Acetal compounds and therapeutic uses thereof
Disclosed herein are acetal and cyclic acetal compounds, compositions, their preparation, and their uses. Some embodiments relate to their use as liver-targeting compounds.
1. A compound having the structure of Formula I:
or a pharmaceutically acceptable salt thereof, wherein:
R 1 is selected from the group consisting of optionally substituted C 1-8 alkyl, —COOR 5 , optionally substituted C 2-10 alkoxyalkyl, and 3-12 membered heterocyclyl optionally substituted with one or more R 15 , or alternatively:
(i) R 1 and R 2 together with the atoms to which they are attached form an optionally substituted 4-10 membered heterocyclyl, or
(ii) R 1 and R 3 together, with the atoms to which they are attached form an optionally substituted 6-10 membered heterocyclyl;
R 2 is selected from the group consisting of H, —C(O)R 6 , and optionally substituted C 2-10 alkoxyalkyl, or alternatively:
(i) R 1 and R 2 together with the atoms to which they are attached form an optionally substituted 4-10 membered heterocyclyl, or
(ii) R 2 and R 3 together with the atoms to which they are attached form a 6-10 membered heterocyclyl, optionally substituted with one or more R 7 ;
R 3 is selected from the group consisting of H, —C(O)R 8 , and optionally substituted C 2-10 alkoxyalkyl, or alternatively:
(i) R 1 and R 3 together with the atoms to which they are attached form an optionally substituted 6-10 membered heterocyclyl, or
(ii) R 2 and R 3 together with the atoms to which they are attached form a 6-10 membered heterocyclyl, optionally substituted with one or more R 7 ;
R 4 is
R 5 is selected from the group consisting of halogen, optionally substituted C 2-6 alkynyl, optionally substituted C 6-10 aryl, and optionally substituted 5-10 membered heteroaryl;
R 6 is selected from the group consisting of H, halogen, optionally substituted C 2-6 alkenyl, optionally substituted C 2-6 alkynyl, optionally substituted C 3-7 carbocyclyl, and optionally substituted 3-10 membered heterocyclyl;
R 8 is selected from the group consisting of H, optionally substituted C 1-6 alkyl, halogen, optionally substituted C 2-6 alkenyl, optionally substituted C 2-6 alkynyl, optionally substituted C 3-7 carbocyclyl, optionally substituted C 6-10 aryl, optionally substituted 5-10 membered heteroaryl, and optionally substituted 3-10 membered heterocyclyl; and
each R 7 is independently selected from the group consisting of optionally substituted C 1-8 alkyl, oxo, optionally substituted C 6-18 aryl, and optionally substituted 5-18 membered heteroaryl;
each R 15 is selected from the group consisting of C 1-6 alkyl, C 1-6 alkenyl, C 1-6 alkynyl, C 1-6 heteroalkyl, C 3-7 carbocyclyl, 3-10 membered heterocyclyl, C 6-18 aryl, C 6-18 aryl C 1-6 alkoxy, 5-10 membered heteroaryl, 5-10 membered heteroaryl C 1-6 alkyl, halo, cyano, hydroxyl, C 1-6 alkoxy, C 2-10 alkoxyalkyl, aryloxy, sulfhydryl, haloC 1-6 alkyl, haloC 1-6 alkoxy, C 1-6 alkylthio, C 6-18 arylthio, and nitro;
wherein when an alkyl group is substituted, it is substituted with one or more substituents selected from the group consisting of: C 1 -C 6 alkyl; C 1 -C 6 alkenyl; C 1 -C 6 alkynyl; C 1 -C 6 heteroalkyl; C 3 -C 7 carbocyclyl optionally substituted with halo, C 1 -C 6 alkyl, C 1 -C 6 alkoxy, C 1 -C 6 haloalkyl, and C 1 -C 6 haloalkoxy; C 3 -C 7 carbocyclyl-C 1 -C 6 -alkyl optionally substituted with halo, C 1 -C 6 alkyl, C 1 -C 6 alkoxy, C 1 -C 6 haloalkyl, and C 1 -C 6 haloalkoxy; 3-10 membered heterocyclyl optionally substituted with halo, C 1 -C 6 alkyl, C 1 -C 6 alkoxy, C 1 -C 6 haloalkyl, and C 1 -C 6 haloalkoxy; 3-10 membered heterocyclyl-C 1 -C 6 -alkyl optionally substituted with halo, C 1 -C 6 alkyl, C 1 -C 6 alkoxy, C 1 -C 6 haloalkyl, and C 1 -C 6 haloalkoxy; aryl optionally substituted with halo, C 1 -C 6 alkyl, C 1 -C 6 alkoxy, C 1 -C 6 haloalkyl, and C 1 -C 6 haloalkoxy; aryl(C 1 -C 6 )alkyl optionally substituted with halo, C 1 -C 6 alkyl, C 1 -C 6 alkoxy, C 1 -C 6 haloalkyl, and C 1 -C 6 haloalkoxy; 5-10 membered heteroaryl optionally substituted with halo, C 1 -C 6 alkyl, C 1 -C 6 alkoxy, C 1 -C 6 haloalkyl, and C 1 -C 6 haloalkoxy; 5-10 membered heteroaryl(C 1 -C 6 )alkyl optionally substituted with halo, C 1 -C 6 alkyl, C 1 -C 6 alkoxy, C 1 -C 6 haloalkyl, and C 1 -C 6 haloalkoxy; halo; cyano; hydroxyl; C 1 -C 6 alkoxy; C 1 -C 6 alkoxy(C 1 -C 6 )alkyl; aryloxy; sulfhydryl; halo(C 1 -C 6 )alkyl; halo(C 1 -C 6 )alkoxy; C 1 -C 6 alkylthio; arylthio; amino; amino(C 1 -C 6 )alkyl; nitro; O-carbamyl ; N-carbamyl; O-thiocarbamyl; N-thiocarbamyl; C-amido; N-amido; S-sulfonamido; N-sulfonamido; C-carboxy; O-carboxy; acyl; cyanate; isocyanato; thiocyanato; isothiocyanato; sulfinyl; and sulfonyl;
wherein at least one of R 2 and R 3 is not H; and
wherein if R 1 and R 3 together with the atoms to which they are attached form a 6 membered heterocyclyl, then R 2 is not H.
2. The compound of claim 1 having the defined 1,3-cis-stereochemistry shown in Formula Ia, lb, Ic, Id, Ie, If, or Ig:
or a pharmaceutically acceptable salt thereof,
wherein X is an optionally substituted C 1-7 alkylene linker;
wherein Y is a C 1-5 alkylene linker, optionally substituted with one or more R 7 ; and
wherein each of R 9 and R 10 is independently an optionally substituted C 1-6 alkyl.
3. The compound of claim 1 , wherein R 1 is a C 1-8 alkyl optionally substituted with one or more R 13 , and wherein R 13 is selected from the group consisting of halo, cyano, hydroxyl, C 1-6 alkoxy, C 6-10 aryloxy, sulfhydryl, halo C 1-6 alkoxy, C 1-6 alkylthio, C 1-6 arylthio, and nitro.
4. The compound of claim 1 , wherein R 1 is —CH2OH.
5. The compound of claim 1 , wherein R 1 is —COOR 5 .
6. The compound of claim 1 , wherein R 1 is a C 2-10 alkoxyalkyl optionally substituted with one or more R 14 , and wherein R 14 selected from the group consisting of halo, cyano, hydroxyl, C 1-6 alkoxy, C 6-10 aryloxy, sulfhydryl, halo C 1-6 alkoxy, C 1-6 alkylthio, C 6-10 arylthio, and nitro.
7. The compound of claim 1 , wherein R1is —CH 2 OCH 2 OCH 2 CH 3 or —CH(OCH 2 CH 3 ) 2 .
8. The compound of claim 1 , wherein R 1 is a 3-12 membered heterocyclyl substituted with one or more R 15 , wherein R 15 is selected from the group consisting of C 1-6 alkyl, C 3-7 carbocyclyl, C 1-6 alkoxy, C 6-18 aryl, and halo.
9. The compound of claim 1 , wherein R 1 is
10. The compound of claim 1 , wherein R 1 is
11. The compound of claim 1 , wherein R 2 is H.
12. The compound of claim 1 , wherein R 2 is —C(O)R 6 .
13. The compound of claim 1 , wherein R 2 is a C 2-10 alkoxyalkyl optionally substituted with one or more R 1 , and wherein R 17 selected from the group consisting of halo, cyano, hydroxyl, C 1-6 alkoxy, C 6-10 aryl, C 6-10 aryloxy, sulfhydryl, haloC 1-6 alkoxy, C 1-6 alkylthio, C 6-10 arylthio, and nitro.
14. The compound of claim 1 , wherein R 2 is —CH 2 OCH 2 CH 3 .
15. The compound of claim 1 , wherein R 3 is H or —C(O)R 8 .
16. The compound of claim 1 , wherein R 8 is a C 1-6 alkyl optionally substituted with one or more R 18 , and wherein R 18 is selected from the group consisting of halo, cyano, hydroxyl, C 1-6 alkoxy, C 6-10 aryl, C 6-10 aryloxy, sulfhydryl, haloC 1-6 alkoxy, C 1-6 alkylthio, C 6-10 arylthio, and nitro.
17. The compound of claim 1 , wherein R 8 is —CH(CH 3 ) 2 .
18. The compound of claim 1 , wherein R 3 is a C 2-10 alkoxyalkyl optionally substituted with one or more R 19 , and wherein R 19 is selected from the group consisting of halo, cyano, hydroxyl, C 1-6 alkoxy, C 6-10 aryl, C 6-10 aryloxy, sulfhydryl, haloC 1-6 alkoxy, C 1-6 alkylthio, C 6-10 arylthio, and nitro.
19. The compound of claim 1 , wherein R 3 is —CH 2 OCH 2 CH 3 .
20. The compound of claim 1 , wherein R 7 is a C 1-8 alkyl optionally substituted with one or more R 20 , and wherein R 20 is selected from the group consisting of halo, cyano, hydroxyl, C 1-6 alkoxy, C 6-10 aryl, C 6-10 aryloxy, sulfhydryl, haloC 1-6 alkoxy, C 1-6 alkylthio, C 6-10 arylthio, and nitro.
21. The compound of claim 1 , wherein R 7 is methyl, —CH 2 CH 2 CH 2 OH, or oxo.
22. The compound of claim 1 , wherein R 7 is a C 6-18 aryl optionally substituted with one or more R 21 , wherein R 21 is selected from the group consisting of C 1-6 alkyl, halo, cyano, hydroxyl, C 1-6 alkoxy, halo C 1-6 alkyl, halo C 16 alkoxy, nitro, —C(=O)NR 22 R 23 , —N(R 24 )C(=O)R 25 , —C(=O)OR 26 , —OC(=O)R 27 , and —C(=O)R 28 , and wherein each of R 22 , R 23 , R 24 , R 25 , R 26 , R 27 , and R 28 is independently selected from the group consisting of hydrogen, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-7 carbocyclyl, C 6-10 aryl, 5-10 membered heteroaryl, and 3-10 membered heterocyclyl.
23. The compound of claim 22 , wherein R 21 is selected from the group consisting of C1-6a1kyl, halo, cyano, hydroxyl, C 1-6 alkoxy, halo C 1-6 alkyl, halo C 16 alkoxy, nitro, —C(=O)NR 22 R 23 , —N(R 24 )C(=O)R 25 , —C(=O)OR 26 , —OC(=O)R 27 , and —C(=O)R 28 , and of R 22 , R 23 , R 24 , R 25 , R 26 , R 27 , and R 28 is independently selected from the group consisting of hydrogen, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-7 carbocyclyl, C 6-10 aryl, 5-10 membered heteroaryl, and 3-10 membered heterocyclyl.
24. The compound of claim 1 , wherein R 7 is a phenyl.
25. The compound of claim 1 , wherein R 7 is
26. The compound of claim 1 , wherein R7is a 5-18 membered heteroaryl optionally substituted with one or more R 29 , wherein R 29 is selected from the group consisting of C 1-6 alkyl, halo, cyano, hydroxy, C 1-6 alkoxy, haloC 1-6 alkyl, haloC 1-6 alkoxy, nitro, —C(═O)NR 30 R 31 , —(R 32 )C(═O)R 33 , —C(═O)OR 34 , —OC(═O)R 35 , and —C(═O)R 36 , and wherein each of R 30 , R 31 , R 32 , R 33 , R 34 , R 35 , and R 36 is independently selected from the group consisting of hydrogen, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-7 carbocyclyl, C 6-10 aryl, 5-10 membered heteroaryl, and 3-10 membered heterocyclyl.
27. The compound of claim 1 , wherein R 7 is a 6 membered heteroaryl.
28. The compound of claim 1 , wherein R 7 is
29. A compound selected from the group consisting of
or pharmaceutically acceptable salts thereof.
30. A pharmaceutical composition comprising a therapeutically effective amount of a compound of claim 1 , and a pharmaceutically acceptable excipient.
31. A method of inhibiting HMG-CoA reductase, comprising administering a compound of claim 1 to a subject in need thereof.