WO2017049409A1 - Compositions permettant de favoriser la translecture de codons de terminaison prématurée, et leurs procédés d'utilisation - Google Patents

Compositions permettant de favoriser la translecture de codons de terminaison prématurée, et leurs procédés d'utilisation 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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Prior art keywords
unsubstituted
substituted
alkyl
independently
lower alkyl
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PCT/CA2016/051119
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English (en)
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
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The Centre For Drug Research And Development
The University Of British Columbia
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Publication of WO2017049409A1 publication Critical patent/WO2017049409A1/fr

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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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    • A61K31/16—Amides, e.g. hydroxamic acids
    • A61K31/18—Sulfonamides
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    • A61K31/185—Acids; Anhydrides, halides or salts thereof, e.g. sulfur acids, imidic, hydrazonic or hydroximic acids
    • A61K31/19—Carboxylic acids, e.g. valproic acid
    • A61K31/195—Carboxylic acids, e.g. valproic acid having an amino group
    • A61K31/196—Carboxylic acids, e.g. valproic acid having an amino group the amino group being directly attached to a ring, e.g. anthranilic acid, mefenamic acid, diclofenac, chlorambucil
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    • A61K31/40—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil
    • A61K31/4015—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil having oxo groups directly attached to the heterocyclic ring, e.g. piracetam, ethosuximide
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    • A61K31/403—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil condensed with carbocyclic rings, e.g. carbazole
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    • A61K31/403—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil condensed with carbocyclic rings, e.g. carbazole
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    • A61K31/4164—1,3-Diazoles
    • A61K31/4184—1,3-Diazoles condensed with carbocyclic rings, e.g. benzimidazoles
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    • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
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    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/445—Non condensed piperidines, e.g. piperocaine
    • A61K31/4523—Non condensed piperidines, e.g. piperocaine containing further heterocyclic ring systems
    • A61K31/454—Non condensed piperidines, e.g. piperocaine containing further heterocyclic ring systems containing a five-membered ring with nitrogen as a ring hetero atom, e.g. pimozide, domperidone
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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

Abstract

L'invention concerne des composés de formule générale (I) qui favorisent la translecture d'un codon de terminaison prématurée (PTC) d'une molécule d'ARN dans un système de traduction, et leur utilisation, seuls ou en combinaison avec d'autres composés, tels qu'un aminoglycoside, pour traiter des maladies ou des troubles améliorés par la modulation d'un codon de terminaison prématurée (PTC) d'une molécule d'ARN dans un système de traduction. Le trouble ou la maladie peut être l'épidermolyse bulleuse dystrophique, la maladie de Batten, la dystrophie musculaire de Duchenne, le cancer et l'amyotrophie spinale. Ar-L-B (I)
PCT/CA2016/051119 2015-09-25 2016-09-23 Compositions permettant de favoriser la translecture de codons de terminaison prématurée, et leurs procédés d'utilisation WO2017049409A1 (fr)

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US62/296,992 2016-02-18

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CN109734677A (zh) * 2019-03-07 2019-05-10 四川大学 抑制组蛋白赖氨酸甲基转移酶nsd2的小分子化合物及其应用
WO2020069194A1 (fr) * 2018-09-26 2020-04-02 Case Western Reserve University Méthodes et compositions pour le traitement d'un trouble à médiation par un codon d'arrêt prématuré
WO2020117832A1 (fr) * 2018-12-04 2020-06-11 University Of Kansas Inhibiteurs à petites molécules de l'interaction bfrb-bfd
US10905778B2 (en) 2018-09-26 2021-02-02 Case Western Reserve University Methods and compositions for treating a premature stop codon-mediated disorder
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 (fr) * 2022-05-23 2023-11-30 재단법인 대구경북첨단의료산업진흥재단 Composition pharmaceutique comprenant un dérivé bicyclique en tant que principe actif pour la prévention ou le traitement du cancer

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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 (fr) * 2018-09-26 2020-04-02 Case Western Reserve University Méthodes et compositions pour le traitement d'un trouble à médiation par un codon d'arrêt prématuré
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 (fr) * 2018-12-04 2020-06-11 University Of Kansas Inhibiteurs à petites molécules de l'interaction bfrb-bfd
CN109734677A (zh) * 2019-03-07 2019-05-10 四川大学 抑制组蛋白赖氨酸甲基转移酶nsd2的小分子化合物及其应用
US11427558B1 (en) 2019-07-11 2022-08-30 ESCAPE Bio, Inc. Indazoles and azaindazoles as LRRK2 inhibitors
WO2023229293A1 (fr) * 2022-05-23 2023-11-30 재단법인 대구경북첨단의료산업진흥재단 Composition pharmaceutique comprenant un dérivé bicyclique en tant que principe actif pour la prévention ou le traitement du cancer

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