BACKGROUND OF THE INVENTION

Antibiotics have been effective tools in the treatment of infectious diseases. However, bacteria have developed several different mechanisms to overcome the action of antibiotics. The emergence of Multidrug Resistant (MDR) bacterial pathogens has increased concerns as to the adequacy of current antimicrobials and pathogen treatment methods. The lethality of pathogens, such asPseudomonas aeruginosa, has often led to treatment methods that are experimental or would otherwise normally be avoided in standard clinical practice. The growing threat from MDR pathogens highlights a critical need for additional antimicrobials. Thus, there is a pressing need for new antibiotics that exhibit novel mechanisms of action or circumvent conventional mechanisms of resistance.

Mechanisms of resistance can be specific such as for a molecule or a family of antibiotics, or the mechanisms can be non-specific. Several mechanisms of resistance can exist in a single bacterial strain, and those mechanisms may act independently or they may act synergistically to overcome the action of an antibiotic or a combination of antibiotics. Specific mechanisms include, for example, degradation of the drug, inactivation of the drug by enzymatic modification, and alteration of the drug target. Additional mechanisms of drug resistance include mechanisms in which access of the antibiotic to the target is prevented or reduced by decreasing the transport of the antibiotic into the cell or by increasing the efflux of the drug from the cell to the outside medium. Both of these mechanisms can lower the concentration of drug at the target site and allow bacterial survival in the presence of one or more antibiotics that would otherwise inhibit or kill the bacterial cells. Some bacteria utilize both mechanisms, combining low permeability of the cell wall (including membranes) with an active efflux of antibiotics. It has been shown that efflux of antibiotics can be mediated by more than one pump in a single organism and that almost all antibiotics are subject to resistance by this mechanism. For example,Pseudomonas aeruginosaexpresses numerous efflux pumps including MexAB-OprM, MexCD-OprJ, MexEF-OprN, and MexXY-OprA(OprM) which actively efflux various antibacterial agents.

These multiple resistance mechanisms have become widespread and threaten the clinical utility of antibacterial therapy. The increase in antibiotic resistant strains has been particularly noted in major hospitals and care centers. The consequences of the increase in resistant strains include, for example higher morbidity and mortality, longer patient hospitalization, and an increase in treatment costs. Accordingly, there is a need for novel antibiotics and agents that can be used in combination to inhibit or mitigate one or more of these mechanisms of bacterial resistance. There is also a need for new methods of treatment for overcoming or mitigating these mechanisms of bacterial resistance.

MreB is a well conserved and essential cytoskeleton-like protein, which represents a bacterial homolog of actin. Studies with various MreB homnologs have established that this protein forms dynamic, actin-like helical filaments in an ATP- or GTP-dependent fashion. The filaments are localized within the bacterial cell on the inner surface of the cytoplasmic membrane. MreB protein provides a critical role in the maintenance of cell shape, polar protein localization, and/or chromosome segregation. Because of its essential role in bacterial growth and function, MreB inhibitors represent a novel class of antibacterial agents.

The MreB homolog ofP. aeruginosais essential for cell viability as well as maintenance of rod-like cell morphology. CBR-4830 was identified as an effective MreB inhibitor inP. aeruginosawhile screening libraries of compounds against aP. aeruginosastrains with defective efflux transporters.


CBR-4830 is a substrate for the MexAB-OprM efflux transporter present in wild-typeP. aeruginosa, which limited its efficacy and clinical promise. Thus, there is an ongoing need for antibacterial agents with novel mechanisms of action (e.g., MreB inhibitors). There is also a need for antibacterial agents (e.g., MreB inhibitors) that have improved properties such as improved formulation characteristics and/or lowered toxicity.

SUMMARY OF THE INVENTION

Compounds disclose herein, when tested alone or in combination with a bacterial efflux pump inhibitor, exhibit antibacterial activities.

Accordingly, one embodiment provides a method of treating or preventing a bacterial infection in an animal (e.g., a mammal such as a human) comprising administering to the animal a bacterial efflux pump inhibitor and a compound of formula I:


or a pharmaceutically acceptable salt thereof, wherein:

R1is hydrogen, halo, cyano, nitro, (C1-C6)alkyl, (C1-C4)alkoxy, phenyl or heteroaryl, wherein the (C1-C6)alkyl, (C1-C4)alkoxy, phenyl or heteroaryl is optionally substituted with one or more groups selected from halo, hydroxy, (C1-C4)alkyl, (C1-C4)haloalkyl, (C1-C4)alkoxy, (C1-C4)haloalkoxy, nitro or cyano;

R2is hydrogen, halo, cyano, nitro, (C1-C6)alkyl, (C1-C4)alkoxy, phenyl or heteroaryl, wherein the (C1-C6)alkyl, (C1-C4)alkoxy, phenyl or heteroaryl is optionally substituted with one or more groups selected from halo, hydroxy, (C1-C4)alkyl, (C1-C4)haloalkyl, (C1-C4)alkoxy, (C1-C4)haloalkoxy, nitro or cyano;

R3is hydrogen, halo, cyano, nitro, (C1-C6)alkyl, (C1-C4)alkoxy, phenyl or heteroaryl, wherein the (C1-C6)alkyl, (C1-C4)alkoxy, phenyl or heteroaryl is optionally substituted with one or more groups selected from halo, hydroxy, (C1-C4)alkyl, (C1-C4)haloalkyl, (C1-C4)alkoxy, (C1-C4)haloalkoxy, nitro or cyano;

R4is hydrogen, halo, cyano, nitro, (C1-C6)alkyl, (C1-C4) alkoxy, phenyl or heteroaryl, wherein the (C1-C6)alkyl, (C1-C4)alkoxy, phenyl or heteroaryl is optionally substituted with one or more groups selected from halo, hydroxy, (C1-C4)alkyl, (C1-C4)haloalkyl, (C1-C4)alkoxy, (C1-C4)haloalkoxy, nitro or cyano;

R5is hydrogen or (C1-C4)alkyl; R6is hydrogen, (C1-C6)alkyl, (C3-C6)cycloalkyl, —C(═O)RX, or —C(═O)ORX, wherein the (C1-C6)alkyl or (C3-C6)cycloalkyl is optionally substituted with one or more groups selected from halo, ORaor NRaRb;

R7ais hydrogen, halo, (C1-C6)alkyl, —C(═O)ORc, —C(═O)NRdRe, —NRfRg, or phenyl, wherein the (C1-C6)alkyl or phenyl is optionally substituted with one or more halogen, ORh, (C1-C6)alkyl, or —NRfRg;

R7bis hydrogen, halo, or (C1-C6)alkyl;

R8ais hydrogen, halo, (C1-C6)alkyl, —C(═O)ORc, —C(═O)NRdRe, —NRfRg, or phenyl, wherein the (C1-C6)alkyl or phenyl is optionally substituted with one or more halogen, ORh, (C1-C6)alkyl, or —NRfRg;

R8bis hydrogen, halo, or (C1-C6)alkyl;

R9ais hydrogen, halo, (C1-C6)alkyl, —C(═O)ORc, —C(═O)NRdRe, —NRfRg, or phenyl, wherein the (C1-C6)alkyl or phenyl is optionally substituted with one or more halogen, ORh, (C1-C6)alkyl, or —NRfRg;

R9bis hydrogen, halo, or (C1-C6)alkyl;

each RXis independently (C1-C6)alkyl, (C3-C6)cycloalkyl, or phenyl, wherein the (C1-C6) alkyl, (C3-C6) cycloalkyl, or phenyl is optionally substituted with one or more groups selected from halo, ORaor NRaRb;

each Rais independently hydrogen or (C1-C4)alkyl;

each Rbis independently hydrogen or (C1-C4)alkyl; or Raand Rbtaken together with the nitrogen to which they are attached form pyrrolidinyl, piperidinyl, piperazinyl or morpholinyl;

Rcis hydrogen or (C1-C4)alkyl;

Rdis hydrogen or (C1-C4)alkyl;

Reis hydrogen or (C1-C4)alkyl wherein the (C1-C4)alkyl is optionally substituted with one or more halo, (C1-C4)alkoxy, —NH2, —NH(C1-C4) alkyl or —N((C1-C4)alkyl)2; or Rdand Retaken together with the nitrogen to which they are attached form pyrrolidinyl, piperidinyl, piperazinyl or morpholinyl;

Rfis hydrogen or (C1-C4)alkyl;

Rgis hydrogen or (C1-C4)alkyl; or Rfand Rgtaken together with the nitrogen to which they are attached form pyrrolidinyl, piperidinyl, piperazinyl or morpholinyl; and

Rhis hydrogen or (C1-C4)alkyl.

One embodiment provides a method of treating or preventing a bacterial infection in an animal (e.g., a mammal such as a human) comprising administering to the animal a bacterial efflux pump inhibitor and a compound of formula Ia (sub-formula of formula I):



or a pharmaceutically acceptable salt thereof, wherein:

R1is hydrogen, halo, cyano, nitro, (C1-C6)alkyl, phenyl or heteroaryl, wherein the (C1-C6)alkyl, phenyl or heteroaryl is optionally substituted with one or more groups selected from halo, hydroxy, (C1-C4)alkyl, (C1-C4)haloalkyl, (C1-C4)alkoxy, nitro or cyano;

R2is hydrogen, halo, cyano, nitro, (C1-C6)alkyl, phenyl or heteroaryl, wherein the (C1-C6)alkyl, phenyl or heteroaryl is optionally substituted with one or more groups selected from halo, hydroxy, (C1-C4)alkyl, (C1-C4)haloalkyl, (C1-C4)alkoxy, nitro or cyano;

R3is hydrogen, halo, cyano, nitro, (C1-C6)alkyl, phenyl or heteroaryl, wherein the (C1-C6)alkyl, phenyl or heteroaryl is optionally substituted with one or more groups selected from halo, hydroxy, (C1-C4)alkyl, (C1-C4)haloalkyl, (C1-C4)alkoxy, nitro or cyano;

R4is hydrogen, halo, cyano, nitro, (C1-C6)alkyl, phenyl or heteroaryl, wherein the (C1-C6)alkyl, phenyl or heteroaryl is optionally substituted with one or more groups selected from halo, hydroxy, (C1-C4)alkyl, (C1-C4)haloalkyl, (C1-C4)alkoxy, nitro or cyano;

R5is hydrogen or (C1-C4)alkyl;

R6is hydrogen, (C1-C6)alkyl, (C3-C6)cycloalkyl, —C(═O)RX, or —C(═O)ORX, wherein the (C1-C6) alkyl or (C3-C6) cycloalkyl is optionally substituted with one or more groups selected from halo, —ORaor —NRaRb;

each RXis independently (C1-C6)alkyl, (C3-C6)cycloalkyl, or phenyl, wherein the (C1-C6)alkyl, (C3-C6)cycloalkyl, or phenyl is optionally substituted with one or more groups selected from halo, —ORaor —NRaRb;

each Rais independently hydrogen or (C1-C4)alkyl; and

each Rbis independently hydrogen or (C1-C4)alkyl; or Raand Rbtaken together with the nitrogen to which they are attached form pyrrolidinyl, piperidinyl, piperazinyl or morpholinyl.

One embodiment provides a method of treating or preventing a bacterial infection in an animal (e.g., a mammal such as a human) comprising administering to the animal in need thereof a compound of formula I (or Ia) or a pharmaceutically acceptable salt thereof as described herein.

One embodiment provides a method of treating or preventing a bacterial infection in an animal (e.g., a mammal such as a human) comprising administering to the animal in need thereof a bacterial efflux pump inhibitor and a compound of formula I (or Ia) or a pharmaceutically acceptable salt thereof as described herein.

One embodiment provides a method of treating or preventing a bacterial infection in an animal (e.g., a mammal such as a human) comprising administering to the animal in need thereof a compound of formula I (or Ia) or a pharmaceutically acceptable salt thereof as described herein.

One embodiment provides a method of treating or preventing a bacterial infection in an animal (e.g., a mammal such as a human) infected with bacteria comprising administering to the animal a bacterial efflux pump inhibitor and a compound of formula I (or Ia) or a pharmaceutically acceptable salt thereof as described herein and one or more antibacterial agents.

One embodiment provides a method of treating or preventing a bacterial infection in an animal (e.g., a mammal such as a human) infected with bacteria comprising administering to the animal a compound of formula I (or Ia) or a pharmaceutically acceptable salt thereof as described herein and one or more antibacterial agents.

One embodiment provides a compound of formula I or a salt thereof as described herein; provided that the compound of formula I is not



or a salt thereof.

One embodiment provides a pharmaceutical composition comprising a compound of formula I (or Ia) or a pharmaceutically acceptable salt thereof as described herein, and a pharmaceutically acceptable vehicle.

One embodiment provides pharmaceutical composition comprising a compound of formula I (or Ia) or a pharmaceutically acceptable salt thereof as described herein, a bacterial efflux pump inhibitor and a pharmaceutically acceptable vehicle.

One embodiment provides a compound of formula I (or Ia) or a pharmaceutically acceptable salt thereof as described herein, combined with a bacterial efflux pump inhibitor, for use in medical therapy.

One embodiment provides a compound of formula I (or Ia) or a pharmaceutically acceptable salt thereof as described herein, for use in medical therapy.

One embodiment provides a compound of formula I (or Ia) or a pharmaceutically acceptable salt thereof as described herein, combined with a bacterial efflux pump inhibitor, for the prophylactic or therapeutic treatment of a bacterial infection.

One embodiment provides a compound of formula I (or Ia) or a pharmaceutically acceptable salt thereof as described herein, for the prophylactic or therapeutic treatment of a bacterial infection.

One embodiment provides the use of a compound of formula I (or Ia) or a pharmaceutically acceptable salt thereof as described herein, combined with a bacterial efflux pump inhibitor, for the preparation of a medicament for treating a bacterial infection in an animal (e.g., a mammal such as a human).

One embodiment provides the use of a compound of formula I (or Ia) or a pharmaceutically acceptable salt thereof as described herein, for the preparation of a medicament for treating a bacterial infection in an animal (e.g., a mammal such as a human).

One embodiment provides processes and intermediates disclosed herein that are useful for preparing compounds of formula I or salts thereof.

