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

Compositions for promoting readthrough of premature termination codons, and methods of using the same Download PDF

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Publication number
WO2017049409A1
WO2017049409A1 PCT/CA2016/051119 CA2016051119W WO2017049409A1 WO 2017049409 A1 WO2017049409 A1 WO 2017049409A1 CA 2016051119 W CA2016051119 W CA 2016051119W WO 2017049409 A1 WO2017049409 A1 WO 2017049409A1
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WO
WIPO (PCT)
Prior art keywords
unsubstituted
substituted
alkyl
independently
lower alkyl
Prior art date
Application number
PCT/CA2016/051119
Other languages
French (fr)
Inventor
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
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Filing date
Publication date
Application filed by The Centre For Drug Research And Development, The University Of British Columbia filed Critical The Centre For Drug Research And Development
Publication of WO2017049409A1 publication Critical patent/WO2017049409A1/en

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    • A61K31/16—Amides, e.g. hydroxamic acids
    • A61K31/165—Amides, e.g. hydroxamic acids having aromatic rings, e.g. colchicine, atenolol, progabide
    • A61K31/166—Amides, e.g. hydroxamic acids having aromatic rings, e.g. colchicine, atenolol, progabide having the carbon of a carboxamide group directly attached to the aromatic ring, e.g. procainamide, procarbazine, metoclopramide, labetalol
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    • A61K31/195—Carboxylic acids, e.g. valproic acid having an amino group
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    • A61K31/4523—Non condensed piperidines, e.g. piperocaine containing further heterocyclic ring systems
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Definitions

  • 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.
  • 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.
  • 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.
  • 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.
  • 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).
  • 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.
  • PTC readthrough compounds referred to herein as "PTC readthrough compounds", or "PTC-RCs”
  • the present invention derives in part from the surprising finding that combinations of certain PTC-RCs exhibit synergistic PTC readthrough activity.
  • 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.
  • 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.
  • 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 is an aryl having general formula (II):
  • R 1 , R 2 , R 3 , R 4 and R 5 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 R 1 and R 2 , taken together with the ring-forming C atoms that they are attached to, form an aryl ring; or R 2 and R 3 , 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:
  • R 6 and R 9 are each independently H, OH, F, CI, substituted or unsubstituted lower alkyl,
  • R 7 and R 8 are each independently H, F, CI, unsubstituted lower alkyl, or C(0)R 12 ;
  • R 10 is substituted or unsubstituted lower alkyl;
  • R 11 is substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, or C(0)R 13 ;
  • R 12 and R 13 are each independently OH, OR 14 , H 2 , HR 15 , substituted or unsubstituted lower alkyl or substituted or unsubstituted heterocycloalkyl;
  • R 14 and R 15 are each independently substituted or unsubstituted lower alkyl;
  • X is -CH 2 -, - H- or - R 16 -;
  • R 16 is substituted or unsubstituted aryl;
  • R 17 is H, substituted or unsubstituted lower alkyl, substituted or unsubstituted aryl, substituted or unsubstituted
  • Ar is an aryl having general formula (III):
  • 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 R 19 and R 20 , taken together with the ring-forming C atoms that they are attached to, form an aryl ring; or R 20 and R 21 , 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-NR 24 -, -S(0) 2 -NR 25 -, -NH-C(0)-NH-, -C(0)-NH- -CH 2 -NH-C(0)-, or -CH 2 -NR 26 -CH 2 -;
  • R 24 and R 25 are each independently H or unsubstituted lower alkyl;
  • R 26 is H or unsubstituted lower alkyl;
  • 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;
  • R 28 , R 28 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;
  • R 29 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 30 , R 30' and R 30" are each independently H
  • R 134 and R 135 are each independently H, halogen, substituted or unsubstituted lower alkyl, substituted or unsubstituted lower alkoxy, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl;
  • Z 1 , Z 2 , Z 3 , Z 4 , Z 5 and Z 6 are each independently -N-, -CH-, or -CR 34 -, wherein at least one of Z 3 , Z 4 , Z 5 and Z 6 is -N-;
  • Z 9 is -0-, - H-, or -CH 2 -;
  • Z 10 and Z 11 are each independently - R 45 - or -CH 2 - wherein at least one of Z 10 and Z 11 is -NR 45 -;
  • Z 12 is
  • Addition of the subject compound and aminoglycoside to the translation system may be done concurrently or consecutively.
  • the compound of general formula (I), or salt thereof is a compound of general formula (IV), or a salt thereof:
  • R 60 , R 61 , R 62 , R 63 , and R 64 are each independently H, CI, I, F, Br, CF 3 or substituted or unsubstituted lower alkoxy, wherein at least one of R 60 , R 61 , R 62 , R 63 , and R 64 is not H; or R 60 and R 61 , taken together with the ring-forming C atoms that they are attached to, form an aryl ring, and R 62 , R 63 , and R 64 are each independently H, CI, I, F, Br, CF 3 or substituted or unsubstituted lower alkoxy; and a) L 2 is -CH 2 - or -(CH 2 ) 2 -, and
  • R and R are each independently H, OH, CI, F, unsubstituted lower alkyl, H 2 ,
  • R 66 and R 67 are each independently H, F, CI, unsubstituted lower alkyl, or C(0)R 130 ;
  • R 69 is unsubstituted lower alkyl, CH 2 OR 71 , CH 2 OC(0)R 131 or (CH 2 ) t N 3 ;
  • R 70 is phenyl or C(0)NH 2 ;
  • R 71 is H or unsubstituted lower alkyl;
  • R 130 is OH, OR 132 , H 2 , HR 133 , substituted or unsubstituted lower alkyl or substituted or unsubstituted heterocycloalkyl;
  • R 131 is unsubstituted lower alkyl;
  • R 132 and R 133 are each independently substituted or unsubstituted lower alkyl;
  • t is 1, 2, 3 or 4; and
  • W 1 is - CH 2 - or -C(O)-; or
  • L 2 is -CH 2 - R
  • R 111 , R 113 and R 136 are each independently H, substituted or unsubstituted arylalkyl, substituted or unsubstituted lower alkyl, substituted or unsubstituted cycloalkyl or carboxy; R 74 , R 74' , R 74" , R 76 , R 76' , R 76" , R 78 , R 78' , R 78" , R 80 , R 80' , R 80" , R 82 , R 82' , R 82” , ⁇ 84 ⁇ 84' ⁇ 84" ⁇ 86 ⁇ 86' ⁇ 86" ⁇ 88 ⁇ 88' ⁇ 88" ⁇ 90 ⁇ 90' ⁇ 90" ⁇ 92 ⁇ 92' ⁇ 92" ⁇ 93 ⁇ 93' ⁇ >93" ⁇ >95 ⁇ >95' ⁇ >95" ⁇ >98' ⁇ >98" ⁇ 100 ⁇ 100' ⁇ 100 ⁇ 100
  • R 137 , R 138 , R 139 , R 139' , and R 139" are each independently H, halogen or substituted or unsubstituted lower alkyl; and R 97 is H, halogen, or substituted or unsubstituted lower alkyl.
  • R is CI, I, F or CF 3 ; R and R are each independently H, CI, I, F or CF 3 , wherein at least one of R 63 and R 64 is not H; and R 61 and R 62 are each H.
  • R 60 and R 64 are each independently CI, I, F or CF 3 ; and R 61 , R 62 and R 63 are each H.
  • L 2 is -CH 2 - and B 2 is
  • R is HC(0)R 69 ; R , R and R are each H; R is CH 3 , CH 2 OR 71 , CH 2 OC(0)CH 3 or CH 2 N 3 ; R 71 is H or unsubstituted lower alkyl; and W 1 is -C(O)-
  • L 2 is -CH 2 - R 72 -, R 72 is H, and B 2 is:
  • the compound of general formula (I), or salt thereof is selected from the compounds shown in Tables 1, 2, and 5, and salts thereof.
  • 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
  • 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, 22
  • the translation system is a cell.
  • the cell is situated in vivo in a subject.
  • the compound of general formula (I), or salt thereof, and the aminoglycoside are administered to the subject.
  • the compound of general formula (I), or salt thereof, and the aminoglycoside are administered to the subject simultaneously.
  • the compound of general formula (I), or salt thereof, and the aminoglycoside are administered to the subject consecutively.
  • the subject has a disorder or disease selected from the group listed in Table 3.
  • the subject has a disorder or disease selected from the group listed in Table 4.
  • 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.
  • the invention provides a compound of general formula (V), or a salt thereof:
  • Ar is an aryl having general formula (VI):
  • R , R , R , R , and R are each independently H, CI, F, Br, I, or CF 3 , wherein at least two of R 200 , R 201 , R 202 , R 203 , and R 204 are not H; or R 200 and R 201 , when taken together with the C atoms they are attached to, form unsubstituted phenyl, and R 202 , R 203 and R 204 are each H; and
  • R 205 and R 208 are each independently H, F, NH 2 , HC(0)R 2 u 0 y 9, N0 2 , N 3 or
  • R 206 and R 207 are each independently H, CI, CH 3 , or C(0)R 211 ;
  • R 210 is phenyl or C(0) H 2 ;
  • R is H or CH 3 ; and wherein at least one of R 205 , R 206 , R 207 and R 208 is not H; 2 13 and R 216 are each independently H, F, NH 2 , HC(0)R 217 , N0 2 , N 3 or R 214 and R 215 are each independently H, F, CI, CH 3 , or C(0)R 219 ; R 217 is CH 3 ,
  • CH2OR 220 CH 2 OC(0)CH 3 or CH 2 N 3 ;
  • R 218 is phenyl or C(0) H 2 ;
  • R 219 is (CH 2 ) 2 OCH 3 ; « ⁇
  • R 220 is H or CH 3 ;
  • R 221 , R 226 , R 231 , R 236 , R 241 , R 247 , R 252 , R 257 , R 262 , R 267 and R 297 are each independently H or unsubstituted Ci -6 alkyl;
  • R 272 , R 273 , R 274 , R 275 , and R 278 are each independently unsubstituted Ci -6 alkyl;
  • R 279 is C 1-6 alkyl optionally substituted with one or more substituents independently selected from the group consisting of R 280 R 281 and OH;
  • R 280 and R 281 are each independently unsubstituted C 1-6 alkyl;
  • Z 14 is -CH2- or -C(O)-; and Z 15 is - N- or -CH- wherein:
  • R 200 and R 201 when taken together with the C atoms they are attached to, form unsubstituted phenyl, and R 202 , R 203 and R 204 are each H, and B is:
  • R 205 , R 206 , R 207 and R 2 2 m 08 are not H, then R .2 U 0 5 5 and
  • R 208 are each independently H, F, H 2 , HC(0)R 209 , N 3 or ; and R 206 and R 207 are each independently H, CI, CH 3 , or C(0)R 211 , wherein R 209 , R 210 and R 211 are as defined above;
  • R 213 , R 214 , R 215 and R 216 then at least one of: R 213 , R 214 , R 215 and R 216 ; or R 236 , R 237 , R 238 , R 239 and R 240 is not H;
  • R 261 is unsubstituted Ci -6 alkyl, then at least one of
  • R 205 , R 206 , R 20 / and R zm is not H
  • R 205 and R 208 are each independently H, F, HC(0)R uy , N 3 or
  • R 206 and R 207 are each independently H, CI, or C(0)R 211 , wherein R 209 , R 210 and R : are as defined above: when R 200 , R 201 , R 202 , R 203 , and R 204 are each a halogen, and B
  • R 205 , R 206 , R 207 and R 208 are H, then R , 205
  • R are each independently H, F, H 2 , HC(0)R z 2 u 0 v 9, N 3 or ;
  • R 206 and R 207 are each independently H, CI, CH 3 , or C(0)R 211 , wherein R 209 , R 210 and R 211 are as defined above;
  • R 249 is a halogen
  • R 248 R 250 and R 251 is nQt R an( j
  • R 257 , R 258 , R 259 , R 260 and R 261 is not
  • R 257 is H or unsubstituted Ci-6 alkyl
  • R 258 , R 259 and R 260 are each independently H, CI, F, Br, I or unsubstituted Ci-6 alkyl
  • R 261 is H, C(0)OR 272 , Ce-io aryl, Ce-io aryl-Ci-e alkyl, or Ci -6 alkyl, wherein C 6 -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 heterocycloal
  • R 200 is CI, F, Br, I, or CF 3 ;
  • R 203 and R 204 are each independently H, CI, F, Br, I, or CF 3 , wherein at least one of R 203 and R 204 is not H; and
  • R 201 and R 202 are each H.
  • R' ou and R 2U4 are each independently CI, F, Br, I, or CF 3 ; and R U1 , R 202 and R 203 are each H.
  • R 200 , R 201 , R 202 , R 203 , and R 204 are each independently H, CI, F, Br, I, or CF 3 , wherein at least two of R 200 , R 201 , R 202 , R 203 , and R 204 are not H; and B is wherein R is HC(0)R 209 ; R , R and R are each H; R is
  • R 200 , R 201 , R 202 , R 203 , and R 204 are each independently H, CI, F, Br, I, or CF 3 , wherein at least two of R 200 , R 201 , R 202 , R 203 , and R 204 are not H; and B is
  • R 224 and R 225 are independently selected from H.
  • R 226 , R 227 R 228 , R 229 and R 230 is not H.
  • R 2UU is CI, F, Br, I, or CF 3 ;
  • R 2U4 is CF 3 ; and
  • R 2U1 , R 2U2 and R 2U3 are each H; and
  • B is:
  • R 221 and R 226 are each independently H or Ci -6 alkyl
  • R 222 , R 223 , R 224 , R 227 , R 228 and R 229 are each independently H, CI, F, Br, I or unsubstituted Ci -6 alkyl
  • R 225 , and R 230 are each independently H, C(0)OR 272 , C 3-6 cycloalkyl, C 6 -io aryl, C 6 -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; C 6 -io aryl of C 6 - 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
  • R 272 , R 273 , R 274 , R 275 , and R 278 are each independently unsubstituted Ci-6 alkyl;
  • R 279 is Ci -6 alkyl optionally substituted with one or more substituents independently selected from the group consisting of R 280 R 281 and OH; and
  • R 280 and R 281 are each independently unsubstituted C 1-6 alkyl.
  • 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.
  • 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
  • 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
  • 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.
  • 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.
  • 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
  • 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, 319, 321, 322, 3
  • 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.
  • 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
  • FIG. 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.
  • 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.
  • FIG. 1 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.
  • FIG. 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.
  • FIG. 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.
  • FIG. 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.
  • H1299 cells express no endogenous p53 because of deletion of the first 954 nucleotides of the TP53 gene.
  • H1299 cells lacking endogenous p53 expression were transfected with p53 expression plasmids that were identical except at R213X.
  • 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.
  • 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 ⁇ (met8-l) or 10 ⁇ ⁇ trp5-48). Yeast growth was measured 40 h after addition of the compounds.
  • FIG. 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)
  • FIG. 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 Baranies-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.
  • FIG. 9 Induction of PTC readthrough by a combination of G418 and 102 in cells derived from patients with rare genetic diseases.
  • 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.
  • 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 ⁇ g of total protein from GM16485 lysates or 5 ⁇ g of total protein from lysates of fibroblasts from unaffected individuals (WT) was incubated in 150 ⁇ of 50 mM sodium acetate pH 4.0 containing a final concentration of 62.5 ⁇ Ala-Ala-Phe-7-amido- 4-methylcoumarin for 2 h at 37°C.
  • TPPl activity was expressed relative to the average activity of untreated primary fibroblasts from two unaffected individuals (WT) (Panel A).
  • WT unaffected individuals
  • 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 Baranies-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.
  • 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.
  • 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.
  • PTC readthrough compounds referred to herein as "PTC readthrough compounds", or "PTC-RCs”
  • the present invention derives in part from the surprising finding that combinations of certain PTC-RCs exhibit synergistic PTC readthrough activity.
  • 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.
  • 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.
  • the invention provides PTC-RCs of general formula (V).
  • the invention provides PTC-RCs selected from Tables 1, 2, and 5.
  • 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.
  • 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.
  • 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.
  • 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.
  • a PTC-RC of the invention is used in combination with an aminoglycoside in compositions and methods disclosed herein.
  • the aminoglycoside is a natural aminoglycoside.
  • the aminoglycoside is an aminoglycoside fraction or component.
  • the aminoglycoside is a synthetic aminoglycoside. Synthetic aminoglycosides include aminoglycoside analogues exhibiting PTC readthrough activity.
  • the aminoglycoside is G418.
  • 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.
  • 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.
  • 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.
  • PTC-RCs 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).
  • 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).
  • aminoglycoside fraction and “aminoglycoside component” refer to fractions and components that may be found within aminoglycoside preparations.
  • PTC-RCs are RTC-13, RTC-14, negamycin, tylosin, GJ71, GJ72 and ataluren and other compounds disclosed in US 2013/0274283.
  • PTC-RCs 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.
  • lower alkyl refers to a straight chain or branched alkyl group of one to six carbon atoms.
  • 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.
  • C1-C4 acyl refers to the group -C(0)R, where R is substituted or unsubstituted C1-C4 alkyl.
  • C1-C4 alkoxy refers to the group -OR, where R is substituted or unsubstituted C1-C4 alkyl.
  • 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.
  • 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
  • therapy and treatment 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.
  • 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.
  • 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.
  • 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.
  • full length protein refers to the translation product of an mRNA having a PTC, refers to a translation product that is not truncated at the PTC.
  • a full length protein translated from an mRNA having a PTC 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.
  • 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.
  • simultaneous (concurrent) 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).
  • 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).
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • PTC-RCs of general formulas (I), (IV) and (V), and of Tables 1, 2, or 5 may appear to lack independent readthrough activity.
  • 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.
  • 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.
  • 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.
  • Certain embodiments further comprise the use of a steroid.
  • 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.
  • 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 may be used in combination with an aminoglycoside and a steroid.
  • the aminoglycoside is a natural aminoglycoside.
  • the aminoglycoside is an aminoglycoside fraction or component.
  • the aminoglycoside is a synthetic aminoglycoside.
  • the aminoglycoside is G418.
  • the aminoglycoside is gentamicin.
  • the aminoglycoside is X2.
  • the aminoglycoside is Bl .
  • 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.
  • 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.
  • the aminoglycoside is a natural aminoglycoside.
  • the aminoglycoside is an aminoglycoside fraction or component.
  • the aminoglycoside is a synthetic aminoglycoside.
  • 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 .
  • compositions, 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.
  • any embodiment discussed herein for the disclosed compounds can be implemented with respect to any method or composition of the disclosure, and vice versa.
  • compositions and kits of the disclosure can be used to achieve methods of the disclosure.
  • the PTC read-through compounds may be compounds of general formula I (Formula I), or salts thereof:
  • Ar is an aryl having general formula II:
  • R 1 to R 5 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 R 1 and R 2 , taken together with the ring-forming C atoms that they are attached to, form an aryl ring; or R 2 and R 3 , taken together with the ring- forming C atoms that they are attached to, form an aryl ring;
  • L is - (CH 2 )n -; n is 1 or 2;
  • R b and R y are each independently H, OH, F, H 2 , HC(0)R 10 , N0 2 , N 3 or
  • R 7 and R 8 are each independently H, F, CI, CH 3 , or C(0)R 12 ;
  • R 10 is substituted or unsubstituted lower alkyl;
  • R 11 is substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, or C(0)R 12 ;
  • R 14 is substituted or unsubstituted lower alkyl;
  • R 12 is OH, OR 14 , H 2 , NHR 14 , or substituted or unsubstituted lower alkyl;
  • R 17 is H, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl;
  • R 18 is H; or R 17 and R 18 , taken together with the C atom they are attached to form cyclopropyl,cyclopentyl or cyclohexyl;
  • W is -CH 2 - or -C(O)-;
  • X is absent, -CH 2 - or
  • Ar is an aryl having general formula III:
  • 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 R 19 and R 20 , taken together with the ring-forming C atoms that they are attached to, form an aryl ring; or R 20 and R 21 , taken together with the ring-forming C atoms that they are attached to, form an aryl ring;
  • L is -CH2- R 24 -, -SO2- R 24 -, - H-C(0)- H-, -C(0)- H- -CH 2 - H-C(0)-, or -CH 2 - R 26 -CH 2 -;
  • R 24 is H or lower alkyl;
  • R 26 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;
  • R 28 is H, substituted or unsubstituted lower alkyl;
  • R 29 is H, substituted or unsubstituted lower alkyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, or substituted or unsubstituted cycloalkyl;
  • R 31 is H, substituted or unsubstituted lower alkyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, or substituted or unsubstituted cycloalkyl;
  • R 33 and R 34 are independently H, halo, substituted or unsubstituted lower alkyl, substituted or unsubstituted lower alkoxy, substitute
  • R 47 is H, halo, substituted or unsubstituted lower alkyl, substituted or unsubstituted lower alkoxy, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl;
  • R 48 is H, substituted or unsubstituted lower alkyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted cycloalkyl, or carboxy;
  • R 49 is H, halo, substituted or unsubstituted lower alkyl, substituted or unsubstituted lower alkoxy, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl;
  • R 50 is H, substituted or unsubstituted lower alkyl, substituted or unsubstituted aryl, substituted or
  • R 56 and R 57 are each independently H, substituted or unsubstituted lower alkyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, or substituted or unsubstituted cycloalkyl;
  • R 58 andR 59 are each independently H, substituted or unsubstituted lower alkyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, or substituted or unsubstituted cycloalkyl;
  • R 45 is H, substituted or unsubstituted lower alkyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted cycloalkyl, or carboxy;
  • Z is -CH 2 -;
  • Z 1 to Z 6 is -N-, -CH-,
  • the PTC read-through compounds may be compounds of general formula I (Formula I), or salts thereof:
  • Ar is an aryl having general formula II (Formula II):
  • R 1 to R 5 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 - (CH 2 )n -; n is 1 or 2; and B is:
  • R 6 and R 9 are each independently H, OH, F, H 2 , HC(0)R 10 , N0 2 , N 3 or
  • R 7 and R 8 are each independently H, F, CI, CH 3 , or C(0)R 12 ;
  • R 10 is substituted or unsubstituted lower alkyl;
  • R 11 is substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, or C(0)R 12 ;
  • R 14 is substituted or unsubstituted lower alkyl;
  • R 12 is OH, OR 14 , H 2 , NHR 14 , substituted or unsubstituted cyclic amines, or substituted or unsubstituted lower alkyl;
  • R 17 is H, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl;
  • R 18 is H; or R 17 and R 18 , taken together with the C atom they are attached to form cyclopropyl, cyclopentyl or cyclohexyl;
  • W is - CH 2 - or -C(O)
  • Ar is an aryl having general formula III (Formula III): wherein:
  • R 19 , R 20 , R 21 , R 22 and R 23 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- R 24 -, -SO2- R 24 - or - H-C(0)- H-;
  • R 24 is H or lower alkyl;
  • B is selected from:
  • R is H, substituted or unsubstituted substituted lower alkyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl;
  • R 28 is H, substituted or unsubstituted substituted lower alkyl;
  • R 29 is H, substituted or unsubstituted substituted lower alkyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl;
  • R 31 is H, substituted or unsubstituted substituted lower alkyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl;
  • R 33 and R 34 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 -CH 2 - and Z 1 to
  • Ar is an aryl having general formula II:
  • R 1 to R 5 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 - (CH 2 )n -; n is 1 or 2; and B is:
  • R 6 and R 9 are each independently H, OH, F, H 2 , HC(0)R 10 , N0 2 , N 3 or
  • R 7 and R 8 are each independently H, F, CI, CH 3 , or C(0)R 12 ;
  • R 10 is substituted or unsubstituted lower alkyl;
  • R 11 is substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, or C(0)R 12 ;
  • R 14 is substituted or unsubstituted lower alkyl;
  • R 12 is OH, OR 14 , H 2 , NHR 14 , or substituted or unsubstituted lower alkyl;
  • R 17 is H, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl;
  • R 18 is H; or R 17 and R 18 , taken together with the C atom they are attached to form cyclopropyl, cyclopentyl or cyclohexyl;
  • W is -CH 2 - or -C(O)-;
  • X is absent, -CH 2 - or
  • Ar is an aryl having general formula III:
  • 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;
  • L is -CH2- R 24 -, -SO2- R 24 - or - H-C(0)- H-;
  • R 24 is H or lower alkyl;
  • B is selected from:
  • R is H, substituted or unsubstituted substituted lower alkyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl;
  • R 28 is H, substituted or unsubstituted substituted lower alkyl;
  • R 29 is H, substituted or unsubstituted substituted lower alkyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl;
  • R 31 is H, substituted or unsubstituted substituted lower alkyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl;
  • R 33 and R 34 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 -CH 2 - and Z 1 to
  • R 1 is H, CI, F, Br, CN, OCH3 or CH 3 ;
  • R 2 is H, CI, F, CF 3 , OCH 3 , or NHC(CH 3 ) 2 , or R 1 and R 2 , when taken together with the C atoms they are attached to, form phenyl;
  • R 3 is H, CI, F, OH, OCH 3 or CH 3 ;
  • R 4 is H, CI, F or CF 3 , and R 5 is H, CI, F, OCH 3 or CH 3 ; and wherein at least one of R ⁇ R 5 is not H; or a N-containing heteroaryl selected from:
  • L is - (CH 2 ) n -; n is 1 or 2; and B is:
  • R b and R y are each independently H, OH, F, H 2 , HC(0)R 1U , N0 2 , N 3 or
  • R 7 and R 8 are each independently H, F, CI, CH 3 , or C(0)R 12 ;
  • R 10 is CH 3 , CH 2 OR CH 2 OC(0)CH 3 or CH 2 N 3 ;
  • R 11 is phenyl or C(0)NH 2 ;
  • R 150 is H or CH 3 ;
  • R 17 is H, (CH 2 ) 2 SCH 3 or phenyl; and R 18 is H; or R 17 and R 18 , taken together with the C atom they are attached to, form cyclopropyl, cyclopentyl or cyclohexyl; W is - CH 2 - or -C(O)-; X is absent, -CH 2 - or - R 151 -, wherein R 151 is H, CH 3 or phenyl, and Y is -CH 2 - or -0-; or
  • Ar is an aryl having general formula III:
  • R 19 , R 20 , R 21 , R 22 and R 23 are each independently H, CI, F or CF 3 ; and wherein at least one of R 19 -R 23 is not H;
  • L is -CH 2 - R 24 -, -S0 2 - H- or - H-C(0)- H-;
  • R 24 is H or CH 3 ;
  • B is selected from:
  • R 27 , R 28 and R 29 are each independently H or CH 3 ;
  • Z is -CH 2 - or -C(O)-, and Z 2 is - N- or -CH.
  • Ar is an aryl having general formula (II), and R 1 is H, CI, F or CN; R 2 is H, CI, F, CF 3 or OCH 3 ; R 3 and R 5 are each independently H, CI or F, and R 4 is H, CI, F or CF 3 .
  • Ar is an aryl having general formula (II), and R 1 is H, CI, F or CN, wherein if R 1 is F, R 4 is F or CF 3 ; R 2 is H, CI, F, CF 3 or OCH 3 , wherein if R 2 is F, at least one of R 1 , R 4 and R 5 is not H or F, or R 3 is F; or R 1 and R 2 , when taken together with the C atoms they are attached to, form phenyl; R 3 is H, F or CI; R 4 is H, CI, F or CF 3 , and R 5 is H, CI or F, wherein if R 5 is F, at least one of R l -R 4 is CI.
  • Ar is an aryl having general formula (II), and at least one, but not more than three, of R ⁇ R 5 are not H.
  • Ar is an aryl having general formula (II), and at least two of R ⁇ R 5 are not H.
  • Ar is an aryl having general formula (II), and when any one of R ⁇ R 5 is F, at least one other of R ⁇ R 5 is not H.
  • Ar is an aryl having general formula (II), and when R 3 is CI, at least one other of R 1 , R 2 , R 4 and R 5 is not H.
  • Ar is an aryl having general formula (II), and when both R 1 and R 2 are not H, one of R 3 -R 5 is also not H.
  • Ar is an aryl having general formula (II), and when R 2 is OCH 3 , n is 2.
  • Ar is an aryl having general formula (II), and R 1 , R 2 , R 3 , R 4 and R 5 are each independently H, CI, F or CF 3 .
  • Ar is an aryl having general formula (II), R 1 , R 2 , R 3 , R 4 and R 5 are each independently H, CI, F or CF 3 , and at least two of R 1 - R 5 are not H.
  • Ar is an aryl having general formula II
  • R 7 and R 8 are each independently H, F, CI or CH 3 .
  • Ar is an aryl having general formula III, and R 19 is H, CI or F; R 20 is H, CI or CF 3 ; R 21 and R 22 are each H, and R 23 is H, CI or F.
  • Ar is an aryl having general formula III, and at least two of R 19 -R 23 are not H.
  • Ar is an aryl having general formula III, and L is -CH 2 - R 24 - or -S0 2 - H-.
  • compounds of general formula I comprise compounds of general formula IV (Formula IV), and salts thereof: wherein
  • R 50 , R 61 , R 62 , R 63 , and R 64 are each independently H, CI, F or CF 3 , wherein at least one of R 60 -R 64 is not H, and
  • L 2 is -CH 2 - or -CH2CH2-, and B 2 is
  • R 115 and R m are each independently H, NHC(0)R N 3 or NH 2 ;
  • R 116 and R 117 are each independently H, CI or F;
  • R 119 is CH 3 , CH2OR 121 , CH 2 OC(0)CH 3 or CH 2 N 3 ;
  • R 120 is phenyl or C(0) H 2 ;
  • R 121 is H or CH 3 ; or
  • L 2 is -CH2- R 122 -;
  • R 122 is is H or lower alkyl, and B 2 2 i ;s c
  • R 123 , R 124 and R 125 are each independently H or CH 3 ;
  • Z 17 is N or CH.
  • the compound of general formula I, or salt thereof is a compound of general formula IV, or a salt thereof:
  • R 60 , R 61 , R 62 , R 63 , and R 64 are each independently are each independently H, CI, I, F or CF 3 , wherein at least one of R 60 -R 64 is not H, and
  • L 2 is -CH 2 - and B 2 is
  • R 115 and R 118 are each independently H, N 3 or H 2 ;
  • R 116 and R 117 are each independently H, CI or F;
  • R 119 is CH 3 , CH 2 OR
  • R 120 is phenyl or C(0) H 2 ; or b) L 2 is -CH 2 - R 122 -; R 122 is H or lower alkyl, and B 2 is
  • the compounds of general formula I are selected from the compounds shown in Tables 1 and 2, and salts thereof:
  • the PTC read-through compounds may be compounds of general formula IA (Formula IA), or a salt thereof:
  • R 1 , R 2 , R 3 , R 4 and R 5 are each independently H, CI, F, I, CF 3 or C1-C4 alkoxy, wherein at least one of R ⁇ R 5 is not H;
  • L is -(CH 2 ) n -; n is 1 or 2;
  • R 6 and R 9 are each independently H, OH, CI, F, C1-C4 alkyl, H 2 , HC(0)R 10 , N0 2 ,
  • R 7 and R 8 are each independently H, F, CI, CH 3 , or C(0)R 12 ;
  • R 10 is C1-C4 alkyl, CH 2 OR 126 , CH 2 OC(0)R 126 or (CH 2 ) m N 3 ;
  • R 11 is phenyl or C(0) H 2 ;
  • R 14 is substituted or unsubstituted lower alkyl;
  • R 12 is OH, OR 14 , NH 2 , HR 14 , substituted or unsubstituted cyclic amines, or substituted or unsubstituted lower alkyl;
  • R 127 is H or C1-4 alkyl;
  • R 128 is H or Me;
  • R 129 is H, substituted or unsubstituted substituted lower alkyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl;
  • R 126 is C1-C4 alkyl;
  • m is 1, 2, 3 or 4;
  • W is -C(O)-, and Z 18 is
  • R 1 , R 2 , R 3 , R 4 and R 5 are each independently H, CI, F, CF 3 or OCH 3 .
  • R 1 , R 2 , R 3 , R 4 and R 5 are each independently H, CI or CF 3 .
  • R ⁇ R 5 are each CI or CF 3 , and the remaining R ⁇ R 5 are H.
  • L is -CH 2 -.
  • R 6 , R 7 , R 8 and R 9 are each
  • R 7 is H.
  • R 127 and R 128 and H or Ci- C 4 alkyl are each H.
  • R 127 is H or C1-C4 alkyl.
  • R 127 is H or CH3.
  • W is -C(O)-.
  • 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.
  • 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
  • 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.
  • the invention provides compounds of general formula I, or salts thereof:
  • Ar is an aryl having general formula II:
  • R 1 is H, CI, F, Br, CN, OCH 3 or CH 3
  • R 2 is H, CI, F, CF 3 , OCH 3 , or HC(CH 3 ) 2 , or R 1 and R 2 , when taken together with the C atoms they are attached to, form phenyl
  • R 3 is H, CI, F, OH, OCH 3 or CH 3
  • R 4 is H, CI, F or CF 3
  • R 5 is H, CI, F, OCH 3 or CH 3
  • at least one of R ⁇ R 5 is not H; or a N-containing heteroaryl selected from:
  • L is - (CH 2 )n -; n is 1 or 2; and B is:
  • R and R are each independently H, OH, F, NH 2 , NHC(0)R 286 , N0 2 , N 3 or
  • R 283 and R 284 are each independently H, F, CI, CH 3 , or C(0)R 289 ;
  • R 286 is CH 3 , CH 2 OR 288 , CH 2 OC(0)CH 3 or CH 2 N 3 ;
  • R 287 is phenyl or C(0)NH 2 ;
  • R 288 is H or CH 3 ;
  • R is H, (CH 2 ) 2 SCH 3 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;
  • W 2 is - CH 2 - or -C(O)-;
  • X 1 is absent, -CH 2 - or - R 292 -, wherein R 292 is H, CH 3 or phenyl, and Y 1 is -CH 2 - or -0-; or
  • Ar is an aryl having general formula III:
  • R , R , R , R and R are each independently H, CI, I, F or CF 3 ; and wherein at least one of R 19 -R 23 is not H; L is -CH 2 - R 293 -, -S0 2 - H- or - H-C(0)- H-; R 293 is H or CH 3 ; B is selected from:
  • R 294 , R 295 and R 296 are each independently H or CH 3 ;
  • Z 19 is -CH 2 - or -C(O)-, and
  • Z 20 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.
  • compounds of general formula I are selected from compounds 2, 5, 7, 9, 12, 13, 15, 16, 41, 107, and 110, and salts thereof.
  • 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, 30
  • the PTC readthrough compounds may be compounds of general formula I (Formula I), or salts thereof:
  • Ar is an aryl having general formula II:
  • R 1 , R 2 , R 3 , R 4 and R 5 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 R 1 and R 2 , taken together with the ring-forming C atoms that they are attached to, form an aryl ring; or R 2 and R 3 , 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 - (CH 2 )n -; n is 1 or 2; and B is:
  • R 6 and R 9 are each independently H, OH, F, CI, substituted or unsubstituted lower alkyl, H 2 , HC(0)R 10 , N0 2 , N 3 ;
  • R 7 and R 8 are each independently H, F, CI, unsubstituted lower alkyl, or C(0)R 12 ;
  • R 10 is substituted or unsubstituted lower alkyl;
  • R 11 is substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, or C(0)R 13 ;
  • R 12 and R 13 are each independently OH, OR 14 , H 2 , HR 15 , substituted or unsubstituted lower alkyl or substituted or unsubstituted heterocycloalkyl;
  • R 14 and R 15 are each independently substituted or unsubstituted lower alkyl;
  • X is -CH 2 -, - H- or - R 16 -;
  • R 16 is substituted or unsubstituted aryl;
  • R 17 is H, substituted or unsubstituted lower alkyl, substituted or unsubstituted aryl, or substituted or unsubstitute
  • 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 R 19 and R 20 , taken together with the ring-forming C atoms that they are attached to, form an aryl ring; or R 20 and R 21 , 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-NR 24 -, -S(0) 2 -NR 25 -, -NH-C(0)-NH-, -C(0)-NH- -CH 2 -NH-C(0)-, or -CH 2 -NR 26 -CH 2 -;
  • R 24 and R 25 are each independently H or unsubstituted lower alkyl;
  • R 26 is H or unsubstituted lower alkyl;
  • B is:
  • 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;
  • R 28 , R 28 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;
  • R 29 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 30 , R 30' and R 30" are each independently H
  • R 134 and R 135 are each independently H, halogen, substituted or unsubstituted lower alkyl, substituted or unsubstituted lower alkoxy, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl;
  • Z 1 , Z 2 , Z 3 , Z 4 , Z 5 and Z 6 are each independently -N-, -CH-, or -CR 34 -, wherein at least one of Z 3 , Z 4 , Z 5 and Z 6 is -N-;
  • Z 9 is -0-, - H-, or -CH 2 -;
  • Z 10 and Z 11 are each independently - R 45 - or -CH 2 - wherein at least one of Z 10 and Z 11 is -NR 45 -;
  • Z 12 is
  • compounds of general formula I comprise compounds of general formula IV (Formula IV), and salts thereof:
  • R 60 , R 61 , R 62 , R 63 , and R 64 are each independently H, CI, I, F, Br, CF 3 or substituted or unsubstituted lower alkoxy, wherein at least one of R 60 , R 61 , R 62 , R 63 , and R 64 is not H; or R 60 and R 61 , taken together with the ring-forming C atoms that they are attached to, form an aryl ring, and R 62 , R 63 , and R 64 are each independently H, CI, I, F, Br, CF 3 or substituted or unsubstituted lower alkoxy; and
  • L 2 is -CH 2 - or -(CH 2 ) 2 -, and B 2 is:
  • CI, F, unsubstituted lower alkyl, NH 2 , R and R are each independently H, F, CI, unsubstituted lower alkyl, or C(0)R ;
  • R 69 is unsubstituted lower alkyl, CH 2 OR 71 , CH 2 OC(0)R 131 or (CH 2 ) t N 3 ;
  • R 70 is phenyl or C(0)NH 2 ;
  • R 71 is H or unsubstituted lower alkyl;
  • R 130 is OH, OR 132 , H 2 , HR 133 , substituted or unsubstituted lower alkyl or substituted or unsubstituted heterocycloalkyl;
  • R 131 is unsubstituted lower alkyl;
  • R 132 and R 133 are each independently substituted or unsubstituted lower alkyl;
  • t is 1, 2, 3 or 4; and
  • W 1 is - CH 2 - or -C(O
  • L 2 is -CH 2 - R 72 -;
  • R 72 is H or unsubstituted lower alkyl, and
  • B 2 is:
  • R 111 , R 113 and R 136 are each independently H, substituted or unsubstituted arylalkyl, substituted or unsubstituted lower alkyl, substituted or unsubstituted cycloalkyl or carboxy; R 74 , R 74' , R 74" , R 76 , R 76' , R 76" , R 78 , R 78' , R 78" , R 80 , R 80' , R 80" , R 82 , R 82' , R 82" , ⁇ 84 ⁇ 84' ⁇ 84" ⁇ 86 ⁇ 86' ⁇ 86" ⁇ 88 ⁇ 88' ⁇ 88" ⁇ 90 ⁇ 90' ⁇ 90" ⁇ 92 ⁇ 92' ⁇ 92" ⁇ 93 ⁇ 93''
  • R 137 , R 138 , R 139 , R 139' , and R 139" are each independently H, halogen or substituted or unsubstituted lower alkyl; and R 97 is H, halogen, or substituted or unsubstituted lower alkyl.
  • R 60 , R 61 , R 62 , R 63 , and R 64 are each independently H, CI, I, F, Br, CF3 or substituted or unsubstituted lower alkoxy, wherein at least one of R 60 , R 61 , R 62 , R 63 , and R 64 is not H.
  • R 60 and R 61 taken together with the ring-forming C atoms that they are attached to, form an aryl ring, and R 62 , R 63 , and R 64 are each independently H, CI, I, F, Br, CF 3 or substituted or unsubstituted lower alkoxy.
  • R 60 and R 61 taken together with the ring-forming C atoms that they are attached to, form a phenyl ring, and R 62 , R 63 , and R 64 are each H.
  • R 60 , R 61 , R 62 , R 63 , and R 64 are each independently H, CI, I, F, Br or CF 3 .
  • At least two of R 60 -R 64 are not H.
  • two of R 60 -R 64 are each CI, I, F or CF 3 , and the remaining R 60 -R 64 are H.
  • two of R 60 -R 64 are each CI, F or CF 3 , and the remaining R 60 -R 64 are H.
  • two of R 60 -R 64 are each CI or CF 3 , and the remaining R 60 -R 64 are H.
  • R 60 -R 64 are each CI, and the remaining R 60 -R 64 are H.
  • R 60 is CI, I, F or CF 3 ;
  • R 63 and R 64 are each independently H, CI, I, F or CF 3 , wherein at least one of R 63 and R 64 is not H; and
  • R 61 and R 62 are each H.
  • R 60 is CI, F or CF 3 ; R 63 and R 64 are each independently H, CI, F or CF 3 , wherein at least one of R 63 and R 64 is not H; and R 61 and R 62 are each H.
  • R is CI or CF 3 ; R and R 64 are each independently H, CI or CF 3 , wherein at least one of R 63 and R 64 is not H; and R 61 and R 62 are each H.
  • R 60 and R 63 are each independently CI, I, F or CF 3 ; and R 61 , R 62 and R 64 are each H.
  • R 60 and R 63 are each independently CI, F or CF 3 ; and R 61 , R 62 and R 64 are each H.
  • R 60 and R 63 are each independently CI or CF 3 ; and R 61 , R 62 and R 64 are each H.
  • R 60 and R 63 are each CI; and R 61 , R 62 and R 64 are each H.
  • R 60 and R 63 are each CF 3 ; and R 61 , R 62 and R 64 are each H.
  • R 60 and R 64 are each independently CI, I, F or CF 3 ; and R 61 , R 62 and R 63 are each H.
  • R 60 and R 64 are each independently CI, F or CF 3 ; and R 61 , R 62 and R 63 are each H.
  • R 60 and R 64 are each independently CI or CF 3 ; and R 61 , R 62 and R 63 are each H.
  • R 60 is CI and R 64 is CF 3 ; and R 61 , R 62 and R 63 are each H.
  • R 60 and R 64 are each CI; and R 61 , R 62 and R 63 are each H.
  • R 60 and R 64 are each CF 3 ; and R 61 , R 62 and R 63 are each H.
  • L 2 is -CH 2 -.
  • L 2 is -(CH 2 ) 2 -.
  • L 2 is -CH2- R 72 -; and R 72 is H or unsubstituted lower alkyl.
  • L 2 is -CH2- R 72 -; and R 72 is H or Ci-4 alkyl.
  • L 2 is -CH2- R 72 -; and R 72 is H or Ci-3 alkyl.
  • L 2 is -CH2- R 72 -; and R 72 is H or Ci-2 alkyl.
  • L 2 is -CH2- R 72 -; and R 72 is H or CH 3 .
  • L 2 is -CH2- R 72 -; and R 72 is unsubstituted lower alkyl.
  • L 2 is -CH2- R 72 -; and R 72 is Ci-4 alkyl.
  • L 2 is -CH2- R 72 -; and R 72 is Ci -3 alkyl.
  • L 2 is -CH2- R 72 -; and R 72 is Ci-2 alkyl.
  • L 2 is -CH2- R 72 -; and R 72 is CH 3 .
  • L 2 is -CH2- R 72 -; and R 72 is H.
  • B 2 is
  • R 65 is HC(0)R 69 ;
  • R 66 , R 67 and R 68 are each H;
  • R 69 is CH 3 , CH 2 OR 71 , CH 2 OC(0)R 131 or CH 2 N 3 ;
  • R 71 is H or unsubstituted lower alkyl;
  • R 131 is CM alkyl; and
  • W 1 is -C(O)-;
  • R , R , R , R and R are each independently H or substituted or unsubstituted lower alkyl; and R 74 , R 74' , R 74" , R 76 , R 76' , R 76" , R 82 , R 82' , R 82" , R 84 , R 84' , R 84" , R 86 , R 86' , ⁇ > 86" T
  • R 137 , R 138 , R 139 , R 139' , and R 139" are each independently H, halogen or unsubstituted lower alkyl.
  • R 73 , R 75 , R 81 , R 83 , R 85 , R 94 , R", R 107 , R 109 and R 136 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)OR 140 , H 2 , R 141 R 142 , HC(0)OR 143 , Ci -6 alkoxy,
  • Ci -6 alkyl independently unsubstituted Ci -6 alkyl; R 144 is Ci -6 alkyl optionally substituted with one or more substituents independently selected from the group consisting of
  • R 145 R 146 and OH; and R 145 and R 146 are each independently unsubstituted Ci-6 alkyl.
  • R 73 , R 75 , R 81 , R 83 , R 85 are independently unsubstituted Ci-6 alkyl.
  • R 94 , R 99 , R 107 , R 109 and R 136 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)OR 140 , H 2 , R 141 R 142 , HC(0)OR 143 , Ci -6 alkoxy, CN, C(0)NHR 144 and CONH 2 ; wherein R 140 , R 141 , R 142 , and R 143 are each independently unsubstituted Ci -6 alkyl; R 144 is Ci -6 alkyl optionally substituted with one or more substituents independently selected from the group consisting of NR 145 R 146 and OH; and R 145 and R 146 are each independently unsubstituted Ci -6 alkyl.
  • R 73 , R 75 , R 81 , R 83 , R 85 , R 94 , R 99 , R 107 , R 109 and R 136 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 CH 3 ; or H.
  • R 74 , R 74 , ⁇ 74" ⁇ 76 ⁇ 76' ⁇ 76" ⁇ 82 ⁇ 82' ⁇ 82" ⁇ 84 ⁇ 84' ⁇ 84" ⁇ 86 ⁇ 86' ⁇ 86" ⁇ 93 ⁇ 93' ⁇ 93" ⁇ 95 ⁇ > 95' ⁇ > 95" ⁇ ⁇ ⁇ 100' ⁇ 100" ⁇ 108 ⁇ 108' ⁇ 108" ⁇ ⁇ ⁇ ⁇ ⁇ ' ⁇ ⁇ ⁇ " ⁇ 137 ⁇ 138 ⁇ 139 ⁇ 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.
  • B 2 is , wherein R 65 is HC(0)R 69 ; R 66 , R 67 and R 68 are each H; R 69 is CH 3 , CH 2 OR 71 , CH 2 OC(0)R 131 or CH 2 N 3 ; R 71 is H or unsubstituted lower alkyl; R 131 is CM alkyl; and W 1 is -C(O)-;
  • R 136 are each independently H or substituted or unsubstituted lower alkyl; and R 74 , R 74 , R 74" , ⁇ 76 ⁇ 76' ⁇ 76" ⁇ 84 ⁇ 84' ⁇ 84" ⁇ 86 ⁇ 86' ⁇ 86" ⁇ 93 ⁇ 93' ⁇ 93" ⁇ 95 ⁇ 95' ⁇ 95" ⁇ 100 ⁇ 100'
  • R 100" , R 108 , R 108' , R 108" , R 110 , R 110' , R 110" , R 137 , R 138 , R 139 , R 139' , and R 139" are each independently H, halogen or unsubstituted lower alkyl.
  • R 73 , R 75 , R 83 , R 85 , R 94 , R 99 , R 107 , R 109 and R 136 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)OR 140 , NH 2 , R 141 R 142 , HC(0)OR 143 , Ci -6 alkoxy, CN, C(0) HR 144 and CO H 2 ; wherein R 140 , R 141 , R 142 , and R 143 are each independently unsubstituted Ci -6 alkyl; R 144 is Ci -6 alkyl optionally substituted with one or more substituents independently selected from the group consisting of R 145 R 146 and OH; and R 145 and R 146 are each independently unsubstit
  • R 73 , R 75 , R 83 , R 85 , R 94 , R", R 107 , R 109 and R 136 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)OR 140 , H 2 , R 141 R 142 , HC(0)OR 143 , Ci-6 alkoxy, CN, C(0)NHR 144 and CONH 2 ; wherein R 140 , R 141 , R 142 , and R 143 are each independently unsubstituted Ci -6 alkyl; R 144 is Ci -6 alkyl optionally substituted with one or more substituents independently selected from the group consisting of NR 145 R 146 and OH; and R 145 and R 146 are each independently unsubstituted Ci-6
  • R 73 , R 75 , R 83 , R 85 , R 94 , R 99 , R 107 , R 109 and R 136 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 CH 3 ; or H.
  • R 138 , R 139 , 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 C3 ⁇ 4; or H.
  • R 65 is NHC(0)R 69 ; R 66 , R 67 and R 68 are each H; R 69 is CH 3 , CH 2 OR 71 , CH 2 OC(0)R or CH 2 N 3 ; R 71 is H or unsubstituted lower alkyl; R 131 is CM alkyl; and W 1 is -C(O)-; or B 2 is: or , wherein R 73 and R 75 are each independently H or substituted or unsubstituted lower alkyl; and R 74 , R 74' , R 74" , R 76 , R 76' , and R 76" are each independently H, halogen or unsubstituted lower alkyl.
  • R 73 and R 75 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)OR 140 , NH 2 ,
  • R 73 and R 75 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,
  • R 73 and R 75 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.
  • R 74 , R 74' , R 74 " , R 76 , 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.
  • B 2 is , wherein R and R are each independently H, OH, CI, F, unsubstituted lower alkyl, H 2 , NHC(0)R 69 , N0 2 , or N 3 ; R and R are each independently H, F, CI, unsubstituted lower alkyl, or C(0)R 130 ; R 69 is unsubstituted lower alkyl, CH 2 OR 71 , CH 2 OC(0)R 131 or (CH 2 ) t N 3 ; R 71 is H or unsubstituted lower alkyl; R 130 is OH, OR 132 , H 2 , HR 133 , substituted or unsubstituted lower alkyl or substituted or unsubstituted heterocycloalkyl; R 131 is unsubstituted lower alkyl; R 132 and R 133 are each independently substituted or unsubstituted lower alkyl; t is 1, 2, 3 or 4;
  • R and R are each independently H, OH, CI, F, unsubstituted lower alkyl, H 2 , NHC(0)R 69 , N0 2 , or N 3 ; R and R are each independently H, F, CI, unsubstituted lower alkyl, or C(0)R 130 ;
  • R 69 is unsubstituted lower alkyl, CH 2 OR 71 , CH 2 OC(0)R 131 or (CH 2 ) t N 3 ;
  • R 71 is H or unsubstituted lower alkyl;
  • R 130 is OH, OR 132 , H 2 , NHR 133 , substituted or unsubstituted lower alkyl or substituted or unsubstituted heterocycloalkyl;
  • R 131 is unsubstituted lower alkyl;
  • R 132 and R 133 are each independently substituted or unsubstituted lower alkyl;
  • t is 1, 2, 3 or 4; and W 1 is
  • R and R are each independently H, CI, F, H 2 , HC(0)R 69 ,
  • R and R are each independently H, F, CI, unsubstituted lower alkyl, or C(0)R R 69 is unsubstituted lower alkyl, CH 2 OR 71 , CH 2 OC(0)R 131 or (CH 2 ) t N 3 ;
  • R 71 is H or unsubstituted lower alkyl;
  • R 130 is OH, OR 132 , H 2 , HR 133 , substituted or unsubstituted lower alkyl or substituted or unsubstituted heterocycloalkyl;
  • R 131 is unsubstituted lower alkyl;
  • R 132 and R 133 are each independently substituted or unsubstituted lower alkyl;
  • t is 1, 2, 3 or 4; and
  • W 1 is -C(O)-.
  • R and R are each independently H, H 2 , HC(0)R 69 , N0 2 , or
  • R and R are each independently H, F, CI, unsubstituted lower alkyl, or C(0)R 13 °; R is unsubstituted lower alkyl, CH 2 OR 71 , CH 2 OC(0)R 131 or (CH 2 ) t N 3 ; R 71 is H or unsubstituted lower alkyl; R 130 is OH, OR 132 , H 2 , NHR 133 , substituted or unsubstituted lower alkyl or substituted or unsubstituted heterocycloalkyl; R 131 is unsubstituted lower alkyl; R 132 and R 133 are each independently substituted or unsubstituted lower alkyl; t is 1, 2, 3 or 4; and W 1 is -C(O)-.
  • R and R are each independently H, H 2 , HC(0)R 69 , N0 2 , or
  • R 66 and R 67 are each H; R 69 is unsubstituted lower alkyl, CH 2 OR 71 , CH 2 OC(0)R 131 or (CH 2 )tN 3 ; R 71 is H or unsubstituted lower alkyl; R 131 is unsubstituted lower alkyl; t is 1, 2, 3 or 4; and W 1 is -C(O)-.
  • B 2 is , wherein R 65 and R 68 are each independently H or H 2 , HC(0)R 69 ; R 66 and R 67 are each H; R 69 is unsubstituted lower alkyl, CH 2 OR 71 , CH 2 OC(0)R 131 or (CH 2 ) t N 3 ; R 71 is H or unsubstituted lower alkyl; R 131 is unsubstituted lower alkyl; t is 1, 2, 3 or 4; and W 1 is - C(O)-.
  • R 65 and R 68 are each independently H or HC(0)R 69 ; R 66 and R 67 are each H; R 69 is unsubstituted lower alkyl, CH 2 OR 71 , CH 2 OC(0)R 131 or (CH 2 ) t N 3 ; R 71 is H or unsubstituted lower alkyl; R 131 is unsubstituted lower alkyl; t is 1, 2, 3 or 4; and W 1 is -C(O)-.
  • R 65 and R 68 are each independently H or HC(0)R 69 ; R 66 and R 67 are each H; R 69 is unsubstituted lower alkyl, CH 2 OR 71 , CH 2 OC(0)R 131 or (CH 2 ) t N 3 ; R 71 is H or unsubstituted Ci-4 alkyl; R 131 is unsubstituted Ci-4 alkyl; t is 1, 2, 3 or 4; and W 1 is -C(O)-.
  • B 2 is , wherein R M is HC(0)R by ; R bb , R b ' and R bS are each H; R by is CH 3 , CH 2 OR 71 , CH 2 OC(0)R 131 or CH 2 N 3 ; R 71 is H or unsubstituted lower alkyl; R 131 is CM alkyl; and W 1 is -C(O)-.
  • R 69 is CH 3 , CH 2 OR 71 , or CH 2 OC(0)R 131 ; R 71 is H or unsubstituted lower alkyl; and R 131 is C 1-4 alkyl.
  • R 69 is CH 3 .
  • R 69 is CH 2 OR 71 ; and R 71 is H or unsubstituted lower alkyl.
  • R 69 is CH 2 OC(0)R 131 ; and R 131 is CM alkyl.
  • B 2 is:
  • R , R , R , R , R", R , R and R 13b are each independently H or substituted or unsubstituted lower alkyl; and R 74 , R 74' , R 74" , R 76 , R 76' , R 76" , R 82 , R 82' , R 82" , R 84 , R 84' , R 84" , R 86 , R 86' , R 86" , R 93 , ⁇ > 93' ⁇
  • R 73 , R 75 , R 81 , R 83 , R 85 , R 94 , R 99 , R 107 , R 109 and R 136 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)OR 140 , H 2 , R 141 R 142 , HC(0)OR 143 , Ci -6 alkoxy, CN, C(0) HR 144 and CO H 2 ; wherein R 140 , R 141 , R 142 , and R 143 are each independently unsubstituted Ci-6 alkyl; R 144 is Ci -6 alkyl optionally substitute
  • R 73 , R 75 , R 81 , R 83 , R 85 , R 94 , R", R 107 , R 109 and R 136 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)OR 140 , H 2 , R 141 R 142 , HC(0)OR 143 , Ci -6 alkoxy, CN, C(0)NHR 144 and CONH 2 ; wherein R 140 , R 141 , R 142 , and R 143 are each independently unsubstituted Ci -6 alkyl; R 144 is Ci -6 alkyl optionally substituted with one or more substituents independently selected from the group consisting of NR 145 R 146 and OH; and R 145 and R 146 are each independently un
  • R 73 , R 75 , R 81 , R 83 , R 85 , R 94 , R 99 , R 107 , R 109 and R 136 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 CH 3 ; or H.
  • R 110' , R 110" , R 137 , R 138 , R 139 , 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 CH 3 ; or H. 00161]
  • B 2 is:
  • R 136 are each independently H or substituted or unsubstituted lower alkyl; and R 74 , R 74' , R 74" , ⁇ 76 ⁇ 76' ⁇ 76" ⁇ 84 ⁇ 84' ⁇ 84" ⁇ 86 ⁇ 86' ⁇ 86" ⁇ 93 ⁇ 93' ⁇ 93" ⁇ 95 ⁇ 95' ⁇ 95" ⁇ 100 ⁇ 100' ⁇ 100" ⁇ 108
  • R 108' , R 108" , R 110 , R 110' , R 110" , R 137 , R 138 , R 139 , R 139' , and R 139" are each independently H, halogen or unsubstituted lower alkyl.
  • R 73 , R 75 , R 83 , R 85 , R 94 , R 99 , R 107 , R 109 and R 136 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)OR 140 , H 2 , R 141 R 142 , HC(0)OR 143 , Ci -6 alkoxy, CN, C(0) HR 144 and CO H 2 ; wherein R 140 , R 141 , R 142 , and R 143 are each independently unsubstituted Ci -6 alkyl; R 144 is Ci -6 alkyl optionally substituted with one or more substituents independently selected from the group consisting of R 145 R 146 and OH; and R 145 and R 146 are each independently unsubstit
  • R 73 , R 75 , R 83 , R 85 , R 94 , R 99 , R 107 , R 109 and R 136 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)OR 140 , H 2 , R 141 R 142 , HC(0)OR 143 , Ci -6 alkoxy, CN, C(0)NHR 144 and CONH 2 ; wherein R 140 , R 141 , R 142 , and R 143 are each independently unsubstituted Ci-6 alkyl; R 144 is Ci -6 alkyl optionally substituted with one or more substituents independently selected from the group consisting of NR 145 R 146 and OH; and R 145 and R 146 are each independently unsubstituted
  • R 73 , R 75 , R 83 , R 85 , R 94 , R 99 , R 107 , R 109 and R 136 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.
  • R 108 , R 108' , R 108" , R 110 , R 110' , R 110" , R 137 , R 138 , R 139 , 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 CH 3 ; or H. 00162]
  • B 2 is:
  • R 74 , R 74' , R 74" , R 76 , R 76' , R 76" , R 108 , R 108' , R 108" , R 110 , R 110' , and R 110" are each independently H, halogen or unsubstituted lower alkyl.
  • R 73 , R 75 , R 107 , and R 109 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)OR 140 , H 2 , R 141 R 142 , HC(0)OR 143 , Ci -6 alkoxy, CN, C(0) HR 144 and CO H 2 ; wherein R 140 , R 141 , R 142 , and R 143 are each independently unsubstituted Ci -6 alkyl; R 144 is Ci -6 alkyl optionally substituted with one or more substituents independently selected from the group consisting of R 145 R 146 and OH; and R 145 and R 146 are each independently unsubstituted Ci -6 alkyl.
  • R 73 , R 75 , R 107 , and R 109 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)OR 140 , H 2 , R 141 R 142 , HC(0)OR 143 , Ci -6 alkoxy, CN, C(0)NHR 144 and CONH 2 ; wherein R 140 , R 141 , R 142 , and R 143 are each independently unsubstituted Ci-6 alkyl; R 144 is Ci -6 alkyl optionally substituted with one or more substituents independently selected from the group consisting of NR 145 R 146 and OH; and R 145 and R 146 are each independently unsubstituted Ci -6 alkyl.
  • R 73 , R 75 , R 107 , and R 109 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 CH 3 ; or H.
  • R 74 , R 74' , R 74" , R 76 , R 76' , R 76 " , R 108 , R 108' , R 108 " , R 110 , 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 CH 3 ; or H.
  • B 2 is:
  • R and R are each independently H or substituted or unsubstituted lower alkyl; and R 84 , R 84' , R 84" , R 86 , R 86' , and R 86" are each independently H, halogen or unsubstituted lower alkyl.
  • R 83 and R 85 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)OR 140 , H 2 , R 141 R 142 , HC(0)OR 143 , Ci-6 alkoxy, CN, C(0) HR 144 and CO H 2 ; wherein R 140 , R 141 , R 142 , and R 143 are each independently unsubstituted Ci -6 alkyl; R 144 is Ci -6 alkyl optionally substituted with one or more substituents independently selected from the group consisting of R 145 R 146 and OH; and R 145 and R 146 are each independently unsubstituted Ci -6 alkyl.
  • R 83 and R 85 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)OR 140 , H 2 , R 141 R 142 , HC(0)OR 143 , Ci-6 alkoxy, CN, C(0)NHR 144 and CONH 2 ; wherein R 140 , R 141 , R 142 , and R 143 are each independently unsubstituted Ci -6 alkyl; R 144 is Ci -6 alkyl optionally substituted with one or more substituents independently selected from the group consisting of NR 145 R 146 and OH; and R 145 and R 146 are each independently unsubstituted Ci -6 alkyl.
  • R 83 and R 85 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 CH 3 ; or H.
  • R 84 , R 84 , R 84" , R 86 , R 86 , 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 CH 3 ; or H.
  • B 2 is: , wherein R 83 is H or substituted or unsubstituted lower alkyl; and R 84 , R 84 , and R 84 " are each independently H, halogen or unsubstituted lower alkyl.
  • R 83 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)OR 140 , H 2 , R 141 R 142 , HC(0)OR 143 , Ci-6 alkoxy, CN, C(0) HR 144 and CO H 2 ; wherein R 140 , R 141 , R 142 , and R 143 are each independently unsubstituted Ci -6 alkyl; R 144 is Ci -6 alkyl optionally substituted with one or more substituents independently selected from the group consisting of R 145 R 146 and OH; and R 145 and R 146 are each independently unsubstituted Ci -6 alkyl.
  • R 83 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)OR 140 , H 2 , R 141 R 142 , HC(0)OR 143 , Ci -6 alkoxy, CN, C(0)NHR 144 and CONH 2 ; wherein R 140 , R 141 , R 142 , and R 143 are each independently unsubstituted Ci -6 alkyl; R 144 is Ci -6 alkyl optionally substituted with one or more substituents independently selected from the group consisting of NR 145 R 146 and OH; and R 145 and R 146 are each independently unsubstituted Ci -6 alkyl.
  • R 83 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 CH 3 ; or H.
  • R 84 , R 84 , and R 84 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 CH 3 ; or H.
  • one of R 84 , R 84 , and R 84 " is H and R 84 , R 84 , and R 84 " are each independently H, CI, F, Br, I, or unsubstituted Ci -6 alkyl. In certain embodiments, one of R 84 , R 84 , and R 84 " is H and R 84 , R 84 , and R 84 " are each independently H or unsubstituted Ci -6 alkyl. In certain embodiments, one of R 84 , R 84 , and R 84 " is H and R 84 , R 84 , and R 84 " are each independently H, CI, F, Br or I.
  • two of R 84 , R 84 , and R 84 " are H and R 84 , R 84 , and R 84 "are each independently H, CI, F, Br, I, or unsubstituted Ci -6 alkyl.
  • two of R 84 , R 84 , and R 84 " are H and R 84 , R 84 , and R 84 " are each independently H or unsubstituted Ci -6 alkyl.
  • two of R 84 , R 84 , and R 84" are H and R 84 , R 84 , and R 84" are each independently H, CI, F, Br or I.
  • B 2 is:
  • R 85 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)OR 140 , H 2 , R 141 R 142 , HC(0)OR 143 , Ci-6 alkoxy, CN, C(0) HR 144 and CO H 2 ; wherein R 140 , R 141 , R 142 , and R 143 are each independently unsubstituted C 1-6 alkyl; R 144 is Ci -6 alkyl optionally substituted with one or more substituents independently selected from the group consisting of R 145 R 146 and
  • R 85 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)OR 140 , H 2 , R 141 R 142 , HC(0)OR 143 , Ci -6 alkoxy, CN, C(0)NHR 144 and CONH 2 ; wherein R 140 , R 141 , R 142 , and R 143 are each independently unsubstituted Ci -6 alkyl; R 144 is C 1-6 alkyl optionally substituted with one or more substituents independently selected from the group consisting of NR 145 R 146 and OH; and R 145 and R 146 are each independently unsubstituted C 1-6 alkyl.
  • R 85 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 CH 3 ; or H.
  • R 86 , R 86 , 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 CH 3 ; or H.
  • one of R 86 , R 86 , and R 86" is H and R 86 , R 86 , and R 86 " are each independently H, CI, F, Br, I, or unsubstituted Ci -6 alkyl.
  • one of R 86 , R 86' , and R 86" is H and R 86 , R 86 , and R 86" are each independently H or unsubstituted C 1-6 alkyl.
  • one of R 86 , R 86 ', and R 86 " is H and R 86 , R 86 ', and R 86 " are each independently H, CI, F, Br or I.
  • two of R 86 , R 86 ', and R 86 " are H and R 86 , R 86 ', and R 86 "are each independently H, CI, F, Br, I, or unsubstituted C 1-6 alkyl. In certain embodiments, two of R 86 , R 86 , and R 86 " are H and R 86 , R 86 , and R 86 " are each independently H or unsubstituted C 1-6 alkyl. In certain embodiments, two of R 86 , R 86 , and R 86 " are H and R 86 , R 86 , and R 86 " are each independently H, CI, F, Br or I.
  • B 2 is:
  • R' is H or substituted or unsubstituted lower alkyl
  • R 82 " are each independently H, halogen or unsubstituted lower alkyl.
  • R 81 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)OR 140 , H 2 , R 141 R 142 , HC(0)OR 143 , Ci-6 alkoxy, CN, C(0) HR 144 and CO H 2 ; wherein R 140 , R 141 , R 142 , and R 143 are each independently unsubstituted C 1-6 alkyl; R 144 is Ci -6 alkyl optionally substituted with one or more substituents independently selected from the group consisting of R 145 R 146 and OH; and R 145 and R 146 are each independently unsubstituted C 1-6 alkyl.
  • R 81 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)OR 140 , H 2 , R 141 R 142 , HC(0)OR 143 , Ci -6 alkoxy, CN, C(0)NHR 144 and CONH 2 ; wherein R 140 , R 141 , R 142 , and R 143 are each independently unsubstituted Ci -6 alkyl; R 144 is C 1-6 alkyl optionally substituted with one or more substituents independently selected from the group consisting of NR 145 R 146 and OH; and R 145 and R 146 are each independently unsubstituted C 1-6 alkyl.
  • R 81 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 CH 3 ; or H.
  • R 82 , R 82 , and R 82 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 CH 3 ; or H.
  • one of R 82 , R 82' , and R 82" is H and R 82 , R 82 , and R 82" are each independently H, CI, F, Br, I, or unsubstituted C 1-6 alkyl. In certain embodiments, one of R 82 , R 82 , and R 82" is H and R 82 , R 82 , and R 82" are each independently H or unsubstituted C 1-6 alkyl. In certain embodiments, one of R 82 , R 82' , and R 82" is H and R 82 , R 82' , and R 82" are each independently H, CI, F, Br or I.
  • R 82 , R 82' , and R 82" are H and R 82 , R 82' , and R 82" are each independently H, CI, F, Br, I, or unsubstituted C 1-6 alkyl.
  • two of R 82 , R 82 , and R 82" are H and R 82 , R 82 , and R 82" are each independently H or unsubstituted C 1-6 alkyl.
  • two of R 82 , R 82 , and R 82" are H and R 82 , R 82 , and R 82" are each independently H, CI, F, Br or I.
  • B 2 is:
  • R 93 , R 93' , R 93" , R 95 , R 95 , R 95" , R 100 , R 100' , R 100" , R 137 , R 138 , R 139 , R 139' , and R 139" are each independently H, halogen or unsubstituted lower alkyl.
  • R 94 , R 99 and R 136 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)OR 140 , H 2 , R 141 R 142 , HC(0)OR 143 , Ci -6 alkoxy, CN, C(0) HR 144 and CO H 2 ; wherein R 140 , R 141 , R 142 , and R 143 are each independently unsubstituted Ci -6 alkyl; R 144 is Ci -6 alkyl optionally substituted with one or more substituents independently selected from the group consisting of R 145 R 146 and OH; and R 145 and R 146 are each independently unsubstituted Ci -6 alkyl.
  • R 94 , R 99 and R 136 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)OR 140 , H 2 , R 141 R 142 , HC(0)OR 143 , Ci -6 alkoxy, CN, C(0) HR 144 and CO H 2 ; wherein R 140 , R 141 , R 142 , and R 143 are each independently unsubstituted Ci-6 alkyl; R 144 is Ci -6 alkyl optionally substituted with one or more substituents independently selected from the group consisting of R 145 R 146 and OH; and R 145 and R 146 are each independently unsubstituted Ci -6 alkyl.
  • R 94 , R 99 and R 136 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 CH 3 ; or H.
  • R 93 , R 93' , R 93 " , R 95 , R 95 , R 95 " , R 100 , R 100' , R 100" , R 137 , R 138 , R 139 , 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 CH 3 ; or H. 00168]
  • B 2 is:
  • R , R and R 136 are each independently H or substituted or unsubstituted lower alkyl; and R 95 , R 95 , R 95" ,
  • R 100 , R 100' , R 100" , R 137 , R 138 , R 139 , R 139' , and R 139" are each independently H, halogen or unsubstituted lower alkyl.
  • R , R and R 136 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)OR 140 , H 2 , R 141 R 142 , HC(0)OR 143 , Ci -6 alkoxy, CN, C(0)NHR 144 and CONH 2 ; wherein R 140 , R 141 , R 142 , and R 143 are each independently unsubstituted Ci -6 alkyl; R 144 is Ci -6 alkyl optionally substituted with one or more substituents independently selected from
  • R 94 , R 99 and R 136 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)OR 14 °, NH 2 , NR 141 R HC(0)OR 143 , Ci-6 alkoxy, CN, C(0) HR 144 and CO H 2 ; wherein R , R , R , and R are each independently unsubstituted Ci -6 alkyl; R 144 is Ci -6 alkyl optionally substituted with one or more substituents independently selected from the group consisting of R 145 R 146 and OH; and R 145 and R 146 are each independently unsubstituted Ci -6 alkyl.
  • R 94 , R 99 and R 136 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 CH 3 ; or H.
  • R 95 , R 95 , R 95 ", R 100 , R 100 ', R 100 ", R 137 , R 138 , R 139 , 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 CH 3 ; or H. 00169]
  • B 2 is:
  • R and R are each independently H or substituted or unsubstituted lower alkyl; and R 95 , R 95 , R 95 “, R 100 , R 100 ', and R 100 " are each independently H, halogen or unsubstituted lower alkyl.
  • R 94 and R 99 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)OR 140 , H 2 , R 141 R 142 , HC(0)OR 143 , Ci-6 alkoxy, CN, C(0)NHR 144 and CONH 2 ; wherein R 140 , R 141 , R 142 , and R 143 are each independently unsubstituted Ci -6 alkyl; R 144 is Ci -6 alkyl optionally substituted with one or more substituents independently selected from the group consisting of NR 145 R 146 and OH; and R 145 and R 146 are each independently unsubstituted Ci -6 alkyl.
  • R 94 and R 99 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)OR 140 , NH 2 , NR 141 R 142 , NHC(0)OR 143 , Ci-6 alkoxy, CN, C(0)NHR 144 and CONH2; wherein R 140 , R 141 , R 142 , and R 143 are each independently unsubstituted Ci -6 alkyl; R 144 is Ci -6 alkyl optionally substituted with one or more substituents independently selected from the group consisting of NR 145 R 146 and OH; and R 145 and R 146 are each independently unsubstituted Ci -6 alkyl.
  • 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 CH 3 ; or H.
  • R 95 , R 95 , R 95 " , R 100 , 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 CH 3 ; or H.
  • B 2 is:
  • R is H or substituted or unsubstituted lower alkyl
  • R 95 , and R 95 are each independently H, halogen or unsubstituted lower alkyl.
  • R 94 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)OR 140 , H 2 , R 141 R 142 , HC(0)OR 143 , Ci -6 alkoxy, CN, C(0) HR 144 and CO H 2 ; wherein R 140 , R 141 , R 142 , and R 143 are each independently unsubstituted C 1-6 alkyl; R 144 is C 1-6 alkyl optionally substituted with one or more substituents independently selected from the group consisting of R 145 R 146 and OH; and R 145 and R 146 are each independently unsubstituted Ci -6 alkyl.
  • R 94 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)OR 140 , H 2 , R 141 R 142 , HC(0)OR 143 , Ci -6 alkoxy, CN, C(0)NHR 144 and CONH 2 ; wherein R 140 , R 141 , R 142 , and R 143 are each independently unsubstituted Ci -6 alkyl; R 144 is C 1-6 alkyl optionally substituted with one or more substituents independently selected from the group consisting of NR 145 R 146 and OH; and R 145 and R 146 are each independently unsubstituted C 1-6 alkyl.
  • R 94 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 CH 3 ; or H.
  • R 95 , R 95 , and R 95 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 CH 3 ; or H.
  • one of R 95 , R 95 , and R 95 is H and R 95 , R 95 , and R 95 are each independently H, CI, F, Br, I, or unsubstituted C 1-6 alkyl. In certain embodiments, one of R 95 , R 95 , and R 95 is H and R 95 , R 95 , and R 95 are each independently H or unsubstituted C 1-6 alkyl. In certain embodiments, one of R 95 , R 95 , and R 95 is H and R 95 , R 95 , and R 95 are each independently H, CI, F, Br or I.
  • R 95 , R 95 , and R 95 are H and R 95 , R 95 , and R 95 are each independently H, CI, F, Br, I, or unsubstituted C 1-6 alkyl. In certain embodiments, two of R 95 , R 95 , and R 95 are H and R 95 , R 95 , and R 95 are each independently H or unsubstituted C 1-6 alkyl. In certain embodiments, two of R 95 , R 95 , and R 95 are H and R 95 , R 95 , and R 95 are each independently H, CI, F, Br or I.
  • B 2 is:
  • R 99 is H or substituted or unsubstituted lower alkyl; and R 100 ,
  • R 100 , and R 100" are each independently H, halogen or unsubstituted lower alkyl.
  • R 99 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)OR 140 , H 2 , R 141 R 142 , HC(0)OR 143 , Ci -6 alkoxy, CN, C(0) HR 144 and CO H 2 ; wherein R 140 , R 141 , R 142 , and R 143 are each independently unsubstituted C 1-6 alkyl; R 144 is C 1-6 alkyl optionally substituted with one or more substituents independently selected from the group consisting of R 145 R 146 and OH; and R 145 and R 146 are each independently unsubstituted Ci -6 alkyl.
  • R 99 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)OR 140 , H 2 , R 141 R 142 , HC(0)OR 143 , Ci -6 alkoxy, CN, C(0)NHR 144 and CONH 2 ; wherein R 140 , R 141 , R 142 , and R 143 are each independently unsubstituted Ci -6 alkyl; R 144 is C 1-6 alkyl optionally substituted with one or more substituents independently selected from the group consisting of NR 145 R 146 and OH; and R 145 and R 146 are each independently unsubstituted C 1-6 alkyl.
  • R 99 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 CH 3 ; or H.
  • R 100 , R 100 ', and R 100 " 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 CH 3 ; or H.
  • one of R 100 , R 100 ', and R 100 " is H and R 100 , R 100 ', and R 100 " are each independently H, CI, F, Br, I, or unsubstituted C 1-6 alkyl. In certain embodiments, one of R 100 , R 100 ', and R 100 " is H and R 100 , R 100 ', and R 100 " are each independently H or unsubstituted Ci -6 alkyl. In certain embodiments, one of R 100 , R 100 ', and R 100 " is H and R 100 , R 100 ', and R 100 " are each independently H, CI, F, Br or I.
  • two of R 100 , R 100 , and R 100 " are H and R 100 , R 100 ', and R 100 " are each independently H, CI, F, Br, I, or unsubstituted Ci -6 alkyl. In certain embodiments, two of R 100 , R 100 ', and R 100 " are H and R 100 , R 100 ', and R 100 " are each independently H or unsubstituted Ci -6 alkyl. In certain embodiments, two of R 100 , R 100 ', and R 100 " are H and R 100 , R 100 ', and R 100 " are each independently H, CI, F, Br or I.
  • B 2 is:
  • R is H or substituted or unsubstituted lower alkyl
  • R 138 , R 139 , R 139 , and R 139 are each independently H, halogen or unsubstituted lower alkyl.
  • R 136 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)OR 140 , H 2 , R 141 R 142 , HC(0)OR 143 , Ci -6 alkoxy, CN, C(0)NHR 144 and CO H 2 ; wherein R 140 , R 141 , R 142 , and R 143 are each independently unsubstituted Ci -6 alkyl; R 144 is Ci -6 alkyl optionally substituted with one or more substituents independently selected from the group consisting of R 145 R 146 and OH; and R 145 and R 146 are each independently un
  • R 136 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)OR 140 , H 2 , R 141 R 142 , HC(0)OR 143 , Ci -6 alkoxy, CN, C(0)NHR 144 and CONH 2 ; wherein R 140 , R 141 , R 142 , and R 143 are each independently unsubstituted Ci -6 alkyl; R 144 is Ci -6 alkyl optionally substituted with one or more substituents independently selected from the group consisting of NR 145 R 146 and OH; and R 145 and R 146 are each independently unsubstituted Ci -6 alkyl.
  • R 136 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 CH 3 ; or H.
  • R 137 , R 138 , R 139 , R 139 , and R 139 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 CH 3 ; or H.
  • one of R 137 , R 138 , R 139 , R 139 ', and R 139 " is H and R 137 , R 138 , R 139 , R 139 ', and R 139 " are each independently H, CI, F, Br, I, or unsubstituted Ci-6 alkyl.
  • one of R 137 , R 138 , R 139 , R 139 ', and R 139 " is H and R 137 , R 138 , R 139 , R 139 , and R 139 " are each independently H or unsubstituted Ci -6 alkyl.
  • one of R 137 , R 138 , R 139 , R 139 ', and R 139 " is H and R 137 , R 138 , R 139 , R 139 ', and R 139 " are each independently H, CI, F, Br or I.
  • two of R 137 , R 138 , R 139 , R 139 ', and R 139 " are H and R 137 , R 138 , R 139 , R 139 ', and R 139 " are each independently H, CI, F, Br, I, or unsubstituted Ci -6 alkyl.
  • two of R 137 , R 138 , R 139 , R 139 ', and R 139 " are H and R 137 , R 138 , R 139 , R 139 ', and R 139 " are each independently H or unsubstituted C 1-6 alkyl.
  • two of R 137 , R 138 , R 139 , R 139 ', and R 139 " are H and R 137 , R 138 , R 139 , R 139 ', and R 139 " are each independently H, CI, F, Br or I.
  • R 137 , R 138 , R 139 , R 139 ', and R 139 " are H and R 137 , R 138 , R 139 , R 139 ', and R 139 " are each independently H, CI, F, Br, I, or unsubstituted C 1-6 alkyl.
  • three of R 137 , R 138 , R 139 , R 139 ', and R 139 " are H and R 137 , R 138 , R 139 , R 139 ', and R 139 " are each independently H or unsubstituted C 1-6 alkyl.
  • R 137 , R 138 , R 139 , R 139 ', and R 139 " are H and R 137 , R 138 , R 139 , R 139 ', and R 139 " are each independently H, CI, F, Br or I.
  • four of R 137 , R 138 , R 139 , R 139 ', and R 139 " are H and R 137 , R 138 , R 139 , R 139 , and R 139 " are each independently H, CI, F, Br, I, or unsubstituted C 1-6 alkyl.
  • R 137 , R 138 , R 139 , R 139 ', and R 139 " are H and R 137 , R 138 , R 139 , R 139 ', and R 139 " are each independently H or unsubstituted C 1-6 alkyl.
  • four of R 137 , R 138 , R 139 , R 139 ', and R 139 " are H and R 137 , R 138 , R 139 , R 139 ', and R 139 " are each independently H, CI, F, Br or I.
  • B 2 is: , wherein R 93 , R 93' , and R 93" are each independently H, halogen or unsubstituted lower alkyl.
  • R 93 , R 93 , 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 CH 3 ; or H.
  • one of R 93 , R 93 , and R 93" is H and R 93 , R 93' , and R 93" are each independently H, CI, F, Br, I, or unsubstituted C 1-6 alkyl.
  • one of R 93 , R 93 , and R 93" is H and R 93 , R 93 , and R 93" are each independently H or unsubstituted Ci -6 alkyl.
  • one of R 93 , R 93 , and R 93" is H and R 93 , R 93 , and R 93" are each independently H, CI, F, Br or I.
  • R 93 , R 93 , and R 93" are H and R 93 , R 93 , and R 93" are each independently H, CI, F, Br, I, or unsubstituted Ci -6 alkyl.
  • two of R 93 , R 93 , and R 93" are H and R 93 , R 93 , and R 93" are each independently H or unsubstituted Ci -6 alkyl.
  • two of R 93 , R 93 , and R 93" are H and R 93 , R 93 , and R 93" are each independently H, CI, F, Br or I.
  • B 2 is:
  • R and R are each independently H or substituted or unsubstituted lower alkyl; and R 74 , R 74' , R 74 " , R 76 , R 76' , and R 76" are each independently H, halogen or unsubstituted lower alkyl.
  • R 73 and R 75 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)OR 140 , H 2 , R 141 R 142 , HC(0)OR 143 , Ci-6 alkoxy, CN, C(0) HR 144 and CO H 2 ; wherein R 140 , R 141 , R 142 , and R 143 are each independently unsubstituted Ci -6 alkyl; R 144 is Ci -6 alkyl optionally substituted with one or more substituents independently selected from the group consisting of R 145 R 146 and OH; and R 145 and R 146 are each independently unsubstituted Ci -6 alkyl.
  • 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)OR 140 , H 2 , R 141 R 142 , HC(0)OR 143 , Ci-6 alkoxy, CN, C(0) HR 144 and CO H 2 ; wherein R 140 , R 141 , R 142 , and R 143 are each independently unsubstituted C 1-6 alkyl; R 144 is Ci -6 alkyl optionally substituted with one or more substituents independently selected from the group consisting of R 145 R 146 and OH; and R 145 and R 146 are each independently unsubstituted C 1-6 alkyl.
  • R 73 and R 75 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 CH 3 ; or H.
  • R 74 , R 74 , R 74 " , R 76 , 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 CH 3 ; or H. 00175]
  • B 2 is:
  • R 73 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)OR 140 , H 2 , R 141 R 142 , HC(0)OR 143 , Ci -6 alkoxy, CN, C(0)NHR 144 and CONH 2 ; wherein R 140 , R 141 , R 142 , and R 143 are each independently unsubstituted C 1-6 alkyl; R 144 is C 1-6 alkyl optionally substituted with one or more substituents independently selected from the group consisting of NR 145 R
  • R 73 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)OR 140 , NH 2 , NR 141 R 142 , NHC(0)OR 143 , Ci -6 alkoxy, CN, C(0)NHR 144 and CONH 2 ; wherein R 140 , R 141 , R 142 , and R 143 are each independently unsubstituted Ci -6 alkyl; R 144 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.
  • R 73 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 CH 3 ; or H.
  • R 74 , R 74 , 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 CH 3 ; or H.
  • one of R 74 , R 74 , and R 74" is H and R 74 , R 74 , and R 74" are each independently H, CI, F, Br, I, or unsubstituted C 1-6 alkyl. In certain embodiments, one of R 74 , R 74 , and R 74" is H and R 74 , R 74 , and R 74" are each independently H or unsubstituted C 1-6 alkyl. In certain embodiments, one of R 74 , R 74 , and R 74" is H and R 74 , R 74 , and R 74" are each independently H, CI, F, Br or I.
  • R 74 , R 74 , and R 74" are H and R 74 , R 74 , and R 74" are each independently H, CI, F, Br, I, or unsubstituted C 1-6 alkyl.
  • two of R 74 , R 74 , and R 74" are H and R 74 , R 74 , and R 74" are each independently H or unsubstituted C 1-6 alkyl.
  • two of R 74 , R 74 , and R 74" are H and R 74 , R 74 , and R 74" are each independently H, CI, F, Br or I.
  • B 2 is:
  • R is H or substituted or unsubstituted lower alkyl
  • R 76 , and R 76" are each independently H, halogen or unsubstituted lower alkyl.
  • R 75 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)OR 140 , NH 2 , NR 141 R 142 , NHC(0)OR 143 , Ci -6 alkoxy, CN, C(0)NHR 144 and CONH 2 ; wherein R 140 , R 141 , R 142 , and R 143 are each independently unsubstituted C 1-6 alkyl; R 144 is C 1-6 alkyl optionally substituted with one or more substituents independently selected from the group consisting of NR 145 R 146 and OH; and R 145 and R 146 are each independently unsubstituted Ci -6
  • R 75 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)OR 14 °, H 2 , R 141 R 142 , HC(0)OR 143 , Ci -6 alkoxy, CN, C(0) HR 144 and CO H 2 ; wherein R 140 , R 141 , R 142 , and R 143 are each independently unsubstituted Ci -6 alkyl; R 144 is Ci -6 alkyl optionally substituted with one or more substituents independently selected from the group consisting of R 145 R 146 and OH; and R 145 and R 146 are each independently unsubstituted Ci -6 alkyl.
  • R 75 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 CH 3 ; or H.
  • R 76 , R 76 , and R 76 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 CH 3 ; or H.
  • one of R 76 , R 76 ', and R 76 " is H and R 76 , R 76 ', and R 76 " are each independently H, CI, F, Br, I, or unsubstituted Ci -6 alkyl. In certain embodiments, one of R 76 , R 76 , and R 76 " is H and R 76 , R 76 , and R 76 " are each independently H or unsubstituted Ci -6 alkyl. In certain embodiments, one of R 76 , R 76 ', and R 76 " is H and R 76 , R 76 ', and R 76 " are each independently H, CI, F, Br or I.
  • two of R 76 , R 76 , and R 76 " are H and R 76 , R 76 , and R 76 " are each independently H, CI, F, Br, I, or unsubstituted Ci -6 alkyl. In certain embodiments, two of R 76 , R 76 , and R 76 " are H and R 76 , R 76 , and R 76 " are each independently H or unsubstituted Ci -6 alkyl. In certain embodiments, two of R 76 , R 76 ', and R 76 " are H and R 76 , R 76 ', and R 76 " are each independently H, CI, F, Br or I.
  • B 2 is:
  • R 1U ' and R luy are each independently H or substituted or unsubstituted lower alkyl; and R 108 , R 108 ', R 108 ", R 110 , R 110 ', and R 110 " are each independently H, halogen or unsubstituted lower alkyl.
  • R 107 and R 109 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)OR 140 , H 2 , R 141 R 142 , HC(0)OR 143 , Ci -6 alkoxy, CN, C(0)NHR 144 and CONH 2 ; wherein R 140 , R 141 , R 142 , and R 143 are each independently unsubstituted Ci -6 alkyl; R 144 is Ci -6 alkyl optionally substituted with one or more substituents independently selected from the group consisting of NR.
  • R and OH; and R 145 and R 146 are each independently unsubstituted Ci -6 alkyl.
  • R 107 and R 109 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)OR 140 , NH 2 , NR 141 R 142 , NHC(0)OR 143 , Ci -6 alkoxy, CN, C(0)NHR 144 and CONH 2 ; wherein R 140 , R 141 , R 142 , and R 143 are each independently unsubstituted C 1-6 alkyl; R 144 is C 1-6 alkyl optionally substituted with one or more substituents independently selected from the group consisting of NR 145 R 146 and OH; and R 145 and R 146 are each independently unsubstituted Ci -6 alkyl.
  • R 107 and R 109 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 CH 3 ; or H.
  • R 108 , R 108 ', R 108 ", R 110 , R 110 ', and R 110 " 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 CH 3 ; or H.
  • B 2 is:
  • R is H or substituted or unsubstituted lower alkyl
  • R 108 , and R 108 " are each independently H, halogen or unsubstituted lower alkyl.
  • R 107 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)OR 140 , NH 2 , NR 141 R 142 , NHC(0)OR 143 , Ci -6 alkoxy, CN, C(0)NHR 144 and CONH 2 ; wherein R 140 , R 141 , R 142 , and R 143 are each independently unsubstituted C 1-6 alkyl; R 144 is C 1-6 alkyl optionally substituted with one or more substituents independently selected from the group consisting of NR 145 R 146 and OH; and R 145 and R 146 are each independently unsubstituted Ci
  • R 107 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)OR 14 °, H 2 , R 141 R 142 , HC(0)OR 143 , Ci -6 alkoxy, CN, C(0) HR 144 and CO H 2 ; wherein R 140 , R 141 , R 142 , and R 143 are each independently unsubstituted Ci -6 alkyl; R 144 is Ci -6 alkyl optionally substituted with one or more substituents independently selected from the group consisting of R 145 R 146 and OH; and R 145 and R 146 are each independently unsubstituted Ci -6 alkyl.
  • R 107 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 CH 3 ; or H.
  • R 108 , R 108 , and R 108 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 CH 3 ; or H.
  • one of R 108 , R 108 ', and R 108 " is H and R 108 , R 108 ', and R 108 " are each independently H, CI, F, Br, I, or unsubstituted Ci -6 alkyl.
  • one of R 108 , R 108 ', and R 108 " is H and R 108 , R 108 ', and R 108 " are each independently H or unsubstituted Ci -6 alkyl.
  • one of R 108 , R 108 ', and R 108 " is H and R 108 , R 108 ', and R 108 " are each independently H, CI, F, Br or I.
  • two of R 108 , R 108 , and R 108 " are H and R 108 , R 108 ', and R 108 " are each independently H, CI, F, Br, I, or unsubstituted Ci -6 alkyl.
  • two of R 108 , R 108 ', and R 108 " are H and R 108 , R 108 ', and R 108 " are each independently H or unsubstituted Ci -6 alkyl.
  • two of R 108 , R 108 ', and R 108 " are H and R 108 , R 108 ', and R 108 " are each independently H, CI, F, Br or I.
  • B 2 is:
  • R 109 is H or substituted or unsubstituted lower alkyl; and R 110 ,
  • R 110 , and R 110 " are each independently H, halogen or unsubstituted lower alkyl.
  • R 109 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)OR 140 , H 2 , R 141 R 142 , HC(0)OR 143 , Ci -6 alkoxy, CN, C(0)NHR 144 and CONH 2 ; wherein R 140 , R 141 , R 142 , and R 143 are each independently unsubstituted Ci -6 alkyl; R 144 is Ci -6 alkyl optionally substituted with one or more substituents independently selected from the group consisting of NR 145 R 146 and OH; and R and R are each independently unsubstituted Ci -6 alkyl.
  • R 109 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)OR 140 , H 2 , R 141 R 142 , HC(0)OR 143 , Ci -6 alkoxy, CN, C(0) HR 144 and CO H 2 ; wherein R 140 , R 141 , R 142 , and R 143 are each independently unsubstituted Ci -6 alkyl; R 144 is Ci -6 alkyl optionally substituted with one or more substituents independently selected from the group consisting of R 145 R 146 and OH; and R 145 and R 146 are each independently unsubstituted Ci -6 alkyl.
  • R 109 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 CH 3 ; or H.
  • R 110 , R 110 , 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 CH 3 ; or H.
  • one of R 110 , R 110' , and R 110" is H and R 110 , R 110' , and R 110" are each independently H, CI, F, Br, I, or unsubstituted Ci -6 alkyl. In certain embodiments, one of R 110 , R 110' , and R 110" is H and R 110 , R 110' , and R 110" are each independently H or unsubstituted Ci -6 alkyl. In certain embodiments, one of R 110 , R 110' , and R 110" is H and R 110 , R 110' , and R 110" are each independently H, CI, F, Br or I.
  • two of R 110 , R 110 , and R 110" are H and R 110 , R 110 , and R 110" are each independently H, CI, F, Br, I, or unsubstituted Ci -6 alkyl.
  • two of R 110 , R 110' , and R 110" are H and R 110 , R 110' , and R 110" are each independently H or unsubstituted Ci -6 alkyl.
  • two of R 110 , R 110' , and R 110" are H and R 110 , R 110 , and R 110" are each independently H, CI, F, Br or I.
  • 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
  • the invention provides compounds of general formula V, or salts thereof:
  • Ar is an aryl having general formula VI:
  • R- xro R 2oi ⁇ R 2(K R 2(B and R 204 are each independently H, CI, F, Br, I, or CF 3, wherein at least two of R 200 , R 201 , R 202 , R 203 , and R 204 are not H; or R 200 and R 201 , when taken together with the C atoms they are attached to, form unsubstituted phenyl, and R 202 , R 203 and R 204 are each H; and B is:
  • R 205 and R 208 are each independently H, F, NH 2 , HC(0)R 2 u 0 y 9, N0 2 , N 3 or
  • R 206 and R 207 are each independently H, CI, CH 3 , or C(0)R 211 ;
  • R 209 is CH 3 , CH 2 OR CH 2 OC(0)CH 3 or CH 2 N 3 ;
  • R 210 is phenyl or C(0) H 2 ;
  • R is H or CH 3 ; and wherein at least one of R 205 , R 206 , R 207 and R 208 is not H;
  • R 213 and R 216 are each independently H, F, NH 2 , HC(0)R 217 , N0 2 , N 3 or
  • R 214 and R 215 are each independently H, F, CI, CH 3 , or C(0)R 219 ;
  • R 217 is CH 3 , CH 2 OR 220 , CH 2 OC(0)CH 3 or CH 2 N 3 ;
  • R 218 is phenyl or C(0) H 2 ;
  • R 219 is (CH 2 ) 2 OCH 3 ; " ⁇
  • R 220 is H or CH 3 ;
  • R 221 , R 226 , R 231 , R 236 , R 241 , R 247 , R 252 , R 257 , R 262 , R 267 and R 297 are each independently H or unsubstituted Ci -6 alkyl;
  • R 225 , R 230 , R 235 , R 240 , R 251 , R 256 , R 261 , R 266 , R 271 and R 303 are each independently H, C(0)OR 272 , 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)OR 273 , NH 2 ,
  • R 272 , R 273 , R 274 , R 275 , and R 278 are each independently unsubstituted C 1-6 alkyl;
  • R 279 is Ci -6 alkyl optionally substituted with one or more substituents independently selected from the group consisting of R 280 R 281 and OH;
  • R 280 and R 281 are each independently unsubstituted Ci -6 alkyl;
  • Z 14 is - CH2- or -C(O)-; and
  • Z 15 is -N- or -CH-, wherein:
  • R 200 and R 201 when taken together with the C atoms they are attached to, form unsubstituted phenyl, and R 202 , R 203 and R 204 are each H, and B and only one of R 205 , R 206 , R 207 and R 208 is not H, then R 205 and R 208 are each independently H, F, H 2 , HC(0)R 209 , N 3
  • R lJb and R lJ / are each independently H, CI, CH 3 , or C(0)R 211 , wherein R 209 , R 210 and R 211 are as defined above;
  • R 200 and R 201 when taken together with the C atoms they are attached to, form unsubstituted phenyl, and R 202 , R 203 and R 204 are each H, and
  • R 213 , R 214 , R 215 and R 216 are as defined above, then at least one of: R 213 , R 214 , R 215 and R 216 ; or R 236 , R 237 , R 238 , R 239 and R 240 is not H;
  • R 200 and R 201 when taken together with the C atoms they are attached to, form unsubstituted phenyl, and R 202 , R 203 and R 204 are each H, and
  • R 261 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
  • R 205 and R 208 are each independently H, F, HC(0)R 209 ,
  • R 206 and R 207 are each independently H, CI, or
  • R 205 and R 208 are each independently H, F, NH 2 , HC(0)R 209 , N 3 or
  • R 206 and R 207 are each independently H, CI, CH 3 , or C(0)R 211 , wherein R 209 , R 210 and R 211 are as defined above;
  • R 213 , R 214 , R 215 and R 216 is not H;
  • R 4y is a halogen, then at least one of R 247 , R 248 , R 250 and R 251 is not H;
  • R 259 , R 260 and R 261 is not H, and when only one of R 257 , R 258 , R 259 , R 260 and R 261 is not H, then R 257 is H or unsubstituted Ci -6 alkyl; R 258 , R 259 and R 260 are each independently H, CI, F, Br, I or unsubstituted Ci -6 alkyl; and R 261 is H, C(0)OR 272 , 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; C 6 -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 cycl
  • R 200 , R 201 , R 202 , R 203 , and R 204 are each independently H, CI, I, F, Br, or CF 3 , wherein at least two of R 200 , R 201 , R 202 , R 203 , and R 204 are not H.
  • R 200 and R 201 taken together with the ring-forming C atoms that they are attached to, form unsubstituted phenyl, and R 202 , R 203 , and R 204 are each H.
  • R 200 , R 201 , R 202 , R 203 , and R 204 are each independently H, CI, I, F, Br, or CF 3 , wherein at least three of R 200 , R 201 , R 202 , R 203 , and R 204 are not H.
  • R 200 , R 201 , R 202 , R 203 , and R 204 are each independently H, CI, I, F, Br, or CF 3 , wherein at least four of R 200 , R 201 , R 202 , R 203 , and R 204 are not H.
  • R 200 , R 201 , R 202 , R 203 , and R 204 are each independently CI, I, F, Br, or CF 3 .
  • R 200 , R 201 , R 202 , R 203 , and R 204 are each independently CI, I, F, Br, or CF 3 , wherein at least one of R 200 , R 201 , R 202 , R 203 , and R 204 is CF 3 .
  • R 200 , R 201 , R 202 , R 203 , and R 204 are each independently H, CI, I, F, Br, or CF 3 , wherein four of R 200 , R 201 , R 202 , R 203 , and R 204 are not H.
  • R 200 , R 201 , R 202 , R 203 , and R 204 are each independently H, CI, I, F, Br, or CF 3 , wherein four of R 200 , R 201 , R 202 , R 203 , and R 204 are not H and at least one of R 200 , R 201 , R 202 , R 203 , and R 204 is CF 3 .
  • R 200 , R 201 , R 202 , R 203 , and R 204 are each independently H, CI, I, F, Br, or CF 3 , wherein three of R 200 , R 201 , R 202 , R 203 , and R 204 are not H.
  • R 200 , R 201 , R 202 , R 203 , and R 204 are each independently H, CI, I, F, Br, or CF 3 , wherein three of R 200 , R 201 , R 202 , R 203 , and R 204 are not H and at least one of R 200 , R 201 , R 202 , R 203 , and R 204 is CF 3 .
  • R 200 , R 201 , R 202 , R 203 , and R 204 are each independently H, CI, I, F, Br, or CF 3 , wherein two of R 200 , R 201 , R 202 , R 203 , and R 204 are not H.
  • R 200 , R 201 , R 202 , R 203 , and R 204 are each independently H, CI, I, F, Br, or CF 3 , wherein two of R 200 , R 201 , R 202 , R 203 , and R 204 are not H and at least one of R 200 , R 201 , R 202 , R 203 , and R 204 is CF 3 .
  • R 200 -R 204 are each CI, I, F or CF 3 , and the remaining R 200 .R 204 are H.
  • R 200 -R 204 are each CI, F or CF 3 , and the remaining R 200 .R 204 are H.
  • two of R 200 -R 204 are each independently CI or CF 3 , and the remaining R 200 .R 204 are H.
  • two of R 200 -R 204 are each CI, and the remaining R 00 .R 204 are H.
  • two of R 200 -R 204 are each CF 3 , and the remaining R 00 .R 204 are H.
  • R 200 is CI, F, Br, I, or CF 3 ;
  • R 203 and R 204 are each independently H, CI, F, Br, I, or CF 3 , wherein at least one of R 203 and R 204 is not H; and
  • R 201 and R 202 are each H.
  • R 200 and R 204 are each independently CI, F, Br, I, or CF 3 ; and
  • R 201 , R 202 and R 203 are each H.
  • R 200 is CI, I, F or CF 3 ; R 203 and R 204 are each independently H, CI, I, F or CF 3 , wherein at least one of R 203 and R 204 is not H; and R 201 and R 202 are each H.
  • R is CI, F or CF 3 ; R and R 204 are each independently H, CI, F or CF 3 , wherein at least one of R 203 and R 204 is not H; and R 201 and R 202 are each H.
  • R 200 is CI or CF 3 ;
  • R 203 and R 204 are each independently H, CI or CF 3 , wherein at least one of R 203 and R 204 is not H; and
  • R 201 and R 202 are each H.
  • R 200 and R 203 are each independently CI, I, F or CF 3 ; and R 201 , R 202 and R 204 are each H.
  • R 200 and R 203 are each independently CI, F or CF 3 ; and R 201 , R 202 and R 204 are each H.
  • R 200 and R 203 are each independently CI or CF 3 ; and R 201 , R 202 and R 204 are each H.
  • R 200 and R 203 are each CI; and R 201 , R 202 and R 204 are each H.
  • R 200 is CI and R 203 is CF 3 ; and R 201 , R 202 and R 204 are each H.
  • R 200 and R 203 are each CF 3 ; and R 201 , R 202 and R 204 are each H.
  • R 200 and R 204 are each independently CI, I, F or CF 3 ; and R 201 , R 202 and R 203 are each H.
  • R 200 and R 204 are each independently CI, F or CF 3 ; and R 201 , R 202 and R 203 are each H.
  • R 200 and R 204 are each independently CI or CF 3 ; and R 201 , R 202 and R 203 are each H.
  • R is CI and R is CF 3 ; and R 201 , R 202 and R 203 are each H.
  • R 200 and R 204 are each CI; and R 201 , R 202 and R 203 are each H.
  • R 200 and R 204 are each CF 3 ; and R 201 , R 202 and R 203 are each H.
  • B is: or wherein R 221 , R 226 , R 222 R 223 , R 224 ,
  • R 227 , R 228 , R 229 , R 225 and R 230 are as defined anywhere herein.
  • R , R , R and R are as defined anywhere herein.
  • R and R are each independently H, NH 2 , HC(0)R 209 , N0 2 , or N 3 wherein at least one of R 205 and R 208 is not H;
  • R 206 and R 207 are each H;
  • R 209 is CH 3 , CH 2 OR 212 , CH 2 OC(0)CH 3 or CH 2 N 3 ; and
  • R 212 is H or CH 3 .
  • R 205 and R 208 are each independently H, H 2 , or HC(0)R 209 wherein at least one of R 205 and R 208 is not H; R 206 and R 207 are each H; R 209 is CH 3 , CH 2 OR 212 , CH 2 OC(0)CH 3 or CH 2 N 3 ; and R 212 is H or CH 3 .
  • R 205 and R 208 are each independently H, HC(0)R 209 or N0 2 wherein at least one of R 205 and R 208 is not H; R 206 and R 207 are each H; R 209 is CH 3 , CH 2 OR 212 , CH 2 OC(0)CH 3 or CH 2 N 3 ; and R 212 is H or CH 3 .
  • R 205 is HC(0)R 209 ;
  • R 206 , R 207 and R 208 are each H;
  • R 209 is CH 3 , CH 2 OR 212 , CH 2 OC(0)CH 3 or CH 2 N 3 ; and
  • R 212 is H or CH 3 .
  • R 209 is CH 3 , CH 2 OR 212 or CH 2 OC(0)CH 3 ; and
  • R 212 is H or CH 3 .
  • B is:
  • R 236 , R 237 , R 238 , R 239 , R 240 and Z 15 are as defined anywhere herein.
  • at least one of R , R , R , R , and R is not H.
  • R 236 , R 237 , R 238 , R 239 , and R 240 are each H.
  • R is H or C 1-4 alkyl; or H or Ci -3 alkyl; or H or Ci -2 alkyl; or; H or CH 3 .
  • R 236 is unsubstituted lower alkyl; or C 1-4 alkyl; or Ci -3 alkyl; or Ci -2 alkyl; or CH 3 .
  • R 236 is H.
  • R 237 , R 238 , and R 239 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 CH 3 ; or H.
  • one of R 237 , R 238 , and R 239 is H and R 237 , R 238 , and R 239 are each independently H, CI, F, Br, I, or unsubstituted Ci -6 alkyl. In certain embodiments, one of R 237 , R 238 , and R 239 is H and R 237 , R 238 , and R 239 are each independently H or unsubstituted C 1-6 alkyl. In certain embodiments, one of R 237 , R 238 , and R 239 is H and R 237 , R 238 , and R 239 are each independently H, CI, F, Br or I.
  • two of R 237 , R 238 , and R 239 are H and R 237 , R 238 , and R 239 are each independently H, CI, F, Br, I, or unsubstituted C 1-6 alkyl. In certain embodiments, two of R 237 , R 238 , and R 239 are H and R 237 , R 238 , and R 239 are each independently H or unsubstituted C 1-6 alkyl. In certain embodiments, two of R 237 , R 238 , and R 239 are H and R 237 , R 238 , and R 239 are each independently H, CI, F, Br or I.
  • R 240 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)OR 273 , H 2 , R 274 R 275 , HC(0)OR 278 , Ci -6 alkoxy, CN, C(0) HR 279 and CO H 2 ; wherein R 273 , R 274 , R 275 , and R 278 are each independently unsubstituted Ci -6 alkyl; R 279 is Ci -6 alkyl optionally substituted with one or more substituents independently selected from the group consisting of R 280 R 281 and OH; and R 280 and R 281 are each independently unsubstituted Ci-6 alkyl.
  • R 240 is unsubstituted Ci -6 alkyl; or unsubstituted Ci -5 alkyl; unsubstituted Ci-4 alkyl; unsubstituted Ci -3 alkyl; or unsubstituted Ci -2 alkyl; or CH 3 ; or H.
  • Z 15 is -N-. In other embodiments, Z 15 is -CH-.
  • R 213 , R 216 , R 214 and R 215 are as defined anywhere herein. In certain embodiments, at least one of R 213 , R 216 , R 214 and R 215 is not H. In other embodiments, R R 216 , R 214 and R 215 are each H. In certain embodiments, R 213 and R 216 are each independently H, H 2 , HC(0)R 217 , N0 2 , or N3 wherein at least one of R 213 and R 216 is not H; R 214 and R 215 are each H; R 217 is CH 3 , CH2OR 220 , CH 2 OC(0)CH 3 or CH 2 N 3 ; and R 220 is H or CH 3 .
  • R 213 and R 216 are each independently H, H 2 , or HC(0)R 217 wherein at least one of R 213 and R 216 is not H;
  • R 214 and R 215 are each H;
  • R 217 is CH 3 , CH2OR 220 , CH 2 OC(0)CH 3 or CH 2 N 3 ; and
  • R 220 is H or CH 3 .
  • R 213 and R 216 are each independently H, N0 2 , or HC(0)R 217 wherein at least one of R 213 and R 216 is not H; R 214 and R 215 are each H; R 217 is CH 3 , CH2OR 220 , CH 2 OC(0)CH 3 or CH 2 N 3 ; and R 220 is H or CH 3 .
  • R 213 is HC(0)R 217 ; R 214 , R 215 and R 216 are each H; R 217 is CH 3 , CH2OR 220 , CH 2 OC(0)CH 3 or CH 2 N 3 ; and R 220 is H or CH 3 .
  • R 217 is CH 3 , CH2OR 220 or CH 2 OC(0)CH 3 ; and R 220 is H or CH 3 .
  • B is:
  • R 241 , R 242 , R 243 , R 244 , R 245 , and R 246 are as defined anywhere herein. In certain embodiments, at least one of R 241 , R 242 , R 243 , R 244 , R 245 , and R 246 is not H. In other embodiments, R 241 , R 242 , R 243 , R 244 , R 245 , and R 246 are each H. In certain embodiments, in compounds of general formula V, R 241 is H or C 1-4 alkyl; or H or Ci -3 alkyl; or H or Ci -2 alkyl; or; H or CH 3 .
  • R 241 is unsubstituted lower alkyl; or C 1-4 alkyl; or Ci -3 alkyl; or Ci-2 alkyl; or CH 3 .
  • R 241 is H.
  • R 242 , R 243 , R 244 , R 245 , and R 246 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 CH 3 ; or H.
  • one of R 242 , R 243 , R 244 , R 245 , and R 246 is H and R 242 , R 243 , R 244 , R 245 , and R 246 are each independently H, CI, F, Br, I, or unsubstituted C 1-6 alkyl.
  • one of R 242 , R 243 , R 244 , R 245 , and R 246 is H and R 242 , R 243 , R 244 , R 245 , and R 246 are each independently H or unsubstituted C 1-6 alkyl.
  • one of R 242 , R 243 , R 244 , R 245 , and R 246 is H and R 242 , R 243 , R 244 , R 245 , and R 246 are each independently H, CI, F, Br or I.
  • two of R 242 , R 243 , R 244 , R 245 , and R 246 are H and R 242 , R 243 , R 244 , R 245 , and R 246 are each independently H, CI, F, Br, I, or unsubstituted C 1-6 alkyl.
  • two of R 242 , R 243 , R 244 , R 245 , and R 246 are H and R 242 , R 243 , R 244 , R 245 , and R 246 are each independently H or unsubstituted Ci -6 alkyl.
  • two of R 242 , R 243 , R 244 , R 245 , and R 246 are H and R 242 , R 243 , R 244 , R 245 , and R 246 are each independently H, CI, F, Br or I.
  • R 242 , R 243 , R 244 , R 245 , and R 246 are H and R 242 , R 243 , R 244 , R 245 , and R 246 are each independently H, CI, F, Br, I, or unsubstituted Ci -6 alkyl.
  • three of R 242 , R 243 , R 244 , R 245 , and R 246 are H and R 242 , R 243 , R 244 , R 245 , and R 246 are each independently H or unsubstituted Ci -6 alkyl.
  • R 242 , R 243 , R 244 , R 245 , and R 246 are H and R 242 , R 243 , R 244 , R 245 , and R 246 are each independently H, CI, F, Br or I.
  • four of R 242 , R 243 , R 244 , R 245 , and R 246 are H and R 242 , R 243 , R 244 , R 245 , and R 246 are each independently H, CI, F, Br, I, or unsubstituted Ci -6 alkyl.
  • R 242 , R 243 , R 244 , R 245 , and R 246 are H and R 242 , R 243 , R 244 , R 245 , and R 246 are each independently H or unsubstituted Ci -6 alkyl.
  • four of R 242 , R 243 , R 244 , R 245 , and R 246 are H and R 242 , R 243 , R 244 , R 245 , and R 246 are each independently H, CI, F, Br or I.
  • R 247 , R 248 , R 249 , R 250 , and R 251 are as defined anywhere herein. In certain embodiments, at least one of R 247 , R 248 , R 249 , R 250 , and R 251 is not H. In other embodiments, R 247 , R 248 , R 249 , R 250 , and R 251 are each H. In certain embodiments, in compounds of general formula V, R 247 is H or Ci-4 alkyl; or H or Ci -3 alkyl; or H or Ci -2 alkyl; or; H or CH 3 .
  • R 247 is unsubstituted lower alkyl; or Ci-4 alkyl; or Ci -3 alkyl; or Ci -2 alkyl; or CH 3 .
  • R 247 is H.
  • R 248 , R 249 and R 250 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 CH 3 ; or H.
  • one of R 248 , R 249 and R 250 is H and R 248 , R 249 and R 250 are each independently H, CI, F, Br, I, or unsubstituted Ci -6 alkyl. In certain embodiments, one of R 248 , R 249 and R 250 is H and R 248 , R 249 and R 250 are each independently H or unsubstituted Ci -6 alkyl. In certain embodiments, one of R 248 , R 249 and R 250 is H and R 248 , R 249 and R 250 are each independently H, CI, F, Br or I.
  • R , R and R are H and R , R and R are each independently H, CI, F, Br, I, or unsubstituted Ci -6 alkyl.
  • two of R 248 , R 249 and R 250 are H and R 248 , R 249 and R 250 are each independently H or unsubstituted Ci -6 alkyl.
  • two of R 248 , R 249 and R 250 are H and R 248 , R 249 and R 250 are each independently H, CI, F, Br or I.
  • R 249 is H or unsubstituted Ci -6 alkyl.
  • R 251 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)OR 273 , H 2 , R 274 R 275 , HC(0)OR 278 , Ci-6 alkoxy, CN, C(0) HR 279 and CO H 2 ; wherein R 273 , R 274 , R 275 , and R 278 are each independently unsubstituted Ci -6 alkyl; R 279 is Ci -6 alkyl optionally substituted with one or more substituents independently selected from the group consisting of R 280 R 281 and OH; and R 280 and R 281 are each independently unsubstituted Ci -6 alkyl.
  • R 251 is unsubstituted Ci -6 alkyl; or unsubstituted Ci -5 alkyl; unsubstituted Ci-4 alkyl; unsubstituted Ci -3 alkyl; or unsubstituted Ci -2 alkyl; or CH 3 ; or H.
  • R 257 , R 258 , R 259 , R 260 and R 261 are as defined anywhere herein.
  • R 257 , R 258 , R 259 , R 260 and R 261 is not H. In other embodiments, R 257 , R 258 , R 259 , R 260 and R 261 are each H. In certain embodiments, in compounds of general formula V, R 257 is H or Ci-4 alkyl; or H or Ci -3 alkyl; or H or Ci -2 alkyl; or; H or CH 3 . In certain embodiments, R 257 is unsubstituted lower alkyl; or Ci-4 alkyl; or Ci -3 alkyl; or Ci -2 alkyl; or CH 3 . In other embodiments, R 257 is H.
  • R 258 , R 259 , and R 260 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 CH 3 ; or H.
  • one of R 258 , R 259 , and R 260 is H and R 258 , R 259 , and R 260 are each independently H, CI, F, Br, I, or unsubstituted Ci -6 alkyl.
  • one of R 258 , R 259 , and R 260 is H and R 258 , R 259 , and R 260 are each independently H or unsubstituted Ci -6 alkyl. In certain embodiments, one of R 258 , R , and R is H and R , R , and R are each independently H, CI, F, Br or I. In certain embodiments, two of R 258 , R 259 , and R 260 are H and R 258 , R 259 , and R 260 are each independently H, CI, F, Br, I, or unsubstituted Ci -6 alkyl.
  • R 242 , R 258 , R 259 , and R 260 are H and R 258 , R 259 , and R 260 are each independently H or unsubstituted Ci -6 alkyl.
  • two of R 258 , R 259 , and R 260 are H and R 258 , R 259 , and R 260 are each independently H, CI, F, Br or I.
  • R 261 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)OR 273 , H 2 , R 274 R 275 , HC(0)OR 278 , Ci -6 alkoxy, CN, C(0) HR 279 and CO H 2 ; wherein R 273 , R 274 , R 275 , and R 278 are each independently unsubstituted Ci -6 alkyl; R 279 is Ci -6 alkyl optionally substituted with one or more substituents independently selected from the group consisting of R 280 R 281 and OH; and R 280 and R 281 are each independently unsubstituted Ci -6 alkyl.
  • R 261 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)OR 273 , H 2 , R 274 R 275 , HC(0)OR 278 , Ci -6 alkoxy, CN, C(0)NHR 279 and CONH2; wherein R 273 , R 274 , R 275 , and R 278 are each independently unsubstituted Ci -6 alkyl; R 279 is Ci-6 alkyl optionally substituted with one or more substituents independently selected from the group consisting of NR 280 R 281 and OH; and R 280 and R 281 are each independently unsubstituted Ci- 6 alkyl.
  • R 261 is unsubstituted Ci -6 alkyl; or unsubstituted Ci -5 alkyl; unsubstituted Ci-4 alkyl; unsubstituted Ci -3 alkyl; or unsubstituted Ci -2 alkyl; or CH 3 ; or H.
  • R 231 , R 232 , R 233 , R 234 , R 235 and Z 14 are as defined anywhere herein.
  • at least one of R 231 , R 232 , R 233 , R 234 , and R 235 is not H.
  • R 231 , R 232 , R 233 , R 234 , and R 235 are each H.
  • R 231 is H or Ci-4 alkyl; or H or Ci -3 alkyl; or H or Ci -2 alkyl; or; H or CH 3 .
  • R 231 is unsubstituted lower alkyl; or C 1-4 alkyl; or Ci -3 alkyl; or Ci -2 alkyl; or CH 3 .
  • R 231 is H.
  • R 232 , R 233 , and R 234 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 CH 3 ; or H.
  • one of R 232 , R 233 , and R 234 is H and R 232 , R 233 , and R 234 are each independently H, CI, F, Br, I, or unsubstituted C 1-6 alkyl. In certain embodiments, one of R 232 , R 233 , and R 234 is H and R 232 , R 233 , and R 234 are each independently H or unsubstituted C 1-6 alkyl. In certain embodiments, one of R 232 , R 233 , and R 234 is H and R 232 , R 233 , and R 234 are each independently H, CI, F, Br or I.
  • two of R 232 , R 233 , and R 234 are H and R 232 , R 233 , and R 234 are each independently H, CI, F, Br, I, or unsubstituted C 1-6 alkyl. In certain embodiments, two of R 232 , R 233 , and R 234 are H and R 232 , R 233 , and R 234 are each independently H or unsubstituted Ci-6 alkyl. In certain embodiments, two of R 232 , R 233 , and R 234 are H and R 232 , R 233 , and R 234 are each independently H, CI, F, Br or I.
  • R 235 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)OR 273 , H 2 , R 274 R 275 , HC(0)OR 278 , Ci -6 alkoxy, CN, C(0) HR 279 and CO H 2 ; wherein R 273 , R 274 , R 275 , and R 278 are each independently
  • R 279 is C 1-6 alkyl optionally substituted with one or more substituents independently selected from the group consisting of R 280 R 281 and OH; and R 280 and R 281 are each independently unsubstituted C 1-6 alkyl.
  • R 235 is unsubstituted C 1-6 alkyl; or unsubstituted C 1-5 alkyl; unsubstituted C 1-4 alkyl; unsubstituted Ci -3 alkyl; or
  • Z 14 is -CH 2 -.
  • Z 14 is -C(O)-.
  • R 252 , R 253 , R 254 , R 255 and R are as defined anywhere herein.
  • at least one of R , R , R , R and R is not H.
  • R , R , R , R and R are each H.
  • R 252 is H or C 1-4 alkyl; or H or Ci -3 alkyl; or H or Ci -2 alkyl; or; H or CH 3 .
  • R 252 is unsubstituted lower alkyl; or C 1-4 alkyl; or Ci -3 alkyl; or Ci -2 alkyl; or CH 3 .
  • R 252 is H.
  • R 253 , R 254 , and R 255 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 CH 3 ; or H.
  • one of R 253 , R 254 , and R 255 is H and R 253 , R 254 , and R 255 are each independently H, CI, F, Br, I, or unsubstituted C 1-6 alkyl.
  • one of R 253 , R 254 , and R 255 is H and R 253 , R 254 , and R 255 are each independently H or unsubstituted C 1-6 alkyl. In certain embodiments, one of R 253 , R 254 , and R 255 is H and R 253 , R 254 , and R 255 are each independently H, CI, F, Br or I. In certain embodiments, two of R 253 , R 254 , and R 255 are H and R 253 , R 254 , and R 255 are each independently H, CI, F, Br, I, or unsubstituted Ci -6 alkyl.
  • R 253 , R 254 , and R 255 are H and R 253 , R 254 , and R 255 are each independently H or unsubstituted C 1-6 alkyl. In certain embodiments, two of R 253 , R 254 , and R 255 are H and R 253 , R 254 , and R 255 are each independently H, CI, F, Br or I.
  • R 256 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)OR 273 , H 2 , R 274 R 275 , HC(0)OR 278 , Ci -6 alkoxy, CN, C(0) HR 279 and CO H 2 ; wherein R 273 , R 274 , R 275 , and R 278 are each independently unsubstituted Ci -6 alkyl; R 279 is Ci -6 alkyl optionally substituted with one or more substituents independently selected from the group consisting of R 280 R 281 and OH; and R 280 and R 281 are each independently unsubstituted Ci -6 alkyl.
  • R 256 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 CH 3 ; or H.
  • R 262 is H or Ci-4 alkyl; or H or Ci -3 alkyl; or H or Ci -2 alkyl; or; H or CH 3 .
  • R 262 is unsubstituted lower alkyl; or Ci-4 alkyl; or Ci -3 alkyl; or Ci -2 alkyl; or CH 3 .
  • R 262 is H.
  • R 263 , R 264 , and R 265 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 CH 3 ; or H.
  • one of R 263 , R 264 , and R 265 is H and R 263 , R 264 , and R 265 are each independently H, CI, F, Br, I, or unsubstituted Ci -6 alkyl.
  • one of R 263 , R 264 , and R 265 is H and R 263 , R 264 , and R 265 are each independently H or unsubstituted Ci -6 alkyl. In certain embodiments, one of R 263 , R 264 , and R 265 is H and R 263 , R 264 , and R 265 are each independently H, CI, F, Br or I. In certain embodiments, two of R 263 , R 264 , and R 265 are H and R 263 , R 264 , and R 265 are each independently H, CI, F, Br, I, or unsubstituted Ci -6 alkyl.
  • two of R 263 , R 264 , and R 265 are H and R 263 , R 264 , and R 265 are each independently H or unsubstituted Ci -6 alkyl. In certain embodiments, two of R 263 , R 264 , and R 265 are H and R 263 , R 264 , and R 265 are each independently H, CI, F, Br or I.
  • R 266 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)OR 273 , H 2 , R 274 R 275 , HC(0)OR 278 , Ci -6 alkoxy, CN, C(0) HR 279 and CO H 2 ; wherein R 273 , R 274 , R 275 , and R 278 are each independently unsubstituted Ci -6 alkyl; R 279 is Ci -6 alkyl optionally substituted with one or more substituents independently selected from the group consisting of R 280 R 281 and OH; and R 280 and R 281 are each independently unsubstituted Ci -6 alkyl.
  • R 266 is unsubstituted Ci -6 alkyl; or unsubstituted Ci -5 alkyl; unsubstituted Ci-4 alkyl; unsubstituted Ci -3 alkyl; or unsubstituted Ci -2 alkyl; or CH 3 ; or H.
  • R , R , R , R , and R 271 are as defined anywhere herein.
  • at least one of R , R , R , R , and R is not H.
  • R , R , R , R , and R are each H.
  • R 267 is H or Ci-4 alkyl; or H or Ci -3 alkyl; or H or Ci -2 alkyl; or; H or CH 3 .
  • R 267 is unsubstituted lower alkyl; or Ci-4 alkyl; or Ci -3 alkyl; or Ci -2 alkyl; or CH 3 .
  • R 267 is H.
  • R 268 , R 269 , and R 270 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 CH 3 ; or H.
  • one of R 268 , R 269 , and R 270 is H and R 268 , R 269 , and R 270 are each independently H, CI, F, Br, I, or unsubstituted Ci -6 alkyl.
  • one of R 268 , R 269 , and R 270 is H and R 268 , R 269 , and R 270 are each independently H or unsubstituted Ci -6 alkyl. In certain embodiments, one of R 268 , R 269 , and R 270 is H and R 268 , R 269 , and R 270 are each independently H, CI, F, Br or I. In certain embodiments, two of R 268 , R 269 , and R 270 are H and R 268 , R 269 , and R 270 are each independently H, CI, F, Br, I, or unsubstituted Ci -6 alkyl.
  • R 268 , R 269 , and R 270 are H and R 268 , R 269 , and R 270 are each independently H or unsubstituted Ci -6 alkyl. In certain embodiments, two of R 268 , R 269 , and R 270 are H and R 268 , R 269 , and R 270 are each independently H, CI, F, Br or I.
  • R 271 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)OR 273 , H 2 , R 274 R 275 , HC(0)OR 278 , Ci -6 alkoxy, CN, C(0) HR 279 and CO H 2 ; wherein R 273 , R 274 , R 275 , and R 278 are each independently unsubstituted Ci -6 alkyl; R 279 is Ci -6 alkyl optionally substituted with one or more substituents independently selected from the group consisting of R 280 R 281 and OH; and R 280 and R 281 are each independently unsubstituted Ci -6 alkyl.
  • R 271 is unsubstituted Ci -6 alkyl; or unsubstituted Ci -5 alkyl; unsubstituted Ci-4 alkyl; unsubstituted Ci -3 alkyl; or unsubstituted Ci -2 alkyl; or CH 3 ; or H.
  • R 297 , R 298 , R 299 , R 300 , R 301 , R 302 , and R 303 are as defined anywhere herein. In certain embodiments, at least one of R 297 , R 298 , R 299 , R 300 , R 301 , R 302 , and R is not H. In other embodiments, R 297 , R 298 , R 299 , R 300 , R 301 , R 302 , and R 303 are each H. In certain embodiments, in compounds of general formula V, R 297 is H or C 1-4 alkyl; or H or Ci -3 alkyl; or H or Ci -2 alkyl; or; H or CH 3 .
  • R 297 is unsubstituted lower alkyl; or C 1-4 alkyl; or Ci -3 alkyl; or Ci -2 alkyl; or CH 3 .
  • R 297 is H.
  • R 298 , R 299 , R 300 , R 301 , and R 302 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 CH 3 ; or H.
  • one of R 298 , R 299 , R 300 , R 301 , and R 302 is H and R 298 , R 299 , R 300 , R 301 , and R 302 are each independently H, CI, F, Br, I, or unsubstituted Ci -6 alkyl.
  • one of R 298 , R 299 , R 300 , R 301 , and R 302 is H and R 298 , R 299 , R 300 , R 301 , and R 302 are each independently H or unsubstituted Ci -6 alkyl.
  • one of R 298 , R 299 , R 300 , R 301 , and R 302 is H and R 298 , R 299 , R 300 , R 301 , and R 302 are each independently H, CI, F, Br or I.
  • two of R 298 , R 299 , R 300 , R 301 , and R 302 are H and R 298 , R 299 , R 300 , R 301 , and R 302 are each independently H, CI, F, Br, I, or unsubstituted Ci -6 alkyl.
  • two of R 298 , R 299 , R 300 , R 301 , and R 302 are H and R 298 , R 299 , R 300 , R 301 , and R 302 are each independently H or unsubstituted Ci -6 alkyl.
  • two of R 298 , R 299 , R 300 , R 301 , and R 302 are H and R 298 , R 299 , R 300 , R 301 , and R 302 are each independently H, CI, F, Br or I.
  • R 298 , R 299 , R 300 , R 301 , and R 302 are H and R 298 , R 299 , R 300 , R 301 , and R 302 are each independently H, CI, F, Br, I, or unsubstituted Ci -6 alkyl.
  • three of R 298 , R 299 , R 300 , R 301 , and R 302 are H and R 298 , R 299 , R 300 , R 301 , and R 302 are each independently H or unsubstituted Ci -6 alkyl.
  • R 298 , R 299 , R 300 , R 301 , and R 302 are H and R 298 , R 299 , R 300 , R 301 , and R 302 are each independently H, CI, F, Br or I.
  • four of R 298 , R 299 , R 300 , R 301 , and R 302 are H and R 298 , R 299 , R 300 , R 301 , and R 302 are each independently H, CI, F, Br, I, or unsubstituted Ci -6 alkyl.
  • R 298 , R 299 , R 300 , R 301 , and R 302 are H and R 298 , R 299 , R 300 , R 301 , and R 302 are each independently H or unsubstituted Ci -6 alkyl.
  • four of R 298 , R 299 , R 300 , R 301 , and R 302 are H and R 298 , R 299 , R 300 , R 301 , and R 302 are each independently H, CI, F, Br or I.
  • R 303 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)OR 273 , H 2 , R 274 R 275 , HC(0)OR 278 , Ci -6 alkoxy, CN, C(0) HR 279 and CO H 2 ; wherein R 273 , R 274 , R 275 , and R 278 are each independently unsubstituted Ci -6 alkyl; R 279 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.
  • R 303 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 CH 3 ; or H.
  • B is:
  • R 221 , R 222 , R 223 , R 224 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 221 , R 222 , R 223 , R 224 and R 225 are each H. In certain embodiments, in compounds of general formula V, R 221 is H or C 1-4 alkyl; or H or Ci -3 alkyl; or H or Ci -2 alkyl; or; H or CH 3 . In certain embodiments, R 221 is unsubstituted lower alkyl; or C 1-4 alkyl; or Ci -3 alkyl; or Ci -2 alkyl; or CH 3 .
  • R 221 is H.
  • R 222 , R 223 , and R 224 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 CH 3 ; or H.
  • one of R 222 , R 223 , and R 224 is H and R 222 , R 223 , and R 224 are each independently H, CI, F, Br, I, or unsubstituted C 1-6 alkyl.
  • one of R 222 , R 223 , and R 224 is H and R 222 , R 223 , and R 224 are each independently H or unsubstituted C 1-6 alkyl. In certain embodiments, one of R 222 , R 223 , and R 224 is H and R 222 , R 223 , and R 224 are each independently H, CI, F, Br or I. In certain embodiments, two of R 222 , R 223 , and R 224 are H and R 222 , R 223 , and R 224 are each independently H, CI, F, Br, I, or unsubstituted C 1-6 alkyl.
  • R 222 , R 223 , and R 224 is H and R 222 , R 223 , and R 224 are each independently H or unsubstituted Ci -6 alkyl.
  • two of R 222 , R 223 , and R 224 are H and R 222 , R 223 , and R 224 are each independently H, CI, F, Br or I.
  • R 225 is unsubstituted Ci -6 alkyl or C 1-6 alkyl substituted with one or more substituents
  • R 273 , R 274 , R 275 , and R 278 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 R 280 R 281 and OH; and
  • R 280 and R 281 are each independently unsubstituted C 1-6 alkyl.
  • R 225 is unsubstituted C 1-6 alkyl; or unsubstituted C 1-5 alkyl; unsubstituted C 1-4 alkyl; unsubstituted Ci -3 alkyl; or
  • R 226 , R 227 , R 228 , R 229 and R 230 are as defined anywhere herein. In certain embodiments, at least one of R 226 , R 227 , R 228 , R 229 and R 230 is not H. In other embodiments, R 226 , R 227 , R 228 , R 229 and R 230 are each H. In certain embodiments, in compounds of general formula V, R 226 is H or C 1-4 alkyl; or H or Ci -3 alkyl; or H or Ci -2 alkyl; or; H or CH 3 .
  • R 226 is unsubstituted lower alkyl; or C 1-4 alkyl; or Ci -3 alkyl; or Ci -2 alkyl; or CH 3 .
  • R 226 is H.
  • R 227 , R 228 , and R 229 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 CH 3 ; or H.
  • one of R 227 , R 228 , and R 229 is H and R 227 , R 228 , and R 229 are each independently H, CI, F, Br, I, or unsubstituted C 1-6 alkyl. In certain embodiments, one of R 227 , R 228 , and R 229 is H and R 227 , R 228 , and R 229 are each independently H or unsubstituted C 1-6 alkyl. In certain embodiments, one of R 227 , R 228 , and R 229 is H and R 227 , R 228 , and R 229 are each independently H, CI, F, Br or I.
  • two of R 227 , R 228 , and R 229 are H and R 227 , R 228 , and R 229 are each independently H, CI, F, Br, I, or unsubstituted Ci -6 alkyl.
  • two of R 227 , R 228 , and R 229 are H and R 227 , R 228 , and R 229 are each independently H or unsubstituted C 1-6 alkyl.
  • two of R 227 , R 228 , and R 229 are H and R 227 , R 228 , and R 229 are each independently H, CI, F, Br or I.
  • R 230 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)OR 273 , H 2 , R 274 R 275 , HC(0)OR 278 , Ci -6 alkoxy, CN, C(0) HR 279 and CO H 2 ; wherein R 273 , R 274 , R 275 , and R 278 are each independently unsubstituted Ci -6 alkyl; R 279 is Ci -6 alkyl optionally substituted with one or more substituents independently selected from the group consisting of R 280 R 281 and OH; and R 280 and R 281 are each independently unsubstituted Ci -6 alkyl.
  • R 230 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 CH 3 ; or H.
  • R 200 , R 201 , R 202 , R 203 , and R 204 are each independently H CI, F, Br, I, or CF 3 , wherein at least two of R 200 , R 201 , R 202 , R 203 ,
  • R 204 are not H; and B is wherein R 205 is HC(0)R 209 ; R 206 , R 207 and R 208 are each H; R 209 is CH 3 , CH 2 OR 212 , CH 2 OC(0)CH 3 or CH 2 N 3 ; and R 212 is H or CH 3 .
  • R 200 , R 201 , R 202 , R 203 , and R 204 are each independently H, CI, F, Br, I, or CF 3 , wherein at least two of R 200 , R 201 , R 202 , R 203 ,
  • R 204 and R 204 are not H; and B wherein at least one of R 221 , R 222 , R 223 , R 224 and R 225 ; or R 226 , R 227 , R 228 , R 229 and R 230 is not H.
  • R 200 is CI, F, Br, I, or CF 3 ;
  • R 204 is CF 3 ; and
  • R 201 , R 202 and R 203 are each H; and
  • B is:
  • R 221 and R 226 are each independently H or Ci -6 alkyl
  • R 222 , R 223 , R 224 , R 227 , R 228 and R 229 are each independently H, CI, F, Br, I or unsubstituted Ci -6 alkyl
  • R 225 , and R 230 are each independently H
  • C(0)OR 272 C 3- 6 cycloalkyl, C 6 -io aryl, C 6 -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)OR 273 , H 2 , R 274 R 275 , HC(0)OR 278 ,
  • R 272 , R 273 , R 274 , R 275 , and R 278 are each independently unsubstituted C 1-6 alkyl;
  • R 279 is C 1-6 alkyl optionally substituted with one or more substituents independently selected from the group consisting of R 280 R 281 and OH; and
  • R 280 and R 281 are each independently unsubstituted C 1-6 alkyl.
  • 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
  • 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
  • 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
  • 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.
  • 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
  • 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.
  • compounds of general formula (I), or salts thereof are selected from the compounds shown in Tables 1 and 2, and salts thereof:
  • 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.
  • pharmaceutically acceptable salt 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.
  • 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.
  • inorganic acids such as hydrochloric acid, hydrobromic acid, hydroiodic acid, sulphuric acid, phosphoric acid, and the like
  • 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.
  • salts examples include 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,
  • 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.
  • 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.
  • 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.
  • Certain embodiments relate to pharmaceutically acceptable solvates of a compound of general formulas (I), (IV) or (V), or Tables 1, 2, or 5.
  • solvents such as water, methanol, ethanol and acetonitrile to form pharmaceutically acceptable solvates such as the corresponding hydrate, methanolate, ethanolate and acetonitrilate.
  • solvents 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.
  • 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.
  • 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.
  • 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.
  • candidate compounds of general formulas (I), (IV) or (V) to promote PTC readthrough 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.
  • the aminoglycoside is a natural aminoglycoside.
  • the aminoglycoside is an aminoglycoside fraction or component.
  • 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 .
  • a TGA PTC is considered to be more leaky than a TAG PTC, which in turn is more leaky than a TAA PTC.
  • 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.
  • 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.
  • 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.
  • 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.
  • the aminoglycoside is a natural aminoglycoside.
  • the aminoglycoside is an aminoglycoside fraction or component.
  • the aminoglycoside is a synthetic aminoglycoside.
  • the aminoglycoside is G418.
  • the aminoglycoside is gentamicin.
  • the aminoglycoside is X2.
  • the aminoglycoside is Bl .
  • 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.
  • 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.
  • 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.
  • the PTC is a TGA PTC.
  • the PTC is a TAG PTC.
  • the PTC is a TAA PTC.
  • the aminoglycoside is a natural aminoglycoside.
  • the aminoglycoside is an aminoglycoside fraction or component.
  • the aminoglycoside is a synthetic aminoglycoside.
  • the aminoglycoside is G418.
  • the aminoglycoside is gentamicin.
  • the aminoglycoside is X2.
  • the aminoglycoside is Bl .
  • 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.
  • 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 .
  • 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.
  • 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.
  • the aminoglycoside is a natural aminoglycoside.
  • 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.
  • 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.
  • parenteral 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.
  • 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.
  • compositions comprising a compound of general formulas (I), (IV) or (V), or Tables 1, 2, or 5, are formulated for parenteral or oral administration.
  • 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.
  • 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.
  • 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.
  • Solid formulations such as tablets may contain the active ingredient in admixture with pharmaceutically acceptable excipients that are suitable for the manufacture of tablets.
  • 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.
  • 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,
  • 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.
  • a time delay material such as glyceryl monostearate or glyceryl distearate may be employed.
  • 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.
  • Aqueous suspensions may contain active materials in admixture with excipients suitable for the manufacture of aqueous suspensions.
  • 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 sorbitol
  • 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.
  • preservatives for example ethyl, or n-propyl- p-hydroxy benzoate
  • colouring agents for example ethyl, or n-propyl- p-hydroxy benzoate
  • flavouring agents for example sucrose or saccharin.
  • sweetening agents such as sucrose or saccharin.
  • 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.
  • 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.
  • a dispersing or wetting agent exemplified by those already mentioned above.
  • Additional excipients for example sweetening, flavouring and colouring agents, may also be present.
  • 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.
  • 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.
  • the acceptable vehicles and solvents that may be employed are water, Ringer's solution and isotonic sodium chloride solution.
  • sterile, fixed oils are conventionally employed as a solvent or suspending medium.
  • any bland fixed oil may be employed including synthetic mono- or diglycerides.
  • 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.
  • compositions 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.
  • 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).
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • the aminoglycoside is a natural aminoglycoside. In certain embodiments, the aminoglycoside is an aminoglycoside fraction or component.
  • 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 .
  • 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.
  • the disclosure relates to methods of treating a disease or disorder associated with a PTC in a subject.
  • 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.
  • the disease or disorder may be any that is associated with a nonsense mutation or a PTC.
  • 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.
  • 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; ⁇ -thai as semi a); familial erythrocytosis; nephrolithiasis; osteogenesis imperfecta; cirrhosis; neurofibrom
  • 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, embryon
  • 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.
  • 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.
  • Intrahepatic cholestasis familial progressive ABCB4 CAG-TAG
  • Glycogen storage disease 3 AGL CGA-TGA
  • Glycogen storage disease 3 AGL CGA-TGA
  • 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 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
  • AMPDl CAA-TAA Adenosine monophosphate deaminase deficiency AMPDl CAA-TAA
  • Adenomatous polyposis coli APC TAT-TAG Adenomatous polyposis coli APC TAT-TAG
  • Adenomatous polyposis coli APC TTG-TAG Adenomatous polyposis coli APC TTG-TAG
  • Adenomatous polyposis coli APC TAT-TAG Adenomatous polyposis coli APC TAT-TAG
  • Adenomatous polyposis coli APC TTG-TAG Adenomatous polyposis coli APC TTG-TAG

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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):
Figure imgf000006_0001
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:
Figure imgf000007_0001
Figure imgf000007_0002
R6 and R9 are each independently H, OH, F, CI, substituted or unsubstituted lower alkyl,
Figure imgf000007_0003
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):
Figure imgf000008_0001
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:
Figure imgf000008_0002
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:
Figure imgf000009_0001
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 R28" 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 R30" 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 R36" 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 R43" 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 R44" 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 R47" 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 R49" 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 R51'" 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:
Figure imgf000012_0001
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:
Figure imgf000012_0002
wherein: R and R are each independently H, OH, CI, F, unsubstituted lower alkyl, H2,
Figure imgf000013_0001
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:
Figure imgf000013_0002
Figure imgf000014_0001
R111, R113 and R136 are each independently H, substituted or unsubstituted arylalkyl, substituted or unsubstituted lower alkyl, substituted or unsubstituted cycloalkyl or carboxy; R74, R74', R74", R76, R76', R76", R78, R78', R78", R80, R80', R80", R82, R82', R82", 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, R139', and R139" 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
Figure imgf000015_0001
, 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:
Figure imgf000015_0002
R , R , R , R , R", R , R and R are each independently H or unsubstituted lower alkyl; and R74, R74', R74", R76, R76', R76", R82, R82', R82", R84, R84', R84", R86, R86', R86", R93, R93', R93", R95, R95 , R95", R100, R100', R100", R108, R108', R108", R110, R110', R110", R137, R138, R139, R139', and R139" 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):
Figure imgf000017_0001
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:
Figure imgf000017_0002
Figure imgf000018_0001
wherein:
R205 and R208 are each independently H, F, NH2, HC(0)R 2u0y9, N02, N3 or
Figure imgf000018_0002
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;
Figure imgf000018_0003
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
Figure imgf000019_0001
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; «
Figure imgf000019_0002
■
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 C1-6 alkyl; R225, R230, R235, R240, R251, R256, R261, R266, R271 and R303 are each independently H, C(0)OR272, C3-6 cycloalkyl, C6-10 aryl, C6-10 aryl-Ci-6 alkyl, or C1-6 alkyl, wherein C6-10 aryl is optionally substituted with one or more substituents independently selected from C1-6 alkyl; C6-10 aryl of C6-10 aryl-Ci-6 alkyl is optionally substituted with one or more substituents independently selected from halogen; and C1-6 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 C1-6 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 C1-6 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:
Figure imgf000020_0001
and only one of R205, R206, R207 and R2 2m08 is not H, then R .2U055 and
R208 are each independently H, F, H2, HC(0)R209, N3 or
Figure imgf000020_0002
; 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
Figure imgf000020_0003
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
Figure imgf000020_0004
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
Figure imgf000021_0001
and only one of R205, R206, R20 / and Rzm is not H,
then R205 and R208 are each independently H, F, HC(0)R uy, N3 or
Figure imgf000021_0002
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
Figure imgf000021_0003
only one of R205, R206, R207 and R208 is not H, then R , 205
and R are each independently H, F, H2, HC(0)Rz 2u0v9, N3 or
Figure imgf000021_0004
; 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
Figure imgf000021_0005
wherein Z15 is as defined above, or
Figure imgf000022_0001
wherein Z15 is as defined above
Figure imgf000022_0002
, 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
Figure imgf000023_0001
wherein R249 is a halogen, then at least one of R247,
R248 R250 and R251 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
Figure imgf000023_0002
, 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; C6-10 aryl of C6-10 aryl-Ci-6 alkyl is optionally substituted with one or more substituents independently selected from halogen; and C1-6 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 R2U4 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
Figure imgf000024_0001
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
Figure imgf000024_0002
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, R2UU is CI, F, Br, I, or CF3; R2U4 is CF3; and R2U1, R2U2 and R2U3 are each H; and B is:
Figure imgf000024_0003
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, C3-6 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, 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; and R280 and R281 are each independently unsubstituted C1-6 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:
Figure imgf000038_0001
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:
Figure imgf000039_0001
wherein:
Rb and Ry are each independently H, OH, F, H2, HC(0)R10, N02, N3 or
Figure imgf000039_0002
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:
Figure imgf000039_0003
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:
Figure imgf000040_0001
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 is -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):
Figure imgf000042_0001
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:
Figure imgf000043_0001
wherein:
R6 and R9 are each independently H, OH, F, H2, HC(0)R10, N02, N3 or
Figure imgf000043_0002
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):
Figure imgf000044_0001
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:
Figure imgf000044_0002
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:
Figure imgf000045_0001
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:
Figure imgf000045_0002
wherein: R6 and R9 are each independently H, OH, F, H2, HC(0)R10, N02, N3 or
Figure imgf000046_0001
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:
Figure imgf000046_0002
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;
L is -CH2- R24-, -SO2- R24- or - H-C(0)- H-; R24 is H or lower alkyl; B is selected from:
Figure imgf000046_0003
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:
Figure imgf000047_0001
L is - (CH2)n -; n is 1 or 2; and B is:
Figure imgf000047_0002
wherein: Rb and Ry are each independently H, OH, F, H2, HC(0)R1U, N02, N3 or
Figure imgf000048_0001
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;
Figure imgf000048_0002
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:
Figure imgf000048_0003
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:
Figure imgf000048_0004
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 Rl-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:
Figure imgf000050_0001
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:
Figure imgf000051_0001
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
Figure imgf000051_0002
wherein:
R115 and Rm are each independently H, NHC(0)R
Figure imgf000051_0003
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 ;sc
Figure imgf000051_0004
wherein:
R123, R124 and R125 are each independently H or CH3; Zlb 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:
Figure imgf000052_0001
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
Figure imgf000052_0002
wherein:
R115 and R118 are each independently H,
Figure imgf000052_0003
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
Figure imgf000052_0004
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:
Figure imgf000053_0001
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:
Figure imgf000053_0002
wherein: R6 and R9 are each independently H, OH, CI, F, C1-C4 alkyl, H2, HC(0)R10, N02,
N3 or
Figure imgf000054_0001
; 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
Figure imgf000054_0002
[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:
Figure imgf000055_0001
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:
Figure imgf000056_0001
L is - (CH2)n -; n is 1 or 2; and B is:
Figure imgf000056_0002
wherein:
R and R are each independently H, OH, F, NH2, NHC(0)R286, N02, N3 or
Figure imgf000056_0003
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;
Figure imgf000056_0004
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:
Figure imgf000057_0001
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:
Figure imgf000057_0002
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:
Figure imgf000058_0001
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:
Figure imgf000059_0001
L is - (CH2)n -; n is 1 or 2; and B is:
Figure imgf000059_0002
wherein:
R6 and R9 are each independently H, OH, F, CI, substituted or unsubstituted lower alkyl, H2, HC(0)R10, N02, N3
Figure imgf000059_0003
;
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:
Figure imgf000060_0001
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:
Figure imgf000060_0002
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:
Figure imgf000060_0003
Figure imgf000061_0001
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 R28" 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 R30" 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 R36" 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 R43" 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 R44" 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 R47" 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 R49" 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 R51'" 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-.
[00111] In certain embodiments, compounds of general formula I comprise compounds of general formula IV (Formula IV), and salts thereof:
Figure imgf000064_0001
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:
Figure imgf000064_0002
wherein: CI, F, unsubstituted lower alkyl, NH2,
Figure imgf000064_0003
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:
Figure imgf000065_0001
Figure imgf000066_0001
R111, R113 and R136 are each independently H, substituted or unsubstituted arylalkyl, substituted or unsubstituted lower alkyl, substituted or unsubstituted cycloalkyl or carboxy; R74, R74', R74", R76, R76', R76", R78, R78', R78", R80, R80', R80", R82, R82', R82", 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, R139', and R139" 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
Figure imgf000070_0001
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)-;
Figure imgf000070_0002
R , R , R , R and R are each independently H or substituted or unsubstituted lower alkyl; and R74, R74', R74", R76, R76', R76", R82, R82', R82", R84, R84', R84", R86, R86', 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, R139', 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, 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 R139" are each independently H or unsubstituted lower alkyl; or halogen; or Ci-5 alkyl; or Ci-4 alkyl; or Ci-3 alkyl; or C1-2 alkyl; or CH3; or H. certain embodiments, in compounds of general formula IV, B2 is
Figure imgf000072_0001
, 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)-;
Figure imgf000072_0002
136 are each independently H or substituted or unsubstituted lower alkyl; and R74, R74 , R74", π76 π76' π76" π84 π84' π 84" π 86 π86' π86" π93 π93' π93" π95 π95' π95" π 100 π 100'
R100", R108, R108', R108", R110, R110', R110", R137, R138, R139, R139', and R139" 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, R74', R74", R76, R76', R76", R84, R84', R84", R86, R86', R86", 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 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 C¾; or H.
[00150] In certain embodiments, in compounds of general formula IV, B is
Figure imgf000073_0001
, 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:
Figure imgf000074_0001
or , wherein R73 and R75 are each independently H or substituted or unsubstituted lower alkyl; and R74, R74', R74", R76, R76', and R76" 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 C1-6 alkyl; R144 is C1-6 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 C1-6 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 C1-6 alkyl; R144 is C1-6 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 C1-6 alkyl. In certain embodiments, in compounds of general formula IV, R73 and R75 are each independently unsubstituted lower alkyl; or unsubstituted C1-5 alkyl; or unsubstituted C1-4 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', R74 ", R76, R76', and R76" are each independently H or unsubstituted lower alkyl; or halogen; or C1-5 alkyl; or C1-4 alkyl; or Ci-3 alkyl; or Ci-2 alkyl; or CH3; or H. certain embodiments, in compounds of general formula IV, B2 is
Figure imgf000075_0001
, 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
Figure imgf000075_0002
, 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
Figure imgf000075_0003
, 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
Figure imgf000076_0001
, 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
Figure imgf000076_0002
, 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
Figure imgf000077_0001
, 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
Figure imgf000077_0002
, 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
Figure imgf000077_0003
, 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
Figure imgf000078_0001
, wherein RM is HC(0)Rby; Rbb, Rb ' and RbS are each H; Rby 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 C1-4 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:
Figure imgf000078_0002
R , R , R , R", R , R and R13b are each independently H or substituted or unsubstituted lower alkyl; and R74, R74', R74", R76, R76', R76", R82, R82', R82", R84, R84', R84", R86, R86', R86", 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, 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 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, R74', R74", R76, R76', R76", R82, R82', R82", 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
R110', R110", 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. 00161] In certain embodiments, in compounds of general formula IV, B2 is:
Figure imgf000079_0001
Figure imgf000080_0001
and R136 are each independently H or substituted or unsubstituted lower alkyl; and R74, R74', R74", 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
R108', R108", R110, R110', R110", R137, R138, R139, R139', and R139" 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, 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, 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, R108', R108", R110, R110', R110", 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. 00162] In certain embodiments, in compounds of general formula IV, B2 is:
Figure imgf000081_0001
or unsubstituted lower alkyl; and R74, R74', R74", R76, R76', R76", 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, 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, R74', R74", R76, R76', R76 ", R108, R108', R108 ", R110, R110', and R110" are each independently H or unsubstituted lower alkyl; or halogen; or Ci-5 alkyl; or C1-4 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:
Figure imgf000082_0001
, wherein R and R are each independently H or substituted or unsubstituted lower alkyl; and R84, R84', R84", R86, R86', and R86" 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, 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 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, 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 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 , R84", R86, R86 , and R86" 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:
Figure imgf000083_0001
, 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 R84" are H and R84, R84 , and R84" are each independently H, CI, F, Br or I.
[00165] In certain embodiments, in compounds of general formula IV, B2 is:
Figure imgf000084_0001
, wherein R' is H or substituted or unsubstituted lower alkyl; and R86, R86 , and R86" 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 C1-6 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 C1-6 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 C1-6 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 C1-6 alkyl. In certain embodiments, in compounds of general formula IV, R85 is unsubstituted lower alkyl; or unsubstituted C1-5 alkyl; or unsubstituted C1-4 alkyl; or unsubstituted C1-3 alkyl; or unsubstituted Ci-2 alkyl; or CH3; or H. In certain embodiments, in compounds of general formula IV, R86, R86 , and R86" are each independently H or unsubstituted lower alkyl; or halogen; or C1-5 alkyl; or C1-4 alkyl; or C1-3 alkyl; or Ci-2 alkyl; or CH3; or H. In certain embodiments, one of R86, R86 , and R86" is H and R86, R86 , and R86 "are each independently H, CI, F, Br, I, or unsubstituted Ci-6 alkyl. In certain embodiments, one of R86, R86', and R86" is H and R86, R86 , and R86" are each independently H or unsubstituted C1-6 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 C1-6 alkyl. In certain embodiments, two of R86, R86 , and R86" are H and R86, R86 , and R86" are each independently H or unsubstituted C1-6 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:
Figure imgf000085_0001
, 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 C1-6 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 C1-6 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 C1-6 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 C1-6 alkyl. In certain embodiments, in compounds of general formula IV, R81 is unsubstituted lower alkyl; or unsubstituted C1-5 alkyl; or unsubstituted C1-4 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 C1-5 alkyl; or C1-4 alkyl; or Ci-3 alkyl; or Ci-2 alkyl; or CH3; or H. In certain embodiments, one of R82, R82', and R82" is H and R82, R82 , and R82" are each independently H, CI, F, Br, I, or unsubstituted C1-6 alkyl. In certain embodiments, one of R82, R82 , and R82" is H and R82, R82 , and R82" are each independently H or unsubstituted C1-6 alkyl. In certain embodiments, one of R82, R82', and R82" is H and R82, R82', and R82" are each independently H, CI, F, Br or I. In certain embodiments, two of R82, R82', and R82" are H and R82, R82', and R82" are each independently H, CI, F, Br, I, or unsubstituted C1-6 alkyl. In certain embodiments, two of R82, R82 , and R82" are H and R82, R82 , and R82" are each independently H or unsubstituted C1-6 alkyl. In certain embodiments, two of R82, R82 , and R82" are H and R82, R82 , and R82" are each independently H, CI, F, Br or I.
[00167] In certain embodiments, in compounds of general formula IV, B2 is:
Figure imgf000086_0001
unsubstituted lower alkyl; and R93, R93', R93", R95, R95 , R95", R100, R100', R100", R137, R138, R139, R139', and R139" 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, 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 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, R93', R93 ", 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. 00168] In certain embodiments, in compounds of general formula IV, B2 is:
Figure imgf000087_0001
, wherein R , R and R136 are each independently H or substituted or unsubstituted lower alkyl; and R95, R95 , R95",
R100, R100', R100", R137, R138, R139, R139', and R139" 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, 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, 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)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:
Figure imgf000088_0001
, 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, 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, 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, C3-6 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 C1-5 alkyl; or unsubstituted C1-4 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', and R100" are each independently H or unsubstituted lower alkyl; or halogen; or Ci-5 alkyl; or C1-4 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:
Figure imgf000089_0001
, 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, 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 C1-6 alkyl; R144 is C1-6 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, 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 C1-6 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 C1-6 alkyl. In certain embodiments, in compounds of general formula IV, R94 is unsubstituted lower alkyl; or unsubstituted C1-5 alkyl; or unsubstituted C1-4 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 C1-5 alkyl; or C1-4 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 C1-6 alkyl. In certain embodiments, one of R95, R95 , and R95 is H and R95, R95 , and R95 are each independently H or unsubstituted C1-6 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 C1-6 alkyl. In certain embodiments, two of R95, R95 , and R95 are H and R95, R95 , and R95 are each independently H or unsubstituted C1-6 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:
Figure imgf000090_0001
, wherein R99 is H or substituted or unsubstituted lower alkyl; and R100,
R100 , and R100" 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, 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 C1-6 alkyl; R144 is C1-6 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, 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 C1-6 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 C1-6 alkyl. In certain embodiments, in compounds of general formula IV, R99 is unsubstituted lower alkyl; or unsubstituted C1-5 alkyl; or unsubstituted C1-4 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 C1-5 alkyl; or C1-4 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 C1-6 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:
Figure imgf000091_0001
, 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, 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 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, 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, R136 is unsubstituted lower alkyl; or unsubstituted C1-5 alkyl; or unsubstituted C1-4 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 C1-5 alkyl; or C1-4 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 C1-6 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 C1-6 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 C1-6 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 C1-6 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 C1-6 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:
Figure imgf000093_0001
, wherein R93, R93', and R93" are each independently H, halogen or unsubstituted lower alkyl. In certain embodiments, in compounds of general formula IV, R93, R93 , and R93" are each independently H or unsubstituted lower alkyl; or halogen; or C1-5 alkyl; or C1-4 alkyl; or Ci-3 alkyl; or Ci-2 alkyl; or CH3; or H. In certain embodiments, one of R93, R93 , and R93" is H and R93, R93', and R93" are each independently H, CI, F, Br, I, or unsubstituted C1-6 alkyl. In certain embodiments, one of R93, R93 , and R93" is H and R93, R93 , and R93" are each independently H or unsubstituted Ci-6 alkyl. In certain embodiments, one of R93, R93 , and R93" is H and R93, R93 , and R93" are each independently H, CI, F, Br or I. In certain embodiments, two of R93, R93 , and R93" are H and R93, R93 , and R93" are each independently H, CI, F, Br, I, or unsubstituted Ci-6 alkyl. In certain embodiments, two of R93, R93 , and R93" are H and R93, R93 , and R93" are each independently H or unsubstituted Ci-6 alkyl. In certain embodiments, two of R93, R93 , and R93" are H and R93, R93 , and R93" are each independently H, CI, F, Br or I. 00174] In certain embodiments, in compounds of general formula IV, B2 is:
Figure imgf000093_0002
, wherein R and R are each independently H or substituted or unsubstituted lower alkyl; and R74, R74', R74 ", R76, R76', and R76" 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, 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, 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 C1-6 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 C1-6 alkyl. In certain embodiments, in compounds of general formula IV, R73 and R75 are each independently unsubstituted lower alkyl; or unsubstituted C1-5 alkyl; or unsubstituted C1-4 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 , R74 ", R76, R76', and R76" are each independently H or unsubstituted lower alkyl; or halogen; or C1-5 alkyl; or C1-4 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:
Figure imgf000094_0001
, wherein R is H or substituted or unsubstituted lower alkyl; and R , R74', and R74" 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, 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 C1-6 alkyl; R144 is C1-6 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, C3-6 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 C1-6 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 C1-6 alkyl. In certain embodiments, in compounds of general formula IV, R73 is unsubstituted lower alkyl; or unsubstituted C1-5 alkyl; or unsubstituted C1-4 alkyl; or unsubstituted C1-3 alkyl; or unsubstituted Ci-2 alkyl; or CH3; or H. In certain embodiments, in compounds of general formula IV, R74, R74 , and R74" are each independently H or unsubstituted lower alkyl; or halogen; or C1-5 alkyl; or C1-4 alkyl; or C1-3 alkyl; or Ci-2 alkyl; or CH3; or H. In certain embodiments, one of R74, R74 , and R74" is H and R74, R74 , and R74" are each independently H, CI, F, Br, I, or unsubstituted C1-6 alkyl. In certain embodiments, one of R74, R74 , and R74" is H and R74, R74 , and R74" are each independently H or unsubstituted C1-6 alkyl. In certain embodiments, one of R74, R74 , and R74" is H and R74, R74 , and R74" are each independently H, CI, F, Br or I. In certain embodiments, two of R74, R74 , and R74" are H and R74, R74 , and R74" are each independently H, CI, F, Br, I, or unsubstituted C1-6 alkyl. In certain embodiments, two of R74, R74 , and R74" are H and R74, R74 , and R74" are each independently H or unsubstituted C1-6 alkyl. In certain embodiments, two of R74, R74 , and R74" are H and R74, R74 , and R74" are each independently H, CI, F, Br or I. 00176] In certain embodiments, in compounds of general formula IV, B2 is:
Figure imgf000095_0001
, wherein R is H or substituted or unsubstituted lower alkyl; and R ,
R76 , and R76" 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, C3-6 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 C1-6 alkyl; R144 is C1-6 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, C3-6 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:
Figure imgf000096_0001
, wherein R1U ' and Rluy 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, 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 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, C3-6 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 C1-6 alkyl; R144 is C1-6 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 C1-5 alkyl; or unsubstituted C1-4 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 C1-5 alkyl; or C1-4 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:
Figure imgf000097_0001
, 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, C3-6 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 C1-6 alkyl; R144 is C1-6 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, C3-6 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:
Figure imgf000098_0001
, 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, 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 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 R110" 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, R110', and R110" is H and R110, R110', and R110" are each independently H, CI, F, Br, I, or unsubstituted Ci-6 alkyl. In certain embodiments, one of R110, R110', and R110" is H and R110, R110', and R110" are each independently H or unsubstituted Ci-6 alkyl. In certain embodiments, one of R110, R110', and R110" is H and R110, R110', and R110" are each independently H, CI, F, Br or I. In certain embodiments, two of R110, R110 , and R110" are H and R110, R110 , and R110" are each independently H, CI, F, Br, I, or unsubstituted Ci-6 alkyl. In certain embodiments, two of R110, R110', and R110" are H and R110, R110', and R110" are each independently H or unsubstituted Ci-6 alkyl. In certain embodiments, two of R110, R110', and R110" are H and R110, R110 , and R110" 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:
Figure imgf000100_0001
wherein:
R-xro R2oi^ R2(K R2(B 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; 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:
Figure imgf000100_0002
Figure imgf000101_0001
wherein:
R205 and R208 are each independently H, F, NH2, HC(0)R 2u0y9, N02, N3 or
Figure imgf000101_0002
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;
Figure imgf000101_0003
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
Figure imgf000102_0001
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; "
Figure imgf000102_0002
■
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, C6-10 aryl, C6-10 aryl-Ci-6 alkyl, or C1-6 alkyl, wherein C6-10 aryl is optionally substituted with one or more substituents independently selected from C1-6 alkyl; C6-10 aryl of C6-10 aryl-Ci-6 alkyl is optionally substituted with one or more substituents independently selected from halogen; and C1-6 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, 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 C1-6 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
Figure imgf000103_0001
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
Figure imgf000103_0002
; 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
Figure imgf000103_0003
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
Figure imgf000103_0004
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
Figure imgf000104_0001
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
Figure imgf000104_0002
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
Figure imgf000104_0003
; 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 R U4 are not H and each is a
halogen, and B is
Figure imgf000104_0004
Z15 is as defined above, or
Figure imgf000105_0001
, then at least one of: R236, R237, R238, R239 and
R240 or R241 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
Figure imgf000105_0002
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 R2UU, R2U1, R2U2, R2U3, and R2U4 are not H and each is a
halogen, and B is
Figure imgf000106_0001
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
Figure imgf000106_0002
, 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:
Figure imgf000110_0001
anywhere herein.
[00218] In certain embodiments, in compounds of general formula V, B is:
Figure imgf000111_0001
[00219] In certain embodiments, in compounds of general formula V, B is:
Figure imgf000111_0002
are as defined anywhere herein.
[00220] In certain embodiments, in compounds of general formula V, B is:
Figure imgf000112_0001
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:
Figure imgf000112_0002
, 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:
Figure imgf000112_0003
, 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 C1-4 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 C1-4 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 C1-6 alkyl; or CI, F, Br, or I; or Ci-5 alkyl; or C1-4 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 C1-6 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 C1-6 alkyl. In certain embodiments, two of R237, R238, and R239 are H and R237, R238, and R239 are each independently H or unsubstituted C1-6 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 C1-6 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, 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:
Figure imgf000113_0001
, 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:
Figure imgf000114_0001
, 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 C1-4 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 C1-4 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 C1-6 alkyl; or CI, F, Br, or I; or C1-5 alkyl; or C1-4 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 C1-6 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 C1-6 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 C1-6 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:
Figure imgf000115_0001
, 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, 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, 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:
Figure imgf000116_0001
, 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:
Figure imgf000117_0001
, 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 C1-4 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 C1-6 alkyl; or CI, F, Br, or I; or C1-5 alkyl; or C1-4 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 C1-6 alkyl. In certain embodiments, one of R232, R233, and R234 is H and R232, R233, and R234 are each independently H or unsubstituted C1-6 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 C1-6 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 C1-6 alkyl or C1-6 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 C1-6 alkyl; R279 is C1-6 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 C1-6 alkyl. In certain embodiments, R235 is unsubstituted C1-6 alkyl; or unsubstituted C1-5 alkyl; unsubstituted C1-4 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:
Figure imgf000118_0001
, 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 C1-4 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 C1-4 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 C1-6 alkyl; or CI, F, Br, or I; or Ci-5 alkyl; or C1-4 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 C1-6 alkyl. In certain embodiments, one of R253, R254, and R255 is H and R253, R254, and R255 are each independently H or unsubstituted C1-6 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 C1-6 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 C1-6 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, R256 is unsubstituted C1-6 alkyl; or unsubstituted C1-5 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:
Figure imgf000119_0001
, 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, 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, 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:
Figure imgf000120_0001
, 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, 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, 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:
Figure imgf000121_0001
, 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 C1-4 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 C1-4 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, 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 NR. R and OH; and R and R are each independently unsubstituted C1-6 alkyl. In certain embodiments, R303 is unsubstituted Ci-6 alkyl; or unsubstituted C1-5 alkyl; unsubstituted C1-4 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:
Figure imgf000123_0001
, 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 C1-4 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 C1-4 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 C1-6 alkyl; or CI, F, Br, or I; or C1-5 alkyl; or C1-4 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 C1-6 alkyl. In certain embodiments, one of R222, R223, and R224 is H and R222, R223, and R224 are each independently H or unsubstituted C1-6 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 C1-6 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 C1-6 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, NH2, NR274R275, NHC(0)OR278, Ci-6 alkoxy, CN, C(0)NHR279 and CONH2; wherein R273, R274, R275, and R278 are each independently unsubstituted C1-6 alkyl; R is C1-6 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 C1-6 alkyl. In certain embodiments, R225 is unsubstituted C1-6 alkyl; or unsubstituted C1-5 alkyl; unsubstituted C1-4 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:
Figure imgf000124_0001
, 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 C1-4 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 C1-4 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 C1-6 alkyl; or CI, F, Br, or I; or Ci-5 alkyl; or C1-4 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 C1-6 alkyl. In certain embodiments, one of R227, R228, and R229 is H and R227, R228, and R229 are each independently H or unsubstituted C1-6 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 C1-6 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 C1-6 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, R230 is unsubstituted C1-6 alkyl; or unsubstituted C1-5 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
Figure imgf000125_0001
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
Figure imgf000125_0002
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:
Figure imgf000125_0003
, 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, C3-6 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 C1-6 alkyl; C6-10 aryl of C6-10 aryl-Ci-6 alkyl is optionally substituted with one or more substituents independently selected from halogen; and C1-6 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 C1-6 alkyl; R279 is C1-6 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 C1-6 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 :
Figure imgf000127_0001
Figure imgf000128_0001

Figure imgf000129_0001
Figure imgf000130_0001

Figure imgf000131_0001
130
Figure imgf000132_0001
Figure imgf000133_0001
Figure imgf000134_0001
Figure imgf000135_0001
Figure imgf000136_0001
Figure imgf000137_0001
-CI CI I
if " ? " :' V ,'·' Μ·: : | ■' I i; ?
-' ■ ■ - ? i i ■ " ) ■ :■ "X■ '- - ■■ H - \ CH
0'
323
322 324
Figure imgf000138_0001
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, C1-4) alkyl, substituted lower alkyl, lower (for example, C1-4) 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
Figure imgf000150_0001
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 recessive ABCC6 CGA-TGA
Pseudoxanthoma elasticum, autosomal dominant 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
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 CAG-TAG
Adrenoleukodystrophy ABCD1 TGG-TGA
Adrenoleukodystrophy ABCD1 CAA-TAA
Adrenoleukodystrophy ABCD1 CAG-TAG
Adrenoleukodystrophy ABCD1 TAC-TAA
Adrenoleukodystrophy ABCD1 TGG-TGA
Adrenoleukodystrophy ABCD1 TGG-TGA
Sitosterolaemia ABCG5 CAG-TAG
Sitosterolaemia ABCG8 TCA-TGA
Chanarin-Dorfman syndrome ABHD5 CGA-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
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 CAG-TAG
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 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 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 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 CGA-TGA
Spherocytosis ANK1 GAG-TAG
Spherocytosis ANK1 CGA-TGA
Spherocytosis ANK1 TCG-TAG
Spherocytosis ANK1 GAA-TAA
Spherocytosis ANK1 CAG-TAG
Spherocytosis ANK1 CAG-TAG
Spherocytosis ANK1 TAC-TAG
Spherocytosis ANK1 CGA-TGA
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 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 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 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
Hypertriglyceridaemia APOA5 CAG-TAG
Hypobetalipoproteinaemia APOB TGG-TGA
Hypobetalipoproteinaemia APOB CAG-TAG
Hypobetalipoproteinaemia APOB TAT-TAA
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 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 GAG-TAG
Androgen insensitivity syndrome AR CAG-TAG
Androgen insensitivity syndrome AR CAG-TAG
Androgen insensitivity syndrome AR CAG-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
Lissencephaly, X-linked, with abnormal genitalia ARX GAG-TAG
Argininosuccinate lyase deficiency ASL CGA-TGA
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 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 TCA-TAA
Ataxia telangiectasia ATM TGG-TAG
Ataxia telangiectasia ATM CGA-TGA
Ataxia telangiectasia ATM CGA-TGA
Ataxia telangiectasia ATM CGA-TGA
Ataxia telangiectasia ATM CAA-TAA
Ataxia telangiectasia ATM CAA-TAA
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 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 GAA-TAA
Menkes syndrome ATP7A TCA-TAA
Menkes syndrome ATP7A GAA-TAA
Menkes syndrome ATP7A CGA-TGA
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, familial progressive ATP8B1 CGA-TGA
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 TGC-TGA
Diabetes insipidus, neurohypophyseal AVP GAG-TAG
Diabetes insipidus, central AVP GAG-TAG
Diabetes insipidus, nephrogenic AVPR2 CAG-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
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 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
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 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 AAA-TAA
Agammaglobulinaemia BTK CAG-TAG
Agammaglobulinaemia BTK CAG-TAG
Agammaglobulinaemia BTK GAG-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
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
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 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 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
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 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 CAG-TAG
CHARGE syndrome CHD7 CAA-TAA
CHARGE syndrome CHD7 CAG-TAG
CHARGE syndrome CHD7 CAG-TAG
CHARGE syndrome CHD7 GAA-TAA
CHARGE syndrome CHD7 CGA-TGA
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 CGA-TGA
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 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
Dent disease CLCN5 CGA-TGA
Low molecular weight proteinuria CLCN5 CGA-TGA
Dent disease 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 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 TGG-TGA
Achromatopsia CNGB3 CGA-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 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 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 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
Ullrich congenital muscular dystrophy COL6A3 CGA-TGA
Epidermolysis bullosa COL7A1 CGA-TGA
Epidermolysis bullosa COL7A1 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 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
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
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 CAG-TAG
3-M syndrome CUL7 CGA-TGA
3-M syndrome CUL7 CGA-TGA
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 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 TGG-TAG
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
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 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
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
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 CAG-TAG
Muscular dystrophy, Duchenne DMD TCA-TAA
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 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 CAG-TAG
Muscular dystrophy, Duchenne DMD CAA-TAA
Muscular dystrophy, Duchenne DMD CAA-TAA
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 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 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 GAA-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, Duchenne DMD CGA-TGA
Muscular dystrophy, Duchenne DMD CGA-TGA
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 CGA- TGA
Primary ciliary dyskinesia DNAH5 CAG- TAG
Primary ciliary dyskinesia DNAH5 CGA- TGA
Primary ciliary dyskinesia DNAH5 CGA- TGA
Primary ciliary dyskinesia DNAH5 CGA- TGA
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
Immunodeficiency, centromeric instability and D MT3B CAG- TAG 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 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- TAG
Muscular dystrophy, limb girdle DYSF TAC- TAA
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
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 CAG-TAG
Haemorrhagic telangiectasia 1 ENG CAG-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
Branchio-oto-renal syndrome EYA1 TAT-TAA
Branchio-oto-renal syndrome EYA1 TAT-TAA
Factor XI deficiency Fll CAA-TAA
Factor XI deficiency Fll TGG-TAG
Factor XI deficiency Fll TGG-TAG
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 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 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 TGC-TGA
Factor VII deficiency F7 CAG-TAG
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 AAA-TAA
Haemophilia A F8 AAA-TAA
Haemophilia A F8 TGG-TGA
Haemophilia A F8 TGG-TGA
Haemophilia A F8 CAA-TAA
Haemophilia A F8 TCA-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 TGG-TGA
Haemophilia A F8 CAA-TAA
Haemophilia A F8 CGA-TGA
Haemophilia A F8 CGA-TGA
Haemophilia A F8 TGG-TAG
Haemophilia A F8 TAC-TAA
Haemophilia A F8 CGA-TGA
Haemophilia A F8 CGA-TGA
Haemophilia A F8 TGG-TGA
Haemophilia A F8 TAC-TAA
Haemophilia A F8 GAG-TAG
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 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 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 CGA-TGA
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 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 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 FANCA CAG-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 CGA-TGA
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 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 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 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 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 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
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 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
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 CAG-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 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 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 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 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 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 CGA-TGA
Hyperglycinaemia, non-ketotic GLDC GAG-TAG
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 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 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 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 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
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 CAG-TAG
Diabetes, MODY3 HNF1A CGA-TGA
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
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
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 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 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
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 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 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 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 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 CAG-TAG
Alagille syndrome JAG1 TCG-TAG
Alagille syndrome JAG1 CAG-TAG
Alagille syndrome JAG1 TGG-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 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 CAG-TAG
Cone dystrophy with supernormal rod ERG KCNV2 GAG-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 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
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
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 CGA-TGA
Epidermolysis bullosa, Herlitz LAMB3 CGA-TGA
Epidermolysis bullosa, Herlitz LAMB3 CAG-TAG
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 TGG-TGA
Hypercholesterolaemia LDLR TGG-TGA
Hypercholesterolaemia LDLR CAG-TAG
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 TGC-TGA
Hypercholesterolaemia LDLR AAG-TAG
Hypercholesterolaemia LDLR TGC-TGA
Hypercholesterolaemia LDLR TGC-TGA
Hypercholesterolaemia LDLR TGG-TGA
Hypercholesterolaemia LDLR GAG-TAG
Hypercholesterolaemia LDLR TGC-TGA
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
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 CGA-TGA
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 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 GAG-TAG
Multiple endocrine neoplasia 1 MEN1 CAG-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 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 CAG-TAG
Multiple endocrine neoplasia 1 MEN1 TAC-TAG
Multiple endocrine neoplasia 1 MEN1 CAG-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
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, 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 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
Methylenetetrahydrofolate reductase deficiency MTHFR CGA-TGA
Homocystinuria MTHFR TGG-TAG
Myotubular myopathy MTM1 CGA-TGA
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 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 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 GAA-TAA
Methylmalonic aciduria MUT CAG-TAG
Methylmalonic aciduria MUT GGA-TGA
Methylmalonic aciduria MUT CGA-TGA
Methylmalonic aciduria MUT CGA-TGA
Methylmalonic aciduria MUT CGA-TGA
Methylmalonic aciduria MUT CGA-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
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 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 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 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 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 CAG-TAG
Neurofibromatosis 2 NF2 CAG-TAG
Neurofibromatosis 2 NF2 CAG-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, steroid resistant NPHS2 CGA-TGA
Nephrotic syndrome NPHS2 GAG-TAG
Acromesomelic dysplasia, Maroteaux type NPR2 CAG-TAG
Acromesomelic dysplasia, Maroteaux type NPR2 CAG-TAG
Acromesomelic dysplasia, Maroteaux type NPR2 CGA-TGA
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 CAG-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 TGG-TGA
Adrenal hypoplasia NR0B1 TAC-TAA
Adrenal hypoplasia NR0B1 TGG-TAG
Adrenal hypoplasia NR0B1 TGG-TAG
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 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
Sotos syndrome NSD1 CGA-TGA
Sotos syndrome NSD1 CGA-TGA
Sotos syndrome NSD1 CGA-TGA
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 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 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 CAA-TAA
Lowe oculocerebrorenal syndrome OCRL TAC-TAG
Lowe oculocerebrorenal syndrome OCRL CGA-TGA
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 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
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 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 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 CAA-TAA
Aniridia PAX6 TGC-TGA
Aniridia PAX6 GAG-TAG
Aniridia PAX6 TGG-TGA
Aniridia PAX6 CAA-TAA
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 CGA-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 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 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
Prolidase deficiency PEPD CGA-TGA
Zellweger syndrome PEX1 CGA-TGA
Peroxisome biogenesis disorder 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 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
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 CAG-TAG
Polycystic kidney disease 1 PKD1 GAG-TAG
Polycystic kidney disease 1 PKD1 CAG-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 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 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 CAG-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 CAG-TAG
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 CGA-TGA
Polycystic kidney disease 2 PKD2 CGA-TGA
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
Xeroderma pigmentosum, variant POLH CAA-TAA
Obesity POMC GAG-TAG
Walker-Warburg syndrome POMT1 CAG-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 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 CAA-TAA
Porphyria, variegate PPOX TGG-TGA
Porphyria, variegate PPOX TTA-TGA
Porphyria, variegate PPOX TGG-TAG
Porphyria, variegate PPOX TGG-TGA
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 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
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
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 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 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 AAA-TAA
Retinoblastoma RBI CAG-TAG
Retinoblastoma RBI TAC-TAA
Retinoblastoma RBI GAA-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 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 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 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 CGA-TGA
Coffin-Lowry syndrome RPS6KA3 CGA-TGA
Coffin-Lowry syndrome RPS6KA3 TGG-TAG
Coffin-Lowry syndrome RPS6KA3 CGA-TGA
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
Platelet disorder, familial RUNX1 CGA-TGA
Cleidocranial dysplasia RUNX2 CAA-TAA
Cleidocranial dysplasia RUNX2 CAG-TAG
Cleidocranial dysplasia RUNX2 CAG-TAG
Cleidocranial dysplasia RUNX2 CAG-TAG
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
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 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 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 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
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 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 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
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
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
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
Netherton syndrome SPINK5 CGA-TGA
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
Peutz-Jeghers syndrome STK11 CAG-TAG
Microphthalmia STRA6 CAG-TAG
Haemophagocytic lymphohistiocytosis, familial STX11 CAG-TAG
Glutaric aciduria 3 SUGCT CGA-TGA
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
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 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
Holt-Oram syndrome TBX5 CAG-TAG
Osteopetrosis, autosomal recessive TCIRG1 CAG-TAG
Osteopetrosis, autosomal recessive TCIRG1 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 CGA-TGA
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 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 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 CAG-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 CGA-TGA
Usher syndrome 2a USH2A CAG-TAG
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 CGA-TGA
Von Hippel-Lindau syndrome VHL CAG-TAG
Von Hippel-Lindau syndrome VHL TTA-TAA
Von Hippel-Lindau syndrome VHL TCG-TAG
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 CGA-TGA
Chorea-acanthocytosis VPS13A GAA-TAA
Chorea-acanthocytosis VPS13A GAA-TAA
Chorea-acanthocytosis VPS13A TCA-TGA
Chorea-acanthocytosis VPS13A TCA-TGA
Chorea-acanthocytosis VPS13A TCA-TGA
Chorea-acanthocytosis VPS13A CGA-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 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 CGA-TGA
Von Willebrand disease 3 VWF CAG-TAG
Von Willebrand disease 3 VWF GAG-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 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 CAA-TAA
Wiskott-Aldrich syndrome WAS GAG-TAG
Wiskott-Aldrich syndrome WAS GAG-TAG
Wiskott-Aldrich syndrome WAS CAG-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
Wiskott-Aldrich syndrome WAS CAG-TAG
Wolfram syndrome WFS1 TAC-TAG
Wolfram syndrome WFS1 TGG-TGA
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 TAC-TAG
Wolfram syndrome WFS1 CAG-TAG
Wolfram syndrome WFS1 TAC-TAA
Wolfram syndrome WFS1 CAG-TAG
Wolfram syndrome WFS1 CAG-TAG
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 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
Xeroderma pigmentosum (C) XPC CGA-TGA
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 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
Figure imgf000207_0001
[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:
Figure imgf000211_0001
[00295] In certain embodiments, the PTC readthrough compound has the following chemical formula:
Figure imgf000211_0002
[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
Figure imgf000214_0001
, 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
Figure imgf000215_0001
Figure imgf000215_0002
31
Figure imgf000215_0003
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
Figure imgf000215_0004
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
Figure imgf000216_0001
49 R14=R15=H
51 R14/R15=-(CH2)4-
52 R14/R15=-(CH2)6- 57 R15=Ph, R15=H
Figure imgf000216_0002
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
Figure imgf000233_0001
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
Figure imgf000235_0001
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
Figure imgf000237_0001
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
Figure imgf000239_0001
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
Figure imgf000240_0001
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
Figure imgf000241_0001
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
Figure imgf000242_0001
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
Figure imgf000242_0002
(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
Figure imgf000243_0001
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
Figure imgf000244_0001
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
Figure imgf000245_0001
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
Figure imgf000246_0001
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
Figure imgf000247_0001
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
Figure imgf000247_0002
Figure imgf000248_0001
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
Figure imgf000250_0001
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
Figure imgf000251_0001
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
Figure imgf000252_0001
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
Figure imgf000252_0002
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.
Figure imgf000253_0001
Figure imgf000253_0002
Figure imgf000253_0003
Figure imgf000253_0004
Figure imgf000254_0001
Figure imgf000254_0002
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.
Figure imgf000258_0001
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.
Figure imgf000259_0001
221 222
Figure imgf000259_0002
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.
Figure imgf000260_0001
224-i 224
Figure imgf000260_0002
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.
Figure imgf000262_0001
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
Figure imgf000263_0001
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
Figure imgf000264_0001
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
Figure imgf000265_0001
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
Figure imgf000267_0001
-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
Figure imgf000267_0002
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
Figure imgf000268_0001
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
Figure imgf000269_0001
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
Figure imgf000269_0002
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
Figure imgf000270_0001
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
Figure imgf000271_0001
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
Figure imgf000272_0001
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
Figure imgf000276_0001
Figure imgf000277_0001
Figure imgf000278_0001
Figure imgf000279_0001
Figure imgf000280_0001
Figure imgf000281_0001
Figure imgf000282_0001
Figure imgf000283_0001
Figure imgf000284_0001
Figure imgf000285_0001
Figure imgf000286_0001
Figure imgf000287_0001
Figure imgf000288_0001
Figure imgf000289_0001
Figure imgf000290_0001
Figure imgf000291_0001
Figure imgf000292_0001
Figure imgf000293_0001
Figure imgf000294_0001
Figure imgf000295_0001
Figure imgf000296_0001
Figure imgf000297_0001
Figure imgf000298_0001
Figure imgf000299_0001
Figure imgf000300_0001
Figure imgf000301_0001
Figure imgf000302_0001
Figure imgf000303_0001
Figure imgf000304_0001
Figure imgf000305_0001
Figure imgf000306_0001
Figure imgf000307_0001
Figure imgf000308_0001
Figure imgf000309_0001
* : 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):
Figure imgf000315_0001
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:
Figure imgf000315_0002
L is - (CH2)„ -; n is 1 or 2; and
B is:
Figure imgf000316_0001
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):
Figure imgf000317_0001
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:
Figure imgf000318_0001
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:
Figure imgf000318_0002
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 R28" 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 R30" 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 R36" 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 R43" 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 R44" 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, R47' and R47" 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 R49" 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 R51'" 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:
Figure imgf000322_0001
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
Figure imgf000323_0001
wherein:
R and R are each independently H, OH, CI, F, unsubstituted lower alkyl, H2,
Figure imgf000323_0002
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-
Figure imgf000324_0001
Figure imgf000324_0002
323
Figure imgf000325_0001
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, R139', and R139" 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
Figure imgf000326_0001
, 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
Figure imgf000326_0002
wherein R73, R75, R81, R83, R85, R94, R99, R107, R109 and R136 are each independently H or unsubstituted lower alkyl; and R74, R74', R74", R76, R76', R76", R82, R82', R82", R84, R84', R84", 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):
Figure imgf000328_0001
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:
Figure imgf000328_0002
Figure imgf000329_0001
328 ach independently H, F, NH2, HC(0)R209, N02, N3 or
Figure imgf000330_0001
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;
Figure imgf000330_0002
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
Figure imgf000330_0003
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 C1-6 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, C6-10 aryl, C6-10 aryl-C1-6 alkyl, or C1-6 alkyl, wherein C6- 10 aryl is optionally substituted with one or more substituents independently selected from Ci-6 alkyl; C6-10 aryl of C6-10 aryl-Ci-6 alkyl is optionally substituted with one or more substituents independently selected from halogen; and C1-6 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 C1-6 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
Figure imgf000332_0001
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
Figure imgf000332_0002
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
Figure imgf000332_0003
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
Figure imgf000332_0004
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
Figure imgf000333_0001
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
Figure imgf000333_0002
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
Figure imgf000333_0003
only one of R205, R206, R207 and R208 is not H, then
R and R2U8 are each independently H, F, NH2, HC(0)R2uy, N3 or
Figure imgf000333_0004
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
Figure imgf000334_0001
Figure imgf000334_0002
Figure imgf000335_0001
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
Figure imgf000335_0002
wherein R249 is a halogen, then at least one of
R247, R248, R250 and R251 is not H; and
(ix) when only two of R2UU, R2U1, R2U2, R2U3, and R2U4 are not H and each is a halog
and B
Figure imgf000335_0003
, 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 C6-10 aryl is optionally substituted with one or more substituents independently selected from Ci-6 alkyl; C6-10 aryl of C6-10 aryl-Ci-6 alkyl is optionally substituted with one or more substituents independently selected from halogen; and C1-6 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
Figure imgf000336_0001
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
Figure imgf000337_0001
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:
Figure imgf000337_0002
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, C3-6 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, 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; 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.
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Cited By (8)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN109734677A (en) * 2019-03-07 2019-05-10 四川大学 The small molecule compound and its application of inhibition of histone lysine methyltransferase NSD2
WO2020069194A1 (en) * 2018-09-26 2020-04-02 Case Western Reserve University Methods and compositions for treating a premature stop codon-mediated disorder
WO2020117832A1 (en) * 2018-12-04 2020-06-11 University Of Kansas Small molecule inhibitors of the bfrb:bfd interaction
US10905778B2 (en) 2018-09-26 2021-02-02 Case Western Reserve University Methods and compositions for treating a premature stop codon-mediated disorder
US20220117937A1 (en) * 2020-10-16 2022-04-21 Board Of Supervisors Of Louisiana State University And Agricultural And Mechanical College Use of small molecule inhibitors of the bfrb:bfd interaction in biofilms
US11427558B1 (en) 2019-07-11 2022-08-30 ESCAPE Bio, Inc. Indazoles and azaindazoles as LRRK2 inhibitors
US11661600B2 (en) 2017-11-02 2023-05-30 University Of Iowa Research Foundation Methods of rescuing stop codons via genetic reassignment with ACE-tRNA
WO2023229293A1 (en) * 2022-05-23 2023-11-30 재단법인 대구경북첨단의료산업진흥재단 Pharmaceutical composition comprising bicycle derivative as active ingredient for prevention or treatment of cancer

Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2004009533A1 (en) * 2002-07-24 2004-01-29 Ptc Therapeutics, Inc. Acetylamino benzoic acid compounds and their use for nonsense suppression and the treatment of disease
WO2004009558A2 (en) * 2002-07-24 2004-01-29 Ptc Therapeutics, Inc. Ureido substituted benzoic acid compounds, their use for nonsense suppression and the treatment of diseases caused by such mutations
US20060167263A1 (en) * 2005-01-21 2006-07-27 Wilde Richard G Acetylamino benzoic acid compounds and their use for nonsense suppression and the treatment of disease
WO2012021707A2 (en) * 2010-08-11 2012-02-16 The Regents Of The University Of California Premature-termination-codons readthrough compounds

Patent Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2004009533A1 (en) * 2002-07-24 2004-01-29 Ptc Therapeutics, Inc. Acetylamino benzoic acid compounds and their use for nonsense suppression and the treatment of disease
WO2004009558A2 (en) * 2002-07-24 2004-01-29 Ptc Therapeutics, Inc. Ureido substituted benzoic acid compounds, their use for nonsense suppression and the treatment of diseases caused by such mutations
US20060167263A1 (en) * 2005-01-21 2006-07-27 Wilde Richard G Acetylamino benzoic acid compounds and their use for nonsense suppression and the treatment of disease
WO2012021707A2 (en) * 2010-08-11 2012-02-16 The Regents Of The University Of California Premature-termination-codons readthrough compounds

Cited By (9)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US11661600B2 (en) 2017-11-02 2023-05-30 University Of Iowa Research Foundation Methods of rescuing stop codons via genetic reassignment with ACE-tRNA
WO2020069194A1 (en) * 2018-09-26 2020-04-02 Case Western Reserve University Methods and compositions for treating a premature stop codon-mediated disorder
US10905778B2 (en) 2018-09-26 2021-02-02 Case Western Reserve University Methods and compositions for treating a premature stop codon-mediated disorder
US11617802B2 (en) 2018-09-26 2023-04-04 Case Western Reserve University Methods and compositions for treating a premature stop codon-mediated disorder
WO2020117832A1 (en) * 2018-12-04 2020-06-11 University Of Kansas Small molecule inhibitors of the bfrb:bfd interaction
CN109734677A (en) * 2019-03-07 2019-05-10 四川大学 The small molecule compound and its application of inhibition of histone lysine methyltransferase NSD2
US11427558B1 (en) 2019-07-11 2022-08-30 ESCAPE Bio, Inc. Indazoles and azaindazoles as LRRK2 inhibitors
US20220117937A1 (en) * 2020-10-16 2022-04-21 Board Of Supervisors Of Louisiana State University And Agricultural And Mechanical College Use of small molecule inhibitors of the bfrb:bfd interaction in biofilms
WO2023229293A1 (en) * 2022-05-23 2023-11-30 재단법인 대구경북첨단의료산업진흥재단 Pharmaceutical composition comprising bicycle derivative as active ingredient for prevention or treatment of cancer

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