is nitrogen substituted with In some embodiments, L 2 is -N(R 4 )-, such as -N(CH 3 )-. In some embodiments, L 2 is -NH-.

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

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

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

[0104] In some embodiments, y is 0.

[0105] In some embodiments, R 1is hydrogen. In some embodiments, R 1 is C 1 ~C 6 is alkyl. In some embodiments, R 1 is C 2 ~C 6 It is alkenyl. In some embodiments, R 1 is C 2 ~C 6 is alkynyl. In some embodiments, R 1 is C 1 ~C 6 is heteroalkyl. In some embodiments, R 1 is C 1 ~C 6 Haloalkyl (e.g., -CF 3 ). In some embodiments, R 1 is C 1 Alkyl (eg, methyl). In some embodiments, R 1 is the unsubstituted C 1 ~C 6 alkyl, unsubstituted C 2 ~C 6 alkenyl, unsubstituted C 2 ~C 6 alkynyl, unsubstituted C 1 ~C 6 heteroalkyl or unsubstituted C 1 ~C 6 is haloalkyl. In some embodiments, R 1 is one or more R 6 C replaced by 1 ~C 6 is alkyl. In some embodiments, R 1 is one or more R 6 C replaced by 2 ~C 6 It is alkenyl. In some embodiments, R 1 is one or more R 6 C replaced by 2 ~C 6 is alkynyl. In some embodiments, R 1 is one or more R 6 C replaced by 1 ~C 6 is heteroalkyl. In some embodiments, R 1 is one or more R 6 C replaced by 1 ~C 6 is haloalkyl. In some embodiments, R 1 is methyl.

[0106] In some embodiments, R 1 is cycloalkyl (eg, 3- to 7-membered cycloalkyl). In some embodiments, R 1 is heterocyclyl (eg, 3- to 7-membered heterocyclyl). In some embodiments, R 1 is aryl. In some embodiments, R 1 is C 1 ~C 6 Alkylene-aryl (eg, benzyl). In some embodiments, R 1 is C 1 ~C 6 alkenylene-aryl. In some embodiments, R 1 is C 1 ~C 6 Alkylene-heteroaryl. In some embodiments, R 1 is heteroaryl. In some embodiments, R 1 is unsubstituted cycloalkyl, unsubstituted heterocyclyl, unsubstituted aryl, unsubstituted C 1 ~C 6 alkylene-aryl, unsubstituted C 1 ~C 6 alkenylene-aryl, unsubstituted C 1 ~C 6 Alkylene-heteroaryl or unsubstituted heteroaryl. In some embodiments, R 1 is one or more R 6 is cycloalkyl substituted with In some embodiments, R 1 is one or more R 6 is heterocyclyl substituted with In some embodiments, R 1 is one or more R 6 is aryl substituted with In some embodiments, R 1 is one or more R 6 C replaced by 1 ~C 6 alkylene-aryl. In some embodiments, R 1 is one or more R 6 C replaced by 1 ~C 6 alkenylene-aryl. In some embodiments, R 1 is one or more R 6 C replaced by 1 ~C 6 Alkylene-heteroaryl. In some embodiments, R 1 is one or more R 6 is heteroaryl substituted with

[0107] In some embodiments, R 1 is -OR A is. In some embodiments, R 1 is -NR B R. C (for example, NH 2 or NMe 2 ). In some embodiments, R 1 is -NR B C(O)R D is. In some embodiments, R 1 is -C(O)NR B R. C is. In some embodiments, R 1 is -C(O)R D is. In some embodiments, R 1 is -C(O)OR D is. In some embodiments, R 1 is -SR E is. In some embodiments, R 1 is -S(O) x R. D is. In some embodiments, R 1 is halo such as fluoro, chloro, bromo or iodo. In some embodiments, R 1 is cyano. In some embodiments, R 1 is nitro (-NO 2 ). In some embodiments, R 1 is oxo.

[0108] In some embodiments, two R 1 The groups together with the atoms to which they are attached form 3- to 7-membered cycloalkyls. In some embodiments, two R 1 The groups together with the atoms to which they are attached form 3- to 7-membered heterocyclyls. In some embodiments, two R 1 The groups together with the atoms to which they are attached form 5- or 6-membered aryls. In some embodiments, two R 1 The groups, together with the atoms to which they are attached, form 5- or 6-membered heteroaryls. Cycloalkyl, heterocyclyl, aryl or heteroaryl is one or more R 6 can be replaced with

[0109] In some embodiments, R 2 is hydrogen. In some embodiments, R 2 is halo (eg fluoro, chloro, bromo or iodo). In some embodiments, R 2 is cyano. In some embodiments, R 2 is C 1 ~C 6 is alkyl. In some embodiments, R 2 is C 2 ~C 6 It is alkenyl. In some embodiments, R 2 is C 2 ~C 6 is alkynyl. In some embodiments, R 2 is -OR A (eg, -OH).

[0110] In some embodiments, R 3a , R 3b or both independently hydrogen, C 1 ~C 6 Alkyl, C 1 ~C 6 heteroalkyl, C 1 ~C 6 haloalkyl, halo, cyano, -OR A , -NR B R. C , -C(O)R D or -C(O)OR D is. In some embodiments, R 3a and R 3b are each independently hydrogen or C 1 ~C 6 is alkyl. In some embodiments, R 3a is hydrogen. In some embodiments, R 3b is hydrogen. In some embodiments, R 3a is C 1 ~C 6 Alkyl (eg, methyl). In some embodiments, R 3b is C 1 ~C 6 Alkyl (eg, methyl). In some embodiments, R 3ais halo (eg fluoro, chloro, bromo or iodo). In some embodiments, R 3b is halo (eg fluoro, chloro, bromo or iodo). In some embodiments, R 3a is cyano. In some embodiments, R 3b is cyano. In some embodiments, R 3a is -OR A (eg, -OH). In some embodiments, R 3b is -OR A (eg, -OH). In some embodiments, R 3a is -NR B R. C is. In some embodiments, R 3b is -NR B R. C is. In some embodiments, R 3a is -C(O)R D is. In some embodiments, R 3b is -C(O)R D is. In some embodiments, R 3a is -C(O)OR D is. In some embodiments, R 3b is -C(O)OR D is. In some embodiments, R 3a and R 3b each form an oxo group with the carbon atom to which they are attached.

[0111] In some embodiments, R 3c is hydrogen. In some embodiments, R 3c is C 1 ~C 6 is alkyl. In some embodiments, R 3c is methyl.

[0112] In some embodiments, R 4 is hydrogen. In some embodiments, R 4 is C 1 ~C 6 is alkyl. In some embodiments, R 4 is C 1 ~C 6 Haloalkyl (e.g., -CF 3 or -CHF 2 ). In some embodiments, R 4 is methyl.

[0113] In some embodiments, R 5 is hydrogen. In some embodiments, R 5 is C 1 ~C 6 is alkyl. In some embodiments, R 5 is C 1 ~C 6 is heteroalkyl. In some embodiments, R 5 is C 1 ~C 6 is haloalkyl. In some embodiments, R 5 is C 1 ~C 6 is cycloalkyl. In some embodiments, R 5 is halo (eg fluoro, chloro, bromo or iodo). In some embodiments, R 5 is cyano. In some embodiments, R 5 is oxo. In some embodiments, R 5 is -OR A is. In some embodiments, R 5 is -NR B R. C is. In some embodiments, R 5 is -C(O)R D or -C(O)OR D is.

[0114] In some embodiments, R 6 is C 1 ~C 6 is alkyl. In some embodiments, R 6 is C 2 ~C 6 It is alkenyl. In some embodiments, R 6 is C 2 ~C 6 is alkynyl. In some embodiments, R 6 is C 1 ~C 6 is heteroalkyl. In some embodiments, R 6 is C 1 ~C 6 is haloalkyl. In some embodiments, R 6 is the unsubstituted C 1 ~C 6 alkyl, unsubstituted C 2 ~C 6 alkenyl, unsubstituted C 2 ~C 6 alkynyl, unsubstituted C 1 ~C 6 haloalkyl or unsubstituted C 1 ~C 6 is heteroalkyl. In some embodiments, R 6 is one or more R 11 C replaced by 1 ~C 6 is alkyl. In some embodiments, R 6 is one or more R 11 C replaced by 2 ~C 6 It is alkenyl. In some embodiments, R 6 is one or more R 11 C replaced by 2 ~C 6 is alkynyl. In some embodiments, R 6 is one or more R 11 C replaced by 1 ~C 6 is haloalkyl. In some embodiments, R 6 is one or more R 11 C replaced by 1 ~C 6 is heteroalkyl.

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

[0116] In some embodiments, R 6 is halo (eg fluoro, chloro, bromo or iodo). In some embodiments, R 6 is cyano. In some embodiments, R 6 is oxo. In some embodiments, R 6 is -OR A is. In some embodiments, R 6 is -NR B R. C is. In some embodiments, R 6 is -NR B C(O)R D is. In some embodiments, R 6 -NO 2 is. In some embodiments, R 6 is -C(O)NR B R. C is. In some embodiments, R 6 is -C(O)R D is. In some embodiments, R 6 is -C(O)OR D is. In some embodiments, R 6 is -SR E is. In some embodiments, R 6 is -S(O) x R. D is.

[0117] In some embodiments, R 7 is C 1 ~C 6 is alkyl. In some embodiments, R 7 is halo (eg fluoro, chloro, bromo or iodo). In some embodiments, R 7 is cyano. In some embodiments, R 7 is oxo. In some embodiments, R 7 is -OR A1 (eg, -OH).

[0118] In some embodiments, R 11 is C 1 ~C 6 is alkyl. In some embodiments, R 11 is C 1 ~C 6 is heteroalkyl. In some embodiments, R11 is C 1 ~C 6 Haloalkyl (e.g., -CF 3 ). 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 a halo. In some embodiments, R 11 is cyano. In some embodiments, R 11 is oxo. In some embodiments, R 11 is -OR A is.

[0119] In some embodiments, R A is hydrogen. In some embodiments, R A is C 1 ~C 6 Alkyl (eg, methyl). In some embodiments, R A is C 1 ~C 6 is haloalkyl. In some embodiments, R A is aryl. In some embodiments, R A is heteroaryl. In some embodiments, R A is C 1 ~C 6 Alkylene-aryl (eg, benzyl). In some embodiments, R A is C 1 ~C 6 Alkylene-heteroaryl. In some embodiments, R A is -C(O)R D is. In some embodiments, R A is -S(O) x R. D is.

[0120] In some embodiments, R B , R C or both independently hydrogen, C 1 ~C 6 Alkyl, C 1 ~C 6 heteroalkyl, cycloalkyl, heterocyclyl or -OR A is. In some embodiments, R B and R C is independently hydrogen. In some embodiments, R B and R C are independently C 1 ~C 6 is alkyl. In some embodiments, R B and R C is hydrogen, and R B and R C the other is C 1 ~C 6 is alkyl. In some embodiments, R B and R C together with the atoms to which they are attached, one or more R 7 forms a 3- to 7-membered heterocyclyl ring optionally substituted with .

[0121] In some embodiments, R D , R E or both 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 (e.g. benzyl) or C 1 ~C 6 Alkylene-heteroaryl. In some embodiments, R D and R E are each independently hydrogen. In some embodiments, R D and R E are each independently C 1 ~C 6 is alkyl. In some embodiments, R D is hydrogen. In some embodiments, R E is hydrogen. In some embodiments, R D is C 1 ~C 6 Alkyl (eg, methyl). In some embodiments, R E is C 1 ~C 6 Alkyl (eg, methyl). In some embodiments, R D is C 1 ~C 6 is heteroalkyl. In some embodiments, R E is C 1 ~C 6 is heteroalkyl. In some embodiments, R D is C 1 ~C 6 is haloalkyl. In some embodiments, R E is C 1 ~C 6 is 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 C 1 ~C 6 Alkylene-aryl (eg, benzyl). In some embodiments, R E is C 1 ~C 6 Alkylene-aryl (eg, benzyl). In some embodiments, R D is C 1 ~C 6 Alkylene-heteroaryl. In some embodiments, R E is C 1 ~C 6 Alkylene-heteroaryl.

[0122] In some embodiments, R A1 is hydrogen. In some embodiments, R A1 is C 1 ~C 6 Alkyl (eg, methyl).

[0123] In some embodiments, m is 0, 1 or 2. In some embodiments, m is 0. In some embodiments, m is 1. In some embodiments, m is two. In some embodiments, x is 0, 1 or 2. In some embodiments, x is 0. In some embodiments, x is one. In some embodiments, x is two. In some embodiments, y is 0 or 1. In some embodiments, y is 0.

[0124] In some embodiments, the compound of formula (I) has formula (I-a): [formation] (In the formula, A and B are each independently one or more R 1 cycloalkyl, heterocyclyl, aryl or heteroaryl optionally substituted with; X, Y and Z are each independently C(R 3a ), C(R 3a )(R 3b ), N, N(R 3c ) or O, and at least one of X, Y and Z is N, N(R 3c ) or O, and the bonds in the ring containing X, Y and Z can be single or double bonds when valences permit; L. 1 and L 2 Each of the independently, absent, C 1 ~C 6 Alkylene, C 1 ~C 6 heteroalkylene, -O-, -C(O)-, -N(R 4 )-, -N(R 4 )C(O)- or -C(O)N(R 4 )- and each alkylene and heteroalkylene is one or more R 5 is optionally replaced with; 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 6haloalkyl, 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, alkynyl, heteroalkyl, haloalkyl, cycloalkyl, heterocyclyl, aryl and heteroaryl is one or more R 6 optionally replaced by 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, each cycloalkyl, heterocyclyl, aryl and heteroaryl being represented by one or more R 6 is optionally replaced with; Each R 2 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, halo, cyano or -OR A is; R. 3a and R 3b are each independently hydrogen, C 1 ~C 6 Alkyl, C 1 ~C 6 heteroalkyl, C 1 ~C 6 haloalkyl, halo, cyano, -OR A , -NR B R. C , -C(O)R D or -C(O)OR D or R. 3a and R 3b each of, together with the carbon atom to which they are attached, form an oxo group; R. 3c is hydrogen or C 1 ~C 6 is an alkyl; Each R 4 are independently hydrogen, C 1 ~C 6 alkyl or C 1 ~C 6 is haloalkyl; Each R 5 are independently hydrogen, C 1 ~C 6 Alkyl, C 1 ~C 6 heteroalkyl, C 1 ~C 6 haloalkyl, cycloalkyl, halo, cyano, oxo, -OR A , -NR B R. C , -C(O)R D or -C(O)OR D is; Each R 6 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 alkyl, alkenyl, alkynyl, heteroalkyl, haloalkyl, cycloalkyl, heterocyclyl, aryl and heteroaryl is one or more R 11 is optionally replaced with; Each R 7 is C 1 ~C 6 alkyl, halo, cyano, oxo or -OR A1 is; Each R 11 independently, C 1 ~C 6 Alkyl, C 1 ~C 6 heteroalkyl, C 1 ~C 6 haloalkyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, halo, cyano, oxo or -OR A is; 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 is; R. B and R C are independently hydrogen, C 1 ~C 6 Alkyl, C 1 ~C 6 heteroalkyl, cycloalkyl, heterocyclyl or -OR A or R. B and R C together with the atoms to which they are attached, one or more R 7 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 is alkylene-heteroaryl; Each R A1 is hydrogen or C 1 ~C 6 is an alkyl; m is 0, 1 or 2; and x is 0, 1 or 2) or a pharmaceutically acceptable salt, solvate, hydrate, tautomer or stereoisomer thereof.

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

[0126] In some embodiments, A is [formation] is selected from

[0127] In some embodiments, A is [formation] is selected from

[0128] In some embodiments, A is [formation] is selected from

[0129] In some embodiments, A is [formation] is. In some embodiments, A is [formation] is. In some embodiments, A is [formation] is. In some embodiments, A is [formation] is. In some embodiments, A is [formation] is. In some embodiments, A is [formation] is. In some embodiments, A is [formation] is. In some embodiments, A is [formation] is. In some embodiments, A is [formation] is. In some embodiments, A is [formation] is. In some embodiments, A is [formation] is. In some embodiments, A is [formation] is. In some embodiments, A is [formation] is. In some embodiments, A is [formation] is. In some embodiments, A is [formation] is. In some embodiments, A is [formation] is. In some embodiments, A is [formation] is. In some embodiments, A is [formation] is. In some embodiments, A is [formation] is. In some embodiments, A is [formation] is. In some embodiments, A is [formation] is. In some embodiments, A is [formation] is. In some embodiments, A is [formation] is. In some embodiments, A is [formation] is. In some embodiments, A is [formation] is. In some embodiments, A is [formation] is. In some embodiments, A is [formation] is.

[0130] In some embodiments, B is [formation] is selected from In some embodiments, B is [formation] is selected from

[0131] In some embodiments, B is [formation] is selected from

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

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

[0134] In some embodiments, [formation] teeth, [formation] is selected from In some embodiments, [formation] teeth, [formation] is. In some embodiments, [formation] teeth, [formation] is.

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

[0136] In some embodiments, the compound of formula (I) has formula (I-b): [formation] (In the formula, A and B are each independently one or more R 1 cycloalkyl, heterocyclyl, aryl or heteroaryl optionally substituted with; X, Y and Z are each independently C(R 3a ), C(R 3a )(R 3b ), N, N(R 3c ) or O, and at least one of X, Y and Z is N, N(R 3c ) or O, and the bonds in the ring containing X, Y and Z can be single or double bonds when valences permit; L. 2 is absent, C 1 ~C 6 Alkylene, C 1 ~C 6 heteroalkylene, -O-, -C(O)-, -N(R 4 )-, -N(R 4 )C(O)- or -C(O)N(R 4 )- and each alkylene and heteroalkylene is one or more R 5 is optionally replaced with; 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, alkynyl, heteroalkyl, haloalkyl, cycloalkyl, heterocyclyl, aryl and heteroaryl is one or more R 6 optionally replaced by 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, each cycloalkyl, heterocyclyl, aryl and heteroaryl being represented by one or more R 6 is optionally replaced with; Each R 2 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, halo, cyano or -OR A is; R. 3a and R 3b are each independently hydrogen, C 1 ~C 6 Alkyl, C 1 ~C 6 heteroalkyl, C 1 ~C 6 haloalkyl, halo, cyano, -OR A , -NR B R. C , -C(O)R D or -C(O)OR D or R. 3a and R 3b each of, together with the carbon atom to which they are attached, form an oxo group; R. 3c is hydrogen or C 1 ~C 6 is an alkyl; Each R 4 are independently hydrogen, C 1 ~C 6 alkyl or C 1 ~C 6 is haloalkyl; Each R 5 are independently hydrogen, C 1 ~C 6 Alkyl, C 1 ~C 6 heteroalkyl, C 1 ~C 6 haloalkyl, cycloalkyl, halo, cyano, oxo, -OR A , -NR B R. C , -C(O)R D or -C(O)OR D is; Each R 6 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 alkyl, alkenyl, alkynyl, heteroalkyl, haloalkyl, cycloalkyl, heterocyclyl, aryl and heteroaryl is one or more R 11 is optionally replaced with; Each R 7 is C 1 ~C 6 alkyl, halo, cyano, oxo or -OR A1 is; Each R 11 independently, C 1 ~C 6 Alkyl, C 1 ~C 6 heteroalkyl, C 1 ~C 6 haloalkyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, halo, cyano, oxo or -OR A is; 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 is; R. B and R C are independently hydrogen, C 1 ~C 6 Alkyl, C 1 ~C 6 heteroalkyl, cycloalkyl, heterocyclyl or -ORA or R. B and R C together with the atoms to which they are attached, one or more R 7 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 is alkylene-heteroaryl; Each R A1 is hydrogen or C 1 ~C 6 is an alkyl; m is 0, 1 or 2; and x is 0, 1 or 2) or a pharmaceutically acceptable salt, solvate, hydrate, tautomer or stereoisomer thereof.

[0137] In some embodiments, A is one or more R 1 is heterocyclyl optionally substituted with . In some embodiments, A is bicyclic heterocyclyl. In some embodiments, A is monocyclic nitrogen-containing heterocyclyl. In some embodiments, A is a bicyclic nitrogen-containing heterocyclyl. In some embodiments, A is optionally substituted piperidinyl. In some embodiments, A is optionally substituted piperazinyl. In some embodiments, A is [formation] (In the formula, each R 1 is independently hydrogen or C 1 ~C 6 alkyl) is. In some embodiments, A is [formation] is. In some embodiments, A is [formation] is.

[0138] In some embodiments, L 2 is absent. In some embodiments, L 2 is one or more R 5 C optionally replaced with 1 ~C 6 It is heteroalkylene. In some embodiments, L 2 is -C(O)N(R 4 )-. In some embodiments, L 2 is -C(O)N(H)-.

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

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

[0141] In some embodiments, A is [formation] is selected from

[0142] In some embodiments, A is [formation] is selected from

[0143] In some embodiments, A is [formation] is selected from

[0144] In some embodiments, A is [formation] is. In some embodiments, A is [formation] is. In some embodiments, A is [formation] is. In some embodiments, A is [formation] is. In some embodiments, A is [formation] is. In some embodiments, A is [formation] is. In some embodiments, A is [formation] is. In some embodiments, A is [formation] is. In some embodiments, A is [formation] is. In some embodiments, A is [formation] is. In some embodiments, A is [formation] is. In some embodiments, A is [formation] is. In some embodiments, A is [formation] is. In some embodiments, A is [formation] is. In some embodiments, A is [formation] is. In some embodiments, A is [formation] is. In some embodiments, A is [formation] is. In some embodiments, A is [formation] is. In some embodiments, A is [formation] is. In some embodiments, A is [formation] is. In some embodiments, A is [formation] is. In some embodiments, A is [formation] is. In some embodiments, A is [formation] is. In some embodiments, A is [formation] is. In some embodiments, A is [formation] is. In some embodiments, A is [formation] is. In some embodiments, A is [formation] is.

[0145] In some embodiments, B is [formation] is selected from In some embodiments, B is [formation] is selected from

[0146] In some embodiments, B is [formation] is selected from

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

[0148] In some embodiments, [formation] teeth, [formation] is selected from In some embodiments, [formation] teeth, [formation] is. In some embodiments, [formation] teeth, [formation] is.

[0149] In some embodiments, the compound of formula (I) has the formula (I-hc): [formation] (In the formula, A and B are each independently one or more R 1 cycloalkyl, heterocyclyl, aryl or heteroaryl optionally substituted with; L. 2 is absent, C 1 ~C 6 Alkylene, C 1 ~C 6 heteroalkylene, -O-, -C(O)-, -N(R 4 )-, -N(R 4 )C(O)- or -C(O)N(R 4 )- and each alkylene and heteroalkylene is one or more R 5 is optionally replaced with; 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, alkynyl, heteroalkyl, haloalkyl, cycloalkyl, heterocyclyl, aryl and heteroaryl is one or more R 6 optionally replaced by 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, each cycloalkyl, heterocyclyl, aryl and heteroaryl being represented by one or more R 6 is optionally replaced with; Each R 2 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, halo, cyano or -OR A is; Each R 3a are independently hydrogen, C 1 ~C 6 Alkyl, C 1 ~C 6 heteroalkyl, C 1 ~C 6 haloalkyl, halo, cyano, -OR A , -NR B R. C , -C(O)R D or -C(O)OR D is; Each R4 are independently hydrogen, C 1 ~C 6 alkyl or C 1 ~C 6 is haloalkyl; Each R 5 are independently hydrogen, C 1 ~C 6 Alkyl, C 1 ~C 6 heteroalkyl, C 1 ~C 6 haloalkyl, cycloalkyl, halo, cyano, oxo, -OR A , -NR B R. C , -C(O)R D or -C(O)OR D is; Each R 6 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 alkyl, alkenyl, alkynyl, heteroalkyl, haloalkyl, cycloalkyl, heterocyclyl, aryl and heteroaryl is one or more R 11 is optionally replaced with; Each R 7 is C 1 ~C 6 alkyl, halo, cyano, oxo or -OR A1 is; Each R 11 independently, C 1 ~C 6 Alkyl, C 1 ~C 6 heteroalkyl, C 1 ~C 6 haloalkyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, halo, cyano, oxo or -OR A is; 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 is; R. B and R C are independently hydrogen, C 1 ~C 6 Alkyl, C 1 ~C 6 heteroalkyl, cycloalkyl, heterocyclyl or -OR A or R. B and R C together with the atoms to which they are attached, one or more R 7 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 is alkylene-heteroaryl; Each R A1 is hydrogen or C 1 ~C 6 is an alkyl; m is 0, 1 or 2; and x is 0, 1 or 2) or a pharmaceutically acceptable salt, solvate, hydrate, tautomer or stereoisomer thereof.

[0150] In some embodiments, A is one or more R 1 is heterocyclyl optionally substituted with . In some embodiments, A is bicyclic heterocyclyl. In some embodiments, A is monocyclic nitrogen-containing heterocyclyl. In some embodiments, A is a bicyclic nitrogen-containing heterocyclyl. In some embodiments, A is optionally substituted piperidinyl. In some embodiments, A is optionally substituted piperazinyl. In some embodiments, A is [formation] (In the formula, each R 1 is independently hydrogen or C 1 ~C 6 alkyl) is. In some embodiments, A is [formation] is. In some embodiments, A is [formation] is.

[0151] In some embodiments, L 2 is absent. In some embodiments, L 2 is one or more R 5 C optionally replaced with 1 ~C 6 It is heteroalkylene. In some embodiments, L 2 is -C(O)N(R 4 )-. In some embodiments, L 2 is -C(O)N(H)-.

[0152] In some embodiments, each R 3a is independently hydrogen or C 1 ~C 6 Alkyl (e.g., CH 3 ). In some embodiments, each R 3a is independently hydrogen. In some embodiments, each R 3a independently, C 1 ~C 6 Alkyl (e.g., CH 3 ).

[0153] In some embodiments, B is one or more R 1 heteroaryl optionally substituted with . In some embodiments, B is monocyclic heteroaryl. In some embodiments, B is bicyclic heteroaryl. In some embodiments, B is monocyclic nitrogen-containing heteroaryl. In some embodiments, B is a bicyclic nitrogen-containing heteroaryl. In some embodiments, B is optionally substituted pyrazolyl. In some embodiments, B is [formation] (In the formula, each R 1 are as defined above) is selected from In some embodiments, B is [formation] is. In some embodiments, B is [formation] is.

[0154] In some embodiments, R 2 is C 1 ~C 6 is alkyl. In some embodiments, R 2 is halo (eg, fluoro). In some embodiments, R 2 is -OR A (eg, -OH). In some embodiments, R 3a is hydrogen. In some embodiments, m is 0.

[0155] In some embodiments, A is [formation] (In the formula, R1 is as defined herein) is selected from

[0156] In some embodiments, A is [formation] is selected from

[0157] In some embodiments, A is [formation] is selected from

[0158] In some embodiments, A is [formation] is selected from

[0159] In some embodiments, A is [formation] is. In some embodiments, A is [formation] is. In some embodiments, A is [formation] is. In some embodiments, A is [formation] is. In some embodiments, A is [formation] is. In some embodiments, A is [formation] is. In some embodiments, A is [formation] is. In some embodiments, A is [formation] is. In some embodiments, A is [formation] is. In some embodiments, A is [formation] is. In some embodiments, A is [formation] is. In some embodiments, A is [formation] is. In some embodiments, A is [formation] is. In some embodiments, A is [formation] is. In some embodiments, A is [formation] is. In some embodiments, A is [formation] is. In some embodiments, A is [formation] is. In some embodiments, A is [formation] is. In some embodiments, A is [formation] is. In some embodiments, A is [formation] is. In some embodiments, A is [formation] is. In some embodiments, A is [formation] is. In some embodiments, A is [formation] is. In some embodiments, A is [formation] is. In some embodiments, A is [formation] is. In some embodiments, A is [formation] is. In some embodiments, A is [formation] is.

[0160] In some embodiments, B is [formation] is selected from In some embodiments, B is [formation] is selected from

[0161] In some embodiments, B is [formation] is selected from

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

[0163] In some embodiments, the compound of formula (I) has formula (I-d): [formation] (In the formula, A and B are each independently one or more R 1cycloalkyl, heterocyclyl, aryl or heteroaryl optionally substituted with; L. 2 is absent, C 1 ~C 6 Alkylene, C 1 ~C 6 heteroalkylene, -O-, -C(O)-, -N(R 4 )-, -N(R 4 )C(O)- or -C(O)N(R 4 )- and each alkylene and heteroalkylene is one or more R 5 is optionally replaced with; 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, alkynyl, heteroalkyl, haloalkyl, cycloalkyl, heterocyclyl, aryl and heteroaryl is one or more R 6 optionally replaced by 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, each cycloalkyl, heterocyclyl, aryl and heteroaryl being represented by one or more R 6 is optionally replaced with; Each R 2 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, halo, cyano or -OR A is; R. 3a is hydrogen, C 1 ~C 6 Alkyl, C 1 ~C 6 heteroalkyl, C 1 ~C 6 haloalkyl, halo, cyano, -OR A , -NR B R. C , -C(O)R D or -C(O)OR D is; R. 3c is hydrogen, C 1 ~C 6 Alkyl, C 1 ~C 6 heteroalkyl, C 1 ~C 6 haloalkyl, halo, cyano or -C(O)R D is; Each R 4 are independently hydrogen, C 1 ~C 6 alkyl or C 1 ~C 6 is haloalkyl; Each R 5 are independently hydrogen, C 1 ~C 6 Alkyl, C 1 ~C 6 heteroalkyl, C 1 ~C 6 haloalkyl, cycloalkyl, halo, cyano, oxo, -OR A , -NR B R. C , -C(O)R D or -C(O)OR D is; Each R 6 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 alkyl, alkenyl, alkynyl, heteroalkyl, haloalkyl, cycloalkyl, heterocyclyl, aryl and heteroaryl is one or more R 11 is optionally replaced with; Each R 7 is C 1 ~C 6 alkyl, halo, cyano, oxo or -OR A1 is; Each R 11 independently, C 1 ~C 6 Alkyl, C 1 ~C 6 heteroalkyl, C 1 ~C 6 haloalkyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, halo, cyano, oxo or -OR A is; 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 is; R. B and R C are independently hydrogen, C 1 ~C 6 Alkyl, C 1 ~C 6 heteroalkyl, cycloalkyl, heterocyclyl or -OR A or R. B and R C together with the atoms to which they are attached, one or more R 7 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 is alkylene-heteroaryl; Each R A1 is hydrogen or C 1 ~C 6 is an alkyl; m is 0, 1 or 2; and x is 0, 1 or 2) or a pharmaceutically acceptable salt, solvate, hydrate, tautomer or stereoisomer thereof.

[0164] In some embodiments, A is one or more R 1 is heterocyclyl optionally substituted with . In some embodiments, A is bicyclic heterocyclyl. In some embodiments, A is monocyclic nitrogen-containing heterocyclyl. In some embodiments, A is a bicyclic nitrogen-containing heterocyclyl. In some embodiments, A is optionally substituted piperidinyl. In some embodiments, A is optionally substituted piperazinyl. In some embodiments, A is [formation] (In the formula, each R 1 is independently hydrogen or C 1 ~C 6 alkyl) is. In some embodiments, A is [formation] is. In some embodiments, A is [formation] is.

[0165] In some embodiments, L 2 is absent. In some embodiments, L 2 is one or more R 5 C optionally replaced with 1 ~C 6 It is heteroalkylene. In some embodiments, L 2 is -C(O)N(R 4 )-. In some embodiments, L 2 is -C(O)N(H)-.

[0166] In some embodiments, R 3a is independently hydrogen or C 1 ~C 6 Alkyl (e.g., CH 3 ). In some embodiments, R 3a is independently hydrogen. In some embodiments, R 3a independently, C 1 ~C 6 Alkyl (e.g., CH 3 ).

[0167] In some embodiments, R 3c is independently hydrogen or C 1 ~C 6 Alkyl (e.g., CH 3 ). In some embodiments, R 3c is independently hydrogen. In some embodiments, R 3c independently, C 1 ~C 6 Alkyl (e.g., CH 3 ).

[0168] In some embodiments, B is one or more R 1 heteroaryl optionally substituted with . In some embodiments, B is monocyclic heteroaryl. In some embodiments, B is bicyclic heteroaryl. In some embodiments, B is monocyclic nitrogen-containing heteroaryl. In some embodiments, B is a bicyclic nitrogen-containing heteroaryl. In some embodiments, B is optionally substituted pyrazolyl. In some embodiments, B is [formation] (In the formula, each R 1 are as defined above) is selected from In some embodiments, B is [formation] is. In some embodiments, B is [formation] is.

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

[0170] In some embodiments, A is [formation] is selected from

[0171] In some embodiments, A is [formation] is selected from

[0172] In some embodiments, A is [formation] is selected from

[0173] In some embodiments, A is [formation] is. In some embodiments, A is [formation] is. In some embodiments, A is [formation] is. In some embodiments, A is [formation] is. In some embodiments, A is [formation] is. In some embodiments, A is [formation] is. In some embodiments, A is [formation] is. In some embodiments, A is [formation] is. In some embodiments, A is [formation] is. In some embodiments, A is [formation] is. In some embodiments, A is [formation] is. In some embodiments, A is [formation] is. In some embodiments, A is [formation] is. In some embodiments, A is [formation] is. In some embodiments, A is [formation] is. In some embodiments, A is [formation] is. In some embodiments, A is [formation] is. In some embodiments, A is [formation] is. In some embodiments, A is [formation] is. In some embodiments, A is [formation] is. In some embodiments, A is [formation] is. In some embodiments, A is [formation] is. In some embodiments, A is [formation] is. In some embodiments, A is [formation] is. In some embodiments, A is [formation] is. In some embodiments, A is [formation] is. In some embodiments, A is [formation] is.

[0174] In some embodiments, B is [formation] is selected from In some embodiments, B is [formation] is selected from

[0175] In some embodiments, B is [formation] is selected from

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

[0177] In some embodiments, R 2 is C 1 ~C 6 is alkyl. In some embodiments, R 2 is halo (eg, fluoro). In some embodiments, R 2 is -OR A (eg, -OH). In some embodiments, R 3a is hydrogen. In some embodiments, R 3c is hydrogen. In some embodiments, m is 0.

[0178] In some embodiments, the compound of formula (I) has formula (I-e): [formation] (In the formula, A and B are each independently one or more R 1 cycloalkyl, heterocyclyl, aryl or heteroaryl optionally substituted with; X, Y and Z are each independently C(R 3a ), C(R 3a )(R 3b ), N, N(R 3c ) or O, and at least one of X, Y and Z is N, N(R 3c ) or O, and the bonds in the ring containing X, Y and Z can be single or double bonds when valences permit; 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, alkynyl, heteroalkyl, haloalkyl, cycloalkyl, heterocyclyl, aryl and heteroaryl is one or more R 6 optionally replaced by 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, each cycloalkyl, heterocyclyl, aryl and heteroaryl being represented by one or more R 6 is optionally replaced with; Each R 2 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, halo, cyano or -OR A is; R. 3a and R 3b are each independently hydrogen, C 1 ~C 6 Alkyl, C 1 ~C 6 heteroalkyl, C 1 ~C 6 haloalkyl, halo, cyano, -OR A , -NR B R. C , -C(O)R D or -C(O)OR D or R. 3a and R 3b each of, together with the carbon atom to which they are attached, form an oxo group; R. 3c is hydrogen or C 1 ~C 6 is an alkyl; Each R 4 are independently hydrogen, C 1 ~C 6 alkyl or C 1 ~C 6 is haloalkyl; Each R 6 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. Dand each alkyl, alkenyl, alkynyl, heteroalkyl, haloalkyl, cycloalkyl, heterocyclyl, aryl and heteroaryl is one or more R 11 is optionally replaced with; Each R 7 is C 1 ~C 6 alkyl, halo, cyano, oxo or -OR A1 is; Each R 11 independently, C 1 ~C 6 Alkyl, C 1 ~C 6 heteroalkyl, C 1 ~C 6 haloalkyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, halo, cyano, oxo or -OR A is; 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 is; R. B and R C are independently hydrogen, C 1 ~C 6 Alkyl, C 1 ~C 6 heteroalkyl, cycloalkyl, heterocyclyl or -OR A or R. B and R C together with the atoms to which they are attached, one or more R 7 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 is alkylene-heteroaryl; Each R A1 is hydrogen or C 1 ~C 6 is an alkyl; m is 0, 1 or 2; and x is 0, 1 or 2) or a pharmaceutically acceptable salt, solvate, hydrate, tautomer or stereoisomer thereof.

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

[0180] In some embodiments, A is [formation] is selected from

[0181] In some embodiments, A is [formation] is selected from

[0182] In some embodiments, A is [formation] is selected from

[0183] In some embodiments, A is [formation] is. In some embodiments, A is [formation] is. In some embodiments, A is [formation] is. In some embodiments, A is [formation] is. In some embodiments, A is [formation] is. In some embodiments, A is [formation] is. In some embodiments, A is [formation] is. In some embodiments, A is [formation] is. In some embodiments, A is [formation] is. In some embodiments, A is [formation] is. In some embodiments, A is [formation] is. In some embodiments, A is [formation] is. In some embodiments, A is [formation] is. In some embodiments, A is [formation] is. In some embodiments, A is [formation] is. In some embodiments, A is [formation] is. In some embodiments, A is [formation] is. In some embodiments, A is [formation] is. In some embodiments, A is [formation] is. In some embodiments, A is [formation] is. In some embodiments, A is [formation] is. In some embodiments, A is [formation] is. In some embodiments, A is [formation] is. In some embodiments, A is [formation] is. In some embodiments, A is [formation] is. In some embodiments, A is [formation] is. In some embodiments, A is [formation] is.

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

[0185] In some embodiments, B is [formation] is selected from In some embodiments, B is [formation] is selected from

[0186] In some embodiments, B is [formation] is selected from

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

[0188] In some embodiments, the compound of formula (I) has formula (I-f): [formation] (In the formula, A and B are each independently one or more R 1 cycloalkyl, heterocyclyl, aryl or heteroaryl optionally substituted with; X, Y and Z are each independently C(R 3a ), C(R 3a )(R 3b ), N, N(R 3c ) or O, and at least one of X, Y and Z is N, N(R 3c ) or O, and the bonds in the ring containing X, Y and Z can be single or double bonds when valences permit; L. 2 is absent, C 1 ~C 6 Alkylene, C 1 ~C 6 heteroalkylene, -O-, -C(O)-, -N(R 4 )-, -N(R 4 )C(O)- or -C(O)N(R 4 )- and each alkylene and heteroalkylene is one or more R 5 is optionally replaced with; D, E, J, K, M and W are each independently N and C(R'), and at least one of D, E, J, K, M and W is N; D , E, J, K, M and W may be single or double bonds when valences permit; 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, alkynyl, heteroalkyl, haloalkyl, cycloalkyl, heterocyclyl, aryl and heteroaryl is one or more R 6 optionally replaced by 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, each cycloalkyl, heterocyclyl, aryl and heteroaryl being represented by one or more R 6 is optionally replaced with; R. ’ is hydrogen, C 1 ~C 6 is alkyl or halo; Each R 2 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, halo, cyano or -OR A is; R. 3a and R 3b are each independently hydrogen, C 1 ~C 6 Alkyl, C 1 ~C 6 heteroalkyl, C 1 ~C 6 haloalkyl, halo, cyano, -OR A , -NR B R. C , -C(O)R D or -C(O)OR D or R. 3a and R 3b each of, together with the carbon atom to which they are attached, form an oxo group; R. 3c is hydrogen or C 1 ~C 6 is an alkyl; Each R 4 are independently hydrogen, C 1 ~C 6 alkyl or C 1 ~C 6 is haloalkyl; Each R 5are independently hydrogen, C 1 ~C 6 Alkyl, C 1 ~C 6 heteroalkyl, C 1 ~C 6 haloalkyl, cycloalkyl, halo, cyano, oxo, -OR A , -NR B R. C , -C(O)R D or -C(O)OR D is; Each R 6 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 alkyl, alkenyl, alkynyl, heteroalkyl, haloalkyl, cycloalkyl, heterocyclyl, aryl and heteroaryl is one or more R 11 is optionally replaced with; Each R 7 is C 1 ~C 6 alkyl, halo, cyano, oxo or -OR A1 is; Each R 11 independently, C 1 ~C 6 Alkyl, C 1 ~C 6 heteroalkyl, C 1 ~C 6 haloalkyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, halo, cyano, oxo or -OR A is; 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 is; R. B and R C are independently hydrogen, C 1 ~C 6 Alkyl, C 1 ~C 6 heteroalkyl, cycloalkyl, heterocyclyl or -OR A or R. B and R C together with the atoms to which they are attached, one or more R 7 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 is alkylene-heteroaryl; Each R A1 is hydrogen or C 1 ~C 6 is an alkyl; m is 0, 1 or 2; p is 0, 1, 2, 3, or 4; and x is 0, 1 or 2) or a pharmaceutically acceptable salt, solvate, hydrate, tautomer or stereoisomer thereof.

[0189] In some embodiments, the compound of formula (I) has formula (I-g): [formation] (In the formula, A and B are each independently one or more R 1 cycloalkyl, heterocyclyl, aryl or heteroaryl optionally substituted with; X, Y and Z are each independently C(R 3a ), C(R 3a )(R 3b ), N, N(R 3c ) or O, and at least one of X, Y and Z is N, N(R 3c ) or O, and the bonds in the ring containing X, Y and Z can be single or double bonds when valences permit; L. 2 is absent, C 1 ~C 6 Alkylene, C 1 ~C 6 heteroalkylene, -O-, -C(O)-, -N(R 4 )-, -N(R 4 )C(O)- or -C(O)N(R 4 )- and each alkylene and heteroalkylene is one or more R 5 is optionally replaced with; D, J, K and M are each independently N and C(R'), and at least one of D, J, K and M is N; D, E, J, K, M and the bonds in the ring containing W can be single or double bonds when valences permit; 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, alkynyl, heteroalkyl, haloalkyl, cycloalkyl, heterocyclyl, aryl and heteroaryl is one or more R 6 optionally replaced by 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, each cycloalkyl, heterocyclyl, aryl and heteroaryl being represented by one or more R 6 is optionally replaced with; R. ’ is hydrogen, C 1 ~C 6 is alkyl or halo; Each R 2 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, halo, cyano or -OR A is; R. 3a and R 3b are each independently hydrogen, C 1 ~C 6 Alkyl, C 1 ~C 6 heteroalkyl, C 1 ~C 6 haloalkyl, halo, cyano, -OR A , -NR B R. C , -C(O)R D or -C(O)OR D or R. 3a and R3b each of, together with the carbon atom to which they are attached, form an oxo group; R. 3c is hydrogen or C 1 ~C 6 is an alkyl; Each R 4 are independently hydrogen, C 1 ~C 6 alkyl or C 1 ~C 6 is haloalkyl; Each R 5 are independently hydrogen, C 1 ~C 6 Alkyl, C 1 ~C 6 heteroalkyl, C 1 ~C 6 haloalkyl, cycloalkyl, halo, cyano, oxo, -OR A , -NR B R. C , -C(O)R D or -C(O)OR D is; Each R 6 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 alkyl, alkenyl, alkynyl, heteroalkyl, haloalkyl, cycloalkyl, heterocyclyl, aryl and heteroaryl is one or more R 11 is optionally replaced with; Each R 7 is C 1 ~C 6 alkyl, halo, cyano, oxo or -OR A1 is; Each R 11 independently, C 1 ~C 6 Alkyl, C 1 ~C 6 heteroalkyl, C 1 ~C 6 haloalkyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, halo, cyano, oxo or -OR A is; 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 is; R. B and R C are independently hydrogen, C 1 ~C 6 Alkyl, C 1 ~C 6 heteroalkyl, cycloalkyl, heterocyclyl or -OR A or R. B and R C together with the atoms to which they are attached, one or more R 7 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 is alkylene-heteroaryl; Each R A1 is hydrogen or C 1 ~C 6 is an alkyl; m is 0, 1 or 2; p is 0, 1, 2, 3, or 4; and x is 0, 1 or 2) or a pharmaceutically acceptable salt, solvate, hydrate, tautomer or stereoisomer thereof.

[0190] In some embodiments, the compound of formula (I) has formula (I-h): [formation] (In the formula, A and B are each independently one or more R 1 cycloalkyl, heterocyclyl, aryl or heteroaryl optionally substituted with; 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, alkynyl, heteroalkyl, haloalkyl, cycloalkyl, heterocyclyl, aryl and heteroaryl is one or more R 6 optionally replaced by 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, each cycloalkyl, heterocyclyl, aryl and heteroaryl being represented by one or more R 6 is optionally replaced with; Each R 2 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, halo, cyano or -OR A is; Each R 3a are independently hydrogen, C 1 ~C 6 Alkyl, C 1 ~C 6 heteroalkyl, C 1 ~C 6 haloalkyl, halo, cyano, -OR A , -NR B R. C , -C(O)R D or -C(O)OR D is; Each R 4 are independently hydrogen, C 1 ~C 6 alkyl or C 1 ~C 6 is haloalkyl; Each R 6 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 , -NRB 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, alkenyl, alkynyl, heteroalkyl, haloalkyl, cycloalkyl, heterocyclyl, aryl and heteroaryl is one or more R 11 is optionally replaced with; Each R 7 is C 1 ~C 6 alkyl, halo, cyano, oxo or -OR A1 is; Each R 11 independently, C 1 ~C 6 Alkyl, C 1 ~C 6 heteroalkyl, C 1 ~C 6 haloalkyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, halo, cyano, oxo or -OR A is; 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 is; R. B and R C are independently hydrogen, C 1 ~C 6 Alkyl, C 1 ~C 6 heteroalkyl, cycloalkyl, heterocyclyl or -OR A or R. B and R C together with the atoms to which they are attached, one or more R 7 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 is alkylene-heteroaryl; Each R A1 is hydrogen or C 1 ~C 6 is an alkyl; m is 0, 1 or 2; and x is 0, 1 or 2) or a pharmaceutically acceptable salt, solvate, hydrate, tautomer or stereoisomer thereof.

[0191] In some embodiments, A is one or more R 1 is heterocyclyl optionally substituted with . In some embodiments, A is bicyclic heterocyclyl. In some embodiments, A is monocyclic nitrogen-containing heterocyclyl. In some embodiments, A is a bicyclic nitrogen-containing heterocyclyl. In some embodiments, A is optionally substituted piperidinyl. In some embodiments, A is optionally substituted piperazinyl. In some embodiments, A is [formation] (In the formula, each R 1 is independently hydrogen or C 1 ~C 6 alkyl) is. In some embodiments, A is [formation] is. In some embodiments, A is [formation] is.

[0192] In some embodiments, each R 3a is independently hydrogen or C 1 ~C 6 Alkyl (e.g., CH 3 ). In some embodiments, each R 3a is independently hydrogen. In some embodiments, each R 3a independently, C 1 ~C 6 Alkyl (e.g., CH 3 ).

[0193] In some embodiments, B is one or more R 1 heteroaryl optionally substituted with . In some embodiments, B is monocyclic heteroaryl. In some embodiments, B is bicyclic heteroaryl. In some embodiments, B is monocyclic nitrogen-containing heteroaryl. In some embodiments, B is a bicyclic nitrogen-containing heteroaryl. In some embodiments, B is optionally substituted pyrazolyl. In some embodiments, B is [formation] (In the formula, each R 1 are as defined above) is selected from In some embodiments, B is [formation] is. In some embodiments, B is [formation] is.

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

[0195] In some embodiments, A is [formation] is selected from

[0196] In some embodiments, A is [formation] is selected from

[0197] In some embodiments, A is [formation] is selected from

[0198] In some embodiments, A is [formation] is. In some embodiments, A is [formation] is. In some embodiments, A is [formation] is. In some embodiments, A is [formation] is. In some embodiments, A is [formation] is. In some embodiments, A is [formation] is. In some embodiments, A is [formation] is. In some embodiments, A is [formation] is. In some embodiments, A is [formation] is. In some embodiments, A is [formation] is. In some embodiments, A is [formation] is. In some embodiments, A is [formation] is. In some embodiments, A is [formation] is. In some embodiments, A is [formation] is. In some embodiments, A is [formation] is. In some embodiments, A is [formation] is. In some embodiments, A is [formation] is. In some embodiments, A is [formation] is. In some embodiments, A is [formation] is. In some embodiments, A is [formation] is. In some embodiments, A is [formation] is. In some embodiments, A is [formation] is. In some embodiments, A is [formation] is. In some embodiments, A is [formation] is. In some embodiments, A is [formation] is. In some embodiments, A is [formation] is. In some embodiments, A is [formation] is.

[0199] In some embodiments, B is [formation] is selected from In some embodiments, B is [formation] is selected from

[0200] In some embodiments, B is [formation] is selected from

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

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

[0203]

table 1

[0204] [Table 2]

[0205] [Table 3]

[0206] [Table 4]

[0207] [Table 5]

[0208] [Table 6]

[0209] [Table 7]

[0210] [Table 8]

[0211] [Table 9]

[0212] [Table 10]

[0213] [Table 11]

[0214] [Table 12]

[0215] [Table 13]

[0216] [Table 14]

[0217] [Table 15]

[0218] [Table 16]

[0219] In some embodiments, for Formula (I), A is monocyclic heterocyclyl (e.g., piperidinyl); B is bicyclic heteroaryl (e.g., imidazo[1,2-b]pyridazinyl); Yes; L 2 is -C(O)N(R 4 )-(e.g., -C(O)N(H)-); X is C(R 3a ) (e.g., CH); Y is C(R 3a )(e.g. C(CH 3 )); Z is O; y is 0; In some embodiments, compounds of Formulas (I), (I-d), (I-e) and (I-f) are compound 118 or a pharmaceutically acceptable salt, solvate, hydrate, tautomer thereof isomers or stereoisomers.

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

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

[0222] Pharmaceutical compositions, kits and administration The present invention provides compounds of formula (I), such as compounds of formula (I) or pharmaceutically acceptable salts, solvates, hydrates, tautomers or stereoisomers as described herein and A pharmaceutical composition is provided that optionally comprises 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 pharmaceutically acceptable excipients. In certain embodiments, a compound of formula (I) or a pharmaceutically acceptable salt, solvate, hydrate, tautomer or stereoisomer thereof is provided in the pharmaceutical composition in an effective amount. be. In certain embodiments, an effective amount is a therapeutically effective amount. In certain embodiments, the effective amount is a prophylactically effective amount.

[0223] The pharmaceutical compositions described herein can be prepared by any method known in the art of pharmacology. In general, such methods of preparation comprise the steps of bringing into association a compound of formula (I) (the “active ingredient”) with the carrier and / or one or more other accessory ingredients and, if necessary and / or desired, then producing a product. into desired single or multiple dose units.

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

[0225] The relative amounts of active ingredient, pharmaceutically acceptable excipients and / or any additional ingredients in the pharmaceutical compositions of the invention will further depend on the identity, size and / or condition of the subject to be treated. It depends on the route by which the substance is administered. By way of example, the composition may contain from 0.1% to 100% (w / w) of active ingredient.

[0226] The term "pharmaceutically acceptable excipient" refers to non-toxic carriers, adjuvants, diluents or vehicles that do not destroy the pharmacological activity of the formulated compound. Pharmaceutically acceptable excipients useful in preparing the pharmaceutical compositions of the invention are any of those well known in the pharmaceutical formulation art, including inert diluents, dispersants and / or granulating agents, interfacial Active agents and / or emulsifiers, disintegrants, binders, preservatives, buffers, lubricants and / or oils. Pharmaceutically acceptable excipients useful in preparing the pharmaceutical compositions of the invention include ion exchangers, alumina, aluminum stearate, lecithin, serum proteins such as human serum albumin, and buffer substances such as phosphate. , glycine, sorbic acid, potassium sorbate, partial glyceride mixture of saturated vegetable fatty acids, water, protamine sulfate salt or electrolytes, disodium hydrogen phosphate, potassium hydrogen phosphate, sodium chloride, zinc salt, colloidal silica, magnesium trisilicate , polyvinylpyrrolidone, cellulose-based materials, polyethylene glycol, sodium carboxymethylcellulose, polyacrylates, waxes, polyethylene-polyoxypropylene-block polymers, polyethylene glycol and wool fat.

[0227] The compositions of this invention may be administered orally, parenterally (including subcutaneously, intramuscularly, intravenously and intradermally), 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.

[0228] The term "parenteral" as used herein includes subcutaneous, intravenous, intramuscular, intraocular, intravitreal, intraarticular, intrasynovial, intrasternal, intrathecal, intrahepatic, intraperitoneal, Including intralesional and intracranial injection or infusion techniques. Preferably, the compositions are administered orally, subcutaneously, intraperitoneally or intravenously. Sterile injectable forms of the compositions of this invention may be aqueous or oleaginous suspension. These suspensions may be formulated according to techniques known in the art using suitable dispersing or wetting agents and suspending agents. The sterile injectable preparation can also be a sterile injectable solution or suspension in a non-toxic parenterally-acceptable diluent or solvent, for example a solution in 1,3-butanediol. Among the acceptable vehicles and solvents that may be employed are water, Ringer's solution and isotonic sodium chloride solution. In addition, sterile, fixed oils are conventionally employed as a solvent or suspending medium.

[0229] The pharmaceutically acceptable compositions of this invention can be orally administered in any orally acceptable dosage form including, but not limited to, capsules, tablets, aqueous suspensions or solutions. In the case of tablets for oral use, carriers that are commonly used include lactose and corn starch. Lubricating agents such as magnesium stearate are also typically added. For oral administration in capsule form, useful diluents include lactose and dried corn starch. When aqueous suspensions are required for oral use, the active ingredient is combined with emulsifying and suspending agents. If desired, certain sweetening, flavoring or coloring agents may be added. In some embodiments, provided oral formulations are formulated for immediate release or sustained / delayed release. In some embodiments, compositions are suitable for buccal or sublingual administration and include tablets, lozenges, pastilles. Provided compounds can be in microencapsulated form.

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

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

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

[0233] Although the description of pharmaceutical compositions provided herein is directed primarily to pharmaceutical compositions suitable for administration to humans, such compositions are generally suitable for administration to all types of animals. will be understood by those skilled in the art. The modification of pharmaceutical compositions suitable for administration to humans to render compositions suitable for administration to various animals is well understood and a veterinary pharmacologist of ordinary skill can perform routine experimentation. can design and / or implement such modifications.

[0234] The compounds provided herein are typically formulated in dosage unit form, eg, single unit dosage form, for ease of administration and uniformity of dosage. It will be understood, however, that the total daily usage of the compositions of the present invention will be decided by the attending physician within the scope of sound medical judgment. A particular therapeutically effective dose level for any particular subject or organism will depend on the severity of the disease and disorder being treated; the activity of the particular active ingredient employed; the particular composition employed; the subject's age, weight, general time of administration, route of administration and excretion rate of the particular active ingredient used; duration of treatment; drugs used in combination or concurrently with the particular active ingredient used; and in the medical field. It depends on a variety of factors, including well-known similar factors.

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

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

[0237] In certain embodiments, the compound of formula (I) is administered at about 0.001 mg / kg to about 100 mg / kg, about 0.01 mg / kg to about 50 mg / kg, preferably about 0.1 mg / kg to about 40 mg / kg, preferably about 0.5 mg / kg to about 30 mg / kg, about 0.01 mg / kg to about 10 mg / kg, about 0.1 mg / kg to about 10 mg / kg, more preferably about 1 mg / kg to about 25 mg / kg.

[0238] It will be appreciated that the dosage ranges described herein provide guidance for administering provided pharmaceutical compositions to adults. For example, the amount administered to children or adolescents can be determined by a physician or one of ordinary skill in the art, and can be lower than or the same as the amount administered to adults.

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

[0240] A compound or composition can be administered simultaneously, before, or after one or more additional agents that may be useful, eg, as a combination therapy. Drugs include therapeutically active agents. Medicaments also include prophylactically active agents. Each additional agent may be administered at the dose and / or time schedule determined for that agent. Additional agents may be administered together and / or with the compounds or compositions described herein in a single dose, or may be administered separately at different doses. The particular combination to use in a regimen will take into consideration the compatibility of the compound of the present invention with the additional agent and / or the desired therapeutic and / or prophylactic effect to be achieved. Generally, additional agents used in combination are expected to be used at levels no greater than the levels at which they are used individually. In some embodiments, the levels used in combination will be lower than the levels used individually.

[0241] Exemplary additional agents include, but are not limited to, anti-proliferative agents, anti-cancer agents, anti-diabetic agents, anti-inflammatory agents, immunosuppressive agents and analgesics. Agents include drug compounds (e.g. compounds listed in the Code of Federal Regulations (CFR) and approved by the US Food and Drug Administration), peptides, proteins, carbohydrates, monosaccharides, oligosaccharides, polysaccharides, nucleoproteins, mucoproteins. , lipoproteins, synthetic polypeptides or proteins, small molecules attached to proteins, glycoproteins, steroids, nucleic acids, DNA, RNA, nucleotides, nucleosides, oligonucleotides, antisense oligonucleotides, lipids, hormones, vitamins and organic compounds such as cells. Contains small molecules.

[0242] Kits (eg, pharmaceutical packs) are also included in the invention. Kits of the invention can be useful, for example, for preventing and / or treating proliferative or non-proliferative diseases, as described herein. Provided kits can include a pharmaceutical composition or compound of the invention and a container (eg, a vial, ampoule, bottle, syringe and / or dispenser package or other suitable container). In some embodiments, provided kits may optionally further comprise a second container comprising a pharmaceutical excipient for diluting or suspending a pharmaceutical composition or compound of the invention. In some embodiments, the pharmaceutical composition or compound of the invention provided in the container and the second container are combined to form a single unit dosage form.

[0243] Thus, in one aspect, a first container comprising a compound as described herein or a pharmaceutically acceptable salt, solvate, hydrate, tautomer or stereoisomer thereof, or a pharmaceutical composition thereof Kits are provided that include: In certain embodiments, kits of the disclosure comprise a first container comprising a compound described herein or a pharmaceutically acceptable salt thereof or a pharmaceutical composition thereof. In certain embodiments, the kits are useful for the prevention and / or treatment of a disease, disorder or condition described herein (eg, proliferative or non-proliferative disease) in a subject. In certain embodiments, the kit comprises administering the compound or a pharmaceutically acceptable salt, solvate, hydrate, tautomer or stereoisomer thereof or a pharmaceutical composition thereof to a proliferative or non-proliferative disease. further comprising instructions for administering to a subject to prevent and / or treat

[0244] how to use Compounds useful for modulating splicing are described herein. In some embodiments, compounds of formula (I) are used to increase or decrease splicing at splice sites to increase or decrease the amount of nucleic acids (e.g., precursor RNAs, such as pre-mRNAs or resulting mRNAs), Structure or composition may be modified. In some embodiments, increasing or decreasing splicing modulates the level or structure of the gene product (eg, RNA or protein) produced. In some embodiments, compounds of formula (I) interact with components of the splicing machinery, e.g., by modulating the interaction of the component of the splicing machinery with another entity (e.g., a nucleic acid, a protein, or a combination thereof). can be adjusted. The splicing machinery referred to herein includes one or more spliceosomal components. Spliceosome components can include, for example, one or more of the major spliceosome members (U1, U2, U4, U5, U6snRNP) or the minor spliceosome members (U11, U12, U4atac, U6atacsnRNP) and their auxiliary splicing factors.

[0245] In another aspect, the disclosure provides a method of modifying a target (e.g., precursor RNA, e.g., pre-mRNA) by including a splice site in the target, the method comprising providing a compound of formula (I) Characterized by In some embodiments, inclusion of a splice site in a target (e.g., precursor RNA, e.g., pre-mRNA or resulting mRNA) results in the addition or deletion of one or more nucleic acids to the target (e.g., new exons, skipped exons). Addition or deletion of one or more nucleic acids to a target can result in increased levels of a gene product (eg, RNA, such as mRNA or protein).

[0246] In another aspect, the present disclosure provides a method of modifying a target (e.g., a precursor RNA, such as a pre-mRNA or a resulting mRNA) by eliminating a splice junction in the target, comprising a compound of formula (I) A method is featured that includes: In some embodiments, elimination of splice sites in the target (e.g., precursor RNA, e.g., pre-mRNA) results in deletion or addition of one or more nucleic acids from the target (e.g., skipped exons, e.g., new exon). Deletion or addition of one or more nucleic acids to a target can result in decreased levels of gene products (eg, RNA, eg, mRNA or protein). In other embodiments, the method of modifying a target (e.g., precursor RNA, e.g., pre-mRNA or resulting mRNA) is, e.g., in the absence of a reference (e.g., a compound of formula (I) or or tissue) compared to the 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, 99% or more) include.

[0247] The methods described herein can be used, for example, to modulate splicing of a nucleic acid containing a particular sequence (eg, target sequence). Exemplary genes encoding target sequences (eg, target sequences comprising DNA or RNA, such as pre-mRNA) include ABCA4, ABCA9, ABCB1, ABCB5, ABCC9, ABCD1, ACADL, ACADM, ACADSB, ACSS2, ACTB, among others. , 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, ANGPTL3, 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, ATP7A, ATP7B, ATR , ATXN2, ATXN3, ATXN7, ATXN10, AXIN1, B2M, B4GALNT3, BBS4, BCL2, BCL2L1, BCL2-like 11 (BIM), BCL11B, BBOX1, BCS1L, BEAN1, BHLHE40, BMPR2, BMP2K, BPTF, BRAF, BRCA1, BRCA2, BRCC3、BRSK1、BRSK2、BTAF1、BTK、C2orf55、C4orf29、C6orf118、C9orf43、C9orf72、C10orf137、C11orf30、C11orf65、C11orf70、C11οrf87、C12orf51、C13orf1、C13orf15、C14orf10l、C14orf118、C15orf29、C15orf42、C15orf60、C16orf33、C16orf38、 C16orf48、C18orf8、C19orf42、C1orf107、C1orf114、C1orf130、C1orf149、C1orf27、C1orf71、C1orf94、C1R、C20orf74、C21orf70、C3orf23、C4orf18、C5orf34、C8B、C8orf33、C9orf114、C9orf86、C9orf98、C3、CA11、CAB39、CACHD1、 CACNA1A, CACNA1B, CACNA1C, CACNA2D1, CACNA1G, CACNA1H, CALCA, CALCOCO2, CAMK1D, CAMKK1, CAPN3, CAPN9, CAPSL, CARD11, CARKD, CASZ1, CAT, CBLB, CBX1, CBX3, CCDC102B, CCDC11, CCDC15, CCDC18, CCDC5, CCDC81, CCDC131, CCDC146, CD4, CD274, CD1B, CDC14A, CDC16, CDC2L5, CDC42BPB, CDCA8, CDH10, CDH11, CDH24, CDH8, CDH9, CDK5RAP2, CDK6, CDK8, CDK11B, CD33, CD46, CDH1, CDH23, CDK6, CDK11B, CDK13, CEBPZ, CEL, CELSR3, CENPA, CENPI, CENPT, CENTB2, CENTG2, CEP110, CEP170, CEP192, CETP, CFB, CFTR, CFH, CGN, CGNL1, CHAF1A, CHD9, CHIC2, CHL1, CHN1, CHM, CLEC16A, CL1C2, CLCN1, CLINT1, CLK1, CLPB, CLPTM1, CMIP, CMYA5, CNGA3, CNOT1, CNOT7, CNTN6, COG3, COL11A1, COL11A2, COL12A1, COL14A1, COL15A1, COL17A1, COL19A1, COL1A1, COL1A2, COL3A1, COL3A1, COL3A1 COL4A1, COL4A2, COL4A5, COL4A6, COL5A2, COL6A1, COL7A1, COL9A1, COL9A2, COL22A1, COL24A1, COL25A1, COL29A1, COLQ, COMTD1, COPA, COPB2, COPS7B, COPZ2, CPSF2, CPXM2, CR1, CRBBP, YZ, EB, CR CRKRS, CSE1L, CSTB, CSTF3, CT45-6, CTNNB1, CUBN, CUL4B, CUL5, CXorf41, CXXC1, CYBB, CYFIP2, CYP3A4, CYP3A43, CYP3A5, CYP4F2, CYP4F3, CYP17, CYP19, CYP24A1, CYP27A1, DAB1, DAZ2, DCBLD1, DCC, DCTN3, DCUN1D4, DDA1, DDEF1, DDX1, DDX24, DDX4, DENND2D, DEPDC2, DES, DGAT2, DHFR, DHRS7, DHRS9, DHX8, DIP2A, DMD, DMTF1, DNAH3, DNAH8, DNAI1, DNAJA4, DNAJC13, DNAJC7, DNMT1, DNTTIP2, DOCK4, DOCK5, DOCK10, 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, ELF2, ELF3, ELF4, EMCN, EMD, EML5, ENO3, ENPP3, EP300, EPAS1, EPB41L5, EPHA3, 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, FAM134A, FAM161A, FAM176B, FAM184A, FAM19A1, FAM20A, FAM23B, FAM65C, FANCA, FANCC, FANCG, FANCM, FANK1, FAR2, FBN1, FBXO15, FBXO18, FBXO38, FCGBP, FECH, 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, GCK, GFI1, GFM1, GH1, GHR, GHV, GJA1, GLA, GLT8D1, GNA11, GNAQ, GNAS, GNB5, GOLGB1, GOLT1A, GOLT1B, GPATCH1, GPR158, GPR160, GPX4, GRAMD3, GRHL1, GRHL2, GRHPR, GRIA1, GRIA3, GRIA4, GRIN2B, GRM3, GRM4, GRN, GSDMB, GSTCD, GSTO2, GTF2I, GTPBP4, HADHA, HAND2, HBA2, HBB, HCK, HDAC3, HDAC5, HDX, HEPACAM2, 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, IDH1, IDS, IFI44L, IKBKAP, IKZF1, IKZF3, IL1R2, IL5RA, IL7RA, IMMT, INPP5D, INSR, INTS3, INTU, IP04, IP08, IQGAP2, IRF2, IRF4, IRF8, IRX3, ISL1, ISL2, ITFG1, ITGA6, ITGAL, ITGB1, ITGB2, 1TGB3, ITGB4, ITIH1, ITPR2, IWS1, JAK1, JAK2, JAG1, JMJD1C, JPH3, KALRN, KAT6A, KATNAL2, KCNN2, KCNT2, KDM2A, KIAA0256, KIAA0528, KIAA0564, KIAA0586, KIAA1033, KIAA1166, KIAA1219, KIAA1409, KIAA1622, KIFKAA1787 KIF16B, KIF5A, KIF5B, KIF9, KIN, KIR2DL5B, KIR3DL2, KIR3DL3, KIT, KLF3, KLF5, KLF7, KLF10, KLF12, KLF16, 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, LRWD1, LUM, LVRN, LYN, LYST, MADD, MAGI1, MAGT1, MALT1, MAP2K1, MAP4K4, MAPK8IP3, MAPK9, MAPT, MARC1, MARCH5, MATN2, MBD3, MCF2L2, MCM6, MDGA2, MDM4, ASXL1, FUS, SPR54, MECOM, MEF2C, MEF2D, MEGF10, MEGF11, MEMO1, MET, MGA, MGAM,MGAT4A, MGAT5, MGC16169, MGC34774, MKKS, MIB1, MIER2, MITF, MKL2, MLANA, MLH1, MLL5, MLX, MME, MPDZ, MPI, MRAP2, MRPL11, MRPL39, MRPS28, MRPS35, MS4A13, MSH2, MSH3, MSMB, MST1R, MTDH, MTERF3, MTF1, MTF2, MTIF2, MTHFR, MUC2, MUT, MVK, MYB, MYBL2, MYC, MYCBP2, MYH2, MYRF, MYT1, MY019, MY03A, MY09B, MYOM2, MYOM3, NAG, NARG1, NARG2, NCOA1, NDC80, NDFIP2, NEB, NEDD4, NEK1, NEK5, ΝΕΚ11, NF1, NF2, NFATC2, NFE2L2, NFIA, NFIB, NFIX, NFKB1, NFKB2, NFKBIL2, NFRKB, NFYA, NFYB, NIPA2, NKAIN2, NKAP, NLRC3, NLRC5, NLRP3, NLRP7, NLRP8, NLRP13, NME1, NME1-NME2, NME2, NME7, NOL10, NOP561, NOS1, NOS2A, NOTCH1, NPAS4, NPM1, NR1D1, NR1H3, NR1H4, NR4A3, NR5A1, NRXN1, NSMAF, NSMCE2, NT5C, NT5C2, NT5C3, NUBP1, NUBPL, NUDT5, NUMA1, NUP88, NUP98, N, UP160, NUPL1, OAT, OAZ1, OBFC2A, OBFC2B, OLIG2, OMA1, OPA1, OPN4, OPTN, OSBPL11, OSBPL8, OSGEPL1, OTC, OTX2, OVOL2, OXT, PA2G4, PADI4, PAH, 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, PIK3C2G, PIK3CA, PIK3CD, PIK3CG, PIK3RI, PIP5K1A, PITRM1, PIWIL3, PKD1, PKHD1L1, PKD2, PKIB, PKLR, PKM1, PKM2, PLAGL2, PLCB1, PLCB4, PLCG1, PLD1, PLEKHA5, PLEKHA7, PLEKHM1, PLKR, PLXNC1, PMFBP1, POLN, POLR3D, POMT2, POSTN, POU2AF1, POU2F2, POU2F3, PPARA, PPFIA2, PPP1R12A, PPP3CB, PPP4C, PPP4R1L, PPP4R2, PRAME, PRC1, PRDM1, PREX1, PREX2, PRIM1, PRIM2, PRKAR1A, PRKCA, PRKG1, PRMT7, PROC, PROCR, PROSC, PRODH, PROX1, PRPF40B, PRPF4B, PRRG2, PRUNE2, PSD3, PSEN1, PSMAL, PTCH1, PTEN, PTK2, PTK2B, PTPN2, PTPN3, PTPN4, PTPN11, PTPN22, PTPRD, PTPRK, PTPRM, PTPRN2, PTPRT, PUS10, PVRL2, PYGM, QRSL1, RAB11FIP2, RAB23, RAF1, RALBP1, RALGDS, RB1CC1, RBL2, RBM39, RBM45, RBPJ, RBSN, REC8, RELB, RFC4, RFT1, RFTN1, RHOA, RHPN2, RIF1, RIT1, RLN3, RMND5B, RNF11, RNF32, RNFT1, RNGTT, ROCK1, ROCK2, RORA, RP1, RP6KA3, RP11-265F1, RP13-36C9, RPAP3, RPN1, RPGR, RPL22, RPL22L1, RPS6KA6, RREB1, RRM1, RRP1B, RSK2, RTEL1, RTF1, RUFY1, RUNX1, RUNX2, RXRA, RYR3, SAAL1, SAE1, SALL4, SAT1, SATB2, SBCAD, SCN1A, SCN2A, SCN3A, SCN4A, SCN5A, SCN8A, SCNA, SCN11A, SCO1, SCYL3, SDC1, SDK1, SDK2, SEC24A, 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, SLC6A13, SLC6A6, SLC7A2, SLC13A1, SLC13A3, SLC22A17, SLC25A14, SLC28A3, SLC33A1, SLC35F6, SLC38A1, SLC38A4, SLC39A10, SLC4A2, SLC6A8, SMARCA1, SMARCA2, 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, TBR1, TBX, TCEB3, TCF3, TCF4, TCF7L2, TCFL5, TCF12, TCP11L2, TDRD3, TEAD1, TEAD3, TEAD4, TECTB, TEK, TERF1, TERF2, TET2, TFAP2A, TFAP2B, TFAP2C, TFAP4, TFDP1, TFRC, TG, TGM7, TGS1, THAP7, THAP12, THOC2, TIAL1, TIAM2, TIMM50, TLK2, TM4SF20, TM6SF1, TMEM27, TMEM77, TMEM156, TMEM194A, TMF1, TMPRSS6, TNFRSF10A, TNFRSF10B, TNFRSF8, TNK2, TNKS, TNKS2, TOM1L1, TOM1L2, TOP2B, TP53, TP53INP1, TP53BP2, TP53I3, TP63, TRAF3IP3, TRAPPC2, TRIM44, TRIM65, TRIML1, TRIML2, TRPM3, TRPM5, TRPM7, TRPS1, TSC1, TSC2, TSHB, TSPAN7, TTC17, TTF1, TTLL5, TTLL9, TTN, TTPAL, TTR, TUSC3, TXNDC10, UBE3A, UCK1, UGT1A1, UHRF1BP1, UNC45B, UNC5C, USH2A, USF2, USP1, USP6, USP18, USP38, USP39, UTP20, UTP15, UTP18, UTRN, UTX, UTY, UVRAG, UXT, VAPA, VEGFA, VPS29, VPS35, VPS39, VT11A, VT11B, VWA3B, WDFY2, WDR16, WDR17, WDR26, WDR44, WDR67, WDTC1, WRN, WRNIP1, WT1, WWC3, XBP1, XRN1, XRN2, XX-FW88277, YAP1, YARS, YBX1, YGM, YY1, ZBTB18, ZBTB20, ZC3HAV1, ZC3HC1, ZC3H7A, ZDHHC19, ZEB1, ZEB2, ZFPM1, ZFYVE1, ZFX, ZIC2, ZNF37A, ZNF91, ZNF114, ZNF155, ZNF169, ZNF205, ZNF236, ZNF317, ZNF320, ZNF326, ZNF335, ZNF365, ZNF367, ZNF407, ZNF468, ZNF506, ZNF511, ZNF511-PRAP1, ZNF519, ZNF521, ZNF68, ZNF68, ZNF68 and ZNF69 included.

[0248] Additional exemplary genes encoding target sequences (eg, target sequences comprising DNA or RNA, such as 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, ZNF1497, AC.01297 1, CAPN3, AC013489.1, DET1, AC016747.4, C2orf74, AC020907.6, FXYD3, AC021087.5, PDCD6, AHRR, AC022137.3, ZNF761, AC025283.3, NAA60, AC027644.4, RABGEF1, 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, CALML4, AC114490.2, ZMYM6, AC138649.1, NIPA1, AC138894.1, CLN3, AC139768.1, AC242426.2, CHD1L, ACADM, ACAP3, ACKR2, RP11-141M3.5, KRBOX1, ACMSD, ACOT9, ACP5, ACPL2, ACSBG1, ACSF2, ACSF3, ACSL1, ACSL3, ACVR1, ADAL, ADAM29, ADAMTS10, ADMTSL5, ADARB1, ADAT2, ADCK3, ADD3, ADGRG1, ADGRG2, ADH1B, ADIPOR1, ADNP, ADPRH, AGBL5, AGPAT1, AGPAT3, AGR2, AGTR1, AHDC1, AHI1, AHNAK, AIFM1, AIFM3, AIMP2, AK4, AKAP1, AKNAD1, CLCC1, AKR1A1, AKT1, AKT1S1, AKT2, AL139011.2, PEX19, AL157935.2, ST6GALNAC6, AL358113.1, TJP2, AL441992.2, KYAT1, AL449266.1, CLCC1, AL590556.3, LINC00339, CDC42, ALAS1, ALB, ALDH16A1, ALDH1B1, ALDH3A1, ALDH3B2, ALDOA, ALKBH2, 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, ARHGAP11A, ARHGAP33, ARHGAP4, ARHGEF10, ARHGEF3, ARHGEF35, OR2A1-AS1, ARHGEF35, OR2A1-AS1, ARHGEF34P, ARID1B, ARHGEF35, OR2A20P, OR2A1-AS1, ARHGEF9, ARL1, 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, ASNS, AC079781.5, ASPSCR1, ASS1, ASUN, ATE1, ATF1, ATF7IP2, 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, B3GALNT1, B3GALT5, AF064860.1, B3GALT5, AF064860.5, B3GNT5, B4GALT43, B9D1, BACH1, BAIAP2, BANF1, BANF2, BAX, BAZ2A, BBIP1, BCHE, BCL2L14, BCL6, BCL9L, BCS1L, BDH1, BDKRB2, AL355102.2, BEST1, BEST3, BEX4, BHLHB9, BID, BIN3, BIRC2, BIVM, BIVM-ERCC5, BIVM, BLCAP, BLK, BLOC1S1, RP11-644F5.10, BLOC1S6, AC090527.2, BLOC1S6, RP11-96O20.4, BLVRA, BMF, BOLA1, BORCS8-MEF2B, BORCS8, BRCA1, BRD1, BRDT, BRINP3, BROX, BTBD10, BTBD3, BTBD9, BTD, BTF3L4, BTNL9, BUB1B-PAK6, PAK6, BUB3, C10orf68, C11orf1, C11orf48, C11orf54, C11orf54, AP001273.2, C11orf57, C11orf63, C11orf54, C11orf24, C51forf82, C51forf2, C51forf82, C12forf82, C12 C12orf79、C14orf159、C14orf93、C17orf62、C18orf21、C19orf12、C19orf40、C19orf47、C19orf48、C19orf54、C1D、C1GALT1、C1QB、C1QTNF1、C1S、C1orf101、C1orf112、C1orf116、C1orf159、C1orf63、C2、C2,CFB、C20orf27、C21orf58、 C2CD4D、C2orf15、LIPT1、MRPL30、C2orf80、C2orf81、C3orf14、C3orf17、C3orf18、C3orf22、C3orf33,AC104472.3、C4orf33、C5orf28、C5orf34、C6orf118、C6orf203、C6orf211、C6orf48、C7orf50、C7orf55、C7orf55-LUC7L2、LUC7L2、 C8orf44-SGK3, C8orf44, C8orf59, C9,DAB2, C9orf153, C9orf9, CA5BP1, CA5B, CABYR, CALCA, CALCOCO1, CALCOCO2, CALM1, CALM3, CALML4, RP11-315D16.2, CALN1, CALU, CANT1, CANX, CAP1, CAPN12, CAPS2, CARD8, CARHSP1, CARNS1, CASC1, CASP3, CASP7, CBFA2T2, CBS, CBY1, CCBL1, CCBL2, RBMXL1, CCDC12, CCDC126, CCDC14, CCDC149, CCDC150, CCDC169-SOHLH2, CCDC169, CCDC171, CCDC37, CCDC41, CCDC57, CCDC63, CCDC7, CCDC74B, CCDC77, CCDC82, CCDC90B, CCDC91, CCDC92, CCNE1, CCHCR1, CCL28, CCNB1IP1, CCNC, CCND3, CCNG1, CCP110, CCR9, CCT7, CCT8, CD151, CD1D, CD200, CD22, CD226, CD276, CD36, CD59, CDC26, CDC42, CDC42SE1, CDC42SE2, CDHR3, CDK10, CDK16, CDK4, CDKAL1, CDKL3, CTD-2410N18.4, CDKN1A, CDKN2A, CDNF, CEBPZOS, CELF1, CEMIP, CENPK, CEP170B, CEP250, CEP57, CEP57L1, CEP63, CERS4, CFL1, CFL2, CFLAR, CGNL1, CHCHD7, CHD1L, CHD8, CHFR, ZNF605, CHIA, CHID1, CHL1, CHM, CHMP1A, CHMP3, RNF103-CHMP3, CHRNA2, CIDEC, CIRBP, CITED1, CKLF-CMTM1, CMTM1, CKMT1B, CLDN12, CTB-13L3.1, CLDND1, AC021660.3, CLDND1, CPOX, CLHC1, CLIP1, CLUL1, CMC4, MTCP1, CNDP2, CNFN, CNOT1, CNOT6, CNOT7, CNOT8, CNR1, CNR2, CNTFR, CNTRL, COA1, COASY, COCH, COL8A1, COLCA1, COLEC11, COMMD3-BMI1, BMI1, COPS5, COPS7B, COQ8A, CORO6, COTL1, COX14,RP4-605O3.4, COX7A2, COX7A2L, COX7B2, CPA4, CPA5, CPEB1, CPNE1, AL109827.1, RBM12, CPNE1, RP1-309K20.6, RBM12, CPNE3, CPSF3L, CPT1C, CREB3L2, CREM, CRP, CRYZ, CS, AC073896.1, CS, RP11-977G19.10, CSAD, CSDE1, CSF2RA, CSGALNACT1, CSK, CSNK2A1, CSRNP2, CT45A4, CT45A4, CT45A5, CT45A6, CTBP2, CTCFL, CTD-2116N17.1, KIAA0101, CTD-2349B8.1, SYT17, CTD-2528L19.4, ZNF607, CTD-2619J13.8, ZNF497, CTNNA1, CTNNBIP1, CTNND1, CTPS2, CTSB, CTSL, CTTN, CUL2, CUL9, CWC15, CXorf40B, CYB561A3, CYBC1, CYLD, CYP11A1, CYP2R1, CYP4B1, CYP4F22, DAG1, DAGLB, KDELR2, DARS, DBNL, DCAF11, DCAF8,PEX19, DCLRE1C, DCTD, DCTN1, DCTN4, DCUN1D2, DDR1, DDX11, DDX19B, AC012184.2, DDX19B, RP11-529K1.3, DDX25, DDX39B, ATP6V1G2-DDX39B, SNORD84, DDX42, DDX60L, DEDD, DEDD2, DEFA1, DEFA1B, DEFA1B, DEFA3, DENND1C, DENND2A, DENND4B, DET1, DGKA, DGKZ, DGLUCY, DHRS4L2, DHRS9, DHX40, DIABLO, AC048338.1, DIAPH1, DICER1, DKKL1, DLG1, DLG3, DLST, DMC1, . DMKN, DMTF1, DMTN, DNAJC14, DNAJC19, DNAL1, DNASE1L1, DNMT3A, DOC2A, DOCK8, DOK1, DOPEY1, DPAGT1, DPP8, DRAM2, DRD2, DROSHA, DSN1, DTNA, DTX2, DTX3, DUOX1, DUOXA1, DUS2, DUSP10, DUSP13, DUSP18, DUSP22, DYDC1, DYDC2, DYNLL1, DYNLT1, DYRK1A, DYRK2, DYRK4, RP11-500M8.7, DZIP1L, E2F6, 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、FAM115C、FAM115C、FAM115D、FAM120B、FAM133B、FAM135A、FAM153A、FAM153B、FAM154B、FAM156A、FAM156B、FAM168B、FAM172A、FAM182B、 FAM192A, FAM19A2, FAM200B, FAM220A, FAM220A, AC009412.1, FAM222B, FAM227B, FAM234A, AC004754.1, FAM3C, FAM45A, FAM49B, FAM60A, FAM63A, FAM81A, FAM86B1, FANAM86B1, FANAM86B1, FAX, FAM86B2, FAX, FAM86B2, FAM60A, FAM63A, FAM81A FBF1, FBH1, FBXL4, FBXO18, FBXO22, FBXO31, FBXO41, FBXO44, FBXO45, FBXW9, FCHO1, 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, FOXO1, FOXP4, AC097634.4, FOXRED1, FPR1, FPR2, FRG1B, FRS2, FTO, FTSJ1, FUK, FUT10, FUT3, FUT6, FXYD3, FZD3, G2E3, GAA, GABARAPL1, GABPB1, GABRA5, GAL3ST1, GALE, GALNT11, 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, GLT8D1, GMFG, GMPR2, GNAI2, GNAQ, GNB1, GNB2, GNE, GNG2, GNGT2, GNPDA1, GNPDA2, GOLGA3, CHFR, GOLGA4, GOLPH3L, GOLT1B, GPBP1L1, GPER1, GPR116, GPR141, EPDR1, GPR155, GPR161, GPR56, GPR63, GPR75-ASB3, ASB3, GPR85, GPSM2, GRAMD1B, GRB10, GRB7, GREM2, GRIA2, GSDMB, GSE1, GSN, GSTA4, GSTZ1, GTDC1, GTF2H1, GTF2H4, VARS2, GTF3C2, GUCY1A3, GUCY1B3, GUK1, GULP1, GYPC, GYS1, GZF1, HAGH, HAO2, HAPLN3, HAVCR1, HAX1, HBG2, AC104389.4, HBG2, AC104389.4, HBE1, HBG2, AC104389.4, HBE1, OR51B5, HBG2, HBE1, AC104389.28, HBS1L, HCFC1R1, HCK, HDAC2, HDAC6, HDAC7, HDLBP, HEATR4, HECTD4, HEXIM2, HHAT, HHATL, CCDC13, HINFP, HIRA, C22orf39, HIVEP3, HJV, HKR1, HLF, HMBOX1, HMGA1, HMGB3, HMGCR, HMGN4, HMOX2, HNRNPC, HNRNPD, HNRNPH1, HNRNPH3, HNRNPR, HOMER3, HOPX, HOXA3, 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, KTBBD2, KTBBD3, KCNAB2, KCNE3, KCNG1, KCNJ16, KCNJ9, KCNMB2, AC117457.1, LINC01014, KCTD20, KCTD7, RABGEF1, KDM1B, KDM4A, AL451062.3, KH040, KIAA0 KIAA0125、KIAA0196、KIAA0226L、PPP1R2P4、KIAA0391、KIAA0391、AL121594.1、KIAA0391、PSMA6、KIAA0753、KIAA0895、KIAA0895L、KIAA1191、KIAA1407、KIAA1841、C2orf74、KIF12、KIF14、KIF27、KIF9、KIFC3、KIN、KIRREL1、KITLG、 KLC1, APOPT1, AL139300.1, KLC4, KLHDC4, KLHDC8A, KLHL13, KLHL18, KLHL2, KLHL24, KLHL7, KLK11, KLK2, KLK5, KLK6, KLK7, KNOP1, KRBA2, AC135178.2, KRBA2, RP11-849F2.7, KRIT1, KRT15, ​​KRT8, KTN1, KXD1, KYAT3, RBMXL1, KYNU, L3MBTL1, LACC1, LARGE, LARP4, LARP7, LAT2, LBHD1, LCA5, LCA5L, LCTL, LEPROTL1, LGALS8, LGALS9C, LGMN, LHFPL2, LIG4, LIMCH1, LIMK2, LIMS2, LINC00921, ZNF263, LIPF, LLGL2, LMAN2L, LMCD1, LMF1, RP11-161M6.2, LMO1, LMO3, LOXHD1, LPAR1, LPAR2, LPAR4, LPAR5, LPAR6, LPHN1, LPIN2, LPIN3, LPP, LRFN5, LRIF1, LRMP, LRRC14, LRRC20, LRRC24, C8orf82, LRRC39, LRRC42, LRRC48, LRRC4C, LRRC8A, LRRC8B, LRRD1, LRTOMT, LRTOMT, AP000812.5, LSM7, LTB4R, LTBP3, LUC7L2, FMC1-LUC7L2, LUC7L3, LUZP1, LYG1, LYL1, LYPD4, LYPD6B, LYRM1, LYRM5, LYSMD4, MACC1, 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, MCFD2, MCM9, MCOLN3, MCRS1, MDC1, MDGA2, MDH2, MDM2, ME1, MEAK7, MECR, MED4, MEF2A, MEF2B, BORCS8-MEF2B, MEF2BNB-MEF2B, MEF2B, MEF2BNB, MEF2C, MEF2D, MEGF10, MEI1, MEIS2, MELK, MET, METTL13, METTL23, MFF, MFN2, MFSD2A, MGST3, MIB2, MICAL1, MICAL3, MICOS10, NBL1, MICOS10-NBL1, MID1, MINA, MINOS1-NBL1, MINOS1, MIOS, MIPOL1, MIS12, MKLN1, MKNK1, MKNK1, MOB3C, MLF2, MLH1, MMP17, MOBP, MOCS1, MOGS, MOK, MORF4L1, MPC1, MPC2, MPG, MPI, MPP1, MPP2, MPPE1, MPST, MRAS, MRO, MROH1, MROH7-TTC4, MROH7, MRPL14, MRPL24, MRPL33, BABAM2, MRPL33, BRE, MRPL47, MRPL48, MRPL55, MRRF, MRTFA, 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, MZF1, N4BP2L2, NAA60, NAB1, NAE1, NAGK, NAP1L1, NAP1L4, NAPG, NARFL, NARG2, NAT1, NAT10, NBPF11, WI2-3658N16.1, NBPF12, NBPF15, NBPF24, NBPF6, NBPF9, NBR1, NCAPG2, NCBP2, NCEH1, NCOA1, NCOA4, NDC1, NDRG1, NDRG2. , NDRG4, NDST1, NDUFAF6, NDUFB2, NDUFC1, NDUFS1, NDUFS8, NDUFV1, NEDD1, NEIL1, NEIL2, NEK10, NEK11, NEK6, NEK9, NELFA, NEU4, NFAT5, NFE2, NFE2L2, AC019080.1, NFRKB, NFYA, NFYC , NIF3L1, NIPA2, NKIRAS1, NKX2-1, NLRC3, NME1, NME1-NME2, NME2, NME1-NME2, NME2, NME4, NME6, NME9, NOD1, NOL10, NOL8, NONO, NPAS1, NPIPA8, RP11-1212A22.1 , NPIPB3, NPIPB4, NPIPB9, NPL, NPM1, NPPA, NQO2, NR1H3, NR2C2, NR2F2, NR4A1, NRDC, NREP, NRF1, NRG4, NRIP1, NSD2, NSDHL, NSG1, NSMCE2, NSRP1, NT5C2, NTF4, NTMT1, NTNG2 , NUBP2, NUCB2, NUDT1, NUDT2, NUDT4, NUF2, NUMBL, NUP50, NUP54, NUP85, NVL, NXF1, NXPE1, NXPE3, OARD1, OAT, OAZ2, OCIAD1, OCLN, ODF2, OGDHL, OGFOD2, AC026362.1, OGFOD2 , RP11-197N18.2, OLA1, OPRL1, OPTN, OR2H1, ORAI2, ORMDL1, ORMDL2, ORMDL3, OSBPL2, OSBPL3, OSBPL5, OSBPL9, OSER1, OSGIN1, OSR2, P2RX4, P2RY2, P2RY6, P4HA2, PABPC1, PACRGL, PACSIN3 , PADI1, PAIP2, PAK1, PAK3, PAK4, PAK7, PALB2, PANK2, PAQR6, PARP11, PARVG, PASK, PAX6, PBRM1, PBXIP1, PCBP3, PCBP4, AC115284.1, PCBP4, RP11-155D18.14, RP11-155D18 .12, PCGF3, PCGF5, PCNP, PCSK9, PDCD10, PDCD6, AHRR, PDDC1, PDGFRB, PDIA6, PDIK1L, PDLIM7, PDP1, PDPK1, PDPN, PDZD11, PEA15, PEX2, PEX5, PEX5L, PFKM, PFN4, PGAP2, PGAP2 , AC090587.2, PGAP3, PGM3, PGPEP1, PHB, PHC2, PHF20, PHF21A, PHF23, PHKB, PHLDB1, PHOSPHO1, PHOSPHO2, KLHL23, PI4KB, PIAS2, PICALM, PIF1, PIGN, PIGO, PIGT, PIK3CD, PILRB, STAG3L5P -PVRIG2P-PILRB, PIP5K1B, PIR, PISD, PIWIL4, FUT4, PKD2, PKIA, PKIG, PKM, PKN2, PLA1A, PLA2G2A, PLA2G5, PLA2G7, PLAC8, PLAGL1, PLD1, PLD3, PLEKHA1, PLEKHA2, PLEKHA6, PLEKHG5, PLIN1 , PLS1, PLS3, PLSCR1, PLSCR2, PLSCR4, PLXNB1, PLXNB2, PMP22, PMS1, PNISR, PNKP, AKT1S1, PNMT, PNPLA4, PNPLA8, PNPO, PNRC1, POC1B, POFUT1, POLB, POLD1, POLH, POLI, POLL, POLR1B , POM121, POM121C, AC006014.7, POM121C, AC211429.1, POMC, POMT1, POP1, PORCN, POU5F1, PSORS1C3, PPARD, PPARG, PPHLN1, PPIL3, PPIL4, PPM1A, PPM1B, AC013717.1, PPP1CB, PPP1R11, PPP1R13L , PPP1R26, PPP1R9A, PPP2R2B, PPP3CA, PPP6R1, PPP6R3, PPT2, PPT2-EGFL8, EGFL8, PPWD1, PRDM2, PRDM8, PRELID3A, PREPL, PRICKLE1, PRKAG1, PRMT2, PRMT5, PRMT7, PROM1, PRPS1, PRPSAP2, PRR14L, PRR15L , PRR5, PRR5-ARHGAP8, PRR5L, PRR7, PRRC2B, PRRT4, PRSS50, PRSS45, PRSS44, PRUNE, PRUNE1, PSEN1, PSMA2, PSMF1, PSORS1C1, PSPH, PSRC1, PTBP3, PTHLH, PTK2, PTPDC1, PTPRM, PUF60, PUM2 , PUS1, PUS10, PXN, PXYLP1, PYCR1, QRICH1, R3HCC1L, R3HDM2, RAB17, RAB23, RAB3A, RAB3D, TMEM205, RAB4B-EGLN2, EGLN2, AC008537.1, RAB5B, RAB7L1, RABL2A, RABL2B, RABL5, RACGAP1, RAD17 , RAD51L3-RFFL, RAD51D, RAD52, RAE1, RAI14, RAI2, RALBP1, RAN, 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, RBSN, RCBTB2, RCC1, RCC1, SNHG3, RCCD1, RECQL, RELL2, REPIN1, AC073111.3 , REPIN1, ZNF775, RER1, RERE, RFWD3, RFX3, RGL2, RGMB, RGS11, RGS3, RGS5, AL592435.1, RHBDD1, RHNO1, TULP3, RHOC, AL603832.3, RHOC, RP11-426L16.10, RHOH, RIC8B , RIMKLB, RIN1, RIPK2, RIT1, RLIM, RNASE4, ANG, AL163636.6, RNASEK, RNASEK-C17orf49, RNF111, RNF123, RNF13, RNF14, RNF185, RNF216, RNF24, RNF32, RNF34, RNF38, RNF4, RNF44, RNH1 , RNMT, RNPS1, RO60, ROPN1, ROPN1B, ROR2, RP1-102H19.8, C6orf163, RP1-283E3.8, CDK11A, RP11-120M18.2, PRKAR1A, RP11-133K1.2, PAK6, RP11-164J13.1 , CAPN3, RP11-21J18.1, ANKRD12, RP11-322E11.6, INO80C, RP11-337C18.10, CHD1L, RP11-432B6.3, TRIM59, RP11-468E2.4, IRF9, RP11-484M3.5, UPK1B , RP11-517H2.6, CCR6, RP11-613M10.9, SLC25A51, RP11-659G9.3, RAB30, RP11-691N7.6, CTNND1, RP11-849H4.2, RP11-896J10.3, NKX2-1, RP11 -96O20.4, SQRDL, RP11-986E7.7, SERPINA3, RP4-769N13.6, GPRASP1, RP4-769N13.6, GPRASP2, RP4-798P15.3, SEC16B, RP5-1021I20.4, ZNF410, RP6-109B7 .3, FLJ27365, RPE, RPH3AL, RPL15, RPL17, RPL17-C18orf32, RPL17, RPL23A, RPL36, HSD11B1L, RPP38, RPS20, RPS27A, RPS3A, RPS6KA3, RPS6KC1, RPS6KL1, RPUSD1, RRAGD, RRAS2, RRBP1, RSL21 , RSRP1, RUBCNL, RUNX1T1, RUVBL2, RWDD1, RWDD4, S100A13, AL162258.1, S100A13, RP1-178F15.5, S100A16, S100A4, S100A3, S100A6, S100PBP, SAA1, SACM1L, SAMD4B, SAR1A, SARAF1, SARNP -762I7.5, SCAMP5, SCAP, SCAPER, SCFD1, SCGB3A2, SCIN, SCML1, SCNN1D, SCO2, SCOC, SCRN1, SDC2, SDC4, SEC13, SEC14L1, SEC14L2, SEC22C, SEC23B, SEC24C, SEC61G, SEMA4A, SEMA4C, SEMA4D , SEMA6C, SENP7, SEPP1, 11-Sep, 2-Sep, SERGEF, AC055860.1, SERP1, SERPINA1, SERPINA5, SERPINB6, SERPING1, SERPINH1, SERTAD3, SETD5, SFMBT1, AC096887.1, SFTPA1, SFTPA2, SFXN2, SGCD , SGCE, SGK3, SGK3, C8orf44, SH2B1, SH2D6, SH3BP1, Z83844.3, SH3BP2, SH3BP5, SH3D19, SH3YL1, SHC1, SHISA5, SHMT1, SHMT2, SHOC2, SHROOM1, SIGLEC5, SIGLEC14, SIL1, SIN3A, SIRT2, SIRT6 、SKP1、STAT4、AC104109.3、SLAIN1、SLC10A3、SLC12A9、SLC14A1、SLC16A6、SLC1A2、SLC1A6、SLC20A2、SLC25A18、SLC25A19、SLC25A22、SLC25A25、SLC25A29、SLC25A30、SLC25A32、SLC25A39、SLC25A44、SLC25A45、SLC25A53、SLC26A11、SLC26A4 、SLC28A1、SLC29A1、SLC2A14、SLC2A5、SLC2A8、SLC35B2、SLC35B3、SLC35C2、SLC37A1、SLC38A1、SLC38A11、SLC39A13、SLC39A14、SLC41A3、SLC44A3、SLC4A7、SLC4A8、SLC5A10、SLC5A11、SLC6A1、SLC6A12、SLC6A9、SLC7A2、SLC7A6、SLC7A7 , SLCO1A2, SLCO1C1, SLCO2B1, SLFN11, SLFN12, SLFNL1, SLMO1, SLTM, SLU7, SMAD2, SMAP2, SMARCA2, SMARCE1, AC073508.2, SMARCE1, KRT222, SMC6, SMG7, SMIM22, SMOX, SMPDL3A, SMTN, SMU1, SMUG1, SNAP25, SNCA, SNRK, SNRPC, SNRPD1, SNRPD2, SNRPN, SNRPN, SNURF, SNUPN, SNX11, SNX16, SNX17, SOAT1, SOHLH2,CCDC169-SOHLH2,CCDC169, SORBS1, SORBS2, SOX5, SP2, SPART, SPATA20, SPATA21, SPATS2, SPATS2L, SPDYE2, SPECC1, SPECC1L, SPECC1L-ADORA2A, SPECC1L-ADORA2A, ADORA2A, SPEG, SPG20, SPG21, SPIDR, SPIN1, SPOCD1, SPOP, SPRR2A, SPRR2B, SPRR2E, SPRR2B, SPRR2F, SPRR2D, SPRR3, SPRY1, SPRY4, SPTBN2, SRC, SRGAP1, SRP68, SRSF11, SSX1, SSX2IP, ST3GAL4, ST3GAL6, ST5, ST6GALNAC6, ST7L, STAC3, STAG1, STAG2, STAMBP, STAMBPL1, STARD3NL, STAT6, STAU1, STAU2, AC022826.2, STAU2, RP11-463D19.2, STEAP2, STEAP3, STIL, STK25, STK33, STK38L, STK40, STMN1, STON1, S. TON1-GTF2A1L, STRAP, STRBP, STRC, AC011330.5, STRC, CATSPER2, STRC, CATSPER2, AC011330.5, STRC, STRCP1, STT3A, STX16-NPEPL1, NPEPL1, STX5, STX6, STX8, STXBP6, STYK1, SULT1A1, SULT1A2, SUMF2, SUN1, SUN2, SUN2, DNAL4, SUOX, SUPT6H, SUV39H2, SV2B, SYBU, SYNCRIP, SYNJ2, 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, TBC1D5, SATB1, TBCA, TBCEL, TBCEL, AP000646.1, TBL1XR1, TBP, TBX5, TBXAS1, TCAF1, TCEA2, TCEAL4, TCEAL8, TCEAL9, TCEALC, TCEB1, TCF19, TCF25, TCF4, TCP1, TCP10L, AP000275.65, TCP11, TCP11L2, TCTN1, TDG, TDP1, TDRD7, TEAD2, TECR, TENC1, TENT4A, TEX264, TEX30, TEX37, TFDP1, TFDP2, TFEB, TFG, TFP1,TF, TFPI, TGIF1, THAP6, THBS3, THOC5, THRAP3, THUMPD3, TIAL1, TIMM9, TIMP1, TIRAP, TJAP1, TJP2, TK2, TLDC1, TLE3, TLE6, TLN1, TLR10, TM9SF1, TMBIM1, TMBIM4, TMBIM6, TMC6, TMCC1, TMCO4, TMEM126A, TMEM139, TMEM150B, TMEM155, TMEM161B, TMEM164, TMEM168, TMEM169, TMEM175, TMEM176B, TMEM182, TMEM196E2,CTB 3, TMEM216, TMEM218, TMEM230, TMEM263, TMEM45A, TMEM45B, TMEM62, TMEM63B, TMEM66, TMEM68, TMEM98, TMEM9B, TMPRSS11D, TMPRSS5, TMSB15B, TMTC4, TMUB2, TMX2-CTNND1, RP11-691N7.6, CTNND1, TNFAIP2, TNFAIP8L2, SCNM1, TNFRSF10C, TNFRSF19, TNFRSF8, TNFSF12-TNFSF13, TNFSF12, TNFSF13, TNFSF12-TNFSF13, TNFSF13, TNIP1, TNK2, TNNT1, TNRC18, TNS3, TOB2, TOM1L1, TOP1MT, TOP3B, TOX2, TP53, RP11-199F11. 2, TP53I11, TP53INP2, TPCN1, TPM3P9, AC022137.3, TPT1, TRA2B, TRAF2, TRAF3, TRAPPC12, TRAPPC3, TREH, TREX1, TREX2, TRIB2, TRIM3, TRIM36, TRIM39, TRIM46, TRIM6, TRIM6-TRIM34, TRIM6- TRIM34, TRIM34, TRIM66, TRIM73, TRIT1, TRMT10B, TRMT2B, TRMT2B-AS1, TRNT1, TRO, TROVE2, TRPS1, TRPT1, TSC2, TSGA10, TSPAN14, TSPAN3, TSPAN4, TSPAN5, TSPAN6, TSPAN9, TSPO, TTC12, TTC23, TTC3, TTC39A, TTC39C, TTLL1, TTLL7, TTPAL, TUBD1, TWNK, TXNL4A, TXNL4B, TXNRD1, TYK2, U2AF1, UBA2, UBA52, UBAP2, UBE2D2, UBE2D3, UBE2E3, UBE2I, UBE2J2, UBE3A, UBL7, UBXN11, UBXN7, UGDH, UGGT1, UGP2, UMAD1, AC007161.3, UNC45A, UQCC1, URGCP-MRPS24, URGCP, USMG5, USP16, USP21, USP28, USP3, USP33, USP35, USP54, USP9Y, USPL1, UTP15, VARS2, VASH2, VAV3, VDAC1, VDAC2, VDR, VEZT, VGF, VIL1, VILL, VIPR1, VPS29, VPS37C, VPS8, VPS9D1, VRK2, VWA1, VWA5A, WARS, WASF1, WASHC5, WBP5, WDHD1, WDPCP, WDR37, WDR53, WDR6, WDR72, WDR74, WDR81, WDR86, WDYHV1, WFDC3, WHSC1, WIPF1, WSCD2, WWP2, XAGE1A, XAGE1B, XKR9, XPNPEP1, XRCC3, XRN2, XXYLT1, YIF1A, YIF1B, YIPF1, YIPF5, YPEL5, YWHAB, YWHAZ, YY1AP1, ZBTB1, ZBTB14, ZBTB18, ZBTB20, ZBTB21, ZBTB25, ZBTB33, ZBTB34, ZBTB38, ZBTB43, ZBTB49, ZBTB7B, ZBTB7C, ZBTB8OS, ZC3H11A, ZBED6, ZC3H13, ZCCHC17, ZCCHC7, ZDHHC11, ZC3H11A, ZBED6, ZC3H13, ZCCHC17, ZCCHC7, ZDHHC11, ZDHHC11, ZDHHC11, ZDHFP6, ZFP6, ZFP6, FANDZF, ZEB2, ZEB2 ZFX, ZFYVE16, ZFYVE19, ZFYVE20, ZFYVE27, ZHX2, AC016405.1, ZHX3, ZIK1, ZIM2, PEG3, ZKSCAN1, ZKSCAN3, ZKSCAN8, ZMAT3, ZMAT5, ZMIZ2, ZMYM6, ZMYND11, ZNF10, AC026786.1, ZNF136, ZNF143, ZNF14 ZNF16, ZNF177, ZNF18, ZNF200, ZNF202, ZNF211, ZNF219, ZNF226, ZNF227, ZNF23, AC010547.4, ZNF23, AC010547.9, ZNF239, ZNF248, ZNF25, ZNF253, ZNF254, ZNF254, AC092279.1, ZNF2263, ZNF226.1 ZNF275, ZNF28, ZNF468, ZNF283, ZNF287, ZNF3, ZNF320, ZNF322, ZNF324B, ZNF331, ZNF334, ZNF34, ZNF350, ZNF385A, ZNF395, FBXO16, ZNF415, ZNF418, ZNF43, ZNF433-AS1, ZNF484, ZNF444, ZNF444, AC00877 ZNF445, ZNF467, ZNF480, ZNF493, ZNF493, CTD-2561J22.3, ZNF502, ZNF507, ZNF512, AC074091.1, ZNF512, RP11-158I13.2, ZNF512B, ZNF512B, SAMD10, ZNF521, ZNF532, ZNF55 AC.02094 ZNF544, CTD-3138B18.4, ZNF559, ZNF177, ZNF562, ZNF567, ZNF569, ZNF570, ZNF571-AS1, ZNF540, ZNF577, ZNF580, ZNF581, ZNF580, ZNF581, CCDC106, ZNF600, ZNF611, ZNF6105, ZNF619, ZNF619, ZNF629, ZNF629 ZNF639、ZNF652、ZNF665、ZNF667、ZNF668、ZNF671、ZNF682、ZNF687、ZNF691、ZNF696、ZNF701、ZNF706、ZNF707、ZNF714、ZNF717、ZNF718、ZNF720、ZNF721、ZNF730、ZNF763、ZNF780B,AC005614.5、ZNF782、ZNF786、 Included are genes including ZNF79, ZNF791, ZNF81, ZNF83, ZNF837, ZNF839, ZNF84, ZNF845, ZNF846, ZNF865, ZNF91, ZNF92, ZNHIT3, ZSCAN21, ZSCAN25, ZSCAN30 and ZSCAN32.

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

[0250] Exemplary genes that may be modulated by the compounds of formula (I) described herein include, among others, .1, AC012531.3, AC034102.2, AC073896.4, AC104472.3, AL109811.3, AL133342.1, AL137782.1, AL157871.5, AF241726.2, AL355336.1, AL358113.1, AL360181.3 , AL445423.2, AL691482.3, AP001267.5, RF01169 and RF02271.

[0251] The compounds described herein can further be used to modulate sequences, including specific splice site sequences, such as RNA sequences (eg, 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, AAAguacugg, AAAguacuuc, AAAguacuug, AAAguagcuu, AAAguaggag, AAAguaggau, AAAguagggg, AAAguaggua, AAAguaguaa, AAAcuguauu, AAAguaucuauu , AAAguaucuc, AAAguaugga, AAAguaugua, AAAguaugug, AAAguauguu, AAAguauugg, AAAguauuuu, AAAgucagau, AAAgucugag, AAAgugaaua, AAAgugagaa, AAAgugagac, AAAgugagag, AAAgugagau, AAAgugagca, AAAgugagcu, AAAgugagg, AAAgugagua, AAAgugaguc, AAAgugagug, AAAgugaguggu, AAAgugguggug, AAAguggugguguc, 、AAAgugguaa、AAAguguaug、AAAgugugug、AAAguguguu、AAAguuaagu、AAAguuacuu、AAAguuagug、AAAguuaugu、AAAguugagu、AAAguuugua、AACguaaaac、AACguaaagc、AACguaaagg、AACguaagca、AACguaaggg、AACguaaguc、AACguaagug、AACguaaugg、AACguaguga、AACguaugua、AACguauguu、AACgugagca、AACgugagga、AACgugauuu、AACgugggau 、AACgugggua、AACguguguu、AACguuggua、AAGgcaaauu、AAGgcaagag、AAGgcaagau、AAGgcaagcc、AAGgcaagga、AAGgcaaggg、AAGgcaagug、AAGgcaaguu、AAGgcacugc、AAGgcagaaa、AAGgcaggau、AAGgcaggca、AAGgcaggga、AAGgcagggg、AAGgcaggua、AAGgcaggug、AAGgcaucuc、AAGgcaugcu、AAGgcaugga、AAGgcauguu、AAGgcauuau、AAGgcgagcu 、AAGgcgaguc、AAGgcgaguu、AAGgcuagcc、AAGguaaaaa、AAGguaaaac、AAGguaaaag、AAGguaaaau、AAGguaaaca、AAGguaaacc、AAGguaaacu、AAGguaaaga、AAGguaaagc、AAGguaaagg、AAGguaaagu、AAGguaaaua、AAGguaaauc、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、AAGguaauag、AAGguaauau、AAGguaauca、AAGguaaucc、AAGguaaucu、AAGguaauga、AAGguaaugc 、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、AAGguagcaa、AAGguagcag、AAGguagcca、AAGguagccu、AAGguagcua、AAGguagcug 、AAGguagcuu、AAGguaggaa、AAGguaggag、AAGguaggau、AAGguaggca、AAGguaggcc、AAGguaggcu、AAGguaggga、AAGguagggc、AAGguagggg、AAGguagggu、AAGguaggua、AAGguagguc、AAGguaggug、AAGguagguu、AAGguaguaa、AAGguaguag、AAGguagucu、AAGguagugc、AAGguagugg、AAGguaguuc、AAGguaguuu、AAGguauaaa、AAGguauaau、AAGguauaca 、AAGguauacu、AAGguauaua、AAGguauauc、AAGguauaug、AAGguauauu、AAGguaucac、AAGguaucag、AAGguauccc、AAGguauccu、AAGguaucuc、AAGguaucug、AAGguaucuu、AAGguaugaa、AAGguaugac、AAGguaugag、AAGguaugau、AAGguaugca、AAGguaugcc、AAGguaugcu、AAGguaugga、AAGguauggc、AAGguauggg、AAGguaugua、AAGguauguc、AAGguaugug 、AAGguauguu、AAGguauuaa、AAGguauuac、AAGguauuag、AAGguauuau、AAGguauucc、AAGguauuga、AAGguauugu、AAGguauuua、AAGguauuuc、AAGguauuug、AAGguauuuu、AAGgucaaau、AAGgucaaga、AAGgucaagu、AAGgucacag、AAGgucagaa、AAGgucagac、AAGgucagag、AAGgucagca、AAGgucagcc、AAGgucagcg、AAGgucagcu、AAGgucagga、AAGgucaggc 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CAGguaggca、CAGguaggga、CAGguagggc、CAGguagggg、CAGguagggu、CAGguaggua、CAGguagguc、CAGguaggug、CAGguagguu、CAGguaguaa、CAGguaguau、CAGguaguca、CAGguagucc、CAGguaguga、CAGguagugu、CAGguaguuc、CAGguaguug、CAGguaguuu、CAGguauaag、CAGguauaca、CAGguauaga、CAGguauauc、CAGguauaug、CAGguauauu、CAGguaucag、 CAGguaucau、CAGguauccu、CAGguaucga、CAGguaucgc、CAGguaucua、CAGguaucug、CAGguaucuu、CAGguaugaa、CAGguaugac、CAGguaugag、CAGguaugau、CAGguaugca、CAGguaugcc、CAGguaugcg、CAGguaugcu、CAGguaugga、CAGguauggg、CAGguauggu、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、CAGgucccug、CAGguccuga、CAGguccugc、CAGguccugg、CAGgucggcc、CAGgucggug、CAGgucguug、CAGgucucuc、CAGgucucuu、CAGgucugag、CAGgucugcc、CAGgucugcg、CAGgucugga、CAGgucuggu、CAGgucugua、CAGgucuguc、CAGgucugug、CAGgucuguu、CAGgucuucc、CAGgucuuuc、 CAGgugaaag, CAGgugaaau, CAGgugaaca, CAGgugaaga, CAGgugaagg, CAGgugaaua, CAGgugaauc, CAGgugaauu, CAGgugacaa,CAGgugacau、CAGgugacca、CAGgugaccc、CAGgugaccg、CAGgugaccu、CAGgugacgg、CAGgugacua、CAGgugacuc、CAGgugacug、CAGgugagaa、CAGgugagac、CAGgugagag、CAGgugagau、CAGgugagca、CAGgugagcc、CAGgugagcg、CAGgugagcu、CAGgugagga、CAGgugaggc、CAGgugaggg、CAGgugaggu、CAGgugagua、CAGgugaguc、CAGgugagug、CAGgugaguu、 CAGgugauaa、CAGgugaucc、CAGgugaucu、CAGgugaugc、CAGgugaugg、CAGgugaugu、CAGgugauua、CAGgugauuc、CAGgugauug、CAGgugauuu、CAGgugcaaa、CAGgugcaag、CAGgugcaca、CAGgugcacg、CAGgugcaga、CAGgugcagg、CAGgugcaua、CAGgugcauc、CAGgugcaug、CAGgugccaa、CAGgugccca、CAGgugcccc、CAGgugcccg、CAGgugccua、CAGgugccug、 CAGgugcgaa, CAGgugcgca, CAGgugcgcc, CAGgugcgcg, CAGgugcgga, CAGgugcggu, CAGgug, cgua、CAGgugcguc、CAGgugcgug、CAGgugcuag、CAGgugcuau、CAGgugcuca、CAGgugcucc、CAGgugcucg、CAGgugcugc、CAGgugcugg、CAGgugcuua、CAGgugcuuc、CAGgugcuug、CAGguggaac、CAGguggaag、CAGguggaau、CAGguggaga、CAGguggagu、CAGguggauu、CAGguggcca、CAGguggcuc、CAGguggcug、CAGgugggaa、CAGgugggac、CAGgugggag、 CAGgugggau、CAGgugggca、CAGgugggcc、CAGgugggcu、CAGgugggga、CAGguggggc、CAGguggggg、CAGguggggu、CAGgugggua、CAGguggguc、CAGgugggug、CAGguggguu、CAGguggucu、CAGguggugg、CAGgugguug、CAGguguaca、CAGguguagg、CAGguguauc、CAGgugucac、CAGgugucag、CAGgugucca、CAGguguccu、CAGgugucua、CAGgugucuc、CAGgugucug、 CAGgugugaa、CAGgugugac、CAGgugugag、CAGgugugau、CAGgugugca、CAGgugugcc、CAGgugugcg、CAGgugugcu、CAGgugugga、CAGguguggc、CAGgugugua、CAGguguguc、CAGgugugug、CAGguguguu、CAGguguuua、CAGguuaaaa、CAGguuaaua、CAGguuaauc、CAGguuaccu、CAGguuagaa、CAGguuagag、CAGguuagau、CAGguuagcc、CAGguuaggg、CAGguuaggu、 CAGguuagua、CAGguuaguc、CAGguuagug、CAGguuaguu、CAGguuauca、CAGguuaugu、CAGguuauua、CAGguuauug、CAGguucaaa、CAGguucaac、CAGguucaag、CAGguucaca、CAGguucacg、CAGguucagg、CAGguucaug、CAGguuccag、CAGguuccca、CAGguucccg、CAGguucgaa、CAGguucgag、CAGguucuau、CAGguucugc、CAGguucuua、CAGguucuuc、CAGguucuuu、 CAGguugaac、CAGguugaag、CAGguugagu、CAGguugaua、CAGguuggag、CAGguuggca、CAGguuggcc、CAGguugguc、CAGguuggug、CAGguugguu、CAGguuguaa、CAGguuguac、CAGguuguau、CAGguuguca、CAGguuguga、CAGguuguug、CAGguuuaag、CAGguuuacc、CAGguuuagc、CAGguuuagu、CAGguuucuu、CAGguuugaa、CAGguuugag、CAGguuugau、CAGguuugcc、 CAGguuugcu、CAGguuuggg、CAGguuuggu、CAGguuugua、CAGguuugug、CAGguuuguu、CAGguuuucu、CAGguuuugg、CAGguuuuuc、CAGguuuuuu、CAUgcagguu、CAUguaaaac、CAUguaacua、CAUguaagaa、CAUguaagag、CAUguaagau、CAUguaagcc、CAUguaagua、CAUguaagug、CAUguaaguu、CAUguaauua、CAUguacaua、CAUguaccac、CAUguacguu、CAUguaggua、 CAUguaggug、CAUguagguu、CAUguaugaa、CAUguaugua、CAUguaugug、CAUguauguu、CAUgugagaa、CAUgugagca、CAUgugagcu、CAUgugagua、CAUgugaguc、CAUgugagug、CAUgugaguu、CAUgugcgua、CAUgugggaa、CAUguggguu、CAUgugugug、CAUguguguu、CAUguuaaua、CAUguuagcc、CCAguaagau、CCAguaagca、CCAguaagcc、CCAguaagcu、CCAguaagga、 CCAguaagua、CCAguaaguc、CCAguaagug、CCAguaaguu、CCAguaauug、CCAguacggg、CCAguagguc、CCAguauugu、CCAgugaggc、CCAgugagua、CCAgugagug、CCAguggguc、CCAguuaguu、CCAguugagu、CCCguaagau、CCCguauguc、CCCguauguu、CCCguccugc、CCCgugagug、CCGguaaaga、CCGguaagau、CCGguaagcc、CCGguaagga、CCGguaaggc、CCGguaaugg、 CCGguacagu、CCGguacuga、CCGguauucc、CCGgucagug、CCGgugaaaa、CCGgugagaa、CCGgugaggg、CCGgugagug、CCGgugaguu、CCGgugcgcg、CCGgugggcg、CCGguugguc、CCUguaaaug、CCUguaaauu、CCUguaagaa、CCUguaagac、CCUguaagag、CCUguaagca、CCUguaagcg、CCUguaagga、CCUguaaguu、CCUguaggua、CCUguaggug、CCUguaucuu、CCUguauggu、 CCUguaugug、CCUgugagaa、CCUgugagca、CCUgugaggg、CCUgugaguc、CCUgugagug、CCUgugaguu、CCUguggcuc、CCUgugggua、CCUgugugua、CCUguuagaa、CGAguaaggg、CGAguaaggu、CGAguagcug、CGAguaggug、CGAguagguu、CGAgugagca、CGCguaagag、CGGgcaggca、CGGguaagcc、CGGguaagcu、CGGguaaguu、CGGguaauuc、CGGguaauuu、CGGguacagu、 CGGguacggg、CGGguaggag、CGGguaggcc、CGGguaggug、CGGguauuua、CGGgucugag、CGGgugaccg、CGGgugacuc、CGGgugagaa、CGGgugaggg、CGGgugaggu、CGGgugagua、CGGgugagug、CGGgugaguu、CGGgugauuu、CGGgugccuu、CGGgugggag、CGGgugggug、CGGguggguu、CGGguguguc、CGGgugugug、CGGguguguu、CGGguucaag、CGGguucaug、CGGguuugcu、 CGUguagggu、CGUguaugca、CGUguaugua、CGUgucugua、CGUgugagug、CGUguuuucu、CUAguaaaug、CUAguaagcg、CUAguaagcu、CUAguaagua、CUAguaaguc、CUAguaagug、CUAguaaguu、CUAguaauuu、CUAguaggua、CUAguagguu、CUAguaugua、CUAguauguu、CUAgugagua、CUCguaagca、CUCguaagug、CUCguaaguu、CUCguaucug、CUCgucugug、CUCgugaaua、 CUCgugagua、CUCgugauua、CUGguaaaaa、CUGguaaaau、CUGguaaacc、CUGguaaacg、CUGguaaagc、CUGguaaaua、CUGguaaauc、CUGguaaaug、CUGguaaauu、CUGguaacac、CUGguaacag、CUGguaaccc、CUGguaaccg、CUGguaacug、CUGguaacuu、CUGguaagaa、CUGguaagag、CUGguaagau、CUGguaagca、CUGguaagcc、CUGguaagcu、CUGguaagga、CUGguaaggc、 CUGguaaggg、CUGguaaggu、CUGguaagua、CUGguaagug、CUGguaaguu、CUGguaauga、CUGguaaugc、CUGguaauuc、CUGguaauuu、CUGguacaac、CUGguacaau、CUGguacaga、CUGguacaua、CUGguacauu、CUGguaccau、CUGguacguu、CUGguacuaa、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、 CUGgugagga、CUGgugaggc、CUGgugaggg、CUGgugaggu、CUGgugagua、CUGgugaguc、CUGgugagug、CUGgugaguu、CUGgugauua、CUGgugauuu、CUGgugcaga、CUGgugcgcu、CUGgugcgug、CUGgugcuga、CUGgugggag、CUGgugggga、CUGgugggua、CUGguggguc、CUGgugggug、CUGguggguu、CUGgugugaa、CUGgugugca、CUGgugugcu、CUGguguggu、CUGgugugug、 CUGguguguu, CUGguuagcu, CUGguuagug, CUGguucgug, CUGguuggcu, CUGguuguuu, CUGguuugua, CUGguuuguc, CUGguuuugg,CUUguaaaug、CUUguaagcu、CUUguaagga、CUUguaaggc、CUUguaagua、CUUguaagug、CUUguaaguu、CUUguacguc、CUUguacgug、CUUguaggua、CUUguagugc、CUUguauagg、CUUgucagua、CUUgugagua、CUUgugaguc、CUUgugaguu、CUUguggguu、CUUgugugua、CUUguuagug、CUUguuugag、GAAguaaaac、GAAguaaagc、GAAguaaagu、GAAguaaaua、GAAguaaauu、 GAAguaagaa、GAAguaagcc、GAAguaagcu、GAAguaagga、GAAguaagua、GAAguaagug、GAAguaaguu、GAAguaauau、GAAguaaugc、GAAguaauua、GAAguaauuu、GAAguaccau、GAAguacgua、GAAguacguc、GAAguaggca、GAAguagguc、GAAguauaaa、GAAguaugcu、GAAguaugug、GAAguauguu、GAAguauuaa、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、GAGguaguug、GAGguauaag、GAGguauacu、GAGguauagc、GAGguauaug、GAGguauauu、GAGguaucau、GAGguaucug、GAGguaucuu、GAGguaugaa、GAGguaugac、GAGguaugag、GAGguaugcc、GAGguaugcg、GAGguaugcu、GAGguaugga、GAGguauggg、GAGguauggu、GAGguaugua、GAGguauguc、GAGguaugug、GAGguauguu、GAGguauucc、GAGguauuga、 GAGguauugu、GAGguauuua、GAGguauuuc、GAGguauuug、GAGguauuuu、GAGgucaaca、GAGgucaagg、GAGgucaaug、GAGgucacug、GAGgucagaa、GAGgucagag、GAGgucagcu、GAGgucagga、GAGgucaggc、GAGgucaggg、GAGgucaggu、GAGgucagua、GAGgucauau、GAGgucaugu、GAGgucauuu、GAGguccaua、GAGguccauc、GAGguccggg、GAGguccggu、GAGguccuug、 GAGgucgggg、GAGgucucgu、GAGgucugag、GAGgucuggu、GAGgucuguc、GAGgucuguu、GAGgucuuuu、GAGgugaaaa、GAGgugaaau、GAGgugaaca、GAGgugaagg、GAGgugaaua、GAGgugaauu、GAGgugacau、GAGgugacca、GAGgugaccu、GAGgugacua、GAGgugacuu、GAGgugagaa、GAGgugagac、GAGgugagag、GAGgugagau、GAGgugagca、GAGgugagcc、GAGgugagcg、 GAGgugagcu、GAGgugagga、GAGgugaggc、GAGgugaggg、GAGgugagua、GAGgugagug、GAGgugaguu、GAGgugauau、GAGgugaucc、GAGgugaucu、GAGgugauga、GAGgugaugg、GAGgugaugu、GAGgugauuc、GAGgugcaca、GAGgugcaga、GAGgugcagc、GAGgugcagg、GAGgugccag、GAGgugccca、GAGgugccuu、GAGgugcggg、GAGgugcgug、GAGgugcucc、GAGgugcugg、 GAGgugcuua、GAGgugcuug、GAGguggaaa、GAGguggaau、GAGguggacc、GAGguggacg、GAGguggagg、GAGguggcug、GAGgugggaa、GAGgugggag、GAGgugggau、GAGgugggca、GAGgugggcg、GAGgugggcu、GAGgugggga、GAGguggggc、GAGguggggg、GAGgugggua、GAGguggguc、GAGgugggug、GAGguggguu、GAGgugguau、GAGgugguuc、GAGgugucau、GAGgugugag、 GAGgugugau、GAGgugugca、GAGgugugcu、GAGgugugga、GAGguguggg、GAGguguggu、GAGgugugua、GAGgugugug、GAGguuaaau、GAGguuaaga、GAGguuaaua、GAGguuaccg、GAGguuagaa、GAGguuagac、GAGguuagag、GAGguuaggu、GAGguuagua、GAGguuaguc、GAGguuagug、GAGguuaguu、GAGguuaugu、GAGguuauuc、GAGguucaaa、GAGguucaua、GAGguucuga、 GAGguugaag、GAGguugcag、GAGguugcug、GAGguuggaa、GAGguuggag、GAGguuggau、GAGguuggua、GAGguugguc、GAGguugguu、GAGguuguag、GAGguuucug、GAGguuugag、GAGguuugga、GAGguuuggg、GAGguuugua、GAGguuuguu、GAGguuuuca、GAGguuuuga、GAGguuuugg、GAGguuuuua、GAGguuuuuc、GAUguaaaau、GAUguaagca、GAUguaagcc、GAUguaaggu、 GAUguaagua、GAUguaagug、GAUguaaguu、GAUguacauc、GAUguaggua、GAUguauggc、GAUguaugua、GAUguauguu、GAUgucagug、GAUgugagag、GAUgugagcc、GAUgugagcu、GAUgugagga、GAUgugaguc、GAUgugagug、GAUgugaguu、GAUgugggua、GAUgugggug、GAUguguguu、GAUguuagcu、GAUguucagu、GAUguucgug、GAUguuuguu、GCAguaaagg、GCAguaagaa、 GCAguaagga、GCAguaagua、GCAguaaguc、GCAguaaguu、GCAguagaug、GCAguaggua、GCAguaugug、GCAguauguu、GCAgucagua、GCAgucagug、GCAguccggu、GCAgugacuu、GCAgugagcc、GCAgugagcg、GCAgugagcu、GCAgugagua、GCAgugagug、GCAgugaguu、GCAgugggua、GCAguuaagu、GCAguugagu、GCCguaaguc、GCCgugagua、GCGguaaagc、GCGguaaaua、 GCGguaagcu、GCGguaaggg、GCGguaagug、GCGguaauca、GCGguacgua、GCGguacuug、GCGguagggu、GCGguagugu、GCGgugagca、GCGgugagcu、GCGgugaguu、GCGguggcuc、GCGgugugca、GCGguguguu、GCGguuaagu、GCGguuugca、GCUgcuguaa、GCUguaaaua、GCUguaagac、GCUguaagag、GCUguaagca、GCUguaagga、GCUguaagua、GCUguaaguc、GCUguaagug、 GCUguaaguu、GCUguaggug、GCUguauggu、GCUgucagug、GCUguccuug、GCUgugagaa、GCUgugagcc、GCUgugagga、GCUgugagua、GCUgugaguc、GCUgugagug、GCUgugaguu、GCUguggguu、GGAguaagag、GGAguaagca、GGAguaagcc、GGAguaagcu、GGAguaagga、GGAguaagug、GGAguaaguu、GGAguaauuu、GGAguacugu、GGAguaggaa、GGAguaggua、GGAguagguu、 GGAguaguau、GGAguaugac、GGAguauggu、GGAgucaagu、GGAgugaggg、GGAgugagua、GGAgugaguc、GGAgugagug、GGAgugaguu、GGAgugcuuu、GGAgugggca、GGAgugggug、GGAguuaagg、GGAguugaga、GGCguaagcc、GGCguaggua、GGCguaggug、GGCgugagcc、GGCgugaguc、GGGguaaaca、GGGguaaacc、GGGguaaacu、GGGguaagaa、GGGguaagag、GGGguaagau、 GGGguaagca, GGGguaagcc, GGGguaagcu, GGGguaagga, GGGguaaggg, GGGguaagua, GGGguaagug, GGGguaaguu, GGGguagaca,GGGguaggag、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、GGGgugagug、GGGgugaguu、GGGgugcgua、GGGguggggu、GGGgugggua、GGGgugggug、GGGguggguu、GGGgugugcg、GGGgugugua、GGGguguguc、GGGgugugug、GGGguuacag、GGGguuggac、GGGguuggga、GGGguuugcc、GGGguuugua、GGUguaagaa、GGUguaagau、GGUguaagca、GGUguaagcc、GGUguaagcg、 GGUguaaguc, GGUguaagug, GGUguagguc, GGUguaggug, GGUguagguu, GGUguccgua, GGUguga, gag、GGUgugagcc、GGUgugagcu、GGUgugagua、GGUgugaguc、GGUgugcuuc、GGUguggcug、GGUgugguga、GGUgugucug、GGUguugaaa、GGUguugcug、GUAguaagau、GUAguaagua、GUAguaagug、GUAguagcuu、GUAguaggua、GUAgucagua、GUAgugagua、GUAguggugg、GUAguuaagu、GUAguuucug、GUCguaagug、GUCgugagug、GUCgugaguu、GUGgcaagua、 GUGgcuugua、GUGguaaaau、GUGguaaaga、GUGguaaauu、GUGguaacau、GUGguaacua、GUGguaagaa、GUGguaagac、GUGguaagag、GUGguaagau、GUGguaagca、GUGguaagcg、GUGguaagcu、GUGguaagga、GUGguaaggc、GUGguaagua、GUGguaaguc、GUGguaagug、GUGguaaguu、GUGguaauga、GUGguaauuc、GUGguaauuu、GUGguacaug、GUGguacgau、GUGguacuau、 GUGguacuug、GUGguagaua、GUGguagcgc、GUGguaggga、GUGguagguc、GUGguaggug、GUGguagguu、GUGguauaaa、GUGguaucuc、GUGguaugaa、GUGguaugau、GUGguaugca、GUGguaugua、GUGguauguu、GUGguccgug、GUGgucuggc、GUGgugaaac、GUGgugagaa、GUGgugagau、GUGgugagca、GUGgugagcu、GUGgugagga、GUGgugaggc、GUGgugagug、GUGgugaguu、 GUGgugauua、GUGgugauuc、GUGgugcgau、GUGgugcuua、GUGgugggaa、GUGgugggua、GUGguggguc、GUGguguccg、GUGguuagca、GUGguuaggu、GUGguuagug、GUGguuugca、GUGguuugua、GUUguaaggu、GUUguaagua、GUUguaaguc、GUUguaaguu、GUUguaccac、GUUguagcgu、GUUguaugug、GUUguauguu、GUUgucugug、GUUgugagcu、GUUgugagug、GUUgugaguu、 GUUgugggua、GUUguggguu、UAAguaaaug、UAAguaacua、UAAguaagaa、UAAguaagag、UAAguaagau、UAAguaagca、UAAguaagcu、UAAguaagga、UAAguaaggu、UAAguaagua、UAAguaaguc、UAAguaagug、UAAguaaguu、UAAguaauaa、UAAguacuag、UAAguaguuu、UAAguauaaa、UAAguauaca、UAAguaugua、UAAguauuau、UAAguauuuu、UAAgucuuuu、UAAgugagac、 UAAgugagga、UAAgugaggg、UAAgugagua、UAAgugaguc、UAAgugagug、UAAgugaguu、UAAgugaucc、UAAgugauuc、UAAgugcgug、UAAguuaagu、UAAguuccag、UAAguucuuu、UAAguuguaa、UAAguuguau、UAAguuuguu、UACguaacug、UACguaagaa、UACguaagau、UACguaagua、UACguaagug、UACguauccu、UACgucuggc、UACgugacca、UAGgcaagac、UAGgcaaguc、 UAGgcagguc、UAGgcgugug、UAGguaaaaa、UAGguaaaac、UAGguaaaag、UAGguaaaau、UAGguaaaca、UAGguaaaga、UAGguaaaua、UAGguaaauc、UAGguaaaug、UAGguaaauu、UAGguaacac、UAGguaacag、UAGguaacau、UAGguaacca、UAGguaacgg、UAGguaacua、UAGguaacuc、UAGguaacug、UAGguaacuu、UAGguaagac、UAGguaagag、UAGguaagau、UAGguaagca、 UAGguaagcc、UAGguaagcu、UAGguaagga、UAGguaaggc、UAGguaaggg、UAGguaagua、UAGguaaguc、UAGguaagug、UAGguaaguu、UAGguaauag、UAGguaauau、UAGguaaucu、UAGguaauga、UAGguaaugg、UAGguaaugu、UAGguaauua、UAGguaauuc、UAGguaauuu、UAGguacagc、UAGguacagu、UAGguacauu、UAGguaccag、UAGguaccua、UAGguaccuu、UAGguacgag、 UAGguacgua、UAGguacguu、UAGguacuau、UAGguacuga、UAGguacugg、UAGguacuuc、UAGguacuuu、UAGguagcgg、UAGguaggaa、UAGguaggac、UAGguaggau、UAGguaggga、UAGguagggg、UAGguaggua、UAGguagguc、UAGguaggug、UAGguagguu、UAGguaguaa、UAGguagucu、UAGguagugg、UAGguagugu、UAGguaguuu、UAGguauaaa、UAGguauaac、UAGguauaag、 UAGguauaau、UAGguauaca、UAGguauacu、UAGguauaua、UAGguauauc、UAGguauauu、UAGguaucag、UAGguaucua、UAGguaucuc、UAGguaugaa、UAGguaugag、UAGguaugca、UAGguaugga、UAGguauggc、UAGguauggu、UAGguaugua、UAGguauguc、UAGguaugug、UAGguauguu、UAGguauuaa、UAGguauuac、UAGguauuau、UAGguauuca、UAGguauucc、UAGguauucu、 UAGguauuga、UAGguauuua、UAGguauuuc、UAGguauuuu、UAGgucacuc、UAGgucagcu、UAGgucaggu、UAGgucagua、UAGgucagug、UAGgucaguu、UAGgucaucu、UAGgucauug、UAGguccaau、UAGguccugu、UAGgucucaa、UAGgucucgc、UAGgucuggc、UAGgucuguc、UAGgucugug、UAGgugaagu、UAGgugaaua、UAGgugaaug、UAGgugaauu、UAGgugacau、UAGgugacca、 UAGgugacua、UAGgugagaa、UAGgugagac、UAGgugagag、UAGgugagau、UAGgugagcc、UAGgugagcu、UAGgugagga、UAGgugaggc、UAGgugaggu、UAGgugagua、UAGgugaguc、UAGgugagug、UAGgugauca、UAGgugauuc、UAGgugauuu、UAGgugcaua、UAGgugcauc、UAGgugccgu、UAGgugccug、UAGgugcgca、UAGgugcgua、UAGgugcgug、UAGgugcuga、UAGguggaua、 UAGgugggaa、UAGgugggac、UAGgugggag、UAGgugggau、UAGgugggcc、UAGgugggcu、UAGguggguu、UAGguggugu、UAGguguaaa、UAGgugugaa、UAGgugugag、UAGgugugca、UAGgugugcc、UAGgugugcg、UAGguguggu、UAGgugugua、UAGgugugug、UAGguguugg、UAGguuaagc、UAGguuagac、UAGguuagcc、UAGguuaggc、UAGguuagua、UAGguuaguc、UAGguuagug、 UAGguucccc、UAGguucuac、UAGguuggua、UAGguugguu、UAGguugucc、UAGguuuauu、UAGguuugcc、UAGguuugua、UAGguuuguc、UAGguuugug、UAGguuuguu、UAGguuuuuc、UAGguuuuug、UAUguaagaa、UAUguaagau、UAUguaagca、UAUguaagcc、UAUguaagua、UAUguaaguc、UAUguaagug、UAUguaaguu、UAUguacgug、UAUguacguu、UAUguagguc、UAUguagguu、 UAUguauccu、UAUguaucuc、UAUguaugua、UAUguauguc、UAUguaugug、UAUguauuau、UAUgucagaa、UAUgucugua、UAUgugaaua、UAUgugacag、UAUgugagua、UAUgugagug、UAUgugaguu、UAUgugggca、UAUgugugua、UAUguguuua、UAUguuuugu、UCAgcgacau、UCAguaaaau、UCAguaaaua、UCAguaacug、UCAguaagaa、UCAguaagag、UCAguaagau、UCAguaagca、 UCAguaagcc、UCAguaagcu、UCAguaaggg、UCAguaagua、UCAguaaguc、UCAguaagug、UCAguaaguu、UCAguaucuu、UCAguaugga、UCAguauggu、UCAgucccca、UCAgugagca、UCAgugagcu、UCAgugagua、UCAgugagug、UCAgugaguu、UCAgugauug、UCAgugggug、UCAguugagc、UCAguugauu、UCAguuuagu、UCCguaagca、UCCguaagcu、UCCguaaguc、UCCguaagug、 UCCguaauag, UCCguacuua, UCCguaugua, UCCguauguu, UCCgugagau, UCCgugaguc, UCGguaaaauu, UCGguaagag, UCGguaagcu,UCGguacauc、UCGguacucc、UCGguagacc、UCGguagguu、UCGguaguaa、UCGguaugug、UCGguauguu、UCGguauuga、UCGgucagua、UCGgucuuag、UCGgugaagu、UCGgugagaa、UCGgugagca、UCGgugaggc、UCGgugagua、UCGgugcgcu、UCGgugcuuu、UCGgugguuu、UCGguuagcu、UCUguaaaag、UCUguaagaa、UCUguaagau、UCUguaagca、UCUguaagcu、UCUguaagua、 UCUguaaguc、UCUguaagug、UCUguaaguu、UCUguaauaa、UCUguaauga、UCUguaaugu、UCUguaggua、UCUguagguu、UCUguauaua、UCUguaugac、UCUguaugua、UCUguccucg、UCUgugagag、UCUgugagcu、UCUgugagga、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、UGAguauaaa、UGAguaugcu、UGAguaugga、UGAguaugua、UGAguauguc、UGAguauguu、UGAgucagag、UGAgucuacg、UGAgugaaua、UGAgugaauu、UGAgugagaa、UGAgugagau、UGAgugagca、UGAgugagcc、UGAgugagga、UGAgugagua、UGAgugagug、UGAgugaguu、 UGAgugggaa、UGAguuaaga、UGAguuaaug、UGAguuacgg、UGAguuaggu、UGAguucuau、UGAguugguu、UGAguuguag、UGAguuuauc、UGCguaaguc、UGCguaagug、UGCguacggc、UGCguacggg、UGCguaugua、UGGgcaaguc、UGGgcaagug、UGGgcacauc、UGGgccacgu、UGGgccccgg、UGGguaaaau、UGGguaaagc、UGGguaaagg、UGGguaaagu、UGGguaaaua、UGGguaaaug、 UGGguaaauu、UGGguaacag、UGGguaacau、UGGguaacua、UGGguaacuu、UGGguaagaa、UGGguaagac、UGGguaagag、UGGguaagau、UGGguaagca、UGGguaagcc、UGGguaagcu、UGGguaaggg、UGGguaaggu、UGGguaagua、UGGguaaguc、UGGguaagug、UGGguaaguu、UGGguaaugu、UGGguaauua、UGGguaauuu、UGGguacaaa、UGGguacagu、UGGguacuac、UGGguaggga、 UGGguagguc、UGGguaggug、UGGguagguu、UGGguaguua、UGGguauagu、UGGguaugaa、UGGguaugac、UGGguaugag、UGGguaugua、UGGguauguc、UGGguaugug、UGGguauguu、UGGguauuug、UGGgucuuug、UGGgugaccu、UGGgugacua、UGGgugagac、UGGgugagag、UGGgugagca、UGGgugagcc、UGGgugagga、UGGgugaggc、UGGgugaggg、UGGgugagua、UGGgugaguc、 UGGgugagug、UGGgugaguu、UGGgugcgug、UGGguggagg、UGGguggcuu、UGGguggggg、UGGgugggua、UGGguggguc、UGGgugggug、UGGguggguu、UGGgugugga、UGGguguguc、UGGgugugug、UGGguguguu、UGGguguuua、UGGguuaaug、UGGguuaguc、UGGguuagug、UGGguuaguu、UGGguucaag、UGGguucgua、UGGguuggug、UGGguuuaag、UGGguuugua、UGUgcaagua、 UGUguaaaua、UGUguaagaa、UGUguaagac、UGUguaagag、UGUguaaggu、UGUguaagua、UGUguaaguc、UGUguaaguu、UGUguacuuc、UGUguaggcg、UGUguaggua、UGUguaguua、UGUguaugug、UGUgucagua、UGUgucugua、UGUgucuguc、UGUgugaccc、UGUgugagau、UGUgugagca、UGUgugagcc、UGUgugagua、UGUgugaguc、UGUgugagug、UGUgugcgug、UGUgugggug、 UGUguggguu、UGUgugugag、UGUguguucu、UGUguuuaga、UUAguaaaua、UUAguaagaa、UUAguaagua、UUAguaagug、UUAguaaguu、UUAguaggug、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、UUGguaggua、UUGguagguc、UUGguaggug、UUGguauaaa、UUGguauaca、UUGguauauu、UUGguaucua、UUGguaucuc、UUGguaugca、UUGguaugua、UUGguaugug、UUGguauguu、UUGguauugu、UUGguauuua、UUGguauuuu、UUGgucagaa、UUGgucagua、UUGgucucug、UUGgucugca、UUGgugaaaa、UUGgugacug、UUGgugagac、UUGgugagau、UUGgugagca、 UUGgugagga、UUGgugaggg、UUGgugagua、UUGgugaguc、UUGgugagug、UUGgugaguu、UUGgugaugg、UUGgugauua、UUGgugauug、UUGgugcaca、UUGgugggaa、UUGguggggc、UUGgugggua、UUGguggguc、UUGgugggug、UUGguggguu、UUGguguggu、UUGguguguc、UUGgugugug、UUGguguguu、UUGguuaagu、UUGguuagca、UUGguuagug、UUGguuaguu、UUGguuggga、 UUGguugguu、UUGguuugua、UUGguuuguc、UUUgcaagug、UUUguaaaua、UUUguaaaug、UUUguaagaa、UUUguaagac、UUUguaagag、UUUguaagca、UUUguaaggu、UUUguaagua、UUUguaaguc、UUUguaagug、UUUguaaguu、UUUguaauuu、UUUguacagg、UUUguacgug、UUUguacuag、UUUguacugu、UUUguagguu、UUUguauccu、UUUguauguu、UUUgugagca、UUUgugagug、 Included are UUUgugcguc, UUUguguguc and uGGguaccug.

[0252] Additional exemplary gene sequences and splice site sequences (e.g., 5' splice site sequences) include AAGgcaagau, AUGguaugug, GGGgugaggc, CAGguaggug, AAGgucagua, AAGguuagag, AUGgcacuua, UAAguaaguc, UGGgugagcu, CGAgcugggc, AAAgcacccc, UAGguggggg, AGAguaacgu, UCGgugaugu, AAUgucaguu、AGGgucugag、GAGgugacug、AUGguagguu、GAGgucuguc、CAGguaugug、CAAguacugc、CACgugcgua、CCGgugagcu、CAGguacuuc、CAGgcgagag、GAAgcaagua、AGGgugagca、CAGgcaaguc、AAGgugaggc、CAGguaagua、CCAguugggu、AAGguguggg、CAGguuggag、CCGguaugaa、UGGguaaugu、CAGgugaggu、AGAguaauag、CAGguaugag、AUGguaaguu、 UUGguggguc、UUUguaagca、CUCguaugcc、UAGguaagag、UAGgcaaguu、GGAguuaagu、GAGguaugcc、AAGguguggu、CAGgugggug、UUAguaagua、AAGguuggcu、UGAguaugug、CCAgccuucc、CCUguacgug、CCUguaggua、CAGguacgcu、GAGguucuuc、AAGguugccu、CGUguucacu、CGGgugggga、UAGgugggau、CGGguaagga、AAGguacuau、GGGguaagcu、ACGguagagc、 CAGgugaaga、GCGguaagag、CAGguguugu、GAAguuugug、AUGgugagca、CGGguucgug、AUUguccggc、GAUgugugug、AUGgucuguu、AAGguaggau、CCGguaagau、AAGguaaaga、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、CAGguuguug、AAAguauggg、UAGgcugguc、AAGguaagga、AAGguuuccu、UUGguaaaac、GAGguaagua、CAGguucaag、UGGguuaugu、GAGgugaguu、ACGgugaaac、GAUguaacca、AAGgugcggg、CCGguacgug、GAUgugagaa、GUGgcgguga、CAGguauuag、GAGguuggga、 AAGgcuagua, AAGgugggcg, CAGgcaggga, AAUguuaguu, GAGguaaagg, CAGgugugcu, CUGguaugau, AUGguuaguc, CUGgugagaa, CAGgccggcg, CAGgugacug, AAAguaaggu, UAAguacuug, AAGguaaagc, UCGguagggg, CAGguaggaa,AGUguaagca、CCCgugagau、GUGguuguuu、CAGguuugcc、AGGguauggg、UAAguaagug、GAGguaagac、GAUguagguc、CAAguaggug、AUAguaaaua、GAGguugggg、GAGgcgagua、CAGguagugu、GUGguaggug、CAAgugagug、AAGgugacaa、CCAgcguaau、ACGgugaggu、GGGguauauu、CAGgugagua、AAGgugcgug、UAUguaaauu、CAGgucagua、ACGguacuua、GAGgucagca、 UAAguaugua、GGGgucagac、AAUgugugag、UCCgucagua、CAGgugcuuc、CCAguuagug、CCGgugggcg、AGGgugcaug、GGGguaggau、UAGgugggcc、GAGguguucg、UUGgcaagaa、UCCguaagua、CAGguguaag、CUCgugagua、GAGguguuuu、GAGgugagca、GAGguaaagu、AAGguacguu、CAGguccagu、AUGgugaaac、GUAgugagcu、CAGgugaaaa、AGGguacagg、AAGguaacgc、 AAGguauacc, CCUguugagau, GGGguaggug, 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、GAGguacuug、 AGAguaaaac、UCUgugagua、AAGgcgggaa、CAGguaugcg、AGGguaaaac、AAGgugacug、AGGguauguu、AAGguaugua、CAGgucucuc、CAGgcaugua、CUGguaggua、AAGgucaugc、CAGguacaca、GAUguacguu、ACAguacgug、ACGguaccca、CAGguagugc、ACAguaagag、GGUgcacacc、GAGguguaac、AAGgugugua、UAGguacuua、GCGguacugc、UGGguaaguc、CAUguaggua、 CAGguaggau、CAGgucuggc、GUGguuuuaa、CAGgugggaa、UGGgugagua、CGAgugagcc、AAGguauggc、AGUguuguca、CAGgugauuu、UAGguaucuc、UAAguauguu、AAGguugagc、AGAguaaaga、GGUguaagua、GGGgugagcu、CAGguauaau、GAGguacaaa、AUGguaccaa、UAGguagggg、UGAgucagaa、AAGgcaauua、UUGguaagau、CAGguacaga、AGAguuagag、CAGgugcguc、 GAGguauuac、ACGguacaga、CAGgucuucc、AAGguaaggu、GAGguaauuu、AGUguaggcu、AAAguaagcg、CCUguaagcc、AGGgugauuu、UGUguaugaa、CUGguacaca、AGGguagaga、AUAguaagca、AGAguaugua、UUGgucagca、CAGgcaaguu、AAGguauaua、AAGgucugga、CAGguacgca、AGGgugcggg、AUGguaagug、AAAgugauga、UGCgugagua、AGAguaggga、UGUguaggua、 UAGguaggau、UAAgugagug、GCUguaagua、GAAguaagaa、UCGgugaggc、UAGguauuuu、AAGguacaca、AAGguaggua、UGGguagguu、ACAgcaagua、GAGguaggag、UGGgugaguu、GCGgugagau、CCUguagguu、CAGgugugua、CUGguaagcc、AAGgugauuc、CAGguagcua、GUUguaagug、AUGguaagca、AUAguaggga、GGGguucgcu、CCGgucagag、GUAguaugag、CGUguaagau、 UGAguaggca、UCAguaugua、GAGguaucug、AGAguauuuu、AAGguuguag、AGUguaaguu、CGGguaaguu、UCGgugcgga、UAGguaagua、GAAguuagau、GCUgugagac、CAGgcaggua、CAGguagggg、UAAguuaaga、AUGguggguu、UAGguaaguu、CUGguaaauu、CCGguaagga、GAGgcaggca、CAUguaagug、AAGgugccua、UUGguaggga、AAGguaaaca、CGGgugugag、GGGgugugag、 UCCguggguc、ACGguaaauc、UCAguaggua、CAGgucagcc、CAGgcggugg、CGAguaagcu、CCCgugagca、AAAguaauga、CUGguaagcu、CGGguaacca、CAGgucgcac、GAGguaggcc、UAGgugagcc、UAGguaggca、GCGgugcgug、AUGgugagua、GGGgugaggg、GAGgucacac、CAGguaggcc、CAAgugcuga、GUCgucuuca、CAUguaagaa、GUAguaagga、UAGguuugua、CAAguuagag、 AAGguagagu、AAGgugagau、AAAguaggua、ACAgugaauc、CAGgugugcg、CAGgucggcc、AAGguaguau、ACUgucaguc、UCUgcagccu、CGAguaagug、AGAguaauua、AGUgugagug、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、GAGguauuca、 AAUguaaagu、CAGguaacaa、UCGguaggug、AAAguaaguc、CGGgugcagu、GGUgugugca、UGAgugagaa、CACguguaag、GUGguuggua、GCAgccuuga、CGAgugugau、CAGguauaua、UAUguaugug、CCCgugguca、AUGguaagac、GAGgugugga、AGUguauccu、UGAguguguc、UGGguaaucu、AUGgcagguu、GAGguaagau、UCAgcagcgu、AAGgugggau、CGGgugcgcu、CAGgugucug、 AGCgugguaa, AAUgugaaug, UCGgugagac, UAGguaaagc, CUGguaaaag, CCGgugcgga, CAGguacuca, CAGguagcaa, GAAguugagu,GAGguggagg、AGGguaugag、UAGguaugcu、UAGgugagac、CAGguaauua、CGUguaagcc、CUUguaaguu、AAGguaacuu、UCGgcaaggc、GAGguucucg、GAGgugggcg、AAGgcaugug、CUGguauguu、UAAgucauuu、CAUguaauua、AAUguaaaga、UAGgugcuca、AAGguaaugg、GAGguacuga、UGGguaagua、UGGguaaaaa、AAGgugagcu、UACgugaguu、AGGgugagcc、CGGgugagga、 UGGgugagag、GGUguaagcu、CGGguggguu、CCAgcuaagu、AAGguuuguc、GAGguuagac、GAGguaccuc、UUUguaaguu、GAGguuagga、CAGguaggga、AGGguaauac、UGCgugugua、CCAguaacca、AGGgucuguc、UGGguaugua、GUGguaagcu、CAGguaaccu、AAGgugaguu、UAGguucgug、AAAguuagua、UGGgcaaguc、AAGgcacagu、GUUguaaguc、AAGguuugcc、CUUgcauggg、 GCGgugagua, GGGguaagcg, GCCguaagaa, GAGgucggga, UUGguauugu, AGUgugagac, CUGgugggga, AGAguaaggu、CCGguggguc、CAGguauucu、UGGguaacgu、UUGgugagag、UAGguacccu、GGGgugcguc、AAGgcaggag、ACGguacauu、GAGguaguua、CAGguauggg、UUUguguguc、CAGguacuua、AUGguauacu、AGUgugagcc、ACAguaacga、CUGguaccca、CAGguaaccc、GGAguaagua、GAGgugggug、ACUguauguc、ACGgugagua、CUGguaaugu、AAGguaucag、CAGgugcccc、 AGUgucagug、AAGguaggag、GGAguaugug、UUGguauuuu、CCUguuguga、UUUguaagaa、UAGguaacau、CAGguaagca、CAGgucacag、CAGgugugag、UAGguuugcg、CUGguaagaa、ACGguuguau、AAGguugggg、AAGgugaauu、GGGguuaguu、ACGguaaggc、CAGguuuaag、CUGguaaguu、GGGgugagag、UGGguggguu、GAGguuuguu、UGGguaaaug、CAGgcaggcc、CACgugcagg、 AAGgugagcc、CAAguaagug、CAGgucaguc、GCGguauaau、UAGguaaagu、UAGguggauu、GAGgucugga、UCGgucaguu、UGGguaacug、AAGguuugau、UGUgcuggug、UGUguaccuc、UGGguacagu、AUCgucagcg、CAGgucuugg、GAAguuggua、GAAguaaaga、UUGguaagcu、UAGguaccag、AGGguaucau、CAGguaaaaa、ACGguaauuu、AUUguaaguu、GAGguacagu、CAGgugaaag、 UGGguuguuu、GGGguaggug、CAGgugccca、AGCgugagau、CCAgugagug、AGGguagaug、UGGguguguc、AUCgcgugag、AGGguaagcc、AGGguagcag、UUCguuuccg、AAGguaagcg、UGGguaagcc、CAGguauggc、UGUguaagua、AAGguagaga、ACGguaauaa、CUGguacggu、GAGgucacag、UAUguaaguu、CUGguacgcc、CAAguaagau、CUAgugagua、CCGguaaccg、CUUguaaguc、 GUGgugagaa、ACCguaugua、GUAguaagug、UUGgugggua、CGGguacuuu、UGGguaaaua、AGAgugagua、AAGguagguu、AAGguaugcg、CCUguaggcu、ACAguagaaa、CCGguuagua、CGGguaggcg、GCAgugagug、GAGgugaguc、CUGguagccu、CAUguaugua、GAAguaacuu、GAAguaagau、AAGguuagau、AAGguaauca、AAUguaugua、UGAguaagau、AGAgugagca、GUAguucuau、 GAGguaauca、UAGguaugga、UAGgugggac、GAGguacaug、UGGguaaggc、CAGguacgcc、CCAguuacgc、ACUgugguga、GAGguaaguc、AUUguaggug、ACCgucagug、AAUgugaggg、ACUgugagug、UGGguguggu、AAGguuggga、AAGguuugga、UCCgugagug、CGGgugagug、AGAguaagcu、CAGgcaagcu、UAGguauauu、AAAguagcag、GAGguaaccu、AAGgugggca、AGGgugagua、 UGGguaaggu、CUUgucagug、UAGgugcgcu、GAGgcaaauu、AGGguaccuc、CAAgugcgua、AGAguaagac、GUGguaaaua、GAUguaagcg、GAGguaaagc、UAGgugagua、CAGguaacau、CCUguacggc、UAGguauguc、UAGguccaua、GAGgugaaaa、AAAguacuga、UUGguaagcg、CAGgcaagcg、UUUgcagguu、CAGguuuaua、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、UUGguagguu、UAUgugagca、CAGgugagcg、AAUguaauaa、AAAguaaggc、UAGguuuguc、UAGgugggag、GAGguaaguu、AAGguagccg、CAGguggugc、 UGAgucaguu、CUGguaggcc、CAAguaagga、CGGguaaggc、AAGgcgagga、CAGguaguuc、CAGguaagga、CCUgugagug、AAGguaaaug、CCGguaauua、CAGguaaguu、AAGgugguca、CAGguaccuc、AUCguaagua、CCGguacaua、GCGgugagug、GAGgugguau、CUGgugugga、GAGguaauuc、CAAguacgua、UCUguaagug、AAUguaagug、AGGgucuguu、GAGguacugc、AGGguaaggc、 AAGgcaagag, CAGguggguu, UAGguuagga, UGAguaagcu, AGAguaagag, AUGgcaggug, UAGgcaagua, AUGguaggua, GCAgcccgca,ACGguaaacu、AGGgugaguu、GUAguagucu、GUGgcugaaa、CAGguuaguc、CUGgugagca、UCAguaagug、AAAgugauug、UAGgucugga、GAGguguuuc、AAGguaaauu、CAUguacauc、AAGguuugaa、CCAgcaagug、UAGguaauaa、GAGgcaagug、CAAgugauuc、CAGgucgugg、GAAguaugcc、UCGgugcccu、GAGgucaguc、CAGgugagac、UUUgucugua、CAGguagaua、UGGguaucag、 UAGgugggcu、AUGgugagau、CAGguaacac、CCGguauccu、UAGguaagcu、UCAguacauc、UAGguuugcc、AUGguaagaa、UUGguaagac、CCGguuaguc、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、UAGguuaagu、GUGguaagaa、CAGguauugg、GCUguaaguu、CUAguaagua、UCGguaaaua、CAGguaacuu、CCUgugagua、CAGguuauau、CUGgugaaca、AAGguauaaa、GAGguaagca、AAGgugaagc、CAGgugaguu、 UUUgugagua、CUUguacgcc、AGAguaagug、UGGguaggug、UGAgcccugc、UGUguaugua、AAGguagagg、GAGguggggg、UAGguaauuc、AAGgcauggu、AGAguaagca、AAGguaggaa、CAAguaagua、ACUguaauug、CAGgucugug、UCGguaccga、CUGgugagag、AAGguuugcu、AUGguaccac、UAAguuaguu、CAGguaggac、AGAgugaggc、CGAgucagua、CAGgucugag、GAGguggugg、 ACGguauugg、GCUgcgagua、CUGguaagug、GUGgugagau、GGGguuugau、UCUgugagug、CUUgucagua、GAGguaaaac、UCUguaagau、CCAguaaguu、CAGguaaagu、GCGgugagca、UAAguaagag、CUGgcaggug、GAGguaaggg、UGAguaaguu、GAGgugagac、GCUgucuguu、AAGguaacaa、GAGguaacgg、CUGguauucu、CAAguaacug、AAGguggggu、UAGguauggc、CAGguauuuu、 GUGguaaacu、GAGgucugag、CUGguaaggu、CAAguaaguu、AAGguagacc、GAGgcgagcg、CUGguaaaua、UGUguaagcg、CAGguuaggg、GGGgugagga、ACAguaugug、CCGgugggga、GAGgucagug、AGGguaaggu、ACAguaagua、GGUguaaggu、GAGguaauaa、CAGguauucc、CUGguauaaa、CCGgucugug、CAGguaacug、GCAguaagua、AAGguagggg、CAAguccacc、CAAguuggug、 CAGgugcggu、CAGguaaaau、ACGguaagga、UGGguaauaa、UAGguaagug、CCGguagguu、AGAguaugga、CUCgugaguc、AAAgccggug、UUGguaauuu、GAGguaaaag、CCUgugugag、AAAguaagga、UGAgugagug、AAGguacaug、CCGguaaaug、CAGgugaagc、CAGguacccg、GAGguaaggc、UUUguauguu、CAGgugcucc、UCGguagguc、CGGgugaggc、AAGguaauua、ACUgugaguc、 AAGgucagca、GUGgugagug、CAUguccacc、AAGgugaccc、CGGguuagua、GCGguaguaa、GCUguaggua、CCUguugagu、UAGgucuggc、GAUgugagcc、CUUgugagua、CUGguguguu、GAGgcaugug、CAGgcaagag、UUGguaagaa、GAGguguggg、GAGguauuuu、CAGguaguaa、AGGguaagac、UUUguaggca、AGGgugagau、GAGguuugua、AAGgugagug、GAGgugggag、AAGgugagaa、 CUGguaagag、AUAguaaaga、GAUgugaguc、AAGgugcagg、CAGgucuguc、GAGgugauuu、CAGguuggcu、CGGguauggg、AUGguccauc、CCGguuggug、GGAguaaguc、AAUguaagga、CAGguuuguu、UAGgugugua、UAUgucuuug、ACGguacuuc、AAGgcacgcg、CUGguaaacc、CUUgugggua、UGAguaaguc、CUGgugggug、GAGguggaga、GUGguggcug、GUGguaagug、AACgugagua、 GAAgcuguaa、CGGguaucuu、CAGgugucag、AAUguacgca、CCGgugggua、UGGgugaggu、AAGguauguu、CAGguauguu、CAGguuugcu、UUGguaaguu、CAGguaguug、CCUgugaaua、GCUgugugug、CAAguaauuc、AGGguaaugu、GCUgugaguc、ACCguaaguu、CGUguaagua、GGGguaaguc、AAUguaugau、AAUgugauua、UCAguaagaa、CAGguccguc、GAAguauuga、UUGguaagga、 CAGgucgguu、UAGguuagug、ACGguaaaac、AAGguagguc、UACgugagua、UUGguaagca、GCGgugaguc、GAAguaaggg、CGCgugaguu、CAGguacccc、UCUguaagac、GAGgugggca、AAUguaagac、CAGgcaaggg、CAAguaacua、AAAguuuguc、CAGguacugu、AAGgucccuc、UCGguaaguc、UGGgugagug、CUUgugagau、AGAgugagcu、UAAgugggga、UAGguaggga、CAGguuagcc、 AGGguaauca、AAGguucagc、UGGgugggug、CAGguuguga、AAGguaagug、CAUgugcgua、CCGguauauu、ACCguaugug、CAGguauagu、CAGguauuac、CAGgugcagg、GUGgugagcu、AAGguaacau、CUGgugaugg、AUGguaaaug、CCGgugagca、AAGguaaacc、AAGguacugg、GCGgucagga、CUGgucaggg、AAAguacguu、AGAguagguu、AGGguaagcu、AUUgugagua、CCGgccacca、 GAGguaacuu、GAGguaugaa、CAGgucagac、UAGgcgugug、AGGguaaguu、CAGgcaugag、CAGguaacgu、CAGgcgagca、UAGguauggu、AGAguaggau、CUGguuucaa、GAGguaaacu、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、 CAAgugagac、GAGguacugg、GAGguguagu、GAGguguccu、CAGgugcgua、AGUgcccuga、AUGgugaguc、UGUgugugua、CAGguaugcu、CUGguacagu、UUGguacgua、UCUguacgua、UAAguaauuc、CACguaugug、CAGgcaagua、UCGgugagug、GGUgugaguc、UCUguaagcu、AAGguucaga、AGGguacuuc、GCGgcagguu、GAGgcccgug、CAGguauaaa、AUGgucaagu、AAGgugagua、 GUGguuu, AGAgugagga, GAGguaugac, UAGgcgugag, AAGguacucc, UGAgugagga, GAGguaugau, GGGgucggua, ACGguaugca,CAGguaccac、UAAguaccug、AGGgugggcu、CUGgucuguu、UAGgucagag、AAGguguguu、CUGgucagug、AAGgugggac、GUGguaguag、CUAguuuagg、CCCgccccau、GCUguacugc、GAGguaauau、UAGguuggug、AAGguccaac、UAGgugagga、GUGguaaguu、AGUgugagag、AAUguacaug、UUGgcaggug、UAGguuauug、CAGguacuga、GCGguggguc、UGUguaagau、GAGgugagua、 GCAgccccgg、CAGgugcuaa、AGUguaagag、CAGguacauc、CAGgugggac、AGGguaaaua、UAAguaauua、CAGguaaccg、AAGguuugca、UAGgugguuu、CAGgugaccg、UGUguaagcu、GGAgugaguc、AGGguaggag、AGGgugggug、AAGgucugag、GAUguaauau、GGGguaauua、UAGguaggua、GAGgcaagua、GAGguaagga、UAGguacuac、UCGgugggug、AAGgugugga、CAGgucugcc、 UAAgugagcc, GAAguaaguu, GAAguaagcc, UAGgugcgac, GAGguauggc, GCAguaagaa, CAGgugugga, U, UGguaacgu、GCUguaaaaa、UUGguuagua、AUAguaaggg、UUGguacuag、CGGgcagccg、CAGgugcugg、UAUgugaguu、CAGgucuggg、UAAguaagaa、AAGguuauua、AGAguaaagc、AGAgugugag、UAGgugcgag、CAAguaaacg、AAGguacgua、CUGgugagua、CCAguaugua、UUGgugagug、UGAguaagua、GAGguuagca、GUGguaagcc、CUGguauggc、AAAguaacac、CAGguacuaa、 UCUguaaguu、GAGgugaggg、ACUgugggua、GAUguuugug、CAGgugucaa、CAGgucacca、CCGgugagua、UUGguaaaua、CAGguggggg、ACUgcaggug、UAGguauguu、GGAgcaagug、UCGgugccuc、CAAguaacuu、GAGguaacca、CAGguaauau、GGAguaagaa、GAGguaccuu、AGGguaagga、CCUgugaguc、GAGguaaugg、AUGguguguc、GGGgugagua、AGGgucaggu、UGGguaaggg、 AGGguagguu、AUAgugaguu、CCCguaggcu、ACAguaugua、GACgugugua、GCGgugagga、CAGgugaccc、UAAguuuagu、ACAguugagu、CGGgugaggg、CAGguggauu、CGGguagagg、UAGgugcgug、GGGguaagaa、GAGguggggu、CACguggguu、ACGguaauug、AGAgugaguc、UUGgcuccaa、AAGgugaugc、AAGguugguc、AGCguaaguu、AUUguaugua、UCAguuaagu、CAAguacgug、 CAGgugcgug、CAGguaggua、AUGguggggu、AUGgugaguu、CAGguaauca、AAGguagggu、CAGgccaagg、GUGgugagag、AAGguuggug、CAGguacucu、UAGgcaugug、UUGguaccuu、CUGgugugcc、ACAguugcca、UUGguaauau、GAGgugcaug、UUGguuugua、UUGguaagug、UGUgugugug、GUGguuugua、GCGguacaca、AGAguaugcu、UUUguaagua、UCUgugcggg、AAGgucagug、 GAGguaggaa、GCGguuagca、AGGgugaggg、GAAgugagua、CAGgugacag、AAGgugauua、GAGgccagcc、GAGgucuccu、UAGguauuac、CAUguaagag、CUGguagggc、GAAguaagua、CGGguaagug、CAGguaaucu、GUGguaggua、CAGgugggua、AAGgccagug、AAAgugaauc、ACGguuacgu、AUGguaggaa、CGGgugagac、GAGguuggaa、UGGgugagcc、CCAgugagua、CUAguacgag、 CAGguaugac、GCUgugaggu、CUGguaugaa、GGUguacgac、CUUgugagug、GUGgugagca、CUGguaacuu、CAGguacuau、AGGguaaggg、UUGguuaguu、GGUguaagca、UCGgugagga、UGGguaaaca、UCGguacgug、UAGguagcag、CUGguaaggc、GUGguaagga、UAAguaagca、GAGguuccaa、CUGguaugga、GGGgugggua、CAGguuuccc、CAGgucucug、GAGgugagga、CUUguggguu、 AUGgugagac、CAGgugaagg、GCGguagggg、GUUguuuccc、AAAgcaucca、GUGguagguu、AAGgugugaa、CAGguacagu、AAGguaccaa、UUGguaauug、AAGgugcuca、AAGguucaac、CAGguuuaca、GCUguaagug、AGGguauguc、GAGgucgggg、AAGgugccug、AAGguaaaaa、GUGgugaguu、UAGguaagaa、AGGguauccu、GUGguaauau、UCUguaagua、UGGguaugga、AUGguaugga、 GACgugagcc、CUGguuuggc、AUGguauauc、AAAguaaacu、AGCgugagug、CUGguauaga、CAGgugggga、AGAguauguu、UAGguacuug、GCAguaggug、AGUguauguc、AAGguuaagc、CUGguggccu、GAAgugaguc、UUGguguaag、CAGguaagaa、CGGgucucgg、GAGgugcaca、CUCguuaguu、AAGgugauca、UAUguaagaa、GAGgugcuug、CAGgugguca、ACGguaaguc、ACAguaaugu、 CCUguaaggu、GAGguuaagu、UCGguaugug、UGGguauguu、AAGguauuac、CAGgugaggg、UUGguaaaca、AAGguagugu、GAGguguggc、CAGguacgga、AAGgucauca、CAAguaggca、CAGgugaaac、CAGguacugc、AAUgcaagug、CAUguaauuc、AAGguaugcu、CUGgugaguu、CAGgugguuu、UGUgugagua、AAGgucggug、AUGguaaauu、AGGguauuac、AGUguaugga、AACguaagau、 GUGguaaggu、ACUguuagua、CAGguaucag、AAGguuaguu、CUGgugagcu、UUGgugagcu、UGUguacgua、GAGgucagcc、GAGguagaau、AAGguaugag、UAGguauuuc、UGUguaacac、AGUguaaggc、GAGgucugcu、AAGguuagca、CAGguaaaug、AACguaagcu、CAGgucugca、CAGguauugu、GUGguaauuc、GAGguauaug、GCCgugagcc、GAGguaagag、UGAguaugua、CAGguaaggg、 GAGguaaauu、CAGgcaacuu、UGUguaaguc、CAGgugcgcu、CGGguaaacc、CCGgucaguc、UAGgugggcg、GCGgucaguu、GGGguggguc、AGCguaauag、ACGgugaguc、CUGguacuug、CAGguuggua、AGAguaugug、CUGgugggua、GAGguggcuu、AUAguauuga、UGAgucgucc、CAGgugcucu、UACguaauau、GCUguccuga、CAGgcugcac、CUGgugcgcu、GCGguaagaa、UAAguuacuu、 GAAgugagug、UAGgcaaguc、UAAguaaaua、ACGgugagug、CAGguagguu、GGGguauaac、GUUgugaguu、CAUgugagua、GAGgugcauu、AAGguuugua、UCGguaaugu、CGAguaaggg、GAGgcacgga、AGGgugugga、CAGguauggu、AAGguagaaa、CAGgugccug、UGGguauaug、UGAgugagac、UGGguaauuu、AUGguaaaua、AAGgcaaagg、AGUguuuguu、AUGguauugg、CUGgugaggc、 UUGguaaaau、ACAgugaguu、CAGgugcugu、GAGguuaaga、AGAguaagaa、GAGguccgcg、GUGgugagga、CAGgugagcc、CAGgugacau、AUGgcaagcu、UCGguaauau、CAGgcaacaa、GGGguaggga、CUGgucucgc、UAGguaacga、CGGguaaggu、UAGguaaugc、CAGgcaagaa、ACAguaggua、CAAguaugag、GCUguucgaa、AAGguuaugc、GAUgugaguu、CAGguggaga、AGAguuaguu、 UGAgugugcg、GAGguacagc、CAGguaagac、CAUgugcuuu、AGGguguguu、ACAguuaagg、ACAgugaggg、GAUguauacc、UUAguaagcu、CAGguaagau、AGAgcugcgu、GAGgcaaguu、GAAguaagug、AAGgugaaaa、AAGguaccua、GAGguaucag、AUGguaugua、AAGguaugaa、UUGgugagcc、AAGguuagga、AGGguaugua、CAGguaccga、AGAguaaacu、AAGgugcaua、AAGguaaugu、 CCGgugugug、AGGguaaauu、GGGguuuggc、CAGguacacg、UUGguaacca、GAGgucaggu、UCUguuggua、CAGguuaguu、UUGguauguc、AAGgugcguc、AGGguaagaa、UUUguaagcc、AAGgucaggu、CUGguaaacu、UCGguaauuu、CUGguaggcu、GAGgucugua、GAGguacuuu、CUGguaaagg、CGGgugugug、CAGguguggu、UCGguacguc、CAGgugccag、GGGgugagaa、ACAgcuagua、 AAGguauagc、CUGguaggag、GCUguacgua、AAGguaaagg、CAAgcacgag、CUAguaagac、CCCguaagcg、CAAgugugag、AUGguaaggg、AAGgugaggg、CAAguaggua、GGUguugcug、GAGguacugu、UAGguaagau、CAGgugcgaa、GAGguccagg、UUGguauaca、GGAgugagua、GAGgugagau、AAGguggggc、CAGguaaacg、UCGguaacuu、CAGguaaauu、GAGgugcgca、ACUgugagua、 ACGgugugac, GUGguaaguc, CAGguaggca, CAGgucagca, GUGguaugug, AAAguaucug, CGGguaugua, AAGguaauaa, GAGgugggga,GCUguaggug、GAAgugaguu、AAAguauuua、UAUguaagua、ACGguaugag、CUGgugagug、AGAguaaaau、GCUguauggc、AUGguaaacc、GCAguaauaa、UAAguauuua、AAUgucagug、AUUgcaggag、CCGguaagaa、AAGgcaaguu、GAGguuuguc、AAGguaacug、AAAguaugag、GAUguuagua、CAGguggguc、AAGguaccga、CCAguaauua、GUGguaugcg、AUGgugcgcu、CAGgucuaug、 AAGguauuua、CUAguaagau、AGAguaauuu、GAGguaacgu、AAGguagcca、CUGgucccgg、GAGguccuuc、ACGgucaccc、AAGguaauac、CAGgugcaug、AUGguaauag、UUUguaacac、UGGguaugau、CAGgcccccc、AGAguaguaa、AGUguaagaa、GAAguauguu、CAGgugugca、UUGgugaggg、UGGguugguu、CAGguacgua、GAGgugcggc、UCUguacggg、CGGgugcgug、UACguaagug、 CAUguaagga, CAGgugacgg, GAUguaugcu, UCUgcaauuc, UGAguaaggc, GAGguauauu, AGAguga, guu、AAGguaagcu、UAGgugaagu、CAGguuagua、UAUguaagug、UUGguggggg、UGAgcucaaa、UCGguaugua、UAAguaugcc、AAUguaagua、CAGguuugca、ACGgugagag、CAGguguuuu、GUGgugagcc、AGGguacaua、UAGguaaccc、GUGgucagua、CUGgugagcc、CAGgugcuua、AUAgucguga、AUAgugagug、GAGgucaaaa、CGUguagcuu、CAGguguuug、CAGguuggac、 CAGguaagcu、AGGgucagaa、CACguauguc、CACgugagug、GGGguacgga、AAGgcaggac、GAGgugaagc、GAGguuugaa、CAGguaagug、CAGguaacca、CAGguacucc、AAGgugcuuu、GAGguaaaua、GAGgcaggug、GAGguucgga、CAGguauuug、CAGguaaaua、CAGgugaugu、CAGgugauac、GAGgugaggc、AGGguggggg、UAAguaaguu、UGGgugaaca、UAGguacugc、CAGgcuccug、 AGGguaggca、CAGgugcccg、GAGguacauc、AGGgugugug、AAGguaguaa、UGGguaugag、GGGgugugug、CUAguaggug、GAGgcaagga、AAGgcaagac、AAAgugcggu、AAGguugguu、GAGguuaaug、UUGgugaguc、UCGguuagcu、GCAguaagca、AAGgcaagca、ACAguaagcu、GAGguaacag、AAAguacgua、GAGguaauac、UUGguaggug、CUGguuaguc、GAGgugacgc、ACAguaagga、 AAUguacuua、GGGguacagu、CGUguaugug、UCCguagguu、GAGguggucg、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、AUUguaauaa、CUGgugaaua、AAGguuuaaa、CCUguacugu、GCGgugagcg、AAGguaaucc、UAUgugagua、CCCgugagug、CAGgugcaga、CAGgucaguu、CAGguaggcu、AAAguaagug、UAGguugguc、CAGguugccu、AAGguaugga、GGUguggacg、AAAgugagaa、 AGGgugagag、GAUguggcau、UCGguaaggu、GAGgugcguc、CGGgugaguc、AAGguacggg、GAGguucuug、AAGgugcuug、UAGguaugua、AUGgucagca、CGGguacuca、AGGgugagga、AUCgugagua、UCAguaagua、UAGguaaaua、AAGguaauug、GAAgucagug、CAGguacaaa、AAAguuaauc、AGCgugagcg、CCGgcuggug、AGUguaauuu、UGAgccacuc、GGGgucugua、AUGgcauguc、 CGGguaaaga、AGGguagcau、CGGguaggag、GAGguucgug、UAAguuauuc、UAUguaagau、AAGguaguuu、CAGgugguau、GUGguaauga、AAGgugauuu、CAGgugaagu、GUAguaauua、AUGguuggug、CCAguaagug、UAGgugagag、AUGgugaggc、AAAguuagug、AAGgugccuu、UAGguaugag、CAGgugugac、CUGguggguu、AUGguaagga、UCUguaagaa、UCCgugaguu、AAAgcaggua、 UAUgugagug、CAGguggagg、CAGguuagac、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 CCUguggug. ,

[0253] 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, AGAguuu, 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、CGAgucgccg、 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、CGGguucagg、AGGguacgac、UCGguaagaa、AGGguuggca、AAAguacagu、UAAguuaagg、AUGguaaugu、GUGguuuuac、AGAguaacaa、AAGguagccc、GCGgugaggc、AUGguucagc、AAGguacuua、AAGguccgug、UAGguaagcg、AUGguaccuu、 GCCguggugg、CUGgugcguc、CAGguggaaa、AAAgucugua、GAGguaaccc、AGAguauggg、UAUgccccug、AAGgugccag、ACGgugcggc、AGGguacuga、AGAguaagcg、CUGgcaaggg、CCAgugugug、GAGguagacg、CGGgugcggg、GAUguaagcu、AUUguauuua、UGCgugagug、CUGgucuaua、GAGgugcuag、GAGgugccau、CAGguacguc、GAGguucagc、AACguaagaa、AGAguaguac、 AAGguaacgg、UAGgugugac、CCGguaauag、CAGguaccag、UUUguaauug、AAUguacgaa、CAGguaauga、AUCgucaagg、CUGguagaug、GGGgugcagu、AGUgugagaa、GGGguuuuau、CCUguccccu、AUUgugaagu、AAGguaaacg、UACgucgugg、AAGgugccau、GGGgucccag、UAUguauggu、CGGguaauua、CGGguacucc、CAGgugacuu、AGUguggguu、AGAguauggc、AAGgccaaca、 AAAgcaagua、UCAguagguc、GUGguggcgg、CAUguauccu、UCGgugagcc、AUAguugggu、AAUguuagcu、AUGgugaaug、CGGguaaugu、UCUguaggug、CCGgugaggc、UGAguccacu、CUAguaagag、CGGguggggc、CGAguaagca、UGUgccaauu、UCGguaagcc、UAUguaggug、UUGgugggcc、GAGgcugggc、AGAguaacuu、ACGguagguc、CAGgcccaga、CCGguggguu、AAGgugacgg、 GGGguacagc、CAUguaaguc、AUUgugagaa、UGUguaagga、UUUguaagau、AGGgucauuu、UGGguuuguu、CGAguaagcc、GUGgugugua、AUGguauaac、UGGguacgua、AAAguagagu、UCGguaacug、AGAguaauga、AUGguggguc、AGAguaauau、CAGguacugg、UAAgucaguu、GCGguagaga、AAGgugaugg、ACAguauguu、GAUguacguc、UAGguuucuc、GAGgcauggg、AUAgcuaagu、 GUAgucugua、AAGgugaacg、GUGguggucg、GAGguugauc、UGAguggguu、ACUguacgug、CUGgugacug、CAAguuaagc、GAGguaccca、AACguaacuu、CAGguuacua、AGAguuaguc、UGGgcacguc、AGUguauggu、AAGguugcaa、CAGguuguua、AAGgcauccc、GAUguaaggc、AGGguacggg、GAGgucaaag、CAAgugagcg、AGAguaaucu、UCGguagcug、AAAguaguag、CAGguucguc、 CGUguaugaa、AGUguaaaaa、AAGgucucac、UAGguggagc、UGAguaggug、AGAguaugcc、GAGguugcau、CAAguaagag、UCUgugugcc、GAGgugaugc、GGGgugauaa、CCCgugagcc、AGAguaacug、GCGguaagua、AGAguacauc、UCGgucuggg、UAAguaucuc、GGCguagguu、AGAguacgcc、GAUgucuucu、AGGgcaaggu、CGAguaugau、AUGguagagu、CAAguacgag、UCGguaugau、 CCGguguguu、AGGgucugug、GGAguaggcu、AAGgucuaug、GCAgugcgug、UGGgugagaa、AGGguaaagu、GAGguaggac、CUAguaagca、UUAguaggcu、CUGgugggau、CUGguuagua、AAGguacgug、CGGgugagau、AAGgugcaug、AAUgugggcu、CAGguugacu、CAGguuacag、GCGguaacau、AUUgucaguc、CAAguauaca、GAUguccgcc、AAGgugcgga、AACguaagag、UGGguuggua、 CAAguguaag、GUGguaacgu、CUGgugauca、AGGguggggc、UCGguaaaga、CAGguacacc、CGGguaaggg、CAAguuugcu、ACAgugcgug、UUGguauggg、GAGgcucauc、CUGguaauag、AUGguggaua、UCAgugaauu、AAUguaauua、GCAgucuaaa、AAGguauucu、GAGgucauca、UGGguccaug、AGAguuugua、AGGguagacu、AAGguaggac、UGUguguuga、UCAguacgug、AUGgucucuc、 UGAguuagua、UGAguaaagu、GAGgugaccg、GAGguauauc、CAGgugccau、AGAgugguga、GUUguaagaa、AGAguaaaua、AGGgugaagg、CUGguagauu、GAGguucagg、AGGgucuuca、CUGguaaccu、ACAguacuga、AGAguggguc、AUGguaugag、AAGguuauau、AGAguauagu、AAAguaugaa、UAGguggcua、ACCguauggg、AAAguauaau、UUUguauggc、GGGgucgcgu、GUGgugguuu、 CAGguuugac、GGAguaggcg、GAGguacccu、AUGgugugca、GUGguuggug、AAAguaugcu、UAAguuacau、ACAguaugag、GGAguauguu、UUUgugagaa、AAUgugcguu、CAGguagagu、AUGguguuaa、CAUgugcguc、AUAguuggau、GAGguacgua、GUUgugagaa、CAAguacauc、GAGguaguuu、ACUguacaga、CCGguuguga、UGGgucagug、GUAguaagaa、GACguacuuu、AGAgucaguc、 UAGguuaguu、AGGgcagcag、AAGguccuac、AAUguaauug、CAGgugcggg、CUGguaaugg、CAAguagccc、GAAgucaguu、ACAguaauug、UUAguuagua、CCUguauuuu、AUCguaagaa、CCAgugagca、GAAguaaggc、UGAgugggua、UCAgugguag、UCUguacagg、CGAgugagug、UCCguaugug、CAUgccguuu、AAAgugacuu、AGAguaggca、GAAguaagag、CAGgcagguu、UUGguagagc、 AAGguggaaa, GAGgcagguc, AUGguacgac, AGGguaggaa, AGGguaggua, UUGguaaggu, AUGguacaga, CAGguagagc, UAGguaaggu, GGGguuagag, AAGguaucaa, GAGguagccc, CAGgugccuc, GCAguaagag, ACGguagagu, UGGguaaugg,CUGgucaguu、GUGguacauu、AAAguagguu、AAGgccaaga、CGGgugggca、ACGguccggg、CGAguaugag、CUGguaugcc、GAGguggaug、CAGgccuuuc、AAAguacauc、AAAguaauca、GAGguaacug、CUGguaaaga、CGUguaagca、UGGgcaagua、GCGguggcga、GAGguggccg、AUUgcaugca、ACGgugacug、CAGgucagau、AGAguaacuc、UGAguaacag、AAGguacccg、AGGguaggcu、 GGGgcaggac、CCUguaagug、AUUguaagug、ACUguacgag、GUAguagugu、AGAguaugag、UCAguguggg、UGGguauaua、UAGguagcua、GGGguaaaga、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、CAGgcagcca、AAGgucacug、AAGgucugac、UAGguuccuu、CUGgugcuuu、UGAguuggug、UUGgugggau、 UGAguagggu、UCGgugaggu、AAAguaaaga、AAGgcaaguc、CGGguaaagc、AAAguuaguu、UUAguaagca、GAGgucacau、UAAgugguau、UAGgugcuuu、GGAguaggca、UGAguaagga、CAGguggagc、GAUguagaag、AAUgccugcc、AUGguaaggc、UGGguaauau、CUGguaccuc、CACgugagcc、UGAguuugug、CCGguagugu、AAAgugacaa、GAAguggguu、CAGgugcagc、GAGgugggcc、 UAUgugcguc、GGGguacugg、CUGguagguu、UUGgcauguu、AAUguaauac、UAGgccggug、AGAgucagua、UAAguaaauc、CAGguuccuc、UAGguacgau、AGAguuagug、GCAguaagug、AGGgugguag、GGAguaaugu、GAUguaaguc、CCAguuucgu、AAGguucggg、AUGguggagu、AAGguaccgg、GAAgugcgaa、UGGgucaguu、AAGguguaga、UGGguaggcc、CCAgugaguc、AAGgucacuu、 AGCgugaggc、UCCgugguaa、AGAguacuua、GGGgucagau、AAGguggacc、AGAgugagcg、AGAgucagau、UAAguauuac、AGAguauuuc、AGAguucagc、AUGgugaagu、UAGgugaucc、GGAguaagau、UAGguaccaa、AGAguugguc、GAAgugagac、AUCguagguu、GAGguacgcu、ACGguaaggg、CAGgcauguc、UUAguaagau、UGAguagguu、AGGguacgaa、ACGguauguu、AGGguacugu、 UUGguaugga、UAAguaacug、GCGgucagcc、UUUgugaguc、GUGgucagug、CUGgucugua、GAGguucuua、AUGguacuga、AAUgugcuuu、AGGguggcgu、CCGgcaggaa、CAUguggguc、UUGguuuguu、CAGguucugu、ACGguaagcg、CUGgucagua、UCAguaggcu、UGAguaggac、CAGguuuuaa、GAGguguccc、AGGguggguu、GUGgugagac、CACguaggga、GUGguauuuu、GAGauauccu、 AAGgugaaca、UAAguagggc、CUGgugcggg、CUGgucaaua、AGAguaaaaa、AAGgugcagu、CGGguaagca、AAAgugagcc、AUGguaauca、GCAguacgug、AUGguacaug、AAGguuaaga、CGGguaaaug、GAGguucgca、GAGgcucugg、AUGgugggac、AACgugguag、AAGgugauag、GGGguuugca、CAUguaaggg、UCAguugagu、AAAgugcggc、AGAgugagcc、AUGgcaagaa、ACAguaaggu、 AAGgucucua、GUGguaaaaa、AAAguaggug、UAGgugcacu、GUCgugguau、CAGguauagg、UGAgugagag、ACUgugagcc、AUCguuaguu、UUUguaccaa、UGGgugagau、AGAgugagaa、AGAguagggg、AGGgcaagua、CGGgucagua、UUGguaugcc、CGGguuagau、GGGgugaagu、CCCgugugaa、GCAguuugga、UGCguaagac、AGAgucugua、CACgugagca、AGGguaaaag、CAGgcugggu、 GAAgucuuca、AAGgcaaaaa、GUAguaaaua、CUAgugagag、GAAguuucug、CCUguacgua、GAGgugcgcg、AAGguguaaa、CCAguauguu、CCGgucagcu、AUGguuccug、CAAguuaaau、AGAguaggcu、AUGgugggca、GGAguaagac、AGGgucacga、UAGgugauau、GAAguaaguc、CGGguaagau、CAAguagcua、UGAguaaaau、GUCguacgug、AUGguacgua、CAGgucucgg、GAGgcauguc、 AGAgugggau、GUGguuagag、UGGgugguga、AAGguuaaac、CUUguuagcu、AAAguaggaa、UAGguuguau、AGGgugcgcc、AAGgugggcu、UAAguaucug、AAGguaacgu、AUGguggggc、CAAguacacg、GGCguaagug、AUAguaggac、AGAgugaggu、UUUguaaaaa、GAAguuugua、CUAguaaucu、AAGguuuuua、GAGgugcguu、UAGgcgagua、ACCgugagua、CAGgucccga、AUGguacugg、 UGAguucagu, AAUguguggu, UCCguugguu, CAGgucagag, CAGgucccua, UAGguagacu, CAAguuaagg, GAGgugugcg, GAAgcugccc,CGAguacgug、CGGguaggua、UUGguauuga、AUUguaugau、UUGguaugaa、GAGgugguca、GCUguaugaa、CAGguguugc、CAGguaaaac、AUAguaaggu、CUGguuagag、AGCgugugag、AAGguuaucu、CACgugagua、AGGgucagua、GAGguauaau、CAGguuauuu、AGGguggacu、AUUguaauuc、UUUguggguu、AUGguacgug、AAGguguucc、CAGgugacgc、GAGguacuaa、ACAguucagu、 GAGgucacgg、CAAguaaggc、AAGguuuggg、AAAgugggcu、GCGguucuug、GAGguggagc、UGAgucagug、CAGgucaagg、AGUguaagcu、GAGgcagaaa、AAGgucacac、GAAguagguu、GUCguaaguu、AGAguaugca、CCUgugcaaa、ACGgugaaaa、CAGguacgaa、CAUgugagga、AGCgugagua、GGUguguagg、AACgugagcu、GAGgugaacu、AGAguucagu、AACgugugua、CAGguugugg、 AAGguacuag, UCAgugaaaa, AAUgucuggu, ACGguaaaau, CUGguguaag, GAGgugcgaa, AGGguuuucuc, CAGguagccc、AUUguauugg、AUGguacuua、GAGgcccgac、UCGguaagac、CGGgcuguag、UAUgugugug、UAGguagaaa、GUGgucauua、UAGgugaaag、ACUguaauuc、GCAguacagg、UCGgugaguc、UAUguaggga、AUGguauguc、GUGgugugug、CUGgugaccu、AAUgugaaua、UAGgucucac、GAGguuauug、UGAguaggcu、CGGgcacgua、GCAguaaaua、CCGgugagag、UAAguugguc、 CCGgugagcc、AAGguuguca、CUGguauuau、GGGguauggg、AAAgucagua、UUUguaugua、UAAguacugc、CAGguaccaa、GAAguucaga、AUGgugcggu、GUGgugaggu、UGAguaagcc、UAUguaaggg、GUGguggaaa、GAGgugauug、GGAguuugua、AAGgucacga、GUGguagagg、UAAguauauc、AAGgugucca、UAUgugguau、GAGguacaau、AAGguggggg、GGAguaggug及びUAGgugacuuがincluded.

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

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

[0256] In one embodiment, the gene sequences or splice site sequences provided herein are associated with mental retardation disorders. In one embodiment, the gene sequences or splice site sequences provided herein are associated with mutations in the SETD5 gene. In one embodiment, the gene sequences or splice site sequences provided herein are associated with immunodeficiency disorders. In one embodiment, the gene sequences and splice site sequences provided herein are associated with mutations in the GATA2 gene.

[0257] In some embodiments, compounds of Formula (I) described herein interact with (eg, bind) splicing complex components (eg, nucleic acids (eg, RNA) or proteins). In some embodiments, the splicing complex components are 9G8, Al hnRNP, A2 hnRNP, ASD-1, ASD-2b, ASF, BRR2, B1 hnRNP, C1 hnRNP, C2 hnRNP, CBP20, CBP80, CELF, F hnRNP , FBP11, Fox-1, Fox-2, GhnRN, HhnRNP, hnRNP1, hnRNP3, hnRNP C, hnRNP G, hnRNP K, hnRNP M, hnRNP U, Hu, HUR, I hnRNP, K hnRNP, KH-type splicing regulation protein (KSRP), L hnRNP, LUC7L, M hnRNP, mBBP, muscle blind-like (MBNL), NF45, NFAR, Nova-1, Nova-2, nPTB, P54 / SFRS11, polypyrimidine tract binding protein (PTB), PRP proteins (e.g. PRP8, PRP6, PRP31, PRP4, PRP3, PRP28, PRP5, PRP2, PRP19), PRP19 complex proteins, RBM42, R hnRNP, RNPC1, SAD1, SAM68, SC35, SF, SF1 / BBP, SF2, SF3A complex body, SF3B complex, SFRS10, Sm proteins (B, D1, D2, D3, F, E, G, etc.), SNU17, SNU66, SNU114, SR proteins, SRm300, SRp20, SRp30c, SRP35C, SRP36, SRP38, SRp40, SRp55, SRp75, SRSF, STAR, GSG, SUP-12, TASR-1, TASR-2, TIA, TIAR, TRA2, TRA2a / b, UhnRNP, U1 snRNP, U11 snRNP, U12 snRNP, U1-70K, U1- A, U1-C, U2 snRNP, U2AF1-RS2, U2AF35, U2AF65, U4 snRNP, U5 snRNP, U6 snRNP, Urp and YB1.

[0258] In some embodiments, the splicing complex components comprise RNA (eg, snRNA). In some embodiments, compounds described herein bind to splicing complex components that include snRNA. The snRNA can be selected from, for example, U1snRNA, U2snRNA, U4snRNA, U5snRNA, U6snRNA, U11snRNA, U12snRNA, U4atacsnRNA and any combination thereof.

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

[0260] In one aspect, the compounds of formula (I) and pharmaceutically acceptable salts, solvates, hydrates, tautomers, stereoisomers and compositions thereof are conjugated to target nucleic acid sequences (e.g., DNA, RNA). or pre-mRNA), for example modulating (e.g. increasing or decrease). In one embodiment the splicing event is an alternative splicing event.

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

[0262] In another aspect, the present disclosure provides spliceosome components (e.g., major spliceosome components or minor spliceosome components), nucleic acids (e.g., DNA, RNA, e.g., pre-mRNA) and compounds of formula (I) or A method of forming a complex comprising a pharmaceutically acceptable salt, solvate, hydrate, tautomer, stereoisomer or composition comprising a nucleic acid (e.g. DNA, RNA, e.g. pre-mRNA ) with said compound of formula (I). In one embodiment, the component of the spliceosome is selected from U1, U2, U4, U5, U6, U11, U12, U4atac, U6atac micronuclear ribonucleoprotein (snRNP) or related cofactors. In one embodiment, the component of the spliceosome is Mobilized to nucleic acids.

[0263] In another aspect, the present disclosure provides a method of modifying the conformation of a nucleic acid (e.g., DNA, RNA, e.g., pre-mRNA) comprising: A method comprising contacting a solvate, hydrate, tautomer, stereoisomer or composition is featured. In one embodiment, the modification comprises forming a bulge or kink in the nucleic acid. In one embodiment, the modification comprises stabilizing bulges or kinks in the nucleic acid. In one embodiment, the modification comprises reducing bulges or kinks in the nucleic acid. In one embodiment, the nucleic acid contains a splice junction. In one embodiment, compounds of formula (I) interact with the nucleobase, ribose or phosphate moieties of nucleic acids (eg DNA, RNA, eg pre-mRNA).

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

[0265] In certain embodiments, the subject to be treated is a mammal. In certain embodiments, the subject is human. In certain embodiments, the subject is a domestic animal such as a dog, cat, cow, pig, horse, sheep or goat. In certain embodiments, the subject is a companion animal such as a dog or cat. In certain embodiments, the subject is a domestic animal such as a cow, pig, horse, sheep or goat. In certain embodiments, the subject is a zoo animal. In another embodiment, the subject is a research animal such as a rodent, dog or non-human primate. In certain embodiments, the subject is a non-human transgenic animal such as a transgenic mouse or transgenic pig.

[0266] A proliferative disease, disorder or condition can also be associated with inhibition of cellular apoptosis in a biological sample or subject. All types of biological samples described herein or known in the art are contemplated within the scope of the present disclosure. Compounds of formula (I) and their pharmaceutically acceptable salts, solvates, hydrates, tautomers, stere...

Claims

1. Formula (I-a): 【Chemical 509】 (wherein A is a nitrogen-containing heterocyclyl optionally substituted with one or more R1; B is a nitrogen-containing heteroaryl optionally substituted with one or more R1; X and Y are each independently C(R ３ａ ), C(R ３ａ ) (R ３ｂ ), N, N(R ３ｃ ) or O; Z is N, N(R3c) or O; The bond within the ring containing X, Y and Z can be a single bond or a double bond when the valence permits; L １ does not exist; L2 is -C(O)N(R4)-; Each R １ is independently hydrogen, C １ -C ６ -C alkyl, C ２ -C ６ -C alkenyl, C ２ -C ６ -C alkynyl, C １ -C ６ -C heteroalkyl, C １ -C ６ -C haloalkyl, cycloalkyl, heterocyclyl, aryl, C １ -C ６ -C alkylene-aryl, C １ -C ６ -C alkenylene-aryl, C １ -C ６ -C 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, alkynyl, heteroalkyl, haloalkyl, cycloalkyl, heterocyclyl, aryl and heteroaryl is optionally substituted with one or more R ６ ; or Two Rs 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 is optionally substituted with one or more Rs ６ ; Each R ２ is independently hydrogen, C １ to C ６ alkyl, C ２ to C ６ alkenyl, C ２ to C ６ alkynyl, C １ to C ６ heteroalkyl, C １ to C ６ haloalkyl, halo, cyano or -OR Ａ ; R ３ａ and R ３ｂ are each independently hydrogen, C １ -C ６ alkyl, C １ -C ６ heteroalkyl, C １ -C ６ haloalkyl, halo, cyano, -OR Ａ , -NR Ｂ R Ｃ , -C(O)R Ｄ or -C(O)OR Ｄ or; or R ３ａ and R ３ｂ each forms an oxo group together with the carbon atom to which it is attached; R ３ｃ is hydrogen or C １ to C ６ alkyl; Each R ４ is, independently, hydrogen, C １ to C ６ alkyl or C １ to C ６ haloalkyl; Each R ６ is independently C １ to C ６ alkyl, C ２ to C ６ alkenyl, C ２ to C ６ alkynyl, C １ to C ６ heteroalkyl, C １ to 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 alkyl, alkenyl, alkynyl, heteroalkyl, haloalkyl, cycloalkyl, heterocyclyl, aryl and heteroaryl is optionally substituted with one or more R １１ ; Each R ７ is C １ to C ６ alkyl, halo, cyano, oxo or -OR Ａ１ ; Each R １１ is, independently, C １ to C ６ alkyl, C １ to C ６ heteroalkyl, C １ to C ６ haloalkyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, halo, cyano, oxo or -OR Ａ ; Each R Ａ is independently hydrogen, C １ to C ６ alkyl, C １ to C ６ haloalkyl, aryl, heteroaryl, C １ to C ６ alkylene-aryl, C １ to C ６ alkylene-heteroaryl, -C(O)R Ｄ or -S(O) ｘ R Ｄ wherein; R Ｂ and R Ｃ each of which is, independently, hydrogen, C １ -C ６ alkyl, C １ -C ６ heteroalkyl, cycloalkyl, heterocyclyl or -OR Ａ or; or R Ｂ and R Ｃ together with the atoms to which they are attached form a 3- to 7-membered heterocyclic ring optionally substituted with one or more R ７ ; Each R Ｄ and R Ｅ is, independently, hydrogen, C １ to C ６ alkyl, C ２ to C ６ alkenyl, C ２ to C ６ alkynyl, C １ to C ６ heteroalkyl, C １ to C ６ haloalkyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, C １ to C ６ alkylene-aryl or C １ to C ６ alkylene-heteroaryl; Each R Ａ１ is hydrogen or C １ to C ６ alkyl; m is 0, 1 or 2; and x is 0, 1 or 2) of the compound or a pharmaceutically acceptable salt, solvate, hydrate, tautomer or stereoisomer thereof.

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

3. A is 【Chemical 510】 selected from, the compound according to claim 1 or 2.

4. A is 【Chemical 511】 selected from, the compound according to any one of claims 1 to 3.

5. A is 【Chemical 512】 selected from, the compound according to any one of claims 1 to 4.

6. B is 【Chemical 513】 selected from, and p is 0, 1, 2, 3 or 4, the compound according to any one of claims 1 to 5.

7. B is 【Chemical 514】 selected from, the compound according to any one of claims 1 to 6.

8. B is 【Chemical 515】 is, the compound according to any one of claims 1 to 7.

9. At least one of X, Y, and Z is N or N(R ３ｃ ), the compound according to any one of claims 1 to 8.

10. One of X and Y is C(R ３ａ ), and the other of X, Y and Z are each independently O, N or N(R ３ｃ ), a compound according to any one of claims 1 to 9.

11. The compound according to any one of claims 1 to 10, wherein at least one of X, Y and Z is O.

12. Z and Y are each independently N or N(R ３ｃ ), and X is C(R ３ａ ), a compound according to any one of claims 1 to 10.

13. X is C(R ３ａ ), and Y and Z are each independently N or N(R ３ｃ ), a compound according to any one of claims 1 to 10.

14. X is C(R ３ａ ) and Y is C(R ３ａ ) and Z is O, a compound according to any one of claims 1 to 8.

15. 【Chemical Formula 516】 is 【Chemical 517】 selected from, the compound according to any one of claims 1 to 8.

16. The compound of formula (I-a) is of formula (I-b): 【Chemical 518】 (wherein A is a nitrogen-containing heterocyclyl optionally substituted with one or more R1; B is a nitrogen-containing heteroaryl optionally substituted with one or more R1; X and Y are each independently C(R ３ａ ), C(R ３ａ )(R ３ｂ ), N, N(R ３ｃ ) or O; Z is N, N(R3c) or O; The bond within the ring containing X, Y and Z can be a single bond or a double bond when the valence permits; L ２ is -C(O)N(R ４ )-; Each R １ is, independently, hydrogen, C １ -C ６ -C alkyl, C ２ -C ６ -C alkenyl, C ２ -C ６ -C alkynyl, C １ -C ６ -C heteroalkyl, C １ -C ６ -C haloalkyl, cycloalkyl, heterocyclyl, aryl, C １ -C ６ -C alkylene-aryl, C １ -C ６ -C alkenylene-aryl, C １ -C ６ -C 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, alkynyl, heteroalkyl, haloalkyl, cycloalkyl, heterocyclyl, aryl and heteroaryl is optionally substituted with one or more R ６ ; or Two Rs １ 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 is optionally substituted with one or more Rs ６ ; Each R ２ is, independently, hydrogen, C １ to C ６ alkyl, C ２ to C ６ alkenyl, C ２ to C ６ alkynyl, C １ to C ６ heteroalkyl, C １ to C ６ haloalkyl, halo, cyano or -OR Ａ ; R ３ａ and R ３ｂ are each independently hydrogen, C １ to C ６ alkyl, C １ to C ６ heteroalkyl, C １ to C ６ haloalkyl, halo, cyano, -OR Ａ , -NR Ｂ R Ｃ , -C(O)R Ｄ or -C(O)OR Ｄ or; or R ３ａ and R ３ｂ each of which, together with the carbon atom to which it is attached, forms an oxo group; R ３ｃ is hydrogen or C １ to C ６ alkyl; Each R ４ is, independently, hydrogen, C １ to C ６ alkyl or C １ to C ６ haloalkyl; Each R ６ is independently C １ to C ６ alkyl, C ２ to C ６ alkenyl, C ２ to C ６ alkynyl, C １ to C ６ heteroalkyl, C １ to 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 alkyl, alkenyl, alkynyl, heteroalkyl, haloalkyl, cycloalkyl, heterocyclyl, aryl and heteroaryl is optionally substituted with one or more R １１ ; Each R ７ is C １ to C ６ alkyl, halo, cyano, oxo or -OR Ａ１ ; Each R １１ is independently C １ -C ６ alkyl, C １ -C ６ heteroalkyl, C １ -C ６ haloalkyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, halo, cyano, oxo or -OR Ａ ; Each R Ａ is independently hydrogen, C １ to C ６ alkyl, C １ to C ６ haloalkyl, aryl, heteroaryl, C １ to C ６ alkylene-aryl, C １ to C ６ alkylene-heteroaryl, -C(O)R Ｄ or -S(O) ｘ R Ｄ wherein; R Ｂ and R Ｃ each independently is hydrogen, C １ -C ６ alkyl, C １ -C ６ heteroalkyl, cycloalkyl, heterocyclyl or -OR Ａ or; or R Ｂ and R Ｃ together with the atoms to which they are attached, form a 3- to 7-membered heterocyclic ring optionally substituted with one or more R ７ ; Each R Ｄ and R Ｅ is, 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 Ａ１ is hydrogen or C １ to C ６ alkyl; m is 0, 1 or 2; and x is 0, 1 or 2) or a pharmaceutically acceptable salt, solvate, hydrate, tautomer or stereoisomer thereof, the compound according to claim 1.

17. The compound of formula (I-a) is of formula (I-c): 【Chemical 519】 (wherein each of A, B, L ２ , R ２ , R ３ａ , m and its sub-variables are defined as in claim 1) of the compound or a pharmaceutically acceptable salt, solvate, hydrate, tautomer or stereoisomer thereof, the compound according to claim 1.

18. The compound of formula (I-a) is a compound of formula (I-d): 【Chemical 520】 (wherein each of A, B, L ２ , R ２ , R ３ａ , R ３ｃ , m and its sub-variables are defined as in claim 1) The compound according to claim 1, which is a compound of formula (I-d) or a pharmaceutically acceptable salt, solvate, hydrate, tautomer or stereoisomer thereof.

19. The compound of formula (I-a) is a compound of formula (I-e): 【Chemical Formula 521】 (wherein each of A, B, X, Y, Z, L ２ , R ２ , R ４ , m and its sub-variables are defined as in claim 1) The compound according to claim 1, which is a compound of formula (I-e) or a pharmaceutically acceptable salt, solvate, hydrate, tautomer or stereoisomer thereof.

20. The compound of formula (I-a) is a compound of formula (I-h): 【Chemical Formula 522】 (wherein each of A, B, L ２ , R ３ａ , R ４ , and its sub-variables are defined as in claim 1) The compound according to claim 1, which is a compound of formula (I-h) or a pharmaceutically acceptable salt, solvate, hydrate, tautomer or stereoisomer thereof.

21. 【Fig. 523】 【Chemical Formula 524】 【Chemical 525】 【Chemical 526】 【Chemical 527】 【Chemical 528】 【Chemical Formula 529】 【Chemical 530】 【Chemical 531】 【Chemical 532】 【Chemical 533】 【Chemical 534】 【Chemical 535】 【Chemical Formula 536】 【Chemical 537】 【Chemical 538】 Or a pharmaceutically acceptable salt, solvate, hydrate, tautomer or stereoisomer thereof, the compound according to claim 1.

22. A pharmaceutical composition comprising the compound according to any one of claims 1 to 21 and a pharmaceutically acceptable excipient.

23. The compound, or the pharmaceutical composition according to claim 22, according to any one of claims 1 to 21, wherein the compound modifies a target nucleic acid.

24. The compound, or the pharmaceutical composition according to claim 22, according to any one of claims 1 to 21, wherein the compound binds to a target nucleic acid.

25. The compound, or the pharmaceutical composition according to claim 22, according to any one of claims 1 to 21, wherein the compound stabilizes a target nucleic acid.

26. The compound, or the pharmaceutical composition according to claim 22, according to any one of claims 1 to 21, wherein the compound increases splicing at a splice site on a target nucleic acid by about 0.5%, 1%, 2%, 3%, 4%, 5%, 6%, 7%, 8%, 9%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95% or more, "about" meaning ±10%.

27. The compound, or the pharmaceutical composition according to claim 22, according to any one of claims 1 to 21, wherein the compound decreases 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, "about" meaning ±10%.

28. A composition for forming a complex, which comprises a compound of formula (I-a) according to any one of claims 1 to 21, or a pharmaceutical composition according to claim 22, wherein the complex comprises a component of a spliceosome, a nucleic acid, and a compound of formula (I-a) according to any one of claims 1 to 21, and the compound of formula (I-a) contacts the nucleic acid. A composition or pharmaceutical composition characterized by this.

29. The composition or pharmaceutical composition according to claim 28, wherein the component of the spliceosome is recruited to the nucleic acid in the presence of the compound of formula (I-a).

30. A composition for modifying the three-dimensional structure of a nucleic acid, which comprises a compound of formula (I-a) according to any one of claims 1 to 21, or a pharmaceutical composition according to claim 22, wherein the compound of formula (I-a) according to any one of claims 1 to 21 or the pharmaceutical composition according to claim 22 contacts the nucleic acid. A composition or pharmaceutical composition characterized by this.

31. The composition or pharmaceutical composition according to claim 30, wherein the modification includes forming a bulge in the nucleic acid.

32. The composition or pharmaceutical composition according to claim 30, wherein the modification includes stabilizing a bulge of the nucleic acid.

33. The composition or pharmaceutical composition according to claim 30, wherein the modification includes reducing a bulge of the nucleic acid.

34. The nucleic acid contains a splice site. The composition or pharmaceutical composition according to any one of claims 30 to 33.

35. A composition for use in the treatment of a disease or disorder in a subject, which comprises administering to the subject a compound of formula (I-a) according to any one of claims 1 to 21 or a pharmaceutical composition according to claim 22. A composition for use in a treatment including this.

36. The composition for use according to claim 35, wherein the disease or disorder includes a proliferative disease.

37. The composition for use according to claim 35, wherein the disease or disorder includes 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 kidney disease or disorder, or an infectious disease.

38. The composition for use according to claim 35, wherein the disease or disorder includes a neurological disease or disorder.

39. The disease or disorder is a composition for use according to claim 35, including Huntington's disease.

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