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WO2025043115A1 - Inhibiteurs de pompe à efflux bactérienne - Google Patents

Inhibiteurs de pompe à efflux bactérienne Download PDF

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Publication number
WO2025043115A1
WO2025043115A1 PCT/US2024/043485 US2024043485W WO2025043115A1 WO 2025043115 A1 WO2025043115 A1 WO 2025043115A1 US 2024043485 W US2024043485 W US 2024043485W WO 2025043115 A1 WO2025043115 A1 WO 2025043115A1
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alkyl
halo
compound
independently selected
optionally substituted
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Inventor
Ajit K. Parhi
Jun Lu
Yongzheng Zhang
Ahmad ALTITI
Jesus D. ROSADO-LUGO
Pratik DATTA
Yi Yuan
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TAXIS PHARMACEUTICALS Inc
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TAXIS PHARMACEUTICALS Inc
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
    • C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
    • C07D403/04—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings directly linked by a ring-member-to-ring-member bond
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A61P31/04—Antibacterial agents
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D491/00—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00
    • C07D491/12—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00 in which the condensed system contains three hetero rings
    • C07D491/14—Ortho-condensed systems
    • C07D491/147—Ortho-condensed systems the condensed system containing one ring with oxygen as ring hetero atom and two rings with nitrogen as ring hetero atom

Definitions

  • 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. 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 agents and methods for inhibiting one or more of these mechanisms of bacterial resistance.
  • One embodiment provides a compound of formula I: or a salt thereof, wherein: X is –(CR 11a R 11b )m-; m is 1 or 2; R 1 is: (a) (C 1 -C 10 )alkyl wherein the (C 1 -C 10 )alkyl is substituted with one or more (e.g., 1, 2, 3, or 4) -NR a1 R b1 , and wherein the (C 1 -C 10 )alkyl is optionally substituted with one or more (e.g., 1, 2, 3, 4, or 5) groups independently selected from the group consisting of halo, (C 1 - C4)alkyl, (C 3 -C 7 )carbocyclyl, -OH, and -OR c1 ; or (b) 4-7 membered monocyclic heterocyclyl-(C 1 -C 6 )alkyl-, wherein the 4-7 membered monocyclic heterocyclyl-(C 1 -C 6
  • One embodiment provides a pharmaceutical composition comprising a compound of formula I or a pharmaceutically acceptable salt thereof as described herein, and a pharmaceutically acceptable vehicle.
  • One embodiment provides a pharmaceutical composition comprising a compound of formula I or a pharmaceutically acceptable salt thereof as described herein, one or more antibacterial agents and a pharmaceutically acceptable vehicle.
  • One embodiment provides a method of inhibiting a bacterial efflux pump in an animal (e.g., a mammal such as a human) comprising administering to the animal a compound of formula I or a pharmaceutically acceptable salt thereof as described herein.
  • One embodiment provides a method of inhibiting a bacterial efflux pump 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 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 co-administering to the animal a compound of formula I 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) comprising co-administering to the animal in need thereof a compound of formula I or a pharmaceutically acceptable salt thereof as described herein and one or more antibacterial agents.
  • One embodiment provides a method of inhibiting a bacterial efflux pump in an animal (e.g., a mammal such as a human) with a bacterial infection comprising administering to the animal a compound of formula I 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 co-administering to the animal a compound of formula I or a pharmaceutically acceptable salt thereof as described herein and one or more antibacterial agents.
  • an animal e.g., a mammal such as a human
  • One embodiment provides a compound of formula I or a pharmaceutically acceptable salt thereof as described herein for use in medical treatment.
  • One embodiment provides a compound of formula I or a pharmaceutically acceptable salt thereof as described herein for the prophylactic or therapeutic inhibition of a bacterial efflux pump for the treatment of a bacterial infection.
  • One embodiment provides a compound of formula I or a pharmaceutically acceptable salt thereof as described herein which is used in combination with one or more antibacterial agents for the prophylactic or therapeutic treatment of a bacterial infection.
  • One embodiment provides the use of a compound of formula I or a pharmaceutically acceptable salt thereof as described herein for the preparation of a medicament for inhibiting a bacterial efflux pump.
  • One embodiment provides the use of a compound of formula I 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 the use of a compound of formula I or a pharmaceutically acceptable salt thereof as described herein for the preparation of a medicament which is used in combination with one or more antibacterial agents 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.
  • DETAILED DESCRIPTION The following definitions are used, unless otherwise described: halo or halogen is fluoro, chloro, bromo, or iodo. Alkyl and alkoxy, etc.
  • (C a -C b )alkyl wherein a and b are integers refers to a straight or branched chain alkyl radical having from a to b carbon atoms.
  • a is 1 and b is 6, for example, the term includes methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, t- butyl, n-pentyl and n-hexyl.
  • aryl refers to a single aromatic ring or a multiple condensed ring system wherein the ring atoms are carbon.
  • an aryl group can have 6 to 10 carbon atoms, or 6 to 12 carbon atoms.
  • Aryl includes a phenyl radical.
  • Aryl also includes multiple condensed ring systems (e.g., ring systems comprising 2 rings) having about 9 to 12 carbon atoms or 9 to 10 carbon atoms in which at least one ring is aromatic.
  • Such multiple condensed ring systems may be optionally substituted with one or more (e.g., 1 or 2) oxo groups on any cycloalkyl portion of the multiple condensed ring system.
  • a multiple condensed ring system can be at any position of the ring system including an aryl or a cycloalkyl portion of the ring.
  • Typical aryl groups include, but are not limited to, phenyl, indenyl, naphthyl, 1, 2, 3, 4-tetrahydronaphthyl, anthracenyl, and the like.
  • heteroaryl refers to a single aromatic ring or a multiple condensed ring system. The term includes single aromatic rings of from about 1 to 6 carbon atoms and about 1-4 heteroatoms selected from the group consisting of oxygen, nitrogen and sulfur in the rings.
  • the sulfur and nitrogen atoms may also be present in an oxidized form provided the ring is aromatic.
  • Such rings include but are not limited to pyridyl, pyrimidinyl, oxazolyl or furyl.
  • the term also includes multiple condensed ring systems (e.g. ring systems comprising 2 rings) wherein a heteroaryl group, as defined above, can be condensed with one or more heteroaryls (e.g., naphthyridinyl), heterocycles, (e.g., 1, 2, 3, 4-tetrahydronaphthyridinyl), cycloalkyls (e.g., 5,6,7,8-tetrahydroquinolyl) or aryls (e.g.
  • a multiple condensed ring system may be optionally substituted with one or more (e.g., 1 or 2) oxo groups on the cycloalkyl or heterocycle portions of the condensed ring.
  • a monocyclic or bicyclic heteroaryl has 5 to 10 ring atoms comprising 1 to 9 carbon atoms and 1 to 4 heteroatoms.
  • the point of attachment of a multiple condensed ring system (as defined above for a heteroaryl) can be at any position of the multiple condensed ring system including a heteroaryl, heterocycle, aryl or cycloalkyl portion of the multiple condensed ring system and at any suitable atom of the multiple condensed ring system including a carbon atom and heteroatom (e.g., a nitrogen).
  • heteroaryls include but are not limited to pyridyl, pyrrolyl, pyrazinyl, pyrimidinyl, pyridazinyl, pyrazolyl, thienyl, indolyl, imidazolyl, oxazolyl, thiazolyl, furyl, oxadiazolyl, thiadiazolyl, quinolyl, isoquinolyl, benzothiazolyl, benzoxazolyl, indazolyl, quinoxalyl, quinazolyl, 5,6,7,8-tetrahydroisoquinolinyl, benzofuranyl, benzimidazolyl and thianaphthenyl.
  • heterocyclyl refers to a single saturated or partially unsaturated ring or a multiple condensed ring system.
  • the term includes single saturated or partially unsaturated rings (e.g., 3, 4, 5, 6 or 7-membered rings) from about 1 to 6 carbon atoms and from about 1 to 3 heteroatoms selected from the group consisting of oxygen nitrogen and sulfur in the ring.
  • the ring may be substituted with one or more (e.g., 1, 2 or 3) oxo groups and the sulfur and nitrogen atoms may also be present in their oxidized forms.
  • Such rings include but are not limited to azetidinyl, tetrahydrofuranyl or piperidinyl.
  • heterocycles include, but are not limited to aziridinyl, azetidinyl, pyrrolidinyl, piperidinyl, homopiperidinyl, morpholinyl, thiomorpholinyl, piperazinyl, tetrahydrofuranyl, dihydrooxazolyl, tetrahydropyranyl and tetrahydrothiopyranyl.
  • haloalkyl includes an alkyl group as defined herein that is substituted with one or more (e.g., 1, 2, 3, or 4) halo groups.
  • halo alkyl is a “(C 1 -C 6 )haloalkyl”.
  • alkoxy refers to -O(alkyl) and the term “haloalkoxy” refers to an alkoxy that is substituted with one or more (e.g., 1, 2, 3, or 4) halo.
  • cycloalkyl, carbocycle, or carbocyclyl includes saturated and partially unsaturated carbocyclic ring systems. In one embodiment the cycloalkyl is a monocyclic carbocyclic ring. Such cycloalkyls include “(C 3 -C 7 )carbocyclyl” and “(C 3 -C 8 )cycloalkyl”.
  • (C 1 -C 6 )alkyl can be methyl, ethyl, propyl, isopropyl, butyl, iso-butyl, sec- butyl, pentyl, 3-pentyl, or hexyl;
  • (C 1 -C 6 )alkoxy can be methoxy, ethoxy, propoxy, isopropoxy, butoxy, iso-butoxy, sec-butoxy, pentoxy, 3-pentoxy, or hexyloxy;
  • (C 3 -C 8 )cycloalkyl can be cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl;
  • (C 1 -C 6 )haloalkyl can be iodomethyl, bromomethyl, chloromethyl,
  • R 3 is hydrogen, halo, (C 1 -C 6 )alkoxy, or (C 1 -C 6 )haloalkoxy or R 3 and R 4 together are -OCH 2 O- or -O(CH 2 ) 2 O-, wherein the -OCH 2 O- or -O(CH 2 ) 2 O- are optionally substituted with one or more groups independently selected from the groups consisting of halo and (C 1 -C 6 )alkyl.
  • R 3 is hydrogen.
  • R 4 is hydrogen, halo, (C 1 -C 6 )alkoxy, or (C 1 -C 6 )haloalkoxy, or R 3 and R 4 or R 4 and R 5 together are -OCH 2 O- or -O(CH 2 ) 2 O-, wherein the -OCH 2 O- or -O(CH 2 ) 2 O-are optionally substituted with one or more groups independently selected from the groups consisting of halo and (C 1 -C 6 )alkyl.
  • R 4 is hydrogen.
  • R 5 is hydrogen, halo, (C 1 -C 6 )alkoxy, or (C 1 -C 6 )haloalkoxy, or R 4 and R 5 or R 5 and R 6 together are -OCH 2 O- or -O(CH 2 ) 2 O-, wherein the -OCH 2 O- or -O(CH 2 ) 2 O- are optionally substituted with one or more groups independently selected from the groups consisting of halo and (C 1 -C 6 )alkyl.
  • R 5 is hydrogen or halo.
  • R 6 is hydrogen, halo, (C 1 -C 6 )alkoxy, or (C 1 -C 6 )haloalkoxy, or R 5 and R 6 together are -OCH 2 O- or -O(CH 2 ) 2 O-, wherein the -OCH 2 O- or -O(CH 2 ) 2 O- are optionally substituted with one or more groups independently selected from the groups consisting of halo and (C 1 -C 6 )alkyl. In one embodiment R 6 is hydrogen.
  • R 7 is hydrogen, halo, (C 1 -C 6 )alkoxy, or (C 1 -C 6 )haloalkoxy or R 6 and R 7 together are -OCH 2 O- or -O(CH 2 ) 2 O-, wherein the -OCH 2 O- or -O(CH 2 ) 2 O- are optionally substituted with one or more groups independently selected from the groups consisting of halo and (C 1 -C 6 )alkyl.
  • R 7 is hydrogen.
  • R 8 is hydrogen, halo, (C 1 -C 6 )alkoxy, or (C 1 -C 6 )haloalkoxy, or R 7 and R 8 or R 8 and R 9 together are -OCH 2 O- or -O(CH 2 ) 2 O-, wherein the -OCH 2 O- or -O(CH 2 ) 2 O- are optionally substituted with one or more groups independently selected from the groups consisting of halo and (C 1 -C 6 )alkyl.
  • R 8 is hydrogen, (C 1 -C 6 )alkoxy, or R 8 and R 9 together are -OCH 2 O-, wherein the -OCH 2 O- is optionally substituted with one or more groups independently selected from the groups consisting of halo and (C 1 -C 6 )alkyl.
  • R 9 is hydrogen, halo, (C 1 -C 6 )alkoxy, or (C 1 -C 6 )haloalkoxy, or R 8 and R 9 or R 9 and R 10 together are -OCH 2 O- or -O(CH 2 ) 2 O-, wherein the -OCH 2 O- or -O(CH 2 ) 2 O- are optionally substituted with one or more groups independently selected from the groups consisting of halo and (C 1 -C 6 )alkyl.
  • R 9 is hydrogen, halo, or (C 1 -C 6 )alkoxy, or R 8 and R 9 together are - OCH 2 O-, wherein the -OCH 2 O- is optionally substituted with one or more groups independently selected from the groups consisting of halo and (C 1 -C 6 )alkyl.
  • R 10 is hydrogen, halo, (C 1 -C 6 )alkoxy, or (C 1 -C 6 )haloalkoxy, or R 9 and R 10 together are -OCH 2 O- or -O(CH 2 ) 2 O-, wherein the -OCH 2 O- or -O(CH 2 ) 2 O- are optionally substituted with one or more groups independently selected from the groups consisting of halo and (C 1 -C 6 )alkyl.
  • R 10 is hydrogen or halo.
  • R 1 is: (a) (C 2 -C 8 )alkyl, wherein the (C 2 -C 8 )alkyl is substituted with one or more -NR a1 R b1 , and wherein the (C 2 -C 8 )alkyl is optionally substituted with one or more groups independently selected from the group consisting of halo, (C 1 -C 4 )alkyl, (C 3 -C 7 )carbocyclyl, -OH, and -OR c1 ; or (b) 4-7 membered monocyclic heterocyclyl-(C 1 -C 3 )alkyl-, wherein the 4-7 membered monocyclic heterocyclyl-(C 1 -C 3 )alkyl- is substituted with one or more groups independently selected from the groups consisting of -NR a2 R b2 and -(C 1 -C 6 )alkyl substituted with one or more -NR a3 R b3
  • R 1 is: (a) (C 2 -C 8 )alkyl, wherein the (C 2 -C 8 )alkyl is substituted with two or more -NR a1 R b1 , and wherein the (C 2 -C 8 )alkyl is optionally substituted with one or more groups independently selected from the group consisting of halo, (C 1 -C 4 )alkyl, (C 3 -C 7 )carbocyclyl, -OH and -OR c1 ; or (b) 4-7 membered monocyclic heterocyclyl-(C 1 -C 3 )alkyl-, wherein the 4-7 membered monocyclic heterocyclyl-(C 1 -C 3 )alkyl- is substituted with one or more groups independently selected from the groups consisting of -NR a2 R b2 and -(C 1 -C 6 )alkyl substituted with one or more -NR a3 R b3 ,
  • R 1 is: (a) (C 2 -C 8 )alkyl, wherein the (C 2 -C 8 )alkyl is substituted with two or more -NR a1 R b1 , and wherein the (C 2 -C 8 )alkyl is optionally substituted with one or more groups independently selected from the group consisting of halo and -OH; or (b) 4-7 membered monocyclic heterocyclyl-(C 1 -C 3 )alkyl-, wherein the 4-7 membered monocyclic heterocyclyl-(C 1 -C 3 )alkyl- is substituted with one or more -(C 1 -C 6 )alkyl substituted with one or more -NR a3 R b3 , and wherein the heterocyclyl-(C 1 -C 3 )alkyl- is optionally substituted with one or more -OH.
  • R 1 is: (a) (C 5 -C 8 )alkyl, wherein the (C 5 -C 8 )alkyl is substituted with one or more -NR a1 R b1 , and wherein the (C 2 -C 8 )alkyl is optionally substituted with one or more groups independently selected from the group consisting of halo, (C 1 -C 4 )alkyl, (C 3 -C 7 )carbocyclyl, -OH, and -OR c1 ; or (b) 4-7 membered monocyclic heterocyclyl-(C 1 -C 3 )alkyl-, wherein the 4-7 membered monocyclic heterocyclyl-(C 1 -C 3 )alkyl- is substituted with one or more groups independently selected from the groups consisting of -NR a2 R b2 and -(C 1 -C 6 )alkyl substituted with one or more -NR a3 R b3
  • R 1 is: (a) (C 5 -C 8 )alkyl, wherein the (C 2 -C 8 )alkyl is substituted with two or more -NR a1 R b1 , and wherein the (C5-C8)alkyl is optionally substituted with one or more groups independently selected from the group consisting of halo, (C 1 -C 4 )alkyl, (C 3 -C 7 )carbocyclyl, -OH, and -OR c1 ; or (b) 4-7 membered monocyclic heterocyclyl-(C 1 -C 3 )alkyl-, wherein the 4-7 membered monocyclic heterocyclyl-(C 1 -C 3 )alkyl- is substituted with one or more groups independently selected from the groups consisting of -NR a2 R b2 and -(C 1 -C 6 )alkyl substituted with one or more -NR a3 R b3 , and wherein
  • R 1 is: (a) (C 5 -C 12 )alkyl, wherein the (C 2 -C 12 )alkyl is substituted with two or more -NR a1 R b1 , and wherein the (C 5 -C 8 )alkyl is optionally substituted with one or more groups independently selected from the group consisting of halo, (C 1 -C 4 )alkyl, (C 3 -C 7 )carbocyclyl, -OH, and -OR c1 ; or (b) 4-7 membered monocyclic heterocyclyl-(C 1 -C 3 )alkyl-, wherein the 4-7 membered monocyclic heterocyclyl-(C 1 -C 3 )alkyl- is substituted with one or more groups independently selected from the groups consisting of -NR a2 R b2 and -(C 1 -C 6 )alkyl substituted with one or more -NR a3 R b3
  • R 1 is (C 2 -C 8 )alkyl, wherein the (C 2 -C 8 )alkyl is substituted with one or more -NR a1 R b1 , and wherein the (C 2 -C 8 )alkyl is optionally substituted with one or more groups independently selected from the group consisting of halo, (C 1 -C 4 )alkyl, (C 3 - C 7 )carbocyclyl, -OH, and -OR c1 .
  • R 1 is (C 2 -C 8 )alkyl, wherein the (C 2 -C 8 )alkyl is substituted with two or more -NR a1 R b1 , and wherein the (C 2 -C 8 )alkyl is optionally substituted with one or more groups independently selected from the group consisting of halo, (C 1 -C 4 )alkyl, (C 3 - C7)carbocyclyl, -OH, and -OR c1 .
  • R 1 is (C 2 -C 8 )alkyl, wherein the (C 2 -C 8 )alkyl is substituted with two or more -NR a1 R b1 , and wherein the (C 2 -C 8 )alkyl is optionally substituted with one or more groups independently selected from the group consisting of halo and -OH.
  • R 1 is 4-7 membered monocyclic heterocyclyl-(C 1 -C 3 )alkyl-, wherein the 4-7 membered monocyclic heterocyclyl-(C 1 -C 3 )alkyl- is substituted with one or more groups independently selected from the groups consisting of -NR a2 R b2 and -(C 1 -C 6 )alkyl substituted with one or more -NR a3 R b3 , and wherein the heterocyclyl-(C 1 -C 3 )alkyl- or -(C 1 -C 3 )alkyl is optionally substituted with one or more groups independently selected from the group consisting of halo, (C 1 -C 4 )alkyl, (C 3 -C 7 )carbocyclyl, -OH, and -OR c2 .
  • R 1 is 4-7 membered monocyclic heterocyclyl-(C 1 -C 3 )alkyl-, wherein the 4-7 membered monocyclic heterocyclyl-(C 1 -C 3 )alkyl- is substituted with one or more -(C 1 - C 6 )alkyl substituted with one or more -NR a3 R b3 , and wherein the heterocyclyl-(C 1 -C 3 )alkyl- is optionally substituted with one or more -OH.
  • R 1 is: (a) (C 2 -C 8 )alkyl, wherein the (C 2 -C 8 )alkyl is substituted with one or more -NR a1 R b1 , and wherein the (C 2 -C 8 )alkyl is optionally substituted with one or more groups independently selected from the group consisting of halo, (C 1 -C 4 )alkyl, (C 3 -C 7 )carbocyclyl, -OH, and -OR c1 ; or (b) 4-7 membered monocyclic heterocyclyl-(C 1 -C 3 )alkyl-, wherein the 4-7 membered monocyclic heterocyclyl-(C 1 -C 3 )alkyl- is substituted with one or more groups independently selected from the groups consisting of -NR a2 R b2 and -(C 1 -C 6 )alkyl substituted with one or more -NR a3 R b3
  • R 1 is: (a) (C 2 -C 8 )alkyl, wherein the (C 2 -C 8 )alkyl is substituted with two or more -NR a1 R b1 , and wherein the (C 2 -C 8 )alkyl is optionally substituted with one or more groups independently selected from the group consisting of halo, (C 1 -C 4 )alkyl, (C 3 -C 7 )carbocyclyl, -OH, and -OR c1 ; or (b) 4-7 membered monocyclic heterocyclyl-(C 1 -C 3 )alkyl-, wherein the 4-7 membered monocyclic heterocyclyl-(C 1 -C 3 )alkyl- is substituted with one or more groups independently selected from the groups consisting of -NR a2 R b2 and -(C 1 -C 6 )alkyl substituted with one or more -NR a3 R b3
  • R 1 is: (a) (C 2 -C 8 )alkyl, wherein the (C 2 -C 8 )alkyl is substituted with two or more -NR a1 R b1 , and wherein the (C 2 -C 8 )alkyl is optionally substituted with one or more groups independently selected from the group consisting of halo and -OH; or (b) 4-7 membered monocyclic heterocyclyl-(C 1 -C 3 )alkyl-, wherein the 4-7 membered monocyclic heterocyclyl-(C 1 -C 3 )alkyl- is substituted with one or more -(C 1 -C 6 )alkyl substituted with one or more -NR a3 R b3 , and wherein the heterocyclyl-(C 1 -C 3 )alkyl- is optionally substituted with one or more -OH.
  • R 1 is (C 2 -C 8 )alkyl, wherein the (C 2 -C 8 )alkyl is substituted with one or more -NR a1 R b1 , and wherein the (C 2 -C 8 )alkyl is optionally substituted with one or more groups independently selected from the group consisting of halo, (C 1 -C 4 )alkyl, (C 3 - C 7 )carbocyclyl -OH and -OR c1
  • R 1 is (C 2 -C 8 )alkyl, wherein the (C 2 -C 8 )alkyl is substituted with two or more -NR a1 R b1 , and wherein the (C 2 -C 8 )alkyl is optionally substituted with one or more groups independently selected from the group consisting of halo, (C 1 -C 4 )alkyl, (C 3 - C 7 )carbocyclyl, -OH, and -OR c1 .
  • R 1 is (C 2 -C 8 )alkyl, wherein the (C 2 -C 8 )alkyl is substituted with two or more -NR a1 R b1 , and wherein the (C 2 -C 8 )alkyl is optionally substituted with one or more groups independently selected from the group consisting of halo and -OH.
  • R 1 is 4-7 membered monocyclic heterocyclyl-(C 1 -C 3 )alkyl-, wherein the 4-7 membered monocyclic heterocyclyl-(C 1 -C 3 )alkyl- is substituted with one or more groups independently selected from the groups consisting of -NR a2 R b2 and -(C 1 -C 6 )alkyl substituted with one or more -NR a3 R b3 , and wherein the heterocyclyl-(C 1 -C 3 )alkyl- or -(C 1 -C 6 )alkyl is optionally substituted with one or more groups independently selected from the group consisting of halo, (C 1 -C 4 )alkyl, (C 3 -C 7 )carbocyclyl, -OH, and -OR c2 .
  • R 1 is 4-7 membered monocyclic heterocyclyl-(C 1 -C 3 )alkyl-, wherein the 4-7 membered monocyclic heterocyclyl-(C 1 -C 3 )alkyl- is substituted with one or more -(C 1 - C 6 )alkyl substituted with one or more -NR a3 R b3 , and wherein the heterocyclyl-(C 1 -C 3 )alkyl- is optionally substituted with one or more -OH.
  • R 1 is .
  • R 1 is . 38.
  • R 1 is .
  • each R a1 and R b1 is independently hydrogen or (C 1 -C 6 )alkyl.
  • each R a1 and R b1 is independently hydrogen. In one embodiment R a1 is hydrogen and R b1 is (C 1 -C 6 )alkyl. In one embodiment each -NR a1 R b1 is independently -NH 2 or -NH(C 1 -C 6 )alkyl. In one embodiment each -NR a1 R b1 is -NH2. In one embodiment each R c1 is independently (C 1 -C 6 )alkyl In one embodiment each R a2 and R b2 is independently hydrogen or (C 1 -C 6 )alkyl. In one embodiment each R a2 and R b2 is independently hydrogen.
  • each R a2 is hydrogen and each R b2 is (C 1 -C 6 )alkyl. In one embodiment each -NR a2 R b2 is independently -NH2 or -NH(C 1 -C 6 )alkyl. In one embodiment each -NR a2 R b2 is -NH 2 . In one embodiment each R c2 is independently (C 1 -C 6 )alkyl In one embodiment each R a3 and R b3 is independently hydrogen or (C 1 -C 6 )alkyl. In one embodiment each R a3 and R b3 is independently hydrogen. In one embodiment each R a3 is hydrogen and each R b3 is (C 1 -C 6 )alkyl.
  • each -NR a3 R b3 is independently -NH2 or -NH(C 1 -C 6 )alkyl. In one embodiment each -NR a3 R b3 is -NH 2 . In one embodiment each R d1 is independently hydrogen or (C 1 -C 6 )alkyl. In one embodiment each R d1 is hydrogen. In one embodiment each R e1 is independently hydrogen or (C 1 -C 6 )alkyl. In one embodiment each R e1 is hydrogen. In one embodiment each R f1 and R g1 is independently hydrogen or (C 1 -C 6 )alkyl. In one embodiment each R f1 and R g1 is hydrogen.
  • each R d2 is independently hydrogen or (C 1 -C 6 )alkyl.
  • each R d2 is hydrogen.
  • each R e2 is independently hydrogen or (C 1 -C 6 )alkyl.
  • each R e2 is hydrogen.
  • each R f2 and R g2 is independently hydrogen or (C 1 -C 6 )alkyl.
  • each R f2 and R g2 is hydrogen.
  • One embodiment provides a compound that is: or or a salt thereof.
  • One embodiment provides a compound that is:
  • variable groups shown below can represent the final corresponding groups present in a compound of formula I or that these groups can represent groups that can be converted to the final corresponding groups present in a compound of formula I at a convenient point in a synthetic sequence.
  • the variable groups can contain one or more protecting groups that can be removed at a convenient point in a synthetic sequence to provide the final corresponding groups in the compound of formula I.
  • Scheme 1 and scheme 2 illustrate general methods for the preparation of compounds of formula I.
  • Scheme 1 Scheme 2 The compounds disclosed herein are bacterial efflux pump inhibitors.
  • An efflux pump inhibitor is a compound that interferes with the ability of an efflux pump to export a substrate.
  • the inhibitor may have intrinsic antibacterial properties of its own.
  • the compounds disclosed herein may be useful for treating bacterial infections (e.g., gram negative and gram positive) when administered with an antibacterial agent.
  • the bacterial infection being treated is a Gram-negative bacterial strain infection.
  • the Gram-negative bacterial strain is selected from the group consisting of Acinetobacter baumannii, Acinetobacter calcoaceticus, Acinetobacter haemolyticus, Acinetobacter lwoffi, Actinobacillus actinomycetemcomitans, Aeromonas hydrophilia, Aggregatibacter actinomycetemcomitans, Agrobacterium tumefaciens, Bacteroides distasonis, Bacteroides eggerthii, Bacteroides forsythus, Bacteroides fragilis, Bacteroides ovalus, Bacteroides splanchnicus, Bacteroides thetaiotaomicron, Bacteroides uniformis, Bacteroides vulgatus, Bordetella bronchiseptica, Bordetella parapertussis, Bordetella pertussis, Borrelia burgdorferi, Branhamella catarrhalis, Burkholderia cepacia,
  • the bacterial infection being treated is a Gram-positive bacterial strain infection.
  • the Gram-positive bacterial strain is selected from the group consisting of Actinomyces naeslundii, Actinomyces viscosus, Bacillus anthracis, Bacillus cereus, Bacillus subtilis, Clostridium difficile, Corynebacterium diphtheriae, Corynebacterium ulcerans, Enterococcus faecalis, Enterococcus faecium, Micrococcus luteus, Mycobacterium avium, Mycobacterium intracellulare, Mycobacterium leprae, Mycobacterium tuberculosis, Propionibacterium acnes, Staphylococcus aureus, Staphylococcus epidermidis, Staphylococcus haemolyticus, Staphylococcus hominis, Staphylococcus hyicus, Staphylococcus intermedius, Staphylococc
  • compositions can, if desired, also contain other active therapeutic agents, such as a narcotic, a non-steroid anti-inflammatory drug (NSAID), an analgesic, an anesthetic, a sedative, a local anesthetic, a neuromuscular blocker, an anti-cancer, an antimicrobial (for example, an aminoglycoside, an antifungal, an antiparasitic, an antiviral, a carbapenem, a cephalosporin (e.g., cefepime), a fluoroquinolone, a macrolide, a penicillin, a sulfonamide, a tetracycline, another antimicrobial), an anti-psoriatic, a corticosteriod, an anabolic steroid, a diabetes-related agent, a mineral, a nutritional, a thyroid agent, a vitamin, a calcium-related hormone, an antidiarrheal, an anti-tussive, an anti-
  • the antibacterial agent is selected from quinolones, tetracyclines, glycopeptides, aminoglycosides, ⁇ -lactams, rifamycins, macrolides, ketolides, oxazolidinones, coumermycins, and chloramphenicol. It will be appreciated that compounds of the invention having a chiral center may exist in and be isolated in optically active and racemic forms. Some compounds may exhibit polymorphism.
  • the present invention encompasses any racemic, optically-active, polymorphic, or stereoisomeric form, or mixtures thereof, of a compound of the invention, which possess the useful properties described herein, it being well known in the art how to prepare optically active forms (for example, by resolution of the racemic form by recrystallization techniques, by synthesis from optically-active starting materials, by chiral synthesis, or by chromatographic separation using a chiral stationary phase.
  • optically active forms for example, by resolution of the racemic form by recrystallization techniques, by synthesis from optically-active starting materials, by chiral synthesis, or by chromatographic separation using a chiral stationary phase.
  • the compound (or composition thereof) may be at least 51% the absolute stereoisomer depicted. In another embodiment, the compound (or composition thereof) may be at least 60% the absolute stereoisomer depicted. In another embodiment, the compound (or composition thereof) may be at least 80% the absolute stereoisomer depicted. In another embodiment, the compound (or composition thereof) may be at least 90% the absolute stereoisomer depicted. In another embodiment, the compound (or composition thereof) may be at least 95 the absolute stereoisomer depicted.
  • the present invention encompasses all tautomeric forms of a compound of formula I as well as mixtures thereof that can exist in equilibrium with non-charged and charged entities depending upon pH which possess the useful properties described herein
  • a salt of a compound of formula I can be useful as an intermediate for isolating or purifying a compound of formula I.
  • administration of a compound of formula I as a pharmaceutically acceptable acid or base salt may be appropriate.
  • Examples of pharmaceutically acceptable salts are organic acid addition salts formed with acids which form a physiological acceptable anion, for example, tosylate, methanesulfonate, acetate, citrate, malonate, tartrate, succinate, fumarate, benzoate, ascorbate, ⁇ -ketoglutarate, and ⁇ -glycerophosphate.
  • Suitable inorganic salts may also be formed, including hydrochloride, sulfate, nitrate, bicarbonate, and carbonate salts. Salts may be obtained using standard procedures well known in the art, for example by reacting a sufficiently basic compound such as an amine with a suitable acid affording the corresponding anion.
  • Alkali metal (for example, sodium, potassium or lithium) or alkaline earth metal (for example calcium) salts of carboxylic acids can also be made.
  • Pharmaceutically suitable counterions include pharmaceutically suitable cations and pharmaceutically suitable anions that are well known in the art. Examples of pharmaceutically suitable anions include, but are not limited to those described above (e.g. physiologically acceptable anions) including Cl-, Br-, I-, CH 3 SO 3 -, H 2 PO 4 -, CF 3 SO 3 -, p-CH 3 C 6 H 4 SO 3 -, citrate, tartrate, phosphate, malate, fumarate, formate, or acetate.
  • a compound of the invention comprising a counterion can be converted to a compound of the invention comprising a different counterion.
  • Such a conversion can be accomplished using a variety of well-known techniques and materials including but not limited to ion exchange resins, ion exchange chromatography and selective crystallization.
  • the compounds of formula I can be formulated as pharmaceutical compositions and administered to a mammalian host, such as a human patient in a variety of forms adapted to the chosen route of administration, i.e., orally or parenterally, by intravenous, intramuscular, topical or subcutaneous routes.
  • the compounds can be formulated as a solid dosage form with or without an enteric coating.
  • the present compounds may be systemically administered, e.g., orally, in combination with a pharmaceutically acceptable vehicle such as an inert diluent, excipient or an assimilable edible carrier. They may be enclosed in hard- or soft-shell gelatin capsules, may be compressed into tablets, or may be incorporated directly with the food of the patient's diet.
  • a pharmaceutically acceptable vehicle such as an inert diluent, excipient or an assimilable edible carrier.
  • the active compound may be combined with one or more excipients and used in the form of ingestible tablets, buccal tablets, troches, capsules, elixirs, suspensions, syrups, wafers, and the like.
  • compositions and preparations should contain at least 01% of active compound
  • the percentage of the compositions and preparations may of course, be varied and may conveniently be between about 2 to about 90% of the weight of a given unit dosage form.
  • the amount of active compound in such therapeutically useful compositions is such that an effective dosage level will be obtained.
  • the tablets, troches, pills, capsules, and the like may also contain the following: binders such as gum tragacanth, acacia, corn starch or gelatin; excipients such as dicalcium phosphate; a disintegrating agent such as corn starch, potato starch, alginic acid and the like; a lubricant such as magnesium stearate; and a sweetening agent such as sucrose, fructose, lactose or aspartame or a flavoring agent such as peppermint, oil of wintergreen, or cherry flavoring may be added.
  • a liquid carrier such as a vegetable oil or a polyethylene glycol.
  • any material used in preparing any unit dosage form should be pharmaceutically acceptable and substantially non-toxic in the amounts employed.
  • the active compound may be incorporated into sustained-release preparations, particles, and devices. The active compound may also be administered intravenously or intramuscularly by infusion or injection.
  • Solutions of the active compound or its salts can be prepared in water, optionally mixed with a nontoxic surfactant. Dispersions can also be prepared in glycerol, liquid polyethylene glycols, triacetin, and mixtures thereof and in oils. Under ordinary conditions of storage and use, these preparations contain a preservative to prevent the growth of microorganisms.
  • the pharmaceutical dosage forms suitable for injection or infusion can include sterile aqueous solutions or dispersions or sterile powders comprising the active ingredient which are adapted for the extemporaneous preparation of sterile injectable or infusible solutions or dispersions, optionally encapsulated in liposomes. In all cases, the ultimate dosage form should be sterile, fluid and stable under the conditions of manufacture and storage.
  • the liquid carrier or vehicle can be a solvent or liquid dispersion medium comprising, for example, water, ethanol, a polyol (for example, glycerol, propylene glycol, liquid polyethylene glycols, and the like), vegetable oils, nontoxic glyceryl esters, and suitable mixtures thereof.
  • a polyol for example, glycerol, propylene glycol, liquid polyethylene glycols, and the like
  • vegetable oils nontoxic glyceryl esters, and suitable mixtures thereof.
  • suitable mixtures thereof can be maintained, for example, by the formation of liposomes, by the maintenance of the required particle size in the case of dispersions or by the use of surfactants.
  • the prevention of the action of microorganisms can be brought about by various antibacterial and antifungal agents for example, parabens, chlorobutanol, phenol, sorbic acid, thimerosal, and the like.
  • isotonic agents for example, sugars, buffers or sodium chloride.
  • Prolonged absorption of the injectable compositions can be brought about by the use in the compositions of agents delaying absorption, for example, aluminum monostearate and gelatin.
  • Sterile injectable solutions are prepared by incorporating the active compound in the required amount in the appropriate solvent with various of the other ingredients enumerated above, as required, followed by filter sterilization.
  • the preferred methods of preparation are vacuum drying and the freeze-drying techniques, which yield a powder of the active ingredient plus any additional desired ingredient present in the previously sterile-filtered solutions.
  • the present compounds may be applied in pure form, i.e., when they are liquids. However, it will generally be desirable to administer them to the skin as compositions or formulations, in combination with a dermatologically acceptable carrier, which may be a solid or a liquid.
  • a dermatologically acceptable carrier which may be a solid or a liquid.
  • Useful solid carriers include finely divided solids such as talc, clay, microcrystalline cellulose, silica, alumina, nanoparticles, and the like.
  • Useful liquid carriers include water, alcohols or glycols or water-alcohol/glycol blends, in which the present compounds can be dissolved or dispersed at effective levels, optionally with the aid of non-toxic surfactants.
  • Adjuvants such as fragrances and additional antimicrobial agents can be added to optimize the properties for a given use.
  • the resultant liquid compositions can be applied from absorbent pads, used to impregnate bandages and other dressings, or sprayed onto the affected area using pump-type or aerosol sprayers.
  • Thickeners such as synthetic polymers, fatty acids, fatty acid salts and esters, fatty alcohols, modified celluloses or modified mineral materials can also be employed with liquid carriers to form spreadable pastes, gels, ointments, soaps, and the like, for application directly to the skin of the user.
  • Useful dosages of the compounds of formula I can be determined by comparing their in vitro activity, and in vivo activity in animal models. Methods for the extrapolation of effective dosages in mice, and other animals, to humans are known to the art; for example, see U.S. Pat.
  • the amount of the compound, or an active salt or derivative thereof, required for use in treatment will vary not only with the particular salt selected but also with the route of administration, the nature of the condition being treated and the age and condition of the patient and will be ultimately at the discretion of the attendant physician or clinician. In general, however, a suitable dose will be in the range of from about 1 to about 500 mg/kg, e.g., from about 5 to about 400 mg/kg of body weight per day, such as 1 to about 250 mg per kilogram body weight of the recipient per day.
  • the compound is conveniently formulated in unit dosage form; for example, containing 5 to 500 mg, 10 to 400 mg, or 5 to 100 mg of active ingredient per unit dosage form.
  • the invention provides a composition comprising a compound of the invention formulated in such a unit dosage form.
  • the desired dose may conveniently be presented in a single dose or as divided doses administered at appropriate intervals, for example, as two, three, four or more sub-doses per day.
  • the sub-dose itself may be further divided, e.g., into a number of discrete loosely spaced administrations.
  • Co-administration of a compound disclosed herein with one or more other active therapeutic agents generally refers to simultaneous or sequential administration of a compound disclosed herein and one or more other active therapeutic agents, such that therapeutically effective amounts of disclosed herein and one or more other active therapeutic agents are both present in the body of the patient.
  • the ability of a compound disclosed herein to inhibit a bacterial efflux pump can be determined using a method as described in Examples 18-20 and as shown in Table 1.
  • Step 1) tert-butyl (R,Z)-4-(3-ethoxy-2-fluoro-3-oxoprop-1-en-1-yl)-2,2-dimethyloxazolidine-3- carboxylate
  • ethyl 2-(diethoxyphosphoryl)-2-fluoroacetate 5.81 g, 24.0 mmol
  • LiHMDS LiHMDS
  • Step 2 tert-butyl (4R)-4-(3-ethoxy-2-fluoro-3-oxopropyl)-2,2-dimethyloxazolidine-3- carboxylate
  • tert-butyl (R,Z)-4-(3-ethoxy-2-fluoro-3-oxoprop-1-en-1-yl)-2,2- dimethyloxazolidine-3-carboxylate 7.65 g, ⁇ 90% purity, 21.8 mmol
  • Pd/C 10% loading, 1.0 g
  • Step 5 tert-butyl (4R)-4-(3-amino-2-fluoropropyl)-2,2-dimethyloxazolidine-3-carboxylate
  • tert-butyl (4R)-4-(3-(1,3-dioxoisoindolin-2-yl)-2-fluoropropyl)-2,2- dimethyloxazolidine-3-carboxylate 7.5 g, 18.5 mmol
  • MeOH 100 mL
  • hydrazine monohydrate 2.90 mL, 37.0 mmol
  • tert-butyl (4R)-4-(3-amino-2-fluoropropyl)-2,2-dimethyloxazolidine-3- carboxylate 5.40 g, ⁇ 93% purity, 18.2 mmol
  • MeOH 100 mL
  • 4 N HCl solution in dioxane (18.2 mL, 72.8 mmol
  • di-tert-butyl ((4R)-2-fluoro-5-hydroxypentane-1,4-diyl)dicarbamate (2.14 g, 6.37 mmol)
  • triphenylphosphine (1.84 g, 7.01 mmol
  • phthalimide (1.03 g, 7.01 mmol) in THF (30 mL) was added DIAD (1.42 mL, 7.01 mmol) at 0 °C.
  • the reaction mixture was stirred at 90 °C for two hours. Then, the volatiles were removed under a vacuum, and the crude material was dissolved in a minimum amount of 10% DCM/MeOH solution and loaded into a RediSep column. The material was then purified using flash chromatography using an ISCO machine and gradient elution of MeOH/DCM. The desired fractions were collected and evaporated to dryness to give a white solid with a 55% yield.
  • reaction mixture was stirred at rt for 3 hours then the solvent was evaporated to dryness, the crude mixture was dissolved in diethyl ether (100 mL) and the solution was treated with saturated aqueous solution of Na 2 S 2 O 3 (100 mL) to get rid of the TEMPO, after stirring vigorously for 1 hour, the reaction mixture was transferred into a separatory funnel, the aqueous layer was extracted with ether (30 mL x3). The combined organic layer was washed with saturated aqueous NaHCO 3 (100 mL), and brine (100 mL), dried over Na 2 SO 4 , filtered and concentrated under vacuum.
  • Step 2 tert-butyl (S)-4-((S)-2-fluoro-3-hydroxypropyl)-2,2-dimethyloxazolidine-3 carboxylate
  • tert-butyl (S)-2,2-dimethyl-4-(3-oxopropyl)oxazolidine-3-carboxylate 2570 mg, 10.0 mmol
  • S- Jorgensen Catalyst® 119 mg, 0.2 mmol
  • methyl t-Butyl ether, MTBE (10.0 mL).
  • reaction mixture was then treated with NaBH 4 (1850 mg, 50.0 mmol) and let stirring at rt for another hour.
  • the reaction mixture was cooled down to 0 °C and treated with a saturated solution of NH4Cl (100 mL); the mixture was warmed up to rt and stirred vigorously for 1 hr.
  • the resulting solid was filtered over a short pad of celite, and the filtrate was transferred into a separatory funnel and was extracted with DCM (100 mL X 3).
  • the combined organic layer was washed with NaHCO 3 (100 mL) and brine (100 mL), dried over anhydrous Na 2 SO 4 , filtered, and concentrated under vacuum at rt.
  • the NMR analysis showed that the compound is a mixture of rotamers; the NMR values are listed for the major rotamer.
  • tert-butyl (S)-4-((S)-3-(1,3-dioxoisoindolin-2-yl)-2-fluoropropyl)-2,2 dimethyloxazolidine-3-carboxylate 1.0 mmol
  • EtOH 20 mL
  • the reaction mixture was heated and stirred at 90 °C for 2 h; the reaction progress was monitored by LCMS; once the starting material was consumed entirely based on the LCMS analysis, the reaction was stopped by evaporating all volatiles under a vacuum. Then, the resulting free amine was treated with 6M HCl/EtOH (5.0 mL) to cleave the acid-labile- protecting groups. The reaction mixture was stirred at 48 °C for three hours. Then, the volatiles were evaporated entirely under a high vacuum for 2 h. The Crude mixture was then suspended in DCM (20 mL) and treated with 3.0 mmol of Boc anhydride and 6.0 mmol of Et 3 N.
  • the reaction mixture was stirred at rt for 16 h Then the reaction mixture was diluted with 20 mL of DCM and transferred into a separatory funnel; the organic layer was washed with 1 M NaOH solution (20 mL), Saturated NH4Cl solution (20 mL), and brine (20 mL). The organic layer was dried over Na 2 SO 4 , filtered, and concentrated under a vacuum. The resulting crude material was loaded into a RediSep silica Column and purified by flash chromatography using an ISCO machine and a gradient elution of EtOAc/Hexane. The final product was collected as clear wax with a 77% yield.
  • Step 5 di-tert-butyl ((2S,4S)-5-(1,3-dioxoisoindolin-2-yl)-2-fluoropentane-1,4-diyl)dicarbamate
  • di-tert-butyl ((2S,4S)-2-fluoro-5-hydroxypentane-1,4-diyl) dicarbamate 793 mg, 2.36 mmol
  • triphenylphosphine 787 mg, 3.0 mmol
  • phthalimide 440 mg, 3.0 mmol
  • the reaction mixture was stirred at 90 °C for 2 hours. Then, the volatiles were removed under a vacuum, and the crude material was dissolved in a minimum amount of 10% DCM/MeOH solution and loaded into a RediSep ® column. The material was then purified using flash chromatography using an ISCO ® machine and gradient elution of MeOH/DCM. The desired fractions were collected and evaporated to dryness to give a white solid with a 95% yield.
  • Step 2 tert-butyl (S)-4-((R)-3-(1,3-dioxoisoindolin-2-yl)-2-fluoropropyl)-2,2-dimethyloxazolidine-3- carboxylate
  • the titled compound was prepared and purified according to the general procedure described above for the synthesis of intermediate E on 5.36 mmol scale. The final product was collected as a white solid with an 80% yield. A sample of the compound was dissolved in CDCl 3 and analyzed by NMR; the analysis showed that the compound is one pure diastereomer. The spectroscopic values are listed for the titled compound.
  • reaction mixture was stirred at rt for 3 hours then the solvent was evaporated to dryness, the crude mixture was dissolved in diethyl ether (100 mL) and the solution was treated with saturated aqueous solution of Na 2 S 2 O 3 (100 mL) to get rid of the TEMPO, after stirring vigorously for 1 hour, the reaction mixture was transferred into a separatory funnel, the aqueous layer was extracted with ether (30 mL x3). The combined organic layer was washed with saturated aqueous NaHCO 3 (100 mL), and brine (100 mL), dried over Na 2 SO 4 , filtered and concentrated under vacuum.
  • the NMR analysis showed that the compound is a mixture of rotamers; the NMR values are listed for the major rotamer.
  • Step 3 tert-butyl (R)-4-((R)-3-(1,3-dioxoisoindolin-2-yl)-2-fluoropropyl)-2,2-dimethyloxazolidine-3- carboxylate
  • the titled compound was prepared and purified according to the general procedure described above for the synthesis of intermediate E on 20.9 mmol scale. The final product was collected as white solid with a 59% yield. A sample (15 mg) of the compound was dissolved in CDCl 3 and analyzed by NMR spectroscopy; the analysis showed that the compound is a mixture of rotamers. The spectroscopic values are listed for the dominant rotamer.
  • Step 4) di-tert-butyl ((2R,4R)-2-fluoro-5-hydroxypentane-1,4-diyl)dicarbamate The titled compound was prepared and purified according to the general procedure described above for the synthesis of intermediate E on 12.3 mmol scale. The final product was collected as clear wax with a 92% yield. A sample of the compound was dissolved in deuterated chloroform, CDCl 3 and analyzed by NMR spectroscopy; the analysis showed that the compound is one pure diastereomer. The spectroscopic values are listed for the titled compound.
  • Step 5 di-tert-butyl ((2R,4R)-5-(1,3-dioxoisoindolin-2-yl)-2-fluoropentane-1,4-diyl)dicarbamate
  • the titled compound was prepared and purified to general procedure described above for the synthesis of intermediate E on 8.35 mmol scale. The final product was collected as a white solid with a 68% yield. A sample of the compound was dissolved in deuterated chloroform, CDCl 3 and analyzed by NMR spectroscopy; the analysis showed that the compound is one pure diastereomer. The spectroscopic values are listed for the titled compound.
  • the reaction mixture was stirred at 90 °C for 2 hours. Then, the volatiles were removed under a vacuum, and the crude material was dissolved in a minimum amount of 10% DCM/MeOH solution and loaded into a RediSep ® column. The material was then purified using flash chromatography using an ISCO ® machine and gradient elution of MeOH/DCM. The desired fractions were collected and evaporated to dryness to give a white solid with a 95% yield. A sample was dissolved in deuterated MeOH and analyzed by NMR spectroscopy.
  • the NMR analysis showed that the compound is a mixture of rotamers; the NMR values are listed for the major rotamer.
  • Step 2 tert-butyl (R)-4-((S)-3-(1,3-dioxoisoindolin-2-yl)-2-fluoropropyl)-2,2-dimethyloxazolidine-3- carboxylate
  • the titled compound was prepared and purified according to the general procedure described above for the synthesis of intermediate E described above on 27.0 mmol scale. The final product was collected as white solid with a 60% yield. A sample of the compound was dissolved in CDCl 3 and analyzed by NMR; the analysis showed that the compound is a mixture of rotamers. The spectroscopic values are listed for the dominant rotamer.
  • Step 3 di-tert-butyl ((2S,4R)-2-fluoro-5-hydroxypentane-1,4-diyl)dicarbamate
  • the titled compound was prepared and purified according to the general procedure described above for the synthesis of intermediate E on 15.7 mmol scale. The final product was collected as clear wax with an 85% yield. A sample of the compound was dissolved in CDCl 3 and analyzed by NMR; the analysis showed that the compound is one pure diastereomer. The spectroscopic values are listed for the titled compound.
  • the titled compound was prepared and purified to general procedure described above for the synthesis of intermediate E on 13.17 mmol scale. The final product was collected as a white solid with an 80% yield. A sample of the compound was dissolved in CDCl 3 and analyzed by NMR; the analysis showed that the compound is one pure diastereomer. The spectroscopic values are listed for the titled compound.
  • reaction mixture was heated at 80 °C overnight, it was extracted with EtOAc and washed with water, brine and dried over Na 2 SO 4 , then concentrated and purified by column chromatography on silica gel with EtOAc in hexane as eluents to give the product (0.30 g, 34% yield) as a white powder.
  • ethyl-3-(2-formylphenyl)-1H-indole-2-carboxylate 100 mg, 0.33 mmol
  • di-tert-butyl (5-aminopentane-1,4-diyl)(S)-dicarbamate 100 mg, 0.32 mmol
  • DCM 5 mL
  • water 0.2 mL
  • reaction mixture was heated at 80 °C overnight, it was extracted with EtOAc and washed with water, brine and dried over Na 2 SO 4 , then concentrated. It was purified by column chromatography on silica gel with EtOAc in hexane as eluents to give the product (0.10 g, 32% yield) as a pale brown powder.
  • ethyl 3-(4-fluoro-2-formylphenyl)-1H-indole-2-carboxylate 40 mg, 0.13 mmol
  • di-tert-butyl (5-aminopentane-1,4-diyl)(S)-dicarbamate 40 mg, 0.13 mmol
  • 1,2-dichloroethane 5 mL
  • water 0.5 mL
  • Step 1) ethyl 3-(3-fluoro-2-formylphenyl)-1H-indole-2-carboxylate
  • ethyl 3-bromo-1H-indole-2-carboxylate (0.17 g, 1 mmol)
  • (2-formyl- 3-fluorophenyl)boronic acid (0.27 g, 1.08 mmol) in a mixture of DMF (5 mL) and K 2 CO 3 solution (2 M, 1 mL, 2 mmol) was degassed and Pd(dppf)Cl 2 (100 mg, 0.14 mmol) was added.
  • reaction mixture was heated at 80 °C overnight, it was extracted with EtOAc and washed with water, brine and dried over Na 2 SO 4 , then concentrated. It was purified by column chromatography on silica gel with EtOAc in hexane as eluents to give the product (0.11 g, 35% yield) as a white powder.
  • ethyl 3-(3-fluoro-2-formylphenyl)-1H-indole-2-carboxylate 40 mg, 0.13 mmol
  • di-tert-butyl (5-aminopentane-1,4-diyl)(S)-dicarbamate 40 mg, 0.13 mmol
  • 1,2-dichloroethane 5 mL
  • water 0.5 mL
  • reaction mixture was heated at 90 °C overnight, it was extracted with EtOAc and washed with water, brine and dried over Na 2 SO 4 , then concentrated. It was purified by column chromatography on silica gel with EtOAc in hexane as eluents to give the product (0.13 g, 39% yield) as a pale brown powder.
  • ethyl 3-(4-chloro-2-formylphenyl)-1H-indole-2-carboxylate 100 mg, 0.3 mmol
  • di-tert-butyl (5-aminopentane-1,4-diyl)(S)-dicarbamate 100 mg, 0.3 mmol
  • NaB(OAc) 3 H 200 mg, 3.8 mmol
  • reaction mixture was heated at 80 °C for 3 hours, it was extracted with EtOAc and washed with water, brine and dried over Na 2 SO 4 , then concentrated. It was purified by column chromatography on silica gel with EtOAc in hexane as eluents to give the product (0.79 g, 84% yield) as a brown powder.
  • Step 2 di-tert-butyl (5-(11-fluoro-7-oxo-7,8-dihydrobenzo[5,6]azepino[3,4-b]indol-6(5H)-yl)pentane- 1,4-diyl)(S)-dicarbamate
  • ethyl-5-fluoro-3-(2-formylphenyl)-1H-indole-2-carboxylate 100 mg, 0.3 mmol
  • di-tert-butyl (5-aminopentane-1,4-diyl)(S)-dicarbamate (100 mg, 0.3 mmol) in 1,4-dioxane (5 mL) was added NaB(OAc) 3 H (200 mg, 0.9 mmol).
  • reaction mixture was heated at 90 °C for 3 hours, it was extracted with EtOAc and washed with water, brine and dried over Na 2 SO 4 , then concentrated. It was purified by column chromatography on silica gel with EtOAc in hexane as eluents to give the product (0.092 g, 28% yield) as a pale-yellow powder.
  • Step 2) di-tert-butyl (5-(3,11-difluoro-7-oxo-7,8-dihydrobenzo[5,6]azepino[3,4-b]indol-6(5H)- yl)pentane-1,4-diyl)(S)-dicarbamate
  • ethyl-5-fluoro-3-(4-fluoro-2-formylphenyl)-1H-indole-2-carboxylate 92 mg, 0.3 mmol
  • di-tert-butyl (5-aminopentane-1,4-diyl)(S)-dicarbamate 100 mg, 0.3 mmol
  • 1,4-dioxane 5 mL
  • Step 2) di-tert-butyl (5-(3-chloro-11-fluoro-7-oxo-7,8-dihydrobenzo[5,6]azepino[3,4-b]indol-6(5H)- yl)pentane-1,4-diyl)(S)-dicarbamate
  • ethyl 3-(4-chloro-2-formylphenyl)-5-fluoro-1H-indole-2-carboxylate 51 mg, 0.15 mmol
  • di-tert-butyl (5-aminopentane-1,4-diyl)(S)-dicarbamate 46 mg, 0.15 mmol
  • NaB(OAc) 3 H 200 mg, 0.9 mmol
  • reaction mixture was heated at 90 °C for 2 hours, it was extracted with EtOAc and washed with water, brine and dried over Na 2 SO 4 , then concentrated. It was purified by column chromatography on silica gel with EtOAc in hexane as eluents to give the product (0.32 g, 47% yield) as a pale-yellow powder.
  • Step 2) di-tert-butyl (5-(11-fluoro-3-methoxy-7-oxo-7,8-dihydrobenzo[5,6]azepino[3,4-b]indol-6(5H)- yl)pentane-1,4-diyl)(S)-dicarbamate
  • ethyl-5-fluoro-3-(4-methoxy-2-formylphenyl)-1H-indole-2-carboxylate 70 mg, 0.2 mmol
  • di-tert-butyl (5-aminopentane-1,4-diyl)(S)-dicarbamate 70 mg, 0.2 mmol
  • NaB(OAc) 3 H 140 mg, 0.66 mmol
  • reaction mixture was heated at 90 °C for 3 hours, it was extracted with EtOAc and washed with water, brine and dried over Na 2 SO 4 , then concentrated. It was purified by column chromatography on silica gel with EtOAc in hexane as eluents to give the product (0.50 g, 59% yield) as a pale-yellow powder.
  • Step 2 di-tert-butyl (5-(11-fluoro-2-methoxy-7-oxo-7,8-dihydrobenzo[5,6]azepino[3,4-b]indol-6(5H)- yl)pentane-1,4-diyl)(S)-dicarbamate
  • ethyl-5-fluoro-3-(5-methoxy-2-formylphenyl)-1H-indole-2-carboxylate 140 mg, 0.4 mmol
  • di-tert-butyl (5-aminopentane-1,4-diyl)(S)-dicarbamate 140 mg, 0.4 mmol
  • NaB(OAc)3H 280 mg, 1.3 mmol
  • ethyl 5-fluoro-3-(6-formylbenzo[d][1,3]dioxol-5-yl)-1H-indole-2- carboxylate 36 mg, 0.1 mmol
  • di-tert-butyl (5-aminopentane-1,4-diyl)(S)-dicarbamate 31 mg, 0.1 mmol) in 1,4-dioxane (5 mL) was added NaB(OAc)3H (64 mg, 0.3 mmol
  • Step 2 di-tert-butyl ((4S)-2-hydroxy-5-(7-oxo-7,8-dihydrobenzo[5,6]azepino[3,4-b]indol-6(5H)- yl)pentane-1,4-diyl)dicarbamate
  • TBAF 1,3-bis(triisopropylsilyl)oxy
  • TBAF 1,3-bis(triisopropylsilyl)oxy
  • the reaction mixture was heated at 60 °C for 16 h. upon completion, the reaction mixture was diluted with 25 mL of DCM and transferred into a separatory funnel. The organic layer was washed with a saturated solution of sodium perborate (NaBO 3 .4H 2 O), 1M NaOH solution, and brine. Then, the organic layer was dried over Na 2 SO 4 , filtered, and evaporated under vacuum. The crude material was purified by flash chemoautotrophy using Silica and gradient elution of EtOAc/Hexane. The final product was collected as a pale-yellow solid in 50% yield.
  • Example 19 Preparation of 6-((2S,4R)-2,5-diamino-4-fluoropentyl)-11-fluoro-5,8- dihydrobenzo [5,6] azepino[3,4-b] indol-7(6H)-one hydrochloride salt 6-((2S,4R)-2,5-diamino-4-fluoropentyl)-11-fluoro-5,8-dihydrobenzo [5,6] azepino[3,4-b] indol- 7(6H)-one hydrochloride salt
  • the titled compound was prepared and purified according to procedure described above on 0.18 mmol scale.
  • Example 20 Preparation of 6-((2R,4R)-2,5-diamino-4-fluoropentyl)-11-fluoro-5,8- dihydrobenzo [5,6] azepino[3,4-b] indol-7(6H)-one hydrochloride salt 6-((2R,4R)-2,5-diamino-4-fluoropentyl)-11-fluoro-5,8-dihydrobenzo [5,6] azepino[3,4-b] indol- 7(6H)-one hydrochloride salt
  • the Titled compound was prepared and purified according to procedure described above on 0.28 mmol scale.
  • Example 21 Preparation of 6-((2R,4S)-2,5-diamino-4-fluoropentyl)-11-fluoro-5,8- dihydrobenzo [5,6] azepino[3,4-b] indol-7(6H)-one hydrochloride salt 6-((2R,4S)-2,5-diamino-4-fluoropentyl)-11-fluoro-5,8-dihydrobenzo [5,6] azepino[3,4-b] indol- 7(6H)-one hydrochloride salt
  • the titled compound was prepared and purified according to procedure described above on 0.54 mmol scale.
  • the reaction mixture was stirred at rt for 48 h. when the starting material was consumed based on the LCMS analysis, the mixture was transferred into a separatory funnel and mixed with (Boc)2O (17.5 mg, 0.08 mmol) and EtOAc (5.0 mL). the reaction mixture was shaken occasionally for 15 min then the mixture was mixed with 1M HCl solution 10 mL. The organic layer was separated, and the aqueous layer was extracted with EtOAc (5.0 mL x 3). The combined organic layer was washed with brine, dried over Na 2 SO 4 , filtered, and evaporated under vacuum. The resulting crude was purified on silica gel and the use of gradient elution of Hexanes/EtOAc.
  • the desired fractions were collected based on the LCMS analysis; after evaporating the volatiles, the resulting crude was dissolved in 6 M HCl/EtOH (1.5 mL) solution to cleave the Boc protecting groups. The reaction mixture was stirred at rt for 30 min and then the volatiles were removed under vacuum to give pale-yellow solid (8.4 mg, 51% (over two steps). The compound was dissolved in DMSO-d6 and analyzed by NMR spectroscopy. The 1 HNMR analysis indicated the presence of mixture of rotamers. The following are the 1 HNMR values listed for the dominant rotamer.
  • the MIC was defined as the lowest compound concentration that inhibited 90% of bacteria growth.
  • the intrinsic MIC of the experimental EPIs was tested with the method described. The 2- fold serial dilution begins with 100 ⁇ g/mL of tested compound in the first column of the 96-well plates. The following Gram-negative bacterial strain was included in these assays: Pseudomonas aeruginosa ATCC 27853.
  • Bacterial EPI assays The EPI assay for the purposes of these studies represents a MIC assay in which the MIC of the antibiotic against the bacteria is tested in the presence of an experimental efflux pump inhibitor (EPI). The highest concentration of the EPI present in the assay typically is 1 ⁇ 2 of the intrinsic MIC of the compound.
  • the EPI assay was tested with 50 ⁇ g/mL. Using serial dilutions of the EPI, its enhancement of antibiotic activity was then evaluated. The relative EPI activity was decided by comparing the MIC of the antibiotic in the presence of the EPI compound with the intrinsic MIC of the antibiotic alone.
  • Example 24 Standard EPI Assays. The impact of the EPIs on the MIC values of three test antibiotics (levofloxacin, ceftazidime and doxycycline) against P aeruginosa ATCC 27853 were evaluated using our standard EPI assay.
  • aeruginosa ATCC 27853 in the absence of EPI is 1 ⁇ g/mL.
  • the MIC of levofloxacin was markedly reduced to 0.063 ⁇ g/mL, a 16-fold reduction relative to the MIC of levofloxacin in the absence of EPI (1 ⁇ g/mL).
  • the MIC of ceftazidime against P. aeruginosa ATCC 27853 in the absence of EPI is 2 ⁇ g/mL.
  • the MIC of ceftazidime was reduced to 0.5 ⁇ g/mL, a 4-fold reduction.
  • Example 25 Fluorescent-Based Cellular Assay for Efflux Inhibition The impact of potential EPI compounds on the activity of efflux pumps was also evaluated with a fluorescence-based cellular assay that measures the efflux of Ethidium Bromide (EtBr), a known substrate of Gram-negative bacterial efflux pumps.
  • EtBr Ethidium Bromide
  • EtBr When bound to intracellular bacterial DNA, EtBr fluoresces brightly, while the unbound fluorophore outside the bacterial cell exhibits little or no fluorescence. Thus, the efflux of EtBr from inside to outside the bacterial cell is associated with a substantive decrease in fluorescence.
  • P. aeruginosa ATCC 27853 bacterial cells are grown overnight in CAMH broth. Bacteria are harvested from the overnight culture by centrifugation, and the cell pellet washed with phosphate-buffered containing 1 mM MgCl 2 (PBSM). The washed cell pellets are resuspended in PBSM to achieve a final OD at 600 nm of 1.0.
  • PBSM phosphate-buffered containing 1 mM MgCl 2
  • Carbonyl cyanide 3-chlorophenylhydrazone (CCCP) is added to the bacterial suspension at a final concentration 50 ⁇ M, along with the addition of EtBr at a final concentration of 200 ⁇ M.
  • the cells are then incubated in the dark at 37°C for 50 minutes to allow for the depletion of ATP by the CCCP, which negatively impacts cellular efflux pump activity and thus results in the concomitant accumulation of ethidium bromide inside the cells. After the 50-minute incubation, the bacteria are spun down, and the supernatant discarded to remove extracellular CCCP and EtBr.
  • the bacterial pellet is resuspended in an equal volume of PBSM, and 200 ⁇ L of the bacterial suspension added to wells of a black, flat-bottom 96-well plate containing test EPI compounds at concentrations ranging from 0.031 - 0.25-fold MIC, or an equivalent volume of the vehicle (DMSO) alone.
  • the plates are pre-incubated at 37°C for 5 minutes.
  • EtBr efflux is initiated by addition of glucose (100 mM) to reenergizes the efflux pumps.
  • a Spectramax iD5 fluorescent plate reader (Molecular Devices, Inc., Sunnyvale, CA) is used to monitor the fluorescence of each well at 37°C once per minute for 240 minutes.
  • Example 26 The following can illustrate representative pharmaceutical dosage forms, containing a compound of formula I ('Compound X') or a pharmaceutically acceptable salt thereof, for therapeutic or prophylactic use in humans.
  • the tablets can optionally comprise an enteric coating.

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Abstract

L'invention concerne des composés de formule I : et des sels de ceux-ci. L'invention concerne également des compositions comprenant des composés de formule I et des procédés d'utilisation des composés de formule I.
PCT/US2024/043485 2023-08-23 2024-08-22 Inhibiteurs de pompe à efflux bactérienne Pending WO2025043115A1 (fr)

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Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4938949A (en) 1988-09-12 1990-07-03 University Of New York Treatment of damaged bone marrow and dosage units therefor
WO2018165611A1 (fr) 2017-03-10 2018-09-13 Rutgers, The State University Of New Jersey Dérivés d'indole utilisés en tant qu'inhibiteurs de pompe d'efflux
WO2018218192A1 (fr) * 2017-05-26 2018-11-29 Rutgers, The State University Of New Jersey Inhibiteurs de pompe d'efflux bactérien
WO2019005841A1 (fr) * 2017-06-26 2019-01-03 Rutgers, The State University Of New Jersey Composés thérapeutiques et méthodes pour traiter une infection
WO2021243273A1 (fr) 2020-05-29 2021-12-02 Taxis Pharmaceuticals, Inc. Inhibiteurs de pompe à efflux bactérien

Patent Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4938949A (en) 1988-09-12 1990-07-03 University Of New York Treatment of damaged bone marrow and dosage units therefor
WO2018165611A1 (fr) 2017-03-10 2018-09-13 Rutgers, The State University Of New Jersey Dérivés d'indole utilisés en tant qu'inhibiteurs de pompe d'efflux
WO2018218192A1 (fr) * 2017-05-26 2018-11-29 Rutgers, The State University Of New Jersey Inhibiteurs de pompe d'efflux bactérien
WO2019005841A1 (fr) * 2017-06-26 2019-01-03 Rutgers, The State University Of New Jersey Composés thérapeutiques et méthodes pour traiter une infection
WO2021243273A1 (fr) 2020-05-29 2021-12-02 Taxis Pharmaceuticals, Inc. Inhibiteurs de pompe à efflux bactérien

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
AURLIEN PUTEY ET AL: "Indolobenzazepin-7-ones and 6-, 8-, and 9-membered ring derivatives as tubulin polymerization inhibitors: synthesis and structure-activity relationship studies", JOURNAL OF MEDICINAL CHEMISTRY, AMERICAN CHEMICAL SOCIETY, US, vol. 52, no. 19, 8 October 2009 (2009-10-08), pages 5916 - 5925, XP002629764, ISSN: 0022-2623, [retrieved on 20090910], DOI: 10.1021/JM900476C *

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