Compositions and methods for inhibiting DNA mismatch repair, as relevant to treatment of nucleotide repeat expansion disorders

Abstract

Disclosed herein are compounds and methods for inhibiting DNA mismatch repair, for example as relevant to the treatment of nucleotide repeat expansion disorders.

Description

[0001] COMPOSITIONS AND METHODS FOR INHIBITING DNA MISMATCH REPAIR, FOR EXAMPLE, AS RELEVANT TO TREATMENT OF NUCLEOTIDE REPEAT EXPANSION DISORDERS CROSS-REFERENCE TO RELATED APPLICATIONS This application claims the benefit of priority to U.S. Provisional Application No. 63 / 698,777, filed September 25, 2024, which is hereby incorporated herein by reference in its entirety. BACKGROUND The human genome contains over one million short tandem repeats. Expansion of some of these repeat tracts is associated with different human disorders, including amyotrophic lateral sclerosis (ALS) and Huntington disease. Trinucleotide repeats (TNRs), a stretch of three nucleotides repeated multiple times in the DNA sequence can, in particular, undergo expansions. Even though the detailed mechanism for TNR expansions is unknown, it has been proposed that expandable repeats have unusual structural characteristics, including hairpin-like or quadruplex- like structures. There remains a need for improved compositions and methods for treating nucleotide repeat expansion disorders. SUMMARY In accordance with the purposes of the disclosed compositions and methods as embodied and broadly described herein, the disclosed subject matter relates to compositions and methods of use thereof. For example, described herein are compounds and methods for inhibiting DNA mismatch repair, which can, for example, be relevant for the treatment of nucleotide repeat expansion disorders. Additional advantages of the disclosed compositions and methods will be set forth in part in the description which follows, and in part will be obvious from the description. The advantages of the disclosed compositions and methods will be realized and attained by means of the elements and combinations particularly pointed out in the appended claims. It is to be understood that both the foregoing general description and the following detailed description are exemplary and explanatory only and are not restrictive of the disclosed compositions and methods, as claimed. The details of one or more embodiments of the invention are set forth in the accompanying drawings and the description below. Other features, objects, and advantages of the invention will be apparent from the description and drawings, and from the claims. BRIEF DESCRIPTION OF THE FIGURES The accompanying figures, which are incorporated in and constitute a part of this specification, illustrate several aspects of the disclosure, and together with the description, serve to explain the principles of the disclosure. Figure 1 depicts fold change of luminescence in cells transduced by MSH3 / MutSbeta or MSH6 / MutSalpha pegRNA-reporter both-in-one lentivirus (from vectors pYJ269 and pYJ276) at an MOI of ~1.5 and treated with compound M786-2431 according to the disclosure. Figure 2 depicts fold change of luminescence in cells transduced by MSH3 / MutSbeta or MSH6 / MutSalpha pegRNA-reporter both-in-one lentivirus (from vectors pYJ269 and pYJ276) at an MOI of ~1.5 and treated with compound M789-0023 according to the disclosure. Figure 3 depicts fold change of luminescence in cells transduced by MSH3 / MutSbeta or MSH6 / MutSalpha pegRNA-reporter both-in-one lentivirus (from vectors pYJ269 and pYJ276) at an MOI of ~1.5 and treated with compound M789-0030 according to the disclosure. Figure 4 depicts fold change of luminescence in cells transduced by MSH3 / MutSbeta or MSH6 / MutSalpha pegRNA-reporter both-in-one lentivirus (from vectors pYJ269 and pYJ276) at an MOI of ~1.5 and treated with compound M789-0078 according to the disclosure. Figure 5 depicts fold change of luminescence in cells transduced by MSH3 / MutSbeta or MSH6 / MutSalpha pegRNA-reporter both-in-one lentivirus (from vectors pYJ269 and pYJ276) at an MOI of ~1.5 and treated with compound M789-0086 according to the disclosure. Figure 6 depicts fold change of luminescence in cells transduced by MSH3 / MutSbeta or MSH6 / MutSalpha pegRNA-reporter both-in-one lentivirus (from vectors pYJ269 and pYJ276) at an MOI of ~1.5 and treated with compound M789-0080 according to the disclosure. Figure 7 depicts fold change of luminescence in cells transduced by MSH3 / MutSbeta or MSH6 / MutSalpha pegRNA-reporter both-in-one lentivirus (from vectors pYJ269 and pYJ276) at an MOI of ~1.5 and treated with compound M789-0091 according to the disclosure. Figure 8 depicts fold change of luminescence in cells transduced by MSH3 / MutSbeta or MSH6 / MutSalpha pegRNA-reporter both-in-one lentivirus (from vectors pYJ269 and pYJ276) at an MOI of ~1.5 and treated with compound M789-0093 according to the disclosure. Figure 9 depicts fold change of luminescence in cells transduced by MSH3 / MutSbeta or MSH6 / MutSalpha pegRNA-reporter both-in-one lentivirus (from vectors pYJ269 and pYJ276) at an MOI of ~1.5 and treated with compound M789-0096 according to the disclosure. Figure 10 depicts fold change of luminescence in cells transduced by MSH3 / MutSbeta or MSH6 / MutSalpha pegRNA-reporter both-in-one lentivirus (from vectors pYJ269 and pYJ276) at an MOI of ~1.5 and treated with compound M789-0098 according to the disclosure. Figure 11 depicts fold change of luminescence in cells transduced by MSH3 / MutSbeta or MSH6 / MutSalpha pegRNA-reporter both-in-one lentivirus (from vectors pYJ269 and pYJ276) at an MOI of ~1.5 and treated with compound M789-0099 according to the disclosure. Figure 12 depicts fold change of luminescence in cells transduced by MSH3 / MutSbeta or MSH6 / MutSalpha pegRNA-reporter both-in-one lentivirus (from vectors pYJ269 and pYJ276) at an MOI of ~1.5 and treated with compound M789-0640 according to the disclosure. Figure 13 depicts fold change of luminescence in cells transduced by MSH3 / MutSbeta or MSH6 / MutSalpha pegRNA-reporter both-in-one lentivirus (from vectors pYJ269 and pYJ276) at an MOI of ~1.5 and treated with compound M789-0643 according to the disclosure. Figure 14 depicts fold change of luminescence in cells transduced by MSH3 / MutSbeta or MSH6 / MutSalpha pegRNA-reporter both-in-one lentivirus (from vectors pYJ269 and pYJ276) at an MOI of ~1.5 and treated with compound M789-0644 according to the disclosure. Figure 15 depicts fold change of luminescence in cells transduced by MSH3 / MutSbeta or MSH6 / MutSalpha pegRNA-reporter both-in-one lentivirus (from vectors pYJ269 and pYJ276) at an MOI of ~1.5 and treated with compound M789-0648 according to the disclosure. Figure 16 depicts fold change of luminescence in cells transduced by MSH3 / MutSbeta or MSH6 / MutSalpha pegRNA-reporter both-in-one lentivirus (from vectors pYJ269 and pYJ276) at an MOI of ~1.5 and treated with compound M789-0652 according to the disclosure. Figure 17 depicts fold change of luminescence in cells transduced by MSH3 / MutSbeta or MSH6 / MutSalpha pegRNA-reporter both-in-one lentivirus (from vectors pYJ269 and pYJ276) at an MOI of ~1.5 and treated with compound M789-0923 according to the disclosure. Figure 18 depicts fold change of luminescence in cells transduced by MSH3 / MutSbeta or MSH6 / MutSalpha pegRNA-reporter both-in-one lentivirus (from vectors pYJ269 and pYJ276) at an MOI of ~1.5 and treated with compound M789-1055 according to the disclosure. Figure 19 depicts fold change of luminescence in cells transduced by MSH3 / MutSbeta or MSH6 / MutSalpha pegRNA-reporter both-in-one lentivirus (from vectors pYJ269 and pYJ276) at an MOI of ~1.5 and treated with compound M789-1056 according to the disclosure. Figure 20 depicts fold change of luminescence in cells transduced by MSH3 / MutSbeta or MSH6 / MutSalpha pegRNA-reporter both-in-one lentivirus (from vectors pYJ269 and pYJ276) at an MOI of ~1.5 and treated with compound M789-1057 according to the disclosure. Figure 21 depicts fold change of luminescence in cells transduced by MSH3 / MutSbeta or MSH6 / MutSalpha pegRNA-reporter both-in-one lentivirus (from vectors pYJ269 and pYJ276) at an MOI of ~1.5 and treated with compound M789-1059 according to the disclosure. Figure 22 depicts fold change of luminescence in cells transduced by MSH3 / MutSbeta or MSH6 / MutSalpha pegRNA-reporter both-in-one lentivirus (from vectors pYJ269 and pYJ276) at an MOI of ~1.5 and treated with compound M789-1060 according to the disclosure. Figure 23 depicts fold change of luminescence in cells transduced by MSH3 / MutSbeta or MSH6 / MutSalpha pegRNA-reporter both-in-one lentivirus (from vectors pYJ269 and pYJ276) at an MOI of ~1.5 and treated with compound M789-1061 according to the disclosure. Figure 24 depicts fold change of luminescence in cells transduced by MSH3 / MutSbeta or MSH6 / MutSalpha pegRNA-reporter both-in-one lentivirus (from vectors pYJ269 and pYJ276) at an MOI of ~1.5 and treated with compound M789-1062 according to the disclosure. Figure 25 depicts fold change of luminescence in cells transduced by MSH3 / MutSbeta or MSH6 / MutSalpha pegRNA-reporter both-in-one lentivirus (from vectors pYJ269 and pYJ276) at an MOI of ~1.5 and treated with compound M789-1063 according to the disclosure. Figure 26 depicts fold change of luminescence in cells transduced by MSH3 / MutSbeta or MSH6 / MutSalpha pegRNA-reporter both-in-one lentivirus (from vectors pYJ269 and pYJ276) at an MOI of ~1.5 and treated with compound M789-1064 according to the disclosure. Figure 27 depicts fold change of luminescence in cells transduced by MSH3 / MutSbeta or MSH6 / MutSalpha pegRNA-reporter both-in-one lentivirus (from vectors pYJ269 and pYJ276) at an MOI of ~1.5 and treated with compound M789-1065 according to the disclosure. Figure 28 depicts fold change of luminescence in cells transduced by MSH3 / MutSbeta or MSH6 / MutSalpha pegRNA-reporter both-in-one lentivirus (from vectors pYJ269 and pYJ276) at an MOI of ~1.5 and treated with compound M789-1066 according to the disclosure. Figure 29 depicts fold change of luminescence in cells transduced by MSH3 / MutSbeta or MSH6 / MutSalpha pegRNA-reporter both-in-one lentivirus (from vectors pYJ269 and pYJ276) at an MOI of ~1.5 and treated with compound M789-1069 according to the disclosure. Figure 30 depicts fold change of luminescence in cells transduced by MSH3 / MutSbeta or MSH6 / MutSalpha pegRNA-reporter both-in-one lentivirus (from vectors pYJ269 and pYJ276) at an MOI of ~1.5 and treated with compound M789-1071 according to the disclosure. Figure 31 depicts fold change of luminescence in cells transduced by MSH3 / MutSbeta or MSH6 / MutSalpha pegRNA-reporter both-in-one lentivirus (from vectors pYJ269 and pYJ276) at an MOI of ~1.5 and treated with compound M789-1073 according to the disclosure. Figure 32 depicts fold change of luminescence in cells transduced by MSH3 / MutSbeta or MSH6 / MutSalpha pegRNA-reporter both-in-one lentivirus (from vectors pYJ269 and pYJ276) at an MOI of ~1.5 and treated with compound M789-1078 according to the disclosure. Figure 33 depicts fold change of luminescence in cells transduced by MSH3 / MutSbeta or MSH6 / MutSalpha pegRNA-reporter both-in-one lentivirus (from vectors pYJ269 and pYJ276) at an MOI of ~1.5 and treated with compound M789-1079 according to the disclosure. Figure 34 depicts fold change of luminescence in cells transduced by MSH3 / MutSbeta or MSH6 / MutSalpha pegRNA-reporter both-in-one lentivirus (from vectors pYJ269 and pYJ276) at an MOI of ~1.5 and treated with compound M789-2211 according to the disclosure. Figure 35 depicts fold change of luminescence in cells transduced by MSH3 / MutSbeta or MSH6 / MutSalpha pegRNA-reporter both-in-one lentivirus (from vectors pYJ269 and pYJ276) at an MOI of ~1.5 and treated with compound M789-2219 according to the disclosure. Figure 36 depicts fold change of luminescence in cells transduced by MSH3 / MutSbeta or MSH6 / MutSalpha pegRNA-reporter both-in-one lentivirus (from vectors pYJ269 and pYJ276) at an MOI of ~1.5 and treated with compound M789-2220 according to the disclosure. Figure 37 depicts fold change of luminescence in cells transduced by MSH3 / MutSbeta or MSH6 / MutSalpha pegRNA-reporter both-in-one lentivirus (from vectors pYJ269 and pYJ276) at an MOI of ~1.5 and treated with compound M789-2221 according to the disclosure. Figure 38 depicts fold change of luminescence in cells transduced by MSH3 / MutSbeta or MSH6 / MutSalpha pegRNA-reporter both-in-one lentivirus (from vectors pYJ269 and pYJ276) at an MOI of ~1.5 and treated with compound M789-2222 according to the disclosure. Figure 39 depicts fold change of luminescence in cells transduced by MSH3 / MutSbeta or MSH6 / MutSalpha pegRNA-reporter both-in-one lentivirus (from vectors pYJ269 and pYJ276) at an MOI of ~1.5 and treated with compound M789-2223 according to the disclosure. Figure 40 depicts fold change of luminescence in cells transduced by MSH3 / MutSbeta or MSH6 / MutSalpha pegRNA-reporter both-in-one lentivirus (from vectors pYJ269 and pYJ276) at an MOI of ~1.5 and treated with compound M789-2226 according to the disclosure. Figure 41 depicts fold change of luminescence in cells transduced by MSH3 / MutSbeta or MSH6 / MutSalpha pegRNA-reporter both-in-one lentivirus (from vectors pYJ269 and pYJ276) at an MOI of ~1.5 and treated with compound M789-2227 according to the disclosure. Figure 42 depicts fold change of luminescence in cells transduced by MSH3 / MutSbeta or MSH6 / MutSalpha pegRNA-reporter both-in-one lentivirus (from vectors pYJ269 and pYJ276) at an MOI of ~1.5 and treated with compound M789-2231 according to the disclosure. Figure 43 depicts fold change of luminescence in cells transduced by MSH3 / MutSbeta or MSH6 / MutSalpha pegRNA-reporter both-in-one lentivirus (from vectors pYJ269 and pYJ276) at an MOI of ~1.5 and treated with compound M789-2233 according to the disclosure. Figure 44 depicts fold change of luminescence in cells transduced by MSH3 / MutSbeta or MSH6 / MutSalpha pegRNA-reporter both-in-one lentivirus (from vectors pYJ269 and pYJ276) at an MOI of ~1.5 and treated with compound M789-2234 according to the disclosure. Figure 45 depicts fold change of luminescence in cells transduced by MSH3 / MutSbeta or MSH6 / MutSalpha pegRNA-reporter both-in-one lentivirus (from vectors pYJ269 and pYJ276) at an MOI of ~1.5 and treated with compound M789-2236 according to the disclosure. Figure 46 depicts fold change of luminescence in cells transduced by MSH3 / MutSbeta or MSH6 / MutSalpha pegRNA-reporter both-in-one lentivirus (from vectors pYJ269 and pYJ276) at an MOI of ~1.5 and treated with compound M789-2237 according to the disclosure. Figure 47 depicts fold change of luminescence in cells transduced by MSH3 / MutSbeta or MSH6 / MutSalpha pegRNA-reporter both-in-one lentivirus (from vectors pYJ269 and pYJ276) at an MOI of ~1.5 and treated with compound M789-2251_ according to the disclosure. Figure 48 depicts fold change of luminescence in cells transduced by MSH3 / MutSbeta or MSH6 / MutSalpha pegRNA-reporter both-in-one lentivirus (from vectors pYJ269 and pYJ276) at an MOI of ~1.5 and treated with compound HKBA-0001 according to the disclosure. Figure 49 depicts fold change of luminescence in cells transduced by MSH3 / MutSbeta or MSH6 / MutSalpha pegRNA-reporter both-in-one lentivirus (from vectors pYJ269 and pYJ276) at an MOI of ~1.5 and treated with compound HKBA-0002 according to the disclosure. Figure 50 depicts fold change of luminescence in cells transduced by MSH3 / MutSbeta or MSH6 / MutSalpha pegRNA-reporter both-in-one lentivirus (from vectors pYJ269 and pYJ276) at an MOI of ~1.5 and treated with compound HKBA-0003 according to the disclosure. Figure 51 depicts fold change of luminescence in cells transduced by MSH3 / MutSbeta or MSH6 / MutSalpha pegRNA-reporter both-in-one lentivirus (from vectors pYJ269 and pYJ276) at an MOI of ~1.5 and treated with compound M786-2979 according to the disclosure. Figure 52 depicts fold change of luminescence in cells transduced by MSH3 / MutSbeta or MSH6 / MutSalpha pegRNA-reporter both-in-one lentivirus (from vectors pYJ269 and pYJ276) at an MOI of ~1.5 and treated with compound M786-3351 according to the disclosure. DETAILED DESCRIPTION The methods and systems described herein may be understood more readily by reference to the following detailed description of specific aspects of the disclosed subject matter and the Examples included therein. Before the present methods and systems are disclosed and described, it is to be understood that the methods and systems are not limited to specific synthetic methods, specific components, or to particular compositions. It is also to be understood that the terminology used herein is for the purpose of describing particular embodiments only and is not intended to be limiting. Also, throughout this specification, various publications are referenced. The disclosures of these publications in their entireties are hereby incorporated by reference into this application in order to more fully describe the state of the art to which the disclosed matter pertains. The references disclosed are also individually and specifically incorporated by reference herein for the material contained in them that is discussed in the sentence in which the reference is relied upon. General Definitions In this specification and in the claims that follow, reference will be made to a number of terms, which shall be defined to have the following meanings. As used in the specification and the appended claims, the singular forms “a,” “an” and “the” include plural referents unless the context clearly dictates otherwise. Ranges may be expressed herein as from “about” one particular value, and / or to “about” another particular value. When such a range is expressed, another embodiment includes from the one particular value and / or to the other particular value. Similarly, when values are expressed as approximations, by use of the antecedent “about,” it will be understood that the particular value forms another embodiment. It will be further understood that the endpoints of each of the ranges are significant both in relation to the other endpoint, and independently of the other endpoint. “Optional” or “optionally” means that the subsequently described event or circumstance may or may not occur, and that the description includes instances where said event or circumstance occurs and instances where it does not. Throughout the description and claims of this specification, the word “comprise” and variations of the word, such as “comprising” and “comprises,” means “including but not limited to,” and is not intended to exclude, for example, other additives, components, integers or steps. “Exemplary” means “an example of” and is not intended to convey an indication of a preferred or ideal embodiment. “Such as” is not used in a restrictive sense, but for explanatory purposes. “Exemplary” means “an example of” and is not intended to convey an indication of a preferred or ideal embodiment. “Such as” is not used in a restrictive sense, but for explanatory purposes. Values can be expressed herein as an “average” value. “Average” generally refers to the statistical mean value. As used herein, the term "and / or" includes any and all combinations of one or more of the associated listed items. By “substantially” is meant within 5%, e.g., within 4%, 3%, 2%, or 1%. It is understood that throughout this specification the identifiers “first” and “second” are used solely to aid in distinguishing the various components and steps of the disclosed subject matter. The identifiers “first” and “second” are not intended to imply any particular order, amount, preference, or importance to the components or steps modified by these terms. References in the specification and concluding claims to parts by weight of a particular element or component in a composition denotes the weight relationship between the element or component and any other elements or components in the composition or article for which a part by weight is expressed. Thus, in a compound containing 2 parts by weight of component X and 5 parts by weight component Y, X and Y are present at a weight ratio of 2:5, and are present in such ratio regardless of whether additional components are contained in the compound. A weight percent (wt. %) of a component, unless specifically stated to the contrary, is based on the total weight of the formulation or composition in which the component is included. The term “or combinations thereof” as used herein refers to all permutations and combinations of the listed items preceding the term. For example, “A, B, C, or combinations thereof” is intended to include at least one of: A, B, C, AB, AC, BC, or ABC, and if order is important in a particular context, also BA, CA, CB, CBA, BCA, ACB, BAC, or CAB. Continuing with this example, expressly included are combinations that contain repeats of one or more item or term, such as BB, AAA, AB, BBC, AAABCCCC, CBBAAA, CABABB, and so forth. The skilled artisan will understand that typically there is no limit on the number of items or terms in any combination, unless otherwise apparent from the context. Disclosed are components that can be used to perform the disclosed methods and systems. These and other components are disclosed herein, and it is understood that when combinations, subsets, interactions, groups, etc. of these components are disclosed that while specific reference of each various individual and collective combinations and permutation of these may not be explicitly disclosed, each is specifically contemplated and described herein, for all methods and systems. This applies to all aspects of this application including, but not limited to, steps in disclosed methods. Thus, if there are a variety of additional steps that can be performed it is understood that each of these additional steps can be performed with any specific embodiment or combination of embodiments of the disclosed methods. Chemical Definitions Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this invention belongs. The organic moieties mentioned when defining variable positions within the general formulae described herein (e.g., the term “halogen”) are collective terms for the individual substituents encompassed by the organic moiety. The prefix Cn-Cm preceding a group or moiety indicates, in each case, the possible number of carbon atoms in the group or moiety that follows. For example, the term "Cn-Cm " (or “Cn-m”) employed alone or in combination with other terms refers to a hydrocarbon group that may be straight-chain or branched, having n to m carbons. It is understood that the terms Cn-m and Cn-Cm can be used interchangeably and just to show that the specific compound has between n to m carbons. The term “ion,” as used herein, refers to any molecule, portion of a molecule, cluster of molecules, molecular complex, moiety, or atom that contains a charge (positive, negative, or both at the same time within one molecule, cluster of molecules, molecular complex, or moiety (e.g., zwitterions)) or that can be made to contain a charge. Methods for producing a charge in a molecule, portion of a molecule, cluster of molecules, molecular complex, moiety, or atom are disclosed herein and can be accomplished by methods known in the art, e.g., protonation, deprotonation, oxidation, reduction, alkylation, acetylation, esterification, de-esterification, hydrolysis, etc. The term “anion” is a type of ion and is included within the meaning of the term “ion.” An “anion” is any molecule, portion of a molecule (e.g., zwitterion), cluster of molecules, molecular complex, moiety, or atom that contains a net negative charge or that can be made to contain a net negative charge. The term “anion precursor” is used herein to specifically refer to a molecule that can be converted to an anion via a chemical reaction (e.g., deprotonation). The term “cation” is a type of ion and is included within the meaning of the term “ion.” A “cation” is any molecule, portion of a molecule (e.g., zwitterion), cluster of molecules, molecular complex, moiety, or atom, that contains a net positive charge or that can be made to contain a net positive charge. The term “cation precursor” is used herein to specifically refer to a molecule that can be converted to a cation via a chemical reaction (e.g., protonation or alkylation). "Zwitterionic" or "zwitterion" as used herein refers to a neutral molecule with a positive (or cationic) and a negative (or anionic) electrical charge at different locations within the same molecule. As used herein, the term “substituted” means that a hydrogen atom is removed and replaced by a substituent. It is contemplated to include all permissible substituents of organic compounds. As used herein, the phrase "optionally substituted" means unsubstituted or substituted. It is to be understood that substitution at a given atom is limited by valency. In a broad aspect, the permissible substituents include acyclic and cyclic, branched and unbranched, carbocyclic and heterocyclic, and aromatic and nonaromatic substituents of organic compounds. Illustrative substituents include, for example, those described below. The permissible substituents can be one or more and the same or different for appropriate organic compounds. For purposes of this disclosure, the heteroatoms, such as nitrogen, can have hydrogen substituents and / or any permissible substituents of organic compounds described herein which satisfy the valencies of the heteroatoms. This disclosure is not intended to be limited in any manner by the permissible substituents of organic compounds. Also, the terms “substitution” or “substituted with” include the implicit proviso that such substitution is in accordance with permitted valence of the substituted atom and the substituent, and that the substitution results in a stable compound, e.g., a compound that does not spontaneously undergo transformation such as by rearrangement, cyclization, elimination, etc. In still further aspects, it is understood that when the disclosure describes a group being substituted, it means that the group is substituted with one or more (i.e., 1, 2, 3, 4, or 5) groups as allowed by valence selected from alkyl, halogenated alkyl, alkoxy, alkenyl, alkynyl, aryl, heteroaryl, aldehyde, amino, carboxylic acid, ester, ether, halide, hydroxy, ketone, nitro, silyl, sulfo-oxo, sulfonyl, sulfone, sulfoxide, or thiol, as described below. The term "compound," as used herein, is meant to include all stereoisomers, geometric isomers, tautomers, and isotopes of the structures depicted. Compounds herein identified by name or structure as one particular tautomeric form are intended to include other tautomeric forms unless otherwise specified. Compounds provided herein can also include tautomeric forms. Tautomeric forms result from the swapping of a single bond with an adjacent double bond together with the concomitant migration of a proton. Tautomeric forms include prototropic tautomers, which are isomeric protonation states having the same empirical formula and total charge. Example prototropic tautomers include ketone - enol pairs, amide - imidic acid pairs, lactam - lactim pairs, enamine - imine pairs, and annular forms where a proton can occupy two or more positions of a heterocyclic system, for example, 1H- and 3H-imidazole, 1H-, 2H- and 4H-1,2,4-triazole, 1H- and 2H- isoindole, and 1H- and 2H-pyrazole. Tautomeric forms can be in equilibrium or sterically locked into one form by appropriate substitution. Compounds provided herein can also include all isotopes of atoms occurring in the intermediates or final compounds. Isotopes include those atoms having the same atomic number but different mass numbers. For example, isotopes of hydrogen include hydrogen, tritium, and deuterium. Compounds disclosed herein may be provided in the form of acceptable salts, for example pharmaceutically acceptable salts. Examples of such salts are acid addition salts formed with inorganic acids, for example, hydrochloric, hydrobromic, sulfuric, phosphoric, and nitric acids and the like; salts formed with organic acids such as acetic, oxalic, tartaric, succinic, maleic, fumaric, gluconic, citric, malic, methanesulfonic, p-toluenesulfonic, napthalenesulfonic, and polygalacturonic acids, and the like; salts formed from elemental anions such as chloride, bromide, and iodide; salts formed from metal hydroxides, for example, sodium hydroxide, potassium hydroxide, calcium hydroxide, lithium hydroxide, and magnesium hydroxide; salts formed from metal carbonates, for example, sodium carbonate, potassium carbonate, calcium carbonate, and magnesium carbonate; salts formed from metal bicarbonates, for example, sodium bicarbonate and potassium bicarbonate; salts formed from metal sulfates, for example, sodium sulfate and potassium sulfate; and salts formed from metal nitrates, for example, sodium nitrate and potassium nitrate. As used herein, chemical structures that contain one or more stereocenters depicted with dashed and bold bonds are meant to indicate the absolute stereochemistry of the stereocenter(s) present in the chemical structure. As used herein, bonds symbolized by a simple line do not indicate a stereo-preference. Unless otherwise indicated to the contrary, chemical structures, which include one or more stereocenters, illustrated herein without indicating absolute or relative stereochemistry encompass all possible stereoisomeric forms of the compound (e.g., diastereomers and enantiomers) and mixtures thereof. Structures with a single bold or dashed line and at least one additional simple line encompass a single enantiomeric series of all possible diastereomers. The terms for various functional groups as used herein are not intended to be limited to monovalent radicals and may include polyvalent radical groups as appropriate, such as divalent, trivalent, tetravalent, pentavalent, and hexavalent groups, and the like, based on the position and location of such groups in the compounds described herein as would be readily understood by the skilled person. “Z1,” “Z2,” “Z3,” and “Z4” are used herein as generic symbols to represent various specific substituents. These symbols can be any substituent, not limited to those disclosed herein, and when they are defined to be certain substituents in one instance, they can, in another instance, be defined as some other substituents. A dash ("-") that is not between two letters or symbols is used to indicate a point of attachment for a substituent. For example, -(C=O)NH2is attached through the carbon of the keto (C=O) group. The term “aliphatic” as used herein refers to a non-aromatic hydrocarbon group and includes branched and unbranched, alkyl, alkenyl, or alkynyl groups. The term "alkyl" refers to a radical of a straight-chain or branched hydrocarbon group having a specified range of carbon atoms (e.g., a "C1-16 alkyl" can have from 1 to 16 carbon atoms). An alkyl group can be a saturated alkyl group or an unsaturated alkyl group, i.e., an alkyl group having one or more carbon-carbon double or triple bonds, i.e., an alkenyl or alkynyl group. Unless specified to the contrary, an “alkyl” group includes both saturated alkyl groups and unsaturated alkyl groups. The term "heteroalkyl" refers to an alkyl group, which further includes at least one heteroatom (e.g., 1, 2, 3, or 4 heteroatoms) selected from oxygen, nitrogen, or sulfur within (i.e., inserted between adjacent carbon atoms of) and / or placed at one or more terminal position(s) of the parent chain. By way of example, a heteroC1-6alkyl (which may also be designated a C1-6heteroalkyl) group includes, but is not limited to, the following structures: The term “heteroalkyl” preceded by a separate heteroatom refers to a heteroalkyl group bonded through the specified heteroatom. By way of example, a OC1-6heteroalkyl group includes, but not limited to, the following structures: O When a range of values is listed, it is intended to encompass each value and sub-range within the range. For example, "C1-6alkyl" is intended to encompass C1, C2, C3, C4, C5, C6, C1-6, C1-5, C1-4, C1-3, C1-2, C2-6, C2-5, C2-4, C2-3, C3-6, C3-5, C3-4, C4-6, C4-5, and C5-6 alkyl. Affixing the suffix "-ene" to a group indicates the group is a polyvalent moiety, e.g., boned to two or more groups. Alkylene is the polyvalent moiety of alkyl, alkenylene is the divalent moiety of alkenyl, alkynylene is the divalent moiety of alkynyl, heteroalkylene is the divalent moiety of heteroalkyl, heteroalkenylene is the divalent moiety of heteroalkenyl, heteroalkynylene is the divalent moiety of heteroalkynyl, carbocyclylene is the divalent moiety of carbocyclyl, heterocyclylene is the divalent moiety of heterocyclyl, arylene is the divalent moiety of aryl, and heteroarylene is the divalent moiety of heteroaryl (each of which parent groups as defined herein). The term "alkoxy" refers to an alkyl group, as defined herein, appended to the parent molecular moiety through an oxygen atom. The term "aryl" refers to a radical of a monocyclic or polycyclic (e.g., bicyclic or tricyclic) 4n+2 aromatic ring system (e.g., having 6, 10, or 14 π electrons shared in a cyclic array) having 6-14 ring carbon atoms and zero heteroatoms provided in the aromatic ring system ("C6-14aryl"). "Aryl" also includes ring systems wherein the aryl ring, as defined above, is fused with one or more carbocyclyl or heterocyclyl groups wherein the radical or point of attachment is on the aryl ring, and in such instances, the number of carbon atoms continue to designate the number of carbon atoms in the aryl ring system. Unless otherwise specified, each instance of an aryl group is independently unsubstituted (an "unsubstituted aryl") or substituted (a "substituted aryl") with one or more substituents. "Aralkyl" is a subset of "alkyl" and refers to an alkyl group substituted by an aryl group, wherein the point of attachment is on the alkyl moiety. The term "heteroaryl" refers to a radical of a 5-14 membered monocyclic or polycyclic (e.g., bicyclic, tricyclic) 4n+2 aromatic ring system (e.g., having 6, 10, or 14 π electrons shared in a cyclic array) having ring carbon atoms and 1-4 ring heteroatoms provided in the aromatic ring system, wherein each heteroatom is independently selected from nitrogen, oxygen, and sulfur ("5-14 membered heteroaryl"). In heteroaryl groups that contain one or more nitrogen atoms, the point of attachment can be a carbon or nitrogen atom, as valency permits. Heteroaryl polycyclic ring systems can include one or more heteroatoms in one or both rings. "Heteroaryl" includes ring systems wherein the heteroaryl ring, as defined above, is fused with one or more carbocyclyl or heterocyclyl groups wherein the point of attachment is on the heteroaryl ring, and in such instances, the number of ring members continue to designate the number of ring members in the heteroaryl ring system. "Heteroaryl" also includes ring systems wherein the heteroaryl ring, as defined above, is fused with one or more aryl groups wherein the point of attachment is either on the aryl or heteroaryl ring, and in such instances, the number of ring members designates the number of ring members in the fused polycyclic (aryl / heteroaryl) ring system. Polycyclic heteroaryl groups wherein one ring does not contain a heteroatom (e.g., indolyl, quinolinyl, carbazolyl, and the like) the point of attachment can be on either ring, i.e., either the ring bearing a heteroatom (e.g., 2-indolyl) or the ring that does not contain a heteroatom (e.g., 5-indolyl). Exemplary heteroaryl and heterocyclyl rings include: benzimidazolyl, benzofuranyl, benzothiofuranyl, benzothiophenyl, benzoxazolyl, benzoxazolinyl, benzthiazolyl, benztriazolyl, benztetrazolyl, benzisoxazolyl, benzisothiazolyl, benzimidazolinyl, carbazolyl, 4aH carbazolyl, carbolinyl, chromanyl, chromenyl, cirrnolinyl, decahydroquinolinyl, 2H,6H~ 1,5,2-dithiazinyl, dihydrofuro[2,3 b]tetrahydrofuran, furanyl, furazanyl, imidazolidinyl, imidazolinyl, imidazolyl, 1H-indazolyl, indolenyl, indolinyl, indolizinyl, indolyl, 3H-indolyl, isatinoyl, isobenzofuranyl, isochromanyl, isoindazolyl, isoindolinyl, isoindolyl, isoquinolinyl, isothiazolyl, isoxazolyl, methylenedioxyphenyl, morpholinyl, naphthyridinyl, octahydroisoquinolinyl, oxadiazolyl, 1,2,3- oxadiazolyl, 1,2,4-oxadiazolyl, 1,2,5-oxadiazolyl, 1,3,4-oxadiazolyl, oxazolidinyl, oxazolyl, oxindolyl, pyrimidinyl, phenanthridinyl, phenanthrolinyl, phenazinyl, phenothiazinyl, phenoxathinyl, phenoxazinyl, phthalazinyl, piperazinyl, piperidinyl, piperidonyl, 4-piperidonyl, piperonyl, pteridinyl, purinyl, pyranyl, pyrazinyl, pyrazolidinyl, pyrazolinyl, pyrazolyl, pyridazinyl, pyridooxazole, pyridoimidazole, pyridothiazole, pyridinyl, pyridyl, pyrimidinyl, pyrrolidinyl, pyrrolinyl, 2H-pyrrolyl, pyrrolyl, quinazolinyl, quinolinyl, 4H-quinolizinyl, quinoxalinyl, quinuclidinyl, tetrahydrofuranyl, tetrahydroisoquinolinyl, tetrahydroquinolinyl, tetrazolyl, 6H-1,2,5-thiadiazinyl, 1,2,3-thiadiazolyl, 1,2,4-thiadiazolyl, 1,2,5-thiadiazolyl, 1,3,4- thiadiazolyl, thianthrenyl, thiazolyl, thienyl, thienothiazolyl, thienooxazolyl, thienoimidazolyl, thiophenyl, and xanthenyl. Unless specified to the contrary, the alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, heteroalkynyl, carbocyclyl, heterocyclyl, aryl, and heteroaryl groups defined herein (and the “ene” versions of said groups) may be substituted or unsubstituted. A substituted group includes a non-hydrogen substituent at a position where in the unsubstituted version a hydrogen atom would be found. Substituents include, but are not limited to, halogen, hydroxy, alkyl, alkoxy, nitro, cyano, oxo, carbocyclyl, carbocycloalkyl, heterocarbocyclyl, heterocarbocycloalkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, -NRaRb, -NRaC(=O)Rb, -NRaC(=O)NRaNRb, - NRaC(=O)ORb, - NRaSO2Rb, -C(=O)Ra, -C(=O)ORa, -C(=O)NRaRb, -OC(=O)NRaRb, -ORa, - SRa, -SORa, - S(=O)2Ra, -OS(=O)2Raand -S(=O)2ORa. Raand Rbin this context can be the same or different and independently hydrogen, halogen, hydroxyl, alkyl, alkoxy, alkyl, amino, alkylamino, dialkylamino, carbocyclyl, carbocycloalkyl, heterocarbocyclyl, heterocarbocycloalkyl, aryl, arylalkyl, heteroaryl, or heteroarylalkyl. As used herein, the designation of a polyvalent moiety without specifying the specific order of attachment is intended to cover all possible arrangements. By way of example, a compound represented by the formula: A-X-B, wherein X is NHC(=O) embraces both: A As used he rein, a chemical bond depicted: represents either a single, dou le, or triplebond, valency permitting. By way of example, Some compounds disclosed herein may exist as one or more tautomers. Tautomers are interconvertible structural isomers that differ in the position of one or more protons or other labile atom. By way of example: Unless stated to the contrary, a substituent drawn without explicitly specifying the point of attachment indicates that the substituent may be attached at any possible atom. For example, in a benzofuran depicted: the substituent may be present at any one of the six possible carbon atoms. As used herein, the term “null,” when referring to a possible identity of a chemical moiety, indicates that the group is absent, and the two adjacent groups are directly bonded to one another. By way of example, for a genus of compounds having the formula CH3-X-CH3, if X is null, then the resulting compound has the formula CH3-CH3. A group having the subscript ‘0’ is understood to represent a null group as well. By way of example, in the compound CH3-(X)z- CH3, if X is CH2and z is 0, then the compound has the formula CH3-CH3. In certain instances, two or more variable groups may together form a ring. It is understood that any depicted atoms separated the identified groups will themselves form part of the ring: When the variable groups are substituted on an aromatic system the new ring will be a fused ring, and unless specified to the contrary may be either aromatic or non-aromatic, carbocyclic or heterocyclic: The ring may further be defined by the number of carbon atoms in the specific ring formed by the variable groups, which includes the atoms separating the variable groups: R1and R2form a C6cycloalkylC6aryl C5heterocyclylC5heteroaryl Each of the above results when R1and R2together form a six membered (or six atom) ring. Other rings, including 3, 4, 5, 7, and 8-member rings may also be formed, and may be further limited by a specified number of carbon atoms. Although the singular “a ring” may be used to define the group unless specified to the contrary both monocyclic and polycyclic rings Unless stated to the contrary, a formula with chemical bonds shown only as solid lines and not as wedges or dashed lines contemplates each possible isomer, e.g., each enantiomer, diastereomer, and meso compound, and a mixture of isomers, such as a racemic or scalemic mixture. Unless stated to the contrary, a formula depicting one or more stereochemical features does not exclude the presence of other isomers. Some compounds disclosed herein may exist as one or more tautomers. Tautomers are interconvertible structural isomers that differ in the position of one or more protons or other labile atom. By way of example: The prevalence of one tautomeric form over another will depend on the specific chemical compound as well as its local chemical environment. Unless specified to the contrary, the depiction of one tautomeric form is inclusive of all possible tautomeric forms. Compounds and Methods Disclosed herein are compounds and methods. In some examples, the compounds and methods disclosed herein are for inhibiting DNA mismatch repair. In some examples, the compounds and methods disclosed herein are for inhibiting DNA mismatch repair, as relevant to strategies for treating a nucleotide repeat expansion disorder in a subject in need thereof. In some examples, the methods comprise administering to the subject a MSH3 / MutSbeta-inhibiting compound. For example, disclosed herein are methods of inhibiting DNA mismatch repair, for example as relevant to treating a nucleotide repeat expansion disorder, in a subject in need thereof, the methods comprising administering to the subject a MSH3 / MutSbeta-inhibiting compound. In some examples, disclosed herein are compounds and methods for treating a nucleotide repeat expansion disorder in a subject in need thereof by administering to the subject a MSH3 / MutSbeta-inhibiting compound. In certain implementations the compound has the formula: o r a pharmaceutically acceptable salt thereof, wherein: X1is C-R1xor N; X2is C-R2xor N; X3is C-R3xor N; X4is C-R4xor N; provided that no more than two of X1, X2, X3, and X4are N; R1xis H, F, Cl, Br, X1*R1x*, wherein X1*is null, O, NH, SO2, C(=O), OC(=O), NHC(=O), or (CH2)nwherein n is 1-4; and R1x*is H, OH, NH2, aryl, C6-10aryl, C1-10heteroaryl, C3-8cycloalkyl, C1-8heterocyclyl; C1-6alkyl, or C1-6heteroalkyl; R2xis H, F, Cl, Br, X2*R2x*, wherein X2*is null, O, NH, SO2, C(=O), OC(=O), NHC(=O), or (CH2)nwherein n is 1-4; and R2x*is H, OH, NH2, aryl, C6-10aryl, C1-10heteroaryl, C3- 8cycloalkyl, C1-8heterocyclyl; C1-6alkyl, or C1-6heteroalkyl; R3xis H, F, Cl, Br, X3*R3x*, wherein X3*is null, O, NH, SO2, C(=O), OC(=O), NHC(=O), or (CH2)nwherein n is 1-4; and R3x*is H, OH, NH2, aryl, C6-10aryl, C1-10heteroaryl, C3-8cycloalkyl, C1-8heterocyclyl; C1-6alkyl, or C1-6heteroalkyl; R4xis H, F, Cl, Br, X4*R4x*, wherein X4*is null, O, NH, SO2, C(=O), OC(=O), NHC(=O), or (CH2)nwherein n is 1-4; and R4x*is H, OH, NH2, aryl, C6-10aryl, C1-10heteroaryl, C3-8cycloalkyl, C1-8heterocyclyl; C1-6alkyl, or C1-6heteroalkyl; wherein any two or more of R1x, R2x, R3x, and R4amay together form a ring; R1is –(CH2)nC≡N, –(CH2)n–C6-10aryl, C6-10aryl, or C1-10heteroaryl, where n is 1-4; R1Nis XaC1-8alkyl, XaC1-8heteroalkyl, XaC1-8cycloalkyl, XaC6-10aryl, or XaC1-10heteroaryl, wherein Xais null or C1 alkylene; and R2N-4 is H; or R1Nand R2N, together with the nitrogen atom to which they are attached, form a C3-10heterocyclyl. or a pharmaceutically acceptable salt thereof, wherein: X1is C-R1xor N; X2is C-R2xor N; X3is C-R3xor N; X4is C-R4xor N; provided that no more than two of X1, X2, X3, and X4are N; R1xis H, F, Cl, Br, X1*R1x*, wherein X1*is null, O, NH, SO2, C(=O), OC(=O), NHC(=O), or (CH2) wherein n is 1-4; and R1x*n is H, OH, NH2, aryl, C6-10aryl, C1-10heteroaryl, C3- 8cycloalkyl, C1-8heterocyclyl; C1-6alkyl, or C1-6heteroalkyl; R2xis H, F, Cl, Br, X2*R2x*, wherein X2*is null, O, NH, SO2, C(=O), OC(=O), NHC(=O), or (CH2) wherein n is 1-4; and R2x*n is H, OH, NH2, aryl, C6-10aryl, C1-10heteroaryl, C3- 8cycloalkyl, C1-8heterocyclyl; C1-6alkyl, or C1-6heteroalkyl; R3xis H, F, Cl, Br, X3*R3x*, wherein X3*is null, O, NH, SO2, C(=O), OC(=O), NHC(=O), or (CH2)nwherein n is 1-4; and R3x*is H, OH, NH2, aryl, C6-10aryl, C1-10heteroaryl, C3-8cycloalkyl, C1-8heterocyclyl; C1-6alkyl, or C1-6heteroalkyl; R4xis H, F, Cl, Br, X4*R4x*, wherein X4*is null, O, NH, SO2, C(=O), OC(=O), NHC(=O), or (CH2) wherein n is 1-4; and R4x*n is H, OH, NH2, aryl, C6-10aryl, C1-10heteroaryl, C3- 8cycloalkyl, C1-8heterocyclyl; C1-6alkyl, or C1-6heteroalkyl; wherein any two or more of R1x, R2x, R3x, and R4amay together form a ring; R1is –(CH2)–C≡N, –(CH2)–C6-10aryl, C6-10aryl, or C1-10heteroaryl; R1Nis XaC1-8alkyl, XaC1-8heteroalkyl, XaC1-8cycloalkyl, XaC6-10aryl, or XaC1-10heteroaryl, wherein Xais null or C1-4alkylene; and R2Nis H; or R1Nand R2N, together with the nitrogen atom to which they are attached, form a C3- 10heterocyclyl. or a pharmaceutically acceptable salt thereof, wherein: X1is C-R1xor N; X2is C-R2xor N; X3is C-R3xor N; X4is C-R4xor N; provided that no more than two of X1, X2, X3, and X4are N; R1xis H, F, Cl, Br, X1*R1x*, wherein X1*is null, O, NH, SO2, C(=O), OC(=O), NHC(=O), or (CH2)nwherein n is 1-4; and R1x*is H, OH, NH2, aryl, C6-10aryl, C1-10heteroaryl, C3-8cycloalkyl, C1-8heterocyclyl; C1-6alkyl, or C1-6heteroalkyl; R2xis H, F, Cl, Br, X2*R2x*, wherein X2*is null, O, NH, SO2, C(=O), OC(=O), NHC(=O), or (CH2) wherein n is 1-4; and R2x*n is H, OH, NH2, aryl, C6-10aryl, C1-10heteroaryl, C3- 8cycloalkyl, C1-8heterocyclyl; C1-6alkyl, or C1-6heteroalkyl; R3xis H, F, Cl, Br, X3*R3x*, wherein X3*is null, O, NH, SO2, C(=O), OC(=O), NHC(=O), or (CH2) wherein n is 1-4; and R3x*n is H, OH, NH2, aryl, C6-10aryl, C1-10heteroaryl, C3- 8cycloalkyl, C1-8heterocyclyl; C1-6alkyl, or C1-6heteroalkyl; R4xis H, F, Cl, Br, X4*R4x*, wherein X4*is null, O, NH, SO2, C(=O), OC(=O), NHC(=O), or (CH2)nwherein n is 1-4; and R4x*is H, OH, NH2, aryl, C6-10aryl, C1-10heteroaryl, C3-8cycloalkyl, C1-8heterocyclyl; C1-6alkyl, or C1-6heteroalkyl; wherein any two or more of R1x, R2x, R3x, and R4amay together form a ring; R1is C6-10aryl or C1-10heteroaryl; R1Nis XaC1-8alkyl, XaC1-8heteroalkyl, XaCa1-8cycloalkyl, XC6-10aryl, or XaC1-10heteroaryl, wherein Xais null or C21-4alkylene; and RNis H; or R1Nand R2N, together with the nitrogen atom to which they are attached, form a C3-10heterocyclyl. wherein: R1xis H, F, Cl, C1-3alkyl, C1-3haloalkyl, C1-3alkoxy, or C1-3haloalkoxy; R1xis H, F, Cl, C1-3alkyl, C1-3haloalkyl, C1-3alkoxy, or C1-3haloalkoxy; and R3xis H, F, Cl, C1-3alkyl, C1-3haloalkyl, C1-3alkoxy, or C1-3haloalkoxy. In some implementations, R1xand R3xare each H; in some implementations, R1x, R2x, and R3xare each H. In some implementations, R1has the formula:

[0002] wherein RNis in each case independently selected from H or C1-3alkyl; R1ais H, F, Cl, Br, Xa1R1a*, wherein Xa1is null, O, NH, SO2, C(=O), OC(=O), NHC(=O), or (CH2)nwherein n is 1-4; and R1a*is H, OH, NH2, NH(C1-3alkyl), N(C1-3alkyl)2, C6-10aryl, C1-10heteroaryl, C3-8cycloalkyl, C1-8heterocyclyl, C1-6alkyl, or C1-6heteroalkyl; R1bis H, F, Cl, Br, Xb1R1b*, wherein Xb1is null, O, NH, SO2, C(=O), OC(=O), NHC(=O), or (CH2)nwherein n is 1-4; and R1b*is H, OH, NH2, NH(C1-3alkyl), N(C1-3alkyl)2, C6-10aryl, C1-10heteroaryl, C3-8cycloalkyl, C1-8heterocyclyl, C1-6alkyl, or C1-6heteroalkyl; R1cis H, F, Cl, Br, Xc1R1c*, wherein Xc1is null, O, NH, SO2, C(=O), OC(=O), NHC(=O), or (CH2)nwherein n is 1-4; and Rc1*is H, OH, NH2, NH(C1-3alkyl), N(C1-3alkyl)2, C6-10aryl, C1-10heteroaryl, C3-8cycloalkyl, C1-8heterocyclyl, C1-6alkyl, or C1-6heteroalkyl; R1dis H, F, Cl, Br, Xd1R1d*, wherein Xd1is null, O, NH, SO2, C(=O), OC(=O), NHC(=O), or (CH2) wherein n is 1-4; and R1d*n is H, OH, NH2, NH(C1-3alkyl), N(C1-3alkyl)2, C6-10aryl, C1- 10heteroaryl, C3-8cycloalkyl, C1-8heterocyclyl, C1-6alkyl, or C1-6heteroalkyl; R1eis H, F, Cl, Br, Xe1R1e*, wherein Xe1is null, O, NH, SO2, C(=O), OC(=O), NHC(=O), or (CH2) wherein n is 1-4; and R1e*n is H, OH, NH2, NH(C1-3alkyl), N(C1-3alkyl)2, C6-10aryl, C1- 10heteroaryl, C3-8cycloalkyl, C1-8heterocyclyl, C1-6alkyl, or C1-6heteroalkyl; wherein any two or more of R1a, R1b, R1c, R1d, and R1emay together form a ring In some implementations, R1has the formula:

[0003] wherein RNis in each case independently selected from H or C1-3alkyl; R1ais H, F, Cl, Br, Xa1R1a*, wherein Xa1is null, O, NH, SO2, C(=O), OC(=O), NHC(=O), or (CH2) wherein n is 1-4; and R1a*n is H, OH, NH2, NH(C1-3alkyl), N(C1-3alkyl)2, C6-10aryl, C1- 10heteroaryl, C3-8cycloalkyl, C1-8heterocyclyl, C1-6alkyl, or C1-6heteroalkyl; R1bis H, F, Cl, Br, Xb1R1b*, wherein Xb1is null, O, NH, SO2, C(=O), OC(=O), NHC(=O), or (CH2) wherein n is 1-4; and R1b*n is H, OH, NH2, NH(C1-3alkyl), N(C1-3alkyl)2, C6-10aryl, C1- 10heteroaryl, C3-8cycloalkyl, C1-8heterocyclyl, C1-6alkyl, or C1-6heteroalkyl; R1cis H, F, Cl, Br, Xc1R1c*, wherein Xc1is null, O, NH, SO2, C(=O), OC(=O), NHC(=O), or (CH2) wherein n is 1-4; and Rc1*n is H, OH, NH2, NH(C1-3alkyl), N(C1-3alkyl)2, C6-10aryl, C1- 10heteroaryl, C3-8cycloalkyl, C1-8heterocyclyl, C1-6alkyl, or C1-6heteroalkyl; R1dis H, F, Cl, Br, Xd1R1d*, wherein Xd1is null, O, NH, SO2, C(=O), OC(=O), NHC(=O), or (CH2)nwherein n is 1-4; and R1d*is H, OH, NH2, NH(C1-3alkyl), N(C1-3alkyl)2, C6-10aryl, C1-10heteroaryl, C3-8cycloalkyl, C1-8heterocyclyl, C1-6alkyl, or C1-6heteroalkyl; R1eis H, F, Cl, Br, Xe1R1e*, wherein Xe1is null, O, NH, SO2, C(=O), OC(=O), NHC(=O), or (CH2) wherein n is 1-4; and R1e*n is H, OH, NH2, NH(C1-3alkyl), N(C1-3alkyl)2, C6-10aryl, C1- 10heteroaryl, C3-8cycloalkyl, C1-8heterocyclyl, C1-6alkyl, or C1-6heteroalkyl; wherein any two or more of R1a, R1b, R1c, R1d, and R1emay together form a ring. In some implementations, the compound has the formula: In certain implementations, R1a, R1b, R1d, and R1eare each H. In some implementations, R1cis H, F, Cl, C1-3alkyl, C1-3haloalkyl, C1-3alkoxy, or C1- 3haloalkoxy, in further implementations, R1cis H, F, Cl, CH3, or CF3. In some implementations, the compound has the formula: In some implementations, R2Nis H and R1Nis (CRq2)zR3, wherein Rqis independently selected from H and CH3, z is 1-3, and R3is C6-10aryl or C1-10heteroaryl. In some implementations, R3has the formula:

[0004] wherein R3Nis in each case independently selected from H or C1-3alkyl; R3ais H, F, Cl, Br, Xa3R3a*, wherein Xa3is null, O, NH, SO2, C(=O), OC(=O), NHC(=O), or (CH2)nwherein n is 1-4; and R3a*is H, OH, NH2, NH(C1-3alkyl), N(C1-3alkyl)2, C6-10aryl, C1-10heteroaryl, C3-8cycloalkyl, C1-8heterocyclyl, C1-6alkyl, or C1-6heteroalkyl; R3bis H, F, Cl, Br, Xb3R3b*, wherein Xb3is null, O, NH, SO2, C(=O), OC(=O), NHC(=O), or (CH2)nwherein n is 1-4; and R3b*is H, OH, NH2, NH(C1-3alkyl), N(C1-3alkyl)2, C6-10aryl, C1-10heteroaryl, C3-8cycloalkyl, C1-8heterocyclyl, C1-6alkyl, or C1-6heteroalkyl; R3cis H, F, Cl, Br, Xc3R3c*, wherein Xc3is null, O, NH, SO2, C(=O), OC(=O), NHC(=O), or (CH2)nwherein n is 1-4; and Rc3*is H, OH, NH2, NH(C1-3alkyl), N(C1-3alkyl)2, C6-10aryl, C1-10heteroaryl, C3-8cycloalkyl, C1-8heterocyclyl, C1-6alkyl, or C1-6heteroalkyl; R3dis H, F, Cl, Br, Xd3R3d*, wherein Xd3is null, O, NH, SO2, C(=O), OC(=O), NHC(=O), or (CH2)nwherein n is 1-4; and R3d*is H, OH, NH2, NH(C1-3alkyl), N(C1-3alkyl)2, C6-10aryl, C1-10heteroaryl, C3-8cycloalkyl, C1-8heterocyclyl, C1-6alkyl, or C1-6heteroalkyl; R3eis H, F, Cl, Br, Xe3R3e*, wherein Xe3is null, O, NH, SO2, C(=O), OC(=O), NHC(=O), or (CH2) wherein n is 1-4; and R3e*n is H, OH, NH2, NH(C1-3alkyl), N(C1-3alkyl)2, C6-10aryl, C1- 10heteroaryl, C3-8cycloalkyl, C1-8heterocyclyl, C1-6alkyl, or C1-6heteroalkyl; wherein any two or more of R3a, R3b, R3c, R3d, and R3emay together form a ring. In certain implementations, R3has the formula: In certain implementations, R3ais H, F, Cl, C1-3alkyl, N(C1-3alkyl)2, C1-3haloalkyl, C1- 3alkoxy, or C1-3haloalkoxy, preferably H, F, Cl, CH3, OCH3, or N(CH3)2. In certain implementations, R3bis H, F, Cl, C1-3alkyl, N(C1-3alkyl)2, C1-3haloalkyl, C1-3alkoxy, or C1-3haloalkoxy, preferably H, F, Cl, CH3, OCH3, or N(CH3)2. In certain implementations, R3cis H, F, Cl, C1-3alkyl, N(C1-3alkyl)2, C1-3haloalkyl, C1- 3alkoxy, or C1-3haloalkoxy, preferably H, F, Cl, CH3, OCH3, or N(CH3)2. In certain implementations, R3dis H, F, Cl, C1-3alkyl, N(C1-3alkyl)2, C1-3haloalkyl, C1-3alkoxy, or C1-3haloalkoxy, preferably H, F, Cl, CH3, OCH3, or N(CH3)2. In certain implementations, R3eis H, F, Cl, C1-3alkyl, N(C1-3alkyl)2, C1-3haloalkyl, C1- 3alkoxy, or C1-3haloalkoxy, preferably H, F, Cl, CH3, OCH3, or N(CH3)2. In certain implementations, R1Nhas the formula: In certain implementations, R1Nand R2N, together with the nitrogen atom to which they are attached, form a ring having the formula: wherein R2ais H, F, Cl, C1-6alkyl, C1-6haloalkyl, C1-6alkoxy, or C1-6haloalkoxy, preferably H or CH3and R2bis H, C1-6alkyl, C(=O)C1-6alkyl, or C2-6alkenyl, preferably n-propyl, isopropyl, n-butyl, isopropyl, or acetyl. In certain implementations, R1Nand R2N, together with the nitrogen atom to which they are attached, form a ring having the formula: In certain implementations, the compound is:

[0005] ,

[0006] 

[0007] 

[0008]

[0009] 

[0010] 

[0011]  In some implementations, the compound is described by one of the following SMILES codes: In some implementations, the compound is described by one of the following SMILES codes:

[0012] In some examples, the compounds (or a derivative or pharmaceutically acceptable salt thereof) disclosed herein can be used to treat any diseases or disorder where inhibition of DNA mismatch repair is therapeutic. For example, disclosed herein are methods of inhibiting DNA mismatch repair in a subject in need thereof by administering any of the compounds (or a derivative or pharmaceutically acceptable salt thereof) disclosed herein. In some examples, the disease or disorder is a nucleotide repeat expansion disorder. For example, disclosed herein are methods treating a nucleotide repeat expansion disorder in a subject in need thereof by administering any of the compounds disclosed herein (or a derivative or pharmaceutically acceptable salt thereof). In some implementations, the nucleotide repeat expansion disorder is Baratela-Scott syndrome, Unverricht-Lundborg disease, glutaminase deficiency, spinocerebellar ataxia, cerebellar ataxia, X-linked dystonia parkinsonism, mytonic dystrophy, Fuchs endothelial corneal dystrophy, myoclonic epilepsy, Fragile XE syndrome, Jacobsen syndrome, neuronal intranuclear inclusion disease, oculopharyngodistal myopathy, dentatorubropallidolysian atrophy, spinal and bulbar muscular atrophy, blepharophimosis, ptosis, epicanthus inversus syndrome, cleidocranial dysplasia, congenital central hypoventilation syndrome, hand-foot-genital syndrome, holoprosencephaly, oculophraryngeal muscular dystrophy, synpolydactylyl 1, X-linked hypopituitarism, Huntington’s disease, fragile X syndrome, fronto-temporal dementia, amyotrophic lateral sclerosis, Friedreich ataxia, or cancer. In some implementations, the cancer is acute lymphoblastic leukemia (ALL), acute myeloid leukemia (AML), cancer in adrenocortical carcinoma, adrenal cortex cancer, AIDS- related cancers, Kaposi sarcoma, AIDS-related lymphoma, primary CNS lymphoma, anal cancer, appendix cancer, carcinoid tumors, astrocytomas, atypical teratoid / rhabdoid tumor, basal cell carcinoma, skin cancer (nonmelanoma), bile duct cancer, extrahepatic bladder cancer, bladder cancer, bone cancer (includes Ewing sarcoma and osteosarcoma and malignant fibrous histiocytoma), brain tumors, breast cancer, bronchial tumors, Burkitt lymphoma (non-Hodgkin), carcinoid tumor, cardiac (heart) tumors, atypical teratoid / rhabdoid tumor, embryonal tumors, germ cell tumors, lymphoma, primary - cervical cancer, cholangiocarcinoma, chordoma, chronic lymphocytic leukemia (CLL), chronic myelogenous leukemia (CML), chronic myeloproliferative neoplasms, colorectal cancer, colorectal cancer, craniopharyngioma, cutaneous T-cell lymphoma, ductal carcinoma in situ (DCIS), embryonal tumors, central nervous system, endometrial cancer, ependymoma, esophageal, esthesioneuroblastoma, Ewing sarcoma, extracranial germ cell tumor, extragonadal germ cell tumor, eye cancer, intraocular melanoma, retinoblastoma, fallopian tube cancer, fibrous histiocytoma of bone, malignant, and osteosarcoma, gallbladder cancer, gastric (stomach) cancer, gastric (stomach) cancer, gastrointestinal carcinoid tumor, gastrointestinal stromal tumors (GIST), gastrointestinal stromal tumors (GIST), germ cell tumors, central nervous system, extracranial, extragonadal, ovarian testicular, gestational trophoblastic disease, gliomas, hairy cell leukemia, head and neck cancer, heart tumors, hepatocellular (liver) cancer, histiocytosis, Langerhans Cell, Hodgkin’s lymphoma, hypopharyngeal cancer, intraocular melanoma, islet cell tumors, pancreatic neuroendocrine tumors, Kaposi sarcoma, kidney - langerhans cell histiocytosis, laryngeal cancer, laryngeal cancer and papillomatosis, leukemia, lip and oral cavity cancer, liver cancer (primary), lung cancer, lung cancer, lymphoma - macroglobulinemia, Waldenström –Non-Hodgkin lymphoma, male breast cancer, malignant fibrous histiocytoma of bone and osteosarcoma, melanoma, intraocular (eye), Merkel cell carcinoma, mesothelioma, malignant, mesothelioma, metastatic squamous neck cancer with occult primary, midline tract carcinoma involving NUT gene, mouth cancer, multiple endocrine neoplasia syndromes, multiple myeloma / plasma cell neoplasms, mycosis fungoides, myelodysplastic syndromes, myelodysplastic / myeloproliferative neoplasms and chronic myeloproliferative neoplasms, myelogenous leukemia, chronic (CML), myeloid leukemia, acute (AML), nasal cavity and paranasal sinus cancer, nasopharyngeal cancer, nasopharyngeal cancer, neuroblastoma, non-Hodgkin lymphoma, non-small cell lung cancer, oral cancer, lip and oral cavity cancer and oropharyngeal cancer, osteosarcoma and malignant fibrous histiocytoma of bone, ovarian cancer, pancreatic cancer and pancreatic neuroendocrine tumors (islet cell tumors), papillomatosis, paraganglioma, paraganglioma, paranasal sinus and nasal cavity cancer, parathyroid cancer, penile cancer, pharyngeal cancer, pheochromocytoma, pheochromocytoma, pituitary tumor, plasma cell neoplasm / multiple myeloma, pleuropulmonary blastoma, pregnancy and breast cancer, primary central nervous system (CNS) lymphoma, primary peritoneal cancer, prostate cancer, rectal cancer, renal cell (kidney) cancer, retinoblastoma, rhabdomyosarcoma, salivary gland cancer, salivary gland tumors, Ewing sarcoma, Kaposi sarcoma, osteosarcoma, rhabdomyosarcoma, uterine sarcoma, Sézary syndrome, skin cancer, small cell lung cancer, small intestine cancer, soft tissue sarcoma, squamous cell carcinoma, squamous neck cancer with occult primary, metastatic, stomach (gastric) cancer, stomach (gastric) cancer, T-cell lymphoma, cutaneous, testicular cancer, throat cancer, thymoma and thymic carcinoma, thyroid cancer, ureter and renal pelvis, transitional cell cancer, urethral cancer, uterine cancer, endometrial and uterine sarcoma, vaginal cancer, vascular tumors, vulvar cancer, Waldenström macroglobulinemia, or Wilms tumor. The compounds (or a derivative or pharmaceutically acceptable salt thereof) disclosed herein may be formulated in pharmaceutical compositions for administration to a subject. Exemplary compositions will include at least one pharmaceutically acceptable excipient A pharmaceutical composition comprising any of the compounds disclosed herein (or a derivative or pharmaceutically acceptable salt thereof) and at least one pharmaceutical excipient. Such compositions include, but are not limited to, unit dosage forms including tablets, capsules (filled with powders, pellets, beads, mini-tablets, pills, micro-pellets, small tablet units, multiple unit pellet systems (MUPS), disintegrating tablets, dispersible tablets, granules, and microspheres, multiparticulates), sachets (filled with powders, pellets, beads, mini-tablets, pills, micro-pellets, small tablet units, MUPS, disintegrating tablets, dispersible tablets, granules, and microspheres, multiparticulates), powders for reconstitution, transdermal patches and sprinkles, however, other dosage forms such as controlled release formulations, lyophilized formulations, modified release formulations, delayed release formulations, extended release formulations, pulsatile release formulations, dual release formulations and the like. Liquid or semisolid dosage form (liquids, suspensions, solutions, dispersions, ointments, creams, emulsions, microemulsions, sprays, patches, spot-on), injection preparations, parenteral, topical, inhalations, buccal, nasal etc. may also be envisaged. Suitable excipients may be used for formulating the dosage forms according to the present invention such as, but not limited to, surface stabilizers or surfactants, viscosity modifying agents, polymers including extended release polymers, stabilizers, disintegrants or super disintegrants, diluents, plasticizers, binders, glidants, lubricants, sweeteners, flavoring agents, anti-caking agents, opacifiers, anti-microbial agents, antifoaming agents, emulsifiers, buffering agents, coloring agents, carriers, fillers, anti-adherents, solvents, taste-masking agents, preservatives, antioxidants, texture enhancers, channeling agents, coating agents or combinations thereof. The compounds (or a derivative or pharmaceutically acceptable salt thereof) disclosed herein may be administered by a number of different routes. For instance, the compounds may be administered orally, topically, transdermally, intravenously, subcutaneously, by inhalation, or by intracerebroventricular delivery. The compounds (or a derivative or pharmaceutically acceptable salt thereof) may be administered to a patient systemically, e.g., by oral or intravenous administration, topically, i.e., by application of a cream, lotion or the like, or locally, e.g., by direct perfusion of a composition containing the compound to a target tissue. EXAMPLES The following examples are for the purpose of illustration of the invention only and are not intended to limit the scope of the present invention in any manner whatsoever. Example 1 K562 stably expressing prime editor (K562PEmax) was transduced by MSH3 / MutSbeta or MSH6 / MutSalpha pegRNA-reporter both-in-one lentivirus (from vectors pYJ269 and pYJ276) at an MOI of ~1.5.48 hours after transduction, cells were dosed by desired concentration of drug molecules (pre-dissolved in DMSO). Cells were incubated for another 48 hours before reading out the luminescence from the cells. For reading out the luminescence, equal volume of the Nano-Glo luciferase assay reagent (Promega, N1110) was added to the cells. Luminescence was read out using a plate reader (Agilent BioTek Synergy HTX). Results are depicted in Figure 1 – Figure 52. EXEMPLARY ASPECTS In view of the described compositions and methods, herein below are described certain more particularly described aspects of the inventions. The particularly recited aspects should not, however, be interpreted to have any limiting effect on any different claims containing different or more general teachings described herein or that the “particular” aspects are somehow limited in some way other than the inherent meanings of the language and formulas literally used therein. Example 1: A method of inhibiting DNA mismatch repair, for example as relevant to treating a nucleotide repeat expansion disorder, in a subject in need thereof, comprising administering to the subject a compound having the formula: or a pharmaceutically acceptable salt thereof, wherein: X1is C-R1xor N; X2is C-R2xor N; X3is C-R3xor N; X4is C-R4xor N; provided that no more than two of X1, X2, X3, and X4are N; R1xis H, F, Cl, Br, X1*R1x*, wherein X1*is null, O, NH, SO2, C(=O), OC(=O), NHC(=O), or (CH2)nwherein n is 1-4; and R1x*is H, OH, NH2, aryl, C6-10aryl, C1-10heteroaryl, C3-8cycloalkyl, C1-8heterocyclyl; C1-6alkyl, or C1-6heteroalkyl; R2xis H, F, Cl, Br, X2*R2x*, wherein X2*is null, O, NH, SO2, C(=O), OC(=O), NHC(=O), or (CH2) wherein n is 1-4; and R2x*n is H, OH, NH2, aryl, C6-10aryl, C1-10heteroaryl, C3-8cycloalkyl, C1-8heterocyclyl; C1-6alkyl, or C1-6heteroalkyl; R3xis H, F, Cl, Br, X3*R3x*, wherein X3*is null, O, NH, SO2, C(=O), OC(=O), NHC(=O), or (CH2) wherein n is 1-4; and R3x*n is H, OH, NH2, aryl, C6-10aryl, C1-10heteroaryl, C3-8cycloalkyl, C1-8heterocyclyl; C1-6alkyl, or C1-6heteroalkyl; R4xis H, F, Cl, Br, X4*R4x*, wherein X4*is null, O, NH, SO2, C(=O), OC(=O), NHC(=O), or (CH2) wherein n is 1-4; and R4x*n is H, OH, NH2, aryl, C6-10aryl, C1-10heteroaryl, C3-8cycloalkyl, C1-8heterocyclyl; C1-6alkyl, or C1-6heteroalkyl; wherein any two or more of R1x, R2x, R3x, and R4amay together form a ring; R1is –(CH2)nC≡N, –(CH2)n–C6-10aryl, C6-10aryl, or C1-10heteroaryl, where n is 1-4; R1Nis XaCa a a1-8alkyl, XC1-8heteroalkyl, XC1-8cycloalkyl, XC6-10aryl, or XaC1-10heteroaryl, wherein Xais null or C1-4alkylene; and R2Nis H; or R1Nand R2N, together with the nitrogen atom to which they are attached, form a C3- 10heterocyclyl Example 2: The method of any example herein. particularly example 1, wherein R1is – (CH2)–C≡N, –(CH2)–C6-10aryl, C6-10aryl, or C1-10heteroaryl. Example 3: A method of inhibiting DNA mismatch repair, for example as relevant to treating a nucleotide repeat expansion disorder, in a subject in need thereof, comprising administering to the subject a compound having the formula: or a pharmaceutically acceptable salt thereof, wherein: X1is C-R1xor N; X2is C-R2xor N; X3is C-R3xor N; X4is C-R4xor N; provided that no more than two of X1, X2, X3, and X4are N; R1xis H, F, Cl, Br, X1*R1x*, wherein X1*is null, O, NH, SO2, C(=O), OC(=O), NHC(=O), or (CH2)n wherein n is 1-4; and R1x*is H, OH, NH2, aryl, C6-10aryl, C1-10heteroaryl, C3- 8cycloalkyl, C1-8heterocyclyl; C1-6alkyl, or C1-6heteroalkyl; R2xis H, F, Cl, Br, X2*R2x*, wherein X2*is null, O, NH, SO2, C(=O), OC(=O), NHC(=O), or (CH2) wherein n is 1-4; and R2x*n is H, OH, NH2, aryl, C6-10aryl, C1-10heteroaryl, C3- 8cycloalkyl, C1-8heterocyclyl; C1-6alkyl, or C1-6heteroalkyl; R3xis H, F, Cl, Br, X3*R3x*, wherein X3*is null, O, NH, SO2, C(=O), OC(=O), NHC(=O), or (CH2)nwherein n is 1-4; and R3x*is H, OH, NH2, aryl, C6-10aryl, C1-10heteroaryl, C3-8cycloalkyl, C1-8heterocyclyl; C1-6alkyl, or C1-6heteroalkyl; R4xis H, F, Cl, Br, X4*R4x*, wherein X4*is null, O, NH, SO2, C(=O), OC(=O), NHC(=O), or (CH2)nwherein n is 1-4; and R4x*is H, OH, NH2, aryl, C6-10aryl, C1-10heteroaryl, C3-8cycloalkyl, C1-8heterocyclyl; C1-6alkyl, or C1-6heteroalkyl; wherein any two or more of R1x, R2x, R3x, and R4amay together form a ring; R1is C6-10aryl or C1-10heteroaryl; R1Nis XaC1 alkyl, XaC heteroalkyl, XaC cycloalkyl, XaC aryl, or Xa-8 1-8 1-8 6-10 C1-10heteroaryl, wherein Xais null or C1 alkylene; and R2N-4 is H; or R1Nand R2N, together with the nitrogen atom to which they are attached, form a C3-10heterocyclyl. Example 4: A method of inhibiting DNA mismatch repair in a subject in need thereof, comprising administering to the subject a compound having the formula: or a pharmaceutically acceptable salt thereof, wherein: X1is C-R1xor N; X2is C-R2xor N; X3is C-R3xor N; X4is C-R4xor N; provided that no more than two of X1, X2, X3, and X4are N; R1xis H, F, Cl, Br, X1*R1x*, wherein X1*is null, O, NH, SO2, C(=O), OC(=O), NHC(=O), or (CH2)nwherein n is 1-4; and R1x*is H, OH, NH2, aryl, C6-10aryl, C1-10heteroaryl, C3-8cycloalkyl, C1-8heterocyclyl; C1-6alkyl, or C1-6heteroalkyl; R2xis H, F, Cl, Br, X2*R2x*, wherein X2*is null, O, NH, SO2, C(=O), OC(=O), NHC(=O), or (CH2)nwherein n is 1-4; and R2x*is H, OH, NH2, aryl, C6-10aryl, C1-10heteroaryl, C3-8cycloalkyl, C1-8heterocyclyl; C1-6alkyl, or C1-6heteroalkyl; R3xis H, F, Cl, Br, X3*R3x*, wherein X3*is null, O, NH, SO2, C(=O), OC(=O), NHC(=O), or (CH2)nwherein n is 1-4; and R3x*is H, OH, NH2, aryl, C6-10aryl, C1-10heteroaryl, C3-8cycloalkyl, C1-8heterocyclyl; C1-6alkyl, or C1-6heteroalkyl; R4xis H, F, Cl, Br, X4*R4x*, wherein X4*is null, O, NH, SO2, C(=O), OC(=O), NHC(=O), or (CH2)nwherein n is 1-4; and R4x*is H, OH, NH2, aryl, C6-10aryl, C1-10heteroaryl, C3-8cycloalkyl, C1-8heterocyclyl; C1-6alkyl, or C1-6heteroalkyl; wherein any two or more of R1x, R2x, R3x, and R4amay together form a ring; R1is C6-10aryl or C1-10heteroaryl; R1Nis XaC1-8alkyl, XaC1-8heteroalkyl, XaC1-8cycloalkyl, XaC6-10aryl, or XaC1-10heteroaryl, wherein Xais null or C1 alkylene; and R2N-4 is H; or R1Nand R2N, together with the nitrogen atom to which they are attached, form a C3-10heterocyclyl. Example 5: The method of any example herein. particularly examples 1-4, wherein the nucleotide repeat expansion disorder comprises Baratela-Scott syndrome, Unverricht-Lundborg disease, glutaminase deficiency, spinocerebellar ataxia, cerebellar ataxia, X-linked dystonia parkinsonism, mytonic dystrophy, Fuchs endothelial corneal dystrophy, myoclonic epilepsy, Fragile XE syndrome, Jacobsen syndrome, neuronal intranuclear inclusion disease, oculopharyngodistal myopathy, dentatorubropallidolysian atrophy, spinal and bulbar muscular atrophy, blepharophimosis, ptosis, epicanthus inversus syndrome, cleidocranial dysplasia, congenital central hypoventilation syndrome, hand-foot-genital syndrome, holoprosencephaly, oculophraryngeal muscular dystrophy, synpolydactylyl 1, X-linked hypopituitarism, Huntington’s disease, fragile X syndrome, fronto-temporal dementia, amyotrophic lateral sclerosis, Friedreich ataxia, or cancer. Example 6: The method of any example herein. particularly examples 1-5, wherein the nucleotide repeat expansion disorder comprises Baratela-Scott syndrome, Unverricht-Lundborg disease, glutaminase deficiency, spinocerebellar ataxia, cerebellar ataxia, X-linked dystonia parkinsonism, mytonic dystrophy, Fuchs endothelial corneal dystrophy, myoclonic epilepsy, Fragile XE syndrome, Jacobsen syndrome, neuronal intranuclear inclusion disease, oculopharyngodistal myopathy, dentatorubropallidolysian atrophy, spinal and bulbar muscular atrophy, blepharophimosis, ptosis, epicanthus inversus syndrome, cleidocranial dysplasia, congenital central hypoventilation syndrome, hand-foot-genital syndrome, holoprosencephaly, oculophraryngeal muscular dystrophy, synpolydactylyl 1, X-linked hypopituitarism, Huntington’s disease, fragile X syndrome, fronto-temporal dementia, amyotrophic lateral sclerosis, or Friedreich ataxia. Example 7: The method of any example herein. particularly examples 1-6, wherein the cancer comprises acute lymphoblastic leukemia (ALL), acute myeloid leukemia (AML), cancer in adrenocortical carcinoma, adrenal cortex cancer, AIDS-related cancers, Kaposi sarcoma, AIDS-related lymphoma, primary CNS lymphoma, anal cancer, appendix cancer, carcinoid tumors, astrocytomas, atypical teratoid / rhabdoid tumor, basal cell carcinoma, skin cancer (nonmelanoma), bile duct cancer, extrahepatic bladder cancer, bladder cancer, bone cancer (includes Ewing sarcoma and osteosarcoma and malignant fibrous histiocytoma), brain tumors, breast cancer, bronchial tumors, Burkitt lymphoma (non-Hodgkin), carcinoid tumor, cardiac (heart) tumors, atypical teratoid / rhabdoid tumor, embryonal tumors, germ cell tumors, lymphoma, primary - cervical cancer, cholangiocarcinoma, chordoma, chronic lymphocytic leukemia (CLL), chronic myelogenous leukemia (CML), chronic myeloproliferative neoplasms, colorectal cancer, colorectal cancer, craniopharyngioma, cutaneous T-cell lymphoma, ductal carcinoma in situ (DCIS), embryonal tumors, central nervous system, endometrial cancer, ependymoma, esophageal, esthesioneuroblastoma, ewing sarcoma, extracranial germ cell tumor, extragonadal germ cell tumor, eye cancer, intraocular melanoma, retinoblastoma, fallopian tube cancer, fibrous histiocytoma of bone, malignant, and osteosarcoma, gallbladder cancer, gastric (stomach) cancer, gastric (stomach) cancer, gastrointestinal carcinoid tumor, gastrointestinal stromal tumors (GIST), gastrointestinal stromal tumors (GIST), germ cell tumors, central nervous system, extracranial, extragonadal, ovarian testicular, gestational trophoblastic disease, gliomas, hairy cell leukemia, head and neck cancer, heart tumors, hepatocellular (liver) cancer, histiocytosis, Langerhans Cell, Hodgkin’s lymphoma, hypopharyngeal cancer, intraocular melanoma, islet cell tumors, pancreatic neuroendocrine tumors, Kaposi sarcoma, kidney - langerhans cell histiocytosis, laryngeal cancer, laryngeal cancer and papillomatosis, leukemia, lip and oral cavity cancer, liver cancer (primary), lung cancer, lung cancer, lymphoma - macroglobulinemia, Waldenström –Non-Hodgkin lymphoma, male breast cancer, malignant fibrous histiocytoma of bone and osteosarcoma, melanoma, intraocular (eye), Merkel cell carcinoma, mesothelioma, malignant, mesothelioma, metastatic squamous neck cancer with occult primary, midline tract carcinoma involving NUT gene, mouth cancer, multiple endocrine neoplasia syndromes, multiple myeloma / plasma cell neoplasms, mycosis fungoides, myelodysplastic syndromes, myelodysplastic / myeloproliferative neoplasms and chronic myeloproliferative neoplasms, myelogenous leukemia, chronic (CML), myeloid leukemia, acute (AML), nasal cavity and paranasal sinus cancer, nasopharyngeal cancer, nasopharyngeal cancer, neuroblastoma, non-Hodgkin lymphoma, non-small cell lung cancer, oral cancer, lip and oral cavity cancer and oropharyngeal cancer, osteosarcoma and malignant fibrous histiocytoma of bone, ovarian cancer, pancreatic cancer and pancreatic neuroendocrine tumors (islet cell tumors), papillomatosis, paraganglioma, paraganglioma, paranasal sinus and nasal cavity cancer, parathyroid cancer, penile cancer, pharyngeal cancer, pheochromocytoma, pheochromocytoma, pituitary tumor, plasma cell neoplasm / multiple myeloma, pleuropulmonary blastoma, pregnancy and breast cancer, primary central nervous system (CNS) lymphoma, primary peritoneal cancer, prostate cancer, rectal cancer, renal cell (kidney) cancer, retinoblastoma, rhabdomyosarcoma, salivary gland cancer, salivary gland tumors, Ewing sarcoma, Kaposi sarcoma, osteosarcoma, rhabdomyosarcoma, uterine sarcoma, Sézary syndrome, skin cancer, small cell lung cancer, small intestine cancer, soft tissue sarcoma, squamous cell carcinoma, squamous neck cancer with occult primary, metastatic, stomach (gastric) cancer, stomach (gastric) cancer, T-cell lymphoma, cutaneous, testicular cancer, throat cancer, thymoma and thymic carcinoma, thyroid cancer, ureter and renal pelvis, transitional cell cancer, urethral cancer, uterine cancer, endometrial and uterine sarcoma, vaginal cancer, vascular tumors, vulvar cancer, Waldenström macroglobulinemia, or Wilms tumor. Example 8: The method of any example herein. particularly examples 1-7, wherein the compound has the formula: wherein: R1xis H, F, Cl, C1-3alkyl, C1-3haloalkyl, C1-3alkoxy, or C1-3haloalkoxy; R1xis H, F, Cl, C1-3alkyl, C1-3haloalkyl, C1-3alkoxy, or C1-3haloalkoxy; and R3xis H, F, Cl, C1-3alkyl, C1-3haloalkyl, C1-3alkoxy, or C1-3haloalkoxy. Example 9: The method of any example herein. particularly examples 1-8, wherein R1xand R3xare each H. Example 10: The method of any example herein. particularly examples 1-9, wherein R1x, R2x, and R3xare each H. Example 11: The method of any example herein. particularly examples 1-10, wherein R1has the formula: RNis in each case independently selected from H or C1-3alkyl; R1ais H, F, Cl, Br, Xa1R1a*, wherein Xa1is null, O, NH, SO2, C(=O), OC(=O), NHC(=O), or (CH2)nwherein n is 1-4; and R1a*is H, OH, NH2, NH(C1-3alkyl), N(C1-3alkyl)2, C6-10aryl, C1-10heteroaryl, C3-8cycloalkyl, C1-8heterocyclyl, C1-6alkyl, or C1-6heteroalkyl; R1bis H, F, Cl, Br, Xb1R1b*, wherein Xb1is null, O, NH, SO2, C(=O), OC(=O), NHC(=O), or (CH2)nwherein n is 1-4; and R1b*is H, OH, NH2, NH(C1-3alkyl), N(C1-3alkyl)2, C6-10aryl, C1-10heteroaryl, C3-8cycloalkyl, C1-8heterocyclyl, C1-6alkyl, or C1-6heteroalkyl; R1cis H, F, Cl, Br, Xc1R1c*, wherein Xc1is null, O, NH, SO2, C(=O), OC(=O), NHC(=O), or (CH2) wherein n is 1-4; and Rc1*n is H, OH, NH2, NH(C1-3alkyl), N(C1-3alkyl)2, C6-10aryl, C1- 10heteroaryl, C3-8cycloalkyl, C1-8heterocyclyl, C1-6alkyl, or C1-6heteroalkyl; R1dis H, F, Cl, Br, Xd1R1d*, wherein Xd1is null, O, NH, SO2, C(=O), OC(=O), NHC(=O), or (CH2) wherein n is 1-4; and R1d*n is H, OH, NH2, NH(C1-3alkyl), N(C1-3alkyl)2, C6-10aryl, C1- 10heteroaryl, C3-8cycloalkyl, C1-8heterocyclyl, C1-6alkyl, or C1-6heteroalkyl; R1eis H, F, Cl, Br, Xe1R1e*, wherein Xe1is null, O, NH, SO2, C(=O), OC(=O), NHC(=O), or (CH2) wherein n is 1-4; and R1e*n is H, OH, NH2, NH(C1-3alkyl), N(C1-3alkyl)2, C6-10aryl, C1- 10heteroaryl, C3-8cycloalkyl, C1-8heterocyclyl, C1-6alkyl, or C1-6heteroalkyl; wherein any two or more of R1a, R1b, R1c, R1d, and R1emay together form a ring. Example 12: The method of any example herein. particularly examples 1-11, wherein R1has the formula: RNis in each case independently selected from H or C1-3alkyl; R1ais H, F, Cl, Br, Xa1R1a*, wherein Xa1is null, O, NH, SO2, C(=O), OC(=O), NHC(=O), or (CH2)nwherein n is 1-4; and R1a*is H, OH, NH2, NH(C1-3alkyl), N(C1-3alkyl)2, C6-10aryl, C1-10heteroaryl, C3-8cycloalkyl, C1-8heterocyclyl, C1-6alkyl, or C1-6heteroalkyl; R1bis H, F, Cl, Br, Xb1R1b*, wherein Xb1is null, O, NH, SO2, C(=O), OC(=O), NHC(=O), or (CH2)nwherein n is 1-4; and R1b*is H, OH, NH2, NH(C1-3alkyl), N(C1-3alkyl)2, C6-10aryl, C1-10heteroaryl, C3-8cycloalkyl, C1-8heterocyclyl, C1-6alkyl, or C1-6heteroalkyl; R1cis H, F, Cl, Br, Xc1R1c*, wherein Xc1is null, O, NH, SO2, C(=O), OC(=O), NHC(=O), or (CH2)nwherein n is 1-4; and Rc1*is H, OH, NH2, NH(C1-3alkyl), N(C1-3alkyl)2, C6-10aryl, C1-10heteroaryl, C3-8cycloalkyl, C1-8heterocyclyl, C1-6alkyl, or C1-6heteroalkyl; R1dis H, F, Cl, Br, Xd1R1d*, wherein Xd1is null, O, NH, SO2, C(=O), OC(=O), NHC(=O), or (CH2)nwherein n is 1-4; and R1d*is H, OH, NH2, NH(C1-3alkyl), N(C1-3alkyl)2, C6-10aryl, C1-10heteroaryl, C3-8cycloalkyl, C1-8heterocyclyl, C1-6alkyl, or C1-6heteroalkyl; R1eis H, F, Cl, Br, Xe1R1e*, wherein Xe1is null, O, NH, SO2, C(=O), OC(=O), NHC(=O), or (CH2)nwherein n is 1-4; and R1e*is H, OH, NH2, NH(C1-3alkyl), N(C1-3alkyl)2, C6-10aryl, C1-10heteroaryl, C3-8cycloalkyl, C1-8heterocyclyl, C1-6alkyl, or C1-6heteroalkyl; wherein any two or more of R1a, R1b, R1c, R1d, and R1emay together form a ring. Example 13: The method of any example herein. particularly examples 1-12, wherein the compound has the formula: Example 14: The method of any example herein. particularly examples 1-13, wherein R1a, R1b, R1d, and R1eare each H. Example 15: The method of any example herein. particularly examples 1-14, wherein R1cis H, F, Cl, C1-3alkyl, C1-3haloalkyl, C1-3alkoxy, or C1-3haloalkoxy. Example 16: The method of any example herein. particularly examples 1-15, wherein R1cis H, F, Cl, CH3, or CF3. Example 17: The method of any example herein. particularly examples 1-16, wherein the compound has the formula: Example 18: The method of any example herein. particularly examples 1-17, wherein R2Nis H and R1Nis (CRq)R32 z , wherein Rqis independently selected from H and CH3, z is 1-3, and R3is C6-10aryl or C1-10heteroaryl. Example 19: The method of any example herein. particularly examples 1-18, wherein R3has the formula:

[0013] wherein R3Nis in each case independently selected from H or C1-3alkyl; R3ais H, F, Cl, Br, Xa3R3a*, wherein Xa3is null, O, NH, SO2, C(=O), OC(=O), NHC(=O), or (CH2) wherein n is 1-4; and R3a*n is H, OH, NH2, NH(C1-3alkyl), N(C1-3alkyl)2, C6-10aryl, C1- 10heteroaryl, C3-8cycloalkyl, C1-8heterocyclyl, C1-6alkyl, or C1-6heteroalkyl; R3bis H, F, Cl, Br, Xb3R3b*, wherein Xb3is null, O, NH, SO2, C(=O), OC(=O), NHC(=O), or (CH2) wherein n is 1-4; and R3b*n is H, OH, NH2, NH(C1-3alkyl), N(C1-3alkyl)2, C6-10aryl, C1- 10heteroaryl, C3-8cycloalkyl, C1-8heterocyclyl, C1-6alkyl, or C1-6heteroalkyl; R3cis H, F, Cl, Br, Xc3R3c*, wherein Xc3is null, O, NH, SO2, C(=O), OC(=O), NHC(=O), or (CH2) wherein n is 1-4; and Rc3*n is H, OH, NH2, NH(C1-3alkyl), N(C1-3alkyl)2, C6-10aryl, C1- 10heteroaryl, C3-8cycloalkyl, C1-8heterocyclyl, C1-6alkyl, or C1-6heteroalkyl; R3dis H, F, Cl, Br, Xd3R3d*, wherein Xd3is null, O, NH, SO2, C(=O), OC(=O), NHC(=O), or (CH2) wherein n is 1-4; and R3d*n is H, OH, NH2, NH(C1-3alkyl), N(C1-3alkyl)2, C6-10aryl, C1- 10heteroaryl, C3-8cycloalkyl, C1-8heterocyclyl, C1-6alkyl, or C1-6heteroalkyl; R3eis H, F, Cl, Br, Xe3R3e*, wherein Xe3is null, O, NH, SO2, C(=O), OC(=O), NHC(=O), or (CH2)nwherein n is 1-4; and R3e*is H, OH, NH2, NH(C1-3alkyl), N(C1-3alkyl)2, C6-10aryl, C1-10heteroaryl, C3-8cycloalkyl, C1-8heterocyclyl, C1-6alkyl, or C1-6heteroalkyl; wherein any two or more of R3a, R3b, R3c, R3d, and R3emay together form a ring. Example 20: The method of any example herein. particularly examples 1-19, wherein R3has the formula: . Example 21: The method of any example herein. particularly examples 1-20, wherein R3has the formula: Example 22: The method of any example herein. particularly examples 1-21, wherein R3ais H, F, Cl, C1-3alkyl, N(C1-3alkyl)2, C1-3haloalkyl, C1-3alkoxy, or C1-3haloalkoxy, preferably H, F, Cl, CH3, OCH3, or N(CH3)2. Example 23: The method of any example herein. particularly examples 1-22, wherein R3bis H, F, Cl, C1-3alkyl, N(C1-3alkyl)2, C1-3haloalkyl, C1-3alkoxy, or C1-3haloalkoxy, preferably H, F, Cl, CH3, OCH3, or N(CH3)2. Example 24: The method of any example herein. particularly examples 1-23, wherein R3cis H, F, Cl, C1-3alkyl, N(C1-3alkyl)2, C1-3haloalkyl, C1-3alkoxy, or C1-3haloalkoxy, preferably H, F, Cl, CH3, OCH3, or N(CH3)2. Example 25: The method of any example herein. particularly examples 1-24, wherein R3dis H, F, Cl, C1-3alkyl, N(C1-3alkyl)2, C1-3haloalkyl, C1-3alkoxy, or C1-3haloalkoxy, preferably H, F, Cl, CH3, OCH3, or N(CH3)2. Example 26: The method of any example herein. particularly examples 1-25, wherein R3eis H, F, Cl, C1-3alkyl, N(C1-3alkyl)2, C1-3haloalkyl, C1-3alkoxy, or C1-3haloalkoxy, preferably H, F, Cl, CH3, OCH3, or N(CH3)2. Example 27: The method of any example herein. particularly examples 1-26, wherein R1Nhas the formula: Example 28: The method of any example herein. particularly examples 1-27, wherein R1Nand R2N, together with the nitrogen atom to which they are attached, form a ring having the formula: ,,wherein R2ais H, F, Cl, C1-6alkyl, C1-6haloalkyl, C1-6alkoxy, or C1-6haloalkoxy, preferably H or CH3 and R2bis H, C1-6alkyl, C(=O)C1-6alkyl, or C2-6alkenyl, preferably n-propyl, isopropyl, n-butyl, isopropyl, or acetyl. Example 29: The method of any example herein. particularly examples 1-28, wherein R1Nand R2N, together with the nitrogen atom to which they are attached, form a ring having the formula: Example 30: The method of any example herein. particularly examples 1-29, wherein the compound is:

[0014] 

[0015] , ,Ċ

[0016] 

[0017] 

[0018] Example 31: The method of any example herein. particularly examples 1-30, wherein the compound is:

[0019] 

[0020] The compositions and methods of the appended claims are not limited in scope by the specific compositions and methods described herein, which are intended as illustrations of a few aspects of the claims and any compositions and methods that are functionally equivalent are intended to fall within the scope of the claims. Various modifications of the compositions and methods in addition to those shown and described herein are intended to fall within the scope of the appended claims. Further, while only certain representative compositions and method steps disclosed herein are specifically described, other combinations of the compositions and method steps also are intended to fall within the scope of the appended claims, even if not specifically recited. Thus, a combination of steps, elements, components, or constituents may be explicitly mentioned herein or less, however, other combinations of steps, elements, components, and constituents are included, even though not explicitly stated. The term “comprising” and variations thereof as used herein is used synonymously with the term “including” and variations thereof and are open, non-limiting terms. Although the terms “comprising” and “including” have been used herein to describe various embodiments, the terms “consisting essentially of” and “consisting of” can be used in place of “comprising” and “including” to provide for more specific embodiments of the invention and are also disclosed. Other than in the examples, or where otherwise noted, all numbers expressing quantities of ingredients, reaction conditions, and so forth used in the specification and claims are to be understood at the very least, and not as an attempt to limit the application of the doctrine of equivalents to the scope of the claims, to be construed in light of the number of significant digits and ordinary rounding approaches

Claims

1. CLAIMS What is claimed is:

1. A method of inhibiting DNA mismatch repair, for example as relevant to treating a nucleotide repeat expansion disorder, in a subject in need thereof, comprising administering to the subject a compound having the formula:or a pharmaceutically acceptable salt thereof, wherein: X1is C-R1xor N; X2is C-R2xor N; X3is C-R3xor N; X4is C-R4xor N; provided that no more than two of X1, X2, X3, and X4are N; R1xis H, F, Cl, Br, X1*R1x*, wherein X1*is null, O, NH, SO2, C(=O), OC(=O), NHC(=O), or (CH2) wherein n is 1-4; and R1x*n is H, OH, NH2, aryl, C6-10aryl, C1-10heteroaryl, C3- 8cycloalkyl, C1-8heterocyclyl; C1-6alkyl, or C1-6heteroalkyl; R2xis H, F, Cl, Br, X2*R2x*, wherein X2*is null, O, NH, SO2, C(=O), OC(=O), NHC(=O), or (CH2) wherein n is 1-4; and R2x*n is H, OH, NH2, aryl, C6-10aryl, C1-10heteroaryl, C3- 8cycloalkyl, C1-8heterocyclyl; C1-6alkyl, or C1-6heteroalkyl; R3xis H, F, Cl, Br, X3*R3x*, wherein X3*is null, O, NH, SO2, C(=O), OC(=O), NHC(=O), or (CH2)nwherein n is 1-4; and R3x*is H, OH, NH2, aryl, C6-10aryl, C1-10heteroaryl, C3-8cycloalkyl, C1-8heterocyclyl; C1-6alkyl, or C1-6heteroalkyl; R4xis H, F, Cl, Br, X4*R4x*, wherein X4*is null, O, NH, SO2, C(=O), OC(=O), NHC(=O), or (CH2)nwherein n is 1-4; and R4x*is H, OH, NH2, aryl, C6-10aryl, C1-10heteroaryl, C3-8cycloalkyl, C1-8heterocyclyl; C1-6alkyl, or C1-6heteroalkyl; wherein any two or more of R1x, R2x, R3x, and R4amay together form a ring; R1is –(CH2)nC≡N, –(CH2)n–C6-10aryl, C6-10aryl, or C1-10heteroaryl, where n is 1-4; R1Nis XaCa a a1-8alkyl, XC1-8heteroalkyl, XC1-8cycloalkyl, XC6-10aryl, or XaC1-10heteroaryl,wherein Xais null or C1-4alkylene; and R2Nis H; or R1Nand R2N, together with the nitrogen atom to which they are attached, form a C3-10heterocyclyl.

2. The method of claim 1, wherein R1is –(CH2)–C≡N, –(CH2)–C6-10aryl, C6-10aryl, or C1- 10heteroaryl.

3. A method of inhibiting DNA mismatch repair, for example as relevant to treating a nucleotide repeat expansion disorder, in a subject in need thereof, comprising administering to the subject a compound having the formula:or a pharmaceutically acceptable salt thereof, wherein: X1is C-R1xor N; X2is C-R2xor N; X3is C-R3xor N; X4is C-R4xor N; provided that no more than two of X1, X2, X3, and X4are N; R1xis H, F, Cl, Br, X1*R1x*, wherein X1*is null, O, NH, SO2, C(=O), OC(=O), NHC(=O), or (CH2)nwherein n is 1-4; and R1x*is H, OH, NH2, aryl, C6-10aryl, C1-10heteroaryl, C3-8cycloalkyl, C1-8heterocyclyl; C1-6alkyl, or C1-6heteroalkyl; R2xis H, F, Cl, Br, X2*R2x*, wherein X2*is null, O, NH, SO2, C(=O), OC(=O), NHC(=O), or (CH2)nwherein n is 1-4; and R2x*is H, OH, NH2, aryl, C6-10aryl, C1-10heteroaryl, C3-8cycloalkyl, C1-8heterocyclyl; C1-6alkyl, or C1-6heteroalkyl; R3xis H, F, Cl, Br, X3*R3x*, wherein X3*is null, O, NH, SO2, C(=O), OC(=O), NHC(=O), or (CH2)nwherein n is 1-4; and R3x*is H, OH, NH2, aryl, C6-10aryl, C1-10heteroaryl, C3-8cycloalkyl, C1-8heterocyclyl; C1-6alkyl, or C1-6heteroalkyl; R4xis H, F, Cl, Br, X4*R4x*, wherein X4*is null, O, NH, SO2, C(=O), OC(=O), NHC(=O), or (CH2) wherein n is 1-4; and R4x*n is H, OH, NH2, aryl, C6-10aryl, C1-10heteroaryl, C3-8cycloalkyl, C1-8heterocyclyl; C1-6alkyl, or C1-6heteroalkyl;wherein any two or more of R1x, R2x, R3x, and R4amay together form a ring; R1is C6-10aryl or C1-10heteroaryl; R1Nis XaC1-8alkyl, XaC1-8heteroalkyl, XaC1-8cycloalkyl, XaC6-10aryl, or XaC1-10heteroaryl, wherein Xais null or C1 alkylene; and R2N-4 is H; or R1Nand R2N, together with the nitrogen atom to which they are attached, form a C3-10heterocyclyl 4. A method of treating a nucleotide repeat expansion disorder in a subject in need thereof, comprising administering to the subject a compound having the formula: or a pharmaceutically acceptable salt thereof, wherein: X1is C-R1xor N; X2is C-R2xor N; X3is C-R3xor N; X4is C-R4xor N; provided that no more than two of X1, X2, X3, and X4are N; R1xis H, F, Cl, Br, X1*R1x*, wherein X1*is null, O, NH, SO2, C(=O), OC(=O), NHC(=O), or (CH2) wherein n is 1-4; and R1x*n is H, OH, NH2, aryl, C6-10aryl, C1-10heteroaryl, C3- 8cycloalkyl, C1-8heterocyclyl; C1-6alkyl, or C1-6heteroalkyl; R2xis H, F, Cl, Br, X2*R2x*, wherein X2*is null, O, NH, SO2, C(=O), OC(=O), NHC(=O), or (CH2) wherein n is 1-4; and R2x*n is H, OH, NH2, aryl, C6-10aryl, C1-10heteroaryl, C3- 8cycloalkyl, C1-8heterocyclyl; C1-6alkyl, or C1-6heteroalkyl; R3xis H, F, Cl, Br, X3*R3x*, wherein X3*is null, O, NH, SO2, C(=O), OC(=O), NHC(=O), or (CH2)nwherein n is 1-4; and R3x*is H, OH, NH2, aryl, C6-10aryl, C1-10heteroaryl, C3-8cycloalkyl, C1-8heterocyclyl; C1-6alkyl, or C1-6heteroalkyl; R4xis H, F, Cl, Br, X4*R4x*, wherein X4*is null, O, NH, SO2, C(=O), OC(=O), NHC(=O), or (CH2)nwherein n is 1-4; and R4x*is H, OH, NH2, aryl, C6-10aryl, C1-10heteroaryl, C3-8cycloalkyl, C1-8heterocyclyl; C1-6alkyl, or C1-6heteroalkyl; wherein any two or more of R1x, R2x, R3x, and R4amay together form a ring;R1is C6-10aryl or C1-10heteroaryl; R1Nis XaC1-8alkyl, XaC1-8heteroalkyl, XaC1-8cycloalkyl, XaC6-10aryl, or XaC1-10heteroaryl, wherein Xais null or C1-4alkylene; and R2Nis H; or R1Nand R2N, together with the nitrogen atom to which they are attached, form a C3- 10heterocyclyl.

5. The method of any preceding claim, wherein the nucleotide repeat expansion disorder comprises Baratela-Scott syndrome, Unverricht-Lundborg disease, glutaminase deficiency, spinocerebellar ataxia, cerebellar ataxia, X-linked dystonia parkinsonism, mytonic dystrophy, Fuchs endothelial corneal dystrophy, myoclonic epilepsy, Fragile XE syndrome, Jacobsen syndrome, neuronal intranuclear inclusion disease, oculopharyngodistal myopathy, dentatorubropallidolysian atrophy, spinal and bulbar muscular atrophy, blepharophimosis, ptosis, epicanthus inversus syndrome, cleidocranial dysplasia, congenital central hypoventilation syndrome, hand-foot-genital syndrome, holoprosencephaly, oculophraryngeal muscular dystrophy, synpolydactylyl 1, X-linked hypopituitarism, Huntington’s disease, fragile X syndrome, fronto-temporal dementia, amyotrophic lateral sclerosis, or Friedreich ataxia.

6. The method of any preceding claim, wherein the compound has the formula:wherein: R1xis H, F, Cl, C1-3alkyl, C1-3haloalkyl, C1-3alkoxy, or C1-3haloalkoxy; R1xis H, F, Cl, C1-3alkyl, C1-3haloalkyl, C1-3alkoxy, or C1-3haloalkoxy; and R3xis H, F, Cl, C1-3alkyl, C1-3haloalkyl, C1-3alkoxy, or C1-3haloalkoxy.

7. The method of any preceding claim, wherein R1xand R3xare each H.

8. The method of any preceding claim, wherein R1x, R2x, and R3xare each H.

9. The method of any preceding claim, wherein R1has the formula:RNis in each case independently selected from H or C1-3alkyl; R1ais H, F, Cl, Br, Xa1R1a*, wherein Xa1is null, O, NH, SO2, C(=O), OC(=O), NHC(=O), or (CH2) wherein n is 1-4; and R1a*n is H, OH, NH2, NH(C1-3alkyl), N(C1-3alkyl)2, C6-10aryl, C1- 10heteroaryl, C3-8cycloalkyl, C1-8heterocyclyl, C1-6alkyl, or C1-6heteroalkyl; R1bis H, F, Cl, Br, Xb1R1b*, wherein Xb1is null, O, NH, SO2, C(=O), OC(=O), NHC(=O), or (CH2) wherein n is 1-4; and R1b*n is H, OH, NH2, NH(C1-3alkyl), N(C1-3alkyl)2, C6-10aryl, C1- 10heteroaryl, C3-8cycloalkyl, C1-8heterocyclyl, C1-6alkyl, or C1-6heteroalkyl; R1cis H, F, Cl, Br, Xc1R1c*, wherein Xc1is null, O, NH, SO2, C(=O), OC(=O), NHC(=O), or (CH2)nwherein n is 1-4; and Rc1*is H, OH, NH2, NH(C1-3alkyl), N(C1-3alkyl)2, C6-10aryl, C1-10heteroaryl, C3-8cycloalkyl, C1-8heterocyclyl, C1-6alkyl, or C1-6heteroalkyl;R1dis H, F, Cl, Br, Xd1R1d*, wherein Xd1is null, O, NH, SO2, C(=O), OC(=O), NHC(=O), or (CH2)nwherein n is 1-4; and R1d*is H, OH, NH2, NH(C1-3alkyl), N(C1-3alkyl)2, C6-10aryl, C1-10heteroaryl, C3-8cycloalkyl, C1-8heterocyclyl, C1-6alkyl, or C1-6heteroalkyl; R1eis H, F, Cl, Br, Xe1R1e*, wherein Xe1is null, O, NH, SO2, C(=O), OC(=O), NHC(=O), or (CH2) wherein n is 1-4; and R1e*n is H, OH, NH2, NH(C1-3alkyl), N(C1-3alkyl)2, C6-10aryl, C1- 10heteroaryl, C3-8cycloalkyl, C1-8heterocyclyl, C1-6alkyl, or C1-6heteroalkyl; wherein any two or more of R1a, R1b, R1c, R1d, and R1emay together form a ring. 10 The method of any preceding claim wherein R1has the formula:RNis in each case independently selected from H or C1-3alkyl; R1ais H, F, Cl, Br, Xa1R1a*, wherein Xa1is null, O, NH, SO2, C(=O), OC(=O), NHC(=O), or (CH2)nwherein n is 1-4; and R1a*is H, OH, NH2, NH(C1-3alkyl), N(C1-3alkyl)2, C6-10aryl, C1-10heteroaryl, C3-8cycloalkyl, C1-8heterocyclyl, C1-6alkyl, or C1-6heteroalkyl;R1bis H, F, Cl, Br, Xb1R1b*, wherein Xb1is null, O, NH, SO2, C(=O), OC(=O), NHC(=O), or (CH2)nwherein n is 1-4; and R1b*is H, OH, NH2, NH(C1-3alkyl), N(C1-3alkyl)2, C6-10aryl, C1-10heteroaryl, C3-8cycloalkyl, C1-8heterocyclyl, C1-6alkyl, or C1-6heteroalkyl; R1cis H, F, Cl, Br, Xc1R1c*, wherein Xc1is null, O, NH, SO2, C(=O), OC(=O), NHC(=O), or (CH2) wherein n is 1-4; and Rc1*n is H, OH, NH2, NH(C1-3alkyl), N(C1-3alkyl)2, C6-10aryl, C1-10heteroaryl, C3-8cycloalkyl, C1-8heterocyclyl, C1-6alkyl, or C1-6heteroalkyl; R1dis H, F, Cl, Br, Xd1R1d*, wherein Xd1is null, O, NH, SO2, C(=O), OC(=O), NHC(=O), or (CH2) wherein n is 1-4; and R1d*n is H, OH, NH2, NH(C1-3alkyl), N(C1-3alkyl)2, C6-10aryl, C1-10heteroaryl, C3-8cycloalkyl, C1-8heterocyclyl, C1-6alkyl, or C1-6heteroalkyl; R1eis H, F, Cl, Br, Xe1R1e*, wherein Xe1is null, O, NH, SO2, C(=O), OC(=O), NHC(=O), or (CH2) wherein n is 1-4; and R1e*n is H, OH, NH2, NH(C1-3alkyl), N(C1-3alkyl)2, C6-10aryl, C1-10heteroaryl, C3-8cycloalkyl, C1-8heterocyclyl, C1-6alkyl, or C1-6heteroalkyl; wherein any two or more of R1a, R1b, R1c, R1d, and R1emay together form a ring.

11. The method of any preceding claim, wherein the compound has the formula:

12. The method of any preceding claim, wherein R1a, R1b, R1d, and R1eare each H.

13. The method of any preceding claim, wherein R1cis H, F, Cl, C1-3alkyl, C1-3haloalkyl, C1- 3alkoxy, or C1-3haloalkoxy.

14. The method of any preceding claim, wherein R1cis H, F, Cl, CH3, or CF3.

15. The method of any preceding claim, wherein the compound has the formula:

16. The method of any preceding claim, wherein R2Nis H and R1Nis (CRq)R3, wherein Rq2 z is independently selected from H and CH3, z is 1-3, and R3is C6-10aryl or C1-10heteroaryl.

17. The method of any preceding claim, wherein R3has the formula:wherein R3Nis in each case independently selected from H or C1-3alkyl; R3ais H, F, Cl, Br, Xa3R3a*, wherein Xa3is null, O, NH, SO2, C(=O), OC(=O), NHC(=O), or (CH2) wherein n is 1-4; and R3a*n is H, OH, NH2, NH(C1-3alkyl), N(C1-3alkyl)2, C6-10aryl, C1- 10heteroaryl, C3-8cycloalkyl, C1-8heterocyclyl, C1-6alkyl, or C1-6heteroalkyl; R3bis H, F, Cl, Br, Xb3R3b*, wherein Xb3is null, O, NH, SO2, C(=O), OC(=O), NHC(=O), or (CH2) wherein n is 1-4; and R3b*n is H, OH, NH2, NH(C1-3alkyl), N(C1-3alkyl)2, C6-10aryl, C1- 10heteroaryl, C3-8cycloalkyl, C1-8heterocyclyl, C1-6alkyl, or C1-6heteroalkyl; R3cis H, F, Cl, Br, Xc3R3c*, wherein Xc3is null, O, NH, SO2, C(=O), OC(=O), NHC(=O), or (CH2)n wherein n is 1-4; and Rc3*is H, OH, NH2, NH(C1-3alkyl), N(C1-3alkyl)2, C6-10aryl, C1- 10heteroaryl, C3-8cycloalkyl, C1-8heterocyclyl, C1-6alkyl, or C1-6heteroalkyl; R3dis H, F, Cl, Br, Xd3R3d*, wherein Xd3is null, O, NH, SO2, C(=O), OC(=O), NHC(=O), or (CH2)nwherein n is 1-4; and R3d*is H, OH, NH2, NH(C1-3alkyl), N(C1-3alkyl)2, C6-10aryl, C1-10heteroaryl, C3-8cycloalkyl, C1-8heterocyclyl, C1-6alkyl, or C1-6heteroalkyl; R3eis H, F, Cl, Br, Xe3R3e*, wherein Xe3is null, O, NH, SO2, C(=O), OC(=O), NHC(=O), or (CH2)nwherein n is 1-4; and R3e*is H, OH, NH2, NH(C1-3alkyl), N(C1-3alkyl)2, C6-10aryl, C1-10heteroaryl, C3-8cycloalkyl, C1-8heterocyclyl, C1-6alkyl, or C1-6heteroalkyl; wherein any two or more of R3a, R3b, R3c, R3d, and R3emay together form a ring.

18. The method of any preceding claim, wherein R3has the formula:

19. The method of any preceding claim, wherein R3has the formula:

20. The method of any preceding claim, wherein R3ais H, F, Cl, C1-3alkyl, N(C1-3alkyl)2, C1-3haloalkyl, C1-3alkoxy, or C1-3haloalkoxy, preferably H, F, Cl, CH3, OCH3, or N(CH3)2.

21. The method of any preceding claim, wherein R3bis H, F, Cl, C1-3alkyl, N(C1-3alkyl)2, C1-3haloalkyl, C1-3alkoxy, or C1-3haloalkoxy, preferably H, F, Cl, CH3, OCH3, or N(CH3)2.

22. The method of any preceding claim, wherein R3cis H, F, Cl, C1-3alkyl, N(C1-3alkyl)2, C1- 3haloalkyl, C1-3alkoxy, or C1-3haloalkoxy, preferably H, F, Cl, CH3, OCH3, or N(CH3)2.

23. The method of any preceding claim, wherein R3dis H, F, Cl, C1-3alkyl, N(C1-3alkyl)2, C1-3haloalkyl, C1-3alkoxy, or C1-3haloalkoxy, preferably H, F, Cl, CH3, OCH3, or N(CH3)2.

24. The method of any preceding claim, wherein R3eis H, F, Cl, C1-3alkyl, N(C1-3alkyl)2, C1-3haloalkyl, C1-3alkoxy, or C1-3haloalkoxy, preferably H, F, Cl, CH3, OCH3, or N(CH3)2.

25. The method of any preceding claim, wherein R1Nhas the formula:

26. The method of any preceding claim, wherein R1Nand R2N, together with the nitrogen atom to which they are attached, form a ring having the formula:,,wherein R2ais H, F, Cl, C1-6alkyl, C1-6haloalkyl, C1-6alkoxy, or C1-6haloalkoxy, preferably H or CH3and R2bis H, C1-6alkyl, C(=O)C1-6alkyl, or C2-6alkenyl, preferably n-propyl, isopropyl, n-butyl, isopropyl, or acetyl.

27. The method of any preceding claim, wherein R1Nand R2N, together with the nitrogen atom to which they are attached, form a ring having the formula:

28. The method of any preceding claim, wherein the compound is:29. The method of any preceding claim, wherein the compound is:

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