초록

Provided herein are inventive enopeptin compounds of Formula (I): and pharmaceutically acceptable salts thereof, and pharmaceutical compositions thereof. Further provided are methods of preparation, use, and treatment.

대표청구항 ▼

1. A compound of Formula (I): or a pharmaceutically acceptable salt thereof; wherein: R1 is hydrogen or —CH3;R2 is hydrogen, and R3 and R4 are joined to form an optionally substituted 6-membered heterocyclyl; orR2 and R3 are joined to form a spiro-fused optionally substituted carbocyclyl or spiro-f

1. A compound of Formula (I): or a pharmaceutically acceptable salt thereof; wherein: R1 is hydrogen or —CH3;R2 is hydrogen, and R3 and R4 are joined to form an optionally substituted 6-membered heterocyclyl; orR2 and R3 are joined to form a spiro-fused optionally substituted carbocyclyl or spiro-fused optionally substituted heterocyclyl, and R4 is optionally substituted alkyl or an amino protecting group; orR2 and R3 are independently hydrogen, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, or optionally substituted heteroaryl, provided that R2 and R3 are not both hydrogen; and R4 is optionally substituted alkyl or an amino protecting group;R5 is a group of formula: wherein: x is an integer between 1 and 10, inclusive;R10a and R10b are independently hydrogen or optionally substituted alkyl; andR9 is hydrogen, halogen, —CN, —NO2,—N3, substituted hydroxyl, substituted thiol, sulfonyl, sulfinyl, acyl, silyl, boronyl, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, or optionally substituted heteroaryl;each instance of R6 is independently halogen, —OH, —SH, —NH2, —CN, —NO2, —N3, —SO2H, —SO3H, substituted hydroxyl, substituted thiol, substituted amino, sulfonyl, sulfinyl, acyl, silyl, boronyl, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, or optionally substituted heteroaryl;m is 0 or an integer of between 1 and 5, inclusive; andR11 is —OH, —SH, —NH2, substituted hydroxyl, substituted thiol, substituted amino, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, or optionally substituted heteroaryl; andR12 is hydrogen, optionally substituted alkyl, or optionally substituted carbocyclyl. 2. A compound of claim 1, wherein the compound is of Formula (III): or a pharmaceutically acceptable salt thereof; wherein: each instance of R7 is independently halogen, —OH, —SH, —NH2, —CN, —NO2, —N3, —SO2H, —SO3H, substituted hydroxyl, substituted thiol, substituted amino, sulfonyl, sulfinyl, acyl, silyl, boronyl, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, or optionally substituted heteroaryl; andn is 0 or an integer of between 1 and 8, inclusive. 3. A compound of claim 1, wherein the compound is of Formula (V): or a pharmaceutically acceptable salt thereof, wherein: each instance of R8 is independently halogen, —OH, —SH, —NH2, —CN, —NO2, —N3, —SO2H, —SO3H, substituted hydroxyl, substituted thiol, substituted amino, sulfonyl, sulfinyl, acyl, silyl, boronyl, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, or optionally substituted heteroaryl;q is 0 or an integer of between 1 and 4, inclusive; andt is 0 or an integer of between 1 and 4, inclusive. 4. A compound of claim 1, wherein the compound is of Formula (VI): or a pharmaceutically acceptable salt thereof. 5. A compound of claim 1, wherein the compound is of Formula (VII): or a pharmaceutically acceptable salt thereof. 6. A compound of claim 1, wherein the compound is of Formula (I-b): or a pharmaceutically acceptable salt thereof. 7. A compound of claim 1, wherein the compound is of Formula (I-c): or a pharmaceutically acceptable salt thereof. 8. The compound of claim 1, wherein the compound is selected from the group consisting of: and pharmaceutically acceptable salts thereof. 9. A method of preparing a compound of Formula (I), the method comprising providing a compound of Formula (G): or salt thereof; and coupling the compound of Formula (G), or salt thereof, with a compound of Formula (H): or salt thereof; to provide a compound of Formula (I): or salt thereof; wherein: R1 is hydrogen or —CH3;R2 is hydrogen, and R3 and R4 are joined to form an optionally substituted 6-membered heterocyclyl; orR2 and R3 are joined to form a spiro-fused optionally substituted carbocyclyl or spiro-fused optionally substituted heterocyclyl, and R4 is optionally substituted alkyl or an amino protecting group; orR2 and R3 are independently hydrogen, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, or optionally substituted heteroaryl, provided that R2 and R3 are not both hydrogen; and R4 is optionally substituted alkyl or an amino protecting group;R5 is a group of formula: wherein: x is an integer between 1 and 10, inclusive;R10a and R10b are independently hydrogen or optionally substituted alkyl; andR9 is hydrogen, halogen, —CN, —NO2 —N3, substituted hydroxyl, substituted thiol, sulfonyl, sulfinyl, acyl, silyl, boronyl, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, or optionally substituted heteroaryl;each instance of R6 is independently halogen, —OH, —SH, —NH2, —CN, —NO2, —N3, —SO2H, —SO3H, substituted hydroxyl, substituted thiol, substituted amino, sulfonyl, sulfinyl, acyl, silyl, boronyl, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, or optionally substituted heteroaryl;m is 0 or an integer of between 1 and 5, inclusive; andR11 is —OH, —SH, —NH2, substituted hydroxyl, substituted thiol, substituted amino, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, or optionally substituted heteroaryl; andR12 is hydrogen, optionally substituted alkyl, or optionally substituted carbocyclyl. 10. A pharmaceutical composition comprising an effective amount of a compound, or pharmaceutically acceptable salt thereof, recited in claim 1, and, optionally, a pharmaceutically acceptable excipient. 11. A method of treating a microbial infection in a subject comprising administering an effective amount of a compound, or pharmaceutically acceptable salt thereof, recited in claim 1 to the subject. 12. The method of claim 11, wherein the microbial infection is a bacterial infection. 13. The method of claim 12, further comprising administering the compound in combination with an antibiotic. 14. The method of claim 13, wherein the antibiotic is a ribosome-targeting antibiotic. 15. The method of claim 12, wherein the bacterial infection is resistant to other treatments. 16. The method of claim 12, wherein the bacterial infection is multi-drug tolerant or multi-drug resistant. 17. A method of treating microbial virulence comprising contacting an effective amount of a compound or salt thereof recited in claim 1 to a microorganism. 18. The method of claim 17, wherein the compound blocks virulence factor production. 19. The compound of claim 1, wherein x is 1. 20. The compound of claim 19, wherein each of R10a and R10b is hydrogen; and R9 is optionally substituted alkyl. 21. The method of claim 9, wherein x is 1. 22. The method of claim 21, wherein each of R10a and R10b is hydrogen; and R9 is optionally substituted alkyl. 23. The compound of claim 1, wherein R11 is optionally substituted alkyl. 24. The compound of claim 23, wherein R11 is —CH3. 25. The method of claim 9, wherein R11 is optionally substituted alkyl. 26. The method of claim 25, wherein R11 is —CH3. 27. The compound of claim 1, wherein R12 is optionally substituted alkyl. 28. The compound of claim 27, wherein R12 is —CH3. 29. The method of claim 9, wherein R12 is optionally substituted alkyl. 30. The method of claim 29, wherein R12 is —CH3.