Methods and compounds for modulating myotonic dystrophy 1

Abstract

The present disclosure relates to transcriptional modulator molecule compounds and methods for regulating the expression of dmpk and treating diseases and conditions in which dmpk plays an active role. The transcriptional modulator comprises: a) a first end comprising a DNA-binding moiety capable of non-covalently binding to a nucleotide repeat sequence CAG or CTG; b) a second end comprising a protein-binding moiety capable of binding to a regulatory molecule that regulates the expression of a gene comprising the nucleotide repeat sequence CAG or CTG; and c) an oligomeric backbone comprising a linker between the first end and the second end.

Claims

1. 1. A transcription modulator molecule, or a pharma- ceutically acceptable salt or solvate thereof, having a first end, a second end, and a linker moiety, a) the first end comprises a DNA-binding moiety capable of non-covalently binding to the nucleotide repeat sequence CTG; b) the second end comprises a protein-binding moiety capable of binding to a regulatory molecule that regulates the expression of a gene comprising the nucleotide repeat sequence CTG; c) the linker moiety connects the first end and the second end; The first end comprises a structure of formula (A-2'), 【Chemistry 1】 During the ceremony, each X １ , X ２ , X ３ , X ４ , X ５ , X ６ , and X ７ are independently O, S, or NR １Ｄ and Each Y １ , Y ２ , Y ３ , Y ４ , Y ５ , Y ６ , and Y ７ is independently CH or N; W １ is hydrogen, optionally substituted 5-10 membered heteroaryl, optionally substituted C １ -C ６ Alkyl, —C(O)—NR １Ｅ R １Ｆ , -NR １Ｅ -C(O)-NR １Ｅ R １Ｆ or W 1 is 【Chemistry 2】 and W ２ optionally substituted 5-10 membered heteroaryl, optionally substituted C １ -C ６ Alkyl, or -C(O)-NR １Ｅ R １Ｆ and m １ is 0, 1, 2, or 3; n １ is 0, 1, 2, or 3; p １ is 1, 2, 3, or 4; Each R １Ｄ and R １Ｅ are independently hydrogen or optionally substituted C １ -C ６ is alkyl, R １Ｆ is hydrogen, optionally substituted C １ -C １０ Alkyl, optionally substituted C １ -C １０ Heteroalkyl, PEG １－２０ or one or more AA, wherein AA is one or more amino acids selected from β-alanine, lysine, and arginine; R １Ｈ is hydrogen, amino, cyano, optionally substituted C １ -C １０ Alkyl, or optionally substituted C ２ -C １０ A transcription modulator molecule, or a pharma- ceutically acceptable salt or solvate thereof, which is heteroalkyl.

2. The first end comprises a structure of formula (A-2), 【Chemistry 3】 During the ceremony, each X 1 , X 2 , X 3 , X 4 , X 5 , X 6 , and X 7 is independently O, S, or NR 1D ; each Y 1 , Y 2 , Y 3 , Y 4 , Y 5 , Y 6 , and Y 7 is independently CH or N; W 1 is hydrogen, optionally substituted 5 to 10 membered heteroaryl, optionally substituted C 1 -C 6 alkyl, —C(O)—NR 1E R 1F , or —NR 1E —C(O)—NR 1E R 1F ; or W 1 is 【Chemistry 4】 and m 1 is 0, 1, 2, or 3; n 1 is 0, 1, 2, or 3; p 1 is 1, 2, 3, or 4; each R 1D and R 1E is independently hydrogen or C 1 -C 6 alkyl; R 1F is hydrogen, optionally substituted C 1 -C 10 alkyl, optionally substituted C 2 -C 10 heteroalkyl, PEG 1-20 , or one or more AA, where AA is one or more amino acids selected from β-alanine, lysine, and arginine; 2. The transcription modulator molecule of claim 1, or a pharma- ceutically acceptable salt or solvate thereof, wherein R1H is hydrogen, amino, cyano, optionally substituted C1-C10 alkyl, or optionally substituted C2-C10 heteroalkyl.

3. The transcription modulator molecule of claim 1 or 2, or a pharma- ceutically acceptable salt or solvate thereof, wherein each of X1, X2, X3, X4, X5, X6, and X7 is independently -NR1D, where R1D is C1-C6 alkyl.

4. The transcription modulator molecule of any one of claims 1 to 3, wherein m 1 is 0 or 1, and n 1 is 0 or 1, or a pharma- ceutically acceptable salt or solvate thereof.

5. The transcription modulator molecule of any one of claims 1 to 4, or a pharma- ceutically acceptable salt or solvate thereof, wherein p1 is 2 or 3.

6. The transcription modulator molecule of any one of claims 1 to 5, wherein W 1 is hydrogen, optionally substituted 5 to 10 membered heteroaryl, optionally substituted C 1 -C 6 alkyl, -C(O)-NR 1E R 1F, or -NR 1E -C(O)-NR 1E R 1F, or a pharma- ceutically acceptable salt or solvate thereof.

7. W 1 is 【Chemistry 5】 7. The transcription modulator molecule of any one of claims 1 to 6, which is: or a pharma- ceutically acceptable salt or solvate thereof.

8. A transcription modulator molecule, or a pharma- ceutically acceptable salt or solvate thereof, according to any one of claims 1 to 7, wherein the linker has a length of less than about 50 angstroms.

9. A transcription modulator molecule, or a pharma- ceutically acceptable salt or solvate thereof, according to any one of claims 1 to 7, wherein the linker has a length of about 10 to 60 angstroms.

10. The method of claim 1, wherein the linker comprises a multimer having 2 to 50 spacing moieties, The spacing moieties are independently selected from the group consisting of -((CR 3a R 3b ) x -O) y -, -((CR 3a R 3b ) x -NR 4a ) y -, -((CR 3a R 3b ) x -CH═CH-(CR 3a R 3b ) x -O) y -, optionally substituted -C 1-12 alkyl, optionally substituted C 2-10 alkenyl, optionally substituted C 2-10 alkynyl, optionally substituted C 6-10 arylene, optionally substituted C 3-7 cycloalkylene, optionally substituted 5- to 10-membered heteroarylene, optionally substituted 4- to 10-membered heterocycloalkylene, an amino acid residue, -O-, -C(O)NR 4a -, -NR 4a selected from the group consisting of C(O)-, -C(O)-, -NR 4a -, -C(O)O-, -O-, -S-, -S(O)-, -SO 2 -, -SO 2 NR 4a -, -NR 4a SO 2 -, and -P(O)OH-, and any combination thereof; each x is independently 2 to 4; each y is independently 1 to 10; each R 3a and R 3b is independently selected from hydrogen, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted alkoxy, optionally substituted amino, carboxyl, carboxyl ester, acyl, acyloxy, acylamino, aminoacyl, optionally substituted alkylamido, sulfonyl, optionally substituted thioalkoxy, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted cycloalkyl, and optionally substituted heterocyclyl; 10. The transcription modulator molecule of any one of claims 1 to 9, or a pharma- ceutically acceptable salt or solvate thereof, wherein each R 4a is independently hydrogen or optionally substituted C 1-6 alkyl.

11. The linker is represented by formula (C-1): 【Chemistry 6】 The structure includes During the ceremony, Ring B is absent, arylene, or heterocycloacrylene; L 5 is absent, optionally substituted alkylene or alkenylene; each Y 8 and Y 9 is independently CH or N; s 1 is 0 to 3; ** indicates a bond to the second end, or The linker is represented by the formula (C-2): 【Chemistry 7】 The structure includes During the ceremony, L 5 is absent, optionally substituted alkylene or alkenylene; Y 9 is CH or N; each Y 10 and Y 11 is independently N or CH; The linker is represented by formula (C-3): 【Chemistry 8】 The structure includes During the ceremony, s 1 is 0 to 3; s 2 is 1 to 3; R 26 is optionally substituted C 1-20 alkylene or heteroalkylene; each R 1G is independently hydrogen or C 1 -C 3 alkyl; 11. The transcription modulator molecule of any one of claims 1 to 10, or a pharma- ceutically acceptable salt or solvate thereof, wherein ** indicates a bond to the second end.

12. The method of claim 11, wherein the linker is selected from the group consisting of -CO-, -NR 1a -, -CONR 1a -, -NR 1a CO-, -CONR 1a C 1-4 alkyl-, -NR 1a CO-C 1-4 alkyl-, -C(O)O-, -OC(O)-, -O-, -S-, -S(O)-, -SO 2 -, -SO 2 NR 1a -, -NR 1a SO 2 -, -P(O)OH-, -((CH 2 ) x -O)-, -((CH 2 ) y -NR 1a )-, optionally substituted C 1-12 alkylene, optionally substituted C 2-10 alkenylene, optionally substituted C 2-10 alkynylene, optionally substituted C 6-10 12. The transcription modulator molecule of any one of claims 1 to 11, or a pharma- ceutically acceptable salt or solvate thereof, wherein the transcription modulator molecule is attached to the first terminus with a group selected from arylene, optionally substituted C3-7cycloalkylene, optionally substituted 5-10 membered heteroarylene, and optionally substituted 4-10 membered heterocycloalkylene, wherein each x and y is independently 1 to 4, and each R1a is independently hydrogen or optionally substituted C1-6alkyl.

13. The transcription modulator molecule of any one of claims 1 to 12, or a pharma- ceutically acceptable salt or solvate thereof, wherein the second end is selected from a bromodomain inhibitor, a BPTF inhibitor, a methylcytosine dioxygenase inhibitor, a DNA demethylase inhibitor, a helicase inhibitor, an acetyltransferase inhibitor, a histone deacetylase inhibitor, a CDK-9 inhibitor, a positive transcription elongation factor inhibitor, and a polycomb repressive complex inhibitor.

14. The method of claim 13, wherein the second end is a group represented by the formula (C): 【Chemistry 9】 The compound includes During the ceremony, Ring A is a 5- to 10-membered heteroaryl or a 5- to 10-membered heterocycloalkyl; A 1 and A 2 are each independently CH or N; B 1 and B 2 are each independently O, S, or NR 5 ; Z 1 is O, S, or NR 5 ; each R 3 and R 4 is independently hydrogen, halogen, or C 1 -C 6 alkyl; R 5 is hydrogen or C 1 -C 6 alkyl; or The second end has the formula (D): 【Chemistry 10】 The compound includes During the ceremony, L 3 is optionally substituted alkylene or optionally substituted heteroalkylene; each R 6 , R 7 , R 8 , and R 9 is independently hydrogen, halogen, optionally substituted C 1-6 alkyl, optionally substituted C 1-6 haloalkyl, or optionally substituted C 1-6 hydroxyalkyl; R 10A is hydrogen, C 1 -C 6 alkyl, or SO 2 —R 10C ; R 10B is independently hydrogen or C 1 -C 6 alkyl; R 10C is C 1 -C 6 alkyl or aryl; or The second end has the formula (E): 【Chemistry 11】 The compound includes During the ceremony, each q 2 and q 3 is independently 1, 2, 3, or 4; R 11 is hydrogen, halogen, optionally substituted C 1-6 alkyl, optionally substituted C 1-6 haloalkyl, or optionally substituted C 1-6 hydroxyalkyl; each R 12 and R 13 is independently an optionally substituted 5-8 membered heterocycloalkyl; or The second end has the formula (F): 【Chemistry 12】 The compound includes During the ceremony, each R 14 and R 17 is independently hydrogen, halogen, optionally substituted C 1-6 alkyl, optionally substituted C 1-6 haloalkyl, or optionally substituted C 1-6 hydroxyalkyl; R 15 is an optionally substituted 5-membered heteroaryl; R 16 is hydrogen or C 1 -C 6 alkyl; or The second end has the formula (G): 【Chemistry 13】 The compound includes During the ceremony, r is 0, 1, or 2; R 18 is hydrogen, optionally substituted C 1-6 alkyl, optionally substituted C 1-6 haloalkyl, or optionally substituted C 1-6 hydroxyalkyl; R 19 is hydrogen, halogen, or optionally substituted C 1-6 alkyl; each R 20 is independently hydrogen, halogen, or C 1 -C 6 alkyl; each R 21 is independently hydrogen or C 1 -C 6 alkyl; or The second end is represented by the formula (H-1): 【Chemistry 14】 or The second end is represented by the formula (H-2): 【Chemistry 15】 or The second end has the formula (J): 【Chemistry 16】 The compound includes During the ceremony, R 23 is —NR 23A R 23B or —NR 23A (R 23B ) 2 + ; R 23A and R 23B are each independently optionally substituted C 1-6 alkyl, optionally substituted C 3 -C 10 cycloalkyl, optionally substituted aryl, or optionally substituted heteroaryl; or R 23A and R 23B together with the nitrogen to which they are attached form an optionally substituted heterocycle; R 24 is hydrogen, halogen, C 1-6 alkyl, C 1-6 haloalkyl, or C 1-6 alkoxy; R 25 is hydrogen or C 1-3 alkyl; R 30 , R 32 , and R 33 are each independently hydrogen, halogen, optionally substituted C 1-6 alkyl, optionally substituted C 1-6 alkoxy, or optionally substituted C 3-6 cycloalkyl; R 31 is C 1-6 alkyl or C 3-10 cycloalkyl; j 1 is 0 or 1; j 2 is 0, 1, 2, or 3; or The second end is represented by formula (J-5): 【Chemistry 17】 The compound includes During the ceremony, Ring C is an optionally substituted 5- to 6-membered heterocyclyl ring; R 23 is —NR 23A R 23B or —NR 23A (R 23B ) 2 + ; R 23A and R 23B are each independently optionally substituted C 1-6 alkyl, optionally substituted C 3 -C 10 cycloalkyl, optionally substituted aryl, or optionally substituted heteroaryl; or R 23A and R 23B together with the nitrogen to which they are attached form an optionally substituted heterocycle; R 24 is hydrogen, halogen, C 1-6 alkyl, C 1-6 haloalkyl, or C 1-6 alkoxy; R 25 is hydrogen or C 1-3 alkyl; R 30 , R 32 , and R 33 are each independently hydrogen, halogen, optionally substituted C 1-6 alkyl, optionally substituted C 1-6 alkoxy, or an optionally substituted C 3 -C 6 cycloalkyl ring; or The second end has the formula (K): 【Chemistry 18】 The compound includes During the ceremony, X 8 is CH or N; Y 8 is —C(O)— or —S(O) 2 —; R 27 is an optionally substituted cation of C 1-6 alkyl, optionally substituted C 3 -C 10 cycloalkyl, or optionally substituted 5-10 membered heteroaryl; R 28 is hydrogen, halogen, or C 1-6 alkyl; 14. The transcription modulator molecule of any one of claims 1 to 13, or a pharma- ceutically acceptable salt or solvate thereof, wherein R29 is hydrogen or C1-3 alkyl.

15. A pharmaceutical composition comprising a transcription modulator molecule according to any one of claims 1 to 14, or a pharma- ceutically acceptable salt or solvate thereof, and a pharma- ceutically acceptable carrier.

16. Use of a transcription modulator molecule according to any one of claims 1 to 14, or a pharma- ceutically acceptable salt thereof, in the manufacture of a medicament for treating myotonic dystrophy type 1 (DM1) in a subject in need thereof.

17. Use of a transcription modulator molecule described in any one of claims 1 to 14, or a pharma- ceutically acceptable salt thereof, in the manufacture of a medicament for treating Fuchs endothelial corneal dystrophy (FECD) in a subject in need thereof.

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