Compounds for enhancing readthrough of genes containing premature termination codons and methods of making and using same

Abstract

Disclosed herein are novel aromatic compounds, compositions including one or more aromatic compounds, and methods of synthesis thereof. Also disclosed herein are methods of enhancing readthrough of genes containing premature termination codons with one or more compounds or compositions described herein.

Claims

1. A compound having a structure of formula (I) or a pharmaceutically acceptable salt thereof, wherein: R 1 , R 2 , R 3 , R 4 and R 5 Each independently selected from the group consisting of 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 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 ;and R 7a and R 7b are each independently selected from the group consisting of hydrogen, optionally substituted C 1-6 Alkyl, optionally substituted C 3-8 Cycloalkyl; optionally substituted aryl, optionally substituted heterocyclyl, and optionally substituted heteroaryl; The condition is that when R 1 and R 2 are hydrogen and R 6 When is an optionally substituted pyrazolyl group, then R 3 is not halogenated and R 4 Not halogenated.

2. The compound of claim 1, wherein L 1 It's O.

3. The compound as claimed in claim 1, wherein L 1 It is CH2.

4. The compound of claim 1, wherein L 1 It's NH.

5. The compound of claim 1, wherein L 2 It is CH2.

6. The compound of claim 1, wherein L 2 It is CHF.

7. The compound of claim 1, wherein L 2 It's CF2.

8. A compound as claimed in any one of claims 1 to 7, wherein Z 1 Yes N, Z 2 is N, and Z 3 It is CH.

9. The compound of any one of claims 1 to 7, wherein Z 1 Yes N, Z 2 is CH, and Z 3 It is CH.

10. The compound of any one of claims 1 to 7, wherein Z 1 It is CH, Z 2 is CH, and Z 3 It is CH.

11. The compound of any one of claims 1 to 7, wherein Z 1 It is CH, Z 2 is CH, and Z 3 It is N.

12. The compound of any one of claims 1 to 7, wherein Z 1 It is CH, Z 2 is CH, and Z 3 It's CF.

13. A compound as claimed in any one of claims 1 to 7, wherein Z 1 Yes N, Z 2 is CH, and Z 3 It is N.

14. The compound of any one of claims 1 to 7, wherein Z 1 It is CH, Z 2 is N, and Z 3 It is N.

15. A compound as claimed in any one of claims 1 to 14, wherein R 1 Selected from the group consisting of: -CN, halo, -C 1-6 Alkyl, -C 1-6 Alkoxy, -C 1-6 Haloalkyl and -C 1-6 Halogenated alkoxy.

16. A compound as claimed in any one of claims 1 to 15, wherein R 1 Selected from the group consisting of -CN, -F, -Cl, -Br, -CH3, -CH2CH3, -CF3, -CF2CH3, -OCF3, -OCHF2 and -cyclopropyl.

17. A compound as claimed in any one of claims 1 to 16, wherein R 2 A group consisting of: -CN, halogen, -C 1-6 Alkyl, -C 1-6 Alkoxy, -C 1-6 Haloalkyl and -C 1-6 Halogenated alkoxy.

18. A compound as claimed in any one of claims 1 to 17, wherein R 2 Selected from the group consisting of -CN, -F, -Cl, -Br, -CH3, -CH2CH3, -CF3, -CF2CH3, -OCF3, -OCHF2 and -cyclopropyl.

19. A compound as claimed in any one of claims 1 to 18, wherein R 3 It is hydrogen or halogenated.

20. A compound as claimed in any one of claims 1 to 19, wherein R 4 It is hydrogen or halogenated.

21. A compound as described in any one of claims 1 to 20, wherein R 5 It is hydrogen or halogenated.

22. A compound as described in any one of claims 1 to 21, wherein R 6 Selected from the group consisting of: wherein q is an integer value selected from 0, 1, and 2; Each R 8 are independently fluorine, phenyl, pyridine, carboxyl, -C(=O)-(C1-C6 alkyl), -(C 1-6 alkyl)-phenyl, -(C 1-6 -(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)2NH2, -S(=O)2-(C 1-6 Alkyl), -(C 1-6 -(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); and Where R 9 It is hydrogen, -C 1-6 Alkyl, -C 3-8 Cycloalkyl, -(C 1-6 Alkyl)-OH, -(C 1-6 Alkyl)-NH2 or -(C 1-6 alkyl)-NC(=O)(C 1-6 alkyl).

23. A compound as described in any one of claims 1 to 21, wherein R 6 Selected from the group consisting of:

24. A compound selected from the group consisting of: and pharmaceutically acceptable salts thereof.

25. A compound as described in any one of claims 1 to 21, wherein R 6 Selected from the group consisting of: wherein q is an integer value selected from 0, 1, and 2; Each R 8 are independently fluorine, phenyl, pyridine, carboxyl, -C(=O)-(C1-C6 alkyl), -(C 1-6 alkyl)-phenyl, -(C 1-6 -(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)2NH2, -S(=O)2-(C 1-6 Alkyl), -(C 1-6 -(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); and Where R 9 It is hydrogen, -C 1-6 Alkyl, -C 3-8 Cycloalkyl, -(C 1-6 Alkyl)-OH, -(C 1-6 Alkyl)-NH2 or -(C 1-6 alkyl)-NC(=O)(C 1-6 alkyl).

26. A compound as described in any one of claims 1 to 21, wherein R 6 Selected from the group consisting of:

27. A compound selected from the group consisting of: and pharmaceutically acceptable salts thereof.

28. A compound selected from the group consisting of: and pharmaceutically acceptable salts thereof.

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

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

31. The pharmaceutical composition of claim 30, wherein the aminoglycoside is selected from the group consisting of kanamycin A, amikacin, tobramycin, dibekacin, gentamicin, geneticin, sisomicin, netilmicin, neomycin B, neomycin C, paromomycin, streptomycin, prazomicin, tobramycin, and pharmaceutically acceptable salts thereof.

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

33. The pharmaceutical composition of any one of claims 29 to 32, further comprising an eRF3 modulator.

34. A method of increasing readthrough of a gene containing a premature stop codon, the method comprising administering to a subject in need thereof: (i) a readthrough regulator; and (ii) an aminoglycoside.

35. The method of claim 34, wherein the read-through modulator is a compound as described in any one of claims 1 to 27.

36. The method of claim 34 or 35, wherein the aminoglycoside is selected from the group consisting of kanamycin A, amikacin, tobramycin, dibekacin, gentamicin, geneticin, sisomicin, netilmicin, neomycin B, neomycin C, paromomycin, streptomycin, prazomicin, tobramycin, and pharmaceutically acceptable salts thereof.

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

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

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

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

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

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

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

44. A method of treating cystic fibrosis, the method comprising administering to a subject in need thereof (i) an eRF3 modulator, (ii) an aminoglycoside, and (iii) a read-through modulator.

45. The method of claim 44, wherein the read-through modulator is a compound as described in any one of claims 1 to 28.

46. ​​The method of claim 44 or 45, wherein the aminoglycoside is selected from the group consisting of kanamycin A, amikacin, tobramycin, dibekacin, gentamicin, geneticin, sisomicin, netilmicin, neomycin B, neomycin C, paromomycin, streptomycin, prazomicin, tobramycin, and pharmaceutically acceptable salts thereof.

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

49. The method of claim 48, wherein the cerebellin E3 ligase modulator is a compound having the formula: or a pharmaceutically acceptable salt thereof, wherein: X A is CH2 or C=O; Z A Yes (CH2) m or NH; m is 0 or 1; R 1A is halogen or (C1-C6)alkyl optionally substituted by one or more halogens; and R 2A is hydrogen, halogen or (C1-C6)alkyl optionally substituted by one or more halogens.

50. The method of claim 48, wherein the cerebellin E3 ligase modulator is a compound having the formula: or a pharmaceutically acceptable salt thereof, wherein: X B is C=O or CH2; R 1B Yes - Y B -R 3B ; R 2B is H or (C1-C6)alkyl; Y B is: a 6- to 10-membered aryl group optionally substituted by one or more halogens; R 3B yes: -(CH2) n -Aryl, -O-(CH2) n -Aryl or -(CH2) n -O-aryl, wherein the aryl is optionally substituted with one or more of the following: (C1-C6)alkyl, which is itself optionally substituted with one or more halogens; (C1-C6)alkoxy, which is itself optionally substituted with one or more halogens; oxo; amino; carboxyl; cyano; hydroxyl; halogen; 6 to 10 membered aryl or heteroaryl, each of which is optionally substituted with one or more (C1-C6)alkyl, (C1-C6)alkoxy or halogen; -CONH2; or -COO-(C1-C6)alkyl, wherein the alkyl may be optionally substituted with one or more halogens; -(CH2), heterocyclic ring, -O-(CH2) n -Heterocycle or -(CH2) n , -O-heterocycle, wherein the heterocycle is optionally substituted by one or more of the following: (C1-C6)alkyl, which is itself optionally substituted by one or more halogens; (C1-C6)alkoxy, which is itself optionally substituted by one or more halogens; oxo; amino; carboxyl; cyano; hydroxyl; halogen; 6 to 10 membered aryl or heteroaryl, each of which is optionally substituted by one or more (C1-C6)alkyl, (C1-C6)alkoxy or halogen; -CONH2; or -COO-(C1-C6)alkyl, wherein the alkyl may be optionally substituted by one or more halogens; or -(CH2) n -heteroaryl, -O-(CH2) n -heteroaryl or -(CH2) n -O-heteroaryl, wherein the heteroaryl is optionally substituted with one or more of: (C1-C6)alkyl, which is itself optionally substituted with one or more halogen; (C1-C6)alkoxy, which is itself optionally substituted with one or more halogen; oxo; amino; carboxyl; cyano; hydroxyl; halogen; 6 to 10 membered aryl or heteroaryl, each of which is optionally substituted with one or more (C1-C6)alkyl, (C1-C6)alkoxy or halogen; -CONH2; or -COO-(C1-C6)alkyl, wherein the alkyl may be optionally substituted by one or more halogens; and n is 0, 1, 2 or 3.

51. The method of claim 48, wherein the cerebellin E3 ligase modulator is a compound having the formula: or a pharmaceutically acceptable salt thereof, wherein: R 1C is optionally substituted cycloalkyl, optionally substituted aryl, optionally substituted heteroaryl or optionally substituted heterocyclyl; R 2C and R 3C Each is halogenated; Where R 1C The substituents on the C , where each Q C are independently (C1-C6)alkyl, halo, (C1-C6)haloalkyl, (C1-C6)alkoxy-(C1-C6)alkyl, oxo, hydroxy, (C1-C6)alkoxy, optionally substituted (C3-C8)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 )N(R 6C )(R 7C ),—C(J C )R 9C or R 4C S(O) t R 8C ; Each R 4C are independently alkylene, alkenylene or a direct bond; Each R 5C are independently hydrogen, (C1-C6)alkyl, (C1-C6)haloalkyl, (C1-C6)hydroxyalkyl, (C1-C6)alkoxy-(C1-C6)alkyl, (C3-C8)cycloalkyl, aryl, heteroaryl, heterocyclyl or heterocyclylalkyl, wherein R 5C The alkyl, haloalkyl, hydroxyalkyl, alkoxyalkyl, cycloalkyl, aryl, heteroaryl, heterocyclyl or heterocyclylalkyl groups in the C’ group substituted, where each Q C’ are independently alkyl, haloalkyl or halo; R 6C and R 7C Make your selection as follows: i)R 6C and R 7C are each independently hydrogen or (C1-C6)alkyl; or ii) R 6C and R 7C Together with the nitrogen atom on which they are substituted, they form a 5- or 6-membered heterocyclyl or heteroaryl ring, which is optionally substituted with one or two halo, (C1-C6)alkyl or haloalkyl groups; R 8C is (C1-C6)alkyl, (C1-C6)haloalkyl or (C1-C6)hydroxyalkyl; R 9C is (C1-C6) alkyl or aryl; J C is O or S; and t is 1 or 2.

52. The method of claim 48, wherein the cerebellin E3 ligase modulator is a compound having the formula: or pharmaceutically acceptable, wherein: R 1D is an optionally substituted (C3-C8)cycloalkyl group, an optionally substituted aryl group, an optionally substituted heteroaryl group or an optionally substituted heterocyclyl group; R 2D and R 3D Each is halogenated; Where R 1D The substituents on the D , where each Q D are independently (C1-C6)alkyl, halo, (C1-C6)haloalkyl, (C1-C6)alkoxy-(C1-C6)alkyl, oxo, hydroxy, (C1-C6)alkoxy, optionally substituted (C3-C8)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 )N(R 6D )(R 7D ),—C(J D )R 9D or R 4D S(O) w R 8D ; Each R 4D are independently alkylene, alkenylene or a direct bond; Each R 5D are independently hydrogen, (C1-C6)alkyl, (C1-C6)haloalkyl, hydroxy(C1-C6)alkyl, (C1-C6)alkoxy-(C1-C6)alkyl, (C3-C8)cycloalkyl, aryl, heteroaryl, heterocyclyl or heterocyclylalkyl, wherein R 5D The alkyl, haloalkyl, hydroxyalkyl, alkoxyalkyl, cycloalkyl, aryl, heteroaryl, heterocyclyl or heterocyclylalkyl groups in the D’ group substituted, where each Q D’ are independently (C1-C6)alkyl, (C1-C6)haloalkyl or halo; R 6D and R 7D Make your selection as follows: i)R 6D and R 7D are each independently hydrogen or (C1-C6)alkyl; or ii) R 6D and R 7D Together with the nitrogen atom on which they are substituted, they form a 5- or 6-membered heterocyclyl or heteroaryl ring, which is optionally substituted with one or two halo, (C1-C6)alkyl or (C1-C6)haloalkyl groups; R 8D is (C1-C6)alkyl, (C1-C6)haloalkyl or hydroxy(C1-C6)alkyl; R 9D is (C1-C6) alkyl or aryl; J D is O or S; and w is 1 or 2.

53. The method of claim 48, wherein the cerebellar protein E3 ligase modulator is selected from the group consisting of: and pharmaceutically acceptable salts thereof.

54. The method of any one of claims 44 to 53, wherein the eRF3 modulator, aminoglycoside and readthrough modulator are selected to increase ribosomal readthrough of an mRNA transcript carrying a premature stop codon mutation of the cystic fibrosis CFTR channel.

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

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

57. The method of claim 54, wherein the mutation is G542X.

58. The method of any one of claims 54 to 57, wherein the increase in read-through is greater than 10% compared to administration of the aminoglycoside alone.

59. The method of any one of claims 54 to 57, wherein the increase in read-through is greater than 50% compared to administration of the aminoglycoside alone.

60. The method of any one of claims 54 to 57, wherein the increase in read-through is greater than 100% compared to administration of the aminoglycoside alone.

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