Bacterial efflux pump inhibitors

Abstract

Disclosed herein are compounds of formula I: I and salts thereof. Also disclosed are compositions comprising compounds of formula I and methods of using compounds of formula I.

Description

[0001] BACTERIAL EFFLUX PUMP INHIBITORS CROSS-REFERENCE TO RELATED APPLICATIONS This application claims priority to United States Provisional Application Number 63 / 534,262 that was filed on August 23, 2023. The entire content of the application referenced above is hereby incorporated by reference herein. 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. These 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. 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. SUMMARY OF THE INVENTION Compounds disclose herein, when tested in combination with an antibiotic, lower the minimum inhibitory concentration of the antibiotic to inhibit bacterial cell growth. Not to be bound by theory the compounds are believed to exert this effect by the inhibition of a bacterial efflux pump(s). Accordingly, one embodiment provides a compound of formula I: wherein: X is –(CR11aR11b)m-; m is 1 or 2; R1is: (a) (C1-C10)alkyl wherein the (C1-C10)alkyl is substituted independently with one or more (e.g., 1, 2, 3, or 4) -NRa1Rb1or -NRd1C(=NRe1)(NRf1Rg1) and wherein the (C1-C10)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, (C1-C4)alkyl, (C3-C7)carbocyclyl, -OH, and -ORc1; or (b) 4-7 membered monocyclic heterocyclyl-(C1-C6)alkyl-, wherein the 4-7 membered monocyclic heterocyclyl-(C1-C6)alkyl- is substituted with one or more (e.g., 1, 2, 3, or 4) groups independently selected from the groups consisting of -NRa2Rb2, -NRd2C(=NRe2)(NRf2Rg2) and -(C1-C6)alkyl substituted with one or more (e.g., 1, 2, 3, or 4) -NRa3Rb3or -NRd2C(=NRe2)(NRf2Rg2), and wherein the heterocyclyl-(C1-C6)alkyl- or -(C1- C6)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, (C1-C4)alkyl, (C3-C7)carbocyclyl, -OH, and -ORc2; R2is hydrogen, (C1-C3)alkyl, or (C3-C7)carbocyclyl; R3is hydrogen, halo, (C1-C6)alkyl, (C1-C6)haloalkyl, (C1-C6)alkoxy, (C1-C6)haloalkoxy, or -OH, or R3and R4together are -OCH2O- or -O(CH2)2O-, wherein the -OCH2O- or -O(CH2)2O- are optionally substituted with one or more (e.g., 1, 2, 3, or 4) groups independently selected from the groups consisting of halo and (C1-C6)alkyl; R4is hydrogen, halo, (C1-C6)alkyl, (C1-C6)haloalkyl, (C1-C6)alkoxy, (C1-C6)haloalkoxy, or -OH, or R3and R4or R4and R5together are -OCH2O- or -O(CH2)2O-, wherein the -OCH2O- or -O(CH2)2O- are optionally substituted with one or more (e.g., 1, 2, 3, or 4) groups independently selected from the groups consisting of halo and (C1-C6)alkyl; R5is hydrogen, halo, (C1-C6)alkyl, (C1-C6)haloalkyl, (C1-C6)alkoxy, (C1-C6)haloalkoxy, or -OH, or R4and R5or R5and R6together are -OCH2O- or -O(CH2)2O-, wherein the -OCH2O- or -O(CH2)2O- are optionally substituted with one or more (e.g., 1, 2, 3, or 4) groups independently selected from the groups consisting of halo and (C1-C6)alkyl; R6is hydrogen, halo, (C1-C6)alkyl, (C1-C6)haloalkyl, (C1-C6)alkoxy, (C1-C6)haloalkoxy, or -OH, or R5and R6together are -OCH2O- or -O(CH2)2O-, wherein the -OCH2O- or - O(CH2)2O- are optionally substituted with one or more (e.g., 1, 2, 3, or 4) groups independently selected from the groups consisting of halo and (C1-C6)alkyl; R7is hydrogen, halo, (C1-C6)alkyl, (C1-C6)haloalkyl, (C1-C6)alkoxy, (C1-C6)haloalkoxy, or -OH, or R7and R8together are -OCH2O- or -O(CH2)2O-, wherein the -OCH2O- or - O(CH2)2O- are optionally substituted with one or more (e.g., 1, 2, 3, or 4) groups independently selected from the groups consisting of halo and (C1-C6)alkyl; R8is hydrogen, halo, (C1-C6)alkyl, (C1-C6)haloalkyl, (C1-C6)alkoxy, (C1-C6)haloalkoxy, or -OH, or R7and R8or R8and R9together are -OCH2O- or -O(CH2)2O-, wherein the -OCH2O- or -O(CH2)2O- are optionally substituted with one or more (e.g., 1, 2, 3, or 4) groups independently selected from the groups consisting of halo and (C1-C6)alkyl; R9is hydrogen, halo, (C1-C6)alkyl, (C1-C6)haloalkyl, (C1-C6)alkoxy, (C1-C6)haloalkoxy, or -OH, or R8and R9or R9and R10together are -OCH2O- or -O(CH2)2O-, wherein the -OCH2O- or -O(CH2)2O- are optionally substituted with one or more (e.g., 1, 2, 3, or 4) groups independently selected from the groups consisting of halo and (C1-C6)alkyl; R10is hydrogen, halo, (C1-C6)alkyl, (C1-C6)haloalkyl, (C1-C6)alkoxy, (C1-C6)haloalkoxy, or -OH, or R9and R10together are -OCH2O- or -O(CH2)2O-, wherein the -OCH2O- or - O(CH2)2O- are optionally substituted with one or more (e.g., 1, 2, 3, or 4) groups independently selected from the groups consisting of halo and (C1-C6)alkyl; each R11aand R11bare independently hydrogen, halo, (C1-C6)alkyl or (C3-C7)carbocyclyl each Ra1and Rb1is independently hydrogen, (C1-C6)alkyl or (C3-C7)carbocyclyl; each Rc1is independently (C1-C6)alkyl or (C3-C7)carbocyclyl, wherein (C1-C6)alkyl or (C3-C7)carbocyclyl is optionally substituted with one or more (e.g., 1, 2, 3, or 4) halo; each Ra2and Rb2is independently hydrogen, (C1-C6)alkyl, or (C3-C7)carbocyclyl; each Rc2is independently (C1-C6)alkyl or (C3-C7)carbocyclyl, wherein (C1-C6)alkyl or (C3-C7)carbocyclyl is optionally substituted with one or more (e.g., 1, 2, 3, or 4) halo; each Ra3and Rb3is independently hydrogen, (C1-C6)alkyl, or (C3-C7)carbocyclyl; each Rd1is independently hydrogen (C1-C6)alkyl or (C3-C7)carbocyclyl; each Re1is independently hydrogen, (C1-C6)alkyl, or (C3-C7)carbocyclyl; each Rf1and Rg1is independently hydrogen, (C1-C6)alkyl, or (C3-C7)carbocyclyl; each Rd2is independently hydrogen, (C1-C6)alkyl, or (C3-C7)carbocyclyl; each Re2is independently hydrogen, (C1-C6)alkyl, or (C3-C7)carbocyclyl; each Rf2and Rg2is independently hydrogen, (C1-C6)alkyl, or (C3-C7)carbocyclyl; provided the compound is not: . One embodiment provides a compound of formula I: or a salt thereof, wherein: X is –(CR11aR11b)m-; m is 1 or 2; R1is: (a) (C1-C10)alkyl wherein the (C1-C10)alkyl is substituted with one or more (e.g., 1, 2, 3, or 4) -NRa1Rb1, and wherein the (C1-C10)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, (C1- C4)alkyl, (C3-C7)carbocyclyl, -OH, and -ORc1; or (b) 4-7 membered monocyclic heterocyclyl-(C1-C6)alkyl-, wherein the 4-7 membered monocyclic heterocyclyl-(C1-C6)alkyl- is substituted with one or more (e.g., 1, 2, 3, or 4) groups independently selected from the groups consisting of -NRa2Rb2and -(C1-C6)alkyl substituted with one or more (e.g., 1, 2, 3, or 4) -NRa3Rb3, and wherein the heterocyclyl-(C1- C6)alkyl- or -(C1-C6)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, (C1-C4)alkyl, (C3-C7)carbocyclyl, -OH, and -ORc2; R2is hydrogen, (C1-C3)alkyl, or (C3-C7)carbocyclyl; R3is hydrogen, halo, (C1-C6)alkyl, (C1-C6)haloalkyl, (C1-C6)alkoxy, (C1-C6)haloalkoxy, or -OH, or R3and R4together are -OCH2O- or -O(CH2)2O-, wherein the -OCH2O- or -O(CH2)2O- are optionally substituted with one or more (e.g., 1, 2, 3, or 4) groups independently selected from the groups consisting of halo and (C1-C6)alkyl; R4is hydrogen, halo, (C1-C6)alkyl, (C1-C6)haloalkyl, (C1-C6)alkoxy, (C1-C6)haloalkoxy, or -OH, or R3and R4or R4and R5together are -OCH2O- or -O(CH2)2O-, wherein the -OCH2O- or -O(CH2)2O- are optionally substituted with one or more (e.g., 1, 2, 3, or 4) groups independently selected from the groups consisting of halo and (C1-C6)alkyl; R5is hydrogen, halo, (C1-C6)alkyl, (C1-C6)haloalkyl, (C1-C6)alkoxy, (C1-C6)haloalkoxy, or -OH, or R4and R5or R5and R6together are -OCH2O- or -O(CH2)2O-, wherein the -OCH2O- or -O(CH2)2O- are optionally substituted with one or more (e.g., 1, 2, 3, or 4) groups independently selected from the groups consisting of halo and (C1-C6)alkyl; R6is hydrogen, halo, (C1-C6)alkyl, (C1-C6)haloalkyl, (C1-C6)alkoxy, (C1-C6)haloalkoxy, or -OH, or R5and R6together are -OCH2O- or -O(CH2)2O-, wherein the -OCH2O- or - O(CH2)2O- are optionally substituted with one or more (e.g., 1, 2, 3, or 4) groups independently selected from the groups consisting of halo and (C1-C6)alkyl; R7is hydrogen, halo, (C1-C6)alkyl, (C1-C6)haloalkyl, (C1-C6)alkoxy, (C1-C6)haloalkoxy, or -OH, or R7and R8together are -OCH2O- or -O(CH2)2O-, wherein the -OCH2O- or - O(CH2)2O- are optionally substituted with one or more (e.g., 1, 2, 3, or 4) groups independently selected from the groups consisting of halo and (C1-C6)alkyl; R8is hydrogen, halo, (C1-C6)alkyl, (C1-C6)haloalkyl, (C1-C6)alkoxy, (C1-C6)haloalkoxy, or -OH, or R7and R8or R8and R9together are -OCH2O- or -O(CH2)2O-, wherein the -OCH2O- or -O(CH2)2O- are optionally substituted with one or more (e.g., 1, 2, 3, or 4) groups independently selected from the groups consisting of halo and (C1-C6)alkyl; R9is hydrogen, halo, (C1-C6)alkyl, (C1-C6)haloalkyl, (C1-C6)alkoxy, (C1-C6)haloalkoxy, or -OH, or R8and R9or R9and R10together are -OCH2O- or -O(CH2)2O-, wherein the -OCH2O- or -O(CH2)2O- are optionally substituted with one or more (e.g., 1, 2, 3, or 4) groups independently selected from the groups consisting of halo and (C1-C6)alkyl; R10is hydrogen, halo, (C1-C6)alkyl, (C1-C6)haloalkyl, (C1-C6)alkoxy, (C1-C6)haloalkoxy, or -OH, or R9and R10together are -OCH2O- or -O(CH2)2O-, wherein the -OCH2O- or - O(CH2)2O- are optionally substituted with one or more (e.g., 1, 2, 3, or 4) groups independently selected from the groups consisting of halo and (C1-C6)alkyl; each R11aand R11bare independently hydrogen, halo, (C1-C6)alkyl or (C3-C7)carbocyclyl each Ra1and Rb1is independently hydrogen, (C1-C6)alkyl or (C3-C7)carbocyclyl; each Rc1is independently (C1-C6)alkyl or (C3-C7)carbocyclyl, wherein (C1-C6)alkyl or (C3-C7)carbocyclyl is optionally substituted with one or more (e.g., 1, 2, 3, or 4) halo; each Ra2and Rb2is independently hydrogen, (C1-C6)alkyl, or (C3-C7)carbocyclyl; each Rc2is independently (C1-C6)alkyl or (C3-C7)carbocyclyl, wherein (C1-C6)alkyl or (C3-C7)carbocyclyl is optionally substituted with one or more (e.g., 1, 2, 3, or 4) halo; and each Ra3and Rb3is independently hydrogen, (C1-C6)alkyl, or (C3-C7)carbocyclyl; provided the compound is not: . 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. 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. denote both straight and branched groups but reference to an individual radical such as propyl embraces only the straight chain radical (a branched chain isomer such as isopropyl being specifically referred to). As used herein, the term "(Ca-Cb)alkyl" wherein a and b are integers refers to a straight or branched chain alkyl radical having from a to b carbon atoms. Thus, when 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. The term “aryl” as used herein refers to a single aromatic ring or a multiple condensed ring system wherein the ring atoms are carbon. For example, 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. It is to be understood that the point of attachment of a multiple condensed ring system, as defined above, 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. The term “heteroaryl” as used herein 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. indazolyl) to form a multiple condensed ring system. Such multiple condensed ring systems 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. In one embodiment a monocyclic or bicyclic heteroaryl has 5 to 10 ring atoms comprising 1 to 9 carbon atoms and 1 to 4 heteroatoms. It is to be understood that 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). Exemplary 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. The term “heterocyclyl” or “heterocycle” as used herein 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. It is to be understood that the point of attachment for a heterocycle can be at any suitable atom of the heterocycle Exemplary heterocycles include, but are not limited to aziridinyl, azetidinyl, pyrrolidinyl, piperidinyl, homopiperidinyl, morpholinyl, thiomorpholinyl, piperazinyl, tetrahydrofuranyl, dihydrooxazolyl, tetrahydropyranyl and tetrahydrothiopyranyl. The term “haloalkyl” includes an alkyl group as defined herein that is substituted with one or more (e.g., 1, 2, 3, or 4) halo groups. One specific halo alkyl is a “(C1-C6)haloalkyl”. The term “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. The term 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 “(C3-C7)carbocyclyl” and “(C3-C8)cycloalkyl”. Specific values listed below for radicals, substituents, and ranges, are for illustration only; they do not exclude other defined values or other values within defined ranges for the radicals and substituents. Specifically, (C1-C6)alkyl can be methyl, ethyl, propyl, isopropyl, butyl, iso-butyl, sec- butyl, pentyl, 3-pentyl, or hexyl; (C1-C6)alkoxy can be methoxy, ethoxy, propoxy, isopropoxy, butoxy, iso-butoxy, sec-butoxy, pentoxy, 3-pentoxy, or hexyloxy; (C3-C8)cycloalkyl can be cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl; (C1-C6)haloalkyl can be iodomethyl, bromomethyl, chloromethyl, fluoromethyl, trifluoromethyl, 2-chloroethyl, 2-fluoroethyl, 2,2,2- trifluoroethyl, or pentafluoroethyl; aryl can be phenyl, indenyl, or naphthyl; and heteroaryl can be furyl, imidazolyl, triazolyl, triazinyl, oxazolyl, isoxazolyl, thiazolyl, isothiazoyl, pyrazolyl, pyrrolyl, pyrazinyl, tetrazolyl, pyridyl, (or its N-oxide), thienyl, pyrimidinyl (or its N-oxide), indolyl, isoquinolyl (or its N-oxide) or quinolyl (or its N-oxide). It is understood that the embodiments provided below are for compounds of formula I and all sub-formulas thereof (e.g., formulas Ia). It is to be understood the two or more embodiments may be combined. In one embodiment X is CH2and m is 1. In one embodiment R2is hydrogen. In one embodiment the compound of formula I is a compound of formula Ia: or a salt thereof. In one embodiment R3is hydrogen, halo, (C1-C6)alkoxy, or (C1-C6)haloalkoxy or R3and R4together are -OCH2O- or -O(CH2)2O-, wherein the -OCH2O- or -O(CH2)2O- are optionally substituted with one or more groups independently selected from the groups consisting of halo and (C1-C6)alkyl. In one embodiment R3is hydrogen. In one embodiment R4is hydrogen, halo, (C1-C6)alkoxy, or (C1-C6)haloalkoxy, or R3and R4or R4and R5together are -OCH2O- or -O(CH2)2O-, wherein the -OCH2O- or -O(CH2)2O-are optionally substituted with one or more groups independently selected from the groups consisting of halo and (C1-C6)alkyl. In one embodiment R4is hydrogen. In one embodiment R5is hydrogen, halo, (C1-C6)alkoxy, or (C1-C6)haloalkoxy, or R4and R5or R5and R6together are -OCH2O- or -O(CH2)2O-, wherein the -OCH2O- or -O(CH2)2O- are optionally substituted with one or more groups independently selected from the groups consisting of halo and (C1-C6)alkyl. In one embodiment R5is hydrogen or halo. In one embodiment R6is hydrogen, halo, (C1-C6)alkoxy, or (C1-C6)haloalkoxy, or R5and R6together are -OCH2O- or -O(CH2)2O-, wherein the -OCH2O- or -O(CH2)2O- are optionally substituted with one or more groups independently selected from the groups consisting of halo and (C1-C6)alkyl. In one embodiment R6is hydrogen. In one embodiment R7is hydrogen, halo, (C1-C6)alkoxy, or (C1-C6)haloalkoxy or R6and R7together are -OCH2O- or -O(CH2)2O-, wherein the -OCH2O- or -O(CH2)2O- are optionally substituted with one or more groups independently selected from the groups consisting of halo and (C1-C6)alkyl. In one embodiment R7is hydrogen. In one embodiment R8is hydrogen, halo, (C1-C6)alkoxy, or (C1-C6)haloalkoxy, or R7and R8or R8and R9together are -OCH2O- or -O(CH2)2O-, wherein the -OCH2O- or -O(CH2)2O- are optionally substituted with one or more groups independently selected from the groups consisting of halo and (C1-C6)alkyl. In one embodiment R8is hydrogen, (C1-C6)alkoxy, or R8and R9together are -OCH2O-, wherein the -OCH2O- is optionally substituted with one or more groups independently selected from the groups consisting of halo and (C1-C6)alkyl. In one embodiment R9is hydrogen, halo, (C1-C6)alkoxy, or (C1-C6)haloalkoxy, or R8and R9or R9and R10together are -OCH2O- or -O(CH2)2O-, wherein the -OCH2O- or -O(CH2)2O- are optionally substituted with one or more groups independently selected from the groups consisting of halo and (C1-C6)alkyl. In one embodiment R9is hydrogen, halo, or (C1-C6)alkoxy, or R8and R9together are - OCH2O-, wherein the -OCH2O- is optionally substituted with one or more groups independently selected from the groups consisting of halo and (C1-C6)alkyl. In one embodiment R10is hydrogen, halo, (C1-C6)alkoxy, or (C1-C6)haloalkoxy, or R9and R10together are -OCH2O- or -O(CH2)2O-, wherein the -OCH2O- or -O(CH2)2O- are optionally substituted with one or more groups independently selected from the groups consisting of halo and (C1-C6)alkyl. In one embodiment R10is hydrogen or halo. In one embodiment R1is: (a) (C2-C8)alkyl, wherein the (C2-C8)alkyl is substituted with one or more -NRa1Rb1, and wherein the (C2-C8)alkyl is optionally substituted with one or more groups independently selected from the group consisting of halo, (C1-C4)alkyl, (C3-C7)carbocyclyl, -OH, and -ORc1; or (b) 4-7 membered monocyclic heterocyclyl-(C1-C3)alkyl-, wherein the 4-7 membered monocyclic heterocyclyl-(C1-C3)alkyl- is substituted with one or more groups independently selected from the groups consisting of -NRa2Rb2and -(C1-C6)alkyl substituted with one or more -NRa3Rb3, and wherein the heterocyclyl-(C1-C3)alkyl- or -(C1-C3)alkyl is optionally substituted with one or more groups independently selected from the group consisting of halo, (C1-C4)alkyl, (C3-C7)carbocyclyl, -OH, and -ORc2. In one embodiment R1is: (a) (C2-C8)alkyl, wherein the (C2-C8)alkyl is substituted with two or more -NRa1Rb1, and wherein the (C2-C8)alkyl is optionally substituted with one or more groups independently selected from the group consisting of halo, (C1-C4)alkyl, (C3-C7)carbocyclyl, -OH and -ORc1; or (b) 4-7 membered monocyclic heterocyclyl-(C1-C3)alkyl-, wherein the 4-7 membered monocyclic heterocyclyl-(C1-C3)alkyl- is substituted with one or more groups independently selected from the groups consisting of -NRa2Rb2and -(C1-C6)alkyl substituted with one or more -NRa3Rb3, and wherein the heterocyclyl-(C1-C3)alkyl- or -(C1-C3)alkyl is optionally substituted with one or more groups independently selected from the group consisting of halo, (C1-C4)alkyl, (C3-C7)carbocyclyl, -OH, and -ORc2. In one embodiment R1is: (a) (C2-C8)alkyl, wherein the (C2-C8)alkyl is substituted with two or more -NRa1Rb1, and wherein the (C2-C8)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-(C1-C3)alkyl-, wherein the 4-7 membered monocyclic heterocyclyl-(C1-C3)alkyl- is substituted with one or more -(C1-C6)alkyl substituted with one or more -NRa3Rb3, and wherein the heterocyclyl-(C1-C3)alkyl- is optionally substituted with one or more -OH. In one embodiment R1is: (a) (C5-C8)alkyl, wherein the (C5-C8)alkyl is substituted with one or more -NRa1Rb1, and wherein the (C2-C8)alkyl is optionally substituted with one or more groups independently selected from the group consisting of halo, (C1-C4)alkyl, (C3-C7)carbocyclyl, -OH, and -ORc1; or (b) 4-7 membered monocyclic heterocyclyl-(C1-C3)alkyl-, wherein the 4-7 membered monocyclic heterocyclyl-(C1-C3)alkyl- is substituted with one or more groups independently selected from the groups consisting of -NRa2Rb2and -(C1-C6)alkyl substituted with one or more -NRa3Rb3, and wherein the heterocyclyl-(C1-C3)alkyl- or -(C1-C3)alkyl is optionally substituted with one or more groups independently selected from the group consisting of halo, (C1-C4)alkyl, (C3-C7)carbocyclyl, -OH, and -ORc2. In one embodiment R1is: (a) (C5-C8)alkyl, wherein the (C2-C8)alkyl is substituted with two or more -NRa1Rb1, and wherein the (C5-C8)alkyl is optionally substituted with one or more groups independently selected from the group consisting of halo, (C1-C4)alkyl, (C3-C7)carbocyclyl, -OH, and -ORc1; or (b) 4-7 membered monocyclic heterocyclyl-(C1-C3)alkyl-, wherein the 4-7 membered monocyclic heterocyclyl-(C1-C3)alkyl- is substituted with one or more groups independently selected from the groups consisting of -NRa2Rb2and -(C1-C6)alkyl substituted with one or more -NRa3Rb3, and wherein the heterocyclyl-(C1-C3)alkyl- or -(C1-C3)alkyl is optionally substituted with one or more groups independently selected from the group consisting of halo, (C1-C4)alkyl, (C3-C7)carbocyclyl, -OH, and -ORc2. In one embodiment R1is: (a) (C5-C12)alkyl, wherein the (C2-C12)alkyl is substituted with two or more -NRa1Rb1, and wherein the (C5-C8)alkyl is optionally substituted with one or more groups independently selected from the group consisting of halo, (C1-C4)alkyl, (C3-C7)carbocyclyl, -OH, and -ORc1; or (b) 4-7 membered monocyclic heterocyclyl-(C1-C3)alkyl-, wherein the 4-7 membered monocyclic heterocyclyl-(C1-C3)alkyl- is substituted with one or more groups independently selected from the groups consisting of -NRa2Rb2and -(C1-C6)alkyl substituted with one or more -NRa3Rb3, and wherein the heterocyclyl-(C1-C3)alkyl- or -(C1-C3)alkyl is optionally substituted with one or more groups independently selected from the group consisting of halo, (C1-C4)alkyl, (C3-C7)carbocyclyl, -OH, and -ORc2. In one embodiment R1is (C2-C8)alkyl, wherein the (C2-C8)alkyl is substituted with one or more -NRa1Rb1, and wherein the (C2-C8)alkyl is optionally substituted with one or more groups independently selected from the group consisting of halo, (C1-C4)alkyl, (C3- C7)carbocyclyl, -OH, and -ORc1. In one embodiment R1is (C2-C8)alkyl, wherein the (C2-C8)alkyl is substituted with two or more -NRa1Rb1, and wherein the (C2-C8)alkyl is optionally substituted with one or more groups independently selected from the group consisting of halo, (C1-C4)alkyl, (C3- C7)carbocyclyl, -OH, and -ORc1. In one embodiment R1is (C2-C8)alkyl, wherein the (C2-C8)alkyl is substituted with two or more -NRa1Rb1, and wherein the (C2-C8)alkyl is optionally substituted with one or more groups independently selected from the group consisting of halo and -OH. In one embodiment R1is 4-7 membered monocyclic heterocyclyl-(C1-C3)alkyl-, wherein the 4-7 membered monocyclic heterocyclyl-(C1-C3)alkyl- is substituted with one or more groups independently selected from the groups consisting of -NRa2Rb2and -(C1-C6)alkyl substituted with one or more -NRa3Rb3, and wherein the heterocyclyl-(C1-C3)alkyl- or -(C1-C3)alkyl is optionally substituted with one or more groups independently selected from the group consisting of halo, (C1-C4)alkyl, (C3-C7)carbocyclyl, -OH, and -ORc2. In one embodiment R1is 4-7 membered monocyclic heterocyclyl-(C1-C3)alkyl-, wherein the 4-7 membered monocyclic heterocyclyl-(C1-C3)alkyl- is substituted with one or more -(C1- C6)alkyl substituted with one or more -NRa3Rb3, and wherein the heterocyclyl-(C1-C3)alkyl- is optionally substituted with one or more -OH. In one embodiment R1is: (a) (C2-C8)alkyl, wherein the (C2-C8)alkyl is substituted independently with one or more -NRa1Rb1or -NRd1C(=NRe1)(NRf1Rg1) and wherein the (C2-C8)alkyl is optionally substituted with one or more groups independently selected from the group consisting of halo, (C1-C4)alkyl, (C3-C7)carbocyclyl, -OH, and -ORc1; or (b) 4-7 membered monocyclic heterocyclyl-(C1-C3)alkyl-, wherein the 4-7 membered monocyclic heterocyclyl-(C1-C3)alkyl- is substituted with one or more groups independently selected from the groups consisting of -NRa2Rb2, -NRd2C(=NRe2)(NRf2Rg2) and - (C1-C6)alkyl substituted with one or more -NRa3Rb3or -NRd2C(=NRe2)(NRf2Rg2) and wherein the heterocyclyl-(C1-C3)alkyl- or -(C1-C6)alkyl is optionally substituted with one or more groups independently selected from the group consisting of halo, (C1-C4)alkyl, (C3-C7)carbocyclyl, -OH, and -ORc2. In one embodiment R1is: (a) (C2-C8)alkyl, wherein the (C2-C8)alkyl is substituted with one or more -NRa1Rb1, and wherein the (C2-C8)alkyl is optionally substituted with one or more groups independently selected from the group consisting of halo, (C1-C4)alkyl, (C3-C7)carbocyclyl, -OH, and -ORc1; or (b) 4-7 membered monocyclic heterocyclyl-(C1-C3)alkyl-, wherein the 4-7 membered monocyclic heterocyclyl-(C1-C3)alkyl- is substituted with one or more groups independently selected from the groups consisting of -NRa2Rb2and -(C1-C6)alkyl substituted with one or more -NRa3Rb3, and wherein the heterocyclyl-(C1-C3)alkyl- or -(C1-C6)alkyl is optionally substituted with one or more groups independently selected from the group consisting of halo, (C1-C4)alkyl, (C3-C7)carbocyclyl, -OH, and -ORc2. In one embodiment R1is: (a) (C2-C8)alkyl, wherein the (C2-C8)alkyl is substituted independently with two or more -NRa1Rb1or -NRd1C(=NRe1)(NRf1Rg1) and wherein the (C2-C8)alkyl is optionally substituted with one or more groups independently selected from the group consisting of halo, (C1-C4)alkyl, (C3-C7)carbocyclyl, -OH, and -ORc1; or (b) 4-7 membered monocyclic heterocyclyl-(C1-C3)alkyl-, wherein the 4-7 membered monocyclic heterocyclyl-(C1-C3)alkyl- is substituted with one or more groups independently selected from the groups consisting of -NRa2Rb2, -NRd2C(=NRe2)(NRf2Rg2) and - (C1-C6)alkyl substituted with one or more -NRa3Rb3or -NRd2C(=NRe2)(NRf2Rg2), and wherein the heterocyclyl-(C1-C3)alkyl- or -(C1-C6)alkyl is optionally substituted with one or more groups independently selected from the group consisting of halo, (C1-C4)alkyl, (C3-C7)carbocyclyl, -OH, and -ORc2. In one embodiment R1is: (a) (C2-C8)alkyl, wherein the (C2-C8)alkyl is substituted with two or more -NRa1Rb1, and wherein the (C2-C8)alkyl is optionally substituted with one or more groups independently selected from the group consisting of halo, (C1-C4)alkyl, (C3-C7)carbocyclyl, -OH, and -ORc1; or (b) 4-7 membered monocyclic heterocyclyl-(C1-C3)alkyl-, wherein the 4-7 membered monocyclic heterocyclyl-(C1-C3)alkyl- is substituted with one or more groups independently selected from the groups consisting of -NRa2Rb2and -(C1-C6)alkyl substituted with one or more -NRa3Rb3, and wherein the heterocyclyl-(C1-C3)alkyl- or -(C1-C6)alkyl is optionally substituted with one or more groups independently selected from the group consisting of halo, (C1-C4)alkyl, (C3-C7)carbocyclyl, -OH, and -ORc2. In one embodiment R1is: (a) (C2-C8)alkyl, wherein the (C2-C8)alkyl is substituted independently with two or more -NRa1Rb1or -NRd1C(=NRe1)(NRf1Rg1) and wherein the (C2-C8)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-(C1-C3)alkyl-, wherein the 4-7 membered monocyclic heterocyclyl-(C1-C3)alkyl- is substituted with one or more -(C1-C6)alkyl substituted with one or more -NRa3Rb3or -NRd2C(=NRe2)(NRf2Rg2), and wherein the heterocyclyl-(C1-C3)alkyl- is optionally substituted with one or more -OH. In one embodiment R1is: (a) (C2-C8)alkyl, wherein the (C2-C8)alkyl is substituted with two or more -NRa1Rb1, and wherein the (C2-C8)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-(C1-C3)alkyl-, wherein the 4-7 membered monocyclic heterocyclyl-(C1-C3)alkyl- is substituted with one or more -(C1-C6)alkyl substituted with one or more -NRa3Rb3, and wherein the heterocyclyl-(C1-C3)alkyl- is optionally substituted with one or more -OH. In one embodiment R1is (C2-C8)alkyl, wherein the (C2-C8)alkyl is substituted independently with one or more -NRa1Rb1or -NRd1C(=NRe1)(NRf1Rg1), and wherein the (C2- C8)alkyl is optionally substituted with one or more groups independently selected from the group consisting of halo, (C1-C4)alkyl, (C3-C7)carbocyclyl, -OH, and -ORc1. In one embodiment R1is (C2-C8)alkyl, wherein the (C2-C8)alkyl is substituted with one or more -NRa1Rb1, and wherein the (C2-C8)alkyl is optionally substituted with one or more groups independently selected from the group consisting of halo, (C1-C4)alkyl, (C3- C7)carbocyclyl -OH and -ORc1 In one embodiment R1is (C2-C8)alkyl, wherein the (C2-C8)alkyl is substituted independently with two or more -NRa1Rb1or -NRd1C(=NRe1)(NRf1Rg1), and wherein the (C2- C8)alkyl is optionally substituted with one or more groups independently selected from the group consisting of halo, (C1-C4)alkyl, (C3-C7)carbocyclyl, -OH, and -ORc1. In one embodiment R1is (C2-C8)alkyl, wherein the (C2-C8)alkyl is substituted with two or more -NRa1Rb1, and wherein the (C2-C8)alkyl is optionally substituted with one or more groups independently selected from the group consisting of halo, (C1-C4)alkyl, (C3- C7)carbocyclyl, -OH, and -ORc1. In one embodiment R1is (C2-C8)alkyl, wherein the (C2-C8)alkyl is substituted independently with two or more -NRa1Rb1or -NRd1C(=NRe1)(NRf1Rg1), and wherein the (C2- C8)alkyl is optionally substituted with one or more groups independently selected from the group consisting of halo and -OH. In one embodiment R1is (C2-C8)alkyl, wherein the (C2-C8)alkyl is substituted with two or more -NRa1Rb1, and wherein the (C2-C8)alkyl is optionally substituted with one or more groups independently selected from the group consisting of halo and -OH. In one embodiment R1is 4-7 membered monocyclic heterocyclyl-(C1-C3)alkyl-, wherein the 4-7 membered monocyclic heterocyclyl-(C1-C3)alkyl- is substituted with one or more groups independently selected from the groups consisting of -NRa2Rb2, -NRd2C(=NRe2)(NRf2Rg2) and - (C1-C6)alkyl substituted with one or more -NRa3Rb3or -NRd2C(=NRe2)(NRf2Rg2), and wherein the heterocyclyl-(C1-C3)alkyl- or -(C1-C6)alkyl is optionally substituted with one or more groups independently selected from the group consisting of halo, (C1-C4)alkyl, (C3-C7)carbocyclyl, -OH, and -ORc2. In one embodiment R1is 4-7 membered monocyclic heterocyclyl-(C1-C3)alkyl-, wherein the 4-7 membered monocyclic heterocyclyl-(C1-C3)alkyl- is substituted with one or more groups independently selected from the groups consisting of -NRa2Rb2and -(C1-C6)alkyl substituted with one or more -NRa3Rb3, and wherein the heterocyclyl-(C1-C3)alkyl- or -(C1-C6)alkyl is optionally substituted with one or more groups independently selected from the group consisting of halo, (C1-C4)alkyl, (C3-C7)carbocyclyl, -OH, and -ORc2. In one embodiment R1is 4-7 membered monocyclic heterocyclyl-(C1-C3)alkyl-, wherein the 4-7 membered monocyclic heterocyclyl-(C1-C3)alkyl- is substituted with one or more -(C1- C6)alkyl substituted with one or more -NRa3Rb3or -NRd1C(=NRe1)(NRf1Rg1), and wherein the heterocyclyl-(C1-C3)alkyl- is optionally substituted with one or more -OH. In one embodiment R1is 4-7 membered monocyclic heterocyclyl-(C1-C3)alkyl-, wherein the 4-7 membered monocyclic heterocyclyl-(C1-C3)alkyl- is substituted with one or more -(C1- C6)alkyl substituted with one or more -NRa3Rb3, and wherein the heterocyclyl-(C1-C3)alkyl- is optionally substituted with one or more -OH. In one embodiment R1is . In one embodiment R1is . 38. In one embodiment R1is . In one embodiment each Ra1and Rb1is independently hydrogen or (C1-C6)alkyl. In one embodiment each Ra1and Rb1is independently hydrogen. In one embodiment Ra1is hydrogen and Rb1is (C1-C6)alkyl. In one embodiment each -NRa1Rb1is independently -NH2or -NH(C1-C6)alkyl. In one embodiment each -NRa1Rb1is -NH2. In one embodiment each Rc1is independently (C1-C6)alkyl In one embodiment each Ra2and Rb2is independently hydrogen or (C1-C6)alkyl. In one embodiment each Ra2and Rb2is independently hydrogen. In one embodiment each Ra2is hydrogen and each Rb2is (C1-C6)alkyl. In one embodiment each -NRa2Rb2is independently -NH2 or -NH(C1-C6)alkyl. In one embodiment each -NRa2Rb2is -NH2. In one embodiment each Rc2is independently (C1-C6)alkyl In one embodiment each Ra3and Rb3is independently hydrogen or (C1-C6)alkyl. In one embodiment each Ra3and Rb3is independently hydrogen. In one embodiment each Ra3is hydrogen and each Rb3is (C1-C6)alkyl. In one embodiment each -NRa3Rb3is independently -NH2 or -NH(C1-C6)alkyl. In one embodiment each -NRa3Rb3is -NH2. In one embodiment each Rd1is independently hydrogen or (C1-C6)alkyl. In one embodiment each Rd1is hydrogen. In one embodiment each Re1is independently hydrogen or (C1-C6)alkyl. In one embodiment each Re1is hydrogen. In one embodiment each Rf1and Rg1is independently hydrogen or (C1-C6)alkyl. In one embodiment each Rf1and Rg1is hydrogen. In one embodiment each -NRd1C(=NRe1)(NRf1Rg1) is -NHC(=NH)NH2. In one embodiment each Rd2is independently hydrogen or (C1-C6)alkyl. In one embodiment each Rd2is hydrogen. In one embodiment each Re2is independently hydrogen or (C1-C6)alkyl. In one embodiment each Re2is hydrogen. In one embodiment each Rf2and Rg2is independently hydrogen or (C1-C6)alkyl. In one embodiment each Rf2and Rg2is hydrogen. In one embodiment each -NRd1C(=NRe1)(NRf1Rg1) is -NHC(=NH)NH2. One embodiment provides a compound that is: or or a salt thereof. One embodiment provides a compound that is:

[0002] Generally, compounds of formula I as well as synthetic intermediates that can be used for preparing compounds of formula I can be prepared as illustrated in the following general schemes. It is understood that variable groups shown below (e.g., R1, R2, R3, R4, R5, R6. R7, R8R9, R10, R11a, R11b) 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. For example, 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. In one embodiment the bacterial infection being treated is a Gram-negative bacterial strain infection. In one embodiment 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, Campylobacter coli, Campylobacter fetus, Campylobacter jejuni, Caulobacter crescentus, Chlamydia trachomatis, Citrobacter diversus, Citrobacter freundii, Enterobacter aerogenes, Enterobacter asburiae, Enterobacter cloacae, Enterobacter sakazakii, Escherchia coli, Francisella tularensis, Fusobacterium nucleatum, Gardnerella vaginalis, Haemophilus ducreyi, Haemophilus haemolyticus, Haemophilus influenzae, Haemophilus parahaemolyticus, Haemophilus parainfluenzae, Helicobacter pylori, Kingella denitrificans, Kingella indologenes, Kingella kingae, Kingella oralis, Klebsiella oxytoca, Klebsiella pneumoniae, Klebsiella rhinoscleromatis, Legionella pneumophila, Listeria monocytogenes, Moraxella bovis, Moraxella catarrhalis, Moraxella lacunata, Morganella morganii, Neisseria gonorrhoeae, Neisseria meningitidis, Pantoea agglomerans, Pasteurella canis, Pasteurella haemolytica, Pasteurella multocida, Pasteurella tularensis, Porphyromonas gingivalis, Proteus mirabilis, Proteus vulgaris, Providencia alcalifaciens, Providencia rettgeri, Providencia stuartii, Pseudomonas acidovorans, Pseudomonas aeruginosa, Pseudomonas alcaligenes, Pseudomonas fluorescens, Pseudomonas putida, Salmonella enteriditis, Salmonella paratyphi, Salmonella typhi, Salmonella typhimurium, Serratia marcescens, Shigella dysenteriae, Shigella jlexneri, Shigella sonnei, Stenotrophomonas maltophilla, Veillonella parvula, Vibrio cholerae, Vibrio parahaemolyticus, Yersinia enterocolitica, Yersinia intermedia, Yersinia pestis and Yersinia pseudotuberculosis. In one embodiment the bacterial infection being treated is a Gram-positive bacterial strain infection. In one embodiment 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, Staphylococcus saccharolyticus, Staphylococcus saprophyticus, Streptococcus agalactiae, Streptococcus mutans, Streptococcus pneumoniae, Streptococcus pyogenes, Streptococcus salivarius and Streptococcus sanguis. The 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-emetic, an anti-ulcer, a laxative, an anticoagulant, an erythropoietin (for example, epoetin alpha), a filgrastim (for example, G-CSF, Neupogen), a sargramostim (GM- CSF, Leukine), an immunization, an immunoglobulin, an immunosuppressive (for example, basiliximab, cyclosporine, daclizumab), a growth hormone, a hormone replacement drug, an estrogen receptor modulator a mydriatic a cycloplegic an alkylating agent an anti-metabolite a mitotic inhibitor, a radiopharmaceutical, an anti-depressant, an anti-manic agent, an anti- psychotic, an anxiolytic, a hypnotic, a sympathomimetic, a stimulant, donepezil, tacrine, an asthma medication, a beta agonist, an inhaled steroid, a leukotriene inhibitor, a methylxanthine, a cromolyn, an epinephrine or analog thereof, dornase alpha (Pulmozyme), a cytokine, or any combination thereof. In one embodiment 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. It is to be understood that 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. When a bond in a compound formula herein is drawn in a non-stereochemical manner (e.g. flat), the atom to which the bond is attached includes all stereochemical possibilities. When a bond in a compound formula herein is drawn in a defined stereochemical manner (e.g. bold, bold-wedge, dashed or dashed-wedge), it is to be understood that the atom to which the stereochemical bond is attached is enriched in the absolute stereoisomer depicted unless otherwise noted. In one embodiment, 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. In another embodiment, the compound (or composition thereof) may be at least 99% the absolute stereoisomer depicted. It will also be appreciated by those skilled in the art that certain compounds of the invention can exist in more than one tautomeric form. For example, a substituent of formula -NH-C(=O)H in a compound of formula (I) could exist in tautomeric form as –N=C(OH)H. 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 In cases where compounds are sufficiently basic or acidic, a salt of a compound of formula I can be useful as an intermediate for isolating or purifying a compound of formula I. Additionally, 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, α-ketoglutarate, and α-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-, CH3SO3-, H2PO4-, CF3SO3-, p-CH3C6H4SO3-, citrate, tartrate, phosphate, malate, fumarate, formate, or acetate. It will be appreciated by those skilled in the art that 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. For oral administration, the compounds can be formulated as a solid dosage form with or without an enteric coating. Thus, 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. For oral therapeutic administration, 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. Such 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. When the unit dosage form is a capsule, it may contain, in addition to materials of the above type, a liquid carrier, such as a vegetable oil or a polyethylene glycol. Various other materials may be present as coatings or to otherwise modify the physical form of the solid unit dosage form. For instance, tablets, pills, or capsules may be coated with gelatin, wax, shellac or sugar and the like. A syrup or elixir may contain the active compound, sucrose or fructose as a sweetening agent, methyl and propylparabens as preservatives, a dye and flavoring such as cherry or orange flavor. Of course, any material used in preparing any unit dosage form should be pharmaceutically acceptable and substantially non-toxic in the amounts employed. In addition, 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. The proper fluidity 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. In many cases, it will be preferable to include 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. In the case of sterile powders for the preparation of sterile injectable solutions, 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. For topical administration, 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. 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. No.4,938,949. 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. In one embodiment, 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 (e.g., antibacterial 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. Table 1 nd at line34x) 8x) 4x) 56x) 4x) x)48x) 56x) 4x) 4x) x) x) 8x) x) 56x) x) ) x) x) x) against Pseudomonas aeruginosa ATCC 27853. 2These data were generated using Ceftazidime as the antibiotic and the various EPIs against Pseudomonas aeruginosa ATCC 27853. 3These data were generated using Doxycycline as the antibiotic and the various EPIs inst Pseudomonas aeruginosa ATCC 27853. 4The concentration of compound was 4 µg / mL. NA: Not available. The invention will now be illustrated by the following non-limiting examples. Preparation of Amine Intermediates A to H Table 2 shows amine intermediates that were used to prepare compounds described ein. Table 2 Intermediates A, C and D can be prepared according to the methods described in WO2018 / 165611 and WO2021 / 243273 both of which are herein incorporated by reference. Schemes 1 and 2 show the general synthetic routes for the preparation of amine intermediates B, E-H. Scheme 1. General method for the preparation of amine intermediate B Scheme 2. General method for the preparation of amine intermediates E-H Preparation of amine intermediate B (di-tert-butyl ((4R)-5-amino-2-fluoropentane-1,4- diyl)dicarbamate) di-tert-butyl ((4R)-5-amino-2-fluoropentane-1,4-diyl)dicarbamate To a solution of di-tert-butyl ((4R)-5-(1,3-dioxoisoindolin-2-yl)-2-fluoropentane-1,4- diyl)dicarbamate (2.51 g, 5.40 mmol) in MeOH (50 mL) was added hydrazine monohydrate (0.84 mL, 10.8 mmol). The mixture was stirred at room temperature and the formed precipitate was filtered off and washed with CH2Cl2. The filtrate was concentrated and diluted with CH2Cl2, washed with saturated NaHCO3, brine and dried over Na2SO4. The organic solution was filtered and concentrated to give a crude product. The crude product was purified on silica gel column chromatography. Elution with EtOAc then 10% MeOH / CH2Cl2with 1% NH3.H2O afforded the product (1.32g, 54% yield) as a colorless gum.1H NMR (300 MHz, CDCl3) δ 4.54 - 4.94 (m, 3H), 3.74 (br s, 1H), 3.33 - 3.54 (m, 1H), 3.14 - 3.30 (m, 1H), 2.76 (m, 3H), 1.66 - 1.86 (m, 2H), 1.44 (s, 18H). The requisite intermediates were prepared as shown in the following steps. Step 1) tert-butyl (R,Z)-4-(3-ethoxy-2-fluoro-3-oxoprop-1-en-1-yl)-2,2-dimethyloxazolidine-3- carboxylate To a solution of ethyl 2-(diethoxyphosphoryl)-2-fluoroacetate (5.81 g, 24.0 mmol) in dry THF (50 mL) at -78 °C under N2was added LiHMDS (1.3 M in hexanes, 18.5 mL, 24.0 mmol) dropwise over 15 min. The reaction mixture was stirred at -78 °C for 1 h. A solution of tert- butyl (S)-4-formyl-2,2-dimethyloxazolidine-3-carboxylate (5.0 g, 21.8 mmol) in THF (10 mL) was added dropwise over 10 min. The reaction mixture was stirred at -78 °C for 1 h then quenched by addition of saturated NH4Cl. The resulting mixture was stirred at room temperature for 30 min, diluted with EtOAc. The organic solution was washed with brine, dried over Na2SO4, filtered and concentrated to give a crude product (7.65 g, ~90% purity) as a light- yellow liquid in quantitative yield. The crude product was used in next step without further purification.1H NMR (300 MHz, CDCl3) δ 5,88 - 6.00 (m, 1H), 5.27 (m, 1H), 4,30 (q, J = 6.9 Hz, 2H), 4.20 (m, 1H), 3.80 (dd, J = 2.4, 9.3 Hz, 1H), 1.39 - 1.63 (m, 15 H), 1.35 (t, J = 7.5 Hz, 3H). Step 2) tert-butyl (4R)-4-(3-ethoxy-2-fluoro-3-oxopropyl)-2,2-dimethyloxazolidine-3- carboxylate To a solution 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) in MeOH (100 mL) was added Pd / C (10% loading, 1.0 g). The reaction mixture was hydrogenated under hydrogen (55 psi) at room temperature overnight. The solid was removed by passing through a Celite plug. The Celite was washed with MeOH. The filtrate was concentrated to afford a residue. The residue was diluted with EtOAc and washed with H2O, saturated NaHCO3, and brine. The organic solution was dried over Na2SO4, filtered and concentrated to give a crude product. (7.4 g, ~90% purity) as a colorless oil in 96% yield.1H NMR (300 MHz, CDCl3) δ 4.85 - 5.15 (m, 1H), 4,26 (q, J = 6.9 Hz, 2H), 3.78 - 4.13 (m, 3H), 1.99 - 2.47 (m, 2H), 1.45 - 1.61 (m, 15H), 1.31 (t, J = 7.5 Hz, 3H). Step 3) tert-butyl (4R)-4-(2-fluoro-3-hydroxypropyl)-2,2-dimethyloxazolidine-3-carboxylate To a solution of tert-butyl (4R)-4-(3-ethoxy-2-fluoro-3-oxopropyl)-2,2- dimethyloxazolidine-3-carboxylate (7.4 g, ~90% purity, 21.0 mmol) in THF (100 mL) at room temperature was added LiBH4 (1.40 g, 63.0 mmol). The reaction mixture was stirred at room temperature overnight then quenched by the addition of acetone in portions and the resulting mixture was concentrated to give a residue. The residue was diluted with EtOAc and washed with H2O, saturated NaHCO3, and brine. The organic solution was dried over Na2SO4, filtered, and concentrated to give the crude product. The crude product was purified on silica gel and elution with 50% EtOAc / Hexanes to afford the desired product (6.08 g) in quantitative yield.1H NMR (300 MHz, CDCl3) δ 4.59 - 4.77 (m, 1H), 3.62 - 4.03 (m, 5H), 1.83 - 2.23 (m, 2H), 1.41 - 1.62 (m, 15H). Step 4) tert-butyl (4R)-4-(3-(1,3-dioxoisoindolin-2-yl)-2-fluoropropyl)-2,2-dimethyloxazolidine-3- carboxylate To a solution of tert-butyl (4R)-4-(2-fluoro-3-hydroxypropyl)-2,2-dimethyloxazolidine- 3-carboxylate (6.08 g, 21.9 mmol), triphenylphosphine (6.33 g, 24.1 mmol) and phthalimide (3.55 g, 24.1 mmol) in THF (100 mL) was added DIAD (4.88 mL, 24.1 mmol) at 0 °C. The reaction mixture was stirred at 0 °C then room temperature overnight. The reaction mixture was concentrated and purified on column chromatography on silica gel using 5-20% EtOAc / hexanes to afford the desired product (7.5 g, 84% yield) as a white solid.1H NMR (300 MHz, CDCl3) δ 7.86 (m, 2H), 7.74 (m, 2H), 4.70 - 5.00 (m, 1H), 3.70 - 4.13 (m, 5H), 1.82 - 2.23 (m, 2H), 1.42 - 1.58 (m, 15H). Step 5) tert-butyl (4R)-4-(3-amino-2-fluoropropyl)-2,2-dimethyloxazolidine-3-carboxylate To a solution of tert-butyl (4R)-4-(3-(1,3-dioxoisoindolin-2-yl)-2-fluoropropyl)-2,2- dimethyloxazolidine-3-carboxylate (7.5 g, 18.5 mmol) in MeOH (100 mL) was added hydrazine monohydrate (2.90 mL, 37.0 mmol). The mixture was stirred at room temperature overnight and the formed precipitate was filtered off and washed with CH2Cl2. The filtrate was concentrated and triturated with CH2Cl2. The solid was removed by filtration. The filtrate was washed with saturated NaHCO3, brine and dried over Na2SO4, filtered, then concentrated to give a crude product. (5.4 g, -93% purity) as a colorless gum in quantitative yield.1H NMR (300 MHz, CDCl3) δ 4.47 - 4.63 (m, 1H), 3.80 - 4.09 (m, 3H), 2.79 - 2.92 (m, 2H), 1.75 - 2.15 (m, 2H), 1.45 - 1.60 (m, 15H). Step 6) di-tert-butyl ((4R)-2-fluoro-5-hydroxypentane-1,4-diyl)dicarbamate To a solution of tert-butyl (4R)-4-(3-amino-2-fluoropropyl)-2,2-dimethyloxazolidine-3- carboxylate (5.40 g, ~93% purity, 18.2 mmol) in MeOH (100 mL) was added 4 N HCl solution in dioxane (18.2 mL, 72.8 mmol). The reaction mixture was stirred at 50 °C for 1 h then concentrated to give a residue. The residue was dissolved in MeOH / CH2Cl2(10 mL / 100 mL) then added TEA (11.0 mL, 72.8 mmol), (Boc)2O (9.92 g, 45.5 mmol), stirred at room temperature for 3 h, then concentrated to afford a residue. The residue was diluted with EtOAc and washed with H2O, saturated NaHCO3, and brine. The organic solution was dried over Na2SO4, filtered, and concentrated to give a crude product. The crude product was purified by column chromatography on silica gel using 50%EtOAc / Hexanes to afford the desired product (4.46 g, 73% yield) as a white solid.1H NMR (300 MHz, CDCl3) δ 4.56 – 5.01 (m, 2H), 3.86 (m, 1H), 3.68 (m, 2H), 3.35 - 3.56 (m, 1H), 3.14 - 3.31 (m, 1H), 2.39 (br s, 1H), 1.64 - 1.88 (m, 2H), 1.44 (s, 18H). Step 7) di-tert-butyl ((4R)-5-(1,3-dioxoisoindolin-2-yl)-2-fluoropentane-1,4-diyl)dicarbamate To a solution of 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) and 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 0 °C then room temperature overnight. The reaction mixture was concentrated and purified on column chromatography on silica gel using 5-20% EtOAc / hexanes to give the desired product (2.51 g, 85% yield) as a white solid.1H NMR (300 MHz, CDCl3) δ 7.84 (m, 2H), 7.70 (m, 2H), 4.78 - 4.94 (m, 2H), 4.65 (m, 1 H), 4.21(br s, 1H), 3.75 (m, 2H), 3.16 – 3.53 (m, 2H), 1.83 - 1.98 (m, 1H), 1.52 - 1.77 (m, 1H), 1.43 (s, 9H), 1.23 (s, 9H). Preparation of Intermediate E (di-tert-butyl ((2S,4S)-5-amino-2-fluoropentane-1,4- diyl)dicarbamate) (di-tert-butyl ((2S,4S)-5-amino-2-fluoropentane-1,4-diyl)dicarbamate) To a solution of the phthalimide derivative di-tert-butyl ((2S,4S)-5-(1,3-dioxoisoindolin- 2-yl)-2-fluoropentane-1,4-diyl)dicarbamate (150 mg, 0.32 mmol) in EtOH (20 mL) was added hydrazine hydrate (50 µL, 1.0 mmol). 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.1HNMR (300 MHz, MeOD-d4) δ 4.58 (dm, J = 50.2 Hz, CHF, 1H), 3.72 (m, 1H), 3.26-3.12 (m, 2H), 2.77-2.59 (m, 2H), 1.82-1.65 (m, 2H), 1.45 (m, 18H).13CNMR (75 MHz, MeOD-d4) δ 158.5, 91.4 (d, J = 170.0 Hz), 80.5, 50.7, 47.045.8 (d, J = 20.8 Hz), 36.6 (d, J = 19.4 Hz), 28.9.19FNMR (282 MHz, MeOD-d4) δ -186.3. MS m / z calculated for C15H31FN3O4 [M+H] 336.23 found 336.00. The requisite intermediates are prepared as follows: Step 1) tert-butyl (S)-2,2-dimethyl-4-(3-oxopropyl)oxazolidine-3-carboxylate To a flask containing tert-butyl (S)-4-(3-hydroxypropyl)-2,2-dimethyloxazolidine-3- carboxylate (2.6 g, 10 mmol) in DCM (10 mL) was added TEMPO (150 mg, 1.0 mmol) followed by iodobenzene diacetate (3.6 g, 11.0 mmol). The 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 Na2S2O3(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 NaHCO3(100 mL), and brine (100 mL), dried over Na2SO4, filtered and concentrated under vacuum. The crude material was purified by silica gel chromatography (10-30% EtOAc / Hexanes to provide the titled compound as viscous liquid which was identical to the compound that is reported in literature. Both enantiomers showed mixture of rotamers in the NMR spectra, the listed values represent the major rotamer which shows the highest intensity. The final product was collected as a clear viscous liquid in 73% yield.1HNMR (300 MHz, CDCl3) δ 9.74 (m, 1H), 3.93-3.83 (m, 2H), 3.66 (d, J = 8.0 Hz, 1H), 2.45 (t, J = 7.6 Hz, 1H), 1.98-1.83 (m, 2H), 1.52 (s, 3H), 1.43 (m, 13H). Step 2) tert-butyl (S)-4-((S)-2-fluoro-3-hydroxypropyl)-2,2-dimethyloxazolidine-3 carboxylate A 100 mL round-bottomed flask equipped with a magnetic stir bar was charged with 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), and methyl t-Butyl ether, MTBE (10.0 mL). The resulting mixture was stirred at rt for 15 min; then the mixture was treated with N- fluorobenzenesulfonimide, NFSI (3150 mg, 10.0 mmol) to give a thick slurry, which was stirred at rt for another 16 hours. The reaction mixture was cooled to -78 °C, diluted with diethyl ether (50 mL), and filtered over a short pad of silica with the aid of the vacuum. The silica was washed twice with -78 °C cold diethyl ether (10 mL). The filtrate was concentrated under vacuum at 0 °C, and the resulting residue was dissolved in MeOH (50 mL) and cooled down to 0 °C. The reaction mixture was then treated with NaBH4(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 NaHCO3(100 mL) and brine (100 mL), dried over anhydrous Na2SO4, filtered, and concentrated under vacuum at rt. The crude material was loaded on a RediSep® silica cartridge and purified on an ISCO Flash Chromatography system from Teledyne Labs® using gradient elution of EtOAc / Hexanes; Rf = 0.42 (40% EtOAc / Hexanes). After evaporation of the desired fractions, the material was collected as a clear, thick oil with a 72% yield. The NMR analysis showed that the compound is a mixture of rotamers; the NMR values are listed for the major rotamer.1HNMR (300 MHz, CDCl3) Major rotamer δ 4.66 (dm, J = 50.7 Hz, CHF, 1H), 3.97- 3.94 (m, 2H), 3.85 (m, 1H), 3.77-3.62 (m, 2H), 1.97 (m, 3H), 1.6 (s, 3H), 1.45 (m, 12H). MS m / z calculated for C13H25FNO4[M+H] 278.18 found 278.00. Step 3) tert-butyl (S)-4-((S)-3-(1,3-dioxoisoindolin-2-yl)-2-fluoropropyl)-2,2 dimethyloxazolidine-3- carboxylate To a solution of the tert-butyl (S)-4-((S)-2-fluoro-3-hydroxypropyl)-2,2- dimethyloxazolidine-3 carboxylate (600 mg, 2.16 mmol) in dry THF (10 mL) was added triphenylphosphine (787 mg, 3.0 mmol) and phthalimide (440 mg, 3.0 mmol). The reaction mixture was cooled down to 0 °C using an ice bath. After 15 min, a solution of DIAD (607 mg, 3.0 mmol) in anhydrous THF (5 mL) was introduced dropwise to the reaction mixture in 30 min. Upon complete addition of the DIAD solution, the reaction mixture was left to warm up to rt and stirred for two hours. The reaction progress was monitored by TLC or LCMS; when the reaction came to completion, the reaction mixture was treated with MeOH (5.0 mL), and the volatiles were removed under vacuum; the crude mixture was then treated with 70% aqueous isopropyl alcohol (25 mL) and heated until all solids were dissolved completely to give a clear solution; the reaction mixture was left to cool down gradually to rt. When the copious-thick white precipitate started forming, it was cooled further utilizing an ice bath; then, the solid was filtered off and washed twice with ice-cold 70% aqueous isopropyl alcohol (10.0 mL); the white solid was dried further inside an oven at 50 °C for 3 hours until reached constant weight. The first crop was collected using this method. The resulting filtrate was concentrated under vacuum; the crude material was dissolved in EtOH (50 mL) and treated with ZnCl2.H2O (6.0 mmol) to precipitate the Ph3PO side product. The reaction mixture was stirred at rt for 16 h; then the resulting solid was filtered and discarded; the filtrate was concentrated again and loaded to a pre-backed RediSep column and purified using flash chromatography on an ISCO machine using gradient elution of EtOAc / Hexane. The final product was collected as a white solid with a 62% yield (1stcrop). a sample of the compound was dissolved in deuterated CDCl3and analyzed by NMR; the analysis showed that the compound is a mixture of rotamers. The spectroscopic values are listed for the dominant rotamer.1HNMR (300 MHz, CDCl3) Major rotamer δ 7.85 (m, 2H), 7.72(m, 2H), 4.87 (dm, J = 52.11 Hz, CHF, 1H), 4.07-3.70 (m, 5H), 2.25-1.90 (m, 2H), 1.51 (m, 3H), 1.44 (m, 12H). MS m / z calculated for C21H28FN2O5 [M+H] 407.20 found 407.00. Step 4) di-tert-butyl ((2S,4S)-2-fluoro-5-hydroxypentane-1,4-diyl) dicarbamate To a solution of tert-butyl (S)-4-((S)-3-(1,3-dioxoisoindolin-2-yl)-2-fluoropropyl)-2,2 dimethyloxazolidine-3-carboxylate (1.0 mmol) in EtOH (20 mL) was added hydrazine hydrate (3.0 mmol). 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 Et3N. 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 Na2SO4, 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. A sample of the compound was dissolved in CDCl3and analyzed by NMR; the analysis showed that the compound is one pure diastereomer. The spectroscopic values are listed for the titled compound.1HNMR (300 MHz, CDCl3) δ 4.98 (m, 2H), 4.65 (dm, J = 49.7 Hz, CHF, 1H), 3.62 (m, 2H), 3.39 (m, 1H), 3.18 (m, 1H), 2.70 (m, 1H), 1.88-1.61 (m, 2H), 1.40 (m, 18H). MS m / z calculated for C15H30FN2O5[M+H] 337.21 found 337.00. Step 5) di-tert-butyl ((2S,4S)-5-(1,3-dioxoisoindolin-2-yl)-2-fluoropentane-1,4-diyl)dicarbamate To a solution of di-tert-butyl ((2S,4S)-2-fluoro-5-hydroxypentane-1,4-diyl) dicarbamate (793 mg, 2.36 mmol) in dry THF (10 mL) was added triphenylphosphine (787 mg, 3.0 mmol) and phthalimide (440 mg, 3.0 mmol). The reaction mixture was cooled down to 0 °C using an ice bath. After 15 min, a solution of DIAD (607 mg, 3.0 mmol) in anhydrous THF (5 mL) was introduced dropwise to the reaction mixture over 30 min. Upon complete addition of the DIAD solution, the reaction mixture was left to warm up to rt and stirred for 2 hours. The reaction progress was monitored by TLC or LCMS; when the reaction came to completion, the reaction mixture was treated with MeOH (5.0 mL), and the volatiles were removed under vacuum; the crude mixture was then treated with 70% aqueous isopropyl alcohol (25 mL) and heated until all solids dissolved completely to give a clear solution; the reaction mixture was left to cool down gradually to rt. When the copious-thick white precipitate started forming, it was cooled further utilizing an ice bath; then, the solid was filtered off and washed twice with ice-cold 70% aqueous isopropyl alcohol (10.0 mL); the white solid was dried further inside an oven at 50 °C for 3 hours until reached constant weight. The first crop was collected in excellent purity using this method, yielding 50-59%. The resulting filtrate was concentrated under vacuum and the crude material was dissolved in EtOH (50 mL) and treated with ZnCl2.H2O (6.0 mmol) to precipitate the Ph3PO side product. The reaction mixture was stirred at rt for 16 h; then the resulting solid was filtered and discarded; the filtrate was concentrated again and loaded to a pre-backed RediSep column and purified using flash chromatography on an ISCO machine using gradient elution of EtOAc / Hexane. The final product was collected as a white solid with a 79% yield. A sample of the compound was dissolved in deuterated chloroform, CDCl3and analyzed by NMR; the analysis showed that the compound is one pure diastereomer. The spectroscopic values are listed for the titled compound.1HNMR (300 MHz, CDCl3) δ 7.78 (m, 2H), 7.65 (m, 2H), 4.95 (m, 2H), 4.69 (dm, J = 49.7 Hz, CHF, 1H), 4.16 (m, 1H), 3.70 (m, 2H), 3.40-3.14 (m, 2H), 1.86-1.66 (m, 2H), 1.37 (s, 9H), 1.17 (s, 9H). MS m / z calculated for C23H33FN3O6 [M+H] 466.24 found 466.00. Preparation of intermediate F (di-tert-butyl ((2R,4S)-5-amino-2-fluoropentane-1,4- diyl)dicarbamate) di-tert-butyl ((2R,4S)-5-amino-2-fluoropentane-1,4-diyl)dicarbamate To a solution of the phthalimide derivative di-tert-butyl ((2R,4S)-5-(1,3-dioxoisoindolin- 2-yl)-2-fluoropentane-1,4-diyl)dicarbamate (230 mg, 0.5 mmol) in EtOH (20 mL)) was added hydrazine hydrate (80%) (63 µL, 1.0 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.1HNMR (300 MHz, MeOD-d4) δ 4.59 (dm, J = 50.0 Hz, CHF, 1H), 3.68 (m, 1H), 3.27 (m, 2H), 2.68 (ddd, J = 4.4, 13.0, 22.8 Hz, 2H), 1.82-1.64 (m, 2H), 1.43 (m, 18H).13CNMR (75 MHz, MeOD-d4) δ 158.6, 158.3, 92.0 (d, J = 169.5 Hz), 80.3, 51.3, 46.1, 45.2 (d, J = 23.2 Hz), 36.3 (d, J = 20.7 Hz), 28.9.19FNMR (282 MHz, MeOD-d4) δ -186.3. MS m / z calculated for C15H31FN3O4[M+H] 336.23 found 336.00. The requisite intermediates are prepared as follows: Step 1) tert-butyl (S)-4-((R)-2-fluoro-3-hydroxypropyl)-2,2-dimethyloxazolidine-3-carboxylate The compound was synthesized using the general fluorination protocol described above for the synthesis of intermediate E using R-Jorgensen catalyst. The crude material was loaded on a RediSep® silica cartridge and purified on an ISCO Flash Chromatography system from Teledyne Labs® using gradient elution of EtOAc / Hexanes; Rf= 0.55 (40% EtOAc / Hexanes). After evaporation of the desired fractions, the material was collected as a clear, thick oil with a 79% yield. The NMR analysis showed that the compound is a mixture of rotamers; the NMR values are listed for the major rotamer.1HNMR (300 MHz, CDCl3) Major rotamer δ 4.62 (dm, J = 49.11 Hz, CHF, 1H), 4.12-3.93 (m, 2H), 3.79-3.63 (m, 3H), 2.19-1.76 (m, 2H), 1.51 (m, 3H), 1.43 (m, 12H). MS m / z calculated for C13H24FNO4[M+H] 278.18 found 278.00. 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 4.3 mmol scale. The final product was collected as white solid with a 73.4% yield. Rf =0.3 (20% EtOAc / Hexane). A sample of the compound was dissolved in deuterated CDCl3and analyzed by NMR; the analysis showed that the compound is a mixture of rotamers. The spectroscopic values are listed for the dominant rotamer.1HNMR (300 MHz, CDCl3) Major rotamer δ 7.81 (m, 2H), 7.69(m, 2H), 4.81 (dm, J = 49.7 Hz, CHF, 1H), 4.17-3.63 (m, 5H), 2.22-1.73 (m, 2H), 1.53 (m, 3H), 1.42 (m, 12H). MS m / z calculated for C21H28FN2O5[M+H] 407.20 found 407.00 Step 3) di-tert-butyl ((2R,4S)-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 14.7 mmol scale. The final product was collected as clear wax with an 83% yield. A sample of the compound was dissolved in deuterated chloroform, CDCl3and analyzed by NMR; the analysis showed that the compound is one pure diastereomer. The spectroscopic values are listed for the titled compound.1HNMR (300 MHz, CDCl3) δ 5.02 (m, 2H), 4.65 (dm, J = 50.1 Hz, CHF, 1H), 3.78 (m, 1H), 3.63 (m, 2H), 3.46-3.19 (m, 2H), 2.95 (m, 1H), 1.95-1.75 (m, 2H), 1.41 (m, 18H). MS m / z calculated for C15H30FN2O5 [M+H] 337.21 found 337.00. Step 4) di-tert-butyl ((2R,4S)-5-(1,3-dioxoisoindolin-2-yl)-2-fluoropentane-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 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 CDCl3and analyzed by NMR; the analysis showed that the compound is one pure diastereomer. The spectroscopic values are listed for the titled compound.1HNMR (300 MHz, CDCl3) δ 7.83 (m, 2H), 7.69 (m, 2H), 4.91 (m, 2H), 4.74 (dm, J = 48.3 Hz, CHF, 1H), 4.12 (m, 1H), 3.76 (m, 2H), 3.36 (m, 2H), 1.84 (m, 2H), 1.41 (s, 9H), 1.24 (s, 9H). MS m / z calculated for C23H33FN3O6 [M+H] 466.24 found 466.00. Preparation of intermediate G (di-tert-butyl ((2R,4R)-5-amino-2-fluoropentane-1,4- diyl)dicarbamate)

[0003] di-tert-butyl ((2R,4R)-5-amino-2-fluoropentane-1,4-diyl)dicarbamate To a solution of the phthalimide derivative di-tert-butyl ((2R,4R)-5-(1,3-dioxoisoindolin- 2-yl)-2-fluoropentane-1,4-diyl)dicarbamate (230 mg, 0.5 mmol) in EtOH (25 mL)) was added Hydrazine hydrate (100 µL, 2.0 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 71% yield. A sample was dissolved in deuterated MeOH and analyzed by NMR spectroscopy.1HNMR (300 MHz, CD3OD) δ 4.59 (dm, J = 50.3 Hz, CHF, 1H), 3.73 (m, 1H), 3.36-3.16 (m, 2H), 2.66 (dddd, J = 29.2, 14.5, 12.9, 4.7 Hz, 2H), 1.85-1.60 (m, 2H), 1.47 (m, 18H).13CNMR (75 MHz, MeOD-d4) δ 158.5, 91.4 (d, J = 169.4 Hz), 80.5, 80.4, 51.1, 47.2, 45.8 (d, J = 22.1 Hz), 36.7 (d, J = 19.6 Hz), 28.9.19FNMR (376.5 MHz, MeOD-d4) δ -186.3. MS m / z calculated for C15H31FN3O4 [M+H] 336.23 found 336.00. The requisite intermediates are prepared as follows: Step 1) tert-butyl (R)-2,2-dimethyl-4-(3-oxopropyl)oxazolidine-3-carboxylate To a flask containing tert-butyl R-4-(3-hydroxypropyl)-2,2-dimethyloxazolidine-3- carboxylate (2.6 g, 10 mmol) in DCM (10 mL) was added TEMPO (150 mg, 1.0 mmol) followed by iodobenzene diacetate (3.6 g, 11.0 mmol). The 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 Na2S2O3(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 NaHCO3(100 mL), and brine (100 mL), dried over Na2SO4, filtered and concentrated under vacuum. The crude material was purified by silica gel chromatography (10-30% EtOAc / Hexanes to provide the titled compound as viscous liquid which was identical to the compound that is reported in literature. Both enantiomers showed mixture of rotamers in the NMR spectra, the listed values represent the major rotamer which shows the highest intensity. The final product was collected a clear viscous liquid in 72% yield.1HNMR (300 MHz, CDCl3) δ 9.74 (m, 1H), 3.92-3.82 (m, 2H), 3.65 (d, J = 8.0 Hz, 1H), 2.45 (t, J = 7.6 Hz, 1H), 1.97-1.80 (m, 2H), 1.51 (s, 3H), 1.43 (m, 13H). Step 2) tert-butyl (R)-4-((R)-2-fluoro-3-hydroxypropyl)-2,2-dimethyloxazolidine-3-carboxylate The compound was synthesized the general Fluorination / Reduction protocol described above for the synthesis of intermediate E using R-Jorgensen catalyst on 10.0 mmol scale. The crude material was loaded on a RediSep® silica cartridge and purified on an ISCO®Flash Chromatography system from Teledyne Lab using gradient elution of EtOAc / Hexanes; Rf = 0.26 (30% EtOAc / Hexanes). After evaporation of the desired fractions, the material was collected as a clear, thick oil with a 71% yield. The NMR analysis showed that the compound is a mixture of rotamers; the NMR values are listed for the major rotamer.1HNMR (300 MHz, CDCl3) Major rotamer δ 4.60 (dm, J = 48.9 Hz, CHF, 1H), 3.92 (m, 2H), 3.81 (m, 1H), 3.64 (m, 2H), 2.71(bs, 1H), 1.90 (m, 2H), 1.48 (s, 3H), 1.41 (m, 12H). MS m / z calculated for C13H25FNO4[M+H] 278.18 found 278.00. 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 CDCl3and analyzed by NMR spectroscopy; the analysis showed that the compound is a mixture of rotamers. The spectroscopic values are listed for the dominant rotamer.1HNMR (300 MHz, CDCl3) Major rotamer δ 7.81 (m, 2H), 7.69(m, 2H), 4.87 (dm, J = 50.0 Hz, CHF, 1H), 4.00-3.65 (m, 5H), 2.23-1.87 (m, 2H), 1.50 (m, 3H), 1.43 (m, 12H). MS m / z calculated for C21H28FN2O5[M+H] 407.20 found 407.00. 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, CDCl3and analyzed by NMR spectroscopy; the analysis showed that the compound is one pure diastereomer. The spectroscopic values are listed for the titled compound.1HNMR (300 MHz, CDCl3) δ 5.09 (m, 2H), 4.64 (dm, J = 50.3 Hz, CHF, 1H), 3.80 (m, 1H), 3.60 (m, 2H), 3.36 (m, 1H), 3.17 (m, 2H), 1.77-1.60 (m, 2H), 1.39 (m, 18H). MS m / z calculated for C15H30FN2O5[M+H] 337.21 found 337.00. 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, CDCl3and analyzed by NMR spectroscopy; the analysis showed that the compound is one pure diastereomer. The spectroscopic values are listed for the titled compound.1HNMR (300 MHz, CDCl3) δ 7.79 (m, 2H), 7.66 (m, 2H), 4.93 (m, 2H), 4.70 (dm, J = 50.6 Hz, CHF, 1H), 4.16 (m, 1H), 3.72 (m, 2H), 3.41-3.15 (m, 2H), 2.00-1.60 (m, 2H), 1.38 (s, 9H), 1.18 (s, 9H). MS m / z calculated for C23H33FN3O6[M+H] 466.24 found 466.00. Preparation of intermediate H (di-tert-butyl ((2S,4R)-5-amino-2-fluoropentane-1,4- diyl)dicarbamate) di-tert-butyl ((2S,4R)-5-amino-2-fluoropentane-1,4-diyl)dicarbamate To a solution of the phthalimide derivativedi-tert-butyl ((2S,4R)-5-(1,3-dioxoisoindolin-2-yl)-2-fluoropentane-1,4-diyl)dicarbamate (230 mg, 0.5 mmol) in EtOH (20 mL)) was added Hydrazine hydrate (80%) (63 µL, 1.0 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. A sample was dissolved in deuterated MeOH and analyzed by NMR spectroscopy.1HNMR (300 MHz, MeOD-d4) δ 4.62 (dm, J = 49.7 Hz, CHF, 1H), 3.68 (m, 1H), 3.30 (m, 2H), 2.67 (dddd, J = 53.5, 18.0, 13.2, 4.8 Hz, 2H), 1.82-1.67 (m, 2H), 1.46 (m, 18H).13CNMR (75 MHz, MeOD-d4) δ 159.0, 158.7, 92.4 (d, J = 169.4 Hz), 80.7, 52.0, 46.6, 45.6 (d, J = 24.0 Hz), 36.7 (d, J = 20.6 Hz), 29.3.19FNMR (282 MHz, MeOD-d4) δ -186.3. MS m / z calculated for C15H31FN3O4[M+H] 336.23 found 336.00. The requisite intermediates are prepared as follows: Step 1) tert-butyl (R)-4-((S)-2-fluoro-3-hydroxypropyl)-2,2-dimethyloxazolidine-3-carboxylate The titled compound was synthesized and purified using the general fluorination / reduction protocol described above for the synthesis of intermediate E using S- Jorgensen catalyst. The crude material was loaded on a RediSep® silica cartridge and purified on an ISCO®Flash Chromatography system from Teledyne®Labs using gradient elution of EtOAc / Hexanes; Rf = 0.43 (40% EtOAc / Hexanes). After evaporation of the desired fractions, the material was collected as a clear, thick oil with a 70% yield. The NMR analysis showed that the compound is a mixture of rotamers; the NMR values are listed for the major rotamer.1HNMR (300 MHz, CDCl3) Major rotamer δ 4.53 (dm, J = 49.8 Hz, CHF, 1H), 4.06-3.86 (m, 2H), 3.75-3.59 (m, 3H), 2.07-1.59 (m, 2H), 1.46 (m, 3H), 1.38 (m, 12H). MS m / z calculated for C13H24FNO4[M+H] 278.18 found 278.00. 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 CDCl3and analyzed by NMR; the analysis showed that the compound is a mixture of rotamers. The spectroscopic values are listed for the dominant rotamer.1HNMR (300 MHz, CDCl3) Major rotamer δ 7.80 (m, 2H), 7.68 (m, 2H), 4.81 (dm, J = 49.6 Hz, CHF, 1H), 4.17- 3.62 (m, 5H), 2.14-1.72 (m, 2H), 1.54 (m, 3H), 1.42 (m, 12H). MS m / z calculated for C21H28FN2O5[M+H] 407.20 found 407.00. 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 CDCl3and analyzed by NMR; the analysis showed that the compound is one pure diastereomer. The spectroscopic values are listed for the titled compound.1HNMR (300 MHz, CDCl3) δ 5.00 (m, 2H), 4.64 (dm, J = 49.5 Hz, CHF, 1H), 3.78 (m, 1H), 3.62 (m, 2H), 3.40-3.20 (m, 2H), 3.00 (m, 1H), 2.06-1.61 (m, 2H), 1.40 (m, 18H). MS m / z calculated for C15H30FN2O5[M+H] 337.21 found 337.00. Step 4) di-tert-butyl ((2S,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 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 CDCl3and analyzed by NMR; the analysis showed that the compound is one pure diastereomer. The spectroscopic values are listed for the titled compound.1HNMR (300 MHz, CDCl3) δ 7.80 (m, 2H), 7.69 (m, 2H), 4.90 (m, 2H), 4.74 (dm, J = 48.1 Hz, CHF, 1H), 4.12 (m, 1H), 3.75 (m, 2H), 3.34 (m, 2H), 1.83 (m, 2H), 1.40 (s, 9H), 1.23 (s, 9H). MS m / z calculated for C23H33FN3O6 [M+H] 466.24 found 466.00. Example 1. Preparation of (S)-6-(2,5-diaminopentyl)-5,8-dihydrobenzo[5,6]azepino[3,4- b]indol-7(6H)-one hydrochloride salt (S)-6-(2,5-diaminopentyl)-5,8-dihydrobenzo[5,6]azepino[3,4-b]indol-7(6H)-one hydrochloride salt To a solution of di-tert-butyl (5-(7-oxo-7,8-dihydrobenzo[5,6]azepino[3,4-b]indol- 6(5H)-yl)pentane-1,4-diyl)(S)-dicarbamate (50 mg, 0.09 mmol) in MeOH (5 mL) was added HCl (4 M in dioxane, 0.25 mL, 1 mmol). The reaction mixture was stirred at 50 °C for 0.5 h then concentrated to give a residue. The residue was purified on a C18 column chromatography to give the desired product (16 mg, 42% yield) as a white solid.1H NMR (D2O) (300 MHz) δ 8.13 (d, J = 7.5 Hz, 1H), 8.09 (d, J = 7.5 Hz, 1H), 7.64 (m, 3H), 7.49 (m, 2H), 7.35 (t, J = 7.5 Hz, 1H), 4.42 (m, 2H), 3.96 (m, 1H), 3.81 (m, 1H) 3.72 (m, 1H), 2.78-3.01 (m, 2H), 1.75 (m, 2H), 1.61 (m, 2H). MS (EPI): Calcd for C21H25N4O+349.20 [M+H]+, found 349.05 [M+H]+. The requisite intermediates were prepared as follows: Step 1) ethyl-3-(2-formylphenyl)-1H-indole-2-carboxylate The mixture of ethyl 3-bromo-1H-indole-2-carboxylate (0.80 g, 3 mmol) and (2- formylphenyl)boronic acid (0.45 g, 3 mmol) in a mixture of DMF (15 mL) and K2CO3solution (2 M, 3 mL, 6 mmol) was degassed and Pd(dppf)Cl2(100 mg, 0.14 mmol) was added. The reaction mixture was heated at 80 °C overnight, it was extracted with EtOAc and washed with water, brine and dried over Na2SO4, 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.1H NMR (CDCl3) (300 MHz) δ 9.90 (s, 1H), 9.20 (s br, 1H), 8.10 (d, J = 7.8 Hz, 1H), 7.68 (td, J = 7.5, 1.5 Hz, 1H), 7.54 (m, 1H), 7.49 (m, 2H), 7.43 (m, 2H), 7.18 (m, 1H), 4.20 (q, J = 7.2 Hz, 2H), 1.10 (t, J = 7.2 Hz, 3H). MS (EPI): Calcd for C18H16NO3+294.11 [M+H]+, found 293.95 [M+H]+. Step 2) di-tert-butyl (5-(7-oxo-7,8-dihydrobenzo[5,6]azepino[3,4-b]indol-6(5H)-yl)pentane-1,4-diyl)(S)- dicarbamate To a solution of ethyl-3-(2-formylphenyl)-1H-indole-2-carboxylate (100 mg, 0.33 mmol) and di-tert-butyl (5-aminopentane-1,4-diyl)(S)-dicarbamate (100 mg, 0.32 mmol) in DCM (5 mL) and water (0.2 mL)was added NaB(OAc)3H (600 mg, 2.8 mmol). It was heated at 50 °C overnight. The reaction was quenched with water, diluted and extracted with DCM. The combined organic phase was washed with water, brine and dried over anhydrous Na2SO4. It was purified on column chromatography on SiO2to give the product as a white powder (118 mg, 68% yield).1H NMR (CDCl3) (300 MHz) δ 8.07 (d, J = 7.8 Hz, 1H), 8.02 (d, J = 7.8 Hz, 1H), 7.50 (m, 3H), 7.36 (m, 2H), 7.24 (m, 1H), 5.17 (s br, 1H), 4.83 (s br, 1H), 4.39 (m, 1H), 4.29 (m, 1H), 3.99 (m, 1H), 3.77 (m, 1H) 3.66 (m, 1H), 2.79-3.21 (m, 2H), 1.53 (m, 2H), 1.46 (m, 2H), 1.39 (s, 12H). MS (EPI): Calcd for C31H41N4O5+549.31 [M+H]+, found 549.25 [M+H]+. Example 2. Preparation of (S)-6-(2,5-diaminopentyl)-3-fluoro-5,8- dihydrobenzo[5,6]azepino[3,4-b]indol-7(6H)-one hydrochloride salt (S)-6-(2,5-diaminopentyl)-3-fluoro-5,8-dihydrobenzo[5,6]azepino[3,4-b]indol-7(6H)-one hydrochloride salt To a solution of di-tert-butyl (5-(3-fluoro-7-oxo-7,8-dihydrobenzo[5,6]azepino[3,4- b]indol-6(5H)-yl)pentane-1,4-diyl)(S)-dicarbamate (20 mg, 0.035 mmol) in MeOH (5 mL) was added HCl (4 M in dioxane, 0.25 mL, 1 mmol). The reaction mixture was stirred at 50 °C for 0.5 h then concentrated. The residue was purified on a C18 column chromatography to give the desired product (5 mg, 33% yield) as a white solid.1H NMR (D2O) (300 MHz) δ 7.96 (m, 2H), 7.63 (d, J = 8.1 Hz, 1H), 7.48 (t, J = 7.5 Hz, 1H), 7.31 (m, 3H), 4.30 (m, 2H), 3.82 (m, 1H), 3.75 (m, 1H), 3.71 (m, 1H), 2.83-3.02 (m, 2H), 1.78 (m, 2H), 1.67 (m, 2H). MS (EPI): Calcd for C21H24FN4O+367.19 [M+H]+, found 367.05 [M+H]+. The requisite intermediates were prepared as follows: Step 1) ethyl 3-(4-fluoro-2-formylphenyl)-1H-indole-2-carboxylate The mixture of ethyl 3-bromo-1H-indole-2-carboxylate (0.25 g, 1 mmol) and (2-formyl- 4-fluorophenyl)boronic acid (0.27 g, 1.08 mmol) in a mixture of DMF (5 mL) and K2CO3solution (1 M, 2 mL, 2 mmol) was degassed and Pd(dppf)Cl2(100 mg, 0.14 mmol) was added. The reaction mixture was heated at 80 °C overnight, it was extracted with EtOAc and washed with water, brine and dried over Na2SO4, 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.1H NMR (CDCl3) (300 MHz) δ 9.83 (s, 1H), 9.24 (s br, 1H), 7.77 (dd, J = 8.7, 3.0 Hz, 1H), 7.50 (m, 2H), 7.41 (m, 3H), 7.19 (t, J = 7.5 Hz, 1H), 4.22 (q, J = 7.2 Hz, 2H), 1.13 (t, J = 7.2 Hz, 3H). MS (EPI): Calcd for C18H15FNO3+312.10 [M+H]+, found 311.90 [M+H]+. Step 2) di-tert-butyl (5-(3-fluoro-7-oxo-7,8-dihydrobenzo[5,6]azepino[3,4-b]indol-6(5H)-yl)pentane- 1,4-diyl)(S)-dicarbamate To a solution of ethyl 3-(4-fluoro-2-formylphenyl)-1H-indole-2-carboxylate (40 mg, 0.13 mmol) and di-tert-butyl (5-aminopentane-1,4-diyl)(S)-dicarbamate (40 mg, 0.13 mmol) in 1,2-dichloroethane (5 mL) and water (0.5 mL)was added NaB(OAc)3H (800 mg, 3.8 mmol). It was heated at 60 °C overnight. The reaction was quenched with water, diluted and extracted with DCM. The combined organic phase was washed with water, brine and dried over anhydrous Na2SO4. It was purified on column chromatography on SiO2to give the product as a white powder (20 mg, 27% yield).1H NMR (CDCl3) (300 MHz) δ 8.00 (m, 2H), 7.53 (d, J = 8.1 Hz, 1H), 7.38 (m, 1H), 7.27 (m, 2H), 7.11 (m, 1H), 4.43 (m, 1H), 4.23 (m, 1H), 3.96 (m, 1H), 3.84 (m, 1H) 3.60 (m, 1H), 3.23 (m, 1H), 3.09 (m, 1H), 1.65 (m, 2H), 1.44 (m, 2H), 1.37 (s, 12H). MS (EPI): Calcd for C31H40FN4O5+567.30 [M+H]+, found 567.25 [M+H]+. Example 3. Preparation of (S)-6-(2,5-diaminopentyl)-2-fluoro-5,8- dihydrobenzo[5,6]azepino[3,4-b]indol-7(6H)-one hydrochloride salt (S)-6-(2,5-diaminopentyl)-2-fluoro-5,8-dihydrobenzo[5,6]azepino[3,4-b]indol-7(6H)-one hydrochloride salt To a solution of di-tert-butyl (5-(2-fluoro-7-oxo-7,8-dihydrobenzo[5,6]azepino[3,4- b]indol-6(5H)-yl)pentane-1,4-diyl)(S)-dicarbamate (58 mg, 0.1 mmol) in MeOH (5 mL) was added HCl (4 M in dioxane, 0.5 mL, 2 mmol). The reaction mixture was stirred at 50 °C for 0.5 h then concentrated to give a residue. The residue was triturated with EtOAc and dried to give the desired product (24 mg, 55% yield) as an off-white solid. MS (EPI): Calcd for C21H24FN4O+ 367.19 [M+H]+, found 367.05 [M+H]+. The requisite intermediates were prepared as follows: Step 1) ethyl 3-(3-fluoro-2-formylphenyl)-1H-indole-2-carboxylate The mixture of ethyl 3-bromo-1H-indole-2-carboxylate (0.17 g, 1 mmol) and (2-formyl- 3-fluorophenyl)boronic acid (0.27 g, 1.08 mmol) in a mixture of DMF (5 mL) and K2CO3solution (2 M, 1 mL, 2 mmol) was degassed and Pd(dppf)Cl2(100 mg, 0.14 mmol) was added. The reaction mixture was heated at 80 °C overnight, it was extracted with EtOAc and washed with water, brine and dried over Na2SO4, 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.1H NMR (CDCl3) (300 MHz) δ 9.97 (s, 1H), 9.53 (s br, 1H), 7.61 (dd, J = 13.6, 7.8 Hz, 1H), 7.48 (d, J = 8.6 Hz, 1H), 7.39 (dd, J = 13.6, 7.8 Hz, 2H), 7.29 (m, 1H), 7.20 (m, 2H), 4.22 (q, J = 7.2 Hz, 2H), 1.15 (t, J = 7.2 Hz, 3H). MS (EPI): Calcd for C18H15FNO3+312.10 [M+H]+, found 311.90 [M+H]+. Step 2) di-tert-butyl (5-(4-fluoro-7-oxo-7,8-dihydrobenzo[5,6]azepino[3,4-b]indol-6(5H)-yl)pentane- 1,4-diyl)(S)-dicarbamate To a solution of ethyl 3-(3-fluoro-2-formylphenyl)-1H-indole-2-carboxylate (40 mg, 0.13 mmol) and di-tert-butyl (5-aminopentane-1,4-diyl)(S)-dicarbamate (40 mg, 0.13 mmol) in 1,2-dichloroethane (5 mL) and water (0.5 mL)was added NaB(OAc)3H (800 mg, 3.8 mmol). It was heated at 60 °C overnight. The reaction was quenched with water, diluted and extracted with DCM. The combined organic phase was washed with water, brine and dried over anhydrous Na2SO4. It was purified on column chromatography on SiO2to give the product as a white powder (48 mg, 65% yield).1H NMR (CDCl3) (300 MHz) δ 10.47 (s br, 1H), 8.03 (d, J = 8.1 Hz, 1H), 7.77 (d, J = 7.5 Hz, 1H), 7.54 (d, J = 7.5 Hz, 1H), 7.40 (m, 2H), 7.26 (m, 1H), 7.10 (m, 1H), 4.74 (br, 2H), 4.10 (m, 1H), 3.93 (m, 1H), 3.84 (m, 1H) 3.60 (m, 1H), 3.23 (m, 1H), 3.10 (m, 2H), 1.53 (m, 2H), 1.42 (m, 2H), 1.29 (s, 12H). MS (EPI): Calcd for C31H40FN4O5+ 567.30 [M+H]+, found 567.25 [M+H]+. Example 4. Preparation of (S)-6-(2,5-diaminopentyl)-4-chloro-5,8- dihydrobenzo[5,6]azepino[3,4-b]indol-7(6H)-one hydrochloride salt (S)-3-chloro-6-(2,5-diaminopentyl)-5,8-dihydrobenzo[5,6]azepino[3,4-b]indol-7(6H)-one hydrochloride salt To a solution of di-tert-butyl (5-(3-chloro-7-oxo-7,8-dihydrobenzo[5,6]azepino[3,4- b]indol-6(5H)-yl)pentane-1,4-diyl)(S)-dicarbamate (6 mg, 0.01 mmol) in MeOH (2 mL) was added HCl (4 M in dioxane, 0.05 mL, 0.2 mmol). The reaction mixture was stirred at 50 °C for 0.5 h then concentrated to give a residue. The residue was triturated with EtOAc and dried to give the desired product (2 mg, 44% yield) as a brown powder.1H NMR (D2O) (300 MHz) δ 8.09 (d, J = 8.1 Hz, 1H), 8.03 (d, J = 8.1 Hz, 1H), 7.65 (m, 3H), 7.50 (t, J = 7.5 Hz, 1H), 7.34 (t, J = 7.5 Hz, 1H), 4.36 (m, 2H), 3.93 (m, 1H) 3.87-3.64 (m, 2H), 2.91 (m, 2H), 1.61-1.92 (m, 4H). MS (EPI): Calcd for C21H24ClN4O+383.16 [M+H]+, found 383.00 [M+H]+. The requisite intermediates were prepared as follows: Step 1) ethyl 3-(4-chloro-2-formylphenyl)-1H-indole-2-carboxylate The mixture of ethyl 3-bromo-1H-indole-2-carboxylate (0.27 g, 1 mmol) and (2-formyl- 4-chlorophenyl)boronic acid (0.20 g, 1.09 mmol) in a mixture of dioxane (10 mL) and K3PO4solution (1 mol / L, 2 mL, 2 mmol) was degassed and Pd(dppf)Cl2(100 mg, 0.14 mmol) was added. The reaction mixture was heated at 90 °C overnight, it was extracted with EtOAc and washed with water, brine and dried over Na2SO4, 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.1H NMR (CDCl3) (300 MHz) δ 9.83 (s, 1H), 9.33 (s br, 1H), 8.06 (d, J = 2.1 Hz, 1H), 7.64 (dd, J = 8.1, 2.1 Hz, 1H), 7.64 (m, 2H), 7.45 (m, 2H), 7.19 (m, 1H), 4.23 (q, J = 7.2 Hz, 2H), 1.14 (t, J = 7.2 Hz, 3H). MS (EPI): Calcd for C18H15ClNO3+328.07 [M+H]+, found 327.90 [M+H]+. Step 2) di-tert-butyl (5-(3-chloro-7-oxo-7,8-dihydrobenzo[5,6]azepino[3,4-b]indol-6(5H)-yl)pentane- 1,4-diyl)(S)-dicarbamate To a solution of ethyl 3-(4-chloro-2-formylphenyl)-1H-indole-2-carboxylate (100 mg, 0.3 mmol) and 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)3H (200 mg, 3.8 mmol). It was heated at 70 °C overnight. The reaction was quenched with water, diluted and extracted with DCM. The combined organic phase was washed with water, brine and dried over anhydrous Na2SO4. It was purified on column chromatography on SiO2to give the product as a white powder (17 mg, 10% yield).1H NMR (CDCl3) (300 MHz) δ 9.48 (s br, 1H), 8.01 (d, J = 8.1 Hz, 1H), 7.95 (d, J = 8.1 Hz, 1H), 7.49 (m, 3H), 7.40 (m, J = 7.5 Hz, 1H), 7.26 (m, 1H), 4.17-4.43 (m, 2H), 3.97 (m, 1H), 3.83 (m, 1H), 3.51 (m, 1H), 3.11 (m, 2H), 1.62 (m, 2H), 1.42 (m, 2H), 1.40 (s, 12H). MS (EPI): Calcd for C31H40ClN4O5+583.27 [M+H]+, found 583.20 [M+H]+. Example 5. Preparation of (S)-6-(2,5-diaminopentyl)- 11-fluoro-5,8- dihydrobenzo[5,6]azepino[3,4-b]indol-7(6H)-one hydrochloride salt (S)-6-(2,5-diaminopentyl)-11-fluoro-5,8-dihydrobenzo[5,6]azepino[3,4-b]indol-7(6H)-one hydrochloride salt To a solution of 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 (72 mg, 0.13 mmol) in MeOH (5 mL) was added HCl (4 M in dioxane, 0.5 mL, 2 mmol). The reaction mixture was stirred at 50 °C for 1 h then concentrated to give a residue. The residue was triturated with EtOAc and dried to give the desired product (24 mg, 42% yield) as an off-white solid.1H NMR (D2O) (300 MHz) δ 7.63 (m, 1H), 7.47 (m, 2H), 7.42 (m, 3H), 7.12 (m, 1H), 4.12 (m, 2H), 3.94-3.72 (m, 1H) 3.70-3.57 (m, 2H), 2.88 (m, 2H), 1.52-1.91 (m, 4H). MS (EPI): Calcd for C21H24FN4O+367.19 [M+H]+, found 367.00 [M+H]+. The requisite intermediates were prepared as follows: Step 1) ethyl-5-fluoro-3-(2-formylphenyl)-1H-indole-2-carboxylate The mixture of ethyl 3-bromo-5-fluoro-1H-indole-2-carboxylate (0.86 g, 3 mmol) and (2-formylphenyl)boronic acid (0.45 g, 3 mmol) in a mixture of dioxane (20 mL) and K3PO4solution (1 mol / L, 6 mL, 6 mmol) was degassed and Pd(dppf)Cl2(500 mg, 0.7 mmol) was added. The reaction mixture was heated at 80 °C for 3 hours, it was extracted with EtOAc and washed with water, brine and dried over Na2SO4, 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.1H NMR (CDCl3) (300 MHz) δ 9.90 (s, 1H), 9.25 (s br, 1H), 8.09 (d, J = 7.8 Hz, 1H), 7.68 (t, J = 7.5 Hz, 1H), 7.48 (s, 1H), 7.45 (m, 1H), 7.55 (m, 1H), 7.18 (m, 1H), 7.10 (m, 1H), 4.20 (q, J = 7.2 Hz, 2H), 1.09 (t, J = 7.2 Hz, 3H). MS (EPI): Calcd for C18H15FNO3+312.10 [M+H]+, found 311.90 [M+H]+. 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 To a solution of ethyl-5-fluoro-3-(2-formylphenyl)-1H-indole-2-carboxylate (100 mg, 0.3 mmol) and 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)3H (200 mg, 0.9 mmol). It was heated at 70 °C overnight. The reaction was quenched with water, diluted and extracted with DCM. The combined organic phase was washed with water, brine and dried over anhydrous Na2SO4. It was purified on column chromatography on SiO2to give the product as a white powder (72 mg, 42% yield).1H NMR (CDCl3) (300 MHz) δ 9.75 (br, 1H), 7.94 (d, J = 7.2 Hz, 1H), 7.71 (d, J = 9.6 Hz, 1H), 7.51 (m, 3H), 7.38 (m, 1H), 7.15 (m, 1H), 4.39 (m, 1H), 4.14 (m, 1H), 3.98 (m, 1H), 3.77 (m, 1H), 3.62 (m, 1H), 3.04 (m, 2H), 1.82 (m, 2H), 1.47 (m, 2H), 1.39 (s, 12H). MS (EPI): Calcd for C31H40FN4O5+567.30 [M+H]+, found 567.20 [M+H]+. Example 6. Preparation of (S)-3-fluoro-6-(2,5-diaminopentyl)- 11-fluoro-5,8- dihydrobenzo[5,6]azepino[3,4-b]indol-7(6H)-one hydrochloride salt (S)-3-fluoro-6-(2,5-diaminopentyl)-11-fluoro-5,8-dihydrobenzo[5,6]azepino[3,4-b]indol-7(6H)- one hydrochloride salt To a solution of 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 (11 mg, 0.02 mmol) in MeOH (5 mL) was added HCl (4 M in dioxane, 0.25 mL, 1 mmol). The reaction mixture was stirred at 50 °C for 1 h then concentrated to give a residue. The residue was triturated with EtOAc and dried to give the desired product (5 mg, 55% yield) as an off-white solid.1H NMR (D2O) (300 MHz) δ 7.83 (m, 1H), 7.63 (d, J = 11.2 Hz, 1H), 7.57 (d, J = 4.5 Hz, 1H), 7.54 (d, J = 4.5 Hz, 1H), 7.32 (m, 1H), 7.23 (m, 1H), 4.32 (d, J = 9.3 Hz, 2H), 3.86 (m, 1H) 3.71 (m, 2H), 2.91 (m, 2H), 1.61-1.85 (m, 4H). MS (EPI): Calcd for C21H23F2N4O+385.18 [M+H]+, found 384.95 [M+H]+. The requisite intermediates were prepared as follows: Step 1) ethyl-5-fluoro-3-(4-fluoro-2-formylphenyl)-1H-indole-2-carboxylate The mixture of ethyl 3-bromo-5-fluoro-1H-indole-2-carboxylate (0.286 g, 1 mmol) and 2-(5,5-dimethyl-1,3,2-dioxaborinan-2-yl)-5-fluorobenzaldehyde (0.236 g, 1 mmol) in a mixture of dioxane (10 mL) and K3PO4 solution (1 mol / L, 2 mL, 2 mmol) was degassed and Pd(dppf)Cl2(100 mg, 0.14 mmol) was added. The reaction mixture was heated at 90 °C for 3 hours, it was extracted with EtOAc and washed with water, brine and dried over Na2SO4, 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.1H NMR (CDCl3) (300 MHz) δ 9.83 (s, 1H), 9.47 (s br, 1H), 8.09 (d, J = 7.8 Hz, 1H), 7.76 (m, 1H), 7.41 (m, 3H), 7.17 (m, 1H), 7.08 (m, 1H), 4.22 (q, J = 7.2 Hz, 2H), 1.11 (t, J = 7.2 Hz, 3H). MS (EPI): Calcd for C18H14F2NO3+330.09 [M+H]+, found 329.90 [M+H]+. 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 To a solution of ethyl-5-fluoro-3-(4-fluoro-2-formylphenyl)-1H-indole-2-carboxylate (92 mg, 0.3 mmol) and 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)3H (200 mg, 3.8 mmol). It was heated at 70 °C overnight. The reaction was quenched with water, diluted and extracted with DCM. The combined organic phase was washed with water, brine and dried over anhydrous Na2SO4. It was purified on column chromatography on SiO2to give the product as a white powder (24 mg, 15% yield).1H NMR (CDCl3) (300 MHz) δ 11.34 (s br, 1H), 10.48 (s br, 1H), 7.86 (m, 1H), 7.62 (d, J = 9.3 Hz, 1H), 7.42 (m, 1H), 7.20 (m, 2H), 7.11 (td, J = 9.0, 2.1 Hz, 1H), 4.35 (m, 1H), 4.28 (m, 1H), 3.96 (m, 1H), 3.81 (m, 1H), 3.64 (m, 1H), 3.08 (m, 2H), 1.52 (m, 2H), 1.40 (m, 2H), 1.36 (s, 12H). MS (EPI): Calcd for C31H29F2N4O5+585.29 [M+H]+, found 585.20 [M+H]+. Example 7. Preparation of (S)-3-chloro-6-(2,5-diaminopentyl)- 11-fluoro-5,8- dihydrobenzo[5,6]azepino[3,4-b]indol-7(6H)-one hydrochloride salt (S)-3-chloro-6-(2,5-diaminopentyl)-11-fluoro-5,8-dihydrobenzo[5,6]azepino[3,4-b]indol-7(6H)- one hydrochloride salt To a solution of 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 (64 mg, 0.1 mmol) in MeOH (5 mL) was added HCl (4 M in dioxane, 0.25 mL, 1 mmol). The reaction mixture was stirred at 45 °C for 1 h then concentrated to give a residue. The residue was triturated with EtOAc and dried to give the desired product (25 mg, 49% yield) as an off-white solid.1H NMR (D2O) (300 MHz) δ 7.95 (d, J = 8.4 Hz, 1H), 7.73 (m, 1H), 7.70 (m, 1H), 7.56 (m, 2H), 7.19 (m, 1H), 4.47 (m, 2H), 3.94-3.88 (m, 1H) 3.76-3.69 (m, 2H), 2.98 (m, 2H), 1.66- 1.96 (m, 4H). MS (EPI): Calcd for C21H23ClFN4O+401.15 [M+H]+, found 400.95 [M+H]+. The requisite intermediates were prepared as follows: Step 1) ethyl 3-(4-chloro-2-formylphenyl)-5-fluoro-1H-indole-2-carboxylate The mixture of ethyl 3-bromo-5-fluoro-1H-indole-2-carboxylate (0.57 g, 2 mmol) and (4-chloro-2-formylphenyl)boronic acid (0.44 g, 2.4 mmol) in a mixture of dioxane (25 mL) and Na2CO3solution (2 mol / L, 4 mL, 8 mmol) was degassed and Pd(dppf)Cl2(100 mg, 0.14 mmol) was added. The reaction mixture was heated at 90 °C for 0.5 hours, it was extracted with EtOAc and washed with water, brine and dried over Na2SO4, then concentrated. It was purified by column chromatography on silica gel with EtOAc in hexane as eluents to give the product (0.45 g, 65% yield) as a pale brown powder. MS (EPI): Calcd for C18H14ClFNO3+346.06 [M+H]+, found 345.90 [M+H]+. 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 To a solution of ethyl 3-(4-chloro-2-formylphenyl)-5-fluoro-1H-indole-2-carboxylate (51 mg, 0.15 mmol) and di-tert-butyl (5-aminopentane-1,4-diyl)(S)-dicarbamate (46 mg, 0.15 mmol) in THF (15 mL) was added NaB(OAc)3H (200 mg, 0.9 mmol). It was heated at 75 °C overnight. The reaction was quenched with water, diluted and extracted with DCM. The combined organic phase was washed with water, brine and dried over anhydrous Na2SO4. It was purified on column chromatography on SiO2to give the product as a white powder (54 mg, 60% yield). MS (EPI): Calcd for C31H34ClFN4O5+601.26 [M+H]+, found 601.10 [M+H]+. Example 8. Preparation of (S)- 6-(2,5-diaminopentyl)- 11-fluoro-3-methoxy-5,8- dihydrobenzo[5,6]azepino[3,4-b]indol-7(6H)-one hydrochloride salt (S)-6-(2,5-diaminopentyl)-11-fluoro-3-methoxy-5,8-dihydrobenzo[5,6]azepino[3,4-b]indol- 7(6H)-one hydrochloride salt To a solution of 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(54 mg, 0.1 mmol) in MeOH (5 mL) was added HCl (4 M in dioxane, 0.25 mL, 1 mmol). The reaction mixture was stirred at 50 °C for 1 h then concentrated to give a residue. The residue was triturated with EtOAc and dried to give the desired product (25 mg, 59% yield) as an off-white solid.1H NMR (D2O) (300 MHz) δ 7.62 (d, J = 8.1 Hz, 1H), 7.50 (m, 1H), 7.39 (m, 1H), 7.17 (m, 1H), 7.03 (s, 2H), 4.16 (s, 2H), 3.87 (s, 3H), 3.73 (m, 1H), 3.67 (m, 2H), 2.91 (m, 2H), 1.51- 1.83 (m, 4H). MS (EPI): Calcd for C22H26FN4O2+397.20 [M+H]+, found 397.00 [M+H]+. The requisite intermediates were prepared as follows: Step 1) ethyl 5-fluoro-3-(2-formyl-4-methoxyphenyl)-1H-indole-2-carboxylate The mixture of ethyl 3-bromo-5-fluoro-1H-indole-2-carboxylate (0.572 g, 2 mmol) and (2- formyl-4-methoxyphenyl)boronic acid (0.40 g, 2.1 mmol) in a mixture of dioxane (20 mL) and K3PO4solution (1 mol / L, 4 mL, 4 mmol) was degassed and Pd(dppf)Cl2(100 mg, 0.14 mmol) was added. The reaction mixture was heated at 90 °C for 2 hours, it was extracted with EtOAc and washed with water, brine and dried over Na2SO4, 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.1H NMR (CDCl3) (300 MHz) δ 9.85 (s, 1H), 9.23 (s br, 1H), 8.09 (d, J = 7.8 Hz, 1H), 7.58 (s, 1H), 7.42 (m, 1H), 7.24 (m, 1H), 7.16 (m, 1H), 7.09 (m, 1H), 4.21 (q, J = 7.2 Hz, 2H), 3.93 (s, 3H), 1.13 (t, J = 7.2 Hz, 3H). 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 To a solution of ethyl-5-fluoro-3-(4-methoxy-2-formylphenyl)-1H-indole-2-carboxylate (70 mg, 0.2 mmol) and di-tert-butyl (5-aminopentane-1,4-diyl)(S)-dicarbamate (70 mg, 0.2 mmol) in 1,4-dioxane (5 mL) was added NaB(OAc)3H (140 mg, 0.66 mmol). It was heated at 70 °C overnight. The reaction was quenched with water, diluted and extracted with DCM. The combined organic phase was washed with water, brine and dried over anhydrous Na2SO4. It was purified on column chromatography on SiO2to give the product as a white powder (54 mg, 45% yield).1H NMR (CDCl3) (300 MHz) δ 11.38 (s br, 1H), 10.93 (s br, 1H), 7.82 (m, 1H), 7.63 (d, J = 9.3 Hz, 1H), 7.45 (s, 1H), 7.13 (m, 3H), 4.36 (m, 1H), 4.20 (m, 1H), 3.98 (m, 1H), 3.87 (s, 3H), 3.81 (m, 1H), 3.65 (m, 1H), 3.05 (m, 2H), 1.52 (m, 2H), 1.40 (m, 2H), 1.39 (s, 12H). MS (EPI): Calcd for C32H42FN4O6+597.31 [M+H]+, found 597.25 [M+H]+. Example 9. Preparation of (S)- 6-(2,5-diaminopentyl)- 11-fluoro-4-methoxy-5,8- dihydrobenzo[5,6]azepino[3,4-b]indol-7(6H)-one hydrochloride salt (S)- 6-(2,5-diaminopentyl)-11-fluoro-4-methoxy-5,8-dihydrobenzo[5,6]azepino[3,4-b]indol- 7(6H)-one hydrochloride salt To a solution of 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(90 mg, 0.15 mmol) in MeOH (5 mL) was added HCl (4 M in dioxane, 0.5 mL, 2 mmol). The reaction mixture was stirred at 50 °C for 0.5 h then concentrated to give a residue. The residue was triturated with EtOAc and dried to give the desired product (45 mg, 64% yield) as an off-white solid.1H NMR (D2O) (300 MHz) δ 7.62 (d, J = 8.1 Hz, 1H), 7.50 (m, 1H), 7.39 (m, 1H), 7.17 (m, 1H), 7.03 (s, 2H), 4.10 (s, 2H), 3.81 (s, 3H), 3.74 (m, 1H), 3.69 (m, 2H), 2.90 (m, 2H), 1.52- 1.84 (m, 4H). MS (EPI): Calcd for C22H26FN4O2+397.20 [M+H]+, found 397.05 [M+H]+. The requisite intermediates were prepared as follows: Step 1) ethyl 5-fluoro-3-(2-formyl-5-methoxyphenyl)-1H-indole-2-carboxylate The mixture of ethyl 3-bromo-5-fluoro-1H-indole-2-carboxylate (0.712 g, 2.5 mmol) and (2-formyl-5-methoxyphenyl)boronic acid (0.450 g, 2.5 mmol) in a mixture of dioxane (20 mL) and K3PO4solution (1 mol / L, 5 mL, 5 mmol) was degassed and Pd(dppf)Cl2(150 mg, 0.2 mmol) was added. The reaction mixture was heated at 90 °C for 3 hours, it was extracted with EtOAc and washed with water, brine and dried over Na2SO4, 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.1H NMR (CDCl3) (300 MHz) δ 9.74 (s, 1H), 9.21 (s br, 1H), 8.07 (d, J = 8.7 Hz, 1H), 7.44 (m, 1H), 7.19 (m, 1H), 7.11 (m, 2H), 6.93 (s, 1H), 4.21 (q, J = 7.2 Hz, 2H), 3.90 (s, 3H), 1.15 (t, J = 7.2 Hz, 3H). 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 To a solution of ethyl-5-fluoro-3-(5-methoxy-2-formylphenyl)-1H-indole-2-carboxylate (140 mg, 0.4 mmol) and di-tert-butyl (5-aminopentane-1,4-diyl)(S)-dicarbamate (140 mg, 0.4 mmol) in 1,4-dioxane (5 mL) was added NaB(OAc)3H (280 mg, 1.3 mmol). It was heated at 70 °C overnight. The reaction was quenched with water, diluted and extracted with DCM. The combined organic phase was washed with water, brine and dried over anhydrous Na2SO4. It was purified on column chromatography on SiO2 to give the product as a white powder (90 mg, 38% yield).1H NMR (CDCl3) (300 MHz) δ 11.40 (s br, 1H), 10.84 (s br, 1H), 7.69 (d, J = 9.6 Hz, 1H), 7.44 (m, 3H), 7.11 (td, J = 9.0, 2.4 Hz, 1H), 6.88 (d, J = 7.8 Hz, 1H), 4.38 (m, 1H), 4.23 (m, 1H), 3.98 (m, 1H), 3.88 (s, 3H), 3.76 (m, 1H), 3.65 (m, 1H), 3.03 (m, 2H), 1.53 (m, 2H), 1.42 (m, 2H), 1.35 (s, 12H). Example 10. Preparation of 6-(2,5-diaminopentyl)-11-fluoro-5,8-dihydro- [1,3]dioxolo[4'',5'':4',5']benzo[1',2':5,6]azepino[3,4-b]indol-7(6H)-one hydrochloride salt (S)-6-(2,5-diaminopentyl)-11-fluoro-5,8-dihydro- [1,3]dioxolo[4'',5'':4',5']benzo[1',2':5,6]azepino[3,4-b]indol-7(6H)-one hydrochloride salt To a solution of 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(15 mg, 0.025 mmol) in MeOH (2 mL) was added HCl (4 M in dioxane, 0.25 mL, 1 mmol). The reaction mixture was stirred at 50 °C for 0.5 h then concentrated to give a residue. The residue was triturated with EtOAc and dried to give the desired product (7 mg, 59% yield) as an off-white solid.1H NMR (D2O) (300 MHz) δ 7.56 (m, 2H), 7.25 (s, 1H), 7.20 (m, 1H), 7.06 (s, 1H), 6.06 (s, 2H), 4.22 (s, 2H), 3.73 (m, 1H), 3.50 (m, 2H), 2.75 (m, 2H), 1.55-1.83 (m, 4H). MS (EPI): Calcd for C22H24FN4O3+411.18 [M+H]+, found 411.00 [M+H]+. The requisite intermediates were prepared as follows: Step 1) ethyl 5-fluoro-3-(6-formylbenzo[d][1,3]dioxol-5-yl)-1H-indole-2-carboxylate The mixture of ethyl 3-bromo-5-fluoro-1H-indole-2-carboxylate (0.712 g, 2.5 mmol) and (6-formylbenzo[d][1,3]dioxol-5-yl)boronic acid (0.485 g, 2.5 mmol) in a mixture of dioxane (20 mL) and K3PO4solution (1 mol / L, 5 mL, 5 mmol) was degassed and Pd(dppf)Cl2(100 mg, 0.14 mmol) was added The reaction mixture was heated at 90 °C for 3 hours it was extracted with EtOAc and washed with water, brine and dried over Na2SO4, then concentrated. It was purified by column chromatography on silica gel with EtOAc in hexane as eluents to give the product (0.56 g, 63% yield) as a white crystal. MS (EPI): Calcd for C19H15FNO5+356.09 [M+H]+, found 355.90 [M+H]+. Step 2) di-tert-butyl (5-(11-fluoro-7-oxo-7,8-dihydro- [1,3]dioxolo[4'',5'':4',5']benzo[1',2':5,6]azepino[3,4-b]indol-6(5H)-yl)pentane-1,4-diyl)(S)- dicarbamate To a solution of ethyl 5-fluoro-3-(6-formylbenzo[d][1,3]dioxol-5-yl)-1H-indole-2- carboxylate (36 mg, 0.1 mmol) and 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). It was heated at 70 °C overnight. The reaction was quenched with water, diluted and extracted with DCM. The combined organic phase was washed with water, brine and dried over anhydrous Na2SO4. It was purified on column chromatography on SiO2to give the product as a white powder (15 mg, 25% yield).1H NMR (CDCl3) (300 MHz) δ 9.68 (s br, 1H), 7.64 (d, J = 9.3 Hz, 1H), 7.45 (m, 1H), 7.40 (s, 1H), 7.13 (m, 2H), 7.01 (s, 1H), 6.05 (s, 2H), 4.31 (m, 1H), 4.16 (m, 1H), 3.94 (m, 1H), 3.72 (m, 1H), 3.58 (m, 1H), 3.06 (m, 2H), 1.58 (m, 2H), 1.46 (m, 2H), 1.39 (s, 12H). MS (EPI): Calcd for C32H40FN4O7+611.29 [M+H]+, found 611.20 [M+H]+. Example 11. Preparation of 6-((2S)-2,5-diamino-4-fluoropentyl)-5,8- dihydrobenzo[5,6]azepino[3,4-b]indol-7(6H)-one hydrochloride salt 6-((2S)-2,5-diamino-4-fluoropentyl)-5,8-dihydrobenzo[5,6]azepino[3,4-b]indol-7(6H)-one hydrochloride salt To a solution of di-tert-butyl ((4S)-2-fluoro-5-(7-oxo-7,8-dihydrobenzo[5,6]azepino[3,4- b]indol-6(5H)-yl)pentane-1,4-diyl)dicarbamate (15 mg, 0.026 mmol) in MeOH (5 mL) was added HCl (4 M in dioxane, 0.25 mL, 1 mmol). The reaction mixture was stirred at 50 °C for 0.5 h then concentrated to give a residue. The residue was purified on a C18 column to give the desired product (4 mg, 35% yield) as a white solid.1H NMR (D2O) (300 MHz) δ 8.03 (m, 1H), 7.62 (m, 1H), 7.56 (m, 2H), 7.48 (m, 2H), 7.31 (m, 1H), 4.33 (s, 2H), 3.75-4.12 (m, 4H), 3.06- 3.24 (m, 2H), 1.81-2.20 (m, 2H). MS (EPI): Calcd for C21H24FN4O+367.19 [M+H]+, found 367.00 [M+H]+. The requisite intermediates were prepared as follows: di-tert-butyl ((4S)-2-fluoro-5-(7-oxo-7,8-dihydrobenzo[5,6]azepino[3,4-b]indol-6(5H)- yl)pentane-1,4-diyl)dicarbamate To a solution of ethyl-3-(2-formylphenyl)-1H-indole-2-carboxylate (30 mg, 0.1 mmol) and di-tert-butyl ((4S)-5-amino-2-fluoropentane-1,4-diyl)dicarbamate (35 mg, 0.1 mmol) in DCM (5 mL) and water (0.2 mL)was added NaB(OAc)3H (210 mg, 0.1 mmol). It was heated at 50 °C overnight. The reaction was quenched with water, diluted and extracted with DCM. The combined organic phase was washed with water, brine and dried over anhydrous Na2SO4. It was purified on column chromatography on SiO2 to give the product as a white powder (15 mg, 26% yield).1H NMR (CDCl3) (300 MHz) δ 11.12 (s br, 1H), 8.09 (d, J = 7.8 Hz, 1H), 8.02 (d, J = 7.5 Hz, 1H), 7.51 (m, 3H), 7.38 (m, 2H), 7.25 (m, 1H), 4.91 (m, 1H), 4.68 (m, 1H), 4.40 (m, 1H), 4.28 (m, 1H), 3.81 (m, 1H), 3.68 (m, 1H), 3.41 (m, 1H), 3.22 (m, 1H), 1.42 (m, 2H), 1.39 (s, 18H). MS (EPI): Calcd for C31H40FN4O5+567.30 [M+H]+, found 567.20 [M+H]+. Example 12. Preparation of 6-((2R)-2,5-diamino-4-fluoropentyl)-5,8- dihydrobenzo[5,6]azepino[3,4-b]indol-7(6H)-one hydrochloride salt 6-((2R)-2,5-diamino-4-fluoropentyl)-5,8-dihydrobenzo[5,6]azepino[3,4-b]indol-7(6H)-one hydrochloride salt To a solution of di-tert-butyl ((4R)-2-fluoro-5-(7-oxo-7,8-dihydrobenzo[5,6]azepino[3,4- b]indol-6(5H)-yl)pentane-1,4-diyl)dicarbamate (29 mg, 0.026 mmol) in MeOH (5 mL) was added HCl (4 M in dioxane, 0.25 mL, 1 mmol). The reaction mixture was stirred at 50 °C for 0.5 h then concentrated to give a residue. The residue was purified on a C18 column to give the desired product (9.5 mg, 41% yield) as a white solid.1H NMR (Methanol-d4) (300 MHz) δ 8.05 (m, 2H), 7.57 (m, 3H), 7.38 (m, 2H), 7.24 (m, 1H), 4.47 (s, 2H), 3.80-4.12 (m, 4H), 3.17 (m, 2H), 1.85-2.38 (m, 2H). MS (EPI): Calcd for C21H23FN4O+366.19 [M+H]+, found 367.05 [M+H]+. The requisite intermediates were prepared as follows: di-tert-butyl ((4R)-2-fluoro-5-(7-oxo-7,8-dihydrobenzo[5,6]azepino[3,4-b]indol-6(5H)- yl)pentane-1,4-diyl)dicarbamate To a solution of ethyl-3-(2-formylphenyl)-1H-indole-2-carboxylate (44 mg, 0.15 mmol) and di-tert-butyl ((4R)-5-amino-2-fluoropentane-1,4-diyl)dicarbamate (50 mg, 0.15 mmol) in dioxane (10 mL)was added NaB(OAc)3H (95 mg, 0.45 mmol). It was heated at 50 °C overnight. The reaction mixture was passed through Celite and the filtrate was concentrated to give a residue. The residue was dissolved in EtOAc and washed with water, brine and dried over Na2SO4and concentrated. It was purified by column chromatography on SiO2and eluted with 30-50% EtOAc / Hexanes to give the product as a white solid (29 mg, 34% yield).1H NMR (CDCl3) (300 MHz) δ 10.18 (s br, 1H), 8.07 (d, J = 7.8 Hz, 1H), 8.02 (d, J = 7.5 Hz, 1H), 7.51 (m, 3H), 7.37 (m, 2H), 7.25 (m, 1H), 4.88 (m, 1H), 4.70 (m, 1H), 4.40 (m, 1H), 4.20 (m, 1H), 3.82 (m, 1H), 3.62 (m, 1H), 3.40 (m, 1H), 3.16 (m, 1H), 1.42 (m, 2H), 1.39 (s, 18H). MS (EPI): Calcd for C31H39FN4O5+566.29 [M+H]+, found 567.30 [M+H]+. Example 13. Preparation of 6-((2R)-2,5-diamino-4-fluoropentyl)-11-fluoro-5,8- dihydrobenzo[5,6]azepino[3,4-b]indol-7(6H)-one hydrochloride 6-((2R)-2,5-diamino-4-fluoropentyl)-11-fluoro-5,8-dihydrobenzo[5,6]azepino[3,4-b]indol- 7(6H)-one hydrochloride salt To a solution of di-tert-butyl ((4R)-2-fluoro-5-(11-fluoro-7-oxo-7,8- dihydrobenzo[5,6]azepino[3,4-b]indol-6(5H)-yl)pentane-1,4-diyl)dicarbamate g, 1.88 mmol) in MeOH (20 mL) was added HCl (4 M in dioxane, 0.94 mL, 3.76 mmol). The reaction mixture was stirred at 50 °C for 0.5 h then concentrated to give a residue. The residue was purified on a C18 column to give the desired product (650 mg, 75% yield) as a white solid.1H NMR (Methanol-d4) (300 MHz) δ 7.99 (d, J = 7.5 Hz, 1H), 7.72 (dd, J = 2.7, 10.2 Hz, 1H), 7.58 (m, 2H), 7.41 (m, 1H), 7.19 (m, 1H), 4.47 (m, 2H), 3.80-4.15 (m, 4H), 3.16 (m, 2H), 1.82- 2.36 (m, 2H). MS (EPI): Calcd for C21H22F2N4O+384.18 [M+H]+, found 385.05 [M+H]+. The requisite intermediates were prepared as follows: di-tert-butyl ((4R)-2-fluoro-5-(11-fluoro-7-oxo-7,8-dihydrobenzo[5,6]azepino[3,4-b]indol- 6(5H)-yl)pentane-1,4-diyl)dicarbamate To a solution of ethyl 5-fluoro-3-(2-formylphenyl)-1H-indole-2-carboxylate (1.30 g, 4.18 mmol) and di-tert-butyl ((4R)-5-amino-2-fluoropentane-1,4-diyl)dicarbamate (1.54 g, 4.59 mmol) in dioxane (50 mL)was added NaB(OAc)3H (2.66 g, 12.5 mmol). It was heated at 50 °C overnight. The reaction mixture was passed through Celite and the filtrate was concentrated to give a residue. The residue was dissolved in EtOAc and washed with water, brine and dried over Na2SO4and concentrated. It was purified by column chromatography on SiO2 and eluted with 30-50% EtOAc / Hexanes to give the product as a white solid (1.1 g, 45% yield).1H NMR (CDCl3) (300 MHz) δ 9.50 (s br, 1H), 7.93 (d, J = 7.5 Hz, 1H), 7.71 (d, J = 7.8 Hz, 1H), 7.43 - 7.54 (m, 3H), 7.37 (m, 1H), 7.15 (m, 1H), 4.86 (m, 1H), 4.69 (m, 1H), 4.40 (m, 1H), 4.15 (m, 1H), 3.76 (m, 1H), 3.62 (m, 1H), 3.43 (m, 1H), 3.19 (m, 1H), 1.42 (m, 2H), 1.40 (s, 18H). MS (EPI): Calcd for C31H38F2N4O5+584.28 [M+H]+, found 585.25 [M+H]+. Example 14. 6-((2R)-2,5-diamino-4-fluoropentyl)-11-fluoro-3-methoxy-5,8- dihydrobenzo[5,6]azepino[3,4-b]indol-7(6H)-one hydrochloride 6-((2R)-2,5-diamino-4-fluoropentyl)-11-fluoro-3-methoxy-5,8-dihydrobenzo[5,6]azepino[3,4- b]indol-7(6H)-one hydrochloride salt To a solution of di-tert-butyl ((4R)-2-fluoro-5-(11-fluoro-3-methoxy-7-oxo-7,8- dihydrobenzo[5,6]azepino[3,4-b]indol-6(5H)-yl)pentane-1,4-diyl)dicarbamate (35 mg, 0.06 mmol) in MeOH (2 mL) was added HCl (4 M in dioxane, 0.06 mL, 0.24 mmol). The reaction mixture was stirred at 50 °C for 0.5 h then concentrated to give a residue. The residue was purified on a C18 column to give the desired product (12 mg, 43% yield) as a white solid.1H NMR (Methanol-d4) (300 MHz) δ 7.90 (d, J = 8.7 Hz, 1H), 7.68 (d, J = 8.4 Hz, 1H), 7.53 (m, 1H), 7.16 (m, 3H), 4.45 (s, 2H), 3.89 (m, 7H), 3.19 (m, 2H), 1.82-2.38 (m, 2H). MS (EPI): Calcd for C21H24F2N4O2+414.19 [M+H]+, found 415.10 [M+H]+. The requisite intermediates were prepared as follows: di-tert-butyl ((4R)-2-fluoro-5-(11-fluoro-3-methoxy-7-oxo-7,8-dihydrobenzo[5,6]azepino[3,4- b]indol-6(5H)-yl)pentane-1,4-diyl)dicarbamate To a solution of ethyl-5-fluoro-3-(4-methoxy-2-formylphenyl)-1H-indole-2-carboxylate (49 mg, 0.15 mmol) and di-tert-butyl ((4R)-5-amino-2-fluoropentane-1,4-diyl)dicarbamate (50 mg, 0.15 mmol) in dioxane (10 mL)was added NaB(OAc)3H (95 mg, 0.45 mmol). It was heated at 50 °C overnight. The reaction mixture was passed through Celite and the filtrate was concentrated to give a residue. The residue was dissolved in EtOAc and washed with water, brine and dried over Na2SO4and concentrated. It was purified by column chromatography on SiO2and eluted with 30-50% EtOAc / Hexanes to give the product as a white solid (35 mg, 37% yield).1H NMR (CDCl3) (300 MHz) δ 10.12 (s br, 1H), 9.82 (s br, 1H), 7.84 (d, J = 9.0 Hz, 1H), 7.65 (d, J = 9.3 Hz, 1H), 7.44 (m, 1H), 7.14 (m, 1H), 6.98 - 7.07 (m, 2H), 4.90 (m, 1H), 4.72 (m, 1H), 4.37 (m, 1H), 4.22 (m, 1H), 3.89 (s, 3H), 3.81 (m, 1H), 3.54 (m, 1H), 3.42 (m, 1H), 3.15 (m, 1H), 1.42 (m, 2H), 1.40 (s, 18H). MS (EPI): Calcd for C32H40F2N4O4+614.29 [M+H]+, found 615.30 [M+H]+. Example 15. Preparation of 6-((2S)-2,5-diamino-4-hydroxypentyl)-5,8- dihydrobenzo[5,6]azepino[3,4-b]indol-7(6H)-one hydrochloride salt 6-((2S)-2,5-diamino-4-hydroxypentyl)-5,8-dihydrobenzo[5,6]azepino[3,4-b]indol-7(6H)-one hydrochloride salt To a solution of 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 (40 mg, 0.08 mmol) in MeOH (5 mL) was added HCl (4 M in dioxane, 0.25 mL, 1 mmol). The reaction mixture was stirred at rt overnight then concentrated to give a residue. The residue was triturated with EtOAc and dried to give the desired product (23 mg, 66% yield) as a white solid.1H NMR (CD3OD) (300 MHz) δ 8.02 (dd, J = 9.0, 4.8 Hz, 1H), 7.39 (d, J = 8.4 Hz, 1H), 7.33 (m, 1H), 7.14 (m, 1H), 7.09 (m, 1H), 6.92 (dd, J = 8.4, 2.1 Hz, 1H), 4.47 (m, 2H), 4.17 (s br, 1H), 3.98 (m, 1H), 3.90 (m, 2H), 3.10 (m, 1H), 3.03 (m, 1H), 2.88 (m, 1H), 1.84 (m, 2H).13C NMR (CD3OD) (75 MHz) 164.73, 137.20, 134.70, 133.37, 128.61, 128.49, 128.24, 127.51, 126.69, 124.98, 124.52, 120.98, 120.70, 118.23, 112.17, 82.38, 64.23, 61.15, 49.18, 44.62, 34.32. MS (EPI): Calcd for C21H25N4O2+365.20 [M+H]+, found 365.00 [M+H]+. The requisite intermediates were prepared as follows: Step 1) di-tert-butyl ((4S)-5-(7-oxo-7,8-dihydrobenzo[5,6]azepino[3,4-b]indol-6(5H)-yl)-2- ((triisopropylsilyl)oxy)pentane-1,4-diyl)dicarbamate To a solution of ethyl 3-(4-chloro-2-formylphenyl)-5-fluoro-1H-indole-2-carboxylate (60 mg, 0.2 mmol) and di-tert-butyl ((4S)-5-amino-2-((triisopropylsilyl)oxy)pentane-1,4- diyl)dicarbamate (90 mg, 0.2 mmol) in MeOH (5 mL) was stirred at room temperature overnight. Then the solvent was removed under vacuo and 1,4-dioxane (5 mL) was added. To the mixture was added NaB(OAc)3H (210 mg, 1 mmol). It was heated at 70 °C overnight. The reaction was quenched with water, diluted and extracted with EtOAc. The combined organic phase was washed with water, brine and dried over anhydrous Na2SO4. It was purified on column chromatography on SiO2 to give the product as a white powder (70 mg, 49% yield).1H NMR (CDCl3) (300 MHz) δ 9.42 (s br, 1H), 8.09 (d, J = 7.5 Hz, 1H), 8.02 (d, J = 7.5 Hz, 1H), 7.50 (m, 2H), 7.38 (m, 3H), 7.32 (m, 1H), 4.21 (m, 2H), 3.70 (m, 2H), 3.15 (m, 4H), 1.52 (m, 2H), 1.43 (s, 18H), 1.04 (s, 18H). 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 To a solution of di-tert-butyl ((4S)-5-(7-oxo-7,8-dihydrobenzo[5,6]azepino[3,4-b]indol- 6(5H)-yl)-2-((triisopropylsilyl)oxy)pentane-1,4-diyl)dicarbamate (70 mg, 0.1 mmol) in THF was added TBAF (1 M solution in THF, 0.5 mL, 0.5 mmol). It was stirred at rt for 1 h, then extracted with EtOAc, washed with water, brine and dried over anhydrous Na2SO4. It was purified on column chromatography on SiO2 with 40-65% EtOAc in hexane as eluent to provide the product (40 mg, 71% yield). MS (EPI): Calcd for C31H41N4O6+565.30 [M+H]+, found 565.30 [M+H]+. Example 16. Preparation of 6-((2S)-2,5-diamino-4-hydroxypentyl)-11-fluoro-3-methoxy-5,8- dihydrobenzo[5,6]azepino[3,4-b]indol-7(6H)-one hydrochloride salt 6-((2S)-2,5-diamino-4-hydroxypentyl)-11-fluoro-3-methoxy-5,8-dihydrobenzo[5,6]azepino[3,4- b]indol-7(6H)-one hydrochloride salt To a solution of di-tert-butyl ((4S)-5-(11-fluoro-3-methoxy-7-oxo-7,8- dihydrobenzo[5,6]azepino[3,4-b]indol-6(5H)-yl)-2-hydroxypentane-1,4-diyl)dicarbamate (28 mg, 0.045 mmol) in MeOH (5 mL) was added HCl (4 M in dioxane, 0.25 mL, 1 mmol). The reaction mixture was stirred at rt overnight then concentrated to give a residue. The residue was purified on C18 column chromatography to give the desired product (12 mg, 55% yield) as a white solid.1H NMR (CD3OD) (300 MHz) δ 7.91 (d, J = 8.4 Hz, 1H), 7.69 (dd, J = 9.9, 2.4 Hz, 1H), 7.53 (dd, J = 4.5 Hz, 1H), 7.25 (d, J = 2.1 Hz, 1H), 7.17 (m, 2H), 4.45 (m, 2H), 4.09 (m, 1H), 3.94 (m, 1H), 3.90 (s, 3H), 3.74 (m, 1H), 3.23 (m, 1H), 3.05 (m, 1H), 2.88 (m, 1H), 1.83 (m, 2H). MS (EPI): Calcd for C21H26FN4O3+413.20 [M+H]+, found 412.95 [M+H]+. The requisite intermediates were prepared as follows: Step 1) di-tert-butyl ((4S)-5-(11-fluoro-3-methoxy-7-oxo-7,8-dihydrobenzo[5,6]azepino[3,4-b]indol- 6(5H)-yl)-2-((triisopropylsilyl)oxy)pentane-1,4-diyl)dicarbamate To a solution of ethyl 3-(4-methoxy-2-formylphenyl)-5-fluoro-1H-indole-2-carboxylate (68 mg, 0.2 mmol) and di-tert-butyl ((4S)-5-amino-2-((triisopropylsilyl)oxy)pentane-1,4- diyl)dicarbamate (90 mg, 0.2 mmol) in MeOH (5 mL) was stirred at r.t. overnight. Then the solvent was removed under vacuo and 1,4-dioxane (5 mL) was added. To the mixture was added NaB(OAc)3H (210 mg, 1 mmol). It was heated at 70 °C overnight. The reaction was quenched with water, diluted and extracted with EtOAc. The combined organic phase was washed with water, brine and dried over anhydrous Na2SO4. It was purified on column chromatography on SiO2 to give the product as a white powder (67 mg, 44% yield). MS (EPI): Calcd for C41H62N4O7Si+769.44 [M+H]+, found 769.55 [M+H]+. Step 2) di-tert-butyl ((4S)-5-(11-fluoro-3-methoxy-7-oxo-7,8-dihydrobenzo[5,6]azepino[3,4-b]indol- 6(5H)-yl)-2-hydroxypentane-1,4-diyl)dicarbamate To a solution of di-tert-butyl ((4S)-5-(11-fluoro-3-methoxy-7-oxo-7,8- dihydrobenzo[5,6]azepino[3,4-b]indol-6(5H)-yl)-2-((triisopropylsilyl)oxy)pentane-1,4- diyl)dicarbamate (67 mg, 0.09 mmol) in THF was added TBAF (1 M solution in THF, 0.5 mL, 0.5 mmol). It was stirred at rt for 1 h, then extracted with EtOAc, washed with water, brine and dried over anhydrous Na2SO4. It was purified on column chromatography on SiO2with 40-65% EtOAc in hexane as eluent to provide the product (28 mg, 51% yield). MS (EPI): Calcd for C32H42N4O7+613.30 [M+H]+, found 613.30 [M+H]+. Example 17. Preparation of 6-(((2R,3S,4S)-4-(aminomethyl)-3-hydroxypyrrolidin-2- yl)methyl)-11-fluoro-5,8-dihydrobenzo[5,6]azepino[3,4-b]indol-7(6H)-one hydrochloride salt 6-(((2R,3S,4S)-4-(aminomethyl)-3-hydroxypyrrolidin-2-yl)methyl)-11-fluoro-5,8- dihydrobenzo[5,6]azepino[3,4-b]indol-7(6H)-one hydrochloride salt To a solution of 6-(((3aR,6R,6aS)-2,5-dibenzylhexahydro-2H-pyrrolo[3,4-d]isoxazol-6- yl)methyl)-11-fluoro-5,8-dihydrobenzo[5,6]azepino[3,4-b]indol-7(6H)-one(30 mg, 0.052 mmol) in MeOH (10 mL) was added Pd / C (10%, 15 mg). The flask was flashed with H2, then stirred at 60 psi at rt overnight. It was filtered through a pad of celite and to the solution was added HCl solution (4 M in dioxane, 0.1 mL). It was concentrated to give the desired product (18 mg, 74% yield) as a white solid.1H NMR (CD3OD) (300 MHz) δ 7.98 (d, J = 7.8 Hz, 1H), 7.72 (dd, J = 9.9, 2.4 Hz, 1H), 7.65 (d, J = 7.5 Hz, 1H), 7.57 (m, 2H), 7.25 (d, J = 7.5 Hz, 1H), 7.53 (dt, J = 9.0, 2.4 Hz, 1H), 4.52 (s, 2H), 4.36 (m, 1H), 3.98 (m, 3H), 3.74 (m, 2H), 3.16 (m, 2H), 2.85 (m, 1H), 1.83 (m, 2H). MS (EPI): Calcd for C22H24FN4O2+395.19 [M+H]+, found 395.05 [M+H]+. The requisite intermediate was prepared as follow: 6-(((3aR,6R,6aS)-2,5-dibenzylhexahydro-2H-pyrrolo[3,4-d]isoxazol-6-yl)methyl)-11-fluoro-5,8- dihydrobenzo[5,6]azepino[3,4-b]indol-7(6H)-one To a solution of ethyl 3-(2-formylphenyl)-5-fluoro-1H-indole-2-carboxylate (29 mg, 0.09 mmol) and ((3aR,6R,6aS)-2,5-dibenzylhexahydro-2H-pyrrolo[3,4-d]isoxazol-6- yl)methanamine (30 mg, 0.09 mmol) in dioxane (2 mL) was mixed. To the mixture was added NaB(OAc)3H (59 mg, 0.27 mmol). It was heated at 70 °C overnight. The reaction was quenched with saturated NaHCO3, diluted and extracted with EtOAc. The combined organic phase was washed with water, brine and dried over anhydrous Na2SO4. It was purified on column chromatography on SiO2to give the product as a white powder (35 mg, 68% yield).1H NMR (CDCl3) (300 MHz) δ 10.74 (br, 1H), 7.91 (d, J = 7.8 Hz, 1H), 7.68 (dd, J = 9.9, 2.4 Hz, 1H), 7.48 (m, 2H), 7.33 (m, 4H), 7.31 (m, 4H), 7.26 (m, 2H), 7.20 (m, 2H), 7.05 (t, J = 9.0 Hz, 1H), 4.72 (s, 1H), 4.31 (m, 2H), 4.01 (m, 1H), 3.89 (m, 4H), 3.30 (m, 1H), 3.10 (m, 1H), 2.93 (m, 1H), 2.86 (m, 1H), 2.50 (m, 1H), 2.27 (m, 1H), 1.89 (m, 1H). MS (EPI): Calcd for C36H34FN4O7+573.27 [M+H]+, found 573.20 [M+H]+. Example 18. Preparation of 6-((2S,4S)-2,5-diamino-4-fluoropentyl)-11-fluoro-5,8- dihydrobenzo [5,6] azepino[3,4-b] indol-7(6H)-one hydrochloride salt 6-((2S,4S)-2,5-diamino-4-fluoropentyl)-11-fluoro-5,8-dihydrobenzo [5,6] azepino[3,4-b] indol- 7(6H)-one hydrochloride salt Di-tert-butyl ((2S,4S)-2-fluoro-5-(11-fluoro-7-oxo-7,8-dihydrobenzo[5,6]azepino[3,4- b]indol6(5H)-yl)pentane-1,4-diyl)dicarbamate (88.0 mg, 0.15 mmol) was treated with 4 M HCl solution in dioxane (2.0 mL), and the reaction mixture was stirred at rt for 30 min; then, the volatiles were removed under vacuum to give crude solid which was loaded on a short C18 column and eluted with gradient 01% formic acid / H2O / 0.1%formic acid / CH3CN. The desired fractions were collected based on the LCMS result. The final product was collected as a pale- yellow solid in 91% yield. A sample was dissolved in DMSO-d6and was analyzed by NMR spectroscopy at 90 °C to favor one dominant rotamer,1HNMR (600 MHz, 90 °C, DMSO-d6) δ 11.99 (s, 1H), 8.46 (m, 4H), 7.97 (d, J = 7.6 Hz, 1H), 7.76-7.73 (m, 2H), 7.66 (dd, J = 9.0, 4.7 Hz, 1H), 7.57 (dt, J = 7.6, 1.0 Hz, 1H), 7.41 (t, J = 7.0 Hz, 1H), 7.23 (dt, J= 9.11, 2.46 Hz, 1H), 5.28 (dddd, J = 49.5, 11.4, 7.98, 3.18 Hz, 1H), 4.58 (ABq, J = 14.8Hz, Dd = 0.04, 2H), 3.94 (ddd, J = 20.64, 14.0, 6.3, 2H), 3.79 (p, J = 12.18, 6.42 Hz, 1H), 3.24-3.04 (m, 2H), 2.27-2.11 (m, 2H).13CNMR (75 MHz, DMSO-d6) δ 162.8, 157.8 (d, J = 191.8 Hz, Sp2-C-F), 135.1, 133.4, 133.2, 131.5, 128.7, 128.5, 126.8 (d, J2= 21 Hz, C-CF), 124.1 (d, J3= 10.2 Hz, C-C-CF), 116.2 (d, J4= 4.8 Hz, C-C-C-CF), 113.5, 113.1, 105.4, (d, J2= 24.7 Hz c-CF), 87.6 (d, J = 169.0 Hz, sp3-C-F), 51.6, 49.0, 46.8, 42.2 (d, J = 20.3 Hz, C-CF), 33.1 (d, J = 22.1 Hz, C-CF).19FNMR (376.5 MHz, DMSO-d6) δ -122.3 (F-sp2C), -184.8, -185.5 (F-sp3-C, 2X Rotamers). MS m / z calculated for C21H23F2N4O [M+H] 385.18 found 385.00. The requisite intermediate was prepared as follows: Step 1) di-tert-butyl ((2S,4S)-2-fluoro-5-(11-fluoro-7-oxo-7,8-dihydrobenzo[5,6]azepino[3,4-b]indol- 6(5H)-yl)pentane-1,4-diyl)dicarbamate In a 50 mL round-bottomed flask charged with a stir bar, was added ethyl-5-fluoro-3-(2- formylphenyl)-1H-indole-2-carboxylate (98.0 mg, 0.3 mmol) and di-tert-butyl ((2S,4S)-5- amino-2-fluoropentane-1,4-diyl)dicarbamate (100.0 mg, 0.3 mmol), DCM (10.0 mL), Water (0.5 mL), and Na(OAc)3BH (572.0 mg, 2.7 mmol). 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 (NaBO3.4H2O), 1M NaOH solution, and brine. Then, the organic layer was dried over Na2SO4, 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. A sample was dissolved in CDCl3and was analyzed by NMR spectroscopy,1HNMR analysis indicated the presence of two rotamers, the NMR values are listed for the dominant rotamer1HNMR (300 MHz,CDCl3) δ 11.8 (m, 1H), 7.89 (d, J = 8.1 Hz, 1H), 7.66 (d, J = 9.6 Hz, 1H), 7.47 (m, 3H), 7.35 (t, J = 9.6, 1H), 7.07 (dt, J = 8.7, 2.1 Hz, 1H), 5.60 (m, 1H), 5.00 (m, 1H), 4.67 (dm, J = 51.0 Hz, 1H), 4.36 (m, 2H), 3.77- 3.08 (m, 3H), 1.39 (m, 20H). 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. The final product was collected as a pale-yellow solid in 85.0% yield A sample was dissolved in DMSO-d6 and was analyzed by NMR spectroscopy at 90 °C to favor one dominant rotamer,1HNMR (600 MHz, 90 °C, DMSO-d6) δ 12.03 (s, 1H), 8.63 (m, 4H), 7.96 (d, J = 7.7 Hz, 1H), 7.77 (d, J = 7.4 Hz, 1H), 7.74 (dd, J = 10.08, 2.34 Hz, 1H), 7.67 (dd, J = 9.00, 4.74 Hz, 1H), 7.56 (t, J = 7.6, 1H), 7.40 (t, J = 7.44 Hz, 1H), 7.23 (dt, J= 9.11, 2.52 Hz, 1H), 5.28 (dddd, J = 48.9, 12.96, 7.80, 3.54 Hz, 1H), 4.59 (m, 2H), 3.96 (m, 2H), 3.81 (p, J = 12.18, 6.42 Hz, 1H), 3.33 (ddd, J = 30.24, 13.98, 2.82 Hz, 1H), 3.11 (ddd, J = 25.14, 17.2, 8.0 Hz, 1H), 2.31-2.18 (m, 2H).13CNMR (75 MHz, DMSO-d6) δ 162.3, 157.8 (d, J = 232.3 Hz, Sp2-C-F), 135.1, 133.3, 132.9, 131.6, 128.7, 128.5, 126.8, 126.7,124.0 (d, J = 10.3 Hz, C-CF), 116.0 (d, J = 4.8 Hz, C-C-CF), 114.1 (d, J = 9.8 Hz) 113.2 (d, J = 27.1 Hz, C-CF), 105.3 (d, J = 23.3 Hz C-CF), 88.1 (d, J = 168.8 Hz, sp3-C-F), 51.4, 48.5, 47.0, 41.9 (d, J = 21.1 Hz, C-CF), 33.2.19FNMR (376.5 MHz, DMSO-d6) δ -122.3 (F-sp2C), -184.8, -185.5 (F-sp3-C, 2X Rotamers). MS m / z calculated for C21H23F2N4O [M+H] 385.18 found 385.00. The requisite intermediate was prepared as follows: Step 1) di-tert-butyl ((2R,4S)-2-fluoro-5-(11-fluoro-7-oxo-7,8-dihydrobenzo[5,6]azepino[3,4-b]indol- 6(5H)-yl)pentane-1,4-diyl)dicarbamate The titled compound was prepared and purified according to procedure described above on 0.3 mmol scale with amine intermediate F. The final product was collected as a pale-yellow solid in 61.2 % yield. A sample was dissolved in DMSO-d6and was analyzed by NMR spectroscopy, HNMR analysis indicated the presence of two rotamers, the NMR values are listed for the dominant rotamer1HNMR (300 MHz,DMSO-d6) δ 12.23 (m, 1H), 7.95 (d, J = 7.8 Hz, 1H), 7.75 (d, J = 9.9 Hz, 1H), 7.57 (m, 3H), 7.40 (d, J = 6.9 Hz, 1H), 7.24 (t, J = 9.3, 1H), 7.05 (m, 2H), 4.60 (dm, J = 49.5 Hz, 1H), 4.38 (m, 2H), 4.07 (m, 1H), 3.73 (m, 1H), 3.15 (m, 3H), 1.77 (m, 2H), 1.40 (m, 18H). 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. The final product was collected as a pale-yellow solid in 90% yield. A sample was dissolved in DMSO-d6 and was analyzed by NMR spectroscopy at 90 °C to favor one dominant rotamer,1HNMR (600 MHz, 90 °C, DMSO-d6) δ 12.01 (s, 1H), 8.64 (m, 4H), 7.96 (d, J = 7.6 Hz, 1H), 7.75 (m, 2H), 7.67 (dd, J = 8.9, 4.7 Hz, 1H), 7.56 (t, J = 7.3 Hz, 1H), 7.40 (t, J = 7.3 Hz, 1H), 7.23 (dt, J= 9.1, 2.2 Hz, 1H), 5.30 (dm, J = 49.4, 1H), 4.58 (m, 2H), 3.96 (m, 2H), 3.80 (m, 1H), 3.24-3.05 (m, 2H), 2.30-2.15 (m, 2H).13CNMR (75 MHz, DMSO- d6) δ 162.7, 157.6 (d, J = 232.0 Hz, Sp2-C-F), 135.1, 133.3, 132.8, 131.5, 128.7, 128.5, 126.7 (d, J2= 18.6 Hz, C-CF), 124.0 (d, J3= 9.7 Hz, C-C-CF), 116.0 (d, J4= 4.8 Hz, C-C-C-CF), 114.1 (d, J = 9.7 Hz), 113.2 (d, J = 26.0 Hz), 105.3 (d, J2= 24.0 Hz c-CF), 87.5 (d, J = 170.4 Hz, sp3- C-F), 51.4, 48.9, 46.7, 42.1 (d, J = 19.9 Hz, C-CF), 33.2 (d, J = 19.9 Hz, C-CF).19FNMR (376.5 MHz, DMSO-d6) δ -122.3 (F-sp2C), -184.1, -187.09 (F-sp3-C, 2X Rotamers). MS m / z calculated for C21H23F2N4O [M+H] 385.18 found 385.00. The requisite intermediate was prepared as follows: Step 1) di-tert-butyl ((2R,4R)-2-fluoro-5-(11-fluoro-7-oxo-7,8-dihydrobenzo[5,6]azepino[3,4-b]indol- 6(5H)-yl)pentane-1,4-diyl)dicarbamate The titled compound was prepared and purified according to procedure described above on 0.28 mmol scale with amine intermediate G. The final product was collected as a pale-yellow solid in 59.8 % yield. A sample was dissolved in DMSO-d6and was analyzed by NMR spectroscopy,1HNMR analysis indicated the presence of two rotamers, the spectroscopic values are listed for the dominant rotamer1HNMR (300 MHz,DMSO-d6) δ 12.24 (m, 1H), 7.95 (d, J = 7.8 Hz, 1H), 7.75 (d, J = 9.6 Hz, 1H), 7.59 (m, 3H), 7.48 (t, J = 7.2 Hz, 1H), 7.27 (t, J = 9.3, 1H), 7.07 (m, 1H), 6.94 (m, 1H), 4.53 (dm, J = 57.9 Hz, 1H), 4.36 (m, 2H), 4.09 (m, 1H), 3.75 (m, 1H), 3.07 (m, 3H), 1.85 (m, 2H), 1.43 (m, 18H). 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 final product was collected as a pale-yellow solid in 45% yield (two steps). A sample of 20 mg was dissolved in DMSO-d6 and was analyzed by NMR spectroscopy at 90 °C to favor one dominant rotamer,1HNMR (600 MHz, 90 °C, DMSO-d6) δ 12.02 (s, 1H), 8.59 (m, 4H), 7.97 (d, J = 7.7 Hz, 1H), 7.75 (m, 2H), 7.66 (dd, J = 9.00, 4.74 Hz, 1H), 7.56 (dt, J = 7.6, 1 Hz, 1H), 7.41 (t, J = 7.4 Hz, 1H), 7.23 (dt, J= 9.11, 2.4 Hz, 1H), 5.26 (dddd, J = 49.3, 12.9, 7.9, 2.8 Hz, 1H), 4.60 (m, 2H), 3.95 (m, 2H), 3.80 (p, J = 13.0, 6.7 Hz, 1H), 3.22 (m, 1H), 3.12 (m, 1H), 2.23 (m, 2H).13CNMR (75 MHz, DMSO-d6) δ 162.7, 157.7 (d, J = 232.5 Hz, Sp2-C-F), 135.0, 133.2, 132.8, 131.5, 128.6, 128.4, 126.8, 126.5, 124.0 (d, J = 9.9 Hz, C-CF), 116.0 (d, J = 5.1 Hz, C-C-CF), 114.0 (d, J = 9.5 Hz) 113.1 (d, J = 26.3 Hz, C-CF), 105.3 (d, J = 23.8 Hz C-CF), 88.1 (d, J = 168.6 Hz, sp3-C-F), 51.3, 48.5, 47.0, 41.9 (d, J = 20.3 Hz, C-CF), 33.2.19FNMR (376.5 MHz, DMSO-d6) δ -122.3 (F-sp2C), -184.8, -185.6 (F-sp3-C, 2X Rotamers). MS m / z calculated for C21H23F2N4O [M+H] 385.18 found 385.00. The requisite intermediate was prepared as follows: Step 1) di-tert-butyl ((2S,4R)-2-fluoro-5-(11-fluoro-7-oxo-7,8-dihydrobenzo[5,6]azepino[3,4-b]indol- 6(5H)-yl)pentane-1,4-diyl)dicarbamate The titled compound was prepared and purified according to procedure described above on 0.54 mmol scale with amine intermediate H. The final product was collected as a pale-yellow solid in 54.8% yield. A sample was dissolved in DMSO-d6and was analyzed by NMR spectroscopy, HNMR analysis indicated the presence of two rotamers, the spectroscopic data are listed for one dominant rotamer,1HNMR (300 MHz, DMSO-d6) δ 12.23 (s, 1H), 7.95 (d, J = 7.8 Hz, 1H), 7.75 (d, J = 9.6 Hz, 1H), 7.58 (m, 3H), 7.42 (t, J = 7.2 Hz, 1H), 7.24 (t, J = 9.3, 1H), 7.06 (m, 2H), 4.60 (dm, J = 56.7 Hz, 1H), 4.37 (m, 2H), 4.04 (m, 1H), 3.72 (m, 1H), 3.15 (m, 3H), 1.76 (m, 2H), 1.40 (m, 18H). Example 22. Preparation of 1-((2S,4R)-4-amino-2-fluoro-5-(11-fluoro-7-oxo-7,8- dihydrobenzo[5,6]azepino[3,4-b]indol-6(5H)-yl)pentyl)guanidine hydrochloride salt 1-((2S,4R)-4-amino-2-fluoro-5-(11-fluoro-7-oxo-7,8-dihydrobenzo[5,6]azepino[3,4-b]indol- 6(5H)-yl)pentyl)guanidine hydrochloride salt To a solution of free amine 6-((2R,4S)-2,5-diamino-4-fluoropentyl)-11-fluoro-5,8- dihydrobenzo [5,6] azepino[3,4-b] indol-7(6H)-one (15 mg, 0.039 mmol) in DMF (1 mL) was added 1,3-DiBoc-2-methylisothiourea (11.5 mg, 0.04 mmol) and Et3N (12 µl, 0.08 mmol). 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 Na2SO4, 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. The1HNMR analysis indicated the presence of mixture of rotamers. The following are the1HNMR values listed for the dominant rotamer.1HNMR (300 MHz, DMSO-d6) δ 12.20 (s, 1H), 8.19 (m, 4H), 7.96 (d, J = 7.9 Hz, 1H), 7.77 (d, J = 6.6 Hz, 1H), 7.57 (m, 2H), 7.40 (m, 3H), 7.27 (t, J =9.6 Hz, 1H), 4.92 (dm, J = 49.8 Hz, 1H), 4.45 (m, 2H), 3.77 (m, 2H), 3.51 (m, 3H), 2.04 (m, 2H). Example 23. Description of General Test Methods: Intrinsic MIC assays MIC assays were conducted in accordance with Clinical and Laboratory Standards Institute (CLSI) guidelines for broth microdilution. A 96-well plate containing cation-adjusted Mueller-Hinton (CAMH broth with 2-fold serial dilution of compounds was inoculated with log- phase bacterial at 5x105CFU / mL. The final volume in each well was 100 µL. Each compound was tested in duplicate. The microtiter plates were incubated in an aerobic environment for 18 hours at 37 °C. Then the bacterial growth was tested by reading the plate with a VersaMax plate reader (Molecular Devices, Inc.) at 600 nm. 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 µg / 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 ½ of the intrinsic MIC of the compound. If the intrinsic MIC of the EPI is greater than 100 µg / mL, the EPI assay was tested with 50 µg / 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. All three antibiotics levofloxacin, ceftazidime and doxycycline are known substrates of efflux pumps in P. aeruginosa, and are thus well-suited to be test antibiotics to assay for EPI activity. In our standard EPI assay, the MIC of the test antibiotic is determined in the absence and presence of sub-inhibitory concentrations of the EPI. For an example, as the intrinsic MIC of Example 2 against P. aeruginosa ATCC 27853 is greater than 100 µg / mL, we used 6.25 µg / mL of the Example 2 in the standard EPI assay. The MIC of levofloxacin against P. aeruginosa ATCC 27853 in the absence of EPI is 1 µg / mL. In the presence of 6.25 µg / mL of the Example 2, the MIC of levofloxacin was markedly reduced to 0.063 µg / mL, a 16-fold reduction relative to the MIC of levofloxacin in the absence of EPI (1 µg / mL). Similarly, the MIC of ceftazidime against P. aeruginosa ATCC 27853 in the absence of EPI is 2 µg / mL. In the presence of 6.25 µg / mL of the Example 2, the MIC of ceftazidime was reduced to 0.5 µg / mL, a 4-fold reduction. For doxycycline, in the presence of 6.25 µg / mL of Example 2, the MIC is reduced 128-fold (0.25 µg / mL vs.32 µg / mL without the EPI). For all the examples in Table 1, the potentiation activities are determined at 6.25 µg / mL except Example 6 which concentration used is 4 µg / mL. 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. 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. Specifically, for this cellular assay, 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 MgCl2(PBSM). The washed cell pellets are resuspended in PBSM to achieve a final OD at 600 nm of 1.0. Carbonyl cyanide 3-chlorophenylhydrazone (CCCP) is added to the bacterial suspension at a final concentration 50 µM, along with the addition of EtBr at a final concentration of 200 µM. 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 µL 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. The excitation and emission wavelengths were set at 510 and 610 nm, respectively. In our EtBr efflux assay, our EPIs increase the level of accumulation of ethidium bromide inside the cell in a concentration-dependent manner suggesting that efflux pump inhibition is their mechanism of action. 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.

[0004] The above formulations may be obtained by conventional procedures well known in the pharmaceutical art. All publications, patents, and patent documents are incorporated by reference herein, as though individually incorporated by reference. The invention has been described with reference to various specific and preferred embodiments and techniques. However, it should be understood that many variations and modifications may be made while remaining within the spirit and scope of the invention.

Claims

CLAIMS 1. A compound of formula I:wherein: X is –(CR11aR11b)m-; m is 1 or 2; R1is: (a) (C1-C10)alkyl wherein the (C1-C10)alkyl is substituted independently with one or more (e.g., 1, 2, 3, or 4) -NRa1Rb1or -NRd1C(=NRe1)(NRf1Rg1) and wherein the (C1-C10)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, (C1-C4)alkyl, (C3-C7)carbocyclyl, -OH, and -ORc1; or (b) 4-7 membered monocyclic heterocyclyl-(C1-C6)alkyl-, wherein the 4-7 membered monocyclic heterocyclyl-(C1-C6)alkyl- is substituted with one or more (e.g., 1, 2, 3, or 4) groups independently selected from the groups consisting of -NRa2Rb2, -NRd2C(=NRe2)(NRf2Rg2) and -(C1-C6)alkyl substituted with one or more (e.g., 1, 2, 3, or 4) -NRa3Rb3or -NRd2C(=NRe2)(NRf2Rg2), and wherein the heterocyclyl-(C1-C6)alkyl- or -(C1- C6)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, (C1-C4)alkyl, (C3-C7)carbocyclyl, -OH, and -ORc2; R2is hydrogen, (C1-C3)alkyl, or (C3-C7)carbocyclyl; R3is hydrogen, halo, (C1-C6)alkyl, (C1-C6)haloalkyl, (C1-C6)alkoxy, (C1-C6)haloalkoxy, or -OH, or R3and R4together are -OCH2O- or -O(CH2)2O-, wherein the -OCH2O- or -O(CH2)2O- are optionally substituted with one or more (e.g., 1, 2, 3, or 4) groups independently selected from the groups consisting of halo and (C1-C6)alkyl; R4is hydrogen, halo, (C1-C6)alkyl, (C1-C6)haloalkyl, (C1-C6)alkoxy, (C1-C6)haloalkoxy, or -OH, or R3and R4or R4and R5together are -OCH2O- or -O(CH2)2O-, wherein the -OCH2O- or -O(CH2)2O- are optionally substituted with one or more (e.g., 1, 2, 3, or 4) groups independently selected from the groups consisting of halo and (C1-C6)alkyl;R5is hydrogen, halo, (C1-C6)alkyl, (C1-C6)haloalkyl, (C1-C6)alkoxy, (C1-C6)haloalkoxy, or -OH, or R4and R5or R5and R6together are -OCH2O- or -O(CH2)2O-, wherein the -OCH2O- or -O(CH2)2O- are optionally substituted with one or more (e.g., 1, 2, 3, or 4) groups independently selected from the groups consisting of halo and (C1-C6)alkyl; R6is hydrogen, halo, (C1-C6)alkyl, (C1-C6)haloalkyl, (C1-C6)alkoxy, (C1-C6)haloalkoxy, or -OH, or R5and R6together are -OCH2O- or -O(CH2)2O-, wherein the -OCH2O- or - O(CH2)2O- are optionally substituted with one or more (e.g., 1, 2, 3, or 4) groups independently selected from the groups consisting of halo and (C1-C6)alkyl; R7is hydrogen, halo, (C1-C6)alkyl, (C1-C6)haloalkyl, (C1-C6)alkoxy, (C1-C6)haloalkoxy, or -OH, or R7and R8together are -OCH2O- or -O(CH2)2O-, wherein the -OCH2O- or - O(CH2)2O- are optionally substituted with one or more (e.g., 1, 2, 3, or 4) groups independently selected from the groups consisting of halo and (C1-C6)alkyl; R8is hydrogen, halo, (C1-C6)alkyl, (C1-C6)haloalkyl, (C1-C6)alkoxy, (C1-C6)haloalkoxy, or -OH, or R7and R8or R8and R9together are -OCH2O- or -O(CH2)2O-, wherein the -OCH2O- or -O(CH2)2O- are optionally substituted with one or more (e.g., 1, 2, 3, or 4) groups independently selected from the groups consisting of halo and (C1-C6)alkyl; R9is hydrogen, halo, (C1-C6)alkyl, (C1-C6)haloalkyl, (C1-C6)alkoxy, (C1-C6)haloalkoxy, or -OH, or R8and R9or R9and R10together are -OCH2O- or -O(CH2)2O-, wherein the -OCH2O- or -O(CH2)2O- are optionally substituted with one or more (e.g., 1, 2, 3, or 4) groups independently selected from the groups consisting of halo and (C1-C6)alkyl; R10is hydrogen, halo, (C1-C6)alkyl, (C1-C6)haloalkyl, (C1-C6)alkoxy, (C1-C6)haloalkoxy, or -OH, or R9and R10together are -OCH2O- or -O(CH2)2O-, wherein the -OCH2O- or - O(CH2)2O- are optionally substituted with one or more (e.g., 1, 2, 3, or 4) groups independently selected from the groups consisting of halo and (C1-C6)alkyl; each R11aand R11bare independently hydrogen, halo, (C1-C6)alkyl or (C3-C7)carbocyclyl each Ra1and Rb1is independently hydrogen, (C1-C6)alkyl or (C3-C7)carbocyclyl; each Rc1is independently (C1-C6)alkyl or (C3-C7)carbocyclyl, wherein (C1-C6)alkyl or (C3-C7)carbocyclyl is optionally substituted with one or more (e.g., 1, 2, 3, or 4) halo; each Ra2and Rb2is independently hydrogen, (C1-C6)alkyl, or (C3-C7)carbocyclyl; each Rc2is independently (C1-C6)alkyl or (C3-C7)carbocyclyl, wherein (C1-C6)alkyl or (C3-C7)carbocyclyl is optionally substituted with one or more (e.g., 1, 2, 3, or 4) halo; each Ra3and Rb3is independently hydrogen, (C1-C6)alkyl, or (C3-C7)carbocyclyl; each Rd1is independently hydrogen, (C1-C6)alkyl, or (C3-C7)carbocyclyl; each Re1is independently hydrogen, (C1-C6)alkyl, or (C3-C7)carbocyclyl; each Rf1and Rg1is independently hydrogen (C1-C6)alkyl or (C3-C7)carbocyclyl;each Rd2is independently hydrogen, (C1-C6)alkyl, or (C3-C7)carbocyclyl; each Re2is independently hydrogen, (C1-C6)alkyl, or (C3-C7)carbocyclyl; each Rf2and Rg2is independently hydrogen, (C1-C6)alkyl, or (C3-C7)carbocyclyl; provided the compound is not:.

2. The compound or salt of claim 1, wherein: X is –(CR11aR11b)m-; m is 1 or 2; R1is: (a) (C1-C10)alkyl wherein the (C1-C10)alkyl is substituted with one or more (e.g., 1, 2, 3, or 4) -NRa1Rb1, and wherein the (C1-C10)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, (C1- C4)alkyl, (C3-C7)carbocyclyl, -OH, and -ORc1; or (b) 4-7 membered monocyclic heterocyclyl-(C1-C6)alkyl-, wherein the 4-7 membered monocyclic heterocyclyl-(C1-C6)alkyl- is substituted with one or more (e.g., 1, 2, 3, or 4) groups independently selected from the groups consisting of -NRa2Rb2and -(C1-C6)alkyl substituted with one or more (e.g., 1, 2, 3, or 4) -NRa3Rb3, and wherein the heterocyclyl-(C1- C6)alkyl- or -(C1-C6)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, (C1-C4)alkyl, (C3-C7)carbocyclyl, -OH, and -ORc2; R2is hydrogen, (C1-C3)alkyl, or (C3-C7)carbocyclyl; R3is hydrogen, halo, (C1-C6)alkyl, (C1-C6)haloalkyl, (C1-C6)alkoxy, (C1-C6)haloalkoxy, or -OH, or R3and R4together are -OCH2O- or -O(CH2)2O-, wherein the -OCH2O- or -O(CH2)2O- are optionally substituted with one or more (e.g., 1, 2, 3, or 4) groups independently selected from the groups consisting of halo and (C1-C6)alkyl; R4is hydrogen, halo, (C1-C6)alkyl, (C1-C6)haloalkyl, (C1-C6)alkoxy, (C1-C6)haloalkoxy, or -OH, or R3and R4or R4and R5together are -OCH2O- or -O(CH2)2O-, wherein the -OCH2O- or -O(CH2)2O- are optionally substituted with one or more (e.g., 1, 2, 3, or 4) groups independently selected from the groups consisting of halo and (C1-C6)alkyl;R5is hydrogen, halo, (C1-C6)alkyl, (C1-C6)haloalkyl, (C1-C6)alkoxy, (C1-C6)haloalkoxy, or -OH, or R4and R5or R5and R6together are -OCH2O- or -O(CH2)2O-, wherein the -OCH2O- or -O(CH2)2O- are optionally substituted with one or more (e.g., 1, 2, 3, or 4) groups independently selected from the groups consisting of halo and (C1-C6)alkyl; R6is hydrogen, halo, (C1-C6)alkyl, (C1-C6)haloalkyl, (C1-C6)alkoxy, (C1-C6)haloalkoxy, or -OH, or R5and R6together are -OCH2O- or -O(CH2)2O-, wherein the -OCH2O- or - O(CH2)2O- are optionally substituted with one or more (e.g., 1, 2, 3, or 4) groups independently selected from the groups consisting of halo and (C1-C6)alkyl; R7is hydrogen, halo, (C1-C6)alkyl, (C1-C6)haloalkyl, (C1-C6)alkoxy, (C1-C6)haloalkoxy, or -OH, or R7and R8together are -OCH2O- or -O(CH2)2O-, wherein the -OCH2O- or - O(CH2)2O- are optionally substituted with one or more (e.g., 1, 2, 3, or 4) groups independently selected from the groups consisting of halo and (C1-C6)alkyl; R8is hydrogen, halo, (C1-C6)alkyl, (C1-C6)haloalkyl, (C1-C6)alkoxy, (C1-C6)haloalkoxy, or -OH, or R7and R8or R8and R9together are -OCH2O- or -O(CH2)2O-, wherein the -OCH2O- or -O(CH2)2O- are optionally substituted with one or more (e.g., 1, 2, 3, or 4) groups independently selected from the groups consisting of halo and (C1-C6)alkyl; R9is hydrogen, halo, (C1-C6)alkyl, (C1-C6)haloalkyl, (C1-C6)alkoxy, (C1-C6)haloalkoxy, or -OH, or R8and R9or R9and R10together are -OCH2O- or -O(CH2)2O-, wherein the -OCH2O- or -O(CH2)2O- are optionally substituted with one or more (e.g., 1, 2, 3, or 4) groups independently selected from the groups consisting of halo and (C1-C6)alkyl; R10is hydrogen, halo, (C1-C6)alkyl, (C1-C6)haloalkyl, (C1-C6)alkoxy, (C1-C6)haloalkoxy, or -OH, or R9and R10together are -OCH2O- or -O(CH2)2O-, wherein the -OCH2O- or - O(CH2)2O- are optionally substituted with one or more (e.g., 1, 2, 3, or 4) groups independently selected from the groups consisting of halo and (C1-C6)alkyl; each R11aand R11bare independently hydrogen, halo, (C1-C6)alkyl or (C3-C7)carbocyclyl each Ra1and Rb1is independently hydrogen, (C1-C6)alkyl or (C3-C7)carbocyclyl; each Rc1is independently (C1-C6)alkyl or (C3-C7)carbocyclyl, wherein (C1-C6)alkyl or (C3-C7)carbocyclyl is optionally substituted with one or more (e.g., 1, 2, 3, or 4) halo; each Ra2and Rb2is independently hydrogen, (C1-C6)alkyl, or (C3-C7)carbocyclyl; each Rc2is independently (C1-C6)alkyl or (C3-C7)carbocyclyl, wherein (C1-C6)alkyl or (C3-C7)carbocyclyl is optionally substituted with one or more (e.g., 1, 2, 3, or 4) halo; and each Ra3and Rb3is independently hydrogen, (C1-C6)alkyl, or (C3-C7)carbocyclyl;provided the compound is not:.

3. The compound or salt of claim 1 or claim 2, wherein X is CH2and m is 1.

4. The compound or salt of any one of claims 1-3, wherein R2is hydrogen.

5. The compound or salt of claim 1, wherein the compound of formula I is a compound of formula Ia:or a salt thereof.

6. The compound or salt of any one of claims 1-5, wherein R3is hydrogen, halo, (C1- C6)alkoxy, or (C1-C6)haloalkoxy or R3and R4together are -OCH2O- or -O(CH2)2O-, wherein the -OCH2O- or -O(CH2)2O- are optionally substituted with one or more groups independently selected from the groups consisting of halo and (C1-C6)alkyl.

7. The compound or salt of any one of claims 1-5, wherein R3is hydrogen.

8. The compound or salt of any one of claims 1-7, wherein R4is hydrogen, halo, (C1- C6)alkoxy, or (C1-C6)haloalkoxy, or R3and R4or R4and R5together are -OCH2O- or -O(CH2)2O-, wherein the -OCH2O- or -O(CH2)2O-are optionally substituted with one or more groups independently selected from the groups consisting of halo and (C1-C6)alkyl.

9. The compound or salt of any one of claims 1-7, wherein R4is hydrogen.

10. The compound or salt of any one of claims 1-9, wherein R5is hydrogen, halo, (C1- C6)alkoxy, or (C1-C6)haloalkoxy, or R4and R5or R5and R6together are -OCH2O- or -O(CH2)2O-, wherein the -OCH2O- or -O(CH2)2O- are optionally substituted with one or more groups independently selected from the groups consisting of halo and (C1-C6)alkyl.

11. The compound or salt of any one of claims 1-9, wherein R5is hydrogen or halo.

12. The compound or salt of any one of claims 1-11, wherein R6is hydrogen, halo, (C1- C6)alkoxy, or (C1-C6)haloalkoxy, or R5and R6together are -OCH2O- or -O(CH2)2O-, wherein the -OCH2O- or -O(CH2)2O- are optionally substituted with one or more groups independently selected from the groups consisting of halo and (C1-C6)alkyl.

13. The compound or salt of any one of claims 1-11, wherein R6is hydrogen.

14. The compound or salt of any one of claims 1-13, wherein R7is hydrogen, halo, (C1- C6)alkoxy, or (C1-C6)haloalkoxy or R6and R7together are -OCH2O- or -O(CH2)2O-, wherein the -OCH2O- or -O(CH2)2O- are optionally substituted with one or more groups independently selected from the groups consisting of halo and (C1-C6)alkyl.

15. The compound or salt of any one of claims 1-13, wherein R7is hydrogen.

16. The compound or salt of any one of claims 1-15, wherein R8is hydrogen, halo, (C1- C6)alkoxy, or (C1-C6)haloalkoxy, or R7and R8or R8and R9together are -OCH2O- or -O(CH2)2O-, wherein the -OCH2O- or -O(CH2)2O- are optionally substituted with one or more groups independently selected from the groups consisting of halo and (C1-C6)alkyl.

17. The compound or salt of any one of claims 1-15, wherein R8is hydrogen, (C1-C6)alkoxy, or R8and R9together are -OCH2O-, wherein the -OCH2O- is optionally substituted with one or more groups independently selected from the groups consisting of halo and (C1-C6)alkyl.

18. The compound or salt of any one of claims 1-17, wherein R9is hydrogen, halo, (C1- C6)alkoxy, or (C1-C6)haloalkoxy, or R8and R9or R9and R10together are -OCH2O- or -O(CH2)2O-, wherein the -OCH2O- or -O(CH2)2O- are optionally substituted with one or more groups independently selected from the groups consisting of halo and (C1-C6)alkyl.

19. The compound or salt of any one of claims 1-17, wherein R9is hydrogen, halo, or (C1- C6)alkoxy, or R8and R9together are -OCH2O-, wherein the -OCH2O- is optionally substituted with one or more groups independently selected from the groups consisting of halo and (C1- C6)alkyl.

20. The compound or salt of any one of claims 1-19, wherein R10is hydrogen, halo, (C1- C6)alkoxy, or (C1-C6)haloalkoxy, or R9and R10together are -OCH2O- or -O(CH2)2O-, wherein the -OCH2O- or -O(CH2)2O- are optionally substituted with one or more groups independently selected from the groups consisting of halo and (C1-C6)alkyl.

21. The compound or salt of any one of claims 1-19, wherein R10is hydrogen or halo.

22. The compound or salt of any one of claims 1-21, wherein R1is: (a) (C2-C8)alkyl, wherein the (C2-C8)alkyl is substituted independently with one or more -NRa1Rb1or -NRd1C(=NRe1)(NRf1Rg1) and wherein the (C2-C8)alkyl is optionally substituted with one or more groups independently selected from the group consisting of halo, (C1-C4)alkyl, (C3-C7)carbocyclyl, -OH, and -ORc1; or (b) 4-7 membered monocyclic heterocyclyl-(C1-C3)alkyl-, wherein the 4-7 membered monocyclic heterocyclyl-(C1-C3)alkyl- is substituted with one or more groups independently selected from the groups consisting of -NRa2Rb2, -NRd2C(=NRe2)(NRf2Rg2) and - (C1-C6)alkyl substituted with one or more -NRa3Rb3or -NRd2C(=NRe2)(NRf2Rg2) and wherein the heterocyclyl-(C1-C3)alkyl- or -(C1-C6)alkyl is optionally substituted with one or more groups independently selected from the group consisting of halo, (C1-C4)alkyl, (C3-C7)carbocyclyl, -OH, and -ORc2.

23. The compound or salt of any one of claims 1-21, wherein R1is: (a) (C2-C8)alkyl, wherein the (C2-C8)alkyl is substituted with one or more -NRa1Rb1, and wherein the (C2-C8)alkyl is optionally substituted with one or more groups independently selected from the group consisting of halo, (C1-C4)alkyl, (C3-C7)carbocyclyl, -OH, and -ORc1; or (b) 4-7 membered monocyclic heterocyclyl-(C1-C3)alkyl-, wherein the 4-7 membered monocyclic heterocyclyl-(C1-C3)alkyl- is substituted with one or more groupsindependently selected from the groups consisting of -NRa2Rb2and -(C1-C6)alkyl substituted with one or more -NRa3Rb3, and wherein the heterocyclyl-(C1-C3)alkyl- or -(C1-C6)alkyl is optionally substituted with one or more groups independently selected from the group consisting of halo, (C1-C4)alkyl, (C3-C7)carbocyclyl, -OH, and -ORc2.

24. The compound or salt of any one of claims 1-21, wherein R1is: (a) (C2-C8)alkyl, wherein the (C2-C8)alkyl is substituted independently with two or more -NRa1Rb1or -NRd1C(=NRe1)(NRf1Rg1) and wherein the (C2-C8)alkyl is optionally substituted with one or more groups independently selected from the group consisting of halo, (C1-C4)alkyl, (C3-C7)carbocyclyl, -OH, and -ORc1; or (b) 4-7 membered monocyclic heterocyclyl-(C1-C3)alkyl-, wherein the 4-7 membered monocyclic heterocyclyl-(C1-C3)alkyl- is substituted with one or more groups independently selected from the groups consisting of -NRa2Rb2, -NRd2C(=NRe2)(NRf2Rg2) and - (C1-C6)alkyl substituted with one or more -NRa3Rb3or -NRd2C(=NRe2)(NRf2Rg2), and wherein the heterocyclyl-(C1-C3)alkyl- or -(C1-C6)alkyl is optionally substituted with one or more groups independently selected from the group consisting of halo, (C1-C4)alkyl, (C3-C7)carbocyclyl, -OH, and -ORc2.

25. The compound or salt of any one of claims 1-21, wherein R1is: (a) (C2-C8)alkyl, wherein the (C2-C8)alkyl is substituted with two or more -NRa1Rb1, and wherein the (C2-C8)alkyl is optionally substituted with one or more groups independently selected from the group consisting of halo, (C1-C4)alkyl, (C3-C7)carbocyclyl, -OH, and -ORc1; or (b) 4-7 membered monocyclic heterocyclyl-(C1-C3)alkyl-, wherein the 4-7 membered monocyclic heterocyclyl-(C1-C3)alkyl- is substituted with one or more groups independently selected from the groups consisting of -NRa2Rb2and -(C1-C6)alkyl substituted with one or more -NRa3Rb3, and wherein the heterocyclyl-(C1-C3)alkyl- or -(C1-C6)alkyl is optionally substituted with one or more groups independently selected from the group consisting of halo, (C1-C4)alkyl, (C3-C7)carbocyclyl, -OH, and -ORc2.

26. The compound or salt of any one of claims 1-21, wherein R1is: (a) (C2-C8)alkyl, wherein the (C2-C8)alkyl is substituted independently with two or more -NRa1Rb1or -NRd1C(=NRe1)(NRf1Rg1) and wherein the (C2-C8)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-(C1-C3)alkyl-, wherein the 4-7 membered monocyclic heterocyclyl-(C1-C3)alkyl- is substituted with one or more -(C1-C6)alkyl substituted with one or more -NRa3Rb3or -NRd2C(=NRe2)(NRf2Rg2), and wherein the heterocyclyl-(C1-C3)alkyl- is optionally substituted with one or more -OH.

27. The compound or salt of any one of claims 1-21, wherein R1is: (a) (C2-C8)alkyl, wherein the (C2-C8)alkyl is substituted with two or more -NRa1Rb1, and wherein the (C2-C8)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-(C1-C3)alkyl-, wherein the 4-7 membered monocyclic heterocyclyl-(C1-C3)alkyl- is substituted with one or more -(C1-C6)alkyl substituted with one or more -NRa3Rb3, and wherein the heterocyclyl-(C1-C3)alkyl- is optionally substituted with one or more -OH.

28. The compound or salt of any one of claims 1-21, wherein R1is (C2-C8)alkyl, wherein the (C2-C8)alkyl is substituted independently with one or more -NRa1Rb1or -NRd1C(=NRe1)(NRf1Rg1), and wherein the (C2-C8)alkyl is optionally substituted with one or more groups independently selected from the group consisting of halo, (C1-C4)alkyl, (C3- C7)carbocyclyl, -OH, and -ORc1.

29. The compound or salt of any one of claims 1-21, wherein R1is (C2-C8)alkyl, wherein the (C2-C8)alkyl is substituted with one or more -NRa1Rb1, and wherein the (C2-C8)alkyl is optionally substituted with one or more groups independently selected from the group consisting of halo, (C1-C4)alkyl, (C3-C7)carbocyclyl, -OH, and -ORc1.

30. The compound or salt of any one of claims 1-21, wherein R1is (C2-C8)alkyl, wherein the (C2-C8)alkyl is substituted independently with two or more -NRa1Rb1or -NRd1C(=NRe1)(NRf1Rg1), and wherein the (C2-C8)alkyl is optionally substituted with one or more groups independently selected from the group consisting of halo, (C1-C4)alkyl, (C3- C7)carbocyclyl, -OH, and -ORc1.

31. The compound or salt of any one of claims 1-21, wherein R1is (C2-C8)alkyl, wherein the (C2-C8)alkyl is substituted with two or more -NRa1Rb1, and wherein the (C2-C8)alkyl is optionally substituted with one or more groups independently selected from the group consisting of halo (C1-C4)alkyl (C3-C7)carbocyclyl -OH and -ORc132. The compound or salt of any one of claims 1-21, wherein R1is (C2-C8)alkyl, wherein the (C2-C8)alkyl is substituted independently with two or more -NRa1Rb1or -NRd1C(=NRe1)(NRf1Rg1), and wherein the (C2-C8)alkyl is optionally substituted with one or more groups independently selected from the group consisting of halo and -OH.

33. The compound or salt of any one of claims 1-21, wherein R1is (C2-C8)alkyl, wherein the (C2-C8)alkyl is substituted with two or more -NRa1Rb1, and wherein the (C2-C8)alkyl is optionally substituted with one or more groups independently selected from the group consisting of halo and -OH.

34. The compound or salt of any one of claims 1-21, wherein R1is 4-7 membered monocyclic heterocyclyl-(C1-C3)alkyl-, wherein the 4-7 membered monocyclic heterocyclyl- (C1-C3)alkyl- is substituted with one or more groups independently selected from the groups consisting of -NRa2Rb2, -NRd2C(=NRe2)(NRf2Rg2) and -(C1-C6)alkyl substituted with one or more -NRa3Rb3or -NRd2C(=NRe2)(NRf2Rg2), and wherein the heterocyclyl-(C1-C3)alkyl- or -(C1- C6)alkyl is optionally substituted with one or more groups independently selected from the group consisting of halo, (C1-C4)alkyl, (C3-C7)carbocyclyl, -OH, and -ORc2.

35. The compound or salt of any one of claims 1-21, wherein R1is 4-7 membered monocyclic heterocyclyl-(C1-C3)alkyl-, wherein the 4-7 membered monocyclic heterocyclyl- (C1-C3)alkyl- is substituted with one or more groups independently selected from the groups consisting of -NRa2Rb2and -(C1-C6)alkyl substituted with one or more -NRa3Rb3, and wherein the heterocyclyl-(C1-C3)alkyl- or -(C1-C6)alkyl is optionally substituted with one or more groups independently selected from the group consisting of halo, (C1-C4)alkyl, (C3-C7)carbocyclyl, -OH, and -ORc2.

36. The compound or salt of any one of claims 1-21, wherein R1is 4-7 membered monocyclic heterocyclyl-(C1-C3)alkyl-, wherein the 4-7 membered monocyclic heterocyclyl- (C1-C3)alkyl- is substituted with one or more -(C1-C6)alkyl substituted with one or more -NRa3Rb3or -NRd1C(=NRe1)(NRf1Rg1), and wherein the heterocyclyl-(C1-C3)alkyl- is optionally substituted with one or more -OH.

37. The compound or salt of any one of claims 1-21, wherein R1is 4-7 membered monocyclic heterocyclyl-(C1-C3)alkyl- wherein the 4-7 membered monocyclic heterocyclyl-(C1-C3)alkyl- is substituted with one or more -(C1-C6)alkyl substituted with one or more -NRa3Rb3, and wherein the heterocyclyl-(C1-C3)alkyl- is optionally substituted with one or more -OH.

38. The compound or salt of any one of claims 1-21, wherein R1is.

39. The compound of claim 1 that is:or a salt thereof.

40. A pharmaceutical composition comprising a compound as described in any one of claims 1-39 or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient.

41. A pharmaceutical composition comprising a compound as described in any one of claims 1-39 or a pharmaceutically acceptable salt thereof, one or more antibacterial agents and a pharmaceutically acceptable excipient.

42. A method of inhibiting a bacterial efflux pump in an animal comprising administering to the animal a compound as described in any one of claims 1-39 or a pharmaceutically acceptable salt thereof.

43. A method of treating or preventing a bacterial infection in an animal comprising co- administering to the animal a compound as described in any one of claims 1-39 or a pharmaceutically acceptable salt thereof and one or more antibacterial agents.

44. The method of claim 42 or claim 43 wherein the animal is infected with bacteria.

45. The method of claim 43 wherein the bacterial infection is a Gram-negative bacterial strain infection.

46. The method of claim 45, wherein 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, Campylobacter coli, Campylobacter fetus, Campylobacter jejuni, Caulobacter crescentus, Chlamydia trachomatis, Citrobacter diversus, Citrobacter freundii, Enterobacter aerogenes, Enterobacter asburiae, Enterobacter cloacae, Enterobacter sakazakii, Escherchia coli, Francisella tularensis, Fusobacterium nucleatum, Gardnerella vaginalis, Haemophilus ducreyi, Haemophilus haemolyticus, Haemophilus influenzae, Haemophilus parahaemolyticus, Haemophilus parainfluenzae, Helicobacter pylori, Kingella denitrificans, Kingella indologenes, Kingella kingae, Kingella oralis, Klebsiella oxytoca, Klebsiella pneumoniae, Klebsiella rhinoscleromatis, Legionella pneumophila, Listeria monocytogenes, Moraxella bovis, Moraxella catarrhalis, Moraxella lacunata, Morganella morganii, Neisseria gonorrhoeae, Neisseria meningitidis, Pantoea agglomerans, Pasteurella canis, Pasteurella haemolytica, Pasteurella multocida, Pasteurella tularensis, Porphyromonas gingivalis, Proteus mirabilis, Proteus vulgaris, Providencia alcalifaciens, Providencia rettgeri, Providencia stuartii, Pseudomonas acidovorans, Pseudomonas aeruginosa, Pseudomonas alcaligenes, Pseudomonas fluorescens, Pseudomonas putida, Salmonella enteriditis, Salmonella paratyphi, Salmonella typhi, Salmonella typhimurium, Serratia marcescens, Shigella dysenteriae, Shigella jlexneri, Shigella sonnei, Stenotrophomonas maltophilla, Veillonella parvula, Vibrio cholerae, Vibrio parahaemolyticus, Yersinia enterocolitica, Yersinia intermedia, Yersinia pestis and Yersinia pseudotuberculosis47. The method of claim 43, wherein the bacterial infection is a Gram-positive bacterial strain infection.

48. The method of claim 47, wherein 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, Staphylococcus saccharolyticus, Staphylococcus saprophyticus, Streptococcus agalactiae, Streptococcus mutans, Streptococcus pneumoniae, Streptococcus pyogenes, Streptococcus salivarius and Streptococcus sanguis.

49. A compound as described in any one of claims 1-39 or a pharmaceutically acceptable salt thereof for use in medical treatment.

50. A compound as described in any one of claims 1-39 or a pharmaceutically acceptable salt thereof for the prophylactic or therapeutic inhibition of a bacterial efflux pump for the treatment of a bacterial infection.

51. A compound as described in any one of claims 1-39 or a pharmaceutically acceptable salt thereof that is used in combination with one or more antibacterial agents for the prophylactic or therapeutic treatment of a bacterial infection.

52. The use of a compound as described in any one of claims 1-39 or a pharmaceutically acceptable salt thereof for the preparation of a medicament for inhibiting a bacterial efflux pump.

53. The use of a compound as described in any one of claims 1-39 or a pharmaceutically acceptable salt thereof for the preparation of a medicament for treating a bacterial infection in an animal.

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