Compounds for the treatment of cystic fibrosis

Abstract

The present disclosure is concerned with piperidinedione compounds, pharmaceutical compositions comprising the compounds, and methods of treating disorders associated with the presence of a premature termination codon such as, for example, cystic fibrosis, Duchenne muscular dystrophy, aniridia, Becker muscular dystrophy, spinal muscular atrophy, Hurler syndrome, hemophilia, epidermolysis bullosa (e.g., dystrophic (DEB) form, junctional (JEB) form). Usher syndrome, and cancer, using the compounds. This abstract is intended as a scanning tool for purposes of searching in the particular art and is not intended to be limiting of the present invention.

Description

COMPOUNDS FOR THE TREATMENT OF CYSTIC FIBROSISCROSS-REFERENCE TO RELATED APPLICATIONS

[0001] This Application claims the benefit of U.S. Application No. 63 / 694,421, filed on September 13, 2024, the contents of which are incorporated herein by reference in their entirety.STATEMENT REGARDING SPONSORED RESEARCH

[0002] Research for this invention was supported by awards from the Cystic Fibrosis Foundation.BACKGROUND

[0003] Cystic fibrosis (CF) is an autosomal recessive disorder caused by mutations in the gene encoding the CF transmembrane conductance regulator (CFTR), an anion channel primarily localized to the apical membranes of secretory epithelial cells lining the airways and multiple organs. Among the most common mutation class, premature termination codons (PTCs) in CFTR lead to translation termination due to an in-frame nonsense mutation in the coding sequence, resulting in nonfunctional CFTR protein (Welsh et al. (1993) Cell 73: 1251- 1254). PTCs are the proximate cause of ~11% of CF causing alleles and many other genetic diseases (Sloane et al. (2010) Current opinion in pulmonary medicine 16: 591-7).

[0004] Efforts to develop treatments for CF patients with nonsense mutations have focused on strategies to promote termination suppression (also known as translational read-through) of PTCs. Translational read-through is accomplished when an amino acid carried by nearcognate aminoacyl tRNA is inserted into a polypeptide chain at the erroneous stop codon, allowing translation to continue, and partially restoring full-length, functional protein (Bedwell et al. (1997) Nat Med 3; 1280-1284; Howard et al. (1996) Nat Med2: 467-469). Several pharmacologic approaches to induce read-through have been discovered, yet none has yielded an optimal combination of efficacy and safety. For instance, in vitro work has demonstrated that certain aminoglycosides can promote read-through and have been tested in clinical trials with mixed results (Clancy et al. (2001 ) Am J Respir Crit Care Med 163: 1683- 1692; Clancy et al. (2007) Am J Respir Cell Mol Biol 37: 57-66; Wilschanski et al. (2003) NEngl J Med 349: 1433-1441; Wilschanski et al. (2000) Am J Respir Crit Care Med 161: 860- 865; Sermet-Gaudelus et al. (2007) BMC Med 5: 5), but are not well-suited for long-term use. Synthetic aminoglycoside derivatives optimized for translation suppression of the eukaryotic ribosome have exhibited improved read-through and reduced toxicity when compared in vitro. Ataluren (formerly PTC 124) is an orally bioavailable small molecule that induces read-through. In a subset analysis, ataluren demonstrated a modest treatment bebefit in CF patients not using chronic inhalaed tobramycin, which interferes with its effect (Kerem et al. (2014) Lancet Respir Med 2: 539-47), a finding currently under prospective evaluation.

[0005] Despite the significance of premature termination mutations in CF, as well as in other genetic diseases and cancers, pharmacological strategies specific to these mutations has remained elusive. Thus, there remains a need for compounds and compositions to stimulate read-through of premature termination codons, and methods of making and using same. These needs and others are met by the present invention. SUMMARY

[0006] In accordance with the purpose(s) of the invention, as embodied and broadly described herein, the invention, in one aspect, relates to substituted piperidinedione compounds, pharmaceutical compositions containing the compounds, and methods of using the compounds in, for example, the prevention and treatment of disorders associated with the presence of a premature termination codon such as, for example, cystic fibrosis, Duchenne muscular dystrophy, aniridia, Becker muscular dystrophy, spinal muscular atrophy, Hurler syndrome, hemophilia, epidermolysis bullosa (e.g., dystrophic (DEB) form, junctional (JEB) form), Usher syndrome, and cancer.

[0007] Thus, in one aspect, disclosed are compounds having a structure represented by a formula:, wherein n is selected from 0 and 1; wherein each of Q1, Q2, and Q3is independently selected from ‒CH2‒ and ‒C(O)‒, provided that at least one of Q1and Q2is ‒C(O)‒; wherein Z is selected from ‒CH(CO2H)‒ and ‒CH(C(O)NH2)‒; wherein each of R1and R2is independently selected from hydrogen and C1-C4 alkyl; wherein Ar1is selected from a 6-membered aryl, an isoxazolyl, an oxadiazolyl, an oxazolyl, and a 9- or 10-membered heteroaryl, and is substituted with 0, 1, 2, or 3 groups independently selected from halogen, ‒CN, ‒NH2, ‒OH, ‒NO2, C1-C4 alkyl, C2-C4 alkenyl, C1-C4 haloalkyl, C1-C4 cyanoalkyl, C1-C4 hydroxyalkyl, C1-C4 haloalkoxy, C1-C4 alkoxy, C1-C4 alkylamino, (C1-C4)(C1-C4) dialkylamino, C1-C4 aminoalkyl, ‒CO2H, and Ar2; and wherein Ar2is selected from a 6- membered aryl and a 6-membered heteroaryl, and is substituted with 0, 1, 2, or 3 groups independently selected from halogen, ‒CN, ‒NH2, ‒OH, ‒NO2, C1-C4 alkyl, C2-C4 alkenyl, C1-C4 haloalkyl, C1-C4 cyanoalkyl, C1-C4 hydroxyalkyl, C1-C4 haloalkoxy, C1-C4 alkoxy, C1-C4 alkylamino, (C1-C4)(C1-C4) dialkylamino, C1-C4 aminoalkyl, ‒CO2H, and ‒C(O)NH2; or a pharmaceutically acceptable salt thereof, provided that when Ar1is a 6- membered aryl, then n is 1, and provided that when Ar1is a 9- or 10-membered heteroaryl, then Ar1is not substituted with an Ar2group.

[0008] Also disclosed are compounds having a structure represented by a formula:, wherein n is selected from 0 and 1; wherein each of Q1, Q2, and Q3is independently selected from ‒CH2‒ and ‒C(O)‒, provided that at least one of Q1and Q2is ‒C(O)‒; wherein Z is selected from ‒CH(CO2H)‒ and ‒CH(C(O)NH2)‒; wherein each of R1and R2is independently selected from hydrogen and C1-C4 alkyl; wherein Ar1is selected from a 6- membered aryl, an isoxazolyl, an oxadiazolyl, and a 9- or 10-membered heteroaryl, and is substituted with 0, 1, 2, or 3 groups independently selected from halogen, ‒CN, ‒NH2, ‒OH, ‒NO2, C1-C4 alkyl, C2-C4 alkenyl, C1-C4 haloalkyl, C1-C4 cyanoalkyl, C1-C4 hydroxyalkyl, C1-C4 haloalkoxy, C1-C4 alkoxy, C1-C4 alkylamino, (C1-C4)(C1-C4) dialkylamino, C1-C4 aminoalkyl, ‒CO2H, and Ar2; and wherein Ar2is a 6-membered aryl substituted with 0, 1, 2, or 3 groups independently selected from halogen, ‒CN, ‒NH2, ‒OH, ‒NO2, C1-C4 alkyl, C2-C4 alkenyl, C1-C4 haloalkyl, C1-C4 cyanoalkyl, C1-C4 hydroxyalkyl, C1-C4 haloalkoxy, C1-C4 alkoxy, C1-C4 alkylamino, (C1-C4)(C1-C4) dialkylamino, C1-C4 aminoalkyl, and ‒CO2H, or a pharmaceutically acceptable salt thereof, provided that when Ar1is a 6-membered aryl, then n is 1, and provided that when Ar1is a 9- or 10-membered heteroaryl, then Ar1is not substituted with an Ar2group.

[0009] Also disclosed are pharmaceutical compositions comprising an effective amount of adisclosed compound or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier.

[0010] Also disclosed are methods for modulating read-through of a premature termination codon in a subject, the method comprising administering to the subject an effective amount of a disclosed compound or a pharmaceutically acceptable salt thereof.

[0011] Also disclosed are methods for modulating read-through of a premature termination codon in a cell, the method comprising contacting the cell with an effective amount of a disclosed compound or a pharmaceutically acceptable salt thereof.

[0012] Also disclosed are methods for treating a disorder associated with the presence of a premature termination codon in a subject in need thereof, the method comprising administering to the subject an effective amount of a compound having a structure represented by a formula:, wherein n is selected from 0 and 1; wherein each of Q1, Q2, and Q3is independently selected from ‒CH2‒ and ‒C(O)‒, provided that at least one of Q1and Q2is ‒C(O)‒; wherein Z is selected from ‒CH(CO2H)‒ and ‒CH(C(O)NH2)‒; wherein each of R1and R2is independently selected from hydrogen and C1-C4 alkyl; wherein Ar1is selected from a 6- membered aryl, an isoxazolyl, an oxadiazolyl, an oxazolyl, and a 9- or 10-membered heteroaryl, and is substituted with 0, 1, 2, or 3 groups independently selected from halogen, ‒CN, ‒NH2, ‒OH, ‒NO2, C1-C4 alkyl, C2-C4 alkenyl, C1-C4 haloalkyl, C1-C4 cyanoalkyl, C1-C4 hydroxyalkyl, C1-C4 haloalkoxy, C1-C4 alkoxy, C1-C4 alkylamino, (C1-C4)(C1-C4) dialkylamino, C1-C4 aminoalkyl, ‒CO2H, and Ar2; and wherein Ar2is selected from a 6- membered aryl and a 6-membered heteroaryl, and is substituted with 0, 1, 2, or 3 groups independently selected from halogen, ‒CN, ‒NH2, ‒OH, ‒NO2, C1-C4 alkyl, C2-C4 alkenyl, C1-C4 haloalkyl, C1-C4 cyanoalkyl, C1-C4 hydroxyalkyl, C1-C4 haloalkoxy, C1-C4 alkoxy, C1-C4 alkylamino, (C1-C4)(C1-C4) dialkylamino, C1-C4 aminoalkyl, ‒CO2H, and ‒C(O)NH2, or a pharmaceutically acceptable salt thereof, provided that when Ar1is a 9- or 10-membered heteroaryl, then Ar1is not substituted with an Ar2group.

[0013] Also disclosed are methods for treating a disorder associated with the presence of a premature termination codon in a subject in need thereof, the method comprisingadministering to the subject an effective amount of a compound having a structure represented by a formula:, wherein n is selected from 0 and 1; wherein each of Q1, Q2, and Q3is independently selected from ‒CH2‒ and ‒C(O)‒, provided that at least one of Q1and Q2is ‒C(O)‒; wherein Z is selected from ‒CH(CO2H)‒ and ‒CH(C(O)NH2)‒; wherein each of R1and R2is independently selected from hydrogen and C1-C4 alkyl; wherein Ar1is selected from a 6- membered aryl, an isoxazolyl, an oxadiazolyl, and a 9- or 10-membered heteroaryl, and is substituted with 0, 1, 2, or 3 groups independently selected from halogen, ‒CN, ‒NH2, ‒OH, ‒NO2, C1-C4 alkyl, C2-C4 alkenyl, C1-C4 haloalkyl, C1-C4 cyanoalkyl, C1-C4 hydroxyalkyl, C1-C4 haloalkoxy, C1-C4 alkoxy, C1-C4 alkylamino, (C1-C4)(C1-C4)dialkylamino, C1-C4 aminoalkyl, ‒CO2H, and Ar2; and wherein Ar2 is a 6-membered arylsubstituted with 0, 1, 2, or 3 groups independently selected from halogen, ‒CN, ‒NH2, ‒OH, ‒NO2, C1-C4 alkyl, C2-C4 alkenyl, C1-C4 haloalkyl, C1-C4 cyanoalkyl, C1-C4 hydroxyalkyl, C1-C4 haloalkoxy, C1-C4 alkoxy, C1-C4 alkylamino, (C1-C4)(C1-C4) dialkylamino, C1-C4 aminoalkyl, and ‒CO2H, or a pharmaceutically acceptable salt thereof, provided that when Ar1is a 9- or 10-membered heteroaryl, then Ar1is not substituted with an Ar2group.

[0014] Also disclosed are methods for treating a disorder in a subject identified as having a premature termination codon, the method comprising administering to the subject an effective amount of a compound having a structure represented by a formula:, wherein n is selected from 0 and 1; wherein each of Q1, Q2, and Q3is independently selected from ‒CH2‒ and ‒C(O)‒, provided that at least one of Q1and Q2is ‒C(O)‒; wherein Z is selected from ‒CH(CO2H)‒ and ‒CH(C(O)NH2)‒; wherein each of R1and R2is independently selected from hydrogen and C1-C4 alkyl; wherein Ar1is selected from a 6-membered aryl, an isoxazolyl, an oxadiazolyl, an oxazolyl, and a 9- or 10-membered heteroaryl, and is substituted with 0, 1, 2, or 3 groups independently selected from halogen, ‒CN, ‒NH2, ‒OH, ‒NO2, C1-C4 alkyl, C2-C4 alkenyl, C1-C4 haloalkyl, C1-C4 cyanoalkyl, C1-C4 hydroxyalkyl, C1-C4 haloalkoxy, C1-C4 alkoxy, C1-C4 alkylamino, (C1-C4)(C1-C4) dialkylamino, C1-C4 aminoalkyl, ‒CO2H, and Ar2; and wherein Ar2is selected from a 6- membered aryl and a 6-membered heteroaryl, and is substituted with 0, 1, 2, or 3 groups independently selected from halogen, ‒CN, ‒NH2, ‒OH, ‒NO2, C1-C4 alkyl, C2-C4 alkenyl, C1-C4 haloalkyl, C1-C4 cyanoalkyl, C1-C4 hydroxyalkyl, C1-C4 haloalkoxy, C1-C4 alkoxy, C1-C4 alkylamino, (C1-C4)(C1-C4) dialkylamino, C1-C4 aminoalkyl, ‒CO2H, and ‒C(O)NH2, or a pharmaceutically acceptable salt thereof, provided that when Ar1is a 9- or 10-membered heteroaryl, then Ar1is not substituted with an Ar2group.

[0015] Also disclosed are methods for treating a disorder in a subject identified as having a premature termination codon, the method comprising administering to the subject an effective amount of a compound having a structure represented by a formula:, wherein n is selected from 0 and 1; wherein each of Q1, Q2, and Q3is independently selected from ‒CH2‒ and ‒C(O)‒, provided that at least one of Q1and Q2is ‒C(O)‒; wherein Z is selected from ‒CH(CO2H)‒ and ‒CH(C(O)NH2)‒; wherein each of R1and R2is independently selected from hydrogen and C1-C4 alkyl; wherein Ar1is selected from a 6- membered aryl, an isoxazolyl, an oxadiazolyl, and a 9- or 10-membered heteroaryl, and is substituted with 0, 1, 2, or 3 groups independently selected from halogen, ‒CN, ‒NH2, ‒OH, ‒NO2, C1-C4 alkyl, C2-C4 alkenyl, C1-C4 haloalkyl, C1-C4 cyanoalkyl, C1-C4 hydroxyalkyl, C1-C4 haloalkoxy, C1-C4 alkoxy, C1-C4 alkylamino, (C1-C4)(C1-C4) dialkylamino, C1-C4 aminoalkyl, ‒CO2H, and Ar2; and wherein Ar2is a 6-membered aryl substituted with 0, 1, 2, or 3 groups independently selected from halogen, ‒CN, ‒NH2, ‒OH, ‒NO2, C1-C4 alkyl, C2-C4 alkenyl, C1-C4 haloalkyl, C1-C4 cyanoalkyl, C1-C4 hydroxyalkyl, C1-C4 haloalkoxy, C1-C4 alkoxy, C1-C4 alkylamino, (C1-C4)(C1-C4) dialkylamino, C1-C4 aminoalkyl, and ‒CO2H, or a pharmaceutically acceptable salt thereof, provided that when Ar1is a 9- or 10-membered heteroaryl, then Ar1is not substituted with an Ar2group.

[0016] Also disclosed are kits comprising a compound having a structure represented by a formula:, wherein n is selected from 0 and 1; wherein each of Q1, Q2, and Q3is independently selected from ‒CH2‒ and ‒C(O)‒, provided that at least one of Q1and Q2is ‒C(O)‒; wherein Z is selected from ‒CH(CO2H)‒ and ‒CH(C(O)NH2)‒; wherein each of R1and R2is independently selected from hydrogen and C1-C4 alkyl; wherein Ar1is selected from a 6- membered aryl, an isoxazolyl, an oxadiazolyl, an oxazolyl, and a 9- or 10-membered heteroaryl, and is substituted with 0, 1, 2, or 3 groups independently selected from halogen, ‒CN, ‒NH2, ‒OH, ‒NO2, C1-C4 alkyl, C2-C4 alkenyl, C1-C4 haloalkyl, C1-C4 cyanoalkyl, C1-C4 hydroxyalkyl, C1-C4 haloalkoxy, C1-C4 alkoxy, C1-C4 alkylamino, (C1-C4)(C1-C4) dialkylamino, C1-C4 aminoalkyl, ‒CO2H, and Ar2; and wherein Ar2is selected from a 6- membered aryl and a 6-membered heteroaryl, and is substituted with 0, 1, 2, or 3 groups independently selected from halogen, ‒CN, ‒NH2, ‒OH, ‒NO2, C1-C4 alkyl, C2-C4 alkenyl, C1-C4 haloalkyl, C1-C4 cyanoalkyl, C1-C4 hydroxyalkyl, C1-C4 haloalkoxy, C1-C4 alkoxy, C1-C4 alkylamino, (C1-C4)(C1-C4) dialkylamino, C1-C4 aminoalkyl, ‒CO2H, and ‒C(O)NH2, or a pharmaceutically acceptable salt thereof, provided that when Ar1is a 9- or 10-membered heteroaryl, then Ar1is not substituted with an Ar2group, and one or more selected from: (a) at least one agent known for the treatment of a disorder associated with the presence of a premature termination codon; (b) at least one device known for the treatment of a disorder associated with the presence of a premature termination codon; (c) instructions for administering the compound in connection with treating a disorder associated with the presence of a premature termination codon; (d) instructions for administering the compound in connection with reducing the risk of a disorder associated with the presence of a premature termination codon; and (e) instructions for treating a disorder associated with the presence of a premature termination codon.

[0017] Also disclosed are kits comprising a compound having a structure represented by a formula:, wherein n is selected from 0 and 1; wherein each of Q1, Q2, and Q3is independently selected from ‒CH2‒ and ‒C(O)‒, provided that at least one of Q1and Q2is ‒C(O)‒; wherein Z is selected from ‒CH(CO2H)‒ and ‒CH(C(O)NH2)‒; wherein each of R1and R2is independently selected from hydrogen and C1-C4 alkyl; wherein Ar1is selected from a 6- membered aryl, an isoxazolyl, an oxadiazolyl, and a 9- or 10-membered heteroaryl, and is substituted with 0, 1, 2, or 3 groups independently selected from halogen, ‒CN, ‒NH2, ‒OH, ‒NO2, C1-C4 alkyl, C2-C4 alkenyl, C1-C4 haloalkyl, C1-C4 cyanoalkyl, C1-C4 hydroxyalkyl, C1-C4 haloalkoxy, C1-C4 alkoxy, C1-C4 alkylamino, (C1-C4)(C1-C4) dialkylamino, C1-C4 aminoalkyl, ‒CO2H, and Ar2; and wherein Ar2is a 6-membered aryl substituted with 0, 1, 2, or 3 groups independently selected from halogen, ‒CN, ‒NH2, ‒OH, ‒NO2, C1-C4 alkyl, C2-C4 alkenyl, C1-C4 haloalkyl, C1-C4 cyanoalkyl, C1-C4 hydroxyalkyl, C1-C4 haloalkoxy, C1-C4 alkoxy, C1-C4 alkylamino, (C1-C4)(C1-C4) dialkylamino, C1-C4 aminoalkyl, and ‒CO2H, or a pharmaceutically acceptable salt thereof, provided that when Ar1is a 9- or 10-membered heteroaryl, then Ar1is not substituted with an Ar2group., and one or more selected from: (a) at least one agent known for the treatment of a disorder associated with the presence of a premature termination codon; (b) at least one device known for the treatment of a disorder associated with the presence of a premature termination codon; (c) instructions for administering the compound in connection with treating a disorder associated with the presence of a premature termination codon; (d) instructions for administering the compound in connection with reducing the risk of a disorder associated with the presence of a premature termination codon; and (e) instructions for treating a disorder associated with the presence of a premature termination codon.

[0018] While aspects of the present invention can be described and claimed in a particular statutory class, such as the system statutory class, this is for convenience only and one of skill in the art will understand that each aspect of the present invention can be described and claimed in any statutory class. Unless otherwise expressly stated, it is in no way intended that any method or aspect set forth herein be construed as requiring that its steps be performed in a specific order. Accordingly, where a method claim does not specifically state in the claims or descriptions that the steps are to be limited to a specific order, it is no way intended that an order be inferred, in any respect. This holds for any possible non-expressbasis for interpretation, including matters of logic with respect to arrangement of steps or operational flow, plain meaning derived fiom grammatical organization or punctuation, or the number or type of aspects described in the specification.BRIEF DESCRIPTION OF THE FIGURES

[0019] The accompanying figures, which are incorporated in and constitute a part of this specification, illustrate several aspects and together with the description serve to explain the principles of the invention.

[0020] FIG. 1 shows a representative schematic illustrating that different compound classes induce PTC readthrough by distinct mechanisms.

[0021] Additional advantages of the invention will be set forth in part in the description which follows, and in part will be obvious from the description, or can be learned by practice of the invention. The advantages of the invention 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 invention.DETAILED DESCRIPTION

[0022] The present invention can be understood more readily by reference to the following detailed description of the invention and the Examples included therein.

[0023] Before the present compounds, compositions, articles, systems, devices, and / or methods are disclosed and described, it is to be understood that they are not limited to specific synthetic methods unless otherwise specified, or to particular reagents unless otherwise specified, as such may, of course, vary. It is also to be understood that the terminology used herein is for the purpose of describing particular aspects only and is not intended to be limiting. Although any methods and materials similar or equivalent to those described herein can be used in the practice or testing of the present invention, example methods and materials are now described.

[0024] While aspects of the present invention can be described and claimed in a particular statutory class, such as the system statutory class, this is for convenience only and one of skill in the art will understand that each aspect of the present invention can be described and claimed in any statutory class. Unless otherwise expressly stated, it is in no way intended that any method or aspect set forth herein be construed as requiring that its steps beperformed in a specific order. Accordingly, where a method claim does not specifically state in the claims or descriptions that the steps are to be limited to a specific order, it is no way intended that an order be inferred, in any respect. This holds for any possible non-express basis for interpretation, including matters of logic with respect to arrangement of steps or operational flow, plain meaning derived from grammatical organization or punctuation, or the number or type of aspects described in the specification.

[0025] Throughout this application, 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 this 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. Nothing herein is to be construed as an admission that the present invention is not entitled to antedate such publication by virtue of prior invention. Further, the dates of publication provided herein may be different from the actual publication dates, which can require independent confirmation. A. DEFINITIONS

[0026] 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. Thus, for example, reference to “a functional group,” “an alkyl,” or “a residue” includes mixtures of two or more such functional groups, alkyls, or residues, and the like.

[0027] As used in the specification and in the claims, the term “comprising” can include the aspects “consisting of” and “consisting essentially of.”

[0028] Ranges can be expressed herein as from “about” one particular value, and / or to “about” another particular value. When such a range is expressed, another aspect 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 aspect. 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. It is also understood that there are a number of values disclosed herein, and that each value is also herein disclosed as “about” that particular value in addition to the value itself. For example, if the value “10” is disclosed, then “about 10” is also disclosed. It is also understood that each unit between two particular units are also disclosed. For example, if10 and 15 are disclosed, then 11, 12, 13, and 14 are also disclosed.

[0029] As used herein, the terms “about” and “at or about” mean that the amount or value in question can be the value designated some other value approximately or about the same. It is generally understood, as used herein, that it is the nominal value indicated ±10% variation unless otherwise indicated or inferred. The term is intended to convey that similar values promote equivalent results or effects recited in the claims. That is, it is understood that amounts, sizes, formulations, parameters, and other quantities and characteristics are not and need not be exact, but can be approximate and / or larger or smaller, as desired, reflecting tolerances, conversion factors, rounding off, measurement error and the like, and other factors known to those of skill in the art. In general, an amount, size, formulation, parameter or other quantity or characteristic is “about” or “approximate” whether or not expressly stated to be such. It is understood that where “about” is used before a quantitative value, the parameter also includes the specific quantitative value itself, unless specifically stated otherwise.

[0030] 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.

[0031] 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.

[0032] As used herein, “IC50” is intended to refer to the concentration of a substance (e.g., a compound or a drag) that is required for 50% inhibition of a biological process, or component of a process, including a protein, subunit, organelle, ribanucleoprotein, etc. In one aspect, an IC50can refer to the concentration of a substance that is required for 50% inhibition in vivo, as further defined elsewhere herein.

[0033] As used herein, “EC50” is intended to refer to the concentration of a substance (e.g., a compound or a drag) that is required for 50% agonism of a biological process, or component of a process, including a protein, subunit, organelle, ribonucleoprotein, etc. In one aspect, an EC50can refer to the concentration of a substance that is required for 50% agonism in vivo, as further defined elsewhere herein. In a further aspect, EC50refers to the concentration of agonist that provokes a response halfway between the basetine and maximum response.

[0034] As used herein, “CC50” is intended to refer to the concentration of a substance (e.g., a compound or a drug) that is required for 50% reduction of cell viability. In one aspect, a CC50can refer to the concentration of a substance that is required for 50% reduction of cell viability in vivo, as further defined elsewhere herein. In a further aspect, CC50can refer to the concentration of a substance that is required for 50% reduction of cell viability in vitro, as further defined elsewhere herein.

[0035] As used herein, the terms “optional” or “optionally” means that the subsequently described event or circumstance can or cannot occur, and that the description includes instances where said event or circumstance occurs and instances where it does not.

[0036] As used herein, the term “subject” can be a vertebrate, such as a mammal, a fish, a bird, a reptile, or an amphibian. Thus, the subject of the herein disclosed methods can be a human, non-human primate, horse, pig, rabbit, dog, sheep, goat, cow, cat, guinea pig or rodent. The term does not denote a particular age or sex. Thus, adult and newborn subjects, as well as fetuses, whether male or female, are intended to be covered. In one aspect, the subject is a mammal. A patient refers to a subject afflicted with a disease or disorder. The term “patient” includes human and veterinary subjects.

[0037] As used herein, the term “treatment” refers to the medical management of a patient with the intent to cure, ameliorate, stabilize, or prevent a disease, pathological condition, or disorder. This term includes active treatment, that is, treatment directed specifically toward the improvement of a disease, pathological condition, or disorder, and also includes causal treatment, that is, treatment directed toward removal of the cause of the associated disease, pathological condition, or disorder. In addition, this term includes palliative treatment, that is, treatment designed for the relief of symptoms rather than the curing of the disease, pathological condition, or disorder; preventative treatment, that is, treatment directed to minimizing or partially or completely inhibiting the development of the associated disease, pathological condition, or disorder; and supportive treatment, that is, treatment employed to supplement another specific therapy directed toward the improvement of the associated disease, pathological condition, or disorder. In various aspects, the term covers any treatment of a subject, including a mammal (e.g., a human), and includes: (i) preventing the disease from occurring in a subject that can be predisposed to the disease but has not yet been diagnosed as having it; (ii) inhibiting the disease, i.e., arresting its development; or (iii) relieving the disease, i.e., causing regression of the disease. In one aspect, the subject is a mammal such as a primate, and, in a further aspect, the subject is a human. The term “subject” also includes domesticated animals (e.g., cats, dogs, etc.), livestock (e.g., cattle,horses, pigs, sheep, goats, etc.), and laboratory animals (e.g. , mouse, rabbit, rat, guinea pig, fruit fly, etc.).

[0038] As used herein, the term "prevent” or preventing” refers to precluding, averting, obviating, forestalling, stopping, or hindering something from happening, especially by advance action. It is understood that where reduce, inhibit or prevent are used herein, unless specifically indicated otherwise, the use of the other two words is also expressly disclosed.

[0039] As used herein, the term “diagnosed” means having been subjected to a physical examination by a person of skill, for example, a physician, and found to have a condition that can be diagnosed or treated by the compounds, compositions, or methods disclosed herein.

[0040] As used herein, the terms “administering” and “administration” refer to any method of providing a pharmaceutical preparation to a subject. Such methods are well known to those skilled in the art and include, but are not limited to, oral administration, transdermal administration, administration by inhalation, nasal administration, topical administration, intravaginal administration, ophthalmic administration, intraaural administration, intracerebral administration, rectal administration, sublingual administration, buccal administration, and parenteral administration, including injectable such as intravenous administration, intra-arterial administration, intramuscular administration, and subcutaneous administration. Administration can be continuous or intermittent. In various aspects, a preparation can be administered therapeutically; that is, administered to treat an existing disease or condition. In further various aspects, a preparation can be administered prophy tactically; that is, administered for prevention of a disease or condition.

[0041] As used herein, the terms “effective amount” and “amount effective” refer to an amount that is sufficient to achieve the desired result or to have an effect on an undesired condition. For example, a “therapeutically effective amount” refers to an amount that is sufficient to achieve the desired therapeutic result or to have an effect on undesired symptoms, but is generally insufficient to cause adverse side effects. The specific therapeutically effective dose level for any particular patient will depend upon a variety of factors including the disorder being treated and the severity of the disorder; the specific composition employed; the age, body weight, general health, sex and diet of the patient; the time of administration; the route of administration; the rate of excretion of the specific compound employed; the duration of the treatment; drugs used in combination or coincidental with the specific compound employed and like factors well known in the medical arts. For example, it is well within the skill of the art to start doses of a compound at levels lower than those required to achieve the desired therapeutic effect and to graduallyincrease the dosage until the desired effect is achieved. If desired, the effective daily dose can be divided into multiple doses for purposes of administration. Consequently, single dose compositions can contain such amounts or submultiples thereof to make up the daily dose. The dosage can be adjusted by the individual physician in the event of any contraindications. Dosage can vary, and can be administered in one or more dose administrations daily, for one or several days. Guidance can be found in the literature for appropriate dosages for given classes of pharmaceutical products. In further various aspects, a preparation can be administered in a “prophylactically effective amount”; that is, an amount effective for prevention of a disease or condition.

[0042] As used herein, “dosage form” means a pharmacologically active material in a medium, carrier, vehicle, or device suitable for administration to a subject. A dosage forms can comprise inventive a disclosed compound, a product of a disclosed method of making, or a salt, solvate, or polymorph thereof, in combination with a pharmaceutically acceptable excipient, such as a preservative, buffer, saline, or phosphate buffered saline. Dosage forms can be made using conventional pharmaceutical manufacturing and compounding techniques. Dosage forms can comprise inorganic or organic buffers (e.g., sodium or potassium salts of phosphate, carbonate, acetate, or citrate) and pH adjustment agents (e.g., hydrochloric acid, sodium or potassium hydroxide, salts of citrate or acetate, amino acids and their salts) antioxidants (e.g., ascorbic acid, alpha-tocopherol), surfactants (e.g., polysorbate 20, polysorbate 80, polyoxyethylene 9-10 nonyl phenol, sodium desoxycholate), solution and / or cryo / lyo stabilizers (e.g., sucrose, lactose, mannitol, trehalose), osmotic adjustment agents (e.g., salts or sugars), antibacterial agents (e.g., benzoic acid, phenol, gentamicin), antifoaming agents (e.g., polydimethylsilozone), preservatives (e.g., thimerosal, 2- phenoxyethanol, EDTA), polymeric stabilizers and viscosity-adjustment agents (e.g., polyvinylpyrrolidone, poloxamer 488, carboxymethylcellulose) and co-solvents (e.g., glycerol, polyethylene glycol, ethanol). A dosage form formulated for injectable use can have a disclosed compound, a product of a disclosed method of making, or a salt, solvate, or polymorph thereof, suspended in sterile saline solution for injection together with a preservative.

[0043] As used herein, “kit” means a collection of at least two components constituting the kit. Together, the components constitute a functional unit for a given purpose. Individual member components may be physically packaged together or separately. For example, a kit comprising an instruction for using the kit may or may not physically include the instruction with other individual member components. Instead, the instruction can be supplied as aseparate member component, either in a paper form or an electronic form which may be supplied on computer readable memory device or downloaded from an internet website, or as recorded presentation.

[0044] As used herein, “instruction(s)” means documents describing relevant materials or methodologies pertaining to a kit. These materials may include any combination of the following: background information, list of components and their availability information (purchase information, etc.), brief or detailed protocols for using the kit, trouble-shooting, references, technical support, and any other related documents. Instructions can be supplied with the kit or as a separate member component, either as a paper form or an electronic form, which may be supplied on computer readable memory device or downloaded from an internet website, or as recorded presentation. Instructions can comprise one or multiple documents, and are meant to include future updates.

[0045] As used herein, the terms “therapeutic agent” include any synthetic or naturally occurring biologically active compound or composition of matter which, when administered to an organism (human or nonhuman animal), induces a desired pharmacologic, immunogenic, and / or physiologic effect by local and / or systemic action. The term therefore encompasses those compounds or chemicals traditionally regarded as drags, vaccines, and biopharmaceuticals including molecules such as proteins, peptides, hormones, nucleic acids, gene constructs and the like. Examples of therapeutic agents are described in well-known literature references such as the Merck Index (14thedition), the Physicians' Desk Reference (64thedition), and The Pharmacological Basis of Therapeutics (12thedition) , and they include, without limitation, medicaments; vitamins; mineral supplements; substances used for the treatment, prevention, diagnosis, cure or mitigation of a disease or illness; substances that affect the structure or function of the body, or pro-drugs, which become biologically active or more active after they have been placed in a physiological environment. For example, the term “therapeutic agent” includes compounds or compositions for use in all of the major therapeutic areas including, but not limited to, adjuvants; anti-infectives such as antibiotics and antiviral agents; analgesics and analgesic combinations, anorexics, anti-inflammatory agents, anti-epileptics, local and general anesthetics, hypnotics, sedatives, antipsychotic agents, neuroleptic agents, antidepressants, anxiolytics, antagonists, neuron blocking agents, anticholinergic and cholinomimetic agents, antimuscarinic and muscarinic agents, antiadrenergics, antiarrhythmics, antihypertensive agents, hormones, and nutrients, antiarthritics, antiasthmatic agents, anticonvulsants, antihistamines, antinauseants, antineoplastics, antipruritics, antipyretics; antispasmodics, cardiovascular preparations(including calcium channel blockers, beta-blockers, beta-agonists and antiarrythmics), antihypertensives, diuretics, vasodilators; central nervous system stimulants; cough and cold preparations; decongestants; diagnostics; hormones; bone growth stimulants and bone resorption inhibitors; immunosuppressives; muscle relaxants; psychostimulants; sedatives; tranquilizers; proteins, peptides, and fragments thereof (whether naturally occurring, chemically synthesized or recombinantly produced); and nucleic acid molecules (polymeric forms of two or more nucleotides, either ribonucleotides (RNA) or deoxyribonucleotides (DNA) including both double- and single-stranded molecules, gene constructs, expression vectors, antisense molecules and the like), small molecules (e.g., doxorubicin) and other biologically active macromolecules such as, for example, proteins and enzymes. The agent may be a biologically active agent used in medical, including veterinary, applications and in agriculture, such as with plants, as well as other areas. The term "therapeutic agent" also includes without limitation, medicaments; vitamins; mineral supplements; substances used for the treatment, prevention, diagnosis, cure or mitigation of disease or illness; or substances which affect the structure or function of the body; or pro- drugs, which become biologically active or more active after they have been placed in a predetermined physiological environment.

[0046] The term ‘'pharmaceutically acceptable” describes a material that is not biologically or otherwise undesirable, i.e., without causing an unacceptable level of undesirable biological effects or interacting in a deleterious manner.

[0047] As used herein, the term “derivative” refers to a compound having a structure derived from the structure of a parent compound (e.g., a compound disclosed herein) and whose structure is sufficiently similar to those disclosed herein and based upon that similarity, would be expected by one skilled in the art to exhibit the same or similar activities and utilities as the claimed compounds, or to induce, as a precursor, the same or similar activities and utilities as the claimed compounds. Exemplary derivatives include salts, esters, and amides, salts of esters or amides, and N-oxides of a parent compound.

[0048] As used herein, the term “pharmaceutically acceptable carrier” refers to sterile aqueous or nonaqueous solutions, dispersions, suspensions or emulsions, as well as sterile powders for reconstitution into sterile injectable solutions or dispersions just prior to use. Examples of suitable aqueous and nonaqueous carriers, diluents, solvents or vehicles include water, ethanol, polyols (such as glycerol, propylene glycol, polyethylene glycol and the like), carboxymethylcellulose and suitable mixtures thereof, vegetable oils (such as olive oil) and injectable organic esters such as ethyl oleate. Proper fluidity can be maintained, for example,by the use of coating materials such as lecithin, by the maintenance of the required particle size in the case of dispersions and by the use of surfactants. These compositions can also contain adjuvants such as preservatives, wetting agents, emulsifying agents and dispersing agents. Prevention of the action of microorganisms can be ensured by the inclusion of various antibacterial and antifungal agents such as paraben, chlorobutanol, phenol, sorbic acid and the like. It can also be desirable to include isotonic agents such as sugars, sodium chloride and the like. Prolonged absorption of the injectable pharmaceutical form can be brought about by the inclusion of agents, such as aluminum monostearate and gelatin, which delay absorption. Injectable depot forms are made by forming microencapsule matrices of the drag in biodegradable polymers such as polylactide-polyglycolide, poly(orthoesters) and poly(anhydrides). Depending upon the ratio of drag to polymer and the nature of the particular polymer employed, the rate of drag release can be controlled. Depot injectable formulations are also prepared by entrapping the drag in liposomes or microemulsions which are compatible with body tissues. The injectable formulations can be sterilized, for example, by filtration through a bacterial-retaining filter or by incorporating sterilizing agents in the form of sterile solid compositions that can be dissolved or dispersed in sterile water or other sterile injectable media just prior to use. Suitable inert carriers can include sugars such as lactose. Desirably, at least 95% by weight of the particles of the active ingredient have an effective particle size in the range of 0.01 to 10 micrometers.

[0049] The compounds according to this disclosure may form prodrags at hydroxyl or amino functionalities using alkoxy, amino acids, etc., groups as the prodrag forming moieties. For instance, the hydroxymethyl position may form mono-, di- or triphosphates and again these phosphates can form prodrags. Preparations of such prodrag derivatives are discussed in various literature sources (examples are: Alexander et al., J. Med. Chem. 1988, 31, 318; Aligas-Martin et al., PCT WO 2000 / 041531, p. 30). The nitrogen function converted in preparing these derivatives is one (or more) of the nitrogen atoms of a compound of the disclosure.

[0050] “Derivatives” of the compounds disclosed herein are pharmaceutically acceptable salts, prodrags, deuterated forms, radioactively labeled forms, isomers, solvates and combinations thereof. The “combinations” mentioned in this context are refer to derivatives falling within at least two of the groups: pharmaceutically acceptable salts, prodrags, deuterated forms, radioactively labeled forms, isomers, and solvates. Examples of radioactively labeled forms include compounds labeled with tritium, phosphorous-32, iodine- 129, carbon- 11, fluorine- 18, and the like.

[0051] Compounds described herein comprise atoms in both their natural isotopic abundance and in non-natural abundance. The disclosed compounds can be isotopically labeled or isotopically substituted compounds identical to those described, but for the fact that one or more atoms are replaced by an atom having an atomic mass or mass number different from the atomic mass or mass number typically found in nature. Examples of isotopes that can be incorporated into compounds of the invention include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorous, fluorine and chlorine, such as2H,3H,13C,14C,15N,18O,17O,35S,18F and36Cl, respectively. Compounds further comprise prodrugs thereof, and pharmaceutically acceptable salts of said compounds or of said prodrugs which contain the aforementioned isotopes and / or other isotopes of other atoms are within the scope of this invention. Certain isotopically labeled compounds of the present invention, for example those into which radioactive isotopes such as3H and14C are incorporated, are useful in drug and / or substrate tissue distribution assays. Tritiated, i.e.,3H, and carbon-14, i.e.,14C, isotopes are particularly preferred for their ease of preparation and detectability. Further, substitution with heavier isotopes such as deuterium, i.e.,2H, can afford certain therapeutic advantages resulting from greater metabolic stability, for example increased in vivo half-life or reduced dosage requirements and, hence, may be preferred in some circumstances. Isotopically labeled compounds of the present invention and prodrugs thereof can generally be prepared by carrying out the procedures below, by substituting a readily available isotopically labeled reagent for a non-isotopically labeled reagent.

[0052] The compounds described in the invention can be present as a solvate. In some cases, the solvent used to prepare the solvate is an aqueous solution, and the solvate is then often referred to as a hydrate. The compounds can be present as a hydrate, which can be obtained, for example, by crystallization from a solvent or from aqueous solution. In this connection, one, two, three or any arbitrary number of solvent or water molecules can combine with the compounds according to the invention to form solvates and hydrates. Unless stated to the contrary, the invention includes all such possible solvates.

[0053] The term “co-crystal” means a physical association of two or more molecules that owe their stability through non-covalent interaction. One or more components of this molecular complex provide a stable framework in the crystalline lattice. In certain instances, the guest molecules are incorporated in the crystalline lattice as anhydrates or solvates, see e.g. “Crystal Engineering of the Composition of Pharmaceutical Phases. Do Pharmaceutical Co-crystals Represent a New Path to Improved Medicines?” Almarasson, O., et. al., The Royal Society of Chemistry, 1889-1896, 2004. Examples of co-crystals include p-toluenesulfonic acid and benzenesulfonic acid.

[0054] It is known that chemical substances form solids that are present in dififerent states of order that are termed polymorphic forms or modifications. The different modifications of a polymorphic substance can differ greatly in their physical properties. The compounds according to the invention can be present in dififerent polymorphic forms, with it being possible for particular modifications to be metastable. Unless stated to the contrary, the invention includes all such possible polymorphic forms.

[0055] Certain materials, compounds, compositions, and components disclosed herein can be obtained commercially or readily synthesized using techniques generally known to those of skill in the art. For example, the starting materials and reagents used in preparing the disclosed compounds and compositions are either available from commercial suppliers such as Aldrich Chemical Co., (Milwaukee, Wis.), Acres Organics (Morris Plains, N.J.), Strem Chemicals (Newburyport, MA), Fisher Scientific (Pittsburgh, Pa.), or Sigma (St. Louis, Mo.) or are prepared by methods known to those skilled in the art following procedures set forth in references such as Fieser and Fieser’s Reagents for Organic Synthesis, Volumes 1-17 (John Wiley and Sons, 1991); Rodd’s Chemistry of Carbon Compounds, Volumes 1-5 and supplemental volumes (Elsevier Science Publishers, 1989); Organic Reactions, Volumes 1-40 (John Wiley and Sons, 1991); March’s Advanced Organic Chemistry, (John Wiley and Sons, 4th Edition); and Larock’s Comprehensive Organic Transformations (VCH Publishers Inc., 1989).

[0056] Unless otherwise expressly stated, it is in no way intended that any method set forth herein be construed as requiring that its steps be performed in a specific order. Accordingly, where a method claim does not actually recite an order to be followed by its steps or it is not otherwise specifically stated in the claims or descriptions that the steps are to be limited to a specific order, it is no way intended that an order be inferred, in any respect. This holds for any possible non-express basis for interpretation, including: matters of logic with respect to arrangement of steps or operational flow; plain meaning derived from grammatical organization or punctuation; and the number or type of embodiments described in the specification.

[0057] Disclosed are the components to be used to prepare the compositions of the invention as well as the compositions themselves to be used within the methods disclosed herein. These and other materials are disclosed herein, and it is understood that when combinations, subsets, interactions, groups, etc. of these materials are disclosed that while specific reference of each various individual and collective combinations and permutation of these compoundscannot be explicitly disclosed, each is specifically contemplated and described herein. For example, if a particular compound is disclosed and discussed and a number of modifications that can be made to a number of molecules including the compounds are discussed, specifically contemplated is each and every combination and permutation of the compound and the modifications that are possible unless specifically indicated to the contrary. Thus, if a class of molecules A, B, and C are disclosed as well as a class of molecules D, E, and F and an example of a combination molecule, A-D is disclosed, then even if each is not individually recited each is individually and collectively contemplated meaning combinations, A-E, A-F, B-D, B-E, B-F, C-D, C-E, and C-F are considered disclosed. Likewise, any subset or combination of these is also disclosed. Thus, for example, the sub-group of A-E, B-F, and C- E would be considered disclosed. This concept applies to all aspects of this application including, but not limited to, steps in methods of making and using the compositions of the invention. 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 methods of the invention.

[0058] It is understood that the compositions disclosed herein have certain functions. Disclosed herein are certain structural requirements for performing the disclosed functions, and it is understood that there are a variety of structures that can perform the same function that are related to the disclosed structures, and that these structures will typically achieve the same result.B. COMPOUNDS

[0059] In one aspect, the invention relates to piperidinedione compounds useful in treating disorders associated with the presence of a premature termination codon such as, for example, cystic fibrosis, Duchenne muscular dystrophy, aniridia, Becker muscular dystrophy, spinal muscular atrophy, Hurler syndrome, hemophilia, epidermolysis bullosa (e.g., dystrophic (DEB) form, junctional (JEB) form). Usher syndrome, and cancer.

[0060] In one aspect, the disclosed compounds modulate read-through of a premature termination codon.

[0061] In one aspect, the compounds of the invention are useful in modulating read-through of a premature termination codon in a subject (e.g., a mammal). In a further aspect, the compounds of the invention are useful in modulating read-through of a premature termination codon in at least one cell.

[0062] In one aspect, the compound has an EC50of less than 10 μM. In a further aspect, the compound has an EC50of less than 8 μM. In a still further aspect, the compound has an EC50of less than 6 μM. In yet a further aspect, the compound has an EC50of less than 4 μM. In an even further aspect, the compound has an EC50of less than 2 μM. In a still further aspect, the compound has an EC50of less than 1 μM. In yet a further aspect, the compound has an EC50of less than 0.8 μM. In an even further aspect, the compound has an EC50of less than 0.6 μM. In a still further aspect, the compound has an EC50of less than 0.4 μM. In yet a further aspect, the compound has an EC50of less than 0.2 μM. In an even further aspect, the compound has an EC50of less than 0.1 μM.

[0063] In one aspect, the compounds of the invention are useful in the treatment of a disorder associated with the presence of a premature termination codon, as further described herein.

[0064] It is contemplated that each disclosed derivative can be optionally further substituted. It is also contemplated that any one or more derivative can be optionally omitted from the invention. It is understood that a disclosed compound can be provided by the disclosed methods. It is also understood that the disclosed compounds can be employed in the disclosed methods of using. 1. STRUCTURE

[0065] In one aspect, disclosed are compounds having a structure represented by a formula:, wherein n is selected from 0 and 1; wherein each of Q1, Q2, and Q3is independently selected from ‒CH2‒ and ‒C(O)‒, provided that at least one of Q1and Q2is ‒C(O)‒; wherein Z is selected from ‒CH(CO2H)‒ and ‒CH(C(O)NH2)‒; wherein each of R1and R2is independently selected from hydrogen and C1-C4 alkyl; wherein Ar1is selected from a 6- membered aryl, an isoxazolyl, an oxadiazolyl, an oxazolyl, and a 9- or 10-membered heteroaryl, and is substituted with 0, 1, 2, or 3 groups independently selected from halogen, ‒CN, ‒NH2, ‒OH, ‒NO2, C1-C4 alkyl, C2-C4 alkenyl, C1-C4 haloalkyl, C1-C4 cyanoalkyl, C1-C4 hydroxyalkyl, C1-C4 haloalkoxy, C1-C4 alkoxy, C1-C4 alkylamino, (C1-C4)(C1-C4) dialkylamino, C1-C4 aminoalkyl, ‒CO2H, and Ar2; and wherein Ar2is selected from a 6- membered aryl and a 6-membered heteroaryl, and is substituted with 0, 1, 2, or 3 groupsindependently selected from halogen, ‒CN, ‒NH2, ‒OH, ‒NO2, C1-C4 alkyl, C2-C4 alkenyl, C1-C4 haloalkyl, C1-C4 cyanoalkyl, C1-C4 hydroxyalkyl, C1-C4 haloalkoxy, C1-C4 alkoxy, C1-C4 alkylamino, (C1-C4)(C1-C4) dialkylamino, C1-C4 aminoalkyl, ‒CO2H, and ‒C(O)NH2; or a pharmaceutically acceptable salt thereof, provided that when Ar1is a 6- membered aryl, then n is 1, and provided that when Ar1is a 9- or 10-membered heteroaryl, then Ar1is not substituted with an Ar2group.

[0066] In one aspect, disclosed are compounds having a structure represented by a formula:, wherein n is selected from 0 and 1; wherein each of Q1, Q2, and Q3is independently selected from ‒CH2‒ and ‒C(O)‒, provided that at least one of Q1and Q2is ‒C(O)‒; wherein Z is selected from ‒CH(CO2H)‒ and ‒CH(C(O)NH2)‒; wherein each of R1and R2is independently selected from hydrogen and C1-C4 alkyl; wherein Ar1is selected from a 6- membered aryl, an isoxazolyl, an oxadiazolyl, and a 9- or 10-membered heteroaryl, and is substituted with 0, 1, 2, or 3 groups independently selected from halogen, ‒CN, ‒NH2, ‒OH, ‒NO2, C1-C4 alkyl, C2-C4 alkenyl, C1-C4 haloalkyl, C1-C4 cyanoalkyl, C1-C4 hydroxyalkyl, C1-C4 haloalkoxy, C1-C4 alkoxy, C1-C4 alkylamino, (C1-C4)(C1-C4) dialkylamino, C1-C4 aminoalkyl, ‒CO2H, and Ar2; and wherein Ar2is a 6-membered aryl substituted with 0, 1, 2, or 3 groups independently selected from halogen, ‒CN, ‒NH2, ‒OH, ‒NO2, C1-C4 alkyl, C2-C4 alkenyl, C1-C4 haloalkyl, C1-C4 cyanoalkyl, C1-C4 hydroxyalkyl, C1-C4 haloalkoxy, C1-C4 alkoxy, C1-C4 alkylamino, (C1-C4)(C1-C4) dialkylamino, C1-C4 aminoalkyl, and ‒CO2H, or a pharmaceutically acceptable salt thereof, provided that when Ar1is a 6-membered aryl, then n is 1, and provided that when Ar1is a 9- or 10-membered heteroaryl, then Ar1is not substituted with an Ar2group.

[0067] In one aspect, disclosed are compounds having a structure represented by a formula:,wherein n is selected from 0 and 1; wherein each of Q1, Q2, and Q3is independently selected from ‒CH2‒ and ‒C(O)‒, provided that at least one of Q1and Q2is ‒C(O)‒; wherein Z is selected from ‒CH(CO2H)‒ and ‒CH(C(O)NH2)‒; wherein each of R1and R2is independently selected from hydrogen and C1-C4 alkyl; wherein Ar1is selected from a 6- membered aryl, an isoxazolyl, an oxadiazolyl, and a 9- or 10-membered heteroaryl, and is substituted with 0, 1, 2, or 3 groups independently selected from halogen, ‒CN, ‒NH2, ‒OH, ‒NO2, C1-C4 alkyl, C2-C4 alkenyl, C1-C4 haloalkyl, C1-C4 cyanoalkyl, C1-C4 hydroxyalkyl, C1-C4 haloalkoxy, C1-C4 alkoxy, C1-C4 alkylamino, (C1-C4)(C1-C4)dialkylamino, C1-C4 aminoalkyl, ‒CO2H, and Ar2; and wherein Ar2 is a 6-membered arylsubstituted with 0, 1, 2, or 3 groups independently selected from halogen, ‒CN, ‒NH2, ‒OH, ‒NO2, C1-C4 alkyl, C2-C4 alkenyl, C1-C4 haloalkyl, C1-C4 cyanoalkyl, C1-C4 hydroxyalkyl, C1-C4 haloalkoxy, C1-C4 alkoxy, C1-C4 alkylamino, (C1-C4)(C1-C4) dialkylamino, C1-C4 aminoalkyl, and ‒CO2H, or a pharmaceutically acceptable salt thereof, provided that when Ar1is a 9- or 10-membered heteroaryl, then Ar1is not substituted with an Ar2group.

[0068] In various aspects, the compound has a structure represented by a formula:, or a pharmaceutically acceptable salt thereof.

[0069] In various aspects, the compound has a structure represented by a formula:, wherein A is selected from –C(R20)– and –N=; wherein R20is selected from hydrogen, halogen, ‒CN, ‒NH2, ‒OH, ‒NO2, C1-C4 alkyl, C2-C4 alkenyl, C1-C4 haloalkyl, C1-C4 cyanoalkyl, C1-C4 hydroxyalkyl, C1-C4 haloalkoxy, C1-C4 alkoxy, C1-C4 alkylamino, (C1- C4)(C1-C4) dialkylamino, C1-C4 aminoalkyl, and ‒CO2H; and wherein each of R10a, R10b,R10c, R10d, and R10eis independently selected from hydrogen, halogen, ‒CN, ‒NH2, ‒OH, ‒NO2, C1-C4 alkyl, C2-C4 alkenyl, C1-C4 haloalkyl, C1-C4 cyanoalkyl, C1-C4 hydroxyalkyl, C1-C4 haloalkoxy, C1-C4 alkoxy, C1-C4 alkylamino, (C1-C4)(C1-C4) dialkylamino, C1-C4 aminoalkyl, and ‒CO2H, provided that at least two of R10a, R10b, R10c, R10d, and R10eis hydrogen, or a pharmaceutically acceptable salt.

[0070] In various aspects, the compound has a structure represented by a formula:, or a pharmaceutically acceptable salt thereof.

[0071] In various aspects, the compound has a structure represented by a formula:, wherein A is selected from –C(R20)– and –N=; wherein R20is selected from hydrogen, halogen, ‒CN, ‒NH2, ‒OH, ‒NO2, C1-C4 alkyl, C2-C4 alkenyl, C1-C4 haloalkyl, C1-C4 cyanoalkyl, C1-C4 hydroxyalkyl, C1-C4 haloalkoxy, C1-C4 alkoxy, C1-C4 alkylamino, (C1- C4)(C1-C4) dialkylamino, C1-C4 aminoalkyl, and ‒CO2H; and wherein each of R10a, R10b, R10c, R10d, and R10eis independently selected from hydrogen, halogen, ‒CN, ‒NH2, ‒OH, ‒NO2, C1-C4 alkyl, C2-C4 alkenyl, C1-C4 haloalkyl, C1-C4 cyanoalkyl, C1-C4 hydroxyalkyl, C1-C4 haloalkoxy, C1-C4 alkoxy, C1-C4 alkylamino, (C1-C4)(C1-C4) dialkylamino, C1-C4 aminoalkyl, and ‒CO2H, provided that at least two of R10a, R10b, R10c, R10d, and R10eis hydrogen, or a pharmaceutically acceptable salt.

[0072] In various aspects, the compound has a structure represented by a formula:, or a pharmaceutically acceptable salt thereof.

[0073] In various aspects, the compound has a structure represented by a formula:, wherein each of R11a, R11b, R11c, and R11dis independently selected from hydrogen, halogen, ‒CN, ‒NH2, ‒OH, ‒NO2, C1-C4 alkyl, C2-C4 alkenyl, C1-C4 haloalkyl, C1-C4 cyanoalkyl, C1-C4 hydroxyalkyl, C1-C4 haloalkoxy, C1-C4 alkoxy, C1-C4 alkylamino, (C1-C4)(C1-C4) dialkylamino, C1-C4 aminoalkyl, and ‒CO2H, provided that at least one of R11a, R11b, R11c, and R11dis hydrogen, or a pharmaceutically acceptable salt thereof.

[0074] In various aspects, the compound has a structure represented by a formula:, or a pharmaceutically acceptable salt thereof.

[0075] In various aspects, the compound has a structure represented by a formula:, wherein R12is selected from ‒CO2H and ‒C(O)NH2; and wherein each of R13a, R13b, R13c, R13d, and R13eis independently selected from hydrogen, halogen, ‒CN, ‒NH2, ‒OH, ‒NO2, C1-C4 alkyl, C2-C4 alkenyl, C1-C4 haloalkyl, C1-C4 cyanoalkyl, C1-C4 hydroxyalkyl, C1- C4 haloalkoxy, C1-C4 alkoxy, C1-C4 alkylamino, (C1-C4)(C1-C4) dialkylamino, C1-C4 aminoalkyl, ‒CO2H, and Ar2, provided that at least two of R13a, R13b, R13c, R13d, and R13eis hydrogen, or a pharmaceutically acceptable salt thereof.

[0076] In various aspects, the compound has a structure represented by a formula:, or a pharmaceutically acceptable salt thereof.

[0077] In various aspects, the compound is selected from:or a pharmaceutically acceptable salt thereof.

[0078] In various aspects, the compound is selected from:or a pharmaceutically acceptable salt thereof.

[0079] In various aspects, the compound is selected from:or a pharmaceutically acceptable salt thereof.

[0080] In various aspects, n is selected from 0 and 1. In a further aspect, n is 0. In a still further aspect, n is 1. a. A GROUPS

[0081] In one aspect, A is selected from –C(R20)– and –N=. In a further aspect, A is – C(R20)– . In a still further aspect, A is –N=. b. Q1, Q2, AND Q3GROUPS

[0082] In one aspect, each of Q1, Q2, and Q3is independently selected from ‒CH2‒ and‒C(O)‒, provided that at least one of Q1and Q2is ‒C(O)‒.

[0083] In various aspects, each of Q1and Q2is ‒C(O)‒.

[0084] In various aspects, Q1is ‒C(O)‒ and Q2is ‒CH2‒.

[0085] In various aspects, Q1is ‒CH2‒ and Q2is ‒C(O)‒.

[0086] In various aspects, Q1is ‒C(O)‒. In a further aspect, Q1is ‒CH2‒.

[0087] In various aspects, Q2is ‒C(O)‒. In a further aspect, Q2is ‒CH2‒.

[0088] In various aspects, Q3is ‒C(O)‒. In a further aspect, Q3is ‒CH2‒.

[0089] In various aspects, each of Q1and Q2is ‒C(O)‒. c. Z GROUPS

[0090] In one aspect, Z is selected from ‒CH(CO2H)‒ and ‒CH(C(O)NH2)‒. In a further aspect, Z is ‒CH(CO2H)‒. In a still further aspect, Z is ‒CH(C(O)NH2)‒. d. R1AND R2GROUPS

[0091] In one aspect, each of R1and R2is independently selected from hydrogen and C1-C4 alkyl. In a further aspect, each of R1and R2is independently selected from hydrogen, methyl, ethyl, n-propyl, and isopropyl. In a still further aspect, each of R1and R2is independently selected from hydrogen, methyl, and ethyl. In yet a further aspect, each of R1and R2is independently selected from hydrogen and methyl.

[0092] In various aspects, each of R1and R2is C1-C4 alkyl. In a further aspect, each of R1and R2is independently selected from methyl, ethyl, n-propyl, and isopropyl. In a still further aspect, each of R1and R2is independently selected from methyl and ethyl. In yet a further aspect, each of R1and R2is methyl.

[0093] In various aspects, each of R1and R2is hydrogen. e. R10A, R10B, R10C, R10D, AND R10EGROUPS

[0094] In various aspects, each of R10a, R10b, R10c, R10d, and R10eis independently selected from hydrogen, halogen, ‒CN, ‒NH2, ‒OH, ‒NO2, C1-C4 alkyl, C2-C4 alkenyl, C1-C4 haloalkyl, C1-C4 cyanoalkyl, C1-C4 hydroxyalkyl, C1-C4 haloalkoxy, C1-C4 alkoxy, C1-C4 alkylamino, (C1-C4)(C1-C4) dialkylamino, C1-C4 aminoalkyl, and ‒CO2H, provided that at least two of R10a, R10b, R10c, R10d, and R10eis hydrogen. In a further aspect, each of R10a, R10b, R10c, R10d, and R10eis independently selected from hydrogen, –F, –Cl, –NH2, –CN, –OH, ‒NO2, methyl, ethyl, n-propyl, i-propyl, ethenyl, propenyl, isopropenyl, –CH2F, –CH2Cl, –CH2CH2F, –CH2CH2Cl, –CH2CH2CH2F, –CH2CH2CH2Cl, –CH(CH3)CH2F, – CH(CH3)CH2Cl, –CH2CN, –CH2CH2CN, –CH2CH2CH2CN, –CH(CH3)CH2CN, –CH2OH, – CH2CH2OH, –CH2CH2CH2OH, –CH(CH3)CH2OH, –OCF3, –OCH2CF3, –OCH2CH2CF3, – OCH(CH3)CF3, –OCH3, –OCH2CH3, –OCH2CH2CH3, –OCH(CH3)CH3, –NHCH3, – NHCH2CH3, –NHCH2CH2CH3, –NHCH(CH3)CH3, –N(CH3)2, –N(CH2CH3)2, – N(CH2CH2CH3)2, –N(CH(CH3)CH3)2, –N(CH3)(CH2CH3), –CH2NH2, –CH2CH2NH2, – CH2CH2CH2NH2, –CH(CH3)CH2NH2, and ‒CO2H. In a further aspect, each of R10a, R10b, R10c, R10d, and R10eis independently selected from hydrogen, –F, –Cl, –NH2, –CN, –OH, ‒NO2, methyl, ethyl, ethenyl, –CH2F, –CH2Cl, –CH2CH2F, –CH2CH2Cl, –CH2CN,– CH2CH2CN, –CH2OH, –CH2CH2OH, –OCF3, –OCH2CF3, –OCH3, –OCH2CH3, –NHCH3, – NHCH2CH3, –N(CH3)2, –N(CH2CH3)2, –N(CH3)(CH2CH3), –CH2NH2, –CH2CH2NH2, and ‒CO2H. In a still further aspect, each of R10a, R10b, R10c, R10d, and R10eis independently selected from hydrogen, –F, –Cl, –NH2, –CN, –OH, ‒NO2, methyl, –CH2F, –CH2Cl, – CH2CN, –CH2OH, –OCF3, –OCH2CF3, –OCH3, –NHCH3, –N(CH3)2, –CH2NH2, and ‒CO2H.

[0095] In various aspects, each of R10a, R10b, R10c, R10d, and R10eis independently selected from hydrogen, halogen, ‒CN, ‒NH2, ‒OH, ‒NO2, C1-C4 alkyl, and C2-C4 alkenyl, provided that at least two of R10a, R10b, R10c, R10d, and R10eis hydrogen. In a further aspect, each of R10a, R10b, R10c, R10d, and R10eis independently selected from hydrogen, –F, –Cl, –NH2, –CN, –OH, ‒NO2, methyl, ethyl, n-propyl, i-propyl, ethenyl, propenyl, and isopropenyl. In a further aspect, each of R10a, R10b, R10c, R10d, and R10eis independently selected from hydrogen, –F, –Cl, –NH2, –CN, –OH, ‒NO2, methyl, ethyl, and ethenyl. In a still further aspect, each of R10a, R10b, R10c, R10d, and R10eis independently selected from hydrogen, –F, – Cl, –NH2, –CN, –OH, ‒NO2, and methyl.

[0096] In various aspects, each of R10a, R10b, R10c, R10d, and R10eis independently selected from hydrogen, halogen, ‒CN, C1-C4 alkyl, and C1-C4 alkoxy, provided that at least two of R10a, R10b, R10c, R10d, and R10eis hydrogen. In a further aspect, each of R10a, R10b, R10c, R10d, and R10eis independently selected from hydrogen, –F, –Cl, ‒CN, methyl, ethyl, n-propyl, i- propyl, –OCH3, –OCH2CH3, –OCH2CH2CH3, and –OCH(CH3)CH3. In a still further aspect, each of R10a, R10b, R10c, R10d, and R10eis independently selected from hydrogen, –F, –Cl, ‒CN, methyl, ethyl, –OCH3, and –OCH2CH3. In yet a further aspect, each of R10a, R10b, R10c, R10d, and R10eis independently selected from hydrogen, –F, –Cl, ‒CN, methyl, and –OCH3.

[0097] In various aspects, each of R10a, R10b, R10c, R10d, and R10eis independently selected from hydrogen and C1-C4 alkyl, provided that at least two of R10a, R10b, R10c, R10d, and R10eis hydrogen. In a further aspect, each of R10a, R10b, R10c, R10d, and R10eis independentlyselected from hydrogen, methyl, ethyl, n-propyl, and i-propyl. In a further aspect, each of R10a, R10b, R10c, R10d, and R10eis independently selected from hydrogen, methyl, and ethyl. In a still further aspect, each of R10a, R10b, R10c, R10d, and R10eis independently selected from from hydrogen and methyl.

[0098] In various aspects, each of R10a, R10b, R10c, R10d, and R10eis independently selected from hydrogen and ‒CO2H, provided that at least two of R10a, R10b, R10c, R10d, and R10eis hydrogen.

[0099] In various aspects, each of R10a, R10b, R10c, R10d, and R10eis independently selected from hydrogen, halogen, ‒CN, ‒NH2, ‒OH, ‒NO2, C1-C4 haloalkyl, and C1-C4 cyanoalkyl, provided that at least two of R10a, R10b, R10c, R10d, and R10eis hydrogen. In a further aspect, each of R10a, R10b, R10c, R10d, and R10eis independently selected from hydrogen, –F, –Cl, – NH2, –CN, –OH, ‒NO2, –CH2F, –CH2Cl, –CH2CH2F, –CH2CH2Cl, –CH2CH2CH2F, – CH2CH2CH2Cl, –CH(CH3)CH2F, –CH(CH3)CH2Cl, –CH2CN, –CH2CH2CN, – CH2CH2CH2CN, and –CH(CH3)CH2CN. In a further aspect, each of R10a, R10b, R10c, R10d, and R10eis independently selected from hydrogen, –F, –Cl, –NH2, –CN, –OH, ‒NO2, –CH2F, –CH2Cl, –CH2CH2F, –CH2CH2Cl, –CH2CN, and –CH2CH2CN. In a still further aspect, each of R10a, R10b, R10c, R10d, and R10eis independently selected from hydrogen, –F, –Cl, –NH2, – CN, –OH, ‒NO2, –CH2F, –CH2Cl, and –CH2CN

[0100] In various aspects, each of R10a, R10b, R10c, R10d, and R10eis independently selected from hydrogen, halogen, ‒CN, ‒NH2, ‒OH, ‒NO2, C1-C4 hydroxyalkyl, C1-C4 haloalkoxy, and C1-C4 alkoxy, provided that at least two of R10a, R10b, R10c, R10d, and R10eis hydrogen. In a further aspect, each of R10a, R10b, R10c, R10d, and R10eis independently selected from hydrogen, –F, –Cl, –NH2, –CN, –OH, ‒NO2, –CH2OH, –CH2CH2OH, – CH2CH2CH2OH, –CH(CH3)CH2OH, –OCF3, –OCH2CF3, –OCH2CH2CF3, –OCH(CH3)CF3, – OCH3, –OCH2CH3, –OCH2CH2CH3, and –OCH(CH3)CH3. In a further aspect, each of R10a, R10b, R10c, R10d, and R10eis independently selected from hydrogen, –F, –Cl, –NH2, –CN, – OH, ‒NO2, –CH2OH, –CH2CH2OH, –OCF3, –OCH2CF3, –OCH3, and –OCH2CH3. In a still further aspect, each of R10a, R10b, R10c, R10d, and R10eis independently selected from hydrogen, –F, –Cl, –NH2, –CN, –OH, ‒NO2, –CH2OH, –OCF3, –OCH2CF3, and –OCH3.

[0101] In various aspects, each of R10a, R10b, R10c, R10d, and R10eis independently selected from hydrogen, halogen, ‒CN, ‒NH2, ‒OH, ‒NO2, C1-C4 alkylamino, (C1-C4)(C1- C4) dialkylamino, and C1-C4 aminoalkyl, provided that at least two of R10a, R10b, R10c, R10d, and R10eis hydrogen. In a further aspect, each of R10a, R10b, R10c, R10d, and R10eis independently selected from hydrogen, –F, –Cl, –NH2, –CN, –OH, ‒NO2, –NHCH3, –NHCH2CH3, –NHCH2CH2CH3, –NHCH(CH3)CH3, –N(CH3)2, –N(CH2CH3)2, – N(CH2CH2CH3)2, –N(CH(CH3)CH3)2, –N(CH3)(CH2CH3), –CH2NH2, –CH2CH2NH2, – CH2CH2CH2NH2, and –CH(CH3)CH2NH2. In a further aspect, each of R10a, R10b, R10c, R10d, and R10eis independently selected from hydrogen, –F, –Cl, –NH2, –CN, –OH, ‒NO2, – NHCH3, –NHCH2CH3, –N(CH3)2, –N(CH2CH3)2, –N(CH3)(CH2CH3), –CH2NH2, and – CH2CH2NH2. In a still further aspect, each of R10a, R10b, R10c, R10d, and R10eis independently selected from hydrogen, –F, –Cl, –NH2, –CN, –OH, ‒NO2, –NHCH3, –N(CH3)2, and – CH2NH2.

[0102] In various aspects, each of R10a, R10b, R10c, R10d, and R10eis independently selected from hydrogen and halogen, provided that at least two of R10a, R10b, R10c, R10d, and R10eis hydrogen. In a further aspect, each of R10a, R10b, R10c, R10d, and R10eis independently selected from hydrogen, –F, and –Cl. In a further aspect, each of R10a, R10b, R10c, R10d, and R10eis independently selected from hydrogen and –Cl. In a still further aspect, each of R10a, R10b, R10c, R10d, and R10eis independently selected from hydrogen and –F.

[0103] In various aspects, each of R10a, R10b, R10c, R10d, and R10eis hydrogen. f. R11A, R11B, R11C, AND R11DGROUPS

[0104] In various aspects, each of R11a, R11b, R11c, and R11dis independently selected from hydrogen, halogen, ‒CN, ‒NH2, ‒OH, ‒NO2, C1-C4 alkyl, C2-C4 alkenyl, C1-C4 haloalkyl, C1-C4 cyanoalkyl, C1-C4 hydroxyalkyl, C1-C4 haloalkoxy, C1-C4 alkoxy, C1-C4 alkylamino, (C1-C4)(C1-C4) dialkylamino, C1-C4 aminoalkyl, and ‒CO2H, provided that at least one of R11a, R11b, R11c, and R11dis hydrogen. In a further aspect, each of R11a, R11b, R11c, and R11dis independently selected from hydrogen, –F, –Cl, –NH2, –CN, –OH, ‒NO2, methyl, ethyl, n-propyl, i-propyl, ethenyl, propenyl, isopropenyl, –CH2F, –CH2Cl, –CH2CH2F, – CH2CH2Cl, –CH2CH2CH2F, –CH2CH2CH2Cl, –CH(CH3)CH2F, –CH(CH3)CH2Cl, –CH2CN, –CH2CH2CN, –CH2CH2CH2CN, –CH(CH3)CH2CN, –CH2OH, –CH2CH2OH, – CH2CH2CH2OH, –CH(CH3)CH2OH, –OCF3, –OCH2CF3, –OCH2CH2CF3, –OCH(CH3)CF3, – OCH3, –OCH2CH3, –OCH2CH2CH3, –OCH(CH3)CH3, –NHCH3, –NHCH2CH3, – NHCH2CH2CH3, –NHCH(CH3)CH3, –N(CH3)2, –N(CH2CH3)2, –N(CH2CH2CH3)2, – N(CH(CH3)CH3)2, –N(CH3)(CH2CH3), –CH2NH2, –CH2CH2NH2, –CH2CH2CH2NH2, – CH(CH3)CH2NH2, and ‒CO2H. In a further aspect, each of R11a, R11b, R11c, and R11dis independently selected from hydrogen, –F, –Cl, –NH2, –CN, –OH, ‒NO2, methyl, ethyl, ethenyl, –CH2F, –CH2Cl, –CH2CH2F, –CH2CH2Cl, –CH2CN,–CH2CH2CN, –CH2OH, –CH2CH2OH, –OCF3, –OCH2CF3, –OCH3, –OCH2CH3, –NHCH3, –NHCH2CH3, –N(CH3)2, – N(CH2CH3)2, –N(CH3)(CH2CH3), –CH2NH2, –CH2CH2NH2, and ‒CO2H. In a still further aspect, each of R11a, R11b, R11c, and R11dis independently selected from hydrogen, –F, –Cl, – NH2, –CN, –OH, ‒NO2, methyl, –CH2F, –CH2Cl, –CH2CN, –CH2OH, –OCF3, –OCH2CF3, – OCH3, –NHCH3, –N(CH3)2, –CH2NH2, and ‒CO2H.

[0105] In various aspects, each of R11a, R11b, R11c, and R11dis independently selected from hydrogen, halogen, ‒CN, ‒NH2, ‒OH, ‒NO2, C1-C4 alkyl, and C2-C4 alkenyl, provided that at least one of R11a, R11b, R11c, and R11dis hydrogen. In a further aspect, each of R11a, R11b, R11c, and R11dis independently selected from hydrogen, –F, –Cl, –NH2, –CN, –OH, ‒NO2, methyl, ethyl, n-propyl, i-propyl, ethenyl, propenyl, and isopropenyl. In a further aspect, each of R11a, R11b, R11c, and R11dis independently selected from hydrogen, –F, –Cl, – NH2, –CN, –OH, ‒NO2, methyl, ethyl, and ethenyl. In a still further aspect, each of R11a, R11b, R11c, and R11dis independently selected from hydrogen, –F, –Cl, –NH2, –CN, –OH, ‒NO2, and methyl.

[0106] In various aspects, each of R11a, R11b, R11c, and R11dis independently selected from hydrogen, halogen, ‒CN, C1-C4 alkyl, and C1-C4 alkoxy, provided that at least one of R11a, R11b, R11c, and R11dis hydrogen. In a further aspect, each of R11a, R11b, R11c, and R11dis independently selected from hydrogen, –F, –Cl, ‒CN, methyl, ethyl, n-propyl, i-propyl, – OCH3, –OCH2CH3, –OCH2CH2CH3, and –OCH(CH3)CH3. In a still further aspect, each of R11a, R11b, R11c, and R11dis independently selected from hydrogen, –F, –Cl, ‒CN, methyl, ethyl, –OCH3, and –OCH2CH3. In yet a further aspect, each of R11a, R11b, R11c, and R11dis independently selected from hydrogen, –F, –Cl, ‒CN, methyl, and –OCH3.

[0107] In various aspects, each of R11a, R11b, R11c, and R11dis independently selected from hydrogen and C1-C4 alkyl, provided that at least one of R11a, R11b, R11c, and R11dis hydrogen. In a further aspect, each of R11a, R11b, R11c, and R11dis independently selected from hydrogen, methyl, ethyl, n-propyl, and i-propyl. In a further aspect, each of R11a, R11b, R11c, and R11dis independently selected from hydrogen, methyl, and ethyl. In a still further aspect, each of R11a, R11b, R11c, and R11dis independently selected from from hydrogen and methyl.

[0108] In various aspects, each of R11a, R11b, R11c, and R11dis independently selected from hydrogen and ‒CO2H, provided that at least one of R11a, R11b, R11c, and R11dis hydrogen.

[0109] In various aspects, each of R11a, R11b, R11c, and R11dis independently selected from hydrogen, halogen, ‒CN, ‒NH2, ‒OH, ‒NO2, C1-C4 haloalkyl, and C1-C4 cyanoalkyl,provided that at least one of R11a, R11b, R11c, and R11dis hydrogen. In a further aspect, each of R11a, R11b, R11c, and R11dis independently selected from hydrogen, –F, –Cl, –NH2, –CN, – OH, ‒NO2, –CH2F, –CH2Cl, –CH2CH2F, –CH2CH2Cl, –CH2CH2CH2F, –CH2CH2CH2Cl, – CH(CH3)CH2F, –CH(CH3)CH2Cl, –CH2CN, –CH2CH2CN, –CH2CH2CH2CN, and – CH(CH3)CH2CN. In a further aspect, each of R11a, R11b, R11c, and R11dis independently selected from hydrogen, –F, –Cl, –NH2, –CN, –OH, ‒NO2, –CH2F, –CH2Cl, –CH2CH2F, – CH2CH2Cl, –CH2CN, and –CH2CH2CN. In a still further aspect, each of R11a, R11b, R11c, and R11dis independently selected from hydrogen, –F, –Cl, –NH2, –CN, –OH, ‒NO2, –CH2F, – CH2Cl, and –CH2CN

[0110] In various aspects, each of R11a, R11b, R11c, and R11dis independently selected from hydrogen, halogen, ‒CN, ‒NH2, ‒OH, ‒NO2, C1-C4 hydroxyalkyl, C1-C4 haloalkoxy, and C1-C4 alkoxy, provided that at least one of R11a, R11b, R11c, and R11dis hydrogen. In a further aspect, each of R11a, R11b, R11c, and R11dis independently selected from hydrogen, –F, –Cl, –NH2, –CN, –OH, ‒NO2, –CH2OH, –CH2CH2OH, –CH2CH2CH2OH, – CH(CH3)CH2OH, –OCF3, –OCH2CF3, –OCH2CH2CF3, –OCH(CH3)CF3, –OCH3, – OCH2CH3, –OCH2CH2CH3, and –OCH(CH3)CH3. In a further aspect, each of R11a, R11b, R11c, and R11dis independently selected from hydrogen, –F, –Cl, –NH2, –CN, –OH, ‒NO2, – CH2OH, –CH2CH2OH, –OCF3, –OCH2CF3, –OCH3, and –OCH2CH3. In a still further aspect, each of R11a, R11b, R11c, and R11dis independently selected from hydrogen, –F, –Cl, – NH2, –CN, –OH, ‒NO2, –CH2OH, –OCF3, –OCH2CF3, and –OCH3.

[0111] In various aspects, each of R11a, R11b, R11c, and R11dis independently selected from hydrogen, halogen, ‒CN, ‒NH2, ‒OH, ‒NO2, C1-C4 alkylamino, (C1-C4)(C1-C4) dialkylamino, and C1-C4 aminoalkyl, provided that at least one of R11a, R11b, R11c, and R11dis hydrogen. In a further aspect, each of R11a, R11b, R11c, and R11dis independently selected from hydrogen, –F, –Cl, –NH2, –CN, –OH, ‒NO2, –NHCH3, –NHCH2CH3, – NHCH2CH2CH3, –NHCH(CH3)CH3, –N(CH3)2, –N(CH2CH3)2, –N(CH2CH2CH3)2, – N(CH(CH3)CH3)2, –N(CH3)(CH2CH3), –CH2NH2, –CH2CH2NH2, –CH2CH2CH2NH2, and – CH(CH3)CH2NH2. In a further aspect, each of R11a, R11b, R11c, and R11dis independently selected from hydrogen, –F, –Cl, –NH2, –CN, –OH, ‒NO2, –NHCH3, –NHCH2CH3, – N(CH3)2, –N(CH2CH3)2, –N(CH3)(CH2CH3), –CH2NH2, and –CH2CH2NH2. In a still further aspect, each of R11a, R11b, R11c, and R11dis independently selected from hydrogen, –F, –Cl, – NH2, –CN, –OH, ‒NO2, –NHCH3, –N(CH3)2, and –CH2NH2.

[0112] In various aspects, each of R11a, R11b, R11c, and R11dis independently selected from hydrogen and halogen, provided that at least one of R11a, R11b, R11c, and R11dishydrogen. In a further aspect, each of R11a, R11b, R11c, and R11dis independently selected from hydrogen, –F, and –Cl. In a further aspect, each of R11a, R11b, R11c, and R11dis independently selected from hydrogen and –Cl. In a still further aspect, each of R11a, R11b, R11c, and R11dis independently selected from hydrogen and –F.

[0113] In various aspects, each of R11a, R11b, R11c, and R11dis hydrogen. g. R12GROUPS

[0114] In one aspect, each of R12is selected from ‒CO2H and ‒C(O)NH2. In a further aspect, R12is ‒CO2H. In a still further aspect, R12is ‒C(O)NH2. a. R13A, R13B, R13C, R13D, AND R13EGROUPS

[0115] In various aspects, each of R13a, R13b, R13c, R13d, and R13eis independently selected from hydrogen, halogen, ‒CN, ‒NH2, ‒OH, ‒NO2, C1-C4 alkyl, C2-C4 alkenyl, C1- C4 haloalkyl, C1-C4 cyanoalkyl, C1-C4 hydroxyalkyl, C1-C4 haloalkoxy, C1-C4 alkoxy, C1-C4 alkylamino, (C1-C4)(C1-C4) dialkylamino, C1-C4 aminoalkyl, and ‒CO2H, provided that at least two of R13a, R13b, R13c, R13d, and R13eis hydrogen. In a further aspect, each of R13a, R13b, R13c, R13d, and R13eis independently selected from hydrogen, –F, –Cl, –NH2, –CN, –OH, ‒NO2, methyl, ethyl, n-propyl, i-propyl, ethenyl, propenyl, isopropenyl, –CH2F, – CH2Cl, –CH2CH2F, –CH2CH2Cl, –CH2CH2CH2F, –CH2CH2CH2Cl, –CH(CH3)CH2F, – CH(CH3)CH2Cl, –CH2CN, –CH2CH2CN, –CH2CH2CH2CN, –CH(CH3)CH2CN, –CH2OH, – CH2CH2OH, –CH2CH2CH2OH, –CH(CH3)CH2OH, –OCF3, –OCH2CF3, –OCH2CH2CF3, – OCH(CH3)CF3, –OCH3, –OCH2CH3, –OCH2CH2CH3, –OCH(CH3)CH3, –NHCH3, – NHCH2CH3, –NHCH2CH2CH3, –NHCH(CH3)CH3, –N(CH3)2, –N(CH2CH3)2, – N(CH2CH2CH3)2, –N(CH(CH3)CH3)2, –N(CH3)(CH2CH3), –CH2NH2, –CH2CH2NH2, – CH2CH2CH2NH2, –CH(CH3)CH2NH2, and ‒CO2H. In a further aspect, each of R13a, R13b, R13c, R13d, and R13eis independently selected from hydrogen, –F, –Cl, –NH2, –CN, –OH, ‒NO2, methyl, ethyl, ethenyl, –CH2F, –CH2Cl, –CH2CH2F, –CH2CH2Cl, –CH2CN,– CH2CH2CN, –CH2OH, –CH2CH2OH, –OCF3, –OCH2CF3, –OCH3, –OCH2CH3, –NHCH3, – NHCH2CH3, –N(CH3)2, –N(CH2CH3)2, –N(CH3)(CH2CH3), –CH2NH2, –CH2CH2NH2, and ‒CO2H. In a still further aspect, each of R13a, R13b, R13c, R13d, and R13eis independently selected from hydrogen, –F, –Cl, –NH2, –CN, –OH, ‒NO2, methyl, –CH2F, –CH2Cl, – CH2CN, –CH2OH, –OCF3, –OCH2CF3, –OCH3, –NHCH3, –N(CH3)2, –CH2NH2, and ‒CO2H.

[0116] In various aspects, each of R13a, R13b, R13c, R13d, and R13eis independentlyselected from hydrogen, halogen, ‒CN, ‒NH2, ‒OH, ‒NO2, C1-C4 alkyl, and C2-C4 alkenyl, provided that at least two of R13a, R13b, R13c, R13d, and R13eis hydrogen. In a further aspect, each of R13a, R13b, R13c, R13d, and R13eis independently selected from hydrogen, –F, –Cl, – NH2, –CN, –OH, ‒NO2, methyl, ethyl, n-propyl, i-propyl, ethenyl, propenyl, and isopropenyl. In a further aspect, each of R13a, R13b, R13c, R13d, and R13eis independently selected from hydrogen, –F, –Cl, –NH2, –CN, –OH, ‒NO2, methyl, ethyl, and ethenyl. In a still further aspect, each of R13a, R13b, R13c, R13d, and R13eis independently selected from hydrogen, –F, – Cl, –NH2, –CN, –OH, ‒NO2, and methyl.

[0117] In various aspects, each of R13a, R13b, R13c, R13d, and R13eis independently selected from hydrogen, halogen, ‒CN, C1-C4 alkyl, and C1-C4 alkoxy, provided that at least two of R13a, R13b, R13c, R13d, and R13eis hydrogen. In a further aspect, each of R13a, R13b, R13c, R13d, and R13eis independently selected from hydrogen, –F, –Cl, ‒CN, methyl, ethyl, npropyl, i-propyl, –OCH3, –OCH2CH3, –OCH2CH2CH3, and –OCH(CH3)CH3. In a still further aspect, each of R13a, R13b, R13c, R13d, and R13eis independently selected from hydrogen, –F, –Cl, ‒CN, methyl, ethyl, –OCH3, and –OCH2CH3. In yet a further aspect, each of R13a, R13b, R13c, R13d, and R13eis independently selected from hydrogen, –F, –Cl, ‒CN, methyl, and –OCH3.

[0118] In various aspects, each of R13a, R13b, R13c, R13d, and R13eis independently selected from hydrogen and C1-C4 alkyl, provided that at least two of R13a, R13b, R13c, R13d, and R13eis hydrogen. In a further aspect, each of R13a, R13b, R13c, R13d, and R13eis independently selected from hydrogen, methyl, ethyl, n-propyl, and i-propyl. In a further aspect, each of R13a, R13b, R13c, R13d, and R13eis independently selected from hydrogen, methyl, and ethyl. In a still further aspect, each of R13a, R13b, R13c, R13d, and R13eis independently selected from from hydrogen and methyl.

[0119] In various aspects, each of R13a, R13b, R13c, R13d, and R13eis independently selected from hydrogen and ‒CO2H, provided that at least two of R13a, R13b, R13c, R13d, and R13eis hydrogen.

[0120] In various aspects, each of R13a, R13b, R13c, R13d, and R13eis independently selected from hydrogen, halogen, ‒CN, ‒NH2, ‒OH, ‒NO2, C1-C4 haloalkyl, and C1-C4 cyanoalkyl, provided that at least two of R13a, R13b, R13c, R13d, and R13eis hydrogen. In a further aspect, each of R13a, R13b, R13c, R13d, and R13eis independently selected from hydrogen, –F, –Cl, –NH2, –CN, –OH, ‒NO2, –CH2F, –CH2Cl, –CH2CH2F, –CH2CH2Cl, – CH2CH2CH2F, –CH2CH2CH2Cl, –CH(CH3)CH2F, –CH(CH3)CH2Cl, –CH2CN, –CH2CH2CN, –CH2CH2CH2CN, and –CH(CH3)CH2CN. In a further aspect, each of R13a, R13b, R13c, R13d,and R13eis independently selected from hydrogen, –F, –Cl, –NH2, –CN, –OH, ‒NO2, –CH2F, –CH2Cl, –CH2CH2F, –CH2CH2Cl, –CH2CN, and –CH2CH2CN. In a still further aspect, each of R13a, R13b, R13c, R13d, and R13eis independently selected from hydrogen, –F, –Cl, –NH2, – CN, –OH, ‒NO2, –CH2F, –CH2Cl, and –CH2CN

[0121] In various aspects, each of R13a, R13b, R13c, R13d, and R13eis independently selected from hydrogen, halogen, ‒CN, ‒NH2, ‒OH, ‒NO2, C1-C4 hydroxyalkyl, C1-C4 haloalkoxy, and C1-C4 alkoxy, provided that at least two of R13a, R13b, R13c, R13d, and R13eis hydrogen. In a further aspect, each of R13a, R13b, R13c, R13d, and R13eis independently selected from hydrogen, –F, –Cl, –NH2, –CN, –OH, ‒NO2, –CH2OH, –CH2CH2OH, – CH2CH2CH2OH, –CH(CH3)CH2OH, –OCF3, –OCH2CF3, –OCH2CH2CF3, –OCH(CH3)CF3, – OCH3, –OCH2CH3, –OCH2CH2CH3, and –OCH(CH3)CH3. In a further aspect, each of R13a, R13b, R13c, R13d, and R13eis independently selected from hydrogen, –F, –Cl, –NH2, –CN, – OH, ‒NO2, –CH2OH, –CH2CH2OH, –OCF3, –OCH2CF3, –OCH3, and –OCH2CH3. In a still further aspect, each of R13a, R13b, R13c, R13d, and R13eis independently selected from hydrogen, –F, –Cl, –NH2, –CN, –OH, ‒NO2, –CH2OH, –OCF3, –OCH2CF3, and –OCH3.

[0122] In various aspects, each of R13a, R13b, R13c, R13d, and R13eis independently selected from hydrogen, halogen, ‒CN, ‒NH2, ‒OH, ‒NO2, C1-C4 alkylamino, (C1-C4)(C1- C4) dialkylamino, and C1-C4 aminoalkyl, provided that at least two of R13a, R13b, R13c, R13d, and R13eis hydrogen. In a further aspect, each of R13a, R13b, R13c, R13d, and R13eis independently selected from hydrogen, –F, –Cl, –NH2, –CN, –OH, ‒NO2, –NHCH3, – NHCH2CH3, –NHCH2CH2CH3, –NHCH(CH3)CH3, –N(CH3)2, –N(CH2CH3)2, – N(CH2CH2CH3)2, –N(CH(CH3)CH3)2, –N(CH3)(CH2CH3), –CH2NH2, –CH2CH2NH2, – CH2CH2CH2NH2, and –CH(CH3)CH2NH2. In a further aspect, each of R13a, R13b, R13c, R13d, and R13eis independently selected from hydrogen, –F, –Cl, –NH2, –CN, –OH, ‒NO2, – NHCH3, –NHCH2CH3, –N(CH3)2, –N(CH2CH3)2, –N(CH3)(CH2CH3), –CH2NH2, and – CH2CH2NH2. In a still further aspect, each of R13a, R13b, R13c, R13d, and R13eis independently selected from hydrogen, –F, –Cl, –NH2, –CN, –OH, ‒NO2, –NHCH3, –N(CH3)2, and – CH2NH2.

[0123] In various aspects, each of R13a, R13b, R13c, R13d, and R13eis independently selected from hydrogen and halogen, provided that at least two of R13a, R13b, R13c, R13d, and R13eis hydrogen. In a further aspect, each of R13a, R13b, R13c, R13d, and R13eis independently selected from hydrogen, –F, and –Cl. In a further aspect, each of R13a, R13b, R13c, R13d, and R13eis independently selected from hydrogen and –Cl. In a still further aspect, each of R13a, R13b, R13c, R13d, and R13eis independently selected from hydrogen and –F.

[0124] In various aspects, each of R13a, R13b, R13c, R13d, and R13eis hydrogen. b. R20GROUPS

[0125] In one aspect, R20is selected from hydrogen, halogen, ‒CN, ‒NH2, ‒OH, ‒NO2, C1-C4 alkyl, C2-C4 alkenyl, C1-C4 haloalkyl, C1-C4 cyanoalkyl, C1-C4 hydroxyalkyl, C1-C4 haloalkoxy, C1-C4 alkoxy, C1-C4 alkylamino, (C1-C4)(C1-C4) dialkylamino, C1-C4 aminoalkyl, and ‒CO2H. In a further aspect, R20is selected from hydrogen, –F, –Cl, –NH2, –CN, –OH, ‒NO2, methyl, ethyl, n-propyl, i-propyl, ethenyl, propenyl, isopropenyl, –CH2F, –CH2Cl, –CH2CH2F, –CH2CH2Cl, –CH2CH2CH2F, – CH2CH2CH2Cl, –CH(CH3)CH2F, –CH(CH3)CH2Cl, –CH2CN, –CH2CH2CN, – CH2CH2CH2CN, –CH(CH3)CH2CN, –CH2OH, –CH2CH2OH, –CH2CH2CH2OH, – CH(CH3)CH2OH, –OCF3, –OCH2CF3, –OCH2CH2CF3, –OCH(CH3)CF3, –OCH3, – OCH2CH3, –OCH2CH2CH3, –OCH(CH3)CH3, –NHCH3, –NHCH2CH3, –NHCH2CH2CH3, – NHCH(CH3)CH3, –N(CH3)2, –N(CH2CH3)2, –N(CH2CH2CH3)2, –N(CH(CH3)CH3)2, – N(CH3)(CH2CH3), –CH2NH2, –CH2CH2NH2, –CH2CH2CH2NH2, –CH(CH3)CH2NH2, and ‒CO2H. In a further aspect, R20is selected from hydrogen, –F, –Cl, –NH2, –CN, –OH, ‒NO2, methyl, ethyl, ethenyl, –CH2F, –CH2Cl, –CH2CH2F, –CH2CH2Cl, –CH2CN,–CH2CH2CN, – CH2OH, –CH2CH2OH, –OCF3, –OCH2CF3, –OCH3, –OCH2CH3, –NHCH3, –NHCH2CH3, – N(CH3)2, –N(CH2CH3)2, –N(CH3)(CH2CH3), –CH2NH2, –CH2CH2NH2, and ‒CO2H. In a still further aspect, R20is selected from from hydrogen, –F, –Cl, –NH2, –CN, –OH, ‒NO2, methyl, –CH2F, –CH2Cl, –CH2CN, –CH2OH, –OCF3, –OCH2CF3, –OCH3, –NHCH3, – N(CH3)2, –CH2NH2, and ‒CO2H.

[0126] In various aspects, R20is selected from hydrogen, halogen, ‒CN, ‒NH2, ‒OH, ‒NO2, C1-C4 alkyl, and C2-C4 alkenyl. In a further aspect, R20is selected from hydrogen, – F, –Cl, –NH2, –CN, –OH, ‒NO2, methyl, ethyl, n-propyl, i-propyl, ethenyl, propenyl, and isopropenyl. In a further aspect, R20is selected from hydrogen, –F, –Cl, –NH2, –CN, –OH, ‒NO2, methyl, ethyl, and ethenyl. In a still further aspect, R20is selected from hydrogen, –F, –Cl, –NH2, –CN, –OH, ‒NO2, and methyl.

[0127] In various aspects, R20is selected from hydrogen, halogen, ‒CN, C1-C4 alkyl, and C1-C4 alkoxy. In a further aspect, R20is selected from hydrogen, –F, –Cl, ‒CN, methyl, ethyl, n-propyl, i-propyl, –OCH3, –OCH2CH3, –OCH2CH2CH3, and –OCH(CH3)CH3. In a still further aspect, R20is selected from hydrogen, –F, –Cl, ‒CN, methyl, ethyl, –OCH3, and – OCH2CH3. In yet a further aspect, R20is selected from hydrogen, –F, –Cl, ‒CN, methyl, and–OCH3.

[0128] In various aspects, R20is selected from hydrogen and C1-C4 alkyl. In a further aspect, R20is selected from hydrogen, methyl, ethyl, n-propyl, and i-propyl. In a further aspect, R20is selected from hydrogen, methyl, and ethyl. In a still further aspect, R20is selected from from hydrogen and methyl.

[0129] In various aspects, R20is C1-C4 alkyl. In a further aspect, R20is selected from methyl, ethyl, n-propyl, and i-propyl. In a further aspect, R20is selected from methyl and ethyl. In a still further aspect, R20is methyl.

[0130] In various aspects, R20is selected from hydrogen and ‒CO2H.

[0131] In various aspects, R20is selected from hydrogen, halogen, ‒CN, ‒NH2, ‒OH, ‒NO2, C1-C4 haloalkyl, and C1-C4 cyanoalkyl. In a further aspect, R20is selected from hydrogen, –F, –Cl, –NH2, –CN, –OH, ‒NO2, –CH2F, –CH2Cl, –CH2CH2F, –CH2CH2Cl, – CH2CH2CH2F, –CH2CH2CH2Cl, –CH(CH3)CH2F, –CH(CH3)CH2Cl, –CH2CN, –CH2CH2CN, –CH2CH2CH2CN, and –CH(CH3)CH2CN. In a further aspect, R20is selected from hydrogen, –F, –Cl, –NH2, –CN, –OH, ‒NO2, –CH2F, –CH2Cl, –CH2CH2F, –CH2CH2Cl, –CH2CN, and – CH2CH2CN. In a still further aspect, R20is selected from hydrogen, –F, –Cl, –NH2, –CN, – OH, ‒NO2, –CH2F, –CH2Cl, and –CH2CN.

[0132] In various aspects, R20is selected from hydrogen, halogen, ‒CN, ‒NH2, ‒OH, ‒NO2, C1-C4 hydroxyalkyl, C1-C4 haloalkoxy, and C1-C4 alkoxy. In a further aspect, R20is selected from hydrogen, –F, –Cl, –NH2, –CN, –OH, ‒NO2, –CH2OH, –CH2CH2OH, – CH2CH2CH2OH, –CH(CH3)CH2OH, –OCF3, –OCH2CF3, –OCH2CH2CF3, –OCH(CH3)CF3, – OCH3, –OCH2CH3, –OCH2CH2CH3, and –OCH(CH3)CH3. In a further aspect, R20is selected from hydrogen, –F, –Cl, –NH2, –CN, –OH, ‒NO2, –CH2OH, –CH2CH2OH, –OCF3, –OCH2CF3, –OCH3, and –OCH2CH3. In a still further aspect, R20is selected from hydrogen, –F, –Cl, –NH2, –CN, –OH, ‒NO2, –CH2OH, –OCF3, –OCH2CF3, and –OCH3.

[0133] In various aspects, R20is selected from hydrogen, halogen, ‒CN, ‒NH2, ‒OH, ‒NO2, C1-C4 alkylamino, (C1-C4)(C1-C4) dialkylamino, and C1-C4 aminoalkyl. In a further aspect, R20is selected from hydrogen, –F, –Cl, –NH2, –CN, –OH, ‒NO2, –NHCH3, – NHCH2CH3, –NHCH2CH2CH3, –NHCH(CH3)CH3, –N(CH3)2, –N(CH2CH3)2, – N(CH2CH2CH3)2, –N(CH(CH3)CH3)2, –N(CH3)(CH2CH3), –CH2NH2, –CH2CH2NH2, – CH2CH2CH2NH2, and –CH(CH3)CH2NH2. In a further aspect, R20is selected from hydrogen, –F, –Cl, –NH2, –CN, –OH, ‒NO2, –NHCH3, –NHCH2CH3, –N(CH3)2, –N(CH2CH3)2, – N(CH3)(CH2CH3), –CH2NH2, and –CH2CH2NH2. In a still further aspect, R20is selected from hydrogen, –F, –Cl, –NH2, –CN, –OH, ‒NO2, –NHCH3, –N(CH3)2, and –CH2NH2.

[0134] In various aspects, R20is selected from hydrogen and halogen. In a further aspect, R20is selected from hydrogen, –F, and –Cl. In a further aspect, R20is selected from hydrogen and –Cl. In a still further aspect, R20is selected from hydrogen and –F.

[0135] In various aspects, R20is a halogen. In a further aspect, R20is selected from – F and –Cl. In a further aspect, R20is –Cl. In a still further aspect, R20is –F.

[0136] In various aspects, R20is hydrogen. c. AR1GROUPS

[0137] In one aspect, Ar1is selected from a 6-membered aryl, an isoxazolyl, an oxadiazolyl, an oxazolyl, and a 9- or 10-membered heteroaryl, and is substituted with 0, 1, 2, or 3 groups independently selected from halogen, ‒CN, ‒NH2, ‒OH, ‒NO2, C1-C4 alkyl, C2- C4 alkenyl, C1-C4 haloalkyl, C1-C4 cyanoalkyl, C1-C4 hydroxyalkyl, C1-C4 haloalkoxy, C1-C4 alkoxy, C1-C4 alkylamino, (C1-C4)(C1-C4) dialkylamino, C1-C4 aminoalkyl, ‒CO2H, and Ar2. In a further aspect, Ar1is selected from a 6-membered aryl, an isoxazolyl, an oxadiazolyl, an oxazolyl, and a 9- or 10-membered heteroaryl, and is substituted with 0, 1, or 2 groups independently selected from halogen, ‒CN, ‒NH2, ‒OH, ‒NO2, C1-C4 alkyl, C2- C4 alkenyl, C1-C4 haloalkyl, C1-C4 cyanoalkyl, C1-C4 hydroxyalkyl, C1-C4 haloalkoxy, C1-C4 alkoxy, C1-C4 alkylamino, (C1-C4)(C1-C4) dialkylamino, C1-C4 aminoalkyl, ‒CO2H, and Ar2. In a still further aspect, Ar1is selected from a 6-membered aryl, an isoxazolyl, an oxadiazolyl, an oxazolyl, and a 9- or 10-membered heteroaryl, and is substituted with 0 or 1 group selected from halogen, ‒CN, ‒NH2, ‒OH, ‒NO2, C1-C4 alkyl, C2-C4 alkenyl, C1-C4 haloalkyl, C1-C4 cyanoalkyl, C1-C4 hydroxyalkyl, C1-C4 haloalkoxy, C1-C4 alkoxy, C1-C4 alkylamino, (C1-C4)(C1-C4) dialkylamino, C1-C4 aminoalkyl, ‒CO2H, and Ar2. In yet a further aspect, Ar1is selected from a 6-membered aryl, an isoxazolyl, an oxadiazolyl, an oxazolyl, and a 9- or 10-membered heteroaryl, and is monosubstituted with a group selected from halogen, ‒CN, ‒NH2, ‒OH, ‒NO2, C1-C4 alkyl, C2-C4 alkenyl, C1-C4 haloalkyl, C1-C4 cyanoalkyl, C1-C4 hydroxyalkyl, C1-C4 haloalkoxy, C1-C4 alkoxy, C1-C4 alkylamino, (C1-C4)(C1-C4) dialkylamino, C1-C4 aminoalkyl, ‒CO2H, and Ar2. In an even further aspect, Ar1is selected from a 6-membered aryl, an isoxazolyl, an oxadiazolyl, an oxazolyl, and a 9- or 10-membered heteroaryl, and is unsubstituted.

[0138] In one aspect, Ar1is selected from a 6-membered aryl, an isoxazolyl, an oxadiazolyl, and a 9- or 10-membered heteroaryl, and is substituted with 0, 1, 2, or 3 groupsindependently selected from halogen, ‒CN, ‒NH2, ‒OH, ‒NO2, C1-C4 alkyl, C2-C4 alkenyl, C1-C4 haloalkyl, C1-C4 cyanoalkyl, C1-C4 hydroxyalkyl, C1-C4 haloalkoxy, C1-C4 alkoxy, C1-C4 alkylamino, (C1-C4)(C1-C4) dialkylamino, C1-C4 aminoalkyl, ‒CO2H, and Ar2. In a further aspect, Ar1is selected from a 6-membered aryl, an isoxazolyl, an oxadiazolyl, and a 9- or 10-membered heteroaryl, and is substituted with 0, 1, or 2 groups independently selected from halogen, ‒CN, ‒NH2, ‒OH, ‒NO2, C1-C4 alkyl, C2-C4 alkenyl, C1-C4 haloalkyl, C1- C4 cyanoalkyl, C1-C4 hydroxyalkyl, C1-C4 haloalkoxy, C1-C4 alkoxy, C1-C4 alkylamino, (C1-C4)(C1-C4) dialkylamino, C1-C4 aminoalkyl, ‒CO2H, and Ar2. In a still further aspect, Ar1is selected from a 6-membered aryl, an isoxazolyl, an oxadiazolyl, and a 9- or 10- membered heteroaryl, and is substituted with 0 or 1 group selected from halogen, ‒CN, ‒NH2, ‒OH, ‒NO2, C1-C4 alkyl, C2-C4 alkenyl, C1-C4 haloalkyl, C1-C4 cyanoalkyl, C1-C4 hydroxyalkyl, C1-C4 haloalkoxy, C1-C4 alkoxy, C1-C4 alkylamino, (C1-C4)(C1-C4) dialkylamino, C1-C4 aminoalkyl, and ‒CO2H, and Ar2. In yet a further aspect, Ar1is selected from a 6-membered aryl, an isoxazolyl, an oxadiazolyl, and a 9- or 10-membered heteroaryl, and is monosubstituted with a group selected from halogen, ‒CN, ‒NH2, ‒OH, ‒NO2, C1-C4 alkyl, C2-C4 alkenyl, C1-C4 haloalkyl, C1-C4 cyanoalkyl, C1-C4 hydroxyalkyl, C1-C4 haloalkoxy, C1-C4 alkoxy, C1-C4 alkylamino, (C1-C4)(C1-C4) dialkylamino, C1-C4 aminoalkyl, and ‒CO2H, and Ar2. In an even further aspect, Ar1is selected from a 6- membered aryl, an isoxazolyl, an oxadiazolyl, and a 9- or 10-membered heteroaryl, and is unsubstituted.

[0139] In various aspects, Ar1is a 6-membered aryl substituted with 0, 1, 2, or 3 groups independently selected from halogen, ‒CN, ‒NH2, ‒OH, ‒NO2, C1-C4 alkyl, C2-C4 alkenyl, C1-C4 haloalkyl, C1-C4 cyanoalkyl, C1-C4 hydroxyalkyl, C1-C4 haloalkoxy, C1- C4 alkoxy, C1-C4 alkylamino, (C1-C4)(C1-C4) dialkylamino, C1-C4 aminoalkyl, ‒CO2H, and Ar2. In a further aspect, Ar1is a 6-membered aryl substituted with 0, 1, or 2 groups independently selected from halogen, ‒CN, ‒NH2, ‒OH, ‒NO2, C1-C4 alkyl, C2-C4 alkenyl, C1-C4 haloalkyl, C1-C4 cyanoalkyl, C1-C4 hydroxyalkyl, C1-C4 haloalkoxy, C1-C4 alkoxy, C1-C4 alkylamino, (C1-C4)(C1-C4) dialkylamino, C1-C4 aminoalkyl, ‒CO2H, and Ar2. In a still further aspect, Ar1is a 6-membered aryl substituted with 0 or 1 group selected from halogen, ‒CN, ‒NH2, ‒OH, ‒NO2, C1-C4 alkyl, C2-C4 alkenyl, C1-C4 haloalkyl, C1-C4 cyanoalkyl, C1-C4 hydroxyalkyl, C1-C4 haloalkoxy, C1-C4 alkoxy, C1-C4 alkylamino, (C1- C4)(C1-C4) dialkylamino, C1-C4 aminoalkyl, ‒CO2H, and Ar2. In yet a further aspect, Ar1is a 6-membered aryl monosubstituted with a selected from halogen, ‒CN, ‒NH2, ‒OH, ‒NO2, C1-C4 alkyl, C2-C4 alkenyl, C1-C4 haloalkyl, C1-C4 cyanoalkyl, C1-C4 hydroxyalkyl, C1-C4 haloalkoxy, C1-C4 alkoxy, C1-C4 alkylamino, (C1-C4)(C1-C4) dialkylamino, C1-C4 aminoalkyl, ‒CO2H, and Ar2. In an even further aspect, Ar1is an unsubstituted 6-membered aryl.

[0140] In various aspects, Ar1is a a 9- or 10-membered heteroaryl substituted with 0, 1, 2, or 3 groups independently selected from halogen, ‒CN, ‒NH2, ‒OH, ‒NO2, C1-C4 alkyl, C2-C4 alkenyl, C1-C4 haloalkyl, C1-C4 cyanoalkyl, C1-C4 hydroxyalkyl, C1-C4 haloalkoxy, C1-C4 alkoxy, C1-C4 alkylamino, (C1-C4)(C1-C4) dialkylamino, C1-C4 aminoalkyl, ‒CO2H, and Ar2. In a further aspect, Ar1is a 9- or 10-membered heteroaryl substituted with 0, 1, or 2 groups independently selected from halogen, ‒CN, ‒NH2, ‒OH, ‒NO2, C1-C4 alkyl, C2-C4 alkenyl, C1-C4 haloalkyl, C1-C4 cyanoalkyl, C1-C4 hydroxyalkyl, C1-C4 haloalkoxy, C1-C4 alkoxy, C1-C4 alkylamino, (C1-C4)(C1-C4) dialkylamino, C1-C4 aminoalkyl, ‒CO2H, and Ar2. In a still further aspect, Ar1is a 9- or 10- membered heteroaryl substituted with 0 or 1 group selected from halogen, ‒CN, ‒NH2, ‒OH, ‒NO2, C1-C4 alkyl, C2-C4 alkenyl, C1-C4 haloalkyl, C1-C4 cyanoalkyl, C1-C4 hydroxyalkyl, C1-C4 haloalkoxy, C1-C4 alkoxy, C1-C4 alkylamino, (C1-C4)(C1-C4) dialkylamino, C1-C4 aminoalkyl, ‒CO2H, and Ar2. In yet a further aspect, Ar1is a 9- or 10- membered heteroaryl monosubstituted a group selected from halogen, ‒CN, ‒NH2, ‒OH, ‒NO2, C1-C4 alkyl, C2-C4 alkenyl, C1-C4 haloalkyl, C1-C4 cyanoalkyl, C1-C4 hydroxyalkyl, C1-C4 haloalkoxy, C1-C4 alkoxy, C1-C4 alkylamino, (C1-C4)(C1-C4) dialkylamino, C1-C4 aminoalkyl, ‒CO2H, and Ar2. In an even further aspect, Ar1is an unsubstituted 9- or 10-membered heteroaryl.

[0141] In various aspects, Ar1is selected from an isoxazolyl, an oxadiazolyl, and an oxazolyl, and is substituted with 0, 1, or 2 groups selected from halogen, ‒CN, ‒NH2, ‒OH, ‒NO2, C1-C4 alkyl, C2-C4 alkenyl, C1-C4 haloalkyl, C1-C4 cyanoalkyl, C1-C4 hydroxyalkyl, C1-C4 haloalkoxy, C1-C4 alkoxy, C1-C4 alkylamino, (C1-C4)(C1-C4) dialkylamino, C1-C4 aminoalkyl, and ‒CO2H, and Ar2. In a further aspect, Ar1is selected from an isoxazolyl, an oxadiazolyl, and an oxazolyl, and is substituted with 0 or 1 group selected from halogen, ‒CN, ‒NH2, ‒OH, ‒NO2, C1-C4 alkyl, C2-C4 alkenyl, C1-C4 haloalkyl, C1-C4 cyanoalkyl, C1-C4 hydroxyalkyl, C1-C4 haloalkoxy, C1-C4 alkoxy, C1-C4 alkylamino, (C1-C4)(C1-C4) dialkylamino, C1-C4 aminoalkyl, and ‒CO2H, and Ar2. In a still further aspect, Ar1is selected from an isoxazolyl, an oxadiazolyl, and an oxazolyl, and is monosubstituted with a group selected from halogen, ‒CN, ‒NH2, ‒OH, ‒NO2, C1-C4 alkyl, C2-C4 alkenyl, C1-C4 haloalkyl, C1-C4 cyanoalkyl, C1-C4 hydroxyalkyl, C1-C4 haloalkoxy, C1-C4 alkoxy, C1-C4 alkylamino, (C1-C4)(C1-C4) dialkylamino, C1-C4aminoalkyl, and ‒CO2H, and Ar2. In yet a further aspect, Ar1is selected from an isoxazolyl, an oxadiazolyl, and an oxazolyl, and is unsubstituted.

[0142] In various aspects, Ar1is selected from an isoxazolyl and an oxadiazolyl, and is substituted with 0, 1, or 2 groups selected from halogen, ‒CN, ‒NH2, ‒OH, ‒NO2, C1-C4 alkyl, C2-C4 alkenyl, C1-C4 haloalkyl, C1-C4 cyanoalkyl, C1-C4 hydroxyalkyl, C1-C4 haloalkoxy, C1-C4 alkoxy, C1-C4 alkylamino, (C1-C4)(C1-C4) dialkylamino, C1-C4 aminoalkyl, and ‒CO2H, and Ar2. In a further aspect, Ar1is selected from an isoxazolyl and an oxadiazolyl, and is substituted with 0 or 1 group selected from halogen, ‒CN, ‒NH2, ‒OH, ‒NO2, C1-C4 alkyl, C2-C4 alkenyl, C1-C4 haloalkyl, C1-C4 cyanoalkyl, C1-C4 hydroxyalkyl, C1-C4 haloalkoxy, C1-C4 alkoxy, C1-C4 alkylamino, (C1-C4)(C1-C4) dialkylamino, C1-C4 aminoalkyl, and ‒CO2H, and Ar2. In a still further aspect, Ar1is selected from an isoxazolyl and an oxadiazolyl, and is monosubstituted with a group selected from halogen, ‒CN, ‒NH2, ‒OH, ‒NO2, C1-C4 alkyl, C2-C4 alkenyl, C1-C4 haloalkyl, C1- C4 cyanoalkyl, C1-C4 hydroxyalkyl, C1-C4 haloalkoxy, C1-C4 alkoxy, C1-C4 alkylamino, (C1-C4)(C1-C4) dialkylamino, C1-C4 aminoalkyl, and ‒CO2H, and Ar2. In yet a further aspect, Ar1is selected from an isoxazolyl and an oxadiazolyl, and is unsubstituted.

[0143] In various aspects, Ar1is an isoxazolyl, and is substituted with 0, 1, or 2 groups selected from halogen, ‒CN, ‒NH2, ‒OH, ‒NO2, C1-C4 alkyl, C2-C4 alkenyl, C1-C4 haloalkyl, C1-C4 cyanoalkyl, C1-C4 hydroxyalkyl, C1-C4 haloalkoxy, C1-C4 alkoxy, C1-C4 alkylamino, (C1-C4)(C1-C4) dialkylamino, C1-C4 aminoalkyl, and ‒CO2H, and Ar2. In a further aspect, Ar1is an isoxazolyl, and is substituted with 0 or 1 group selected from halogen, ‒CN, ‒NH2, ‒OH, ‒NO2, C1-C4 alkyl, C2-C4 alkenyl, C1-C4 haloalkyl, C1-C4 cyanoalkyl, C1-C4 hydroxyalkyl, C1-C4 haloalkoxy, C1-C4 alkoxy, C1-C4 alkylamino, (C1- C4)(C1-C4) dialkylamino, C1-C4 aminoalkyl, and ‒CO2H, and Ar2. In a still further aspect, Ar1is a monosubstituted isoxazolyl with a group selected from halogen, ‒CN, ‒NH2, ‒OH, ‒NO2, C1-C4 alkyl, C2-C4 alkenyl, C1-C4 haloalkyl, C1-C4 cyanoalkyl, C1-C4 hydroxyalkyl, C1-C4 haloalkoxy, C1-C4 alkoxy, C1-C4 alkylamino, (C1-C4)(C1-C4) dialkylamino, C1-C4 aminoalkyl, and ‒CO2H, and Ar2. In yet a further aspect, Ar1is an unsubstituted isoxazolyl.

[0144] In various aspects, Ar1is an oxadiazolyl, and is substituted with 0, 1 or 2 groups selected from halogen, ‒CN, ‒NH2, ‒OH, ‒NO2, C1-C4 alkyl, C2-C4 alkenyl, C1-C4 haloalkyl, C1-C4 cyanoalkyl, C1-C4 hydroxyalkyl, C1-C4 haloalkoxy, C1-C4 alkoxy, C1-C4 alkylamino, (C1-C4)(C1-C4) dialkylamino, C1-C4 aminoalkyl, and ‒CO2H, and Ar2. In a further aspect, Ar1is an oxadiazolyl, and is substituted with 0 or 1 group selected fromhalogen, ‒CN, ‒NH2, ‒OH, ‒NO2, C1-C4 alkyl, C2-C4 alkenyl, C1-C4 haloalkyl, C1-C4 cyanoalkyl, C1-C4 hydroxyalkyl, C1-C4 haloalkoxy, C1-C4 alkoxy, C1-C4 alkylamino, (C1- C4)(C1-C4) dialkylamino, C1-C4 aminoalkyl, and ‒CO2H, and Ar2. In a still further aspect, Ar1is a monosubstituted oxadiazolyl with a group selected from halogen, ‒CN, ‒NH2, ‒OH, ‒NO2, C1-C4 alkyl, C2-C4 alkenyl, C1-C4 haloalkyl, C1-C4 cyanoalkyl, C1-C4 hydroxyalkyl, C1-C4 haloalkoxy, C1-C4 alkoxy, C1-C4 alkylamino, (C1-C4)(C1-C4) dialkylamino, C1-C4 aminoalkyl, and ‒CO2H, and Ar2. In yet a further aspect, Ar1is an unsubstituted oxadiazolyl.

[0145] In various aspects, Ar1is an oxazolyl, and is substituted with 0, 1 or 2 groups selected from halogen, ‒CN, ‒NH2, ‒OH, ‒NO2, C1-C4 alkyl, C2-C4 alkenyl, C1-C4 haloalkyl, C1-C4 cyanoalkyl, C1-C4 hydroxyalkyl, C1-C4 haloalkoxy, C1-C4 alkoxy, C1-C4 alkylamino, (C1-C4)(C1-C4) dialkylamino, C1-C4 aminoalkyl, and ‒CO2H, and Ar2. In a further aspect, Ar1is an oxazolyl, and is substituted with 0 or 1 group selected from halogen, ‒CN, ‒NH2, ‒OH, ‒NO2, C1-C4 alkyl, C2-C4 alkenyl, C1-C4 haloalkyl, C1-C4 cyanoalkyl, C1-C4 hydroxyalkyl, C1-C4 haloalkoxy, C1-C4 alkoxy, C1-C4 alkylamino, (C1-C4)(C1-C4) dialkylamino, C1-C4 aminoalkyl, and ‒CO2H, and Ar2. In a still further aspect, Ar1is a monosubstituted oxazolyl with a group selected from halogen, ‒CN, ‒NH2, ‒OH, ‒NO2, C1- C4 alkyl, C2-C4 alkenyl, C1-C4 haloalkyl, C1-C4 cyanoalkyl, C1-C4 hydroxyalkyl, C1-C4 haloalkoxy, C1-C4 alkoxy, C1-C4 alkylamino, (C1-C4)(C1-C4) dialkylamino, C1-C4 aminoalkyl, and ‒CO2H, and Ar2. In yet a further aspect, Ar1is an unsubstituted oxazolyl.

[0146] In various aspects, Ar1is selected from an isoxazolyl, an oxadiazolyl, and an oxazolyl, and is monosubstituted with an Ar2group. In a further aspect, Ar1is an isoxazolyl and is monosubstituted with an Ar2group. In a still further aspect, Ar1is an oxadiazolyl and is monosubstituted with an Ar2group. In yet a further aspect, Ar1is an oxazolyl and is monosubstituted with an Ar2group.

[0147] In various aspects, Ar1is selected from an isoxazolyl and an oxadiazolyl, and is monosubstituted with an Ar2group. In a further aspect, Ar1is an isoxazolyl and is monosubstituted with an Ar2group. In a still further aspect, Ar1is an oxadiazolyl and is monosubstituted with an Ar2group. d. AR2GROUPS

[0148] In one aspect, Ar2is selected from a 6-membered aryl and a 6-membered heteroaryl, and is substituted with 0, 1, 2, or 3 groups independently selected from halogen,‒CN, ‒NH2, ‒OH, ‒NO2, C1-C4 alkyl, C2-C4 alkenyl, C1-C4 haloalkyl, C1-C4 cyanoalkyl, C1-C4 hydroxyalkyl, C1-C4 haloalkoxy, C1-C4 alkoxy, C1-C4 alkylamino, (C1-C4)(C1-C4) dialkylamino, C1-C4 aminoalkyl, ‒CO2H, and ‒C(O)NH2. In a further aspect, Ar2is selected from a 6-membered aryl and a 6-membered heteroaryl, and is substituted with 0, 1, or 2 groups independently selected from halogen, ‒CN, ‒NH2, ‒OH, ‒NO2, C1-C4 alkyl, C2-C4 alkenyl, C1-C4 haloalkyl, C1-C4 cyanoalkyl, C1-C4 hydroxyalkyl, C1-C4 haloalkoxy, C1- C4 alkoxy, C1-C4 alkylamino, (C1-C4)(C1-C4) dialkylamino, C1-C4 aminoalkyl, ‒CO2H, and ‒C(O)NH2. In a still further aspect, Ar2is selected from a 6-membered aryl and a 6- membered heteroaryl, and is substituted with 0 or 1 group selected from halogen, ‒CN, ‒NH2, ‒OH, ‒NO2, C1-C4 alkyl, C2-C4 alkenyl, C1-C4 haloalkyl, C1-C4 cyanoalkyl, C1-C4 hydroxyalkyl, C1-C4 haloalkoxy, C1-C4 alkoxy, C1-C4 alkylamino, (C1-C4)(C1-C4) dialkylamino, C1-C4 aminoalkyl, ‒CO2H, and ‒C(O)NH2. In yet a further aspect, Ar2is selected from a 6-membered aryl and a 6-membered heteroaryl, and is monosubstituted with a group selected from halogen, ‒CN, ‒NH2, ‒OH, ‒NO2, C1-C4 alkyl, C2-C4 alkenyl, C1-C4 haloalkyl, C1-C4 cyanoalkyl, C1-C4 hydroxyalkyl, C1-C4 haloalkoxy, C1-C4 alkoxy, C1-C4 alkylamino, (C1-C4)(C1-C4) dialkylamino, C1-C4 aminoalkyl, ‒CO2H, and ‒C(O)NH2. In an even further aspect, Ar2is selected from a 6-membered aryl and a 6-membered heteroaryl, and is unsubstituted.

[0149] In one aspect, Ar2is a 6-membered aryl substituted with 0, 1, 2, or 3 groups independently selected from halogen, ‒CN, ‒NH2, ‒OH, ‒NO2, C1-C4 alkyl, C2-C4 alkenyl, C1-C4 haloalkyl, C1-C4 cyanoalkyl, C1-C4 hydroxyalkyl, C1-C4 haloalkoxy, C1-C4 alkoxy, C1-C4 alkylamino, (C1-C4)(C1-C4) dialkylamino, C1-C4 aminoalkyl, and ‒CO2H. In a further aspect, Ar1is a 6-membered aryl substituted with 0, 1, or 2 groups independently selected from halogen, ‒CN, ‒NH2, ‒OH, ‒NO2, C1-C4 alkyl, C2-C4 alkenyl, C1-C4 haloalkyl, C1-C4 cyanoalkyl, C1-C4 hydroxyalkyl, C1-C4 haloalkoxy, C1-C4 alkoxy, C1-C4 alkylamino, (C1-C4)(C1-C4) dialkylamino, C1-C4 aminoalkyl, and ‒CO2H. In a still further aspect, Ar1is a 6-membered aryl substituted with 0 or 1 group selected from halogen, ‒CN, ‒NH2, ‒OH, ‒NO2, C1-C4 alkyl, C2-C4 alkenyl, C1-C4 haloalkyl, C1-C4 cyanoalkyl, C1-C4 hydroxyalkyl, C1-C4 haloalkoxy, C1-C4 alkoxy, C1-C4 alkylamino, (C1-C4)(C1-C4) dialkylamino, C1-C4 aminoalkyl, and ‒CO2H. In yet a further aspect, Ar1is a 6-membered aryl monosubstituted with a selected from halogen, ‒CN, ‒NH2, ‒OH, ‒NO2, C1-C4 alkyl, C2-C4 alkenyl, C1-C4 haloalkyl, C1-C4 cyanoalkyl, C1-C4 hydroxyalkyl, C1-C4 haloalkoxy, C1-C4 alkoxy, C1-C4 alkylamino, (C1-C4)(C1-C4) dialkylamino, C1-C4 aminoalkyl, and ‒CO2H. In an even further aspect, Ar1is an unsubstituted 6-membered aryl.

[0150] In various aspects, Ar2is a 6-membered aryl substituted with 0, 1, 2, or 3 groups independently selected from halogen, ‒CN, ‒NH2, ‒OH, ‒NO2, C1-C4 alkyl, C2-C4 alkenyl, C1-C4 haloalkyl, C1-C4 cyanoalkyl, C1-C4 hydroxyalkyl, C1-C4 haloalkoxy, C1- C4 alkoxy, C1-C4 alkylamino, (C1-C4)(C1-C4) dialkylamino, C1-C4 aminoalkyl, ‒CO2H, and ‒C(O)NH2. In a further aspect, Ar2is a 6-membered aryl substituted with 0, 1, or 2 groups independently selected from halogen, ‒CN, ‒NH2, ‒OH, ‒NO2, C1-C4 alkyl, C2-C4 alkenyl, C1-C4 haloalkyl, C1-C4 cyanoalkyl, C1-C4 hydroxyalkyl, C1-C4 haloalkoxy, C1- C4 alkoxy, C1-C4 alkylamino, (C1-C4)(C1-C4) dialkylamino, C1-C4 aminoalkyl, ‒CO2H, and ‒C(O)NH2. In a still further aspect, Ar2is a 6-membered aryl substituted with 0 or 1 group selected from halogen, ‒CN, ‒NH2, ‒OH, ‒NO2, C1-C4 alkyl, C2-C4 alkenyl, C1-C4 haloalkyl, C1-C4 cyanoalkyl, C1-C4 hydroxyalkyl, C1-C4 haloalkoxy, C1-C4 alkoxy, C1-C4 alkylamino, (C1-C4)(C1-C4) dialkylamino, C1-C4 aminoalkyl, ‒CO2H, and ‒C(O)NH2. In yet a further aspect, Ar2is a 6-membered aryl monosubstituted with a group selected from halogen, ‒CN, ‒NH2, ‒OH, ‒NO2, C1-C4 alkyl, C2-C4 alkenyl, C1-C4 haloalkyl, C1-C4 cyanoalkyl, C1-C4 hydroxyalkyl, C1-C4 haloalkoxy, C1-C4 alkoxy, C1-C4 alkylamino, (C1- C4)(C1-C4) dialkylamino, C1-C4 aminoalkyl, ‒CO2H, and ‒C(O)NH2. In an even further aspect, Ar2is an unsubstituted 6-membered aryl.

[0151] In various aspects, Ar2is a 6-membered heteroaryl substituted with 0, 1, 2, or 3 groups independently selected from halogen, ‒CN, ‒NH2, ‒OH, ‒NO2, C1-C4 alkyl, C2-C4 alkenyl, C1-C4 haloalkyl, C1-C4 cyanoalkyl, C1-C4 hydroxyalkyl, C1-C4 haloalkoxy, C1- C4 alkoxy, C1-C4 alkylamino, (C1-C4)(C1-C4) dialkylamino, C1-C4 aminoalkyl, ‒CO2H, and ‒C(O)NH2. Examples of 6-membered heteroaryls include, but are not limited to, pyridinyl, pyridazinyl, pyrimidinyl, pyrazinyl, and triazinyl. In a further aspect, Ar2is a 6- membered heteroaryl substituted with 0, 1, or 2 groups independently selected from halogen, ‒CN, ‒NH2, ‒OH, ‒NO2, C1-C4 alkyl, C2-C4 alkenyl, C1-C4 haloalkyl, C1-C4 cyanoalkyl, C1-C4 hydroxyalkyl, C1-C4 haloalkoxy, C1-C4 alkoxy, C1-C4 alkylamino, (C1-C4)(C1-C4) dialkylamino, C1-C4 aminoalkyl, ‒CO2H, and ‒C(O)NH2. In a still further aspect, Ar2is a 6- membered heteroaryl substituted with 0 or 1 group selected from halogen, ‒CN, ‒NH2, ‒OH, ‒NO2, C1-C4 alkyl, C2-C4 alkenyl, C1-C4 haloalkyl, C1-C4 cyanoalkyl, C1-C4 hydroxyalkyl, C1-C4 haloalkoxy, C1-C4 alkoxy, C1-C4 alkylamino, (C1-C4)(C1-C4) dialkylamino, C1-C4 aminoalkyl, ‒CO2H, and ‒C(O)NH2. In yet a further aspect, Ar2is a 6- membered heteroaryl monosubstituted with a group selected from halogen, ‒CN, ‒NH2, ‒OH, ‒NO2, C1-C4 alkyl, C2-C4 alkenyl, C1-C4 haloalkyl, C1-C4 cyanoalkyl, C1-C4 hydroxyalkyl, C1-C4 haloalkoxy, C1-C4 alkoxy, C1-C4 alkylamino, (C1-C4)(C1-C4)dialkylamino, C1-C4 aminoalkyl, ‒CO2H, and ‒C(O)NH2. In an even further aspect, Ar2is an unsubstituted 6-membered heteroaryl.

[0152] In various aspects, Ar2is pyridinyl substituted with 0, 1, 2, or 3 groups independently selected from halogen, ‒CN, ‒NH2, ‒OH, ‒NO2, C1-C4 alkyl, C2-C4 alkenyl, C1-C4 haloalkyl, C1-C4 cyanoalkyl, C1-C4 hydroxyalkyl, C1-C4 haloalkoxy, C1-C4 alkoxy, C1-C4 alkylamino, (C1-C4)(C1-C4) dialkylamino, C1-C4 aminoalkyl, ‒CO2H, and ‒C(O)NH2. In a further aspect, Ar2is pyridinyl substituted with 0, 1, or 2 groups independently selected from halogen, ‒CN, ‒NH2, ‒OH, ‒NO2, C1-C4 alkyl, C2-C4 alkenyl, C1-C4 haloalkyl, C1-C4 cyanoalkyl, C1-C4 hydroxyalkyl, C1-C4 haloalkoxy, C1-C4 alkoxy, C1-C4 alkylamino, (C1-C4)(C1-C4) dialkylamino, C1-C4 aminoalkyl, ‒CO2H, and ‒C(O)NH2. In a still further aspect, Ar2is pyridinyl substituted with 0 or 1 group selected from halogen, ‒CN, ‒NH2, ‒OH, ‒NO2, C1-C4 alkyl, C2-C4 alkenyl, C1-C4 haloalkyl, C1- C4 cyanoalkyl, C1-C4 hydroxyalkyl, C1-C4 haloalkoxy, C1-C4 alkoxy, C1-C4 alkylamino, (C1-C4)(C1-C4) dialkylamino, C1-C4 aminoalkyl, ‒CO2H, and ‒C(O)NH2. In yet a further aspect, Ar2is pyridinyl monosubstituted with a group selected from halogen, ‒CN, ‒NH2, ‒OH, ‒NO2, C1-C4 alkyl, C2-C4 alkenyl, C1-C4 haloalkyl, C1-C4 cyanoalkyl, C1-C4 hydroxyalkyl, C1-C4 haloalkoxy, C1-C4 alkoxy, C1-C4 alkylamino, (C1-C4)(C1-C4) dialkylamino, C1-C4 aminoalkyl, ‒CO2H, and ‒C(O)NH2. In an even further aspect, Ar2is an unsubstituted pyridinyl.

[0153] In various aspects, Ar2is a 6-membered heteroaryl substituted with 0, 1, 2, or 3 groups independently selected from halogen and C1-C4 alkyl. In a further aspect, Ar2is a 6-membered heteroaryl substituted with 0, 1, or 2 groups independently selected from halogen and C1-C4 alkyl. In a still further aspect, Ar2is a 6-membered heteroaryl substituted with 0 or 1 group selected from halogen and C1-C4 alkyl. In yet a further aspect, Ar2is a 6- membered heteroaryl monosubstituted with a selected from halogen and C1-C4 alkyl. In an even further aspect, Ar2is an unsubstituted 6-membered heteroaryl.

[0154] In various aspects, Ar2is a 6-membered aryl substituted with 0, 1, 2, or 3 groups independently selected from halogen and C1-C4 alkyl. In a further aspect, Ar2is a 6- membered aryl substituted with 0, 1, or 2 groups independently selected from halogen and C1-C4 alkyl. In a still further aspect, Ar2is a 6-membered aryl substituted with 0 or 1 group selected from halogen and C1-C4 alkyl. In yet a further aspect, Ar2is a 6-membered aryl monosubstituted with a selected from halogen and C1-C4 alkyl. In an even further aspect, Ar2is an unsubstituted 6-membered aryl.

[0155] In various aspects, Ar2is a 6-membered heteroaryl substituted with 0, 1, 2, or3 groups independently selected from ‒F, ‒Cl, methyl, ethyl, n-propyl, and i-propyl. In a further aspect, Ar2is a 6-membered heteroaryl substituted with 0, 1, 2, or 3 groups independently selected from ‒F, ‒Cl, methyl, and ethyl. In a still further aspect, Ar2is a 6- membered heteroaryl substituted with 0, 1, 2, or 3 groups independently selected from ‒F, ‒Cl, and methyl.

[0156] In various aspects, Ar2is a 6-membered aryl substituted with 0, 1, 2, or 3 groups independently selected from ‒F, ‒Cl, methyl, ethyl, n-propyl, and i-propyl. In a further aspect, Ar2is a 6-membered aryl substituted with 0, 1, 2, or 3 groups independently selected from ‒F, ‒Cl, methyl, and ethyl. In a still further aspect, Ar2is a 6-membered aryl substituted with 0, 1, 2, or 3 groups independently selected from ‒F, ‒Cl, and methyl. 2. EXAMPLE COMPOUNDS

[0157] In one aspect, a compound can be present as one or more of the following structures:or a pharmaceutically acceptable salt thereof.3. PROPHETIC COMPOUND EXAMPLES

[0158] The following compound examples are prophetic, and can be prepared using the synthesis methods described herein above and other general methods as needed as would be known to one skilled in the art. It is anticipated that the prophetic compounds would be active as modulators of read-through of a premature termination codon, and such activity can be determined using the assay methods described herein below.

[0159] In one aspect, a compound can be present as one or more of the following structures:59or a pharmaceutically acceptable salt thereof. C. PHARMACEUTICAL COMPOSITIONS

[0160] In one aspect, disclosed are pharmaceutical compositions comprising a therapeutically effective amount of a disclosed compound or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier. In a further aspect, disclosed are pharmaceutical compositions comprising a therapeutically effective amount of a compound having a structure represented by a formula:, wherein n is selected from 0 and 1; wherein each of Q1, Q2, and Q3is independently selected from ‒CH2‒ and ‒C(O)‒, provided that at least one of Q1and Q2is ‒C(O)‒; wherein Z is selected from ‒CH(CO2H)‒ and ‒CH(C(O)NH2)‒; wherein each of R1and R2is independently selected from hydrogen and C1-C4 alkyl; wherein Ar1is selected from a 6- membered aryl, an isoxazolyl, an oxadiazolyl, an oxazolyl, and a 9- or 10-membered heteroaryl, and is substituted with 0, 1, 2, or 3 groups independently selected from halogen, ‒CN, ‒NH2, ‒OH, ‒NO2, C1-C4 alkyl, C2-C4 alkenyl, C1-C4 haloalkyl, C1-C4 cyanoalkyl, C1-C4 hydroxyalkyl, C1-C4 haloalkoxy, C1-C4 alkoxy, C1-C4 alkylamino, (C1-C4)(C1-C4) dialkylamino, C1-C4 aminoalkyl, ‒CO2H, and Ar2; and wherein Ar2is selected from a 6- membered aryl and a 6-membered heteroaryl, and is substituted with 0, 1, 2, or 3 groups independently selected from halogen, ‒CN, ‒NH2, ‒OH, ‒NO2, C1-C4 alkyl, C2-C4 alkenyl, C1-C4 haloalkyl, C1-C4 cyanoalkyl, C1-C4 hydroxyalkyl, C1-C4 haloalkoxy, C1-C4 alkoxy, C1-C4 alkylamino, (C1-C4)(C1-C4) dialkylamino, C1-C4 aminoalkyl, ‒CO2H, and ‒C(O)NH2; or a pharmaceutically acceptable salt thereof, provided that when Ar1is a 6- membered aryl, then n is 1, and provided that when Ar1is a 9- or 10-membered heteroaryl, then Ar1is not substituted with an Ar2group, and a pharmaceutically acceptable carrier.

[0161] In a further aspect, disclosed are pharmaceutical compositions comprising a therapeutically effective amount of a compound having a structure represented by a formula:, wherein n is selected from 0 and 1; wherein each of Q1, Q2, and Q3is independently selected from ‒CH2‒ and ‒C(O)‒, provided that at least one of Q1and Q2is ‒C(O)‒; wherein Z is selected from ‒CH(CO2H)‒ and ‒CH(C(O)NH2)‒; wherein each of R1and R2is independently selected from hydrogen and C1-C4 alkyl; wherein Ar1is selected from a 6- membered aryl, an isoxazolyl, an oxadiazolyl, and a 9- or 10-membered heteroaryl, and is substituted with 0, 1, 2, or 3 groups independently selected from halogen, ‒CN, ‒NH2, ‒OH, ‒NO2, C1-C4 alkyl, C2-C4 alkenyl, C1-C4 haloalkyl, C1-C4 cyanoalkyl, C1-C4hydroxyalkyl, C1-C4 haloalkoxy, C1-C4 alkoxy, C1-C4 alkylamino, (C1-C4)(C1-C4) dialkylamino, C1-C4 aminoalkyl, ‒CO2H, and Ar2; and wherein Ar2is a 6-membered aryl substituted with 0, 1, 2, or 3 groups independently selected from halogen, ‒CN, ‒NH2, ‒OH, ‒NO2, C1-C4 alkyl, C2-C4 alkenyl, C1-C4 haloalkyl, C1-C4 cyanoalkyl, C1-C4 hydroxyalkyl, C1-C4 haloalkoxy, C1-C4 alkoxy, C1-C4 alkylamino, (C1-C4)(C1-C4) dialkylamino, C1-C4 aminoalkyl, and ‒CO2H, or a pharmaceutically acceptable salt thereof, provided that when Ar1is a 6-membered aryl, then n is 1, and provided that when Ar1is a 9- or 10-membered heteroaryl, then Ar1is not substituted with an Ar2group.

[0162] In various aspects, the compounds and compositions of the invention can be administered in pharmaceutical compositions, which are formulated according to the intended method of administration. The compounds and compositions described herein can be formulated in a conventional manner using one or more physiologically acceptable carriers or excipients. For example, a pharmaceutical composition can be formulated for local or systemic administration, e.g., administration by drops or injection into the ear, insufflation (such as into the ear), intravenous, topical, or oral administration.

[0163] The nature of the pharmaceutical compositions for administration is dependent on the mode of administration and can readily be determined by one of ordinary skill in the art. In various aspects, the pharmaceutical composition is sterile or sterilizable. The therapeutic compositions featured in the invention can contain carriers or excipients, many of which are known to skilled artisans. Excipients that can be used include buffers (for example, citrate buffer, phosphate buffer, acetate buffer, and bicarbonate buffer), amino acids, urea, alcohols, ascorbic acid, phospholipids, polypeptides (for example, serum albumin), EDTA, sodium chloride, liposomes, mannitol, sorbitol, water, and glycerol. The nucleic acids, polypeptides, small molecules, and other modulatory compounds featured in the invention can be administered by any standard route of administration. For example, administration can be parenteral, intravenous, subcutaneous, or oral. A modulatory compound can be formulated in various ways, according to the corresponding route of administration. For example, liquid solutions can be made for administration by drops into the ear, for injection, or for ingestion; gels or powders can be made for ingestion or topical application. Methods for making such formulations are well known and can be found in, for example, Remington's Pharmaceutical Sciences, 18th Ed., Gennaro, ed., Mack Publishing Co., Easton, PA 1990.

[0164] In various aspects, the disclosed pharmaceutical compositions comprise a disclosed compound (including pharmaceutically acceptable salt(s) thereof) as an activeingredient, a pharmaceutically acceptable carrier, and, optionally, other therapeutic ingredients or adjuvants. The instant compositions include those suitable for oral, rectal, topical, and parenteral (including subcutaneous, intramuscular, and intravenous) administration, although the most suitable route in any given case will depend on the particular host, and nature and severity of the conditions for which the active ingredient is being administered. The pharmaceutical compositions can be conveniently presented in unit dosage form and prepared by any of the methods well known in the art of pharmacy.

[0165] In various aspects, the pharmaceutical compositions of this invention can include a pharmaceutically acceptable carrier and a compound or a pharmaceutically acceptable salt of the compounds of the invention. The compounds of the invention, or pharmaceutically acceptable salts thereof, can also be included in pharmaceutical compositions in combination with one or more other therapeutically active compounds.

[0166] The pharmaceutical carrier employed can be, for example, a solid, liquid, or gas. Examples of solid carriers include lactose, terra alba, sucrose, talc, gelatin, agar, pectin, acacia, magnesium stearate, and stearic acid. Examples of liquid carriers are sugar syrup, peanut oil, olive oil, and water. Examples of gaseous carriers include carbon dioxide and nitrogen.

[0167] In preparing the compositions for oral dosage form, any convenient pharmaceutical media can be employed. For example, water, glycols, oils, alcohols, flavoring agents, preservatives, coloring agents and the like can be used to form oral liquid preparations such as suspensions, elixirs and solutions; while carriers such as starches, sugars, microcrystalline cellulose, diluents, granulating agents, lubricants, binders, disintegrating agents, and the like can be used to form oral solid preparations such as powders, capsules and tablets. Because of their ease of administration, tablets and capsules are the preferred oral dosage units whereby solid pharmaceutical carriers are employed. Optionally, tablets can be coated by standard aqueous or nonaqueous techniques.

[0168] A tablet containing the composition of this invention can be prepared by compression or molding, optionally with one or more accessory ingredients or adjuvants. Compressed tablets can be prepared by compressing, in a suitable machine, the active ingredient in a free-flowing form such as powder or granules, optionally mixed with a binder, lubricant, inert diluent, surface active or dispersing agent. Molded tablets can be made by molding in a suitable machine, a mixture of the powdered compound moistened with an inert liquid diluent.

[0169] The pharmaceutical compositions of the present invention comprise acompound of the invention (or pharmaceutically acceptable salts thereof) as an active ingredient, a pharmaceutically acceptable carrier, and optionally one or more additional therapeutic agents or adjuvants. The instant compositions include compositions suitable for oral, rectal, topical, and parenteral (including subcutaneous, intramuscular, and intravenous) administration, although the most suitable route in any given case will depend on the particular host, and nature and severity of the conditions for which the active ingredient is being administered. The pharmaceutical compositions can be conveniently presented in unit dosage form and prepared by any of the methods well known in the art of pharmacy.

[0170] Pharmaceutical compositions of the present invention suitable for parenteral administration can be prepared as solutions or suspensions of the active compounds in water. A suitable surfactant can be included such as, for example, hydroxypropylcellulose. Dispersions can also be prepared in glycerol, liquid polyethylene glycols, and mixtures thereof in oils. Further, a preservative can be included to prevent the detrimental growth of microorganisms.

[0171] Pharmaceutical compositions of the present invention suitable for injectable use include sterile aqueous solutions or dispersions. Furthermore, the compositions can be in the form of sterile powders for the extemporaneous preparation of such sterile injectable solutions or dispersions. In all cases, the final injectable form must be sterile and must be effectively fluid for easy syringability. The pharmaceutical compositions must be stable under the conditions of manufacture and storage; thus, preferably should be preserved against the contaminating action of microorganisms such as bacteria and fungi. The carrier can be a solvent or dispersion medium containing, for example, water, ethanol, polyol (e.g., glycerol, propylene glycol and liquid polyethylene glycol), vegetable oils, and suitable mixtures thereof.

[0172] Pharmaceutical compositions of the present invention can be in a form suitable for topical use such as, for example, an aerosol, cream, ointment, lotion, dusting powder, mouth washes, gargles, and the like. Further, the compositions can be in a form suitable for use in transdermal devices. These formulations can be prepared, utilizing a compound of the invention, or pharmaceutically acceptable salts thereof, via conventional processing methods. As an example, a cream or ointment is prepared by mixing hydrophilic material and water, together with about 5 wt% to about 10 wt% of the compound, to produce a cream or ointment having a desired consistency.

[0173] Pharmaceutical compositions of this invention can be in a form suitable for rectal administration wherein the carrier is a solid. It is preferable that the mixture forms unitdose suppositories. Suitable carriers include cocoa butter and other materials commonly used in the art. The suppositories can be conveniently formed by first admixing the composition with the softened or melted cameras) followed by chilling and shaping in molds.

[0174] In addition to the aforementioned carrier ingredients, the pharmaceutical formulations described above can include, as appropriate, one or more additional carrier ingredients such as diluents, buffers, flavoring agents, binders, surface-active agents, thickeners, lubricants, preservatives (including anti-oxidants) and the like. Furthermore, other adjuvants can be included to render the formulation isotonic with the blood of the intended recipient. Compositions containing a compound of the invention, and / or pharmaceutically acceptable salts thereof, can also be prepared in powder or liquid concentrate form.

[0175] In a further aspect, the effective amount is a therapeutically effective amount. In a still further aspect, the effective amount is a prophylactically effective amount.

[0176] In a further aspect, the pharmaceutical composition is administered to a mammal. In a still further aspect, the mammal is a human. In an even further aspect, the human is a patient.

[0177] In a further aspect, the pharmaceutical composition is used to treat a disorder associated with the presence of a premature termination codon such as, for example, cystic fibrosis, Duchenne muscular dystrophy, aniridia, Becker muscular dystrophy, spinal muscular atrophy, Hurler syndrome, hemophilia, epidermolysis bullosa (e.g., dystrophic (DEB) harm, junctional (JEB) form), Usher syndrome, and cancer. In a still further aspect, the pharmaceutical composition is used to treat a disorder in a subject identified as having a premature termination codon.

[0178] It is understood that the disclosed compositions can be prepared from the disclosed compounds. It is also understood that the disclosed compositions can be employed in the disclosed methods of using.D. METHODS OF MAKING A COMPOUND

[0179] The compounds of this invention can be prepared by employing reactions as shown in the following schemes, in addition to other standard manipulations that are known in the literature, exemplified in the experimental sections or clear to one skilled in the art. For clarity, examples having a single substituent are shown where multiple substituents are allowed under the definitions disclosed herein.

[0180] Reactions used to generate the compounds of this invention are prepared by employing reactions as shown in the following Reaction Schemes, as described and exemplified below. In certain specific examples, the disclosed compounds can be prepared by Routes I and II, as described and exemplified below. The following examples are provided so that the invention might be more fully understood, are illustrative only, and should not be construed as limiting.1. ROUTE I

[0181] In one aspect, substituted heteroaryl analogs can be prepared as shown below.SCHEME 1A.

[0182] Compounds are represented in generic form, with substituents as noted in compound descriptions elsewhere herein. A more specific example is set forth below. SCHEME 1B.

[0183] In one aspect, compounds of type 1.16 and similar compounds can be preparedaccording to reaction Scheme 1B above. Thus, compounds of type 1.10 can be prepared by a palladium catalyzed cyanation reaction of an appropriate aryl bromide, e.g., 1.9 as shown above. Appropriate aryl bromide are commercially available or prepared by methods known to one skilled in the art. The cyanation reaction is carried out with an appropriate cyanation reagent, e.g., zinc cyanide, in the presence of an appropriate catalyst, e.g., tris(dibenzylideneacetone)dipalladium(0), and an appropriate ligand, e.g., 1,1′-ferrocenediyl- bis(diphenylphosphine), in an appropriate solvent, e.g., dimethylformamide, at an appropriate temperature, e.g., 100 °C. Compounds of type 1.11 can be prepared by condensation reaction of an appropriate aryl nitrile, e.g., 1.10 as shown above with hydoxy amine. The condensation reaction is carried out in an appropriate solvent, e.g., ethanol, at an appropriate temperature, e.g., 80 °C. Compounds of type 1.12 can be prepared by reaction of an appropriate hydroxy amidine, e.g., 1.11 as shown above, with triphosgene. The reaction is carried out in an appropriate solvent, e.g., tetrahydrofuran, at an appropriate temperature, e.g., 0 °C. Compounds of type 1.14 can be prepared by coupline of an appropriate hydroxyl oxadiazole, e.g., 1.12 as shown above, and an appropriate amine, e.g., 1.13 as shown above. The coupling reaction is carried out in the presence of an appropriate activating agent, e.g., 4- bromo tris(dimethylamino) phosphonium hexafluorophosphate (Brop), and an appropriate base, e.g., diisopropylethyl amine, in an appropriate solvent, e.g., dioxane, at an appropriate temperature, e.g., 50 °C. Compounds of type 1.15 can be prepared by demethylation of an appropriate aryl methyl ether, e.g., 1.14 as shown above. The demethylation is carried out in the presence of an appropriate deprotecting agent, e.g., boron tribromide, n an appropriate solvent, e.g., dichloromethane, at an appropriate temperature, e.g., 0 °C. Compounds of type 1.16 can be prepared by intramolecular cyclization of an appropriate amino oxadiazole, e.g., 1.15 as shown above. The cyclization is carried out in an appropriate solvent, e.g., dimethylsulfoxide, at an appropriate temperature, e.g., 50 °C. As can be appreciated by one skilled in the art, the above reaction provides an example of a generalized approach wherein compounds similar in structure to the specific reactants above (compounds similar tocompounds of type 1.1, 1.2, 1.3, 1.4, 1.5, 1.6, and 1.7) can be substituted in the reaction to provide substituted analogs similar to Formula 1.8. 2. ROUTE II

[0184] In one aspect, substituted piperidinedione analogs can be prepared as shown below. SCHEME 2A.

[0185] Compounds are represented in generic form, wherein X represents an appropriate leaving group (e.g., ‒Cl and para-nitrophenol) and with other substituents as noted in compound descriptions elsewhere herein. A more specific example is set forth below. SCHEME 2B.

[0186] In one aspect, compounds of type 2.8 and similar compounds can be prepared according to reaction Scheme 2B above. Thus, compounds of type 2.6 can be prepared by a carbonylation reaction of an appropriate amine, e.g., 2.5 as shown above, and an appropriate carbonylation reagent, e.g., bis(4-nitrophenyl) carbonate. Appropriate amines and appropriate carbonylation reagents are commercially available or prepared by methods known to one of skill in the art. The carbonylation reaction is carried out in the presence of an appropriate base, e.g., N,N-diisopropylethylamine (DIPEA), in an appropriate solvent, e.g., dimethylformamide (DMF), at an appropriate temperature, e.g., room temperature. Compounds of type 2.8 can be prepared by reaction of an appropriate activated carbonyl, e.g., 2.6 as shown above, and an appropriate amine, e.g., 2.7 as shown above. Appropriate amines are commercially available or prepared by methods known to one of skill in the art. The reaction is carried out in the presence of an appropriate base, e.g., N,N-diisopropylethylamine (DIPEA), in an appropriate solvent, e.g., dimethylformamide, at an appropriate temperature, e.g., room temperature. As can be appreciated by one skilled in the art, the above reaction provides an example of a generalized approach wherein compounds similar in structure to the specific reactants above (compounds similar to compounds of type 2.1, 2.2 and 2.3) can be substituted in the reaction to provide substituted piperidinedione analogs similar to Formula 2.4. E. METHODS OF MODULATING READ-THROUGH OF A PREMATURE TERMINATION CODON IN A SUBJECT

[0187] The compounds and pharmaceutical compositions of the invention are alsouseful in modulating read-through of a premature termination codon in a subject. Exemplary disorders associated with the presence of a premature termination codon include, but are not limited to, cystic fibrosis, Duchenne muscular dystrophy, aniridia, Becker muscular dystrophy, spinal muscular atrophy, Hurler syndrome, hemophilia, epidermolysis bullosa (e.g., dystrophic (DEB) form, junctional (JEB) form), Usher syndrome, and cancer.

[0188] Nonsense suppression therapy is an approach utilized to treat disorders such as cystic fibrosis in patients who carry a nonsense mutation or a premature termination codon (PTC). Without wishing to be bound by theory, this therapeutic strategy utilizes small molecules to suppress translation termination at in-fram PTCs, allowing partial levels of full- length, functional protein to be restored. PTC suppression agents increase the frequency that aminoacyl tRNAs become incorporated at a PTC, resulting in insertion of an amino acid into the anscent polypeptide at the site of the PTC. This mechanism, termed “readthrough,” suppresses translation termination at a PTC, allowing translation elongation to continue downstream of the PTC in the correct reading frame to generate a full-length protein. The instantly disclosed compounds induce readthrough by targeting the translation termination factor, eRF1, to the proteasome for degradation. This results in reduced intracellular eRF1 levels, which promotes a corresponding increase in readthrough of PTCs.

[0189] Thus, in one aspect, disclosed are methods for modulating read-through of a premature termination codon in a subject in need thereof, the method comprising administering to the subject an effective amount of a disclosed compound. In a further aspect, the compound has a structure represented by a formula:, wherein n is selected from 0 and 1; wherein each of Q1, Q2, and Q3is independently selected from ‒CH2‒ and ‒C(O)‒, provided that at least one of Q1and Q2is ‒C(O)‒; wherein Z is selected from ‒CH(CO2H)‒ and ‒CH(C(O)NH2)‒; wherein each of R1and R2is independently selected from hydrogen and C1-C4 alkyl; wherein Ar1is selected from a 6- membered aryl, an isoxazolyl, an oxadiazolyl, an oxazolyl, and a 9- or 10-membered heteroaryl, and is substituted with 0, 1, 2, or 3 groups independently selected from halogen, ‒CN, ‒NH2, ‒OH, ‒NO2, C1-C4 alkyl, C2-C4 alkenyl, C1-C4 haloalkyl, C1-C4 cyanoalkyl, C1-C4 hydroxyalkyl, C1-C4 haloalkoxy, C1-C4 alkoxy, C1-C4 alkylamino, (C1-C4)(C1-C4)dialkylamino, C1-C4 aminoalkyl, ‒CO2H, and Ar2; and wherein Ar2is selected from a 6- membered aryl and a 6-membered heteroaryl, and is substituted with 0, 1, 2, or 3 groups independently selected from halogen, ‒CN, ‒NH2, ‒OH, ‒NO2, C1-C4 alkyl, C2-C4 alkenyl, C1-C4 haloalkyl, C1-C4 cyanoalkyl, C1-C4 hydroxyalkyl, C1-C4 haloalkoxy, C1-C4 alkoxy, C1-C4 alkylamino, (C1-C4)(C1-C4) dialkylamino, C1-C4 aminoalkyl, ‒CO2H, and ‒C(O)NH2; or a pharmaceutically acceptable salt thereof, provided that when Ar1is a 6- membered aryl, then n is 1, and provided that when Ar1is a 9- or 10-membered heteroaryl, then Ar1is not substituted with an Ar2group.

[0190] In a further aspect, disclosed are methods for modulating read-through of a premature termination codon in a subject in need thereof, the method comprising administering to the subject an effective amount of a compound having a structure represented by a formula:, wherein n is selected from 0 and 1; wherein each of Q1, Q2, and Q3is independently selected from ‒CH2‒ and ‒C(O)‒, provided that at least one of Q1and Q2is ‒C(O)‒; wherein Z is selected from ‒CH(CO2H)‒ and ‒CH(C(O)NH2)‒; wherein each of R1and R2is independently selected from hydrogen and C1-C4 alkyl; wherein Ar1is selected from a 6- membered aryl, an isoxazolyl, an oxadiazolyl, and a 9- or 10-membered heteroaryl, and is substituted with 0, 1, 2, or 3 groups independently selected from halogen, ‒CN, ‒NH2, ‒OH, ‒NO2, C1-C4 alkyl, C2-C4 alkenyl, C1-C4 haloalkyl, C1-C4 cyanoalkyl, C1-C4 hydroxyalkyl, C1-C4 haloalkoxy, C1-C4 alkoxy, C1-C4 alkylamino, (C1-C4)(C1-C4) dialkylamino, C1-C4 aminoalkyl, ‒CO2H, and Ar2; and wherein Ar2is a 6-membered aryl substituted with 0, 1, 2, or 3 groups independently selected from halogen, ‒CN, ‒NH2, ‒OH, ‒NO2, C1-C4 alkyl, C2-C4 alkenyl, C1-C4 haloalkyl, C1-C4 cyanoalkyl, C1-C4 hydroxyalkyl, C1-C4 haloalkoxy, C1-C4 alkoxy, C1-C4 alkylamino, (C1-C4)(C1-C4) dialkylamino, C1-C4 aminoalkyl, and ‒CO2H, or a pharmaceutically acceptable salt thereof, provided that when Ar1is a 6-membered aryl, then n is 1, and provided that when Ar1is a 9- or 10-membered heteroaryl, then Ar1is not substituted with an Ar2group.

[0191] To treat or control the disorder, the compounds and pharmaceutical compositions comprising the compounds are administered to a subject in need thereof, suchas a vertebrate, e.g., a mammal, a fish, a bird, a reptile, or an amphibian. The subject can be a human, non-human primate, horse, pig, rabbit, dog, sheep, goat, cow, cat, guinea pig, or rodent. The term does not denote a particular age or sex. Thus, adult and newborn subjects, as well as fetuses, whether male or female, are intended to be covered. The subject is preferably a mammal, such as a human. Prior to administering the compounds or compositions, the subject can be diagnosed with a need for treatment of a disorder associated with the presence of a premature termination codon, such as, for example, cystic fibrosis.

[0192] The compounds or compositions can be administered to the subject according to any method. Such methods are well known to those skilled in the art and include, but are not limited to, oral administration, transdermal administration, administration by inhalation, nasal administration, topical administration, intravaginal administration, ophthalmic administration, intraaural administration, intracerebral administration, rectal administration, sublingual administration, buccal administration and parenteral administration, including injectable such as intravenous administration, intra-arterial administration, intramuscular administration, and subcutaneous administration. Administration can be continuous or intermittent. A preparation can be administered therapeutically; that is, administered to treat an existing disease or condition. A preparation can also be administered prophylactically; that is, administered for prevention of a disorder associated with the presence of a premature termination codon, such as, for example, cystic fibrosis.

[0193] In a further aspect, modulating is increasing.

[0194] In a further aspect, the premature termination codon is selected from E60X, Y122X, Q493X, G542X, G550X, R553X, Y1092X, R1162X, and W1282X.

[0195] In a further aspect, the subject has been diagnosed with a disorder selected from cystic fibrosis, Duchenne muscular dystrophy, aniridia, Becker muscular dystrophy, spinal muscular atrophy, Hurler syndrome, hemophilia, epidermolysis bullosa, Usher syndrome, neurofibromatosis, and cancer prior to the administering step. In a still further aspect, the subject has been diagnosed with a need for modulating read-through of a premature termination codon prior to the administering step.

[0196] In a further aspect, the subject is a mammal. In a still further aspect, the mammal is a human.

[0197] In a further aspect, the method further comprises the step of identifying a subject in need of treatment of a disorder caused by a premature termination codon, wherein the disorder is selected from cystic fibrosis, Duchenne muscular dystrophy, aniridia, Becker muscular dystrophy, spinal muscular atrophy, Hurler syndrome, hemophilia, epidermolysisbullosa, Usher syndrome, neurofibromatosis, and cancer.

[0198] In a further aspect, the disorder is cystic fibrosis.

[0199] The therapeutically effective amount or dosage of each active agent can vary within wide limits. Such a dosage is adjusted to the individual requirements in each particular case including the specific compound(s) being administered, the route of administration, the condition being treated, as well as the patient being treated. In general, in the case of nasal or parenteral administration to adult humans weighing approximately 70 Kg or more, a daily dosage of about 10 mg to about 10,000 mg, preferably from about 200 mg to about 1,000 mg, should be appropriate, although the upper limit may be exceeded. The daily dosage can be administered as a single dose or in divided doses, or for parenteral administration, as a continuous infusion. Single dose compositions can contain such amounts or submultiples thereof of the compound or composition to make up the daily dose. The dosage can be adjusted by the individual physician in the event of any contraindications. Dosage can vary, and can be administered in one or more dose administrations daily, for one or several days.

[0200] In a further aspect, the effective amount is a therapeutically effective amount. In a still further aspect, the effective amount is a prophylactically effective amount.

[0201] In a further aspect, the compound exhibits activation of read-through of a premature termination codon. Thus, in various aspects, the compound exhibits activation of read-through of a premature termination codon with an EC50of less than 10 μM. In a further aspect, the compound has an EC50of less than 8 μM. In a still further aspect, the compound has an EC50of less than 6 μM. In yet a further aspect, the compound has an EC50of less than 4 μM. In an even further aspect, the compound has an EC50of less than 2 μM. In a still further aspect, the compound has an EC50of less than 1 μM. In yet a further aspect, the compound has an EC50of less than 0.8 μM. In an even further aspect, the compound has an EC50of less than 0.6 μM. In a still further aspect, the compound has an EC50of less than 0.4 μM. In yet a further aspect, the compound has an EC50of less than 0.2 μM. In an even further aspect, the compound has an EC50of less than 0.1 μM.

[0202] In a further aspect, the subject is a mammal. In a still further aspect, the subject is a human.

[0203] In a further aspect, administering stimulates read-through of the premature termination codon. In a still further aspect, administering increases the stability of an mRNA containing the premature termination codon.

[0204] In a further aspect, the effective amount is a therapeutically effective amount. In a still further aspect, the effective amount is a prophylactically effective amount.

[0205] In a further aspect, the disorder is selected from cystic fibrosis, Duchenne muscular dystrophy, aniridia, Becker muscular dystrophy, spinal muscular atrophy, Hurler syndrome, hemophilia, epidermolysis bullosa (e.g., dystrophic (DEB) form, junctional (JEB) form), Usher syndrome, neurofibromatosis, and cancer.

[0206] In a further aspect, the disorder is cancer. In a still further aspect, the cancer is associated with one or more mutations selected from a P53 mutation and an APC mutation.

[0207] In a further aspect, the disorder is cystic fibrosis.

[0208] In a further aspect, the subject has been diagnosed with a need for treatment of the disorder prior to the administering step. In a still further aspect, the method further comprises the step of identifying a subject in need of treatment of the disorder. In yet a further aspect, identifying comprises identifying the presence of a premature termination codon in the subject.

[0209] In a further aspect, the method further comprises administering a second active agent to the subject. While many pharmacological readthrough compounds have been identified, to date, none have been able to rescue the 25-35% of normal CFTR function that is needed to alleviate lung defects in CF patients. In contrast, the instantly disclosed compounds induce modest readthrough alone specifically at PTCs. When combined with aminoglycosides such as G418 (which mediates readthrough by reducing ribosomal proofreading), synergistic increases in readthrough are observed that are significantly higher than either compound alone (see FIG. 1). Without wishing to be bound by theory', this suggests that combining agents that mediate or augment readthrough by different mechanisms is similarly likely to amplify the amount of CFTR function rescued. Additional studies have demonstrated that combining readthrough compounds with distinct mechanisms can promote synergistic PTC suppression that further enhances the level of CFTR production from CFTR alleles containing a nonsense mutation. Thus, in various aspects, the second active agent is selected from a CFTR modulator, an NMD inhibitor, and an agent that increases mRNA levels. In yet a further aspect, the CFTR polypeptide modulator is a CFTR potentiator (e.g., ivacaftor, VX-770, PG-01, tetrahydrobenzothiophene, GP-5), a CFTR amplifier, or a CFTR corrector (e.g., elexacaftor, lumacaftor, tezacaftor, Corr-4a, VX-809, CI, C2).

[0210] In a further aspect, the second active agent is a NMD inhibitor. Examples of NMD inhibitors include, but are not limited to, NMDI-1, NMDI-9, NMDI-25, and NMDI-14.

[0211] In a further aspect, the second active agent is an agent that increases mRNA levels. In a still further aspect, the agent that increases mRNA levels is a histone deacetylaseinhibitor. In yet a further aspect, the histone deacetylase inhibitor is selected from vorinostat, romidepsin, panobinostat, and belinostat.

[0212] In a further aspect, the second active agent is an agent that increases general pulmonary function. In a still further aspect, the agent that increases general pulmonary function is selected from albuterol, salbuterol, recombinant DNAse, dornase alpha, inhaled tobramycin, amikracin, azithromycin, and hypertonic saline.

[0213] In a further aspect, the premature termination codon is in a CFTR.

[0214] In a further aspect, the secod active agent is an aminoglycoside. Examples of aminoglycosides include, but are not limited to, G418, geneticin, amikacin, tobramycin, ELX-02, NB54, NB124, NB127, and NB83.

[0215] In a further aspect, the compound and the second active agent each modulate read-through of a premature termination codon via different mechanism. In a still further aspect, the compound and the second active agent each modulate read-through of a premature termination codon via the same mechanism. In yet a further aspect, the compound modulates read-through of a premature termination codon via degradation of translation termination factor eRF1. In an even further aspect, the second active agent modulates read-through of a premature termination codon via degradation of translation termination factor eRF3 (e.g., CC-9009) or via inhibition of SMG1 (e.g., via a SMG1 inhibitor).

[0216] In a further aspect, the second active agent is selected from erythromycin, artesunate, atazanavir, ataluren, genistein, and Y-320.

[0217] In a further aspect, the compound and the second active agent are administered sequentially. In a still further aspect, the compound and the second active agent are administered simultaneously.

[0218] In a further aspect, the compound and the second active agent are co- formulated. In a still further aspect, the compound and the second active agent are co- packaged. F. METHODS OF MODULATING READ-THROUGH OF A PREMATURE TERMINATION CODON IN A CELL

[0219] The compounds and pharmaceutical compositions of the invention are also useful in modulating read-through of a premature termination codon in a cell. Exemplary disorders associated with the presence of a premature termination codon include, but are not limited to, cystic fibrosis, Duchenne muscular dystrophy, aniridia, Becker musculardystrophy, spinal muscular atrophy, Hurler syndrome, hemophilia, epidermolysis bullosa (e.g., dystrophic (DEB) form, junctional (JEB) form), Usher syndrome, and cancer.

[0220] Thus, in one aspect, disclosed are methods for modulating read-through of a premature termination codon in a cell, the method comprising contacting the cell with an effective amount of a disclosed compound. In a further aspect, the compound has a structure represented by a formula:, wherein n is selected from 0 and 1; wherein each of Q1, Q2, and Q3is independently selected from ‒CH2‒ and ‒C(O)‒, provided that at least one of Q1and Q2is ‒C(O)‒; wherein Z is selected from ‒CH(CO2H)‒ and ‒CH(C(O)NH2)‒; wherein each of R1and R2is independently selected from hydrogen and C1-C4 alkyl; wherein Ar1is selected from a 6- membered aryl, an isoxazolyl, an oxadiazolyl, an oxazolyl, and a 9- or 10-membered heteroaryl, and is substituted with 0, 1, 2, or 3 groups independently selected from halogen, ‒CN, ‒NH2, ‒OH, ‒NO2, C1-C4 alkyl, C2-C4 alkenyl, C1-C4 haloalkyl, C1-C4 cyanoalkyl, C1-C4 hydroxyalkyl, C1-C4 haloalkoxy, C1-C4 alkoxy, C1-C4 alkylamino, (C1-C4)(C1-C4) dialkylamino, C1-C4 aminoalkyl, ‒CO2H, and Ar2; and wherein Ar2is selected from a 6- membered aryl and a 6-membered heteroaryl, and is substituted with 0, 1, 2, or 3 groups independently selected from halogen, ‒CN, ‒NH2, ‒OH, ‒NO2, C1-C4 alkyl, C2-C4 alkenyl, C1-C4 haloalkyl, C1-C4 cyanoalkyl, C1-C4 hydroxyalkyl, C1-C4 haloalkoxy, C1-C4 alkoxy, C1-C4 alkylamino, (C1-C4)(C1-C4) dialkylamino, C1-C4 aminoalkyl, ‒CO2H, and ‒C(O)NH2; or a pharmaceutically acceptable salt thereof, provided that when Ar1is a 6- membered aryl, then n is 1, and provided that when Ar1is a 9- or 10-membered heteroaryl, then Ar1is not substituted with an Ar2group.

[0221] In a further aspect, disclosed are methods for modulating read-through of apremature termination codon in a cell, the method comprising contacting the cell with an effective amount of a compound having a structure represented by a formula:,wherein n is selected from 0 and 1; wherein each of Q1, Q2, and Q3is independently selected from ‒CH2‒ and ‒C(O)‒, provided that at least one of Q1and Q2is ‒C(O)‒; wherein Z is selected from ‒CH(CO2H)‒ and ‒CH(C(O)NH2)‒; wherein each of R1and R2is independently selected from hydrogen and C1-C4 alkyl; wherein Ar1is selected from a 6- membered aryl, an isoxazolyl, an oxadiazolyl, and a 9- or 10-membered heteroaryl, and is substituted with 0, 1, 2, or 3 groups independently selected from halogen, ‒CN, ‒NH2, ‒OH, ‒NO2, C1-C4 alkyl, C2-C4 alkenyl, C1-C4 haloalkyl, C1-C4 cyanoalkyl, C1-C4 hydroxyalkyl, C1-C4 haloalkoxy, C1-C4 alkoxy, C1-C4 alkylamino, (C1-C4)(C1-C4) dialkylamino, C1-C4 aminoalkyl, ‒CO2H, and Ar2; and wherein Ar2is a 6-membered aryl substituted with 0, 1, 2, or 3 groups independently selected from halogen, ‒CN, ‒NH2, ‒OH, ‒NO2, C1-C4 alkyl, C2-C4 alkenyl, C1-C4 haloalkyl, C1-C4 cyanoalkyl, C1-C4 hydroxyalkyl, C1-C4 haloalkoxy, C1-C4 alkoxy, C1-C4 alkylamino, (C1-C4)(C1-C4) dialkylamino, C1-C4 aminoalkyl, and ‒CO2H, or a pharmaceutically acceptable salt thereof, provided that when Ar1is a 6-membered aryl, then n is 1, and provided that when Ar1is a 9- or 10-membered heteroaryl, then Ar1is not substituted with an Ar2group.

[0222] In a further aspect, modulating is increasing.

[0223] In a further aspect, the cell is mammalian. In a still further aspect, the cell is human. In yet a further aspect, the cell has been isolated from a human prior to the contacting step.

[0224] In a further aspect, contacting is via administration to a subject. In a still further aspect, the subject has been diagnosed with a need for modulating read-through of a premature termination codon prior to the administering step. In yet a further aspect, the subject has been diagnosed with a need for treatment of cystic fibrosis, Duchenne muscular dystrophy, aniridia, Becker muscular dystrophy, spinal muscular atrophy, Hurler syndrome, hemophilia, epidermolysis bullosa, Usher syndrome, neurofibromatosis, and cancer prior to the administering step.

[0225] In a further aspect, the premature termination codon is selected from E60X, Y122X, Q493X, G542X, G550X, R553X, Y1092X, R1162X, and W1282X.

[0226] In a further aspect, the compound exhibits activation of read-through of a premature termination codon. Thus, in various aspects, the compound exhibits activation of read-through of a premature termination codon with an EC50of less than 10 μM. In a further aspect, the compound has an EC50of less than 8 μM. In a still further aspect, the compound has an EC50of less than 6 μM. In yet a further aspect, the compound has an EC50of less than 4 μM. In an even further aspect, the compound has an EC50of less than 2 μM. In a stillfurther aspect, the compound has an EC50of less than 1 μM. In yet a further aspect, the compound has an EC50of less than 0.8 μM. In an even further aspect, the compound has an EC50of less than 0.6 μM. In a still further aspect, the compound has an EC50of less than 0.4 μM. In yet a further aspect, the compound has an EC50of less than 0.2 μM. In an even further aspect, the compound has an EC50of less than 0.1 μM.

[0227] In a further aspect, the subject is a mammal. In a still further aspect, the subject is a human.

[0228] In a further aspect, administering stimulates read-through of the premature termination codon. In a still further aspect, administering increases the stability of a mRNA containing the premature termination codon.

[0229] In a further aspect, the effective amount is a therapeutically effective amount. In a still further aspect, the effective amount is a prophylactically effective amount.

[0230] In a further aspect, the disorder is selected from cystic fibrosis, Duchenne muscular dystrophy, aniridia, Becker muscular dystrophy, spinal muscular atrophy, Hurler syndrome, hemophilia, epidermolysis bullosa (e.g., dystrophic (DEB) form, junctional (JEB) form), Usher syndrome, neurofibromatosis, and cancer.

[0231] In a further aspect, the disorder is cancer. In a still further aspect, the cancer is associated with one or more mutations selected from a P53 mutation and an APC mutation.

[0232] In a further aspect, the disorder is cystic fibrosis.

[0233] In a further aspect, the subject has been diagnosed with a need for treatment of the disorder prior to the administering step. In a still further aspect, the method further comprises the step of identifying a subject in need of treatment of the disorder. In yet a further aspect, identifying comprises identifying the presence of a premature termination codon in the subject.

[0234] In a further aspect, the premature termination codon is selected from E60X, Y122X, Q493X, G542X, G550X, R553X, Y1092X, R1162X, and W1282X.

[0235] In a further aspect, the method further comprises administering a second active agent to the subject. In a still further aspect, the second active agent is selected from a CFTR modulator, an NMD inhibitor, and an agent that increases mRNA levels. In yet a further aspect, the CFTR polypeptide modulator is a CFTR potentiator (e.g., ivacaftor, VX-770, PG- 01, tetrahydrobenzothiophene, GP-5), a CFTR amplifier, or a CFTR corrector (e.g., elexacaftor, lumacaftor, tezacaftor, Corr-4a, VX-809, CI, C2).

[0236] In a further aspect, the second active agent is a NMD inhibitor. Examples of NMD inhibitors include, but are not limited to, NMDI-1, NMDI-9, NMDI-25, and NMDI-14.

[0237] In a further aspect, the second active agent is an agent that increases mRNA levels. In a still further aspect, the agent that increases mRNA levels is a histone deacetylase inhibitor. In yet a further aspect, the histone deacetylase inhibitor is selected from vorinostat, romidepsin, panobinostat, and belinostat.

[0238] In a further aspect, the second active agent is an agent that increases general pulmonary function. In a still further aspect, the agent that increases general pulmonary function is selected from albuterol, salbuterol, recombinant DNAse, domase alpha, inhaled tobramycin, amikracin, azithromycin, and hypertonic saline.

[0239] In a further aspect, the premature termination codon is in a CFTR.

[0240] In a further aspect, the secod active agent is an aminoglycoside. Examples of aminoglycosides include, but are not limited to, G418, geneticin, amikacin, tobramycin, ELX-02, NB54, NB124, NB127, and NB83.

[0241] In a further aspect, the compound and the second active agent each modulate read-through of a premature termination codon via different mechanism. In a still further aspect, the compound and the second active agent each modulate read-through of a premature termination codon via the same mechanism. In yet a further aspect, the compound modulates read-through of a premature termination codon via degradation of translation termination factor eRFl . In an even further aspect, the second active agent modulates read-through of a premature termination codon via degradation of translation termination factor eRF3 (e.g. , CC-9009) or via inhibition of SMG1 (e.g., via a SMG1 inhibitor).

[0242] In a further aspect, the second active agent is selected from erythromycin, artesunate, atazanavir, ataluren, genistein, and Y-320.G. METHODS OF TREATING A DISORDER ASSOCIATED WITH THE PRESENCE OF APREMATURE TERMINATION CODON IN A SUBJECT

[0243] In various aspects, the compounds and pharmaceutical compositions of the invention are useful in treating or controlling disorders associated with the presence of a premature termination codon. See, e.g., Dabrowski et al. (2018) Molecular Medicine 24: 25; Lombardi et al. (2020) Int. J. Mol. Sci. 21: 9449. Examples of such disorders include, but are not limited to, cystic fibrosis, Duchenne muscular dystrophy, aniridia, Becker muscular dystrophy, spinal muscular atrophy, Hurler syndrome, hemophilia, epidermolysis bullosa (e.g., dystrophic (DEB) form, junctional (JEB) form), Usher syndrome, and cancer.

[0244] Thus, in one aspect, disclosed are methods for treating a disorder associatedwith the presence of a premature termination codon in a subject in need thereof, the method comprising administering to the subject an effective amount of a disclosed compound, or a pharmaceutically acceptable salt thereof, thereby treating the disorder in the subject. In a further aspect, disclosed are methods for treating a disorder associated with the presence of a premature termination codon in a subject in need thereof, the method comprising administering to the subject an effective amount of a compound having a structure represented by a formula:, wherein n is selected from 0 and 1; wherein each of Q1, Q2, and Q3is independently selected from ‒CH2‒ and ‒C(O)‒, provided that at least one of Q1and Q2is ‒C(O)‒; wherein Z is selected from ‒CH(CO2H)‒ and ‒CH(C(O)NH2)‒; wherein each of R1and R2is independently selected from hydrogen and C1-C4 alkyl; wherein Ar1is selected from a 6- membered aryl, an isoxazolyl, an oxadiazolyl, an oxazolyl, and a 9- or 10-membered heteroaryl, and is substituted with 0, 1, 2, or 3 groups independently selected from halogen, ‒CN, ‒NH2, ‒OH, ‒NO2, C1-C4 alkyl, C2-C4 alkenyl, C1-C4 haloalkyl, C1-C4 cyanoalkyl, C1-C4 hydroxyalkyl, C1-C4 haloalkoxy, C1-C4 alkoxy, C1-C4 alkylamino, (C1-C4)(C1-C4) dialkylamino, C1-C4 aminoalkyl, ‒CO2H, and Ar2; and wherein Ar2is selected from a 6- membered aryl and a 6-membered heteroaryl, and is substituted with 0, 1, 2, or 3 groups independently selected from halogen, ‒CN, ‒NH2, ‒OH, ‒NO2, C1-C4 alkyl, C2-C4 alkenyl, C1-C4 haloalkyl, C1-C4 cyanoalkyl, C1-C4 hydroxyalkyl, C1-C4 haloalkoxy, C1-C4 alkoxy, C1-C4 alkylamino, (C1-C4)(C1-C4) dialkylamino, C1-C4 aminoalkyl, ‒CO2H, and ‒C(O)NH2, or a pharmaceutically acceptable salt thereof, provided that when Ar1is a 9- or 10-membered heteroaryl, then Ar1is not substituted with an Ar2group.

[0245] In a further aspect, disclosed are methods for treating a disorder associated with the presence of a premature termination codon in a subject in need thereof, the method comprising administering to the subject an effective amount of a compound having a structure represented by a formula:, wherein n is selected from 0 and 1; wherein each of Q1, Q2, and Q3is independently selected from ‒CH2‒ and ‒C(O)‒, provided that at least one of Q1and Q2is ‒C(O)‒; wherein Z is selected from ‒CH(CO2H)‒ and ‒CH(C(O)NH2)‒; wherein each of R1and R2is independently selected from hydrogen and C1-C4 alkyl; wherein Ar1is selected from a 6- membered aryl, an isoxazolyl, an oxadiazolyl, and a 9- or 10-membered heteroaryl, and is substituted with 0, 1, 2, or 3 groups independently selected from halogen, ‒CN, ‒NH2, ‒OH, ‒NO2, C1-C4 alkyl, C2-C4 alkenyl, C1-C4 haloalkyl, C1-C4 cyanoalkyl, C1-C4 hydroxyalkyl, C1-C4 haloalkoxy, C1-C4 alkoxy, C1-C4 alkylamino, (C1-C4)(C1-C4) dialkylamino, C1-C4 aminoalkyl, ‒CO2H, and Ar2; and wherein Ar2is a 6-membered aryl substituted with 0, 1, 2, or 3 groups independently selected from halogen, ‒CN, ‒NH2, ‒OH, ‒NO2, C1-C4 alkyl, C2-C4 alkenyl, C1-C4 haloalkyl, C1-C4 cyanoalkyl, C1-C4 hydroxyalkyl, C1-C4 haloalkoxy, C1-C4 alkoxy, C1-C4 alkylamino, (C1-C4)(C1-C4) dialkylamino, C1-C4 aminoalkyl, and ‒CO2H, or a pharmaceutically acceptable salt thereof, provided that when Ar1is a 9- or 10-membered heteroaryl, then Ar1is not substituted with an Ar2group.

[0246] In a further aspect, the compound exhibits activition of read-through of a premature termination codon. Thus, in various aspects, the compound exhibits activation of read-through of a premature termination codon with an EC50of less than 10 μM. In a further aspect, the compound has an EC50of less than 8 μM. In a still further aspect, the compound has an EC50of less than 6 μM. In yet a further aspect, the compound has an EC50of less than 4 μM. In an even further aspect, the compound has an EC50of less than 2 μM. In a still further aspect, the compound has an EC50of less than 1 μM. In yet a further aspect, the compound has an EC50of less than 0.8 μM. In an even further aspect, the compound has an EC50of less than 0.6 μM. In a still further aspect, the compound has an EC50of less than 0.4 μM. In yet a further aspect, the compound has an EC50of less than 0.2 μM. In an even further aspect, the compound has an EC50of less than 0.1 μM.

[0247] In a further aspect, the subject is a mammal. In a still further aspect, the subject is a human.

[0248] In a further aspect, the subject has been diagnosed with a need for treatment of the disorder prior to the administering step.

[0249] In a further aspect, the method further comprising the step of identifying a subject in need of treatment of the disorder. In a still further aspect, identifying comprises identifying the presence of a premature termination codon in the subject.

[0250] In a further aspect, administering stimulates read-through of the premature termination codon. In a still further aspect, administering increases the stability of an mRNA containing the premature termination codon.

[0251] In a further aspect, the effective amount is a therapeutically effective amount. In a still further aspect, the effective amount is a prophylactically effective amount.

[0252] In a further aspect, the disorder is selected from cystic fibrosis, Duchenne muscular dystrophy, aniridia, Becker muscular dystrophy, spinal muscular atrophy, Hurler syndrome, hemophilia, epidermolysis bullosa (e.g., dystrophic (DEB) form, junctional (JEB) form), Usher syndrome, neurofibromatosis, and cancer.

[0253] In a further aspect, the disorder is cancer. In a still further aspect, the cancer is associated with one or more mutations selected from a P53mutation and an APC mutation.

[0254] In a further aspect, the disorder is cystic fibrosis.

[0255] In a further aspect, the subject has been diagnosed with a need for treatment of the disorder prior to the administering step. In a still further aspect, the method further comprises the step of identifying a subject in need of treatment of the disorder. In yet a further aspect, identifying comprises identifying the presence of a premature termination codon in the subject.

[0256] In a further aspect, the premature termination codon is selected from E60X, Y122X, Q493X, G542X, G550X, R553X, Y1092X, R1162X, and W1282X.

[0257] In a further aspect, the method further comprises administering a second active agent to the subject. In a still further aspect, the second active agent is selected from a CFTR modulator, an NMD inhibitor, and an agent that increases mRNA levels. In yet a further aspect, the CFTR polypeptide modulator is a CFTR potentiator (e.g., ivacaftor, VX-770, PG- 01, tetrahydrobenzothiophene, GP-5), a CFTR amplifier, or a CFTR corrector (e.g., elexacaftor, lumacaftor, tezacaftor, Corr-4a, VX-809, CI, C2).

[0258] In a further aspect, the second active agent is a NMD inhibitor. Examples of NMD inhibitors include, but are not limited to, NMDI-1, NMDI-9, NMDI-25, and NMDI-14.

[0259] In a further aspect, the second active agent is an agent that increases mRNA levels. In a still further aspect, the agent that increases mRNA levels is a histone deacetylase inhibitor. In yet a further aspect, the histone deacetylase inhibitor is selected from vorinostat, romidepsin, panobinostat, and belinostat.

[0260] In a further aspect, the second active agent is an agent that increases general pulmonary function. In a still further aspect, the agent that increases general pulmonary function is selected from albuterol, salbuterol, recombinant DNAse, dornase alpha, inhaled tobramycin, amikracin, azithromycin, and hypertonic saline.

[0261] In a further aspect, the premature termination codon is in a CFTR.

[0262] In a further aspect, the secod active agent is an aminoglycoside. Examples of aminoglycosides include, but are not limited to, G418, geneticin, amikacin, tobramycin, ELX-02, NB54, NB124, NB127, and NB83.

[0263] In a further aspect, the compound and the second active agent each modulate read-through of a premature termination codon via different mechanism. In a still further aspect, the compound and the second active agent each modulate read-through of a premature termination codon via the same mechanism. In yet a further aspect, the compound modulates read-through of a premature termination codon via degradation of translation termination factor eRF1. In an even further aspect, the second active agent modulates read-through of a premature termination codon via degradation of translation termination factor eRF3 (e.g., CC-9009) or via inhibition of SMG1 (e.g., via a SMG1 inhibitor).

[0264] In a further aspect, the second active agent is selected from erythromycin, artesunate, atazanavir, ataluren, genistein, and Y-320. H. METHODS OF TREATING A DISORDER IN A SUBJECT IDENTIFIED AS HAVING A PREMATURE TERMINATION CODON

[0265] In various aspects, the compounds and pharmaceutical compositions of the invention are useful in treating or controlling disorders in a subject identified as having a premature termination codon. Exemplary disorders include, but are not limited to, cystic fibrosis, Duchenne muscular dystrophy, aniridia, Becker muscular dystrophy, spinal muscular atrophy, Hurler syndrome, hemophilia, epidermolysis bullosa (e.g., dystrophic (DEB) form, junctional (JEB) form), Usher syndrome, and cancer.

[0266] Thus, in one aspect, disclosed are methods for treating a disorder in a subject identified as having a premature termination codon, the method administering to the subject an effective amount of a disclosed compound, or a pharmaceutically acceptable salt thereof, thereby treating the disorder in the subject. In a further aspect, disclosed are methods for treating a disorder in a subject identified as having a premature termination codon, the method comprising administering to the subject an effective amount of a compound having astructure represented by a formula:wherein n is selected from 0 and 1; wherein each of Q1, Q2, and Q3is independently selected from ‒CH2‒ and ‒C(O)‒, provided that at least one of Q1and Q2is ‒C(O)‒; wherein Z is selected from ‒CH(CO2H)‒ and ‒CH(C(O)NH2)‒; wherein each of R1and R2is independently selected from hydrogen and C1-C4 alkyl; wherein Ar1is selected from a 6- membered aryl, an isoxazolyl, an oxadiazolyl, an oxazolyl, and a 9- or 10-membered heteroaryl, and is substituted with 0, 1, 2, or 3 groups independently selected from halogen, ‒CN, ‒NH2, ‒OH, ‒NO2, C1-C4 alkyl, C2-C4 alkenyl, C1-C4 haloalkyl, C1-C4 cyanoalkyl, C1-C4 hydroxyalkyl, C1-C4 haloalkoxy, C1-C4 alkoxy, C1-C4 alkylamino, (C1-C4)(C1-C4) dialkylamino, C1-C4 aminoalkyl, ‒CO2H, and Ar2; and wherein Ar2is selected from a 6- membered aryl and a 6-membered heteroaryl, and is substituted with 0, 1, 2, or 3 groups independently selected from halogen, ‒CN, ‒NH2, ‒OH, ‒NO2, C1-C4 alkyl, C2-C4 alkenyl, C1-C4 haloalkyl, C1-C4 cyanoalkyl, C1-C4 hydroxyalkyl, C1-C4 haloalkoxy, C1-C4 alkoxy, C1-C4 alkylamino, (C1-C4)(C1-C4) dialkylamino, C1-C4 aminoalkyl, ‒CO2H, and ‒C(O)NH2, or a pharmaceutically acceptable salt thereof, provided that when Ar1is a 9- or 10-membered heteroaryl, then Ar1is not substituted with an Ar2group.

[0267] In a further aspect, disclosed are methods for treating a disorder in a subject identified as having a premature termination codon, the method comprising administering to the subject an effective amount of a compound having a structure represented by a formula:wherein n is selected from 0 and 1; wherein each of Q1, Q2, and Q3is independently selected from ‒CH2‒ and ‒C(O)‒, provided that at least one of Q1and Q2is ‒C(O)‒; wherein Z is selected from ‒CH(CO2H)‒ and ‒CH(C(O)NH2)‒; wherein each of R1and R2is independently selected from hydrogen and C1-C4 alkyl; wherein Ar1is selected from a 6- membered aryl, an isoxazolyl, an oxadiazolyl, and a 9- or 10-membered heteroaryl, and issubstituted with 0, 1, 2, or 3 groups independently selected from halogen, ‒CN, ‒NH2, ‒OH, ‒NO2, C1-C4 alkyl, C2-C4 alkenyl, C1-C4 haloalkyl, C1-C4 cyanoalkyl, C1-C4 hydroxyalkyl, C1-C4 haloalkoxy, C1-C4 alkoxy, C1-C4 alkylamino, (C1-C4)(C1-C4) dialkylamino, C1-C4 aminoalkyl, ‒CO2H, and Ar2; and wherein Ar2is a 6-membered aryl substituted with 0, 1, 2, or 3 groups independently selected from halogen, ‒CN, ‒NH2, ‒OH, ‒NO2, C1-C4 alkyl, C2-C4 alkenyl, C1-C4 haloalkyl, C1-C4 cyanoalkyl, C1-C4 hydroxyalkyl, C1-C4 haloalkoxy, C1-C4 alkoxy, C1-C4 alkylamino, (C1-C4)(C1-C4) dialkylamino, C1-C4 aminoalkyl, and ‒CO2H, or a pharmaceutically acceptable salt thereof, provided that when Ar1is a 9- or 10-membered heteroaryl, then Ar1is not substituted with an Ar2group.

[0268] In a further aspect, the compound exhibits activation of read-through of a premature termination codon. Thus, in various aspects, the compound exhibits activation of read-through of a premature termination codon with an EC50of less than 10 μM. In a further aspect, the compound has an EC50of less than 8 μM. In a still further aspect, the compound has an EC50of less than 6 μM. In yet a further aspect, the compound has an EC50of less than 4 μM. In an even further aspect, the compound has an EC50of less than 2 μM. In a still further aspect, the compound has an EC50of less than 1 μM. In yet a further aspect, the compound has an EC50of less than 0.8 μM. In an even further aspect, the compound has an EC50of less than 0.6 μM. In a still further aspect, the compound has an EC50of less than 0.4 μM. In yet a further aspect, the compound has an EC50of less than 0.2 μM. In an even further aspect, the compound has an EC50of less than 0.1 μM.

[0269] In a further aspect, the subject is a mammal. In a still further aspect, the subject is a human.

[0270] In a further aspect, administering stimulates read-through of the premature termination codon. In a still further aspect, administering increases the stability of a mRNA containing the premature termination codon.

[0271] In a further aspect, the effective amount is a therapeutically effective amount. In a still further aspect, the effective amount is a prophylactically effective amount.

[0272] In a further aspect, the disorder is selected from cystic fibrosis, Duchenne muscular dystrophy, aniridia, Becker muscular dystrophy, spinal muscular atrophy, Hurler syndrome, hemophilia, epidermolysis bullosa (e.g., dystrophic (DEB) form, junctional (JEB) form), Usher syndrome, neurofibromatosis, and cancer.

[0273] In a further aspect, the disorder is cancer. In a still further aspect, the cancer is associated with one or more mutations selected from a P53 mutation and an APC mutation.

[0274] In a further aspect, the disorder is cystic fibrosis.

[0275] In a further aspect, the subject has been diagnosed with a need for treatment of the disorder prior to the administering step. In a still further aspect, the method further comprises the step of identifying a subject in need of treatment of the disorder. In yet a further aspect, identifying comprises identifying the presence of a premature termination codon in the subject.

[0276] In a further aspect, the premature termination codon is selected from E60X, Y122X, Q493X, G542X, G550X, R553X, Y1092X, R1162X, and W1282X.

[0277] In a further aspect, the method further comprises administering a second active agent to the subject. In a still further aspect, the second active agent is selected from a CFTR modulator, an NMD inhibitor, and an agent that increases mRNA levels. In yet a further aspect, the CFTR polypeptide modulator is a CFTR potentiator (e.g. , ivacaftor, VX-770, PG- 01 , tetrahydrobenzothiophene, GP-5 ), a CFTR amplifier, or a CFTR corrector (e.g. , elexacaftor, lumacaftor, tezacaftor, Corr-4a, VX-809, CI, C2).

[0278] In a further aspect, the second active agent is a NMD inhibitor. Examples of NMD inhibitors include, but are not limited to, NMDI-1 , NMDI-9, NMDI-25, and NMDI-14.

[0279] In a further aspect, the second active agent is an agent that increases mRNA levels. In a still further aspect, the agent that increases mRNA levels is a histone deacetylase inhibitor. In yet a further aspect, the histone deacetylase inhibitor is selected from vorinostat, romidepsin, panobinostat, and belinostat.

[0280] In a further aspect, the second active agent is an agent that increases general pulmonary function. In a still further aspect, the agent that increases general pulmonary function is selected from albuterol, salbuterol, recombinant DNAse, domase alpha, inhaled tobramycin, amikracin, azithromycin, and hypertonic saline.

[0281] In a further aspect, the premature termination codon is in a CFTR

[0282] In a further aspect, the secod active agent is an aminoglycoside. Examples of aminoglycosides include, but are not limited to, G418, geneticin, amikacin, tobramycin, ELX-02, NB54, NB124, NB127, and NB83.

[0283] In a further aspect, the compound and the second active agent each modulate read-through of a premature termination codon via different mechanism. In a still further aspect, the compound and the second active agent each modulate read-through of a premature termination codon via the same mechanism. In yet a further aspect, the compound modulates read-through of a premature termination codon via degradation of translation termination factor eRFl . In an even further aspect, the second active agent modulates read-through of apremature termination codon via degradation of translation termination factor eRF3 (e.g. , CC-9009) or via inhibition of SMG1 (e.g., via a SMG1 inhibitor).

[0284] In a further aspect, the second active agent is selected from erythromycin, artesunate, atazanavir, ataluren, genistein, and Y-320.I. USE OF COMPOUNDS

[0285] In one aspect, the invention relates to the use of a disclosed compound or a product of a disclosed method. In a further aspect, a use relates to the manufacture of a medicament for the treatment of a disorder associated with the presence of a premature termination codon such as, for example, cystic fibrosis, Duchenne muscular dystrophy, aniridia, Becker muscular dystrophy, spinal muscular atrophy, Hurler syndrome, hemophilia, epidermolysis bullosa (e.g., dystrophic (DEB) form, junctional (JEB) form), Usher syndrome, and cancer.

[0286] Also provided are the uses of the disclosed compounds and products. In one aspect, the invention relates to use of at least one disclosed compound; or a pharmaceutically acceptable salt, hydrate, solvate, or polymorph thereof. In a further aspect, the compound used is a product of a disclosed method of making.

[0287] In a further aspect, the use relates to a process for preparing a pharmaceutical composition comprising a therapeutically effective amount of a disclosed compound or a product of a disclosed method of making, or a pharmaceutically acceptable salt, solvate, or polymorph thereof, for use as a medicament.

[0288] In a further aspect, the use relates to a process for preparing a pharmaceutical composition comprising a therapeutically effective amount of a disclosed compound or a product of a disclosed method of making, or a pharmaceutically acceptable salt, solvate, or polymorph thereof, wherein a pharmaceutically acceptable carrier is intimately mixed with a therapeutically effective amount of the compound or the product of a disclosed method of making.

[0289] In various aspects, the use relates to a treatment of a disorder associated with the presence of a premature termination codon in a subject. Also disclosed is the use of a compound for inhibition of read-through of a premature termination codon. In one aspect, the use is characterized in that the subject is a human. In one aspect, the use is characterized in that the disorder is cystic fibrosis.

[0290] In a further aspect, the use relates to the manufacture of a medicament for thetreatment of a disorder associated with the presence of a premature termination codon in a subject.

[0291] In a further aspect, the use relates to modulation of read-through of a premature termination codon in a subject. In a further aspect, the use relates to modulation of read-through of a premature termination codon in a subject. In a still further aspect, the use relates to modulation of read-through of a premature termination codon in a cell. In yet a further aspect, the subject is a human.

[0292] It is understood that the disclosed uses can be employed in connection with the disclosed compounds, products of disclosed methods of making, methods, compositions, and kits. In a further aspect, the invention relates to the use of a disclosed compound or a disclosed product in the manufacture of a medicament for the treatment of a disorder associated with the presence of a premature termination codon in a mammal. In a further aspect, the disorder is selected from cystic fibrosis, Duchenne muscular dystrophy, aniridia, Becker muscular dystrophy, spinal muscular atrophy, Hurler syndrome, hemophilia, epidermolysis bullosa (e.g., dystrophic (DEB) form, junctional (JEB) form), Usher syndrome, and cancer.J. MANUFACTURE OF A MEDICAMENT

[0293] In one aspect, the invention relates to a method for the manufacture of a medicament for treating a disorder associated with the presence of a premature termination codon in a subject in need thereof, the method comprising combining a therapeutically effective amount of a disclosed compound or product of a disclosed method with a pharmaceutically acceptable carrier or diluent.

[0294] As regards these applications, the present method includes the administration to an animal, particularly a mammal, and more particularly a human, of a therapeutically effective amount of the compound effective in the inhibition of read-through of a premature termination codon. The dose administered to an animal, particularly a human, in the context of the present invention should be sufficient to affect a therapeutic response in the animal over a reasonable timeframe. One skilled in the art will recognize that dosage will depend upon a variety of factors including the condition of the animal and the body weight of the animal.

[0295] The total amount of the compound of the present disclosure administered in a typical treatment is preferably between about 10 mg / kg and about 1000 mg / kg of bodyweight for mice, and between about 100 mg / kg and about 500 mg / kg of body weight, and more preferably between 200 mg / kg and about 400 mg / kg of body weight for humans per daily dose. This total amount is typically, but not necessarily, administered as a series of smaller doses over a period of about one time per day to about three times per day for about 24 months, and preferably over a period of twice per day for about 12 months.

[0296] The size of the dose also will be determined by the route, timing and frequency of administration as well as the existence, nature and extent of any adverse side effects that might accompany the administration of the compound and the desired physiological effect. It will be appreciated by one of skill in the art that various conditions or disease states, in particular chronic conditions or disease states, may require prolonged treatment involving multiple administrations.

[0297] Thus, in one aspect, the invention relates to the manufacture of a medicament comprising combining a disclosed compound or a product of a disclosed method of making, or a pharmaceutically acceptable salt, solvate, or polymorph thereof, with a pharmaceutically acceptable carrier or diluent.K. KITS

[0298] In one aspect, disclosed are kits comprising an effective amount of a disclosed compound, or a pharmaceutically acceptable salt thereof, and one or more selected from: (a) at least one agent known for the treatment of a disorder associated with the presence of a premature termination codon; (b) at least one device known for the treatment of a disorder associated with the presence of a premature termination codon; (c) instructions for administering the compound in connection with treating a disorder associated with the presence of a premature termination codon; (d) instractions for administering the compound in connection with reducing the risk of a disorder associated with the presence of a premature termination codon; and (e) instructions for treating a disorder associated with the presence of a premature termination codon.

[0299] In one aspect, disclosed are kits comprising a compound having a structure represented by a formula:wherein n is selected from 0 and 1; wherein each of Q1, Q2, and Q3is independently selected from ‒CH2‒ and ‒C(O)‒, provided that at least one of Q1and Q2is ‒C(O)‒; wherein Z is selected from ‒CH(CO2H)‒ and ‒CH(C(O)NH2)‒; wherein each of R1and R2is independently selected from hydrogen and C1-C4 alkyl; wherein Ar1is selected from a 6- membered aryl, an isoxazolyl, an oxadiazolyl, an oxazolyl, and a 9- or 10-membered heteroaryl, and is substituted with 0, 1, 2, or 3 groups independently selected from halogen, ‒CN, ‒NH2, ‒OH, ‒NO2, C1-C4 alkyl, C2-C4 alkenyl, C1-C4 haloalkyl, C1-C4 cyanoalkyl, C1-C4 hydroxyalkyl, C1-C4 haloalkoxy, C1-C4 alkoxy, C1-C4 alkylamino, (C1-C4)(C1-C4) dialkylamino, C1-C4 aminoalkyl, ‒CO2H, and Ar2; and wherein Ar2is selected from a 6- membered aryl and a 6-membered heteroaryl, and is substituted with 0, 1, 2, or 3 groups independently selected from halogen, ‒CN, ‒NH2, ‒OH, ‒NO2, C1-C4 alkyl, C2-C4 alkenyl, C1-C4 haloalkyl, C1-C4 cyanoalkyl, C1-C4 hydroxyalkyl, C1-C4 haloalkoxy, C1-C4 alkoxy, C1-C4 alkylamino, (C1-C4)(C1-C4) dialkylamino, C1-C4 aminoalkyl, ‒CO2H, and ‒C(O)NH2, or a pharmaceutically acceptable salt thereof, provided that when Ar1is a 9- or 10-membered heteroaryl, then Ar1is not substituted with an Ar2group, and one or more selected from: (a) at least one agent known for the treatment of a disorder associated with the presence of a premature termination codon; (b) at least one device known for the treatment of a disorder associated with the presence of a premature termination codon; (c) instructions for administering the compound in connection with treating a disorder associated with the presence of a premature termination codon; (d) instructions for administering the compound in connection with reducing the risk of a disorder associated with the presence of a premature termination codon; and (e) instructions for treating a disorder associated with the presence of a premature termination codon.

[0300] In one aspect, disclosed are kits comprising a compound having a structure represented by a formula:, wherein n is selected from 0 and 1; wherein each of Q1, Q2, and Q3is independently selected from ‒CH2‒ and ‒C(O)‒, provided that at least one of Q1and Q2is ‒C(O)‒; wherein Z is selected from ‒CH(CO2H)‒ and ‒CH(C(O)NH2)‒; wherein each of R1and R2is independently selected from hydrogen and C1-C4 alkyl; wherein Ar1is selected from a 6-membered aryl, an isoxazolyl, an oxadiazolyl, and a 9- or 10-membered heteroaryl, and is substituted with 0, 1, 2, or 3 groups independently selected from halogen, ‒CN, ‒NH2, ‒OH, ‒NO2, C1-C4 alkyl, C2-C4 alkenyl, C1-C4 haloalkyl, C1-C4 cyanoalkyl, C1-C4 hydroxyalkyl, C1-C4 haloalkoxy, C1-C4 alkoxy, C1-C4 alkylamino, (C1-C4)(C1-C4) dialkylamino, C1-C4 aminoalkyl, ‒CO2H, and Ar2; and wherein Ar2is a 6-membered aryl substituted with 0, 1, 2, or 3 groups independently selected from halogen, ‒CN, ‒NH2, ‒OH, ‒NO2, C1-C4 alkyl, C2-C4 alkenyl, C1-C4 haloalkyl, C1-C4 cyanoalkyl, C1-C4 hydroxyalkyl, C1-C4 haloalkoxy, C1-C4 alkoxy, C1-C4 alkylamino, (C1-C4)(C1-C4) dialkylamino, C1-C4 aminoalkyl, and ‒CO2H, or a pharmaceutically acceptable salt thereof, provided that when Ar1is a 9- or 10-membered heteroaryl, then Ar1is not substituted with an Ar2group, and one or more selected from: (a) at least one agent known for the treatment of a disorder associated with the presence of a premature termination codon; (b) at least one device known for the treatment of a disorder associated with the presence of a premature termination codon; (c) instructions for administering the compound in connection with treating a disorder associated with the presence of a premature termination codon; (d) instructions for administering the compound in connection with reducing the risk of a disorder associated with the presence of a premature termination codon; and (e) instructions for treating a disorder associated with the presence of a premature termination codon.

[0301] Examples of disorders associated with the presence of a premature termination codon include, but are not limited to, cystic fibrosis, Duchenne muscular dystrophy, aniridia, Becker muscular dystrophy, spinal muscular atrophy, Hurler syndrome, hemophilia, epidermolysis bullosa (e.g., dystrophic (DEB) form, junctional (JEB) form), Usher syndrome, neurofibromatosis, and cancer.

[0302] In a further aspect, the kit comprises the agent known for the treatment of a disorder associated with the presence of a premature termination codon. In a still further aspec, the agent is a nonsense suppression agent. Examples of nonsense suppression agents include, but are not limited to, eRF3 degraders (e.g., CC-885, CC-9009), aminoglycosides (e.g., G418, gentamicin, paromomycin, amikacin, ELX-02), macrolides (e.g., erythromycin), PRC124 (ataluren), 2,6-diaminopurines, and G418 enhancers (e.g., Y320, CDX5-1). In yet a further aspect, the agent is selected from a CFTR modulator (e.g., a CFTR potentiator, a CFTR amplifier, a CFTR corrector), an NMD inhibitor (e.g., NMDI-1, NMDI-9, NMDI-25, NMDI-14), an agent that increases mRNA levels (e.g., a histone deacetylase inhibitor), an agent that increases general pulmonary function, an aminoglycoside (e.g., G418, geneticin, amikacin, tobramycin, ELX-02, NB54, NB124, NB83), erythromycin, artesunate, atazanavir,ataluren, genistein, Y-320, ELX-02, and CC-9009. In an even further aspect, the agent is known for the treatment of cystic fibrosis. In a still further aspect, the agent is selected from elexacaftor, ivacaftor, tezacaftor, lumacaftor, a mucus thinner (e.g., hypertonic saline, domase alfa), and a bronchodilator (e.g. , a beta-adrenergic bronchodilator such as albuterol, levalbuterol, an epinephrine injection, salmeterol, azithromycin, clarithromycin, and formoterol, an anticholinergic bronchodilator such as ipratropium and tiotropium, a xanthine derivative such as theophylline and aminophylline).

[0303] In a further aspect, the kit comprises the device known for the treatment of a disorder associated with the presence of a premature termination codon. In a still further aspect, the device is selected from a nebulizer and a vascular access device. Examples of vascular devices include, but are not limited to, a peripheral intravenous catheter (PIV), a peripherally inserted central catheter (PICC), a centrally inserted central catheter (CICC), a subcutaneous catheter device, and an implanted venous port.

[0304] In a further aspect, the compound and the agent are co-packaged. In a still further aspect, the compound and the agent are co-fonnulated.

[0305] The kits can also comprise compounds and / or products co-packaged, coformulated, and / or co-delivered with other components. For example, a drug manufacturer, a drag reseller, a physician, a compounding shop, or a pharmacist can provide a kit comprising a disclosed compound and / or product and another component for delivery to a patient.

[0306] It is understood that the disclosed kits can be prepared from the disclosed compounds, products, and pharmaceutical compositions. It is also understood that the disclosed kits can be employed in connection with the disclosed methods of using.

[0307] The foregoing description illustrates and describes the disclosure. Additionally, the disclosure shows and describes only the preferred embodiments but, as mentioned above, it is to be understood that it is capable to use in various other combinations, modifications, and environments and is capable of changes or modifications within the scope of the invention concepts as expressed herein, commensurate with the above teachings and / or the skill or knowledge of the relevant art. The embodiments described herein above are further intended to explain best modes known by applicant and to enable others skilled in the art to utilize the disclosure in such, or other, embodiments and with the various modifications required by the particular applications or uses thereof. Accordingly, the description is not intended to limit the invention to the form disclosed herein. Also, it is intended to the appended claims be construed to include alternative embodiments.

[0308] All publications and patent applications cited in this specification are hereinincorporated by reference, and for any and all purposes, as if each individual publication or patent application were specifically and individually indicated to be incorporated by reference. In the event of an inconsistency between the present disclosure and any publications or patent application incorporated herein by reference, the present disclosure controls. L. EXAMPLES

[0309] The following examples are put forth so as to provide those of ordinary skill in the art with a complete disclosure and description of how the compounds, compositions, articles, devices and / or methods claimed herein are made and evaluated, and are intended to be purely exemplary of the invention and are not intended to limit the scope of what the inventors regard as their invention. Efforts have been made to ensure accuracy with respect to numbers (e.g., amounts, temperature, etc.), but some errors and deviations should be accounted for. Unless indicated otherwise, parts are parts by weight, temperature is in °C or is at ambient temperature, and pressure is at or near atmospheric.

[0310] The Examples are provided herein to illustrate the invention, and should not be construed as limiting the invention in any way. Examples are provided herein to illustrate the invention and should not be construed as limiting the invention in any way. 1. CHEMISTRY EXPERIMENTALS a. GENERAL EXPERIMENTAL METHOD

[0311] All reactions were carried out in an oven-dried glassware under argon atmosphere using standard gas-tight syringe, cannula, and septa. The reaction temperatures were measured externally. Stirring was achieved with oven dried magnetic bars. All the reactions were done in anhydrous solvents (CH2Cl2, THF, MeOH) purchased from Sigma- Aldrich. All commercially purchased reagents were used without purification. The reactions were monitored by thin-layer chromatography (TLC) on a pre-coated silica gel (60 F254) glass plates from EMD Millipore and visualized using UV light (254 nm). Purification of the compounds was performed on Teledyne-ISCO Combiflash Rf 200 purification system using Redisep Rf® normal phase silica gel columns 230-400 mesh or Shimadzu HPLC system (Phenomenex Gemini NX-C18). ESI-MS spectra were recorded on a BioTof-2 time-of-flight mass spectrometer. Proton NMR spectra were recorded on a Varian Unity 400 NMR spectrometer operating at 400 MHz calibrated to the solvent peak and TMS peak. Thechemical formula and Exact Mass for target compounds were determined from the (M+H)+by high resolution mass spectroscopy using an Agilent 6210 Electrospray Time of Flight. Determination of % purity was obtained by HPLC using an Agilent 1100 LC equipped with a diode array UV detector and monitored at multiple wavelengths.

[0312] A list of exemplary compounds that were prepared as described herein isshown in Table 1 below. TABLE 1.b. SYNTHESIS OF REPRESENTATIVE EXAMPLE COMPOUND NO.1i. SYNTHESIS OF 3-CHLORO-2-METHOXY-4- METHYLBENZONITRILE (1.2)

[0313] To a stirred mixture of 1-bromo-3-chloro-2-methoxy-4-methylbenzene 1.1 (500 mg, 2.123 mmol) and zinc cyanide (498.5 mg, 4.246 mmol) in DMF (10 mL) were added Pd2(dba)3(194.4 mg, 0.212 mmol) and Dppf (234.5 mg, 0.425 mmol) in portions at room temperature under nitrogen atmosphere. The resulting mixture was stirred for 8 h at 100 °C under nitrogen atmosphere. The reaction was quenched with water at room temperature. The resulting mixture was extracted with EtOAc (3 × 3 mL). The combined organic layers were washed with water (3 × 3 mL), dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The crude product 1.2 was used in the next step directly without further purification. ii. SYNTHESIS OF 3-CHLORO-N-HYDROXY-2-METHOXY-4- METHYLBENZENECARBOXIMIDAMIDE (1.3)

[0314] To a stirred mixture of 1.2 (1 g, 5.506 mmol, 1 equiv) in EtOH (10 mL) wasadded hydroxylamine hydrate (0.56 g, 11.012 mmol) in portions at room temperature under nitrogen atmosphere. The resulting mixture was stirred for 2 h at 80 °C under nitrogen atmosphere. Once complete by LCMS, the product mixture was evaporated under reduced pressure, and the residue was purified by reversed-phase flash chromatography (column: C18 silica gel; mobile phase: MeCN in water (0.1% FA), 10% to 50% gradient in 10 min; detector: UV 254 nm) to give 3-chloro-N-hydroxy-2-methoxy-4- methylbenzenecarboximidamide 1.3 (150 mg, 12.69%) as a off-white solid. LCMS (ESI): [M+H]+= 215. iii. SYNTHESIS OF 3-(3-CHLORO-2-METHOXY-4-METHYLPHENYL)- 1,2,4-OXADIAZOL-5-OL (1.4)

[0315] To a stirred mixture of 1.3 (120 mg, 0.559 mmol) in THF (4 mL) were added ditrichloromethyl carbonate (58.0 mg, 0.196 mmol) in THF (4 mL) dropwise at 0 °C under nitrogen atmosphere. The resulting mixture was stirred for 2 h at room temperature under nitrogen atmosphere. The reaction was quenched with water at room temperature. The precipitated solids were collected by filtration and washed with water (3 × 3 mL). The crude product 1.4 (100 mg) was used in the next step directly without further purification. LCMS (ESI): [M+H]+= 241. iv. SYNTHESIS OF 3-[5-({[3-(3-CHLORO-2-METHOXY-4- METHYLPHENYL)-1,2,4-OXADIAZOL-5-YL]AMINO}METHYL)-1- OXO-3H-ISOINDOL-2-YL]PIPERIDINE-2,6-DIONE (1.6)

[0316] To a stirred mixture of 1.4 (80 mg, 0.332 mmol) and 1.5 (123.5 mg, 0.398 mmol) in dioxane (4 mL) were added bromotris(dimethylamino)phosphanium (154.8 mg, 0.398 mmol) and DIEA (171.8mg, 1.328 mmol) in portions at room temperature under nitrogen atmosphere. The resulting mixture was stirred for 1 h at 50 °C under nitrogen atmosphere. The mixture was allowed to cool down to room temperature. The residue was purified by reversed-phase flash chromatography (column: C18 silica gel; mobile phase: MeCN in Water (0.1% FA), 10% to 50% gradient in 10 min; detector: UV 254 nm) to give 3- [5-({[3-(3-chloro-2-methoxy-4-methylphenyl)-1,2,4-oxadiazol-5-yl]amino}methyl)-1-oxo- 3H-isoindol-2-yl]piperidine-2,6-dione 1.6 (95 mg, 57.0 %) as a white solid. LCMS (ESI): [M+H]+= 496.1H-NMR (500 MHz, DMSO-d6) δ 10.99 (s, 1H), 9.14 – 9.12 (m, 1H), 7.74 (d, J = 7.8 Hz, 1H), 7.66 (d, J = 8.0 Hz, 1H), 7.61 (s, 1H), 7.53 (d, J = 7.9 Hz, 1H), 7.26 (d, J =8.1 Hz, 1H), 5.11 – 5.09 (m, 1H), 4.65 (d, J = 6.0 Hz, 2H), 4.50 – 4.30 (m, 2H), 3.78 (s, 3H), 2.92 – 2.88 (m, 1H), 2.64 – 2.57 (m, 1H), 2.40 (s, 4H), 2.00 – 1.98 (m, 1H). v. SYNTHESIS OF 3-[5-({[3-(3-CHLORO-2-HYDROXY-4- METHYLPHENYL)-1,2,4-OXADIAZOL-5-YL]AMINO}METHYL)-1- OXO-3H-ISOINDOL-2-YL]PIPERIDINE-2,6-DIONE (1.7)

[0317] To a stirred mixture of 1.6 (55 mg, 0.111 mmol) in DCM (2 mL) was added boron tribromide (0.54 mL (1 mmol / mL, 0.333 mmol) dropwise at 0 °C under nitrogen atmosphere. The resulting mixture was stirred for 1h at room temperature under nitrogen atmosphere. Once complete by LCMS, the reaction was quenched by the addition of water (1 mL) at room temperature. The resulting mixture was concentrated under reduced pressure. The residue was purified by reversed-phase flash chromatography (column: C18 silica gel; mobile phase: MeCN in water (0.1% TFA), 10% to 50% gradient in 10 min; detector: UV 254 nm) to give 3-[5-({[3-(3-chloro-2-hydroxy-4-methylphenyl)-1,2,4-oxadiazol-5- yl]amino}methyl)-1-oxo-3H-isoindol-2-yl]piperidine-2,6-dione 1.7 (21 mg, 39.2 %) as a white solid. LCMS (ESI): [M+H]+= 482. vi. SYNTHESIS OF 1-(7-CHLORO-6-METHYL-1,2-BENZOXAZOL-3- YL)-3-{[2-(2,6-DIOXOPIPERIDIN-3-YL)-1-OXO-3H-ISOINDOL-5- YL]METHYL}UREA (1)

[0318] To a stirred mixture of 1.7 (21 mg, 0.044 mmol) in DMSO (1.5 mL) was added in portions at room temperature under nitrogen atmosphere. The resulting mixture was stirred for 48 h at room temperature under a nitrogen atmosphere. The crude product was purified by Prep-HPLC with the following conditions (Column: XBridge Prep OBD C18 Column, 30*150 mm, 5μm; Mobile Phase A: water(0.05% TFA), Mobile Phase B: ACN; Flow rate: 60 mL / min; Gradient: 30% B to 55% B in 9 min; Wavelength: 254nm / 220nm; RT1(min): 8.7) to afford 1-(7-chloro-6-methyl-1,2-benzoxazol-3-yl)-3-{[2-(2,6- dioxopiperidin-3-yl)-1-oxo-3H-isoindol-5-yl]methyl}urea 1 (8.1 mg, 36.9% yield) as a white solid. LCMS (ESI): [M+H]+= 482.1H-NMR (300 MHz, DMSO-d6) δ 10.99 (s, 1H), 10.27 (s, 1H), 8.01 (d, J = 8.2 Hz, 1H), 7.83 – 7.67 (m, 2H), 7.57 (s, 1H), 7.49 – 7.46 (m, 1H), 7.36 (d, J = 8.3 Hz, 1H), 5.12 – 5.09 (m, 1H), 4.56 (d, J = 5.9 Hz, 2H), 4.51 – 4.27 (m, 2H), 2.92 – 2.90 (m, 1H), 2.60 (d, J = 16.5 Hz, 1H), 2.48 (s, 3H) 2.37 – 2.35 (m, 1H), 2.06 – 1.92 (m, 1H).c. SYNTHESIS OF REPRESENTATIVE EXAMPLE COMPOUND NO.2i. SYNTHESIS OF 2-BROMO-4-CHLORO-5-METHYLPHENOL (2.2)

[0319] A solution of 4-chloro-3-methylphenol 2.1 (1 g, 7.01 mmol) and bromine (556 mg, 7.03 mmol) in AcOH (8.6 mL) and H2O (1 mL) was stirred for 1 hour at roomtemperature under nitrogen atmosphere. Once complete by LCMS, the reaction was quenched by the addition of Na2SO3(3 g) at room temperature. The resulting mixture was concentrated under reduced pressure. The residue was diluted with EtOAc (15 mL). The resulting mixture was washed with 3 × 15 mL of saturated aqueous NaHCO3. The combined organic layers were dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with PE / DCM (0-100%) to afford 2-bromo-4-chloro-5-methylphenol 2.2 (1.10 g, 70.8%) as a white solid. LCMS (ESI): [M+H]+=220. ii. SYNTHESIS OF 1-BROMO-5-CHLORO-2-[(4- METHOXYPHENYL)METHOXY]-4-METHYLBENZENE (2.3)

[0320] A solution of 2.2 (1.10 g, 4.96 mmol), K2CO3(1.37 g, 9.93 mmol) and 4- methoxybenzyl chloride (816 mg, 5.21 mmol) in DMF (11 mL) was stirred for 1 hour at 90 °C under nitrogen atmosphere. The residue was dissolved in brine (15 mL). The aqueous layer was extracted with EtOAc (3 × 15 mL). Organic layers were combined and dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with PE / EA (0-100%) to afford 1-bromo-5-chloro-2-[(4-methoxyphenyl)methoxy]-4-methylbenzene 2.3 (937 mg, 54.2%) as a white solid. iii. SYNTHESIS OF 5-CHLORO-2-[(4-METHOXYPHENYL)METHOXY]- 4-METHYLBENZONITRILE (2.4)

[0321] A solution of 2.3 (937 mg, 3.22 mmol), DPPF (355 mg, 0.644 mmol), Pd2(dba)3(296 mg, 0.322 mmol) and zinc cyanide (302 mg, 2.57 mmol) in DMF (12 mL) was stirred for 2 hours at 100 °C under nitrogen atmosphere. Once complete by LCMS, the product mixture was evaporated under reduced pressure and the residue was dissolved in brine (15 mL). The aqueous layer was extracted with EtOAc (3 × 15 mL), Organic layers were combined and dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The crude product mixture was used in the next step directly without further purification. This resulted in 5-chloro-2-[(4- methoxyphenyl)methoxy]-4-methylbenzonitrile 2.4 (835 mg, 90.1%, crude) as a white solid.iv. SYNTHESIS OF (Z)-5-CHLORO-N'-HYDROXY-2-[(4- METHOXYPHENYL) METHOXY]-4- METHYLBENZENECARBOXIMIDAMIDE (2.5)

[0322] A solution of 2.4 (835 mg, 2.90 mmol) and hydroxylamine hydrate (417 mg, 8.18 mmol) in EtOH (23 mL) was stirred overnight at 60 °C under nitrogen atmosphere. The product mixture was evaporated, and the residue was purified by silica gel column chromatography, eluted with CH2Cl2 / MeOH (10:1) to afford (Z)-5-chloro-N'-hydroxy-2-[(4- methoxyphenyl) methoxy]-4-methylbenzenecarboximidamide 2.5 (405 mg, 41.3%) as a white solid. LCMS (ESI): [M+H]+=321. v. SYNTHESIS OF 3-{5-CHLORO-2-[(4- METHOXYPHENYL)METHOXY]-4-METHYLPHENYL}-1,2,4- OXADIAZOL-5-OL (2.6)

[0323] A solution of 2.5 (405 mg, 1.26 mmol) and triphosgene (123 mg, 0.417 mmol) in THF (4 mL) was stirred at 0 °C under nitrogen atmosphere for 2 hours at room temperature. Once complete by LCMS, the reaction was quenched with water at room temperature. The aqueous layer was extracted with EtOAc (3 × 3 mL). Organic layers were combined and dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure to give 3-{5-chloro-2-[(4-methoxyphenyl)methoxy]-4- methylphenyl}-1,2,4-oxadiazol-5-ol 2.6 (392 mg, 89.5%) as a white solid. LCMS (ESI): [M+H]+=347. vi. SYNTHESIS OF 3-(5-{[(3-{5-CHLORO-2-[(4- METHOXYPHENYL)METHOXY]-4-METHYLPHENYL}-1,2,4- OXADIAZOL-5-YL)AMINO]METHYL}-1-OXO-3H-ISOINDOL-2- YL)PIPERIDINE-2,6-DIONE (2.8)

[0324] A solution of 2.6 (392 mg, 1.130 mmol), DIPEA (876 mg, 6.78 mmol), BrOP (610 mg, 1.35 mmol) and 3-[5-(aminomethyl)-1-oxo-3H-isoindol-2-yl]piperidine-2,6-dione HCl 2.7 (370 mg, 1.35 mmol) in dioxane (6 mL) was stirred for 2 hours at 50 °C under nitrogen atmosphere. The resulting mixture was concentrated under reduced pressure and the residue was diluted with brine (15 mL). The aqueous layer was extracted with EtOAc (3 × 15 mL). The organic layers were combined and dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure and purified by silica gel columnchromatography, eluted with CH2Cl2 / MeOH (10:1) to afford 3-(5-{[(3-{5-chloro-2-[(4- methoxyphenyl)methoxy]-4-methylphenyl}-1,2,4-oxadiazol-5-yl)amino]methyl}-1-oxo-3H- isoindol-2-yl)piperidine-2,6-dione 2.8 (145 mg, 21.0%) as a white solid. LCMS (ESI): [M+H]+= 602. vii. SYNTHESIS OF 3-[5-({[3-(5-CHLORO-2-HYDROXY-4- METHYLPHENYL)-1,2,4-OXADIAZOL-5-YL]AMINO}METHYL)-1- OXO-3H-ISOINDOL-2-YL]PIPERIDINE-2,6-DIONE (2.9)

[0325] A solution of 2.8 (145 mg, 0.241 mmol) and TFA (3 mL, 40.3 mmol) in CH2Cl2(1 mL) was stirred for 1 hour at room temperature under nitrogen atmosphere. The resulting mixture was concentrated under reduced pressure. The crude product was purified by Prep-HPLC (Column: XBridge Prep Shield RP OBD C18 Column, 30*150 mm, 5 μm; Mobile Phase A: Water (0.1% FA), Mobile Phase B: ACN; Flow rate: 60 mL / min; Gradient: 38% B to 53% B in 10 min; Wavelength: 254 nm / 220 nm) to afford 3-[5-({[3-(5-chloro-2- hydroxy-4-methylphenyl)-1,2,4-oxadiazol-5-yl]amino}methyl)-1-oxo-3H-isoindol-2- yl]piperidine-2,6-dione 2.9 (16.9 mg, 14.5%) as a white solid. LCMS (ESI): [M+H]+= 482. viii. SYNTHESIS OF 1-(5-CHLORO-6-METHYL-1,2-BENZOXAZOL-3- YL)-3-{[2-(2,6-DIOXOPIPERIDIN-3-YL)-1-OXO-3H-ISOINDOL-5- YL]METHYL}UREA (2)

[0326] A solution of 3-[5-({[3-(5-chloro-2-hydroxy-4-methylphenyl)-1,2,4-oxadiazol- 5-yl]amino}methyl)-1-oxo-3H-isoindol-2-yl]piperidine-2,6-dione 2.9 (15.2 mg, 0.032 mmol) in DMSO (1 mL) was stirred for overnight at room temperature under nitrogen atmosphere before water was added and the mixture was freeze dried to give 1-(5-chloro-6-methyl-1,2- benzoxazol-3-yl)-3-{[2-(2,6-dioxopiperidin-3-yl)-1-oxo-3H-isoindol-5-yl]methyl}urea 2 (9.3 mg, 59.9% yield) as a white solid. LCMS (ESI): [M+H]+= 482,1H NMR (300 MHz, DMSO- d6) δ 10.98 (s, 1H), 10.19 (s, 1H), 8.26 (s, 1H), 8.09 – 7.60 (m, 3H), 7.57 (s, 1H), 7.49 (d, J = 7.9 Hz, 1H), 5.11 (dd, J = 13.2, 5.1 Hz, 1H), 4.56 (d, J = 5.9 Hz, 2H), 4.53 – 4.28 (m, 2H), 2.90 (d, J = 13.2 Hz, 1H), 2.63 (s, 1H),2.60 – 2.41(m, 3H), 2.35 – 2.25(m, 1H), 2.20 – 1.47(m, 1H). d. SYNTHESIS OF REPRESENTATIVE EXAMPLE COMPOUND NO.3i. SYNTHESIS OF 4-NITROPHENYL ((2-(2,6-DIOXOPIPERIDIN-3-YL)- 1-OXOISOINDOLIN-5-YL)METHYL)CARBAMATE (3.2)

[0327] A solution of 3-[5-(aminomethyl)-1-oxo-3H-isoindol-2-yl] piperidine-2,6- dione hydrochloride 3.1 (100 mg, 0.3 mmol), DIPEA (83.4 mg, 0.6 mmol), and bis(4- nitrophenyl) carbonate (98.2 mg, 0.3 mmol) in DMF (2.5 mL) was stirred for 1h at room temperature under nitrogen atmosphere. Once complete by LCMS, the resulting mixture 4- nitrophenyl N-{[2-(2,6-dioxopiperidin-3-yl)-1-oxo-3H-isoindol-5-yl] methyl} carbamate 3.2 was used in the next step directly without further purification. LCMS (ESI): [M+H]+= 439. ii. SYNTHESIS OF (3-CHLORO-4-METHYLPHENYL) [({[2-(2,6- DIOXOPIPERIDIN-3-YL)-1-OXO-3H-ISOINDOL-5-YL] METHYL} CARBAMOYL) AMINO] ACETIC ACID (3)

[0328] A solution of 3.2 (38 mg, crude), DIPEA (22.4 mg, 0.2 mmol), and amino(3- chloro-4-methylphenyl) acetic acid (34.6 mg, 0.2 mmol) in DMF (1 mL) was stirred for overnight at room temperature under nitrogen atmosphere. The resulting mixture was filtered, the filter cake was washed with DMF (1 × 0.1 mL). The filtrate was concentrated underreduced pressure. The crude product was purified by Prep-HPLC (Column: Xselect CSH OBD Column, 30*150mm, 5um; Mobile Phase A: Water (0.1% FA), Mobile Phase B: ACN; Flow rate: 60 mL / min; Gradient: 21% B to 36% B in 10 min; Wavelength: 254 / 220 nm; RT(min): 9.62) to afford (3-chloro-4-methylphenyl) [({[2-(2,6-dioxopiperidin-3-yl)-1-oxo- 3H-isoindol-5-yl] methyl} carbamoyl) amino] acetic acid 3 (19.6 mg, 44.0% yield) as a white solid. LCMS (ESI): [M+H]+= 499.1H NMR (300 MHz, DMSO-d6) δ 12.94 (s, 1H), 11.00 (s, 1H), 7.66 (d, J = 7.8 Hz, 1H), 7.44 (s, 1H), 7.41 – 7.30 (m, 3H), 7.28 – 7.19 (m, 1H), 6.93 (d, J = 7.5 Hz, 1H), 6.76 (d, J = 6.0 Hz, 1H), 5.22 – 5.05 (m, 2H), 4.49 – 4.37 (m, 1H), 4.37 – 4.22 (m, 3H), 3.01 – 2.83 (m, 1H), 2.66 – 2.54 (m, 1H), 2.48 – 2.34 (m, 1H), 2.31 (s, 3H), 2.06 – 1.93 (m, 1H). e. SYNTHESIS OF REPRESENTATIVE EXAMPLE COMPOUND NO.4i. SYNTHESIS OF 4-CHLOROMORPHOLINE (4.2)

[0329] To a solution of morpholine 4.1 (20.0 g, 229.563 mmol) in water (80.0 mL) and diethyl ether (200.0 mL) was added sodium hypochlorite solution (240.0 mL) dropwise at 0 °C. Then the solution was stirred at 0 °C for 1 h under nitrogen atmosphere. Water was added and the resulting mixture was extracted with EtOAc (3 × 50 mL). The combined organic layers were washed with water, dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure to afford 4-chloromorpholine 4.2 (7.5 g, crude) as a colorless oil. LCMS (ESI): [M+H]+= 122. ii. SYNTHESIS OF 5-CHLORO-6-METHYL-2H-1,2-BENZOXAZOL-3-ONE (4.4)

[0330] To a solution of 6-methyl-2H-1,2-benzoxazol-3-one 4.3 (1.0 g, 6.705 mmol) in trifluoroacetic acid (15.0 mL) was added 4.2 (815.0 mg, 6.705 mmol) in portions at 0 °C under nitrogen atmosphere. Then the solution was stirred at 0 °C for 2.5 h under nitrogen atmosphere. Once complete by LCMS, 1 M HCl (aq.) was added and the resulting mixture was extracted with EtOAc (3 × 50 mL). The combined organic layers were washed with water and dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure and purified by silica gel column chromatography, eluted with dichloromethane / methanol = 10 / 1 to afford 5-chloro-6-methyl-2H-1,2-benzoxazol-3-one 4.4 (920.0 mg, 74%) as an off-white solid. LCMS (ESI): [M+H]+= 184.iii. SYNTHESIS OF 3,5-DICHLORO-6-METHYL-1,2-BENZOXAZOLE (4.5)

[0331] To a solution of 4.4 (500.0 mg, 2.723 mmol) in phosphoryl chloride (10.0 mL) was added Et3N (839.2 mg, 8.293 mmol) dropwise at 0 °C. The solution was heated to 120 °C with stirring for 2 h. After the reaction was complete by LCMS, the mixture was concentrated under reduced pressure and purified by flash chromatography with dichloromethane / methanol = 12 / 1 to afford 3,5-dichloro-6-methyl-1,2-benzoxazole 4.5 (260.0 mg, 47%) as a white solid. LCMS (ESI): [M+H]+= 202. iv. SYNTHESIS OF 5-CHLORO-N,6-DIMETHYL-1,2-BENZOXAZOL-3- AMINE (4.6)

[0332] To a solution of 4.5 (120.0 mg, 0.594 mmol) and methanamine hydrochloride (81.0 mg, 1.200 mmol) in DMSO (10.0 mL) was added CsF (452.0 mg, 2.976 mmol) in portions at room temperature. The solution was stirred at 100 °C for 16 h under nitrogen atmosphere. Once complete by LCMS, water was added, the resulting mixture was extracted with EtOAc (3 × 50 mL). The combined organic layers were washed with water, dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure and purified by silica gel column chromatography, eluted with dichloromethane / methanol = 10 / 1 to afford 5-chloro-N,6-dimethyl-1,2-benzoxazol-3-amine 4.6 (50.0 mg, 42%) as a white solid. LCMS (ESI): [M+H]+= 197. v. SYNTHESIS OF 3-{5-[(METHYLAMINO)METHYL]-1-OXO-3H- ISOINDOL-2-YL}PIPERIDINE-2,6-DIONE (4.8)

[0333] To a solution of 2-(2,6-dioxopiperidin-3-yl)-1-oxo-3H-isoindole-5- carbaldehyde 4.7 (580.0 mg, 2.130 mmol) and methylamine hydrochloride (173.0 mg, 2.562 mmol) in THF (40.0 mL) and MeOH (10.0 mL) was added NaBH3CN (335.0 mg, 5.331 mmol) in portions at 0 °C. Then the solution was stirred at 25 °C for 16 h under nitrogen atmosphere. Water was added, the resulting mixture was extracted with EtOAc (3 × 50 mL). The combined organic layers were washed with water, dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure and purified by silica gel column chromatography, eluted with dichloromethane / methanol = 10 / 1 to afford 3-{5- [(methylamino)methyl]-1-oxo-3H-isoindol-2-yl}piperidine-2,6-dione 4.8 (200.0 mg, 32%) as a white solid. LCMS (ESI): [M+H]+= 288.vi. SYNTHESIS OF 3-(5-CHLORO-6-METHYL-1,2-BENZOXAZOL-3- YL)-1-{[2-(2,6-DIOXOPIPERIDIN-3-YL)-1-OXO-3H-ISOINDOL-5- YL]METHYL}-1,3-DIMETHYLUREA (4)

[0334] To a stirred solution of 4.6 (50.0 mg, 0.254 mmol) and triphosgene (25.3 mg,0.085 mmol) in THF (8.0 mL) was added Et3N (83.2 mg, 0.822 mmol) at 0 °C under nitrogen atmosphere. The resulting mixture was stirred at 0 °C for 1 h under nitrogen atmosphere. To the above mixture was added 4.8 (93.6 mg, 0.326 mmol,) dropwise over 1 min at 0 °C. The resulting mixture was stirred at 50 °C for an additional 16 h. After the reaction was complete, the resulting mixture was concentrated under reduced pressure. The crude product was purified by Prep-HPLC (Column: Xselect CSH Phenyl Hexy Column, 30 ×150 mm, 5 μm; Mobile Phase A: Water (10 mmoL / L NH4HCO3), Mobile Phase B: ACN; Flow rate: 60 mL / min; Gradient: 22% B to 52% B in 7 min; Wavelength: 254 / 220 nm; RT(min): 6.7) to afford 3-(5-chloro-6-methyl-1,2-benzoxazol-3-yl)-1-{[2-(2,6-dioxopiperidin-3-yl)-1-oxo-3H- isoindol-5-yl]methyl}-1,3-dimethylurea 4 (20.6 mg, 15%) as a white solid. LCMS (ESI): [M+H]+= 510.1H NMR (400 MHz, DMSO-d6) δ 10.98 (s, 1H), 7.77 - 7.70 (m, 2H), 7.61 (s, 1H), 7.53 - 7.50 (m, 1H), 7.45 (s, 1H), 5.13 - 5.11 (m, 1H), 4.65 (s, 2H), 4.43 - 4.38 (m, 2H), 3.32 (s, 3H), 2.97 - 2.85 (m, 4H), 2.61 - 2.65 (m, 1H), 2.44 - 2.33 (m, 4H), 1.99 (s,1H). f. SYNTHESIS OF REPRESENTATIVE EXAMPLE COMPOUND NO.5i. SYNTHESIS OF (Z)-3-CHLORO-N'-HYDROXY-4- METHYLBENZENECARBOXIMIDAMIDE (5.2)

[0335] To a stirred mixture of 3-chloro-4-methylbenzonitrile 5.1 (1 g, 6.597 mmol) in EtOH (10 mL) was added hydroxylamine (0.88 g, 13.194 mmol, 50% aqueous solution) in portions at room temperature under nitrogen atmosphere. The resulting mixture was stirred at 50 °C for 2 h under nitrogen atmosphere. Once complete by LCMS, the product mixture was evaporated and the residue was purified by silica gel column chromatography, eluted with PE / EA = 10 / 1 to afford (Z)-3-chloro-N'-hydroxy-4- methylbenzenecarboximidamide 5.2 (1.1 g, 90.3%) as a white solid. LCMS (ESI): [M+H]+= 185. ii. SYNTHESIS OF 3-(3-CHLORO-4-METHYLPHENYL)-1,2,4- OXADIAZOL-5-AMINE (5.3)

[0336] To a stirred mixture of 5.2 (0.5 g, 2.708 mmol) in toluene (5 mL) was added triphosgene (1.086 g, 3.520 mmol) in portions at room temperature under nitrogen atmosphere. The resulting mixture was stirred at 110 °C for 2 h under nitrogen atmosphere. The resulting mixture was concentrated under reduced pressure. To the above mixture was added ammonia (0.4 M in 1,4-dioxane) (8 ml) dropwise over 5 min at room temperature. The resulting mixture was stirred at room temperature for an additional 1 hour. Once complete by LCMS, the product mixture was evaporated and the residue was purified by silica gel column chromatography, eluted with PE / EA = 5 / 1 to afford 3-(3-chloro-4-methylphenyl)-1,2,4-oxadiazol-5-amine 5.3 (400 mg, 70.4%) as a white solid. LCMS (ESI): [M+H]+= 210.iii. SYNTHESIS OF 3-[3-(3-CHLORO-4-METHYLPHENYL)-1,2,4- OXADIAZOL-5-YL]-1-{[2-(2,6-DIOXOPIPERIDIN-3-YL)-1-OXO- 3H-ISOINDOL-5-YL] METHYL} UREA (5)

[0337] To a stirred mixture of 5.3 (100 mg, 0.477 mmol) and bis(4-nitrophenyl) carbonate (145.1 mg, 0.477 mmol) in DMF (2 mL) was added DIEA (246.6 mg, 1.908 mmol) dropwise at room temperature under nitrogen. The resulting mixture was stirred at room temperature for 1 h. To the above mixture was added 3-[5-(aminomethyl)-1-oxo-3H- isoindol-2-yl] piperidine-2,6-dione hydrochloride 5.4 (177.3 mg, 0.572 mmol) in portions over 5 min at room temperature. The resulting mixture was stirred at 50 °C for an additional 2h. The resulting mixture was extracted with EtOAc (3 × 20mL). The combined organic layers were washed with brine (3 × 30 mL), dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The crude product was purified by Prep- HPLC (Column: Xselect CSH Phenyl Hexy Column, 30*150 mm, 5 μm; Mobile Phase A: Water (0.1% FA), Mobile Phase B: ACN; Flow rate: 60 mL / min; Gradient: 31% B to 45% B in 10 min; Wavelength: 254 / 220 nm; RT1(min): 8.45) to afford 3-[3-(3-chloro-4- methylphenyl)-1,2,4-oxadiazol-5-yl]-1-{[2-(2,6-dioxopiperidin-3-yl)-1-oxo-3H-isoindol-5-yl] methyl} urea 5 (9.8 mg, 4.0%) as a white solid. LCMS (ESI): [M+H]+= 509.1H NMR (300 MHz, DMSO-d6) δ 11.59 (s, 1H), 10.98 (s, 1H), 8.50 – 8.24 (m, 1H), 8.02 (d, J = 1.7 Hz, 1H), 7.93 – 7.84 (m, 1H), 7.71 (d, J = 7.8 Hz, 1H), 7.61 – 7.46 (m, 3H), 5.17 – 5.05 (m, 1H), 4.62 – 4.27 (m, 4H), 3.00 – 2.82 (m, 1H), 2.65 – 2.53 (m, 1H), 2.46 – 2.23 (m, 4H), 2.06 – 1.93 (m, 1H). g. SYNTHESIS OF REPRESENTATIVE EXAMPLE COMPOUND NO.6i. SYNTHESIS OF 1-{[2-(2,6-DIOXOPIPERIDIN-3-YL)-1-OXO-3H- ISOINDOL-5-YL]METHYL}-3-(4-METHOXY-1,2-BENZOXAZOL-3- YL)UREA (6)

[0338] To a stirred solution of 4-methoxy-1,2-benzoxazol-3-amine 6.1 (300 mg, 1.827 mmol, 1.00 equiv) in MeCN (6 mL) was added 4-nitrophenyl chloroformate (368.4 mg, 1.828 mmol, 1.00 equiv) at 0 °C under nitrogen atmosphere. The resulting mixture was stirred for 2h at 70 °C. To the above mixture was added pyridine (144.5 mg, 1.827 mmol, 1.00 equiv) and 3-[5-(aminomethyl)-1-oxo-3H-isoindol-2-yl]piperidine-2,6-dione hydrochloride 6.2 (397 mg, 1.282 mmol, 0.70 equiv) at room temperature. The resulting mixture was stirred for 2h at 70 °C. The crude product was purified by flash chromatography on C18 column eluting with (0.1% FA) water / ACN (43%) to afford 200mg of crude product. The residue was purified by trituration with EtOAc (4 ml) at rt. The resulting slurry was stirred over 4h and then filtered. The solid was collected and then dried over 45°C to afford 1-{[2-(2,6-dioxopiperidin-3-yl)-1-oxo-3H-isoindol-5-yl]methyl}-3-(4-methoxy-1,2- benzoxazol-3-yl)urea 6 (86.4 mg, 10.2% yield, 98.8 %purity) as a white solid. LCMS (ESI): [M+H]+= 464.1H NMR (300 MHz, DMSO-d6) δ 10.99 (s, 1H), 8.40 (s, 1H), 8.04 (t, J = 5.9 Hz, 1H), 7.72 (d, J = 7.8 Hz, 1H), 7.63 – 7.53 (m, 2H), 7.49 (dd, J = 7.9, 1.4 Hz, 1H), 7.19 (d, J = 8.4 Hz, 1H), 6.85 (d, J = 8.0 Hz, 1H), 5.12 (dd, J = 13.3, 5.1 Hz, 1H), 4.56 – 4.41 (m, 3H), 4.32 (d, J = 17.3 Hz, 1H), 3.96 (s, 3H), 2.92 (ddd, J = 17.0, 13.6, 5.4 Hz, 1H), 2.60 (d, J = 17.5 Hz, 1H), 2.48 – 2.29 (m, 1H), 2.01 (ddd, J = 12.5, 4.9, 2.2 Hz, 1H). h. SYNTHESIS OF REPRESENTATIVE EXAMPLE COMPOUND NO.7i. SYNTHESIS OF 3-AMINO-1,2-BENZOXAZOLE-5-CARBONITRILE (7.3)

[0339] A solution of 4-fluorobenzene-1,3-dicarbonitrile 7.1 (1 g, 6.844 mmol), acetohydroxamic acid 7.2 (1.54 g, 20.532 mmol) and K2CO3(2.84 g, 20.532 mmol) in DMF (10 mL) was stirred at room temperature for 2 h under nitrogen atmosphere. Once complete by LCMS, the reaction was quenched by the addition of sat. NH4Cl (aq.) (50 mL) at 0°C. The resulting mixture was extracted with EtOAc (3 × 100 mL). The combined organic layers were washed with water (3 × 100 mL), dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with PE / EA= 5 / 1 to afford 3-amino-1,2-benzoxazole-5-carbonitrile 7.3 (400 mg, 36.7% yield, 95% purity) as a white solid. LCMS (ESI): [M+H]+= 160. ii. SYNTHESIS OF 4-NITROPHENYL (5-CYANOBENZO[D]ISOXAZOL- 3-YL)CARBAMATE (7.5)

[0340] A solution of 7.3 (200 mg, 1.257 mmol) in THF (2 mL) was treated with DIEA (240.3 mg, 1.860 mmol) at room temperature for 10 min under nitrogen atmospherefollowed by the addition of 4-nitrophenyl carbonochloridate 7.4 (207.7 mg, 1.031 mmol) in portions at 0 °C. The resulting mixture was stirred at room temperature for 3 h under nitrogen atmosphere. The crude product mixture 4-nitrophenyl N-(5-cyano-1,2-benzoxazol-3- yl)carbamate 7.5 was used in the next step directly without further purification. LCMS (ESI): [M+H]+= 325. iii. SYNTHESIS OF 3-(5-CYANO-1,2-BENZOXAZOL-3-YL)-1-{[2-(2,6- DIOXOPIPERIDIN-3-YL)-1-OXO-3H-ISOINDOL-5- YL]METHYL}UREA (7)

[0341] A solution of 7.5 (100 mg, 0.308 mmol), 3-[5-(aminomethyl)-1-oxo-3H- isoindol-2-yl]piperidine-2,6-dione hydrochloride 7.6 (95.5 mg, 0.308 mmol) and DIEA (79.7 mg, 0.616 mmol) in THF (1 mL) was stirred at room temperature overnight under nitrogen atmosphere. The resulting mixture was diluted with water (30 mL), extracted with EtOAc (3 × 50 mL). The combined organic layers were washed with water (3 × 50 mL), dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by reversed-phase flash chromatography (column: C18 silica gel; mobile phase: MeCN in Water (0.1% FA), 10% to 50% gradient in 10 min; detector: UV 254 nm). The crude product (100 mg) was purified by Prep-HPLC (Column: Xselect CSH OBD Column, 30*150mm, 5um; Mobile Phase A: Water (0.1% FA), Mobile Phase B: ACN; Flow rate: 60 mL / min; Gradient: 13% B to 28% B in 10 min; Wavelength: 254 / 220 nm; RT(min): 10.55) to afford 3-(5-cyano-1,2-benzoxazol-3-yl)-1-{[2-(2,6-dioxopiperidin-3-yl)-1-oxo-3H- isoindol-5-yl]methyl}urea 7 (32.7 mg, 23.1% yield, 98.7% purity) as a white solid. LCMS (ESI): [M+H]+= 459.1H NMR (500 MHz, DMSO-d6) δ 10.98 (s, 1H), 10.38 (s, 1H), 8.70 (d, J = 1.6 Hz, 1H), 8.11 – 8.06 (m, 1H), 7.90 (d, J = 8.7 Hz, 1H), 7.76 – 7.69 (m, 2H), 7.57 (s, 1H), 7.51 – 7.47 (m, 1H), 5.15 – 5.06 (m, 1H), 4.56 (d, J = 6.0 Hz, 2H), 4.46 (d, J = 17.3 Hz, 1H), 4.32 (d, J = 17.3 Hz, 1H), 2.97 – 2.84 (m, 1H), 2.66 – 2.55 (m, 1H), 2.42 – 2.33 (m, 1H), 2.04 – 1.96 (m, 1H). i. SYNTHESIS OF REPRESENTATIVE EXAMPLE COMPOUND NO.8i. SYNTHESIS OF TERT-BUTYL N-{[(3-CHLORO-4- METHYLPHENYL)FORMAMIDO]METHANIMIDOYL}CARBAMATE (8.3)

[0342] To a stirred mixture of 3-chloro-4-methylbenzoic acid 8.1 (3 g, 17.586 mmol) and tert-butyl N-carbamimidoylcarbamate 8.2 (7.00 g, 43.965 mmol) in DMF (30 mL) were added 4-methylmorpholine (7.12 g, 70.344 mmol) and benzotriazole-1-yl-oxytripyrrolidinophosphonium hexafluorophosphate PyBOP (13.73 g, 26.379 mmol) in portions at room temperature under nitrogen atmosphere. The resulting mixture was stirred at room temperature for 2 h under nitrogen atmosphere. Once complete by LCMS, the product mixture was evaporated under reduced pressure. The residue was purified by reversed-phase flash chromatography (column: C18 silica gel; mobile phase: MeCN in water (0.1% FA), 10% to 50% gradient in 10 min; detector: UV 254 nm) to give tert-butyl N-{[(3-chloro-4- methylphenyl)formamido]methanimidoyl} carbamate 8.3 (3 g, 54.7 %) as an off-white solid. LCMS (ESI): [M+H]+= 312. ii. SYNTHESIS OF TERT-BUTYL N-[5-(3-CHLORO-4- METHYLPHENYL)-1,2,4-OXADIAZOL-3-YL]CARBAMATE (8.4)

[0343] To a stirred mixture of 8.3 (3 g, 9.622 mmol) in DMF (30 mL) were added (diacetoxyiodo)benzene (9.30 g, 28.866 mmol) in portions at room temperature under nitrogen atmosphere. The resulting mixture was stirred at room temperature overnight. Once complete by LCMS, the reaction was quenched with water at room temperature. The resulting mixture was extracted with EtOAc (3 × 30 mL). The combined organic layers were washed with water (3 × 30 mL), dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with PE / EA = 1 / 1 to afford tert-butyl N-[5-(3-chloro-4- methylphenyl)-1,2,4-oxadiazol-3-yl]carbamate 8.4 (600 mg, 20.1 %) as a white solid. LCMS (ESI): [M+H]+= 310. iii. SYNTHESIS OF 5-(3-CHLORO-4-METHYLPHENYL)-1,2,4- OXADIAZOL-3-AMINE (8.5)

[0344] To a stirred mixture of 8.4 (600 mg, 1.937 mmol) in trifluoroacetic acid (0.5 mL) and 1,1,1,3,3,3-hexafluoropropan-2-ol (9.5 mL) in portions at room temperature under nitrogen atmosphere. The resulting mixture was stirred at room temperature overnight under nitrogen atmosphere. The resulting mixture was concentrated under reduced pressure to give 5-(3-chloro-4-methylphenyl)-1,2,4-oxadiazol-3-amine 8.5 (600 mg crude) as an off-white solid. LCMS (ESI): [M+H]+= 210.iv. SYNTHESIS OF 3-[5-(3-CHLORO-4-METHYLPHENYL)-1,2,4- OXADIAZOL-3-YL]-1-{[2-(2,6-DIOXOPIPERIDIN-3-YL)-1-OXO- 3H-ISOINDOL-5-YL]METHYL}UREA (8)

[0345] To a stirred mixture of 8.5 (300 mg, 1.431 mmol) and DIEA (369.9 mg, 2.862 mmol) in DMF (3 mL) was added bis(4-nitrophenyl) carbonate (435.3 mg, 1.431 mmol) in portions at room temperature under nitrogen atmosphere. The resulting mixture was stirred at room temperature for 1 h before 3-[5-(aminomethyl)-1-oxo-3H-isoindol-2-yl]piperidine-2,6- dione hydrochloride 8.6 (443.2 mg, 1.431 mmol) and DIEA (369.9 mg, 2.862 mmol) were added in portions at room temperature. The resulting mixture was stirred at 50 °C overnight. Once complete by LCMS, the mixture was allowed to cool down to room temperature and evaporated under reduced pressure. The residue was purified by reversed-phase flash chromatography (column: C18 silica gel; mobile phase: MeCN in water (0.1% FA), 10% to 50% gradient in 10 min; detector: UV 254 nm). The crude product was purified by Prep- HPLC (Column: Xselect CSH Phenyl Hexy Column, 19*250 mm, 5 μm; Mobile Phase A: water(0.1% FA), Mobile Phase B: ACN; Flow rate: 20 mL / min; Gradient: 41%B to 52%B in 12 min; Wavelength: 254 / 220 nm; RT1(min): 11.3) to afford 3-[5-(3-chloro-4-methylphenyl)- 1,2,4-oxadiazol-3-yl]-1-{[2-(2,6-dioxopiperidin-3-yl)-1-oxo-3H-isoindol-5-yl]methyl}urea 8 (14.8 mg, 2% yield) as a white solid. LCMS (ESI): [M+H]+= 509.1H-NMR (500 MHz, DMSO-d6) δ 11.11 (s, 1H), 10.98 (s, 1H), 8.17 – 8.11 (m, 1H), 7.82 (d, J = 1.7 Hz, 1H), 7.76 – 7.68 (m, 2H), 7.60 – 7.54 (m, 2H), 7.48 – 7.46 (m, J = 7.8, 1.4 Hz, 1H), 5.11 – 5.09 (m, 1H), 4.54 (d, J = 6.0 Hz, 2H), 4.46 (d, J = 17.3 Hz, 1H), 4.32 (d, J = 17.3 Hz, 1H), 2.91 – 2.89 (m, 1H), 2.60 – 2.58 (m, 1H), 2.45 – 2.32 (m, 4H), 2.00 – 1.98 (m, 1H). 2. EVALUATION OF COMPOUND ACTIVITY

[0346] The compounds shown in Table 1 were evaluated for their ability to stimulate read-through of a premature termination codon, and their respective activities are shown in Tables 2 and 3 below. TABLE 2.TABLE 3.

[0347] It will be apparent to those skilled in the art that various modifications and variations can be made in the present invention without departing from the scope or spirit of the invention. Other embodiments of the invention will be apparent to those skilled in the art from consideration of the specification and practice of the invention disclosed herein. It is intended that the specification and examples be considered as exemplary only, with a true scope and spirit of the invention being indicated by the following claims.

Claims

1. CLAIMS What is claimed is:

1. A compound having a structure represented by a formula:, wherein n is selected from 0 and 1; wherein each of Q1, Q2, and Q3is independently selected from ‒CH2‒ and ‒C(O)‒, provided that at least one of Q1and Q2is ‒C(O)‒; wherein Z is selected from ‒CH(CO2H)‒ and ‒CH(C(O)NH2)‒; wherein each of R1and R2is independently selected from hydrogen and C1-C4 alkyl; wherein Ar1is selected from a 6-membered aryl, an isoxazolyl, an oxadiazolyl, an oxazolyl, and a 9- or 10-membered heteroaryl, and is substituted with 0, 1, 2, or 3 groups independently selected from halogen, ‒CN, ‒NH2, ‒OH, ‒NO2, C1-C4 alkyl, C2-C4 alkenyl, C1-C4 haloalkyl, C1-C4 cyanoalkyl, C1-C4 hydroxyalkyl, C1-C4 haloalkoxy, C1-C4 alkoxy, C1-C4 alkylamino, (C1-C4)(C1-C4) dialkylamino, C1-C4 aminoalkyl, ‒CO2H, and Ar2; and wherein Ar2is selected from a 6-membered aryl and a 6-membered heteroaryl, and is substituted with 0, 1, 2, or 3 groups independently selected from halogen, ‒CN, ‒NH2, ‒OH, ‒NO2, C1-C4 alkyl, C2-C4 alkenyl, C1-C4 haloalkyl, C1-C4 cyanoalkyl, C1-C4 hydroxyalkyl, C1-C4 haloalkoxy, C1-C4 alkoxy, C1-C4 alkylamino, (C1- C4)(C1-C4) dialkylamino, C1-C4 aminoalkyl, ‒CO2H, and ‒C(O)NH2; or a pharmaceutically acceptable salt thereof, provided that when Ar1is a 6-membered aryl, then n is 1, and provided that when Ar1is a 9- or 10-membered heteroaryl, then Ar1is not substituted with an Ar2group.

2. The compound of claim 1, wherein Ar1is selected from a 6-membered aryl, an isoxazolyl, an oxadiazolyl, and a 9- or 10-membered heteroaryl, and is substituted with 0, 1, 2, or 3 groups independently selected from halogen, ‒CN, ‒NH2, ‒OH, ‒NO2, C1-C4 alkyl, C2-C4 alkenyl, C1-C4 haloalkyl, C1-C4 cyanoalkyl, C1-C4 hydroxyalkyl, C1-C4 haloalkoxy, C1-C4 alkoxy, C1-C4 alkylamino, (C1-C4)(C1-C4) dialkylamino, C1-C4 aminoalkyl, ‒CO2H, and Ar2; and wherein Ar2is a 6-membered aryl substituted with 0, 1, 2, or 3 groups independently selected from halogen, ‒CN, ‒NH2, ‒OH, ‒NO2, C1-C4 alkyl, C2- C4 alkenyl, C1-C4 haloalkyl, C1-C4 cyanoalkyl, C1-C4 hydroxyalkyl, C1-C4 haloalkoxy, C1-C4 alkoxy, C1-C4 alkylamino, (C1-C4)(C1-C4) dialkylamino, C1-C4 aminoalkyl, and ‒CO2H.

3. The compound of claim 1 or claim 2, wherein n is 0.

4. The compound of claim 1 or claim 2, wherein n is 1.

5. The compound of any one of claims 1 to 4, wherein each of Q1and Q2is ‒C(O)‒.

6. The compound of any one of claims 1 to 5, wherein Q3is ‒CH2‒.

7. The compound of any one of claims 1 to 6, wherein Z is ‒CH(CO2H)‒.

8. The compound of any one of claims 1 to 7, wherein each of R1and R2is hydrogen.

9. The compound of any one of claims 1 to 7, wherein each of R1and R2is C1-C4 alkyl.

10. The compound of any one of claims 1 to 7, wherein each of R1and R2is methyl.

11. The compound of any one of claims 1 to 10, wherein Ar1is a 6-membered aryl substituted with 0, 1, 2, or 3 groups independently selected from halogen, ‒CN, ‒NH2, ‒OH, ‒NO2, C1-C4 alkyl, C2-C4 alkenyl, C1-C4 haloalkyl, C1-C4 cyanoalkyl, C1-C4 hydroxyalkyl, C1-C4 haloalkoxy, C1-C4 alkoxy, C1-C4 alkylamino, (C1-C4)(C1-C4) dialkylamino, C1-C4 aminoalkyl, ‒CO2H, and Ar2.

12. The compound of any one of claims 1 to 10, wherein Ar1is a 6-membered aryl substituted with 0, 1, 2, or 3 groups independently selected from halogen and C1-C4 alkyl.

13. The compound of any one of claims 1 to 10, wherein Ar1is selected from an isoxazolyl and an oxadiazolyl, and is substituted with 0, 1, 2, or 3 groups independentlyselected from halogen, ‒CN, ‒NH2, ‒OH, ‒NO2, C1-C4 alkyl, C2-C4 alkenyl, C1-C4 haloalkyl, C1-C4 cyanoalkyl, C1-C4 hydroxyalkyl, C1-C4 haloalkoxy, C1-C4 alkoxy, C1-C4 alkylamino, (C1-C4)(C1-C4) dialkylamino, C1-C4 aminoalkyl, ‒CO2H, and Ar2.

14. The compound of any one of claims 1 to 10, wherein Ar1is selected from an isoxazolyl and an oxadiazolyl, and is monosubstituted with an Ar2group.

15. The compound of claim 14, wherein Ar2is a 6-membered aryl substituted with 0, 1, 2, or 3 groups independently selected from halogen and C1-C4 alkyl.

16. The compound of claim 1 or claim 2, wherein the compound has a structure represented by a formula:, or a pharmaceutically acceptable salt thereof.

17. The compound of claim 1 or claim 2, wherein the compound has a structure represented by a formula:, wherein A is selected from –C(R20)– and –N=; wherein R20is selected from hydrogen, halogen, ‒CN, ‒NH2, ‒OH, ‒NO2, C1-C4 alkyl, C2-C4 alkenyl, C1-C4 haloalkyl, C1-C4 cyanoalkyl, C1-C4 hydroxyalkyl, C1- C4 haloalkoxy, C1-C4 alkoxy, C1-C4 alkylamino, (C1-C4)(C1-C4) dialkylamino, C1- C4 aminoalkyl, and ‒CO2H; andwherein each of R10a, R10b, R10c, R10d, and R10eis independently selected from hydrogen, halogen, ‒CN, ‒NH2, ‒OH, ‒NO2, C1-C4 alkyl, C2-C4 alkenyl, C1-C4 haloalkyl, C1-C4 cyanoalkyl, C1-C4 hydroxyalkyl, C1-C4 haloalkoxy, C1-C4 alkoxy, C1-C4 alkylamino, (C1- C4)(C1-C4) dialkylamino, C1-C4 aminoalkyl, and ‒CO2H, provided that at least two of R10a, R10b, R10c, R10d, and R10eis hydrogen, or a pharmaceutically acceptable salt thereof.

18. The compound of claim 17, wherein R20is hydrogen.

19. The compound of claim 17, wherein the compound has a structure represented by a formula:, or a pharmaceutically acceptable salt thereof.

20. The compound of claim 1 or claim 2, wherein the compound has a structure represented by a formula:, wherein A is selected from –C(R20)– and –N=; wherein R20is selected from hydrogen, halogen, ‒CN, ‒NH2, ‒OH, ‒NO2, C1-C4 alkyl, C2-C4 alkenyl, C1-C4 haloalkyl, C1-C4 cyanoalkyl, C1-C4 hydroxyalkyl, C1-C4 haloalkoxy, C1-C4 alkoxy, C1-C4 alkylamino, (C1-C4)(C1-C4) dialkylamino, C1- C4 aminoalkyl, and ‒CO2H; and wherein each of R10a, R10b, R10c, R10d, and R10eis independently selected from hydrogen, halogen, ‒CN, ‒NH2, ‒OH, ‒NO2, C1-C4 alkyl, C2-C4 alkenyl, C1-C4 haloalkyl, C1-C4 cyanoalkyl, C1-C4 hydroxyalkyl, C1-C4 haloalkoxy, C1-C4 alkoxy, C1-C4 alkylamino, (C1- C4)(C1-C4) dialkylamino, C1-C4 aminoalkyl, and ‒CO2H, provided that at least two of R10a, R10b, R10c, R10d, and R10eis hydrogen, or a pharmaceutically acceptable salt thereof.

21. The compound of claim 20, wherein R20 is hydrogen.

22. The compound of claim 20, wherein the compound has a structure represented by a formula:, or a pharmaceutically acceptable salt thereof.

23. The compound of claim 1 or claim 2, wherein the compound has a structure represented by a formula:, wherein each of R11a, R11b, R11c, and R11dis independently selected from hydrogen, halogen, ‒CN, ‒NH2, ‒OH, ‒NO2, C1-C4 alkyl, C2-C4 alkenyl, C1-C4 haloalkyl, C1-C4 cyanoalkyl, C1-C4 hydroxyalkyl, C1-C4 haloalkoxy, C1-C4 alkoxy, C1-C4 alkylamino, (C1-C4)(C1-C4) dialkylamino, C1-C4 aminoalkyl, and ‒CO2H, provided that at least one of R11a, R11b, R11c, and R11dis hydrogen, or a pharmaceutically acceptable salt thereof.

24. The compound of claim 23, wherein the compound has a structure represented by a formula:, or a pharmaceutically acceptable salt thereof.

25. The compound of claim 1 or claim 2, wherein the compound has a structure represented by a formula:, wherein R12is selected from ‒CO2H and ‒C(O)NH2; and wherein each of R13a, R13b, R13c, R13d, and R13eis independently selected from hydrogen, halogen, ‒CN, ‒NH2, ‒OH, ‒NO2, C1-C4 alkyl, C2-C4 alkenyl, C1-C4 haloalkyl, C1-C4 cyanoalkyl, C1-C4 hydroxyalkyl, C1-C4 haloalkoxy, C1-C4 alkoxy, C1-C4 alkylamino, (C1- C4)(C1-C4) dialkylamino, C1-C4 aminoalkyl, ‒CO2H, and Ar2, provided that at least two of R13a, R13b, R13c, R13d, and R13eis hydrogen, or a pharmaceutically acceptable salt thereof.

26. The compound of claim 25, wherein R12is ‒CO2H.

27. The compound of claim 25 or claim 26, wherein each of R13a, R13b, R13c, R13d, and R13eis independently selected from hydrogen, halogen, ‒CN, ‒NH2, ‒OH, ‒NO2, C1-C4 alkyl, C2-C4 alkenyl, C1-C4 haloalkyl, C1-C4 cyanoalkyl, C1-C4 hydroxyalkyl, C1-C4 haloalkoxy, C1-C4 alkoxy, C1-C4 alkylamino, (C1-C4)(C1-C4) dialkylamino, C1-C4 aminoalkyl, and ‒CO2H, provided that at least two of R13a, R13b, R13c, R13d, and R13eis hydrogen.

28. The compound of claim 25, wherein the compound has a structure represented by a formula:, or a pharmaceutically acceptable salt thereof.

29. The compound of claim 1 or claim 2, wherein the compound is selected from:or a pharmaceutically acceptable salt thereof.

30. A pharmaceutical composition comprising an effective amount of the compound of any one of claims 1 to 29 or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier.

31. A method for modulating read-through of a premature termination codon in a subject, the method comprising administering to the subject an effective amount of the compound of any one of claims 1 to 29 or a pharmaceutically acceptable salt thereof.

32. The method of claim 31, wherein modulating is increasing.

33. The method of claim 31 or claim 32, wherein the premature termination codon is selected fiom wE60X, Y122X, Q493X, G542X, G550X, R553X, Y1092X, R1162X, and W1282X.

34. The method of any one of claims 31 to 33, wherein the subject has been diagnosed with a disorder selected from cystic fibrosis, Duchenne muscular dystrophy, aniridia, Becker muscular dystrophy, spinal muscular atrophy, Hurler syndrome, hemophilia, epidermolysis bullosa, Usher syndrome, neurofibromatosis, and cancer prior to the administering step.

35. The method of any one of claims 31 to 34, wherein the subject has been diagnosed with a need for modulating read-through of a premature termination codon prior to the administering step.

36. The method of any one of claims 31 to 35, further comprising the step of identifying a subject in need of treatment of a disorder caused by a premature termination codon, wherein the disorder is selected from cystic fibrosis, Duchenne muscular dystrophy, aniridia, Becker muscular dystrophy, spinal muscular atrophy, Hurler syndrome, hemophilia, epidermolysis bullosa, Usher syndrome, and cancer.

37. A method for modulating read-through of a premature termination codon in a cell, the method comprising contacting the cell with an effective amount of the compound of any one of claims 1 to 29 or a pharmaceutically acceptable salt thereof.

38. The method of claim 37, wherein modulating is increasing.

39. The method of claim 37 or claim 38, wherein the cell is human.

40. The method of any one of claims 37 to 39, wherein the cell has been isolated from a human prior to the administering step.

41. The method of any one of claims 37 to 40, wherein contacting is via administration to a subject.

42. The method of claim 41, wherein the subject has been diagnosed with a need for modulating read-through of a premature termination codon prior to the administering step.

43. The method of claim 41, wherein the subject has been diagnosed with a need for treatment of cystic fibrosis, Duchenne muscular dystrophy, aniridia, Becker muscular dystrophy, spinal muscular atrophy, Hurler syndrome, hemophilia, epidermolysis bullosa, Usher syndrome, and cancer prior to the administering step.

44. The method of any one of claims 37 to 43, wherein the premature termination codon is selected from E60X, Y122X, Q493X, G542X, G550X, R553X, Y1092X, R1162X, and W1282X.

45. A method for treating a disorder associated with the presence of a premature termination codon in a subject in need thereof, the method comprising administering to the subject an effective amount of a compound having a structure represented by a formula:, wherein n is selected from 0 and 1; wherein each of Q1, Q2, and Q3is independently selected from ‒CH2‒ and ‒C(O)‒, provided that at least one of Q1and Q2is ‒C(O)‒; wherein Z is selected from ‒CH(CO2H)‒ and ‒CH(C(O)NH2)‒; wherein each of R1and R2is independently selected from hydrogen and C1-C4 alkyl; wherein Ar1is selected from a 6-membered aryl, an isoxazolyl, an oxadiazolyl, an oxazolyl, and a 9- or 10-membered heteroaryl, and is substituted with 0, 1, 2, or 3 groups independently selected from halogen, ‒CN, ‒NH2, ‒OH, ‒NO2, C1-C4 alkyl, C2-C4 alkenyl, C1-C4 haloalkyl, C1-C4 cyanoalkyl, C1-C4 hydroxyalkyl, C1-C4 haloalkoxy, C1-C4 alkoxy, C1-C4 alkylamino, (C1-C4)(C1-C4) dialkylamino, C1-C4 aminoalkyl, ‒CO2H, and Ar2; and wherein Ar2is selected from a 6-membered aryl and a 6-membered heteroaryl, and is substituted with 0, 1, 2, or 3 groups independently selected from halogen, ‒CN, ‒NH2, ‒OH, ‒NO2, C1-C4 alkyl, C2-C4 alkenyl, C1-C4 haloalkyl, C1-C4 cyanoalkyl, C1-C4 hydroxyalkyl, C1-C4 haloalkoxy, C1-C4 alkoxy, C1-C4 alkylamino, (C1- C4)(C1-C4) dialkylamino, C1-C4 aminoalkyl, ‒CO2H, and ‒C(O)NH2, or a pharmaceutically acceptable salt thereof, provided that when Ar1is a 9- or 10-membered heteroaryl, then Ar1is not substituted with an Ar2group.

46. The method of claim 45, wherein the subject is a mammal.

47. The method of claim 45, wherein the subject is a human.

48. The method of any one of claims 45 to 47, wherein the subject has been diagnosed with a need for treatment of the disorder prior to the administering step.

49. The method of any one of claims 45 to 48, further comprising the step of identifying a subject in need of treatment of the disorder.

50. The method of claim 45, wherein identifying comprises identifying the presence of a premature termination codon in the subject.

51. The method of any one of claims 45 to 50, wherein administering stimulates read- through of the premature termination codon.

52. The method of any one of claims 45 to 51, wherein administering increases the stability of a mRNA containing the premature termination codon.

53. The method of any one of claims 45 to 52, wherein the effective amount is a therapeutically effective amount.

54. The method of any one of claims 45 to 52, wherein the effective amount is a prophylactically effective amount.

55. The method of any one of claims 45 to 54, wherein the disorder is selected from cystic fibrosis, Duchenne muscular dystrophy, aniridia, Becker muscular dystrophy, spinal muscular atrophy, Hurler syndrome, hemophilia, epidermolysis bullosa (e.g., dystrophic (DEB) form, junctional (JEB) form), Usher syndrome, and cancer.

56. The method of claim 55, wherein the cancer is associated with one or more mutations selected from a P53 mutation and an APC mutation.

57. The method of any one of claims 45 to 54, wherein the disorder is cystic fibrosis.

58. The method of any one of claims 45 to 57, wherein the premature termination codon is selected from E60X, Y122X, Q493X, G542X, G550X, R553X, Y1092X, R1162X, and W1282X59. The method of any one of claims 45 to 58, further comprising administering a second active agent to the subject.

60. The method of claim 59, wherein the second active agent is selected from a CFTR modulator, an NMD inhibitor, and an agent that increases mRNA levels.

61. The method of claim 60, wherein the CFTR polypeptide modulator is a CFTR potentiator, a CFTR amplifier, or a CFTR corrector.

62. The method of claim 61, wherein the CFTR potentiator is selected fiom ivacaftor, VX-770, PG-01, tetrahydrobenzothiophene, and GP-5.

63. The method of claim 61, wherein the CFTR corrector is selected fiom elexacaftor, lumacaftor, tezacaftor, Corr-4a, VX-809, Cl, and C2.

64. The method of claim 60, wherein the NMD inhibitor is selected fiom NMDI-1, NMDI-9, NMDI-25, and NMDI-14.

65. The method of claim 60, wherein the agent that increases mRNA levels is a histone deacetylase inhibitor.

66. The method of claim 65, wherein the histone deacetylase inhibitor is selected fiom vorinostat, romidepsin, panobinostat, and belinostat.

67. The method of claim 59, wherein the second active agent is an agent that increases general pulmonary function.

68. The method of claim 67, wherein the agent that increases general pulmonary function is selected fiom albuterol, salbuterol, recombinant DNAse, domase alpha, inhaled tobramycin, amikracin, azithromycin, and hypertonic saline.

69. The method of claim 59, wherein the premature termination codon is in a CFTR.

70. The method of claim 59, wherein the second active agent is an aminoglycoside.

71. The method of claim 70, wherein the aminoglycoside is selected from G418, geneticin, amikacin, tobramycin, ELX-02, NB54, NB124, NB127, andNB83.

72. The method of claim 59, wherein the compound and the second active agent each modulate read-through of a premature termination codon via different mechanism.

73. The method of claim 72, wherein the compound modulates read-through of a premature termination codon via degradation of translation termination factor eRF1.

74. The method of claim 72, wherein the second active agent modulates read-through of a premature termination codon via degradation of translation termination factor eRF3 (e.g., CC-9009) or via inhibition of SMG1 (e.g., via a SMG1 inhibitor).

75. The method of claim 72, wherein the second active agent is selected from erythromycin, artesunate, atazanavir, ataluren, genistein, and Y-320.

76. A method for treating a disorder in a subject identified as having a premature termination codon, the method comprising administering to the subject an effective amount of a compound having a structure represented by a formula:, wherein n is selected from 0 and 1; wherein each of Q1, Q2, and Q3is independently selected from ‒CH2‒ and ‒C(O)‒, provided that at least one of Q1and Q2is ‒C(O)‒; wherein Z is selected from ‒CH(CO2H)‒ and ‒CH(C(O)NH2)‒; wherein each of R1and R2is independently selected from hydrogen and C1-C4 alkyl; wherein Ar1is selected from a 6-membered aryl, an isoxazolyl, an oxadiazolyl, an oxazolyl, and a 9- or 10-membered heteroaryl, and is substituted with 0, 1, 2, or 3 groups independently selected from halogen, ‒CN, ‒NH2, ‒OH, ‒NO2, C1-C4 alkyl, C2-C4 alkenyl, C1-C4 haloalkyl, C1-C4 cyanoalkyl, C1-C4 hydroxyalkyl, C1-C4 haloalkoxy, C1-C4 alkoxy, C1-C4 alkylamino, (C1-C4)(C1-C4) dialkylamino, C1-C4 aminoalkyl, ‒CO2H, and Ar2; and wherein Ar2is selected from a 6-membered aryl and a 6-membered heteroaryl, and is substituted with 0, 1, 2, or 3 groups independently selected from halogen, ‒CN, ‒NH2, ‒OH, ‒NO2, C1-C4 alkyl, C2-C4 alkenyl, C1-C4 haloalkyl, C1-C4 cyanoalkyl,C1-C4 hydroxyalkyl, C1-C4 haloalkoxy, C1-C4 alkoxy, C1-C4 alkylamino, (C1- C4)(C1-C4) dialkylamino, C1-C4 aminoalkyl, ‒CO2H, and ‒C(O)NH2, or a pharmaceutically acceptable salt thereof, provided that when Ar1is a 9- or 10-membered heteroaryl, then Ar1is not substituted with an Ar2group.

77. The method of claim 76, wherein the disorder is selected from cystic fibrosis, Duchenne muscular dystrophy, aniridia, Becker muscular dystrophy, spinal muscular atrophy, Hurler syndrome, hemophilia, epidermolysis bullosa (e.g., dystrophic (DEB) form, junctional (JEB) form), Usher syndrome, and cancer.

78. A kit comprising a compound having a structure represented by a formula:, wherein n is selected from 0 and 1; wherein each of Q1, Q2, and Q3is independently selected from ‒CH2‒ and ‒C(O)‒, provided that at least one of Q1and Q2is ‒C(O)‒; wherein Z is selected from ‒CH(CO2H)‒ and ‒CH(C(O)NH2)‒; wherein each of R1and R2is independently selected from hydrogen and C1-C4 alkyl; wherein Ar1is selected from a 6-membered aryl, an isoxazolyl, an oxadiazolyl, an oxazolyl, and a 9- or 10-membered heteroaryl, and is substituted with 0, 1, 2, or 3 groups independently selected from halogen, ‒CN, ‒NH2, ‒OH, ‒NO2, C1-C4 alkyl, C2-C4 alkenyl, C1-C4 haloalkyl, C1-C4 cyanoalkyl, C1-C4 hydroxyalkyl, C1-C4 haloalkoxy, C1-C4 alkoxy, C1-C4 alkylamino, (C1-C4)(C1-C4) dialkylamino, C1-C4 aminoalkyl, ‒CO2H, and Ar2; and wherein Ar2is selected from a 6-membered aryl and a 6-membered heteroaryl, and is substituted with 0, 1, 2, or 3 groups independently selected from halogen, ‒CN, ‒NH2, ‒OH, ‒NO2, C1-C4 alkyl, C2-C4 alkenyl, C1-C4 haloalkyl, C1-C4 cyanoalkyl,C1-C4 hydroxyalkyl, C1-C4 haloalkoxy, C1-C4 alkoxy, C1-C4 alkylamino, (C1- C4)(C1-C4) dialkylamino, C1-C4 aminoalkyl, ‒CO2H, and ‒C(O)NH2, or a pharmaceutically acceptable salt thereof, provided that when Ar1is a 9- or 10-membered heteroaryl, then Ar1is not substituted with an Ar2group, and one or more selected from: (a) at least one agent known for the treatment of a disorder associated with the presence of a premature termination codon; (b) at least one device known for the treatment of a disorder associated with the presence of a premature termination codon; (c) instructions for administering the compound in connection with treating a disorder associated with the presence of a premature termination codon; (d) instructions for administering the compound in connection with reducing the risk of a disorder associated with the presence of a premature termination codon; and (e) instructions for treating a disorder associated with the presence of a premature termination codon.

79. The kit of claim 78, wherein the disorder is selected from cystic fibrosis, Duchenne muscular dystrophy, aniridia, Becker muscular dystrophy, spinal muscular atrophy, Hurler syndrome, hemophilia, epidermolysis bullosa (e.g., dystrophic (DEB) form, junctional (JEB) form), Usher syndrome, and cancer.

80. The kit of claim 78, wherein the agent is a nonsense suppression agent.

81. The kit of claim 80, wherein the nonsense suppression agent is an eRF3 degrader (e.g., CC-885, CC-9009), an aminoglycoside (e.g., G418, gentamicin, paromomycin, amikacin, ELX-02), a macrolide (e.g., erythromycin), PRC124 (ataluren), a 2,6- diaminopurine, or a G418 enhancer (e.g., Y320, CDX5-1).

82. The kit of claim 78, wherein the agent is selected from a CFTR modulator (e.g., a CFTR potentiator, a CFTR amplifier, a CFTR corrector), an NMD inhibitor (e.g., NMDI-1,NMDI-9, NMDI-25, NMDI-14), an agent that increases mRNA levels (e.g., a histone deacetylase inhibitor), an agent that increases general pulmonary function, an aminoglycoside (e.g., G418, geneticin, amikacin, tobramycin, ELX-02, NB54, NB124, NB83), erythromycin, artesunate, atazanavir, ataluren, genistein, Y-320, ELX-02, and CC-9009.

83. The kit of claim 78, wherein the agent is known for the treatment of cystic fibrosis.

84. The kit of claim 83, wherein the agent is selected from elexacaftor, ivacaftor, tezacaftor, lumacaftor, a mucus thinner, and a bronchodilator.

85. The kit of claim 84, wherein the mucus thinner is selected from hypertonic saline and domase alfa.

86. The kit of claim 84, wherein the bronchodilator is selected from a beta-adrenergic bronchodilator, an anticholinergic bronchodilator, and a xanthine derivative.

87. The kit of claim 86, wherein the beta-adrenergic bronchodilator is selected from albuterol, levalbuterol, an epinephrine injection, salmeterol, azithromycin, clarithromycin, and formoterol.

88. The kit of claim 86, wherein the anticholinergic bronchodilator is selected from ipratropium and tiotropium.

89. The kit of claim 86, wherein the xanthine derivative is selected from theophylline and aminophylline.

90. The kit of claim 78, wherein the device is selected from a nebulizer and a vascular access device.

91. The kit of claim 90, wherein the vascular access device is selected from a peripheral intravenous catheter (PIV), a peripherally inserted central catheter (PICC), a centrally inserted central catheter (CICC), a subcutaneous catheter device, and an implanted venous port.

92. The kit of claim 78, wherein the compound and the agent are co-packaged.

93. The kit of claim 78, wherein the compound and the agent are co-formulated.

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