Moenomycin analogs, methods of synthesis, and uses thereof

1. A compound of Formula (I):

or a pharmaceutically acceptable salt, solvate, hydrate, tautomer, isomer, enantiomer, diastereomer, or polymorph thereof;

wherein:

G is a group of Formula (a), (b), or (c):

wherein a is 3, 4, or 5;

wherein:

X 1 , X 2 , X 3 , X 4 , X 5 , X 6 , and X 7 are each independently hydrogen or halogen;

d is an integer between 1 and 25, inclusive; and

e is an integer of between 2 and 25, inclusive;

provided that at least one of X 1 , X 2 , X 3 , X 4 , X 5 , X 6 , and X 7 is halogen; and

the sum of d and e is greater than 16;

or

wherein:

Y is —O—, —S—, —NR Y —, or an optionally substituted methylene group, wherein R Y is hydrogen, optionally substituted aliphatic, or an amino protecting group;

each instance of R c is independently —F, —Br, —I, —Cl, optionally substituted aliphatic, optionally substituted heteroaliphatic, optionally substituted carbocycyl, optionally substituted heterocycyl, optionally substituted aryl, optionally substituted heteroaryl, —OR e , —SR e , —NHR e , or —N(R e ) 2 , wherein each instance of R e is independently hydrogen, optionally substituted aliphatic, optionally substituted heteroaliphatic, optionally substituted carbocycyl, optionally substituted heterocycyl, optionally substituted aryl, or optionally substituted heteroaryl, or two R e groups are joined to form a 5- to 6-membered optionally substituted heterocycyl or optionally substituted heteroaryl ring;

each instance of R d is independently —F, —Br, —I, —Cl, optionally substituted aliphatic, optionally substituted heteroaliphatic, optionally substituted carbocycyl, optionally substituted heterocycyl, optionally substituted aryl, optionally substituted heteroaryl, —OR f , —SR f , —NHR f , or —N(R f ) 2 , wherein each instance of R f is independently hydrogen, optionally substituted aliphatic, optionally substituted heteroaliphatic, optionally substituted carbocycyl, optionally substituted heterocycyl, optionally substituted aryl, or optionally substituted heteroaryl, or two R f groups are joined to form a 5- to 6-membered optionally substituted heterocycyl or optionally substituted heteroaryl ring;

R z is hydrogen, —F, —Br, —I, —Cl, optionally substituted aliphatic, optionally substituted heteroaliphatic, optionally substituted carbocycyl, optionally substituted heterocycyl, optionally substituted aryl, optionally substituted heteroaryl, —OR g , —SR g , —NHR g , or —N(R g ) 2 , wherein each instance of R g is independently hydrogen, optionally substituted aliphatic, optionally substituted heteroaliphatic, optionally substituted carbocycyl, optionally substituted heterocycyl, optionally substituted aryl, or optionally substituted heteroaryl or two R g groups are joined to form a 5- to 6-membered optionally substituted heterocycyl or optionally substituted heteroaryl ring;

each instance of n is, independently, 0, 1, 2, 3, or 4;

each instance of m is, independently, 0, 1, 2, 3, or 4; and

x is 1, 2, 3, 4, 5, or 6;

R xx is hydrogen, a hydroxyl protecting group, or a group of Formula:

R 12 is hydrogen, a hydroxyl protecting group, or the group (D):

wherein R 13 , R 14 , R 15 , R 16 , and R 17 are each independently hydrogen or a hydroxyl protecting group;

R 1 , R 2 , R 3 , and R 4 are each independently hydrogen or an amino protecting group;

R 5 is hydrogen, an amino protecting group, or the group (A):

R 6 , R 7 , R 8 , R 9 , R 10 , and R 11 are each independently hydrogen or a hydroxyl protecting group; and

R a and R b are each independently hydrogen or a hydroxyl protecting group.

2. The compound of claim 1 of Formula (II):

or a pharmaceutically acceptable salt, solvate, hydrate, tautomer, isomer, enantiomer, diastereomer, or polymorph thereof.

3. The compound of claim 1 of Formula (III):

or a pharmaceutically acceptable salt, solvate, hydrate, tautomer, isomer, enantiomer, diastereomer, or polymorph thereof; wherein R 17 is hydrogen or a hydroxyl protecting group.

4. The compound of claim 1 of Formula (IV):

or a pharmaceutically acceptable salt, solvate, hydrate, tautomer, isomer, enantiomer, diastereomer, or polymorph thereof; wherein R 18 is hydrogen or a hydroxyl protecting group.

5. The compound of claim 1 wherein G is a group of Formula (a).

6. The compound of claim 5 , wherein the group of Formula (a) is selected from the group consisting of:

7. The compound of claim 1 wherein G is a group of Formula (b).

8. The compound of claim 7 wherein at least one of X 1 , X 2 , X 3 , X 4 , X 5 , X 6 , and X 7 is halogen.

9. The compound of claim 7 wherein X 1 and X 2 are each hydrogen, X 3 and X 4 are each fluoro, and X 5 , X 6 , and X 7 are each fluoro.

10. The compound of claim 7 , wherein the group of Formula (b) is selected from the group consisting of:

11. The compound of claim 1 wherein G is a group of Formula (c).

12. The compound of claim 11 , wherein the group of Formula (c) is selected from the group consisting of:

wherein:

R c1 , R c2 , R c3 , R c4 , R c5 , and R c6 , each independently —F, —Br, —I, —Cl, optionally substituted aliphatic, optionally substituted heteroaliphatic, optionally substituted carbocycyl, optionally substituted heterocycyl, optionally substituted aryl, optionally substituted heteroaryl, —OR e , —SR e , —NHR e , or —N(R e ) 2 , wherein each instance of R e is independently hydrogen, optionally substituted aliphatic, optionally substituted heteroaliphatic, optionally substituted carbocycyl, optionally substituted heterocycyl, optionally substituted aryl, or optionally substituted heteroaryl, or two R e groups are joined to form a 5- to 6-membered optionally substituted heterocycyl or optionally substituted heteroaryl ring;

R d1 , R d2 , R d3 , R d4 , R d5 , and R d6 , each independently —F, —Br, —I, —Cl, optionally substituted aliphatic, optionally substituted heteroaliphatic, optionally substituted carbocycyl, optionally substituted heterocycyl, optionally substituted aryl, optionally substituted heteroaryl, —OR f , —SR f , —NHR f , or —N(R f ) 2 , wherein each instance of R f is independently hydrogen, optionally substituted aliphatic, optionally substituted heteroaliphatic, optionally substituted carbocycyl, optionally substituted heterocycyl, optionally substituted aryl, or optionally substituted heteroaryl, or two R f groups are joined to form a 5- to 6-membered optionally substituted heterocycyl or optionally substituted heteroaryl ring;

Y 1 , Y 2 , Y 3 , Y 4 , Y 5 , and Y 6 , each independently corresponds to —O—, —S—, —NR Y —, or an optionally substituted methylene group, wherein R Y is hydrogen, optionally substituted aliphatic, or an amino protecting group;

n1, n2, n3, n4, n5, and n6 each independently 0, 1, 2, 3, or 4; and

m1, m2, m3, m4, m5, and m6 each independently 0, 1, 2, 3, or 4.

13. The compound of claim 1 wherein G is selected from the group consisting of:

14. A pharmaceutical composition comprising an effective amount of a compound of claim 1 , or a pharmaceutically acceptable salt, solvate, hydrate, tautomer, isomer, enantiomer, diastereomer, or polymorph thereof, and optionally a pharmaceutically acceptable excipient.

15. A method of treating a bacterial infection comprising administering to a subject an effective amount of a compound of claim 1 , or a pharmaceutically acceptable salt, solvate, hydrate, tautomer, isomer, enantiomer, diastereomer, or polymorph thereof.

16. The method of claim 15 , wherein the bacterial infection being treated is caused by Gram-positive bacteria.

17. The method of claim 15 , wherein bacterial infection being treated is caused by Gram-negative bacteria.

18. The method of claim 15 , wherein bacterial infection being treated is caused by vancomycin-resistant bacteria.

19. The method of claim 15 , wherein bacterial infection being treated is caused by methicillin-resistant bacteria.

20. An in vitro method of inhibiting bacterial growth by contacting a bacterium with an effective amount of a compound of claim 1 , or a pharmaceutically acceptable salt, solvate, hydrate, tautomer, isomer, enantiomer, diastereomer, or polymorph thereof.

21. The method of claim 15 , wherein the bacterial infection being treated is caused by vancomycin-resistant Staphylococcus aureus , vancomycin-resistant Enterococci, or methicillin-resistant Staphylococcus aureus.

22. The compound of claim 1 , wherein the compound is of Formula (I):

or a pharmaceutically acceptable salt.

23. A pharmaceutical composition comprising an effective amount of a compound of claim 1 , or a pharmaceutically acceptable salt thereof, and optionally a pharmaceutically acceptable excipient.

24. A method of treating a bacterial infection comprising administering to a subject an effective amount of a compound of claim 1 , or a pharmaceutically acceptable salt thereof.