Compounds for enhancing read-through of genes containing stop codons, methods for producing the same, and methods of use

Abstract

This specification discloses novel aromatic compounds, compositions containing one or more aromatic compounds, and methods for their synthesis. Also disclosed herein are methods for enhancing the read-through of genes containing premature stop codons using one or more of the compounds or compositions described herein.

Description

Technical Field

[0001] Cross - reference to Related Applications This application claims the priority and benefit of U.S. Provisional Patent Application No. 63 / 347,973, filed on June 1, 2022, the disclosure of which is hereby incorporated by reference in its entirety.

[0002] This application relates to the fields of chemistry, biochemistry, and medicine. More specifically, novel compounds, compositions comprising one or more compounds, and methods of using and synthesizing the same are disclosed herein. Also disclosed herein are methods of enhancing read - through of genes containing premature stop codons using one or more of the compounds or compositions described herein.

Background Art

[0003] A premature stop codon is a codon sequence introduced into DNA by a single - base mutation that shifts a normal triplet codon sequence to one of the three stop codons, TAA, TAG, or TGA, causing transcription to stop prematurely. As a result, protein expression is lost or a truncated protein with only the function remaining is produced. Premature stop codons can cause many genetic diseases and disorders, including cystic fibrosis, amyloidosis, Duchenne muscular dystrophy, and various cancers, by reducing the amount of protein expressed. However, sometimes the premature stop codon is bypassed and a full - length protein is synthesized. This phenomenon is known as stop - codon read - through.

[0004] Diseases and disorders associated with premature termination codons may be amenable to treatments that enable readthrough of the premature termination codon. Aminoglycoside compounds were shown to promote readthrough of premature termination codons over 30 years ago. See, e.g., Burke J.F., Mogg A.E. Suppression of a nonsense mutation in mammalian cells in vivo by the aminoglycoside antibiotics G-418 and paromomycin. Nucleic Acids Res. 1985;13:6265-6272. Since this initial identification, many more aminoglycoside and non-aminoglycoside compounds, such as geneticin, paromomycin, neomycin, 2,6-diaminopurine, have been found to possess activity that promotes readthrough. The non-aminoglycoside agent ataluren has been found to have a therapeutic effect in relation to premature termination codon readthrough and is approved for use as a therapeutic in several countries for patients with nonsense mutation Duchenne muscular dystrophy. SUMMARY OF THE INVENTION PROBLEMS TO BE SOLVED BY THE INVENTION

[0005] Since regulation of premature termination codon readthrough has shown promising results in the treatment of various diseases, there is a need for additional compounds and treatments that promote gene readthrough and would be beneficial to patients suffering from diseases associated with premature termination codons. MEANS FOR SOLVING THE PROBLEMS

[0006] Some embodiments disclosed herein are compounds having the structure of formula (I): CHEMICAL STRUCTURE or a pharmaceutically acceptable salt thereof, wherein R 1 、R 2 、R 3 、R 4, and R 5 is, independently of one another, hydrogen, halo, -CN, -NO2, -OH, C 1~6 alkyl, C 1~6 haloalkyl, C 1~6 alkoxy, C 1~6 haloalkoxy, and C 3~8 selected from the group consisting of cycloalkyl; L 1 is O, N or CH2; L 2 is CH2, CHF or CF2; Z 1 is CH, N or C-OCH3; Z 2 is CH or N; Z 3 is CH, N or CF; R 6 is optionally substituted heterocyclyl, optionally substituted heteroaryl, or -NR 7a R 7b ; R 7a and R 7b are, independently of one another, hydrogen, optionally substituted C 1~6 alkyl, optionally substituted C 3~8 cycloalkyl; optionally substituted aryl, optionally substituted heterocyclyl, and optionally substituted heteroaryl, and include a compound or a pharmaceutically acceptable salt thereof selected from the group consisting of.

[0007] In some embodiments, R 1 and R 2 are both hydrogen, and when R 6 is optionally substituted pyrazolyl, R 3 is not halo, and R 4 is not halo.

[0008] In some embodiments, L 1 is O. In another embodiment, L 1 is CH2. In yet another embodiment, L 1 is NH. In some embodiments, L 1is CHD. In some embodiments, L 1 is CD2.

[0009] In some embodiments, L 2 is CH2. In another embodiment, L 2 is CHF. In yet another embodiment, L 2 is CF2. In some embodiments, L 2 is CHD. In some embodiments, L 2 is CD2.

[0010] In some embodiments, Z 1 is N, and Z 2 is N, and Z 3 is CH. In another embodiment, Z 1 is N, and Z 2 is CH, and Z 3 is CH. In yet another embodiment, Z 1 is CH, and Z 2 is CH, and Z 3 is CH. In some embodiments, Z 1 is CH, and Z 2 is CH, and Z 3 is N. In yet another embodiment, Z 1 is CH, and Z 2 is CH, and Z 3 is CF. In some embodiments, Z 1 is N, and Z 2 is CH, and Z 3 is N. In another embodiment, Z 1 is CH, and Z 2 is N, and Z 3 is N.

[0011] In some embodiments, R 1 is -CN, halo, -C 1~6 alkyl, -C 1~6 alkoxy, -C 1~6 haloalkyl, and -C 1~6is selected from the group consisting of haloalkoxy. In some embodiments, R 1 is selected from the group consisting of: -CN, -F, -Cl, -Br, -CH3, -CH2CH3, -CF3, -CF2CH3, -OCF3, -OCHF2, and -cyclopropyl.

[0012] In some embodiments, R 2 is -CN, halo, -C 1~6 alkyl, -C 1~6 alkoxy, -C 1~6 haloalkyl, and -C 1~6 haloalkoxy. In some embodiments, R 2 is selected from the group consisting of: -CN, -F, -Cl, -Br, -CH3, -CH2CH3, -CF3, -CF2CH3, -OCF3, -OCHF2, and -cyclopropyl.

[0013] In some embodiments, R 3 is hydrogen, and in other embodiments, R 3 is halo.

[0014] In some embodiments, R 4 is hydrogen, and in other embodiments, R 4 is halo.

[0015] In some embodiments, R 5 is hydrogen, and in other embodiments, R 5 is halo.

[0016] In some embodiments, R 6 is selected from the group consisting of:

Chemical formula

[0017] In some embodiments, R 6 is selected from the group consisting of:

Chemical formula

Chemical formula

[0018] In some embodiments, R 6 is selected from the group consisting of: [Chemical formula] wherein q is an integer value selected from 0, 1, and 2; each R 8 is independently fluorine, phenyl, pyridine, carboxyl, -C(=O)-(C1-C6 alkyl), -(C 1~6 alkyl)-phenyl, -(C 1~6 alkyl)-phenyl-O-(C1-C6 alkyl), -CF3, -C 1~6 alkyl, -(C 1~6 alkyl)-CN, -C 1~6 alkenyl, -C 3~8 cycloalkyl, -(C 1~6 alkyl)-OH, -(C 1~6 alkyl)-NH2, -S(=O)2-NH2, -S(=O)2-(C 1~6 alkyl), -C 1~6 alkyl)-N(CH3)2, -(C1-C6 alkyl)-O-alkyl, -(C1-C6 alkyl)-O-(C1-C6 alkyl)-OH, -(C 1~6 alkyl)-NH2, C 1~6 alkyl-O-alkenyl, -C(=O)NH2, -C(=O)OH, -C(=O)OCH3, -C(=O)NH(C 1~6 alkyl), C(=O)N(C 1~6 alkyl)2, -C(=O)-O-(C 1~6 alkyl), -(C 1~6 alkyl)-NC(=O)-H, -OH, -(C 1~6 alkyl)-NC(=O)-CF3, or -(C 1~6 alkyl)-NC(=O)(C 1~6 alkyl); R 9 is hydrogen, -C 1~6 alkyl, -C 3~8Cycloalkyl, -(C 1~6 alkyl)-OH, -(C 1~6 alkyl)-NH2, or -(C 1~6 alkyl)-NC(=O)(C 1~6 alkyl).

[0019] In some embodiments, R 6 is selected from the group consisting of:

Chemical formula

[0020] In some embodiments, R 6 may include a group that is isotopically enriched in one or more atoms including the R 8 group. In some embodiments, one or more hydrogen atoms found in the R 6 group may be enriched with deuterium.

[0021] In some embodiments, the compound is a lead-through modulator disclosed herein, or a pharmaceutically acceptable salt thereof.

[0022] In a further embodiment, provided herein is a pharmaceutical composition comprising a therapeutically effective amount of one or more lead-through modulator compounds disclosed herein. In some embodiments, the pharmaceutical composition further comprises an aminoglycoside. In some embodiments, the aminoglycoside is kanamycin A, amikacin, tobramycin, dibekacin, gentamicin, geneticin, sisomicin, netilmicin, neomycin B, neomycin C, paromomycin, streptomycin, plazomycin, tobramycin,

Chemical formula

[0023] In a further embodiment, provided herein is a method of enhancing readthrough of a gene containing a premature stop codon, the method comprising administering to a subject in need thereof: (i) a readthrough modulator; and (ii) an aminoglycoside. In some embodiments, the readthrough modulator is a readthrough modulator disclosed herein. In some embodiments, the aminoglycoside is selected from the group consisting of kanamycin A, amikacin, tobramycin, dibekacin, gentamicin, geneticin, sisomicin, netilmicin, neomycin B, neomycin C, paromomycin, streptomycin, plazomycin, tobramycin, ELX-02, and pharmaceutically acceptable salts thereof.

[0024] In some embodiments, the compound and the aminoglycoside are selected to increase ribosome read-through of mRNA transcripts having a premature stop codon mutation in the cystic fibrosis CFTR channel. In some embodiments, the mutation is selected from one or more of G542X, R553X, R1162X, and W1282X. In some embodiments, the mutation is R1162X. In another embodiment, the mutation is G542X. In some embodiments, the increase in read-through is greater than 10% compared to aminoglycoside administration alone. In another embodiment, the increase in read-through is greater than 50% compared to aminoglycoside administration alone. In yet another embodiment, the increase in read-through is greater than 100% compared to aminoglycoside administration alone.

[0025] In a further embodiment, provided herein is a method of treating cystic fibrosis, the method comprising administering (i) an eRF3 modulator, (ii) an aminoglycoside, and (iii) a read-through modulator to a subject in need thereof. In some embodiments, the read-through modulator is a read-through modulator compound disclosed herein. In some embodiments, the aminoglycoside is selected from the group consisting of kanamycin A, amikacin, tobramycin, dibekacin, gentamicin, geneticin, sisomicin, netilmicin, neomycin B, neomycin C, paromomycin, streptomycin, plazomycin, tobramycin, ELX-02, and pharmaceutically acceptable salts thereof. In some specific embodiments, the aminoglycoside is selected from the group consisting of geneticin, ELX-02, and paromomycin. In some embodiments, the eRF3 modulator is a cereblon E3 ligase modulator. In some embodiments, the eRF3 modulator is a cereblon E3 disclosed herein.

[0026] In some embodiments, the eRF3 modulator, the aminoglycoside, and the readthrough modulator are selected to increase ribosomal readthrough of mRNA transcripts having a premature stop codon mutation in the cystic fibrosis CFTR channel. In some embodiments, the mutation is selected from one or more of G542X, R553X, R1162X, and W1282X. In some embodiments, the mutation is R1162X. In another embodiment, the mutation is G542X. In some embodiments, the increase in readthrough is greater than 10% compared to administration of the aminoglycoside alone. In another embodiment, the increase in readthrough is greater than 50% compared to administration of the aminoglycoside alone. In yet another embodiment, the increase in readthrough is greater than 100% compared to administration of the aminoglycoside alone.

Mode for Carrying Out the Invention

[0027] Provided herein are compounds having readthrough modulating activity. In some embodiments, the readthrough modulator compounds provided herein have the structure of formula (I):

Chemical Formula

[0028] In some embodiments of formula (I), when R 1 and R 2 are both hydrogen and R 6 is optionally substituted pyrazolyl, R 3 is not halo and R 4 is not halo.

[0029] In some embodiments of formula (I), L 1 can be O. In another embodiment of formula (I), L 1 can be N. In yet another embodiment of formula (I), L 1 can be CH2. In some embodiments of formula (I), L 2 can be CH2. In some embodiments of formula (I), L 1 can be O, L 2 can be CH2. In another embodiment of formula (I), L 1 can be O and L 2 can be CF2. In yet another embodiment of formula (I), L 1 can be O and L 2 can be CHF. In some embodiments of formula (I), L 1 can be CH2, L 2can be CH2.

[0030] In some embodiments of formula (I), Z 1 can be N. In some embodiments of formula (I), Z 1 can be CH. In some embodiments of formula (I), Z 2 can be N. In another embodiment of formula (I), Z 2 can be CH. In some embodiments of formula (I), Z 3 can be N, but in another embodiment of formula (I), Z 3 can be CH. In yet another embodiment of formula (I), Z 3 can be CF. In some embodiments of formula (I), Z 1 is N, Z 2 is CH, Z 3 is CH. In some embodiments of formula (I), Z 1 is CH, Z 2 is CH, Z 3 is CH. In another embodiment of formula (I), Z 1 is CH, Z 2 is N, Z 3 is CH. In yet another embodiment of formula (I), Z 1 is CH, Z 2 is CH, Z 3 is N. In some embodiments of formula (I), Z 1 is CH, Z 2 is CH, and Z 3 is CF. In some embodiments of formula (I), Z 1 is N, Z 2 is CH, Z 3 is N. In another embodiment of formula (I), Z 1 is CH, Z 2 is N, Z 3 is N.

[0031] In some embodiments of formula (I), L 1 is O, L 2When it is CH2, Z 1 can be N. In some embodiments of formula (I), L 1 is O, and when L 2 is CH2, Z 1 can be CH. In some embodiments of formula (I), L 1 is O, and when L 2 is CH2, Z 2 can be N. In another embodiment of formula (I), L 1 is O, and when L 2 is CH2, Z 2 can be CH. In some embodiments of formula (I), L 1 is O, and when L 2 is CH2, Z 3 can be N. In another embodiment of formula (I), L 1 is O, and when L 2 is CH2, Z 3 can be CH. In yet another embodiment of formula (I), L 1 is O, and when L 2 is CH2, Z 3 can be CF. In some embodiments of formula (I), L 1 is O, and when L 2 is CH2, Z 1 is N, Z 2 is CH, and Z 3 is CH. In some embodiments of formula (I), L 1 is O, and when L 2 is CH2, Z 1 is CH, Z 2 is CH, and Z 3 is CH. In another embodiment of formula (I), L 1 is O, and when L 2 is CH2, Z 1 is CH, Z 2 is N, and Z 3 is CH. In yet another embodiment, in formula (I), L 1 is O, and when L 2 is CH2, Z 1 is CH, and Z2 is CH, and Z 3 is N. In some embodiments of formula (I), L 1 is O, and when L 2 is CH2, Z 1 is CH, and Z 2 is CH, and Z 3 is CF. In some embodiments of formula (I), L 1 is O, and when L 2 is CH2, Z 1 is N, and Z 2 is CH, and Z 3 is N. In some embodiments of formula (I), L 1 is O, and when L 2 is CH2, Z 1 is CH, and Z 2 is N, and Z 3 is N.

[0032] In some embodiments of formula (I), when L 1 is O and L 2 is CF2, Z 1 can be N. In some embodiments of formula (I), when L 1 is O and L 2 is CF2, Z 1 can be CH. In some embodiments of formula (I), when L 1 is O and L 2 is CF2, Z 2 can be N. In another embodiment of formula (I), when L 1 is O and L 2 is CF2, Z 2 can be CH. In some embodiments of formula (I), when L 1 is O and L 2 is CF2, Z 3 can be N. In another embodiment of formula (I), when L 1 is O and L 2 is CF2, Z 3 can be CH. In yet another embodiment of formula (I), when L 1 is O and L2 When it is CF2, Z 3 can be CF. In some embodiments of formula (I), L 1 is O, and when L 2 is CF2, Z 1 is N, Z 2 is CH, Z 3 is CH. In some embodiments of formula (I), L 1 is O, and when L 2 is CF2, Z 1 is CH, Z 2 is CH, Z 3 is CH. In another embodiment of formula (I), L 1 is O, and when L 2 is CF2, Z 1 is CH, Z 2 is N, Z 3 is CH. In yet another embodiment of formula (I), when L 1 is O and L 2 is CF2, Z 1 is CH, Z 2 is CH, Z 3 is N. In some embodiments of formula (I), when L 1 is O and L 2 is CF2, Z 1 is CH, Z 2 is CH, Z 3 is CF.

[0033] In some embodiments of formula (I), R 1 may be halo, -CN, -C 1~6 alkyl, -C 1~6 alkoxy, -C 1~6 haloalkyl, -C 1~6 haloalkoxy, or -cyclopropyl. In some embodiments, R 1 may be halo. In some specific embodiments, R 1 may be -F, -Cl, -Br, or -I. In another embodiment, R 1 is -C 1~6It may be alkyl. In some specific embodiments, R 1 may be -CH3 or -CH2CH3. In another embodiment, R 1 may be -C 1~6 haloalkyl. In some specific embodiments, R 1 may be -CF3 or -CF2CH3. In some embodiments, R 1 may be -C 1~6 alkoxy. In some specific embodiments, R 1 may be -OCH3 or -OCH2CH3. In another embodiment, R 1 may be -C 1~6 haloalkoxy. In some specific embodiments, R 1 may be -OCF3 or -OCHF2.

[0034] In some embodiments of formula (I), R 2 may be halo, -CN, -C 1~6 alkyl, -C 1~6 alkoxy, -C 1~6 haloalkyl, -C 1~6 haloalkoxy, or -cyclopropyl. In some embodiments, R 2 may be halo. In some specific embodiments, R 2 may be -F, -Cl, -Br, or -I. In other embodiments, R 2 may be -C 1~6 alkyl. In some specific embodiments, R 1 may be -CH3 or -CH2CH3. In another embodiment, R 2 may be -C 1~6 haloalkyl. In some specific embodiments, R 2 may be -CF3 or -CF2CH3. In some embodiments, R 2 may be -C 1~6 alkoxy. In some specific embodiments, R 2may be -OCH3 or -OCH2CH3. In another embodiment, R 2 may be -C 1~6 haloalkoxy. In some specific embodiments, R 2 may be -OCF3 or -OCHF2.

[0035] In some embodiments of formula (I), R 3 may be hydrogen. In some embodiments of formula (I), R 3 may be halo. In some embodiments, R 3 may be -F, -Cl, or Br.

[0036] In some embodiments of formula (I), R 4 may be hydrogen. In some embodiments of formula (I), R 4 may be halo. In some embodiments, R 4 may be -F, -Cl, or Br.

[0037] In some embodiments of formula (I), R 5 may be hydrogen. In some embodiments of formula (I), R 5 may be halo. In some embodiments, R 5 may be -F, -Cl, or Br.

[0038] In some embodiments of formula (I), R 1 may be halo, and R 2 may be -C 1~6 alkyl. In some embodiments of formula (I), R 1 may be -halo, and R 2 may be -C 1~6 alkoxy. In some embodiments of formula (I), R 1 may be -halo, and R 2 may be -C 1~6 haloalkoxy. In some embodiments of formula (I), R 1may be -C 1~6 and may be alkyl, and R 2 may be -C 1~6 and may be haloalkoxy. In some embodiments of formula (I), R 1 may be -C 1~6 and may be alkyl, and R 2 may be -C 1~6 and may be haloalkyl. In some embodiments of formula (I), R 1 may be -halo, and R 2 may be -C 1~6 and may be haloalkyl. In some embodiments of formula (I), R 1 may be -cyclopropyl, and R 2 may be -halo. In some embodiments of formula (I), R 1 may be -CN, and R 2 may be -halo. In some embodiments of formula (I), R 1 may be -C 1~6 and may be alkyl, and R 2 may be -C 1~6 and may be alkyl.

[0039] In some embodiments of formula (I), R 1 may be -Cl, and R 2 may be -Cl. In some embodiments of formula (I), R 1 may be -CF3, and R 2 may be -CH3. In some embodiments of formula (I), R 1 may be -CF3, and R 2 may be -CH2CH3. In some embodiments of formula (I), R 1 may be -Cl, and R 2 may be -CF3. In some embodiments of formula (I), R 1 may be -F, and R 2 may be -CF3. In some embodiments of formula (I), R 1 may be -Br, and R 2may also be -Br. In some embodiments of formula (I), R 1 may be -F, and R 2 may be -F. In some embodiments of formula (I), R 1 may be -CH3, and R 2 may be -CH3. In some embodiments of formula (I), R 1 may be -CN, and R 2 may be -Cl. In some embodiments of formula (I), R 1 may be -OCH3, and R 2 may be -Cl. In some embodiments of formula (I), R 1 may be -OCH3, and R 2 may be -Br. In some embodiments of formula (I), R 1 may be -OCHF2, and R 2 may be -Cl. In some embodiments of formula (I), R 1 may be -CF3, and R 2 may be -OCF3. In some embodiments of formula (I), R 1 may be -CH3, and R 2 may be -OCHF2.

[0040] In some embodiments of formula (I), R 6 may be selected from the following

Chemical formula

Chemical formula

Chemical formula

[0041] In some embodiments of formula (I), each R 8is independently fluorine, phenyl, carboxyl, -C(=O)-(C1-C6 alkyl), -(C 1~6 alkyl)-phenyl, -(C 1~6 alkyl)-phenyl-O-(C1-C6 alkyl), -CF3, -C 1~6 alkyl, -C 1~6 alkenyl, -C 3~8 cycloalkyl, -(C 1~6 alkyl)-OH, -(C 1~6 alkyl)-NH2, -S(=O)2NH2, -S(=O)2-(C 1~6 alkyl), -C 1~6 alkyl)-N(CH3)2, -(C1-C6 alkyl)-O-alkyl, -(C1-C6 alkyl)-O-(C 1~6 alkyl)-OH, -(C 1~-6 alkyl)-NH2, C 1~6 alkyl-O-alkenyl, -C(=O)NH2, -OH, -C(=O)NH(C 1~6 alkyl), C(=O)N(C 1~6 alkyl)2, -C(=O)-O-(C 1~6 alkyl), -(C 1~6 alkyl)-NC(=O)-H, -(C 1~6 alkyl)-NC(=O)-CF3, or -(C 1~6 alkyl)-NC(=O)(C 1~6 alkyl). In some specific embodiments, each R 8 may be -CH2OH. In other specific embodiments, each R 8 may be -C(=O)NH2. In some embodiments, one or more atoms of each R 8 may be isotopically enriched.

[0042] In some embodiments of formula (I), R 6 may be defined as above, and q may be 0. In other embodiments of formula (I), R 6 and R 8 may be defined as above, and q may be 1. In some embodiments of formula (I), R 6 and R8 may be defined as described above, and q may be 2.

[0043] In some embodiments of formula (I), R 9 may be hydrogen. In some embodiments of formula (I), R 9 may be -C 1~6 alkyl. In some embodiments of formula (I), R 9 may be -C 3~8 cycloalkyl. In some embodiments of formula (I), R 9 may be -(C 1~6 alkyl)-OH. In some embodiments of formula (I), R 9 may be -(C 1~6 alkyl)-NH2. In some embodiments of formula (I), R 9 may be -(C 1~6 alkyl)-NC(=O)(C 1~6 alkyl).

[0044] In some embodiments of formula (I), R 6 may be any of the following:

Chemical formula

Chemical formula

Chemical formula

[0045] In another embodiment of formula (I), R 6 may be selected from the group consisting of:

Chemical formula

[0046] In some embodiments of formula (I), R 6 is selected from the group consisting of:

Chemical formula

[0047] In some embodiments, the lead-through modulator compounds described herein consist of the group: [Chemical formula] [Chemical formula] [Chemical formula] [Chemical formula] [Chemical formula] [Chemical formula] [Chemical formula] [Chemical formula] [Chemical formula] [Chemical formula] [Chemical formula] [Chemical formula] [Chemical formula] [Chemical formula] [Chemical formula] [Chemical formula] [Chemistry] [Chemistry] [Chemistry] [Chemistry] [Chemistry] [Chemistry] [Chemistry] [Chemistry] [Chemistry] [Chemistry] [Chemistry] [Chemistry] [Chemistry] and may be selected from the pharmaceutically acceptable salts thereof.

[0048] In some embodiments, the lead-through modulator compounds described herein consist of the group: [Chemistry] [Chemistry] [Chemistry] [Chemical] [Chemical] [Chemical] [Chemical] [Chemical] [Chemical] [Chemical] [Chemical] [Chemical] [Chemical] [Chemical] [Chemical] [Chemical] [Chemical] [Chemical] and may be selected from the pharmaceutically acceptable salts thereof.

[0049] In some embodiments, the lead-through modulator compounds described herein consist of the group: [Chemical] [Chemical] [Chemical] and may be selected from the compound and its pharmaceutically acceptable salts.

[0050] Definition As used herein, "subject" means a human or a non-human mammal including, but not limited to, dog, cat, horse, donkey, mule, cow, domestic buffalo, camel, llama, alpaca, bison, yak, goat, sheep, pig, sika deer, elk, domestic serow, or non-human primates other than humans selected for treatment or therapy.

[0051] "Subject in need thereof" means a subject identified as in need of therapy or treatment.

[0052] The therapeutic effect includes, to some extent, reducing one or more symptoms of a disease or disorder and curing the disease or disorder. "Cure" means the disappearance of the symptoms of an active disease. However, even after a cure is achieved, there may be some long-term or permanent effects (such as extensive tissue damage).

[0053] "Therapeutically effective amount" means an amount of a compound or combination of compounds that improves, attenuates or eliminates one or more symptoms of a particular disease or condition, or prevents, modifies or delays the onset of one or more symptoms of a particular disease or condition.

[0054] As used herein, "treating", "treat" or "treatment" refers to administering a pharmaceutical composition for prophylactic and / or therapeutic purposes. The term "prophylactic treatment" refers to treating a patient who has not yet developed, but is susceptible to, or at risk of developing, a particular disease or disorder, such that the treatment reduces the likelihood that the patient will develop the disease or disorder. The term "therapeutic treatment" refers to treating a patient who already has a disease or disorder.

[0055] "Prevent" or "prevention" refers to delaying or preventing the onset, development or progression of a condition or disease over a period of time, including weeks, months, years.

[0056] "Alleviate" means that the severity of at least one indicator of a condition or disease is reduced. In certain embodiments, alleviation includes delaying or slowing the progression of one or more indicators of a condition or disease. The severity of an indicator may be determined by subjective or objective measures known to those of skill in the art.

[0057] "Modulate" or "modulating" means modulating a function or activity. In certain embodiments, modulate means increasing gene expression. In certain embodiments, modulate means decreasing gene expression. In certain embodiments, modulate means increasing or decreasing the total serum level of a particular protein. In certain embodiments, modulate means increasing or decreasing the free serum level of a particular protein. In certain embodiments, modulate means increasing or decreasing the total serum level of a particular non-protein factor. In certain embodiments, modulate means increasing or decreasing the free serum level of a particular non-protein factor. In certain particular embodiments, modulate means increasing or decreasing the total bioavailability of a particular protein. In certain particular embodiments, modulate means increasing or decreasing the total bioavailability of a particular non-protein factor.

[0058] As used herein, a "readthrough modulator" refers to a compound that modulates the readthrough of a stop codon, and such modulation occurs upon treatment with the readthrough modulator alone and / or upon treatment in combination with an aminoglycoside of the readthrough modulator. In some embodiments, the readthrough modulator modulates the readthrough of a stop codon when administered in combination with an aminoglycoside in an amount less than an effective amount, less than an optimal amount, or less than a maximal amount.

[0059] "Administering" means providing a pharmaceutical agent or composition to a subject, including but not limited to administration by a healthcare provider and self-administration.

[0060] Administration of a compound disclosed herein or a pharmaceutically acceptable salt thereof, or of another agent disclosed herein, can be effected via any of the modes of administration recognized for agents of similar utility including, but not limited to, oral, subcutaneous, intravenous, nasal, topical, transdermal, intraperitoneal, intramuscular, intravaginal, rectal, or intraocular. Oral and parenteral administrations are conventional in the treatment of the indications that are the subject of the preferred embodiments.

[0061] "Parenteral administration" means administration by injection or infusion. Parenteral administration includes, but is not limited to, subcutaneous administration, intravenous administration, intramuscular administration, intraarterial administration, and intracranial administration.

[0062] "Subcutaneous administration" means administration immediately under the skin.

[0063] "Intravenous administration" means administration into a vein.

[0064] "Intraarterial administration" means administration into an artery.

[0065] The term "agent" includes any substance, molecule, element, compound, entity, or combination thereof. This includes, for example, but is not limited to, proteins, polypeptides, peptides or mimetics, small organic molecules, polysaccharides, polynucleotides, etc. It can be a natural product, a synthetic compound, or a chemical compound, or a combination of two or more substances.

[0066] "Pharmaceutical agent" means a substance that provides a therapeutic effect when administered to a subject.

[0067] "Pharmaceutical composition" means a mixture of substances suitable for administration to an individual containing a pharmaceutical agent.

[0068] The term "pharmaceutically acceptable salt" refers to salts that retain the biological effectiveness and properties of the relevant compound and are not undesirable in a biological or other respect. In many cases, the compounds herein can form acid salts and / or base salts due to the presence of a phenol group and / or a phosphonate group, or groups similar thereto. One skilled in the art will recognize that any or all of the protonation states of these compounds can vary depending on the pH and the ionic properties of the surrounding solution, and thus this disclosure contemplates multiple charge states for each compound. Pharmaceutically acceptable acid addition salts can be formed with inorganic acids and organic acids. Examples of inorganic acids from which salts can be derived include, for example, hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, and the like. Examples of organic acids from which salts can be derived include, for example, acetic acid, propionic acid, glycolic acid, pyruvic acid, oxalic acid, maleic acid, malonic acid, succinic acid, fumaric acid, tartaric acid, citric acid, benzoic acid, cinnamic acid, mandelic acid, methanesulfonic acid, ethanesulfonic acid, p-toluenesulfonic acid, salicylic acid, and the like. Pharmaceutically acceptable base addition salts can be formed using inorganic bases and organic bases. Examples of inorganic bases from which salts can be derived include, for example, sodium, potassium, lithium, ammonium, calcium, magnesium, iron, zinc, copper, manganese, aluminum, and the like, and particularly preferred are ammonium salts, potassium salts, sodium salts, calcium salts, magnesium salts. Examples of organic bases from which salts can be derived include, for example, primary amines, secondary amines, tertiary amines, substituted amines including naturally occurring substituted amines, cyclic amines, basic ion exchange resins, and the like, and specifically include isopropylamine, trimethylamine, diethylamine, triethylamine, tripropylamine, ethanolamine, and the like. Many such salts are known in the art as described in International Publication No. WO 87 / 05297 published on September 11, 1987 by Johnston et al. (which is hereby incorporated by reference in its entirety).

[0069] "Solvate" refers to a compound formed by the interaction of a solvent with EPI, a metabolite, or a salt thereof. Preferred solvates are pharmaceutically acceptable solvates including hydrates.

[0070] As used herein, "C a to C b " or "C a~b ", when "a" and "b" are integers, means the number of carbon atoms in the specified group. That is, this group can contain carbon atoms from "a" to "b". Thus, for example, a "C1 to C4 alkyl" or "C 1~4 alkyl" group refers to all alkyl groups having 1 to 4 carbons, i.e., CH3-, CH3CH2-, CH3CH2CH2-, (CH3)2CH-, CH3CH2CH2CH2-, CH3CH2CH(CH3)-, and (CH3)3C-.

[0071] The term "halogen" or "halo", as used herein, means any one of the radio-stable atoms in column 7 of the periodic table of elements, e.g., fluorine, chlorine, bromine, or iodine, with fluorine and chlorine being preferred.

[0072] As used herein, "alkyl" refers to a straight-chain or branched hydrocarbon chain that is fully saturated (i.e., contains no double or triple bonds). An alkyl group may have from 1 to 20 carbon atoms (whenever a numerical range such as "1 to 20" is described herein, it means each integer within the given range; for example, "from 1 to 20 carbon atoms" means that the alkyl group may be composed of 1 carbon atom, 2 carbon atoms, 3 carbon atoms, etc., up to and including 20 carbon atoms, but this definition also applies to the occurrence of the term "alkyl" when no numerical range is specified). An alkyl group may also be a medium-sized alkyl having 1 to 9 carbon atoms. An alkyl group can also be a lower alkyl having 1 to 4 carbon atoms. The alkyl group of a compound may sometimes be designated as "C 1~4 alkyl" or a similar designation. By way of illustration only, "C1~4 "Alkyl" means that there are 1 to 4 carbon atoms in the alkyl chain, that is, the alkyl chain is selected from the group consisting of methyl, ethyl, propyl, iso-propyl, n-butyl, iso-butyl, sec-butyl, and t-butyl. Representative alkyl groups include, but are not limited to, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tertiary butyl, pentyl, hexyl, and the like.

[0073] As used herein, "haloalkyl" refers to a straight-chain or branched-chain alkyl group having 1 to 12 carbon atoms in the chain, in which one or more hydrogens are replaced by halogens. Examples of haloalkyl groups include -CF3, -CHF2, -CH2F, -CH2CF3, -CH2CHF2, -CH2CH2F, -CH2CH2Cl, -CH2CF2CF3, and other groups that are considered equivalent to any one of the foregoing examples in light of the ordinary skills of those skilled in the art and the teachings provided herein, but are not limited thereto.

[0074] As used herein, "alkoxy" refers to the formula -OR, where R is alkyl as defined above. For example, "C 1~9 alkoxy", etc., and examples include methoxy, ethoxy, n-propoxy, 1-methylethoxy (isopropoxy), n-butoxy, iso-butoxy, sec-butoxy, tert-butoxy, and the like, but are not limited thereto.

[0075] As used herein, "polyethylene glycol" refers to the formula

Chemical formula

[0076] As used herein, “heteroalkyl” refers to a straight-chain or branched hydrocarbon chain containing one or more heteroatoms, i.e., elements other than carbon including, but not limited to, nitrogen, oxygen, and sulfur, in the backbone. The heteroalkyl group may have from 1 to 20 carbon atoms, but this definition also applies to the occurrence of the term “heteroalkyl” where no numerical range is specified. The heteroalkyl group may also be a medium-sized heteroalkyl having from 1 to 9 carbon atoms. The heteroalkyl group may also be a lower heteroalkyl having from 1 to 4 carbon atoms. In various embodiments, the heteroalkyl may have from 1 to 4 heteroatoms, from 1 to 3 heteroatoms, 1 or 2 heteroatoms, or 1 heteroatom. The heteroalkyl group of a compound may sometimes be designated as “C 1~4 heteroalkyl” or a similar designation. The heteroalkyl group may contain one or more heteroatoms. By way of example only, “C 1~4 heteroalkyl” indicates that there are from 1 to 4 carbon atoms in the heteroalkyl chain and one or more heteroatoms in the backbone of the chain.

[0077] The term “aromatic” refers to a ring or ring system having a conjugated pi electron system and includes both carbocyclic aromatic groups (e.g., phenyl) and heterocyclic aromatic groups (e.g., pyridine). This term includes monocyclic groups or fused-ring polycyclic groups (i.e., rings sharing a pair of adjacent atoms), provided that the entire ring system is aromatic.

[0078] As used herein, "aryl" refers to an aromatic ring or ring system (i.e., two or more fused rings sharing two adjacent carbon atoms) containing only carbon in the ring backbone. When aryl is a ring system, all rings within the system are aromatic. An aryl group may have from 6 to 18 carbon atoms, but this definition also encompasses occurrences of the term "aryl" for which no numerical range is specified. In some embodiments, the aryl group has from 6 to 10 carbon atoms. An aryl group may be designated by " 6~10 "C 10 aryl", "C6 or C

[0079] aryl", or similar designations. Examples of aryl groups include, but are not limited to, phenyl, naphthyl, azulenyl, anthracenyl, etc. 6~10 As used herein, "aryloxy" and "arylthio" refer to RO- and RS-, where R is aryl as defined above, e.g., " 6~10 aryloxy" or "

[0080] arylthio", etc., and include, but are not limited to, phenyloxy. 7~14 "Aralkyl" or "arylalkyl" is an aryl group bonded as a substituent via an alkylene group, e.g., " 1~4 aralkyl", etc., and includes, but is not limited to, benzyl, 2-phenylethyl, 3-phenylpropyl, naphthylalkyl, etc. In some cases, the alkylene group is a lower alkylene group (i.e., a

[0081] As used herein, "heteroaryl" refers to an aromatic ring or ring system (i.e., two or more fused rings sharing two adjacent atoms), which contains one or more heteroatoms, i.e., elements other than carbon including, but not limited to, nitrogen, oxygen, and sulfur, in the ring backbone. When the heteroaryl is a ring system, all rings of the ring system are aromatic. The heteroaryl group may have 5 to 18 ring members (i.e., the number of atoms constituting the ring backbone including carbon atoms and heteroatoms), but this definition also applies to the occurrence of the term "heteroaryl" for which no numerical range is specified. In some embodiments, the heteroaryl group has 5 to 10 ring members or 5 to 7 ring members. The heteroaryl group may be designated as "5- to 7-membered heteroaryl", "5- to 10-membered heteroaryl", or a similar name. In various embodiments, the heteroaryl contains from 1 to 4 heteroatoms, from 1 to 3 heteroatoms, from 1 to 2 heteroatoms, or 1 heteroatom. For example, in various embodiments, the heteroaryl contains from 1 to 4 nitrogen atoms, from 1 to 3 nitrogen atoms, from 1 to 2 nitrogen atoms, 2 nitrogen atoms and 1 sulfur or oxygen atom, 1 nitrogen atom and 1 sulfur or oxygen atom, or 1 sulfur or oxygen atom. Examples of heteroaryl rings include furyl, thienylphthalazinyl, pyrrolyl, oxazolyl, thiazolyl, imidazolyl, pyrazolyl, isoxazolyl, isothiazolyl, triazolyl, thiadiazolyl, pyridinyl, pyridazinylpyrimidinyl, pyrazinyl, triazinyl, quinolinyl, isoquinolinyl, benzimidazolyl, benzoxazolyl, benzothiazolyl, indolyl, isoindolyl, and benzothienyl, among others.

[0082] "Heteroaralkyl" or "heteroarylalkyl" is a heteroaryl group linked via an alkylene group as a substituent. Examples include, but are not limited to, 2-thienylmethyl, 3-thienylmethyl, furylmethyl, thienylethyl, pyrrolylalkyl, pyridylalkyl, isoxazolylalkyl, imidazolylalkyl, and the like. In some cases, the alkylene group is a lower alkylene group (i.e., C1~4 is an alkylene group).

[0083] As used herein, "carbocyclic" means a non-aromatic cyclic ring or ring system containing only carbon atoms in the ring system skeleton. When the carbocyclic is a ring system, two or more rings may be fused, bridged, or spiro-bonded. The carbocyclic is not limited in the degree of saturation as long as at least one ring of the ring system is not aromatic. Therefore, the carbocyclic includes cycloalkyl, cycloalkenyl, and cycloalkynyl. The carbocyclic group may have 3 to 20 carbon atoms, but this definition also applies to the appearance of the term "carbocyclic" for which no numerical range is specified. The carbocyclic group may also be a medium-sized carbocyclic having 3 to 10 carbon atoms. The carbocyclic group may also be a carbocyclic having 3 to 6 carbon atoms. The carbocyclic group may be designated by "C 3~6 "carbocyclic" or a similar name. Examples of the carbocyclic ring include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cyclohexenyl, 2,3-dihydro-indene, bicyclic[2.2.2]octanyl, adamantyl, spiro[4.4]nonanyl, etc.

[0084] "(carbocyclic)alkyl" is, for example, a carbocyclic group linked via an alkylene group as a substituent such as "C 4~10 (carbocyclic)alkyl", etc., and examples include, but are not limited to, cyclopropylmethyl, cyclobutylmethyl, cyclopropylethyl, cyclopropylbutyl, cyclobutylethyl, cyclopropylisopropyl, cyclopentylmethyl, cyclopentylethyl, cyclohexylmethyl, cyclohexylethyl, cycloheptylmethyl, etc. In some cases, the alkylene group is a lower alkylene group.

[0085] As used herein, "cycloalkyl" means a fully saturated carbocyclic ring or ring system. Examples include cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl.

[0086] As used herein, "cycloalkenyl" means a carbocyclic ring or ring system having at least one double bond, and the rings in the ring system are not aromatic. An example thereof is cyclohexenyl.

[0087] As used herein, "heterocyclyl" means a non-aromatic cyclic ring or ring system containing at least one heteroatom in the ring skeleton. Heterocyclyls may be bonded to each other by condensation, bridging or spiro bonds. Heterocyclyl may have any degree of saturation, provided that at least one of the rings in the ring system is not aromatic. The heteroatom may be present in either the non-aromatic or aromatic rings of the ring system. The heterocyclyl group may have from 3 to 20 ring members (i.e., the number of atoms constituting the ring skeleton including carbon atoms and heteroatoms), but this definition also applies to occurrences of the term "heterocyclyl" for which no numerical range is specified. The heterocyclyl group may also be a medium-sized heterocyclyl having from 3 to 10 ring members. The heterocyclyl group may also be a heterocyclyl having from 3 to 6 ring members. The heterocyclyl group may be designated by "3-6 membered heterocyclyl" or a similar designation.

[0088] In various embodiments, the heterocyclyl contains from 1 to 4 heteroatoms, from 1 to 3 heteroatoms, from 1 to 2 heteroatoms, or 1 heteroatom. For example, in various embodiments, the heterocyclyl contains from 1 to 4 nitrogen atoms, from 1 to 3 nitrogen atoms, from 1 to 2 nitrogen atoms, 2 nitrogen atoms and 1 sulfur or oxygen atom, 1 nitrogen atom and 1 sulfur or oxygen atom, or 1 sulfur or oxygen atom. In a preferred 6-membered monocyclic heterocyclyl compound, the heteroatom is selected from 1 to 3 of O, N, or S, and in a preferred 5-membered monocyclic heterocyclyl compound, the heteroatom is selected from 1 or 2 heteroatoms selected from O, N, or S. Examples of heterocyclyl rings include, but are not limited to, azepinyl, acridinyl, carbazolyl, cinnolinyl, dioxolanyl, imidazolinyl, imidazolidinyl, morpholinyl, oxolannyl, oxepanyl, thiepanyl, piperidinyl, piperazinyl, dioxopiperazinyl, pyrrolidinyl, pyrrolidonyl, pyrrolidonyl, 4-piperidonyl, pyrazolinyl, pyrazolidinyl, 1,3-dioxinyl, 1,3-dioxanyl, 1,4-dioxinyl, 1,4-dioxanyl, 1,3-oxathianyl, 1,4-oxathianyl 1,4-oxathianyl, 2H-1,2-dioxinyl, trioxanyl, hexahydro-1,3,5-triazinyl, 1,3-dioxolyl, 1,3-dioxolanyl, 1,3-dithiolyl, 1,3-dithiolanyl, isoxazolidinyl, oxazolidinyl, oxazolidinonyl, thiazolidinyl, thiazolinyl, 1,3-oxathiolanyl, indolinyl, isoindolinyl, tetrahydrofuranyl, tetrahydropyranyl, tetrahydrothiophenyl, tetrahydrothiopyranyl, tetrahydro-1,4-thiazinyl, thiamorpholinyl, dihydrobenzofuranyl, benzimidazolidinyl, tetrahydroquinoline, and the like.

[0089] “(heterocyclyl)alkyl” is a heterocyclyl group linked via an alkylene group as a substituent. Examples include, but are not limited to, imidazolinylmethyl and indolinylethyl.

[0090] As used herein, "acyl" refers to -C(=O)R where R is hydrogen, C 1~6 alkyl, C 2~6 alkenyl, C 2~6 alkynyl, C 3~7 carbocyclic, aryl, 5- to 10-membered heteroaryl, and 5- to 10-membered heterocyclic. Non-limiting examples include formyl, acetyl, propanoyl, benzoyl, acrylyl, and the like.

[0091] The "O-carboxy" group refers to the "-OC(=O)R" group having R selected from hydrogen, C 1~6 alkyl, C 2~6 alkenyl, C 2~6 alkynyl, C 3~7 carbocyclic, aryl, 5- to 10-membered heteroaryl, and 5- to 10-membered heterocyclic as defined herein.

[0092] The "C-carboxy" group refers to the "C(=O)OR" group having R selected from hydrogen, C 1~6 alkyl, C 2~6 alkenyl, C 2~6 alkynyl, C 3~7 carbocyclic, aryl, 5- to 10-membered heteroaryl, and 5- to 10-membered heterocyclic as defined herein. Non-limiting examples include carboxyl (i.e., -C(=O)OH).

[0093] The "cyano" group refers to the "-CN" group.

[0094] The "cyanato" group refers to the "-OCN" group.

[0095] The "isocyanato" group refers to the "-NCO" group.

[0096] The "thiocyanato" group refers to the "-SCN" group.

[0097] The "isothiocyanato" group refers to the "-NCS" group.

[0098] The "sulfinyl" group refers to the "-S(=O)R" group containing R selected from hydrogen, C 1~6 alkyl, C 2~6 alkenyl, C 2~6 alkynyl, C 3~7 carbocyclic, C 6~10 aryl, 5- to 10-membered heteroaryl, and 5- to 10-membered heterocyclic.

[0099] The "sulfonyl" group refers to the "-SO2R" group containing R selected from hydrogen, C 1~6 alkyl, C 2~6 alkenyl, C 2~6 alkynyl, C 3~7 carbocyclic, C 6~10 aryl, 5- to 10-membered heteroaryl, and 5- to 10-membered heterocyclic.

[0100] The "S-sulfonamide" group refers to the "-SO2NR A R B " group, where R A and R B are each independently selected from hydrogen, C 1~6 alkyl, C 2~6 alkenyl, C 2~6 alkynyl, C 3~7 carbocyclic, C 6~10 aryl, 5- to 10-membered heteroaryl, and 5- to 10-membered heterocyclic.

[0101] The "N-sulfonamide" group refers to the "-N(R A )SO2R B " group, where R A and R b are each independently hydrogen, C 1~6 alkyl, C 2~6 alkenyl, C 2~6 alkynyl, C 3~7 carbocyclic, C 6~10It is selected from aryl, 5- to 10-membered heteroaryl, and 5- to 10-membered heterocyclyl.

[0102] The "O-carbamyl" group refers to the "-OC(=O)NR A R B " group, and R A and R B are each independently hydrogen, C 1~6 alkyl, C 2~6 alkenyl, C 2~6 alkynyl, C 3~7 carbocyclic, C 6~10 aryl, 5- to 10-membered heteroaryl, and 5- to 10-membered heterocyclyl.

[0103] The "N-carbamyl" group refers to the "-N(R A )OC(=O)R B " group, and R A and R B are each independently hydrogen, C 1~6 alkyl, C 2~6 alkenyl, C 2~6 alkynyl, C 3~7 carbocyclic, C 6~10 aryl, 5- to 10-membered heteroaryl, and 5- to 10-membered heterocyclyl, each independently selected.

[0104] The "O-thiocarbamyloxy" group refers to the "-OC(=S)NR A R B " group, and R A and R B are each independently hydrogen, C 1~6 alkyl, C 2~6 alkenyl, C 2~6 alkynyl, C 3~7 carbocyclic, C 6~10 aryl, 5- to 10-membered heteroaryl, and 5- to 10-membered heterocyclyl, each independently selected.

[0105] The "N-thiocarbamyl" group refers to the "-N(R A )OC(=S)R B " group, and R A and RB is independently selected from hydrogen, C 1~6 alkyl, C 2~6 alkenyl, C 2~6 alkynyl, C 3~7 carbocyclic, C 6~10 aryl, 5- to 10-membered heteroaryl, and 5- to 10-membered heterocyclyl, respectively and independently.

[0106] The "C-amide" group refers to the "-C(=O)NR A R B " group. As defined herein, R A and R B are each independently hydrogen, C 1~6 alkyl, C 2~6 alkenyl, C 2~6 alkynyl, C 3~7 carbocyclic, C 6~10 aryl, 5- to 10-membered heteroaryl, and 5- to 10-membered heterocyclyl, respectively and independently selected.

[0107] The "N-amide" group refers to the "-N(R A )C(=O)R B " group. Here, R A and R B are each independently, as defined herein, hydrogen, C 1~6 alkyl, C 2~6 alkenyl, C 2~6 alkynyl, C 3~7 carbocyclic, C 6~10 aryl, 5- to 10-membered heteroaryl, and 5- to 10-membered heterocyclyl, respectively and independently selected.

[0108] The "amino" group refers to the "-NR A R B " group. Here, R A and R B are each independently, as defined herein, hydrogen, C 1~6 alkyl, C 2~6 alkenyl, C 2~6 alkynyl, C 3~7 carbocyclic, C 6~10It is selected from aryl, 5- to 10-membered heteroaryl, and 5- to 10-membered heterocyclyl.

[0109] The "aminoalkyl" group refers to an amino group bonded via an alkylene group.

[0110] The "alkoxyalkyl" group refers to an alkoxy group linked via an alkylene group such as, for example, "C 2~8 alkoxyalkyl".

[0111] As used herein, a substituent is a group derived from an unsubstituted parent group in which one or more hydrogen atoms have been replaced with other atoms or groups. Unless otherwise indicated, when a group is considered to be "substituted", the group is C1-C6 alkyl, C1-C6 alkenyl, C1-C6 alkynyl, C1-C6 heteroalkyl, C3-C7 carbocyclic (optionally substituted with halo, C1-C6 alkyl, C1-C6 alkoxy, C1-C6 haloalkyl, and C1-C6 haloalkoxy), C3-C7-carbocyclic-C1-C6-alkyl (optionally substituted with halo, C1-C6 alkyl, C1-C6 alkoxy, C1-C6 haloalkyl, and C1-C6 haloalkoxy), 5-10 membered heterocyclyl (optionally substituted with halo, C1-C6 alkyl, C1-C6 alkoxy, C1-C6 haloalkyl, and C1-C6 haloalkoxy), 5-10 membered heterocyclyl-C1-C6-alkyl (optionally substituted with halo, C1-C6 alkyl, C1-C6 alkoxy, C1-C6 haloalkyl, and C1-C6 haloalkoxy), aryl (optionally substituted with halo, C1-C6 alkyl, C1-C6 alkoxy, C1-C6 haloalkyl, and C1-C6 haloalkoxy), aryl(C1-C6)alkyl (optionally substituted with halo, C1-C6 alkyl, C1-C6 alkoxy, C1-C6 haloalkyl, and C1-C6 haloalkoxy), 5-10 membered heteroaryl (optionally substituted with halo, C1-C6 alkyl, C1-C6 alkoxy, C1-C6 haloalkyl, and C1-C6 haloalkoxy), 5-10 membered heteroaryl(C1-C6)alkyl (optionally substituted with halo, C1-C6 alkyl, C1-C6 alkoxy, C1-C6 haloalkyl, and C1-C6 haloalkoxy), halo, cyano, hydroxy, C1-C6 alkoxy, C1-C6 alkoxy(C1-C6)alkyl (i.e., ether), aryloxy, sulfhydryl (mercapto), halo(C1-C6)alkyl (e.g., -CF3), halo(C1-C6)alkoxy (e.g., -OCF3), C1-C6 alkylthio, arylthio, amino, amino(C1-C6)alkyl, nitro, O-carbamyl, N-carbamyl, O-thiocarbamyl, N-thiocarbamyl, C-amide, N-amide,It means being substituted with one or more substituents independently selected from S-sulfonamide, N-sulfonamide, C-carboxy, O-carboxy, acyl, cyanato, isocyanato, thiocyanato, isothiocyanato, sulfinyl, sulfonyl, and oxo (=O). When a group is described as "optionally substituted", the group may be substituted with the above substituents.,

[0112] In some embodiments, the substituent is substituted with one or more substituents individually and independently selected from C1-C4 alkyl, amino, hydroxy and halogen.,

[0113] It should be understood that certain radical naming rules may include either monoradicals or diradicals depending on the context. For example, when a substituent requires two attachment points to the rest of the molecule, the substituent is understood to be a diradical. For example, a substituent identified as an alkyl requiring two attachment points includes diradicals such as -CH2-, -CH2CH2-, -CH2CH(CH3)CH2-. Other radical naming rules clearly indicate that the radical is a diradical such as "alkylene" or "alkenylene".

[0114] When two R groups are said to "together with the atoms to which they are attached" form a ring (e.g., a carbocyclic, heterocyclic, aryl, heteroaryl ring), it means that the atom and the set unit of the two R groups are the ring cited. The ring, in another way, is not limited by the definition of each R group when obtained individually. For example, when the following partial structure exists:

Chemical formula

Chemical formula

[0115] Similarly, when it is said that two "adjacent" R groups "together with the atoms to which they are attached" form a ring, it means that the atoms, the intervening bonds, and the aggregate of the two R groups are the ring being referred to. For example, when the following substructure exists:

Chemical formula

Chemical formula

[0116] When a substituent is depicted as a diradical (i.e., when there are two points of attachment to the rest of the molecule), it should be understood that, unless otherwise specified, the substituent can be attached in either direction. Thus, for example, -AE-, or

Chemical formula

[0117] Isotopes may be present in the compounds described. Each chemical element represented in the compound structure may include any isotope of said element. For example, in a compound structure, a hydrogen atom may be explicitly disclosed or understood to be present in the compound. At any position in the compound where a hydrogen atom may be present, the hydrogen atom may be any isotope of hydrogen, including but not limited to hydrogen-1 (protium) and hydrogen-2 (deuterium). Accordingly, references to compounds herein include all potential isotopic forms unless the context clearly indicates otherwise.

[0118] Combination with additional pharmaceutical agents The compounds of formula (I) shown herein may be administered in combination with one or more additional pharmaceutical agents. In some embodiments, the above compounds may be administered in combination with one additional pharmaceutical agent. In some embodiments, the above compounds may be administered in combination with two additional pharmaceutical agents. In some embodiments, the above compounds may be administered in combination with three or more additional pharmaceutical agents.

[0119] In some embodiments, the compounds of formula (I) presented herein may be administered simultaneously with one or more additional pharmaceutical agents. In another embodiment, the compounds of the present disclosure may be administered sequentially with one or more additional pharmaceutical agents.

[0120] Aminoglycoside In some embodiments, the compounds of formula (I) presented herein may be administered in combination with an aminoglycoside. An aminoglycoside is a compound having an amino-modified glycoside. Such compounds have pharmaceutical uses, for example, as antibiotics and by promoting readthrough of premature termination codons (PTCs). In some specific embodiments, the aminoglycoside may increase ribosomal readthrough of mRNA transcripts having PTC mutations in the cystic fibrosis CFTR channel. Aminoglycosides include, but are not limited to, kanamycin A, amikacin, tobramycin, dibekacin, gentamicin, geneticin, sisomicin, netilmicin, neomycin B, neomycin C, paromomycin, streptomycin, plazomycin, tobramycin,

Chemical formula

[0121] Enhancement of nonsense codon readthrough using the lead-through modulator compounds disclosed herein can be observed, for example, when the lead-through modulator compound is co-administered with an aminoglycoside. For example, co-administration of a lead-through modulator compound disclosed herein and an aminoglycoside can result in enhanced readthrough of nonsense codons even when the effective dosage of the aminoglycoside is below its maximum value. This has the advantage of maximizing readthrough of PTC mutants while suppressing harmful side effects of aminoglycosides. Without being bound by a particular theory, the lead-through modulator compounds disclosed herein may increase the potency and / or efficacy of aminoglycosides. In some embodiments, administration of a lead-through modulator compound disclosed herein can reduce the concentration of aminoglycoside required to achieve maximum effectiveness by 5%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, or more, or within a range defined by any of the foregoing percentages, compared to the maximum effective concentration of aminoglycoside when administered alone. Thus, for example, some embodiments include co-administering a compound of formula (I) with an aminoglycoside, where the amount of aminoglycoside is 5% or more and 90% or less, 5% or more and 80% or less, 5% or more and 60% or less, 5% or more and 40% or less, or 10% or more and 30% or less of the maximum effective amount of aminoglycoside. In some embodiments, the aminoglycoside can be G418, ELX-02, or any aminoglycoside disclosed herein.

[0122] eRF3 modulator In some embodiments, the compounds of formula (I) presented herein can be administered in combination with one or more compounds that reduce the level of eRF3 protein in a subject. The eRF3 protein is involved in translation termination and post-termination events. See, for example, Baradaran-Heravi et al. Nucleic Acids Research 2021, 1-17. In some embodiments, the compounds of formula (I) presented herein may be administered in combination with both aminoglycosides and eRF3 modulators.

[0123] Enhanced nonsense codon readthrough using the lead-through modulator compounds disclosed herein may also be observed when the lead-through modulator compounds are used in combination with aminoglycosides and eRF3 modulators, such as cereblon E3 ligase modulators. Co-administration of the lead-through modulator compounds disclosed herein with aminoglycosides and eRF3 modulators can result in enhanced readthrough of nonsense codons even when the effective dosage of the aminoglycoside is below its maximum value. In some embodiments, administration of the lead-through modulator compounds disclosed herein in combination with an eRF3 modulator can reduce the concentration of aminoglycoside required to achieve maximum effect by 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%, or more, as compared to the maximum effective concentration of aminoglycoside when administered alone. Thus, for example, some embodiments include co-administering a compound of formula (I) with an aminoglycoside and an eRF3 modulator, wherein the amount of aminoglycoside is 5% or more and 90% or less, 5% or more and 80% or less, 5% or more and 60% or less, 5% or more and 40% or less, or 10% or more and 30% or less of the maximum effective amount of aminoglycoside. In some embodiments, the aminoglycoside can be G418, ELX-02, or any aminoglycoside disclosed herein. In some embodiments, the eRF3 modulator can be a cereblon E3 ligase modulator disclosed herein.

[0124] Compounds that modulate eRF3 levels in a subject include cereblon E3 ligase modulators. Cereblon E3 ligase modulators can be used for targeted proteolysis in a subject. In some embodiments, the cereblon E3 ligase modulator has the formula

Chemical Formula

[0125] In some embodiments, the cereblon E3 ligase modulator is of the formula

Chemical formula

[0126] In some embodiments, the cereblon E3 ligase modulator has the formula

Chemical formula

[0127] In some embodiments, the cereblon E3 ligase modulator is a compound having the formula

Chemical formula

[0128] In some embodiments, the cereblon E3 ligase modulator may be

Chemical formula

[0129] Pharmaceutical composition The compounds of formula (I) above and / or the additional pharmaceutical agents above can be formulated into pharmaceutical compositions for use in the treatment of the medical conditions described herein. For example, standard pharmaceutical formulation techniques such as those disclosed in Remington's The Science and Practice of Pharmacy, 21st Ed., Lippincott Williams & Wilkins (2005), which is hereby incorporated by reference in its entirety, are used. Accordingly, some embodiments include pharmaceutical compositions comprising: (a) a safe and therapeutically effective amount of a compound described herein or a pharmaceutically acceptable salt thereof; and (b) a pharmaceutically acceptable carrier, diluent, excipient, or a combination thereof.

[0130] In some embodiments, the compounds of formula (I) provided herein and one or more additional pharmaceutical agents provided herein can be formulated into a single pharmaceutical composition for use in the treatment of the conditions described herein. In some embodiments, a formulation comprising a compound of formula (I) provided herein can be administered in combination with one or more additional pharmaceutical agents provided herein, or a pharmaceutical composition comprising one or more additional pharmaceutical agents provided herein. In some embodiments, the pharmaceutical composition can comprise one or more compounds of formula (I) provided herein and one or more aminoglycosides. In another embodiment, the pharmaceutical composition may comprise one or more compounds of formula (I) provided herein and one or more eRF3 modulators. In some embodiments, the pharmaceutical composition may comprise one or more compounds of formula (I) provided herein, one or more aminoglycosides, and one or more eRF3 modulators. In some embodiments, the pharmaceutical composition may comprise one or more aminoglycosides and one or more eRF3 modulators. In some embodiments, the eRF3 modulator can be a cereblon E3 ligase modulator.

[0131] The terms "pharmaceutically acceptable carrier" or "pharmaceutically acceptable excipient" include any solvent, diluent, emulsifying agent, binder, buffer, dispersion medium, coating agent, antibacterial and antifungal agent, isotonic agent and absorption delaying agent, etc., or other such compounds known to those skilled in the art to be useful in the formulation of pharmaceutical preparations. The use of such media and agents with pharmaceutically active substances is well known in the art. Their use in therapeutic compositions is contemplated, except where any conventional media or agent is incompatible with the active ingredient. Auxiliary active ingredients can also be incorporated into the composition. Furthermore, various adjuvants as commonly used in the art can also be included. These and other such compounds are described in the literature, for example, Merck Index, Merck & Company, Rahway, NJ. Considerations regarding the formulation of the various components in pharmaceutical compositions are described, for example, in Gilman et al. (Eds.) (1990); Goodman and Gilman’s: The Pharmacological Basis of Therapeutics, 8th Ed., Pergamon Press.

[0132] Examples of substances that can be used as a pharmaceutically acceptable carrier or its components include sugars such as lactose, glucose, and sucrose; starches such as corn starch and potato starch; cellulose and its derivatives such as sodium carboxymethyl cellulose, ethyl cellulose, and methyl cellulose; powdered tragacanth; malt; gelatin; talc; solid lubricants such as stearic acid and magnesium stearate; calcium sulfate; vegetable oils such as peanut oil, cottonseed oil, sesame oil, olive oil, corn oil, and theobroma oil; propylene glycol, glycerin, sorbitol, mannitol, and polyethylene glycol; alginic acid; emulsifying agents such as TWEENS; wetting agents such as sodium lauryl sulfate; coloring agents; flavors; tableting agents, stabilizers; antioxidants; preservatives; water free of pyrogens; isotonic saline; and phosphate buffer solutions.

[0133] The selection of a pharmaceutically acceptable carrier to be used with the subject compound is determined by the manner in which the compound is to be administered.

[0134] The compositions described herein are preferably provided in unit dosage form. As used herein, a "unit dosage form" is a composition containing an amount of the compound suitable for a single administration to a subject in accordance with good medical practice. However, a formulation of a single-dose or unit-dose preparation does not mean that such a dosage preparation is administered once a day or once per treatment cycle. A unit dosage form can include a once-daily dosage, or a divided dosage in which a plurality of unit dosage forms are administered during the day to complete a once-daily administration. According to the present disclosure, a unit dosage form can be administered more or less frequently than once a day and may be administered more than once during the course of treatment. Such dosage forms can be administered by any method appropriate to the formulation, such as orally, parenterally, etc., and may be administered by infusion over a period of time (e.g., from about 30 minutes to about 2 - 6 hours). Although single administration is particularly contemplated, on the other hand, the compositions administered according to the methods described herein can also be administered as a continuous infusion or via an implantable infusion pump.

[0135] The methods described herein can utilize any of a variety of suitable forms for various routes of administration, for example, oral, nasal, rectal, topical (including transdermal administration), ocular, intracerebral, intracranial, intrathecal, intraarterial, intravenous, intramuscular, or other parenteral routes of administration. One of ordinary skill in the art will understand that oral and nasal compositions include compositions administered by inhalation and manufactured using available methodologies. Depending on the particular desired route of administration, a variety of pharmaceutically acceptable carriers well known in the art may be used. Pharmaceutically acceptable carriers include, for example, solid or liquid fillers, diluents, hydrotropes, surfactants, and encapsulating substances. Optionally, pharmaceutically active substances that do not substantially inhibit the activity of the compound may also be included. The amount of carrier used in combination with the present compound is an amount sufficient to provide a practical amount for administration per unit dose of the present compound. Techniques and compositions for manufacturing dosage forms useful in the methods described herein are described in the following references, all of which are incorporated herein by reference: Modern Pharmaceutics, 4th Ed., Chapters 9 and 10 (Banker & Rhodes, editors, 2002); Lieberman et al., Pharmaceutical Dosage Forms: Tablets (1989); and Ansel, Introduction to Pharmaceutical Dosage Forms 8th Edition (2004).

[0136] A variety of oral dosage forms can be used, such as solid dosage forms such as tablets, capsules, granules, powders, etc. Tablets can be compression tablets, tablet triturates, enteric coatings, sugar coatings, film coatings, or multiple compression tablets containing suitable binders, lubricants, diluents, disintegrants, colorants, flavorants, flow inducing agents, and melting agents. Liquid oral dosage forms include aqueous solutions, emulsions, suspensions, solutions and / or suspensions reconstituted from non-foaming granules, and foaming preparations reconstituted from foaming granules, and include suitable solvents, preservatives, emulsifying agents, suspending agents, diluents, sweeteners, melting agents, colorants, and flavorants.

[0137] Pharmaceutically acceptable carriers suitable for unit dosage forms for oral administration are well known in the art. Tablets typically contain inert diluents such as calcium carbonate, sodium carbonate, mannitol, lactose, and cellulose; binders such as starch, gelatin, and sucrose; disintegrants such as starch, alginic acid, and croscarmellose; and conventional pharmaceutically compatible adjuvants such as lubricants such as magnesium stearate, stearic acid, microcrystalline cellulose, carboxymethyl cellulose, and talc. Tablets may also contain solubilizing or emulsifying agents, such as poloxamer, Cremophor / Coliphor (registered trademark) / Lutrol (registered trademark), methyl cellulose, hydroxypropyl methyl cellulose, or others known in the art. Lubricants such as silicon dioxide can be used to improve the flow properties of powder mixtures. Colorants such as FD&C dyes can also be added to improve the appearance. Sweeteners and flavors such as aspartame, saccharin, menthol, peppermint, and fruit flavors are useful as adjuvants for chewable tablets. Capsules usually contain one or more of the solid diluents disclosed above. The selection of carrier components is influenced by secondary considerations such as taste, cost, storage stability, etc., which can be readily performed by those skilled in the art.

[0138] Oral (PO) compositions include solutions, emulsions, suspensions, etc. Pharmaceutically acceptable carriers suitable for the preparation of such compositions are well known in the art. Representative components of carriers for syrups, elixirs, emulsions, and suspensions include ethanol, glycerol, propylene glycol, polyethylene glycol, liquid sucrose, sorbitol, water, etc. Typical suspending agents include methyl cellulose, sodium carboxymethyl cellulose, Avicel RC-591, tragacanth, sodium alginate, etc., typical wetting agents include lecithin, polysorbate 80, etc., and typical preservatives include methyl paraben, sodium benzoate, etc. Peroral liquid compositions may also contain one or more components such as the sweeteners, flavoring agents, and colorants disclosed above.

[0139] Such compositions can also be coated by conventional methods, typically pH- or time-dependent coatings, whereby the subject compound can be released in the gastrointestinal tract in the vicinity of the desired site of action or at various times to extend the desired action. Such dosage forms typically include, but are not limited to, one or more of cellulose acetate phthalate, polyvinyl acetate phthalate, hydroxypropyl methylcellulose phthalate, ethyl cellulose, Eudragit coatings, waxes, and shellac.

[0140] The compositions described herein may optionally contain other pharmaceutically active substances.

[0141] Other compositions useful for achieving systemic delivery of the subject compound include sublingual, buccal, and nasal formulations. Such compositions typically include one or more soluble filler substances such as sucrose, sorbitol, and mannitol; and binders such as acacia, microcrystalline cellulose, carboxymethyl cellulose, and hydroxypropyl methylcellulose. The lubricants, glidants, sweeteners, colorants, antioxidants, and flavoring agents disclosed above may also be included.

[0142] Liquid compositions that are topical ophthalmic formulations are formulated to be topically administered to the eye. Comfort can be maximized as much as possible, but formulation considerations (e.g., drug stability) may sometimes be required over optimal comfort. If comfort cannot be maximized, the liquid can be formulated to be acceptable to the patient as an ophthalmic solution. In addition, ophthalmically acceptable solutions may be packaged for single use or may contain preservatives to prevent contamination over multiple uses.

[0143] For ophthalmic use, solutions or agents are often prepared using physiological saline as the main vehicle. It is desirable to maintain the eye drops at a comfortable pH using an appropriate buffer system. The formulation may also contain conventional pharmaceutically acceptable preservatives, stabilizers, and surfactants.

[0144] Examples of preservatives that can be used in the pharmaceutical compositions disclosed in this specification include, but are not limited to, benzalkonium chloride, PHMB, chlorobutanol, thimerosal, phenyl mercaptan, acetate, and phenyl mercaptan nitrate. A useful surfactant is, for example, Tween 80. Similarly, various useful solvents can be used in the ophthalmic preparations disclosed in this specification. These solvents include, but are not limited to, polyvinyl alcohol, povidone, hydroxypropyl methylcellulose, poloxamer, carboxymethyl cellulose, hydroxyethyl cellulose, purified water, etc.

[0145] If necessary, or for convenience, an osmotic pressure regulator may be added. These include salts, especially sodium chloride, potassium chloride, mannitol, glycerin, or other suitable ophthalmically acceptable osmotic pressure regulators, but are not limited thereto.

[0146] As long as the resulting preparation is ophthalmically acceptable, various buffer solutions and pH adjustment means can be used. In many compositions, the pH is between 4 and 9. Therefore, examples of buffer agents include acetate buffer, citrate buffer, phosphate buffer, borate buffer, etc. An acid or a base may be used as necessary to adjust the pH of these preparations.

[0147] Examples of ophthalmically acceptable antioxidants include, but are not limited to, sodium metabisulfite, sodium thiosulfate, acetylcysteine, butylated hydroxyanisole, and butylated hydroxytoluene.

[0148] Another excipient component that can be included in the ophthalmic preparation is a chelating agent. A useful chelating agent is sodium edetate, but other chelating agents may be used instead of or in combination with this.

[0149] For topical use, including transdermal administration, creams, ointments, gels, solutions or suspensions containing the compounds disclosed herein are employed. Topical formulations generally may contain a pharmaceutical carrier, co-solvent, emulsifier, penetration enhancer, preservative system, and emollient agent.

[0150] For intravenous administration, the compounds and compositions described herein may be dissolved or dispersed in a pharmaceutically acceptable diluent such as saline or glucose solution. Appropriate excipients can be included to achieve the desired pH, which may include, but is not limited to, NaOH, sodium carbonate, sodium acetate, HCl, citric acid, etc. In various embodiments, the pH of the final composition ranges from 2 to 8, preferably from 4 to 7. Antioxidant excipients include sodium bisulfite, sodium acetone bisulfite, sodium formaldehyde sulfoxylate, sulfoxylate, thiourea, EDTA, etc. Other non-limiting examples of suitable excipients found in the final intravenous composition include sodium or potassium phosphate, citric acid, tartaric acid, gelatin, and carbohydrates such as dextrose, mannitol, dextran. Further acceptable excipients are described in Powell, et al., Compendium of Excipients for Parenteral Formulations, PDA J Pharm Sci and Tech 1998, 52 238-311, and Nema et al., Excipients and Their Role in Approved Injectable Products: Current Usage and Future Directions, PDA J.Pharm.Sci.Tech.2011, 65 287-332, which are hereby incorporated by reference in their entirety. Antimicrobial agents may also include, but are not limited to, phenylmercuric nitrate, thimerosal, benzethonium chloride, benzalkonium chloride, phenol, cresol, chlorobutanol, etc.

[0151] Compositions for intravenous administration can also be provided to caregivers in one or more solid forms reconstituted with a suitable diluent such as sterile water, saline, or glucose aqueous solution immediately before administration. In another embodiment, the composition is provided as a solution that can be administered parenterally. In yet another embodiment, the composition is provided as a solution that is further diluted before administration. In embodiments that include administering a combination of a compound described herein with another agent, the combination can be provided to the caregiver as a mixture, or the caregiver can mix the two agents before administration, or the two agents can be administered separately.

[0152] The actual unit dosage of the lead-through modulator compounds described herein and / or the additional pharmaceutical agents described herein depends on the particular compound and the condition being treated. In some embodiments, the dosage can be from about 0.01 mg / kg to about 120 mg / kg or more, from about 0.05 mg / kg or less to about 70 mg / kg, from about 0.1 mg / kg to about 50 mg / kg, from about 1.0 mg / kg to about 10 mg / kg, from about 5.0 mg / kg to about 10 mg / kg, or from about 10.0 mg / kg to about 20.0 mg / kg based on body weight. In some embodiments, the dosage can be less than 100 mg / kg, less than 90 mg / kg, less than 80 mg / kg, less than 70 mg / kg, less than 60 mg / kg, less than 50 mg / kg, less than 40 mg / kg, less than 30 mg / kg, less than 25 mg / kg, less than 20 mg / kg, less than 10 mg / kg, less than 7.5 mg / kg, less than 6 mg / kg, less than 5 mg / kg, less than 4 mg / kg, less than 3 mg / kg, less than 2.5 mg / kg, less than 1 mg / kg, less than 0.5 mg / kg, less than 0.1 mg / kg, less than 0.05 mg / kg, or less than 0.005 mg / kg based on body weight. In some embodiments, the actual unit dosage is in the range of 0.05, 0.07, 0.1, 0.3, 1.0, 3.0, 5.0, 10.0 or 25.0 mg / kg based on body weight, or in the range between any two of these values. Thus, for administration to a 70 kg person, the dosage range is from about 0.1 mg to about 70 mg, from about 1 mg to about 50 mg, from about 0.5 mg to about 10 mg, from about 1 mg to about 10 mg, from about 2.5 mg to about 30 mg, from about 35 mg or less to about 700 mg or more, from about 7 mg to about 600 mg, from about 10 mg to about 500 mg, or from about 20 mg to about 300 mg, or from about 200 mg to about 2000 mg. In some embodiments, the actual unit dosage is 0.1 mg. In some embodiments, the actual unit dosage is 0.5 mg. In some embodiments, the actual unit dosage is 1 mg. In some embodiments, the actual unit dosage is 1.5 mg. In some embodiments, the actual unit dosage is 2 mg. In some embodiments, the actual unit dosage is 2.5 mg.In some embodiments, the actual unit dose is 3 mg. In some embodiments, the actual unit dose is 3.5 mg. In some embodiments, the actual unit dose is 4 mg. In some embodiments, the actual unit dose is 4.5 mg. In some embodiments, the actual unit dose is 5 mg. In some embodiments, the actual unit dose is 10 mg. In some embodiments, the actual unit dose is 25 mg. In some embodiments, the actual unit dose is 250 mg or less. In some embodiments, the actual unit dose is 100 mg or less. In some embodiments, the actual unit dose is 70 mg or less.

[0153] In some embodiments, the lead-through modulator compound described herein is about 1 to 50 mg / m of body surface area 2It may be administered at a dosage within the range. In some embodiments, the lead-through modulator compounds described herein are about 1-2, 1-3, 1-4, 1-5, 1-6, 1-7, 1-8, 1-9, 1-10, 1-11, 1-12, 1-13, 1-13.75, 1-14, 1-15, 1-16, 1-17, 1-18, 1-19, 1-20, 1-22.5, 1-25, 1-27.5, 1-30, 1.5-2, 1.5-3, 1.5-4, 1.5-5, 1.5-6, 1.5-7, 1.5-8, 1.5-9, 1.5-10, 1.5-11, 1.5-12, 1.5-13, 1.5-13.75, 1.5-14, 1.5-15, 1.5-16, 1.5-17, 1.5-18, 1.5-19, 1.5-20, 1.5-22.5, 1.5-25, 1.5-27.5, 1.5-30, 2.5-2, 2.5-3, 2.5-4, 2.5-5, 2.5-6, 2.5-7, 2.5-8, 2.5-9, 2.5-10, 2.5-11, 2.5-12, 2.5-13, 2.5-13.75, 2.5-14, 2.5-15, 2.5-16, 2.5-17, 2.5-18, 2.5-19, 2.5-20, 2.5-22.5, 2.5-25, 2.5-27.5, 2.5-30, 2.5-7.5, 3-4, 3-5, 3-6, 3-7, 3-8, 3-9, 3-10, 3-11, 3-12, 3-13, 3-13.75, 3-14, 3-15, 3-16, 3-17, 3-18, 3-19, 3-20, 3-22.5, 3-25, 3-27.5, 3-30, 3.5-6.5, 3.5-13.75, 3.5-15, 2.5-17.5, 4-5, 4-6, 4-7, 4-8, 4-9, 4-10, 4-11, 4-12, 4-13, 4-13.75, 4-14, 4-15, 4-16, 4-17, 4-18, 4-19, 4-20, 4-22.5, 4-25, 4-27.5, 4-30, 5-6, 5-7, 5-8, 5-9, 5-10, 5-11, 5-12, 5-13, 5-13.75, 5-14, 5-15, 5-16, 5-17, 5-18, 5-19, 5-20, 5-22.5, 5-25, 5-27.5, 5-30, 6-7, 6-8, 6-9, 6-10, 6-11, 6-12, 6-13, 6-13.75, 6-14, 6-15, 6-16, 6-17, 6-18, 6-19, 6-20, 6-22.5, 6-25, 6-27. per body surface area.5, 6 to 30, 7 to 8, 7 to 9, 7 to 10, 7 to 11, 7 to 12, 7 to 13, 7 to 13.75, 7 to 14, 7 to 15, 7 to 16, 7 to 17, 7 to 18, 7 to 19, 7 to 20, 7 to 22.5, 7 to 25, 7 to 27.5, 7 to 30, 7.5 to 12.5, 7.5 to 13.5, 7.5 to 15, 8 to 9, 8 to 10, 8 to 11, 8 to 12, 8 to 13, 8 to 13.75, 8 to 14, 8 to 15, 8 to 16, 8 to 17, 8 to 18, 8 to 19, 8 to 20, 8 to 22.5, 8 to 25, 8 to 27.5, 8 to 30, 9 to 10, 9 to 11, 9 to 12, 9 to 13, 9 to 13.75, 9 to 14, 9 to 15, 9 to 16, 9 to 17, 9 to 18, 9 to 19, 9 to 20, 9 to 22.5, 9 to 25, 9 to 27.5, 9 to 30, 10 to 11, 10 to 12, 10 to 13, 10 to 13.75, 10 to 14, 10 to 15, 10 to 16, 10 to 17, 10 to 18, 10 to 19, 10 to 20, 10 to 22.5, 10 to 25, 10 to 27.5, 10 to 30, 11.5 to 15.5, 12.5 to 14.5, 7.5 to 22.5, 8.5 to 32.5, 9.5 to 15.5, 15.5 to 24.5, 5 to 35, 17.5 to 22.5, 22.5 to 32.5, 25 to 35, 25.5 to 24.5, 27.5 to 32.5, 2 to 20, 2.5 to 22.5, or 9.5 to 21.5 mg / m 2 It may be administered at a dosage in the range of. In some embodiments, the lead-through modulator compound described herein is about 0.5, 1, 1.5, 2, 2.5, 3, 3.5, 4, 4.5, 5, 5.5, 6, 6.5, 7, 7.5, 8, 8.5, 9, 9.5, 10, 10.5, 11, 11.5, 12, 12.5, 13, 13.5, 14, 14.5, 15, 15.5, 16, 16.5, 17, 17.5, 18, 18.5, 19, 19.5, 20, 20.5, 21, 21.5, 22, 22.5, 23, 23.5, 24, 24.5, 25, 25.5, 26, 26.5, 27, 27.5, 28, 28.5, 29, 29.5, 30, 30.5, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40 mg / m of body surface area 2It can be administered at a dose of. In some embodiments, the lead-through modulator compounds described herein are about 0.5, 1, 1.5, 2, 2.5, 3, 3.5, 4, 4.5, 5, 5.5, 6, 6.5, 7, 7.5, 8, 8.5, 9, 9.5, 10, 10.5, 11, 11.5, 12, 12.5, 13, 13.5, 14, 14.5, 15, 15.5, 16, 16.5, 17, 17.5, 18, 18.5, 19, 19.5, 20, 20.5, 21, 21.5, 22, 22.5, 23, 23.5, 24, 24.5, 25, 25.5, 26, 26.5, 27, 27.5, 28, 28.5, 29, 29.5, 30, 30.5, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40 mg / m 2 It can be administered at a dose of less than. In some embodiments, the lead-through modulator compounds described herein are about 0.5, 1, 1.5, 2, 2.5, 3, 3.5, 4, 4.5, 5, 5.5, 6, 6.5, 7, 7.5, 8, 8.5, 9, 9.5, 10, 10.5, 11, 11.5, 12, 12.5, 13, 13.5, 14, 14.5, 15, 15.5, 16, 16.5, 17, 17.5, 18, 18.5, 19, 19.5, 20, 20.5, 21, 21.5, 22, 22.5, 23, 23.5, 24, 24.5, 25, 25.5, 26, 26.5, 27, 27.5, 28, 28.5, 29, 29.5, 30, 30.5, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50 mg / m 2 It may be administered at a dose in the range of.

[0154] In some embodiments, the dosage of the lead-through modulator compound is from about 0.1 mg to 100 mg, 0.1 mg to 50 mg, 0.1 mg to 20 mg, 0.1 mg to 10 mg, 0.5 mg to 100 mg, 0.5 mg to 50 mg, 0.5 mg to 20 mg, 0.5 mg to 10 mg, 1 mg to 100 mg, 1 mg to 50 mg, 1 mg to 20 mg, 1 mg to 10 mg, 2.5 mg to 50 mg, 2.5 mg to 20 mg, 2.5 mg to 10 mg, or about 2.5 mg to 5 mg. In some embodiments, the dosage of the lead-through modulator compound is from about 5 mg to 300 mg, about 5 mg to 200 mg, about 7.5 mg to 200 mg, 10 mg to 100 mg, 15 mg to 100 mg, 20 mg to 100 mg, 30 mg to 100 mg, 40 mg to 100 mg, 10 mg to 80 mg, 15 mg to 80 mg, 20 mg to 80 mg, 30 mg to 80 mg, 40 mg to 80 mg, 10 mg to 60 mg, 15 mg to 60 mg, 20 mg to 60 mg, 30 mg to 60 mg, or about 40 mg to 60 mg. In some embodiments, the lead-through modulator compound is from about 20 mg to 60 mg, 27 mg to 60 mg, 20 mg to 45 mg, or 27 mg to 45 mg. In some embodiments, the dosage of the lead-through modulator compound is from about 5 mg to 7.5 mg, 5 mg to 9 mg, 5 mg to 10 mg, 5 mg to 12 mg, 5 mg to 14 mg, 5 mg to 15 mg, 5 mg to 16 mg, 5 mg to 18 mg, 5 mg to 20 mg, 5 mg to 22 mg, 5 mg to 24 mg, 5 mg to 26 mg, 5 mg to 28 mg, 5 mg to 30 mg, 5 mg to 32 mg, 5 mg to 34 mg, 5 mg to 36 mg, 5 mg to 38 mg, 5 mg to 40 mg, 5 mg to 42 mg, 5 mg to 44 mg, 5 mg to 46 mg, 5 mg to 48 mg, 5 mg to 50 mg, 5 mg to 52 mg, 5 mg to 54 mg, 5 mg to 56 mg, 5 mg to 58 mg, 5 mg to 60 mg, 7 mg to 7.7 mg, 7 mg to 9 mg, 7 mg to 10 mg, 7 mg to 12 mg, 7 mg to 14 mg, 7 mg to 15 mg, 7 mg to 16 mg, 7 mg to 18 mg, 7 mg to 20 mg, 7 mg to 22 mg, 7 mg to 24 mg, 7 mg to 26 mg, 7 mg to 28 mg, 7 mg to 30 mg, 7 mg to 32 mg, 7 mg to 34 mg, 7 mg to 36 mg, 7 mg to 38 mg, 7 mg to 40 mg, 7 mg to 42 mg,7 mg to 44 mg, 7 mg to 46 mg, 7 mg to 48 mg, 7 mg to 50 mg, 7 mg to 52 mg, 7 mg to 54 mg, 7 mg to 56 mg, 7 mg to 58 mg, 7 mg to 60 mg, 9 mg to 10 mg, 9 mg to 12 mg, 9 mg to 14 mg, 9 mg to 15 mg, 9 mg to 16 mg, 9 mg to 18 mg, 9 mg to 20 mg, 9 mg to 22 mg, 9 mg to 24 mg, 9 mg to 26 mg, 9 mg to 28 mg, 9 mg to 30 mg, 9 mg to 32 mg, 9 mg to 34 mg, 9 mg to 36 mg, 9 mg to 38 mg, 9 mg to 40 mg, 9 mg to 42 mg, 9 mg to 44 mg, 9 mg to 46 mg, 9 mg to 48 mg, 9 mg to 50 mg, 9 mg to 52 mg, 9 mg to 54 mg, 9 mg to 56 mg, 9 mg to 58 mg, 9 mg to 60 mg, 10 mg to 12 mg, 10 mg to 14 mg, 10 mg to 15 mg, 10 mg to 16 mg, 10 mg to 18 mg, 10 mg to 20 mg, 10 mg to 22 mg, 10 mg to 24 mg, 10 mg to 26 mg, 10 mg to 28 mg, 10 mg to 30 mg, 10 mg to 32 mg, 10 mg to 34 mg, 10 mg to 36 mg, 10 mg to 38 mg, 10 mg to 40 mg, 10 mg to 42 mg, 10 mg to 44 mg, 10 mg to 46 mg, 10 mg to 48 mg, 10 mg to 50 mg, 10 mg to 52 mg, 10 mg to 54 mg, 10 mg to 56 mg, 10 mg to 58 mg, 10 mg to 60 mg, 12 mg to 14 mg, 12 mg to 15 mg, 12 mg to 16 mg, 12 mg to 18 mg, 12 mg to 20 mg, 12 mg to 22 mg, 12 mg to 24 mg, 12 mg to 26 mg, 12 mg to 28 mg, 12 mg to 30 mg, 12 mg to 32 mg, 12 mg to 34 mg, 12 mg to 36 mg, 12 mg to 38 mg, 12 mg to 40 mg, 12 mg to 42 mg, 12 mg to 44 mg, 12 mg to 46 mg, 12 mg to 48 mg, 12 mg to 50 mg, 12 mg to 52 mg, 12 mg to 54 mg, 12 mg to 56 mg, 12 mg to 58 mg, 12 mg to 60 mg, 15 mg to 16 mg, 15 mg to 18 mg, 15 mg to 20 mg, 15 mg to 22 mg, 15 mg to 24 mg, 15 mg to 26 mg, 15 mg to 28 mg, 15 mg to 30 mg, 15 mg to 32 mg, 15 mg to 34 mg, 15 mg to 36 mg, 15 mg to 38 mg, 15 mg to 40 mg, 15 mg to 42 mg, 15 mg to 44 mg, 15 mg to 46 mg,15 mg to 48 mg, 15 mg to 50 mg, 15 mg to 52 mg, 15 mg to 54 mg, 15 mg to 56 mg, 15 mg to 58 mg, 15 mg to 60 mg, 17 mg to 18 mg, 17 mg to 20 mg, 17 mg to 22 mg, 17 mg to 24 mg, 17 mg to 26 mg, 17 mg to 28 mg, 17 mg to 30 mg, 17 mg to 32 mg, 17 mg to 34 mg, 17 mg to 36 mg, 17 mg to 38 mg, 17 mg to 40 mg, 17 mg to 42 mg, 17 mg to 44 mg, 17 mg to 46 mg, 17 mg to 48 mg, 17 mg to 50 mg, 17 mg to 52 mg, 17 mg to 54 mg, 17 mg to 56 mg, 17 mg to 58 mg, 17 mg to 60 mg, 20 mg to 22 mg, 20 mg to 24 mg, 20 mg to 26 mg, 20 mg to 28 mg, 20 mg to 30 mg, 20 mg to 32 mg, 20 mg to 34 mg, 20 mg to 36 mg, 20 mg to 38 mg, 20 mg to 40 mg, 20 mg to 42 mg, 20 mg to 44 mg, 20 mg to 46 mg, 20 mg to 48 mg, 20 mg to 50 mg, 20 mg to 52 mg, 20 mg to 54 mg, 20 mg to 56 mg, 20 mg to 58 mg, 20 mg to 60 mg, 22 mg to 24 mg, 22 mg to 26 mg, 22 mg to 28 mg, 22 mg to 30 mg, 22 mg to 32 mg, 22 mg to 34 mg, 22 mg to 36 mg, 22 mg to 38 mg, 22 mg to 40 mg, 22 mg to 42 mg, 22 mg to 44 mg, 22 mg to 46 mg, 22 mg to 48 mg, 22 mg to 50 mg, 22 mg to 52 mg, 22 mg to 54 mg, 22 mg to 56 mg, 22 mg to 58 mg, 22 mg to 60 mg, 25 mg to 26 mg, 25 mg to 28 mg, 25 mg to 30 mg, 25 mg to 32 mg, 25 mg to 34 mg, 25 mg to 36 mg, 25 mg to 38 mg, 25 mg to 40 mg, 25 mg to 42 mg, 25 mg to 44 mg, 25 mg to 46 mg, 25 mg to 48 mg, 25 mg to 50 mg, 25 mg to 52 mg, 25 mg to 54 mg, 25 mg to 56 mg, 25 mg to 58 mg, 25 mg to 60 mg, 27 mg to 28 mg, 27 mg to 30 mg, 27 mg to 32 mg, 27 mg to 34 mg, 27 mg to 36 mg, 27 mg to 38 mg, 27 mg to 40 mg, 27 mg to 42 mg, 27 mg to 44 mg, 27 mg to 46 mg, 27 mg to 48 mg, 27 mg to 50 mg, 27 mg to 52 mg, 27 mg to 54 mg,27 mg to 56 mg, 27 mg to 58 mg, 27 mg to 60 mg, 30 mg to 32 mg, 30 mg to 34 mg, 30 mg to 36 mg, 30 mg to 38 mg, 30 mg to 40 mg, 30 mg to 42 mg, 30 mg to 44 mg, 30 mg to 46 mg, 30 mg to 48 mg, 30 mg to 50 mg, 30 mg to 52 mg, 30 mg to 54 mg, 30 mg to 56 mg, 30 mg to 58 mg, 30 mg to 60 mg, 33 mg to 34 mg, 33 mg to 36 mg, 33 mg to 38 mg, 33 mg to 40 mg, 33 mg to 42 mg, 33 mg to 44 mg, 33 mg to 46 mg, 33 mg to 48 mg, 33 mg to 50 mg, 33 mg to 52 mg, 33 mg to 54 mg, 33 mg to 56 mg, 33 mg to 58 mg, 33 mg to 60 mg, 36 mg to 38 mg, 36 mg to 40 mg, 36 mg to 42 mg, 36 mg to 44 mg, 36 mg to 46 mg, 36 mg to 48 mg, 36 mg to 50 mg, 36 mg to 52 mg, 36 mg to 54 mg, 36 mg to 56 mg, 36 mg to 58 mg, 36 mg to 60 mg, 40 mg to 42 mg, 40 mg to 44 mg, 40 mg to 46 mg, 40 mg to 48 mg, 40 mg to 50 mg, 40 mg to 52 mg, 40 mg to 54 mg, 40 mg to 56 mg, 40 mg to 58 mg, 40 mg to 60 mg, 43 mg to 46 mg, 43 mg to 48 mg, 43 mg to 50 mg, 43 mg to 52 mg, 43 mg to 54 mg, 43 mg to 56 mg, 43 mg to 58 mg, 42 mg to 60 mg, 45 mg to 48 mg, 45 mg to 50 mg, 45 mg to 52 mg, 45 mg to 54 mg, 45 mg to 56 mg, 45 mg to 58 mg, 45 mg to 60 mg, 48 mg to 50 mg, 48 mg to 52 mg, 48 mg to 54 mg, 48 mg to 56 mg, 48 mg to 58 mg, 48 mg to 60 mg, 50 mg to 52 mg, 50 mg to 54 mg, 50 mg to 56 mg, 50 mg to 58 mg, 50 mg to 60 mg, 52 mg to 54 mg, 52 mg to 56 mg, 52 mg to 58 mg, or 52 mg to 60 mg. In some embodiments, the dosage of the lead-through modulator compound is about 5 mg, about 10 mg, about 12.5 mg, about 13.5 mg, about 15 mg, about 17.5 mg, about 20 mg, about 22.5 mg, about 25 mg, about 27 mg, about 30 mg, about 40 mg, about 50 mg, about 60 mg, about 70 mg, about 80 mg, about 90 mg, about 100 mg,It is about 125 mg, about 150 mg, or about 200 mg. In some embodiments, the dosage of the lead-through modulator compound is less than about 5 mg, about 10 mg, about 12.5 mg, about 13.5 mg, about 15 mg, about 17.5 mg, about 20 mg, about 22.5 mg, about 25 mg, about 27 mg, about 30 mg, about 40 mg, about 50 mg, about 60 mg, about 70 mg, about 80 mg, about 90 mg, about 100 mg, about 125 mg, about 150 mg, or about 200 mg. In some embodiments, the dosage of the lead-through modulator compound is about 5 mg, about 10 mg, about 12.5 mg, about 13.5 mg, about 15 mg, about 17.5 mg, about 20 mg, about 22.5 mg, about 25 mg, about 27 mg, about 30 mg, about 40 mg, about 50 mg, about 60 mg, about 70 mg, about 80 mg, about 90 mg, about 100 mg, about 125 mg, about 150 mg, about 200 mg, about 225 mg, about 250 mg, about 275 mg, or about 300 mg.,

[0155] In some embodiments, the additional pharmaceutical agent is about 1 to 50 mg / m of body surface area 2It is administered at a dosage within the range. In some embodiments, the additional pharmaceutical agent is about 1 to 2, 1 to 3, 1 to 4, 1 to 5, 1 to 6, 1 to 7, 1 to 8, 1 to 9, 1 to 10, 1 to 11, 1 to 12, 1 to 13, 1 to 13.75, 1 to 14, 1 to 15, 1 to 16, 1 to 17, 1 to 18, 1 to 19, 1 to 20, 1 to 22.5, 1 to 25, 1 to 27.5, 1 to 30, 1.5 to 2, 1.5 to 3, 1.5 to 4, 1.5 to 5, 1.5 to 6, 1.5 to 7, 1.5 to 8, 1.5 to 9, 1.5 to 10, 1.5 to 11, 1.5 to 12, 1.5 to 13, 1.5 to 13.75, 1.5 to 14, 1.5 to 15, 1.5 to 16, 1.5 to 17, 1.5 to 18, 1.5 to 19, 1.5 to 20, 1.5 to 22.5, 1.5 to 25, 1.5 to 27.5, 1.5 to 30, 2.5 to 2, 2.5 to 3, 2.5 to 4, 2.5 to 5, 2.5 to 6, 2.5 to 7, 2.5 to 8, 2.5 to 9, 2.5 to 10, 2.5 to 11, 2.5 to 12, 2.5 to 13, 2.5 to 13.75, 2.5 to 14, 2.5 to 15, 2.5 to 16, 2.5 to 17, 2.5 to 18, 2.5 to 19, 2.5 to 20, 2.5 to 22.5, 2.5 to 25, 2.5 to 27.5, 2.5 to 30, 2.5 to 7.5, 3 to 4, 3 to 5, 3 to 6, 3 to 7, 3 to 8, 3 to 9, 3 to 10, 3 to 11, 3 to 12, 3 to 13, 3 to 13.75, 3 to 14, 3 to 15, 3 to 16, 3 to 17, 3 to 18, 3 to 19, 3 to 20, 3 to 22.5, 3 to 25, 3 to 27.5, 3 to 30, 3.5 to 6.5, 3.5 to 13.75, 3.5 to 15, 2.5 to 17.5, 4 to 5, 4 to 6, 4 to 7, 4 to 8, 4 to 9, 4 to 10, 4 to 11, 4 to 12, 4 to 13, 4 to 13.75, 4 to 14, 4 to 15, 4 to 16, 4 to 17, 4 to 18, 4 to 19, 4 to 20, 4 to 22.5, 4 to 25, 4 to 27.5, 4 to 30, 5 to 6, 5 to 7, 5 to 8, 5 to 9, 5 to 10, 5 to 11, 5 to 12, 5 to 13, 5 to 13.75, 5 to 14, 5 to 15, 5 to 16, 5 to 17, 5 to 18, 5 to 19, 5 to 20, 5 to 22.5, 5 to 25, 5 to 27.5, 5 to 30, 6 to 7, 6 to 8, 6 to 9, 6 to 10, 6 to 11, 6 to 12, 6 to 13, 6 to 13.75, 6 to 14, 6 to 15, 6 to 16, 6 to 17, 6 to 18, 6 to 19, 6 to 20, 6 to 22.5, 6 to 25, 6 to 27.5, 6 to 30, 7 to 8, 7 to 9, 7 to 10, 7 to 11, 7 to 12, 7 to 13, 7 to 13.75, 7 to 14, 7 to 15, 7 to 16, 7 to 17, 7 to 18, 7 to 19, 7 to 20, 7 to 22.5, 7 to 25, 7 to 27.5, 7 to 30, 7 to 13.75, 7 to 15, 7 to 17.5, 8 to 9, 8 to 10, 8 to 11, 8 to 12, 8 to 13, 8 to 13.75, 8 to 14, 8 to 15, 8 to 16, 8 to 17, 8 to 18, 8 to 19, 8 to 20, 8 to 22.5, 8 to 25, 8 to 27.5, 8 to 30, 9 to 10, 9 to 11, 9 to 12, 9 to 13, 9 to 13.75, 9 to 14, 9 to 15, 9 to 16, 9 to 17, 9 to 18, 9 to 19, 9 to 20, 9 to 22.5, 9 to 25, 9 to 27.5, 9 to 30, 10 to 11, 10 to 12, 10 to 13, 10 to 13.75, 10 to 14, 10 to 15, 10 to 16, 10 to 17, 10 to 18, 10 to 19, 10 to 20, 10 to 22.5, 10 to 25, 10 to 27.5, 10 to 30, 11 to 12, 11 to 13, 11 to 13.75, 11 to 14, 11 to 15, 11 to 16, 11 to 17, 11 to 18, 11 to 19, 11 to 20, 11 to 22.5, 11 to 25, 11 to 27.5, 11 to 30, 12 to 13, 12 to 13.75, 12 to 14, 12 to 15, 12 to 16, 12 to 17, 12 to 18, 12 to 19, 12 to 20, 12 to 22.5, 12 to 25, 12 to 27.5, 12 to 30, 13 to 13.75, 13 to 14, 13 to 15, 13 to 16, 13 to 17, 13 to 18, 13 to 19, 13 to 20, 13 to 22.5, 13 to 25, 13 to 27.5, 13 to 30, 13.75 to 14, 13.75 to 15, 13.75 to 16, 13.75 to 17, 13.75 to 18, 13.75 to 19, 13.75 to 20, 13.75 to 22.5, 13.75 to 25, 13.75 to 27.5, 13.75 to 30, 14 to 15, 14 to 16, 14 to 17, 14 to 18, 14 to 19, 14 to 20, 14 to 22.5, 14 to 25, 14 to 27.5, 14 to 30, 15 to 16, 15 to 17, 15 to 18, 15 to 19, 15 to 20, 15 to 22.5, 15 to 25, 15 to 27.5, 15 to 30, 16 to 17, 16 to 18, 16 to 19, 16 to 20, 16 to 22.5, 16 to 25, 16 to 27.5, 16 to 30, 17 to 18, 17 to 19, 17 to 20, 17 to 22.5, 17 to 25, 17 to 27.5, 17 to 30, 18 to 19, 18 to 20, 18 to 22.5, 18 to 25, 18 to 27.5, 18 to 30, 19 to 20, 19 to 22.5, 19 to 25, 19 to 27.5, 19 to 30, 20 to 22.5, 20 to 25, 20 to 27.5, 20 to 30, 22.5 to 25, 22.5 to 27.5, 22.5 to 30, 25 to 27.5, 25 to 30, 27.5 to 30 of body surface area.75, 7 - 14, 7 - 15, 7 - 16, 7 - 17, 7 - 18, 7 - 19, 7 - 20, 7 - 22.5, 7 - 25, 7 - 27.5, 7 - 30, 7.5 - 12.5, 7.5 - 13.5, 7.5 - 15, 8 - 9, 8 - 10, 8 - 11, 8 - 12, 8 - 13, 8 - 13.75, 8 - 14, 8 - 15, 8 - 16, 8 - 17, 8 - 18, 8 - 19, 8 - 20, 8 - 22.5, 8 - 25, 8 - 27.5, 8 - 30, 9 - 10, 9 - 11, 9 - 12, 9 - 13, 9 - 13.75, 9 - 14, 9 - 15, 9 - 16, 9 - 17, 9 - 18, 9 - 19, 9 - 20, 9 - 22.5, 9 - 25, 9 - 27.5, 9 - 30, 10 - 11, 10 - 12, 10 - 13, 10 - 13.75, 10 - 14, 10 - 15, 10 - 16, 10 - 17, 10 - 18, 10 - 19, 10 - 20, 10 - 22.5, 10 - 25, 10 - 27.5, 10 - 30, 11.5 - 15.5, 12.5 - 14.5, 7.5 - 22.5, 8.5 - 32.5, 9.5 - 15.5, 15.5 - 24.5, 5 - 35, 17.5 - 22.5, 22.5 - 32.5, 25 - 35, 25.5 - 24.5, 27.5 - 32.5, 2 - 20, 2.5 - 22.5, or 9.5 - 21.5 mg / m 2 is administered at a dosage in the range of. In some embodiments, the additional pharmaceutical agent is about 0.5, 1, 1.5, 2, 2.5, 3, 3.5, 4, 4.5, 5, 5.5, 6, 6.5, 7, 7.5, 8, 8.5, 9, 9.5, 10, 10.5, 11, 11.5, 12, 12.5, 13, 13.5, 14, 14.5, 15, 15.5, 16, 16.5, 17, 17.5, 18, 18.5, 19, 19.5, 20, 20.5, 21, 21.5, 22, 22.5, 23, 23.5, 24, 24.5, 25, 25.5, 26, 26.5, 27, 27.5, 28, 28.5, 29, 29.5, 30, 30.5, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40 mg / m 2It is administered at a rate per body surface area. In some embodiments, the additional pharmaceutical agent is about 0.5, 1, 1.5, 2, 2.5, 3, 3.5, 4, 4.5, 5, 5.5, 6, 6.5, 7, 7.5, 8, 8.5, 9, 9.5, 10, 10.5, 11, 11.5, 12, 12.5, 13, 13.5, 14, 14.5, 15, 15.5, 16, 16.5, 17, 17.5, 18, 18.5, 19, 19.5, 20, 20.5, 21, 21.5, 22, 22.5, 23, 23.5, 24, 24.5, 25, 25.5, 26, 26.5, 27, 27.5, 28, 28.5, 29, 29.5, 30, 30.5, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40 mg / m 2 It is administered at a dose in the range of less than. In some embodiments, the additional pharmaceutical agent is about 0.5, 1, 1.5, 2, 2.5, 3, 3.5, 4, 4.5, 5, 5.5, 6, 6.5, 7, 7.5, 8, 8.5, 9, 9.5, 10, 10.5, 11, 11.5, 12, 12.5, 13, 13.5, 14, 14.5, 15, 15.5, 16, 16.5, 17, 17.5, 18, 18.5, 19, 19.5, 20, 20.5, 21, 21.5, 22, 22.5, 23, 23.5, 24, 24.5, 25, 25.5, 26, 26.5, 27, 27.5, 28, 28.5, 29, 29.5, 30, 30.5, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50 mg / m 2 It is administered at a dose in the range of.

[0156] In some embodiments, the dosage of the additional pharmaceutical agent is from about 5 mg to 300 mg, 5 mg to 200 mg, 7.5 mg to 200 mg, 10 mg to 100 mg, 15 mg to 100 mg, 20 mg to 100 mg, 30 mg to 100 mg, 40 mg to 100 mg, 10 mg to 80 mg, 15 mg to 80 mg, 20 mg to 80 mg, 30 mg to 80 mg, 40 mg to 80 mg, 10 mg to 60 mg, 15 mg to 60 mg, 20 mg to 60 mg, 30 mg to 60 mg, or about 40 mg to 60 mg. In some embodiments, the dosage of the additional pharmaceutical agent administered is from about 20 mg to 60 mg, 27 mg to 60 mg, 20 mg to 45 mg, or 27 mg to 45 mg. In some embodiments, the dosage of the additional pharmaceutical agent administered is from about 5 mg to 7.5 mg, 5 mg to 9 mg, 5 mg to 10 mg, 5 mg to 12 mg, 5 mg to 14 mg, 5 mg to 15 mg, 5 mg to 16 mg, 5 mg to 18 mg, 5 mg to 20 mg, 5 mg to 22 mg, 5 mg to 24 mg, 5 mg to 26 mg, 5 mg to 28 mg, 5 mg to 30 mg, 5 mg to 32 mg, 5 mg to 34 mg, 5 mg to 36 mg, 5 mg to 38 mg, 5 mg to 40 mg, 5 mg to 42 mg, 5 mg to 44 mg, 5 mg to 46 mg, 5 mg to 48 mg, 5 mg to 50 mg, 5 mg to 52 mg, 5 mg to 54 mg, 5 mg to 56 mg, 5 mg to 58 mg, 5 mg to 60 mg, 7 mg to 7.7 mg, 7 mg to 9 mg, 7 mg to 10 mg, 7 mg to 12 mg, 7 mg to 14 mg, 7 mg to 15 mg, 7 mg to 16 mg, 7 mg to 18 mg, 7 mg to 20 mg, 7 mg to 22 mg, 7 mg to 24 mg, 7 mg to 26 mg, 7 mg to 28 mg, 7 mg to 30 mg, 7 mg to 32 mg, 7 mg to 34 mg, 7 mg to 36 mg, 7 mg to 38 mg, 7 mg to 40 mg, 7 mg to 42 mg, 7 mg to 44 mg, 7 mg to 46 mg, 7 mg to 48 mg, 7 mg to 50 mg, 7 mg to 52 mg, 7 mg to 54 mg, 7 mg to 56 mg, 7 mg to 58 mg, 7 mg to 60 mg, 9 mg to 10 mg, 9 mg to 12 mg, 9 mg to 14 mg, 9 mg to 15 mg, 9 mg to 16 mg, 9 mg to 18 mg, 9 mg to 20 mg, 9 mg to 22 mg, 9 mg to 24 mg, 9 mg to 26 mg, 9 mg to 28 mg, 9 mg to 30 mg, 9 mg to 32 mg, 9 mg to 34 mg, 9 mg to 36 mg, 9 mg to 38 mg, 9 mg to 40 mg,9 mg to 42 mg, 9 mg to 44 mg, 9 mg to 46 mg, 9 mg to 48 mg, 9 mg to 50 mg, 9 mg to 52 mg, 9 mg to 54 mg, 9 mg to 56 mg, 9 mg to 58 mg, 9 mg to 60 mg, 10 mg to 12 mg, 10 mg to 14 mg, 10 mg to 15 mg, 10 mg to 16 mg, 10 mg to 18 mg, 10 mg to 20 mg, 10 mg to 22 mg, 10 mg to 24 mg, 10 mg to 26 mg, 10 mg to 28 mg, 10 mg to 30 mg, 10 mg to 32 mg, 10 mg to 34 mg, 10 mg to 36 mg, 10 mg to 38 mg, 10 mg to 40 mg, 10 mg to 42 mg, 10 mg to 44 mg, 10 mg to 46 mg, 10 mg to 48 mg, 10 mg to 50 mg, 10 mg to 52 mg, 10 mg to 54 mg, 10 mg to 56 mg, 10 mg to 58 mg, 10 mg to 60 mg, 12 mg to 14 mg, 12 mg to 15 mg, 12 mg to 16 mg, 12 mg to 18 mg, 12 mg to 20 mg, 12 mg to 22 mg, 12 mg to 24 mg, 12 mg to 26 mg, 12 mg to 28 mg, 12 mg to 30 mg, 12 mg to 32 mg, 12 mg to 34 mg, 12 mg to 36 mg, 12 mg to 38 mg, 12 mg to 40 mg, 12 mg to 42 mg, 12 mg to 44 mg, 12 mg to 46 mg, 12 mg to 48 mg, 12 mg to 50 mg, 12 mg to 52 mg, 12 mg to 54 mg, 12 mg to 56 mg, 12 mg to 58 mg, 12 mg to 60 mg, 15 mg to 16 mg, 15 mg to 18 mg, 15 mg to 20 mg, 15 mg to 22 mg, 15 mg to 24 mg, 15 mg to 26 mg, 15 mg to 28 mg, 15 mg to 30 mg, 15 mg to 32 mg, 15 mg to 34 mg, 15 mg to 36 mg, 15 mg to 38 mg, 15 mg to 40 mg, 15 mg to 42 mg, 15 mg to 44 mg, 15 mg to 46 mg, 15 mg to 48 mg, 15 mg to 50 mg, 15 mg to 52 mg, 15 mg to 54 mg, 15 mg to 56 mg, 15 mg to 58 mg, 15 mg to 60 mg, 17 mg to 18 mg, 17 mg to 20 mg, 17 mg to 22 mg, 17 mg to 24 mg, 17 mg to 26 mg, 17 mg to 28 mg, 17 mg to 30 mg, 17 mg to 32 mg, 17 mg to 34 mg, 17 mg to 36 mg, 17 mg to 38 mg, 17 mg to 40 mg, 17 mg to 42 mg, 17 mg to 44 mg, 17 mg to 46 mg, 17 mg to 48 mg, 17 mg to 50 mg,17 mg to 52 mg, 17 mg to 54 mg, 17 mg to 56 mg, 17 mg to 58 mg, 17 mg to 60 mg, 20 mg to 22 mg, 20 mg to 24 mg, 20 mg to 26 mg, 20 mg to 28 mg, 20 mg to 30 mg, 20 mg to 32 mg, 20 mg to 34 mg, 20 mg to 36 mg, 20 mg to 38 mg, 20 mg to 40 mg, 20 mg to 42 mg, 20 mg to 44 mg, 20 mg to 46 mg, 20 mg to 48 mg, 20 mg to 50 mg, 20 mg to 52 mg, 20 mg to 54 mg, 20 mg to 56 mg, 20 mg to 58 mg, 20 mg to 60 mg, 22 mg to 24 mg, 22 mg to 26 mg, 22 mg to 28 mg, 22 mg to 30 mg, 22 mg to 32 mg, 22 mg to 34 mg, 22 mg to 36 mg, 22 mg to 38 mg, 22 mg to 40 mg, 22 mg to 42 mg, 22 mg to 44 mg, 22 mg to 46 mg, 22 mg to 48 mg, 22 mg to 50 mg, 22 mg to 52 mg, 22 mg to 54 mg, 22 mg to 56 mg, 22 mg to 58 mg, 22 mg to 60 mg, 25 mg to 26 mg, 25 mg to 28 mg, 25 mg to 30 mg, 25 mg to 32 mg, 25 mg to 34 mg, 25 mg to 36 mg, 25 mg to 38 mg, 25 mg to 40 mg, 25 mg to 42 mg, 25 mg to 44 mg, 25 mg to 46 mg, 25 mg to 48 mg, 25 mg to 50 mg, 25 mg to 52 mg, 25 mg to 54 mg, 25 mg to 56 mg, 25 mg to 58 mg, 25 mg to 60 mg, 27 mg to 28 mg, 27 mg to 30 mg, 27 mg to 32 mg, 27 mg to 34 mg, 27 mg to 36 mg, 27 mg to 38 mg, 27 mg to 40 mg, 27 mg to 42 mg, 27 mg to 44 mg, 27 mg to 46 mg, 27 mg to 48 mg, 27 mg to 50 mg, 27 mg to 52 mg, 27 mg to 54 mg, 27 mg to 56 mg, 27 mg to 58 mg, 27 mg to 60 mg, 30 mg to 32 mg, 30 mg to 34 mg, 30 mg to 36 mg, 30 mg to 38 mg, 30 mg to 40 mg, 30 mg to 42 mg, 30 mg to 44 mg, 30 mg to 46 mg, 30 mg to 48 mg, 30 mg to 50 mg, 30 mg to 52 mg, 30 mg to 54 mg, 30 mg to 56 mg, 30 mg to 58 mg, 30 mg to 60 mg, 33 mg to 34 mg, 33 mg to 36 mg, 33 mg to 38 mg, 33 mg to 40 mg, 33 mg to 42 mg, 33 mg to 44 mg,33 mg to 46 mg, 33 mg to 48 mg, 33 mg to 50 mg, 33 mg to 52 mg, 33 mg to 54 mg, 33 mg to 56 mg, 33 mg to 58 mg, 33 mg to 60 mg, 36 mg to 38 mg, 36 mg to 40 mg, 36 mg to 42 mg, 36 mg to 44 mg, 36 mg to 46 mg, 36 mg to 48 mg, 36 mg to 50 mg, 36 mg to 52 mg, 36 mg to 54 mg, 36 mg to 56 mg, 36 mg to 58 mg, 36 mg to 60 mg, 40 mg to 42 mg, 40 mg to 44 mg, 40 mg to 46 mg, 40 mg to 48 mg, 40 mg to 50 mg, 40 mg to 52 mg, 40 mg to 54 mg, 40 mg to 56 mg, 40 mg to 58 mg, 40 mg to 60 mg, 43 mg to 46 mg, 43 mg to 48 mg, 43 mg to 50 mg, 43 mg to 52 mg, 43 mg to 54 mg, 43 mg to 56 mg, 43 mg to 58 mg, 42 mg to 60 mg, 45 mg to 48 mg, 45 mg to 50 mg, 45 mg to 52 mg, 45 mg to 54 mg, 45 mg to 56 mg, 45 mg to 58 mg, 45 mg to 60 mg, 48 mg to 50 mg, 48 mg to 52 mg, 48 mg to 54 mg, 48 mg to 56 mg, 48 mg to 58 mg, 48 mg to 60 mg, 50 mg to 52 mg, 50 mg to 54 mg, 50 mg to 56 mg, 50 mg to 58 mg, 50 mg to 60 mg, 52 mg to 54 mg, 52 mg to 56 mg, 52 mg to 58 mg, or 52 mg to 60 mg. In some embodiments, the dosage of the additional pharmaceutical agent is about 5 mg, about 10 mg, about 12.5 mg, about 13.5 mg, about 15 mg, about 17.5 mg, about 20 mg, about 22.5 mg, about 25 mg, about 27 mg, about 30 mg, about 40 mg, about 50 mg, about 60 mg, about 70 mg, about 80 mg, about 90 mg, about 100 mg, about 125 mg, about 150 mg, or about 200 mg. In some embodiments, the dosage of the additional pharmaceutical agent is less than about 5 mg, about 10 mg, about 12.5 mg, about 13.5 mg, about 15 mg, about 17.5 mg, about 20 mg, about 22.5 mg, about 25 mg, about 27 mg, about 30 mg, about 40 mg, about 50 mg, about 60 mg, about 70 mg, about 80 mg, about 90 mg, about 100 mg, about 125 mg, about 150 mg, or about 200 mg. In some embodiments, the dosage of the additional pharmaceutical agent is about 5 mg, about 10 mg, about 12.5 mg, about 13.5 mg, about 15 mg,It is about 17.5 mg, about 20 mg, about 22.5 mg, about 25 mg, about 27 mg, about 30 mg, about 40 mg, about 50 mg, about 60 mg, about 70 mg, about 80 mg, about 90 mg, about 100 mg, about 125 mg, about 150 mg, about 200 mg, about 225 mg, about 250 mg, about 275 mg, or about 300 mg.

[0157] In some embodiments, the additional pharmaceutical agent may be an aminoglycoside as described herein. In another embodiment, the additional pharmaceutical agent may be an eRF3 modulator. In some particular embodiments, the eRF3 modulator may be a cereblon E3 ligase modulator. In yet another embodiment, two or more additional pharmaceutical agents may be administered in combination with the lead-through modulator described herein. In some embodiments, the lead-through modulator may be administered in combination with two additional pharmaceutical agents, and the two additional pharmaceutical agents may be an aminoglycoside and an eRF3 modulator. In some particular embodiments, the eRF3 modulator may be a cereblon E3 ligase modulator.

[0158] In some embodiments, the mass ratio of the lead-through modulator compound to any additional pharmaceutical agent is from about 10:1 to about 1:10. In some embodiments, the mass ratio of the lead-through modulator compound to any additional pharmaceutical agent is from about 7:1 to about 1:7. In some embodiments, the mass ratio of the lead-through modulator compound to any additional pharmaceutical agent is from about 5:1 to about 1:5. In some embodiments, the mass ratio of the lead-through modulator compound to any additional pharmaceutical agent is from about 3:1 to about 1:3. In some embodiments, the mass ratio of the lead-through modulator compound to any additional pharmaceutical agent is from about 2:1 to about 1:2. In some embodiments, the mass ratio of the lead-through modulator compound to any additional pharmaceutical agent is from about 10:1 to about 1:1, from about 7:1 to about 1:1, from about 5:1 to about 1:1, from about 3:1 to about 1:1, or from about 2:1 to about 1:1. In some embodiments, the mass ratio of the lead-through modulator compound to any additional pharmaceutical agent is from about 1:1 to about 1:2, from about 1:1 to about 1:3, from about 1:1 to about 1:5, from about 1:1 to about 1:7, or from about 1:1 to about 1:10. In some embodiments, the mass ratio of the lead-through modulator compound to any additional pharmaceutical agent is about 10:1, 9:1, 8:1, 7:1, 6:1, 5:1, 4:1, 3:1, 2:1, 1:1, 1:2, 1:3, 1:4, 1:5, 1:6, 1:7, 1:8, 1:9, or 1:10, or any range between two of these values.

[0159] In some embodiments, the lead-through modulator compounds presented herein may be administered simultaneously with one or more additional pharmaceutical agents. In another embodiment, the compounds of the present disclosure may be administered sequentially with one or more additional pharmaceutical agents.

[0160] In some embodiments, the read-through modulator compound may be administered prior to the administration of an additional pharmaceutical agent. In some embodiments, the read-through modulator compound may be administered about 15 minutes, about 30 minutes, about 45 minutes, about 1 hour, about 2 hours, about 3 hours, about 4 hours, about 6 hours, about 8 hours, about 12 hours, or about 24 hours before the administration of the additional pharmaceutical agent provided herein. In some embodiments, the read-through modulator compound may be administered after the administration of an additional pharmaceutical agent. In some embodiments, the read-through modulator compound may be administered about 15 minutes, about 30 minutes, about 45 minutes, about 1 hour, about 2 hours, about 3 hours, about 4 hours, about 6 hours, about 8 hours, about 12 hours, or about 24 hours after the administration of the additional pharmaceutical agent provided herein.

[0161] Method of treatment Some embodiments according to the methods and compositions of the present disclosure relate to a method of enhancing read-through of a gene containing a stop codon, comprising administering to a subject in need thereof an effective amount of a read-through modulator compound described herein in combination with one or more additional pharmaceutical agents (e.g., aminoglycosides).

[0162] Disorders and diseases associated with stop codons include chronic fibrosis, muscular dystrophy, retinitis pigmentosa, hemophilia A, hemophilia B, Hurler syndrome, anuria, ataxia telangiectasia, tuberous sclerosis, Usher syndrome, multiple kidney diseases, central nervous system diseases, amyloidosis, cancer, Parkinson's disease, mucopolysaccharidosis type 1, mucopolysaccharidosis type 3, spinal muscular atrophy, neurofibromatosis type 1 and type 2, Marfan syndrome, dwarfism, hyperthyroidism, hypothyroidism, Rett syndrome, cystic fibrosis, spinal muscular atrophy, and the like. In some particular embodiments described herein, the disease or disorder may be cystic fibrosis. In some embodiments, the disease or disorder may be cancer. Exemplary cancers include Ewing sarcoma, hemangiosarcoma, myeloma, glioblastoma, acute myeloid leukemia (AML), pancreatic cancer, glioma (e.g., high grade glioma (HGG) or diffuse glioma), glioblastoma, non-small cell lung cancer, diffuse large B cell lymphoma (DLBCL), breast cancer, head and neck cancer, melanoma, non-small cell lung cancer, ovarian cancer, prostate cancer, endometrial cancer, and the like. The cancer can be a solid tumor (such as glioma, breast tumor, lung tumor, etc.) or a hematological malignancy (such as AML, DLBCL, myeloma, etc.).

[0163] In some embodiments, the disease or disorder associated with a premature stop codon is cystic fibrosis. Mutations in the gene that produces the cystic fibrosis transmembrane conductance regulator (CFTR) protein, which has 1,480 amino acids, can inhibit the normal production or function of the CFTR protein found in cells of the lungs and other parts of the body. In some embodiments, the compounds described herein may be used to increase ribosome readthrough of mRNA transcripts having premature stop codon mutations in the cystic fibrosis CFTR channel. In some embodiments, the mutation can be one or more of G542X, R553X, R1162X, S1255X, W1282X, W1316X. In some embodiments, the mutation is G542X. In another embodiment, the mutation is R1162X.

[0164] In some embodiments, the compounds described herein, alone, in combination with one or more additional pharmaceutical agents, or compositions containing them, may result in improved readthrough of premature stop codons. In some embodiments, administration of the readthrough modulator compounds described herein results in at least 5%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, 100%, 110%, 120%, 130%, 140%, 150%, 160%, 170%, 180%, 190%, 200% or more readthrough of premature stop codons compared to readthrough in the absence of administration of the readthrough modulator compounds described herein. In some embodiments, the compounds described herein may be administered in combination with an aminoglycoside. In some embodiments, administration of the readthrough modulator compounds described herein in combination with an aminoglycoside may result in at least 5%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, 100%, 110%, 120%, 130%, 140%, 150%, 160%, 170%, 180%, 190%, 200%, or more readthrough of premature stop codons compared to administration of the aminoglycoside alone. In some embodiments, combinations of the readthrough modulator compounds described herein may be administered in combination with a compound that reduces eRF3 protein levels in a subject.In some embodiments, the combination of a lead-through modulator compound, an aminoglycoside, and a compound that reduces eRF3 protein levels in a subject described herein may result in a lead-through of stop codons that is at least 5%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, 100%, 110%, 120%, 130%, 140%, 150%, 160%, 170%, 180%, 190%, 200%, or more compared to administration of the aminoglycoside alone. In some embodiments, the compound that reduces eRF3 protein levels in a subject is a cereblon E3 ligase modulator described herein.

[0165] Formulation method The compounds disclosed in this specification can be synthesized by the methods described below, or by modifications of these methods. Methods of modifying the methods include, inter alia, temperature, solvent, reagents, etc., which are known to those skilled in the art. Generally, in any of the processes for preparing the compounds disclosed herein, it may be necessary and / or desirable to protect sensitive or reactive groups on the molecules involved. This can also be achieved by means of conventional protecting groups, as described, for example, in Protective Groups in Organic Chemistry (ed. J.F.W. McOmie, Plenum Press, 1973); and P.G.M. Green, T.W. Wuts, Protecting Groups in Organic Synthesis (3rd ed.) Wiley, New York (1999), which are hereby incorporated by reference in their entirety. The protecting groups can also be removed at a convenient later stage using methods known in the art. Synthetic chemical transformations useful for synthesizing the applicable compounds are known in the art and include, for example, those described in R. Larock, Comprehensive Organic Transformations, VCH Publishers, 1989, or L. Paquette, ed., Encyclopedia of Reagents for Organic Synthesis, John Wiley and Sons, 1995, all of which are hereby incorporated by reference in their entirety. The pathways shown and described herein are merely illustrative and are not intended to limit, nor should they be construed as limiting, the scope of the claims in any way. Those skilled in the art will be able to recognize modifications of the disclosed syntheses and devise alternative pathways based on the disclosure herein. All such modifications and alternative pathways are included within the scope of the claims.

[0166] Synthesis of the compound of formula (I) The following exemplary schemes are provided for the reader's guidance and collectively represent exemplary methods for making the compounds encompassed herein. Further, other methods for preparing the compounds described herein will be readily apparent to those skilled in the art in light of the following reaction schemes and examples. Unless otherwise noted, all variables are as defined above. Characterization by 1H-NMR and LCMS spectra of the final products is summarized in Table A.

[0167] The compounds of formula (I) were synthesized by two different strategies depicted in Scheme 1. X is halogen and is complemented by additional operations of functional groups and protecting groups and / or inserted steps.

Chemical formula

Examples

[0168] Examples 1 and 2 Synthesis of [1-[5-[(2,6-dichlorophenyl)methoxy]pyrimidin-2-yl]imidazol-4-yl]methanol (Compound 2)

Chemical formula

[0169] Example 2:

Chemical formula

[0170] Example 3:

Chemical formula

[0171] Example 4:

Chemical formula

[0172] Example 5:

Chemical formula

[0173] Example 6:

Chemical Structure

[0174] Example 7:

Chemical Structure

[0175] Example 8:

Chemical Structure

[0176] Example 9:

Chemical formula

[0177] Example 10:

Chemical formula

[0178] Example 11: [Chemical formula] To a solution of MDN_007-4 (85 mg, 0.175 mmol) and Et3N (53 mg, 0.525 mmol) in THF (1 mL) was added carbonyldiimidazole (CDI) (43 mg, 0.262 mmol). The mixture was stirred overnight at room temperature. The mixture was concentrated and purified by silica gel column (DCM:MeOH = 40:1) to obtain the title compound MDN_007 as a brown solid (35 mg, yield 53%).

[0179] Example 12: [Chemical formula] To a solution of MDN_034-3 (80 mg, 0.210 mmol) in DMF (2 mL) were added oxiran-2-ylmethyl butyrate (91 mg, 0.630 mmol) and Cs2CO3 (205 mg, 0.630 mmol). The reaction solution was stirred overnight at 80 °C. The reaction mixture was filtered and purified by preparative HPLC (NH4HCO3), and freeze-dried to obtain the title compound (27.7 mg, yield 34.6%).

[0180] Example 13: [Chemical formula] To a solution of MDN_038-1 (77 mg, 0.3 mmol) in DMF (2 mL) were added intermediate-3 (63 mg, 0.3 mmol) and K2CO3 (235 mg, 0.9 mmol). The reaction was stirred at room temperature for 16 hours under an argon atmosphere. The reaction mixture was diluted with H2O (30 mL) and extracted with EtOAc (30 mL × 3). The organic layer was dried over Na2SO4, filtered, and concentrated. The residue was purified by flash chromatography (EtOAc:PE = 0% - 50%) to obtain a white solid (36 mg, yield 33%).

[0181] Example 14: [Chemical formula] A mixture of MDN_063-2 (200 mg, 0.53 mmol), 2-(oxiran-2-ylmethyl) butyrate (153 mg, 1.06 mmol) and Cs2CO3 (345 mg, 1.06 mmol) in DMF (2 mL) was stirred in a microwave reactor at 100 °C for 1 hour. The mixture was filtered and purified by preparative HPLC and SFC to obtain the title compound MDN_063 as a white solid (21 mg, 10% yield).

[0182] Example 15:

Chemical formula

[0183] Example 16:

Chemical formula

[0184] Example 17:

Chemical formula

[0185] Example 19:

Chemical formula

[0186] Example 20:

Chemical formula

[0187] Example 21:

Chemical Structure

[0188] Example 22:

Chemical Structure

[0189] Example 23: [Chemical formula] To a mixture of MDN_076-1 (100 mg, 0.264 mmol) in DMF (2 mL), (1H-pyrazol-4-yl)methanol (25.0 mg, 0.264 mmol), Cu2O (2 mg, 0.016 mmol), Cs2CO3 (258 mg, 0.792 mmol) and salicylaldoxime (7 mg, 0.053 mmol) were added. The reaction was stirred at 90 °C for 16 h under an Ar atmosphere. The reaction mixture was diluted with H2O (30 mL) and extracted with EtOAc (50 mL × 3). The organic layer was dried over Na2SO4, filtered and concentrated under reduced pressure. The residue was purified by flash chromatography (EA:PE = 0% - 30%) to give a white solid (39.0 mg, yield 42.3%).

[0190] Example 24: [Chemical formula] A mixture of MDN_080-2 (70 mg, 0.136 mmol) in CM / TFA 2:1 (4 mL / 2 mL) was stirred at room temperature for 2 h. LCMS indicated that most of the starting material had been consumed and the desired product was detected. The reaction mixture was diluted with H2O (30 mL) and extracted with DCM (30 mL × 3). The combined organic layers were adjusted to pH = 7 - 8, washed with brine (20 mL × 2), dried over anhydrous Na2SO4 and concentrated to give the crude product (130 mg) as a solid. The crude product was purified by flash chromatography (silica gel, 20 g, CH3CN / H2O = 0% - 100%) to give the target product MDN_080 (10 mg, yield 16.0%).

[0191] Example 25: [Chemical formula] A mixture of MDN_096-3 (100 mg, 0.520 mmol), 2-(bromomethyl)-1,3-dichlorobenzene (137 mg, 0.570 mmol) and K2CO3 (144 mg, 1.04 mmol) in DMF (2 mL) was stirred at room temperature for 16 h. The mixture was filtered and purified by preparative HPLC (TFA) to give MDN_096 (29.1 mg, yield 15.9%) as a white solid.

[0192] Example 26: [Chemical formula] A mixture of MDN_098-3 (100 mg, 0.520 mmol), K2CO3 (144 mg, 1.04 mmol) and 2-(bromomethyl)-1,3-dichlorobenzene (137 mg, 0.570 mmol) in DMF (2 mL) was stirred at room temperature for 16 h. The mixture was filtered and purified by preparative HPLC (TFA) to give MDN_098 as a white solid (11.5 mg, yield 6.3%).

[0193] Example 27: [Chemical formula] To a solution of MDN_070-2 (145 mg, 0.384 mmol) in anhydrous THF (4 mL) was added LiAlH4 (29 mg, 0.769 mmol) at 0 °C. The reaction mixture was stirred overnight at room temperature under Ar. The reaction mixture was diluted with H2O (50 mL) and extracted with EtOAc (50 mL × 3). The organic layer was dried over Na2SO4, filtered and concentrated under reduced pressure. The residue was purified by flash chromatography (EtOAc:PE = 0% - 50%) to give a white solid (25.59 mg, yield 19.06%).

[0194] Example 28: [Chemical formula] A mixture of MDN_078-1 (130 mg, 0.812 mmol), MDN_078-2 (311 mg, 1.13 mmol) and Cs2CO3 (793 mg, 2.44 mmol) in DMF (5 mL) was stirred at room temperature for 2 h. The reaction mixture was diluted with H2O (30 mL) and extracted with EtOAc (30 mL×3). The combined organic layers were washed with brine (20 mL×2), dried over anhydrous Na2SO4 and concentrated to give the crude product (278 mg) as a solid. The crude product was purified by flash chromatography (silica gel, 40 g, CH3CN / H2O 0% - 100%) to give the target product MDN_078 (60 mg, yield 23.2%).

[0195] Example 29:

Chemical formula

[0196] Example 30:

Chemical formula

[0197] Example 31:

Chemical formula

[0198] Example 32:

Chemical formula

[0199] Example 33:

Chemical formula

[0200] Example 34:

Chemical formula

[0201] Example 35:

Chemical formula

[0202] Example 36:

Chemical formula

[0203] Example 37: [Chemical] A mixture of Tol (4 ml) containing 1,3-dichloro-2-((4-iodophenoxy)methyl)benzene (400 mg, 1.06 mmol), morpholin-2-ylmethanol (124 mg, 1.06 mmol), t-BuONa (152 mg, 1.58 mmol), Pd(OAc)2 (12 mg, 0.053 mmol), dicyclohexyl[2’,4’,6’-tris(propan-2-yl)[1,1’-biphenyl]-2-yl]phosphane (XPhos) (51 mg, 0.106 mmol) and t-BuOH (4 ml) was charged into a microwave tube. Argon was bubbled through the mixture for 1 minute. The reaction vessel was sealed and stirred at 100 °C for 16 hours. After cooling, the reaction mixture was concentrated to remove excess volatiles. The residue was diluted with H2O (20 ml) and extracted with EtOAc (30 ml × 3). The organic layer was dried over Na2SO4, filtered, concentrated to give the crude product, which was purified by flash chromatography on silica gel (EA / PE = 0 - 50%) to give the title compound as a yellow solid (66 mg, yield 16.9%).

[0204] Example 38: [Chemical] To a solution of MDN_135-2 (200 mg, 0.677 mmol) and prop-2-yn-1-ol (42 mg, 0.744 mmol) in t-BuOH / H2O (2 ml / 1 ml), CuSO4 5H2O (169 mg, 0.677 mmol) and sodium L-ascorbate (67 mg, 0.338 mmol) were added. The mixture was stirred at 100 °C for 16 hours. The mixture was extracted with DCM, concentrated to give a residue, which was purified by preparative HPLC to give the title compound MDN_135 as a white solid (20 mg, yield 8%).

[0205] Example 39: [Chemical] A solution of 3513-AF-146-001 (283 mg, 0.59 mmol, 1 equiv) in HCl (4 M in dioxane) (3 mL) was stirred at room temperature for 2 h. Workup: The reaction mixture was concentrated under reduced pressure. Diluted with DMSO (3 ml), and purified by preparative HPLC autopurification (ISCO ACCQ HP125, preparative HPLC column: Big Gemini-NX C18 size: 30 mm × 250 mm 5 μM; sample: 3.20 ml from tube 1), eluting with 5-95% ACN / aqueous solution of 0.1% FA / 0.1% formic acid (FA). The desired fractions were combined to give 3-{5-[(3,5-dichlorophenyl)methoxy]pyridin-2-yl}-5-(hydroxymethyl)-1,3-oxazolidin-2-one (103 mg, 0.28 mmol, 47.66%) as a white solid (purity: >95%).

[0206] Example 40:

Chemical formula

[0207] Example 41:

Chemical formula

[0208] Example 42:

Chem.

[0209] Example 43:

Chem.

[0210] Example 44:

Chem.

[0211] Example 45:

Chem.

[0212] Example 46:

Chemical Structure

[0213] Example 47:

Chemical Structure

[0214] Example 48:

Chemical Structure

[0215] Example 49:

Chemical Structure

[0216] Example 50:

Chem.

[0217] Example 51:

Chem.

[0218] Example 52:

Chem.

[0219] Example 53:

Chemical formula

[0220] Example 54:

Chemical Structure

[0221] Example 55:

Chemical Structure

[0222] Example 56:

Chemical Structure

[0223] Example 57:

Chemical Structure

[0224] Example 58:

Chemical formula

[0225] Example 59:

Chem.

[0226] Example 60:

Chem.

[0227] Example 61:

Chem.

[0228] Example 62:

Chem.

[0229] Example 63:

Chemical formula

[0230] Example 64:

Chemical formula

[0231] The reaction mixture was stirred at room temperature for 4 h. The reaction mixture was diluted with H2O (20 mL) and extracted with EtOAc (15 mL × 3). The organic layer was dried over Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by preparative HPLC (NH4HCO3) and lyophilized to give the title compound (44.4 mg, yield 56.9%).

[0232] Example 65:

Chemical formula

[0233] Example 66:

Chem.

[0234] Example 67:

Chem.

[0235] Example 68:

Chem.

[0236] Example 69: [Chemical formula] A solution of 2-chloro-5-[(2,6-dichlorophenyl)methoxy]pyrimidine (50 mg, 0.17 mmol, 1 equiv), (S)-2-(hydroxymethyl)morpholine HCl (39.79 mg, 0.26 mmol, 1.5 equiv) and potassium carbonate (71.6 mg, 0.52 mmol, 3 equiv) in DMSO (1 mL) was purged with nitrogen. After capping the vial, it was heated to 120 °C and maintained there for 2 h. The reaction mixture was stirred at room temperature overnight, diluted with EtOAc, washed with water and then with brine. The organic extract was dried (MgSO4) and then the solvent was distilled off under reduced pressure. The resulting residue was dissolved in DMSO, filtered, and purified by preparative HPLC automated flash chromatography (ISCO ACCQ HP150, preparative HPLC column: gemini 150×20 5um size: 20mm×150mm 5μM; sample: 1.20 ml from tube 1) eluting with 5 - 95% ACN / 0.1% aqueous FA / 0.1% FA. The desired fractions were collected and lyophilized to give [(2S)-4-{5-[(2,6-dichlorophenyl)methoxy]pyrimidin-2-yl}morpholin-2-yl]methanol (18.6 mg, 0.05 mmol, 29.09%) as a white solid (purity: >95%).

[0237] Example 70:

Chemical formula

[0238] Example 71:

Chemical formula

[0239] Example 72:

Chemical Structure

[0240] Example 73:

Chemical Structure

[0241] Example 74: [Chemical formula] To a stirred solution of 2-[5-(tert-butoxymethyl)-1H-1,2,4-triazol-3-yl]-5-[(2,6-dichlorophenyl)methoxy]pyridine (46.5 mg, 0.11 mmol, 1 equiv) in DCM (3 mL) was added trifluoroacetic acid (170.17 μL, 1.53 g / mL, 2.28 mmol, 20 equiv). The reaction mixture was stirred at room temperature for 18 h. No conversion to the product was shown by LCMS. Trifluoroacetic acid (170.17 μL, 1.53 g / mL, 2.28 mmol, 20 equiv) was added and the reaction was stirred for 2 h. The reaction was further stirred for 18 h. The reaction mixture was dried to dryness to obtain a light brown film. This film was purified by preparative HPLC automated flash chromatography (ISCO ACCQ HP150, preparative HPLC column: gemini 150×20 5um size: 20 mm×150 mm 5 μM; sample: 2.50 ml from tube 1 RediSep column) eluting with 5 - 95% ACN / 0.1% aqueous FA / 0.1% FA to give (5-{5-[(2,6-dichlorophenyl)methoxy]pyridin-2-yl}-1H-1,2,4-triazol-3-yl)methanol (12.2 mg, 0.03 mmol, 30.43%) as a white powder (purity: >95%).

[0242] Example 75: [Chemical formula] To a suspension of 3555-AF-023-001 (100 mg, 0.52 mmol, 1 equiv) in DMF (2 mL) was added 2-methyl-6-trifluoromethylbenzyl bromide (82.73 μL, 1.6 g / cm 3, 0.52 mmol, 1 equivalent) and potassium carbonate (144.57 mg, 1.05 mmol, 2 equivalents) were added at room temperature under nitrogen, and the reaction mixture was stirred overnight. The reaction mixture was filtered, washed with DMSO (1 mL), and purified by preparative HPLC (ISCO ACCQ HP125, sample: 2 × 1.90 ml from tube 1, preparative HPLC column: Big Gemini-NX C18 size: 30 mm × 250 mm 5 μM) eluting with 10 to 95% ACN / 0.1% aqueous FA / 0.1%. The desired fraction was concentrated to give [1-(4-{[2-methyl-6-(trifluoromethyl)phenyl]methoxy}phenyl)-1,2,4-triazol-3-yl]methanol (88 mg, 0.24 mmol, 46.31%) as a white solid (purity: >98%).

[0243] Example 76: [Chemical formula] To a mixture of MDN_203-2 (0.147 g, 0.494 mmol) in DCM (4 mL) was added 1-[bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium-3-oxide hexafluorophosphate (HATU) (0.187 g, 0.494 mmol), diisopropylethylamine (137 mg, 0.988 mmol), and NH3(MeOH) (0.5 mL, 0.988 mmol). The reaction mixture was stirred at room temperature under Ar for 2 h. The reaction mixture was diluted with H2O (20 mL) and extracted with DCM (20 mL × 3). The organic phase was dried over Na2SO4 and concentrated. The crude product was purified by silica gel column to give the title compound as a yellow solid (20 mg, yield 14%).

[0244] Example 77: [Chemical formula] A solution of 2-chloro-5-[(2,6-dichlorophenyl)methoxy]pyrimidine (100 mg, 0.35 mmol, 1 equiv), 1-acetylpiperazine (66.4 mg, 0.52 mmol, 1.5 equiv) and potassium carbonate (143.2 mg, 1.04 mmol, 3 equiv) in DMSO (2 mL) was purged with nitrogen. After closing the vial cap, it was heated to 120 °C and maintained at that temperature for about 2.5 hours. After cooling the reaction mixture to room temperature, it was diluted with EtOAc and washed with water and then brine. The organic extract was dried (MgSO4) and then the solvent was distilled off under reduced pressure. The obtained residue was dissolved in DMSO, filtered and then purified by preparative HPLC automated flash chromatography (ISCO ACCQ HP150, preparative HPLC column: B / J column size: 30 mm × 250 mm 5 μM; sample: 1.50 ml from tube 1) eluting with 5 - 95% ACN / 0.1% aqueous FA / 0.1% FA. The desired fractions were combined and lyophilized to give 1-(4-{5-[(2,6-dichlorophenyl)methoxy]pyrimidin-2-yl}piperazin-1-yl)ethanone (44.22 mg, 0.12 mmol, 33.58%) as a white solid (purity: >95%).

[0245] Example 78:

Chemical formula

[0246] Example 79: [Chemical formula] A solution of 2-chloro-6-(trifluoromethyl)benzyl bromide (51.79 mg, 0.19 mmol, 1 equiv), 2-[2-(hydroxymethyl)morpholin-4-yl]pyrimidin-5-ol (40 mg, 0.19 mmol, 1 equiv) and potassium carbonate (130.87 mg, 0.95 mmol, 5 equiv) in DMF (2 mL) was stirred at room temperature for about 4 days. The reaction mixture was diluted with EtOAc, washed with water and then with brine. The organic extract was dried (MgSO4) and the solvent was then removed under reduced pressure. The obtained residue was dissolved in DMSO, filtered, and purified by preparative HPLC automated flash chromatography (ISCO ACCQ HP150, preparative HPLC column: Gemini-NX C18 size: 21 mm × 150 mm 5 μM; sample: 1.50 ml from tube 1) eluting with 5 - 95% ACN / 0.1% FA aqueous solution / 0.1% FA. The desired fractions were combined and MeCN was removed under reduced pressure. The aqueous layer was extracted with EtOAc (×2), the organic extracts were dried (MgSO4), and the solvent was removed under reduced pressure. The obtained residue was transferred to a vial using DCM and the solvent was removed under a nitrogen stream. The sample was dried under reduced pressure at 40 °C overnight to give [4-(5-{[2-chloro-6-(trifluoromethyl)phenyl]methoxy}pyrimidin-2-yl)morpholin-2-yl]methanol (27.5 mg, 0.07 mmol, 35.96%) as a colorless gum (purity: >95%).

[0247] Example 80:

Chemical formula

[0248] Example 81: [Chemical Structure] A solution of 2-fluoro-6-(trifluoromethyl)benzyl bromide (80.31 mg, 0.31 mmol, 1 equiv), 2-[2-(hydroxymethyl)morpholin-4-yl]pyrimidin-5-ol (66 mg, 0.31 mmol, 1 equiv), and potassium carbonate (215.93 mg, 1.56 mmol, 5 equiv) in DMF (2 mL) was stirred at room temperature overnight. The reaction mixture was diluted with EtOAc, washed with water, and then with brine. The organic extract was dried (MgSO4), and the solvent was removed under reduced pressure. The resulting residue was dissolved in DMSO, filtered, and purified by preparative HPLC (ISCO ACCQ HP150, preparative HPLC column: Gemini-NX C18 size: 21 mm × 150 mm 5 μM; sample: 1.50 ml from tube 1) eluting with 5 - 95% ACN / 0.1% aqueous FA / 0.1% FA. The desired fractions were combined, and MeCN was removed under reduced pressure. The aqueous layer was extracted with EtOAc (×2), the organic extracts were dried (MgSO4), and the solvent was removed under reduced pressure. The resulting residue was transferred to a submission vial using DCM, and the solvent was removed under a nitrogen stream. The compound was dried under reduced pressure at 40 °C overnight to give [4-(5-{[2-fluoro-6-(trifluoromethyl)phenyl]methoxy}pyrimidin-2-yl)morpholin-2-yl]methanol (43.4 mg, 0.11 mmol, 35.86%) as a colorless gum (purity: >95%).

[0249] Example 82:

Chemical Structure

[0250] Example 83:

Chemical formula

[0251] Example 84:

Chemical Structure

[0252] Example 85:

Chemical formula

[0253] Example 86:

Chem.

[0254] Example 87: [Chemical Structure] A solution of 2-chloro-5-[(2,6-dichlorophenyl)methoxy]pyrimidine, 3527-RJP-037-001 (50 mg, 0.17 mmol, 1 equiv), 1H-1,2,3-triazol-4-ylmethanol (17.11 mg, 0.17 mmol, 1 equiv), and potassium carbonate (47.73 mg, 0.35 mmol, 2 equiv) in 1-methyl-2-pyrrolidone (1 mL, 1.02 g / mL, 10.29 mmol, 59.58 equiv) was heated at 80 °C and maintained at that temperature overnight. LCMS indicated the main peak of the correct mass of the product. The reaction mixture was poured into water and extracted with EtOAc. The organic extract was washed with brine, dried (MgSO4), and the solvent was evaporated under reduced pressure. The resulting residue was dissolved in DMSO, filtered, and purified by preparative HPLC automated chromatography (ISCO ACCQ HP150, preparative HPLC column: Gemini-NX C18 size: 21 mm × 150 mm 5 μM; sample: 1.40 ml from tube 1) eluting with 5–95% ACN / 0.1% aqueous FA / 0.1% FA. Both fraction 15 and fraction 16 showed the correct mass, but had different retention times by LCMS (fraction 15 (from shoulder to peak) was 0.908 min, fraction 16 was 0.926 min). The samples were freeze-dried separately. From fraction 15 (6.36 mg), (2-{5-[(2,6-dichlorophenyl)methoxy]pyrimidin-2-yl}-1,2,3-triazol-4-yl)methanol (6.36 mg, 0.02 mmol, 10.46%) was obtained as a white solid (purity: >95%). From fraction 16 (6.08 mg), 1-{5-[(2,6-dichlorophenyl)methoxy]pyrimidin-2-yl}-1,2,3-triazol-4-yl)methanol (6.08 mg, 0.02 mmol, 10%) was obtained as a white solid (purity: >95%).

[0255] Example 88:

Chemical formula

[0256] Example 89:

Chemical formula

[0257] Example 90:

Chem.

[0258] Example 91:

Chem.

[0259] Example 92: [Chemistry] To a solution of MDN_217-4 (150 mg, 0.390 mmol) in THF (1 mL) was added LiBHEt3 (1 M, 1.18 mL, 1.18 mmol) at 0 °C. The reaction mixture was stirred at room temperature for 2 hours. The reaction mixture was diluted with H2O and extracted with EA. The organic layer was dried over Na2SO4, filtered, and concentrated. The residue was purified by preparative HPLC (TFA) to give MDN_217 (15 mg, 11.4% yield, white solid).

[0260] Example 93: [Chemistry] In a microwave vial, a solution of 2-chloro-5-[(2,6-dichlorophenyl)methoxy]pyrimidine (75 mg, 0.26 mmol, 1 equiv), hexahydro-1H-[1,3]oxazolo[3,4-a]piperazin-3-one hydrochloride (69.4 mg, 0.39 mmol, 1.5 equiv) and potassium carbonate (107.4 mg, 0.78 mmol, 3 equiv) in DMSO (1.5 mL) was purged with nitrogen. After capping the vial, it was heated to 100 °C and left standing there overnight. After cooling the reaction mixture to room temperature, it was diluted with EtOAc and washed with water and then brine. The organic extract was dried (MgSO4) and the solvent was distilled off under reduced pressure. The resulting residue was dissolved in DMSO, filtered, and then purified by preparative HPLC (ISCO ACCQ HP150, preparative HPLC column: Big Gemini-NX C18 size: 30 mm × 250 mm 5 μM; sample: 1.60 ml from tube 1) eluting with 5 - 95% ACN / 0.1% aqueous FA / 0.1% FA. Fractions 45 - 47 were combined and then lyophilized. 3527-RJP-168-001 (34 mg) was obtained. Since the purity was less than 95%, the sample was further purified. The compound was dissolved in DMSO and purified by preparative HPLC (ISCO ACCQ HP150, sample: 1.30 ml from tube 1, preparative HPLC column: Big Gemini-NX C18 size: 30 mm × 250 mm 5 μM) eluting with 5 - 95% ACN / 0.1% aqueous FA / 0.1% FA. Fractions 12 - 13 were combined and then lyophilized. 5-{5-[(2,6-dichlorophenyl)methoxy]pyrimidin-2-yl}-tetrahydro-3H-[1,3]oxazolo[3,4-a]piperazin-1-one (17.62 mg, 0.04 mmol, 17.21%) was obtained as a white solid (purity: >95%).

[0261] Example 94:

Chemical Structure

[0262] Example 95:

Chemical Structure

[0263] Example 96: [Chemical Structure] 2-Chloro-6-(trifluoromethyl)benzyl bromide (62.15 mg, 0.23 mmol, 1 equiv), 2-[(2S)-2-(hydroxymethyl)morpholin-4-yl]pyrimidin-5-ol (48 mg, 0.23 mmol, 1 equiv), and potassium carbonate (157.04 mg, 1.14 mmol, 5 equiv) in DMF (2 mL) were stirred at room temperature overnight. The reaction mixture was diluted with EtOAc, washed with water, and then with brine. The organic extract was dried (MgSO4), and the solvent was removed under reduced pressure. The resulting residue was dissolved in DMSO, filtered, and purified by preparative HPLC (ISCO ACCQ HP150, sample: 1.60 mL from tube 1, preparative HPLC column: Big Gemini-NX C18 size: 30 mm × 250 mm 5 μM) eluting with 5 - 95% ACN / 0.1% FA aqueous solution / 0.1% FA. Fractions 20 - 25 were combined, and then MeCN was removed under reduced pressure. The aqueous solution was extracted with EtOAc (×2), the organic extract was washed with brine, dried (MgSO4), and the solvent was removed under reduced pressure. The resulting residue was transferred to a vial using DCM. The solvent was removed under a nitrogen stream, and then the sample was dried under reduced pressure at 40 °C overnight. [(2S)-4-(5-{[2-Chloro-6-(trifluoromethyl)phenyl]methoxy}pyrimidin-2-yl)morpholin-2-yl]methanol (59.26 mg, 0.15 mmol, 64.58%) was obtained as a colorless gum (purity: >95%).

[0264] Example 97:

Chemical formula

[0265] Example 98:

Chemical formula

[0266] Example 99:

Chemical Structure

[0267] Example 100:

Chemical Structure

[0268] Example 101:

Chemical formula

[0269] Example 102:

Chem.

[0270] Example 103:

Chem.

[0271] Example 104:

Chem.

[0272] Example 105:

Chemical Structure

[0273] Example 106:

Chemical Structure

[0274] Example 108:

Chemical Structure

[0275] Example 109:

Chemical Structure

[0276] Example 110:

Chemical formula

[0277] Example 111: [Chemical formula] To a microwave vial containing 2-chloro-5-[(2,6-dichlorophenyl)methoxy]pyrimidine (100 mg, 0.35 mmol, 1 equiv) and N,N-diisopropylethylamine (0.17 mL, 0.78 g / mL, 1.04 mmol, 3 equiv) in DMSO (3 mL), methyl 6-oxopiperazine-2-carboxylate (60.08 mg, 0.38 mmol, 1.1 equiv) was added. The reaction mixture was sealed and heated to 100 °C for 18 h. Then, the vial was irradiated to 120 °C for 1 h using an SEM reactor. The reaction mixture was directly purified by preparative LCMS (Big Gem 30 min method, low mass trigger) using water. The desired fractions were combined and concentrated to dryness to afford methyl 4-{5-[(2,6-dichlorophenyl)methoxy]pyrimidin-2-yl}-6-oxopiperazine-2-carboxylate (38.6 mg, 0.09 mmol, 27.18%) as an off-white powder (purity: >95%).

[0278] Example 112:

Chem.

[0279] Example 114:

Chem.

[0280] Example 115: [ka] MDN_257-1 (50 mg, 0.106 mmol), 2,4,6-trimethyl-1,3,5,2,4,6-trioxatriborinane (0.15 mL, 0.528 mmol), K2CO3 (44 mg, 0.318 mmol) and Pd(dppf)Cl2 (15 mg, 0.021 mmol) were stirred in 1,4-dioxane (1 mL) and H2O (0.1 mL) under Ar atmosphere at 100 °C overnight. The reaction mixture was diluted with H2O (20 mL) and extracted with EtOAc (20 mL × 2). The organic layer was dried over Na2SO4, filtered and concentrated under reduced pressure. The residue was purified by TLC (PE:EA = 2:1) to give MDN_257 as a white solid (14 mg, 32.5% yield).

[0281] Example 116: [ka] To a stirred solution of methyl 4-{5-[(2,6-dichlorophenyl)methoxy]pyrimidin-2-yl}-6-oxopiperazine-2-carboxylate (37.5 mg, 0.09 mmol, 1 equiv) in ethanol (3 mL) was added sodium borohydride (4.14 mg, 0.11 mmol, 1.2 equiv). The reaction was stirred at room temperature for 4 h. 2M HCl (1 mL) was added to quench the reaction which foamed. The resulting solution was concentrated to dryness to afford a white film. The film was purified by preparative HPLC automated flash chromatography (ISCO ACCQ HP150, preparative HPLC column: Gemini-NX C18 size: 21 mm × 150 mm 5 μM; sample: 2.50 ml from tube 1 RediSep column) eluting with 5-95% ACN / 0.1% FA aqueous solution / 0.1% FA. The desired fractions were combined and concentrated to dryness to afford 4-{5-[(2,6-dichlorophenyl)methoxy]pyrimidin-2-yl}-6-(hydroxymethyl)piperazin-2-one (12.5 mg, 0.03 mmol, 35.77%) as a white powder (purity: >95%).

[0282] Example 117:

Chemical Structure

[0283] Example 118:

Chemical Structure

[0284] Example 119:

Chemical formula

[0285] Example 120:

Chemical formula

[0286] Example 121:

Chemical Structure

[0287] Example 122:

Chemical Structure

[0288] Example 123:

Chemical Structure

[0289] Example 124: [Chemical Structure] 2-Bromo-5-[(2,6-dichlorophenyl)methoxy]pyrimidine (47 mg, 0.14 mmol, 1 equiv), 1-butylhydantoin (54.95 mg, 0.35 mmol, 2.5 equiv), and copper(I) oxide (20.14 mg, 0.14 mmol, 1 equiv) were dissolved in DMF (1 mL) under nitrogen and stirred at 150 °C for 4 h in a sealed HPLC vial. The reaction mixture was filtered through celite, eluted with ethyl acetate (40 mL), washed with saturated aqueous ammonium chloride (30 mL), 5% aqueous lithium chloride (25 mL), brine (25 mL), filtered through hydrophobic filter paper, and concentrated under reduced pressure to give a pale yellow oil. The crude mixture was diluted with DMSO and purified by preparative HPLC (ISCO ACCQ HP125, preparative HPLC column: Big Gemini-NX C18 size: 30 mm × 250 mm 5 μM; sample: 2.20 ml from tube 2) eluting with 5–95% ACN / 0.1% FA aqueous solution / 0.FA. The fractions (22–24) containing the desired product were lyophilized, diluted with methanol, transferred to a vial, concentrated on a Biotage V10, and dried under reduced pressure at 40 °C overnight to give 1-butyl-3-{5-[(2,6-dichlorophenyl)methoxy]pyrimidin-2-yl}imidazolidine-2,4-dione (10.4 mg, 0.03 mmol, 18.06%) as a white solid (purity: >95%).

[0290] Example 125:

Chemical formula

[0291] Example 126:

Chem.

[0292] Example 127:

Chem.

[0293] Example 128:

Chemical formula

[0294] Example 129: [Chemical formula] A solution of 2-chloro-5-[(2,6-dichlorophenyl)methoxy]pyrimidine (100 mg, 0.35 mmol, 1 equiv), (5-methylmorpholin-2-yl)methanol (45.3 mg, 0.35 mmol, 1 equiv) and potassium carbonate (143.2 mg, 1.04 mmol, 3 equiv) in DMSO (2 mL) was purged with nitrogen. The tube was sealed and then heated to 100 °C and allowed to stand for about 24 hours. After the reaction mixture was cooled to room temperature, it was diluted with EtOAc and washed with water and then brine. The organic extract was dried (MgSO4) and the solvent was distilled off under reduced pressure. The resulting residue was dissolved in DMSO, filtered, and purified by preparative HPLC (ISCO ACCQ HP150, sample: 1.40 ml from tube 1, preparative HPLC column: Big Gemini-NX C18 size: 30 mm × 250 mm 5 μM) eluting with 5 - 95% ACN / 0.1% aqueous FA / 0.1% FA. Fractions 42 - 43 (trans) were combined and lyophilized. The resulting glass was transferred to a submission vial using DCM and the solvent was removed under a nitrogen stream. This compound was dried under reduced pressure at 40 °C overnight. This compound was shown to be the trans form by NMR. As a result, [(2S,5S)-4-{5-[(2,6-dichlorophenyl)methoxy]pyrimidin-2-yl}-5-methylmorpholin-2-yl]methanol + [(2R,5R)-4-{5-[(2,6-dichlorophenyl)methoxy]pyrimidin-2-yl}-5-methylmorpholin-2-yl]methanol (2.6 mg, 0.01 mmol, 1.96%) was obtained as a colorless glass (purity: >95%).

[0295] Example 130:

Chemical Structure

[0296] Example 132:

Chemical formula

[0297] Example 133:

Chemical formula

[0298] Example 134: [Chemical formula] A solution of 2-chloro-5-[(2,6-dichlorophenyl)methoxy]pyrimidine (100 mg, 0.35 mmol, 1 equiv), [6-(trifluoromethyl)morpholin-2-yl]methanol (63.94 mg, 0.35 mmol, 1 equiv), and potassium carbonate (143.2 mg, 1.04 mmol, 3 equiv) in DMSO (2 mL) was purged with nitrogen. The tube was sealed and then heated to 100 °C and allowed to stand for about 24 hours. After the reaction mixture was cooled to room temperature, it was diluted with EtOAc and washed with water and then brine. The organic extract was dried (MgSO4) and the solvent was removed under reduced pressure. The resulting residue was dissolved in DMSO, filtered, and purified by preparative HPLC (ISCO ACCQ HP150, sample: 1.40 ml from tube 1, preparative HPLC column: Big Gemini-NX C18 size: 30 mm × 250 mm 5 μM) eluting with 5 - 95% ACN / 0.1% FA aqueous solution / 0.1% FA. Fraction 44 was lyophilized (3527-RJP-196-001). The resulting glass was transferred to a submission vial using DCM / MeOH and the solvent was removed under a nitrogen stream. This compound was dried at 40 °C overnight under reduced pressure. This compound was shown to be the trans form by NMR. As a result, [(2S,6S)-4-{5-[(2,6-dichlorophenyl)methoxy]pyrimidin-2-yl}-6-(trifluoromethyl)morpholin-2-yl]methanol + [(2R,6R)-4-{5-[(2,6-dichlorophenyl)methoxy]pyrimidin-2-yl}-6-(trifluoromethyl)morpholin-2-yl]methanol (8.34 mg, 0.02 mmol, 5.51%) was obtained as a colorless glass (3527-RJP-196-001, purity: >95%) (methanol, 5.5 equiv). Due to the presence of a large amount of MeOH, this glassy material was dissolved in DCM, the solvent was removed, and then dried under reduced pressure at 40 °C overnight. As a result, [(2S,6S)-4-{5-[(2,6-dichlorophenyl)methoxy]pyrimidin-2-yl}-6-(trifluoromethyl)morpholin-2-yl]methanol (4.25 mg, 0.01 mmol, 2.81%) was obtained as a colorless glass (purity: 90 - 95%). Fractions 50 - 52 were combined and then lyophilized. The resulting solid was transferred to a submission vial.This compound was shown to be cis-type by NMR. As a result, [(2R,6S)-4-{5-[(2,6-dichlorophenyl)methoxy]pyrimidin-2-yl}-6-(trifluoromethyl)morpholin-2-yl]methanol + [(2S,6R)-4-{5-[(2,6-dichlorophenyl)methoxy]pyrimidin-2-yl}-6-(trifluoromethyl)morpholin-2-yl]methanol (16.32 mg, 0.04 mmol, 10.78%) was obtained as a white solid (purity: 90 - 95%).

[0299] Example 135:

Chemical formula

[0300] Example 136:

Chemical Structure

[0301] Example 137:

Chemical formula

[0302] Example 138: [Chemical formula] A solution of 2-chloro-5-[(2,6-dichlorophenyl)methoxy]pyrimidine (100 mg, 0.35 mmol, 1 equiv), 1-(morpholin-2-yl)ethan-1-ol (45.3 mg, 0.35 mmol, 1 equiv), and potassium carbonate (143.2 mg, 1.04 mmol, 3 equiv) in DMSO (2 mL) was purged with nitrogen. The tube was sealed and then heated to 100 °C and allowed to stand for about 24 h. After the reaction mixture was cooled to room temperature, it was diluted with EtOAc and washed with water and then brine. The organic extract was dried (MgSO4) and the solvent was evaporated under reduced pressure. The resulting residue was dissolved in DMSO, filtered, and purified by preparative HPLC (ISCO ACCQ HP150, sample: 1.40 ml from tube 1, preparative HPLC column: Big Gemini-NX C18 size: 30 mm×250 mm 5 μM) eluting with 5–95% ACN / 0.1% aqueous FA / 0.1% FA. Fractions 31–33 were combined and lyophilized. The resulting glass was transferred to a submission vial using DCM and the solvent was removed under a stream of nitrogen. The compound was dried under reduced pressure at 40 °C overnight. NMR and modeling indicated that it was a mixture of SS and RR. (1R)-1-[(2R)-4-{5-[(2,6-dichlorophenyl)methoxy]pyrimidin-2-yl}morpholin-2-yl]ethanol (30.66 mg, 0.08 mmol, 23.1%) was obtained as a white glass (purity: >95%). Fractions 35–36 were combined and then lyophilized. The resulting glass was transferred to a submission vial using DCM / MeOH and the solvent was removed under a stream of nitrogen. The compound was dried under reduced pressure at 40 °C overnight. NMR and modeling indicated that it was a mixture of SR and RS. (1R)-1-[(2S)-4-{5-[(2,6-dichlorophenyl)methoxy]pyrimidin-2-yl}morpholin-2-yl]ethanol (17.43 mg, 0.05 mmol, 13.13%) was obtained as a colorless glass (purity: 90–95%) (methanol, 2.3 equiv). Because of the large amount of MeOH, the compound was dissolved in a minimal amount of DCM and then the solvent was removed. The sample was dried under reduced pressure at 40 °C overnight.As a result, (1R)-1-[(2S)-4-{5-[(2,6-dichlorophenyl)methoxy]pyrimidin-2-yl}morpholin-2-yl]ethanol (16.52 mg, 0.04 mmol, 12.45%) was obtained as a colorless glass (purity: 90 - 95%).

[0303] Example 139:

Chemical formula

[0304] Example 140:

Chemical formula

[0305] Example 141:

Chemical formula

[0306] Example 142:

Chemical formula

[0307] Example 165: [Chemical formula] 5-(Benzyloxy)-2-bromopyrimidine (500 mg, 1.89 mmol, 1 equiv), N-benzylhydantoin (538.08 mg, 2.83 mmol, 1.5 equiv), and copper(I) oxide (269.88 mg, 1.89 mmol, 1 equiv) were diluted with DMF (3 mL) under a nitrogen atmosphere and stirred at 150 °C for 3 h. The reaction mixture was filtered through celite, eluted with ethyl acetate, washed with a saturated aqueous solution of ammonium chloride (30 mL), extracted with ethyl acetate (30 mL), washed with 5% aqueous lithium chloride solution (2 × 30 mL) and brine (30 mL), passed through hydrophobic filter paper, adsorbed onto Isolute HM-N, concentrated under reduced pressure, and purified by automated flash chromatography (Combiflash Rf, silica 24 g RediSep column) eluting with 12–100% ethyl acetate in heptane. Fractions containing the pure product as determined by TLC (3:1 EtOAc:n-heptane) (5–8) were concentrated under reduced pressure to give 1-benzyl-3-[5-(benzyloxy)pyrimidin-2-yl]imidazolidine-2,4-dione (336 mg (69%), 0.62 mmol, 32.83%) as a cream gum (purity: 50–85%). Fraction 3 was allowed to stand for 48 h to crystallize. The crystals were filtered, washed with n-heptane, and dried at 40 °C for 2 h to give 1-benzyl-3-[5-(benzyloxy)pyrimidin-2-yl]urea (16 mg, 0.05 mmol, 2.54%) as white crystals (purity: >95%).

[0308] Example 166:

Chem.

[0309] H2O (30 mL) was added to the reaction mixture, and the mixture was extracted with EtOAc (30 mL × 3). The organic layer was dried over Na2SO4, filtered, and concentrated under reduced pressure. The crude product was purified by preparative HPLC (FA) and lyophilized to obtain the title compound as a white solid (6.77 mg, yield 10.9%).

[0310] Example 167:

Chemical Structure

[0311] Example 168:

Chemical Structure

[0312] Example 170:

Chemical formula

[0313] Example 171:

Chemical Structure

[0314] Example 172: [Chemical formula] Sodium cyanoborohydride (25.53 mg, 0.41 mmol, 3 eq) was added to a stirred (cloudy) solution of (4-{5-[(2,6-dichlorophenyl)methoxy]pyrimidin-2-yl}morpholin-2-yl)methanamine (50 mg, 0.14 mmol, 1 eq) and formaldehyde (37% aqueous solution) (0.1 mL (37%), 1.35 mmol, 10 eq) in acetonitrile (3 mL). Acetic acid, purity 99.5% (0.05 mL, 1.05 g / mL, 0.87 mmol, 6.46 eq) was added (the reaction became clear), and the reaction mixture was stirred at room temperature for about 2 h. The reaction solution was quenched with a saturated aqueous solution. Then, the NaHCO3 solution was extracted with EtOAc (×2). The organic extract was washed with brine, dried (MgSO4), and the solvent was evaporated under reduced pressure. The resulting residue was dissolved in DMSO, filtered, and then purified by preparative HPLC (ISCO ACCQ HP150, preparative HPLC column: Gemini-NX C18 size: 21 mm × 150 mm 5 μM; sample: 1.30 ml from tube 1) eluting with 5 - 95% ACN / 0.1% aqueous FA / 0.1% FA. Fractions 4 - 7 were combined and then lyophilized. The resulting residue was dissolved in DCM, transferred to a submission vial. Under a nitrogen stream, the solvent was then removed with V10, and the sample was dried under reduced pressure at 40 °C over the weekend. As a result, [(4-{5-[(2,6-dichlorophenyl)methoxy]pyrimidin-2-yl}morpholin-2-yl)methyl]dimethylamine (24.51 mg, 0.06 mmol, 45.56%) was obtained as a colorless gum (purity: >95%).

[0315] Example 173:

Chemical Structure

[0316] Example 174: [Chemical formula] To a mixture of MDN_258-2 (76 mg, 0.190 mmol) in 1,4-dioxane / H2O (1 mL / 0.1 mL) were added 2,4,6-trimethyl-1,3,5,2,4,6-trioxatriphosphorinane (0.5 mL), Pd(dppf)Cl2 (27 mg, 0.038 mmol) and K2CO3 (77 mg, 0.570 mmol). The reaction was stirred at 100 °C overnight under an Ar atmosphere. The reaction mixture was diluted with H2O (50 mL) and extracted with EtOAc (50 mL × 3). The organic phase was dried over Na2SO4, concentrated, and the crude product was purified by silica gel column to give the title compound as a yellow solid (20 mg, yield 31%).

[0317] Example 175: [Chemical formula] To a solution of (39 mg, 0.1 mmol, 1 equiv) in DMF (3 mL), ammonium chloride (27.64 mg, 0.52 mmol, 5 equiv), Hunig's base (0.14 mL, 0.83 mmol, 8 equiv) and HATU O-(7-azabenzotriazol-1-yl)-N,N,N’,N’-tetramethyluronium hexafluorophosphate (78.6 mg, 0.21 mmol, 2 equiv) were added at room temperature under N2. Stirred at room temperature overnight. The reaction mixture was concentrated under reduced pressure. Dissolved in DMSO (2.2 mL) and purified by HPLC. From pH 4 fractions 28 - 33, 1-(4-{[2-methyl-6-(trifluoromethyl)phenyl]methoxy}phenyl)-1,2,4-triazole-3-carboxamide (20 mg, 0.05 mmol, 51.42%) was obtained as a white solid (purity: >95%).

[0318] Example 176:

Chemical formula

[0319] Example 179:

Chemical formula

[0320] Example 180:

Chemical formula

[0321] Example 181:

Chemical formula

[0322] Example 182:

Chemical Structure

[0323] Example 183:

Chemical formula

[0324] Example 185:

Chemical formula

[0325] Example 186:

Chemical formula

[0326] Example 187:

Chemical Structure

[0327] Example 188:

Chemical Structure

[0328] Example 189:

Chemical Structure

[0329] Example 190:

Chemical Structure

[0330] Example 191:

Chemical Structure

[0331] Example 192:

Chemical Structure

[0332] Example 193:

Chemical formula

[0333] Example 195:

Chemical formula

[0334] Example 196:

Chemical Structure

[0335] Example 197:

Chemical Structure

[0336] Example 198: [Chemical formula] Trimethylsilyl isocyanate, 94% (0.03 mL, 0.85 g / mL, 0.19 mmol, 1.5 eq) was added to a stirred solution of (4-{5-[(2,6-dichlorophenyl)methoxy]pyrimidin-2-yl}morpholin-2-yl)methanamine (48 mg, 0.13 mmol, 1 eq) and triethylamine (0.05 mL, 0.73 g / mL, 0.39 mmol, 3 eq) in DCM (3 mL). The reaction mixture was stirred at room temperature overnight. The solvent was removed under reduced pressure, and the resulting residue was dissolved in DMSO, filtered, and purified by preparative HPLC (ISCO ACCQ HP150, sample: 1.40 ml from tube 1, preparative HPLC column: Gemini-NX C18 size: 21 mm × 150 mm 5 μM) eluting with 5 - 95% ACN / 0.1% aqueous FA / 0.1% FA. Fractions 15 - 16 were combined and then lyophilized. As a result, (4-{5-[(2,6-dichlorophenyl)methoxy]pyrimidin-2-yl}morpholin-2-yl)methylurea (23.77 mg, 0.06 mmol, 44.35%) was obtained as a white solid (purity: >95%).

[0337] Example 199:

Chemical formula

[0338] Example 200:

Chemical Structure

[0339] Example 201:

Chemical formula

[0340] Example 202: [Chemical formula] In a microwave vial, a solution of 2-chloro-5-{[2-methyl-6-(trifluoromethyl)phenyl]methoxy}pyrimidine (50 mg, 0.17 mmol, 1 equiv), 4-(methylamino)butan-1-ol (25.56 mg, 0.25 mmol, 1.5 equiv) and N,N-diisopropylethylamine (0.08 mL, 0.78 g / mL, 0.5 mmol, 3 equiv) in ethanol (1 mL) was purged with nitrogen. The reaction mixture was sealed and then heated to 100 °C and left standing overnight. The reaction was cooled to room temperature and the solvent was removed under reduced pressure. The resulting residue was dissolved in DMSO, filtered, and purified by preparative HPLC (ISCO ACCQ HP150, sample: 1.30 ml from tube 1, preparative HPLC column: Gemini-NX C18 size: 21 mm × 150 mm 5 μM) eluting with 5 - 95% ACN / 0.1% aqueous FA / 0.1% FA. Fractions 5 - 7 were combined and then lyophilized. The resulting glass was transferred to a submission vial using DCM. The solvent was removed under a nitrogen stream and then dried overnight at 40 °C under reduced pressure. As a result, 4-[methyl(5-{[2-methyl-6-(trifluoromethyl)phenyl]methoxy}pyrimidin-2-yl)amino]butan-1-ol (31.18 mg, 0.08 mmol, 51.1%) was obtained as a colorless gum (purity: >95%).

[0341] Example 203:

Chemical formula

[0342] Example 204:

Chemical Structure

[0343] Example 205: [Chemical formula] In a microwave vial, a solution of 2-chloro-5-{[2-methyl-6-(trifluoromethyl)phenyl]methoxy}pyrimidine (50 mg, 0.17 mmol, 1 equiv), (S)-3-hydroxypiperidine hydrochloride, VERC112415:1 (34.1 mg, 0.25 mmol, 1.5 equiv), and N,N-diisopropylethylamine (0.14 mL, 0.78 g / mL, 0.83 mmol, 5 equiv) in ethanol (0.5 mL) was purged with nitrogen. The reaction was sealed and heated by microwave at 130 °C for 2 h. The reaction was cooled to room temperature and the solvent was removed under reduced pressure. The resulting residue was dissolved in DMSO, filtered, and purified by preparative HPLC automated chromatography (ISCO ACCQ HP150, sample: 1.30 ml from tube 1, preparative HPLC column: Gemini-NX C18 size: 21 mm × 150 mm 5 μM) eluting with 5 - 95% ACN / 0.1% aqueous FA / 0.1% FA. Fractions 6 and 7 were combined and then lyophilized. The resulting glass was transferred to a submission vial using DCM. After removing the solvent under a nitrogen stream, it was dried under reduced pressure at 40 °C overnight with V10. As a result, (3S)-1-(5-{[2-methyl-6-(trifluoromethyl)phenyl]methoxy}pyrimidin-2-yl)piperidin-3-ol (33.5 mg, 0.09 mmol, 55.2%) was obtained as a colorless gum (purity: >95%).

[0344] Example 206:

Chemical formula

[0345] Example 207:

Chemical formula

[0346] Example 208:

Chemical formula

[0347] Example 209:

Chemical formula

[0348] Example 210:

Chemical formula

[0349] Example 211:

Chemical formula

[0350] Example 212:

Chemical formula

[0351] Example 213: [Chemical Structure] A solution of 2-chloro-5-{[2-methyl-6-(trifluoromethyl)phenyl]methoxy}pyrimidine (100 mg, 0.33 mmol, 1 equiv), (S)-tert-butyl (morpholin-2-ylmethyl)carbamate (107.18 mg, 0.5 mmol, 1.5 equiv), and N,N-diisopropylethylamine (0.16 mL, 0.78 g / mL, 0.99 mmol, 3 equiv) in ethanol (2 mL) was purged with nitrogen. The reaction mixture was sealed and then heated to 100 °C and allowed to stand overnight. LCMS showed mainly the product, but starting material remained. The solvent was removed in vacuo, and the resulting residue was dissolved in DCM (3 mL), and hydrochloric acid (4N in 1,4-dioxane) (0.5 mL, 4 M, 1.98 mmol, 6 equiv) was added. The reaction mixture was stirred at room temperature for about 5 h. The solvent was removed in vacuo, and the resulting residue was dissolved in MeOH and applied to an scx-2 cartridge (2 g prewashed with MeOH). The column was washed with MeOH and then the compound was eluted with 3.5N NH3 in MeOH. The solvent was removed in vacuo. As a result, [(2R)-4-(5-{[2-methyl-6-(trifluoromethyl)phenyl]methoxy}pyrimidin-2-yl)morpholin-2-yl]methanamine (93 mg, 0.24 mmol, 73.62%) was obtained as a beige gum. Preparative HPLC (ISCO ACCQ HP150, preparative HPLC column: Gemini-NX C18 size: 21 mm × 150 mm 5 μM; sample: 1.30 ml from tube 1) was eluted with 5–95% ACN / 0.1% FA aqueous solution / 0.1% FA for purification. Fractions 9 and 10 were combined and then lyophilized. As a result, (2R)-4-(5-{[2-methyl-6-(trifluoromethyl)phenyl]methoxy}pyrimidin-2-yl)morpholin-2-yl]methanamine (23.54 mg, 0.06 mmol, 18.63%) was obtained as a white solid (purity: >95%) (formate, 0.6 equiv).

[0352] Example 214:

Chemical formula

[0353] Example 215:

Chemical Structure

[0354] Example 216:

Chemical Structure

[0355] Example 217:

Chemical Structure

Claims

1. A compound having the structure of formula (I): 【Chemical 1】 or a pharmaceutically acceptable salt thereof, wherein R １ 、 R ２ 、 R ３ 、 R ４ 、 and R ５ are each independently selected from the group consisting of hydrogen, halo, -CN, -NO ２ , -OH, C １～６ alkyl, C １～６ haloalkyl, C １～６ alkoxy, C １～６ haloalkoxy, and C ３～８ cycloalkyl; L １ is O, N or CH ２ ; L ２ is CH ２ , CHF or CF ２ ; Z １ is CH, N or C—OCH ３ ; Z ２ is CH or N; Z ３ is CH, N or CF; R ６ is optionally substituted heterocyclyl, optionally substituted heteroaryl, or -NR ７ａ R ７ｂ and; R ７ａ and R ７ｂ each independently is hydrogen, optionally substituted C １～６ alkyl, optionally substituted C ３～８ cycloalkyl; optionally substituted aryl, optionally substituted heterocyclyl, and optionally substituted heteroaryl, selected from the group consisting of; However, R １ and R ２ are both hydrogen, and when R ６ is pyrazolyl optionally substituted, R ３ is not halo, and R ４ is not halo, the compound, or a pharmaceutically acceptable salt thereof.

2. L １ The compound according to claim 1, wherein L is O.

3. L １ is CH ２ The compound according to claim 1, wherein

4. L １ The compound according to claim 1, wherein L is NH.

5. L ２ is CH ２ The compound according to claim 1, wherein

6. L ２ The compound according to claim 1, wherein L is CHF.

7. L ２ is CF ２ The compound according to claim 1, wherein

8. Z １ is N, and Z ２ is N, and Z ３ is CH, the compound according to any one of claims 1 to 7.

9. Z １ is N, and Z ２ is CH, and Z ３ is CH, the compound according to any one of claims 1 to 7.

10. Z １ is CH, and Z ２ is CH, and Z ３ is CH, the compound according to any one of claims 1 to 7.

11. Z １ is CH, and Z ２ is CH, and Z ３ is N, the compound according to any one of claims 1 to 7.

12. Z １ is CH, and Z ２ is CH, and Z ３ is CF, the compound according to any one of claims 1 to 7.

13. Z １ is N, and Z ２ is CH, and Z ３ is N, the compound according to any one of claims 1 to 7.

14. Z １ is CH, and Z ２ is N, and Z ３ is N, the compound according to any one of claims 1 to 7.

15. R １ is selected from the group consisting of -CN, halo, -C １～６ alkyl, -C １～６ alkoxy, -C １～６ haloalkyl and -C １～６ haloalkoxy, and is a compound according to any one of claims 1 to 14.

16. R １ is -CN, -F, -Cl, -Br, -CH ３ , -CH ２ CH ３ , -CF ３ , -CF ２ CH ３ , -OCF ３ , -OCHF ２ , and - A compound according to any one of claims 1 to 15, selected from the group consisting of - cyclopropyl.

17. R ２ is selected from the group consisting of -CN, halo, -C １～６ alkyl, -C １～６ alkoxy, -C １～６ haloalkyl, and -C １～６ haloalkoxy, and is a compound according to any one of claims 1 to 16.

18. R ２ is selected from the group consisting of -CN, -F, -Cl, -Br, -CH ３ , -CH ２ CH ３ , -CF ３ , -CF ２ CH ３ , -OCF ３ , -OCHF ２ and -cyclopropyl, and is a compound according to any one of claims 1 to 17.

19. R ３ The compound according to any one of claims 1 to 18, wherein R is hydrogen or a halo.

20. R ４ The compound according to any one of claims 1 to 19, wherein R is hydrogen or a halo.

21. R ５ The compound according to any one of claims 1 to 20, wherein R is hydrogen or a halo.

22. R ６ is 【Chemical Formula 2】 selected from the group consisting of wherein q is an integer value selected from 0, 1, and 2; Each R ８ is independently fluorine, phenyl, pyridine, carboxyl, -C(=O)-(C １ ~C ６ alkyl), -(C １～６ alkyl)-phenyl, -(C １～６ alkyl)-phenyl-O-(C １ ~C ６ alkyl), -CF ３ -, -C １～６ alkyl, -(C １～６ alkyl)-CN, -C １～６ alkenyl, -C ３～８ cycloalkyl, -(C １～６ alkyl)-OH, -(C １～６ alkyl)-NH ２ , -S(=O) ２ -NH ２ , -S(=O) ２ -(C １～６ alkyl), -C １～６ alkyl)-N(CH ３ ) ２ , -(C １ ~C ６ alkyl)-O-alkyl, -(C １ ~C ６ alkyl)-O-(C １ ~C ６ alkyl)-OH, -(C １～６ alkyl)-NH ２ , C １～６ alkyl-O-alkenyl, -C(=O)NH ２ , -C(=O)OH, -C(=O)OCH ３ , -C(=O)NH(C １～６ alkyl), C(=O)N(C １～６ alkyl) ２ , -C(=O)-O-(C １～６ alkyl), -(C １～６ alkyl)-NC(=O)-H, -OH, -(C １～６ alkyl)-NC(=O)-CF ３ , or -(C １～６ alkyl)-NC(=O)(C １～６ alkyl); R ９ is hydrogen, -C １～６ alkyl, -C ３～８ cycloalkyl, -(C １～６ alkyl)-OH, -(C １～６ alkyl)-NH ２ , or -(C １～６ alkyl)-NC(=O)(C １～６ alkyl), a compound according to any one of claims 1 to 21.

23. R ６ is [Chemical 3] 【Chemical Formula 4】 【Chemical Formula 5】 - A compound according to any one of claims 1 to 21, selected from the group consisting of.

24. 【Chemical Formula 6】 【Chemical Formula 7】 【Chemical Formula 8】 【Chemical Formula 9】 【Chemical Formula 10】 【Chemical 11】 【Chemical 12】 【Chemical 13】 【Chemical 14】 【Chemical Formula 15】 【Chemical 16】 【Chemical 17】 【Chemical Formula 18】 【Chemical Formula 19】 【Chemical 20】 【Chemical 21】 ​ 【Chemical 23】 【Chemical 24】 【Chemical Formula 25】 【Chemical Formula 26】 【Chemical 27】 【Chemical formula 28】 【Chemical 29】 【Chemical Formula 30】 【Chemical Formula 31】 【Chemical 32】 【Chemical 33】 【Chemical 34】 【Chemical 35】 A compound selected from the group consisting of, and a pharmaceutically acceptable salt thereof.

25. R ６ is 【Chemical Formula 36】 selected from the group consisting of q is an integer value selected from 0, 1, and 2; Each R ８ is independently fluorine, phenyl, pyridine, carboxyl, -C(=O)-(C １ ~C ６ alkyl), -(C １～６ alkyl)-phenyl, -(C １～６ alkyl)-phenyl-O-(C １ ~C ６ alkyl), -CF ３ , -C １～６ alkyl, -(C １～６ alkyl)-CN, -C １～６ alkenyl, -C ３～８ cycloalkyl, -(C １～６ alkyl)-OH, -(C １～６ alkyl)-NH ２ , -S(=O) ２ -NH ２ , -S(=O) ２ -(C １～６ alkyl), -C １～６ alkyl)-N(CH ３ ) ２ , -(C １ ~C ６ alkyl)-O-alkyl, -(C １ ~C ６ alkyl)-O-(C １ ~C ６ alkyl)-OH, -(C １～６ alkyl)-NH ２ , C １～６ alkyl-O-alkenyl, -C(=O)NH ２ , -C(=O)OH, -C(=O)OCH ３ , -C(=O)NH(C １～６ alkyl), C(=O)N(C １～６ alkyl) ２ , -C(=O)-O-(C １～６ alkyl), -(C １～６ alkyl)-NC(=O)-H, -OH, -(C １～６ alkyl)-NC(=O)-CF ３ , or -(C １～６ alkyl)-NC(=O)(C １～６ alkyl); R ９ is hydrogen, -C １～６ alkyl, -C ３～８ cycloalkyl, -(C １～６ alkyl)-OH, -(C １～６ alkyl)-NH ２ , or -(C １～６ alkyl)-NC(=O)(C １～６ alkyl), a compound according to any one of claims 1 to 21.

26. R ６ is 【Chemical 37】 - A compound according to any one of claims 1 to 21, selected from the group consisting of.

27. 【Fig. 38】 【Chemical 39】 【Chemical 40】 【Chemical Formula 41】 【Chemical 42】 【Chemical 43】 【Chemical 44】 【Chemical 45】 【Chemical 46】 【Chemical 47】 【Chemical 48】 【Chemical 49】 【Chemical Formula 50】 【Chemical 51】 【Chemical 52】 【Chemical 53】 【Chemical 54】 A compound selected from the group consisting of, and a pharmaceutically acceptable salt thereof.

28. 【Fig. 55】 【Chemical 56】 【Chemical 57】 A compound selected from the group consisting of, and a pharmaceutically acceptable salt thereof.

29. A pharmaceutical composition comprising a therapeutically effective amount of one or more of the compounds according to any one of claims 1 to 28 and a pharmaceutically acceptable excipient.

30. The pharmaceutical composition according to claim 29, further comprising an aminoglycoside.

31. The aminoglycoside is kanamycin A, amikacin, tobramycin, dibekacin, gentamicin, geneticin, sisomicin, netilmicin, neomycin B, neomycin C, paromomycin, streptomycin, plazomycin, tobramycin, 【Chemical Formula 58】 and the pharmaceutical composition according to claim 30, selected from the group consisting of pharmaceutically acceptable salts thereof.

32. The pharmaceutical composition according to claim 31, wherein the aminoglycoside is selected from the group consisting of geneticin, ELX-02, and paromomycin.

33. The pharmaceutical composition according to any one of claims 29 to 32, wherein the composition further comprises an eRF3 modulator.

34. A method for enhancing the readthrough of a gene containing a premature termination codon, said method comprising administering to a subject in need thereof: (i) a readthrough modulator; and (ii) an aminoglycoside.

35. The method according to claim 34, wherein the readthrough modulator is a compound according to any one of claims 1 to 27.

36. The aminoglycoside is selected from the group consisting of kanamycin A, amikacin, tobramycin, dibekacin, gentamicin, geneticin, sisomicin, netilmicin, neomycin B, neomycin C, paromomycin, streptomycin, plazomycin, tobramycin, 【Chemical Formula 59】 and a pharmaceutically acceptable salt thereof, according to the method of claim 34 or 35.

37. The method according to any one of claims 34 to 36, wherein the compound and the aminoglycoside are selected to increase ribosomal readthrough of an mRNA transcript having a premature termination codon mutation in the cystic fibrosis CFTR channel.

38. The method according to claim 37, wherein the mutation is selected from one or more of G542X, R553X, R1162X, and W1282X.

39. The method according to claim 37, wherein the mutation is R1162X.

40. The method according to claim 37, wherein the mutation is G542X.

41. The method according to any one of claims 37 to 40, wherein the increase in readthrough is greater than 10% compared to administration of the aminoglycoside alone.

42. The method according to any one of claims 37 to 40, wherein the increase in readthrough is greater than 50% compared to administration of the aminoglycoside alone.

43. The method according to any one of claims 37 to 40, wherein the increase in readthrough is greater than 100% compared to administration of the aminoglycoside alone.

44. A method for treating cystic fibrosis, said method comprising administering to a subject in need thereof: (i) an eRF3 modulator; (ii) an aminoglycoside; and (iii) a readthrough modulator.

45. The method according to claim 44, wherein the readthrough modulator is a compound according to any one of claims 1 to 28.

46. The aminoglycoside is selected from the group consisting of kanamycin A, amikacin, tobramycin, dibekacin, gentamicin, geneticin, sisomicin, netilmicin, neomycin B, neomycin C, paromomycin, streptomycin, plazomycin, tobramycin, 【Chemical Formula 60】 The method according to claim 44 or 45, selected from the group consisting of and pharmaceutically acceptable salts thereof.

47. The method according to any one of claims 44 to 46, wherein the aminoglycoside is selected from the group consisting of geneticin, ELX-02, and paromomycin.

48. The method according to any one of claims 44 to 47, wherein the eRF3 modulator is a cereblon E3 ligase modulator.

49. The cereblon E3 ligase modulator is a compound having the formula: 【Chemical Formula 61】 or a pharmaceutically acceptable salt thereof, wherein in the formula, X Ａ is CH ２ or C=O, and Z Ａ is (CH ２ ), or NH, and ｍ is as follows m is 0 or 1, R １Ａ is halogen, or (C １ -C ６ )alkyl optionally substituted with one or more halogens; R ２Ａ is hydrogen, halogen, or (C １ -C ６ ) alkyl optionally substituted with one or more halogens, The method according to claim 48.

50. The cereblon E3 ligase modulator is a compound having the formula: 【Chemical Formula 62】 or a pharmaceutically acceptable salt thereof, wherein in the formula, X Ｂ is C=O or CH ２ and R １Ｂ is -Y Ｂ -R ３Ｂ and R ２Ｂ is H or (C １ -C ６ ) alkyl, Y Ｂ is: a 6- to 10-membered aryl optionally substituted with one or more halogens; R ３Ｂ is: -(CH ２ ) ｎ -aryl, -O-(CH ２ ) ｎ -aryl, or -(CH ２ ) ｎ -O-aryl, wherein the aryl is (C １ ~C ６ )alkyl optionally substituted with one or more halogens by itself; (C １ ~C ６ )alkoxy substituted with one or more halogens by itself; oxo; amino; carboxyl; cyano; hydroxyl; halogen; 6- to 10-membered aryl or heteroaryl optionally substituted with one or more (C １ ~C ６ )alkyl, (C １ ~C ６ )alkoxy or halogen; -CONH ２ ; or, -COO-(C １ ~C ６ )alkyl, wherein the alkyl may be optionally substituted with one or more halogens, -COO-(C １ ~C ６ )alkyl, optionally substituted with one or more of, -(CH2)n-aryl, -O-(CH2)n-aryl, or -(CH2)n-O-aryl, - (CH ２ ), -heterocycle, -O-(CH ２ ) ｎ -Heterocycle or -(CH ２ ) ｎ , —O-heterocycle, which is itself optionally substituted with one or more halogens (C １ ~C ６ ) alkyl; itself substituted with one or more halogens (C １ ~C ６ )alkoxy; oxo; amino; carboxyl; cyano; hydroxyl; halogen; each of which is one or more (C １ ~C ６ ) alkyl, (C １ ~C ６ ) 6- to 10-membered aryl or heteroaryl optionally substituted with alkoxy or halogen; ２ Or -COO-(C １ ~C ６ )alkyl, said alkyl being optionally substituted with one or more halogens; １ ~C ６ )alkyl, -(CH2),-heterocycle, -O-(CH2)n-heterocycle or -(CH2)n,-O-heterocycle; or -(CH ２ ) ｎ -heteroaryl, -O-(CH ２ ) ｎ -heteroaryl, or -(CH ２ ) ｎ -O-heteroaryl, wherein the heteroaryl is (C １ ~C ６ )alkyl optionally substituted with one or more halogens; (C １ ~C ６ )alkoxy substituted with one or more halogens; oxo; amino; carboxyl; cyano; hydroxyl; halogen; 6- to 10-membered aryl or heteroaryl optionally substituted with one or more (C １ ~C ６ )alkyl, (C １ ~C ６ )alkoxy or halogen; -CONH ２ ; or, -COO-(C １ ~C ６ )alkyl, wherein the alkyl may be optionally substituted with one or more halogens, -COO-(C １ ~C ６ )alkyl, and is optionally substituted with one or more of -(CH2)n-heteroaryl, -O-(CH2)n-heteroaryl, or -(CH2)n-O-heteroaryl; n is 0, 1, 2, or 3, The method according to claim 48.

51. The cereblon E3 ligase modulator is a compound having the formula: 【Chemical Formula 63】 or a pharmaceutically acceptable salt thereof, wherein in the formula, R １Ｃ is an optionally substituted cycloalkyl, an optionally substituted aryl, an optionally substituted heteroaryl, or an optionally substituted heterocyclyl; R ２Ｃ and R ３Ｃ are each halo; R １Ｃ When present, the substituents above are 1 to 3 groups Q Ｃ and each Q Ｃ is independently (C １ ~C ６ )alkyl, halo, (C １ ~C ６ )haloalkyl, (C １ ~C ６ )alkoxy-(C １ ~C ６ )alkyl, oxo, hydroxyl, (C １ ~C ６ )alkoxy, optionally substituted (C ３ ~C ８ )cycloalkyl, optionally substituted cycloalkylalkyl, optionally substituted heterocyclyl, optionally substituted heterocyclylalkyl, optionally substituted aryl, optionally substituted heteroaryl, -R ４Ｃ OR ５Ｃ , -R ４Ｃ OR ５Ｃ -R ４Ｃ OR ５Ｃ , -R ４Ｃ N(R ６Ｃ )(R ７Ｃ ), -R ４Ｃ SR ５Ｃ , -R ４Ｃ OR ４Ｃ N(R ６Ｃ )(R ７Ｃ ), -R ４Ｃ OR ４Ｃ C(J Ｃ )(R ６Ｃ )(R ７Ｃ ), -C(J Ｃ )R ９Ｃ or R ４Ｃ S(O) ｔ R ８Ｃ ; Each R ４Ｃ is independently an alkylene, alkenylene or a direct bond; Each R ５Ｃ is independently hydrogen, (C １ ~C ６ -C １ ~C ６ -C １ ~C ６ -C １ ~C ６ -alkoxy-(C １ ~C ６ -alkyl, (C ３ ~C ８ -cycloalkyl, aryl, heteroaryl, heterocyclyl or heterocyclylalkyl, where the alkyl group, haloalkyl group, hydroxyalkyl group, alkoxyalkyl group, cycloalkyl group, aryl group, heteroaryl group, heterocyclyl group or heterocyclylalkyl group of R ５Ｃ is each independently optionally substituted with 1 to 3 Q Ｃ’ groups, and each Q Ｃ’ is independently alkyl, haloalkyl or halo; R ６Ｃ and R ７Ｃ are as follows: i) R ６Ｃ and R ７Ｃ are each independently hydrogen or (C １ ~C ６ ) alkyl; or ii) R ６Ｃ and R ７Ｃ are selected such that, together with the nitrogen atom to which they are attached, they form a 5- or 6-membered heterocyclyl or heteroaryl ring optionally substituted with one or two halo, (C １ -C ６ )alkyl or haloalkyl; R ８Ｃ is (C １ to C ６ ) alkyl, (C １ to C ６ ) haloalkyl, or (C １ to C ６ ) hydroxyalkyl; R ９Ｃ is (C １ ~C ６ ) alkyl or aryl; J Ｃ is O or S; t is 1 or 2, The method according to claim 48.

52. The cereblon E3 ligase modulator is a compound having the formula: 【Chemical Formula 64】 or a pharmaceutically acceptable one thereof, wherein in the formula, R １Ｄ is optionally substituted (C ３ to C ８ ) cycloalkyl, optionally substituted aryl, optionally substituted heteroaryl, or optionally substituted heterocyclyl; R ２Ｄ and R ３Ｄ are each halo; R １Ｄ When present, the substituent(s) on the upper part is / are 1 to 3 groups Q Ｄ and each Q Ｄ is independently (C １ -C ６ )alkyl, halo, (C １ -C ６ )haloalkyl, (C １ -C ６ )alkoxy-(C １ -C ６ )alkyl, oxo, hydroxyl, (C １ -C ６ )alkoxy, optionally substituted (C ３ -C ８ )cycloalkyl, optionally substituted cycloalkylalkyl, optionally substituted heterocyclyl, optionally substituted heterocyclylalkyl, optionally substituted aryl, optionally substituted heteroaryl, -R ４Ｄ OR ５Ｄ , -R ４Ｄ OR ５Ｄ -R ４Ｄ OR ５Ｄ , -R ４Ｄ N(R ６Ｄ )(R ７Ｄ ), -R ４Ｄ SR ５Ｄ , -R ４Ｄ OR ４Ｄ N(R ６Ｄ )(R ７Ｄ ), -R ４Ｄ OR ４Ｄ C(J Ｄ )(R ６Ｄ )(R ７Ｄ ), -C(J Ｄ )R ９Ｄ or R ４Ｄ S(O) ｗ R ８Ｄ ; Each R ４Ｄ is independently an alkylene, alkenylene or a direct bond; Each R ５Ｄ is, independently, hydrogen, (C １ ~C ６ ), alkyl, (C １ ~C ６ ), haloalkyl, hydroxy(C １ ~C ６ ), alkyl, (C １ ~C ６ ), alkoxy-(C １ ~C ６ ), alkyl, (C ３ ~C ８ ), cycloalkyl, aryl, heteroaryl, heterocyclyl or heterocyclylalkyl, where the alkyl group, haloalkyl group, hydroxyalkyl group, alkoxyalkyl group, cycloalkyl group, aryl group, heteroaryl group, heterocyclyl group or heterocyclylalkyl group of R ５Ｄ is each independently optionally substituted with 1 to 3 Q Ｄ’ groups, and each Q Ｄ’ is independently (C １ ~C ６ ), alkyl, (C １ ~C ６ ), haloalkyl or halo; R ６Ｄ and R ７Ｄ are as follows: i) R ６Ｄ and R ７Ｄ are each independently hydrogen or (C １ -C ６ ) alkyl; or ii) R ６Ｄ and R ７Ｄ together with the nitrogen atom to which they are attached form a 5- or 6-membered heterocyclyl or heteroaryl ring optionally substituted with one or two halo, (C １ ~C ６ )alkyl or (C １ ~C ６ )haloalkyl is selected as follows; R ８Ｄ is (C １ ~C ６ ) alkyl, (C １ ~C ６ ) haloalkyl, or hydroxy(C １ ~C ６ ) alkyl; R ９Ｄ is (C １ ~C ６ ) alkyl or aryl; J Ｄ is O or S; w is 1 or 2, The method according to claim 48.

53. The cereblon E3 ligase modulator is 【Chemical Formula 65】 【Chemical Formula 66】 The method according to claim 48, selected from the group consisting of and pharmaceutically acceptable salts thereof.

54. The method according to any one of claims 44 to 53, wherein the eRF3 modulator, aminoglycoside, and readthrough modulator are selected to increase ribosome readthrough of mRNA transcripts having premature stop codon mutations in the cystic fibrosis CFTR channel.

55. The method according to claim 54, wherein the mutation is selected from one or more of G542X, R553X, R1162X, W1282X, and W1316X.

56. The method according to claim 54, wherein the mutation is R1162X.

57. The method according to claim 54, wherein the mutation is G542X. Claim 58 The method according to any one of claims 54 to 57, wherein the increase in lead-through is greater than 10% compared to administration of the aminoglycoside alone. Claim 59 The method according to any one of claims 54 to 57, wherein the increase in lead-through is greater than 50% compared to administration of the aminoglycoside alone. Claim 60 The method according to any one of claims 54 to 57, wherein the increase in lead-through is greater than 100% compared to administration of the aminoglycoside alone.

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