Pyridazine derivatives for regulating nucleic acid splicing

Abstract

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

Description

[Technical Field]

[0001] Claim of priority This application claims priority to U.S. Patent Application No. 62 / 983,537 filed on 28 February 2020; U.S. Patent Application No. 63 / 007,134 filed on 8 April 2020; U.S. Patent Application No. 63 / 040,474 filed on 17 June 2020; U.S. Patent Application No. 63 / 072,781 filed on 31 August 2020; and U.S. Patent Application No. 63 / 126,491 filed on 16 December 2020. The disclosures of each of the aforementioned applications are incorporated herein by reference in their entirety. [Background technology]

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

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

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

[0005] In one embodiment, this disclosure relates to formula (I): [ka] (In the formula, A and B are each independently of one or more R 1 The cycloalkyl, heterocyclyl, aryl, or heteroaryl is optionally substituted; L is absent, C1-C6 alkylene, C1-C6 heteroalkylene, -O-, -C(O)-, -N(R 3)-, -S(O) x -, -N(R 3 )C(O)- or -C(O)N(R 3 )-; each alkylene and heteroalkylene is optionally substituted with one or more R 4 ; M and P are each independently C(R 2 ) or N; X and Y are each independently C, C(R 5a ), C(R 5a )(R 5b ), N or N(R 5c ); the bond between X and Y can be a single bond or a double bond when the valence allows, and it is not necessary that both X and Y are C(R 5a )(R 5b ); each R 1 is independently hydrogen, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 heteroalkyl, C1-C6 haloalkyl, cycloalkyl, heterocyclyl, aryl, C1-C6 alkylene-aryl, C1-C6 alkenylene-aryl, C1-C6 alkylene-heteroaryl, heteroaryl, halo, cyano, oxo, -OR A , -NR B R C , -NR B C(O)R D , -NO2, -C(O)NR B R C , -C(O)R D , -C(O)OR D , -SR E or -S(O) x R D ; each alkyl, alkylene, alkenyl, alkenylene, alkynyl, heteroalkyl, haloalkyl, cycloalkyl, heterocyclyl, aryl and heteroaryl is optionally substituted with one or more R 8 ; or two R 1 groups together with the atoms to which they are attached form a 3- to 7-membered cycloalkyl, heterocyclyl, aryl or heteroaryl, and each cycloalkyl, heterocyclyl, aryl and heteroaryl is optionally substituted with one or more R 8 ; each R2 These are independently hydrogen, halo, cyano, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, or -OR A and; each R 3 These are independently hydrogen, C1-C6 alkyl, C1-C6 heteroalkyl, C1-C6 haloalkyl, cycloalkyl, or heterocyclyl; each alkyl, heteroalkyl, haloalkyl, cycloalkyl, and heterocyclyl is one or more R 12 It is replaced by arbitrary selection; each R 4 C1-C6 alkyl, C1-C6 heteroalkyl, C1-C6 haloalkyl, cycloalkyl, halo, cyano, oxo, -OR A , -NR B R C , -C(O)R D or -C(O)OR D And; R 5a This is hydrogen, C1-C6 alkyl or -OR F And; R 5b is hydrogen or a C1-C6 alkyl group; or R 5a and R 5b They form an oxo group together with the carbon atoms to which they are bonded; each R 5c This refers to hydrogen, C1-C6 alkyl, C1-C6 haloalkyl, or C(O)R D and; each R 7 These are independently C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 heteroalkyl, C1-C6 haloalkyl, halo, oxo, cyano, and NR. B C(O)R D -C(O)NR B R C , -C(O)R D or -SR E Alkyl, alkenyl, alkynyl, heteroalkyl and haloalkyl are one or more R 9 Replaced by arbitrary selection; or two R 7The groups, together with the atoms to which they are bonded (e.g., X or Y), form 4- to 7-membered cycloalkyl, heterocyclyl, aryl, or heteroaryl groups, and each cycloalkyl, heterocyclyl, aryl, and heteroaryl group has one or more R 9 It is replaced by choice; R 8 and R 9 These are, independently, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 heteroalkyl, C1-C6 haloalkyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, halo, cyano, oxo, and -OR. A , -NR B R C , -NR B C(O)R D -NO2, -C(O)NR B R C , -C(O)R D , -C(O)OR D , -SR E or -S(O) x R D Each of alkyl, alkenyl, alkynyl, heteroalkyl, haloalkyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl is one or more R 11 It is replaced by arbitrary selection; each R A These are independently hydrogen, C1-C6 alkyl, C1-C6 haloalkyl, aryl, heteroaryl, C1-C6 alkylene-aryl, C1-C6 alkylene-heteroaryl, and -C(O)R D or -S(O) x R D And; R B and R C Each of these independently consists of hydrogen, C1-C6 alkyl, C1-C6 heteroalkyl, cycloalkyl, heterocyclyl, and -OR. A is; or R B and R C Along with the atoms to which they are bonded, one or more R 10 They form a 3- to 7-membered heterocyclyl ring which is optionally substituted; each R D and R ER is independently hydrogen, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 heteroalkyl, C1-C6 haloalkyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, C1-C6 alkylene-aryl, or C1-C6 alkylene-heteroaryl; F R is hydrogen or a C1-C6 alkyl group; 10 is a C1-C6 alkyl or halo; each R 11 These are independently C1-C6 alkyl, C1-C6 heteroalkyl, C1-C6 haloalkyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, halo, cyano, oxo, or -OR A and; each R 12 These are independently deuterium, C1-C6 alkyl, C1-C6 heteroalkyl, C1-C6 haloalkyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, halo, cyano, oxo, or -OR A (where n is 0, 1, 2, 3, or 4; and x is 0, 1, or 2) The present invention provides compounds or pharmaceutically acceptable salts, solvates, hydrates, tautomers, or stereoisomers thereof.

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

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

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

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

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

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

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

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

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

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

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

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

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

[0019] As used herein, "alkyl" refers to a linear or branched saturated hydrocarbon group having 1 to 24 carbon atoms ("C1-C24"). 24 This refers to an alkyl radical ("C1-C12"). In some embodiments, an alkyl group has 1 to 12 carbon atoms. 12 ("Alkyl"). In some embodiments, the alkyl group has 1 to 8 carbon atoms ("C1-C8 alkyl"). In some embodiments, the alkyl group has 1 to 6 carbon atoms ("C1-C6 alkyl"). In some embodiments, the alkyl group has 2 to 6 carbon atoms ("C2-C6 alkyl"). In some embodiments, the alkyl group has 1 carbon atom ("C1 alkyl"). Examples of C1-C6 alkyl groups include methyl (C1), ethyl (C2), n-propyl (C3), isopropyl (C3), n-butyl (C4), tert-butyl (C4), sec-butyl (C4), isobutyl (C4), n-pentyl (C5), 3-pentanyl (C5), amyl (C5), neopentyl (C5), 3-methyl-2-butanyl (C5), tertiary amyl (C5), and n-hexyl (C6). Further examples of alkyl groups include n-heptyl (C7), n-octyl (C8), and the like. Each example of an alkyl group can be independently and optionally substituted, i.e., unsubstituted ("unsubstituted alkyl") or substituted with one or more substituents, e.g., 1 to 5 substituents, 1 to 3 substituents, or 1 substituent ("substituted alkyl"). In certain embodiments, the alkyl group is unsubstituted C1-C10 It is alkyl (e.g., -CH3). In certain embodiments, the alkyl group is substituted C1-C6 alkyl.

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

[0021] As used herein, the term "alkynyl" refers to a radical of a straight-chain or branched hydrocarbon group having 2 to 24 carbon atoms and one or more carbon-carbon triple bonds ("C2-C24 This refers to an "alkenyl" group. In some embodiments, the alkynyl group has 2 to 10 carbon atoms ("C2-C10"). 10 ("Alkynyl"). In some embodiments, the alkynyl group has 2 to 8 carbon atoms ("C2-C8 alkynyl"). In some embodiments, the alkynyl group has 2 to 6 carbon atoms ("C2-C6 alkynyl"). In some embodiments, the alkynyl group has 2 carbon atoms ("C2 alkynyl"). One or more carbon-carbon triple bonds may be internal (e.g., 2-butynyl) or terminal (e.g., 1-butynyl). Examples of C2-C4 alkynyl groups include ethynyl (C2), 1-propynyl (C3), 2-propynyl (C3), 1-butynyl (C4), 2-butynyl (C4), etc. Each example of an alkynyl group may be independently and optionally substituted, i.e., unsubstituted ("unsubstituted alkynyl") or substituted with one or more substituents, e.g., 1 to 5 substituents, 1 to 3 substituents, or 1 substituent ("substituted alkynyl"). In certain embodiments, the alkynyl group is an unsubstituted C 2~10 It is an alkynyl group. In certain embodiments, the alkynyl group is a substituted C 2~6 It is alkinyl.

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

[0056] The term "approximately" is used herein to mean a typical acceptable range in the art. For example, "approximately" can be understood as about two standard deviations from the mean. In certain embodiments, approximately means ±1 This means 0%. In certain embodiments, approximately, ±5 It means "percentage". When "approximately" precedes a series of numbers or a range, it is understood that "approximately" can modify each number in the series or range.

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

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

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

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

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

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

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

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

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

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

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

[0068] compound This disclosure is based on formula (I): [ka] (In the formula, A and B are each independently of one or more R 1 The cycloalkyl, heterocyclyl, aryl, or heteroaryl is optionally substituted; L is absent, C1-C6 alkylene, C1-C6 heteroalkylene, -O-, -C(O)-, -N(R 3 )-,-S(O) x -, -N(R 3 )C(O)- or -C(O)N(R 3)- and each alkylene and heteroalkylene is one or more R 4 It is replaced by arbitrary selection; M and P are independently replaced by C(R 2 ) or N; X and Y are independently C, C(R 5a ), C(R 5a )(R 5b ), N or N(R 5c ) and the bond between X and Y can be a single bond or a double bond, if the valence allows, and both X and Y are C(R 5a )(R 5b ) or C(R 5a ) is not necessarily the case; each R 1 These are independently hydrogen, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 heteroalkyl, C1-C6 haloalkyl, cycloalkyl, heterocyclyl, aryl, C1-C6 alkylene-aryl, C1-C6 alkenylene-aryl, C1-C6 alkylene-heteroaryl, heteroaryl, halo, cyano, oxo, -OR A , -NR B R C , -NR B C(O)R D -NO2, -C(O)NR B R C , -C(O)R D , -C(O)OR D , -SR E or -S(O) x R D Each alkyl, alkylene, alkenyl, alkenylene, alkynyl, heteroalkyl, haloalkyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl is one or more R 8 Replaced by arbitrary selection; or two R 1 The groups, together with the atoms to which they are bonded, form 3- to 7-membered cycloalkyl, heterocyclyl, aryl, or heteroaryl groups, and each cycloalkyl, heterocyclyl, aryl, and heteroaryl group has one or more R groups. 8 It is replaced by arbitrary selection; each R 2These are independently hydrogen, halo, cyano, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, or -OR A and; each R 4 These are independently hydrogen, C1-C6 alkyl, C1-C6 heteroalkyl, C1-C6 haloalkyl, cycloalkyl, or heterocyclyl, and each alkyl, heteroalkyl, haloalkyl, cycloalkyl, and heterocyclyl is one or more R 12 It is replaced by arbitrary selection; each R 4 C1-C6 alkyl, C1-C6 heteroalkyl, C1-C6 haloalkyl, cycloalkyl, halo, cyano, oxo, -OR A , -NR B R C , -C(O)R D or -C(O)OR D And; R 5a This includes hydrogen, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 heteroalkyl, C1-C6 haloalkyl, halo, and -NR. B R C OR F And; R 5b is hydrogen or a C1-C6 alkyl group; or R 5a and R 5b They form an oxo group together with the carbon atoms to which they are bonded; each R 5c This refers to hydrogen, C1-C6 alkyl, C1-C6 haloalkyl, or C(O)R D and; each R 7 These are independently C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 heteroalkyl, C1-C6 haloalkyl, halo, oxo, cyano, -OR A , -NR B R C , NR B C(O)R D -C(O)NR B R C , -C(O)R D or -SR E Alkyl, alkenyl, alkynyl, heteroalkyl and haloalkyl are one or more R 9Replaced by arbitrary selection; or two R 7 The groups, together with the atoms to which they are bonded (e.g., X or Y), form 4- to 7-membered cycloalkyl, heterocyclyl, aryl, or heteroaryl groups, and each cycloalkyl, heterocyclyl, aryl, and heteroaryl group has one or more R 9 It is replaced by choice; R 8 and R 9 These are, independently, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 heteroalkyl, C1-C6 haloalkyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, halo, cyano, oxo, and -OR. A , -NR B R C , -NR B C(O)R D -NO2, -C(O)NR B R C , -C(O)R D , -C(O)OR D , -SR E or -S(O) x R D Each of alkyl, alkenyl, alkynyl, heteroalkyl, haloalkyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl is one or more R 11 It is replaced by arbitrary selection; each R A These are independently hydrogen, C1-C6 alkyl, C1-C6 haloalkyl, aryl, heteroaryl, C1-C6 alkylene-aryl, C1-C6 alkylene-heteroaryl, and -C(O)R D or -S(O) x R D And; R B and R C Each of these independently consists of hydrogen, C1-C6 alkyl, C1-C6 heteroalkyl, cycloalkyl, heterocyclyl, and -OR. A is; or R B and R C Along with the atoms to which they are bonded, one or more R 10 They form a 3- to 7-membered heterocyclyl ring which is optionally substituted; each RD and R E R is independently hydrogen, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 heteroalkyl, C1-C6 haloalkyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, C1-C6 alkylene-aryl, or C1-C6 alkylene-heteroaryl; F R is hydrogen, C1-C6 alkyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl; 10 is a C1-C6 alkyl or halo; each R 11 These are independently C1-C6 alkyl, C1-C6 heteroalkyl, C1-C6 haloalkyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, halo, cyano, oxo, or -OR A and; each R 12 These are independently deuterium, halo, cyano, and -OR. A , -NR B R C , -NR B C(O)R D -C(O)NR B R C , -C(O)R D , -C(O)OR D or -C(O)R D (where n is 0, 1, 2, 3, or 4; and x is 0, 1, or 2) The compound is characterized by the pharmaceutically acceptable salt, solvate, hydrate, tautomer, or stereoisomer thereof.

[0069] In another aspect, this disclosure is defined as formula (Ia): [ka] (In the formula, A and B are each independently of one or more R 1 The cycloalkyl, heterocyclyl, aryl, or heteroaryl is optionally substituted; L is absent, C1-C6 alkylene, C1-C6 heteroalkylene, -O-, -C(O)-, -N(R 3 )-,-S(O) x -, -N(R3 )C(O)- or -C(O)N(R 3 )- and each alkylene and heteroalkylene is one or more R 4 It is replaced by arbitrary selection; M and P are independently replaced by C(R 2 ) or N; X and Y are independently C, C(R 5a ), C(R 5a )(R 5b ), N or N(R 5c ) and the bond between X and Y can be a single bond or a double bond, if the valence allows, and both X and Y are C(R 5a )(R 5b ) is not necessarily the case; each R 1 These are independently hydrogen, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 heteroalkyl, C1-C6 haloalkyl, cycloalkyl, heterocyclyl, aryl, C1-C6 alkylene-aryl, C1-C6 alkenylene-aryl, C1-C6 alkylene-heteroaryl, heteroaryl, halo, cyano, oxo, -OR A , -NR B R C , -NR B C(O)R D -NO2, -C(O)NR B R C , -C(O)R D , -C(O)OR D , -SR E or -S(O) x R D Each alkyl, alkylene, alkenyl, alkenylene, alkynyl, heteroalkyl, haloalkyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl is one or more R 8 Replaced by arbitrary selection; or two R 1 The groups, together with the atoms to which they are bonded, form 3- to 7-membered cycloalkyl, heterocyclyl, aryl, or heteroaryl groups, and each cycloalkyl, heterocyclyl, aryl, and heteroaryl group has one or more R groups. 8 It is replaced by arbitrary selection; each R 2These are independently hydrogen, halo, cyano, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, or -OR A and; each R 3 R is independently hydrogen, C1-C6 alkyl, or C1-C6 haloalkyl; each R 4 C1-C6 alkyl, C1-C6 heteroalkyl, C1-C6 haloalkyl, cycloalkyl, halo, cyano, oxo, -OR A , -NR B R C , -C(O)R D or -C(O)OR D And; R 5a This includes hydrogen, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 heteroalkyl, C1-C6 haloalkyl, halo, and -NR. B R C OR F And; R 5b is hydrogen or a C1-C6 alkyl group; or R 5a and R 5b They form an oxo group together with the carbon atoms to which they are bonded; each R 5c This refers to hydrogen, C1-C6 alkyl, C1-C6 haloalkyl, or C(O)R D and; each R 7 These are independently C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 heteroalkyl, C1-C6 haloalkyl, halo, oxo, cyano, -OR A , -NR B R C , NR B C(O)R D -C(O)NR B R C , -C(O)R D or -SR E Alkyl, alkenyl, alkynyl, heteroalkyl and haloalkyl are one or more R 9 Replaced by arbitrary selection; or two R 7The groups, together with the atoms to which they are bonded (e.g., X or Y), form 4- to 7-membered cycloalkyl, heterocyclyl, aryl, or heteroaryl groups, and each cycloalkyl, heterocyclyl, aryl, and heteroaryl group has one or more R 9 It is replaced by choice; R 8 and R 9 These are, independently, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 heteroalkyl, C1-C6 haloalkyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, halo, cyano, oxo, and -OR. A , -NR B R C , -NR B C(O)R D -NO2, -C(O)NR B R C , -C(O)R D , -C(O)OR D , -SR E or -S(O) x R D Each of alkyl, alkenyl, alkynyl, heteroalkyl, haloalkyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl is one or more R 11 It is replaced by arbitrary selection; each R A These are independently hydrogen, C1-C6 alkyl, C1-C6 haloalkyl, aryl, heteroaryl, C1-C6 alkylene-aryl, C1-C6 alkylene-heteroaryl, and -C(O)R D or -S(O) x R D And; R B and R C Each of these independently consists of hydrogen, C1-C6 alkyl, C1-C6 heteroalkyl, cycloalkyl, heterocyclyl, and -OR. A is; or R B and R C Along with the atoms to which they are bonded, one or more R 10 They form a 3- to 7-membered heterocyclyl ring which is optionally substituted; each R D and R ER is independently hydrogen, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 heteroalkyl, C1-C6 haloalkyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, C1-C6 alkylene-aryl, or C1-C6 alkylene-heteroaryl; F R is hydrogen, C1-C6 alkyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl; 10 is a C1-C6 alkyl or halo; each R 11 These are independently C1-C6 alkyl, C1-C6 heteroalkyl, C1-C6 haloalkyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, halo, cyano, oxo, or -OR A (where n is 0, 1, 2, 3, or 4; and x is 0, 1, or 2) The compound is characterized by the pharmaceutically acceptable salt, solvate, hydrate, tautomer, or stereoisomer thereof.

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

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

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

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

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

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

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

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

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

[0079] In some embodiments, A and B are [ka] [ka] [ka] [ka] [ka] [ka] [ka] [ka] [ka] (In the formula, each R 1 (as defined herein) They are independently selected from each other. In one embodiment, A and B are each independently a saturated, partially saturated, or unsaturated (e.g., aromatic) derivative of the above ring. In one embodiment, A and B are each independently a stereoisomer of the above ring.

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

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

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

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

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

[0085] In some embodiments, A is [ka] In some embodiments, A is [ka] In some embodiments, A is [ka] In some embodiments, A is [ka] In some embodiments, A is [ka] In some embodiments, A is [ka] In some embodiments, A is [ka] In some embodiments, A is [ka] In some embodiments, A is [ka] In some embodiments, A is [ka] In some embodiments, A is [ka] That is the case.

[0086] In some embodiments, B is [ka] (In the formula, R 1 (as defined herein) Selected from. In some embodiments, B is [ka] Selected from. In some embodiments, B is [ka] In some embodiments, B is [ka] In some embodiments, B is [ka] In some embodiments, B is [ka] In some embodiments, B is [ka] In some embodiments, B is [ka] In some embodiments, B is [ka] In some embodiments, B is [ka] That is the case.

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

[0088] In some embodiments, B is [ka] (In the formula, R 1 (as defined herein) Selected from. In some embodiments, B is [ka] Selected from. In some embodiments, B is [ka] (In the formula, R 1 (as defined herein) In some embodiments, B is [ka] Selected from. In some embodiments, B is [ka] In some embodiments, B is [ka] In some embodiments, B is [ka] In some embodiments, B is [ka] In some embodiments, B is [ka] In some embodiments, B is [ka] In some embodiments, B is [ka] In some embodiments, B is [ka] That is the case.

[0089] As generally described herein, L is either absent or C1-C6 alkylene, C1-C6 heteroalkylene, -O-, -C(O)-, -N(R 3 )-,-S(O) x , -N(R 3 )C(O)- or -C(O)N(R 3 )- may refer to a group, and each alkylene and heteroalkylene may have one or more R 4 It is optionally substituted. In some embodiments, L is absent or C1-C6 alkylene, C1-C6 heteroalkylene, -O-, -C(O)-, -N(R 3 )-,-N(R 3 )C(O)- or -C(O)N(R 3 )- may refer to a group, and each alkylene and heteroalkylene may have one or more R 4 It is replaced by an optional choice.

[0090] In some embodiments, L is absent. In some embodiments, L is a C1-C6 alkylene (e.g., C1 alkylene, C2 alkylene, C3 alkylene, C4 alkylene, C5 alkylene, or C6 alkylene). In some embodiments, L is an unsubstituted C1-C6 alkylene. In some embodiments, L is a substituted C1-C6 alkylene, e.g., one or more R 4 These are C1-C6 alkylenes substituted with R. In some embodiments, L is one R 4 It is a C1 alkylene substituted with . In some embodiments, L is -CH2- (or methylene). In some embodiments, L is -C(O)- (or carbonyl).

[0091] In some embodiments, L is absent, C1-C6 alkylene, C1-C6 heteroalkylene, -N(R 3 )C(O)- or -C(O)N(R 3 )- and each alkylene and heteroalkylene is one or more R 4 It is replaced by an optional choice.

[0092] In some embodiments, L is a C1-C6 heteroalkylene (e.g., C1 heteroalkylene, C2 heteroalkylene, C3 heteroalkylene, C4 heteroalkylene, C5 heteroalkylene, or C6 heteroalkylene). In some embodiments, L is an unsubstituted C1-C6 heteroalkylene. In some embodiments, L is one or more R 4 It is a C1-C6 heteroalkylene substituted with . In some embodiments, the heteroalkylene contains one or more heteroatoms. In some embodiments, the heteroalkylene contains one or more of oxygen, sulfur, nitrogen, boron, silicon, or phosphorus. In some embodiments, L is -N(R 3 )C(O)-. In some embodiments, L is -C(O)N(R 3 )-is.

[0093] In some embodiments, L is oxygen. In some embodiments, L is nitrogen, and R3 It can be replaced by one R. In some embodiments, L is one R 3 It is nitrogen substituted with -N(R). In some embodiments, L is -N(R 3 )-. In some embodiments, L is -N(CH3)-. In some embodiments, L is -NH-. In some embodiments, L is -O-.

[0094] In some embodiments, L is -S(O) x -. In some embodiments, x is 0, 1, or 2. In some embodiments, L is -S- or -S(O)2-. In some embodiments, L is -S-.

[0095] As generally described herein, M and P are, independently, C(R 2 ) or N. In some embodiments, M and P are independently C(R 2 ) or N. In some embodiments, M and P are independently C(R 2 ), for example, CH. In some embodiments, one of M and P is C(R 2 ) and the other of M and P is N. In some embodiments, M is C(R 2 ) is. In some embodiments, M is N. In some embodiments, P is C(R 2 ) is. In some embodiments, P is N. In some embodiments, M is C(R 2 )(for example, CH), and P is N. In some embodiments, M is N, and P is C(R 2 )(For example, CH).

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

[0097] As generally described herein, X and Y are, respectively, independently C, C(R 5a ), C(R 5a )(R 5b ), N or N(R 5c ) refers to. In some embodiments, X and Y are each independently C. In some embodiments, X and Y are each C(R 5a ) In some embodiments, X and Y are both C(R 5a ) is not necessarily the case.

[0098] In some embodiments, Y is N and X is C(R 5a )(For example, CH), then L is -N(R 3 )-(for example, -N(CH3)-). In some embodiments, if Y is N and X is CH, then L is -N(R 3 )-(for example, -N(CH3)-). In some embodiments, Y is N and X is C(R 5a )(for example, CH), then L is not -N(CH3)-. In some embodiments, if Y is N and X is CH, then L is not -N(CH3)-. In some embodiments, if Y is N and L is -N(R 3 ) If R 3 It is not a C1-C6 alkylene. In some embodiments, Y is N and L is -N(R 3 ) If R 3 is not CH3. In some embodiments, if Y is N, then X is also N. In some embodiments, X is C(R 5aIf (for example, CH), then Y is not N. In some embodiments, if Y contains N, the bond between X and Y is not a double bond. In some embodiments, if Y contains N, the bond between X and Y is a single bond. In some embodiments, if Y is N, then B is not an aryl or heteroaryl. In some embodiments, if Y is N, then B is not an aryl. In some embodiments, if Y is N, then B is not a heteroaryl. In some embodiments, if Y is N, then B is a cycloalkyl or heterocyclyl. In some embodiments, if Y is N, then B is a cycloalkyl. In some embodiments, if Y is N, then B is a heterocyclyl.

[0099] In some embodiments, X and Y are independently R 7 C is substituted by optional choice. In some embodiments, two R 7 The groups, together with the atoms to which they are bonded, form cycloalkyl, heterocyclyl, aryl, or heteroaryl groups. In some embodiments, X and Y are independently R 7 C is substituted with two R 7 The groups, together with X and Y, form cycloalkyl, heterocyclyl, aryl, or heteroaryl groups (e.g., 3- to 7-membered cycloalkyl, heterocyclyl, aryl, or heteroaryl groups). In some embodiments, R 7 The groups X and Y combine to form a 4- to 7-membered heterocycline. In some embodiments, R 7 The groups X and Y combine to form a 4- to 7-membered heteroaryl. In some embodiments, R 7 The group, together with X and Y, forms a 5-membered heterocycline. In some embodiments, R 7 The groups X and Y combine to form a 5-membered heteroaryl. Cycloalkyl, heterocyclyl, aryl, or heteroaryl consists of one or more R 9 It can be replaced with.

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

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

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

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

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

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

[0106] In some embodiments, one of D, E, and F is N(R 5f ) and the others of D, E and F are, independently of each other, C(R 5d )(R 5e ) In some embodiments, D, E, and F are independently N(R 5f ) and the others of D, E and F are C(R 5d )(R 5e ) In some embodiments, D is N(R 5f ) and E and F are independent of each other, C(R 5d )(R 5e ) is. In some embodiments, E is N(R 5f ) and D and F are independent of each other, C(R 5d )(R 5e ) is. In some embodiments, F is N(R 5f ) and D and E are independently C(R 5d )(R 5e ) In some embodiments, D is NH, E is C(O), and F is CH2. In some embodiments, D is CH2, E is NH, and F is C(O). In some embodiments, D is NH, E is CH, and F is C(O).

[0107] In some embodiments, [ka] teeth, [ka] (In the formula, R 7 (and n are as defined above.) Alternatively, they are selected from their tautomers.

[0108] In some embodiments, [ka] teeth, [ka] Selected from.

[0109] In some embodiments, [ka] teeth, [ka] Selected from: In some embodiments, [ka] teeth, [ka] That is the case.

[0110] In some embodiments, R 1 is hydrogen. In some embodiments, R 1 is a C1-C6 alkyl group. In some embodiments, R 1 R is a C2-C6 alkenyl. In some embodiments, R 1 R is a C2-C6 alkynyl. In some embodiments, R 1 R is a C1-C6 heteroalkyl group. In some embodiments, R 1 is a C1-C6 haloalkyl group (e.g., -CF3). In some embodiments, R 1 is a C1 alkyl group (e.g., methyl). In some embodiments, R 1R is an unsubstituted C1-C6 alkyl, an unsubstituted C2-C6 alkenyl, an unsubstituted C2-C6 alkynyl, an unsubstituted C1-C6 heteroalkyl, or an unsubstituted C1-C6 haloalkyl. In some embodiments, R 1 is one or more R 8 It is a C1-C6 alkyl group substituted with R. In some embodiments, 1 is one or more R 8 It is a C2-C6 alkenyl substituted with R. In some embodiments, 1 is one or more R 8 It is a C2-C6 alkynyl substituted with R. In some embodiments, 1 is one or more R 8 It is a C1-C6 heteroalkyl substituted with R. In some embodiments, 1 is one or more R 8 It is a C1-C6 haloalkyl substituted with R. In some embodiments, R 1 It is methyl.

[0111] In some embodiments, R 1 is a cycloalkyl group (e.g., a 3- to 7-membered cycloalkyl group). In some embodiments, R 1 is a heterocycline (e.g., a 3- to 7-membered heterocycline). In some embodiments, R 1 is an arrow. In some embodiments, R 1 is a C1-C6 alkylene-aryl (e.g., benzyl). In some embodiments, R 1 R is a C1-C6 alkenylene-aryl. In some embodiments, R 1 R is a C1-C6 alkylene heteroaryl. In some embodiments, R 1 is a heteroaryl compound. In some embodiments, R 1 R is an unsubstituted cycloalkyl, unsubstituted heterocyclyl, unsubstituted aryl, unsubstituted C1-C6 alkylene-aryl, unsubstituted C1-C6 alkenylene-aryl, unsubstituted C1-C6 alkylene-heteroaryl, or unsubstituted heteroaryl. In some embodiments, R 1 is one or more R8 It is a cycloalkyl substituted with R. In some embodiments, R 1 is one or more R 8 It is a heterocyclyl substituted with R. In some embodiments, 1 is one or more R 8 This is an aryl that has been replaced with R. In some embodiments, R 1 is one or more R 8 It is a C1-C6 alkylene-aryl substituted with R. In some embodiments, 1 is one or more R 8 It is a C1-C6 alkenylene-aryl substituted with R. In some embodiments, 1 is one or more R 8 It is a C1-C6 alkylene heteroaryl substituted with R. In some embodiments, 1 is one or more R 8 It is a heteroaryl substituted with [the specified compound].

[0112] In some embodiments, R 1 is -OR A In some embodiments, R 1 -NR B R C (For example, NH2 or NMe2). In some embodiments, R 1 -NR B C(O)R D In some embodiments, R 1 is -C(O)NR B R C In some embodiments, R 1 is -C(O)R D In some embodiments, R 1 is -C(O)OR D In some embodiments, R 1 -SR E In some embodiments, R 1 is -S(O) x R D In some embodiments, R 1is a halo, for example, fluoro, chloro, bromo, or iodine. In some embodiments, R 1 is cyano. In some embodiments, R 1 is nitro(-NO2). In some embodiments, R 1 It is oxo.

[0113] In some embodiments, two R 1 The groups, together with the atoms to which they are bonded, form a 3- to 7-membered cycloalkyl group. In some embodiments, two R groups 1 The groups, together with the atoms to which they are bonded, form a 3- to 7-membered heterocycline. In some embodiments, two R groups 1 The groups, together with the atoms to which they are bonded, form a 5- or 6-membered aryl group. In some embodiments, two R groups 1 The groups, together with the atoms to which they are bonded, form a 5- or 6-membered heteroaryl. Cycloalkyl, heterocyclyl, aryl, or heteroaryl consists of one or more R groups. 8 It can be replaced with.

[0114] In some embodiments, R 2 is hydrogen. In some embodiments, R 2 is a C1-C6 alkyl group. In some embodiments, R 2 R is a C2-C6 alkenyl. In some embodiments, R 2 R is a C2-C6 alkynyl. In some embodiments, R 2 is a C1 alkyl group (e.g., methyl). In some embodiments, R 2 is methyl. In some embodiments, R 2 is -OR A In some embodiments, R 2 is a halo (e.g., fluoro, chloro, bromo, or iodine). In some embodiments, R 2 is fluoro. In some embodiments, R 2 It is cyano.

[0115] In some embodiments, R 3 is hydrogen. In some embodiments, R 3 is a C1-C6 alkyl group. In some embodiments, R 3 is a C1-C6 haloalkyl. In some embodiments, R 3 is a C1 alkyl group (e.g., methyl). In some embodiments, R 3 is methyl. In some embodiments, R 3 is one or more R 12 It is modified by R. In some embodiments, 12 is deuterium. In some embodiments, R 3 This is CD3.

[0116] In some embodiments, R 4 is a C1-C6 alkyl group. In some embodiments, R 4 R is a C1-C6 heteroalkyl group. In some embodiments, R 4 is a C1-C6 haloalkyl. In some embodiments, R 4 is a cycloalkyl group. In some embodiments, R 4 is a halo (e.g., fluoro, chloro, bromo, or iodine). In some embodiments, R 4 is cyano. In some embodiments, R 4 is an oxo. In some embodiments, R 4 is -OR A In some embodiments, R 4 -NR B R C In some embodiments, R 4 is -C(O)R D or -C(O)OR D That is the case.

[0117] In some embodiments, R 5a and R 5b Each is independently hydrogen or a C1-C6 alkyl group. In some embodiments, R 5a is hydrogen. In some embodiments, R5b is hydrogen. In some embodiments, R 5a and R 5b These combine to form an oxo group. In some embodiments, R 5c is hydrogen. In some embodiments, R 5c is a C1-C6 alkyl group. In some embodiments, R 5c is a C1-C6 haloalkyl group (e.g., -CF3 or -CHF2). In some embodiments, R 5c is -CF3. In some embodiments, R 5c is -CHF2. In some embodiments, R 5c is -C(O)R D (For example, -C(O)CH3). In some embodiments, R 5c It is -C(O)CH3).

[0118] In some embodiments, R 5d , R 5e and R 5f Each of these is independently hydrogen, a C1-C6 alkyl group, a halo, or R 5d , R 5e They combine to form an oxo group. In some embodiments, R 5d is hydrogen. In some embodiments, R 5e is hydrogen. In some embodiments, R 5f is hydrogen. In some embodiments, R 5e and R 5f They both form an oxo group.

[0119] In some embodiments, R 7 is a C1-C6 alkyl group. In some embodiments, R 7 R is a C2-C6 alkenyl. In some embodiments, R 7 R is a C2-C6 alkynyl. In some embodiments, R 7 R is a C1-C6 heteroalkyl group. In some embodiments, R 7 is a C1-C6 haloalkyl. In some embodiments, R 7R is an unsubstituted C1-C6 alkyl, an unsubstituted C2-C6 alkenyl, an unsubstituted C2-C6 alkynyl, an unsubstituted C1-C6 heteroalkyl, or an unsubstituted C1-C6 haloalkyl. In some embodiments, R 7 is one or more R 9 It is a C1-C6 alkyl group substituted with R. In some embodiments, 7 is one or more R 9 It is a C2-C6 alkenyl substituted with R. In some embodiments, 7 is one or more R 9 It is a C2-C6 alkynyl substituted with R. In some embodiments, 7 is one or more R 9 It is a C1-C6 heteroalkyl substituted with R. In some embodiments, 7 is one or more R 9 It is a C1-C6 haloalkyl substituted with R. In some embodiments, R 7 is a halo, for example, fluoro, chloro, bromo, or iodine. In some embodiments, R 7 is fluoro. In some embodiments, R 7 is cyano. In some embodiments, R 7 is an oxo. In some embodiments, R 7 -NR B C(O)R D In some embodiments, R 7 is -C(O)NR B R C In some embodiments, R 7 is -C(O)R D In some embodiments, R 7 -SR E That is the case.

[0120] In some embodiments, two R 7 The groups, together with the atoms to which they are bonded (e.g., X or Y), form a 4- to 7-membered cycloalkyl group. In some embodiments, two R groups 7The groups, together with the atoms to which they are bonded (e.g., X or Y), form a 4- to 7-membered heterocycline. In some embodiments, two R groups 7 The groups, together with the atoms to which they are bonded (e.g., X or Y), form a 5- or 6-membered aryl group. In some embodiments, two R groups 7 The groups, together with the atoms to which they are bonded (e.g., X or Y), form a 5- or 6-membered heteroaryl. In some embodiments, two R groups 7 The groups, together with the atoms to which they are bonded (e.g., X or Y), form a five-membered heterocycline. In some embodiments, two R groups 7 The groups, together with the atoms to which they are bonded (e.g., X or Y), form a five-membered heteroaryl. Cycloalkyl, heterocyclyl, aryl, or heteroaryl consists of one or more R 9 It can be replaced with.

[0121] In some embodiments, R 8 is a C1-C6 alkyl group. In some embodiments, R 8 R is a C2-C6 alkenyl. In some embodiments, R 8 R is a C2-C6 alkynyl. In some embodiments, R 8 R is a C1-C6 heteroalkyl group. In some embodiments, R 8 is a C1-C6 haloalkyl. In some embodiments, R 8 R is an unsubstituted C1-C6 alkyl, an unsubstituted C2-C6 alkenyl, an unsubstituted C2-C6 alkynyl, an unsubstituted C1-C6 haloalkyl, or an unsubstituted C1-C6 heteroalkyl. In some embodiments, R 8 is one or more R 11 It is a C1-C6 alkyl group substituted with R. In some embodiments, 8 is one or more R 11 It is a C2-C6 alkenyl substituted with R. In some embodiments, 8 is one or more R 11 It is a C2-C6 alkynyl substituted with R. In some embodiments, 8 is one or more R11 It is a C1-C6 haloalkyl substituted with R. In some embodiments, R 8 is one or more R 11 These are C1-C6 heteroalkyl groups substituted with [the specified character].

[0122] In some embodiments, R 8 is a cycloalkyl group. In some embodiments, R 8 is a heterocycline. In some embodiments, R 8 is an arrow. In some embodiments, R 8 is a heteroaryl compound. In some embodiments, R 8 R is an unsubstituted cycloalkyl, unsubstituted heterocyclyl, unsubstituted aryl, or unsubstituted heteroaryl. In some embodiments, R 8 is one or more R 11 It is a cycloalkyl substituted with R. In some embodiments, R 8 is one or more R 11 It is a heterocyclyl substituted with R. In some embodiments, 8 is one or more R 11 This is an aryl that has been replaced with R. In some embodiments, R 8 is one or more R 11 It is a heteroaryl substituted with [the specified compound].

[0123] In some embodiments, R 8 is a halo (e.g., fluoro, chloro, bromo, or iodine). In some embodiments, R 8 is cyano. In some embodiments, R 8 is an oxo. In some embodiments, R 8 is -OR A In some embodiments, R 8 -NR B R C In some embodiments, R 8 -NR B C(O)R D In some embodiments, R 8is -NO2. In some embodiments, R 8 is -C(O)NR B R C In some embodiments, R 8 is -C(O)R D In some embodiments, R 8 is -C(O)OR D In some embodiments, R 8 -SR E In some embodiments, R 8 is -S(O) x R D That is the case.

[0124] In some embodiments, R 9 is a C1-C6 alkyl group. In some embodiments, R 9 R is a C2-C6 alkenyl. In some embodiments, R 9 R is a C2-C6 alkynyl. In some embodiments, R 9 R is a C1-C6 heteroalkyl group. In some embodiments, R 9 is a C1-C6 haloalkyl. In some embodiments, R 9 R is an unsubstituted C1-C6 alkyl, an unsubstituted C2-C6 alkenyl, an unsubstituted C2-C6 alkynyl, an unsubstituted C1-C6 haloalkyl, or an unsubstituted C1-C6 heteroalkyl. In some embodiments, R 9 is one or more R 11 It is a C1-C6 alkyl group substituted with R. In some embodiments, 9 is one or more R 11 It is a C2-C6 alkenyl substituted with R. In some embodiments, 9 is one or more R 11 It is a C2-C6 alkynyl substituted with R. In some embodiments, 9 is one or more R 11 It is a C1-C6 haloalkyl substituted with R. In some embodiments, R 9 is one or more R 11 These are C1-C6 heteroalkyl groups substituted with [the specified character].

[0125] In some embodiments, R 9 is a cycloalkyl group. In some embodiments, R 9 is a heterocycline. In some embodiments, R 9 is an arrow. In some embodiments, R 9 is a heteroaryl compound. In some embodiments, R 9 R is an unsubstituted cycloalkyl, unsubstituted heterocyclyl, unsubstituted aryl, or unsubstituted heteroaryl. In some embodiments, R 9 is one or more R 11 It is a cycloalkyl substituted with R. In some embodiments, R 9 is one or more R 11 It is a heterocyclyl substituted with R. In some embodiments, 9 is one or more R 11 This is an aryl that has been replaced with R. In some embodiments, R 9 is one or more R 11 It is a heteroaryl substituted with [the specified compound].

[0126] In some embodiments, R 9 is a halo (e.g., fluoro, chloro, bromo, or iodine). In some embodiments, R 9 is cyano. In some embodiments, R 9 is an oxo. In some embodiments, R 9 is -OR A In some embodiments, R 9 -NR B R C In some embodiments, R 9 -NR B C(O)R D In some embodiments, R 9 is -NO2. In some embodiments, R 9 is -C(O)NR B R C In some embodiments, R 9 is -C(O)R DIn some embodiments, R 9 is -C(O)OR D In some embodiments, R 9 -SR E In some embodiments, R 9 is -S(O) x R D That is the case.

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

[0128] In some embodiments, R 11 is a C1-C6 alkyl group. In some embodiments, R 11 R is a C1-C6 heteroalkyl group. In some embodiments, R 11 is a C1-C6 haloalkyl group (e.g., -CF3). In some embodiments, R 11 is a cycloalkyl group. In some embodiments, R 11 is a heterocycline. In some embodiments, R 11 is an arrow. In some embodiments, R 11 is a heteroaryl compound. In some embodiments, R 11 is a halo. In some embodiments, R 11 is cyano. In some embodiments, R 11 is an oxo. In some embodiments, R 11 is -OR A That is the case.

[0129] In some embodiments, R A is hydrogen. In some embodiments, R A is a C1-C6 alkyl group (e.g., methyl). In some embodiments, R A is a C1-C6 haloalkyl. In some embodiments, R Ais an arrow. In some embodiments, R A is a heteroaryl compound. In some embodiments, R A is a C1-C6 alkylene-aryl (e.g., benzyl). In some embodiments, R A R is a C1-C6 alkylene heteroaryl. In some embodiments, R A is -C(O)R D In some embodiments, R A is -S(O) x R D That is the case.

[0130] In some embodiments, R B , R C Or both, independently, are hydrogen, C1-C6 alkyl, C1-C6 heteroalkyl, cycloalkyl, heterocyclyl, or -OR A In some embodiments, R B and R C Each of them is independently hydrogen. In some embodiments, R B and R C Each of them is independently a C1-C6 alkyl group. In some embodiments, R B and R C One of them is hydrogen, R B and R C The other is a C1-C6 alkyl group. In some embodiments, R B and R C Along with the atoms to which they are bonded, one or more R 10 (For example, one, two or three R 10 ) forms a 3- to 7-membered heterocyclyl ring which is optionally substituted.

[0131] In some embodiments, R D , R EOr both are independently hydrogen, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 heteroalkyl, C1-C6 haloalkyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, C1-C6 alkylene-aryl (e.g., benzyl), or C1-C6 alkylene-heteroaryl. In some embodiments, R D and R E Each of these is independently hydrogen. In some embodiments, R D and R E Each of these is independently a C1-C6 alkyl group. In some embodiments, R D is hydrogen. In some embodiments, R E is hydrogen. In some embodiments, R D is a C1-C6 alkyl group (e.g., methyl). In some embodiments, R E is a C1-C6 alkyl group (e.g., methyl). In some embodiments, R D R is a C1-C6 heteroalkyl group. In some embodiments, R E R is a C1-C6 heteroalkyl group. In some embodiments, R D is a C1-C6 haloalkyl. In some embodiments, R E is a C1-C6 haloalkyl. In some embodiments, R D is a cycloalkyl group. In some embodiments, R E is a cycloalkyl group. In some embodiments, R D is a heterocycline. In some embodiments, R E is a heterocycline. In some embodiments, R D is an arrow. In some embodiments, R E is an arrow. In some embodiments, R D is a heteroaryl compound. In some embodiments, R E is a heteroaryl compound. In some embodiments, R D is a C1-C6 alkylene-aryl (e.g., benzyl). In some embodiments, RE is a C1-C6 alkylene-aryl (e.g., benzyl). In some embodiments, R D R is a C1-C6 alkylene heteroaryl. In some embodiments, R E These are C1-C6 alkylene heteroaryl compounds.

[0132] In some embodiments, m is an integer between 0 and 2 (e.g., 0, 1, or 2). In some embodiments, m is 0. In some embodiments, m is 1. In some embodiments, m is 2. In some embodiments, n is an integer between 0 and 4 (e.g., 0, 1, 2, 3, or 4). In some embodiments, n is 0. In some embodiments, n is 1. In some embodiments, n is 2. In some embodiments, n is 3. In some embodiments, n is 4. In some embodiments, x is an integer between 0 and 2 (e.g., 0, 1, or 2). In some embodiments, x is 0. In some embodiments, x is 1. In some embodiments, x is 2.

[0133] In some embodiments, the compound is of formula (Ib): [ka] (In the formula, A and B are each independently of one or more R 1 The cycloalkyl, heterocyclyl, aryl, or heteroaryl is optionally substituted; L is absent, C1-C6 alkylene, C1-C6 heteroalkylene, -O-, -C(O)-, -N(R 3 )-,-S(O) x -, -N(R 3 )C(O)- or -C(O)N(R 3 )- and each alkylene and heteroalkylene is one or more R 4 It is replaced by arbitrary selection; M and P are independently replaced by C(R 2 ) or N; X and Y are independently C, C(R5a ), C(R 5a )(R 5b ), N or N(R 5c ) and the bond between X and Y can be a single bond or a double bond, if the valence allows, and both X and Y are C(R 5a )(R 5b ) is not necessarily the case; each R 1 These are independently hydrogen, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 heteroalkyl, C1-C6 haloalkyl, cycloalkyl, heterocyclyl, aryl, C1-C6 alkylene-aryl, C1-C6 alkenylene-aryl, C1-C6 alkylene-heteroaryl, heteroaryl, halo, cyano, oxo, -OR A , -NR B R C , -NR B C(O)R D -NO2, -C(O)NR B R C , -C(O)R D , -C(O)OR D , -SR E or -S(O) x R D Each alkyl, alkylene, alkenyl, alkenylene, alkynyl, heteroalkyl, haloalkyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl is one or more R 8 Replaced by arbitrary selection; or two R 1 The groups, together with the atoms to which they are bonded, form 3- to 7-membered cycloalkyl, heterocyclyl, aryl, or heteroaryl groups, and each cycloalkyl, heterocyclyl, aryl, and heteroaryl group has one or more R groups. 8 It is replaced by arbitrary selection; each R 2 These are independently hydrogen, halo, cyano, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, or -OR A and; each R 3 R is independently hydrogen, C1-C6 alkyl, or C1-C6 haloalkyl; each R 4C1-C6 alkyl, C1-C6 heteroalkyl, C1-C6 haloalkyl, cycloalkyl, halo, cyano, oxo, -OR A , -NR B R C , -C(O)R D or -C(O)OR D And; R 5a This is hydrogen, C1-C6 alkyl or -OR F And; R 5b is hydrogen or a C1-C6 alkyl group; or R 5a and R 5b They form an oxo group together with the carbon atoms to which they are bonded; each R 5c This refers to hydrogen, C1-C6 alkyl, C1-C6 haloalkyl, or C(O)R D and; each R 7 These are independently C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 heteroalkyl, C1-C6 haloalkyl, halo, oxo, cyano, and NR. B C(O)R D -C(O)NR B R C , -C(O)R D or -SR E Alkyl, alkenyl, alkynyl, heteroalkyl and haloalkyl are one or more R 9 Replaced by arbitrary selection; or two R 7 The groups, together with the atoms to which they are bonded (e.g., X or Y), form 4- to 7-membered cycloalkyl, heterocyclyl, aryl, or heteroaryl groups, and each cycloalkyl, heterocyclyl, aryl, and heteroaryl group has one or more R 9 It is replaced by choice; R 8 and R 9 These are, independently, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 heteroalkyl, C1-C6 haloalkyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, halo, cyano, oxo, and -OR. A , -NR B R C , -NR B C(O)RD 、 -NO2, -C(O)NR B R C 、 -C(O)R D 、 -C(O)OR D 、 -SR E or -S(O) x R D and each of alkyl, alkenyl, alkynyl, heteroalkyl, haloalkyl, cycloalkyl, heterocyclyl, aryl and heteroaryl is optionally substituted with one or more R 11 ; each R A is independently hydrogen, C1-C6 alkyl, C1-C6 haloalkyl, aryl, heteroaryl, C1-C6 alkylene-aryl, C1-C6 alkylene-heteroaryl, -C(O)R D or -S(O) x R D ; R B and R C are each independently hydrogen, C1-C6 alkyl, C1-C6 heteroalkyl, cycloalkyl, heterocyclyl, -OR A ; or R B and R C together with the atom to which they are attached form a 3- to 7-membered heterocyclyl ring optionally substituted with one or more R 10 ; each R D and R E are independently hydrogen, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 heteroalkyl, C1-C6 haloalkyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, C1-C6 alkylene-aryl or C1-C6 alkylene-heteroaryl; R F is hydrogen or C1-C6 alkyl; R 10 is C1-C6 alkyl or halo; each R 11 is independently C1-C6 alkyl, C1-C6 heteroalkyl, C1-C6 haloalkyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, halo, cyano, oxo or -OR A ; n is 0, 1, 2, 3 or 4; and x is 0, 1 or 2) is a compound or a pharmaceutically acceptable salt, solvate, hydrate, tautomer or stereoisomer thereof.

[0134] In some embodiments, the present disclosure provides a compound of formula (I-c): [Chemical formula] (wherein A and B are each independently a cycloalkyl, heterocyclyl, aryl or heteroaryl optionally substituted with one or more R 1 ; L is absent, C1-C6 alkylene, C1-C6 heteroalkylene, -O-, -C(O)-, -N(R 3 )-, -N(R 3 )C(O)- or -C(O)N(R 3 )-, and each alkylene and heteroalkylene is optionally substituted with one or more R 4 ; M and P are each independently C(R 2 ) or N; X and Y are each independently C, C(R 5a ), C(R 5a )(R 5b ), N or N(R 5c ), and the bond between X and Y can be a single bond or a double bond when valence allows, and it is not necessary that both X and Y are C(R 5a )(R 5b ); each R 1 is independently hydrogen, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 heteroalkyl, C1-C6 haloalkyl, cycloalkyl, heterocyclyl, aryl, C1-C6 alkylene-aryl, C1-C6 alkenylene-aryl, C1-C6 alkylene-heteroaryl, heteroaryl, halo, cyano, oxo, -OR A , -NR B R C , -NR B C(O)R D , -NO2, -C(O)NR B R C , -C(O)R D , -C(O)ORD , -SR E or -S(O) x R D Each alkyl, alkylene, alkenyl, alkenylene, alkynyl, heteroalkyl, haloalkyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl is one or more R 8 Replaced by arbitrary selection; or two R 1 The groups, together with the atoms to which they are bonded, form 3- to 7-membered cycloalkyl, heterocyclyl, aryl, or heteroaryl groups, and each cycloalkyl, heterocyclyl, aryl, and heteroaryl group has one or more R groups. 8 It is replaced by arbitrary selection; each R 2 These are independently hydrogen, halo, cyano, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, or -OR A and; each R 3 R is independently hydrogen, C1-C6 alkyl, or C1-C6 haloalkyl; each R 4 C1-C6 alkyl, C1-C6 heteroalkyl, C1-C6 haloalkyl, cycloalkyl, halo, cyano, oxo, -OR A , -NR B R C , -C(O)R D or -C(O)OR D And; R 5a This is hydrogen, C1-C6 alkyl or -OR F And; R 5b is hydrogen or a C1-C6 alkyl group; or R 5a and R 5b They form an oxo group together with the carbon atoms to which they are bonded; each R 5c This refers to hydrogen, C1-C6 alkyl, C1-C6 haloalkyl, or C(O)R D and; each R 7 These are independently C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 heteroalkyl, C1-C6 haloalkyl, halo, oxo, cyano, and NR. B C(O)R D -C(O)NR B R C , -C(O)RD or -SR E where alkyl, alkenyl, alkynyl, heteroalkyl and haloalkyl are optionally substituted with one or more R 9 groups; or two R 7 groups together with the atom to which they are attached (e.g., X or Y) form a 4- to 7-membered cycloalkyl, heterocyclyl, aryl or heteroaryl, and each cycloalkyl, heterocyclyl, aryl and heteroaryl is optionally substituted with one or more R 9 groups; R 8 and R 9 are each independently C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 heteroalkyl, C1-C6 haloalkyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, halo, cyano, oxo, -OR A , -NR B R C , -NR B C(O)R D , -NO2, -C(O)NR B R C , -C(O)R D , -C(O)OR D , -SR E or -S(O) x R D where each of alkyl, alkenyl, alkynyl, heteroalkyl, haloalkyl, cycloalkyl, heterocyclyl, aryl and heteroaryl is optionally substituted with one or more R 11 groups; each R A is independently hydrogen, C1-C6 alkyl, C1-C6 haloalkyl, aryl, heteroaryl, C1-C6 alkylene-aryl, C1-C6 alkylene-heteroaryl, -C(O)R D or -S(O) x R D ; and each of R B and R C is independently hydrogen, C1-C6 alkyl, C1-C6 heteroalkyl, cycloalkyl, heterocyclyl, -OR A ; or R B and RC Along with the atoms to which they are bonded, one or more R 10 They form a 3- to 7-membered heterocyclyl ring which is optionally substituted; each R D and R E R is independently hydrogen, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 heteroalkyl, C1-C6 haloalkyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, C1-C6 alkylene-aryl, or C1-C6 alkylene-heteroaryl; F R is hydrogen or a C1-C6 alkyl group; 10 is a C1-C6 alkyl or halo; each R 11 These are independently C1-C6 alkyl, C1-C6 heteroalkyl, C1-C6 haloalkyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, halo, cyano, oxo, or -OR A (where n is 0, 1, 2, 3, or 4; and x is 0, 1, or 2) The compound is characterized by the pharmaceutically acceptable salt, solvate, hydrate, tautomer, or stereoisomer thereof.

[0135] In some embodiments, the compound of formula (I) is formula (Id): [ka] (In the formula, A and B each independently have one or more R 1 The cycloalkyl, heterocyclyl, aryl, or heteroaryl elements are optionally substituted; L is absent, C1-C6 alkylene, C1-C6 heteroalkylene, -O-, -C(O)-, -N(R 3 )-,-N(R 3 )C(O)- or -C(O)N(R 3 )- and each alkylene and heteroalkylene is one or more R 4 It is replaced by optional selection; M and P are independent of each other, C(R 2) or N; D, E, and F are each independent of C(R 5d ), C(R 5d )(R 5e ), N, N(R 5f ), S or O, and the bonds between atoms in a ring containing D, E and F can be single or double bonds, depending on the valence; Each R 1 These are independently hydrogen, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 heteroalkyl, C1-C6 haloalkyl, cycloalkyl, heterocyclyl, aryl, C1-C6 alkylene-aryl, C1-C6 alkenylene-aryl, C1-C6 alkylene-heteroaryl, heteroaryl, halo, cyano, oxo, -OR A , -NR B R C , -NR B C(O)R D -NO2, -C(O)NR B R C , -C(O)R D , -C(O)OR D , -SR E or -S(O) x R D Each alkyl, alkylene, alkenyl, alkenylene, alkynyl, heteroalkyl, haloalkyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl is one or more R 8 It is replaced by an optional choice; or Two R's 1 The groups, together with the atoms to which they are bonded, form 3- to 7-membered cycloalkyl, heterocyclyl, aryl, or heteroaryl groups, and each cycloalkyl, heterocyclyl, aryl, and heteroaryl group has one or more R groups. 8 It is replaced by optional selection; Each R 2 These are independently hydrogen, halo, cyano, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, or -OR A and; Each R 3These are independently hydrogen, C1-C6 alkyl, C1-C6 heteroalkyl, C1-C6 haloalkyl, cycloalkyl, or heterocyclyl, and each alkyl, heteroalkyl, haloalkyl, cycloalkyl, and heterocyclyl is one or more R 12 It is replaced by optional selection; Each R 4 C1-C6 alkyl, C1-C6 heteroalkyl, C1-C6 haloalkyl, cycloalkyl, halo, cyano, oxo, -OR A , -NR B R C , -C(O)R D or -C(O)OR D and; R 5d and R 5e Each of these is independently hydrogen, a halo, or a C1-C6 alkyl group; or R 5d and R 5e They combine to form an oxo group; R 5f is hydrogen, halo, or C1-C6 alkyl; Each R 7 These are independently C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 heteroalkyl, C1-C6 haloalkyl, halo, oxo, cyano, and NR. B C(O)R D -C(O)NR B R C , -C(O)R D or -SR E Alkyl, alkenyl, alkynyl, heteroalkyl and haloalkyl are one or more R 9 It is replaced by an optional choice; or Two R's 7 The groups, together with the atoms to which they are bonded (e.g., X or Y), form 4- to 7-membered cycloalkyl, heterocyclyl, aryl, or heteroaryl groups, and each cycloalkyl, heterocyclyl, aryl, and heteroaryl group has one or more R 9 It is replaced by optional selection; R 8 and R 9These are, independently, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 heteroalkyl, C1-C6 haloalkyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, halo, cyano, oxo, and -OR. A , -NR B R C , -NR B C(O)R D -NO2, -C(O)NR B R C , -C(O)R D , -C(O)OR D , -SR E or -S(O) x R D Each of alkyl, alkenyl, alkynyl, heteroalkyl, haloalkyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl is one or more R 11 It is replaced by optional selection; Each R A These are independently hydrogen, C1-C6 alkyl, C1-C6 haloalkyl, aryl, heteroaryl, C1-C6 alkylene-aryl, C1-C6 alkylene-heteroaryl, and -C(O)R D or -S(O) x R D and; R B and R C Each of these independently consists of hydrogen, C1-C6 alkyl, C1-C6 heteroalkyl, cycloalkyl, heterocyclyl, and -OR. A is; or R B and R C Along with the atoms to which they are bonded, one or more R 10 It forms a 3- to 7-membered heterocyclyl ring which is optionally substituted; Each R D and R EThese are independently hydrogen, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 heteroalkyl, C1-C6 haloalkyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, C1-C6 alkylene-aryl, or C1-C6 alkylene-heteroaryl; Each R 10 These are independently C1-C6 alkyl or halo; Each R 11 These are independently C1-C6 alkyl, C1-C6 heteroalkyl, C1-C6 haloalkyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, halo, cyano, oxo, or -OR A and; Each R 12 These are independently deuterium, C1-C6 alkyl, C1-C6 heteroalkyl, C1-C6 haloalkyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, halo, cyano, oxo, or -OR A and; n is 0, 1, 2, 3 or 4; and x is 0, 1, or 2. The compound or its pharmaceutically acceptable salt, solvate, hydrate, tautomer, or stereoisomer.

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

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

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

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

[0140] In some embodiments, A is [ka] In some embodiments, A is [ka] In some embodiments, A is [ka] In some embodiments, A is [ka] In some embodiments, A is [ka] In some embodiments, A is [ka] In some embodiments, A is [ka] In some embodiments, A is [ka] In some embodiments, A is [ka] In some embodiments, A is [ka] In some embodiments, A is [ka] That is the case.

[0141] In some embodiments, B is [ka] (In the formula, R 1 (as defined herein) Selected from. In some embodiments, B is [ka] Selected from. In some embodiments, B is [ka] In some embodiments, B is [ka] In some embodiments, B is [ka] In some embodiments, B is [ka] In some embodiments, B is [ka] In some embodiments, B is [ka] In some embodiments, B is [ka] In some embodiments, B is [ka] That is the case.

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

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

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

[0145] In some embodiments, one of D, E, and F is N(R 5f ) and the others of D, E and F are, independently of each other, C(R 5d )(R5e ) In some embodiments, D, E, and F are independently N(R 5f ) and the others of D, E and F are C(R 5d )(R 5e ) In some embodiments, D is N(R 5f ) and E and F are independent of each other, C(R 5d )(R 5e ) is. In some embodiments, E is N(R 5f ) and D and F are independent of each other, C(R 5d )(R 5e ) is. In some embodiments, F is N(R 5f ) and D and E are independently C(R 5d )(R 5e ) In some embodiments, D is NH, E is C(O), and F is CH2. In some embodiments, D is CH2, E is NH, and F is C(O). In some embodiments, D is NH, E is CH, and F is C(O).

[0146] In some embodiments, [ka] teeth, [ka] (In the formula, R 7 (and n are as defined above.) Alternatively, they are selected from their tautomers.

[0147] In some embodiments, [ka] teeth, [ka] Selected from.

[0148] In some embodiments, [ka] teeth, [ka] Selected from: In some embodiments, [ka] teeth, [ka] That is the case.

[0149] In some embodiments, the compound of formula (I) is formula (Ie): [ka] (In the formula, A and B each independently have one or more R 1 The cycloalkyl, heterocyclyl, aryl, or heteroaryl elements are optionally substituted; L is absent, C1-C6 alkylene, C1-C6 heteroalkylene, -O-, -C(O)-, -N(R 3 )-,-N(R 3 )C(O)- or -C(O)N(R 3 )- and each alkylene and heteroalkylene is one or more R 4 It is replaced by optional selection; D, E, and F are each independent of C(R 5d ), C(R 5d )(R 5e ), N, N(R 5f), S or O, and the bonds between atoms in a ring containing D, E and F can be single or double bonds, depending on the valence; Each R 1 These are independently hydrogen, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 heteroalkyl, C1-C6 haloalkyl, cycloalkyl, heterocyclyl, aryl, C1-C6 alkylene-aryl, C1-C6 alkenylene-aryl, C1-C6 alkylene-heteroaryl, heteroaryl, halo, cyano, oxo, -OR A , -NR B R C , -NR B C(O)R D -NO2, -C(O)NR B R C , -C(O)R D , -C(O)OR D , -SR E or -S(O) x R D Each alkyl, alkylene, alkenyl, alkenylene, alkynyl, heteroalkyl, haloalkyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl is one or more R 8 It is replaced by an optional choice; or Two R's 1 The groups, together with the atoms to which they are bonded, form 3- to 7-membered cycloalkyl, heterocyclyl, aryl, or heteroaryl groups, and each cycloalkyl, heterocyclyl, aryl, and heteroaryl group has one or more R groups. 8 It is replaced by optional selection; Each R 2 These are independently hydrogen, halo, cyano, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, or -OR A and; Each R 3 These are independently hydrogen, C1-C6 alkyl, C1-C6 heteroalkyl, C1-C6 haloalkyl, cycloalkyl, or heterocyclyl; each alkyl, heteroalkyl, haloalkyl, cycloalkyl, and heterocyclyl is one or more R 12 It is replaced by optional selection; Each R 4 C1-C6 alkyl, C1-C6 heteroalkyl, C1-C6 haloalkyl, cycloalkyl, halo, cyano, oxo, -OR A , -NR B R C , -C(O)R D or -C(O)OR D and; R 5d and R 5e Each of these is independently hydrogen, a halo, or a C1-C6 alkyl group; or R 5d and R 5e They combine to form an oxo group; R 5f is hydrogen, halo, or C1-C6 alkyl; Each R 7 These are independently C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 heteroalkyl, C1-C6 haloalkyl, halo, oxo, cyano, and NR. B C(O)R D -C(O)NR B R C , -C(O)R D or -SR E Alkyl, alkenyl, alkynyl, heteroalkyl and haloalkyl are one or more R 9 It is replaced by an optional choice; or Two R's 7 The groups, together with the atoms to which they are bonded (e.g., X or Y), form 4- to 7-membered cycloalkyl, heterocyclyl, aryl, or heteroaryl groups, and each cycloalkyl, heterocyclyl, aryl, and heteroaryl group has one or more R 9 It is replaced by optional selection; R 8 and R 9 These are, independently, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 heteroalkyl, C1-C6 haloalkyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, halo, cyano, oxo, and -OR. A , -NR B RC , -NR B C(O)R D -NO2, -C(O)NR B R C , -C(O)R D , -C(O)OR D , -SR E or -S(O) x R D Each of alkyl, alkenyl, alkynyl, heteroalkyl, haloalkyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl is one or more R 11 It is replaced by optional selection; Each R A These are independently hydrogen, C1-C6 alkyl, C1-C6 haloalkyl, aryl, heteroaryl, C1-C6 alkylene-aryl, C1-C6 alkylene-heteroaryl, and -C(O)R D or -S(O) x R D and; R B and R C Each of these independently consists of hydrogen, C1-C6 alkyl, C1-C6 heteroalkyl, cycloalkyl, heterocyclyl, and -OR. A is; or R B and R C Along with the atoms to which they are bonded, one or more R 10 It forms a 3- to 7-membered heterocyclyl ring which is optionally substituted; Each R D and R E These are independently hydrogen, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 heteroalkyl, C1-C6 haloalkyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, C1-C6 alkylene-aryl, or C1-C6 alkylene-heteroaryl; Each R 10 These are independently C1-C6 alkyl or halo; Each R 11These are independently C1-C6 alkyl, C1-C6 heteroalkyl, C1-C6 haloalkyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, halo, cyano, oxo, or -OR A and; Each R 12 These are independently deuterium, C1-C6 alkyl, C1-C6 heteroalkyl, C1-C6 haloalkyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, halo, cyano, oxo, or -OR A and; m is 0, 1, or 2. n is 0, 1, 2, 3 or 4; and x is 0, 1, or 2. The compound or its pharmaceutically acceptable salt, solvate, hydrate, tautomer, or stereoisomer.

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

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

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

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

[0154] In some embodiments, A is [ka] In some embodiments, A is [ka] In some embodiments, A is [ka] In some embodiments, A is [ka] In some embodiments, A is [ka] In some embodiments, A is [ka] In some embodiments, A is [ka] In some embodiments, A is [ka] In some embodiments, A is [ka] In some embodiments, A is [ka] In some embodiments, A is [ka] That is the case.

[0155] In some embodiments, B is [ka] (In the formula, R 1 (as defined herein) Selected from. In some embodiments, B is [ka] Selected from. In some embodiments, B is [ka] In some embodiments, B is [ka] In some embodiments, B is [ka] In some embodiments, B is [ka] In some embodiments, B is [ka] In some embodiments, B is [ka] In some embodiments, B is [ka] In some embodiments, B is [ka] That is the case.

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

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

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

[0159] In some embodiments, one of D, E, and F is N(R 5f ) and the others of D, E and F are, independently of each other, C(R 5d )(R 5e ) In some embodiments, D, E, and F are independently N(R 5f ) and the others of D, E and F are C(R 5d )(R 5e ) In some embodiments, D is N(R 5f ) and E and F are independent of each other, C(R 5d)(R 5e ) is. In some embodiments, E is N(R 5f ) and D and F are independent of each other, C(R 5d )(R 5e ) is. In some embodiments, F is N(R 5f ) and D and E are independently C(R 5d )(R 5e ) In some embodiments, D is NH, E is C(O), and F is CH2. In some embodiments, D is CH2, E is NH, and F is C(O). In some embodiments, D is NH, E is CH, and F is C(O).

[0160] In some embodiments, [ka] teeth, [ka] (In the formula, R 7 (and n are as defined above.) Alternatively, they are selected from their tautomers.

[0161] In some embodiments, [ka] teeth, [ka] Selected from.

[0162] In some embodiments, [ka] teeth, [ka] Selected from: In some embodiments, [ka] teeth, [ka] That is the case.

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

[0164] In some embodiments, the compound of formula (I) is formula (If): [ka] (In the formula, A 1 Each of these is one or more R 1 A 6-membered cycloalkyl, heterocyclyl, aryl, or heteroaryl which is optionally substituted; B 1 Each of these is one or more R 1 A 5-membered cycloalkyl, heterocyclyl, aryl, or heteroaryl which is optionally substituted, L is absent, C1-C6 alkylene, C1-C6 heteroalkylene, -O-, -C(O)-, -N(R 3 )-,-N(R 3 )C(O)- or -C(O)N(R 3 )- and each alkylene and heteroalkylene is one or more R4 It is replaced by optional selection; M and P are independent of each other, C(R 2 ) or N; D, E, and F are each independent of C, C(R) 5d ), C(R 5d )(R 5e ), N, N(R 5f ), S or O; Each R 1 These are independently hydrogen, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 heteroalkyl, C1-C6 haloalkyl, cycloalkyl, heterocyclyl, aryl, C1-C6 alkylene-aryl, C1-C6 alkenylene-aryl, C1-C6 alkylene-heteroaryl, heteroaryl, halo, cyano, oxo, -OR A , -NR B R C , -NR B C(O)R D -NO2, -C(O)NR B R C , -C(O)R D , -C(O)OR D , -SR E or -S(O) x R D Each alkyl, alkylene, alkenyl, alkenylene, alkynyl, heteroalkyl, haloalkyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl is one or more R 8 It is replaced by an optional choice; or Two R's 1 The groups, together with the atoms to which they are bonded, form 3- to 7-membered cycloalkyl, heterocyclyl, aryl, or heteroaryl groups, and each cycloalkyl, heterocyclyl, aryl, and heteroaryl group has one or more R groups. 8 It is replaced by optional selection; Each R 2 These are independently hydrogen, halo, cyano, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, or -OR A and; Each R 3These are independently hydrogen, C1-C6 alkyl, or C1-C6 haloalkyl; Each R 4 C1-C6 alkyl, C1-C6 heteroalkyl, C1-C6 haloalkyl, cycloalkyl, halo, cyano, oxo, -OR A , -NR B R C , -C(O)R D or -C(O)OR D and; R 5d and R 5e Each of these is independently hydrogen, a halo, or a C1-C6 alkyl group; or R 5d and R 5e They combine to form an oxo group; R 5f is hydrogen, halo, or C1-C6 alkyl; Each R 7 These are independently C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 heteroalkyl, C1-C6 haloalkyl, halo, oxo, cyano, and NR. B C(O)R D -C(O)NR B R C , -C(O)R D or -SR E Alkyl, alkenyl, alkynyl, heteroalkyl and haloalkyl are one or more R 9 It is replaced by an optional choice; or Two R's 7 The groups, together with the atoms to which they are bonded (e.g., X or Y), form 4- to 7-membered cycloalkyl, heterocyclyl, aryl, or heteroaryl groups, and each cycloalkyl, heterocyclyl, aryl, and heteroaryl group has one or more R 9 It is replaced by optional selection; R 8 and R 9These are, independently, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 heteroalkyl, C1-C6 haloalkyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, halo, cyano, oxo, and -OR. A , -NR B R C , -NR B C(O)R D -NO2, -C(O)NR B R C , -C(O)R D , -C(O)OR D , -SR E or -S(O) x R D Each of alkyl, alkenyl, alkynyl, heteroalkyl, haloalkyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl is one or more R 11 It is replaced by optional selection; Each R A These are independently hydrogen, C1-C6 alkyl, C1-C6 haloalkyl, aryl, heteroaryl, C1-C6 alkylene-aryl, C1-C6 alkylene-heteroaryl, and -C(O)R D or -S(O) x R D and; R B and R C Each of these independently consists of hydrogen, C1-C6 alkyl, C1-C6 heteroalkyl, cycloalkyl, heterocyclyl, and -OR. A is; or R B and R C Along with the atoms to which they are bonded, one or more R 10 It forms a 3- to 7-membered heterocyclyl ring which is optionally substituted; Each R D and R EThese are independently hydrogen, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 heteroalkyl, C1-C6 haloalkyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, C1-C6 alkylene-aryl, or C1-C6 alkylene-heteroaryl; Each R 10 These are independently C1-C6 alkyl or halo; Each R 11 These are independently C1-C6 alkyl, C1-C6 heteroalkyl, C1-C6 haloalkyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, halo, cyano, oxo, or -OR A and; m is 0, 1, or 2. n is 0, 1, 2, 3 or 4; and x is 0, 1, or 2. The compound or its pharmaceutically acceptable salt, solvate, hydrate, tautomer, or stereoisomer.

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

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

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

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

[0169] In some embodiments, A is [ka] In some embodiments, A is [ka] In some embodiments, A is [ka] In some embodiments, A is [ka] In some embodiments, A is [ka] In some embodiments, A is [ka] In some embodiments, A is [ka] In some embodiments, A is [ka] In some embodiments, A is [ka] In some embodiments, A is [ka] In some embodiments, A is [ka] That is the case.

[0170] In some embodiments, B is [ka] (In the formula, R 1 (as defined herein) Selected from. In some embodiments, B is [ka] Selected from. In some embodiments, B is [ka] In some embodiments, B is [ka] In some embodiments, B is [ka] In some embodiments, B is [ka] In some embodiments, B is [ka] In some embodiments, B is [ka] In some embodiments, B is [ka] In some embodiments, B is [ka] That is the case.

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

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

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

[0174] In some embodiments, one of D, E, and F is N(R 5f ) and the others of D, E and F are, independently of each other, C(R 5d )(R 5e ) In some embodiments, D, E, and F are independently N(R 5f ) and the others of D, E and F are C(R 5d )(R5e ) In some embodiments, D is N(R 5f ) and E and F are independent of each other, C(R 5d )(R 5e ) is. In some embodiments, E is N(R 5f ) and D and F are independent of each other, C(R 5d )(R 5e ) is. In some embodiments, F is N(R 5f ) and D and E are independently C(R 5d )(R 5e ) In some embodiments, D is NH, E is C(O), and F is CH2. In some embodiments, D is CH2, E is NH, and F is C(O). In some embodiments, D is NH, E is CH, and F is C(O).

[0175] In some embodiments, [ka] teeth, [ka] (In the formula, R 7 (and n are as defined above.) Alternatively, they are selected from their tautomers.

[0176] In some embodiments, [ka] teeth, [ka] Selected from.

[0177] In some embodiments, [ka] teeth, [ka] Selected from: In some embodiments, [ka] teeth, [ka] That is the case.

[0178] In some embodiments, L is absent. In some embodiments, L is oxygen. In some embodiments, L is R 3 This is nitrogen optionally substituted with R. In some embodiments, L is R 3 It is nitrogen substituted with R. In some embodiments, 3 L is a C1-C6 alkyl group. In some embodiments, L is -N(CH3)-. In some embodiments, L is -NH-.

[0179] In some embodiments, the compound of formula (I) is formula (Ig): [ka] (In the formula, A 1 Each of these is one or more R 1 A 6-membered cycloalkyl, heterocyclyl, aryl, or heteroaryl which is optionally substituted; B 1 Each of these is one or more R 1 A 5-membered cycloalkyl, heterocyclyl, aryl, or heteroaryl which is optionally substituted, L is absent, C1-C6 alkylene, C1-C6 heteroalkylene, -O-, -C(O)-, -N(R3 )-,-N(R 3 )C(O)- or -C(O)N(R 3 )- and each alkylene and heteroalkylene is one or more R 4 It is replaced by optional selection; D, E, and F are each independent of C, C(R) 5d ), C(R 5d )(R 5e ), N, N(R 5f ), S or O; Each R 1 These are independently hydrogen, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 heteroalkyl, C1-C6 haloalkyl, cycloalkyl, heterocyclyl, aryl, C1-C6 alkylene-aryl, C1-C6 alkenylene-aryl, C1-C6 alkylene-heteroaryl, heteroaryl, halo, cyano, oxo, -OR A , -NR B R C , -NR B C(O)R D -NO2, -C(O)NR B R C , -C(O)R D , -C(O)OR D , -SR E or -S(O) x R D Each alkyl, alkylene, alkenyl, alkenylene, alkynyl, heteroalkyl, haloalkyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl is one or more R 8 It is replaced by an optional choice; or Two R's 1 The groups, together with the atoms to which they are bonded, form 3- to 7-membered cycloalkyl, heterocyclyl, aryl, or heteroaryl groups, and each cycloalkyl, heterocyclyl, aryl, and heteroaryl group has one or more R groups. 8 It is replaced by optional selection; Each R 2 These are independently hydrogen, halo, cyano, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, or -OR Aand; Each R 3 These are independently hydrogen, C1-C6 alkyl, or C1-C6 haloalkyl; Each R 4 C1-C6 alkyl, C1-C6 heteroalkyl, C1-C6 haloalkyl, cycloalkyl, halo, cyano, oxo, -OR A , -NR B R C , -C(O)R D or -C(O)OR D and; R 5d and R 5e Each of these is independently hydrogen, a halo, or a C1-C6 alkyl group; or R 5d and R 5e They combine to form an oxo group; R 5f is hydrogen, halo, or C1-C6 alkyl; Each R 7 These are independently C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 heteroalkyl, C1-C6 haloalkyl, halo, oxo, cyano, and NR. B C(O)R D -C(O)NR B R C , -C(O)R D or -SR E Alkyl, alkenyl, alkynyl, heteroalkyl and haloalkyl are one or more R 9 It is replaced by an optional choice; or Two R's 7 The groups, together with the atoms to which they are bonded (e.g., X or Y), form 4- to 7-membered cycloalkyl, heterocyclyl, aryl, or heteroaryl groups, and each cycloalkyl, heterocyclyl, aryl, and heteroaryl group has one or more R 9 It is replaced by optional selection; R 8 and R 9These are, independently, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 heteroalkyl, C1-C6 haloalkyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, halo, cyano, oxo, and -OR. A , -NR B R C , -NR B C(O)R D -NO2, -C(O)NR B R C , -C(O)R D , -C(O)OR D , -SR E or -S(O) x R D Each of alkyl, alkenyl, alkynyl, heteroalkyl, haloalkyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl is one or more R 11 It is replaced by optional selection; Each R A These are independently hydrogen, C1-C6 alkyl, C1-C6 haloalkyl, aryl, heteroaryl, C1-C6 alkylene-aryl, C1-C6 alkylene-heteroaryl, and -C(O)R D or -S(O) x R D and; R B and R C Each of these independently consists of hydrogen, C1-C6 alkyl, C1-C6 heteroalkyl, cycloalkyl, heterocyclyl, and -OR. A is; or R B and R C Along with the atoms to which they are bonded, one or more R 10 It forms a 3- to 7-membered heterocyclyl ring which is optionally substituted; Each R D and R EThese are independently hydrogen, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 heteroalkyl, C1-C6 haloalkyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, C1-C6 alkylene-aryl, or C1-C6 alkylene-heteroaryl; Each R 10 These are independently C1-C6 alkyl or halo; Each R 11 These are independently C1-C6 alkyl, C1-C6 heteroalkyl, C1-C6 haloalkyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, halo, cyano, oxo, or -OR A and; m is 0, 1, or 2. n is 0, 1, 2, 3 or 4; and x is 0, 1, or 2. The compound or its pharmaceutically acceptable salt, solvate, hydrate, tautomer, or stereoisomer.

[0180] In some embodiments, A 1 is one or more R 1 A is a 6-membered heterocycline that has been optionally substituted. In some embodiments, A 1 A is a 6-membered nitrogen-containing heterocycline. In some embodiments, A 1 is a piperidinil that has been optionally substituted. In some embodiments, A 1 teeth, [ka] In some embodiments, A 1 teeth, [ka] In some embodiments, A 1 teeth, [ka] In some embodiments, A 1 teeth, [ka] In some embodiments, A 1 teeth, [ka] In some embodiments, A1 is [ka] In some embodiments, A1 is [ka] In some embodiments, A1 is [ka] In some embodiments, A1 is [ka] That is the case.

[0181] In some embodiments, L is R 3 It is nitrogen substituted with. In some embodiments, L is -N(CH3)-. In some embodiments, L is -NH-. In some embodiments, B 1 is one or more R 1 It is a 5-membered heteroaryl substituted by optional choice. In some embodiments, B 1 This is a 5-membered nitrogen-containing heteroaryl. In some embodiments, B 1 is a pyrazolyl that has been optionally substituted. In some embodiments, B1 is [ka] In some embodiments, B1 is [ka] In some embodiments, B1 is [ka] In some embodiments, B1 is [ka] In some embodiments, B1 is [ka] In some embodiments, B1 is [ka] In some embodiments, B1 is [ka] In some embodiments, B1 is [ka] In some embodiments, B1 is [ka] In some embodiments, B1 is [ka] In some embodiments, B1 is [ka] In some embodiments, B1 is [ka] In some embodiments, B1 is [ka] That is the case.

[0182] In some embodiments, [ka] teeth, [ka] Selected from.

[0183] In some embodiments, [ka] teeth, [ka] Selected from: In some embodiments, [ka] teeth, [ka] That is the case.

[0184] In some embodiments, the compound of formula (I) is of formula (Ih): [ka] (In the formula, A and B each independently have one or more R 1 The cycloalkyl, heterocyclyl, aryl, or heteroaryl elements are optionally substituted; M and P are independent of each other, C(R 2 ) or N; D, E, and F are each independent of C(R 5d ), C(R 5d )(R 5e ), N, N(R 5f ), S or O, and the bonds between atoms in a ring containing D, E and F can be single or double bonds, depending on the valence; Each R 1 These are independently hydrogen, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 heteroalkyl, C1-C6 haloalkyl, cycloalkyl, heterocyclyl, aryl, C1-C6 alkylene-aryl, C1-C6 alkenylene-aryl, C1-C6 alkylene-heteroaryl, heteroaryl, halo, cyano, oxo, -OR A , -NR B R C , -NR B C(O)R D -NO2, -C(O)NR B R C , -C(O)R D , -C(O)OR D , -SR E or -S(O) x R D Each alkyl, alkylene, alkenyl, alkenylene, alkynyl, heteroalkyl, haloalkyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl is one or more R 8 It is replaced by an optional choice; or Two R's 1 The groups, together with the atoms to which they are bonded, form 3- to 7-membered cycloalkyl, heterocyclyl, aryl, or heteroaryl groups, and each cycloalkyl, heterocyclyl, aryl, and heteroaryl group has one or more R groups. 8It is replaced by optional selection; Each R 2 These are independently hydrogen, halo, cyano, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, or -OR A and; Each R 3 These are independently hydrogen, C1-C6 alkyl, C1-C6 heteroalkyl, C1-C6 haloalkyl, cycloalkyl, or heterocyclyl; each alkyl, heteroalkyl, haloalkyl, cycloalkyl, and heterocyclyl is one or more R 12 It is replaced by optional selection; R 5d and R 5e Each of these is independently hydrogen, a halo, or a C1-C6 alkyl group; or R 5d and R 5e They combine to form an oxo group; R 5f is hydrogen, halo, or C1-C6 alkyl; Each R 7 These are independently C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 heteroalkyl, C1-C6 haloalkyl, halo, oxo, cyano, and NR. B C(O)R D -C(O)NR B R C , -C(O)R D or -SR E Alkyl, alkenyl, alkynyl, heteroalkyl and haloalkyl are one or more R 9 It is replaced by an optional choice; or Two R's 7 The groups, together with the atoms to which they are bonded (e.g., X or Y), form 4- to 7-membered cycloalkyl, heterocyclyl, aryl, or heteroaryl groups, and each cycloalkyl, heterocyclyl, aryl, and heteroaryl group has one or more R 9 It is replaced by optional selection; R 8 and R 9These are, independently, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 heteroalkyl, C1-C6 haloalkyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, halo, cyano, oxo, and -OR. A , -NR B R C , -NR B C(O)R D -NO2, -C(O)NR B R C , -C(O)R D , -C(O)OR D , -SR E or -S(O) x R D Each of alkyl, alkenyl, alkynyl, heteroalkyl, haloalkyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl is one or more R 11 It is replaced by optional selection; Each R A These are independently hydrogen, C1-C6 alkyl, C1-C6 haloalkyl, aryl, heteroaryl, C1-C6 alkylene-aryl, C1-C6 alkylene-heteroaryl, and -C(O)R D or -S(O) x R D and; R B and R C Each of these independently consists of hydrogen, C1-C6 alkyl, C1-C6 heteroalkyl, cycloalkyl, heterocyclyl, and -OR. A is; or R B and R C Along with the atoms to which they are bonded, one or more R 10 It forms a 3- to 7-membered heterocyclyl ring which is optionally substituted; Each R D and R EThese are independently hydrogen, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 heteroalkyl, C1-C6 haloalkyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, C1-C6 alkylene-aryl, or C1-C6 alkylene-heteroaryl; Each R 10 These are independently C1-C6 alkyl or halo; Each R 11 These are independently C1-C6 alkyl, C1-C6 heteroalkyl, C1-C6 haloalkyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, halo, cyano, oxo, or -OR A and; Each R 12 These are independently deuterium, C1-C6 alkyl, C1-C6 heteroalkyl, C1-C6 haloalkyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, halo, cyano, oxo, or -OR A and; m is 0, 1, or 2. n is 0, 1, 2, 3 or 4; and x is 0, 1, or 2. The compound or its pharmaceutically acceptable salt, solvate, hydrate, tautomer, or stereoisomer.

[0185] In some embodiments, the compound of formula (I) is formula (Ii): [ka] (In the formula, A and B each independently have one or more R 1 The cycloalkyl, heterocyclyl, aryl, or heteroaryl elements are optionally substituted; M and P are independent of each other, C(R 2 ) or N; D, E, and F are each independent of C(R 5d ), C(R 5d )(R 5e ), N, N(R 5f), S or O, and the bonds between atoms in a ring containing D, E and F can be single or double bonds, depending on the valence; Each R 1 These are independently hydrogen, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 heteroalkyl, C1-C6 haloalkyl, cycloalkyl, heterocyclyl, aryl, C1-C6 alkylene-aryl, C1-C6 alkenylene-aryl, C1-C6 alkylene-heteroaryl, heteroaryl, halo, cyano, oxo, -OR A , -NR B R C , -NR B C(O)R D -NO2, -C(O)NR B R C , -C(O)R D , -C(O)OR D , -SR E or -S(O) x R D Each alkyl, alkylene, alkenyl, alkenylene, alkynyl, heteroalkyl, haloalkyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl is one or more R 8 It is replaced by an optional choice; or Two R's 1 The groups, together with the atoms to which they are bonded, form 3- to 7-membered cycloalkyl, heterocyclyl, aryl, or heteroaryl groups, and each cycloalkyl, heterocyclyl, aryl, and heteroaryl group has one or more R groups. 8 It is replaced by optional selection; Each R 2 These are independently hydrogen, halo, cyano, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, or -OR A and; R 5d and R 5e Each of these is independently hydrogen, a halo, or a C1-C6 alkyl group; or R 5d and R 5e They combine to form an oxo group; R 5fis hydrogen, halo, or C1-C6 alkyl; Each R 7 These are independently C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 heteroalkyl, C1-C6 haloalkyl, halo, oxo, cyano, and NR. B C(O)R D -C(O)NR B R C , -C(O)R D or -SR E Alkyl, alkenyl, alkynyl, heteroalkyl and haloalkyl are one or more R 9 It is replaced by an optional choice; or Two R's 7 The groups, together with the atoms to which they are bonded (e.g., X or Y), form 4- to 7-membered cycloalkyl, heterocyclyl, aryl, or heteroaryl groups, and each cycloalkyl, heterocyclyl, aryl, and heteroaryl group has one or more R 9 It is replaced by optional selection; R 8 and R 9 These are, independently, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 heteroalkyl, C1-C6 haloalkyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, halo, cyano, oxo, and -OR. A , -NR B R C , -NR B C(O)R D -NO2, -C(O)NR B R C , -C(O)R D , -C(O)OR D , -SR E or -S(O) x R D Each of alkyl, alkenyl, alkynyl, heteroalkyl, haloalkyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl is one or more R 11 It is replaced by optional selection; Each R AThese are independently hydrogen, C1-C6 alkyl, C1-C6 haloalkyl, aryl, heteroaryl, C1-C6 alkylene-aryl, C1-C6 alkylene-heteroaryl, and -C(O)R D or -S(O) x R D and; R B and R C Each of these independently consists of hydrogen, C1-C6 alkyl, C1-C6 heteroalkyl, cycloalkyl, heterocyclyl, and -OR. A is; or R B and R C Along with the atoms to which they are bonded, one or more R 10 It forms a 3- to 7-membered heterocyclyl ring which is optionally substituted; Each R D and R E These are independently hydrogen, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 heteroalkyl, C1-C6 haloalkyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, C1-C6 alkylene-aryl, or C1-C6 alkylene-heteroaryl; Each R 10 These are independently C1-C6 alkyl or halo; Each R 11 These are independently C1-C6 alkyl, C1-C6 heteroalkyl, C1-C6 haloalkyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, halo, cyano, oxo, or -OR A and; m is 0, 1, or 2. n is 0, 1, 2, 3 or 4; and x is 0, 1, or 2. The compound or its pharmaceutically acceptable salt, solvate, hydrate, tautomer, or stereoisomer.

[0186] In some embodiments, the compound of formula (I) is formula (Ij): [ka] (In the formula, A and B each independently have one or more R 1 The cycloalkyl, heterocyclyl, aryl, or heteroaryl elements are optionally substituted; M and P are independent of each other, C(R 2 ) or N; D, E, and F are each independent of C(R 5d ), C(R 5d )(R 5e ), N, N(R 5f ), S or O, and the bonds between atoms in a ring containing D, E and F can be single or double bonds, depending on the valence; Each R 1 These are independently hydrogen, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 heteroalkyl, C1-C6 haloalkyl, cycloalkyl, heterocyclyl, aryl, C1-C6 alkylene-aryl, C1-C6 alkenylene-aryl, C1-C6 alkylene-heteroaryl, heteroaryl, halo, cyano, oxo, -OR A , -NR B R C , -NR B C(O)R D -NO2, -C(O)NR B R C , -C(O)R D , -C(O)OR D , -SR E or -S(O) x R D Each alkyl, alkylene, alkenyl, alkenylene, alkynyl, heteroalkyl, haloalkyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl is one or more R 8 It is replaced by an optional choice; or Two R's 1 The groups, together with the atoms to which they are bonded, form 3- to 7-membered cycloalkyl, heterocyclyl, aryl, or heteroaryl groups, and each cycloalkyl, heterocyclyl, aryl, and heteroaryl group has one or more R groups. 8It is replaced by optional selection; Each R 2 These are independently hydrogen, halo, cyano, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, or -OR A and; R 5d and R 5e Each of these is independently hydrogen, a halo, or a C1-C6 alkyl group; or R 5d and R 5e They combine to form an oxo group; R 5f is hydrogen, halo, or C1-C6 alkyl; Each R 7 These are independently C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 heteroalkyl, C1-C6 haloalkyl, halo, oxo, cyano, and NR. B C(O)R D -C(O)NR B R C , -C(O)R D or -SR E Alkyl, alkenyl, alkynyl, heteroalkyl and haloalkyl are one or more R 9 It is replaced by an optional choice; or Two R's 7 The groups, together with the atoms to which they are bonded (e.g., X or Y), form 4- to 7-membered cycloalkyl, heterocyclyl, aryl, or heteroaryl groups, and each cycloalkyl, heterocyclyl, aryl, and heteroaryl group has one or more R 9 It is replaced by optional selection; R 8 and R 9 These are, independently, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 heteroalkyl, C1-C6 haloalkyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, halo, cyano, oxo, and -OR. A , -NR B R C , -NR B C(O)R D -NO2, -C(O)NRB R C , -C(O)R D , -C(O)OR D , -SR E or -S(O) x R D Each of alkyl, alkenyl, alkynyl, heteroalkyl, haloalkyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl is one or more R 11 It is replaced by optional selection; Each R A These are independently hydrogen, C1-C6 alkyl, C1-C6 haloalkyl, aryl, heteroaryl, C1-C6 alkylene-aryl, C1-C6 alkylene-heteroaryl, and -C(O)R D or -S(O) x R D and; R B and R C Each of these independently consists of hydrogen, C1-C6 alkyl, C1-C6 heteroalkyl, cycloalkyl, heterocyclyl, and -OR. A is; or R B and R C Along with the atoms to which they are bonded, one or more R 10 It forms a 3- to 7-membered heterocyclyl ring which is optionally substituted; Each R D and R E These are independently hydrogen, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 heteroalkyl, C1-C6 haloalkyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, C1-C6 alkylene-aryl, or C1-C6 alkylene-heteroaryl; Each R 10 These are independently C1-C6 alkyl or halo; Each R 11 These are independently C1-C6 alkyl, C1-C6 heteroalkyl, C1-C6 haloalkyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, halo, cyano, oxo, or -OR A and; m is 0, 1, or 2. n is 0, 1, 2, 3 or 4; and x is 0, 1, or 2. The compound or its pharmaceutically acceptable salt, solvate, hydrate, tautomer, or stereoisomer.

[0187] In some embodiments, the compound of formula (I) is formula (Ik): [ka] (In the formula, A and B each independently have one or more R 1 The cycloalkyl, heterocyclyl, aryl, or heteroaryl elements are optionally substituted; L is absent, C1-C6 alkylene, C1-C6 heteroalkylene, -O-, -C(O)-, -N(R 3 )-,-N(R 3 )C(O)- or -C(O)N(R 3 )- and each alkylene and heteroalkylene is one or more R 4 It is replaced by optional selection; M and P are independent of each other, C(R 2 ) or N; F is C(R 5d ) or N; Each R 1 These are independently hydrogen, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 heteroalkyl, C1-C6 haloalkyl, cycloalkyl, heterocyclyl, aryl, C1-C6 alkylene-aryl, C1-C6 alkenylene-aryl, C1-C6 alkylene-heteroaryl, heteroaryl, halo, cyano, oxo, -OR A , -NR B R C , -NR B C(O)R D -NO2, -C(O)NR B R C , -C(O)R D , -C(O)ORD , -SR E or -S(O) x R D Each alkyl, alkylene, alkenyl, alkenylene, alkynyl, heteroalkyl, haloalkyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl is one or more R 8 It is replaced by an optional choice; or Two R's 1 The groups, together with the atoms to which they are bonded, form 3- to 7-membered cycloalkyl, heterocyclyl, aryl, or heteroaryl groups, and each cycloalkyl, heterocyclyl, aryl, and heteroaryl group has one or more R groups. 8 It is replaced by optional selection; Each R 2 These are independently hydrogen, halo, cyano, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, or -OR A and; Each R 3 These are independently hydrogen, C1-C6 alkyl, C1-C6 heteroalkyl, C1-C6 haloalkyl, cycloalkyl, or heterocyclyl; each alkyl, heteroalkyl, haloalkyl, cycloalkyl, and heterocyclyl is one or more R 12 It is replaced by optional selection; Each R 4 C1-C6 alkyl, C1-C6 heteroalkyl, C1-C6 haloalkyl, cycloalkyl, halo, cyano, oxo, -OR A , -NR B R C , -C(O)R D or -C(O)OR D and; R 5d is hydrogen, halo, or C1-C6 alkyl; R 5f is hydrogen, halo, or C1-C6 alkyl; Each R 7 These are independently C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 heteroalkyl, C1-C6 haloalkyl, halo, oxo, cyano, and NR. B C(O)RD -C(O)NR B R C , -C(O)R D or -SR E Alkyl, alkenyl, alkynyl, heteroalkyl and haloalkyl are one or more R 9 It is replaced by an optional choice; or Two R's 7 The groups, together with the atoms to which they are bonded (e.g., X or Y), form 4- to 7-membered cycloalkyl, heterocyclyl, aryl, or heteroaryl groups, and each cycloalkyl, heterocyclyl, aryl, and heteroaryl group has one or more R 9 It is replaced by optional selection; R 8 and R 9 These are, independently, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 heteroalkyl, C1-C6 haloalkyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, halo, cyano, oxo, and -OR. A , -NR B R C , -NR B C(O)R D -NO2, -C(O)NR B R C , -C(O)R D , -C(O)OR D , -SR E or -S(O) x R D Each of alkyl, alkenyl, alkynyl, heteroalkyl, haloalkyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl is one or more R 11 It is replaced by optional selection; Each R A These are independently hydrogen, C1-C6 alkyl, C1-C6 haloalkyl, aryl, heteroaryl, C1-C6 alkylene-aryl, C1-C6 alkylene-heteroaryl, and -C(O)R D or -S(O) x R D and; R B and RC Each of these independently consists of hydrogen, C1-C6 alkyl, C1-C6 heteroalkyl, cycloalkyl, heterocyclyl, and -OR. A is; or R B and R C Along with the atoms to which they are bonded, one or more R 10 It forms a 3- to 7-membered heterocyclyl ring which is optionally substituted; Each R D and R E These are independently hydrogen, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 heteroalkyl, C1-C6 haloalkyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, C1-C6 alkylene-aryl, or C1-C6 alkylene-heteroaryl; Each R 10 These are independently C1-C6 alkyl or halo; Each R 11 These are independently C1-C6 alkyl, C1-C6 heteroalkyl, C1-C6 haloalkyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, halo, cyano, oxo, or -OR A and; Each R 12 These are independently deuterium, C1-C6 alkyl, C1-C6 heteroalkyl, C1-C6 haloalkyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, halo, cyano, oxo, or -OR A and; m is 0, 1, or 2. n is 0, 1, 2, 3 or 4; and x is 0, 1, or 2. The compound or its pharmaceutically acceptable salt, solvate, hydrate, tautomer, or stereoisomer.

[0188] In some embodiments, the compound of formula (I) is: [ka] (In the formula, A and B each independently have one or more R 1 The cycloalkyl, heterocyclyl, aryl, or heteroaryl elements are optionally substituted; L is absent, C1-C6 alkylene, C1-C6 heteroalkylene, -O-, -C(O)-, -N(R 3 )-,-N(R 3 )C(O)- or -C(O)N(R 3 )- and each alkylene and heteroalkylene is one or more R 4 It is replaced by optional selection; F is C(R 5d ) or N; Each R 1 These are independently hydrogen, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 heteroalkyl, C1-C6 haloalkyl, cycloalkyl, heterocyclyl, aryl, C1-C6 alkylene-aryl, C1-C6 alkenylene-aryl, C1-C6 alkylene-heteroaryl, heteroaryl, halo, cyano, oxo, -OR A , -NR B R C , -NR B C(O)R D -NO2, -C(O)NR B R C , -C(O)R D , -C(O)OR D , -SR E or -S(O) x R D Each alkyl, alkylene, alkenyl, alkenylene, alkynyl, heteroalkyl, haloalkyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl is one or more R 8 It is replaced by an optional choice; or Two R's 1 The groups, together with the atoms to which they are bonded, form 3- to 7-membered cycloalkyl, heterocyclyl, aryl, or heteroaryl groups, and each cycloalkyl, heterocyclyl, aryl, and heteroaryl group has one or more R groups. 8 It is replaced by optional selection; Each R 2 These are independently hydrogen, halo, cyano, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, or -OR A and; Each R 3 These are independently hydrogen, C1-C6 alkyl, C1-C6 heteroalkyl, C1-C6 haloalkyl, cycloalkyl, or heterocyclyl; each alkyl, heteroalkyl, haloalkyl, cycloalkyl, and heterocyclyl is one or more R 12 It is replaced by optional selection; Each R 4 C1-C6 alkyl, C1-C6 heteroalkyl, C1-C6 haloalkyl, cycloalkyl, halo, cyano, oxo, -OR A , -NR B R C , -C(O)R D or -C(O)OR D and; R 5d is hydrogen, halo, or C1-C6 alkyl; R 5f is hydrogen, halo, or C1-C6 alkyl; Each R 7 These are independently C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 heteroalkyl, C1-C6 haloalkyl, halo, oxo, cyano, and NR. B C(O)R D -C(O)NR B R C , -C(O)R D or -SR E Alkyl, alkenyl, alkynyl, heteroalkyl and haloalkyl are one or more R 9 It is replaced by an optional choice; or Two R's 7 The groups, together with the atoms to which they are bonded (e.g., X or Y), form 4- to 7-membered cycloalkyl, heterocyclyl, aryl, or heteroaryl groups, and each cycloalkyl, heterocyclyl, aryl, and heteroaryl group has one or more R 9 It is replaced by optional selection; R 8 and R 9 These are, independently, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 heteroalkyl, C1-C6 haloalkyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, halo, cyano, oxo, and -OR. A , -NR B R C , -NR B C(O)R D -NO2, -C(O)NR B R C , -C(O)R D , -C(O)OR D , -SR E or -S(O) x R D Each of alkyl, alkenyl, alkynyl, heteroalkyl, haloalkyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl is one or more R 11 It is replaced by optional selection; Each R A These are independently hydrogen, C1-C6 alkyl, C1-C6 haloalkyl, aryl, heteroaryl, C1-C6 alkylene-aryl, C1-C6 alkylene-heteroaryl, and -C(O)R D or -S(O) x R D and; R B and R C Each of these independently consists of hydrogen, C1-C6 alkyl, C1-C6 heteroalkyl, cycloalkyl, heterocyclyl, and -OR. A is; or R B and R C Along with the atoms to which they are bonded, one or more R 10 It forms a 3- to 7-membered heterocyclyl ring which is optionally substituted; Each R D and R EThese are independently hydrogen, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 heteroalkyl, C1-C6 haloalkyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, C1-C6 alkylene-aryl, or C1-C6 alkylene-heteroaryl; Each R 10 These are independently C1-C6 alkyl or halo; Each R 11 These are independently C1-C6 alkyl, C1-C6 heteroalkyl, C1-C6 haloalkyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, halo, cyano, oxo, or -OR A and; Each R 12 These are independently deuterium, C1-C6 alkyl, C1-C6 heteroalkyl, C1-C6 haloalkyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, halo, cyano, oxo, or -OR A and; m is 0, 1, or 2. n is 0, 1, 2, 3 or 4; and x is 0, 1, or 2. The compound or its pharmaceutically acceptable salt, solvate, hydrate, tautomer, or stereoisomer.

[0189] In some embodiments, the compound of formula (I) is formula (Im): [ka] (In the formula, A and B each independently have one or more R 1 The cycloalkyl, heterocyclyl, aryl, or heteroaryl elements are optionally substituted; L is absent, C1-C6 alkylene, C1-C6 heteroalkylene, -O-, -C(O)-, -N(R 3 )-,-N(R 3 )C(O)- or -C(O)N(R 3 )- and each alkylene and heteroalkylene is one or more R4 It is replaced by optional selection; M and P are independent of each other, C(R 2 ) or N; F is C(R 5d ) or N; Each R 1 These are independently hydrogen, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 heteroalkyl, C1-C6 haloalkyl, cycloalkyl, heterocyclyl, aryl, C1-C6 alkylene-aryl, C1-C6 alkenylene-aryl, C1-C6 alkylene-heteroaryl, heteroaryl, halo, cyano, oxo, -OR A , -NR B R C , -NR B C(O)R D -NO2, -C(O)NR B R C , -C(O)R D , -C(O)OR D , -SR E or -S(O) x R D Each alkyl, alkylene, alkenyl, alkenylene, alkynyl, heteroalkyl, haloalkyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl is one or more R 8 It is replaced by an optional choice; or Two R's 1 The groups, together with the atoms to which they are bonded, form 3- to 7-membered cycloalkyl, heterocyclyl, aryl, or heteroaryl groups, and each cycloalkyl, heterocyclyl, aryl, and heteroaryl group has one or more R groups. 8 It is replaced by optional selection; Each R 2 These are independently hydrogen, halo, cyano, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, or -OR A and; Each R 3These are independently hydrogen, C1-C6 alkyl, C1-C6 heteroalkyl, C1-C6 haloalkyl, cycloalkyl, or heterocyclyl; each alkyl, heteroalkyl, haloalkyl, cycloalkyl, and heterocyclyl is one or more R 12 It is replaced by optional selection; Each R 4 C1-C6 alkyl, C1-C6 heteroalkyl, C1-C6 haloalkyl, cycloalkyl, halo, cyano, oxo, -OR A , -NR B R C , -C(O)R D or -C(O)OR D and; R 5d is hydrogen, halo, or C1-C6 alkyl; R 5f is hydrogen, halo, or C1-C6 alkyl; Each R 7 These are independently C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 heteroalkyl, C1-C6 haloalkyl, halo, oxo, cyano, and NR. B C(O)R D -C(O)NR B R C , -C(O)R D or -SR E Alkyl, alkenyl, alkynyl, heteroalkyl and haloalkyl are one or more R 9 It is replaced by an optional choice; or Two R's 7 The groups, together with the atoms to which they are bonded (e.g., X or Y), form 4- to 7-membered cycloalkyl, heterocyclyl, aryl, or heteroaryl groups, and each cycloalkyl, heterocyclyl, aryl, and heteroaryl group has one or more R 9 It is replaced by optional selection; R 8 and R 9These are, independently, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 heteroalkyl, C1-C6 haloalkyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, halo, cyano, oxo, and -OR. A , -NR B R C , -NR B C(O)R D -NO2, -C(O)NR B R C , -C(O)R D , -C(O)OR D , -SR E or -S(O) x R D Each of alkyl, alkenyl, alkynyl, heteroalkyl, haloalkyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl is one or more R 11 It is replaced by optional selection; Each R A These are independently hydrogen, C1-C6 alkyl, C1-C6 haloalkyl, aryl, heteroaryl, C1-C6 alkylene-aryl, C1-C6 alkylene-heteroaryl, and -C(O)R D or -S(O) x R D and; R B and R C Each of these independently consists of hydrogen, C1-C6 alkyl, C1-C6 heteroalkyl, cycloalkyl, heterocyclyl, and -OR. A is; or R B and R C Along with the atoms to which they are bonded, one or more R 10 It forms a 3- to 7-membered heterocyclyl ring which is optionally substituted; Each R D and R EThese are independently hydrogen, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 heteroalkyl, C1-C6 haloalkyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, C1-C6 alkylene-aryl, or C1-C6 alkylene-heteroaryl; Each R 10 These are independently C1-C6 alkyl or halo; Each R 11 These are independently C1-C6 alkyl, C1-C6 heteroalkyl, C1-C6 haloalkyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, halo, cyano, oxo, or -OR A and; Each R 12 These are independently deuterium, C1-C6 alkyl, C1-C6 heteroalkyl, C1-C6 haloalkyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, halo, cyano, oxo, or -OR A and; m is 0, 1, or 2. n is 0, 1, 2, 3 or 4; and x is 0, 1, or 2. The compound or its pharmaceutically acceptable salt, solvate, hydrate, tautomer, or stereoisomer.

[0190] In some embodiments, the compound of formula (I) is of formula (In): [ka] (In the formula, A and B each independently have one or more R 1 The cycloalkyl, heterocyclyl, aryl, or heteroaryl elements are optionally substituted; L is absent, C1-C6 alkylene, C1-C6 heteroalkylene, -O-, -C(O)-, -N(R 3 )-,-N(R 3 )C(O)- or -C(O)N(R 3 )- and each alkylene and heteroalkylene is one or more R4 It is replaced by optional selection; M and P are independent of each other, C(R 2 ) or N; F is C(R 5d ) or N; Each R 1 These are independently hydrogen, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 heteroalkyl, C1-C6 haloalkyl, cycloalkyl, heterocyclyl, aryl, C1-C6 alkylene-aryl, C1-C6 alkenylene-aryl, C1-C6 alkylene-heteroaryl, heteroaryl, halo, cyano, oxo, -OR A , -NR B R C , -NR B C(O)R D -NO2, -C(O)NR B R C , -C(O)R D , -C(O)OR D , -SR E or -S(O) x R D Each alkyl, alkylene, alkenyl, alkenylene, alkynyl, heteroalkyl, haloalkyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl is one or more R 8 It is replaced by an optional choice; or Two R's 1 The groups, together with the atoms to which they are bonded, form 3- to 7-membered cycloalkyl, heterocyclyl, aryl, or heteroaryl groups, and each cycloalkyl, heterocyclyl, aryl, and heteroaryl group has one or more R groups. 8 It is replaced by optional selection; Each R 2 These are independently hydrogen, halo, cyano, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, or -OR A and; Each R 3These are independently hydrogen, C1-C6 alkyl, C1-C6 heteroalkyl, C1-C6 haloalkyl, cycloalkyl, or heterocyclyl; each alkyl, heteroalkyl, haloalkyl, cycloalkyl, and heterocyclyl is one or more R 12 It is replaced by optional selection; Each R 4 C1-C6 alkyl, C1-C6 heteroalkyl, C1-C6 haloalkyl, cycloalkyl, halo, cyano, oxo, -OR A , -NR B R C , -C(O)R D or -C(O)OR D and; R 5d is hydrogen, halo, or C1-C6 alkyl; Each R 7 These are independently C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 heteroalkyl, C1-C6 haloalkyl, halo, oxo, cyano, and NR. B C(O)R D -C(O)NR B R C , -C(O)R D or -SR E Alkyl, alkenyl, alkynyl, heteroalkyl and haloalkyl are one or more R 9 It is replaced by an optional choice; or Two R's 7 The groups, together with the atoms to which they are bonded (e.g., X or Y), form 4- to 7-membered cycloalkyl, heterocyclyl, aryl, or heteroaryl groups, and each cycloalkyl, heterocyclyl, aryl, and heteroaryl group has one or more R 9 It is replaced by optional selection; R 8 and R 9 These are, independently, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 heteroalkyl, C1-C6 haloalkyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, halo, cyano, oxo, and -OR. A , -NR B RC , -NR B C(O)R D -NO2, -C(O)NR B R C , -C(O)R D , -C(O)OR D , -SR E or -S(O) x R D Each of alkyl, alkenyl, alkynyl, heteroalkyl, haloalkyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl is one or more R 11 It is replaced by optional selection; Each R A These are independently hydrogen, C1-C6 alkyl, C1-C6 haloalkyl, aryl, heteroaryl, C1-C6 alkylene-aryl, C1-C6 alkylene-heteroaryl, and -C(O)R D or -S(O) x R D and; R B and R C Each of these independently consists of hydrogen, C1-C6 alkyl, C1-C6 heteroalkyl, cycloalkyl, heterocyclyl, and -OR. A is; or R B and R C Along with the atoms to which they are bonded, one or more R 10 It forms a 3- to 7-membered heterocyclyl ring which is optionally substituted; Each R D and R E These are independently hydrogen, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 heteroalkyl, C1-C6 haloalkyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, C1-C6 alkylene-aryl, or C1-C6 alkylene-heteroaryl; Each R 10 These are independently C1-C6 alkyl or halo; Each R 11These are independently C1-C6 alkyl, C1-C6 heteroalkyl, C1-C6 haloalkyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, halo, cyano, oxo, or -OR A and; Each R 12 These are independently deuterium, C1-C6 alkyl, C1-C6 heteroalkyl, C1-C6 haloalkyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, halo, cyano, oxo, or -OR A and; m is 0, 1, or 2. n is 0, 1, 2, 3 or 4; and x is 0, 1, or 2. The compound or its pharmaceutically acceptable salt, solvate, hydrate, tautomer, or stereoisomer.

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

[0192] [Table 1]

[0193] [Table 2]

[0194] [Table 3]

[0195] [Table 4]

[0196] [Table 5]

[0197] [Table 6]

[0198] Table 7

[0199] Table 8

[0200] Table 9

[0201] Table 10

[0202] Table 11

[0203] Table 12

[0204] Table 13

[0205] Table 14

[0206] Table 15

[0207] Table 16

[0208] [Table 17]

[0209] [Table 18]

[0210] [Table 19]

[0211] [Table 20]

[0212] [Table 21]

[0213] [Table 22]

[0214] Pharmaceutical compositions, kits, and administrations The present invention provides a pharmaceutical composition comprising a compound of formula (I), for example, a compound of formula (I) or a pharmaceutically acceptable salt, solvate, hydrate, tautomer or stereoisomer described herein, and optionally a pharmaceutically acceptable excipient. In certain embodiments, the pharmaceutical composition described herein comprises a compound of formula (I) or a pharmaceutically acceptable salt thereof, and optionally a pharmaceutically acceptable excipient. In certain embodiments, the compound of formula (I) or a pharmaceutically acceptable salt thereof, solvate, hydrate, tautomer or stereoisomer is provided in an effective amount in the pharmaceutical composition. In certain embodiments, the effective amount is a therapeutic effective amount. In certain embodiments, the effective amount is a prophylactic effective amount.

[0215] The pharmaceutical compositions described herein can be prepared by any method known in the field of pharmacology. Generally, such preparation methods include the steps of associating a compound of formula (I) ("active ingredient") with a carrier and / or one or more other auxiliary ingredients, and, if necessary and / or desirable, then shaping and / or packaging the product into desired single or multi-dose units.

[0216] Pharmaceutical compositions may be prepared, packaged and / or sold in bulk as a single unit dose and / or as multiple single unit doses. As used herein, “unit dose” refers to a specific amount of a pharmaceutical composition containing a predetermined amount of the active ingredient. The amount of the active ingredient is generally equal to the dose of the active ingredient that would be administered to a subject and / or a convenient proportion of such a dose, for example, half or one-third of such a dose.

[0217] The relative amounts of the active ingredient, pharmaceutically acceptable excipients, and / or any further components in the pharmaceutical composition of the present invention vary depending on the identity, size, and / or condition of the target being treated, and further on the route through which the composition is administered. For example, the composition may contain 0.1% to 100% (w / w) of the active ingredient.

[0218] The term "pharmaceutically acceptable excipient" refers to a non-toxic carrier, adjuvant, diluent, or vehicle that does not impair the pharmacological activity of the compound being formulated. Pharmaceutically acceptable excipients useful in the manufacture of the pharmaceutical compositions of the present invention are any of those well known in the field of pharmaceutical formulations and include inert diluents, dispersants and / or granulators, surfactants and / or emulsifiers, disintegrants, binders, preservatives, buffers, lubricants and / or oils. pharmaceutically acceptable excipients useful in the production of the pharmaceutical compositions of the present invention include, but are not limited to, ion exchangers, alumina, aluminum stearate, lecithin, serum proteins such as human serum albumin, buffering substances such as phosphates, glycine, sorbic acid, potassium sorbate, partial glyceride mixtures of saturated vegetable fatty acids, water, protamine sulfate or electrolytes, disodium hydrogen phosphate, potassium hydrogen phosphate, sodium chloride, zinc salts, colloidal silica, magnesium trisilicate, polyvinylpyrrolidone, cellulose-based substances, polyethylene glycol, sodium carboxymethylcellulose, polyacrylates, waxes, polyethylene-polyoxypropylene-block polymers, polyethylene glycol, and lanolin fat.

[0219] The compositions of the present invention may be administered orally, parenterally (including subcutaneously, intramuscularly, intravenously, and intradermally), by inhalation spray, topically, rectally, nasally, orally, vaginally, or via an implanted reservoir. In some embodiments, the provided compounds or compositions may be administered intravenously and / or orally.

[0220] As used herein, the term “parenteral” includes subcutaneous, intravenous, intramuscular, intraocular, intravitreous, intraarticular, intrasynovial, intrasternal, subarachnoid, intrahepatic, intraperitoneal, intralesional, and intracranial injection or infusion techniques. Preferably, the composition is administered orally, subcutaneously, intraperitoneally, or intravenously. The sterile injectable forms of the compositions of the present invention may be aqueous or oily suspensions. These suspensions may be formulated according to techniques known in the art using appropriate dispersing or wetting and suspending agents. The sterile injectable formulation may also be a sterile injectable solution or suspension in a non-toxic, parenterally acceptable diluent or solvent, such as a solution in 1,3-butanediol. Acceptable vehicles and solvents that may be used include water, Ringer's solution, and isotonic sodium chloride solution. Furthermore, sterile fixative oils have conventionally been used as solvents or suspension media.

[0221] The pharmaceutically acceptable compositions of the present invention may be administered orally in any orally acceptable dosage form, including but not limited to capsules, tablets, aqueous suspensions, or solutions. For tablets for oral administration, commonly used carriers include lactose and corn starch. Lubricants such as magnesium stearate are also typically added. For oral administration in capsule form, useful diluents include lactose and dried corn starch. If an aqueous suspension is required for oral administration, the active ingredient is combined with an emulsifier and suspending agent. Specific sweeteners, flavorings, or colorings may be added as needed. In some embodiments, the oral formulations provided are formulated for immediate release or sustained / delayed release. In some embodiments, the compositions are suitable for oral or sublingual administration and include tablets, lozenges, and troches. The compounds provided may be in microencapsulated form.

[0222] Alternatively, the pharmaceutically acceptable compositions of the present invention may be administered in the form of suppositories for rectal administration. The pharmaceutically acceptable compositions of the present invention may be administered topically, particularly when the target of treatment includes areas or organs that are easily accessible by topical application, including diseases of the eyes, skin, or lower intestines. Appropriate topical formulations can be readily prepared for each of these areas or organs.

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

[0224] To prolong the effects of a drug, it is often desirable to slow down its absorption from subcutaneous or intramuscular injection. This can be achieved by using a liquid suspension of crystalline or amorphous material with low solubility in water. The absorption rate of the drug then depends on its dissolution rate, which may also depend on the crystal size and form. Alternatively, delayed absorption of parenterally administered drug dosage forms is achieved by dissolving or suspending the drug in an oil vehicle.

[0225] The descriptions of pharmaceutical compositions provided herein primarily concern pharmaceutical compositions suitable for administration to humans, but it will be understood by those skilled in the art that such compositions are generally suitable for administration to all kinds of animals. Modifications of pharmaceutical compositions suitable for administration to humans to make them suitable for administration to various animals are well understood, and veterinary pharmacologists with ordinary skills can design and / or carry out such modifications in ordinary experiments.

[0226] The compounds provided herein are typically formulated in dose unit form, e.g., single-unit dosage form, for ease of administration and uniformity of dosage. However, it will be understood that the total daily dose of the compositions of the present invention is to be determined by the attending physician within the bounds of sound medical judgment. A specific therapeutically effective dose level for any particular subject or organism depends on a variety of factors, including the severity of the disease and disorder being treated; the activity of the specific active ingredient used; the specific composition used; the subject's age, weight, general health, sex, and diet; the timing of administration, route of administration, and rate of excretion of the specific active ingredient used; the duration of treatment; drugs used in combination with or concurrently with the specific active ingredient used; and similar factors well known in the medical field.

[0227] The precise amount of compound required to achieve an effective dose varies from subject to subject, depending on factors such as the species, age, and overall health condition of the subject, the severity of side effects or disorders, the identity of the specific compound, and the mode of administration. The desired dose can be delivered three times a day, twice a day, once a day, every other day, every three days, weekly, every two weeks, every three weeks, or every four weeks. In certain embodiments, the desired dose can be delivered using multiple doses (e.g., two, three, four, five, six, seven, eight, nine, ten, eleven, twelve, thirteen, fourteen or more doses).

[0228] In certain embodiments, an effective amount of the compound for administration to a 70 kg adult human being once or more daily may contain, per unit dosage form, about 0.0001 mg to about 3000 mg, about 0.0001 mg to about 2000 mg, about 0.0001 mg to about 1000 mg, about 0.001 mg to about 1000 mg, about 0.01 mg to about 1000 mg, about 0.1 mg to about 1000 mg, about 1 mg to about 1000 mg, about 1 mg to about 100 mg, about 10 mg to about 1000 mg, or about 100 mg to about 1000 mg of the compound.

[0229] In certain embodiments, the compound of formula (I) may be at a dose level sufficient to deliver, at least once daily, about 0.001 mg / kg to about 100 mg / kg, about 0.01 mg / kg to about 50 mg / kg, preferably about 0.1 mg / kg to about 40 mg / kg, preferably about 0.5 mg / kg to about 30 mg / kg, about 0.01 mg / kg to about 10 mg / kg, about 0.1 mg / kg to about 10 mg / kg, more preferably about 1 mg / kg to about 25 mg / kg relative to the subject's body weight per day.

[0230] It will be understood that the dose ranges described herein are intended to provide guidelines for administering the provided pharmaceutical compositions to adults. For example, the amount administered to children or adolescents may be determined by a physician or a person skilled in the art and may be lower or the same as the amount administered to adults.

[0231] It will also be understood that the compounds or compositions described herein may be administered in combination with one or more additional agents. The compounds or compositions may be administered in combination with further agents that improve their bioavailability, reduce and / or alter their metabolism, inhibit their excretion, and / or alter their distribution in the body. It will also be understood that the treatments employed may achieve the desired effect on the same disorder and / or different effects.

[0232] The compound or composition may be administered simultaneously with, or before or after, one or more additional agents that may be useful, for example, as a combination therapy. The agents may include therapeutic activators. The agents may also include prophylactic activators. Each additional agent may be administered in a dose and / or time schedule determined for that agent. The additional agents may be administered together and / or in single doses with the compounds or compositions described herein, or separately in different doses. The specific combination used in the regimen should take into account the compatibility of the compounds of the present invention with the additional agents and / or the desired therapeutic and / or prophylactic effects to be achieved. Generally, additional agents used in combination are expected to be used at levels not exceeding those used individually. In some embodiments, the combined level is lower than the level used individually.

[0233] Further exemplary drugs include, but are not limited to, antiproliferative agents, anticancer agents, antidiabetic agents, anti-inflammatory agents, immunosuppressants, and analgesics. Drugs include drug compounds (e.g., compounds listed in the Code of Federal Regulations (CFR) and approved by the U.S. Food and Drug Administration), peptides, proteins, carbohydrates, monosaccharides, oligosaccharides, polysaccharides, nucleoproteins, mucoproteins, lipoproteins, synthetic polypeptides or proteins, small molecules bound to proteins, glycoproteins, steroids, nucleic acids, DNA, RNA, nucleotides, nucleosides, oligonucleotides, antisense oligonucleotides, lipids, hormones, vitamins, and small organic molecules such as cells.

[0234] Kits (e.g., pharmaceutical packs) are also included in the present invention. Kits of the present invention may be useful for preventing and / or treating proliferative or nonproliferative disorders, for example, as described herein. A kit provided may comprise a pharmaceutical composition or compound of the present invention and a container (e.g., a vial, ampoule, bottle, syringe and / or dispenser package or other suitable container). In some embodiments, a kit provided may optionally further comprise a second container containing a pharmaceutical excipient for dilution or suspension of the pharmaceutical composition or compound of the present invention. In some embodiments, the container and the pharmaceutical composition or compound of the present invention provided in the second container are combined to form a single dosage form.

[0235] Accordingly, in one embodiment, a kit is provided comprising a first container containing a compound described herein or a pharmaceutically acceptable salt, solvate, hydrate, tautomer or stereoisomer thereof, or a pharmaceutical composition thereof. In a particular embodiment, the kit of the present disclosure comprises a first container containing a compound described herein or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof. In a particular embodiment, the kit is useful for the prevention and / or treatment of a disease, disorder or condition described herein (e.g., proliferative or non-proliferative disorders) in a subject. In a particular embodiment, the kit further comprises instructions for administering the compound or a pharmaceutically acceptable salt, solvate, hydrate, tautomer or stereoisomer thereof, or a pharmaceutical composition thereof, to a subject for the prevention and / or treatment of a proliferative or non-proliferative disorder.

[0236] How to use Compounds useful for modulating splicing are described herein. In some embodiments, compounds of formula (I) can be used to increase or decrease splicing at splice sites, thereby altering the quantity, structure, or composition of nucleic acids (e.g., precursor RNA, e.g., premRNA or the resulting mRNA). In some embodiments, increasing or decreasing splicing modulates the level or structure of the gene product produced (e.g., RNA or protein). In some embodiments, compounds of formula (I) can modulate components of a splicing mechanism, for example, by modulating the interaction between components of the splicing mechanism and another entity (e.g., nucleic acids, proteins or combinations thereof). The splicing mechanisms referred to herein include one or more spliceosome components. Spliceosome components may include, for example, major spliceosome members (U1, U2, U4, U5, U6snRNP) or minor spliceosome members (U11, U12, U4atac, U6atacsnRNP) and one or more of their co-splicing factors.

[0237] In another embodiment, the present disclosure features a method for modifying a target (e.g., precursor RNA, e.g., premRNA) by including a splice site in the target, comprising providing a compound of formula (I). In some embodiments, the inclusion of a splice site in the target (e.g., precursor RNA, e.g., premRNA or the resulting mRNA) results in the addition or deletion of one or more nucleic acids to the target (e.g., new exons, e.g., skipped exons). The addition or deletion of one or more nucleic acids to the target may result in an increase in the level of the gene product (e.g., RNA, e.g., mRNA or protein).

[0238] In another embodiment, the present disclosure features a method for modifying a target (e.g., precursor RNA, e.g., premRNA or obtained mRNA) by eliminating a splice site in the target, the method comprising providing a compound of formula (I). In some embodiments, the elimination of a splice site in the target (e.g., precursor RNA, e.g., premRNA) results in the deletion or addition of one or more nucleic acids from the target (e.g., skipped exons, e.g., new exons). The deletion or addition of one or more nucleic acids to the target may result in a decrease in the level of the gene product (e.g., RNA, e.g., mRNA or protein). In other embodiments, a method for modifying a target (e.g., precursor RNA, e.g., premRNA or the resulting mRNA) includes, for example, suppressing or enhancing splicing at the splice site (e.g., more than about 0.5%, e.g., 1%, 5%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, 99%, or more) compared to a reference (e.g., the absence of the compound of formula (I) or healthy or diseased cells or tissue).

[0239] The methods described herein can be used, for example, to modulate the splicing of nucleic acids containing a specific sequence (e.g., a target sequence). Exemplary genes encoding a target sequence (e.g., DNA or RNA, including premRNA) include, in particular, ABCA4, ABCA9, ABCB1, ABCB5, ABCC9, ABCD1, ACADL, ACADM, ACADSB, ACSS2, ACTB, ACTG2, ADA, ADAL, ADAM10, ADAM15, ADAM22, ADAM32, ADAMTS12, ADAMTS13, ADAMTS20, ADAMTS6, ADAMTS9, ADAR, ADCY3, ADCY10, ADCY8, ADNP, ADRBK2, AFP, AGL, AGT, AHCTF1, AHR, AKAP10, AKAP3, AKNA, ALAS1, ALS2CL, ALB, ALDH3A2, ALG6, AMBRA1, ANK3, ANTXR2, ANXA10, ANXA11, A NGPTL3, AP2A2, AP4E1, APC, APOA1, APOB, APOC3, APOH, AR, ARID2, ARID3A, ARID3B, ARFGEF1, ARFGEF2, ARHGAP1, ARHGAP8, ARHGAP18, ARHGAP26 , ARHGEF18, ARHGEF2, ARPC3, ARS2, ASH1L, ASH1L-IT1, ASNSD1, ASPM, ATAD5, ATF1, ATG4A, ATG16L2, ATM, ATN1, ATP11C, ATP6V1G3, ATP13A5, AT P7A, ATP7B, ATR, ATXN2, ATXN3, ATXN7, ATXN10, AXIN1, B2M, B4GALNT3, BBS4, BCL2, BCL2L1, BCL2-like 11 (BIM), BCL11B, BBOX1, BCS1L, BEAN1, BHLH E40, BMPR2, BMP2K, BPTF, BRAF, BRCA1, BRCA2, BRCC3, BRSK1, BRSK2, BTAF1, BTK, C2orf55, C4orf29, C6orf118, C9orf43, C9orf72, C10orf137, C11orf30, C11orf65, C11orf70, C11οrf87, C12orf51, C13orf1, C13orf15, C14orf10l, C14orf118, C15orf29, C15orf42, C15orf60, C16orf33,C16orf38、C16orf48、C18orf8、C19orf42、C1orf107、C1orf114、C1orf130、 C1orf149、C1orf27、C1orf71、C1orf94、C1R、C20orf74、C21orf70、C3orf23 、C4orf18、C5orf34、C8B、C8orf33、C9orf114、C9orf86、C9orf98、C3、CA11、 CAB39、CACHD1、CACNA1A、CACNA1B、CACNA1C、CACNA2D1、CACNA1G、CACNA1H、C ALCA、CALCOCO2、CAMK1D、CAMKK1、CAPN3、CAPN9、CAPSL、CARD11、CARKD、CAS Z1、CAT、CBLB、CBX1、CBX3、CCDC102B、CCDC11、CCDC15、CCDC18、CCDC5、CCDC 81、CCDC131、CCDC146、CD4、CD274、CD1B、CDC14A、CDC16、CDC2L5、CDC42BPB 、CDCA8、CDH10、CDH11、CDH24、CDH8、CDH9、CDK5RAP2、CDK6、CDK8、CDK11B、CD 33、CD46、CDH1、CDH23、CDK6、CDK11B、CDK13、CEBPZ、CEL、CELSR3、CENPA、CE NPI、CENPT、CENTB2、CENTG2、CEP110、CEP170、CEP192、CETP、CFB、CFTR、CFH 、CGN、CGNL1、CHAF1A、CHD9、CHIC2、CHL1、CHN1、CHM、CLEC16A、CL1C2、CLCN1 、CLINT1、CLK1、CLPB、CLPTM1、CMIP、CMYA5、CNGA3、CNOT1、CNOT7、CNTN6、COG 3、COL11A1、COL11A2、COL12A1、COL14A1、COL15A1、COL17A1、COL19A1、COL1 A1、COL1A2、COL2A1、COL3A1、COL4A1、COL4A2、COL4A5、COL4A6、COL5A2、COL6 A1、COL7A1、COL9A1、COL9A2、COL22A1、COL24A1、COL25A1、COL29A1、COLQ、C OMTD1、COPA、COPB2、COPS7B、COPZ2、CPSF2、CPXM2、CR1、CRBN、CRYZ、CREBBP、CRKRS、CSE1L、CSTB、CSTF3、CT45-6、CTNNB1、CUBN、CUL4B、CUL5、CXorf41、C XXC1、CYBB、CYFIP2、CYP3A4、CYP3A43、CYP3A5、CYP4F2、CYP4F3、CYP17、CYP 19, CYP24A1, CYP27A1, DAB1, DAZ2, DCBLD1, DCC, DCTN3, DCUN1D4, DDA1, DDEF1, DDX1, DDX24, DDX4, DENND2D, DEPDC2, DES, DGAT2, DHFR, DHRS7, DHRS9, DH X8, DIP2A, DMD, DMTF1, DNAH3, DNAH8, DNAI1, DNAJA4, DNAJC13, DNAJC7, DNM T1、DNTTIP2、DOCK4、DOCK5、DOCK10、DOCK11、DOT1L、DPP3、DPP4、DPY19L2P2、 DR1、DSCC1、DVL3、DUX4、DYNC1H1、DYSF、E2F1、E2F3、E2F8、E4F1、EBF1、EBF3 、ECM2、EDEM3、EFCAB3、EFCAB4B、EFNA4、EFTUD2、EGFR、EIF3A、ELA1、ELA2A、E LF2、ELF3、ELF4、EMCN、EMD、EML5、ENO3、ENPP3、EP300、EPAS1、EPB41L5、EPH A3、EPHA4、EPHB1、EPHB2、EPHB3、EPS15、ERBB4、ERCC1、ERCC8、ERGIC3、ERMN、 ERMP1, ERN1, ERN2, ESR1, ESRRG, ETS2, ETV3, ETV4, ETV5, ETV6, EVC2, EWSR1, EXO1, EXOC4, F3, F11, F13A1, F5, F7, F8, FAH, FAM13A1, FAM13B1, FAM13C1, F AM134A, FAM161A, FAM176B, FAM184A, FAM19A1, FAM20A, FAM23B, FAM65C, FANCA, FANCC, FANCG, FANCM, FANK1, FAR2, FBN1, FBXO15, FBXO18, FBXO38, FCGB P、FECH、FEZ2、FGA、FGD6、FGFR2、FGFR1OP、FGFR1OP2、FGFR2、FGG、FGR、FIX、 FKBP3、FLI1、FLJ35848、FLJ36070、FLNA、FN1、FNBP1L、FOLH1、FOSL1、FOSL2、FOXK1, FOXM1, FOXO1, FOXP4, FRAS1, FUT9, FXN, FZD3, FZD6, GAB1, GABPA, GALC, GALNT3, GAPDH, GART, GAS2L3, GATA3, GATAD2A, GBA, GBGT1, GCG, GCGR, G CK、GFI1、GFM1、GH1、GHR、GHV、GJA1、GLA、GLT8D1、GNA11、GNAQ、GNAS、GNB5、 GOLGB1、GOLT1A、GOLT1B、GPATCH1、GPR158、GPR160、GPX4、GRAMD3、GRHL1、GR HL2, GRHPR, GRIA1, GRIA3, GRIA4, GRIN2B, GRM3, GRM4, GRN, GSDMB, GSTCD, GSTO2, GTF2I, GTPBP4, HADHA, HAND2, HBA2, HBB, HKK, HDAC3, HDAC5, HDX, HEP ACAM2、HERC1、HES7、HEXA、HEXB、HHEX、HIPK3、HLA-DPB1、HLA-G、HLCS、HLTF 、HMBS、HMGA1、HMGCL、HNF1A、HNF1B、HNF4A、HNF4G、HNRNPH1、HOXC10、HP1BP3 、HPGD、HPRT1、HPRT2、HSF1、HSF4、HSF2BP、HSPA9、HSPG2、HTT、HXA、ICA1、ID H1、IDS、IFI44L、IKBKAP、IKZF1、IKZF3、IL1R2、IL5RA、IL7RA、IMMT、INPP5D 、INSR、INTS3、INTU、IP04、IP08、IQGAP2、IRF2、IRF4、IRF8、IRX3、ISL1、ISL 2、ITFG1、ITGA6、ITGAL、ITGB1、ITGB2、1TGB3、ITGB4、ITIH1、ITPR2、IWS1、JA K1、JAK2、JAG1、JMJD1C、JPH3、KALRN、KAT6A、KATNAL2、KCNN2、KCNT2、KDM2A 、KIAA0256、KIAA0528、KIAA0564、KIAA0586、KIAA1033、KIAA1166、KIAA121 9, KIAA1409, KIAA1622, KIAA1787, KIF3B, KIF15, KIF16B, KIF5A, KIF5B, KIF9, KIN, KIR2DL5B, KIR3DL2, KIR3DL3, KIT, KLF3, KLF5, KLF7, KLF10, KLF12KLF16、KLHL20、KLK12、KLKB1、KMT2A、KMT2B、KPNA5、KRAS、KREMEN1、KRIT1、 KRT5、KRTCAP2、KYNU、L1CAM、L3MBTL、L3MBTL2、LACE1、LAMA1、LAMA2、LAMA3、 LAMB1、LARP7、LDLR、LEF1、LENG1、LGALS3、LGMN、LHCGR、LHX3、LHX6、LIMCH1 、LIMK2、LIN28B、LIN54、LMBRD1、LMBRD2、LMLN、LMNA、LMO2、LMO7、LOC389634 、LOC390110、LPA、LPCAT2、LPL、LRP4、LRPPRC、LRRK2、LRRC19、LRRC42、LRWD 1、LUM、LVRN、LYN、LYST、MADD、MAGI1、MAGT1、MALT1、MAP2K1、MAP4K4、MAPK8I P3、MAPK9、MAPT、MARC1、MARCH5、MATN2、MBD3、MCF2L2、MCM6、MDGA2、MDM4、A SXL1、FUS、SPR54、MECOM、MEF2C、MEF2D、MEGF10、MEGF11、MEMO1、MET、MGA、MG AM、MGAT4A、MGAT5、MGC16169、MGC34774、MKKS、MIB1、MIER2、MITF、MKL2、ML ANA、MLH1、MLL5、MLX、MME、MPDZ、MPI、MRAP2、MRPL11、MRPL39、MRPS28、MRPS3 5、MS4A13、MSH2、MSH3、MSMB、MST1R、MTDH、MTERF3、MTF1、MTF2、MTIF2、MTHF R、MUC2、MUT、MVK、MYB、MYBL2、MYC、MYCBP2、MYH2、MYRF、MYT1、MY019、MY03A、 MY09B、MYOM2、MYOM3、NAG、NARG1、NARG2、NCOA1、NDC80、NDFIP2、NEB、NEDD4 、NEK1、NEK5、ΝΕΚ11、NF1、NF2、NFATC2、NFE2L2、NFIA、NFIB、NFIX、NFKB1、NFK B2, NFKBIL2, NFRKB, NFYA, NFYB, NIPA2, NKAIN2, NKAP, NLRC3, NLRC5, NLRP3, NLRP7, NLRP8, NLRP13, NME1, NME1-NME2, NME2, NME7, NOL10, NOP561, NOS1NOS2A, NOTCH1, NPAS4, NPM1, NR1D1, NR1H3, NR1H4, NR4A3, NR5A1, NRXN1, NSMAF, NSMCE2, NT5C, NT5C2, NT5C3, NUBP1, NUBPL, NUDT5, NUMA1, NUP88, NUP98, N UP160、NUPL1、OAT、OAZ1、OBFC2A、OBFC2B、OLIG2、OMA1、OPA1、OPN4、OPTN、OSBPL11、OSBPL8、OSGEPL1、OTC、OTX2、OVOL2、OXT、PA2G4、PADI4、PAH、PAN2 PAOX、PAPOLG、PARD3、PARP1、PARVB、PAWR、PAX3、PAX8、PBGD、PBRM1、PBX2、PCBP4、PCCA、PCGF2、PCNX、PCOTH、PDCD4、PDE4D、PDE8B、PDE10A、PD1A3、PDH1、 PDLIM5、PDXK、PDZRN3、PELI2、PDK4、PDS5A、PDS5B、PGK1、PGM2、PHACTR4、PHEX、PHKB、PHLDB2、PHOX2B、PHTF1、PIAS1、PIEZO1、PIGF、PIGN、PIGT、PIK3C2 G、PIK3CA、PIK3CD、PIK3CG、PIK3RI、PIP5K1A、PITRM1、PIWIL3、PKD1、PKHD1L1、PKD2、PKIB、PKLR、PKM1、PKM2、PLAGL2、PLCB1、PLCB4、PLCG1、PLD1、PLEKH A5, PLEKHA7, PLEKHM1, PLKR, PLXNC1, PMFBP1, POLN, POLR3D, POMT2, POSTN, POU2AF1, POU2F2, POU2F3, PPARA, PPFIA2, PPP1R12A, PPP3CB, PPP4C, PPP4R1L, PPP4R2, PRAME, PRC1, PRDM1, PREX1, PREX2, PRIM1, PRIM2, PRKAR1A, PRKCA, PRKG1, PRMT7, PROC, PROCR, PROSC, PRODH, PROX1, PRPF40B, PRPF4B, PRRG 2、PRUNE2、PSD3、PSEN1、PSMAL、PTCH1、PTEN、PTK2、PTK2B、PTPN2、PTPN3、PTPN4、PTPN11、PTPN22、PTPRD、PTPRK、PTPRM、PTPRN2、PTPRT、PUS10、PVRL2、PY GM、QRSL1、RAB11FIP2、RAB23、RAF1、RALBP1、RALGDS、RB1CC1、RBL2、RBM39、RBM45、RBPJ、RBSN、REC8、RELB、RFC4、RFT1、RFTN1、RHOA、RHPN2、RIF1、RIT1RLN3、RMND5B、RNF11、RNF32、RNFT1、RNGTT、ROCK1、ROCK2、RORA、RP1、RP6KA3、RP11-265F1、RP13-36C9、RPAP3、RPN1、RPGR、RPL22、RPL22L1、RP6KA6、R REB1、RRM1、RRP1B、RSK2、RTEL1、RTF1、RUFY1、RUNX1、RUNX2、RXRA、RYR3、SAAL1、SAE1、SALL4、SAT1、SATB2、SBCAD、SCN1A、SCN2A、SCN3A、SCN4A、SCN5A、S CN8A, SCNA, SCN11A, SCO1, SCYL3, SDC1, SDK1, SDK2, SEC24A, SEC24D, SEC31A, SEL1L, SENP3, SENP6, SENP7, SERPINA1, SETD3, SETD4, SETDB1, SEZ6, SFRS12, SGCE, SGOL2, SGPL1, SH2D1A, SH3BGRL2, SH3PXD2A, SH3PXD2B, SH3RF2, SH3TC2, SHOC2, SIPA1L2, SIPA1L3, SIVA1, SKAP1, SKIV2L2, SLC6A11, SLC6A1 3、SLC6A6、SLC7A2、SLC12A3、SLC13A1、SLC22A17、SLC25A14、SLC28A3、SLC33A1、SLC35F6、SLC38A1、SLC38A4、SLC39A10、SLC4A2、SLC6A8、SMARCA1、SMA RCA2、SMARCA5、SMARCC2、SMC5、SMN2、SMOX、SMS、SMTN、SNCAIP、SNORD86、SNRK、SNRP70、SNX5、SNX6、SOD1、SOD10、SOS、SOS2、SOX5、SOX6、SOX8、SP1、SP2、 SP3、SP110、SPAG9、SPATA13、SPATA4、SPATS1、SPECC1L、SPDEF、SPI1、SPINK5、SPP2、SPTA1、SRF、SRM、SRP72、SSX3、SSX5、SSX9、STAG1、STAG2、STAMBPLI、 STARD6、STAT1、STAT3、STAT5A、STAT5B、STAT6、STK17B、STX3、STXBP1、SUCLG2、SULF2、SUPT6H、SUPT16H、SV2C、SYCP2、SYT6、SYCPI、SYTL3、SYTL5、TAF2、TARDBP、TBC1D3G、TBC1D8B、TBC1D26、TBC1D29、TBCEL、TBK1、TBP、TBPL1、TB R1、TBX、TCEB3、TCF3、TCF4、TCF7L2、TCFL5、TCF12、TCP11L2、TDRD3、TEAD1、T EAD3, TEAD4, TECTB, TEK, TERF1, TERF2, TET2, TFAP2A, TFAP2B, TFAP2C, TFAP4, TFDP1, TFRC, TG, TGM7, TGS1, THAP7, THAP12, THOC2, TIAL1, TIAM2, TIMM5 0、TLK2、TM4SF20、TM6SF1、TMEM27、TMEM77、TMEM156、TMEM194A、TMF1、TMPR SS6、TNFRSF10A、TNFRSF10B、TNFRSF8、TNK2、TNKS、TNKS2、TOM1L1、TOM1L2、T OP2B、TP53、TP53INP1、TP53BP2、TP53I3、TP63、TRAF3IP3、TRAPPC2、TRIM44 、TRIM65、TRIML1、TRIML2、TRPM3、TRPM5、TRPM7、TRPS1、TSC1、TSC2、TSHB、TS PAN7、TTC17、TTF1、TTLL5、TTLL9、TTN、TTPAL、TTR、TUSC3、TXNDC10、UBE3A、 UCK1、UGT1A1、UHRF1BP1、UNC45B、UNC5C、USH2A、USF2、USP1、USP6、USP18、US P38、USP39、UTP20、UTP15、UTP18、UTRN、UTX、UTY、UVRAG、UXT、VAPA、VEGFA、 VPS29、VPS35、VPS39、VT11A、VT11B、VWA3B、WDFY2、WDR16、WDR17、WDR26、WDR 44, WDR67, WDTC1, WRN, WRNIP1, WT1, WWC3, XBP1, XRN1, XRN2, XX-FW88277, YAP1, YARS, YBX1, YGM, YY1, ZBTB18, ZBTB20, ZC3HAV1, ZC3HC1, ZC3H7A, ZDHHC 19、ZEB1、ZEB2、ZFPM1、ZFYVE1、ZFX、ZIC2、ZNF37A、ZNF91、ZNF114、ZNF155、 ZNF169、ZNF205、ZNF236、ZNF317、ZNF320、ZNF326、ZNF335、ZNF365、ZNF367、This includes ZNF407, ZNF468, ZNF506, ZNF511, ZNF511-PRAP1, ZNF519, ZNF521, ZNF592, ZNF618, ZNF763, and ZWINT.

[0240] Further exemplary genes encoding target sequences (e.g., DNA or RNA, including premRNA) include A1CF, A4GALT, AAR2, ABAT, ABCA11P, ZNF721, ABCA5, ABHD10, ABHD13, ABHD2, ABHD6, AC000120.3, KRIT1, AC004076.1, ZNF772, AC004076.9, ZNF772, AC004223.3, RAD51D, AC004381.6, AC006486.1, ERF, AC007390.5, AC007780.1, PRKAR1A, AC007998.2, INO80C, AC009070.1, CMC2, AC009879.2, AC009879.3, ADHFE1, AC010487.3, ZNF816 -ZNF321P, ZNF816, AC010328.3, AC010522.1, ZNF587B, AC010547.4, ZNF19, AC012313.3, ZNF497, AC012651.1, CAPN3, AC013489.1, DE T1, AC016747.4, C2orf74, AC020907.6, FXYD3, AC021087.5, PDCD6, AHRR, AC022137.3, ZNF761, AC025283.3, NAA60, AC027644.4, RAB GEF1, AC055811.2, FLCN, AC069368.3, ANKDD1A, AC073610.3, ARF3, AC074091.1, GPN1, AC079447.1, LIPT1, AC092587.1, AC079594.2, TRIM59, AC091060.1, C18orf21, AC092143.3, MC1R, AC093227.2, ZNF607, AC093512.2, ALDOA, AC098588.1, ANAPC10, AC107871.1, CAL ML4, AC114490.2, ZMYM6, AC138649.1, NIPA1, AC138894.1, CLN3, AC139768.1, AC242426.2, CHD1L, ACADM, ACAP3, ACKR2,RP11-141M3.5、KRBOX1、ACMSD、ACOT9、ACP5、ACPL2、ACSBG1、ACSF2、ACSF3、ACSL1、ACSL3、ACVR1、ADAL、ADAM29、ADAMTS10、ADAMTSL5、ADARB1、ADAT2、ADCK3、ADD3、ADGRG1、ADGRG2、ADH1B、ADIPOR1、ADNP、ADPRH、AGBL5、AGPAT1、AGPAT3、AGR2、AGTR1、AHDC1、AHI1、AH NAK、AIFM1、AIFM3、AIMP2、AK4、AKAP1、AKNAD1、CLCC1、AKR1A1、AKT1、AKT1S1、AKT2、AL139011.2、PEX19、AL157935.2、ST6GAL NAC6、AL358113.1、TJP2、AL441992.2、KYAT1、AL449266.1、CLCC1、AL590556.3、LINC00339、CDC42、ALAS1、ALB、ALDH16A1、ALD H1B1、ALDH3A1、ALDH3B2、ALDOA、ALKBH2、ALPL、AMD1、AMICA1、AMN1、AMOTL2、AMY1B、AMY2B、ANAPC10、ANAPC11、ANAPC15、ANG、 RNASE4、AL163636.2、ANGEL2、ANGPTL1、ANKMY1、ANKRD11、ANKRD28、ANKRD46、ANKRD9、ANKS3、ANKS3、RP11-127I20.7、ANKS6、 ANKZF1、ANPEP、ANXA11、ANXA2、ANXA8L2、AL603965.1、AOC3、AP000304.12、CRYZL1、AP000311.1、CRYZL1、AP000893.2、RAB30 、AP001267.5、ATP5MG、AP002495.2、AP003175.1、OR2AT4、AP003419.1、CLCF1、AP005263.1、ANKRD12、AP006621.5、AP006621.1, AP1G1, AP3M1, AP3M2, APBA2, APBB1, APLP2, APOA2, APOL1, APOL3, APTX, ARAP1, STARD10, ARF4, ARFIP1, ARFIP2, ARFRP1, AHRGAP11A, AHRGAP33, AHRGAP4, AHRGEF10, AHRGEF3, AHRGEF35, OR2A1-AS1, AHRGEF35, OR2A1-AS1, AHRGEF34P, ARID1B, AHRGEF35, OR2A20P, OR2A1-AS1, AHRGEF9, AR L1, ARL13B, ARL16, ARL6, ARMC6, ARMC8, ARMCX2, ARMCX5, RP4-769N13.6, ARMCX5-GPRASP2, BHLHB9, ARMCX5-GPRASP2, GPRASP1, ARMCX5-GPRASP2, GPRASP2, ARMCX6, ARNT2, ARPP19, ARRB2, ARSA, ART3, ASB3, GPR75-ASB3, ASCC2, ASNS, AC079781.5, ASPSCRI1, ASS1, ASUN, ATE1, ATF1, ATF 7IP2、ATG13、ATG4D、ATG7、ATG9A、ATM、ATOX1、ATP1B3、ATP2C1、ATP5F1A 、ATP5G2、ATP5J、ATP5MD、ATP5PF、ATP6AP2、ATP6V0B、ATP6V1C1、ATP6V1D 、ATP7B、ATXN1、ATXN1L,IST1、ATXN3、ATXN7L1、AURKA、AURKB、AXDND1、B 3GALNT1、B3GALT5,AF064860.1、B3GALT5,AF064860.5、B3GNT5、B4GALT3 、B4GALT4、B9D1、BACH1、BAIAP2、BANF1、BANF2、BAX、BAZ2A、BBIP1、BCHE 、BCL2L14、BCL6、BCL9L、BCS1L、BDH1、BDKRB2,AL355102.2、BEST1、BEST3 、BEX4、BHLHB9、BID、BIN3、BIRC2、BIVM、BIVM-ERCC5、BIVM、BLCAP、BLK、 BLOC1S1、RP11-644F5.10、BLOC1S6、AC090527.2、BLOC1S6、RP11-96O20.4、BLVRA、BMF、BOLA1、BORCS8-MEF2B、BORCS8、BRCA1、BRD1、BRDT、BRINP3、BROX、BTBD10、BTBD3、BTBD9、BTD、BTF3L4、BTNL9、BUB1B-PAK6、PAK6、BUB3、C10orf68、C11orf1、C11orf48、C11orf54、C11orf54,AP001273.2、C11orf5 7、C11orf63、C11orf82、C12orf23、C12orf4、C12orf65、C12orf79、C14orf159、C14orf93、C17orf62、C18orf21、 C19orf12、C19orf40、C19orf47、C19orf48、C19orf54、C1D、C1GALT1、C1QB、C1QTNF1、C1S、C1orf101、C1orf112、C 1orf116、C1orf159、C1orf63、C2、C2,CFB、C20orf27、C21orf58、C2CD4D、C2orf15、LIPT1、MRPL30、C2orf80、C2o rf81、C3orf14、C3orf17、C3orf18、C3orf22、C3orf33、AC104472.3、C4orf33、C5orf28、C5orf34、C6orf118、C6orf f203、C6orf211、C6orf48、C7orf50、C7orf55、C7orf55-LUC7L2、LUC7L2、C8orf44-SGK3、C8orf44、C8orf59、C9,D AB2、C9orf153、C9orf9、CA5BP1,CA5B、CABYR、CALCA、CALCOCO1、CALCOCO2、CALM1、CALM3、CALML4、RP11-315D16.2、CALN1、CALU、CANT1、CANX、CAP1、CAPN12、CAPS2、CARD8、CARHSP1、CARNS1、CASC1、CASP3、CASP7、CBFA2T2、CBS、CBY1、CCBL1、CCBL2、RBMXL1、CCDC12、CCDC126、CCDC14、CCDC149、CCDC150、CCDC169-SOHLH2、CCDC169、CCDC171、CCDC37、CCDC41、CCDC57、CCDC63、CCDC7、CCDC74B、CCDC77、CCDC82、CCDC90B、CCDC91、CCDC92、CCNE1、CCHCR1、CCL28、CCNB1IP1、CCNC、CCND3、CCNG1、CCP110、CCR9、CCT7、CCT8、CD151、CD1D、CD200、CD22、CD226、CD276、CD36、CD59、CDC26、CDC42、CDC42SE1、CDC42SE2、CDHR3、CDK10、CDK16、CDK4、CDKAL1、CDKL3,CTD-2410N18.4、CDKN1A、CDKN2A、CDNF、CEBPZOS、CELF1、CEMIP、CENPK、CEP170B、CEP250、CEP57、CEP57L1、CEP63、CERS4、CFL1、CFL2、CFLAR、CGNL1、CHCHD7、CHD1L、CHD8、CHFR,ZNF605、CHIA、CHID1、CHL1、CHM、CHMP1A、CHMP3、RNF103-CHMP3、CHRNA2、CIDEC、CIRBP、CITED1、CKLF-CMTM1、CMTM1、CKMT1B、CLDN12,CTB-13L3.1、CLDND1,AC021660.3、CLDND1,CPOX、CLHC1、CLIP1、CLUL1、CMC4、MTCP1、CNDP2、CNFN、CNOT1、CNOT6、CNOT7、CNOT8、CNR1、CNR2、CNTFR、CNTRL、COA1、COASY、COCH、COL8A1、COLCA1、COLEC11、COMMD3-BMI1、BMI1、COPS5、COPS7B、COQ8A、CORO6、COTL1、COX14,RP4-605O3.4、COX7A2、COX7A2L、COX7B2、CPA4、CPA5、CPEB1、CPNE1、AL109827.1、RBM12、CPNE1、RP1-309K20.6、RBM12、CPNE3、CPSF3L、CPT1C、CREB3L2、CREM、CRP、CRYZ、CS,AC073896.1、CS、R P11-977G19.10、CSAD、CSDE1、CSF2RA、CSGALNACT1、CSK、CSNK2A1、CSRNP2、CT45A4、CT45A4、CT45A5、CT45A6、CT BP2、CTCFL、CTD-2116N17.1、KIAA0101、CTD-2349B8.1、SYT17、CTD-2528L19.4、ZNF607、CTD-2619J13.8、ZNF49 7、CTNNA1、CTNNBIP1、CTNND1、CTPS2、CTSB、CTSL、CTTN、CUL2、CUL9、CWC15、CXorf40B、CYB561A3、CYBC1、CYLD、CY P11A1、CYP2R1、CYP4B1、CYP4F22、DAG1、DAGLB,KDELR2、DARS、DBNL、DCAF11、DCAF8,PEX19、DCLRE1C、DCTD、DCTN 1、DCTN4、DCUN1D2、DDR1、DDX11、DDX19B、AC012184.2、DDX19B、RP11-529K1.3、DDX25、DDX39B、ATP6V1G2-DDX39 B, SNORD84, DDX42, DDX60L, DEDD, DEDD2, DEFA1, DEFA1B, DEFA1B, DEFA3, DENND1C, DENND2A, DENND4B, DET1, DGKA, DGKZ, DGLUCY, DHRS4L2, DHRS9, DHX40, DIABLO, AC048338.1, DIAPH1, DICER1, DKKL1, DLG1, DLG3, DLST, DMC1. DMKN、DMTF1、DMTN、DNAJC14、DNAJC19、DNAL1、DNASE1L1、DNMT3A、DOC2A、DOCK8、DOK1、DOPEY1、DPAGT1、DPP8、DRAM2、DRD2、DROSHA、DSN1、DTNA、DTX2、DTX3、DUOX1、DUOXA1、DUS2、DUSP10、DUSP13 SP18、DUSP22、DYDC1、DYDC2、DYNLL1、DYNLT1、DYRK1A、DYRK2、DYRK4、RP11-500M8.7、DZIP1L、E2F6 、ECHDC1、ECSIT、ECT2、EDC3、EDEM1、EDEM2、MMP24-AS1、RP4-614O4.11、EEF1AKNMT、EEF1D、EFEMP1、 EFHC1, EGFL7, EHF, EI24, EIF1AD, EIF2B5, EIF4G1, EIF2B5, POLR2H, EIF3E, EIF3K, EIF4E3, EIF4G1, ELF1, ELMO2, ELMOD1, AP000889.3, ELMOD3, ELOC, ELOF1, ELOVL1, ELOVL7, ELP1, ELP6, EML3, EMP3, ENC1, ENDOV, ENO1, ENPP5, ENTHD2, ENTPD6, EP400NL, EPB41L1, EPDR1, NME8, EPHX1, EPM2A, EPN1, EPN2, EPN3, EPS8L2, ERBB3, ERC1, ERCC1, ERG, ERI2, ERI2, DCUN1D3, ERLIN2, ERMARD, ERRFI1, ESR2,RP11-544I20.2、ESRRA、ESRRB、ESRRG、ETFA、ETFRF1、ETV1、ETV4、ETV7 、EVA1A、EVC2、EVX1、EXD2、EXO5、EXOC1、EXOC2、FAAP24、FABP6、FADS1、 FADS2、FAHD2B、FAM107B、FAM111A、FAM111B、FAM114A1、FAM114A2、FAM 115C、FAM115C、FAM115D、FAM120B、FAM133B、FAM135A、FAM153A、FAM15 3B、FAM154B、FAM156A、FAM156B、FAM168B、FAM172A、FAM182B、FAM192A 、FAM19A2、FAM200B、FAM220A、FAM220A、AC009412.1、FAM222B、FAM227 B, FAM234A, AC004754.1, FAM3C, FAM45A, FAM49B, FAM60A, FAM63A, FAM81A, FAM86B1, FAM86B2, FANCI, FANK1, FAR2, FAXC, FAXDC2, FBF1, FBH1 FBXL4、FBXO18、FBXO22、FBXO31、FBXO41、FBXO44、FBXO45、FBXW9、FCHO 1、FCHSD2、FDFT1、FDPS、FER、FETUB、FGD4、FGF1、FGFR1、FGFRL1、FGL1、 FHL2、FIBCD1、FIGNL1、FIGNL1,DDC、FKBP5、FKRP、FLRT2、FLRT3、FMC1、 LUC7L2、FMC1-LUC7L2、FNDC3B、FOLH1、FOLR1、FOXP1、FOXK1、FOXM1、FO XO1, FOXP4, AC097634.4, FOXRED1, FPR1, FPR2, FRG1B, FRS2, FTO, FTSJ 1、FUK、FUT10、FUT3、FUT6、FXYD3、FZD3、G2E3、GAA、GABARAPL1、GABPB1 、GABRA5、GAL3ST1、GALE、GALNT11、GALNT14、GALNT6、GAPVD1、GARNL3、 GAS2L3、GAS8、GATA1、GATA2、GATA4、GBA、GCNT1、GDPD2、GDPD5、GEMIN7,MARK4、GEMIN8、GGA3、GGACT、AL356966.1、GGPS1、GHRL、GID8、GIGYF2、GIMAP8、GIPC1、GJB1、GJB6、GLB1L、GLI1、GLT8D 1、GMFG、GMPR2、GNAI2、GNAQ、GNB1、GNB2、GNE、GNG2、GNGT2、GNPDA1、GNPDA2、GOLGA3、CHFR、GOLGA4、GOLPH3L、GOLT1B、G PBP1L1、GPER1、GPR116、GPR141、EPDR1、GPR155、GPR161、GPR56、GPR63、GPR75-ASB3,ASB3、GPR85、GPSM2、GRAMD1B、GR B10、GRB7、GREM2、GRIA2、GSDMB、GSE1、GSN、GSTA4、GSTZ1、GTDC1、GTF2H1、GTF2H4、VARS2、GTF3C2、GUCY1A3、GUCY1B3、G UK1, GULP1, GYPC, GYS1, GZF1, HAGH, HAO2, HAPLN3, HAVCR1, HAX1, HBG2, AC104389.4, HBG2, AC104389.4, HBE1, HBG2, AC104389.4, HBE1, OR51B5, HBG2, HBE1, AC104389.28, HBS1L, HCFC1R1, HCK, HDAC2, HDAC6, HDAC7, HDLBP, HEATR4, HECTD 4、HEXIM2、HHAT、HHATL、CCDC13、HINFP、HIRA、C22orf39、HIVEP3、HJV、HKR1、HLF、HMBOX1、HMGA1、HMGB3、HMGCR、HMGN4 、HMOX2、HNRNPC、HNRNPD、HNRNPH1、HNRNPH3、HNRNPR、HOMER3、HOPX、HOXA3、HOXB3、HOXB3、HOXB4、HOXC4、HOXD3、HOXD3、HOXD4、HPCAL1、HPS4、HPS5、HRH1、HS3ST3A1、HSH2D、HSP90AA1、HSPD1、HTT、HUWE1、HYOU1、IAH1、ICA1L、ICAM2、ICE2、ICK、IDH2、IDH3G、IDS、IFI27、IFI44、IFT20、IFT22、IFT88、IGF2、INS-IGF2、IGF2BP3、IGFBP6、IKBKAP、IKBKB、IL11、IL18BP、IL18RAP、IL1RAP、IL1RL1、IL18R1、IL1RN、IL32、IL4I1,NUP62,AC011452.1、IL4I1,NUP62,CTC-326K19.6、IL6ST、ILVBL、IMMP1L、IMPDH1、INCA1、ING1、INIP、INPP1、INPP5J、INPP5K、INSIG2、INTS11、INTS12、INTS14、IP6K2、IP6K3、IPO11、LRRC70、IQCE、IQGAP3、IRAK4、IRF3、IRF5、IRF6、ISG20、IST1、ISYNA1、ITFG2、ITGB1BP1、ITGB7、ITIH4、RP5-966M1.6、ITPRIPL1、JADE1、JAK2、JARID2、JDP2、KANK1、KANK1,RP11-31F19.1、KANK2、KANSL1L、KAT6A、KBTBD2、KBTBD3、KCNAB2、KCNE3、KCNG1、KCNJ16、KCNJ9、KCNMB2,AC117457.1,LINC01014、KCTD20、KCTD7,RABGEF1、KDM1B、KDM4A,AL451062.3、KHNYN、KIAA0040、KIAA0125、KIAA0196、KIAA0226L、PPP 1R2P4、KIAA0391、KIAA0391、AL121594.1、KIAA0391、PSMA6、KIAA0753 、KIAA0895、KIAA0895L、KIAA1191、KIAA1407、KIAA1841、C2orf74、KI F12、KIF14、KIF27、KIF9、KIFC3、KIN、KIRREL1、KITLG、KLC1、APOPT1、A L139300.1、KLC4、KLHDC4、KLHDC8A、KLHL13、KLHL18、KLHL2、KLHL24、 KLHL7、KLK11、KLK2、KLK5、KLK6、KLK7、KNOP1、KRBA2、AC135178.2、KRB A2, RP11-849F2.7, KRIT1, KRT15, ​​KRT8, KTN1, KXD1, KYAT3, RBMXL1, KYNU, L3MBTL1, LACC1, LARGE, LARP4, LARP7, LAT2, LBHD1, LCA5, LCA5L, L CTL、LEPROTL1、LGALS8、LGALS9C、LGMN、LHFPL2、LIG4、LIMCH1、LIMK2 、LIMS2、LINC00921、ZNF263、LIPF、LLGL2、LMAN2L、LMCD1、LMF1、RP11- 161M6.2、LMO1、LMO3、LOXHD1、LPAR1、LPAR2、LPAR4、LPAR5、LPAR6、LP HN1、LPIN2、LPIN3、LPP、LRFN5、LRIF1、LRMP、LRRC14、LRRC20、LRRC24、 C8orf82、LRRC39、LRRC42、LRRC48、LRRC4C、LRRC8A、LRRC8B、LRRD1、LRTOMT、LRTOMT、AP000812.5、LSM7、LTB4R、LTBP3、LUC7L2、FMC1-LUC7L 2、LUC7L3、LUZP1、LYG1、LYL1、LYPD4、LYPD6B、LYRM1、LYRM5、LYSMD4、M ACC1、MAD1L1、MAD1L1、AC069288.1、MAEA、MAFF、MAFG、MAFK、MAGEA12,CSAG4, MAGEA2, MAGEA2B, MAGEA4, MAGEB1, MAGOHB, MAN2A2, MANBAL, MAOB, MAP2K3, MAP3K7CL, MAP3K8, MAP7, MAP9, MAPK6, MAPK7, MAPK8, MAPKAP1, 10-Mar, 7-Mar, 8-Mar, MARK2, MASP1, MATK, MATR3, MATR3, SNHG4, MB, MBD5, MBNL1, MBOAT7, MCC, M CFD2、MCM9、MCOLN3、MCRS1、MDC1、MDGA2、MDH2、MDM2、ME1、MEAK7、MECR、MED4、MEF2A、MEF2B,BORCS8-MEF2B、MEF2BNB-MEF 2B、MEF2B、MEF2BNB、MEF2C、MEF2D、MEGF10、MEI1、MEIS2、MELK、MET、METTL13、METTL23、MFF、MFN2、MFSD2A、MGST3、MIB2、MI CAL1、MICAL3、MICOS10、NBL1,MICOS10-NBL1、MID1、MINA、MINOS1-NBL1,MINOS1、MIOS、MIPOL1、MIS12、MKLN1、MKNK1、MKN MRO MROH1、MROH7-TTC4、MROH7、MRPL14、MRPL24、MRPL33,BABAM2、MRPL33、BRE、MRPL47、MRPL48、MRPL55、MRRF、MRTFA、MRTFB、 MRVI1、MS4A1、MS4A15、MS4A3、MS4A6E、MS4A7、MS4A14、MSANTD3、MSANTD4、MSH5、MSH5-SAPCD1、MSL2、MSRB3、MSS51、MTCP1,CMC4、MTERF、MTERF1、MTERF3、MTERFD2、MTERFD3、MTF2、MTG2、MTHFD2、MTHFD2L、MTIF2、MTIF3、MTMR10、MTRF1 、MTRR、MTUS2、MUTYH、MVK、MX1、MX2、MYH10、MYL12A、MYB、MYD88、MYL5、MYLIP、MYNN、MYO15A、MYO1B、MYOM2、MZ F1、N4BP2L2、NAA60、NAB1、NAE1、NAGK、NAP1L1、NAP1L4、NAPG、NARFL、NARG2、NAT1、NAT10、NBPF11、WI2-3658N 16.1、NBPF12、NBPF15、NBPF24、NBPF6、NBPF9、NBR1、NCAPG2、NCBP2、NCEH1、NCOA1、NCOA4、NDC1、NDRG1、NDRG2, 、NDRG4、NDST1、NDUFAF6、NDUFB2、NDUFC1、NDUFS1、NDUFS8、NDUFV1、NEDD1、NEIL1、NEIL2、NEK10、NEK11、NEK6、NEK9、NELFA、NEU4、N FAT5、NFE2、NFE2L2、AC019080.1、NFRKB、NFYA、NFYC、NIF3L1、NIPA2、NKIRAS1、NKX2-1、NLRC3、NME1、NME1-NME2、NME2、NME1-NME2、 NME2、NME4、NME6、NME9、NOD1、NOL10、NOL8、NONO、NPAS1、NPIPA8、RP11-1212A22.1、NPIPB3、NPIPB4、NPIPB9、NPL、NPM1、NPPA、NQO2 、NR1H3、NR2C2、NR2F2、NR4A1、NRDC、NREP、NRF1、NRG4、NRIP1、NSD2、NSDHL、NSG1、NSMCE2、NSRP1、NT5C2、NTF4、NTMT1、NTNG2、NUBP2、 NUCB2、NUDT1、NUDT2、NUDT4、NUF2、NUMBL、NUP50、NUP54、NUP85、NVL、NXF1、NXPE1、NXPE3、OARD1、OAT、OAZ2、OCIAD1、OCLN、ODF2、OG DHL、OGFOD2、AC026362.1、OGFOD2、RP11-197N18.2、OLA1、OPRL1、OPTN、OR2H1、ORAI2、ORMDL1、ORMDL2、ORMDL3、OSBPL2、OSBPL3、OSB PL5、OSBPL9、OSER1、OSGIN1、OSR2、P2RX4、P2RY2、P2RY6、P4HA2、PABPC1、PACRGL、PACSIN3、PADI1、PAIP2、PAK1、PAK3、PAK4、PAK7、P 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PRICKLE1, PRKAG1, PRMT2, PRMT5, PRMT7, PROM1, PRPS1, PRPSAP2, PRR14L PRR15L, PRR5, PRR5-ARHGAP8, PRR5L, PRR7, PRRC2B, PRRT4, PRSS50, PRSS4 5. PRSS44, PRUNE, PRUNE1, PSEN1, PSMA2, PSMF1, PSORS1C1, PSPH, PSRC1, PT BP3, PTHLH, PTK2, PTPDC1, PTPRM, PUF60, PUM2, PUS1, PUS10, PXN, PXYLP1 YCR1, QRICH1, R3HCC1L, R3HDM2, RAB17, RAB23, RAB3A, RAB3D,TMEM205, RAB 4B-EGLN2, EGLN2, AC008537.1, RAB5B, RAB7L1, RABL2A, RABL2B, RABL5, RAC GAP1, RAD17, RAD51L3-RFFL, RAD51D, RAD52, RAE1, RAI14, RAI2, RALBP1, RA N, RANGAP1, RAP1A, RAP1B, RAP1GAP, RAPGEF4, RAPGEFL1, RASGRP2, RASSF1 RBCK1, RBM12B, RBM14, RBM4, RBM14-RBM4, RBM23, RBM4, RBM14-RBM4, RBM47 RBM7,AP002373.1, RBM7, RP11-212D19.4, RBMS2, RBMY1E, RBPJ, RBPMS, RB SN, RCBTB2, RCC1, RCC1, SNHG3, RCCD1, RECQL, RELL2, REPIN1, AC073111.3. REPIN1, ZNF775, RER1, RERE, RFWD3, RFX3, RGL2, RGMB, RGS11, RGS3, RGS5, A L592435.1 RHBDD1 RHNO1 TULP3 RHOC AL603832.3 RHOC,RP11-426L16. 10. RHOH, RIC8B, RIMKLB, RIN1, RIPK2, RIT1, RLIM, RNASE4, ANG, AL16、RNASEK、RNASEK-C17orf49、RNF111、RNF123、RNF13、RNF14、RNF185、RNF216、RNF24、RNF32、RNF34、RNF38、RNF4、RNF44、RNH1、RNMT、RNPS1、RO60、ROPN1、ROPN1B、ROR2、RP1-102H19.8、C6orf163、RP1-283E3.8,CDK11A、RP11-120M18.2,PRKAR1A、RP11-133K1.2、PAK6、RP11-164J13.1,CAPN3、RP11-21J18.1、ANKRD12、RP11-322E11.6,INO80C、RP11-337C18.10,CHD1L、RP11-432B6.3、TRIM59、RP11-468E2.4,IRF9、RP11-484M3.5,UPK1B、RP11-517H2.6、CCR6、RP11-613M10.9、SLC25A51、RP11-659G9.3、RAB30、RP11-691N7.6,CTNND1、RP11-849H4.2、RP11-896J10.3、NKX2-1、RP11-96O20.4,SQRDL、RP11-986E7.7、SERPINA3、RP4-769N13.6、GPRASP1、RP4-769N13.6,GPRASP2、RP4-798P15.3、SEC16B、RP5-1021I20.4、ZNF410、RP6-109B7.3、FLJ27365、RPE、RPH3AL、RPL15、RPL17、RPL17-C18orf32,RPL17、RPL23A、RPL36,HSD11B1L、RPP38、RPS20、RPS27A、RPS3A、RPS6KA3、RPS6KC1、RPS6KL1、RPUSD1、RRAGD、RRAS2、RRBP1、RSL1D1、RSRC2、RSRP1、RUBCNL、RUNX1T1、RUVBL2、RWDD1、RWDD4、S100A13,AL162258.1、S100A13,RP1-178F15.5、S100A16、S100A4、S100A3、S100A6、S100PBP、SAA1、SACM1L、SAMD4B、SAR1A、SARAF、SARNP,RP11-762I7.5、SCAMP5、SCAP、SCAPER、SCFD1、SCGB3A2、SCIN、SCML1、SCNN1D、SCO2、S COC、SCRN1、SDC2、SDC4、SEC13、SEC14L1、SEC14L2、SEC22C、SEC23B、SEC2 4C、SEC61G、SEMA4A、SEMA4C、SEMA4D、SEMA6C、SENP7、SEPP1、11-Sep、2-S ep、SERGEF、AC055860.1、SERP1、SERPINA1、SERPINA5、SERPINB6、SERPIN G1、SERPINH1、SERTAD3、SETD5、SFMBT1、AC096887.1、SFTPA1、SFTPA2、S FXN2、SGCD、SGCE、SGK3、SGK3,C8orf44、SH2B1、SH2D6、SH3BP1,Z83844.3 、SH3BP2、SH3BP5、SH3D19、SH3YL1、SHC1、SHISA5、SHMT1、SHMT2、SHOC2、S HROOM1、SIGLEC5,SIGLEC14、SIL1、SIN3A、SIRT2、SIRT6、SKP1、STAT4、AC 104109.3, SLAIN1, SLC10A3, SLC12A9, SLC14A1, SLC16A6, SLC1A2, SLC1A6, SLC20A2, SLC25A18, SLC25A19, SLC25A22, SLC25A25, SLC25A29, SLC2 5A30, SLC25A32, SLC25A39, SLC25A44, SLC25A45, SLC25A53, SLC26A11, SLC26A4, SLC28A1, SLC29A1, SLC2A14, SLC2A5, SLC2A8, SLC35B2, SLC35B3 SLC35C2, SLC37A1, SLC38A1, SLC38A11, SLC39A13, SLC39A14, SLC41A3, SLC44A3, SLC4A7, SLC4A8, SLC5A10, SLC5A11, SLC6A1, SLC6A12, SLC6A9 、SLC7A2、SLC7A6、SLC7A7、SLCO1A2、SLCO1C1、SLCO2B1、SLFN11、SLFN12、 SLFNL1、SLMO1、SLTM、SLU7、SMAD2、SMAP2、SMARCA2、SMARCE1、AC073508.2、SMARCE1、KRT222、SMC6、SMG7、SMIM22、SMOX、SMPDL3A、SMTN、SMU1、SMUG1、SNAP25、SNCA、SNRK、SNRPC、SNRPD1、SNRPD2、SNRPN、SNRPN、SNURF、SNUPN、SNX11、SNX16、SNX17、SOAT1、SOHLH2、CCDC169-SOHLH2、CCDC169、SORBS1、SORBS2、SOX5、SP2、SPART、SPATA20、SPATA21、SPATS2、SPATS2L、SPDYE2、SPECC1、SPECC1L、SPECC1L-ADORA2A、SPECC1L-ADORA2A、ADORA2A、SPEG、SPG20、SPG20、SPG2 1、SPIDR、SPIN1、SPOCD1、SPOP、SPRR2A、SPRR2B、SPRR2E、SPRR2B、SPRR2F、SPRR2D、SPRR3、SPRY1、SPRY4、SPTBN2、SRC、SRGAP1、SRP68、SRSF11、SSX1、SSX2IP、ST3GAL4、ST3GAL6、ST5、ST6GALNA C6、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、NPEP L1、STX5、STX6、STX8、STXBP6、STYK1、SULT1A1、SULT1A2、SUMF2、SUN1、 SUN2、SUN2、DNAL4、SUOX、SUPT6H、SUV39H2、SV2B、SYBU、SYNCRIP、SYNJ 2、SYT1、SYTL4、TAB2、TACC1、TADA2B、TAF1C、TAF6,AC073842.2、TAF6 、RP11-506M12.1、TAF9、TAGLN、TANK、TAPSAR1,PSMB9、TAPT1、TATDN1、 TAZ、TBC1D1、TBC1D12、HELLS、TBC1D15、TBC1D3H、TBC1D3G、TBC1D5、TB C1D5,SATB1、TBCA、TBCEL、TBCEL、AP000646.1、TBL1XR1、TBP、TBX5、TB XAS1、TCAF1、TCEA2、TCEAL4、TCEAL8、TCEAL9、TCEANC、TCEB1"TCF19、 TCF25、TCF4、TCP1、TCP10L、AP000275.65、TCP11、TCP11L2、TCTN1、TDG 、TDP1、TDRD7、TEAD2、TECR、TENC1、TENT4A、TEX264、TEX30、TEX37、TFD P1、TFDP2、TFEB、TFG、TFP1,TF、TFPI、TGIF1、THAP6、THBS3、THOC5、THR AP3、THUMPD3、TIAL1、TIMM9、TIMP1、TIRAP、TJAP1、TJP2、TK2、TLDC1、T LE3、TLE6、TLN1、TLR10、TM9SF1、TMBIM1、TMBIM4、TMBIM6、TMC6、TMCC1 、TMCO4、TMEM126A、TMEM139、TMEM150B、TMEM155、TMEM161B、TMEM164、TMEM168、TMEM169、TMEM175、TMEM176B、TMEM182、TMEM199,CTB-96E2.3、TMEM216、TMEM218、TMEM230、TMEM263、TMEM45A、TMEM45B、TMEM62、TMEM63B、TMEM66、TMEM68、TMEM98、TMEM9B、TMPRSS11D、TMP RSS5、TMSB15B、TMTC4、TMUB2、TMX2-CTNND1、RP11-691N7.6,CTNND1、TNFAIP2、TNFAIP8L2、SCNM1、TNFRSF10C、TNFRSF19、TNFRSF 8、TNFSF12-TNFSF13、TNFSF12、TNFSF13、TNFSF12-TNFSF13、TNFSF13、TNIP1、TNK2、TNNT1、TNRC18、TNS3、TOB2、TOM1L1、TOP1MT、 TRAP PC3、TREH、TREX1、TREX2、TRIB2、TRIM3、TRIM36、TRIM39、TRIM46、TRIM6、TRIM6-TRIM34、TRIM6-TRIM34、TRIM34、TRIM66、TRIM73 、TRIT1、TRMT10B、TRMT2B、TRMT2B-AS1、TRNT1、TRO、TROVE2、TRPS1、TRPT1、TSC2、TSGA10、TSPAN14、TSPAN3、TSPAN4、TSPAN5、TSPA N6、TSPAN9、TSPO、TTC12、TTC23、TTC3、TTC39A、TTC39C、TTLL1、TTLL7、TTPAL、TUBD1、TWNK、TXNL4A、TXNL4B、TXNRD1、TYK2、U2AF1 、UBA2、UBA52、UBAP2、UBE2D2、UBE2D3、UBE2E3、UBE2I、UBE2J2、U BE3A、UBL7、UBXN11、UBXN7、UGDH、UGGT1、UGP2、UMAD1,AC007161.3、UNC45A、UQCC1、URGCP-MRPS24,URGCP、USMG5、USP16、USP21、USP 28、USP3、USP33、USP35、USP54、USP9Y、USPL1、UTP15、VARS2、VASH2、 VAV3、VDAC1、VDAC2、VDR、VEZT、VGF、VIL1、VILL、VIPR1、VPS29、VPS 37C、VPS8、VPS9D1、VRK2、VWA1、VWA5A、WARS、WASF1、WASHC5、WBP5、W DHD1、WDPCP、WDR37、WDR53、WDR6、WDR72、WDR74、WDR81、WDR86、WDY HV1、WFDC3、WHSC1、WIPF1、WSCD2、WWP2、XAGE1A、XAGE1B、XKR9、XPNP EP1、XRCC3、XRN2、XXYLT1、YIF1A、YIF1B、YIPF1、YIPF5、YPEL5、YWH AB、YWHAZ、YY1AP1、ZBTB1、ZBTB14、ZBTB18、ZBTB20、ZBTB21、ZBTB25 、ZBTB33、ZBTB34、ZBTB38、ZBTB43、ZBTB49、ZBTB7B、ZBTB7C、ZBTB8 OS、ZC3H11A、ZBED6、ZC3H13、ZCCHC17、ZCCHC7、ZDHHC11、ZDHHC13、Z EB2、ZFAND5、ZFAND6、ZFP1、ZFP62、ZFX、ZFYVE16、ZFYVE19、ZFYVE2 0、ZFYVE27、ZHX2、AC016405.1、ZHX3、ZIK1、ZIM2,PEG3、ZKSCAN1、ZK SCAN3、ZKSCAN8、ZMAT3、ZMAT5、ZMIZ2、ZMYM6、ZMYND11、ZNF10,AC0 26786.1、ZNF133、ZNF146、ZNF16、ZNF177、ZNF18、ZNF200、ZNF202、Z NF211、ZNF219、ZNF226、ZNF227、ZNF23、AC010547.4、ZNF23、AC010 547.9、ZNF239、ZNF248、ZNF25、ZNF253、ZNF254、ZNF254、AC092279.1, ZNF263, ZNF274, ZNF275, ZNF28, ZNF468, ZNF283, ZNF287, ZNF3, ZNF320, ZNF322, ZNF324B, ZNF331, ZNF334, ZNF34, ZNF 350, ZNF385A, ZNF395, FBXO16, ZNF415, ZNF418, ZNF43, ZNF433-AS1, AC008770.4, ZNF438, ZNF444, ZNF445, ZNF467, ZNF48 0, ZNF493, ZNF493, CTD-2561J22.3, ZNF502, ZNF507, ZNF512, AC074091.1, ZNF512, RP11-158I13.2, ZNF512B, ZNF512B, SA MD10, ZNF521, ZNF532, ZNF544, AC020915.5, ZNF544, CTD-3138B18.4, ZNF559, ZNF177, ZNF562, ZNF567, ZNF569, ZNF570, Z NF571-AS1,ZNF540,ZNF577,ZNF580,ZNF581,ZNF580,ZNF581,CCDC106,ZNF600,ZNF611,ZNF613,ZNF615,ZNF619,ZNF620 , ZNF639, ZNF652, ZNF665, ZNF667, ZNF668, ZNF671, ZNF682, ZNF687, ZNF691, ZNF696, ZNF701, ZNF706, ZNF707, ZNF714, ZN This includes genes such as F717, ZNF718, ZNF720, ZNF721, ZNF730, ZNF763, ZNF780B, AC005614.5, ZNF782, ZNF786, ZNF79, ZNF791, ZNF81, ZNF83, ZNF837, ZNF839, ZNF84, ZNF845, ZNF846, ZNF865, ZNF91, ZNF92, ZNHIT3, ZSCAN21, ZSCAN25, ZSCAN30, and ZSCAN32.

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

[0242] Exemplary genes that can be regulated by compounds of formula (I) described herein include, in particular, AC005258.1, AC005943.1, AC007849.1, AC008770.2, AC010487.3, AC011477.4, AC012651.1, AC012531.3, AC034102.2, AC073896.4, AC 104472.3, AL109811.3, AL133342.1, AL137782.1, AL157871.5, AF241726.2, AL355336.1, AL358113.1, AL360181.3, AL445423.2, AL691482.3, AP001267.5, RF01169 and RF02271 may also be included.

[0243] The compounds described herein may be further used to modulate sequences including specific splice site sequences, such as RNA sequences (e.g., premRNA sequences). In some embodiments, the splice site sequence includes a 5' splice site sequence. In some embodiments, the splice site sequence includes a 3' splice site sequence. Examples of gene sequences and splice site sequences (e.g., 5' splice site sequences) include AAAgcaaguu, AAAguaaaaa, AAAguaaaau, AAAguaaagu, AAAguaaaua, AAAguaaaug, AAAguaaauu, AAAguaacac, AAAguaacca, AAAguaacuu, AAAguaagaa, AAAguaagac, AAAguaagag, AAAguaagau, AAAguaagca, AAAguaagcc, AAAguaagcu, AAAguaagga, AAAguaaggg, AAAguaaggu, AAAguaagua, AAAguaaguc, AAAguaagug, AAAguaaguu, AAAguaaucu, AAAguaauua, AAAguacaaa, AAAguaccgg, AAAguacuag, AAAguacugg, AAAguacuuc, AAAguacuug, AAAguagcuu, AAAguaggag, AAAguaggau, AA Aguagggg, AAAguaggua, AAAguaguaa, AAAguauauu, AAAguauccu, AAAguaucuc, AAAguaugga, AAAguaugua, AAAguaugu, AAAguauguu, AAAguauugg, AAAguauuuu, AAAgucagau, AAAgucugag, AAAgugaaua, AAAgugagaa, AAAgugagac, AAAgugag, AAAgugagau, AAAgug agca, AAAgugagcu, AAAgugagg, AAAgugagua, AAAgugaguc, AAAgugagu, AAAgugaguu, AAAgugcguc, AAAgugcuga, AAAguggguc, AAAguggguu, AAAgugguaa, AAAguguaug, AAAgugugu, AAAguguguu, AAAguuaagu, AAAguuacuu, AAAguuagug, AAAguuaugu, AAAguugagu,AAAguuugua、AACguaaaac、AACguaaagc、AACguaaagg、AACguaagca、AACguaaggg、AACguaaguc、AACguaagug、AACguaaugg、AACguaguga、AACguaugua、AACguauguu、AACgugagca、AACgugagga、AACgugauuu、AACgugggau、AACgugggua、AACgugguguu、AACguuggua、AAGgcaaauu、AAGgcaagag、AAGgcaagau、AAGgcaag cc、AAGgcaagga、AAGgcaaggg、AAGgcaagug、AAGgcaaguu、AAGgcacugc、AAGgcagaaa、AAGgcaggau、AAGgcaggca、AAGgcaggga、AAGgcagggg、AAGgcaggua、AAGgcaggug、AAGgcaucuc、AAGgcaugcu、AAGgcaugga、AAGgcauguu、AAGgcauuau、AAGgcgagcu、AAGgcgaguu、AAGgcuagcc、AAGguaaaaa、AAGgu aaaac, AAGguaaaag, AAGguaaaau, AAGguaaaca, AAGguaaacc, AAGguaaacu, AAGguaaaga, AAGguaaagc, AAGguaaagg, AAGguaaagu, AAGguaaaua, AAGguaaauc, AAGguaaaug, AAGguaaauu, AAGguaacaa, AAGguaacau, AAGguaaccc, AAGguaacua, AAGguaacuc, AAGguaacug, AAGguaacuu, AAGguaagaa, AAGguaagac, AAGguaagag, AAGguaagau, AAGguaagca, AAGguaagcc, AAGguaagcg, AAGguaagcu, AAGguaagga, AAGguaaggc, AAGguaaggg, AAGguaaggu, AAGguaagua, AAGguaaguc, AAGguaagug, AAGguaaguu, AAGguaauaa, AAGguaauac, AAGguaauagc,AAGguaaugg, AAGguaaugu, AAGguaauua, AAGguaauuc, AAGguaauug, AAGguaauuu, AAGguacaaa, AAGguacaag, AAGguacaau, AAGguacacc, AAGguacacu, AAGguacagg, AAGguacagu, AAGguacaua, AAGguacaug, AAGguacauu, AAGguaccaa, AAGguaccag, AAGguaccca, AAGguacccu, AAGguaccuc, AAGguaccug, AAGguaccuu, AAGguacgaa, AAGguacggg, AAGguacggu, AAGguacguc, AAGguacguu, AAGguacuaa, AAGguacuau, AAGguacucu, AAGguacuga, AAGguacugc, AAGguacugu, AAGguacuuc, AAGguacuug, AAGguacuuu, AAGguagaaa, AAGguagaac, AAGguagaca, AAGguagacc, AAGguagacu, AAGguagagu, AAGguagaua, AAGguagca, AAGguagacuu, AAGguagagu, AAGguagaua, AAGguagca, AAGguagacuu, AAGguagaaa, AAGguagaac, AAGguagaca, AAGguagacc, AAGguagacu, AAGguagagu, AAGguagaua, AAGguagca, AAGguagacuu, AAGguagagu, AAGguagacaa, AAGguagca, AAGguagagu, AAGguagacaa, AAGguagca, AAGguagagu, AAGguagagua, AAGguagacaa, AAGguagca, AAGguagagu, AAGguagagua, AAGguagacaa, AAGguagcaa, AAGguagaguca, AAGguagacaa, AAGguagaguca, AAGguagacaa, AAGguagaguca, AAGguagaguaga, AAGguagaca, AAGguagaca, AAGguagacu agcag, AAGguagcca, AAGguagccu, AAGguagcua, AAGguagcug, AAGguagcuu, AAGguaggaa, AAGguaggag, AAGguaggau, AAGguaggca, AAGguaggcc, AAGguaggcu, AAGguaggga, AAGguagggc, AAGguagggg, AAGguagggu, AAGguaggua, AAGguagguc, AAGguaggug, AAGguagguu, AAGguaguaa, AAGguaguag, AAGguagucu, AAGguagugc, AAGguagugg, AAGguaguuc, AAGguaguuu, AAGguauaaa, AAGguauaau, AAGguauaca, AAGguauacu, AAGguauaua, AAGguauauc, AAGguauaug, AAGguauauu, AAGguaucac, AAGguaucag, AAGguauccc, AAGguauccu, AAGguaucuc, AAGguaucug, AAGguaucuu, AAGguaugaa, AAGguaugac, AAGguaugauga, AAGguaugau,AAGguaugca, AAGguaugcc, AAGguaugcu, AAGguaugga, AAGguauggc, AAGguauggg, AAGguaugua, AAGguauguc, AAGguaugug, AAGguauguu, AAGguauuaa, AAGguauuac, AAGguauuag, AAGguauuau, AAGguauucc, AAGguauuga, AAGguauugu, AAGguauuua, AAGguauuuc, AAGguauuug, AAGguauuuu, AAGgucaaau, AAGgucaaga, AAGgucaagu, AAGgucacag, AAGgucagaa, AAGgucagac, AAGgucagag, AAGgucagca, AAGgucagcc, AAGgucagcg, AAGgucagcu, AAGgucagga, AAGgucaggc, AAGgucaggu, AAGgucagua, AAGgucagu cccag, AAGgucccuc, AAGguccuuc, AAGgucgagg, AAGgucuaau, AAGgucuacc, AAGgucuaua, AAGgucucucu, AAGgucucug, AAGgucucuu, AAGgucugaa, AAGgucugag, AAGgucugga, AAGgucugga, AAGgucuggg, AAGgucugua, AAGgucuguu, AAGgucuucu, AAGgucuuuu, AAGgugaaac, AAGgugaaag, AAGgugaaau, AAGgugaacu, AAGgugaagc, AA Ggugaagg、AAGgugaagu、AAGgugaaua、AAGgugaaug、AAGgugaauu、AAGgugacaa、AAGgugacag、AAGgugacau、AAGgugacug、AAGgugacuu、AAGgugagaa、AAGgugagac、AAGgugagag、AAGgugagau、AAGgugagca、AAGgugagcc、AAGgugagcg、AAGgugagcu、AAGgugaga、AAGgugaggc、AAGgugaggg、AAGgugaggu、AAGgugagua、AAGgugaguc、AAGgugagug、AAGgugaguu、AAGgugauaa、AAGgugauca、AAGgugaucc、AAGgugauga、AAGgugaugc、AAGgugaugu、AAGgugauua、AAGgugauug、AAGgugauuu、AAGgugcaca、AAGgugcauc、AAGgugcccu、AAGgugccug、AAGgugcgug、AAGgugcguu、AAGgugcucc、AAGgugcuga、AAGgugcugcugg、AAGgugcu ua、AAGgugcuuu、AAGguggaua、AAGguggcua、AAGguggcug、AAGguggcuu、AAGgugggaa、AAGgugggag、AAGgugggau、AAGgugggca、AAGguggcc、AAGguggcg、AAGguggga、AAGgugggu、AAGgugggua、AAGgugggug、AAGgugguu、AAGguggguaa、AAGguguc、AAGguguu、AAGgugguggugg、AAGguguua、AAGguguuuc、AAGgu gguuu, AAGguguaag, AAGgugucaa, AAGgugucag, AAGgugucug, AAGgugugaa, AAGgugugag, AAGgugugca, AAGgugugga, AAGguguggu, AAGgugugua, AAGguguguc, AAGgugugugu, AAGguguucu, AAGguguugc, AAGguguugg, AAGguguuug, AAGguuaaaa, AAGguuaaca, AAGguuaagc, AAGguuaauu, AAGguuacau, AAGguuaagaa, AAGguuagau, AAGguuagca, AAGguuagcc, AAGguuagga, AAGguuaggc, AAGguuagua, AAGguuaguc, AAGguuagug, AAGguuaguu, AAGguuauaag, AAGguuauga, AAGguucaaa, AAGguucaag, AAGguuccuu, AAGguucgg, AAGguucguu, AAGguucuaa, AAGguucuga, AAGguucuua, AAGguugaau, AAGguugacu, AAGguugagg,AAGguugagu、AAGguugaua、AAGguugcac、AAGguugcug、AAGguuggaa、AAGguuggca、AAGguuggga、AAGguuggg、AAGguuggua、AAGguugguc、AAGgu、 uggug、AAGguugguu、AAGguugua、AAGguugucc、AAGguugugc、AAGguuguua、AAGguuuacc、AAGguuuaua、AAGguuuauu、AAGguuuccu、AAGguuucgu、AAGguuug A AGguuuugc、AAGguuuugu、AAGguuuuu、AAUgcaagua、AAUgcaaguc、AAUguaaaca、AAUguaaaua、AAUguaaauc、AAUguaaaug、AAUguaaaua、AAUguaacua、AAUg uaagaa、AAUguaagag、AAUguaagau、AAUguaagcc、AAUguaagcu、AAUguaagga、AAUguaagua、AAUguaaguc、AAUguaagug、AAUguaaguu、AAUguaauca、AAUguaau ga、AAUguaaugu、AAUguacauc、AAUguacaug、AAUguacgau、AAUguacgua、AAUguacguc、AAUguacgug、AAUguacucu、AAUguaggca、AAUguagguu、AAUguaucua、AAUguaugaa、AAUguauguga、AAUguaugug、AAUguauguu、AAUgucagag、AAUgucagau、AAUgucagcu、AAUgucagua、AAUgucagug、AAUgucaguu、AAUg ucggua、AAUgucuguu、AAUgugagaa、AAUgugagca、AAUgugagcc、AAUgugagag、AAUgugagua、AAUgugaguc、AAUgugagug、AAUgugaguu、AAUgugauau、AAUgugcaua、AAUgugcgua、AAUgugcguc、AAUgugggac、AAUguggguc、AAUguggguc、AAUgugggug、AAUgugguu、AAUgugugua、AAUguuaagu、AAUguuagaa、AAUguuagau、AAUguuagua、AAUguuggug、ACAgcaagua、ACAguaaaua、ACAguaaaug、ACAguaagaa、ACAguaagca、ACAguaagua、ACAguaaguc、ACAguaagug、ACAguaaguu、ACAguacgua、ACAguaggug、ACAguauaac、ACAguaugua、ACAgucaguu、ACAgugagaa、ACAgugagcc、ACAgugagcu、ACAgugagga、ACAgugaggu、ACAgugagua、ACAgugaguc、ACAgugag A CCgugagca、ACCgugaguu、ACCguggug、ACGguaaaac、ACGguaacua、ACGguaagua、ACGguaagug、ACGguaaguu、ACGguaauua、ACGguaauuu、ACGguacaau、ACGgu acagu、ACGguaccag、ACGguacggu、ACGguagua、ACGguaggaa、ACGguaggag、ACGguaggug、ACGguaguaa、ACGguauaau、ACGguaugac、ACGguaugcg、ACGguaugu a. Ggugaguu、ACGgugcgug、ACGguggcac、ACGguggggc、ACGguggug、ACGguguagu、ACGgugucac、ACGgugugua、ACGguguguu、ACGguuagug、ACGguuaguu、ACGguucaau、ACUguaaaua、ACUguaagaa、ACUguaagac、ACUguaagca、ACUguaagcu、ACUguaagua、ACUguaaguc、ACUguaaguu、ACUguacguu、ACUguacugc、ACUguaggcu、ACUguaggua、ACUguauauu、ACUguaugaa、ACUguaugcu、ACUguaugug、ACUguauucc、ACUgucagcu、ACUgucagug、ACUgugaacg、ACUgugagca、ACUgugagcg、ACUg ugagcu、ACUgugagua、ACUgugaguc、ACUgugagug、ACUgugaguu、ACUgugggua、ACUgugugug、ACUguuaagu、AGAgcaagua、AGAguaaaac、AGAguaaacg、AGAguaaa ga、AGAguaaagu、AGAguaaauc、AGAguaaaug、AGAguaacau、AGAguaacua、AGAguaagaa、AGAguaagac、AGAguaagag、AGAguaagau、AGAguaagca、AGAguaagcu、A GAguaagga、AGAguaaggc、AGAguaaggg、AGAguaaggu、AGAguaaguc、AGAguaagug、AGAguaauaa、AGAguaaugu、AGAguaauuc、AGAguaauuu、AGAgu acacc, AGAguaccug, AGAguacgug, AGAguacucu, AGAguacuga, AGAguacuuu, AGAguagga, AGAguaggga, AGAguagggu, AGAguagguc, AGAguaggu g、AGAguagguu、AGAguauaua、AGAguauauu、AGAguaugaa、AGAguaugac、AGAguaugau、AGAguauguc、AGAguaugug、AGAguauguu、AGAguauuaa、AGAguauuau、AG Agucagug、AGAgugagac、AGAgugagag、AGAgugagau、AGAgugagca、AGAgugagua、AGAgugaguc、Agagugagug、Agagugaguu、Agagugcguc、Agagugggga、AGAgug ggug、AGAgugugug、AGAguguuuc、AGAguuagua、AGAguugaga、AGAguugagu、AGAguugguu、AGAguuugau、AGCguaagcu、AGCguaagug、AGCgugagcc、AGCgugagug、AGCguuguuc、AGGgcagagu、AGGgcagccu、AGGgcuagua、AGGguaaaga、AGGguaaaua、AGGguaaauc、AGGguaaauu、AGGguaacca、AGGguaacug、AGGguaacuu、AGGguaagaa、AGGguaagag、AGGguaagau、AGGguaagca、AGGguaagga、AGGguaaggc、AGGguaaggg、AGGguaagua、AGGguaaguc、AGGguaagug、AGGguaaguu、AGGguaauac、AGGguaauga、AGGguaauua、AGGguaauuu、AGGguacacc、AGGguacagu、AGGguacggu、AGGguaggac、AGGguaggag、AGGguaggca、AGGguaggcc、AGGguaggga、AGGguagggu、AGGguagguc、AGGguaggug、AGGguagguu、AGGguauaua、AGGguaugac、AGGguaugag、AGGguaugau、AGGguaugca、AGGguaugcu、AGGguauggg、AGGguauggu、AGGguaugua、AGGguauguc、AGGguaugug、AGGguauuac、AGGguauucu、AGGguauuuc、AGGgucagag、AGGgucagca、AGGgucagga、AGGgucaggg、AGGgucagug、AGGgucaguu、AGGguccccu、AGGgucggga、AGGgucugca、AGGgucuguu、AGGgugaaga、AGGgugacua、AGGgugagaa、AGGgugagac、AGGgugagag、AGGgugagca、AGGgugagcc、AGGgugagcu、AGGgugagga、AGGgugaggg、AGGgugaggu、AGGgugagua、AGGgugaguc、AGGgugagug、AGGgugaguu、AGGgugggga、AGGguggggu、AGGgugggua、AGGgugggug、AGGgugugua、AGGgugugug、AGGguuaaug、AGGguuagaa、AGGguuaguu、AGGguuggug、AGGguuugug、AGGguuuguu、AGUguaaaag、AGUguaaaua、AGUuauu、AGUguaagaa、AGUguaagag、AGUguaaau、AGUguaagca、AGUguaagcc、AGUguaagua、AGUguaagc、AGUguaaugu、AGUguaauug、AGUguaggac、AGUguagguc、AGUguaugag、AGUguaugua、AGUguauguu、AGUuaugu、AGUguauuua、AGUguagca. A UAguaagau、AUAguaagca、AUAguaagua、AUAguaagug、AUAguaaguu、AUAguaggua、AUAguauguu、AUAgucucac、AUAgugagac、AUAgugagag、AUAgugagau、AUAgu gagcc、AUAgugaggc、AUAgugagua、AUAgugaguc、AUAgugagug、AUAgugcguc、AUAgugugua、AUAguucagu、AUCguaagcc、AUCguaaguu、AUCguauucc、AUCgugagu a、AUGgcaagcg、AUGgcaagga、AUGgcaaugu、AUGgcaggua、AUGgcaugug、AUGgcgccau、AUGgcuugug、AUGguaaaac、AUGguaaau、AUGguaaacc、AUGguaaaga、AU Gguaaaua、AUGguaaaug、AUGguaaauu、AUGguaacag、AUGguaacau、AUGguaacua、AUGguaacuc、AUGguaacuu、AUGguaagaa、AUGguaagac、AUGguaagag、AUGguaagau、AUGguaagca、AUGguaagcc、AUGguaagcu、AUGguaagga、AUGguaagg、AUGguaagua、AUGguaagc、AUGguaagg、AUGguaaugu、AUGguaauaa、AUGguaauo、AUGguaauga、AUGguaaugg、AUGguaauug、AUGguaauuu、AUGguacagc、AUGguacauc、AUGguaccag、AUGguaccug、AUGguacgag、AUGguacggu、AUGguagauc、 AUGguagcag、AUGguagcug、AUGguaggaa、AUGguaggau、AUGguaggca、AUGguaggcu、AUGguagggg、AUGguagggu、AUGguaggua、AUGguaggug、AUGguaguuu、AUGguauagu、AUGguauaua、AUGguaucag、AUGguaucuu、AUGguaugau、AUGguaugca、AUGguaugcc、AUGguaugcg、AUGguaugcu、AUGguaugga、AUGguauggc、AUGguaugug、AUGguauguu、AUGguauuau、AUGguauuga、AUGguauuug、AUGgucaggg、AUGgucaguc、AUGgucagug、AUGgucauuu、AUGgugaaaa、AUGgugaaac、AUGgugaaau、AUGgugaacu、AUGgugaaga、AUGgugacgu、AUGgugagaa、AUGgugagac、AUGgugagag、AUGgugagca、AUGgugagcc、AUGgugagcg、AUGgugagcu、AUGgugaggc、AUGgugaggg、AUGgugagua、AUGgugaguc、AUGgugagug、AUGgugaguu、AUGgugauuu、AUGgugcgau、AUGgugcgug、AUGgugggua、AUGgugggug、AUGguggguu、AUGgugguua、AUGguguaag、AUGgugugaa、AUGgugugua、AUGgugugug、AUGguuacuc、AUGguuagca、AUGguuaguc、AUGguuagug、AUGguuaguu、AUGguucagu、AUGguucguc、AUGguuggua、AUGguugguc、AUGguugguu、AUGguuguuu、AUGguuugca、AUGguuugua、AUUgcaagua、AUUguaaaua、AUUguaagau、AUUguaagca、AUUguaagga、AUUguaaggc、AUUguaagua、AUUguaaguc、AUUguaaguu、AUUguaauua、AUUguaauuu、AUUguacaaa、AUUguaccuc、AUUguacgug、AUUguacuug、AUUguaggua、AUUguaugag、AUUguaugua、AUUgucuguu、AUUgugagcu、AUUgugagua、AUUgugaguc、AUUgugaguu、AUUgugcgug、AUUgugggug、AUUguuagug、CAAguaaaaa、CAAguaaaua、CAAguaaauc、CAAguaaaug、CAAguaaccc、CAAguaacua、CAAguaacug、CAAguaagaa、CAAguaagac、CAAguaagau、CAAguaaggu、CAAguaagua、CAAguaaguc、CAAguaagug、CAAguaaguu、CAAguaaucc、CAAguaaucu、CAAguaauua、CAAguaauuc、CAAguaauug、CAAguaauuu、CAAguacaca、CAAguacguu、CAAguacuuu、CAAguagcug、CAAguaggau、CAAguaggua、CAAguagguc、CAAguaggug、CAAguagguu、CAAguaguuu、CAAguauaac、CAAguauaug、CAAguaucuu、CAAguaugag、CAAguaugua、CAAguauguc、CAAguaugug、CAAguauguu、CAAguauuga、CAAguauuuc、CAAgucagac、CAAgucagua、CAAgucuaua、CAAgucugau、CAAgugacuu、CAAgugagaa、CAAgugagac、CAAgugagca、CAAgugaggc、CAAgugaggg、CAAgugagua、CAAgugaguc、CAAgugagug、CAAgugaucc、CAAgugaucu、CAAgugauuc、CAAgugauug、CAAgugauuu、CAAgugccuu、CAAgugggua、CAAguggguc、CAAgugggug、CAAgugugag、CAAguuaaaa、CAAguuaagu、CAAguuaauc、CAAguuagaa、CAAguuaguu、CAAguucaag、CAAguuccgu、CAAguuggua、CAAguuuagu、CAAguuucca、CAAguuuguu、CACguaagag、CACguaagca、CACguaauug、CACguaggac、CACguaucga、CACgucaguu、CACgugagcu、CACgugaguc, CACgugagug, CAGgcaagaa, CAGgcaagac, CAGgcaagag, CAGgcaagga, CAGgcaagua, CAGgcaagug, CAGgcaaguu, CAGgcacgca, CAGgcagagg, CAGgcaggug, CAGgcaucau, CAGgcaugaa, CAGgcaugag, CAGgcaugca, CAGgcaugcg, CAGgcaugug, CAGgcgagag, CAGgcgccug, CAGgcgugug, CAGguaaaaa, CAGguaaaag, CAGguaaaca, CAGguaaacc, CAGguaaaga, CAGguaaagc, CAGguaaagu, CAGguaaaua, CAGguaaauc, CAGguaaaug, CAGguaaauu, CAGguaacag, CAGguaacau, CAGguaacca, CAGguaaccg, CAGguaacgu, CAGguaacgu, CAGguaacua, CAGguaacuc, CAGguaacug, CAGguaacuu, CAGguaagaa, CAGguaagac, CAGguaaga, CAGguaagau, CAGgu aagcc、CAGguaagga、CAGguaaggc、CAGguaaggg、CAGguaaggu、CAGguaagua、CAGguaag、CAGguaaugu、CAGguaauaa、CAGguaauo、CAGguaaucc、CAGguaaugc、CAGguaaugg、CAGguaaugu、CAGguaauua、CAGguaauuc、CAGguaauug、CAGguaauuu、CAGguaaaa、CAGguacaag、CAGguacaau、CAGguacaca、CAGguacacg、CA Gguacaga、CAGguacagg、CAGguacagu、CAGguacaua、CAGguacaug、CAGguacauu、CAGguaccac、CAGguaccca、CAGguacccg、CAGguacccu、CAGguaccgc、CAGgua ccgg、CAGguaccuc、CAGguaccug、CAGguaccuu、CAGguacgag、CAGguacgca、CAGguacgcc、CAGguacggu、CAGguacgua、CAGguacgug、CAGguacuaa、CAGguacuag、CAGguacuau、CAGguacucc、CAGguacucu、CAGguacuga、CAGguacugc、CAGguacugu、CAGguacuua、CAGguacuuu、CAGguagaaa、CAGguagaac、CAGguagaag、CAGguagaca、CAGguagacc、CAGguagaga、CAGguagauu、CAGguagcaa、CAGguagcac、CAGguaccua、CAGguagcuc、CAGguagc ug、CAGguagcuu、CAGguaggaa、CAGguaggac、CAGguaggag、CAGguaggca、CAGguaggga、CAGguagggc、CAGguagggg、CAGguagggu、CAGguaggua、CAGguagguc、CAGguaggug、CAGguagguu、CAGguaguaa、CAGguaguau、CAGguaguca、CAGguagucc、CAGguaguga、CAGguagugu、CAGguaguu、CAGguu auaag, CAGguauaca, CAGguauaga, CAGguauauc, CAGguauaug, CAGguauauu, CAGguaucag, CAGguaucau, CAGguauccu, CAGguaucga, CAGguaucgc, CAGguaucua, CAGguaucug, CAGguaucuu, CAGguaugaa, CAGguaugac, CAGguaugag, CAGguaugau, CAGguaugca, CAGguaugcc, CAGguaugcg, CAGguaugcu, CAGguaugg, CAGguaugggu, CAGguaugua, CAGguauguc, CAGguaugug, CAGguauguu, CAGguauuau, CAGguauuca, CAGguauucu, CAGguauuga, CAGguauugg, CAGguauugu, CAGguauuua, CAGguauuuc, CAGguauuug, CAGguauuuu, CAGgucaaca, CAGgucaaug, CAGgucacgu, CAGgucagaa, CAGgucagac, CAGgucagca, CAGgucagcc,CAGgucagcg, CAGgucagga, CAGgucagua, CAGgucaguc, CAGgucagug, CAGgucaguu, CAGgucaucc, CAGgucaugc, CAGgucauua, CAGgucauuu, CAGguccacc, CAGguccacu, CAGguccagu, CAGguccauc, CAGguccauu, CAGgucccag, CAGguccug, CAGguccuga, CAGguccugc, CAGguccugg, CAGgucggcc, CAGgucggug, CAGgucu C AGgucuucc、CAGguuuc、CAGgugaaau、CAGgugaaau、CAGgugaa、CAGgugaa、CAGgugaagg、CAGgugaaua、CAGgugaauc、CAGgugaaau、CAGgugaagaa、CAGgu gacau、CAGgugacca、CAGgugaccc、CAGgugaccg、CAGgugaccu、CAGgugacgg、CAGgugacua、CAGgugacuc、CAGgugacuc、CAGgugagaa、CAGgugagac、CAGgugaga g、CAGgugagau、CAGgugagca、CAGgugagcc、CAGgugagcg、CAGgugagcu、CAGgugagga、CAGgugaggc、CAGgugaggg、CAGgugaggu、CAGgugagua、CAGgugaguc、CA Ggugagug, CAGgugaguu, CAGgugauaa, CAGgugaucc, CAGgugaucu, CAGgugaugc, CAGgugaugg, CAGgugaugu, CAGgugauua, CAGgugauuc, CAGgugauug, CAGgugauuu, CAGgugcaaa, CAGgugcaag, CAGgugcaca, CAGgugcacg, CAGgugcaga, CAGgugcagg, CAGgugcaua, CAGgugcauc, CAGgugcaug, CAGgugccaa, CAGgugccca,CAGgugcccc、CAGgugcccg、CAGgugccua、CAGgugccug、CAGgugcgaa、CAGgugcgca、CAGgugcgcc、CAGgugcgc、CAGgugcgga、CAGgugcggu、CAGgugcggu、CAGgug、 cgua、CAGgugcguc、CAGgugcgug、CAGgugcuag、CAGgugcuau、CAGgugcuca、CAGgugcucc、CAGgugcucg、CAGgugcugc、CAGgugcugg、CAGgugcuua、CAGgugcuu C AGgugggac, CAGgugggag, CAGgugggau, CAGgugggaca, CAGguggcc, CAGgugggcu, CAGguggga, CAGguggggc, CAGgugggggg, CAGgugggu, CAGgugggua, CAGgugguc, CAGguggug, CAGguggguu, CAGguggucu, CAGguggugg, CAGguguug, CAGguguaca, CAGguguagg, CAGguguauc, CAGgugucac, CAGgugucag, CAGguguc ca、CAGguguccu、CAGgugucua、CAGguguguc、CAGguguguc、CAGgugugaa、CAGgugugac、CAGgugugaa、CAGgugugau、CAGgugugca、CAGgugugcc、CAGgugugcg、CAGgugugcu、CAGgugugga、CAGgugugc、CAGgugugua、CAGgugugua、CAGgugugc、CAGgugugaa、CAGguguuaa、CAGguuaaa、CAGguuaaua、CAGguuaauc、CAGg uuaccu、CAGguuagaa、CAGguuagag、CAGguuagau、CAGguuagcc、CAGguuagg、CAGguuaggu、CAGguuagua、CAGguuagc、CAGguuag、CAGguuagu、CAGguuag uca、CAGguuaugu、CAGguuaua、CAGguuag、CAGguucaa、CAGguac、CAGguucaag、CAGguucaca、CAGguucacg、CAGguucaag、CAGguucag、CAGguuccaag、CAGguuccca, CAGguucccg, CAGguucgaa, CAGguucgag, CAGguucuau, CAGguucugc, CAGguucuua, CAGguucuuc, CAGguucuuu, CAGguugaac, CAGguugaag, CAGguugagu, CAGguugaua, CAGguuggag, CAGguuggca, CAGguuggcc, CAGguugguc, CAGguuggug, CAGguugguu, CAGguuguaa, CAGguuguac, CAGguuguau, CAGguugu C AGuuuuuuuuuuuuuuuuuuuuuuuuuuuuuuuuuuuuuuuuuuuuuuuuuuuuuuuuuuuuuuuuuu aaaac、CAUguaacua、CAUguaagaa、CAUguaagag、CAUguaagau、CAUguaagcc、CAUguaagua、CAUguaagug、CAUguaaguu、CAUguaauua、CAUguacaua、CAUguacca c. Ugugagua、CAUguguguc、CAUgugagug、CAUgugaguu、CAUgugcgua、CAUgugggaa、CAUguggguu、CAUgugugguu、CAUguguguu、CAUguuaaua、CAUguuagcc、CCAgua agau、CCAguaagca、CCAguaagcc、CCAguaagcu、CCAguaagga、CCAguaagua、CCAguaaguc、CCAguaagug、CCAguaaguu、CCAguaauug、CCAguacggg、CCAguagguc、CCAguauugu, CCAGugaggc, CCAGugagua, CCAGugagug, CCAGuggguc, CCAGuguu, CCAguugagu, CCCguaagau, CCCguauguc, CCCguauguu, CCCguccugc, CCCgugagug, CCGguaaaga, CCGguaagau, CCGguaagcc, CCGguaagga, CCGguaaggc, CCGguaaugg, CCGguacagu, CCGguacuga, CCGguauucc, CCGgucagug, CCGgugaa aa、CCGgugagaa、CCGgugaggg、CCGgugagug、CCGgugaguu、CCGgugcgcg、CCGgugggcg、CCGguugguc、CCUguaaaug、CCUguaaauu、CCUguaagaa、CCUguaagac、C CCUguaagg、CCUguaagca、CCUguaagcg、CCUguaagga、CCUguaagu gagca, CCUgugaggg, CCUgugaguc, CCUgugagug, CCUgugaguu, CCUguggcuc, CCUgugggua, CCUgugugua, CCUguuagaa, CGAguaaggg, CGAguaaggu, CGAguagcug, CGAguaggug, CGAguagguu, CGAgugagca, CGCguaagag, CGGgcaggca, CGGguaagcc, CGGguaagcu, CGGguaaguu, CGGguaauuc, CGGguaauuu, CGGguacagu, CG Gguacggg、CGGguaggag、CGGguaggcc、CGGguaggug、CGGguauuua、CGGgucugag、CGGgugaccg、CGGgugacuc、CGGgugagaa、CGGgugaggg、CGGgugaggu、CGGgugagua、CGGgugagug、CGGgugaguu、CGGgugauuu、CGGgugccuu、CGGguggag、CGGguggug、CGGgugguu、CGGguguguc、CGGgugugug、CGGguguguu、CGGguucaag、CGGguucaug、CGGguuugcu、CGUguagggu、CGUguaugca、CGUguaugua、CGUgucugua、CGUgugagug、CGUguuuucu、CUAguaaaug、CUAguaagcg、CUAguaagcu、CUAg uaagua、CUAguaaguc、CUAguaagug、CUAguaaugu、CUAguaauuu、CUAguaggua、CUAguagguu、CUAguaugua、CUAguauguu、CUAgugagua、CUCguaagca、CUCguaag ug、CUCguaaguu、CUCguaucug、CUCgucugug、CUCgugaaua、CUCgugagua、CUCgugauua、CUGguaaaaa、CUGguaaaau、CUGguaaacc、CUGguaaacg、CUGguaaagc、C UGguaaaua、CUGguaaauc、CUGguaaaug、CUGguaaauu、CUGguaacc、CUGguaacag、CUGguaaccc、CUGguaaccg、CUGguaacug、CUGguaacuu、CUGguaagaa、CUGgu aagag、CUGguaagau、CUGguaagca、CUGguaagcc、CUGguaagcu、CUGguaagga、CUGguaaggc、CUGguaaggg、CUGguaaggu、CUGguaagua、CUGguaagg、CUGguaagu CU Gguacuaa、CUGguacuug、CUGguacuuu、CUGguagaga、CUGguagaua、CUGguagcgu、CUGguaggau、CUGguaggca、CUGguaggua、CUGguagguc、CUGguaggug、CUGguaucaa、CUGguaugau、CUGguauggc、CUGguauggu、CUGguaugua、CUGguaugug、CUGguauguu、CUGguauuga、CUGguauuuc、CUGguauuuu、CUGgucaaca、CUGgucagag、CUGgucccgc、CUGgucggua、CUGgucuggg、CUGgugaagu、CUGgugaaua、CUGgugaauu、CUGgugacua、CUGgugagaa、CUGgugagac、CUGgugagca、CUGgugagcu、CUGgugaga、CUGgugaggc、CUGgugaggg、CUGgugagaggu、CUGgugagua、CUGgugaguc、CUGgugagug、CUGgugaguu、CUGgugauua、CUGgugauuu、CUGgugcaga、CUGgugcg C UGgugggu、CUGguggugu、CUGguggugu、CUGguagcu、CUGguuggu、CUGguguggu、CUGguuggcu、CUGguugguuu、CUGguuugua、CUGguuuggu、CUGguuuggu、CUUgu aaaug, CUUguaagcu, CUUguaagga, CUUguaaggc, CUUguaagua, CUUguaagug, CUUguaaguu, CUUguacguc, CUUguacgug, CUUguaggua, CUUguagugc, CUUguauagg, CUUgucugua, CUUgugagua, CUUgugaguc, CUUgugaguu, CUUgugguguu, CUUgugugua, CUUguuagug, CUUguuugag, GAAguaaaac, GAAguaaagc, GAAguaaagu, GA Aguaaaua、GAAguaaauu、GAAguaagaa、GAAguaagcc、GAAguaagcu、GAAguaagga、GAAguaagua、GAAguaagug、GAAguaaguu、GAAguaauo、GAAguaaugc、GAAguaauua、GAAguaauuu、GAAguaccau、GAAguacgua、GAAguacguc、GAAguaggca、GAAguagguc、GAAguaaaa、GAAguaugcu、GAAguaugug、GAAguauguu、GAAguauau、GAAgucagug、GAAgugagag、GAAgugagcg、GAAgugaggu、GAAgugaguc、GAAgugagug、GAAgugaguu、GAAgugauaa、GAAgugauuc、GAAgugcgug、GAAguguggg、G、 AAguguguc、GAAguuggug、GACguaaagu、GACguaagcu、GACguaagua、GACguaaugg、GACguaugcc、GACguauguu、GACgugagcc、GACgugagug、GAGgcaaaug、GAGgcaagag、GAGgcaagua、GAGgcaagug、GAGgcaaguu、GAGgcacgag、GAGgcaggga、GAGgcaugug、GAGgcgaagg、GAGguaaaaa、GAGguaaaac、GAGguaaaag、GAGguaaaau、GAGguaaacc、GAGguaaaga、GAGguaaagc、GAGguaaagu、GAGguaaaua、GAGguaaauc、GAGguaaaug、GAGguaaauu、GAGguaacaa、GAGguaacag、GAGguaacca、GAGguaaccu、GAGguaacuu、GAGguaagaa、GAGguaagag、GAGguaagau、GAGguaagca、GAGguaagcc、GAGguaagcg、GAGguaagcu、GAGguaagga、GAGguaaggc、GAGguaaggg、GAGguaaggu、GAGguaagua、GAGguaaguc、GAGguaauaa、GAGguaauac、GAGguaauau、GAGguaauca、GAGguaaucu、GAGguaaugg、GAGguaaugu、GAGguaauug、GAGguaauuu、GAGguacaaa、GAGguacaac、GAGguacaga、GAGguacagc、GAGguacagu、GAGguacaua、GAGguacauu、GAGguaccag、GAGguaccga、GAGguaccug、GAGguaccuu、GAGguacuag、GAGguacuau、GAGguacucc、GAGguacugc、GAGguacugg、GAGguacugu、GAGguacuug、GAGguacuuu、GAGguagaag、GAGguagaga、GAGguagagg、GAGguagagu、GAGguagauc、GAGguagcua、GAGguagcug、GAGguaggaa、GAGguaggag、GAGguaggca、GAGguaggcu、GAGguaggga、GAGguagggc、GAGguagggg、GAGguaggua、GAGguaggug、GAGguagguu、GAGguaguaa、GAGguaguag、GAGguaguau、GAGguagucu、GAGguagugc、GAGguagugg、GAGguaguua、GAGguagug、GAGguauaag、GAGguauacu、GAGguauagc、GAGguauaug、GAGguauau、GAGguacau、GAGguaucug、GAGguaucuu、GAGguaugaa、GAGguaugac、GAGguaugag、GAGguaug cc、GAGguaugcg、GAGguaugcu、GAGguaugga、GAGguauggg、GAGguauggu、GAGguaugua、GAGguauguc、GAGguaugug、GAGguauguu、GAGguauucc、GAGguauuga、GAGguauugu、GAGguauuua、GAGguauuuc、GAGguauuug、GAGguauuuu、GAGgucaaca、GAGgucaagg、GAGgucaaug、GAGgucag、GAGgucagaa、GAGgucagag、GAGgu cagcu、GAGgucagga、GAGgucaggc、GAGgucaggg、GAGgucaggu、GAGgucagua、GAGgucauau、GAGgucaugu、GAGgucauuu、GAGguccaua、GAGguccauc、GAGguccgg g. Ggugaaca、GAGgugaagg、GAGgugaaua、GAGgugaauu、GAGgugacau、GAGgugacca、GAGgugaccu、GAGgugacua、GAGgugacuu、GAGgugagaa、GAGgugagac、GAGgugagag、GAGgugagau、GAGgugagca、GAGgugagcc、GAGgugagcg、GAGgugagcu、GAGgugagga、GAGgugaggc、GAGgugaggg、GAGgugaggg、GAGgugaggua、GAGgugagu、GAGgugaguu、GAGgugauau, GAGgugaucc, GAGgugaucu, GAGgugauga, GAGgugaugg, GAGgugaugu, GAGgugauuc, GAGgugcaca, GAGgugcaga, GAGgugcagc, GAGgugcagg, GAGgugccag, GAGgugccca, GAGgugccuu, GAGgugcggg, GAGgugcgug, GAGgugcucc, GAGgugcugg, GAGgugcuua, GAGgugcuug, GAGguggaaa, GAGguggaau, GAGgugga cc、GAGguggacg、GAGguggagg、GAGguggcug、GAGgugggaa、GAGguggag、GAGgugggau、GAGguggca、GAGgugggcg、GAGgugggcu、GAGguggga、GAGgugggc、GAGgugggg、GAGgugggua、GAGgugguc、GAGguggug、GAGgugguu、GAGguguau、GAGgugguuc、GAGgugucau、GAGgugugga、GAGgugugca、GAGgu gugcu、GAGguggga、GAGguggugg、GAGgugugu、GAGgugugua、GAGgugugua、GAGguuaaau、GAGguuaaga、GAGguuaaua、GAGguuaccg、GAGguuagaa、GAGguuaga c. Gguugaag、GAGguugcag、GAGguugcug、GAGguuggaa、GAGguuggag、GAGguuggau、GAGguuggua、GAGguugguc、GAGguugguu、GAGguuguag、GAGguuucug、GAGguu ugag、GAGguuugga、GAGguuuggg、GAGguuugua、GAGguuuguu、GAGguuuuca、GAGguuuuga、GAGguuuugg、GAGguuuuuua、GAGguuuuuc、GAUguaaau、GAUguaagca、GAUguaagcc、GAUguaaggu、GAUguaagua、GAUguaagug、GAUguaaguu、GAUguacauc、GAUguaggua、GAUguauggc、GAUguaugua、GAUguauguu、GAUgucagug、GAUg ugagag、GAUgugagcc、GAUgugagcu、GAUgugagga、GAUgugaguc、GAUgugagug、GAUgugaguu、GAUgugggua、GAUguggug、GAUguguguu、GAUguuagcu、GAUguuca gu, GAUguucgug, GAUguuuguu, GCAguaaagg, GCAguaagaa, GCAguaagga, GCAguaagua, GCAguaaguc, GCAguaaguu, GCAguagaug, GCAguaggua, GCAguaugug, GCAguauguu, GCAgucagua, GCAgucagug, GCAguccggu, GCAgugacuu, GCAgugagcc, GCAgugagcg, GCAgugagcu, GCAgugagua, GCAgugagug, GCAgugaguu, GCAgu gggua、GCAguuaagu、GCAguugagu、GCCguaaguc、GCCgugagua、GCGguaaagc、GCGguaaaua、GCGguaagcu、GCGguaaggg、GCGguaagug、GCGguaauca、GCGguacgu a. Ugcuguaa、GCUguaaaua、GCUguaagac、GCUguaagag、GCUguaagca、GCUguaagga、GCUguaagua、GCUguaaguc、GCUguaagug、GCUguaaguu、GCUguaggug、GCUguauggu、GCUgucagug、GCUguccuug、GCUgugagaa、GCUgugagcc、GCUgugagga、GCUgugagua、GCUgugaguc、GCUgugaguu、GCUgugguu、GGAguaagag、GGAguaagca、GGAguaagcc、GGAguaagcu、GGAguaagga、GGAguaagug、GGAguaaguu、GGAguaauuu、GGAguacugu、GGAguaggaa、GGAguaggua、GGAguagguu、GGAguaguau、GGAguaugac、GGAguauggu、GGAgucaagu、GGAgugaggg、GGAgugagua、GGAgugaguc、GGAgugagug、GGAgugaguu、GGAgugcuuu、GGAgugggca、GGAguggg ug、GGAguuaagg、GGAguugaga、GGCguaagcc、GGCguaggua、GGCguaggug、GGCgugagcc、GGCgugaguc、GGGguaaaca、GGGguaaacc、GGGguaaacu、GGGguaagaa、GGGguaagag、GGGguaagau、GGGguaagca、GGGguaagcc、GGGguaagcu、GGGguaagga、GGGguaaggg、GGGguaagua、GGGguaagug、GGGguaaguu、GGGguagaca、GGGgu aggag、GGGguaggcc、GGGguaggga、GGGguaggua、GGGguaggug、GGGguagguu、GGGguagugc、GGGguaucug、GGGguaugac、GGGguaugga、GGGguaugua、GGGguauguc、GGGguaugug、GGGguauguu、GGGgucagua、GGGguccgug、GGGgucggag、GGGgucugug、GGGgugaaca、GGGgugaaga、GGGgugagaa、GGGgugagau、GGGgugagcc、GGGgugagcg、GGGgugagcu、GGGgugagga、GGGgugaggc、GGGgugaggg、GGGgugaguc、GGGgugaguc、GGGgugaguc、GGGgugaguc、GGGgugagucgua、GGGgugggu、GGGgugggua、GGGguggug、GGGgugguu、GGGgugugcg、GGGgugugua、GGGgugugc、GGGguguuga、GGGguucag、GGGguuggac、GGGguugga、GGGguuugcc、GGGguuugua、GGUguaagaa、GGUguaagau, GGUguaagca, GGUguaagcc, GGUguaagcg, GGUguaaguc, GGUguaagug, GGUguagguc, GGUguaggug, GGUguagguu, GGUguccgua, GGUguga, gag、GGUgugagcc、GGUgugagcu、GGUgugagua、GGUgugaguc、GGUgugcuuc、GGUguggcug、GGUgugug、GGUgugcug、GGUgugaaa、GGUguugcug、GUAGUAGUA 、GUAGUAGUAGUA、GUAGUAGUAGUAGUA、GUAGUAGUAGUAGUA、GUAGUAGUAGUAGUA、GUAGUAGUAGUAUM、GUAGUAGUAGUAUM、GUAGUAGUAGUAUM、GUAGUAAUGUG、GUGUGAGU、GUAGUGA Cgugaguu、GUGgcaagua、GUGguaaaau、GUGguaaaau、GUGguaaaau、GUGguaacau、GUGguaaaaa、GUGguaagaa、GUGguaagac、GUGGAG、GUGgua aagau、GUGguaagca、GUGguaagcg、GUGguaagcu、GUGguaaggc、GUGguaagc、GUGguaagua、GUGguaaguc、GUGguaagug、GUGguaagua、GUGguaagua、GUGGUAAUGAUS c. UGguauaaa、GUGguaacuc、GUGguaugaa、GUGguaugau、GUGguaugca、GUGguaugua、GUGguaugua、GUGguccgug、GUGgucuggc、GUGgugaaac、GUGgugagaa、GUGgugagaa ugagau、GUGgugagca、GUGgugagcu、GUGgugagga、GUGgugaggc、GUGgugagug、GUGgugaguu、GUGgugauua、GUGgugauuc、GUGgugcgau、GUGGGUGGUGUUA gaa、GUGgugggua、GUGguggguc、GUGguguccg、GUGguuagca、GUGguuaggu、GUGguuagug、GUGguuugca、GUGguuugua、GUUguaaggua、GUUguaagua、GUUagua、GUUaguaGUUguaaguu, GUUguaccac, GUUguagcgu, GUUguaugug, GUUguauguu, GUUgucugug, GUUgugagcu, GUUgugagug, GUUgugaguu, GUUgugggua, GUUguggguu, UAAguaaaug, UAAguaacua, UAAguaagaa, UAAguaagag, UAAguaagau, UAAguaagca, UAAguaagcu, UAAguaagga, UAAguaaggu, UAAguaagua, UAAguaaguc, UAAguaag ug、UAAguaaugu、UAAguaauaa、UAAguacuag、UAAguaguuu、UAAguauaaa、UAAguauaca、UAAguaugua、UAAguauuau、UAAguauuuu、UAAgucuuuuu、UAAgugagac、U AAgugagga、UAAgugagg、UAAgugagua、UAAgugaguc、UAAgugaguc、UAAgugaguu、UAAgugaucc、UAAgugauuc、UAAgugcgug、UAAguuaagu、UAAguuccag、UAAgu ucuuu, UAAguuguaa, UAAguuguau, UAAguuuguu, UACguaacug, UACguaagaa, UACguaagau, UACguaagua, UACguaagug, UACguauccu, UACgucuggc, UACgugacca, UAGgcaagac, UAGgcaaguc, UAGgcagguc, UAGgcgugug, UAGguaaaaa, UAGguaaaac, UAGguaaaag, UAGguaaaau, UAGguaaaca, UAGguaaaga, UAGguaaaua, UAGguaaauc, UAGguaaaug, UAGguaaauu, UAGguaacac, UAGguaacag, UAGguaacau, UAGguaacca, UAGguaacgg, UAGguaacua, UAGguaacuc, UAGguaacug, UAGguaacuu, UAGguaagac, UAGguaagag, UAGguaagau, UAGguaagca, UAGguaagcc, UAGguaagcu, UAGguaagga, UAGguaaggc, UAGguaaggg, UAGguaagua, UAGguaaguc,UAGguaagug、UAGguaaguu、UAGguaauag、UAGguaauau、UAGguaaucu、UAGguaauga、UAGguaaugg、UAGguaaugu、UAGguaauua、UAGguaauuc、UAGguaauuu、UAGguacagc、UAGguacagu、UAGguacauu、UAGguaccag、UAGguaccua、UAGguaccuu、UAGguacgag、UAGguacgua、UAGguacguu、UAGguacuau、UAGguacuga、UAGguacugg、UAGguacuuc、UAGguacuuu、UAGguagcgg、UAGguaggaa、UAGguaggac、UAGguaggau、UAGguaggga、UAGguagggg、UAGguaggua、UAGguagguc、UAGguaggug、UAGguagguu、UAGguaguaa、UAGguagucu、UAGguagugg、UAGguagugu、UAGguaguuu、UAGguauaaa、UAGguauaac、UAGguauaag、UAGguauaau、UAGguauaca、UAGguauacu、UAGguauaua、UAGguauauc、UAGguauauu、UAGguaucag、UAGguaucua、UAGguaucuc、UAGguaugaa、UAGguaugag、UAGguaugca、UAGguaugga、UAGguauggc、UAGguauggu、UAGguaugua、UAGguauguc、UAGguaugug、UAGguauguu、UAGguauuaa、UAGguauuac、UAGguauuau、UAGguauuca、UAGguauucc、UAGguauucu、UAGguauuga、UAGguauuua、UAGguauuuc、UAGguauuuu、UAGgucacuc、UAGgucagcu、UAGgucaggu、UAGgucagua、UAGgucagug、UAGgucaguu、UAGgucaucu、UAGgucauug、UAGguccaau、UAGguccugu、UAGgucucaa、UAGgucucgc、UAGgucuggc、UAGgucuguc、UAGgucugug、UAGgugaagu、UAGgugaaua、UAGgugaaug、UAGgugaauu、UAGgugacau, UAGgugacca, UAGgugacua, UAGgugagaa, UAGgugagac, UAGgugagag, UAGgugagau, UAGgugagcc, UAGgugagcu, UAGgugagga, UAGgugaggc, UAGgugaggu, UAGgugagua, UAGgugaguc, UAGgugagug, UAGgugauca, UAGgugauuc, UAGgugauuu, UAGgugacaua, UAGgugcauc, UAGgugccgu, UAGgugccug, UAGgugcgca, UAGgugcgua, UAGgugcgug, UAGgugcuga, UAGgugaua, UAGgugggaa, UAGguggac, UAGguggag, UAGgugggau, UAGguggcc, UAGguggcu, UAGgugguu, UAGguguaa, UAGgugugaa, UAGgugugag, UAGguguga, UAGgugugca, UAGgugugcc, UAGgugugcg, UAGgugug, UAGgugugua, UAGgugug, UAGguguugg, UAGguguugg, UAGgu uaagc、UAGguuagac、UAGguuagcc、UAGguuaggc、UAGguuagua、UAGguuaguc、UAGguuagug、UAGguuccc、UAGguucuac、UAGguuggua、UAGguuggu、UAGguuguc c. Uguaagcc、UAUguaagua、UAUguaaguc、UAUguaagug、UAUguaaguu、UAUguacgug、UAUguacgu、UAUguagguc、UAUguagguu、UAUguauccu、UAUguaucuc、UAUgua ugua、UAUguauguc、UAUguaugug、UAUguauuau、UAUgucagaa、UAUgugugua、UAUgugaaua、UAUgugacag、UAUgugagua、UAUgugagug、UAUgugagu、UAUgugggca、UAUgugugua, UAUguguuua, UAUguuuugu, UCAgcgacau, UCAguaaaau, UCAguaaaua, UCAguaacug, UCAguaagaa, UCAguaagag, UCAguaagau, UCAguaagca, UCAguaagcc, UCAguaagcu, UCAguaaggg, UCAguaagua, UCAguaaguc, UCAguaagug, UCAguaaguu, UCAguaucuu, UCAguaugga, UCAguauggu, UCAgucccca, UCAgugagca, UCAgugagcu, UCAgugagua, UCAgugagug, UCAgugaguu, UCAgugauug, UCAgugggug, UCAguugagc, UCAguugauu, UCAguuuagu, UCCguaagca, UCCguaagcu, UCCguaaguc, UCCguaagug, UCCguaauag, UCCguacuua, UCCguaugua, UCCguauguu, UCCgugagau, UCCgugaguc, UCCgugaag, UCCgugaguc, UCCgu acauc、UCGguacucc、UCGguagacc、UCGguagguu、UCGguaguaa、UCGguaugug、UCGguauguu、UCGguauuga、UCGgucagua、UCGgucuuag、UCGguagau、UCGgugaga a. Uguaagcu、UCUguaagua、UCUguaaguc、UCUguaagug、UCUguaaguu、UCUguaauaa、UCUguaauga、UCUguaaugu、UCUguaggua、UCUguagguu、UCUguauaua、UCUguaugac、UCUguaugua、UCUguccucg、UCUgugagag、UCUgugagcu、UCUgugagag、UCUgugagua、UCUgugaguc、UCUgugagug、UCUgugaguu、UCUgugcgua、UCUgugugag、UGAguaacuu, UGAguaagau, UGAguaagca, UGAguaagcu, UGAguaaggc, UGAguaaggu, UGAguaagua, UGAguaaguc, UGAguaagug, UGAguaaguu, UGAguaaucc, UG, Aguaauua、UGAguacagu、UGAguacgua、UGAguacguu、UGAguacugu、UGAguagcug、UGAguaggua、UGAguauaaa、UGAguagcu、UGAguauggu、UGAguaugua、UGAguaguc、UGAguauguu、UGAgucagag、UGAgucuacg、UGAguagaaua、UGAgugaaau、UGAgugagaa a. Cguaaguc、UGCguaagug、UGCguacggc、UGCguacggg、UGCguaugua、UGGcaaguc、UGGgcaagug、UGGcacauc、UGGgccacgu、UGGgccccgg、UGGguaaau、UGGgua aagc、UGGguaaagg、UGGguaaagu、UGGguaaaua、UGGguaaaug、UGGguaaauu、UGGguaacag、UGGguaacau、UGGguaacua、UGGguaacuu、UGGguaagaa、UGGguaagac、UGGguaagag、UGGguaagau、UGGguaagca、UGGguaagcc、UGGguaagcu、UGGguaaggg、UGGguaaggu、UGGguaagua、UGGguaaguc、UGGguaagug、UGGguaaguu、UGG guaaugu, UGGguaauua, UGGguaauuu, UGGguacaaa, UGGguacagu, UGGguacuac, UGGguaggga, UGGguagguc, UGGguaggug, UGGguagguu, UGGguaguua, UGGguauagu, UGGguaugaa, UGGguaugac, UGGguaugag, UGGguaugua, UGGguauguc, UGGguaugug, UGGguauguu, UGGguauuug, UGGgucuuug, UGGgugaccu, UGGgugacua,UGGgugagac、UGGgugagag、UGGgugagca、UGGgugagcc、UGGugagga、UGGgugaggc、UGGgugaggg、UGGgugagua、UGGgugaguc、UGGgugagu、UGGgugagu、UGGg ugcgug、UGGuggagg、UGGguggcuu、UGGgugggg、UGGgugggua、UGGgugguc、UGGguggug、UGGguggguu、UGGguggga、UGGgugguc、UGGguggug、UGGgugg uu, UGGguguuua, UGGguuaaug, UGGguuaguc, UGGguuagug, UGGguuaguu, UGGguucaag, UGGguucgua, UGGguuggug, UGGguuuaag, UGGguuugua, UGUgcaagua, UGUguaaaua, UGUguaagaa, UGUguaagac, UGUguaagag, UGUguaaggu, UGUguaagua, UGUguaaguc, UGUguaaguu, UGUguacuuc, UGUguaggcg, UGUguaggua, UGUgu aguua, UGUguaugug, UGUgucagua, UGUgucugua, UGUgucuguc, UGUgugaccc, UGUgugagau, UGUgugagca, UGUgugagagcc, UGUgugagua, UGUgugaguc, UGUgugagug, UGUgugugcgug, UGUgugggug, UGUgugguguu, UGUgugugag, UGUguguucu, UGUguuuaga, UUAguaaaua, UUAguaagaa, UUAguaagua, UUAguaagug, UUAguaaguu, UU Aguaggug, UUAgugagca, UUAgugaguu, UUAguuaagu, UUCguaaguc, UUCguaaguu, UUCguaauua, UUCgugagua, UUCgugaguu, UUGgcaagug, UUGgccgagu, UUGguaaaaa, UUGguaaaau, UUGguaaaga, UUGguaaagg, UUGguaaagu, UUGguaaauc, UUGguaaaug, UUGguaaauu, UUGguaacug, UUGguaacuu, UUGguaagaa, UUGguaagag,UUGguaagcu, UUGguaagga, UUGguaaggg, UUGguaagua, UUGguaagug, UUGguaaguu, UUGguaauac, UUGguaauca, UUGguaaugc, UUGguaaugu, UUGguaauug, UUGguaauuu, UUGguacaua, UUGguacgug, UUGguagagg, UUGguaggac, UUGguaggcg, UUGguaggcu, UUGguaggga, UUGguagua, UUGguagguc, UUGguaggug, UUGguaua aa、UUGguauaca、UUGguauauu、UUGguaucua、UUGguaucucuc、UUGguaugca、UUGguauguga、UUGguaugug、UUGguauguu、UUGguauugu、UUGguauuua、UUGguauuuu、UUGgucagaa、UUGgucagua、UUGgucucug、UUGgucugca、UUGgugaaaa、UUGgugacug、UUGgugagac、UUGgugagau、UUGgugagca、UUGgugagag、UUGgugaggg、UUGgu gagua、UUGgugaguc、UUGgugagug、UUGgugaguu、UUGgugaugg、UUGgugauua、UUGgugauug、UUGgugcaca、UUGgugggaa、UUGguggggaa、UUGguggggc、UUGgugggua、UUGgugguc、UUGgugggug、UUGgugguu、UUGguguggu、UUGguguguc、UUGgugug、UUGgugugug、UUGgugugug、UUGgugugug、UUGguguguu、UUGguuaagu、UUGguuagca、UUGguuagug、UUGguuaguu、UUGguuggga、UU Gguugguu, UUGguuugua, UUGguuuguc, UUUgcaagug, UUUguaaaua, UUUguaaug, UUUguaagaa, UUUguaagac, UUUguaagag, UUUguaagca, UUUguaaggu, UUUguaagua, UUUguaaguc, UUUguaagug, UUUguaaguu, UUUguaauuu, UUUguacagg, UUUguacgug, UUUguacuag, UUUguacugu, UUUguagguu, UUUguauccu, UUUguauguu,This includes UUUgugagca, UUUgugagug, UUUgugcguc, UUUguguguc, and uGGguaccug.

[0244] Further exemplary gene sequences and splice site sequences (e.g., 5' splice site sequences) include AAGgcaagau, AUGguaugug, GGGgugaggc, CAGguaggug, AAGgucagua, AAGguuagag, AUGgcacuua, UAAguaaguc, UGGgugagcu, CGAgcugggc, AAAgcacccc, UAGguggggg, AGAguaacgu, UCGgugaugu, AAUgucaguu, AGGgucugag, GAGgugacug, AUGguagguu, GAGgucug uc, CAGguaugu, CAAguacugc, CACgugcgua, CCGgugagcu, CAGguacuuc, CAGgcgagag, GAAgcaagua, AGGgugagca, CAGgcaaguc, AAGgugaggc, CAGguaagua, C CAguugggu, AAGgugugg, CAGguuggag, CCGguaugaa, UGGguaaugu, CAGgugaggu, AGAguaauag, CAGguaugag, AUGguaaguu, UUGguggguc, UUUguaagca, CUCgu augcc, UAGguaagag, UAGgcaaguu, GGAguuaagu, GAGguaugcc, AAGgugugu, CAGgugggug, UUAguaagua, AAGguuggcu, UGAguaugug, CCAgccuucc, CCUguacgu g, CCUguaggua, CAGguacgcu, GAGguucuuc, AAGguugccu, CGUguucacu, CGGgugggga, UAGgugggau, CGGguaagga, AAGguacuau, GGGguaagcu, ACGguagagc, CA Ggugaaga, GCGguaagag, CAGguguugu, GAAguuugug, AUGgugagca, CGGguucgug, AUUguccggc, GAUgugugug, AUGgucuguu, AAGguaggau, CCGguaagau, AAGgua aaga, GGGgugaguu, AGGguuggug, GGAgugagug, AGUguaagga, UAGguaacug, AAGgugaaga, UGGguaagug, CAGguaagag, UAGgugagcg, GAGguaaaaa, GCCguaaguu,AAGguuuugu、CAGgugagga、ACAgcccaug、GCGgugagcc、CAGguaugca、AUGguaccua、CAAguaugua、AUGguggugc、UAAguggcag、UAGguauagu、CUGguauuua、AGGguaaacg、AUAguaagug、UUGguacuga、GGUguaagcc、GAGguggaua、GAUguaagaa、ACGgucaguu、UAAguaaaca、AAGguaucug、AGGguauuug、AAGgugaaug、CUGgugaauu、CAGguuuuuu、CAUguaugug、UUGguagagg、AAGguaugcc、CAGgugccac、UCGguauuga、AAGguuugug、AAUguacagg、CAUguggguu、CAUgugaguu、UUGguaaugu、AGUguaggug、GAGguaacuc、GAGguggcgc、CUGguaauug、GAGguuugcu、UGUguacgug、UAGguaaaga、CUAguaggca、UCUgugaguc、UCUguaaggc、CAGguuugug、GAGguagggc、AAGguaacca、ACUgugaguu、UAGguaauag、AAAguaagcu、AUGgugagug、UAGguuugug、AACguaggac、GUAgcaggua、GAGgucagac、AGGguaugaa、GAGguuagug、CAGgcacgug、GGGgcaagac、CAGguguguc、CAGguauuga、CAGguauguc、AAGgcaaggu、UUGgugagaa、AAGguaaaau、GGGguaagua、AAGguaucuu、GACgugaguc、UAUguaugcu、AAGguacugu、CAGgugaacu、CACguaaaug、AAGgugugau、GAAguauuug、AAGgucugug、AAGguggagg、AAGguauaug、CAGguucuua、AGGguaacca、CAGgugucac、AAAguucugu、UUGgugaguu、CAAgugaguc、UAGguagguc、GCGgugagcu、AUUgugagga、CAGgugcaca、CAGguuggaa、CUGgucacuu、GGAguaagug、GAGgugggcu、AAGguacuug、AGGguaggau、AAUguguguu、ACAguuaagu、GAGgugugug、AAGgcgggcu、AUAgcaagua、AAGguuguua、CAAgcaaggc、GUGguaauua、UCUguucagu、AGGguaggcc、AAGguaucau、UAGguaccuu、AAGguaugac、GGAguaggua、UAAguuggca、AGUgugaggc、GAGguuugug、UGGgucugcu、CAGgugaucc、CAGgucagug、AAGguaaggg、CAGgugcagu、GAGguggguc、GCUgugagug、AAGguggagu、GGGgucaguu、AGCguaagug、AGAguaugaa、GGGguagggu、AAGgccagca、CGAguaugcc、GUGgugagcg、AAUguaaauu、CAGgugcgca、GGUguaugaa、CUUgugaguu、AAGguaucuc、AGAguaagga、UAGguaagac、GAGgugagug、CAGguguguu、UUGgugagua、AGGgcgaguu、CAGguuuugc、UUUgugaguu、AGGguaagca、GAGguccucu、CCAgcaggua、GAGguucgcg、CAGgugaucu、ACUguaagua、AAGguaaauc、CAGgcaaaua、GUGguaagca、CAGguuaaau、UUGguaauaa、UAUguaggua、CAGguaguau、AAGgugugcc、UGGguaagag、CAGgcaagca、UUGguaaggg、AAGgcaggug、ACGguaaaug、GCUgugagca、AUGguacaca、GUAguguguu、ACUguaagag、CCCgcagguc、GAGgugagcc、GAGgugcugu、UAAguaugcu、GAGgccaucu、UCAgugagug、CAGgugcuac、AAUgugggug、GAGgugugaa、CUGguagguc、GUGgcgcgcg、CAGgugcaaa、UAAguggagg、CAUgugggua、GAGguagggu、AAAgugaguu、AGGguucuag、UGUgugagcu、AGGgugaauc、CAGgucaggg、AAGgucccug、CUGguagagu、UAGgucaguu、AAAguaaggg、CAAguaugug、CAGgugcuuu、AAGguaauuc、GGGgugcacg、ACUgugcuac、CAGguaccua、CAGguagcuu、UGGgugaggc、CUGguacauu、AGGguaaucu、CAGguacaag、CAGguaauuc、AGGgcacuug、UAGgugagaa、GAGguaaugc、CCAgugaguu、AAAguaugug、CUGgugaauc、UAUguaugua、CCUgcaggug、CAGguaucug、GAGgugaggu、CUGguaaaac、UGUgugugcu、CAGguuaagu、CAGguaaucc、UAGguauuug、UGGguagguc、CAGguaacag、AGCgugcgug、AAGgucagga、GGUgugagcc、CUGguaagua、GGGgugggca、AAGgugggaa、CAGgugagug、CUGguuguua、CAGguaauag、UAGgugaguu、AGAguaaguu、UAGguaaucc、CCGgugacug、GUCgugauua、CUUguaagug、UAGguaguca、CUGguaaguc、AGGgugagcg、CAGguaugga、AUUgugacca、GUUgugggua、AAGguacaag、CUAgcaagug、CUGgugagau、CAGgugggca、AUGgcucgag、CUGguacguu、UUGgugugua、GAGgugucug、GAGgugggac、GGGgugggag、GCAgcgugag、GAGguaaaga、GAGguaugua、AAGgugagac、AAGguacaau、CUGguaugag、AACguaaaau、GUGguaggga、CUGguaugug、CUUguaagca、AAGguaggga、AUUguaagcc、AUGguaagcu、CAGgugaauu、UAGgugaaua、CAAguaugga、AUGguauggc、GAGgucaugc、CAGguacccu、ACAgugagac、CAGgucugau、GAAguugggu、CUGgugcgug、CAGguacgag、ACAgugagcc、AAGguaagua、GGAguaaggc、GAGgugugua、AAGgucauuu, CAGguagucu, AUGguaucug, AAGguaaacu, GAGguaggug, CUGguaagca, AGGguaagag, AAAguaaagc, CAGguuugag, GAGgcgggua, CGAguacgau, CAGg uuguug、AAAguauggg、UAGgcugguc、AAGguaagga、AAGguuuccu、UUGguaaaac、GAGguaagua、CAGguucaag、UGGguuaugu、GAGgugaguu、ACGgugaaac、GAUguaac ca、AAGguggcggg、CCGguacgug、GAUgugagaa、GUGgcgguga、CAGguauuag、GAGguuggga、AAGgcuagua、AAGgugggcg、CAGgcaggga、AAUguuaguu、GAGguaaagg、C AGgugugcu、CUGguaugau、AUGguuaguc、CUGgugagaa、CAGgccggcg、CAGgugacug、AAAguaaggu、UAAguacuug、AAGguaaagc、UCGguagggg、CAGguaggaa、AGUgu aagca、CCCgugagau、GUGguuguuu、CAGguuugcc、AGGguauggg、UAAguaagug、GAGguaagac、GAUguagguc、CAAguaggug、AUAguaaaua、GAGguugggg、GAGgcgagu a、CAGguagugu、GUGguaggug、CAAgugagug、AAGgugacaa、CCAgcguaau、ACGgugaggu、GGGguauauu、CAGgugagua、AAGgugcgug、UAUguaaauu、CAGgucagua、AC Gguacuua, GGgucagca, UAAguaugua, GGGgucagac, AAUgugugag, UCCgucagua, CAGgugcuuc, CCAguuagug, CCGgugggcg, AGGgugcaug, GGGguaggau, UAGgug ggcc、GAGguguucg、UUGgcaagaa、UCCguaagua、CAGguguaag、CUCgugagua、GAGguguuuu、GAGgugagca、GAGguaaagu、AAGguacguu、CAGguccagu、AUGgugaaac、GUAgugagcu、CAGgugaaaa、AGGguacagg、AAGguaacgc、AAGguauacc、CCUgugagau、GGGguacgug、GAGguauggu、UAGguauuau、GAAguaggag、UCGgu、 aaggg、CCGguaagcg、GAAguaauua、CAGgugaguc、AAGgucaaga、AUGguaaguc、CAGgugagcu、CCAguuuuug、CAGgugggag、AAGguauuau、AAGguaaaua、AAGgugcugu、AAAguacacc、CUGguucgug、UCAguaaguc、GAAguacgug、CAGgugacaa、UGGguaagaa、UGUguagggg、GAGguaggca、UUGgugaggc、AUGgugugua、CAGguccucc、UUGguaaaug、GCUgugaguu、AUGgucugua、CAUgcaggug、CUGguacacc、CAGguccuua、CAAguaaucu、AUGgcagccu、AAGgucagaa、AACgugaggc、CAGgcacgca、ACGguccagg、UCUguacaua、GAGgugauua、ACGguaaaua、AUGguaacug、CAGgcgcguu、CAGguauaga、AAGguuuguu、CAGguaugaa、UAGguuggua、CUGgugagac、CAGguuagga、AUGgugacug、UUGguauccc、CUUguaggac、AAAguguguu、CAGguuucuu、GGGguauggc、GGGguaggac、ACUguaaguc、AUCguaagcu、UAGguucccc、GGUgugagca、CUGguuggua、GGGguuaggg、UGAguaagaa、GAGguauucc、UGGguuaguc、CAGgcucgug、UAGguagagu、UAGgugcccu、AAAgugagua、GAGguucaua、UUGguaagag、ACCgugugua、UAUguaguau、UGGguaauag、CAGgucugaa、AAAguauaaa、GUGgugaguc、AGUgugauua、UUGgugugug、CAGgugaugg、GCUgugagua、CAGguacaug、AAGguacagu、GAAguuguag、CAGgugauua、UAGgugaauu、GGUguuaaua、CAGguauuua、CAAguacucg、CAAguaagaa、AAGguaccuu、ACGgugaggg、UGAgcaggca、GGGgugaccg、GAGguaaaug、CGGguuugug、AAGgugagcg、GUGguaugga、CUGguaagga、GAGguaccag、CCGgugagug、AAGguuaga、GAGguacuug、AGAguaaaac、UCUgugagua、AAGg cgggaa, CAGguaugcg, AGGguaaaac, AAGgugacug, AGGguauguu, AAGguaugua, CAGgucucuc, CAGgcaugua, CUGguaggua, AAGgucaugc, CAGguacaca, GAUguacg uu、ACAguacgug、ACGguaccca、CAGguagugc、ACAguaagag、GGUgcacacc、GAGguguaac、AAGgugugua、UAGguacuua、GCGguacugc、UGGguaaguc、CAUguagguaC AGguaggau, CAGgucuggc, GUGguuuuaa, CAGgugggaa, UGGgugagua, CGAgugagcc, AAGguauggc, AGUguuguca, CAGgugauuu, UAGguaucuc, UAAguauguu, AAGgu ugagc, AGAguaaaga, GGUguaagua, GGGgugagcu, CAGguauaau, GAGguacaaa, AUGguaccaa, UAGguagggg, UGAgucagaa, AAGgcaauua, UUGguaagau, CAGguacag a、AGAguuagag、CAGgugcguc、GAGguauuac、ACGguacaga、CAGgucuucc、AAGguaaggu、GAGguaauuu、AGUguaggcu、AAAguaagcg、CCUguaagcc、AGGgugauuu、UG There are many different types of characters in the film agug、AAAgugauga、UGCgugagua、AGAguaggga、UGUguaggua、UAGguaggau、UAAgugagug、GCUguaagua、GAAguaagaa、UCGgugaggc、UAGguauuuu、AAGguacaca、AAGguaggua, UGGguagguu, ACAgcaagua, GAGguaggag, UGGgugaguu, GCGgugagau, CCUguagguu, CAGgugugua, CUGguaagcc, AAGgugauuc, CAGguagcua, GUUg uaagug、AUGguaagca、AUAguaggga、GGGguucgcu、CCGgucagag、GUAguaugag、CGUguaagau、UGAguaggca、UCAguaugua、GAGguaucug、AGAguauuuu、AAGguugu ag、AGUguaaguu、CGGguaaguu、UCGgugcgga、UAGguaagua、GAAguuagau、GCUgugagac、CAGgcaggua、CAGguagggg、UAAguuaaga、AUGguggguu、UAGguaaguu、C UGguaaauu, CCGguaagga, GAGgcaggca, CAUguaagug, AAGgugccua, UUGguaaggga, AAGguaaaca, CGGgugugag, GGGgugugag, UCCguggguc, ACGguaaauc, UCAgu aggua、CAGgucagcc、CAGgcggugg、CGAguaagcu、CCCgugagca、AAAguaauga、CUGguaagcu、CGGguaacca、CAGgucgcac、GAGguaggcc、UAGgugagcc、UAGguaggc a、GCGgugcgug、AUGgugagua、GGGgugaggg、GAGgucacac、CAGguaggcc、CAAgugcuga、GUCgucuuca、CAUguaagaa、GUAguaagga、UAGguuugua、CAAguuagag、AA Gguagagu, AAGgugagau, AAAguaggua, ACAgugaauc, CAGgugugcg, CAGgucggcc, AAGguaguau, ACUgucaguc, UCUgcagccu, CGAguaagug, AGAguaauua, AGUgug agug、CCGgugagcg、AAGguaaccu、AAGguugugg、AAGgcauggg、AAGgucagag、ACGguaaggu、GGGgugagca、GAGguugcuu、AAGguaucgc、CCGguaaagg、AAAguuaaug、UAGguacgag、ACCguaauua、GGGguaagga、CCGguaacgc、CAGgucagaa、AAGguacuga、GAGgugacca、GGGgugagcc、AAGguacagg、AUGguaauua、CAGgugagag、AAGgugacuc、AUAguaagua、GAGguaaacc、CAGgugggau、CAGgugagaa、AGGguaaaaa、GAGgugugac、CACguaagcu、CAGguccccc、CAGgucaggu、CGGguaaguc、ACGguauggg、GAUguaaguu、CAAguaauau、CAGguugggg、CCUgugcugg、AAGguaugau、AGGguagagg、AAGguggguu、CAGgugugaa、UUGguaugug、UUGguaucuc、GGGgugagug、CUGgugugug、AGGguagggc、GUGgugagua、CAGguaugua、AAGguacauu、UUAguaagug、AAUguauauc、CUUguaagua、GAGguuagua、CAGguaaggu、CAGguaaugu、AGGgugaggc、CAGguauuuc、CAGgucugga、GGGgugugcu、UAGgugagug、AAUguaaccu、UAAgugaguc、CAGgugcacu、ACGguaagua、GAGguauccu、UCUguaaguc、CAGguauuca、UGUguaagug、CCAgcaaggc、GAGgugaagg、AAUguggggu、UCGgugcgug、UUGguaaggc、GAGguaagug、AAAguaagau、UAGgucuuuu、GAGgucugau、CCAguuagag、UGGgugaaaa、AGAguaagau、CAGguaauug、CAGgccgguc、CCGguaagag、GAGgugagcu、CUGguaagac、CAGgugagau、CUGguuuguu、UGGguaggua、CAGguuagug、CAGguguucg、CGGguagguc、GUGguacaua、AAGguacuaa、GAUgugagua、UGUguaagac、GAGguagccg、UAGgugaucu、CAGguacgug、CUUgucaguc、GAGguaucac、GAGguaauga、AAGguaacac, CAGguaaagc, AAGgcaagua, CGCgugagcc, AGUgugcguu, GAUguaagca, AAGguaauag, GGAgcaguug, AGCguaagau, AAGgucaggc, GGguauuca, AAUg uaaagu, CAGguaacaa, UCGguaggug, AAAguaaguc, CGGgugcagu, GGUgugugca, UGAgugagaa, CACguguaag, GCAgccuuga, CGAgugugau, CAGguaua ua、UAUguaugug、CCCgugguca、AUGguaagac、GAGgugugga、AGUguauccu、UGAguguguc、UGGguaaucu、AUGgcagguu、GAGguaagau、UCAgcagcgu、AAGgugggau、C GGgugcgcu、CAGgugucug、AGCgugguaa、AAUgugaaug、UCGgugagac、UAGguaaagc、CUGguaaaag、CCGgugcgga、CAGguacuca、CAGguagcaa、GAAguugagu、GAGgu ggagg、AGGguaugag、UAGguaugcu、UAGgugagac、CAGguaauua、CGUguaagcc、CUUguaaguu、AAGguaacuu、UCGgcaaggc、GAGguucucg、GAGgugggcg、AAGgcaugu g、CUGguauguu、UAAgucauuu、CAUguaauua、AAUguaaaga、UAGgugcuca、AAGguaaugg、GAGguacuga、UGGguaagua、UGGguaaaaa、AAGgugagcu、UACgugaguu、AG Ggugagcc、CGGgugagga、UGGgugagag、GGUguaagcu、CGGguggguu、CCAgcuaagu、AAGguuuguc、GAGguuagac、GAGguaccuc、UUUguaaguu、GAGguuagga、CAGgua ggga、AGGguaauac、UGCgugugua、CCAguaacca、AGGgucuguc、UGGguaugua、GUGguaagcu、CAGguaaccu、AAGgugaguu、UAGguucgug、AAAguuagua、UGGgcaaguc、AAGgcacagu、GUUguaaguc、AAGguuugcc、CUUgcauggg、GCGgugagua、GGGguaagcg、GCCguaagaa、GAGgucggga、UUGguauugu、AGUgugagac、CUGguggga、 AGAguaaggu、CCGguggguc、CAGguauucu、UGGguaacgu、UUGgugagag、UAGguacccu、GGGgugcguc、AAGgcaggag、ACGguacauu、GAGguaguua、CAGguauggg、UUUguguguc、CAGguacuua、AUGguauacu、AGUgugagcc、ACAguaacga、CUGguaccca、CAGguaaccc、GGAguaagua、GAGgugggug、ACUguauguc、ACGgugagua、CUGguaaugu、AAGguaucag、CAGgugcccc、AGUgucagug、AAGguaggag、GGAguaugug、UUGguauuuu、CCUguuguga、UUUguaagaa、UAGguaacau、CAGguaagca、CAGgucacag、CAGgugugag、UAGguuugcg、CUGguaagaa、ACGguuguau、AAGguugggg、AAGgugaauu、GGGguuaguu、ACGguaaggc、CAGguuuaag、CUGguaaguu、GGGgugagag、UGGguggguu、GAGguuuguu、UGGguaaaug、CAGgcaggcc、CACgugcagg、AAGgugagcc、CAAguaagug、CAGgucaguc、GCGguauaau、UAGguaaagu、UAGguggauu、GAGgucugga、UCGgucaguu、UGGguaacug、AAGguuugau、UGUgcuggug、UGUguaccuc、UGGguacagu、AUCgucagcg、CAGgucuugg、GAAguuggua、GAAguaaaga、UUGguaagcu、UAGguaccag、AGGguaucau、CAGguaaaaa、ACGguaauuu、AUUguaaguu、GAGguacagu、CAGgugaaag、UGGguuguuu、GGGguaggug、CAGgugccca、AGCgugagau、CCAgugagug、AGGguagaug、UGGguguguc、AUCgcgugag、AGGguaagcc、AGGguagcag、UUCguuuccg、AAGguaagcg、UGGguaagcc、CAGguauggc、UGUguaagua、AAGguagaga、ACGguaauaa、CUGguacggu、GAGgucacag、UAUguaaguu、CUGguacgcc、CAAguaagau、CUAgugagua、CCGguaaccg、CUUguaaguc、GUGgugagaa、ACCguaugua、GUAg uaagug、UUGgugggua、CGGguacuuu、UGGguaaaua、AGAgugagua、AAGguagguu、AAGguaugcg、CCUguaggcu、ACAguagaaa、CCGguaagua、CGGguaggcg、GCAgugag ug、GAGgugaguc、CUGguagccu、CAUguaugua、GAAguaacuu、GAAguaagau、AAGguuagau、AAGguaauca、AAUguaugua、UGAguaagau、AGAgugagca、GUAguucuau、G AGguaauca, UAGguaugga, UAGgugggac, GAGguacaug, UGGguaaggc, CAGguacgcc, CCAguuacgc, ACUgugguga, GAGguaaguc, AUUguaggug, ACCgucagug, AAUgu gaggg、ACUgugagug、UGGguguggu、AAGguuggga、AAGguuugga、UCCgugagug、CGGgugagug、AGAguaagcu、CAGgcaagcu、UAGguauauu、AAAguagcag、GAGguaacc u、AAGgugggca、AGGgugagua、UGGguaaggu、CUUgucagug、UAGgugcgcu、GAGgcaaauu、AGGguaccuc、CAAgugcgua、AGAguaagac、GUGguaaaua、GAUguaagcg、GA Gguaaagc, UAGgugagua, CAGguaacau, CCUguacggc, UAGguauguc, UAGguccaua, GGgugaaaa, AAAguacuga, UUGguaagcg, CAGgcaagcg, UUUgcagguu, CAGguu uaua、CUGguaaagc、AUGgugagcu、CAGgugguug、GUAguaaguu、CAGguaauac、CAGgcaaggc、AAGguaauuu、UUUguccgug、GAGguagguu、ACCgugagug、CAAguaagcu、ACAgugagua、UUGgugagau、AAGguagucu、CAGguaaagg、GGGguaugga、UUUguaagug、GUGguaagag、AGUgugaguu、AAGgcaagcg、UAAgugagua、AGGgugagug、AGUguacgug、AGGgugcgua、GGCgugagcc、CGAguuauga、CAGguaaaga、UUGgugaaga、AGGguaaugg、AAGguccaga、AGUgugaguc、CAGguaauuu、CAGguaacgc、CUGguacacu、CUGguuagug、CAGguacuug、CACguaagua、GUGgugcggc、GAGgucaguu、AUGguaugcc、AAGgugugug、CUGguggguc、CAGgugaggc、AAGguuaguc、AAGguagcug、GAGgucagga、GUUguaggua、UGGguacaag、AUGguaggug、GAGguaagcc、AUGgcaagua、AAGguauauu、GCGgugagag、AAGgugcuuc、UAGguacauc、ACUgugguaa、GAGguaggcu、GAGguaugca、AGGguaguuc、CAGguauccu、AGGguaaguc、AGGgucaguu、CAGguuggga、CAGguggaua、GGAguagguu、GAGguaggau、GGGguuugug、UAGguaauug、AAGguaaccc、ACGguaagaa、GAGguagggg、CGAguaggug、UCCguaagug、UCGguacagg、CAAguaagcg、AAGguccgcg、AAUgugagua、CAGgugaaug、GUGguaaggc、AGAgugagug、UCUguauguc、UGGgugaguc、UCGguuagua、GAUguaugca、GAGguuggug、GAGguggggc、UGGgucaguc、GCAgugagua、CAGguugcuu、AGGguagagu、UAGgucaggu、CGCguaugua、GAGguauuaa、CAGguaaacu、AAAguaaguu、GGGgucuggc、GCUguggggu、UUGguaaguc、AAGguagaag、AAUgugaguc、AAGgucagcu、AAGguaagag、AUGgugagga、AAGguacuuc、AAGguaagaa、CCGguacagc、GCGgugcgga、CAGguacaua、CUGgugagga、CUGguaggug、AACguagguu、AUGgugugug、UUGguacuau、CAGgucggug、CAGgcauggg、AUGguaucuu、AAGguaacua、CAGgugggcg、CACgugagga、AAGgugguuc、UGGgcauucu、AUGguaagcc、AGGgucagug、AGAguacgua、AAGguaggca、AAGguauuca、CAGguagauu、GAGguauuua、GAGgucuaca、GUUguagguc、CAGguacucg、GUCguauguu、AAGguacuuu、AGAgugagau、AGUguuggua、AAUgugagug、AAGguagauu、AUGguuugua、GAGgccccag、AUGgucaguu、UCUguaagga、CAGgucgggc、CAGguaagcc、UAGgucagug、AGAguaggaa、CUGguacuuc、CUCguaagca、CAGguaacua、CAGguggcug、UGGguccgua、GAGguugugc、CAGgugcgcg、AAAguauggc、UGAguacgua、CUGguacgga、CAAgugaccu、AAGgugaugu、AAGgucugca、AAAguuugua、AAGgugagca、GAUguaagcc、CAAguaauuu、CAGgugugug、UGGgugaggg、AAGgugaccu、UAGgugugag、CAGgcagguc、UCAguaaguu、UCAgcaguga、AAGguaccac、UAAguaggug、AAGgucagcc、CAGguaacuc、AAAguaagag、AAGguagaua、AAGgcaaggg、CAGgugucgg、CAGguggcua、GAGguugcca、CAGgccgugg、UUGguauaug、GAGguugagu、GAGguagguc、GUGguaagac、UAGguccuuc、GAGgcaaguc、GAGguaacau、CAGguauauc、UCGguugguu、CAGgugaacc、CAGgucuuuu、CAGgcauggc、AAAguacuug、CAGgugauuc ucaguu, CUGguaggcc, CAAguaagga, CGGguaaggc, AAGgcgagga, CAGguaguuc, CAGguaagga, CCUgugagug, AAGguaaaug, CCGguaauua, CAGguaaguu, AAGguggu ca、CAGguaccuc、AUCguaagua、CCGguacaua、GCGgugagug、GAGgugguau、CUGgugugga、GAGguaauuc、CAAguacgua、UCUguaagug、AAUguaagug、AGGgucuguuG AGguacugc, AGGguaaggc, AAGgcaagag, CAGguggguu, UAGguuagga, UGAguaagcu, AGAguaagag, AUGgcaggug, UAGgcaagua, AUGguaggua, GCAgcccgca, ACGgu aaacu、AGGgugaguu、GUAguagucu、GUGgcugaaa、CAGguuaguc、CUGgugagca、UCAguaagug、AAAgugauug、UAGgucugga、GAGguguuuc、AAGguaaauu、CAUguacau c、AAGguuugaa、CCAgcaagug、UAGguaauaa、GAGgcaagug、CAAgugauuc、CAGgucgugg、GAAguaugcc、UCGgugcccu、GAGgucaguc、CAGgugagac、UUUgucugua、CA Gguagaua, UGGguaucag, UAGgugggcu, AUGgugagau, CAGguaacac, CCGguauccu, UAGguaagcu, UCAguacauc, UAGguuugcc, AUGguaagaa, UUGguaagac, CCGguu aguc、GAGguaagaa、UGGguaaguu、CCGgugagaa、CCUgugaggg、ACGguaggag、ACAguauguc、CAGguauuaa、CAGguggauc、AGAgugcgua、AAGgugaccg、AGAguaggug、ACUguaugua、UAGgucaauu、AGUguguaag、CGGguaccuu、CUAgugaguu、CUAguaagug、CAGguacaac、UAGgugugug、CAUguacggc、AUGgugugag、AGGgug、 gaag、CAGgugcgag、UAGgugcucc、AAGguggugg、AAGgucuguu、CAGgugggcc、AAGgucaguc、CAGguuuuua、AACgugaggu、CGGguaagag、UUUgucggua、UAGguuaag u、GUGguaagaa、CAGguauugg、GCUguaaguu、CUAguaagua、UCGguaaaua、CAGguaacuu、CCUgugagua、CAGguuauau、CUGgugaaca、AAGguauaaa、GAGguaagca、A AGgugaagc、CAGgugaguu、UUUgugagua、CUUguacgcc、AGAguaagug、UGGguaggug、UGAgcccugc、UGUguaugua、AAGguagagg、GAGguggggg、UAGguaauuc、AAGg cauggu、AGAguaagca、AAGguaggaa、CAAguaagua、ACUguaauug、CAGgucugug、UCGguaccga、CUGgugagag、AAGguuugcu、AUGguaccac、UAAguuaguu、CAGguagg ac、AGAgugaggc、CGAgucagua、CAGgucugag、GAGguggugg、ACGguauugg、GCUgcgagua、CUGguaagug、GUGgugagau、GGGguuugau、UCUgugagug、CUUgucagua、 GAGguaaaac, UCUguaagau, CCAguaaguu, CAGguaaagu, GCGgugagca, UAAguaagag, CUGgcaggug, GAGguaaggg, UGAguaaguu, GAGgugagac, GCUgucuguu, AAGg uaacaa、GAGguaacgg、CUGguauucu、CAAguaacug、AAGguggggu、UAGguauggc、CAGguauuuu、GUGguaaacu、GAGgucugag、CUGguaaggu、CAAguaaguu、AAGguag acc、GAGgcgagcg、CUGguaaaua、UGUguaagcg、CAGguuaggg、GGGgugagga、ACAguaugug、CCGgugggga、GAGgucagug、AGGguaaggu、ACAguaagua、GGUguaaggu、GAGguaauaa、CAGguauucc、CUGguauaaa、CCGgucugug、CAGguaacug、GCAguaagua、AAGguagggg、CAAguccacc、CAAguuggug、CAGgugcggu、CAGguaaaau、ACGguaagga、UGGguaauaa、UAGguaagug、CCGguagguu、AGAguaugga、CUCgugaguc、AAAgccggug、UUGguaauuu、GAGguaaaag、CCUgugugag、AAAguaagga、UGAgugagug、AAGguacaug、CCGguaaaug、CAGgugaagc、CAGguacccg、GAGguaaggc、UUUguauguu、CAGgugcucc、UCGguagguc、CGGgugaggc、AAGguaauua、ACUgugaguc、AAGgucagca、GUGgugagug、CAUguccacc、AAGgugaccc、CGGguuagua、GCGguaguaa、GCUguaggua、CCUguugagu、UAGgucuggc、GAUgugagcc、CUUgugagua、CUGguguguu、GAGgcaugug、CAGgcaagag、UUGguaagaa、GAGguguggg、GAGguauuuu、CAGguaguaa、AGGguaagac、UUUguaggca、AGGgugagau、GAGguuugua、AAGgugagug、GAGgugggag、AAGgugagaa、CUGguaagag、AUAguaaaga、GAUgugaguc、AAGgugcagg、CAGgucuguc、GAGgugauuu、CAGguuggcu、CGGguauggg、AUGguccauc、CCGguuggug、GGAguaaguc、AAUguaagga、CAGguuuguu、UAGgugugua、UAUgucuuug、ACGguacuuc、AAGgcacgcg、CUGguaaacc、CUUgugggua、UGAguaaguc、CUGgugggug、GAGguggaga、GUGguggcug、GUGguaagug、AACgugagua、GAAgcuguaa、CGGguaucuu、CAGgugucag、AAUguacgca、CCGgugggua、UGGgugaggu、AAGguauguu、CAGguauguu, CAGguuugcu, UUGguaaguu, CAGguaguug, CCUgugaaua, GCUgugugug, CAAguaauuc, AGGguaaugu, GCUgugaguc, ACCguaaguu, CGUguaagua, GGGg uaaguc、AAUguaugau、AAUgugauua、UCAguaagaa、CAGguccguc、GAAguauuga、UUGguaagga、CAGgucgguu、UAGguuagug、ACGguaaaac、AAGguagguc、UACgugag ua, UUGguaagca, GCGgugaguc, GAAguaaggg, CGCgugaguu, CAGguacccc, UCUguaagac, GAGgugggca, AAUguaagac, CAGgcaaggg, CAAguaacua, AAAguuuguc AGguacugu, AAGgucccuc, UCGguaaguc, UGGgugagug, CUUgugagau, AGAgugagcu, UAAgugggga, UAGguaggga, CAGguuagcc, AGGguaauca, AAGguucagc, UGGgu gggug、CAGguuguga、AAGguaagug、CAUgugcgua、CCGguauauu、ACCguaugug、CAGguauagu、CAGguauuac、CAGgugcagg、GUGgugagcu、AAGguaacau、CUGgugaug g、AUGguaaaug、CCGgugagca、AAGguaaacc、AAGguacugg、GCGgucagga、CUGgucaggg、AAAguacguu、AGAguagguu、AGGguaagcu、AUUgugagua、CCGgccacca、GA There are many ways to get the best results from your search aacu, CAGgcaugca, UUGguaaucu, AGGgcagaau, AUGguaaaac, GCUgcaggug, GAAgcacgug, CAUguaaaca, UGGguaagau, AGGguagcua, AGGguggggu, CCUguaaguu.UGAgugaguu、GGAguaugua、CAGgugaccu、AAAguacgga、GAGguacaga、GAUguaggua、GGGguaauug、UAGguggguu、GUGguacgua、AAGguacagc、GAGgugaaga、GGGguaagca、UGAguagguc、GGGguaaguu、AUUgugaguu、UCAguaagac、AGUgugagcu、AAGgcaaaac、CUGgugaguc、AAGgucucug、GAGgcugugc、AGAgugagac、GAGgugaugu、AGAguauggu、UGGguggguc、GCUgcugagc、CAGguagcug、UAGgucagaa、CCGguaggug、GCAguaugau、CAGguuucag、GAGguuugcc、GGGguggggg、AAGguacaua、UGGguguguu、AGAguaaggc、GCGguuagug、AAGgugacuu、AUGguaagau、AUGguaguug、CAUguaagac、CUGguaugua、UUCguaagga、GAAguaugac、CGGguaauuc、UGGguaacuu、CAGgugccua、CAUguagggc、ACCgucagga、CGUguucgau、GAGgcaggac、UAGguaauau、UCGguauacu、UAGguugugc、CCGgugaguc、CAGgugccaa、CAGgugaugc、AAGgugagga、GUGgugaggg、UGGgucagua、GAGgucaggg、UAGguacgua、GAGgcaagag、CCUguuggua、GAGguaucca、UAAguaagcu、AAGgucaguu、AAAguuaaag、GAGgugcuau、ACGguaaguu、CUGgugaggg、GAGguuaugu、CUUgugugca、UGAgcugggg、AAGguauagu、UAGguaaaac、GGGgugaggu、GAGgcaagca、GGAguaacgu、AGAguaagua、AAAguaagua、GAGgcaacca、UGUguaaguu、UAGgugaggc、ACAguaagaa、UGAguaagug、CAAgucagua、AGGguaaaug、AAGguaugca、GCUgugcgug、GAGguucgcc、AAGgcuugca, CAGgcaagug, AUAguaaguc, UUGguaggua, GCAgcaggua, AAGguauauc, AGCguaagcc, CUGguucgaa, ACGgugggug, CUGgucauug, CAGgucagga, CAAg ugagac、GAGguacugg、GAGguguagu、GAGguguccu、CAGgugcgua、AGUgcccuga、AUGgugaguc、UGUgugugua、CAGguaugcu、CUGguacagu、UUGguacgua、UCUguacg ua、UAAguaauuc、CACguaugug、CAGgcaagua、UCGgugagug、GGUgugaguc、UCUguaagcu、AAGguucaga、AGGguacuuc、GCGgcagguu、GAGgcccgug、CAGguauaaa、A UGgucaagu、AAGgugagua、GUGguuuguu、AGAgugagga、GAGguaugac、UAGgcgugag、AAGguacucc、UGAgugagga、GAGguaugau、GGGgucggua、ACGguaugca、CAGgu accac、UAAguaccug、AGGgugggcu、CUGgucuguu、UAGgucagag、AAGguguguu、CUGgucagug、AAGgugggac、GUGguaguag、CUAguuuagg、CCCgccccau、GCUguacug c、GAGguaauau、UAGguuggug、AAGguccaac、UAGgugagga、GUGguaaguu、AGUgugagag、AAUguacaug、UUGgcaggug、UAGguuauug、CAGguacuga、GCGguggguc、UG There are many ways to get the best results from your search 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ugaggg、GAAgugagua、CAGgugacag、AAGgugauua、GAGgccagcc、GAGgucuccu、UAGguauuac、CAUaguaagag、CUGguagggc、GAAguaagua、CGGguaagua、CAGaguagua、 cu、GUGguaggua、CAGgugggua、AAAGgccagug、AAAgugaauc、ACGguuacgu、AUGguaggaa、CGGgugagac、GAGguaggaa、UGGgugagcc、CCAgugagua、gA、CU AGguaugac、GCUgugaggu、CUGguaugaa、GGUguacgac、CUUgugagug、GUGgugagca、CUGguaacuu、CAGguacuau、AGGguaaggg、UUGguuaguuG、Gguuaagca、GUguaagca gagga、UGGguaaaca、UCGguacgug、UAGguagcag、CUGguaaggc、GUGguaagga、UAAguaagca、GAGguuccaa、CUGguaugga、GGGgugggua、cuCAGCAGuuccc、cuGguuuccc、 g. Gguaauug、AAGgugcuca、AAGguucaac、CAGguuuaca、GCUguaagug、AGGguauguc、GAGgucgggg、AAGgugccug、AAGguaaaaa、GUGgugaguuAGGaa、UAGgua uccu.AGAguauguu、UAGguacuug、GCAguaggug、AGUguauguc、AAGguuaagc、CUGguggccu、GAAgugaguc、UUGguguaag、CAGguaagaa、CGGgucucgg、GAGgugcaca、CUCguuaguu、AAGgugauca、UAUguaagaa、GAGgugcuug、CAGgugguca、ACGguaaguc、ACAguaaugu、CCUguaaggu、GAGguuaagu、UCGguaugug、UGGguauguu、AAGguauuac、CAGgugaggg、UUGguaaaca、AAGguagugu、GAGguguggc、CAGguacgga、AAGgucauca、CAAguaggca、CAGgugaaac、CAGguacugc、AAUgcaagug、CAUguaauuc、AAGguaugcu、CUGgugaguu、CAGgugguuu、UGUgugagua、AAGgucggug、AUGguaaauu、AGGguauuac、AGUguaugga、AACguaagau、GUGguaaggu、ACUguuagua、CAGguaucag、AAGguuaguu、CUGgugagcu、UUGgugagcu、UGUguacgua、GAGgucagcc、GAGguagaau、AAGguaugag、UAGguauuuc、UGUguaacac、AGUguaaggc、GAGgucugcu、AAGguuagca、CAGguaaaug、AACguaagcu、CAGgucugca、CAGguauugu、GUGguaauuc、GAGguauaug、GCCgugagcc、GAGguaagag、UGAguaugua、CAGguaaggg、GAGguaaauu、CAGgcaacuu、UGUguaaguc、CAGgugcgcu、CGGguaaacc、CCGgucaguc、UAGgugggcg、GCGgucaguu、GGGguggguc、AGCguaauag、ACGgugaguc、CUGguacuug、CAGguuggua、AGAguaugug、CUGgugggua、GAGguggcuu、AUAguauuga、UGAgucgucc、CAGgugcucu、UACguaauau、GCUguccuga、CAGgcugcac、CUGgugcgcu、GCGguaagaa、UAAguuacuu、GAAgugagug、UAGgcaaguc、UAAguaaaua、ACGgugagug、CAGguagguu、GGGguauaac、GUUgugaguu、CAUgugagua、GAGgugcauu、AAGg uuugua、UCGguaaugu、CGAguaaggg、GAGgcacgga、AGGgugugga、CAGguauggu、AAGguagaaa、CAGgugccug、UGGguauaug、UGAgugagac、UGGguaauuu、AUGguaaa ua、AAGgcaaagg、AGUguuuguu、AUGguauugg、CUGgugaggc、UUGguaaaau、ACAgugaguu、CAGgugcugu、GAGguuaaga、AGAguaagaa、GAGguccgcg、GUGgugagga、C AGgugagcc, CAGgugacau, AUGgcaagcu, UCGguaauau, CAGgcaacaa, GGGguaggga, CUGgucucgc, UAGguaacga, CGGguaaggu, UAGguaaugc, CAGgcaagaa, ACAgu aggua、CAAguaugag、GCUguucgaa、AAGguuaugc、GAUgugaguu、CAGguggaga、AGAguuaguu、UGAgugugcg、GAGguacagc、CAGguaagac、CAUgugcuuu、AGGgugugu u、ACAguuaagg、ACAgugaggg、GAUguauacc、UUAguaagcu、CAGguaagau、AGAgcugcgu、GAGgcaaguu、GAAguaagug、AAGgugaaaa、AAGguaccua、GAGguaucag、AU There are many ways to get the best results from your search results uggc、CAGguacacg、UUGguaacca、GAGgucaggu、UCUguuggua、CAGguauguu、UUGguauguc、AAGgugcguc、AGGguaagaa、UUUguaagcc、AAGgucaggu、CUGguaaacu、UCGguaauuu, CUGguaggcu, GGgucugua, GGguacuuu, CUGguaaagg, CGGgugugug, CAGguguggu, UCGguacguc, CAGgugccag, GGGgugagaa, ACAgcuagua, AAGg uauagc、CUGguaggag、GCUguacgua、AAGguaaagg、CAAgcacgag、CUAguaagac、CCCguaagcg、CAAgugugag、AUGguaaggg、AAGgugaggg、CAAguaggua、GGUguugc ug、GAGguacugu、UAGguaagau、CAGgugcgaa、GAGguccagg、UUGguauaca、GGAgugagua、GAGgugagau、AAGguggggc、CAGguaaacg、UCGguaacuu、CAGguaaauu、G AGgugcgca, ACUgugagua, ACGgugugac, GUGguaaguc, CAGguaggca, CAGgucagca, GUGguaugug, AAAguaucug, CGGguaugua, AAGguauaaa, GAGgugggga, GCUgu aggug, GAAgugaguu, AAAguauuua, UAUguaagua, ACGguaugag, CUGgugagug, AGAguaaaau, GCUguauggc, AUGguaaacc, GCAguauaaa, UAAguauuua, AAUgucagu g、AUUgcaggag、CCGguaagaa、AAGgcaaguu、GAGguuuguc、AAGguaacug、AAAguaugag、GAUguuagua、CAGguggguc、AAGguaccga、CCAguaauua、GUGguaugcg、AU Ggugcgcu, CAGgucuaug, AAGguauuua, CUAguaagau, AGAguaauuu, GGguaacgu, AAGguagcca, CUGgucccgg, GGguccuuc, ACGgucaccc, AAGguaauac, CAGgug caug.GAGgugcggc, UCUguacggg, CGGgugcgug, UACguaagug, CAUguaagga, CAGgugacgg, GAUguaugcu, UCUgcaauuc, UGAguaaggc, GAGguauauu, AGAguga, guu、AAGguaagcu、UAGgugaagu、CAGguuagua、UAUguaagug、UUGguggggg、UGAgcucaaa、UCGguaugua、UAAguaugcc、AAUguaagua、CAGguuugca、ACGgugagag 、CAGguguuuu、GUGgugagcc、AGGguacaua、UAGguaaccc、GUGgucagua、CUGgugagcc、CAGgugcuua、AUAgucguga、AUAgugagug、GAGgucaaaa、CGUguagcuu、CA Gguguuug、CAGguuggac、CAGguaagcu、AGGgucagaa、CACguauguc、CACgugagug、GGGguacgga、AAGgcaggac、GAGgugaagc、GAGguuugaa、CAGguaagug、CAGgu aacca、CAGguacucc、AAGgugcuuu、GAGguaaaua、GAGgcaggug、GAGguucgga、CAGguauuug、CAGguaaaua、CAGgugaugu、CAGgugauac、GAGgugaggc、AGGgugggg g、UAAguaaguu、UGGgugaaca、UAGguacugc、CAGgcuccug、AGGguaggca、CAGgugcccg、GAGguacauc、AGGgugugug、AAGguaguaa、UGGguaugag、GGGguguCguC UAguaggug、GAGgcaagga、AAGgcaagac、AAAgugcggu、AAGguugguu、GAGguuaaug、UUGgugaguc、UCGguuagcu、GCaguaagca、AAGgcaagca、ACAguaaggcu、GAGAGgcu uaacag、AAAguacgua、GAGguaauac、UUGguaggug、CUGguuaguc、GAGgugacgc、ACAguaagga、AAUguacuua、GGGguacagu、CGUguaugug、UCCguagguu、GAGgugg ucg、UCAgugaguc、AAAguaagca、GAGgucuggu、GAGguaauua、GUAguaagua、AAGgugggga、UCUgugagca、GAAguucgug、ACGgugaggc、UCAgugagua、UAGguaguug、GGUgucuggg、GGGguaagug、GAGguggguu、UGUgugaguu、CAUguaagua、AAGguaggug、AAUguaggag、GAGgcacguc、CAAguacauu、UUGguacaga、GAGguaguag、AAAgugaggg、UUGgucagug、AGGgugaguc、CAGgugaaca、GGUgugggcc、CGGgugagcu、GGGgugaguc、ACAgugagag、AGGgugaggu、GCUguaaguc、AUAguagguu、CAGgcaugug、AAGguaaguu、CAGguccgug、GAGgcaggua、AUGguggaag、AUGgugggcg、GAGgugagaa、AGUgugagca、UUGguaagua、CAAguaagca、GGUgugagcu、CCCgugggua、CAGguagaau、CAGgcugagc、CUGguggccc、UGAguaagag、CACguuagcu、AAGgugaguc、AAGguagcuc、UCGgugaguu、GAGgcccuuc、CAGguuaugc、CCUguaagcu、CAGgucuccu、UAGguaggcu、GGGguagggg、AAGguaguga、GAGguuguug、CAGguugguu、AAAguaagcc、ACAgugagug、UGGgugugau、CCCguaacua、AAGguguugc、AAAgcuggug、GAGguauagu、ACGguaagag、AUGguacggu、GAGgccaguu、GAGguaugcg、UCGgugggag、AAGguggaua、CCAguguggc、AGGguaagug、UCUguagguc、CAGgcaagga、CGGguaauuu、AUUgugaguc、CAGguaaacc、AAGgucaauu、AAGgugaaua、GUCguaagaa、GCGguaaguc、CUGguagagc、GAGgucgguc、CAGguaaaca、AAGgcaagga、CAGgucgucu、GGGguagggc、CUGguacuaa、GAGguagcug、CUUgucagcu、UAGguaaggc、CUGguauuac、UAAguacguc、AAGguaagcc、ACGgugaaag、CCAgccaaua、CAGguuuguc、AAGguauaau、AAGgucuuag、AGGgugagcu、AAGguuaggg、CGGguaaauu、CAGguaacgg、AGAgugugua、ACAguaaguu、GAUguaauuu、GAGguaggga、UUGgcaagug、AAAgugagga、AAGguagugc、AGAguaauuc、GGAguaaaua、GUGguaccca、CAGguauugc、GAUgugaggg、CAAguaaauc、CAGgugucuc、AAGguaacag、UUGguaaaag、CAGguaucau、ACGgugagac、CUGguaugac、CAGguucacu、GAGgugauca、AGUguaaguc、AACguaagua、AAAgugagug、GAGguacagg、CAAguaauga、GAUguaagga、UCAguucccc、GCGguaagga、UAGguacuaa、AAGgugaaag、ACUguaagug、UGGguaugug、AUGguaacag、CAGguagggu、ACAguaagug、AAGgugcucc、AAGgugugcu、AAGgugguga、ACGgugcgcc、AAGguauugc、GGGguaugug、CAGgugggcu、GAGguauguu、AACgugaaua、CAGguaaugg、UAGguaugau、CAGgcaggug、GGGguugguc、AAGguauggg、UAAgugaggc、CAAgugaucg、AAAguacggg、AGAgcuacag、GAGgugggaa、CAGguacuuu、GAGgugagag、CAGguagguc、UGGguacagc、AAGgugucag、AAGgcaagaa、GAGguaaaca、AAGguaaagu、AAGguaguca、CUGguauguc、GAGguauggg、AAGguauugu、CUGguacuga、GAGguaagcu、UGGgugggua、CAGguucgug、AAGguauggu、CAGgugagca、UGGguaaauu、UGUguaggug、UGUgugagcc、CUGguaauau、AAAguauguu、UGUguaagaa、CUAgugagaa、AGGguagguc、AAGgugggug、UCGguaagug、AGUguaaaua、GAUguaagug、AAGguuagug、UAGguaagca、CAAgugagaa、AGUguaagua、CAGgugaauc、UGGgugagac、AAGguagggc、CUGguuugug、GCGguagggc、GAGguaaucc、AUUguauaaa、CUGg ugaaua, AAGguuuaaa, CCUguacugu, GCGgugagcg, AAGguaaucc, UAUgugagua, CCCgugagug, CAGgugcaga, CAGgucaguu, CAGguaggcu, AAAguaagug, UAGguugg uc、CAGguugccu、AAGguaugga、GGUguggacg、AAAgugagaa、AGGgugagag、GAUguggcau、UCGguaaggu、GAGgugcguc、CGGgugaguc、AAGguacggg、GAGguucuug、A AGgugcuug, UAGguaugua, AUGgucagca, CGGguacuca, AGGgugagga, AUCgugagua, UCAguaagua, UAGguaaaua, AAGguaauug, GAAgucagug, CAGguacaaa, AAAgu uaauc、AGCgugagcg、CCGgcuggug、AGUguaauuu、UGAgccacuc、GGGgucugua、AUGgcauguc、CGGguaaaga、AGGguagcau、CGGguaggag、GAGguucgug、UAAguauu c、UAUguaagau、AAGguaguuu、CAGgugguau、GUGguaauga、AAGgugauuu、CAGgugaagu、GUAguaauua、AUGguuggug、CCAguaagug、UAGgugagag、AUGgugaggc、AA Aguuagug、AAGgugccuu、UAGguaugag、CAGgugugac、CUGguggguu、AUGguaagga、UCUguaagaa、UCCgugaguu、AAAgcaggua、UAUgugagug、CAGguggagg、CAGguu agac、AUAguaagac、AAGguguugu、GAGgucugug、AAGguaagau、CAUguaaguu、CUGguaauua、CAGguaggcg、AGAguaaguc、UGGgugagga、AAUguaggua、UAGguuagca、GGGguaggua, GAGguauugc, AUUguacaca, GAAguaggua, GGAguaagcu, UAGguaugug, GAGgugaaua, GAGgugggau, AAGguaaucu, GGUgugaguu, AACgugaguu, GAGguaaccg, UAGguaagga, AUUguaagaa, UGGgugagca, AAGguaaggc, CCAguaucgu, CCGgugggug, GAGguagugu, ACGgugggaa, GAGgugaccu, CACguaugua, AGGgugggga, AAUguaaguc, AAAguuaagu, CAUgugagug, AGAguauguc, GCGguaugac, CGGgugaguu, CCGguauuuu, GAGguagaac, UAGguaugaa, CAGgcgcgug, CAAguaaguc, AGUguaagau, AAGguucuac, CCAguaagua, GAGguagcag, CAGgucuguu, CAGguacaau, CCGguaaaga, UAAgugcugu, AGGgugagaa, CUCguaaggu, CAGgucagcu, CAGguaaggc, AGGgugcagg, GAGgugaaac, AGGguaagua, AAUguaugcc, AAGguaagca, ACGguacggu, AAGguaauga, UCUgcucaau, ACGguaaugu, AAGguaguug, ACGguaagug, CAGgugauga, GAGguaacac, GAGguaggua, CAGguaccuu, CAGguaauaa, UUGgugggug, CUGguaauga, UAGguaaguc, AGGgugugac, GAGgcaauaa, GUGguaaagc, CUGgugggcg, GAUguauguu, AGGgugagac, UCGgucagca, AUGgugauua, CGAgugugua, CAGguuggug, AGCgcaagua, UGGguacguu, GAGguauuug, AGUguacaua, AUGguaagua, ACAguagguu, AAGgugagag, UUGgugaagu, AAAguaugua, UGGguaagga, UAGgugccuu and CCUgugggug are included.,

[0245] Additional exemplary gene sequences and splice site sequences (e.g., 5' splice site sequences) include UCCguaaguu, GUGguaaacg, CGGgugcggu, CAUguacuuc, AGAguaaagg, CGCgugagua, AGAgugggca, AGAguaagcc, AGAguaaaca, GUGguuauga, AGGguaauaa, UGAguaagac, AGAguuuguu, CGGgucugca, CAGguaaguc, AAGguagaau, CAGgucccuc, AGAguaaugg, GAGgucuaag, AGAguagagu, AUGgucagua, GAGgccuggg, AAGguguggc, AGAgugaucu, AAGguaucca, UUCguaagua, UAAgugggug, GCCgugaacg, GAGguugugg, UAUguaugca, UGUguaacaa, AGGguauuag, UGAguauauc, AGAguuugug, GAGgucgcug, GAGgucaucg, ACGguaaagc, UGAguacuug, CGAgucccg, CUGguacguc, AGGguauugc, GAAgugaaug, CAGaugaguc, UGGguauugg, UGAguaaaga, GUGguuccug, UGAgcaagua, UAUguaagag, AAGgucuugc, AAAgcaugug, AGAguacagu, GUGguaaucc, CAGguagagg, AAGguacaac, UGGgcagcau, CCGgucauca, CCGguuugua, UGAguaaggg, GAAguaugua, GGGguagcuc, GCUguacaua, CUGgucucuu, GUGguaaaug, AUCguaagug, GAGgcaugua, AAGgucuccc, UGGgugcguu, UGUguagguu, GAAgugagca, GGUguaauuu, CUGgugaaau, AUCguaaguc, AGAguaaucc, GGAguagguc, GAGguaccaa, CUUguaggug, AAGguauaag, AGAguuggua, AUGguuugug, UGGgucagau, AGAguaggac, AGAguagugu, AGAguaggag, CAGgucucua, AAGguggaug, UGGguaucaa, GAUguaugga,AAGguguuuc、GCAguguaaa、UUAguaugua、UCUguaugca、AAUguaaaau、AGAguaaauu、GGGguacuuu、GAAguuugau、AAAguagauu、UGUguagagu、UGGguaagcg、CGGg uucagg, AGGguacgac, UCGguaagaa, AGGguuggca, AAAguacagu, UAAguuaagg, AUGguaaugu, GUGguuuuac, AGAguaacaa, AAGguagccc, GCGgugaggc, AUGguuca gc、AAGguacuua、AAGguccgug、UAGguaagcg、AUGguaccuu、GCCguggugg、CUGgugcguc、CAGguggaaa、AAAgucugua、GAGguaaccc、AGAguauggg、UAUgccccug、A AGgugccag, ACGgugcggc, AGGguacuga, AGAguaagcg, CUGgcaaggg, CCAgugugug, GAGguagacg, CGGgugcggg, GAUguaagcu, AUUguauuua, UGCgugagug, CUGgu cuaua, GAGgugcuag, GAGgugccau, CAGguacguc, GAGguucagc, AACguaagaa, AGAguaguac, AAGguaacgg, UAGgugugac, CCGguaauag, CAGguaccag, UUUguaauu g、AAUguacgaa、CAGguaauga、AUCgucaagg、CUGguagaug、GGGgugcagu、AGUgugagaa、GGGguuuuau、CCUguccccu、AUUgugaagu、AAGguaaacg、UACgucgugg、AA Ggugccau, GGGgucccag, UAUguauggu, CGGguaauua, CGGguacucc, CAGgugacuu, AGUguggguu, AGAguauggc, AAGgccaaca, AAAgcaagua, UCAguagguc, GUGgug gcgg, CAUguauccu, UCGgugagcc, AUAguugggu, AAUguuagcu, AUGgugaaug, CGGguaaugu, UCUguaggug, CCGgugaggc, UGAguccacu, CUAguaagag, CGGguggggc,CGAguaagca、UGUgccaauu、UCGguaagcc、UAUguaggug、UUGgugggcc、GAGgcugggc、AGAguaacuu、ACGguagguc、CAGgcccaga、CCGguggguu、AAGgugacgg、GGGg uacagc, CAUguaaguc, AUUgugagaa, UGUguaagga, UUUguaagau, AGGgucauuu, UGGguuuguu, CGAguaagcc, GUGgugugua, AUGguauaac, UGGguacgua, AAAguaga gu、UCGguaacug、AGAguaauga、AUGguggguc、AGAguaauau、CAGguacugg、UAAgucaguu、GCGguagaga、AAGgugaugg、ACAguauguu、GAUguacguc、UAGguuucuc、G AGgcauggg、AUAgcuaagu、GUAgucugua、AAGgugaacg、GUGguggucg、GAGguugauc、UGAguggguu、ACUguacgug、CUGgugacug、CAAguuaagc、GAGguaccca、AACgu aacuu、CAGguuacua、AGAguuaguc、UGGgcacguc、AGUguauggu、AAGguugcaa、CAGguuguua、AAGgcauccc、GAUguaaggc、AGGguacggg、GAGgucaaag、CAAgugagc g、AGAguaaucu、UCGguagcug、AAAguaguag、CAGguucguc、CGUguaugaa、AGUguaaaaa、AAGgucucac、UAGguggagc、UGAguaggug、AGAguaugcc、GAGguugcau、CA Aguaagag, UCUgugugcc, GGgugaugc, GGGgugauaa, CCCgugagcc, AGAguaacug, GCGguaagua, AGAguacauc, UCGguc...

Claims

1. Formula (I-d): 【Chemical 417】 (In the formula, A is one or more R １ It is a nitrogen-containing heterocycline that is optionally substituted; B has one or more R １ A nitrogen-containing heterocycline or heteroaryl which is optionally substituted; L is absent, -O-, or -N(R) ３ ) - and; M is C(R ２ ) and; P is C(R ２ ) or N; D, E, and F are each independently C(R ５ｄ ), C(R ５ｄ )(R ５ｅ ), N, N(R ５ｆ ), S, or O, and the bonds between atoms within the ring containing D, E, and F can be single or double bonds when the valence allows; Each R １ These are, independently, hydrogen and C １ ~C ６ Alkyl, C ２ ~C ６ Alkenil, C ２ ~C ６ Alkinyl, 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 Each alkyl, alkylene, alkenyl, alkenylene, alkynyl, heteroalkyl, haloalkyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl is one or more R ８ It is replaced by an optional choice; or Two R's １ The groups, together with the atoms to which they are bonded, form 3- to 7-membered cycloalkyl, heterocyclyl, aryl, or heteroaryl groups, and each cycloalkyl, heterocyclyl, aryl, and heteroaryl group has one or more R groups. ８ It is replaced by optional selection; Each R ２ These are independently hydrogen, halo, cyano, and C. １ ~C ６ Alkyl, C ２ ~C ６ Alkenil, C ２ ~C ６ Alkinyl or -OR Ａ And; Each R ３ These are, independently, hydrogen and C １ ~C ６ Alkyl, C １ ~C ６ Heteroalkyl, C １ ~C ６ They are haloalkyl, cycloalkyl or heterocycline; each alkyl, heteroalkyl, haloalkyl, cycloalkyl and heterocycline is one or more R １２ It is replaced by optional selection; R ５ｄ and R ５ｅ These are, independently, hydrogen, halo, or C. １ ~C ６ It is alkyl; or R ５ｄ and R ５ｅ They combine to form an oxo group; R ５ｆ is hydrogen, halo, or C １ ~C ６ It is alkyl; Each R ７ Independently, C １ ~C ６ Alkyl, C ２ ~C ６ Alkenil, C ２ ~C ６ Alkinyl, C １ ~C ６ Heteroalkyl, C １ ~C ６ Haloalkyl, halo, oxo, cyano, NR Ｂ C(O)R Ｄ , -C(O)NR Ｂ R Ｃ , -C(O)R Ｄ or -SR Ｅ Alkyl, alkenyl, alkynyl, heteroalkyl and haloalkyl are one or more R ９ It is replaced by optional selection; R ８ and R ９ are each 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 wherein each of alkyl, alkenyl, alkynyl, heteroalkyl, haloalkyl, cycloalkyl, heterocyclyl, aryl and heteroaryl is optionally substituted with one or more R １１ ; Each R Ａ These are, independently, hydrogen, C １ ~C ６ Alkyl, C １ ~C ６ Haloalkyl, aryl, heteroaryl, C １ ~C ６ Alkylene-aryl, C １ ~C ６ Alkylene-heteroaryl, -C(O)R Ｄ or -S(O) ｘ R Ｄ And; R Ｂ and R Ｃ Each of them independently contains hydrogen and C １ ~C ６ Alkyl, C １ ~C ６ Heteroalkyl, cycloalkyl, heterocyclyl, -OR Ａ is; or R Ｂ and R Ｃ It, along with the atoms to which they are bonded, one or more R １０ It forms a 3- to 7-membered heterocyclyl ring which is optionally substituted; Each R Ｄ and R Ｅ These are, independently, hydrogen, C １ ~C ６ Alkyl, C ２ ~C ６ Alkenil, C ２ ~C ６ Alkinyl, 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 It is alkylene-heteroaryl; Each R １０ Independently, C １ ~C ６ Alkyl or halo; 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 And; Each R １２ Independently, deuterium, C １ ~C ６ Alkyl, C １ ~C ６ Heteroalkyl, C １ ~C ６ Haloalkyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, halo, cyano, oxo, or -OR Ａ And; n is 0, 1, 2, 3 or 4; and x is 0, 1, or 2. The compound or its pharmaceutically acceptable salts, solvates, hydrates, tautomers, or stereoisomers.

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

3. A is, 【Chemical 418】 A compound selected from any one of claims 1 to 2.

4. A is, 【Chemical 419】 A compound selected from any one of claims 1 to 3.

5. A is, 【Chemical 420】 A compound selected from any one of claims 1 to 4.

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

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

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

9. L is -O- or -N(R ３ The compound according to any one of claims 1 to 8, wherein the compound is:

10. L is -N(R ３ ) - and R ３ is hydrogen, C １ ~C ６ It is an alkyl or cycloalkyl group, and each alkyl and cycloalkyl group has one or more R １２ The compound according to any one of claims 1 to 9, wherein each of the above is optionally substituted.

11. L is -N(CH ３ The compound according to any one of claims 1 to 10, wherein it is - or -N(H)-.

12. L is -N(CH ３ The compound according to any one of claims 1 to 11, wherein the compound is: 【Request Item 13】 【Chemistry 424】 teeth, 【Chemical 425】 A compound according to any one of claims 1 to 12, selected from the above. 【Request Item 14】 【Chemistry 426】 teeth, 【Chemistry 427】 The compound according to any one of claims 1 to 13.

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

16. One of M and P is independently C(R) ２ The compound according to any one of claims 1 to 12, wherein the other of M and P is independently N.

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

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

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

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

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

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

23. F is C(R ５ｄ ) or C (R ５ｄ ) (Caution ５ｅ The compound according to any one of claims 1 to 22, which is: 【Request Item 24】 【Chemistry 428】 teeth, 【Chemistry 429】 A compound according to any one of claims 1 to 17, selected from the above. 【Request Item 25】 【Chemistry 430】 teeth, 【Chemistry 431】 A compound according to claim 24, selected from the above. 【Request Item 26】 【Chemistry 432】 teeth, 【Chemistry 433】 The compound according to claim 25.

27. Equation (I-e): 【Chemistry 434】 (In the formula, m is 0 or 1, and A, B, L, D, E, F, R) ２ , R ７ (n and its subvariables are as described in claim 1.) The compound according to any one of claims 1 to 15, 18 to 26, which is a compound or a pharmaceutically acceptable salt, solvate, hydrate, tautomer or stereoisomer thereof.

28. Formula (If): 【Chemical 435】 (In the formula, A １ is one or more R １ It is a six-member heterocycline that has been optionally substituted; B １ Each of these is one or more R １ A five-membered heterocyclyl or heteroaryl which is optionally substituted; and L, M, P, D, E, F, R １ , R ７ (n and its subvariables are as described in claim 1.) The compound according to any one of claims 1 to 27, which is a compound or a pharmaceutically acceptable salt, solvate, hydrate, tautomer or stereoisomer thereof.

29. Formula (Ig): 【Chemistry 436】 (In the formula, A １ is one or more R １ It is a six-membered heterocycline that has been optionally substituted; B １ Each of these is one or more R １ A five-membered heterocyclyl or heteroaryl which is optionally substituted; m is 0 or 1; and L, D, E, F, R １ , R ２ , R ７ (n and its subvariables are as described in claim 1.) The compound according to any one of claims 1 to 28, which is a compound or a pharmaceutically acceptable salt, solvate, hydrate, tautomer or stereoisomer thereof.

30. Formula (Ih): 【Chemistry 437】 (In the formula, A, B, M, P, D, E, F, R ３ , R ７ (n and its subvariables are as described in claim 1.) The compound according to any one of claims 1 to 29, which is a compound or a pharmaceutically acceptable salt, solvate, hydrate, tautomer or stereoisomer thereof.

31. Formula (Ik): 【Chemistry 438】 (In the formula, A, B, M, P, L, F, R ５ｆ , R ７ (n and its subvariables are as described in claim 1.) The compound according to any one of claims 1 to 30, which is a compound or a pharmaceutically acceptable salt, solvate, hydrate, tautomer or stereoisomer thereof.

32. Equation (I - n): 【Chemistry 439】 (In the formula, A, B, M, P, L, F, R ５ｄ , R ７ (n and its subvariables are as described in claim 1.) The compound according to any one of claims 1 to 17, 20, 23 to 25, and 27 to 30, which is a compound or a pharmaceutically acceptable salt, solvate, hydrate, tautomer or stereoisomer thereof.

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

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

36. The aforementioned compound, (i) Modify the target nucleic acid; (ii) Binds to target nucleic acid: and / or (iii) Stabilize target nucleic acids, A compound according to any one of claims 1 to 34 or a pharmaceutical composition according to claim 35.

37. The aforementioned compound, (i) Increase the splicing at the splice site on the target nucleic acid by approximately 0.5%, 1%, 2%, 3%, 4%, 5%, 6%, 7%, 8%, 9%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, or more, where “approximately” means within ±10% of the above values; or (ii) Reduce splicing at splice sites on the target nucleic acid by approximately 0.5%, 1%, 2%, 3%, 4%, 5%, 6%, 7%, 8%, 9%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, or more, where “approximately” means within ±10% of the above values. A compound according to any one of claims 1 to 34 or a pharmaceutical composition according to claim 35.

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

39. The method according to claim 38, wherein the components of the spliceosome are recruited to the nucleic acid in the presence of the compound of formula (I-d).

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

41. The aforementioned modification is, (i) Forming a bulge in the nucleic acid; (ii) Stabilizing the bulge of the nucleic acid; and / or (iii) Reducing the bulge of the nucleic acid. The method according to claim 40, including the method described in claim 40.

42. A composition for use in the treatment of a target disease or disorder, comprising a compound of formula (I-d) as described in any one of claims 1 to 34.

43. The composition for use according to claim 42, wherein the disease or disorder includes proliferative disorders.

44. The composition for use according to claim 42, wherein the disease or disorder includes 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, kidney diseases or disorders, or infectious diseases.

45. The composition for use according to claim 42, wherein the disease or disorder includes neurological diseases or disorders.

46. The composition for use according to claim 42, wherein the disease or disorder includes Huntington's disease.

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