2-(indazole-5-yl)-6-(piperidine-4-yl)-1,7-naphthirizine derivatives and related compounds as modulators for nucleic acid splicing and treatment of proliferative disorders

Abstract

To provide compounds and methods for regulating splicing. [Solution] This disclosure relates to formulas (Ia) and (II) TIFF2026148821000526.tif62167 The present invention is characterized by the compound and its pharmaceutical composition. Exemplary compounds include, for example, 2-(indazole-5-yl)-6-(piperidine-4-yl)-l,7-naphthirizine derivatives and similar compounds.

Description

[Technical Field]

[0001] Claim of priority This application claims priority to U.S. Patent Application No. 63 / 047,898, filed 2 July 2020; U.S. Patent Application No. 63 / 072,921, filed 31 August 2020; and U.S. Patent Application No. 63 / 126,495, filed 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 the splicing of premRNA, and methods of using them. In one embodiment, the compounds described herein are compounds of formula (I) or (II) and their pharmaceutically acceptable salts, solvates, hydrates, tautomers, or stereoisomers. This disclosure further provides methods of using the compounds of this disclosure (e.g., compounds of formula (I) and (II) and their pharmaceutically acceptable salts, solvates, hydrates, tautomers, and stereoisomers) and their compositions for, for example, against a target, which in embodiment binds to or forms 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, such as 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 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 splicing, such as alternative splicing. In some embodiments, the compounds described herein (e.g., formula (I), Compounds of formula (II) and their pharmaceutically acceptable salts, solvates, hydrates, tautomers, and 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 formulas (I) and (II) and their pharmaceutically acceptable salts, solvates, hydrates, tautomers, and stereoisomers) and compositions thereof are used for the prevention and / or treatment of non-proliferative disorders, disorders, or conditions. In some embodiments, the compounds described herein (e.g., compounds of formulas (I) and (II) and their pharmaceutically acceptable salts, solvates, hydrates, tautomers, and 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, B, L 1 , L 2 X, Y, Z, R 2 , R 3 (Each of the variables m, n, and their sub-variables is as defined herein.) The present invention provides compounds or pharmaceutically acceptable salts, solvates, hydrates, tautomers, or stereoisomers thereof.

[0006] In another aspect, this disclosure relates to formula (II): [ka] (In the formula, A, B, L 1 , L 2 W, Z, R 2 , R 3 (Each of the variables m, n, and their sub-variables is as defined herein.) The present invention provides compounds or pharmaceutically acceptable salts, solvates, hydrates, tautomers, or stereoisomers thereof.

[0007] In another embodiment, the present invention provides a pharmaceutical composition comprising a compound of formula (I) or (II) 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 a therapeutically effective amount of a compound of formula (I) or (II) or a pharmaceutically acceptable salt, solvate, hydrate, tautomer or stereoisomer thereof.

[0008] In another aspect, the Disclosure provides a method for modifying splicing, for example, the splicing of nucleic acids (e.g., DNA or RNA, e.g., premRNA) using a compound of formula (I) or (II) or a pharmaceutically acceptable salt, solvate, hydrate, tautomer or stereoisomer thereof. In another aspect, the Disclosure provides a method for modifying splicing, for example, the splicing of nucleic acids (e.g., DNA or RNA, e.g., premRNA) using a compound of formula (I) or (II) or a pharmaceutically acceptable salt, solvate, hydrate, tautomer or stereoisomer thereof. The present invention provides compositions for use in the regulation of splicing, for example, the splicing of nucleic acids (e.g., DNA or RNA, e.g., premRNA). The regulation 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) or (II) binds to a target, for example, 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) or (II) 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) or (II) 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., in the absence of the compound of formula (I) or (II), e.g., healthy or diseased cells or tissue). In some embodiments, the presence of a compound of formula (I) or (II) 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 the reference (e.g., in the absence of a compound of formula (I) or (II), e.g., in healthy or diseased cells or tissues).

[0009] 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) or (II) or a pharmaceutically acceptable salt, solvate, hydrate, tautomer, or stereoisomer thereof, or a related composition. 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 yet more 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 infections.

[0010] 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) or (II) 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) or (II) or a pharmaceutically acceptable salt, solvate, hydrate, tautomer, or stereoisomer thereof. In another aspect, the Disclosure provides a method for modifying the isoform of a target protein in a biological sample or subject using a compound of formula (I) or (II) 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) or (II) to a biological sample, cells, or subject includes inhibition of cell growth or induction of cell death.

[0011] In another embodiment, 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) or (II) or a pharmaceutically acceptable salt, solvate, hydrate, tautomer or stereoisomer thereof, or related compositions. In some embodiments, the disease or disorder is an undesirable or abnormal condition. Splicing is involved. In some embodiments, the disease or disorder is a proliferative disease, disorder or condition. Exemplary proliferative diseases include cancer, benign neoplasms or angiogenesis. In other embodiments, the disclosure provides methods for treating and / or preventing nonproliferative diseases, disorders or conditions. In yet other embodiments, the disclosure provides compositions for use in 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 infections.

[0012] In another aspect, the Disclosure provides compositions for use in downregulating the expression (e.g., level or rate of production) of a target protein in a biological sample or subject, using a compound of formula (I) or (II) or a pharmaceutically acceptable salt, solvate, hydrate, tautomer or stereoisomer thereof. In another aspect, the Disclosure provides compositions for use in upregulating the expression (e.g., level or rate of production) of a target protein in a biological sample or subject, using a compound of formula (I) or (II) or a pharmaceutically acceptable salt, solvate, hydrate, tautomer or stereoisomer thereof. In another aspect, the Disclosure provides compositions for use in modifying isoforms of a target protein in a biological sample or subject, using a compound of formula (I) or (II) or a pharmaceutically acceptable salt, solvate, hydrate, tautomer or stereoisomer thereof. Another aspect of the Disclosure relates to compositions for use in inhibiting the activity of a target protein in a biological sample or subject. In some embodiments, administration of a compound of formula (I) or (II) to a biological sample, cells, or subject includes inhibition of cell growth or induction of cell death.

[0013] In another embodiment, the present disclosure features a kit comprising a container having a compound of formula (I) or (II) 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 (II) or a pharmaceutically acceptable salt, solvate, hydrate, tautomer, stereoisomer, or pharmaceutical composition thereof.

[0014] 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 used 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, International Publication No. 2017 / 100726, International Publication No. 2018 / 232039, International Publication No. 2018 / 098446, International Publication No. 2018 / 226622, and International Publication No. 2019 / 028440. Compounds other than those described in one of the following brochures: International Publication No. 2019 / 060917, International Publication No. 2019 / 199972, International Publication No. 2019 / 005993, International Publication No. 2019 / 005980, International Publication No. 2020 / 005882, International Publication No. 2020 / 005877, International Publication No. 2020 / 005873 and International Publication No. 2020 / 004594 (each of which is incorporated herein in whole by reference): 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, International Publication No. 2017 / 100726, International Publication No. 2018 / 232039, International Publication No. 2018 / 098446, and International It is a compound, a target nucleic acid (e.g., DNA, RNA, e.g., pre-mRNA) or a target protein described in any one of Publication No. 2018 / 226622 pamphlet, International Publication No. 2019 / 028440 pamphlet, International Publication No. 2019 / 060917 pamphlet, International Publication No. 2019 / 199972 pamphlet, International Publication No. 2019 / 005993 pamphlet, International Publication No. 2019 / 005980 pamphlet, International Publication No. 2020 / 005882 pamphlet, International Publication No. 2020 / 005877 pamphlet, International Publication No. 2020 / 005873 pamphlet, and International Publication No. 2020 / 004594 pamphlet, each of which is incorporated herein by reference in its entirety.

[0015] The details of one or more embodiments of the present invention are described herein. Other features, objects and advantages of the present invention will be apparent from the detailed description, the examples, and the claims. Mode for Carrying Out the Invention

[0016] Selected Chemical Definitions 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., inside the front cover, and specific functional groups are generally defined as described therein. Furthermore, general principles of organic chemistry, as well as 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 thEdition, 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 This information is found in Edition, Cambridge University Press, Cambridge, 1987.

[0017] 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 valence known in the field of chemistry.

[0018] 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.

[0019] 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.

[0020] 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. In some embodiments, an alkyl group has 1 to 12 carbon atoms ("C1-C12"). 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, alkyl groups have one 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 so on. 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-C 10 The alkyl group is an alkyl group (e.g., -CH3). In certain embodiments, the alkyl group is a substituted C1-C6 alkyl group.

[0021] As used herein, "alkenyl" refers to a radical of a linear or branched hydrocarbon group having 2 to 24 carbon atoms, one or more carbon-carbon double bonds, and no triple bonds ("C"). 2に ~C 24 This refers to an alkenyl group. In some embodiments, the alkenyl group has 2 to 10 carbon atoms ("C2-C10"). 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 (e.g., 2-butenyl) or terminal (e.g., 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 C2~4 Alkenyl groups include pentenyl (C5), pentadienyl (C5), hexenyl (C6), and the like. Further examples of alkenyls include heptenyl (C7), octenyl (C8), octatrienyl (C8), and the like. Each example of an alkenyl group can be independently and optionally substituted, i.e., unsubstituted ("unsubstituted alkenyl") or substituted with one or more substituents, e.g., 1 to 5 substituents, 1 to 3 substituents, or 1 substituent ("substituted alkenyl"). In certain embodiments, the alkenyl group is unsubstituted C1-C 10 It is an alkenyl. In certain embodiments, the alkenyl group is a substituted C2-C6 alkenyl.

[0022] As used herein, the term "alkynyl" refers to a radical of a linear or branched hydrocarbon group having 2 to 24 carbon atoms and one or more carbon-carbon triple bonds ("C2- 24 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.

[0023] As used herein, the term "haloalkyl" means at least one carbon source This refers to an acyclic, stable linear or branched chain, or a combination thereof, containing 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 within 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").

[0024] 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 heteroalkyl groups include, but are not limited to, -CH2-CH2-O-CH3, -CH2-CH2-NH-CH3, -CH2-CH2-N(CH3)-CH3, -CH2-S-CH2-CH3, -CH2-CH2, -S(O)-CH3, -CH2-CH2-S(O)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 DWhen 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., 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").

[0025] 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, and the term “member” 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-C14 It is Ariel.

[0026] As used herein, "heteroaryl" refers to a 5-10 membered monocyclic or bicyclic 4n+2 aromatic compound having a ring carbon atom and 1-4 ring heteroatoms that contribute to an aromatic ring system. The term "heteroaryl" refers to a group cyclic radical (e.g., a cyclic array having 6 or 10 π electrons shared), 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 can be on a carbon or nitrogen atom, where the valence allows. A heteroaryl bicyclic ring system can 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 on an 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 in which one ring does not contain a heteroatom (e.g., indolyl, quinolinyl, carbazolyl, etc.), the bond site can be 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). A heteroaryl group may be described, for example, as a 6- to 10-membered heteroaryl, where the term "member" refers to a non-hydrogen ring atom within the moiety. Each example of a heteroaryl group may be independently and optionally substituted, i.e., unsubstituted ("unsubstituted heteroaryl") or substituted with one or more substituents, e.g., 1 to 5 substituents, 1 to 3 substituents, or 1 substituent ("substituted heteroaryl").

[0027] 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.

[0028] 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 described, for example, as C4-C7 member cycloalkyl groups, where the term "member" refers to the non-hydrogen ring atom within the group. Exemplary C3-C6 cycloalkyl groups include cyclopropyl(C3), cyclopropyl(C3), cyclopropyl(C3) Examples of C3-C8 cycloalkyl groups include, but are not limited to, the aforementioned C3-C6 cycloalkyl groups, as well as cycloheptyl (C7), cycloheptenyl (C7), cycloheptadienyl (C7), cycloheptatrienyl (C7), cyclooctyl (C8), cyclooctenyl (C8), cubanyl (C8), bicyclo[1.1.1]pentanyl (C5), bicyclo[2.2.2]octanyl (C8), bicyclo[2.1.1]hexanyl (C6), and bicyclo[3.1.1]heptanyl (C7). Abstract C3-C 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.

[0029] 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.

[0030] Exemplary three-membered heterocyclyl groups containing one heteroatom include, but are not limited to, azilidinyl, oxyranyl, and thiorenyl. Exemplary four-membered heterocyclyl groups containing one heteroatom include, but are not limited to, azetidinyl, oxetanyl, and thietanyl. Exemplary five-membered heterocyclyl groups containing one heteroatom include, tetrahydrofuranyl, dihydrofuranyl, 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, triazolinil, oxadiazolinil, and thiadiazolinil. Examples of six-membered heterocyclyl groups containing one heteroatom include, but are not limited to, piperidinil, tetrahydropyranil, dihydropyridinil, and thianil. Examples of six-membered heterocyclyl groups containing two heteroatoms include, but are not limited to, piperazinil, morpholinil, dithianil, and dioxanil. Examples of six-membered heterocyclyl groups containing two heteroatoms include, but are not limited to, triazinanil. Examples of seven-membered heterocyclyl groups containing one heteroatom include, but are not limited to, azepanil, oxepanil, and thiepanil. Exemplary eight-membered heterocyclyl groups containing one heteroatom include, but are not limited to, azokanyl, oxekanyl, and thiokanyl. Exemplary 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. Exemplary six-membered heterocyclyl groups condensed to an aryl ring (also referred to herein as 6,6-bicyclic heterocyclyl rings) include, but are not limited to, tetrahydroquinolinyl and tetrahydroisoquinolinyl.

[0031] 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-.

[0032] 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.

[0033] As used herein, the terms "halogen" or "halo" refer to fluorine, chlorine, bromine, or iodine.

[0034] As used herein, the term "hydroxy" refers to the -OH group.

[0035] As used herein, the term "nitro" refers to a substituent having two oxygen atoms bonded to a nitrogen atom, such as -NO2.

[0036] As used herein, the term "nucleic acid base" refers to nitrogen-containing biocompounds found to be linked to sugars within nucleosides, including deoxyribonucleic acid (DNA) and ri Nucleic acid bases are the basic building blocks of nucleic acids (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 types. In one embodiment, nucleic acid bases may be chemically modified, for example, with alkyl (e.g., methyl), halo, -O-alkyl, or other modifications.

[0037] 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.

[0038] As used herein, "oxo" refers to the carbonyl group, i.e., -C(O)-.

[0039] The symbols used herein with respect to compounds of formula (I) or (II) [ka] This refers to a bond point to another part or functional group within the compound.

[0040] 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 any such combination 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.

[0041] 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... In this case, the ring-forming substituents are bonded to non-adjacent members of the basic structure.

[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, a diastereomerically pure compound may be present together with other active or inactive components. For example, a pharmaceutical composition containing a diastereomerically pure exo compound may contain, for example, about 90% excipients and about 10% diastereomerically pure exo compound. In certain embodiments, the diastereomerically pure exo compound in such a composition may contain, 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 contain, for example, about 90% excipients and about 10% diastereomerically pure endo compound. In certain embodiments, The diastereomerically pure endo compound in such a composition may, for example, consist of 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 is1 H, 2 H (D or deuterium) and 3 It can be any isotopic form containing H (T or tritium); C is 11 C, 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, the prodrugs can be converted to the compounds of the present invention by chemical or biochemical methods in an ex vivo environment. For example, the prodrug can be converted to a suitable enzyme Alternatively, when placed in a transdermal patch reservoir with a chemical reagent, it can be slowly converted into the compound of the present invention.

[0051] The term "solvate" typically refers to the form of a compound associated with a solvent by 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) or (II) may 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 isolateable 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 +10%. In certain embodiments, “approximately” means +5%. When “approximately” precedes a series of numbers or ranges, it is understood that “approximately” can modify each number in the series of numbers or ranges.

[0057] As used herein, “to obtain” or “to acquire” 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 (e.g., performing an analytical method or protocol) to obtain the value or physical entity. “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). This refers to obtaining a value or physical entity directly, which includes performing a process that involves the physical change of a physical substance or the use of a machine or apparatus. An example of obtaining a value directly is obtaining a sample from a human subject. Obtaining a value directly also includes performing a process that uses a machine or device, such as a mass spectrometer, to obtain mass spectrometry data.

[0058] As used herein, the terms “administer,” “give delivery,” or “dosage” 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 amount” of a compound of formula (I) or (II) refers to an amount sufficient to induce a desired biological response, i.e., to treat a condition. As will be understood by those skilled in the art, the effective amount of a compound of formula (I) or (II) 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 amounts include therapeutic and prophylactic treatments. For example, in the treatment of cancer, an effective amount 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) or (II) 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) or (II)) 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 to be administered include 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); cattle, pigs, horses, sheep, goats, cats, and / or dogs, etc.) This includes, but is not limited to, commercially relevant mammals (such as chickens, ducks, geese and / or turkeys) and birds (such as commercially relevant birds). In certain embodiments, an animal is a mammal. An animal may be male or female and may be at any stage of development. A 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) or (II)). 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 a 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 tissue type of the subject. Exemplary nonproliferative disorders include neurological diseases or disorders (e.g., recurrent and expanding diseases); autoimmune diseases or disorders; immunodeficiency diseases or disorders; lysosomal storage diseases or disorders; inflammatory diseases or disorders; cardiovascular conditions, diseases, or disorders; metabolic diseases or disorders; respiratory conditions, diseases, or disorders; renal diseases or disorders; and infections.

[0068] compound 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 Replace by optional selection It is a cycloalkyl, heterocyclyl, aryl, or heteroaryl; L 1 and L 2 These are, independently, absent, C1-C6 alkylene, C1-C6 heteroalkylene, -O-, -C(O)-, -N(R) 4 )-,-N(R 4 )C(O)-, -C(O)N(R 4 )-,-N(R 4 )C(O)N(R4 )- or C1~C6 alkylene-N(R 4 )C(O)N(R 4 )-, and each alkylene and heteroalkylene is optionally substituted with one or more R 5 ; X, Y and Z are each N or C(R 6 ), and at least one of X, Y and Z is N; 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 or -S(O) x R D , and each alkyl, alkylene, alkenyl, alkynyl, heteroalkyl, haloalkyl, cycloalkyl, heterocyclyl, aryl and heteroaryl is optionally substituted with one or more R 7 ; or two R 1 groups, together with the atoms to which they are bonded, 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 7 ; each R 2 and R 3 is independently C1~C6 alkyl, C2~C6 alkenyl, C2~C6 alkynyl, C1~C6 heteroalkyl, C1~C6 haloalkyl, halo, cyano, -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 or -S(O) x R D ; and each R 4 is independently hydrogen, C1~C6 alkyl or C1~C6 haloalkyl; and each R 5 is C1~C6 alkyl, C2~C6 alkenyl, C2~C6 alkynyl, C1~C6 heteroalkyl, C1~C6 haloalkyl, halo, cyano, oxo, -OR A or -NR B R C ; and each R 6 is independently hydrogen, halo, C1~C6 alkyl, C1~C6 haloalkyl or -OR A ; and each R 7 is 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 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 8 ; and each R A is independently hydrogen, C1~C6 alkyl, C1~C6 heteroalkyl, C1~C6 haloalkyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, C1~C6 alkylene-aryl, C1~C6 alkylene-heteroaryl, -C(O)R D or -S(O) x R DEach alkyl, alkylene, heteroalkyl, haloalkyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl is one or more R 9 It is replaced by arbitrary selection in each R B and R C These are independently hydrogen, C1-C6 alkyl, C1-C6 heteroalkyl, cycloalkyl, heterocyclyl, or -OR A Each alkyl, alkylene, heteroalkyl, haloalkyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl is one or more R 9 It is replaced by optional selection in R B and R C Along with the atoms to which they are bonded, one or more R 9 They form a 3- to 7-membered heterocyclyl ring which is optionally substituted; each R D 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; each R 8 These are independently C1-C6 alkyl, C1-C6 heteroalkyl, C1-C6 haloalkyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, halo, cyano, oxo, or -ORA; each R 9 This refers to C1-C6 alkyl, halo, cyano, oxo, or -OR A1 and; each R A1 is hydrogen or C1 (~C6 alkyl; m is 0 or 1; n is 0, 1 or 2; and x is 0, 1 or 2) The compound is characterized by a pharmaceutically acceptable salt, solvate, hydrate, tautomer or stereoisomer thereof. In one embodiment, when X is CH and Y and Z are independently N, L 1 and L 2 One of them is not independently N(CH3) or O. In one embodiment, when X is CH and Y and Z are independently N, L 1is not N(CH3) or O. In one embodiment, when X is CH and Y and Z are independently N, L 2 is not N(CH3) or O. In one embodiment, when X is CH and Y and Z are independently N, L 1 and L 2 Each of these is independently not N(CH3) or O.

[0069] In another embodiment, the present invention relates to formula (II): [ka] (In the formula, A and B are each independently of one or more R 1 A cycloalkyl, heterocyclyl, aryl, or heteroaryl which is optionally substituted; L 1 and L 2 These are, independently, absent, C1-C6 alkylene, C1-C6 heteroalkylene, -O-, -C(O)-, -N(R) 4 )-,-N(R 4 )C(O)-, -C(O)N(R 4 )-,-N(R 4 )C(O)N(R 4 )- or C1~C6 alkylene-N(R 4 )C(O)N(R 4 )- and each alkylene and heteroalkylene is one or more R 5 They are replaced by arbitrary selection; W and Z are N or C(R 6 ) and at least one of W and Z is 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 or -S(O) x R D Each alkyl, alkylene, alkenyl, alkynyl, heteroalkyl, haloalkyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl is one or more R 7 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. 7 It is replaced by arbitrary selection in each R 2 and R 3 These are independently C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 heteroalkyl, C1-C6 haloalkyl, 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 or -S(O) x R D and; each R 4 R is independently hydrogen, C1-C6 alkyl, or C1-C6 haloalkyl; each R 5 C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 heteroalkyl, C1-C6 haloalkyl, halo, cyano, oxo, -OR A or -NR B R C and; each R 6 These are independently hydrogen, halo, C1-C6 alkyl, C1-C6 haloalkyl, or -OR A and; each R 7These are independently C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 heteroalkyl, C1-C6 haloalkyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, halo, cyano, oxo, -OR A , -NR B R C , -NR B C(O)R D -NO2, -C(O)NR B R C , -C(O)R D , -C(O)OR D or -S(O) x R D Alkyl, alkenyl, alkynyl, heteroalkyl, haloalkyl, cycloalkyl, heterocyclyl Each of the aryl and heteroaryl compounds contains one or more R 8 It is replaced by arbitrary selection in each R A These are independently hydrogen, C1-C6 alkyl, C1-C6 heteroalkyl, C1-C6 haloalkyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, C1-C6 alkylene-aryl, C1-C6 alkylene-heteroaryl, and -C(O)R D or -S(O) x R D Each alkyl, alkylene, heteroalkyl, haloalkyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl is one or more R 9 It is replaced by arbitrary selection in each R B and R C These are independently hydrogen, C1-C6 alkyl, C1-C6 heteroalkyl, C1-C6 haloalkyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, C1-C6 alkylene-cycloalkyl, C1-C6 alkylene-heterocyclyl, -OR A Each alkyl, alkylene, heteroalkyl, haloalkyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl is one or more R 9 It is replaced by optional selection in R B and R CAlong with the atoms to which they are bonded, one or more R 9 They form a 3- to 7-membered heterocyclyl ring which is optionally substituted; each R D 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; each R 8 These are independently C1-C6 alkyl, C1-C6 heteroalkyl, C1-C6 haloalkyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, halo, cyano, oxo, or -ORA; each R 9 This refers to C1-C6 alkyl, halo, cyano, oxo, or -OR A1 and; each R A1 (where is hydrogen or a C1-C6 alkyl group; m and n are independently 0, 1, or 2; and x is 0, 1, or 2) The compound is characterized by the pharmaceutically acceptable salt, solvate, hydrate, tautomer, or stereoisomer thereof.

[0070] As is generally described herein for compounds of formulas (I) and (II), A and B each independently comprise one or more R 1 The cycloalkyl, heterocyclyl, aryl, or heteroaryl molecules are optionally substituted.

[0071] In some embodiments, for each of formulas (I) and (II), A and B are independently monocyclic rings, such as monocyclic cycloalkyl, monocyclic heterocyclyl, monocyclic aryl, or monocyclic heteroaryl. The monocyclic rings may 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 monoring that has been substituted by arbitrary selection.

[0072] In some embodiments, A and B are independently bicyclic rings, such as bicyclic cycloalkyl, bicyclic heterocyclyl, bicyclic aryl, or bicyclic heteroaryl. The bicyclic rings can be saturated, partially unsaturated, or fully unsaturated (e.g., aromatic). In some embodiments, A or B are independently bicyclic rings containing condensation, bridging, or spirocycle systems. In some embodiments, A or B are independently bicyclic rings 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 biring ring. In some embodiments, A is a 7-membered biring ring. In some embodiments, B is a 7-membered biring ring. In some embodiments, A is an 8-membered biring 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 independently comprises one or more R 1 It is a biring ring that has been substituted by arbitrary choice.

[0073] In some embodiments, A and B are independently tricyclic rings, such as tricyclic cycloalkyl, tricyclic heterocyclyl, tricyclic aryl, or tricyclic heteroaryl. The tricyclic rings can be saturated, partially unsaturated, or fully unsaturated (e.g., aromatic). In some embodiments, A or B are independently tricyclic rings comprising condensation, bridging, or spirocyclic systems or combinations thereof. In some embodiments, A or B are independently tricyclic rings 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 It is a triring ring that has been substituted by arbitrary choice.

[0074] In some embodiments, A and B are independently monocyclic cycloalkyl, monocyclic heterocyclil, monocyclic aryl, or monocyclic heteroaryl. In some embodiments, A or B are independently bicyclic cycloalkyl, bicyclic heterocyclil, bicyclic aryl, or bicyclic heteroaryl. In some embodiments, A or B are independently tricyclic cycloalkyl, tricyclic heterocyclil, tricyclic aryl, or 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 and B are independently nitrogen-containing heterocyclines, for example, heterocyclines 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 monocyclic, bicyclic, or tricyclic. In some embodiments, A or B are independently heterocyclines 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 heterocyclyl containing four nitrogen atoms. In some embodiments, A or B is independently a nitrogen-containing heterocycline 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 heterocycline are, for example, R 1 It has been replaced with.

[0076] In some embodiments, A and B are independently nitrogen-containing heteroaryls, for example, heteroaryls 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 are independently heteroaryls 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 1 It is a six-membered nitrogen-containing heterocycline in which the nitrogen atoms are optionally substituted. In some embodiments, one or more nitrogen atoms of the six-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 heterocyclyl or heteroaryl, for example, a five-membered heterocyclyl or heteroaryl containing one or more nitrogen atoms. In some embodiments, B is a five-membered heterocyclyl 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 heterocyclyl 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 heterocyclyl 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 heterocyclyl 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 2It is a 5-membered nitrogen-containing heteroaryl that is optionally substituted with R. 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 heterocycline or heteroali containing one or more further heteroatoms, such as one or more oxygen, sulfur, boron, silicon, or phosphorus. It is.

[0079] In some embodiments, each of A and B is, [ka] [ka] [ka] [ka] [ka] [ka] [ka] [ka] [ka] (In the formula, each R 1 (as defined herein) They are independently selected from. 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, each of A and B is, [ka] [ka] (In the formula, each R 1 (as defined herein) They are independently selected from. 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, one of A and B independently has one or more R 1 It is a monocyclic heteroaryl or bicyclic heteroaryl which is optionally substituted. In some embodiments, one of A and B is independently one or more R 1 It is a bicyclic heteroaryl which is optionally substituted. In some embodiments, one of A and B is independently one or more R 1 Nitrogen-containing heteroaryls that are optionally substituted. In some embodiments, one of A and B independently comprises one or more R 1 It is a 5- to 10-membered heteroaryl that is optionally substituted. In some embodiments, one of A and B is [ka] (In the formula, R 1 (As described herein) It is selected independently from. In some embodiments, one of A and B is [ka] (In the formula, R 1 (As described herein) It is selected independently from. In some embodiments, one of A and B is [ka] (In the formula, R 1 (As described herein) It is selected independently of others.

[0082] In some embodiments, one of A and B is [ka] (In the formula, each R 1a These are independently C1-C6 alkyl, C1-C6 heteroalkyl, C1-C6 haloalkyl, halo, cyano, or -OR A Each alkyl, heteroalkyl, and haloalkyl is one or more R 7 (It is replaced by an optional choice.) It is selected independently from. In some embodiments, one of A and B is [ka] (In the formula, each R 1a These are independently C1-C6 alkyl, C1-C6 heteroalkyl, C1-C6 haloalkyl, halo, cyano, or -OR A Each alkyl, heteroalkyl, and haloalkyl is one or more R 7 (It is replaced by an optional choice.) It is selected independently of R. In some embodiments, R 1a At least one of them is a C1-C6 alkyl, halo, or -OR A In some embodiments, R 1a is -OR A And R A H is H.

[0083] In some embodiments, one of A or B is [ka] (In the formula, R 1 (As described herein) In some embodiments, one of A or B is [ka] (In the formula, R 1 (As described herein) In some embodiments, one of A or B is [ka] (In the formula, R 1 (As described herein) In some embodiments, one of A or B is [ka] (In the formula, R 1 (As described herein) That is the case.

[0084] In some embodiments, one of A and B is [ka] It is selected independently from. In some embodiments, one of A and B is [ka] It is selected independently from. In some embodiments, one of A or B is [ka] In some embodiments, one of A or B is [ka] In some embodiments, one of A or B is [ka] In some embodiments, one of A or B is [ka] In some embodiments, one of A or B is [ka] In some embodiments, one of A or B is [ka] In some embodiments, one of A or B is [ka] That is the case.

[0085] In some embodiments, one of A and B independently has one or more R 1 A monocyclic or bicyclic heterocycline is optionally substituted. In some embodiments, one of A and B is independently one or more R 1 It is a nitrogen-containing heterocycline that is optionally substituted. In some embodiments, one of A and B is independently one or more R 1 It is a 4- to 8-membered heterocycline that is optionally substituted. In some embodiments, one of A and B is [ka] (In the formula, R 1 (As described herein) It is selected independently from. In some embodiments, one of A and B is [ka] (In the formula, R 1 (As described herein) It is selected independently from. In some embodiments, one of A or B is [ka] In some embodiments, one of A or B is [ka] In some embodiments, one of A or B is [ka] That is the case.

[0086] In some embodiments, one of A and B is independently [ka] And R 1 This is as described herein. In some embodiments, one of A and B is [ka] Selected independently from, and R 1 This is as described herein.

[0087] In some embodiments, one of A and B is independently [ka] And R B1 and R C1 Each of these is selected from hydrogen, C1-C6 alkyl, C1-C6 heteroalkyl, C1-C6 haloalkyl, cycloalkyl, heterocyclyl, C1-C6 alkylene-cycloalkyl, and C1-C6 alkylene-heterocyclyl, and each alkyl, alkylene, heteroalkyl, haloalkyl, cycloalkyl, and heterocyclyl is one or more R 9 It is optionally replaced by R. In some embodiments, B1 is hydrogen, and R C1The elements are selected from hydrogen, C1-C6 alkyl, C1-C6 heteroalkyl, C1-C6 haloalkyl, cycloalkyl, heterocyclyl, C1-C6 alkylene-cycloalkyl and C1-C6 alkylene-heterocyclyl, and each alkyl, a Lukilen, heteroalkyl, haloalkyl, cycloalkyl, and heterocyclyl are one or more R 9 It is replaced by an optional choice.

[0088] In some embodiments, one of A and B is [ka] Selected independently from and R B1 and R C1 Each of these is selected from hydrogen, C1-C6 alkyl, C1-C6 heteroalkyl, C1-C6 haloalkyl, cycloalkyl, heterocyclyl, C1-C6 alkylene-cycloalkyl, and C1-C6 alkylene-heterocyclyl, and each alkyl, alkylene, heteroalkyl, haloalkyl, cycloalkyl, and heterocyclyl is one or more R 9 It is optionally replaced by R. In some embodiments, B1 is hydrogen, and R C1 The R is selected from hydrogen, C1-C6 alkyl, C1-C6 heteroalkyl, C1-C6 haloalkyl, cycloalkyl, heterocyclyl, C1-C6 alkylene-cycloalkyl, and C1-C6 alkylene-heterocyclyl, and each alkyl, alkylene, heteroalkyl, haloalkyl, cycloalkyl, and heterocyclyl is one or more R 9 It is replaced by an optional choice.

[0089] In some embodiments, one of A and B is [ka] [ka] It is selected independently from. In some embodiments, one of A and B is [ka] It is selected independently from. In some embodiments, one of A or B is [ka] In some embodiments, one of A or B is [ka] In some embodiments, one of A or B is [ka] In some embodiments, one of A or B is [ka] In some embodiments, one of A or B is [ka] In some embodiments, one of A or B is [ka] In some embodiments, one of A or B is [ka] In some embodiments, one of A or B is [ka] That is the case.

[0090] In some embodiments, A and B are not heteroaryl compounds, independently of each other. In some embodiments, A and B are not heterocyclyl compounds, independently of each other.

[0091] In some embodiments, A is 0 or 1 R1 It is replaced by. In some embodiments, B is 0, 1 or 2 R 1 It is replaced by R 1 C1-C6 alkyl, -OR A Or a halo (e.g., CH3, OH, or F). In some embodiments, R 1 is CH3. In some embodiments, R 1 is OH. In some embodiments, R 1 It is F.

[0092] In some embodiments, A is independently one or more R 1 A is a monocyclic or bicyclic heteroaryl that is optionally substituted. In some embodiments, A is one or more R 1 It is a bicyclic heteroaryl which is optionally substituted with R. In some embodiments, A is one or more R 1 Replaced by optional selection It is a nitrogen-containing heteroaryl. In some embodiments, A is one or more R 1 A is a 5-10 member heteroaryl that is optionally substituted. In some embodiments, A is [ka] (In the formula, R 1 (As described herein) Selected from. In some embodiments, A is [ka] (In the formula, R 1 (As described herein) Selected from. In some embodiments, A is [ka] (In the formula, R 1 (As described herein) Selected from.

[0093] In some embodiments, A is [ka] (In the formula, each R 1a These are independently C1-C6 alkyl, C1-C6 heteroalkyl, C1-C6 haloalkyl, halo, cyano, or -ORA, and each alkyl, heteroalkyl and haloalkyl has one or more R 7 (It is replaced by an optional choice.) Selected from. In some embodiments, A is [ka] (In the formula, each R 1a These are independently C1-C6 alkyl, C1-C6 heteroalkyl, C1-C6 haloalkyl, halo, cyano, or -ORA, and each alkyl, heteroalkyl and haloalkyl has one or more R 7 (It is replaced by an optional choice.) Selected from. In some embodiments, R 1a At least one of them is a C1-C6 alkyl, halo, or -OR A In some embodiments, R 1a is -OR A And R A H is H.

[0094] In some embodiments, A is [ka] (In the formula, R 1 (As described herein) In some embodiments, A is [ka] (In the formula, R 1 (As described herein) In some embodiments, A is [ka] (In the formula, R 1 (As described herein) In some embodiments, A is [ka] (In the formula, R 1 (As described herein) That is the case.

[0095] In some embodiments, A is [ka] Selected from. In some embodiments, A is [ka] Selected from. In some embodiments, A is [ka] In some embodiments, A is [ka] In some embodiments, A is [ka] 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.

[0096] In some embodiments, A is one or more R 1 A is a monocyclic or bicyclic heterocycline that is optionally substituted with R. In some embodiments, A is one or more R 1 It is a nitrogen-containing heterocycline that is optionally substituted with R. In some embodiments, A is one or more R 1 It is a 4- to 8-membered heterocycline that is optionally substituted. In some embodiments, A is [ka] (In the formula, R 1 (As described herein) Selected from. In some embodiments, A is [ka] (In the formula, R 1 (As described herein) Selected from. In some embodiments, A is [ka] In some embodiments, one of A or B is [ka] In some embodiments, A is [ka] That is the case.

[0097] In some embodiments, A is [ka] (In the formula, R 1(As described herein) In some embodiments, A is [ka] (In the formula, R 1 (As described herein) Selected from.

[0098] In some embodiments, A is [ka] (In the formula, R B1 and R C1 Each of these is selected from hydrogen, C1-C6 alkyl, C1-C6 heteroalkyl, C1-C6 haloalkyl, cycloalkyl, heterocyclyl, C1-C6 alkylene-cycloalkyl, and C1-C6 alkylene-heterocyclyl, and each alkyl, alkylene, heteroalkyl, haloalkyl, cycloalkyl, and heterocyclyl is one or more R 9 (It is replaced by optional selection.) In some embodiments, R B1 is hydrogen, and R C1 These are hydrogen, C1-C6 alkyl, C1-C6 heteroalkyl, C1-C6 haloalkyl, cycloalkyl, heteroalkyl Selected from rocyclyl, C1-C6 alkylene-cycloalkyl and C1-C6 alkylene-heterocyclyl, each alkyl, alkylene, heteroalkyl, haloalkyl, cycloalkyl and heterocyclyl is one or more R 9 It is replaced by an optional choice.

[0099] In some embodiments, A is [ka] (In the formula, R B1 and R C1Each of these is selected from hydrogen, C1-C6 alkyl, C1-C6 heteroalkyl, C1-C6 haloalkyl, cycloalkyl, heterocyclyl, C1-C6 alkylene-cycloalkyl, and C1-C6 alkylene-heterocyclyl, and each alkyl, alkylene, heteroalkyl, haloalkyl, cycloalkyl, and heterocyclyl is one or more R 9 (It is replaced by optional selection.) Selected from. In some embodiments, R B1 is hydrogen, and R C1 The R is selected from hydrogen, C1-C6 alkyl, C1-C6 heteroalkyl, C1-C6 haloalkyl, cycloalkyl, heterocyclyl, C1-C6 alkylene-cycloalkyl, and C1-C6 alkylene-heterocyclyl, and each alkyl, alkylene, heteroalkyl, haloalkyl, cycloalkyl, and heterocyclyl is one or more R 9 It is replaced by an optional choice.

[0100] In some embodiments, A is [ka] [ka] [ka] Selected from. In some embodiments, A is [ka] Selected from. In some embodiments, one of A or B is [ka] In some embodiments, A is [ka] In some embodiments, A is [ka] In some embodiments, A is [ka] 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.

[0101] In some embodiments, A is not a heteroaryl compound. In some embodiments, A is not a heterocyclyl compound.

[0102] In some embodiments, B is one or more R 1 It is a monocyclic or bicyclic heteroaryl that is optionally substituted. In some embodiments, B is one or more R 1 It is a bicyclic heteroaryl which is optionally substituted. In some embodiments, B is one or more R 1 It is a nitrogen-containing heteroaryl which is optionally substituted. In some embodiments, B is one or more R 1 It is a 5-10 member heteroaryl that is optionally substituted. In some embodiments, B is [ka] (In the formula, R 1 (As described herein) Selected from. In some embodiments, B is [ka] (In the formula, R 1 (As described herein) Selected from. In some embodiments, B is [ka] (In the formula, R 1 (As described herein) Selected from.

[0103] In some embodiments, B is [ka] (In the formula, each R 1a These are independently C1-C6 alkyl, C1-C6 heteroalkyl, C1-C6 haloalkyl, halo, cyano, or -OR A Each alkyl, heteroalkyl, and haloalkyl is one or more R 7 (It is replaced by an optional choice.) Selected from. In some embodiments, B is [ka] (In the formula, each R 1a These are independently C1-C6 alkyl, C1-C6 heteroalkyl, C1-C6 haloalkyl, halo, cyano, or -OR A Each alkyl, heteroalkyl, and haloalkyl is one or more R 7 (It is replaced by an optional choice.) Selected from. In some embodiments, R 1a At least one of them is a C1-C6 alkyl, halo, or -OR A In some embodiments, R 1a is -OR A And R A H is H.

[0104] In some embodiments, B is [ka] (In the formula, R 1 (As described herein) In some embodiments, B is [ka] (In the formula, R 1 (As described herein) In some embodiments, B is [ka] (In the formula, R 1 (As described herein) In some embodiments, B is [ka] (In the formula, R 1 (As described herein) That is the case.

[0105] In some embodiments, B is [ka] 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] That is the case.

[0106] In some embodiments, B is one or more R 1 It is a monocyclic or bicyclic heterocycline that is optionally substituted. In some embodiments, B is one or more R 1 It is a nitrogen-containing heterocycline that is optionally substituted with R. In some embodiments, B is one or more R 1 It is a 4- to 8-membered heterocycline that is optionally substituted. In some embodiments, B is [ka] (In the formula, R 1 (As described herein) Selected from. In some embodiments, B is [ka] (In the formula, R 1 (As described herein) Selected from. In some embodiments, B is [ka] In some embodiments, B is [ka] In some embodiments, B is [ka] That is the case.

[0107] In some embodiments, B is [ka] (In the formula, R 1 (As described herein) In some embodiments, B is [ka] (In the formula, R 1 (As described herein) Selected from.

[0108] In some embodiments, B is [ka] (In the formula, R B1 and R C1 Each of these is selected from hydrogen, C1-C6 alkyl, C1-C6 heteroalkyl, C1-C6 haloalkyl, cycloalkyl, heterocyclyl, C1-C6 alkylene-cycloalkyl, and C1-C6 alkylene-heterocyclyl, and each alkyl, alkylene, heteroalkyl, haloalkyl, cycloalkyl, and heterocyclyl is one or more R 9 (It is replaced by optional selection.) In some embodiments, R B1 is hydrogen, and R C1The elements are selected from hydrogen, C1-C6 alkyl, C1-C6 heteroalkyl, C1-C6 haloalkyl, cycloalkyl, heterocyclyl, C1-C6 alkylene-cycloalkyl and C1-C6 alkylene-heterocyclyl, and each alkyl, alkylene, heteroalkyl, haloalkyl, cycloalkyl Roalkyl and heterocyclyl compounds consist of one or more R 9 It is replaced by an optional choice.

[0109] In some embodiments, B is [ka] (In the formula, R B1 and R C1 Each of these is selected from hydrogen, C1-C6 alkyl, C1-C6 heteroalkyl, C1-C6 haloalkyl, cycloalkyl, heterocyclyl, C1-C6 alkylene-cycloalkyl, and C1-C6 alkylene-heterocyclyl, and each alkyl, alkylene, heteroalkyl, haloalkyl, cycloalkyl, and heterocyclyl is one or more R 9 (It is replaced by optional selection.) Selected from. In some embodiments, R B1 is hydrogen, and R C1 The R is selected from hydrogen, C1-C6 alkyl, C1-C6 heteroalkyl, C1-C6 haloalkyl, cycloalkyl, heterocyclyl, C1-C6 alkylene-cycloalkyl, and C1-C6 alkylene-heterocyclyl, and each alkyl, alkylene, heteroalkyl, haloalkyl, cycloalkyl, and heterocyclyl is one or more R 9 It is replaced by an optional choice.

[0110] In some embodiments, B is [ka] [ka] [ka] 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.

[0111] In some embodiments, B is not a heteroaryl compound. In some embodiments, B is not a heterocyclyl compound.

[0112] As is generally stated for equations (I) and (II), L 1 and L 2Each of these is either absent or C1-C6 alkylene, C1-C6 heteroalkylene, -O-, -C(O)-, -N(R 4 )-,-N(R 4 )C(O)-, -C(O)N(R 4 )-,-N(R 4 )C(O)N(R 4 )- or C1~C6 alkylene-N(R 4 )C(O)N(R 4 )- may refer to a group, and each alkylene and heteroalkylene may have one or more R 5 It is replaced by optional selection. In some embodiments, L 1 and L 2 One of them is absent or C1-C6 heteroalkylene. In some embodiments, L 1 and L 2 One of them is, independently, absent. In some embodiments, L is a C1-C6 heteroalkylene (e.g., -N(CH3)-). In some embodiments, L 1 and L 2 One of them is, independently, non-existent, L 1 and L 2 The other is independently a heteroalkylene (e.g., NHC(O)NH or NHC(O)NHCH2 or N(CH3)C(O)NH). In some embodiments, L 1 and L 2 Each of them is independent and nonexistent.

[0113] As is generally stated for equation (I), X, Y, and Z are each independently N or C(R 6 ) may be. In some embodiments, X is C(R 6 )(for example, CH). In some embodiments, X is N. In some embodiments, Y is C(R 6 )(for example, CH). In some embodiments, Y is N. In some embodiments, Z is C(R 6 )(for example, CH). In some embodiments, Z is N. In some embodiments, X and Y are independently C(R 6)(for example, CH). In some embodiments, X and Y are each independently N. In some embodiments, Y and Z are each independently N. In one embodiment, X and Z are each independently N. In some embodiments, one of X and Y is independently N, and Z is N. In some embodiments, X and Z are independently N, and Y is N. In some embodiments, X, Y, and Z are each independently N.

[0114] In some embodiments, m is 0. In some embodiments, m is 1. In some embodiments, n is 0. In some embodiments, n is 0.

[0115] In some embodiments, the compound of formula (I) is formula (Ia): [ka] (In the formula, A and B are each independently of one or more R 1 A cycloalkyl, heterocyclyl, aryl, or heteroaryl which is optionally substituted; L 1 and L 2 These are, independently, absent, C1-C6 alkylene, C1-C6 heteroalkylene, -O-, -C(O)-, -N(R) 4 )-,-N(R 4 )C(O)-, -C(O)N(R 4 )-,-N(R 4 )C(O)N(R 4 )- or C1~C6 alkylene-N(R 4 )C(O)N(R 4 )- and each alkylene and heteroalkylene is one or more R 5 They are replaced by arbitrary selection; X and Y are N or C(R 6 ) and; each R 1These are independently hydrogen, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 heteroalkyl, C1-C6 haloalkyl, cycloalkyl, heterocyclyl, heteroaryl, aryl, C1-C6 alkylene-aryl, C1-C6 alkenylene-aryl, C1-C6 alkylene-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 or -S(O) x R D Each alkyl, alkylene, alkenyl, alkenylene, alkynyl, heteroalkyl, haloalkyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl is one or more R 7 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. 7 It is replaced by arbitrary selection in each R 2 and R 3 These are independently C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 heteroalkyl, C1-C6 haloalkyl, halo, cyano, -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 or -S(O) x R D and; each R 4 R is independently hydrogen, C1-C6 alkyl, or C1-C6 haloalkyl; each R 5C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 heteroalkyl, C1-C6 haloalkyl, halo, cyano, oxo, -OR A or -NR B R C and; each R 6 These are independently hydrogen, halo, cyano, C1-C6 alkyl, C1-C6 haloalkyl, or -OR A and; each R 7 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, -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 or -S(O) x R D Each of alkyl, alkenyl, alkynyl, heteroalkyl, haloalkyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl is one or more R 8 It is replaced by arbitrary selection in each R A These are independently hydrogen, C1-C6 alkyl, C1-C6 heteroalkyl, C1- C6 haloalkyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, C1-C6 alkylene-aryl, C1-C6 alkylene-heteroaryl, -C(O)R D or -S(O) x R D Each alkyl, alkylene, heteroalkyl, haloalkyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl is one or more R 9 It is replaced by arbitrary selection in each R B and R CThese are independently hydrogen, C1-C6 alkyl, C1-C6 heteroalkyl, C1-C6 haloalkyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, C1-C6 alkylene-cycloalkyl, C1-C6 alkylene-heterocyclyl, -OR A Each alkyl, alkylene, heteroalkyl, haloalkyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl is one or more R 9 It is replaced by optional selection in R B and R C Along with the atoms to which they are bonded, one or more R 9 They form a 3- to 7-membered heterocyclyl ring which is optionally substituted; each R D These are independently hydrogen, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 heteroalkyl, and C1-C6 haloalkyl, and each alkyl, alkenyl, alkynyl, heteroalkyl and haloalkyl has one or more R 9 It is optionally replaced with; each R 8 These are independently C1-C6 alkyl, C1-C6 heteroalkyl, C1-C6 haloalkyl, halo, cyano, oxo, or -ORA; each R 9 This refers to C1-C6 alkyl, halo, cyano, oxo, or -OR A1 and; each R A1 (where is hydrogen or C1-C6 alkyl; n is 0, 1, or 2; m is 0 or 1; and x is 0, 1, or 2) The compound or its pharmaceutically acceptable salts, solvates, hydrates, tautomers, or stereoisomers.

[0116] In some embodiments, the compound of formula (I) is formula (Ib): [ka] (In the formula, A and B are each independently of one or more R 1 The cycloalkyl, heterocyclyl, aryl, or heteroaryl elements are optionally substituted; X, Y, and Z are N or C(R)6 ) and at least one of X, Y, and Z is 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 or -S(O) x R D Each alkyl, alkylene, alkenyl, alkynyl, heteroalkyl, haloalkyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl is one or more R 7 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. 7 It is replaced by arbitrary selection in each R 2 and R 3 These are independently C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 heteroalkyl, C1-C6 haloalkyl, 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 or -S(O) x R D And each R 6These are independently hydrogen, halo, C1-C6 alkyl, C1-C6 haloalkyl, or -OR A and; each R 7 These are independently C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, and 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 or -S(O) x R D Each of alkyl, alkenyl, alkynyl, heteroalkyl, haloalkyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl is one or more R 8 It is replaced by arbitrary selection in 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; each R B and R C These are independently hydrogen, C1-C6 alkyl, C1-C6 heteroalkyl, cycloalkyl, heterocyclyl, or -OR A is; or R B and R C Along with the atoms to which they are bonded, one or more R 9 They form a 3- to 7-membered heterocyclyl ring which is optionally substituted; each R D 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; each R8 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 9 This refers to C1-C6 alkyl, halo, cyano, oxo, or -OR A1 and; each R A1 (where is hydrogen or a C1-C6 alkyl group; m and n are independently 0, 1, or 2; and x is 0, 1, or 2) The compound or its pharmaceutically acceptable salts, solvates, hydrates, tautomers, or stereoisomers.

[0117] In some embodiments, the compound of formula (I) is formula (Ic): [ka] (In the formula, A and B are each independently of one or more R 1 X and Y are cycloalkyl, heterocyclyl, aryl, or heteroaryl molecules that are optionally substituted; X and Y are N or C(R 6 ) and; 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 or -S(O) x R DEach alkyl, alkylene, alkenyl, alkynyl, heteroalkyl, haloalkyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl is one or more R 7 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. 7 It is replaced by arbitrary selection in each R 2 and R 3 These are independently C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 heteroalkyl, C1-C6 haloalkyl, 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 or -S(O) x R D And each R 6 These are independently hydrogen, halo, C1-C6 alkyl, C1-C6 haloalkyl, or -OR A and; each R 7 These are independently C1-C6 alkyl and C2-C6 alke Nyl, 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 or -S(O) x R DEach of alkyl, alkenyl, alkynyl, heteroalkyl, haloalkyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl is one or more R 8 It is replaced by arbitrary selection in 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; each R B and R C These are independently hydrogen, C1-C6 alkyl, C1-C6 heteroalkyl, cycloalkyl, heterocyclyl, or -OR A is; or R B and R C Along with the atoms to which they are bonded, one or more R 9 They form a 3- to 7-membered heterocyclyl ring which is optionally substituted; each R D 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; each R 8 These are independently C1-C6 alkyl, C1-C6 heteroalkyl, C1-C6 haloalkyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, halo, cyano, oxo, or -ORA; each R 9 This refers to C1-C6 alkyl, halo, cyano, oxo, or -OR A1 and; each R A1 (where is hydrogen or a C1-C6 alkyl group; m and n are independently 0, 1, or 2; and x is 0, 1, or 2) The compound or its pharmaceutically acceptable salts, solvates, hydrates, tautomers, or stereoisomers.

[0118] In some embodiments, the compound of formula (I) is formula (Id): [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; X and Z are N or C(R 6 ) and; 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 or -S(O) x R D Each alkyl, alkylene, alkenyl, alkynyl, heteroalkyl, haloalkyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl is one or more R 7 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. 7 It is replaced by arbitrary selection in each R 2 and R 3 These are independently C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 heteroalkyl, C1-C6 haloalkyl, and -OR A , -NR B R C , -NR B C(O)R D -NO2, -C(O)NR B RC , -C(O)R D , -C(O)OR D or -S(O) x R D And each R 6 These are independently hydrogen, halo, C1-C6 alkyl, and C1-C6 haloal Kill or -OR A and; each R 7 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, -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 or -S(O) x R D Each of alkyl, alkenyl, alkynyl, heteroalkyl, haloalkyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl is one or more R 8 It is replaced by arbitrary selection in 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; each R B and R C These are independently hydrogen, C1-C6 alkyl, C1-C6 heteroalkyl, cycloalkyl, heterocyclyl, or -OR A is; or R B and R C Along with the atoms to which they are bonded, one or more R 9 They form a 3- to 7-membered heterocyclyl ring which is optionally substituted; each R DR 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; each R 8 These are independently C1-C6 alkyl, C1-C6 heteroalkyl, C1-C6 haloalkyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, halo, cyano, oxo, or -ORA; each R 9 This refers to C1-C6 alkyl, halo, cyano, oxo, or -OR A1 and; each R A1 (where is hydrogen or a C1-C6 alkyl group; m and n are independently 0, 1, or 2; and x is 0, 1, or 2) The compound or its pharmaceutically acceptable salts, solvates, hydrates, tautomers, or stereoisomers.

[0119] In some embodiments, the compound of formula (I) is formula (Ie): [ka] (In the formula, A and B are each independently of one or more R 1 X is a cycloalkyl, heterocyclyl, aryl, or heteroaryl which is optionally substituted; X is N or C(R 6 ) and; 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 or -S(O) x R D Each alkyl, alkylene, alkenyl, alkynyl, heteroalkyl, haloalkyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl is one or more R 7 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. 7 It is replaced by arbitrary selection in each R 2 and R 3 These are independently C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 heteroalkyl, C1-C6 haloalkyl, 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 or -S(O) x R D And each R 6 These are independently hydrogen, halo, C1-C6 alkyl, C1-C6 haloalkyl, or -OR A and; each R 7 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, -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 or -S(O) x RD Each of alkyl, alkenyl, alkynyl, heteroalkyl, haloalkyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl is one or more R 8 It is replaced by arbitrary selection in 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; each R B and R C These are independently hydrogen, C1-C6 alkyl, C1-C6 heteroalkyl, cycloalkyl, heterocyclyl, or -OR A is; or R B and R C Along with the atoms to which they are bonded, one or more R 9 They form a 3- to 7-membered heterocyclyl ring which is optionally substituted; each R D 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; each R 8 These are independently C1-C6 alkyl, C1-C6 heteroalkyl, C1-C6 haloalkyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, halo, cyano, oxo, or -ORA; each R 9 This refers to C1-C6 alkyl, halo, cyano, oxo, or -OR A1 and; each R A1 (where is hydrogen or a C1-C6 alkyl group; m and n are independently 0, 1, or 2; and x is 0, 1, or 2) The compound or its pharmaceutically acceptable salts, solvates, hydrates, tautomers, or stereoisomers.

[0120] In some embodiments, the compound of formula (I) is formula (If): [ka] (In the formula, A and B are each independently of one or more R 1 The cycloalkyl, heterocyclyl, aryl, or heteroaryl are optionally substituted; 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 or -S(O) x R D Each alkyl, alkylene, alkenyl, alkynyl, heteroalkyl, haloalkyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl is one or more R 7 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. 7 It is replaced by arbitrary selection in each R 2 and R 3 These are independently C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 heteroalkyl, C1-C6 haloalkyl, and -OR A , -NR B R C , -NR B C(O)R D -NO2, -C(O)NR B R C , -C(O)RD , -C(O)OR D or -S(O) x R D and; each R 7 These are independently C1~C6 A Kill, 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 or -S(O) x R D Each of alkyl, alkenyl, alkynyl, heteroalkyl, haloalkyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl is one or more R 8 It is replaced by arbitrary selection in 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; each R B and R C These are independently hydrogen, C1-C6 alkyl, C1-C6 heteroalkyl, cycloalkyl, heterocyclyl, or -OR A is; or R B and R C Along with the atoms to which they are bonded, one or more R 9 They form a 3- to 7-membered heterocyclyl ring which is optionally substituted; each R DR 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; each R 8 These are independently C1-C6 alkyl, C1-C6 heteroalkyl, C1-C6 haloalkyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, halo, cyano, oxo, or -ORA; each R 9 This refers to C1-C6 alkyl, halo, cyano, oxo, or -OR A1 and; each R A1 (where is hydrogen or a C1-C6 alkyl group; m and n are independently 0, 1, or 2; and x is 0, 1, or 2) The compound or its pharmaceutically acceptable salts, solvates, hydrates, tautomers, or stereoisomers.

[0121] In some embodiments, the compound of formula (I) is formula (Ig): [ka] (In the formula, A and B are each independently of one or more R 1 Y is a cycloalkyl, heterocyclyl, aryl, or heteroaryl which is optionally substituted; Y is N or C(R 6 ) and; 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 or -S(O) x R D Each alkyl, alkylene, alkenyl, alkynyl, heteroalkyl, haloalkyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl is one or more R 7 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. 7 It is replaced by arbitrary selection in each R 2 and R 3 These are independently C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 heteroalkyl, C1-C6 haloalkyl, 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 or -S(O) x R D And each R 6 These are independently hydrogen, halo, C1-C6 alkyl, C1-C6 haloalkyl, or -OR A and; each R 7 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, -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 or -S(O) x RD Each of alkyl, alkenyl, alkynyl, heteroalkyl, haloalkyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl is one or more R 8 It is replaced by arbitrary selection in 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; each R B and R C These are independently hydrogen, C1-C6 alkyl, C1-C6 heteroalkyl, cycloalkyl, heterocyclyl, or -OR A is; or R B and R C Along with the atoms to which they are bonded, one or more R 9 They form a 3- to 7-membered heterocyclyl ring which is optionally substituted; each R D 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; each R 8 These are independently C1-C6 alkyl, C1-C6 heteroalkyl, C1-C6 haloalkyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, halo, cyano, oxo, or -ORA; each R 9 This refers to C1-C6 alkyl, halo, cyano, oxo, or -OR A1 and; each R A1 (where is hydrogen or a C1-C6 alkyl group; m and n are independently 0, 1, or 2; and x is 0, 1, or 2) The compound or its pharmaceutically acceptable salts, solvates, hydrates, tautomers, or stereoisomers.

[0122] In some embodiments, the compound of formula (I) is of formula (Ih): [ka] (In the formula, A and B are each independently of one or more R 1 Y is a cycloalkyl, heterocyclyl, aryl, or heteroaryl which is optionally substituted; Y is N or C(R 6 ) and; 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 or -S(O) x R D Each alkyl, alkylene, alkenyl, alkynyl, heteroalkyl, haloalkyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl is one or more R 7 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. 7 It is replaced by arbitrary selection in each R 2 and R 3 These are independently C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 heteroalkyl, C1-C6 haloalkyl, and -OR A , -NR B R C , -NR B C(O)R D -NO2, -C(O)NR B RC , -C(O)R D , -C(O)OR D or -S(O) x R D And each R 6 These are independently hydrogen, halo, C1-C6 alkyl, C1-C6 haloalkyl, or -OR A and; each R 7 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, -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 or -S(O) x R D Each of alkyl, alkenyl, alkynyl, heteroalkyl, haloalkyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl is one or more R 8 It is replaced by arbitrary selection in 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; each R B and R C These are independently hydrogen, C1-C6 alkyl, C1-C6 heteroalkyl, cycloalkyl, heterocyclyl, or -OR A is; or R B and R C Along with the atoms to which they are bonded, one or more R 9 They form a 3- to 7-membered heterocyclyl ring which is optionally substituted; each R DR 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; each R 8 These are independently C1-C6 alkyl, C1-C6 heteroalkyl, C1-C6 haloalkyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, halo, cyano, oxo, or -ORA; each R 9 This refers to C1-C6 alkyl, halo, cyano, oxo, or -OR A1 and; each R A1 (where is hydrogen or a C1-C6 alkyl group; m and n are independently 0, 1, or 2; and x is 0, 1, or 2) The compound or its pharmaceutically acceptable salts, solvates, hydrates, tautomers, or stereoisomers.

[0123] In some embodiments, the compound of formula (I) is formula (Ii): [ka] (wherein A' is a bicyclic heteroaryl or heterocyclyl; B is one or more R 1 The cycloalkyl, heterocyclyl, aryl, or heteroaryl elements are optionally substituted; X, Y, and Z are N or C(R) 6 ) and at least one of X, Y, and Z is 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)NRB R C , -C(O)R D , -C(O)OR D or -S(O) x R D , and each alkyl, alkylene, alkenyl, alkynyl, heteroalkyl, haloalkyl, cycloalkyl, heterocyclyl, aryl and heteroaryl is optionally substituted with one or more R 7 ; or two R 1 groups, together with the atoms to which they are bonded, 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 7 ; R 1a is C1-C6 alkyl, C1-C6 heteroalkyl, C1-C6 haloalkyl, halo, -OR A , -NR B R C , -NR B C(O)R D , -C(O)NR B R C , -C(O)R D or -C(O)OR D ; each R 2 and R 3 are independently C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 heteroalkyl, C1-C6 haloalkyl, -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 or -S(O) x R D , and each R 6 is independently hydrogen, halo, C1-C6 alkyl, C1-C6 haloalkyl or -OR A ; and each R 7 ​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, -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 or -S(O) x R D Each of alkyl, alkenyl, alkynyl, heteroalkyl, haloalkyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl is one or more R 8 It is replaced by arbitrary selection in 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; each R B and R C These are independently hydrogen, C1-C6 alkyl, C1-C6 heteroalkyl, cycloalkyl, heterocyclyl, or -OR A is; or R B and R C Along with the atoms to which they are bonded, one or more R 9 They form a 3- to 7-membered heterocyclyl ring which is optionally substituted; each R D 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; each R 8These are independently C1-C6 alkyl, C1-C6 heteroalkyl, C1-C6 haloalkyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, halo, cyano, oxo, or -ORA; each R 9 This refers to C1-C6 alkyl, halo, cyano, oxo, or -OR A1 and; each R A1 (where is hydrogen or a C1-C6 alkyl group; m and n are independently 0, 1, or 2; and x is 0, 1, or 2) The compound or its pharmaceutically acceptable salts, solvates, hydrates, tautomers, or stereoisomers.

[0124] In some embodiments, the compound of formula (I) is formula (Ij): [ka] (In the formula, A is one or more R 1 B' is a cycloalkyl, heterocyclyl, aryl, or heteroaryl that is optionally substituted; B' is a bicyclic heteroaryl or heterocyclyl; X, Y, and Z are N or C(R 6 ) and at least one of X, Y, and Z is 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 or -S(O) x R D, and each alkyl, alkylene, alkenyl, alkynyl, heteroalkyl, haloalkyl, cycloalkyl, heterocyclyl, aryl and heteroaryl is optionally substituted with one or more R 7 ; or two R 1 groups, together with the atoms to which they are bonded, form a 3 to 7-membered cycloalkyl, heterocyclyl, aryl or heteroar yl, and each cycloalkyl, heterocyclyl, aryl and heteroaryl is optionally substituted with one or more R 7 ; R 1a is C1-C6 alkyl, C1-C6 heteroalkyl, C1-C6 haloalkyl, halo, -OR A , -NR B R C , -NR B C(O)R D , -C(O)NR B R C , -C(O)R D or -C(O)OR D ; each R 2 and R 3 is independently C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 heteroalkyl, C1-C6 haloalkyl, -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 or -S(O) x R D , and each R 6 is independently hydrogen, halo, C1-C6 alkyl, C1-C6 haloalkyl or -OR A ; each R 7 is 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 BR C , -NR B C(O)R D -NO2, -C(O)NR B R C , -C(O)R D , -C(O)OR D or -S(O) x R D Each of alkyl, alkenyl, alkynyl, heteroalkyl, haloalkyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl is one or more R 8 It is replaced by arbitrary selection in 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; each R B and R C These are independently hydrogen, C1-C6 alkyl, C1-C6 heteroalkyl, cycloalkyl, heterocyclyl, or -OR A is; or R B and R C Along with the atoms to which they are bonded, one or more R 9 They form a 3- to 7-membered heterocyclyl ring which is optionally substituted; each R D 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; each R 8 These are independently C1-C6 alkyl, C1-C6 heteroalkyl, C1-C6 haloalkyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, halo, cyano, oxo, or -ORA; each R 9 This refers to C1-C6 alkyl, halo, cyano, oxo, or -OR A1 and; each R A1(where is hydrogen or a C1-C6 alkyl group; m and n are independently 0, 1, or 2; and x is 0, 1, or 2) The compound or its pharmaceutically acceptable salts, solvates, hydrates, tautomers, or stereoisomers.

[0125] In some embodiments, the compound of formula (I) is formula (Ik): [ka] (In the formula, A is one or more R 1 The cycloalkyl, heterocyclyl, aryl, or heteroaryl elements are optionally substituted; X, Y, and Z are N or C(R) 6 ) and at least one of X, Y, and Z is 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 or -S(O) x R D Each alkyl, alkylene, alkenyl, Alkynyl, heteroalkyl, haloalkyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl are one or more R 7 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.7 It is replaced by arbitrary selection in each R 2 and R 3 These are independently C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 heteroalkyl, C1-C6 haloalkyl, 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 or -S(O) x R D And each R 6 These are independently hydrogen, halo, C1-C6 alkyl, C1-C6 haloalkyl, or -OR A and; each R 7 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, -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 or -S(O) x R D Each of alkyl, alkenyl, alkynyl, heteroalkyl, haloalkyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl is one or more R 8 It is replaced by arbitrary selection in 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; each R B and R CThese are independently hydrogen, C1-C6 alkyl, C1-C6 heteroalkyl, cycloalkyl, heterocyclyl, or -OR A is; or R B and R C Along with the atoms to which they are bonded, one or more R 9 They form a 3- to 7-membered heterocyclyl ring which is optionally substituted; each R D 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; each R 8 These are independently C1-C6 alkyl, C1-C6 heteroalkyl, C1-C6 haloalkyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, halo, cyano, oxo, or -ORA; each R 9 This refers to C1-C6 alkyl, halo, cyano, oxo, or -OR A1 and; each R A1 (where is hydrogen or a C1-C6 alkyl group; m and n are independently 0, 1, or 2; p is 0, 1, 2, or 3; and x is 0, 1, or 2) The compound or its pharmaceutically acceptable salts, solvates, hydrates, tautomers, or stereoisomers.

[0126] In some embodiments, the compound of formula (I) is formula (Il): [ka] (In the formula, B is one or more R 1 The cycloalkyl, heterocyclyl, aryl, or heteroaryl elements are optionally substituted; X, Y, and Z are N or C(R) 6 ) and at least one of X, Y, and Z is N; each R 1These 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 , -N R B R C , -NR B C(O)R D -NO2, -C(O)NR B R C , -C(O)R D , -C(O)OR D or -S(O) x R D Each alkyl, alkylene, alkenyl, alkynyl, heteroalkyl, haloalkyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl is one or more R 7 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. 7 It is replaced by arbitrary selection in each R 2 and R 3 These are independently C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 heteroalkyl, C1-C6 haloalkyl, 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 or -S(O) x R D And each R 6 These are independently hydrogen, halo, C1-C6 alkyl, C1-C6 haloalkyl, or -OR A and; each R7 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, -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 or -S(O) x R D Each of alkyl, alkenyl, alkynyl, heteroalkyl, haloalkyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl is one or more R 8 It is replaced by arbitrary selection in 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; each R B and R C These are independently hydrogen, C1-C6 alkyl, C1-C6 heteroalkyl, cycloalkyl, heterocyclyl, or -OR A is; or R B and R C Along with the atoms to which they are bonded, one or more R 9 They form a 3- to 7-membered heterocyclyl ring which is optionally substituted; each R D 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; each R 8These are independently C1-C6 alkyl, C1-C6 heteroalkyl, C1-C6 haloalkyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, halo, cyano, oxo, or -ORA; each R 9 This refers to C1-C6 alkyl, halo, cyano, oxo, or -OR A1 and; each R A1 (where is hydrogen or a C1-C6 alkyl group; m and n are independently 0, 1, or 2; p is 0, 1, 2, or 3; and x is 0, 1, or 2) The compound or its pharmaceutically acceptable salts, solvates, hydrates, tautomers, or stereoisomers.

[0127] In some embodiments, the compound of formula (I) is selected from the compounds in Table 1 or their pharmaceutically acceptable salts, solvates, hydrates, tautomers, or stereoisomers.

[0128] [Table 1]

[0129] [Table 2]

[0130] [Table 3]

[0131] [Table 4]

[0132] [Table 5]

[0133] [Table 6]

[0134] Table 7

[0135] Table 8

[0136] Table 9

[0137] Table 10

[0138] Table 11

[0139] Table 12

[0140] Table 13

[0141] Table 14

[0142] Table 15

[0143] Table 16

[0144] Table 17

[0145] Table 18

[0146] Table 19

[0147] Table 20

[0148] Table 21

[0149] Table 22

[0150] Table 23

[0151] Table 24

[0152] Table 25

[0153] Table 26

[0154] Table 27

[0155] [Table 28]

[0156] In some embodiments of formula (I), A is a bicyclic heteroaryl (e.g., 6-hydroxy-2-methyl-2H-indazolyl); B is a monocyclic heterocyclyl (e.g., piperidinyl); L 1 and L 2 Each of them is absent; X is C(R 6 (For example, CH); Y and Z are N; m and n are 0. In some embodiments, the compounds of formulas (I), (Ia), (Ib), (Ic), and (Id) are compound 100 or its pharmaceutically acceptable salts, solvates, hydrates, tautomers, or stereoisomers.

[0157] In some embodiments of formula (I), A is a bicyclic heteroaryl (e.g., 6-hydroxy-2,7-dimethyl-2H-indazolyl); B is a monocyclic heterocyclyl (e.g., piperidinyl); L 1 and L 2 Each of them is absent; X is C(R 6 (For example, CH); Y and Z are N; m and n are 0. In some embodiments, the compounds of formulas (I), (Ia), (Ib), (Ic), and (Id) are compound 101 or its pharmaceutically acceptable salts, solvates, hydrates, tautomers, or stereoisomers.

[0158] In some embodiments of formula (I), A is a bicyclic heteroaryl (e.g., 7-fluoro-6-hydroxy-2-methyl-2H-indazolyl); B is a monocyclic heterocyclyl (e.g., piperidinyl); L 1 and L 2 Each of them is absent; X is C(R 6(For example, CH); Y and Z are N; m and n are 0. In some embodiments, the compounds of formulas (I), (Ia), (Ib), (Ic), and (Id) are compound 102 or its pharmaceutically acceptable salts, solvates, hydrates, tautomers, or stereoisomers.

[0159] In some embodiments of formula (I), A is a bicyclic heteroaryl (e.g., 7-hydroxy-2-methyl-2H-4λ). 4 - is imidazo[2,1-f]pyridadyl); B is a monocyclic heterocyclyl (e.g., piperidinyl); L 1 and L 2 Each of them is absent; X is C(R 6 (For example, CH); Y and Z are N; m and n are 0. In some embodiments, the compounds of formulas (I), (Ia), (Ib), (Ic), and (Id) are compound 103 or its pharmaceutically acceptable salts, solvates, hydrates, tautomers, or stereoisomers.

[0160] In some embodiments of formula (I), A is a bicyclic heteroaryl (e.g., 6-hydroxy-2-methyl-2H-indazolyl); B is a monocyclic heterocyclyl (e.g., piperidinyl); L 1 and L 2 Each of them is absent; Y is C(R 6 )(for example, CH); X and Z are N; m and n are 0. In some embodiments, the compounds of formulas (I), (Ia), (Ib), and (Id) are compound 104 or its pharmaceutically acceptable salts, solvates, hydrates, tautomers, or stereoisomers.

[0161] In some embodiments of formula (I), A is a bicyclic heteroaryl (e.g., 4-hydroxy-2-methyl-2H-indazolyl); B is a monocyclic heterocyclyl (e.g., piperidinyl); L 1 and L 2 Each of them is absent; X is C(R 6(For example, CH); Y and Z are N; m and n are 0. In some embodiments, the compounds of formulas (I), (Ia), (Ib), (Ic), and (Id) are compound 105 or its pharmaceutically acceptable salts, solvates, hydrates, tautomers, or stereoisomers.

[0162] In some embodiments of formula (I), A is a bicyclic heteroaryl (e.g., 4-hydroxy-2-methyl-2H-indazolyl); B is a monocyclic heterocyclyl (e.g., piperidinyl); L 1 and L 2 Each of them is absent; Y is C(R 6 (For example, CH); X and Z are N; m and n are 0. In some embodiments, the compounds of formulas (I), (Ia), (Ib), and (Id) are compound 106 or its pharmaceutically acceptable salts, solvates, hydrates, tautomers, or stereoisomers.

[0163] In some embodiments of formula (I), A is a bicyclic heteroaryl (e.g., 6-hydroxy-2-methyl-2H-indazolyl); B is a monocyclic heterocyclyl (e.g., piperidinyl); L 1 and L 2 Each of the following is absent; X, Y, and Z are N; and m and n are 0. In some embodiments, the compounds of formulas (I), (Ia), (Ib), (Ic), and (Id) are compound 107 or its pharmaceutically acceptable salts, solvates, hydrates, tautomers, or stereoisomers.

[0164] In some embodiments of formula (I), A is a bicyclic heteroaryl (e.g., 4-hydroxy-2-methyl-2H-indazolyl); B is a monocyclic heterocyclyl (e.g., piperidinyl); L 1 and L 2Each of the following is absent; X, Y, and Z are N; and m and n are 0. In some embodiments, the compounds of formulas (I), (Ia), (Ib), (Ic), and (Id) are compound 108 or its pharmaceutically acceptable salts, solvates, hydrates, tautomers, or stereoisomers.

[0165] In some embodiments of formula (I), A is a bicyclic heteroaryl (e.g., 6-hydroxy-2-methyl-2H-indazolyl); B is a monocyclic heterocyclyl (e.g., piperidinyl); L 1 and L 2 Each of them is absent; X and Z are independently C(R) 6 (For example, CH); Y is N; m and n are 0. In some embodiments, the compounds of formulas (I), (Ia), (Ic), and (Id) are compound 109 or its pharmaceutically acceptable salts, solvates, hydrates, tautomers, or stereoisomers.

[0166] In some embodiments of formula (I), A is a bicyclic heteroaryl (e.g., 6-hydroxy-2-methyl-2H-indazolyl); B is a monocyclic heterocyclyl (e.g., piperidinyl); L 1 and L 2 Each of them is absent; X is C(R 6 )(for example, CH); Y and Z are N and R 2 is a halo (e.g., F); m is 1; and n is 0. In some embodiments, the compounds of formulas (I), (Ia), (Ib), (Ic), and (Id) are compound 113 or its pharmaceutically acceptable salts, solvates, hydrates, tautomers, or stereoisomers.

[0167] In some embodiments of formula (I), A is a bicyclic heteroaryl (e.g., 6-hydroxy-2-methyl-2H-indazolyl); B is a monocyclic heterocyclyl (e.g., piperidinyl); L 1 and L 2Each of them is absent; X is C (R 6 )(for example, CH); Y and Z are N and R 3 is a halo (e.g., F); m is 0; and n is 1. In some embodiments, the compounds of formulas (I), (Ia), (Ib), (Ic), and (Id) are compound 114 or its pharmaceutically acceptable salts, solvates, hydrates, tautomers, or stereoisomers.

[0168] In some embodiments of formula (I), A is a bicyclic heteroaryl (e.g., 6-hydroxy-2-methyl-2H-indazolyl); B is a monocyclic heterocyclyl (e.g., piperidinyl); L 1 and L 2 Each of them is absent; X is C(R 6 )(for example, CH); Y is N; Z is C(R 6 )(e.g., CF); m and n are 0. In some embodiments, the compounds of formulas (I), (Ia), (Ic), and (Id) are compound 115 or its pharmaceutically acceptable salts, solvates, hydrates, tautomers, or stereoisomers.

[0169] In some embodiments of formula (I), A is a bicyclic heteroaryl (e.g., 6-hydroxy-2-methyl-2H-indazolyl); B is a monocyclic heterocyclyl (e.g., 1-methylpiperazyl); L 1 and L 2 Each of them is absent; X is C(R 6 (For example, CH); Y and Z are N; m and n are 0. In some embodiments, the compounds of formulas (I), (Ia), (Ib), (Ic), and (Id) are compound 116 or its pharmaceutically acceptable salts, solvates, hydrates, tautomers, or stereoisomers.

[0170] In some embodiments of formula (I), A is a bicyclic heteroaryl (e.g., 6-hydroxy-2-methyl-2H-indazolyl); B is a monocyclic heterocyclyl (e.g., 2-methylpiperazyl); L 1 and L 2 Each of them is absent; X is C(R 6 )(for example, CH); Y and Z are N; m and n are 0. In some embodiments, the compounds of formulas (I), (Ia), (Ib), (Ic), and (Id) are compound 117 or its pharmaceutically acceptable salts, solvates, hydrates, tautomers, or stereoisomers.

[0171] In some embodiments of formula (I), A is a bicyclic heteroaryl (e.g., 6-hydroxy-2-methyl-2H-indazolyl); B is a monocyclic heterocyclyl (e.g., 1,2-dimethylpiperazyl); L 1 and L 2 Each of them is absent; X is C(R 6 )(for example, CH); Y and Z are N; m and n are 0. In some embodiments, the compounds of formulas (I), (Ia), (Ib), (Ic), and (Id) are compound 118 or its pharmaceutically acceptable salts, solvates, hydrates, tautomers, or stereoisomers.

[0172] In some embodiments of formula (I), A is a bicyclic heteroaryl (e.g., 6-hydroxy-2-methyl-2H-indazolyl); B is a monocyclic heterocyclyl (e.g., 2-ethylpiperazyl); L 1 and L 2 Each of them is absent; X is C(R 6 (For example, CH); Y and Z are N; m and n are 0. In some embodiments, the compounds of formulas (I), (Ia), (Ib), (Ic), and (Id) are compound 119 or its pharmaceutically acceptable salts, solvates, hydrates, tautomers, or stereoisomers.

[0173] In some embodiments of formula (I), A is a bicyclic heteroaryl (e.g., 6-hydroxy-2-methyl-2H-indazolyl); B is a monocyclic heterocyclyl (e.g., 2,2-dimethylpiperazyl); L 1 and L 2 Each of them is absent; X is C(R 6 )(for example, CH); Y and Z are N; m and n are 0. In some embodiments, formulas (I), (Ia), (Ib), (Ic) and The compound of (Id) is compound 120 or a pharmaceutically acceptable salt, solvate, hydrate, tautomer, or stereoisomer thereof.

[0174] In some embodiments of formula (I), A is a bicyclic heteroaryl (e.g., 6-hydroxy-2-methyl-2H-indazolyl); B is a monocyclic heterocyclyl (e.g., 4,7-diazaspiro[2.5]octanyl); L 1 and L 2 Each of them is absent; X is C(R 6 (For example, CH); Y and Z are N; m and n are 0. In some embodiments, the compounds of formulas (I), (Ia), (Ib), (Ic), and (Id) are compound 121 or its pharmaceutically acceptable salts, solvates, hydrates, tautomers, or stereoisomers.

[0175] In some embodiments of formula (I), A is a bicyclic heteroaryl (e.g., 6-hydroxy-2-methyl-2H-indazolyl); B is a monocyclic heterocyclyl (e.g., 2,2,6,6-tetramethylpiperazyl); L 1 and L 2 Each of them is absent; X is C(R 6 (For example, CH); Y and Z are N; m and n are 0. In some embodiments, the compounds of formulas (I), (Ia), (Ib), (Ic), and (Id) are compound 122 or its pharmaceutically acceptable salts, solvates, hydrates, tautomers, or stereoisomers.

[0176] In some embodiments of formula (I), A is a bicyclic heteroaryl (e.g., 6-hydroxy-2-methyl-2H-indazolyl); B is a monocyclic heterocyclyl (e.g., 2-methyl-2,6-diazaspiro[3.3]heptanyl); L 1 and L 2 Each of them is absent; X is C(R 6 (For example, CH); Y and Z are N; m and n are 0. In some embodiments, the compounds of formulas (I), (Ia), (Ib), (Ic), and (Id) are compound 123 or its pharmaceutically acceptable salts, solvates, hydrates, tautomers, or stereoisomers.

[0177] In some embodiments of formula (I), A is a bicyclic heteroaryl (e.g., 6-hydroxy-2-methyl-2H-indazolyl); B is a monocyclic heterocyclyl (e.g., 2,6-diazaspiro[3.3]heptanyl); L 1 and L 2 Each of them is absent; X is C(R 6 )(for example, CH); Y and Z are N; m and n are 0. In some embodiments, the compounds of formulas (I), (Ia), (Ib), (Ic), and (Id) are compound 124 or its pharmaceutically acceptable salts, solvates, hydrates, tautomers, or stereoisomers.

[0178] In some embodiments of formula (I), A is a bicyclic heteroaryl (e.g., 6-hydroxy-2-methyl-2H-indazolyl); B is a monocyclic heterocyclyl (e.g., 1,3'-bipyrrolidinyl); L 1 and L 2 Each of them is absent; X is C(R 6(For example, CH); Y and Z are N; m and n are 0. In some embodiments, the compounds of formulas (I), (Ia), (Ib), (Ic), and (Id) are compound 125 or its pharmaceutically acceptable salts, solvates, hydrates, tautomers, or stereoisomers.

[0179] In some embodiments of formula (I), A is a bicyclic heteroaryl (e.g., 6-hydroxy-2-methyl-2H-indazolyl); B is a monocyclic heterocyclyl (e.g., 1-methylpiperazinyl); L 1 L is nonexistent; 2 is -N(R 4 )-(For example, -N(CH3)-) and X is C(R 6 (For example, CH); Y and Z are N; m and n are 0. In some embodiments, the compound of formula (I) is compound 126 or a pharmaceutically acceptable salt, solvate, hydrate, tautomer or stereoisomer thereof.

[0180] In formula (I), in some embodiments, A is a bicyclic heteroaryl (e.g., 6-hydroxy-2-methyl-2H-indazolyl); B is one R 1 It is a monocyclic heterocycline (e.g., pyrrolidinyl) that is substituted with; L 1 and L 2 Each of them is absent; X is C(R 6 )(for example, CH); Y and Z are N; R 1 -NR B R C (For example, -NH( t Bu)) and m and n are 0. In some embodiments, the compounds of formula (I), (Ia), (Ib), (Ic), and (Id) are compounds 127, 153, 154 or their pharmaceutically acceptable salts, solvates, hydrates, tautomers, or stereoisomers.

[0181] In formula (I), in some embodiments, A is a bicyclic heteroaryl (e.g., 6-hydroxy-2-methyl-2H-indazolyl); B is one R 1 It is a monocyclic heterocycline (e.g., pyrrolidinyl) that is substituted with; L 1 and L 2 Each of them is absent; X is C(R 6 )(for example, CH); Y and Z are N; R 1 -NR B R C (For example, -N(Me)2); m and n are 0. In some embodiments, the compounds of formulas (I), (Ia), (Ib), (Ic), and (Id) are compound 129 or its pharmaceutically acceptable salts, solvates, hydrates, tautomers, or stereoisomers.

[0182] In some embodiments of formula (I), A is a bicyclic heteroaryl (e.g., 6-hydroxy-2-methyl-2H-indazolyl); B is a monocyclic heterocyclyl (e.g., 2,2,6,6-tetramethylpiperazinyl); L 1 L is nonexistent; 2 is -N(R 4 )-(For example, -N(CH3)-) and X is C(R 6 (For example, CH); Y and Z are N; m and n are 0. In some embodiments, the compound of formula (I) is compound 130 or a pharmaceutically acceptable salt, solvate, hydrate, tautomer or stereoisomer thereof.

[0183] In formula (I), in some embodiments, A is a bicyclic heteroaryl (e.g., 6-hydroxy-2-methyl-2H-indazolyl); B is one R 1 It is a monocyclic heterocycline (e.g., piperidinyl) that is substituted with; L 1 and L 2 Each of them is absent; X is C(R 6 )(for example, CH); Y and Z are N; R 1 -NR BR C (For example, -NH(Et)); m and n are 0. In some embodiments, the compounds of formulas (I), (Ia), (Ib), (Ic), and (Id) are compound 131 or its pharmaceutically acceptable salts, solvates, hydrates, tautomers, or stereoisomers.

[0184] In formula (I), in some embodiments, A is a bicyclic heteroaryl (e.g., 6-hydroxy-2-methyl-2H-indazolyl); B is one R 1 It is a monocyclic heterocycline (e.g., piperidinyl) that is substituted with; L 1 and L 2 Each of them is absent; X is C(R 6 )(for example, CH); Y and Z are N; R 1 -NR B R C (For example, -NH( t Bu)) and m and n are 0. In some embodiments, the compounds of formulas (I), (Ia), (Ib), (Ic), and (Id) are compound 132 or its pharmaceutically acceptable salts, solvates, hydrates, tautomers, or stereoisomers.

[0185] In formula (I), in some embodiments, A is a bicyclic heteroaryl (e.g., 6-hydroxy-2-methyl-2H-indazolyl); B is one R 1 It is a monocyclic heterocycline (e.g., piperidinyl) that is substituted with; L 1 and L 2 Each of them is absent; X is C(R 6 )(for example, CH); Y and Z are N; R 1 -NR B R C (For example, -N(Me)²; m and n are 0. In some embodiments, the compounds of formulas (I), (Ia), (Ib), (Ic), and (Id) are compound 133 or its pharmaceutically acceptable salts, solvates, hydrates, tautomers, or stereoisomers.

[0186] In some embodiments of formula (I), A is a bicyclic heteroaryl (e.g., 6-hydroxy-2-methyl-2H-indazolyl); B is a monocyclic heterocyclyl (e.g., octahydropyrrolo[1,2-a]pyradyl); L 1 and L 2 Each of them is absent; X is C(R 6 (For example, CH); Y and Z are N; m and n are 0. In some embodiments, the compounds of formulas (I), (Ia), (Ib), (Ic), and (Id) are compound 134 or its pharmaceutically acceptable salts, solvates, hydrates, tautomers, or stereoisomers.

[0187] Regarding formula (I), in some embodiments, A is a bicyclic heteroaryl (e.g., 6-hydroxy-2-methyl-2H-indazolyl); B is a monocyclic heterocyclyl (e.g., 3,8-diazabicyclo[3.2.1]octanyl); L 1 and L 2 Each of them is absent; X is C(R 6 (For example, CH); Y and Z are N; m and n are 0. In some embodiments, the compounds of formulas (I), (Ia), (Ib), (Ic), and (Id) are compound 135 or its pharmaceutically acceptable salts, solvates, hydrates, tautomers, or stereoisomers.

[0188] In some embodiments of formula (I), A is a bicyclic heteroaryl (e.g., 6-hydroxy-2-methyl-2H-indazolyl); B is a monocyclic heterocyclyl (e.g., piperadyl); L 1 and L 2 Each of them is absent; X is C(R 6)(for example, CH); Y and Z are N; m and n are 0. In some embodiments, the compounds of formulas (I), (Ia), (Ib), (Ic), and (Id) are compound 136 or its pharmaceutically acceptable salts, solvates, hydrates, tautomers, or stereoisomers.

[0189] In some embodiments of formula (I), A is a bicyclic heteroaryl (e.g., 6-hydroxy-2-methyl-2H-indazolyl); B is a monocyclic heterocyclyl (e.g., 2,6-dimethylpiperidinyl); L 1 and L 2 Each of them is absent; X is C(R 6 (For example, CH); Y and Z are N; m and n are 0. In some embodiments, the compounds of formulas (I), (Ia), (Ib), (Ic), and (Id) are compound 137 or its pharmaceutically acceptable salts, solvates, hydrates, tautomers, or stereoisomers.

[0190] In some embodiments of formula (I), A is a bicyclic heteroaryl (e.g., 6-hydroxy-2-methyl-2H-indazolyl); B is a monocyclic heterocyclyl (e.g., 1-ethylpiperidinyl); L 1 and L 2 Each of them is absent; X is C(R 6 )(for example, CH); Y and Z are N; m and n are 0. In some embodiments, the compounds of formulas (I), (Ia), (Ib), (Ic), and (Id) are compound 138 or its pharmaceutically acceptable salts, solvates, hydrates, tautomers, or stereoisomers.

[0191] In some embodiments of formula (I), A is a bicyclic heteroaryl (e.g., 6-hydroxy-2-methyl-2H-indazolyl); B is a monocyclic heterocyclyl (e.g., 2-methylpiperidinyl); L 1 and L 2 Each of them is absent; X is C(R 6)(e.g., CH); Y and Z are N; m and n are 0. In some embodiments, the compounds of formulas (I), (Ia), (Ib), (Ic), and (Id) are compounds 139, 140 or their pharmaceutically acceptable salts, solvates, These are hydrates, tautomers, or stereoisomers.

[0192] In some embodiments of formula (I), A is a bicyclic heteroaryl (e.g., 7-bromo-4-hydroxy-2-methyl-2H-indazolyl); B is a monocyclic heterocyclyl (e.g., piperidinyl); L 1 and L 2 Each of them is absent; Y is C(R 6 )(for example, CH); X and Z are N; m and n are 0. In some embodiments, the compounds of formulas (I), (Ia), (Ib), and (Id) are compound 141 or its pharmaceutically acceptable salts, solvates, hydrates, tautomers, or stereoisomers.

[0193] In some embodiments of formula (I), A is a bicyclic heteroaryl (e.g., 6-hydroxy-2-methyl-2H-indazolyl); B is a monocyclic heterocyclyl (e.g., 1-methylpiperidinyl); L 1 and L 2 Each of them is absent; X is C(R 6 (For example, CH); Y and Z are N; m and n are 0. In some embodiments, the compounds of formulas (I), (Ia), (Ib), (Ic), and (Id) are compound 142 or its pharmaceutically acceptable salts, solvates, hydrates, tautomers, or stereoisomers.

[0194] In some embodiments of formula (I), A is a bicyclic heteroaryl (e.g., 6-methoxy-2-methyl-2H-indazolyl); B is a monocyclic heterocyclyl (e.g., piperidinyl); L 1 and L 2 Each of them is absent; X is C(R 6)(for example, CH); Y is N; Z is C(R 6 )(e.g., CF); m and n are 0. In some embodiments, the compounds of formulas (I), (Ia), (Ic), and (Id) are compound 143 or its pharmaceutically acceptable salts, solvates, hydrates, tautomers, or stereoisomers.

[0195] In some embodiments of formula (I), A is a bicyclic heteroaryl (e.g., 6-hydroxy-2-methyl-2H-indazolyl); B is a monocyclic heterocyclyl (e.g., piperidinyl); L 1 and L 2 Each of them is absent; X is C(R 6 )(for example, CH); Y is N; Z is C(R 6 ) and (for example, CH);R 3 is a halo (e.g., F); m is 0; and n is 1. In some embodiments, the compounds of formulas (I), (Ia), (Ic), and (Id) are compound 144 or its pharmaceutically acceptable salts, solvates, hydrates, tautomers, or stereoisomers.

[0196] In some embodiments of formula (I), A is a bicyclic heteroaryl (e.g., 6-methoxy-2-methyl-2H-indazolyl); B is a monocyclic heterocyclyl (e.g., piperidinyl); L 1 and L 2 Each of them is absent; X is C(R 6 )(for example, CH); Y is N; Z is C(R 6 ) and (for example, CH);R 3 is a halo (e.g., F); m is 0; and n is 1. In some embodiments, the compounds of formulas (I), (Ia), (Ic), and (Id) are compound 145 or its pharmaceutically acceptable salts, solvates, hydrates, tautomers, or stereoisomers.

[0197] In some embodiments of formula (I), A is a bicyclic heteroaryl (e.g., 5-hydroxy-2-methyl-2H-indazolyl); B is a monocyclic heterocyclyl (e.g., piperidinyl); L 1 and L 2 Each of them is absent; X is C(R 6 (e.g., CH); Y and Z are N; m and n are 0. In some embodiments, the compounds of formulas (I), (Ia), (Ib), (Ic), and (Id) are compound 146 or its pharmaceutically acceptable salts, solvates, hydrates, and tautomers. Alternatively, they are stereoisomers.

[0198] In some embodiments of formula (I), A is a bicyclic heteroaryl (e.g., 5-hydroxy-2-methylbenzo[d]oxazolyl); B is a monocyclic heterocyclyl (e.g., piperidinyl); L 1 and L 2 Each of them is absent; X is C(R 6 )(for example, CH); Y and Z are N; m and n are 0. In some embodiments, the compounds of formulas (I), (Ia), (Ib), (Ic), and (Id) are compound 147 or its pharmaceutically acceptable salts, solvates, hydrates, tautomers, or stereoisomers.

[0199] In some embodiments of formula (I), A is a bicyclic heteroaryl (e.g., 5-hydroxy-2-methylbenzo[d]thiazolyl); B is a monocyclic heterocyclyl (e.g., piperidinyl); L 1 and L 2 Each of them is absent; X is C(R 6 (For example, CH); Y and Z are N; m and n are 0. In some embodiments, the compounds of formulas (I), (Ia), (Ib), (Ic), and (Id) are compound 148 or its pharmaceutically acceptable salts, solvates, hydrates, tautomers, or stereoisomers.

[0200] In some embodiments of formula (I), A is a bicyclic heteroaryl (e.g., 7-hydroxy-2-methylimidazo[1,2-a]pyridinyl); B is a monocyclic heterocyclyl (e.g., piperidinyl); L 1 and L 2 Each of them is absent; X is C(R 6 (For example, CH); Y and Z are N; m and n are 0. In some embodiments, the compounds of formulas (I), (Ia), (Ib), (Ic), and (Id) are compound 149 or its pharmaceutically acceptable salts, solvates, hydrates, tautomers, or stereoisomers.

[0201] In some embodiments of formula (I), A is a bicyclic heteroaryl (e.g., 3-hydroxy-4,6-dimethylpyrazolo[1,5-a]pyradinyl); B is a monocyclic heterocyclyl (e.g., piperidinyl); L 1 and L 2 Each of them is absent; X is C(R 6 (For example, CH); Y and Z are N; m and n are 0. In some embodiments, the compounds of formulas (I), (Ia), (Ib), (Ic), and (Id) are compound 150 or its pharmaceutically acceptable salts, solvates, hydrates, tautomers, or stereoisomers.

[0202] In some embodiments of formula (I), A is a bicyclic heteroaryl (e.g., 7-hydroxy-2,8-dimethylimidazo[1,2-a]pyridinyl); B is a monocyclic heterocyclyl (e.g., piperidinyl); L 1 and L 2 Each of them is absent; X is C(R 6 (For example, CH); Y and Z are N; m and n are 0. In some embodiments, the compounds of formulas (I), (Ia), (Ib), (Ic), and (Id) are compound 151 or its pharmaceutically acceptable salts, solvates, hydrates, tautomers, or stereoisomers.

[0203] In some embodiments of formula (I), A is a monocyclic heteroaryl (e.g., 1H-imidazolyl); B is a monocyclic heterocyclyl (e.g., piperidinyl); L 1 and L 2 Each of them is absent; X is C(R 6 (For example, CH); Y and Z are N; m and n are 0. In some embodiments, the compounds of formulas (I), (Ia), (Ib), (Ic), and (Id) are compound 152 or its pharmaceutically acceptable salts, solvates, hydrates, tautomers, or stereoisomers.

[0204] In some embodiments of formula (I), A is a bicyclic heteroaryl (for example, (7-Fluoro-6-hydroxy-2-methyl-2H-indazolyl); B is a monocyclic heterocycline (e.g., pyrrolidinyl); L 1 and L 2 Each of the following is absent; X, Y, and Z are N; and m and n are 0. In some embodiments, the compounds of formulas (I), (Ia), (Ib), (Ic), and (Id) are compound 155 or its pharmaceutically acceptable salts, solvates, hydrates, tautomers, or stereoisomers.

[0205] In formula (I), in some embodiments, A is a bicyclic heteroaryl (e.g., 6-hydroxy-2-methyl-2H-indazolyl); B is one R 1 It is a monocyclic heterocycline (e.g., pyrrolidinyl) that is substituted with; L 1 and L 2 Each of them is absent; X is C(R 6 )(for example, CH); Y and Z are N; R 1 -NR B R C And; R B is hydrogen; R Cis a cycloalkyl (e.g., cyclobutanyl); m and n are 0. In some embodiments, the compounds of formulas (I), (Ia), (Ib), (Ic), and (Id) are compounds 156, 157, 262 or their pharmaceutically acceptable salts, solvates, hydrates, tautomers, or stereoisomers.

[0206] In formula (I), in some embodiments, A is a bicyclic heteroaryl (e.g., 6-hydroxy-2-methyl-2H-indazolyl); B is one R 1 It is a monocyclic heterocycline (e.g., pyrrolidinyl) that is substituted with; L 1 and L 2 Each of them is absent; X is C(R 6 )(for example, CH); Y and Z are N; R 1 -NR B R C And; R B is hydrogen; R C is a cycloalkyl (e.g., cyclopropyl); m and n are 0. In some embodiments, the compounds of formulas (I), (Ia), (Ib), (Ic), and (Id) are compound 158 or its pharmaceutically acceptable salts, solvates, hydrates, tautomers, or stereoisomers.

[0207] In some embodiments of formula (I), A is a bicyclic heteroaryl (e.g., 6-hydroxy-2-methyl-2H-indazolyl); B is a monocyclic heterocyclyl (e.g., azetidinyl); L 1 L is nonexistent; 2 is -O-; X is C(R 6 (For example, CH); Y and Z are N; m and n are 0. In some embodiments, the compound of formula (I) is compound 159 or a pharmaceutically acceptable salt, solvate, hydrate, tautomer or stereoisomer thereof.

[0208] In some embodiments of formula (I), A is a bicyclic heteroaryl (e.g., 6-hydroxy-2-methyl-2H-indazolyl); B is a monocyclic heterocyclyl (e.g., decahydrocyclopenta[2,1-b:5,1-b']dipyrrolyl); L 1 and L 2 Each of them is absent; X is C(R 6 (For example, CH); Y and Z are N; m and n are 0. In some embodiments, the compounds of formulas (I), (Ia), (Ib), (Ic), and (Id) are compound 160 or its pharmaceutically acceptable salts, solvates, hydrates, tautomers, or stereoisomers.

[0209] In some embodiments of formula (I), A is a bicyclic heteroaryl (e.g., 6-methoxyisoquinolinyl); B is one R 1 It is a monocyclic heterocycline (e.g., pyrrolidinyl) that is substituted with; L 1 and L 2 Each of them is absent; X is C(R 6 )(for example, CH); Y and Z are N; R 1 -NR B R C (For example, -NH( t Bu)) and m and n are 0. In some embodiments, the compounds of formulas (I), (Ia), (Ib), (Ic), and (Id) are compound 161 or its pharmaceutically acceptable salts, solvates, hydrates, tautomers, or stereoisomers.

[0210] In some embodiments of formula (I), A is a bicyclic heteroaryl (e.g., 6-hydroxy-2-methyl-2H-indazolyl); B is a monocyclic heterocyclyl (e.g., 1,6-diazaspiro[3.4]octanyl); L 1 and L 2 Each of them is absent; X is C(R 6)(for example, CH); Y and Z are N; m and n are 0. In some embodiments, the compounds of formulas (I), (Ia), (Ib), (Ic), and (Id) are compound 162 or its pharmaceutically acceptable salts, solvates, hydrates, tautomers, or stereoisomers.

[0211] In some embodiments of formula (I), A is a bicyclic heteroaryl (e.g., 6-hydroxy-2-methyl-2H-indazolyl); B is a monocyclic heterocyclyl (e.g., 1,6-diazaspiro[3.5]nonanyl); L 1 and L 2 Each of them is absent; X is C(R 6 )(for example, CH); Y and Z are N; m and n are 0. In some embodiments, the compounds of formulas (I), (Ia), (Ib), (Ic), and (Id) are compound 163 or its pharmaceutically acceptable salts, solvates, hydrates, tautomers, or stereoisomers.

[0212] In some embodiments of formula (I), A is a bicyclic heteroaryl (e.g., 6-hydroxy-2-methyl-2H-indazolyl); B is a monocyclic heterocyclyl (e.g., 1,7-diazaspiro[3.5]nonanyl); L 1 and L 2 Each of them is absent; X is C(R 6 (For example, CH); Y and Z are N; m and n are 0. In some embodiments, the compounds of formulas (I), (Ia), (Ib), (Ic), and (Id) are compound 164 or its pharmaceutically acceptable salts, solvates, hydrates, tautomers, or stereoisomers.

[0213] In formula (I), in some embodiments, A is a bicyclic heteroaryl (e.g., 6-hydroxy-2-methyl-2H-indazolyl); B is one R 1 It is a monocyclic heterocycline (e.g., azetidinyl) substituted with; L 1 and L 2Each of them is absent; X is C(R 6 )(for example, CH); Y and Z are N; R 1 -NR B R C (For example, -NH( t Bu)) and m and n are 0. In some embodiments, the compounds of formulas (I), (Ia), (Ib), (Ic), and (Id) are compound 165 or its pharmaceutically acceptable salts, solvates, hydrates, tautomers, or stereoisomers.

[0214] In some embodiments of formula (I), A is a bicyclic heteroaryl (e.g., 6-hydroxyisoquinolinyl); B is one R 1 It is a monocyclic heterocycline (e.g., pyrrolidinyl) that is substituted with; L 1 and L 2 Each of them is absent; X is C(R 6 )(for example, CH); Y and Z are N; R 1 -NR B R C (For example, -NH( t Bu)) and m and n are 0. In some embodiments, the compounds of formulas (I), (Ia), (Ib), (Ic), and (Id) are compound 166 or its pharmaceutically acceptable salts, solvates, hydrates, tautomers, or stereoisomers.

[0215] In formula (I), in some embodiments, A is a bicyclic heteroaryl (e.g., 6-hydroxy-3-methylquinazoline-4(3H)-onyl); B is one R 1 It is a monocyclic heterocycline (e.g., pyrrolidinyl) that is substituted with; L 1 and L 2 Each of them is absent; X is C(R 6 )(for example, CH); Y and Z are N; R 1 -NR B R C (For example, -NH( tBu)) and m and n are 0. In some embodiments, the compounds of formulas (I), (Ia), (Ib), (Ic), and (Id) are compound 167 or its pharmaceutically acceptable salts, solvates, hydrates, tautomers, or stereoisomers.

[0216] In formula (I), in some embodiments, A is a bicyclic heteroaryl (e.g., 6-methoxy-3-methylquinazoline-4(3H)-onyl); B is one R 1 It is a monocyclic heterocycline (e.g., pyrrolidinyl) that is substituted with; L 1 and L 2 Each of them is absent; X is C(R 6 )(for example, CH); Y and Z are N; R 1 -NR B R C (For example, -NH( t Bu)) and m and n are 0. In some embodiments, the compounds of formulas (I), (Ia), (Ib), (Ic), and (Id) are compound 168 or its pharmaceutically acceptable salts, solvates, hydrates, tautomers, or stereoisomers.

[0217] In formula (I), in some embodiments, A is a bicyclic heteroaryl (e.g., 2-methyl-6-hydroxy-2H-indazolyl); B is one R 1 It is a bicyclic heterocycline (e.g., 1,7-diazaspiro[3.5]nonanyl) substituted with; L 1 and L 2 Each of them is absent; X is C(R 6 )(for example, CH); Y and Z are N; R 1 is a C1-C6 alkyl group (e.g., -CH3); m and n are 0. In some embodiments, the compounds of formulas (I), (Ia), (Ib), (Ic), and (Id) are compound 169 or its pharmaceutically acceptable salts, solvates, hydrates, tautomers, or stereoisomers.

[0218] In formula (I), in some embodiments, A is a bicyclic heteroaryl (e.g., 2-methyl-6-hydroxy-2H-indazolyl); B is one R 1 It is a monocyclic heterocycline (e.g., pyrrolidinyl) that is substituted with; L 1 and L 2 Each of them is absent; X is C(R 6 )(for example, CH); Y and Z are N; R 1 -NR B R C (For example, -NH(CH3)); m and n are 0. In some embodiments, the compounds of formulas (I), (Ia), (Ib), (Ic), and (Id) are compounds 170, 172, 263 or their pharmaceutically acceptable salts, solvates, hydrates, tautomers, or stereoisomers.

[0219] In formula (I), in some embodiments, A is a bicyclic heteroaryl (e.g., 2-methyl-6-hydroxy-2H-indazolyl); B is one R 1 It is a monocyclic heterocycline (e.g., pyrrolidinyl) that is substituted with; L 1 and L 2 Each of them is absent; X is C(R 6 )(for example, CH); Y and Z are N; R 1 -NR B R C (For example, -NH( i Pr)) and m and n are 0. In some embodiments, the compounds of formulas (I), (Ia), (Ib), (Ic), and (Id) are compounds 171, 173, 264 or their pharmaceutically acceptable salts, solvates, hydrates, tautomers, or stereoisomers.

[0220] In formula (I), in some embodiments, A is a bicyclic heteroaryl (e.g., 6-hydroxy-2-methyl-4H-chromene-4-onyl); B is one R 1 It is a monocyclic heterocycline (e.g., pyrrolidinyl) that is substituted with; L 1and L 2 Each of them is absent; X is C(R 6 )(for example, CH); Y and Z are N; R 1 -NR B R C (For example, -NH( t Bu)) and m and n are 0. In some embodiments, the compounds of formulas (I), (Ia), (Ib), (Ic), and (Id) are compound 174 or its pharmaceutically acceptable salts, solvates, hydrates, tautomers, or stereoisomers.

[0221] In formula (I), in some embodiments, A is a bicyclic heteroaryl (e.g., 5-hydroxy-2-methylbenzo[d]oxazolyl); B is one R 1 It is a monocyclic heterocycline (e.g., pyrrolidinyl) that is substituted with; L 1 and L 2 Each of them is absent; X is C(R 6 )(for example, CH); Y and Z are N ri;R 1 -NR B R C (For example, -NH( t Bu)) and m and n are 0. In some embodiments, the compounds of formulas (I), (Ia), (Ib), (Ic), and (Id) are compound 175 or its pharmaceutically acceptable salts, solvates, hydrates, tautomers, or stereoisomers.

[0222] In formula (I), in some embodiments, A is a bicyclic heteroaryl (e.g., 5-methoxy-2-methylbenzo[d]thiazolyl); B is one R 1 It is a monocyclic heterocycline (e.g., pyrrolidinyl) that is substituted with; L 1 and L 2 Each of them is absent; X is C(R 6 )(for example, CH); Y and Z are N; R 1 -NR B R C (For example, -NH(t Bu)) and m and n are 0. In some embodiments, the compounds of formulas (I), (Ia), (Ib), (Ic), and (Id) are compound 176 or its pharmaceutically acceptable salts, solvates, hydrates, tautomers, or stereoisomers.

[0223] In some embodiments of formula (I), A is a bicyclic heteroaryl (e.g., 5-methoxy-2-methylbenzo[d]oxazolyl); B is one R 1 It is a monocyclic heterocycline (e.g., pyrrolidinyl) that is substituted with; L 1 and L 2 Each of them is absent; X is C(R 6 )(for example, CH); Y and Z are N; R 1 -NR B R C (For example, -NH( t Bu)) and m and n are 0. In some embodiments, the compounds of formulas (I), (Ia), (Ib), (Ic), and (Id) are compound 177 or its pharmaceutically acceptable salts, solvates, hydrates, tautomers, or stereoisomers.

[0224] In some embodiments of formula (I), A is a bicyclic heteroaryl (e.g., 2-methyl-6-hydroxy-2H-indazolyl); B is a bicyclic heterocyclyl (e.g., 1,6-diazaspiro[3.4]octanyl); L 1 and L 2 Each of them is absent; X is C(R 6 (For example, CH); Y and Z are N; m and n are 0. In some embodiments, the compounds of formulas (I), (Ia), (Ib), (Ic), and (Id) are compound 178 or its pharmaceutically acceptable salts, solvates, hydrates, tautomers, or stereoisomers.

[0225] In formula (I), in some embodiments, A is a bicyclic heteroaryl (e.g., 2-methyl-6-hydroxy-2H-indazolyl); B is one R 1 It is a monocyclic heterocycline (e.g., pyrrolidinyl) that is substituted with; L 1 and L 2 Each of them is absent; X is C(R 6 )(for example, CH); Y and Z are N; R 1 -NR B R C (For example, -NH(Et)); m and n are 0. In some embodiments, the compounds of formulas (I), (Ia), (Ib), (Ic), and (Id) are compounds 179, 180, 265 or their pharmaceutically acceptable salts, solvates, hydrates, tautomers, or stereoisomers.

[0226] In formula (I), in some embodiments, A is a bicyclic heteroaryl (e.g., 2-methyl-6-hydroxy-2H-indazolyl); B is one R 1 It is a bicyclic heterocycline (e.g., 1,6-diazaspiro[3.4]octanyl) substituted with; L 1 and L 2 Each of them is absent; X is C(R 6 )(for example, CH); Y and Z are N; R 1 is a C1-C6 alkyl group (e.g., -CH3); m and n are 0. In some embodiments, the compounds of formulas (I), (Ia), (Ib), (Ic), and (Id) are compound 181 or its pharmaceutically acceptable salts, solvates, hydrates, tautomers, or stereoisomers.

[0227] In some embodiments of formula (I), A is a bicyclic heteroaryl (for example, (2-methyl-6-hydroxy-2H-indazolyl); B is one R 1 It is a monocyclic heterocycline (e.g., pyrrolidinyl) that is substituted with; L 1 and L 2Each of them is absent; X is C(R 6 )(for example, CH); Y and Z are N; R 1 -NR B R C (For example, -NH(CH2CF3)); m and n are 0. In some embodiments, the compounds of formulas (I), (Ia), (Ib), (Ic), and (Id) are compounds 182, 245, 266 or their pharmaceutically acceptable salts, solvates, hydrates, tautomers, or stereoisomers.

[0228] In formula (I), in some embodiments, A is a bicyclic heteroaryl (e.g., 6-fluoro-2-methyl-2H-indazolyl); B is one R 1 It is a monocyclic heterocycline (e.g., pyrrolidinyl) that is substituted with; L 1 and L 2 Each of them is absent; X is C(R 6 )(for example, CH); Y and Z are N; R 1 -NR B R C (For example, -NH( t Bu)) and m and n are 0. In some embodiments, the compounds of formulas (I), (Ia), (Ib), (Ic), and (Id) are compound 183 or its pharmaceutically acceptable salts, solvates, hydrates, tautomers, or stereoisomers.

[0229] In some embodiments of formula (I), A is a bicyclic heteroaryl (e.g., 2-methyl-2H-indazolyl); B is a monocyclic heterocyclyl (e.g., piperidinyl); L 1 and L 2 Each of them is absent; X is C(R 6 )(for example, CH); Y and Z are N; m and n are 0. In some embodiments, the compounds of formulas (I), (Ia), (Ib), (Ic), and (Id) are compound 184 or its pharmaceutically acceptable salts, solvates, hydrates, tautomers, or stereoisomers.

[0230] In some embodiments of formula (I), A is a bicyclic heteroaryl (e.g., 7-fluoro-2-methyl-2H-indazolyl); B is a monocyclic heterocyclyl (e.g., piperidinyl); L 1 and L 2 Each of them is absent; X is C(R 6 (For example, CH); Y and Z are N; m and n are 0. In some embodiments, the compounds of formulas (I), (Ia), (Ib), (Ic), and (Id) are compound 185 or its pharmaceutically acceptable salts, solvates, hydrates, tautomers, or stereoisomers.

[0231] In formula (I), in some embodiments, A is a bicyclic heteroaryl (e.g., 2,8-dimethylimidazo[1,2-b]pyridazinyl); B is one R 1 It is a monocyclic heterocycline (e.g., pyrrolidinyl) that is substituted with; L 1 and L 2 Each of them is absent; X is C(R 6 )(for example, CH); Y and Z are N; R 1 -NR B R C (For example, -NH( t Bu)) and m and n are 0. In some embodiments, the compounds of formulas (I), (Ia), (Ib), (Ic), and (Id) are compound 186 or its pharmaceutically acceptable salts, solvates, hydrates, tautomers, or stereoisomers.

[0232] In formula (I), in some embodiments, A is a bicyclic heteroaryl (e.g., 4,6-dimethylpyrazolo[1,5-a]pyradinyl); B is one R 1 It is a monocyclic heterocycline (e.g., pyrrolidinyl) that is substituted with; L 1 and L 2 Each of them is absent; X is C(R 6 )(for example, CH); Y and Z are N; R 1-NR B R C (For example, -NH( t Bu)) and m and n are 0. In some embodiments, the compounds of formulas (I), (Ia), (Ib), (Ic), and (Id) are compound 187 or its pharmaceutically acceptable salts, solvates, hydrates, tautomers, or stereoisomers.

[0233] In formula (I), in some embodiments, A is a bicyclic heteroaryl (e.g., 2-methyl-6-hydroxy-2H-indazolyl); B is one R 1 It is a monocyclic heterocycline (e.g., pyrrolidinyl) that is substituted with; L 1 and L 2 Each of them is absent; X is C(R 6 )(for example, CH); Y and Z are N; R 1 -NR B R C (For example, -NH(CHCH2OCH2)); m and n are 0. In some embodiments, the compounds of formulas (I), (Ia), (Ib), (Ic), and (Id) are compounds 188, 189, 267 or their pharmaceutically acceptable salts, solvates, hydrates, tautomers, or stereoisomers.

[0234] In formula (I), in some embodiments, A is a bicyclic heteroaryl (e.g., 5-hydroxy-2-methylbenzo[d]thiazolyl); B is one R 1 It is a monocyclic heterocycline (e.g., pyrrolidinyl) that is substituted with; L 1 and L 2 Each of them is absent; X is C(R 6 )(for example, CH); Y and Z are N; R 1 -NR B R C (For example, -NH( tBu)) and m and n are 0. In some embodiments, the compounds of formulas (I), (Ia), (Ib), (Ic), and (Id) are compound 190 or its pharmaceutically acceptable salts, solvates, hydrates, tautomers, or stereoisomers.

[0235] In formula (I), in some embodiments, A is a bicyclic heteroaryl (e.g., 6-hydroxy-2,7-dimethyl-2H-indazolyl); B is one R 1 It is a monocyclic heterocycline (e.g., pyrrolidinyl) that is substituted with; L 1 and L 2 Each of them is absent; X is C(R 6 )(for example, CH); Y and Z are N; R 1 -NR B R C (For example, -NH( t Bu)) and m and n are 0. In some embodiments, the compounds of formulas (I), (Ia), (Ib), (Ic), and (Id) are compound 191 or its pharmaceutically acceptable salts, solvates, hydrates, tautomers, or stereoisomers.

[0236] In formula (I), in some embodiments, A is a bicyclic heteroaryl (e.g., 2-methyl-6-hydroxy-2H-indazolyl); B is one R 1 It is a bicyclic heterocycline (e.g., 1,6-diazaspiro[3.5]nonanyl) substituted with; L 1 and L 2 Each of them is absent; X is C(R 6 )(for example, CH); Y and Z are N; R 1 is a C1-C6 alkyl group (e.g., -CH3); m and n are 0. In some embodiments, the compounds of formulas (I), (Ia), (Ib), (Ic), and (Id) are compound 192 or its pharmaceutically acceptable salts, solvates, hydrates, tautomers, or stereoisomers.

[0237] In some embodiments of formula (I), A is a bicyclic heteroaryl (e.g., 2-methyl-6-fluoro-2H-indazolyl); B is a monocyclic heterocyclyl (e.g., piperidinyl); L 1 and L 2 Each of them is absent; X is C(R 6 (For example, CH); Y and Z are N; m and n are 0. In some embodiments, the compounds of formulas (I), (Ia), (Ib), (Ic), and (Id) are compound 193 or its pharmaceutically acceptable salts, solvates, hydrates, tautomers, or stereoisomers.

[0238] In formula (I), in some embodiments, A is a bicyclic heteroaryl (e.g., 2-methyl-6-hydroxy-2H-indazolyl); B is one R 1 It is a monocyclic heterocycline (e.g., pyrrolidinyl) that is substituted with; L 1 and L 2 Each of them is absent; X is C(R 6 )(for example, CH); Y and Z are N; R 1 -NR B R C (For example, -NH(CH2CHCH2CH2)); m and n is 0. In some embodiments, the compounds of formulas (I), (Ia), (Ib), (Ic), and (Id) are compounds 194, 195, 268 or their pharmaceutically acceptable salts, solvates, hydrates, tautomers, or stereoisomers.

[0239] In some embodiments of formula (I), A is a bicyclic heteroaryl (e.g., 6-(difluoromethyl)-2-methyl-2H-indazolyl); B is a monocyclic heterocyclyl (e.g., piperidinyl); L 1 and L 2 Each of them is absent; X is C(R 6(For example, CH); Y and Z are N; m and n are 0. In some embodiments, the compounds of formulas (I), (Ia), (Ib), (Ic), and (Id) are compound 196 or its pharmaceutically acceptable salts, solvates, hydrates, tautomers, or stereoisomers.

[0240] In formula (I), in some embodiments, A is a bicyclic heteroaryl (e.g., 2-methyl-6-hydroxy-2H-indazolyl); B is one R 1 It is a monocyclic heterocycline (e.g., pyrrolidinyl) that is substituted with; L 1 and L 2 Each of them is absent; X is C(R 6 )(for example, CH); Y and Z are N; R 1 -NR B R C (For example, -NH(cyclopropyl)); m and n are 0. In some embodiments, the compounds of formulas (I), (Ia), (Ib), (Ic), and (Id) are compounds 197, 198, 269 or their pharmaceutically acceptable salts, solvates, hydrates, tautomers, or stereoisomers.

[0241] In some embodiments of formula (I), A is a bicyclic heteroaryl (e.g., 2-methyl-2H-pyrazolo[4,3-b]pyridinyl); B is a monocyclic heterocyclyl (e.g., piperidinyl); L 1 and L 2 Each of them is absent; X is C(R 6 (For example, CH); Y and Z are N; m and n are 0. In some embodiments, the compounds of formulas (I), (Ia), (Ib), (Ic), and (Id) are compound 199 or its pharmaceutically acceptable salts, solvates, hydrates, tautomers, or stereoisomers.

[0242] In some embodiments of formula (I), A is a bicyclic heteroaryl (e.g., 2-methyl-2H-pyrazolo[3,4-c]pyridinyl); B is a monocyclic heterocyclyl (e.g., piperidinyl); L 1 and L 2 Each of them is absent; X is C(R 6 )(for example, CH); Y and Z are N; m and n are 0. In some embodiments, the compounds of formulas (I), (Ia), (Ib), (Ic), and (Id) are compound 200 or its pharmaceutically acceptable salts, solvates, hydrates, tautomers, or stereoisomers.

[0243] In formula (I), in some embodiments, A is a bicyclic heteroaryl (e.g., 2,8-dimethylimidazo[1,2-a]pyridinyl); B is one R 1 It is a monocyclic heterocycline (e.g., pyrrolidinyl) that is substituted with; L 1 and L 2 Each of them is absent; X is C(R 6 )(for example, CH); Y and Z are N; R 1 -NR B R C (For example, -NH( t Bu)) and m and n are 0. In some embodiments, the compounds of formulas (I), (Ia), (Ib), (Ic), and (Id) are compound 201 or its pharmaceutically acceptable salts, solvates, hydrates, tautomers, or stereoisomers.

[0244] In formula (I), in some embodiments, A is a bicyclic heteroaryl (e.g., 6-hydroxy-7-fluoro-2-methyl-2H-indazolyl); B is one R 1 It is a monocyclic heterocycline (e.g., pyrrolidinyl) that is substituted with; L 1 and L 2 Each of them is absent; X is C(R 6 ) (for example, CH) and Y and Z is N; R 1-NR B R C (For example, -NH( t Bu)) and m and n are 0. In some embodiments, the compounds of formulas (I), (Ia), (Ib), (Ic), and (Id) are compound 202 or its pharmaceutically acceptable salts, solvates, hydrates, tautomers, or stereoisomers.

[0245] In formula (I), in some embodiments, A is a bicyclic heteroaryl (e.g., 3-hydroxy-4,6-dimethylpyrazolo[1,5-a]pyradinyl); B is one R 1 It is a monocyclic heterocycline (e.g., pyrrolidinyl) that is substituted with; L 1 and L 2 Each of them is absent; X is C(R 6 )(for example, CH); Y and Z are N; R 1 -NR B R C (For example, -NH( t Bu)) and m and n are 0. In some embodiments, the compounds of formulas (I), (Ia), (Ib), (Ic), and (Id) are compound 203 or its pharmaceutically acceptable salts, solvates, hydrates, tautomers, or stereoisomers.

[0246] In some embodiments of formula (I), A is a bicyclic heteroaryl (e.g., 6-cyano-2-methyl-2H-indazolyl); B is a monocyclic heterocyclyl (e.g., piperidinyl); L 1 and L 2 Each of them is absent; X is C(R 6 )(for example, CH); Y and Z are N; m and n are 0. In some embodiments, the compounds of formulas (I), (Ia), (Ib), (Ic), and (Id) are compound 204 or its pharmaceutically acceptable salts, solvates, hydrates, tautomers, or stereoisomers.

[0247] In some embodiments of formula (I), A is a bicyclic heteroaryl (e.g., 6-fluoro-2-methyl-2H-pyrazolo[4,3-b]pyridinyl); B is a monocyclic heterocyclyl (e.g., piperidinyl); L 1 and L 2 Each of them is absent; X is C(R 6 (For example, CH); Y and Z are N; m and n are 0. In some embodiments, the compounds of formulas (I), (Ia), (Ib), (Ic), and (Id) are compound 205 or its pharmaceutically acceptable salts, solvates, hydrates, tautomers, or stereoisomers.

[0248] In formula (I), in some embodiments, A is a bicyclic heteroaryl (e.g., 2,8-dimethylimidazo[1,2-a]pyrazinyl); B is one R 1 It is a monocyclic heterocycline (e.g., pyrrolidinyl) that is substituted with; L 1 and L 2 Each of them is absent; X is C(R 6 )(for example, CH); Y and Z are N; R 1 -NR B R C (For example, -NH( t Bu)) and m and n are 0. In some embodiments, the compounds of formulas (I), (Ia), (Ib), (Ic), and (Id) are compound 206 or its pharmaceutically acceptable salts, solvates, hydrates, tautomers, or stereoisomers.

[0249] In formula (I), in some embodiments, A is a bicyclic heteroaryl (e.g., 6-fluoro-2-methyl-2H-pyrazolo[4,3-b]pyridinyl); B is one R 1 It is a monocyclic heterocycline (e.g., pyrrolidinyl) that is substituted with; L 1 and L 2 Each of them is absent; X is C(R 6 )(for example, CH); Y and Z are N; R 1 -NRB R C (For example, -NH( t Bu)) and m and n are 0. In some embodiments, the compounds of formulas (I), (Ia), (Ib), (Ic), and (Id) are compound 207 or its pharmaceutically acceptable salts, solvates, hydrates, tautomers, or stereoisomers.

[0250] In formula (I), in some embodiments, A is a bicyclic heteroaryl (e.g., 2,7-dimethyl-2H-pyrazolo[3,4-c]pyridinyl); B is one R 1 It is a monocyclic heterocycline (e.g., pyrrolidinyl) that is substituted with; L 1 and L 2 Each of them is absent; X is C(R 6 )(for example, CH); Y and Z are N; R 1 -NR B R C (For example, -NH( t Bu)) and m and n are 0. In some embodiments, the compounds of formulas (I), (Ia), (Ib), (Ic), and (Id) are compound 208 or its pharmaceutically acceptable salts, solvates, hydrates, tautomers, or stereoisomers.

[0251] In formula (I), in some embodiments, A is a bicyclic heteroaryl (e.g., 5-hydroxy-2-methylbenzo[d]oxazolyl); B is one R 1 It is a monocyclic heterocycline (e.g., pyrrolidinyl) that is substituted with; L 1 and L 2 Each of them is absent; X is C(R 6 )(for example, CH); Y and Z are N; R 1 -NR B R C (For example, -NH( tBu)) and m and n are 0. In some embodiments, the compounds of formulas (I), (Ia), (Ib), (Ic), and (Id) are compounds 209, 210, 270 or their pharmaceutically acceptable salts, solvates, hydrates, tautomers, or stereoisomers.

[0252] In formula (I), in some embodiments, A is a bicyclic heteroaryl (e.g., 5-hydroxy-2-methylbenzo[d]oxazolyl); B is one R 1 It is a monocyclic heterocycline (e.g., pyrrolidinyl) that is substituted with; L 1 and L 2 Each of them is absent; X is C(R 6 )(for example, CH); Y and Z are N; R 1 -NR B R C (For example, -NH(cyclopropyl)); m and n are 0. In some embodiments, the compounds of formulas (I), (Ia), (Ib), (Ic), and (Id) are compounds 211, 212, 271 or their pharmaceutically acceptable salts, solvates, hydrates, tautomers, or stereoisomers.

[0253] In some embodiments of formula (I), A is a bicyclic heteroaryl (e.g., 5-methoxy-2-methylbenzo[d]thiazolyl); B is a monocyclic heterocyclyl (e.g., piperidinyl); L 1 and L 2 Each of them is absent; X is C(R 6 )(for example, CH); Y and Z are N; m and n are 0. In some embodiments, the compounds of formulas (I), (Ia), (Ib), (Ic), and (Id) are compound 213 or its pharmaceutically acceptable salts, solvates, hydrates, tautomers, or stereoisomers.

[0254] In formula (I), in some embodiments, A is a bicyclic heteroaryl (e.g., 5-hydroxy-2,4-dimethylbenzo[d]oxazolyl); B is one R1 It is a monocyclic heterocycline (e.g., pyrrolidinyl) that is substituted with; L 1 and L 2 Each of them is absent; X is C(R 6 )(for example, CH); Y and Z are N; R 1 -NR B R C (For example, -NH( t -Bu)) and m and n are 0. In some embodiments, the compounds of formula (I), (Ia), (Ib), (Ic), and (Id) are compounds 214, 215, 272 or their pharmaceutically acceptable salts, solvates, hydrates, tautomers, or stereoisomers.

[0255] In formula (I), in some embodiments, A is a bicyclic heteroaryl (e.g., 5-hydroxy-2,4-dimethylbenzo[d]oxazolyl); B is one R 1 It is a monocyclic heterocycline (e.g., pyrrolidinyl) that is substituted with; L 1 and L 2 Each of them is absent; X is C(R 6 )(for example, CH); Y and Z are N; R 1 -NR B R C (For example, -NH(cyclopropyl)); m and n are 0. In some embodiments, the compounds of formulas (I), (Ia), (Ib), (Ic), and (Id) are compounds 216, 217, 273 or their pharmaceutically acceptable salts, solvates, hydrates, tautomers, or stereoisomers.

[0256] In formula (I), in some embodiments, A is a bicyclic heteroaryl (e.g., 6-hydroxy-2-methyl-2H-indazolyl); B is one R 1 It is a monocyclic heterocycline (e.g., pyrrolidinyl) that is substituted with; L 1 and L 2 Each of them is absent; Y is C(R 6)(for example, CH); X and Z are N; R 1 -NR B R C (For example, -NH( t -Bu)) and m and n are 0. In some embodiments, the compounds of formula (I), (Ia), (Ib), and (Id) are compound 218 or its pharmaceutically acceptable salts, solvates, hydrates, tautomers, or stereoisomers.

[0257] In formula (I), in some embodiments, A is a bicyclic heteroaryl (e.g., 6-hydroxy-2-methyl-2H-indazolyl); B is one R 1 It is a monocyclic heterocycline (e.g., pyrrolidinyl) that is substituted with; L 1 and L 2 Each of them is absent; X is C(R 6 )(for example, CH); Y and Z are N; R 1 -NR B R C (For example, -NH(C(CH3)CH2CH2); m and n are 0. In some embodiments, the compounds of formulas (I), (Ia), (Ib), (Ic), and (Id) are compounds 219, 220, 221 or their pharmaceutically acceptable salts, solvates, hydrates, tautomers, or stereoisomers.

[0258] In formula (I), in some embodiments, A is a bicyclic heteroaryl (e.g., 6-hydroxy-7-fluoro-2-methyl-2H-indazolyl); B is one R 1 It is a monocyclic heterocycline (e.g., pyrrolidinyl) that is substituted with; L 1 and L 2 Each of them is absent; X is C(R 6 )(for example, CH); Y and Z are N; R 1 -NR B R C(For example, -NH(C(CH3)CH2CH2); m and n are 0. In some embodiments, the compounds of formulas (I), (Ia), (Ib), (Ic), and (Id) are compounds 222, 223, 274 or their pharmaceutically acceptable salts, solvates, hydrates, tautomers, or stereoisomers.

[0259] In formula (I), in some embodiments, A is a bicyclic heteroaryl (e.g., 6-hydroxy-2,7-dimethyl-2H-indazolyl); B is one R 1 It is a monocyclic heterocycline (e.g., pyrrolidinyl) that is substituted with; L 1 and L 2 Each of them is absent; X is C(R 6 )(for example, CH); Y and Z are N; R 1 -NR B R C (For example, -NH(C(CH3)CH2CH2); m and n are 0. In some embodiments, the compounds of formulas (I), (Ia), (Ib), (Ic), and (Id) are compounds 224, 225, 226 or their pharmaceutically acceptable salts, solvates, hydrates, tautomers, or stereoisomers.

[0260] In formula (I), in some embodiments, A is a bicyclic heteroaryl (e.g., 5-hydroxy-2-methylbenzo[d]oxazolyl); B is one R 1 It is a monocyclic heterocycline (e.g., pyrrolidinyl) that is substituted with; L 1 and L 2 Each of them is absent; X is C(R 6 )(for example, CH); Y and Z are N; R 1 -NR B R C(For example, -NH(cyclobutyl)); m and n are 0. In some embodiments, the compounds of formulas (I), (Ia), (Ib), (Ic), and (Id) are compounds 228, 229, 230 or their pharmaceutically acceptable salts, solvates, hydrates, tautomers, or stereoisomers.

[0261] In formula (I), in some embodiments, A is a bicyclic heteroaryl (e.g., 5-hydroxy-2-methylbenzo[d]oxazolyl); B is one R 1 It is a monocyclic heterocycline (e.g., pyrrolidinyl) that is substituted with; L 1 and L 2 Each of them is absent; X is C(R 6 )(for example, CH); Y and Z are N ri;R 1 -NR B R C (For example, -NH(isopropyl)); m and n are 0. In some embodiments, the compounds of formulas (I), (Ia), (Ib), (Ic), and (Id) are compounds 231, 232, 233 or their pharmaceutically acceptable salts, solvates, hydrates, tautomers, or stereoisomers.

[0262] In formula (I), in some embodiments, A is a bicyclic heteroaryl (e.g., 5-hydroxy-2-methylbenzo[d]oxazolyl); B is one R 1 It is a monocyclic heterocycline (e.g., pyrrolidinyl) that is substituted with; L 1 and L 2 Each of them is absent; X is C(R 6 )(for example, CH); Y and Z are N; R 1 -NR B R C (For example, -NH2); m and n are 0. In some embodiments, the compounds of formulas (I), (Ia), (Ib), (Ic), and (Id) are compound 234 or its pharmaceutically acceptable salts, solvates, hydrates, tautomers, or stereoisomers.

[0263] In formula (I), in some embodiments, A is a bicyclic heteroaryl (e.g., 5-hydroxy-2,4-dimethylbenzo[d]oxazolyl); B is one R 1 It is a monocyclic heterocycline (e.g., pyrrolidinyl) that is substituted with; L 1 and L 2 Each of them is absent; X is C(R 6 )(for example, CH); Y and Z are N; R 1 -NR B R C (For example, -NH(cyclobutyl)); m and n are 0. In some embodiments, the compounds of formulas (I), (Ia), (Ib), (Ic), and (Id) are compounds 235, 236, 237 or their pharmaceutically acceptable salts, solvates, hydrates, tautomers, or stereoisomers.

[0264] In formula (I), in some embodiments, A is a bicyclic heteroaryl (e.g., 6-hydroxy-7-fluoro-2-methyl-2H-indazolyl); B is one R 1 It is a monocyclic heterocycline (e.g., pyrrolidinyl) that is substituted with; L 1 and L 2 Each of them is absent; X is C(R 6 )(for example, CH); Y and Z are N; R 1 -NR B R C (For example, -NH2); m and n are 0. In some embodiments, the compounds of formulas (I), (Ia), (Ib), (Ic), and (Id) are compound 238 or its pharmaceutically acceptable salts, solvates, hydrates, tautomers, or stereoisomers.

[0265] In some embodiments of formula (I), A is a bicyclic heteroaryl (e.g., 6-hydroxy-7-fluoro-2-methyl-2H-indazolyl); B is a monocyclic heterocyclyl (e.g., piperidinyl); L1 and L 2 Each of them is absent; X and Z are C(R 6 (For example, CH); Y is N; m and n are 0. In some embodiments, the compounds of formulas (I), (Ia), (Ib), and (Id) are compound 241 or its pharmaceutically acceptable salts, solvates, hydrates, tautomers, or stereoisomers.

[0266] In formula (I), in some embodiments, A is a bicyclic heteroaryl (e.g., 6-hydroxy-2-methyl-2H-indazolyl); B is one R 1 It is a monocyclic heterocycline (e.g., pyrrolidinyl) that is substituted with; L 1 and L 2 Each of them is absent; X is C(R 6 )(for example, CH); Y and Z are N; R 1 -NR B R C (For example, -NH(CH2CF3)); m and n are 0. In some embodiments, the compounds of formulas (I), (Ia), (Ib), (Ic), and (Id) are compound 245 or its pharmaceutically acceptable salts, solvates, hydrates, tautomers, or stereoisomers.

[0267] In some embodiments of formula (I), A is a bicyclic heteroaryl (for example, (6-hydroxy-2-methyl-2H-indazolyl); B is one R 1 It is a monocyclic heterocycline (e.g., pyrrolidinyl) that is substituted with; L 1 and L 2 Each of them is absent; X is C(R 6 )(for example, CH); Y and Z are N; R 1 -NR B R C(For example, -NH(CHCH2CHFCH2)); m and n are 0. In some embodiments, the compounds of formulas (I), (Ia), (Ib), (Ic), and (Id) are compounds 246, 247, 277 or their pharmaceutically acceptable salts, solvates, hydrates, tautomers, or stereoisomers.

[0268] In formula (I), in some embodiments, A is a bicyclic heteroaryl (e.g., 2,7-dimethyl-2H-pyrazolo[4,3-b]pyridinyl); B is one R 1 It is a monocyclic heterocycline (e.g., pyrrolidinyl) that is substituted with; L 1 and L 2 Each of them is absent; X and Z are C(R 6 )(for example, CH); Y is N; R 1 -NR B R C (For example, -NH( t- Bu)) and m and n are 0. In some embodiments, the compounds of formulas (I), (Ia), (Ib), (Ic), and (Id) are compound 248 or its pharmaceutically acceptable salts, solvates, hydrates, tautomers, or stereoisomers.

[0269] In formula (I), in some embodiments, A is a bicyclic heteroaryl (e.g., 6-hydroxy-2,7-dimethyl-2H-indazolyl); B is one R 1 It is a monocyclic heterocycline (e.g., pyrrolidinyl) that is substituted with; L 1 and L 2 Each of them is absent; X and Z are C(R 6 )(for example, CH); Y is N; R 1 -NR B R C (For example, -NH( t-Bu)) and m and n are 0. In some embodiments, the compounds of formulas (I), (Ia), (Ib), (Ic), and (Id) are compounds 249, 250, 275 or their pharmaceutically acceptable salts, solvates, hydrates, tautomers, or stereoisomers.

[0270] In formula (I), in some embodiments, A is a bicyclic heteroaryl (e.g., 6-methoxy-7-methyl-2H-indazolyl); B is one R 1 It is a monocyclic heterocycline (e.g., pyrrolidinyl) that is substituted with; L 1 and L 2 Each of them is absent; X and Z are C(R 6 )(for example, CH); Y is N; R 1 -NR B R C (For example, -NH( t- Bu)) and m and n are 0. In some embodiments, the compounds of formulas (I), (Ia), (Ib), (Ic), and (Id) are compound 251 or its pharmaceutically acceptable salts, solvates, hydrates, tautomers, or stereoisomers.

[0271] In formula (I), in some embodiments, A is a bicyclic heteroaryl (e.g., 3-hydroxy-4,6-dimethylpyrazolo[1,5-a]pyradinyl); B is one R 1 It is a monocyclic heterocycline (e.g., pyrrolidinyl) that is substituted with; L 1 and L 2 Each of them is absent; X and Z are C(R 6 )(for example, CH); Y is N; R 1 -NR B R C (For example, -NH(cyclopropyl)); m and n are 0. In some embodiments, the compounds of formulas (I), (Ia), (Ib), (Ic), and (Id) are compound 252 or its pharmaceutically acceptable salts, solvates, hydrates, tautomers, or stereoisomers.

[0272] In formula (I), in some embodiments, A is a bicyclic heteroaryl (e.g., 5-hydroxy-4-fluoro-2-methylbenzo[d]oxazolyl); B is one R 1 It is a monocyclic heterocycline (e.g., pyrrolidinyl) that is substituted with; L 1 and L 2 Each of them is absent; X and Z are C(R 6 )(for example, CH); Y is N; R 1 -NR B R C (For example, -NH(cyclopropyl)); m and n are 0. In some embodiments, formulas (I), (Ia), (Ib) The compounds (Ic) and (Id) are compounds 253, 254, 278 or their pharmaceutically acceptable salts, solvates, hydrates, tautomers, or stereoisomers.

[0273] In formula (I), in some embodiments, A is a bicyclic heteroaryl (e.g., 5-hydroxy-4-fluoro-2-methylbenzo[d]oxazolyl); B is one R 1 It is a monocyclic heterocycline (e.g., pyrrolidinyl) that is substituted with; L 1 and L 2 Each of them is absent; X and Z are C(R 6 )(for example, CH); Y is N; R 1 -NR B R C (For example, -NH( t- Bu)) and m and n are 0. In some embodiments, the compounds of formulas (I), (Ia), (Ib), (Ic), and (Id) are compounds 255, 256, 279 or their pharmaceutically acceptable salts, solvates, hydrates, tautomers, or stereoisomers.

[0274] In formula (I), in some embodiments, A is a bicyclic heteroaryl (e.g., 5-hydroxy-2-methylbenzo[d]oxazolyl); B is one R1 It is a monocyclic heterocycline (e.g., pyrrolidinyl) that is substituted with; L 1 and L 2 Each of them is absent; X is C(R 6 )(for example, CH); Y and Z are N; R 1 -NR B R C (For example, -NH(C(CH3)CH2CH2)); m and n are 0. In some embodiments, the compounds of formulas (I), (Ia), (Ib), (Ic), and (Id) are compounds 257, 258, 280 or their pharmaceutically acceptable salts, solvates, hydrates, tautomers, or stereoisomers.

[0275] In formula (I), in some embodiments, A is a bicyclic heteroaryl (e.g., 6-hydroxy-2,7-dimethyl-2H-indazolyl); B is one R 1 It is a monocyclic heterocycline (e.g., pyrrolidinyl) that is substituted with; L 1 and L 2 Each of them is absent; X is C(R 6 )(for example, CH); Y and Z are N; R 1 -NR B R C (For example, -NH(cyclopropyl)); m and n are 0. In some embodiments, the compounds of formulas (I), (Ia), (Ib), (Ic), and (Id) are compounds 259, 260, 281 or their pharmaceutically acceptable salts, solvates, hydrates, tautomers, or stereoisomers.

[0276] As is generally stated for equation (II), W and Z are independently N or C(R 6 ) may be. In some embodiments, W is C(R 6 )(for example, CH). In some embodiments, W is N. In some embodiments, Z is C(R 6)(for example, CH). In some embodiments, Z is N. In some embodiments, W and Z are N independently. In some embodiments, one of W and Z is N independently, and the other of W and Z is C(R 6 )(For example, CH).

[0277] In some embodiments, the compound of formula (II) is formula (II-a): [ka] (In the formula, A and B are each independently of one or more R 1 A cycloalkyl, heterocyclyl, aryl, or heteroaryl which is optionally substituted; L 1 and L 2 These are, independently, absent, C1-C6 alkylene, C1-C6 heteroalkylene, -O-, -C(O)-, -N(R) 4 )-,-N(R 4 )C(O)-, -C(O) N(R 4 )-,-N(R 4 )C(O)N(R 4 )- or C1~C6 alkylene-N(R 4 )C(O)N(R 4 )- and each alkylene and heteroalkylene is one or more R 5 It is replaced by arbitrary selection in 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 or -S(O) x R D Each alkyl, alkylene, alkenyl, alkynyl, heteroalkyl, haloalkyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl is one or more R 7 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. 7 It is replaced by arbitrary selection in each R 2 and R 3 These are independently C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 heteroalkyl, C1-C6 haloalkyl, 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 or -S(O) x R D and; each R 4 R is independently hydrogen, C1-C6 alkyl, or C1-C6 haloalkyl; each R 5 C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 heteroalkyl, C1-C6 haloalkyl, halo, cyano, oxo, -OR A or -NR B R C and; each R 7 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, -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 or -S(O) x R D Each of alkyl, alkenyl, alkynyl, heteroalkyl, haloalkyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl is one or more R 8 It is replaced by arbitrary selection in 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; each R B and R C These are independently hydrogen, C1-C6 alkyl, C1-C6 heteroalkyl, cycloalkyl, heterocyclyl, or -OR A is; or R B and R C Along with the atoms to which they are bonded, one or more R 9 They form a 3- to 7-membered heterocyclyl ring which is optionally substituted; each R D 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; each R 8 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 9 This refers to C1-C6 alkyl, halo, cyano, oxo, or -OR A1 and; each R A1 (where is hydrogen or a C1-C6 alkyl group; m and n are independently 0, 1, or 2; and x is 0, 1, or 2) The compound or its pharmaceutically acceptable salts, solvates, hydrates, tautomers, or stereoisomers.

[0278] In some embodiments, the compound of formula (II) is formula (II-b): [ka] (In the formula, A and B are each independently of one or more R 1 The cycloalkyl, heterocyclyl, aryl, or heteroaryl elements are optionally substituted; W and Z are N or C(R) 6 ) and at least one of W and Z is 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 or -S(O) x R D Each alkyl, alkylene, alkenyl, alkynyl, heteroalkyl, haloalkyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl is one or more R 7 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. 7 It is replaced by arbitrary selection in each R 2 and R 3These are independently C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 heteroalkyl, C1-C6 haloalkyl, 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 or -S(O) x R D And each R 6 These are independently hydrogen, halo, C1-C6 alkyl, C1-C6 haloalkyl, or -OR A and; each R 7 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, -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 or -S(O) x R D Each of alkyl, alkenyl, alkynyl, heteroalkyl, haloalkyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl is one or more R 8 It is replaced by arbitrary selection in 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; each R B and R C These are independently hydrogen, C1-C6 alkyl, C1-C6 heteroalkyl, cycloalkyl, heterocyclyl, or -ORA is; or R B and R C Along with the atoms to which they are bonded, one or more R 9 They form a 3- to 7-membered heterocyclyl ring which is optionally substituted; each R D 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; each R 8 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 9 This refers to C1-C6 alkyl, halo, cyano, oxo, or -OR A1 and; each R A1 (where is hydrogen or a C1-C6 alkyl group; m and n are independently 0, 1, or 2; and x is 0, 1, or 2) The compound or its pharmaceutically acceptable salts, solvates, hydrates, tautomers, or stereoisomers.

[0279] In some embodiments, the compound of formula (II) is formula (II-c): [ka] (In the formula, A and B are each independently of one or more R 1 The cycloalkyl, heterocyclyl, aryl, or heteroaryl elements are optionally substituted; W and Z are N or C(R) 6 ) and at least one of W and Z is N; L 1a is absent or C1-C6 alkylene; each R 1These 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 or -S(O) x R D Each alkyl, alkylene, alkenyl, alkynyl, heteroalkyl, haloalkyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl is one or more R 7 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. 7 It is replaced by arbitrary selection in each R 2 and R 3 These are independently C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 heteroalkyl, C1-C6 haloalkyl, 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 or -S(O) x R D And each R 6 These are independently hydrogen, halo, C1-C6 alkyl, C1-C6 haloalkyl, or -OR A and; each R 7These are independently C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 heteroalkyl, C1-C6 haloalkyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, halo, cyano, oxo, -OR A , -NR B R C , -NR B C(O)R D -NO2, -C(O)NR B R C , -C(O)R D , -C(O)OR D or -S(O) x R D Each of alkyl, alkenyl, alkynyl, heteroalkyl, haloalkyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl is one or more R 8 It is replaced by arbitrary selection in 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; each R B and R C These are independently hydrogen, C1-C6 alkyl, C1-C6 heteroalkyl, cycloalkyl, heterocyclyl, or -OR A is; or R B and R C Along with the atoms to which they are bonded, one or more R 9 They form a 3- to 7-membered heterocyclyl ring which is optionally substituted; each R D 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; each R 8These are independently C1-C6 alkyl, C1-C6 heteroalkyl, C1-C6 haloalkyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, halo, cyano, oxo, or -OR A and; each R 9 This refers to C1-C6 alkyl, halo, cyano, oxo, or -OR A1 and; each R A1 (where is hydrogen or a C1-C6 alkyl group; m and n are independently 0, 1, or 2; and x is 0, 1, or 2) The compound or its pharmaceutically acceptable salts, solvates, hydrates, tautomers, or stereoisomers.

[0280] In some embodiments, the compound of formula (II) is selected from the compounds in Table 2 or their pharmaceutically acceptable salts, solvates, hydrates, tautomers, or stereoisomers.

[0281] [Table 29]

[0282] In some embodiments of formula (II), A is a monocyclic heteroaryl (e.g., 1H-pyrazolyl); B is a monocyclic heterocyclyl (e.g., piperadyl); L 1 is -N(R 4 )C(O)N(R 4 )-(for example, -NHC(O)N(CH3)-) and L 2 is absent; W and Z are N; and m and n are 0. In some embodiments, the compounds of formulas (II), (II-a), (II-b), and (II-c) are compound 110 or its pharmaceutically acceptable salts, solvates, hydrates, tautomers, or stereoisomers.

[0283] In some embodiments of formula (II), A is a monocyclic heteroaryl (e.g., 1H-pyrazolyl); B is a monocyclic heterocyclyl (e.g., piperadyl); L 1 is -N(R 4)C(O)N(R 4 )-(for example, -NHC(O)NH-) and L 2 is absent; W and Z are N; m and n are 0. In some embodiments, the compounds of formulas (II), (II-a), (II-b), and (II-c) are compound 111 or its pharmaceutically acceptable salts, solvates, hydrates, tautomers, or stereoisomers.

[0284] In some embodiments of formula (II), A is a monocyclic heteroaryl (e.g., 1H-pyrazolyl); B is a monocyclic heterocyclyl (e.g., piperadyl); L 1 C1~C6 alkylene-N(R 4 )C(O)N(R 4 )-(for example, -CH2NHC(O)NH-) and L 2 is absent; W and Z are N; m and n are 0. In some embodiments, the compounds of formulas (II), (II-a), (II-b), and (II-c) are compound 112 or its pharmaceutically acceptable salts, solvates, hydrates, tautomers, or stereoisomers.

[0285] Pharmaceutical compositions, kits, and administrations The present invention provides pharmaceutical compositions comprising a compound of formula (I) or (II), for example, a compound of formula (I) or (II), or a pharmaceutically acceptable salt, solvate, hydrate, tautomer or stereoisomer described herein, and optionally a pharmaceutically acceptable excipient. In certain embodiments, the pharmaceutical compositions described herein comprise a compound of formula (I) or (II) or a pharmaceutically acceptable salt thereof and optionally a pharmaceutically acceptable excipient. In certain embodiments, a compound of formula (I) or (II) 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.

[0286] 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) or (II) ("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.

[0287] 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.

[0288] 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.

[0289] 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.

[0290] 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.

[0291] 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, for example, a solution in 1,3-butanediol. Acceptable vehicles and solvents include water, Ringer's solution, and isotonic sodium chloride solution. Furthermore, sterile fixative oils have traditionally been used as solvents or suspension media.

[0292] 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.

[0293] 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.

[0294] For use in the eyes, the pharmaceutically acceptable compositions provided may be formulated as a micronized suspension or in an ointment such as petrolatum.

[0295] 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.

[0296] 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.

[0297] 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.

[0298] 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 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, multiple doses (e.g., two, three, four, five, six, seven, eight, nine, ten, eleven, twelve, thirteen, fourteen or more doses) are used to deliver the desired dose. It is possible to reach it.

[0299] 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.

[0300] In certain embodiments, the compound of formula (I) or (II) 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.

[0301] 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.

[0302] 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.

[0303] 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.

[0304] 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.

[0305] 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. The kits provided include the pharmaceutical composition or compound of the present invention and a container (e.g.) For example, this may include vials, ampoules, bottles, syringes and / or dispenser packages or other suitable containers. In some embodiments, the provided kit may optionally further include 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.

[0306] 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.

[0307] How to use Compounds useful for modulating splicing are described herein. In some embodiments, compounds of formula (I) or (II) 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) or (II) 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.

[0308] 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) or (II). 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).

[0309] 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, comprising providing a compound of formula (I) or (II). 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, the method for modifying the target (e.g., precursor RNA, e.g., premRNA or obtained mRNA) results in, for example, the absence of a splice site compared to a reference (e.g., the absence of a compound of formula (I) or (II) or healthy or diseased cells or tissue). This includes suppression of splicing or enhancement of 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).

[0310] 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、CALCA、CALCOCO2、CAMK1D、CAMKK1、CAPN3、CAPN9、CAPSL、CARD11、CARKD、CASZ1、CAT、CBLB、CBX1、CBX3、CCDC102B、CCDC11、CCDC15、CCDC18、CCDC5、CCDC81、CCDC131、CCDC146、CD4、CD274、CD1B、CDC14A、CDC16、CDC2L5、CDC42BPB、CDCA8、CDH10、CDH11、CDH24、CDH8、CDH9、CDK5RAP2、CDK6、CDK8、CDK11B、CD33、CD46、CDH1、CDH23、CDK6、CDK11B、CDK13、CEBPZ、CEL、CELSR3、CENPA、CENPI、CENPT、CENTB2、CENTG2、CEP110、CEP170、CEP192、CETP、CFB、CFTR、CFH、CGN、CGNL1、CHAF1A、CHD9、CHIC2、CHL1、CHN1、CHM、CLEC16A、CL1C2、CLCN1、CLINT1、CLK1、CLPB、CLPTM1、CMIP、CMYA5、CNGA3、CNOT1、CNOT7、CNTN6、COG3、COL11A1、COL11A2、COL12A1、COL14A1、COL15A1、COL17A1、C、 OL19A1、COL1A1、COL1A2、COL2A1、COL3A1、COL4A1、COL4A2、COL4A5、COL4A6 、COL5A2、COL6A1、COL7A1、COL9A1、COL9A2、COL22A1、COL24A1、COL25A1、COL 29A1、COLQ、COMTD1、COPA、COPB2、COPS7B、COPZ2、CPSF2、CPXM2、CR1、CRBN、 CRYZ、CREBBP、CRKRS、CSE1L、CSTB、CSTF3、CT45-6、CTNNB1、CUBN、CUL4B、CUL 5、CXorf41、CXXC1、CYBB、CYFIP2、CYP3A4、CYP3A43、CYP3A5、CYP4F2、CYP4F 3、CYP17、CYP19、CYP24A1、CYP27A1、DAB1、DAZ2、DCBLD1、DCC、DCTN3、DCUN1D 4, DDA1, DDEF1, DDX1, DDX24, DDX4, DENND2D, DEPDC2, DES, DGAT2, DHFR, DHRS7, DHRS9, DHX8, DIP2A, DMD, DMTF1, DNAH3, DNAH8, DNAI1, DNAJA4, DNAJC13 DNAJC7、DNMT1、DNTTIP2、DOCK4、DOCK5、DOCK10、DOCK11、DOT1L、DPP3、DPP4 、DPY19L2P2、DR1、DSCC1、DVL3、DUX4、DYNC1H1、DYSF、E2F1、E2F3、E2F8、E4F1 、EBF1、EBF3、ECM2、EDEM3、EFCAB3、EFCAB4B、EFNA4、EFTUD2、EGFR、EIF3A、E LA1、ELA2A、ELF2、ELF3、ELF4、EMCN、EMD、EML5、ENO3、ENPP3、EP300、EPAS1、E PB41L5、EPHA3、EPHA4、EPHB1、EPHB2、EPHB3、EPS15、ERBB4、ERCC1、ERCC8、E RGIC3、ERMN、ERMP1、ERN1、ERN2、ESR1、ESRRG、ETS2、ETV3、ETV4、ETV5、ETV6、 EVC2, EWSR1, EXO1, EXOC4, F3, F11, F13A1, F5, F7, F8, FAH, FAM13A1, FAM13B1, FAM13C1, FAM134A, FAM161A, FAM176B, FAM184A, FAM19A1, FAM20A, FAM23BFAM65C, FANCA, FANCC, FANCG, FANCM, FANK1, FAR2, FBN1, FBXO15, FBXO18, FBXO38, FCGBP, FECH, FEZ2, FGA, FGD6, FGFR2, FGFR1OP, FGFR1OP2, FGFR2, FGG 、FGR、FIX、FKBP3、FLI1、FLJ35848、FLJ36070、FLNA、FN1、FNBP1L、FOLH1、FO SL1、FOSL2、FOXK1、FOXM1、FOXO1、FOXP4、FRAS1、FUT9、FXN、FZD3、FZD6、GAB1 GABPA, GALC, GALNT3, GAPDH, GART, GAS2L3, GATA3, GATAD2A, GBA, GBGT1, GCG, GCGR, GKK, GFI1, GFM1, GH1, GHR, GHV, GJA1, GLA, GLT8D1, GNA11, GNAQ, GN AS、GNB5、GOLGB1、GOLT1A、GOLT1B、GPATCH1、GPR158、GPR160、GPX4、GRAMD3 、GRHL1、GRHL2、GRHPR、GRIA1、GRIA3、GRIA4、GRIN2B、GRM3、GRM4、GRN、GSDMB 、GSTCD、GSTO2、GTF2I、GTPBP4、HADHA、HAND2、HBA2、HBB、HCK、HDAC3、HDAC5 、HDX、HEPACAM2、HERC1、HES7、HEXA、HEXB、HHEX、HIPK3、HLA-DPB1、HLA-G、HL CS、HLTF、HMBS、HMGA1、HMGCL、HNF1A、HNF1B、HNF4A、HNF4G、HNRNPH1、HOXC1 0、HP1BP3、HPGD、HPRT1、HPRT2、HSF1、HSF4、HSF2BP、HSPA9、HSPG2、HTT、HXA、 ICA1、IDH1、IDS、IFI44L、IKBKAP、IKZF1、IKZF3、IL1R2、IL5RA、IL7RA、IMMT 、INPP5D、INSR、INTS3、INTU、IP04、IP08、IQGAP2、IRF2、IRF4、IRF8、IRX3、IS L1、ISL2、ITFG1、ITGA6、ITGAL、ITGB1、ITGB2、1TGB3、ITGB4、ITIH1、ITPR2、 IWS1、JAK1、JAK2、JAG1、JMJD1C、JPH3、KALRN、KAT6A、KATNAL2、KCNN2、KCNT、2、KDM2A、KIAA0256、KIAA0528、KIAA0564、KIAA0586、KIAA1033、KIAA1166、 KIAA1219、KIAA1409、KIAA1622、KIAA1787、KIF3B、KIF15、KIF16B、KIF5A、KI F5B, KIF9, KIN, KIR2DL5B, KIR3DL2, KIR3DL3, KIT, KLF3, KLF5, KLF7, KLF10, KLF12, KLF16, KLHL20, KLK12, KLKB1, KMT2A, KMT2B, KPNA5, KRAS, KREMEN1 KRIT1、KRT5、KRTCAP2、KYNU、L1CAM、L3MBTL、L3MBTL2、LACE1、LAMA1、LAMA2 、LAMA3、LAMB1、LARP7、LDLR、LEF1、LENG1、LGALS3、LGMN、LHCGR、LHX3、LHX6、 LIMCH1、LIMK2、LIN28B、LIN54、LMBRD1、LMBRD2、LMLN、LMNA、LMO2、LMO7、LO C389634、LOC390110、LPA、LPCAT2、LPL、LRP4、LRPPRC、LRRK2、LRRC19、LRRC4 2、LRWD1、LUM、LVRN、LYN、LYST、MADD、MAGI1、MAGT1、MALT1、MAP2K1、MAP4K4 、MAPK8IP3、MAPK9、MAPT、MARC1、MARCH5、MATN2、MBD3、MCF2L2、MCM6、MDGA2、 MDM4、ASXL1、FUS、SPR54、MECOM、MEF2C、MEF2D、MEGF10、MEGF11、MEMO1、MET 、MGA、MGAM、MGAT4A、MGAT5、MGC16169、MGC34774、MKKS、MIB1、MIER2、MITF、M KL2, MLANA, MLH1, MLL5, MLX, MME, MPDZ, MPI, MRAP2, MRPL11, MRPL39, MRPS28, MRPS35, MS4A13, MSH2, MSH3, MSMB, MST1R, MTDH, MTERF3, MTF1, MTF2, MTIF 2、MTHFR、MUC2、MUT、MVK、MYB、MYBL2、MYC、MYCBP2、MYH2、MYRF、MYT1、MY019、 MY03A、MY09B、MYOM2、MYOM3、NAG、NARG1、NARG2、NCOA1、NDC80、NDFIP2、NEB、NEDD4、NEK1、NEK5、ΝΕΚ11、NF1、NF2、NFATC2、NFE2L2、NFIA、NFIB、NFIX、NFKB1、NFKB2、NFKBIL2、NFRKB、NFYA、NFYB、NIPA2、NKAIN2、NKAP、NLRC3、NLRC5、NLRP3、NLRP7、NLRP8、NLRP13、NME1、NME1- NME2、NME2、NME7、NOL10、NOP561、NOS1、NOS2A、NOTCH1、NPAS4、NPM1、NR1D1、NR1H3、NR1H4、NR4A3 、NR5A1、NRXN1、NSMAF、NSMCE2、NT5C、NT5C2、NT5C3、NUBP1、NUBPL、NUDT5、NUMA1、NUP88、NUP98、N、 UP160、NUPL1、OAT、OAZ1、OBFC2A、OBFC2B、OLIG2、OMA1、OPA1、OPN4、OPTN、OSBPL11、OSBPL8、OSGEPL1、OTC、OTX2、OVOL2、OXT、PA2G4、PADI4、PAH、PAN2、PAOX、PAPOLG、PARD3、PARP1、PARVB、PAWR、P AX3、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、P HLDB2、PHOX2B、PHTF1、PIAS1、PIEZO1、PIGF、PIGN、PIGT、PIK3C2G、PIK3CA、PIK3CD、PIK3CG、PIK3RI、PIP5K1A、PITRM1、PIWIL3、PKD1、PKHD1L1、PKD2、PKIB、PKLR、PKM1、PKM2、PLCB1、PLCG 4、PLCG1、PLD1、PLEKHA5、PLEKHA7、PLEKHM1、PLKR、PLXNC1、PMFBP1、POLN、POLR3D、POMT2、POSTN、POU2AF1、POU2F2、POU2F3、PPARA、PPFIA2、PPP1R12A、PPP3CB、PPP4C、PPP4R1L、PPP4R2、PRAME C1、PRDM1、PREX1、PREX2、PRIM1、PRIM2、PRKAR1A、PRKCA、PRKG1、PRMT7、PROC、PROCR、PROSC、PRODH、PROX1、PRPF40B、PRPF4B、PRRG2、PRUNE2、PSD3、PSEN 1、PSMAL、PTCH1、PTEN、PTK2、PTK2B、PTPN2、PTPN3、PTPN4、PTPN11、PTPN22、PTPRD、PTPRK、PTPRM、PTPRN2、PTPRT、PUS10、PVRL2、PYGM、QRSL1、RAB11FIP2 、RAB23、RAF1、RALBP1、RALGDS、RB1CC1、RBL2、RBM39、RBM45、RBPJ、RBSN、REC8、RELB、RFC4、RFT1、RFTN1、RHOA、RHPN2、RIF1、RIT1、RLN3、RMND5B、RNF11、 RNF32、RNFT1、RNGTT、ROCK1、ROCK2、RORA、RP1、RP6KA3、RP11-265F1、RP13-36C9、RPAP3、RPN1、RPGR、RPL22、RPL22L1、RPS6KA6、RREB1、RRM1、RRP1B、RSK 2, RTEL1, RTF1, RUFY1, RUNX1, RUNX2, RXRA, RYR3, SAAL1, SAE1, SALL4, SAT1, SATB2, SBCAD, SCN1A, SCN2A, SCN3A, SCN4A, SCN5A, SCN8A, SCNA, SCN11A, SCO1, SCYL3, SDC1, SDK1, SDK2, SEC24A, SEC24D, SEC31A, SEL1L, SENP3, SENP6, SENP7, SERPINA1, SETD3, SETD4, SETDB1, SEZ6, SFRS12, SGCE, SGOL2, SGPL1 、SH2D1A、SH3BGRL2、SH3PXD2A、SH3PXD2B、SH3RF2、SH3TC2、SHOC2、SIPA1L2、SIPA1L3、SIVA1、SKAP1、SKIV2L2、SLC6A11、SLC6A13、SLC6A6、SLC7A2、SLC1 2A3、SLC13A1、SLC22A17、SLC25A14、SLC28A3、SLC33A1、SLC35F6、SLC38A1、SLC38A4、SLC39A10、SLC4A2、SLC6A8、SMARCA1、SMARCA2、SMARCA5、SMARCA2SMC5、SMN2、SMOX、SMS、SMTN、SNCAIP、SNORD86、SNRK、SNRP70、SNX5、SNX6、S OD1、SOD10、SOS、SOS2、SOX5、SOX6、SOX8、SP1、SP2、SP3、SP110、SPAG9、SPATA 13、SPATA4、SPATS1、SPECC1L、SPDEF、SPI1、SPINK5、SPP2、SPTA1、SRF、SRM、 SRP72、SSX3、SSX5、SSX9、STAG1、STAG2、STAMBPLI、STARD6、STAT1、STAT3、ST AT5A、STAT5B、STAT6、STK17B、STX3、STXBP1、SUCLG2、SULF2、SUPT6H、SUPT1 6H、SV2C、SYCP2、SYT6、SYCPI、SYTL3、SYTL5、TAF2、TARDBP、TBC1D3G、TBC1D8 B、TBC1D26、TBC1D29、TBCEL、TBK1、TBP、TBPL1、TBR1、TBX、TCEB3、TCF3、TCF 4、TCF7L2、TCFL5、TCF12、TCP11L2、TDRD3、TEAD1、TEAD3、TEAD4、TECTB、TEK、 TERF1、TERF2、TET2、TFAP2A、TFAP2B、TFAP2C、TFAP4、TFDP1、TFRC、TG、TGM7 、TGS1、THAP7、THAP12、THOC2、TIAL1、TIAM2、TIMM50、TLK2、TM4SF20、TM6SF1 、TMEM27、TMEM77、TMEM156、TMEM194A、TMF1、TMPRSS6、TNFRSF10A、TNFRSF1 0B、TNFRSF8、TNK2、TNKS、TNKS2、TOM1L1、TOM1L2、TOP2B、TP53、TP53INP1、TP 53BP2、TP53I3、TP63、TRAF3IP3、TRAPPC2、TRIM44、TRIM65、TRIML1、TRIML2 、TRPM3、TRPM5、TRPM7、TRPS1、TSC1、TSC2、TSHB、TSPAN7、TTC17、TTF1、TTLL5 、TTLL9、TTN、TTPAL、TTR、TUSC3、TXNDC10、UBE3A、UCK1、UGT1A1、UHRF1BP1、U NC45B、UNC5C、USH2A、USF2、USP1、USP6、USP18、USP38、USP39、UTP20、UTP15、 、UTP18、UTRN、UTX、UTY、UVRAG、UXT、VAPA、VEGFA、VPS29、VPS35、VPS39、VT11A、VT11B、VWA3B、WDFY2、WDR16、WDR17、WDR26、WDR44、WDR 67、WDTC1、WRN、WRNIP1、WT1、WWC3、XBP1、XRN1、XRN2、XX-FW88277、YAP1、YARS、YBX1、YGM、YY1、ZBTB18、ZBTB20、ZC3HAV1、ZC3HC1、ZC3H 7A、ZDHHC19、ZEB1、ZEB2、ZFPM1、ZFYVE1、ZFX、ZIC2、ZNF37A、ZNF91、ZNF114、ZNF155、ZNF169、ZNF205、ZNF236、ZNF317、ZNF320、ZNF32 6、ZNF335、ZNF365、ZNF367、ZNF407、ZNF468、ZNF506、ZNF511、ZNF511-PRAP1、ZNF519、ZNF521、ZNF592、ZNF618、ZNF763、ZWINT are included.

[0311] 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、AHNAK、AIFM1、AIFM3、AIMP2、AK4、AKAP1、AKNAD1、CLCC1、AKR1A1、AKT1、AKT1S1、AKT2、AL139011.2、PEX19、AL157 935.2、ST6GALNAC6、AL358113.1、TJP2、AL441992.2、KYAT1、AL449266.1、CLCC1、AL59055 6.3、LINC00339、CDC42、ALAS1、ALB、ALDH16A1、ALDH1B1、ALDH3A1、ALDH3B2、ALDOA、ALKBH2 、ALPL、AMD1、AMICA1、AMN1、AMOTL2、AMY1B、AMY2B、ANAPC10、ANAPC11、ANAPC15、ANG、RNASE4、AL163636.2、ANGEL2、ANGPTL1、ANKMY1、ANKRD11、ANKRD28、ANKRD46、ANKRD9、ANKS3. NKS3,RP11-127I20.7、ANKS6、ANKZF1、ANPEP、ANXA11、ANXA2、ANXA8L2、AL603965.1、AOC3、AP000304.12、CRYZL1、AP000311.1、CRYZL1、AP000 0893.2,RAB30、AP001267.5、ATP5MG、AP002495.2、AP003175.1、OR2AT4、AP003419.1、CLCF1、AP005263.1、ANKRD12、AP006621.5、AP006621. 1、AP1G1、AP3M1、AP3M2、APBA2、APBB1、APLP2、APOA2、APOL1、APOL3、APTX、ARAP1、STARD10、ARF4、ARFIP1、ARFIP2、ARFRP1、ARHGAP11A、ARHGA P33、ARHGAP4、ARHGEF10、ARHGEF3、ARHGEF35、OR2A1-AS1、ARHGEF35、OR2A1-AS1、ARHGEF34P、ARID1B、ARHGEF35、OR2A20P、OR2A1-AS1、ARHGE F9、ARL1、ARL13B、ARL16、ARL6、ARMC6、ARMC8、ARMCX2、ARMCX5、RP4-769N13.6、ARMCX5-GPRASP2、BHLHB9、ARMCX5-GPRASP2、GPRASP1、ARMCX5 -GPRASP2,GPRASP2、ARMCX6、ARNT2、ARPP19、ARRB2、ARSA、ART3、ASB3、GPR75-ASB3、ASCC2、ASNS、ASNS、AC079781.5、ASPSCR1、ASS1、ASUN、AT E1, ATF1, ATF7IP2, ATG13, ATG4D, ATG7, ATG9A, ATM, ATOX1, ATP1B3, ATP2C1, ATP5F1A, ATP5G2, ATP5J, ATP5MD, ATP5PF, ATP6AP2, ATP6V0B, ATP6V1C1, ATP6V1D, ATP7B, ATXN1, ATXN1L, IST1, ATXN3, ATXN7L1, AURKA, AURKB, AXDND1, B3GALNT1, B3GALT5, AF064860.1, B3GALT5, AF064860.5、B3GNT5、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、C11orf57、C11orf63、C11orf82、C12orf23、C12orf4、C12orf65、C12orf79、C14 orf159、C14orf93、C17orf62、C18orf21、C19orf12、C19orf40、C19orf47、C19orf48、C19orf54、C1D、C1GALT1、C1QB、C1QTNF1、C1S、C1orf101、C1orf11 2、C1orf116、C1orf159、C1orf63、C2、C2,CFB、C20orf27、C21orf58、C2CD4D、C2orf15、LIPT1、MRPL30、C2orf80、C2orf81、C3orf14、C3orf17、C3orf18、C3orf15 3orf22、C3orf33,AC104472.3、C4orf33、C5orf28、C5orf34、C6orf118、C6orf203、C6orf211、C6orf48、C7orf50、C7orf55、C7orf55、LUC7L2、LUC7L2 8orf44-SGK3、C8orf44、C8orf59、C9,DAB2、C9orf153、C9orf9、CA5BP1,CA5B、CABYR、CALCA、CALCOCO1、CALCOCO2、CALM1、CALM3、CALML4、RP11-315D16.2、CALN1、CALU、CANT1、CANX、CAP1、CAPN12、CAPS2、CARD8、CARHSP1、CARNS1、CASC1、CASP3、C. ASP7、CBFA2T2、CBS、CBY1、CCBL1、CCBL2、RBMXL1、CCDC12、CCDC126、CCDC14、CCDC149、CCDC150、CCDC169-SOHLH2、CCDC169、CCDC171、CCDC37、CCDC41、CCDC57、CCDC63、CCDC7、CCDC74B、CCDC77、CCDC82、CCDC90B、CCDC91、CCDC92、CCNE1、CCHCR1、CCL28、CCNB1IP1、CCNC、CCND3、CCNG1、CCP110、CCR9、CCT7、CCT8、CD151、CD1D、CD200、CD22、CD226、CD276、CD36、CD59、CDC26、CDC42、CDC42SE1、CDC42SE2、CDHR3、CDK10、CDK16、CDK4、CDKAL1、CDKL3,CTD-2410N18.4、CDKN1A、CDKN2A、CDNF、CEBPZOS、CELF1、CEMIP、CENPK、CEP170B、CEP250、CEP57、CEP57L1、CEP63、CERS4、CFL1、CFL2、CFLAR、CGNL1、CHCHD7、CHD1L、CHD8、CHFR,ZNF605、CHIA、CHID1、CHL1、CHM、CHMP1A、CHMP3、RNF103-CHMP3、CHRNA2、CIDEC、CIRBP、CITED1、CKLF-CMTM1、CMTM1、CKMT1B、CLDN12,CTB-13L3.1、CLDND1,AC021660.3、CLDND1,CPOX、CLHC1、CLIP1、CLUL1、CMC4、MTCP1、CNDP2、CNFN、CNOT1、CNOT6、CNOT7、CNOT8、CNR1、CNR2、CNTFR、CNTRL、COA1、COASY、COCH、COL8A1、COLCA1、COLEC11、COMMD3-BMI1、BMI1、COPS5、COPS7B、COQ8A、CORO6、COTL1、COX14,RP4-605O3.4、COX7A2、COX7A2L、COX7B2、CPA4、CPA5、CPEB1、CPNE1、AL109827.1、RBM12、CPNE1、RP1-309K20.6、RBM12、CPNE3、CPSF3L、CPT1C、CREB3L2、CREM、CRP、CRYZ、CS,AC073896.1、CS、RP11-977G19.10、CSAD、CSDE1、CSF2RA、CSGALNACT1、CSK、CSNK2A1、CSRNP2、CT45A4、CT45A4 、CT45A5、CT45A6、CTBP2、CTCFL、CTD-2116N17.1、KIAA0101、CTD-2349B8.1、SYT17、CTD-2528L19.4 、ZNF607、CTD-2619J13.8、ZNF497、CTNNA1、CTNNBIP1、CTNND1、CTPS2、CTSB、CTSL、CTTN、CUL2、CUL 9、CWC15、CXorf40B、CYB561A3、CYBC1、CYLD、CYP11A1、CYP2R1、CYP4B1、CYP4F22、DAG1、DAGLB,KDEL R2、DARS、DBNL、DCAF11、DCAF8,PEX19、DCLRE1C、DCTD、DCTN1、DCTN4、DCUN1D2、DDR1、DDX11、DDX19 B、AC012184.2、DDX19B、RP11-529K1.3、DDX25、DDX39B、ATP6V1G2-DDX39B、SNORD84、DDX42、DDX60L DEDD, DEDD2, DEFA1, DEFA1B, DEFA1B, DEFA3, DENND1C, DENND2A, DENND4B, DET1, DGKA, DGKZ, DGLUCY, DHRS4L2, DHRS9, DHX40, DIABLO, AC048338.1, DIAPH1, DICER1, DKKL1, DLG1, DLG3, DLST, DMC1. DMKN、DMTF1、DMTN、DNAJC14、DNAJC19、DNAL1、DNASE1L1、DNMT3A、DOC2A、DOCK8、DOK1、DOPEY1、DP AGT1、DPP8、DRAM2、DRD2、DROSHA、DSN1、DTNA、DTX2、DTX3、DUOX1、DUOXA1、DUS2、DUSP10、DUSP13、 DUSP18、DUSP22、DYDC1、DYDC2、DYNLL1、DYNLT1、DYRK1A、DYRK2、DYRK4、RP11-500M8.7、DZIP1L、E 2F6、ECHDC1、ECSIT、ECT2、EDC3、EDEM1、EDEM2、MMP24-AS1、RP4-614O4.11、EEF1AKNMT、EEF1D、EF EMP1、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、EN1、E NDOV、ENO1、ENPP5、ENTHD2、ENTPD6、EP400NL、EPB41L1、EPDR1、NME8、EPHX1、EPM2A、EPN1、EPN2、EPN3、EPS 8L2、ERBB3、ERC1、ERCC1、ERG、ERI2、ERI2、DCUN1D3、ERLIN2、ERMARD、ERRFI1、ESR2、RP11-544I20.2、ESRR A、ESRRB、ESRRG、ETFA、ETFRF1、ETV1、ETV4、ETV7、EVA1A、EVC2、EVX1、EXD2、EXO5、EXOC1、EXOC2、FAAP24、F ABP6、FADS1、FADS2、FAHD2B、FAM107B、FAM111A、FAM111B、FAM114A1、FAM114A2、FAM115C、FAM115C、FAM11 5D、FAM120B、FAM133B、FAM135A、FAM153A、FAM153B、FAM154B、FAM156A、FAM156B、FAM168B、FAM172A、FAM1 82B、FAM192A、FAM19A2、FAM200B、FAM220A、FAM220A、AC009412.1、FAM222B、FAM227B、FAM234A、AC004754.1、FAM3C、FAM45A、FAM49B、FAM60A、FAM63A、FAM81A、FAM86B1、FAM86B2、FANCI、FANK1、FAR 2、FAXC、FAXDC2、FBF1、FBH1、FBXL4、FBXO18、FBXO22、FBXO31、FBXO41、FBXO44、FBXO45、FBX W9、FCHO1、FCHSD2、FDFT1、FDPS、FER、FETUB、FGD4、FGF1、FGFR1、FGFRL1、FGL1、FHL2、FIBC D1、FIGNL1、FIGNL1,DDC、FKBP5、FKRP、FLRT2、FLRT3、FMC1、LUC7L2、FMC1-LUC7L2、FNDC3B、 FOLH1、FOLR1、FOXP1、FOXK1、FOXM1、FOXO1、FOXP4、AC097634.4、FOXRED1、FPR1、FPR2、FRG 1B、FRS2、FTO、FTSJ1、FUK、FUT10、FUT3、FUT6、FXYD3、FZD3、G2E3、GAA、GABARAPL1、GABPB1、 GABRA5、GAL3ST1、GALE、GALNT11、GALNT14、GALNT6、GAPVD1、GARNL3、GAS2L3、GAS8、GATA1 、GATA2、GATA4、GBA、GCNT1、GDPD2、GDPD5、GEMIN7,MARK4、GEMIN8、GGA3、GGACT、AL356966.1、GGPS1、GHRL、GID8、GIGYF2、GIMAP8、GIPC1、GJB1、GJB6、GLB1L、GLI1、GLT8D1、GMFG、GMPR2、GNAI2、GNAQ、 GNB1、GNB2、GNE、GNG2、GNGT2、GNPDA1、GNPDA2、GOLGA3、CHFR、GOLGA4、GOLPH3L、GOLT1B、GPBP1L1、GPER1、GP R116、GPR141、EPDR1、GPR155、GPR161、GPR56、GPR63、GPR75-ASB3、ASB3、GPR85、GPSM2、GRAMD1B、GRB10、GR B7、GREM2、GRIA2、GSDMB、GSE1、GSN、GSTA4、GSTZ1、GTDC1、GTF2H1、GTF2H4、VARS2、GTF3C2、GUCY1A3、GUCY1B 3、GUK1、GULP1、GYPC、GYS1、GZF1、HAGH、HAO2、HAPLN3、HAVCR1、HAX1、HBG2、AC104389.4、HBG2、AC104389.4、HBE1、HBG2、AC104389.4、HBE1,OR51B5、HBG2、HBE1、AC104389.28、HBS1L、HCFC1R1、HCK、HDAC2、HDAC6、HDA C7、HDLBP、HEATR4、HECTD4、HEXIM2、HHAT、HHATL、CCDC13、HINFP、HIRA、C22orf39、HIVEP3、HJV、HKR1、HLF、HMBOX1、HMGA1、HMGB3、HMGCR、HMGN4、HMOX2、HNRNPC、HNRNP、HOMER3、HOPX. XA3、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、PPP1R2P4、KIAA0391、KIAA0391、AL121594.1、KIAA0391、PSMA6、KIAA0753、KIAA0895、KIAA0895L、KIAA1191、KIAA1407、KIAA1841、C2orf74、KIF12、KIF14、KIF27、KIF9、KIFC3、KIN、KIRREL1、KITLG、KLC1、APOPT1、AL139300.1、KLC4、KLHDC4、KLHDC8A、KLHL13、KLHL18、KLHL2、KLHL24、KLHL7、KLK11、KLK2、KLK5、KLK6、KLK7、 KNOP1、KRBA2、AC135178.2、KRBA2、RP11-849F2.7、KRIT1、KRT15、KRT8、KTN1、KXD1、KYAT3、RBMXL1、 KYNU, L3MBTL1, LACC1, LARGE, LARP4, LARP7, LAT2, LBHD1, LCA5, LCA5L, LCTL, LEPROTL1, LGALS8, LGALS9C, LGMN, LHFPL2, LIG4, LIMCH1, LIMK2, LIMS2, LINC00921, ZNF263, LIPF, LLGL2, LMAN2L, LMCD1 、LMF1、RP11-161M6.2、LMO1、LMO3、LOXHD1、LPAR1、LPAR2、LPAR4、LPAR5、LPAR6、LPHN1、LPIN2、LPI N3、LPP、LRFN5、LRIF1、LRMP、LRRC14、LRRC20、LRRC24、C8orf82、LRRC39、LRRC42、LRRC48、LRRC4C、L RRC8A、LRRC8B、LRRD1、LRTOMT、LRTOMT、AP000812.5、LSM7、LTB4R、LTBP3、LUC7L2、FMC1-LUC7L2、LU C7L3、LUZP1、LYG1、LYL1、LYPD4、LYPD6B、LYRM1、LYRM5、LYSMD4、MACC1、MAD1L1、MAD1L1、AC069288.1、MAEA、MAFF、MAFG、MAFK、MAGEA12,CSAG4、MAGEA2、MAGEA2B、MAGEA4、MAGEB1、MAGOHB、MAN2A2、MANBAL、MAOB、MAP2K3、 MAP3K7CL、MAP3K8、MAP7、MAP9、MAPK6、MAPK7、MAPK8、MAPKAP1、10-Mar、7-Mar、8-Mar、MARK2、MASP1、MATK、MATR3、MATR 3,SNHG4、MB、MBD5、MBNL1、MBOAT7、MCC、MCFD2、MCM9、MCOLN3、MCRS1、MDC1、MDGA2、MDH2、MDM2、ME1、MEAK7、MECR、MED4、 MEF2A、MEF2B,BORCS8-MEF2B、MEF2BNB-MEF2B、MEF2B、MEF2BNB、MEF2C、MEF2D、MEGF10、MEI1、MEIS2、MELK、MET、METTL1. 3、METTL23、MFF、MFN2、MFSD2A、MGST3、MIB2、MICAL1、MICAL3、MICOS10、NBL1,MICOS10-NBL1、MID1、MINA、MINOS1-NBL1,M INOS1、MIOS、MIPOL1、MIS12、MKLN1、MKNK1、MKNK1,MOB3C、MLF2、MLH1、MMP17、MOBP、MOCS1、MOGS、MOK、MORF4L1、MPC1、MPC 2、MPG、MPI、MPP1、MPP2、MPPE1、MPST、MRAS、MRO、MROH1、MROH7-TTC4、MROH7、MRPL14、MRPL24、MRPL33,BABAM2、MRPL33、BR E、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、M THFD2L, MTIF2, MTIF3, MTMR10, MTRF1, MTRR, MTUS2, MUTYH, MVK, MX1, MX2, MYH10, MYL12A, MYB, MYD88, MYL5, MYLIP, MYNN. MYO15A、MYO1B、MYOM2、MZF1、N4BP2L2、NAA60、NAB1、NAE1、NAGK、NAP1L1、NAP1L4、NAPG、NARFL、NARG2、NAT1、NAT10、NBPF1 1、WI2-3658N16.1、NBPF12、NBPF15、NBPF24、NBPF6、NBPF9、NBR1、NCAPG2、NCBP2、NCEH1、NCOA1、NCOA4、NDC1、NDRG1、NDRG2 、NDRG4、NDST1、NDUFAF6、NDUFB2、NDUFC1、NDUFS1、NDUFS8、NDUFV1、NEDD1、NEIL1、NEIL2、NEK10、NEK11、NEK6、NEK9、NELFA、NEU4、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 ALB2、PANK2、PAQR6、PARP11、PARVG、PASK、PAX6、PBRM1、PBXIP1、PCBP3、PCBP4、AC115284.1、PCBP4、RP11-155D18.14、RP11-155D18.12、PCGF3、PCGF5、PCNP、PCSK9、PDCD10、PDCD6、AHRR、PDDC1、PDGFRB、PDIA6、PDIK1L、PDLIM7、PDP1、PDPK1、PDPN、PDZD11、PEA15、PEX2、PEX5、PEX5L、PFKM、PFN4、PGAP2、PGAP2、AC090587.2、PGAP3、PGM3、PGPEP1、PHB、PHC2、PHF20、PHF21A、PHF23、PHKB、PHLDB1、PHOSPHO1、PHOSPHO2、KLHL23、PI4KB、PIAS2、PICALM、PIF1、PIGN、PIGO、PIGT、PIK3CD、PILRB、STA. G3L5P-PVRIG2P-PILRB、PIP5K1B、PIR、PISD、PIWIL4,FUT4、PKD2、PKIA、PKIG、PKM、PKN2、PLA1A、PLA2G2A、PLA2G5、PLA2G7、PLAC8、PLAGL1、PLD1、PLD3、PLEKHA1、PLEKHA2、PLEKHA6、PLEKHG5、PLIN1、PLS1、PLS3、PLSCR1、PLSCR2、PLSCR4、PLXNB1、PLXNB2、PMP22、PMS1、PNISR、PNKP,AKT1S1、PNMT、PNPLA4、PNPLA8、PNPO、PNRC1、POC1B、POFUT1、POLB、POLD1、POLH、POLI、POLL、POLR1B、POM121、POM121C,AC006014.7、POM121C、AC211429.1、POMC、POMT1、POP1、PORCN、POU5F1、PSORS1C3、PPARD、PPARG、PPHLN1、PPIL3、PPIL4、PPM1A、PPM1B,AC013717.1、PPP1CB、PPP1R11、PPP1R13L、PPP1R26、PPP1R9A、PPP2R2B、PPP3CA、PPP6R1、PPP6R3、PPT2、PPT2-EGFL8、EGFL8、PPWD1、PRDM2、PRDM8、PRELID3A、PREPL、PRICKLE1、PRKAG1、PRMT2、PRMT5、PRMT7、PROM1、PRPS1、PRPSAP2、PRR14L、PRR15L、PRR5、PRR5-ARHGAP8、PRR5L、PRR7、PRRC2B、PRRT4、PRSS50、PRSS45、PRSS44、PRUNE、PRUNE1、PSEN1、PSMA2、PSMF1、PSORS1C1、PSPH、PSRC1、PTBP3、PTHLH、PTK2、PTPDC1、PTPRM、PUF60、PUM2、PUS1、PUS10、PXN、PXYLP1、PYCR1、QRICH1、R3HCC1L、R3HDM2、RAB17、RAB23、RAB3A、RAB3D,TMEM205、RAB4B-EGLN2、EGLN2、AC008537.1、RAB5B、RAB7L1、RABL2A、RABL2B、RABL5、RACGAP1、RAD17、RAD51L3-RFFL、RAD51D、RAD52、RAE1、RAI14、RAI2、RALBP1、RAN、RANGAP1、RAP1A、RAP1B、RA P1GAP、RAPGEF4、RAPGEFL1、RASGRP2、RASSF1、RBCK1、RBM12B、RBM14、RBM4、RBM14-RBM4、RBM23、RBM4、RBM14-RBM4、RBM47、RBM7 AP002373.1、RBM7、RP1 1-212D19.4, RBMS2, RBMY1E, RBPJ, RBPMS, RBSN, RCBTB2, RCC1, RCC1, SNHG3, RCCD1, RECQL, RELL2, REPIN1, AC073111.3, REPIN1, ZNF775, RER1, RERE, RFWD3, RFX3, RGL2, RGMB, RGS11, RGS3, RGS5, AL592435.1, RHBDD1, RHNO1, TULP3, RHOC, AL603832.3, RHOC, RP11-426L16.10, RHOH, RIC8B, RIMKLB, RIN1, R IPK2, RIT1, RLIM, RNASE4, ANG, AL163636.6, RNASEK, RNASEK-C17orf49, RNF111, RNF123, RNF13, RNF14, RNF185, RNF216, RNF24, RNF32, RNF34, RNF38 NF4、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、RPL23 A、RPL36,HSD11B1L、RPP38、RPS20、RPS27A、RPS3A、RPS6KA3、RPS6KC1、RPS6KL1、RPUSD1、RRAGD、RRAS2、RRBP1、RSL1D1、RSRC2、RSRP 1、RUBCNL、RUNX1T1、RUVBL2、RWDD1、RWDD4、S100A13,AL162258. 1、S100A13,RP1-178F15.5、S100A16、S100A4、S100A3、S100A6、S1 00PBP、SAA1、SACM1L、SAMD4B、SAR1A、SARAF、SARNP,RP11-762I7.5、SCAMP5、SCAP、SCAPER、SCFD1、SCGB3A2、SCIN、SCML1、SCNN1D、S CO2, SCOC, SCRN1, SDC2, SDC4, SEC13, SEC14L1, SEC14L2, SEC22C, SEC23B, SEC24C, SEC61G, SEMA4A, SEMA4C, SEMA4D, SEMA6C, SENP7, SEPP1, 11-Sep, 2-Sep, SERGEF, AC055860.1, SERP1, SERPINA1, SERPINA5, SERPINB6, SERPING1, SERPINH1, SERTAD3, SETD5, SFMB T1、AC096887.1、SFTPA1、SFTPA2、SFXN2、SGCD、SGCE、SGK3、SGK3,C8orf44、SH2B1、SH2D6、SH3BP1,Z83844.3、SH3BP2、SH3BP5、SH3D 19、SH3YL1、SHC1、SHISA5、SHMT1、SHMT2、SHOC2、SHROOM1、SIGLEC5,SIGLEC14、SIL1、SIN3A、SIRT2、SIRT6、SKP1、STAT4、AC104109.3、SLAIN1、SLC10A3、SLC12A9、SLC14A1、SLC16A6、SLC1A2、SLC1A6、SLC 20A2、SLC25A18、SLC25A19、SLC25A22、SLC25A25、SLC25A29、SLC25A30、 SLC25A32、SLC25A39、SLC25A44、SLC25A45、SLC25A53、SLC26A11、SLC26 A4、SLC28A1、SLC29A1、SLC2A14、SLC2A5、SLC2A8、SLC35B2、SLC35B3、SL C35C2、SLC37A1、SLC38A1、SLC38A11、SLC39A13、SLC39A14、SLC41A3、SL C44A3、SLC4A7、SLC4A8、SLC5A10、SLC5A11、SLC6A1、SLC6A12、SLC6A9、S LC7A2、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、USP28、USP3、USP33、USP35、USP54、USP9Y、USPL1、UTP15、VARS2、VASH2、VAV3、VDAC1、VDAC2、VDR、VEZT、VGF、VIL1、VILL、VIPR1、VPS29、VPS37C、VPS8、VPS9D1、VRK2、VWA1、VWA5A、WARS、WASF1、WASHC5、WBP5、WDH. D1、WDPCP、WDR37、WDR53、WDR6、WDR72、WDR74、WDR81、WDR86、WDYHV1、WFDC3、WHSC1、WIPF1、WSCD2、WWP2、XAGE1A、XAGE1B、XKR9、XPNPEP1、XRCC3、XRN2、XXYLT1、YIF1A、YIF1B、YIPF1、YIPF5、YPEL5、YWHAB、YWHAZ、YY1AP1、ZBTB1、ZBTB14、ZBTB18、ZBTB20、ZBTB21、ZBTB25、ZBTB33、ZBTB34、ZBTB38、ZBTB43、ZBTB49、ZBTB7B、ZBTB7C、ZBTB8OS、ZC3H11A、ZBED6、ZC3H13、ZCCHC17、ZCCHC7、ZDHHC11、ZDHHC13、ZEB2、ZFAND5、ZFAND6、ZFP1、ZFP62、ZFX、ZFYVE16、ZFYVE19、ZFYVE20、ZFYVE27、ZHX2、AC016405.1、ZHX3、ZIK1、ZIM2,PEG3、ZKSCAN1、ZKSCAN3、ZKSCAN8、ZMAT3、ZMAT5、ZMIZ2、ZMYM6、ZMYND11、ZNF10,AC026786.1、ZNF133、ZNF146、ZNF16、ZNF177、ZNF18、ZNF200、ZNF202、ZNF211、ZNF219、ZNF226、ZNF227、ZNF23、AC010547.4、ZNF23、AC010547.9、ZNF239、ZNF248、ZNF25、ZNF253、ZNF254、ZNF254、AC092279.1、ZNF263、ZNF274、ZNF275、ZNF28、ZNF468、ZNF283、ZNF287、ZNF3、ZNF320、ZNF322、ZNF324B、ZNF331、ZNF334、ZNF34、ZNF350、ZNF385A、ZNF395、FBXO16、ZNF415、ZNF418、ZNF43、ZNF433-AS1、AC008770.4、ZNF438、ZNF444、ZNF445、ZNF467、ZNF480、ZNF493、ZNF493,CTD-2561J22.3、ZNF502、ZNF507、ZNF512、AC074091.1、ZNF512,RP11-158I13.2、ZNF512B、ZNF512B、SAMD10、ZNF521、ZNF532、ZNF544、AC020915.5, ZNF544, CTD-3138B18.4, ZNF559, ZNF177, ZNF562, ZNF567, ZNF569, ZNF570, ZNF571-AS1, ZNF540, ZNF577, ZNF580, ZNF581, ZNF580, ZNF581 ,CCDC106, ZNF600, ZNF611, ZNF613, ZNF615, ZNF619, ZNF620, ZNF639, ZNF652, ZNF665, ZNF667, ZNF668, ZNF671, ZNF682, ZNF687, ZNF691, ZNF6 This includes genes such as 96, ZNF701, ZNF706, ZNF707, ZNF714, ZNF717, ZNF718, ZNF720, ZNF721, ZNF730, ZNF763, ZNF780B, AC005614.5, ZNF782, ZNF786, ZNF79, ZNF791, ZNF81, ZNF83, ZNF837, ZNF839, ZNF84, ZNF845, ZNF846, ZNF865, ZNF91, ZNF92, ZNHIT3, ZSCAN21, ZSCAN25, ZSCAN30, and ZSCAN32.

[0312] In some embodiments, the gene encoding the target sequence includes the HTT gene. In some embodiments, the gene encoding the target sequence includes the SMN2 gene.

[0313] Exemplary genes that can be regulated by compounds of formula (I) or (II) described herein include, in particular, AC005258.1, AC005943.1, AC007849.1, AC008770.2, AC010487.3, AC011477.4, AC012651.1, AC012531.3, AC034102.2, and AC073896.4. This may also include AC104472.3, AL109811.3, AL133342.1, AL137782.1, AL157871.5, AF241726.2, AL355336.1, AL358113.1, AL360181.3, AL445423.2, AL691482.3, AP001267.5, RF01169 and RF02271.

[0314] 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 (SEQ ID NO: 1), AAAguaaaaa (SEQ ID NO: 2), AAAguaaaau (SEQ ID NO: 3), AAAguaaagu (SEQ ID NO: 4), AAAguaaaua (SEQ ID NO: 5), AAAguaaaug (SEQ ID NO: 6), AAAguaaauu (SEQ ID NO: 7), AAAguaacac (SEQ ID NO: 8), AAAguaacca (SEQ ID NO: 9), AAAguaacuu (SEQ ID NO: 10), AAAguaagaa (SEQ ID NO: 11), AAAguaagac (SEQ ID NO: 12), AAAguaagag (SEQ ID NO: 13), AAAguaagau (SEQ ID NO: 14), AAAguaagca (SEQ ID NO: 15), AAAguaagcc (SEQ ID NO: 16), AAAguaagcu (SEQ ID NO: 17), AAAguaagga (SEQ ID NO: 18), AAAguaaggg (SEQ ID NO: 19), AAAguaaggu (SEQ ID NO: 20), AAAguaagua (sequence) Number 21), AAAguaaguc (SEQ ID NO: 22), AAAguaagug (SEQ ID NO: 23), AAAguaaguu (SEQ ID NO: 24), AAAguaaucu (SEQ ID NO: 25), AAAguaauua (SEQ ID NO: 26), AAAguacaaa (SEQ ID NO: 27), AAAguaccgg (SEQ ID NO: 28), AAAguacuag (SEQ ID NO: 29), AAAguacugg (SEQ ID NO: 30), AAAguacuuc (SEQ ID NO: 31), AAAguacuug (SEQ ID NO: 32), AAAguagcuu (SEQ ID NO: 33), AAAguaggag (SEQ ID NO: 34), AAAguaggau (SEQ ID NO: 35), AAAguagggg (SEQ ID NO: 36), AAAguaggua (SEQ ID NO: 37), AAAguaguaa (SEQ ID NO: 38), AAAguauauu (SEQ ID NO: 39), AAAguauccu (SEQ ID NO: 40), AAAguaucuc (SEQ ID NO: 41), AAAguaugga (SEQ ID NO: 42), AAAguaugua (SEQ ID NO: 43),AAAguaugug (SEQ ID NO: 44), AAAguauguu (SEQ ID NO: 45), AAAguauugg (SEQ ID NO: 46), AAAguauuuu (SEQ ID NO: 47), AAAgucagau (SEQ ID NO: 48), AAAgucugag (SEQ ID NO: 49), AAAgugaaua (SEQ ID NO: 50), AAAgugagaa (SEQ ID NO: 51), AAAgugagac (SEQ ID NO: 52), AAAgugagag (SEQ ID NO: 53), AAAgugagau (SEQ ID NO: 54), AAAgugagca (SEQ ID NO: 55), AAAgugagcu (SEQ ID NO: 56), AAAgugaggg (sequence number 57), AAAgugagua (sequence number 58), AAAgugaguc (sequence number 59), AAAgugagug (sequence number 60), AAAgugaguu (sequence number 61), AAAgugcguc (sequence number 62), AAAgugcuga (sequence number 63), AAAguggguc (sequence number 64), AAAguggguu (sequence number 65), AAAgugguaa (sequence number 66), AAAguguaug (sequence number 67), AAAgugugug (sequence number 68), AAAguguguu (sequence number 69), AAAguuaagu (SEQ ID NO: 70), AAAguuacuu (SEQ ID NO: 71), AAAguuagug (SEQ ID NO: 72), AAAguuaugu (SEQ ID NO: 73), AAAguugagu (SEQ ID NO: 74), AAAguuugua (SEQ ID NO: 75), AACguaaaac (SEQ ID NO: 76), AACguaaagc (SEQ ID NO: 77), AACguaaagg (SEQ ID NO: 78), AACguaagca (SEQ ID NO: 79), AACguaaggg (SEQ ID NO: 80), AACguaaguc (SEQ ID NO: 81), AACguaagug (SEQ ID NO: 82), AACguaaugg (SEQ ID NO: 83), AACguaguga (SEQ ID NO: 84), AACguaugua (SEQ ID NO: 85), AACguauguu (SEQ ID NO: 86), AACgugagca (SEQ ID NO: 87), AACgugagga (SEQ ID NO: 88), AACgugauuu (SEQ ID NO: 89), AACgugggau (SEQ ID NO: 90), AACgugggua (SEQ ID NO: 91), AACguguguu (SEQ ID NO: 92), AACguuggua (SEQ ID NO: 93), AAGgcaaauu (SEQ ID NO: 94), AAGgcaagag (SEQ ID NO: 95),AAGgcaagau(Sequence No. 9, 6) AAGgcaagcc (SEQ ID NO: 97), AAGgcaagga (SEQ ID NO: 98), AAGgcaaggg (SEQ ID NO: 99), AAGgcaagug (SEQ ID NO: 100), AAGgcaaguu (SEQ ID NO: 101), AAGgcacugc (SEQ ID NO: 102), AAGgcagaaa (SEQ ID NO: 103), AAGgcaggau (SEQ ID NO: 104), AAGgcaggca (SEQ ID NO: 105), AAGgcaggga (SEQ ID NO: 106), AAGgcagggg (SEQ ID NO: 107), AAGgcaggua (SEQ ID NO: 108), AAGgcaggug (SEQ ID NO: 109), AAGgcaucuc (SEQ ID NO: 110), AAGgcaugcu (SEQ ID NO: 111), AAGgcaugga (SEQ ID NO: 112), AAGgcauguu (SEQ ID NO: 113), AAGgcauuau (SEQ ID NO: 114), AAGgcgagcu (SEQ ID NO: 115), AAGgcgaguc (SEQ ID NO: 116), AAGgcgaguu (SEQ ID NO: 117), AAGgcuagcc (SEQ ID NO: 118), AAGguaaaaa (SEQ ID NO: 119), AAGguaaaac (SEQ ID NO: 120), AAGguaaaag (SEQ ID NO: 121), AAGguaaaau (SEQ ID NO: 122), AAGguaaaca (SEQ ID NO: 123), AAGguaaacc (SEQ ID NO: 124), AAGguaaacu (SEQ ID NO: 125), AAGguaaaga (SEQ ID NO: 126), AAGguaaagc (SEQ ID NO: 127), AAGguaaagg (SEQ ID NO: 128), AAGguaaagu (SEQ ID NO: 129), AAGguaaaua (SEQ ID NO: 130), AAGguaaauc (SEQ ID NO: 131), AAGguaaaug (SEQ ID NO: 132), AAGguaaauu (SEQ ID NO: 133), AAGguaacaa (SEQ ID NO: 134), AAGguaacau (SEQ ID NO: 135), AAGguaaccc (SEQ ID NO: 136), AAGguaacua (SEQ ID NO: 137), AAGguaacuc (SEQ ID NO: 138), AAGguaacug (SEQ ID NO: 139), AAGguaacuu (SEQ ID NO: 140), AAGguaagaa (SEQ ID NO: 141), AAGguaagac (SEQ ID NO: 142), AAGguaagag (SEQ ID NO: 143), AAGguaagau (SEQ ID NO: 144), AAGguaagca (SEQ ID NO: 145), AAGguaagcc (SEQ ID NO: 146),AAGguaagcg (SEQ ID NO: 147), AAGguaagcu (SEQ ID NO: 148), AAGguaagga (SEQ ID NO: 149), AAGguaaggc (SEQ ID NO: 150), AAGguaaggg (SEQ ID NO: 151), AAGguaaggu (SEQ ID NO: 152), AAGguaagua (SEQ ID NO: 153), AAGguaaguc (SEQ ID NO: 154), AAGguaagug (SEQ ID NO: 155), AAGguaaguu (SEQ ID NO: 156), AAGguaauaa (SEQ ID NO: 157), AAGguaauac (SEQ ID NO: 158), AAGguaauag (SEQ ID NO: 159), AAGguaauau (SEQ ID NO: 160), AAGguaauca (SEQ ID NO: 161), AAGguaaucc (SEQ ID NO: 162), AAGguaaucu (SEQ ID NO: 163), AAGguaauga (SEQ ID NO: 164), AAGguaaugc (SEQ ID NO: 165), AAGguaaugg (SEQ ID NO: 166), AAGguaaugu (SEQ ID NO: 167), AAGguaauua (SEQ ID NO: 168), AAGguaauuc (SEQ ID NO: 169), AAGguaauug (SEQ ID NO: 170), AAGguaauuu (SEQ ID NO: 171), AAGguacaaa (SEQ ID NO: 172), AAGguacaag (SEQ ID NO: 173), AAGguacaau (SEQ ID NO: 174), AAGguacacc (SEQ ID NO: 175), AAGguacacu (SEQ ID NO: 176), AAGguacagg (SEQ ID NO: 177), AAGguacagu (SEQ ID NO: 178), AAGguacaua (SEQ ID NO: 179), AAGguacaug (SEQ ID NO: 180), AAGguacauu (SEQ ID NO: 181), AAGguaccaa (SEQ ID NO: 182), AAGguaccag (SEQ ID NO: 183), AAGguaccca (SEQ ID NO: 184), AAGguacccu (SEQ ID NO: 185), AAGguaccuc (SEQ ID NO: 186), AAGguaccug (SEQ ID NO: 187), AAGguaccuu (SEQ ID NO: 188), AAGguacgaa (SEQ ID NO: 189), AAGguacggg (SEQ ID NO: 190), AAGguacggu (SEQ ID NO: 191), AAGguacguc (SEQ ID NO: 192), AAGguacguu (SEQ ID NO: 193), AAGguacuaa (SEQ ID NO: 194), AAGguacuau (SEQ ID NO: 195), AAGguacucu (SEQ ID NO: 196),AAGguacuga (SEQ ID NO: 197), AAGguacugc (SEQ ID NO: 198), AAGguacugu (SEQ ID NO: 199), AAGguacuuc (SEQ ID NO: 200), AAGguacuug (SEQ ID NO: 201), AAGguacuuu (SEQ ID NO: 202), AAGguagaaa (SEQ ID NO: 203), AAGguagaac (SEQ ID NO: 204), AAGguagaca (SEQ ID NO: 205), AAGguagacc (SEQ ID NO: 206), AAGguagacu (SEQ ID NO: 207), AAGguagagu (SEQ ID NO: 208), AAGguagaua (SEQ ID NO: 209), AAGguagcaa (SEQ ID NO: 210), AAGguagcag (SEQ ID NO: 211), AAGguagcca (SEQ ID NO: 212), AAGguagccu (SEQ ID NO: 213), AAGguagcua (SEQ ID NO: 214), AAGguagcug (SEQ ID NO: 215), AAGguagcuu (SEQ ID NO: 216), AAGguaggaa (SEQ ID NO: 217), AAGguaggag (SEQ ID NO: 218), AAGguaggau (SEQ ID NO: 219), AAGguaggca (SEQ ID NO: 220), AAGguaggcc (SEQ ID NO: 221), AAGguaggcu (SEQ ID NO: 222), AAGguaggga (SEQ ID NO: 223), AAGguagggc (SEQ ID NO: 224), AAGguagggg (SEQ ID NO: 225), AAGguagggu (SEQ ID NO: 226), AAGguaggua (SEQ ID NO: 227), AAGguagguc (SEQ ID NO: 228), AAGguaggug (SEQ ID NO: 229), AAGguagguu (SEQ ID NO: 230), AAGguaguaa (SEQ ID NO: 231), AAGguaguag (SEQ ID NO: 232), AAGguagucu (SEQ ID NO: 233), AAGguagugc (SEQ ID NO: 234), AAGguagugg (SEQ ID NO: 235), AAGguaguuc (SEQ ID NO: 236), AAGguaguuu (SEQ ID NO: 237), AAGguauaaa (SEQ ID NO: 238), AAGguauaau (SEQ ID NO: 239), AAGguauaca (SEQ ID NO: 240), AAGguauacu (SEQ ID NO: 241), AAGguauaua (SEQ ID NO: 242), AAGguauauc (SEQ ID NO: 243), AAGguauaug (SEQ ID NO: 244), AAGguauauu (SEQ ID NO: 245), AAGguaucac (SEQ ID NO: 246),AAGguaucag (SEQ ID NO: 247), AAGguauccc (SEQ ID NO: 248), AAGguauccu (SEQ ID NO: 249), AAGguaucuc (SEQ ID NO: 250), AAGguaucug (SEQ ID NO: 251), AAGguaucuu (SEQ ID NO: 252), A, AGguaugaa (SEQ ID NO: 253), AAGguaugac (SEQ ID NO: 254), AAGguaugag (SEQ ID NO: 255), AAGguaugau (SEQ ID NO: 256), AAGguaugca (SEQ ID NO: 257), AAGguaugcc (SEQ ID NO: 258), AAGguaugcu (SEQ ID NO: 259), AAGguaugga (SEQ ID NO: 260), AAGguauggc (SEQ ID NO: 261), AAGguauggg (SEQ ID NO: 262), AAGguaugua ( SEQ ID NO: 263), AAGguauguc (SEQ ID NO: 264), AAGguaugug (SEQ ID NO: 265), AAGguauguu (SEQ ID NO: 266), AAGguauuaa (SEQ ID NO: 267), AAGguauuac (SEQ ID NO: 268), AAGguauuag (SEQ ID NO: 269), AAGguauuau (SEQ ID NO: 270), AAGguauucc (SEQ ID NO: 271), AAGguauuga (SEQ ID NO: 272), AAGguauugu (SEQ ID NO: 273), A AGguauuua (SEQ ID NO: 274), AAGguauuuc (SEQ ID NO: 275), AAGguauuug (SEQ ID NO: 276), AAGguauuuu (SEQ ID NO: 277), AAGgucaaau (SEQ ID NO: 278), AAGgucaaga (SEQ ID NO: 279), AAGgucaagu (SEQ ID NO: 280), AAGgucacag (SEQ ID NO: 281), AAGgucagaa (SEQ ID NO: 282), AAGgucagac (SEQ ID NO: 283), AAGgucagag ( SEQ ID NO: 284), AAGgucagca (SEQ ID NO: 285), AAGgucagcc (SEQ ID NO: 286), AAGgucagcg (SEQ ID NO: 287), AAGgucagcu (SEQ ID NO: 288), AAGgucagga (SEQ ID NO: 289), AAGgucaggc (SEQ ID NO: 290), AAGgucaggg (SEQ ID NO: 291), AAGgucaggu (SEQ ID NO: 292), AAGgucagua (SEQ ID NO: 293), AAGgucaguc (SEQ ID NO: 294), A AGgucagug (SEQ ID NO: 295), AAGgucaguu (SEQ ID NO: 296), AAGgucauag (SEQ ID NO: 297), AAGgucaucu (SEQ ID NO: 298), AAGguccaca (SEQ ID NO: 299), AAGguccaga (SEQ ID NO: 300), AAGguccaua (SEQ ID NO: 301), AAGgucccag (SEQ ID NO: 302), AAGgucccuc (SEQ ID NO: 303), AAGguccuuc (SEQ ID NO: 304), AAGgucgagg (SEQ ID NO: 305), AAGgucuaau (SEQ ID NO: 306), AAGgucuacc (SEQ ID NO: 307), AAGgucuaua (SEQ ID NO: 308), AAGgucuccu (SEQ ID NO: 309), AAGgucucug (SEQ ID NO: 310), AAGgucucuu (SEQ ID NO: 311), AAGgucugaa (SEQ ID NO: 312), AAGgucugag (SEQ ID NO: 313), AAGgucugga (SEQ ID NO: 314), AAGgucuggg (SEQ ID NO: 315), AAGgucugua (SEQ ID NO: 316), AAGgucuguu (SEQ ID NO: 317), AAGgucuucu (SEQ ID NO: 318), AAGgucuuuu (SEQ ID NO: 319), AAGgugaaac (SEQ ID NO: 320), AAGgugaaag (SEQ ID NO: 321), AAGgugaaau (SEQ ID NO: 322), AAGgugaacu (SEQ ID NO: 323), AAGgugaagc (SEQ ID NO: 324), AAGgugaagg (SEQ ID NO: 325), AAGgugaagu (SEQ ID NO: 326), AAGgugaaua (SEQ ID NO: 327), AAGgugaaug (SEQ ID NO: 328), AAGgugaauu (SEQ ID NO: 329), AAGgugacaa (SEQ ID NO: 330), AAGgugacag (SEQ ID NO: 331), AAGgugacau (SEQ ID NO: 332), AAGgugacug (SEQ ID NO: 333), AAGgugacuu (SEQ ID NO: 334), AAGgugagaa (SEQ ID NO: 335), AAGgugagac (SEQ ID NO: 336), AAGgugagag (SEQ ID NO: 337), AAGgugagau (SEQ ID NO: 338), AAGgugagca (SEQ ID NO: 339), AAGgugagcc (SEQ ID NO: 340), AAGgugagcg (SEQ ID NO: 341), AAGgugagcu (SEQ ID NO: 342), AAGgugagga (SEQ ID NO: 343), AAGgugaggc (SEQ ID NO: 344),AAGgugaggg (SEQ ID NO: 345), AAGgugaggu (SEQ ID NO: 346), AAGgugagua (SEQ ID NO: 347), AAGgugaguc (SEQ ID NO: 348), AAGgugagug (SEQ ID NO: 349), AAGgugaguu (SEQ ID NO: 350), AAGgugauaa (SEQ ID NO: 351), AAGgugauca (SEQ ID NO: 352), AAGgugaucc (SEQ ID NO: 353), AAGgugauga (SEQ ID NO: 354), AAGgugaugc (SEQ ID NO: 355), AAGgugaugu (SEQ ID NO: 356), AAGgugauua (SEQ ID NO: 357), AAGgugauug (SEQ ID NO: 358), AAGgugauuu (SEQ ID NO: 359), AAGgugcaca (SEQ ID NO: 360), AAGgugcauc (SEQ ID NO: 361), AAGgugcccu (SEQ ID NO: 362), AAGgugccug (SEQ ID NO: 363), AAGgugcgug (SEQ ID NO: 364), AAGgugcguu (SEQ ID NO: 365), AAGgugcucc (SEQ ID NO: 366), AAGgugcuga (SEQ ID NO: 367), AAGgugcugc (SEQ ID NO: 368), AAGgugcugg (SEQ ID NO: 369), AAGgugcuua (SEQ ID NO: 370), AAGgugcuuu (SEQ ID NO: 371), AAGguggaua (SEQ ID NO: 372), AAGguggcua (SEQ ID NO: 373), AAGguggcug (SEQ ID NO: 374), AAGguggcuu (SEQ ID NO: 375), AAGgugggaa (SEQ ID NO: 376), AAGgugggag (SEQ ID NO: 377), AAGgugggau (SEQ ID NO: 378), AAGgugggca (SEQ ID NO: 379), AAGgugggcc (SEQ ID NO: 380), AAGgugggcg (SEQ ID NO: 381), AAGgugggga (SEQ ID NO: 382), AAGguggggu (SEQ ID NO: 383), AAGgugggua (SEQ ID NO: 384), AAGgugggug (SEQ ID NO: 385), AAGguggguu (SEQ ID NO: 386), AAGgugguaa (SEQ ID NO: 387), AAGgugguac (SEQ ID NO: 388), AAGgugguau (SEQ ID NO: 389), AAGguggugg (SEQ ID NO: 390), AAGgugguua (SEQ ID NO: 391), AAGgugguuc (SEQ ID NO: 392), AAGgugguuu (SEQ ID NO: 393), AAGguguaag (SEQ ID NO: 394),A、 AGgugucaa (SEQ ID NO: 395), AAGgugucag (SEQ ID NO: 396), AAGgugucug (SEQ ID NO: 397), AAGgugugaa (SEQ ID NO: 398), AAGgugugag (SEQ ID NO: 399), AAGgugugca (SEQ ID NO: 400), AAGgugugga (SEQ ID NO: 401), AAGguguggu (SEQ ID NO: 402), AAGgugugua (SEQ ID NO: 403), AAGguguguc (SEQ ID NO: 404), AAGgugugug (SEQ ID NO: 405), AAGguguguu (SEQ ID NO: 406), AAGguguucu (SEQ ID NO: 407), AAGguguugc (SEQ ID NO: 408), AAGguguugg (SEQ ID NO: 409), AAGguguuug (SEQ ID NO: 410), AAGguuaaaa (SEQ ID NO: 411), AAGguuaaca (SEQ ID NO: 412), AAGguuaagc (SEQ ID NO: 413), AAGguuaauu (SEQ ID NO: 414), AAGguuacau (SEQ ID NO: 415), AAGguuagaa (SEQ ID NO: 416), AAGguuagau (SEQ ID NO: 417), AAGguuagca (SEQ ID NO: 418), AAGguuagcc (SEQ ID NO: 419), AAGguuagga (SEQ ID NO: 420), AAGguuaggc (SEQ ID NO: 421), AAGguuagua (SEQ ID NO: 422), AAGguuaguc (SEQ ID NO: 423), AAGguuagug (SEQ ID NO: 424), AAGguuaguu (SEQ ID NO: 425), AAGguuauag (SEQ ID NO: 426), AAGguuauga (SEQ ID NO: 427), AAGguucaaa (SEQ ID NO: 428), AAGguucaag (SEQ ID NO: 429), AAGguuccuu (SEQ ID NO: 430), AAGguucggc (SEQ ID NO: 431), AAGguucguu (SEQ ID NO: 432), AAGguucuaa (SEQ ID NO: 433), AAGguucuga (SEQ ID NO: 434), AAGguucuua (SEQ ID NO: 435), AAGguugaau (SEQ ID NO: 436), AAGguugacu (SEQ ID NO: 437), AAGguugagg (SEQ ID NO: 438), AAGguugagu (SEQ ID NO: 439), AAGguugaua (SEQ ID NO: 440), AAGguugcac (SEQ ID NO: 441), AAGguugcug (SEQ ID NO: 442), AAGguuggaa (SEQ ID NO: 443), AAGguuggca (SEQ ID NO: 444),AAGguuggga (SEQ ID NO: 445), AAGguugggg (SEQ ID NO: 446), AAGguuggua (SEQ ID NO: 447), AAGguugguc (SEQ ID NO: 448), AAGguuggug (SEQ ID NO: 449), AAGguugguu (SEQ ID NO: 450), AAGguuguaa (SEQ ID NO: 451), AAGguugucc (SEQ ID NO: 452), AAGguugugc (SEQ ID NO: 453), AAGguuguua (SEQ ID NO: 454), AAGguuuacc (SEQ ID NO: 455), AAGguuuaua (SEQ ID NO: 456), AAGguuuauu (SEQ ID NO: 457), AAGguuuccu (SEQ ID NO: 458), AAGguuucgu (SEQ ID NO: 459), AAGguuugag (SEQ ID NO: 460), AAGguuugca (SEQ ID NO: 461), AAGguuugcc (SEQ ID NO: 462), AAGguuugcu (SEQ ID NO: 463), AAGguuugga (SEQ ID NO: 464), AAGguuuggu (SEQ ID NO: 465), AAGguuugua (SEQ ID NO: 466), AAGguuuguc (SEQ ID NO: 467), AAGguuugug (SEQ ID NO: 468), AAGguuuuaa (SEQ ID NO: 469), AAGguuuuca (SEQ ID NO: 470), AAGguuuucg (SEQ ID NO: 471), AAGguuuugc (SEQ ID NO: 472), AAGguuuugu (SEQ ID NO: 473), AAGguuuuuu (SEQ ID NO: 474), AAUgcaagua (SEQ ID NO: 475), AAUgcaaguc (SEQ ID NO: 476), AAUguaaaca (SEQ ID NO: 477), AAUguaaaua (SEQ ID NO: 478), AAUguaaauc (SEQ ID NO: 479), AAUguaaaug (SEQ ID NO: 480), AAUguaaauu (SEQ ID NO: 481), AAUguaacua (SEQ ID NO: 482), AAUguaagaa (SEQ ID NO: 483), AAUguaagag (SEQ ID NO: 484), AAUguaagau (SEQ ID NO: 485), AAUguaagcc (SEQ ID NO: 486), AAUguaagcu (SEQ ID NO: 487), AAUguaagga (SEQ ID NO: 488), AAUguaagua (SEQ ID NO: 489), AAUguaaguc (SEQ ID NO: 490), AAUguaagug (SEQ ID NO: 491), AAUguaaguu (SEQ ID NO: 492), AAUguaauca (SEQ ID NO: 493), AAUguaauga (SEQ ID NO: 494),A, AUguaaugu (SEQ ID NO: 495), AAUguacauc (SEQ ID NO: 496), AAUguacaug (SEQ ID NO: 497), AAUguacgau (SEQ ID NO: 498), AAUguacgua (SEQ ID NO: 499), AAUguacguc (SEQ ID NO: 500), AAUguacgug (SEQ ID NO: 501), AAUguacucu (SEQ ID NO: 502), AAUguaggca (SEQ ID NO: 503), AAUguagguu (SEQ ID NO: 504), AAUguaucua (SEQ ID NO: 505), AAUguaugaa (SEQ ID NO: 506), AAUguaugua (SEQ ID NO: 507), AAUguaugug (SEQ ID NO: 508), AA Uguauguu (SEQ ID NO: 509), AAUgucagag (SEQ ID NO: 510), AAUgucagau (SEQ ID NO: 511), AAUgucagcu (SEQ ID NO: 512), AAUgucagua (SEQ ID NO: 513), AAUgucaguc (SEQ ID NO: 514), AAUgucagug (SEQ ID NO: 515), AAUgucaguu (SEQ ID NO: 516), AAUgucggua (SEQ ID NO: 517), AAUgucuguu (SEQ ID NO: 518), AAUgugagaa (SEQ ID NO: 519), AAUgugagca (SEQ ID NO: 520), AAUgugagcc ( SEQ ID NO: 521), AAUgugagga (SEQ ID NO: 522), AAUgugagua (SEQ ID NO: 523), AAUgugaguc (SEQ ID NO: 524), AAUgugagug (SEQ ID NO: 525), AAUgugaguu (SEQ ID NO: 526), ​​AAUgugauau (SEQ ID NO: 527), AAUgugcaua (SEQ ID NO: 528), AAUgugcgua (SEQ ID NO: 529), AAUgugcguc (SEQ ID NO: 530), AAUgugggac (SEQ ID NO: 531), AAUguggguc (SEQ ID NO: 532), AAUgugggug (SEQ ID NO: 533), A AUgugguuu (SEQ ID NO: 534), AAUgugugua (SEQ ID NO: 535), AAUguuaagu (SEQ ID NO: 536), AAUguuagaa (SEQ ID NO: 537), AAUguuagau (SEQ ID NO: 538), AAUguuagua (SEQ ID NO: 539), AAUguuggug (SEQ ID NO: 540), ACAgcaagua (SEQ ID NO: 541), ACAguaaaua (SEQ ID NO: 542), ACAguaaaug (SEQ ID NO: 543), ACAguaagaa (SEQ ID NO: 544), ACAguaagca (SEQ ID NO: 545), ACAguaagua (SEQ ID NO: 546), ACAguaaguc (SEQ ID NO: 547), ACAguaagug (SEQ ID NO: 548), ACAguaaguu (SEQ ID NO: 549), ACAguacgua (SEQ ID NO: 550), ACAguaggug (SEQ ID NO: 551), ACAguauaac (SEQ ID NO: 552), ACAguaugua (SEQ ID NO: 553), ACAgucaguu (SEQ ID NO: 554), ACAgugagaa (SEQ ID NO: 555), ACAgugagcc (SEQ ID NO: 556), ACAgugagcu (SEQ ID NO: 557), ACAgugagga (SEQ ID NO: 558),ACAgugaggu (SEQ ID NO: 559), ACAgugagua (SEQ ID NO: 560), ACAgugaguc (SEQ ID NO: 561), ACAgugagug (SEQ ID NO: 562), ACAgugaguu (SEQ ID NO: 563), ACAgugggua (SEQ ID NO: 564), ACAguggguu (SEQ ID NO: 565), ACAguguaaa (SEQ ID NO: 566), ACAguuaagc (SEQ ID NO: 567), ACAguuaagu (SEQ ID NO: 568), ACAguuaugu (SEQ ID NO: 569), ACAguugagu (SEQ ID NO: 570), ACAguuguga (SEQ ID NO: 571), ACCguaagua (SEQ ID NO: 572), ACCgugagaa (SEQ ID NO: 573), ACCgugagca (SEQ ID NO: 574), ACCgugaguu (SEQ ID NO: 575), A CCgugggug (SEQ ID NO: 576), ACGguaaaac (SEQ ID NO: 577), ACGguaacua (SEQ ID NO: 578), ACGguaagua (SEQ ID NO: 579), ACGguaagug (SEQ ID NO: 580), ACGguaaguu (SEQ ID NO: 581), ACGguaauua (SEQ ID NO: 582), ACGguaauuu (SEQ ID NO: 583), ACGguacaau (SEQ ID NO: 584), ACGguacagu (SEQ ID NO: 585), ACGguaccag (SEQ ID NO: 586), ACGguacggu (SEQ ID NO: 587), ACGguacgua (SEQ ID NO: 588), ACGguaggaa (SEQ ID NO: 589), ACGguaggag (SEQ ID NO: 590), ACGguaggug (SEQ ID NO: 591), ACGguaguaa (SEQ ID NO: 592), AC, Gguauaau (SEQ ID NO: 593), ACGguaugac (SEQ ID NO: 594), ACGguaugcg (SEQ ID NO: 595), ACGguaugua (SEQ ID NO: 596), ACGguauguc (SEQ ID NO: 597), ACGgugaaac (SEQ ID NO: 598), ACGgugaagu (SEQ ID NO: 599), ACGgugaauc (SEQ ID NO: 600), ACGgugacag (SEQ ID NO: 601), ACGgugacca (SEQ ID NO: 602), ACGgugagaa (SEQ ID NO: 603), ACGgugagau (SEQ ID NO: 604), ACGgugagcc ( SEQ ID NO: 605), ACGgugagua (SEQ ID NO: 606), ACGgugagug (SEQ ID NO: 607), ACGgugaguu (SEQ ID NO: 608), ACGgugcgug (SEQ ID NO: 609), ACGguggcac (SEQ ID NO: 610), ACGguggggc (SEQ ID NO: 611), ACGgugggug (SEQ ID NO: 612), ACGguguagu (SEQ ID NO: 613), ACGgugucac (SEQ ID NO: 614), ACGgugugua (SEQ ID NO: 615), ACGguguguu (SEQ ID NO: 616), ACGguuagug (SEQ ID NO: 617), A CGguuaguu (SEQ ID NO: 618), ACGguucaau (SEQ ID NO: 619), ACUguaaaua (SEQ ID NO: 620), ACUguaagaa (SEQ ID NO: 621), ACUguaagac (SEQ ID NO: 622), ACUguaagca (SEQ ID NO: 623), ACUguaagcu (SEQ ID NO: 624), ACUguaagua (SEQ ID NO: 625), ACUguaaguc (SEQ ID NO: 626), ACUguaaguu (SEQ ID NO: 627), ACUguacguu (SEQ ID NO: 628), ACUguacugc (SEQ ID NO: 629), ACUguaggcu (SEQ ID NO: 630), ACUguaggua (SEQ ID NO: 631), ACUguauauu (SEQ ID NO: 632), ACUguaugaa (SEQ ID NO: 633), ACUguaugcu (SEQ ID NO: 634), ACUguaugug (SEQ ID NO: 635), ACUguauucc (SEQ ID NO: 636), ACUgucagcu (SEQ ID NO: 637), ACUgucagug (SEQ ID NO: 638), ACUgugaacg (SEQ ID NO: 639), ACUgugagca (SEQ ID NO: 640), ACUgugagcg (SEQ ID NO: 641), ACUgugagcu (SEQ ID NO: 642),ACUgugagua (SEQ ID NO: 643), ACUgugaguc (SEQ ID NO: 644), ACUgugagug (SEQ ID NO: 645), ACUgugaguu (SEQ ID NO: 646), ACUgugggua (SEQ ID NO: 647), ACUgugugug (SEQ ID NO: 648), ACUguuaagu (SEQ ID NO: 649), AGAgcaagua (SEQ ID NO: 650), AGAguaaaac (SEQ ID NO: 651), AGAguaaacg (SEQ ID NO: 652), AGAguaaaga (SEQ ID NO: 653), AGAguaaagu (SEQ ID NO: 654), AGAguaaauc (SEQ ID NO: 655), AGAguaaaug (SEQ ID NO: 656), AGAguaacau (SEQ ID NO: 657), AGAguaacua (SEQ ID NO: 658), AGAguaagaa (SEQ ID NO: 659), AGAguaagac (SEQ ID NO: 660), AGAguaagag (SEQ ID NO: 661), AGAguaagau (SEQ ID NO: 662), AGAguaagca (SEQ ID NO: 663), AGAguaagcu (SEQ ID NO: 664), AGAguaagga (SEQ ID NO: 665), AGAguaaggc (SEQ ID NO: 666), AGAguaaggg (SEQ ID NO: 667), AGAguaaggu (SEQ ID NO: 668), AGAguaaguc (SEQ ID NO: 669), AGAguaagug (SEQ ID NO: 670), AGAguaaguu (SEQ ID NO: 671), AGAguaauaa (SEQ ID NO: 672), AGAguaaugu (SEQ ID NO: 673), AGAguaauuc (SEQ ID NO: 674), AGAguaauuu (SEQ ID NO: 675), AGAguacacc (SEQ ID NO: 676), AGAguaccug (SEQ ID NO: 677), AGAguacgug (SEQ ID NO: 678), AGAguacucu (SEQ ID NO: 679), AGAguacuga (SEQ ID NO: 680), AGAguacuuu (SEQ ID NO: 681), AGAguagcug (SEQ ID NO: 682), AGAguaggaa (SEQ ID NO: 683), AGAguaggga (SEQ ID NO: 684), AGAguagggu (SEQ ID NO: 685), AGAguagguc (SEQ ID NO: 686), AGAguaggug (SEQ ID NO: 687), AGAguagguu (SEQ ID NO: 688), AGAguauaua (SEQ ID NO: 689), AGAguauauu (SEQ ID NO: 690), AGAguaugaa (SEQ ID NO: 691), AGAguaugac (SEQ ID NO: 692),AT、 Aguaugau (SEQ ID NO: 693), AGAguauguc (SEQ ID NO: 694), AGAguaugug (SEQ ID NO: 695), AGAguauguu (SEQ ID NO: 696), AGAguauuaa (SEQ ID NO: 697), AGAguauuau (SEQ ID NO: 698), AGAgucagug (SEQ ID NO: 699), AGAgugagac (SEQ ID NO: 700), AGAgugagag (SEQ ID NO: 701), AGAgugagau (SEQ ID NO: 702), AGAgugagca (SEQ ID NO: 703), AGAgugagua (SEQ ID NO: 704), AGAgugaguc ( SEQ ID NO: 705), AGAgugagug (SEQ ID NO: 706), AGAgugaguu (SEQ ID NO: 707), AGAgugcguc (SEQ ID NO: 708), AGAgugggga (SEQ ID NO: 709), AGAgugggug (SEQ ID NO: 710), AGAgugugug (SEQ ID NO: 711), AGAguguuuc (SEQ ID NO: 712), AGAguuagua (SEQ ID NO: 713), AGAguugaga (SEQ ID NO: 714), AGAguugagu (SEQ ID NO: 715), AGAguugguu (SEQ ID NO: 716), AGAguuugau (SEQ ID NO: 717), A GCguaagcu (SEQ ID NO: 718), AGCguaagug (SEQ ID NO: 719), AGCgugagcc (SEQ ID NO: 720), AGCgugagug (SEQ ID NO: 721), AGCguuguuc (SEQ ID NO: 722), AGGgcagagu (SEQ ID NO: 723), AGGgcagccu (SEQ ID NO: 724), AGGgcuagua (SEQ ID NO: 725), AGGguaaaga (SEQ ID NO: 726), AGGguaaaua (SEQ ID NO: 727), AGGguaaauc (SEQ ID NO: 728), AGGguaaauu (SEQ ID NO: 729), AGGguaacca (SEQ ID NO: 730), AGGguaacug (SEQ ID NO: 731), AGGguaacuu (SEQ ID NO: 732), AGGguaagaa (SEQ ID NO: 733), AGGguaagag (SEQ ID NO: 734), AGGguaagau (SEQ ID NO: 735), AGGguaagca (SEQ ID NO: 736), AGGguaagga (SEQ ID NO: 737), AGGguaaggc (SEQ ID NO: 738), AGGguaaggg (SEQ ID NO: 739), AGGguaagua (SEQ ID NO: 740), AGGguaaguc (SEQ ID NO: 741), AGGguaagug (SEQ ID NO: 742),AGGguaaguu (SEQ ID NO: 743), AGGguaauac (SEQ ID NO: 744), AGGguaauga (SEQ ID NO: 745), AGGguaauua (SEQ ID NO: 746), AGGguaauuu (SEQ ID NO: 747), AGGguacacc (SEQ ID NO: 748), AGGguacagu (SEQ ID NO: 749), AGGguacggu (SEQ ID NO: 750), AGGguaggac (SEQ ID NO: 751), AGGguaggag (SEQ ID NO: 752), AGGguaggca (SEQ ID NO: 753), AG Gguaggcc (SEQ ID NO: 754), AGGguaggga (SEQ ID NO: 755), AGGguagggu (SEQ ID NO: 756), AGGguagguc (SEQ ID NO: 757), AGGguaggug (SEQ ID NO: 758), AGGguagguu (SEQ ID NO: 759), AGGguauaua (SEQ ID NO: 760), AGGguaugac (SEQ ID NO: 761), AGGguaugag (SEQ ID NO: 762), AGGguaugau (SEQ ID NO: 763), AGGguaugca (SEQ ID NO: 764), AGG, guaugcu (SEQ ID NO: 765), AGGguauggg (SEQ ID NO: 766), AGGguauggu (SEQ ID NO: 767), AGGguaugua (SEQ ID NO: 768), AGGguauguc (SEQ ID NO: 769), AGGguaugug (SEQ ID NO: 770), AGGguauuac (SEQ ID NO: 771), AGGguauucu (SEQ ID NO: 772), AGGguauuuc (SEQ ID NO: 773), AGGgucagag (SEQ ID NO: 774), AGGgucagca (SEQ ID NO: 775), AGGgucagga (SEQ ID NO: 776), AGGgucaggg (SEQ ID NO: 777), AGG gucagug (SEQ ID NO: 778), AGGgucaguu (SEQ ID NO: 779), AGGguccccu (SEQ ID NO: 780), AGGgucggga (SEQ ID NO: 781), AGGgucugca (SEQ ID NO: 782), AGGgucuguu (SEQ ID NO: 783), AGGgugaaga (SEQ ID NO: 784), AGGgugacua (SEQ ID NO: 785), AGGgugagaa (SEQ ID NO: 786), AGGgugagac (SEQ ID NO: 787), AGGgugagag (SEQ ID NO: 788), AGGgugagca (SEQ ID NO: 789), AGGgugagcc (SEQ ID NO: 790), AGG gugagcu (SEQ ID NO: 791), AGGgugagga (SEQ ID NO: 792), AGGgugaggg (SEQ ID NO: 793), AGGgugaggu (SEQ ID NO: 794), AGGgugagua (SEQ ID NO: 795), AGGgugaguc (SEQ ID NO: 796), AGGgugagug (SEQ ID NO: 797), AGGgugaguu (SEQ ID NO: 798), AGGgugggga (SEQ ID NO: 799), AGGguggggu (SEQ ID NO: 800), AGGgugggua (SEQ ID NO: 801), AGGgugggug (SEQ ID NO: 802), AGGgugugua (SEQ ID NO: 791), AGGgugagga (SEQ ID NO: 792), AGGgugaggg (SEQ ID NO: 793), AGGgugaggu (SEQ ID NO: 794), AGGgugagua (SEQ ID NO: 795), AGGgugaguc (SEQ ID NO: 796), AGGgugagug (SEQ ID NO: 797), AGGgugaguu (SEQ ID NO: 798), AGGgugggga (SEQ ID NO: 800), AGGgugggua (SEQ ID NO: 801), AGGgugggug (SEQ ID NO: 802), AGGgugugua (SEQ ID NO: 791), AGGgugagga (SEQ ID NO: 792), AGGgugaggg (SEQ ID NO: 793), AGGgugaggu (SEQ ID NO: 794), AGGgugagua (SEQ ID NO: 795), AGGgugaguc (SEQ ID NO: 796), AGGgugagug (SEQ ID NO: 797), AGGgugaguu (SEQ ID Column number 803), AGGgugugug (sequence number 804), AGGguuaaug (sequence number 805), AGGguuagaa (sequence number 806), AGGguuaguu (sequence number 807), AGGguuggug (sequence number 808), AGGguuugug (sequence number 809), AGGguuuguu (sequence number 810), AGUguaaaag (sequence number 811), AGUguaaaua (sequence number 812), AGUguaaauu (sequence number 813), AGUguaagaa (sequence number 814), AGUguaagag (sequence number 815), A GUguaagau (SEQ ID NO: 816), AGUguaagca (SEQ ID NO: 817), AGUguaagcc (SEQ ID NO: 818), AGUguaagua (SEQ ID NO: 819), AGUguaagug (SEQ ID NO: 820), AGUguaaguu (SEQ ID NO: 821), AGUguaauug (SEQ ID NO: 822), AGUguaggac (SEQ ID NO: 823), AGUguagguc (SEQ ID NO: 824), AGUguaugag (SEQ ID NO: 825), AGUguaugua (SEQ ID NO: 826), AGUguauguu (SEQ ID NO: 827), AGUguauugu (SEQ ID NO: 828), AGUguauuua (SEQ ID NO: 829), AGUgucaguc (SEQ ID NO: 830), AGUgugagag (SEQ ID NO: 831), AGUgugagca (SEQ ID NO: 832), AGUgugagcc (SEQ ID NO: 833), AGUgugagcu (SEQ ID NO: 834), AGUgugagua (SEQ ID NO: 835), AGUgugaguc (SEQ ID NO: 836), AGUgugagug (SEQ ID NO: 837), AGUgugaguu (SEQ ID NO: 838), AGUgugggua (SEQ ID NO: 839), AGUgugggug (SEQ ID NO: 840),AGUgugugua (SEQ ID NO: 841), AGUguuccua (SEQ ID NO: 842), AGUguugggg (SEQ ID NO: 843), AGUguuucag (SEQ ID NO: 844), AUAguaaaua (SEQ ID NO: 845), AUAguaagac (SEQ ID NO: 846), AUAguaagau (SEQ ID NO: 847), AUAguaagca (SEQ ID NO: 848), AUAguaagua (SEQ ID NO: 849), AUAguaagug (SEQ ID NO: 850), AUAguaaguu (SEQ ID NO: 851), AUAguaggua (SEQ ID NO: 852), AUAguauguu (SEQ ID NO: 853), AUAgucucac (SEQ ID NO: 854), AUAgugagac (SEQ ID NO: 855), AUAgugagag (SEQ ID NO: 856), AUAgugagau (SEQ ID NO: 857), AUAgugagcc (SEQ ID NO: 858), AUAgugaggc (SEQ ID NO: 859), AUAgugagua (SEQ ID NO: 860), AUAgugaguc (SEQ ID NO: 861), AUAgugagug (SEQ ID NO: 862), AUAgugcguc (SEQ ID NO: 863), AUAgugugua (SEQ ID NO: 864), AUAguucagu (SEQ ID NO: 865), AUCguaagcc (SEQ ID NO: 866), AUCguaaguu (SEQ ID NO: 867), AUCguauucc (SEQ ID NO: 868), AUCgugagua (SEQ ID NO: 869), AUGgcaagcg (SEQ ID NO: 870), AUGgcaagga (SEQ ID NO: 871), AUGgcaaguu (SEQ ID NO: 872), AUGgcaggua (SEQ ID NO: 873), AUGgcaugug (SEQ ID NO: 874), AUGgcgccau (SEQ ID NO: 875), AUGgcuugug (SEQ ID NO: 876), AUGguaaaac (SEQ ID NO: 877), AUGguaaaau (SEQ ID NO: 878), AUGguaaacc (SEQ ID NO: 879), AUGguaaaga (SEQ ID NO: 880), AUGguaaaua (SEQ ID NO: 881), AUGguaaaug (SEQ ID NO: 882), AUGguaaauu (SEQ ID NO: 883), AUGguaacag (SEQ ID NO: 884), AUGguaacau (SEQ ID NO: 885), AUGguaacua (SEQ ID NO: 886), AUGguaacuc (SEQ ID NO: 887), AUGguaacuu (SEQ ID NO: 888), AUGguaagaa (SEQ ID NO: 889), AUGguaagac (SEQ ID NO: 890),AUG、 guaagag (SEQ ID NO: 891), AUGguaagau (SEQ ID NO: 892), AUGguaagca (SEQ ID NO: 893), AUGguaagcc (SEQ ID NO: 894), AUGguaagcu (SEQ ID NO: 895), AUGguaagga (SEQ ID NO: 896), AUGguaaggg (SEQ ID NO: 897), AUGguaagua (SEQ ID NO: 898), AUGguaaguc (SEQ ID NO: 899), AUGguaagug (SEQ ID NO: 900), AUGguaaguu (SEQ ID NO: 901), AUGguaauaa (SEQ ID NO: 902), AUGguaau1), AUGguaagca (SEQ ID NO: 893), AUGguaagcc (SEQ ID NO: 894), AUGguaagcu (SEQ ID NO: 895), AUGguaagga (SEQ ID NO: 896), AUGguaaggg (SEQ ID NO: 897), AUGguaag (SEQ ID NO: 898), AUGguaag (SEQ ID NO: 894), AUGguaagcu (SEQ ID NO: 895), AUGguaagga (SEQ ID NO: 896), AUGguaag (SEQ ID NO: 897), AUGguaag (SEQ ID NO: 898), Column number 903), AUGguaauga (sequence number 904), AUGguaaugg (sequence number 905), AUGguaauug (sequence number 906), AUGguaauuu (sequence number 907), AUGguacagc (sequence number 908), AUGguacauc (sequence number 909), AUGguaccag (sequence number 910), AUGguaccug (sequence number 911), AUGguacgag (sequence number 912), AUGguacggu (sequence number 913), AUGguagauc (sequence number 914), AUGguagcag (sequence number 915), A UGguagcug (SEQ ID NO: 916), AUGguaggaa (SEQ ID NO: 917), AUGguaggau (SEQ ID NO: 918), AUGguaggca (SEQ ID NO: 919), AUGguaggcu (SEQ ID NO: 920), AUGguagggg (SEQ ID NO: 921), AUGguagggu (SEQ ID NO: 922), AUGguaggua (SEQ ID NO: 923), AUGguaggug (SEQ ID NO: 924), AUGguaguuu (SEQ ID NO: 925), AUGguauagu (SEQ ID NO: 926), AUGguauaua (SEQ ID NO: 927), AUGguaucag (SEQ ID NO: 928), AUGguaucuu (SEQ ID NO: 929), AUGguaugau (SEQ ID NO: 930), AUGguaugca (SEQ ID NO: 931), AUGguaugcc (SEQ ID NO: 932), AUGguaugcg (SEQ ID NO: 933), AUGguaugcu (SEQ ID NO: 934), AUGguaugga (SEQ ID NO: 935), AUGguauggc (SEQ ID NO: 936), AUGguaugug (SEQ ID NO: 937), AUGguauguu (SEQ ID NO: 938), AUGguauuau (SEQ ID NO: 939), AUGguauuga (SEQ ID NO: 940),AUGguauuug (SEQ ID NO: 941), AUGgucaggg (SEQ ID NO: 942), AUGgucaguc (SEQ ID NO: 943), AUGgucagug (SEQ ID NO: 944), AUGgucauuu (SEQ ID NO: 945), AUGgugaaaa (SEQ ID NO: 946), AUGgugaaac (SEQ ID NO: 947), AUGgugaaau (SEQ ID NO: 948), AUGgugaacu (SEQ ID NO: 949), AUGgugaaga (SEQ ID NO: 950), AUGgugacgu (SEQ ID NO: 951), AUGgugagaa (SEQ ID NO: 952), AUGgugagac (SEQ ID NO: 953), AUGgugagag (SEQ ID NO: 954), AUGgugagca (SEQ ID NO: 955), AUGgugagcc (SEQ ID NO: 956), AUGgugagcg (SEQ ID NO: 957), AUGgugagcu (SEQ ID NO: 958), AUGgugaggc (SEQ ID NO: 959), AUGgugaggg (SEQ ID NO: 960), AUGgugagua (SEQ ID NO: 961), AUGgugaguc (SEQ ID NO: 962), AUGgugagug (SEQ ID NO: 963), AUGgugaguu (SEQ ID NO: 964), AUGgugauuu (SEQ ID NO: 965), AUGgugcgau (SEQ ID NO: 966), AUGgugcgug (SEQ ID NO: 967), AUGgugggua (SEQ ID NO: 968), AUGgugggug (SEQ ID NO: 969), AUGguggguu (SEQ ID NO: 970), AUGgugguua (SEQ ID NO: 971), AUGguguaag (SEQ ID NO: 972), AUGgugugaa (SEQ ID NO: 973), AUGgugugua (SEQ ID NO: 974), AUGgugugug (SEQ ID NO: 975), AUGguuacuc (SEQ ID NO: 976), AUGguuagca (SEQ ID NO: 977), AUGguuaguc (SEQ ID NO: 978), AUGguuagug (SEQ ID NO: 979), AUGguuaguu (SEQ ID NO: 980), AUGguucagu (SEQ ID NO: 981), AUGguucguc (SEQ ID NO: 982), AUGguuggua (SEQ ID NO: 983), AUGguugguc (SEQ ID NO: 984), AUGguugguu (SEQ ID NO: 985), AUGguuguuu (SEQ ID NO: 986), AUGguuugca (SEQ ID NO: 987), AUGguuugua (SEQ ID NO: 988), AUUgcaagua (SEQ ID NO: 989), AUUguaaaua (SEQ ID NO: 990),AUU, guaagau (sequence number 991), AUUguaagca (sequence number 992), AUUguaagga (sequence number 993), AUUguaaggc (sequence number 994), AUUguaagua (sequence number 995), AUUguaaguc (sequence number 996), AUUguaaguu (sequence number 997), AUUguaauua (sequence number 998), AUUguaauuu (sequence number 999), AUUguacaaa (sequence number 1000), AUUguaccuc (sequence number 1001), AUUguacgug (sequence number 1002), AUUguacuug (sequence number 1003), AUUguaggua (sequence number 1004), AUUguaugag (sequence number 100 5) AUUguaugua (SEQ ID NO: 1006), AUUgucuguu (SEQ ID NO: 1007), AUUgugagcu (SEQ ID NO: 1008), AUUgugagua (SEQ ID NO: 1009), AUUgugaguc (SEQ ID NO: 1010), AUUgugaguu (SEQ ID NO: 1011), AUUgugcgug (SEQ ID NO: 1012), AUUgugggug (SEQ ID NO: 1013), AUUguuagug (SEQ ID NO: 1014), CAAguaaaaa (SEQ ID NO: 1015), CAAguaaaua (SEQ ID NO: 1016), CAAguaaauc (SEQ ID NO: 1017), CAAguaaaug (SEQ ID NO: 1018), CAAguaaccc (SEQ ID NO: 1019), CAAg uaacua (SEQ ID NO: 1020), CAAguaacug (SEQ ID NO: 1021), CAAguaagaa (SEQ ID NO: 1022), CAAguaagac (SEQ ID NO: 1023), CAAguaagau (SEQ ID NO: 1024), CAAguaaggu (SEQ ID NO: 1025), CAAguaagua (SEQ ID NO: 1026), CAAguaaguc (SEQ ID NO: 1027), CAAguaagug (SEQ ID NO: 1028), CAAguaaguu (SEQ ID NO: 1029), CAAguaaucc (SEQ ID NO: 1030), CAAguaaucu (SEQ ID NO: 103 1) CAAguaauua (SEQ ID NO: 1032), CAAguaauuc (SEQ ID NO: 1033), CAAguaauug (SEQ ID NO: 1034), CAAguaauuu (SEQ ID NO: 1035), CAAguacaca (SEQ ID NO: 1036), CAAguacguu (SEQ ID NO: 1037), CAAguacuuu (SEQ ID NO: 1038), CAAguagcug (SEQ ID NO: 1039), CAAguaggau (SEQ ID NO: 1040), CAAguaggua (SEQ ID NO: 1041), CAAguagguc (SEQ ID NO: 1042), CAAguaggug (SEQ ID NO: 1032), CAAguaauua (SEQ ID NO: 1032), CAAguaauuc (SEQ ID NO: 1033), CAAguaauug (SEQ ID NO: 1034), CAAguaauuu (SEQ ID NO: 1035), CAAguacaca (SEQ ID NO: 1036), CAAguaacguu (SEQ ID NO: 1037), CAAguacuuu (SEQ ID NO: 1038), CAAguagcug (SEQ ID NO: 1039), CAAguaggau (SEQ ID NO: 1041), CAAguagguc (SEQ ID NO: 1042), CAAguaggug (SEQ ID NO: 1032), CAAguaauua (SEQ ID NO: 1033), CAAguaauug (SEQ ID NO: 1034), CAAguaauuu (SEQ ID NO: 1035), CAAguacaca (SEQ ID NO: 1036), CAAguaacguu (SEQ ID NO: 1037), CAAguacuuu (SEQ ID NO: 1034), CAAguaau (Column number 1043), CAAguagguu (SEQ ID NO: 1044), CAAguaguuu (SEQ ID NO: 1045), CAAguauaac (SEQ ID NO: 1046), CAAguauaug (SEQ ID NO: 1047), CAAguaucuu (SEQ ID NO: 1048), CAAguaugag (SEQ ID NO: 1049), CAAguaugua (SEQ ID NO: 1050), CAAguauguc (SEQ ID NO: 1051), CAAguaugug (SEQ ID NO: 1052), CAAguauguu (SEQ ID NO: 1053), CAAguauuga (SEQ ID NO: 1054), CAAgua uuuc (sequence number 1055), CAAgucagac (sequence number 1056), CAAgucagua (sequence number 1057), CAAgucuaua (sequence number 1058), CAAgucugau (sequence number 1059), CAAgugacuu (sequence number 1060), CAAgugagaa (sequence number 1061), CAAgugagac (sequence number 1062), CAAgugagca (sequence number 1063), CAAgugaggc (sequence number 1064), CAAgugaggg (sequence number 1065), CAAgugagua (sequence number 1066),CAAgugaguc (SEQ ID NO: 1067), CAAgugagug (SEQ ID NO: 1068), CAAgugaucc (SEQ ID NO: 1069), CAAgugaucu (SEQ ID NO: 1070), CAAgugauuc (SEQ ID NO: 1071), CAAgugauug (SEQ ID NO: 1072), CAAgugauuu (SEQ ID NO: 1073), CAAgugccuu (SEQ ID NO: 1074), CAAgugggua (SEQ ID NO: 1075), CAAguggguc (SEQ ID NO: 1076), CAAgugggug (SEQ ID NO: 1077), CAAgugugag (SEQ ID NO: 1078), CAAguuaaaa (SEQ ID NO: 1079), CAAguuaagu (SEQ ID NO: 1080), CAAguuaauc (SEQ ID NO: 1081), CAAguuagaa (SEQ ID NO: 1082), CAAguuaguu (SEQ ID NO: 1083), CAAguucaag (SEQ ID NO: 1084), CAAguuccgu (SEQ ID NO: 1085), CAAguuggua (SEQ ID NO: 1086), CAAguuuagu (SEQ ID NO: 1087), CAAguuucca (SEQ ID NO: 1088), CAAguuuguu (SEQ ID NO: 1089), CACguaagag (SEQ ID NO: 1090), CACguaagca (SEQ ID NO: 1091), CACguaauug (SEQ ID NO: 1092), CACguaggac (SEQ ID NO: 1093), CACguaucga (SEQ ID NO: 1094), CACgucaguu (SEQ ID NO: 1095), CACgugagcu (SEQ ID NO: 1085) 1096), CACgugaguc (SEQ ID NO: 1097), CACgugagug (SEQ ID NO: 1098), CAGgcaagaa (SEQ ID NO: 1099), CAGgcaagac (SEQ ID NO: 1100), CAGgcaagag (SEQ ID NO: 1101), CAGgcaagga (SEQ ID NO: 1102), CAGgcaagua (SEQ ID NO: 1103), CAGgcaagug (SEQ ID NO: 1104), CAGgcaaguu (SEQ ID NO: 1105), CAGgcacgca (SEQ ID NO: 1106), CAGgcagagg (SEQ ID NO: 1107), CAGgcaggug (SEQ ID NO: 1108), CAGgcaucau (SEQ ID NO: 1109), CAGgcaugaa (SEQ ID NO: 1110), CAGgcaugag (SEQ ID NO: 1111), CAGgcaugca (SEQ ID NO: 1112), CAGgcaugcg (SEQ ID NO: 1113), CAGgcaugug (SEQ ID NO: 1114), CAGgcgagag (SEQ ID NO: 1115), CAGgcgccug (SEQ ID NO: 1116), CAGgcgugug (SEQ ID NO: 1117), CAGguaaaaa (SEQ ID NO: 1118), CAGguaaaag (SEQ ID NO: 1119), CAGgu aaaca (SEQ ID NO: 1120), CAGguaaacc (SEQ ID NO: 1121), CAGguaaaga (SEQ ID NO: 1122), CAGguaaagc (SEQ ID NO: 1123), CAGguaaagu (SEQ ID NO: 1124), CAGguaaaua (SEQ ID NO: 1125), CAGguaaauc (SEQ ID NO: 1126), CAGguaaaug (SEQ ID NO: 1127), CAGguaaauu (SEQ ID NO: 1128), CAGguaacag (SEQ ID NO: 1129), CAGguaacau (SEQ ID NO: 1130), CAGguaacca (SEQ ID NO: 1131),CAGguaaccg (SEQ ID NO: 1132), CAGguaacgu (SEQ ID NO: 1133), CAGguaacua (SEQ ID NO: 1134), CAGguaacuc (SEQ ID NO: 1135), CAGguaacug (SEQ ID NO: 1136), CAGguaacuu (SEQ ID NO: 1137), CAGguaagaa (SEQ ID NO: 1138), CAGguaagac (SEQ ID NO: 1139), CAGguaagag (SEQ ID NO: 1140), CAGguaagau (SEQ ID NO: 1141), CAGguaagcc (SEQ ID NO: 1142), CAGguaagga (SEQ ID NO: 1132) 1143), CAGguaaggc (sequence number 1144), CAGguaaggg (sequence number 1145), CAGguaaggu (sequence number 1146), CAGguaagua (sequence number 1147), CAGguaagug (sequence number 1148), CAGguaaguu (sequence number 1149), CAGguaauaa (sequence number 1150), CAGguaauau (sequence number 1151), CAGguaaucc (sequence number 1152), CAGguaaugc (sequence number 1153), CAGguaaugg (sequence number 1154), CAGguaaugu (SEQ ID NO: 1155), CAGguaauua (SEQ ID NO: 1156), CAGguaauuc (SEQ ID NO: 1157), CAGguaauug (SEQ ID NO: 1158), CAGguaauuu (SEQ ID NO: 1159), CAGguacaaa (SEQ ID NO: 1160), CAGguacaag (SEQ ID NO: 1161), CAGguacaau (SEQ ID NO: 1162), CAGguacaca (SEQ ID NO: 1163), CAGguacacg (SEQ ID NO: 1164), CAGguacaga (SEQ ID NO: 1165), CAGguacagg (SEQ ID NO: 1166), CAGgu acagu (sequence number 1167), CAGguacaua (sequence number 1168), CAGguacaug (sequence number 1169), CAGguacauu (sequence number 1170), CAGguaccac (sequence number 1171), CAGguaccca (sequence number 1172), CAGguacccg (sequence number 1173), CAGguacccu (sequence number 1174), CAGguaccgc (sequence number 1175), CAGguaccgg (sequence number 1176), CAGguaccuc (sequence number 1177), CAGguaccug (sequence number 1178),CAGguaccuu (SEQ ID NO: 1179), CAGg, uacgag (SEQ ID NO: 1180), CAGguacgca (SEQ ID NO: 1181), CAGguacgcc (SEQ ID NO: 1182), CAGguacggu (SEQ ID NO: 1183), CAGguacgua (SEQ ID NO: 1184), CAGguacgug (SEQ ID NO: 1185), CAGguacuaa (SEQ ID NO: 1186), CAGguacuag (SEQ ID NO: 1187), CAGguacuau (SEQ ID NO: 1188), CAGguacucc (SEQ ID NO: 1189), CAGguacucu (SEQ ID NO: 1190), CAGguacuga (SEQ ID NO: 119 1) CAGguacugc (SEQ ID NO: 1192), CAGguacugu (SEQ ID NO: 1193), CAGguacuua (SEQ ID NO: 1194), CAGguacuuu (SEQ ID NO: 1195), CAGguagaaa (SEQ ID NO: 1196), CAGguagaac (SEQ ID NO: 1197), CAGguagaag (SEQ ID NO: 1198), CAGguagaca (SEQ ID NO: 1199), CAGguagacc (SEQ ID NO: 1200), CAGguagaga (SEQ ID NO: 1201), CAGguagauu (SEQ ID NO: 1202), CAGguagcaa (SEQ ID NO: 1192), (Sequence number 1203), CAGguagcac (Sequence number 1204), CAGguagcag (Sequence number 1205), CAGguagcca (Sequence number 1206), CAGguagcgu (Sequence number 1207), CAGguagcua (Sequence number 1208), CAGguagcuc (Sequence number 1209), CAGguagcug (Sequence number 1210), CAGguagcuu (Sequence number 1211), CAGguaggaa (Sequence number 1212), CAGguaggac (Sequence number 1213), CAGguaggag (Sequence number 1214), CAGgua ggca (SEQ ID NO: 1215), CAGguaggga (SEQ ID NO: 1216), CAGguagggc (SEQ ID NO: 1217), CAGguagggg (SEQ ID NO: 1218), CAGguagggu (SEQ ID NO: 1219), CAGguaggua (SEQ ID NO: 1220), CAGguagguc (SEQ ID NO: 1221), CAGguaggug (SEQ ID NO: 1222), CAGguagguu (SEQ ID NO: 1223), CAGguaguaa (SEQ ID NO: 1224), CAGguaguau (SEQ ID NO: 1225), CAGguaguca (SEQ ID NO: 1226),CAGguagucc (SEQ ID NO: 1227), CAGguaguga (SEQ ID NO: 1228), CAGguagugu (SEQ ID NO: 1229), CAGguaguuc (SEQ ID NO: 1230), CAGguaguug (SEQ ID NO: 1231), CAGguaguuu (SEQ ID NO: 1232), CAGguauaag (SEQ ID NO: 1233), CAGguauaca (SEQ ID NO: 1234), CAGguauaga (SEQ ID NO: 1235), CAGguauauc (SEQ ID NO: 1236), CAGguauaug (SEQ ID NO: 1237), CAGguauauu (SEQ ID NO: 1238), CAGguaucag (SEQ ID NO: 1239), CAGguaucau (SEQ ID NO: 1240), CAGguauccu (SEQ ID NO: 1241), CAGguaucga (SEQ ID NO: 1242), CAGguaucgc (SEQ ID NO: 1243), CAGguaucua (SEQ ID NO: 1244), CAGguaucug ( SEQ ID NO: 1245), CAGguaucuu (SEQ ID NO: 1246), CAGguaugaa (SEQ ID NO: 1247), CAGguaugac (SEQ ID NO: 1248), CAGguaugag (SEQ ID NO: 1249), CAGguaugau (SEQ ID NO: 1250), CAGguaugca (SEQ ID NO: 1251), CAGguaugcc (SEQ ID NO: 1252), CAGguaugcg (SEQ ID NO: 1253), CAGguaugcu (SEQ ID NO: 12 54), CAGguaugga (SEQ ID NO: 1255), CAGguauggg (SEQ ID NO: 1256), CAGguauggu (SEQ ID NO: 1257), CAGguaugua (SEQ ID NO: 1258), CAGguauguc (SEQ ID NO: 1259), CAGguaugug (SEQ ID NO: 1260), CAGguauguu (SEQ ID NO: 1261), CAGguauuau (SEQ ID NO: 1262), CAGguauuca (SEQ ID NO: 1263), C, AGguauucu (SEQ ID NO: 1264), CAGguauuga (SEQ ID NO: 1265), CAGguauugg (SEQ ID NO: 1266), CAGguauugu (SEQ ID NO: 1267), CAGguauuua (SEQ ID NO: 1268), CAGguauuuc (SEQ ID NO: 1269), CAGguauuug (SEQ ID NO: 1270), CAGguauuuu (SEQ ID NO: 1271), CAGgucaaca (SEQ ID NO: 1272), CAGgucaaugu (SEQ ID NO: 1269), CAGguauuug (SEQ ID NO: 1266), CAGguauuu (SEQ ID NO: 1267), CAGguauuua (SEQ ID NO: 1268), CAGguauuucu (SEQ ID NO: 1269), CAGguauuug (SEQ ID NO:(Sequence number 1273), CAGgucacgu (Sequence number 1274), CAGgucagaa (Sequence number 1275), CAGgucagac (Sequence number 1276), CAGgucagca (Sequence number 1277), CAGgucagcc (Sequence number 1278), CAGgucagcg (Sequence number 1279), CAGgucagga (Sequence number 1280), CAGgucagua (Sequence number 1281), CAGgucaguc (Sequence number 1282), CAGgucagug (Sequence number 1283), CAGgucaguu (Sequence number 1284), CAGgucauc c (sequence number 1285), CAGgucaugc (sequence number 1286), CAGgucauua (sequence number 1287), CAGgucauuu (sequence number 1288), CAGguccacc (sequence number 1289), CAGguccacu (sequence number 1290), CAGguccagu (sequence number 1291), CAGguccauc (sequence number 1292), CAGguccauu (sequence number 1293), CAGgucccag (sequence number 1294), CAGgucccug (sequence number 1295), CAGguccuga (sequence number 1296), CAGguc cugc (sequence number 1297), CAGguccugg (sequence number 1298), CAGgucggcc (sequence number 1299), CAGgucggug (sequence number 1300), CAGgucguug (sequence number 1301), CAGgucucuc (sequence number 1302), CAGgucucuu (sequence number 1303), CAGgucugag (sequence number 1304), CAGgucugcc (sequence number 1305), CAGgucugcg (sequence number 1306), CAGgucugga (sequence number 1307), CAGgucuggu (sequence number 1308), CAG gucugua (SEQ ID NO: 1309), CAGgucuguc (SEQ ID NO: 1310), CAGgucugug (SEQ ID NO: 1311), CAGgucuguu (SEQ ID NO: 1312), CAGgucuucc (SEQ ID NO: 1313), CAGgucuuuc (SEQ ID NO: 1314), CAGgugaaag (SEQ ID NO: 1315), CAGgugaaau (SEQ ID NO: 1316), CAGgugaaca (SEQ ID NO: 1317), CAGgugaaga (SEQ ID NO: 1318), CAGgugaagg (SEQ ID NO: 1319), CAGgugaaua (SEQ ID NO: 1320),CAGgugaauc (SEQ ID NO: 1321), CAGgugaauu (SEQ ID NO: 1322), CAGgugacaa (SEQ ID NO: 1323), CAGgugacau (SEQ ID NO: 1324), CAGgugacca (SEQ ID NO: 1325), CAGgugaccc (SEQ ID NO: 1326), CAGgugaccg (SEQ ID NO: 1327), CAGgugaccu (SEQ ID NO: 1328), CAGgugacgg (SEQ ID NO: 1329), CAGgugacua (SEQ ID NO: 1330), CAGgugacuc (SEQ ID NO: 1331), CAGgugacug (SEQ ID NO: 1321) 1332), CAGgugagaa (SEQ ID NO: 1333), CAGgugagac (SEQ ID NO: 1334), CAGgugagag (SEQ ID NO: 1335), CAGgugagau (SEQ ID NO: 1336), CAGgugagca (SEQ ID NO: 1337), CAGgugagcc (SEQ ID NO: 1338), CAGgugagcg (SEQ ID NO: 1339), CAGgugagcu (SEQ ID NO: 1340), CAGgugagga (SEQ ID NO: 1341), CAGgugaggc (SEQ ID NO: 1342), CAGgugaggg (SEQ ID NO: 1343), CAGgugaggu (SEQ ID NO: 1344), CAGgugagua (SEQ ID NO: 1345), CAGgugaguc (SEQ ID NO: 1346), CAGgugagug (SEQ ID NO: 1347), CAGgugaguu (SEQ ID NO: 1348), CAGgugauaa (SEQ ID NO: 1349), CAGgugaucc (SEQ ID NO: 1350), CAGgugaucu (SEQ ID NO: 1351), CAGgugaugc (SEQ ID NO: 1352), CAGgugaugg (SEQ ID NO: 1353), CAGgugaugu (SEQ ID NO: 1354), CAGgugauua (SEQ ID NO: 1355), CAGgu gauuc (sequence number 1356), CAGgugauug (sequence number 1357), CAGgugauuu (sequence number 1358), CAGgugcaaa (sequence number 1359), CAGgugcaag (sequence number 1360), CAGgugcaca (sequence number 1361), CAGgugcacg (sequence number 1362), CAGgugcaga (sequence number 1363), CAGgugcagg (sequence number 1364), CAGgugcaua (sequence number 1365), CAGgugcauc (sequence number 1366), CAGgugcaug (sequence number 1367),CAGgugccaa(Sequence No. 13, 68), CAGgugccca (SEQ ID NO: 1369), CAGgugcccc (SEQ ID NO: 1370), CAGgugcccg (SEQ ID NO: 1371), CAGgugccua (SEQ ID NO: 1372), CAGgugccug (SEQ ID NO: 1373), CAGgugcgaa (SEQ ID NO: 1374), CAGgugcgca (SEQ ID NO: 1375), CAGgugcgcc (SEQ ID NO: 1376), CAGgugcgcg (SEQ ID NO: 1377), CAGgugcgga (SEQ ID NO: 1378), CAGgugcggu (SEQ ID NO: 1379), CAGgugcgua (SEQ ID NO: 1379) Column number 1380), CAGgugcguc (sequence number 1381), CAGgugcgug (sequence number 1382), CAGgugcuag (sequence number 1383), CAGgugcuau (sequence number 1384), CAGgugcuca (sequence number 1385), CAGgugcucc (sequence number 1386), CAGgugcucg (sequence number 1387), CAGgugcugc (sequence number 1388), CAGgugcugg (sequence number 1389), CAGgugcuua (sequence number 1390), CAGgugcuuc (sequence number 1391), CAGgugcu ug (sequence number 1392), CAGguggaac (sequence number 1393), CAGguggaag (sequence number 1394), CAGguggaau (sequence number 1395), CAGguggaga (sequence number 1396), CAGguggagu (sequence number 1397), CAGguggauu (sequence number 1398), CAGguggcca (sequence number 1399), CAGguggcuc (sequence number 1400), CAGguggcug (sequence number 1401), CAGgugggaa (sequence number 1402), CAGgugggac (sequence number 1403), CAGg ugggag (sequence number 1404), CAGgug...

Claims

[Claim 1] The invention described in the specification.

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