Compounds and methods for modulating splicing

Abstract

The disclosure features, inter alia, compounds and related compositions that modulate nucleic acid splicing, eg, pre-mRNA splicing, and methods of their use.

Description

[Technical Field]

[0001] Priority claim This application claims priority to U.S. Patent Application No. 63 / 238,687, filed August 30, 2021; U.S. Patent Application No. 63 / 238,693, filed August 30, 2021; U.S. Patent Application No. 63 / 238,424, filed August 30, 2021; U.S. Patent Application No. 63 / 282,902, filed November 24, 2021; and U.S. Patent Application No. 63 / 393,202, filed July 28, 2022. The disclosures of each of the above applications are incorporated herein by reference in their entirety. [Background technology]

[0002] Alternative splicing is a major source of protein diversity in higher eukaryotes and is frequently regulated in a tissue- or developmental stage-specific manner. Disease-associated alternative splicing patterns in pre-mRNAs are often associated with alterations in splice site signals or sequence motifs and regulatory splicing factors (Faustino and Cooper (2003), Genes Dev 17(4):419-37). Current treatments for modulating RNA expression involve oligonucleotide targeting and gene therapy. However, each of these modalities presents unique challenges as they currently present. Therefore, novel technologies for modulating RNA expression, including the development of small molecule compounds that target splicing, are needed. [Prior art documents] [Non-patent literature]

[0003] [Non-Patent Document 1] Faustino and Cooper(2003),Genes Dev 17(4):419-37 Summary of the Invention

[0004] The present disclosure features, among other things, compounds and related compositions that modulate nucleic acid splicing, eg, pre-mRNA splicing, and methods of their use. In one embodiment, the compounds described herein are compounds of Formula (I), (II), or (III) (e.g., compounds of Formula (Ia), (Ib), (Ic), (Id), (Ie), (If), (Ig), (Ih), (Ii), (Ij), (Ik), (Ik), (II-a), (II-b), (II-c), (II-d), (II-e), (III-a), (III-b), (III-c), (III-d), (III-e), (III-f), (III-g), (III-h), (III-i), (III-j), or (III-k)), and pharmaceutically acceptable salts, solvates, hydrates, tautomers, or stereoisomers thereof. The present disclosure provides methods for detecting and regulating the expression of proteins, e.g., nucleic acids (e.g., pre-mRNA, or small nuclear ribonucleoproteins (snRNPs) or nucleic acid components of the spliceosome), proteins (e.g., protein components of the snRNPs or spliceosomes, e.g., members of the splicing machinery, e.g., U1, U2, U4, U5, U6, U11, U12, U4atac, U6 ... Further provided are methods of using compounds of the present disclosure (e.g., compounds of Formula (Ia), (Ib), (Ic), (Id), (Ie), (If), (Ig), (Ih), (Ii), (Ij), (Ik), (Ik), (II-a), (II-b), (II-c), (II-d), (II-e), (III-a), (III-b), (III-c), (III-d), (III-e), (III-f), (III-g), (III-h), (III-i), (III-j), or (III-k), and pharmaceutically acceptable salts, solvates, hydrates, tautomers, stereoisomers thereof), and compositions thereof, that target, and in embodiments bind to, or form a complex with, one or more of the following:In another aspect, the compounds described herein can be used to alter the composition or structure of a nucleic acid (e.g., a pre-mRNA or mRNA (e.g., a pre-mRNA and an mRNA generated from a pre-mRNA)), for example, by increasing or decreasing splicing at a splice site. In some embodiments, increasing or decreasing splicing results in modulation of the level of a gene product (e.g., RNA or protein) produced. In another aspect, the compounds described herein can be used for the prevention and / or treatment of a disease, disorder, or condition, e.g., a disease, disorder, or condition associated with splicing, e.g., alternative splicing. In some embodiments, the compounds described herein (e.g., compounds of Formula (Ia), (Ib), (Ic), (Id), (Ie), (If), (Ig), (Ih), (Ii), (Ij), (Ik), (Ik), (II-a), (II-b), (II-c), (II-d), (II-e), (III-a), (III-b), (III-c), (III-d), (III-e), (III-f), (III-g), (III-h), (III-i), (III-j), or (III-k), and pharmaceutically acceptable salts, solvates, hydrates, tautomers, stereoisomers thereof) and compositions thereof are used for the prevention and / or treatment of a proliferative disease, disorder, or condition in a subject (e.g., a disease, disorder, or condition characterized by unwanted cell proliferation, e.g., cancer or benign neoplasm). In some embodiments, the compounds described herein (e.g., compounds of Formula (Ia), (Ib), (Ic), (Id), (Ie), (If), (Ig), (Ih), (Ii), (Ij), (Ik), (Ik), (II-a), (II-b), (II-c), (II-d), (II-e), (III-a), (III-b), (III-c), (III-d), (III-e), (III-f), (III-g), (III-h), (III-i), (III-j), or (III-k), and pharmaceutically acceptable salts, solvates, hydrates, tautomers, stereoisomers thereof) and compositions thereof are used for the prevention and / or treatment of non-proliferative diseases, disorders, or conditions.In some embodiments, a compound described herein (e.g., Formula (Ia), (Ib), (Ic), (Id), (Ie), (If), (Ig), (Ih), (Ii), (Ij), (Ik), (Ik), (II-a), (II-b), (II-c), (II-d), (II-e), (III-a), (III-b), (III-c), (III-d), (III-e), (III-f), (III-g), (III-h), (III-i), (I The compounds of formula II-j), or (III-k), and pharmaceutically acceptable salts, solvates, hydrates, tautomers, stereoisomers thereof) and compositions thereof are used for the prevention and / or treatment of a nervous system disease or disorder, an autoimmune disease or disorder, an immunodeficiency disease or disorder, a lysosomal storage disease or disorder, a cardiovascular disease or disorder, a metabolic disease or disorder, a respiratory disease or disorder, a renal disease or disorder, or an infectious disease in a subject.

[0005] In another aspect, the present disclosure provides a compound of formula (I) [ka] or a pharmaceutically acceptable salt, solvate, hydrate, tautomer, or stereoisomer thereof, wherein A, B, W, X, Y, Z, L 1 , R 2 , m, and its subvariables are defined as described herein.

[0006] In another aspect, the present disclosure provides a compound of formula (II) [ka] or a pharmaceutically acceptable salt, solvate, hydrate, tautomer, or stereoisomer thereof, wherein A, B, M, P, W, X, Y, Z, L 1 , L 2 , and its subvariables are defined as described herein.

[0007] In another aspect, the present disclosure provides a compound of formula (III) [ka] or a pharmaceutically acceptable salt, solvate, hydrate, tautomer, or stereoisomer thereof, wherein A, B, L 1 , L 2 , R 2 , m, and its subvariables are defined as described herein.

[0008] In another aspect, the present invention provides a pharmaceutical composition comprising a compound of Formula (I) (e.g., a compound of Formula (Ia), (Ib), (Ic), (Id), (Ie), (If), (Ig), (Ih), (Ii), (Ij), or (Ik)), or a pharmaceutically acceptable salt, solvate, hydrate, tautomer, or stereoisomer thereof, and optionally a pharmaceutically acceptable excipient. In one embodiment, the pharmaceutical compositions described herein comprise an effective amount (e.g., a therapeutically effective amount) of a compound of Formula (I) (e.g., a compound of Formula (Ia), (Ib), (Ic), (Id), (Ie), (If), (Ig), (Ih), (Ii), (Ij), (Ik), (Ik), (II-a), (II-b), (II-c), (II-d), (II-e), (III-a), (III-b), (III-c), (III-d), (III-e), (III-f), (III-g), (III-h), (III-i), (III-j), or (III-k), or a pharmaceutically acceptable salt, solvate, hydrate, tautomer, or stereoisomer thereof.

[0009] In another aspect, the disclosure provides a compound of Formula (I) (e.g., a compound of Formula (Ia), (Ib), (Ic), (Id), (Ie), (If), (Ig), (Ih), (Ii), (Ij), (Ik), (Ik), (II-a), (II-b), (II-c), (II-d), (II-e), (III-a), (III-b), (III-c), (III-d), (III-e), (III-f), (III-g), (III-h), (III-i), (III-j), or (III-k), or a pharmaceutically acceptable salt thereof. In another aspect, the present disclosure provides a method for modulating splicing, e.g., splicing of a nucleic acid (e.g., DNA or RNA, e.g., pre-mRNA), by an acceptable salt, solvate, hydrate, tautomer, or stereoisomer. In another aspect, the present disclosure provides a compound of Formula (I) (e.g., Formulas (Ia), (Ib), (Ic), (Id), (Ie), (If), (Ig), (Ih), (Ii), (Ij), (Ik), (Ik), (II-a), (II-b), (II-c), (II-d), (II-e), (III-a), (III-b), (II-c), (II-d), (II-e), (III-a), (III-b), (III ... (III-b), (III-c), (III-d), (III-e), (III-f), (III-g), (III-h), (III-i), (III-j), or (III-k), or a pharmaceutically acceptable salt, solvate, hydrate, tautomer, or stereoisomer thereof. Modulation of splicing can include, but is not limited to, modulating splicing of a nucleic acid (e.g., DNA or RNA, e.g., pre-mRNA). The effects of splicing may include affecting any step involved in splicing, including events upstream or downstream of the splicing event. For example, in some embodiments, the compound of formula (I) binds to a target, e.g., a target nucleic acid (e.g., DNA or RNA, e.g., an RNA precursor, e.g., pre-mRNA), a target protein, or a combination thereof (e.g., snRNP and pre-mRNA). The target may include a pre-mRNA or a component of the splicing machinery, e.g., a splice site in U1 snRNP.In some embodiments, the compound of Formula (I) alters a target nucleic acid (e.g., DNA or RNA, e.g., an RNA precursor, e.g., a pre-mRNA), a target protein, or a combination thereof. In some embodiments, the compound of Formula (I) increases or decreases splicing at a splice site on a target nucleic acid (e.g., RNA, e.g., an RNA precursor, e.g., a pre-mRNA) by about 0.5% or more (e.g., about 1%, 2%, 3%, 4%, 5%, 10%, 20%, 30%, 40%, 50%, 75%, 90%, 95% or more) relative to a reference (e.g., the absence of the compound of Formula (I), e.g., in a normal or abnormal cell or tissue). In some embodiments, the presence of a compound of Formula (I) results in an increase or decrease of about 0.5% or more (e.g., about 1%, 2%, 3%, 4%, 5%, 10%, 20%, 30%, 40%, 50%, 75%, 90%, 95% or more) in transcription of a target nucleic acid (e.g., RNA) relative to a reference (e.g., the absence of a compound of Formula (I), e.g., in a normal or abnormal cell or tissue).

[0010] In another aspect, the disclosure provides a method for preventing and / or treating a disease, disorder, or condition in a subject by administering a compound of Formula (I) (e.g., a compound of Formula (Ia), (Ib), (Ic), (Id), (Ie), (If), (Ig), (Ih), (Ii), (Ij), (Ik), (Ik), (II-a), (II-b), (II-c), (II-d), (II-e), (III-a), (III-b), (III-c), (III-d), (III-e), (III-f), (III-g), (III-h), (III-i), (III-j), or (III-k), or a pharmaceutically acceptable salt, solvate, hydrate, tautomer, or stereoisomer thereof, or a related composition. In some embodiments, the disease or disorder causes unwanted or aberrant splicing. In some embodiments, the disease or disorder is a proliferative disease, disorder, or condition. Exemplary proliferative diseases include cancer, benign neoplasms, or angiogenesis. In other embodiments, the disclosure provides methods for treating and / or preventing a non-proliferative disease, disorder, or condition. In still other embodiments, the disclosure provides methods for treating and / or preventing a nervous system disease or disorder, an autoimmune disease or disorder, an immunodeficiency disease or disorder, a lysosomal storage disease or disorder, a cardiovascular disease or disorder, a metabolic disease or disorder, a respiratory disease or disorder, a renal disease or disorder, or an infectious disease.

[0011] In another aspect, the disclosure provides a method of downregulating the expression (e.g., level or rate of production) of a target protein in a biological sample or a subject with a compound of Formula (I) (e.g., a compound of Formula (Ia), (Ib), (Ic), (Id), (Ie), (If), (Ig), (Ih), (Ii), (Ij), (Ik), (Ik), (II-a), (II-b), (II-c), (II-d), (II-e), (III-a), (III-b), (III-c), (III-d), (III-e), (III-f), (III-g), (III-h), (III-i), (III-j), or (III-k), or a pharmaceutically acceptable salt, solvate, hydrate, tautomer, or stereoisomer thereof. In this regard, the present disclosure provides a method of upregulating the expression (e.g., level or rate of production) of a target protein in a biological sample or a subject with a compound of Formula (I), (II) or (III) (e.g., a compound of Formula (Ia), (Ib), (Ic), (Id), (Ie), (If), (Ig), (Ih), (Ii), (Ij), (Ik), (Ik), (II-a), (II-b), (II-c), (II-d), (II-e), (III-a), (III-b), (III-c), (III-d), (III-e), (III-f), (III-g), (III-h), (III-i), (III-j), or (III-k), or a pharmaceutically acceptable salt, solvate, hydrate, tautomer, or stereoisomer thereof.In another aspect, the present disclosure provides a method for detecting a compound of Formula (I), (II), or (III) (e.g., Formulas (Ia), (Ib), (Ic), (Id), (Ie), (If), (Ig), (Ih), (Ii), (Ij), (Ik), (Ik), (II-a), (II-b), (II-c), (II-d), (II-e), (III-a), (III-b), (III-c), (III-d), (III-e), (III-f), (III-g), (III-h), (III

[0010] Another aspect of the present disclosure relates to a method for inhibiting the activity of a target protein in a biological sample or a subject. In some embodiments, administering a compound of Formula (I), (II) or (III) to a biological sample, a cell, or a subject comprises inhibiting cell growth or inducing cell death.

[0012] In another aspect, the disclosure relates to preventing and / or treating a disease, disorder, or condition in a subject by administering a compound of Formula (I), (II), or (III) (e.g., a compound of Formula (Ia), (Ib), (Ic), (Id), (Ie), (If), (Ig), (Ih), (Ii), (Ij), (Ik), (Ik), (II-a), (II-b), (II-c), (II-d), (II-e), (III-a), (III-b), (III-c), (III-d), (III-e), (III-f), (III-g), (III-h), (III-i), (III-j), or (III-k), or a pharmaceutically acceptable salt, solvate, hydrate, tautomer, or stereoisomer thereof, or a related composition. In some embodiments, the disease or disorder causes unwanted or aberrant splicing. In some embodiments, the disease or disorder is a proliferative disease, disorder, or condition. Exemplary proliferative diseases include cancer, benign neoplasms, or angiogenesis. In other embodiments, the disclosure provides methods for treating and / or preventing non-proliferative diseases, disorders, or conditions. In still other embodiments, the disclosure provides methods for treating and / or preventing a nervous system disease or disorder, an autoimmune disease or disorder, an immunodeficiency disease or disorder, a lysosomal storage disease or disorder, a cardiovascular disease or disorder, a metabolic disease or disorder, a respiratory disease or disorder, a renal disease or disorder, or an infectious disease.

[0013] In another aspect, the disclosure provides a composition for use in downregulating the expression (e.g., level or rate of production) of a target protein in a biological sample or a subject with a compound of Formula (I), (II) or (III) (e.g., a compound of Formula (Ia), (Ib), (Ic), (Id), (Ie), (If), (Ig), (Ih), (Ii), (Ij), (Ik), (Ik), (II-a), (II-b), (II-c), (II-d), (II-e), (III-a), (III-b), (III-c), (III-d), (III-e), (III-f), (III-g), (III-h), (III-i), (III-j), or (III-k), or a pharmaceutically acceptable salt, solvate, hydrate, tautomer, or stereoisomer thereof. In another aspect, the disclosure provides a composition for use in upregulating the expression (e.g., level or rate of production) of a target protein in a biological sample or a subject with a compound of Formula (I), (II) or (III) (e.g., a compound of Formula (Ia), (Ib), (Ic), (Id), (Ie), (If), (Ig), (Ih), (Ii), (Ij), (Ik), (Ik), (II-a), (II-b), (II-c), (II-d), (II-e), (III-a), (III-b), (III-c), (III-d), (III-e), (III-f), (III-g), (III-h), (III-i), (III-j), or (III-k), or a pharmaceutically acceptable salt, solvate, hydrate, tautomer, or stereoisomer thereof.In another aspect, the present disclosure provides a method for detecting a compound of Formula (I), (II), or (III) (e.g., Formulas (Ia), (Ib), (Ic), (Id), (Ie), (If), (Ig), (Ih), (Ii), (Ij), (Ik), (Ik), (II-a), (II-b), (II-c), (II-d), (II-e), (III-a), (III-b), (III-c), (III-d), (III-e), (III-f), (III-g), (III-h), (III-i), (III-j), or (III-k), or a pharmaceutically acceptable salt, solvate, hydrate, tautomer, or stereoisomer thereof, for use in changing the isoform of a target protein. Another aspect of the present disclosure relates to a composition for use in inhibiting the activity of a target protein in a biological sample or a subject. In some embodiments, administering a compound of Formula (I), (II), or (III) to a biological sample, cell, or subject includes inhibiting cell growth or inducing cell death.

[0014] In another aspect, the disclosure provides a compound of Formula (I), (II), or (III) (e.g., Formula (Ia), (Ib), (Ic), (Id), (Ie), (If), (Ig), (Ih), (Ii), (Ij), (Ik), (Ik), (II-a), (II-b), (II-c), (II-d), (II-e), (III-a), (III-b), (III-c), (III-d), (III-e), (III-f), (III-g), (III-h), (III-i)

[0013] The present invention also features a kit comprising a container having a compound of Formula (I), (II), or (III), or a pharmaceutically acceptable salt, solvate, hydrate, tautomer, stereoisomer, or pharmaceutical composition thereof. In certain embodiments, the kits described herein further comprise instructions for administering the compound of Formula (I), (II), or (III), or a pharmaceutically acceptable salt, solvate, hydrate, tautomer, stereoisomer, or pharmaceutical composition thereof.

[0015] In any and all aspects of the present disclosure, in some embodiments, the compounds described herein, target nucleic acids (e.g., DNA, RNA, e.g., pre-mRNA), or target proteins can be synthesized using methods described in U.S. Pat. No. 8,729,263, U.S. Patent Application Publication No. 2015 / 0005289, WO 2014 / 028459, WO 2016 / 128343, WO 2016 / 196386, WO 2017 / 100726, WO 2018 / 232039, WO 2018 / 098 The compound is a compound other than a compound, target nucleic acid (e.g., DNA, RNA, e.g., pre-mRNA), or target protein described in one of WO 446, WO 2019 / 028440, WO 2019 / 060917, WO 2019 / 199972, WO 2021 / 174164, WO 2021 / 174165, and WO 2021 / 174174.In some embodiments, the compounds described herein, target nucleic acids (e.g., DNA, RNA, e.g., pre-mRNA), or target proteins are prepared using methods described in U.S. Pat. No. 8,729,263, U.S. Patent Application Publication No. 2015 / 0005289, WO 2014 / 028459, WO 2016 / 128343, WO 2016 / 196386, WO 2017 / 100726, WO 2018 / 232039, WO 2018 / 098446, or the like. The compound is a compound described in one of the following publications: International Publication Nos. WO 2019 / 028440, WO 2019 / 060917, and WO 2019 / 199972, WO 2021 / 174164, WO 2021 / 174165, and WO 2021 / 174174 (each of which is incorporated by reference in its entirety), a target nucleic acid (e.g., DNA, RNA, e.g., pre-mRNA), or a target protein.

[0016] The details of one or more embodiments of the invention are set forth herein. Other features, objects, and advantages of the invention will be apparent from the detailed description, examples, and claims. DETAILED DESCRIPTION OF THE INVENTION

[0017] Selected Chemistry Definitions The definitions of specific functional groups and chemical terms are described in more detail below. Chemical elements are identified according to the Periodic Table of the Elements, CAS version, Handbook of Chemistry and Physics, 75th Edition, inside cover, and specific functional groups are generally defined as described therein. Furthermore, general principles of organic chemistry, as well as specific functional moieties and reactivities, are described in Thomas Sorrell, Organic Chemistry, University Science Books, Sausalito, 1999; Smith and March, March's Advanced Organic Chemistry, 5th Edition, John Wiley & Sons, Inc., New York, 2001; Larock, Comprehensive Organic Transformations, VCH Publishers, Inc., New York, 1989; and Carruthers, Some Modern Methods of Organic Synthesis, 3rd Edition, Cambridge University Press, Cambridge, 1987.

[0018] The abbreviations used herein have their usual meaning within the chemical and biological arts. The chemical structures and formulas set forth herein are constructed according to the standard rules of chemical valency known in the chemical arts.

[0019] When a range of values ​​is listed, it is intended to encompass 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.

[0020] The following terms are intended to have the meanings presented below and are useful in understanding the description and intended scope of the present invention.

[0021] As used herein, "alkyl" refers to a group of linear or branched saturated hydrocarbon groups having 1 to 24 carbon atoms ("C1-C 24 In some embodiments, an alkyl group has 1 to 12 carbon atoms ("C1-C 12 In some embodiments, an alkyl group has 1 to 8 carbon atoms ("C1-C8 alkyl"). In some embodiments, an alkyl group has 1 to 6 carbon atoms ("C1-C6 alkyl"). In some embodiments, an alkyl group has 2 to 6 carbon atoms ("C2-C6 alkyl"). In some embodiments, an alkyl group has 1 carbon atom ("C1 alkyl"). Examples of C1-C6 alkyl groups include methyl (C1), ethyl (C2), n-propyl (C3), isopropyl (C3), n-butyl (C4), tert-butyl (C4), sec-butyl (C4), iso-butyl (C4), n-pentyl (C5), 3-pentanyl (C5), amyl (C5), neopentyl (C5), 3-methyl-2-butanyl (C5), tertiary amyl (C5), and n-hexyl (C6). Further examples of alkyl groups include n-heptyl (C7), n-octyl (C8), and the like. Each instance of an alkyl group can independently be optionally substituted, i.e., unsubstituted (an "unsubstituted alkyl") or substituted with one or more substituents, e.g., 1 to 5 substituents, 1 to 3 substituents, or 1 substituent (a "substituted alkyl"). In certain embodiments, an alkyl group is an unsubstituted C1 to C8 10 Alkyl (e.g., -CH3). In certain embodiments, the alkyl group is a substituted C1-C6 alkyl.

[0022] As used herein, "alkenyl" refers to a group of straight-chain or branched hydrocarbon groups having 2 to 24 carbon atoms, one or more carbon-carbon double bonds, and zero triple bonds ("C2-C 24 In some embodiments, an alkenyl group has 2 to 10 carbon atoms (“C-C 10In some embodiments, an alkenyl group has 2 to 8 carbon atoms ("C2-C8 alkenyl"). In some embodiments, an alkenyl group has 2 to 6 carbon atoms ("C2-C6 alkenyl"). In some embodiments, an alkenyl group has 2 carbon atoms ("C2 alkenyl"). The one or more carbon-carbon double bonds can be internal (e.g., in 2-butenyl) or terminal (e.g., in 1-butenyl). Examples of C2-C4 alkenyl groups include ethenyl (C2), 1-propenyl (C3), 2-propenyl (C3), 1-butenyl (C4), 2-butenyl (C4), butadienyl (C4), and the like. Examples of C2-C6 alkenyl groups include the C2-C6 alkenyl groups listed above. 2~4 Alkenyl groups include pentenyl (C5), pentadienyl (C5), hexenyl (C6), and the like. Further examples of alkenyl include heptenyl (C7), octenyl (C8), octatrienyl (C8), and the like. Each instance of an alkenyl group can independently be optionally substituted, i.e., unsubstituted (an "unsubstituted alkenyl") or substituted with one or more substituents, e.g., 1 to 5 substituents, 1 to 3 substituents, or 1 substituent (a "substituted alkenyl"). In certain embodiments, an alkenyl group is an unsubstituted C1-C6 10 alkenyl. In certain embodiments, the alkenyl group is a substituted C2-C6 alkenyl.

[0023] As used herein, the term "alkynyl" refers to a group of straight-chain or branched hydrocarbon groups having 2 to 24 carbon atoms and one or more carbon-carbon triple bonds ("C2-C 24 In some embodiments, an alkynyl group has 2 to 10 carbon atoms (“C-C 10In some embodiments, an alkynyl group has 2 to 8 carbon atoms ("C2-C8 alkynyl"). In some embodiments, an alkynyl group has 2 to 6 carbon atoms ("C2-C6 alkynyl"). In some embodiments, an alkynyl group has 2 carbon atoms ("C2 alkynyl"). The one or more carbon-carbon triple bonds can be internal (e.g., in 2-butynyl) or terminal (e.g., in 1-butynyl). Examples of C2-C4 alkynyl groups include ethynyl (C2), 1-propynyl (C3), 2-propynyl (C3), 1-butynyl (C4), 2-butynyl (C4), and the like. Each instance of an alkynyl group can independently be optionally substituted, i.e., unsubstituted (an "unsubstituted alkynyl") or substituted with one or more substituents, e.g., 1 to 5 substituents, 1 to 3 substituents, or 1 substituent (a "substituted alkynyl"). In certain embodiments, an alkynyl group is an unsubstituted C 2~10 In certain embodiments, the alkynyl group is a substituted C 2~6 It is alkynyl.

[0024] As used herein, the term "haloalkyl" refers to an acyclic, stable, straight or branched chain, or combination thereof, containing at least one carbon atom and at least one halogen selected from the group consisting of F, Cl, Br, and I. The halogens F, Cl, Br, and I may be located at any position of the haloalkyl group. Exemplary haloalkyl groups include, but are not limited to, -CF3, -CCl3, -CH2-CF3, -CH2-CCl 3、 -CH2-CBr 3、 -CH2-CI 3、Examples include -CH2-CH2-CH(CF3)-CH3, -CH2-CH2-CH(Br)-CH3, and -CH2-CH=CH-CH2-CF3. Each instance of a haloalkyl group can independently be optionally substituted, i.e., unsubstituted (an "unsubstituted haloalkyl") or substituted with one or more substituents, e.g., 1 to 5 substituents, 1 to 3 substituents, or 1 substituent (a "substituted haloalkyl").

[0025] As used herein, the term "heteroalkyl" refers to an acyclic, stable, straight or branched chain, or combination thereof, containing at least one carbon atom and at least one heteroatom selected from the group consisting of O, N, P, Si, and S, wherein the nitrogen and sulfur atoms are optionally oxidized and the nitrogen heteroatom is optionally quaternized. The heteroatoms O, N, P, S, and Si can be located at any position of the heteroalkyl group. Exemplary heteroalkyl groups include, but are not limited to, -CH2-CH2-O-CH3, -CH2-CH2-NH-CH3, -CH2-CH2-N(CH3)-CH3, -CH2-S-CH2-CH3, -CH2-CH2, -S(O)-CH3, -CH2-CH2-S(O)-CH3, -CH=CH-O-CH3, -Si(CH3)3, -CH2-CH=N-OCH3, -CH=CH-N(CH3)-CH3, -O-CH3, and -O-CH2-CH3. Up to two or three heteroatoms can be consecutive, e.g., -CH2-NH-OCH3 and -CH2-O-Si(CH3)3. "Heteroalkyl" is recited followed by a specific heteroalkyl group, e.g., -CHO, -NR C R D In the case of -, heteroalkyl and -CH2O or -NR C R D It is understood that the terms "heteroalkyl" and "heteroalkyl-" are not redundant or mutually exclusive. Rather, specific heteroalkyl groups are recited to add clarity. Thus, the term "heteroalkyl" is used herein to refer to specific heteroalkyl groups, e.g., -CHO, -NR C RD etc. Each instance of a heteroalkyl group can independently be optionally substituted, i.e., unsubstituted (an "unsubstituted heteroalkyl") or substituted with one or more substituents, e.g., 1 to 5 substituents, 1 to 3 substituents, or 1 substituent (a "substituted heteroalkyl").

[0026] As used herein, "aryl" refers to a group of monocyclic or polycyclic (e.g., bicyclic or tricyclic) 4n+2 aromatic ring systems (e.g., having 6, 10, or 14 pi electrons shared in a cyclic arrangement) having 6 to 14 ring carbon atoms and 0 heteroatoms provided in the aromatic ring system ("C6-C 14 In some embodiments, an aryl group has 6 ring carbon atoms ("C aryl"; e.g., phenyl). In some embodiments, an aryl group has 10 ring carbon atoms ("C 10 aryl"; e.g., naphthyl, e.g., 1-naphthyl and 2-naphthyl). In some embodiments, an aryl group has 14 ring carbon atoms ("C 14 Aryl"; for example, anthracyl). The aryl group is, for example, C6-C 10

[0023] In certain embodiments, an aryl group may be described as an unsubstituted C6-C6 alkyl group, where the term "membered" refers to a non-hydrogen ring atom within the moiety. Aryl groups include phenyl, naphthyl, indenyl, and tetrahydronaphthyl. Each instance of an aryl group may independently be optionally substituted, i.e., unsubstituted (an "unsubstituted aryl") or substituted with one or more substituents (a "substituted aryl"). In certain embodiments, an aryl group is an unsubstituted C6-C6 alkyl group. 14 In certain embodiments, the aryl group is a substituted C-C 14 It is aryl.

[0027] As used herein, "heteroaryl" refers to a group of 5-10 membered monocyclic or bicyclic 4n+2 aromatic ring systems (e.g., having 6 or 10 π electrons shared in a cyclic arrangement) having ring carbon atoms and 1-4 ring heteroatoms (where each heteroatom is independently selected from nitrogen, oxygen, and sulfur) provided in the aromatic ring system ("5-10 membered heteroaryl"). In heteroaryl groups containing one or more nitrogen atoms, the point of attachment can be at a carbon or nitrogen atom, as valence allows. Heteroaryl bicyclic ring systems can contain one or more heteroatoms in one or both rings. "Heteroaryl" also includes ring systems in which a heteroaryl ring, as defined above, is fused to one or more aryl groups, where the point of attachment is on the aryl or heteroaryl ring; in such cases, the number of ring members refers to the number of ring members in the fused (aryl / heteroaryl) ring system. In bicyclic heteroaryl groups in which one ring does not contain heteroatoms (e.g., indolyl, quinolinyl, carbazolyl, etc.), the point of attachment can be on either ring, i.e., the ring bearing a heteroatom (e.g., 2-indolyl) or the ring without a heteroatom (e.g., 5-indolyl). Heteroaryl groups may be described, for example, as 6- to 10-membered heteroaryl, where the term "member" refers to a non-hydrogen ring atom within the moiety. Each instance of a heteroaryl group may independently be optionally substituted, i.e., unsubstituted ("unsubstituted heteroaryl") or substituted with one or more substituents, e.g., 1 to 5 substituents, 1 to 3 substituents, or 1 substituent ("substituted heteroaryl").

[0028] Exemplary 5-membered heteroaryl groups containing one heteroatom include, but are not limited to, pyrrolyl, furanyl, and thiophenyl. Exemplary 5-membered heteroaryl groups containing two heteroatoms include, but are not limited to, imidazolyl, pyrazolyl, oxazolyl, isoxazolyl, thiazolyl, and isothiazolyl. Exemplary 5-membered heteroaryl groups containing three heteroatoms include, but are not limited to, triazolyl, oxadiazolyl, and thiadiazolyl. Exemplary 5-membered heteroaryl groups containing four heteroatoms include, but are not limited to, tetrazolyl. Exemplary 6-membered heteroaryl groups containing one heteroatom include, but are not limited to, pyridinyl. Exemplary 6-membered heteroaryl groups containing two heteroatoms include, but are not limited to, pyridazinyl, pyrimidinyl, and pyrazinyl. Exemplary 6-membered heteroaryl groups containing three or four heteroatoms include, but are not limited to, triazinyl and tetrazinyl, respectively. Exemplary 7-membered heteroaryl groups containing one heteroatom include, but are not limited to, azepinyl, oxepinyl, and thiepinyl. Exemplary 5,6-bicyclic heteroaryl groups include, but are not limited to, indolyl, isoindolyl, indazolyl, benzotriazolyl, benzothiophenyl, isobenzothiophenyl, benzofuranyl, benzoisofuranyl, benzimidazolyl, benzoxazolyl, benzisoxazolyl, benzoxadiazolyl, benzothiazolyl, benzisothiazolyl, benzothiadiazolyl, indolizinyl, and purinyl. Exemplary 6,6-bicyclic heteroaryl groups include, but are not limited to, naphthyridinyl, pteridinyl, quinolinyl, isoquinolinyl, cinnolinyl, quinoxalinyl, phthalazinyl, and quinazolinyl. Other exemplary heteroaryl groups include heme and heme derivatives.

[0029] As used herein, "cycloalkyl" refers to a group having 3 to 10 ring carbon atoms ("C3-C6") in a non-aromatic ring system. 10"Cycloalkyl" refers to a group of non-aromatic cyclic hydrocarbon groups having 3 to 8 ring carbon atoms ("C3-C8 cycloalkyl"). In some embodiments, a cycloalkyl group has 3 to 6 ring carbon atoms ("C3-C6 cycloalkyl"). In some embodiments, a cycloalkyl group has 3 to 6 ring carbon atoms ("C3-C6 cycloalkyl"). In some embodiments, a cycloalkyl group has 5 to 10 ring carbon atoms ("C5-C 10 A cycloalkyl group may be described, for example, as a C4-C7 membered cycloalkyl, where the term "member" refers to a non-hydrogen ring atom within the moiety. Exemplary C3-C6 cycloalkyl groups include, but are not limited to, cyclopropyl (C3), cyclopropenyl (C3), cyclobutyl (C4), cyclobutenyl (C4), cyclopentyl (C5), cyclopentenyl (C5), cyclohexyl (C6), cyclohexenyl (C6), cyclohexadienyl (C6), and the like. Exemplary C3-C8 cycloalkyl groups include, but are not limited to, the C3-C6 cycloalkyl groups listed above, as well as cycloheptyl (C7), cycloheptenyl (C7), cycloheptadienyl (C7), cycloheptatrienyl (C7), cyclooctyl (C8), cyclooctenyl (C8), cubanyl (C8), bicyclo[1.1.1]pentanyl (C5), bicyclo[2.2.2]octanyl (C8), bicyclo[2.1.1]hexanyl (C6), bicyclo[3.1.1]heptanyl (C7), and the like. 10 Cycloalkyl groups include, but are not limited to, the C3 to C8 cycloalkyl groups listed above, as well as cyclononyl (C9), cyclononenyl (C9), cyclodecyl (C 10 ), cyclodecenyl (C 10 ), octahydro-1H-indenyl (C9), decahydronaphthalenyl (C 10 ), spiro[4.5]decanyl (C 10), and the like. As the examples above illustrate, in certain embodiments, a cycloalkyl group is monocyclic ("monocyclic cycloalkyl") or contains fused, bridged, or spiro ring systems, e.g., bicyclic systems ("bicyclic cycloalkyl"), and may be saturated or partially unsaturated. "Cycloalkyl" also includes ring systems in which a cycloalkyl ring, as defined above, is fused to one or more aryl groups, where the point of attachment is on the cycloalkyl ring; in such cases, the number of carbons continues to refer to the number of carbons in the cycloalkyl ring system. Each instance of a cycloalkyl group independently may be optionally substituted, i.e., unsubstituted ("unsubstituted cycloalkyl") or substituted with one or more substituents ("substituted cycloalkyl"). In certain embodiments, a cycloalkyl group is an unsubstituted C3-C6 10 In certain embodiments, the cycloalkyl group is a substituted C-C 10 It is cycloalkyl.

[0030] "Heterocyclyl," as used herein, refers to a radical of a 3- to 16-membered non-aromatic ring system having ring carbon atoms and 1 to 8 ring heteroatoms, where each heteroatom is independently selected from nitrogen, oxygen, sulfur, boron, phosphorus, and silicon ("3- to 16-membered heterocyclyl"). In heterocyclyl groups containing one or more nitrogen atoms, the point of attachment may be at a carbon or nitrogen atom, as valence allows. Heterocyclyl groups may be monocyclic ("monocyclic heterocyclyl") or fused, bridged, or spiro ring systems, e.g., bicyclic systems ("bicyclic heterocyclyl"), and may be saturated or partially unsaturated. Heterocyclyl bicyclic ring systems may contain one or more heteroatoms in one or both rings. "Heterocyclyl" also includes ring systems in which a heterocyclyl ring, as defined above, is fused to one or more cycloalkyl groups (where the point of attachment is on the cycloalkyl or heterocyclyl ring), or to one or more aryl or heteroaryl groups (where the point of attachment is on the heterocyclyl ring); in such cases, the number of ring members continues to indicate the number of ring members in the heterocyclyl ring system. A heterocyclyl group may be described, for example, as a 3- to 7-membered heterocyclyl, where the term "member" refers to the non-hydrogen ring atoms in the moiety, i.e., carbon, nitrogen, oxygen, sulfur, boron, phosphorus, and silicon. Each instance of heterocyclyl may independently be optionally substituted, i.e., unsubstituted (an "unsubstituted heterocyclyl") or substituted with one or more substituents (a "substituted heterocyclyl"). In certain embodiments, the heterocyclyl group is unsubstituted 3-16 membered heterocyclyl. In certain embodiments, the heterocyclyl group is substituted 3-16 membered heterocyclyl.

[0031] Exemplary 3-membered heterocyclyl groups containing one heteroatom include, but are not limited to, azirdinyl, oxiranyl, and thiorenyl. Exemplary 4-membered heterocyclyl groups containing one heteroatom include, but are not limited to, azetidinyl, oxetanyl, and thietanyl. Exemplary 5-membered heterocyclyl groups containing one heteroatom include, but are not limited to, tetrahydrofuranyl, dihydrofuranyl, tetrahydrothiophenyl, dihydrothiophenyl, pyrrolidinyl, dihydropyrrolyl, and pyrrolyl-2,5-dione. Exemplary 5-membered heterocyclyl groups containing two heteroatoms include, but are not limited to, dioxolanyl, oxasulfuranyl, disulfuranyl, and oxazolidin-2-one. Exemplary 5-membered heterocyclyl groups containing three heteroatoms include, but are not limited to, triazolinyl, oxadiazolinyl, and thiadiazolinyl. Exemplary 6-membered heterocyclyl groups containing one heteroatom include, but are not limited to, piperidinyl (e.g., 2,2,6,6-tetramethylpiperidinyl), tetrahydropyranyl, dihydropyridinyl, pyridinonyl (e.g., 1-methylpyridin-2-onyl), and thianyl. Exemplary 6-membered heterocyclyl groups containing two heteroatoms include, but are not limited to, piperazinyl, morpholinyl, pyridazinonyl (2-methylpyridazin-3-onyl), pyrimidinonyl (e.g., 1-methylpyrimidin-2-onyl, 3-methylpyrimidin-4-onyl), dithianyl, and dioxanyl. Exemplary 6-membered heterocyclyl groups containing two heteroatoms include, but are not limited to, triazinanyl. Exemplary 7-membered heterocyclyl groups containing one heteroatom include, but are not limited to, azepanyl, oxepanyl, and thiepanyl. Exemplary 8-membered heterocyclyl groups containing 1 heteroatom include, but are not limited to, azocanyl, oxecanyl, and thiocanyl.Exemplary 5-membered heterocyclyl groups (also referred to herein as 5,6-bicyclic heterocyclyl rings) fused to a C6 aryl ring include, but are not limited to, indolinyl, isoindolinyl, dihydrobenzofuranyl, dihydrobenzothienyl, benzoxazolinonyl, etc. Exemplary 5-membered heterocyclyl groups (also referred to herein as 5,5-bicyclic heterocyclyl rings) fused to a heterocyclyl ring include, but are not limited to, octahydropyrrolopyrrolyl (e.g., octahydropyrrolo[3,4-c]pyrrolyl), etc. Exemplary 6-membered heterocyclyl groups (also referred to as 4,6-membered heterocyclyl rings) fused to a heterocyclyl ring include, but are not limited to, diazaspirononanyl (e.g., 2,7-diazaspiro[3.5]nonanyl). Exemplary 6-membered heterocyclyl groups fused to an aryl ring (also referred to herein as 6,6-bicyclic heterocyclyl rings) include, but are not limited to, tetrahydroquinolinyl, tetrahydroisoquinolinyl, and the like. Exemplary 6-membered heterocyclyl groups fused to a cycloalkyl ring (also referred to herein as 6,7-bicyclic heterocyclyl rings) include, but are not limited to, azabicyclooctanyl (e.g., (1,5)-8-azabicyclo[3.2.1]octanyl). Exemplary 6-membered heterocyclyl groups fused to a cycloalkyl ring (also referred to herein as 6,8-bicyclic heterocyclyl rings) include, but are not limited to, azabicyclononanyl (e.g., 9-azabicyclo[3.3.1]nonanyl).

[0032] The terms "alkylene," "alkenylene," "alkynylene," "haloalkylene," "heteroalkylene," "cycloalkylene," or "heterocyclylene," by themselves or as part of another substituent, mean, unless otherwise stated, a divalent radical derived from an alkyl, alkenyl, alkynyl, haloalkylene, heteroalkylene, cycloalkyl, or heterocyclyl, respectively. For example, the term "alkenylene," by itself or as part of another substituent, means, unless otherwise stated, a divalent radical derived from an alkene. An alkylene, alkenylene, alkynylene, haloalkylene, heteroalkylene, cycloalkylene, or heterocyclylene group may be described, for example, as a C-C-membered alkylene, a C-C-membered alkenylene, a C-C-membered alkynylene, a C-C-membered haloalkylene, a C-C-membered heteroalkylene, a C-C-membered cycloalkylene, or a C-C-membered heterocyclylene, where the term "membered" refers to a non-hydrogen atom within the moiety. For heteroalkylene and heterocyclylene groups, heteroatoms can also occupy either or both of the chain termini (e.g., alkyleneoxy, alkylenedioxy, alkyleneamino, alkylenediamino, etc.). Furthermore, no orientation of the linking group is implied by the direction in which the formula of the linking group is written. For example, the formula -C(O)2R'- can represent both -C(O)2R'- and -R'C(O)2-.

[0033] As used herein, the term "cyano" or "-CN" refers to a substituent having a carbon atom joined to a nitrogen atom by a triple bond, e.g., C≡N.

[0034] As used herein, the term "halogen" or "halo" refers to fluorine, chlorine, bromine, or iodine.

[0035] As used herein, the term "hydroxy" refers to --OH.

[0036] As used herein, the term "nitro" refers to a substituent having two oxygen atoms attached to a nitrogen atom, eg, --NO.sub.2.

[0037] As used herein, the term "nucleobase" refers to a nitrogen-containing biological compound found linked to a sugar in a nucleoside (the basic building block of deoxyribonucleic acid (DNA) and ribonucleic acid (RNA)). The primary, or naturally occurring, nucleobases are cytosine (DNA and RNA), guanine (DNA and RNA), adenine (DNA and RNA), thymine (DNA), and uracil (RNA), abbreviated as C, G, A, T, and U, respectively. Because A, G, C, and T occur in DNA, these molecules are referred to as DNA bases; A, G, C, and U are referred to as RNA bases. Adenine and guanine belong to a double-ring class of molecules called purines (abbreviated as R). Cytosine, thymine, and uracil are all pyrimidines. Other nucleobases that do not function as a normal part of the genetic code are referred to as non-naturally occurring. In one embodiment, the nucleobase may be chemically modified, for example, with alkyl (eg, methyl), halo, -O-alkyl, or other modification.

[0038] As used herein, the term "nucleic acid" refers to deoxyribonucleic acid (DNA) or ribonucleic acid (RNA) and polymers thereof in single- or double-stranded form. The term "nucleic acid" includes genes, cDNAs, pre-mRNAs, or mRNAs. In one embodiment, a nucleic acid molecule is synthetic (e.g., chemically synthesized) or recombinant. Unless expressly limited, the term encompasses nucleic acids containing analogs or derivatives of natural nucleotides that have similar binding properties as the reference nucleic acid and are metabolized in a manner similar to naturally occurring nucleotides. Unless otherwise indicated, a particular nucleic acid sequence also implicitly encompasses conservatively modified variants thereof (e.g., degenerate codon substitutions), alleles, orthologs, SNPs, and complementary sequences, as well as the explicitly indicated sequence.

[0039] As used herein, "oxo" refers to carbonyl, i.e., --C(O)--.

[0040] symbol [ka] as used herein with respect to a compound of Formula (I), (II), or (III), refers to a point of attachment to another moiety or functional group within the compound.

[0041] Alkyl, alkenyl, alkynyl, haloalkyl, heteroalkyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl groups as defined herein are optionally substituted. In general, the term "substituted," whether preceded by the term "optionally" or not, means that at least one hydrogen atom present on the group (e.g., a carbon or nitrogen atom) is replaced with a permissible substituent, e.g., a substituent that, upon substitution, results in a stable compound, e.g., a compound that does not spontaneously undergo transformation by rearrangement, cyclization, elimination, or other reaction. Unless otherwise indicated, a "substituted" group has a substituent at one or more substitutable positions of the group, and when multiple positions in any given structure are substituted, the substituents are the same or different at each position. The term "substituted" is intended to include substitution with all permissible substituents of organic compounds, e.g., any of the substituents described herein that result in the formation of a stable compound. The present disclosure contemplates any and all such combinations to arrive at stable compounds. For purposes of this invention, the heteroatoms, e.g., nitrogen, may have hydrogen substituents and / or any suitable substituents as described herein that satisfy the valence of the heteroatom and result in the formation of a stable moiety.

[0042] Two or more substituents may optionally join to form an aryl, heteroaryl, cycloalkyl, or heterocyclyl group. Such so-called ring-forming substituents are typically, but not necessarily, found attached to a cyclic base structure. In one embodiment, the ring-forming substituents are attached to adjacent members of the base structure. For example, two ring-forming substituents attached to adjacent members of the cyclic base structure create a fused ring structure. In another embodiment, the ring-forming substituents are attached to a single member of the base structure. For example, two ring-forming substituents attached to a single member of the cyclic base structure create a spirocyclic structure. In yet another embodiment, the ring-forming substituents are attached to non-adjacent members of the base structure.

[0043] The compounds provided herein may exist in one or more particular geometric, optical, enantiomeric, diastereomeric, epimeric, stereoisomeric, tautomeric, conformational, or anomeric forms, including, but not limited to, cis- and trans-forms; E- and Z-forms; endo- and exo-forms; R-, S-, and meso-forms; D- and L-forms; d- and l-forms; (+) and (-) forms; keto-, enol-, and enolate-forms; syn- and anti-forms; synclinal- and anticlinal-forms; α- and β-forms; axial and equatorial forms; boat-, chair-, twist-, envelope-, and half-chair-forms; and combinations thereof, hereinafter collectively referred to as "isomers" (or "isomeric forms").

[0044] The compounds described herein may contain one or more asymmetric centers and therefore may exist in various isomeric forms, e.g., enantiomers and / or diastereomers. For example, the compounds described herein may be in the form of individual enantiomers, diastereomers, or geometric isomers, or may be in the form of mixtures of stereoisomers, including racemic mixtures and mixtures enriched in one or more stereoisomers. In one embodiment, the stereochemical configuration depicted in a compound is relative rather than absolute. Isomers can be isolated from mixtures by methods known to those skilled in the art, including chiral high-pressure liquid chromatography (HPLC) and the formation and crystallization of chiral salts; or preferred isomers can be prepared by asymmetric synthesis. See, for example, Jacques et al., Enantiomers, Racemates and Resolutions (Wiley Interscience, New York, 1981); Wilen et al., Tetrahedron 33:2725 (1977); Eliel, Stereochemistry of Carbon Compounds (McGraw-Hill, NY, 1962); and Wilen, Tables of Resolving Agents and Optical Resolutions p. 268 (EL Eliel, Ed., Univ. of Notre Dame Press, Notre Dame, IN 1972). The present disclosure further encompasses the compounds described herein as individual isomers substantially free of other isomers, and alternatively, as mixtures of various isomers.

[0045] As used herein, a pure enantiomer is substantially free of other enantiomers or stereoisomers of the compound (i.e., in enantiomeric excess). In other words, the "S" form of a compound is substantially free of the "R" form of the compound, and the "R" form is in enantiomeric excess. The term "enantiomerically pure" or "pure enantiomer" indicates that a compound contains more than 75%, more than 80%, more than 85%, more than 90%, more than 91%, more than 92%, more than 93%, more than 94%, more than 95%, more than 96%, more than 97%, more than 98%, more than 99%, more than 99.5%, or more than 99.9% by weight of an enantiomer. In certain embodiments, weights are based on the total weight of all enantiomers or stereoisomers of a compound.

[0046] In the compositions provided herein, the enantiomerically pure compound may be present together with other active or inactive ingredients. For example, a pharmaceutical composition containing an enantiomerically pure R-compound may contain, for example, about 90% additives and about 10% enantiomerically pure R-compound. In certain embodiments, the enantiomerically pure R-compound in such a composition may contain, for example, at least about 95% by weight of the R-compound and at most about 5% by weight of the S-compound, based on the total weight of the compound. For example, a pharmaceutical composition containing an enantiomerically pure S-compound may contain, for example, about 90% additives and about 10% of the enantiomerically pure S-compound. In certain embodiments, the enantiomerically pure S-compound in such a composition may contain, for example, at least about 95% by weight of the S-compound and at most about 5% by weight of the R-compound, based on the total weight of the compound.

[0047] In some embodiments, diastereomerically pure compounds can be present together with other active or inactive ingredients. For example, a pharmaceutical composition containing a diastereomerically pure exo compound can contain, for example, about 90% of an additive and about 10% of a diastereomerically pure exo compound. In certain embodiments, the diastereomerically pure exo compound in such a composition can contain, for example, at least about 95% by weight of the exo compound and at most 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 can contain, for example, about 90% of an additive and about 10% of the diastereomerically pure endo compound. In certain embodiments, the diastereomerically pure endo compound in such a composition can contain, for example, at least about 95% by weight of the endo compound and at most about 5% by weight of the exo compound, based on the total weight of the compound.

[0048] In some embodiments, isomerically pure compounds may be present together with other active or inactive ingredients. For example, a pharmaceutical composition containing an isomerically pure exo compound may contain, for example, about 90% additives and about 10% isomerically pure exo compound. In certain embodiments, the isomerically pure exo compound in such a composition may contain, for example, at least about 95% by weight of the exo compound and at most 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 contain, for example, about 90% additives and about 10% isomerically pure endo compound. In certain embodiments, the isomerically pure endo compound in such a composition may contain, for example, at least about 95% by weight of the endo compound and at most about 5% by weight of the exo compound, based on the total weight of the compound.

[0049] In certain embodiments, the active ingredient may be formulated with few or no additives or carriers.

[0050] The compounds described herein may also contain one or more isotopic substitutions. For example, H is 1 H, 2 H (D or deuterium), and 3 H (T or tritium); C can be in any isotopic form, 12 C. 13 C, and 14 C can be in any isotopic form; 16 O and 18 N can be in any isotopic form, including O; 14 N and 15 N may be in any isotopic form; F may be in any isotopic form, including 18 F, 19 It can be in any isotopic form, including F, etc.

[0051] The term "pharmaceutically acceptable salts" refers to salts of active compounds prepared with relatively non-toxic acids or bases, depending on the specific substituents found on the compounds described herein.When the compounds of the present disclosure contain relatively acidic functionalities, base addition salts can be obtained by contacting the neutral form of such compounds with a sufficient amount of the desired base, either neat or in a suitable inert solvent.Examples of pharmaceutically acceptable base addition salts include sodium, potassium, calcium, ammonium, organic amino, or magnesium salts, or similar salts.When the compounds of the present invention contain relatively basic functionalities, acid addition salts can be obtained by contacting the neutral form of such compounds with a sufficient amount of the desired acid, either neat or in a suitable inert solvent. Examples of pharmaceutically acceptable acid addition salts include those derived from inorganic acids such as hydrochloric acid, hydrobromic acid, nitric acid, carbonic acid, monohydrogencarbonic acid, phosphoric acid, monohydrogenphosphate, dihydrogenphosphate, sulfuric acid, monohydrogensulfuric acid, hydroiodic acid, or phosphorous acid, and 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, methanesulfonic acid, etc. Also included are salts of amino acids such as alginic acid, and organic acids such as glucuronic acid or galactunoric acid (see, e.g., Berge et al., Journal of Pharmaceutical Science 66:1-19 (1977)). Certain compounds of the present invention contain both basic and acidic functionalities that allow the compounds to be converted into either base or acid addition salts. These salts can be prepared by methods known to those of ordinary skill in the art. Other pharmaceutically acceptable carriers known to those of ordinary skill in the art are suitable for the present invention.

[0052] In addition to salt forms, the present disclosure provides compounds in prodrug form. Prodrugs of the compounds described herein are those compounds that readily undergo chemical changes under physiological conditions to provide the compounds of the present invention. Furthermore, prodrugs can be converted to the compounds of the present invention by chemical or biochemical methods in an ex vivo environment. For example, prodrugs can be slowly converted to the compounds of the present invention when placed in a transdermal patch reservoir with a suitable enzyme or chemical reagent.

[0053] The term "solvate" refers to a form of a compound that is associated with a solvent, typically through solvolysis. This physical association may involve hydrogen bonding. Common solvents include water, methanol, ethanol, acetic acid, DMSO, THF, diethyl ether, and the like. The compounds of formula (I), (II), or (III) may be prepared, for example, in crystalline form, and may be solvated. Suitable solvates include pharmaceutically acceptable solvates, and further include both stoichiometric and non-stoichiometric solvates. In certain cases, a solvate may be isolated, for example, when one or more solvent molecules are incorporated into the crystal lattice of a crystalline solid. "Solvate" encompasses both solution-phase and isolatable solvates. Representative solvates include hydrates, ethanolates, and methanolates.

[0054] The term "hydrate" refers to a compound associated with water. Typically, the number of water molecules contained in a hydrate of a compound is a defined ratio to the number of compound molecules in the hydrate. Thus, a hydrate of a compound may be represented, for example, by the general formula R·xH2O, where R is the compound and x is a number greater than 0. A given compound may form multiple types of hydrates, including, for example, monohydrates (x is 1), hypohydrates (x is a number greater than 0 and less than 1, e.g., hemihydrate (R·0.5H2O)), and polyhydrates (x is a number greater than 1, e.g., dihydrate (R·2H2O) and hexahydrate (R·6H2O)).

[0055] The term "tautomer" refers to compounds that are interchangeable forms of a particular compound structure and differ in the displacement of hydrogen atoms and electrons. Thus, two structures can be in equilibrium through the displacement of π electrons and atoms (usually H). For example, enols and ketones are tautomers because they are rapidly interconverted by treatment with acid or base. Another example of tautomerism is the aci- and nitro-forms of phenylnitromethane, which are similarly formed by treatment with acid or base. Tautomeric forms can be relevant to achieving optimal chemical reactivity and biological activity of a compound of interest.

[0056] Other definitions The following definitions are of more general terms used throughout this disclosure.

[0057] The articles "a" and "an" refer to one or to more than one (e.g., at least one) of the grammatical object of the article. By way of example, "an element" means one element or more than one element. The term "and / or" means "and" or "or" unless otherwise indicated.

[0058] The term "about" is used herein to mean within the typical tolerance range in the art. For example, "about" can be understood as about 2 standard deviations from the mean. In certain embodiments, about means ±10%. In certain embodiments, about means ±5%. When about is presented before a series of numbers or ranges, it is understood that "about" can modify each number in the series or range.

[0059] "Obtain" or "obtaining," as used herein, refers to possessing a value, e.g., a numerical value, or 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" refers to receiving a value or physical entity from another party or source (e.g., a third-party laboratory that directly obtained the physical entity or value). Directly obtaining a value or physical entity includes performing a process that involves a physical change in the physical entity or the use of a machine or device. An example of directly obtaining a value includes obtaining a sample from a human subject. Directly obtaining a value includes performing a process that uses a machine or device, e.g., a mass spectrometer to obtain mass spectrometry data.

[0060] The terms "administer," "administering," or "administration," as used herein, refer to implanting, absorbing, ingesting, injecting, inhaling, or otherwise introducing a compound of the invention, or a pharmaceutical composition thereof.

[0061] As used herein, the terms "condition," "disease," and "disorder" are used interchangeably.

[0062] An "effective amount" of a compound of Formula (I), (II), or (III) refers to an amount sufficient to elicit a desired biological response, i.e., treat a condition. As those skilled in the art will recognize, the effective amount of a compound of Formula (I), (II), or (III) can 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. An effective amount encompasses therapeutic and prophylactic treatments. For example, in the treatment of cancer, an effective amount of a compound of the present invention can reduce tumor burden or halt tumor growth or spread.

[0063] A "therapeutically effective amount" of a compound of Formula (I), (II), or (III) is an amount sufficient to provide a therapeutic benefit in the treatment of a condition or to delay or minimize one or more symptoms associated with the condition. In some embodiments, a therapeutically effective amount is an amount sufficient to provide a therapeutic benefit in the treatment of a condition or to minimize one or more symptoms associated with the condition. A therapeutically effective amount of a compound means an amount of a therapeutic agent, alone or in combination with other therapies, that provides a therapeutic benefit in the treatment of a condition. The term "therapeutically effective amount" can encompass an amount that improves overall treatment, reduces or avoids the symptoms or causes of a condition, or enhances the therapeutic effectiveness of another therapeutic agent.

[0064] The terms "peptide," "polypeptide," and "protein" are used interchangeably and refer to compounds consisting of amino acid residues covalently linked by peptide bonds. A protein or peptide must contain at least two amino acids, and there is no limit to the maximum number of amino acids it can contain. A polypeptide includes any peptide or protein that contains two or more amino acids joined to each other by peptide bonds. As used herein, the term refers to both short chains (also commonly referred to in the art as, for example, peptides, oligopeptides, and oligomers) and longer chains (commonly referred to in the art as proteins, of which there are many types).

[0065] "Prevention," "prevent," and "preventing," as used herein, refer to treatment that includes administering a therapy, e.g., a compound described herein (e.g., a compound of Formula (I), (II), or (III)), prior to the onset of a disease, disorder, or condition, to hinder the physical manifestation of the disease, disorder, or condition. In some embodiments, "prevention," "prevent," and "preventing" require that signs or symptoms of the disease, disorder, or condition have not occurred or have not yet been observed. In some embodiments, treatment includes prevention, and in other embodiments, it does not.

[0066] "Subjects" to which administration is intended include, but are not limited to, humans (i.e., male or female of any age group, e.g., a pediatric subject (e.g., infant, child, adolescent) or an adult subject (e.g., young adult, middle-aged adult, or elderly adult)) and / or other non-human animals, e.g., mammals (e.g., primates (e.g., cynomolgus monkeys, rhesus monkeys); commercially relevant mammals, e.g., cows, pigs, horses, sheep, goats, cats, and / or dogs) and birds (e.g., commercially relevant birds, e.g., chickens, ducks, geese, and / or turkeys). In certain embodiments, the animal is a mammal. The animal can be male or female and at any stage of development. The non-human animal can be a transgenic animal.

[0067] As used herein, the terms "treatment," "treat," and "treating" refer to reversing, alleviating, delaying the onset of, or inhibiting the progression of one or more of the symptoms, manifestations, or underlying causes of a disease, disorder, or condition (e.g., as described herein), e.g., by administering a therapy, e.g., a compound described herein (e.g., a compound of Formula (I), (II), or (III)). In one embodiment, treating includes reducing, reversing, alleviating, delaying the onset of, or inhibiting the progression of, a symptom of a disease, disorder, or condition. In one embodiment, treating includes reducing, reversing, alleviating, delaying the onset of, or inhibiting the progression of, a manifestation of a disease, disorder, or condition. In one embodiment, treating includes reducing, reversing, alleviating, reducing, or delaying the onset of, an underlying cause of a disease, disorder, or condition. In some embodiments, "treatment," "treat," and "treating" require that a sign or symptom of a disease, disorder, or condition has occurred or has been observed. In other embodiments, treatment may be administered in the absence of signs or symptoms of a disease or condition, e.g., in prophylactic treatment. For example, treatment may be administered to a susceptible individual prior to the onset of symptoms (e.g., in light of a history of symptoms and / or in light of genetic or other susceptibility factors). Treatment may also continue after symptoms have resolved, e.g., to delay or prevent recurrence. Treatment may also continue after symptoms have resolved, e.g., to delay or prevent recurrence. In some embodiments, treatment includes prophylaxis, while in other embodiments it does not.

[0068] "Proliferative disease" refers to a disease caused by abnormal growth of cells (Walker, Cambridge Dictionary of Biology; Cambridge University Press: Cambridge, UK, 1990). Proliferative diseases can be associated with 1) pathological proliferation of normally quiescent cells; 2) pathological migration of cells from their normal location (e.g., metastasis of neoplastic cells); 3) pathological expression of proteolytic enzymes, such as matrix metalloproteinases (e.g., collagenase, gelatinase, and elastase); 4) pathological angiogenesis, such as in proliferative retinopathy and tumor metastasis; or 5) evasion of host immune surveillance and elimination of neoplastic cells. Exemplary proliferative diseases include cancer (i.e., "malignant neoplasms"), benign neoplasms, and angiogenesis.

[0069] "Non-proliferative disease" refers to a disease that is not primarily driven by abnormal cell proliferation. Non-proliferative diseases can be associated with any cell or tissue type in a subject. Exemplary non-proliferative diseases include nervous system diseases or disorders (e.g., repeat expansion diseases); autoimmune diseases or disorders; immunodeficiency diseases or disorders; lysosomal storage diseases or disorders; inflammatory diseases or disorders; cardiovascular conditions, diseases or disorders; metabolic diseases or disorders; respiratory conditions, diseases or disorders; renal diseases or disorders; and infectious diseases.

[0070] compound In one aspect, the present disclosure provides a compound of formula (Ia) [ka] or a pharmaceutically acceptable salt, solvate, hydrate, tautomer, or stereoisomer thereof, wherein A and B are each independently cycloalkyl, heterocyclyl, aryl, or heteroaryl, each of which is selected from the group consisting of one or more R 1 W, X, Y, and Z are each independently selected from the group consisting of C(R 3a ) or N, wherein at least one of W, X, Y, and Z is independently N; L 1is absent, C1-C6-alkylene, C1-C6-heteroalkylene, -O-, -C(O)-, -N(R 4 )-, -N(R 4 )C(O)-, or -C(O)N(R 4 )-, where each alkylene and heteroalkylene is selected from one or more R 5 and each R 1 are independently hydrogen, C1-C6-alkyl, C2-C6-alkenyl, C2-C6-alkynyl, C1-C6-heteroalkyl, C1-C6-haloalkyl, cycloalkyl, heterocyclyl, aryl, C1-C6 alkylene-aryl, C1-C6 alkenylene-aryl, C1-C6 alkylene-heteroaryl, heteroaryl, halo, cyano, oxo, -OR A , -NR B R C , -NR B C(O)R D , -NO2, -C(O)NR B R C , -C(O)R D , -C(O)OR D , -SR E , or -S(O) x R D wherein each alkyl, alkylene, alkenyl, alkynyl, heteroalkyl, haloalkyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl is selected from one or more R 6 optionally substituted with; or two R 1 The groups, together with the atoms to which they are attached, form a 3- to 7-membered cycloalkyl, heterocyclyl, aryl, or heteroaryl, where each cycloalkyl, heterocyclyl, aryl, and heteroaryl is selected from one or more R 6 and each R 2 are independently hydrogen, C1-C6-alkyl, C2-C6-alkenyl, C2-C6-alkynyl, C1-C6-heteroalkyl, C1-C6-haloalkyl, halo, cyano, -OR A , N.R. B R C , -C(O)RD , or -C(O)OR D and;R 3a is hydrogen, C1-C6-alkyl, C2-C6-alkenyl, C2-C6-alkynyl, C1-C6-heteroalkyl, C1-C6-haloalkyl, halo, cyano, -OR A , -NR B R C , -C(O)R D , or -C(O)OR D and each R 4 are independently hydrogen, C1-C6-alkyl, or C1-C6-haloalkyl; each R 5 are independently hydrogen, C1-C6-alkyl, C1-C6-heteroalkyl, C1-C6-haloalkyl, cycloalkyl, halo, cyano, oxo, -OR A , -NR B R C , -C(O)R D , or -C(O)OR D and each R 6 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 , -SR E , or -S(O) x R D wherein each alkyl, alkenyl, alkynyl, heteroalkyl, haloalkyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl is selected from one or more R 11 and each R Aare independently hydrogen, C1-C6 alkyl, C1-C6 haloalkyl, aryl, heteroaryl, C1-C6 alkylene-aryl, C1-C6 alkylene-heteroaryl, -C(O)R D , or -S(O) x R D and;R B and R C each independently represents hydrogen, C1-C6 alkyl, C1-C6 heteroalkyl, cycloalkyl, heterocyclyl, or -OR A or R B and R C together with the atoms to which they are attached, form one or more R 7 forming a 3- to 7-membered heterocyclyl ring optionally substituted with D and R E are independently hydrogen, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 heteroalkyl, C1-C6 haloalkyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, C1-C6 alkylene-aryl, or C1-C6 alkylene-heteroaryl; each R 7 is C1-C6-alkyl, halo, cyano, oxo, or -OR A1 and each R 11 are independently C1-C6-alkyl, C1-C6-heteroalkyl, C1-C6-haloalkyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, halo, cyano, oxo, or -OR A and each R A1 is hydrogen or C1-C6-alkyl; m is 0, 1, or 2; and x is 0, 1, or 2.

[0071] As generally described herein, A and B are each independently a cycloalkyl, heterocyclyl, aryl, or heteroaryl, each of which may be selected from one or more R 1 is optionally replaced by

[0072] In some embodiments, each of A and B is independently a monocyclic ring, e.g., a monocyclic cycloalkyl, a monocyclic heterocyclyl, a monocyclic aryl, or a monocyclic heteroaryl. The monocyclic ring can be saturated, partially unsaturated, or fully unsaturated (e.g., aromatic). In some embodiments, A or B is independently a monocyclic ring containing 3 to 10 ring atoms (e.g., 3, 4, 5, 6, 7, 8, 9, or 10 ring atoms). In some embodiments, A is a 4-membered monocyclic ring. In some embodiments, B is a 4-membered monocyclic ring. In some embodiments, A is a 5-membered monocyclic ring. In some embodiments, B is a 5-membered monocyclic ring. In some embodiments, A is a 6-membered monocyclic ring. In some embodiments, B is a 6-membered monocyclic ring. In some embodiments, A is a 7-membered monocyclic ring. In some embodiments, B is a 7-membered monocyclic ring. In some embodiments, A is an 8-membered monocyclic ring. In some embodiments, B is an 8-membered monocyclic ring. In some embodiments, A or B independently comprises one or more R 1 is a monocyclic ring optionally substituted with

[0073] In some embodiments, A or B is independently a bicyclic ring, e.g., a bicyclic cycloalkyl, a bicyclic heterocyclyl, a bicyclic aryl, or a bicyclic heteroaryl. The bicyclic ring can be saturated, partially unsaturated, or fully unsaturated (e.g., aromatic). In some embodiments, A or B is independently a bicyclic ring containing a fused ring system, a bridged ring system, or a spiro ring system. In some embodiments, A or B is independently a bicyclic ring containing 4 to 18 ring atoms (e.g., 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, or 18 ring atoms). In some embodiments, A is a 6-membered bicyclic ring. In some embodiments, B is a 6-membered bicyclic ring. In some embodiments, A is a 7-membered bicyclic ring. In some embodiments, B is a 7-membered bicyclic ring. In some embodiments, A is an 8-membered bicyclic ring. In some embodiments, B is an 8-membered bicyclic ring. In some embodiments, A is a 9-membered bicyclic ring. In some embodiments, B is a 9-membered bicyclic ring. In some embodiments, A is a 10-membered bicyclic ring. In some embodiments, B is a 10-membered bicyclic ring. In some embodiments, A is an 11-membered bicyclic ring. In some embodiments, B is an 11-membered bicyclic ring. In some embodiments, A is a 12-membered bicyclic ring. In some embodiments, B is a 12-membered bicyclic ring. In some embodiments, A or B independently selects one or more R 1 is a bicyclic ring optionally substituted with

[0074] In some embodiments, A or B is independently a tricyclic ring, e.g., a tricyclic cycloalkyl, a tricyclic heterocyclyl, a tricyclic aryl, or a tricyclic heteroaryl. The tricyclic ring can be saturated, partially unsaturated, or fully unsaturated (e.g., aromatic). In some embodiments, A or B is independently a tricyclic ring containing a fused ring system, a bridged ring system, or a spiro ring system, or a combination thereof. In some embodiments, A or B is independently a tricyclic ring containing 6 to 24 ring atoms (e.g., 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, or 24 ring atoms). In some embodiments, A is an 8-membered tricyclic ring. In some embodiments, B is an 8-membered tricyclic ring. In some embodiments, A is a 9-membered tricyclic ring. In some embodiments, B is a 9-membered tricyclic ring. In some embodiments, A is a 10-membered tricyclic ring. In some embodiments, B is a 10-membered tricyclic ring. In some embodiments, A or B independently selects one or more R 1 is a tricyclic ring optionally substituted with

[0075] In some embodiments, A or B is independently a monocyclic cycloalkyl, a monocyclic heterocyclyl, a monocyclic aryl, or a monocyclic heteroaryl. In some embodiments, A or B is independently a bicyclic cycloalkyl, a bicyclic heterocyclyl, a bicyclic aryl, or a bicyclic heteroaryl. In some embodiments, A or B is independently a tricyclic cycloalkyl, a tricyclic heterocyclyl, a tricyclic aryl, or a tricyclic heteroaryl. In some embodiments, A is a monocyclic heterocyclyl. In some embodiments, B is a monocyclic heterocyclyl. In some embodiments, A is a bicyclic heterocyclyl. In some embodiments, B is a bicyclic heterocyclyl. In some embodiments, A is a monocyclic heteroaryl. In some embodiments, B is a monocyclic heteroaryl. In some embodiments, A is a bicyclic heteroaryl. In some embodiments, B is a bicyclic heteroaryl.

[0076] In some embodiments, A or B is independently a nitrogen-containing heterocyclyl, for example, a heterocyclyl containing one or more nitrogen atoms. The nitrogen atom or atoms of the nitrogen-containing heterocyclyl can be at any position in the ring. In some embodiments, the nitrogen-containing heterocyclyl is monocyclic, bicyclic, or tricyclic. In some embodiments, A or B is independently a heterocyclyl containing at least 1, at least 2, at least 3, at least 4, at least 5, or at least 6 nitrogen atoms. In some embodiments, A is a heterocyclyl containing one nitrogen atom. In some embodiments, B is a heterocyclyl containing one nitrogen atom. In some embodiments, A is a heterocyclyl containing two nitrogen atoms. In some embodiments, B is a heterocyclyl containing two nitrogen atoms. In some embodiments, A is a heterocyclyl containing three nitrogen atoms. In some embodiments, B is a heterocyclyl containing three nitrogen atoms. In some embodiments, A is a heterocyclyl containing four nitrogen atoms. In some embodiments, B is a heterocyclyl containing four nitrogen atoms. In some embodiments, A or B is independently a nitrogen-containing heterocyclyl containing one or more additional heteroatoms, such as one or more of oxygen, sulfur, boron, silicon, or phosphorus. In some embodiments, one or more nitrogens of the nitrogen-containing heterocyclyl can be, for example, R 1 is replaced by .

[0077] In some embodiments, A or B is independently a nitrogen-containing heteroaryl, e.g., a heteroaryl containing one or more nitrogen atoms. The nitrogen atom or atoms of the nitrogen-containing heteroaryl can be at any position in the ring. In some embodiments, the nitrogen-containing heteroaryl is monocyclic, bicyclic, or tricyclic. In some embodiments, A or B is independently a heteroaryl containing at least 1, at least 2, at least 3, at least 4, at least 5, or at least 6 nitrogen atoms. In some embodiments, A is a heteroaryl containing one nitrogen atom. In some embodiments, B is a heteroaryl containing one nitrogen atom. In some embodiments, A is a heteroaryl containing two nitrogen atoms. In some embodiments, B is a heteroaryl containing two nitrogen atoms. In some embodiments, A is a heteroaryl containing three nitrogen atoms. In some embodiments, B is a heteroaryl containing three nitrogen atoms. In some embodiments, A is a heteroaryl containing four nitrogen atoms. In some embodiments, B is a heteroaryl containing four nitrogen atoms. In some embodiments, A or B is independently a nitrogen-containing heteroaryl containing one or more additional heteroatoms, such as one or more of oxygen, sulfur, boron, silicon, or phosphorus. In some embodiments, the nitrogen or nitrogens of the nitrogen-containing heteroaryl can be, for example, R 1 is replaced by .

[0078] In some embodiments, A is a 6-membered nitrogen-containing heterocyclyl, for example, a 6-membered heterocyclyl containing one or more nitrogen atoms. In some embodiments, A is a 6-membered heterocyclyl containing one nitrogen atom. In some embodiments, A is a 6-membered heterocyclyl containing two nitrogen atoms. In some embodiments, A is a 6-membered heterocyclyl containing three nitrogen atoms. In some embodiments, A is a 6-membered heterocyclyl containing four nitrogen atoms. The one or more nitrogen atoms of the 6-membered nitrogen-containing heterocyclyl can be at any position on the ring. In some embodiments, A is a 6-membered heterocyclyl containing one or more R 1In some embodiments, one or more nitrogens of the 6-membered nitrogen-containing heterocyclyl are optionally substituted, for example, by R 1 In some embodiments, A is a 6-membered nitrogen-containing heterocyclyl containing one or more additional heteroatoms, such as one or more of oxygen, sulfur, boron, silicon, or phosphorus.

[0079] In some embodiments, B is a 5-membered nitrogen-containing heterocyclyl or heteroaryl, for example, a 5-membered heterocyclyl or heteroaryl containing one or more nitrogen atoms. In some embodiments, B is a 5-membered heterocyclyl containing one nitrogen atom. In some embodiments, B is a 5-membered heteroaryl containing one nitrogen atom. In some embodiments, B is a 5-membered heterocyclyl containing two nitrogen atoms. In some embodiments, B is a 5-membered heteroaryl containing two nitrogen atoms. In some embodiments, B is a 5-membered heterocyclyl containing three nitrogen atoms. In some embodiments, B is a 5-membered heteroaryl containing three nitrogen atoms. The one or more nitrogen atoms of the 5-membered nitrogen-containing heterocyclyl or heteroaryl can be at any position on the ring. In some embodiments, B is a 5-membered heterocyclyl containing one or more R 1 In some embodiments, B is a 5-membered nitrogen-containing heterocyclyl optionally substituted with one or more R 1 In some embodiments, one or more nitrogens of the 5-membered nitrogen-containing heterocyclyl or heteroaryl may be optionally substituted, for example, by R 1 In some embodiments, B is a 5-membered nitrogen-containing heterocyclyl or heteroaryl containing one or more additional heteroatoms, such as one or more of oxygen, sulfur, boron, silicon, or phosphorus.

[0080] In some embodiments, B is one or more R 1In some embodiments, B is a nitrogen-containing bicyclic heteroaryl (e.g., a 9-membered nitrogen-containing bicyclic heteroaryl) optionally substituted with one or more R. In some embodiments, B is a 9-membered bicyclic heteroaryl containing one nitrogen atom. In some embodiments, B is a 9-membered bicyclic heteroaryl containing two nitrogen atoms. In some embodiments, B is a 9-membered bicyclic heteroaryl containing three nitrogen atoms. In some embodiments, B is a 9-membered bicyclic heteroaryl containing four nitrogen atoms. The one or more nitrogen atoms of the 9-membered bicyclic heteroaryl can be at any position on the ring. In some embodiments, B is a 9-membered bicyclic heteroaryl containing one or more R 1 is a 9-membered bicyclic heteroaryl substituted with

[0081] In some embodiments, each of A and B is independently: [ka] [ka] [ka] [ka] [ka] [ka] [ka] [ka] [ka] wherein each R 1is as defined herein. In one embodiment, A and B are each independently a saturated, partially saturated, or unsaturated (e.g., aromatic) derivative of one of the above rings. In one embodiment, A and B are each independently a stereoisomer of one of the above rings.

[0082] In some embodiments, each of A and B is [ka] [ka] wherein each R 1 is as defined herein. In one embodiment, A and B are each independently a saturated, partially saturated, or unsaturated (e.g., aromatic) derivative of one of the above rings. In one embodiment, A and B are each independently a stereoisomer of one of the above rings.

[0083] In some embodiments, one of A and B is independently: [ka] wherein R 1 In some embodiments, one of A and B is independently: [ka] wherein each R 1a are independently C1-C6-alkyl, C1-C6-heteroalkyl, C1-C6-haloalkyl, halo, cyano, or -OR A and each alkyl, heteroalkyl, and haloalkyl is selected from one or more R 7 In some embodiments, one of A and B is independently [ka] where each R 1aare independently C1-C6-alkyl, C1-C6-heteroalkyl, C1-C6-haloalkyl, halo, cyano, or -OR A and each alkyl, heteroalkyl, and haloalkyl is selected from one or more R 7 is optionally replaced by

[0084] In some embodiments, one of A and B is independently: [ka] In some embodiments, one of A and B is independently selected from: [ka] In some embodiments, one of A and B is independently selected from: [ka] is.

[0085] In some embodiments, one of A and B is independently a monocyclic heterocyclyl or a bicyclic heterocyclyl, each of which is selected from the group consisting of one or more R 1 In some embodiments, one of A and B is independently nitrogen-containing heterocyclyl and one or more R 1 In some embodiments, one of A and B is independently 4-8 membered heterocyclyl and one or more R 1 In some embodiments, one of A and B is independently [ka] wherein R 1 In some embodiments, one of A and B is independently: [ka] wherein R 1is as described herein. In some embodiments, one of A and B is [ka] where R 1 is as described herein. In some embodiments, A is [ka] wherein R 1 is as described herein. In some embodiments, B is [ka] wherein R 1 is as described herein. In some embodiments, B is [ka] wherein R 1 is as described herein. In some embodiments, A is [ka] In some embodiments, A is one of A and B selected independently from: [ka] In some embodiments, one of A and B is selected from: [ka] is.

[0086] As generally described herein, L 1 may be absent or may be C1-C6-alkylene, C1-C6-heteroalkylene, -O-, -C(O)-, -N(R 4 )-, -N(R 4 )C(O)- or -C(O)N(R 4)-group, where each alkylene and heteroalkylene is selected from one or more R 5 is optionally replaced by

[0087] In some embodiments, L 1 is absent. In some embodiments, L 1 is C1-C6-alkylene (e.g., C1-alkylene, C2-alkylene, C3-alkylene, C4-alkylene, C5-alkylene, or C6-alkylene). 1 is an unsubstituted C1-C6 alkylene. 1 is a substituted C1-C6-alkylene, for example, one or more R 5 In some embodiments, L is a C1-C6 alkylene substituted with 1 is one R 5 In some embodiments, L is a C1-alkylene substituted with 1 is —CH— (or methylene). In some embodiments, L 1 is —C(O)— (or carbonyl).

[0088] As generally described herein, L 1 may be absent or may be C1-C6-alkylene, C1-C6-heteroalkylene, -O-, -C(O)-, -N(R 4 )-, -N(R 4 )C(O)- or -C(O)N(R 4 )-group, where each alkylene and heteroalkylene is selected from one or more R 5 is optionally replaced by

[0089] In some embodiments, L 1 is absent, C1-C6-alkylene, C1-C6-heteroalkylene, -N(R 4 )C(O)-, or -C(O)N(R 4 )-, where each alkylene and heteroalkylene is selected from one or more R 5In some embodiments, L 1 is unsubstituted C1-C6 heteroalkylene. 1 is a substituted heteroalkylene, e.g., one or more R 5 In some embodiments, the heteroalkylene includes one or more heteroatoms. In some embodiments, the heteroalkylene includes one or more of oxygen, sulfur, nitrogen, boron, silicon, or phosphorus. In some embodiments, L 1 is -N(R 4 )C(O)—. In some embodiments, L 1 is -C(O)N(R 4 In some embodiments, L 1 is -C(O)N(H)-.

[0090] In some embodiments, L 1 is R 4 In some embodiments, L is a nitrogen optionally substituted with 1 is R 4 In some embodiments, L 1 is -N(R 4 )-, for example, -N(CH3)-. In some embodiments, L 1 is -NH-.

[0091] As generally described herein, W, X, Y, and Z are each independently C(R 3a ), C(R 3a )(R 3b ), N, or N(R 3c ), or O. In some embodiments, at least one of W, X, Y, and Z is N or N(R 3c In some embodiments, at least two of W, X, Y, and Z are N or N(R 3c In some embodiments, at least two of X, Y, and Z are N or N(R 3c In some embodiments, at least one of Y and Z is N or N(R 3c). In some embodiments, X is N. In some embodiments, X is N(R 3c ). In some embodiments, at least one of W, X, Y, and Z is O. In some embodiments, X is O. In some embodiments, X is C(R 3a ) (e.g., CH). In some embodiments, X is C(R 3a )(R 3b ). In some embodiments, Y is N. In some embodiments, Y is N(R 3c In some embodiments, Y is C(R 3a ) (e.g., CH). In some embodiments, Y is C(R 3a )C(R 3b ). In some embodiments, Z is N. In some embodiments, Z is N(R 3c In some embodiments, Z is C(R 3a ) (e.g., CH). In some embodiments, Z is C(R 3a )C(R 3b In some embodiments, two of X, Y, and Z are N and the remaining X, Y, and Z are C(R 3a ) (e.g., CH). In some embodiments, one of X, Y, and Z is C(R 3a ) (e.g., CH), and the remaining X, Y, and Z are each independently N. In some embodiments, X and Y are each independently N, and Z is C(R 3a ) (e.g., CH). In some embodiments, X is C(R 3a ) (e.g., CH), and Y and Z are each independently N.

[0092] In some embodiments, W is C(R 3a ) (e.g., CH) or C(R 3a )(R 3b ) (e.g., CH). In some embodiments, W is C(R 3a ) (e.g., CH). In some embodiments, W is C(R 3a )(R 3b In some embodiments, W is C(R 3a) (e.g., CH), where two of X, Y, and Z are N and the remaining X, Y, and Z are C(R 3a ) (e.g., CH). In some embodiments, W is C(R 3a ) (e.g., CH), and one of X, Y, and Z is C(R 3a ) (e.g., CH), and the remaining X, Y, and Z are each independently N. In some embodiments, X and Y are each independently N, and W and Z are each independently C(R 3a ) (e.g., CH). In some embodiments, W and X are each independently C(R 3a ) (e.g., CH), and Y and Z are each independently N.

[0093] In some embodiments, X, Y, and Z are each independently N or C(R 3a ) wherein at least one of X, Y, and Z is N, and the bond of the ring containing X, Y, and Z can be a single bond or a double bond, as valences allow.

[0094] In some embodiments, X is C(R 3a ), and Y is C(R 3a ) and Z is O. In some embodiments, X is C(R 3a ), and Y is C(R 3a ), Z is O, and y is 0. In some embodiments, X is C(R 3a ), and Y is C(R 3a ), Z is O, and the bond between X and Y is a double bond. In some embodiments, X is C(R 3a ), and Y is C(R 3a ), Z is O, and the bond between Y and Z is a single bond.

[0095] In some embodiments, [ka] wherein R 3a is as defined herein. In some embodiments, [ka] wherein R 3a is as defined herein. In some embodiments, R 3a is C1-C6-alkyl or C1-C6-heteroalkyl.

[0096] In some embodiments, [ka] In some embodiments, [ka] In some embodiments, [ka] In some embodiments, [ka] In some embodiments, [ka] is.

[0097] In some embodiments, [ka] is selected from.

[0098] In some embodiments, [ka] In some embodiments, [ka] is.

[0099] In some embodiments, R1 is hydrogen. In some embodiments, R 1 is C1-C6-alkyl. In some embodiments, R 1 is C2-C6-alkenyl. In some embodiments, R 1 is C2-C6-alkynyl. In some embodiments, R 1 is C1-C6-heteroalkyl. In some embodiments, R 1 is C1-C6-haloalkyl (e.g., -CF3). In some embodiments, R 1 is C-alkyl (e.g., methyl). In some embodiments, R 1 is unsubstituted C1-C6-alkyl, unsubstituted C2-C6-alkenyl, unsubstituted C2-C6-alkynyl, unsubstituted C1-C6-heteroalkyl, or unsubstituted C1-C6-haloalkyl. 1 is one or more R 6 In some embodiments, R 1 is one or more R 6 In some embodiments, R is a C-C-alkenyl substituted with 1 is one or more R 6 In some embodiments, R is a C2-C6 alkynyl substituted with 1 is one or more R 6 In some embodiments, R is a C1-C6-heteroalkyl substituted with 1 is one or more R 6 In some embodiments, R 1 is methyl.

[0100] In some embodiments, R 1 is cycloalkyl (e.g., 3- to 7-membered cycloalkyl). In some embodiments, R 1 is heterocyclyl (e.g., 3- to 7-membered heterocyclyl). 1 is aryl. In some embodiments, R 1is C1-C6 alkylene-aryl (e.g., benzyl). 1 is C1-C6 alkenylene-aryl. In some embodiments, R 1 is C1-C6 alkylene-heteroaryl. In some embodiments, R 1 is heteroaryl. In some embodiments, R 1 is an unsubstituted cycloalkyl, an unsubstituted heterocyclyl, an unsubstituted aryl, an unsubstituted C1-C6 alkylene-aryl, an unsubstituted C1-C6 alkenylene-aryl, an unsubstituted C1-C6 alkylene-heteroaryl, or an unsubstituted heteroaryl. 1 is one or more R 6 In some embodiments, R is a cycloalkyl substituted with 1 is one or more R 6 In some embodiments, R is a heterocyclyl substituted with 1 is one or more R 6 In some embodiments, R 1 is one or more R 6 In some embodiments, R 1 is one or more R 6 In some embodiments, R is a C1-C6 alkenylene-aryl substituted with 1 is one or more R 6 In some embodiments, R is a C1-C6 alkylene-heteroaryl substituted with 1 is one or more R 6 and heteroaryl substituted with

[0101] In some embodiments, R 1 -OR A In some embodiments, R 1 is -NR B R C (e.g., NH or NMe). In some embodiments, R 1 is -NR BC(O)R D In some embodiments, R 1 is -C(O)NR B R C In some embodiments, R 1 is -C(O)R D In some embodiments, R 1 is -C(O)OR D In some embodiments, R 1 -SR E In some embodiments, R 1 is -S(O) x R D In some embodiments, R 1 is halo, e.g., fluoro, chloro, bromo, or iodo. In some embodiments, R 1 is cyano. In some embodiments, R 1 is nitro (—NO). In some embodiments, R 1 is oxo.

[0102] In some embodiments, two R 1 The groups, taken together with the atoms to which they are attached, form a 3- to 7-membered cycloalkyl. In some embodiments, two R 1 The groups, taken together with the atoms to which they are attached, form a 3- to 7-membered heterocyclyl. 1 The groups, together with the atoms to which they are attached, form a 5- or 6-membered aryl. In some embodiments, two R 1 The groups, taken together with the atom to which they are attached, form a 5- or 6-membered heteroaryl. A cycloalkyl, heterocyclyl, aryl, or heteroaryl can be joined by one or more R 6 may be substituted with.

[0103] In some embodiments, R 2 is hydrogen. In some embodiments, R 2 is halo (e.g., fluoro, chloro, bromo, or iodo). In some embodiments, R 2is cyano. In some embodiments, R 2 is C1-C6-alkyl. In some embodiments, R 2 is C2-C6-alkenyl. In some embodiments, R 2 is C2-C6-alkynyl. In some embodiments, R 2 -OR A (e.g., —OH).

[0104] In some embodiments, R 3a is hydrogen, C1-C6-alkyl, C1-C6-heteroalkyl, C1-C6-haloalkyl, halo, cyano, -OR A , -NR B R C , -C(O)R D , or -C(O)OR D In some embodiments, R 3a is hydrogen or C1-C6-alkyl. In some embodiments, R 3a is hydrogen. In some embodiments, R 3a is C1-C6 alkyl (e.g., methyl). In some embodiments, R 3a is halo (e.g., fluoro, chloro, bromo, or iodo). In some embodiments, R 3a is cyano. In some embodiments, R 3a -OR A (e.g., —OH). In some embodiments, R 3a is -NR B R C In some embodiments, R 3a is -C(O)R D In some embodiments, R 3a is -C(O)OR D is.

[0105] In some embodiments, R 4 is hydrogen. In some embodiments, R 4 is C1-C6 alkyl. In some embodiments, R 4is C1-C6 haloalkyl (e.g., —CF3 or —CHF2). In some embodiments, R 4 is methyl.

[0106] In some embodiments, R 5 is hydrogen. In some embodiments, R 5 is C1-C6-alkyl. In some embodiments, R 5 is C1-C6-heteroalkyl. In some embodiments, R 5 is C1-C6-haloalkyl. In some embodiments, R 5 is cycloalkyl. In some embodiments, R 5 is halo (e.g., fluoro, chloro, bromo, or iodo). In some embodiments, R 5 is cyano. In some embodiments, R 5 is oxo. In some embodiments, R 5 -OR A In some embodiments, R 5 is -NR B R C In some embodiments, R 5 is -C(O)R D or -C(O)OR D is.

[0107] In some embodiments, R 6 is C1-C6-alkyl. In some embodiments, R 6 is C2-C6-alkenyl. In some embodiments, R 6 is C2-C6-alkynyl. In some embodiments, R 6 is C1-C6-heteroalkyl. In some embodiments, R 6 is C1-C6-haloalkyl. In some embodiments, R 6 is unsubstituted C1-C6-alkyl, unsubstituted C2-C6-alkenyl, unsubstituted C2-C6-alkynyl, unsubstituted C1-C6-haloalkyl, or unsubstituted C1-C6-heteroalkyl. 6 is one or more R11 In some embodiments, R 6 is one or more R 11 In some embodiments, R is a C-C-alkenyl substituted with 6 is one or more R 11 In some embodiments, R is a C2-C6 alkynyl substituted with 6 is one or more R 11 In some embodiments, R 6 is one or more R 11 is a C1-C6-heteroalkyl substituted with

[0108] In some embodiments, R 6 is cycloalkyl. In some embodiments, R 6 is heterocyclyl. In some embodiments, R 6 is aryl. In some embodiments, R 6 is heteroaryl. In some embodiments, R 6 is an unsubstituted cycloalkyl, an unsubstituted heterocyclyl, an unsubstituted aryl, or an unsubstituted heteroaryl. 6 is one or more R 11 In some embodiments, R is a cycloalkyl substituted with 6 is one or more R 11 In some embodiments, R is a heterocyclyl substituted with 6 is one or more R 11 In some embodiments, R 6 is one or more R 11 and heteroaryl substituted with

[0109] In some embodiments, R 6 is halo (e.g., fluoro, chloro, bromo, or iodo). In some embodiments, R 6 is cyano. In some embodiments, R 6is oxo. In some embodiments, R 6 -OR A In some embodiments, R 6 is -NR B R C In some embodiments, R 6 is -NR B C(O)R D In some embodiments, R 6 is —NO. In some embodiments, R 6 is -C(O)NR B R C In some embodiments, R 6 is -C(O)R D In some embodiments, R 6 is -C(O)OR D In some embodiments, R 6 -SR E In some embodiments, R 6 is -S(O) x R D is.

[0110] In some embodiments, R 7 is C1-C6-alkyl. In some embodiments, R 7 is halo (e.g., fluoro, chloro, bromo, or iodo). In some embodiments, R 7 is cyano. In some embodiments, R 7 is oxo. In some embodiments, R 7 -OR A1 (e.g., —OH).

[0111] In some embodiments, R 11 is C1-C6-alkyl. In some embodiments, R 11 is C1-C6-heteroalkyl. In some embodiments, R 11 is C1-C6-haloalkyl (e.g., -CF3). In some embodiments, R 11 is cycloalkyl. In some embodiments, R 11 is heterocyclyl. In some embodiments, R11 is aryl. In some embodiments, R 11 is heteroaryl. In some embodiments, R 11 is halo. In some embodiments, R 11 is cyano. In some embodiments, R 11 is oxo. In some embodiments, R 11 -OR A is.

[0112] In some embodiments, R A is hydrogen. In some embodiments, R A is C1-C6 alkyl (e.g., methyl). In some embodiments, R A is C1-C6 haloalkyl. In some embodiments, R A is aryl. In some embodiments, R A is heteroaryl. In some embodiments, R A is C1-C6 alkylene-aryl (e.g., benzyl). A is C1-C6 alkylene-heteroaryl. In some embodiments, R A is C(O)R D In some embodiments, R A is -S(O) x R D is.

[0113] In some embodiments, R B , R C , or both are independently hydrogen, C1-C6-alkyl, C1-C6-heteroalkyl, cycloalkyl, heterocyclyl, or -OR A In some embodiments, R B and R C Each of R is independently hydrogen. B and R C Each of is independently C1-C6 alkyl. B and R C is hydrogen and R B and RC and the other is C1-C6 alkyl. In some embodiments, R B and R C together with the atoms to which they are attached, form one or more R 7 forming a 3- to 7-membered heterocyclyl ring optionally substituted with

[0114] In some embodiments, R D , R E , or both are independently hydrogen, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 heteroalkyl, C1-C6 haloalkyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, C1-C6 alkylene-aryl (e.g., benzyl), or C1-C6 alkylene-heteroaryl. D and R E Each of R is independently hydrogen. D and R E Each of is independently C1-C6 alkyl. D is hydrogen. In some embodiments, R E is hydrogen. In some embodiments, R D is C1-C6 alkyl (e.g., methyl). In some embodiments, R E is C1-C6 alkyl (e.g., methyl). In some embodiments, R D is C1-C6 heteroalkyl. In some embodiments, R E is C1-C6 heteroalkyl. In some embodiments, R D is C1-C6 haloalkyl. In some embodiments, R E is C1-C6 haloalkyl. In some embodiments, R D is cycloalkyl. In some embodiments, R E is cycloalkyl. In some embodiments, R D is heterocyclyl. In some embodiments, R E is heterocyclyl. In some embodiments, R Dis aryl. In some embodiments, R E is aryl. In some embodiments, R D is heteroaryl. In some embodiments, R E is heteroaryl. In some embodiments, R D is C1-C6 alkylene-aryl (e.g., benzyl). E is C1-C6 alkylene-aryl (e.g., benzyl). D is C1-C6 alkylene-heteroaryl. In some embodiments, R E is a C1-C6 alkylene-heteroaryl.

[0115] In some embodiments, R A1 is hydrogen. In some embodiments, R A1 is C1-C6-alkyl (eg, methyl).

[0116] In some embodiments, m is 0, 1, or 2. In some embodiments, m is 0. In some embodiments, m is 1. In some embodiments, m is 2. In some embodiments, x is 0, 1, or 2. In some embodiments, x is 0. In some embodiments, x is 1. In some embodiments, x is 2. In some embodiments, y is 0 or 1. In some embodiments, y is 0. In some embodiments, y is 1.

[0117] In some embodiments, the compound is a compound of formula (I) [ka] or a pharmaceutically acceptable salt, solvate, hydrate, tautomer, or stereoisomer thereof, wherein: A and B are each independently cycloalkyl, heterocyclyl, aryl, or heteroaryl, each of which is selected from one or more R 1 is optionally replaced by; W, X, Y, and Z each independently represent C(R 3a ) or N, and at least one of W, X, Y, and Z is independently N; L 1 is absent, C1-C6-alkylene, C1-C6-heteroalkylene, -O-, -C(O)-, -N(R 4 )-, -N(R 4 )C(O)-, or -C(O)N(R 4 )-, where each alkylene and heteroalkylene is selected from one or more R 5 is optionally replaced by; Each R 1 are independently hydrogen, C1-C6-alkyl, C2-C6-alkenyl, C2-C6-alkynyl, C1-C6-heteroalkyl, C1-C6-haloalkyl, cycloalkyl, heterocyclyl, aryl, C1-C6 alkylene-aryl, C2-C6 alkenylene-aryl, heteroaryl, C1-C6 alkylene-heteroaryl, C2-C6 alkenylene-heteroaryl, halo, cyano, oxo, -OR A , -NR B R C , -NR B C(O)R D , -NO2, -C(O)NR B R C , -C(O)R D , -C(O)OR D , -SR E , or -S(O) x R D wherein each alkyl, alkylene, alkenyl, alkynyl, heteroalkyl, haloalkyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl is selected from one or more R 6 optionally replaced by; or 2 R's 1 The groups, together with the atoms to which they are attached, form a 3- to 7-membered cycloalkyl, heterocyclyl, aryl, or heteroaryl, where each cycloalkyl, heterocyclyl, aryl, and heteroaryl is selected from one or more R 6 is optionally replaced by; Each R 2 are independently C1-C6-alkyl, C2-C6-alkenyl, C2-C6-alkynyl, C1-C6-heteroalkyl, C1-C6-haloalkyl, halo, cyano, or -OR A and; R 3a is hydrogen, C1-C6-alkyl, C1-C6-heteroalkyl, C1-C6-haloalkyl, halo, cyano, -OR A , -NR B R C , -C(O)R D , or -C(O)OR D and; Each R 4 are independently hydrogen, C1-C6-alkyl, or C1-C6-haloalkyl; Each R 5 are independently hydrogen, C1-C6-alkyl, C1-C6-heteroalkyl, C1-C6-haloalkyl, cycloalkyl, halo, cyano, oxo, -OR A , -NR B R C , -C(O)R D , or -C(O)OR D and; Each R 6 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 , -SR E , or -S(O) x R D wherein each alkyl, alkenyl, alkynyl, heteroalkyl, haloalkyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl is selected from one or more R 11is optionally replaced by; Each R A are independently hydrogen, C1-C6 alkyl, C1-C6 haloalkyl, aryl, heteroaryl, C1-C6 alkylene-aryl, C1-C6 alkylene-heteroaryl, -C(O)R D , or -S(O) x R D and; R B and R C each independently represents hydrogen, C1-C6 alkyl, C1-C6 heteroalkyl, cycloalkyl, heterocyclyl, or -OR A or R B and R C together with the atoms to which they are attached, form one or more R 7 forming a 3- to 7-membered heterocyclyl ring optionally substituted with; Each R D are independently hydrogen, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 heteroalkyl, C1-C6 haloalkyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, C1-C6 alkylene-aryl, or C1-C6 alkylene-heteroaryl; each R 7 is C1-C6-alkyl, halo, cyano, oxo, or -OR A1 and; Each R 11 are independently C1-C6-alkyl, C1-C6-heteroalkyl, C1-C6-haloalkyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, halo, cyano, oxo, or -OR A and; Each R A1 is hydrogen or C1-C6-alkyl; m is 0, 1, or 2; x is 0, 1, or 2].

[0118] In some embodiments, the compound is a compound of formula (Ia): [ka] or a pharmaceutically acceptable salt, solvate, hydrate, tautomer, or stereoisomer thereof, wherein A and B are each independently cycloalkyl, heterocyclyl, aryl, or heteroaryl, each of which is selected from the group consisting of one or more R 1 X, Y, and Z are each independently selected from the group consisting of C(R 3a ), C(R 3a )(R 3b ), N, N(R 3c ), or O, where at least one of X, Y, and Z is N, N(R 3c ), or O, where the bonds in the ring containing X, Y, and Z may be single or double bonds as valences permit; L 1 is absent, C1-C6-alkylene, C1-C6-heteroalkylene, -O-, -C(O)-, -N(R 4 )-, -N(R 4 )C(O)-, or -C(O)N(R 4 )-, where each alkylene and heteroalkylene is selected from one or more R 5 and each R 1 are independently hydrogen, C1-C6-alkyl, C2-C6-alkenyl, C2-C6-alkynyl, C1-C6-heteroalkyl, C1-C6-haloalkyl, cycloalkyl, heterocyclyl, aryl, C1-C6 alkylene-aryl, C1-C6 alkenylene-aryl, C1-C6 alkylene-heteroaryl, heteroaryl, halo, cyano, oxo, -OR A , -NR B R C , -NR B C(O)R D , -NO2, -C(O)NR B R C , -C(O)R D , -C(O)OR D , -SR E , or -S(O) x R Dwherein each alkyl, alkylene, alkenyl, alkynyl, heteroalkyl, haloalkyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl is selected from one or more R 6 optionally substituted with; or two R 1 The groups, together with the atoms to which they are attached, form a 3- to 7-membered cycloalkyl, heterocyclyl, aryl, or heteroaryl, where each cycloalkyl, heterocyclyl, aryl, and heteroaryl is selected from one or more R 6 and each R 2 are independently hydrogen, C1-C6-alkyl, C2-C6-alkenyl, C2-C6-alkynyl, C1-C6-heteroalkyl, C1-C6-haloalkyl, halo, cyano, -OR A , N.R. B R C , -C(O)R D , or -C(O)OR D and;R 3a and R 3b are each independently hydrogen, C1-C6-alkyl, C2-C6-alkenyl, C 2~ C6-alkynyl, C1-C6-heteroalkyl, C 1~ C6-haloalkyl, halo, cyano, -OR A , -NR B R C , -C(O)R D , or -C(O)OR D or R 3a and R 3b together with the atom to which they are attached form an oxo group; R 3c is hydrogen or C1-C6-alkyl; each R 4 are independently hydrogen, C1-C6-alkyl, or C1-C6-haloalkyl; each R 5 are independently hydrogen, C1-C6-alkyl, C1-C6-heteroalkyl, C1-C6-haloalkyl, cycloalkyl, halo, cyano, oxo, -OR A , -NR B R C , -C(O)R D, or -C(O)OR D and each R 6 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 , -SR E , or -S(O) x R D wherein each alkyl, alkenyl, alkynyl, heteroalkyl, haloalkyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl is selected from one or more R 11 and each R 7 is C1-C6-alkyl, halo, cyano, oxo, or -OR A1 and each R 11 are independently C1-C6-alkyl, C1-C6-heteroalkyl, C1-C6-haloalkyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, halo, cyano, oxo, or -OR A and each R A are independently hydrogen, C1-C6 alkyl, C1-C6 haloalkyl, aryl, heteroaryl, C1-C6 alkylene-aryl, C1-C6 alkylene-heteroaryl, -C(O)R D , or -S(O) x R D and;R B and R C each independently represents hydrogen, C1-C6 alkyl, C1-C6 heteroalkyl, cycloalkyl, heterocyclyl, or -OR A or R B and R C together with the atoms to which they are attached, form one or more R 7forming a 3- to 7-membered heterocyclyl ring optionally substituted with D and R E are independently hydrogen, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 heteroalkyl, C1-C6 haloalkyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, C1-C6 alkylene-aryl, or C1-C6 alkylene-heteroaryl; each R A1 is hydrogen or C1-C6-alkyl; m is 0, 1, or 2; and x is 0, 1, or 2.

[0119] In some embodiments, the compound is a compound of formula (Ib): [ka] or a pharmaceutically acceptable salt, solvate, hydrate, tautomer, or stereoisomer thereof, wherein A and B are each independently cycloalkyl, heterocyclyl, aryl, or heteroaryl, each of which is selected from the group consisting of one or more R 1 X, Y, and Z are each independently selected from the group consisting of C(R 3a ) or N;L 1 is absent, C1-C6-alkylene, C1-C6-heteroalkylene, -O-, -C(O)-, -N(R 4 )-, -N(R 4 )C(O)-, or -C(O)N(R 4 )-, where each alkylene and heteroalkylene is selected from one or more R 5 and each R 1 are independently hydrogen, C1-C6-alkyl, C2-C6-alkenyl, C2-C6-alkynyl, C1-C6-heteroalkyl, C1-C6-haloalkyl, cycloalkyl, heterocyclyl, aryl, C1-C6 alkylene-aryl, C1-C6 alkenylene-aryl, C1-C6 alkylene-heteroaryl, heteroaryl, halo, cyano, oxo, -OR A , -NR B R C, -NR B C(O)R D , -NO2, -C(O)NR B R C , -C(O)R D , -C(O)OR D , -SR E , or -S(O) x R D wherein each alkyl, alkylene, alkenyl, alkynyl, heteroalkyl, haloalkyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl is selected from one or more R 6 optionally substituted with; or two R 1 The groups, together with the atoms to which they are attached, form a 3- to 7-membered cycloalkyl, heterocyclyl, aryl, or heteroaryl, where each cycloalkyl, heterocyclyl, aryl, and heteroaryl is selected from one or more R 6 and each R 2 are independently hydrogen, C1-C6-alkyl, C2-C6-alkenyl, C2-C6-alkynyl, C1-C6-heteroalkyl, C1-C6-haloalkyl, halo, cyano, -OR A , N.R. B R C , -C(O)R D , or -C(O)OR D and;R 3a is hydrogen, C1-C6-alkyl, C2-C6-alkenyl, C2-C6-alkynyl, C1-C6-heteroalkyl, C1-C6-haloalkyl, halo, cyano, -OR A , -NR B R C , -C(O)R D , or -C(O)OR D or each R 4 are independently hydrogen, C1-C6-alkyl, or C1-C6-haloalkyl; each R 5 are independently hydrogen, C1-C6-alkyl, C1-C6-heteroalkyl, C1-C6-haloalkyl, cycloalkyl, halo, cyano, oxo, -OR A , -NR B R C, -C(O)R D , or -C(O)OR D and each R 6 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 , -SR E , or -S(O) x R D wherein each alkyl, alkenyl, alkynyl, heteroalkyl, haloalkyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl is selected from one or more R 11 and each R 7 is C1-C6-alkyl, halo, cyano, oxo, or -OR A1 and each R 11 are independently C1-C6-alkyl, C1-C6-heteroalkyl, C1-C6-haloalkyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, halo, cyano, oxo, or -OR A and each R A are independently hydrogen, C1-C6 alkyl, C1-C6 haloalkyl, aryl, heteroaryl, C1-C6 alkylene-aryl, C1-C6 alkylene-heteroaryl, -C(O)R D , or -S(O) x R D and;R B and R C each independently represents hydrogen, C1-C6 alkyl, C1-C6 heteroalkyl, cycloalkyl, heterocyclyl, or -OR A or R B and R Ctogether with the atoms to which they are attached, form one or more R 7 forming a 3- to 7-membered heterocyclyl ring optionally substituted with D and R E are independently hydrogen, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 heteroalkyl, C1-C6 haloalkyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, C1-C6 alkylene-aryl, or C1-C6 alkylene-heteroaryl; each R A1 is hydrogen or C1-C6-alkyl; m is 0, 1, or 2; and x is 0, 1, or 2.

[0120] In some embodiments, the compound of Formula (I) is a compound of Formula (Ic) [ka] or a pharmaceutically acceptable salt, solvate, hydrate, tautomer, or stereoisomer thereof, wherein A and B are each independently cycloalkyl, heterocyclyl, aryl, or heteroaryl, each of which is selected from the group consisting of one or more R 1 W, X, Y, and Z are each independently selected from the group consisting of C(R 3a ) or N, where at least one of W, X, Y, and Z is N; 1 are independently hydrogen, C1-C6-alkyl, C2-C6-alkenyl, C2-C6-alkynyl, C1-C6-heteroalkyl, C1-C6-haloalkyl, cycloalkyl, heterocyclyl, aryl, C1-C6 alkylene-aryl, C1-C6 alkenylene-aryl, C1-C6 alkylene-heteroaryl, heteroaryl, halo, cyano, oxo, -OR A , -NR B R C , -NR B C(O)R D , -NO2, -C(O)NR B R C , -C(O)R D , -C(O)OR D, -SR E , or -S(O) x R D wherein each alkyl, alkylene, alkenyl, alkynyl, heteroalkyl, haloalkyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl is selected from one or more R 6 optionally substituted with; or two R 1 The groups, together with the atoms to which they are attached, form a 3- to 7-membered cycloalkyl, heterocyclyl, aryl, or heteroaryl, where each cycloalkyl, heterocyclyl, aryl, and heteroaryl is selected from one or more R 6 and each R 2 are independently hydrogen, C1-C6-alkyl, C2-C6-alkenyl, C2-C6-alkynyl, C1-C6-heteroalkyl, C1-C6-haloalkyl, halo, cyano, -OR A , N.R. B R C , -C(O)R D , or -C(O)OR D and;R 3a is hydrogen, C1-C6-alkyl, C2-C6-alkenyl, C2-C6-alkynyl, C1-C6-heteroalkyl, C1-C6-haloalkyl, halo, cyano, -OR A , -NR B R C , -C(O)R D , or -C(O)OR D or each R 6 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 , -SRE , or -S(O) x R D wherein each alkyl, alkenyl, alkynyl, heteroalkyl, haloalkyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl is selected from one or more R 11 and each R 7 is C1-C6-alkyl, halo, cyano, oxo, or -OR A1 and each R 11 are independently C1-C6-alkyl, C1-C6-heteroalkyl, C1-C6-haloalkyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, halo, cyano, oxo, or -OR A and each R A are independently hydrogen, C1-C6 alkyl, C1-C6 haloalkyl, aryl, heteroaryl, C1-C6 alkylene-aryl, C1-C6 alkylene-heteroaryl, -C(O)R D , or -S(O) x R D and;R B and R C each independently represents hydrogen, C1-C6 alkyl, C1-C6 heteroalkyl, cycloalkyl, heterocyclyl, or -OR A or R B and R C together with the atoms to which they are attached, form one or more R 7 forming a 3- to 7-membered heterocyclyl ring optionally substituted with D and R E are independently hydrogen, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 heteroalkyl, C1-C6 haloalkyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, C1-C6 alkylene-aryl, or C1-C6 alkylene-heteroaryl; each R A1 is hydrogen or C1-C6-alkyl; m is 0, 1, or 2; and x is 0, 1, or 2.

[0121] In some embodiments, the compound of formula (I) is a compound of formula (Id) [ka] or a pharmaceutically acceptable salt, solvate, hydrate, tautomer, or stereoisomer thereof, wherein A and B are each independently cycloalkyl, heterocyclyl, aryl, or heteroaryl, each of which is selected from the group consisting of one or more R 1 Optionally replaced by ;L 1 is absent, C1-C6-alkylene, C1-C6-heteroalkylene, -O-, -C(O)-, -N(R 4 )-, -N(R 4 )C(O)-, or -C(O)N(R 4 )-, where each alkylene and heteroalkylene is selected from one or more R 5 and each R 1 are independently hydrogen, C1-C6-alkyl, C2-C6-alkenyl, C2-C6-alkynyl, C1-C6-heteroalkyl, C1-C6-haloalkyl, cycloalkyl, heterocyclyl, aryl, C1-C6 alkylene-aryl, C1-C6 alkenylene-aryl, C1-C6 alkylene-heteroaryl, heteroaryl, halo, cyano, oxo, -OR A , -NR B R C , -NR B C(O)R D , -NO2, -C(O)NR B R C , -C(O)R D , -C(O)OR D , -SR E , or -S(O) x R D wherein each alkyl, alkylene, alkenyl, alkynyl, heteroalkyl, haloalkyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl is selected from one or more R 6 optionally substituted with; or two R 1The groups, together with the atoms to which they are attached, form a 3- to 7-membered cycloalkyl, heterocyclyl, aryl, or heteroaryl, where each cycloalkyl, heterocyclyl, aryl, and heteroaryl is selected from one or more R 6 and each R 2 are independently hydrogen, C1-C6-alkyl, C2-C6-alkenyl, C2-C6-alkynyl, C1-C6-heteroalkyl, C1-C6-haloalkyl, halo, cyano, -OR A , N.R. B R C , -C(O)R D , or -C(O)OR D and each R 3a are independently hydrogen, C1-C6-alkyl, C2-C6-alkenyl, C2-C6-alkynyl, C1-C6-heteroalkyl, C1-C6-haloalkyl, halo, cyano, -OR A , -NR B R C , -C(O)R D , or -C(O)OR D and each R 4 are independently hydrogen, C1-C6-alkyl, or C1-C6-haloalkyl; each R 5 are independently hydrogen, C1-C6-alkyl, C1-C6-heteroalkyl, C1-C6-haloalkyl, cycloalkyl, halo, cyano, oxo, -OR A , -NR B R C , -C(O)R D , or -C(O)OR D and each R 6 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)RD , -C(O)OR D , -SR E , or -S(O) x R D wherein each alkyl, alkenyl, alkynyl, heteroalkyl, haloalkyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl is selected from one or more R 11 and each R 7 is C1-C6-alkyl, halo, cyano, oxo, or -OR A1 and each R 11 are independently C1-C6-alkyl, C1-C6-heteroalkyl, C1-C6-haloalkyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, halo, cyano, oxo, or -OR A and each R A are independently hydrogen, C1-C6 alkyl, C1-C6 haloalkyl, aryl, heteroaryl, C1-C6 alkylene-aryl, C1-C6 alkylene-heteroaryl, -C(O)R D , or -S(O) x R D and;R B and R C each independently represents hydrogen, C1-C6 alkyl, C1-C6 heteroalkyl, cycloalkyl, heterocyclyl, or -OR A or R B and R C together with the atoms to which they are attached, form one or more R 7 forming a 3- to 7-membered heterocyclyl ring optionally substituted with D and R E are independently hydrogen, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 heteroalkyl, C1-C6 haloalkyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, C1-C6 alkylene-aryl, or C1-C6 alkylene-heteroaryl; each R A1 is hydrogen or C1-C6-alkyl; m is 0, 1, or 2; and x is 0, 1, or 2.

[0122] In some embodiments, the compound of formula (I) is a compound of formula (Ie) [ka] or a pharmaceutically acceptable salt, solvate, hydrate, tautomer, or stereoisomer thereof, wherein A and B are each independently cycloalkyl, heterocyclyl, aryl, or heteroaryl, each of which is selected from the group consisting of one or more R 1 Optionally replaced by ;L 1 is absent, C1-C6-alkylene, C1-C6-heteroalkylene, -O-, -C(O)-, -N(R 4 )-, -N(R 4 )C(O)-, or -C(O)N(R 4 )-, where each alkylene and heteroalkylene is selected from one or more R 5 and each R 1 are independently hydrogen, C1-C6-alkyl, C2-C6-alkenyl, C2-C6-alkynyl, C1-C6-heteroalkyl, C1-C6-haloalkyl, cycloalkyl, heterocyclyl, aryl, C1-C6 alkylene-aryl, C1-C6 alkenylene-aryl, C1-C6 alkylene-heteroaryl, heteroaryl, halo, cyano, oxo, -OR A , -NR B R C , -NR B C(O)R D , -NO2, -C(O)NR B R C , -C(O)R D , -C(O)OR D , -SR E , or -S(O) x R D wherein each alkyl, alkylene, alkenyl, alkynyl, heteroalkyl, haloalkyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl is selected from one or more R 6 optionally substituted with; or two R 1The groups, together with the atoms to which they are attached, form a 3- to 7-membered cycloalkyl, heterocyclyl, aryl, or heteroaryl, where each cycloalkyl, heterocyclyl, aryl, and heteroaryl is selected from one or more R 6 and each R 2 are independently hydrogen, C1-C6-alkyl, C2-C6-alkenyl, C2-C6-alkynyl, C1-C6-heteroalkyl, C1-C6-haloalkyl, halo, cyano, -OR A , N.R. B R C , -C(O)R D , or -C(O)OR D and each R 3a are independently hydrogen, C1-C6-alkyl, C2-C6-alkenyl, C2-C6-alkynyl, C1-C6-heteroalkyl, C1-C6-haloalkyl, halo, cyano, -OR A , -NR B R C , -C(O)R D , or -C(O)OR D and each R 4 are independently hydrogen, C1-C6-alkyl, or C1-C6-haloalkyl; each R 5 are independently hydrogen, C1-C6-alkyl, C1-C6-heteroalkyl, C1-C6-haloalkyl, cycloalkyl, halo, cyano, oxo, -OR A , -NR B R C , -C(O)R D , or -C(O)OR D and each R 6 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)RD , -C(O)OR D , -SR E , or -S(O) x R D wherein each alkyl, alkenyl, alkynyl, heteroalkyl, haloalkyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl is selected from one or more R 11 and each R 7 is C1-C6-alkyl, halo, cyano, oxo, or -OR A1 and each R 11 are independently C1-C6-alkyl, C1-C6-heteroalkyl, C1-C6-haloalkyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, halo, cyano, oxo, or -OR A and each R A are independently hydrogen, C1-C6 alkyl, C1-C6 haloalkyl, aryl, heteroaryl, C1-C6 alkylene-aryl, C1-C6 alkylene-heteroaryl, -C(O)R D , or -S(O) x R D and;R B and R C each independently represents hydrogen, C1-C6 alkyl, C1-C6 heteroalkyl, cycloalkyl, heterocyclyl, or -OR A or R B and R C together with the atoms to which they are attached, form one or more R 7 forming a 3- to 7-membered heterocyclyl ring optionally substituted with D and R E are independently hydrogen, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 heteroalkyl, C1-C6 haloalkyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, C1-C6 alkylene-aryl, or C1-C6 alkylene-heteroaryl; each R A1 is hydrogen or C1-C6-alkyl; m is 0, 1, or 2; and x is 0, 1, or 2.

[0123] In some embodiments, the compound of formula (I) is a compound of formula (If) [ka] or a pharmaceutically acceptable salt, solvate, hydrate, tautomer, or stereoisomer thereof, wherein A and B are each independently cycloalkyl, heterocyclyl, aryl, or heteroaryl, each of which is selected from the group consisting of one or more R 1 Optionally replaced by ;L 1 is absent, C1-C6-alkylene, C1-C6-heteroalkylene, -O-, -C(O)-, -N(R 4 )-, -N(R 4 )C(O)-, or -C(O)N(R 4 )-, where each alkylene and heteroalkylene is selected from one or more R 5 and each R 1 are independently hydrogen, C1-C6-alkyl, C2-C6-alkenyl, C2-C6-alkynyl, C1-C6-heteroalkyl, C1-C6-haloalkyl, cycloalkyl, heterocyclyl, aryl, C1-C6 alkylene-aryl, C1-C6 alkenylene-aryl, C1-C6 alkylene-heteroaryl, heteroaryl, halo, cyano, oxo, -OR A , -NR B R C , -NR B C(O)R D , -NO2, -C(O)NR B R C , -C(O)R D , -C(O)OR D , -SR E , or -S(O) x R D wherein each alkyl, alkylene, alkenyl, alkynyl, heteroalkyl, haloalkyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl is selected from one or more R 6 optionally substituted with; or two R 1The groups, together with the atoms to which they are attached, form a 3- to 7-membered cycloalkyl, heterocyclyl, aryl, or heteroaryl, where each cycloalkyl, heterocyclyl, aryl, and heteroaryl is selected from one or more R 6 and each R 2 are independently hydrogen, C1-C6-alkyl, C2-C6-alkenyl, C2-C6-alkynyl, C1-C6-heteroalkyl, C1-C6-haloalkyl, halo, cyano, -OR A , N.R. B R C , -C(O)R D , or -C(O)OR D and each R 3a are independently hydrogen, C1-C6-alkyl, C2-C6-alkenyl, C2-C6-alkynyl, C1-C6-heteroalkyl, C1-C6-haloalkyl, halo, cyano, -OR A , -NR B R C , -C(O)R D , or -C(O)OR D and each R 4 are independently hydrogen, C1-C6-alkyl, or C1-C6-haloalkyl; each R 5 are independently hydrogen, C1-C6-alkyl, C1-C6-heteroalkyl, C1-C6-haloalkyl, cycloalkyl, halo, cyano, oxo, -OR A , -NR B R C , -C(O)R D , or -C(O)OR D and each R 6 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)RD , -C(O)OR D , -SR E , or -S(O) x R D wherein each alkyl, alkenyl, alkynyl, heteroalkyl, haloalkyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl is selected from one or more R 11 and each R 7 is C1-C6-alkyl, halo, cyano, oxo, or -OR A1 and each R 11 are independently C1-C6-alkyl, C1-C6-heteroalkyl, C1-C6-haloalkyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, halo, cyano, oxo, or -OR A and each R A are independently hydrogen, C1-C6 alkyl, C1-C6 haloalkyl, aryl, heteroaryl, C1-C6 alkylene-aryl, C1-C6 alkylene-heteroaryl, -C(O)R D , or -S(O) x R D and;R B and R C each independently represents hydrogen, C1-C6 alkyl, C1-C6 heteroalkyl, cycloalkyl, heterocyclyl, or -OR A or R B and R C together with the atoms to which they are attached, form one or more R 7 forming a 3- to 7-membered heterocyclyl ring optionally substituted with D and R E are independently hydrogen, C 1~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 A1 is hydrogen or C1-C6-alkyl; m is 0, 1, or 2; and x is 0, 1, or 2.

[0124] In some embodiments, the compound of formula (I) is a compound of formula (Ig) [ka] or a pharmaceutically acceptable salt, solvate, hydrate, tautomer, or stereoisomer thereof, wherein B is cycloalkyl, heterocyclyl, aryl, or heteroaryl, each of which is selected from the group consisting of one or more R 1 X, Y, and Z are each independently selected from the group consisting of C(R 3a ) or N, wherein at least one of X, Y, and Z is independently N; each R 1 are independently hydrogen, C1-C6-alkyl, C2-C6-alkenyl, C2-C6-alkynyl, C1-C6-heteroalkyl, C1-C6-haloalkyl, cycloalkyl, heterocyclyl, aryl, C1-C6 alkylene-aryl, C1-C6 alkenylene-aryl, C1-C6 alkylene-heteroaryl, heteroaryl, halo, cyano, oxo, -OR A , -NR B R C , -NR B C(O)R D , -NO2, -C(O)NR B R C , -C(O)R D , -C(O)OR D , -SR E , or -S(O) x R D wherein each alkyl, alkylene, alkenyl, alkynyl, heteroalkyl, haloalkyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl is selected from one or more R 6 optionally substituted with; or two R 1 The groups, together with the atoms to which they are attached, form a 3- to 7-membered cycloalkyl, heterocyclyl, aryl, or heteroaryl, where each cycloalkyl, heterocyclyl, aryl, and heteroaryl is selected from one or more R 6 and each R2 are independently hydrogen, C1-C6-alkyl, C2-C6-alkenyl, C2-C6-alkynyl, C1-C6-heteroalkyl, C1-C6-haloalkyl, halo, cyano, -OR A , N.R. B R C , -C(O)R D , or -C(O)OR D and each R 3a are independently hydrogen, C1-C6-alkyl, C2-C6-alkenyl, C2-C6-alkynyl, C1-C6-heteroalkyl, C1-C6-haloalkyl, halo, cyano, -OR A , -NR B R C , -C(O)R D , or -C(O)OR D and each R 6 are independently, C 1~C6 -Alkyl, C2-C6-alkenyl, C2-C6-alkynyl, C1-C6-heteroalkyl, C1-C6-haloalkyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, halo, cyano, oxo, -OR A , -NR B R C , -NR B C(O)R D , -NO2, -C(O)NR B R C , -C(O)R D , -C(O)OR D , -SR E , or -S(O) x R D wherein each alkyl, alkenyl, alkynyl, heteroalkyl, haloalkyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl is selected from one or more R 11 and each R 7 is C1-C6-alkyl, halo, cyano, oxo, or -OR A1 and each R 11 are independently C1-C6-alkyl, C1-C6-heteroalkyl, C1-C6-haloalkyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, halo, cyano, oxo, or -ORA and each R A are independently hydrogen, C1-C6 alkyl, C1-C6 haloalkyl, aryl, heteroaryl, C1-C6 alkylene-aryl, C1-C6 alkylene-heteroaryl, -C(O)R D , or -S(O) x R D and;R B and R C each independently represents hydrogen, C1-C6 alkyl, C1-C6 heteroalkyl, cycloalkyl, heterocyclyl, or -OR A or R B and R C together with the atoms to which they are attached, form one or more R 7 forming a 3- to 7-membered heterocyclyl ring optionally substituted with D and R E are independently hydrogen, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 heteroalkyl, C1-C6 haloalkyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, C1-C6 alkylene-aryl, or C1-C6 alkylene-heteroaryl; each R A1 is hydrogen or C1-C6-alkyl; m is 0, 1, or 2; and x is 0, 1, or 2.

[0125] In some embodiments, the compound of formula (I) is a compound of formula (Ih) [ka] or a pharmaceutically acceptable salt, solvate, hydrate, tautomer, or stereoisomer thereof, wherein A is cycloalkyl, heterocyclyl, aryl, or heteroaryl, each of which is selected from the group consisting of one or more R 1 X, Y, and Z are each independently selected from the group consisting of C(R 3a ) or N, wherein at least one of X, Y, and Z is independently N; each R 1are independently hydrogen, C1-C6-alkyl, C2-C6-alkenyl, C2-C6-alkynyl, C1-C6-heteroalkyl, C1-C6-haloalkyl, cycloalkyl, heterocyclyl, aryl, C1-C6 alkylene-aryl, C1-C6 alkenylene-aryl, C1-C6 alkylene-heteroaryl, heteroaryl, halo, cyano, oxo, -OR A , -NR B R C , -NR B C(O)R D , -NO2, -C(O)NR B R C , -C(O)R D , -C(O)OR D , -SR E , or -S(O) x R D wherein each alkyl, alkylene, alkenyl, alkynyl, heteroalkyl, haloalkyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl is selected from one or more R 6 optionally substituted with; or two R 1 The groups, together with the atoms to which they are attached, form a 3- to 7-membered cycloalkyl, heterocyclyl, aryl, or heteroaryl, where each cycloalkyl, heterocyclyl, aryl, and heteroaryl is selected from one or more R 6 and each R 2 are independently hydrogen, C1-C6-alkyl, C2-C6-alkenyl, C2-C6-alkynyl, C1-C6-heteroalkyl, C1-C6-haloalkyl, halo, cyano, -OR A , N.R. B R C , -C(O)R D , or -C(O)OR D and each R 3a are independently hydrogen, C1-C6-alkyl, C2-C6-alkenyl, C2-C6-alkynyl, C1-C6-heteroalkyl, C1-C6-haloalkyl, halo, cyano, -OR A , -NR B R C , -C(O)R D, or -C(O)OR D and each R 6 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 , -SR E , or -S(O) x R D wherein each alkyl, alkenyl, alkynyl, heteroalkyl, haloalkyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl is selected from one or more R 11 and each R 7 is C1-C6-alkyl, halo, cyano, oxo, or -OR A1 and each R 11 are independently C1-C6-alkyl, C1-C6-heteroalkyl, C1-C6-haloalkyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, halo, cyano, oxo, or -OR A and each R A are independently hydrogen, C1-C6 alkyl, C1-C6 haloalkyl, aryl, heteroaryl, C1-C6 alkylene-aryl, C1-C6 alkylene-heteroaryl, -C(O)R D , or -S(O) x R D and;R B and R C each independently represents hydrogen, C1-C6 alkyl, C1-C6 heteroalkyl, cycloalkyl, heterocyclyl, or -OR A or R B and R C together with the atoms to which they are attached, form one or more R 7forming a 3- to 7-membered heterocyclyl ring optionally substituted with D and R E are independently hydrogen, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 heteroalkyl, C1-C6 haloalkyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, C1-C6 alkylene-aryl, or C1-C6 alkylene-heteroaryl; each R A1 is hydrogen or C1-C6-alkyl; m is 0, 1, or 2; p is 1, 2, 3, or 4; and x is 0, 1, or 2.

[0126] In some embodiments, the compound of formula (I) is a compound of formula (Ii) [ka] or a pharmaceutically acceptable salt, solvate, hydrate, tautomer, or stereoisomer thereof, wherein X, Y, and Z are each independently C(R 3a ) or N, where at least one of X, Y, and Z is N; T is N(R 1 ) or C(R 1 )2; U and V are each independently N or C; each R 1 are independently hydrogen, C1-C6-alkyl, C2-C6-alkenyl, C2-C6-alkynyl, C1-C6-heteroalkyl, C1-C6-haloalkyl, cycloalkyl, heterocyclyl, aryl, C1-C6 alkylene-aryl, C1-C6 alkenylene-aryl, C1-C6 alkylene-heteroaryl, heteroaryl, halo, cyano, oxo, -OR A , -NR B R C , -NR B C(O)R D , -NO2, -C(O)NR B R C , -C(O)R D , -C(O)OR D , -SR E , or -S(O) x R Dwherein each alkyl, alkylene, alkenyl, alkynyl, heteroalkyl, haloalkyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl is selected from one or more R 6 optionally substituted with; or two R 1 The groups, together with the atoms to which they are attached, form a 3- to 7-membered cycloalkyl, heterocyclyl, aryl, or heteroaryl, where each cycloalkyl, heterocyclyl, aryl, and heteroaryl is selected from one or more R 6 and each R 6 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 , -SR E , or -S(O) x R D wherein each alkyl, alkenyl, alkynyl, heteroalkyl, haloalkyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl is selected from one or more R 11 and each R 7 is C1-C6-alkyl, halo, cyano, oxo, or -OR A1 and each R 11 are independently C1-C6-alkyl, C1-C6-heteroalkyl, C1-C6-haloalkyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, halo, cyano, oxo, or -OR A and each R Aare independently hydrogen, C1-C6 alkyl, C1-C6 haloalkyl, aryl, heteroaryl, C1-C6 alkylene-aryl, C1-C6 alkylene-heteroaryl, -C(O)R D , or -S(O) x R D and;R B and R C each independently represents hydrogen, C1-C6 alkyl, C1-C6 heteroalkyl, cycloalkyl, heterocyclyl, or -OR A or R B and R C together with the atoms to which they are attached, form one or more R 7 forming a 3- to 7-membered heterocyclyl ring optionally substituted with D and R E are independently hydrogen, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 heteroalkyl, C1-C6 haloalkyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, C1-C6 alkylene-aryl, or C1-C6 alkylene-heteroaryl; each R A1 is hydrogen or C1-C6-alkyl; R U is halo, C1-C6-alkyl, or C1-C6-haloalkyl; p is 0, 1, or 2.

[0127] In some embodiments, the compound of formula (I) is a compound of formula (Ij) [ka] or a pharmaceutically acceptable salt, solvate, hydrate, tautomer, or stereoisomer thereof, wherein A and B are each independently cycloalkyl, heterocyclyl, aryl, or heteroaryl, each of which is selected from the group consisting of one or more R 1 W, X, and Z are each independently selected from the group consisting of C(R 3a ) or N; each R 1are independently hydrogen, C1-C6-alkyl, C2-C6-alkenyl, C2-C6-alkynyl, C1-C6-heteroalkyl, C1-C6-haloalkyl, cycloalkyl, heterocyclyl, aryl, C1-C6 alkylene-aryl, C1-C6 alkenylene-aryl, C1-C6 alkylene-heteroaryl, heteroaryl, halo, cyano, oxo, -OR A , -NR B R C , -NR B C(O)R D , -NO2, -C(O)NR B R C , -C(O)R D , -C(O)OR D , -SR E , or -S(O) x R D wherein each alkyl, alkylene, alkenyl, alkynyl, heteroalkyl, haloalkyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl is selected from one or more R 6 optionally substituted with; or two R 1 The groups, together with the atoms to which they are attached, form a 3- to 7-membered cycloalkyl, heterocyclyl, aryl, or heteroaryl, where each cycloalkyl, heterocyclyl, aryl, and heteroaryl is selected from one or more R 6 and each R 2 are independently hydrogen, C1-C6-alkyl, C2-C6-alkenyl, C2-C6-alkynyl, C1-C6-heteroalkyl, C1-C6-haloalkyl, halo, cyano, -OR A , N.R. B R C , -C(O)R D , or -C(O)OR D and;R 3a is hydrogen, C1-C6-alkyl, C2-C6-alkenyl, C2-C6-alkynyl, C1-C6-heteroalkyl, C1-C6-haloalkyl, halo, cyano, -OR A , -NR B R C , -C(O)R D, or -C(O)OR D or each R 6 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 , -SR E , or -S(O) x R D wherein each alkyl, alkenyl, alkynyl, heteroalkyl, haloalkyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl is selected from one or more R 11 and each R 7 is C1-C6-alkyl, halo, cyano, oxo, or -OR A1 and each R 11 are independently C1-C6-alkyl, C1-C6-heteroalkyl, C1-C6-haloalkyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, halo, cyano, oxo, or -OR A and each R A are independently hydrogen, C1-C6 alkyl, C1-C6 haloalkyl, aryl, heteroaryl, C1-C6 alkylene-aryl, C1-C6 alkylene-heteroaryl, -C(O)R D , or -S(O) x R D wherein each alkyl, haloalkyl, aryl, heteroaryl, alkylene-aryl, alkylene-heteroaryl is selected from one or more R 11 is optionally replaced by ; B and R Ceach independently represents hydrogen, C1-C6 alkyl, C1-C6 heteroalkyl, cycloalkyl, heterocyclyl, or -OR A or R B and R C together with the atoms to which they are attached, form one or more R 7 forming a 3- to 7-membered heterocyclyl ring optionally substituted with D and R E are independently hydrogen, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 heteroalkyl, C1-C6 haloalkyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, C1-C6 alkylene-aryl, or C1-C6 alkylene-heteroaryl; each R A1 is hydrogen or C1-C6-alkyl; m is 0, 1, or 2; x is 0, 1, or 2; y is 1.

[0128] In some embodiments, the compound of formula (I) is a compound of formula (Ik) [ka] or a pharmaceutically acceptable salt, solvate, hydrate, tautomer, or stereoisomer thereof, wherein A and B are each independently cycloalkyl, heterocyclyl, aryl, or heteroaryl, each of which is selected from the group consisting of one or more R 1 Optionally replaced by ;L 2 is absent, C1-C6-alkylene, C1-C6-heteroalkylene, -O-, -C(O)-, -N(R 4 )-, -N(R 4 )C(O)-, or -C(O)N(R 4 )-, where each alkylene and heteroalkylene is selected from one or more R 5 and each R 1are independently hydrogen, C1-C6-alkyl, C2-C6-alkenyl, C2-C6-alkynyl, C1-C6-heteroalkyl, C1-C6-haloalkyl, cycloalkyl, heterocyclyl, aryl, C1-C6 alkylene-aryl, C1-C6 alkenylene-aryl, C1-C6 alkylene-heteroaryl, heteroaryl, halo, cyano, oxo, -OR A , -NR B R C , -NR B C(O)R D , -NO2, -C(O)NR B R C , -C(O)R D , -C(O)OR D , -SR E , or -S(O) x R D wherein each alkyl, alkylene, alkenyl, alkynyl, heteroalkyl, haloalkyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl is selected from one or more R 6 optionally substituted with; or two R 1 The groups, together with the atoms to which they are attached, form a 3- to 7-membered cycloalkyl, heterocyclyl, aryl, or heteroaryl, where each cycloalkyl, heterocyclyl, aryl, and heteroaryl is selected from one or more R 6 and each R 2 are independently hydrogen, C1-C6-alkyl, C2-C6-alkenyl, C2-C6-alkynyl, C1-C6-heteroalkyl, C1-C6-haloalkyl, halo, cyano, -OR A , N.R. B R C , -C(O)R D , or -C(O)OR D and each R 4 are independently hydrogen, C1-C6-alkyl, or C1-C6-haloalkyl; each R 5 are independently hydrogen, C1-C6-alkyl, C1-C6-heteroalkyl, C1-C6-haloalkyl, cycloalkyl, halo, cyano, oxo, -OR A , -NRB R C , -C(O)R D , or -C(O)OR D and each R 6 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 , -SR E , or -S(O) x R D wherein each alkyl, alkenyl, alkynyl, heteroalkyl, haloalkyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl is selected from one or more R 11 and each R 7 is C1-C6-alkyl, halo, cyano, oxo, or -OR A1 and each R 11 are independently C1-C6-alkyl, C1-C6-heteroalkyl, C1-C6-haloalkyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, halo, cyano, oxo, or -OR A and each R A are independently hydrogen, C1-C6 alkyl, C1-C6 haloalkyl, aryl, heteroaryl, C1-C6 alkylene-aryl, C1-C6 alkylene-heteroaryl, -C(O)R D , or -S(O) x R D and;R B and R C each independently represents hydrogen, C1-C6 alkyl, C1-C6 heteroalkyl, cycloalkyl, heterocyclyl, or -OR A or R B and R Ctogether with the atoms to which they are attached, form one or more R 7 forming a 3- to 7-membered heterocyclyl ring optionally substituted with D and R E are independently hydrogen, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 heteroalkyl, C1-C6 haloalkyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, C1-C6 alkylene-aryl, or C1-C6 alkylene-heteroaryl; each R A1 is hydrogen or C1-C6-alkyl; m is 0, 1, or 2; and x is 0, 1, or 2.

[0129] In some embodiments, the compound of formula (I) is a compound of formula (II) [ka] or a pharmaceutically acceptable salt, solvate, hydrate, tautomer, or stereoisomer thereof, wherein A is cycloalkyl, heterocyclyl, aryl, or heteroaryl, each of which is selected from the group consisting of one or more R 1 X, Y, and Z are each independently selected from the group consisting of C(R 3a ) or N, wherein at least one of X, Y, and Z is independently N; each R 1 are independently hydrogen, C1-C6-alkyl, C2-C6-alkenyl, C2-C6-alkynyl, C1-C6-heteroalkyl, C1-C6-haloalkyl, cycloalkyl, heterocyclyl, aryl, C1-C6 alkylene-aryl, C1-C6 alkenylene-aryl, C1-C6 alkylene-heteroaryl, heteroaryl, halo, cyano, oxo, -OR A , -NR B R C , -NR B C(O)R D , -NO2, -C(O)NR B R C , -C(O)R D , -C(O)OR D , -SRE , or -S(O) x R D wherein each alkyl, alkylene, alkenyl, alkynyl, heteroalkyl, haloalkyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl is selected from one or more R 6 optionally substituted with; or two R 1 The groups, together with the atoms to which they are attached, form a 3- to 7-membered cycloalkyl, heterocyclyl, aryl, or heteroaryl, where each cycloalkyl, heterocyclyl, aryl, and heteroaryl is selected from one or more R 6 and each R 2 are independently hydrogen, C1-C6-alkyl, C2-C6-alkenyl, C2-C6-alkynyl, C1-C6-heteroalkyl, C1-C6-haloalkyl, halo, cyano, -OR A , N.R. B R C , -C(O)R D , or -C(O)OR D and each R 3a are independently hydrogen, C1-C6-alkyl, C2-C6-alkenyl, C2-C6-alkynyl, C1-C6-heteroalkyl, C1-C6-haloalkyl, halo, cyano, -OR A , -NR B R C , -C(O)R D , or -C(O)OR D and each R 6 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 , -SR E, or -S(O) x R D wherein each alkyl, alkenyl, alkynyl, heteroalkyl, haloalkyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl is selected from one or more R 11 and each R 7 is C1-C6-alkyl, halo, cyano, oxo, or -OR A1 and each R 11 are independently C1-C6-alkyl, C1-C6-heteroalkyl, C1-C6-haloalkyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, halo, cyano, oxo, or -OR A and each R A are independently hydrogen, C1-C6 alkyl, C1-C6 haloalkyl, aryl, heteroaryl, C1-C6 alkylene-aryl, C1-C6 alkylene-heteroaryl, -C(O)R D , or -S(O) x R D and;R B and R C each independently represents hydrogen, C1-C6 alkyl, C1-C6 heteroalkyl, cycloalkyl, heterocyclyl, or -OR A or R B and R C together with the atoms to which they are attached, form one or more R 7 forming a 3- to 7-membered heterocyclyl ring optionally substituted with D and R E are independently hydrogen, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 heteroalkyl, C1-C6 haloalkyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, C1-C6 alkylene-aryl, or C1-C6 alkylene-heteroaryl; each R A1 is hydrogen or C1-C6-alkyl; m is 0, 1, or 2; and x is 0, 1, or 2.

[0130] In some embodiments, the compound of Formula (I) is selected from the compounds in Table 1, or a pharmaceutically acceptable salt, solvate, hydrate, tautomer, or stereoisomer thereof.

[0131] [Table 1-1] [Table 1-2] [Table 1-3] [Table 1-4] [Table 1-5] [Table 1-6] [Table 1-7] [Table 1-8] [Table 1-9] [Table 1-10] [Table 1-11] [Table 1-12] [Table 1-13] [Table 1-14] Table 1-15 Table 1-16 Table 1-17 Table 1-18 Table 1-19 Table 1-20 Table 1-21 Table 1-22 Table 1-23 Table 1-24 Table 1-25 Table 1-26 Table 1-27 Table 1-28 Table 1-29 Table 1-30 Table 1-31 Table 1-32 Table 1-33 Table 1-34 Table 1-35 Table 1-36 Table 1-37 Table 1-38 Table 1-39 Table 1-40 Table 1-41 Table 1-42 Table 1-43 Table 1-44 Table 1-45 Table 1-46 Table 1-47 Table 1-48 Table 1-49 Table 1-50 Table 1-51 Table 1-52 Table 1-53 Table 1-54 Table 1-55 Table 1-56 Table 1-57 Table 1-58 Table 1-59 Table 1-60 Table 1-61 Table 1-62 Table 1-63 Table 1-64 Table 1-65 [Table 1-66] [Table 1-67]

[0132] In some embodiments, the compound of Formula (I) is selected from compounds 161-184. In some embodiments, the compound of Formula (I) is a compound other than compounds 100-160. In some embodiments, the compound of Formula (I) is selected from compounds 101, 103, 112, 128, 130, 137, 146, 147, 149, 151, 153, 157, 158, 159, 161, 162, 165, 169, 171, 172, or 173. In some embodiments, the compound of Formula (Ig) is selected from compounds 101, 103, 112, 128, 130, 137, 146, 147, 149, 151, 153, 157, 158, 159, 161, 162, 165, 169, 171, 172, or 173.

[0133] In some embodiments, the compound of Formula (I) is a) Compound 161; b) Compound 162; c) Compound 163; d) Compound 164; e) Compound 165; f) Compound 166; g) Compound 167; h) Compound 168; i) Compound 169; j) Compound 170; k) Compound 171; l) Compound 172; m) Compound 173; n) Compound 174; p) Compound 176; q) Compound 177; r) Compound 178; s) Compound 179; t) Compound 180; u) Compound 181; v) Compound 182; w) Compound 183; or x) Compound 184. In some embodiments, for Formula (I), A is monocyclic heterocyclyl (e.g., piperazinyl); B is bicyclic heteroaryl (e.g., 2,8-dimethylimidazo[1,2-b]pyridazinyl); and L is a cyclic heteroaryl (e.g., 2,8-dimethylimidazo[1,2-b]pyridazinyl). 1 is non-existent;L 2 is -C(O)N(R 4 )—(e.g., —C(O)N(H)—); W and X are each independently C(R 3a) (e.g., CH); Y and Z are N; and y is 1. In some embodiments, the compound of Formula (I), (Ia), (Ib), (Id), (Ie), and (If) is Compound 100, or a pharmaceutically acceptable salt, solvate, hydrate, tautomer, or stereoisomer thereof.

[0134] In some embodiments, for Formula (I), A is a monocyclic heterocyclyl (e.g., piperazinyl); B is a bicyclic heteroaryl (e.g., 8-fluoro-2-methylimidazo[1,2-a]pyridinyl); L 1 is non-existent;L 2 is -C(O)N(R 4 )—(e.g., —C(O)N(H)—); W and X are each independently C(R 3a ) (e.g., CH); Y and Z are N; and y is 1. In some embodiments, the compound of Formula (I), (Ia), (Ib), (Id), (Ie), (If), and (Ig) is Compound 101, or a pharmaceutically acceptable salt, solvate, hydrate, tautomer, or stereoisomer thereof.

[0135] In some embodiments, for Formula (I), A is a monocyclic heterocyclyl (e.g., piperidinyl); B is a bicyclic heteroaryl (e.g., 8-fluoro-2-methylimidazo[1,2-a]pyridinyl); L 1 is non-existent;L 2 is -C(O)N(R 4 )—(e.g., —C(O)N(H)—); W and X are each independently C(R 3a ) (e.g., CH); Y and Z are N; and y is 1. In some embodiments, the compound of Formula (I), (Ia), (Ib), (Id), (Ie), (If), and (Ig) is Compound 103, or a pharmaceutically acceptable salt, solvate, hydrate, tautomer, or stereoisomer thereof.

[0136] In some embodiments, for Formula (I), A is a monocyclic heterocyclyl (e.g., 2,2,6,6-tetramethylpiperazinyl); B is a bicyclic heteroaryl (e.g., 8-fluoro-2-methylimidazo[1,2-a]pyridinyl); L 1 is non-existent;L 2 is -C(O)N(R 4 )—(e.g., —C(O)N(H)—); W and X are each independently C(R 3a ) (e.g., CH); Y and Z are N; and y is 1. In some embodiments, the compound of Formula (I), (Ia), (Ib), (Id), (Ie), (If), and (Ig) is Compound 104, or a pharmaceutically acceptable salt, solvate, hydrate, tautomer, or stereoisomer thereof.

[0137] In some embodiments, for Formula (I), A is a bicyclic heterocyclyl (e.g., 4,7-diazaspiro[2.5]octanyl); B is a bicyclic heteroaryl (e.g., 8-fluoro-2-methylimidazo[1,2-a]pyridinyl); L 1 is non-existent;L 2 is -C(O)N(R 4 )—(e.g., —C(O)N(H)—); W and X are each independently C(R 3a ) (e.g., CH); Y and Z are N; and y is 1. In some embodiments, the compound of Formula (I), (Ia), (Ib), (Id), (Ie), (If), and (Ig) is Compound 105, or a pharmaceutically acceptable salt, solvate, hydrate, tautomer, or stereoisomer thereof.

[0138] In some embodiments, for Formula (I), A is a monocyclic heterocyclyl (e.g., 2,2-dimethylpiperazinyl); B is a bicyclic heteroaryl (e.g., 8-fluoro-2-methylimidazo[1,2-a]pyridinyl); L 1 is non-existent;L 2 is -C(O)N(R 4)—(e.g., —C(O)N(H)—); W and X are each independently C(R 3a ) (e.g., CH); Y and Z are N; and y is 1. In some embodiments, the compound of Formula (I), (Ia), (Ib), (Id), (Ie), (If), and (Ig) is Compound 106, or a pharmaceutically acceptable salt, solvate, hydrate, tautomer, or stereoisomer thereof.

[0139] In some embodiments, for Formula (I), A is a bicyclic heterocyclyl (e.g., octahydropyrrolo[1,2-a]pyrazinyl); B is a bicyclic heteroaryl (e.g., 8-fluoro-2-methylimidazo[1,2-a]pyridinyl); L 1 is non-existent;L 2 is -C(O)N(R 4 )—(e.g., —C(O)N(H)—); W and X are each independently C(R 3a ) (e.g., CH); Y and Z are N; and y is 1. In some embodiments, the compound of Formula (I), (Ia), (Ib), (Id), (Ie), (If), and (Ig) is compound 107, 153, 154, or a pharmaceutically acceptable salt, solvate, hydrate, tautomer, or stereoisomer thereof.

[0140] In some embodiments, for Formula (I), A is a bicyclic heterocyclyl (e.g., (1R,5S)-3,8-diazabicyclo[3.2.1]octanyl); B is a bicyclic heteroaryl (e.g., 8-fluoro-2-methylimidazo[1,2-a]pyridinyl); and L 1 is non-existent;L 2 is -C(O)N(R 4 )—(e.g., —C(O)N(H)—); W and X are each independently C(R 3a) (e.g., CH); Y and Z are N; and y is 1. In some embodiments, the compound of Formula (I), (Ia), (Ib), (Id), (Ie), (If), and (Ig) is Compound 108, or a pharmaceutically acceptable salt, solvate, hydrate, tautomer, or stereoisomer thereof.

[0141] In some embodiments, for Formula (I), A is a monocyclic heterocyclyl (e.g., 3-(tert-butylamino)pyrrolidinyl); B is a bicyclic heteroaryl (e.g., 8-fluoro-2-methylimidazo[1,2-a]pyridinyl); L 1 is non-existent;L 2 is -C(O)N(R 4 )—(e.g., —C(O)N(H)—); W and X are each independently C(R 3a ) (e.g., CH); Y and Z are N; and y is 1. In some embodiments, the compound of Formula (I), (Ia), (Ib), (Id), (Ie), and (If) is Compound 109, or a pharmaceutically acceptable salt, solvate, hydrate, tautomer, or stereoisomer thereof.

[0142] In some embodiments, for Formula (I), A is a monocyclic heterocyclyl (e.g., piperazinyl); B is a bicyclic heteroaryl (e.g., 8-fluoro-2-methylimidazo[1,2-a]pyridinyl); L 1 is non-existent;L 2 is -C(O)N(R 4 )—(e.g., —C(O)N(H)—); X is C(R 3a ) (e.g., CH); W, Y, and Z are each N; and y is 1. In some embodiments, the compound of Formula (I), (Ia), and (Ie) is Compound 110, or a pharmaceutically acceptable salt, solvate, hydrate, tautomer, or stereoisomer thereof.

[0143] In some embodiments, for Formula (I), A is a monocyclic heterocyclyl (e.g., piperazinyl); B is a bicyclic heteroaryl (e.g., 8-fluoro-2-methylimidazo[1,2-a]pyridinyl); L 1 is non-existent;L 2 is -C(O)N(R 4 )—(e.g., —C(O)N(H)—); X and Y are each independently C(R 3a ) (e.g., CH); W and Z are N; and y is 1. In some embodiments, the compound of Formula (I), (Ia), and (Ie) is Compound 111, or a pharmaceutically acceptable salt, solvate, hydrate, tautomer, or stereoisomer thereof.

[0144] In some embodiments, for Formula (I), A is a monocyclic heterocyclyl (e.g., piperazinyl); B is a bicyclic heteroaryl (e.g., 8-fluoro-2-methylimidazo[1,2-a]pyridinyl); L 1 is non-existent;L 2 is -C(O)N(R 4 )—(e.g., —C(O)N(H)—); W and Y are each independently C(R 3a ) (e.g., CH); X and Z are N; and y is 1. In some embodiments, the compound of Formula (I), (Ia), (Ib), (Ie), (If), and (Ig) is Compound 112, or a pharmaceutically acceptable salt, solvate, hydrate, tautomer, or stereoisomer thereof.

[0145] In some embodiments, for Formula (I), A is a monocyclic heterocyclyl (e.g., piperidinyl); B is a bicyclic heteroaryl (e.g., 2,8-dimethylimidazo[1,2-b]pyridazyl); L 1 is non-existent;L 2 is -C(O)N(R 4 )—(e.g., —C(O)N(H)—); W and X are each independently C(R 3a) (e.g., CH); Y and Z are N; and y is 1. In some embodiments, the compound of Formula (I), (Ia), (Ib), (Id), (Ie), and (If) is Compound 113, or a pharmaceutically acceptable salt, solvate, hydrate, tautomer, or stereoisomer thereof.

[0146] In some embodiments, for Formula (I), A is a monocyclic heterocyclyl (e.g., piperazinyl); B is a bicyclic heteroaryl (e.g., 8-fluoro-2-methylimidazo[1,2-a]pyridinyl); L 1 is non-existent;L 2 is non-existent; W is C(R 3a ) (e.g., CH); X is C(R 3a ) (e.g., CH); Y is C(R 3a ) (e.g., C(OCH3)); Z is N; and y is 1. In some embodiments, the compound of Formula (I), (Ia), and (Ib) is Compound 114, or a pharmaceutically acceptable salt, solvate, hydrate, tautomer, or stereoisomer thereof.

[0147] In some embodiments, for Formula (I), A is a monocyclic heterocyclyl (e.g., piperazinyl); B is a bicyclic heteroaryl (e.g., 2-methyl-2H-indazolyl); L 1 is non-existent;L 2 is -C(O)N(R 4 )—(e.g., —C(O)N(H)—); W and X are each independently C(R 3a ) (e.g., CH); Y and Z are N; and y is 1. In some embodiments, the compound of Formula (I), (Ia), (Ib), (Id), (Ie), and (If) is Compound 115, or a pharmaceutically acceptable salt, solvate, hydrate, tautomer, or stereoisomer thereof.

[0148] In some embodiments, for Formula (I), A is a monocyclic heterocyclyl (e.g., piperazinyl); B is a bicyclic heteroaryl (e.g., 4-fluoro-2-methyl-2H-indazolyl); L 1 is non-existent;L 2 is -C(O)N(R 4 )—(e.g., —C(O)N(H)—); W and X are each independently C(R 3a ) (e.g., CH); Y and Z are N; and y is 1. In some embodiments, the compound of Formula (I), (Ia), (Ib), (Id), (Ie), and (If) is Compound 116, or a pharmaceutically acceptable salt, solvate, hydrate, tautomer, or stereoisomer thereof.

[0149] In some embodiments, for Formula (I), A is a monocyclic heterocyclyl (e.g., piperazinyl); B is a bicyclic heteroaryl (e.g., 4-fluoro-2-methylbenzo[d]oxazolyl); L 1 is non-existent;L 2 is -C(O)N(R 4 )—(e.g., —C(O)N(H)—); W and X are each independently C(R 3a ) (e.g., CH); Y and Z are N; and y is 1. In some embodiments, the compound of Formula (I), (Ia), (Ib), (Id), (Ie), and (If) is Compound 117, or a pharmaceutically acceptable salt, solvate, hydrate, tautomer, or stereoisomer thereof.

[0150] In some embodiments, for Formula (I), A is a monocyclic heterocyclyl (e.g., piperazinyl); B is a bicyclic heteroaryl (e.g., 4-fluoro-2-methylbenzo[d]thiazolyl); L 1 is non-existent;L 2 is -C(O)N(R 4 )—(e.g., —C(O)N(H)—); W and X are each independently C(R 3a) (e.g., CH); Y and Z are N; and y is 1. In some embodiments, the compound of Formula (I), (Ia), (Ib), (Id), (Ie), and (If) is Compound 118, or a pharmaceutically acceptable salt, solvate, hydrate, tautomer, or stereoisomer thereof.

[0151] In some embodiments, for Formula (I), A is a monocyclic heterocyclyl (e.g., piperazinyl); B is a bicyclic heteroaryl (e.g., 2,7-dimethylimidazo[1,2-a]pyridinyl); L 1 is non-existent;L 2 is -C(O)N(R 4 )—(e.g., —C(O)N(H)—); W and X are each independently C(R 3a ) (e.g., CH); Y and Z are N; and y is 1. In some embodiments, the compound of Formula (I), (Ia), (Ib), (Id), (Ie), and (If) is Compound 119, or a pharmaceutically acceptable salt, solvate, hydrate, tautomer, or stereoisomer thereof.

[0152] In some embodiments, for Formula (I), A is a monocyclic heterocyclyl (e.g., piperazinyl); B is a bicyclic heteroaryl (e.g., 2-methylimidazo[1,2-a]pyrazinyl); L 1 is non-existent;L 2 is -C(O)N(R 4 )—(e.g., —C(O)N(H)—); W and X are each independently C(R 3a ) (e.g., CH); Y and Z are N; and y is 1. In some embodiments, the compound of Formula (I), (Ia), (Ib), (Id), (Ie), (If), and (Ig) is Compound 120, or a pharmaceutically acceptable salt, solvate, hydrate, tautomer, or stereoisomer thereof.

[0153] In some embodiments, for Formula (I), A is a monocyclic heterocyclyl (e.g., piperazinyl); B is a bicyclic heteroaryl (e.g., 6,8-dimethylimidazo[1,2-a]pyrazinyl); L 1 is non-existent;L 2 is -C(O)N(R 4 )—(e.g., —C(O)N(H)—); W and X are each independently C(R 3a ) (e.g., CH); Y and Z are N; and y is 1. In some embodiments, the compound of Formula (I), (Ia), (Ib), (Id), (Ie), and (If) is Compound 121, or a pharmaceutically acceptable salt, solvate, hydrate, tautomer, or stereoisomer thereof.

[0154] In some embodiments, for Formula (I), A is a monocyclic heterocyclyl (e.g., piperazinyl); B is a bicyclic heteroaryl (e.g., 6,8-dimethyl-[1,2,4]triazolo[1,5-a]pyrazinyl); L 1 is non-existent;L 2 is -C(O)N(R 4 )—(e.g., —C(O)N(H)—); W and X are each independently C(R 3a ) (e.g., CH); Y and Z are N; and y is 1. In some embodiments, the compound of Formula (I), (Ia), (Ib), (Id), (Ie), and (If) is Compound 122, or a pharmaceutically acceptable salt, solvate, hydrate, tautomer, or stereoisomer thereof.

[0155] In some embodiments, for Formula (I), A is a monocyclic heterocyclyl (e.g., piperazinyl); B is a bicyclic heteroaryl (e.g., 4,6-dimethylpyrazolo[1,5-a]pyrazinyl); L 1 is non-existent;L 2 is -C(O)N(R 4 )—(e.g., —C(O)N(H)—); W and X are each independently C(R 3a) (e.g., CH); Y and Z are N; and y is 1. In some embodiments, the compound of Formula (I), (Ia), (Ib), (Id), (Ie), and (If) is compound 123, or a pharmaceutically acceptable salt, solvate, hydrate, tautomer, or stereoisomer thereof.

[0156] In some embodiments, for Formula (I), A is a monocyclic heterocyclyl (e.g., piperazinyl); B is a bicyclic heteroaryl (e.g., 8-chloro-2-methylimidazo[1,2-a]pyridinyl); L 1 is non-existent;L 2 is -C(O)N(R 4 )—(e.g., —C(O)N(H)—); W and X are each independently C(R 3a ) (e.g., CH); Y and Z are N; and y is 1. In some embodiments, the compound of Formula (I), (Ia), (Ib), (Id), (Ie), (If), and (Ig) is Compound 124, or a pharmaceutically acceptable salt, solvate, hydrate, tautomer, or stereoisomer thereof.

[0157] In some embodiments, for Formula (I), A is a monocyclic heterocyclyl (e.g., piperazinyl); B is a bicyclic heteroaryl (e.g., 2,8-dimethylimidazo[1,2-a]pyridinyl); L 1 is non-existent;L 2 is -C(O)N(R 4 )—(e.g., —C(O)N(H)—); W and X are each independently C(R 3a ) (e.g., CH); Y and Z are N; and y is 1. In some embodiments, the compound of Formula (I), (Ia), (Ib), (Id), (Ie), (If), and (Ig) is Compound 125, or a pharmaceutically acceptable salt, solvate, hydrate, tautomer, or stereoisomer thereof.

[0158] In some embodiments, for Formula (I), A is monocyclic heterocyclyl (e.g., piperazinyl); B is monocyclic heteroaryl (e.g., pyrazyl); L 1 is non-existent;L 2 is -C(O)N(R 4 )—(e.g., —C(O)N(H)—); W and X are each independently C(R 3a ) (e.g., CH); Y and Z are N; and y is 1. In some embodiments, the compound of Formula (I), (Ia), (Ib), (Id), (Ie), and (If) is Compound 126, or a pharmaceutically acceptable salt, solvate, hydrate, tautomer, or stereoisomer thereof.

[0159] In some embodiments, for Formula (I), A is a monocyclic heterocyclyl (e.g., 1-methylpiperazinyl); B is a bicyclic heteroaryl (e.g., 8-fluoro-2-methylimidazo[1,2-a]pyridinyl); L 1 is non-existent;L 2 is -C(O)N(R 4 )—(e.g., —C(O)N(H)—); W and X are each independently C(R 3a ) (e.g., CH); Y and Z are N; and y is 1. In some embodiments, the compound of Formula (I), (Ia), (Ib), (Id), (Ie), (If), and (Ig) is Compound 127, or a pharmaceutically acceptable salt, solvate, hydrate, tautomer, or stereoisomer thereof.

[0160] In some embodiments, for Formula (I), A is a monocyclic heterocyclyl (e.g., 2-methylpiperazinyl); B is a bicyclic heteroaryl (e.g., 8-fluoro-2-methylimidazo[1,2-a]pyridinyl); L 1 is non-existent;L 2 is -C(O)N(R 4 )—(e.g., —C(O)N(H)—); W and X are each independently C(R 3a) (e.g., CH); Y and Z are N; and y is 1. In some embodiments, the compound of Formula (I), (Ia), (Ib), (Id), (Ie), (If), and (Ig) is compound 128, 146, 147, or a pharmaceutically acceptable salt, solvate, hydrate, tautomer, or stereoisomer thereof.

[0161] In some embodiments, for Formula (I), A is a monocyclic heterocyclyl (e.g., 1,2-dimethylpiperazinyl); B is a bicyclic heteroaryl (e.g., 8-fluoro-2-methylimidazo[1,2-a]pyridinyl); L 1 is non-existent;L 2 is -C(O)N(R 4 )—(e.g., —C(O)N(H)—); W and X are each independently C(R 3a ) (e.g., CH); Y and Z are N; and y is 1. In some embodiments, the compound of Formula (I), (Ia), (Ib), (Id), (Ie), (If), and (Ig) is compound 129, 149, 150, or a pharmaceutically acceptable salt, solvate, hydrate, tautomer, or stereoisomer thereof.

[0162] In some embodiments, for Formula (I), A is a monocyclic heterocyclyl (e.g., 2-ethylpiperazinyl); B is a bicyclic heteroaryl (e.g., 8-fluoro-2-methylimidazo[1,2-a]pyridinyl); L 1 is non-existent;L 2 is -C(O)N(R 4 )—(e.g., —C(O)N(H)—); W and X are each independently C(R 3a ) (e.g., CH); Y and Z are N; and y is 1. In some embodiments, the compound of Formula (I), (Ia), (Ib), (Id), (Ie), (If), and (Ig) is compound 130, 151, 152, or a pharmaceutically acceptable salt, solvate, hydrate, tautomer, or stereoisomer thereof.

[0163] In some embodiments, for Formula (I), A is a bicyclic heterocyclyl (e.g., 2,6-diazaspiro[3.3]heptanyl); B is a bicyclic heteroaryl (e.g., 8-fluoro-2-methylimidazo[1,2-a]pyridinyl); L 1 is non-existent;L 2 is -C(O)N(R 4 )—(e.g., —C(O)N(H)—); W and X are each independently C(R 3a ) (e.g., CH); Y and Z are N; and y is 1. In some embodiments, the compound of Formula (I), (Ia), (Ib), (Id), (Ie), (If), and (Ig) is Compound 131, or a pharmaceutically acceptable salt, solvate, hydrate, tautomer, or stereoisomer thereof.

[0164] In some embodiments, for Formula (I), A is a bicyclic heterocyclyl (e.g., 2-methyl-2,6-diazaspiro[3.3]heptanyl); B is a bicyclic heteroaryl (e.g., 8-fluoro-2-methylimidazo[1,2-a]pyridinyl); L 1 is non-existent;L 2 is -C(O)N(R 4 )—(e.g., —C(O)N(H)—); W and X are each independently C(R 3a ) (e.g., CH); Y and Z are N; and y is 1. In some embodiments, the compound of Formula (I), (Ia), (Ib), (Id), (Ie), (If), and (Ig) is Compound 132, or a pharmaceutically acceptable salt, solvate, hydrate, tautomer, or stereoisomer thereof.

[0165] In some embodiments, for Formula (I), A is a monocyclic heterocyclyl (e.g., 1,3′-bipyrrolidinyl); B is a bicyclic heteroaryl (e.g., 8-fluoro-2-methylimidazo[1,2-a]pyridinyl); L 1 is non-existent;L 2 is -C(O)N(R 4)—(e.g., —C(O)N(H)—); W and X are each independently C(R 3a ) (e.g., CH); Y and Z are N; and y is 1. In some embodiments, the compound of Formula (I), (Ia), (Ib), (Id), (Ie), (If), and (Ig) is Compound 133, or a pharmaceutically acceptable salt, solvate, hydrate, tautomer, or stereoisomer thereof.

[0166] In some embodiments, for Formula (I), A is a monocyclic heterocyclyl (e.g., 3-(N,N-dimethyl)aminopyrrolidinyl); B is a bicyclic heteroaryl (e.g., 8-fluoro-2-methylimidazo[1,2-a]pyridinyl); L 1 is non-existent;L 2 is -C(O)N(R 4 )—(e.g., —C(O)N(H)—); W and X are each independently C(R 3a ) (e.g., CH); Y and Z are N; and y is 1. In some embodiments, the compound of Formula (I), (Ia), (Ib), (Id), (Ie), (If), and (Ig) is Compound 134, or a pharmaceutically acceptable salt, solvate, hydrate, tautomer, or stereoisomer thereof.

[0167] In some embodiments, for Formula (I), A is a monocyclic heterocyclyl (e.g., 2,2,6,6-tetramethylpiperidinyl); B is a bicyclic heteroaryl (e.g., 8-fluoro-2-methylimidazo[1,2-a]pyridinyl); L 1 is -N(R 4 )-(e.g., -N(CH3)-); L 2 is -C(O)N(R 4 )—(e.g., —C(O)N(H)—); W and X are each independently C(R 3a) (e.g., CH); Y and Z are N; and y is 1. In some embodiments, the compound of Formula (I), (Ia), (Ib), (Id), (Ie), (If), and (Ig) is Compound 135, or a pharmaceutically acceptable salt, solvate, hydrate, tautomer, or stereoisomer thereof.

[0168] In some embodiments, for Formula (I), A is a monocyclic heterocyclyl (e.g., 2-methylpiperidinyl); B is a bicyclic heteroaryl (e.g., 8-fluoro-2-methylimidazo[1,2-a]pyridinyl); L 1 is -N(R 4 )-(e.g., -N(CH3)-); L 2 is -C(O)N(R 4 )—(e.g., —C(O)N(H)—); W and X are each independently C(R 3a ) (e.g., CH); Y and Z are N; and y is 1. In some embodiments, the compound of Formula (I), (Ia), (Ib), (Id), (Ie), (If), and (Ig) is Compound 136, or a pharmaceutically acceptable salt, solvate, hydrate, tautomer, or stereoisomer thereof.

[0169] In some embodiments, for Formula (I), A is a monocyclic heterocyclyl (e.g., 4-(N,N-dimethyl)aminopiperidinyl); B is a bicyclic heteroaryl (e.g., 8-fluoro-2-methylimidazo[1,2-a]pyridinyl); L 1 is non-existent;L 2 is -C(O)N(R 4 )—(e.g., —C(O)N(H)—); W and X are each independently C(R 3a ) (e.g., CH); Y and Z are N; and y is 1. In some embodiments, the compound of Formula (I), (Ia), (Ib), (Id), (Ie), (If), and (Ig) is Compound 137, or a pharmaceutically acceptable salt, solvate, hydrate, tautomer, or stereoisomer thereof.

[0170] In some embodiments, for Formula (I), A is a monocyclic heterocyclyl (e.g., 4-(N-tert-butyl)aminopiperidinyl); B is a bicyclic heteroaryl (e.g., 8-fluoro-2-methylimidazo[1,2-a]pyridinyl); L 1 is non-existent;L 2 is -C(O)N(R 4 )—(e.g., —C(O)N(H)—); W and X are each independently C(R 3a ) (e.g., CH); Y and Z are N; and y is 1. In some embodiments, the compound of Formula (I), (Ia), (Ib), (Id), (Ie), (If), and (Ig) is Compound 138, or a pharmaceutically acceptable salt, solvate, hydrate, tautomer, or stereoisomer thereof.

[0171] In some embodiments, for Formula (I), A is a monocyclic heterocyclyl (e.g., 4-(N ethyl)aminopiperidinyl); B is a bicyclic heteroaryl (e.g., 8-fluoro-2-methylimidazo[1,2-a]pyridinyl); L 1 is non-existent;L 2 is -C(O)N(R 4 )—(e.g., —C(O)N(H)—); W and X are each independently C(R 3a ) (e.g., CH); Y and Z are N; and y is 1. In some embodiments, the compound of Formula (I), (Ia), (Ib), (Id), (Ie), (If), and (Ig) is Compound 139, or a pharmaceutically acceptable salt, solvate, hydrate, tautomer, or stereoisomer thereof.

[0172] In some embodiments, for Formula (I), A is a monocyclic heterocyclyl (e.g., 1-methylpiperidinyl); B is a bicyclic heteroaryl (e.g., 8-fluoro-2-methylimidazo[1,2-a]pyridinyl); L 1 is non-existent;L 2 is -C(O)N(R 4)—(e.g., —C(O)N(H)—); W and X are each independently C(R 3a ) (e.g., CH); Y and Z are N; and y is 1. In some embodiments, the compound of Formula (I), (Ia), (Ib), (Id), (Ie), (If), and (Ig) is Compound 140, or a pharmaceutically acceptable salt, solvate, hydrate, tautomer, or stereoisomer thereof.

[0173] In some embodiments, for Formula (I), A is a monocyclic heterocyclyl (e.g., 1-ethylpiperidinyl); B is a bicyclic heteroaryl (e.g., 8-fluoro-2-methylimidazo[1,2-a]pyridinyl); L 1 is non-existent;L 2 is -C(O)N(R 4 )—(e.g., —C(O)N(H)—); W and X are each independently C(R 3a ) (e.g., CH); Y and Z are N; and y is 1. In some embodiments, the compound of Formula (I), (Ia), (Ib), (Id), (Ie), (If), and (Ig) is Compound 141, or a pharmaceutically acceptable salt, solvate, hydrate, tautomer, or stereoisomer thereof.

[0174] In some embodiments, for Formula (I), A is a monocyclic heterocyclyl (e.g., 2,6-dimethylpiperidinyl); B is a bicyclic heteroaryl (e.g., 8-fluoro-2-methylimidazo[1,2-a]pyridinyl); L 1 is non-existent;L 2 is -C(O)N(R 4 )—(e.g., —C(O)N(H)—); W and X are each independently C(R 3a ) (e.g., CH); Y and Z are N; and y is 1. In some embodiments, the compound of Formula (I), (Ia), (Ib), (Id), (Ie), (If), and (Ig) is Compound 142, or a pharmaceutically acceptable salt, solvate, hydrate, tautomer, or stereoisomer thereof.

[0175] In some embodiments, for Formula (I), A is a monocyclic heterocyclyl (e.g., 2,2,6,6-tetramethylpiperidinyl); B is a bicyclic heteroaryl (e.g., 8-fluoro-2-methylimidazo[1,2-a]pyridinyl); L 1 is non-existent;L 2 is -C(O)N(R 4 )—(e.g., —C(O)N(H)—); W and X are each independently C(R 3a ) (e.g., CH); Y and Z are N; and y is 1. In some embodiments, the compound of Formula (I), (Ia), (Ib), (Id), (Ie), (If), and (Ig) is compound 143, or a pharmaceutically acceptable salt, solvate, hydrate, tautomer, or stereoisomer thereof.

[0176] In some embodiments, for Formula (I), A is a monocyclic heterocyclyl (e.g., piperazinyl); B is a bicyclic heteroaryl (e.g., 8-fluoro-2-methylimidazo[1,2-a]pyridinyl); L 1 and L 2 is non-existent; W is C(R 3a ) (e.g., CH); Y is C(R 3a ) (e.g., CH); X is C(R 3a ) (e.g., C(OH)); Z is N; and y is 1. In some embodiments, the compound of Formula (I), (Ia), and (Ib) is compound 144, or a pharmaceutically acceptable salt, solvate, hydrate, tautomer, or stereoisomer thereof.

[0177] In some embodiments, for Formula (I), A is a bicyclic heterocyclyl (e.g., (1R,5S)-3,8-diazabicyclo[3.2.1]octanyl); B is a bicyclic heteroaryl (e.g., 8-fluoro-2-methylimidazo[1,2-a]pyridinyl); and L 1 is non-existent;L 2 is -C(O)N(R 4)—(e.g., —C(O)N(H)—); W and X are each independently C(R 3a ) (e.g., CH); Y and Z are N; and y is 1. In some embodiments, the compound of Formula (I), (Ia), (Ib), (Id), (Ie), (If), and (Ig) is Compound 145, or a pharmaceutically acceptable salt, solvate, hydrate, tautomer, or stereoisomer thereof.

[0178] In some embodiments, for Formula (I), A is a bicyclic heterocyclyl (e.g., 5-methylamino-2-azabicyclo[2.1.1]hexanyl); B is a bicyclic heteroaryl (e.g., 8-fluoro-2-methylimidazo[1,2-a]pyridinyl); and L 1 is non-existent;L 2 is -C(O)N(R 4 )—(e.g., —C(O)N(H)—); W and X are each independently C(R 3a ) (e.g., CH); Y and Z are N; and y is 1. In some embodiments, the compound of Formula (I), (Ia), (Ib), (Id), (Ie), (If), and (Ig) is compound 148, 160, or a pharmaceutically acceptable salt, solvate, hydrate, tautomer, or stereoisomer thereof.

[0179] In some embodiments, for Formula (I), A is a monocyclic heterocyclyl (e.g., (1R,4S)-5-dimethylamino-2-azabicyclo[2.1.1]hexanyl); B is a bicyclic heteroaryl (e.g., 8-fluoro-2-methylimidazo[1,2-a]pyridinyl); and L 1 is non-existent;L 2 is -C(O)N(R 4 )—(e.g., —C(O)N(H)—); W and X are each independently C(R 3a) (e.g., CH); Y and Z are N; and y is 1. In some embodiments, the compound of Formula (I), (Ia), (Ib), (Id), (Ie), (If), and (Ig) is Compound 155, or a pharmaceutically acceptable salt, solvate, hydrate, tautomer, or stereoisomer thereof.

[0180] In some embodiments, for Formula (I), A is a bicyclic heterocyclyl (e.g., (1R,5S)-8-azabicyclo[3.2.1]octanyl); B is a bicyclic heteroaryl (e.g., 8-fluoro-2-methylimidazo[1,2-a]pyridinyl); and L 1 is -N(R 4 )-(e.g., -N(CH3)-); L 2 is -C(O)N(R 4 )—(e.g., —C(O)N(H)—); W and X are each independently C(R 3a ) (e.g., CH); Y and Z are N; and y is 1. In some embodiments, the compound of Formula (I), (Ia), (Ib), (Id), (Ie), (If), and (Ig) is Compound 156, or a pharmaceutically acceptable salt, solvate, hydrate, tautomer, or stereoisomer thereof.

[0181] In some embodiments, for Formula (I), A is a monocyclic heterocyclyl (e.g., 2-methylpiperazinyl); B is a bicyclic heteroaryl (e.g., 8-fluoro-2-methylimidazo[1,2-a]pyridinyl); L 1 is non-existent;L 2 is -C(O)N(R 4 )—(e.g., —C(O)N(H)—); X and Y are each independently C(R 3a ) (e.g., CH); W and Z are N; and y is 1. In some embodiments, the compound of Formula (I), (Ia), and (Ie) is compound 157, or a pharmaceutically acceptable salt, solvate, hydrate, tautomer, or stereoisomer thereof.

[0182] In some embodiments, for Formula (I), A is a monocyclic heterocyclyl (e.g., 4-(N,N-dimethyl)aminopiperidinyl); B is a bicyclic heteroaryl (e.g., 8-fluoro-2-methylimidazo[1,2-a]pyridinyl); L 1 is non-existent;L 2 is -C(O)N(R 4 )—(e.g., —C(O)N(H)—); X and Y are each independently C(R 3a ) (e.g., CH); W and Z are N; and y is 1. In some embodiments, the compound of Formula (I), (Ia), and (Ie) is compound 158, or a pharmaceutically acceptable salt, solvate, hydrate, tautomer, or stereoisomer thereof.

[0183] In some embodiments, for Formula (I), A is a monocyclic heterocyclyl (e.g., piperazinyl); B is a bicyclic heteroaryl (e.g., 8-fluoro-2-methylimidazo[1,2-a]pyridinyl); L 1 is non-existent;L 2 is -C(O)N(R 4 )—(e.g., —C(O)N(H)—); W is C(R 3a ) (e.g., CH); X is C(R 3a ) (e.g., C(CH3)); Y and Z are N; and y is 1. In some embodiments, the compound of Formula (I), (Ia), (Ib), (Ie), (If), and (Ig) is compound 159, or a pharmaceutically acceptable salt, solvate, hydrate, tautomer, or stereoisomer thereof.

[0184] In some embodiments, for Formula (I), A is a monocyclic heterocyclyl (e.g., (2S,6R)-2,6-dimethyl-4-piperazinyl); B is a bicyclic heteroaryl (e.g., 8-fluoro-2-methylimidazo[1,2-a]pyridinyl); L 1 is non-existent;L 2 is -C(O)N(R 4)—(e.g., —C(O)N(H)—); W and X are each independently C(R 3a ) (e.g., CH); Y and Z are N; and y is 1. In some embodiments, the compound of Formula (I), (Ia), (Ib), (Id), (Ie), (If), and (Ig) is Compound 161, or a pharmaceutically acceptable salt, solvate, hydrate, tautomer, or stereoisomer thereof.

[0185] In some embodiments, for Formula (I), A is a monocyclic heterocyclyl (e.g., piperazinyl); B is a bicyclic heteroaryl (e.g., 8-fluoro-2-methylimidazo[1,2-a]pyridinyl); L 1 is non-existent;L 2 is -C(O)N(R 4 )—(e.g., —C(O)N(H)—); W is C(R 3a ) (e.g., CH); X is C(R 3a ) (e.g., CH); Y is C(R 3a ) (e.g., C(CH3)); Z is N; and y is 1. In some embodiments, the compound of Formula (I), (Ia), (Ib), (Ie), (If), and (Ig) is Compound 162, or a pharmaceutically acceptable salt, solvate, hydrate, tautomer, or stereoisomer thereof.

[0186] In some embodiments, for Formula (I), A is a monocyclic heterocyclyl (e.g., piperazinyl); B is a bicyclic heteroaryl (e.g., 1-(2-methylimidazo[1,2-a]yridin-8-yl)ethane-1-I); L 1 is non-existent;L 2 is -C(O)N(R 4 )—(e.g., —C(O)N(H)—); W and X are each independently C(R 3a) (e.g., CH); Y and Z are N; and y is 1. In some embodiments, the compound of Formula (I), (Ia), (Ib), (Id), (Ie), and (If) is compound 163, or a pharmaceutically acceptable salt, solvate, hydrate, tautomer, or stereoisomer thereof.

[0187] In some embodiments, for Formula (I), A is a monocyclic heterocyclyl (e.g., piperazinyl); B is a bicyclic heteroaryl (e.g., 2,8-dimethylimidazo[1,2-a]pyrazinyl); L 1 is non-existent;L 2 is -C(O)N(R 4 )—(e.g., —C(O)N(H)—); W and X are each independently C(R 3a ) (e.g., CH); Y and Z are N; and y is 1. In some embodiments, the compound of Formula (I), (Ia), (Ib), (Id), (Ie), (If), and (Ig) is Compound 164, or a pharmaceutically acceptable salt, solvate, hydrate, tautomer, or stereoisomer thereof.

[0188] In some embodiments, for Formula (I), A is a monocyclic heterocyclyl (e.g., piperazinyl); B is a bicyclic heteroaryl (e.g., 8-fluoro-2-methylimidazo[1,2-a]pyridinyl); L 1 is non-existent;L 2 is -C(O)N(R 4 )—(e.g., —C(O)N(H)—); W is C(R 3a ) (e.g., CH); X is C(R 3a ) (e.g., CH); Y is C(R 3a ) (e.g., CH); Z is N; and y is 1. In some embodiments, the compound of Formula (I), (Ia), (Ib), (Ie), (If), and (Ig) is Compound 165, or a pharmaceutically acceptable salt, solvate, hydrate, tautomer, or stereoisomer thereof.

[0189] In some embodiments, for Formula (I), A is a monocyclic heterocyclyl (e.g., piperazinyl); B is a bicyclic heteroaryl (e.g., 8-fluoro-2-methylimidazo[1,2-a]pyridinyl); L 1 is non-existent;L 2 is -C(O)N(R 4 )—(e.g., —C(O)N(H)—); W is N; X is N; Y is C(R 3a ) (e.g., CH); Z is C(R 3a ) (e.g., CH); and y is 1. In some embodiments, the compound of Formula (I), (Ia), and (Ie) is compound 166, or a pharmaceutically acceptable salt, solvate, hydrate, tautomer, or stereoisomer thereof.

[0190] In some embodiments, for Formula (I), A is a monocyclic heterocyclyl (e.g., piperazinyl); B is a bicyclic heteroaryl (e.g., 8-cyano-2-methylimidazo[1,2-a]pyridinyl); L 1 is non-existent;L 2 is -C(O)N(R 4 )—(e.g., —C(O)N(H)—); W and X are each independently C(R 3a ) (e.g., CH); Y and Z are N; and y is 1. In some embodiments, the compound of Formula (I), (Ia), (Ib), (Id), (Ie), (If), and (Ig) is Compound 167, or a pharmaceutically acceptable salt, solvate, hydrate, tautomer, or stereoisomer thereof.

[0191] In some embodiments, for Formula (I), A is a monocyclic heterocyclyl (e.g., piperazinyl); B is a bicyclic heteroaryl (e.g., 8-ethyl-2-methylimidazo[1,2-b]pyridazinyl); L 1 is non-existent;L 2 is -C(O)N(R 4 )—(e.g., —C(O)N(H)—); W and X are each independently C(R 3a) (e.g., CH); Y and Z are N; and y is 1. In some embodiments, the compound of Formula (I), (Ia), (Ib), (Id), (Ie), and (If) is compound 168, or a pharmaceutically acceptable salt, solvate, hydrate, tautomer, or stereoisomer thereof.

[0192] In some embodiments, for Formula (I), A is a monocyclic heterocyclyl (e.g., piperazinyl); B is a bicyclic heteroaryl (e.g., 8-fluoro-2-methylimidazo[1,2-a]pyridinyl); L 1 is non-existent;L 2 is -C(O)N(R 4 )—(e.g., —C(O)N(H)—); W is C(R 3a ) (e.g., CH); X is C(R 3a ) (e.g., CH); Y is C(R 3a ) (e.g., C(OCH3)); Z is N; and y is 1. In some embodiments, the compound of Formula (I), (Ia), (Ib), (Ie), (If), and (Ig) is compound 169, or a pharmaceutically acceptable salt, solvate, hydrate, tautomer, or stereoisomer thereof.

[0193] In some embodiments, for Formula (I), A is a bicyclic heterocycle (e.g., 2,8-dimethylimidazo[1,2-b]pyridazinyl); B is a monocyclic heterocyclyl (e.g., piperazinyl); L 1 is non-existent;L 2 is -C(O)N(R 4 )—(e.g., —C(O)N(H)—); W and X are each independently C(R 3a ) (e.g., CH); Y and Z are N; and y is 1. In some embodiments, the compound of Formula (I), (Ia), (Ib), (Id), (Ie), (If), and (Ig) is Compound 170, or a pharmaceutically acceptable salt, solvate, hydrate, tautomer, or stereoisomer thereof.

[0194] In some embodiments, for Formula (I), A is a bicyclic heterocyclyl (e.g., 1,7-diazaspiro[3.5]nonanyl); B is a bicyclic heteroaryl (e.g., 8-fluoro-2-methylimidazo[1,2-a]pyridinyl); L 1 is non-existent;L 2 is -C(O)N(R 4 )—(e.g., —C(O)N(H)—); W is C(R 3a ) (e.g., CH); X is C(R 3a ) (e.g., CH); Y is N; Z is N; and y is 1. In some embodiments, the compound of Formula (I), (Ia), (Ib), (Ie), (If), and (Ig) is Compound 171, or a pharmaceutically acceptable salt, solvate, hydrate, tautomer, or stereoisomer thereof.

[0195] In some embodiments, for Formula (I), A is a monocyclic heterocyclyl (e.g., (2S,6R)-2,6-dimethyl-4-piperazinyl); B is a bicyclic heteroaryl (e.g., 2,8-dimethylimidazo[1,2-a]pyrazinyl); L 1 is non-existent;L 2 is -C(O)N(R 4 )—(e.g., —C(O)N(H)—); W and X are each independently C(R 3a ) (e.g., CH); Y and Z are N; and y is 1. In some embodiments, the compound of Formula (I), (Ia), (Ib), (Id), (Ie), (If), and (Ig) is Compound 172, or a pharmaceutically acceptable salt, solvate, hydrate, tautomer, or stereoisomer thereof.

[0196] In some embodiments, for Formula (I), A is a monocyclic heterocyclyl (e.g., piperazinyl); B is a bicyclic heteroaryl (e.g., 8-fluoro-2-methylimidazo[1,2-a]pyridinyl); L 1 is non-existent;L 2 is -C(O)N(R 4)—(e.g., —C(O)N(H)—); W is C(R 3a ) (e.g., CH); X is C(R 3a ) (e.g., CH); Y is C(R 3a ) (e.g., C(OCH2CH2OCH3)); Z is N; and y is 1. In some embodiments, the compound of Formula (I), (Ia), (Ib), (Ie), (If), and (Ig) is compound 173, or a pharmaceutically acceptable salt, solvate, hydrate, tautomer, or stereoisomer thereof.

[0197] In some embodiments, for Formula (I), A is a monocyclic heterocyclyl (e.g., piperazinyl); B is a bicyclic heteroaryl (e.g., 8-methoxy-2-methylimidazo[1,2-a]pyridinyl); L 1 is non-existent;L 2 is -C(O)N(R 4 )—(e.g., —C(O)N(H)—); W and X are each independently C(R 3a ) (e.g., CH); Y and Z are N; and y is 1. In some embodiments, the compound of Formula (I), (Ia), (Ib), (Id), (Ie), (If), and (Ig) is Compound 176, or a pharmaceutically acceptable salt, solvate, hydrate, tautomer, or stereoisomer thereof.

[0198] In some embodiments, for Formula (I), A is a monocyclic heterocyclyl (e.g., piperazinyl); B is a bicyclic heteroaryl (e.g., 2-methylimidazo[1,2-a]pyrazine-8(7H)-I); L 1 is non-existent;L 2 is -C(O)N(R 4 )—(e.g., —C(O)N(H)—); W and X are each independently C(R 3a) (e.g., CH); Y and Z are N; and y is 1. In some embodiments, the compound of Formula (I), (Ia), (Ib), (Id), (Ie), (If), and (Ig) is Compound 177, or a pharmaceutically acceptable salt, solvate, hydrate, tautomer, or stereoisomer thereof.

[0199] In some embodiments, for Formula (I), A is a monocyclic heterocyclyl (e.g., piperazinyl); B is a bicyclic heteroaryl (e.g., 2,7-dimethyl-2H-pyrazolo[3,4-c]pyridinyl); L 1 is non-existent;L 2 is -C(O)N(R 4 )—(e.g., —C(O)N(H)—); W and X are each independently C(R 3a ) (e.g., CH); Y and Z are N; and y is 1. In some embodiments, the compound of Formula (I), (Ia), (Ib), (Id), (Ie), and (If) is compound 178, or a pharmaceutically acceptable salt, solvate, hydrate, tautomer, or stereoisomer thereof.

[0200] In some embodiments, for Formula (I), A is a monocyclic heterocyclyl (e.g., piperazinyl); B is a bicyclic heteroaryl (e.g., 8-methoxy-2-methylimidazo[1,2-a]pyrazinyl); L 1 is non-existent;L 2 is -C(O)N(R 4 )—(e.g., —C(O)N(H)—); W and X are each independently C(R 3a ) (e.g., CH); Y and Z are N; and y is 1. In some embodiments, the compound of Formula (I), (Ia), (Ib), (Id), (Ie), (If), and (Ig) is Compound 179, or a pharmaceutically acceptable salt, solvate, hydrate, tautomer, or stereoisomer thereof.

[0201] In some embodiments, for Formula (I), A is a monocyclic heterocyclyl (e.g., piperazinyl); B is a bicyclic heteroaryl (e.g., 8-fluoro-2-methylimidazo[1,2-a]pyridinyl); L 1 is non-existent;L 2 is -C(O)N(R 4 )—(e.g., —C(O)N(H)—); W is C(R 3a ) (e.g., CH); X is N; Y is C(R 3a ) (e.g., C(OCH2CH2OCH3)); Z is N; and y is 1. In some embodiments, the compound of Formula (I), (Ia), (Ib), (Ie), (If), and (Ig) is compound 180, or a pharmaceutically acceptable salt, solvate, hydrate, tautomer, or stereoisomer thereof.

[0202] In some embodiments, for Formula (I), A is a monocyclic heterocyclyl (e.g., piperazinyl); B is a bicyclic heteroaryl (e.g., 6-hydroxy-2,7-dimethyl-2H-indazolyl); L 1 is non-existent;L 2 is -C(O)N(R 4 )—(e.g., —C(O)N(H)—); W and X are each independently C(R 3a ) (e.g., CH); Y and Z are N; and y is 1. In some embodiments, the compound of Formula (I), (Ia), (Ib), (Id), (Ie), and (If) is compound 181, or a pharmaceutically acceptable salt, solvate, hydrate, tautomer, or stereoisomer thereof.

[0203] In some embodiments, for Formula (I), A is a monocyclic heterocyclyl (e.g., piperazinyl); B is a bicyclic heteroaryl (e.g., 1-(2-methylimidazo[1,2-a]yridin-8-yl)ethan-1-olyl); L 1 is non-existent;L 2 is -C(O)N(R 4)—(e.g., —C(O)N(H)—); W and X are each independently C(R 3a ) (e.g., CH); Y and Z are N; and y is 1. In some embodiments, the compound of Formula (I), (Ia), (Ib), (Id), (Ie), (If), and (Ig) is Compound 182, or a pharmaceutically acceptable salt, solvate, hydrate, tautomer, or stereoisomer thereof.

[0204] In some embodiments, for Formula (I), A is a monocyclic heterocyclyl (e.g., piperazinyl); B is a bicyclic heteroaryl (e.g., 8-fluoro-2-methylimidazo[1,2-a]pyridinyl); L 1 is non-existent;L 2 is -C(O)N(R 4 )—(e.g., —C(O)N(H)—); W is C(R 3a ) (e.g., CH); X is C(R 3a ) (e.g., C(OCH3)); Y and Z are N; and y is 1. In some embodiments, the compound of Formula (I), (Ia), (Ib), (Id), (Ie), (If), and (Ig) is compound 183, or a pharmaceutically acceptable salt, solvate, hydrate, tautomer, or stereoisomer thereof.

[0205] In some embodiments, for Formula (I), A is a monocyclic heterocyclyl (e.g., piperazinyl); B is a bicyclic heteroaryl (e.g., 8-fluoro-2-methylimidazo[1,2-a]pyridinyl); L 1 is non-existent;L 2 is -C(O)N(R 4 )—(e.g., —C(O)N(H)—); W is C(R 3a ) (e.g., CH); X is C(R 3a) (e.g., C(CHCH)); Y and Z are N; and y is 1. In some embodiments, the compound of Formula (I), (Ia), (Ib), (Id), (Ie), (If), and (Ig) is Compound 185, or a pharmaceutically acceptable salt, solvate, hydrate, tautomer, or stereoisomer thereof.

[0206] In some embodiments, for Formula (I), A is a monocyclic heterocyclyl (e.g., 2,6-dimethylpiperazinyl); B is a bicyclic heteroaryl (e.g., 8-fluoro-2-methylimidazo[1,2-a]pyridinyl); L 1 is non-existent;L 2 is -C(O)N(R 4 )—(e.g., —C(O)N(H)—); W is N; X is C(R 3a ) (e.g., CH); Y is C(R 3a ) (e.g., CH); Z is N; and y is 1. In some embodiments, the compound of Formula (I), (Ia), and (Ie) is compound 186, or a pharmaceutically acceptable salt, solvate, hydrate, tautomer, or stereoisomer thereof.

[0207] In some embodiments, for Formula (I), A is a monocyclic heterocyclyl (e.g., 2-methylpiperazinyl); B is a bicyclic heteroaryl (e.g., 8-fluoro-2-methylimidazo[1,2-a]pyridinyl); L 1 is non-existent;L 2 is -C(O)N(R 4 )—(e.g., —C(O)N(H)—); W is N; X is C(R 3a ) (e.g., CH); Y is C(R 3a ) (e.g., CH); Z is N; and y is 1. In some embodiments, the compound of Formula (I), (Ia), and (Ie) is compound 187, 188, or a pharmaceutically acceptable salt, solvate, hydrate, tautomer, or stereoisomer thereof.

[0208] In some embodiments, for Formula (I), A is a monocyclic heterocyclyl (e.g., 1,7-diazaspiro[3.5]nonanyl); B is a bicyclic heteroaryl (e.g., 8-fluoro-2-methylimidazo[1,2-a]pyridinyl); L 1 is non-existent;L 2 is -C(O)N(R 4 )—(e.g., —C(O)N(H)—); W is N; X is C(R 3a ) (e.g., CH); Y is C(R 3a ) (e.g., CH); Z is N; and y is 1. In some embodiments, the compound of Formula (I), (Ia), and (Ie) is compound 189, or a pharmaceutically acceptable salt, solvate, hydrate, tautomer, or stereoisomer thereof.

[0209] In some embodiments, for Formula (I), A is a monocyclic heterocyclyl (e.g., 3-(N-methylamino)pyrrolidinyl); B is a bicyclic heteroaryl (e.g., 8-fluoro-2-methylimidazo[1,2-a]pyridinyl); L 1 is non-existent;L 2 is -C(O)N(R 4 )—(e.g., —C(O)N(H)—); W is N; X is C(R 3a ) (e.g., CH); Y is C(R 3a ) (e.g., CH); Z is N; and y is 1. In some embodiments, the compound of Formula (I), (Ia), and (Ie) is compound 190, 193, 194, or a pharmaceutically acceptable salt, solvate, hydrate, tautomer, or stereoisomer thereof.

[0210] In some embodiments, for Formula (I), A is a monocyclic heterocyclyl (e.g., 4-(N-ethylamino)piperidinyl); B is a bicyclic heteroaryl (e.g., 8-fluoro-2-methylimidazo[1,2-a]pyridinyl); L 1 is non-existent;L 2 is -C(O)N(R 4)—(e.g., —C(O)N(H)—); W is N; X is C(R 3a ) (e.g., CH); Y is C(R 3a ) (e.g., CH); Z is N; and y is 1. In some embodiments, the compound of Formula (I), (Ia), and (Ie) is compound 191, or a pharmaceutically acceptable salt, solvate, hydrate, tautomer, or stereoisomer thereof.

[0211] In some embodiments, for Formula (I), A is a monocyclic heterocyclyl (e.g., 4-(N-methyl)aminomethanyl)piperidinyl); B is a bicyclic heteroaryl (e.g., 8-fluoro-2-methylimidazo[1,2-a]pyridinyl); L 1 is non-existent;L 2 is -C(O)N(R 4 )—(e.g., —C(O)N(H)—); W is N; X is C(R 3a ) (e.g., CH); Y is C(R 3a ) (e.g., CH); Z is N; and y is 1. In some embodiments, the compound of Formula (I), (Ia), and (Ie) is compound 192, or a pharmaceutically acceptable salt, solvate, hydrate, tautomer, or stereoisomer thereof.

[0212] As generally described herein, for formula (II), each of M and P independently represents C(R 2 ) or N. In some embodiments, each of M and P independently refers to C(R 2 ) or N. In some embodiments, M and P are each independently C(R 2 ), e.g., CH. In some embodiments, one of M and P is C(R 2 ) and the other of M and P is N. In some embodiments, M is C(R 2 ). In some embodiments, M is N. In some embodiments, P is C(R 2 In some embodiments, P is N. In some embodiments, M is C(R 2) (e.g., CH) and P is N. In some embodiments, M is N and P is C(R 2 ) (e.g., CH).

[0213] In some embodiments, [ka] wherein R 2 is as defined above. In some embodiments, R 2 is hydrogen.

[0214] As generally described herein, for formula (II), W, X, Y, and Z are each independently C(R 3 ) or N. In some embodiments, at least one of W, X, Y, and Z is N. In some embodiments, at least two of W, X, Y, and Z are N. In some embodiments, at least two of X, Y, and Z are N. In some embodiments, at least one of Y and Z is N. In some embodiments, X is N. In some embodiments, X is C(R 3 ) (e.g., CH). In some embodiments, Y is N. In some embodiments, Y is C(R 3 ) (e.g., CH). In some embodiments, Z is N. In some embodiments, Z is C(R 3 ) (e.g., CH).

[0215] In some embodiments, W is C(R 3 In some embodiments, W is C(R 3 ) (e.g., CH), where two of X, Y, and Z are N and the remaining X, Y, and Z are C(R 3 ) (e.g., CH). In some embodiments, W is C(R 3 ) (e.g., CH), and one of X, Y, and Z is C(R 3) (e.g., CH), and the remaining X, Y, and Z are each independently N. In some embodiments, X and Y are each independently N, and W and Z are each independently C(R 3 ) (e.g., CH). In some embodiments, W and X are each independently C(R 3 ) (e.g., CH), and Y and Z are each independently N.

[0216] In some embodiments, L 1 and L 2 Each of the is independently absent, -N(R 3 )-(e.g., -N(CH3)-, C6-C 12 -arylene, -N(R 4 )C(O)-, or -C(O)N(R 4 )-, and the arylene is one or more R 1 In some embodiments, L 1 and L 2 One of them is independently absent, -N(R 4 )C(O)-, or -C(O)N(R 4 In some embodiments, L 1 and L 2 Each of is independently absent. 1 is -C(O)N(R 4 In some embodiments, L 2 is absent. In some embodiments, L 1 is -C(O)NH-, and L 2 is non-existent.

[0217] In some embodiments, [ka] is selected from.

[0218] In some embodiments, R 1 is hydrogen. In some embodiments, R 1 is C1-C6-alkyl. In some embodiments, R 1is C2-C6-alkenyl. In some embodiments, R 1 is C2-C6-alkynyl. In some embodiments, R 1 is C1-C6-heteroalkyl. In some embodiments, R 1 is C1-C6-haloalkyl (e.g., -CF3). In some embodiments, R 1 is C-alkyl (e.g., methyl). In some embodiments, R 1 is unsubstituted C1-C6-alkyl, unsubstituted C2-C6-alkenyl, unsubstituted C2-C6-alkynyl, unsubstituted C1-C6-heteroalkyl, or unsubstituted C1-C6-haloalkyl. 1 is one or more R 6 In some embodiments, R 1 is one or more R 6 In some embodiments, R is a C-C-alkenyl substituted with 1 is one or more R 6 In some embodiments, R is a C2-C6 alkynyl substituted with 1 is one or more R 6 In some embodiments, R is a C1-C6-heteroalkyl substituted with 1 is one or more R 6 In some embodiments, R 1 is methyl.

[0219] In some embodiments, R 1 is cycloalkyl (e.g., 3- to 7-membered cycloalkyl). In some embodiments, R 1 is heterocyclyl (e.g., 3- to 7-membered heterocyclyl). 1 is aryl. In some embodiments, R 1 is C1-C6 alkylene-aryl (e.g., benzyl). 1 is C1-C6 alkenylene-aryl. In some embodiments, R1 is C1-C6 alkylene-heteroaryl. In some embodiments, R 1 is heteroaryl. In some embodiments, R 1 is an unsubstituted cycloalkyl, an unsubstituted heterocyclyl, an unsubstituted aryl, an unsubstituted C1-C6 alkylene-aryl, an unsubstituted C1-C6 alkenylene-aryl, an unsubstituted C1-C6 alkylene-heteroaryl, or an unsubstituted heteroaryl. 1 is one or more R 6 In some embodiments, R is a cycloalkyl substituted with 1 is one or more R 6 In some embodiments, R is a heterocyclyl substituted with 1 is one or more R 6 In some embodiments, R 1 is one or more R 6 In some embodiments, R 1 is one or more R 6 In some embodiments, R is a C1-C6 alkenylene-aryl substituted with 1 is one or more R 6 In some embodiments, R is a C1-C6 alkylene-heteroaryl substituted with 1 is one or more R 6 and heteroaryl substituted with

[0220] In some embodiments, R 1 -OR A In some embodiments, R 1 is -NR B R C (e.g., NH or NMe). In some embodiments, R 1 is -NR B C(O)R D In some embodiments, R 1 is -C(O)NR B R CIn some embodiments, R 1 is -C(O)R D In some embodiments, R 1 is -C(O)OR D In some embodiments, R 1 -SR E In some embodiments, R 1 is -S(O) x R D In some embodiments, R 1 is halo, e.g., fluoro, chloro, bromo, or iodo. In some embodiments, R 1 is cyano. In some embodiments, R 1 is nitro (—NO). In some embodiments, R 1 is oxo.

[0221] In some embodiments, two R 1 The groups, taken together with the atoms to which they are attached, form a 3- to 7-membered cycloalkyl. In some embodiments, two R 1 The groups, taken together with the atoms to which they are attached, form a 3- to 7-membered heterocyclyl. 1 The groups, together with the atoms to which they are attached, form a 5- or 6-membered aryl. In some embodiments, two R 1 The groups, taken together with the atom to which they are attached, form a 5- or 6-membered heteroaryl. A cycloalkyl, heterocyclyl, aryl, or heteroaryl can be joined by one or more R 6 may be substituted with.

[0222] In some embodiments, R 2 is hydrogen. In some embodiments, R 2 is C1-C6-alkyl. In some embodiments, R 2 is C2-C6-alkenyl. In some embodiments, R 2 is C2-C6-alkynyl. In some embodiments, R 2 is C-alkyl (e.g., methyl). In some embodiments, R2 is methyl. In some embodiments, R 2 -OR A In some embodiments, R 2 is halo (e.g., fluoro, chloro, bromo, or iodo). In some embodiments, R 2 is fluoro. In some embodiments, R 2 is cyano.

[0223] In some embodiments, R A is hydrogen. In some embodiments, R A is C1-C6 alkyl (e.g., methyl). In some embodiments, R A is C1-C6 haloalkyl. In some embodiments, R A is aryl. In some embodiments, R A is heteroaryl. In some embodiments, R A is C1-C6 alkylene-aryl (e.g., benzyl). A is C1-C6 alkylene-heteroaryl. In some embodiments, R A is C(O)R D In some embodiments, R A is -S(O) x R D is.

[0224] In some embodiments, R B , R C , or both, each independently, hydrogen, C1-C6-alkyl, C1-C6-heteroalkyl, cycloalkyl, heterocyclyl, or -OR A In some embodiments, R B and R C Each of R is independently hydrogen. B and R C Each of is independently C1-C6 alkyl. B and R C is hydrogen and R B and R Cand the other is C1-C6 alkyl. In some embodiments, R B and R C together with the atoms to which they are attached, form one or more R 8 (e.g., 1, 2, or 3 R 8 ) to form a 3- to 7-membered heterocyclyl ring optionally substituted with

[0225] In some embodiments, R D is hydrogen, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 heteroalkyl, C1-C6 haloalkyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, C1-C6 alkylene-aryl (e.g., benzyl), or C1-C6 alkylene-heteroaryl. D and R E Each of R is independently hydrogen. D is C1-C6 alkyl. In some embodiments, R D is hydrogen. In some embodiments, R D is heterocyclyl. In some embodiments, R E is heterocyclyl. In some embodiments, R D is aryl. In some embodiments, R E is aryl. In some embodiments, R D is heteroaryl. In some embodiments, R E is heteroaryl. In some embodiments, R D is C1-C6 alkylene-aryl (e.g., benzyl). E is C1-C6 alkylene-aryl (e.g., benzyl). D is C1-C6 alkylene-heteroaryl. In some embodiments, R E is a C1-C6 alkylene-heteroaryl.

[0226] In some embodiments, x is 0. In some embodiments, x is 1. In some embodiments, x is 2.

[0227] In some embodiments, the compound of formula (II) is a compound of formula (II-a) [ka] or a pharmaceutically acceptable salt, solvate, hydrate, tautomer, or stereoisomer thereof, wherein A and B are each independently cycloalkyl, heterocyclyl, aryl, or heteroaryl, each of which is selected from the group consisting of one or more R 1 W, X, Y, and Z are each independently selected from the group consisting of C(R 3 ) or N, wherein at least one of W, X, Y, and Z is N; L 1 and L 2 each independently represents absent, C1-C6-alkylene, C1-C6-heteroalkylene, —O—, —C(O)—, —N(R 4 )-, -N(R 4 )C(O)-, or -C(O)N(R 4 )-, where each alkylene and heteroalkylene is selected from one or more R 5 and each R 1 are independently hydrogen, C1-C6-alkyl, C2-C6-alkenyl, C2-C6-alkynyl, C1-C6-heteroalkyl, C1-C6-haloalkyl, cycloalkyl, heterocyclyl, aryl, C1-C6 alkylene-aryl, C2-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 Dwherein each alkyl, alkylene, alkenyl, alkynyl, heteroalkyl, haloalkyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl is selected from one or more R 6 optionally substituted with; or two R 1 The groups, together with the atoms to which they are attached, form a 3- to 7-membered cycloalkyl, heterocyclyl, aryl, or heteroaryl, where each cycloalkyl, heterocyclyl, aryl, and heteroaryl is selected from one or more R 6 is optionally replaced by ; 3 is hydrogen, 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)OR D , or -S(O) x R D , or -C(O)R D and each R 4 are independently hydrogen, C1-C6-alkyl, or C1-C6-haloalkyl; each R 5 are independently hydrogen, C1-C6-alkyl, C1-C6-heteroalkyl, C1-C6-haloalkyl, cycloalkyl, halo, cyano, oxo, -OR A , -NR B R C , -C(O)R D , or -C(O)OR D and each R 6 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)RD , -NO2, -C(O)NR B R C , -C(O)R D , -C(O)OR D , or -S(O) x R D wherein each alkyl, alkenyl, alkynyl, heteroalkyl, haloalkyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl is selected from one or more R 11 and each R A are independently hydrogen, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 heteroalkyl, C1-C6 haloalkyl, aryl, heteroaryl, C1-C6 alkylene-aryl, C1-C6 alkylene-heteroaryl, -C(O)R D , or -S(O) x R D and;R B and R C each independently represents hydrogen, C1-C6 alkyl, 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, -OR A , -C(O)NR B R C , -C(O)R D , -C(O)OR D , or -S(O) x R D or R B and R C together with the atoms to which they are attached, form one or more R 7 forming a 3- to 7-membered heterocyclyl ring optionally substituted with D are independently hydrogen, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 heteroalkyl, C1-C6 haloalkyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, C1-C6 alkylene-aryl, or C1-C6 alkylene-heteroaryl; each R 7is C1-C6-alkyl, halo, cyano, oxo, or -OR A1 and each R 11 are independently C1-C6-alkyl, C1-C6-heteroalkyl, C1-C6-haloalkyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, halo, cyano, oxo, or -OR A and each R A1 is hydrogen or C1-C6-alkyl; x is 0, 1, or 2.

[0228] In some embodiments, the compound of formula (II) is a compound of formula (II-b) [ka] or a pharmaceutically acceptable salt, solvate, hydrate, tautomer, or stereoisomer thereof, wherein A and B are each independently cycloalkyl, heterocyclyl, aryl, or heteroaryl, each of which is selected from the group consisting of one or more R 1 W, X, Y, and Z are each independently selected from the group consisting of C(R 3 ) or N, wherein at least one of W, X, Y, and Z is N; L 1 and L 2 each independently represents absent, C1-C6-alkylene, C1-C6-heteroalkylene, —O—, —C(O)—, —N(R 4 )-, -N(R 4 )C(O)-, or -C(O)N(R 4 )-, where each alkylene and heteroalkylene is selected from one or more R 5 and each R 1 are independently hydrogen, C1-C6-alkyl, C2-C6-alkenyl, C2-C6-alkynyl, C1-C6-heteroalkyl, C1-C6-haloalkyl, cycloalkyl, heterocyclyl, aryl, C1-C6 alkylene-aryl, C2-C6 alkenylene-aryl, C1-C6 alkylene-heteroaryl, 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 wherein each alkyl, alkylene, alkenyl, alkynyl, heteroalkyl, haloalkyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl is selected from one or more R 6 optionally substituted with; or two R 1 The groups, together with the atoms to which they are attached, form a 3- to 7-membered cycloalkyl, heterocyclyl, aryl, or heteroaryl, where each cycloalkyl, heterocyclyl, aryl, and heteroaryl is selected from one or more R 6 is optionally replaced by ; 3 is hydrogen, 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)OR D , or -S(O) x R D , or -C(O)R D and each R 4 are independently hydrogen, C1-C6-alkyl, or C1-C6-haloalkyl; each R 5 are independently hydrogen, C1-C6-alkyl, C1-C6-heteroalkyl, C1-C6-haloalkyl, cycloalkyl, halo, cyano, oxo, -OR A , -NR B R C , -C(O)R D , or -C(O)OR D and each R 6are 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 alkyl, alkenyl, alkynyl, heteroalkyl, haloalkyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl is selected from one or more R 11 and each R A are independently hydrogen, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 heteroalkyl, C1-C6 haloalkyl, aryl, heteroaryl, C1-C6 alkylene-aryl, C1-C6 alkylene-heteroaryl, -C(O)R D , or -S(O) x R D and;R B and R C each independently represents hydrogen, C1-C6 alkyl, 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, -OR A , -C(O)NR B R C , -C(O)R D , -C(O)OR D , or -S(O) x R D or R B and R C together with the atoms to which they are attached, form one or more R 7forming a 3- to 7-membered heterocyclyl ring optionally substituted with D are independently hydrogen, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 heteroalkyl, C1-C6 haloalkyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, C1-C6 alkylene-aryl, or C1-C6 alkylene-heteroaryl; each R 7 is C1-C6-alkyl, halo, cyano, oxo, or -OR A1 and each R 11 are independently C1-C6-alkyl, C1-C6-heteroalkyl, C1-C6-haloalkyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, halo, cyano, oxo, or -OR A and each R A1 is hydrogen or C1-C6-alkyl; x is 0, 1, or 2.

[0229] In some embodiments, the compound of formula (II) is a compound of formula (II-c) [ka] or a pharmaceutically acceptable salt, solvate, hydrate, tautomer, or stereoisomer thereof, wherein A and B are each independently cycloalkyl, heterocyclyl, aryl, or heteroaryl, each of which is selected from the group consisting of one or more R 1 M and P are each independently selected from the group consisting of C(R 2 ) or N, wherein at least one of M and P is independently N; W, X, Y, and Z are each independently C(R 3 ) or N, where at least one of W, X, Y, and Z is N; 1are independently hydrogen, C1-C6-alkyl, C2-C6-alkenyl, C2-C6-alkynyl, C1-C6-heteroalkyl, C1-C6-haloalkyl, cycloalkyl, heterocyclyl, aryl, C1-C6 alkylene-aryl, C2-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 wherein each alkyl, alkylene, alkenyl, alkynyl, heteroalkyl, haloalkyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl is selected from one or more R 6 optionally substituted with; or two R 1 The groups, together with the atoms to which they are attached, form a 3- to 7-membered cycloalkyl, heterocyclyl, aryl, or heteroaryl, where each cycloalkyl, heterocyclyl, aryl, and heteroaryl is selected from one or more R 6 and each R 2 are independently hydrogen, C1-C6-alkyl, C2-C6-alkenyl, C2-C6-alkynyl, C1-C6-heteroalkyl, C1-C6-haloalkyl, halo, cyano, or -OR A and;R 3 is hydrogen, 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)OR D , or -S(O)x R D , or -C(O)R D and each R 6 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 wherein each alkyl, alkenyl, alkynyl, heteroalkyl, haloalkyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl is selected from one or more R 11 and each R A are independently hydrogen, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 heteroalkyl, C1-C6 haloalkyl, aryl, heteroaryl, C1-C6 alkylene-aryl, C1-C6 alkylene-heteroaryl, -C(O)R D , or -S(O) x R D and;R B and R C each independently represents hydrogen, C1-C6 alkyl, 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, -OR A , -C(O)NR B R C , -C(O)R D , -C(O)OR D , or -S(O) x R D or R B and RC together with the atoms to which they are attached, form one or more R 7 forming a 3- to 7-membered heterocyclyl ring optionally substituted with D are independently hydrogen, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 heteroalkyl, C1-C6 haloalkyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, C1-C6 alkylene-aryl, or C1-C6 alkylene-heteroaryl; each R 7 is C1-C6-alkyl, halo, cyano, oxo, or -OR A1 and each R 11 are independently C1-C6-alkyl, C1-C6-heteroalkyl, C1-C6-haloalkyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, halo, cyano, oxo, or -OR A and each R A1 is hydrogen or C1-C6-alkyl; x is 0, 1, or 2.

[0230] In some embodiments, the compound of formula (II) is a compound of formula (II-d) [ka] or a pharmaceutically acceptable salt, solvate, hydrate, tautomer, or stereoisomer thereof, wherein A and B are each independently cycloalkyl, heterocyclyl, aryl, or heteroaryl, each of which is selected from the group consisting of one or more R 1 Optionally replaced by ;L 1 and L 2 each independently represents absent, C1-C6-alkylene, C1-C6-heteroalkylene, —O—, —C(O)—, —N(R 4 )-, -N(R 4 )C(O)-, or -C(O)N(R 4 )-, where each alkylene and heteroalkylene is selected from one or more R 5 and each R 1are independently hydrogen, C1-C6-alkyl, C2-C6-alkenyl, C2-C6-alkynyl, C1-C6-heteroalkyl, C1-C6-haloalkyl, cycloalkyl, heterocyclyl, aryl, C1-C6 alkylene-aryl, C2-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 wherein each alkyl, alkylene, alkenyl, alkynyl, heteroalkyl, haloalkyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl is selected from one or more R 6 optionally substituted with; or two R 1 The groups, together with the atoms to which they are attached, form a 3- to 7-membered cycloalkyl, heterocyclyl, aryl, or heteroaryl, where each cycloalkyl, heterocyclyl, aryl, and heteroaryl is selected from one or more R 6 and each R 4 are independently hydrogen, C1-C6-alkyl, or C1-C6-haloalkyl; each R 5 are independently hydrogen, C1-C6-alkyl, C1-C6-heteroalkyl, C1-C6-haloalkyl, cycloalkyl, halo, cyano, oxo, -OR A , -NR B R C , -C(O)R D , or -C(O)OR D and each R 6 are independently C1-C6-alkyl, C2-C6-alkenyl, C2-C6-alkynyl, C1-C6-heteroalkyl, C1-C6-haloalkyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, halo, cyano, oxo, -ORA , -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 alkyl, alkenyl, alkynyl, heteroalkyl, haloalkyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl is selected from one or more R 11 and each R A are independently hydrogen, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 heteroalkyl, C1-C6 haloalkyl, aryl, heteroaryl, C1-C6 alkylene-aryl, C1-C6 alkylene-heteroaryl, -C(O)R D , or -S(O) x R D and;R B and R C each independently represents hydrogen, C1-C6 alkyl, 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, -OR A , -C(O)NR B R C , -C(O)R D , -C(O)OR D , or -S(O) x R D or R B and R C together with the atoms to which they are attached, form one or more R 7 forming a 3- to 7-membered heterocyclyl ring optionally substituted with Dare 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 7 is C1-C6-alkyl, halo, cyano, oxo, or -OR A1 and each R 11 are independently C1-C6-alkyl, C1-C6-heteroalkyl, C1-C6-haloalkyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, halo, cyano, oxo, or -OR A and each R A1 is hydrogen or C1-C6-alkyl; x is 0, 1, or 2.

[0231] In some embodiments, the compound of formula (II) is a compound of formula (II-e) [ka] or a pharmaceutically acceptable salt, solvate, hydrate, tautomer, or stereoisomer thereof, wherein A and B are each independently cycloalkyl, heterocyclyl, aryl, or heteroaryl, each of which is selected from the group consisting of one or more R 1 Optionally replaced by ;L 1 and L 2 each independently represents absent, C1-C6-alkylene, C1-C6-heteroalkylene, —O—, —C(O)—, —N(R 4 )-, -N(R 4 )C(O)-, or -C(O)N(R 4 )-, where each alkylene and heteroalkylene is selected from one or more R 5 and each R 1are independently hydrogen, C1-C6-alkyl, C2-C6-alkenyl, C2-C6-alkynyl, C1-C6-heteroalkyl, C1-C6-haloalkyl, cycloalkyl, heterocyclyl, aryl, C1-C6 alkylene-aryl, C2-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 wherein each alkyl, alkylene, alkenyl, alkynyl, heteroalkyl, haloalkyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl is selected from one or more R 6 optionally substituted with; or two R 1 The groups, together with the atoms to which they are attached, form a 3- to 7-membered cycloalkyl, heterocyclyl, aryl, or heteroaryl, where each cycloalkyl, heterocyclyl, aryl, and heteroaryl is selected from one or more R 6 and each R 4 are independently hydrogen, C1-C6-alkyl, or C1-C6-haloalkyl; each R 5 are independently hydrogen, C1-C6-alkyl, C1-C6-heteroalkyl, C1-C6-haloalkyl, cycloalkyl, halo, cyano, oxo, -OR A , -NR B R C , -C(O)R D , or -C(O)OR D and each R 6 are independently C1-C6-alkyl, C2-C6-alkenyl, C2-C6-alkynyl, C1-C6-heteroalkyl, C1-C6-haloalkyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, halo, cyano, oxo, -ORA , -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 alkyl, alkenyl, alkynyl, heteroalkyl, haloalkyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl is selected from one or more R 11 and each R A are independently hydrogen, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 heteroalkyl, C1-C6 haloalkyl, aryl, heteroaryl, C1-C6 alkylene-aryl, C1-C6 alkylene-heteroaryl, -C(O)R D , or -S(O) x R D and;R B and R C each independently represents hydrogen, C1-C6 alkyl, 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, -OR A , -C(O)NR B R C , -C(O)R D , -C(O)OR D , or -S(O) x R D or R B and R C together with the atoms to which they are attached, form one or more R 7 forming a 3- to 7-membered heterocyclyl ring optionally substituted with Dare 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 7 is C1-C6-alkyl, halo, cyano, oxo, or -OR A1 and each R 11 are independently C1-C6-alkyl, C1-C6-heteroalkyl, C1-C6-haloalkyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, halo, cyano, oxo, or -OR A and each R A1 is hydrogen or C1-C6-alkyl; x is 0, 1, or 2.

[0232] In some embodiments, the compound of Formula (II) is selected from the compounds in Table 2 or a pharmaceutically acceptable salt thereof.

[0233] [Table 2]

[0234] In another aspect, the present disclosure provides a compound of formula (III) [ka] or a pharmaceutically acceptable salt, solvate, hydrate, tautomer, or stereoisomer thereof, wherein A and B are each independently cycloalkyl, heterocyclyl, aryl, or heteroaryl, each of which is selected from the group consisting of one or more R 1 Optionally replaced by ;L 1 and L 2 are each independently absent, C1-C6-alkylene, C1-C6-heteroalkylene, -O-, -C(O)-, -N(R 3 )-, -N(R 3 )C(O)-, or -C(O)N(R 3)-, where each alkylene and heteroalkylene is selected from one or more R 4 and each R 1 are independently hydrogen, C1-C6-alkyl, C2-C6-alkenyl, C2-C6-alkynyl, C1-C6-heteroalkyl, C1-C6-haloalkyl, cycloalkyl, heterocyclyl, aryl, C1-C6 alkylene-aryl, C1-C6 alkenylene-aryl, C1-C6 alkylene-heteroaryl, heteroaryl, halo, cyano, oxo, -OR A , -NR B R C , -NR B C(O)R D , -NO2, -C(O)NR B R C , -C(O)R D , -C(O)OR D , -SR E , or -S(O) x R D wherein each alkyl, alkylene, alkenyl, alkynyl, heteroalkyl, haloalkyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl is selected from one or more R 5 optionally substituted with; or two R 1 The groups, together with the atoms to which they are attached, form a 3- to 7-membered cycloalkyl, heterocyclyl, aryl, or heteroaryl, where each cycloalkyl, heterocyclyl, aryl, and heteroaryl is selected from one or more R 5 and each R 2 are independently C1-C6-alkyl, C2-C6-alkenyl, C2-C6-alkynyl, C1-C6-heteroalkyl, C1-C6-haloalkyl, halo, cyano, or -OR A and each R 3 are independently hydrogen, C1-C6-alkyl, or C1-C6-haloalkyl; each R 4 are independently C1-C6-alkyl, C1-C6-heteroalkyl, C1-C6-haloalkyl, cycloalkyl, halo, cyano, oxo, -OR A , -NRB R C , -C(O)R D , or -C(O)OR D and each R 5 are independently C1-C6-alkyl, C2-C6-alkenyl, C2-C6-alkynyl, C1-C6-heteroalkyl, C1-C6-haloalkyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, halo, oxo, 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 , -SR E , or -S(O) x R D wherein each alkyl, alkenyl, alkynyl, heteroalkyl, haloalkyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl is selected from one or more R 11 and each R 7 is independently C1-C6-alkyl or halo; each R 11 are independently C1-C6-alkyl, C1-C6-heteroalkyl, C1-C6-haloalkyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, halo, cyano, oxo, or -OR A and each R A are independently hydrogen, C1-C6 alkyl, C1-C6 haloalkyl, aryl, heteroaryl, C1-C6 alkylene-aryl, C1-C6 alkylene-heteroaryl, -C(O)R D , or -S(O) x R D and;R B and R C each independently represents hydrogen, C1-C6 alkyl, C1-C6 heteroalkyl, cycloalkyl, heterocyclyl, -OR A or R B and R Ctogether with the atoms to which they are attached, form one or more R 7 forming a 3- to 7-membered heterocyclyl ring optionally substituted with D and R E are independently hydrogen, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 heteroalkyl, C1-C6 haloalkyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, C1-C6 alkylene-aryl, or C1-C6 alkylene-heteroaryl; m is 0, 1, or 2; and x is 0, 1, or 2.

[0235] As generally described herein, for formula (III), L 1 and L 2 may independently be absent or selected from C-C-alkylene, C-C-heteroalkylene, —O—, —C(O)—, —N(R 3 )-, -N(R 3 )C(O)- or -C(O)N(R 3 )-group, where each alkylene and heteroalkylene is selected from one or more R 4 is optionally replaced by

[0236] In some embodiments, L 1 is absent. In some embodiments, L 1 is C1-C6-alkylene (e.g., C1-alkylene, C2-alkylene, C3-alkylene, C4-alkylene, C5-alkylene, or C6-alkylene). 1 is an unsubstituted C1-C6 alkylene. 1 is a substituted C1-C6-alkylene, for example, one or more R 4 In some embodiments, L is a C1-C6 alkylene substituted with 1 is one R 4 In some embodiments, L is a C1-alkylene substituted with 1 is —CH— (or methylene). In some embodiments, L1 is —C(O)— (or carbonyl).

[0237] In some embodiments, L 1 is absent, C1-C6-alkylene, C1-C6-heteroalkylene, -N(R 3 )C(O)-, or -C(O)N(R 3 )-, where each alkylene and heteroalkylene is selected from one or more R 4 is optionally replaced by

[0238] In some embodiments, L 2 is absent. In some embodiments, L 2 is C1-C6-alkylene (e.g., C1-alkylene, C2-alkylene, C3-alkylene, C4-alkylene, C5-alkylene, or C6-alkylene). 2 is an unsubstituted C1-C6 alkylene. 2 is a substituted C1-C6-alkylene, for example, one or more R 4 In some embodiments, L is a C1-C6 alkylene substituted with 2 is one R 4 In some embodiments, L is a C1-alkylene substituted with 2 is —CH— (or methylene). In some embodiments, L 2 is —C(O)— (or carbonyl).

[0239] In some embodiments, L 2 is absent, C1-C6-alkylene, C1-C6-heteroalkylene, -N(R 3 )C(O)-, or -C(O)N(R 3 )-, where each alkylene and heteroalkylene is selected from one or more R 4 is optionally replaced by

[0240] In some embodiments, L 1is C1-C6-heteroalkylene (e.g., C1-heteroalkylene, C2-heteroalkylene, C3-heteroalkylene, C4-heteroalkylene, C5-heteroalkylene, or C6-heteroalkylene). 1 is unsubstituted C1-C6 heteroalkylene. 1 is one or more R 4 In some embodiments, the heteroalkylene includes one or more heteroatoms. In some embodiments, the heteroalkylene includes one or more of oxygen, sulfur, nitrogen, boron, silicon, or phosphorus. In some embodiments, L 1 is non-existent, -N(R 3 )C(O)-, or -C(O)N(R 3 In some embodiments, L 1 is -N(R 3 )C(O)—. In some embodiments, L 1 is -C(O)N(R 3 )-.

[0241] In some embodiments, L 2 is C1-C6-heteroalkylene (e.g., C1-heteroalkylene, C2-heteroalkylene, C3-heteroalkylene, C4-heteroalkylene, C5-heteroalkylene, or C6-heteroalkylene). 2 is unsubstituted C1-C6 heteroalkylene. 2 is one or more R 4 In some embodiments, the heteroalkylene includes one or more heteroatoms. In some embodiments, the heteroalkylene includes one or more of oxygen, sulfur, nitrogen, boron, silicon, or phosphorus. In some embodiments, L 2 is non-existent, -N(R 3 )C(O)-, or -C(O)N(R 3 In some embodiments, L 2 is -N(R3 )C(O)—. In some embodiments, L 2 is -C(O)N(R 3 )-.

[0242] In some embodiments, L 1 and L 2 and each of L is not both absent. 1 is non-existent, and L 2 is -N(R 3 )C(O)- or -C(O)N(R 3 In some embodiments, L 2 is non-existent, and L 1 is -N(R 3 )C(O)- or -C(O)N(R 3 )-.

[0243] In some embodiments, L 1 is oxygen. In some embodiments, L 1 is nitrogen and R 3 In some embodiments, L 1 is one R 3 In some embodiments, L 1 is -N(R 3 In some embodiments, L 1 is —N(CH)—. In some embodiments, L 1 In some embodiments, L 1 is -O-.

[0244] In some embodiments, L 2 is oxygen. In some embodiments, L 2 is nitrogen and R 3 In some embodiments, L 2 is one R 3 In some embodiments, L 2 is -N(R 3 In some embodiments, L 2 is —N(CH)—. In some embodiments, L2 In some embodiments, L 2 is -O-.

[0245] In some embodiments, [ka] wherein each X is independently halo (e.g., fluoro, chloro, bromo, or iodo). [ka] In some embodiments, [ka] In some embodiments, [ka] is.

[0246] In some embodiments, R 1 is hydrogen. In some embodiments, R 1 is C1-C6-alkyl. In some embodiments, R 1 is C2-C6-alkenyl. In some embodiments, R 1 is C2-C6-alkynyl. In some embodiments, R 1 is C1-C6-heteroalkyl. In some embodiments, R 1 is C1-C6-haloalkyl (e.g., -CF3). In some embodiments, R 1 is C-alkyl (e.g., methyl). In some embodiments, R 1 is unsubstituted C1-C6-alkyl, unsubstituted C2-C6-alkenyl, unsubstituted C2-C6-alkynyl, unsubstituted C1-C6-heteroalkyl, or unsubstituted C1-C6-haloalkyl. 1 is one or more R 5 In some embodiments, R1 is one or more R 5 In some embodiments, R is a C-C-alkenyl substituted with 1 is one or more R 5 In some embodiments, R is a C2-C6 alkynyl substituted with 1 is one or more R 5 In some embodiments, R is a C1-C6-heteroalkyl substituted with 1 is one or more R 5 In some embodiments, R 1 is methyl.

[0247] In some embodiments, R 1 is cycloalkyl (e.g., 3- to 7-membered cycloalkyl). In some embodiments, R 1 is heterocyclyl (e.g., 3- to 7-membered heterocyclyl). 1 is aryl. In some embodiments, R 1 is C1-C6 alkylene-aryl (e.g., benzyl). 1 is C1-C6 alkenylene-aryl. In some embodiments, R 1 is C1-C6 alkylene-heteroaryl. In some embodiments, R 1 is heteroaryl. In some embodiments, R 1 is an unsubstituted cycloalkyl, an unsubstituted heterocyclyl, an unsubstituted aryl, an unsubstituted C1-C6 alkylene-aryl, an unsubstituted C1-C6 alkenylene-aryl, an unsubstituted C1-C6 alkylene-heteroaryl, or an unsubstituted heteroaryl. 1 is one or more R 5 In some embodiments, R is a cycloalkyl substituted with 1 is one or more R 5 In some embodiments, R is a heterocyclyl substituted with 1 is one or more R 5In some embodiments, R 1 is one or more R 5 In some embodiments, R 1 is one or more R 5 In some embodiments, R is a C1-C6 alkenylene-aryl substituted with 1 is one or more R 5 In some embodiments, R is a C1-C6 alkylene-heteroaryl substituted with 1 is one or more R 5 and heteroaryl substituted with

[0248] In some embodiments, R 1 -OR A In some embodiments, R 1 is -NR B R C (e.g., NH or NMe). In some embodiments, R 1 is -NR B C(O)R D In some embodiments, R 1 is -C(O)NR B R C In some embodiments, R 1 is -C(O)R D In some embodiments, R 1 is -C(O)OR D In some embodiments, R 1 -SR E In some embodiments, R 1 is -S(O) x R D In some embodiments, R 1 is halo, e.g., fluoro, chloro, bromo, or iodo. In some embodiments, R 1 is cyano. In some embodiments, R 1 is nitro (—NO). In some embodiments, R 1 is oxo.

[0249] In some embodiments, two R 1 The groups, taken together with the atoms to which they are attached, form a 3- to 7-membered cycloalkyl. In some embodiments, two R 1 The groups, taken together with the atoms to which they are attached, form a 3- to 7-membered heterocyclyl. 1 The groups, together with the atoms to which they are attached, form a 5- or 6-membered aryl. In some embodiments, two R 1 The groups, taken together with the atom to which they are attached, form a 5- or 6-membered heteroaryl. A cycloalkyl, heterocyclyl, aryl, or heteroaryl can be joined by one or more R 5 may be substituted with.

[0250] In some embodiments, R 2 is C1-C6-alkyl. In some embodiments, R 2 is C2-C6-alkenyl. In some embodiments, R 2 is C2-C6-alkynyl. In some embodiments, R 2 is halo (e.g., fluoro, chloro, bromo, or iodo). In some embodiments, R 2 is fluoro. In some embodiments, R 2 is cyano. In some embodiments, R 2 -OR A (e.g., —OH).

[0251] In some embodiments, R 3 is hydrogen. In some embodiments, R 3 is C1-C6 alkyl. In some embodiments, R 3 is C1-C6 haloalkyl. In some embodiments, R 3 is methyl.

[0252] In some embodiments, R 4 is C1-C6 alkyl. In some embodiments, R 4is C1-C6-heteroalkyl. In some embodiments, R 4 is C1-C6 haloalkyl (e.g., —CF3 or —CHF2). In some embodiments, R 4 is cycloalkyl. In some embodiments, R 4 is halo (e.g., fluoro, chloro, bromo, or iodo). In some embodiments, R 4 is cyano. In some embodiments, R 4 is oxo. In some embodiments, R 4 -OR A In some embodiments, R 4 is -NR B R C In some embodiments, R 4 is -C(O)R D or -C(O)OR D is.

[0253] In some embodiments, R 5 is C1-C6-alkyl. In some embodiments, R 5 is C2-C6-alkenyl. In some embodiments, R 5 is C2-C6-alkynyl. In some embodiments, R 5 is C1-C6-heteroalkyl. In some embodiments, R 5 is C1-C6-haloalkyl. In some embodiments, R 5 is unsubstituted C1-C6-alkyl, unsubstituted C2-C6-alkenyl, unsubstituted C2-C6-alkynyl, unsubstituted C1-C6-haloalkyl, or unsubstituted C1-C6-heteroalkyl. 5 is one or more R 11 In some embodiments, R 5 is one or more R 11 In some embodiments, R is a C-C-alkenyl substituted with 5 is one or more R 11 In some embodiments, R is a C2-C6 alkynyl substituted with5 is one or more R 11 In some embodiments, R 5 is one or more R 11 is a C1-C6-heteroalkyl substituted with

[0254] In some embodiments, R 5 is cycloalkyl. In some embodiments, R 5 is heterocyclyl. In some embodiments, R 5 is aryl. In some embodiments, R 5 is heteroaryl. In some embodiments, R 5 is an unsubstituted cycloalkyl, an unsubstituted heterocyclyl, an unsubstituted aryl, or an unsubstituted heteroaryl. 5 is one or more R 11 In some embodiments, R is a cycloalkyl substituted with 5 is one or more R 11 In some embodiments, R is a heterocyclyl substituted with 5 is one or more R 11 In some embodiments, R 5 is one or more R 11 and heteroaryl substituted with

[0255] In some embodiments, R 5 is halo (e.g., fluoro, chloro, bromo, or iodo). In some embodiments, R 5 is cyano. In some embodiments, R 5 is oxo. In some embodiments, R 5 -OR A In some embodiments, R 5 is -NR B R C In some embodiments, R 5 is -NR B C(O)R DIn some embodiments, R 5 is —NO. In some embodiments, R 5 is -C(O)NR B R C In some embodiments, R 5 is -C(O)R D In some embodiments, R 5 is -C(O)OR D In some embodiments, R 5 -SR E In some embodiments, R 5 is -S(O) x R D is.

[0256] In some embodiments, R 7 is C1-C6-alkyl. In some embodiments, R 7 is halo (e.g., fluoro, chloro, bromo, or iodo).

[0257] In some embodiments, R 11 is C1-C6-alkyl. In some embodiments, R 11 is C1-C6-heteroalkyl. In some embodiments, R 11 is C1-C6 haloalkyl (e.g., —CF3 or —CHF2). In some embodiments, R 11 is cycloalkyl. In some embodiments, R 11 is heterocyclyl. In some embodiments, R 11 is aryl. In some embodiments, R 11 is heteroaryl. In some embodiments, R 11 is halo. In some embodiments, R 11 is cyano. In some embodiments, R 11 is oxo. In some embodiments, R 11 -OR A is.

[0258] In some embodiments, R A is hydrogen. In some embodiments, RA is C1-C6 alkyl (e.g., methyl). In some embodiments, R A is C1-C6 haloalkyl. In some embodiments, R A is aryl. In some embodiments, R A is heteroaryl. In some embodiments, R A is C1-C6 alkylene-aryl (e.g., benzyl). A is C1-C6 alkylene-heteroaryl. In some embodiments, R A is C(O)R D In some embodiments, R A is -S(O) x R D is.

[0259] In some embodiments, R B , R C , or both are independently hydrogen, C1-C6-alkyl, C1-C6-heteroalkyl, cycloalkyl, heterocyclyl, or -OR A In some embodiments, R B and R C Each of R is independently hydrogen. B and R C Each of is independently C1-C6 alkyl. B and R C is hydrogen and R B and R C and the other is C1-C6 alkyl. In some embodiments, R B and R C together with the atoms to which they are attached, form one or more R 7 (e.g., 1, 2, or 3 R 7 ) to form a 3- to 7-membered heterocyclyl ring optionally substituted with

[0260] In some embodiments, R D , R E, or both are independently hydrogen, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 heteroalkyl, C1-C6 haloalkyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, C1-C6 alkylene-aryl (e.g., benzyl), or C1-C6 alkylene-heteroaryl. D and R E Each of R is independently hydrogen. D and R E Each of is independently C1-C6 alkyl. D is hydrogen. In some embodiments, R E is hydrogen. In some embodiments, R D is C1-C6 alkyl (e.g., methyl). In some embodiments, R E is C1-C6 alkyl (e.g., methyl). In some embodiments, R D is C1-C6 heteroalkyl. In some embodiments, R E is C1-C6 heteroalkyl. In some embodiments, R D is C1-C6 haloalkyl. In some embodiments, R E is C1-C6 haloalkyl. In some embodiments, R D is cycloalkyl. In some embodiments, R E is cycloalkyl. In some embodiments, R D is heterocyclyl. In some embodiments, R E is heterocyclyl. In some embodiments, R D is aryl. In some embodiments, R E is aryl. In some embodiments, R D is heteroaryl. In some embodiments, R E is heteroaryl. In some embodiments, R D is C1-C6 alkylene-aryl (e.g., benzyl). Eis C1-C6 alkylene-aryl (e.g., benzyl). D is C1-C6 alkylene-heteroaryl. In some embodiments, R E is a C1-C6 alkylene-heteroaryl.

[0261] In some embodiments, m is an integer between 0 and 2 (e.g., 0, 1, or 2). In some embodiments, m is 0 or 1. In some embodiments, m is 0. In some embodiments, m is 1. In some embodiments, m is 1 and R 2 In some embodiments, m is 1 and R 2 is fluoro. In some embodiments, m is 2. In some embodiments, x is an integer between 0 and 2 (e.g., 0, 1, or 2). In some embodiments, x is 0. In some embodiments, x is 1. In some embodiments, x is 2.

[0262] In some embodiments, the compound of formula (III) is a compound of formula (III-a) [ka] or a pharmaceutically acceptable salt, solvate, hydrate, tautomer, or stereoisomer thereof, wherein A and B are each independently cycloalkyl, heterocyclyl, aryl, or heteroaryl, each of which is selected from the group consisting of one or more R 1 Optionally replaced by ;L 1 is absent, C1-C6-alkylene, C1-C6-heteroalkylene, -O-, -C(O)-, -N(R 3 )-, -N(R 3 )C(O)-, or -C(O)N(R 3 )-, where alkylene and heteroalkylene are each independently one or more R 4 and each R 1are independently hydrogen, C1-C6-alkyl, C2-C6-alkenyl, C2-C6-alkynyl, C1-C6-heteroalkyl, C1-C6-haloalkyl, cycloalkyl, heterocyclyl, aryl, C1-C6 alkylene-aryl, C1-C6 alkenylene-aryl, C1-C6 alkylene-heteroaryl, heteroaryl, halo, cyano, oxo, -OR A , -NR B R C , -NR B C(O)R D , -NO2, -C(O)NR B R C , -C(O)R D , -C(O)OR D , -SR E , or -S(O) x R D wherein each alkyl, alkylene, alkenyl, alkynyl, heteroalkyl, haloalkyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl is selected from one or more R 5 optionally substituted with; or two R 1 The groups, together with the atoms to which they are attached, form a 3- to 7-membered cycloalkyl, heterocyclyl, aryl, or heteroaryl, where each cycloalkyl, heterocyclyl, aryl, and heteroaryl is selected from one or more R 5 and each R 2 are independently C1-C6-alkyl, C2-C6-alkenyl, C2-C6-alkynyl, C1-C6-heteroalkyl, C1-C6-haloalkyl, halo, cyano, or -OR A and each R 3 are independently hydrogen, C1-C6-alkyl, or C1-C6-haloalkyl; each R 4 are independently C1-C6-alkyl, C1-C6-heteroalkyl, C1-C6-haloalkyl, cycloalkyl, halo, cyano, oxo, -OR A , -NR B R C , -C(O)R D , or -C(O)OR D and each R5 are independently C1-C6-alkyl, C2-C6-alkenyl, C2-C6-alkynyl, C1-C6-heteroalkyl, C1-C6-haloalkyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, halo, oxo, 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 , -SR E , or -S(O) x R D wherein each alkyl, alkenyl, alkynyl, heteroalkyl, haloalkyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl is selected from one or more R 11 and each R 7 is independently C1-C6-alkyl or halo; each R 11 are independently C1-C6-alkyl, C1-C6-heteroalkyl, C1-C6-haloalkyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, halo, cyano, oxo, or -OR A and each R A are independently hydrogen, C1-C6 alkyl, C1-C6 haloalkyl, aryl, heteroaryl, C1-C6 alkylene-aryl, C1-C6 alkylene-heteroaryl, -C(O)R D , or -S(O) x R D and;R B and R C each independently represents hydrogen, C1-C6 alkyl, C1-C6 heteroalkyl, cycloalkyl, heterocyclyl, -OR A or R B and R C together with the atoms to which they are attached, form one or more R 7 forming a 3- to 7-membered heterocyclyl ring optionally substituted with D and RE are independently hydrogen, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 heteroalkyl, C1-C6 haloalkyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, C1-C6 alkylene-aryl, or C1-C6 alkylene-heteroaryl; m is 0, 1, or 2; and x is 0, 1, or 2.

[0263] In some embodiments, the compound of formula (III) is a compound of formula (III-b) [ka] or a pharmaceutically acceptable salt, solvate, hydrate, tautomer, or stereoisomer thereof, wherein A and B are each independently cycloalkyl, heterocyclyl, aryl, or heteroaryl, each of which is selected from the group consisting of one or more R 1 Optionally replaced by ;L 2 is absent, C1-C6-alkylene, C1-C6-heteroalkylene, -O-, -C(O)-, -N(R 3 )-, -N(R 3 )C(O)-, or -C(O)N(R 3 )-, where alkylene and heteroalkylene are each independently selected from one or more R 4 and each R 1 are independently hydrogen, C1-C6-alkyl, C2-C6-alkenyl, C2-C6-alkynyl, C1-C6-heteroalkyl, C1-C6-haloalkyl, cycloalkyl, heterocyclyl, aryl, C1-C6 alkylene-aryl, C1-C6 alkenylene-aryl, C1-C6 alkylene-heteroaryl, heteroaryl, halo, cyano, oxo, -OR A , -NR B R C , -NR B C(O)R D , -NO2, -C(O)NR B R C , -C(O)R D , -C(O)OR D , -SRE , or -S(O) x R D wherein each alkyl, alkylene, alkenyl, alkynyl, heteroalkyl, haloalkyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl is selected from one or more R 5 optionally substituted with; or two R 1 The groups, together with the atoms to which they are attached, form a 3- to 7-membered cycloalkyl, heterocyclyl, aryl, or heteroaryl, where each cycloalkyl, heterocyclyl, aryl, and heteroaryl is selected from one or more R 5 and each R 2 are independently C1-C6-alkyl, C2-C6-alkenyl, C2-C6-alkynyl, C1-C6-heteroalkyl, C1-C6-haloalkyl, halo, cyano, or -OR A and each R 3 are independently hydrogen, C1-C6-alkyl, or C1-C6-haloalkyl; each R 4 are independently C1-C6-alkyl, C1-C6-heteroalkyl, C1-C6-haloalkyl, cycloalkyl, halo, cyano, oxo, -OR A , -NR B R C , -C(O)R D , or -C(O)OR D and each R 5 are independently C1-C6-alkyl, C2-C6-alkenyl, C2-C6-alkynyl, C1-C6-heteroalkyl, C1-C6-haloalkyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, halo, oxo, 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 , -SR E , or -S(O) x R Dwherein each alkyl, alkenyl, alkynyl, heteroalkyl, haloalkyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl is selected from one or more R 11 and each R 7 is independently C1-C6-alkyl or halo; each R 11 are independently C1-C6-alkyl, C1-C6-heteroalkyl, C1-C6-haloalkyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, halo, cyano, oxo, or -OR A and each R A are independently hydrogen, C1-C6 alkyl, C1-C6 haloalkyl, aryl, heteroaryl, C1-C6 alkylene-aryl, C1-C6 alkylene-heteroaryl, -C(O)R D , or -S(O) x R D and;R B and R C each independently represents hydrogen, C1-C6 alkyl, C1-C6 heteroalkyl, cycloalkyl, heterocyclyl, -OR A or R B and R C together with the atoms to which they are attached, form one or more R 7 forming a 3- to 7-membered heterocyclyl ring optionally substituted with D and R E are independently hydrogen, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 heteroalkyl, C1-C6 haloalkyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, C1-C6 alkylene-aryl, or C1-C6 alkylene-heteroaryl; m is 0, 1, or 2; and x is 0, 1, or 2.

[0264] In some embodiments, the compound of formula (III) is a compound of formula (III-c) [ka] or a pharmaceutically acceptable salt, solvate, hydrate, tautomer, or stereoisomer thereof, wherein A and B are each independently cycloalkyl, heterocyclyl, aryl, or heteroaryl, each of which is selected from the group consisting of one or more R 1 Optionally replaced by ;L 1 and L 2 are each independently absent, C1-C6-alkylene, C1-C6-heteroalkylene, -O-, -C(O)-, -N(R 3 )-, -N(R 3 )C(O)-, or -C(O)N(R 3 )-, where each alkylene and heteroalkylene is selected from one or more R 4 and each R 1 are independently hydrogen, C1-C6-alkyl, C2-C6-alkenyl, C2-C6-alkynyl, C1-C6-heteroalkyl, C1-C6-haloalkyl, cycloalkyl, heterocyclyl, aryl, C1-C6 alkylene-aryl, C1-C6 alkenylene-aryl, C1-C6 alkylene-heteroaryl, heteroaryl, halo, cyano, oxo, -OR A , -NR B R C , -NR B C(O)R D , -NO2, -C(O)NR B R C , -C(O)R D , -C(O)OR D , -SR E , or -S(O) x R D wherein each alkyl, alkylene, alkenyl, alkynyl, heteroalkyl, haloalkyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl is selected from one or more R 5 optionally substituted with; or two R 1The groups, together with the atoms to which they are attached, form a 3- to 7-membered cycloalkyl, heterocyclyl, aryl, or heteroaryl, where each cycloalkyl, heterocyclyl, aryl, and heteroaryl is selected from one or more R 5 and each R 3 are independently hydrogen, C1-C6-alkyl, or C1-C6-haloalkyl; each R 4 are independently C1-C6-alkyl, C1-C6-heteroalkyl, C1-C6-haloalkyl, cycloalkyl, halo, cyano, oxo, -OR A , -NR B R C , -C(O)R D , or -C(O)OR D and each R 5 are independently C1-C6-alkyl, C2-C6-alkenyl, C2-C6-alkynyl, C1-C6-heteroalkyl, C1-C6-haloalkyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, halo, oxo, 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 , -SR E , or -S(O) x R D wherein each alkyl, alkenyl, alkynyl, heteroalkyl, haloalkyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl is selected from one or more R 11 and each R 7 is independently C1-C6-alkyl or halo; each R 11 are independently C1-C6-alkyl, C1-C6-heteroalkyl, C1-C6-haloalkyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, halo, cyano, oxo, or -OR A and each R Aare independently hydrogen, C1-C6 alkyl, C1-C6 haloalkyl, aryl, heteroaryl, C1-C6 alkylene-aryl, C1-C6 alkylene-heteroaryl, -C(O)R D , or -S(O) x R D and;R B and R C each independently represents hydrogen, C1-C6 alkyl, C1-C6 heteroalkyl, cycloalkyl, heterocyclyl, -OR A or R B and R C together with the atoms to which they are attached, form one or more R 7 forming a 3- to 7-membered heterocyclyl ring optionally substituted with D and R E are independently hydrogen, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 heteroalkyl, C1-C6 haloalkyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, C1-C6 alkylene-aryl, or C1-C6 alkylene-heteroaryl; and x is 0, 1, or 2.

[0265] In some embodiments, the compound of formula (III) is a compound of formula (III-d) [ka] or a pharmaceutically acceptable salt, solvate, hydrate, tautomer, or stereoisomer thereof, wherein A and B are each independently cycloalkyl, heterocyclyl, aryl, or heteroaryl, each of which is selected from the group consisting of one or more R 1 Optionally replaced by ;L 1 and L 2 are each independently absent, C1-C6-alkylene, C1-C6-heteroalkylene, -O-, -C(O)-, -N(R 3 )-, -N(R 3 )C(O)-, or -C(O)N(R 3)-, where each alkylene and heteroalkylene is selected from one or more R 4 and each R 1 are independently hydrogen, C1-C6-alkyl, C2-C6-alkenyl, C2-C6-alkynyl, C1-C6-heteroalkyl, C1-C6-haloalkyl, cycloalkyl, heterocyclyl, aryl, C1-C6 alkylene-aryl, C1-C6 alkenylene-aryl, C1-C6 alkylene-heteroaryl, heteroaryl, halo, cyano, oxo, -OR A , -NR B R C , -NR B C(O)R D , -NO2, -C(O)NR B R C , -C(O)R D , -C(O)OR D , -SR E , or -S(O) x R D wherein each alkyl, alkylene, alkenyl, alkynyl, heteroalkyl, haloalkyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl is selected from one or more R 5 optionally substituted with; or two R 1 The groups, together with the atoms to which they are attached, form a 3- to 7-membered cycloalkyl, heterocyclyl, aryl, or heteroaryl, where each cycloalkyl, heterocyclyl, aryl, and heteroaryl is selected from one or more R 5 and each R 3 are independently hydrogen, C1-C6-alkyl, or C1-C6-haloalkyl; each R 4 are independently C1-C6-alkyl, C1-C6-heteroalkyl, C1-C6-haloalkyl, cycloalkyl, halo, cyano, oxo, -OR A , -NR B R C , -C(O)R D , or -C(O)OR D and each R 5are independently C1-C6-alkyl, C2-C6-alkenyl, C2-C6-alkynyl, C1-C6-heteroalkyl, C1-C6-haloalkyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, halo, oxo, 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 , -SR E , or -S(O) x R D wherein each alkyl, alkenyl, alkynyl, heteroalkyl, haloalkyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl is selected from one or more R 11 and each R 7 is independently C1-C6-alkyl or halo; each R 11 are independently C1-C6-alkyl, C1-C6-heteroalkyl, C1-C6-haloalkyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, halo, cyano, oxo, or -OR A and each R A are independently hydrogen, C1-C6 alkyl, C1-C6 haloalkyl, aryl, heteroaryl, C1-C6 alkylene-aryl, C1-C6 alkylene-heteroaryl, -C(O)R D , or -S(O) x R D and;R B and R C each independently represents hydrogen, C1-C6 alkyl, C1-C6 heteroalkyl, cycloalkyl, heterocyclyl, -OR A or R B and R C together with the atoms to which they are attached, form one or more R 7 forming a 3- to 7-membered heterocyclyl ring optionally substituted with D and R Eare independently hydrogen, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 heteroalkyl, C1-C6 haloalkyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, C1-C6 alkylene-aryl, or C1-C6 alkylene-heteroaryl; and x is 0, 1, or 2.

[0266] In some embodiments, the compound of formula (III) is a compound of formula (III-e) [ka] or a pharmaceutically acceptable salt, solvate, hydrate, tautomer, or stereoisomer thereof, wherein A and B are each independently cycloalkyl, heterocyclyl, aryl, or heteroaryl, each of which is selected from the group consisting of one or more R 1 Optionally replaced by ;L 1 is absent, C1-C6-alkylene, C1-C6-heteroalkylene, -O-, -C(O)-, -N(R 3 )-, -N(R 3 )C(O)-, or -C(O)N(R 3 )-, where alkylene and heteroalkylene are each independently one or more R 4 and each R 1 are independently hydrogen, C1-C6-alkyl, C2-C6-alkenyl, C2-C6-alkynyl, C1-C6-heteroalkyl, C1-C6-haloalkyl, cycloalkyl, heterocyclyl, aryl, C1-C6 alkylene-aryl, C1-C6 alkenylene-aryl, C1-C6 alkylene-heteroaryl, heteroaryl, halo, cyano, oxo, -OR A , -NR B R C , -NR B C(O)R D , -NO2, -C(O)NR B R C , -C(O)R D , -C(O)OR D , -SR E , or -S(O)x R D wherein each alkyl, alkylene, alkenyl, alkynyl, heteroalkyl, haloalkyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl is selected from one or more R 5 optionally substituted with; or two R 1 The groups, together with the atoms to which they are attached, form a 3- to 7-membered cycloalkyl, heterocyclyl, aryl, or heteroaryl, where each cycloalkyl, heterocyclyl, aryl, and heteroaryl is selected from one or more R 5 and each R 2 are independently C1-C6-alkyl, C2-C6-alkenyl, C2-C6-alkynyl, C1-C6-heteroalkyl, C1-C6-haloalkyl, halo, cyano, or -OR A and;R 3 is hydrogen, C1-C6-alkyl, or C1-C6-haloalkyl; each R 4 are independently C1-C6-alkyl, C1-C6-heteroalkyl, C1-C6-haloalkyl, cycloalkyl, halo, cyano, oxo, -OR A , -NR B R C , -C(O)R D , or -C(O)OR D and each R 5 are independently C1-C6-alkyl, C2-C6-alkenyl, C2-C6-alkynyl, C1-C6-heteroalkyl, C1-C6-haloalkyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, halo, oxo, 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 , -SR E , or -S(O) x R Dwherein each alkyl, alkenyl, alkynyl, heteroalkyl, haloalkyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl is selected from one or more R 11 and each R 7 is independently C1-C6-alkyl or halo; each R 11 are independently C1-C6-alkyl, C1-C6-heteroalkyl, C1-C6-haloalkyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, halo, cyano, oxo, or -OR A and each R A are independently hydrogen, C1-C6 alkyl, C1-C6 haloalkyl, aryl, heteroaryl, C1-C6 alkylene-aryl, C1-C6 alkylene-heteroaryl, -C(O)R D , or -S(O) x R D and;R B and R C each independently represents hydrogen, C1-C6 alkyl, C1-C6 heteroalkyl, cycloalkyl, heterocyclyl, -OR A or R B and R C together with the atoms to which they are attached, form one or more R 7 forming a 3- to 7-membered heterocyclyl ring optionally substituted with D and R E are independently hydrogen, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 heteroalkyl, C1-C6 haloalkyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, C1-C6 alkylene-aryl, or C1-C6 alkylene-heteroaryl; m is 0, 1, or 2; and x is 0, 1, or 2.

[0267] In some embodiments, the compound of formula (III) is a compound of formula (III-f) [ka] or a pharmaceutically acceptable salt, solvate, hydrate, tautomer, or stereoisomer thereof, wherein A and B are each independently cycloalkyl, heterocyclyl, aryl, or heteroaryl, each of which is selected from the group consisting of one or more R 1 Optionally replaced by ;L 1 is absent, C1-C6-alkylene, C1-C6-heteroalkylene, -O-, -C(O)-, -N(R 3 )-, -N(R 3 )C(O)-, or -C(O)N(R 3 )-, where alkylene and heteroalkylene are each independently one or more R 4 and each R 1 are independently hydrogen, C1-C6-alkyl, C2-C6-alkenyl, C2-C6-alkynyl, C1-C6-heteroalkyl, C1-C6-haloalkyl, cycloalkyl, heterocyclyl, aryl, C1-C6 alkylene-aryl, C1-C6 alkenylene-aryl, C1-C6 alkylene-heteroaryl, heteroaryl, halo, cyano, oxo, -OR A , -NR B R C , -NR B C(O)R D , -NO2, -C(O)NR B R C , -C(O)R D , -C(O)OR D , -SR E , or -S(O) x R D wherein each alkyl, alkylene, alkenyl, alkynyl, heteroalkyl, haloalkyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl is selected from one or more R 5 optionally substituted with; or two R 1 The groups, together with the atoms to which they are attached, form a 3- to 7-membered cycloalkyl, heterocyclyl, aryl, or heteroaryl, where each cycloalkyl, heterocyclyl, aryl, and heteroaryl is selected from one or more R 5is optionally replaced by ; 2 is C1-C6-alkyl, C2-C6-alkenyl, C2-C6-alkynyl, C1-C6-heteroalkyl, C1-C6-haloalkyl, halo, cyano, or -OR A and;R 2a is hydrogen, C1-C6-alkyl, C2-C6-alkenyl, C2-C6-alkynyl, C1-C6-heteroalkyl, C1-C6-haloalkyl, halo, cyano, or -OR A and;R 3 is hydrogen, C1-C6-alkyl, or C1-C6-haloalkyl; each R 4 are independently C1-C6-alkyl, C1-C6-heteroalkyl, C1-C6-haloalkyl, cycloalkyl, halo, cyano, oxo, -OR A , -NR B R C , -C(O)R D , or -C(O)OR D and each R 5 are independently C1-C6-alkyl, C2-C6-alkenyl, C2-C6-alkynyl, C1-C6-heteroalkyl, C1-C6-haloalkyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, halo, oxo, 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 , -SR E , or -S(O) x R D wherein each alkyl, alkenyl, alkynyl, heteroalkyl, haloalkyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl is selected from one or more R 11 and each R 7 is independently C1-C6-alkyl or halo; each R 11are independently C1-C6-alkyl, C1-C6-heteroalkyl, C1-C6-haloalkyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, halo, cyano, oxo, or -OR A and each R A are independently hydrogen, C1-C6 alkyl, C1-C6 haloalkyl, aryl, heteroaryl, C1-C6 alkylene-aryl, C1-C6 alkylene-heteroaryl, -C(O)R D , or -S(O) x R D and;R B and R C each independently represents hydrogen, C1-C6 alkyl, C1-C6 heteroalkyl, cycloalkyl, heterocyclyl, -OR A or R B and R C together with the atoms to which they are attached, form one or more R 7 forming a 3- to 7-membered heterocyclyl ring optionally substituted with D and R E are independently hydrogen, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 heteroalkyl, C1-C6 haloalkyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, C1-C6 alkylene-aryl, or C1-C6 alkylene-heteroaryl; and x is 0, 1, or 2.

[0268] In some embodiments, the compound of formula (III) is a compound of formula (III-g) [ka] or a pharmaceutically acceptable salt, solvate, hydrate, tautomer, or stereoisomer thereof, wherein A and B are each independently cycloalkyl, heterocyclyl, aryl, or heteroaryl, each of which is selected from the group consisting of one or more R 1 and each R 1are independently hydrogen, C1-C6-alkyl, C2-C6-alkenyl, C2-C6-alkynyl, C1-C6-heteroalkyl, C1-C6-haloalkyl, cycloalkyl, heterocyclyl, aryl, C1-C6 alkylene-aryl, C1-C6 alkenylene-aryl, C1-C6 alkylene-heteroaryl, heteroaryl, halo, cyano, oxo, -OR A , -NR B R C , -NR B C(O)R D , -NO2, -C(O)NR B R C , -C(O)R D , -C(O)OR D , -SR E , or -S(O) x R D wherein each alkyl, alkylene, alkenyl, alkynyl, heteroalkyl, haloalkyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl is selected from one or more R 5 optionally substituted with; or two R 1 The groups, together with the atoms to which they are attached, form a 3- to 7-membered cycloalkyl, heterocyclyl, aryl, or heteroaryl, where each cycloalkyl, heterocyclyl, aryl, and heteroaryl is selected from one or more R 5 is optionally replaced by ; 2 is C1-C6-alkyl, C2-C6-alkenyl, C2-C6-alkynyl, C1-C6-heteroalkyl, C1-C6-haloalkyl, halo, cyano, or -OR A and;R 3 is hydrogen, C1-C6-alkyl, or C1-C6-haloalkyl; each R 5 are independently C1-C6-alkyl, C2-C6-alkenyl, C2-C6-alkynyl, C1-C6-heteroalkyl, C1-C6-haloalkyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, halo, oxo, cyano, -OR A , -NR B R C , -NR BC(O)R D , -NO2, -C(O)NR B R C , -C(O)R D , -C(O)OR D , -SR E , or -S(O) x R D wherein each alkyl, alkenyl, alkynyl, heteroalkyl, haloalkyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl is selected from one or more R 11 and each R 7 is independently C1-C6-alkyl or halo; each R 11 are independently C1-C6-alkyl, C1-C6-heteroalkyl, C1-C6-haloalkyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, halo, cyano, oxo, or -OR A and each R A are independently hydrogen, C1-C6 alkyl, C1-C6 haloalkyl, aryl, heteroaryl, C1-C6 alkylene-aryl, C1-C6 alkylene-heteroaryl, -C(O)R D , or -S(O) x R D and;R B and R C each independently represents hydrogen, C1-C6 alkyl, C1-C6 heteroalkyl, cycloalkyl, heterocyclyl, -OR A or R B and R C together with the atoms to which they are attached, form one or more R 7 forming a 3- to 7-membered heterocyclyl ring optionally substituted with D and R E are independently hydrogen, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 heteroalkyl, C1-C6 haloalkyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, C1-C6 alkylene-aryl, or C1-C6 alkylene-heteroaryl; and x is 0, 1, or 2.

[0269] In some embodiments, the compound of formula (III) is a compound of formula (III-h) [ka] or a pharmaceutically acceptable salt, solvate, hydrate, tautomer, or stereoisomer thereof, wherein A 1 is a monocyclic or bicyclic heterocyclyl, each of which is substituted by one or more R 1 Optionally replaced by B 1 is a monocyclic or bicyclic heteroaryl, each of which is substituted with one or more R 1 and each R 1 are independently hydrogen, C1-C6-alkyl, C2-C6-alkenyl, C2-C6-alkynyl, C1-C6-heteroalkyl, C1-C6-haloalkyl, cycloalkyl, heterocyclyl, aryl, C1-C6 alkylene-aryl, C1-C6 alkenylene-aryl, C1-C6 alkylene-heteroaryl, heteroaryl, halo, cyano, oxo, -OR A , -NR B R C , -NR B C(O)R D , -NO2, -C(O)NR B R C , -C(O)R D , -C(O)OR D , -SR E , or -S(O) x R D wherein each alkyl, alkylene, alkenyl, alkynyl, heteroalkyl, haloalkyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl is selected from one or more R 5 optionally substituted with; or two R 1 The groups, together with the atoms to which they are attached, form a 3- to 7-membered cycloalkyl, heterocyclyl, aryl, or heteroaryl, where each cycloalkyl, heterocyclyl, aryl, and heteroaryl is selected from one or more R 5 is optionally replaced by ;3 is hydrogen, C1-C6-alkyl, or C1-C6-haloalkyl; each R 5 are independently C1-C6-alkyl, C2-C6-alkenyl, C2-C6-alkynyl, C1-C6-heteroalkyl, C1-C6-haloalkyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, halo, oxo, 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 , -SR E , or -S(O) x R D wherein each alkyl, alkenyl, alkynyl, heteroalkyl, haloalkyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl is selected from one or more R 11 and each R 7 is independently C1-C6-alkyl or halo; each R 11 are independently C1-C6-alkyl, C1-C6-heteroalkyl, C1-C6-haloalkyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, halo, cyano, oxo, or -OR A and each R A are independently hydrogen, C1-C6 alkyl, C1-C6 haloalkyl, aryl, heteroaryl, C1-C6 alkylene-aryl, C1-C6 alkylene-heteroaryl, -C(O)R D , or -S(O) x R D and;R B and R C each independently represents hydrogen, C1-C6 alkyl, C1-C6 heteroalkyl, cycloalkyl, heterocyclyl, -OR A or R B and R C together with the atoms to which they are attached, form one or more R 7forming a 3- to 7-membered heterocyclyl ring optionally substituted with D and R E are independently hydrogen, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 heteroalkyl, C1-C6 haloalkyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, C1-C6 alkylene-aryl, or C1-C6 alkylene-heteroaryl; and x is 0, 1, or 2.

[0270] In some embodiments of Formula (III), A is one or more R 1 In some embodiments, A is a heterocyclyl optionally substituted with. In some embodiments, A is a bicyclic heterocyclyl. In some embodiments, A is a monocyclic nitrogen-containing heterocyclyl. In some embodiments, A is a bicyclic nitrogen-containing heterocyclyl. In some embodiments, A is an optionally substituted piperidinyl. In some embodiments, A is an optionally substituted piperazinyl. In some embodiments, A is [ka] where each R 1 is independently hydrogen or C1-C6-alkyl. In some embodiments, A is [ka] In some embodiments, A is [ka] In some embodiments, A is [ka] In some embodiments, A is [ka] In some embodiments, A is [ka] is.

[0271] In some embodiments, B is one or more R 1 In some embodiments, B is a heteroaryl optionally substituted with . In some embodiments, B is a monocyclic heteroaryl. In some embodiments, B is a bicyclic heteroaryl. In some embodiments, B is a monocyclic nitrogen-containing heteroaryl. In some embodiments, B is a bicyclic nitrogen-containing heteroaryl.

[0272] In some embodiments, B is [ka] wherein each R 1 is as defined above. In some embodiments, B is [ka] In some embodiments, B is [ka] is.

[0273] In some embodiments, the compound of formula (III) is a compound of formula (III-i) [ka] or a pharmaceutically acceptable salt, solvate, hydrate, tautomer, or stereoisomer thereof, wherein B is cycloalkyl, heterocyclyl, aryl, or heteroaryl, each of which is selected from the group consisting of one or more R 1 and each R 1are independently hydrogen, C1-C6-alkyl, C2-C6-alkenyl, C2-C6-alkynyl, C1-C6-heteroalkyl, C1-C6-haloalkyl, cycloalkyl, heterocyclyl, aryl, C1-C6 alkylene-aryl, C1-C6 alkenylene-aryl, C1-C6 alkylene-heteroaryl, heteroaryl, halo, cyano, oxo, -OR A , -NR B R C , -NR B C(O)R D , -NO2, -C(O)NR B R C , -C(O)R D , -C(O)OR D , -SR E , or -S(O) x R D wherein each alkyl, alkylene, alkenyl, alkynyl, heteroalkyl, haloalkyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl is selected from one or more R 5 optionally substituted with; or two R 1 The groups, together with the atoms to which they are attached, form a 3- to 7-membered cycloalkyl, heterocyclyl, aryl, or heteroaryl, where each cycloalkyl, heterocyclyl, aryl, and heteroaryl is selected from one or more R 5 is optionally replaced by ; 2 is C1-C6-alkyl, C2-C6-alkenyl, C2-C6-alkynyl, C1-C6-heteroalkyl, C1-C6-haloalkyl, halo, cyano, or -OR A and;R 3 is hydrogen, C1-C6-alkyl, or C1-C6-haloalkyl; each R 5 are independently C1-C6-alkyl, C2-C6-alkenyl, C2-C6-alkynyl, C1-C6-heteroalkyl, C1-C6-haloalkyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, halo, oxo, cyano, -OR A , -NR B R C , -NR BC(O)R D , -NO2, -C(O)NR B R C , -C(O)R D , -C(O)OR D , -SR E , or -S(O) x R D wherein each alkyl, alkenyl, alkynyl, heteroalkyl, haloalkyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl is selected from one or more R 11 and each R 7 is independently C1-C6-alkyl or halo; each R 11 are independently C1-C6-alkyl, C1-C6-heteroalkyl, C1-C6-haloalkyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, halo, cyano, oxo, or -OR A and each R A are independently hydrogen, C1-C6 alkyl, C1-C6 haloalkyl, aryl, heteroaryl, C1-C6 alkylene-aryl, C1-C6 alkylene-heteroaryl, -C(O)R D , or -S(O) x R D and;R B and R C each independently represents hydrogen, C1-C6 alkyl, C1-C6 heteroalkyl, cycloalkyl, heterocyclyl, -OR A or R B and R C together with the atoms to which they are attached, form one or more R 7 forming a 3- to 7-membered heterocyclyl ring optionally substituted with D and R E are independently hydrogen, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 heteroalkyl, C1-C6 haloalkyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, C1-C6 alkylene-aryl, or C1-C6 alkylene-heteroaryl; m is 0, 1, 2, 3, or 4; and x is 0, 1, or 2.

[0274] In some embodiments, the compound of formula (III) is a compound of formula (III-j) [ka] or a pharmaceutically acceptable salt, solvate, hydrate, tautomer, or stereoisomer thereof, wherein each of J, K, and M is selected from N and C(R'); W is selected from O and C(R'); at least one of J, K, and M is N, and wherein the bond in the ring containing J, K, and M can be a single bond or a double bond, valences permitting; 1 are independently hydrogen, C1-C6-alkyl, C2-C6-alkenyl, C2-C6-alkynyl, C1-C6-heteroalkyl, C1-C6-haloalkyl, cycloalkyl, heterocyclyl, aryl, C1-C6 alkylene-aryl, C1-C6 alkenylene-aryl, C1-C6 alkylene-heteroaryl, heteroaryl, halo, cyano, oxo, -OR A , -NR B R C , -NR B C(O)R D , -NO2, -C(O)NR B R C , -C(O)R D , -C(O)OR D , -SR E , or -S(O) x R D wherein each alkyl, alkylene, alkenyl, alkynyl, heteroalkyl, haloalkyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl is selected from one or more R 5 optionally substituted with; or two R 1 The groups, together with the atoms to which they are attached, form a 3- to 7-membered cycloalkyl, heterocyclyl, aryl, or heteroaryl, where each cycloalkyl, heterocyclyl, aryl, and heteroaryl is selected from one or more R 5 is optionally replaced by ; 2is C1-C6-alkyl, C2-C6-alkenyl, C2-C6-alkynyl, C1-C6-heteroalkyl, C1-C6-haloalkyl, halo, cyano, or -OR A and;R 3 is hydrogen, C1-C6-alkyl, or C1-C6-haloalkyl; each R 5 are independently C1-C6-alkyl, C2-C6-alkenyl, C2-C6-alkynyl, C1-C6-heteroalkyl, C1-C6-haloalkyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, halo, oxo, 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 , -SR E , or -S(O) x R D wherein each alkyl, alkenyl, alkynyl, heteroalkyl, haloalkyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl is selected from one or more R 11 and each R 7 is independently C1-C6-alkyl or halo; each R 11 are independently C1-C6-alkyl, C1-C6-heteroalkyl, C1-C6-haloalkyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, halo, cyano, oxo, or -OR A and each R A are independently hydrogen, C1-C6 alkyl, C1-C6 haloalkyl, aryl, heteroaryl, C1-C6 alkylene-aryl, C1-C6 alkylene-heteroaryl, -C(O)R D , or -S(O) x R D and;R B and R C each independently represents hydrogen, C1-C6 alkyl, C1-C6 heteroalkyl, cycloalkyl, heterocyclyl, -ORA or R B and R C together with the atoms to which they are attached, form one or more R 7 forming a 3- to 7-membered heterocyclyl ring optionally substituted with D and R E are independently hydrogen, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 heteroalkyl, C1-C6 haloalkyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, C1-C6 alkylene-aryl, or C1-C6 alkylene-heteroaryl; R' is hydrogen, halo, or C1-C6-alkyl; p is 0, 1, 2, 3, or 4; and x is 0, 1, or 2.

[0275] In some embodiments, the compound of formula (III) is a compound of formula (III-k) [ka] or a pharmaceutically acceptable salt, solvate, hydrate, tautomer, or stereoisomer thereof, wherein each of J, K, and M is selected from N and C(R'); at least one of J, K, and M is N, and wherein the bond in the ring comprising J, K, and M can be a single bond or a double bond, valence permitting; 1 are independently hydrogen, C1-C6-alkyl, C2-C6-alkenyl, C2-C6-alkynyl, C1-C6-heteroalkyl, C1-C6-haloalkyl, cycloalkyl, heterocyclyl, aryl, C1-C6 alkylene-aryl, C1-C6 alkenylene-aryl, C1-C6 alkylene-heteroaryl, heteroaryl, halo, cyano, oxo, -OR A , -NR B R C , -NR B C(O)R D , -NO2, -C(O)NR B R C , -C(O)R D , -C(O)OR D , -SR E, or -S(O) x R D wherein each alkyl, alkylene, alkenyl, alkynyl, heteroalkyl, haloalkyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl is selected from one or more R 5 optionally substituted with; or two R 1 The groups, together with the atoms to which they are attached, form a 3- to 7-membered cycloalkyl, heterocyclyl, aryl, or heteroaryl, where each cycloalkyl, heterocyclyl, aryl, and heteroaryl is selected from one or more R 5 is optionally replaced by ; 2 is C1-C6-alkyl, C2-C6-alkenyl, C2-C6-alkynyl, C1-C6-heteroalkyl, C1-C6-haloalkyl, halo, cyano, or -OR A and;R 3 is hydrogen, C1-C6-alkyl, or C1-C6-haloalkyl; each R 5 are independently C1-C6-alkyl, C2-C6-alkenyl, C2-C6-alkynyl, C1-C6-heteroalkyl, C1-C6-haloalkyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, halo, oxo, 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 , -SR E , or -S(O) x R D wherein each alkyl, alkenyl, alkynyl, heteroalkyl, haloalkyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl is selected from one or more R 11 and each R 7 is independently C1-C6-alkyl or halo; each R 11are independently C1-C6-alkyl, C1-C6-heteroalkyl, C1-C6-haloalkyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, halo, cyano, oxo, or -OR A and each R A are independently hydrogen, C1-C6 alkyl, C1-C6 haloalkyl, aryl, heteroaryl, C1-C6 alkylene-aryl, C1-C6 alkylene-heteroaryl, -C(O)R D , or -S(O) x R D and;R B and R C each independently represents hydrogen, C1-C6 alkyl, C1-C6 heteroalkyl, cycloalkyl, heterocyclyl, -OR A or R B and R C together with the atoms to which they are attached, form one or more R 7 forming a 3- to 7-membered heterocyclyl ring optionally substituted with D and R E are independently hydrogen, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 heteroalkyl, C1-C6 haloalkyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, C1-C6 alkylene-aryl, or C1-C6 alkylene-heteroaryl; R' is hydrogen, halo, or C1-C6-alkyl; p is 0, 1, 2, 3, or 4; and x is 0, 1, or 2.

[0276] In some embodiments, the compound of Formula (III) is selected from the compounds in Table 3, or a pharmaceutically acceptable salt, solvate, hydrate, tautomer, or stereoisomer thereof.

[0277] [Table 3-1] [Table 3-2] [Table 3-3] [Table 3-4] [Table 3-5] [Table 3-6] [Table 3-7] [Table 3-8] [Table 3-9] [Table 3-10] [Table 3-11] [Table 3-12] [Table 3-13] [Table 3-14] [Table 3-15] [Table 3-16]

[0278] Pharmaceutical Compositions, Kits, and Administration The present invention provides pharmaceutical compositions comprising a compound of Formula (I), (II), or (III), e.g., a compound of Formula (I), (II), or (III) as described herein, or a pharmaceutically acceptable salt, solvate, hydrate, tautomer, or stereoisomer thereof, and optionally a pharmaceutically acceptable excipient. In certain embodiments, the pharmaceutical compositions described herein comprise a compound of Formula (I), (II), or (III), or a pharmaceutically acceptable salt thereof, and optionally a pharmaceutically acceptable excipient. In certain embodiments, the compound of Formula (I), (II), or (III), or a pharmaceutically acceptable salt, solvate, hydrate, tautomer, or stereoisomer thereof, is provided in an effective amount in the pharmaceutical composition. In certain embodiments, the effective amount is a therapeutically effective amount. In certain embodiments, the effective amount is a prophylactically effective amount.

[0279] The pharmaceutical compositions described herein can be prepared by any method known in the art of pharmacology. In general, such methods include the step of bringing into association a compound of Formula (I), (II), or (III) (the "active ingredient") with the carrier and / or one or more other accessory ingredients, and then, if necessary and / or desired, shaping and / or packaging the product into the desired single- or multi-dose unit.

[0280] Pharmaceutical compositions can be prepared, packaged, and / or sold in bulk as a single unit dose and / or as a plurality of single unit doses.As used herein, a "unit dose" is a discrete amount of pharmaceutical composition that contains a predetermined amount of active ingredient.The amount of active ingredient is generally equal to the dosage of the active ingredient that is administered to a subject and / or a convenient fraction of such a dosage, for example, half or one-third of such a dosage.

[0281] The relative amounts of the active ingredient, pharmaceutically acceptable excipient, and / or any additional ingredients in a pharmaceutical composition of the invention will vary depending on the identity, size, and / or condition of the subject being treated, as well as the route by which the composition is administered. By way of example, the composition may contain from 0.1% to 100% (w / w) of the active ingredient.

[0282] The term "pharmaceutically acceptable excipient" refers to a non-toxic carrier, adjuvant, excipient, or vehicle that does not destroy the pharmacological activity of the compound with which it is formulated. Pharmaceutically acceptable excipients useful in preparing the pharmaceutical compositions of the present invention are any of those well known in the art of pharmaceutical formulation, and include inert excipients, dispersing and / or granulating agents, surfactants and / or emulsifying agents, disintegrants, binders, preservatives, buffers, lubricants, and / or oils. Pharmaceutically acceptable excipients useful in the preparation of pharmaceutical compositions of the present invention include, but are not limited to, ion exchangers, alumina, aluminum stearate, lecithin, serum proteins such as human serum albumin, buffer substances such as phosphates, glycine, sorbic acid, potassium sorbate, partial glyceride mixtures of saturated vegetable fatty acids, water, salts or electrolytes such as protamine sulfate, disodium hydrogen phosphate, potassium hydrogen phosphate, sodium chloride, zinc salts, colloidal silica, magnesium trisilicate, polyvinylpyrrolidone, cellulose-based substances, polyethylene glycol, sodium carboxymethylcellulose, polyacrylates, waxes, polyethylene-polyoxypropylene-block polymers, polyethylene glycol and wool fat.

[0283] Compositions of the present invention may be administered orally, parenterally (including subcutaneously, intramuscularly, intravenously, and intradermally), by inhalation spray, topically, rectally, nasally, bucally, vaginally, or via an implanted reservoir. In some embodiments, provided compounds or compositions can be administered intravenously and / or orally.

[0284] The term "parenteral" as used herein includes subcutaneous, intravenous, intramuscular, intraocular, intravitreal, intra-articular, intrasynovial, intrasternal, intrathecal, intrahepatic, intraperitoneal, intralesional, and intracranial injection or infusion techniques. Preferably, the compositions are administered orally, subcutaneously, intraperitoneally, or intravenously. Sterile injectable forms of the compositions of the present invention may be aqueous or oily suspensions. These suspensions may be formulated using suitable dispersing or wetting agents and suspending agents according to techniques known in the art. The sterile injectable preparation may also be a sterile injectable solution or suspension in a non-toxic parenterally acceptable excipient or solvent, such as a solution in 1,3-butanediol. Among the acceptable vehicles and solvents that may be used are water, Ringer's solution, and isotonic saline. Additionally, sterile, fixed oils are conventionally used as solvents or suspending media.

[0285] The pharmaceutically acceptable compositions of the present invention can be orally administered in any orally acceptable dosage form, including, but not limited to, capsules, tablets, aqueous suspensions, or solutions. For tablets for oral use, commonly used carriers include lactose and cornstarch. Lubricants, such as magnesium stearate, are also typically added. For oral administration in capsule form, useful excipients include lactose and dried cornstarch. When aqueous suspensions are required for oral use, the active ingredient is combined with emulsifying and suspending agents. If necessary, certain sweeteners, flavoring agents, or coloring agents may also be added. In some embodiments, the provided oral formulations are formulated for immediate release or sustained / delayed release. In some embodiments, the compositions are suitable for intraoral buccal or sublingual administration, including tablets, lozenges, and pastilles. The provided compounds may also be in microencapsulated form.

[0286] Alternatively, the pharmaceutically acceptable compositions of the present invention can be administered in the form of suppositories for rectal administration.The pharmaceutically acceptable compositions of the present invention can also be administered topically, especially when the target of treatment includes areas or organs that are easily accessible by topical application, including diseases of the eyes, skin, or lower intestinal tract.Suitable topical formulations are easily prepared for each of these areas or organs.

[0287] For ophthalmic use, provided pharmaceutically acceptable compositions may be formulated as a micronized suspension or in an ointment, such as petrolatum.

[0288] In order to prolong the effect of a drug, it is often desirable to slow down the absorption of the drug from subcutaneous or intramuscular injection.This can be achieved by using a liquid suspension of crystalline or amorphous material with poor water solubility.The absorption rate of a drug depends on its rate of dissolution, which can depend on crystal size and crystalline form.Alternatively, delayed absorption of a parenterally administered drug form can be achieved by dissolving or suspending the drug in an oil vehicle.

[0289] Although the description of pharmaceutical compositions provided herein is primarily directed to pharmaceutical compositions suitable for administration to humans, those skilled in the art will understand that such compositions are generally suitable for administration to any type of animal. Modifications of pharmaceutical compositions suitable for administration to humans to make them suitable for administration to a variety of animals are well understood, and an ordinarily skilled veterinary pharmacologist can design and / or perform such modifications with routine experimentation.

[0290] The compound provided herein is typically formulated in dosage unit form, for example, single unit dosage form, for the purpose of easy administration and uniformity of dosage.But it is understood that the total daily use amount of the composition of the present invention is determined by attending physician within the scope of sound medical judgment.The specific therapeutically effective dose level for any specific subject or organism depends on various factors, including the severity of the disease or disorder being treated; the activity of the specific active ingredient used; the specific composition used; the age, weight, general health, sex and diet of subject; the administration time, administration route and excretion rate of the specific active ingredient used; the duration of treatment; the drug used in combination with or simultaneously with the specific active ingredient used; and similar factors well known in the medical field.

[0291] The exact amount of compound required to achieve an effective dose will vary from subject to subject, depending, for example, on the subject's species, age, and general condition, the severity of any side effects or disorders, the identity of the particular compound, the mode of administration, etc. A desirable dose can be delivered three times daily, twice daily, once daily, every other day, every third day, weekly, once every two weeks, once every three weeks, or once every four weeks. In certain embodiments, a desirable dose can be delivered using multiple administrations (e.g., 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, or more administrations).

[0292] In certain embodiments, an effective amount of a compound for single or multiple daily administration to a 70 kg adult human may include from 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 per unit dosage form.

[0293] In certain embodiments, the compounds of Formula (I), (II), or (III) may be at a dosage level sufficient to deliver 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 of body weight of the subject per day (one or more times per day) to obtain the desired therapeutic effect.

[0294] It should be appreciated that the dosage ranges as set forth herein provide guidance for administration of the pharmaceutical compositions provided to adults. For example, the amount administered to a child or adolescent can be determined by a practitioner or person skilled in the art and may be lower than or the same as that administered to an adult.

[0295] It is also recognized that the compounds or compositions described herein can be administered in combination with one or more additional pharmaceutical agents. The compounds or compositions can be administered in combination with additional pharmaceutical agents that improve their bioavailability, reduce and / or modify their metabolism, inhibit their excretion, and / or modify their distribution in the body. It is also understood that the treatments used can achieve the desired effect for the same disorder and / or can achieve different effects.

[0296] The compound or composition can be administered concurrently, prior to, or subsequent to one or more additional pharmaceutical agents that may be useful, for example, as a combination therapy. The pharmaceutical agent includes a therapeutically active agent. The pharmaceutical agent also includes a prophylactically active agent. Each additional pharmaceutical agent can be administered at a dose and / or time schedule determined for that pharmaceutical agent. The additional pharmaceutical agents can also be administered together with each other and / or with the compounds or compositions described herein in a single dose, or can be administered separately in different doses. The specific combination used in the regimen takes into account the compatibility of the compound of the present invention with the additional pharmaceutical agent and / or the desired therapeutic and / or prophylactic effect to be achieved. Generally, it is expected that the additional pharmaceutical agents used in combination will be used at levels that do not exceed the levels at which they are used individually. In some embodiments, the levels used in combination are lower than the levels at which they are used individually.

[0297] Exemplary additional pharmaceutical agents include, but are not limited to, antiproliferative agents, anticancer agents, antidiabetic agents, anti-inflammatory agents, immunosuppressants, and analgesics. Pharmaceutical agents include small organic molecules, such as drug compounds (e.g., compounds approved by the U.S. Food and Drug Administration as provided in the Code of Federal Regulations (CFR)), peptides, proteins, carbohydrates, monosaccharides, oligosaccharides, polysaccharides, nucleoproteins, mucoproteins, lipoproteins, synthetic polypeptides or proteins, small molecules linked to proteins, glycoproteins, steroids, nucleic acids, DNA, RNA, nucleotides, nucleosides, oligonucleotides, antisense oligonucleotides, lipids, hormones, vitamins, and cells.

[0298] Also encompassed by the present invention are kits (e.g., pharmaceutical packs). The kits of the present invention can be useful, for example, for preventing and / or treating proliferative or non-proliferative diseases as described herein. The provided kits can include a pharmaceutical composition or compound of the present invention and a container (e.g., a vial, an ampoule, a bottle, a syringe, and / or a dispenser package, or other suitable container). In some embodiments, the provided kits can optionally further include a second container containing a pharmaceutical excipient for diluting or suspending the pharmaceutical composition or compound of the present invention. In some embodiments, the pharmaceutical composition or compound of the present invention provided in the container and the second container are combined to form a single-unit dosage form.

[0299] Thus, in one aspect, a kit is provided that includes 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 certain embodiments, the kit of the present disclosure includes a first container containing a compound described herein, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof. In certain embodiments, the kit is useful in preventing and / or treating a disease, disorder, or condition described herein (e.g., a proliferative or non-proliferative disease) in a subject. In certain embodiments, the kit further includes instructions for administering the compound, or a pharmaceutically acceptable salt, solvate, hydrate, tautomer, or stereoisomer thereof, or a pharmaceutical composition thereof to a subject to prevent and / or treat a proliferative or non-proliferative disease.

[0300] How to use Described herein are compounds useful for modulating splicing. In some embodiments, compounds of formula (I), (II), or (III) can be used to increase or decrease splicing at splice sites, thereby changing the amount, structure, or composition of nucleic acids (e.g., RNA precursors, e.g., pre-mRNAs, or resulting mRNAs). In some embodiments, increasing or decreasing splicing results in adjusting the level or structure of the produced gene product (e.g., RNA or protein). In some embodiments, compounds of formula (I), (II), or (III) can modulate components of the splicing machinery, for example, by modulating the interaction of the component with another entity (e.g., nucleic acids, proteins, or combinations thereof). The splicing machinery referred to herein includes one or more spliceosome components. Spliceosome components can include, for example, major spliceosome members (U1, U2, U4, U5, U6 snRNPs) or minor spliceosome members (U11, U12, U4atac, U6atac snRNPs) and one or more of their accessory splicing factors.

[0301] In another aspect, the disclosure features a method of modifying a target (e.g., an RNA precursor, e.g., a pre-mRNA) by including a splice site in the target, wherein the method includes providing a compound of Formula (I), (II), or (III). In some embodiments, including a splice site in the target (e.g., an RNA precursor, e.g., a pre-mRNA, or a resulting mRNA) results in the addition or deletion of one or more nucleic acids to the target (e.g., a novel exon, e.g., a skipped exon). The addition or deletion of one or more nucleic acids to the target can result in an increased level of a gene product (e.g., an RNA, e.g., an mRNA, or a protein).

[0302] In another aspect, the disclosure features a method of modifying a target (e.g., an RNA precursor, e.g., a pre-mRNA, or a resulting mRNA) by eliminating a splice site in the target, wherein the method includes providing a compound of Formula (I), (II), or (III). In some embodiments, eliminating a splice site in the target (e.g., an RNA precursor, e.g., a pre-mRNA) results in the deletion or addition of one or more nucleic acids from the target (e.g., a skipped exon, e.g., a novel exon). The deletion or addition of one or more nucleic acids from the target can result in a decrease in the level of a gene product (e.g., an RNA, e.g., an mRNA, or a protein). In other embodiments, the method of modifying a target (e.g., an RNA precursor, e.g., a pre-mRNA, or a resulting mRNA) includes suppressing splicing at a splice site or enhancing splicing at a splice site (e.g., by more than about 0.5%, e.g., 1%, 5%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, 99%, or more), e.g., compared to a reference (e.g., in the absence of a compound of Formula (I), (II), or (III), or in a normal or abnormal cell or tissue).

[0303] The methods described herein can be used, for example, to regulate splicing of nucleic acids containing a particular sequence (e.g., a target sequence). Exemplary genes encoding a target sequence (e.g., a target sequence comprising DNA or RNA, e.g., a pre-mRNA) include, among others, ABCA4, ABCA9, ABCB1, ABCB5, ABCC9, ABCD1, ACADL, ACADM, ACADSB, ACSS2, ACTB, ACTG2, ADA, ADAL, ADAM10, ADAM15, ADAM22, ADAM32, ADAMTS12, ADAMTS13, ADAMTS20, ADAMTS6, ADAMTS9, ADAR, ADCY3, ADCY10, ADCY8, ADNP, ADRBK2, AFP, AGL, AGT, AHCTF1, AHR, AKAP10, AKAP3, AKNA, ALAS1, ALS2CL, ALB, ALDH3A2, ALG6, AMBRA1, ANK3, ANTXR 2, ANXA10, ANXA11, ANGPTL3, AP2A2, AP4E1, APC, APOA1, APOB, APOC3, APOH, AR, ARID2, ARID3A, ARID3B, ARFGEF1, ARFGEF2, ARHGAP1, ARHGAP8, ARHGAP18, ARHGAP26, ARHGEF18, ARHGEF2, ARPC3, ARS2, ASH1 L, 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, BHLHE40, BMPR2, BMP2K, BPTF, BRAF, BRCA1, BRCA2, BRCC3, BRSK1, BRSK2, BTAF1, BTK, C2orf55, C4orf29, C6orf118, C9o rf43, C9orf72, C10orf137, C11orf30, C11orf65, C11orf70, C11οrf87, C12orf5 1, C13orf1, C13orf15, C14orf10l, C14orf118, C15orf29, C15orf42, C15orf60,C16orf33、C16orf38、C16orf48、C18orf8、C19orf42、C1orf107、C1orf114、 C1orf130、C1orf149、C1orf27、C1orf71、C1orf94、C1R、C20orf74、C21orf7 0、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、CC DC5、CCDC81、CCDC131、CCDC146、CD4、CD274、CD1B、CDC14A、CDC16、CDC2L5、 CDC42BPB、CDCA8、CDH10、CDH11、CDH24、CDH8、CDH9、CDK5RAP2、CDK6、CDK8、C DK11B、CD33、CD46、CDH1、CDH23、CDK6、CDK11B、CDK13、CEBPZ、CEL、CELSR3、 CENPA、CENPI、CENPT、CENTB2、CENTG2、CEP110、CEP170、CEP192、CETP、CFB、C FTR、CFH、CGN、CGNL1、CHAF1A、CHD9、CHIC2、CHL1、CHN1、CHM、CLEC16A、CL1C 2、CLCN1、CLINT1、CLK1、CLPB、CLPTM1、CMIP、CMYA5、CNGA3、CNOT1、CNOT7、CN TN6、COG3、COL11A1、COL11A2、COL12A1、COL14A1、COL15A1、COL17A1、COL19 A1、COL1A1、COL1A2、COL2A1、COL3A1、COL4A1、COL4A2、COL4A5、COL4A6、COL5 A2、COL6A1、COL7A1、COL9A1、COL9A2、COL22A1、COL24A1、COL25A1、COL29A1 、COLQ、COMTD1、COPA、COPB2、COPS7B、COPZ2、CPSF2、CPXM2、CR1、CRBN、CRYZ、CREBBP、CRKRS、CSE1L、CSTB、CSTF3、CT45-6、CTNNB1、CUBN、CUL4B、CUL5、CX orf41、CXXC1、CYBB、CYFIP2、CYP3A4、CYP3A43、CYP3A5、CYP4F2、CYP4F3、CYP 17, CYP19, CYP24A1, CYP27A1, DAB1, DAZ2, DCBLD1, DCC, DCTN3, DCUN1D4, DDA1, DDEF1, DDX1, DDX24, DDX4, DENND2D, DEPDC2, DES, DGAT2, DHFR, DHRS7, DH RS9、DHX8、DIP2A、DMD、DMTF1、DNAH3、DNAH8、DNAI1、DNAJA4、DNAJC13、DNAJ C7、DNMT1、DNTTIP2、DOCK4、DOCK5、DOCK10、DOCK11、DOT1L、DPP3、DPP4、DPY1 9L2P2、DR1、DSCC1、DVL3、DUX4、DYNC1H1、DYSF、E2F1、E2F3、E2F8、E4F1、EBF 1、EBF3、ECM2、EDEM3、EFCAB3、EFCAB4B、EFNA4、EFTUD2、EGFR、EIF3A、ELA1、E LA2A, ELF2, ELF3, ELF4, EMCN, EMD, EML5, ENO3, ENPP3, EP300, EPAS1, EPB41L5, EPHA3, EPHA4, EPHB1, EPHB2, EPHB3, EPS15, ERBB4, ERCC1, ERCC8, ERGIC3 、ERMN、ERMP1、ERN1、ERN2、ESR1、ESRRG、ETS2、ETV3、ETV4、ETV5、ETV6、EVC2、EWSR1、EXO1、EXOC4、F3、F11、F13A1、F5、F7、F8、FAH、FAM13A1、FAM13B1、FAM 13C1, FAM134A, FAM161A, FAM176B, FAM184A, FAM19A1, FAM20A, FAM23B, FAM65C, FANCA, FANCC, FANCG, FANCM, FANK1, FAR2, FBN1, FBXO15, FBXO18, FBXO3 8、FCGBP、FECH、FEZ2、FGA、FGD6、FGFR2、FGFR1OP、FGFR1OP2、FGFR2、FGG、FG R、FIX、FKBP3、FLI1、FLJ35848、FLJ36070、FLNA、FN1、FNBP1L、FOLH1、FOSL1、FOSL2, FOXK1, FOXM1, FOXO1, FOXP4, FRAS1, FUT9, FXN, FZD3, FZD6, GAB1, GABPA, GALC, GALNT3, GAPDH, GART, GAS2L3, GATA3, GATAD2A, GBA, GBGT1, GCG GCGR、GCK、GFI1、GFM1、GH1、GHR、GHV、GJA1、GLA、GLT8D1、GNA11、GNAQ、GNAS 、GNB5、GOLGB1、GOLT1A、GOLT1B、GPATCH1、GPR158、GPR160、GPX4、GRAMD3、GR HL1, GRHL2, GRHPR, GRIA1, GRIA3, GRIA4, GRIN2B, GRM3, GRM4, GRN, GSDMB, GSTCD, GSTO2, GTF2I, GTPBP4, HADHA, HAND2, HBA2, HBB, HKK, HDAC3, HDAC5, H DX、HEPACAM2、HERC1、HES7、HEXA、HEXB、HHEX、HIPK3、HLA-DPB1、HLA-G、HLC S、HLTF、HMBS、HMGA1、HMGCL、HNF1A、HNF1B、HNF4A、HNF4G、HNRNPH1、HOXC10、 HP1BP3、HPGD、HPRT1、HPRT2、HSF1、HSF4、HSF2BP、HSPA9、HSPG2、HTT、HXA、I CA1、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、I WS1、JAK1、JAK2、JAG1、JMJD1C、JPH3、KALRN、KAT6A、KATNAL2、KCNN2、KCNT2 、KDM2A、KIAA0256、KIAA0528、KIAA0564、KIAA0586、KIAA1033、KIAA1166、K IAA1219, KIAA1409, KIAA1622, KIAA1787, KIF3B, KIF15, KIF16B, KIF5A, KIF5B, KIF9, KIN, KIR2DL5B, KIR3DL2, KIR3DL3, KIT, KLF3, KLF5, KLF7, KLF10KLF12、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、LOC 389634、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、NFK B1、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、 NUP160、NUPL1、OAT、OAZ1、OBFC2A、OBFC2B、OLIG2、OMA1、OPA1、OPN4、OPTN、OSBPL11、OSBPL8、OSGEPL1、OTC、OTX2、OVOL2、OXT、PA2G4、PADI4、PAH、PAN2 、PAOX、PAPOLG、PARD3、PARP1、PARVB、PAWR、PAX3、PAX8、PBGD、PBRM1、PBX2、PCBP4、PCCA、PCGF2、PCNX、PCOTH、PDCD4、PDE4D、PDE8B、PDE10A、PD1A3、PDH1 、PDLIM5、PDXK、PDZRN3、PELI2、PDK4、PDS5A、PDS5B、PGK1、PGM2、PHACTR4、PHEX、PHKB、PHLDB2、PHOX2B、PHTF1、PIAS1、PIEZO1、PIGF、PIGN、PIGT、PIK3C2 G、PIK3CA、PIK3CD、PIK3CG、PIK3RI、PIP5K1A、PITRM1、PIWIL3、PKD1、PKHD1L1、PKD2、PKIB、PKLR、PKM1、PKM2、PLAGL2、PLCB1、PLCB4、PLCG1、PLD1、PLEKH A5, PLEKHA7, PLEKHM1, PLKR, PLXNC1, PMFBP1, POLN, POLR3D, POMT2, POSTN, POU2AF1, POU2F2, POU2F3, PPARA, PPFIA2, PPP1R12A, PPP3CB, PPP4C, PPP4R1L, PPP4R2, PRAME, PRC1, PRDM1, PREX1, PREX2, PRIM1, PRIM2, PRKAR1A, PRKCA, PRKG1, PRMT7, PROC, PROCR, PROSC, PRODH, PROX1, PRPF40B, PRPF4B, PRRG 2、PRUNE2、PSD3、PSEN1、PSMAL、PTCH1、PTEN、PTK2、PTK2B、PTPN2、PTPN3、PTPN4、PTPN11、PTPN22、PTPRD、PTPRK、PTPRM、PTPRN2、PTPRT、PUS10、PVRL2、PY GM、QRSL1、RAB11FIP2、RAB23、RAF1、RALBP1、RALGDS、RB1CC1、RBL2、RBM39、RBM45、RBPJ、RBSN、REC8、RELB、RFC4、RFT1、RFTN1、RHOA、RHPN2、RIF1、RIT1RLN3、RMND5B、RNF11、RNF32、RNFT1、RNGTT、ROCK1、ROCK2、RORA、RP1、RP6KA3、RP11-265F1、RP13-36C9、RPAP3、RPN1、RPGR、RPL22、RPL22L1、RP6KA6、R REB1、RRM1、RRP1B、RSK2、RTEL1、RTF1、RUFY1、RUNX1、RUNX2、RXRA、RYR3、SAAL1、SAE1、SALL4、SAT1、SATB2、SBCAD、SCN1A、SCN2A、SCN3A、SCN4A、SCN5A、S CN8A, SCNA, SCN11A, SCO1, SCYL3, SDC1, SDK1, SDK2, SEC24A, SEC24D, SEC31A, SEL1L, SENP3, SENP6, SENP7, SERPINA1, SETD3, SETD4, SETDB1, SEZ6, SFRS12, SGCE, SGOL2, SGPL1, SH2D1A, SH3BGRL2, SH3PXD2A, SH3PXD2B, SH3RF2, SH3TC2, SHOC2, SIPA1L2, SIPA1L3, SIVA1, SKAP1, SKIV2L2, SLC6A11, SLC6A1 3、SLC6A6、SLC7A2、SLC12A3、SLC13A1、SLC22A17、SLC25A14、SLC28A3、SLC33A1、SLC35F6、SLC38A1、SLC38A4、SLC39A10、SLC4A2、SLC6A8、SMARCA1、SMA RCA2、SMARCA5、SMARCC2、SMC5、SMN2、SMOX、SMS、SMTN、SNCAIP、SNORD86、SNRK、SNRP70、SNX5、SNX6、SOD1、SOD10、SOS、SOS2、SOX5、SOX6、SOX8、SP1、SP2、 SP3、SP110、SPAG9、SPATA13、SPATA4、SPATS1、SPECC1L、SPDEF、SPI1、SPINK5、SPP2、SPTA1、SRF、SRM、SRP72、SSX3、SSX5、SSX9、STAG1、STAG2、STAMBPLI、 STARD6、STAT1、STAT3、STAT5A、STAT5B、STAT6、STK17B、STX3、STXBP1、SUCLG2、SULF2、SUPT6H、SUPT16H、SV2C、SYCP2、SYT6、SYCPI、SYTL3、SYTL5、TAF2、TARDBP、TBC1D3G、TBC1D8B、TBC1D26、TBC1D29、TBCEL、TBK1、TBP、TBPL1、TB R1、TBX、TCEB3、TCF3、TCF4、TCF7L2、TCFL5、TCF12、TCP11L2、TDRD3、TEAD1、T EAD3, TEAD4, TECTB, TEK, TERF1, TERF2, TET2, TFAP2A, TFAP2B, TFAP2C, TFAP4, TFDP1, TFRC, TG, TGM7, TGS1, THAP7, THAP12, THOC2, TIAL1, TIAM2, TIMM5 0、TLK2、TM4SF20、TM6SF1、TMEM27、TMEM77、TMEM156、TMEM194A、TMF1、TMPR SS6、TNFRSF10A、TNFRSF10B、TNFRSF8、TNK2、TNKS、TNKS2、TOM1L1、TOM1L2、T OP2B、TP53、TP53INP1、TP53BP2、TP53I3、TP63、TRAF3IP3、TRAPPC2、TRIM44 、TRIM65、TRIML1、TRIML2、TRPM3、TRPM5、TRPM7、TRPS1、TSC1、TSC2、TSHB、TS PAN7、TTC17、TTF1、TTLL5、TTLL9、TTN、TTPAL、TTR、TUSC3、TXNDC10、UBE3A、 UCK1、UGT1A1、UHRF1BP1、UNC45B、UNC5C、USH2A、USF2、USP1、USP6、USP18、US P38、USP39、UTP20、UTP15、UTP18、UTRN、UTX、UTY、UVRAG、UXT、VAPA、VEGFA、 VPS29、VPS35、VPS39、VT11A、VT11B、VWA3B、WDFY2、WDR16、WDR17、WDR26、WDR 44, WDR67, WDTC1, WRN, WRNIP1, WT1, WWC3, XBP1, XRN1, XRN2, XX-FW88277, YAP1, YARS, YBX1, YGM, YY1, ZBTB18, ZBTB20, ZC3HAV1, ZC3HC1, ZC3H7A, ZDHHC 19、ZEB1、ZEB2、ZFPM1、ZFYVE1、ZFX、ZIC2、ZNF37A、ZNF91、ZNF114、ZNF155、 ZNF169、ZNF205、ZNF236、ZNF317、ZNF320、ZNF326、ZNF335、ZNF365、ZNF367、These include ZNF407, ZNF468, ZNF506, ZNF511, ZNF511-PRAP1, ZNF519, ZNF521, ZNF592, ZNF618, ZNF763, and ZWINT.

[0304] Additional exemplary genes encoding target sequences (e.g., target sequences comprising DNA or RNA, e.g., pre-mRNA) include A1CF, A4GALT, AAR2, ABAT, ABCA11P, ZNF721, ABCA5, ABHD10, ABHD13, ABHD2, ABHD6, AC000120.3, KRIT1, AC004076.1, ZNF772, AC004076.9, ZNF772, AC004223.3, RAD51D, AC004381.6, AC006486.1, ER F, AC007390.5, AC007780.1, PRKAR1A, AC007998.2, INO80C, AC009070.1, CMC2, AC009879.2, AC009879.3, ADHFE1, AC010487.3, ZNF81 6-ZNF321P, ZNF816, AC010328.3, AC010522.1, ZNF587B, AC010547.4, ZNF19, AC012313.3, ZNF497, AC012651.1, CAPN3, AC013489.1, D ET1, AC016747.4, C2orf74, AC020907.6, FXYD3, AC021087.5, PDCD6, AHRR, AC022137.3, ZNF761, AC025283.3, NAA60, AC027644.4, RAB GEF1, AC055811.2, FLCN, AC069368.3, ANKDD1A, AC073610.3, ARF3, AC074091.1, GPN1, AC079447.1, LIPT1, AC092587.1, AC079594.2, TRIM59, AC091060.1, C18orf21, AC092143.3, MC1R, AC093227.2, ZNF607, AC093512.2, ALDOA, AC098588.1, ANAPC10, AC107871.1, CAL ML4, AC114490.2, ZMYM6, AC138649.1, NIPA1, AC138894.1, CLN3, AC139768.1, AC242426.2, CHD1L, ACADM, ACAP3, ACKR2, RP11-141M3.5、KRBOX1、ACMSD、ACOT9、ACP5、ACPL2、ACSBG1、ACSF2、ACSF3、ACSL1、ACSL3、ACVR1、ADAL、ADAM29、ADAMTS10、ADAMTSL5、ADARB1、ADAT2、ADCK3、ADD3、ADGRG1、ADGRG2、ADH1B、ADIPOR1、ADNP、ADPRH、AGBL5、AGPAT1、AGPAT3、AGR2、AGTR1、AHDC1、AHI1、AH NAK、AIFM1、AIFM3、AIMP2、AK4、AKAP1、AKNAD1、CLCC1、AKR1A1、AKT1、AKT1S1、AKT2、AL139011.2、PEX19、AL157935.2、ST6GAL NAC6、AL358113.1、TJP2、AL441992.2、KYAT1、AL449266.1、CLCC1、AL590556.3、LINC00339、CDC42、ALAS1、ALB、ALDH16A1、ALD H1B1、ALDH3A1、ALDH3B2、ALDOA、ALKBH2、ALPL、AMD1、AMICA1、AMN1、AMOTL2、AMY1B、AMY2B、ANAPC10、ANAPC11、ANAPC15、ANG、 RNASE4、AL163636.2、ANGEL2、ANGPTL1、ANKMY1、ANKRD11、ANKRD28、ANKRD46、ANKRD9、ANKS3、ANKS3、RP11-127I20.7、ANKS6、 ANKZF1、ANPEP、ANXA11、ANXA2、ANXA8L2、AL603965.1、AOC3、AP000304.12、CRYZL1、AP000311.1、CRYZL1、AP000893.2、RAB30 、AP001267.5、ATP5MG、AP002495.2、AP003175.1、OR2AT4、AP003419.1、CLCF1、AP005263.1、ANKRD12、AP006621.5、AP006621.1, AP1G1, AP3M1, AP3M2, APBA2, APBB1, APLP2, APOA2, APOL1, APOL3, APTX, ARAP1, STARD10, ARF4, ARFIP1, ARFIP2, ARFRP1, ARHGAP11A, ARHGAP33, ARHGAP4, ARHGEF10, ARHGEF3, ARHGEF35, OR2A1-AS1, ARHGEF35, OR2A1-AS1, ARHGEF34P, ARID1B, ARHGEF35, OR2A20P, OR2A1-AS1, ARHGEF9, AR L1, ARL13B, ARL16, ARL6, ARMC6, ARMC8, ARMCX2, ARMCX5, RP4-769N13.6, ARMCX5-GPRASP2, BHLHB9, ARMCX5-GPRASP2, GPRASP1, ARMCX5-GPRASP2, GPRASP2, ARMCX6, ARNT2, ARPP19, ARRB2, ARSA, ART3, ASB3, GPR75-ASB3, ASCC2, ASNS, ASNS, AC079781.5, ASPSCR1, ASS1, ASUN, ATE1, ATF1, ATF 7IP2、ATG13、ATG4D、ATG7、ATG9A、ATM、ATOX1、ATP1B3、ATP2C1、ATP5F1A 、ATP5G2、ATP5J、ATP5MD、ATP5PF、ATP6AP2、ATP6V0B、ATP6V1C1、ATP6V1D 、ATP7B、ATXN1、ATXN1L、IST1、ATXN3、ATXN7L1、AURKA、AURKB、AXDND1、B 3GALNT1、B3GALT5、AF064860.1、B3GALT5、AF064860.5、B3GNT5、B4GALT3 、B4GALT4、B9D1、BACH1、BAIAP2、BANF1、BANF2、BAX、BAZ2A、BBIP1、BCHE 、BCL2L14、BCL6、BCL9L、BCS1L、BDH1、BDKRB2、AL355102.2、BEST1、BEST3 、BEX4、BHLHB9、BID、BIN3、BIRC2、BIVM、BIVM-ERCC5、BIVM、BLCAP、BLK、 BLOC1S1、RP11-644F5.10、BLOC1S6、AC090527.2、BLOC1S6、RP11-96O20.4、BLVRA、BMF、BOLA1、BORCS8-MEF2B、BORCS8、BRCA1、BRD1、BRDT、BRINP3、BROX、BTBD10、BTBD3、BTBD9、BTD、BTF3L4、BTNL9、BUB1B-PAK6、PAK6、BUB3、C10orf68、C11orf1、C11orf48、C11orf54、C11orf54、AP001273.2、C11orf5 7、C11orf63、C11orf82、C12orf23、C12orf4、C12orf65、C12orf79、C14orf159、C14orf93、C17orf62、C18orf21、 C19orf12、C19orf40、C19orf47、C19orf48、C19orf54、C1D、C1GALT1、C1QB、C1QTNF1、C1S、C1orf101、C1orf112、C 1orf116、C1orf159、C1orf63、C2、C2、CFB、C20orf27、C21orf58、C2CD4D、C2orf15、LIPT1、MRPL30、C2orf80、C2o rf81、C3orf14、C3orf17、C3orf18、C3orf22、C3orf33、AC104472.3、C4orf33、C5orf28、C5orf34、C6orf118、C6orf f203、C6orf211、C6orf48、C7orf50、C7orf55、C7orf55-LUC7L2、LUC7L2、C8orf44-SGK3、C8orf44、C8orf59、C9、D AB2、C9orf153、C9orf9、CA5BP1、CA5B、CABYR、CALCA、CALCOCO1、CALCOCO2、CALM1、CALM3、CALML4、RP11-315D16.2、CALN1、CALU、CANT1、CANX、CAP1、CAPN12、CAPS2、CARD8、CARHSP1、CARNS1、CASC1、CASP3、CASP7、CBFA2T2、CBS、CBY1、CCBL1、CCBL2、RBMXL1、CCDC12、CCDC126、CCDC14、CCDC149、CCDC150、CCDC169-SOHLH2、CCDC169、CCDC171、CCDC37、CCDC41、CCDC57、CCDC63、CCDC7、CCDC74B、CCDC77、CCDC82、CCDC90B、CCDC91、CCDC92、CCNE1、CCHCR1、CCL28、CCNB1IP1、CCNC、CCND3、CCNG1、CCP110、CCR9、CCT7、CCT8、CD151、CD1D、CD200、CD22、CD226、CD276、CD36、CD59、CDC26、CDC42、CDC42SE1、CDC42SE2、CDHR3、CDK10、CDK16、CDK4、CDKAL1、CDKL3、CTD-2410N18.4、CDKN1A、CDKN2A、CDNF、CEBPZOS、CELF1、CEMIP、CENPK、CEP170B、CEP250、CEP57、CEP57L1、CEP63、CERS4、CFL1、CFL2、CFLAR、CGNL1、CHCHD7、CHD1L、CHD8、CHFR、ZNF605、CHIA、CHID1、CHL1、CHM、CHMP1A、CHMP3、RNF103-CHMP3、CHRNA2、CIDEC、CIRBP、CITED1、CKLF-CMTM1、CMTM1、CKMT1B、CLDN12、CTB-13L3.1、CLDND1、AC021660.3、CLDND1、CPOX、CLHC1、CLIP1、CLUL1、CMC4、MTCP1、CNDP2、CNFN、CNOT1、CNOT6、CNOT7、CNOT8、CNR1、CNR2、CNTFR、CNTRL、COA1、COASY、COCH、COL8A1、COLCA1、COLEC11、COMMD3-BMI1、BMI1、COPS5、COPS7B、COQ8A、CORO6、COTL1、COX14、RP4-605O3.4、COX7A2、COX7A2L、COX7B2、CPA4、CPA5、CPEB1、CPNE1、AL109827.1、RBM12、CPNE1、RP1-309K20.6、RBM12、CPNE3、CPSF3L、CPT1C、CREB3L2、CREM、CRP、CRYZ、CS、AC073896.1、CS、R 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EEF1AKNMT, EEF1D, EFEMP1, EFHC1, EGFL7, EHF, EI24, EIF1AD, EIF2B5, EIF4G1, EIF2B5, POLR2H, EIF3E, EIF3K, EIF4E3, EIF4G1, ELF1, ELMO2, ELMOD1, AP000889.3, ELMOD3, ELOC, ELOF1, ELOVL1, ELOVL7, ELP1, ELP6, EML3, EMP3, ENC1, EN DOV、ENO1、ENPP5、ENTHD2、ENTPD6、EP400NL、EPB41L1、EPDR1、NME8、EPHX1、EPM2A、EPN1、EPN2、EPN3、EPS8L2、ERBB3、ERC1、ERCC1、ERG、ERI2、ERI2、DCU N1D3、ERLIN2、ERMARD、ERRFI1、ESR2、RP11-544I20.2、ESRRA、ESRRB、ESRRG、ETFA、ETFRF1、ETV1、ETV4、ETV7、EVA1A、EVC2、EVX1、EXD2、EXO5、EXOC1、EX OC2、FAAP24、FABP6、FADS1、FADS2、FAHD2B、FAM107B、FAM111A、FAM111B、FAM114A1、FAM114A2、FAM115C、FAM115C、FAM115D、FAM120B、FAM133B、FAM135 A、FAM153A、FAM153B、FAM154B、FAM156A、FAM156B、FAM168B、FAM172A、FAM182B、FAM192A、FAM19A2、FAM200B、FAM220A、FAM220A、AC009412.1、FAM222B、FAM227B, FAM234A, AC004754.1, FAM3C, FAM45A, FAM49B, FAM60A, FAM63A, FAM81A, FAM86B1, FAM86B2, FANCI, FANK1, FAR2, FAXC, FAXDC2, FBF1, FBH1, F BXL4、FBXO18、FBXO22、FBXO31、FBXO41、FBXO44、FBXO45、FBXW9、FCHO1、FCH SD2、FDFT1、FDPS、FER、FETUB、FGD4、FGF1、FGFR1、FGFRL1、FGL1、FHL2、FIBCD 1、FIGNL1、FIGNL1、DDC、FKBP5、FKRP、FLRT2、FLRT3、FMC1、LUC7L2、FMC1-LU C7L2、FNDC3B、FOLH1、FOLR1、FOXP1、FOXK1、FOXM1、FOXO1、FOXP4、AC097634. 4、FOXRED1、FPR1、FPR2、FRG1B、FRS2、FTO、FTSJ1、FUK、FUT10、FUT3、FUT6、F XYD3,FZD3,G2E3,GAA,GABARAPL1,GABPB1,GABRA5,GAL3ST1,GALE,GALNT11 、GALNT14、GALNT6、GAPVD1、GARNL3、GAS2L3、GAS8、GATA1、GATA2、GATA4、GB A、GCNT1、GDPD2、GDPD5、GEMIN7、MARK4、GEMIN8、GGA3、GGACT、AL356966.1、 GGPS1, GHRL, GID8, GIGYF2, GIMAP8, GIPC1, GJB1, GJB6, GLB1L, GLI1, GLT8D1, GMFG, GMPR2, GNAI2, GNAQ, GNB1, GNB2, GNE, GNG2, GNGT2, GNPDA1, GNPDA2 GOLGA3、CHFR、GOLGA4、GOLPH3L、GOLT1B、GPBP1L1、GPER1、GPR116、GPR141、 EPDR1、GPR155、GPR161、GPR56、GPR63、GPR75-ASB3、ASB3、GPR85、GPSM2、GRA MD1B、GRB10、GRB7、GREM2、GRIA2、GSDMB、GSE1、GSN、GSTA4、GSTZ1、GTDC1、G TF2H1、GTF2H4、VARS2、GTF3C2、GUCY1A3、GUCY1B3、GUK1、GULP1、GYPC、GYS1、GZF1、HAGH、HAO2、HAPLN3、HAVCR1、HAX1、HBG2、AC104389.4、HBG2、AC10438 9.4、HBE1、HBG2、AC104389.4、HBE1、OR51B5、HBG2、HBE1、AC104389.28、HBS 1L、HCFC1R1、HCK、HDAC2、HDAC6、HDAC7、HDLBP、HEATR4、HECTD4、HEXIM2、HH AT、HHATL、CCDC13、HINFP、HIRA、C22orf39、HIVEP3、HJV、HKR1、HLF、HMBOX1 、HMGA1、HMGB3、HMGCR、HMGN4、HMOX2、HNRNPC、HNRNPD、HNRNPH1、HNRNPH3、H NRNPR、HOMER3、HOPX、HOXA3、HOXB3、HOXB3、HOXB4、HOXC4、HOXD3、HOXD3、HO XD4, HPCAL1, HPS4, HPS5, HRH1, HS3ST3A1, HSH2D, HSP90AA1, HSPD1, HTT, HU WE1、HYOU1、IAH1、ICA1L、ICAM2、ICE2、ICK、IDH2、IDH3G、IDS、IFI27、IFI44 、IFT20、IFT22、IFT88、IGF2、INS-IGF2、IGF2BP3、IGFBP6、IKBKAP、IKBKB、I L11、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、INTS 14、IP6K2、IP6K3、IPO11、LRRC70、IQCE、IQGAP3、IRAK4、IRF3、IRF5、IRF6、I SG20、IST1、ISYNA1、ITFG2、ITGB1BP1、ITGB7、ITIH4、RP5-966M1.6、ITPRIP L1、JADE1、JAK2、JARID2、JDP2、KANK1、KANK1、RP11-31F19.1、KANK2、KANSL 1L、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、KIAA039 1、KIAA0391、AL121594.1、KIAA0391、PSMA6、KIAA0753、KIAA0895、KIAA089 5L、KIAA1191、KIAA1407、KIAA1841、C2orf74、KIF12、KIF14、KIF27、KIF9、KI FC3、KIN、KIRREL1、KITLG、KLC1、APOPT1、AL139300.1、KLC4、KLHDC4、KLHDC 8A、KLHL13、KLHL18、KLHL2、KLHL24、KLHL7、KLK11、KLK2、KLK5、KLK6、KLK7、 KNOP1、KRBA2、AC135178.2、KRBA2、RP11-849F2.7、KRIT1、KRT15、KRT8、KTN 1、KXD1、KYAT3、RBMXL1、KYNU、L3MBTL1、LACC1、LARGE、LARP4、LARP7、LAT2、L BHD1, LCA5, LCA5L, LCTL, LEPROTL1, LGALS8, LGALS9C, LGMN, LHFPL2, LIG4, LIMCH1, LIMK2, LIMS2, LINC00921, ZNF263, LIPF, LLGL2, LMAN2L, LMCD1, LM F1、RP11-161M6.2、LMO1、LMO3、LOXHD1、LPAR1、LPAR2、LPAR4、LPAR5、LPAR6 、LPHN1、LPIN2、LPIN3、LPP、LRFN5、LRIF1、LRMP、LRRC14、LRRC20、LRRC24、C8 orf82、LRRC39、LRRC42、LRRC48、LRRC4C、LRRC8A、LRRC8B、LRRD1、LRTOMT、L RTOMT、AP000812.5、LSM7、LTB4R、LTBP3、LUC7L2、FMC1-LUC7L2、LUC7L3、LUZ P1、LYG1、LYL1、LYPD4、LYPD6B、LYRM1、LYRM5、LYSMD4、MACC1、MAD1L1、MAD1 L1、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、M ASP1、MATK、MATR3、MATR3、SNHG4、MB、MBD5、MBNL1、MBOAT7、MCC、MCFD2、MCM 9、MCOLN3、MCRS1、MDC1、MDGA2、MDH2、MDM2、ME1、MEAK7、MECR、MED4、MEF2A、M EF2B、BORCS8-MEF2B、MEF2BNB-MEF2B、MEF2B、MEF2BNB、MEF2C、MEF2D、MEGF 10、MEI1、MEIS2、MELK、MET、METTL13、METTL23、MFF、MFN2、MFSD2A、MGST3、MI B2, MICAL1, MICAL3, MICOS10, NBL1, MICOS10-NBL1, MID1, MINA, MINOS1-NBL1, MINOS1, MIOS, MIPOL1, MIS12, MKLN1, MKNK1, MKNK1, MOB3C, MLF2, MLH1, M MP17、MOBP、MOCS1、MOGS、MOK、MORF4L1、MPC1、MPC2、MPG、MPI、MPP1、MPP2、M PPE1、MPST、MRAS、MRO、MROH1、MROH7-TTC4、MROH7、MRPL14、MRPL24、MRPL33、 BABAM2、MRPL33、BRE、MRPL47、MRPL48、MRPL55、MRRF、MRTFA、MRTFB、MRVI1、 MS4A1、MS4A15、MS4A3、MS4A6E、MS4A7、MS4A14、MSANTD3、MSANTD4、MSH5、MSH 5-SAPCD1、MSL2、MSRB3、MSS51、MTCP1、CMC4、MTERF、MTERF1、MTERF3、MTERF D2、MTERFD3、MTF2、MTG2、MTHFD2、MTHFD2L、MTIF2、MTIF3、MTMR10、MTRF1、MT RR、MTUS2、MUTYH、MVK、MX1、MX2、MYH10、MYL12A、MYB、MYD88、MYL5、MYLIP、MY NN、MYO15A、MYO1B、MYOM2、MZF1、N4BP2L2、NAA60、NAB1、NAE1、NAGK、NAP1L1、NAP1L4、NAPG、NARFL、NARG2、NAT1、NAT10、NBPF11、WI2-3658N16.1、NBPF12、NBPF15、NBPF24、NBPF6、NBPF9、NBR1、NCAPG2、NCBP2、NCEH1、NCOA1、NCOA4、NDC1、NDRG1、NDR、 G2、NDRG4、NDST1、NDUFAF6、NDUFB2、NDUFC1、NDUFS1、NDUFS8、NDUFV1、NEDD1、NEIL1、NEIL2、NEK10、NEK11、NEK6、NEK9、NELFA、NEU4 、NFAT5、NFE2、NFE2L2、AC019080.1、NFRKB、NFYA、NFYC、NIF3L1、NIPA2、NKIRAS1、NKX2-1、NLRC3、NME1、NME1-NME2、NME2、NME1-NME2 、NME2、NME4、NME6、NME9、NOD1、NOL10、NOL8、NONO、NPAS1、NPIPA8、RP11-1212A22.1、NPIPB3、NPIPB4、NPIPB9、NPL、NPM1、NPPA、NQO 2、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、O GDHL、OGFOD2、AC026362.1、OGFOD2、RP11-197N18.2、OLA1、OPRL1、OPTN、OR2H1、ORAI2、ORMDL1、ORMDL2、ORMDL3、OSBPL2、OSBPL3、OS BPL5、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、STAG3L5P-PVRIG2P-PILRB、PIP5K1B、PIR、PISD、PIWIL4、FUT4、PKD2、PKIA、PKIG、PKM、PKN2、PLA1A、PLA2G2A、PLA2G5、PLA2G7、PLAC8、PLAGL1、PLD1、PLD3、PLEKHA1、PLEKHA2、PLEKHA6、PLEKHG5、PLIN1、PLS1、PLS3、PLSCR1、PLSCR2、PLSCR4、PLXNB1、PLXNB2、PMP22、PMS1、PNISR、PNKP、AKT1S1、PNMT、PNPLA4、PNPLA8、PNPO、PNRC1、POC1B、POFUT1、POLB、POLD1、POLH、POLI、POLL、POLR1B、POM121、POM121C、AC006014.7、POM121C、AC211429.1、POMC、POMT1、POP1、PORCN、POU5F1、PSORS1C3、PPARD、PPARG、PPHLN1、PPIL3、PPIL4、PPM1A、PPM1B、AC013717.1, PPP1CB, PPP1R11, PPP1R13L, PPP1R26, PPP1R9A, PPP2R2B, PPP3CA, PPP6R 1, PPP6R3, PPT2, PPT2-EGFL8, EGFL8, PPWD1, PRDM2, PRDM8, PRELID3A, PREP L, PRICKLE1, PRKAG1, PRMT2, PRMT5, PRMT7, PROM1, PRPS1, PRPSAP2, PRR14L PRR15L, PRR5, PRR5-ARHGAP8, PRR5L, PRR7, PRRC2B, PRRT4, PRSS50, PRSS4 5. PRSS44, PRUNE, PRUNE1, PSEN1, PSMA2, PSMF1, PSORS1C1, PSPH, PSRC1, PT BP3, PTHLH, PTK2, PTPDC1, PTPRM, PUF60, PUM2, PUS1, PUS10, PXN, PXYLP1 YCR1, QRICH1, R3HCC1L, R3HDM2, RAB17, RAB23, RAB3A, RAB3D, TMEM205, RAB 4B-EGLN2, EGLN2, AC008537.1, RAB5B, RAB7L1, RABL2A, RABL2B, RABL5, RAC GAP1, RAD17, RAD51L3-RFFL, RAD51D, RAD52, RAE1, RAI14, RAI2, RALBP1, RA N, RANGAP1, RAP1A, RAP1B, RAP1GAP, RAPGEF4, RAPGEFL1, RASGRP2, RASSF1 RBCK1, RBM12B, RBM14, RBM4, RBM14-RBM4, RBM23, RBM4, RBM14-RBM4, RBM47 RBM7, AP002373.1, RBM7, RP11-212D19.4, RBMS2, RBMY1E, RBPJ, RBPMS, RB SN, RCBTB2, RCC1, RCC1, SNHG3, RCCD1, RECQL, RELL2, REPIN1, AC073111.3. REPIN1, ZNF775, RER1, RERE, RFWD3, RFX3, RGL2, RGMB, RGS11, RGS3, RGS5, A L592435.1 RHBDD1 RHNO1 TULP3 RHOC AL603832.3 RHOC RP11-426L16. 10. RHOH, RIC8B, RIMKLB, RIN1, RIPK2, RIT1, RLIM, RNASE4, ANG, AL16、RNASEK、RNASEK-C17orf49、RNF111、RNF123、RNF13、RNF14、RNF185、RNF216、RNF24、RNF32、RNF34、RNF38、RNF4、RNF44、RNH1、RNMT、RNPS1、RO60、ROPN1、ROPN1B、ROR2、RP1-102H19.8、C6orf163、RP1-283E3.8、CDK11A、RP11-120M18.2、PRKAR1A、RP11-133K1.2、PAK6、RP11-164J13.1、CAPN3、RP11-21J18.1、ANKRD12、RP11-322E11.6、INO80C、RP11-337C18.10、CHD1L、RP11-432B6.3、TRIM59、RP11-468E2.4、IRF9、RP11-484M3.5、UPK1B、RP11-517H2.6、CCR6、RP11-613M10.9、SLC25A51、RP11-659G9.3、RAB30、RP11-691N7.6、CTNND1、RP11-849H4.2、RP11-896J10.3、NKX2-1、RP11-96O20.4、SQRDL、RP11-986E7.7、SERPINA3、RP4-769N13.6、GPRASP1、RP4-769N13.6、GPRASP2、RP4-798P15.3、SEC16B、RP5-1021I20.4、ZNF410、RP6-109B7.3、FLJ27365、RPE、RPH3AL、RPL15、RPL17、RPL17-C18orf32、RPL17、RPL23A、RPL36、HSD11B1L、RPP38、RPS20、RPS27A、RPS3A、RPS6KA3、RPS6KC1、RPS6KL1、RPUSD1、RRAGD、RRAS2、RRBP1、RSL1D1、RSRC2、RSRP1、RUBCNL、RUNX1T1、RUVBL2、RWDD1、RWDD4、S100A13、AL162258.1、S100A13、RP1-178F15.5、S100A16、S100A4、S100A3、S100A6、S100PBP、SAA1、SACM1L、SAMD4B、SAR1A、SARAF、SARNP、RP11-762I7.5、SCAMP5、SCAP、SCAPER、SCFD1、SCGB3A2、SCIN、SCML1、SCNN1D、SCO2、S COC、SCRN1、SDC2、SDC4、SEC13、SEC14L1、SEC14L2、SEC22C、SEC23B、SEC2 4C、SEC61G、SEMA4A、SEMA4C、SEMA4D、SEMA6C、SENP7、SEPP1、11-Sep、2-S ep、SERGEF、AC055860.1、SERP1、SERPINA1、SERPINA5、SERPINB6、SERPIN G1、SERPINH1、SERTAD3、SETD5、SFMBT1、AC096887.1、SFTPA1、SFTPA2、S FXN2、SGCD、SGCE、SGK3、SGK3、C8orf44、SH2B1、SH2D6、SH3BP1、Z83844.3 、SH3BP2、SH3BP5、SH3D19、SH3YL1、SHC1、SHISA5、SHMT1、SHMT2、SHOC2、S HROOM1、SIGLEC5、SIGLEC14、SIL1、SIN3A、SIRT2、SIRT6、SKP1、STAT4、AC 104109.3, SLAIN1, SLC10A3, SLC12A9, SLC14A1, SLC16A6, SLC1A2, SLC1A6, SLC20A2, SLC25A18, SLC25A19, SLC25A22, SLC25A25, SLC25A29, SLC2 5A30, SLC25A32, SLC25A39, SLC25A44, SLC25A45, SLC25A53, SLC26A11, SLC26A4, SLC28A1, SLC29A1, SLC2A14, SLC2A5, SLC2A8, SLC35B2, SLC35B3 SLC35C2, SLC37A1...

Claims

1. Compounds of formula (I) 【Chemical 1】 or a pharmaceutically acceptable salt, solvate, hydrate, tautomer, or stereoisomer thereof, wherein: A and B are each independently a cycloalkyl, heterocyclyl, aryl, or heteroaryl, each of which is selected from one or more R １ optionally substituted with; W, X, Y, and Z each independently represent C(R ３ａ ) or N, and at least one of W, X, Y, and Z is independently N; L １ is non-existent, C １ ~C ６ - alkylene, C １ ~C ６ -heteroalkylene, -O-, -C(O)-, -N(R ４ ) -, -N(R ４ )C(O)-, or -C(O)N(R ４ )-, where each alkylene and heteroalkylene is selected from one or more R ５ optionally substituted with; Each R １ are independently hydrogen, C １ ~C ６ -Alkyl, C ２ ~C ６ -alkenyl, C ２ ~C ６ -alkynyl, C １ ~C ６ -heteroalkyl, C １ ~C ６ -haloalkyl, cycloalkyl, heterocyclyl, aryl, C １ ~C ６ Alkylene-aryl, C ２ ~C ６ Alkenylene-aryl, heteroaryl, C １ ~C ６ Alkylene-heteroaryl, C ２ ~C ６ Alkenylene-heteroaryl, halo, cyano, oxo, -OR Ａ , -NR Ｂ R Ｃ , -NR Ｂ C(O)R Ｄ , -NO ２ , —C(O)NR Ｂ R Ｃ , -C(O)R Ｄ , -C(O)OR Ｄ , or -S(O) ｘ R Ｄ wherein each alkyl, alkylene, alkenyl, alkynyl, heteroalkyl, haloalkyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl is selected from one or more R ６ optionally replaced by Two R's １ The groups, together with the atom to which they are attached, form a 3- to 7-membered cycloalkyl, heterocyclyl, aryl, or heteroaryl, where each cycloalkyl, heterocyclyl, aryl, and heteroaryl is selected from one or more R ６ optionally substituted with; Each R ２ are independently １ ~C ６ -Alkyl, C ２ ~C ６ -alkenyl, C ２ ~C ６ -alkynyl, C １ ~C ６ -heteroalkyl, C １ ~C ６ -haloalkyl, halo, cyano, -OR Ａ , -NR Ｂ R Ｃ , -C(O)R Ｄ , or —C(O)OR Ｄ and R ３ａ is hydrogen, C １ ~C ６ -Alkyl, C ２ ~C ６ -alkenyl, C ２ ~C ６ -alkynyl, C １ ~C ６ -heteroalkyl, C １ ~C ６ -haloalkyl, halo, cyano, -OR Ａ , -NR Ｂ R Ｃ , -C(O)R Ｄ , or —C(O)OR Ｄ and Each R ４ are independently hydrogen, C １ ~C ６ - alkyl, or C １ ~C ６ -haloalkyl; Each R ５ are independently hydrogen, C １ ~C ６ -Alkyl, C １ ~C ６ -heteroalkyl, C １ ~C ６ -haloalkyl, cycloalkyl, halo, cyano, oxo, -OR Ａ , -NR Ｂ R Ｃ , -C(O)R Ｄ , or —C(O)OR Ｄ and Each R ６ are independently １ ~C ６ -Alkyl, C ２ ~C ６ -alkenyl, C ２ ~C ６ -alkynyl, C １ ~C ６ -heteroalkyl, C １ ~C ６ -haloalkyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, halo, cyano, oxo, -OR Ａ , -NR Ｂ R Ｃ , -NR Ｂ C(O)R Ｄ , -NO ２ , —C(O)NR Ｂ R Ｃ , -C(O)R Ｄ , -C(O)OR Ｄ , or -S(O) ｘ R Ｄ wherein each alkyl, alkenyl, alkynyl, heteroalkyl, haloalkyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl is selected from one or more R １１ optionally substituted with; Each R Ａ are independently hydrogen, C １ ~C ６ Alkyl, C １ ~C ６ Haloalkyl, aryl, heteroaryl, C １ ~C ６ Alkylene-aryl, C １ ~C ６ alkylene-heteroaryl, —C(O)R Ｄ , or -S(O) ｘ R Ｄ and R Ｂ and R Ｃ each independently represents hydrogen, C １ ~C ６ Alkyl, C １ ~C ６ heteroalkyl, cycloalkyl, heterocyclyl, or —OR Ａ or R Ｂ and R Ｃ together with the atoms to which they are attached form one or more R ７ forming a 3- to 7-membered heterocyclyl ring optionally substituted with Each R Ｄ are independently hydrogen, C １ ~C ６ Alkyl, C ２ ~C ６ Alkenyl, C ２ ~C ６ Alkynyl, C １ ~C ６ Heteroalkyl, C １ ~C ６ Haloalkyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, C １ ~C ６ Alkylene-aryl, or C １ ~C ６ alkylene-heteroaryl; and each R ７ is C １ ~C ６ -alkyl, halo, cyano, oxo, or -OR Ａ１ and Each R １１ are independently １ ~C ６ -Alkyl, C １ ~C ６ -heteroalkyl, C １ ~C ６ -haloalkyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, halo, cyano, oxo, or -OR Ａ and Each R Ａ１ is hydrogen or C １ ~C ６ - alkyl; m is 0, 1, or 2; x is 0, 1, or 2].

2. Each of A and B is independently heteroaryl or heterocyclyl, each of which is selected from one or more R １ 10. The compound of claim 1, or a pharmaceutically acceptable salt, solvate, hydrate, tautomer, or stereoisomer thereof, optionally substituted with:

3. One of A and B is independently 【Chemistry 2】 wherein R １ 2. The compound of claim 1, or a pharmaceutically acceptable salt, solvate, hydrate, tautomer, or stereoisomer thereof, wherein:

4. One of A and B is independently 【Chemistry 10-1】 【Chemistry 10-2】 2. The compound of claim 1, or a pharmaceutically acceptable salt, solvate, hydrate, tautomer, or stereoisomer thereof, selected from:

5. One of A and B is independently nitrogen-containing heterocyclyl and one or more R １ 10. The compound of claim 1, or a pharmaceutically acceptable salt, solvate, hydrate, tautomer, or stereoisomer thereof, optionally substituted with:

6. One of A and B is independently 【Chemistry 17】 wherein R １ 2. The compound of claim 1, or a pharmaceutically acceptable salt, solvate, hydrate, tautomer, or stereoisomer thereof, wherein:

7. One of A and B is independently 【Chemistry 24-1】 【Chemistry 24-2】 【Chemistry 24-3】 2. The compound of claim 1, or a pharmaceutically acceptable salt, solvate, hydrate, tautomer, or stereoisomer thereof, selected from:

8. B, 【Chemical Formula 28】 2. The compound of claim 1, or a pharmaceutically acceptable salt, solvate, hydrate, tautomer, or stereoisomer thereof, selected from:

9. L １ is absent, -N(R ４ )C(O)-, or -C(O)N(R ４ 2. The compound of claim 1, or a pharmaceutically acceptable salt, solvate, hydrate, tautomer, or stereoisomer thereof, wherein:

10. 2. The compound of claim 1, or a pharmaceutically acceptable salt, solvate, hydrate, tautomer, or stereoisomer thereof, wherein at least two of W, X, Y, and Z are independently N.

11. 【Chemical 31】 wherein R ３ａ 2. The compound of claim 1, wherein:

12. (i) The compound of formula (I) is represented by formula (I-b) 【Chemical 33】 or a pharmaceutically acceptable salt, solvate, hydrate, tautomer, or stereoisomer thereof, wherein A, B, L １ , X, Y, Z, R ２ , m, and each of its subvariables are as defined in claim 1; (ii) The compound of formula (I) is a compound of formula (I-c) 【Chemical 34】 or a pharmaceutically acceptable salt, solvate, hydrate, tautomer, or stereoisomer thereof, wherein A, B, W, X, Y, Z, R 2 , m, and each of its subvariables are as defined in claim 1; (iii) The compound of formula (I) is a compound of formula (I-d) 【Chemistry 35】 or a pharmaceutically acceptable salt, solvate, hydrate, tautomer, or stereoisomer thereof, wherein A, B, L 2 , R 2 , R 3a , m, and each of the subvariables thereof are as defined in claim 1; (iv) The compound of formula (I) is a compound of formula (I-e) 【Chemical 36】 or a pharmaceutically acceptable salt, solvate, hydrate, tautomer, or stereoisomer thereof, wherein A, B, L 2 , R 2 , R 3a , m, and each of the subvariables thereof are as defined in claim 1; (v) The compound of formula (I) is a compound of formula (If) 【Chemical 37】 or a pharmaceutically acceptable salt, solvate, hydrate, tautomer, or stereoisomer thereof, wherein A, B, L 2 , R 2 , R 3a , m, and each of the subvariables thereof are as defined in claim 1; (vi) The compound of formula (I) is a compound of formula (I-g) 【Chemical 38】 or a pharmaceutically acceptable salt, solvate, hydrate, tautomer, or stereoisomer thereof, wherein B, X, Y, Z, R 1 , R 2 , m, and each of the subvariables thereof are as defined in claim 1; (vii) The compound of formula (I) is a compound of formula (I-h): 【Chemical 39】 or a pharmaceutically acceptable salt, solvate, hydrate, tautomer, or stereoisomer thereof, wherein p is 0, 1, 2, or 3, and each of A, X, Y, Z, R 1 , R 2 , m, p, and subvariables thereof are as defined in claim 1; (viii) The compound of formula (I) is a compound of formula (I-l) 【Chemistry 40】 or a pharmaceutically acceptable salt, solvate, hydrate, tautomer, or stereoisomer thereof, wherein p is 0, 1, 2, or 3, and wherein A, X, Y, Z, R 1 , R 2 , m, and each of its subvariables are as defined in claim 1. The compound of claim 1, or a pharmaceutically acceptable salt, solvate, hydrate, tautomer, or stereoisomer thereof.

13. A is heteroaryl (e.g., bicyclic heteroaryl), and R １ optionally substituted with; B is heterocyclyl (e.g., monocyclic heterocyclyl) and one or more R １ optionally substituted with; L １ is -C(O)N(R ４ ) and R ３ａ But hydrogen, C １ ~C ６ - alkyl, or C １ ~C ６ -heteroalkyl; In the formula, R １ and R ８ 2. The compound of claim 1, or a pharmaceutically acceptable salt, solvate, hydrate, tautomer, or stereoisomer thereof, wherein each of:

14. 2. The compound of claim 1, or a pharmaceutically acceptable salt, solvate, hydrate, tautomer, or stereoisomer thereof, selected from the compounds listed in Table 1.

15. Compound of formula (II): 【Chemistry 41】 or a pharmaceutically acceptable salt, solvate, hydrate, tautomer, or stereoisomer thereof, wherein: A and B are each independently a cycloalkyl, heterocyclyl, aryl, or heteroaryl, each of which is selected from one or more R １ optionally substituted with; M and P each independently represent C(R ２ ) or N, wherein at least one of M and P is independently N; W, X, Y, and Z each independently represent C(R ３ ) or N, and at least one of W, X, Y, and Z is N; L １ and L ２ Each of １ ~C ６ - alkylene, C １ ~C ６ -heteroalkylene, -O-, -C(O)-, -N(R ４ ) -, -N(R ４ )C(O)-, or -C(O)N(R ４ )-, where each alkylene and heteroalkylene is selected from one or more R ５ optionally substituted with; Each R １ are independently hydrogen, C １ ~C ６ -Alkyl, C ２ ~C ６ -alkenyl, C ２ ~C ６ -alkynyl, C １ ~C ６ -heteroalkyl, C １ ~C ６ -haloalkyl, cycloalkyl, heterocyclyl, aryl, C １ ~C ６ Alkylene-aryl, C ２ ~C ６ Alkenylene-aryl, C １ ~C ６ Alkylene-heteroaryl, heteroaryl, halo, cyano, oxo, -OR Ａ , -NR Ｂ R Ｃ , -NR Ｂ C(O)R Ｄ , -NO ２ , —C(O)NR Ｂ R Ｃ , -C(O)R Ｄ , -C(O)OR Ｄ , or -S(O) ｘ R Ｄ wherein each alkyl, alkylene, alkenyl, alkynyl, heteroalkyl, haloalkyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl is selected from one or more R ６ optionally replaced by Two R's １ The groups, together with the atom to which they are attached, form a 3- to 7-membered cycloalkyl, heterocyclyl, aryl, or heteroaryl, where each cycloalkyl, heterocyclyl, aryl, and heteroaryl is selected from one or more R ６ optionally substituted with; Each R ２ are independently hydrogen, C １ ~C ６ -Alkyl, C ２ ~C ６ -alkenyl, C ２ ~C ６ -alkynyl, C １ ~C ６ -heteroalkyl, C １ ~C ６ -haloalkyl, halo, cyano, -OR Ａ , -NR Ｂ R Ｃ , -NR Ｂ C(O)R Ｄ , -NO ２ , —C(O)NR Ｂ R Ｃ , -C(O)OR Ｄ , or -S(O) ｘ R Ｄ , or -C(O)R Ｄ and R ３ is hydrogen, C １ ~C ６ -Alkyl, C ２ ~C ６ -alkenyl, C ２ ~C ６ -alkynyl, C １ ~C ６ -heteroalkyl, C １ ~C ６ -haloalkyl, halo, cyano, -OR Ａ , -NR Ｂ R Ｃ , -NR Ｂ C(O)R Ｄ , -NO ２ , —C(O)NR Ｂ R Ｃ , -C(O)OR Ｄ , or -S(O) ｘ R Ｄ , or -C(O)R Ｄ and Each R ４ are independently hydrogen, C １ ~C ６ - alkyl, or C １ ~C ６ -haloalkyl; Each R ５ are independently hydrogen, C １ ~C ６ -Alkyl, C １ ~C ６ -heteroalkyl, C １ ~C ６ -haloalkyl, cycloalkyl, halo, cyano, oxo, -OR Ａ , -NR Ｂ R Ｃ , -C(O)R Ｄ , or —C(O)OR Ｄ and Each R ６ are independently １ ~C ６ -Alkyl, C ２ ~C ６ -alkenyl, C ２ ~C ６ -alkynyl, C １ ~C ６ -heteroalkyl, C １ ~C ６ -haloalkyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, halo, cyano, oxo, -OR Ａ , -NR Ｂ R Ｃ , -NR Ｂ C(O)R Ｄ , -NO ２ , —C(O)NR Ｂ R Ｃ , -C(O)R Ｄ , -C(O)OR Ｄ , or -S(O) ｘ R Ｄ wherein each alkyl, alkenyl, alkynyl, heteroalkyl, haloalkyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl is selected from one or more R １１ optionally substituted with; Each R Ａ are independently hydrogen, C １ ~C ６ Alkyl, C ２ ~C ６ Alkenyl, C ２ ~C ６ Alkynyl, C １ ~C ６ Heteroalkyl, C １ ~C ６ Haloalkyl, aryl, heteroaryl, C １ ~C ６ Alkylene-aryl, C １ ~C ６ Alkylene-heteroaryl, —C(O)R Ｄ , or -S(O) ｘ R Ｄ and R Ｂ and R Ｃ each independently represents hydrogen, C １ ~C ６ Alkyl, C ２ ~C ６ Alkenyl, C ２ ~C ６ Alkynyl, C １ ~C ６ Heteroalkyl, C １ ~C ６ Haloalkyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, C １ ~C ６ Alkylene-aryl, or C １ ~C ６ alkylene-heteroaryl, -OR Ａ , —C(O)NR Ｂ R Ｃ , -C(O)R Ｄ , -C(O)OR Ｄ , or -S(O) ｘ R Ｄ or R Ｂ and R Ｃ together with the atoms to which they are attached form one or more R ７ forming a 3- to 7-membered heterocyclyl ring optionally substituted with Each R Ｄ are independently hydrogen, C １ ~C ６ Alkyl, C ２ ~C ６ Alkenyl, C ２ ~C ６ Alkynyl, C １ ~C ６ Heteroalkyl, C １ ~C ６ Haloalkyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, C １ ~C ６ Alkylene-aryl, or C １ ~C ６ alkylene-heteroaryl; Each R ７ is C １ ~C ６ -alkyl, halo, cyano, oxo, or -OR Ａ１ and Each R １１ are independently １ ~C ６ -Alkyl, C １ ~C ６ -heteroalkyl, C １ ~C ６ -haloalkyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, halo, cyano, oxo, or -OR Ａ and Each R Ａ１ is hydrogen or C １ ~C ６ - alkyl; x is 0, 1, or 2].

16. One of A and B is independently a nitrogen-containing heteroaryl, and one or more R １ 16. The compound of claim 15, or a pharmaceutically acceptable salt, solvate, hydrate, tautomer, or stereoisomer thereof, optionally substituted with:

17. One of A and B is independently 【Chemistry 42】 wherein R １ 16. The compound of claim 15, or a pharmaceutically acceptable salt, solvate, hydrate, tautomer, or stereoisomer thereof, wherein:

18. One of A and B is independently 【Chemistry 50】 16. The compound of claim 15, or a pharmaceutically acceptable salt, solvate, hydrate, tautomer, or stereoisomer thereof, selected from:

19. One of A and B is independently nitrogen-containing heterocyclyl and one or more R １ 16. The compound of claim 15, or a pharmaceutically acceptable salt, solvate, hydrate, tautomer, or stereoisomer thereof, optionally substituted with:

20. One of A and B is independently 【Chemical Formula 57】 wherein R １ 16. The compound of claim 15, wherein: is as described in claim 1, or a pharmaceutically acceptable salt, solvate, hydrate, tautomer, or stereoisomer thereof.

21. One of A and B is independently 【Hua 64】 16. The compound of claim 15, or a pharmaceutically acceptable salt, solvate, hydrate, tautomer, or stereoisomer thereof, selected from:

22. L １ and L ２ each independently being absent, -N(R ４ )C(O)-, or -C(O)N(R ４ 16. The compound of claim 15, or a pharmaceutically acceptable salt, solvate, hydrate, tautomer, or stereoisomer thereof, wherein:

23. M is C (R ２ ) (e.g., CH) and P is N, or a pharmaceutically acceptable salt, solvate, hydrate, tautomer, or stereoisomer thereof.

24. M is N and P is C(R ２ 16. The compound of claim 15, wherein R is 1 or 2 (e.g., CH), or a pharmaceutically acceptable salt, solvate, hydrate, tautomer, or stereoisomer thereof.

25. 16. The compound of claim 15, or a pharmaceutically acceptable salt, solvate, hydrate, tautomer, or stereoisomer thereof, wherein W is independently N.

26. 【Catalog 71】 16. The compound of claim 15, or a pharmaceutically acceptable salt, solvate, hydrate, tautomer, or stereoisomer thereof, selected from: (i) The compound of formula (II) is represented by formula (II-a): 【Chemical Formula 72】 or a pharmaceutically acceptable salt, solvate, hydrate, tautomer, or stereoisomer thereof, wherein A, B, W, X, Y, Z, M, P, L １ , L ２ and each of its subvariables are as set forth in claim 15; (ii) The compound of formula (II) is represented by formula (II-b) 【Chemical 73】 or a pharmaceutically acceptable salt, solvate, hydrate, tautomer, or stereoisomer thereof, wherein A, B, W, X, Y, Z, L 1 , L 2 , and each of the subvariables thereof are as defined in claim 15; (iii) The compound of formula (II) is represented by formula (II-c) 【Chemical Formula 74】 or a pharmaceutically acceptable salt, solvate, hydrate, tautomer, or stereoisomer thereof, wherein A, B, W, X, Y, Z, M, P, and each of its subvariables are as defined in claim 15; (iv) The compound of formula (II) is represented by formula (II-d) 【Chemistry 75】 or a pharmaceutically acceptable salt, solvate, hydrate, tautomer, or stereoisomer thereof, wherein A, B, L 1 , L 2 , and each of its subvariables are as defined in claim 15; (v) The compound of formula (II) is represented by formula (II-e) 【Chemical 76】 or a pharmaceutically acceptable salt, solvate, hydrate, tautomer, or stereoisomer thereof, wherein A, B, L 1 , L 2 , and each of its subvariables are as described in claim 15, or a pharmaceutically acceptable salt, solvate, hydrate, tautomer, or stereoisomer thereof.

28. 16. The compound of claim 15, or a pharmaceutically acceptable salt, solvate, hydrate, tautomer, or stereoisomer thereof, selected from any one of the compounds shown in Table 2.

29. A pharmaceutical composition comprising a compound according to any one of claims 1 to 28, or a pharmaceutically acceptable salt, solvate, hydrate, tautomer, or stereoisomer thereof, and a pharmaceutically acceptable excipient.

30. The compound is (i) altering a target nucleic acid (e.g., RNA, e.g., pre-mRNA); (ii) binds to a target nucleic acid (e.g., RNA, e.g., pre-mRNA); and / or (iii) stabilizes a target nucleic acid (e.g., an RNA, e.g., a pre-mRNA); 29. A compound according to any one of claims 1 to 28, or a pharmaceutically acceptable salt, solvate, hydrate, tautomer, or stereoisomer thereof, or a pharmaceutical composition comprising said compound and a pharmaceutically acceptable excipient.

31. The compound is (i) increases splicing at a splice site on a target nucleic acid (e.g., an RNA, e.g., a pre-mRNA) by about 0.5%, 1%, 2%, 3%, 4%, 5%, 6%, 7%, 8%, 9%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, or more, as determined, for example, by qPCR; or (ii) reduces splicing at a splice site on a target nucleic acid (e.g., an RNA, e.g., a pre-mRNA) by about 0.5%, 1%, 2%, 3%, 4%, 5%, 6%, 7%, 8%, 9%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, or more, as determined, for example, by qPCR; 29. A compound according to any one of claims 1 to 28, or a pharmaceutically acceptable salt, solvate, hydrate, tautomer, or stereoisomer thereof, or a pharmaceutical composition comprising said compound and a pharmaceutically acceptable excipient.

32. A method for forming a complex comprising a spliceosome component (e.g., a major spliceosome component or a minor spliceosome component), a nucleic acid (e.g., DNA, RNA, e.g., pre-mRNA), and a compound of formula (I), (II), or (III) described herein, the method comprising contacting the nucleic acid (e.g., DNA, RNA, e.g., pre-mRNA) with a compound of formula (I), (II), or (III).

33. A method for altering the higher-order structure of a nucleic acid (e.g., DNA, RNA, e.g., pre-mRNA), comprising contacting the nucleic acid with a compound of formula (I), (II), or (III), or a pharmaceutically acceptable salt or composition thereof.

34. The varying (i) forming a bulge in the nucleic acid; (ii) stabilizing a bulge in the nucleic acid; and / or (iii) reducing bulges in the nucleic acid; 34. The method of claim 33.

35. A composition for treating a disease or disorder in a subject, the composition comprising a compound of formula (I), formula (II), or formula (III), or a pharmaceutically acceptable salt thereof.

36. 36. The composition of claim 35, wherein the disease or disorder comprises a proliferative disease (e.g., cancer, benign neoplasm, or angiogenesis); or a nervous system disease or disorder, an autoimmune disease or disorder, an immunodeficiency disease or disorder, a lysosomal storage disease or disorder, a cardiovascular disease or disorder, a metabolic disease or disorder, a respiratory disease or disorder, a renal disease or disorder, or an infectious disease.

37. A composition for treating a proliferative disease in a subject, the composition comprising a compound of formula (III) and a pharmaceutically acceptable excipient, wherein the compound of formula (III) is 【Hua 77-1】 or a pharmaceutically acceptable salt, solvate, hydrate, tautomer, or stereoisomer thereof, wherein: A and B are each independently a cycloalkyl, heterocyclyl, aryl, or heteroaryl, each of which is selected from one or more R １ optionally substituted with; L ２ is non-existent, C １ ~C ６ - alkylene, C １ ~C ６ -heteroalkylene, -O-, -C(O)-, -N(R ３ ) -, -N(R ３ )C(O)-, or -C(O)N(R ３ )-, where alkylene and heteroalkylene are each independently one or more R ４ optionally substituted with; Each R １ are independently hydrogen, C １ ~C ６ -Alkyl, C ２ ~C ６ -alkenyl, C ２ ~C ６ -alkynyl, C １ ~C ６ -heteroalkyl, C １ ~C ６ -haloalkyl, cycloalkyl, heterocyclyl, aryl, C １ ~C ６ Alkylene-aryl, C １ ~C ６ Alkenylene-aryl, C １ ~C ６ Alkylene-heteroaryl, heteroaryl, halo, cyano, oxo, -OR Ａ , -NR Ｂ R Ｃ , -NR Ｂ C(O)R Ｄ , -NO ２ , —C(O)NR Ｂ R Ｃ , -C(O)R Ｄ , -C(O)OR Ｄ , -SR Ｅ , or -S(O) ｘ R Ｄ wherein each alkyl, alkylene, alkenyl, alkynyl, heteroalkyl, haloalkyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl is selected from one or more R ５ optionally replaced by Two R's １ The groups, together with the atom to which they are attached, form a 3- to 7-membered cycloalkyl, heterocyclyl, aryl, or heteroaryl, where each cycloalkyl, heterocyclyl, aryl, and heteroaryl is selected from one or more R ５ optionally substituted with; Each R ２ are independently １ ~C ６ -Alkyl, C ２ ~C ６ -alkenyl, C ２ ~C ６ -alkynyl, C １ ~C ６ -heteroalkyl, C １ ~C ６ -haloalkyl, halo, cyano, or -OR Ａ and Each R ３ are independently hydrogen, C １ ~C ６ - alkyl, or C １ ~C ６ -haloalkyl; Each R ４ are independently １ ~C ６ -Alkyl, C １ ~C ６ -heteroalkyl, C １ ~C ６ -haloalkyl, cycloalkyl, halo, cyano, oxo, -OR Ａ , -NR Ｂ R Ｃ , -C(O)R Ｄ , or —C(O)OR Ｄ and Each R ５ are independently １ ~C ６ -Alkyl, C ２ ~C ６ -alkenyl, C ２ ~C ６ -alkynyl, C １ ~C ６ -heteroalkyl, C １ ~C ６ -haloalkyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, halo, oxo, cyano, -OR Ａ , -NR Ｂ R Ｃ , -NR Ｂ C(O)R Ｄ , -NO ２ , —C(O)NR Ｂ R Ｃ , -C(O)R Ｄ , -C(O)OR Ｄ , -SR Ｅ , or -S(O) ｘ R Ｄ wherein each alkyl, alkenyl, alkynyl, heteroalkyl, haloalkyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl is selected from one or more R １１ optionally substituted with; Each R ７ are independently １ ~C ６ - alkyl or halo; Each R １１ are independently １ ~C ６ -Alkyl, C １ ~C ６ -heteroalkyl, C １ ~C ６ -haloalkyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, halo, cyano, oxo, or -OR Ａ and Each R Ａ are independently hydrogen, C １ ~C ６ Alkyl, C １ ~C ６ Haloalkyl, aryl, heteroaryl, C １ ~C ６ Alkylene-aryl, C １ ~C ６ Alkylene-heteroaryl, —C(O)R Ｄ , or -S(O) ｘ R Ｄ and R Ｂ and R Ｃ each independently represents hydrogen, C １ ~C ６ -Alkyl, C ２ ~C ６ -alkenyl, C ２ ~C ６ -alkynyl, C １ ~C ６ -heteroalkyl, C １ ~C ６ -haloalkyl, cycloalkyl, heterocyclyl, -OR Ａ wherein each alkyl, heteroalkyl, haloalkyl, cycloalkyl, heterocyclyl is selected from one or more R ７ optionally substituted with; R Ｂ and R Ｃ together with the nitrogen atom to which they are attached form a 3- to 7-membered heterocyclyl or heteroaryl, where each heterocyclyl or heteroaryl is selected from one or more R ７ optionally substituted with; Each R Ｄ and R Ｅ are independently hydrogen, C １ ~C ６ Alkyl, C ２ ~C ６ Alkenyl, C ２ ~C ６ Alkynyl, C １ ~C ６ Heteroalkyl, C １ ~C ６ Haloalkyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, C １ ~C ６ Alkylene-aryl, or C １ ~C ６ alkylene-heteroaryl; m is 0, 1, or 2; x is 0, 1, or 2.

38. administering to the subject a compound of formula (III) 【Hua99】 or a pharmaceutically acceptable salt, solvate, hydrate, tautomer, or stereoisomer thereof, wherein: A and B are each independently a cycloalkyl, heterocyclyl, aryl, or heteroaryl, each of which is selected from one or more R １ optionally substituted with; L ２ is non-existent, C １ ~C ６ - alkylene, C １ ~C ６ -heteroalkylene, -O-, -C(O)-, -N(R ３ ) -, -N(R ３ )C(O)-, or -C(O)N(R ３ )-, where alkylene and heteroalkylene are each independently one or more R ４ optionally substituted with; Each R １ are independently hydrogen, C １ ~C ６ -Alkyl, C ２ ~C ６ -alkenyl, C ２ ~C ６ -alkynyl, C １ ~C ６ -heteroalkyl, C １ ~C ６ -haloalkyl, cycloalkyl, heterocyclyl, aryl, C １ ~C ６ Alkylene-aryl, C １ ~C ６ Alkenylene-aryl, C １ ~C ６ Alkylene-heteroaryl, heteroaryl, halo, cyano, oxo, -OR Ａ , -NR Ｂ R Ｃ , -NR Ｂ C(O)R Ｄ , -NO ２ , —C(O)NR Ｂ R Ｃ , -C(O)R Ｄ , -C(O)OR Ｄ , -SR Ｅ , or -S(O) ｘ R Ｄ wherein each alkyl, alkylene, alkenyl, alkynyl, heteroalkyl, haloalkyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl is selected from one or more R ５ optionally replaced by Two R's １ The groups, together with the atom to which they are attached, form a 3- to 7-membered cycloalkyl, heterocyclyl, aryl, or heteroaryl, where each cycloalkyl, heterocyclyl, aryl, and heteroaryl is selected from one or more R ５ optionally substituted with; Each R ２ are independently １ ~C ６ -Alkyl, C ２ ~C ６ -alkenyl, C ２ ~C ６ -alkynyl, C １ ~C ６ -heteroalkyl, C １ ~C ６ -haloalkyl, halo, cyano, or -OR Ａ and Each R ３ are independently hydrogen, C １ ~C ６ - alkyl, or C １ ~C ６ -haloalkyl; Each R ４ are independently １ ~C ６ -Alkyl, C １ ~C ６ -heteroalkyl, C １ ~C ６ -haloalkyl, cycloalkyl, halo, cyano, oxo, -OR Ａ , -NR Ｂ R Ｃ , -C(O)R Ｄ , or —C(O)OR Ｄ and Each R ５ are independently １ ~C ６ -Alkyl, C ２ ~C ６ -alkenyl, C ２ ~C ６ -alkynyl, C １ ~C ６ -heteroalkyl, C １ ~C ６ -haloalkyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, halo, oxo, cyano, -OR Ａ , -NR Ｂ R Ｃ , -NR Ｂ C(O)R Ｄ , -NO ２ , —C(O)NR Ｂ R Ｃ , -C(O)R Ｄ , -C(O)OR Ｄ , -SR Ｅ , or -S(O) ｘ R Ｄ wherein each alkyl, alkenyl, alkynyl, heteroalkyl, haloalkyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl is selected from one or more R １１ optionally substituted with; Each R ７ are independently １ ~C ６ - alkyl or halo; Each R １１ are independently １ ~C ６ -Alkyl, C １ ~C ６ -heteroalkyl, C １ ~C ６ -haloalkyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, halo, cyano, oxo, or -OR Ａ and Each R Ａ are independently hydrogen, C １ ~C ６ Alkyl, C １ ~C ６ Haloalkyl, aryl, heteroaryl, C １ ~C ６ Alkylene-aryl, C １ ~C ６ Alkylene-heteroaryl, —C(O)R Ｄ , or -S(O) ｘ R Ｄ and R Ｂ and R Ｃ each independently represents hydrogen, C １ ~C ６ -Alkyl, C ２ ~C ６ -alkenyl, C ２ ~C ６ -alkynyl, C １ ~C ６ -heteroalkyl, C １ ~C ６ -haloalkyl, cycloalkyl, heterocyclyl, -OR Ａ wherein each alkyl, heteroalkyl, haloalkyl, cycloalkyl, heterocyclyl is selected from one or more R ７ optionally substituted with; R Ｂ and R Ｃ together with the nitrogen atom to which they are attached form a 3- to 7-membered heterocyclyl or heteroaryl, where each heterocyclyl or heteroaryl is selected from one or more R ７ optionally substituted with; Each R Ｄ and R Ｅ are independently hydrogen, C １ ~C ６ Alkyl, C ２ ~C ６ Alkenyl, C ２ ~C ６ Alkynyl, C １ ~C ６ Heteroalkyl, C １ ~C ６ Haloalkyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, C １ ~C ６ Alkylene-aryl, or C １ ~C ６ alkylene-heteroaryl; m is 0, 1, or 2; x is 0, 1, or 2] for use in treating a proliferative disease in said subject.

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