Nitroheteroaryl-containing rifamycin derivatives

1. A compound of structural formula (I) as defined below:

or their pharmaceutically acceptable salt thereof,

wherein R 1 is a hydrogen or acetyl group, G is a structure of formula II, III, IV or V:

wherein, in formula II, III, IV or V, Q is N— or CR 2 —, which is bonded to a linkage group “L”, which in turn is bonded to a structure

and R 2 is a group selected from hydrogen, (C 1 -C 6 )alkyl, aryl, heteroaryl, or heterocycloalkyl group;

L is a bond, or a linker group selected from one or a combination of two to five of the following groups:

1) (C 1 -C 6 )alkylene,

2) (C 3 -C 8 )cycloalkylene,

3) arylene,

4) heteroarylene,

5) heterocycloalkylene containing 1 to 3 heteroatoms,

6) —C(═O)—,

7) —C(═N—O—R 3 )—,

8) —C═N—,

9) —O—,

10) —S(O) n —, wherein n is number between 0 and 2,

11) —N(R 4 )—,

wherein the carbon or nitrogen atoms of the linker group are unsubstituted or are independently substituted by 1 to 3 substituents selected from (C 1 -C 6 )alkyl, (C 1 -C 6 )alkyl, amino, (C 1 -C 6 )alkylamino, di(C 1 -C 6 )alkylamino, hydroxyl, (C 1 -C 6 )alkoxy or heterocycloalkyl group; R 3 and R 4 are independently a group selected from hydrogen, substituted or unsubstituted (C 1 -C 6 )alkyl, aryl, heteroaryl or heterocycloalkyl group; and

structure

is a structural formula VI, VII, VIII or IX:

wherein Y is a bond which is bonded to linkage group “L”, defined as above; and Z is a carbon (—CR 7 R 8 —), carbonyl (—C(O)—), amide (—C(O)NH—), sulfonamide (—S(O 2 )N—), or a heteroatom selected from N, O, S, SO or SO 2 ; wherein R 5 , R 6 , R 7 , and R 8 are independently a group selected from hydrogen, (C 1 -C 6 )alkyl, aryl, heteroaryl, or heterocycloalkyl group; R 5 and R 6 , R 7 and R 8 can join together to form a five to seven-member ring system optionally containing one to three heteroatoms, and

wherein if R 1 is an acetyl group, G is II, Q is N—, and L is —C(═O)—, then

is not VIII in which R 5 and R 6 are hydrogen.

2. The compound of claim 1 , wherein R 1 is acetyl group.

3. The compound of claim 1 , wherein L is a bond or a group selected from one or a combination of two to three groups of:

1) (C 1 -C 6 )alkylene,

2) (C 3 -C 8 )cycloalkylene,

3) heterocycloalkylene containing 1 to 3 heteroatoms,

4) —C(═O)—,

5) —O—, and

6) —N(R 4 )—,

wherein R 4 is selected from hydrogen, (C 1 -C 6 )alkyl, aryl, heteroaryl, and heterocycloalkyl groups that are all optionally substituted.

4. The compound of claim 1 , wherein the structure

is selected from the following nitroheteroaryl groups:

5. A compound selected from:

a. 4-Deoxy-3,4-[2-spiro-[1-[2-(2-methyl-5-nitro-imidazol-1-yl)ethyl]-piperidin-4-yl]]-(1H)-imidazo-(2,5-dihydro)rifamycin S,

b. 4-Deoxy-3,4-[2-spiro-[1-[(5-nitro-thiazol-2-ylcarbamoyl)-methyl]-piperidin-4-yl]]-(1H)-imidazo-(2,5-dihydro)rifamycin S,

c. 3′-Hydroxy-5′-[4-[2-(2-methyl-5-nitro-imidazol-1-yl)ethyl]-1-piperazinyl]benzoxazinorifamycin,

d. 3-[[[4-[2-(2-methyl-5-nitro-imidazol-1-yl)ethyl]-1-piperazinyl]imino]methyl]rifamycin SV,

e. 4-Deoxy-3,4-[2-spiro-[1-(2-methyl-6-nitro-2,3-dihydro-imidazo[2,1-b]oxazol-2-ylmethyl)-piperidin-4-yl]]-(1H)-imidazo-(2,5-dihydro)rifamycin S,

f. 3-{4-[4-(6-Nitro-2,3-dihydro-imidazo[2,1-b]oxazol-2-ylmethoxy)-benzyl]-piperazin-1-yl}rifamycin S,

g. 4-Deoxy-3,4-[2-[4-(6-nitro-2,3-dihydro-imidazo[2,1-b]oxazol-2-ylmethoxy)-phenyl]]-(1H)-imidazo-rifamycin SV,

h. 3-{4-[4-(2-Methyl-6-nitro-2,3-dihydro-imidazo[2,1-b]oxazol-2-ylmethoxy)-benzoyl]-piperazin-1-yl}rifamycin S,

i. 4-Deoxy-3,4-[2-spiro-[1-[4-[6S-(2-nitro-6,7-dihydro-5H-imidazo[2,1-b][1,3]oxazin-6-yloxymethyl)]-benzyl]-piperidin-4-yl]]-(1H)-imidazo-(2,5-dihydro)rifamycin S,

j. 3-{4-[4-[(65)-(2-Nitro-6,7-dihydro-5H-imidazo[2,1-b][1,3]oxazin-6-yloxymethyl)]-benzyl]-piperazin-1-yl}rifamycin S,

k. 3-{4-[4-(2-Methyl-6-nitro-2,3-dihydro-imidazo[2,1-b]oxazol-2-ylmethoxy)-benzyl]-piperazin-1-yl}rifamycin S,

l. 3′-Hydroxy-5′-[4-[4-(6S-2-nitro-6,7-dihydro-5H-imidazo[2,1-b][1,3]oxazin-6-yloxymethyl)-benzyl]-1-piperazinyl]benzoxazinorifamycin,

m. 4-Deoxy-3,4-[2-spiro-[1-[3-(6S-2-nitro-6,7-dihydro-5H-imidazo[2,1-b][1,3]oxazin-6-yloxymethyl)]-benzyl]-piperidin-4-yl]]-(1H)-imidazo-(2,5-dihydro)rifamycin S,

n. 3-{4-[3-(6S-(2-Nitro-6,7-dihydro-5H-imidazo[2,1-b][1,3]oxazin-6-yloxymethyl)]-benzyl]-piperazin-1-yl}rifamycin S,

o. 3′-Hydroxy-5′-[4-[3-(65′-2-nitro-6,7-dihydro-5H-imidazo[2,1-b][1,3]oxazin-6-yloxymethyl)-benzyl]-1-piperazinyl]benzoxazinorifamycin,

p. 3-[[[4-[4-(6S-2-Nitro-6,7-dihydro-5H-imidazo[2,1-b][1,3]oxazin-6-yloxymethyl)-benzyl]-piperazin-1-yl]imino]methyl]rifamycin SV,

q. 4-Deoxy-3,4-[2-spiro-[1-[[4-(6S-2-nitro-6,7-dihydro-5H-imidazo[2,1-b][1,3]oxazin-6-yloxymethyl)-phenoxy]-acetyl]-piperidin-4-yl]-(1H)-imidazo-(2,5-dihydro)rifamycin S,

r. 3-[4-[1-[4-(6S-2-Nitro-6,7-dihydro-5H-imidazo[2,1-b][1,3]oxazin-6-yloxymethyl)-benzyl]-1H-[1,2,3]triazol-4-ylmethyl]-piperazin-1-yl]rifamycin S,

s. 3′-Hydroxy-5′-[4-[1-[4-(6S-2-nitro-6,7-dihydro-5H-imidazo[2,1-b][1,3]oxazin-6-yloxymethyl)-benzyl]-1H-[1,2,3]triazol-4-ylmethyl]-piperazin-1-yl]-benzoxazinorifamycin,

t. 3′-Hydroxy-5′-{4-[4-(2-methyl-6-nitro-2,3-dihydro-imidazo[2,1-b]oxazol-2-ylmethoxy)-phenyl]-piperazin-1-yl}-benzoxazinorifamycin,

u. 3-(2-{4-[4-(2-Methyl-6-nitro-2,3-dihydro-imidazo[2,1-b]oxazol-2-ylmethoxy)-phenyl]-piperazin-1-yl}) Rifamycin S,

v. 3-[4-(2-{4-[4-(2-methyl-6-nitro-2,3-dihydro-imidazo[2,1-b]oxazol-2-ylmethoxy)-phenyl]-piperazin-1-yl}-acetyl)-piperazin-1-yl]-rifamycin S,

w. 4-Deoxy-3,4-[2-spiro-[1-[2-(2-nitro-6,7-dihydro-5H-imidazo[2,1-b][1,3]oxazin-6-yloxy)-acetyl]-piperidin-4-yl]]-(1H)-imidazo-(2,5-dihydro)rifamycin S,

x. 2-[4-(2-Bromo-4-nitro-imidazol-1-ylmethyl)-4-hydroxy-piperidin-1-yl]-rifamycin S,

y. 3-{4-[2-(6S-2-Nitro-6,7-dihydro-5H-imidazo[2,1-b][1,3]oxazin-6-yloxy)-acetyl]-piperazin-1-yl}-rifamycin S, and

z. 3-[4-(2-Methyl-6-nitro-2,3-dihydro-imidazo[2,1-b]oxazol-2-ylmethyl)-piperazin-1-yl]rifamycin S.

6. A pharmaceutical composition, useful as a medicament for treatment of bacterial infections, comprising therapeutically effective amount of a compound in accordance with claim 1 in combination with a pharmaceutically acceptable carrier.

7. A method of treating bacterial infections in a patient in need of such treatment by administering a pharmaceutical composition as defined by claim 6 .