Beta-lactamase inhibitors
Described herein are compounds and compositions that modulate the activity of beta-lactamases. In some embodiments, the compounds described herein inhibit beta-lactamase. In certain embodiments, the compounds described herein are useful in the treatment of bacterial infections.
1. A method of treating an upper or lower respiratory tract infection, a urinary tract infection, an intra-abdominal infection, or a skin infection; the method comprising administering to a subject in need thereof a therapeutically effective amount of a compound of Formula (I) or Formula (Ia), a pharmaceutically acceptable salt, solvate, polymorph, stereoisomer, tautomer, prodrug, N-oxide, or isomer thereof:
wherein:
M is a bond, —O—, —S—, —S(O)—, SO 2 —, or —N(R 4 )—;
m is 0, 1, or 2;
n is 0, 1, 2, or 3;
provided that
when n is 0, then M is a bond;
p is 2, 3, 4, or 5;
X 1 and X 2 are independently selected from —OH, —OR 8 , or F;
Z is >C═0, >C═S, or >SO 2 ;
ArA is an aromatic or heteroaromatic ring system optionally substituted with one or more substituents selected from the group consisting of fluoro, chloro, bromo, —CN, optionally substituted C 1 -C 6 alkyl, optionally substituted C 3 -C 6 cycloalkyl, optionally substituted heterocycle, optionally substituted aryl, optionally substituted heteroaryl, —OH, —OR 10 , and —SR 10 ;
each Y is selected from the group consisting of
—NR 4 R 5 , —(CR 6 R 7 ) v NR 4 R 5 , —NR 4 (CR 6 R 7 ) v NR 4 R 5 , —O(CR 6 R 7 ) v NR 4 R 5 , —S(O) 0,1,2 (CR 6 R 7 ) v NR 4 R 5 , —N(R 4 )C(O)(CR 6 R 7 ) v NR 4 R 5 , —(CR 6 R 7 ) v N(R 4 )C(O)(CR 6 R 7 ) v NR 4 R 5 , —(CR 6 R 7 ) v N R 4 (CR 6 R 7 ) v NR 4 R 5 , —NR 4 (CR 6 R 7 ) v OR 10 , —NR 4 (CR 6 R 7 ) v S(O) 0,1,2 R 10 , —C(O)NR 4 (CR 6 R 7 ) v NR 4 R 5 , —S(O) 0,1,2 NR 4 (CR 6 R 7 ) v NR 4 R 5 , —NR 5 C(O)NR 4 (CR 6 R 7 ) v NR 4 R 5 , —OC(O)NR 4 (CR 6 R 7 ) v NR 4 R 5 , —NR 5 C(═NR 7 )NR 4 (CR 6 R 7 ) v NR 4 R 5 , —N(R 4 )C(═NR 5 )R 6 , —(CR 6 R 7 ) v N(R 4 )C(═NR 5 )R 6 , —NR 4 (CR 6 R 7 ) v N(R 4 )C(═NR 5 )R 6 , —O(CR 6 R 7 ) v N(R 4 )C(═NR 5 )R 6 , —S(O) 0,1,2 (CR 6 R 7 ) v N(R 4 )C(═NR 5 )R 6 , —(CR 6 R 7 ) v C(═NR 5 )NR 4 R 5 , —NR 4 (CR 6 R 7 ) v C(═NR 5 )NR 4 R 5 , —O(C R 6 R 7 ) v C(═NR 5 )NR 4 R 5 , —S(O) 0,1,2 (CR 6 R 7 ) v C(═NR 5 )NR 4 R 5 , —(CR 6 R 7 ) v N(R 4 )C(═NR 5 )NR 4 R 5 , —NR 4 (CR 6 R 7 ) v N(R 4 )C(═NR 5 )NR 4 R 5 , —O(CR 6 R 7 ) v N(R 4 )C(═NR 5 )NR 4 R 5 , —S(O) 0,1,2 (CR 6 R 7 ) v N(R 4 )C(═NR 5 )NR 4 R 5 , —NR 4 C(═NR 5 )NR 4 C(═NR 5 )NR 4 R 5 , —(CR 6 R 7 ) v C(═NR 4 )N R 5 C(═NR 4 )NR 4 R 5 , —NR 4 (CR 6 R 7 ) v C(═NR 4 )NR 5 C(═NR 4 )NR 4 R 5 , —O(CR 6 R 7 ) v C(═NR 4 )N R 5 C(═NR 4 )NR 4 R 5 , —S(O) 0,1,2 —(CR 6 R 7 ) v C(═NR 4 )NR 5 C(═NR 4 )NR 4 R 5 , —NR 4 C(═NR 5 )NR 4 R 5 , —C(═NR 4 )NR 4 R 5 , —C(═NR 4 )NR 4 C(O)R 6 , —NR 4 SO 2 R 6 , —NR 4 C(O)R 6 , —NR 4 C(═O)OR 6 , —C(O)NR 4 R 5 , —(CR 6 R 7 ) v C(O)NR 4 R 5 , —SO 2 NR 4 R 5 , -Heteroaryl-NR 4 R 5 , -Heterocyclyl-NR 4 R 5 , -Heteroaryl-N(R 4 )C(═NR 5 )NR 4 R 5 , -Heterocyclyl-N(R 4 )C(═NR 5 )NR 4 R 5 , —N(R 4 )-Heteroaryl-NR 4 R 5 , —N(R 4 )—Heterocyclyl-NR 4 R 5 , —(CR 6 R 7 ) v Heteroaryl-NR 4 R 5 , —(CR 6 R 7 ) v Heterocyclyl-NR 4 R 5 , —(CR 6 R 7 ) v Heteroaryl-N(R 4 )C(═NR 5 )NR 4 R 5 , —(CR 6 R 7 ) v Heterocyclyl-N(R 4 )C(═NR 5 )NR 4 R 5 , —(CR 6 R 7 ) v Heteroaryl, —(CR 6 R 7 ) v Heterocyclyl, —O-Heteroaryl, —O-Heterocyclyl, —NR 4 (CR 6 R 7 ) v Heteroaryl, —NR 4 (CR 6 R 7 ) v Heterocyclyl, —O(CR 6 R 7 ) v Heteroaryl, —O(CR 6 R 7 ) v Heterocyclyl, —NR 4 (CR 6 R 7 ) v NR 5 -Heteroaryl, —NR 4 (CR 6 R 7 ) v NR 5 -Heterocyclyl, —O(CR 6 R 7 ) v NR 5 -Heteroaryl, —O(CR 6 R 7 ) v NR 5 -Heterocyclyl, —O(CR 6 R 7 ) v O-Heterocyclyl, —NR 4 R 5 R 9+ Q − , —(CR 6 R 7 ) v NR 4 R 5 R 9+ Q − , —NR 4 (CR 6 R 7 ) v NR 4 R 5 R 9+ Q − , —NR 4 R 9+ (CR 6 R 7 ) v NR 4 R 5 R 9+ Q − 2 , —(CR 6 R 7 ) v (T) + Q − , and —O(CR 6 R 7 ) v NR 4 R 5 R 9+ Q − ;
or two Ys taken together with the carbon atoms to which they are attached to ArA form an optionally substituted carbocycle or an optionally substituted heterocycle;
T is pyridine-1-yl, pyrimidin-1-yl, or thiazol-3-yl;
Q is a pharmaceutically acceptable counterion;
v is 1-4;
R a R b , and R c are independently selected from the group consisting of hydrogen, fluoro, chloro, bromo, optionally substituted C 1 -C 6 alkyl, optionally substituted C 3 -C 6 cycloalkyl, optionally substituted heterocyclyl, optionally substituted aryl, optionally substituted heteroaryl, —OH, —OR 10 , —NR 4 R 5 , and —SR 10 ;
R 1 and R 2 are independently selected from the group consisting of hydrogen, fluoro, chloro, bromo, optionally substituted C 1 -C 6 alkyl, optionally substituted C 3 -C 6 cycloalkyl, —OH, —OR 10 , —SR 10 , and —NR 4 R 5 ;
or R 1 and R 2 taken together form an oxo, oxime, or an optionally substituted carbocycle or optionally substituted heterocycle with the carbon to which they are attached;
R 3 is hydrogen, optionally substituted C 1 -C 6 alkyl, or a pharmaceutically acceptable prodrug;
R d , R 4 and R 5 are independently selected from the group consisting of hydrogen, —OH, —CN, optionally substituted C 1 -C 6 alkyl, optionally substituted alkoxyalkyl, optionally substituted hydroxyalkyl, optionally substituted aminoalkyl, optionally substituted cycloalkyl, optionally substituted heterocyclyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted cycloalkylalkyl, optionally substituted heterocyclylalkyl, optionally substituted aralkyl, optionally substituted heteroaralkyl, (poly-ethylene-glycol)-ethyl, and an optionally substituted saccharide;
or R 4 and R 5 taken together form an optionally substituted heterocycle with the nitrogen to which they are attached;
R 6 and R 7 are independently selected from the group consisting of hydrogen, fluoro, chloro, bromo, optionally substituted C 1 -C 6 alkyl, optionally substituted alkoxyalkyl, optionally substituted hydroxyalkyl, optionally substituted C 3 -C 6 cycloalkyl, —OH, —OR 10 , —SR 10 , —NR 4 R 5 , —NR 4 C(O)R 5 , —C(O)NR 4 R 5 , —NR 4 SO 2 R 5 , optionally substituted heterocyclyl, optionally substituted aryl, and optionally substituted heteroaryl;
or R 6 and R 7 taken together form an oxo, oxime, or an optionally substituted carbocycle or an optionally substituted heterocycle with the carbon to which they are attached;
R 8 is optionally substituted C 1 -C 6 alkyl, optionally substituted C 3 -C 6 cycloalkyl, or a pharmaceutically acceptable boronate ester group;
R 9 is optionally substituted C 1 -C 6 alkyl; and
R 10 is optionally substituted C 1 -C 6 alkyl or optionally substituted C 3 -C 6 cycloalkyl.
2. The method of claim 1 , wherein R a , R b , and R c are hydrogen.
3. The method of claim 1 , wherein R 3 is hydrogen.
4. The method of claim 1 , wherein X 1 and X 2 are —OH.
5. The method of claim 1 , wherein R d is hydrogen or C 1 -C 4 -alkyl.
6. The method of claim 1 , wherein R d is hydrogen.
7. The method of claim 1 , wherein Z is >C═O.
8. The method of claim 1 , wherein:
M is a bond; and
m and n are 0.
9. The method of claim 1 , wherein:
M is a bond; and
m or n are 1.
10. The method of claim 1 , wherein ArA is selected from the group consisting of benzene, naphthalene, pyridine, pyrimidine pyrazine, pyridazine, triazine, thiophene, furan, pyrrole, pyrazole, triazole, imidazole, thiazole, isothiazole, oxazole, isoxazole, indole, indazole, azaindole, azaindazole, indolizine, imidazopyridine, pyrazolo-pyridine, thiazolo-pyridine pyrrolo-pyrimidine, thieno-pyrazole, benzimidazole, benzothiazole, benzoxazole, benzofuran, benzisoxazole, benzisothiazole, quinoline, isoquinoline, quinoxaline, quinazoline, cinnoline, benzotriazine napthyridine, pyrido-pyrimidine, pyrido-pyrazine, pyridopyridazine, isoxazolo-pyridine, and oxazolo-pyridine.
11. The method of claim 1 , wherein ArA is selected from the group consisting of benzene, pyridine, pyrimidine, thiophene, thiazole, triazole, indole, benzimidazole, azaindole, thienopyrazole, quinoline, quinazoline, and quinoxaline.
12. The method of claim 1 , wherein at least one Y is selected from the group consisting of —NR 4 R 5 , —NR 4 C(═NR 5 )NR 4 R 5 , —C(═NR 4 )NR 4 R 5 , —N(R 4 )C(═NR 5 )R 6 , —(CR 6 R 7 ) v NR 4 R 5 , —(CR 6 R 7 ) v N(R 4 )C(═NR 5 )NR 4 R 5 , —NR 4 (CR 6 R 7 ) v NR 4 R 5 , —NR 4 (CR 6 R 7 ) v OR 10 , —(CR 6 R 7 ) v NR 4 (CR 6 R 7 ) v N R 4 R 5 ,
NR 5 C(═NR 5 )NR 4 (CR 6 R 7 ) v NR 4 R 5 , —NR 4 (CR 6 R 7 ) v N(R 4 )C(═NR 5 )NR 4 R 5 , —NR 5 C(O)CR 6 (NR 4 R 5 ) (CR 6 R 7 ) v NR 4 R 5 , —(CR 6 R 7 ) v C(═NR 5 )NR 4 R 5 , —(CR 6 R 7 ) v N(R 4 )C(O)(CR 6 R 7 ) v NR 4 R 5 , —C(═NR 4 )N R 4 C(O)R 6 , —NR 4 (CR 6 R 7 ) v Heteroaryl, and —O(CR 6 R 7 ) v NR 4 R 5 .
13. The method of claim 1 , wherein two Y groups, together with the atoms to which they are attached form a pyrroline or tetrahydropyridine ring.
14. The method of claim 1 , wherein p is 2 or 3.
15. The method of claim 1 , wherein R 4 and R 5 are independently hydrogen or optionally substituted C 1 -C 6 alkyl.
16. The method of claim 1 , wherein each R 6 and R 7 are independently hydrogen, fluoro, or optionally substituted C 1 -C 6 alkyl.
17. The method of claim 1 , wherein v is 1.
18. The method of claim 1 , wherein the compound is selected from the group represented by the following structures:
or a pharmaceutically acceptable salt, solvate, polymorph, stereoisomer, tautomer, prodrug, N-oxide, or isomer thereof, wherein the compound is present in a closed, cyclic form according to Formula I and as shown in the structures above, an open, acyclic form according to Formula Ia, or mixtures thereof.
19. The method of claim 1 , further comprising administering a beta-lactam antibiotic selected from penicillin, a cephalosporin, a carbapenem, a monobactam, a bridged monobactam, and a combination thereof.
20. The method of claim 1 , wherein the bacterial infection comprises a bacteria selected from Pseudomonas aeruginosa, Escherichia coli, Citrobacter freundii, Enterobacter cloacae, Enterobacter aerogenes, Klebsiella pneumoniae, Klebsiella oxytoca, Serratia marcescens, Proteus mirabilis, Proteus vulgaris, Providencia alcalifaciens, Providencia rettgeri, Providencia stuartii, Bacteroides fragilis, Bacteroides distasonis, Bacteroides 3452A homology group, Bacteroides vulgatus, Bacteroides ovalus, Bacteroides thetaiotaomicron, Bacteroides uniformis, Bacteroides eggerthii, Bacteroides splanchnicus, Clostridium difficile, Enterococcus faecalis, Enterococcus faecium, Staphylococcus aureus, Staphylococcus epidermidis, Staphylococcus saprophyticus, Staphylococcus intermedius, Staphylococcus hyicus subsp. hyicus, Staphylococcus haemolyticus, Staphylococcus hominis , and Staphylococcus saccharolyticus.