Spiro-rifamycin derivatives targeting RNA polymerase

1. A compound having a structure of Formula I:

wherein,

R 1 is hydrogen, (C 1–C 6 )alkyl, substituted (C 1 –C 6 )alkyl, —C(O)CH 2 R 10 , or —C(O)NR 11 R 12 ,

wherein R 10 is hydrogen, halogen, hydroxyl, amino, (C 1 –C 6 )alkyl, (C 1 –C 6 )alkoxy, (C 1 –C 6 )alkylthio, (C 1 –C 6 )acyloxy, (C 1 –C 6 )alkylamino, di(C 1 – 6 )alkylamino, aryl, heteroaryl, or -L 25 -Q 25 ,

wherein L 25 is a linker group and Q 25 is an antibacterial pharmacophore selected from quinolones, macrolides, oxazolidinones, and β-lactams, and

wherein R 11 and R 12 independently are the same or different and are hydrogen, (C 1 –C 6 )alkyl, substituted (C 1 –C 6 )alkyl, or -L 25 -Q 25 , or

R 11 and R 12 , together with the nitrogen atom to which they are attached, form a 3-to 8-membered heterocyclic ring, optionally containing up to two heteroatoms, wherein one or more of the carbon or nitrogen atoms of the heterocyclic ring is optionally substituted by (C 1 –C 6 )alkyl or -L 25 -Q 25 ;

one of Y 1 and Y 2 is —OH and the other is hydrogen, or Y 1 and Y 2 together with the carbon to which they are attached are C═O or C═N—O—R 21,

wherein R 21 is hydrogen, (C 1 –C 6 )alkyl or -L 11 -Q 11 ,

wherein L 11 is a linker group and Q 11 is an antibacterial pharmacophore selected from quinolones, macrolides, oxazolidinones, and β-lactams;

X is —CR 31 R 32 —, —NR 33 —, —S—or —O—,

wherein R 31 , R 32 and R 33 independently are the same or different and are hydrogen or (C 1 –C 6 )alkyl, and

m and n independently are the same or different and are an integer between 1 and 3; and

Z is —NR 41 —, —CR 42 R 43 —, —O—, or —S(O) p —,

wherein p is an integer between 0 and 2,

R 41 is hydrogen, (C 1 –C 6 )alkyl, (C 1 –C 6 )alkyl sulfonyl, aryl sulfonyl, (C 1 –C 6 )alkoxycarbonyl, aryloxycarbonyl, (C 1 –C 6 )alkyl amino carbonyl, aryl amino carbonyl, which are all optionally substituted, or -L-Q,

wherein L is a linker group comprising any combination of from 1 to 5 groups selected from (C 1 –C 6 )alkylene, (C 3 –C 8 )cycloalkylene, arylene, heteroarylene, bivalent heterocyclic group containing 1 to 3 heteroatoms, —C(═O)—, —C(═N—(O)—R 13 )—, —C═N—, —O—, —S(O) n —, and —N(R 14 )—,

wherein n is an integer between 0 and 2, the carbon or nitrogen atoms of the linker group are optionally substituted by 1 to 3 substituents selected from (C 1 –C 6 )alkyl, amino, (C 1 –C 6 )alkylamino, di(C 1 –C 6 )alkylamino, hydroxyl, (C 1 –C 6 )alkoxy, and heterocyclic group,R 13 and R 14 are independently the same or different and are hydrogen, (C 1 –C 6 )alkyl, aryl, heteroaryl, or heterocyclic group, and Q is an antibacterial pharmacophore selected from quinolones, macrolides, oxazolidinones, and β-lactams, and

R 42 and R 43 independently are the same or different and are hydrogen, hydroxyl, amino, carboxyl, halo, cyano, (C 1 –C 6 )alkyl, (C 3 –C 6 )cycloalkyl, (C 1 –C 6 )heteroaryl, or heterocyclic group.

2. The compound of claim 1 , wherein L, L 11 , and L 25 independently are the same or different and comprise any combination of from one to three of the following structures:

3. A method of treating a bacterial infection in a subject comprising: administering to the subject an effective amount of the compound of claim 1 .

4. The method of claim 3 , wherein the bacterial infection is caused by a drug-resistant bacterium.

5. A compound having a structure of Formula II:

wherein,

R 1 is hydrogen, (C 1 –C 6 )alkyl, substituted (C 1 – 6 )alkyl, —C(O)CH 2 R 10 , or —C(O)NR 11 1 R 12 ,

wherein R 10 is hydrogen, halogen, hydroxyl, amino, (C 1 –C 6 )alkyl, (C 1 –C 6 )alkoxy, (C 1 –C 6 )alkylthio, (C 1 –C 6 )acyloxy, i -C6)alkylamino, di(C 1 –C6)alkylamino, aryl, heteroaryl, or -L 25 -Q 25 ,

wherein L 25 is a linker group and Q 25 is an antibacterial pharmacophore selected from quinolones, macrolides, oxazolidinones, and β-lactams, and

wherein R 11 and R 12 independently are the same or different and are hydrogen, (C 1 –C 6 )alkyl, substituted (C 1 –C 6 )alkyl, or -L 25 -Q 25 , or

R 11 and R 12 , together with the nitrogen atom to which they are attached, form a 3- to 8-membered heterocyclic ring, optionally containing up to two heteroatoms, wherein one or more of the carbon or nitrogen atoms of the heterocyclic ring is optionally substituted by (C 1 –C 6 )alkyl or -L 25 -Q 25;

one of Y 1 and Y 2 is —OH and the other is hydrogen, or Y 1 and Y 2 together with the carbon to which they are attached form C═O or CN═O—R 21 ,

wherein R 21 is hydrogen, (C 1 –C 6 )alkyl or -L 11 -Q 11 ,

wherein L 11 is a linker group and Q 11 is an antibacterial pharmacophore selected from quinolones, macrolides, oxazolidinones, and β-lactams;

R 33 is hydrogen or (C 1 –C 6 )alkyl;

R 41 is hydrogen, (C 1 –C 6 )alkyl, (C 1 –C 6 )alkyl sulfonyl, aryl sulfonyl, (C 1 –C 6 )alkoxycarbonyl, aryloxycarbonyl, (C 1 –C 6 )alkyl amino carbonyl, aryl amino carbonyl, which are all optionally substituted, or -L-Q,

wherein L is a linker group comprising any combination of from 1 to 5 groups selected from (C 1 –C 6 )alkylene, (C 3 –C 8 )cycloalkylene, arylene, heteroarylene, bivalent heterocyclic group containing 1 to 3 heteroatoms, —C(═O)—, —C(═N—O—R 13 )—, —C═N, —O—, —S(O) n —, and —N(R 14 )—,

wherein n is an integer between 0 and 2, the carbon or nitrogen atoms of the linker group are optionally substituted by 1 to 3 substituents selected from (C 1 –C 6 )alkyl, amino, (C 1 –C6)alkylamino, di(C 1 –C6)alkylamino, hydroxyl, (C 1 –C 6 )alkoxy, and heterocyclic group,R 13 and R 14 are independently the same or different and are hydrogen, (C 1 –C 6 )alkyl, aryl, heteroaryl, or heterocyclic group, and Q is an antibacterial pharmacophore selected from quinolones, macrolides, oxazolidinones, and β-lactams.

6. The compound of claim 5 , wherein L, L 11 , and L 25 independently are the same or different and comprise any combination of from one to three of the following structures:

7. A method of treating a bacterial infection in a subject comprising: administering to the subject an effective amount of the compound of claim 5 .

8. The method of claim 7 , wherein the bacterial infection is caused by a drug-resistant bacterium.

9. A compound having a structure of Formula III:

wherein,

R 1 is hydrogen, (C 1 –C 6 )alkyl, substituted (C 1 –C 6 )alkyl, —C(O)CH 2 R 10 , or —C(O)NR 11 R 12 ,

wherein R 10 is hydrogen, halogen, hydroxyl, amino, (C 1 –C 6 )alkyl, (C 1 –C 6 )alkoxy, (C 1 –C 6 )alkylthio, (C 1 –C 6 )acyloxy, i -C6)alkylamino, di(C 1 –C 6 )alkylamino, aryl, heteroaryl, or -L 25 -Q 25 ,

wherein L 25 is a linker group and Q 25 is an antibacterial pharmacophore selected from quinolones, macrolides, oxazolidinones, and β-lactams, and

wherein R 11 and R 12 independently are the same or different and are hydrogen, (C 1 –C 6 )alkyl, substituted (C 1 –C 6 )alkyl, or -L 25 -Q 25 , or

R 11 and R 12 , together with the nitrogen atom to which they are attached, form a 3-to 8-membered heterocyclic ring, optionally containing up to two heteroatoms, wherein one or more of the carbon or nitrogen atoms of the heterocyclic ring is optionally substituted by (C 1 –C 6 )alkyl or -L 25 -Q 25 ;

one of Y 1 and Y 2 is —OH and the other is hydrogen, or Y 1 and Y 2 together with the carbon to which they are attached form C═O or C═N—O—R 21,

wherein R 21 is hydrogen, (C 1 –C 6 )alkyl or L- 11 -Q 11 ,

wherein L 11 is a linker group and Q 11 is an antibacterial pharmacophore selected from quinolones, macrolides, oxazolidinones, and β-lactams;

R 33 is hydrogen or (C 1 –C 6 )alkyl; and

R 41 is hydrogen, (C 1 –C 6 )alkyl, (C 1 –C 6 )alkyl sulfonyl, aryl sulfonyl, (C 1 –C 6 )alkoxycarbonyl, aryloxycarbonyl, (C 1 –C 6 )alkyl amino carbonyl, aryl amino carbonyl, which are all optionally substituted, or -L-Q,

wherein L is a linker group comprising any combination of from 1 to 5 groups selected from (C 1 –C 6 )alkylene, (C 3 –C 8 )cycloalkylene, arylene, heteroarylene, bivalent heterocyclic group containing 1 to 3 heteroatoms, —C(═O)—, —C(N═O—R 13 )—, —C═N—, —O—, —S(O) n —, and —N(R 14 )—,

wherein n is an integer between 0 and 2, the carbon or nitrogen atoms of the linker group are optionally substituted by 1 to 3 substituents selected from (C 1 –C 6 )alkyl, amino, (C 1 –C 6 )alkylamino, di(C 1 –C 6 )alkylamino, hydroxyl, (C 1 –C 6 )alkoxy, and heterocyclic group, R 13 and R 14 are independently the same or different and are hydrogen, (C 1 –C 6 )alkyl, aryl, heteroaryl, or heterocyclic group, and Q is an antibacterial pharmacophore selected from quinolones, macrolides, oxazolidinones, and β-lactams.

10. The compound of claim 9 , wherein L, L 11 , and L 25 independently are the same or different and comprise any combination of from one to three of the following structures:

11. A method of treating a bacterial infection in a subject comprising: administering to the subject an effective amount of the compound of claim 9 .

12. The method of claim 11 , wherein the bacterial infection is caused by a drug-resistant bacterium.

13. A compound having a structure of Formula IV:

wherein,

R 1 is hydrogen, (C 1 –C 6 )alkyl, substituted (C 1 –C 6 )alkyl, —C(O)CH 2 R 10 , or —C(O)NR 11 R 12,

wherein R 10 is hydrogen, halogen, hydroxyl, amino, (C 1 –C 6 )alkyl, (C 1 –C 6 )alkoxy, (C 1 –C 6 )alkylthio, (C 1 –C 6 )acyloxy, (C 1 –C 6 )alkylamino, di(C 1≧C 6 )alkylamino, aryl, heteroaryl, or -L 25 -Q 25,

wherein L 25 is a linker group and Q 25 is an antibacterial pharmacophore selected from quinolones, macrolides, oxazolidinones, and β-lactams, and

wherein R 11 and R 12 independently are the same or different and are hydrogen, (C 1 –C 6 )alkyl, substituted (C 1 –C 6 )alkyl, or -L 25 -Q 25 , or

R 11 and R 12 , together with the nitrogen atom to which they are attached, form a 3-to 8-membered heterocyclic ring, optionally containing up to two heteroatoms, wherein one or more of the carbon or nitrogen atoms of the heterocyclic ring is optionally substituted by (C 1 –C 6 )alkyl or -L 25 -Q 25;

one of Y 1 and Y 2 is —OH and the other is hydrogen, or Y 1 and Y 2 together with the carbon to which they are attached form C═O or C═N—O—R 21 ,

wherein R 21 is hydrogen, (C 1 –C 6 )alkyl or -L 11 -Q 11 ,

wherein L 11 is a linker group and Q 11 is an antibacterial pharmacophore selected from quinolones, macrolides, oxazolidinones, and β-lactams;

R 33 is hydrogen or (C 1 –C 6 )alkyl;

R 41 is hydrogen, (C 1 –C 6 )alkyl, (C 1 –C 6 )alkyl sulfonyl, aryl sulfonyl, (C 1 – 6 )alkoxycarbonyl, aryloxycarbonyl, (C 1 –C 6 )alkyl amino carbonyl, aryl amino carbonyl, which are all optionally substituted, or -L-Q,

wherein L is a linker group comprising any combination of from 1 to 5 groups selected from (C 1 –C 6 )alkylene, (C 3 –C 8 )cycloalkylene, arylene, heteroarylene, bivalent heterocyclic group containing 1 to 3 heteroatoms, —C(═O), —C(═N—O—R 13 )—, —C═N—, —O—, —S(O) n —, and —N(R 14 )—,

wherein n is an integer between 0 and 2, the carbon or nitrogen atoms of the linker group are optionally substituted by 1 to 3 substituents selected from (C 1 –C 6 )alkyl, amino, (C 1 –C 6 )alkylamino, di(C 1 –C 6 )alkylamino, hydroxyl, (C 1 –C 6 )alkoxy, and heterocyclic group, R 13 and R 14 are independently the same or different and are hydrogen, (C 1 –C 6 )alkyl, aryl, heteroaryl, or heterocyclic group, and Q is an antibacterial pharmacophore selected from quinolones, macrolides, oxazolidinones, and β-lactams.

14. The compound of claim 13 , wherein L, L 11 , and L 25 independently are the same or different and comprise any combination of from one to three of the following structures:

15. A method of treating a bacterial infection in a subject comprising: administering to the subject an effective amount of the compound of claim 13 .

16. The method of claim 15 , wherein the bacterial infection is caused by a drug-resistant bacterium.

17. A compound having the formula:

18. A compound having the formula 2′,2′-Dimethyl-3,4-piperazinorifamycin S:

19. A compound having the formula 3,4-(2,2-Dimethyl-piperazino)-11-deoxy-11-hydroxyimino-rifamycin S:

20. A compound having the formula Spiro[N-methyl-piperidine-3,4-piperazinorifamycin S]:

21. A compound having the formula Spiro[N-methyl-piperidine-3,4-piperazino-11 -deoxy- 11 -hydroxyimino-rifamycin S]:

22. A compound having the formula [N-Boc-piperidine-3,4-piperazinorifamycin S]:

23. A compound having the formula Spiro[N-isobutyl-piperidine-3,4-piperazinorifamycin S]:

24. A compound having the formula Spiro [N-allyl-piperidine-3 ,4- piperazinorifamycin S]:

25. A compound having the formula Spiro[N-(quinolin-3-ylmethyl)-piperidine-3,4-piperazinorifamycin S]:

26. A compound having the formula Spiro[N-benzyl-piperidine-3,4-piperazinorifamycin S]:

27. A compound having the formula Spiro[N-(2,2,2-trichloro-1,1-dimethyl-ethoxycarbonyl)-piperidine-3,4-piperazinorifamycin S]:

28. A compound having the formula Spiro[N-alloc-piperidine-3,4-piperazinorifamycin S]:

29. A compound having the formula Spiro[piperidine-3,4-piperazinorifamycin S]:

30. A compound having the formula Spiro[N-benzyl-pyrrolidine-3,4-piperazinorifamycin S]:

31. A compound having the formula Spiro [N-methyl-pyrrolidine-3,4-piperazinorifamycin S]:

32. A compound having the formula Spiro[N-isobutyl-pyrrolidine-3,4-piperazinorifamycin S]:

33. A compound having the formula Spiro[N-(quinolin-3-ylmethyl)-pyrrolidine-3,4-piperazinorifamycin S]:

34. A compound having the formula Spiro[N-Boc-pyrrolidine-3,4-piperazinorifamycin S]: