WO2017049409A1

WO2017049409A1 - Compositions for promoting readthrough of premature termination codons, and methods of using the same

Info

Publication number: WO2017049409A1
Application number: PCT/CA2016/051119
Authority: WO
Inventors: Michel Roberge; Alireza BARADARAN-HERAVI; Aruna D. BALGI; Carla D. ZIMMERMANN; Alexandra KRAUSE; Thomas Arthur Pfeifer; James Brian JAQUITH; Jason Samuel TAN; Fahimeh S. SHIDMOOSSAVEE; Stephen Paul ARNS; Davy Jérémy BAUDELET
Original assignee: The Centre For Drug Research And Development; The University Of British Columbia
Priority date: 2015-09-25
Filing date: 2016-09-23
Publication date: 2017-03-30

Abstract

Disclosed are compounds of general formula (I) that promote readthrough of a premature termination codon (PTC) of an RNA molecule in a translation system, and their use, alone or in combination with other compounds, such as aminoglycoside, to treat diseases or disorders ameliorated by modulation of a premature termination codon (PTC) of an RNA molecule in a translation system. The disorder or disease may be Dystrophic epidermolysis bullosa, Batten disease, Duchenne muscular dystrophy, cancer, and spinal muscular atrophy. Ar-L-B (I)

Description

COMPOSITIONS FOR PROMOTING READTHROUGH OF PREMATURE TERMINATION CODONS, AND METHODS OF USING

THE SAME

REFERENCE TO RELATED APPLICATIONS

[0001] This application claims the benefit of U.S. Provisional Patent Application Serial No. 62/233,168, filed on 25 September 2015, and U.S. Provisional Patent Application Serial No. 62/296,992, filed on 18 February 2016, which are hereby incorporated by reference for all purposes as if fully set forth herein.

FIELD

[0002] The present disclosure relates to the phenomena of nonsense mutations and premature termination codons, as well as to diseases and disorders associated with nonsense mutations and premature termination codons. The present disclosure further relates to compositions useful for promoting readthrough at premature termination codons, and methods for treating diseases and disorders associated with nonsense mutations and premature termination codons.

BACKGROUND

[0003] Nonsense mutations are point mutations that change an amino acid codon to a premature termination codon (PTC). Premature termination of the translation of mRNA results in the formation of a truncated protein that may be unstable, non-functional, and/or toxic. In addition, rriRNAs containing a PTC, and the proteins encoded thereby, may be decreased due to degradation of the mRNA by the nonsense-mediated degradation pathway. Nonsense mutations resulting in the termination codons UGA, UAG, and UAA are thought to account for 11% of all described gene lesions causing human inherited disease and 20% of disease-associated single-base pair substitutions affecting gene coding regions (Mort et al, 2008, Human Mutation, 29(8): 1037- 1047). Prominent examples of diseases caused by such mutations include certain forms of cystic fibrosis, Duchenne/Becker muscular dystrophy, and various cancers. Nonsense mutations are also associated with other diseases including thalassemia, haemophilia A and B, von Willebrand's disease, Tay-Sachs disease, neurofibromatosis, ataxia telangiectasia, the lysosomal storage disease mucopolysaccharidosis I, Hurler's syndrome, cystinosis, and late infantile neuronal ceroid lipofuscinosis.

[0004] One approach being developed to treat diseases caused by PTCs is the use of small molecule compounds that induce translational readthrough of PTCs, resulting in production of full length protein. High concentrations of certain aminoglycoside antibiotics were found in 1979 to suppress several nonsense alleles in yeast (Singh A., et al., Phenotypic suppression and misreading in Saccharomyces cerevisiae. Nature 1979;277: 146-148; Palmer E., et al., Phenotypic suppression of nonsense mutants in yeast by aminoglycoside antibiotics. Nature 1979;277: 148-150) and subsequently in a reporter gene introduced into mammalian cells (Burke J.F., et al., Suppression of a nonsense mutation in mammalian cells in vivo by the aminoglycoside antibiotics G418 and paromomycin. Nucleic Acids Res. 1985; 13 :6265-6272).

[0005] Aminoglycosides exert their PTC readthrough activity by binding at the decoding center of the eukaryotic ribosome. Binding alters the ability of translation termination factors to accurately recognize a PTC. Consequently, aminoglycosides increase the frequency of pairing of near-cognate aminoacyl-tRNAs to the PTC and enables formation of full-length protein (Francois B., et al., Crystal structures of complexes between aminoglycosides and decoding A site oligonucleotides: role of the number of rings and positive charges in the specific binding leading to miscoding. Nucleic Acids Res. 2005;33 :5677-5690; De Loubresse N.G., et al., Structural basis for the inhibition of the eukaryotic ribosome. Nature 2014;513 :517-522).

[0006] The therapeutic potential of the aminoglycoside, gentamicin, has been investigated in preclinical models of genetic disease and in patients. Studies in mice bearing the human CFTR G542X transgene demonstrated increased CFTR function upon gentamicin administration (Du M., et al., . Aminoglycoside suppression of a premature stop mutation in a Cftr-/- mouse carrying a human CFTR-G542X transgene. J. Mol. Med. 2002;80:595-604.) Gentamicin treatment also elevated CFTR chloride conductance in patients with CFTR nonsense mutations (Clancy J. P., et al., . Evidence that systemic gentamicin suppresses premature stop mutations in patients with cystic fibrosis. Am. J. Respir. Crit. Care Med. 2001;163 : 1683-1692; Wilschanski M., et al., . Gentamicin-induced correction of CFTR function in patients with cystic fibrosis and CFTR stop mutations. N. Engl. J. Med. 2003;349: 1433-1441). However, improvements were small and patient response was variable (Linde L., et al., Nonsense-mediated mRNA decay affects nonsense transcript levels and governs response of cystic fibrosis patients to gentamicin. J. Clin. Invest. 2007; 117:683-692). PTC readthrough by gentamicin was also demonstrated in mdx mice (Barton- Davis E.R., et al., Aminoglycoside antibiotics restore dystrophin function to skeletal muscles of mdx mice. J. Clin. Invest. 1999; 104:375-381) harboring nonsense mutations in their Dmd gene to model human Duchenne muscular dystrophy (DMD). The first small trial in DMD patients showed no effect and two others showed dystrophin expression in some patients (Malik V., et al., Gentamicin-induced readthrough of stop codons in Duchenne muscular dystrophy. Ann. Neurol. 2010;67:771-780) but the level of expression was insufficient for patient improvement. The lack of potency of gentamicin and its recognized nephrotoxicity and ototoxicity at high dosage may have discouraged its further development.

[0007] Major efforts have been put into developing aminoglycoside derivatives with reduced toxicity (Shulman E., et al., Designer aminoglycosides that selectively inhibit cytoplasmic rather than mitochondrial ribosomes show decreased ototoxicity: a strategy for the treatment of genetic diseases. J. Biol. Chem. 2014;289:2318-2330; Xue X., et al., Synthetic aminoglycosides efficiently suppress cystic fibrosis transmembrane conductance regulator nonsense mutations and are enhanced by ivacaftor. Am. J. Respir. Cell Mol. Biol. 2014;50:805-816) and discovering non- aminoglycoside readthrough compounds such as negamycin, tylosin, RTC13, RTC14, GJ71, GJ72 and ataluren (Gatti R.A., SMRT compounds correct nonsense mutations in primary immunodeficiency and other genetic models. Ann. N. Y. Acad. Sci. 2012; 1250:33-40; Du M., et al., PTC124 is an orally bioavailable compound that promotes suppression of the human CFTR- G542Xnonsense allele in a CF mouse model. Proc. Natl. Acad. Sci. U.S.A. 2008; 105:2064-2069; Du L., et al., A new series of small molecular weight compounds induce read through of all three types of nonsense mutations in the ATM gene. Mol. Ther. 2013;21 : 1653-1660; Zilberberg A., et al., Restoration of ARC gene function in colorectal cancer cells by aminoglycoside- and macrolide- induced readthrough of premature termination codons. Gut 2010;59:496-507; Arakawa M., et al., Negamycin restores dystrophin expression in skeletal and cardiac muscles of mdx mice. J. Biochem. 2003; 134:751-758). [0008] Other non-aminoglycoside compounds said to induce PTC readthrough have been described in International Patent Application Publication Nos. WO 2004/009533; WO 2004/009558; WO 2004/009609; WO 2004/009610; WO 2004/091502; WO 2006/044502; WO 2006/0044503; WO 2006/044505; WO 2006/044456; WO 2006/044682; WO 2008/130370; WO 2012/021707 and WO 2013/142346.

[0009] Restoration of normal levels of expression of full length protein may not be necessary in order for a PTC readthrough promoting compound to be effective. In certain diseases, even a small amount of full length functional protein may be sufficient to improve clinical symptoms of the disease. Clinical trials in haemophilia A patients, for example, indicate that even a small increase in expression of clotting factor can result in clinical improvement (White, 2001, Thromb. Haemost., 86: 172-177) and in cystic fibrosis patients, levels of CFTR mRNA that are just 5% of normal may be sufficient to avoid the severe complications of this disease (Ramalho et al., 2002, Am. J. Respir. CellMol. Biol, 27:619-627). Additionally, reports have suggested that restoration of 20% and 30% of functional dystrophin in mouse and human, respectively, is sufficient to protect myofibers from muscular dystrophy (van Putte M. et al. The effects of low levels of dystrophin on mouse muscle function and pathology. PlosONE 2012 e31937. Neri M, Torelli S, Brown S, et al. Dystrophin levels as low as 30% are sufficient to avoid muscular dystrophy in the human. Neuromuscul Disord 2007; 17:913-918).

[0010] Despite efforts in the field to reduce the unwanted effects of aminoglycosides through design, and to discover certain non-aminoglycoside readthrough compositions, there remains a need for compositions that can promote readthrough in required systems at sufficient levels with limited or acceptable adverse/unwanted effects for use in the treatment of subjects with diseases and disorders associated with nonsense mutations and premature termination codons.

[0011] This background information is provided for the purpose of making known background information believed by the applicant to be of help in understanding the present invention. No admission is intended, nor should be construed, that any of the preceding information necessarily constitutes prior art against the present invention.

SUMMARY [0012] The present disclosure relates generally to compositions that are capable of promoting readthrough of premature termination codons (referred to herein as "PTC readthrough compounds", or "PTC-RCs") and methods of using the same. The present invention derives in part from the surprising finding that combinations of certain PTC-RCs exhibit synergistic PTC readthrough activity. Notably, certain PTC-RCs of the invention may appear to lack independent readthrough activity, yet these compounds can synergize with other PTC-RCs to effectively promote readthrough of PTCs. In particular, compounds of general formulas (I), (IV) and (V), as disclosed herein, and compounds of Tables 1, 2, and 5, have been found to synergize with aminoglycosides to promote readthrough of PTCs. [0013] Accordingly, in one aspect, the invention provides a method of promoting readthrough of a premature termination codon (PTC) of an RNA molecule in a translation system, comprising adding (i) a compound of general formula (I), or a salt thereof; and (ii) an aminoglycoside, to the translation system in amounts that, in combination, are effective to promote readthrough, wherein:

Ar - L - B (I) wherein

1) Ar is an aryl having general formula (II):

wherein:

R¹, R², R³, R⁴ and R⁵ are each independently selected from the group consisting of H, OH, CN, halogen, substituted or unsubstituted lower alkyl, substituted or unsubstituted lower alkoxy, substituted or unsubstituted naphthyl, substituted or unsubstituted heteroaryl, and substituted amino; or R¹ and R², taken together with the ring-forming C atoms that they are attached to, form an aryl ring; or R² and R³, taken together with the ring-forming C atoms that they are attached to, form an aryl ring; or s an N-containing heteroaryl selected from the group consisting of:

R⁶ and R⁹ are each independently H, OH, F, CI, substituted or unsubstituted lower alkyl,

R⁷ and R⁸ are each independently H, F, CI, unsubstituted lower alkyl, or C(0)R¹²; R¹⁰ is substituted or unsubstituted lower alkyl; R¹¹ is substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, or C(0)R¹³; R¹² and R¹³ are each independently OH, OR¹⁴, H₂, HR¹⁵, substituted or unsubstituted lower alkyl or substituted or unsubstituted heterocycloalkyl; R¹⁴ and R¹⁵ are each independently substituted or unsubstituted lower alkyl; X is -CH₂-, - H- or - R¹⁶-; R¹⁶ is substituted or unsubstituted aryl; R¹⁷ is H, substituted or unsubstituted lower alkyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl; R¹⁸ is H; or R¹⁷ and R¹⁸, taken together with the C atom they are attached to form cyclopropyl, cyclopentyl or cyclohexyl; or X and R , taken together with the C atom that R is attached cyclopropyl; W is -CH₂- or -C(O)-; and Y is -CH₂- or -0-; or

Ar is an aryl having general formula (III):

wherein:

R , R , R , R and R are each independently selected from the group consisting of H, OH, CN, halogen, substituted or unsubstituted lower alkyl, substituted or unsubstituted lower alkoxy, substituted or unsubstituted naphthyl, substituted or unsubstituted heteroaryl, and substituted amino; or R¹⁹ and R²⁰, taken together with the ring-forming C atoms that they are attached to, form an aryl ring; or R²⁰ and R²¹, taken together with the ring-forming C atoms that they are attached to, form an aryl ring; or

Ar is an N-containing heteroaryl selected from the group consisting of:

L is -CH2-NR²⁴-, -S(0)₂-NR²⁵-, -NH-C(0)-NH-, -C(0)-NH- -CH₂-NH-C(0)-, or -CH₂-NR²⁶-CH₂-; R²⁴ and R²⁵ are each independently H or unsubstituted lower alkyl; R²⁶ is H or unsubstituted lower alkyl;

B is:

wherein:

R is H, substituted or unsubstituted lower alkyl, substituted or unsubstituted aryl, substituted or unsubstituted arylalkyl, substituted or unsubstituted heteroaryl, substituted or unsubstituted cycloalkyl or carboxy; R²⁸, R²⁸ and R^28" are each independently H, halogen, substituted or unsubstituted lower alkyl, substituted or unsubstituted lower alkoxy, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl; R²⁹ is H, substituted or unsubstituted lower alkyl, substituted or unsubstituted aryl, substituted or unsubstituted arylalkyl, substituted or unsubstituted heteroaryl, substituted or unsubstituted cycloalkyl or carboxy; R³⁰, R^30' and R^30" are each independently H, halogen, substituted or unsubstituted lower alkyl, substituted or unsubstituted lower alkoxy, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl; R³¹ is H, substituted or unsubstituted lower alkyl, substituted or unsubstituted aryl, substituted or unsubstituted arylalkyl, substituted or unsubstituted heteroaryl, substituted or unsubstituted cycloalkyl or carboxy; R³², R³² and R³² are each independently H, halogen, substituted or unsubstituted lower alkyl, substituted or unsubstituted lower alkoxy, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl; R³³, R³³ and R³³ are each independently H, halogen, substituted or unsubstituted lower alkyl, substituted or unsubstituted lower alkoxy, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl; each R³⁴ is independently H, halogen, substituted or unsubstituted lower alkyl, substituted or unsubstituted lower alkoxy, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl; R³⁵ is H, substituted or unsubstituted lower alkyl, substituted or unsubstituted aryl, substituted or unsubstituted arylalkyl, substituted or unsubstituted heteroaryl, substituted or unsubstituted cycloalkyl or carboxy; R³⁶, R³⁶ and R^36" are each independently H, halogen, substituted or unsubstituted lower alkyl, substituted or unsubstituted lower alkoxy, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl; R³⁷, R³⁸, R³⁹, and R⁴⁰ are each independently H, halogen, substituted or unsubstituted lower alkyl, substituted or unsubstituted lower alkoxy, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl; R⁴¹ is H, halogen, substituted or unsubstituted lower alkyl, substituted or unsubstituted lower alkoxy, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl; R⁴² is H, substituted or unsubstituted lower alkyl, substituted or unsubstituted aryl, substituted or unsubstituted arylalkyl, substituted or unsubstituted heteroaryl, substituted or unsubstituted cycloalkyl or carboxy; R⁴³, R⁴³ and R^43" are each independently H, halogen, substituted or unsubstituted lower alkyl, substituted or unsubstituted lower alkoxy, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl; R⁴⁴, R^44' and R^44" are each independently H, halogen, substituted or unsubstituted lower alkyl, substituted or unsubstituted lower alkoxy, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl; R⁴⁵ is H, substituted or unsubstituted lower alkyl, substituted or unsubstituted aryl, substituted or unsubstituted arylalkyl, substituted or unsubstituted heteroaryl, substituted or unsubstituted cycloalkyl or carboxy; R⁴⁶ is H, substituted or unsubstituted lower alkyl, substituted or unsubstituted aryl, substituted or unsubstituted arylalkyl, substituted or unsubstituted heteroaryl, substituted or unsubstituted cycloalkyl or carboxy; R , R and R^47" are each independently H, halogen, substituted or unsubstituted lower alkyl, substituted or unsubstituted lower alkoxy, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl; R⁴⁸ is H, substituted or unsubstituted lower alkyl, substituted or unsubstituted aryl, substituted or unsubstituted arylalkyl, substituted or unsubstituted heteroaryl, substituted or unsubstituted cycloalkyl or carboxy; R⁴⁹, R⁴⁹ and R^49" are each independently H, halogen, substituted or unsubstituted lower alkyl, substituted or unsubstituted lower alkoxy, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl; R⁵⁰ is H, substituted or unsubstituted lower alkyl, substituted or unsubstituted aryl, substituted or unsubstituted arylalkyl, substituted or unsubstituted heteroaryl, substituted or unsubstituted cycloalkyl or carboxy; R⁵¹, R⁵¹ , R⁵¹ and R^51'" are each independently H, halogen, substituted or unsubstituted lower alkyl, substituted or unsubstituted lower alkoxy, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl; R⁵² is H, substituted or unsubstituted lower alkyl, substituted or unsubstituted aryl, substituted or unsubstituted arylalkyl, substituted or unsubstituted heteroaryl, substituted or unsubstituted cycloalkyl or carboxy; R⁵³, R⁵³ , R⁵³ and R⁵³ are each independently H, halogen, substituted or unsubstituted lower alkyl, substituted or unsubstituted lower alkoxy, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl; R⁵⁴ is -C(0)- R⁵⁶R⁵⁷ or -S(0)₂- R⁵⁸R⁵⁹ and R⁵⁵ is H, or R⁵⁴ is H and R⁵⁵ is -C(O)- R⁵⁶R⁵⁷ or -S(0)₂- R⁵⁸R⁵⁹; R⁵⁶ and R⁵⁷ are each independently H, substituted or unsubstituted lower alkyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, or substituted or unsubstituted cycloalkyl; R⁵⁸ and R⁵⁹ are each independently H, substituted or unsubstituted lower alkyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, or substituted or unsubstituted cycloalkyl;

R¹³⁴ and R¹³⁵ are each independently H, halogen, substituted or unsubstituted lower alkyl, substituted or unsubstituted lower alkoxy, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl; Z¹, Z², Z³, Z⁴, Z⁵ and Z⁶ are each independently -N-, -CH-, or -CR³⁴-, wherein at least one of Z³, Z⁴, Z⁵ and Z⁶ is -N-; Z⁸ Z⁷ [_s _ CR³⁷R³⁸-CR³⁹R⁴⁰-, -CR¹³⁴=CR¹³⁵- or -N=CR⁴¹-; Z⁹ is -0-, - H-, or -CH₂-; Z¹⁰ and Z¹¹ are each independently - R⁴⁵- or -CH₂- wherein at least one of Z¹⁰ and Z¹¹ is -NR⁴⁵-; Z¹² is -CH₂- -NH-, -S-, or -0-; and Z¹³ is -CH- or -N-.

[0014] Addition of the subject compound and aminoglycoside to the translation system may be done concurrently or consecutively.

[0015] In one embodiment, the compound of general formula (I), or salt thereof, is a compound of general formula (IV), or a salt thereof:

wherein

R⁶⁰, R⁶¹, R⁶², R⁶³, and R⁶⁴ are each independently H, CI, I, F, Br, CF₃ or substituted or unsubstituted lower alkoxy, wherein at least one of R⁶⁰, R⁶¹, R⁶², R⁶³, and R⁶⁴ is not H; or R⁶⁰ and R⁶¹, taken together with the ring-forming C atoms that they are attached to, form an aryl ring, and R⁶², R⁶³, and R⁶⁴ are each independently H, CI, I, F, Br, CF₃ or substituted or unsubstituted lower alkoxy; and a) L² is -CH₂- or -(CH₂)₂-, and

B² is:

wherein: R and R are each independently H, OH, CI, F, unsubstituted lower alkyl, H₂,

R⁶⁶ and R⁶⁷ are each independently H, F, CI, unsubstituted lower alkyl, or C(0)R¹³⁰; R⁶⁹ is unsubstituted lower alkyl, CH₂OR⁷¹, CH₂OC(0)R¹³¹ or (CH₂)_tN₃; R⁷⁰ is phenyl or C(0)NH₂; R⁷¹ is H or unsubstituted lower alkyl; R¹³⁰ is OH, OR¹³², H₂, HR¹³³, substituted or unsubstituted lower alkyl or substituted or unsubstituted heterocycloalkyl; R¹³¹ is unsubstituted lower alkyl; R¹³² and R¹³³ are each independently substituted or unsubstituted lower alkyl; t is 1, 2, 3 or 4; and W¹ is - CH₂- or -C(O)-; or L² is -CH₂- R⁷²-; R⁷² is H or unsubstituted lower alkyl, and

B² is:

R¹¹¹, R¹¹³ and R¹³⁶ are each independently H, substituted or unsubstituted arylalkyl, substituted or unsubstituted lower alkyl, substituted or unsubstituted cycloalkyl or carboxy; R⁷⁴, R^74', R^74", R⁷⁶, R^76', R^76", R⁷⁸, R^78', R^78", R⁸⁰, R^80', R^80", R⁸², R^82', R^82", π84 π84' π84" π86 π86' π 86" π 88 π88' π88" π90 π90' π90" π92 π92' π92" π93 π93' τ>93" τ>95 τ>95' τ>95" τ>98 τ>98' τ>98" π 100 π 100' π 100" π 102 π 102' π 102" π 104 π 104' π 104" τ>106 τ>106' π 106" π 108 π 108' π 108" πΐΐθ πΐΐθ' πΐΐθ" τ>112 τ>112' τ>112" τ>114 τ>114' τ>114"

R¹³⁷, R¹³⁸, R¹³⁹, R^139', and R^139" are each independently H, halogen or substituted or unsubstituted lower alkyl; and R⁹⁷ is H, halogen, or substituted or unsubstituted lower alkyl. [0016] In one embodiment, R is CI, I, F or CF₃; R and R are each independently H, CI, I, F or CF₃, wherein at least one of R⁶³ and R⁶⁴ is not H; and R⁶¹ and R⁶² are each H.

[0017] In one embodiment, R⁶⁰ and R⁶⁴ are each independently CI, I, F or CF₃; and R⁶¹, R⁶² and R⁶³ are each H. [0018] In one embodiment, L² is -CH₂- and B² is

, wherein R is HC(0)R⁶⁹; R , R and R are each H; R is CH₃, CH₂OR⁷¹, CH₂OC(0)CH₃ or CH₂N₃; R⁷¹ is H or unsubstituted lower alkyl; and W¹ is -C(O)-

[0019] In one embodiment, L² is -CH₂- R⁷²-, R⁷² is H, and B² is:

R , R , R , R , R", R , R and R are each independently H or unsubstituted lower alkyl; and R⁷⁴, R^74', R^74", R⁷⁶, R^76', R^76", R⁸², R^82', R^82", R⁸⁴, R^84', R^84", R⁸⁶, R^86', R^86", R⁹³, R^93', R^93", R⁹⁵, R⁹⁵ , R^95", R¹⁰⁰, R^100', R^100", R¹⁰⁸, R^108', R^108", R¹¹⁰, R^110', R^110", R¹³⁷, R¹³⁸, R¹³⁹, R^139', and R^139" are each independently H, halogen or unsubstituted lower alkyl.

[0020] In one embodiment, the compound of general formula (I), or salt thereof, is selected from the compounds shown in Tables 1, 2, and 5, and salts thereof. [0021] In one embodiment, the compound of general formula (I), or salt thereof, is selected from compounds 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50, 51, 52, 53, 54, 55, 56, 57, 58, 59, 60, 61, 62, 63, 64, 65, 66, 67, 68, 69, 70, 71, 72, 73, 74, 75, 76, 77, 78, 79, 80, 81, 82, 83, 84, 85, 86, 87, 88, 89, 90, 91, 92, 93, 94, 95, 96, 97, 98, 99, 100, 101, 102, 103, 104, 105, 106, 107, 108, 109, 110, 111, 112, 113, 114, 115, 116, 117, 118, 200, 201, 202, 203, 204, 205, 206, 207, 208, 209, 210, 211, 212, 213, 214, 215, 216, 217, 218, 219, 220, 221, 222, 223, 225, 226, 227, 228, 229, 230, 231, 300, 301, 302, 303, 304, 305, 306, 307, 308, 309-a, 310, 311, 312, 313-a, 314, 315, 316, 317, 318, 319, 320, 321, 322, 323, 324, and 325, and salts thereof

[0022] In one embodiment, the compound of general formula (I), or salt thereof, is selected from compounds 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50, 51, 52, 53, 54, 55, 56, 57, 58, 59, 60, 61, 62, 63, 64, 65, 66, 67, 68, 69, 70, 71, 72, 73, 74, 75, 76, 77, 78, 79, 102, 103, 104, 105, 106, 107, 108, 109, 110, 111, 112, 113, 114, 115, 116, 117, 118, 200, 201, 202, 203, 204, 205, 206, 207, 208, 209, 210, 221, 222, 223, 225, 226, 227, 228, 229, 303, 305, 306, 308, 310, 314, 315, 316, 317, 318, 319, 320, 321, 322, 323, 324, and 325, and salts thereof.

[0023] In one embodiment, the translation system is a cell. In one embodiment, the cell is situated in vivo in a subject. In one embodiment, the compound of general formula (I), or salt thereof, and the aminoglycoside, are administered to the subject. In one embodiment, the compound of general formula (I), or salt thereof, and the aminoglycoside, are administered to the subject simultaneously. In one embodiment, the compound of general formula (I), or salt thereof, and the aminoglycoside, are administered to the subject consecutively. In one embodiment, the subject has a disorder or disease selected from the group listed in Table 3. In one embodiment, the subject has a disorder or disease selected from the group listed in Table 4. In one embodiment, the disease is selected from the group consisting of Dystrophic epidermolysis bullosa, Batten disease, Duchenne muscular dystrophy, cancer, and spinal muscular atrophy. In one embodiment, the disease is Duchenne muscular dystrophy. In one embodiment, the disease is cancer. In one embodiment, the disease is spinal muscular atrophy. In one embodiment, the disease is Batten disease. In one embodiment, the disease is dystrophic epidermolysis bullosa.

[0024] In one aspect, the invention provides a compound of general formula (V), or a salt thereof:

Ar - B (V) wherein:

Ar is an aryl having general formula (VI):

wherein:

R , R , R , R , and R are each independently H, CI, F, Br, I, or CF₃, wherein at least two of R²⁰⁰, R²⁰¹, R²⁰², R²⁰³, and R²⁰⁴ are not H; or R²⁰⁰ and R²⁰¹, when taken together with the C atoms they are attached to, form unsubstituted phenyl, and R²⁰², R²⁰³ and R²⁰⁴ are each H; and

B is:

wherein:

R²⁰⁵ and R²⁰⁸ are each independently H, F, NH₂, HC(0)R 2^u0^y9, N0₂, N₃ or

R²⁰⁶ and R²⁰⁷ are each independently H, CI, CH₃, or C(0)R²¹¹; R²⁰ CH2OR²¹², CH₂OC(0)CH₃ or CH₂N₃; R²¹⁰ is phenyl or C(0) H₂;

(CH₂)₂OCH₃;

R is H or CH₃; and wherein at least one of R²⁰⁵, R²⁰⁶, R²⁰⁷ and R²⁰⁸ is not H; 2¹³ and R²¹⁶ are each independently H, F, NH₂, HC(0)R²¹⁷, N0₂, N₃ or

R²¹⁴ and R²¹⁵ are each independently H, F, CI, CH₃, or C(0)R²¹⁹; R²¹⁷ is CH₃,

CH2OR²²⁰, CH₂OC(0)CH₃ or CH₂N₃; R²¹⁸ is phenyl or C(0) H₂;

R²¹⁹ is (CH₂)₂OCH₃; «

^■

R²²⁰ is H or CH₃; R²²¹, R²²⁶, R²³¹, R²³⁶, R²⁴¹, R²⁴⁷, R²⁵², R²⁵⁷, R²⁶², R²⁶⁷ and R²⁹⁷ are each independently H or unsubstituted Ci_-6 alkyl; R²²², R²²³, R²²⁴, R²²⁷, R²²⁸, R²²⁹, τ> 232 > 233 τ> 234 τ> 237 τ> 238 τ> 239 τ> 242 τ> 243 τ> 244 τ> 245 τ> 246 τ> 248 τ> 249 τ> 250 τ> 253 τ> 254 j^255 j^258 j^259 j^260 j^263 j^264 j^265 j^268 j^269 j^270 j^298 j^299 j^300 j^301 _¾n(j j^302 are each independently H, CI, F, Br, I or unsubstituted C_1-6 alkyl; R²²⁵, R²³⁰, R²³⁵, R²⁴⁰, R²⁵¹, R²⁵⁶, R²⁶¹, R²⁶⁶, R²⁷¹ and R³⁰³ are each independently H, C(0)OR²⁷², C_3-6 cycloalkyl, C_6-10 aryl, C_6-10 aryl-Ci-6 alkyl, or C_1-6 alkyl, wherein C_6-10 aryl is optionally substituted with one or more substituents independently selected from C_1-6 alkyl; C_6-10 aryl of C_6-10 aryl-Ci-6 alkyl is optionally substituted with one or more substituents independently selected from halogen; and C_1-6 alkyl is optionally substituted with one or more substituents independently selected from the group consisting of OH, C3-6 cycloalkyl, 5- to 10-membered heterocycloalkyl, C(0)OH, C(0)OR²⁷³, H₂, R²⁷⁴R²⁷⁵, HC(0)OR²⁷⁸, Ci_-6 alkoxy, CN, C(0) HR²⁷⁹ and

CO H2; R²⁷², R²⁷³, R²⁷⁴, R²⁷⁵, and R²⁷⁸ are each independently unsubstituted Ci_-6 alkyl; R²⁷⁹ is C_1-6 alkyl optionally substituted with one or more substituents independently selected from the group consisting of R²⁸⁰R²⁸¹ and OH; R²⁸⁰ and R²⁸¹ are each independently unsubstituted C_1-6 alkyl; Z¹⁴ is -CH2- or -C(O)-; and Z¹⁵ is - N- or -CH- wherein:

(i) when R²⁰⁰ and R²⁰¹, when taken together with the C atoms they are attached to, form unsubstituted phenyl, and R²⁰², R²⁰³ and R²⁰⁴ are each H, and B is:

and only one of R²⁰⁵, R²⁰⁶, R²⁰⁷ and R² 2^m08 is not H, then R .2^U0⁵5 and

R²⁰⁸ are each independently H, F, H₂, HC(0)R²⁰⁹, N₃ or

; and R²⁰⁶ and R²⁰⁷ are each independently H, CI, CH₃, or C(0)R²¹¹, wherein R²⁰⁹, R²¹⁰ and R²¹¹ are as defined above;

(ii) when R²⁰⁰ and R²⁰¹, when taken together with the C atoms they are attached to, form unsubstituted phenyl, and R²⁰², R²⁰³ and R²⁰⁴ are each H, and B is

or wherein Z¹⁵ is as defined above, then at least one of: R²¹³, R²¹⁴, R²¹⁵ and R²¹⁶; or R²³⁶, R²³⁷, R²³⁸, R²³⁹ and R²⁴⁰ is not H;

(iii) when R²⁰⁰ and R²⁰¹, when taken together with the C atoms they are attached to, form unsubstituted phenyl, and R²⁰², R²⁰³ and R²⁰⁴ are each H, and B is

wherein R²⁶¹ is unsubstituted Ci_-6 alkyl, then at least one of

_R257 _R258 _R259 _an(j _R260 _{ig nQt ¾} (iv) when onl two of R²⁰⁰, R²⁰¹, R²⁰², R²⁰³, and R²⁰⁴ are not H and each is a halogen,

and B

and only one of R²⁰⁵, R²⁰⁶, R^{20 /} and R^zm is not H,

then R²⁰⁵ and R²⁰⁸ are each independently H, F, HC(0)R ^uy, N₃ or

and R²⁰⁶ and R²⁰⁷ are each independently H, CI, or C(0)R²¹¹, wherein R²⁰⁹, R²¹⁰ and R^: are as defined above: when R²⁰⁰, R²⁰¹, R²⁰², R²⁰³, and R²⁰⁴ are each a halogen, and B

only one of R²⁰⁵, R²⁰⁶, R²⁰⁷ and R²⁰⁸ is not H, then R , 205

and R are each independently H, F, H₂, HC(0)R^z 2^u0^v9, N₃ or

; and

R²⁰⁶ and R²⁰⁷ are each independently H, CI, CH₃, or C(0)R²¹¹, wherein R²⁰⁹, R²¹⁰ and R²¹¹ are as defined above;

(vi) when only three of R²⁰⁰, R²⁰¹, R²⁰², R²⁰³, and R²⁰⁴ are not H and each is a halogen,

and B is

wherein Z¹⁵ is as defined above, or

wherein Z¹⁵ is as defined above

, then at least one of:

R²¹³, R²¹⁴, R²¹⁵ and R²¹⁶; or R²²¹, R²²², R²²³, R²²⁴ and R²²⁵; or R²²⁶, R²²⁷, R²²⁸, R²²⁹ and R²³⁰; or R²³¹, R²³², R²³³, R²³⁴ and R²³⁵; or R²³⁶, R²³⁷, R²³⁸, R²³⁹ and R²⁴⁰; or R²⁴¹, R²⁴², R²⁴³, R²⁴⁴, R²⁴⁵ and R²⁴⁶; or R²⁶², R²⁵³, R²⁶⁴, R²⁶⁵ and R²⁵⁵ is not H; (viii) when only two of R²⁰⁰, R²⁰¹, R²⁰², R²⁰³, and R²2⁰0⁴4 are not H and each is a halogen,

and B

wherein R²⁴⁹ is a halogen, then at least one of R²⁴⁷,

_R248 _R250 _{and R}251 _{is nQt R an(}j

(ix) when only two of R , R , R , R² , and R are not H and each is a halog

and B is

, then at least one of R²⁵⁷, R²⁵⁸, R²⁵⁹, R²⁶⁰ and R²⁶¹ is not

H, and when only one of R²⁵⁷, R²⁵⁸, R²⁵⁹, R²⁶⁰ and R²⁶¹ is not H, then R²⁵⁷ is H or unsubstituted Ci-6 alkyl; R²⁵⁸, R²⁵⁹ and R²⁶⁰ are each independently H, CI, F, Br, I or unsubstituted Ci-6 alkyl; and R²⁶¹ is H, C(0)OR²⁷², Ce-io aryl, Ce-io aryl-Ci-e alkyl, or Ci_-6 alkyl, wherein C₆-io aryl is optionally substituted with one or more substituents independently selected from Ci_-6 alkyl; C_6-10 aryl of C_6-10 aryl-Ci-6 alkyl is optionally substituted with one or more substituents independently selected from halogen; and C_1-6 alkyl is substituted with one or more substituents independently selected from the group consisting of OH, C3-6 cycloalkyl, 5- to 10-membered heterocycloalkyl, C(0)OH, C(0)OR²⁷³, H₂, NR²⁷⁴R²⁷⁵, NHC(0)OR²⁷⁸, Ci_-6 alkoxy, CN, C(0) HR²⁷⁹ and CONH₂, wherein R²⁷², R²⁷³, R²⁷⁴, R²⁷⁵, R²⁷⁸ and R²⁷⁹ are as defined above.

[0025] In one embodiment, R²⁰⁰ is CI, F, Br, I, or CF₃; R²⁰³ and R²⁰⁴ are each independently H, CI, F, Br, I, or CF₃, wherein at least one of R²⁰³ and R²⁰⁴ is not H; and R²⁰¹ and R²⁰² are each H.

[0026] In one embodiment, R'^ou and R^2U4 are each independently CI, F, Br, I, or CF₃; and R ^U1, R²⁰² and R²⁰³ are each H.

[0027] In one embodiment, R²⁰⁰, R²⁰¹, R²⁰², R²⁰³, and R²⁰⁴ are each independently H, CI, F, Br, I, or CF₃, wherein at least two of R²⁰⁰, R²⁰¹, R²⁰², R²⁰³, and R²⁰⁴ are not H; and B is

wherein R is HC(0)R²⁰⁹; R , R and R are each H; R is

CH₃, CH₂OR , CH₂OC(0)CH₃ or CH₂N₃; and R is H or CH₃.

[0028] In one embodiment, R²⁰⁰, R²⁰¹, R²⁰², R²⁰³, and R²⁰⁴ are each independently H, CI, F, Br, I, or CF₃, wherein at least two of R²⁰⁰, R²⁰¹, R²⁰², R²⁰³, and R²⁰⁴ are not H; and B is

wherein at least one of R²²¹, R²²² R²²³,

R²²⁴ and R²²⁵; or R²²⁶, R²²⁷ R²²⁸, R²²⁹ and R²³⁰ is not H.

[0029] In one embodiment, R^2UU is CI, F, Br, I, or CF₃; R^2U4 is CF₃; and R^2U1, R^2U2 and R^2U3 are each H; and B is:

or , wherein R²²¹ and R²²⁶ are each independently H or Ci_-6 alkyl; R²²², R²²³, R²²⁴, R²²⁷, R²²⁸ and R²²⁹ are each independently H, CI, F, Br, I or unsubstituted Ci_-6 alkyl; and R²²⁵, and R²³⁰ are each independently H, C(0)OR²⁷², C_3-6 cycloalkyl, C₆-io aryl, C₆-io aryl-Ci-6 alkyl, or Ci_-6 alkyl, wherein C6-10 aryl is optionally substituted with one or more substituents independently selected from Ci_-6 alkyl; C₆-io aryl of C₆- 10 aryl-Ci-6 alkyl is optionally substituted with one or more substituents independently selected from halogen; and Ci_-6 alkyl is optionally substituted with one or more substituents

independently selected from the group consisting of OH, C_3-6 cycloalkyl, 5- to 10-membered heterocycloalkyl, C(0)OH, C(0)OR²⁷³, H₂, R²⁷⁴R²⁷⁵, HC(0)OR²⁷⁸, Ci_-6 alkoxy, CN, C(0) HR²⁷⁹ and CO H₂; R²⁷², R²⁷³, R²⁷⁴, R²⁷⁵, and R²⁷⁸ are each independently unsubstituted Ci-6 alkyl; R²⁷⁹ is Ci_-6 alkyl optionally substituted with one or more substituents independently selected from the group consisting of R²⁸⁰R²⁸¹ and OH; and R²⁸⁰ and R²⁸¹ are each independently unsubstituted C_1-6 alkyl.

[0030] In one embodiment, the compound, or salt thereof, is selected from the group consisting of compound 2, 5, 9, 11, 12, 13, 14, 15, 16, 17, 19, 29, 41, 42, 43, 44, 45, 46, 47, 68, 74, 76, 103, 104, 105, 107, 109, 204, 205, 211, 213, 214, 300, 301, 302, 303, 304, 305, 306, 307, 308, 309-a, 310, 311, 312, 313-a, 314, 315, 316, 317, 318, 319, 320, 321, 322, 323-a, and 324, and salts thereof.

[0031] In one embodiment, a PTC-RC for use in methods and pharmaceutical compositions disclosed herein is selected from the group consisting of compounds 2, 3, 4, 5, 6, 12, 13, 15, 16, 34, 55, 102, 103, 104, 105, 106, 108, 109, 110, 111, 112, 200, 203, 204, 205, 206, 207, 208, 209, 210, 211, 212, 213, 214, 215, 216, 221, 225, 226, 227, 228, 229, 230, 231, 302, 303, 305, 306, 308, 309-a, 310, 311, 313-a, 314, 315, 316, 317, 318, 319, 321, 322, 323-a, 324, and 325 In another embodiment, a PTC-RC for use in methods and pharmaceutical compositions disclosed herein is selected from the group consisting of compounds 3, 15, 16, 102, 104, 106, 110, 111, 112, 200, 203, 204, 205, 206, 208, 209, 212, 213, 214, 215, 221, 225, 226, 227, 229, 230, 302, 303, 305, 308, 309-a, 310, 313-a, 314, 316, 317, 319, 321, 322, 323-a, and 324. In another embodiment, a PTC-RC for use in methods and pharmaceutical compositions disclosed herein is selected from the group consisting of compounds 3, 102, 204, 205, 206, 208, 212, 215, 221, 229, 230, 303, 308, 310, 313-a, 314, 317, 319, 321, 322, and 323-a. In another embodiment, a PTC-RC for use in methods and pharmaceutical compositions disclosed herein is selected from the group consisting of compounds 205, 212, 215, 229, 303, 310, 313-a, 314, 317, and 322.

[0032] In one embodiment, the invention provides a PTC-RC selected from the group consisting of compounds 2, 5, 12, 13, 15, 16, 34, 55, 103, 104, 105, 109, 110, 204, 205, 207, 208, 210, 211, 212, 213, 214, 215, 216, 221, 225, 226, 227, 228, 229, 230, 231, 302, 303, 305, 306, 308, 309-a, 310, 311, 313-a, 314, 315, 316, 317, 318, 319, 321, 322, 323-a, 324, and 325 In another embodiment, the invention provides a PTC-RC selected from the group consisting of compounds 15, 16, 104, 110, 204, 205, 208, 212, 213, 214, 215, 221, 225, 226, 227, 229, 230, 302, 303, 305, 308, 309-a, 310, 313-a, 314, 316, 317, 319, 321, 322, 323-a, and 324. In another embodiment, the invention provides a PTC-RC selected from the group consisting of compounds 204, 205, 208, 212, 215, 221, 229, 230, 303, 308, 310, 313-a, 314, 317, 319, 321, 322, and 323-a. In another embodiment, the invention provides a PTC-RC selected from the group consisting of compounds 205, 212, 215, 229, 303, 310, 313-a, 314, 317, and 322

[0033] This summary does not necessarily describe all features of the invention. Other aspects, features and advantages of the invention will be apparent to those of ordinary skill in the art upon review of the following description of specific embodiments of the invention.

BRIEF DESCRIPTION OF THE DRAWINGS

[0034] Figure 1. Panels A and B: Automated p53 immunofluorescence 96-well plate assay results. HDQ-Pl cells were exposed to the indicated concentrations of compound 1 or G418, alone or in combination, for 72 h. The cells were fixed, immunostained for p53 (green) and nuclei were stained with Hoechst 33342 (blue). Images are shown in panel A and the percentage of p53- positive cells is shown in panel B. Panel C, D and E: Automated electrophoresis western analysis assay results. HDQ-Pl cells were exposed to the indicated concentrations of compound 1 or G418, alone or in combination for 96 h, and the amount of full-length p53 (FL-p53) and truncated p53 (TR-p53) was measured. Panel C shows the electropherograms obtained and panel D shows the same data, represented as "pseudoblots", shown in this and other figures for ease of visualization. In panel E, a value of 1 was assigned to the amount of TR-p53 found in untreated cells and the amount of FL-p53 and TR-p53 is expressed relative to that band.

[0035] Figure 2. Different human cancer cell lines with homozygous TP53 nonsense mutations (position shown in brackets) were exposed to the indicated concentrations of compound 102 and G418, alone or in combination, for 96 h and the amount of full-length p53 (FL-p53) and truncated p53 (TR-p53) was measured by automated electrophoresis western analysis. Within each panel, a value of 1 was assigned to the amount of the faintest FL-p53 or TR-p53 that was detected and the amount of the other bands is expressed relative to that band. The top arrowhead points to FL-p53 and the bottom arrowhead points to TR-p53. Where only a single arrowhead appears, it points to FL-p53. To determine whether compound 102 in combination with G418 can induce readthrough in cell lines other than HDQ-Pl, and at nonsense mutations other than R213X, ten human cancer cell lines with homozygous nonsense mutations in the TP53 gene were acquired. H1299 cells that do not express p53 because of a large gene deletion and HCT116 cells that express WT p53 were also used as controls. The cells were exposed to compound 102 alone, G418 alone, both, or no compound and truncated p53 and full-length p53 were determined quantitatively using the automated electrophoresis p53 western analysis assay. Some of these cell lines expressed detectable amounts of truncated p53, as shown with a black arrow in Figure B. None of the cells expressed detectable full length p53 (red arrow), as expected. Upon exposure to compound 102 and G418, eight of the ten cell lines with TP53 nonsense mutations showed detectable full length p53. The amount of full-length p53 produced varied from cell line to cell line. The results show that the compound combination can induce p53 readthrough in multiple cancer cell lines from different tissue origins and with nonsense mutations at different positions.

[0036] Figure 3. FIDQ-P1 cells were exposed to the indicated concentrations of compounds, alone or in combination, for 48 h and the amount of full-length p53 (FL-p53) and truncated p53 (TR-p53) was measured by automated electrophoresis western analysis. Vinculin was also detected as a loading control. A value of 1 was assigned to the amount of TR-p53 found in untreated cells and the amount of the other bands is expressed relative to that band.

[0037] Figure 4. FIDQ-P1 cells were exposed to the indicated concentrations of compounds, alone or in combination, for 96 h and the amount of full-length p53 (FL-p53) and truncated p53 (TR-p53) was measured by automated electrophoresis western analysis. Vinculin was also detected as a loading control. A value of 1 was assigned to the amount of TR-p53 found in untreated cells and the amount of the other bands is expressed relative to that band.

[0038] Figure 5. Human H1299 cancer cells were transiently transfected with expression plasmids for WT TP53, empty plasmid (mock), or TP53 containing a TGA, TAG or TAA premature termination codon at R213X. The cells were exposed to the indicated concentrations of compounds, alone or in combination, for 48 h and the amount of full-length p53 (FL-p53) and truncated p53 (TR-p53) was measured by automated electrophoresis western analysis. For each panel, a value of 1 was assigned to the amount of TR-p53 found in untreated cells and the amount of the other bands is expressed relative to that band. Note that H1299 cells express no endogenous p53 because of deletion of the first 954 nucleotides of the TP53 gene. To determine whether the combination of compound 102 and G418 differs in its ability to induce PTC readthrough at the three termination codons (TGA, TAG, TAA), H1299 cells lacking endogenous p53 expression were transfected with p53 expression plasmids that were identical except at R213X. In figure E, p53-WT has no premature termination codon at R213, Mock is the expression vector without the p53 coding sequence and the cells expressing p53 with TGA, TAG or TAA are indicated. The cells expressing WT p53 showed only full-length p53 and the cells expressing R213X showed only truncated p53, as expected. Exposure to the combination of compound 102 and G418 induced detectable full-length p53 at the three different premature termination codons. Readthrough was most efficient at TGA and lest efficient at TAA.

[0039] Figure 6. Examples of compounds that can suppress nonsense mutations (i.e. induce PTC readthrough) in yeast alone and in combination with the aminoglycoside paromomycin. Yeast carrying the nonsense alleles met8-l and trp5-48 were grown in medium lacking methionine (met8-l) or tryptophan {trp5-48). In these conditions, the yeast cannot grow because the PTC in these genes prevents the production of these enzymes, which are required for methionine biosynthesis and tryptophan biosynthesis. The example shows that addition of compound 1 or compound 39 to the growth medium enables the yeast to grow, showing that the compounds at a higher concentration than used in combination with aminoglycoside induce PTC readthrough when used alone. The example also shows that combining compound 1 or 39 at a lower concerntraion potentiates a sub-active concentration of paromomycin of 2.5 μΜ (met8-l) or 10 μΜ {trp5-48). Yeast growth was measured 40 h after addition of the compounds.

[0040] Figure 7. FIDQ-P1 cells were exposed to the indicated compound concentrations for 72 h and the amount of full-length p53 (FL-p53) and truncated p53 (TR-p53) was measured by automated electrophoresis western analysis. Vinculin was also detected as a loading control. A value of 1 was assigned to the amount of TR-p53 found in untreated cells and the amount of the other bands is expressed relative to that band. The figure shows that the compound combination showing most readthrough was compound 102-gentamicin Bl, followed by compound 102-G418, compound 102-gentamicin X2 and compound 102-gentamicin. Gentamicin Bl was purchased from MicroCombiChem (MCC3436) Gentamicin X2 was purchased from TokuOE (G036) G418 was purchased from Life Technologies (11811-023) Gentamicin was purchased from Sigma (G1264)

[0041] Figure 8. Potentiation of G418-induced PTC readthrough by a variety of compounds. Methods: Human HDQ-Pl breast carcinoma cells with a homozygous R213X nonsense mutation in the TP 53 gene were exposed to the indicated concentrations of G418 alone, compound alone, or G418 and compound for 72 h and subjected to p53 western analysis using Santa Cruz DO-1 p53 antibody as described in Baradaran-Heravi et al. (2016) to measure formation of truncated p53 and full-length p53, where full-length p53 is the PTC readthrough product. The increase in p53 signal intensity relative to the amount of truncated p53 found in untreated cells is shown below each lane. Vinculin was used as a loading control. The migration of molecular weight standards in kDa is shown at the left. The results show that a number of compounds can enhance PTC readthrough by the aminoglycoside G418.

[0042] Figure 9. Induction of PTC readthrough by a combination of G418 and 102 in cells derived from patients with rare genetic diseases. Methods: Panels A and B: GM16485 primary fibroblasts derived from a Neuronal Ceroid Lipofuscinosis patient with compound heterozygous nonsense mutations in the TPPl (tripeptidylpeptidase 1) gene (R127X/R208X) were exposed to the indicated concentrations of G418, 102 or G418 and 102 for up to 9 days. Cell lysates were prepared and TPPl enzyme activity was determined as in Lojewski et al. (2014) with modifications: Lysates were diluted 1 :5 in 50 mM sodium acetate pH 4.0 and pre-incubated at 37°C for 1 h. After pre-incubation, 20 μg of total protein from GM16485 lysates or 5 μg of total protein from lysates of fibroblasts from unaffected individuals (WT) was incubated in 150 μΐ of 50 mM sodium acetate pH 4.0 containing a final concentration of 62.5 μΜ Ala-Ala-Phe-7-amido- 4-methylcoumarin for 2 h at 37°C. Fluorescence was measured using a TEC AN Infinite M200 spectrophotometer with an excitation wavelength of 360 nm and an emission wavelength of 460 nm. Assays were carried out under conditions where product formation was linear with respect to protein concentration and time. TPPl activity was expressed relative to the average activity of untreated primary fibroblasts from two unaffected individuals (WT) (Panel A). For panel B, the same cell extracts were analysed for formation of TPPl by automated capillary electrophoresis western analysis using the Abeam ab54685 a- TPPl antibody as in Baradaran-Heravi et al (2016). Extracts from WT fibroblasts were also analysed, using 20% of the amount of protein used for GM16485. Panel C: HSK001 myoblasts derived from a Duchenne Muscular Dystrophy patient with nonsense mutation {DMD: E2035X) were differentiated into myotubes and exposed to the indicated concentrations of G418, 102 or G418 and 102 for 3 days and dystrophin expression level was determined by automated capillary electrophoresis western analysis using Abeam ab 15277 a- dystrophin antibody. Extracts from WT myotubes were also analyzed, using 5% of the amount of protein used for DMD cells. Beta-actin was used as a loading control. Panel D: SD123 fibroblasts from a patient with Schimke Immuno-Osseous Dysplasia, with a homozygous SMARCAL1 nonsense mutation (R17X) were exposed to the indicated concentrations of G418, 102 or G418 and 102 for 6 days and SMARCALl levels were determined by western blotting using an anti SMARCALl antibody provided by Dr. Cornelius Boerkoel (University of British Columbia). Extracts from WT fibroblasts were also analyzed, using 10% of the amount of protein used for SIOD cells. Beta-actin was used as a loading control. [0043] The results show that 102 can enhance the PTC readthrough activity of the aminoglycoside G418 in cells derived from patients with nonsense mutations in three different genes.

[0044] Figure 10. Induction of PTC readthrough by a combination of gentamicin Bl and 102 or 110 in cells derived from a Duchenne Muscular Dystrophy patient. Methods. HSK001 myoblasts derived from a Duchenne Muscular Dystrophy patient with nonsense mutation {DMD: E2035X) were differentiated into myotubes and exposed to the indicated concentrations of gentamicin Bl (Bl), 102, 110, Bl and 102 or Bl and 110 for 3 days and dystrophin expression level was determined by automated capillary electrophoresis western analysis using Abeam ab 15277 a-dystrophin antibody. Extracts from WT myotubes were also analyzed, using 5% of the amount of protein used for DMD cells. The lower band is likely Dp71, a small dystrophin isoform that reacts with the Abeam ab 15277 antibody and is expressed more highly in undifferentiated myoblasts than in differentiated myoblasts. The migration of molecular weight standards in kDa is shown at the left.

[0045] The results show that 102 and 110 can enhance the PTC readthrough activity of the aminoglycoside gentamicin B 1 in cells derived from patients with nonsense mutations in the DMD gene.

DETAILED DESCRIPTION OF THE DISCLOSURE

[0046] The present disclosure relates generally to compositions that are capable of promoting readthrough of premature termination codons (referred to herein as "PTC readthrough compounds", or "PTC-RCs") and methods of using the same. The present invention derives in part from the surprising finding that combinations of certain PTC-RCs exhibit synergistic PTC readthrough activity. Notably, certain PTC-RCs of the invention may appear to lack independent readthrough activity, yet these compounds can synergize with other PTC-RCs to effectively promote readthrough of PTCs. In particular, compounds of general formulas (I), (IV) and (V), as disclosed herein, and compounds of Tables 1, 2, and 5, have been found to synergize with aminoglycosides to promote readthrough of PTCs.

[0047] In one aspect, the invention provides PTC-RCs of general formula (V). In one aspect, the invention provides PTC-RCs selected from Tables 1, 2, and 5. In one embodiment, the invention provides a PTC-RC selected from the group consisting of compounds 2, 5, 12, 13, 15, 16, 34, 55, 103, 104, 105, 109, 110, 204, 205, 207, 208, 210, 211, 212, 213, 214, 215, 216, 221, 225, 226, 227, 228, 229, 230, 231, 302, 303, 305, 306, 308, 309-a, 310, 311, 313-a, 314, 315, 316, 317, 318, 319, 321, 322, 323-a, 324, and 325. In another embodiment, the invention provides a PTC-RC selected from the group consisting of compounds 15, 16, 104, 110, 204, 205, 208, 212, 213, 214, 215, 221, 225, 226, 227, 229, 230, 302, 303, 305, 308, 309-a, 310, 313-a, 314, 316, 317, 319, 321, 322, 323-a, and 324. In another embodiment, the invention provides a PTC-RC selected from the group consisting of compounds 204, 205, 208, 212, 215, 221, 229, 230, 303, 308, 310, 313-a, 314, 317, 319, 321, 322, and 323-a. In another embodiment, the invention provides a PTC- RC selected from the group consisting of compounds 205, 212, 215, 229, 303, 310, 313-a, 314, 317, and 322.

[0048] In one aspect, a PTC-RC of the invention, particularly a PTC-RC of general formulas (I), (IV) or (V), or a PTC-RC of Table 1, 2, or 5, is used in combination with an aminoglycoside in compositions and methods disclosed herein. In certain embodiments, the aminoglycoside is a natural aminoglycoside. In certain embodiments, the aminoglycoside is an aminoglycoside fraction or component. In certain embodiments, the aminoglycoside is a synthetic aminoglycoside. Synthetic aminoglycosides include aminoglycoside analogues exhibiting PTC readthrough activity. In certain embodiments, the aminoglycoside is G418. In certain embodiments, the aminoglycoside is gentamicin. In certain embodiments, the aminoglycoside is gentamicin X2 (X2). In certain embodiments, the aminoglycoside is gentamicin B l (Bl). In certain embodiments, compositions of the invention further comprise a steroid. In certain embodiments, methods of the invention further comprise the use of a steroid.

Definitions [0049] Unless defined otherwise, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this disclosure belongs.

[0050] The term "PTC readthrough compound" and "PTC-RC" are used interchangeably and refer generally to compounds that are capable of promoting readthrough of premature termination codons. Included among PTC-RCs are compounds of general formulas (I), (IV) and (V), and Tables 1, 2, and 5. As noted above, certain PTC-RCs of the invention may appear to lack independent readthrough activity, but are embraced by the present invention due to the fact that such compounds can synergize with other PTC-RCs to effectively promote readthrough of PTCs. Accordingly, included in the present invention are compounds of general formulas (I), (IV) and (V), and compounds of Tables 1, 2, and 5, that appear to lack independent readthrough activity but potentiate the activity of another PTC-RC, preferably an aminoglycoside. As disclosed herein, compounds of general formulas (I), (IV) and (V), and compounds of Tables 1, 2, and 5, have been found to synergize with aminoglycosides to promote readthrough of PTCs. Also included in the term "PTC-RCs" are aminoglycosides, including but not limited to G418, gentamicin, tobramycin, amikacin, netilmicin, paromomycin, hygromycin, neomycin, kanamycin and streptomycin, and aminoglycoside fractions and components, including but not limited to gentamicin Bl (Bl) and gentamicin X2 (X2). It will be understood by one of skill in the art that many aminoglycosides may be produced within a single microorganism, and that a preparation of an aminoglycoside may include several component compounds (e.g., a gentamicin preparation may include gentamicin B 1 and gentamicin X2, among other components). As used herein, "aminoglycoside fraction" and "aminoglycoside component" refer to fractions and components that may be found within aminoglycoside preparations. Also included among PTC-RCs are RTC-13, RTC-14, negamycin, tylosin, GJ71, GJ72 and ataluren and other compounds disclosed in US 2013/0274283. Also included among PTC-RCs are compounds disclosed in International Patent Application Publication Nos. WO 2004/009533; WO 2004/009558; WO 2004/009609; WO 2004/009610; WO 2004/091502; WO 2006/044502; WO 2006/0044503; WO 2006/044505; WO 2006/044456; WO 2006/044682; WO 2008/130370; WO 2012/021707 and WO 2013/142346.

[0051] The term "lower alkyl" refers to a straight chain or branched alkyl group of one to six carbon atoms. For example, "C1-C4 alkyl" is a lower alkyl and refers to a straight chain or branched alkyl group of one to four carbon atoms, with examples including methyl, ethyl, propyl, isopropyl, butyl, isobutyl, secbutyl and tert-butyl (t-butyl). A lower alkyl may be substituted or unsubstituted.

[0052] The term "C1-C4 acyl" refers to the group -C(0)R, where R is substituted or unsubstituted C1-C4 alkyl. [0053] The term "C1-C4 alkoxy" refers to the group -OR, where R is substituted or unsubstituted C1-C4 alkyl.

[0054] The term "carboxy" refers to the group -C(0)OR, where R may be hydrogen, alkyl, substituted alkyl, aryl, substituted aryl, hetaryl, substituted hetaryl and the like. In certain embodiments, R is a substituted or unsubstituted C1-C4 alkyl. [0055] The term "substituted" when used with one of the foregoing terms indicates that the named group is substituted at one or more positions with a group such as hydroxyl, thiol, alkylthiol, halogen, alkyl, alkoxy, amino, amido, azido, -C(0)NHR where R may be substituted or unsubstituted lower alkyl, carboxyl, cycloalkyl, substituted cycloalkyl, heterocycle, cycloheteroalkyl, substituted cycloheteroalkyl, acyl, oxo (so as to form a carbonyl), aryl, substituted aryl, aryloxy, hetaryl, substituted hetaryl, aralkyl, heteroaralkyl, alkyl alkenyl, alkyl alkynyl, alkyl cycloalkyl, alkyl cycloheteroalkyl, nitro, cyano or - R'R" where R' and R" may independently be H, lower alkyl or carboxy.

[0056] The terms "therapy" and "treatment," as used interchangeably herein, refer to an intervention performed with the intention of alleviating the symptoms associated with, preventing the development of, or altering the pathology of a disease, disorder or condition. Thus, the terms therapy and treatment are used in the broadest sense, and in various embodiments include one or more of the prevention (prophylaxis), moderation, reduction, and/or curing of a disease, disorder or condition at various stages. Those in need of therapy/treatment thus may in various embodiments include those already having the disease, disorder or condition as well as those prone to, or at risk of developing, the disease, disorder or condition and those in whom the disease, disorder or condition is to be prevented. [0057] The terms "subj ect" and "patient" as used herein may refer to human, non-human primate, rat, mouse, cow, horse, pig, sheep, goat, dog, cat, etc. The subject may be suspected of having or at risk of having a medical condition associated with a PTC.

[0058] As used herein, a "disease or disorder" may be associated with PTC and may be defined as any medical condition caused in whole or in part by a nonsense codon, which may result in decreased mRNA stability as well as protein truncation resulting in a decrease in full length protein, which in turn may directly or indirectly result in the medical condition.

[0059] As will be appreciated by the artisan of reasonable skill in the art, "full length protein", as it refers to the translation product of an mRNA having a PTC, refers to a translation product that is not truncated at the PTC. As will also be appreciated by the artisan of reasonable skill, a full length protein translated from an mRNA having a PTC, though nearly identical, may not have exactly the same amino acid sequence or exactly the same number of amino acids as a protein translated from an mRNA that is identical in nucleotide sequence except for the amino acid coding sequence in place of a PTC. [0060] Administration or addition of a compound as disclosed herein "in combination with" one or more further therapeutic agents is intended to include simultaneous (concurrent) administration/addition and consecutive administration/addition. For example, administration of a PTC-RC of general formulas (I), (IV) or (V), or of Tables 1, 2, or 5, in combination with an aminoglycoside incldes simultaneous (concurrent) administration and consecutive administration. Consecutive administration/addition is intended to encompass various orders of administration/addition of the therapeutic agent(s) and the disclosed compound(s) to a subject or translation system, with administration/addition of the therapeutic agent(s) and the compound(s) being separated by a defined time period that may be short (for example in the order of minutes) or extended (for example in the order of days or weeks). [0061] The term "effective amount," as used herein, means the amount of a compound or composition that will produce a desired biological response in a subject or system. An "effective amount" of a pharmaceutical composition as described herein includes a therapeutically effective amount or a prophylactically effective amount. A "therapeutically effective amount" refers to an amount effective, at dosages and for periods of time necessary, to achieve the desired therapeutic result, such as reduced tumor size, increased life span or increased life expectancy. A therapeutically effective amount of a compound may vary according to factors such as the disease state, age, sex, and weight of the subject, and the ability of the compound to elicit a desired response in the subject. Dosage regimens may be adjusted to provide the optimum therapeutic response. A therapeutically effective amount is also one in which any toxic or detrimental effects of the compound are outweighed by the therapeutically beneficial effects. A "prophylactically effective amount" refers to an amount effective, at dosages and for periods of time necessary, to achieve the desired prophylactic result (for example, smaller tumors, increased life span, increased life expectancy or prevention of the progression of the medical condition associated with a premature termination codon). Typically, a prophylactic dose is used in subjects prior to or at an earlier stage of disease, so that a prophylactically effective amount may be less than a therapeutically effective amount. For example, an "effective amount" of a PTC-RC may be defined as the amount of the compound that promotes sufficient readthrough of a PTC in a protein coding sequence to produce an increase in full length protein as compared to that produced in the absence of the PTC-RC. In certain embodiments, determination of an effective amount of a compound of general formulas (I), (IV) or (V), or of Tables 1, 2, or 5, will involve administration or addition of a second PTC-RC other than that of general formulas (I), (IV) or (V), or of Tables 1, 2, or 5, preferably an aminoglycoside. In certain embodiments, a compound of general formulas (I), (IV) or (V), or of Tables 1, 2, or 5, and an aminoglycoside will be combined in various amounts in separate test mixtures. In certain embodiments, a compound of general formulas (I), (IV) or (V), or of Tables 1, 2, or 5, and/or an aminoglycoside will be titrated to produce test mixtures of different amounts of one or both agents. In certain embodiments, an effective amount will be determinable from the measurement of protein amount, for example by Western assay, ELISA, or immunohistochemistry. In certain embodiments, an effective amount will be determinable from the measurement of protein activity, for example by an enzymatic assay or protein interaction assay. In certain embodiments, an effective amount will be determinable by observation of a physiological effect on a cell or tissue or organ or subject.

[0062] In certain embodiments, a PTC-RC according to general formulas (I), (IV) or (V), or of Tables 1, 2, or 5, is used in combination with another PTC-RC. An effective amount of the PTC- RC of general formulas (I), (IV) or (V), or of Tables 1, 2, or 5, used in combination with the other PTC-RC may be less than an effective amount of the PTC-RC of general formulas (I), (IV) or (V), or of Tables 1, 2, or 5, when used on its own. Notably, PTC-RCs of general formulas (I), (IV) and (V), and of Tables 1, 2, or 5, may appear to lack independent readthrough activity.

[0063] In certain embodiments, a PTC-RC according to general formulas (I), (IV) or (V), or of Tables 1, 2, or 5, is used in combination with an aminoglycoside. As disclosed herein, compounds of general formulas (I), (IV) and (V), and of Tables 1, 2, or 5, have been found to synergize with aminoglycosides to promote readthrough of PTCs. An effective amount of the PTC-RC of general formulas (I), (IV) or (V), or of Tables 1, 2, or 5, used in combination with an aminoglycoside may be less than an effective amount of the PTC-RC when used on its own. Notably, PTC-RCs of general formulas (I), (IV) and (V), and of Tables 1, 2, or 5, may appear to lack independent readthrough activity. An effective amount of aminoglycoside used in combination with a PTC- RC of general formulas (I), (IV) or (V), or of Tables 1, 2, or 5, may be less than an effective amount of aminoglycoside when used on its own. An effective amount of aminoglycoside used in combination with a PTC-RC of general formulas (I), (IV) or (V), or of Tables 1, 2, or 5, may be less than an amount of aminoglycoside that produces toxicity. [0064] Certain embodiments further comprise the use of a steroid. In certain embodiments, an effective amount of PTC-RC(s) used in combination with a steroid may be less than an effective amount of PTC-RC(s) when used alone. Examples of steroids include: Medroxyprogesterone; Betamethasone; Dexamethasone; Beclomethasone; Budesonide; Clobetasol propionate; Cortisone acetate; Flumethasone Pivalate; Fluticasone Propionate; Hydrocortisone; Methylprednisolone; Paramethasone; Prednisolone; Prednisone; Triamcinolone; Danazol; Fludrocortisone; Mifepristone; Megestrol acetate; and Progesterone. The present PTC-RC according to general formulas (I), (IV) or (V), or of Tables 1, 2, or 5, may be used in combination with an aminoglycoside and a steroid. In certain embodiments, the aminoglycoside is a natural aminoglycoside. In certain embodiments, the aminoglycoside is an aminoglycoside fraction or component. In certain embodiments, the aminoglycoside is a synthetic aminoglycoside. In certain embodiments, the aminoglycoside is G418. In certain embodiments, the aminoglycoside is gentamicin. In certain embodiments, the aminoglycoside is X2. In certain embodiments, the aminoglycoside is Bl . [0065] In certain embodiments, an effective amount of a PTC-RC of general formulas (I), (IV) or (V), or of Tables 1, 2, or 5, preferably in combination with another PTC-RC other than that of general formulas (I), (IV) or (V), or of Tables 1, 2, or 5, preferably an aminoglycoside, produces an amount of full length protein in a cell that is approximately 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 15, 20, 25, 30, 35, 40, 45, 50, 55, 60, 65, 70, 75, 80, 85, 90, 95, or 100% of the amount of full length protein observed in the same cell type expressing normal mRNA lacking a PTC. In certain embodiments, an effective amount of a PTC-RC of general formulas (I), (IV) or (V), or of Tables 1, 2, or 5, preferably in combination with another PTC-RC other than that of general formulas (I), (IV) or (V), or of Tables 1, 2, or 5, preferably an aminoglycoside, produces an amount of full length protein in a cell that is greater than 100% of the amount of full length protein observed in the same cell type expressing normal mRNA lacking a premature termination codon. In certain embodiments, the aminoglycoside is a natural aminoglycoside. In certain embodiments, the aminoglycoside is an aminoglycoside fraction or component. In certain embodiments, the aminoglycoside is a synthetic aminoglycoside. In certain embodiments, the aminoglycoside is G418. In certain embodiments, the aminoglycoside is gentamicin. In certain embodiments, the aminoglycoside is X2. In certain embodiments, the aminoglycoside is Bl .

[0066] The use of the word "a" or "an" when used herein in conjunction with the term "comprising" may mean "one," but it is also consistent with the meaning of "one or more", "at least one" and "one or more than one." [0067] As used herein, the terms "comprising" "having" "including" and "containing," and grammatical variations thereof, are inclusive or open-ended and do not exclude additional, unrecited elements and/or method steps. The term "consisting essentially of when used herein in connection with a composition, use or method, denotes that additional elements and/or method steps may be present, but that these additions do not materially affect the manner in which the recited composition, method or use functions. The term "consisting of when used herein in connection with a composition, use or method, excludes the presence of additional elements and/or method steps. A composition, use or method described herein as comprising certain elements and/or steps may also, in certain embodiments consist essentially of those elements and/or steps, and in other embodiments consist of those elements and/or steps, whether or not these embodiments are specifically referred to. [0068] It is contemplated that any embodiment discussed herein for the disclosed compounds can be implemented with respect to any method or composition of the disclosure, and vice versa. Furthermore, compositions and kits of the disclosure can be used to achieve methods of the disclosure. COMPOUNDS

[0069] In one aspect, the PTC read-through compounds may be compounds of general formula I (Formula I), or salts thereof:

Ar - L - B (I) wherein

Ar is an aryl having general formula II:

wherein:

R¹ to R⁵ are each independently selected from the group consisting of H, halogen, substituted or unsubstituted lower alkyl, substituted or unsubstituted lower alkoxy, substituted or unsubstituted naphthyl, substituted or unsubstituted heteroaryl, and substituted amino; or R¹ and R², taken together with the ring-forming C atoms that they are attached to, form an aryl ring; or R² and R³, taken together with the ring- forming C atoms that they are attached to, form an aryl ring;

L is - (CH₂)n -; n is 1 or 2; and

B is:

wherein:

R^b and R^y are each independently H, OH, F, H₂, HC(0)R¹⁰, N0₂, N₃ or

R⁷ and R⁸ are each independently H, F, CI, CH₃, or C(0)R¹²; R¹⁰ is substituted or unsubstituted lower alkyl; R¹¹ is substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, or C(0)R¹²; R¹⁴ is substituted or unsubstituted lower alkyl; R¹² is OH, OR¹⁴, H₂, NHR¹⁴, or substituted or unsubstituted lower alkyl; R¹⁷ is H, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl; R¹⁸ is H; or R¹⁷ and R¹⁸, taken together with the C atom they are attached to form cyclopropyl,cyclopentyl or cyclohexyl; W is -CH₂- or -C(O)-; X is absent, -CH₂- or - H, and Y is -CH₂- or -0-; or

2) Ar is an aryl having general formula III:

wherein: R , R , R , R and R are each independently selected from the group consisting of H, halo, substituted or unsubstituted lower alkyl, substituted or unsubstituted lower alkoxy, substituted or unsubstituted naphthyl, substituted or unsubstituted heteroaryl, and substituted amino; or R¹⁹ and R²⁰, taken together with the ring-forming C atoms that they are attached to, form an aryl ring; or R²⁰ and R²¹, taken together with the ring-forming C atoms that they are attached to, form an aryl ring;

L is -CH2- R²⁴-, -SO2- R²⁴-, - H-C(0)- H-, -C(0)- H- -CH₂- H-C(0)-, or -CH₂- R²⁶-CH₂-; R²⁴ is H or lower alkyl; R²⁶ is H or lower alkyl;

B is selected from:

R is H, substituted or unsubstituted lower alkyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, or substituted or unsubstituted cycloalkyl; R²⁸ is H, substituted or unsubstituted lower alkyl; R²⁹ is H, substituted or unsubstituted lower alkyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, or substituted or unsubstituted cycloalkyl; R³¹ is H, substituted or unsubstituted lower alkyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, or substituted or unsubstituted cycloalkyl; R³³ and R³⁴ are independently H, halo, substituted or unsubstituted lower alkyl, substituted or unsubstituted lower alkoxy, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl; R³⁵ is H, substituted or unsubstituted lower alkyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, or substituted or unsubstituted cycloalkyl; R³⁶ is H, halo, substituted or unsubstituted lower alkyl, substituted or unsubstituted lower alkoxy, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl; R³⁷, R³⁸, R³⁹, and R⁴⁰ are each independently H, halo, substituted or unsubstituted lower alkyl, substituted or unsubstituted lower alkoxy, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl; R⁴¹ is H, halo, substituted or unsubstituted lower alkyl, substituted or unsubstituted lower alkoxy, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl; R⁴² is H, substituted or unsubstituted lower alkyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, or substituted or unsubstituted cycloalkyl; R⁴³ is H, halo, substituted or unsubstituted lower alkyl, substituted or unsubstituted lower alkoxy, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl; R⁴⁴ is H, halo, substituted or unsubstituted lower alkyl, substituted or unsubstituted lower alkoxy, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl; R⁴⁶ is H, substituted or unsubstituted lower alkyl, substituted or unsubstituted aryl, substituted or

unsubstituted heteroaryl, or substituted or unsubstituted cycloalkyl; R⁴⁷ is H, halo, substituted or unsubstituted lower alkyl, substituted or unsubstituted lower alkoxy, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl; R⁴⁸ is H, substituted or unsubstituted lower alkyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted cycloalkyl, or carboxy; R⁴⁹ is H, halo, substituted or unsubstituted lower alkyl, substituted or unsubstituted lower alkoxy, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl; R⁵⁰ is H, substituted or unsubstituted lower alkyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, or substituted or unsubstituted cycloalkyl; R⁵¹ is H, halo, substituted or unsubstituted lower alkyl, substituted or unsubstituted lower alkoxy, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl; R⁵² is H, substituted or unsubstituted lower alkyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, or substituted or unsubstituted cycloalkyl; R⁵³ is H, halo, substituted or unsubstituted lower alkyl, substituted or unsubstituted lower alkoxy, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl; R⁵⁴ is -C(0)- R⁵⁶R⁵⁷ or -S(0₂)- R⁵⁸R⁵⁹ and R⁵⁵ is H, or R⁵⁴ is H and R⁵⁵ is

-C(0)- R⁵⁶R⁵⁷ or -S(0₂)- R⁵⁸R⁵⁹; R⁵⁶ and R⁵⁷ are each independently H, substituted or unsubstituted lower alkyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, or substituted or unsubstituted cycloalkyl; R⁵⁸ andR⁵⁹ are each independently H, substituted or unsubstituted lower alkyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, or substituted or unsubstituted cycloalkyl; R⁴⁵ is H, substituted or unsubstituted lower alkyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted cycloalkyl, or carboxy; Z is -CH₂-; Z¹ to Z⁶ is -N-, -CH-, or CR³⁴; wherein at least one of Z³ to Z⁶ is -N-; Z⁸ Z i_s -CR³⁷R³⁸-CR³⁹R⁴⁰- or -N=CR⁴¹-; Z⁹ is -0-, - H-, or -CH₂-; Z¹⁰ and Z¹¹ are each independently - R⁴⁵- or -CH₂- wherein at least one of Z¹⁰ and Z¹¹ is -NR⁴⁵-; Z¹² is -CH₂- -NH-, -S-, or -0-; and Z¹³ is -CH- or -N-.

[0070] In one aspect, the PTC read-through compounds may be compounds of general formula I (Formula I), or salts thereof:

Ar - L - B (I) wherein

Ar is an aryl having general formula II (Formula II):

wherein: R¹ to R⁵ are selected from the group consisting of H, halogen, substituted or unsubstituted lower alkyl, substituted or unsubstituted lower alkoxy, substituted or unsubstituted naphthyl, or substituted or unsubstituted heteroaryl, and substituted amino;

L is - (CH₂)n -; n is 1 or 2; and B is:

wherein:

R⁶ and R⁹ are each independently H, OH, F, H₂, HC(0)R¹⁰, N0₂, N₃ or

R⁷ and R⁸ are each independently H, F, CI, CH₃, or C(0)R¹²; R¹⁰ is substituted or unsubstituted lower alkyl; R¹¹ is substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, or C(0)R¹²; R¹⁴ is substituted or unsubstituted lower alkyl; R¹² is OH, OR¹⁴, H₂, NHR¹⁴, substituted or unsubstituted cyclic amines, or substituted or unsubstituted lower alkyl; R¹⁷ is H, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl; R¹⁸ is H; or R¹⁷ and R¹⁸, taken together with the C atom they are attached to form cyclopropyl, cyclopentyl or cyclohexyl; W is - CH₂- or -C(O)-; X is absent, -CH₂- or - H, and Y is -CH₂- or -0-; or

2) Ar is an aryl having general formula III (Formula III):

wherein:

R¹⁹, R²⁰, R²¹, R²² and R²³ are selected from the group consisting of H, halo, substituted or unsubstituted lower alkyl, substituted or unsubstituted lower alkoxy, substituted or unsubstituted naphthyl, substituted or unsubstituted heteroaryl, or substituted amino;

L is -CH2- R²⁴-, -SO2- R²⁴- or - H-C(0)- H-; R²⁴ is H or lower alkyl; B is selected from:

wherein:

R is H, substituted or unsubstituted substituted lower alkyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl; R²⁸ is H, substituted or unsubstituted substituted lower alkyl; R²⁹ is H, substituted or unsubstituted substituted lower alkyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl; R³¹ is H, substituted or unsubstituted substituted lower alkyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl; R³³ and R³⁴ are independently H, halo, substituted or unsubstituted substituted lower alkyl, substituted or unsubstituted substituted lower alkoxy, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl; Z is -CH₂- and Z¹ to Z⁶ is -N-, -CH-, or CR³⁴; wherein at least one of Z³ to Z⁶ are -N-. [0071] In one aspect, the PTC read-through compounds may be compounds of general formula I (Formula I), or salts thereof:

Ar - L - B (I) wherein

Ar is an aryl having general formula II:

wherein:

R¹ to R⁵ are selected from the group consisting of H, halogen, substituted or unsubstituted lower alkyl, substituted or unsubstituted lower alkoxy, substituted or unsubstituted naphthyl, or substituted or unsubstituted heteroaryl, and substituted amino;

L is - (CH₂)n -; n is 1 or 2; and B is:

wherein: R⁶ and R⁹ are each independently H, OH, F, H₂, HC(0)R¹⁰, N0₂, N₃ or

R⁷ and R⁸ are each independently H, F, CI, CH₃, or C(0)R¹²; R¹⁰ is substituted or unsubstituted lower alkyl; R¹¹ is substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, or C(0)R¹²; R¹⁴ is substituted or unsubstituted lower alkyl; R¹² is OH, OR¹⁴, H₂, NHR¹⁴, or substituted or unsubstituted lower alkyl; R¹⁷ is H, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl; R¹⁸ is H; or R¹⁷ and R¹⁸, taken together with the C atom they are attached to form cyclopropyl, cyclopentyl or cyclohexyl; W is -CH₂- or -C(O)-; X is absent, -CH₂- or - H, and Y is -CH₂- or -0-; or

2) Ar is an aryl having general formula III:

wherein:

R , R , R , R and R are selected from the group consisting of H, halo, substituted or unsubstituted lower alkyl, substituted or unsubstituted lower alkoxy, substituted or unsubstituted naphthyl, substituted or unsubstituted heteroaryl, or substituted amino;

wherein:

R is H, substituted or unsubstituted substituted lower alkyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl; R²⁸ is H, substituted or unsubstituted substituted lower alkyl; R²⁹ is H, substituted or unsubstituted substituted lower alkyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl; R³¹ is H, substituted or unsubstituted substituted lower alkyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl; R³³ and R³⁴ are independently H, halo, substituted or unsubstituted substituted lower alkyl, substituted or unsubstituted substituted lower alkoxy, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl; Z is -CH₂- and Z¹ to Z⁶ is -N-, -CH-, or CR³⁴; wherein at least one of Z³ to Z⁶ are -N-.

[0072] In certain embodiments, in compounds of general formula I, R¹ is H, CI, F, Br, CN, OCH3 or CH₃; R² is H, CI, F, CF₃, OCH₃, or NHC(CH₃)₂, or R¹ and R², when taken together with the C atoms they are attached to, form phenyl; R³ is H, CI, F, OH, OCH₃ or CH₃; R⁴ is H, CI, F or CF₃, and R⁵ is H, CI, F, OCH₃ or CH₃; and wherein at least one of R^R⁵ is not H; or a N-containing heteroaryl selected from:

L is - (CH₂)_n -; n is 1 or 2; and B is:

wherein: R^b and R^y are each independently H, OH, F, H₂, HC(0)R^1U, N0₂, N₃ or

R⁷ and R⁸ are each independently H, F, CI, CH₃, or C(0)R¹²; R¹⁰ is CH₃, CH₂OR CH₂OC(0)CH₃ or CH₂N₃; R¹¹ is phenyl or C(0)NH₂; R¹⁵⁰ is H or CH₃;

R¹⁷ is H, (CH₂)₂SCH₃ or phenyl; and R¹⁸ is H; or R¹⁷ and R¹⁸, taken together with the C atom they are attached to, form cyclopropyl, cyclopentyl or cyclohexyl; W is - CH₂- or -C(O)-; X is absent, -CH₂- or - R¹⁵¹-, wherein R¹⁵¹ is H, CH₃ or phenyl, and Y is -CH₂- or -0-; or

2) Ar is an aryl having general formula III:

wherein:

R¹⁹, R²⁰, R²¹, R²² and R²³ are each independently H, CI, F or CF₃; and wherein at least one of R¹⁹-R²³ is not H;

L is -CH₂- R²⁴-, -S0₂- H- or - H-C(0)- H-; R²⁴ is H or CH₃; B is selected from:

wherein: R²⁷, R²⁸ and R²⁹ are each independently H or CH₃; Z is -CH₂- or -C(O)-, and Z² is - N- or -CH.

[0073] In certain embodiments, in compounds of general formula I, Ar is an aryl having general formula (II), and R¹ is H, CI, F or CN; R² is H, CI, F, CF₃ or OCH₃; R³ and R⁵ are each independently H, CI or F, and R⁴ is H, CI, F or CF₃.

[0074] In certain embodiments, Ar is an aryl having general formula (II), and R¹ is H, CI, F or CN, wherein if R¹ is F, R⁴ is F or CF₃; R² is H, CI, F, CF₃ or OCH₃, wherein if R² is F, at least one of R¹, R⁴ and R⁵ is not H or F, or R³ is F; or R¹ and R², when taken together with the C atoms they are attached to, form phenyl; R³ is H, F or CI; R⁴ is H, CI, F or CF₃, and R⁵ is H, CI or F, wherein if R⁵ is F, at least one of R^l-R⁴ is CI.

[0075] In certain embodiments, in compounds of general formula I, Ar is an aryl having general formula (II), and at least one, but not more than three, of R^R⁵ are not H.

[0076] In certain embodiments, in compounds of general formula I, Ar is an aryl having general formula (II), and at least two of R^R⁵ are not H. [0077] In certain embodiments, in compounds of general formula I, Ar is an aryl having general formula (II), and when any one of R^R⁵ is F, at least one other of R^R⁵ is not H.

[0078] In certain embodiments, in compounds of general formula I, Ar is an aryl having general formula (II), and when R³ is CI, at least one other of R¹, R², R⁴ and R⁵ is not H.

[0079] In certain embodiments, in compounds of general formula I, Ar is an aryl having general formula (II), and when both R¹ and R² are not H, one of R³-R⁵ is also not H.

[0080] In certain embodiments, in compounds of general formula I, Ar is an aryl having general formula (II), and when R² is OCH₃, n is 2.

[0081] In certain embodiments, in compounds of general formula I, Ar is an aryl having general formula (II), and R¹, R², R³, R⁴ and R⁵ are each independently H, CI, F or CF₃. [0082] In certain embodiments, in compounds of general formula I, Ar is an aryl having general formula (II), R¹, R², R³, R⁴ and R⁵ are each independently H, CI, F or CF₃, and at least two of R¹- R⁵ are not H.

[0083] In certain embodiments, in compounds of general formula I, Ar is an aryl having general formula II,

B is:

and R⁷ and R⁸ are each independently H, F, CI or CH₃.

[0084] In certain embodiments, in compounds of general formula I, Ar is an aryl having general formula III, and R¹⁹ is H, CI or F; R²⁰ is H, CI or CF₃; R²¹ and R²² are each H, and R²³ is H, CI or F.

[0085] In certain embodiments, in compounds of general formula I, Ar is an aryl having general formula III, and at least two of R¹⁹-R²³ are not H.

[0086] In certain embodiments, in compounds of general formula I, Ar is an aryl having general formula III, and L is -CH₂- R²⁴- or -S0₂- H-.

[0087] In certain embodiments, compounds of general formula I comprise compounds of general formula IV (Formula IV), and salts thereof:

wherein

R⁵⁰, R⁶¹, R⁶², R⁶³, and R⁶⁴ are each independently H, CI, F or CF₃, wherein at least one of R⁶⁰-R⁶⁴ is not H, and

L² is -CH₂- or -CH2CH2-, and B² is

wherein:

R¹¹⁵ and R^m are each independently H, NHC(0)R

N₃ or NH₂;

R¹¹⁶ and R¹¹⁷ are each independently H, CI or F; R¹¹⁹ is CH₃, CH2OR¹²¹, CH₂OC(0)CH₃ or CH₂N₃; R¹²⁰ is phenyl or C(0) H₂; R¹²¹ is H or CH₃; or b) L² is -CH2- R¹²²-; R¹²² is is H or lower alkyl, and B² 2 i ;s_c

wherein:

R¹²³, R¹²⁴ and R¹²⁵ are each independently H or CH₃; Z^lb is CH₂ or C=0, and Z¹⁷ is N or CH.

[0088] In certain emodiments, the compound of general formula I, or salt thereof, is a compound of general formula IV, or a salt thereof:

wherein

R⁶⁰, R⁶¹, R⁶², R⁶³, and R⁶⁴ are each independently are each independently H, CI, I, F or CF₃, wherein at least one of R⁶⁰-R⁶⁴ is not H, and

L² is -CH₂- and B² is

wherein:

R¹¹⁵ and R¹¹⁸ are each independently H,

N₃ or H₂; R¹¹⁶ and R¹¹⁷ are each independently H, CI or F; R¹¹⁹ is CH₃, CH₂OR

CH₂OC(0)CH₃ or CH₂N₃; R¹²⁰ is phenyl or C(0) H₂; or b) L² is -CH₂- R¹²²-; R¹²² is H or lower alkyl, and B² is

wherein:

R , R and R are each independently H or CH₃; Z¹⁶ is CH₂ or C=0, and Z¹⁷ is N or CH.

[0089] Combinations of any of the foregoing embodiments described for compounds of general formula IV are also contemplated and each combination forms a separate embodiment for the purposes of the present disclosure.

[0090] In certain embodiments, the compounds of general formula I are selected from the compounds shown in Tables 1 and 2, and salts thereof:

[0091] In another aspect, the PTC read-through compounds may be compounds of general formula IA (Formula IA), or a salt thereof:

wherein:

R¹, R², R³, R⁴ and R⁵ are each independently H, CI, F, I, CF₃ or C1-C4 alkoxy, wherein at least one of R^R⁵ is not H;

L is -(CH₂)_n-; n is 1 or 2;

B is:

wherein: R⁶ and R⁹ are each independently H, OH, CI, F, C1-C4 alkyl, H₂, HC(0)R¹⁰, N0₂,

N3 or

; R⁷ and R⁸ are each independently H, F, CI, CH₃, or C(0)R¹²;

R¹⁰ is C1-C4 alkyl, CH₂OR¹²⁶, CH₂OC(0)R¹²⁶ or (CH₂)_mN₃; R¹¹ is phenyl or C(0) H₂; R¹⁴ is substituted or unsubstituted lower alkyl; R¹² is OH, OR¹⁴, NH₂, HR¹⁴, substituted or unsubstituted cyclic amines, or substituted or unsubstituted lower alkyl; R¹²⁷ is H or C1-4 alkyl; R¹²⁸ is H or Me; R¹²⁹ is H, substituted or unsubstituted substituted lower alkyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl; R¹²⁶ is C1-C4 alkyl; m is 1, 2, 3 or 4; W is -C(O)-, and Z¹⁸ is

-CH₂- or -C(O)-. [0092] In certain embodiments, in compounds of general formula IA, R¹, R², R³, R⁴ and R⁵ are each independently H, CI, F, CF₃ or OCH₃.

[0093] In certain embodiments, in compounds of general formula IA, R¹, R², R³, R⁴ and R⁵ are each independently H, CI or CF₃.

[0094] In certain embodiments, in compounds of general formula IA, at least two of R^R⁵ are not H.

[0095] In certain embodiments, in compounds of general formula IA, two of R^R⁵ are each CI or CF₃, and the remaining R^R⁵ are H.

[0096] In certain embodiments, in compounds of general formula IA, L is -CH₂-.

[0097] In certain embodiments, in compounds of general formula IA, R⁶, R⁷, R⁸ and R⁹ are each

independently H, CI, F, H₂, HC(0)R¹⁰, N₃ or

[0098] In certain embodiments, in compounds of general formula IA, R⁷ is H.

[0099] In certain embodiments, in compounds of general formula IA, R¹²⁷ and R¹²⁸ and H or Ci- C₄ alkyl. [00100] In certain embodiments, in compounds of general formula IA, R and R are each H.

[00101] In certain embodiments, in compounds of general formula 1 A, R¹²⁷ is H or C1-C4 alkyl.

[00102] In certain embodiments, in compounds of general formula 1 A, R¹²⁷ is H or CH3.

[00103] In certain embodiments, in compounds of general formula IA, W is -C(O)-. [00104] In certain embodiments, compounds of general formula IA are selected from compounds 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 19, 20, 21, 22, 23, 24, 26, 27, 28, 29, 30, 35, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 60, 61, 64, 65, 66, 71, 72, 73, 74, 75, 76, 77, 78, 79, 80, 81, 82, 83, 84, 85, 86, 87, 88, 89, 90, 91, 92, 93, 94, 100, 101, 102, 103, 104, 106, 107, 108, 109, 110, 113, 114 and 115, and salts thereof. [00105] In certain embodiments, compounds of general formula IA are selected from compounds 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 19, 20, 21, 22, 23, 24, 26, 27, 28, 29, 30, 35, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 60, 61, 64, 65, 66, 71, 72, 73, 74, 75, 76, 77, 78, 79, 102, 103, 104, 106, 107, 108, 109, 110, 113, 114 and 115, and salts thereof

[00106] In certain embodiments, the compounds of general formula IA are selected from compounds 1, 2, 3, 4, 5, 6, 7, 8, 9, 11, 12, 13, 14, 15, 16, 17, 41, 102, 103, 104, 106, 107, 109 and 110, and salts thereof.

[00107] In another aspect, the invention provides compounds of general formula I, or salts thereof:

Ar - L - B (I) wherein

Ar is an aryl having general formula II:

wherein:

R¹ is H, CI, F, Br, CN, OCH₃ or CH₃; R² is H, CI, F, CF₃, OCH₃, or HC(CH₃)₂, or R¹ and R², when taken together with the C atoms they are attached to, form phenyl; R³ is H, CI, F, OH, OCH₃ or CH₃; R⁴ is H, CI, F or CF₃, and R⁵ is H, CI, F, OCH₃ or CH₃; and wherein at least one of R^R⁵ is not H; or a N-containing heteroaryl selected from:

L is - (CH₂)n -; n is 1 or 2; and B is:

wherein:

R and R are each independently H, OH, F, NH₂, NHC(0)R²⁸⁶, N0₂, N₃ or

R²⁸³ and R²⁸⁴ are each independently H, F, CI, CH₃, or C(0)R²⁸⁹; R²⁸⁶ is CH₃, CH₂OR²⁸⁸, CH₂OC(0)CH₃ or CH₂N₃; R²⁸⁷ is phenyl or C(0)NH₂; R²⁸⁸ is H or CH₃;

R is H, (CH₂)₂SCH₃ or phenyl; and R is H; or R and R , taken together with the C atom they are attached to, form cyclopropyl, cyclopentyl or cyclohexyl; W² is - CH₂- or -C(O)-; X¹ is absent, -CH₂- or - R²⁹²-, wherein R²⁹² is H, CH₃ or phenyl, and Y¹ is -CH₂- or -0-; or

2) Ar is an aryl having general formula III:

wherein:

R , R , R , R and R are each independently H, CI, I, F or CF₃; and wherein at least one of R¹⁹-R²³ is not H; L is -CH₂- R²⁹³-, -S0₂- H- or - H-C(0)- H-; R²⁹³ is H or CH₃; B is selected from:

wherein:

R²⁹⁴, R²⁹⁵ and R²⁹⁶ are each independently H or CH₃; Z¹⁹ is -CH₂- or -C(O)-, and Z²⁰ is -N- or -CH-; with the proviso that the compound is not 1, 3, 4, 6, 8, 10, 18, 20, 21, 25, 26, 30, 31, 32, 33, 35, 37, 39, 49, 50, 51, 52, 53, 54, 59, 60, 61, 62, 63, 65, 66, 71, 72, 73, 75, 80, 82, 83, 84, 88, 89, 90, 91, 92, 94, 95, 101, 102, 108, 111, 112, 113, 114, 115 or 117.

[00108] In certain embodiments, compounds of general formula I are selected from compounds 2, 5, 7, 9, 12, 13, 15, 16, 41, 107, and 110, and salts thereof. [00109] In another aspect, the invention provides compounds that are selected from compounds 2, 5, 7, 0, 11, 12, 13, 14, 15, 16, 17, 19, 21, 22, 23, 24, 27, 28, 29, 34, 36, 38, 40, 41, 42, 43, 44, 45, 46, 47, 48, 55, 56, 57, 58, 64, 67, 68, 69, 70, 74, 76, 77, 78, 79, 81, 85, 86, 93, 96, 97, 98, 99, 100, 118, 103, 104, 105, 107, 109, 110, 116, 204, 205, 207, 208, 210, 211, 212, 213, 214, 215, 2216, 217, 218, 219, 220, 221, 222, 225, 226, 227, 228, 229, 230, 231, 300, 301, 302, 303, 304, 305, 306, 307, 308, 309-a, 310, 311, 312, 313-a, 314, 315, 316, 317, 318, 319, 320, 321, 322, 323- a, 324, and 325, and salts thereof.

[00110] In one aspect, the PTC readthrough compounds may be compounds of general formula I (Formula I), or salts thereof:

Ar - L - B (I) wherein

Ar is an aryl having general formula II:

wherein:

R¹, R², R³, R⁴ and R⁵ are each independently selected from the group consisting of H, OH, CN, halogen, substituted or unsubstituted lower alkyl, substituted or unsubstituted lower alkoxy, substituted or unsubstituted naphthyl, substituted or unsubstituted heteroaryl, and substituted amino; or R¹ and R², taken together with the ring-forming C atoms that they are attached to, form an aryl ring; or R² and R³, taken together with the ring-forming C atoms that they are attached to, form an aryl ring; or

Ar is an N-containing heteroaryl selected from the group consisting of:

L is - (CH₂)n -; n is 1 or 2; and B is:

wherein:

R⁶ and R⁹ are each independently H, OH, F, CI, substituted or unsubstituted lower alkyl, H₂, HC(0)R¹⁰, N0₂, N₃

;

R⁷ and R⁸ are each independently H, F, CI, unsubstituted lower alkyl, or C(0)R¹²; R¹⁰ is substituted or unsubstituted lower alkyl; R¹¹ is substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, or C(0)R¹³; R¹² and R¹³ are each independently OH, OR¹⁴, H₂, HR¹⁵, substituted or unsubstituted lower alkyl or substituted or unsubstituted heterocycloalkyl; R¹⁴ and R¹⁵ are each independently substituted or unsubstituted lower alkyl; X is -CH₂-, - H- or - R¹⁶-; R¹⁶ is substituted or unsubstituted aryl; R¹⁷ is H, substituted or unsubstituted lower alkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl; R¹⁸ is H; or R¹⁷ and R¹⁸, taken together with the C atom they are attached to form cyclopropyl, cyclopentyl or cyclohexyl; or X and R¹⁷, taken together with the C atom that R¹⁷ is attached to form cyclopropyl; W is -CH₂- or -C(O)-; and Y is -CH₂- or -0-; or Ar is an aryl having general formula III:

wherein:

Ar is an N-containing heteroaryl selected from the group consisting of:

L is -CH2-NR²⁴-, -S(0)₂-NR²⁵-, -NH-C(0)-NH-, -C(0)-NH- -CH₂-NH-C(0)-, or -CH₂-NR²⁶-CH₂-; R²⁴ and R²⁵ are each independently H or unsubstituted lower alkyl; R²⁶ is H or unsubstituted lower alkyl; B is:

wherein:

R is H, substituted or unsubstituted lower alkyl, substituted or unsubstituted aryl, substituted or unsubstituted arylalkyl, substituted or unsubstituted heteroaryl, substituted or unsubstituted cycloalkyl or carboxy; R²⁸, R²⁸ and R^28" are each independently H, halogen, substituted or unsubstituted lower alkyl, substituted or unsubstituted lower alkoxy, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl; R²⁹ is H, substituted or unsubstituted lower alkyl, substituted or unsubstituted aryl, substituted or unsubstituted arylalkyl, substituted or unsubstituted heteroaryl, substituted or unsubstituted cycloalkyl or carboxy; R³⁰, R^30' and R^30" are each independently H, halogen, substituted or unsubstituted lower alkyl, substituted or unsubstituted lower alkoxy, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl; R³¹ is H, substituted or unsubstituted lower alkyl, substituted or unsubstituted aryl, substituted or unsubstituted arylalkyl, substituted or unsubstituted heteroaryl, substituted or unsubstituted cycloalkyl or carboxy; R³², R³² and R³² are each independently H, halogen, substituted or unsubstituted lower alkyl, substituted or unsubstituted lower alkoxy, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl; R³³, R^33' and R³³ are each independently H, halogen, substituted or unsubstituted lower alkyl, substituted or unsubstituted lower alkoxy, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl; each R³⁴ is independently H, halogen, substituted or unsubstituted lower alkyl, substituted or unsubstituted lower alkoxy, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl; R³⁵ is H, substituted or unsubstituted lower alkyl, substituted or unsubstituted aryl, substituted or unsubstituted arylalkyl, substituted or unsubstituted heteroaryl, substituted or unsubstituted cycloalkyl or carboxy; R³⁶, R³⁶ and R^36" are each independently H, halogen, substituted or unsubstituted lower alkyl, substituted or unsubstituted lower alkoxy, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl; R³⁷, R³⁸, R³⁹, and R⁴⁰ are each independently H, halogen, substituted or unsubstituted lower alkyl, substituted or unsubstituted lower alkoxy, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl; R⁴¹ is H, halogen, substituted or unsubstituted lower alkyl, substituted or unsubstituted lower alkoxy, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl; R⁴² is H, substituted or unsubstituted lower alkyl, substituted or unsubstituted aryl, substituted or unsubstituted arylalkyl, substituted or unsubstituted heteroaryl, substituted or unsubstituted cycloalkyl or carboxy; R⁴³, R⁴³ and R^43" are each independently H, halogen, substituted or unsubstituted lower alkyl, substituted or unsubstituted lower alkoxy, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl; R⁴⁴, R^44' and R^44" are each independently H, halogen, substituted or unsubstituted lower alkyl, substituted or unsubstituted lower alkoxy, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl; R⁴⁵ is H, substituted or unsubstituted lower alkyl, substituted or unsubstituted aryl, substituted or unsubstituted arylalkyl, substituted or unsubstituted heteroaryl, substituted or unsubstituted cycloalkyl or carboxy; R⁴⁶ is H, substituted or unsubstituted lower alkyl, substituted or unsubstituted aryl, substituted or unsubstituted arylalkyl, substituted or unsubstituted heteroaryl, substituted or unsubstituted cycloalkyl or carboxy; R , R and R^47" are each independently H, halogen, substituted or unsubstituted lower alkyl, substituted or unsubstituted lower alkoxy, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl; R⁴⁸ is H, substituted or unsubstituted lower alkyl, substituted or unsubstituted aryl, substituted or unsubstituted arylalkyl, substituted or unsubstituted heteroaryl, substituted or unsubstituted cycloalkyl or carboxy; R⁴⁹, R⁴⁹ and R^49" are each independently H, halogen, substituted or unsubstituted lower alkyl, substituted or unsubstituted lower alkoxy, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl; R⁵⁰ is H, substituted or unsubstituted lower alkyl, substituted or unsubstituted aryl, substituted or unsubstituted arylalkyl, substituted or unsubstituted heteroaryl, substituted or unsubstituted cycloalkyl or carboxy; R⁵¹, R⁵¹ , R⁵¹ and R^51'" are each independently H, halogen, substituted or unsubstituted lower alkyl, substituted or unsubstituted lower alkoxy, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl; R⁵² is H, substituted or unsubstituted lower alkyl, substituted or unsubstituted aryl, substituted or unsubstituted arylalkyl, substituted or unsubstituted heteroaryl, substituted or unsubstituted cycloalkyl or carboxy; R⁵³, R⁵³ , R⁵³ and R⁵³ are each independently H, halogen, substituted or unsubstituted lower alkyl, substituted or unsubstituted lower alkoxy, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl; R⁵⁴ is -C(0)- R⁵⁶R⁵⁷ or -S(0)₂- R⁵⁸R⁵⁹ and R⁵⁵ is H, or R⁵⁴ is H and R⁵⁵ is -C(O)- R⁵⁶R⁵⁷ or -S(0)₂- R⁵⁸R⁵⁹; R⁵⁶ and R⁵⁷ are each independently H, substituted or unsubstituted lower alkyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, or substituted or unsubstituted cycloalkyl; R⁵⁸ and R⁵⁹ are each independently H, substituted or unsubstituted lower alkyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, or substituted or unsubstituted cycloalkyl;

[00111] In certain embodiments, compounds of general formula I comprise compounds of general formula IV (Formula IV), and salts thereof:

wherein

R⁶⁰, R⁶¹, R⁶², R⁶³, and R⁶⁴ are each independently H, CI, I, F, Br, CF₃ or substituted or unsubstituted lower alkoxy, wherein at least one of R⁶⁰, R⁶¹, R⁶², R⁶³, and R⁶⁴ is not H; or R⁶⁰ and R⁶¹, taken together with the ring-forming C atoms that they are attached to, form an aryl ring, and R⁶², R⁶³, and R⁶⁴ are each independently H, CI, I, F, Br, CF₃ or substituted or unsubstituted lower alkoxy; and

L² is -CH₂- or -(CH₂)₂-, and B² is:

wherein: CI, F, unsubstituted lower alkyl, NH₂,

R and R are each independently H, F, CI, unsubstituted lower alkyl, or C(0)R ; R⁶⁹ is unsubstituted lower alkyl, CH₂OR⁷¹, CH₂OC(0)R¹³¹ or (CH₂)_tN₃; R⁷⁰ is phenyl or C(0)NH₂; R⁷¹ is H or unsubstituted lower alkyl; R¹³⁰ is OH, OR¹³², H₂, HR¹³³, substituted or unsubstituted lower alkyl or substituted or unsubstituted heterocycloalkyl; R¹³¹ is unsubstituted lower alkyl; R¹³² and R¹³³ are each independently substituted or unsubstituted lower alkyl; t is 1, 2, 3 or 4; and W¹ is - CH₂- or -C(O)-; or

L² is -CH₂- R⁷²-; R⁷² is H or unsubstituted lower alkyl, and B² is:

R¹¹¹, R¹¹³ and R¹³⁶ are each independently H, substituted or unsubstituted arylalkyl, substituted or unsubstituted lower alkyl, substituted or unsubstituted cycloalkyl or carboxy; R⁷⁴, R^74', R^74", R⁷⁶, R^76', R^76", R⁷⁸, R^78', R^78", R⁸⁰, R^80', R^80", R⁸², R^82', R^82", π84 π84' π84" π86 π86' π 86" π 88 π88' π88" π90 π90' π90" π92 π92' π92" π93 π93'

IV , IV , IV , IV , IV , IV , IV , IV , IV , IV , IV , IV , IV , IV , IV , IV , IV ,

ΙΛ τ>93" τ>95 τ>95' τ>95" τ>98 τ>98' τ>98" π 100 π 100' π 100" π 102 π 102' π 102" π 104 π 104' π 104"

1U IV , IV , IV , IV , IV , IV , IV , IV , IV , IV , IV , IV , IV , IV , IV , IV , π106 π106' π 106" π 108 π 108' π 108" πΐΐθ πΐΐθ' πΐΐθ" π112 π112' π112" π114 π114' π114"

IV , IV , IV , IV , IV , IV , IV , IV , IV , IV , IV , IV , IV , IV , IV ,

R¹³⁷, R¹³⁸, R¹³⁹, R^139', and R^139" are each independently H, halogen or substituted or unsubstituted lower alkyl; and R⁹⁷ is H, halogen, or substituted or unsubstituted lower alkyl.

15 [00112] In certain embodiments, in compounds of general formula IV, R⁶⁰, R⁶¹, R⁶², R⁶³, and R⁶⁴ are each independently H, CI, I, F, Br, CF3 or substituted or unsubstituted lower alkoxy, wherein at least one of R⁶⁰, R⁶¹, R⁶², R⁶³, and R⁶⁴ is not H. [00113] In certain embodiments, in compounds of general formula IV, R⁶⁰ and R⁶¹, taken together with the ring-forming C atoms that they are attached to, form an aryl ring, and R⁶², R⁶³, and R⁶⁴ are each independently H, CI, I, F, Br, CF₃ or substituted or unsubstituted lower alkoxy.

[00114] In certain embodiments, in compounds of general formula IV, R⁶⁰ and R⁶¹, taken together with the ring-forming C atoms that they are attached to, form a phenyl ring, and R⁶², R⁶³, and R⁶⁴ are each H.

[00115] In certain embodiments, in compounds of general formula IV, R⁶⁰, R⁶¹, R⁶², R⁶³, and R⁶⁴ are each independently H, CI, I, F, Br or CF₃.

[00116] In certain embodiments, in compounds of general formula IV, at least two of R⁶⁰-R⁶⁴ are not H.

[00117] In certain embodiments, in compounds of general formula IV, two of R⁶⁰-R⁶⁴ are each CI, I, F or CF₃, and the remaining R⁶⁰-R⁶⁴ are H.

[00118] In certain embodiments, in compounds of general formula IV, two of R⁶⁰-R⁶⁴ are each CI, F or CF₃, and the remaining R⁶⁰-R⁶⁴ are H. [00119] In certain embodiments, in compounds of general formula IV, two of R⁶⁰-R⁶⁴ are each CI or CF₃, and the remaining R⁶⁰-R⁶⁴ are H.

[00120] In certain embodiments, in compounds of general formula IV, two of R⁶⁰-R⁶⁴ are each CI, and the remaining R⁶⁰-R⁶⁴ are H.

[00121] In certain embodiments, in compounds of general formula IV, R⁶⁰ is CI, I, F or CF₃; R⁶³ and R⁶⁴ are each independently H, CI, I, F or CF₃, wherein at least one of R⁶³ and R⁶⁴ is not H; and R⁶¹ and R⁶² are each H.

[00122] In certain embodiments, in compounds of general formula TV, R⁶⁰ is CI, F or CF₃; R⁶³ and R⁶⁴ are each independently H, CI, F or CF₃, wherein at least one of R⁶³ and R⁶⁴ is not H; and R⁶¹ and R⁶² are each H. [00123] In certain embodiments, in compounds of general formula IV, R is CI or CF₃; R and R⁶⁴ are each independently H, CI or CF₃, wherein at least one of R⁶³ and R⁶⁴ is not H; and R⁶¹ and R⁶² are each H.

[00124] In certain embodiments, in compounds of general formula IV, R⁶⁰ and R⁶³ are each independently CI, I, F or CF₃; and R⁶¹, R⁶² and R⁶⁴ are each H.

[00125] In certain embodiments, in compounds of general formula IV, R⁶⁰ and R⁶³ are each independently CI, F or CF₃; and R⁶¹, R⁶² and R⁶⁴ are each H.

[00126] In certain embodiments, in compounds of general formula IV, R⁶⁰ and R⁶³ are each independently CI or CF₃; and R⁶¹, R⁶² and R⁶⁴ are each H. [00127] In certain embodiments, in compounds of general formula IV, R⁶⁰ and R⁶³ are each CI; and R⁶¹, R⁶² and R⁶⁴ are each H.

[00128] In certain embodiments, in compounds of general formula IV, R⁶⁰ and R⁶³ are each CF₃; and R⁶¹, R⁶² and R⁶⁴ are each H.

[00129] In certain embodiments, in compounds of general formula IV, R⁶⁰ and R⁶⁴ are each independently CI, I, F or CF₃; and R⁶¹, R⁶² and R⁶³ are each H.

[00130] In certain embodiments, in compounds of general formula IV, R⁶⁰ and R⁶⁴ are each independently CI, F or CF₃; and R⁶¹, R⁶² and R⁶³ are each H.

[00131] In certain embodiments, in compounds of general formula IV, R⁶⁰ and R⁶⁴ are each independently CI or CF₃; and R⁶¹, R⁶² and R⁶³ are each H. [00132] In certain embodiments, in compounds of general formula IV, R⁶⁰ is CI and R⁶⁴ is CF₃; and R⁶¹, R⁶² and R⁶³ are each H.

[00133] In certain embodiments, in compounds of general formula IV, R⁶⁰ and R⁶⁴ are each CI; and R⁶¹, R⁶² and R⁶³ are each H.

[00134] In certain embodiments, in compounds of general formula IV, R⁶⁰ and R⁶⁴ are each CF₃; and R⁶¹, R⁶² and R⁶³ are each H. [00135] In certain embodiments, in compounds of general formula IV, L² is -CH₂-.

[00136] In certain embodiments, in compounds of general formula IV, L² is -(CH₂)₂-.

[00137] In certain embodiments, in compounds of general formula IV, L² is -CH2- R⁷²-; and R⁷² is H or unsubstituted lower alkyl.

[00138] In certain embodiments, in compounds of general formula IV, L² is -CH2- R⁷²-; and R⁷² is H or Ci-4 alkyl.

[00139] In certain embodiments, in compounds of general formula IV, L² is -CH2- R⁷²-; and R⁷² is H or Ci-3 alkyl.

[00140] In certain embodiments, in compounds of general formula IV, L² is -CH2- R⁷²-; and R⁷² is H or Ci-2 alkyl.

[00141] In certain embodiments, in compounds of general formula IV, L² is -CH2- R⁷²-; and R⁷² is H or CH₃.

[00142] In certain embodiments, in compounds of general formula IV, L² is -CH2- R⁷²-; and R⁷² is unsubstituted lower alkyl.

[00143] In certain embodiments, in compounds of general formula IV, L² is -CH2- R⁷²-; and R⁷² is Ci-4 alkyl.

[00144] In certain embodiments, in compounds of general formula IV, L² is -CH2- R⁷²-; and R⁷² is Ci_-3 alkyl.

[00145] In certain embodiments, in compounds of general formula IV, L² is -CH2- R⁷²-; and R⁷² is Ci-2 alkyl.

[00146] In certain embodiments, in compounds of general formula IV, L² is -CH2- R⁷²-; and R⁷² is CH₃.

[00147] In certain embodiments, in compounds of general formula IV, L² is -CH2- R⁷²-; and R⁷² is H. 48] In certain embodiments, in compounds of general formula IV, B² is

wherein R⁶⁵ is HC(0)R⁶⁹; R⁶⁶, R⁶⁷ and R⁶⁸ are each H; R⁶⁹ is CH₃, CH₂OR⁷¹, CH₂OC(0)R¹³¹ or CH₂N₃; R⁷¹ is H or unsubstituted lower alkyl; R¹³¹ is CM alkyl; and W¹ is -C(O)-;

R , R , R , R and R are each independently H or substituted or unsubstituted lower alkyl; and R⁷⁴, R^74', R^74", R⁷⁶, R^76', R^76", R⁸², R^82', R^82", R⁸⁴, R^84', R^84", R⁸⁶, R^86', τ> 86" T

, IV> 93 τ

, IV> 93' τ

, IV> 93" τ

, IV> 95 τ

, IV> 95' τ

, IV> 95" π

, IV 100 π

, IV 100' π

, IV 100" π

, IV 108 π

, IV 108' π

, IV 108" πΐΐθ πΐΐθ' πΐΐθ' , IV , IV , IV

R¹³⁷, R¹³⁸, R¹³⁹, R^139', and R^139" are each independently H, halogen or unsubstituted lower alkyl. In certain embodiments, in compounds of general formula IV, R⁷³, R⁷⁵, R⁸¹, R⁸³, R⁸⁵, R⁹⁴, R", R¹⁰⁷, R¹⁰⁹ and R¹³⁶ are each independently H, unsubstituted lower alkyl or lower alkyl substituted with one or more substituents independently selected from the group consisting of OH, C3-6 cycloalkyl, 5- to 10-membered heterocycloalkyl, C(0)OH, C(0)OR¹⁴⁰, H₂, R¹⁴¹R¹⁴², HC(0)OR¹⁴³, Ci_-6 alkoxy,

CN, C(0) HR¹⁴⁴ and CO H₂; wherein R¹⁴⁰, R¹⁴¹, R¹⁴², and R¹⁴³ are each

independently unsubstituted Ci_-6 alkyl; R¹⁴⁴ is Ci_-6 alkyl optionally substituted with one or more substituents independently selected from the group consisting of

R¹⁴⁵R¹⁴⁶ and OH; and R¹⁴⁵ and R¹⁴⁶ are each independently unsubstituted Ci-6 alkyl. In certain embodiments, in compounds of general formula IV, R⁷³, R⁷⁵, R⁸¹, R⁸³, R⁸⁵,

R⁹⁴, R⁹⁹, R¹⁰⁷, R¹⁰⁹ and R¹³⁶ are each independently unsubstituted lower alkyl or lower alkyl substituted with one or more substituents independently selected from the group consisting of OH, C3-6 cycloalkyl, 5- to 10-membered heterocycloalkyl, C(0)OH, C(0)OR¹⁴⁰, H₂, R¹⁴¹R¹⁴², HC(0)OR¹⁴³, Ci_-6 alkoxy, CN, C(0)NHR¹⁴⁴ and CONH₂; wherein R¹⁴⁰, R¹⁴¹, R¹⁴², and R¹⁴³ are each independently unsubstituted Ci_-6 alkyl; R¹⁴⁴ is Ci_-6 alkyl optionally substituted with one or more substituents independently selected from the group consisting of NR¹⁴⁵R¹⁴⁶ and OH; and R¹⁴⁵ and R¹⁴⁶ are each independently unsubstituted Ci_-6 alkyl. In certain embodiments, in compounds of general formula IV, R⁷³, R⁷⁵, R⁸¹, R⁸³, R⁸⁵, R⁹⁴, R⁹⁹, R¹⁰⁷, R¹⁰⁹ and R¹³⁶ are each independently unsubstituted lower alkyl; or unsubstituted Ci_-5 alkyl; or unsubstituted Ci-4 alkyl; or unsubstituted Ci_-3 alkyl; or unsubstituted Ci_-2 alkyl; or CH₃; or H. In certain embodiments, in compounds of general formula IV, R⁷⁴, R⁷⁴ , π 74" π 76 π 76' π 76" π 82 π 82' π 82" π 84 π 84' π 84" π 86 π 86' π 86" π 93 π 93' π 93" π 95 τ> 95' τ> 95" π ΙΟΟ π 100' π 100" π 108 π 108' π 108" π ΐ ΐθ π ΐΐθ' π ΐ ΐθ" π 137 π 138 π 139 π 139' and R^139" are each independently H or unsubstituted lower alkyl; or halogen; or Ci_-5 alkyl; or Ci-4 alkyl; or Ci-3 alkyl; or C_1-2 alkyl; or CH3; or H. certain embodiments, in compounds of general formula IV, B² is

, wherein R⁶⁵ is HC(0)R⁶⁹; R⁶⁶, R⁶⁷ and R⁶⁸ are each H; R⁶⁹ is CH₃, CH₂OR⁷¹, CH₂OC(0)R¹³¹ or CH₂N₃; R⁷¹ is H or unsubstituted lower alkyl; R¹³¹ is CM alkyl; and W¹ is -C(O)-;

¹³⁶ are each independently H or substituted or unsubstituted lower alkyl; and R⁷⁴, R⁷⁴ , R^74", π76 π76' π76" π84 π84' π 84" π 86 π86' π86" π93 π93' π93" π95 π95' π95" π 100 π 100'

R^100", R¹⁰⁸, R^108', R^108", R¹¹⁰, R^110', R^110", R¹³⁷, R¹³⁸, R¹³⁹, R^139', and R^139" are each independently H, halogen or unsubstituted lower alkyl. In certain embodiments, in compounds of general formula IV, R⁷³, R⁷⁵, R⁸³, R⁸⁵, R⁹⁴, R⁹⁹, R¹⁰⁷, R¹⁰⁹and R¹³⁶ are each independently H, unsubstituted lower alkyl or lower alkyl substituted with one or more substituents independently selected from the group consisting of OH, C3-6 cycloalkyl, 5- to 10-membered heterocycloalkyl, C(0)OH, C(0)OR¹⁴⁰, NH₂, R¹⁴¹R¹⁴², HC(0)OR¹⁴³, Ci_-6 alkoxy, CN, C(0) HR¹⁴⁴ and CO H₂; wherein R¹⁴⁰, R¹⁴¹, R¹⁴², and R¹⁴³ are each independently unsubstituted Ci_-6 alkyl; R¹⁴⁴ is Ci_-6 alkyl optionally substituted with one or more substituents independently selected from the group consisting of R¹⁴⁵R¹⁴⁶ and OH; and R¹⁴⁵ and R¹⁴⁶ are each independently unsubstituted Ci_-6 alkyl. In certain embodiments, in compounds of general formula IV, R⁷³, R⁷⁵, R⁸³, R⁸⁵, R⁹⁴, R", R¹⁰⁷, R¹⁰⁹ and R¹³⁶ are each independently unsubstituted lower alkyl or lower alkyl substituted with one or more substituents independently selected from the group consisting of OH, C3-6 cycloalkyl, 5- to 10- membered heterocycloalkyl, C(0)OH, C(0)OR¹⁴⁰, H₂, R¹⁴¹R¹⁴², HC(0)OR¹⁴³, Ci-6 alkoxy, CN, C(0)NHR¹⁴⁴ and CONH₂; wherein R¹⁴⁰, R¹⁴¹, R¹⁴², and R¹⁴³ are each independently unsubstituted Ci_-6 alkyl; R¹⁴⁴ is Ci_-6 alkyl optionally substituted with one or more substituents independently selected from the group consisting of NR¹⁴⁵R¹⁴⁶ and OH; and R¹⁴⁵ and R¹⁴⁶ are each independently unsubstituted Ci-6 alkyl. In certain embodiments, in compounds of general formula IV, R⁷³, R⁷⁵, R⁸³, R⁸⁵, R⁹⁴, R⁹⁹, R¹⁰⁷, R¹⁰⁹ and R¹³⁶ are each independently unsubstituted lower alkyl; or unsubstituted Ci_-5 alkyl; unsubstituted Ci-4 alkyl; unsubstituted Ci_-3 alkyl; or unsubstituted Ci_-2 alkyl; or CH₃; or H. In certain embodiments, in compounds of general formula IV, R⁷⁴, R^74', R^74", R⁷⁶, R^76', R^76", R⁸⁴, R^84', R^84", R⁸⁶, R^86', R^86", R⁹³, τ τ πΐΐθ" π

IV> 93' τ

, IV> 93" T

, IV> 95, IV> 95' τ

, IV> 95" π ΐΐθ πΐΐθ'

, IV 100 π

, IV 100' π

, IV 100" π

, IV 108 π

, IV 108' π

, IV 108" π

, IV , IV , IV , IV 137,

R¹³⁸, R¹³⁹, R¹³⁹ , and R^139" are each independently H or unsubstituted lower alkyl; or halogen; or Ci_-5 alkyl; or Ci-4 alkyl; or Ci-3 alkyl; or Ci_-2 alkyl; or C¾; or H.

[00150] In certain embodiments, in compounds of general formula IV, B is

, wherein R⁶⁵ is NHC(0)R⁶⁹; R⁶⁶, R⁶⁷ and R⁶⁸ are each H; R⁶⁹ is CH₃, CH₂OR⁷¹, CH₂OC(0)R or CH₂N₃; R⁷¹ is H or unsubstituted lower alkyl; R¹³¹ is CM alkyl; and W¹ is -C(O)-; or B² is:

or , wherein R⁷³ and R⁷⁵ are each independently H or substituted or unsubstituted lower alkyl; and R⁷⁴, R^74', R^74", R⁷⁶, R^76', and R^76" are each independently H, halogen or unsubstituted lower alkyl. In certain embodiments, in compounds of general formula IV, R⁷³ and R⁷⁵ are each independently H, unsubstituted lower alkyl or lower alkyl substituted with one or more substituents independently selected from the group consisting of OH, C3-6 cycloalkyl, 5- to 10-membered heterocycloalkyl, C(0)OH, C(0)OR¹⁴⁰, NH₂,

R¹⁴¹R¹⁴², HC(0)OR¹⁴³, Ci_-6 alkoxy, CN, C(0) HR¹⁴⁴ and CO H₂; wherein R¹⁴⁰, R¹⁴¹, R¹⁴², and R¹⁴³ are each independently unsubstituted C_1-6 alkyl; R¹⁴⁴ is C_1-6 alkyl optionally substituted with one or more substituents independently selected from the group consisting of R¹⁴⁵R¹⁴⁶ and OH; and R¹⁴⁵ and R¹⁴⁶ are each independently unsubstituted C_1-6 alkyl. In certain embodiments, in compounds of general formula IV, R⁷³ and R⁷⁵ are each independently unsubstituted lower alkyl or lower alkyl substituted with one or more substituents independently selected from the group consisting of OH, C3-6 cycloalkyl, 5- to 10-membered heterocycloalkyl, C(0)OH,

C(0)OR¹⁴⁰, H₂, R¹⁴¹R¹⁴², HC(0)OR¹⁴³, Ci_-6 alkoxy, CN, C(0)NHR¹⁴⁴ and CONH₂; wherein R¹⁴⁰, R¹⁴¹, R¹⁴², and R¹⁴³ are each independently unsubstituted C_1-6 alkyl; R¹⁴⁴ is C_1-6 alkyl optionally substituted with one or more substituents independently selected from the group consisting of NR¹⁴⁵R¹⁴⁶ and OH; and R¹⁴⁵ and R¹⁴⁶ are each independently unsubstituted C_1-6 alkyl. In certain embodiments, in compounds of general formula IV, R⁷³ and R⁷⁵ are each independently unsubstituted lower alkyl; or unsubstituted C_1-5 alkyl; or unsubstituted C_1-4 alkyl; or unsubstituted Ci-3 alkyl; or unsubstituted Ci_-2 alkyl; or CH3; or H. In certain embodiments, in compounds of general formula IV, R⁷⁴, R^74', R^{74 "}, R⁷⁶, R^76', and R^76" are each independently H or unsubstituted lower alkyl; or halogen; or C_1-5 alkyl; or C_1-4 alkyl; or Ci-3 alkyl; or Ci_-2 alkyl; or CH3; or H. certain embodiments, in compounds of general formula IV, B² is

, wherein R and R are each independently H, OH, CI, F, unsubstituted lower alkyl, H₂, NHC(0)R⁶⁹, N0₂, or N₃; R and R are each independently H, F, CI, unsubstituted lower alkyl, or C(0)R¹³⁰; R⁶⁹ is unsubstituted lower alkyl, CH₂OR⁷¹, CH₂OC(0)R¹³¹ or (CH₂)_tN₃; R⁷¹ is H or unsubstituted lower alkyl; R¹³⁰ is OH, OR¹³², H₂, HR¹³³, substituted or unsubstituted lower alkyl or substituted or unsubstituted heterocycloalkyl; R¹³¹ is unsubstituted lower alkyl; R¹³² and R¹³³ are each independently substituted or unsubstituted lower alkyl; t is 1, 2, 3 or 4; and W¹ is -CH₂- or -C(O)-.

[00152] In certain embodiments, in compounds of general formula IV, B² is

, wherein R and R are each independently H, OH, CI, F, unsubstituted lower alkyl, H₂, NHC(0)R⁶⁹, N0₂, or N₃; R and R are each independently H, F, CI, unsubstituted lower alkyl, or C(0)R¹³⁰; R⁶⁹ is unsubstituted lower alkyl, CH₂OR⁷¹, CH₂OC(0)R¹³¹ or (CH₂)_tN₃; R⁷¹ is H or unsubstituted lower alkyl; R¹³⁰ is OH, OR¹³², H₂, NHR¹³³, substituted or unsubstituted lower alkyl or substituted or unsubstituted heterocycloalkyl; R¹³¹ is unsubstituted lower alkyl; R¹³² and R¹³³ are each independently substituted or unsubstituted lower alkyl; t is 1, 2, 3 or 4; and W¹ is -C(O)-.

[00153] In certain embodiments, in compounds of general formula IV, B² is

, wherein R and R are each independently H, CI, F, H₂, HC(0)R⁶⁹,

N0₂, or N₃; R and R are each independently H, F, CI, unsubstituted lower alkyl, or C(0)R R⁶⁹ is unsubstituted lower alkyl, CH₂OR⁷¹, CH₂OC(0)R¹³¹ or (CH₂)_tN₃; R⁷¹ is H or unsubstituted lower alkyl; R¹³⁰ is OH, OR¹³², H₂, HR¹³³, substituted or unsubstituted lower alkyl or substituted or unsubstituted heterocycloalkyl; R¹³¹ is unsubstituted lower alkyl; R¹³² and R¹³³ are each independently substituted or unsubstituted lower alkyl; t is 1, 2, 3 or 4; and W¹ is -C(O)-. [00154] In certain embodiments, in compounds of general formula IV, B² is

, wherein R and R are each independently H, H₂, HC(0)R⁶⁹, N0₂, or

N₃; R and R are each independently H, F, CI, unsubstituted lower alkyl, or C(0)R¹³°; R is unsubstituted lower alkyl, CH₂OR⁷¹, CH₂OC(0)R¹³¹ or (CH₂)_tN₃; R⁷¹ is H or unsubstituted lower alkyl; R¹³⁰ is OH, OR¹³², H₂, NHR¹³³, substituted or unsubstituted lower alkyl or substituted or unsubstituted heterocycloalkyl; R¹³¹ is unsubstituted lower alkyl; R¹³² and R¹³³ are each independently substituted or unsubstituted lower alkyl; t is 1, 2, 3 or 4; and W¹ is -C(O)-.

[00155] In certain embodiments, in compounds of general formula IV, B² is

, wherein R and R are each independently H, H₂, HC(0)R⁶⁹, N0₂, or

N₃; R⁶⁶ and R⁶⁷ are each H; R⁶⁹ is unsubstituted lower alkyl, CH₂OR⁷¹, CH₂OC(0)R¹³¹ or (CH₂)tN₃; R⁷¹ is H or unsubstituted lower alkyl; R¹³¹ is unsubstituted lower alkyl; t is 1, 2, 3 or 4; and W¹ is -C(O)-.

[00156] In certain embodiments, in compounds of general formula IV, B² is

, wherein R⁶⁵ and R⁶⁸ are each independently H or H₂, HC(0)R⁶⁹; R⁶⁶ and R⁶⁷ are each H; R⁶⁹ is unsubstituted lower alkyl, CH₂OR⁷¹, CH₂OC(0)R¹³¹ or (CH₂)_tN₃; R⁷¹ is H or unsubstituted lower alkyl; R¹³¹ is unsubstituted lower alkyl; t is 1, 2, 3 or 4; and W¹ is - C(O)-.

[00157] In certain embodiments, in compounds of general formula IV, B² is

, wherein R⁶⁵ and R⁶⁸ are each independently H or HC(0)R⁶⁹; R⁶⁶ and R⁶⁷ are each H; R⁶⁹ is unsubstituted lower alkyl, CH₂OR⁷¹, CH₂OC(0)R¹³¹ or (CH₂)_tN₃; R⁷¹ is H or unsubstituted lower alkyl; R¹³¹ is unsubstituted lower alkyl; t is 1, 2, 3 or 4; and W¹ is -C(O)-.

[00158] In certain embodiments, in compounds of general formula IV, B² is

, wherein R⁶⁵ and R⁶⁸ are each independently H or HC(0)R⁶⁹; R⁶⁶ and R⁶⁷ are each H; R⁶⁹ is unsubstituted lower alkyl, CH₂OR⁷¹, CH₂OC(0)R¹³¹ or (CH₂)_tN₃; R⁷¹ is H or unsubstituted Ci-4 alkyl; R¹³¹ is unsubstituted Ci-4 alkyl; t is 1, 2, 3 or 4; and W¹ is -C(O)-.

[00159] In certain embodiments, in compounds of general formula IV, B² is

, wherein R^M is HC(0)R^by; R^bb, R^b ' and R^bS are each H; R^by is CH₃, CH₂OR⁷¹, CH₂OC(0)R¹³¹ or CH₂N₃; R⁷¹ is H or unsubstituted lower alkyl; R¹³¹ is CM alkyl; and W¹ is -C(O)-. In another embodiment, R⁶⁹ is CH₃, CH₂OR⁷¹, or CH₂OC(0)R¹³¹; R⁷¹ is H or unsubstituted lower alkyl; and R¹³¹ is C_1-4 alkyl. In a further embodiment, R⁶⁹ is CH₃. In another embodiment, R⁶⁹ is CH₂OR⁷¹; and R⁷¹ is H or unsubstituted lower alkyl. In a further

embodiment, R⁶⁹ is CH₂OC(0)R¹³¹; and R¹³¹ is CM alkyl. 00160] In certain embodiments, in compounds of general formula IV, B² is:

R , R , R , R", R , R and R^13b are each independently H or substituted or unsubstituted lower alkyl; and R⁷⁴, R^74', R^74", R⁷⁶, R^76', R^76", R⁸², R^82', R^82", R⁸⁴, R^84', R^84", R⁸⁶, R^86', R^86", R⁹³, τ> 93' τ

, IV> 93" T

, IV> 95 τ

, IV> 95' τ

, IV> 95" π

, IV 100 π

, IV 100' π

, IV 100" π

, IV 108 π

, IV 108' π ΐΐθ' πΐΐθ" π

ΓΥ , IV 108" πΐΐθ π

, IV , IV , IV , IV 137 π

, IV 138 π

, IV 139 π , IV 139', and R¹³⁹ are each independently H, halogen or unsubstituted lower alkyl. In certain embodiments, in compounds of general formula IV, R⁷³, R⁷⁵, R⁸¹, R⁸³, R⁸⁵, R⁹⁴, R⁹⁹, R¹⁰⁷, R¹⁰⁹ and R¹³⁶ are each independently H, unsubstituted lower alkyl or lower alkyl substituted with one or more substituents independently selected from the group consisting of OH, C3-6 cycloalkyl, 5- to 10-membered heterocycloalkyl, C(0)OH, C(0)OR¹⁴⁰, H₂, R¹⁴¹R¹⁴², HC(0)OR¹⁴³, Ci_-6 alkoxy, CN, C(0) HR¹⁴⁴ and CO H₂; wherein R¹⁴⁰, R¹⁴¹, R¹⁴², and R¹⁴³ are each independently unsubstituted Ci-6 alkyl; R¹⁴⁴ is Ci_-6 alkyl optionally substituted with one or more substituents independently selected from the group consisting of NR¹⁴⁵R¹⁴⁶ and OH; and R¹⁴⁵ and R¹⁴⁶ are each independently unsubstituted Ci_-6 alkyl. In certain embodiments, in compounds of general formula IV, R⁷³, R⁷⁵, R⁸¹, R⁸³, R⁸⁵, R⁹⁴, R", R¹⁰⁷, R¹⁰⁹ and R¹³⁶ are each independently unsubstituted lower alkyl or lower alkyl substituted with one or more substituents independently selected from the group consisting of OH, C_3-6 cycloalkyl, 5- to 10-membered heterocycloalkyl, C(0)OH, C(0)OR¹⁴⁰, H₂, R¹⁴¹R¹⁴², HC(0)OR¹⁴³, Ci_-6 alkoxy, CN, C(0)NHR¹⁴⁴ and CONH₂; wherein R¹⁴⁰, R¹⁴¹, R¹⁴², and R¹⁴³ are each independently unsubstituted Ci_-6 alkyl; R¹⁴⁴ is Ci_-6 alkyl optionally substituted with one or more substituents independently selected from the group consisting of NR¹⁴⁵R¹⁴⁶ and OH; and R¹⁴⁵ and R¹⁴⁶ are each independently unsubstituted Ci_-6 alkyl. In certain embodiments, in compounds of general formula IV, R⁷³, R⁷⁵, R⁸¹, R⁸³, R⁸⁵, R⁹⁴, R⁹⁹, R¹⁰⁷, R¹⁰⁹ and R¹³⁶ are each independently unsubstituted lower alkyl; or unsubstituted C 1-5 alkyl; or unsubstituted Ci-4 alkyl; or unsubstituted Ci_-3 alkyl; or unsubstituted Ci_-2 alkyl; or CH₃; or H. In certain embodiments, in compounds of general formula IV, R⁷⁴, R^74', R^74", R⁷⁶, R^76', R^76", R⁸², R^82', R^82", π 84 π 84' π 84" π 86 π 86' π 86" π 93 π 93' π 93" π 95 π 95' π 95" π 100 π 100' π 100" π 108 π 108' π 108" π ΐ ΐθ

R^110', R^110", R¹³⁷, R¹³⁸, R¹³⁹, R^139', and R^139" are each independently H or unsubstituted lower alkyl; or halogen; or Ci_-5 alkyl; or Ci-4 alkyl; or Ci_-3 alkyl; or Ci_-2 alkyl; or CH₃; or H. 00161] In certain embodiments, in compounds of general formula IV, B² is:

and R¹³⁶ are each independently H or substituted or unsubstituted lower alkyl; and R⁷⁴, R^74', R^74", π 76 π 76' π 76" π 84 π 84' π 84" π 86 π 86' π 86" π 93 π 93' π 93" π 95 π 95' π 95" π 100 π 100' π 100" π 108

R^108', R^108", R¹¹⁰, R^110', R^110", R¹³⁷, R¹³⁸, R¹³⁹, R^139', and R^139" are each independently H, halogen or unsubstituted lower alkyl. In certain embodiments, in compounds of general formula IV, R⁷³, R⁷⁵, R⁸³, R⁸⁵, R⁹⁴, R⁹⁹, R¹⁰⁷, R¹⁰⁹ and R¹³⁶ are each independently H, unsubstituted lower alkyl or lower alkyl substituted with one or more substituents independently selected from the group consisting of OH, C_3-6 cycloalkyl, 5- to 10-membered heterocycloalkyl, C(0)OH, C(0)OR¹⁴⁰, H₂, R¹⁴¹R¹⁴², HC(0)OR¹⁴³, Ci_-6 alkoxy, CN, C(0) HR¹⁴⁴ and CO H₂; wherein R¹⁴⁰, R¹⁴¹, R¹⁴², and R¹⁴³ are each independently unsubstituted Ci_-6 alkyl; R¹⁴⁴ is Ci_-6 alkyl optionally substituted with one or more substituents independently selected from the group consisting of R¹⁴⁵R¹⁴⁶ and OH; and R¹⁴⁵ and R¹⁴⁶ are each independently unsubstituted Ci_-6 alkyl. In certain embodiments, in compounds of general formula IV, R⁷³, R⁷⁵, R⁸³, R⁸⁵, R⁹⁴, R⁹⁹, R¹⁰⁷, R¹⁰⁹ and R¹³⁶ are each independently unsubstituted lower alkyl or lower alkyl substituted with one or more substituents independently selected from the group consisting of OH, C3-6 cycloalkyl, 5- to 10-membered heterocycloalkyl, C(0)OH, C(0)OR¹⁴⁰, H₂, R¹⁴¹R¹⁴², HC(0)OR¹⁴³, Ci_-6 alkoxy, CN, C(0)NHR¹⁴⁴ and CONH₂; wherein R¹⁴⁰, R¹⁴¹, R¹⁴², and R¹⁴³ are each independently unsubstituted Ci-6 alkyl; R¹⁴⁴ is Ci_-6 alkyl optionally substituted with one or more substituents independently selected from the group consisting of NR¹⁴⁵R¹⁴⁶ and OH; and R¹⁴⁵ and R¹⁴⁶ are each independently unsubstituted Ci_-6 alkyl. In certain embodiments, in compounds of general formula IV, R⁷³, R⁷⁵, R⁸³, R⁸⁵, R⁹⁴, R⁹⁹, R¹⁰⁷, R¹⁰⁹ and R¹³⁶ are each independently unsubstituted lower alkyl; or unsubstituted Ci_-5 alkyl; or unsubstituted Ci-4 alkyl; or unsubstituted Ci-3 alkyl; or unsubstituted Ci_-2 alkyl; or CH3; or H. In certain embodiments, in compounds of general formula IV, R⁷⁴, R⁷⁴ , π 74" π 76 π 76' π 76" π 84 π 84' π 84" π 86 π 86' π 86" π 93 π 93' π 93" π 95 π 95' π 95" π 100 π 100' π 100" R¹⁰⁸, R^108', R^108", R¹¹⁰, R^110', R^110", R¹³⁷, R¹³⁸, R¹³⁹, R^139', and R^139" are each independently H or unsubstituted lower alkyl; or halogen; or Ci_-5 alkyl; or Ci-4 alkyl; or Ci-3 alkyl; or Ci_-2 alkyl; or CH₃; or H. 00162] In certain embodiments, in compounds of general formula IV, B² is:

or unsubstituted lower alkyl; and R⁷⁴, R^74', R^74", R⁷⁶, R^76', R^76", R¹⁰⁸, R^108', R^108", R¹¹⁰, R^110', and R^110" are each independently H, halogen or unsubstituted lower alkyl. In certain embodiments, in compounds of general formula IV, R⁷³, R⁷⁵, R¹⁰⁷, and R¹⁰⁹ are each independently H, unsubstituted lower alkyl or lower alkyl substituted with one or more substituents independently selected from the group consisting of OH, C3-6 cycloalkyl, 5- to 10-membered heterocycloalkyl, C(0)OH, C(0)OR¹⁴⁰, H₂, R¹⁴¹R¹⁴², HC(0)OR¹⁴³, Ci_-6 alkoxy, CN, C(0) HR¹⁴⁴ and CO H₂; wherein R¹⁴⁰, R¹⁴¹, R¹⁴², and R¹⁴³ are each independently unsubstituted Ci_-6 alkyl; R¹⁴⁴ is Ci_-6 alkyl optionally substituted with one or more substituents independently selected from the group consisting of R¹⁴⁵R¹⁴⁶ and OH; and R¹⁴⁵ and R¹⁴⁶ are each independently unsubstituted Ci_-6 alkyl. In certain embodiments, in compounds of general formula IV, R⁷³, R⁷⁵, R¹⁰⁷, and R¹⁰⁹ are each independently unsubstituted lower alkyl or lower alkyl substituted with one or more substituents independently selected from the group consisting of OH, C3-6 cycloalkyl, 5- to 10-membered heterocycloalkyl, C(0)OH, C(0)OR¹⁴⁰, H₂, R¹⁴¹R¹⁴², HC(0)OR¹⁴³, Ci_-6 alkoxy, CN, C(0)NHR¹⁴⁴ and CONH₂; wherein R¹⁴⁰, R¹⁴¹, R¹⁴², and R¹⁴³ are each independently unsubstituted Ci-6 alkyl; R¹⁴⁴ is Ci_-6 alkyl optionally substituted with one or more substituents independently selected from the group consisting of NR¹⁴⁵R¹⁴⁶ and OH; and R¹⁴⁵ and R¹⁴⁶ are each independently unsubstituted Ci_-6 alkyl. In certain embodiments, in compounds of general formula IV, R⁷³, R⁷⁵, R¹⁰⁷, and R¹⁰⁹ are each independently unsubstituted lower alkyl; or unsubstituted Ci_-5 alkyl; or unsubstituted Ci-4 alkyl; or unsubstituted Ci_-3 alkyl; or unsubstituted Ci_-2 alkyl; or CH₃; or H. In certain embodiments, in compounds of general formula IV, R⁷⁴, R^74', R^74", R⁷⁶, R^76', R^{76 "}, R¹⁰⁸, R^108', R^{108 "}, R¹¹⁰, R^110', and R^110" are each independently H or unsubstituted lower alkyl; or halogen; or Ci-5 alkyl; or C_1-4 alkyl; or Ci_-3 alkyl; or Ci_-2 alkyl; or CH₃; or H.

[00163] In certain embodiments, in compounds of general formula IV, B² is:

, wherein R and R are each independently H or substituted or unsubstituted lower alkyl; and R⁸⁴, R^84', R^84", R⁸⁶, R^86', and R^86" are each independently H, halogen or unsubstituted lower alkyl. In certain embodiments, in compounds of general formula IV, R⁸³ and R⁸⁵ are each independently H, unsubstituted lower alkyl or lower alkyl substituted with one or more substituents independently selected from the group consisting of OH, C_3-6 cycloalkyl, 5- to 10-membered heterocycloalkyl, C(0)OH, C(0)OR¹⁴⁰, H₂, R¹⁴¹R¹⁴², HC(0)OR¹⁴³, Ci-6 alkoxy, CN, C(0) HR¹⁴⁴ and CO H₂; wherein R¹⁴⁰, R¹⁴¹, R¹⁴², and R¹⁴³ are each independently unsubstituted Ci_-6 alkyl; R¹⁴⁴ is Ci_-6 alkyl optionally substituted with one or more substituents independently selected from the group consisting of R¹⁴⁵R¹⁴⁶ and OH; and R¹⁴⁵ and R¹⁴⁶ are each independently unsubstituted Ci_-6 alkyl. In certain embodiments, in compounds of general formula IV, R⁸³ and R⁸⁵ are each independently unsubstituted lower alkyl or lower alkyl substituted with one or more substituents independently selected from the group consisting of OH, C_3-6 cycloalkyl, 5- to 10-membered heterocycloalkyl, C(0)OH, C(0)OR¹⁴⁰, H₂, R¹⁴¹R¹⁴², HC(0)OR¹⁴³, Ci-6 alkoxy, CN, C(0)NHR¹⁴⁴ and CONH₂; wherein R¹⁴⁰, R¹⁴¹, R¹⁴², and R¹⁴³ are each independently unsubstituted Ci_-6 alkyl; R¹⁴⁴ is Ci_-6 alkyl optionally substituted with one or more substituents independently selected from the group consisting of NR¹⁴⁵R¹⁴⁶ and OH; and R¹⁴⁵ and R¹⁴⁶ are each independently unsubstituted Ci_-6 alkyl. In certain embodiments, in compounds of general formula IV, R⁸³ and R⁸⁵ are each independently unsubstituted lower alkyl; or unsubstituted Ci_-5 alkyl; or unsubstituted Ci-4 alkyl; or unsubstituted Ci_-3 alkyl; or unsubstituted Ci_-2 alkyl; or CH₃; or H. In certain embodiments, in compounds of general formula IV, R⁸⁴, R⁸⁴ , R^84", R⁸⁶, R⁸⁶ , and R^86" are each independently H or unsubstituted lower alkyl; or halogen; or Ci_-5 alkyl; or Ci-4 alkyl; or Ci_-3 alkyl; or Ci_-2 alkyl; or CH₃; or H.

[00164] In certain embodiments, in compounds of general formula IV, B² is:

, wherein R⁸³ is H or substituted or unsubstituted lower alkyl; and R⁸⁴, R⁸⁴ , and R⁸⁴" are each independently H, halogen or unsubstituted lower alkyl. In certain embodiments, in compounds of general formula IV, R⁸³ is H, unsubstituted lower alkyl or lower alkyl substituted with one or more substituents independently selected from the group consisting of OH, C3-6 cycloalkyl, 5- to 10-membered heterocycloalkyl, C(0)OH, C(0)OR¹⁴⁰, H₂, R¹⁴¹R¹⁴², HC(0)OR¹⁴³, Ci-6 alkoxy, CN, C(0) HR¹⁴⁴ and CO H₂; wherein R¹⁴⁰, R¹⁴¹, R¹⁴², and R¹⁴³ are each independently unsubstituted Ci_-6 alkyl; R¹⁴⁴ is Ci_-6 alkyl optionally substituted with one or more substituents independently selected from the group consisting of R¹⁴⁵R¹⁴⁶ and OH; and R¹⁴⁵ and R¹⁴⁶ are each independently unsubstituted Ci_-6 alkyl. In certain embodiments, in compounds of general formula IV, R⁸³ is unsubstituted lower alkyl or lower alkyl substituted with one or more substituents independently selected from the group consisting of OH, C3-6 cycloalkyl, 5- to 10- membered heterocycloalkyl, C(0)OH, C(0)OR¹⁴⁰, H₂, R¹⁴¹R¹⁴², HC(0)OR¹⁴³, Ci_-6 alkoxy, CN, C(0)NHR¹⁴⁴ and CONH₂; wherein R¹⁴⁰, R¹⁴¹, R¹⁴², and R¹⁴³ are each independently unsubstituted Ci_-6 alkyl; R¹⁴⁴ is Ci_-6 alkyl optionally substituted with one or more substituents independently selected from the group consisting of NR¹⁴⁵R¹⁴⁶ and OH; and R¹⁴⁵ and R¹⁴⁶ are each independently unsubstituted Ci_-6 alkyl. In certain embodiments, in compounds of general formula IV, R⁸³ is unsubstituted lower alkyl; or unsubstituted Ci_-5 alkyl; or unsubstituted Ci-4 alkyl; or unsubstituted Ci_-3 alkyl; or unsubstituted Ci_-2 alkyl; or CH₃; or H. In certain embodiments, in compounds of general formula IV, R⁸⁴, R⁸⁴ , and R⁸⁴" are each independently H or unsubstituted lower alkyl; or halogen; or Ci_-5 alkyl; or Ci-4 alkyl; or Ci_-3 alkyl; or Ci_-2 alkyl; or CH₃; or H. In certain embodiments, one of R⁸⁴, R⁸⁴ , and R⁸⁴" is H and R⁸⁴, R⁸⁴ , and R⁸⁴" are each independently H, CI, F, Br, I, or unsubstituted Ci_-6 alkyl. In certain embodiments, one of R⁸⁴, R⁸⁴ , and R⁸⁴" is H and R⁸⁴, R⁸⁴ , and R⁸⁴" are each independently H or unsubstituted Ci_-6 alkyl. In certain embodiments, one of R⁸⁴, R⁸⁴ , and R⁸⁴" is H and R⁸⁴, R⁸⁴ , and R⁸⁴" are each independently H, CI, F, Br or I. In certain embodiments, two of R⁸⁴, R⁸⁴ , and R⁸⁴" are H and R⁸⁴, R⁸⁴ , and R⁸⁴"are each independently H, CI, F, Br, I, or unsubstituted Ci_-6 alkyl. In certain embodiments, two of R⁸⁴, R⁸⁴ , and R⁸⁴" are H and R⁸⁴, R⁸⁴ , and R⁸⁴" are each independently H or unsubstituted Ci_-6 alkyl. In certain embodiments, two of R⁸⁴, R⁸⁴ , and R^84" are H and R⁸⁴, R⁸⁴ , and R^84" are each independently H, CI, F, Br or I.

[00165] In certain embodiments, in compounds of general formula IV, B² is:

, wherein R' is H or substituted or unsubstituted lower alkyl; and R⁸⁶, R⁸⁶ , and R^86" are each independently H, halogen or unsubstituted lower alkyl. In certain embodiments, in compounds of general formula IV, R⁸⁵ is H, unsubstituted lower alkyl or lower alkyl substituted with one or more substituents independently selected from the group consisting of OH, C3-6 cycloalkyl, 5- to 10-membered heterocycloalkyl, C(0)OH, C(0)OR¹⁴⁰, H₂, R¹⁴¹R¹⁴², HC(0)OR¹⁴³, Ci-6 alkoxy, CN, C(0) HR¹⁴⁴ and CO H₂; wherein R¹⁴⁰, R¹⁴¹, R¹⁴², and R¹⁴³ are each independently unsubstituted C_1-6 alkyl; R¹⁴⁴ is Ci_-6 alkyl optionally substituted with one or more substituents independently selected from the group consisting of R¹⁴⁵R¹⁴⁶ and OH; and R¹⁴⁵ and R¹⁴⁶ are each independently unsubstituted C_1-6 alkyl. In certain embodiments, in compounds of general formula IV, R⁸⁵ is unsubstituted lower alkyl or lower alkyl substituted with one or more substituents independently selected from the group consisting of OH, C3-6 cycloalkyl, 5- to 10- membered heterocycloalkyl, C(0)OH, C(0)OR¹⁴⁰, H₂, R¹⁴¹R¹⁴², HC(0)OR¹⁴³, Ci_-6 alkoxy, CN, C(0)NHR¹⁴⁴ and CONH₂; wherein R¹⁴⁰, R¹⁴¹, R¹⁴², and R¹⁴³ are each independently unsubstituted Ci_-6 alkyl; R¹⁴⁴ is C_1-6 alkyl optionally substituted with one or more substituents independently selected from the group consisting of NR¹⁴⁵R¹⁴⁶ and OH; and R¹⁴⁵ and R¹⁴⁶ are each independently unsubstituted C_1-6 alkyl. In certain embodiments, in compounds of general formula IV, R⁸⁵ is unsubstituted lower alkyl; or unsubstituted C_1-5 alkyl; or unsubstituted C_1-4 alkyl; or unsubstituted C_1-3 alkyl; or unsubstituted Ci_-2 alkyl; or CH₃; or H. In certain embodiments, in compounds of general formula IV, R⁸⁶, R⁸⁶ , and R^86" are each independently H or unsubstituted lower alkyl; or halogen; or C_1-5 alkyl; or C_1-4 alkyl; or C_1-3 alkyl; or Ci_-2 alkyl; or CH₃; or H. In certain embodiments, one of R⁸⁶, R⁸⁶ , and R^86" is H and R⁸⁶, R⁸⁶ , and R^{86 "}are each independently H, CI, F, Br, I, or unsubstituted Ci_-6 alkyl. In certain embodiments, one of R⁸⁶, R^86', and R^86" is H and R⁸⁶, R⁸⁶ , and R^86" are each independently H or unsubstituted C_1-6 alkyl. In certain embodiments, one of R⁸⁶, R⁸⁶', and R⁸⁶" is H and R⁸⁶, R⁸⁶', and R⁸⁶" are each independently H, CI, F, Br or I. In certain embodiments, two of R⁸⁶, R⁸⁶', and R⁸⁶" are H and R⁸⁶, R⁸⁶', and R⁸⁶"are each independently H, CI, F, Br, I, or unsubstituted C_1-6 alkyl. In certain embodiments, two of R⁸⁶, R⁸⁶ , and R⁸⁶" are H and R⁸⁶, R⁸⁶ , and R⁸⁶" are each independently H or unsubstituted C_1-6 alkyl. In certain embodiments, two of R⁸⁶, R⁸⁶ , and R⁸⁶" are H and R⁸⁶, R⁸⁶ , and R⁸⁶" are each independently H, CI, F, Br or I.

[00166] In certain embodiments, in compounds of general formula IV, B² is:

, wherein R' is H or substituted or unsubstituted lower alkyl; and R⁸², R⁸² , and

R⁸²" are each independently H, halogen or unsubstituted lower alkyl. In certain embodiments, in compounds of general formula IV, R⁸¹ is H, unsubstituted lower alkyl or lower alkyl substituted with one or more substituents independently selected from the group consisting of OH, C3-6 cycloalkyl, 5- to 10-membered heterocycloalkyl, C(0)OH, C(0)OR¹⁴⁰, H₂, R¹⁴¹R¹⁴², HC(0)OR¹⁴³, Ci-6 alkoxy, CN, C(0) HR¹⁴⁴ and CO H₂; wherein R¹⁴⁰, R¹⁴¹, R¹⁴², and R¹⁴³ are each independently unsubstituted C_1-6 alkyl; R¹⁴⁴ is Ci_-6 alkyl optionally substituted with one or more substituents independently selected from the group consisting of R¹⁴⁵R¹⁴⁶ and OH; and R¹⁴⁵ and R¹⁴⁶ are each independently unsubstituted C_1-6 alkyl. In certain embodiments, in compounds of general formula IV, R⁸¹ is unsubstituted lower alkyl or lower alkyl substituted with one or more substituents independently selected from the group consisting of OH, C3-6 cycloalkyl, 5- to 10- membered heterocycloalkyl, C(0)OH, C(0)OR¹⁴⁰, H₂, R¹⁴¹R¹⁴², HC(0)OR¹⁴³, Ci_-6 alkoxy, CN, C(0)NHR¹⁴⁴ and CONH₂; wherein R¹⁴⁰, R¹⁴¹, R¹⁴², and R¹⁴³ are each independently unsubstituted Ci_-6 alkyl; R¹⁴⁴ is C_1-6 alkyl optionally substituted with one or more substituents independently selected from the group consisting of NR¹⁴⁵R¹⁴⁶ and OH; and R¹⁴⁵ and R¹⁴⁶ are each independently unsubstituted C_1-6 alkyl. In certain embodiments, in compounds of general formula IV, R⁸¹ is unsubstituted lower alkyl; or unsubstituted C_1-5 alkyl; or unsubstituted C_1-4 alkyl; or unsubstituted Ci_-3 alkyl; or unsubstituted Ci_-2 alkyl; or CH₃; or H. In certain embodiments, in compounds of general formula IV, R⁸², R⁸² , and R⁸²" are each independently H or unsubstituted lower alkyl; or halogen; or C_1-5 alkyl; or C_1-4 alkyl; or Ci_-3 alkyl; or Ci_-2 alkyl; or CH₃; or H. In certain embodiments, one of R⁸², R^82', and R^82" is H and R⁸², R⁸² , and R^82" are each independently H, CI, F, Br, I, or unsubstituted C_1-6 alkyl. In certain embodiments, one of R⁸², R⁸² , and R^82" is H and R⁸², R⁸² , and R^82" are each independently H or unsubstituted C_1-6 alkyl. In certain embodiments, one of R⁸², R^82', and R^82" is H and R⁸², R^82', and R^82" are each independently H, CI, F, Br or I. In certain embodiments, two of R⁸², R^82', and R^82" are H and R⁸², R^82', and R^82" are each independently H, CI, F, Br, I, or unsubstituted C_1-6 alkyl. In certain embodiments, two of R⁸², R⁸² , and R^82" are H and R⁸², R⁸² , and R^82" are each independently H or unsubstituted C_1-6 alkyl. In certain embodiments, two of R⁸², R⁸² , and R^82" are H and R⁸², R⁸² , and R^82" are each independently H, CI, F, Br or I.

[00167] In certain embodiments, in compounds of general formula IV, B² is:

unsubstituted lower alkyl; and R⁹³, R^93', R^93", R⁹⁵, R⁹⁵ , R^95", R¹⁰⁰, R^100', R^100", R¹³⁷, R¹³⁸, R¹³⁹, R^139', and R^139" are each independently H, halogen or unsubstituted lower alkyl. In certain embodiments, in compounds of general formula IV, R⁹⁴, R⁹⁹ and R¹³⁶ are each independently H, unsubstituted lower alkyl or lower alkyl substituted with one or more substituents independently selected from the group consisting of OH, C_3-6 cycloalkyl, 5- to 10-membered heterocycloalkyl, C(0)OH, C(0)OR¹⁴⁰, H₂, R¹⁴¹R¹⁴², HC(0)OR¹⁴³, Ci_-6 alkoxy, CN, C(0) HR¹⁴⁴ and CO H₂; wherein R¹⁴⁰, R¹⁴¹, R¹⁴², and R¹⁴³ are each independently unsubstituted Ci_-6 alkyl; R¹⁴⁴ is Ci_-6 alkyl optionally substituted with one or more substituents independently selected from the group consisting of R¹⁴⁵R¹⁴⁶ and OH; and R¹⁴⁵ and R¹⁴⁶ are each independently unsubstituted Ci_-6 alkyl. In certain embodiments, in compounds of general formula IV, R⁹⁴, R⁹⁹ and R¹³⁶ are each independently unsubstituted lower alkyl or lower alkyl substituted with one or more substituents independently selected from the group consisting of OH, C3-6 cycloalkyl, 5- to 10-membered heterocycloalkyl, C(0)OH, C(0)OR¹⁴⁰, H₂, R¹⁴¹R¹⁴², HC(0)OR¹⁴³, Ci_-6 alkoxy, CN, C(0) HR¹⁴⁴ and CO H₂; wherein R¹⁴⁰, R¹⁴¹, R¹⁴², and R¹⁴³ are each independently unsubstituted Ci-6 alkyl; R¹⁴⁴ is Ci_-6 alkyl optionally substituted with one or more substituents independently selected from the group consisting of R¹⁴⁵R¹⁴⁶ and OH; and R¹⁴⁵ and R¹⁴⁶ are each independently unsubstituted Ci_-6 alkyl. In certain embodiments, in compounds of general formula IV, R⁹⁴, R⁹⁹ and R¹³⁶ are each independently unsubstituted lower alkyl; or unsubstituted Ci_-5 alkyl; or unsubstituted Ci-4 alkyl; or unsubstituted Ci_-3 alkyl; or unsubstituted Ci_-2 alkyl; or CH₃; or H. In certain embodiments, in compounds of general formula IV, R⁹³, R^93', R^{93 "}, R⁹⁵, R⁹⁵ , R^{95 "}, R¹⁰⁰, R^100', R^100", R¹³⁷, R¹³⁸, R¹³⁹, R^139', and R^139" are each independently H or unsubstituted lower alkyl; or halogen; or Ci_-5 alkyl; or Ci-4 alkyl; or Ci_-3 alkyl; or Ci_-2 alkyl; or CH₃; or H. 00168] In certain embodiments, in compounds of general formula IV, B² is:

, wherein R , R and R¹³⁶ are each independently H or substituted or unsubstituted lower alkyl; and R⁹⁵, R⁹⁵ , R^95",

R¹⁰⁰, R^100', R^100", R¹³⁷, R¹³⁸, R¹³⁹, R^139', and R^139" are each independently H, halogen or unsubstituted lower alkyl. In certain embodiments, in compounds of general formula IV, R , R and R¹³⁶ are each independently H, unsubstituted lower alkyl or lower alkyl substituted with one or more substituents independently selected from the group consisting of OH, C_3-6 cycloalkyl, 5- to 10-membered heterocycloalkyl, C(0)OH, C(0)OR¹⁴⁰, H₂, R¹⁴¹R¹⁴², HC(0)OR¹⁴³, Ci_-6 alkoxy, CN, C(0)NHR¹⁴⁴ and CONH₂; wherein R¹⁴⁰, R¹⁴¹, R¹⁴², and R¹⁴³ are each independently unsubstituted Ci_-6 alkyl; R¹⁴⁴ is Ci_-6 alkyl optionally substituted with one or more substituents independently selected from the group consisting of NR¹⁴⁵R¹⁴⁶ and OH; and R¹⁴⁵ and R¹⁴⁶ are each independently unsubstituted Ci_-6 alkyl. In certain embodiments, in compounds of general formula IV, R⁹⁴, R⁹⁹ and R¹³⁶ are each independently unsubstituted lower alkyl or lower alkyl substituted with one or more substituents independently selected from the group consisting of OH, C_3-6 cycloalkyl, 5- to 10-membered heterocycloalkyl, C(0)OH, C(0)OR¹⁴°, NH₂, NR¹⁴¹R HC(0)OR¹⁴³, Ci-6 alkoxy, CN, C(0) HR¹⁴⁴ and CO H₂; wherein R , R , R , and R are each independently unsubstituted Ci_-6 alkyl; R¹⁴⁴ is Ci_-6 alkyl optionally substituted with one or more substituents independently selected from the group consisting of R¹⁴⁵R¹⁴⁶ and OH; and R¹⁴⁵ and R¹⁴⁶ are each independently unsubstituted Ci_-6 alkyl. In certain embodiments, in compounds of general formula IV, R⁹⁴, R⁹⁹ and R¹³⁶ are each independently unsubstituted lower alkyl; or unsubstituted Ci_-5 alkyl; or unsubstituted Ci-4 alkyl; or unsubstituted Ci_-3 alkyl; or unsubstituted Ci-2 alkyl; or CH₃; or H. In certain embodiments, in compounds of general formula IV, R⁹⁵, R⁹⁵ , R⁹⁵", R¹⁰⁰, R¹⁰⁰', R¹⁰⁰", R¹³⁷, R¹³⁸, R¹³⁹, R¹³⁹', and R¹³⁹" are each independently H or unsubstituted lower alkyl; or halogen; or Ci_-5 alkyl; or Ci-4 alkyl; or Ci_-3 alkyl; or Ci_-2 alkyl; or CH₃; or H. 00169] In certain embodiments, in compounds of general formula IV, B² is:

, wherein R and R are each independently H or substituted or unsubstituted lower alkyl; and R⁹⁵, R⁹⁵ , R⁹⁵", R¹⁰⁰, R¹⁰⁰', and R¹⁰⁰" are each independently H, halogen or unsubstituted lower alkyl. In certain embodiments, in compounds of general formula IV, R⁹⁴ and R⁹⁹ are each independently H, unsubstituted lower alkyl or lower alkyl substituted with one or more substituents independently selected from the group consisting of OH, C_3-6 cycloalkyl, 5- to 10-membered heterocycloalkyl, C(0)OH, C(0)OR¹⁴⁰, H₂, R¹⁴¹R¹⁴², HC(0)OR¹⁴³, Ci-6 alkoxy, CN, C(0)NHR¹⁴⁴ and CONH₂; wherein R¹⁴⁰, R¹⁴¹, R¹⁴², and R¹⁴³ are each independently unsubstituted Ci_-6 alkyl; R¹⁴⁴ is Ci_-6 alkyl optionally substituted with one or more substituents independently selected from the group consisting of NR¹⁴⁵R¹⁴⁶ and OH; and R¹⁴⁵ and R¹⁴⁶ are each independently unsubstituted Ci_-6 alkyl. In certain embodiments, in compounds of general formula IV, R⁹⁴ and R⁹⁹ are each independently unsubstituted lower alkyl or lower alkyl substituted with one or more substituents independently selected from the group consisting of OH, C_3-6 cycloalkyl, 5- to 10-membered heterocycloalkyl, C(0)OH, C(0)OR¹⁴⁰, NH₂, NR¹⁴¹R¹⁴², NHC(0)OR¹⁴³, Ci-6 alkoxy, CN, C(0)NHR¹⁴⁴ and CONH2; wherein R¹⁴⁰, R¹⁴¹, R¹⁴², and R¹⁴³ are each independently unsubstituted Ci_-6 alkyl; R¹⁴⁴ is Ci_-6 alkyl optionally substituted with one or more substituents independently selected from the group consisting of NR¹⁴⁵R¹⁴⁶ and OH; and R¹⁴⁵ and R¹⁴⁶ are each independently unsubstituted Ci_-6 alkyl. In certain embodiments, in compounds of general formula IV, R and R are each independently unsubstituted lower alkyl; or unsubstituted C_1-5 alkyl; or unsubstituted C_1-4 alkyl; or unsubstituted Ci_-3 alkyl; or unsubstituted Ci_-2 alkyl; or CH₃; or H. In certain embodiments, in compounds of general formula IV, R⁹⁵, R⁹⁵ , R^{95 "}, R¹⁰⁰, R^100', and R^100" are each independently H or unsubstituted lower alkyl; or halogen; or Ci-5 alkyl; or C_1-4 alkyl; or Ci_-3 alkyl; or Ci_-2 alkyl; or CH₃; or H. 00170] In certain embodiments, in compounds of general formula IV, B² is:

, wherein R is H or substituted or unsubstituted lower alkyl; and R ,

R⁹⁵ , and R⁹⁵ are each independently H, halogen or unsubstituted lower alkyl. In certain embodiments, in compounds of general formula IV, R⁹⁴ is H, unsubstituted lower alkyl or lower alkyl substituted with one or more substituents independently selected from the group consisting of OH, C_3-6 cycloalkyl, 5- to 10-membered heterocycloalkyl, C(0)OH, C(0)OR¹⁴⁰, H₂, R¹⁴¹R¹⁴², HC(0)OR¹⁴³, Ci_-6 alkoxy, CN, C(0) HR¹⁴⁴ and CO H₂; wherein R¹⁴⁰, R¹⁴¹, R¹⁴², and R¹⁴³ are each independently unsubstituted C_1-6 alkyl; R¹⁴⁴ is C_1-6 alkyl optionally substituted with one or more substituents independently selected from the group consisting of R¹⁴⁵R¹⁴⁶ and OH; and R¹⁴⁵ and R¹⁴⁶ are each independently unsubstituted Ci_-6 alkyl. In certain embodiments, in compounds of general formula IV, R⁹⁴ is unsubstituted lower alkyl or lower alkyl substituted with one or more substituents independently selected from the group consisting of OH, C_3-6 cycloalkyl, 5- to 10-membered heterocycloalkyl, C(0)OH, C(0)OR¹⁴⁰, H₂, R¹⁴¹R¹⁴², HC(0)OR¹⁴³, Ci_-6 alkoxy, CN, C(0)NHR¹⁴⁴ and CONH₂; wherein R¹⁴⁰, R¹⁴¹, R¹⁴², and R¹⁴³ are each independently unsubstituted Ci_-6 alkyl; R¹⁴⁴ is C_1-6 alkyl optionally substituted with one or more substituents independently selected from the group consisting of NR¹⁴⁵R¹⁴⁶ and OH; and R¹⁴⁵ and R¹⁴⁶ are each independently unsubstituted C_1-6 alkyl. In certain embodiments, in compounds of general formula IV, R⁹⁴ is unsubstituted lower alkyl; or unsubstituted C_1-5 alkyl; or unsubstituted C_1-4 alkyl; or unsubstituted Ci_-3 alkyl; or unsubstituted Ci_-2 alkyl; or CH₃; or H. In certain embodiments, in compounds of general formula IV, R⁹⁵, R⁹⁵ , and R⁹⁵ are each independently H or unsubstituted lower alkyl; or halogen; or C_1-5 alkyl; or C_1-4 alkyl; or Ci_-3 alkyl; or Ci_-2 alkyl; or CH₃; or H. In certain embodiments, one of R⁹⁵, R⁹⁵ , and R⁹⁵ is H and R⁹⁵, R⁹⁵ , and R⁹⁵ are each independently H, CI, F, Br, I, or unsubstituted C_1-6 alkyl. In certain embodiments, one of R⁹⁵, R⁹⁵ , and R⁹⁵ is H and R⁹⁵, R⁹⁵ , and R⁹⁵ are each independently H or unsubstituted C_1-6 alkyl. In certain embodiments, one of R⁹⁵, R⁹⁵ , and R⁹⁵ is H and R⁹⁵, R⁹⁵ , and R⁹⁵ are each independently H, CI, F, Br or I. In certain embodiments, two of R⁹⁵, R⁹⁵ , and R⁹⁵ are H and R⁹⁵, R⁹⁵ , and R⁹⁵ are each independently H, CI, F, Br, I, or unsubstituted C_1-6 alkyl. In certain embodiments, two of R⁹⁵, R⁹⁵ , and R⁹⁵ are H and R⁹⁵, R⁹⁵ , and R⁹⁵ are each independently H or unsubstituted C_1-6 alkyl. In certain embodiments, two of R⁹⁵, R⁹⁵ , and R⁹⁵ are H and R⁹⁵, R⁹⁵ , and R⁹⁵ are each independently H, CI, F, Br or I.

[00171] In certain embodiments, in compounds of general formula IV, B² is:

, wherein R⁹⁹ is H or substituted or unsubstituted lower alkyl; and R¹⁰⁰,

R¹⁰⁰ , and R^100" are each independently H, halogen or unsubstituted lower alkyl. In certain embodiments, in compounds of general formula IV, R⁹⁹ is H, unsubstituted lower alkyl or lower alkyl substituted with one or more substituents independently selected from the group consisting of OH, C_3-6 cycloalkyl, 5- to 10-membered heterocycloalkyl, C(0)OH, C(0)OR¹⁴⁰, H₂, R¹⁴¹R¹⁴², HC(0)OR¹⁴³, Ci_-6 alkoxy, CN, C(0) HR¹⁴⁴ and CO H₂; wherein R¹⁴⁰, R¹⁴¹, R¹⁴², and R¹⁴³ are each independently unsubstituted C_1-6 alkyl; R¹⁴⁴ is C_1-6 alkyl optionally substituted with one or more substituents independently selected from the group consisting of R¹⁴⁵R¹⁴⁶ and OH; and R¹⁴⁵ and R¹⁴⁶ are each independently unsubstituted Ci_-6 alkyl. In certain embodiments, in compounds of general formula IV, R⁹⁹ is unsubstituted lower alkyl or lower alkyl substituted with one or more substituents independently selected from the group consisting of OH, C_3-6 cycloalkyl, 5- to 10-membered heterocycloalkyl, C(0)OH, C(0)OR¹⁴⁰, H₂, R¹⁴¹R¹⁴², HC(0)OR¹⁴³, Ci_-6 alkoxy, CN, C(0)NHR¹⁴⁴ and CONH₂; wherein R¹⁴⁰, R¹⁴¹, R¹⁴², and R¹⁴³ are each independently unsubstituted Ci_-6 alkyl; R¹⁴⁴ is C_1-6 alkyl optionally substituted with one or more substituents independently selected from the group consisting of NR¹⁴⁵R¹⁴⁶ and OH; and R¹⁴⁵ and R¹⁴⁶ are each independently unsubstituted C_1-6 alkyl. In certain embodiments, in compounds of general formula IV, R⁹⁹ is unsubstituted lower alkyl; or unsubstituted C_1-5 alkyl; or unsubstituted C_1-4 alkyl; or unsubstituted Ci_-3 alkyl; or unsubstituted Ci_-2 alkyl; or CH₃; or H. In certain embodiments, in compounds of general formula IV, R¹⁰⁰, R¹⁰⁰', and R¹⁰⁰" are each independently H or unsubstituted lower alkyl; or halogen; or C_1-5 alkyl; or C_1-4 alkyl; or Ci_-3 alkyl; or Ci_-2 alkyl; or CH₃; or H. In certain embodiments, one of R¹⁰⁰, R¹⁰⁰', and R¹⁰⁰" is H and R¹⁰⁰, R¹⁰⁰', and R¹⁰⁰" are each independently H, CI, F, Br, I, or unsubstituted C_1-6 alkyl. In certain embodiments, one of R¹⁰⁰, R¹⁰⁰', and R¹⁰⁰" is H and R¹⁰⁰, R¹⁰⁰', and R¹⁰⁰" are each independently H or unsubstituted Ci_-6 alkyl. In certain embodiments, one of R¹⁰⁰, R¹⁰⁰', and R¹⁰⁰" is H and R¹⁰⁰, R¹⁰⁰', and R¹⁰⁰" are each independently H, CI, F, Br or I. In certain embodiments, two of R¹⁰⁰, R¹⁰⁰ , and R¹⁰⁰" are H and R¹⁰⁰, R¹⁰⁰', and R¹⁰⁰" are each independently H, CI, F, Br, I, or unsubstituted Ci_-6 alkyl. In certain embodiments, two of R¹⁰⁰, R¹⁰⁰', and R¹⁰⁰" are H and R¹⁰⁰, R¹⁰⁰', and R¹⁰⁰" are each independently H or unsubstituted Ci_-6 alkyl. In certain embodiments, two of R¹⁰⁰, R¹⁰⁰', and R¹⁰⁰" are H and R¹⁰⁰, R¹⁰⁰', and R¹⁰⁰" are each independently H, CI, F, Br or I.

[00172] In certain embodiments, in compounds of general formula IV, B² is:

, wherein R is H or substituted or unsubstituted lower alkyl; and R ,

R¹³⁸, R¹³⁹, R¹³⁹ , and R¹³⁹" are each independently H, halogen or unsubstituted lower alkyl. In certain embodiments, in compounds of general formula IV, R¹³⁶ is H, unsubstituted lower alkyl or lower alkyl substituted with one or more substituents independently selected from the group consisting of OH, C_3-6 cycloalkyl, 5- to 10-membered heterocycloalkyl, C(0)OH, C(0)OR¹⁴⁰, H₂, R¹⁴¹R¹⁴², HC(0)OR¹⁴³, Ci_-6 alkoxy, CN, C(0)NHR¹⁴⁴ and CO H₂; wherein R¹⁴⁰, R¹⁴¹, R¹⁴², and R¹⁴³ are each independently unsubstituted Ci_-6 alkyl; R¹⁴⁴ is Ci_-6 alkyl optionally substituted with one or more substituents independently selected from the group consisting of R¹⁴⁵R¹⁴⁶ and OH; and R¹⁴⁵ and R¹⁴⁶ are each independently unsubstituted Ci_-6 alkyl. In certain embodiments, in compounds of general formula TV, R¹³⁶ is unsubstituted lower alkyl or lower alkyl substituted with one or more substituents independently selected from the group consisting of OH, C_3-6 cycloalkyl, 5- to 10-membered heterocycloalkyl, C(0)OH, C(0)OR¹⁴⁰, H₂, R¹⁴¹R¹⁴², HC(0)OR¹⁴³, Ci_-6 alkoxy, CN, C(0)NHR¹⁴⁴ and CONH₂; wherein R¹⁴⁰, R¹⁴¹, R¹⁴², and R¹⁴³ are each independently unsubstituted Ci_-6 alkyl; R¹⁴⁴ is Ci_-6 alkyl optionally substituted with one or more substituents independently selected from the group consisting of NR¹⁴⁵R¹⁴⁶ and OH; and R¹⁴⁵ and R¹⁴⁶ are each independently unsubstituted Ci_-6 alkyl. In certain embodiments, in compounds of general formula IV, R¹³⁶ is unsubstituted lower alkyl; or unsubstituted C_1-5 alkyl; or unsubstituted C_1-4 alkyl; or unsubstituted Ci_-3 alkyl; or unsubstituted Ci_-2 alkyl; or CH₃; or H. In certain embodiments, in compounds of general formula IV, R¹³⁷, R¹³⁸, R¹³⁹, R¹³⁹ , and R¹³⁹" are each independently H or unsubstituted lower alkyl; or halogen; or C_1-5 alkyl; or C_1-4 alkyl; or Ci_-3 alkyl; or C1-2 alkyl; or CH₃; or H. In certain embodiments, one of R¹³⁷, R¹³⁸, R¹³⁹, R¹³⁹', and R¹³⁹" is H and R¹³⁷, R¹³⁸, R¹³⁹, R¹³⁹', and R¹³⁹" are each independently H, CI, F, Br, I, or unsubstituted Ci-6 alkyl. In certain embodiments, one of R¹³⁷, R¹³⁸, R¹³⁹, R¹³⁹', and R¹³⁹" is H and R¹³⁷, R¹³⁸, R¹³⁹, R¹³⁹ , and R¹³⁹" are each independently H or unsubstituted Ci_-6 alkyl. In certain embodiments, one of R¹³⁷, R¹³⁸, R¹³⁹, R¹³⁹', and R¹³⁹" is H and R¹³⁷, R¹³⁸, R¹³⁹, R¹³⁹', and R¹³⁹" are each independently H, CI, F, Br or I. In certain embodiments, two of R¹³⁷, R¹³⁸, R¹³⁹, R¹³⁹', and R¹³⁹" are H and R¹³⁷, R¹³⁸, R¹³⁹, R¹³⁹', and R¹³⁹" are each independently H, CI, F, Br, I, or unsubstituted Ci_-6 alkyl. In certain embodiments, two of R¹³⁷, R¹³⁸, R¹³⁹, R¹³⁹', and R¹³⁹" are H and R¹³⁷, R¹³⁸, R¹³⁹, R¹³⁹', and R¹³⁹" are each independently H or unsubstituted C_1-6 alkyl. In certain embodiments, two of R¹³⁷, R¹³⁸, R¹³⁹, R¹³⁹', and R¹³⁹" are H and R¹³⁷, R¹³⁸, R¹³⁹, R¹³⁹', and R¹³⁹" are each independently H, CI, F, Br or I. In certain embodiments, three of R¹³⁷, R¹³⁸, R¹³⁹, R¹³⁹', and R¹³⁹" are H and R¹³⁷, R¹³⁸, R¹³⁹, R¹³⁹', and R¹³⁹" are each independently H, CI, F, Br, I, or unsubstituted C_1-6 alkyl. In certain embodiments, three of R¹³⁷, R¹³⁸, R¹³⁹, R¹³⁹', and R¹³⁹" are H and R¹³⁷, R¹³⁸, R¹³⁹, R¹³⁹', and R¹³⁹" are each independently H or unsubstituted C_1-6 alkyl. In certain embodiments, three of R¹³⁷, R¹³⁸, R¹³⁹, R¹³⁹', and R¹³⁹" are H and R¹³⁷, R¹³⁸, R¹³⁹, R¹³⁹', and R¹³⁹" are each independently H, CI, F, Br or I. In certain embodiments, four of R¹³⁷, R¹³⁸, R¹³⁹, R¹³⁹', and R¹³⁹" are H and R¹³⁷, R¹³⁸, R¹³⁹, R¹³⁹ , and R¹³⁹" are each independently H, CI, F, Br, I, or unsubstituted C_1-6 alkyl. In certain embodiments, four of R¹³⁷, R¹³⁸, R¹³⁹, R¹³⁹', and R¹³⁹" are H and R¹³⁷, R¹³⁸, R¹³⁹, R¹³⁹', and R¹³⁹" are each independently H or unsubstituted C_1-6 alkyl. In certain embodiments, four of R¹³⁷, R¹³⁸, R¹³⁹, R¹³⁹', and R¹³⁹" are H and R¹³⁷, R¹³⁸, R¹³⁹, R¹³⁹', and R¹³⁹" are each independently H, CI, F, Br or I.

[00173] In certain embodiments, in compounds of general formula IV, B² is:

, wherein R⁹³, R^93', and R^93" are each independently H, halogen or unsubstituted lower alkyl. In certain embodiments, in compounds of general formula IV, R⁹³, R⁹³ , and R^93" are each independently H or unsubstituted lower alkyl; or halogen; or C_1-5 alkyl; or C_1-4 alkyl; or Ci_-3 alkyl; or Ci_-2 alkyl; or CH₃; or H. In certain embodiments, one of R⁹³, R⁹³ , and R^93" is H and R⁹³, R^93', and R^93" are each independently H, CI, F, Br, I, or unsubstituted C_1-6 alkyl. In certain embodiments, one of R⁹³, R⁹³ , and R^93" is H and R⁹³, R⁹³ , and R^93" are each independently H or unsubstituted Ci_-6 alkyl. In certain embodiments, one of R⁹³, R⁹³ , and R^93" is H and R⁹³, R⁹³ , and R^93" are each independently H, CI, F, Br or I. In certain embodiments, two of R⁹³, R⁹³ , and R^93" are H and R⁹³, R⁹³ , and R^93" are each independently H, CI, F, Br, I, or unsubstituted Ci_-6 alkyl. In certain embodiments, two of R⁹³, R⁹³ , and R^93" are H and R⁹³, R⁹³ , and R^93" are each independently H or unsubstituted Ci_-6 alkyl. In certain embodiments, two of R⁹³, R⁹³ , and R^93" are H and R⁹³, R⁹³ , and R^93" are each independently H, CI, F, Br or I. 00174] In certain embodiments, in compounds of general formula IV, B² is:

, wherein R and R are each independently H or substituted or unsubstituted lower alkyl; and R⁷⁴, R^74', R^{74 "}, R⁷⁶, R^76', and R^76" are each independently H, halogen or unsubstituted lower alkyl. In certain embodiments, in compounds of general formula IV, R⁷³ and R⁷⁵ are each independently H, unsubstituted lower alkyl or lower alkyl substituted with one or more substituents independently selected from the group consisting of OH, C_3-6 cycloalkyl, 5- to 10-membered heterocycloalkyl, C(0)OH, C(0)OR¹⁴⁰, H₂, R¹⁴¹R¹⁴², HC(0)OR¹⁴³, Ci-6 alkoxy, CN, C(0) HR¹⁴⁴ and CO H₂; wherein R¹⁴⁰, R¹⁴¹, R¹⁴², and R¹⁴³ are each independently unsubstituted Ci_-6 alkyl; R¹⁴⁴ is Ci_-6 alkyl optionally substituted with one or more substituents independently selected from the group consisting of R¹⁴⁵R¹⁴⁶ and OH; and R¹⁴⁵ and R¹⁴⁶ are each independently unsubstituted Ci_-6 alkyl. In certain embodiments, in compounds of general formula IV, R and R are each independently unsubstituted lower alkyl or lower alkyl substituted with one or more substituents independently selected from the group consisting of OH, C_3-6 cycloalkyl, 5- to 10-membered heterocycloalkyl, C(0)OH, C(0)OR¹⁴⁰, H₂, R¹⁴¹R¹⁴², HC(0)OR¹⁴³, Ci-6 alkoxy, CN, C(0) HR¹⁴⁴ and CO H₂; wherein R¹⁴⁰, R¹⁴¹, R¹⁴², and R¹⁴³ are each independently unsubstituted C_1-6 alkyl; R¹⁴⁴ is Ci_-6 alkyl optionally substituted with one or more substituents independently selected from the group consisting of R¹⁴⁵R¹⁴⁶ and OH; and R¹⁴⁵ and R¹⁴⁶ are each independently unsubstituted C_1-6 alkyl. In certain embodiments, in compounds of general formula IV, R⁷³ and R⁷⁵ are each independently unsubstituted lower alkyl; or unsubstituted C_1-5 alkyl; or unsubstituted C_1-4 alkyl; or unsubstituted Ci_-3 alkyl; or unsubstituted Ci_-2 alkyl; or CH₃; or H. In certain embodiments, in compounds of general formula IV, R⁷⁴, R⁷⁴ , R^{74 "}, R⁷⁶, R^76', and R^76" are each independently H or unsubstituted lower alkyl; or halogen; or C_1-5 alkyl; or C_1-4 alkyl; or Ci_-3 alkyl; or Ci_-2 alkyl; or CH₃; or H. 00175] In certain embodiments, in compounds of general formula IV, B² is:

, wherein R is H or substituted or unsubstituted lower alkyl; and R , R^74', and R^74" are each independently H, halogen or unsubstituted lower alkyl. In certain embodiments, in compounds of general formula IV, R⁷³ is H, unsubstituted lower alkyl or lower alkyl substituted with one or more substituents independently selected from the group consisting of OH, C_3-6 cycloalkyl, 5- to 10-membered heterocycloalkyl, C(0)OH, C(0)OR¹⁴⁰, H₂, R¹⁴¹R¹⁴², HC(0)OR¹⁴³, Ci_-6 alkoxy, CN, C(0)NHR¹⁴⁴ and CONH₂; wherein R¹⁴⁰, R¹⁴¹, R¹⁴², and R¹⁴³ are each independently unsubstituted C_1-6 alkyl; R¹⁴⁴ is C_1-6 alkyl optionally substituted with one or more substituents independently selected from the group consisting of NR¹⁴⁵R¹⁴⁶ and OH; and R¹⁴⁵ and R¹⁴⁶ are each independently unsubstituted Ci_-6 alkyl. In certain embodiments, in compounds of general formula IV, R⁷³ is unsubstituted lower alkyl or lower alkyl substituted with one or more substituents independently selected from the group consisting of OH, C_3-6 cycloalkyl, 5- to 10-membered heterocycloalkyl, C(0)OH, C(0)OR¹⁴⁰, NH₂, NR¹⁴¹R¹⁴², NHC(0)OR¹⁴³, Ci_-6 alkoxy, CN, C(0)NHR¹⁴⁴ and CONH₂; wherein R¹⁴⁰, R¹⁴¹, R¹⁴², and R¹⁴³ are each independently unsubstituted Ci_-6 alkyl; R¹⁴⁴ is C_1-6 alkyl optionally substituted with one or more substituents independently selected from the group consisting of NR R and OH; and R and R are each independently unsubstituted C_1-6 alkyl. In certain embodiments, in compounds of general formula IV, R⁷³ is unsubstituted lower alkyl; or unsubstituted C_1-5 alkyl; or unsubstituted C_1-4 alkyl; or unsubstituted C_1-3 alkyl; or unsubstituted Ci_-2 alkyl; or CH₃; or H. In certain embodiments, in compounds of general formula IV, R⁷⁴, R⁷⁴ , and R^74" are each independently H or unsubstituted lower alkyl; or halogen; or C_1-5 alkyl; or C_1-4 alkyl; or C_1-3 alkyl; or Ci_-2 alkyl; or CH₃; or H. In certain embodiments, one of R⁷⁴, R⁷⁴ , and R^74" is H and R⁷⁴, R⁷⁴ , and R^74" are each independently H, CI, F, Br, I, or unsubstituted C_1-6 alkyl. In certain embodiments, one of R⁷⁴, R⁷⁴ , and R^74" is H and R⁷⁴, R⁷⁴ , and R^74" are each independently H or unsubstituted C_1-6 alkyl. In certain embodiments, one of R⁷⁴, R⁷⁴ , and R^74" is H and R⁷⁴, R⁷⁴ , and R^74" are each independently H, CI, F, Br or I. In certain embodiments, two of R⁷⁴, R⁷⁴ , and R^74" are H and R⁷⁴, R⁷⁴ , and R^74" are each independently H, CI, F, Br, I, or unsubstituted C_1-6 alkyl. In certain embodiments, two of R⁷⁴, R⁷⁴ , and R^74" are H and R⁷⁴, R⁷⁴ , and R^74" are each independently H or unsubstituted C_1-6 alkyl. In certain embodiments, two of R⁷⁴, R⁷⁴ , and R^74" are H and R⁷⁴, R⁷⁴ , and R^74" are each independently H, CI, F, Br or I. 00176] In certain embodiments, in compounds of general formula IV, B² is:

, wherein R is H or substituted or unsubstituted lower alkyl; and R ,

R⁷⁶ , and R^76" are each independently H, halogen or unsubstituted lower alkyl. In certain embodiments, in compounds of general formula IV, R⁷⁵ is H, unsubstituted lower alkyl or lower alkyl substituted with one or more substituents independently selected from the group consisting of OH, C_3-6 cycloalkyl, 5- to 10-membered heterocycloalkyl, C(0)OH, C(0)OR¹⁴⁰, NH₂, NR¹⁴¹R¹⁴², NHC(0)OR¹⁴³, Ci_-6 alkoxy, CN, C(0)NHR¹⁴⁴ and CONH₂; wherein R¹⁴⁰, R¹⁴¹, R¹⁴², and R¹⁴³ are each independently unsubstituted C_1-6 alkyl; R¹⁴⁴ is C_1-6 alkyl optionally substituted with one or more substituents independently selected from the group consisting of NR¹⁴⁵R¹⁴⁶ and OH; and R¹⁴⁵ and R¹⁴⁶ are each independently unsubstituted Ci_-6 alkyl. In certain embodiments, in compounds of general formula IV, R⁷⁵ is unsubstituted lower alkyl or lower alkyl substituted with one or more substituents independently selected from the group consisting of OH, C_3-6 cycloalkyl, 5- to 10-membered heterocycloalkyl, C(0)OH, C(0)OR¹⁴°, H₂, R¹⁴¹R¹⁴², HC(0)OR¹⁴³, Ci_-6 alkoxy, CN, C(0) HR¹⁴⁴ and CO H₂; wherein R¹⁴⁰, R¹⁴¹, R¹⁴², and R¹⁴³ are each independently unsubstituted Ci_-6 alkyl; R¹⁴⁴ is Ci_-6 alkyl optionally substituted with one or more substituents independently selected from the group consisting of R¹⁴⁵R¹⁴⁶ and OH; and R¹⁴⁵ and R¹⁴⁶ are each independently unsubstituted Ci_-6 alkyl. In certain embodiments, in compounds of general formula IV, R⁷⁵ is unsubstituted lower alkyl; or unsubstituted Ci_-5 alkyl; or unsubstituted Ci-4 alkyl; or unsubstituted Ci_-3 alkyl; or unsubstituted Ci_-2 alkyl; or CH₃; or H. In certain embodiments, in compounds of general formula IV, R⁷⁶, R⁷⁶ , and R⁷⁶" are each independently H or unsubstituted lower alkyl; or halogen; or Ci_-5 alkyl; or Ci-4 alkyl; or Ci_-3 alkyl; or Ci_-2 alkyl; or CH₃; or H. In certain embodiments, one of R⁷⁶, R⁷⁶', and R⁷⁶" is H and R⁷⁶, R⁷⁶', and R⁷⁶" are each independently H, CI, F, Br, I, or unsubstituted Ci_-6 alkyl. In certain embodiments, one of R⁷⁶, R⁷⁶ , and R⁷⁶" is H and R⁷⁶, R⁷⁶ , and R⁷⁶" are each independently H or unsubstituted Ci_-6 alkyl. In certain embodiments, one of R⁷⁶, R⁷⁶', and R⁷⁶" is H and R⁷⁶, R⁷⁶', and R⁷⁶" are each independently H, CI, F, Br or I. In certain embodiments, two of R⁷⁶, R⁷⁶ , and R⁷⁶" are H and R⁷⁶, R⁷⁶ , and R⁷⁶" are each independently H, CI, F, Br, I, or unsubstituted Ci_-6 alkyl. In certain embodiments, two of R⁷⁶, R⁷⁶ , and R⁷⁶" are H and R⁷⁶, R⁷⁶ , and R⁷⁶" are each independently H or unsubstituted Ci_-6 alkyl. In certain embodiments, two of R⁷⁶, R⁷⁶', and R⁷⁶" are H and R⁷⁶, R⁷⁶', and R⁷⁶" are each independently H, CI, F, Br or I.

[00177] In certain embodiments, in compounds of general formula IV, B² is:

, wherein R^1U ' and R^luy are each independently H or substituted or unsubstituted lower alkyl; and R¹⁰⁸, R¹⁰⁸', R¹⁰⁸", R¹¹⁰, R¹¹⁰', and R¹¹⁰" are each independently H, halogen or unsubstituted lower alkyl. In certain embodiments, in compounds of general formula IV, R¹⁰⁷ and R¹⁰⁹ are each independently H, unsubstituted lower alkyl or lower alkyl substituted with one or more substituents independently selected from the group consisting of OH, C_3-6 cycloalkyl, 5- to 10-membered heterocycloalkyl, C(0)OH, C(0)OR¹⁴⁰, H₂, R¹⁴¹R¹⁴², HC(0)OR¹⁴³, Ci_-6 alkoxy, CN, C(0)NHR¹⁴⁴ and CONH₂; wherein R¹⁴⁰, R¹⁴¹, R¹⁴², and R¹⁴³ are each independently unsubstituted Ci_-6 alkyl; R¹⁴⁴ is Ci_-6 alkyl optionally substituted with one or more substituents independently selected from the group consisting of NR. R and OH; and R¹⁴⁵ and R¹⁴⁶ are each independently unsubstituted Ci_-6 alkyl. In certain embodiments, in compounds of general formula IV, R¹⁰⁷ and R¹⁰⁹ are each independently unsubstituted lower alkyl or lower alkyl substituted with one or more substituents independently selected from the group consisting of OH, C_3-6 cycloalkyl, 5- to 10-membered heterocycloalkyl, C(0)OH, C(0)OR¹⁴⁰, NH₂, NR¹⁴¹R¹⁴², NHC(0)OR¹⁴³, Ci_-6 alkoxy, CN, C(0)NHR¹⁴⁴ and CONH₂; wherein R¹⁴⁰, R¹⁴¹, R¹⁴², and R¹⁴³ are each independently unsubstituted C_1-6 alkyl; R¹⁴⁴ is C_1-6 alkyl optionally substituted with one or more substituents independently selected from the group consisting of NR¹⁴⁵R¹⁴⁶ and OH; and R¹⁴⁵ and R¹⁴⁶ are each independently unsubstituted Ci_-6 alkyl. In certain embodiments, in compounds of general formula IV, R¹⁰⁷ and R¹⁰⁹ are each independently unsubstituted lower alkyl; or unsubstituted C_1-5 alkyl; or unsubstituted C_1-4 alkyl; or unsubstituted Ci_-3 alkyl; or unsubstituted Ci_-2 alkyl; or CH₃; or H. In certain embodiments, in compounds of general formula IV, R¹⁰⁸, R¹⁰⁸', R¹⁰⁸", R¹¹⁰, R¹¹⁰', and R¹¹⁰" are each independently H or unsubstituted lower alkyl; or halogen; or C_1-5 alkyl; or C_1-4 alkyl; or Ci_-3 alkyl; or Ci_-2 alkyl; or CH₃; or H.

[00178] In certain embodiments, in compounds of general formula IV, B² is:

, wherein R is H or substituted or unsubstituted lower alkyl; and R

R¹⁰⁸ , and R¹⁰⁸" are each independently H, halogen or unsubstituted lower alkyl. In certain embodiments, in compounds of general formula IV, R¹⁰⁷ is H, unsubstituted lower alkyl or lower alkyl substituted with one or more substituents independently selected from the group consisting of OH, C_3-6 cycloalkyl, 5- to 10-membered heterocycloalkyl, C(0)OH, C(0)OR¹⁴⁰, NH₂, NR¹⁴¹R¹⁴², NHC(0)OR¹⁴³, Ci_-6 alkoxy, CN, C(0)NHR¹⁴⁴ and CONH₂; wherein R¹⁴⁰, R¹⁴¹, R¹⁴², and R¹⁴³ are each independently unsubstituted C_1-6 alkyl; R¹⁴⁴ is C_1-6 alkyl optionally substituted with one or more substituents independently selected from the group consisting of NR¹⁴⁵R¹⁴⁶ and OH; and R¹⁴⁵ and R¹⁴⁶ are each independently unsubstituted Ci_-6 alkyl. In certain embodiments, in compounds of general formula IV, R¹⁰⁷ is unsubstituted lower alkyl or lower alkyl substituted with one or more substituents independently selected from the group consisting of OH, C_3-6 cycloalkyl, 5- to 10-membered heterocycloalkyl, C(0)OH, C(0)OR¹⁴°, H₂, R¹⁴¹R¹⁴², HC(0)OR¹⁴³, Ci_-6 alkoxy, CN, C(0) HR¹⁴⁴ and CO H₂; wherein R¹⁴⁰, R¹⁴¹, R¹⁴², and R¹⁴³ are each independently unsubstituted Ci_-6 alkyl; R¹⁴⁴ is Ci_-6 alkyl optionally substituted with one or more substituents independently selected from the group consisting of R¹⁴⁵R¹⁴⁶ and OH; and R¹⁴⁵ and R¹⁴⁶ are each independently unsubstituted Ci_-6 alkyl. In certain embodiments, in compounds of general formula IV, R¹⁰⁷ is unsubstituted lower alkyl; or unsubstituted Ci_-5 alkyl; or unsubstituted Ci-4 alkyl; or unsubstituted Ci_-3 alkyl; or unsubstituted Ci_-2 alkyl; or CH₃; or H. In certain embodiments, in compounds of general formula IV, R¹⁰⁸, R¹⁰⁸ , and R¹⁰⁸" are each independently H or unsubstituted lower alkyl; or halogen; or Ci_-5 alkyl; or Ci-4 alkyl; or Ci_-3 alkyl; or Ci_-2 alkyl; or CH₃; or H. In certain embodiments, one of R¹⁰⁸, R¹⁰⁸', and R¹⁰⁸" is H and R¹⁰⁸, R¹⁰⁸', and R¹⁰⁸" are each independently H, CI, F, Br, I, or unsubstituted Ci_-6 alkyl. In certain embodiments, one of R¹⁰⁸, R¹⁰⁸', and R¹⁰⁸" is H and R¹⁰⁸, R¹⁰⁸', and R¹⁰⁸" are each independently H or unsubstituted Ci_-6 alkyl. In certain embodiments, one of R¹⁰⁸, R¹⁰⁸', and R¹⁰⁸" is H and R¹⁰⁸, R¹⁰⁸', and R¹⁰⁸" are each independently H, CI, F, Br or I. In certain embodiments, two of R¹⁰⁸, R¹⁰⁸ , and R¹⁰⁸" are H and R¹⁰⁸, R¹⁰⁸', and R¹⁰⁸" are each independently H, CI, F, Br, I, or unsubstituted Ci_-6 alkyl. In certain embodiments, two of R¹⁰⁸, R¹⁰⁸', and R¹⁰⁸" are H and R¹⁰⁸, R¹⁰⁸', and R¹⁰⁸" are each independently H or unsubstituted Ci_-6 alkyl. In certain embodiments, two of R¹⁰⁸, R¹⁰⁸', and R¹⁰⁸" are H and R¹⁰⁸, R¹⁰⁸', and R¹⁰⁸" are each independently H, CI, F, Br or I.

[00179] In certain embodiments, in compounds of general formula IV, B² is:

, wherein R¹⁰⁹ is H or substituted or unsubstituted lower alkyl; and R¹¹⁰,

R¹¹⁰ , and R¹¹⁰" are each independently H, halogen or unsubstituted lower alkyl. In certain embodiments, in compounds of general formula IV, R¹⁰⁹ is H, unsubstituted lower alkyl or lower alkyl substituted with one or more substituents independently selected from the group consisting of OH, C_3-6 cycloalkyl, 5- to 10-membered heterocycloalkyl, C(0)OH, C(0)OR¹⁴⁰, H₂, R¹⁴¹R¹⁴², HC(0)OR¹⁴³, Ci_-6 alkoxy, CN, C(0)NHR¹⁴⁴ and CONH₂; wherein R¹⁴⁰, R¹⁴¹, R¹⁴², and R¹⁴³ are each independently unsubstituted Ci_-6 alkyl; R¹⁴⁴ is Ci_-6 alkyl optionally substituted with one or more substituents independently selected from the group consisting of NR¹⁴⁵R¹⁴⁶ and OH; and R and R are each independently unsubstituted Ci_-6 alkyl. In certain embodiments, in compounds of general formula IV, R¹⁰⁹ is unsubstituted lower alkyl or lower alkyl substituted with one or more substituents independently selected from the group consisting of OH, C3-6 cycloalkyl, 5- to 10-membered heterocycloalkyl, C(0)OH, C(0)OR¹⁴⁰, H₂, R¹⁴¹R¹⁴², HC(0)OR¹⁴³, Ci_-6 alkoxy, CN, C(0) HR¹⁴⁴ and CO H₂; wherein R¹⁴⁰, R¹⁴¹, R¹⁴², and R¹⁴³ are each independently unsubstituted Ci_-6 alkyl; R¹⁴⁴ is Ci_-6 alkyl optionally substituted with one or more substituents independently selected from the group consisting of R¹⁴⁵R¹⁴⁶ and OH; and R¹⁴⁵ and R¹⁴⁶ are each independently unsubstituted Ci_-6 alkyl. In certain embodiments, in compounds of general formula IV, R¹⁰⁹ is unsubstituted lower alkyl; or unsubstituted Ci_-5 alkyl; or unsubstituted Ci-4 alkyl; or unsubstituted Ci_-3 alkyl; or unsubstituted Ci_-2 alkyl; or CH₃; or H. In certain embodiments, in compounds of general formula IV, R¹¹⁰, R¹¹⁰ , and R^110" are each independently H or unsubstituted lower alkyl; or halogen; or Ci_-5 alkyl; or Ci-4 alkyl; or Ci_-3 alkyl; or Ci_-2 alkyl; or CH₃; or H. In certain embodiments, one of R¹¹⁰, R^110', and R^110" is H and R¹¹⁰, R^110', and R^110" are each independently H, CI, F, Br, I, or unsubstituted Ci_-6 alkyl. In certain embodiments, one of R¹¹⁰, R^110', and R^110" is H and R¹¹⁰, R^110', and R^110" are each independently H or unsubstituted Ci_-6 alkyl. In certain embodiments, one of R¹¹⁰, R^110', and R^110" is H and R¹¹⁰, R^110', and R^110" are each independently H, CI, F, Br or I. In certain embodiments, two of R¹¹⁰, R¹¹⁰ , and R^110" are H and R¹¹⁰, R¹¹⁰ , and R^110" are each independently H, CI, F, Br, I, or unsubstituted Ci_-6 alkyl. In certain embodiments, two of R¹¹⁰, R^110', and R^110" are H and R¹¹⁰, R^110', and R^110" are each independently H or unsubstituted Ci_-6 alkyl. In certain embodiments, two of R¹¹⁰, R^110', and R^110" are H and R¹¹⁰, R¹¹⁰ , and R^110" are each independently H, CI, F, Br or I.

[00180] In certain embodiments, the compounds of general formula I are selected from compounds 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50, 51, 52, 53, 54, 55, 56, 57, 58, 59, 60, 61, 62, 63, 64, 65, 66, 67, 68, 69, 70, 71, 72, 73, 74, 75, 76, 77, 78, 79, 80, 81, 82, 83, 84, 85, 86, 87, 88, 89, 90, 91, 92, 93, 94, 95, 96, 97, 98, 99, 100, 101, 102, 103, 104, 105, 106, 107, 108, 109, 110, 111, 112, 113, 114, 115, 116, 117, 118, 200, 201, 202, 203, 204, 205, 206, 207, 208, 209, 210, 211, 212, 213, 214, 215, 216, 217, 218, 219, 220, 221, 222, 223, 225, 226, 227, 228, 229, 230, 231, 300, 301, 302, 303, 304, 305, 306, 307, 308, 309-a, 310, 311, 312, 313-a, 314, 315, 316, 317, 318, 319, 320, 321, 322, 323-a, 324, and 325, and salts thereof. [00181] Combinations of any of the foregoing embodiments described for compounds of general formula IV are also contemplated and each combination forms a separate embodiment for the purposes of the present disclosure.

[00182] In another aspect, the invention provides compounds of general formula V, or salts thereof:

Ar - B (V) wherein:

Ar is an aryl having general formula VI:

wherein:

_R-xro _R2oi^ _R2(K _R2(B _{and R}204 _{are each} independently H, CI, F, Br, I, or CF_3, wherein at least two of R²⁰⁰, R²⁰¹, R²⁰², R²⁰³, and R²⁰⁴ are not H; or R²⁰⁰ and R²⁰¹, when taken together with the C atoms they are attached to, form unsubstituted phenyl, and R²⁰², R²⁰³ and R²⁰⁴ are each H; and B is:

wherein:

R²⁰⁶ and R²⁰⁷ are each independently H, CI, CH₃, or C(0)R²¹¹; R²⁰⁹ is CH₃, CH₂OR CH₂OC(0)CH₃ or CH₂N₃; R²¹⁰ is phenyl or C(0) H₂;

R is H or CH₃; and wherein at least one of R²⁰⁵, R²⁰⁶, R²⁰⁷ and R²⁰⁸ is not H;

R²¹³ and R²¹⁶ are each independently H, F, NH₂, HC(0)R²¹⁷, N0₂, N₃ or

R²¹⁴ and R²¹⁵ are each independently H, F, CI, CH₃, or C(0)R²¹⁹; R²¹⁷ is CH₃, CH₂OR²²⁰, CH₂OC(0)CH₃ or CH₂N₃; R²¹⁸ is phenyl or C(0) H₂;

R²¹⁹ is (CH₂)₂OCH₃; ^"

^■

R²²⁰ is H or CH₃; R²²¹, R²²⁶, R²³¹, R²³⁶, R²⁴¹, R²⁴⁷, R²⁵², R²⁵⁷, R²⁶², R²⁶⁷ and R²⁹⁷ are each independently H or unsubstituted Ci_-6 alkyl; R²²², R²²³, R²²⁴, R²²⁷, R²²⁸, R²²⁹, R²³², R²³³, R²³⁴, > 237 > 238 τ> 239 τ> 242 τ> 243 τ> 244 τ> 245 τ> 246 τ> 248 τ> 249 τ> 250 τ> 253 τ> 254 τ> 255 τ> 258 τ> 259 τ> 260 R²⁶³, R²⁶⁴, R²⁶⁵, R²⁶⁸, R²⁶⁹, R²⁷⁰, R²⁹⁸, R²⁹⁹, R³⁰⁰, R³⁰¹, and R³⁰² are each independently H, CI,

F, Br, I or unsubstituted Ci_-6 alkyl; R²²⁵, R²³⁰, R²³⁵, R²⁴⁰, R²⁵¹, R²⁵⁶, R²⁶¹, R²⁶⁶, R²⁷¹ and R³⁰³ are each independently H, C(0)OR²⁷², C3-6 cycloalkyl, C_6-10 aryl, C_6-10 aryl-Ci-6 alkyl, or C_1-6 alkyl, wherein C_6-10 aryl is optionally substituted with one or more substituents independently selected from C_1-6 alkyl; C_6-10 aryl of C_6-10 aryl-Ci-6 alkyl is optionally substituted with one or more substituents independently selected from halogen; and C_1-6 alkyl is optionally substituted with one or more substituents independently selected from the group consisting of OH, C_3-6 cycloalkyl, 5- to 10-membered heterocycloalkyl, C(0)OH, C(0)OR²⁷³, NH₂,

R²⁷⁴R²⁷⁵, HC(0)OR²⁷⁸, Ci_-6 alkoxy, CN, C(0) HR²⁷⁹ and CO H₂; R²⁷², R²⁷³, R²⁷⁴, R²⁷⁵, and R²⁷⁸ are each independently unsubstituted C_1-6 alkyl; R²⁷⁹ is Ci_-6 alkyl optionally substituted with one or more substituents independently selected from the group consisting of R²⁸⁰R²⁸¹ and OH; R²⁸⁰ and R²⁸¹ are each independently unsubstituted Ci_-6 alkyl; Z¹⁴ is - CH2- or -C(O)-; and Z¹⁵ is -N- or -CH-, wherein:

(i) when R²⁰⁰ and R²⁰¹, when taken together with the C atoms they are attached to, form unsubstituted phenyl, and R²⁰², R²⁰³ and R²⁰⁴ are each H, and B

and only one of R²⁰⁵, R²⁰⁶, R²⁰⁷ and R²⁰⁸ is not H, then R²⁰⁵ and R²⁰⁸ are each independently H, F, H₂, HC(0)R²⁰⁹, N₃

or

; and R ^lJb and R ^{lJ /} are each independently H, CI, CH₃, or C(0)R²¹¹, wherein R²⁰⁹, R²¹⁰ and R²¹¹ are as defined above;

(ii) when R²⁰⁰ and R²⁰¹, when taken together with the C atoms they are attached to, form unsubstituted phenyl, and R²⁰², R²⁰³ and R²⁰⁴ are each H, and

is as defined above, then at least one of: R²¹³, R²¹⁴, R²¹⁵ and R²¹⁶; or R²³⁶, R²³⁷, R²³⁸, R²³⁹ and R²⁴⁰ is not H;

(iii) when R²⁰⁰ and R²⁰¹, when taken together with the C atoms they are attached to, form unsubstituted phenyl, and R²⁰², R²⁰³ and R²⁰⁴ are each H, and

B

wherein R²⁶¹ is unsubstituted Ci_-6 alkyl, then at least one of R , R , R and R is not H; (iv) when only R , R , and R are not H and each is a

halogen, and B

and only one of R²⁰⁵, R²⁰⁶, R²⁰⁷ and R²⁰⁸ is not H, then R²⁰⁵ and R²⁰⁸ are each independently H, F, HC(0)R²⁰⁹,

N==N

,210

N₃ or ⁴ ^ ; and R²⁰⁶ and R²⁰⁷ are each independently H, CI, or

C(0)R²¹¹, wherein R²⁰⁹, R²¹⁰ and R²¹¹ are as defined above; v) when R²⁰⁰, R²⁰¹, R²⁰², R²⁰³, and R²⁰⁴ are each a halogen, and B is

and only one of R²⁰⁵, R²⁰⁶, R²⁰⁷ and R²⁰⁸ is not H, then R²⁰⁵ and R²⁰⁸ are each independently H, F, NH₂, HC(0)R²⁰⁹, N₃ or

(vi) when only three of R²⁰⁰ R²⁰¹, R²⁰², R²⁰³, and R ^U4 are not H and each is a

halogen, and B is

Z¹⁵ is as defined above, or

, then at least one of: R²³⁶, R²³⁷, R²³⁸, R²³⁹ and

_R240 _{or R}241 _R242 _R243 _R244 _R245 ^ _R246 _{{ nQt ¾}

(vii) when only two of R²⁰⁰, R²⁰¹, R²⁰², R²⁰³, and R²⁰⁴ are not H and each is a halogen, and B is

ast one of: R²¹³, R²¹⁴, R²¹⁵ and R²¹⁶; or R²²¹, R²²², R²²³, R²²⁴ and R²²⁵; or R²²⁶, R²²⁷, R²²⁸, R²²⁹ and R²³⁰; or R²³¹, R²³², R²³³, R²³⁴ and R²³⁵; or R²³⁶, R²³⁷, R²³⁸, R²³⁹ and R²⁴⁰; or R²⁴¹, R²⁴², R²⁴³, R²⁴⁴, R²⁴⁵ and R²⁴⁶; or R²⁶², R²⁶³, R²⁶⁴, R²⁶⁵ and R²⁶⁶ is not H;

(viii) when only two of R^2UU, R^2U1, R^2U2, R^2U3, and R^2U4 are not H and each is a

halogen, and B is

wherein R ^4y is a halogen, then at least one of R²⁴⁷, R²⁴⁸, R²⁵⁰ and R²⁵¹ is not H; and

(ix) when only t f R²⁰⁰, R²⁰¹, R²⁰², R²⁰³, and R²⁰⁴ are not H and each is a

halogen, and B is

, then at least one of R²⁵⁷, R²⁵⁸,

R²⁵⁹, R²⁶⁰ and R²⁶¹ is not H, and when only one of R²⁵⁷, R²⁵⁸, R²⁵⁹, R²⁶⁰ and R²⁶¹ is not H, then R²⁵⁷ is H or unsubstituted Ci_-6 alkyl; R²⁵⁸, R²⁵⁹ and R²⁶⁰ are each independently H, CI, F, Br, I or unsubstituted Ci_-6 alkyl; and R²⁶¹ is H, C(0)OR²⁷², C6-io aryl, C6-10 aryl-Ci-6 alkyl, or Ci_-6 alkyl, wherein C6-10 aryl is optionally substituted with one or more substituents independently selected from Ci-6 alkyl; C₆-io aryl of C6-10 aryl-Ci-6 alkyl is optionally substituted with one or more substituents independently selected from halogen; and Ci_-6 alkyl is substituted with one or more substituents independently selected from the group consisting of OH, C3-6 cycloalkyl, 5- to 10-membered heterocycloalkyl, C(0)OH, C(0)OR²⁷³, H₂, R²⁷⁴R²⁷⁵, HC(0)OR²⁷⁸, Ci_-6 alkoxy, CN, C(0) HR²⁷⁹ and CO H₂, wherein R²⁷², R²⁷³, R²⁷⁴, R²⁷⁵, R²⁷⁸ and R²⁷⁹ are as defined above.

[00183] In certain embodiments, in compounds of general formula V, R²⁰⁰, R²⁰¹, R²⁰², R²⁰³, and R²⁰⁴ are each independently H, CI, I, F, Br, or CF₃, wherein at least two of R²⁰⁰, R²⁰¹, R²⁰², R²⁰³, and R²⁰⁴ are not H. [00184] In certain embodiments, in compounds of general formula V, R²⁰⁰ and R²⁰¹, taken together with the ring-forming C atoms that they are attached to, form unsubstituted phenyl, and R²⁰², R²⁰³, and R²⁰⁴ are each H.

[00185] In certain embodiments, in compounds of general formula V, R²⁰⁰, R²⁰¹, R²⁰², R²⁰³, and R²⁰⁴ are each independently H, CI, I, F, Br, or CF₃, wherein at least three of R²⁰⁰, R²⁰¹, R²⁰², R²⁰³, and R²⁰⁴ are not H.

[00186] In certain embodiments, in compounds of general formula V, R²⁰⁰, R²⁰¹, R²⁰², R²⁰³, and R²⁰⁴ are each independently H, CI, I, F, Br, or CF₃, wherein at least four of R²⁰⁰, R²⁰¹, R²⁰², R²⁰³, and R²⁰⁴ are not H. [00187] In certain embodiments, in compounds of general formula V, R²⁰⁰, R²⁰¹, R²⁰², R²⁰³, and R²⁰⁴ are each independently CI, I, F, Br, or CF₃.

[00188] In certain embodiments, in compounds of general formula V, R²⁰⁰, R²⁰¹, R²⁰², R²⁰³, and R²⁰⁴ are each independently CI, I, F, Br, or CF₃, wherein at least one of R²⁰⁰, R²⁰¹, R²⁰², R²⁰³, and R²⁰⁴ is CF₃. [00189] In certain embodiments, in compounds of general formula V, R²⁰⁰, R²⁰¹, R²⁰², R²⁰³, and R²⁰⁴ are each independently H, CI, I, F, Br, or CF₃, wherein four of R²⁰⁰, R²⁰¹, R²⁰², R²⁰³, and R²⁰⁴ are not H.

[00190] In certain embodiments, in compounds of general formula V, R²⁰⁰, R²⁰¹, R²⁰², R²⁰³, and R²⁰⁴ are each independently H, CI, I, F, Br, or CF₃, wherein four of R²⁰⁰, R²⁰¹, R²⁰², R²⁰³, and R²⁰⁴ are not H and at least one of R²⁰⁰, R²⁰¹, R²⁰², R²⁰³, and R²⁰⁴ is CF₃.

[00191] In certain embodiments, in compounds of general formula V, R²⁰⁰, R²⁰¹, R²⁰², R²⁰³, and R²⁰⁴ are each independently H, CI, I, F, Br, or CF₃, wherein three of R²⁰⁰, R²⁰¹, R²⁰², R²⁰³, and R²⁰⁴ are not H.

[00192] In certain embodiments, in compounds of general formula V, R²⁰⁰, R²⁰¹, R²⁰², R²⁰³, and R²⁰⁴ are each independently H, CI, I, F, Br, or CF₃, wherein three of R²⁰⁰, R²⁰¹, R²⁰², R²⁰³, and R²⁰⁴ are not H and at least one of R²⁰⁰, R²⁰¹, R²⁰², R²⁰³, and R²⁰⁴ is CF₃. [00193] In certain embodiments, in compounds of general formula V, R²⁰⁰, R²⁰¹, R²⁰², R²⁰³, and R²⁰⁴ are each independently H, CI, I, F, Br, or CF₃, wherein two of R²⁰⁰, R²⁰¹, R²⁰², R²⁰³, and R²⁰⁴ are not H.

[00194] In certain embodiments, in compounds of general formula V, R²⁰⁰, R²⁰¹, R²⁰², R²⁰³, and R²⁰⁴ are each independently H, CI, I, F, Br, or CF₃, wherein two of R²⁰⁰, R²⁰¹, R²⁰², R²⁰³, and R²⁰⁴ are not H and at least one of R²⁰⁰, R²⁰¹, R²⁰², R²⁰³, and R²⁰⁴is CF₃.

[00195] In certain embodiments, in compounds of general formula V, two of R²⁰⁰-R²⁰⁴ are each CI, I, F or CF₃, and the remaining R²⁰⁰.R²⁰⁴ are H.

[00196] In certain embodiments, in compounds of general formula V, two of R²⁰⁰-R²⁰⁴ are each CI, F or CF₃, and the remaining R²⁰⁰.R²⁰⁴ are H.

[00197] In certain embodiments, in compounds of general formula V, two of R²⁰⁰-R²⁰⁴ are each independently CI or CF₃, and the remaining R²⁰⁰.R²⁰⁴ are H.

[00198] In certain embodiments, in compounds of general formula V, two of R²⁰⁰-R²⁰⁴ are each CI, and the remaining R ⁰⁰.R²⁰⁴ are H. [00199] In certain embodiments, in compounds of general formula V, two of R²⁰⁰-R²⁰⁴ are each CF₃, and the remaining R ⁰⁰.R²⁰⁴ are H.

[00200] In certain embodiments, in compounds of general formula V, R²⁰⁰ is CI, F, Br, I, or CF₃; R²⁰³ and R²⁰⁴ are each independently H, CI, F, Br, I, or CF₃, wherein at least one of R²⁰³ and R²⁰⁴ is not H; and R²⁰¹ and R²⁰² are each H. [00201] In certain embodiments, in compounds of general formula V, R²⁰⁰ and R²⁰⁴ are each independently CI, F, Br, I, or CF₃; and R²⁰¹, R²⁰² and R²⁰³ are each H.

[00202] In certain embodiments, in compounds of general formula V, R²⁰⁰ is CI, I, F or CF₃; R²⁰³ and R²⁰⁴ are each independently H, CI, I, F or CF₃, wherein at least one of R²⁰³ and R²⁰⁴ is not H; and R²⁰¹ and R²⁰² are each H. [00203] In certain embodiments, in compounds of general formula V, R is CI, F or CF₃; R and R²⁰⁴ are each independently H, CI, F or CF₃, wherein at least one of R²⁰³ and R²⁰⁴ is not H; and R²⁰¹ and R²⁰² are each H.

[00204] In certain embodiments, in compounds of general formula V, R²⁰⁰ is CI or CF₃; R²⁰³ and R²⁰⁴ are each independently H, CI or CF₃, wherein at least one of R²⁰³ and R²⁰⁴ is not H; and R²⁰¹ and R²⁰² are each H.

[00205] In certain embodiments, in compounds of general formula V, R²⁰⁰ and R²⁰³ are each independently CI, I, F or CF₃; and R²⁰¹, R²⁰² and R²⁰⁴ are each H.

[00206] In certain embodiments, in compounds of general formula V, R²⁰⁰ and R²⁰³ are each independently CI, F or CF₃; and R²⁰¹, R²⁰² and R²⁰⁴ are each H.

[00207] In certain embodiments, in compounds of general formula V, R²⁰⁰ and R²⁰³ are each independently CI or CF₃; and R²⁰¹, R²⁰² and R²⁰⁴ are each H.

[00208] In certain embodiments, in compounds of general formula V, R²⁰⁰ and R²⁰³ are each CI; and R²⁰¹, R²⁰² and R²⁰⁴ are each H. [00209] In certain embodiments, in compounds of general formula V, R²⁰⁰ is CI and R²⁰³ is CF₃; and R²⁰¹, R²⁰² and R²⁰⁴ are each H.

[00210] In certain embodiments, in compounds of general formula V, R²⁰⁰ and R²⁰³ are each CF₃; and R²⁰¹, R²⁰² and R²⁰⁴ are each H.

[00211] In certain embodiments, in compounds of general formula V, R²⁰⁰ and R²⁰⁴ are each independently CI, I, F or CF₃; and R²⁰¹, R²⁰² and R²⁰³ are each H.

[00212] In certain embodiments, in compounds of general formula V, R²⁰⁰ and R²⁰⁴ are each independently CI, F or CF₃; and R²⁰¹, R²⁰² and R²⁰³ are each H.

[00213] In certain embodiments, in compounds of general formula V, R²⁰⁰ and R²⁰⁴ are each independently CI or CF₃; and R²⁰¹, R²⁰² and R²⁰³ are each H. [00214] In certain embodiments, in compounds of general formula V, R is CI and R is CF₃; and R²⁰¹, R²⁰² and R²⁰³ are each H.

[00215] In certain embodiments, in compounds of general formula V, R²⁰⁰ and R²⁰⁴ are each CI; and R²⁰¹, R²⁰² and R²⁰³ are each H.

[00216] In certain embodiments, in compounds of general formula V, R²⁰⁰ and R²⁰⁴ are each CF₃; and R²⁰¹, R²⁰² and R²⁰³ are each H.

[00217] In certain embodiments, in compounds of general formula V, B is:

anywhere herein.

[00218] In certain embodiments, in compounds of general formula V, B is:

[00219] In certain embodiments, in compounds of general formula V, B is:

are as defined anywhere herein.

[00220] In certain embodiments, in compounds of general formula V, B is:

or wherein R²²¹, R²²⁶, R²²² R²²³, R²²⁴,

R²²⁷, R²²⁸, R²²⁹, R²²⁵ and R²³⁰ are as defined anywhere herein.

[00221] In certain embodiments, in compounds of general formula V, B is:

, wherein R , R , R and R are as defined anywhere herein. In certain embodiments, R and R are each independently H, NH₂, HC(0)R²⁰⁹, N0₂, or N₃ wherein at least one of R²⁰⁵ and R²⁰⁸ is not H; R²⁰⁶ and R²⁰⁷ are each H; R²⁰⁹ is CH₃, CH₂OR²¹², CH₂OC(0)CH₃ or CH₂N₃; and R²¹² is H or CH₃. In certain embodiments, R²⁰⁵ and R²⁰⁸ are each independently H, H₂, or HC(0)R²⁰⁹ wherein at least one of R²⁰⁵ and R²⁰⁸ is not H; R²⁰⁶ and R²⁰⁷ are each H; R²⁰⁹ is CH₃, CH₂OR²¹², CH₂OC(0)CH₃ or CH₂N₃; and R²¹² is H or CH₃. In certain embodiments, R²⁰⁵ and R²⁰⁸ are each independently H, HC(0)R²⁰⁹ or N0₂ wherein at least one of R²⁰⁵ and R²⁰⁸ is not H; R²⁰⁶ and R²⁰⁷ are each H; R²⁰⁹ is CH₃, CH₂OR²¹², CH₂OC(0)CH₃ or CH₂N₃; and R²¹² is H or CH₃. In certain embodiments, R²⁰⁵ is HC(0)R²⁰⁹; R²⁰⁶, R²⁰⁷ and R²⁰⁸ are each H; R²⁰⁹ is CH₃, CH₂OR²¹², CH₂OC(0)CH₃ or CH₂N₃; and R²¹² is H or CH₃. In certain embodiments, R²⁰⁹ is CH₃, CH₂OR²¹² or CH₂OC(0)CH₃; and R²¹² is H or CH₃. 00222] In certain embodiments, in compounds of general formula V, B is:

, wherein R²³⁶, R²³⁷, R²³⁸, R²³⁹, R²⁴⁰ and Z¹⁵ are as defined anywhere herein. In certain embodiments, at least one of R , R , R , R , and R is not H. In other embodiments, R²³⁶, R²³⁷, R²³⁸, R²³⁹, and R²⁴⁰ are each H. In certain embodiments, in compounds of general formula V, R is H or C_1-4 alkyl; or H or Ci_-3 alkyl; or H or Ci_-2 alkyl; or; H or CH₃. In certain embodiments, R²³⁶ is unsubstituted lower alkyl; or C_1-4 alkyl; or Ci_-3 alkyl; or Ci_-2 alkyl; or CH₃. In other embodiments, R²³⁶ is H. In certain embodiments, in compounds of general formula V, R²³⁷, R²³⁸, and R²³⁹ are each independently H or unsubstituted C_1-6 alkyl; or CI, F, Br, or I; or Ci-5 alkyl; or C_1-4 alkyl; or Ci_-3 alkyl; or Ci_-2 alkyl; or CH₃; or H. In certain embodiments, one of R²³⁷, R²³⁸, and R²³⁹ is H and R²³⁷, R²³⁸, and R²³⁹ are each independently H, CI, F, Br, I, or unsubstituted Ci_-6 alkyl. In certain embodiments, one of R²³⁷, R²³⁸, and R²³⁹ is H and R²³⁷, R²³⁸, and R²³⁹ are each independently H or unsubstituted C_1-6 alkyl. In certain embodiments, one of R²³⁷, R²³⁸, and R²³⁹ is H and R²³⁷, R²³⁸, and R²³⁹ are each independently H, CI, F, Br or I. In certain embodiments, two of R²³⁷, R²³⁸, and R²³⁹ are H and R²³⁷, R²³⁸, and R²³⁹ are each independently H, CI, F, Br, I, or unsubstituted C_1-6 alkyl. In certain embodiments, two of R²³⁷, R²³⁸, and R²³⁹ are H and R²³⁷, R²³⁸, and R²³⁹ are each independently H or unsubstituted C_1-6 alkyl. In certain embodiments, two of R²³⁷, R²³⁸, and R²³⁹ are H and R²³⁷, R²³⁸, and R²³⁹ are each independently H, CI, F, Br or I. In certain embodiments, in compounds of general formula V, R²⁴⁰ is unsubstituted Ci-6 alkyl or C_1-6 alkyl substituted with one or more substituents independently selected from the group consisting of OH, C_3-6 cycloalkyl, 5- to 10-membered heterocycloalkyl, C(0)OH, C(0)OR²⁷³, H₂, R²⁷⁴R²⁷⁵, HC(0)OR²⁷⁸, Ci_-6 alkoxy, CN, C(0) HR²⁷⁹ and CO H₂; wherein R²⁷³, R²⁷⁴, R²⁷⁵, and R²⁷⁸ are each independently unsubstituted Ci_-6 alkyl; R²⁷⁹ is Ci_-6 alkyl optionally substituted with one or more substituents independently selected from the group consisting of R²⁸⁰R²⁸¹ and OH; and R²⁸⁰ and R²⁸¹ are each independently unsubstituted Ci-6 alkyl. In certain embodiments, R²⁴⁰ is unsubstituted Ci_-6 alkyl; or unsubstituted Ci_-5 alkyl; unsubstituted Ci-4 alkyl; unsubstituted Ci_-3 alkyl; or unsubstituted Ci_-2 alkyl; or CH₃; or H. In certain embodiments, Z¹⁵ is -N-. In other embodiments, Z¹⁵ is -CH-.

[00223] In certain embodiments, in compounds of general formula V, B is:

, wherein R²¹³, R²¹⁶, R²¹⁴ and R²¹⁵ are as defined anywhere herein. In certain embodiments, at least one of R²¹³, R²¹⁶, R²¹⁴ and R²¹⁵ is not H. In other embodiments, R R²¹⁶, R²¹⁴ and R²¹⁵ are each H. In certain embodiments, R²¹³ and R²¹⁶ are each independently H, H₂, HC(0)R²¹⁷, N0₂, or N3 wherein at least one of R²¹³ and R²¹⁶ is not H; R²¹⁴ and R²¹⁵ are each H; R²¹⁷ is CH₃, CH2OR²²⁰, CH₂OC(0)CH₃ or CH₂N₃; and R²²⁰ is H or CH₃. In certain embodiments, R²¹³ and R²¹⁶ are each independently H, H₂, or HC(0)R²¹⁷ wherein at least one of R²¹³ and R²¹⁶ is not H; R²¹⁴ and R²¹⁵ are each H; R²¹⁷ is CH₃, CH2OR²²⁰, CH₂OC(0)CH₃ or CH₂N₃; and R²²⁰ is H or CH₃. In certain embodiments, R²¹³ and R²¹⁶ are each independently H, N0₂, or HC(0)R²¹⁷ wherein at least one of R²¹³ and R²¹⁶ is not H; R²¹⁴ and R²¹⁵ are each H; R²¹⁷ is CH₃, CH2OR²²⁰, CH₂OC(0)CH₃ or CH₂N₃; and R²²⁰ is H or CH₃. In certain embodiments, R²¹³ is HC(0)R²¹⁷; R²¹⁴, R²¹⁵ and R²¹⁶ are each H; R²¹⁷ is CH₃, CH2OR²²⁰, CH₂OC(0)CH₃ or CH₂N₃; and R²²⁰ is H or CH₃. In certain embodiments, R²¹⁷ is CH₃, CH2OR²²⁰ or CH₂OC(0)CH₃; and R²²⁰ is H or CH₃. 00224] In certain embodiments, in compounds of general formula V, B is:

, wherein R²⁴¹, R²⁴², R²⁴³, R²⁴⁴, R²⁴⁵, and R²⁴⁶ are as defined anywhere herein. In certain embodiments, at least one of R²⁴¹, R²⁴², R²⁴³, R²⁴⁴, R²⁴⁵, and R²⁴⁶ is not H. In other embodiments, R²⁴¹, R²⁴², R²⁴³, R²⁴⁴, R²⁴⁵, and R²⁴⁶ are each H. In certain embodiments, in compounds of general formula V, R²⁴¹ is H or C_1-4 alkyl; or H or Ci_-3 alkyl; or H or Ci_-2 alkyl; or; H or CH₃. In certain embodiments, R²⁴¹ is unsubstituted lower alkyl; or C_1-4 alkyl; or Ci_-3 alkyl; or Ci-2 alkyl; or CH₃. In other embodiments, R²⁴¹ is H. In certain embodiments, in compounds of general formula V, R²⁴², R²⁴³, R²⁴⁴, R²⁴⁵, and R²⁴⁶ are each independently H or unsubstituted C_1-6 alkyl; or CI, F, Br, or I; or C_1-5 alkyl; or C_1-4 alkyl; or Ci_-3 alkyl; or Ci_-2 alkyl; or CH₃; or H. In certain embodiments, one of R²⁴², R²⁴³, R²⁴⁴, R²⁴⁵, and R²⁴⁶ is H and R²⁴², R²⁴³, R²⁴⁴, R²⁴⁵, and R²⁴⁶ are each independently H, CI, F, Br, I, or unsubstituted C_1-6 alkyl. In certain embodiments, one of R²⁴², R²⁴³, R²⁴⁴, R²⁴⁵, and R²⁴⁶ is H and R²⁴², R²⁴³, R²⁴⁴, R²⁴⁵, and R²⁴⁶ are each independently H or unsubstituted C_1-6 alkyl. In certain embodiments, one of R²⁴², R²⁴³, R²⁴⁴, R²⁴⁵, and R²⁴⁶ is H and R²⁴², R²⁴³, R²⁴⁴, R²⁴⁵, and R²⁴⁶ are each independently H, CI, F, Br or I. In certain embodiments, two of R²⁴², R²⁴³, R²⁴⁴, R²⁴⁵, and R²⁴⁶ are H and R²⁴², R²⁴³, R²⁴⁴, R²⁴⁵, and R²⁴⁶ are each independently H, CI, F, Br, I, or unsubstituted C_1-6 alkyl. In certain embodiments, two of R²⁴², R²⁴³, R²⁴⁴, R²⁴⁵, and R²⁴⁶ are H and R²⁴², R²⁴³, R²⁴⁴, R²⁴⁵, and R²⁴⁶ are each independently H or unsubstituted Ci_-6 alkyl. In certain embodiments, two of R²⁴², R²⁴³, R²⁴⁴, R²⁴⁵, and R²⁴⁶ are H and R²⁴², R²⁴³, R²⁴⁴, R²⁴⁵, and R²⁴⁶ are each independently H, CI, F, Br or I. In certain embodiments, three of R²⁴², R²⁴³, R²⁴⁴, R²⁴⁵, and R²⁴⁶ are H and R²⁴², R²⁴³, R²⁴⁴, R²⁴⁵, and R²⁴⁶ are each independently H, CI, F, Br, I, or unsubstituted Ci_-6 alkyl. In certain embodiments, three of R²⁴², R²⁴³, R²⁴⁴, R²⁴⁵, and R²⁴⁶ are H and R²⁴², R²⁴³, R²⁴⁴, R²⁴⁵, and R²⁴⁶ are each independently H or unsubstituted Ci_-6 alkyl. In certain embodiments, three of R²⁴², R²⁴³, R²⁴⁴, R²⁴⁵, and R²⁴⁶ are H and R²⁴², R²⁴³, R²⁴⁴, R²⁴⁵, and R²⁴⁶ are each independently H, CI, F, Br or I. In certain embodiments, four of R²⁴², R²⁴³, R²⁴⁴, R²⁴⁵, and R²⁴⁶ are H and R²⁴², R²⁴³, R²⁴⁴, R²⁴⁵, and R²⁴⁶ are each independently H, CI, F, Br, I, or unsubstituted Ci_-6 alkyl. In certain embodiments, four of R²⁴², R²⁴³, R²⁴⁴, R²⁴⁵, and R²⁴⁶ are H and R²⁴², R²⁴³, R²⁴⁴, R²⁴⁵, and R²⁴⁶ are each independently H or unsubstituted Ci_-6 alkyl. In certain embodiments, four of R²⁴², R²⁴³, R²⁴⁴, R²⁴⁵, and R²⁴⁶ are H and R²⁴², R²⁴³, R²⁴⁴, R²⁴⁵, and R²⁴⁶ are each independently H, CI, F, Br or I.

[00225] In certain embodiments, in compounds of general formula V, B is:

, wherein R²⁴⁷, R²⁴⁸, R²⁴⁹, R²⁵⁰, and R²⁵¹ are as defined anywhere herein. In certain embodiments, at least one of R²⁴⁷, R²⁴⁸, R²⁴⁹, R²⁵⁰, and R²⁵¹ is not H. In other embodiments, R²⁴⁷, R²⁴⁸, R²⁴⁹, R²⁵⁰, and R²⁵¹ are each H. In certain embodiments, in compounds of general formula V, R²⁴⁷ is H or Ci-4 alkyl; or H or Ci_-3 alkyl; or H or Ci_-2 alkyl; or; H or CH₃. In certain embodiments, R²⁴⁷ is unsubstituted lower alkyl; or Ci-4 alkyl; or Ci_-3 alkyl; or Ci_-2 alkyl; or CH₃. In other embodiments, R²⁴⁷ is H. In certain embodiments, in compounds of general formula V, R²⁴⁸, R²⁴⁹ and R²⁵⁰ are each independently H or unsubstituted Ci_-6 alkyl; or CI, F, Br, or I; or Ci-5 alkyl; or Ci-4 alkyl; or Ci_-3 alkyl; or Ci_-2 alkyl; or CH₃; or H. In certain embodiments, one of R²⁴⁸, R²⁴⁹ and R²⁵⁰ is H and R²⁴⁸, R²⁴⁹ and R²⁵⁰ are each independently H, CI, F, Br, I, or unsubstituted Ci_-6 alkyl. In certain embodiments, one of R²⁴⁸, R²⁴⁹ and R²⁵⁰ is H and R²⁴⁸, R²⁴⁹ and R²⁵⁰ are each independently H or unsubstituted Ci_-6 alkyl. In certain embodiments, one of R²⁴⁸, R²⁴⁹ and R²⁵⁰ is H and R²⁴⁸, R²⁴⁹ and R²⁵⁰ are each independently H, CI, F, Br or I. In certain embodiments, two of R , R and R are H and R , R and R are each independently H, CI, F, Br, I, or unsubstituted Ci_-6 alkyl. In certain embodiments, two of R²⁴⁸, R²⁴⁹ and R²⁵⁰ are H and R²⁴⁸, R²⁴⁹ and R²⁵⁰ are each independently H or unsubstituted Ci_-6 alkyl. In certain embodiments, two of R²⁴⁸, R²⁴⁹ and R²⁵⁰ are H and R²⁴⁸, R²⁴⁹ and R²⁵⁰ are each independently H, CI, F, Br or I. In certain embodiments, R²⁴⁹ is H or unsubstituted Ci_-6 alkyl. In certain embodiments, in compounds of general formula V, R²⁵¹ is unsubstituted Ci_-6 alkyl or Ci_-6 alkyl substituted with one or more substituents independently selected from the group consisting of OH, C_3-6 cycloalkyl, 5- to 10-membered heterocycloalkyl, C(0)OH, C(0)OR²⁷³, H₂, R²⁷⁴R²⁷⁵, HC(0)OR²⁷⁸, Ci-6 alkoxy, CN, C(0) HR²⁷⁹ and CO H₂; wherein R²⁷³, R²⁷⁴, R²⁷⁵, and R²⁷⁸ are each independently unsubstituted Ci_-6 alkyl; R²⁷⁹ is Ci_-6 alkyl optionally substituted with one or more substituents independently selected from the group consisting of R²⁸⁰R²⁸¹ and OH; and R²⁸⁰ and R²⁸¹ are each independently unsubstituted Ci_-6 alkyl. In certain embodiments, R²⁵¹ is unsubstituted Ci_-6 alkyl; or unsubstituted Ci_-5 alkyl; unsubstituted Ci-4 alkyl; unsubstituted Ci_-3 alkyl; or unsubstituted Ci_-2 alkyl; or CH₃; or H.

[00226] In certain embodiments, in compounds of general formula V, B is:

, wherein R²⁵⁷, R²⁵⁸, R²⁵⁹, R²⁶⁰ and R²⁶¹ are as defined anywhere herein.

In certain embodiments, at least one of R²⁵⁷, R²⁵⁸, R²⁵⁹, R²⁶⁰ and R²⁶¹ is not H. In other embodiments, R²⁵⁷, R²⁵⁸, R²⁵⁹, R²⁶⁰ and R²⁶¹ are each H. In certain embodiments, in compounds of general formula V, R²⁵⁷ is H or Ci-4 alkyl; or H or Ci_-3 alkyl; or H or Ci_-2 alkyl; or; H or CH₃. In certain embodiments, R²⁵⁷ is unsubstituted lower alkyl; or Ci-4 alkyl; or Ci_-3 alkyl; or Ci_-2 alkyl; or CH₃. In other embodiments, R²⁵⁷ is H. In certain embodiments, in compounds of general formula V, R²⁵⁸, R²⁵⁹, and R²⁶⁰ are each independently H or unsubstituted Ci_-6 alkyl; or CI, F, Br, or I; or Ci-5 alkyl; or Ci-4 alkyl; or Ci_-3 alkyl; or Ci_-2 alkyl; or CH₃; or H. In certain embodiments, one of R²⁵⁸, R²⁵⁹, and R²⁶⁰ is H and R²⁵⁸, R²⁵⁹, and R²⁶⁰ are each independently H, CI, F, Br, I, or unsubstituted Ci_-6 alkyl. In certain embodiments, one of R²⁵⁸, R²⁵⁹, and R²⁶⁰ is H and R²⁵⁸, R²⁵⁹, and R²⁶⁰ are each independently H or unsubstituted Ci_-6 alkyl. In certain embodiments, one of R²⁵⁸, R , and R is H and R , R , and R are each independently H, CI, F, Br or I. In certain embodiments, two of R²⁵⁸, R²⁵⁹, and R²⁶⁰ are H and R²⁵⁸, R²⁵⁹, and R²⁶⁰ are each independently H, CI, F, Br, I, or unsubstituted Ci_-6 alkyl. In certain embodiments, two of R²⁴², R²⁵⁸, R²⁵⁹, and R²⁶⁰ are H and R²⁵⁸, R²⁵⁹, and R²⁶⁰ are each independently H or unsubstituted Ci_-6 alkyl. In certain embodiments, two of R²⁵⁸, R²⁵⁹, and R²⁶⁰ are H and R²⁵⁸, R²⁵⁹, and R²⁶⁰ are each independently H, CI, F, Br or I. In certain embodiments, in compounds of general formula V, R²⁶¹ is unsubstituted Ci-6 alkyl or Ci_-6 alkyl substituted with one or more substituents independently selected from the group consisting of OH, C3-6 cycloalkyl, 5- to 10-membered heterocycloalkyl, C(0)OH, C(0)OR²⁷³, H₂, R²⁷⁴R²⁷⁵, HC(0)OR²⁷⁸, Ci_-6 alkoxy, CN, C(0) HR²⁷⁹ and CO H₂; wherein R²⁷³, R²⁷⁴, R²⁷⁵, and R²⁷⁸ are each independently unsubstituted Ci_-6 alkyl; R²⁷⁹ is Ci_-6 alkyl optionally substituted with one or more substituents independently selected from the group consisting of R²⁸⁰R²⁸¹ and OH; and R²⁸⁰ and R²⁸¹ are each independently unsubstituted Ci_-6 alkyl. In certain embodiments, R²⁶¹ is Ci_-6 alkyl substituted with one or more substituents independently selected from the group consisting of OH, C3-6 cycloalkyl, 5- to 10-membered heterocycloalkyl, C(0)OH, C(0)OR²⁷³, H₂, R²⁷⁴R²⁷⁵, HC(0)OR²⁷⁸, Ci_-6 alkoxy, CN, C(0)NHR²⁷⁹ and CONH2; wherein R²⁷³, R²⁷⁴, R²⁷⁵, and R²⁷⁸ are each independently unsubstituted Ci_-6 alkyl; R²⁷⁹ is Ci-6 alkyl optionally substituted with one or more substituents independently selected from the group consisting of NR²⁸⁰R²⁸¹ and OH; and R²⁸⁰ and R²⁸¹ are each independently unsubstituted Ci- 6 alkyl. In certain embodiments, R²⁶¹ is unsubstituted Ci_-6 alkyl; or unsubstituted Ci_-5 alkyl; unsubstituted Ci-4 alkyl; unsubstituted Ci_-3 alkyl; or unsubstituted Ci_-2 alkyl; or CH₃; or H.

[00227] In certain embodiments, in compounds of general formula V, B is:

, wherein R²³¹, R²³², R²³³, R²³⁴, R²³⁵ and Z¹⁴ are as defined anywhere herein. In certain embodiments, at least one of R²³¹, R²³², R²³³, R²³⁴, and R²³⁵ is not H. In other embodiments, R²³¹, R²³², R²³³, R²³⁴, and R²³⁵ are each H. In certain embodiments, in compounds of general formula V, R²³¹ is H or Ci-4 alkyl; or H or Ci_-3 alkyl; or H or Ci_-2 alkyl; or; H or CH₃. In certain embodiments, R²³¹ is unsubstituted lower alkyl; or C_1-4 alkyl; or Ci_-3 alkyl; or Ci_-2 alkyl; or CH₃. In other embodiments, R²³¹ is H. In certain embodiments, in compounds of general formula V, R²³², R²³³, and R²³⁴ are each independently H or unsubstituted C_1-6 alkyl; or CI, F, Br, or I; or C_1-5 alkyl; or C_1-4 alkyl; or Ci_-3 alkyl; or Ci_-2 alkyl; or CH₃; or H. In certain embodiments, one of R²³², R²³³, and R²³⁴ is H and R²³², R²³³, and R²³⁴ are each independently H, CI, F, Br, I, or unsubstituted C_1-6 alkyl. In certain embodiments, one of R²³², R²³³, and R²³⁴ is H and R²³², R²³³, and R²³⁴ are each independently H or unsubstituted C_1-6 alkyl. In certain embodiments, one of R²³², R²³³, and R²³⁴ is H and R²³², R²³³, and R²³⁴ are each independently H, CI, F, Br or I. In certain embodiments, two of R²³², R²³³, and R²³⁴ are H and R²³², R²³³, and R²³⁴ are each independently H, CI, F, Br, I, or unsubstituted C_1-6 alkyl. In certain embodiments, two of R²³², R²³³, and R²³⁴ are H and R²³², R²³³, and R²³⁴ are each independently H or unsubstituted Ci-6 alkyl. In certain embodiments, two of R²³², R²³³, and R²³⁴ are H and R²³², R²³³, and R²³⁴ are each independently H, CI, F, Br or I. In certain embodiments, in compounds of general formula V, R²³⁵ is unsubstituted C_1-6 alkyl or C_1-6 alkyl substituted with one or more substituents independently selected from the group consisting of OH, C_3-6 cycloalkyl, 5- to 10-membered heterocycloalkyl, C(0)OH, C(0)OR²⁷³, H₂, R²⁷⁴R²⁷⁵, HC(0)OR²⁷⁸, Ci_-6 alkoxy, CN, C(0) HR²⁷⁹ and CO H₂; wherein R²⁷³, R²⁷⁴, R²⁷⁵, and R²⁷⁸ are each independently

unsubstituted C_1-6 alkyl; R²⁷⁹ is C_1-6 alkyl optionally substituted with one or more substituents independently selected from the group consisting of R²⁸⁰R²⁸¹ and OH; and R²⁸⁰ and R²⁸¹ are each independently unsubstituted C_1-6 alkyl. In certain embodiments, R²³⁵ is unsubstituted C_1-6 alkyl; or unsubstituted C_1-5 alkyl; unsubstituted C_1-4 alkyl; unsubstituted Ci_-3 alkyl; or

unsubstituted Ci_-2 alkyl; or CH₃; or H. In some embodiments, Z¹⁴ is -CH₂-. In other

embodiments, Z¹⁴ is -C(O)-.

[00228] In certain embodiments, in compounds of general formula V, B is:

, wherein R²⁵², R²⁵³, R²⁵⁴, R²⁵⁵ and R are as defined anywhere herein. In certain embodiments, at least one of R , R , R , R and R is not H. In other embodiments, R , R , R , R and R are each H. In certain embodiments, in compounds of general formula V, R²⁵² is H or C_1-4 alkyl; or H or Ci_-3 alkyl; or H or Ci_-2 alkyl; or; H or CH₃. In certain embodiments, R²⁵² is unsubstituted lower alkyl; or C_1-4 alkyl; or Ci_-3 alkyl; or Ci_-2 alkyl; or CH₃. In other embodiments, R²⁵² is H. In certain embodiments, in compounds of general formula V, R²⁵³, R²⁵⁴, and R²⁵⁵ are each independently H or unsubstituted C_1-6 alkyl; or CI, F, Br, or I; or Ci-5 alkyl; or C_1-4 alkyl; or Ci_-3 alkyl; or Ci_-2 alkyl; or CH₃; or H. In certain embodiments, one of R²⁵³, R²⁵⁴, and R²⁵⁵ is H and R²⁵³, R²⁵⁴, and R²⁵⁵ are each independently H, CI, F, Br, I, or unsubstituted C_1-6 alkyl. In certain embodiments, one of R²⁵³, R²⁵⁴, and R²⁵⁵ is H and R²⁵³, R²⁵⁴, and R²⁵⁵ are each independently H or unsubstituted C_1-6 alkyl. In certain embodiments, one of R²⁵³, R²⁵⁴, and R²⁵⁵ is H and R²⁵³, R²⁵⁴, and R²⁵⁵ are each independently H, CI, F, Br or I. In certain embodiments, two of R²⁵³, R²⁵⁴, and R²⁵⁵ are H and R²⁵³, R²⁵⁴, and R²⁵⁵ are each independently H, CI, F, Br, I, or unsubstituted Ci_-6 alkyl. In certain embodiments, two of R²⁵³, R²⁵⁴, and R²⁵⁵ are H and R²⁵³, R²⁵⁴, and R²⁵⁵ are each independently H or unsubstituted C_1-6 alkyl. In certain embodiments, two of R²⁵³, R²⁵⁴, and R²⁵⁵ are H and R²⁵³, R²⁵⁴, and R²⁵⁵ are each independently H, CI, F, Br or I. In certain embodiments, in compounds of general formula V, R²⁵⁶ is unsubstituted Ci-6 alkyl or C_1-6 alkyl substituted with one or more substituents independently selected from the group consisting of OH, C_3-6 cycloalkyl, 5- to 10-membered heterocycloalkyl, C(0)OH, C(0)OR²⁷³, H₂, R²⁷⁴R²⁷⁵, HC(0)OR²⁷⁸, Ci_-6 alkoxy, CN, C(0) HR²⁷⁹ and CO H₂; wherein R²⁷³, R²⁷⁴, R²⁷⁵, and R²⁷⁸ are each independently unsubstituted Ci_-6 alkyl; R²⁷⁹ is Ci_-6 alkyl optionally substituted with one or more substituents independently selected from the group consisting of R²⁸⁰R²⁸¹ and OH; and R²⁸⁰ and R²⁸¹ are each independently unsubstituted Ci_-6 alkyl. In certain embodiments, R²⁵⁶ is unsubstituted C_1-6 alkyl; or unsubstituted C_1-5 alkyl; unsubstituted Ci-4 alkyl; unsubstituted Ci_-3 alkyl; or unsubstituted Ci_-2 alkyl; or CH₃; or H.

[00229] In certain embodiments, in compounds of general formula V, B is:

, wherein R , R , R , R , and R are as defined anywhere herein. In certain embodiments, at least one of R , R , R , R , and R is not H. In other embodiments, R , R , R , R , and R are each H. In certain embodiments, in compounds of general formula V, R²⁶² is H or Ci-4 alkyl; or H or Ci_-3 alkyl; or H or Ci_-2 alkyl; or; H or CH₃. In certain embodiments, R²⁶² is unsubstituted lower alkyl; or Ci-4 alkyl; or Ci_-3 alkyl; or Ci_-2 alkyl; or CH₃. In other embodiments, R²⁶² is H. In certain embodiments, in compounds of general formula V, R²⁶³, R²⁶⁴, and R²⁶⁵ are each independently H or unsubstituted Ci_-6 alkyl; or CI, F, Br, or I; or Ci-5 alkyl; or Ci-4 alkyl; or Ci_-3 alkyl; or Ci_-2 alkyl; or CH₃; or H. In certain embodiments, one of R²⁶³, R²⁶⁴, and R²⁶⁵ is H and R²⁶³, R²⁶⁴, and R²⁶⁵ are each independently H, CI, F, Br, I, or unsubstituted Ci_-6 alkyl. In certain embodiments, one of R²⁶³, R²⁶⁴, and R²⁶⁵ is H and R²⁶³, R²⁶⁴, and R²⁶⁵ are each independently H or unsubstituted Ci_-6 alkyl. In certain embodiments, one of R²⁶³, R²⁶⁴, and R²⁶⁵ is H and R²⁶³, R²⁶⁴, and R²⁶⁵ are each independently H, CI, F, Br or I. In certain embodiments, two of R²⁶³, R²⁶⁴, and R²⁶⁵ are H and R²⁶³, R²⁶⁴, and R²⁶⁵ are each independently H, CI, F, Br, I, or unsubstituted Ci_-6 alkyl. In certain embodiments, two of R²⁶³, R²⁶⁴, and R²⁶⁵ are H and R²⁶³, R²⁶⁴, and R²⁶⁵ are each independently H or unsubstituted Ci_-6 alkyl. In certain embodiments, two of R²⁶³, R²⁶⁴, and R²⁶⁵ are H and R²⁶³, R²⁶⁴, and R²⁶⁵ are each independently H, CI, F, Br or I. In certain embodiments, in compounds of general formula V, R²⁶⁶ is unsubstituted Ci-6 alkyl or Ci_-6 alkyl substituted with one or more substituents independently selected from the group consisting of OH, C_3-6 cycloalkyl, 5- to 10-membered heterocycloalkyl, C(0)OH, C(0)OR²⁷³, H₂, R²⁷⁴R²⁷⁵, HC(0)OR²⁷⁸, Ci_-6 alkoxy, CN, C(0) HR²⁷⁹ and CO H₂; wherein R²⁷³, R²⁷⁴, R²⁷⁵, and R²⁷⁸ are each independently unsubstituted Ci_-6 alkyl; R²⁷⁹ is Ci_-6 alkyl optionally substituted with one or more substituents independently selected from the group consisting of R²⁸⁰R²⁸¹ and OH; and R²⁸⁰ and R²⁸¹ are each independently unsubstituted Ci_-6 alkyl. In certain embodiments, R²⁶⁶ is unsubstituted Ci_-6 alkyl; or unsubstituted Ci_-5 alkyl; unsubstituted Ci-4 alkyl; unsubstituted Ci_-3 alkyl; or unsubstituted Ci_-2 alkyl; or CH₃; or H.

[00230] In certain embodiments, in compounds of general formula V, B is:

, wherein R , R , R , R , and R²⁷¹ are as defined anywhere herein. In certain embodiments, at least one of R , R , R , R , and R is not H. In other embodiments, R , R , R , R , and R are each H. In certain embodiments, in compounds of general formula V, R²⁶⁷ is H or Ci-4 alkyl; or H or Ci_-3 alkyl; or H or Ci_-2 alkyl; or; H or CH₃. In certain embodiments, R²⁶⁷ is unsubstituted lower alkyl; or Ci-4 alkyl; or Ci_-3 alkyl; or Ci_-2 alkyl; or CH₃. In other embodiments, R²⁶⁷ is H. In certain embodiments, in compounds of general formula V, R²⁶⁸, R²⁶⁹, and R²⁷⁰ are each independently H or unsubstituted Ci_-6 alkyl; or CI, F, Br, or I; or Ci-5 alkyl; or Ci-4 alkyl; or Ci_-3 alkyl; or Ci_-2 alkyl; or CH₃; or H. In certain embodiments, one of R²⁶⁸, R²⁶⁹, and R²⁷⁰ is H and R²⁶⁸, R²⁶⁹, and R²⁷⁰ are each independently H, CI, F, Br, I, or unsubstituted Ci_-6 alkyl. In certain embodiments, one of R²⁶⁸, R²⁶⁹, and R²⁷⁰ is H and R²⁶⁸, R²⁶⁹, and R²⁷⁰ are each independently H or unsubstituted Ci_-6 alkyl. In certain embodiments, one of R²⁶⁸, R²⁶⁹, and R²⁷⁰ is H and R²⁶⁸, R²⁶⁹, and R²⁷⁰ are each independently H, CI, F, Br or I. In certain embodiments, two of R²⁶⁸, R²⁶⁹, and R²⁷⁰ are H and R²⁶⁸, R²⁶⁹, and R²⁷⁰ are each independently H, CI, F, Br, I, or unsubstituted Ci_-6 alkyl. In certain embodiments, two of R²⁶⁸, R²⁶⁹, and R²⁷⁰ are H and R²⁶⁸, R²⁶⁹, and R²⁷⁰ are each independently H or unsubstituted Ci_-6 alkyl. In certain embodiments, two of R²⁶⁸, R²⁶⁹, and R²⁷⁰ are H and R²⁶⁸, R²⁶⁹, and R²⁷⁰ are each independently H, CI, F, Br or I. In certain embodiments, in compounds of general formula V, R²⁷¹ is unsubstituted Ci-6 alkyl or Ci_-6 alkyl substituted with one or more substituents independently selected from the group consisting of OH, C_3-6 cycloalkyl, 5- to 10-membered heterocycloalkyl, C(0)OH, C(0)OR²⁷³, H₂, R²⁷⁴R²⁷⁵, HC(0)OR²⁷⁸, Ci_-6 alkoxy, CN, C(0) HR²⁷⁹ and CO H₂; wherein R²⁷³, R²⁷⁴, R²⁷⁵, and R²⁷⁸ are each independently unsubstituted Ci_-6 alkyl; R²⁷⁹ is Ci_-6 alkyl optionally substituted with one or more substituents independently selected from the group consisting of R²⁸⁰R²⁸¹ and OH; and R²⁸⁰ and R²⁸¹ are each independently unsubstituted Ci_-6 alkyl. In certain embodiments, R²⁷¹ is unsubstituted Ci_-6 alkyl; or unsubstituted Ci_-5 alkyl; unsubstituted Ci-4 alkyl; unsubstituted Ci_-3 alkyl; or unsubstituted Ci_-2 alkyl; or CH₃; or H.

[00231] In certain embodiments, in compounds of general formula V, B is:

, wherein R²⁹⁷, R²⁹⁸, R²⁹⁹, R³⁰⁰, R³⁰¹, R³⁰², and R³⁰³ are as defined anywhere herein. In certain embodiments, at least one of R²⁹⁷, R²⁹⁸, R²⁹⁹, R³⁰⁰, R³⁰¹, R³⁰², and R is not H. In other embodiments, R²⁹⁷, R²⁹⁸, R²⁹⁹, R³⁰⁰, R³⁰¹, R³⁰², and R³⁰³ are each H. In certain embodiments, in compounds of general formula V, R²⁹⁷ is H or C_1-4 alkyl; or H or Ci_-3 alkyl; or H or Ci_-2 alkyl; or; H or CH₃. In certain embodiments, R²⁹⁷ is unsubstituted lower alkyl; or C_1-4 alkyl; or Ci_-3 alkyl; or Ci_-2 alkyl; or CH₃. In other embodiments, R²⁹⁷ is H. In certain embodiments, in compounds of general formula V, R²⁹⁸, R²⁹⁹, R³⁰⁰, R³⁰¹, and R³⁰² are each independently H or unsubstituted Ci_-6 alkyl; or CI, F, Br, or I; or Ci_-5 alkyl; or Ci-4 alkyl; or Ci_-3 alkyl; or Ci_-2 alkyl; or CH₃; or H. In certain embodiments, one of R²⁹⁸, R²⁹⁹, R³⁰⁰, R³⁰¹, and R³⁰² is H and R²⁹⁸, R²⁹⁹, R³⁰⁰, R³⁰¹, and R³⁰² are each independently H, CI, F, Br, I, or unsubstituted Ci_-6 alkyl. In certain embodiments, one of R²⁹⁸, R²⁹⁹, R³⁰⁰, R³⁰¹, and R³⁰² is H and R²⁹⁸, R²⁹⁹, R³⁰⁰, R³⁰¹, and R³⁰² are each independently H or unsubstituted Ci_-6 alkyl. In certain embodiments, one of R²⁹⁸, R²⁹⁹, R³⁰⁰, R³⁰¹, and R³⁰² is H and R²⁹⁸, R²⁹⁹, R³⁰⁰, R³⁰¹, and R³⁰² are each independently H, CI, F, Br or I. In certain embodiments, two of R²⁹⁸, R²⁹⁹, R³⁰⁰, R³⁰¹, and R³⁰² are H and R²⁹⁸, R²⁹⁹, R³⁰⁰, R³⁰¹, and R³⁰² are each independently H, CI, F, Br, I, or unsubstituted Ci_-6 alkyl. In certain embodiments, two of R²⁹⁸, R²⁹⁹, R³⁰⁰, R³⁰¹, and R³⁰² are H and R²⁹⁸, R²⁹⁹, R³⁰⁰, R³⁰¹, and R³⁰² are each independently H or unsubstituted Ci_-6 alkyl. In certain embodiments, two of R²⁹⁸, R²⁹⁹, R³⁰⁰, R³⁰¹, and R³⁰² are H and R²⁹⁸, R²⁹⁹, R³⁰⁰, R³⁰¹, and R³⁰² are each independently H, CI, F, Br or I. In certain embodiments, three of R²⁹⁸, R²⁹⁹, R³⁰⁰, R³⁰¹, and R³⁰² are H and R²⁹⁸, R²⁹⁹, R³⁰⁰, R³⁰¹, and R³⁰² are each independently H, CI, F, Br, I, or unsubstituted Ci_-6 alkyl. In certain embodiments, three of R²⁹⁸, R²⁹⁹, R³⁰⁰, R³⁰¹, and R³⁰² are H and R²⁹⁸, R²⁹⁹, R³⁰⁰, R³⁰¹, and R³⁰² are each independently H or unsubstituted Ci_-6 alkyl. In certain embodiments, three of R²⁹⁸, R²⁹⁹, R³⁰⁰, R³⁰¹, and R³⁰² are H and R²⁹⁸, R²⁹⁹, R³⁰⁰, R³⁰¹, and R³⁰² are each independently H, CI, F, Br or I. In certain embodiments, four of R²⁹⁸, R²⁹⁹, R³⁰⁰, R³⁰¹, and R³⁰² are H and R²⁹⁸, R²⁹⁹, R³⁰⁰, R³⁰¹, and R³⁰² are each independently H, CI, F, Br, I, or unsubstituted Ci_-6 alkyl. In certain embodiments, four of R²⁹⁸, R²⁹⁹, R³⁰⁰, R³⁰¹, and R³⁰² are H and R²⁹⁸, R²⁹⁹, R³⁰⁰, R³⁰¹, and R³⁰² are each independently H or unsubstituted Ci_-6 alkyl. In certain embodiments, four of R²⁹⁸, R²⁹⁹, R³⁰⁰, R³⁰¹, and R³⁰² are H and R²⁹⁸, R²⁹⁹, R³⁰⁰, R³⁰¹, and R³⁰² are each independently H, CI, F, Br or I. In certain embodiments, in compounds of general formula V, R³⁰³ is unsubstituted Ci_-6 alkyl or Ci_-6 alkyl substituted with one or more substituents independently selected from the group consisting of OH, C_3-6 cycloalkyl, 5- to 10-membered heterocycloalkyl, C(0)OH, C(0)OR²⁷³, H₂, R²⁷⁴R²⁷⁵, HC(0)OR²⁷⁸, Ci_-6 alkoxy, CN, C(0) HR²⁷⁹ and CO H₂; wherein R²⁷³, R²⁷⁴, R²⁷⁵, and R²⁷⁸ are each independently unsubstituted Ci_-6 alkyl; R²⁷⁹ is Ci_-6 alkyl optionally substituted with one or more substituents independently selected from the group consisting of NR. R and OH; and R and R are each independently unsubstituted C_1-6 alkyl. In certain embodiments, R³⁰³ is unsubstituted Ci_-6 alkyl; or unsubstituted C_1-5 alkyl; unsubstituted C_1-4 alkyl; unsubstituted Ci_-3 alkyl; or unsubstituted Ci_-2 alkyl; or CH₃; or H. [00232] In certain embodiments, in compounds of general formula V, B is:

, wherein R²²¹, R²²², R²²³, R²²⁴ and R are as defined anywhere herein. In certain embodiments, at least one of R , R , R , R and R is not H. In other embodiments, R²²¹, R²²², R²²³, R²²⁴ and R²²⁵ are each H. In certain embodiments, in compounds of general formula V, R²²¹ is H or C_1-4 alkyl; or H or Ci_-3 alkyl; or H or Ci_-2 alkyl; or; H or CH₃. In certain embodiments, R²²¹ is unsubstituted lower alkyl; or C_1-4 alkyl; or Ci_-3 alkyl; or Ci_-2 alkyl; or CH₃. In other embodiments, R²²¹ is H. In certain embodiments, in compounds of general formula V, R²²², R²²³, and R²²⁴ are each independently H or unsubstituted C_1-6 alkyl; or CI, F, Br, or I; or C_1-5 alkyl; or C_1-4 alkyl; or Ci_-3 alkyl; or Ci_-2 alkyl; or CH₃; or H. In certain embodiments, one of R²²², R²²³, and R²²⁴ is H and R²²², R²²³, and R²²⁴ are each independently H, CI, F, Br, I, or unsubstituted C_1-6 alkyl. In certain embodiments, one of R²²², R²²³, and R²²⁴ is H and R²²², R²²³, and R²²⁴ are each independently H or unsubstituted C_1-6 alkyl. In certain embodiments, one of R²²², R²²³, and R²²⁴ is H and R²²², R²²³, and R²²⁴ are each independently H, CI, F, Br or I. In certain embodiments, two of R²²², R²²³, and R²²⁴ are H and R²²², R²²³, and R²²⁴ are each independently H, CI, F, Br, I, or unsubstituted C_1-6 alkyl. In certain embodiments, two R²²², R²²³, and R²²⁴ is H and R²²², R²²³, and R²²⁴ are each independently H or unsubstituted Ci_-6 alkyl. In certain embodiments, two of R²²², R²²³, and R²²⁴ are H and R²²², R²²³, and R²²⁴ are each independently H, CI, F, Br or I. In certain embodiments, in compounds of general formula V, R²²⁵ is unsubstituted Ci_-6 alkyl or C_1-6 alkyl substituted with one or more substituents

independently selected from the group consisting of OH, C_3-6 cycloalkyl, 5- to 10-membered heterocycloalkyl, C(0)OH, C(0)OR²⁷³, NH₂, NR²⁷⁴R²⁷⁵, NHC(0)OR²⁷⁸, Ci_-6 alkoxy, CN, C(0)NHR²⁷⁹ and CONH₂; wherein R²⁷³, R²⁷⁴, R²⁷⁵, and R²⁷⁸ are each independently unsubstituted C_1-6 alkyl; R is C_1-6 alkyl optionally substituted with one or more substituents independently selected from the group consisting of R²⁸⁰R²⁸¹ and OH; and R²⁸⁰ and R²⁸¹ are each independently unsubstituted C_1-6 alkyl. In certain embodiments, R²²⁵ is unsubstituted C_1-6 alkyl; or unsubstituted C_1-5 alkyl; unsubstituted C_1-4 alkyl; unsubstituted Ci_-3 alkyl; or

unsubstituted Ci_-2 alkyl; or CH₃; or H.

[00233] In certain embodiments, in compounds of general formula V, B is:

, wherein R²²⁶, R²²⁷, R²²⁸, R²²⁹ and R²³⁰ are as defined anywhere herein. In certain embodiments, at least one of R²²⁶, R²²⁷, R²²⁸, R²²⁹ and R²³⁰ is not H. In other embodiments, R²²⁶, R²²⁷, R²²⁸, R²²⁹ and R²³⁰ are each H. In certain embodiments, in compounds of general formula V, R²²⁶ is H or C_1-4 alkyl; or H or Ci_-3 alkyl; or H or Ci_-2 alkyl; or; H or CH₃. In certain embodiments, R²²⁶ is unsubstituted lower alkyl; or C_1-4 alkyl; or Ci_-3 alkyl; or Ci_-2 alkyl; or CH₃. In other embodiments, R²²⁶ is H. In certain embodiments, in compounds of general formula V, R²²⁷, R²²⁸, and R²²⁹ are each independently H or unsubstituted C_1-6 alkyl; or CI, F, Br, or I; or Ci-5 alkyl; or C_1-4 alkyl; or Ci_-3 alkyl; or Ci_-2 alkyl; or CH₃; or H. In certain embodiments, one of R²²⁷, R²²⁸, and R²²⁹ is H and R²²⁷, R²²⁸, and R²²⁹ are each independently H, CI, F, Br, I, or unsubstituted C_1-6 alkyl. In certain embodiments, one of R²²⁷, R²²⁸, and R²²⁹ is H and R²²⁷, R²²⁸, and R²²⁹ are each independently H or unsubstituted C_1-6 alkyl. In certain embodiments, one of R²²⁷, R²²⁸, and R²²⁹ is H and R²²⁷, R²²⁸, and R²²⁹ are each independently H, CI, F, Br or I. In certain embodiments, two of R²²⁷, R²²⁸, and R²²⁹ are H and R²²⁷, R²²⁸, and R²²⁹ are each independently H, CI, F, Br, I, or unsubstituted Ci_-6 alkyl. In certain embodiments, two of R²²⁷, R²²⁸, and R²²⁹ are H and R²²⁷, R²²⁸, and R²²⁹ are each independently H or unsubstituted C_1-6 alkyl. In certain embodiments, two of R²²⁷, R²²⁸, and R²²⁹ are H and R²²⁷, R²²⁸, and R²²⁹ are each independently H, CI, F, Br or I. In certain embodiments, in compounds of general formula V, R²³⁰ is unsubstituted Ci-6 alkyl or C_1-6 alkyl substituted with one or more substituents independently selected from the group consisting of OH, C_3-6 cycloalkyl, 5- to 10-membered heterocycloalkyl, C(0)OH, C(0)OR²⁷³, H₂, R²⁷⁴R²⁷⁵, HC(0)OR²⁷⁸, Ci_-6 alkoxy, CN, C(0) HR²⁷⁹ and CO H₂; wherein R²⁷³, R²⁷⁴, R²⁷⁵, and R²⁷⁸ are each independently unsubstituted Ci_-6 alkyl; R²⁷⁹ is Ci_-6 alkyl optionally substituted with one or more substituents independently selected from the group consisting of R²⁸⁰R²⁸¹ and OH; and R²⁸⁰ and R²⁸¹ are each independently unsubstituted Ci_-6 alkyl. In certain embodiments, R²³⁰ is unsubstituted C_1-6 alkyl; or unsubstituted C_1-5 alkyl; unsubstituted Ci-4 alkyl; unsubstituted Ci_-3 alkyl; or unsubstituted Ci_-2 alkyl; or CH₃; or H. [00234] In certain embodiments, in compounds of general formula V, R²⁰⁰, R²⁰¹, R²⁰², R²⁰³, and R²⁰⁴ are each independently H CI, F, Br, I, or CF₃, wherein at least two of R²⁰⁰, R²⁰¹, R²⁰², R²⁰³,

and R²⁰⁴ are not H; and B is

wherein R²⁰⁵ is HC(0)R²⁰⁹; R²⁰⁶, R²⁰⁷ and R²⁰⁸ are each H; R²⁰⁹ is CH₃, CH₂OR²¹², CH₂OC(0)CH₃ or CH₂N₃; and R²¹² is H or CH₃.

[00235] In certain embodiments, in compounds of general formula V, R²⁰⁰, R²⁰¹, R²⁰², R²⁰³, and R²⁰⁴ are each independently H, CI, F, Br, I, or CF₃, wherein at least two of R²⁰⁰, R²⁰¹, R²⁰², R²⁰³,

and R²⁰⁴ are not H; and B

wherein at least one of R²²¹, R²²², R²²³, R²²⁴ and R²²⁵; or R²²⁶, R²²⁷, R²²⁸, R²²⁹ and R²³⁰ is not H.

[00236] In certain embodiments, in compounds of general formula V, R²⁰⁰ is CI, F, Br, I, or CF₃; R²⁰⁴ is CF₃; and R²⁰¹, R²⁰² and R²⁰³ are each H; and B is:

, wherein R²²¹ and R²²⁶ are each independently H or Ci_-6 alkyl; R²²², R²²³, R²²⁴, R²²⁷, R²²⁸ and R²²⁹ are each independently H, CI, F, Br, I or unsubstituted Ci_-6 alkyl; and R²²⁵, and R²³⁰ are each independently H,

C(0)OR²⁷², C_3-6 cycloalkyl, C₆-io aryl, C₆-io aryl-Ci-6 alkyl, or Ci_-6 alkyl, wherein C6-10 aryl is optionally substituted with one or more substituents independently selected from C_1-6 alkyl; C_6-10 aryl of C_6-10 aryl-Ci-6 alkyl is optionally substituted with one or more substituents independently selected from halogen; and C_1-6 alkyl is optionally substituted with one or more substituents independently selected from the group consisting of OH, C3-6 cycloalkyl, 5- to 10-membered heterocycloalkyl, C(0)OH, C(0)OR²⁷³, H₂, R²⁷⁴R²⁷⁵, HC(0)OR²⁷⁸,

Ci-6 alkoxy, CN, C(0) HR²⁷⁹ and CO H₂; R²⁷², R²⁷³, R²⁷⁴, R²⁷⁵, and R²⁷⁸ are each independently unsubstituted C_1-6 alkyl; R²⁷⁹ is C_1-6 alkyl optionally substituted with one or more substituents independently selected from the group consisting of R²⁸⁰R²⁸¹ and OH; and R²⁸⁰ and R²⁸¹ are each independently unsubstituted C_1-6 alkyl. [00237] In certain embodiments, compounds of general formula V are selected from compounds 2, 5, 9, 11, 12, 13, 14, 15, 16, 17, 19, 29, 41, 42, 43, 44, 45, 46, 47, 68, 74, 76, 103, 104, 105, 107, 109, 204, 205, 211, 213, 214, 300, 301, 302, 303, 304, 305, 306, 307, 308, 309-a, 310, 311, 312, 313-a, 314, 315, 316, 317, 318, 319, 320, 321, 322, 323-a, 324 and 325, and salts thereof

[00238] In certain embodiments, compounds of general formula V are selected from compounds 2, 5, 9, 11, 12, 13, 14, 15, 16, 17, 19, 29, 41, 42, 43, 44, 45, 46, 47, 68, 74, 76, 103, 104, 105, 107, 109, 204, 205, 211, 213, 214, 300, 301, 302, 303, 304, 305, 306, 307, 308, 309-a, 310, 311, 312, 313-a, 314, 315, 316, 317, 318, 319, 320, 321, 322, 323-a, and 324, and salts thereof

[00239] In certain embodiments, compounds of general formula V are selected from compounds 2, 5, 12, 13, 15, 16, 103, 104, 105, 109, 204, 205, 211, 213, 214, 302, 303, 305, 306, 308, 309-a, 310, 311, 313-a, 314, 315, 316, 317, 318, 319, 321, 322, 323-a, 324, and 325, and salt thereof

[00240] In certain embodiments, compounds of general formula V are selected from compounds 15, 16, 104, 204, 205, 213, 214, 302, 303, 305, 308, 309-a, 310, 313-a, 314, 316, 317, 319, 321, 322, 323-a, and 324, and salts thereof.

[00241] In certain embodiments, compounds of general formula V are selected from compounds 204, 205, 303, 308, 310, 313-a, 314, 317, 319, 321, 322, and 323-a, and salts thereof

[00242] In certain embodiments, compounds of general formula V are selected from compounds 205, 303, 310, 313-a, 314, 317, and 322, and salts thereof. [00243] Combinations of any of the foregoing embodiments described for compounds of general formula V are also contemplated and each combination forms a separate embodiment for the purposes of the present disclosure.

[00244] In certain embodiments, compounds of general formula (I), or salts thereof, are selected from the compounds shown in Tables 1 and 2, and salts thereof:

[00245] Table 1 :





130

-CI CI I

if " ? ^" :^' V ,'·' Μ·: : | ^■' I i; ?

-' ^{■ ■} - ? i i ^{■ "} ) ^■ :^■ "X^{■ '}- - ^■■ H - \ CH

0^'

323

322 324

325 224

[00246] Combinations of any of the foregoing embodiments described for compounds of general formula I are also contemplated and each combination forms a separate embodiment for the purposes of the present disclosure. [00247] In certain embodiments, compounds of general formulas (I), (IV) or (V), or Tables 1, 2, or 5, may possess a sufficiently acidic group, a sufficiently basic group, or both functional groups, and accordingly react with a number of organic and inorganic bases, or organic and inorganic acids, to form pharmaceutically acceptable salts. The term "pharmaceutically acceptable salt" as used herein, refers to a salt of a compound that is substantially non-toxic to living organisms. Typical pharmaceutically acceptable salts include those salts prepared by reaction of a compound with a pharmaceutically acceptable mineral or organic acid or an organic or inorganic base. Such salts are known as acid addition and base addition salts.

[00248] Acids commonly employed to form acid addition salts are inorganic acids such as hydrochloric acid, hydrobromic acid, hydroiodic acid, sulphuric acid, phosphoric acid, and the like, and organic acids such as p-toluenesulphonic acid, methanesulphonic acid, oxalic acid, p- bromophenylsulphonic acid, carbonic acid, succinic acid, citric acid, benzoic acid, acetic acid, and the like. Examples of such pharmaceutically acceptable salts are the sulphate, pyrosulphate, bisulphate, sulphite, phosphate, monohydrogenphosphate, dihydrogenphosphate, metaphosphate, pyrophosphate, bromide, iodide, acetate, propionate, decanoate, caprylate, acrylate, formate, hydrochloride, dihydrochloride, isobutyrate, caproate, heptanoate, propiolate, oxalate, malonate, succinate, suberate, sebacate, fumarate, maleate, butyne-l,4-dioate, hexyne-l,6-dioate, benzoate, chlorobenzoate, methylbenzoate, hydroxybenzoate, methoxybenzoate, phthalate, xylenesulphonate, phenyl acetate, phenylpropionate, phenylbutyrate, citrate, lactate, gamma- hydroxybutyrate, glycolate, tartrate, methanesulphonate, propanesulphonate, naphthalene- 1- sulfonate, napththalene-2-sulfonate, mandelate and the like. Commonly used pharmaceutically acceptable acid addition salts include those formed with mineral acids such as hydrochloric acid and hydrobromic acid, and those formed with organic acids such as maleic acid and methanesulphonic acid.

[00249] Salts of amine groups may also comprise quarternary ammonium salts in which the amino nitrogen carries a suitable organic group such as a lower (for example, C_1-4) alkyl, substituted lower alkyl, lower (for example, C_1-4) alkenyl, substituted lower alkenyl, lower (for example, Ci- ₄) alkynyl, substituted lower alkynyl, or aralkyl moiety.

[00250] Base addition salts include those derived from inorganic bases, such as ammonium or alkali or alkaline earth metal hydroxides, carbonates, bicarbonates, and the like. Bases useful in preparing pharmaceutically acceptable salts thus include sodium hydroxide, potassium hydroxide, ammonium hydroxide, potassium carbonate, sodium carbonate, sodium bicarbonate, potassium bicarbonate, calcium hydroxide, calcium carbonate, and the like.

[00251] One skilled in the art will understand that the particular counterion forming a part of a pharmaceutically acceptable salt is usually not of a critical nature, so long as the salt as a whole is pharmacologically acceptable and as long as the counterion does not contribute undesired qualities to the salt as a whole.

[00252] Certain embodiments relate to pharmaceutically acceptable solvates of a compound of general formulas (I), (IV) or (V), or Tables 1, 2, or 5. One skilled in the art will appreciate that certain compounds of general formulas (I), (IV) or (V), or Tables 1, 2, or 5, may combine with solvents such as water, methanol, ethanol and acetonitrile to form pharmaceutically acceptable solvates such as the corresponding hydrate, methanolate, ethanolate and acetonitrilate. Other examples of solvents that may be used to prepare solvates include isopropanol, dimethyl sulfoxide, ethyl acetate, acetic acid, ethanolamine, or acetone, as well as miscible formulations of solvate mixtures as would be known to the skilled artisan. [00253] One skilled in the art will appreciate that certain compounds of general formulas (I), (IV) or (V), or Tables 1, 2, or 5, may exhibit tautomerism. It is therefore to be understood that the structural formulae herein are intended to represent any tautomeric form of the depicted compound and should not to be limited to any specific compound form depicted by the structural formulae. [00254] In addition, the skilled person will appreciate that certain compounds of general formulas (I), (IV) or (V), or Tables 1, 2, or 5, may have one or more asymmetric (chiral) centres and/or one or more unsaturated bonds. As a consequence, these compounds can be present as racemates, individual enantiomers, mixtures of enantiomers, individual diastereomers, mixtures of diastereomers, individual isomers (for example, E and Z isomers) and mixtures of isomers. Certain embodiments of the disclosure thus relate to compounds of general formulas (I), (IV) or (V), or Tables 1, 2, or 5, in a substantially pure enantiomeric, diastereomeric or isomeric form. By "substantially pure" it is meant that the compound is in a form that is pharmaceutically acceptable which may, for example, be at least 80% optically pure, that is, a form that comprises at least 80% of a single isomer. In certain embodiments, chiral compounds may be in a form that is at least 85% optically pure, for example, at least 90%, at least 95%, at least 97.5%, or at least 99% optically pure. Certain embodiments relate to compounds of general formulas (I), (IV) or (V), or Tables 1, 2, or 5, in the form of mixtures of enantiomers, diastereomers or isomers, including racemic mixtures.

[00255] The preparation of salts and solvates and the separation of enantiomers, diastereomers or isomers may be carried out by methods known in the art. It will be appreciated that non- pharmaceutically acceptable salts or solvates also fall within the scope of certain embodiments since these may be useful for example in the preparation of pharmaceutically acceptable salts or solvates.

Preparation of Compounds [00256] Compounds of general formulas (I), (IV) or (V), or Tables 1, 2, or 5, may be synthesized from readily available starting materials using standard organic synthesis techniques. Representative synthetic pathways are described in the Examples. One skilled in the art will recognize that alternative methods may be employed to synthesize compounds of general formulas (I), (IV) or (V), or Tables 1, 2, or 5, and that the approaches described herein are therefore not intended to be exhaustive, but rather to provide the skilled person with examples of some broadly applicable and practical routes to representative compounds. Some compounds may also be commercially available.

Activity of Compounds [00257] The ability of candidate compounds of general formulas (I), (IV) or (V) to promote PTC readthrough, either alone or in combination with one or more other PTC readthrough compounds, may be assessed using a variety of techniques. For example, a cell line comprising a PTC mutation in a gene encoding a target protein may be contacted with a candidate compound, alone and in combination with another PTC readthrough compound, preferably an aminoglycoside, for a suitable amount of time and the amount of full-length target protein expressed by the cells is monitored. In certain embodiments, the aminoglycoside is a natural aminoglycoside. In certain embodiments, the aminoglycoside is an aminoglycoside fraction or component. In certain embodiments, the aminoglycoside is a synthetic aminoglycoside. In certain embodiments, the aminoglycoside is G418. In certain embodiments, the aminoglycoside is gentamicin. In certain embodiments, the aminoglycoside is X2. In certain embodiments, the aminoglycoside is Bl .

[00258] Exemplary techniques utilizing fluorescence microscopy or Western blot analysis and cell lines comprising PTC mutations in the gene encoding p53 are described in the Examples.

[00259] Other non-limiting examples of techniques that may be employed to test candidate compounds for PTC readthrough activity include the ELISA- and FACS-based assays described in Du et al. (2009, J. Exp. Med, 206(10):2285-2297) and in International Patent Application Publication No. WO 2012/021707, and the luciferase-based assays described in International Patent Application Publication No. WO 2004/009533. Exemplary methods for analysing PTC suppression in yeast and mammalian cells are also described in Current Protocols in Cell Biology (Eds. Bonifacino, et al., J. Wiley & Sons, New York, NY). See also Baradaran-Heravi, A., et al., Nucleic Acids Res. 44: 6538-6598 (2016).

[00260] As is known in the art, some PTCs are considered to be more "leaky" and thus more amenable to readthrough than others. For example, a TGA PTC is considered to be more leaky than a TAG PTC, which in turn is more leaky than a TAA PTC. In certain embodiments, compounds of general formulas (I), (IV) or (V), or Tables 1, 2, or 5, preferably in combination with another PTC-RC other than that of general formulas (I), (IV) or (V), or Tables 1, 2, or 5, preferably an aminoglycoside, are capable of promoting readthrough of at least a TGA PTC. In some embodiments, compounds of general formulas (I), (IV) or (V), or Tables 1, 2, or 5, preferably in combination with another PTC-RC other than that of general formulas (I), (IV) or (V), or Tables 1, 2, or 5, preferably an aminoglycoside, are capable of promoting readthrough of both TGA and TAG PTCs. In some embodiments, compounds of general general formulas (I), (IV) or (V), or Tables 1, 2, or 5, preferably in combination with another PTC-RC other than that of general formulas (I), (IV) or (V), or Tables 1, 2, or 5, preferably an aminoglycoside, are capable of promoting readthrough of TGA, TAG and TAA PTCs. Notably, PTC-RCs of general formulas (I), (IV) and (V), and Tables 1, 2, and 5, may appear to lack independent readthrough activity but are capable of promoting readthrough in the presence of an aminoglycoside, and are embraced by the invention. In certain embodiments, the aminoglycoside is a natural aminoglycoside. In certain embodiments, the aminoglycoside is an aminoglycoside fraction or component. In certain embodiments, the aminoglycoside is a synthetic aminoglycoside. In certain embodiments, the aminoglycoside is G418. In certain embodiments, the aminoglycoside is gentamicin. In certain embodiments, the aminoglycoside is X2. In certain embodiments, the aminoglycoside is Bl .

[00261] It will be appreciated that in order to be effective, a candidate compound does not need to promote 100% readthrough of a PTC or restore the level of full length protein expressed to the level found in a normal cell that contains the corresponding gene without a PTC. The compound may, therefore, promote only a small amount of readthrough and still be effective. In certain embodiments, therefore, a candidate compound may be considered to be active (that is, capable of promoting PTC readthrough) when treatment of a cell comprising a PTC mutation in the gene encoding a protein of interest with the compound, preferably in combination with another PTC- RC other than that of general formulas (I), (IV) or (V), or Tables 1, 2, or 5, preferably an aminoglycoside, produces at least 1% of the amount of full length protein produced by the same cell type comprising a gene encoding the protein of interest which gene lacks a PTC mutation.

[00262] In certain embodiments, a candidate compound may be considered active if the candidate compound in combination with another PTC-RC other than that of general formulas (I), (IV) or (V), or Tables 1, 2, or 5, preferably an aminoglycoside, produces an amount of full length protein in a cell that is at least 2, 3, 4, 5, 6, 7, 8, 9, 10, 15, 20, 25, 30, 35, 40, 45, 50, 55, 60, 65, 70, 75, 80, 85, 90, 95, or 100% of the amount of full length protein observed in the same cell type expressing normal mRNA lacking a premature termination codon. In certain embodiments, the PTC is a TGA PTC. In some embodiments, the PTC is a TAG PTC. In some embodiments, the PTC is a TAA PTC. In certain embodiments, the aminoglycoside is a natural aminoglycoside. In certain embodiments, the aminoglycoside is an aminoglycoside fraction or component. In certain embodiments, the aminoglycoside is a synthetic aminoglycoside. In certain embodiments, the aminoglycoside is G418. In certain embodiments, the aminoglycoside is gentamicin. In certain embodiments, the aminoglycoside is X2. In certain embodiments, the aminoglycoside is Bl . [00263] Candidate compounds of general formulas (I), (IV) or (V) may also be tested in an appropriate animal model for their ability to promote PTC readthrough. For example, candidate compounds may be tested for biological activity using art-known animal models for a disease or disorder of interest (see, for example, Current Protocols in Pharmacology, Eds. Enna, et al, J. Wiley & Sons, New York, NY) that have been engineered to contain the target PTC -containing gene. Non-limiting examples of mouse models that have been developed which possess a PTC in a disease-causing gene include the max mouse (a model of muscular dystrophy) and the transgenic G542X-hCFTR mouse (a model of cystic fibrosis). Candidate compounds of general formulas (I), (IV) or (V) are preferably tested in combination with an aminoglycoside. In certain embodiments, the aminoglycoside is a natural aminoglycoside. In certain embodiments, the aminoglycoside is an aminoglycoside fraction or component. In certain embodiments, the aminoglycoside is a synthetic aminoglycoside. In certain embodiments, the aminoglycoside is G418. In certain embodiments, the aminoglycoside is gentamicin. In certain embodiments, the aminoglycoside is X2. In certain embodiments, the aminoglycoside is Bl .

PHARMACEUTICAL COMPOSITIONS [00264] Compounds of general formulas (I), (IV) or (V), or Tables 1, 2, or 5, are typically formulated for therapeutic use. Certain embodiments of the disclosure thus relate to pharmaceutical compositions comprising a compound of general formulas (I), (IV) or (V), or Tables 1, 2, or 5, and a pharmaceutically acceptable carrier, diluent, or excipient. The pharmaceutical compositions may be prepared using readily available ingredients and procedures. In certain embodiments, the pharmaceutical compositions additionally comprise another PTC-RC other than that of general formulas (I), (IV) or (V), or Tables 1, 2, or 5, preferably an aminoglycoside. In certain embodiments, the aminoglycoside is a natural aminoglycoside. In certain embodiments, the aminoglycoside is an aminoglycoside fraction or component. In certain embodiments, the aminoglycoside is a synthetic aminoglycoside. In certain embodiments, the aminoglycoside is G418. In certain embodiments, the aminoglycoside is gentamicin. In certain embodiments, the aminoglycoside is X2. In certain embodiments, the aminoglycoside is Bl . In certain embodiments, pharmaceutical compositions comprise a steroid.

[00265] Pharmaceutical compositions comprising compounds of general formulas (I), (IV) or (V), or Tables 1, 2, or 5, may be formulated for administration to a subject by one of a variety of standard routes, for example, orally (including, for example, buccally or sublingually), topically, parenterally, by inhalation or spray, ocularly, rectally or vaginally, in dosage unit formulations containing conventional pharmaceutically acceptable carriers, diluents or excipients. The term parenteral as used herein may include subcutaneous injection, intradermal injection or infusion, intra-articular injection or infusion, intravenous injection or infusion, intramuscular injection or infusion, intravascular injection or infusion, intrasternal injection or infusion, and intrathecal injection or infusion. The pharmaceutical composition is formulated in a suitable format for administration by the selected route to the subject. For example, the composition may be formulated as a syrup, elixir, tablet, troche, lozenge, hard or soft capsule, pill, suppository, eye drops, ointment, gel, oily or aqueous suspension, dispersible powder or granule, emulsion, injectable or solution. In certain embodiments, pharmaceutical compositions comprising a compound of general formulas (I), (IV) or (V), or Tables 1, 2, or 5, are formulated for parenteral or oral administration. In certain embodiments, pharmaceutical compositions comprising a compound of general formulas (I), (IV) or (V), or Tables 1, 2, or 5, and an aminoglycoside are formulated for a particular route of administration. In certain embodiments, pharmaceutical compositions comprising a compound of general formulas (I), (IV) or (V), or Tables 1, 2, or 5, and an aminoglycoside are formulated for parenteral or oral administration.

[00266] Compositions intended for oral use may be prepared in any suitable form such as solid or fluid unit dosage forms. Fluid unit dosage forms can be prepared according to known methods for the manufacture of pharmaceutical compositions. Such compositions may contain one or more agents selected from the group consisting of sweetening agents, flavouring agents, colouring agents and preserving agents in order to provide pharmaceutically elegant and palatable preparations. An elixir may be prepared by using a hydroalcoholic (for example, ethanol) vehicle with suitable sweeteners such as sugar and saccharin, together with an aromatic flavoring agent. Suspensions may be prepared with an aqueous vehicle with the aid of a suspending agent such as acacia, tragacanth, methylcellulose and the like.

[00267] Solid formulations such as tablets may contain the active ingredient in admixture with pharmaceutically acceptable excipients that are suitable for the manufacture of tablets. These excipients may be. for example, diluents, such as calcium carbonate, sodium carbonate, lactose, calcium phosphate or sodium phosphate: granulating and disintegrating agents for example, corn starch, or alginic acid: binding agents, for example starch, gelatin or acacia, and lubricating agents, for example magnesium stearate, stearic acid or talc and other conventional ingredients such as dicalcium phosphate, magnesium aluminum silicate, calcium sulfate, starch, lactose, methylcellulose, and functionally similar materials. The tablets may be uncoated or they may be coated by known techniques to delay disintegration and absorption in the gastrointestinal tract and thereby provide a sustained action over a longer period. For example, a time delay material such as glyceryl monostearate or glyceryl distearate may be employed.

[00268] Formulations for oral use may also be presented as hard gelatin capsules wherein the active ingredient is mixed with an inert solid diluent, for example, calcium carbonate, calcium phosphate or kaolin, or as soft gelatin capsules wherein the active ingredient is mixed with water or an oil medium, for example peanut oil, liquid paraffin or olive oil. Soft gelatin capsules are prepared by machine encapsulation of a slurry of the compound with an acceptable vegetable oil, light liquid petrolatum or other inert oil.

[00269] Aqueous suspensions may contain active materials in admixture with excipients suitable for the manufacture of aqueous suspensions. Such excipients are suspending agents, for example sodium carboxylmethylcellulose, methyl cellulose, hydropropylmethylcellulose, sodium alginate, polyvinylpyrrolidone, gum tragacanth and gum acacia: dispersing or wetting agents may be a naturally-occurring phosphatide, for example, lecithin, or condensation products of an alkylene oxide with fatty acids, for example polyoxyethylene stearate, or condensation products of ethylene oxide with long chain aliphatic alcohols, for example hepta-decaethyleneoxycetanol, or condensation products of ethylene oxide with partial esters derived from fatty acids and a hexitol such as polyoxyethylene sorbitol monooleate, or condensation products of ethylene oxide with partial esters derived from fatty acids and hexitol anhydrides, for example polyethylene sorbitan monooleate. The aqueous suspensions may also contain one or more preservatives, for example ethyl, or n-propyl- p-hydroxy benzoate, one or more colouring agents, one or more flavouring agents or one or more sweetening agents, such as sucrose or saccharin.

[00270] Oily suspensions may be formulated by suspending the active ingredients in a vegetable oil, for example peanut oil, olive oil, sesame oil or coconut oil, or in a mineral oil such as liquid paraffin. The oily suspensions may contain a thickening agent, for example beeswax, hard paraffin or cetyl alcohol. Sweetening agents such as those set forth above, and flavouring agents may be added to provide palatable oral preparations. These compositions may be preserved by the addition of an anti -oxidant such as ascorbic acid.

[00271] Dispersible powders and granules suitable for preparation of an aqueous suspension by the addition of water provide the active ingredient in admixture with a dispersing or wetting agent, suspending agent and one or more preservatives. Suitable dispersing or wetting agents and suspending agents are exemplified by those already mentioned above. Additional excipients, for example sweetening, flavouring and colouring agents, may also be present.

[00272] Pharmaceutical compositions of the disclosure may also be in the form of oil-in-water emulsions. The oil phase may be a vegetable oil, for example olive oil or peanut oil, or a mineral oil, for example liquid paraffin or mixtures of these. Suitable emulsifying agents may be naturally- occurring gums, for example gum acacia or gum tragacanth, naturally-occurring phosphatides, for example soy bean, lecithin, and esters or partial esters derived from fatty acids and hexitol, anhydrides, for example sorbitan monooleate, and condensation products of the said partial esters with ethylene oxide, for example polyoxyethylene sorbitan monooleate. The emulsions may also contain sweetening and flavoring agents.

[00273] The pharmaceutical compositions may be in the form of a sterile injectable aqueous or oleaginous suspension. This suspension may be formulated according to known art using those suitable dispersing or wetting agents and suspending agents that have been mentioned above. The sterile injectable preparation may also be a sterile injectable solution or a suspension in a non-toxic parentally acceptable diluent or solvent, for example as a solution in 1,3-butanediol. Among the acceptable vehicles and solvents that may be employed are water, Ringer's solution and isotonic sodium chloride solution. In addition, sterile, fixed oils are conventionally employed as a solvent or suspending medium. For this purpose any bland fixed oil may be employed including synthetic mono- or diglycerides. In addition, fatty acids such as oleic acid find use in the preparation of injectables. Adjuvants such as local anaesthetics, preservatives and buffering agents can also be included in the injectable solution or suspension.

[00274] In certain embodiments, other agents may be included in the pharmaceutical composition, for example, to aid uptake or metabolism, and/or delay dispersion within the subject. For example, the composition may be formulated as a controlled release formulation, which may be formed by microencapsulation using suitable agents, by embolism within a carbohydrate or polymer matrix, or the like.

[00275] Other pharmaceutical compositions and methods of preparing pharmaceutical compositions are known in the art and are described, for example, in "Remington: The Science and Practice of Pharmacy" (formerly "Remingtons Pharmaceutical Sciences"); Gennaro, A., Lippincott, Williams & Wilkins, Philadelphia, PA (2000).

METHODS AND USES

[00276] In one aspect, the disclosure relates to methods comprising use of compounds of general formulas (I), (IV) or (V), or Tables 1, 2, or 5, preferably in combination with another PTC-RC other than that of general formulas (I), (IV) or (V), or Tables 1, 2, or 5, preferably an aminoglycoside, to promote readthrough of a PTC in an RNA molecule in a translation system, wherein the RNA molecule encodes a protein of interest. That is, the RNA molecule with an amino acid encoding codon in place of the PTC encodes a protein of interest. The "translation system" may be, for example a cell, which cell is a eukaryotic cell, which cell may be, for example a yeast cell or a mammalian cell. In some embodiments the cell may be present in a subject. In some embodiments, a compound of general formula (I), (IV) or (V), or Table 1, 2, or 5, is administered in combination with an aminoglycoside to the subject comprising the cell in order to promote PTC readthrough of the RNA molecule in the cell. In one embodiment, the subject has a disease or disorder associated with a nonsense mutation or PTC. In other embodiments, a "translation system" may be a reconstituted in vitro preparation capable of translating the RNA molecule into a polypeptide. In such embodiments, a compound of general formula (I), (IV) or (V), or Table 1, 2, or 5, may be added to the in vitro preparation in combination with an aminoglycoside in order to promote PTC readthrough of the RNA molecule in the preparation. In one embodiment, the cell is a yeast cell, and a compound of general formula (I), (IV) or (V), or Table 1, 2, or 5, is contacted to the yeast cell in combination with an aminoglycoside in order to promote PTC readthrough of the RNA molecule in the yeast cell.

[00277] Administration or addition of a compound of general formula (I), (IV) or (V), or Table 1, 2, or 5, and an aminoglycoside to a subject or translation system may be done concurrently or consecutively.

[00278] In certain embodiments, the disclosure relates to methods of promoting production of a functional form of a protein of interest in a cell, where the protein is encoded by a nucleotide sequence comprising (i.e., interrupted by) a PTC. In certain embodiments, the disclosure relates to methods of promoting production of a full-length form of a protein of interest in a cell, where the protein is encoded by a nucleotide sequence comprising (i.e., interrupted by) a PTC. In certain embodiments, the aminoglycoside is a natural aminoglycoside. In certain embodiments, the aminoglycoside is an aminoglycoside fraction or component. In certain embodiments, the aminoglycoside is a synthetic aminoglycoside. In certain embodiments, the aminoglycoside is G418. In certain embodiments, the aminoglycoside is gentamicin. In certain embodiments, the aminoglycoside is X2. In certain embodiments, the aminoglycoside is Bl .

[00279] The methods may be in vitro methods or they may be in vivo methods. The protein of interest may be one in which the occurrence of a PTC in its encoding mRNA is associated with a disease or disorder. [00280] In certain embodiments, the disclosure relates to methods of treating a disease or disorder associated with a PTC in a subject. In some embodiments, the disease or disorder may be due, at least in part, to reduced expression of a full length protein due to the presence of a PTC in the gene encoding the protein. [00281] The disease or disorder may be any that is associated with a nonsense mutation or a PTC. In one embodiment, the disease or disorder may be selected from the group consisting of: central nervous system disease; peripheral nervous system disease; neurodegenerative disease; autoimmune disease; DNA repair disease; inflammatory disease; collagen disease; kidney disease; pulmonary disease; eye disease; cardiovascular disease; blood disease; metabolic disease; neuromuscular diseases; neoplastic disease.

[00282] In one embodiment, the disease or disorder may be selected from the group consisting of: ataxia-telangiectasia; muscular dystrophy; Duchenne muscular dystrophy; Dravet syndrome; myotonic dystrophy; multiple sclerosis; infantile neuronal ceroid lipofuscinosis; Alzheimer's disease; Tay-Sachs disease; neural tissue degeneration; Parkinson's disease; chronic rheumatoid arthritis; lupus erythematosus; graft-versus-host disease; primary immunodeficiencies; severe combined immunodeficiency; DNA Ligase IV deficiency; Nijmegen breakage disorders; xeroderma pigmentosum (XP); rheumatoid arthritis; hemophilia; von Willebrand disease; thalassemia (for example; β -thai as semi a); familial erythrocytosis; nephrolithiasis; osteogenesis imperfecta; cirrhosis; neurofibroma; bullous disease; lysosomal storage diseases; Hurler's disease; familial chole sterol emi a; cerebellar ataxia; tuberous sclerosis; immune deficiency; cystic fibrosis; familial hypercholesterolemia; pigmentary retinopathy; retinitis pigmentosa; amyloidosis; atherosclerosis; giantism; dwarfism; hypothyroidism; hyperthyroidism; aging; obesity; diabetes mellitus; familial polycythemia; Niemann-Pick disease; epidermolysis bullosa; Marfan syndrome; Becker muscular dystrophy (BMD); spinal muscular atrophy; cancer.

[00283] In one embodiment, the disease or disorder may be cancer. The cancer may be, for example, of the head and neck, eye, skin, mouth, throat, esophagus, chest, bone, blood, lung, colon, sigmoid, rectum, stomach, prostate, breast, ovaries, kidney, liver, pancreas, brain, intestine, heart or adrenals. The cancer may be sarcoma, carcinoma, fibrosarcoma, myxosarcoma, liposarcoma, chondrosarcoma, osteogenic sarcoma, chordoma, angiosarcoma, endotheliosarcoma, lymphangiosarcoma, lymphangioendotheliosarcoma, synovioma, mesothelioma, Ewing's tumor, leiomyosarcoma, rhabdomyosarcoma, colon carcinoma, pancreatic cancer, breast cancer, ovarian cancer, prostate cancer, squamous cell carcinoma, basal cell carcinoma, adenocarcinoma, sweat gland carcinoma, sebaceous gland carcinoma, papillary carcinoma, papillary adenocarcinomas, cystadenocarcinoma, medullary carcinoma, bronchogenic carcinoma, renal cell carcinoma, hepatoma, bile duct carcinoma, choriocarcinoma, seminoma, embryonal carcinoma, Wilms' tumor, cervical cancer, testicular tumor, lung carcinoma, small cell lung carcinoma, bladder carcinoma, epithelial carcinoma, glioma, astrocytoma, medulloblastoma, craniopharyngioma, ependymoma, Kaposi's sarcoma, pinealoma, hemangioblastoma, acoustic neuroma, oligodendroglioma, menangioma, melanoma, neuroblastoma, retinoblastoma, a blood-born tumor or multiple myeloma. The cancer may be acute lymphoblastic leukemia, acute lymphoblastic B-cell leukemia, acute lymphoblastic T-cell leukemia, acute myeloblastic leukemia, acute promyelocytic leukemia, acute monoblastic leukemia, acute erythroleukemic leukemia, acute megakaryoblastic leukemia, acute myelomonocytic leukemia, acute nonlymphocyctic leukemia, acute undifferentiated leukemia, chronic myelocytic leukemia, chronic lymphocytic leukemia, hairy cell leukemia, or multiple myeloma.

[00284] Examples of diseases and disorders associated with the presence of a PTC include, but are not limited to, those listed in the table below. The following list of codon changes identified as of the priority date in the listed indications is not to be construed as exhaustive or limiting.

Table 3: Medical Conditions Associated with PTC

Intrahepatic cholestasis, familial progressive ABCB4 CAG-TAG

Intrahepatic cholestasis, familial progressive ABCB4 CGA-TGA

Dubin-Johnson syndrome ABCC2 TCA-TGA

Dubin-Johnson syndrome ABCC2 CGA-TGA

Dubin-Johnson syndrome ABCC2 TAC-TAG

Pseudoxanthoma elasticum ABCC6 GAG-TAG

Pseudoxanthoma elasticum ABCC6 CAG-TAG

Pseudoxanthoma elasticum ABCC6 TGG-TAG

Pseudoxanthoma elasticum, autosomal recessive ABCC6 CAG-TAG

Pseudoxanthoma elasticum ABCC6 CAG-TAG

Pseudoxanthoma elasticum ABCC6 CGA-TGA

Pseudoxanthoma elasticum, autosomal recessive ABCC6 TAC-TAG

Pseudoxanthoma elasticum, autosomal recessive ABCC6 CGA-TGA

Pseudoxanthoma elasticum, autosomal dominant ABCC6 CGA-TGA

Pseudoxanthoma elasticum, autosomal dominant ABCC6 CAG-TAG

Pseudoxanthoma elasticum, autosomal dominant ABCC6 TAC-TAA

Pseudoxanthoma elasticum ABCC6 AAG-TAG

Hyperinsulinism ABCC8 CGA-TGA

Hyperinsulinism ABCC8 CAG-TAG

Hypoglycaemia, persistent hyperinsulinaemic ABCC8 GGA-TGA

Hypoglycaemia, persistent hyperinsulinaemic ABCC8 TAC-TAA

Hyperinsulinism ABCC8 CAG-TAG

Adrenoleukodystrophy ABCD1 CAG-TAG

Adrenoleukodystrophy ABCD1 TGG-TAG

Adrenoleukodystrophy ABCD1 CAG-TAG

Adrenoleukodystrophy ABCD1 TAC-TAG

Adrenoleukodystrophy ABCD1 CGA-TGA

Adrenoleukodystrophy ABCD1 CAG-TAG

Adrenoleukodystrophy ABCD1 TGG-TGA

Adrenoleukodystrophy ABCD1 CAA-TAA

Adrenoleukodystrophy ABCD1 CAG-TAG

Adrenoleukodystrophy ABCD1 TAC-TAA

Adrenoleukodystrophy ABCD1 TGG-TGA

Sitosterolaemia ABCG5 CAG-TAG

Sitosterolaemia ABCG8 TCA-TGA

Chanarin-Dorfman syndrome ABHD5 CGA-TGA

Blood group variation ABO CAG-TAG

Blood group variation ABO TGG-TAG

Blood group variation ABO TGG-TGA

Medium chain acyl CoA dehydrogenase deficiency ACADM TTA-TGA

Very long chain acyl-CoA dehydrogenase deficiency ACADVL TCG-TAG

Duffy blood group variation ACKR1 TGG-TGA

Duffy blood group variation ACKR1 TGG-TAG

Alpha actin 3 deficiency ACTN3 CGA-TGA

Haemorrhagic telangiectasia 2 ACVRL1 CGA-TGA

Haemorrhagic telangiectasia 2 ACVRL1 CAG-TAG

Haemorrhagic telangiectasia 2 ACVRL1 TGG-TGA

Haemorrhagic telangiectasia 2 ACVRL1 CAG-TAG

Haemorrhagic telangiectasia 2 ACVRL1 GAG-TAG

Haemorrhagic telangiectasia 2 ACVRL1 CGA-TGA Adenosine deaminase deficiency ADA CAG-TAG

Adenosine deaminase deficiency ADA CGA-TGA

Weill-Marchesani syndrome ADAMTSIO CGA-TGA

Thrombotic thrombocytopaenic purpura ADAMTS13 AGA-TGA

Upshaw-Schulman syndrome ADAMTS13 CGA-TGA

Thrombotic thrombocytopaenic purpura ADAMTS13 CAG-TAG

Thrombotic thrombocytopaenic purpura ADAMTS13 TGG-TAG

Geleophysic dysplasia ADAMTSL2 TGG-TGA

Ectopia lentis, isolated form ADAMTSL4 TAT-TAG

Dyschromatosis symmetrica hereditaria ADAR CAG-TAG

Dyschromatosis symmetrica hereditaria ADAR AGA-TGA

Dyschromatosis symmetrica hereditaria ADAR CAG-TAG

Dyschromatosis symmetrica hereditaria ADAR TGT-TGA

Dyschromatosis symmetrica hereditaria ADAR TCA-TGA

Parkinson disease, association with ADH1C GGA-TGA

Glycogen storage disease 3 AGL TAC-TAG

Glycogen storage disease 3 AGL CGA-TGA

Glycogen storage disease 3 AGL AAG-TAG

Glycogen storage disease 3 AGL CGA-TGA

Glycogen storage disease 3 AGL TGG-TGA

Glycogen storage disease 3a AGL CGA-TGA

Glycogen storage disease 3a AGL TGG-TAG

Glycogen storage disease 3a AGL CGA-TGA

Glycogen storage disease 3a AGL TCA-TGA

Glycogen storage disease 3a AGL TTG-TAG

Renal tubular dysgenesis AGT CAG-TAG

Hyperoxaluria AGXT TAC-TAG

Hyperoxaluria AGXT TGG-TGA

Hyperoxaluria AGXT CGA-TGA

Molar tooth sign & superior vermian dysplasia AHI1 CGA-TGA

Joubert syndrome AHI1 AAA-TAA

Joubert syndrome AHI1 TAT-TAA

Joubert syndrome AHI1 TTA-TGA

Joubert syndrome AHI1 TGG-TAG

Pituitary adenoma AIP AAG-TAG

Leber congenital amaurosis IV AIPL1 TGG-TGA

APECED AIRE CAG-TAG

Adenylate kinase deficiency AK1 CGA-TGA

Analbuminaemia ALB GAA-TAA

Sj oegren-Larsson syndrome ALDH3A2 TTA-TGA

Sj oegren-Larsson syndrome ALDH3A2 TGG-TAG

Sj oegren-Larsson syndrome ALDH3A2 CAG-TAG

Succinic semialdehyde dehydrogenase deficiency ALDH5A1 CGA-TGA

Succinic semialdehyde dehydrogenase deficiency ALDH5A1 TAC-TAG

Succinic semialdehyde dehydrogenase deficiency ALDH5A1 CAA-TAA

Succinic semialdehyde dehydrogenase deficiency ALDH5A1 AAG-TAG

Succinic semialdehyde dehydrogenase deficiency ALDH5A1 CGA-TGA

Epilepsy, pyridoxine-dependent ALDH7A1 TGG-TGA

Epilepsy, pyridoxine-dependent ALDH7A1 CGA-TGA

Aldolase A deficiency ALDOA CGA-TGA

Fructose intolerance ALDOB TGC-TGA

Fructose intolerance ALDOB CAA-TAA

Fructose intolerance ALDOB TGG-TGA

Fructose intolerance ALDOB CGA-TGA

Fructose intolerance ALDOB TAT-TAA

Fructose intolerance ALDOB TAT-TAG

Fructose intolerance ALDOB CGA-TGA

Alstrom syndrome ALMS1 TAC-TAG Alstrom syndrome ALMS1 CAA-TAA

Alstrom syndrome ALMS1 CAG-TAG

Alstrom syndrome ALMS1 TGG-TGA

Alstrom syndrome ALMS1 CAA-TAA

Ichthyosis, congenital, autosomal recessive ALOX12B CGA-TGA

Ichthyosis, congenital, autosomal recessive ALOXE3 CAG-TAG

Hypophosphatasia ALPL TTA-TAA

Hypophosphatasia ALPL GAG-TAG

Hypophosphatasia ALPL CGA-TGA

Hypophosphatasia ALPL TGG-TAG

Spastic paralysis, infantile-onset ALS2 CAG-TAG

Spastic paralysis, infantile-onset ALS2 CGA-TGA

Frontorhiny ALX3 TAT-TAA

Amelogenesis imperfecta AMELX

Adenosine monophosphate deaminase deficiency AMPDl CAA-TAA

Spherocytosis ANK1 TGG-TGA

Spherocytosis ANK1 CGA-TGA

Spherocytosis ANK1 GAG-TAG

Spherocytosis ANK1 CGA-TGA

Spherocytosis ANK1 TCG-TAG

Spherocytosis ANK1 GAA-TAA

Spherocytosis ANK1 CAG-TAG

Spherocytosis ANK1 TAC-TAG

Spherocytosis ANK1 CGA-TGA

Mental retardation AP1S2 CAG-TAG

Mental retardation AP1S2 CGA-TGA

Mental retardation AP1S2 GAA-TAA

Hermansky-Pudlak syndrome AP3B1 GAA-TAA

Hermansky-Pudlak syndrome AP3B1 CGA-TGA

Adenomatous polyposis coli APC CAA-TAA

Adenomatous polyposis coli APC AGA-TGA

Adenomatous polyposis coli APC GAA-TAA

Adenomatous polyposis coli APC GGA-TGA

Adenomatous polyposis coli APC TAT-TAG

Adenomatous polyposis coli APC CAA-TAA

Adenomatous polyposis coli APC TTG-TAG

Adenomatous polyposis coli APC CAA-TAA

Adenomatous polyposis coli APC GAA-TAA

Adenomatous polyposis coli APC CAG-TAG

Adenomatous polyposis coli APC TGC-TGA

Adenomatous polyposis coli APC TCA-TAA

Adenomatous polyposis coli APC TGG-TAG

Adenomatous polyposis coli APC TAC-TAA

Adenomatous polyposis coli APC TAT-TAG

Adenomatous polyposis coli APC TCA-TAA

Adenomatous polyposis coli APC GAA-TAA

Adenomatous polyposis coli APC CAG-TAG

Adenomatous polyposis coli APC GAA-TAA

Adenomatous polyposis coli APC TCA-TAA

Adenomatous polyposis coli APC CAA-TAA

Adenomatous polyposis coli APC TTG-TAG

Apolipoprotein Al deficiency APOA1 CAG-TAG

HDL deficiency with periorbital xanthelasmas APOA1 CAG-TAG

HDL deficiency APOA1 GAG-TAG Apolipoprotein Al deficiency APOA1 TGG-TAG

Apolipoprotein Al deficiency APOA1 CAG-TAG

Hypertriglyceridaemia APOA5 CAG-TAG

Hypobetalipoproteinaemia APOB TGG-TGA

Hypobetalipoproteinaemia APOB CAG-TAG

Hypobetalipoproteinaemia APOB TAT-TAA

Hypobetalipoproteinaemia APOB CAA-TAA

Apolipoprotein B deficiency APOB CGA-TGA

Apolipoprotein C2 deficiency APOC2 TAC-TAA

Adenine phosphoribosyltransferase deficiency APRT TGG-TGA

Diabetes insipidus, nephrogenic AQP2 GGA-TGA

Androgen insensitivity syndrome AR CAG-TAG

Androgen insensitivity syndrome AR TCA-TAA

Androgen insensitivity syndrome AR GAG-TAG

Androgen insensitivity syndrome AR CAG-TAG

Androgen insensitivity syndrome AR CAA-TAA

Androgen insensitivity syndrome AR TAC-TAA

Androgen insensitivity syndrome AR TTA-TGA

Androgen insensitivity syndrome AR TAT-TAA

Androgen insensitivity syndrome AR GAG-TAG

Androgen insensitivity syndrome AR CAG-TAG

Arginase deficiency ARG1 AAA-TAA

X-linked with epilepsy ARHGEF9 CAG-TAG Mental retardation

Bardet-Biedl syndrome ARL6

Cancer, association with ARL11 TGG-TAG

Metachromatic leukodystrophy ARSA CAG-TAG

Metachromatic leukodystrophy ARSA TGG-TGA

Metachromatic leukodystrophy ARSA CGA-TGA

Mucopolysaccharidosis VI ARSB CAA-TAA

Mucopolysaccharidosis VI ARSB GAA-TAA

Mucopolysaccharidosis VI ARSB TGG-TGA

Mucopolysaccharidosis VI ARSB TGG-TAG

Mucopolysaccharidosis VI ARSB TGG-TGA

Chondrodysplasia punctata ARSE TGG-TGA

Chondrodysplasia punctata ARSE CGA-TGA

Dombrock blood group variation ART4 CAG-TAG

Lissencephaly, X-linked, with abnormal genitalia ARX GAG-TAG

Argininosuccinate lyase deficiency ASL CGA-TGA

Canavan disease ASPA TAC-TAA

Canavan disease ASPA GAA-TAA

Canavan disease ASPA CAA-TAA

Primary microcephaly ASPM TAT-TAG

Primary microcephaly ASPM CGA-TGA

Primary microcephaly ASPM CAA-TAA

Primary microcephaly ASPM TAT-TAG

Primary microcephaly ASPM CAG-TAG

Primary microcephaly ASPM CGA-TGA

Primary microcephaly ASPM AAA-TAA

Primary microcephaly ASPM TAT-TAA Primary microcephaly ASPM GAA-TAA

Primary microcephaly ASPM TTA-TGA

Primary microcephaly ASPM CAA-TAA

Primary microcephaly ASPM GAA-TAA

Primary microcephaly ASPM TCA-TGA

Primary microcephaly ASPM TGG-TGA

Primary microcephaly ASPM CGA-TGA

Polycystic kidney disease 1 ASS1 CGA-TGA

Citrullinaemia ASS1 CAG-TAG

Ataxia telangiectasia ATM CAG-TAG

Ataxia telangiectasia ATM TGG-TAG

Ataxia telangiectasia ATM AGA-TGA

Ataxia telangiectasia ATM CAA-TAA

Ataxia telangiectasia ATM CAG-TAG

Ataxia telangiectasia ATM TTA-TGA

Ataxia telangiectasia ATM TAT-TAA

Ataxia telangiectasia ATM GAA-TAA

Ataxia telangiectasia ATM CAG-TAG

Ataxia telangiectasia ATM TGG-TAG

Ataxia telangiectasia ATM TGT-TGA

Ataxia telangiectasia ATM TTG-TAG

Ataxia telangiectasia ATM TCA-TAA

Ataxia telangiectasia ATM TGG-TAG

Ataxia telangiectasia ATM CGA-TGA

Ataxia telangiectasia ATM CAA-TAA

Ataxia telangiectasia ATM TTA-TGA

Ataxia telangiectasia ATM TAC-TAG

Ataxia telangiectasia ATM TGG-TGA

Ataxia telangiectasia ATM CAG-TAG

Ataxia telangiectasia ATM GGA-TGA

Mantle cell lymphoma ATM CGA-TGA

Hemiplegic migraine ATP1A2 TAT-TAA

Darier disease ATP2A2 TGT-TGA

Darier disease ATP2A2 TGC-TGA

Darier disease ATP2A2 CGA-TGA

Darier disease ATP2A2 GAA-TAA

Darier disease ATP2A2 GAG-TAG

Darier disease ATP2A2 TAC-TAA

Darier disease ATP2A2 TGC-TGA

Darier disease ATP2A2 CAG-TAG

Darier disease ATP2A2 CGA-TGA

Hailey-Hailey disease ATP2C1 TGG-TAG

Hailey-Hailey disease ATP2C1 TCA-TAA

Hailey-Hailey disease ATP2C1 CAG-TAG

Hailey-Hailey disease ATP2C1 CAA-TAA

Hailey-Hailey disease ATP2C1 CAG-TAG

Hailey-Hailey disease ATP2C1 CGA-TGA

Hailey-Hailey disease ATP2C1 TCA-TGA

Hailey-Hailey disease ATP2C1 CGA-TGA

Hailey-Hailey disease ATP2C1 CAG-TAG

Hailey-Hailey disease ATP2C1 CAA-TAA

Hailey-Hailey disease ATP2C1 TTA-TAA

Cutis laxa, autosomal recessive, type 2 ATP6V0A2 TAC-TAA

Cutis laxa, autosomal recessive, type 2 ATP6V0A2 TTG-TAG

Distal renal tubular acidosis, autosomal recessive ATP6V0A4 CAA-TAA Menkes syndrome ATP7A AAA-TAA

Menkes syndrome ATP7A TAC-TAG

Menkes syndrome ATP7A CGA-TGA

Menkes syndrome ATP7A CAA-TAA

Menkes syndrome ATP7A CGA-TGA

Menkes syndrome ATP7A TTA-TAA

Menkes syndrome ATP7A CAA-TAA

Menkes syndrome ATP7A TCA-TGA

Menkes syndrome ATP7A CGA-TGA

Menkes syndrome ATP7A CAA-TAA

Menkes syndrome ATP7A CAG-TAG

Menkes syndrome ATP7A TGG-TAG

Menkes syndrome ATP7A TGC-TGA

Menkes syndrome ATP7A GAA-TAA

Menkes syndrome ATP7A TCA-TAA

Menkes syndrome ATP7A GAA-TAA

Menkes syndrome ATP7A CGA-TGA

Wilson disease ATP7B CAG-TAG

Wilson disease ATP7B TGG-TGA

Wilson disease ATP7B CAG-TAG

Wilson disease ATP7B TGG-TGA

Wilson disease ATP7B GAA-TAA

Wilson disease ATP7B CAA-TAA

Wilson disease ATP7B CAG-TAG

Wilson disease ATP7B TAT-TAA

Wilson disease ATP7B CAA-TAA

Wilson disease ATP7B TTG-TAG

Wilson disease ATP7B CGA-TGA

Wilson disease ATP7B CAG-TAG

Wilson disease ATP7B TGG-TAG

Wilson disease ATP7B CAG-TAG

Wilson disease ATP7B TGT-TGA

Wilson disease ATP7B TTG-TAG

Wilson disease ATP7B CAG-TAG

Intrahepatic cholestasis, familial progressive ATP8B1 GAA-TAA

Intrahepatic cholestasis, familial progressive ATP8B1 CGA-TGA

Intrahepatic cholestasis, benign recurrent ATP8B1 CGA-TGA

Intrahepatic cholestasis, familial progressive ATP8B1 CGA-TGA

Intrahepatic cholestasis, familial progressive ATP8B1 CAA-TAA

Intrahepatic cholestasis, familial progressive ATP8B1 TAT-TAA

ATRX syndrome ATRX CGA-TGA

3-methylglutaconic aciduria type 1 AUH CGA-TGA

Diabetes insipidus, neurohypophyseal AVP GAG-TAG

Diabetes insipidus, neurohypophyseal AVP TGC-TGA

Diabetes insipidus, neurohypophyseal AVP GAG-TAG

Diabetes insipidus, central AVP GAG-TAG

Diabetes insipidus, nephrogenic AVPR2 CAG-TAG

Diabetes insipidus, nephrogenic AVPR2 TGG-TAG

Diabetes insipidus, nephrogenic AVPR2 GAG-TAG

Tooth agenesis and colorectal cancer AXIN2 CGA-TGA

B3GALNT1 deficiency (P2K phenotype) B3GALNT1 CGA-TGA

Blood group variation BCAM TGC-TGA

Blood group variation BCAM CGA-TGA Blood group variation BCAM CGA-TGA

Cholinesterasaemia BCHE TGC-TGA

Butyrylcholinesterase variant BCHE CAA-TAA

Maple syrup urine disease BCKDHA CGA-TGA

Maple syrup urine disease BCKDHB AAA-TAA

Maple syrup urine disease BCKDHB CGA-TGA

Oculofaciocardiodental syndrome BCOR CGA-TGA

Bestrophinopathy BEST1 CGA-TGA

Cleft lip and palate BMP4 CGA-TGA

Juvenile polyposis syndrome BMPR1A TAC-TAA

Polyposis, juvenile intestinal BMPR1A TGG-TAG

Polyposis, juvenile intestinal BMPR1A CAA-TAA

Pulmonary hypertension, primary BMPR2 CAA-TAA

Pulmonary hypertension, primary BMPR2 TGG-TGA

Pulmonary hypertension, primary BMPR2 TTA-TGA

Pulmonary hypertension, primary BMPR2 TGG-TGA

Pulmonary hypertension, primary BMPR2 TTA-TAA

Pulmonary hypertension, primary BMPR2 TCA-TGA

Pulmonary hypertension, primary BMPR2 TGG-TAG

Pulmonary hypertension, primary BMPR2 CAA-TAA

Pulmonary hypertension, primary BMPR2 TCA-TAA

Pulmonary hypertension, primary BMPR2 TAT-TAG

Pulmonary hypertension, primary BMPR2 TGC-TGA

Pulmonary arterial hypertension BMPR2 CAG-TAG

Pulmonary hypertension, primary BMPR2 CGA-TGA

Pulmonary hypertension, primary BMPR2 GAG-TAG

Pulmonary hypertension, primary BMPR2 TCA-TGA

Pulmonary hypertension, primary BMPR2 TAC-TAG

Pulmonary hypertension, primary BMPR2 TGG-TAG

Pulmonary hypertension, primary BMPR2 CGA-TGA

Breast cancer BRCA1 CAA-TAA

Breast cancer BRCA1 CAG-TAG

Breast cancer BRCA1 GAG-TAG

Breast cancer BRCA1 CGA-TGA

Breast and/or ovarian cancer BRCA1 CAG-TAG

Breast and/or ovarian cancer BRCA1 GAA-TAA

Breast cancer BRCA1 GGA-TGA

Breast cancer BRCA1 TGG-TAG

Breast cancer BRCA1 CAG-TAG

Breast cancer BRCA1 TTA-TAA

Breast and/or ovarian cancer BRCA1 TGG-TAG

Breast and/or ovarian cancer BRCA1 CAA-TAA

Breast cancer BRCA1 TAC-TAA

Breast cancer BRCA1 CAG-TAG

Breast cancer BRCA1 TGG-TAG

Breast cancer BRCA1 CAG-TAG

Breast and/or ovarian cancer BRCA1 CAG-TAG

Breast cancer BRCA1 CAG-TAG

Breast cancer BRCA1 CAA-TAA

Breast cancer BRCA1 TGG-TAG

Breast cancer BRCA1 TGG-TGA

Breast cancer BRCA1 TCA-TAA

Breast cancer BRCA1 CAA-TAA

Breast and/or ovarian cancer BRCA1 TTA-TGA

Breast cancer BRCA1 TAT-TAG

Breast cancer BRCA1 CAG-TAG

Breast cancer BRCA1 GAG-TAG

Breast cancer BRCA1 CAG-TAG

Breast cancer BRCA1 CAG-TAG Breast cancer BRCA2 CAG-TAG

Breast cancer BRCA2 CAG-TAG

Breast and/or ovarian cancer BRCA2 AAG-TAG

Breast cancer BRCA2 AAA-TAA

Breast cancer BRCA2 GAA-TAA

Breast cancer BRCA2 TCA-TGA

Breast cancer BRCA2 CAA-TAA

Breast and/or ovarian cancer BRCA2 TAT-TAA

Breast cancer BRCA2 CGA-TGA

Breast cancer BRCA2 TCA-TGA

Breast cancer BRCA2 GAA-TAA

Breast and/or ovarian cancer BRCA2 CAA-TAA

Breast cancer BRCA2 TCA-TAA

Breast cancer BRCA2 TCA-TGA

Breast cancer BRCA2 CGA-TGA

Breast cancer BRCA2 AAA-TAA

Breast and/or ovarian cancer BRCA2 TGT-TGA

Breast cancer BRCA2 TAC-TAG

Breast cancer BRCA2 AAA-TAA

Breast cancer BRCA2 GAA-TAA

Breast cancer BRCA2 CAG-TAG

Breast cancer BRCA2 GAA-TAA

Berardinelli-Seip lipodystrophy BSCL2 CGA-TGA

Bartter syndrome with sensorineural deafness BSND CAG-TAG

Biotinidase deficiency BTD GAG-TAG

Biotinidase deficiency BTD CAG-TAG

Agammaglobulinaemia BTK CAA-TAA

Agammaglobulinaemia BTK AAA-TAA

Agammaglobulinaemia BTK TGG-TGA

Agammaglobulinaemia BTK TTA-TAA

Agammaglobulinaemia BTK TAC-TAA

Agammaglobulinaemia BTK AAG-TAG

Agammaglobulinaemia BTK TGG-TGA

Agammaglobulinaemia BTK CAA-TAA

Agammaglobulinaemia BTK GAG-TAG

Agammaglobulinaemia BTK GAA-TAA

Agammaglobulinaemia BTK TGG-TAG

Agammaglobulinaemia BTK CAG-TAG

Agammaglobulinaemia BTK CGA-TGA

Agammaglobulinaemia BTK GAA-TAA

Agammaglobulinaemia BTK TGG-TAG

Agammaglobulinaemia BTK AAA-TAA

Agammaglobulinaemia BTK CAG-TAG

Agammaglobulinaemia BTK GAG-TAG

Agammaglobulinaemia BTK GGA-TGA

Agammaglobulinaemia BTK TAC-TAA

Premature chromatid separation syndrome BUBIB CGA-TGA

Complement CIS deficiency CIS GAA-TAA

Complement CIS deficiency CIS CGA-TGA

Complement C3 deficiency C3 CGA-TGA

Complement C3 deficiency C3 TGG-TAG

Complement C5 deficiency C5 CAG-TAG

Complement C5 deficiency C5 CGA-TGA

Complement C5 deficiency C5 CAA-TAA Complement C7 deficiency C7 GAG-TAG

Complement C7 deficiency C7 CAG-TAG

Complement C8 alpha-gamma deficiency C8A CGA-TGA

Carbonic anhydrase deficiency CA2 TAT-TAG

Cone-rod synaptic disorder CABP4 CGA-TGA

Episodic ataxia 2 CACNA1A CGA-TGA

Episodic ataxia 2 CACNA1A TGG-TAG

Episodic ataxia 2 CACNA1A CAG-TAG

Episodic ataxia 2 CACNA1A CGA-TGA

Night blindness, congenital stationary, incomplete CACNA1F AAA-TAA

Night blindness, congenital stationary, incomplete CACNA1F CAG-TAG

Night blindness, congenital stationary, incomplete CACNA1F CGA-TGA

Muscular dystrophy, limb girdle CAPN3 CAG-TAG

Muscular dystrophy, limb girdle CAPN3 TGG-TAG

Muscular dystrophy, limb girdle CAPN3 CGA-TGA

Ventricular tachycardia, polymorphic CASQ2 CGA-TGA

Hypercalcaemia, hypocalciuric CASR CGA-TGA

Hypercalcaemia, hypocalciuric CASR TCG-TAG

Hypercalcaemia, hypocalciuric CASR AAG-TAG

Hypercalcaemia, hypocalciuric CASR CGA-TGA

Berardinelli-Seip lipodystrophy CAV1 GAG-TAG

Joubert syndrome CC2D2A CGA-TGA

Cerebral cavernous malformations CCM2 CAG-TAG

CD36 deficiency CD36 TTA-TGA

Hyper-IgM syndrome CD40LG GAA-TAA

Hyper-IgM syndrome CD40LG GGA-TGA

Hyper-IgM syndrome CD40LG AAG-TAG

Hyper-IgM syndrome CD40LG TCA-TAA

Hyper-IgM syndrome CD40LG TGG-TGA

Hyper-IgM syndrome CD40LG TGC-TGA

Hyper-IgM syndrome CD40LG TCG-TAG

Hyper-IgM syndrome CD40LG GAA-TAA

Hyper-IgM syndrome CD40LG CAA-TAA

Hyper-IgM syndrome CD40LG CGA-TGA

Cromer blood group CD55 CGA-TGA

Agammaglobulinaemia CD79B CAG-TAG

Hyperparathyroidism, primary CDC73 TGG-TGA

Gastric cancer CDH1 CAG-TAG

Gastric cancer CDH1 TGG-TAG

Usher syndrome Id CDH23 CAA-TAA

Usher syndrome Id CDH23 GAG-TAG

Usher syndrome Id CDH23 CGA-TGA

Usher syndrome Id CDH23 CAG-TAG

Usher syndrome Id CDH23 TGG-TAG

Usher syndrome Id CDH23 GAG-TAG

Usher syndrome Id CDH23 CGA-TGA

Hypotrichosis with juvenile macular dystrophy CDH3 CGA-TGA

Hypotrichosis with juvenile macular dystrophy CDH3 TAT-TAA

Rett syndrome, atypical CDKL5 CAG-TAG

Pituitary and parathyroid tumours CDKN1B TGG-TAG

Melanoma CDKN2A CGA-TGA

Melanoma CDKN2A TGG-TGA

Melanoma CDKN2A TGG-TAG

Hypotrichosis simplex of the scalp CDSN CAG-TAG

Hypotrichosis simplex of the scalp CDSN CAG-TAG Hypotrichosis simplex of the scalp CDSN TAC-TAG

Bardet-Biedl syndrome CEP290 AA.G-TAG

Leber congenital amaurosis CEP290 TCA-TGA

Leber congenital amaurosis CEP290 TAC-TAA

Leber congenital amaurosis CEP290 CAA-TAA

Leber congenital amaurosis CEP290 GAA-TAA

Leber congenital amaurosis CEP290 CAA-TAA

Leber congenital amaurosis CEP290 CAG-TAG

Leber congenital amaurosis CEP290 AAG-TAG

Cholesterol ester transfer protein deficiency CETP CAA-TAA

Cholesterol ester transfer protein deficiency CETP TAT-TAG

Cholesterol ester transfer protein deficiency CETP GGA-TGA

Drusen, basal laminar CFH CAG-TAG

Cystic fibrosis CFTR GAA-TAA

Cystic fibrosis CFTR CAG-TAG

Cystic fibrosis CFTR TAC-TAA

Cystic fibrosis CFTR TGG-TAG

Cystic fibrosis CFTR TGC-TGA

Cystic fibrosis CFTR TCA-TAA

Cystic fibrosis CFTR TAT-TAA

Congenital absence of vas deferens CFTR AAA-TAA

Cystic fibrosis CFTR CGA-TGA

Cystic fibrosis CFTR TGG-TAG

Cystic fibrosis CFTR TTA-TGA

Cystic fibrosis CFTR GAA-TAA

Cystic fibrosis CFTR TTA-TAA

Cystic fibrosis CFTR GGA-TGA

Cystic fibrosis CFTR TTA-TGA

Cystic fibrosis CFTR CGA-TGA

Cystic fibrosis CFTR GGA-TGA

Cystic fibrosis CFTR CAG-TAG

Cystic fibrosis CFTR TGG-TGA

Cystic fibrosis CFTR CAG-TAG

Cystic fibrosis CFTR CGA-TGA

Cystic fibrosis CFTR GAG-TAG

Cystic fibrosis CFTR CGA-TGA

Cystic fibrosis CFTR TGG-TGA

Cystic fibrosis CFTR AAA-TAA

Cystic fibrosis CFTR CAA-TAA

Elevated sweat chloride concentration CFTR TCA-TGA

CHARGE syndrome CHD7 CAA-TAA

CHARGE syndrome CHD7 TAC-TAG

CHARGE syndrome CHD7 TGG-TGA

CHARGE syndrome CHD7 CAG-TAG

CHARGE syndrome CHD7 CAA-TAA

CHARGE syndrome CHD7 CAG-TAG

CHARGE syndrome CHD7 GAA-TAA

CHARGE syndrome CHD7 CGA-TGA

CHARGE syndrome CHD7 CAG-TAG

CHARGE syndrome CHD7 AAG-TAG

CHARGE syndrome CHD7 CGA-TGA

CHARGE syndrome CHD7 CAG-TAG

CHARGE syndrome CHD7 CGA-TGA

CHARGE syndrome CHD7 TGG-TGA CHARGE syndrome CHD7 TGG-TGA

CHARGE syndrome CHD7 TGG-TGA

CHARGE syndrome CHD7 TGG-TAG

CHARGE syndrome CHD7 TGG-TGA

CHARGE syndrome CHD7 CGA-TGA

CHARGE syndrome CHD7 TCA-TGA

CHARGE syndrome CHD7 GAA-TAA

Choroideraemia CHM TCA-TAA

Choroideraemia CHM CGA-TGA

Choroideraemia CHM CAA-TAA

Choroideraemia CHM CGA-TGA

Choroideraemia CHM GAA-TAA

Choroideraemia CHM TAT-TAG

Choroideraemia CHM TGC-TGA

Choroideraemia CHM TGG-TGA

Frontotemporal dementia CHMP2B CGA-TGA

Frontotemporal dementia CHMP2B CAA-TAA

Fetal akinesia deformation sequence disorder CHRND TGG-TGA

Fetal akinesia deformation sequence disorder CHRND CGA-TGA

Congenital myasthenic syndrome CHRNE CAG-TAG

Slow channel myasthenic syndrome CHRNE CGA-TGA

Macular corneal dystrophy, type 1 CHST6 CAA-TAA

Macular corneal dystrophy, type 1 CHST6 CAG-TAG

Macular corneal dystrophy, type 1 CHST6 CGA-TGA

Macular corneal dystrophy, type 1 CHST6 TGC-TGA

Macular corneal dystrophy, type 1 CHST6 TGG-TGA

Macular corneal dystrophy, type 1 CHST6 GGA-TGA

Macular corneal dystrophy, type 1 CHST6 CAG-TAG

Macular corneal dystrophy, type 1 CHST6 GAA-TAA

Macular corneal dystrophy CHST6 TCG-TAG

Macular corneal dystrophy, type 1 CHST6 CAG-TAG

Immunodeficiency CIITA TGG-TAG

Myotonia congenita CLCN1 CGA-TGA

Myotonia, Becker CLCN1 CAG-TAG

Myotonia congenita CLCN1 TGC-TGA

Myotonia congenita CLCN1 CAA-TAA

Myotonia CLCN1 GAA-TAA

Low molecular weight proteinuria CLCN5 GAG-TAG

Dent disease CLCN5 TAC-TAA

Dent disease CLCN5 CGA-TGA

Low molecular weight proteinuria CLCN5 CGA-TGA

Dent disease CLCN5 CGA-TGA

Dent disease CLCN5 TGG-TGA

Dent disease CLCN5 GAG-TAG

Dent disease CLCN5 TAT-TAG

Low molecular weight proteinuria CLCN5 CGA-TGA

Dent (Japan) disease CLCN5 TGG-TAG

Dent disease CLCN5 TGT-TGA

Dent disease CLCN5 TGG-TAG

Dent disease CLCN5 TTA-TGA

Dent disease CLCN5 CGA-TGA

Bartter syndrome 4, digenic CLCNKA CAG-TAG

Bartter syndrome 3 CLCNKB CAG-TAG

Neuronal ceroid lipofuscinosis, juvenile CLN3 TCA-TGA

Neuronal ceroid lipofuscinosis, juvenile CLN3 CAG-TAG

Neuronal ceroid lipofuscinosis, juvenile CLN3 CAG-TAG Neuronal ceroid lipofuscinosis, juvenile CLN3 CAG-TAG

Neuronal ceroid lipofuscinosis, late infantile CLN5 TGG-TGA

Neuronal ceroid lipofuscinosis, late infantile CLN6 TAC-TAG

Retinitis pigmentosa CNGA1 GAG-TAG

Retinitis pigmentosa CNGA1 AAA-TAA

Achromatopsia CNGB3 TGG-TGA

Achromatopsia CNGB3 CGA-TGA

Achromatopsia CNGB3 CAG-TAG

Achromatopsia CNGB3 CGA-TGA

Achromatopsia CNGB3 GAA-TAA

Congenital disorder of glycosylation Ilh COG8 TAC-TAG

Metaphyseal chondrodysplasia, Schmid COL10A1 TGG-TAG

Metaphyseal chondrodysplasia, Schmid COL10A1 TGG-TGA

Metaphyseal chondrodysplasia, Schmid COL10A1 TAC-TAG

Stickler syndrome, without eye involvement COL11A2 CGA-TGA

Epidermolysis bullosa COL17A1 CGA-TGA

Epidermolysis bullosa, junctional COL17A1 CAG-TAG

Epidermolysis bullosa, junctional COL17A1 CGA-TGA

Epidermolysis bullosa, atrophic benign COL17A1 GGA-TGA

Epidermolysis bullosa, atrophic benign COL17A1 CAG-TAG

Epidermolysis bullosa, junctional COL17A1 CAA-TAA

Epidermolysis bullosa, atrophic benign COL17A1 GGA-TGA

Epidermolysis bullosa, junctional COL17A1 CAG-TAG

Epidermolysis bullosa COL17A1 CAG-TAG

Osteogenesis imperfecta I COL1A1 CGA-TGA

Osteogenesis imperfecta I COL1A1 CAA-TAA

Osteogenesis imperfecta COL1A1 CAG-TAG

Osteogenesis imperfecta COL1A1 CGA-TGA

Ehlers-Danlos syndrome VII COL1A2 GAA-TAA

Stickler syndrome COL2A1 TGC-TGA

Spondyloperipheral dysplasia COL2A1 TGC-TGA

Ehlers-Danlos syndrome IV COL3A1 CGA-TGA

Alport syndrome COL4A3 CGA-TGA

Alport syndrome COL4A3 TCA-TGA

Alport syndrome COL4A5 GGA-TGA

Alport syndrome COL4A5 GAA-TAA

Alport syndrome COL4A5 CAG-TAG

Alport syndrome COL4A5 CGA-TGA

Alport syndrome COL4A5 GAA-TAA

Alport syndrome COL4A5 GGA-TGA

Alport syndrome COL4A5 CAG-TAG

Alport syndrome COL4A5 TGG-TGA

Alport syndrome COL4A5 GGA-TGA

Alport syndrome COL4A5 TGC-TGA

Alport syndrome COL4A5 CAA-TAA

Alport syndrome COL4A5 CAG-TAG

Alport syndrome COL4A5 CGA-TGA

Ullrich congenital muscular dystrophy COL6A1 TAC-TAG

Myosclerosis myopathy COL6A2 CAA-TAA

Ullrich congenital muscular dystrophy COL6A3 CGA-TGA

Epidermolysis bullosa COL7A1 CGA-TGA

Epidermolysis bullosa dystrophica COL7A1 CGA-TGA Epidermolysis bullosa dystrophica COL7A1 CGA-TGA

Epidermolysis bullosa dystrophica COL7A1 CAG-TAG

Epidermolysis bullosa dystrophica COL7A1 GAG-TAG

Epidermolysis bullosa dystrophica COL7A1 GGA-TGA

Epidermolysis bullosa dystrophica COL7A1 CGA-TGA

Epidermolysis bullosa dystrophica COL7A1 CAG-TAG

Endplate acetylcholinesterase deficiency COLQ CGA-TGA

Aceruloplasminaemia with diabetes CP TGG-TAG

Aceruloplasminaemia CP CGA-TGA

Coproporphyria CPOX TGG-TGA

Harderoporphyria CPOX CGA-TGA

Coproporphyria CPOX CAG-TAG

Carbamoyl phosphate synthetase I deficiency CPS1 TAC-TAA

Carbamoyl phosphate synthetase I deficiency CPS1 CAA-TAA

Carbamoyl phosphate synthetase I deficiency CPS1 CGA-TGA

Carnitine palmitoyltransferase 1 deficiency CPT1A TGG-TGA

Carnitine palmitoyltransferase 1 deficiency CPT1A CGA-TGA

Carnitine palmitoyltransferase 1 deficiency CPT1A TAC-TAA

Leber congenital amaurosis CRB1 CGA-TGA

Mental retardation, non-syndromic, autosomal CRBN CGA-TGA recessive

Rubinstein-Taybi syndrome CREBBP CGA-TGA

Rubinstein-Taybi syndrome CREBBP GGA-TGA

Rubinstein-Taybi syndrome CREBBP CAA-TAA

Crisponi syndrome CRLF1 AAG-TAG

Congenital cataract CRYAA TGG-TGA

Cataract, autosomal dominant CRYBB1 CAG-TAG

Cataract, autosomal dominant CRYBB1 GGA-TGA

Cataract CRYGC TGC-TGA

Cataract CRYGC TGG-TAG

Cataract, pediatric CRYGD CGA-TGA

Cataract CRYGD TAC-TAG

Cystinosis CTNS TGG-TGA

Pancreatitis, chronic CTRC TGG-TAG

Papillon-Lefevre syndrome CTSC CAG-TAG

Papillon-Lefevre syndrome CTSC TAC-TAA

Papillon-Lefevre syndrome CTSC CAG-TAG

Papillon-Lefevre syndrome CTSC TGG-TAG

Papillon-Lefevre syndrome CTSC CGA-TGA

Papillon-Lefevre syndrome CTSC TGG-TAG

Papillon-Lefevre syndrome CTSC CAG-TAG

Pycnodysostosis CTSK CGA-TGA

3-M syndrome CUL7 CAG-TAG

3-M syndrome CUL7 CGA-TGA

3-M syndrome CUL7 TGG-TAG

3-M syndrome CUL7 CGA-TGA

Methaemoglobinaemia 2 CYB5R3 CGA-TGA

Methaemoglobinaemia CYB5R3 TAC-TAA

Chronic granulomatous disease CYBA TGG-TGA

Chronic granulomatous disease CYBA TGG-TAG

Chronic granulomatous disease CYBA CAG-TAG

Chronic granulomatous disease CYBA TGC-TGA

Chronic granulomatous disease CYBB CAG-TAG Chronic granulomatous disease CYBB CAA-TAA

Chronic granulomatous disease CYBB AAA-TAA

Chronic granulomatous disease CYBB CAA-TAA

Chronic granulomatous disease CYBB GAG-TAG

Chronic granulomatous disease CYBB TGG-TGA

Chronic granulomatous disease CYBB GAA-TAA

Chronic granulomatous disease CYBB TGC-TGA

Chronic granulomatous disease CYBB GAG-TAG

Chronic granulomatous disease CYBB CAA-TAA

Chronic granulomatous disease CYBB TGG-TGA

Chronic granulomatous disease CYBB TAC-TAA

Chronic granulomatous disease CYBB TGG-TAG

Chronic granulomatous disease CYBB CAA-TAA

Chronic granulomatous disease CYBB TAT-TAA

Chronic granulomatous disease CYBB TGG-TGA

Chronic granulomatous disease CYBB TGG-TAG

Chronic granulomatous disease CYBB GAA-TAA

Chronic granulomatous disease CYBB TGG-TAG

Chronic granulomatous disease CYBB TGG-TGA

Chronic granulomatous disease CYBB TAC-TAA

Chronic granulomatous disease CYBB TAC-TAG

Trichoepithelioma, multiple familial CYLD CAA-TAA

Adrenal hyperplasia CYP11B1 CAG-TAG

Steroid-11 beta-hydroxylase deficiency CYP11B1 CAA-TAA

Steroid-11 beta-hydroxylase deficiency CYP11B1 TGG-TAG

Steroid-11 beta-hydroxylase deficiency CYP11B1 AAG-TAG

Steroid-11 beta-hydroxylase deficiency CYP11B1 CAG-TAG

Adrenal hyperplasia CYP11B1 TGG-TAG

Steroid-11 beta-hydroxylase deficiency CYP11B1 TAT-TAG

17-alpha-hydroxylase/17 , 20-lyase deficiency CYP17A1 AAG-TAG

17-alpha-hydroxylase/17 , 20-lyase deficiency CYP17A1 CGA-TGA

Glaucoma, primary congenital CYP1B1 GAG-TAG

Glaucoma, primary congenital CYP1B1 TGG-TGA

Glaucoma, primary congenital CYP1B1 GAG-TAG

Glaucoma, primary congenital CYP1B1 CGA-TGA

Glaucoma, primary congenital CYP1B1 CAG-TAG

Adrenal hyperplasia CYP21A2 TGG-TGA

Adrenal hyperplasia CYP21A2 CAG-TAG

Adrenal hyperplasia CYP21A2 TGG-TGA

Non-classic 21-hydroxylase deficiency CYP21A2 TAC-TAG

Adrenal hyperplasia CYP21A2 TGG-TAG

Adrenal hyperplasia CYP21A2 TAC-TAA

Pseudovitamin D-deficiency rickets CYP27B1 TGG-TAG

Pseudovitamin D-deficiency rickets CYP27B1 TGG-TGA

Null allele CYP2A13 CGA-TGA

Cytochrome P450 deficiency CYP2D6 GGA-TGA

CYP2G deficiency, association with CYP2G2P CGA-TGA

Null allele CYP4A22 CAG-TAG

Bietti crystalline corneoretinal dystrophy CYP4V2 TTA-TGA

Spastic paraplegia CYP7B1 CGA-TGA

Spastic paraplegia CYP7B1 TAT-TAA

Maple syrup urine disease DBT GAA-TAA

Immunodeficiency, severe combined DCLRE1C TAC-TAA

Subcortical band heterotopia DCX GAA-TAA

Subcortical band heterotopia DCX AAA-TAA Double cortex syndrome DCX CGA-TGA

Double cortex syndrome DCX CAG-TAG

Double cortex syndrome DCX CGA-TGA

Usher syndrome 2 DFNB31 CAG-TAG

Progressive hearing loss, autosomal recessive DFNB59 CGA-TGA

Mitochondrial DNA depletion syndrome DGUOK CGA-TGA

Mitochondrial DNA depletion syndrome DGUOK TGG-TAG

Mitochondrial DNA depletion syndrome DGUOK TGG-TGA

Smith-Lemli-Opitz syndrome DHCR7 CAG-TAG

Smith-Lemli-Opitz syndrome DHCR7 TGG-TGA

Smith-Lemli-Opitz syndrome DHCR7 TGG-TAG

Smith-Lemli-Opitz syndrome DHCR7 TGG-TGA

Spondylocostal dysostosis DLL3 CGA-TGA

Spondylocostal dysostosis DLL3 TGC-TGA

Muscular dystrophy, Duchenne DMD TAT-TAG

Muscular dystrophy, Duchenne DMD AAG-TAG

Muscular dystrophy, Duchenne DMD CAA-TAA

Muscular dystrophy, Duchenne DMD GGA-TGA

Muscular dystrophy, Duchenne DMD TAT-TAA

Muscular dystrophy, Duchenne DMD AAA-TAA

Muscular dystrophy, Duchenne DMD TGG-TAG

Dystrophinopathy DMD CAG-TAG

Muscular dystrophy, Duchenne DMD TTA-TGA

Muscular dystrophy, Duchenne DMD CAA-TAA

Muscular dystrophy, Duchenne DMD CGA-TGA

Muscular dystrophy, Duchenne DMD TAT-TAG

Muscular dystrophy, Duchenne DMD GGA-TGA

Muscular dystrophy, Duchenne DMD GAA-TAA

Muscular dystrophy, Duchenne DMD CAG-TAG

Muscular dystrophy, Duchenne DMD GAG-TAG

Muscular dystrophy, Duchenne DMD CAG-TAG

Muscular dystrophy, Duchenne DMD TCA-TAA

Muscular dystrophy, Duchenne DMD TTG-TAG

Muscular dystrophy, Duchenne DMD AAA-TAA

Muscular dystrophy, Duchenne DMD TGG-TGA

Muscular dystrophy, Duchenne DMD AAA-TAA

Muscular dystrophy, Duchenne DMD TGG-TAG

Muscular dystrophy, Duchenne DMD TGG-TGA

Muscular dystrophy, Duchenne DMD CAA-TAA

Muscular dystrophy, Duchenne DMD TGG-TAG

Muscular dystrophy, Becker DMD TCG-TAG

Muscular dystrophy, Becker DMD GAA-TAA

Muscular dystrophy, Duchenne DMD TAT-TAA

Muscular dystrophy, Duchenne DMD CAA-TAA

Muscular dystrophy, Duchenne DMD GGA-TGA

Muscular dystrophy, Duchenne DMD CGA-TGA

Muscular dystrophy, Duchenne DMD GAG-TAG

Muscular dystrophy, Duchenne DMD CAG-TAG

Muscular dystrophy, Becker DMD TCA-TAA

Muscular dystrophy, Duchenne DMD CAG-TAG

Muscular dystrophy, Duchenne DMD CAA-TAA

Muscular dystrophy, Duchenne DMD CAG-TAG

Muscular dystrophy, Duchenne DMD CAG-TAG Muscular dystrophy, Duchenne DMD GAA-TAA

Muscular dystrophy, Duchenne DMD CAG-TAG

Muscular dystrophy, Duchenne DMD TGG-TAG

Muscular dystrophy, Duchenne DMD GAG-TAG

Muscular dystrophy, Duchenne DMD CAG-TAG

Muscular dystrophy, Duchenne DMD AAG-TAG

Muscular dystrophy, Duchenne DMD TCA-TGA

Muscular dystrophy, Duchenne DMD CAG-TAG

Muscular dystrophy, Duchenne DMD GAG-TAG

Muscular dystrophy, Duchenne DMD CAG-TAG

Muscular dystrophy, Duchenne DMD CGA-TGA

Muscular dystrophy, Duchenne DMD CAG-TAG

Muscular dystrophy, Duchenne DMD CGA-TGA

Muscular dystrophy, Duchenne DMD CAA-TAA

Muscular dystrophy, Duchenne DMD TAC-TAA

Muscular dystrophy, Duchenne DMD GAA-TAA

Muscular dystrophy, Duchenne DMD GAG-TAG

Muscular dystrophy, Duchenne DMD AAA-TAA

Muscular dystrophy, Duchenne DMD CGA-TGA

Muscular dystrophy, Duchenne DMD TGG-TAG

Muscular dystrophy, Duchenne DMD TGG-TGA

Muscular dystrophy, Duchenne DMD CAA-TAA

Muscular dystrophy, Duchenne DMD CAG-TAG

Muscular dystrophy, Duchenne DMD GGA-TGA

Muscular dystrophy, Becker DMD TTA-TAA

Muscular dystrophy, Duchenne DMD GAG-TAG

Muscular dystrophy, Becker DMD TGG-TAG

Muscular dystrophy, Duchenne DMD AAG-TAG

Muscular dystrophy, Duchenne DMD TTG-TAG

Muscular dystrophy, Duchenne DMD TGG-TGA

Muscular dystrophy, Duchenne DMD CAA-TAA

Muscular dystrophy, Duchenne DMD CAG-TAG

Muscular dystrophy, Duchenne DMD GAA-TAA

Muscular dystrophy, Duchenne DMD TGG-TGA

Muscular dystrophy, Duchenne DMD CAG-TAG

Muscular dystrophy, Duchenne DMD CGA-TGA

Muscular dystrophy, Becker DMD CAG-TAG

Muscular dystrophy, Duchenne DMD GAA-TAA

Muscular dystrophy, Becker DMD TGG-TGA

Muscular dystrophy, Becker DMD GAG-TAG

Muscular dystrophy, Duchenne DMD CAG-TAG

Muscular dystrophy, Duchenne DMD GAA-TAA

Muscular dystrophy, Duchenne DMD CAA-TAA

Muscular dystrophy, Duchenne DMD TCA-TGA

Muscular dystrophy, Duchenne DMD GAG-TAG

Muscular dystrophy, Duchenne DMD TCA-TGA

Muscular dystrophy, Becker DMD GAA-TAA

Muscular dystrophy, Becker DMD GAG-TAG

Muscular dystrophy, Duchenne DMD CAG-TAG

Primary ciliary dyskinesia and situs inversus DNAH11 TAC-TAG

Primary ciliary dyskinesia and situs inversus DNAH11 CGA-TGA

Primary ciliary dyskinesia DNAH5 GAG-TAG

Primary ciliary dyskinesia DNAH5 CAG-TAG Primary ciliary dyskinesia DNAH5 CGA- TGA

Primary ciliary dyskinesia DNAH5 AAA- TAA

Primary ciliary dyskinesia DNAH5 CGA- TGA

Primary ciliary dyskinesia DNAH5 CAG- TAG

Primary ciliary dyskinesia DNAH5 CGA- TGA

Primary ciliary dyskinesia DNAH5 CAG- TAG

Primary ciliary dyskinesia DNAH5 CGA- TGA

Primary ciliary dyskinesia DNAH5 CAG- TAG

Primary ciliary dyskinesia DNAH5 TAT- TAG

Primary ciliary dyskinesia DNAH5 CAG- TAG

Primary ciliary dyskinesia DNAH5 CGA- TGA

Primary ciliary dyskinesia DNAI1 TGG- TGA

Primary ciliary dyskinesia DNAI2 CGA- TGA

Systemic lupus erythematosus DNASE1 AAG- TAG

Immunodeficiency, centromeric instability and D MT3B CAG- TAG facial anomalies syndrome

Immunodeficiency, centromeric instability and D MT3B CGA- TGA facial anomalies syndrome

Dihydropyrimidine dehydrogenase deficiency DPYD TGC- TGA

Receptor deficiency DRD5 TGC- TGA

Striate palmoplantar keratoderma DSG1 TCA- TAA

Cardiomyopathy, arrhythmogenic right ventricular DSG2 CAA- TAA

Dilated cardiomyopathy, woolly hair, keratoderma DSP CGA- TGA

Dentinogenesis imperfecta Shields type II DSPP CAG- TAG

Hypothyroidism DUOX2 CGA- TGA

Hypothyroidism, transient DUOX2 CGA- TGA

Hypothyroidism, transient DUOX2 CAG- TAG

Hypothyroidism DUOX2 CGA- TGA

Hypothyroidism DUOXA2 TAC- TAG

Smith-McCort dysplasia DYM CGA- TGA

Dyggve-Melchior-Clausen syndrome DYM CGA- TGA

Dyggve-Melchior-Clausen syndrome DYM TTA- TGA

Dyggve-Melchior-Clausen syndrome DYM CAG- TAG

Dyggve-Melchior-Clausen syndrome DYM CGA- TGA

Muscular dystrophy, limb girdle DYSF TCG- TAG

Miyoshi myopathy DYSF TGG- TAG

Miyoshi myopathy DYSF TAC- TAG

Muscular dystrophy, limb girdle DYSF TAC- TAG

Muscular dystrophy, limb girdle DYSF TAC- TAA

Muscular dystrophy, limb girdle DYSF TGG- TAG

Chondrodysplasia punctata, X-linked EBP TGG- TAG

Chondrodysplasia punctata, X-linked EBP CAG- TAG

Chondrodysplasia punctata, X-linked EBP TGG- TAG

CHILD syndrome EBP CGA- TGA

Chondrodysplasia punctata, X-linked EBP TAC- TAA

Chondrodysplasia punctata, X-linked EBP TGG- TAG

Chondrodysplasia punctata, X-linked EBP TAC- TAG

Lipoid proteinosis ECM1 CAG- TAG

Lipoid proteinosis ECM1 CGA- TGA

Lipoid proteinosis ECM1 TGG- TGA

Lipoid proteinosis ECM1 CGA- TGA Ectodermal dysplasia EDA CGA-TGA

Ectodermal dysplasia EDA GAG-TAG

Ectodermal dysplasia, hypohidrotic EDAR GAG-TAG

Waardenburg-Hirschsprung disease EDNRB CGA-TGA

ABCD syndrome EDNRB CGA-TGA

Craniofrontonasal syndrome EFNB1 GAG-TAG

Erythrocytesis EGLN1 CAA-TAA

Mental retardation EHMT1 CGA-TGA

Wolcott-Rallison syndrome EIF2AK3 GAG-TAG

Leukoencephalopathy with vanishing white matter EIF2B4 CGA-TGA

Prostate cancer ELAC2 GAG-TAG

Supravalvular aortic stenosis ELN GGA-TGA

Supravalvular aortic stenosis ELN CGA-TGA

Supravalvular aortic stenosis ELN CAG-TAG

Supravalvular aortic stenosis ELN TAC-TAG

Supravalvular aortic stenosis ELN TAC-TAA

Supravalvular aortic stenosis ELN AAG-TAG

Amelogenesis imperfecta, hypoplastic ENAM AAA-TAA

Amelogenesis imperfecta, hypoplastic ENAM TCA-TAA

Haemorrhagic telangiectasia 1 ENG CAG-TAG

Haemorrhagic telangiectasia 1 ENG TTA-TGA

Haemorrhagic telangiectasia 1 ENG GAA-TAA

Haemorrhagic telangiectasia 1 ENG GAG-TAG

Haemorrhagic telangiectasia 1 ENG CAG-TAG

Haemorrhagic telangiectasia 1 ENG CAA-TAA

Haemorrhagic telangiectasia 1 ENG TGC-TGA

Haemorrhagic telangiectasia 1 ENG TAC-TAA

Haemorrhagic telangiectasia 1 ENG GAG-TAG

Haemorrhagic telangiectasia 1 ENG TGG-TGA

Idiopathic infantile arterial calcification ENPP1 TAC-TAG

Idiopathic infantile arterial calcification ENPP1 CGA-TGA

Prostate cancer, increased risk, in African EPHB2 AAA-TAA

Americans, association with

Erythrocytesis EPOR GAA-TAA

Xeroderma pigmentosum (B) ERCC3 CGA-TGA

Xeroderma pigmentosum/Cockayne syndrome ERCC3 CAG-TAG

Cockayne syndrome ERCC8 GAG-TAG

SC Phocomelia ESC02 TGG-TGA

SC Phocomelia ESC02 CAA-TAA

Glutaricacidaemia 2a ETFA CGA-TGA

Electron transfer flavoprotein deficiency ETFA

Multiple exostoses EXT1 TGG-TGA

Multiple exostoses EXT1 TGG-TAG

Multiple exostoses EXT1 TAC-TAA

Multiple exostoses EXT1 CAG-TAG

Multiple exostoses EXT1 TAC-TAG

Multiple exostoses EXT1 TGG-TGA

Multiple exostoses EXT1 AAA-TAA

Multiple exostoses EXT2 CAG-TAG

Multiple exostoses EXT2 TAT-TAA

Multiple exostoses EXT2 GGA-TGA

Multiple exostoses EXT2 CAG-TAG

Multiple exostoses EXT2 TGG-TAG

Multiple exostoses EXT2 CAG-TAG

Multiple exostoses EXT2 TAC-TAG

Multiple exostoses EXT2 CAG-TAG Multiple exostoses EXT2 AAG-TAG

Multiple exostoses EXT2 TGG-TGA

Branchio-oto-renal / branchiootic syndrome EYA1 GAG-TAG

Branchio-oto-renal syndrome EYA1 TCA-TGA

Branchio-oto-renal syndrome EYA1 CAG-TAG

Branchio-oto-renal syndrome EYA1 TAC-TAG

Branchio-oto-renal syndrome EYA1 TAT-TAA

Factor XI deficiency Fll CAA-TAA

Factor XI deficiency Fll TGG-TAG

Factor XI deficiency Fll GAA-TAA

Factor XI deficiency Fll TAC-TAA

Factor XI deficiency Fll TGC-TGA

Factor XI deficiency Fll CAA-TAA

Factor XI deficiency Fll TGT-TGA

Factor XI deficiency Fll CGA-TGA

Factor XI deficiency Fll CAA-TAA

Factor XIII deficiency F13A1 CGA-TGA

Factor XIII deficiency F13A1 TGG-TAG

Factor XIII deficiency F13A1 CGA-TGA

Factor XIII deficiency F13A1 TAC-TAA

Factor V deficiency F5 CGA-TGA

Factor V deficiency F5 TGG-TGA

Factor V deficiency F5 CGA-TGA

Factor V deficiency F5 AAA-TAA

Factor V deficiency F5 CAA-TAA

Factor VII deficiency F7 AAG-TAG

Factor VII deficiency F7 TGC-TGA

Factor VII deficiency F7 CAG-TAG

Factor VII deficiency F7 TCA-TGA

Factor VII deficiency F7 TGC-TGA

Factor VII deficiency F7 CAG-TAG

Factor VII deficiency F7 TGG-TAG

Haemophilia A F8 TGG-TAG

Haemophilia A F8 AAA-TAA

Haemophilia A F8 TGG-TGA

Haemophilia A F8 CAA-TAA

Haemophilia A F8 TCA-TAA

Haemophilia A F8 TGG-TAG

Haemophilia A F8 CAG-TAG

Haemophilia A F8 AAA-TAA

Haemophilia A F8 CAA-TAA

Haemophilia A F8 TGG-TGA

Haemophilia A F8 AAA-TAA

Haemophilia A F8 TAT-TAG

Haemophilia A F8 TGG-TGA

Haemophilia A F8 TAC-TAA

Haemophilia A F8 GAG-TAG

Haemophilia A F8 CAG-TAG Haemophilia A F8 AAA-TAA

Haemophilia A F8 CAA-TAA

Haemophilia A F8 TAT-TAA

Haemophilia A F8 TGG-TAG

Haemophilia A F8 TGG-TGA

Haemophilia A F8 TAC-TAA

Haemophilia A F8 CAA-TAA

Haemophilia A F8 TAT-TAA

Haemophilia A F8 AAA-TAA

Haemophilia A F8 TAC-TAA

Haemophilia A F8 TTA-TAA

Haemophilia A F8 TGG-TGA

Haemophilia A F8 CAA-TAA

Haemophilia A F8 CGA-TGA

Haemophilia A F8 TGG-TAG

Haemophilia A F8 TAC-TAA

Haemophilia A F8 CGA-TGA

Haemophilia A F8 TGG-TGA

Haemophilia A F8 TAC-TAA

Haemophilia A F8 GAG-TAG

Haemophilia A F8 CAG-TAG

Haemophilia A F8 AGA-TGA

Haemophilia A F8 GAG-TAG

Haemophilia A F8 CAA-TAA

Haemophilia A F8 TGC-TGA

Haemophilia A F8 CAA-TAA

Haemophilia A F8 CAG-TAG

Haemophilia A F8 TCA-TGA

Haemophilia A F8 CAG-TAG

Haemophilia A F8 AAA-TAA

Haemophilia A F8 TGG-TGA

Haemophilia A F8 AAG-TAG

Haemophilia A F8 AAA-TAA

Haemophilia A F8 TCA-TAA

Haemophilia A F8 GAG-TAG

Haemophilia A F8 TCA-TGA

Haemophilia A F8 AGA-TGA

Haemophilia A F8 CAG-TAG

Haemophilia A F8 CAA-TAA

Haemophilia A F8 CAG-TAG

Haemophilia A F8 TCA-TGA

Haemophilia A F8 CAA-TAA

Haemophilia A F8 TCA-TGA

Haemophilia A F8 TGG-TAG

Haemophilia A F8 CAA-TAA

Haemophilia A F8 TAT-TAA

Haemophilia A F8 GAA-TAA

Haemophilia A F8 TGG-TAG

Haemophilia A F8 TGC-TGA

Haemophilia A F8 GAA-TAA

Haemophilia A F8 AAG-TAG

Haemophilia A F8 TAT-TAA

Haemophilia A F8 CGA-TGA

Haemophilia A F8 AAA-TAA Haemophilia A F8 TGG-TAG

Haemophilia A F8 CAG-TAG

Haemophilia A F8 TAT-TAA

Haemophilia A F8 GGA-TGA

Haemophilia A F8 TAT-TAA

Haemophilia A F8 TGG-TGA

Haemophilia A F8 TTG-TAG

Haemophilia A F8 GAA-TAA

Haemophilia A F8 CAA-TAA

Haemophilia A F8 TCG-TAG

Haemophilia A F8 TGT-TGA

Haemophilia A F8 CAG-TAG

Haemophilia B F9 CGA-TGA

Haemophilia B F9 TAT-TAG

Haemophilia B F9 AGA-TGA

Haemophilia B F9 TAC-TAG

Haemophilia B F9 TTA-TAA

Haemophilia B F9 GGA-TGA

Haemophilia B F9 TAC-TAA

Haemophilia B F9 TAC-TAG

Haemophilia B F9 TGG-TAG

Haemophilia B F9 TGC-TGA

Haemophilia B F9 TGG-TGA

Haemophilia B F9 CGA-TGA

Haemophilia B F9 TCA-TGA

Haemophilia B F9 TAC-TAA

Tyrosinaemia 1 FAH CGA-TGA

Tyrosinaemia 1 FAH GAA-TAA

Tyrosinaemia 1 FAH TGG-TAG

Tyrosinaemia 1 FAH CAG-TAG

Amelogenesis imperfecta, hypoplastic local FAM83H CGA-TGA

Amelogenesis imperfecta, hypoplastic local FAM83H CAG-TAG

Amelogenesis imperfecta, hypocalcified FAM83H TAT-TAA

Amelogenesis imperfecta, hypocalcified FAM83H TGG-TGA

Amelogenesis imperfecta, hypocalcified FAM83H CAG-TAG

Amelogenesis imperfecta, hypocalcified FAM83H GAG-TAG

Fanconi anaemia FANCA CAG-TAG

Fanconi anaemia FANCC CGA-TGA

Fanconi anaemia FANCG CAG-TAG

Cytochrome c oxidase deficiency FASTKD2 CGA-TGA

Marfan syndrome FBN1 TAT-TAG

Marfan syndrome FBN1 CGA-TGA

Marfan syndrome FBN1 GAA-TAA

Ectopia lentis FBN1 GAG-TAG

Marfan syndrome FBN1 GAG-TAG

Marfan syndrome FBN1 GGA-TGA

Marfan syndrome FBN1 TCA-TAA

Marfan syndrome FBN1 TGC-TGA

Marfan syndrome FBN1 GAG-TAG

Marfan syndrome FBN1 TGC-TGA

Marfan syndrome FBN1 TCA-TGA

Marfan syndrome FBN1 CGA-TGA Marfan syndrome FBN1 CGA-TGA

Marfan syndrome FBN1 GAG-TAG

Marfan syndrome FBN1 CGA-TGA

Marfan syndrome FBN1 TAC-TAG

Marfan syndrome FBN1 GAA-TAA

Marfan syndrome FBN1 GAG-TAG

Marfan syndrome FBN1 TAC-TAG

Marfan syndrome FBN1 TGC-TGA

Marfan syndrome FBN1 TGT-TGA

Marfan syndrome FBN1 TGC-TGA

Marfan syndrome FBN1 CAG-TAG

Marfan syndrome FBN1 CAA-TAA

Marfan syndrome FBN1 TGT-TGA

Marfan syndrome FBN1 CGA-TGA

Marfan syndrome FBN1 TGC-TGA

Marfan syndrome FBN1 TAC-TAG

Marfan syndrome FBN1 CAG-TAG

Marfan syndrome FBN1 AAG-TAG

Marfan syndrome FBN1 TAT-TAA

Marfan syndrome FBN1 AAG-TAG

Marfan syndrome FBN1 CGA-TGA

Marfan syndrome FBN1 TGC-TGA

Marfan syndrome FBN1 TGG-TGA

Marfan syndrome FBN1 TGC-TGA

Marfan syndrome FBN1 TGT-TGA

Marfan syndrome FBN1 CGA-TGA

Fibrillinopathy FBN1 GAA-TAA

Fibrillinopathy FBN1 TGC-TGA

Fibrillinopathy FBN1 CAG-TAG

Kindler syndrome FERMT1 TGC-TGA

Afibrinogenaemia FGA CAG-TAG

Afibrinogenaemia FGA CGA-TGA

Afibrinogenaemia FGA GGA-TGA

Afibrinogenaemia FGA TGG-TGA

Afibrinogenaemia FGA CGA-TGA

Afibrinogenaemia FGA GGA-TGA

Afibrinogenaemia FGA TCA-TGA

Dysfibrinogenaemia FGA GAA-TAA

Hypofibrinogenaemia FGB TAT-TAG

Afibrinogenaemia FGB TGG-TAG

Afibrinogenaemia FGB CGA-TGA

Charcot-Marie-Tooth disease 4H FGD4 CGA-TGA

Lacrimo-auriculo-dento-digital syndrome FGF10 AAG-TAG

Kallmann syndrome FGFR1 CGA-TGA

Kallmann syndrome FGFR1 GAG-TAG

Kallmann syndrome FGFR1 TAC-TAA

Afibrinogenaemia FGG GAG-TAG

Afibrinogenaemia FGG CGA-TGA

Leiomyomatosis and renal cell cancer FH TCA-TGA

Fumarase deficiency FH TGG-TAG

Cutaneous leiomyomatosis FH GAG-TAG

Muscular dystrophy, Fukuyama FKTN TGT-TGA

Pneumothorax, primary spontaneous FLCN GAG-TAG

Birt-Hogg-Dub syndrome FLCN CGA-TGA

Birt-Hogg-Dub syndrome FLCN TAC-TAG

Ichthyosis vulgaris FLG TCA-TAA Ichthyosis vulgaris FLG GAA- TAA

Ichthyosis vulgaris FLG CAG- TAG

Ichthyosis vulgaris FLG CGA- TGA

Ichthyosis vulgaris FLG TCA- TAA

Ichthyosis vulgaris FLG CAG- TAG

Ichthyosis vulgaris flgl0.2 CGA- TGA

Heterotopia, periventricular FLNA CGA- TGA

Heterotopia, periventricular FLNA CAG- TAG

Heterotopia, periventricular FLNA CGA- TGA

Myopathy, myofibrillar FLNC TGG- TGA

FM01 variant FMOl CGA- TGA

FM02 variant FM02 CAG- TAG

Trimethylaminuria FM03 GAA- TAA

Trimethylaminuria FM03 CAG- TAG

Trimethylaminuria FM03 TGG- TGA

Trimethylaminuria FM03 GAG- TAG

Trimethylaminuria FM03 CGA- TGA fmo6 variant FM06P CAG- TAG

Axenfeld-Rieger & Peters ' anomaly FOXC1 CAG- TAG

Axenfeld-Rieger anomaly FOXC1 CAG- TAG

Axenfeld-Rieger anomaly FOXC1 TCG- TAG

Axenfeld-Rieger anomaly FOXC1 CAG- TAG

Axenfeld-Rieger anomaly FOXC1 TGG- TGA

Lymphoedema-distichiasis FOXC2 CAG- TAG

Lymphoedema-distichiasis FOXC2 TGC- TGA

Lymphoedema-distichiasis FOXC2 TAC- TAG

Aphakia, congenital, primary FOXE3 TGC- TGA

ACD/MPV with cardiovascular malformations FOXF1 TAC- TAA

Blepharophimosis/ptosis/epicanthus inversus FOXL2 CAG- TAG syndrome

Blepharophimosis/ptosis/epicanthus inversus FOXL2 GAG- TAG syndrome

Blepharophimosis/ptosis/epicanthus inversus FOXL2 TAC- TAG syndrome

Blepharophimosis/ptosis/epicanthus inversus FOXL2 TGG- TGA syndrome

Blepharophimosis/ptosis/epicanthus inversus FOXL2 CAG- TAG syndrome

Blepharophimosis/ptosis/epicanthus inversus FOXL2 TCG- TAG syndrome

Developmental verbal dyspraxia FOXP2 CGA- TGA

Follicle-stimulating hormone deficiency FSHB TAC- TAA

Mental retardation FTSJ1 CAA- TAA

Fucosidosis FUCA1 GGA- TGA

Fucosidosis FUCA1 TGG- TGA

Fucosidosis FUCA1 TGG- TAG

Fucosidosis FUCA1 CAG- TAG

Fucosidosis FUCA1 TAC- TAA

H antigen, Bombay phenotype FUT1 TGG- TAG

H antigen, para-Bombay phenotype FUT1 CAG- TAG

Non-secretor phenotype FUT2 TGG- TAG

Fucosyltransferase deficiency FUT2 CGA- TGA

Non-secretor phenotype FUT2 TGG- TGA

Fucosyltransferase deficiency FUT6 TAC- TAA

Friedreich ataxia FXN TAC- TAG

Exudative vitreoretinopathy FZD4 CAG- TAG Exudative vitreoretinopathy FZD4 TGG-TGA

Glycogen storage disease la G6PC CAA-TAA

Glycogen storage disease la G6PC CAG-TAG

Glucose- 6-phosphate dehydrogenase deficiency G6PD TAC-TAA

Glycogen storage disease 2 GAA CAG-TAG

Glycogen storage disease 2 GAA TGG-TAG

Glycogen storage disease 2 GAA. TAC-TAA

Krabbe disease GALC TAC-TAG

Krabbe disease GALC TGG-TGA

Krabbe disease GALC GAA-TAA

Krabbe disease GALC CGA-TGA

Krabbe disease GALC TGG-TAG

Krabbe disease GALC TCG-TAG

Galactosaemia epimerase deficiency GALE TGG-TAG

Mucopolysaccharidosis IVa GALNS TGG-TAG

Mucopolysaccharidosis IVa GALNS CAG-TAG

Mucopolysaccharidosis IVa GALNS AAG-TAG

Tumoural calcinosis GALNT3 CAG-TAG

Tumoural calcinosis GALNT3 TAT-TAG

Tumoural calcinosis GALNT3 AAA-TAA

Tumoural calcinosis GALNT3 CAG-TAG

Tumoural calcinosis GALNT3 TGG-TAG

Galactosaemia GALT CAG-TAG

Giant axonal neuropathy GAN CGA-TGA

Giant axonal neuropathy GAN AAG-TAG

Giant axonal neuropathy GAN CGA-TGA

Giant axonal neuropathy GAN TGG-TGA

Giant axonal neuropathy GAN TGT-TGA

Giant axonal neuropathy GAN CAG-TAG

Giant axonal neuropathy GAN CGA-TGA

Hypoparathyroidism, deafness and renal dysplasia GATA3 CGA-TGA

Hypoparathyroidism, deafness and renal dysplasia GATA3 GAG-TAG

Hypoparathyroidism, deafness and renal dysplasia GATA3 CAG-TAG

Hypoparathyroidism, deafness and renal dysplasia GATA3 GGA-TGA

Gaucher disease 2 GBA GAA-TAA

Glycogen storage disease 4 GBE1 CGA-TGA

Glycogen storage disease 4 GBE1 GAA-TAA

Dystonia, dopa-responsive GCH1 CAG-TAG

Dystonia, dopa-responsive GCH1 CAA-TAA

Dystonia, dopa-responsive GCH1 TCA-TAA

Dystonia, dopa-responsive GCH1 GAG-TAG

Dystonia, dopa-responsive GCH1 CAA-TAA

Diabetes, NIDDM GCK CGA-TGA

Diabetes, NIDDM GCK GAG-TAG

Diabetes, MODY2 GCK TGC-TGA

Diabetes, MODY GCK TCG-TAG

Diabetes, MODY GCK GAG-TAG

Diabetes, MODY GCK TAC-TAA

Diabetes, MODY GCK GAG-TAG

Diabetes, MODY GCK TCG-TAG

Diabetes, MODY GCK CAG-TAG

Congenital cataract GCNT2 TGG-TAG

Demyelinating peripheral neuropathy GDAP1 TTG-TAG

Charcot-Marie-Tooth disease 4A GDAP1 TCA-TGA

Charcot-Marie-Tooth disease 4A GDAP1 TGG-TAG

Charcot-Marie-Tooth disease, autosomal recessive GDAP1 CGA-TGA Brachydactyly, type C GDF5 TAT-TAG

Laron dwarfism GHR CGA-TGA

Laron dwarfism GHR TGC-TGA

Growth hormone insensitivity GHR TGC-TGA

Laron dwarfism GHR TGG-TGA

Laron dwarfism GHR TTA-TAA

Laron dwarfism GHR TGG-TGA

Laron dwarfism GHR TGG-TAG

Laron dwarfism GHR CAG-TAG

Laron dwarfism GHR CGA-TGA

Laron dwarfism GHR GAA-TAA

Growth hormone deficiency GHRHR GAG-TAG

Growth hormone deficiency GHRHR CAA-TAA

Growth hormone deficiency, isolated GHSR

Oculodentodigital dysplasia GJA1 CGA-TGA

Charcot-Marie-Tooth disease GJB1 TGG-TGA

Charcot-Marie-Tooth disease GJB1 CGA-TGA

Charcot-Marie-Tooth disease GJB1 GAG-TAG

Charcot-Marie-Tooth disease GJB1 TGT-TGA

Charcot-Marie-Tooth disease GJB1 CGA-TGA

Deafness, autosomal recessive 1 GJB2 GAA-TAA

Deafness GJB2 GGA-TGA

Deafness, non-syndromic, autosomal dominant GJB3 CGA-TGA

Pelizaeus-Merzbacher-like disease GJC2 CGA-TGA

Glycerol kinase deficiency GK CGA-TGA

Fabry disease GLA CGA-TGA

Fabry disease GLA TGG-TAG

Fabry disease GLA TTA-TGA

Fabry disease GLA CAG-TAG

Fabry disease GLA GAA-TAA

Fabry disease GLA CAG-TAG

Fabry disease GLA TAT-TAG

Fabry disease GLA CAG-TAG

Fabry disease GLA TCA-TGA

Fabry disease GLA TAC-TAA

Fabry disease GLA TGG-TAG

Fabry disease GLA GAG-TAG

Fabry disease GLA CAG-TAG

Fabry disease GLA CAA-TAA

Fabry disease GLA CGA-TGA

Fabry disease GLA TGG-TAG

Fabry disease GLA CAG-TAG

Fabry disease GLA TGG-TAG

Fabry disease GLA AAA-TAA

Fabry disease GLA TAC-TAA

Fabry disease GLA CAA-TAA

Fabry disease GLA TGG-TAG

Fabry disease GLA TAT-TAG

Gangliosidosis GM1 GLB1 CGA-TGA

Hyperglycinaemia, non-ketotic GLDC CGA-TGA

Hyperglycinaemia, non-ketotic GLDC GAG-TAG

Hyperglycinaemia, non-ketotic GLDC CGA-TGA

Pallister-Hall syndrome GLI3 GAG-TAG

Greig cephalopolysyndactyly syndrome GLI3 CAA-TAA

Pallister-Hall syndrome GLI3 CAA-TAA Pallister-Hall syndrome GLI3 CAG-TAG

Pallister-Hall syndrome GLI3 TCG-TAG

Pallister-Hall syndrome GLI3 GAA-TAA

Pallister-Hall syndrome GLI3 TAC-TAG

Pallister-Hall syndrome GLI3 CAG-TAG

Greig cephalopolysyndactyly syndrome GLI3 CGA-TGA

Pallister-Hall syndrome GLI3 TAC-TAG

Postaxial Polydactyly A/B GLI3 CGA-TGA

Pallister-Hall syndrome GLI3 GAG-TAG

Greig cephalopolysyndactyly syndrome GLI3 CAG-TAG

Hyperekplexia GLRA1 TAC-TAA

Gangliosidosis GM2 GM2A GAG-TAG

Albright hereditary osteodystrophy GNAS CAG-TAG

Progressive osseous heteroplasia GNAS CAG-TAG

Mucolipidosis II GNPTAB TGG-TAG

Mucolipidosis II GNPTAB CGA-TGA

Mucolipidosis II GNPTAB CAG-TAG

Mucolipidosis II GNPTAB TCA-TGA

Mucopolysaccharidosis Hid GNS CAA-TAA

Mucopolysaccharidosis Hid GNS CGA-TGA

Mucopolysaccharidosis Hid GNS CAG-TAG

Bernard-Soulier syndrome GP1BA TGG-TGA

Bernard-Soulier syndrome GP1BA TCA-TAA

Giant platelet disorder GP1BB TGG-TAG

Bernard-Soulier syndrome GP9 TGG-TGA

Simpson-Golabi-Behmel syndrome GPC3 AAG-TAG

Simpson-Golabi-Behmel syndrome GPC3 TGT-TGA

Simpson-Golabi-Behmel syndrome GPC3 CGA-TGA

Glucosephosphate isomerase deficiency GPI CGA-TGA

Albinism, ocular GPR143 AGA-TGA

Albinism, ocular GPR143 CGA-TGA

Albinism, ocular GPR143 TGG-TGA

Febrile and afebrile seizures GPR98 TCA-TAA

Hyperoxaluria II GRHPR CGA-TGA

Frontotemporal dementia GRN TGG-TAG

Frontotemporal dementia GRN CGA-TGA

Alzheimer disease GRN CGA-TGA

Glutathione synthetase deficiency GSS CGA-TGA

Leber congenital amaurosis GUCY2D CAG-TAG

Mucopolysaccharidosis VII GUSB TGG-TGA

Hypoglycaemia, hyperinsulinaemic HADH CGA-TGA

Thalassaemia alpha HBA2 CAG-TAG

Thalassaemia alpha HBA2 GAG-TAG

Thalassaemia beta HBB AAG-TAG

Thalassaemia beta HBB CAG-TAG

Thalassaemia beta HBB AAG-TAG

Thalassaemia beta HBB CAG-TAG

Thalassaemia beta HBB TGT-TGA

Thalassaemia beta HBB TGG-TGA

Thalassaemia beta HBB GAG-TAG

Thalassaemia beta HBB TGG-TAG

Thalassaemia beta HBB GAA-TAA

Microphthalmia, syndromic 7 HCCS CGA-TGA

Tay-Sachs disease HEXA CGA-TGA

Tay-Sachs disease HEXA TGG-TAG

Sandhoff disease HEXB CAA-TAA

Sandhoff disease HEXB CGA-TGA Haemochromatosis HFE GAG-TAG

Haemochromatosis HFE TGG-TAG

Haemochromatosis HFE CGA-TGA

Haemochromatosis HFE TAC-TAG

Haemochromatosis HFE2 GGA-TGA

Alkaptonuria HGD

Mucopolysaccharidosis IIIC HGSNAT TGG-TAG

Mucopolysaccharidosis IIIC HGSNAT CGA-TGA

Mucopolysaccharidosis IIIC HGSNAT TTA-TGA

Mucopolysaccharidosis IIIC HGSNAT CGA-TGA

Mucopolysaccharidosis IIIC HGSNAT TGG-TGA

HLA-A null allele HLA-A TGC-TGA

HLA-B null allele HLA-B CAG-TAG

Holocarboxylase synthetase deficiency HLCS CGA-TGA

Holocarboxylase synthetase deficiency HLCS CAA-TAA

Porphyria, acute intermittent HMBS CAA-TAA

Porphyria, acute intermittent HMBS CGA-TGA

Porphyria, acute intermittent HMBS CAG-TAG

Porphyria, acute intermittent HMBS TGG-TAG

Porphyria, acute intermittent HMBS CAG-TAG

Porphyria, acute intermittent HMBS TAC-TAA

Porphyria, acute intermittent HMBS CAG-TAG

Porphyria, acute intermittent HMBS CAA-TAA

Porphyria, acute intermittent HMBS TGC-TGA

Porphyria, acute intermittent HMBS TCA-TAA

Porphyria, acute intermittent HMBS TAT-TAG

Porphyria, acute intermittent HMBS TGG-TAG

Porphyria, acute intermittent HMBS TGG-TGA

HMG-CoA lyase deficiency HMGCL GAA-TAA

3-hydroxy-3-methylglutaric aciduria HMGCL TGG-TAG

3-hydroxy-3-methylglutaric aciduria HMGCL GAG-TAG

HMG-CoA lyase deficiency HMGCL CAG-TAG

HMG-CoA lyase deficiency HMGCL CAA-TAA

Diabetes, MODY3 HNF1A CAG-TAG

Diabetes, MODY3 HNF1A CGA-TGA

Diabetes, MODY HNF1B CGA-TGA

GCKD with early-onset diabetes HNF1B GAG-TAG

Diabetes, MODY1 HNF4A CGA-TGA

Hand-foot-genital syndrome HOXA13 CAG-TAG

Hand-foot-genital syndrome HOXA13 TCG-TAG

Hand-foot-genital syndrome HOXA13 CAG-TAG

Hand-foot-genital syndrome HOXA13 TGG-TGA

Tyrosinaemia 3 HPD TAT-TAG

Tyrosinaemia 3 HPD TAC-TAG

Lesch-Nyhan syndrome HPRT1 CAG-TAG

Lesch-Nyhan syndrome HPRT1 TCA-TGA

Hypoxanthine guanine phosphoribosyltransferase HPRT1 TAT-TAG deficiency

Hermansky-Pudlak syndrome HPS1 GAG-TAG

Hermansky-Pudlak syndrome HPS4 CGA-TGA

Hermansky-Pudlak syndrome HPS4 GAG-TAG

Atrichia with papular lesions HR CAG-TAG

Atrichia with papular lesions HR CGA-TGA

Atrichia with papular lesions HR CAG-TAG

Atrichia with papular lesions HR CAG-TAG Atrichia with papular lesions HR CGA-TGA

Atrichia with papular lesions HR CAG-TAG

Congenital atrichia HR CGA-TGA

Adrenal hyperplasia HSD3B2 GAA-TAA

Adrenal hyperplasia HSD3B2 TGG-TAG

Cataract, autosomal recessive hsf4b CGA-TGA

Schwartz-Jampel syndrome type 1 HSPG2 CAA-TAA

Schwartz-Jampel syndrome type 1 HSPG2 CGA-TGA

CARASIL HTRAl CGA-TGA

Mucopolysaccharidosis II IDS TCA-TGA

Mucopolysaccharidosis II IDS CAA-TAA

Mucopolysaccharidosis II IDS CAG-TAG

Mucopolysaccharidosis II IDS TGG-TGA

Mucopolysaccharidosis II IDS CAG-TAG

Mucopolysaccharidosis II IDS TGG-TAG

Mucopolysaccharidosis II IDS TGG-TGA

Mucopolysaccharidosis II IDS TCA-TGA

Mucopolysaccharidosis II IDS CAA-TAA

Mucopolysaccharidosis II IDS TTA-TGA

Mucopolysaccharidosis II IDS TGG-TGA

Mucopolysaccharidosis II IDS CGA-TGA

Mucopolysaccharidosis II IDS TAC-TAG

Mucopolysaccharidosis II IDS TAC-TAA

Mucopolysaccharidosis II IDS TGG-TGA

Mucopolysaccharidosis II IDS GAG-TAG

Mucopolysaccharidosis II IDS TGG-TAG

Mucopolysaccharidosis II IDS GAG-TAG

Mucopolysaccharidosis II IDS TTA-TGA

Mucopolysaccharidosis II IDS TGC-TGA

Mucopolysaccharidosis II IDS GAG-TAG

Mucopolysaccharidosis II IDS TAT-TAA

Mucopolysaccharidosis II IDS CGA-TGA

Hurler syndrome IDUA CGA-TGA

Hurler syndrome IDUA GAG-TAG

Hurler syndrome IDUA TGC-TGA

Hurler syndrome IDUA TAC-TAA

Hurler syndrome IDUA CAG-TAG

Hurler syndrome IDUA CGA-TGA

Scheie syndrome IDUA TAC-TAA

Hurler syndrome IDUA CAG-TAG

Scheie syndrome IDUA CAG-TAG

Hurler syndrome IDUA CGA-TGA

Reduced activity IFIH1 GAA-TAA

Growth retardation IGF1R CGA-TGA

Acid-labile subunit deficiency IGFALS CAG-TAG

Spinal muscular atrophy with respiratory distress IGHMBP2 CGA-TGA 1

Spinal muscular atrophy with respiratory distress IGHMBP2 TTA-TGA 1

Spinal muscular atrophy with respiratory distress IGHMBP2 CAG-TAG 1

Spinal muscular atrophy with respiratory distress IGHMBP2 CAG-TAG 1 Spinal muscular atrophy with respiratory distress IGHMBP2 CGA-TGA 1

Spinal muscular atrophy with respiratory distress IGHMBP2 CAG-TAG 1

Incontinentia pigmenti IKBKG GAA-TAA

Incontinentia pigmenti, familial IKBKG CAG-TAG

Incontinentia pigmenti, familial IKBKG TCG-TAG

Incontinentia pigmenti, familial IKBKG CGA-TGA

Incontinentia pigmenti, familial IKBKG CAG-TAG

Incontinentia pigmenti, familial IKBKG CAA-TAA

Incontinentia pigmenti, familial IKBKG CAG-TAG

Mental retardation, X-linked IL1RAPL1 TAC-TAA

Immunodeficiency, severe combined IL2RG CAG-TAG

Immunodeficiency, severe combined IL2RG AAG-TAG

Immunodeficiency, severe combined IL2RG TAT-TAA

Immunodeficiency, severe combined IL7R CGA-TGA

Leprechaunism INSR CGA-TGA

Insulin resistance INSR CGA-TGA

Insulin resistance INSR TGG-TAG

Insulin resistance A INSR CGA-TGA

Leprechaunism INSR AAG-TAG

Leprechaunism INSR CAG-TAG

Insulin resistance A INSR TAT-TAA

Insulin resistance INSR TAC-TAA

Leprechaunism INSR CGA-TGA

Insulin resistance INSR CGA-TGA

Leprechaunism INSR CAG-TAG

Senior-Loken syndrome 5 IQCB1 TGG-TGA

Senior-Loken syndrome 5 IQCB1 CGA-TGA

Van der Woude syndrome IRF6 TGG-TGA

Van der Woude syndrome IRF6 TGT-TGA

Van der Woude syndrome IRF6 TAC-TAA

Van der Woude syndrome IRF6 CGA-TGA

Van der Woude syndrome IRF6 TGG-TGA

Van der Woude syndrome IRF6 TAT-TAA

Van der Woude syndrome IRF6 TGC-TGA

Van der Woude syndrome IRF6 TAC-TAA

Van der Woude syndrome IRF6 CAG-TAG

Van der Woude syndrome IRF6 GAA-TAA

Popliteal pterygium syndrome IRF6 CAG-TAG

Diabetes, type 2 ISL1 CAA-TAA

Glanzmann thrombasthenia ITGA2B TCG-TAG

Glanzmann thrombasthenia ITGA2B CAG-TAG

Glanzmann thrombasthenia ITGA2B CGA-TGA

Glanzmann thrombasthenia ITGA2B CAG-TAG

Glanzmann thrombasthenia ITGA2B GAG-TAG

Glanzmann thrombasthenia ITGA2B TGG-TGA

Leukocyte adhesion deficiency ITGB2 CAG-TAG

Leukocyte adhesion deficiency ITGB2 GAG-TAG

Glanzmann thrombasthenia ITGB3 CGA-TGA

Glanzmann thrombasthenia ITGB3 GAG-TAG

Glanzmann thrombasthenia ITGB3 GAA-TAA

Glanzmann thrombasthenia ITGB3 TAC-TAA

Epidermolysis bullosa with pyloric atresia ITGB4 CGA-TGA

Epidermolysis bullosa with pyloric atresia ITGB4 CAG-TAG

Epidermolysis bullosa with pyloric atresia ITGB4 TGC-TGA Epidermolysis bullosa with pyloric atresia ITGB4 CAG-TAG

Alagille syndrome JAG1 GAG-TAG

Alagille syndrome JAG1 CAG-TAG

Alagille syndrome JAG1 GAG-TAG

Alagille syndrome JAG1 CAG-TAG

Alagille syndrome JAG1 TAC-TAG

Alagille syndrome JAG1 GAG-TAG

Alagille syndrome JAG1 TCA-TGA

Alagille syndrome JAG1 CAA-TAA

Alagille syndrome JAG1 TGC-TGA

Alagille syndrome JAG1 CAG-TAG

Alagille syndrome JAG1 CGA-TGA

Alagille syndrome JAG1 CAG-TAG

Alagille syndrome JAG1 TAC-TAG

Alagille syndrome JAG1 TAC-TAA

Alagille syndrome JAG1 TGC-TGA

Alagille syndrome JAG1 TGG-TAG

Alagille syndrome JAG1 GAG-TAG

Alagille syndrome JAG1 TAC-TAA

Alagille syndrome JAG1 TGG-TGA

Alagille syndrome JAG1 CAG-TAG

Alagille syndrome JAG1 TCG-TAG

Alagille syndrome JAG1 CAG-TAG

Alagille syndrome JAG1 TGG-TAG

Alagille syndrome JAG1 CAG-TAG

Alagille syndrome JAG1 AAG-TAG

Alagille syndrome JAG1 CGA-TGA

Alagille syndrome JAG1 CAG-TAG

Alagille syndrome JAG1 CGA-TGA

Alagille syndrome JAG1 CAG-TAG

Alagille syndrome JAG1 TGT-TGA

Alagille syndrome JAG1 TCA-TGA

Alagille syndrome JAG1 TGT-TGA

Alagille syndrome JAG1 CAG-TAG

Immunodeficiency, severe combined JAK3 TGC-TGA

Immunodeficiency, severe combined JAK3 TAT-TAG

Kallmann syndrome KALI CGA-TGA

Atrial fibrillation KCNA5 GAA-TAA

Miscarriage and intrauterine foetal loss KCNH2 CAG-TAG

Long QT syndrome KCNH2 TGC-TGA

Long QT syndrome KCNH2 GAG-TAG

Long QT syndrome KCNH2 CAG-TAG

Long QT syndrome KCNH2 CGA-TGA

Long QT syndrome KCNH2 GAG-TAG

Long QT syndrome KCNH2 TAC-TAA

Hyperinsulinism KCNJ11 TAC-TAA

Long QT syndrome KCNQ1 CAG-TAG

Long QT syndrome KCNQ1 TAT-TAA

Cone dystrophy with supernormal rod ERG KCNV2 AAG-TAG

Cone dystrophy with supernormal rod ERG KCNV2 AAA-TAA

Cone dystrophy with supernormal rod ERG KCNV2 CAG-TAG

Cone dystrophy with supernormal rod ERG KCNV2 GAG-TAG

Mental retardation, X-linked KDM5C CGA-TGA

Mental retardation, X-linked KDM5C TGG-TGA Mental retardation, X-linked KDM5C CGA-TGA

Kell blood group variation KEL TGG-TGA

K(null) phenotype KEL CAA-TAA

Cornea plana 2 KERA CGA-TGA

Goldberg-Shprintzen syndrome KIAA1279 CGA-TGA

Goldberg-Shprintzen syndrome KIAA1279 GAG-TAG

Piebaldism KIT CAG-TAG

Prostate cancer KLF6 CAA-TAA

Cerebral cavernous malformations KRIT1 TCA-TGA

Cerebral cavernous malformations KRIT1 GAA-TAA

Dowling-Degos disease KRT5

Epidermolysis bullosa, Dowling-Meara KRT5

Epidermolysis bullosa simplex KRT5

Epidermolytic hyperkeratosis KRT10 CAA-TAA

Epidermolysis bullosa, Koebner KRT14 CAG-TAG

Epidermolysis bullosa, Koebner KRT14 GAG-TAG

Epidermolysis bullosa, Koebner KRT14 TGG-TGA

Naegeli syndrome KRT14 CAG-TAG

Dermatopathia pigmentosa reticularis KRT14 TGC-TGA

Hydrocephalus, X-linked L1CA TGG-TGA

Hydrocephalus, X-linked L1CA CAG-TAG

Hydrocephalus, X-linked L1CA GGA-TGA

Hydrocephalus, X-linked L1CA CAG-TAG

Hydrocephalus, X-linked L1CA CGA-TGA

Hydrocephalus, X-linked L1CA GAA-TAA

Hydrocephalus, X-linked L1CA CAG-TAG

Hydrocephalus, X-linked L1CA GAA-TAA

L-2-Hydroxyglutaric aciduria L2HGDH TAT-TAA

L-2-Hydroxyglutaric aciduria L2HGDH CGA-TGA

Muscular dystrophy, merosin deficient LAMA2 TGG-TGA

Muscular dystrophy, merosin deficient LAMA2 GAA-TAA

Muscular dystrophy, merosin deficient LAMA2 CGA-TGA

Muscular dystrophy, merosin deficient LAMA2 CAA-TAA

Muscular dystrophy, merosin deficient LAMA2 TAC-TAA

Muscular dystrophy, merosin deficient LAMA2 CAA-TAA

Muscular dystrophy, merosin deficient LAMA2 CGA-TGA

Muscular dystrophy, merosin deficient LAMA2 TGC-TGA

Muscular dystrophy, merosin deficient LAMA2 CAA-TAA

Muscular dystrophy, merosin deficient LAMA2 TGC-TGA

Muscular dystrophy, merosin deficient LAMA2 TGG-TGA

Muscular dystrophy, merosin deficient LAMA2 CAG-TAG

Laminin alpha 2 chain deficiency, partial LAMA2 CGA-TGA

Epidermolysis bullosa, Herlitz LAMA3 CGA-TGA

Epidermolysis bullosa, Herlitz LAMA3 AAG-TAG

Epidermolysis bullosa, Herlitz LAMA3 GAA-TAA

Laryngo-onycho-cutaneous syndrome LAMA3 CGA-TGA

Cardiomyopathy, dilated LAMA4 CGA-TGA

Epidermolysis bullosa, Herlitz LAMB3 TGG-TGA

Epidermolysis bullosa, junctional LAMB3 CGA-TGA

Epidermolysis bullosa, Herlitz LAMB3 CAG-TAG

Epidermolysis bullosa, Herlitz LAMB3 TGG-TGA

Epidermolysis bullosa, Herlitz LAMB3 CGA-TGA

Epidermolysis bullosa, Herlitz LAMB3 CAG-TAG

Epidermolysis bullosa, Herlitz LAMB3 TGT-TGA Epidermolysis bullosa, Herlitz LAMB3 CGA-TGA

Epidermolysis bullosa, Herlitz LAMC2 AAA-TAA

Epidermolysis bullosa, Herlitz LAMC2 TGC-TGA

Epidermolysis bullosa, Herlitz LAMC2 TAC-TAG

Epidermolysis bullosa, junctional LAMC2 CAA-TAA

Danon disease LAMP2 CAA-TAA

Danon disease LAMP2 TTA-TGA

Pelger-Huet anomaly LBR CGA-TGA

Pelger-Huet anomaly LBR TGG-TGA

Leber congenital amaurosis LCA5 CAG-TAG

Lecithin : cholesterol acyltransferase deficiency LCAT TAC-TAA

Lactase deficiency, congenital LCT TAT-TAA

Lactate dehydrogenase deficiency LDHB TAT-TAG

Hypercholesterolaemia LDLR CAG-TAG

Hypercholesterolaemia LDLR TAC-TAG

Hypercholesterolaemia LDLR TGC-TGA

Hypercholesterolaemia LDLR TGG-TGA

Hypercholesterolaemia LDLR CAG-TAG

Hypercholesterolaemia LDLR TGG-TAG

Hypercholesterolaemia LDLR TAC-TAG

Hypercholesterolaemia LDLR TAC-TAA

Hypercholesterolaemia LDLR GAG-TAG

Hypercholesterolaemia LDLR GGA-TGA

Hypercholesterolaemia LDLR AAG-TAG

Hypercholesterolaemia LDLR TCA-TAA

Hypercholesterolaemia LDLR CAG-TAG

Hypercholesterolaemia LDLR TGC-TGA

Hypercholesterolaemia LDLR AAG-TAG

Hypercholesterolaemia LDLR TGC-TGA

Hypercholesterolaemia LDLR TGG-TGA

Hypercholesterolaemia LDLR GAG-TAG

Hypercholesterolaemia LDLR TGC-TGA

Hypercholesterolaemia LDLR TCA-TGA

Left-right axis malformation LEFTY2 CGA-TGA

Osteopoikilosis LEMD3 TTA-TAA

Leydig cell hypoplasia LHCGR TGC-TGA

Pseudohermaphroditism LHCGR TAT-TAG

Wolman syndrome LIPA CAG-TAG

Factor V and factor VIII deficiency, combined LMAN1 CAG-TAG

Factor V and factor VIII deficiency, combined LMAN1 GGA-TGA

Factor V and factor VIII deficiency, combined LMAN1 CGA-TGA

Muscular dystrophy, limb girdle LMNA TAT-TAA

Muscular dystrophy, Emery-Dreifuss LMNA CAG-TAG

Cardiomyopathy, dilated LMNA CAG-TAG

Cardiomyopathy, dilated LMNA CGA-TGA

Nail patella syndrome LMXIB CAA-TAA

Nail patella syndrome LMXIB TCG-TAG

Nail patella syndrome LMXIB CGA-TGA

Nail patella syndrome LMXIB CAG-TAG

Lipoprotein lipase deficiency LPL TGG-TGA

Hypertriglyceridaemia LPL TGC-TGA

Lipoprotein lipase deficiency, association with LPL TCA-TGA

Lipoprotein lipase deficiency LPL CAG-TAG

Lipoprotein lipase deficiency LPL TGG-TAG Lipoprotein lipase deficiency LPL TGG-TAG

Lipoprotein lipase deficiency LPL TAT-TAA

Lipoprotein lipase deficiency LPL TGG-TGA

Lipoprotein lipase deficiency LPL TGC-TGA

Lipoprotein lipase deficiency LPL TAC-TAA

Deafness, non-syndromic lrtomt2 TAC-TAG

Oligodontia LTBP3 TAC-TAG

Chediak-Higashi syndrome LYST CGA-TGA

Hypospadias MAMLD1 CAG-TAG

Hypospadias MAMLD1 GAG-TAG

Hypospadias MAMLD1 CGA-TGA

Mannosidosis , alpha MAN2B1 CAG-TAG

Mannosidosis , alpha MAN2B1 CGA-TGA

Mannosidosis, alpha MAN2B1 GAG-TAG

Mannosidosis, alpha MAN2B1 TGG-TGA

Mannosidosis, alpha MAN2B1 TAC-TAA

Mannosidosis, beta, lysosomal MANBA TGG-TGA

Mannosidosis, beta, lysosomal MANBA GAA-TAA

Mannosidosis, beta, lysosomal MANBA CAG-TAG

Obesity, autosomal dominant MC4R TGG-TGA

Obesity, autosomal dominant MC4R TAC-TAA

3-methylcrotonyl-CoA carboxylase deficiency MCCC1 CAA-TAA

3-methylcrotonyl-CoA carboxylase deficiency MCCC1 TGC-TGA

3-methylcrotonyl-CoA carboxylase deficiency MCCC1 GAA-TAA

3-methylcrotonyl-CoA carboxylase deficiency MCCC2 CAG-TAG

3-methylcrotonyl-CoA carboxylase deficiency MCCC2 CAA-TAA

3-methylcrotonyl-CoA carboxylase deficiency MCCC2 CAG-TAG

3-methylcrotonyl-CoA carboxylase deficiency MCCC2 CGA-TGA

Methylmalonic aciduria MCEE CGA-TGA

Factor V and Factor VIII deficiency, combined MCFD2 TCA-TGA

Mucolipidosis IV MCOLN1 CAG-TAG

Rett syndrome MECP2 TCA-TGA

Rett syndrome MECP2 CAG-TAG

Rett syndrome MECP2 GAG-TAG

Rett syndrome MECP2 CGA-TGA

Rett syndrome MECP2 CAG-TAG

Rett syndrome MECP2 AAA-TAA

Rett syndrome MECP2 CGA-TGA

Rett syndrome MECP2 TCA-TGA

Rett syndrome MECP2 AAG-TAG

Rett syndrome MECP2 TCA-TAA

Myocardial infarction MEF2A CGA-TGA

Mediterranean fever, familial MEFV TAC-TAG

Multiple endocrine neoplasia 1 MEN1 GAG-TAG

Multiple endocrine neoplasia 1 MEN1 TCG-TAG

Multiple endocrine neoplasia 1 MEN1 TGG-TGA

Multiple endocrine neoplasia 1 MEN1 CGA-TGA

Multiple endocrine neoplasia 1 MEN1 TGG-TGA

Multiple endocrine neoplasia 1 MEN1 TGG-TAG

Multiple endocrine neoplasia 1 MEN1 CAG-TAG

Multiple endocrine neoplasia 1 MEN1 TGG-TGA

Multiple endocrine neoplasia 1 MEN1 TAT-TAG

Multiple endocrine neoplasia 1 MEN1 TAC-TAG

Multiple endocrine neoplasia 1 MEN1 CAG-TAG

Multiple endocrine neoplasia 1 MEN1 TGG-TAG

Multiple endocrine neoplasia 1 MEN1 TGG-TAG Multiple endocrine neoplasia 1 MEN1 TGG-TAG

Multiple endocrine neoplasia 1 MEN1 GAG-TAG

Multiple endocrine neoplasia 1 MEN1 CAG-TAG

Multiple endocrine neoplasia 1 MEN1 AAG-TAG

Multiple endocrine neoplasia 1 MEN1 TGG-TGA

Multiple endocrine neoplasia 1 MEN1 CAA-TAA

Multiple endocrine neoplasia 1 MEN1 TAT-TAG

Multiple endocrine neoplasia 1 MEN1 CGA-TGA

Multiple endocrine neoplasia 1 MEN1 TAC-TAG

Multiple endocrine neoplasia 1 MEN1 CAG-TAG

Multiple endocrine neoplasia 1 MEN1 TAC-TAA

Multiple endocrine neoplasia 1 MEN1 GAG-TAG

Multiple endocrine neoplasia 1 MEN1 GAA-TAA

Multiple endocrine neoplasia 1 MEN1 TGG-TAG

Multiple endocrine neoplasia 1 MEN1 TAC-TAA

Multiple endocrine neoplasia 1 MEN1 CAG-TAG

Multiple endocrine neoplasia 1 MEN1 TAC-TAG

Multiple endocrine neoplasia 1 MEN1 CAG-TAG

Multiple endocrine neoplasia 1 MEN1 GAG-TAG

Multiple endocrine neoplasia 1 MEN1 TCG-TAG

Spondylocostal dysostosis MESP2 CAA-TAA

Spondylocostal dysostosis MESP2 GAG-TAG

Neuronal ceroid lipofuscinoses, late infantile MFSD8 GAA-TAA

Neuronal ceroid lipofuscinoses, late infantile MFSD8 CGA-TGA

Opitz G/BBB syndrome MIDI GAG-TAG

Opitz G/BBB syndrome MIDI TGT-TGA

Opitz G/BBB syndrome MIDI CAG-TAG

Opitz G/BBB syndrome MIDI GAG-TAG

Bardet-Biedl syndrome MKKS TAT-TAA

Colorectal cancer, non-polyposis MLH1 GAG-TAG

Colorectal cancer, non-polyposis MLH1 TGG-TAG

Colorectal cancer, non-polyposis MLH1 GAA-TAA

Colorectal cancer, non-polyposis MLH1 TTA-TAA

Colorectal cancer, non-polyposis MLH1 CAA-TAA

Colorectal cancer, non-polyposis MLH1 GAA-TAA

Colorectal cancer, non-polyposis MLH1 CAG-TAG

Colorectal cancer, young-onset MLH1

Colorectal cancer MLH1

Gastrointestinal cancer MLH1

Lynch syndrome-associated breast cancer MLH1

Colorectal cancer, early onset MLH1

Methylmalonic aciduria MMAB GAG-TAG

Methylmalonic aciduria, cblB type MMAB CAA-TAA

Fetomaternal alloimmunisation MME CGA-TGA

Osteolysis, idiopathic, Saudi type MMP2 TAC-TAA

Currarino syndrome MNX1 GAG-TAG

Currarino syndrome MNX1 CAG-TAG

Currarino syndrome MNX1 TCG-TAG

Xanthinuria, type 2 MOCOS CGA-TGA

Amegakaryocytic thrombocytopaenia, congenital MPL CAA-TAA

Amegakaryocytic thrombocytopaenia, congenital MPL CGA-TGA

Amegakaryocytic thrombocytopaenia, congenital MPL CGA-TGA Mercaptopyruvate sulphurtransferase deficiency, MPST TAC-TAA association with

Mitochondrial DNA depletion syndrome, MPV17 TGG-TAG hepatocerebral

Charcot-Marie-Tooth disease lb MPZ GAA-TAA

Charcot-Marie-Tooth disease 1 MPZ GGA-TGA

Charcot-Marie-Tooth disease 1 MPZ TAT-TAA

Charcot-Marie-Tooth disease lb MPZ TAC-TAG

Charcot-Marie-Tooth disease lb MPZ TAC-TAA

Ataxia telangiectasia-like disease MRE11A CGA-TGA

Mitochondrial respiratory chain disorder MRPS16 CGA-TGA

Atopy MS4A2 GGA-TGA

Colorectal cancer, non-polyposis MSH2 TTG-TAG

Colorectal cancer, non-polyposis MSH2 TCG-TAG

Colorectal cancer, non-polyposis MSH2 TAT-TAG

Colorectal cancer, non-polyposis MSH2 CAG-TAG

Colorectal cancer, non-polyposis MSH2 AGA-TGA

Colorectal cancer, non-polyposis MSH2 CAG-TAG

Colorectal cancer, non-polyposis MSH2 GAA-TAA

Colorectal cancer, non-polyposis MSH2 TGT-TGA

Colorectal cancer, non-polyposis MSH2 TAT-TAG

Colorectal cancer, non-polyposis MSH2 CGA-TGA

Colorectal cancer, non-polyposis MSH2 CAA-TAA

Colorectal cancer, non-polyposis MSH2 GAA-TAA

Colorectal cancer, non-polyposis MSH2 TCA-TAA

Colorectal cancer, non-polyposis MSH2 TCA-TGA

Colorectal cancer, non-polyposis MSH6 TCA-TAA

Colorectal cancer, non-polyposis MSH6 CAA-TAA

Colorectal cancer, non-polyposis MSH6 CGA-TGA

Colorectal cancer, early onset MSH6 TAC-TAG

Colorectal cancer, non-polyposis MSH6 TCA-TAA

Colorectal cancer, non-polyposis MSH6 TGG-TGA

Colorectal cancer, non-polyposis MSH6 GAG-TAG

Prostate cancer MSR1 TCA-TGA

Prostate cancer MSR1 CGA-TGA

Witkop syndrome MSX1 TCG-TAG

Homocystinuria MTHFR CGA-TGA

Methylenetetrahydrofolate reductase deficiency MTHFR TAC-TAG

Methylenetetrahydrofolate reductase deficiency MTHFR AAG-TAG

Methylenetetrahydrofolate reductase deficiency MTHFR CGA-TGA

Homocystinuria MTHFR TGG-TAG

Myotubular myopathy MTM1 CGA-TGA

Myotubular myopathy MTM1 TCA-TGA

Myotubular myopathy MTM1 GAA-TAA

Myotubular myopathy MTM1 TAC-TAA

Myotubular myopathy MTM1 TCA-TGA

Myotubular myopathy MTM1 TGG-TGA

Methionine synthase deficiency MTR CGA-TGA

Methionine synthase deficiency MTR GAA-TAA

Methionine synthase reductase deficiency MTRR CGA-TGA

Abetalipoproteinaemia MTTP CGA-TGA

Abetalipoproteinaemia MTTP AAA-TAA

Abetalipoproteinaemia MTTP TGG-TAG

Abetalipoproteinaemia MTTP GGA-TGA

Methylmalonic aciduria MUT AAA-TAA

Methylmalonic aciduria MUT CAG-TAG Methylmalonic aciduria MUT CAA-TAA

Methylmalonic aciduria MUT CGA-TGA

Methylmalonic aciduria MUT TCA-TAA

Methylmalonic aciduria MUT CGA-TGA

Methylmalonic aciduria MUT GGA-TGA

Methylmalonic aciduria MUT GAA-TAA

Methylmalonic aciduria MUT TAC-TAG

Methylmalonic aciduria MUT GGA-TGA

Methylmalonic aciduria MUT TCA-TAA

Methylmalonic aciduria MUT GAA-TAA

Methylmalonic aciduria MUT CAG-TAG

Methylmalonic aciduria MUT GGA-TGA

Methylmalonic aciduria MUT CGA-TGA

Mevalonic kinase deficiency MVK AAA-TAA

Hyperiittmunoglobulin D and periodic fever syndrome MVK TGG-TAG

Hyperimmunoglobulin D and periodic fever syndrome MVK TAC-TAG

Cardiomyopathy, hypertrophic MYBPC3 CAG-TAG

Cardiomyopathy, hypertrophic MYBPC3 CAA-TAA

Cardiomyopathy, hypertrophic MYBPC3 TAC-TAG

Cardiomyopathy, hypertrophic MYBPC3 CAG-TAG

Feingold syndrome MYCN TCG-TAG

Feingold syndrome MYCN GGA-TGA

Feingold syndrome MYCN TGG-TGA

Feingold syndrome MYCN GAG-TAG

Hearing impairment MYH14 TCG-TAG

Cardiomyopathy, hypertrophic MYH7 CGA-TGA

May-Hegglin anomaly MYH9 CGA-TGA

Deafness, non-syndromic, autosomal recessive MY015A AAA-TAA

Deafness, non-syndromic, autosomal recessive MY015A TGC-TGA

Sensorineural deafness, nonsyndromic MY01A CGA-TGA

Microvillus inclusion disease MY05B CAG-TAG

Microvillus inclusion disease MY05B CGA-TGA

Microvillus inclusion disease MY05B TGG-TGA

Deafness, autosomal dominant 22 MY06 CGA-TGA

Deafness, autosomal recessive MY06 CGA-TGA

Usher syndrome lb MY07A TGC-TGA

Usher syndrome lb MY07A TTG-TAG

Usher syndrome lb MY07A GAG-TAG

Usher syndrome lb MY07A CAG-TAG

Usher syndrome lb MY07A CGA-TGA

Sanfilippo syndrome B NAGLU TGG-TAG

Sanfilippo syndrome B NAGLU CAG-TAG

Sanfilippo syndrome B NAGLU GAG-TAG

Sanfilippo syndrome B NAGLU TGG-TGA

Fertility defects NBN TAT-TAG

Fertility defects NBN TGG-TGA

Chronic granulomatous disease NCF1 TGT-TGA

Chronic granulomatous disease NCF1 CAG-TAG

Chronic granulomatous disease NCF2 CGA-TGA

Chronic granulomatous disease NCF2 CAG-TAG

Chronic granulomatous disease NCF2 CGA-TGA Norrie disease NDP TAC-TAA

Norrie disease NDP CGA-TGA

Norrie disease NDP TGC-TGA

Mitochondrial complex I deficiency NDUFAF2

Complex 1 deficiency NDUFS4 TGG-TAG

Nemaline myopathy NEB CGA-TGA

Nemaline myopathy NEB CAA-TAA

Nemaline myopathy NEB TAC-TAG

Nemaline myopathy NEB TAC-TAA

Nemaline myopathy NEB CGA-TGA

Charcot-Marie-Tooth disease NEFL GAG-TAG

Sialidosis NEU1 TGG-TGA

Sialidosis 2 NEU1 TGG-TGA

Sialidosis 2 NEU1 CGA-TGA

Neurofibromatosis 1 NF1 TAC-TAA

Neurofibromatosis 1 NF1 TAC-TAG

Neurofibromatosis 1 NF1 CAG-TAG

Neurofibromatosis 1 NF1 CGA-TGA

Neurofibromatosis 1 NF1 CAA-TAA

Neurofibromatosis 1 NF1 GAA-TAA

Neurofibromatosis 1 NF1 TCA-TGA

Neurofibromatosis 1 NF1 TAT-TAG

Neurofibromatosis 1 NF1 GAG-TAG

Neurofibromatosis 1 NF1 CAG-TAG

Neurofibromatosis 1 NF1 TGG-TAG

Neurofibromatosis 1 NF1 CAG-TAG

Neurofibromatosis 1 NF1 CGA-TGA

Neurofibromatosis 1 NF1 AGA-TGA

Neurofibromatosis 1 NF1 CAG-TAG

Neurofibromatosis 1 NF1 CGA-TGA

Neurofibromatosis 1 NF1 AAA-TAA

Neurofibromatosis 1 NF1 TAT-TAG

Neurofibromatosis 1 NF1 AAA-TAA

Neurofibromatosis 1 NF1 TTA-TAA

Neurofibromatosis 1 NF1 TGC-TGA

Neurofibromatosis 1 NF1 TCA-TGA

Neurofibromatosis 1 NF1 CAG-TAG

Neurofibromatosis 1 NF1 TGG-TGA

Neurofibromatosis 1 NF1 CAG-TAG

Neurofibromatosis 1 NF1 CGA-TGA

Neurofibromatosis 1 NF1 CAA-TAA

Neurofibromatosis 1 NF1 GAA-TAA

Neurofibromatosis 1 NF1 TGG-TGA

Neurofibromatosis 1 NF1 CGA-TGA

Neurofibromatosis 1 NF1 TCA-TGA

Neurofibromatosis 1 NF1 TGG-TGA

Neurofibromatosis 1 NF1 CGA-TGA

Neurofibromatosis 1 NF1 TGG-TAG

Neurofibromatosis 1 NF1 AAA-TAA

Neurofibromatosis 1 NF1 GAA-TAA

Neurofibromatosis 1 NF1 CAA-TAA

Neurofibromatosis 1 NF1 TCA-TAA

Neurofibromatosis 1 NF1 TCA-TGA

Neurofibromatosis 1 NF1 AAA-TAA

Neurofibromatosis 1 NF1 CAG-TAG

Neurofibromatosis 1 NF1 GAA-TAA

Neurofibromatosis 1 NF1 CAA-TAA

Neurofibromatosis 1 NF1 CAG-TAG Neurofibromatosis 1 NF1 CGA-TGA

Neurofibromatosis 1 NF1 TGG-TGA

Neurofibromatosis 1 NF1 CAA-TAA

Neurofibromatosis 1 NF1 TGT-TGA

Neurofibromatosis 1 NF1 CAG-TAG

Neurofibromatosis 1 NF1 GGA-TGA

Neurofibromatosis 1 NF1 CGA-TGA

Neurofibromatosis 2 NF2 TGG-TAG

Neurofibromatosis 2 NF2 CAG-TAG

Neurofibromatosis 2 NF2 CGA-TGA

Neurofibromatosis 2 NF2 TAC-TAG

Neurofibromatosis 2 NF2 CAG-TAG

Neurofibromatosis 2 NF2 GAG-TAG

Neurofibromatosis 2 NF2 CAA-TAA

Neurofibromatosis 2 NF2 GAG-TAG

Neurofibromatosis 2 NF2 GAA-TAA

Neurofibromatosis 2 NF2 CAG-TAG

Neurofibromatosis 2 NF2 TAC-TAA

Neurofibromatosis 2 NF2 GAA-TAA

Neurofibromatosis 2 NF2 GAG-TAG

Neurofibromatosis 2 NF2 CAG-TAG

Neurofibromatosis 2 NF2 TGG-TGA

Neurofibromatosis 2 NF2 TAC-TAG

Neurofibromatosis 2 NF2 CAG-TAG

Neurofibromatosis 2 NF2 TGG-TGA

Neurofibromatosis 2 NF2 TAT-TAA

Neurofibromatosis 2 NF2 CAA-TAA

Neurofibromatosis 2 NF2 TGG-TGA

Neurofibromatosis 2 NF2 TGC-TGA

Neurofibromatosis 2 NF2 CAG-TAG

Ectodermal dysplasia, anhidrotic with immune NFKBIA GAG-TAG deficiency

Myoclonic epilepsy of Lafora NHLRC1 GAG-TAG

Myoclonic epilepsy of Lafora NHLRC1 TGG-TAG

Myoclonic epilepsy of Lafora NHLRC1 TGC-TGA

Myoclonic epilepsy of Lafora NHLRC1 CGA-TGA

Nance-Horan syndrome NHS CAG-TAG

Ichthyosis, autosomal recessive NIPAL4 CGA-TGA

Cornelia de Lange syndrome NIPBL TCA-TGA

Benign hereditary chorea NKX2-1 CAG-TAG

Benign hereditary chorea NKX2-1 GAG-TAG

Hypothyroidism NKX2-1 TGC-TGA

Hypothyroidism NKX2-1 TCG-TAG

Periodic fever syndrome NLRP12 CGA-TGA

Familial cold autoinflammatory syndrome NLRP3 CGA-TGA

Primary ciliary dyskinesia NME8 TTG-TAG

Stapes ankylosis with broad thumb and toes NOG CAG-TAG

Niemann-Pick disease C NPC1 CAG-TAG

Niemann-Pick type C2 disease NPC2 CAA-TAA

Niemann-Pick type C2 disease NPC2 TGC-TGA

Niemann-Pick type C2 disease NPC2 GAA-TAA

Nephronophthisis 1 NPHP1 CGA-TGA

Nephronophthisis 3 NPHP3 CGA-TGA

Nephronophthisis 4 NPHP4 CGA-TGA

Congenital nephrotic syndrome, Finnish type NPHS1 TGC-TGA

Congenital nephrotic syndrome, Finnish type NPHS1 TCA-TAA Congenital nephrotic syndrome, Finnish type NPHS1 CAG-TAG

Congenital nephrotic syndrome, Finnish type NPHS1 TAC-TAG

Congenital nephrotic syndrome, Finnish type NPHS1 CAG-TAG

Congenital nephrotic syndrome, Finnish type NPHS1 GAG-TAG

Congenital nephrotic syndrome, Finnish type NPHS1 CGA-TGA

Congenital nephrotic syndrome, Finnish type NPHS1 CAG-TAG

Congenital nephrotic syndrome, Finnish type NPHS1 TAC-TAG

Nephrotic syndrome NPHS1 CGA-TGA

Nephrotic syndrome, steroid resistant NPHS2 CGA-TGA

Nephrotic syndrome NPHS2 GAG-TAG

Acromesomelic dysplasia, Maroteaux type NPR2 CAG-TAG

Acromesomelic dysplasia, Maroteaux type NPR2 CGA-TGA

Adrenal hypoplasia NR0B1 TAC-TAA

Adrenal hypoplasia NR0B1 TAC-TAG

Adrenal hypoplasia NR0B1 CAG-TAG

Adrenal hypoplasia NR0B1 TCA-TGA

Adrenal hypoplasia NR0B1 CAG-TAG

Adrenal hypoplasia NR0B1 TGC-TGA

Adrenal hypoplasia NR0B1 CAG-TAG

Adrenal hypoplasia NR0B1 TGG-TGA

Adrenal hypoplasia NR0B1 TAC-TAA

Adrenal hypoplasia NR0B1 TGG-TAG

Enhanced S cone syndrome NR2E3 CAA-TAA

Pseudohypoaldosteronism 1 NR3C2 CGA-TGA

Pseudohypoaldosteronism 1 NR3C2 TGT-TGA

Pseudohypoaldosteronism 1 NR3C2 TAT-TAA

Pseudohypoaldosteronism 1 NR3C2 TGC-TGA

Pseudohypoaldosteronism 1 NR3C2 TCA-TGA

Pseudohypoaldosteronism 1 NR3C2 CGA-TGA

XY sex reversal, without adrenal failure NR5A1 TAC-TAA

XY sex reversal, without adrenal failure NR5A1 TGC-TGA

Sotos syndrome NSD1 TCA-TGA

Sotos syndrome NSD1 TGT-TGA

Sotos syndrome NSD1 CGA-TGA

Sotos syndrome NSD1 AGA-TGA

Sotos syndrome NSD1 TCA-TGA

Sotos syndrome NSD1 GAA-TAA

Sotos syndrome NSD1 CGA-TGA

Sotos syndrome NSD1 CAG-TAG

Sotos syndrome NSD1 GAA-TAA

Sotos syndrome NSD1 AAA-TAA

Sotos syndrome NSD1 TGG-TAG

Sotos syndrome NSD1 CAA-TAA

Sotos syndrome NSD1 CGA-TGA

CHILD syndrome NSDHL GAG-TAG

Pain insensitivity, congenital NTRK1 CAG-TAG

Pain insensitivity, congenital NTRK1 CGA-TGA Pain insensitivity, congenital NTRK1 GAG-TAG

Pain insensitivity, congenital NTRK1 TAC-TAA

Gyrate atrophy OAT TGG-TGA

Gyrate atrophy OAT TAC-TAG

Gyrate atrophy OAT TAT-TAA

Gyrate atrophy OAT CGA-TGA

Albinism, oculocutaneous II OCA2 TGG-TGA

Lowe oculocerebrorenal syndrome OCRL CGA-TGA

Lowe oculocerebrorenal syndrome OCRL CAG-TAG

Lowe oculocerebrorenal syndrome OCRL TAT-TAG

Lowe oculocerebrorenal syndrome OCRL GAG-TAG

Lowe oculocerebrorenal syndrome OCRL CAG-TAG

Lowe oculocerebrorenal syndrome OCRL CGA-TGA

Lowe oculocerebrorenal syndrome OCRL GAA-TAA

Lowe oculocerebrorenal syndrome OCRL CGA-TGA

Lowe oculocerebrorenal syndrome OCRL CAA-TAA

Lowe oculocerebrorenal syndrome OCRL TAC-TAG

Lowe oculocerebrorenal syndrome OCRL CGA-TGA

Lowe oculocerebrorenal syndrome OCRL CAG-TAG

Lowe oculocerebrorenal syndrome OCRL GAA-TAA

Oral-facial-digital syndrome 1 OFD1 CGA-TGA

Oral-facial-digital syndrome 1 OFD1 CAA-TAA

Oral-facial-digital syndrome 1 OFD1 TTA-TAA

Oral-facial-digital syndrome 1 OFD1 AAA-TAA

Oral-facial-digital syndrome 1 OFD1 CAA-TAA

Oral-facial-digital syndrome 1 OFD1 TAC-TAG

Oral-facial-digital syndrome 1 OFD1 CAA-TAA

Oral-facial-digital syndrome 1 OFD1 CGA-TGA

Oral-facial-digital syndrome 1 OFD1 CAA-TAA

Oral-facial-digital syndrome 1 OFD1 CAG-TAG

Oral-facial-digital syndrome 1 OFD1 CAA-TAA

Oral-facial-digital syndrome 1 OFD1 TTA-TAA

Optic atrophy 1 OPA1 GAG-TAG

Optic atrophy 1 OPA1 CGA-TGA

Optic atrophy 1 OPA1 CAA-TAA

Optic atrophy 1 OPA1 CAG-TAG

Optic atrophy 1 OPA1 TTG-TAG

Optic atrophy 1 OPA1 CGA-TGA

Optic atrophy 1 OPA1 CAG-TAG

Optic atrophy 1 OPA1 AGA-TGA

Optic atrophy 1 OPA1 CGA-TGA

Mental retardation syndrome, X-linked OPHN1 CAG-TAG

X-linked cone dystrophy orf15 GGA-TGA

Atrophic macular degeneration orf15 GAA-TAA

Retinitis pigmentosa, X-linked orf15 GAG-TAG

Retinitis pigmentosa, X-linked orf15 GAA-TAA

Retinitis pigmentosa, X-linked orf15 CAA-TAA

Retinitis pigmentosa, X-linked orf15 GGA-TGA

Osteopetrosis, autosomal recessive OSTM1 TGT-TGA

Ornithine transcarbamylase deficiency OTC TAC-TAA

Ornithine transcarbamylase deficiency OTC GAA-TAA

Ornithine transcarbamylase deficiency OTC GGA-TGA

Ornithine transcarbamylase deficiency OTC CAG-TAG Deafness, autosomal recessive 9 OTOF TAC-TAG

Deafness, autosomal recessive 9 OTOF TGG-TAG

Deafness, autosomal recessive 9 OTOF CGA-TGA

Deafness, non-syndromic OTOF TAT-TAA

Lissencephaly, isolated PAFAHIBI TGG-TAG

Lissencephaly, isolated PAFAHIBI CAA-TAA

Subcortical band heterotopia PAFAHIBI CGA-TGA

Phenylketonuria PAH TAC-TAG

Phenylketonuria PAH CGA-TGA

Phenylketonuria PAH TCA-TGA

Phenylketonuria PAH CAA-TAA

Phenylketonuria PAH TAC-TAG

Phenylketonuria PAH CGA-TGA

Phenylketonuria PAH TGG-TAG

Phenylketonuria PAH TAC-TAA

HARP syndrome PANK2 CGA-TGA

Pantothenate kinase-associated neurodegeneration PANK2 TCG-TAG

Spondyloepiphyseal dysplasia PAPSS2 TCA-TAA

Parkinsonism, juvenile, autosomal recessive PARK2 TGG-TAG

Renal hypoplasia PAX2 CAG-TAG

Renal hypoplasia PAX2 TAC-TAA

Waardenburg syndrome PAX3 TGG-TAG

Waardenburg syndrome PAX3 GAA-TAA

Waardenburg syndrome PAX3 CAG-TAG

Aniridia PAX6 TGG-TAG

Aniridia PAX6 CAA-TAA

Aniridia PAX6 TGC-TGA

Aniridia PAX6 GAG-TAG

Aniridia PAX6 TGG-TGA

Aniridia PAX6 CAA-TAA

Aniridia PAX6 AGA-TGA

Aniridia PAX6 CAA-TAA

Aniridia PAX6 TCA-TGA

Aniridia PAX6 CGA-TGA

Aniridia PAX6 CAG-TAG

Aniridia PAX6 TAT-TAG

Aniridia PAX6 AGA-TGA

Aniridia PAX6 GAA-TAA

Oligodontia PAX9 CAG-TAG

Oligodontia PAX9 AAG-TAG

Hyperphenylalaninaemia PCBD1 GAG-TAG

Hyperphenylalaninaemia PCBD1 GAA-TAA

Propionic acidaemia PCCA CGA-TGA

Propionic acidaemia PCCB TGG-TGA

Propionic acidaemia PCCB GGA-TGA

Usher syndrome If PCDH15 CGA-TGA

Usher syndrome If PCDH15 TAC-TAA

Usher syndrome If PCDH15 TCA-TGA

Usher syndrome If PCDH15 AGA-TGA

Usher syndrome If PCDH15 CGA-TGA

Usher syndrome If PCDH15 GAA-TAA

Epilepsy and mental retardation limited to females PCDH19 CAG-TAG

Epilepsy and mental retardation limited to females PCDH19 TCA-TGA

Schizophrenia PCM1 GAG-TAG Obesity and impaired prohormone processing PCSK1 GAG-TAG

Low LDL cholesterol PCSK9 TAC-TAG

Low LDL cholesterol, association with PCSK9 TGC-TGA

Low LDL cholesterol PCSK9 TGG-TGA

Cerebral cavernous malformation PDCD10 CGA-TGA

Cerebral cavernous malformation PDCD10 CAG-TAG

Retinitis pigmentosa PDE6B CGA-TGA

Retinitis pigmentosa PDE6B CAG-TAG

Pyruvate dehydrogenase deficiency PDHA1 TCA-TAA

Pyruvate dehydrogenase complex deficiency PDHX TGG-TAG

Pyruvate dehydrogenase complex deficiency PDHX CAG-TAG

Pyruvate dehydrogenase phosphatase deficiency PDP1 GAA-TAA

Prolidase deficiency PEPD CGA-TGA

Zellweger syndrome PEX1 CGA-TGA

Peroxisome biogenesis disorder PEX1 CGA-TGA

Neonatal adrenoleukodystrophy PEX10 CGA-TGA

Zellweger syndrome H PEX13 TGG-TGA

Zellweger syndrome PEX14 CAG-TAG

Zellweger syndrome, complementation group D PEX16 CGA-TGA

Rhizomelic chondrodysplasia punctata PEX7 CGA-TGA

Glycogen storage disease 7 PFKM CGA-TGA

Rickets, hypophosphataemic PHEX GAG-TAG

Rickets, hypophosphataemic PHEX TAT-TAA

Rickets, hypophosphataemic PHEX GAA-TAA

Rickets, hypophosphataemic PHEX GAG-TAG

Rickets, hypophosphataemic PHEX TAC-TAG

Rickets, hypophosphataemic PHEX TGG-TGA

Rickets, hypophosphataemic PHEX CGA-TGA

Rickets, hypophosphataemic PHEX TTG-TAG

Rickets, hypophosphataemic PHEX GAA-TAA

Rickets, hypophosphataemic PHEX TGG-TGA

Rickets, hypophosphataemic PHEX TAC-TAA

Rickets, hypophosphataemic PHEX CGA-TGA

Rickets, hypophosphataemic PHEX CAG-TAG

Rickets, hypophosphataemic PHEX TAT-TAA

Rickets, hypophosphataemic PHEX CGA-TGA

Rickets, hypophosphataemic PHEX CAG-TAG

Rickets, hypophosphataemic PHEX AAA-TAA

Rickets, hypophosphataemic PHEX TGG-TGA

X-linked mental retardation & cleft lip/palate PHF8 AAA-TAA

Phosphorylase kinase deficiency PHKA1 GAG-TAG

Liver glycogenosis 1 PHKA2 CGA-TGA

Liver glycogenosis PHKB TAT-TAA

Liver glycogenosis PHKB CAG-TAG

Liver glycogenosis PHKB CGA-TGA

Fibrosis of extraocular muscles type 2 PHOX2A CAG-TAG

Central hypoventilation syndrome PHOX2B TAT-TAG

Central hypoventilation syndrome PHOX2B TAC-TAA

Central hypoventilation syndrome PHOX2B AAG-TAG

Parkinson disease, early-onset PINK1 TAC-TAA

Parkinson disease, early-onset PINK1 TGG-TGA

Axenfeld-Rieger syndrome PITX2 TAC-TAA

Axenfeld-Rieger syndrome PITX2 GAG-TAG

Polycystic kidney disease 1 PKDl CAG-TAG

Polycystic kidney disease 1 PKDl TAC-TAA Polycystic kidney disease 1 PKD1 CAG-TAG

Polycystic kidney disease 1 PKD1 CAG-TAG

Polycystic kidney disease 1 PKD1 TGC-TGA

Polycystic kidney disease 1 PKD1 CAG-TAG

Polycystic kidney disease 1 PKD1 GAG-TAG

Polycystic kidney disease 1 PKD1 CAG-TAG

Polycystic kidney disease 1 PKD1 CGA-TGA

Polycystic kidney disease 1 PKD1 CAG-TAG

Polycystic kidney disease 1 PKD1 GAG-TAG

Polycystic kidney disease 1 PKD1 CAG-TAG

Polycystic kidney disease 1 PKD1 TAC-TAA

Polycystic kidney disease 1 PKD1 CGA-TGA

Polycystic kidney disease 1 PKD1 CAG-TAG

Polycystic kidney disease 1 PKD1 TGG-TGA

Polycystic kidney disease 1 PKD1 CGA-TGA

Polycystic kidney disease 1 PKD1 TGG-TGA

Polycystic kidney disease 1 PKD1 CAG-TAG

Polycystic kidney disease 1 PKD1 TCA-TGA

Polycystic kidney disease 1 PKD1 CAG-TAG

Polycystic kidney disease 1 PKD1 CAA-TAA

Polycystic kidney disease 1 PKD1 TGT-TGA

Polycystic kidney disease 1 PKD1 CGA-TGA

Polycystic kidney disease 1 PKD1 TAC-TAA

Polycystic kidney disease 1 PKD1 TGC-TGA

Polycystic kidney disease 1 PKD1 TGG-TGA

Polycystic kidney disease 1 PKD1 CAG-TAG

Polycystic kidney disease 1 PKD1 TCG-TAG

Polycystic kidney disease 1 PKD1 GAG-TAG

Polycystic kidney disease 1 PKD1 CAG-TAG

Polycystic kidney disease 1 PKD1 TCA-TGA

Polycystic kidney disease 1 PKD1 TGT-TGA

Polycystic kidney disease 1 PKD1 CAG-TAG

Polycystic kidney disease 1 PKD1 CGA-TGA

Polycystic kidney disease 1 PKD1 CAG-TAG

Polycystic kidney disease 1 PKD1 CGA-TGA

Polycystic kidney disease 2 PKD2 CGA-TGA

Polycystic kidney disease 2 PKD2 GAA-TAA

Polycystic kidney disease 2 PKD2 CAG-TAG

Polycystic kidney disease 2 PKD2 CGA-TGA

Polycystic kidney disease 2 PKD2 CAA-TAA

Polycystic kidney disease 2 PKD2 TGG-TAG

Polycystic kidney disease 2 PKD2 CAG-TAG

Polycystic kidney disease 2 PKD2 TAC-TAA

Polycystic kidney disease 2 PKD2 TAT-TAA

Polycystic kidney disease 2 PKD2 CGA-TGA

Polycystic kidney disease 2 PKD2 CAG-TAG

Polycystic kidney disease PKHD1 TTA-TGA

Polycystic kidney disease PKHD1 TCA-TAA

Polycystic kidney disease PKHD1 TGG-TGA Polycystic kidney disease PKHD1 CAG-TAG

Pyruvate kinase deficiency PKLR GAG-TAG

Haemolytic anaemia PKLR TGG-TGA

Haemolytic anaemia PKLR CAG-TAG

Haemolytic anaemia PKLR CGA-TGA

Pyruvate kinase deficiency PKLR CGA-TGA

Ectodermal dysplasia/skin fragility syndrome PKP1 CGA-TGA

Infantile neuroaxonal dystrophy 1 PLA2G6 CGA-TGA

Epidermolysis bullosa with pyloric atresia PLEC CGA-TGA

Epidermolysis bullosa with pyloric atresia PLEC CAG-TAG

Muscular dystrophy with epidermolysis bullosa PLEC GAG-TAG

Muscular dystrophy with epidermolysis bullosa PLEC CAG-TAG

Epidermolysis bullosa simplex PLEC CAG-TAG

Muscular dystrophy with epidermolysis bullosa PLEC AAG-TAG

Muscular dystrophy with epidermolysis bullosa PLEC CAG-TAG

Muscular dystrophy with epidermolysis bullosa PLEC GAG-TAG

Epidermolysis bullosa simplex PLEC CAG-TAG

Epidermolysis bullosa simplex PLEC CGA-TGA

Muscular dystrophy with epidermolysis bullosa PLEC CGA-TGA

Plasminogen deficiency PLG TGC-TGA

Ehlers-Danlos syndrome VI PLOD1 TAC-TAG

Pelizaeus-Merzbacher disease PLP1 CAA-TAA

Spastic paraplegia PLP1 TGG-TAG

Congenital disorder of glycosylation la PMM2 CGA-TGA

Turcot syndrome PMS2 CAG-TAG

PNPO deficiency PNPO CAG-TAG

Alpers syndrome POLG CGA-TGA

Xeroderma pigmentosum, variant POLH CAA-TAA

Xeroderma pigmentosum, variant POLH CAG-TAG

Xeroderma pigmentosum, variant POLH CAA-TAA

Obesity POMC GAG-TAG

Walker-Warburg syndrome POMT1 CAG-TAG

Focal dermal hypoplasia PORCN GAA-TAA

Focal dermal hypoplasia PORCN TAC-TAA

Focal dermal hypoplasia PORCN TGG-TAG

Focal dermal hypoplasia PORCN CGA-TGA

Focal dermal hypoplasia PORCN TAC-TAA

Pituitary hormone deficiency POU1F1 CGA-TGA

Pituitary hormone deficiency POU1F1 GAA-TAA

Partial lipodystrophy PPARG TAC-TAG

Porphyria, variegate PPOX GAG-TAG

Porphyria, variegate PPOX CAG-TAG

Porphyria, variegate PPOX TGG-TGA

Porphyria, variegate PPOX CAA-TAA

Porphyria, variegate PPOX TGG-TGA

Porphyria, variegate PPOX TTA-TGA

Porphyria, variegate PPOX TGG-TAG

Porphyria, variegate PPOX TGG-TGA

Neuronal ceroid lipofuscinosis, juvenile PPT1 TTG-TAG

Neuronal ceroid lipofuscinosis, juvenile PPT1 CGA-TGA

Neuronal ceroid lipofuscinosis, infantile PPT1 CGA-TGA

Neuronal ceroid lipofuscinosis, late infantile PPT1 TGG-TGA

Haemophagocytic lymphohistiocytosis, familial PRF1 TAT-TAA

Haemophagocytic lymphohistiocytosis, familial PRF1 TGG-TAG

Haemophagocytic lymphohistiocytosis, familial PRF1 TGG-TGA Haemophagocytic lymphohistiocytosis, familial PRF1 TCG-TAG

Haemophagocytic lymphohistiocytosis, familial PRF1 CAA-TAA

Haemophagocytic lymphohistiocytosis, familial PRF1 TGG-TGA

Perforin deficiency PRF1 GAG-TAG

Haemophagocytic lymphohistiocytosis, familial PRF1 TAC-TAA

Camptodactyly-arthropathy-coxa vara-pericarditis PRG4 AGA-TGA

Carney complex PRKAR1A CAA-TAA

Carney complex PRKAR1A CGA-TGA

Carney complex PRKARIA CGA-TGA

Carney complex PRKARIA TCA-TGA

Carney complex PRKARIA AAA-TAA

Carney complex PRKARIA TAT-TAG

Carney complex PRKARIA TGG-TGA

Carney complex PRKARIA CGA-TGA

Carney complex PRKARIA CAG-TAG

Carney complex PRKARIA TGG-TGA

Carney complex PRKARIA TGG-TAG

Carney complex PRKARIA GAA-TAA

Carney complex PRKARIA CAG-TAG

Carney complex PRKARIA GAG-TAG

Azoospermia PRM2 CAG-TAG

Protein C deficiency PROC CGA-TGA

Protein C deficiency PROC TGG-TAG

Hypogonadotropic hypogonadism PROKR2 TAC-TAG

Hypogonadotropic hypogonadism PROP1 TGG-TGA

Protein S deficiency PROS1 CAG-TAG

Protein S deficiency PROS1 TCA-TGA

Protein S deficiency PROS1 GAA-TAA

Protein S deficiency PROS1 AAA-TAA

Protein S deficiency PROS1 TCA-TGA

Protein S deficiency PROS1 TCA-TAA

Protein S deficiency PROS1 CAA-TAA

Protein S deficiency PROS1 TGC-TGA

Protein S deficiency PROS1 GAG-TAG

Protein S deficiency PROS1 CAG-TAG

Protein S deficiency PROS1 GGA-TGA

High myopia PRPH CGA-TGA

Pattern dystrophy PRPH2 TAC-TAA

Pattern dystrophy PRPH2 CAG-TAG

Pancreatitis, protection against PRSS1 TAC-TAA

Dej erine-Sottas syndrome PRX CGA-TGA

Charcot-Marie-Tooth disease 4 PRX CGA-TGA

Gaucher disease, atypical PSAP CAG-TAG

Nevoid basal cell carcinoma syndrome PTCH1 TGG-TAG

Nevoid basal cell carcinoma syndrome PTCH1 TAC-TAA

Nevoid basal cell carcinoma syndrome PTCH1 GAG-TAG

Nevoid basal cell carcinoma syndrome PTCH1 TCA-TGA

Nevoid basal cell carcinoma syndrome PTCH1 GAG-TAG

Nevoid basal cell carcinoma syndrome PTCH1 TGG-TAG

Nevoid basal cell carcinoma syndrome PTCH1 CAG-TAG

Nevoid basal cell carcinoma syndrome PTCH1 TTA-TAA

Nevoid basal cell carcinoma syndrome PTCH1 TGG-TAG

Nevoid basal cell carcinoma syndrome PTCH1 TCA-TGA

Nevoid basal cell carcinoma syndrome PTCH1 GAG-TAG

Nevoid basal cell carcinoma syndrome PTCH1 GAA-TAA

Nevoid basal cell carcinoma syndrome PTCH1 CAA-TAA Nevoid basal cell carcinoma syndrome PTCH1 GGA-TGA

Cowden disease PTEN CAG-TAG

Cowden disease PTEN CAA-TAA

Cowden disease PTEN TAT-TAG

Cowden disease PTEN CGA-TGA

Cowden disease PTEN GAA-TAA

Cowden disease PTEN CAG-TAG

Cowden disease PTEN CAA-TAA

Cowden disease PTEN TTA-TAA

Cowden disease PTEN AGA-TGA

Cowden disease PTEN CGA-TGA

Hypertension PTGIS CGA-TGA

Osteochondrodysplasia, Blomstrand, type 1 PTH1R CGA-TGA

Mitochondrial myopathy and sideroblastic anaemia PUS1 GAG-TAG

McArdle disease PYGM CGA-TGA

McArdle disease PYGM TGG-TAG

McArdle disease PYGM CGA-TGA

McArdle disease PYGM TAC-TAA

McArdle disease PYGM GAA-TAA

McArdle disease PYGM TAC-TAG

McArdle disease PYGM AAG-TAG

McArdle disease PYGM TGG-TAG

McArdle disease PYGM GAA-TAA

McArdle disease PYGM CAG-TAG

McArdle disease PYGM GAG-TAG

McArdle disease PYGM TGC-TGA

Dihydropteridine reductase deficiency QDPR TGG-TGA

Acrocephalopolysyndactyly, type II RAB23 TTA-TAA

Immunodeficiency, severe combined RAG2

Immunodeficiency, severe combined, B cell -ve RAG2

Omenn syndrome RAG2

Smith-Magenis syndrome RAIl CGA-TGA

Anophthalmia RAX TAC-TAG

Retinoblastoma RBI AAA-TAA

Retinoblastoma RBI CAG-TAG

Retinoblastoma RBI TAC-TAA

Retinoblastoma RBI GAA-TAA

Retinoblastoma RBI TGC-TGA

Retinoblastoma RBI TAT-TAA

Retinoblastoma RBI TCA-TAA

Retinoblastoma RBI CAA-TAA

Retinoblastoma RBI CAG-TAG

Retinoblastoma RBI GAA-TAA

Retinoblastoma RBI TCA-TGA

Retinoblastoma RBI CAA-TAA

Retinoblastoma RBI TAC-TAA

Retinoblastoma RBI TCA-TGA

Retinoblastoma RBI TGT-TGA

Retinoblastoma RBI CAG-TAG

Retinoblastoma RBI GAA-TAA

Retinoblastoma RBI CGA-TGA

Retinoblastoma RBI CAA-TAA

Retinoblastoma RBI TGG-TAG

Retinoblastoma RBI TAT-TAG

Retinoblastoma RBI GAA-TAA

Retinoblastoma RBI GAA-TAA Retinoblastoma RBI TTA-TAA

RAPADILINO syndrome RECQL4 AGA-TGA

RAPADILINO syndrome RECQL4 CAG-TAG

RAPADILINO syndrome RECQL4 TGG-TAG

Spastic paraplegia 31 REEP1 TAC-TAA

Hirschsprung disease RET GAG-TAG

Hirschsprung disease RET CGA-TGA

MHC class II deficiency RFXANK CGA-TGA

Rhesus negative blood group RHD TAT-TAG

Rhesus negative blood group RHD TAC-TAA

Retinitis pigmentosa RHO GAG-TAG

Ribonuclease L deficiency RNASEL GAG-TAG

Brachydactyly, type B ROR2 TGG-TAG

Brachydactyly, type B ROR2 TAC-TAA

Robinow syndrome, autosomal recessive ROR2 CGA-TGA

Robinow syndrome, autosomal recessive ROR2 CAG-TAG

Robinow syndrome, autosomal recessive ROR2 TGG-TGA

Brachydactyly, type B ROR2 CAG-TAG

Retinitis pigmentosa RP1 TGT-TGA

Retinitis pigmentosa RP1 GAG-TAG

Retinitis pigmentosa RP1 CAA-TAA

Retinitis pigmentosa RP1 CGA-TGA

Retinitis pigmentosa RP1 AAA-TAA

Retinitis pigmentosa, X-linked RP2 CAG-TAG

Retinitis pigmentosa, X-linked RP2 TAC-TAG

Leber congenital amaurosis RPE65 AAA-TAA

Retinitis pigmentosa, X-linked RPGR TGG-TAG

Retinitis pigmentosa, X-linked RPGR GGA-TGA

Retinitis pigmentosa, X-linked RPGR TGG-TGA

Retinitis pigmentosa, X-linked RPGR GAA-TAA

Retinitis pigmentosa, X-linked RPGR CAG-TAG

Retinitis pigmentosa, X-linked RPGR TCA-TAA

Diamond-Blackfan anaemia RPS19 TGG-TAG

Diamond-Blackfan anaemia RPS19 CGA-TGA

Diamond-Blackfan anaemia RPS19 TGG-TAG

Diamond-Blackfan anaemia RPS19 CAG-TAG

Diamond-Blackfan anaemia RPS19 TAC-TAA

Diamond-Blackfan anaemia RPS24 CAA-TAA

Diamond-Blackfan anaemia RPS24 CGA-TGA

Coffin-Lowry syndrome RPS6KA3 CGA-TGA

Coffin-Lowry syndrome RPS6KA3 TCA-TAA

Coffin-Lowry syndrome RPS6KA3 AAG-TAG

Coffin-Lowry syndrome RPS6KA3 CGA-TGA

Coffin-Lowry syndrome RPS6KA3 GGA-TGA

Coffin-Lowry syndrome RPS6KA3 CGA-TGA

Coffin-Lowry syndrome RPS6KA3 CAA-TAA

Coffin-Lowry syndrome RPS6KA3 CAG-TAG

Coffin-Lowry syndrome RPS6KA3 TGG-TAG

Coffin-Lowry syndrome RPS6KA3 GAA-TAA

Coffin-Lowry syndrome RPS6KA3 CAA-TAA

Coffin-Lowry syndrome RPS6KA3 CGA-TGA

Coffin-Lowry syndrome RPS6KA3 TGG-TAG

Coffin-Lowry syndrome RPS6KA3 CGA-TGA

Mitochondrial DNA depletion syndrome RRM2B CAG-TAG

Retinoschisis, X linked juvenile RSI TGC-TGA Retinoschisis, X linked juvenile RSI CAG-TAG

Retinoschisis, X linked juvenile RSI TGG-TGA

Retinoschisis, X linked juvenile RSI TGT-TGA

Retinoschisis, X linked juvenile RSI TGG-TAG

Retinoschisis, X linked juvenile RSI GAG-TAG

Retinoschisis, X linked juvenile RSI CAG-TAG

Retinoschisis, X linked juvenile RSI TAT-TAA

Retinoschisis, X linked juvenile RSI TCG-TAG

Retinoschisis, X linked juvenile RSI GAG-TAG

Retinoschisis, X linked juvenile RSI TGG-TGA

Platelet disorder, familial RUNX1 CGA-TGA

Cleidocranial dysplasia RUNX2 CAA-TAA

Cleidocranial dysplasia RUNX2 CAG-TAG

Cleidocranial dysplasia RUNX2 GAA-TAA

Ataxia SACS CGA-TGA

Townes-Brocks syndrome SALL1 TCA-TGA

Townes-Brocks syndrome SALL1 CGA-TGA

Goldenhar syndrome SALL1 TTG-TAG

Townes-Brocks syndrome SALL1 CAA-TAA

Townes-Brocks syndrome SALL1 GGA-TGA

Townes-Brocks syndrome SALL1 AAA-TAA

Townes-Brocks syndrome SALL1 GAG-TAG

Okihiro syndrome SALL4 CGA-TGA

Tumoural calcinosis, normophosphataemic SAMD9 CGA-TGA

Chylomicron retention disease SARIB GAA-TAA

Cleft palate, osteoporosis and cognitive defects SATB2 CGA-TGA

Charcot-Marie-Tooth disease 4b2 SBF2 CGA-TGA

Charcot-Marie-Tooth disease 4b2 SBF2 CAG-TAG

Action myoclonus-renal failure syndrome SCARB2 TGG-TAG

Myoclonic epilepsy of infancy SCN1A TGG-TAG

Myoclonic epilepsy of infancy SCN1A CGA-TGA

Myoclonic epilepsy of infancy SCN1A TGG-TGA

Myoclonic epilepsy of infancy SCN1A CGA-TGA

Myoclonic epilepsy of infancy SCN1A TGG-TAG

Myoclonic epilepsy of infancy SCN1A AAA-TAA

Myoclonic epilepsy of infancy SCN1A CGA-TGA

Myoclonic epilepsy of infancy SCN1A TGG-TAG

Myoclonic epilepsy of infancy SCN1A GAA-TAA

Myoclonic epilepsy of infancy SCN1A CGA-TGA

Dravet syndrome or Dravet syndrome C or Dravet SCN1A

syndrome B

Generalized epilepsy with febrile seizures plus SCN1A

Intractable epilepsy SCN1A

Intractable epilepsy and mental decline SCN2A CGA-TGA

Brugada syndrome SCN5A CGA-TGA

Brugada syndrome SCN5A TGG-TAG

Cardiac conduction disease SCN5A TGG-TAG

Brugada syndrome SCN5A CAG-TAG

Cardiac conduction disease SCN5A TGG-TGA

Channelopathy-associated insensitivity to pain SCN9A TGG-TGA

Channelopathy-associated insensitivity to pain SCN9A TCA-TGA Cardioencephalomyopathy, fatal infantile SC02 TGG-TAG

Cytochrome c oxidase deficiency SC02 CGA-TGA

Leigh syndrome SDHA TGG-TAG

Phaeochromocytoma SDHB CGA-TGA

Paraganglioma, autosomal dominant 3 SDHC TGG-TGA

Paraganglioma SDHD CGA-TGA

SEPN-related myopathy SEPN1 CGA-TGA

Antitrypsin alpha 1 deficiency SERPINA1 TGG-TGA

Venous thromboembolic disease SERPINA10 TGG-TGA

Venous thromboembolic disease SERPINA10 CGA-TGA

Thyroxine-binding globulin deficiency SERPINA7 TGG-TAG

Thyroxine-binding globulin deficiency SERPINA7 TGG-TGA

Antithrombin deficiency SERPINC1 TAT-TAA

Antithrombin deficiency SERPINC1 CGA-TGA

Antithrombin deficiency SERPINC1 TTA-TAA

Antithrombin deficiency SERPINC1 TAT-TAA

Antithrombin deficiency SERPINC1 TCA-TGA

Antithrombin deficiency SERPINC1 TGC-TGA

Antithrombin deficiency SERPINC1 CAG-TAG

Antithrombin deficiency SERPINC1 TGC-TGA

Antithrombin deficiency SERPINC1 GAG-TAG

Deep vein thrombosis SERPINC1

Angioneurotic oedema SERPING1 TCA-TGA

Angioneurotic oedema SERPING1 TGG-TGA

Angioneurotic oedema SERPING1 GAG-TAG

Angioneurotic oedema SERPING1 TGG-TGA

Angioneurotic oedema SERPING1 TCA-TGA

Angioneurotic oedema SERPING1 TAC-TAG

Angioneurotic oedema SERPING1 CAG-TAG

Angioneurotic oedema SERPING1 TGG-TAG

Angioneurotic oedema SERPING1 AAG-TAG

Angioneurotic oedema SERPING1 CAG-TAG

Angioneurotic oedema SERPING1 AAG-TAG

Angioneurotic oedema SERPING1 TTG-TAG

Angioneurotic oedema SERPING1 CAA-TAA

Angioneurotic oedema SERPING1 GAA-TAA

Surfactant protein B deficiency SFTPB TGG-TGA

Surfactant protein B deficiency SFTPB TGC-TGA

Muscular dystrophy, limb girdle SGCD GAA-TAA

Muscular dystrophy, limb girdle SGCD TGG-TAG

Muscular dystrophy, limb girdle SGCD CGA-TGA

Myoclonus dystonia SGCE GAA-TAA

Myoclonus dystonia SGCE TGG-TGA

Muscular dystrophy, limb girdle SGCG TGG-TGA

Sanfilippo syndrome A SGSH TAC-TAG

Sanfilippo syndrome A SGSH TGG-TAG

Lymphoproliferative syndrome, X-linked SH2D1A TGG-TAG

Holoprosencephaly SHH TGG-TAG

Holoprosencephaly SHH CAG-TAG

Holoprosencephaly SHH GAG-TAG

Leri-Weill dyschondrosteosis SHOX GAG-TAG

JK-null variant SLC14A1 CAA-TAA

Cataract, juvenile with microcornea and renal SLC16A12 CAG-TAG glucosuria

Monocarboxylate transporter 8 deficiency SLC16A2 CAA-TAA

Salla disease SLC17A5 TGG-TGA

Salla disease SLC17A5 TGG-TAG Sialic acid storage disease, infantile SLC17A5 TAT- TAG

Sialic acid storage disease, infantile SLC17A5 TGG- TAG

Megaloblastic anaemia, thiamine responsive SLC19A2 GAG- TAG

Organic cation transporter deficiency SLC22A4 CGA- TGA

Intrahepatic cholestasis, neonatal SLC25A13 CGA- TGA

HHH syndrome SLC25A15 CAG- TAG

HHH syndrome SLC25A15 CGA- TGA

Diarrhoea, congenital chloride SLC26A3 TTA- TGA

Diarrhoea, congenital chloride SLC26A3 CAA- TAA

Diarrhoea, congenital chloride SLC26A3 GGA- TGA

Glucose transporter 1 deficiency syndrome SLC2A1 CAG- TAG

Glucose transporter 1 deficiency syndrome SLC2A1 CGA- TGA

Glucose transporter 1 deficiency syndrome SLC2A1 TAC- TAA

Glucose transporter 1 deficiency syndrome SLC2A1 AAA- TAA

Fanconi-Bickel syndrome SLC2A2 CAG- TAG

Fanconi-Bickel syndrome SLC2A2 TGG- TAG

Fanconi-Bickel syndrome SLC2A2 CAG- TAG

Fanconi-Bickel syndrome SLC2A2 CGA- TGA

Fanconi-Bickel syndrome SLC2A2 TCA- TGA

Hereditary hypophosphataemic rickets with SLC34A3 CAG- TAG hypercalciuria

Acrodermatitis enteropathica SLC39A4 TTA- TGA

Acrodermatitis enteropathica SLC39A4 TGG- TGA

Cystinuria SLC3A1 CGA- TGA

Cystinuria SLC3A1 CAG- TAG

Spherocytosis SLC4A1 CAG- TAG

Spherocytosis SLC4A1 CGA- TGA

Spherocytosis SLC4A1 TGG- TGA

Spherocytosis SLC4A1 TAC- TAA

Corneal endothelial dystrophy 2 SLC4A11 CGA- TGA

Corneal endothelial dystrophy 2 SLC4A11 CAG- TAG

Corneal endothelial dystrophy 2 SLC4A11 TGG- TGA

Corneal endothelial dystrophy 2 SLC4A11 AGA- TGA

Corneal endothelial dystrophy 2 SLC4A11 CGA- TGA

Corneal endothelial dystrophy 2 SLC4A11 CAG- TAG

Corneal endothelial dystrophy 2 SLC4A11 CGA- TGA

Proximal renal tubular acidosis SLC4A4 CAG- TAG

Glucose / galactose malabsorption SLC5A1 CGA- TGA

Renal glucosuria SLC5A2 TGG- TGA

Iodide transport defect SLC5A5 TGC- TGA

Iodide transport defect SLC5A5 TAC- TAG

Hyperekplexia SLC6A5 TAC- TAA

Hyperekplexia SLC6A5 CAG- TAG

Creatine deficiency SLC6A8 CGA- TGA

Creatine deficiency SLC6A8 TAC- TAG

Lysinuric protein intolerance SLC7A7 CGA- TGA

Lysinuric protein intolerance SLC7A7 TGG- TGA

Lysinuric protein intolerance SLC7A7 CGA- TGA

Cystinuria, type I/III SLC7A9 GAG- TAG

Mai de Meleda SLURP1 CGA- TGA

Juvenile polyposis syndrome SMAD4 CGA- TGA

Pulmonary arterial hypertension SMAD9 TGC- TGA

Schimke immuno-osseous dysplasia SMARCALl GAG- TAG

Schimke immuno-osseous dysplasia SMARCALl TCA- TGA

Schimke immuno-osseous dysplasia SMARCALl TCG- TAG

Schimke immuno-osseous dysplasia SMARCALl GAG- TAG

Schimke immuno-osseous dysplasia SMARCALl CAG- TAG

Schimke immuno-osseous dysplasia SMARCALl CGA- TGA

Spinal muscular atrophy SM 1 CAA- TAA Spinal muscular atrophy SMN1 TGG-TAG

Spinal muscular atrophy SMN1 CAG-TAG

Niemann-Pick disease SMPD1 TTG-TAG

Amyotrophic lateral sclerosis SOD1 AAG-TAG

Sclerosteosis SOST CAG-TAG

Sclerosteosis SOST TGG-TGA

Sclerosteosis SOST CGA-TGA

PC H SOX10 CAG-TAG

PC H SOX10 TAC-TAG

Shah-Waardenburg syndrome and neuropathy SOX10 TCA-TGA

Hypotrichosis-Lymphoedema-Telangiectasia SOX18 TGC-TGA

Anophthalmia, hearing loss and brain abnormalities SOX2 CAG-TAG

Anophthalmia-oesophageal-genital syndrome SOX2 CAG-TAG

Campomelic dysplasia SOX9 TGG-TAG

Campomelic dysplasia SOX9 GAG-TAG

Campomelic dysplasia SOX9 CAG-TAG

Spastic paraplegia SPAST TTA-TGA

Spastic paraplegia, autosomal dominant SPAST CAA-TAA

Spastic paraplegia, autosomal dominant SPAST TAC-TAG

Spastic paraplegia, autosomal dominant SPAST TCA-TAA

Spastic paraplegia, autosomal dominant SPAST CGA-TGA

Spastic paraplegia, autosomal dominant SPAST AAA-TAA

Spastic paraplegia, autosomal dominant SPAST CGA-TGA

Spastic paraplegia, autosomal dominant SPAST AAA-TAA

Spastic paraplegia, autosomal dominant SPAST CAA-TAA

Spastic paraplegia, autosomal dominant SPAST TAC-TAA

Spastic paraplegia, autosomal dominant SPAST TCA-TGA

Spastic paraplegia, autosomal dominant SPAST AGA-TGA

Spastic paraplegia, autosomal dominant SPAST TCA-TGA

Spastic paraplegia, autosomal dominant SPAST CAA-TAA

Retiniitis pigmentosa, juvenile SPATA7 CGA-TGA

Leber congenital amaurosis IV SPATA7 CGA-TGA

Spastic paraplegia, autosomal recessive SPG11 CGA-TGA

Spastic paraplegia, autosomal recessive SPG11 TGG-TGA

Spastic paraplegia, autosomal recessive SPG11 CGA-TGA

Spastic paraplegia, autosomal recessive SPG11 CAG-TAG

Spastic paraplegia, autosomal recessive SPG11 CGA-TGA

Spastic paraplegia, autosomal recessive SPG11 TTA-TGA

Spastic paraplegia, autosomal recessive SPG11 TAC-TAA

Spastic paraplegia, autosomal recessive SPG11 TCA-TGA

Spastic paraplegia, autosomal recessive SPG11 CGA-TGA

Spastic paraplegia, autosomal recessive SPG11 GAG-TAG

Spastic paraplegia, autosomal recessive SPG11 CGA-TGA

Spastic paraplegia, autosomal recessive SPG11 TGG-TGA

Spastic paraplegia, autosomal recessive SPG11 TAC-TAG

Spastic paraplegia, autosomal recessive SPG11 TCA-TGA

Spastic paraplegia, autosomal recessive SPG11 CAG-TAG

Spastic paraplegia with thin corpus callosum SPG11 TAT-TAA

Netherton syndrome SPINK5 CGA-TGA

Neurofibromatosis 1-like syndrome SPRED1

Legius syndrome SPRED1

Cafe-au-lait macules SPRED1

Pyropoikilocytosis SPTA1 CGA-TGA

Spherocytosis SPTB CAG-TAG

Steroid-5 alpha-reductase deficiency SRD5A2 TGG-TAG

XY sex reversal SRY CAG-TAG

XY sex reversal SRY TAT-TAG XY sex reversal SRY CAG-TAG

XY sex reversal SRY TGG-TAG

Gonadal dysgenesis SRY TAT-TAA

Gonadal dysgenesis SRY TGG-TAG

Amish infantile epilepsy syndrome ST3GAL5 CGA-TGA

Congenital lipoid adrenal hyperplasia STAR TGG-TAG

Congenital lipoid adrenal hyperplasia STAR CAG-TAG

Growth hormone insensitivity STAT5B CGA-TGA

Gonadotrophin-independent precocious puberty STK11 AAG-TAG

Peutz-Jeghers syndrome STK11 TAC-TAA

Peutz-Jeghers syndrome STK11 AAG-TAG

Peutz-Jeghers syndrome STK11 TAC-TAA

Peutz-Jeghers syndrome STK11 CAG-TAG

Peutz-Jeghers syndrome STK11 CAA-TAA

Peutz-Jeghers syndrome STK11 CAG-TAG

Microphthalmia STRA6 CAG-TAG

Haemophagocytic lymphohistiocytosis, familial STX11 CAG-TAG

Glutaric aciduria 3 SUGCT CGA-TGA

Sulphite oxidase deficiency SUOX CAG-TAG

Sulphite oxidase deficiency suox TAC-TAG

Leigh syndrome SURF1 CAG-TAG

Leigh syndrome SURF1 TGG-TGA

Epilepsy SYN1 TGG-TAG

Schizophrenia syngrlc TGG-TAG

Corneal dystrophy, gelatinous drop-like TACSTD2 AAG-TAG

Tyrosinaemia 2 TAT CGA-TGA

Tyrosinaemia 2 TAT TCA-TGA

Barth syndrome TAZ CAG-TAG

Cardiomyopathy, X-linked infantile TAZ GAA-TAA

Amyotrophic lateral sclerosis TBK1

ACTH deficiency, isolated TBX19 CGA-TGA

Congenital heart disease TBX20 CAA-TAA

Cleft palate and ankyloglossia TBX22 GAG-TAG

Ulnar-mammary syndrome TBX3 AAA-TAA

Holt-Oram syndrome TBX5 GAA-TAA

Holt-Oram syndrome TBX5 TAC-TAA

Holt-Oram syndrome TBX5 CAG-TAG

Osteopetrosis, autosomal recessive TCIRG1 CAG-TAG

Osteopetrosis, autosomal recessive TCIRG1 CGA-TGA

Transcobalamin II deficiency TCN2 TAT-TAG

Treacher-Collins syndrome TCOF1 CGA-TGA

Treacher-Collins syndrome TCOF1 AAG-TAG

Treacher-Collins syndrome TCOF1 CAA-TAA

Haemochromatosis TFR2 CGA-TGA

Haemochromatosis TFR2 TAC-TAG

Goitre with hypothyroidism TG CGA-TGA

Goitre, simple TG CGA-TGA

Holoprosencephaly TGIF1 TAC-TAG

Ichthyosis, congenital, autosomal recessive TGM1 TAC-TAG

Ichthyosis, congenital, autosomal recessive TGM1 TCA-TGA

Ichthyosis, lamellar TGM1 TGG-TAG

Ichthyosis, congenital, autosomal recessive TGM1 CAG-TAG

Ichthyosis, congenital, autosomal recessive TGM1 CGA-TGA Dystonia THAP1

Thyroid hormone resistance THRB GAA-TAA

Epidermodysplasia verruciformis TMC6 GAG-TAG

Epidermodysplasia verruciformis TMC6 CGA-TGA

Epidermodysplasia verruciformis TMC6 TAC-TAA

Epidermodysplasia verruciformis TMC8 CGA-TGA

Epidermodysplasia verruciformis TMC8 TGG-TAG

Epidermodysplasia verruciformis TMC8 GAG-TAG

Enteropeptidase deficiency TMPRSS15 CAA-TAA

Enteropeptidase deficiency TMPRSS15 CGA-TGA

Enteropeptidase deficiency TMPRSS15 TCA-TGA

Microcytic anaemia & iron deficiency TMPRSS6 CGA-TGA

Microcytic anaemia & iron deficiency TMPRSS6 TAT-TAG

Li-Fraumeni syndrome TP53 CGA-TGA

Li-Fraumeni syndrome TP53 GAG-TAG

Multiple cancers TP53 CGA-TGA

Li-Fraumeni syndrome TP53 CAA-TAA

Osteosarcoma TP53 AGA-TGA

Adrenocortical carcinoma TP53 CGA-TGA

Split-hand/split-foot malformation TP63 CAG-TAG

Nemaline myopathy TPM3 CAG-TAG

Goitrous hypothyroidism TPO CAA-TAA

Neuronal ceroid lipofuscinosis, late infantile TPP1 CAG-TAG

Neuronal ceroid lipofuscinosis, late infantile TPP1 CGA-TGA

Neuronal ceroid lipofuscinosis, late infantile TPP1 CAG-TAG

Spondyloepiphyseal dysplasia tarda TPAPPC2 TCA-TAA

Spondyloepiphyseal dysplasia tarda TPAPPC2 TGG-TGA

Spondyloepiphyseal dysplasia tarda TPAPPC2 CGA-TGA

Spondyloepiphyseal dysplasia tarda TPAPPC2 TCG-TAG

Spondyloepiphyseal dysplasia tarda TPAPPC2 TTG-TAG

Deafness, non-syndromic TRIOBP CAG-TAG

Deafness, non-syndromic TRIOBP CGA-TGA

Deafness, non-syndromic TRIOBP CAG-TAG

Deafness, non-syndromic TRIOBP CGA-TGA

Hypomagnesaemia with secondary hypocalcaemia TRPM6 TAC-TAA

Tricho-rhino-phalangeal syndrome I TRPS1 TAC-TAG

Tricho-rhino-phalangeal syndrome I TRPS1 CGA-TGA

Tricho-rhino-phalangeal syndrome I TRPS1 TGC-TGA

Tricho-rhino-phalangeal syndrome I TRPS1 CGA-TGA

Tuberous sclerosis TSC1 TGG-TGA

Tuberous sclerosis TSC1 CAG-TAG

Tuberous sclerosis TSC1 TAC-TAA

Tuberous sclerosis TSC1 CGA-TGA

Tuberous sclerosis TSC1 TGG-TAG

Tuberous sclerosis TSC1 AGA-TGA

Tuberous sclerosis TSC1 CAG-TAG

Tuberous sclerosis TSC1 CAA-TAA

Tuberous sclerosis TSC1 CAG-TAG

Tuberous sclerosis TSC2 AAG-TAG

Tuberous sclerosis TSC2 TGG-TGA

Tuberous sclerosis TSC2 CGA-TGA

Tuberous sclerosis TSC2 CAG-TAG

Tuberous sclerosis TSC2 TCG-TAG

Tuberous sclerosis TSC2 CGA-TGA

Tuberous sclerosis TSC2 CAG-TAG

Tuberous sclerosis TSC2 GAG-TAG

Tuberous sclerosis TSC2 GAG-TAG Tuberous sclerosis TSC2 CAG-TAG

Tuberous sclerosis TSC2 CAG-TAG

Tuberous sclerosis TSC2 CGA-TGA

Tuberous sclerosis TSC2 TGT-TGA

Hypothyroidism TSHB GAA-TAA

Hyperthyroidism TSHR TAC-TAG

Tibial muscular dystrophy TTN CAA-TAA

Cardiomyopathy, dilated ttntvn2b CAG-TAG

Saethre-Chotzen syndrome TWIST1 TAC-TAG

Saethre-Chotzen syndrome TWIST1 CAG-TAG

Saethre-Chotzen syndrome TWIST1 GAG-TAG

Saethre-Chotzen syndrome TWIST1 GGA-TGA

Saethre-Chotzen syndrome TWIST1 GAG-TAG

Saethre-Chotzen syndrome TWIST1 TAC-TAA

Saethre-Chotzen syndrome TWIST1 TCG-TAG

Baller-Gerold syndrome TWIST1

Albinism, oculocutaneous 1 TYR TGG-TAG

Albinism, oculocutaneous 1A TYR GAG-TAG

Albinism, oculocutaneous 1 TYR CAG-TAG

Albinism, oculocutaneous 1 TYR CAA-TAA

Albinism, oculocutaneous 1 TYR TGG-TGA

Albinism, oculocutaneous 1 TYR CGA-TGA

Albinism, oculocutaneous 1 TYR TGG-TAG

Albinism, oculocutaneous 3 TYRP1 TCA-TGA

Hypotrichosis, Marie Unna type u2hr CAA-TAA

Hypotrichosis, Marie Unna type u2hr TCG-TAG

Angelman syndrome UBE3A CGA-TGA

Crigler-Naj j ar syndrome 1 UGT1A1 CAG-TAG

Crigler-Naj j ar syndrome 2 UGT1A1 TAC-TAG

Crigler-Naj j ar syndrome 1 UGT1A1 TGC-TGA

Crigler-Naj j ar syndrome 1 UGT1A1 CGA-TGA

Haemophagocytic lymphohistiocytosis, familial UNC13D CGA-TGA

Mental retardation UPF3B CGA-TGA

Porphyria, hepatoerythropoietic UROD CAG-TAG

Porphyria, cutanea tarda UROD CGA-TGA

Porphyria, cutanea tarda UROD TGG-TAG

Porphyria, cutanea tarda UROD TAC-TAG

Porphyria, erythropoietic UROS CAA-TAA

Usher syndrome lc USH1C CGA-TGA

Usher syndrome lg USH1G TGG-TAG

Usher syndrome 2a USH2A CGA-TGA

Usher syndrome 2a USH2A CAG-TAG

Usher syndrome 2a USH2A TGC-TGA

Retinitis pigmentosa, recessive, no hearing loss USH2A CAA-TAA

Usher syndrome 2 USH2A TGG-TGA

Rickets, vitamin D resistant VDR CGA-TGA

Rickets, vitamin D resistant VDR CAG-TAG

Von Hippel-Lindau syndrome VHL CAG-TAG

Von Hippel-Lindau syndrome VHL TAC-TAA

Von Hippel-Lindau syndrome VHL GAA-TAA

Von Hippel-Lindau syndrome VHL GAG-TAG

Von Hippel-Lindau syndrome VHL GAA-TAA

Von Hippel-Lindau syndrome VHL TGG-TAG

Von Hippel-Lindau syndrome VHL GAG-TAG Von Hippel-Lindau syndrome VHL TAC-TAG

Von Hippel-Lindau syndrome VHL GAG-TAG

Von Hippel-Lindau syndrome VHL CGA-TGA

Von Hippel-Lindau syndrome VHL CAG-TAG

Von Hippel-Lindau syndrome VHL TTA-TAA

Von Hippel-Lindau syndrome VHL TCG-TAG

Cerebellar hypoplasia and quadrupedal locomotion VLDLR CGA-TGA

Dysequilibrium syndrome VLDLR CGA-TGA

Chorea-acanthocytosis VPS13A CGA-TGA

Chorea-acanthocytosis VPS13A GAA-TAA

Chorea-acanthocytosis VPS13A TCA-TGA

Chorea-acanthocytosis VPS13A CGA-TGA

Chorea-acanthocytosis VPS13A TAC-TAG

Chorea-acanthocytosis VPS13A TGG-TGA

Chorea-acanthocytosis VPS13A TGG-TAG

Chorea-acanthocytosis VPS13A AAA-TAA

Chorea-acanthocytosis VPS13A CAG-TAG

Chorea-acanthocytosis VPS13A CGA-TGA

Cohen syndrome VPS13B TGG-TAG

Cohen syndrome VPS13B CGA-TGA

Cohen syndrome VPS13B TGC-TGA

Cohen syndrome VPS13B GAA-TAA

Cohen syndrome VPS13B CGA-TGA

Cohen syndrome VPS13B TCA-TGA

Cohen syndrome VPS13B GAG-TAG

Cohen syndrome VPS13B TGG-TGA

Von Willebrand disease 3 VWF CGA-TGA

Von Willebrand disease 3 VWF GAG-TAG

Von Willebrand disease 3 VWF CGA-TGA

Von Willebrand disease 3 VWF CAG-TAG

Von Willebrand disease 3 VWF GAG-TAG

Von Willebrand disease 3 VWF TAC-TAG

Von Willebrand disease 3 VWF TCA-TGA

Von Willebrand disease 3 VWF CGA-TGA

Von Willebrand disease 3 VWF CAG-TAG

Von Willebrand disease 3 VWF TGG-TGA

Von Willebrand disease 3 VWF TAC-TAA

Von Willebrand disease 3 VWF CAG-TAG

Von Willebrand disease 3 VWF TGC-TGA

Von Willebrand disease VWF CGA-TGA

Von Willebrand disease 3 VWF CGA-TGA

Von Willebrand disease 2n VWF CAA-TAA

Von Willebrand disease 3 VWF TTG-TAG

Von Willebrand disease 3 VWF CAG-TAG

Von Willebrand disease 3 VWF CAA-TAA

Von Willebrand disease 3 VWF GAG-TAG

Von Willebrand disease 3 VWF CGA-TGA

Von Willebrand disease 3 VWF TAC-TAA

Von Willebrand disease 3 VWF TGG-TGA Wiskott-Aldrich syndrome WAS CAG-TAG

Wiskott-Aldrich syndrome WAS TAC-TAA

Wiskott-Aldrich syndrome WAS CAG-TAG

Wiskott-Aldrich syndrome WAS GAG-TAG

Wiskott-Aldrich syndrome WAS CAG-TAG

Wiskott-Aldrich syndrome WAS TGG-TGA

Wiskott-Aldrich syndrome WAS CAA-TAA

Wiskott-Aldrich syndrome WAS GAG-TAG

Wiskott-Aldrich syndrome WAS CAG-TAG

Wiskott-Aldrich syndrome WAS GAG-TAG

Wiskott-Aldrich syndrome WAS GGA-TGA

Wiskott-Aldrich syndrome WAS TCA-TGA

Wiskott-Aldrich syndrome WAS CGA-TGA

Wiskott-Aldrich syndrome WAS CAG-TAG

Wolfram syndrome WFS1 TAC-TAG

Wolfram syndrome WFS1 TGG-TGA

Wolfram syndrome WFS1 TGG-TAG

Wolfram syndrome WFS1 CAG-TAG

Wolfram syndrome WFS1 TGG-TAG

Wolfram syndrome WFS1 TAC-TAG

Wolfram syndrome WFS1 CAG-TAG

Wolfram syndrome WFS1 TAC-TAA

Wolfram syndrome WFS1 CAG-TAG

Wolfram syndrome WFS1 GAG-TAG

Wolfram syndrome WFS1 TGG-TAG

Wolfram syndrome WFS1 GAG-TAG

Neuropathy, hereditary sensory, type II wnkltv3 CGA-TGA

Odonto-onycho-dermal dysplasia WNT10A GAG-TAG

Tetra-amelia WNT3 CAG-TAG

Werner syndrome WRN CGA-TGA

Werner syndrome WRN CAG-TAG

Wi1ms tumour WT1 CAG-TAG

Renal dysfunction & renal blastema WT1 CAG-TAG

Wi1ms tumour WT1 TAC-TAA

Wi1ms tumour WT1 CAG-TAG

Wi1ms tumour WT1 AGA-TGA

Wi1ms tumour WT1 TGC-TGA

Wi1ms tumour WT1 CGA-TGA

Wi1ms tumour WT1 TCG-TAG

Wi1ms tumour WT1 CAG-TAG

Wi1ms tumour WT1 CGA-TGA

Xanthinuria, type 1 XDH AAG-TAG

Xanthinuria, type 1 XDH CGA-TGA

Xeroderma pigmentosum (A) XPA CGA-TGA

Xeroderma pigmentosum (A) XPA TAT-TAA

Xeroderma pigmentosum (A) XPA CGA-TGA

Xeroderma pigmentosum (C) XPC CGA-TGA

Xeroderma pigmentosum (C) XPC AAA-TAA

Xeroderma pigmentosum (C) XPC CGA-TGA

Xeroderma pigmentosum (C) XPC AAG-TAG

Xeroderma pigmentosum (C) XPC CAG-TAG Xeroderma pigmentosum (C) XPC GAA-TAA

Xeroderma pigmentosum (C) XPC CGA-TGA

Posterior polymorphous corneal dystrophy ZEB1 TAC-TAG

Posterior polymorphous corneal dystrophy ZEB1 CAG-TAG

Posterior polymorphous corneal dystrophy ZEB1 CGA-TGA

Posterior polymorphous corneal dystrophy ZEB1 CAA-TAA

Posterior polymorphous corneal dystrophy ZEB1 GAA-TAA

Mowat-Wilson syndrome ZEB2 CAG-TAG

Mowat-Wilson syndrome ZEB2 GAA-TAA

Mowat-Wilson syndrome ZEB2 TAC-TAA

Mowat-Wilson syndrome ZEB2 TAC-TAG

Mowat-Wilson syndrome ZEB2 CAG-TAG

Mowat-Wilson syndrome ZEB2 GAA-TAA

Mowat-Wilson syndrome ZEB2 AAA-TAA

Mowat-Wilson syndrome ZEB2 TAC-TAG

Mowat-Wilson syndrome ZEB2 TTA-TGA

Mowat-Wilson syndrome ZEB2 CAG-TAG

Mowat-Wilson syndrome ZEB2 TCG-TAG

Mowat-Wilson syndrome ZEB2 CAG-TAG

Mowat-Wilson syndrome ZEB2 AGA-TGA

Mowat-Wilson syndrome ZEB2 CGA-TGA

Cardiac malformation ZIC3 AAG-TAG

Situs abnormality ZIC3 CAG-TAG

Situs abnormality ZIC3 TGC-TGA

Cardiac malformation ZIC3 TCA-TAA

Cardiac malformation ZIC3 CAG-TAG

Mental retardation, X-linked ZNF674 GAA-TAA

Table 4: Short List of Medical Conditions Associated with PTC

[00285] Compounds of general formulas (I), (IV) or (V), or Tables 1, 2 or 5, may be used in combination with one or more other PTC-RCs, preferably an aminoglycoside, in methods disclosed herein. Compounds of general formulas (I), (IV) or (V), or Tables 1, 2 or 5, may exhibit maximal and synergistic effects when used in combination with an aminoglycoside. Accordingly, in one aspect, the disclosure relates to methods of using compounds of general formulas (I), (IV) or (V), or Tables 1, 2 or 5, as described herein, in combination with one or more aminoglycosides. In certain embodiments, the aminoglycoside is a natural aminoglycoside. In certain embodiments, the aminoglycoside is an aminoglycoside fraction or component. In certain embodiments, the aminoglycoside is a synthetic aminoglycoside. In certain embodiments, the aminoglycoside is G418. In certain embodiments, the aminoglycoside is gentamicin. In certain embodiments, the aminoglycoside is X2. In certain embodiments, the aminoglycoside is B l . In one embodiment, the combination further comprises a steroid.

[00286] In certain embodiments, a PTC-RC of general formulas (I), (IV) or (V), or Tables 1, 2 or 5, may be used in combination with another non-aminoglycoside active agent known in the art to promote readthrough of PTCs. Examples of such other compounds include, but are not limited to, Ataluren and compounds described in International Patent Application Publication Nos. WO 2004/009533; WO 2004/009558; WO 2004/009609; WO 2004/009610; WO 2004/091502; WO 2006/044502; WO 2006/0044503; WO 2006/044505; WO 2006/044456; WO 2006/044682; WO 2008/130370; WO 2012/021707 and WO 2013/142346. In one embodiment, the combination further comprises an aminoglycoside. In one embodiment, the combination further comprises a steroid.

[00287] Examples of aminoglycosides include, but are not limited to, G418, gentamicin, tobramycin, amikacin, netilmicin, paromomycin, hygromycin, neomycin, kanamycin and streptomycin, and fractions or components thereof, including but not limited to gentamicin X2 and gentamicin B 1. In some embodiments, in the described methods, the compound of general formula (I), (IV) or (V), or Table 1, 2 or 5, is used in combination with gentamicin. In some embodiments, in the described methods, the compound of general formulas(I), (IV) or (V), or Table 1, 2 or 5, is used in combination with G418. In some embodiments, in the described methods, the compound of general formula (I), (IV) or (V), or Table 1, 2 or 5, is used in combination with X2. In some embodiments, in the described methods, the compound of general formula (I), (IV) or (V), or Table 1, 2 or 5, is used in combination with Bl .

[00288] In certain embodiments, compounds of general formulas (I), (IV) or (V), or Tables 1, 2 or 5, act to potentiate the PTC readthrough activity of an aminoglycoside. In some embodiments, such potentiation observed with the use of the combination of a compound of general formulas (I), (IV) or (V), or Tables 1, 2 or 5, and an aminoglycoside may allow for lower aminoglycoside dosage. This may in turn allow for a reduction in side effects or toxicity and/or for a less frequent dosing schedule, for example. Accordingly, when a compound of general formulas (I), (IV) or (V), or Tables 1, 2 or 5, is used in the described methods in combination with an aminoglycoside, the amount of the compound of general formulas (I), (IV) or (V), or Tables 1, 2 or 5, and/or the amount of aminoglycoside that is used may be an effective amount in such combination yet may be less than an effective amount as used alone. In certain embodiments, the aminoglycoside is a natural aminoglycoside. In certain embodiments, the aminoglycoside is an aminoglycoside fraction or component. In certain embodiments, the aminoglycoside is a synthetic aminoglycoside. In certain embodiments, the aminoglycoside is G418. In certain embodiments, the aminoglycoside is gentamicin. In certain embodiments, the aminoglycoside is X2. In certain embodiments, the aminoglycoside is Bl .

PHARMACEUTICAL KITS

[00289] Certain embodiments of the disclosure relate to pharmaceutical kits or packs containing a compound of general formulas (I), (IV) or (V), or Tables 1, 2 or 5, or a pharmaceutical composition comprising a compound of general formulas (I), (IV) or (V), or Tables 1, 2 or 5. In those embodiments in which the compounds of general formulas (I), (IV) or (V), or Tables 1, 2 or 5, are intended for use as part of a combination therapy, the kit may optionally contain the other therapeutic(s) that makes up the combination. [00290] Individual components of the kit may be packaged in separate containers and, associated with such containers, can be a notice in the form prescribed by a governmental agency regulating the manufacture, use or sale of pharmaceuticals or biological products, which notice reflects approval by the agency of manufacture, for use or sale for human or animal administration. If appropriate, one or more components of the kit may be lyophilized or provided in a dry form, such as a powder or granules, and the kit can additionally contain a suitable solvent for reconstitution of the lyophilized or dried component(s).

[00291] In those embodiments in which the compound of general formula (I), (IV) or (V), or Table 1, 2 or 5, is included in the kit in the form of a pharmaceutical composition suitable for administration to a subject, the container may optionally be itself in a form allowing for administration to a subject, for example, an inhaler, syringe, pipette, eye dropper, pre-soaked gauze or pad, or other such like apparatus, from which the composition may be administered to the subject.

[00292] Kits of the invention may include additional compounds. In certain embodiments, kits include one or more aminoglycosides. In certain embodiments, kits include a natural aminoglycoside. In certain embodiments, kits include an aminoglycoside fraction or component. In certain embodiments, kits include a synthetic aminoglycoside. In certain embodiments, kits include G418. In certain embodiments, kits include gentamicin. In certain embodiments, kits include gentamicin X2. In certain embodiments, kits include gentamicin Bl . In one embodiment, kits include a steroid.

ADDITIONAL PTC READTHROUGH COMPOSITIONS

[00293] US2013/0274283 describes certain compounds having the ability to promote readthrough of PTCs. For example, compounds according to Formula III, Formula IV, Formula V, Formula VI, Formula VII, or combinations thereof, as described in US2013/0274283 may be used in the present invention in combination with PTC-RCs of general formulas (I), (IV) or (V), or Tables 1, 2 or 5, as described herein. In one embodiment, non-aminoglycoside PTC-RC compounds, or compounds particularly described in US2013/0274283, are used in place of aminoglycosides in the present compositions and methods in combination with PTC-RCs of general formulas (I), (IV) or (V), or Tables 1, 2 or 5. Thus, in certain embodiments, the invention provides compositions and methods, including but not limited to pharmaceutical compositions, pharmaceutical kits, and methods of promoting readthrough at a PTC, involving the use of or comprising a compound disclosed in US2013/0274283. In certain embodiments, compound RTC-13 as disclosed in US2013/0274283 is used. In certain embodiments, compound RTC-14 as disclosed in US2013/0274283 is used. Methods for producing such PTC readthrough compounds are disclosed in US 2013/0274283.

[00294] In certain embodiments, the PTC readthrough compound has the following chemical formula:

[00295] In certain embodiments, the PTC readthrough compound has the following chemical formula:

[00296] In one aspect, the disclosure provides a pharmaceutical composition comprising a combination of a PTC-RC, for example those disclosed in US2013/0274283, and a compound of general formulas (I), (IV) or (V), or Tables 1, 2 or 5, as disclosed herein. In certain embodiments, the PTC-RC is a compound according to Formula III, Formula IV, Formula V, Formula VI, or Formula VII as described in US2013/0274283. In certain embodiments, the PTC-RC is RTC-13 disclosed in US2013/0274283. In cerain embodiments, the PTC-RC is RTC-14 disclosed in US2013/0274283.

[00297] In one embodiment, a non-aminoglycoside PTC-RC, which PTC-RC is aminoglycosidase-like in its mechanism of action, is used in place of aminoglycosides in the present compositions and methods in combination with PTC-RCs of general formulas (I), (IV) or (V), or Tables 1, 2 or 5. [00298] In one embodiment, a PTC-RC that is an aminoglycocide analogue is used in place of a natural aminoglycoside, for example gentamicin, in the present compositions and methods in combination with PTC-RCs of general formulas (I), (IV) or (V), or Tables 1, 2 or 5.

[00299] In certain embodiments, the pharmaceutical composition further comprises an aminoglycoside. In certain embodiments, the aminoglycoside is a natural aminoglycoside. In certain embodiments, the aminoglycoside is an aminoglycoside fraction or component. In certain embodiments, the aminoglycoside is a synthetic aminoglycoside. In certain embodiments, the aminoglycoside is G418. In certain embodiments, the aminoglycoside is gentamicin. In certain embodiments, the aminoglycoside is X2. In certain embodiments, the aminoglycoside is Bl . [00300] In certain embodiments, a pharmaceutical composition of the invention further comprises a steroid.

[00301] Such pharmaceutical compositions find use in the methods disclosed herein for pharmaceutical compositions comprising a compound of general formulas (I), (IV) or (V), or Tables 1, 2 or 5, herein. [00302] In one aspect, the disclosure provides methods of using a composition comprising a combination of a PTC-RC, for example those disclosed in US2013/0274283 and a compound of general formulas (I), (IV) or (V), or Tables 1, 2 or 5, herein, to promote readthrough of a PTC. In certain embodiments, the PTC-RC is a compound according to Formula III, Formula IV, Formula V, Formula VI, or Formula VII as described in US2013/0274283. In certain embodiments, the PTC-RC is RTC-13 disclosed in US2013/0274283. In cerain embodiments, the PTC-RC is RTC- 14 disclosed in US2013/0274283.

[00303] In certain embodiments, the composition used further comprises an aminoglycoside. In certain embodiments, the aminoglycoside is a natural aminoglycoside. In certain embodiments, the aminoglycoside is an aminoglycoside fraction or component. In certain embodiments, the aminoglycoside is a synthetic aminoglycoside. In certain embodiments, the aminoglycoside is G418. In certain embodiments, the aminoglycoside is gentamicin. In certain embodiments, the aminoglycoside is X2. In certain embodiments, the aminoglycoside is Bl .

[00304] In certerain embodiments, the composition used further comprises a steroid. EXAMPLES

[00305] To gain a better understanding of the invention described herein, the following examples are set forth. It will be understood that these examples are intended to describe illustrative embodiments of the invention and are not intended to limit the scope of the invention in any way. Compounds mentioned in the present examples are shown in Tables 1 & 2 above. [00306] ¾ and ¹³C NMR spectra were recorded with Bruker Avance III™ 400 MHz or Bruker Avance II+. Analytical thin-layer chromatography (TLC) was performed on aluminum plates pre- coated with silica gel 60F-254 as the absorbent. The developed plates were air-dried, exposed to UV light and/or dipped in KMn0₄ solution and heated. Column chromatography was performed with silica gel 60 (230-400 mesh). Automated flash chromatography was carried out on Biotage Isolera Flash Purification Systems using commercial 50 μπι silica gel cartridges. All the Chemicals were of analytical grade or better and were purchased commercial suppliers. The following compounds were purchased from Enamine Screening Libraries 53 (item # Z 16394905), 54 (item # Z15555244), and, 71 (item # Z16106997).

LIST OF ABBREVIATIONS:

ACN Acetonitrile

Ac₂0 acetic anhydride

AcCl acetyl chloride

AcOH Acetic acid

Cat. catalytic

cone. concentrated

DCM Dichloromethane

DIEA Diisopropylethylamine

DMAP 4-dimethlaminopyridine

DMF N,N-dimethylformamide

DMSO Dimethylsulfoxide

Et₂0 Ditheyl ether

Et₃N Triethylamine

EtOAc Ethyl Acetate

EtOH Ethanol

h hour

HATU (l-[Bis(dimethylamino)methylene]-lH-l,2,3-triazolo[4,5-b]pyridinium

hexafluorophosphate) MeOH Methanol

min minutes

rt Room temperature

sat. saturated

t-BuOH tert-butanol

THF Tetrahydrofuran

EXAMPLE 1: Synthesis and characterization of compounds 1, 5, 6, 8, 10, 18-28, 30-35, 38- 41, 48-52, 56-58, 60-66, 72, 73, 75, 77-96, 100, 101, X-1, Y-1, Z-1

, 90,

91, 95, 101, X-1 , Y-1, Z-1

Compound R R² R³ R⁴ R⁵ R⁶ R⁷ R⁸ R⁹

1 CI H H H CI H H H H

6 H CI CI H H H H H H

18 CN H H H H H H H H

19 CI H H H CI H CI CI H

26 H CI H H H H H H H

30 CI H H H H H H H H

38 CI CF₃ H H CI H H H H

39 CI H H H F H H H H

40 F H H CI F H H H H

63 CH₃ H H H H H H H H

66 CI H H H CI NO2 H H H

77 F F H F F H H H H

78 F H H F F H H H H

79 Br H H H F H H H H

80 H H CI H H H H H H

90 H H F H H H H H H

91 F H H H F H H H H

95 H H CH₃ H H H H H H

101 F F F F F H H H H

X-1 H NO2 CH₃ H H H H H H

Y-1 H NO2 H H H H H H H

Z-1 CH₃ NO2 H H H H H H H

31

5, 8, 10, 20-24, 27, 28, 32, 33, 35, 41 , 60-62, 64, 65, 72, 73, 75, 81 -89, 92-94, 96, 00

Compound n X Y Z R² R⁵ R⁶ R⁷ R⁸ R⁹

5 1 C-CI C-H C-H C-H CI H CI H H

8 1 C-CI C-H C-H CF₃ H H H H H

21 1 C-H C-F C-F H H H H H H

22 1 C-F C-H C-H F H H H H H

23 1 C-F C-H C-H CF₃ H H H H H

24 1 C-H C-H C-F CF₃ H H H H H

27 1 C-CI C-H C-H H CI H CI H H

28 1 C-CI C-H C-H H CI OH H H H

32 1 C-H N C-H H H H H H H

33 1 N C-H N H H H H H H

35 1 C-CI C-H C-CI H H H H H H

41 1 C-CI C-H C-H C-H CI F H H F

60 1 C-OCHs C-H C-H H H H H H H

61 1 C-H C-OCHs C-H H H H H H H

62 1 C-H C-OH C-H H H H H H H

64 1 C-OCHs C-F C-H H H H H H H

65 1 C-H C-OCHs C-H C-OCHs H H H H H

72 1 C-OCHs C-H C-H C-H OCH3 H H H H

73 1 C-CH3 C-H C-H H CH₃ H H H H

75 1 C-H C-CI C-H CI H NO2 H H H

81 1 C-CI C-H C-CI H H NO2 H H H

82 1 C-H C-H C-H OCH3 H H H H H

83 1 C-F C-H C-H H H H H H H

84 1 C-H C-H C-H F H H H H H

85 1 C-H C-H C-F F H H H H H

86 1 C-F C-H C-H C-CF3 H H H H H

87 1 C-F C-F C-H H H H H H H

88 1 C-OCHs C-OCHs C-H H H H H H H 89 1 C-H C-OCHs C-H C-F H H H H H

92 2 C-H C-OCH3 C-H OCH3 H H H H H

93 2 C-CI C-H C-H H CI H H H H

94 2 C-H C-CI C-H H H H H H H

96 1 C-Br C-H C-F H H H H H H

100 1 C-CI C-H C-CF3 H H NO2 H H H

49 R¹⁴=R¹⁵=H

51 R¹⁴/R¹⁵=-(CH₂)₄-

52 R¹⁴/R¹⁵=-(CH₂)₆- 57 R¹⁵=Ph, R¹⁵=H

50 X = CH₂

56 X = 0 General procedures for the coupling reactions: Unless otherwise noted, the following compounds were synthesized according to the general procedures A to F.

Procedure A: A mixture of appropriate benzyl halide (1 mmol) and potassium phthalimide (1 mmol) in DMF (1.5 mL) was heated at 120 °C under nitrogen for 2-3 h. The product was then precipitated out by addition of water (5 mL) to the mixture. The solids were filtered and washed with water. The solids were dried under vacuum to give the pure compound. If the product was not pure, it was purified by recrystallization from ethanol.

Procedure B: To a solution of phthalic anhydride (1 mmol) in acetic acid (2 mL) was added appropriate benzyl amine or phenethylamine (1 mmol). The mixture was then heated at 100 °C under nitrogen for 3-4 h. After sitting at rt overnight, the solution yielded crystals that were collected by filtration and washed with ethanol. If the product was not crystallized from the solution, it was precipitated out by pouring the solution onto ice/water (5 mL). The precipitate was filtered and washed with ethanol. If the product was not pure, it was purified by recrystallization from ethanol.

Procedure C: A mixture of the appropriate benzyl amine (1 mmol) and the appropriate cyclic anhydride (1 mmol) in AcOH (2 mL) was heated at 105 °C until completion of reaction (up to 24 h). Upon cooling to room temperature, the resultant precipitate was filtered, washed with H₂0:EtOH (1 : 1) and dried to give the desired product in 30-80% yield. Further purification, if required, can be performed via recrystallization in EtOH or via preparative HPLC.

Procedure D: A mixture of the appropriate imide (1 mmol), 2,6-dichlorobenzyl bromide (1 mmol), K₂C0₃ (2 mmol), and KI (cat.) in DMF (0.5 M) was heated at 60 °C to 100 °C until completion of the reaction (24 to 48 h). The reaction mixture was quenched with H₂0:EtOH (1 : 1) and the resultant precipitate was filtered, washed with EtOH and dried to give the desired product in 50-80% yield.

Procedure E: A mixture of the appropriate anhydride (1 mmol) and the appropriate amine (1 mmol) in THF (5 mL) was stirred at room temperature for 2 h. The reaction mixture was concentrated and acetic anhydride (2 mL) was added and the reaction was heated at 100 °C for 2 h. The reaction mixture was quenched with sat. NaHC0₃ and extracted with EtOAc. Purification via preperative HPLC gave the desired product in 30-40% yield.

Procedure F: A mixture of the appropriate anhydride (1 mmol) and the appropriate amine (1 mmol) in toluene (5 mL) was heated at 100 °C for 24 h. The reaction mixture was concentrated and acetic anhydride (2 mL) was added and the reaction was heated at 100 °C for 24 h. The reaction mixture was quenched with sat. NaHC0₃ and extracted with EtOAc. The crude material was recrystallized in EtOH to give the desired product in 30% yield.

2-(2,6-dichlorobenzyl)isoindoline-l,3-dione (1): Compound 1 was prepared from 2,6- dichlorobenzyl bromide and potassium phthalimide using general Procedure A. Yield = 67%, off white solid. ¾ NMR (400 MHz, CDC1₃) δ 7.84 - 7.77 (m, 2H), 7.74 - 7.66 (m, 2H), 7.33 (d, J = 8.0 Hz, 2H), 7.19 (dd, J = 8.5, 7.6 Hz, 1H), 5.14 (s, 2H). ¹³C NMR (101 MHz, CDC1₃) δ 167.68 (s), 136.63 (s), 134.16 (s), 131.97 (s), 130.85 (s), 129.74 (s), 128.59 (s), 123.46 (s), 38.38 (s).

5-chloro-2-(2,6-dichlorobenzyl)isoindoline-l,3-dione (5): Compound 5 was prepared from 4- chlorophthalic anhydride and 2,6-dichlorobenzylamine using general Procedure C. ¾ NMR (400 MHz, DMSO- e) δ 7.96 - 7.83 (m, 3H), 7.52 - 7.45 (m, 2H), 7.38 (dd, J= 8.8, 7.3 Hz, 1H), 5.02 (s, 2H). ¹³C NMR (101 MHz, DMSO) δ 166.65, 166.28, 139.91, 135.95, 135.09, 134.89, 133.72, 131.10, 130.86, 130.29, 129.18, 125.43, 123.82, 123.64, 38.54.

2-(3,4-dichlorobenzyl)isoindoline-l,3-dione (6): Compound 6 was prepared from 3,4- dichlorobenzyl chloride and potassium phthalimide using general Procedure A. Yield = 55%, white solid. ¾ NMR (400 MHz, CDC1₃) δ 7.86 (dd, J = 5.4, 3.1 Hz, 2H), 7.73 (dd, J = 5.5, 3.1 Hz, 2H), 7.52 (d, J= 2.0 Hz, 1H), 7.39 (d, J= 8.2 Hz, 1H), 7.28 (dd, J= 8.5, 2.2 Hz, 1H), 4.79 (s, 2H). ¹³C NMR (101 MHz, CDC1₃) δ 167.95 (s), 136.52 (s), 134.37 (s), 132.08 (s), 130.81 (s), 130.76 (s), 128.21 (s), 123.68 (s), 40.65 (s).

2-(2-chloro-5-(trifluoromethyl)benzyl)isoindoline-l,3-dione (8): Compound 8 was prepared from 2-chloro-5-(trifluoromethyl)benzyl amine and phthalic anhydride using general Procedure B. Yield = 20%, white solid. ¾ NMR (400 MHz, CDC1₃) δ 7.91 (dd, J = 5.3, 3.2 Hz, 2H), 7.78 (dd, J = 4.1, 3.0 Hz, 2H), 7.51 (t, J = 9.4 Hz, 3H), 5.02 (s, 2H). ¹³C NMR (101 MHz, CDC1₃) δ 167.90 (s), 137.10 (s), 134.70 (s), 134.50 (s), 131.97 (s), 130.41 (s), 129.61 (q, J= 33.0 Hz), 125.97 (p, J= 3.8 Hz), 123.82 (s), 39.34 (s). 2-(3-methoxyphenethyl)isoindoline-l,3-dione (10): Compound 10 was prepared from 3- Methoxy-2-phenylethylamine and phthalic anhydride using general Procedure B. Yield = 81%, white solid ¾ NMR (400 MHz, CDC1₃) δ 7.83 (dd, J= 5.4, 3.0 Hz, 2H), 7.71 (dd, J= 5.4, 3.1 Hz, 2H), 7.20 (t, J= 7.8 Hz, 1H), 6.85 (d, J= 7.4 Hz, 1H), 6.81 - 6.71 (m, 2H), 3.93 (dd, J= 8.6, 6.9 Hz, 2H), 3.77 (s, 3H), 3.02 - 2.88 (m, 2H). ¹³C NMR (101 MHz, CDCb) δ 168.32 (s), 159.87 (s), 139.70 (s), 134.06 (s), 132.24 (s), 129.69 (s), 123.38 (s), 121.35 (s), 114.43 (s), 112.45 (s), 55.32 (s), 39.33 (s), 34.81 (s).

2-((l,3-dioxoisoindolin-2-yl)methyl)benzonitrile (18): Compound 18 was prepared from 2- (Bromom ethyl )benzonitrile and potassium phthalimide using general Procedure A. Yield = 61%, pale yellow solid. ¾ NMR (400 MHz, CDCb) δ 7.89 (dd, J= 5.5, 3.1 Hz, 2H), 7.76 (dd, J= 5.5, 3.1 Hz, 2H), 7.68 (dd, J = 7.4, 1.4 Hz, 1H), 7.57 - 7.50 (m, 1H), 7.37 (t, J = 7.6 Hz, 2H), 5.10 (s, 2H). ¹³C NMR (101 MHz, CDCb) δ 167.82 (s), 139.67 (s), 134.47 (s), 133.27 (s), 133.23 (s), 132.01 (s), 128.34 (s), 128.32 (s), 123.80 (s), 117.24 (s), 112.04 (s), 39.80 (s). 5,6-dichloro-2-(2,6-dichlorobenzyl)isoindoline-l,3-dione (19): Compound 19 was prepared from 4,5-dichlorophthalimide and 2,6-dichlorobenzyl bromide using general Procedure D. ¾ NMR (400 MHz, Chloroform- ) δ 7.90 (s, 2H), 7.35 (d, J= 8.0 Hz, 2H), 7.23 (dd, J= 8.7, 7.4 Hz, 1H), 5.16 (s, 2H). ¹³C NMR (107 MHz, CDCb) δ 165.51, 139.03, 136.46, 130.93, 130.18, 129.82' ^8.53, 125.45, 38.62. 2-(3-(trifluoromethyl)benzyl)isoindoline-l,3-dione (20): Compound 20 was prepared from 3- (trifluoromethyl)benzyl amine and phthalic anhydride using general Procedure B. Yield = 25%, white solid ¾ NMR (400 MHz, CDCb) δ 7.87 (dd, J= 5.4, 3.1 Hz, 2H), 7.73 (dd, J= 5.5, 3.0 Hz, 2H), 7.69 (s, 1H), 7.62 (d, J= 7.6 Hz, 1H), 7.54 (d, J= 7.8 Hz, 1H), 7.44 (t, J= 7.7 Hz, 1H), 4.89 (s, 2H). ¹³C NMR (101 MHz, CDCb) δ 167.89 (s), 137.21 (s), 134.19 (s), 132.16 - 131.93 (m), 131.98 (s), 131.10 (q, J = 32.3 Hz), 129.22 (s), 125.44 (q, J = 3.8 Hz), 124.79 (q, J = 3.8 Hz), 123.54 (s), 41.15 (s).

2-(3,4-difluorobenzyl)isoindoline-l,3-dione (21): Compound 21 was prepared from 3,4- difluorobenzyl amine and phthalic anhydride using general Procedure B. Yield = 42%, off white solid. ¾ NMR (400 MHz, CDCb) δ 7.86 (dd, J = 5.4, 3.1 Hz, 2H), 7.73 (dd, J = 5.4, 3.1 Hz, 2H), 7.31 - 7.23 (m, 2H), 7.17 (s, 1H), 7.14 - 7.05 (m, 1H), 4.79 (s, 2H). ¹³C NMR (101 MHz, CDCb) δ 167.96 (s), 150.34 (dd, J= 249.1, 12.8 Hz), 150.15 (dd, J = 248.6, 12.6 Hz), 134.31 (s), 133.35 (dd, J= 5.4, 4.0 Hz), 132.07 (s), 124.99 (dd, J= 6.4, 3.7 Hz), 123.61 (s), 117.94 (d, J= 17.6 Hz), 117.56 (d, J= 17.4 Hz), 40.74 (d, J= 1.1 Hz). 2-(2,5-difluorobenzyl)isoindoline-l,3-dione (22): Compound 22 was prepared from 2,5- difluorobenzyl amine and phthalic anhydride using general Procedure B. Yield = 64%, off white solid. ¾ NMR (400 MHz, CDCb) δ 7.88 (dd, J = 5.4, 3.1 Hz, 2H), 7.75 (dd, J = 5.5, 3.1 Hz, 2H), 7.08 - 6.98 (m, 2H), 6.97 - 6.88 (m, 1H), 4.91 (s, 2H). ¹³C NMR (101 MHz, CDCb) δ 168.13 (s), 159.16 (dd, J= 211.6, 2.5 Hz), 156.75 (dd, J = 212.5, 2.5 Hz), 134.66 (s), 132.35 (s), 125.20 (dd, J= 17.4, 7.6 Hz), 123.97 (s), 117.07 (dd, J= 24.5, 8.7 Hz), 116.76 (dd, J= 24.9, 4.2 Hz), 116.35 (dd, J= 24.0, 8.5 Hz), 35.50 (d, J= 4.4 Hz).

2-(2-fluoro-5-(trifluoromethyl)benzyl)isoindoline-l,3-dione (23): Compound 23 was prepared from 2-fluoro-5(trifluoromethyl)benzyl amine and phthalic anhydride using general Procedure B. Yield = 14%, white solid. ¾ NMR (400 MHz, CDCb) δ 7.89 (dd, J= 5.4, 3.1 Hz, 2H), 7.75 (dd, J = 5.5, 3.0 Hz, 2H), 7.63 (d, J = 6.6 Hz, 1H), 7.59 - 7.52 (m, 1H), 7.17 (t, J = 8.9 Hz, 1H), 4.96 (s, 2H). ¹³C NMR (101 MHz, CDCb) δ 167.81 (s), 162.52 (d, J = 254.2 Hz), 134.42 (s), 132.01 (s), 127.92 (dq, J= 7.7, 3.8 Hz), 127.27 (dq, J= 9.2, 3.7 Hz), 124.37 (d, J= 15.8 Hz), 123.76 (s), 116.44 (d, J= 23.0 Hz), 35.14 (d, J= 4.5 Hz). 2-(3-fluoro-5-(trifluoromethyl)benzyl)isoindoline-l,3-dione (24): Compound 24 was prepared from 3-fluoro-5-(trifluoromethyl)benzyl amine and phthalic anhydride using general Procedure B. Yield = 27%, off white solid. ¾ NMR (400 MHz, CDCb) δ 7.88 (dd, J= 5.4, 3.1 Hz, 2H), 7.75 (dd, J= 5.5, 3.0 Hz, 2H), 7.49 (s, 1H), 7.33 (d, J= 8.7 Hz, 1H), 7.25 (d, J= 11.1 Hz, 1H), 4.88 (s, 2H). ¹³C NMR (101 MHz, CDCb) δ 167.87 (s), 162.65 (d, J= 249.8 Hz), 140.02 (d, J = 7.3 Hz), 134.45 (s), 133.03 (qd, J = 33.4, 8.1 Hz), 123.18 (qd, J = 272.6, 3.0 Hz), 131.98 (s), 123.76 (s), 121.28 (p, J = 3.6 Hz), 1 19.28 (d, J = 21.9 Hz), 112.57 (dq, J = 24.5, 3.8 Hz), 40.85 (d, J = 1.5 Hz).

2-(naphthalen-l-ylmethyl)isoindoline-l,3-dione (25): Compound 25 was prepared from 1- (chloromethyl)naphthalene and potassium phthalimide using general Procedure A. Yield = 56%, white solid. ¾ NMR (400 MHz, CDCb) δ 8.37 (d, J= 8.4 Hz, 1H), 7.88 - 7.82 (m, 3H), 7.80 (d, J= 8.2 Hz, 1H), 7.74 - 7.69 (m, 2H), 7.64 - 7.56 (m, 2H), 7.54 - 7.47 (m, 1H), 7.43 (dd, J= 8.0, 7.3 Hz, 1H), 5.34 (s, 2H). ¹³C NMR (101 MHz, CDCb) δ 168.40 (s), 134.19 (s), 133.90 (s), 132.20 (s), 131.48 (s), 131.31 (s), 128.87 (s), 128.81 (s), 127.44 (s), 126.67 (s), 125.96 (s), 125.42 (s), 123.61 (s), 123.53 (s), 39.67 (s). 2-(3-chlorobenzyl)isoindoline-l,3-dione (26): Compound 26 was prepared from 3-chlorobenzyl bromide and potassium phthalimide using general Procedure A. Yield = 67%, creamy white solid. ¾ NMR (400 MHz, CDCh) δ 7.86 (dd, J= 5.5, 3.0 Hz, 2H), 7.72 (dd, J= 5.4, 3.1 Hz, 2H), 7.41 (s, 1H), 7.34 - 7.29 (m, 1H), 7.26 - 7.22 (m, 2H), 4.81 (s, 2H). ¹³C NMR (101 MHz, CDCb) δ 168.03 (s), 138.34 (s), 134.65 (s), 134.27 (s), 132.16 (s), 130.11 (s), 128.79 (s), 128.24 (s), 126.90 (s), 123.62 (s), 41.17 (s).

2-(2,6-dichlorobenzyl)-5-methylisoindoline-l,3-dione (27): Compound 27 was prepared from 4-methylphthalic anhydride and 2,6-dichlorobenzylamine using general Procedure C. ¾ NMR (400 MHz, Chloroform- ) δ 7.71 (d, J = 7.6 Hz, 1H), 7.65 - 7.60 (m, 1H), 7.51 (dt, J = 7.6, 1.1 Hz, 1H), 7.34 (d, J = 8.0 Hz, 2H), 7.20 (dd, J = 8.6, 7.4 Hz, 1H), 5.14 (s, 2H), 2.52 (s, 3H). ¹³C NMR (101 MHz, CDCb) δ 167.71, 167.63, 145.28, 136.48, 134.55, 132.24, 130.86, 129.53, 129.27, 128.45, 123.86, 123.23, 38.19, 22.03.

2- (2,6-dichlorobenzyl)-4-hydroxyisoindoline-l,3-dione (28): Compound 28 was prepared from

3- hydroxyphthalic anhydride and 2,6-dichlorobenzylamine using general Procedure C. ¾ NMR (400 MHz, Chloroform- ) δ 7.65 - 7.54 (m, 2H), 7.42 - 7.33 (m, 3H), 7.24 (dd, J = 8.7, 7.4 Hz,

1H), 7.17 (d, J= 8.4 Hz, 1H), 5.13 (s, 2H). ¹³C NMR (101 MHz, CDCb) δ 169.76, 166.98, 154.73, 136.50, 136.45, 131.80, 130.44, 129.78, 128.51, 122.73, 116.08, 114.39, 38.12.

2-(2-chlorobenzyl)isoindoline-l,3-dione (30): Compound 30 was prepared from 2-chlorobenzyl bromide and potassium phthalimide using general Procedure A. Yield = 65%, white solid. ¾ NMR (400 MHz, CDCb) δ 7.89 (dd, J = 5.4, 3.1 Hz, 2H), 7.75 (dd, J = 5.4, 3.1 Hz, 2H), 7.40 - 7.35 (m, 1H), 7.24 - 7.14 (m, 3H), 5.00 (s, 2H). ¹³C NMR (101 MHz, CDCb) δ 168.05 (s), 134.31 (s), 133.47 (s), 133.16 (s), 132.12 (s), 129.81 (s), 129.00 (s), 128.71 (s), 127.03 (s), 123.64 (s), 39.49 (s).

2-(quinolin-2-ylmethyl)isoindoline-l,3-dione (31): Compound 31 was prepared from 2- (bromomethyl)quinoline and potassium phthalimide using general Procedure A. Yield = 54%, light yellow solid. ¾ NMR (400 MHz, CDCb) δ 8.11 (d, J = 8.5 Hz, 1H), 7.98 (d, J = 8.5 Hz, 1H), 7.94 - 7.89 (m, 2H), 7.80 - 7.73 (m, 3H), 7.65 (t, J = 7.6 Hz, 1H), 7.49 (t, J = 7.5 Hz, 1H), 7.37 (d, J= 8.5 Hz, 1H), 5.20 (s, 2H). ¹³C NMR (101 MHz, CDCb) δ 168.37 (s), 155.51 (s), 148.33 - 147.37 (m), 137.13 (s), 134.22 (s), 132.40 (s), 129.75 (s), 129.52 (s), 127.60 (s), 127.48 (s), 126.58 (s), 123.67 (s), 43.78 (s).

2-(pyridin-4-ylmethyl)isoindoline-l,3-dione (32): Compound 32 was prepared from pyridin-4- ylmethanamine and phthalic anhydride using general Procedure B. Yield = 70%, white solid. ¾ NMR (400 MHz, CDCb) δ 8.56 (d, J = 6.0 Hz, 2H), 7.88 (dd, J = 5.4, 3.1 Hz, 2H), 7.75 (dd, J = 5.4, 3.1 Hz, 2H), 7.29 (d, J= 5.9 Hz, 2H), 4.85 (s, 2H). ¹³C NMR (101 MHz, CDCb) δ 167.97 (s), 151.15 (s), 144.36 (s), 143.81 (s), 134.30 (s), 132.14 (s), 123.69 (s), 40.73 (s).

2-(pyrazin-2-ylmethyl)isoindoline-l,3-dione (33): Compound 33 was prepared from 2- aminomethylpyrazine and phthalic anhydride using general Procedure B. Yield = 72%, light brown solid. ¾ NMR (400 MHz, CDCb) δ 8.68 (s, 2H), 8.51 (s, 4H), 7.92 (dd, J = 5.4, 3.1 Hz, 4H), 7.78 (dd, J = 5.5, 3.1 Hz, 4H), 7.29 (s, 2H), 5.08 (s, 2H). ¹³C NMR (101 MHz, CDCb) δ 167.84 (s), 150.28 (s), 144.91 (s), 134.39 (s), 131.94 (s), 123.67 (s), 123.02 (s), 40.55 (s).

1- ((2,6-dichlorobenzyl)oxy)isoquinolin-3-ol (34): Compound 34 was prepared from 1,2,3,4- Tetrahydroisoquinoline-l,3-dione and 2,6-dichlorobenzyl bromide using general Procedure D. ¾ NMR (400 MHz, DMSO-d₆) δ 11.56 (s, 1H), 7.95 (dd, J= 7.8, 1.5 Hz, 1H), 7.38 - 7.28 (m, 4H), 7.28 - 7.13 (m, 3H), 6.84 - 6.68 (m, 1H), 4.18 - 3.77 (m, 4H). ¹³C NMR (101 MHz, DMSO) δ 176.01, 164.37, 140.64, 136.70, 133.62, 132.55, 130.13, 129.12, 128.93, 128.11, 127.87, 125.36, 53.38, 41.16.

2- (2,5-dichlorobenzyl)isoindoline-l,3-dione (35): Compound 35 was prepared from 2,5- dichlorobenzyl amine and phthalic anhydride using general Procedure B. Yield = 91%, off white solid. ¾ NMR (400 MHz, CDCb) δ 7.94 - 7.88 (m, 2H), 7.80 - 7.75 (m, 2H), 7.31 (d, J= 8.4 Hz, 1H), 7.22 - 7.13 (m, 2H), 4.95 (s, 2H). ¹³C NMR (101 MHz, CDCb) δ 167.92 (s), 135.28 (s), 134.47 (s), 133.04 (s), 132.00 (s), 131.42 (s), 130.91 (s), 129.11 (s), 128.55 (s), 123.81 (s), 39.17 (s). 2-(2,6-dichloro-3-(trifluoromethyl)benzyl)isoindoline-l,3-dione (38): Compound 38 was prepared from 2-(bromomethyl)-l,3-dichloro-4-(trifluoromethyl)benzene and potassium phthalimide using general Procedure A. Yield = 40%, white solid. ¾ NMR (400 MHz, CDCb) δ 7.82 (dd, J= 5.4, 3.0 Hz, 2H), 7.72 (dd, J= 5.3, 3.1 Hz, 2H), 7.61 (d, J= 8.6 Hz, 1H), 7.46 (d, J = 8.5 Hz, 1H), 5.20 (s, 2H). ¹³C NMR (101 MHz, Chloroform- ) δ 167.55 (s) , 140.74 (s), 134.93 (s), 134.32 (s), 133.37 (s), 131.86 (s), 128.28 (s), 127.99 (s), 127.77 (q, J = 5.6 Hz), 123.57 (s), 122.63 (q, J= 273.4 Hz), 38.42 (s).

2-(2-chloro-6-fluorobenzyl)isoindoline-l,3-dione (39): Compound 39 was prepared from 2- (bromomethyl)-l-chloro-3-fluorobenzene and potassium phthalimide using general Procedure A. Yield = 65%, light brown solid. ¾ NMR (400 MHz, CDCb) δ 7.83 (dd, J = 5.4, 3.1 Hz, 2H), 7.70 (dd, J = 5.4, 3.0 Hz, 2H), 7.25 - 7.16 (m, 2H), 6.99 (dd, J = 13.2, 5.5 Hz, 1H), 5.03 (s, 2H). ¹³C NMR (101 MHz, CDCb) δ 167.63 (s), 162.16 (d, J = 251.4 Hz), 135.53 (d, J = 5.0 Hz), 134.15 (s), 132.07 (s), 129.94 (d, J= 9.9 Hz), 125.61 (d, J= 3.5 Hz), 123.49 (s), 121.46 (d, J= 16.0 Hz), 114.37 (d, J= 22.8 Hz), 34.00 (d, J= 4.2 Hz).

2-(3-chloro-2,6-difluorobenzyl)isoindoline-l,3-dione (40): Compound 40 was prepared from 2- (bromomethyl)-4-chloro-l,3-difluorobenzene and potassium phthalimide using general Procedure A. Yield = 35%, light brown solid. ¾ NMR (400 MHz, CDCh) δ 7.84 (dd, J = 5.4, 3.1 Hz, 1H), 7.72 (dd, J= 5.5, 3.1 Hz, 1H), 7.31 (td, J= 8.6, 5.7 Hz, 1H), 6.86 (td, J= 8.9, 1.7 Hz, 1H), 4.96 (s, 1H). ¹³C NMR (101 MHz, CDCb) δ 167.42 (s), 159.94 (dd, J= 250.9, 6.3 Hz), 156.94 (dd, J= 252.7, 7.8 Hz), 134.27 (s), 132.03 (s), 130.28 (d, J= 10.0 Hz), 123.60 (s), 116.95 (dd, J = 18.4, 4.1 Hz), 113.39 (t, J= 17.2 Hz), 112.11 (dd, J= 23.5, 4.2 Hz), 30.45 (s).

2-(2,6-dichlorobenzyl)-4,7-difluoroisoindoline-l,3-dione (41): Compound 41 was prepared from 3,6-difluorophthalic anhydride and 2,6-dichlorobenzylamine using general Procedure C. ¾ NMR (400 MHz, Chloroform- ) δ 7.48 - 7.31 (m, 4H), 7.22 (dd, J = 8.7, 7.4 Hz, 1H), 5.15 (s, 2H). ¹³C NMR (101 MHz, CDCb) δ 163.07, 155.00, 154.96, 152.37, 152.33, 136.52, 130.01, 129.85, 128.52, 125.06, 124.93, 124.88, 124.75, 38.50.

2-(2,6-dichlorobenzyl)-3-hydroxyisoquinolin-l(2H)-one (48): Compound 48 was prepared from l,2,3,4-Tetrahydroisoquinoline-l,3-dione and 2,6-dichlorobenzyl bromide using general Procedure D. ¾ NMR (400 MHz, DMSO- e) δ 11.43 (s, 1H), 7.95 - 7.81 (m, 1H), 7.72 - 7.59 (m, 1H), 7.52 (ddd, J= 10.4, 7.2, 1.9 Hz, 2H), 7.37 - 7.28 (m, 2H), 7.23 (dd, J= 9.0, 6.9 Hz, 1H), 6.32 (s, 1H), 3.59 - 3.38 (m, 2H). ¹³C NMR (101 MHz, DMSO) δ 175.57, 164.26, 142.79, 137.43, 133.96, 131.11, 130.01, 128.87, 128.69, 127.29, 126.97, 125.16, 75.32, 44.88. 1- (2,6-dichlorobenzyl)pyrrolidine-2,5-dione (49): Compound 49 was prepared from succinic anhydride and 2,6-dichlorobenzylamine using general Procedure C. ¾ MR (400 MHz, Chloroform- ) δ 7.37 - 7.31 (m, 2H), 7.20 (dd, J= 8.7, 7.4 Hz, 1H), 4.98 (s, 2H), 2.73 (s, 4H). ¹³C NMR (101 MHz, CDCb) δ 176.25, 136.31, 130.18, 129.56, 128.47, 38.94, 28.12. l-(2,6-dichlorobenzyl)piperidine-2,6-dione (50): Compound 50 was prepared from glutaric anhydride and 2,6-dichlorobenzylamine using general Procedure E. ¾ NMR (400 MHz, Methanol-^) δ 7.44 (d, J= 8.1 Hz, 2H), 7.31 (dd, J= 8.8, 7.4 Hz, 1H), 4.68 (s, 2H), 2.30 (dt, J = 24.4, 7.5 Hz, 4H), 1.92 (q, J= 7.5 Hz, 2H). ¹³C NMR (101 MHz, MeOD) δ 136.11, 132.96, 129.69, 128.26, 38.91, 34.43, 32.96, 21.09. 2-(2,6-dichlorobenzyl)-2-azaspiro[4.4]nonane-l,3-dione (51): Compound 51 was prepared from 2-Azaspiro[4.4]nonane-l,3-dione and 2,6-dichlorbenzyl bromide using general Procedure D. ¾ NMR (400 MHz, Chloroform- ) δ 7.33 (d, J= 8.0 Hz, 2H), 7.19 (dd, J= 8.6, 7.4 Hz, 1H), 4.98 (s, 2H), 2.60 (s, 2H), 2.12 (ddd, J= 13.5, 7.4, 3.2 Hz, 2H), 1.90 (tt, J= 9.6, 2.8 Hz, 2H), 1.69 (dddd, J = 17.8, 14.1, 6.1, 2.5 Hz, 4H). ¹³C NMR (101 MHz, CDCb) δ 182.30, 175.32, 136.27, 130.42, 129.47, 128.47, 50.19, 43.73, 39.00, 38.30, 25.28.

2- (2,6-dichlorobenzyl)-2-azaspiro[4.5]decane-l,3-dione (52): Compound 52 was prepared from 2-Azaspiro[4.5]decane-l,3-dione and 2,6-dichlorobenzyl bromide using general Procedure D. ¾ NMR (400 MHz, Chloroform- ) δ 7.33 (d, J= 8.0 Hz, 2H), 7.19 (dd, J= 8.7, 7.4 Hz, 1H), 4.96 (s, 2H), 2.56 (s, 2H), 1.92 - 1.65 (m, 5H), 1.52 (d, J = 12.6 Hz, 2H), 1.44 - 1.19 (m, 3H). ¹³C NMR (101 MHz, CDCb) δ 181.97, 175.33, 136.27, 130.43, 129.47, 128.46, 44.91, 40.09, 38.85, 33.34, 24.97, 22.09.

4-(2,6-dichlorobenzyl)morpholine-3,5-dione (56): Compound 56 was prepared from glycolic anhydride and 2,6-dichlorobenzylamine using general Procedure E. ¾ NMR (400 MHz, Chloroform- ) δ 7.33 (d, J= 8.0 Hz, 2H), 7.18 (t, J= 8.1 Hz, 1H), 5.26 (s, 2H), 4.38 (s, 4H). ¹³C NMR (101 MHz, CDCb) δ 168.87, 136.06, 131.12, 129.29, 128.63, 67.82, 38.75. l-(2,6-dichlorobenzyl)-3-phenylpyrrolidine-2,5-dione (57): Compound 57 was prepared from phenylsuccinic anhydride and 2,6-dichlorobenzylamine using general Procedure F. ¾NMR (400 MHz, Chloroform- ) δ 7.45 - 7.30 (m, 5H), 7.28 - 7.16 (m, 3H), 5.05 (s, 2H), 4.03 (dd, J = 9.7, 5.0 Hz, 1H), 3.23 (dd, J= 18.5, 9.7 Hz, 1H), 2.88 (dd, J= 18.5, 5.1 Hz, 1H). ¹³C NMR (101 MHz, CDC1₃) 5 176.73, 175.14, 136.94, 136.37, 130.10, 129.65, 129.15, 128.49, 127.93, 127.54, 45.88, 39.31, 37.01.

3-(2,6-dichlorobenzyl)-3-azabicyclo[3.1.0]hexane-2,4-dione (58): Compound 58 was prepared from 3-oxabicyclo[3.1.0]hexane-2,4-dione and 2,6-dichlorobenzylamine using general Procedure C. ¾ NMR (400 MHz, Methanol-^) δ 7.44 - 7.35 (m, 2H), 7.28 (dd, J = 8.8, 7.3 Hz, 1H), 4.81 (s, 2H), 2.53 (dd, J= 8.1, 3.6 Hz, 2H), 1.55 (td, J= 8.0, 4.4 Hz, 1H), 1.43 (q, J= 3.8 Hz, 1H). ¹³C NMR (101 MHz, MeOD) δ 174.74, 135.94, 130.49, 129.59, 129.57, 128.27, 128.25, 37.45, 19.88, 19.52. 2-(2-methoxybenzyl)isoindoline-l,3-dione (60): Compound 60 was prepared from 2- methoxybenzylamine and phthalic anhydride using general Procedure B. Yield = 70%, white solid. ¾ NMR (400 MHz, CDCb) δ 7.86 (dd, J = 5.4, 3.1 Hz, 2H), 7.71 (dd, J = 5.5, 3.0 Hz, 2H), 7.23 (td, J = 8.0, 1.7 Hz, 1H), 7.17 (d, J = 7.3 Hz, 1H), 6.88 (dd, J = 12.3, 4.7 Hz, 2H), 4.91 (s, 2H), 3.85 (s, 3H). ¹³C NMR (101 MHz, CDCb) δ 168.26 (s), 157.20 (s), 134.03 (s), 132.36 (s), 128.89 (s), 128.56 (s), 124.26 (s), 123.42 (s), 120.52 (s), 110.55 (s), 55.58 (s), 37.04 (s).

2-(4-methoxybenzyl)isoindoline-l,3-dione (61): Compound 61 was prepared from 4- methoxybenzylamine and phthalic anhydride using general Procedure B. Yield = 63%, white solid. ¾ NMR (400 MHz, CDCb) δ 7.83 (dd, J= 5.4, 3.1 Hz, 2H), 7.69 (dd, J= 5.4, 3.0 Hz, 2H), 7.38 (d, J= 8.6 Hz, 2H), 6.84 (d, J= 8.6 Hz, 2H), 4.78 (s, 2H), 3.77 (s, 3H). ¹³C NMR (101 MHz, CDCb) δ 168.21 (s), 159.33 (s), 134.05 (s), 132.30 (s), 130.28 (s), 128.79 (s), 123.41 (s), 114.12 (s), 55.39 (s), 41.19 (s).

2-(4-hydroxybenzyl)isoindoline-l,3-dione (62): Compound 62 was prepared from 4- hydroxybenzylamine and phthalic anhydride using general Procedure B. Yield = 56%, white solid. ¾ NMR (400 MHz, CDCb) δ 7.87 - 7.81 (m, 2H), 7.72 - 7.65 (m, 2H), 7.34 (d, J= 8.2 Hz, 2H), 6.76 (d, J = 8.3 Hz, 2H), 4.78 (s, 1H), 4.77 (s, 2H). ¹³C NMR (101 MHz, CDCb) δ 162.79 (s), 133.96 (s), 132.16 (s), 130.39 (s), 128.85 (s), 123.33 (s), 119.37 (s), 115.43 (s), 41.04 (s).

2-(2-methylbenzyl)isoindoline-l,3-dione (63): Compound 63 was prepared from 2- methylbenzylamine and potassium phthalimide using general Procedure A. Yield = 52%, creamy white solid. ¾ NMR (400 MHz, CDCb) δ 7.86 (dd, J = 5.4, 3.1 Hz, 2H), 7.72 (dd, J = 5.5, 3.1 Hz, 2H), 7.26 (s, 1H), 7.19 - 7.09 (m, 3H), 4.87 (s, 2H), 2.49 (s, 3H). ¹³C NMR (101 MHz, CDCb) δ 168.02 (s), 135.86 (s), 133.97 (s), 133.84 (s), 131.93 (s), 130.28 (s), 128.03 (s), 127.52 (s), 125.96 (s), 123.18 (s), 39.01 (s), 19.25 (s). 2-(4-fluoro-2-methoxybenzyl)isoindoline-l,3-dione (64): Compound 64 was prepared from 4- fluoro-2-methoxybenzylamine and phthalic anhydride using general Procedure B. Yield = 21%, off white solid. ¾ NMR (400 MHz, CDCb) δ 7.85 (dd, J= 5.4, 3.1 Hz, 2H), 7.72 (dd, J= 5.4, 3.1 Hz, 2H), 7.21 - 7.13 (m, 1H), 6.63 - 6.52 (m, 2H), 4.85 (s, 2H), 3.83 (s, 3H). ¹³C NMR (101 MHz, CDCb) δ 168.21 (s), 163.37 (d, J = 245.5 Hz), 158.38 (d, J = 9.9 Hz), 134.10 (s), 132.29 (s), 129.93 (d, J= 10.1 Hz), 123.45 (s), 120.01 (d, J= 3.3 Hz), 106.76 (d, J = 21.4 Hz), 99.07 (d, J = 25.9 Hz), 55.86 (s), 36.59 (s).

2-(3,4-dimethoxybenzyl)isoindoline-l,3-dione (65): Compound 65 was prepared from 3,4- dimethoxybenzylamine and phthalic anhydride using general Procedure B. Yield = 75%, white solid. ¾ NMR (400 MHz, CDCb) δ 7.84 (dd, J = 5.4, 3.1 Hz, 2H), 7.70 (dd, J = 5.5, 3.0 Hz, 2H), 7.09 - 6.98 (m, 2H), 6.80 (d, J = 8.7 Hz, 1H), 4.78 (s, 2H), 3.86 (d, J = 13.9 Hz, 6H). ¹³C NMR (101 MHz, CDCb) δ 168.25 (s), 149.11 (s), 148.83 (s), 134.10 (s), 132.30 (s), 129.18 (s), 123.47 (s), 121.48 (s), 112.26 (s), 111.21 (s), 56.04 (s), 41.62 (s).

2-(2,6-dichlorobenzyl)-4-nitroisoindoline-l,3-dione (66): Compound 66 was prepared form 3- nitrophthalic anhydride and 2,6-dichlorobenzylamine using general Procedure C. ¾ NMR (400 MHz, Chloroform- ) δ 8.12 (ddd, J = 7.3, 6.2, 0.9 Hz, 2H), 7.93 (t, J = 7.8 Hz, 1H), 7.36 (d, J = 8.0 Hz, 2H), 7.24 (dd, J = 8.7, 7.4 Hz, 1H), 5.20 (s, 2H). ¹³C NMR (101 MHz, CDCb) δ 164.96, 162.03, 136.50, 135.37, 133.91, 129.94, 129.90, 128.69, 128.59, 127.13, 123.50, 38.86.

2-(2,6-dimethoxybenzyl)isoindoline-l,3-dione (72): Compound 72 was prepared from 2,6- dimethoxybenzylamine and phthalic anhydride using general Procedure B. Yield = 33%, white solid. ¹³C NMR (101 MHz, CDCb) δ 168.13 (s), 159.04 (s), 133.67 (s), 132.47 (s), 129.21 (s), 123.05 (s), 111.97 (s), 103.92 (s), 56.06 (s), 31.76 (s). ¹³C NMR (101 MHz, CDCb) δ 168.13 (s), 159.04 (s), 133.67 (s), 132.47 (s), 129.21 (s), 123.05 (s), 111.97 (s), 103.92 (s), 56.06 (s), 31.76 (s). 2-(2,6-dimethylbenzyl)isoindoline-l,3-dione (73): Compound 73 was prepared from 2,6- dimethylbenzylamine and phthalic anhydride using general Procedure B. Yield = 33%, white solid. ¾ NMR (400 MHz, CDCb) δ 7.80 (dd, J = 5.4, 3.1 Hz, 2H), 7.69 (dd, J = 5.5, 3.0 Hz, 1H), 7.10 (dd, J= 8.3, 6.6 Hz, 1H), 7.03 (d, J= 7.5 Hz, 1H), 4.89 (s, 1H), 2.44 (s, 3H). ¹³C MR (101 MHz, CDCI3) δ 167.88 (s), 137.84 (s), 133.78 (s), 131.70 (s), 131.45 (s), 128.28 (s), 127.69 (s), 123.04 (s), 37.10 (s), 20.33 (s).

2-(3,4-dichlorobenzyl)-4-nitroisoindoline-l,3-dione (75): Compound 75 was prepared from 3,4- dichlorobenzylamine and 3-nitrophthalic anhydride using general Procedure B. Yield = 91%, off white solid. ¾ NMR (400 MHz, CDCb) δ 8.13 (d, J= 7.8 Hz, 2H), 7.93 (t, J= 7.8 Hz, 1H), 7.53 (d, J= 1.9 Hz, 1H), 7.40 (d, J= 8.2 Hz, 1H), 7.30 (dd, J= 8.2, 1.9 Hz, 1H), 4.81 (s, 2H). ¹³C MR (101 MHz, CDCb) δ 165.43 (s), 162.54 (s), 135.75 (s), 135.53 (s), 134.05 (s), 133.01 (s), 132.71 (s), 131.06 (s), 130.94 (s), 128.99 (s), 128.56 (s), 127.47 (s), 41.33 (s).

2-(2,3,5,6-tetrafluorobenzyl)isoindoline-l,3-dione (77): Compound 77 was prepared from 2,3,5,6-tetrafluorobenzyl bromide and potassium phthalimide using general Procedure A. Yield = 60%, white solid. ¾ MR (400 MHz, CDCb) δ 7.86 (dd, J = 5.5, 3.1 Hz, 2H), 7.74 (dd, J = 5.5, 3.1 Hz, 2H), 7.11 - 6.94 (m, 1H), 5.00 (s, 2H). ¹³C NMR (101 MHz, CDCb) δ 167.30 (s), 145.92 (dddd, J= 248.6, 14.3, 9.9, 4.1 Hz), 145.21 (dddd, J= 249.2, 14.1, 5.3, 4.0 Hz), 134.42 (s), 131.95 (s), 123.71 (s), 115.07 (d, J= 15.6 Hz), 106.07 (t, J= 22.5 Hz), 30.36 (s).

2-(2,3,6-trifluorobenzyl)isoindoline-l,3-dione (78): Compound 78 was prepared from 2,3,6- trifluorobenzyl bromide and potassium phthalimide using general Procedure A. Yield = 55%, pale yellow solid. ¾ NMR (400 MHz, CDCb) δ 7.85 (dd, J= 5.4, 3.1 Hz, 2H), 7.72 (dd, J = 5.5, 3.0 Hz, 2H), 7.08 (qd, J= 9.2, 5.0 Hz, 1H), 6.82 (tdd, J= 9.1, 3.6, 2.3 Hz, 1H), 4.97 (s, 2H). ¹³C NMR (101 MHz, CDCb) δ 167.30 (s), 156.64 (ddd, J= 247.1, 5.3, 2.8 Hz), 149.25 (ddd, J= 252.8, 14.8, 8.1 Hz),147.06 (ddd, J = 245.1, 13.0, 3.7 Hz), 134.15 (s), 131.91 (s), 123.48 (s), 116.69 (dd, J = 19.3, 10.1 Hz), 113.54 (d, J= 14.6 Hz), 110.73 (ddd, J= 24.4, 6.4, 4.2 Hz), 30.22 (d, J= 2.0 Hz).

2-(2-bromo-6-fluorobenzyl)isoindoline-l,3-dione (79): Compound 79 was prepared from 2- bromo-6-fluorobenzyl bromide and potassium phthalimide using general Procedure A. Yield = 55%, light brown solid. ¾ NMR (400 MHz, CDCb) δ 7.89 - 7.79 (m, 2H), 7.73 - 7.67 (m, 2H), 7.38 (d, J= 8.0 Hz, 1H), 7.16 (dd, J= 14.6, 7.5 Hz, 1H), 7.04 (t, J= 9.0 Hz, 1H), 5.04 (s, 2H). ¹³C MR QOl MHz, CDCb) δ 167.62 (s), 162.02 (d, J = 252.4 Hz), 134.14 (s), 132.04 (s), 130.39 (d, J = 9.6 Hz), 128.90 (d, J = 3.5 Hz), 125.14 (d, J = 4.2 Hz), 123.47 (s), 122.98 (d, J = 15.5 Hz), 114.98 (d, J= 22.9 Hz), 36.63 (d, J= 3.9 Hz). 2-(4-chlorobenzyl)isoindoline-l,3-dione (80): Compound 80 was prepared from 4-chlorobenzyl bromide and potassium phthalimide using general Procedure A. Yield = 62%, off white solid. ¾ NMR (400 MHz, CDCb) δ 7.85 (dd, J = 5.5, 3.1 Hz, 2H), 7.71 (dd, J = 5.5, 3.0 Hz, 2H), 7.40 - 7.35 (m, 2H), 7.31 - 7.27 (m, 2H), 4.81 (s, 2H). ¹³C NMR (101 MHz, CDCb) δ 167.94 (s), 134.81 (s), 134.11 (s), 133.80 (s), 132.04 (s), 130.11 (s), 128.86 (s), 123.44 (s), 40.94 (s). 2-(2,5-dichlorobenzyl)-4-nitroisoindoline-l,3-dione (81): Compound 81 was prepared from 2,5- dichlorobenzylamine and 3-nitrophthalic anhydride using general Procedure B. Yield = 40%, yellow solid. ¾ NMR (400 MHz, CDCb) δ 8.16 (d, J= 8.0 Hz, 2H), 7.96 (t, J= 7.8 Hz, 1H), 7.32 (d, J= 8.4 Hz, 1H), 7.22 (dd, J= 11.2, 2.8 Hz, 2H), 4.98 (s, 2H). ¹³C NMR (101 MHz, CDCb) δ 165.38 (s), 162.48 (s), 135.81 (s), 134.42 (s), 134.06 (s), 133.14 (s), 131.70 (s), 131.06 (s), 129.58 (s), 129.40 (s), 129.08 (s), 127.56 (s), 123.83 (s), 39.90 (s).

2-(3-methoxybenzyl)isoindoline-l,3-dione (82): Compound 82 was prepared from 3- methoxybenzylamine and phthalic anhydride using general Procedure B. Yield = 70%, off white solid. ¾ NMR (400 MHz, CDCb) δ 7.85 (dd, J = 5.4, 3.1 Hz, 2H), 7.71 (dd, J = 5.5, 3.0 Hz, 2H), 7.23 (t, J = 7.9 Hz, 1H), 7.01 (d, J = 7.6 Hz, 1H), 6.99 - 6.95 (m, 1H), 6.81 (dd, J = 8.3, 2.0 Hz, 1H), 4.82 (s, 2H), 3.79 (s, 3H). ¹³C NMR (101 MHz, CDCb) δ 168.48 (s), 160.24 (s), 138.28 (s), 134.45 (s), 132.59 (s), 130.17 (s), 123.82 (s), 121.26 (s), 114.49 (s), 113.89 (s), 55.70 (s), 42.02 (s).

2-(2-fluorobenzyl)isoindoline-l,3-dione (83): Compound 83 was prepared from 2- fluorobenzylamine and phthalic anhydride using general Procedure B. Yield = 87%, off white solid. ¾ NMR (400 MHz, CDCb) δ 7.87 (dd, J = 5.4, 3.1 Hz, 2H), 7.73 (dd, J = 5.5, 3.0 Hz, 2H), 7.34 (t, J = 7.6 Hz, 1H), 7.26 (s, 3H), 7.13 - 7.01 (m, 2H), 4.94 (s, 2H). ¹³C NMR (101 MHz, CDCb) δ 167.99 (s), 160.75 (d, J = 248.1 Hz), 134.22 (s), 132.20 (s), 130.24 (d, J = 3.8 Hz), 129.71 (d, J = 8.1 Hz), 124.33 (d, J = 3.7 Hz), 123.59 (s), 115.72 (d, J = 21.4 Hz), 35.49 (d, J = 4.8 Hz). 2-(3-fluorobenzyl)isoindoline-l,3-dione (84): Compound 84 was prepared from 3- fluorobenzylamine and phthalic anhydride using general Procedure B. Yield = 65%, off white solid. ¾ NMR (400 MHz, CDCb) δ 7.86 (dd, J = 5.4, 3.1 Hz, 2H), 7.72 (dd, J = 5.5, 3.0 Hz, 2H), 7.26 (s, 2H), 7.20 (d, J= 7.8 Hz, 1H), 7.13 (dd, J= 9.5, 2.1 Hz, 1H), 6.96 (td, J= 8.1, 1.7 Hz, 1H), 4.83 (s, 2H). ¹³C NMR (101 MHz, CDCb) δ 168.01 (s), 162.95 (d, J = 246.6 Hz), 138.76 (d, J = 7.2 Hz), 134.23 (s), 132.12 (s), 130.34 (d, J = 8.2 Hz), 124.23 (d, J= 3.0 Hz), 123.56 (s), 115.59 (d, J= 21.9 Hz), 114.94 (d, J= 21.0 Hz), 41.17 (d, J= 1.9 Hz).

2-(3,5-difluorobenzyl)isoindoline-l,3-dione (85): Compound 84 was prepared from 3,5- difluorobenzylamine and phthalic anhydride using general Procedure B. Yield = 20%, white solid. ¾ NMR (400 MHz, CDCb) δ 7.91 - 7.85 (m, 2H), 7.75 (d, J= 4.1 Hz, 2H), 6.94 (d, J= 6.6 Hz, 2H), 6.71 (t, J= 8.9 Hz, 1H), 4.81 (s, 2H). ¹³C NMR (101 MHz, CDCb) δ 167.77 (s), 163.07 (dd, J= 249.4, 12.7 Hz), 139.87 (t, J= 9.0 Hz), 134.26 (s), 131.91 (s), 123.57 (s), 111.36 (dd, J = 11 ), 103.40 (t, J = 25.2 Hz), 40.78 (t, J= 2.1 Hz).

2-(2-fluoro-3-(trifluoromethyl)benzyl)isoindoline-l,3-dione (86): Compound 86 was prepared from 2-fluoro-3(trifluoromethyl)benzylamine and phthalic anhydride using general Procedure B. Yield = 40%, white solid. ¾ NMR (400 MHz, CDCb) δ 7.88 (dd, J= 5.7, 2.8 Hz, 2H), 7.75 (dd, J= 5.7, 2.7 Hz, 2H), 7.55 (q, J= 7.6 Hz, 2H), 7.19 (t, J= 7.8 Hz, 1H), 4.98 (s, 2H). ¹³C NMR (101 MHz, CDCb) δ 167.80 (s), 157.79 (dq, J = 258.0, 2.0 Hz), 134.40 (s), 134.17 (d, J = 3.8 Hz), 132.02 (s), 126.91 (qd, J = 4.5, 1.5 Hz), 125.00 (d, J = 14.2 Hz), 124.17 (d, J = 4.6 Hz), 123.71 (s), 121.25 (s), 118.79 (qd, J= 33.0, 11.4 Hz).

2-(2,4-difluorobenzyl)isoindoline-l,3-dione (87): Compound 87 was prepared from 2,4- difluorobenzylamine and phthalic anhydride using general Procedure B. Yield = 76%, off white solid. ¾ NMR (400 MHz, CDCb) δ 7.86 (dd, J = 5.4, 3.1 Hz, 2H), 7.73 (dd, J = 5.5, 3.0 Hz, 2H), 7.37 (dt, J= 14.6, 7.3 Hz, 1H), 6.90 - 6.74 (m, 2H), 4.89 (s, 2H). ¹³C NMR (101 MHz, CDCb) δ 167.78 (s), 162.60 (dd, J = 249.2, 11.8 Hz), 160.71 (dd, J = 250.9, 12.0 Hz), 134.15 (s), 131.96 (s), 131.39 (dd, J = 9.8, 5.3 Hz), 123.47 (s), 119.18 (dd, J = 15.1, 3.8 Hz), 111.40 (dd, J = 21.3, 3.8 Hz), 104.01 (t, J= 25.4 Hz), 34.82 (d, J= 4.0 Hz).

2-(2,4-dimethoxybenzyl)isoindoline-l,3-dione (88): Compound 88 was prepared from 2,4- difluorobenzylamine and phthalic anhydride using general Procedure B. Yield = 37%, white solid. ¾ NMR (400 MHz, CDCh) δ 7.84 (dd, J= 5.4, 3.0 Hz, 2H), 7.70 (dd, J= 5.5, 3.0 Hz, 2H), 7.17 (d, J = 8.2 Hz, 1H), 6.44 - 6.39 (m, 2H), 4.83 (s, 2H), 3.81 (s, 3H), 3.77 (s, 3H). ¹³C MR (101 MHz, CDCh) δ 168.29 (s), 160.66 (s), 158.35 (s), 133.95 (s), 132.40 (s), 130.08 (s), 123.35 (s), 116.84 (s), 104.10 (s), 98.66 (s), 55.56 (d, J= 12.0 Hz), 36.76 (s). 2-(3-fluoro-4-methoxybenzyl)isoindoline-l,3-dione (89): Compound 89 was prepared from 3- fluoro-4-methoxybenzylamine and phthalic anhydride using general Procedure B. Yield = 74%, white solid. ¾ NMR (400 MHz, CDCh) δ 7.85 (dd, J = 5.4, 3.1 Hz, 1H), 7.71 (dd, J = 5.5, 3.0 Hz, 1H), 7.22 - 7.14 (m, 1H), 6.89 (t, J = 8.6 Hz, 1H), 4.76 (s, 1H), 3.85 (s, 2H). ¹³C NMR (101 MHz, CDCh) δ 168.10 (s), 152.33 (d, J= 246.6 Hz), 147.48 (d, J = 10.7 Hz), 134.20 (s), 132.21 (s), 129.46 (d, J = 6.1 Hz), 124.83 (d, J = 3.6 Hz), 123.54 (s), 116.74 (d, J = 18.8 Hz), 113.50 (d, J = 2.1 Hz), 56.42 (s), 40.89 (s).

2-(4-fluorobenzyl)isoindoline-l,3-dione (90): Compound 90 was prepared from 4-fluorobenzyl bromide and potassium phthalimide using general Procedure A. Yield = 57%, white solid. ¾ NMR (400 MHz, CDCh) δ 7.85 (dd, J= 5.5, 3.0 Hz, 1H), 7.71 (dd, J= 5.4, 3.1 Hz, 1H), 7.42 (dd, J= 8.6, 5.4 Hz, 1H), 6.99 (t, J= 8.7 Hz, 1H), 4.81 (s, 1H). ¹³C NMR (101 MHz, CDCh) δ 168.40 (s), 162.79 (d, J= 246.4 Hz), 134.48 (s), 132.65 (d, J= 3.3 Hz), 132.48 (s), 130.98 (d, J= 8.2 Hz), 123.81 (s), 115.96 (d, J= 21.5 Hz), 41.30 (s).

2-(2,6-difluorobenzyl)isoindoline-l,3-dione (91): Compound 91 was prepared from 2,6- difluorobenzyl bromide and potassium phthalimide using general Procedure A. Yield = 75%, white solid. ¾ NMR (400 MHz, CDCh) δ 7.84 (dd, J = 5.5, 3.1 Hz, 2H), 7.71 (dd, J = 5.5, 3.1 Hz, 2H), 7.29 - 7.19 (m, 2H), 6.92 - 6.83 (m, 2H), 4.96 (s, 2H). ¹³C NMR (101 MHz, CDCh) δ 167.45 (s), 161.56 (dd, J = 250.6, 7.5 Hz), 134.04 (s), 131.99 (s), 129.80 (t, J = 10.4 Hz), 123.40 (s), 111.41 (d, J= 25.3 Hz), 111.41 (d, J= 12.7 Hz), 30.07 (s).

2-(3,4-dimethoxyphenethyl)isoindoline-l,3-dione (92): Compound 92 was prepared from 3,4- dimethoxyphen ethyl amine and phthalic anhydride using general Procedure B. Yield = 76%, white solid. ¾ NMR (400 MHz, CDCh) δ 7.82 (dd, J= 5.4, 3.1 Hz, 2H), 7.70 (dd, J= 5.4, 3.0 Hz, 2H), 6.84 - 6.72 (m, 3H), 3.95 - 3.87 (m, 2H), 3.83 (d, J= 10.3 Hz, 6H), 2.98 - 2.90 (m, 2H). ¹³C NMR (101 MHz, CDCh) δ 168.03 (s), 148.63 (s), 147.48 (s), 133.74 (s), 131.85 (s), 130.25 (s), 123.03 (s), 120.66 (s), 111.69 (s), 111.01 (s), 55.63 (d, J= 4.9 Hz), 39.16 (s), 33.90 (s). 2-(2,6-dichlorophenethyl)isoindoline-l,3-dione (93): Compound 93 was prepared from 2,6- dichlorophenethylamine and phthalic anhydride using general Procedure B. Yield = 76%, white solid. ¹³C NMR (101 MHz, CDCh) δ 168.28 (s), 135.99 (s), 134.49 (s), 134.00 (s), 132.22 (s), 128.65 (s), 128.32 (s), 123.32 (s), 36.08 (s), 30.35 (s). ¹³C NMR (101 MHz, CDCh) δ 168.28 (s), 135.99 (s), 134.49 (s), 134.00 (s), 132.22 (s), 128.65 (s), 128.32 (s), 123.32 (s), 36.08 (s), 30.35 (s).

2-(4-chlorophenethyl)isoindoline-l,3-dione (94): Compound 94 was prepared from 4- chlorophenethylamine and phthalic anhydride using general Procedure B. Yield = 68%, white solid. ¾ NMR (400 MHz, CDC1₃) 6 7.83 (dd, J = 5.5, 3.0 Hz, 1H), 7.71 (dd, J = 5.4, 3.1 Hz, 1H), 7.21 (dd, J = 27.0, 8.5 Hz, 2H), 3.93 - 3.87 (m, 1H), 3.00 - 2.93 (m, 1H). ¹³C NMR (101 MHz, CDC1₃) δ 168.27 (s), 136.54 (s), 134.14 (s), 132.62 (s), 132.09 (s), 130.34 (s), 128.83 (s), 123.43 (s), 39.15 (s), 34.04 (s).

2-(4-methylphenethyl)isoindoline-l,3-dione (95): Compound 95 was prepared from 4- methylbenzyl bromide and potassium phthalimide using general Procedure A. Yield = 61%, white solid. ¾ NMR (400 MHz, CDC1₃) δ 7.83 (dd, J = 5.4, 3.1 Hz, 2H), 7.69 (dd, J = 5.5, 3.0 Hz, 2H), 7.33 (d, J= 7.9 Hz, 2H), 7.12 (d, J= 7.8 Hz, 2H), 4.81 (s, 2H), 2.30 (s, 3H). ¹³C NMR (101 MHz, CDC1₃) δ 168.09 (s), 137.59 (s), 133.95 (s), 133.42 (s), 132.16 (s), 129.34 (s), 128.65 (s), 123.32 (s), 41.37 (s), 21.15 (s).

2-(2-bromo-5-fluorobenzyl)isoindoline-l,3-dione (96): Compound 96 was prepared from 2- bromo-5-fluorobenzylamine and phthalic anhydride using general Procedure B. Yield = 55%, white solid. ¾ NMR (400 MHz, Chloroform- ) δ 7.91 (dd, J= 5.5, 3.1 Hz, 2H), 7.78 (dd, J= 5.5, 3.1 Hz, 2H), 7.53 (dd, J= 8.7, 5.2 Hz, 1H), 6.91 - 6.78 (m, 2H), 4.93 (s, 2H). ¹³C NMR (101 MHz, Chloroform- ) δ 167.92 (s), 162.23 (d, J = 247.3 Hz), 137.31 (d, J = 7.2 Hz), 134.52 (s), 134.33 (d, J = 8.0 Hz), 132.00 (s), 123.82 (s), 116.81 (d, J = 3.3 Hz), 116.36 (d, J = 22.4 Hz), 115.45 (d, J= 24.0 Hz), 41.77 (s).

2-(2-chloro-5-(trifluoromethyl)benzyl)-4-nitroisoindoline-l,3-dione (100): Compound 100 was prepared from 2-chloro-5-(trifluoromethyl)benzylamine and 3-nitrophthalic anhydride using general Procedure B. Yield = 75%, yellow solid. ¾ NMR (400 MHz, CDC1₃) δ 8.17 (d, J= 7.8 Hz, 2H), 7.96 (t, J = 7.8 Hz, 1H), 7.61 - 7.46 (m, 3H), 5.05 (s, 2H). ¹³C NMR (101 MHz, Chloroform- ) δ 165.41 (s), 162.45 (s), 137.35 (s), 135.87 (s), 133.97 (s), 133.79 (s), 130.59 (s), 129.89 (s), 129.56 (s), 129.15 (s), 127.62 (s), 126.80 (q, 7= 3.8 Hz), 126.41 (q, 7= 3.7 Hz), 123.77 (s), 40.06 (s).

2-((perfluorophenyl)methyl)isoindoline-l,3-dione (101): Compound 101 was prepared from 2,3,4,5, 6-Pentafluorobenzyl bromide and potassium phthalimide using general Procedure A. Yield = 21%, light brown solid. ¾ NMR (400 MHz, CDCb) δ 7.86 (dd, 7= 5.4, 3.1 Hz, 2H), 7.74 (dd, 7= 5.4, 3.1 Hz, 2H), 4.96 (s, 2H). ¹³C NMR (101 MHz, CDCb) δ 167.09 (s), 147.14 - 143.70 (m), 142.82 - 139.58 (m), 139.03 - 135.92 (m), 134.35 (s), 131.73 (s), 123.59 (s), 109.83 - 108.66 (m), 29.64 (s). Compounds X-l, Y-l, and Z-l (as follow) are to synthesize compounds 36, 97, and 98.

2-(4-methyl-3-nitrobenzyl)isoindoline-l,3-dione (X-l): Compound X-l was prepared from 4- Methyl-3-nitrobenzyl chloride and potassium phthalimide using general procedure A. Yield = 77%, off white solid. ¾ NMR (400 MHz, CDCb) δ 7.88 (dd, 7 = 5.2, 3.1 Hz, 2H), 7.76 (dd, 7 = 5.3, 3.1 Hz, 2H), 7.67 (d, 7= 8.0 Hz, 1H), 7.54 (d, 7= 7.7 Hz, 1H), 4.93 (s, 2H), 2.57 (s, 3H). ¹³C NMR (101 MHz, CDCb) δ 168.09 (s), 151.58 (s), 137.05 (s), 134.50 (s), 132.66 (s), 131.96 (s), 130.54 (s), 126.65 (s), 123.74 (s), 123.61 (s), 39.40 (s), 14.90 (s).

2-(3-nitrobenzyl)isoindoline-l,3-dione (Y-l): Compound Y-l was prepared from 3-nitrobenzyl chloride and potassium phthalimide using general procedure A. Yield = 42%, white solid. ¾ NMR (400 MHz, CDCb) δ 8.27 (s, 1H), 8.14 (dd, 7= 8.2, 1.3 Hz, 1H), 7.88 (dd, 7= 5.4, 3.1 Hz, 2H), 7.81 - 7.71 (m, 3H), 7.51 (t, 7 = 8.0 Hz, 1H), 4.94 (s, 2H). ¹³C NMR (101 MHz, CDCb) δ 167.94 (s), 148.60 (s), 138.36 (s), 134.79 (s), 134.47 (s), 132.02 (s), 129.90 (s), 123.78 (s), 123.61 (s), 123.13 (s), 40.98 (s).

2-(2-methyl-3-nitrobenzyl)isoindoline-l,3-dione (Z-l): Compound Z-l was prepared from 2- methyl-3-nitrobenzyl chloride and potassium phthalimide using general procedure A. Yield = 84%, white solid. ¾ NMR (400 MHz, CDCb) δ 8.02 (d, 7 = 1.5 Hz, 1H), 7.86 (dd, 7 = 5.4, 3.1 Hz, 2H), 7.74 (dd, 7 = 5.5, 3.0 Hz, 2H), 7.56 (dd, 7 = 7.9, 1.7 Hz, 1H), 7.29 (d, 7 = 7.9 Hz, 1H), 4.87 (s, 2H), 2.55 (s, 3H). ¹³C NMR (101 MHz, CDCb) δ 167.96 (s), 149.39 (s), 135.72 (s), 134.48 (s), 134.40 (s), 133.31 (s), 133.23 (s), 132.02 (s), 124.77 (s), 123.76 (s), 123.72 (s), 40.65 (s), 20.31 (s).

EXAMPLE 2: Synthesis and characterization of compounds 3, 4, 9, and 37, X-2, Y-2, and Z- 2

Compounds X-2, Y-2, and Z-2 (as follow) are used to synthesize compounds 36, 97, and 98.

F₃

X-1 R¹=H; R³=CH₃ X-2 R -H; R^=CH₃ Y-1 R¹=R³=H Y-2 R¹=R²=H

Z-1 R¹ =CH₃; R²=H Z-2 R¹=CH₃; R²=H

General procedure for the synthesis of 3, 4, 9, and 37:

To a solution of the corresponding nitro derivative (1 mmol) in glacial acetic acid (4 mL) was added reduced iron powder (4 mmol). The mixture was then heated at 60 ^oC and stirred under N₂ atmosphere for 3-4 h. The mixture was then cooled to rt and filtered. The filter cake was then washed with EtOH (2 X 10 mL) and EtOAc (2 X 10 mL). The filtrate was subsequently concentrated under reduced pressure. Water (20 mL) was added and the aqueous solution was extracted with EtOAc (3 X 20 mL). The combined organic layer was washed with brine, dried over Na₂SC"4, and evaporated. The remaining residue was crystallized from EtOH to give the pure desired product. 4-amino-2-(2,5-dichlorobenzyl)isoindoline-l,3-dione (3): Compound 3 was prepared from 2- (2,5-dichlorobenzyl)-4-nitroisoindoline-l,3-dione (81). Yield = 87%, brightyellow solid. ¾NMR (400 MHz, CDCb) δ 7.45 (dd, J= 8.3, 7.2 Hz, 2H), 7.31 (d, J= 8.4 Hz, 2H), 7.23 - 7.12 (m, 3H), 6.92 - 6.86 (m, 1H), 5.27 (s, 2H), 4.89 (s, 2H). ¹³C NMR (101 MHz, CDCb) δ 169.36 (s), 167.86 (s), 145.31 (s), 135.39 (s), 135.32 (s), 132.75 (s), 132.38 (s), 131.04 (s), 130.53 (s), 128.66 (s), 128.11 (s), 121.15 (s), 112.98 (s), 110.86 (s), 38.41 (s).

4-amino-2-(2,6-dichlorobenzyl)isoindoline-l,3-dione (4): Compound 4 was prepared from 2- (2,6-dichlorobenzyl)-4-nitroisoindoline-l,3-dione (66). Yield = 30%, brightyellow solid. ¾NMR (400 MHz, DMSO) δ 6.64 - 6.45 (m, 2H), 6.09 (dd, J = 10.7, 7.7 Hz, 2H), 5.61 (s, 2H), 4.08 (s, 2H). ¹³C NMR (101 MHz, DMSO) δ 168.60 (s), 167.19 (s), 146.52 (s), 135.46 (s), 135.21 (s), 132.09 (s), 131.22 (s), 130.16 (s), 128.66 (s), 121.51 (s), 110.72 (s), 108.57 (s), 37.40 (s).

4-amino-2-(2-chloro-5-(trifluoromethyl)benzyl)isoindoline-l,3-dione (9): Compound 9 was prepared from 2-(2-chloro-5-(trifluoromethyl)benzyl)-4-nitroisoindoline-l,3-dione (100). Yield = 75%, yellow solid. ¾ NMR (400 MHz, CDCb) δ 7.55 - 7.39 (m, 4H), 7.20 (d, J = 7.1 Hz, 1H), 6.89 (d, J = 8.3 Hz, 1H), 4.96 (s, 2H). ¹³C NMR (101 MHz, Chloroform- ) δ 169.67, 168.19 (s), 145.62 (s), 137.00 (s), 135.69 (s), 135.07 (s), 132.61 (s), 130.35 (s), 129.59 (q, J= 33.2 Hz), 125.80 (p, J= 3.7 Hz), 121.52 (s), 113.35 (s), 111.10 (s), 38.89 (s).

4-amino-2-(3,4-dichlorobenzyl)isoindoline-l,3-dione (37): Compound 37 was prepared from 2- (3,4-dichlorobenzyl)-4-nitroisoindoline-l,3-dione (75). Yield = 93%, yellow solid. ¾ NMR (400 MHz, DMSO) δ 7.57 - 7.49 (m, 1H), 7.41 (dd, J= 8.3, 7.1 Hz, 1H), 7.23 (dd, J= 8.3, 2.0 Hz, 1H), 6.96 (dd, J = 7.7, 4.2 Hz, 1H), 6.46 (s, 1H), 4.66 (s, 2H). ¹³C NMR (101 MHz, DMSO) δ 169.19 (s), 167.95 (s), 146.85 (s), 138.37 (s), 135.48 (s), 132.44 (s), 131.30 (s), 130.97 (s), 130.22 (s), 129.73 (s), 127.92 (s), 121.81 (s), 111.17 (s), 108.97 (s).

2-(3-amino-4-methylbenzyl)isoindoline-l,3-dione (X-2): Compound X-2 was prepared from 2- (4-methyl-3-nitrobenzyl)isoindoline-l,3-dione (X-l). Yield = 44%, pale yellow solid. ¾ NMR (400 MHz, CDCb) δ 7.85 (dd, J= 5.3, 3.1 Hz, 2H), 7.71 (dd, J= 5.4, 3.1 Hz, 2H), 6.96 (t, J= 7.8 Hz, 1H), 6.76 (d, J= 7.6 Hz, 1H), 6.62 (d, J= 7.9 Hz, 1H), 4.87 (s, 2H), 3.63 (s, 2H), 2.26 (s, 3H). ¹³C NMR (101 MHz, CDCb) δ 168.34 (s), 145.06 (s), 134.85 (s), 134.12 (s), 132.24 (s), 126.52 (s), 123.46 (s), 120.59 (s), 119.24 (s), 114.93 (s), 39.94 (s), 12.67 (s). 2-(3-aminobenzyl)isoindoline-l,3-dione (Y-2): Compound Y-2 was prepared from 2-(3- nitrobenzyl)isoindoline-l,3-dione (Y-1). Yield = 47%, off white solid. ¾ NMR (400 MHz, CDCb) δ 7.84 (dd, J = 5.3, 3.1 Hz, 2H), 7.70 (dd, J = 5.4, 3.0 Hz, 2H), 7.09 (t, J = 7.8 Hz, 1H), 6.82 (d, J = 7.6 Hz, 1H), 6.75 (s, 1H), 6.64 - 6.51 (m, 1H), 4.75 (s, 2H), 3.66 (s, 2H). ¹³C NMR (101 MHz, CDCb) δ 167.91 (s), 146.49 (s), 137.32 (s), 133.76 (s), 131.95 (s), 129.43 (s), 123.13 (s), 118.57 (s), 114.87 (s), 114.35 (s), 41.39 (s).

2-(3-amino-2-methylbenzyl)isoindoline-l,3-dione (Z-2): Compound Z-2 was prepared 2-(2- methyl-3-nitrobenzyl)isoindoline-l,3-dione (Z-1). Yield = 76%, pale orange solid. ¾ NMR (400 MHz, CDCb) δ 7.82 (dd, J= 5.4, 3.1 Hz, 2H), 7.69 (dd, J= 5.4, 3.0 Hz, 2H), 6.98 (d, J= 7.6 Hz, 1H), 6.82 - 6.72 (m, 2H), 4.73 (s, 2H), 3.60 (s, 2H), 2.11 (s, 3H). 13C NMR (101 MHz, CDCB) δ 168.19 (s), 144.85 (s), 135.31 (s), 133.98 (s), 132.28 (s), 130.74 (s), 123.34 (s), 122.01 (s), 118.91 (s), 115.06 (s), 41.54 (s), 17.16 (s).

EXAMPLE 3: Synthesis and characterization of compounds 36, 97, and 98

For com ounds 36, 97, and 98 the starting material intermediates are X-1, X-2, Y-1, Y-2, Z-1, and

X-2 R¹=H; R³=CH₃ 36 R¹= H; R³=CH₃

Y-2 R¹=R³=H 97 R¹=R³=H Z-2 R¹ =CH₃; R³=H 98 R¹=CH₃; R³=H

General procedures for synthesis of compounds 36, 97, and 98

To a solution of the related aminophthalimido derivative (1 mmol) in MeOH (10 mL), was added acetone (10 mmol) and the resulting solution stirred at rt for 15 min. After adding NaCNBH₃ (5 mmol) and a few drops of glacial acetic acid, the resultant solution was stirred at rt overnight. After quenching the reaction mixture with acetic acid (5 mL), it was added dropwise into sat. NaHC0₃ (50 mL) over a period of 30 min. The product was then extracted with EtOAc (3 X 50 mL), and the combined organic layers were washed with brine, and dried over Na₂S0₄. After evaporating the solvent under reduced pressure, the remaining residue was purified by crystallization from EtOH to afford the desired product.

2-(3-(isopropylamino)-4-methylbenzyl)isoindoline-l,3-dione (36): Compound 36 was prepared from 2-(3-amino-4-methylbenzyl)isoindoline-l,3-dione (X-2). Yield = 62%, off white solid. ¹³C NMR (101 MHz, CDCb) δ 168.13 (s), 149.01 (s), 137.95 (s), 137.20 (s), 134.31 (s), 132.16 (s), 130.44 (s), 130.23 (s), 129.50 (s), 129.07 (s), 123.64 (s), 52.49 (s), 41.14 (s), 21.02 (s). ¹³C NMR (101 MHz, CDCb) δ 168.13 (s), 149.01 (s), 137.95 (s), 137.20 (s), 134.31 (s), 132.16 (s), 130.44 (s), 130.23 (s), 129.50 (s), 129.07 (s), 123.64 (s), 52.49 (s), 41.14 (s), 21.02 (s).

2-(3-(isopropylamino)benzyl)isoindoline-l,3-dione (97): Compound 97 was prepared from 2- (3-aminobenzyl)isoindoline-l,3-dione (Y-2). Yield = 71%, white solid. ¾ NMR (400 MHz, CDCb) δ 7.87 (dd, J = 5.4, 3.1 Hz, 2H), 7.73 (dd, J= 5.4, 3.1 Hz, 2H), 7.48 (d, J = 7.7 Hz, 1H), 7.37 (t, J = 7.8 Hz, 1H), 7.26 - 7.22 (m, 2H), 7.06 (d, J = 7.8 Hz, 1H), 4.86 (s, 2H), 4.76 - 4.54 (m, 1H), 1.13 (d, J= 6.7 Hz, 6H). ¹³C NMR (101 MHz, CDCb) δ 168.03 (s), 138.88 - 138.46 (m), 137.73 (s), 134.31 (s), 132.11 (s), 130.55 (s), 129.66 (s), 129.61 (s), 129.13 (s), 52.52 (s), 41.30 (s), 21.04 (s).

2-(3-(isopropylamino)-2-methylbenzyl)isoindoline-l,3-dione (98): Compound 98 was prepared from 2-(3-amino-2-methylbenzyl)isoindoline-l,3-dione (Z-2). Yield = 53%, white solid. ¾ NMR (400 MHz, CDCb) δ 7.86 (dd, J= 5.4, 3.1 Hz, 2H), 7.72 (dd, J= 5.4, 3.0 Hz, 2H), 7.36 (d, J= 7.9 Hz, 1H), 7.26 - 7.18 (m, 2H), 4.87 (d, J = 14.6 Hz, 1H), 4.78 (d, J = 14.6 Hz, 1H), 4.48 (dt, J = 13.6, 6.8 Hz, 1H), 2.26 (s, 3H), 1.35 (d, J= 6.7 Hz, 3H), 1.03 (d, J= 6.8 Hz, 3H). ¹³C NMR (101 MHz, CDCb) δ 168.08 (s), 138.69 - 138.46 (m), 137.12 - 136.96 (m), 135.19 (s), 134.27 (s), 132.15 (s), 131.79 (s), 129.90 (s), 129.21 (s), 123.60 (s), 53.93 (s), 41.09 (s), 21.66 (s), 19.75 (s), 18.18 (s).

EXAMPLE 4: Synthesis and characterization of compounds 2, 11, 12, 15, 42, 43, 45, and 46

R2=R3_=R5_{=H ;} R1 = R _=C| 2 R²=R³=R⁵=H; R¹=R⁴=CI; R¹⁰=CH₃

R²=R³=R⁵=H; R¹=CI; R⁴=CF₃ 11 R²=R³=R⁵=H; R¹=R⁴=CI; R¹⁰=CH₂OAc

R =R⁴=R⁵=H; R²=R³=CI 12 R²=R³=R⁵=H; R¹=CI; R⁴=CF₃; R¹⁰=CH₂OAc

15 R¹=R⁴=R⁵=H; R²=R³=CI; R¹⁰=CH₂OMe

42 R²=R³=R₅=H; R¹=R⁴=CI; R¹⁰=CH₂OH

43 R²=R³=R⁵=H; R¹=R⁴=CI; R¹⁰=CH₂OMe

45 R²=R³=R⁵=H; R¹=CI; R⁴=CF₃; R¹⁰=CH₂OMe

46 R¹= R⁴=R⁵=H; R²=R³=CI; R¹⁰=CH₂OAc

General procedure for the synthesis of 11, 12, 15, 43, 45, and 46

To a solution of the corresponding aminophthalimido derivative (1 mmol) in THF (50 mL) was added appropriate acyl chloride (2 mmol) at rt under N₂ atmosphere. The mixture was then heated at 45-50 °C and stirred under N₂ atmosphere for 2-3 h. The volatiles were removed under reduced pressure, and the remaining residue was triturated from Et₂0 to give the pure desired product.

N-(2-(2,5-dichlorobenzyl)-l,3-dioxoisoindolin-4-yl)acetamide (2): To compound 3 (0.09 mmol) was added acetyl chloride (excess) followed by trimethylamine (excess) at room temperature and stirred for 15 min. The reaction was quenched with sat. NaHC0₃ and extracted with EtOAc. The combined organic layers was washed with 1M HCl and brine, dried over Na₂S0₄ and filtered. The crude material was recrystallized in EtOH to give 2 in 31% yield. ¾ NMR (400 MHz, Chloroform- ) δ 9.50 (s, 1H), 8.85 (d, J= 8.5 Hz, 1H), 7.74 (dd, J= 8.6, 7.3 Hz, 1H), 7.64 - 7.55 (m, 1H), 7.36 (d, J= 8.3 Hz, 1H), 7.27 - 7.18 (m, 2H), 4.95 (s, 2H), 2.30 (s, 3H). ¹³C NMR (101 MHz, CDC1₃) δ 169.61, 169.28, 167.20, 137.69, 136.27, 134.90, 133.03, 131.35, 131.29, 130.88, 129.21, 128.73, 125.09, 118.38, 115.38, 38.94, 25.00.

2-((2-(2,5-dichlorobenzyl)-l,3-dioxoisoindolin-4-yl)amino)-2-oxoethyl acetate (11):

Compound 11 was prepared from 4-amino-2-(2,5-dichlorobenzyl)isoindoline-l,3-dione (3) and acetoxyacetyl chloride. Yield = 76%, white solid. ¾ NMR (400 MHz, CDC1₃) δ 10.26 (s, 1H), 8.82 (d, J = 8.4 Hz, 1H), 7.74 (t, J = 7.9 Hz, 1H), 7.61 (d, J = 7.3 Hz, 1H), 7.33 (d, J = 8.4 Hz, 1H), 7.25 - 7.16 (m, 2H), 4.92 (s, 2H), 4.76 (s, 2H), 2.33 (s, 3H). ¹³C NMR (101 MHz, CDC1₃) δ 169.53 (s), 169.34 (s), 167.15 - 166.99 (m), 166.51 (s), 136.46 (s), 136.37 (s), 134.82 (s), 132.98 (s), 131.38 (s), 131.37 - 131.35 (m), 130.87 (s), 129.20 (s), 128.72 (s), 125.01 (s), 119.02 (s), 116.36 (s), 62.68 (s), 39.02 (s), 20.65 (s).

2-((2-(2-chloro-5-(trifluoromethyl)benzyl)-l,3-dioxoisoindolin-4-yl)amino)-2-oxoethyl acetate (12): Compound 12 was prepared from 4-amino-2-(2-chloro-5- (trifluoromethyl)benzyl)isoindoline-l,3-dione (9) and acetoxyacetyl chloride. Yield = 65%, creamy white solid. ¾ NMR (400 MHz, CDCb) δ 10.25 (s, 1H), 8.82 (d, J= 8.4 Hz, 1H), 7.74 (t, J= 7.9 Hz, 1H), 7.60 (d, J= 7.3 Hz, 1H), 7.58 - 7.47 (m, 3H), 4.99 (s, 2H), 4.76 (s, 2H), 2.31 (s, 3H). ¹³C NMR (101 MHz, CDCb) δ 169.50 (s), 169.43 (s), 166.98 (s), 166.53 (s), 137.13 (s), 136.46 (s), 136.40 (s), 134.16 (s), 131.33 (s), 130.39 (s), 129.50 (d, J = 33.1 Hz), 126.61 (d, J = 3.8 Hz), 126.09 (d, J= 3.7 Hz), 125.01 (s), 123.50 (d, J= 272.4 Hz), 119.05 (s), 116.29 (s), 62.66 (s), 39.33 (s), 20.54 (s).

N-(2-(3,4-dichlorobenzyl)-l,3-dioxoisoindolin-4-yl)-2-methoxyacetamide (15): Compound 15 was prepared from 4-amino-2-(3,4-dichlorobenzyl)isoindoline-l,3-dione (37) and methoxyacetyl chloride. Yield = 73%, white solid. ¾ NMR (400 MHz, CDCb) δ 10.45 (s, 1H), 8.83 (d, J= 8.5 Hz, 1H), 7.69 (t, J= 7.9 Hz, 1H), 7.55 (d, J= 7.3 Hz, 1H), 7.51 (d, J= 1.5 Hz, 1H), 7.39 (d, J = 8.2 Hz, 1H), 7.26 (s, 1H), 4.76 (s, 2H), 4.09 (s, 2H), 3.60 (s, 3H). ¹³C NMR (101 MHz, CDCb) δ 169.32 (s), 169.17 (s), 167.48 (s), 136.69 (s), 136.26 (s), 136.20 (s), 132 93 (s), 132.38 (s), 131.69 (s), 130.86 (s), 130.66 (s), 128.13 (s), 125.20 (s), 118.73 (s), 116.44 (s), 72.31 (s), 59.91 (s), 40.54 (s^}.

N-(2-(2,5-dichlorobenzyl)-l,3-dioxoisoindolin-4-yl)-2-methoxyacetamide (43): Compound 43 was prepared from 4-amino-2-(2,5-dichlorobenzyl)isoindoline-l,3-dione (3) and methoxyacetyl chloride. Yield = 91%, creamy white solid. ¾ NMR (400 MHz, CDCb) δ 10.47 (s, 1H), 8.87 (d, J = 8.3 Hz, 1H), 7.73 (t, J= 7.8 Hz, 1H), 7.60 (d, J = 7.2 Hz, 1H), 7.32 (d, J= 8.5 Hz, 1H), 7.20 (d, J = 8.4 Hz, 1H), 7.14 (s, 1H), 4.93 (s, 2H), 4.09 (s, 2H), 3.57 (s, 3H). ¹³C NMR (101 MHz, CDCb) δ 169.03 (s), 168.85 (s), 167.10 (s), 136.46 (s), 136.00 (s), 134.76 (s), 132.82 (s), 131.34 (s), 131.04 (s), 130.64 (s), 128.87 (s), 128.00 (s), 124.99 (s), 118.54 (s), 116.10 (s), 71.98 (s), 59.56 (s), 38.74 (s). N-(2-(2-chloro-5-(trifluoromethyl)benzyl)-l,3-dioxoisoindolin-4-yl)-2-methoxyacetamide (45): Compound 45 was prepared from 4-amino-2-(2-chloro-5- (trifluoromethyl)benzyl)isoindoline-l,3-dione (9) and methoxyacetyl chloride. Yield = 83%, white solid. ¾ NMR (400 MHz, CDCb) δ 10.47 (s, 1H), 8.88 (d, J = 8.3 Hz, 1H), 7.74 (t, J = 8.0 Hz, 1H), 7.60 (d, J = 7.0 Hz, 1H), 7.57 - 7.40 (m, 3H), 5.00 (s, 2H), 4.09 (s, 2H), 3.57 (s, 3H). ¹³C NMR (101 MHz, CDCb) δ 169.23 (s), 169.05 (s), 167.30 (s), 136.93 (s), 136.69 (s), 136.24 (s), 134.35 (s), 131.47 (s), 130.34 (s), 129.56 (q, J = 33.0 Hz), 125.93 (q, J = 3.7 Hz), 125.68 (q, J = 3.8 Hz), 125.21 (s), 123.52 (q, J = 272.3 Hz), 118.77 (s), 116.25 (s), 72.17 (s), 59.74 (s), 39.13 (s).

2-((2-(3,4-dichlorobenzyl)-l,3-dioxoisoindolin-4-yl)amino)-2-oxoethyl acetate (46): Compound 46 was prepared from 4-amino-2-(3,4-dichlorobenzyl)isoindoline-l,3-dione (37) and acetoxycetyl chloride. Yield = 76%, white solid. ¾ NMR (400 MHz, CDCb) δ 10.47 (s, 1H), 8.88 (d, J= 8.3 Hz, 1H), 7.74 (t, J= 8.0 Hz, 1H), 7.60 (d, J= 7.0 Hz, 1H), 7.57 - 7.40 (m, 3H), 5.00 (s, 2H), 4.09 (s, 2H), 3.57 (s, 3H). ¹³C NMR (101 MHz, CDCb) δ 169.23 (s), 169.04 (s), 167.30 (s), 136.93 (s), 136.69 (s), 136.24 (s), 134.35 (s), 131.47 (s), 130.34 (s), 129.56 (q, J= 66.1, 33.1 Hz), 125.93 (q, J = 7.0, 3.3 Hz), 125.67 (q, J = 7.2, 3.4 Hz), 125.21 (s), 118.77 (s), 116.25 (s), 72.17 (s), 59.74 (s), 39.13 (s).

EXAMPLE 5: Synthesis and characterization of compound 42

N-(2-(2,5-dichlorobenzyl)-l,3-dioxoisoindolin-4-yl)-2-hydroxyacetamide (42): To a solution of 11 (1 mmol) in dry MeOH (5 mL) was added methanolic sodium methoxide solution (1 mmol) drop wise at 0 °C under N₂ atmosphere. After stirring at 0 °C for 1 h, the solution was neutralized by addition of Amberlite IR-120 (H⁺ form) , which was removed by filtration, was then washed several times with methanol. The combined filtrate was concentrated under reduced pressure to give the pure product (yield = 90%, white solid). ¾ NMR (400 MHz, CDCb) δ 10.45 (s, 1H), 8.86 (d, J = 8.5 Hz, 1H), 7.75 (t, J = 7.9 Hz, 1H), 7.61 (d, J = 7.3 Hz, 1H), 7.32 (d, J = 8.4 Hz, 1H), 7.24 - 7.14 (m, 2H), 4.93 (s, 2H), 4.34 (d, J = 4.8 Hz, 2H), 2.56 (s, 1H), 1.56 (s, 3H). ¾ NMR (400 MHz, CDCb) δ 10.45 (s, 1H), 8.86 (d, J= 8.5 Hz, 1H), 7.75 (t, J= 7.9 Hz, 1H), 7.61 (d, J = 7.3 Hz, 1H), 7.32 (d, J = 8.4 Hz, 1H), 7.24 - 7.14 (m, 2H), 4.93 (s, 2H), 4.34 (d, J = 4.8 Hz, 2H), 2.56 (s, 1H), 1.56 (s, 3H).

EXAMPLE 6: Synthesis and characterization of compounds 44 and 47

3 R²=R³=R⁵=H; R¹=R⁴=CI 44 R²=R³=R⁵=H; R¹=R⁴=CI; R¹⁰=CH₂N₃ 37 R¹=R⁴=R⁵=H; R²=R³=CI 47 R =R⁴=R⁵=H; R²=R³=CI; R¹⁰=CH₂N₃

General procedure for the synthesis of 44 and 47

The related amino derivative (1 mmol) was dissolved in THF (50 mL), to which bromoacetyl chloride (1.1 mmol) was added at rt. After refluxing for 30 min, the volatiles were removed under reduced pressure. The remaining residue was then dissolved in acetone (50 mL), to which NaN₃ (1.5 mmol) was added. After refluxing for 3 h, the solvent was evaporated. Water (50 mL) was then added and the product was extracted with EtOAc (3 X 50 mL). The combined organic layer was then washed with brine, dried over Na₂S0₄ and evaporated under reduced pressure. Subsequently, the crude was purified by trituration from Et₂0 to give the desired product.

2-azido-N-(2-(2,5-dichlorobenzyl)-l,3-dioxoisoindolin-4-yl)acetamide (44): Compound 44 was prepared from 4-amino-2-(2,5-dichlorobenzyl)isoindoline-l,3-dione (3). Yield = 75%, off white solid. ¾ NMR (400 MHz, CDCb) δ 10.28 (s, 1H), 8.82 (d, J= 8.5 Hz, 1H), 7.75 (t, J= 7.9 Hz, 1H), 7.62 (d, J= 7.3 Hz, 1H), 7.33 (d, J= 8.5 Hz, 1H), 7.21 (dd, J= 8.5, 2.1 Hz, 1H), 7.16 (d, J= 1.9 Hz, 1H), 4.94 (s, 2H), 4.21 (s, 2H). ¹³C NMR (101 MHz, CDCb) δ 169.33 (s), 167.24 (s), 166.12 (s), 136.54 (s), 136.45 (s), 134.93 (s), 133.16 (s), 131.62 (s), 131.43 (s), 131.02 (s), 129.31 (s), 128.53 (s), 125.25 (s), 119.30 (s), 116.64 (s), 53.30 (s), 39.16 (s). 2-azido-N-(2-(3,4-dichlorobenzyl)-l,3-dioxoisoindolin-4-yl)acetamide (47): Compound 47 was prepared from 4-amino-2-(3,4-dichlorobenzyl)isoindoline-l,3-dione (37). Yield = 78%, white solid. ¾ NMR (400 MHz, CDCb) δ 10.27 (s, 1H), 8.78 (d, J = 8.4 Hz, 1H), 7.71 (t, J = 7.9 Hz, 1H), 7.58 (d, J = 7.3 Hz, 1H), 7.52 (d, J = 1.6 Hz, 1H), 7.41 (d, J = 8.3 Hz, 1H), 7.30 - 7.26 (m, 1H), 4.77 (s, 2H), 4.21 (s, 2H), 1.55 (s, 6H). ¹³C NMR (101 MHz, CDCb) δ 169.20 (s), 167.46 - 166.90 (m), 165.94 (s), 136.31 (s), 136.21 (s), 135.98 (s), 132.94 - 132.77 (m), 132.40 - 132.30 (m), 131.52 (s), 130.78 (s), 130.58 (s), 128.05 (s), 125.02 (s), 119.06 (s), 116.65 - 116.39 (m), 53.18 (s), 40.50 (s).

EXAMPLE 7: Synthesis and characterization of compound 29

N-(2-(2,6-dichlorobenzyl)-l,3-dioxoisoindolin-4-yl)acetamide (29): To 4-amino-2-(2,6- dichlorobenzyl)isoindoline-l,3-dione (0.09 mmol) in DCM (5 mL) was added acetyl chloride (excess) and trimethylamine (excess). The reaction was stirred at room temperature for 19 h. The reaction mixture was concentrated and the crude material was recrystallized in EtOH to give compound 29 in 90% yield. ¾ NMR (400 MHz, DMSO- e) δ 9.68 (s, 1H), 8.44 (d, J = 8.1 Hz, 1H), 7.78 (dd, J = 8.4, 7.3 Hz, 1H), 7.56 (dd, J= 7.3, 0.8 Hz, 1H), 7.53 - 7.46 (m, 2H), 7.38 (dd, J = 8.8, 7.4 Hz, 1H), 5.01 (s, 2H), 2.17 (s, 3H). ¹³C NMR (101 MHz, DMSO) δ 169.80, 168.13, 166.94, 136.80, 136.21, 135.96, 132.05, 131.22, 130.85, 129.22, 126.57, 118.55, 117.26, 38.26, 24.66.

EXAMPLE 8: Synthesis and characterization of compound 55

55

(lS,2R,3S,4R)-3-((2,6-dichlorobenzyl)carbamoyl)-7-oxabicyclo[2.2.1]heptane-2-carboxylic acid (55): A mixture of norcantharidin (0.3 mmol) and 2,6-dichlorobenzylamine (0.36 mmol) in toluene (5 mL) was heated at 100 °C for 19 h. The reaction mixture was quenched with 1M HCl (5 mL) and EtOAc (5 mL). The resultant precipitate was filtered to give 55 in 78% yield. ¾ NMR (400 MHz, DMSO- e) δ 7.74 (t, J = 4.7 Hz, 1H), 7.49 (d, J = 8.0 Hz, 2H), 7.37 (dd, J = 8.7, 7.4 Hz, 1H), 4.74 (d, J= 3.7 Hz, 1H), 4.51 (dd, J= 13.7, 5.1 Hz, 1H), 4.46 - 4.36 (m, 2H), 3.01 - 2.70 (m, 2H), 1.74 - 1.34 (m, 4H). ¹³C NMR (101 MHz, DMSO) δ 172.82, 170.69, 136.00, 133.99, 130.66, 129.03, 79.65, 77.26, 53.10, 51.56, 39.26, 29.37, 28.89.

EXAMPLE 9: Synthesis and characterization of compounds 67-70

(67) R., = CH₂CH₂OMe; R₂ = H

(68) R._| ,R₂ = -CH₂CH₂N(CH₃)CH₂CH₂-

(69) R = CH₂CH₂-N(-(CH₂)₅-); R₂ = H

(70) R₁ = CH₂-(2-furan); R₂ = H

General procedure for the synthesis of 67-70

To 2-(2,6-dichlorobenzyl)-l,3-dioxoisoindoline-5-carboxylic acid (0.086 mmol) in DMF (0.5 mL) was added successively the appropriate amine (0.086 mmol), DIEA (0.26 mmol) , and HATU (0.11 mmol). The reaction mixture was stirred at room temperature overnight. The crude material was purified via HPLC to give compounds 67-70 in 40-60% yields.

2-(2,6-dichlorobenzyl)-N-(2-methoxyethyl)-l,3-dioxoisoindoline-5-carboxamide (67): ¾

NMR (400 MHz, Chloroform- ) δ 8.28 - 8.13 (m, 2H), 7.90 (dd, J= 7.8, 0.8 Hz, 1H), 7.41 - 7.32 (m, 2H), 7.22 (dd, J= 8.7, 7.4 Hz, 1H), 6.64 (s, 1H), 5.18 (s, 2H), 3.82 - 3.64 (m, 2H), 3.59 (dd, J = 5.6, 4.4 Hz, 2H), 3.42 (s, 3H). ¹³C NMR (101 MHz, CDCh) δ 166.69, 165.38, 140.16, 136.48, 133.91, 133.39, 132.19, 130.40, 129.75, 128.51, 123.71, 121.50, 70.77, 58.94, 40.03, 38.48.

2-(2,6-dichlorobenzyl)-5-(4-methylpiperazine-l-carbonyl)isoindoline-l,3-dione (68): ¾ NMR (400 MHz, DMSO-d₆) δ 7.92 (d, J= 7.7 Hz, 1H), 7.83 (d, J= 7.7 Hz, 2H), 7.50 (d, J= 8.1 Hz, 2H), 7.38 (dd, J= 8.8, 7.3 Hz, 1H), 5.04 (s, 2H), 3.68 (s, 2H), 3.31 (s, 4H), 2.40 (s, 2H), 2.29 (s, 3H). ¹³C MR (101 MHz, DMSO) δ 167.50, 166.93, 163.57, 142.26, 135.98, 133.41, 132.21, 132.04, 131.19, 130.85, 129.17, 124.03, 121.83, 54.60, 54.21, 46.97, 45.56, 41.55, 38.48.

2-(2,6-dichlorobenzyl)-l,3-dioxo-N-(2-(piperidin-l-yl)ethyl)isoindoline-5-carboxamide (69): ¾ NMR (400 MHz, Methanol-^) δ 8.34 - 8.28 (m, 2H), 7.98 (d, J= 8.2 Hz, 1H), 7.47 - 7.40 (m, 2H), 7.32 (dd, J = 8.8, 7.3 Hz, 1H), 5.19 (s, 2H), 3.82 (t, J = 6.0 Hz, 2H), 3.73 (d, J = 12.4 Hz, 2H), 3.37 (t, J= 6.0 Hz, 2H), 3.10 - 2.98 (m, 2H), 2.02 (d, J= 14.6 Hz, 2H), 1.93 - 1.70 (m, 3H), 1.58 (qd, J = 12.5, 3.8 Hz, 1H). ¹³C NMR (101 MHz, MeOD) δ 167.77, 166.59, 166.50, 139.13, 136.07, 134.18, 133.41, 132.08, 130.62, 129.70, 128.33, 123.07, 121.58, 56.59, 53.38, 37.89, 34.69, 22.95, 21.19.

2-(2,6-dichlorobenzyl)-N-(furan-2-ylmethyl)-l,3-dioxoisoindoline-5-carboxamide (70): ¾

NMR (400 MHz, DMSO-d₆) δ 9.38 (s, 1H), 8.37 - 8.19 (m, 2H), 8.00 - 7.90 (m, 1H), 7.61 (dd, J = 1.8, 0.9 Hz, 1H), 7.55 - 7.46 (m, 2H), 7.38 (dd, J = 8.7, 7.3 Hz, 1H), 6.38 (ddd, J = 34.2, 3.2, 1.4 Hz, 2H), 5.05 (s, 2H), 4.51 (d, J= 5.6 Hz, 2H). ¹³C NMR (101 MHz, DMSO) δ 166.96, 164.82, 152.28, 142.70, 140.01, 135.93, 134.34, 133.79, 132.02, 131.17, 130.84, 129.20, 123.84, 122.12, 110.99, 107.68, 38.52, 36.77.

EXAMPLE 10: Synthesis and characterization of compounds 74 and 76

R²=R³=R⁵=H; R¹=CI; R⁴=CF₃ R²=R³=R⁵=H; R¹=CI; R⁴=CF₃

R¹=R⁴=R⁵=H; R²=R³=CI R¹=R⁴=R⁵=H; R²=R³=CI General procedure for the synthesis of 74 and 76

To a solution of the corresponding amino derivative (1 mmol) in DCM (5 mL) was added Et₃N (1.5 mmol) at 0 °C under N₂ atmosphere. After stirring for 15 min at 0 °C, acetyl chloride (1.4 mmol) was added to the reaction mixture and stirred for 30 min at rt. The mixture was then diluted with DCM (20 mL), and it was washed with water (10 mL) and dried over Na₂S0₄. The solvent was removed under reduced pressure, and the remaining residue was crystallized from EtOH to give the pure desired product.

N-(2-(2-chloro-5-(trifluoromethyl)benzyl)-l,3-dioxoisoindolin-4-yl)acetamide (74): Using the above method, compound 74 was prepared from 4-amino-2-(2-chloro-5-

(trifluoromethyl)benzyl)isoindoline-l,3-dione (9). Yield = 71%, pale yellow solid. ¾ NMR (400 MHz, CDC1₃) δ 9.45 (s, 1H), 8.82 (d, J = 8.5 Hz, 1H), 7.71 (t, J = 7.9 Hz, 1H), 7.59 - 7.47 (m, 4H), 4.99 (s, 2H), 2.27 (s, 3H). ¹³C NMR (101 MHz, CDC1₃) δ 169.72 (s), 169.43 (s), 167.34 (s), 137.85 (s), 137.17 (s), 136.45 (s), 134.43 (s), 131.37 (s), 130.53 (s), 130.13 - 128.70 (m), 126.32 (dd, J= 7.5, 3.8 Hz), 126.19 (q, J= 7.4, 3.7 Hz), 125.27 (s), 118.55 (s), 115.47 (s), 39.26 (s), 25.14 (s).

N-(2-(3,4-dichlorobenzyl)-l,3-dioxoisoindolin-4-yl)acetamide (76): Using the above method, compound 76 was prepared from 4-amino-2-(3,4-dichlorobenzyl)isoindoline-l,3-dione (37). Yield = 70%, pale yellow solid. ¾ NMR (400 MHz, CDC1₃) δ 9.45 (s, 1H), 8.78 (d, J = 8.5 Hz, 1H), 7.67 (t, J= 7.9 Hz, 1H), 7.54 - 7.48 (m, 2H), 7.40 (d, J = 8.2 Hz, 1H), 7.26 (s, 1H), 4.75 (s, 2H), 2.27 (s, 3H). ¹³C NMR (101 MHz, CDC1₃) δ 169.77 (s), 169.37 (s), 167.36 (s), 137.74 (s), 136.31 (s), 136.19 (s), 133.00 (s), 132.47 (s), 131.44 (s), 130.90 (s), 130.68 (s), 128.10 (s), 125.13 (s), 118.41 (s), 115.53 (s), 40.58 (s), 25.12 (s).

EXAMPLE 11: Synthesis and characterization of compounds 16 and 17

3 R²=R³=R⁵=H; R¹=R⁴=CI 16 R²=R³=R⁵=H; R =R⁴=CI

37 R =R⁴=R⁵=H; R²=R³=CI 17 R =R⁴=R⁵=H; R²=R³=CI General procedure for the synthesis of 16 and 17

To a 0 °C solution of the corresponding amino derivative (1 mmol) in concentrated HC1 (12 mL) was added a solution of NaN0₂ (2 mmol) drop wise over a period of 10 min with stirring. After stirring for 6 h at rt, the reaction mixture was cooled to 0 °C, and NaN₃ (2 mmol) was added with stirring. The reaction mixture was warmed to rt and stirred for 2 h. The precipitated azide derivative was filtered and washed with EtOH to afford the desired product.

4-azido-2-(2,5-dichlorobenzyl)isoindoline-l,3-dione (16): Compound 16 was prepared from 4- amino-2-(2,5-dichlorobenzyl)isoindoline-l,3-dione (3). Yield = 84%, light orange solid. ¾ NMR (400 MHz, CDC1₃) δ 7.70 (dd, J= 29.4, 6.5 Hz, 2H), 7.45 (d, J= 7.4 Hz, 1H), 7.30 (d, J= 8.2 Hz, 1H), 7.19 (d, J= 7.9 Hz, 2H), 4.92 (s, 2H). ¹³C NMR (101 MHz, CDC1₃) δ 166.92 (s), 165.77 (s), 138.72 (s), 135.85 (s), 135.04 (s), 134.08 (s), 133.01 (s), 131.51 (s), 130.90 (s), 129.20 (s), 128.91 (s), 125.39 (s), 120.62 (s), 119.95 (s), 39.30 (s).

4-azido-2-(3,4-dichlorobenzyl)isoindoline-l,3-dione (17): Compound 17 was prepared from 4- amino-2-(3,4-dichlorobenzyl)isoindoline-l,3-dione (37). Yield = 74%, off white solid. ¾ NMR (400 MHz, CDC1₃) δ 7.71 (t, J= 7.6 Hz, 1H), 7.62 (d, J= 7.2 Hz, 1H), 7.52 (s, 1H), 7.40 (dd, J = 12.0, 8.2 Hz, 2H), 7.27 (d, J = 9.9 Hz, 1H), 4.76 (s, 2H). ¹³C NMR (101 MHz, CDC1₃) δ 166.68 (s), 165.57 (s), 138.34 (s), 135.93 (s), 135.46 (s), 133.85 (s), 132.58 (s), 132.07 (s), 130.60 (s), 130.50 (s), 128.08 (s), 124.98 (s), 40.40 (s).

EXAMPLE 12: Synthesis and characterization of compound 99

2-(3-fluoro-4-hydroxybenzyl)isoindoline-l,3-dione (99): BBr₃ (2 mL, 1 0 M in DCM, 2 mmol) was added slowly to a solution of 99 (1 mmol) in DCM (5 mL) at 0 °C under N₂ atmosphere. After stirring at rt for 3 h, the reaction mixture was cooled back to 0 °C, and quenched with ice-cold water (50 mL). The reaction mixture was extracted with EtOAc (3 X 50 mL). The combined organic layer was washed with brine, dried over Na₂S0₄, and concentrated under reduced pressure. The residue was purified by crystallization from EtOH to afford compound 99 (Yield = 66 %, white solid). ¾ NMR (400 MHz, CDCh) δ 7.87 - 7.82 (m, 2H), 7.76 - 7.68 (m, 2H), 7.19 (d, J = 11.1 Hz, 1H), 7.12 (d, J = 8.4 Hz, 1H), 6.93 (t, J = 8.6 Hz, 1H), 5.19 (s, 1H), 4.75 (s, 2H). ¹³C MR (101 MHz, CDCb) δ 168.02 (s), 150.70 (d, J= 238.3 Hz), 143.23 (d, J= 14.2 Hz), 134.11 (s), 132.03 (s), 129.25 (d, J = 5.9 Hz), 125.37 (d, J = 3.4 Hz), 123.44 (s), 117.30 (d, J = 2.1 Hz), 116.12 (d, J= 18.7 Hz), 40.78 (s).

EXAMPLE 13: Synthesis and characterization of compounds 13 and 14

General procedure for the synthesis of 13 and 14

To a solution of 16 (1 mmol) in t-BuOH:H₂0 (1 : 1, 30 mL) was added a freshly-made solution of sodium ascorbate (1 M, 150 μί, 0.15 mmol) and CuS0₄.6H₂0 (1 M, 170 μί, 0.17 mmol). After degassing for 15 min, the proper acetylene reagent, phenyl acetylene or 2-propynamide (1.5 mmol) was added to the reaction mixture and it was stirred at 85 °C for 5-6 h. After removing the volatiles under reduced pressure, water (50 mL) was added and the mixture was extracted with EtOAc (3 X 50 mL). The combined organic layer was washed with brine, dried over Na₂S0₄ and evaporated. The remaining residue was triturated using Et₂0 to afford the desired pure product.

2-(2,5-dichlorobenzyl)-4-(4-phenyl-lH-l,2,3-triazol-l-yl)isoindoline-l,3-dione (13):

Compound 13 was prepared from 4-azido-2-(2,5-dichlorobenzyl)isoindoline-l,3-dione (16) and phenyl acetylene. Yield = 73%, yellow solid. ¾NMR (400 MHz, CDCb) δ 9.08 (s, 1H), 8.51 (dd, J= 8.0, 0.8 Hz, 1H), 8.04 - 7.91 (m, 4H), 7.47 (t, J= 7.5 Hz, 2H), 7.42 - 7.31 (m, 2H), 7.25 - 7.17 (m, 2H), 4.99 (s, 2H). ¹³C NMR (101 MHz, CDCb) δ 166.37 (s), 165.89 (s), 148.14 (s), 136.23 (s), 134.65 (s), 134.27 (s), 133.66 (s), 133.19 (s), 131.52 (s), 131.07 (s), 130.06 (s), 129.92 (s), 129.45 (s), 129.06 (s), 128.82 (s), 128.71 (s), 126.20 (s), 123.90 (s), 122.47 (s), 120.38 (s), 39.63

l-(2-(2,5-dichlorobenzyl)-l,3-dioxoisoindolin-4-yl)-lH-l,2,3-triazole-4-carboxamide (14):

Compound 14 was prepared from 4-azido-2-(2,5-dichlorobenzyl)isoindoline-l,3-dione (16) and 2- propynamide. Yield = 23%, yellow solid. ¾ NMR (400 MHz, DMSO) δ 9.15 (s, 1H), 8.21 (d, J = 7.4 Hz, 1H), 8.17 - 8.06 (m, 3H), 7.67 (s, 1H), 7.58 - 7.52 (m, 2H), 7.42 (dd, J = 8.5, 2.4 Hz, 1H), 4.83 (s, 2H). ¹³C NMR (101 MHz, DMSO) δ 166.48 (s), 165.27 (s), 161.06 (s), 142.83 (s), 135.96 (s), 135.38 (s), 133.21 (s), 132.18 (s), 132.09 (s), 130.95 (s), 130.61 (s), 130.39 (s), 129.19 (s), 129.15 (s), 128.50 (s), 124.28 (s), 123.79 (s). EXAMPLE 14: Synthesis and characterization of compounds 102, 105-115

102 R¹⁶=R²°=CI; R¹⁷=R²³=H

106 R ⁷=R²⁰=CI; R²=R²³= H

107 R²=H; R¹⁷=CF₃; R²⁰=CI; R²³= H;

109 R¹⁶=R²⁰=CI, R¹⁷=H; R²³=CH₃

113 R ⁷=R²⁰= H; R¹⁶=CI; R²³=H

114 R¹⁷=H; R¹⁶=CI; R²⁰=F; R²³=H

115 R¹⁷=H; R¹⁶=R²⁰=F; R²³=H

General procedure for the synthesis of 102, 105-115

A mixture of the appropriate amine (1 mmol) and the appropriate benzyl bromide (1 mmol) in DMF (0.5 M) was stirred at room temperature up to 100 °C until completion of the reaction (up to 5 days). The reaction mixture was either diluted with EtOAc and the resultant precipitate filtered to give pure product or quenched with sat. NaHC0₃ and extracted with EtOAc. Crude material was purified either by automated flash chromatography (EtOAc :hexanes mixture) or by preparative HPLC to give the desired compound in 10-50% yield.

5-((2,6-dichlorobenzyl)amino)isoindoline-l,3-dione (102): ¾ NMR (400 MHz, DMSO- e) δ 10.80 (s, 1H), 7.55 (dd, J = 13.2, 8.2 Hz, 3H), 7.48 - 7.40 (m, 1H), 7.15 (t, J= 4.7 Hz, 1H), 7.03 (d, J= 2.1 Hz, 1H), 6.97 (dd, J= 8.4, 2.1 Hz, 1H), 4.53 (d, J= 4.6 Hz, 2H). ¹³C NMR (101 MHz, DMSO) 5 170.07, 169.81, 154.14, 136.18, 135.86, 133.44, 131.11, 129.23, 125.00, 118.91, 115.96, 105.49, 43.32.

4-(2,6-dichlorobenzyl)isoindoline-l,3-dione (105): ¾ NMR (400 MHz, DMSO- e) δ 11.04 (s, 1H), 7.61 (dd, J= 8.4, 7.2 Hz, 1H), 7.56 (d, J = 8.1 Hz, 2H), 7.42 (dd, J = 8.7, 7.5 Hz, 1H), 7.27 (d, J= 8.5 Hz, 1H), 7.02 (d, J= 7.1 Hz, 1H), 6.61 (t, J= 6.0 Hz, 1H), 4.75 (d, J= 6.0 Hz, 2H). ¹³C NMR (101 MHz, DMSO) δ 172.00, 169.62, 145.97, 136.58, 135.60, 133.99, 133.71, 131.27, 129.52, 117.18, 112.15, 111.38, 42.49. 5- ((2,5-dichlorobenzyl)amino)isoindoline-l,3-dione (106): ¾ NMR (400 MHz, DMSO- e) δ 10.82 (s, 1H), 7.60 - 7.47 (m, 3H), 7.41 (dq, J= 4.2, 2.6 Hz, 2H), 6.94 - 6.78 (m, 2H), 4.49 (d, J = 5.9 Hz, 2H). ¹³C NMR (101 MHz, DMSO) δ 169.97, 169.68, 153.84, 138.61, 135.86, 132.46, 131.69, 129.25, 128.87, 125.16, 119.43, 116.21, 105.70, 44.26. 5-((2-chloro-5-(trifluoromethyl)benzyl)amino)isoindoline-l,3-dione (107): ¾ NMR (400 MHz, DMSO- e) δ 10.83 (s, 1H), 7.86 - 7.66 (m, 3H), 7.54 (dd, J= 11.7, 7.0 Hz, 2H), 7.01 - 6.77 (m, 2H), 4.57 (d, J= 5.9 Hz, 2H). ¹³C NMR (101 MHz, DMSO) δ 169.95, 169.68, 153.87, 138.00, 137.55, 135.85, 131.15, 128.60, 128.28, 126.29, 126.25, 126.06, 126.02, 125.98, 125.15, 119.49, 116.22, 105.72, 44.35. N-(2,6-dichlorobenzyl)-lH-indol-5-amine (108): ¾ NMR (400 MHz, DMSO- e) δ 10.66 (s, 1H), 7.51 (d, J= 8.0 Hz, 2H), 7.37 (dd, J= 8.7, 7.4 Hz, 1H), 7.20 - 7.08 (m, 2H), 6.80 (d, J= 2.1 Hz, 1H), 6.65 (dd, J= 8.6, 2.2 Hz, 1H), 6.26 - 6.12 (m, 1H), 5.06 (s, 1H), 4.41 (s, 2H). ¹³C NMR (101 MHz, DMSO) δ 142.49, 136.09, 135.29, 130.43, 130.28, 129.07, 128.79, 125.19, 112.06, 112.00, 101.21, 100.56, 44.93. 5-((2,6-dichlorobenzyl)amino)-6-methylisoindoline-l,3-dione (109): ¾ NMR (400 MHz, DMSO- e) δ 10.72 (s, 1H), 7.52 (d, J= 8.1 Hz, 2H), 7.46 - 7.34 (m, 2H), 7.01 (s, 1H), 6.17 (t, J =

4.8 Hz, 1H), 4.64 (d, J= 4.7 Hz, 2H), 2.20 (s, 3H). ¹³C NMR (101 MHz, DMSO) δ 170.31, 170.09, 151.63, 136.29, 133.98, 133.53, 130.81, 129.21, 127.86, 124.88, 119.60, 102.63, 43.81, 18.92.

6- ((2,6-dichlorobenzyl)amino)isoindolin-l-one (110): ¾NMR (400 MHz, DMSO- e) δ 8 35 (s, 1H), 7.53 (d, J= 8.1 Hz, 2H), 7.40 (dd, J= 8.7, 7.4 Hz, 1H), 7.27 (d, J= 8.1 Hz, 1H), 7.00 - 6.90

(m, 2H), 6.04 (t, J = 5.0 Hz, 1H), 4.44 (d, J = 4.9 Hz, 2H), 4.21 (s, 2H). ¹³C NMR (101 MHz, DMSO) 6 171.02, 149.07, 136.14, 134.47, 133.96, 132.10, 130.70, 129.13, 124.19, 117.37, 104.69, 44.75, 43.76Λ

N-(2,6-dichlorobenzyl)-lH-indazol-5-amine (111): ¾ NMR (400 MHz, DMSO- e) δ 12.65 (s, 1H), 7.80 (d, J= 1.0 Hz, 1H), 7.53 (d, J= 8.0 Hz, 2H), 7.39 (dd, J= 8.7, 7.4 Hz, 1H), 7.30 (d, J =

8.9 Hz, 1H), 6.93 (dd, J = 8.9, 2.1 Hz, 1H), 6.82 (d, J= 2.0 Hz, 1H), 5.50 (s, 1H), 4.40 (d, J= 3.3 Hz, 2H). ¹³C NMR (101 MHz, DMSO) δ 143.46, 136.15, 135.18, 134.84, 132.21, 130.59, 129.09, 124.13, 118.57, 111.04, 97.57, 44.42. N-(2,6-dichlorobenzyl)quinoxalin-6-amine (112): ¾ NMR (400 MHz, DMSO-d₆) δ 8 67 (d, J = 2.0 Hz, 1H), 8.50 (d, J= 2.0 Hz, 1H), 7.76 (d, J= 9.2 Hz, 1H), 7.57 (d, J= 8.1 Hz, 2H), 7.51 - 7.31 (m, 2H), 6.98 (d, J= 2.5 Hz, 1H), 6.89 (t, J= 4.7 Hz, 1H), 4.56 (d, J= 4.6 Hz, 2H). ¹³C NMR (101 MHz, DMSO) δ 150.05, 145.65, 145.46, 140.40, 137.46, 136.22, 133.79, 130.96, 129.85, 129.21, 122.98, 102.16, 43.40.

5-((2-chlorobenzyl)amino)isoindoline-l,3-dione (113): ¾ NMR (400 MHz, DMSO- e) δ 10 79 (s, 1H), 7.61 - 7.46 (m, 3H), 7.36 (ddd, J= 22.4, 5.8, 3.6 Hz, 3H), 6.91 - 6.77 (m, 2H), 4.49 (d, J = 5.9 Hz, 2H). ¹³C NMR (101 MHz, DMSO) δ 170.02, 169.71, 154.12, 136.07, 135.83, 132.97, 129.95, 129.43, 129.40, 127.84, 125.09, 119.05, 116.12, 105.62, 44.48. 5-((2-chloro-6-fluorobenzyl)amino)isoindoline-l,3-dione (114): ¾ NMR (400 MHz, DMSO- d₆) δ 10.79 (s, 1H), 7.52 (d, J= 8.3 Hz, 1H), 7.49 - 7.38 (m, 2H), 7.35 - 7.23 (m, 2H), 7.02 (d, J = 2.1 Hz, 1H), 6.95 (dd, J= 8.3, 2.2 Hz, 1H), 4.46 (dd, J= 5.2, 1.6 Hz, 2H). ¹³C NMR (101 MHz, DMSO) δ 170.03, 169.76, 163.02, 160.55, 153.99, 135.88, 135.48, 135.43, 131.16, 131.06, 128.17, 126.23, 126.19, 125.00, 123.98, 123.80, 118.98, 115.95, 115.33, 115.10, 105.37, 38.80, 38.77. 5-((2,6-difluorobenzyl)amino)isoindoline-l,3-dione (115): ¾ NMR (400 MHz, DMSO- e) δ 10.79 (s, 1H), 7.51 (d, J = 8.3 Hz, 1H), 7.45 (ddd, J = 8.4, 6.6, 1.8 Hz, 1H), 7.37 (t, J = 5.6 Hz, 1H), 7.16 (t, J= 8.0 Hz, 2H), 6.99 (d, J= 2.1 Hz, 1H), 6.92 (dd, J= 8.3, 2.2 Hz, 1H), 4.42 (d, J = 5.5 Hz, 2H). ¹³C NMR (101 MHz, DMSO) δ 170.02, 169.75, 162.83, 162.75, 160.38, 160.30, 153.89, 135.89, 130.92, 130.82, 130.72, 125.01, 119.00, 115.92, 114.22, 112.35, 112.28, 112.16, 112.10, 105.20, 34.95.

EXAMPLE 15: Synthesis and characterization of compound 103

5-((2,6-dichlorobenzyl)(methyl)amino)isoindoline-l,3-dione (103): A mixture of compound 102 (0.09 mmol) and methyl iodide (0.09 mmol) in DMF (0.2 mL)was stirred at 80 °C for 72 h. The reaction was quenched with 0.5M NaOH and extracted with EtOAc. The organic layer was dried over Na₂S0₄ and filtered. Purification via preparative HPLC gave 103 in 3% yield. ¾ NMR (400 MHz, DMSO- e) δ 10.88 (s, 1H), 7.62 (d, J= 8.5 Hz, 1H), 7.57 (d, J= 8.0 Hz, 2H), 7.44 (dd, J= 8.7, 7.4 Hz, 1H), 7.21 (d, J= 2.4 Hz, 1H), 7.16 (dd, J= 8.6, 2.4 Hz, 1H), 4.88 (s, 2H), 2.82 (s, 3H). ¹³C NMR (101 MHz, DMSO) δ 170.15, 154.47, 136.34, 135.65, 132.51, 131.17, 129.54, 124.77, 116.47, 106.25, 50.31, 36.36.

EXAMPLE 16: Synthesis and characterization of compound 104

5-((2,6-dichlorobenzyl)amino)-2-methylisoindoline-l,3-dione (104): To compound 102 (0.09 mmol) in DMF (0.2 mL) was added NaH (0.09 mmol) followed by methyl iodide (0.09 mmol). The reaction mixture was stirred at room temperature for 1 h then quenched with H₂0. The aqueous layer was extracted with EtOAc and the combined organic layers was dried over Na₂S0₄ and filtered. The crude material was triturated in mixture of DMSO:ACN:H₂0 (1 : 1 : 1) followed by another trituration in EtOH and filtered to give compound 104 in 33% yield. ¾ NMR (400 MHz, DMSO- e) δ 7.57 (dd, J= 8.2, 3.7 Hz, 3H), 7.43 (dd, J= 8.7, 7.4 Hz, 1H), 7.17 (t, J= 4.7 Hz, 1H), 7.09 (d, J= 2.1 Hz, 1H), 6.95 (dd, J= 8.3, 2.2 Hz, 1H), 4.54 (d, J= 4.6 Hz, 2H), 2.98 (s, 3H). ¹³C NMR (101 MHz, DMSO) δ 168.83, 168.59, 154.10, 136.18, 135.05, 133.43, 131.11, 129.24, 125.08, 117.92, 115.46, 105.96, 43.33, 23.95.

EXAMPLE 17: Synthesis and characterization of compound 116

116

2,6-dichloro-N-(l,3-dioxoisoindolin-5-yl)benzenesulfonamide (116): A mixture of 4- aminophthalimide (1.2 mmol), 2,6-dichlorobenzenesulfonyl chloride (1.2 mmol), trimethylamine (1.4 mmol), and DMAP (cat.) in toluene was heated at 100 °C for 72 h. The reaction mixture was quenched with H₂0 and extracted with EtOAc. The combined organic layers was dried over Na₂SC"4 and filtered. Purification via preparative HPLC gave compound 116 in 3% yield. ¾NMR (400 MHz, DMSO- e) δ 11.75 (s, 1H), 11.22 (s, 1H), 7.74 (d, J = 8.1 Hz, 1H), 7.71 - 7.64 (m, 2H), 7.59 (dd, J = 8.9, 7.1 Hz, 1H), 7.48 - 7.36 (m, 2H). ¹³C MR (101 MHz, DMSO) δ 169.04, 169.01, 135.08, 135.04, 134.91, 132.60, 127.08, 125.13, 122.59, 111.35.

EXAMPLE 18: Synthesis and characterization of compound 117

l-(2,6-dichlorophenyl)-3-(l,3-dioxoisoindolin-5-yl)urea (117): A mixture of 4- aminophthalimide (0.62 mmol), 2,6-dichlorophenylisocyanate (0.62 mmol), and DMF (cat.) in toluene (3 mL) was heated at 105 °C for 19 h. The reaction mixture was concentrated and the crude material was purified via preparative HPLC to give compound 117 in 1% yield. ¾ NMR (400 MHz, DMSO- e) δ 11.15 (s, 1H), 9.78 (s, 1H), 8.60 (s, 1H), 8.05 (t, J = 1.2 Hz, 1H), 7.73 (d, J = 1.2 Hz, 2H), 7.57 (d, J = 8.1 Hz, 2H), 7.36 (t, J = 8.1 Hz, 1H). ¹³C NMR (101 MHz, DMSO) δ 169.63, 169.49, 152.71, 146.11, 134.78, 134.62, 133.35, 129.33, 129.00, 125.49, 124.55, 122.71, 111.96. EXAMPLE 19: Synthesis and characterization of compounds 200-219.

216 217 218 219

General procedure for the synthesis of 200-219.

A mixture of the appropriate amine (1.0 eq) and the aldehyde (1.0 eq) was dissolved in 1,2- dichloroethane (0.1 M) and treated with NaBH(OAc)₃ (1.3 eq) and AcOH (1.0 eq). The resulting mixture was stirred at room temperature until completion of the reaction. The reaction was quenched by the addition of sat. NaHC0₃. If a precipitate formed it was isolated by filtration and purified by crystallization. If no precipitate formed, the aqueous layer was extracted with DCM. The combined organic layers were washed with water and brine, dried over Na₂S0₄, filtered and concentrated. Crude material was purified by automated flash chromatography (EtOAc:hexanes mixture) to give the desired compound in 17-85 % yield.

N-(2,6-dichlorobenzyl)-lH-indazol-4-amine (200): ¾ MR (400 MHz, DMSO-d₆) δ = 12 69 (s, 1H), 8.21 (t, J = 1.3 Hz, 1H), 7.53 (d, J = 8.4 Hz, 2H), 7.40 (dd, J = 8.7, 7.4 Hz, 1H), 7.10 (t, J = 7.9 Hz, 1H), 6.71 (d, J = 8.3 Hz, 1H), 6.31 (t, J = 4.6 Hz, 1H), 6.19 (d, J = 7.5 Hz, 1H), 4.53 (d, J = 4.7 Hz, 2H). ¹³C MR (101 MHz, DMSO-d₆) δ = 141.7, 141.2, 135.9, 133.7, 132.1, 130.2, 128.6, 127.6, 113.2, 97.8, 97.4, 43.1.

6-((2,6-dichlorobenzyl)amino)-2H-benzo[b] [l,4]oxazin-3(4H)-one (201): ¾ MR (400 MHz, CDC1₃) δ = 10.50 (s, 1H), 7.50 (d, J = 8.4 Hz, 2H), 7.37 (dd, J = 8.7, 7.4 Hz, 1H), 6.72 (d, J = 8.5 Hz, 1H), 6.30 (d, J = 2.6 Hz, 1H), 6.26 (dd, J = 8.6, 2.7 Hz, 1H), 5.58 (t, J = 5.2 Hz, 1H), 4.40 (s, 2H), 4.29 (d, J = 5.1 Hz, 2H). C NMR (101 MHz, CDCb) δ = 165.6, 144.4, 135.6, 134.6, 134.1, 130.1, 128.6, 127.8, 116.4, 106.4, 100.0, 67.0, 43.6.

4-((2,6-dichlorobenzyl)amino)benzenesulfonamide (202): ¾ NMR (400 MHz, DMSO-<f₆) δ = 7.55 - 7.51 (m, 4H), 7.40 (dd, J = 8.7, 7.3 Hz, 1H), 6.93 (s, 2H), 6.75 (d, J = 8.8 Hz, 2H), 6.56 (t, J = 4.8 Hz, 1H), 4.44 (d, J = 4.7 Hz, 2H). ¹³C NMR (101 MHz, DMSO-d₆) δ = 151.1, 135.6, 133.4, 130.6, 130.4, 128.7, 127.3, 110.9, 42.7.

4- ((2,6-dichlorobenzyl)amino)benzamide (203): ¾ NMR (400 MHz, DMSO-d₆) δ = 7 66 (d, J = 8.7 Hz, 2H), 7.55 (bs, 1H), 7.52 (d, J = 7.6 Hz, 2H), 7.39 (dd, J = 8.7, 7.4 Hz, 1H), 6.87 (bs, 1H), 6.67 (d, J = 8.7 Hz, 2H), 6.34 (t, J = 4.8 Hz, 1H), 4.43 (d, J = 4.8 Hz, 2H). ¹³C NMR (101 MHz, DMSO- e) δ = 167.9, 151.0, 135.6, 133.7, 130.3, 129.0, 128.7, 121.4, 110.8, 42.7.

5- ((2,6-dichlorobenzyl)amino)indolin-2-one (204): ¾ NMR (400 MHz, DMSO-d₆) δ = 9 97 (s, 1H), 7.50 (d, J = 8.3 Hz, 2H), 7.36 (dd, J = 8.7, 7.4 Hz, 1H), 6.67 (d, J = 2.1 Hz, 1H), 6.59 (d, J = 8.3 Hz, 1H), 6.51 (dd, J = 8.3, 2.3 Hz, 1H), 5.31 (t, J = 5.4 Hz, 1H), 4.32 (d, J = 5.4 Hz, 2H), 3.36 (s, 2H). ¹³C NMR (101 MHz, DMSO-dis) δ = 175.8, 144.0, 135.6, 134.4, 134.0, 130.1, 128.6, 126.7, 110.6, 110.2, 109.3, 43.9, 36.2.

7-((2,6-dichlorobenzyl)amino)-3,4-dihydroquinolin-2(lH)-one (205): ¾ NMR (400 MHz, DMSO- e) δ = 9.86 (s, 1H), 7.49 (d, J = 8.1 Hz, 2H), 7.37 (dd, J = 8.7, 7.4 Hz, 1H), 6.87 (d, J = 8.1 Hz, 1H), 6.27 (dd, J = 8.1, 2.3 Hz, 1H), 6.24 (d, J = 2.2 Hz, 1H), 5.70 (s, 1H), 4.31 (s, 2H), 2.74 - 2.66 (m, 2H), 2.42 - 2.33 (m, 2H). ¹³C NMR (101 MHz, DMSO-d₆) δ = 170.5, 147.9, 138.7, 135.6, 134.1, 130.1, 128.6, 128.0, 111.2, 106.1, 99.3, 43.2, 31.2, 24.1.

N-(2,6-dichlorobenzyl)-lH-indazol-7-amine (206): ¾ NMR (400 MHz, DMSO-d₆) δ = 12.55 (s, 1H), 7.93 (s, 1H), 7.58 (d, J = 8.1 Hz, 2H), 7.44 (dd, J = 8.7, 7.5 Hz, 1H), 7.02 (d, J = 8.0 Hz, 1H), 6.95 (t, J = 7.6 Hz, 1H), 6.55 (d, J = 7.2 Hz, 1H), 5.63 (t, J = 4.8 Hz, 1H), 4.58 (d, J = 4.8 Hz, 2H). ¹³C NMR (101 MHz, DMSO-dis) δ = 135.8, 133.7, 133.1, 131.1, 130.6, 128.8, 123.2, 121.8, 108.2, 103.0, 43.1.

6- ((2,6-dichlorobenzyl)amino)-2-(fluoromethyl)-3-(o-tolyl)quinazolin-4(3H)-one (207): ¾

NMR (400 MHz, DMSO- e) δ = 7.59 (d, J = 8.8 Hz, 1H), 7.53 (d, J = 8.4 Hz, 2H), 7.45 - 7.36 (m, 5H), 7.33 (dd, J = 8.9, 2.8 Hz, 1H), 7.26 (d, J = 2.7 Hz, 1H), 6.65 (t, J = 4.8 Hz, 1H), 4.96 (dd, JH-F = 47.1 Hz, JAB = 1 1.6 Hz, 1H), 4.91 (dd, JH-F = 46.8 Hz, JAB = 11.6 Hz, 1H), 4.50 (d, J = 4.7 Hz, 2H), 2.02 (s, 3H). ¹³C NMR (101 MHz, DMSO- ₆) δ = 160.3, 148.4, 145.5 (d, JC-F = 15.8 Hz), 137.8, 136.1, 135.7, 135.4, 133.5, 130.8, 130.4, 129.4, 128.7, 128.7, 128.6, 127.0, 122.2, 122.0, 103.4, 81.6 (d, JC-F = 170.2 Hz), 43.0, 17.0.

N-(2,6-dichlorobenzyl)-lH-benzo[d]imidazol-5-amine (208): ¾ NMR (400 MHz, DMSO- e) δ = 11.98 (s, 1H), 7.91 (s, 1H), 7.50 (d, J = 8.2 Hz, 2H), 7.37 (dd, J = 8.7, 7.5 Hz, 1H), 7.31 (d, J = 8.7 Hz, 1H), 6.77 (d, J = 2.1 Hz, 1H), 6.68 (dd, J = 8.6, 2.2 Hz, 1H), 5.54 (t, J = 5.3 Hz, 1H), 4.41 (d, J = 5.2 Hz, 2H). ¹³C NMR (101 MHz, DMSO-dis) δ = 144.9, 139.6, 135.6, 134.4, 130.1, 128.6, 117.0, 110.9, 94.3, 43.9.

5-((2,6-dichlorobenzyl)amino)-l,3-dihydro-2H-benzo[d]imidazol-2-one (209): ¾ NMR (400 MHz, DMSO- e) δ = 10.26 (s, 1H), 10.09 (s, 1H), 7.49 (d, J = 8.3 Hz, 2H), 7.36 (dd, J = 8.7, 7.4 Hz, 1H), 6.66 (d, J = 8.2 Hz, 1H), 6.37 (d, J = 2.1 Hz, 1H), 6.32 (dd, J = 8.3, 2.2 Hz, 1H), 5.30 (t, J = 5.4 Hz, 1H), 4.33 (d, J = 5.4 Hz, 2H). ¹³C NMR (101 MHz, DMSO-d₆) δ = 155.5, 143.7, 135.6, 134.4, 130.6, 130.0, 128.6, 121.1, 108.7, 105.2, 94.1, 44.0.

N-(2,6-dichlorobenzyl)-lH-indazol-3-amine (210): ¾ NMR (400 MHz, DMSO-d₆) δ = 1 1.50 (s, 1H), 7.75 (d, J = 9.1 Hz, 1H), 7.51 (d, J = 7.6 Hz, 2H), 7.38 (dd, J = 8.7, 7.4 Hz, 1H), 7.26 - 7.19 (m, 2H), 6.87 (ddd, J = 7.9, 5.7, 2.0 Hz, 1H), 6.09 (t, J = 5.1 Hz, 1H), 4.65 (d, J = 5.1 Hz, 2H). ¹³C NMR (101 MHz, DMSO-dis) δ = 149.6, 141.8, 135.9, 134.6, 130.0, 128.5, 126.3, 120.4, 117.4, 113.5, 109.3, 43.1.

2-(cyclopropylmethyl)-5-((2,6-dichlorobenzyl)amino)isoindoline-l,3-dione (211): ¾ NMR

(400 MHz, DMSO- e) δ = 7.60 - 7.54 (m, 3H), 7.43 (dd, J = 8.7, 7.4 Hz, 1H), 7.22 (t, J = 4.6 Hz, 1H), 7.09 (d, J = 2.1 Hz, 1H), 6.95 (dd, J = 8.4, 2.2 Hz, 1H), 4.53 (d, J = 4.6 Hz, 2H), 3.37 (d, J = 7.1 Hz, 2H), 1.11 - 1.00 (m, 1H), 0.46 - 0.39 (m, 2H), 0.31 - 0.24 (m, 2H). ¹³C NMR (101 MHz, DMSO- e) δ = 168.3, 168.0, 153.8, 135.7, 134.4, 133.0, 130.7, 128.8, 124.8, 117.2, 115.3, 105.4, 42.9, 41.4, 10.5, 3.5.

7-((2,6-dichlorobenzyl)amino)-3,4-dihydroisoquinolin-l(2H)-one (212): ¾ NMR (400 MHz, DMSO- e) δ = 7.78 (s, 1H), 7.53 - 7.49 (m, 2H), 7.37 (dd, J = 8.7, 7.4 Hz, 1H), 7.19 (d, J = 2.5 Hz, 1H), 7.02 (d, J = 8.2 Hz, 1H), 6.81 (dd, J = 8.2, 2.6 Hz, 1H), 5.86 (t, J = 5.1 Hz, 1H), 4.38 (d, J = 5.0 Hz, 2H), 3.29 (td, J = 6.5, 2.6 Hz, 2H), 2.72 (t, J = 6.5 Hz, 2H). ¹³C NMR (101 MHz, DMSO-i&) 6 = 165.1, 147.4, 135.7, 134.1, 130.2, 129.8, 128.7, 127.9, 126.7, 1 16.0, 1 10.0, 43.2, 39.6, 26.9. 5-((2,6-dichlorobenzyl)amino)-2-((tetrahydrofuran-2-yl)methyl)isoindoline-l,3-dione (213):

¾ NMR (400 MHz, DMSO- ₆) δ = 7.58 - 7.54 (m, 3H), 7.42 (dd, J = 8.7, 7.4 Hz, 1H), 7.22 (t, J = 4.6 Hz, 1H), 7.08 (d, J = 2.1 Hz, 1H), 6.95 (dd, J = 8.3, 2.2 Hz, 1H), 4.53 (d, J = 4.6 Hz, 2H), 4.09 - 4.01 (m, 1H), 3.78 - 3.67 (m, 1H), 3.62 - 3.53 (m, 2H), 3.45 (dd, J = 13.8, 5.5 Hz, 1H), 1.95 - 1.74 (m, 3H), 1.64 - 1.51 (m, 1H). ¹³C NMR (101 MHz, DMSO-d₆) δ = 168.2, 167.9, 153.8, 135.7, 134.3, 132.9, 130.7, 128.8, 124.8, 1 17.1, 1 15.3, 105.4, 75.5, 67.0, 42.9, 41.1, 28.7, 24.8.

2-cyclopropyl-5-((2,6-dichlorobenzyl)amino)isoindoline-l,3-dione (214): ¾ NMR (400 MHz, DMSO- e) δ = 7.56 - 7.51 (m, 3H), 7.42 (dd, J = 8.7, 7.4 Hz, 1H), 7.16 (t, J = 4.6 Hz, 1H), 7.02 (d, J = 2.1 Hz, 1H), 6.93 (dd, J = 8.4, 2.2 Hz, 1H), 4.52 (d, J = 4.6 Hz, 2H), 2.61 - 2.54 (m, 1H), 0.91 - 0.78 (m, 4H). ¹³C NMR (101 MHz, DMSO-d₆) δ = 168.8, 168.5, 153.7, 135.7, 134.1, 133.0, 130.7, 128.8, 124.5, 1 17.1, 1 15.4, 105.1, 42.8, 20.3, 5.0.

6-((2,6-dichlorobenzyl)amino)quinazolin-4(3H)-one (215): ¾ NMR (400 MHz, DMSO-d₆) δ = 7.81 (s, 1H), 7.53 (d, J = 8.1 Hz, 2H), 7.45 - 7.37 (m, 2H), 7.24 - 7.19 (m, 2H), 6.39 (t, J = 4.8 Hz, 1H), 4.45 (d, J = 4.8 Hz, 2H). N-(2,6-dichlorobenzyl)-l-(l-methyl-lH-indol-3-yl)methanamine (216): ¾ NMR (400 MHz, DMSO- e) δ = 7.55 (d, J = 7.8 Hz, 1H), 7.46 (d, J = 8.0 Hz, 2H), 7.37 (d, J = 8.3 Hz, 1H), 7.32 (dd, J = 8.6, 7.5 Hz, 1H), 7.23 (s, 1H), 7.12 (ddd, J = 8.2, 7.0, 1.2 Hz, 1H), 6.99 (ddd, J = 7.9, 7.0, 1.1 Hz, 1H), 4.00 (s, 2H), 3.88 (s, 2H), 3.73 (s, 3H). 1.94 (s, 1H). ¹³C NMR (101 MHz, OMSO-d₆) 6 = 136.8, 135.8, 135.2, 129.6, 128.5, 127.8, 127.2, 121.1, 1 18.9, 1 18.4, 1 12.7, 109.5, 47.7, 44.0, 32.2.

N-(2,6-dichlorobenzyl)-l-(l-methyl-lH-indol-2-yl)methanamine (217): ¾ NMR (400 MHz, DMSO- e) δ = 7.46 (d, J = 8.1 Hz, 2H), 7.38 (d, J = 7.9 Hz, 1H), 7.32 (dd, J = 8.6, 7.5 Hz, 1H), 7.09 (ddd, J = 8.2, 7.0, 1.2 Hz, 1H), 6.97 (td, J = 7.4, 7.0, 1.0 Hz, 1H), 6.38 (s, 1H), 3.98 (d, J = 7.0 Hz, 2H), 3.92 (d, J = 5.7 Hz, 2H), 3.72 (s, 3H), 2.27 (s, 1H). ¹³C NMR (101 MHz, DMSO- d₆) δ = 138.7, 137.5, 135.5, 135.3, 129.8, 128.6, 126.9, 120.6, 1 19.7, 1 18.8, 109.2, 100.4, 47.3, 44.8, 29.4.

N-(2,6-dichlorobenzyl)-l-(quinoxalin-6-yl)methanamine (218): ¾ NMR (400 MHz, CDCb) δ = 8.77 (d, J = 1.9 Hz, 1H), 8.75 (d, J = 1.9 Hz, 1H), 8.03 - 7.99 (m, 2H), 7.78 (dd, J = 8.7, 1.9 Hz, 1H), 7.24 (d, J = 8.0 Hz, 2H), 7.07 (dd, J = 8.5, 7.6 Hz, 1H), 4.10 (s, 2H), 4.01 (s, 2H), 2.04 (s, 1H). ¹³C NMR (101 MHz, CDCb) δ = 145.0, 144.5, 143.0, 142.8, 142.4, 136.0, 135.6, 130.8, 129.3, 129.0, 128.4, 127.7, 52.6, 48.1.

N-((lH-indazol-5-yl)methyl)-l-(2,6-dichlorophenyl)methanamine (219): The compound precipitated out of the reaction mixture and was isolated by suction filtration without quenching with NaHC0₃. The compound was isolated as the acetic acid salt. ¾ NMR (400 MHz, DMSO- d₆) δ = 8.00 (d, J = 1.0 Hz, 1H), 7.68 (s, 1H), 7.49 - 7.44 (m, Hz, 3H), 7.36 (dd, J = 8.6, 1.5 Hz, 1H), 7.31 (dd, J = 8.6, 7.5 Hz, 1H), 3.91 (s, 2H), 3.83 (s, 2H), 1.86 (s, 3H). ¹³C NMR (101 MHz, OMSO-d₆) 6 = 172.4, 139.3, 135.8, 135.3, 133.1, 132.3, 129.7, 128.5, 126.8, 122.8, 1 19.0, 109.8, 52.7, 47.4, 21.8.

EXAMPLE 20: Synthesis and characterization of compound 220.

N-(2,6-dichlorobenzyl)-N-(quinoxalin-6-ylmethyl)ethanamine (220): Amine 218 (59 mg, 1.0 eq) was dissolved in DCE (2 mL) and treated with acetaldehyde (100 μί, 10 eq), NaBH(OAc)₃ (51 mg, 1.3 eq) and AcOH (1 1 μί, 1.0 eq). The reaction was stirred at room temperature for 24 h after which it was quenched by the addition of sat. NaHC0₃. The aqueous layer was extracted with DCM (2 x). The combined organic layers were washed with water and brine, dried over Na₂S0₄, filtered and concentrated. Crude material was purified by automated flash

chromatography (EtOAc:hexanes mixture) to give 220 (44 mg, 68 %) as an off-white solid. ¾ NMR (400 MHz, CDCb) δ = 8.82 (d, J = 1.9 Hz, 1H), 8.80 (d, J = 1.9 Hz, 1H), 8.02 - 7.97 (m, 2H), 7.80 (dd, J = 8.7, 1.9 Hz, 1H), 7.31 - 7.26 (m, 2H), 7.10 (dd, J = 8.4, 7.6 Hz, 1H), 4.00 (s, 2H), 3.85 (s, 2H), 2.64 (q, J = 7.1 Hz, 2H), 1.14 (t, J = 7.1 Hz, 3H). ¹³C MR (101 MHz, CDC1₃) 5 = 144.9, 144.4, 143.4, 143.0, 142.5, 137.2, 135.1, 131.6, 129.0, 128.9, 128.5, 128.1, 57.1, 53.1, 47.7, 11.2. EXAMPLE 21: Synthesis and characterization of compounds 221-223.

221 222

General procedure for the synthesis of 221-223.

A mixture of the appropriate amine (1.0 eq) and the carboxylic acid (1.0 eq) was dissolved in DCM (0.1 M) and treated with DIPEA (5.0 eq) and HATU (1.3 eq). The resulting mixture was stirred at room temperature until completion of the reaction. The reaction was concentrated and the crude material was purified by automated flash chromatography (EtOAc:hexanes mixture) to give the desired compound in 10-48 % yield. N-(2,6-dichlorobenzyl)-lH-indole-2-carboxamide (221): ¾ NMR (400 MHz, DMSO-d₆) δ = 11.56 (s, 1H), 8.61 (t, J = 4.6 Hz, 1H), 7.57 (d, J = 8.0 Hz, 3H), 7.55 - 7.48 (m, 2H), 7.45 - 7.35 (m, 2H), 7.21 - 7.12 (m, 1H), 7.02 (ddd, J = 7.9, 6.9, 1.0 Hz, 1H), 4.74 (d, J = 4.5 Hz, 2H). ¹³C NMR (101 MHz, DMSO-d₆) δ = 160.9, 136.4, 135.8, 133.2, 131.2, 130.2, 128.6, 127.0, 123.3, 121.5, 119.7, 112.2, 103.2, 39.2.

N-(2,6-dichlorobenzyl)quinoxaline-6-carboxamide (222): ¾ NMR (400 MHz, DMSO-<f₆) δ = 9.10 (t, J = 4.4 Hz, 1H), 9.03 - 9.01 (m, 2H), 8.61 (d, J = 1.9 Hz, 1H), 8.28 (dd, J = 8.7, 2.0 Hz, 1H), 8.16 (d, J = 8.7 Hz, 1H), 7.52 (d, J = 8.4 Hz, 2H), 7.40 (dd, J = 8.7, 7.4 Hz, 1H), 4.78 (d, J = 4.4 Hz, 2H). ¹³C NMR (101 MHz, DMSO-dis) δ = 165.2, 147.0, 146.7, 143.3, 141.6, 135.8, 135.1, 133.0, 130.3, 129.3, 128.8, 128.6, 128.5.

2,6-dichloro-N-(lH-indazol-5-yl)benzamide (223): ¾ NMR (400 MHz, DMSO-d₆) δ = 13 04 (s, 1H), 10.71 (s, 1H), 8.23 (s, 1H), 8.07 (s, 1H), 7.62 - 7.55 (m, 2H), 7.55 - 7.48 (m, 3H). ¹³C NMR (101 MHz, DMSO-d₆) δ = 161.9, 137.2, 136.5, 133.6, 131.5, 131.3, 128.2, 122.7, 120.3, 110.4, 110.3. EXAMPLE 22: Synthesis and characterization of compounds 224-227.

224-i 224

225: R₁ = cyclohexyl, R₂ = H

226: R = benzyl, R₂ = H

227: R., = R₂ = Et 4-((2,6-dichlorobenzyl)amino)benzoic acid (224): Methyl 4-aminobenzoate (519 mg, 1.0 eq) was dissolved in DCE (34 mL) and treated with 2,6-dichlorobenzaldehyde (601 mg, 1.0 eq), NaBH(OAc)₃ (946 mg, 1.3 eq) and AcOH (0.20 mL, 1.0 eq) and the reaction was stirred at room temperature for 24 h. Additonal amounts of 2,6-dichlorobenzaldehyde (601 mg, 1.0 eq) and NaBH(OAc)₃ (946 mg, 1.3 eq) were added, and the reaction was stirred for a further 48 h. The reaction was quenched by the addition of sat. NaHC0₃ and the aqueous layer was extracted with DCM (2 x). The combined organic layers were washed with water and brine, dried over

Na₂S0₄, filtered and concentrated. The crude material was purified by automated flash chromatography (20 % EtOAc/hexanes, Rf = 0.35) to give compound 224-i (583 mg, 57 %) as a white solid.

Compound 224-i (496 mg, 1.0 eq) was dissolved in THF/H₂0 (3 : 1, 16 mL) and treated with LiOH-H₂0 (10 eq). The reaction was heated to reflux for 5 days, after which it was cooled to room temperature. The aqueous layer was washed with Et₂0 (3 ^χ). The aqueous layer was then acidified to pH = 1 with 1 N HC1. The resulting precipitate was isolated by suction filtration, washed with H₂0 and dried to give compound 224 (364 mg, 77 %) as a white solid. ¾ NMR (400 MHz, DMSO- e) δ = 12.00 (bs, 1H), 7.70 (d, J = 8.8 Hz, 2H), 7.53 (d, J = 7.6 Hz, 2H), 7.40 (dd, J = 8.7, 7.4 Hz, 1H), 6.70 (d, J = 8.9 Hz, 2H), 6.61 (bs, 1H). ¹³C NMR (101 MHz, DMSO- d₆) 6 = 167.5, 152.2, 135.7, 133.4, 131.1, 130.4, 128.7, 1 17.4, 1 1 1.0, 42.6.

General procedure for the synthesis of 225-227. Compounds 225-227 were prepared according to the general procedure for amide bond formation described in Example 21.

N-cyclohexyl-4-((2,6-dichlorobenzyl)amino)benzamide (225): ¾ NMR (400 MHz, DMSO- d₆) δ = 7.72 (d, J = 8.0 Hz, 1H), 7.64 (d, J = 8.8 Hz, 2H), 7.52 (d, J = 8.4 Hz, 2H), 7.39 (dd, J = 8.7, 7.4 Hz, 1H), 6.67 (d, J = 8.8 Hz, 2H), 6.31 (t, J = 4.9 Hz, 1H), 4.44 (d, J = 4.9 Hz, 2H), 3.75 - 3.66 (m, 1H), 1.81 - 1.68 (m, 4H), 1.63 - 1.56 (m, 1H), 1.3 - 1.22 (m, 4H), 1.16 - 1.05 (m,

1H). ¹³C NMR (101 MHz, DMSO- e) δ = 165.2, 150.7, 135.6, 133.7, 130.3, 128.7, 128.6, 122.0, 1 10.8, 48.0, 42.7, 32.7, 25.3, 25.0. N-benzyl-4-((2,6-dichlorobenzyl)amino)benzamide (226): ¾ NMR (400 MHz, DMSO- e) δ = 8.61 (t, J = 6.1 Hz, 1H), 7.70 (d, J = 8.7 Hz, 2H), 7.52 (d, J = 7.6 Hz, 2H), 7.39 (dd, J = 8.7, 7.4 Hz, 1H), 7.34 - 7.26 (m, 4H), 7.26 - 7.17 (m, 1H), 6.70 (d, J = 8.8 Hz, 2H), 6.37 (t, J = 4.8 Hz, 1H), 4.46 - 4.42 (m, 4H). ¹³C NMR (101 MHz, DMSO-dis) δ = 166.1, 151.0, 140.3, 135.6, 133.7, 130.3, 128.7, 128.2, 127.1, 126.5, 121.4, 110.9, 42.7, 42.4.

4-((2,6-dichlorobenzyl)amino)-N,N-diethylbenzamide (227): ¾ NMR (400 MHz, CDCb) δ = 7.32 (d, J = 8.0 Hz, 2H), 7.26 (d, J = 8.6 Hz, 2H), 7.18 (dd, J = 8.6, 7.5 Hz, 1H), 6.72 (d, J = 8.5 Hz, 2H), 4.60 (d, J = 5.3 Hz, 2H), 4.18 - 4.14 (m, 1H), 3.42 (q, J = 7.1 Hz, 4H), 1.17 (t, J = 7.1 Hz, 6H). ¹³C NMR (101 MHz, CDCb) δ = 171.8, 148.7, 136.2, 134.3, 129.6, 128.7, 128.5, 126.5, 112.7, 43.7, 13.8.

EXAMPLE 23: Synthesis and characterization of compounds 228-231.

228: X = NBoc, Y, Z = CH₂, n = 0 229: X = NH, Y, Z = CH₂, n = 0

230- i: X, Y = CH₂, Z = NBoc, n = 1 230: X, Y = CH₂, Z = NH, n = 1

231 - i: X = CH₂, Y = NBoc, Z = CH₂, n = 1 231 : X = CH₂, Y = NH, Z = CH₂, n = 1

General procedure for the synthesis of compounds 228, 230-i and 231-i.

Compounds 228, 230-i and 231-i were prepared according to the general procedure for reductive amination described in Example 19. tert-butyl 6-((2,6-dichlorobenzyl)amino)indoline-l-carboxylate (228): Significant signal broadening observed in NMR spectra. ¾ NMR (400 MHz, DMSO- ₆) δ = 7.49 (d, J = 7.6 Hz, 2H), 7.36 (dd, J = 8.7, 7.4 Hz, 1H), 7.18 (bs, 1H), 6.89 (d, J = 8.0 Hz, 1H), 6.27 (dd, J = 8.1, 2.1 Hz, 1H), 5.64 (t, J = 5.0 Hz, 1H), 4.34 (d, J = 5.0 Hz, 2H), 3.90 - 3.78 (m, 2H), 2.89 (t, J = 8.5 Hz, 2H), 1.50 (s, 9H). ¹³C NMR (101 MHz, DMSO-dis) δ = 151.7, 148.2, 135.6, 134.2, 130.1, 128.6, 124.8, 118.7, 106.2, 99.3, 79.7, 48.0, 43.4, 28.1. General procedure for the synthesis of compounds 229-231.

The appropriate Boc-protected amine was dissolved in DCM/TFA (1 : 1, 0.1 M) and stirred at room temperature. After 1 h, the reaction was concentrated. The residue was co-evaporated with toluene (2 ^χ) and then dissolved in DCM. This solution was washed with 2 M NaOH, H₂0 and brine, dried over Na₂S0₄, filtered and concentrated to give the desired compound in 91-94 % yield.

N-(2,6-dichlorobenzyl)indolin-6-amine (229): ¾ NMR (400 MHz, DMSO-d₆) δ = 7 48 (d, J = 7.6 Hz, 2H), 7.35 (dd, J = 8.7, 7.4 Hz, 1H), 6.73 (d, J = 7.8 Hz, 1H), 5.95 (d, J = 2.0 Hz, 1H), 5.91 (dd, J = 7.8, 2.1 Hz, 1H), 5.25 (t, J = 5.3 Hz, 1H), 5.22 (bs, 1H), 4.31 (d, J = 5.3 Hz, 2H), 3.31 (t, J = 8.2 Hz, 2H), 2.74 (t, J = 8.2 Hz, 1H). ¹³C NMR (101 MHz, DMSO-d₆) δ = 153.3,

148.3, 135.6, 134.5, 130.0, 128.6, 124.1, 116.9, 101.5, 94.1, 46.8, 43.5, 28.6.

N-(2,6-dichlorobenzyl)-l,2,3,4-tetrahydroisoquinolin-6-amine (230): ¾ NMR (400 MHz, CDCb) 5 = 7.31 (d, J = 8.1 Hz, 2H), 7.15 (dd, J = 8.5, 7.5 Hz, 1H), 6.83 (d, J = 8.2 Hz, 1H), 6.58 (dd, J = 8.2, 2.5 Hz, 1H), 6.51 (d, J = 2.4 Hz, 1H), 4.55 (s, 2H), 3.90 (s, 2H), 3.08 (t, J = 6.0 Hz, 2H), 2.72 (t, J = 6.0 Hz, 2H). ¹³C NMR (101 MHz, CDCb) δ = 146.0, 136.1, 135.5, 134.7,

129.4, 128.6, 127.0, 125.7, 113.7, 112.1, 47.7, 44.2, 43.9, 29.5.

N-(2,6-dichlorobenzyl)-l,2,3,4-tetrahydroisoquinolin-7-amine (231): ¾ NMR (400 MHz, DMSO- e) δ = 7.49 (d, J = 8.0 Hz, 2H), 7.36 (dd, J = 8.7, 7.4 Hz, 1H), 6.81 (d, J = 8.2 Hz, 1H), 6.53 (dd, J = 8.2, 2.5 Hz, 1H), 6.37 (d, J = 2.4 Hz, 1H), 5.52 (t, J = 5.2 Hz, 1H), 4.34 (d, J = 5.2 Hz, 2H), 3.84 (s, 2H), 2.99 (t, J = 6.0 Hz, 2H), 2.60 (t, J = 6.0 Hz, 2H). ¹³C NMR (101 MHz, DMSO- e) δ = 146.6, 135.6, 134.6, 134.3, 130.1, 129.2, 128.6, 121.7, 111.6, 108.9, 47.1, 43.3, 43.2, 26.8.

Example 24: Synthesis and characterization of compound 300

6-((2,6-dichloro-4-fluorobenzyl)amino)isoindolin-l-one (300): To a solution of 6- aminoisoindolin-l-one (0.675 mmol) in 1,2-dichloroethane (0.2 M) was added 2,6-dichloro-4- fluorobenzaldehyde (0.675 mmol), NaBH(OAc)₃ (2.025 mmol), and acetic acid (0.675 mmol, 39 μΕ). The mixture was stirred at 80 °C for 24 hours. The reaction mixture was quenched with sat. NaHC0₃ and extracted with EtOAc. The organic layer was then washed with water and brine, dried over Na₂S0₄, filtered and evaporated. The crude was purified by preparative HPLC to give the desired compound 300 (Yield = 21%, white cotton). ¾ NMR (400 MHz, DMSO) δ 8.36 (s, 1H), 7.61 (d, J = 8.6 Hz, 2H), 7.28 (d, J = 8.1 Hz, 1H), 7.05 - 6.82 (m, 2H), 6.02 (t, J = 4.9 Hz, 1H), 4.40 (d, J= 4.9 Hz, 2H), 4.21 (s, 2H). ¹³C NMR (101 MHz, DMSO) δ 170.99 (s), 148.98 (s), 136.86 (s), 136.74 (s), 133.95 (s), 132.17 (s), 131.24 (s), 124.22 (s), 117.36 (s), 116.88 (s), 116.63 (s), 104.66 (s), 44.75 (s), 43.23 (s).

Example 25: Synthesis and characterization of compounds 301 and 302

General procedure for the synthesis of 301 and 302

A mixture of the appropriate amine (1 mmol) and the appropriate benzyl bromide (1 mmol) in DMF (0.5 M) was stirred at 60 °C until completion of the reaction (up to 40 hours). The reaction mixture was quenched with sat. NaHC0₃ and extracted with EtOAc. Crude material was purified by automated flash chromatography (EtOAc:hexanes mixture) to give the desired compound in 12-20% yield.

5-((2,6-dichloro-4-fluorobenzyl)amino)isoindoline-l,3-dione (301): ¾ NMR (400 MHz, DMSO) δ 10.81 (s, 1H), 7.64 (d, J= 8.5 Hz, 2H), 7.53 (d, J= 8.5 Hz, 1H), 7.12 (s, 1H), 7.02 (d, J = 2.1 Hz, 1H), 6.95 (dd, J= 8.5, 2.1 Hz, 1H), 4.49 (s, 2H). ¹³C NMR (101 MHz, DMSO) δ 170.03 (s), 169.78 (s), 161.37 (d, J= 250.6 Hz), 154.06 (s), 136.95 (s), 136.83 (s), 135.86 (s), 130.28 (s), 125.00 (s), 119.02 (s), 117.02 (s), 116.77 (s), 42.79 (s).

6-((2,6-dichlorobenzyl)amino)benzo[d]oxazol-2(3H)-one (302): ¾ NMR (400 MHz, DMSO) δ 11.12 (s, 1H), 7.58 - 7.49 (m, 2H), 7.39 (dd, J = 8.7, 7.4 Hz, 1H), 6.84 (d, J = 8.4 Hz, 1H), 6.69 (d, J = 2.1 Hz, 1H), 6.50 (dd, J = 8.4, 2.1 Hz, 1H), 5.70 (t, J = 5.1 Hz, 1H), 4.36 (d, J = 5.1 Hz, 2H). ¹³C NMR (101 MHz, DMSO) δ 155.19 (s), 145.36 (s), 145.00 (s), 136.08 (s), 134.50 (s), 130.68 (s), 129.11 (s), 120.76 (s), 110.42 (s), 108.01 (s), 95.04 (s), 44.18 (s).

Example 26: Synthesis and characterization of compounds 303-308

General procedure for the synthesis of compounds 303-308

To a solution of compound 102 (0.156 mmol) in DMF (0.4M) was added K₂C0₃ (0.312 mmol), KI (catalytic amount), and the appropriate halide (0.156 mmol). The mixture was stirred at 70 up to 110 °C until the completion of the reaction (up to 3 days). The product was either precipitated by adding water in the mixture and crystallized in diethyl ether or the reaction mixture was diluted in EtOAc, washed with water, dried over Na₂S0₄, concentrated and purified by preparative HPLC to give the desired compound in 27-54% yield.

2-(2,6-dichlorobenzyl)-5-((2,6-dichlorobenzyl)amino)isoindoline-l,3-dione (303): ¾ NMR

(400 MHz, DMSO) δ 7.55 (m, 3H), 7.46 (m, 3H), 7.39 - 7.32 (m, 1H), 7.24 (t, J = 4.5 Hz, 1H), 7.05 (d, J= 2.1 Hz, 1H), 6.96 (dd, J= 8.3, 2.1 Hz, 1H), 4.95 (s, 2H), 4.53 (d, J= 4.5 Hz, 2H). ¹³C NMR (101 MHz, DMSO) δ 167.83 (s), 167.52 (s), 154.25 (s), 136.15 (s), 135.86 (s), 134.52 (s), 131.72 (s), 131.11 (s), 130.56 (s), 129.23 (s), 129.10 (s), 125.30 (s), 117.34 (s), 43.29 (s), 38.02 (s).

5-((2,6-dichlorobenzyl)amino)-2-(2-morpholinoethyl)isoindoline-l,3-dione (304): ¾ NMR

(400 MHz, DMSO) δ 7.63 (d, J = 8.4 Hz, 1H), 7.57 (d, J = 8.4 Hz, 2H), 7.44 (t, J = 8.4 Hz, 1H), 7.30 (t, J = 4.5 Hz, 1H), 7.13 (d, J = 2.1 Hz, 1H), 7.00 (dd, J = 8.4, 2.1 Hz, 1H), 4.56 (d, J = 4.5 Hz, 2H), 4.01 (m, 2H), 3.89 (m, 2H), 3.75 - 3.45 (m, 6H), 3.25 - 3.15 (M, 2H). LCMS (M+l) = 434.0.

5-((2,6-dichlorobenzyl)amino)-2-(2-hydroxyethyl)isoindoline-l,3-dione (305): ¾ NMR (400 MHz, DMSO) δ 7.57 (m, 3H), 7.43 (t, J= 8.5 Hz, 1H), 7.18 (t, J= 4.5 Hz, 1H), 7.09 (s, 1H), 6.96 (d, J = 8.3 Hz, 1H), 4.82 (broad s, 1H), 4.55 (d, J = 4.5 Hz, 2H), 3.62 - 3.49 (m, 4H). ¹³C NMR (101 MHz, DMSO) δ 168.77 (s), 168.51 (s), 154.12 (s), 136.16 (s), 135.00 (s), 133.44 (s), 131.09 (s), 129.23 (s), 125.04 (s), 117.88 (s), 58.58 (s), 43.31 (s).

5-((2,6-dichlorobenzyl)amino)-2-(3-hydroxypropyl)isoindoline-l,3-dione (306): ¾ NMR (400 MHz, DMSO) δ 7.56 (m, 3H), 7.47 - 7.40 (m, 1H), 7.18 (t, J= 4.5 Hz, 1H), 7.08 (d, J= 2.1 Hz, 1H), 6.95 (dd, J= 8.3, 2.1 Hz, 1H), 4.54 (d, J= 4.5 Hz, 2H), 4.49 (t, J= 5.0 Hz, 1H), 3.56 (t, J= 7.3 Hz, 2H), 3.42 (q, J= 5.8 Hz, 2H), 1.70 (p, J= 6.6 Hz, 2H). ¹³C NMR (101 MHz, DMSO) δ 168.70 (s), 168.47 (s), 154.15 (s), 136.17 (s), 134.92 (s), 133.42 (s), 131.11 (s), 129.23 (s), 125.09 (s), 117.76 (S), 59.02 (s), 43.32 (s), 35.23 (s), 31.94 (s).

5-((2,6-dichlorobenzyl)amino)-2-(3-(dimethylamino)propyl)isoindoline-l,3-dione (307): ¾

NMR (400 MHz, MeOD) δ 7.62 (d, J= 8.3 Hz, 1H), 7.47 (d, J= 8.1 Hz, 2H), 7.38 - 7.32 (m, 1H), 7.16 (d, J= 2.1 Hz, 1H), 6.98 (dd, J= 8.4, 2.1 Hz, 1H), 4.68 (s, 2H), 3.75 (t, J= 6.5 Hz, 2H), 3.20 (m, 2H), 2.91 (s, 6H), 2.08 (p, J= 6.7 Hz, 2H). LCMS (M+l) = 406.0.

tert-butyl (3-(5-((2,6-dichlorobenzyl)amino)-l,3-dioxoisoindolin-2-yl)propyl)carbamate (308): ¾ NMR (400 MHz, DMSO) δ 7.57 (dd, J= 8.2, 2.5 Hz, 3H), 7.43 (m, 1H), 7.20 (broad s, 1H), 7.08 (d, J = 2.1 Hz, 1H), 6.96 (d, J = 8.3 Hz, 1H), 6.79 (broad s, 1H), 4.54 (d, J = 4.6 Hz, 2H), 3.49 (t, J= 7.2 Hz, 2H), 2.93 (d, J= 6.6 Hz, 2H), 1.73 - 1.61 (m, 2H), 1.37 (s, 9H). ¹³C NMR (101 MHz, DMSO) δ 168.67 (s), 168.40 (s), 154.18 (s), 136.16 (s), 134.87 (s), 133.41 (s), 131.10 (s), 129.23 (s), 125.14 (s), 117.66 (s), 43.31 (s), 35.52 (s), 28.70 (s). Example 27: Synthesis and characterization of compound 309

-aminopropyl)-5-((2,6-dichlorobenzyl)amino)isoindoline-l,3-dione, 2,2,2- trifluoroacetate salt (309): To a solution of 308 (0.05 mmol) in DCM (0.25M) was added TFA (4 mL/mmol, 160 μί). The reaction was stirred at room temperature for 1 hour. The mixture was evaporated and dried to give the pure compound (Yield = 98%, yellow oil). ¾ NMR (400 MHz, DMSO) δ 7.67 (broad s, 3H), 7.63 - 7.54 (m, 3H), 7.44 (m, 1H), 7.25 (t, J= 4.6 Hz, 1H), 7.10 (d, J= 2.1 Hz, 1H), 6.97 (dd, J= 8.4, 2.1 Hz, 1H), 4.55 (d, J = 4.6 Hz, 2H), 3.58 (t, J= 6.8 Hz, 2H), 2.82 (t, J = 7.8 Hz, 2H), 1.83 (p, J = 6.9 Hz, 2H). ¹³C NMR (101 MHz, DMSO) δ 168.80 (s), 168.52 (s), 154.23 (s), 136.14 (s), 134.90 (s), 133.35 (s), 131.16 (s), 129.26 (s), 125.27 (s), 117.56 (s), 43.31 (s), 37.33 (s), 34.82 (s), 27.06 (s).

Example 28: Synthesis and characterization of compound 310

2-(2,6-dichlorobenzyl)-4-((2,6-dichlorobenzyl)amino)isoindoline-l,3-dione (310): This compound was synthesized from compound 105, using the same procedure as described in the Example 26. The compound was precipitated out by adding water. The precipitate was filtered and crystallized in Et₂0 to give the pure compound (Yield = 27%, yellow powder). ¾ NMR (400 MHz, DMSO) δ 7.62 (t, J= 8.0 Hz, 1H), 7.55 (d, J= 8.0 Hz, 2H), 7.51 - 7.24 (m, 5H), 7.05 (d, J = 7.2 Hz, 1H), 6.57 (t, J= 5.9 Hz, 1H), 4.94 (s, 2H), 4.74 (d, J= 5.9 Hz, 2H). ¹³C NMR (101 MHz,

DMSO) δ 169.54 (s), 167.39 (s), 145.88 (s), 136.70 (s), 135.85 (s), 135.60 (s), 133.57 (s), 132.63 (s), 131.44 (s), 131.26 (s), 130.69 (s), 129.49 (s), 129.15 (s), 117.60 (s), 111.73 (s), 110.62 (s), 42.51 (s), 37.95 (s).

Example 29: Synthesis and characterization of compounds 311-312

General procedure for the synthesis of compounds 311 and 312

These two compounds were synthesized from compound 302, using the same procedure as described in the Example 26. They both were purified by automated flash chromatography (EtOAc:hexanes mixture) to give the desired compound in 37-95% yield.

6-((2,6-dichlorobenzyl)amino)-3-(3-(dimethylamino)propyl)benzo[d]oxazol-2(3H)-one (311): ¾ NMR (400 MHz, DMSO) δ 7.53 (d, J= 8.0 Hz, 2H), 7.39 (t, J= 8.0 Hz, 1H), 7.03 (d, J = 8.4 Hz, 1H), 6.74 (d, J = 2.1 Hz, 1H), 6.57 (dd, J = 8.4, 2.1 Hz, 1H), 5.80 (t, J = 5.0 Hz, 1H), 4.37 (d, J= 5.0 Hz, 2H), 3.75 (t, J= 6.9 Hz, 2H), 2.22 (t, J= 6.9 Hz, 2H), 2.11 (s, 6H), 1.78 (t, J = 6.9 Hz, 2H). ¹³C NMR (101 MHz, DMSO) δ 154.34 (s), 145.65 (s), 143.60 (s), 136.08 (s), 134.43 (s), 130.72 (s), 129.13 (s), 121.76 (s), 109.88 (s), 107.88 (s), 95.12 (s), 56.38 (s), 45.55 (s), 44.14 (s), 25.78 (s). tert-butyl (3-(6-((2,6-dichlorobenzyl)amino)-2-oxobenzo [d] oxazol-3(2H)- yl)propyl)carbamate (312): ¾ NMR (400 MHz, DMSO) δ 7.52 (d, J= 8.0 Hz, 2H), 7.43 - 7.36 (m, 1H), 7.03 (d, J= 8.5 Hz, 1H), 6.91 (t, J= 5.0 Hz, 1H), 6.75 (d, J= 2.1 Hz, 1H), 6.56 (dd, J = 8.5, 2.1 Hz, 1H), 5.81 (t, J= 5.1 Hz, 1H), 4.37 (d, J = 5.0 Hz, 2H), 3.73 (t, J= 7.1 Hz, 2H), 2.97 (d, J= 6.7 Hz, 2H), 1.78 (t, J = 7.1 Hz, 2H), 1.38 (s, 9H). ¹³C NMR (101 MHz, DMSO) δ 156.03 (s), 154.28 (s), 145.71 (s), 143.60 (s), 136.07 (s), 134.42 (s), 130.72 (s), 129.13 (s), 121.56 (s), 109.87 (s), 107.83 (s), 95.14 (s), 78.11 (s), 44.11 (s), 37.90 (s), 28.70 (s), 28.18 (s).

Example 30: Synthesis and characterization of compound 313

3-(6-((2,6-dichlorobenzyl)amino)-2-oxobenzo[d]oxazol-3(2H)-yl)propan-l-aminium 2,2,2- trifluoroacetate salt (313): This compound was synthesized from compound 312, using the same procedure as described in the Example 27 (Yield = 100%, off-white powder). ¾ NMR (400 MHz, DMSO) δ 7.71 (broad s, 3H), 7.53 (d, J = 8.0 Hz, 2H), 7.40 (t, J = 8.0 Hz, 1H), 7.09 (d, J = 8.4 Hz, 1H), 6.77 (s, 1H), 6.59 (d, J = 8.4 Hz, 1H), 4.38 (s, 2H), 3.83 (t, J = 6.8 Hz, 2H), 2.86 (q, J = 6.8 Hz, 2H), 1.94 (t, J= 7.7 Hz, 2H (101 MHz). LCMS (M+l) = 366.0.

Exam le 31: Synthesis and characterization of compound 315

tert-butyl 6-((2,6-dichlorobenzyl)amino)-l-oxoisoindoline-2-carboxylate (315):

A mixture of 102 (0.065 mmol), Boc-anhydride (0.078 mmol), and DMAP (catalytic) in DMF (0.1 mL) was stirred at room temperature overnight. The reaction mixture was concentrated to afford 315. Yield = quantitative. ¾ NMR (400 MHz, DMSO-i¾) δ 7.58 - 7.48 (m, 2H), 7.44 - 7.29 (m, 2H), 7.08 (dd, J= 8.3, 2.3 Hz, 1H), 6.96 (d, J= 2.2 Hz, 1H), 6.21 (t, J= 4.9 Hz, 1H), 4.62 (s, 2H), 4.44 (d, J= 4.9 Hz, 2H), 1.52 (s, 9H). ¹³C NMR (101 MHz, DMSO-i¾) δ 166.88, 150.24, 149.44, 136.11, 134.25, 132.01, 130.75, 129.51, 129.14, 124.41, 120.04, 104.63, 82.10, 48.97, 43.61, 28.25.

Example 32: Synthesis and characterization of compounds 316-319, 321-322

102

X = Br, CI R =

316 CH2CH2OCH2CH3

317 CH₂CH₃

318 CH₂C0₂f-Bu

319 CH2CH2CH2CH2CH3

321 CH₂CN

322 CH(CH₃)₂

General procedure for the synthesis of compounds 316-319, 321-322

To compound 102 (1 mmol) and 60% sodium hydride (1 to 2 mmol) in DMF (0.5M) was added potassium iodide (catalytic) and the appropriate alkyl halide (1 to 2 mmol). The reaction mixture was stirred at room temperature to 90 °C until completion (1 hour to 4 days). The product was precipitated out with acetonitrile: water (1 : 1), filtered and dried to give the desired product. Further purification if required was perfromed via flash chromatography using EtOAc:hexanes or MeOFFDCM.

6-((2,6-dichlorobenzyl)amino)-2-(2-ethoxyethyl)isoindolin-l-one (316): Compound 316 was prepared from 102 and l-chloro-2-ethoxyethane according to the above general procedure. Yield = 43%. ¾ NMR (400 MHz, DMSO- ₆) δ 7.57 - 7.47 (m, 2H), 7.39 (dd, J= 8.7, 7.4 Hz, 1H), 7.28 (d, J = 8.9 Hz, 1H), 6.94 (d, J = 6.7 Hz, 2H), 6.05 (t, J = 5.0 Hz, 1H), 4.43 (d, J = 5.0 Hz, 2H), 4.36 (s, 2H), 3.66 - 3.52 (m, 4H), 3.45 (q, J= 7.0 Hz, 2H), 1.10 (t, J= 7.0 Hz, 3H). ¹³C MR (101 MHz, DMSO- e) δ 168.30, 149.12, 136.11, 134.45, 133.70, 130.68, 129.97, 129.12, 123.84, 117.14, 104.73, 68.51, 65.80, 50.33, 43.74, 42.12, 15.58.

6-((2,6-dichlorobenzyl)amino)-2-ethylisoindolin-l-one (317): Compound 317 was prepared from 102 and bromoethane according to the above general procedure. Yield = 25%. ¾ NMR (400 MHz, DMSO- e) δ 7.57 - 7.48 (m, 2H), 7.39 (dd, J = 8.7, 7.4 Hz, 1H), 7.28 (d, J = 9.0 Hz, 1H), 7.02 - 6.84 (m, 2H), 6.02 (t, J = 5.0 Hz, 1H), 4.44 (d, J = 5.0 Hz, 2H), 4.30 (s, 2H), 3.51 (q, J = 7.2 Hz, 2H), 1.15 (t, J = 7.2 Hz, 3H). ¹³C NMR (101 MHz, DMSO- e) δ 167.91, 149.13, 136.11, 134.46, 134.02, 130.67, 129.72, 129.11, 123.86, 117.00, 104.74, 48.71, 43.74, 36.82, 13.94. tert-butyl 2-(6-((2,6-dichlorobenzyl)amino)-l-oxoisoindolin-2-yl)acetate (318): Compound 318 was prepared from 102 and tert-butyl 2-bromoacetate according to the above general procedure. Yield = 72%. ¾ NMR (400 MHz, DMSO- ₆) 5 7.57 - 7.48 (m, 2H), 7.39 (dd, J= 8.7, 7.4 Hz, 1H), 7.30 (d, J = 8.1 Hz, 1H), 7.04 - 6.92 (m, 2H), 6.09 (t, J = 5.0 Hz, 1H), 4.44 (d, J = 5.0 Hz, 2H), 4.34 (s, 2H), 4.22 (s, 2H), 1.43 (s, 9H). ¹³C NMR (101 MHz, DMSO-d₆) δ 168.83, 168.79, 149.19, 136.12, 134.41, 132.94, 130.70, 130.09, 129.12, 124.00, 117.57, 104.80, 81.77, 50.15, 44.68, 43.72, 28.19.

6-((2,6-dichlorobenzyl)amino)-2-pentylisoindolin-l-one (319): Compound 319 was prepared from 102 and bromopentane according to the above general procedure. Yield = 57%. ¾ NMR (400 MHz, DMSO- e) δ 7.57 - 7.47 (m, 2H), 7.39 (dd, J= 8.7, 7.4 Hz, 1H), 7.31 - 7.22 (m, 1H), 6.99 - 6.87 (m, 2H), 6.03 (t, J= 5.0 Hz, 1H), 4.44 (d, J= 5.0 Hz, 2H), 4.29 (s, 2H), 3.47 (t, J= 7.1 Hz, 2H), 1.58 (p, J= 7.3 Hz, 2H), 1.41 - 1.13 (m, 4H), 0.87 (t, J= 7.2 Hz, 3H). ¹³C NMR (101 MHz, DMSO- e) δ 168.21, 149.13, 136.11, 134.45, 133.91, 130.68, 129.70, 129.11, 123.85, 116.99, 104.77, 49.23, 43.74, 41.94, 28.98, 27.95, 22.24, 14.37.

2-(6-((2,6-dichlorobenzyl)amino)-l-oxoisoindolin-2-yl)acetonitrile (321): Compound 321 was prepared from 102 and bromoacetonitrile according to the above general procedure. Yield = 44%.¾ NMR (400 MHz, DMSO- e) δ 7.57 - 7.47 (m, 2H), 7.44 - 7.30 (m, 2H), 7.04 - 6.95 (m, 2H), 6.15 (d, J = 5.0 Hz, 1H), 4.68 (s, 2H), 4.45 (d, J = 4.9 Hz, 2H), 4.41 (s, 2H). ¹³C NMR (101 MHz, DMSO- e) δ 168.53, 149.38, 136.12, 134.33, 131.95, 130.72, 129.80, 129.13, 124.32, 118.12, 116.97, 104.72, 49.65, 43.67, 31.04.

6-((2,6-dichlorobenzyl)amino)-2-isopropylisoindolin-l-one (322): Compound 322 was prepared from 102 and 2-bromopropane according to the above general procedure. Yield = 16%. ¾ NMR (400 MHz, DMSO-d₆) δ 7.55 - 7.48 (m, 2H), 7.39 (dd, J = 8.7, 7.4 Hz, 1H), 7.28 (dd, J = 7.8, 1.0 Hz, 1H), 6.94 (d, J= 7.8 Hz, 2H), 6.02 (t, J= 5.1 Hz, 1H), 4.41 (dd, J= 20.7, 5.9 Hz, 3H), 4.25 (s, 2H), 1.21 (d, J= 6.7 Hz, 6H). ¹³C NMR (101 MHz, OMSO-d₆) δ 167.61, 149.12, 136.10, 134.47, 134.24, 130.66, 129.78, 129.11, 123.92, 117.02, 104.63, 44.67, 43.75, 42.64, 20.95.

Example 33: Synthesis and characterization of compound 320

2-(6-((2,6-dichlorobenzyl)amino)-l-oxoisoindolin-2-yl)acetic acid (320):

A mixture of 318 (0.21 mmol) and TFA (3 mL) in DCM (3 mL) was stirred at room temperature for 45 min. The reaction was concentrated to give 320. Yield = quantitative. ¾ NMR (400 MHz, DMSO- e) δ 7.57 - 7.48 (m, 2H), 7.39 (dd, J= 8.7, 7.4 Hz, 1H), 7.33 - 7.27 (m, 1H), 7.00 - 6.94 (m, 2H), 6.07 (s, 1H), 4.45 (d, J = 4.3 Hz, 2H), 4.35 (s, 2H), 4.24 (s, 2H). ¹³C NMR (101 MHz, DMSO- e) δ 171.12, 168.80, 149.18, 136.12, 134.42, 133.07, 130.69, 130.11, 129.12, 123.98, 117.53, 104.80, 50.15, 43.95, 43.74.

Exam le 34: Synthesis and characterization of compound 323-325

R =

323 CH₂CH₂NMe₂

324 CH₂CH₂OH

325 CH₂CONH₂

General procedure for the synthesis of compounds 323-325

To a solution of 320 (1 mmol) in DCM (0.1M) was added DIEA (3 mmol) followed by the appropriate amine (1 mmol) and HATU (1.3 mmol). The reaction mixture was stirred at room temperature overnight. The reaction was partitioned with EtOAc and sat. NaHC0₃. The organic layer was separated and dried over Na₂s0₄ and concentrated to give the desired product.

2-(6-((2,6-dichlorobenzyl)amino)-l-oxoisoindolin-2-yl)-N-(2- (dimethylamino)ethyl)acetamide hydrochloride (323):

Compound 323 was prepared from 320 and Nl,Nl-dimethylethane-l,2-diamine according to the above general procedure. Yield = quantitative. ¾ NMR (400 MHz, DMSO- e) δ 10.01 (s, 1H), 8.32 (t, J = 5.8 Hz, 1H), 7.52 (d, J = 8.0 Hz, 2H), 7.39 (dd, J = 8.7, 7.4 Hz, 1H), 7.30 (d, J = 8.1 Hz, 1H), 6.98 (d, J= 7.8 Hz, 2H), 4.45 (s, 2H), 4.37 (s, 2H), 4.17 (s, 2H), 3.14 (q, J= 6.0 Hz, 2H), 2.79 (d, J = 4.9 Hz, 6H). ¹³C NMR (101 MHz, DMSO- e) δ 169.38, 168.94, 149.11, 136.11, 134.41, 133.21, 130.71, 130.33, 129.13, 123.91, 117.51, 104.85, 56.17, 50.62, 45.61, 43.76, 42.83, 34.45. 2-(6-((2,6-dichlorobenzyl)amino)-l-oxoisoindolin-2-yl)-N-(2-hydroxyethyl)acetamide (324):

Compound 324 was prepared from 320 and ethanolamine according to the above general procedure. Yield = 41%. ¾ NMR (400 MHz, DMSO- ₆) δ 8.03 (t, J = 5.6 Hz, 1H), 7.57 - 7.47 (m, 2H), 7.39 (dd, J= 8.7, 7.4 Hz, 1H), 7.28 (d, J= 8.9 Hz, 1H), 7.01 - 6.92 (m, 2H), 6.05 (t, J = 5.0 Hz, 1H), 4.67 (t, J= 5.5 Hz, 1H), 4.45 (d, J= 5.0 Hz, 2H), 4.34 (s, 2H), 4.12 (s, 2H), 3.41 (q, J = 5.9 Hz, 2H), 3.15 (q, J = 5.9 Hz, 2H). ¹³C NMR (101 MHz, DMSO- e) δ 168.79, 168.53, 149.11, 136.12, 134.45, 133.33, 130.68, 130.23, 129.12, 123.87, 117.36, 104.85, 60.20, 50.48, 45.35, 43.75, 41.99.

2-(6-((2,6-dichlorobenzyl)amino)-l-oxoisoindolin-2-yl)acetamideacetamide (325): Compound 325 was prepared from 320 and 0.5M ammonia in dioxane according to the above general procedure. Yield = quantitative. ¾ NMR (400 MHz, DMSO- e) δ 7.57 - 7.45 (m, 3H), 7.39 (dd, J = 8.7, 7.4 Hz, 1H), 7.28 (d, J = 8.9 Hz, 1H), 7.10 (s, 1H), 6.97 (dd, J = 6.2, 2.4 Hz, 2H), 6.04 (t, J = 5.0 Hz, 1H), 4.45 (d, J = 5.0 Hz, 2H), 4.34 (s, 2H), 4.09 (s, 2H). ¹³C NMR (101 MHz, DMSO- e) δ 170.55, 168.80, 149.10, 136.12, 134.46, 133.37, 130.68, 130.25, 129.12, 123.85, 117.34, 104.85, 50.47, 45.06, 43.76.

EXAMPLE 35

MATERIALS AND METHODS

p53 PTC Readthrough in a Human Cell Line.

Compounds were tested for PTC readthrough in human cells, wherein mammary carcinoma HDQ- Pl cells homozygous for TGA (R213X) in exon 6 of the TP53 gene were selected on the basis of convincing evidence of readthrough by the aminoglycoside G418 (Floquet, C. et al. 2011). Western analysis using a quantitative automated capillary electrophoresis system showed that HDQ-Pl cells express very low levels of truncated p53 and no full-length p53 and that 50 μΜ G418 induces the formation of full-length p53 while also increasing truncated p53 levels as reported (Floquet, C. et al. 2011).

Nuclear localization sequences and a tetramenzation domain located in the p53 C-terminus contribute to retaining p53 in the nucleus (Shaulsky, G et al. 1990; Liang, S.H and Clark, M.F. 2001) and p53 truncated at R213 lacks these sequences. To enable analysis of p53 R213X readthrough at a high throughput an automated 96-well fluorescence microscopy assay was established to detect and quantitate nuclear p53 signal. G418 induced a concentration-dependent increase in nuclear p53 consistent with readthrough induction. During 72 h exposure, 50 μΜ G418 induced nuclear 53 expression in 9% of cells. Automated p53 Immunofluorescence 96-well Plate Assay

HDQ-P1 cells were cultured in DMEM containing 10% FBS and lx Gibco™ antibiotic/antimicotic. Cells were seeded at 4000 per well of PerkinElmer View™ 96-well plates. The next day, the medium was replaced with fresh culture medium containing the compounds to be tested. After 72 h, the culture medium was removed by aspiration, the cells were fixed with 3% paraformaldehyde, 0.3% Triton X-100 and 1.5 μg/ml Hoechst 33342 in phosphate-buffered saline pH 7.2 (PBS) for 20 min at room temp. The cells were rinsed once with PBS and incubated for 2 h at room temp with a blocking solution of 3% BSA in PBS. The blocking solution was removed by aspiration and cells were incubated with 0.1 μg/ml DO-1 p53 mouse monoclonal p53 antibody (Santa Cruz™) in blocking solution for 90 min at room temp. The wells were washed once with PBS for 5 min and the cells were incubated with Alexa 488 -conjugated goat anti-mouse antibody (Invitrogen Life Technologies Al 1029™) in blocking buffer for 90 min at room temp. The wells were washed once with PBS for 5 min, 75 μΐ PBS was added, the plates were covered with a black adherent membrane and stored at 4°C overnight. Nuclear p53 immunofluorescence intensity was measured using a Cellomics ArrayScan VTI™ automated fluorescence imager. Briefly, images were acquired with a 20x objective in the Hoechst™ and GFP (XF53) channels. Images of 15 fields were acquired for each well, corresponding to -2000 cells. The Compartment Analysis bioapplication was used to identify the nuclei and define their border. The nuclear Alexa 488™ fluorescence intensity was then measured and expressed as average nuclear fluorescence intensity or % positive nuclei, using as a threshold the fluorescence intensity of nuclei from untreated cells (50-75, depending on experiment).

Automated Electrophoresis p53 Western Analysis Assay

HDQ-P1 cells were seeded at 100,000 cells per well of TC-treated 6-well plates. The next day, the medium was replaced with fresh medium containing compounds to be tested and were incubated for 48 to 96 h. The medium was removed by aspiration, cell monolayers were rinsed with 1 ml ice- cold PBS. Cells were lysed in 80 μΐ lysis buffer (20 mM Tris-HCl pH 7.5, 150 mM NaCl, 1 mM EDTA, 1 mM EGTA, 1% (v/v) Triton XI 00™, 2.5 mM sodium pyrophosphate, 1 mM beta- glycerophosphate supplemented with fresh 1 mM Na3 V04, 1 mM dithiothreitol and lx complete protease inhibitor cocktail (Roche Molecular Biochemicals™)). Lysates were pre-cleared by centrifugation at 18,000 g for 15 min at 4°C. Supernatants were collected, protein was quantitated using the Bradford assay and lysates were adjusted to 1 mg/ml protein. Capillary electrophoresis and western analysis conditions were carried out with manufacturers reagents according to the user manual (ProteinSimple WES™). Briefly, 5.6 μΐ of cell lysate was mixed with 1.4 μΐ fluorescent master mix and heated at 95°C for 5min. The samples, blocking reagent, wash buffer, DO-1 p53 antibody (0.5 μg/ml) and vinculin antibody (1 :2000, R&D clone 728526,), secondary antibody and chemiluminescent substrate were dispensed into the microplate provided by the manufacturer. The electrophoretic separation and immunodetection was performed automatically using default settings. The data was analyzed with inbuilt Compass™ software (Proteinsimple™). The truncated and full length p53 peak intensities were normalized to that of the vinculin peak, used as a loading control. Results were visualized as pseudo blots and as electropherograms.

EXAMPLE 36: PREMATURE TERMINATION CODON READTHROUGH ACTIVITY OF COMPOUNDS

The ability of exemplary compounds, when used in combination with G418, to promote readthrough of a TGA premature termination codon (PTC) in the p53 coding sequence (p53 R213X) was assessed using the fluorescence microscopy and Western blot assays described in Example 31. The results are presented in Table 5.

Table 5: Activity of Representative Compounds

* : Compounds were tested at 30 or 50μΜ as noted in parentheses, in combination with 50μΜ G418 : Compounds were tested at 10 or 50μΜ as noted in parentheses in combination with 25 μΜ G418

- : Not determined Example 36: Aminoglycoside and PTC-RC in Combination Promote Readthrough and p53 Production in vivo in TP53 Tumour Xenograft Model A human cell line in which the TP53 gene contains a premature termination codon (e.g. HDQ-P1 cells) is injected subcutaneously in immunocompromised mice. Once the tumour xenografts have grown to a palpable size, the mice are administered test composition (e.g. a combination of compound 102 and an aminoglycoside (e.g., G418)). Test composition is administered intravenously or intraperitoneally daily at 10-100 mg/kg for a period of 2-4 weeks. The animals are sacrificed, the tumour is excised, lysed and subjected to western analysis to measure the amount of full-length (and hence the amount of PTC readthrough) p53 protein produced.

Example 37: Aminoglycoside and PTC-RC in Combination Promote Readthrough and Dystrophin Production in vivo in Dystrophin Duchenne Muscular Dystrophy Model Spontaneous mutation mdx mice with a PTC mutation in the DMD gene are administered test composition (e.g. a combination of compound 102 and an aminoglycoside (e.g., G418)). Test composition is administered intravenously or intraperitoneally daily at 10-100 mg/kg for a period of 2-4 weeks. The animals are sacrificed, muscle tissue is excised, lysed and subjected to western analysis to measure the amount of full-length (and hence the amount of PTC readthrough) dystrophin produced.

Example 38: Aminoglycoside and PTC-RC in Combination Promote Readthrough and palmitoyl-protein thioesterase 1 production in vivo in Infantile neuronal ceroid lipofuscinosis model

Mice harboring a "knocked-in" PTC mutation (ClnlR151X mouse) are used (see Miller, TN et al. Hum. Mol. Genet. 24: 185-196, 2014). Mice are administered test composition (e.g. a combination of compound 102 and an aminoglycoside (e.g., G418)). Test composition is administered intravenously or intraperitoneally daily at 10-100 mg/kg for a period of 2-4 weeks. The animals are sacrificed, the brain is excised, lysed and subjected to western analysis to measure the amount of full-length (and hence the amount of PTC readthrough) palmitoyl-protein thioesterase 1 (PPTl) produced. Alternatively, a PPTl enzyme assay is used to determine the amount of active PPTl produced.

References

Singh A, et al., Phenotypic suppression and misreading in Saccharomyces cerevisiae. Nature. 1979;277:146-8. Burke JF, et al., Suppression of a nonsense mutation in mammalian cells in vivo by the aminoglycoside antibiotics G418 and paromomycin. Nucl Acids Res. 1985;13:6265-72.

Bedwell DM, et al., Suppression of a CFTR premature stop mutation in a bronchial epithelial cell line. Nat Med. 1997;3:1280-4.

Du M, et al., Aminoglycoside suppression of a premature stop mutation in a Cftr-/- mouse carrying a human CFTRG542X transgene. J Mol Med. 2002;80:595-604.

Clancy JP, et al., Evidence that Systemic Gentamicin Suppresses Premature Stop Mutations in Patients with Cystic Fibrosis. Am J Respir Crit Care Med. 2001;163:1683-92.

Wilschanski M, et al., Gentamicin-induced correction of CFTR function in patients with cystic fibrosis and CFTR stop mutations. N Engl J Med. 2003;349:1433-41.

Linde L, et al., Nonsensemediated mRNA decay affects nonsense transcript levels and governs response of cystic fibrosis patients to gentamicin. J Clin Invest. 2007;117:683-92.

Barton-Davis ER, et al.,. Aminoglycoside antibiotics restore dystrophin function to skeletal muscles of mdx mice. J Clin Invest. 1999;104:375-81.

Malik V, et al., Gentamicininduced readthrough of stop codons in Duchenne muscular dystrophy. Ann Neurol. 2010;67:771-80.

Shulman E, et al., Designer aminoglycosides that selectively inhibit cytoplasmic rather than mitochondrial ribosomes show decreased ototoxicity: a strategy for the treatment of genetic diseases. J Biol Chem. 2014;289:2318-30.

Xue X, et al., Synthetic aminoglycosides efficiently suppress cystic fibrosis transmembrane conductance regulator nonsense mutations and are enhanced by ivacaftor. Am J Respir Cell Mol Biol. 2014;50:805-16.

Gatti RA. SMRT compounds correct nonsense mutations in primary immunodeficiency and other genetic models. Ann N Y Acad Sci. 2012;1250:33-40.

Welch EM, et al., PTC124 targets genetic disorders caused by nonsense mutations. Nature. 2007;447:87-91.

McElroy SP, et al., A lack of premature termination codon readthrough efficacy of PTC124 (Ataluren) in a diverse array of reporter assays. PLoS Biol. 20i3;ii:eiooi593.

Du M, Liu X, et al., PTC124 is an orally bioavailable compound that promotes suppression of the human CFTR-G542X nonsense allele in a CF mouse model. Proc Natl Acad Sci U S A. 2008;105:2064-9. Kerem E. Ataluren for the treatment of nonsense-mutation cystic fibrosis : a randomised, double- blind, placebo-controlled phase 3 trial. Lancet Respir Med. 2014;18:11-2.

Bushby K, et al., Ataluren treatment of patients with nonsense mutation dystrophinopathy. Muscle Nerve. 2014;50:477-87.

Finkel, 2013, J Child Neurol, 25(9): 1158-1164

Howard et al, 2000, Ann. Neurol, 48:164-169;

Manuvakhova et al, 2000, RNA, 6:1044-1055;

Stephenson, 2001, JAMA, 285:2067-2068

Ryan NJ. Ataluren: first global approval. Drugs. 2014;74:1709-14.

Karijolich J, and Yu, Y-T, Therapeutic suppression of premature termination codons: Mechanisms and clinical considerations (Review) Int J Mol Med 2014;34:355-362.

Mort, M., et al., AMeta-Analysis of Nonsense Mutations Causing Human Genetic Disease. Human Mutation 20o8;29(8):i037-i047.

Kohlhepp S. J., et al. Nephrotoxicity of the constituents of the gentamicin complex. J. Infectious Diseases I984;i49(4):605-6i4.

Wang C.S. et al. Establishment and characterization of a new cell line derived from a human primary breast carcinoma. Cancer Genet Cytogenet. 2θθθ;ΐ2θ(ι):58-72.

Floquet C, et al., Rescue of non-sense mutated P53 tumor suppressor gene by aminoglycosides. Nucleic Acids Res. 2011;39:3350-3362. Floquet C. et al. Statistical analysis of readthrough levels for nonsense mutations in mammalian cells reveals a major determinant of response to gentamicin. PLoS Genet. 20i2;8(3):eioo26o8.

Liang, S.H. and Clarke M.F. Regulation of p53 localization. Eur J Biochem. 200i;268(io):2779- 2783·

Shaulsky, G. et al. Nuclear accumulation of P53 protein is mediated by several nuclear localization signals and plays a role in tumorigenesis. Mol Cell Biol. i990;(i2):6505-6577.

Keeling, K. M. etal. Therapeutics Based on Stop Codon Readthrough. Annu. Rev. Genomics Hum. Genet. 20i4;i5:8.i-8.24. Frischmeyer PA, Dietz HC: Nonsense-mediated mRNA decay in health and disease. Hum Mol Genet 1999, 8(io):i893-i900.

Chang YF, Imam JS, Wilkinson MF: The nonsense-mediated decay RNA surveillance pathway. Annu Rev Biochem 2007, 76:51-74.

Isken O, Maquat LE: Quality control of eukaryotic mRNA: safeguarding cells from abnormal mRNA function. Genes Dev 2007, 2i(i5):i833-i856.

Rebbapragada I, Lykke-Andersen J: Execution of nonsense-mediated mRNA decay: what defines a substrate? Curr Opin Cell Biol 2009, 2i(3):394-402.

Rehwinkel J, Raes J, Izaurralde E: Nonsense-mediated mRNA decay: Target genes and functional diversification of effectors. Trends Biochem Sci 2006, 3i(ii):639-646.

Muhlemann O, et al.,: Recognition and elimination of nonsense mRNA. Biochim Biophys Acta 2008, ΐ779(9):538-549·

Petitjean A, et al., Impact of Mutant p53 Functional Properties on TP53 Mutation Patterns and Tumor Phenotype : Lessons from Recent Developments in the IARC TP53 Database. Hum Mutat. 2007;28:622-9.

Vogelstein B, et al., Cancer Genome Landscapes. Science (80- ). 2013;339:1546-58.

Baradaran-Heravi, et al., Novel small molecules potentiate premature termination codon readthrough by aminoglycosides. Nucleic Acids Res. 44: 6538-6598 (2016)

[00307] Lojewski,X., et al., (2014) Human iPSC models of neuronal ceroid lipofuscinosis capture distinct effects of TPP1 and CLN3 mutations on the endocytic pathway. Hum. Mol. Genet., 23 : 2005-2022 (2014).

[00308] It is contemplated that the different parts of the present description may be combined in any suitable manner. For instance, the present examples, methods, aspects, embodiments or the like may be suitably implemented or combined with any other embodiment, method, example or aspect of the invention.

[00309] Unless defined otherwise, all technical and scientific terms used herein have the same meaning as is commonly understood by one of ordinary skill in the art to which this invention belongs. Unless otherwise specified, the disclosures of all patents, patent applications, publications and database entries referenced in this specification are hereby specifically incorporated by reference in their entirety to the same extent as if each such individual patent, patent application, publication and database entry were specifically and individually indicated to be incorporated by reference. If a definition set forth in this section is contrary to or otherwise inconsistent with a definition set forth in the patents, applications, published applications and other publications that are herein incorporated by reference, the definition set forth in this section prevails over the definition that is incorporated herein by reference. Citation of references herein is not to be construed nor considered as an admission that such references are prior art to the present invention.

[00310] Use of examples in the specification, including examples of terms, is for illustrative purposes only and is not intended to limit the scope and meaning of the embodiments of the invention herein. Numeric ranges are inclusive of the numbers defining the range. In the specification, the word "comprising" is used as an open-ended term, substantially equivalent to the phrase "including, but not limited to," and the word "comprises" has a corresponding meaning.

[00311] The invention includes all embodiments, modifications and variations substantially as hereinbefore described and with reference to the examples and figures. It will be apparent to persons skilled in the art that a number of variations and modifications can be made without departing from the scope of the invention as defined in the claims. Examples of such modifications include the substitution of known equivalents for any aspect of the invention in order to achieve the same result in substantially the same way. All citations are expressly incorporated herein in their entirety by reference.

Claims

WE CLAIM:

1. A method of promoting readthrough of a premature termination codon (PTC) of an RNA molecule in a translation system, comprising adding (i) a compound of general formula (I), or a salt thereof; and (ii) an aminoglycoside, to the translation system in amounts that, in combination, are effective to promote readthrough, wherein:

Ar - L - B (I) wherein

1) Ar is an aryl having general formula (II):

wherein:

Ar is an N-containing heteroaryl selected from the group consisting of:

L is - (CH₂)„ -; n is 1 or 2; and

B is:

R⁷ and R⁸ are each independently H, F, CI, unsubstituted lower alkyl, or C(0)R¹²; R¹⁰ is substituted or unsubstituted lower alkyl;

R¹¹ is substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, or C(0)R¹³;

R¹² and R¹³ are each independently OH, OR¹⁴, H₂, HR¹⁵, substituted or unsubstituted lower alkyl or substituted or unsubstituted heterocycloalkyl;

R¹⁴ and R¹⁵ are each independently substituted or unsubstituted lower alkyl;

X is -CH₂-, -NH- or - R¹⁶-;

R¹⁶ is substituted or unsubstituted aryl; R is H, substituted or unsubstituted lower alkyl, substituted or unsubstituted substituted or unsubstituted heteroaryl; is H; or R¹⁷ and R¹⁸, taken together with the C atom they are attached to form cyclopropyl, cyclopentyl or cyclohexyl; or X and R¹⁷, taken together with the C atom that R¹⁷ is attached to form cyclopropyl; W is -CH2- or -C(O)-; and Y is -CH₂- or -0-; or 2) Ar is an aryl having general formula (III):

wherein:

Ar is an N-containing heteroaryl selected from the group consisting of:

L is -CH₂- R²⁴-, -S(0)₂- R²⁵-, - H-C(0)- H-, -C(0)- H- -CH₂- H-C(0)- or - CH₂- R²⁶-CH₂-;

R²⁴ and R²⁵ are each independently H or unsubstituted lower alkyl; R²⁶ is H or unsubstituted lower alkyl; B is:

wherein: R is H, substituted or unsubstituted lower alkyl, substituted or unsubstituted aryl, substituted or unsubstituted arylalkyl, substituted or unsubstituted heteroaryl, substituted or unsubstituted cycloalkyl or carboxy;

R²⁸, R²⁸ and R^28" are each independently H, halogen, substituted or unsubstituted lower alkyl, substituted or unsubstituted lower alkoxy, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl;

R²⁹ is H, substituted or unsubstituted lower alkyl, substituted or unsubstituted aryl, substituted or unsubstituted arylalkyl, substituted or unsubstituted heteroaryl, substituted or unsubstituted cycloalkyl or carboxy;

R³⁰, R³⁰ and R^30" are each independently H, halogen, substituted or unsubstituted lower alkyl, substituted or unsubstituted lower alkoxy, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl;

R³¹ is H, substituted or unsubstituted lower alkyl, substituted or unsubstituted aryl, substituted or unsubstituted arylalkyl, substituted or unsubstituted heteroaryl, substituted or unsubstituted cycloalkyl or carboxy;

R³², R^32' and R³² are each independently H, halogen, substituted or unsubstituted lower alkyl, substituted or unsubstituted lower alkoxy, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl;

R³³, R³³ and R³³ are each independently H, halogen, substituted or unsubstituted lower alkyl, substituted or unsubstituted lower alkoxy, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl; each R³⁴ is independently H, halogen, substituted or unsubstituted lower alkyl, substituted or unsubstituted lower alkoxy, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl;

R³⁵ is H, substituted or unsubstituted lower alkyl, substituted or unsubstituted aryl, substituted or unsubstituted arylalkyl, substituted or unsubstituted heteroaryl, substituted or unsubstituted cycloalkyl or carboxy; R³⁶, R³⁶ and R^36" are each independently H, halogen, substituted or unsubstituted lower alkyl, substituted or unsubstituted lower alkoxy, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl;

R³⁷, R³⁸, R³⁹, and R⁴⁰ are each independently H, halogen, substituted or unsubstituted lower alkyl, substituted or unsubstituted lower alkoxy, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl;

R⁴¹ is H, halogen, substituted or unsubstituted lower alkyl, substituted or unsubstituted lower alkoxy, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl;

R⁴² is H, substituted or unsubstituted lower alkyl, substituted or unsubstituted aryl, substituted or unsubstituted arylalkyl, substituted or unsubstituted heteroaryl, substituted or unsubstituted cycloalkyl or carboxy;

R⁴³, R^43' and R^43" are each independently H, halogen, substituted or unsubstituted lower alkyl, substituted or unsubstituted lower alkoxy, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl;

R⁴⁴, R⁴⁴ and R^44" are each independently H, halogen, substituted or unsubstituted lower alkyl, substituted or unsubstituted lower alkoxy, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl;

R⁴⁵ is H, substituted or unsubstituted lower alkyl, substituted or unsubstituted aryl, substituted or unsubstituted arylalkyl, substituted or unsubstituted heteroaryl, substituted or unsubstituted cycloalkyl or carboxy;

R⁴⁶ is H, substituted or unsubstituted lower alkyl, substituted or unsubstituted aryl, substituted or unsubstituted arylalkyl, substituted or unsubstituted heteroaryl, substituted or unsubstituted cycloalkyl or carboxy;

R⁴⁷, R^47' and R^47" are each independently H, halogen, substituted or unsubstituted lower alkyl, substituted or unsubstituted lower alkoxy, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl; R is H, substituted or unsubstituted lower alkyl, substituted or unsubstituted aryl, substituted or unsubstituted arylalkyl, substituted or unsubstituted heteroaryl, substituted or unsubstituted cycloalkyl or carboxy;

R⁴⁹, R⁴⁹ and R^49" are each independently H, halogen, substituted or unsubstituted lower alkyl, substituted or unsubstituted lower alkoxy, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl;

R⁵⁰ is H, substituted or unsubstituted lower alkyl, substituted or unsubstituted aryl, substituted or unsubstituted arylalkyl, substituted or unsubstituted heteroaryl, substituted or unsubstituted cycloalkyl or carboxy;

R⁵¹, R⁵¹ , R⁵¹ and R^51'" are each independently H, halogen, substituted or unsubstituted lower alkyl, substituted or unsubstituted lower alkoxy, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl;

R⁵² is H, substituted or unsubstituted lower alkyl, substituted or unsubstituted aryl, substituted or unsubstituted arylalkyl, substituted or unsubstituted heteroaryl, substituted or unsubstituted cycloalkyl or carboxy;

R⁵³, R⁵³ , R⁵³ and R⁵³ are each independently H, halogen, substituted or unsubstituted lower alkyl, substituted or unsubstituted lower alkoxy, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl;

R⁵⁴ is -C(0)- R⁵⁶R⁵⁷ or -S(0)₂- R⁵⁸R⁵⁹ and R⁵⁵ is H, or R⁵⁴ is H and R⁵⁵ is -C(O)- R⁵⁶R⁵⁷ or -S(0)₂- R⁵⁸R⁵⁹;

R⁵⁶ and R⁵⁷ are each independently H, substituted or unsubstituted lower alkyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, or substituted or unsubstituted cycloalkyl;

R⁵⁸ and R⁵⁹ are each independently H, substituted or unsubstituted lower alkyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, or substituted or unsubstituted cycloalkyl; R and R are each independently H, halogen, substituted or unsubstituted lower alkyl, substituted or unsubstituted lower alkoxy, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl;

Z¹, Z², Z³, Z⁴, Z⁵ and Z⁶ are each independently -N-, -CH-, or -CR³⁴-, wherein at least one of Z³, Z⁴, Z⁵ and Z⁶ is -N-;

Z* Z' is -CR³⁷R³⁸-CR³⁹R⁴⁰-, -CR¹³⁴=CR¹³⁵- or -N=CR⁴¹-; Z⁹ is -0-, - H-, or -CH₂-;

Z¹⁰ and Z¹¹ are each independently - R⁴⁵- or -CH₂- wherein at least one of Z¹⁰ and

Z¹¹ is -NR⁴⁵-;

Z¹² is -CH₂- -NH-, -S-, or -0-; and Z¹³ is -CH- or -N-.

2. The method according to claim 1, wherein the compound of general formula (I), or salt thereof, is a compound of general formula (IV), or a salt thereof:

wherein

R⁶⁰, R⁶¹, R⁶², R⁶³, and R⁶⁴ are each independently H, CI, I, F, Br, CF₃ or substituted or unsubstituted lower alkoxy, wherein at least one of R⁶⁰, R⁶¹, R⁶², R⁶³, and R⁶⁴ is not H; or R⁶⁰ and R⁶¹, taken together with the ring-forming C atoms that they are attached to, form an aryl ring, and R⁶², R⁶³, and R⁶⁴ are each independently H, CI, I, F, Br, CF₃ or substituted or unsubstituted lower alkoxy; and a) L² is -CH2- or -(CH₂)₂-, and

B² is

wherein:

R and R are each independently H, OH, CI, F, unsubstituted lower alkyl, H₂,

R⁶⁶ and R⁶⁷ are each independently H, F, CI, unsubstituted lower alkyl, or C(0)R 130.

R⁶⁹ is unsubstituted lower alkyl, CHbOR⁷ 7¹1, CH₂OC(0)R , ¹1³3¹1 or (CH₂)_tN₃;

R is phenyl or C(0) H₂;

R is H or unsubstituted lower alkyl;

R¹³⁰ is OH, OR¹³², H₂, HR¹³³, substituted or unsubstituted lower alkyl or substituted or unsubstituted heterocycloalkyl;

R¹³¹ is unsubstituted lower alkyl;

R¹³² and R¹³³ are each independently substituted or unsubstituted lower alkyl; t is 1, 2, 3 or 4; and

W¹ is -CH₂- or -C(O)-; or b) L² is -CH2-NR⁷²-

323

R¹⁰⁹, R¹¹¹, R¹¹³ and R¹³⁶ are each independently H, substituted or unsubstituted arylalkyl, substituted or unsubstituted lower alkyl, substituted or unsubstituted cycloalkyl or carboxy; 74 74' 74" π76 π76' π76" π78 π78' π78" π80 π 80' π80" π 82 π82' π82" π 84 π84' π84" π86 π 86' π86" π 88 π88' π88" π90 π90' π90" π92 π92' π92" π93 π93' π93" π95 τ>95' τ>95" τ>98 τ>98' τ>98" π 100 π 100' π 100" π 102 π 102' π 102" π 104 π 104' π 104" π 106 τ>106' τ>106" π 108 π 108' π 108" πΐΐθ πΐΐθ' πΐΐθ" τ>112 τ>112' τ>112" τ>114 τ>114' τ>114"

R¹³⁷, R¹³⁸, R¹³⁹, R^139', and R^139" are each independently H, halogen or substituted or unsubstituted lower alkyl; and

R⁹⁷ is H, halogen, or substituted or unsubstituted lower alkyl.

3. The method according to claim 1 or 2, wherein R⁶⁰ is CI, I, F or CF3; R⁶³ and R⁶⁴ are each independently H, CI, I, F or CF3, wherein at least one of R⁶³ and R⁶⁴ is not H; and R⁶¹ and R⁶² are each H.

4. The method according to any one of claims 1 to 3, wherein R⁶⁰ and R⁶⁴ are each independently CI, I, F or CF₃; and R⁶¹, R⁶² and R⁶³ are each H.

5. The method according to any one of claims 1 to 4, wherein L² is -CH2- and B² is

, wherein R⁶⁵ is HC(0)R⁶⁹; R⁶⁶, R⁶⁷ and R⁶⁸ are each H; R⁶⁹ is

CH₃, CH₂OR⁷¹, CH₂OC(0)CH₃ or CH₂N₃; R⁷¹ is H or unsubstituted lower alkyl; and W¹ is - C(O)-.

6. The method accordin to any one of claims 1 to 4, wherein L² is -CH₂- R⁷²-, R⁷² is H, and B²

wherein R⁷³, R⁷⁵, R⁸¹, R⁸³, R⁸⁵, R⁹⁴, R⁹⁹, R¹⁰⁷, R¹⁰⁹ and R¹³⁶ are each independently H or unsubstituted lower alkyl; and R⁷⁴, R^74', R^74", R⁷⁶, R^76', R^76", R⁸², R^82', R^82", R⁸⁴, R^84', R^84", R⁸⁶, τ> 86' τ> 86" τ> 93 τ> 93' τ> 93" τ> 95 τ> 95' τ> 95" π 100 π 100' π 100" π 108 π 108' π 108" χ 110 π ΐ ΐθ' π ΐ ΐθ" η ΐ

R¹³⁸, R¹³⁹, R¹³⁹ , and R¹³⁹ are each independently H, halogen or unsubstituted lower alkyl.

The method according to claim 1, wherein the compound is selected from the compounds in Tables 1, 2 and 5, and salts thereof.

8. The method according to claim 1, wherein the compound is selected from compounds 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50, 51, 52, 53, 54, 55, 56, 57, 58, 59, 60, 61, 62, 63, 64, 65, 66, 67, 68, 69, 70, 71, 72, 73, 74, 75, 76, 77, 78, 79, 80, 81, 82, 83, 84, 85, 86, 87, 88, 89, 90, 91, 92, 93, 94, 95, 96, 97, 98, 99, 100, 101, 102, 103, 104, 105, 106, 107, 108, 109, 110, 111, 112, 113, 114, 115, 116, 117, 118, 200, 201, 202, 203, 204, 205, 206, 207, 208, 209, 210, 211, 212, 213, 214, 215, 216, 217, 218, 219, 220, 221, 222, 223, 225, 226, 227, 228, 229, 230, 231, 300, 301, 302, 303, 304, 305, 306, 307, 308, 309-a, 310, 311, 312, 313- a, 314, 315, 316, 317, 318, 319, 320, 321, 322, 323, 324, and 325, and salts thereof

9. The method according to claim 1, wherein the compound is selected from compounds 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50, 51, 52, 53, 54, 55, 56, 57, 58, 59, 60, 61, 62, 63, 64, 65, 66, 67, 68, 69, 70, 71, 72, 73, 74, 75, 76, 77, 78, 79, 102, 103, 104, 105, 106, 107, 108, 109, 110, 111, 112, 113, 114, 115, 116, 117, 118, 200, 201, 202, 203, 204, 205, 206, 207, 208, 209, 210, 221, 222, 223, 225, 226, 227, 228, 229, 303, 305, 306, 308, 310, 314, 315, 316, 317, 318, 319, 320, 321, 322, 323, 324, and 325, and salts thereof

10. The method according to any one of claims 1 to 9, wherein said translation system is a cell.

11. The method according to claim 10, wherein said cell is situated in vivo in a subject.

12. The method according to claim 11, wherein said compound of general formula (I), or salt thereof, and said aminoglycoside, are administered to said subject.

13. The method according to claim 12, wherein said compound of general formula (I), or salt thereof, and said aminoglycoside, are administered to said subject concurrently.

14. The method according to any one of claims 11 to 13, wherein said subject has a disorder or disease selected from the group consisting of Dystrophic epidermolysis bullosa, Batten disease, Duchenne muscular dystrophy, cancer, and spinal muscular atrophy.

15. A compound of general formula (V), or a salt thereof: Ar - B (V) wherein:

Ar is an aryl having general formula (VI):

wherein:

R , R , R , R , and R are each independently H, CI, F, Br, I, or CF₃, wherein at least two of R²⁰⁰, R²⁰¹, R²⁰², R²⁰³, and R²⁰⁴ are not H; or

R²⁰⁰ and R²⁰¹, when taken together with the C atoms they are attached to, form unsubstituted phenyl, and R²⁰², R²⁰³ and R²⁰⁴ are each H; and

B is:

328 ach independently H, F, NH₂, HC(0)R²⁰⁹, N0₂, N₃ or

R²⁰⁶ and R²⁰⁷ are each independently H, CI, CH₃, or C(0)R²¹¹; R²⁰⁹ is CH₃, CH₂OR²¹², CH₂OC(0)CH₃ or CH₂N₃; R²¹⁰ is phenyl or C(0) H₂;

R²¹¹ is (CH₂)₂OCH₃;

R²¹² is H or CH₃; and wherein at least one of R²⁰⁵, R²⁰⁶, R²⁰⁷ and R²⁰⁸ is not H; R²¹³ and R²¹⁶ are each independently H, F, H₂, HC(0)R²¹⁷, N0₂, N₃ or

R²¹⁴ and R²¹⁵ are each independently H, F, CI, CH₃, or C(0)R²¹⁹; R²¹⁷ is CH₃, CH₂OR²²⁰, CH₂OC(0)CH₃ or CH₂N₃; R²¹⁸ is phenyl or C(0) H₂; _^^^N\ / - - ^/ ^N-CHa l]

R²¹⁹ is (CH₂)₂OCH₃; 1 ; or ^■

R²²⁰ is H or CH₃;

R²²¹, R²²⁶, R²³¹, R²³⁶, R²⁴¹, R²⁴⁷, R²⁵², R²⁵⁷, R²⁶², R²⁶⁷ and R²⁹⁷ are each independently H or unsubstituted C_1-6 alkyl; τ>222 τ>223 τ>224 τ>227 τ>228 τ>229 τ>232 τ>233 τ>234 τ>237 τ>238 τ>239 τ>242 τ>243 τ>244 τ>245 τ>246 τ>248 τ>249 τ>250 τ>253 τ>254 τ>255 τ>258 τ>259 τ>260 τ>263 τ>264 τ>265 τ>268 τ>269 τ>270

R²⁹⁸, R²⁹⁹, R³⁰⁰, R³⁰¹, and R³⁰² are each independently H, CI, F, Br, I or unsubstituted Ci-6 alkyl;

R²²⁵, R²³⁰, R²³⁵, R²⁴⁰, R²⁵¹, R²⁵⁶, R²⁶¹, R²⁶⁶, R²⁷¹ and R³⁰³ are each independently H, C(0)OR²⁷², C3-6 cycloalkyl, C_6-10 aryl, C_6-10 aryl-C_1-6 alkyl, or C_1-6 alkyl, wherein C_6- 10 aryl is optionally substituted with one or more substituents independently selected from Ci-6 alkyl; C_6-10 aryl of C_6-10 aryl-Ci-6 alkyl is optionally substituted with one or more substituents independently selected from halogen; and C_1-6 alkyl is optionally substituted with one or more substituents independently selected from the group consisting of OH, C3-6 cycloalkyl, 5- to 10-membered heterocycloalkyl, C(0)OH, C(0)OR²⁷³, H₂, R²⁷⁴R²⁷⁵, HC(0)OR²⁷⁸, Ci_-6 alkoxy, CN, C(0) HR²⁷⁹ and CO H2;

R²⁷², R²⁷³, R²⁷⁴, R²⁷⁵, and R²⁷⁸ are each independently unsubstituted Ci_-6 alkyl;

R²⁷⁹ is Ci-6 alkyl optionally substituted with one or more substituents independently selected from the group consisting of R²⁸⁰R²⁸¹ and OH;

R²⁸⁰ and R²⁸¹ are each independently unsubstituted C_1-6 alkyl;

Z¹⁴ is -CH2- or-C(O)-; and

Z¹⁵ is -N- or -CH-, wherein:

(i) when R²⁰⁰ and R²⁰¹, when taken together with the C atoms they are attached to, form unsubstituted phenyl, and R²⁰², R²⁰³ and R²⁰⁴ are each H, and B is

and only one of R , R , R and R is not H, then

R ^U5 and R ^US are each independently H, F, NH₂, HC(0)R ^uy, N₃ or

and R²⁰⁶ and R²⁰⁷ are each independently H, CI, CH₃, or C(0)R²¹¹, wherein R²⁰⁹, R²¹⁰ and R²¹¹ are as defined above;

wherein Z¹⁵ is as defined above, then at least one of: R²¹³, R²¹⁴, R²¹⁵ and R²¹⁶; or R²³⁶, R²³⁷, R²³⁸, R²³⁹ and R²⁴⁰ is not H;

wherein R²⁶¹ is unsubstituted Ci_-6 alkyl, then at least one of R²⁵⁷, R²⁵⁸, R²⁵⁹ and R²⁶⁰ is not H; (iv) when onl two of R , R , R , R , and R are not H and each is a halogen,

and B

only one of R ^U5, R ^Ub, R ^U and R ^US is not

H, then R²⁰⁵ and R²⁰⁸ are each independently H, F, HC(0)R²⁰⁹, N₃ or

R²⁰⁶ and R²⁰⁷ are each independently H, CI, or C(0)R²¹¹, wherein R²⁰⁹, R²¹⁰ and R²¹¹ are as defined above;

(v) when R²⁰⁰, R²⁰¹, R²⁰², R²⁰³, and R²⁰⁴ are each a halogen, and B is

only one of R²⁰⁵, R²⁰⁶, R²⁰⁷ and R²⁰⁸ is not H, then

R and R^2U8 are each independently H, F, NH₂, HC(0)R^2uy, N₃ or

and

R²⁰⁶ and R²⁰⁷ are each independently H, CI, CH₃, or C(0)R²¹¹, wherein R²⁰⁹, R²¹⁰ and R²¹¹ are as defined above; (vi) when only three of R²⁰⁰, R²⁰¹, R²⁰² R²⁰³, and R²⁰⁴ are not H and each is a hal

then at least one of: R²¹³, R²¹⁴, R²¹⁵ and R²¹⁶; or R²²¹, R²²², R²²³, R²²⁴ and R²²⁵; or R²²⁶, R²²⁷, R²²⁸, R²²⁹ and R²³⁰; or R²³¹, R²³², R²³³, R²³⁴ and R²³⁵; or R²³⁶, R²³⁷, R²³⁸, R²³⁹ and R²⁴⁰; or R²⁴¹, R²⁴², R²⁴³, R²⁴⁴, R²⁴⁵ and R²⁴⁶; or R²⁶², R²⁶³, R²⁶⁴, R²⁶⁵ and R²⁶⁶ is not H;

(viii) when only two of R²⁰⁰, R²⁰¹, R²⁰², R²⁰³, and R²⁰⁴ are not H and each is a halogen,

and B

wherein R²⁴⁹ is a halogen, then at least one of

R²⁴⁷, R²⁴⁸, R²⁵⁰ and R²⁵¹ is not H; and

(ix) when only two of R^2UU, R^2U1, R^2U2, R^2U3, and R^2U4 are not H and each is a halog

and B

, then at least one of R²⁵⁷, R²⁵⁸, R²⁵⁹, R²⁶⁰ and R²⁶¹ is not H, and when only one of R²⁵⁷, R²⁵⁸, R²⁵⁹, R²⁶⁰ and R²⁶¹ is not H, then R²⁵⁷ is H or unsubstituted Ci_-6 alkyl; R²⁵⁸, R²⁵⁹ and R²⁶⁰ are each independently H, CI, F, Br, I or unsubstituted Ci_-6 alkyl; and R²⁶¹ is H, C(0)OR²⁷², Ce-io aryl, Ce-io aryl-Ci-e alkyl, or Ci_-6 alkyl, wherein C_6-10 aryl is optionally substituted with one or more substituents independently selected from Ci_-6 alkyl; C_6-10 aryl of C_6-10 aryl-Ci-6 alkyl is optionally substituted with one or more substituents independently selected from halogen; and C_1-6 alkyl is substituted with one or more substituents independently selected from the group consisting of OH, C3-6 cycloalkyl, 5- to 10-membered heterocycloalkyl, C(0)OH, C(0)OR²⁷³, H₂, R²⁷⁴R²⁷⁵, HC(0)OR²⁷⁸, Ci_-6 alkoxy, CN, C(0) HR²⁷⁹ and CO H2, wherein R²⁷², R²⁷³, R²⁷⁴, R²⁷⁵, R²⁷⁸ and R²⁷⁹ are as defined above.

16. The compound or salt according to claim 15, wherein R²⁰⁰ is CI, F, Br, I, or CF3; R²⁰³ and R²⁰⁴ are each independently H, CI, F, Br, I, or CF3, wherein at least one of R²⁰³ and R²⁰⁴ is not H; and R²⁰¹ and R²⁰² are each H.

17. The compound or salt according to claim 15 or 16, wherein R²⁰⁰ and R²⁰⁴ are each independently CI, F, Br, I, or CF₃; and R²⁰¹, R²⁰² and R²⁰³ are each H.

18. The compound or salt according to claim 15, wherein R²⁰⁰, R²⁰¹, R²⁰², R²⁰³, and R²⁰⁴ are each independently H CI, F, Br, I, or CF₃, wherein at least two of R²⁰⁰, R²⁰¹, R²⁰², R²⁰³, and R²⁰⁴

are not H; and B is

wherein R²⁰⁵ is HC(0)R²⁰⁹; R²⁰⁶, R²⁰⁷ and

R²⁰⁸ are each H; R²⁰⁹ is CH₃, CH2OR²¹², CH₂OC(0)CH₃ or CH2N3; and R²¹² is H or CH₃.

19. The compound or salt according to claim 15, wherein R²⁰⁰, R²⁰¹, R²⁰², R²⁰³, and R²⁰⁴ are each independently H, CI, F, Br, I, or CF₃, wherein at least two of R²⁰⁰, R²⁰¹, R²⁰², R²⁰³, and R²⁰⁴

20. The compound or salt according to claim 15, wherein R is CI, F, Br, I, or CF₃; R is CF₃; and R²⁰¹, R²⁰² and R²⁰³ are each H; and B is:

are each independently H or Ci_-6 alkyl; R²²², R , R²²⁴, R²²⁷, R and R are each

independently H, CI, F, Br, I or unsubstituted Ci_-6 alkyl; and R²²⁵, and R²³⁰ are each

independently H, C(0)OR²⁷², C_3-6 cycloalkyl, C6-10 aryl, C₆-io aryl-Ci-6 alkyl, or Ci_-6 alkyl, wherein C₆-io aryl is optionally substituted with one or more substituents independently selected from Ci-6 alkyl; C₆-io aryl of C6-10 aryl-Ci-6 alkyl is optionally substituted with one or more substituents independently selected from halogen; and Ci_-6 alkyl is optionally substituted with one or more substituents independently selected from the group consisting of OH, C_3-6 cycloalkyl, 5- to 10-membered heterocycloalkyl, C(0)OH, C(0)OR²⁷³, H₂, R²⁷⁴R²⁷⁵,

HC(0)OR²⁷⁸, Ci-6 alkoxy, CN, C(0) HR²⁷⁹ and CO H₂; R²⁷², R²⁷³, R²⁷⁴, R²⁷⁵, and R²⁷⁸ are each independently unsubstituted Ci_-6 alkyl; R²⁷⁹ is Ci_-6 alkyl optionally substituted with one or more substituents independently selected from the group consisting of R²⁸⁰R²⁸¹ and OH; and R²⁸⁰ and R²⁸¹ are each independently unsubstituted Ci_-6 alkyl.

21. The compound according to claim 15, wherein the compound is compound 2, 5, 9, 11, 12, 13, 14, 15, 16, 17, 19, 29, 41, 42, 43, 44, 45, 46, 47, 68, 74, 76, 103, 104, 105, 107, 109, 204, 205, 211, 213, 214, 300, 301, 302, 303, 304, 305, 306, 307, 308, 309-a, 310, 311, 312, 313-a, 314, 315, 316, 317, 318, 319, 320, 321, 322, 323-a, 324 or 325, or a salt thereof.

22. A pharmaceutical composition comprising a compound of general formula (I) as used claim 1, or a salt thereof, and an aminoglycoside.

23. A pharmaceutical composition comprising a compound according to claim 15.

24. The pharmaceutical composition according to claim 23, further comprising aminoglycoside.