WO2019140254A1 - Multicyclic compounds and use of same for treating tuberculosis - Google Patents

Multicyclic compounds and use of same for treating tuberculosis Download PDF

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WO2019140254A1
WO2019140254A1 PCT/US2019/013290 US2019013290W WO2019140254A1 WO 2019140254 A1 WO2019140254 A1 WO 2019140254A1 US 2019013290 W US2019013290 W US 2019013290W WO 2019140254 A1 WO2019140254 A1 WO 2019140254A1
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alkyl
cycloalkyl
compound
formula
optionally substituted
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PCT/US2019/013290
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French (fr)
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Daniel E. Kahne
Vadim BAIDIN
Eric J. RUBIN
Rebecca E. AUDETTE
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President And Fellows Of Harvard College
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D263/00—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings
    • C07D263/02—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings not condensed with other rings
    • C07D263/30—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
    • C07D263/32—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to ring carbon atoms
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D209/00—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom
    • C07D209/02—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom condensed with one carbocyclic ring
    • C07D209/04—Indoles; Hydrogenated indoles
    • C07D209/08—Indoles; Hydrogenated indoles with only hydrogen atoms or radicals containing only hydrogen and carbon atoms, directly attached to carbon atoms of the hetero ring
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
    • C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
    • C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D213/24—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with substituted hydrocarbon radicals attached to ring carbon atoms
    • C07D213/36—Radicals substituted by singly-bound nitrogen atoms
    • C07D213/38—Radicals substituted by singly-bound nitrogen atoms having only hydrogen or hydrocarbon radicals attached to the substituent nitrogen atom
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
    • C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
    • C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D213/60—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D213/78—Carbon atoms having three bonds to hetero atoms, with at the most one bond to halogen, e.g. ester or nitrile radicals
    • C07D213/79—Acids; Esters
    • C07D213/80—Acids; Esters in position 3
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D307/00—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom
    • C07D307/77—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom ortho- or peri-condensed with carbocyclic rings or ring systems
    • C07D307/78—Benzo [b] furans; Hydrogenated benzo [b] furans
    • C07D307/79—Benzo [b] furans; Hydrogenated benzo [b] furans with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to carbon atoms of the hetero ring
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D311/00—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only hetero atom, condensed with other rings
    • C07D311/02—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only hetero atom, condensed with other rings ortho- or peri-condensed with carbocyclic rings or ring systems
    • C07D311/76—Benzo[c]pyrans
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D333/00—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom
    • C07D333/02—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom not condensed with other rings
    • C07D333/04—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom not condensed with other rings not substituted on the ring sulphur atom
    • C07D333/06—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom not condensed with other rings not substituted on the ring sulphur atom with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to the ring carbon atoms
    • C07D333/14—Radicals substituted by singly bound hetero atoms other than halogen
    • C07D333/20—Radicals substituted by singly bound hetero atoms other than halogen by nitrogen atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D333/00—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom
    • C07D333/50—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom condensed with carbocyclic rings or ring systems
    • C07D333/52—Benzo[b]thiophenes; Hydrogenated benzo[b]thiophenes
    • C07D333/54—Benzo[b]thiophenes; Hydrogenated benzo[b]thiophenes with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to carbon atoms of the hetero ring

Definitions

  • Multi-Drug Resistant (MDR) TB strains are challenging to treat.
  • Multi-drug resistant TB strains are resistant to at least the two main first-line TB drugs— isoniazid and rifampicin; and Extremely Drug Resistant (XDR) TB, strains are also resistant to three or more of the six classes of second-line drugs.
  • EEC AC Eastern Europe Central Asia countries
  • MDR/XDR strains can account for up to 22% of infections, with mortality rates for XDR reaching up to 100% of those infected (Eur. Respir. I, 33,
  • the present invention provides compounds represented by structural formula (I): or a pharmaceutically acceptable salt thereof;
  • L 5 is (Ci-C2)alkylene, optionally substituted with (Ci-Ce)alkyl, hydroxyl, hydroxyl(Ci-C6)alkyl, (C3-C6)cycloalkyl, phenyl, halo(Ci-C6)alkyl, (Ci-C6)alkoxyl(Ci- Ce)alkyl, -C(0)0H, or -C(0)0-(Ci-C 6 )alkyl;
  • L 6 is (Ci-C2)alkylene, optionally substituted with (Ci-Ce)alkyl, hydroxyl, hydroxyl(Ci-C6)alkyl, (C3-C6)cycloalkyl, phenyl, halo(Ci-C6)alkyl, (Ci-C6)alkoxyl(Ci- Ce)alkyl, -C(0)0H, or -C(0)0-(Ci-C 6 )alkyl; is unsubstituted adamantyl;
  • R 6 is optionally substituted phenyl
  • R 7 is H, alkyl, hydroxyalkyl, cycloalkyl, (cycloalkyl)alkyl, aralkyl, or heteroaralkyl; wherein when (a) L 5 and L 6 are both optionally substituted (Ci)alkylene, or (b) when
  • L 5 is optionally substituted (C2)alkylene and L 6 is optionally substituted (Ci)alkylene, then
  • R 6 is phenyl substituted with one or more substituents, wherein the one or more substituents are selected from the group consisting of (C2-C6)alkyl, cycloalkyl, aryl, heteroaryl, halo, haloalkyl, hydroxyalkyl, alkoxy, (cycloalkyl)alkyl, and aralkyl, or wherein two adjacent substituents on phenyl, taken together with the intervening atoms, form a heteroaryl, aryl, cycloalkyl, or heterocycloalkyl ring.
  • substituents are selected from the group consisting of (C2-C6)alkyl, cycloalkyl, aryl, heteroaryl, halo, haloalkyl, hydroxyalkyl, alkoxy, (cycloalkyl)alkyl, and aralkyl, or wherein two adjacent substituents on phenyl, taken together with the intervening atoms, form a heteroary
  • the present invention provides a compound of formula (G):
  • L 5 is (Ci-C2)alkylene, optionally substituted with (Ci-Ce)alkyl, hydroxyl, hydroxyl(Ci-C6)alkyl, (C3-C6)cycloalkyl, phenyl, halo(Ci-C6)alkyl, (Ci-C6)alkoxyl(Ci- C 6 )alkyl, -C(0)0H, or -C(0)0-(Ci-C 6 )alkyl;
  • L 6 is (Ci-C2)alkylene, optionally substituted with (Ci-Ce)alkyl, hydroxyl, hydroxyl(Ci-C6)alkyl, (C3-C6)cycloalkyl, phenyl, halo(Ci-C6)alkyl, (Ci-C6)alkoxyl(Ci- C 6 )alkyl, -C(0)0H, or -C(0)0-(Ci-C 6 )alkyl; unsubstituted adamantyl; R 6 is phenyl substituted with one or more substituents, wherein the one or more substituents are selected from the group consisting of (C2-C6)alkyl, cycloalkyl, aryl, heteroaryl, halo, haloalkyl, hydroxyalkyl, alkoxy, (cycloalkyl)alkyl, and aralkyl, or wherein two adjacent substituents on phenyl, taken together with the intervening
  • R 7 is H, alkyl, hydroxyalkyl, cycloalkyl, (cycloalkyl)alkyl, aralkyl, or heteroaralkyl.
  • the invention provides a method for treating tuberculosis, comprising administering to a subject in need thereof a therapeutically effective amount of a compound of formula (II):
  • L 1 is absent or is optionally substituted alkylene
  • L 2 is absent or is optionally substituted alkylene; is optionally substituted adamantyl;
  • R 2 is optionally substituted phenyl
  • R 3 is H, alkyl, hydroxyalkyl, cycloalkyl, (cycloalkyl)alkyl, aralkyl, or heteroaralkyl.
  • the invention provides a compound according to formula (X):
  • X is -0-, -CH2-, or -C(R 20 ) 2- ;
  • each R 20 is independently selected from the group consisting of H and alkyl
  • L 25 is absent or is optionally substituted alkylene; optionally adamantyl; R 21 is a substituent selected from the group consisting of alkyl, cycloalkyl, aryl, heteroaryl, (cycloalkyl)alkyl, aralkyl, hydroxyl, hydroxyalkyl, alkoxy, halo, and haloalkyl; and m is an integer from 0 to 4; and
  • R 27 is H, alkyl, hydroxyalkyl, cycloalkyl, (cycloalkyl)alkyl, aralkyl, or heteroaralkyl.
  • Alkyl means an optionally substituted saturated aliphatic branched or straight- chain monovalent hydrocarbon radical having the specified number of carbon atoms.
  • (Ci-Ce) alkyl means a radical having from 1-6 carbon atoms in a linear or branched arrangement.
  • (Ci-Ce)alkyl includes methyl, ethyl, propyl, butyl, pentyl and hexyl.
  • Alkylene means an optionally substituted saturated aliphatic branched or straight-chain divalent hydrocarbon radical having the specified number of carbon atoms.
  • “(Ci-C 6 )alkylene” includes a divalent saturated aliphatic radical having from 1-6 carbon atoms in a linear arrangement, e.g.,— [(CH 2 )n]— , where n is an integer from 1 to 6, “(Ci-C 6 )alkylene” includes methylene, ethylene, propylene, butylene, pentylene and hexylene.“(Ci-C 6 )alkylene” also includes a divalent saturated radical having from 1-6 carbon atoms in a branched arrangement, for example:— [(CHiCHiCHiCHiCH ⁇ )]— ,— [(CH2CH2CH2CH 2 C(CH3)2]— ,— [(CH 2 C(CH3) 2 CH(CH3))]— , and the like.
  • Aryl or“aromatic” means an aromatic monocyclic or polycyclic (e.g. bicyclic or tricyclic) carbocyclic ring system.
  • “aryl” is a 6-12 membered monocylic or bicyclic system.
  • Aryl systems include, but not limited to, phenyl, naphthyl, fluorenyl, indenyl, azulenyl, and anthracenyl.
  • “aryl” is phenyl.
  • Carbocyclyl means a cyclic group with only ring carbon atoms.“Carbocyclyl” includes 3-12 membered saturated or unsaturated aliphatic cyclic hydrocarbon rings or 6-12 membered aryl rings. A carbocyclyl moiety can be monocyclic, fused bicyclic, bridged bicyclic, spiro bicyclic, or polycyclic. [0016] Monocyclic carbocyclyls are saturated or unsaturated aliphatic cyclic
  • Monocyclic carbocyclyls include cycloalkyl, cycloalkenyl, cycloalkynyl and phenyl.
  • a fused bicyclic carbocyclyl has two rings which have two adjacent ring atoms in common.
  • the first ring is a monocyclic carbocyclyl and the second ring is a monocyclic carbocyclyl or a monocyclic heterocyclyl.
  • a bridged bicyclic carbocyclyl has two rings which have three or more adjacent ring atoms in common.
  • the first ring is a monocyclic carbocyclyl and the second ring is a monocyclic carbocyclyl or a monocyclic heterocyclyl.
  • a bridged bicyclic carbocylyl is adamantyl.
  • a spiro bicyclic carbocyclyl has two rings which have only one ring atom in common.
  • the first ring is a monocyclic carbocyclyl and the second ring is a monocyclic carbocyclyl or a monocyclic heterocyclyl.
  • Polycyclic carbocyclyls have more than two rings (e.g., three rings resulting in a tricyclic ring system) and adjacent rings have at least one ring atom in common.
  • the first ring is a monocyclic carbocyclyl and the remainder of the ring structures are monocyclic carbocyclyls or monocyclic heterocyclyl s.
  • Polycyclic ring systems include fused, bridged and spiro ring systems.
  • a fused polycyclic ring system has at least two rings that have two adjacent ring atoms in common.
  • a spiro polycyclic ring system has at least two rings that have only one ring atom in common.
  • a bridged polycyclic ring system has at least two rings that have three or more adjacent ring atoms in common.
  • Cycloalkyl means a saturated aliphatic cyclic hydrocarbon ring.
  • (C3- C7)cycloalkyl means a hydrocarbon radical of a (3-7 membered) saturated aliphatic cyclic hydrocarbon ring.
  • a C3-C7cycloalkyl includes, but is not limited to cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and cycloheptyl.
  • Cycloalkene means an aliphatic cyclic hydrocarbon ring having one or more double bonds in the ring.
  • Cycloalkyne means an aliphatic cyclic hydrocarbon ring having one or more triple bonds in the ring.
  • Hetero refers to the replacement of at least one carbon atom member in a ring system with at least one heteroatom selected from N, S, and O.“Hetero” also refers to the replacement of at least one carbon atom member in a acyclic system.
  • a hetero ring system or a hetero acyclic system may have 1, 2, 3 or 4 carbon atom members replaced by a heteroatom.
  • Heterocyclyl means a cyclic 4-12 membered saturated or unsaturated aliphatic or aromatic ring containing 1, 2, 3, 4 or 5 heteroatoms independently selected from N, O or S. When one heteroatom is S, it can be optionally mono- or di-oxygenated (i.e.— S(O)— or — S(0) 2— ).
  • the heterocyclyl can be monocyclic, fused bicyclic, bridged bicyclic, spiro bicyclic or polycyclic.
  • “Saturated heterocyclyl” means an aliphatic heterocyclyl group without any degree of un saturation (i.e., no double bond or triple bond). It can be monocyclic, fused bicyclic, bridged bicyclic, spiro bicyclic or polycyclic.
  • Examph 5S of monocyclic saturated heterocyciyls include, but are not limited to, azetidine, pyrrolidine, piperidine, piperazine, azepane, hexahydropyrimidine,
  • a fused bicyclic heterocyclyl has two rings which have two adjacent ring atoms in common.
  • the first ring is a monocyclic heterocyclyl and the second ring is a monocyclic carbocycie (such as a cycloalkyl or phenyl) or a monocyclic heterocyclyl.
  • the second ring is a (CiwCejcycloaikyl, such as cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl.
  • the second ring is phenyl. Examples of fused bicyclic
  • heterocyciyls include, but are not limited to, octahydrocyclopenta[c]pyrrolyl, indoline, isoindoline, 2,3-dihydro-lH-benzo[d]imidazole, 2,3-dihydrobenzo[d]oxazo!e, 2,3- dihydrohenzo[d]thiazole, oetahydrobenzo[d]oxazo!e, octahydro-lH-benzo[d]imidazole, octahydrobenzo[d]thiazo3e, octahydroeyciopenta[c]pyrrole, 3-azabicyclo[3.l .O]bexane, and 3-azabicyclo[3.2.0]heptane.
  • a spiro bicyclic heterocyclyl has two rings which have only one ring atom in common.
  • the first ring is a monocyclic heterocyclyl and the second ring is a monocyclic carbocycie (such as a cycloalkyl or phenyl) or a monocyclic heterocyclyl.
  • the second ring is a (Cs-Cejcycloaikyl.
  • the second ring is phenyl.
  • Example of spiro bicyclic heterocyclyl includes, but are not limited to, azaspiro[4.4]nonane, 7- azaspiro[4.4]nonane, azaspiro[4.5]deeane, 8-azaspiro[4.5]decane, azaspiro[5.5]undecane, 3- azaspiro[5.5]undecane and 3,9-diazaspiro[5.5]undecane.
  • a bridged bicyclic heterocyclyl has two rings which have three or more adjacent ring atoms in common. The first ring is a monocyclic heterocyclyl and the other ring is a monocyclic carbocycle (such as a cycloalkyl or phenyl) or a monocyclic heterocyclyl.
  • bri dged bicyclic heterocyclyls include, but are not limited to,
  • Polycyclic heterocyclyls have more than two rings, one of which is a heterocyclyl (e.g., three rings resulting in a tricyclic ring system) and adjacent rings having at least one ring atom in common.
  • Polycyclic ring systems include fused, bridged and spiro ring systems.
  • a fused polycyclic ring system has at least two rings that have twO adjacent ring atoms in common.
  • a spiro polycyclic ring system has at least two rings that have only one ring atom in common.
  • a bridged polycyclic ring system has at least two rings that have three or more adjacent ring atoms in common.
  • Heteroaryl or“heteroaromatic ring” means a 5-12 membered monovalent heteroaromatic monocyclic or bicyiic ring radical.
  • a herteroaryl contains 1, 2, 3 or 4 heteroatoms independently selected from N, O, and S.
  • Heteroaryls include, but are not limited to furan, oxazole, thiophene, 1,2,3-triazole, 1 ,2,4-triazine, 1,2, 4-triazole, 1,2,5- thiadi azole 1,1 -dioxide, 1,2,5-thiadiazole 1-oxide, 1,2,5-thiadiazole, 1,3,4-oxadiazole, 1,3,4- thiadi azole, 1,3,5-triazine, imidazole, isothiazole, isoxazole, pyrazole, pyridazine, pyridine, pyridine-N-oxide, pyrazine, pyrimidine, pyrrole, tetrazole, and thi azole.
  • Bicyclic heteroaryl rings include, but are not limited to, bicyc!o[4.4 Q]and bicyclo[4.3.0]fused ring systems such as indolizine, indole, isoindole, indazole, benzimidazole, benzthiazole, purine, quinoline, isoquinoline, cinnoline, phthalazine, quinazoline, quinoxaline, l,8-naphthyridine, and pteridine.
  • a group such as alkylene, adamantyl, naphthyl, or aryl may be optionally substituted.
  • substituents include halo, (Ci- Cejalkyl,—OH, -O, (Ci-Cejalkoxy, (Cr-Cejalkoxy-CCi-Cejalkylene, (Ci-Cejhaloalkyl, (Ci- C fi jhaloalkoxy, and— C(O)— (Ci-Csjalkyl.
  • a phenyl group may have two adjacent substituents that, taken together with the intervening atoms, form an optionally substituted heteroaryl, aryl, cycloalkyl, or heterocycloalkyl ring.
  • a phenyl group having two adjacent substituents that, taken together with the intervening atoms, form a pyridinyl group can have the structure any positional isomer thereof.
  • a phenyl group having two adjacent substituents that, taken together with the intervening atoms, form a tetrahydropyranyl group can have the
  • Halogen and“halo” are interchangeably used herein and each refers to fluorine, chlorine, bromine, or iodine.
  • Alkoxy means an alkyl radical attached through an oxygen linking atom.
  • (Ci- C6)-alkoxy includes methoxy, ethoxy, propoxy, butoxy, pentoxy and hexoxy.
  • Haioalky includes mono, poly, and perhaloalkyl groups where each halogen is independently selected from fluorine, chlorine, and bromine.
  • “Pharmaceutically acceptable carrier” means non-therapeutic components that are of sufficient purity and quality for use in the formulation of a composition of the invention that, when appropriately administered to an animal or human, typically do not produce an adverse reaction, and that are used as a vehicle for a drug substance (i.e. a compound of the present invention).
  • compositions of the present invention are also included.
  • an acid salt of a compound of the present invention containing an amine or other basic group can be obtained by reacting the compound with a suitable organic or inorganic acid, resulting in pharmaceutically acceptable anionic salt forms.
  • anionic salts include the acetate, benzenesulfonate, benzoate, bicarbonate, hi tartrate, bromide, calcium edetate, camsylate, carbonate, chloride, citrate, dihydrochloride, edetate, edisylate, estolate, esylate, fumarate, glyceptate, gluconate, glutamate,
  • Salts of the compounds of the present invention containing a carboxylic acid or other acidic functional group can be prepared by reacting with a suitable base.
  • Such a pharmaceutically acceptable salt may be made with a base which affords a pharmaceutically acceptable cation, which includes alkali metal salts (especially sodium and potassium), alkaline earth metal salts (especially calcium and magnesium), aluminum salts and ammonium salts, as well as salts made from physiologically acceptable organic bases such as trimethylamine, triethylamine, morpholine, pyridine, piperidine, picoline,
  • dicyclohexylamine N,N'-dibenzylethylenediamine
  • 2-hydroxyethylamine 2-hydroxyethylamine
  • bis-(2- hydroxyethyi)amine bis-(2- hydroxyethyi)amine
  • tri-(2-hydroxyethyl)amine procaine
  • dibenzylpiperidine dicyclohexylamine, N,N'-dibenzylethylenediamine, 2-hydroxyethylamine, bis-(2- hydroxyethyi)amine, tri-(2-hydroxyethyl)amine, procaine, dibenzylpiperidine,
  • dehydroabietylamine N,N'-bisdehydroabietylamine, giucamine, N-methylg!ucamine, collidine, quinine, quinoline, and basic amino acids such as lysine and arginine.
  • the invention provides compounds represented by structural formula (I):
  • L 5 is (Ci-C2)alkylene, optionally substituted with (Ci-Ce)alkyl, hydroxyl,
  • L 6 is (Ci-C2)alkylene, optionally substituted with (Ci-Ce)alkyl, hydroxyl,
  • R 6 is optionally substituted phenyl
  • R 7 is H, alkyl, hydroxyalkyl, cycloalkyl, (cycloalkyl)alkyl, aralkyl, or heteroaralkyl; wherein when (a) L 5 and L 6 are both optionally substituted (Ci)alkylene, or (b) when
  • L 5 is optionally substituted (C2)alkylene and L 6 is optionally substituted (Ci)alkylene, then
  • R 6 is phenyl substituted with one or more substituents, wherein the one or more substituents are selected from the group consisting of (C2-C6)alkyl, cycloalkyl, aryl, heteroaryl, halo, haloalkyl, hydroxyalkyl, alkoxy, (cycloalkyl)alkyl, and aralkyl, or wherein two adjacent substituents on phenyl, taken together with the intervening atoms, form a heteroaryl, aryl, cycloalkyl, or heterocycloalkyl ring.
  • substituents are selected from the group consisting of (C2-C6)alkyl, cycloalkyl, aryl, heteroaryl, halo, haloalkyl, hydroxyalkyl, alkoxy, (cycloalkyl)alkyl, and aralkyl, or wherein two adjacent substituents on phenyl, taken together with the intervening atoms, form a heteroary
  • the present invention provides a compound of formula
  • L 5 is (Ci-C2)alkylene, optionally substituted with (Ci-Ce)alkyl, hydroxyl, hydroxyl(Ci-C6)alkyl, (C3-C6)cycloalkyl, phenyl, halo(Ci-C6)alkyl, (Ci-C6)alkoxyl(Ci- Cejalkyl, -C(0)0H, or -C(0)0-(Ci-C 6 )alkyl;
  • L 6 is (Ci-C2)alkylene, optionally substituted with (Ci-Ce)alkyl, hydroxyl, hydroxyl(Ci-C6)alkyl, (C3-C6)cycloalkyl, phenyl, halo(Ci-C6)alkyl, (Ci-C6)alkoxyl(Ci- C 6 )alkyl, -C(0)0H, or -C(0)0-(Ci-C 6 )alkyl; is unsubstituted adamantyl;
  • R 6 is phenyl substituted with one or more substituents, wherein the one or more substituents are selected from the group consisting of (C2-C6)alkyl, cycloalkyl, aryl, heteroaryl, halo, haloalkyl, hydroxyalkyl, alkoxy, (cycloalkyl)alkyl, and aralkyl, or wherein two adjacent substituents on phenyl, taken together with the intervening atoms, form a heteroaryl, aryl, cycloalkyl, or heterocycloalkyl ring; and
  • R 7 is H, alkyl, hydroxyalkyl, cycloalkyl, (cycloalkyl)alkyl, aralkyl, or heteroaralkyl.
  • L 5 is unsubstituted methylene. Alternatively, in certain embodiments, L 5 is unsubstituted ethylene.
  • L 5 is methylene substituted with (Ci-Ce)alkyl, e.g., methyl.
  • L 5 is ethylene substituted with (Ci-Ce)alkyl, e.g., methyl.
  • ring is unsubstituted l-adamantyl.
  • L 6 is
  • L 6 is unsubstituted ethylene.
  • L 6 is methylene substituted with (Ci-Ce)alkyl, e.g., methyl.
  • L 6 is ethylene substituted with (Ci-Ce)alkyl, e.g., methyl.
  • R 6 is
  • R 6 is represented by , wherein:
  • R is a substituent selected from the group consisting of (C2-C6)alkyl, cycloalkyl, aryl, heteroaryl, halo, haloalkyl, hydroxylalkyl, alkoxy, (cycloalkyl)alkyl, and aralkyl; and
  • n is an integer from 0 to 5.
  • R 6 is represented
  • each occurrence of R is independently selected from the group consisting of (C2-C6)alkyl, alkoxy, and halo.
  • R is alkyl.
  • R may be alkoxy.
  • R is halo, e.g., fluoro.
  • R 6 is phenyl substituted with two or more substituents, wherein two adjacent substituents on phenyl, taken together with the intervening atoms, form a heteroaryl, aryl, cycloalkyl, or heterocycloalkyl ring.
  • R 6 may be represented represents an optionally substituted heteroaryl, aryl, cycloalkyl, or heterocycloalkyl ring.
  • R 2 may be optionally substituted.
  • moiety may represent optionally substituted tetralin, e.g., wherein the saturated ring of the tetralin system is optionally substituted by a substituent such as fluorine.
  • R 7 represents H, alkyl, or cycloalkyl. In further embodiments, R 7 represents H or alkyl, e.g., methyl. Preferably, R 7 is H.
  • the compound has the structure of formula (la):
  • the compound has the structure of formula (lb):
  • the compound has the structure of formula (Ic):
  • the compound has the structure of formula (Id):
  • the compound has the structure of formula (Ie):
  • the compound has the structure of formula (If):
  • the compound has the structure of formula (Ig):
  • the compound has the structure of formula (Ih):
  • R is a substituent selected from the group consisting of (C2-C6)alkyl, cycloalkyl, aryl, heteroaryl, halo, haloalkyl, hydroxyalkyl, alkoxy, (cycloalkyl)alkyl, and aralkyl; and n is an integer from 0 to 5.
  • the compound has the structure of formula (Ii):
  • R is a substituent selected from the group consisting of (C2-C6)alkyl, cycloalkyl, aryl, heteroaryl, halo, haloalkyl, hydroxyalkyl, alkoxy, (cycloalkyl)alkyl, and aralkyl; and n is an integer from 0 to 5.
  • the compound has the structure of formula (Ij):
  • R is a substituent selected from the group consisting of (C2-C6)alkyl, cycloalkyl, aryl, heteroaryl, halo, haloalkyl, hydroxyalkyl, alkoxy, (cycloalkyl)alkyl, and aralkyl; and n is an integer from 1 to 5.
  • the compound has the structure of formula (Ik):
  • R is a substituent selected from the group consisting of (C2-C6)alkyl, cycloalkyl, aryl, heteroaryl, halo, haloalkyl, hydroxyalkyl, alkoxy, (cycloalkyl)alkyl, and aralkyl; and n is an integer from 0 to 5.
  • the compound has the structure of formula (II):
  • R is a substituent selected from the group consisting of (C2-C6)alkyl, cycloalkyl, aryl, heteroaryl, halo, haloalkyl, hydroxyalkyl, alkoxy, (cycloalkyl)alkyl, and aralkyl; and n is an integer from 0 to 5.
  • the compound has the structure of formula (Im):
  • R is a substituent selected from the group consisting of (C2-C6)alkyl, cycloalkyl, aryl, heteroaryl, halo, haloalkyl, hydroxyalkyl, alkoxy, (cycloalkyl)alkyl, and aralkyl; and n is an integer from 0 to 5.
  • the compound has the structure of formula (In):
  • R is a substituent selected from the group consisting of (C2-C6)alkyl, cycloalkyl, aryl, heteroaryl, halo, haloalkyl, hydroxyalkyl, alkoxy, (cycloalkyl)alkyl, and aralkyl; and n is an integer from 0 to 5.
  • the invention provides any one of the compounds in Table 1 or a pharmaceutically acceptable salt thereof:
  • the invention provides a compound according to formula
  • X is -0-, -CH2-, or -C(R 20 ) 2- ;
  • each R 20 is independently selected from the group consisting of H and alkyl
  • L 25 is absent or is optionally substituted alkylene; ring is optionally adamantyl;
  • R 21 is a substituent selected from the group consisting of alkyl, cycloalkyl, aryl, heteroaryl, (cycloalkyl)alkyl, aralkyl, hydroxyl, hydroxyalkyl, alkoxy, halo, and haloalkyl; and m is an integer from 0 to 4; and
  • R 27 is H, alkyl, hydroxyalkyl, cycloalkyl, (cycloalkyl)alkyl, aralkyl, or heteroaralkyl.
  • Exemplary compounds of formula (X) include
  • the invention provides a method for treating tuberculosis, comprising administering to a subject in need thereof a therapeutically effective amount of a compound of formula (II):
  • L 1 is absent or is optionally substituted alkylene
  • L 2 is absent or is optionally substituted alkylene; is optionally substituted adamantyl;
  • R 2 is optionally substituted phenyl
  • R 3 is H, alkyl, hydroxyalkyl, cycloalkyl, (cycloalkyl)alkyl, aralkyl, or heteroaralkyl.
  • L 1 is unsubstituted methylene. Alternatively, in certain embodiments, L 1 is unsubstituted ethylene.
  • L 1 is methylene substituted with (Ci-Ce)alkyl, e.g., methyl.
  • L 1 is ethylene substituted with (Ci-Ce)alkyl, e.g., methyl.
  • L 2 is optionally substituted alkylene; e.g. optionally substituted (Ci-C2)alkylene.
  • L 2 is unsubstituted methylene. Alternatively, in certain embodiments, L 2 is unsubstituted ethylene.
  • L 2 is methylene substituted with (Ci-Ce)alkyl, e.g., methyl.
  • L 2 is ethylene substituted with (Ci-Ce)alkyl, e.g., methyl.
  • ring is optionally substituted l-adamantyl.
  • ring is l-adamantyl, substituted with one or more substituents selected from the group consisting of alkyl, hydroxyl, hydroxyalkyl, halo, and haloalkyl.
  • substituents selected from the group consisting of alkyl, hydroxyl, hydroxyalkyl, halo, and haloalkyl.
  • ring is l-adamantyl, substituted with methyl or hydroxyl.
  • ring may be unsubstituted l-adamantyl.
  • ring is optionally substituted 2-adamantyl.
  • ring is 2-adamantyl, substituted with one or more substituents selected from the group consisting of alkyl, hydroxyl, hydroxyalkyl, halo, and haloalkyl.
  • substituents selected from the group consisting of alkyl, hydroxyl, hydroxyalkyl, halo, and haloalkyl.
  • ring is 2-adamantyl, substituted with methyl or hydroxyl.
  • ring may be unsubstituted 2-adamantyl.
  • R 2 is represented by , wherein R is a substituent and n is an integer from 0 to 5.
  • each R is independently selected from the group consisting of alkyl, cycloalkyl, aryl, heteroaryl, (cycloalkyl)alkyl, aralkyl, hydroxyl, hydroxyalkyl, alkoxy, halo, and haloalkyl.
  • R 2 is represented
  • R represents alkyl, e.g., methyl.
  • R may represent fluoro.
  • R 2 is represented by , wherein R is a substituent and n is 0.
  • R 2 is phenyl substituted with two or more substituents, wherein two adjacent substituents on phenyl, taken together with the intervening atoms, form a heteroaryl, aryl, cycloalkyl, or heterocycloalkyl ring.
  • R 2 may be represented represents an optionally substituted heteroaryl, aryl, cycloalkyl, or heterocycloalkyl ring.
  • R 2 is represented by
  • moiety may be optionally substituted.
  • R 3 represents H, alkyl, or cycloalkyl.
  • R 3 represents H or alkyl, e.g., methyl.
  • R 3 is H.
  • L 1 is (Ci-C2)alkylene, optionally substituted with (Ci-Ce)alkyl, hydroxyl, hydroxyl(Ci-C6)alkyl, (C3-C6)cycloalkyl, phenyl, halo(Ci-C6)alkyl, (Ci-Ce)alkoxyl(Ci- Ce)alkyl, -C(0)OH, or -C(0)0-(Ci-C 6 )alkyl;
  • L 2 is (Ci-C2)alkylene, optionally substituted with (Ci-Ce)alkyl, hydroxyl, hydroxyl(Ci-C6)alkyl, (C3-C6)cycloalkyl, phenyl, halo(Ci-C6)alkyl, (Ci-Ce)alkoxyl(Ci- C 6 )alkyl, -C(0)OH, or -C(0)0-(Ci-C 6 )alkyl; is unsubstituted adamantyl;
  • R 2 is optionally substituted phenyl
  • R 3 is H, alkyl, or cycloalkyl
  • L 1 and L 2 are both optionally substituted (Ci)alkylene, or (b) when (a) L 1 and L 2 are both optionally substituted (Ci)alkylene, or (b) when (a) L 1 and L 2 are both optionally substituted (Ci)alkylene, or (b) when (a) L 1 and L 2 are both optionally substituted (Ci)alkylene, or (b) when
  • L 1 is optionally substituted (C2)alkylene and L 2 is optionally substituted (Ci)alkylene, then
  • R 2 is phenyl substituted with one or more substituents, wherein the one or more substituents are selected from the group consisting of (C2-C6)alkyl, cycloalkyl, aryl, heteroaryl, halo, haloalkyl, hydroxyalkyl, alkoxy, (cycloalkyl)alkyl, and aralkyl, or wherein two adjacent substituents on phenyl, taken together with the intervening atoms, form a heteroaryl, aryl, cycloalkyl, or heterocycloalkyl ring.
  • substituents are selected from the group consisting of (C2-C6)alkyl, cycloalkyl, aryl, heteroaryl, halo, haloalkyl, hydroxyalkyl, alkoxy, (cycloalkyl)alkyl, and aralkyl, or wherein two adjacent substituents on phenyl, taken together with the intervening atoms, form a heteroary
  • L 1 is (Ci-C2)alkylene, optionally substituted with (Ci-Ce)alkyl, hydroxyl, hydroxyl(Ci-C6)alkyl, (C3-C6)cycloalkyl, phenyl, halo(Ci-C6)alkyl, (Ci-Ce)alkoxyl(Ci- C 6 )alkyl, -C(0)OH, or -C(0)0-(Ci-C 6 )alkyl;
  • L 2 is (Ci-C2)alkylene, optionally substituted with (Ci-Ce)alkyl, hydroxyl, hydroxyl(Ci-C6)alkyl, (C3-C6)cycloalkyl, phenyl, halo(Ci-C6)alkyl, (Ci-Ce)alkoxyl(Ci- C 6 )alkyl, -C(0)OH, or -C(0)0-(Ci-C 6 )alkyl; is unsubstituted adamantyl;
  • R 2 is phenyl substituted with one or more substituents, wherein the one or more substituents are selected from the group consisting of (C2-C6)alkyl, cycloalkyl, aryl, heteroaryl, halo, haloalkyl, hydroxyalkyl, alkoxy, (cycloalkyl)alkyl, and aralkyl, or wherein two adjacent substituents on phenyl, taken together with the intervening atoms, form a heteroaryl, aryl, cycloalkyl, or heterocycloalkyl ring; and
  • R 3 is H, alkyl, hydroxyalkyl, cycloalkyl, (cycloalkyl)alkyl, aralkyl, or heteroaralkyl.
  • the compound has the structure of formula (Ha):
  • the compound has the structure of formula (lib):
  • the compound has the structure of formula (He):
  • the compound has the structure of formula (lid):
  • the compound has the structure of formula (He):
  • the compound has the structure of formula (Ilf): [00113] In some embodiments of the compounds of formula (II), the compound has the structure of formula (Ilg):
  • the compound has the structure of formula (Ilh):
  • R is a substituent selected from the group consisting of alkyl, cycloalkyl, aryl, heteroaryl, (cycloalkyl)alkyl, aralkyl, hydroxyl, hydroxyalkyl, alkoxy, halo, and haloalkyl; and n is an integer from 0 to 5.
  • the compound has the structure of formula (Hi):
  • R is a substituent selected from the group consisting of alkyl, cycloalkyl, aryl, heteroaryl, (cycloalkyl)alkyl, aralkyl, hydroxyl, hydroxyalkyl, alkoxy, halo, and haloalkyl; and n is an integer from 0 to 5.
  • the compound has the structure of formula (Ilj):
  • R is a substituent selected from the group consisting of alkyl, cycloalkyl, aryl, heteroaryl, (cycloalkyl)alkyl, aralkyl, hydroxyl, hydroxyalkyl, alkoxy, halo, and haloalkyl; and n is an integer from 0 to 5.
  • the compound has the structure of formula (Ilk):
  • R is a substituent selected from the group consisting of alkyl, cycloalkyl, aryl, heteroaryl, (cycloalkyl)alkyl, aralkyl, hydroxyl, hydroxyalkyl, alkoxy, halo, and haloalkyl; and n is an integer from 0 to 5.
  • the compound has the structure of formula (III):
  • R is a substituent selected from the group consisting of alkyl, cycloalkyl, aryl, heteroaryl, (cycloalkyl)alkyl, aralkyl, hydroxyl, hydroxyalkyl, alkoxy, halo, and haloalkyl; and n is an integer from 0 to 5.
  • the compound has the structure of formula (Ilm):
  • R is a substituent selected from the group consisting of alkyl, cycloalkyl, aryl, heteroaryl, (cycloalkyl)alkyl, aralkyl, hydroxyl, hydroxyalkyl, alkoxy, halo, and haloalkyl; and n is an integer from 0 to 5.
  • the compound has the structure of formula (Iln):
  • R is a substituent selected from the group consisting of alkyl, cycloalkyl, aryl, heteroaryl, (cycloalkyl)alkyl, aralkyl, hydroxyl, hydroxyalkyl, alkoxy, halo, and haloalkyl; and n is an integer from 0 to 5.
  • compounds useful in the method of treating tuberculosis is selected from any one of the compounds in Table 3 or a pharmaceutically acceptable salt thereof.
  • Anti-tuberculosis activity is shown in Table 3:
  • the subject treated by the methods of the invention is a mammal, e.g., a human.
  • the invention provides a method for inhibiting non-tuberculosis mycobacteria, comprising contacting the non-tuberculosis mycobacteria with an effective amount of a compound of formula (I).
  • the invention provides a method for treating an infection caused by non-tuberculosis mycobacteria, comprising administering to a subject in need thereof a therapeutically effective amount of a compound of formula (I).
  • Exemplary non-tuberculosis pathogenic mycobacteria for use in the methods of the invention include Runyon I organisms (photochromogens), such as Mycobacterium kansasii, Mycobacterium marinum , and Mycobacterium simiae; Runyon II organisms (scotochromogens), such as Mycobacterium scrofulaceum , and Mycobacterium szulgai , Mycobacterium gordonae; Runyon III organisms (nonchromogens), such as Mycobacterium avium complex, Mycobacterium ulcerous, Mycobacterium xenopi , Mycobacterium malmoense , Mycobacterium terrae complex, Mycobacterium haemophilum , and
  • Mycobacterium genavense and Runyon IV organisms, such as Mycobacterium abscessus complex, Mycobacterium chelonae , Mycobacterium fortuitum complex, and Mycobacterium peregrinum.
  • the invention provides a method for inhibiting pathogenic nocardia, comprising contacting the pathogenic nocardia with an effective amount of a compound of formula (I).
  • the invention provides a method for treating an infection caused by pathogenic nocardia, comprising administering to a subject in need thereof a therapeutically effective amount of a compound of formula (I).
  • Exemplary pathogenic nocardia useful in the methods of the invention include the following Nocardia species: N. concava, N. cyriacigeorgica, N donostiensis, N elegans, N exalbida, N. farcinica, N harenae, N. higoensis, N. ignorata, N. inohanensis, N. jinanensis, N kroppenstedtii, N. kruczakiae, N. mexicana, N. mikamii, N neocaledoniensis, N niigatensis, N ninae, N niwae, N nova, N. otitidiscaviarum, N. paucivorans, N
  • pneumoniae N. pseudobrasiliensis, N puris, N shinanonensis, N sienata, N takedensis, N terpenica, N testaceae, N. thailandica, N. transvalensis, N vermiculata, N veter ana, N vulneris, N wallacei, and N yamanashiensis .
  • the invention provides a method for inhibiting pathogenic actinomyces, comprising contacting the pathogenic actinomyces with an effective amount of a compound of formula (I).
  • the invention provides a method for treating an infection caused by pathogenic actinomyces, comprising administering to a subject in need thereof a therapeutically effective amount of a compound of formula (I).
  • Exemplary pathogenic actinomyces useful in the methods of the invention include the following Actinomyces species: A. israelii, A. viscosus, A. meyeri, A. naeslundii, A. odontolyticus, A. gerencseriae, A. neuii, A. turicensis, and A. radingae.
  • the methods of the invention further comprise administering one or more additional therapeutic agents.
  • additional therapeutic agents are anti-tuberculosis agents including, but not limited to, amikacin, aminosalicylic acid, capreomycin, cycloserine, ethambutol, ethionamide, isoniazid, kanamycin, pyrazinamide, rifamycins (such as rifampin, rifapentine and rifabutin), streptomycin, clarithromycin, azithromycin, oxazolidinones and fluoroquinolones (such as ofloxacin, ciprofloxacin, moxifloxacin and gatifloxacin).
  • “First-line” chemotherapeutic agents used to treat a Mycobacterium tuberculosis infection that is not drug resistant include isoniazid, rifampin, ethambutol, streptomycin and pyrazinamide.
  • “Second-line” chemotherapeutic agents used to treat a Mycobacterium tuberculosis infection that has demonstrated drug resistance to one or more“first-line” drugs include ofloxacin, ciprofloxacin, ethionamide, aminosalicylic acid, cycloserine, amikacin, kanamycin, capreomycin, clofazimine, bedaquiline, delaminid, and linezolid.
  • new anti-tuberculosis therapeutic agents emerging from clinical studies may also be employed as the one or more additional therapeutic agents in a combination with a compound of the invention, including, but not limited to LL-3858 and SQ-109.
  • the one or more additional therapeutic agents is selected from therapeutic vaccines, anti -bacterial agents, anti-viral agents; antibiotics and agents for the treatment of HIV/AIDS.
  • therapeutic agents include isoniazid (INH), ethambutol, rifampin, pyrazinamide, streptomycin, capreomycin, ciprofloxacin and clofazimine.
  • I he compound the invention, or a pharmaceutically acceptable salt thereof may be either i) administered to an individual who has previously been vaccinated against a mycobacterial infection; ii) administered to an individual who is subsequently vaccinated against a mycobacterial infection; or iii) may be co-administered with a vaccine against a mycobacterial infection, either by administering the compound of the invention and the vaccine together in the same dosage form or co-administering the compound of the invention and the vaccine in separate dosage forms.
  • the dose of the compound or agent may differ from that when the compound or agent is used alone.
  • the amount of a compound of the invention and the one or more additional therapeutic agents required for use in treatment will vary with the nature of the condition being treated and the age and the condition of the patient and will be ultimately at the discretion of the attendant physician or veterinarian.
  • a pharmaceutical combination comprising a compound of the invention, or a pharmaceutically acceptable salt thereof, together with one or more additional therapeutic agents, and one or more pharmaceutically acceptable carriers, excipients or diluents.
  • components of such combinations may be administered either sequentially or simultaneously in separate or combined pharmaceutical formulations by any convenient route.
  • either the compound of the present invention or one or more additional therapeutic agent may be administered first.
  • administration is simultaneous, the combination may be administered either in the same or different pharmaceutical composition.
  • the compound and agents When combined in the same formulation it will be appreciated that the compound and agents must be stable and compatible with each other and the other components of the formulation. When formulated separately they may be provided in any convenient formulation, conveniently in such manner as are known for such compounds in the art.
  • the invention also provides a pharmaceutical composition
  • a pharmaceutical composition comprising a compound of the invention (e.g., a compound of formula I, G, or X), and a pharmaceutically acceptable carrier.
  • the invention further includes the process for making the composition
  • compositions resulting from such a process comprising mixing one or more of the present compounds and an optional pharmaceutically acceptable carrier; and includes those compositions resulting from such a process, which process includes conventional pharmaceutical techniques.
  • compositions of the invention include ocular, oral, nasal, transdermal, topical with or without occlusion, intravenous (both bolus and infusion), inhalable, and injection (intraperitoneally, subcutaneously, intramuscularly, intralesionally, or parenterally) formulations.
  • the composition may be in a dosage unit such as a tablet, pill, capsule, powder, granule, liposome, ion exchange resin, sterile ocular solution, or ocular delivery device (such as a contact lens and the like facilitating immediate release, timed release, or sustained release), parenteral solution or suspension, metered aerosol or liquid spray, drop, ampoule, auto-injector device, or suppository; for administration ocularly, orally, intranasally, sublingually, parenterally, or rectally, or by inhalation or insufflation.
  • a dosage unit such as a tablet, pill, capsule, powder, granule, liposome, ion exchange resin, sterile ocular solution, or ocular delivery device (such as a contact lens and the like facilitating immediate release, timed release, or sustained release), parenteral solution or suspension, metered aerosol or liquid spray, drop, ampoule, auto-injector device, or suppository; for administration
  • compositions of the invention suitable for oral administration include solid forms such as pills, tablets, caplets, capsules (each including immediate release, timed release, and sustained release formulations), granules and powders; and, liquid forms such as solutions, syrups, elixirs, emulsions, and suspensions.
  • forms useful for ocular administration include sterile solutions or ocular delivery devices.
  • forms useful for parenteral administration include sterile solutions, emulsions, and suspensions.
  • compositions of the invention may be administered in a form suitable for once-weekly or once-monthly administration.
  • an insoluble salt of the active compound may be adapted to provide a depot preparation for intramuscular injection (e.g., a decanoate salt) or to provide a solution for ophthalmic administration.
  • the dosage form containing the composition of the invention contains an effective amount of the active ingredient necessary to provide a therapeutic effect.
  • the composition may contain from about 5,000 mg to about 0.5 mg (preferably, from about 1,000 mg to about 0.5 mg) of a compound of the invention or salt form thereof and may be constituted into any form suitable for the selected mode of administration.
  • the composition may be administered about 1 to about 5 times per day. Daily administration or post-periodic dosing may be employed.
  • the composition is preferably in the form of a tablet or capsule containing, e.g., 500 to 0.5 milligrams of the active compound. Dosages will vary depending on factors associated with the particular patient being treated (e.g., age, weight, diet, and time of administration), the severity of the condition being treated, the compound being employed, the mode of administration, and the strength of the preparation.
  • the oral composition is preferably formulated as a homogeneous composition, wherein the active ingredient is dispersed evenly throughout the mixture, which may be readily subdivided into dosage units containing equal amounts of a compound of the invention.
  • the compositions are prepared by mixing a compound of the invention (or pharmaceutically acceptable salt thereof) with one or more optionally present
  • pharmaceutical carriers such as a starch, sugar, diluent, granulating agent, lubricant, glidant, binding agent, and disintegrating agent
  • one or more optionally present inert pharmaceutical excipients such as water, glycols, oils, alcohols, flavoring agents, preservatives, coloring agents, and syrup
  • one or more optionally present conventional tableting ingredients such as corn starch, lactose, sucrose, sorbitol, talc, stearic acid, magnesium stearate, dicalcium phosphate, and any of a variety of gums
  • an optional diluent such as water.
  • Binder agents include starch, gelatin, natural sugars (e.g., glucose and beta- lactose), com sweeteners and natural and synthetic gums (e.g., acacia and tragacanth).
  • natural sugars e.g., glucose and beta- lactose
  • com sweeteners e.g., com sweeteners
  • natural and synthetic gums e.g., acacia and tragacanth
  • Disintegrating agents include starch, methyl cellulose, agar, and bentonite.
  • Tablets and capsules represent an advantageous oral dosage unit form. Tablets may be sugarcoated or film-coated using standard techniques. Tablets may also be coated or otherwise compounded to provide a prolonged, control-release therapeutic effect.
  • the dosage form may comprise an inner dosage and an outer dosage component, wherein the outer component is in the form of an envelope over the inner component.
  • the two components may further be separated by a layer which resists disintegration in the stomach (such as an enteric layer) and permits the inner component to pass intact into the duodenum or a layer which delays or sustains release.
  • enteric and non-enteric layer or coating materials such as polymeric acids, shellacs, acetyl alcohol, and cellulose acetate or combinations thereof may be used.
  • Compounds of the invention may also be administered via a slow release composition; wherein the composition includes a compound of the invention and a biodegradable slow release carrier (e.g., a polymeric carrier) or a pharmaceutically acceptable non-biodegradable slow release carrier (e.g., an ion exchange carrier).
  • a biodegradable slow release carrier e.g., a polymeric carrier
  • a pharmaceutically acceptable non-biodegradable slow release carrier e.g., an ion exchange carrier
  • Biodegradable and non-biodegradable slow release carriers are well known in the art.
  • Biodegradable carriers are used to form particles or matrices which retain an active agent(s) and which slowly degrade/dissolve in a suitable environment (e.g., aqueous, acidic, basic and the like) to release the agent.
  • a suitable environment e.g., aqueous, acidic, basic and the like
  • Such particles degrade/dissolve in body fluids to release the active compound(s) therein.
  • the particles are preferably nanoparticles or nanoemulsions (e.g., in the range of about 1 to 500 nm in diameter, preferably about 50-200 nm in diameter, and most preferably about 100 nm in diameter).
  • a slow release carrier and a compound of the invention are first dissolved or dispersed in an organic solvent.
  • the resulting mixture is added into an aqueous solution containing an optional surface-active agent(s) to produce an emulsion.
  • the organic solvent is then evaporated from the emulsion to provide a colloidal suspension of particles containing the slow release carrier and the compound of the invention.
  • the compound disclosed herein may be incorporated for administration orally or by injection in a liquid form such as aqueous solutions, suitably flavored syrups, aqueous or oil suspensions, flavored emulsions with edible oils such as cottonseed oil, sesame oil, coconut oil or peanut oil and the like, or in elixirs or similar pharmaceutical vehicles.
  • aqueous solutions suitably flavored syrups, aqueous or oil suspensions, flavored emulsions with edible oils such as cottonseed oil, sesame oil, coconut oil or peanut oil and the like, or in elixirs or similar pharmaceutical vehicles.
  • Suitable dispersing or suspending agents for aqueous suspensions include synthetic and natural gums such as tragacanth, acacia, alginate, dextran, sodium carboxymethylcellulose, methylcellulose, polyvinyl-pyrrolidone, and gelatin.
  • the liquid forms in suitably flavored suspending or dispersing agents may also include synthetic and natural gums.
  • sterile suspensions and solutions are desired.
  • Isotonic preparations which generally contain suitable preservatives, are employed when intravenous administration is desired.
  • a parenteral formulation may consist of the active ingredient dissolved in or mixed with an appropriate inert liquid carrier.
  • Acceptable liquid carriers usually comprise aqueous solvents and other optional ingredients for aiding solubility or preservation.
  • aqueous solvents include sterile water, Ringer's solution, or an isotonic aqueous saline solution.
  • Other optional ingredients include vegetable oils (such as peanut oil, cottonseed oil, and sesame oil), and organic solvents (such as solketal, glycerol, and formyl).
  • a sterile, non-volatile oil may be employed as a solvent or suspending agent.
  • the parenteral formulation is prepared by dissolving or suspending the active ingredient in the liquid carrier whereby the final dosage unit contains from 0.005 to 10% by weight of the active ingredient.
  • Other additives include preservatives, isotonizers, solubilizers, stabilizers, and pain-soothing agents.
  • injectable suspensions may also be prepared, in which case appropriate liquid carriers, suspending agents and the like may be employed.
  • Compounds of the invention may be administered intranasally using a suitable intranasal vehicle.
  • the compounds of this invention may be administered directly to the lungs by inhalation.
  • Compounds of the invention may also be administered topically or enhanced by using a suitable topical transdermal vehicle or a transdermal patch.
  • the composition is preferably in the form of an ophthalmic composition.
  • the ophthalmic compositions are preferably formulated as eye- drop formulations and filled in appropriate containers to facilitate administration to the eye, for example a dropper fitted with a suitable pipette.
  • the compositions are sterile and aqueous based, using purified water.
  • an ophthalmic composition may contain one or more of: a) a surfactant such as a
  • a thickening agents such as cellulose, cellulose derivatives, carboxyvinyl polymers, polyvinyl polymers, and polyvinylpyrrolidones, typically at a concentration n the range of about 0.05 to about 5.0% (wt/vol); c) (as an alternative to or in addition to storing the composition in a container containing nitrogen and optionally including a free oxygen absorber such as Fe), an anti-oxidant such as butylated hydroxyanisol, ascorbic acid, sodium thiosulfate, or butylated hydroxytoluene at a concentration of about 0.00005 to about 0.1% (wt/vol); d) ethanol at a concentration of about 0.01 to 0.5% (wt/vol); and e) other excipients such as an isotonic agent, buffer, preservative, and/or pH-controlling agent.
  • the pH of the ophthalmic composition is desirably within the range of 4 to 8.
  • the composition of this invention includes one or more additional agents.
  • the other therapeutic agent may be any agent that is capable of treating, preventing or reducing the symptoms of a tuberculosis.
  • the other therapeutic agent may be an antibacterial compound.
  • the other therapeutic agent may be any agent of benefit to a patient when administered in combination with the compound in this invention.
  • bromoethyl)benzene (24 mmol) was slowly added dropwise to a mixture of adamantan-2-ylmethanamine (20 mmol) and Et 3 N (24 mmol, 3.3 mL) in anhydrous CH2CI2 (20 mL) at 0 °C.
  • the reaction mixture was warmed to room temperature and stirred for an additional 20 h. After the solvent was removed under reduced pressure, the residue was washed with ice water (3.x. 20 mL) and the precipitate was separated by filtration.
  • the crude product was purified using HPLC. Yield: 45 %. Yellow oil.
  • Step A methyl 2-(2-aminoethyl)benzoate (0.5 mmol) and adamantane-2-carbaldehyde (0.55 mmol) were dissolved in 0.6 ml MeOH, heated at 100° C for 2 hours, then mixture was cooled, NaBH 4 (0.5 mmol) was added and stirred for 4 hours. The mixture was heated for 2 hours at 60° C, 3 ml of methanol and 0.2 g of C-18 chromatographic phase were added, stirred for 2 hours, filtered, evaporated and dissolved in 0.5 ml of DMSO. The residue was purified using HPLC. Yield: 41%.
  • Step B Under nitrogen atmosphere, at 0 °C, to a suspension of LiAiH 4 (0.2 M in THF, 11 mL, 2.2 mmol) in dry THF (5 mL), a solution of methyl 2-(2-((adamantan-2-ylmethyl)amino)ethyl)benzoate (0.55 mmol,) in dry THF (0.5 mL) was added dropwise. The resulting mixture was stirred at r.t. for 3h, then cooled to 0 °C and H 2 0 (1 mL) was slowly added, followed by a 0.3 M KOH solution (1 mL) and additional H2O (1.5 mL).
  • A105 Adamantan-2-ylmethanamine (0.5 mmol) and 3-cyclopropyl-4-methylbenzaldehyde (0.55 mmol) were dissolved in 0.6 ml MeOH, heated at 100° C for 2 hours, then mixture was cooled, NaBH 4 (0.5 mmol) was added and stirred for 4 hours. The mixture was heated for 2 hours at 60° C, 3 ml of methanol and 0.2 g of C-18 chromatographic phase were added, stirred for 2 hours, filtered, evaporated and dissolved in 0.5 ml of DMSO. The residue was purified using HPLC. Yield: 36 %. Yellow gum.
  • Step 2 To borane tetrahydrofuran complex (1.6 ml, 1.6 mmol) was slowly added at 0°C compound N- (adamantan-2-ylmethyl)-2,3,6-trimethylbenzamide (0.89 mmol) in tetrahydrofuran (3 ml). The reaction mixture was then stirred at 60 °C for 3 hours, cooled to room temperature and quenched with 6N aqueous hydrochloric acid. The solvent was removed by distillation and water (10 ml) 5 was added. The residue was purified using HPLC. Yellow solid. Yield: 23%.
  • Step 1 Adamantan-2-ylmethanamine (0.5 mmol) and 5,6,7,8-tetrahydronaphthalene-2-carbaldehyde (0.55 mmol) were dissolved in 0.6 ml MeOH, heated at 100° C for 2 hours, then mixture was cooled, NaBH 4 (0.5 mmol) was added and stirred for 4 hours. The mixture was heated for 2 hours at 60° C, 3 ml of methanol and 0.2 g of C-18 chromatographic phase were added, stirred for 2 hours, filtered, evaporated. The residue was purified using HPLC. Yield: 31%.
  • Step 2 l-(adamantan-2-yl)- N-((5,6,7,8-tetrahydronaphthalen-2-yl)methyl)methanamine (0.5 mmol) and cyclobutanone (0.55 mmol) were dissolved in 0.6 ml CHCb, NaBH(OAc)3 (1.5 mmol) was added and stirred for 4 hours. The mixture was heated for 12 hours at 60°C, 3 ml of methanol and 0.2 g of C-18 chromatographic phase were added, stirred for 2 hours, filtered, evaporated. The residue was purified using HPLC. Yellow gum. Yield: 38%.
  • Step A Adamantan-2-ylmethanamine (1 mmol) and CDI (2 mmol) were dissolved in 0.6 ml CH3CN, the mixture was kept at a temperature of 70°C for 1 hour, then 2,3,6-trimethylbenzoic acid (1 mmol) was added. The mixture was heated for 2 hours at 70°C, then filtered, evaporated. The residue was purified by HPLC.
  • Step B N-(adamantan-2-ylmethyl)-2,3,6-trimethylbenzamide (0.5 mmol) was dissolved in anhydrous THF (5 mL); subsequently a suspension of LiAlH 4 in THF (2N solution, 2 mmol) was added dropwise under argon.
  • reaction mixture was warmed to reflux for 3-6 h. Excess reactants were decomposed by addition of few drops of AcOEt, NaOH (1N water solution, 1 equiv), and water. After filtration of the salts over Celite, the clear solution was dried over Na2S0 4 and concentrated in vacuo. Residue was purified by HPLC. Yield: 28%. Yellow solid.
  • Step A Adamantan-2-ylmethanamine (1 mmol) and CDI (2 mmol) were dissolved in 0.6 ml CH3CN, the mixture was kept at a temperature of 70°C for 1 hour, then 2-(5,6,7,8-tetrahydronaphthalen-2-yl)acetic acid (1 mmol) was added. The mixture was heated for 2 hours at 70°C, then filtered, evaporated. The residue was purified by HPLC.
  • Step B N-(adamantan-2-ylmethyl)-2-(5, 6,7,8- tetrahydronaphthalen-2-yl)acetamide (0.5 mmol) was dissolved in anhydrous THF (5 mL); subsequently a suspension of LiAlH 4 in THF (2N solution, 2 mmol) was added dropwise under argon. The reaction mixture was warmed to reflux for 3-6 h. Excess reactants were decomposed by addition of few drops of AcOEt, NaOH (1N water solution, 1 equiv), and water. After filtration of the salts over Celite, the clear solution was dried over Na2S0 4 and concentrated in vacuo. Residue was purified by HPLC. Yield: 41%. Yellow solid.
  • Step A Adamantan-2-ylmethanamine (1 mmol) and 5,6,7,8-tetrahydronaphthalene-2-carbaldehyde (1 mmol) were dissolved in 0.9 ml MeOH, heated at l00°C for 2 hours, then mixture was cooled; NaBH 4 (1 mmol) was added and stirred for 4 hours. The mixture was heated for 2 hours at 60°C, 5 ml of methanol and 0.4 g of C-18 chromatographic phase were added, stirred for 2 hours, filtered, evaporated.
  • Step B l-(adamantan-2-yl)-N-((5,6,7,8-tetrahydronaphthalen-2-yl)methyl)methanamine (0.5 mmol) and acetone (0.55 mmol) were dissolved in 0.6 ml CHCb; NaBH(OAc)3 (1.5 mmol) was added and stirred for 4 hours. The mixture was heated for 12 hours at 60°C, 3 ml of methanol and 0.2 g of C-18 chromatographic phase were added, stirred for 2 hours, filtered, evaporated and dissolved in 0.5 ml of DMSO. The residue was purified by HPLC. Yield: 32%. Yellow solid.
  • Step A Adamantan-2-ylmethanamine (1 mmol) and 5,6,7,8-tetrahydronaphthalene-2-carbaldehyde (1 mmol) were dissolved in 0.9 ml MeOH and heated at lOO°C for 2 hours; then the mixture was cooled, NaBH 4 (1 mmol) was added and stirred for 4 hours. The mixture was heated for 2 hours at 60 °C; 5 ml of methanol and 0.4 g of C-18 chromatographic phase were added, stirred for 2 hours, filtered, evaporated.
  • Step B l-(adamantan-2-yl)-N-((5,6,7,8-tetrahydronaphthalen-2- yl)methyl)methanamine (0.5 mmol) and cyclohexanone (0.55 mmol) were dissolved in 0.6 ml CHCb; NaBH(OAc)3 (1.5 mmol) was added and stirred for 4 hours. The mixture was heated for 12 hours at 60 °C; 3 ml of methanol and 0.2 g of C-18 chromatographic phase were added, stirred for 2 hours, filtered, evaporated and dissolved in 0.5 ml of DMSO. The residue was purified by HPLC. Yield: 41%. Light brown solid.
  • Step B N-(adamantan-2-ylmethyl)-2-(3-fluorophenyl)ethan-l -amine (0.5 mmol), CH3I (0.75 mmol), and NaOH (0.5 mmol) were dissolved in 30 mL of ethanol. The mixture was stirred and refluxed for 5 h and then washed 3 times with 30 mL of distilled water. The aqueous phase was extracted by CHCh (30mL> ⁇ 3). The organic phases were combined and dried by Na2S0 4 . After the solvent had been removed under reduced pressure, the residue was purified by HPLC. Yield: 37%. Yellow gum. 1H NMR (400 MHz,
  • Step A Adamantan-2-ylmethanamine (2 mmol) and CDI (4 mmol) were dissolved in 1.2 ml CH3CN; the mixture was kept at a temperature of 70 °C for 1 hour, then 5-methyl-5,6,7,8-tetrahydronaphthalene-2-carboxylic acid (2 mmol) was added. The mixture was heated for 2 hours at 70 °C, then filtered and evaporated. The residue was purified by LC. Yield: 36 %.
  • Step B N-(adamantan-2- ylmethyl)-5-methyl-5,6,7,8-tetrahydronaphthalene-2-carboxamide (0.5 mmol) was dissolved in anhydrous THF (5 mL); subsequently a suspension of LiAlH 4 in THF (2N solution, 2 mmol) was added dropwise under argon. The reaction mixture was warmed to reflux for 3-6 h. Excess reactants were decomposed by addition of few drops of AcOEt, NaOH (1N water solution, 1 equiv), and water. After filtration of the salts over Celite, the clear solution was dried over Na2S0 4 and concentrated in vacuo. Residue was purified by HPLC. Yield: 28%.
  • Step A Adamantan-2-ylmethanamine (10 mmol) and CDI (20 mmol) were dissolved in 10 ml CH3CN; the mixture was kept at a temperature of 70 °C for 1 hour, then 5-oxo-5,6,7,8-tetrahydronaphthalene-2-carboxylic acid (10 mmol) was added. The mixture was heated for 2 hours at 70 °C, then evaporated, and the residue was purified by LC. Yield: 62 %.
  • Step B N-(adamantan-2-ylmethyl)-5-oxo-5, 6,7,8- tetrahydronaphthalene-2-carboxamide (6 mmol) was dissolved in EtOH; then NaBH 4 (6.6 mmol) was added and stirred for 5 hours at room temperature. The mixture was poured into the water, the organic layer was extracted with EtOAc, evaporated. The residue was purified by LC. Yield: 58 %.
  • Step C N-(adamantan-2-ylmethyl)-5-hydroxy-5, 6,7,8- tetrahydronaphthalene-2-carboxamide (3 mmol) was dissolved in anhydrous THF (10 mL); subsequently a suspension of LiAlH 4 in THF (2 N solution, 3 mmol) was added dropwise under argon. The reaction mixture was warmed to reflux for 3-6 h. Excess reactants were decomposed by addition of few drops of AcOEt, NaOH (1 N water solution, 1 equiv), and water. After filtration of the salts over Celite, the clear solution was dried over Na2S0 4 and concentrated in vacuo. The residue was purified by HPLC. Yield: 61 %.
  • Step D To a solution of 6-(((adamantan-2-ylmethyl)amino)methyl)-l,2,3,4-tetrahydronaphthalen-l-ol (2 mmol) in CH2CI2 (30 mL) was added (BOC)20 (2 mmol). The resulting solution was stirred at room temperature overnight. The reaction was quenched by the addition of saturated NaElCCh and separated. The organic layer was washed with brine, dried over Na2S0 4 , filtered, and concentrated under reduced pressure. The crude product was purified by flash chromatography using 10% EtOAc in hexanes as eluent. Yield: 49 %. Step F:
  • Step J To a solution of tert-butyl (adamantan-2-ylmethyl)((5-fluoro-5,6,7,8-tetrahydronaphthalen-2- yl)methyl)carbamate (0.5 mmol) in dichloromethane (2mL) was slowly added trifluoroacetic acid (3 mmol) at 0 °C. The reaction solution was stirred at room temperature for 5 h, and then 1N NaOH was added. The mixture was extracted with dichloromethane, and the organic layer was washed with brine, dried (Na2S0 4 ), and filtered.
  • Step A Adamantan-2-ylmethanamine (2 mmol), and CDI (4 mmol) were dissolved in 1.2 ml CH3CN; the mixture was kept at a temperature of 70 °C for 1 hour, then 6,7,8,9-tetrahydro-5H-benzo[7]annulene-2-carboxylic acid (2 mmol) was added. The mixture was heated for 2 hours at 70 °C, then evaporated, and the residue was purified by LC. Yield: 36 %.
  • Step B N-(adamantan-2-ylmethyl)-6,7,8,9- tetrahydro-5H-benzo[7]annulene-2-carboxamide (0.5 mmol) were dissolved in anhydrous THF (5 mL); subsequently a suspension of LiAlH 4 in THF (2N solution, 2 mmol) was added dropwise under argon atmosphere. The reaction mixture was warmed to reflux for 3-6 h. Excess reactants were decomposed by addition of few drops of AcOEt, NaOH (1N water solution, 1 equiv), and water. After filtration of the salts over Celite, the clear solution was dried over Na2S0 4 and concentrated in vacuo. Residue was purified by HPLC. Yield: 28%.
  • Step A 5-oxo-5, 6,7,8- tetrahydronaphthalene-2-carboxylic acid (2 mmol), and CDI (2 mmol) were dissolved in 2 ml CH3CN; the mixture was heated at 70 °C for 1 hour, then adamantan-2-ylmethanamine (2 mmol) was added. The mixture was heated for 2 hours at 70 °C. Water (25 ml) were added; the organic layer was extracted with EtOAc (3* 15ml) and concentrated in vacuo. The crude product was purified by LC. Yield: 48 %.
  • Step B N-(adamantan-2-ylmethyl)-5-oxo-5, 6,7,8- tetrahydronaphthalene-2-carboxamide (0.5 mmol) was dissolved in anhydrous THF (5 mL); subsequently a suspension of LiAlHi in THF (2N solution, 3 mmol) was added dropwise under argon. The reaction mixture was warmed to reflux for 3-6 h. Excess reactants were decomposed by addition of few drops of AcOEt, NaOH (1N water solution, 1 equiv), and water. After filtration of the salts over Celite, the clear solution was dried over Na2S0 4 and concentrated in vacuo. Residue was purified by HPLC. Yield: 39%.
  • Step A 2-(2-aminoethyl)phenol (5 mmol) and adamantane-2-carbaldehyde (5 mmol) were dissolved in 1 ml MeOH, heated at 100° C for 2 hours; then the mixture was cooled, NaBH 4 (5 mmol) was added and stirred for 4 hours. The mixture was heated for 2 hours at 60° C; 3 ml of methanol and 0.8 g of C- 18
  • Step B To a solution of 2-(2-((adamantan-2- ylmethyl)amino)ethyl)phenol (3 mmol) in CH2CI2 (20 mL) was added (BOC)20 (3 mmol).
  • Step C To a solution of Succinic acid tert-butyl pentafluorophenyl ester (2 mmol) HATU (2mmol) and DIPEA (3mmol) were added. The mixture was stirred at 50 °C for 5 h, then tert-butyl (adamantan-2-ylmethyl)(2-hydroxyphenethyl)carbamate (1.5 mmol) in THF was added. The resulting solution was refluxed for 2 h. The solvent was evaporated, and the crude product was purified by HPLC. Yield: 22 %.
  • Step D To a solution of 2-(2- ((adamantan-2-ylmethyl)(tert-butoxycarbonyl)amino)ethyl)phenyl tert-butyl succinate (0.5 mmol) in dichloromethane (2mL) trifluoroacetic acid (3 mmol) was slowly added at 0°C. The reaction was stirred at room temperature for 5 h, and then 1N NaOH was added. The mixture was extracted with dichloromethane, and the organic layer was washed with brine, dried (Na2S0 4 ), and filtered. The solvent was evaporated under reduced pressure to give the final compound. Yield: 12 %.
  • Step A 2-(2-aminoethyl)phenol (5 mmol) and adamantane-2-carbaldehyde (5 mmol) were dissolved in 1 ml MeOH, heated at 100° C for 2 hours; then mixture was cooled, NaBH 4 (5 mmol) was added and stirred for 4 hours. The mixture was heated for 2 hours at 60° C; 3 ml of methanol and 0.8 g of C- 18
  • Step B To a solution of 2-(2-((adamantan-2- ylmethyl)amino)ethyl)phenol (3 mmol) in CH2CI2 (20 mL) was added (BOC)20 (3 mmol). The resulting solution was stirred at room temperature overnight. The reaction was quenched by the addition of saturated NaHCCb and separated. The organic layer was washed with brine, dried over Na2S0 4 , filtered, and concentrated under reduced pressure. The crude product was purified by flash chromatography using 10% EtOAc in hexanes as eluent.
  • Step C To a solution of the nicotinic acid (2 mmol) in THF (5 ml) were added HATU (2mmol) and DIPEA (3mmol). The mixture was stirred at 50 °C for 5h, then tert-butyl (adamantan-2-ylmethyl)(2-hydroxyphenethyl)carbamate (1.5 mmol) in THF was added. The resulting solution was refluxed for 2 h. The solvent was evaporated and the crude product was purified by HPLC. Yield: 31 %.
  • Step D To a solution of 2-(2-((adamantan-2- ylmethyl)(tert-butoxycarbonyl)amino)ethyl)phenyl nicotinate (0.5 mmol) in dichloromethane (2mL) trifluoroacetic acid (3 mmol) was slowly added at 0°C. The reaction was stirred at room temperature for 5 h, and then 1N NaOH was added. The mixture was extracted with dichloromethane, and the organic layer was washed with brine, dried (Na2S0 4 ), and filtered. The solvent was evaporated under reduced pressure to give the final compound. Yield: 17 %.
  • Step A 2-(2-aminoethyl)phenol (5 mmol) and adamantane-2-carbaldehyde (5 mmol) were dissolved in 1 ml of MeOH, heated at 100° C for 2 hours; then the mixture was cooled, NaBH 4 (5 mmol) was added and stirred for 4 hours. The mixture was heated for 2 hours at 60° C; 3 ml of methanol and 0.8 g of C-18
  • Step B To a solution of 2-(2-((adamantan-2- ylmethyl)amino)ethyl)phenol (3 mmol) in CH2CI2 (20 mL) was added (BOC)20 (3 mmol). The resulting solution was stirred at room temperature overnight. The reaction was quenched by the addition of saturated NaHCCb and separated. The organic layer was washed with brine, dried over Na2S0 4 , filtered, and concentrated under reduced pressure. The crude product was purified by flash chromatography using 10% EtOAc in hexanes as eluent.
  • Step C To a solution of the dimethylglycine (2 mmol) in THF (5 ml) were added HATU (2mmol) and DIPEA (3mmol). The mixture was stirred at 50 °C for 5 h, then tert-butyl (adamantan-2-ylmethyl)(2-hydroxyphenethyl)carbamate (1.5 mmol) in THF was added. The resulting solution was refluxed for 2 h. The solvent was evaporated, and the crude product was purified by HPLC. Yield: 28 %.
  • Step D To a solution of 2-(2- ((adamantan-2-ylmethyl)(tert-butoxycarbonyl)amino)ethyl)phenyl dimethylglycinate (0.5 mmol) in dichloromethane (2mL) was slowly added trifluoroacetic acid (3 mmol) at 0°C.
  • N-(adamantan-2-ylmethyl)-6-hydroxy-5,6,7,8-tetrahydronaphthalene-2- carboxamide (10 mmol) was dissolved in anhydrous THF (12 mL); subsequently a suspension of L1AIH4 in THF (2N solution, 10 mmol) was added dropwise under argon atmosphere. The reaction mixture was warmed to reflux for 3-6 h. The excess of reactants was decomposed by addition of a few drops of AcOEt, NaOH (1N water solution, 1 equiv), and water. After filtration of the salts over Celite, a clear solution was dried over Na2S0 4 and concentrated in vacuo. Residue was purified using HPLC. Yield: 61%.
  • a luminescence assay was carried out via the following steps.
  • the strain used in the luminescence assay was H37RvMA with the LuxCDABE operon integrated at the L5 site on a Kanamycin marked plasmid (pMV306hsp+LuxGl3):
  • Luminescence endpoint parameters ls integration time, gain 200, read height lmm
  • ADC was plated on LB-agar plates containing A51 at 5 mM, 9 pM, and 14 pM. A total of 8 resistant mutants were obtained from 3 mL of culture (approx. 3xl0 9 frequency of resistance). 20-mL cultures of each of the resistant mutants as well as of the parent strain were grown in Middlebrook 7H9-ADC, and cells were harvested by centrifugation at 4,000
  • RNAse A was added to the final concentration of 25 pg/mL, and the samples were incubated for 1 hour at 37°C.
  • SDS was added to the final concentration of 1% and proteinase K to the final concentration of 100 pg/mL. The samples were incubated for 3 hours at 50°C and then mixed with an equal volume of phenol:chloroform:isoamyl alcohol (25:24: 1).
  • the samples were incubated for 30 min at room temperature, rocked for 30 min at room temperature, and centrifuged for 15 min at l0,000xg at 4°C.
  • the top layer (aqueous phase) was transferred into new tubes and mixed with 1 ⁇ 2 volume of chloroform; the tubes were centrifuged for 15 min at l0,000xg at 4°C.
  • the top layer (aqueous phase) was transferred into new tubes, and DNA was precipitated with 1/10 volume of 3M NaOAc pH 5.2 and 1 volume of IPA.
  • the tubes were incubated overnight at -20 °C.
  • the compounds of the invention gave favorable results in toxicity testing relative to three known inhibitors of the target (SQ109, BM212, and SQ609).
  • the cells were cultured in media (MEM+O.OlmM
  • IC50 absolute IC50

Abstract

Provided herein are multicyclic compounds useful for treating tuberculosis. Also provided are methods of treating tuberculosis using the compounds of the invention.

Description

MULTICYCLIC COMPOUNDS AND USE OF SAME FOR TREATING
TUBERCULOSIS
CROSS-REFERENCE TO RELATED APPLICATION
[0001] This application claims the benefit of U.S. Provisional Application No.
62/616,952, filed January 12, 2018, which is hereby incorporated by reference in its entirety.
GOVERNMENT SUPPORT
[0002] This invention was made with government support under U19 AI109764 from the National Institute of Allergy and Infectious Disease. The government has certain rights in the invention.
BACKGROUND OF THE INVENTION
[0003] Synthetic drugs for treating tuberculosis (TB) have been available for over half a century, but incidences of the disease continue to rise world-wide. In 2004, it is estimated that 24,500 people developed active disease and close to 5,500 died each day from TB (World Health Organization, Global Tuberculosis Control: Surveillance, Planning,
Financing. WHO Report 2006, Geneva, Switzerland, ISBN 92-4 156314-1). The threat this disease represents is still a painful reality for the ten million people now infected, and for the two million that die each year (WHO Report 2007: Global Tuberculosis Control Report). Co-infection with HIV is driving the increase in incidence (Williams, B. G.; Dye,
C. Science, 2003, 301, 1535) and the cause of death in 31% of AIDS patients in Africa can be attributed to TB (Corbett, E. L.; Watt, C. J.; Catherine, J.; Walker, N.; Maher D.;
Williams, B. G, Raviglione, M. C.; Dye, C. Arch. Inti Med. , 2003, 163, 1009, Septkowitz, A.; Raffaili, J.; Riley, T.; Kiehn, T. E.; Armstrong, D. Clin. Microbiol Rev. 1995, 8, 180). When coupled with the emergence of multi-drug resistant strains of Mycobacterium tuberculosis , the scale of the problem is amplified. It is no more than a decade since the WHO declared TB“a global health emergency” (World Health Organization, Global Tuberculosis Control: Surveillance, Planning, Financing. WHO Report 2006, Geneva, Switzerland, ISBN 92-4 156314-1).
[0004] The limitations of tuberculosis therapy and prevention are well-known. The current available vaccine, BCG was introduced in 1921 and fails to protect most people past childhood. Patients who do become infected with active disease currently endure
combination therapy with isoniazid (INH), rifampin, pyrazinamide and ethambutol for two months and then continue taking isoniazid and rifampin for a further four months;
furthermore, daily dosing is required. This first-line drug treatment is effective in active, drug-susceptible TB as long as patients complete the course. However, there is a poor patient compliance due to many factors such as the cost of drugs, side effects, long time necessary for full treatment and the number of drug doses required (Current Medicinal Chemistry,
2008, 15, 1956-1967). In addition, poor patient compliance drives the emergence and spread of Multi -Drug Resistant (MDR) TB strains, which are challenging to treat. Multi-drug resistant TB strains are resistant to at least the two main first-line TB drugs— isoniazid and rifampicin; and Extremely Drug Resistant (XDR) TB, strains are also resistant to three or more of the six classes of second-line drugs. In some Eastern Europe Central Asia Countries (EEC AC) such as Azerbaijan, MDR/XDR strains can account for up to 22% of infections, with mortality rates for XDR reaching up to 100% of those infected (Eur. Respir. I, 33,
2009, 871). A recently-published detailed review discusses many aspects of TB such as pathogenesis, epidemiology, drug discovery and vaccine development to date (Nature Medicine, Vol 13(3), pages 263-312).
[0005] Shorter courses of more active agents which can be taken less frequently and which present a high barrier to the emergence of resistance, i.e. agents which are effective against multi-drug resistant strains of TB, are urgently required. An additional problem is the drug-drug interaction of current TB drugs with other disease treatments, like HIV or diabetes. There is therefore an urgent need to develop new chemical entities to treat TB, focused particularly on: a) shortening current therapy of six months; b) activity against MDR- XDR strains, c) possible co-administration with other medications, for example by targeting novel biochemical pathways. Recent synthetic leads are reviewed in: Baflelf, L.; Field, R. A.; Duncan, K.; Young, R. J. Antimicrob. Agents Chemother. 2005, 49, 2153.
SUMMARY OF THE INVENTION
[0006] In certain aspects, the present invention provides compounds represented by structural formula (I):
Figure imgf000003_0001
or a pharmaceutically acceptable salt thereof;
wherein:
L5 is (Ci-C2)alkylene, optionally substituted with (Ci-Ce)alkyl, hydroxyl, hydroxyl(Ci-C6)alkyl, (C3-C6)cycloalkyl, phenyl, halo(Ci-C6)alkyl, (Ci-C6)alkoxyl(Ci- Ce)alkyl, -C(0)0H, or -C(0)0-(Ci-C6)alkyl;
L6 is (Ci-C2)alkylene, optionally substituted with (Ci-Ce)alkyl, hydroxyl, hydroxyl(Ci-C6)alkyl, (C3-C6)cycloalkyl, phenyl, halo(Ci-C6)alkyl, (Ci-C6)alkoxyl(Ci- Ce)alkyl, -C(0)0H, or -C(0)0-(Ci-C6)alkyl;
Figure imgf000004_0001
is unsubstituted adamantyl;
R6 is optionally substituted phenyl;
R7 is H, alkyl, hydroxyalkyl, cycloalkyl, (cycloalkyl)alkyl, aralkyl, or heteroaralkyl; wherein when (a) L5 and L6 are both optionally substituted (Ci)alkylene, or (b) when
L5 is optionally substituted (C2)alkylene and L6 is optionally substituted (Ci)alkylene, then
R6 is phenyl substituted with one or more substituents, wherein the one or more substituents are selected from the group consisting of (C2-C6)alkyl, cycloalkyl, aryl, heteroaryl, halo, haloalkyl, hydroxyalkyl, alkoxy, (cycloalkyl)alkyl, and aralkyl, or wherein two adjacent substituents on phenyl, taken together with the intervening atoms, form a heteroaryl, aryl, cycloalkyl, or heterocycloalkyl ring.
[0007] In further aspects, the present invention provides a compound of formula (G):
Figure imgf000004_0002
or a pharmaceutically acceptable salt thereof;
wherein:
L5 is (Ci-C2)alkylene, optionally substituted with (Ci-Ce)alkyl, hydroxyl, hydroxyl(Ci-C6)alkyl, (C3-C6)cycloalkyl, phenyl, halo(Ci-C6)alkyl, (Ci-C6)alkoxyl(Ci- C6)alkyl, -C(0)0H, or -C(0)0-(Ci-C6)alkyl;
L6 is (Ci-C2)alkylene, optionally substituted with (Ci-Ce)alkyl, hydroxyl, hydroxyl(Ci-C6)alkyl, (C3-C6)cycloalkyl, phenyl, halo(Ci-C6)alkyl, (Ci-C6)alkoxyl(Ci- C6)alkyl, -C(0)0H, or -C(0)0-(Ci-C6)alkyl;
Figure imgf000004_0003
unsubstituted adamantyl; R6 is phenyl substituted with one or more substituents, wherein the one or more substituents are selected from the group consisting of (C2-C6)alkyl, cycloalkyl, aryl, heteroaryl, halo, haloalkyl, hydroxyalkyl, alkoxy, (cycloalkyl)alkyl, and aralkyl, or wherein two adjacent substituents on phenyl, taken together with the intervening atoms, form a heteroaryl, aryl, cycloalkyl, or heterocycloalkyl ring; and
[0008] R7 is H, alkyl, hydroxyalkyl, cycloalkyl, (cycloalkyl)alkyl, aralkyl, or heteroaralkyl.
[0009] In other aspects, the invention provides a method for treating tuberculosis, comprising administering to a subject in need thereof a therapeutically effective amount of a compound of formula (II):
Figure imgf000005_0001
or a pharmaceutically acceptable salt thereof;
wherein:
L1 is absent or is optionally substituted alkylene;
L2 is absent or is optionally substituted alkylene;
Figure imgf000005_0002
is optionally substituted adamantyl;
R2 is optionally substituted phenyl; and
R3 is H, alkyl, hydroxyalkyl, cycloalkyl, (cycloalkyl)alkyl, aralkyl, or heteroaralkyl.
[0010] In other aspects, the invention provides a compound according to formula (X):
Figure imgf000005_0003
or a pharmaceutically acceptable salt thereof;
wherein:
X is -0-, -CH2-, or -C(R20)2-;
each R20 is independently selected from the group consisting of H and alkyl;
L25 is absent or is optionally substituted alkylene;
Figure imgf000005_0004
optionally adamantyl; R21 is a substituent selected from the group consisting of alkyl, cycloalkyl, aryl, heteroaryl, (cycloalkyl)alkyl, aralkyl, hydroxyl, hydroxyalkyl, alkoxy, halo, and haloalkyl; and m is an integer from 0 to 4; and
R27 is H, alkyl, hydroxyalkyl, cycloalkyl, (cycloalkyl)alkyl, aralkyl, or heteroaralkyl.
DETAILED DESCRIPTION OF THE INVENTION
[0011] A description of example embodiments of the invention follows.
Definitions
[0012] “Alkyl” means an optionally substituted saturated aliphatic branched or straight- chain monovalent hydrocarbon radical having the specified number of carbon atoms. Thus, “(Ci-Ce) alkyl” means a radical having from 1-6 carbon atoms in a linear or branched arrangement.“(Ci-Ce)alkyl” includes methyl, ethyl, propyl, butyl, pentyl and hexyl.
[0013] “Alkylene” means an optionally substituted saturated aliphatic branched or straight-chain divalent hydrocarbon radical having the specified number of carbon atoms. Thus,“(Ci-C6)alkylene” includes a divalent saturated aliphatic radical having from 1-6 carbon atoms in a linear arrangement, e.g.,— [(CH2)n]— , where n is an integer from 1 to 6, “(Ci-C6)alkylene” includes methylene, ethylene, propylene, butylene, pentylene and hexylene.“(Ci-C6)alkylene” also includes a divalent saturated radical having from 1-6 carbon atoms in a branched arrangement, for example:— [(CHiCHiCHiCHiCHiCH^)]— ,— [(CH2CH2CH2CH2C(CH3)2]— ,— [(CH2C(CH3)2CH(CH3))]— , and the like. Where indicated, alkylene is optionally and independently substituted with one or more substituents independently selected from halo, (Ci-Ce)alkyl,— OH, =0, (Ci-Ce)alkoxy, and (Ci- C6)haloalkyl.
[0014] “Aryl” or“aromatic” means an aromatic monocyclic or polycyclic (e.g. bicyclic or tricyclic) carbocyclic ring system. In one embodiment,“aryl” is a 6-12 membered monocylic or bicyclic system. Aryl systems include, but not limited to, phenyl, naphthyl, fluorenyl, indenyl, azulenyl, and anthracenyl. In certain preferred embodiments,“aryl” is phenyl.
[0015] “Carbocyclyl” means a cyclic group with only ring carbon atoms.“Carbocyclyl” includes 3-12 membered saturated or unsaturated aliphatic cyclic hydrocarbon rings or 6-12 membered aryl rings. A carbocyclyl moiety can be monocyclic, fused bicyclic, bridged bicyclic, spiro bicyclic, or polycyclic. [0016] Monocyclic carbocyclyls are saturated or unsaturated aliphatic cyclic
hydrocarbon rings or aromatic hydrocarbon rings having the specified number of carbon atoms. Monocyclic carbocyclyls include cycloalkyl, cycloalkenyl, cycloalkynyl and phenyl.
[0017] A fused bicyclic carbocyclyl has two rings which have two adjacent ring atoms in common. The first ring is a monocyclic carbocyclyl and the second ring is a monocyclic carbocyclyl or a monocyclic heterocyclyl.
[0018] A bridged bicyclic carbocyclyl has two rings which have three or more adjacent ring atoms in common. The first ring is a monocyclic carbocyclyl and the second ring is a monocyclic carbocyclyl or a monocyclic heterocyclyl. In some preferred embodiments, a bridged bicyclic carbocylyl is adamantyl.
[0019] A spiro bicyclic carbocyclyl has two rings which have only one ring atom in common. The first ring is a monocyclic carbocyclyl and the second ring is a monocyclic carbocyclyl or a monocyclic heterocyclyl.
[0020] Polycyclic carbocyclyls have more than two rings (e.g., three rings resulting in a tricyclic ring system) and adjacent rings have at least one ring atom in common. The first ring is a monocyclic carbocyclyl and the remainder of the ring structures are monocyclic carbocyclyls or monocyclic heterocyclyl s. Polycyclic ring systems include fused, bridged and spiro ring systems. A fused polycyclic ring system has at least two rings that have two adjacent ring atoms in common. A spiro polycyclic ring system has at least two rings that have only one ring atom in common. A bridged polycyclic ring system has at least two rings that have three or more adjacent ring atoms in common.
[0021] “Cycloalkyl” means a saturated aliphatic cyclic hydrocarbon ring. Thus,“(C3- C7)cycloalkyl” means a hydrocarbon radical of a (3-7 membered) saturated aliphatic cyclic hydrocarbon ring. A C3-C7cycloalkyl includes, but is not limited to cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and cycloheptyl.
[0022] “Cycloalkene” means an aliphatic cyclic hydrocarbon ring having one or more double bonds in the ring.
[0023] “Cycloalkyne” means an aliphatic cyclic hydrocarbon ring having one or more triple bonds in the ring.
[0024] “Hetero” refers to the replacement of at least one carbon atom member in a ring system with at least one heteroatom selected from N, S, and O.“Hetero” also refers to the replacement of at least one carbon atom member in a acyclic system. A hetero ring system or a hetero acyclic system may have 1, 2, 3 or 4 carbon atom members replaced by a heteroatom.
[0025] “Heterocyclyl” means a cyclic 4-12 membered saturated or unsaturated aliphatic or aromatic ring containing 1, 2, 3, 4 or 5 heteroatoms independently selected from N, O or S. When one heteroatom is S, it can be optionally mono- or di-oxygenated (i.e.— S(O)— or — S(0)2— ). The heterocyclyl can be monocyclic, fused bicyclic, bridged bicyclic, spiro bicyclic or polycyclic.
[0026] “Saturated heterocyclyl” means an aliphatic heterocyclyl group without any degree of un saturation (i.e., no double bond or triple bond). It can be monocyclic, fused bicyclic, bridged bicyclic, spiro bicyclic or polycyclic.
[0027] Examph 5S of monocyclic saturated heterocyciyls include, but are not limited to, azetidine, pyrrolidine, piperidine, piperazine, azepane, hexahydropyrimidine,
tetrahydrofuran, tetrahydropyran, morpholine, thiomorpholine, thiomorpholine 1,1 -dioxide, tetrahydro-2H- 1 ,2-thiazine, tetrahydro-2H- 1 ,2-thiazine 1 , 1 -dioxide, i sothi azolidine, isothiazolidine 1 , 1 -dioxide.
[0028] A fused bicyclic heterocyclyl has two rings which have two adjacent ring atoms in common. The first ring is a monocyclic heterocyclyl and the second ring is a monocyclic carbocycie (such as a cycloalkyl or phenyl) or a monocyclic heterocyclyl. For example, the second ring is a (CiwCejcycloaikyl, such as cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl. Alternatively, the second ring is phenyl. Examples of fused bicyclic
heterocyciyls include, but are not limited to, octahydrocyclopenta[c]pyrrolyl, indoline, isoindoline, 2,3-dihydro-lH-benzo[d]imidazole, 2,3-dihydrobenzo[d]oxazo!e, 2,3- dihydrohenzo[d]thiazole, oetahydrobenzo[d]oxazo!e, octahydro-lH-benzo[d]imidazole, octahydrobenzo[d]thiazo3e, octahydroeyciopenta[c]pyrrole, 3-azabicyclo[3.l .O]bexane, and 3-azabicyclo[3.2.0]heptane.
[0029] A spiro bicyclic heterocyclyl has two rings which have only one ring atom in common. The first ring is a monocyclic heterocyclyl and the second ring is a monocyclic carbocycie (such as a cycloalkyl or phenyl) or a monocyclic heterocyclyl. For example, the second ring is a (Cs-Cejcycloaikyl. Alternatively, the second ring is phenyl. Example of spiro bicyclic heterocyclyl includes, but are not limited to, azaspiro[4.4]nonane, 7- azaspiro[4.4]nonane, azaspiro[4.5]deeane, 8-azaspiro[4.5]decane, azaspiro[5.5]undecane, 3- azaspiro[5.5]undecane and 3,9-diazaspiro[5.5]undecane. [0030] A bridged bicyclic heterocyclyl has two rings which have three or more adjacent ring atoms in common. The first ring is a monocyclic heterocyclyl and the other ring is a monocyclic carbocycle (such as a cycloalkyl or phenyl) or a monocyclic heterocyclyl.
Examples of bri dged bicyclic heterocyclyls include, but are not limited to,
azabicyclo[3.3.1]nonane, 3-azabicyclo[3.3.1]nonane, azabicyclo[3.2.l]octane, 3- azabicydo[3 2, ljoctane, 6-azabi cyclo[3.2.1 joctane and azabicyclo[2.2.2]octane, 2- azabicyclo[2.2.2]octane.
[0031] Polycyclic heterocyclyls have more than two rings, one of which is a heterocyclyl (e.g., three rings resulting in a tricyclic ring system) and adjacent rings having at least one ring atom in common. Polycyclic ring systems include fused, bridged and spiro ring systems. A fused polycyclic ring system has at least two rings that have twO adjacent ring atoms in common. A spiro polycyclic ring system has at least two rings that have only one ring atom in common. A bridged polycyclic ring system has at least two rings that have three or more adjacent ring atoms in common.
[0032] “Heteroaryl” or“heteroaromatic ring” means a 5-12 membered monovalent heteroaromatic monocyclic or bicyiic ring radical. A herteroaryl contains 1, 2, 3 or 4 heteroatoms independently selected from N, O, and S. Heteroaryls include, but are not limited to furan, oxazole, thiophene, 1,2,3-triazole, 1 ,2,4-triazine, 1,2, 4-triazole, 1,2,5- thiadi azole 1,1 -dioxide, 1,2,5-thiadiazole 1-oxide, 1,2,5-thiadiazole, 1,3,4-oxadiazole, 1,3,4- thiadi azole, 1,3,5-triazine, imidazole, isothiazole, isoxazole, pyrazole, pyridazine, pyridine, pyridine-N-oxide, pyrazine, pyrimidine, pyrrole, tetrazole, and thi azole. Bicyclic heteroaryl rings include, but are not limited to, bicyc!o[4.4 Q]and bicyclo[4.3.0]fused ring systems such as indolizine, indole, isoindole, indazole, benzimidazole, benzthiazole, purine, quinoline, isoquinoline, cinnoline, phthalazine, quinazoline, quinoxaline, l,8-naphthyridine, and pteridine.
[0033] In certain embodiments, where indicated, a group such as alkylene, adamantyl, naphthyl, or aryl may be optionally substituted. Exemplary substituents include halo, (Ci- Cejalkyl,—OH, -O, (Ci-Cejalkoxy, (Cr-Cejalkoxy-CCi-Cejalkylene, (Ci-Cejhaloalkyl, (Ci- Cfijhaloalkoxy, and— C(O)— (Ci-Csjalkyl.
[0034] In certain embodiments, where indicated, a phenyl group may have two adjacent substituents that, taken together with the intervening atoms, form an optionally substituted heteroaryl, aryl, cycloalkyl, or heterocycloalkyl ring. By way of example, a phenyl group having two adjacent substituents that, taken together with the intervening atoms, form a pyridinyl group can have the structure
Figure imgf000010_0001
any positional isomer thereof. In another example, a phenyl group having two adjacent substituents that, taken together with the intervening atoms, form a tetrahydropyranyl group can have the
structure
Figure imgf000010_0002
any positional isomer thereof.
[0035] Halogen” and“halo” are interchangeably used herein and each refers to fluorine, chlorine, bromine, or iodine.
[0036] “Alkoxy” means an alkyl radical attached through an oxygen linking atom.“(Ci- C6)-alkoxy” includes methoxy, ethoxy, propoxy, butoxy, pentoxy and hexoxy.
[0037] Haioalky] includes mono, poly, and perhaloalkyl groups where each halogen is independently selected from fluorine, chlorine, and bromine.
[0038] “Pharmaceutically acceptable carrier” means non-therapeutic components that are of sufficient purity and quality for use in the formulation of a composition of the invention that, when appropriately administered to an animal or human, typically do not produce an adverse reaction, and that are used as a vehicle for a drug substance (i.e. a compound of the present invention).
[0039] Pharmaceutically acceptable salts of the compounds of the present invention are also included. For example, an acid salt of a compound of the present invention containing an amine or other basic group can be obtained by reacting the compound with a suitable organic or inorganic acid, resulting in pharmaceutically acceptable anionic salt forms.
Examples of anionic salts include the acetate, benzenesulfonate, benzoate, bicarbonate, hi tartrate, bromide, calcium edetate, camsylate, carbonate, chloride, citrate, dihydrochloride, edetate, edisylate, estolate, esylate, fumarate, glyceptate, gluconate, glutamate,
glycollylarsanilate, hexy!resorcinate, hydrobromide, hydrochloride, hydroxynaphthoate, iodide, isethionate, lactate, lactobionate, malate, maleate, mandelate, mesylate,
methylsulfate, mucate, napsylate, nitrate, pamoate, pantothenate, phosphate/diphosphate, poiygalacturonate, salicylate, stearate, subacetate, succinate, sulfate, tannate, tartrate, teoclate, tosylate, and triethiodide salts. [0040] Salts of the compounds of the present invention containing a carboxylic acid or other acidic functional group can be prepared by reacting with a suitable base. Such a pharmaceutically acceptable salt may be made with a base which affords a pharmaceutically acceptable cation, which includes alkali metal salts (especially sodium and potassium), alkaline earth metal salts (especially calcium and magnesium), aluminum salts and ammonium salts, as well as salts made from physiologically acceptable organic bases such as trimethylamine, triethylamine, morpholine, pyridine, piperidine, picoline,
dicyclohexylamine, N,N'-dibenzylethylenediamine, 2-hydroxyethylamine, bis-(2- hydroxyethyi)amine, tri-(2-hydroxyethyl)amine, procaine, dibenzylpiperidine,
dehydroabietylamine, N,N'-bisdehydroabietylamine, giucamine, N-methylg!ucamine, collidine, quinine, quinoline, and basic amino acids such as lysine and arginine.
Compounds of the Invention
[0041] In certain aspects, the invention provides compounds represented by structural formula (I):
Figure imgf000011_0001
or a pharmaceutically acceptable salt thereof;
wherein:
L5 is (Ci-C2)alkylene, optionally substituted with (Ci-Ce)alkyl, hydroxyl,
hydroxyl(Ci-C6)alkyl, (C3-C6)cycloalkyl, phenyl, halo(Ci-C6)alkyl, (Ci-Ce)alkoxyl(Ci- Ce)alkyl, -C(0)0H, or -C(0)0-(Ci-C6)alkyl;
L6 is (Ci-C2)alkylene, optionally substituted with (Ci-Ce)alkyl, hydroxyl,
hydroxyl(Ci-C6)alkyl, (C3-C6)cycloalkyl, phenyl, halo(Ci-C6)alkyl, (Ci-Ce)alkoxyl(Ci- Ce)alkyl, -C(0)0H, or -C(0)0-(Ci-C6)alkyl;
Figure imgf000011_0002
is unsubstituted adamantyl;
R6 is optionally substituted phenyl;
R7 is H, alkyl, hydroxyalkyl, cycloalkyl, (cycloalkyl)alkyl, aralkyl, or heteroaralkyl; wherein when (a) L5 and L6 are both optionally substituted (Ci)alkylene, or (b) when
L5 is optionally substituted (C2)alkylene and L6 is optionally substituted (Ci)alkylene, then
R6 is phenyl substituted with one or more substituents, wherein the one or more substituents are selected from the group consisting of (C2-C6)alkyl, cycloalkyl, aryl, heteroaryl, halo, haloalkyl, hydroxyalkyl, alkoxy, (cycloalkyl)alkyl, and aralkyl, or wherein two adjacent substituents on phenyl, taken together with the intervening atoms, form a heteroaryl, aryl, cycloalkyl, or heterocycloalkyl ring.
[0042] In further embodiments, the present invention provides a compound of formula
( ):
Figure imgf000012_0001
or a pharmaceutically acceptable salt thereof;
wherein:
L5 is (Ci-C2)alkylene, optionally substituted with (Ci-Ce)alkyl, hydroxyl, hydroxyl(Ci-C6)alkyl, (C3-C6)cycloalkyl, phenyl, halo(Ci-C6)alkyl, (Ci-C6)alkoxyl(Ci- Cejalkyl, -C(0)0H, or -C(0)0-(Ci-C6)alkyl;
L6 is (Ci-C2)alkylene, optionally substituted with (Ci-Ce)alkyl, hydroxyl, hydroxyl(Ci-C6)alkyl, (C3-C6)cycloalkyl, phenyl, halo(Ci-C6)alkyl, (Ci-C6)alkoxyl(Ci- C6)alkyl, -C(0)0H, or -C(0)0-(Ci-C6)alkyl;
Figure imgf000012_0002
is unsubstituted adamantyl;
R6 is phenyl substituted with one or more substituents, wherein the one or more substituents are selected from the group consisting of (C2-C6)alkyl, cycloalkyl, aryl, heteroaryl, halo, haloalkyl, hydroxyalkyl, alkoxy, (cycloalkyl)alkyl, and aralkyl, or wherein two adjacent substituents on phenyl, taken together with the intervening atoms, form a heteroaryl, aryl, cycloalkyl, or heterocycloalkyl ring; and
R7 is H, alkyl, hydroxyalkyl, cycloalkyl, (cycloalkyl)alkyl, aralkyl, or heteroaralkyl.
[0043] In certain embodiments of the compounds of formula (I) or (G), L5 is unsubstituted methylene. Alternatively, in certain embodiments, L5 is unsubstituted ethylene.
[0044] In certain embodiments of the compounds of formula (I) or (G), L5 is methylene substituted with (Ci-Ce)alkyl, e.g., methyl.
[0045] In certain embodiments of the compounds of formula (I) or (G), L5 is ethylene substituted with (Ci-Ce)alkyl, e.g., methyl. [0046] In certain embodiments of the compounds of formula (I) or (G), ring
Figure imgf000013_0001
is unsubstituted l-adamantyl.
[0047] In alternative embodiments, wherein ring
Figure imgf000013_0002
is unsubstituted 2-adamantyl.
[0048] In certain embodiments of the compounds of formula (I) or (G), L6 is
unsubstituted methylene. Alternatively, in certain embodiments, L6 is unsubstituted ethylene.
[0049] In certain embodiments of the compounds of formula (I) or (G), L6 is methylene substituted with (Ci-Ce)alkyl, e.g., methyl.
[0050] In certain embodiments of the compounds of formula (I) or (G), L6 is ethylene substituted with (Ci-Ce)alkyl, e.g., methyl.
[0051] In certain embodiments of the compounds of formula (I) or (G), R6 is
unsubstituted phenyl.
[0052] Alternatively, in certain embodiments, R6 is represented by
Figure imgf000013_0003
, wherein:
R is a substituent selected from the group consisting of (C2-C6)alkyl, cycloalkyl, aryl, heteroaryl, halo, haloalkyl, hydroxylalkyl, alkoxy, (cycloalkyl)alkyl, and aralkyl; and
n is an integer from 0 to 5.
In certain embodiments, R6 is represented
Figure imgf000013_0004
Figure imgf000013_0005
[0054] In certain such embodiments, each occurrence of R is independently selected from the group consisting of (C2-C6)alkyl, alkoxy, and halo. For example, in some embodiments, R is alkyl. Alternatively, R may be alkoxy. In other alternative embodiments, R is halo, e.g., fluoro.
[0055] In certain embodiments, R6 is phenyl substituted with two or more substituents, wherein two adjacent substituents on phenyl, taken together with the intervening atoms, form a heteroaryl, aryl, cycloalkyl, or heterocycloalkyl ring. For example, R6 may be represented
Figure imgf000014_0001
represents an optionally substituted heteroaryl, aryl, cycloalkyl, or heterocycloalkyl ring.
[0056] In certain such embodiments,
Figure imgf000014_0002
represents an optionally substituted heteroaryl ring such as thiophene. Alternatively,
Figure imgf000014_0003
may represent an optionally substituted cycloalkyl ring such as cyclohexane. In other alternative embodiments,
Figure imgf000014_0004
represents an optionally substituted heterocycloalkyl ring such as tetrahydropyran.
[0057] In some embodiments in which R2 is represented by
Figure imgf000014_0005
, moiety
Figure imgf000014_0006
may be optionally substituted. For example,
Figure imgf000014_0007
may represent optionally substituted tetralin, e.g., wherein the saturated ring of the tetralin system is optionally substituted by a substituent such as fluorine.
[0058] In certain embodiments, R7 represents H, alkyl, or cycloalkyl. In further embodiments, R7 represents H or alkyl, e.g., methyl. Preferably, R7 is H.
[0059] In some embodiments of the compounds of formula (I) or (F), the compound has the structure of formula (la):
Figure imgf000014_0008
[0060] In some embodiments of the compounds of formula (I) or (F), the compound has the structure of formula (lb):
Figure imgf000014_0009
[0061] In some embodiments of the compounds of formula (I) or (F), the compound has the structure of formula (Ic):
Figure imgf000015_0001
[0062] In some embodiments of the compounds of formula (I) or (G), the compound has the structure of formula (Id):
Figure imgf000015_0002
[0063] In some embodiments of the compounds of formula (I) or (G), the compound has the structure of formula (Ie):
Figure imgf000015_0003
[0064] In some embodiments of the compounds of formula (I) or (G), the compound has the structure of formula (If):
Figure imgf000015_0004
[0065] In some embodiments of the compounds of formula (I) or (G), the compound has the structure of formula (Ig):
Figure imgf000015_0005
[0066] In some embodiments of the compounds of formula (I) or (G), the compound has the structure of formula (Ih):
Figure imgf000015_0006
[0067] wherein R is a substituent selected from the group consisting of (C2-C6)alkyl, cycloalkyl, aryl, heteroaryl, halo, haloalkyl, hydroxyalkyl, alkoxy, (cycloalkyl)alkyl, and aralkyl; and n is an integer from 0 to 5.
[0068] In some embodiments of the compounds of formula (I) or (G), the compound has the structure of formula (Ii):
Figure imgf000015_0007
wherein R is a substituent selected from the group consisting of (C2-C6)alkyl, cycloalkyl, aryl, heteroaryl, halo, haloalkyl, hydroxyalkyl, alkoxy, (cycloalkyl)alkyl, and aralkyl; and n is an integer from 0 to 5.
[0069] In some embodiments of the compounds of formula (I) or (G), the compound has the structure of formula (Ij):
Figure imgf000016_0001
[0070] wherein R is a substituent selected from the group consisting of (C2-C6)alkyl, cycloalkyl, aryl, heteroaryl, halo, haloalkyl, hydroxyalkyl, alkoxy, (cycloalkyl)alkyl, and aralkyl; and n is an integer from 1 to 5.
[0071] In some embodiments of the compounds of formula (I) or (G), the compound has the structure of formula (Ik):
Figure imgf000016_0002
[0072] wherein R is a substituent selected from the group consisting of (C2-C6)alkyl, cycloalkyl, aryl, heteroaryl, halo, haloalkyl, hydroxyalkyl, alkoxy, (cycloalkyl)alkyl, and aralkyl; and n is an integer from 0 to 5.
[0073] In some embodiments of the compounds of formula (I) or (G), the compound has the structure of formula (II):
Figure imgf000016_0003
[0074] wherein R is a substituent selected from the group consisting of (C2-C6)alkyl, cycloalkyl, aryl, heteroaryl, halo, haloalkyl, hydroxyalkyl, alkoxy, (cycloalkyl)alkyl, and aralkyl; and n is an integer from 0 to 5.
[0075] In some embodiments of the compounds of formula (I) or (G), the compound has the structure of formula (Im):
Figure imgf000016_0004
[0076] wherein R is a substituent selected from the group consisting of (C2-C6)alkyl, cycloalkyl, aryl, heteroaryl, halo, haloalkyl, hydroxyalkyl, alkoxy, (cycloalkyl)alkyl, and aralkyl; and n is an integer from 0 to 5.
[0077] In some embodiments of the compounds of formula (I) or (G), the compound has the structure of formula (In):
Figure imgf000017_0001
[0078] wherein R is a substituent selected from the group consisting of (C2-C6)alkyl, cycloalkyl, aryl, heteroaryl, halo, haloalkyl, hydroxyalkyl, alkoxy, (cycloalkyl)alkyl, and aralkyl; and n is an integer from 0 to 5.
[0079] In certain embodiments, the invention provides any one of the compounds in Table 1 or a pharmaceutically acceptable salt thereof:
TABLE 1 :
Figure imgf000017_0002
Figure imgf000018_0001
Figure imgf000019_0001
Figure imgf000020_0001
Figure imgf000021_0005
[0080] In further embodiments, the invention provides a compound according to formula
Figure imgf000021_0001
or a pharmaceutically acceptable salt thereof;
wherein:
X is -0-, -CH2-, or -C(R20)2-;
each R20 is independently selected from the group consisting of H and alkyl;
L25 is absent or is optionally substituted alkylene; ring
Figure imgf000021_0002
is optionally adamantyl;
R21 is a substituent selected from the group consisting of alkyl, cycloalkyl, aryl, heteroaryl, (cycloalkyl)alkyl, aralkyl, hydroxyl, hydroxyalkyl, alkoxy, halo, and haloalkyl; and m is an integer from 0 to 4; and
R27 is H, alkyl, hydroxyalkyl, cycloalkyl, (cycloalkyl)alkyl, aralkyl, or heteroaralkyl.
[0081] Exemplary compounds of formula (X) include
Figure imgf000021_0003
Figure imgf000021_0004
pharmaceutically acceptable salts thereof.
Methods of Treating Tuberculosis [0082] In certain aspects, the invention provides a method for treating tuberculosis, comprising administering to a subject in need thereof a therapeutically effective amount of a compound of formula (II):
Figure imgf000022_0001
or a pharmaceutically acceptable salt thereof;
wherein:
L1 is absent or is optionally substituted alkylene;
L2 is absent or is optionally substituted alkylene;
Figure imgf000022_0002
is optionally substituted adamantyl;
R2 is optionally substituted phenyl; and
R3 is H, alkyl, hydroxyalkyl, cycloalkyl, (cycloalkyl)alkyl, aralkyl, or heteroaralkyl.
[0083] In certain embodiments of the compounds of formula (II), L1 is unsubstituted methylene. Alternatively, in certain embodiments, L1 is unsubstituted ethylene.
[0084] In certain embodiments of the compounds of formula (II), L1 is methylene substituted with (Ci-Ce)alkyl, e.g., methyl.
[0085] In certain embodiments of the compounds of formula (II), L1 is ethylene substituted with (Ci-Ce)alkyl, e.g., methyl.
[0086] In certain embodiments of the compounds of formula (II), L2 is optionally substituted alkylene; e.g. optionally substituted (Ci-C2)alkylene.
[0087] In certain embodiments, L2 is unsubstituted methylene. Alternatively, in certain embodiments, L2 is unsubstituted ethylene.
[0088] In certain embodiments of the compounds of formula (II), L2 is methylene substituted with (Ci-Ce)alkyl, e.g., methyl.
[0089] In certain embodiments of the compounds of formula (II), L2 is ethylene substituted with (Ci-Ce)alkyl, e.g., methyl.
[0090] In certain embodiments of the compounds of formula (II), ring
Figure imgf000022_0003
is optionally substituted l-adamantyl. [0091] In certain such embodiments, ring
Figure imgf000023_0001
is l-adamantyl, substituted with one or more substituents selected from the group consisting of alkyl, hydroxyl, hydroxyalkyl, halo, and haloalkyl. For example, ring
Figure imgf000023_0002
is l-adamantyl, substituted with methyl or hydroxyl.
[0092] Alternatively, ring
Figure imgf000023_0003
may be unsubstituted l-adamantyl.
[0093] In certain embodiments of the compounds of formula (II), ring
Figure imgf000023_0004
is optionally substituted 2-adamantyl.
[0094] In certain such embodiments, ring
Figure imgf000023_0005
is 2-adamantyl, substituted with one or more substituents selected from the group consisting of alkyl, hydroxyl, hydroxyalkyl, halo, and haloalkyl. For example, ring
Figure imgf000023_0006
is 2-adamantyl, substituted with methyl or hydroxyl.
[0095] Alternatively, ring
Figure imgf000023_0007
may be unsubstituted 2-adamantyl.
[0096] In certain embodiments of the compounds of formula (II), R2 is represented by
Figure imgf000023_0008
, wherein R is a substituent and n is an integer from 0 to 5.
[0097] In certain such embodiments, each R is independently selected from the group consisting of alkyl, cycloalkyl, aryl, heteroaryl, (cycloalkyl)alkyl, aralkyl, hydroxyl, hydroxyalkyl, alkoxy, halo, and haloalkyl. [0098] In certain such embodiments, R2 is represented
Figure imgf000024_0001
Figure imgf000024_0002
[0099] In certain such embodiments, R represents alkyl, e.g., methyl. Alternatively, R may represent fluoro.
[00100] In still further embodiments, R2 is represented by
Figure imgf000024_0003
, wherein R is a substituent and n is 0.
[00101] In certain embodiments, R2 is phenyl substituted with two or more substituents, wherein two adjacent substituents on phenyl, taken together with the intervening atoms, form a heteroaryl, aryl, cycloalkyl, or heterocycloalkyl ring. For example, R2 may be represented
Figure imgf000024_0004
represents an optionally substituted heteroaryl, aryl, cycloalkyl, or heterocycloalkyl ring.
[00102] In certain such embodiments,
Figure imgf000024_0005
represents an optionally substituted heteroaryl ring such as thiophene. Alternatively,
Figure imgf000024_0006
may represent an optionally substituted cycloalkyl ring such as cyclohexane. In other alternative embodiments,
Figure imgf000024_0007
represents an optionally substituted heterocycloalkyl ring such as tetrahydropyran.
[00103] In some embodiments in which R2 is represented by
Figure imgf000024_0008
, moiety
Figure imgf000024_0009
may be optionally substituted. For example, may represent optionally substituted tetralin, e.g., wherein the saturated ring of the tetralin system is optionally substituted by a substituent such as fluorine. [00104] In certain embodiments of the compounds of formula (II), R3 represents H, alkyl, or cycloalkyl. In further embodiments, R3 represents H or alkyl, e.g., methyl. Preferably R3 is H.
[00105] In certain embodiments of the compounds of formula (II):
L1 is (Ci-C2)alkylene, optionally substituted with (Ci-Ce)alkyl, hydroxyl, hydroxyl(Ci-C6)alkyl, (C3-C6)cycloalkyl, phenyl, halo(Ci-C6)alkyl, (Ci-Ce)alkoxyl(Ci- Ce)alkyl, -C(0)OH, or -C(0)0-(Ci-C6)alkyl;
L2 is (Ci-C2)alkylene, optionally substituted with (Ci-Ce)alkyl, hydroxyl, hydroxyl(Ci-C6)alkyl, (C3-C6)cycloalkyl, phenyl, halo(Ci-C6)alkyl, (Ci-Ce)alkoxyl(Ci- C6)alkyl, -C(0)OH, or -C(0)0-(Ci-C6)alkyl;
Figure imgf000025_0001
is unsubstituted adamantyl;
R2 is optionally substituted phenyl;
R3 is H, alkyl, or cycloalkyl;
wherein when (a) L1 and L2 are both optionally substituted (Ci)alkylene, or (b) when
L1 is optionally substituted (C2)alkylene and L2 is optionally substituted (Ci)alkylene, then
R2 is phenyl substituted with one or more substituents, wherein the one or more substituents are selected from the group consisting of (C2-C6)alkyl, cycloalkyl, aryl, heteroaryl, halo, haloalkyl, hydroxyalkyl, alkoxy, (cycloalkyl)alkyl, and aralkyl, or wherein two adjacent substituents on phenyl, taken together with the intervening atoms, form a heteroaryl, aryl, cycloalkyl, or heterocycloalkyl ring.
[00106] In further embodiments of the compounds of formula (II):
L1 is (Ci-C2)alkylene, optionally substituted with (Ci-Ce)alkyl, hydroxyl, hydroxyl(Ci-C6)alkyl, (C3-C6)cycloalkyl, phenyl, halo(Ci-C6)alkyl, (Ci-Ce)alkoxyl(Ci- C6)alkyl, -C(0)OH, or -C(0)0-(Ci-C6)alkyl;
L2 is (Ci-C2)alkylene, optionally substituted with (Ci-Ce)alkyl, hydroxyl, hydroxyl(Ci-C6)alkyl, (C3-C6)cycloalkyl, phenyl, halo(Ci-C6)alkyl, (Ci-Ce)alkoxyl(Ci- C6)alkyl, -C(0)OH, or -C(0)0-(Ci-C6)alkyl;
Figure imgf000025_0002
is unsubstituted adamantyl;
R2 is phenyl substituted with one or more substituents, wherein the one or more substituents are selected from the group consisting of (C2-C6)alkyl, cycloalkyl, aryl, heteroaryl, halo, haloalkyl, hydroxyalkyl, alkoxy, (cycloalkyl)alkyl, and aralkyl, or wherein two adjacent substituents on phenyl, taken together with the intervening atoms, form a heteroaryl, aryl, cycloalkyl, or heterocycloalkyl ring; and
R3 is H, alkyl, hydroxyalkyl, cycloalkyl, (cycloalkyl)alkyl, aralkyl, or heteroaralkyl.
[00107] In some embodiments of the compounds of formula (II), the compound has the structure of formula (Ha):
Figure imgf000026_0001
[00108] In some embodiments of the compounds of formula (II), the compound has the structure of formula (lib):
Figure imgf000026_0002
[00109] In some embodiments of the compounds of formula (II), the compound has the structure of formula (He):
Figure imgf000026_0003
[00110] In some embodiments of the compounds of formula (II), the compound has the structure of formula (lid):
Figure imgf000026_0004
[00111] In some embodiments of the compounds of formula (II), the compound has the structure of formula (He):
Figure imgf000026_0005
[00112] In some embodiments of the compounds of formula (II), the compound has the structure of formula (Ilf):
Figure imgf000026_0006
[00113] In some embodiments of the compounds of formula (II), the compound has the structure of formula (Ilg):
Figure imgf000027_0001
[00114] In some embodiments of the compounds of formula (II), the compound has the structure of formula (Ilh):
Figure imgf000027_0002
[00115] wherein R is a substituent selected from the group consisting of alkyl, cycloalkyl, aryl, heteroaryl, (cycloalkyl)alkyl, aralkyl, hydroxyl, hydroxyalkyl, alkoxy, halo, and haloalkyl; and n is an integer from 0 to 5.
[00116] In some embodiments of the compounds of formula (II), the compound has the structure of formula (Hi):
Figure imgf000027_0003
[00117] wherein R is a substituent selected from the group consisting of alkyl, cycloalkyl, aryl, heteroaryl, (cycloalkyl)alkyl, aralkyl, hydroxyl, hydroxyalkyl, alkoxy, halo, and haloalkyl; and n is an integer from 0 to 5.
[00118] In some embodiments of the compounds of formula (II), the compound has the structure of formula (Ilj):
Figure imgf000027_0004
[00119] wherein R is a substituent selected from the group consisting of alkyl, cycloalkyl, aryl, heteroaryl, (cycloalkyl)alkyl, aralkyl, hydroxyl, hydroxyalkyl, alkoxy, halo, and haloalkyl; and n is an integer from 0 to 5.
[00120] In some embodiments of the compounds of formula (II), the compound has the structure of formula (Ilk):
Figure imgf000027_0005
wherein R is a substituent selected from the group consisting of alkyl, cycloalkyl, aryl, heteroaryl, (cycloalkyl)alkyl, aralkyl, hydroxyl, hydroxyalkyl, alkoxy, halo, and haloalkyl; and n is an integer from 0 to 5.
[00121] In some embodiments of the compounds of formula (II), the compound has the structure of formula (III):
Figure imgf000028_0001
wherein R is a substituent selected from the group consisting of alkyl, cycloalkyl, aryl, heteroaryl, (cycloalkyl)alkyl, aralkyl, hydroxyl, hydroxyalkyl, alkoxy, halo, and haloalkyl; and n is an integer from 0 to 5.
[00122] In some embodiments of the compounds of formula (II), the compound has the structure of formula (Ilm):
Figure imgf000028_0002
wherein R is a substituent selected from the group consisting of alkyl, cycloalkyl, aryl, heteroaryl, (cycloalkyl)alkyl, aralkyl, hydroxyl, hydroxyalkyl, alkoxy, halo, and haloalkyl; and n is an integer from 0 to 5.
[00123] In some embodiments of the compounds of formula (II), the compound has the structure of formula (Iln):
Figure imgf000028_0003
wherein R is a substituent selected from the group consisting of alkyl, cycloalkyl, aryl, heteroaryl, (cycloalkyl)alkyl, aralkyl, hydroxyl, hydroxyalkyl, alkoxy, halo, and haloalkyl; and n is an integer from 0 to 5.
[00124] Exemplary compounds of formula (II) are shown in Table 2, below: TABLE 2
Figure imgf000029_0001
Figure imgf000030_0001

Figure imgf000031_0001
30
Figure imgf000032_0001
31
Figure imgf000033_0001
32
Figure imgf000034_0002
[00125] In certain embodiments, compounds useful in the method of treating tuberculosis is selected from any one of the compounds in Table 3 or a pharmaceutically acceptable salt thereof. Anti-tuberculosis activity is shown in Table 3:
TABLE 3
Figure imgf000034_0001
Figure imgf000035_0001
Figure imgf000036_0001
Figure imgf000037_0001
Figure imgf000038_0001
Figure imgf000039_0001
Figure imgf000040_0001
Figure imgf000041_0001
Figure imgf000042_0001
Figure imgf000043_0001
Figure imgf000044_0001
Figure imgf000045_0001
Figure imgf000046_0001
Figure imgf000047_0001
Figure imgf000048_0001
Figure imgf000049_0001
[00126] In certain aspects, the subject treated by the methods of the invention is a mammal, e.g., a human. [00127] In certain aspects, the invention provides a method for inhibiting non-tuberculosis mycobacteria, comprising contacting the non-tuberculosis mycobacteria with an effective amount of a compound of formula (I).
[00128] In further aspects, the invention provides a method for treating an infection caused by non-tuberculosis mycobacteria, comprising administering to a subject in need thereof a therapeutically effective amount of a compound of formula (I).
[00129] Exemplary non-tuberculosis pathogenic mycobacteria for use in the methods of the invention include Runyon I organisms (photochromogens), such as Mycobacterium kansasii, Mycobacterium marinum , and Mycobacterium simiae; Runyon II organisms (scotochromogens), such as Mycobacterium scrofulaceum , and Mycobacterium szulgai , Mycobacterium gordonae; Runyon III organisms (nonchromogens), such as Mycobacterium avium complex, Mycobacterium ulcerous, Mycobacterium xenopi , Mycobacterium malmoense , Mycobacterium terrae complex, Mycobacterium haemophilum , and
Mycobacterium genavense; and Runyon IV organisms, such as Mycobacterium abscessus complex, Mycobacterium chelonae , Mycobacterium fortuitum complex, and Mycobacterium peregrinum.
[00130] In certain aspects, the invention provides a method for inhibiting pathogenic nocardia, comprising contacting the pathogenic nocardia with an effective amount of a compound of formula (I).
[00131] In further aspects, the invention provides a method for treating an infection caused by pathogenic nocardia, comprising administering to a subject in need thereof a therapeutically effective amount of a compound of formula (I).
[00132] Exemplary pathogenic nocardia useful in the methods of the invention include the following Nocardia species: N. concava, N. cyriacigeorgica, N donostiensis, N elegans, N exalbida, N. farcinica, N harenae, N. higoensis, N. ignorata, N. inohanensis, N. jinanensis, N kroppenstedtii, N. kruczakiae, N. mexicana, N. mikamii, N neocaledoniensis, N niigatensis, N ninae, N niwae, N nova, N. otitidiscaviarum, N. paucivorans, N
pneumoniae, N. pseudobrasiliensis, N puris, N shinanonensis, N sienata, N takedensis, N terpenica, N testaceae, N. thailandica, N. transvalensis, N vermiculata, N veter ana, N vulneris, N wallacei, and N yamanashiensis .
[00133] In certain aspects, the invention provides a method for inhibiting pathogenic actinomyces, comprising contacting the pathogenic actinomyces with an effective amount of a compound of formula (I). [00134] In further aspects, the invention provides a method for treating an infection caused by pathogenic actinomyces, comprising administering to a subject in need thereof a therapeutically effective amount of a compound of formula (I).
[00135] Exemplary pathogenic actinomyces useful in the methods of the invention include the following Actinomyces species: A. israelii, A. viscosus, A. meyeri, A. naeslundii, A. odontolyticus, A. gerencseriae, A. neuii, A. turicensis, and A. radingae.
[00136] In certain embodiments, the methods of the invention further comprise administering one or more additional therapeutic agents. Examples of such one or more additional therapeutic agents are anti-tuberculosis agents including, but not limited to, amikacin, aminosalicylic acid, capreomycin, cycloserine, ethambutol, ethionamide, isoniazid, kanamycin, pyrazinamide, rifamycins (such as rifampin, rifapentine and rifabutin), streptomycin, clarithromycin, azithromycin, oxazolidinones and fluoroquinolones (such as ofloxacin, ciprofloxacin, moxifloxacin and gatifloxacin). Such chemotherapy is determined by the judgment of the treating physician using preferred drug combinations.“First-line” chemotherapeutic agents used to treat a Mycobacterium tuberculosis infection that is not drug resistant include isoniazid, rifampin, ethambutol, streptomycin and pyrazinamide. “Second-line” chemotherapeutic agents used to treat a Mycobacterium tuberculosis infection that has demonstrated drug resistance to one or more“first-line” drugs include ofloxacin, ciprofloxacin, ethionamide, aminosalicylic acid, cycloserine, amikacin, kanamycin, capreomycin, clofazimine, bedaquiline, delaminid, and linezolid. In addition to the aforementioned, there is a number of new anti-tuberculosis therapeutic agents emerging from clinical studies that may also be employed as the one or more additional therapeutic agents in a combination with a compound of the invention, including, but not limited to LL-3858 and SQ-109.
[00137] In further embodiments, the one or more additional therapeutic agents is selected from therapeutic vaccines, anti -bacterial agents, anti-viral agents; antibiotics and agents for the treatment of HIV/AIDS. Examples of such therapeutic agents include isoniazid (INH), ethambutol, rifampin, pyrazinamide, streptomycin, capreomycin, ciprofloxacin and clofazimine.
[00138] I he compound the invention, or a pharmaceutically acceptable salt thereof, may be either i) administered to an individual who has previously been vaccinated against a mycobacterial infection; ii) administered to an individual who is subsequently vaccinated against a mycobacterial infection; or iii) may be co-administered with a vaccine against a mycobacterial infection, either by administering the compound of the invention and the vaccine together in the same dosage form or co-administering the compound of the invention and the vaccine in separate dosage forms.
[00139] When a compound of the invention, or a pharmaceutically acceptable salt thereof, is used in combination with one or more additional therapeutic agents, the dose of the compound or agent may differ from that when the compound or agent is used alone.
Appropriate doses will be readily appreciated by those skilled in the art. It will be
appreciated that the amount of a compound of the invention and the one or more additional therapeutic agents required for use in treatment will vary with the nature of the condition being treated and the age and the condition of the patient and will be ultimately at the discretion of the attendant physician or veterinarian.
[00140] I he combinations may conveniently be presented for use in the form of a pharmaceutical formulation. In a further aspect of the present invention there is provided a pharmaceutical combination comprising a compound of the invention, or a pharmaceutically acceptable salt thereof, together with one or more additional therapeutic agents, and one or more pharmaceutically acceptable carriers, excipients or diluents. The individual
components of such combinations may be administered either sequentially or simultaneously in separate or combined pharmaceutical formulations by any convenient route.
[00141] When administration is sequential, either the compound of the present invention or one or more additional therapeutic agent may be administered first. When administration is simultaneous, the combination may be administered either in the same or different pharmaceutical composition. When combined in the same formulation it will be appreciated that the compound and agents must be stable and compatible with each other and the other components of the formulation. When formulated separately they may be provided in any convenient formulation, conveniently in such manner as are known for such compounds in the art.
Pharmaceutical Compositions
[00142] In certain aspects, the invention also provides a pharmaceutical composition comprising a compound of the invention (e.g., a compound of formula I, G, or X), and a pharmaceutically acceptable carrier.
[00143] The invention further includes the process for making the composition
comprising mixing one or more of the present compounds and an optional pharmaceutically acceptable carrier; and includes those compositions resulting from such a process, which process includes conventional pharmaceutical techniques.
[00144] The compositions of the invention include ocular, oral, nasal, transdermal, topical with or without occlusion, intravenous (both bolus and infusion), inhalable, and injection (intraperitoneally, subcutaneously, intramuscularly, intralesionally, or parenterally) formulations. The composition may be in a dosage unit such as a tablet, pill, capsule, powder, granule, liposome, ion exchange resin, sterile ocular solution, or ocular delivery device (such as a contact lens and the like facilitating immediate release, timed release, or sustained release), parenteral solution or suspension, metered aerosol or liquid spray, drop, ampoule, auto-injector device, or suppository; for administration ocularly, orally, intranasally, sublingually, parenterally, or rectally, or by inhalation or insufflation.
[00145] Compositions of the invention suitable for oral administration include solid forms such as pills, tablets, caplets, capsules (each including immediate release, timed release, and sustained release formulations), granules and powders; and, liquid forms such as solutions, syrups, elixirs, emulsions, and suspensions. Forms useful for ocular administration include sterile solutions or ocular delivery devices. Forms useful for parenteral administration include sterile solutions, emulsions, and suspensions.
[00146] The compositions of the invention may be administered in a form suitable for once-weekly or once-monthly administration. For example, an insoluble salt of the active compound may be adapted to provide a depot preparation for intramuscular injection (e.g., a decanoate salt) or to provide a solution for ophthalmic administration.
[00147] The dosage form containing the composition of the invention contains an effective amount of the active ingredient necessary to provide a therapeutic effect. The composition may contain from about 5,000 mg to about 0.5 mg (preferably, from about 1,000 mg to about 0.5 mg) of a compound of the invention or salt form thereof and may be constituted into any form suitable for the selected mode of administration. The composition may be administered about 1 to about 5 times per day. Daily administration or post-periodic dosing may be employed.
[00148] For oral administration, the composition is preferably in the form of a tablet or capsule containing, e.g., 500 to 0.5 milligrams of the active compound. Dosages will vary depending on factors associated with the particular patient being treated (e.g., age, weight, diet, and time of administration), the severity of the condition being treated, the compound being employed, the mode of administration, and the strength of the preparation. [00149] The oral composition is preferably formulated as a homogeneous composition, wherein the active ingredient is dispersed evenly throughout the mixture, which may be readily subdivided into dosage units containing equal amounts of a compound of the invention. Preferably, the compositions are prepared by mixing a compound of the invention (or pharmaceutically acceptable salt thereof) with one or more optionally present
pharmaceutical carriers (such as a starch, sugar, diluent, granulating agent, lubricant, glidant, binding agent, and disintegrating agent), one or more optionally present inert pharmaceutical excipients (such as water, glycols, oils, alcohols, flavoring agents, preservatives, coloring agents, and syrup), one or more optionally present conventional tableting ingredients (such as corn starch, lactose, sucrose, sorbitol, talc, stearic acid, magnesium stearate, dicalcium phosphate, and any of a variety of gums), and an optional diluent (such as water).
[00150] Binder agents include starch, gelatin, natural sugars (e.g., glucose and beta- lactose), com sweeteners and natural and synthetic gums (e.g., acacia and tragacanth).
Disintegrating agents include starch, methyl cellulose, agar, and bentonite.
[00151] Tablets and capsules represent an advantageous oral dosage unit form. Tablets may be sugarcoated or film-coated using standard techniques. Tablets may also be coated or otherwise compounded to provide a prolonged, control-release therapeutic effect. The dosage form may comprise an inner dosage and an outer dosage component, wherein the outer component is in the form of an envelope over the inner component. The two components may further be separated by a layer which resists disintegration in the stomach (such as an enteric layer) and permits the inner component to pass intact into the duodenum or a layer which delays or sustains release. A variety of enteric and non-enteric layer or coating materials (such as polymeric acids, shellacs, acetyl alcohol, and cellulose acetate or combinations thereof) may be used.
[00152] Compounds of the invention may also be administered via a slow release composition; wherein the composition includes a compound of the invention and a biodegradable slow release carrier (e.g., a polymeric carrier) or a pharmaceutically acceptable non-biodegradable slow release carrier (e.g., an ion exchange carrier).
[00153] Biodegradable and non-biodegradable slow release carriers are well known in the art. Biodegradable carriers are used to form particles or matrices which retain an active agent(s) and which slowly degrade/dissolve in a suitable environment (e.g., aqueous, acidic, basic and the like) to release the agent. Such particles degrade/dissolve in body fluids to release the active compound(s) therein. The particles are preferably nanoparticles or nanoemulsions (e.g., in the range of about 1 to 500 nm in diameter, preferably about 50-200 nm in diameter, and most preferably about 100 nm in diameter). In a process for preparing a slow release composition, a slow release carrier and a compound of the invention are first dissolved or dispersed in an organic solvent. The resulting mixture is added into an aqueous solution containing an optional surface-active agent(s) to produce an emulsion. The organic solvent is then evaporated from the emulsion to provide a colloidal suspension of particles containing the slow release carrier and the compound of the invention.
[00154] The compound disclosed herein may be incorporated for administration orally or by injection in a liquid form such as aqueous solutions, suitably flavored syrups, aqueous or oil suspensions, flavored emulsions with edible oils such as cottonseed oil, sesame oil, coconut oil or peanut oil and the like, or in elixirs or similar pharmaceutical vehicles.
Suitable dispersing or suspending agents for aqueous suspensions, include synthetic and natural gums such as tragacanth, acacia, alginate, dextran, sodium carboxymethylcellulose, methylcellulose, polyvinyl-pyrrolidone, and gelatin. The liquid forms in suitably flavored suspending or dispersing agents may also include synthetic and natural gums. For parenteral administration, sterile suspensions and solutions are desired. Isotonic preparations, which generally contain suitable preservatives, are employed when intravenous administration is desired.
[00155] The compounds may be administered parenterally via injection. A parenteral formulation may consist of the active ingredient dissolved in or mixed with an appropriate inert liquid carrier. Acceptable liquid carriers usually comprise aqueous solvents and other optional ingredients for aiding solubility or preservation. Such aqueous solvents include sterile water, Ringer's solution, or an isotonic aqueous saline solution. Other optional ingredients include vegetable oils (such as peanut oil, cottonseed oil, and sesame oil), and organic solvents (such as solketal, glycerol, and formyl). A sterile, non-volatile oil may be employed as a solvent or suspending agent. The parenteral formulation is prepared by dissolving or suspending the active ingredient in the liquid carrier whereby the final dosage unit contains from 0.005 to 10% by weight of the active ingredient. Other additives include preservatives, isotonizers, solubilizers, stabilizers, and pain-soothing agents. Injectable suspensions may also be prepared, in which case appropriate liquid carriers, suspending agents and the like may be employed.
[00156] Compounds of the invention may be administered intranasally using a suitable intranasal vehicle. [00157] In other embodiments, the compounds of this invention may be administered directly to the lungs by inhalation.
[00158] Compounds of the invention may also be administered topically or enhanced by using a suitable topical transdermal vehicle or a transdermal patch.
[00159] For ocular administration, the composition is preferably in the form of an ophthalmic composition. The ophthalmic compositions are preferably formulated as eye- drop formulations and filled in appropriate containers to facilitate administration to the eye, for example a dropper fitted with a suitable pipette. Preferably, the compositions are sterile and aqueous based, using purified water. In addition to the compound of the invention, an ophthalmic composition may contain one or more of: a) a surfactant such as a
polyoxyethylene fatty acid ester; b) a thickening agents such as cellulose, cellulose derivatives, carboxyvinyl polymers, polyvinyl polymers, and polyvinylpyrrolidones, typically at a concentration n the range of about 0.05 to about 5.0% (wt/vol); c) (as an alternative to or in addition to storing the composition in a container containing nitrogen and optionally including a free oxygen absorber such as Fe), an anti-oxidant such as butylated hydroxyanisol, ascorbic acid, sodium thiosulfate, or butylated hydroxytoluene at a concentration of about 0.00005 to about 0.1% (wt/vol); d) ethanol at a concentration of about 0.01 to 0.5% (wt/vol); and e) other excipients such as an isotonic agent, buffer, preservative, and/or pH-controlling agent. The pH of the ophthalmic composition is desirably within the range of 4 to 8.
[00160] In certain embodiments, the composition of this invention includes one or more additional agents. The other therapeutic agent may be any agent that is capable of treating, preventing or reducing the symptoms of a tuberculosis. Alternatively, the other therapeutic agent may be an antibacterial compound. Alternatively, the other therapeutic agent may be any agent of benefit to a patient when administered in combination with the compound in this invention.
EXAMPLES
Example 1: General Synthetic Procedure
[00161] The compounds listed below were synthesized according to the following general procedure:
Figure imgf000057_0001
[00162] Amine 1 (0.5 mmol), aldehyde 2 (0.55 mmol) were dissolved in 0.6 ml MeOH, heated at 100° C for 2 hours, then mixture was cooled, NaBH4 (0.5 mmol) was added and stirred for 4 hours. The mixture was heated for 2 hours at 60° C, 3 ml of methanol and 0.2 g of C-18 chromatographic phase were added, stirred for 2 hours, filtered, evaporated. The residue was purified using HPLC. Yield: 28-63%.
[00163]
Figure imgf000057_0002
Chloroform-d) d 7.61
(d, J = 7.6 Hz, 1H), 7.56 (s, 1H), 7.51 - 7.29 (m, 3H), 3.88 (s, 1H), 2.76 (d, J = 7.1 Hz, 1H), 1.88 (d, J = 12.0 Hz, 2H), 1.80 (s, 1H), 1.75 (d, J = 16.0 Hz, 2H), 1.52 (d, J = 12.0 Hz, 1H).
[00164]
Figure imgf000057_0003
1H NMR (400 MHz, Chloroform-d) d 7.27 (q, J =
8.0 Hz, 6H), 7.14 (t, J = 7.4 Hz, 1H), 3.83 (s, 3H), 3.24 (q, J = 6.8 Hz, 1H), 2.76 (d, J = 7.2 Hz, 3H), 1.87 (d, J = 14.2 Hz, 1H), 1.75 (s, 1H), 1.52 (d, J = 11.7 Hz, 3H), 1.25 (d, J = 6.9 Hz, 8H).
[00165]
Figure imgf000057_0004
7.17 (d, J =
8.0 Hz, 1H), 6.77 (d, J = 8.1 Hz, 1H), 3.64 (s, 1H), 2.98 (s, 1H), 2.62 - 2.52 (m, 1H), 1.89 (s, OH), 1.79 (d, J = 15.3 Hz, 3H), 1.74 (s, 1H), 1.71 (s, 1H), 1.48 (d, J = 11.9 Hz, 1H).
[00166]
Figure imgf000057_0005
1H NMR (400 MHz, DMSO-d6) d 7.13 (t, J =
7.9 Hz, 1H), 6.87 - 6.79 (m, 2H), 6.73 - 6.66 (m, 1H), 2.98 (s, 3H), 2.60 (d, J = 7.2 Hz, 2H), 2.53 - 2.48 (m, 4H), 1.89 (s, 1H), 1.86 - 1.69 (m, 13H), 1.48 (d, J = 12.0 Hz, 2H).
[00167]
Figure imgf000057_0006
1H NMR (400 MHz, DMSO-d6) d 7.29 - 7.22 (m,
1H), 7.11 - 7.01 (m, 2H), 6.93 - 6.86 (m, 1H), 3.00 (s, 3H), 2.69 (d, J = 7.2 Hz, 2H), 2.05 (q, J = 6.9, 6.1 Hz, 1H), 1.89 (s, 1H), 1.81 (dd, J = 16.3, 7.3 Hz, 9H), 1.73 (d, J = 11.9 Hz, 4H), 1.49 (d, J = 11.7 Hz, 2H), 1.25 (s, 1H), 0.90 (d, J = 8.0 Hz, 2H), 0.62 (d, J = 5.4 Hz, 2H).
[00168]
Figure imgf000058_0001
1H NMR (400 MHz, Chloroform-d) d 7.27 (s,
2H), 7.18 (d, J = 7.7 Hz, 1H), 7.10 (s, 2H), 7.03 (s, 3H), 2.88 (d, J = 6.9 Hz, 4H), 2.79 (d, J = 7.3 Hz, 3H), 2.72 (d, J = 7.1 Hz, 3H), 2.33 (d, J = 3.9 Hz, 5H), 1.88 (s, 6H), 1.81 (s, 12H), 1.73 (d, J = 10.5 Hz, 7H).
[00169]
Figure imgf000058_0002
1H NMR (400 MHz, DMSO-d6) d 7.23 (d, J =
7.7 Hz, 1H), 7.15 (d, J = 7.6 Hz, 1H), 2.68 (s, 1H), 2.60 - 2.49 (m, 1H), 1.78 (s, 2H), 1.70 (s, 3H), 1.46 (d, J = 12.1 Hz, 1H), 1.23 (dd, J = 7.1, 2.3 Hz, 1H).
[00170]
Figure imgf000058_0003
7.05 (s, 1H),
6.95 (s, 2H), 3.67 (s, 2H), 2.67 (d, J = 7.2 Hz, 2H), 2.54 (s, 2H), 2.26 (s, 3H), 2.21 (s, 3H), 1.89 (s, 1H), 1.82 (s, 5H), 1.71 (s, 4H), 1.49 (d, J = 12.1 Hz, 2H), 1.42 (s, OH), 1.24 (s, 3H).
[00171]
Figure imgf000058_0004
1H NMR (400 MHz, Chloroform-d) d 7.08
(t, J = 7.6 Hz, 1H), 6.62 (d, J = 7.6 Hz, 1H), 6.55 (s, 2H), 6.53 (d, J = 2.5 Hz, 1H), 3.62 (s, 2H), 2.87 (t, J = 7.2 Hz, 2H), 2.72 (dd, J = 9.0, 6.9 Hz, 4H), 1.88 (s, 1H), 1.86 - 1.78 (m, 6H), 1.73 (d, J = 10.9 Hz, 6H), 1.52 (d, J = 12.0 Hz, 2H).
Figure imgf000058_0005
[00175]
Figure imgf000059_0001
1H NMR (400 MHz, DMSO-d6) d 6.99 - 6.89 (m,
2H), 6.58 (d, J = 7.8 Hz, 1H), 6.47 (t, J = 7.4 Hz, 1H), 5.23 (s, 2H), 3.61 (s, 2H), 2.59 - 2.52 (m, 3H), 1.85 (s, 1H), 1.76 (d, J = 6.0 Hz, 7H), 1.74 - 1.65 (m, 7H), 1.44 (d, J = 11.6 Hz, 2H).
[00176]
Figure imgf000059_0002
1H NMR (400 MHz, DMSO-d6) d 6.97 - 6.85
(m, 1H), 6.66 - 6.52 (m, 1H), 2.85 - 2.78 (m, 1H), 2.70 (t, J = 7.4 Hz, 2H), 1.93 - 1.71 (m, 7H), 1.53 (d, J = 12.0 Hz, 1H).
[00177]
Figure imgf000059_0003
1H NMR (400 MHz, DMSO-d6) d 6.87 (dd, J =
11.6, 7.3 Hz, 2H), 6.58 (d, J = 7.9 Hz, 1H), 6.45 (t, J = 7.3 Hz, 1H), 4.91 (s, 2H), 2.70 - 2.50 (m, 6H), 1.84 (d, J = 12.7 Hz, 1H), 1.79 (d, J = 12.1 Hz, 7H), 1.69 (s, 5H), 1.46 (d, J = 12.2 Hz, 2H).
[00178]
Figure imgf000059_0004
1H NMR (400 MHz, DMSO-d6) d 7.45 (d, J = 7.1
Hz, 1H), 7.37 (q, J = 7.5 Hz, 4H), 7.27 (dq, J = 20.4, 6.9 Hz, 3H), 7.17 (d, J = 7.1 Hz, 1H), 3.01 (s, 1H), 2.54 (d, J = 7.1 Hz, 2H), 1.87 (s, 1H), 1.78 (q, J = 9.8, 7.3 Hz, 7H), 1.68 (d, J = 12.1 Hz, 5H), 1.46 (d, J = 11.8 Hz, 2H), 1.16 (s, 1H).
[00179]
Figure imgf000059_0005
1H NMR (400 MHz, DMSO-d6) d 7.22 (t, J = 7.5
Hz, 2H), 7.13 (dd, J = 13.9, 7.2 Hz, 3H), 2.78 (dd, J = 10.8, 4.3 Hz, 2H), 2.71 (dd, J = 8.7, 5.6 Hz, 2H), 2.62 (d, J = 7.2 Hz, 2H), 1.88 (s, 1H), 1.80 (t, J = 13.1 Hz, 7H), 1.71 (s, 5H), 1.48 (d, J = 12.0 Hz, 2H). [00180]
Figure imgf000060_0001
7.04 (s, 1H), 6.87 (s,
1H), 3.58 (s, 2H), 3.34 (s, 3H), 2.60 (d, J = 7.1 Hz, 2H), 2.50 (s, 1H), 2.19 (s, 3H), 2.14 (d, J = 2.9 Hz, 6H), 1.86 (s, 1H), 1.83 - 1.73 (m, 9H), 1.69 (d, J = 9.4 Hz, 5H), 1.46 (d, J = 11.9 Hz, 2H).
[00181]
Figure imgf000060_0002
Chloroform-d) d 7.10 (t,
J = 7.7 Hz, 1H), 6.74 - 6.66 (m, 2H), 6.57 (dd, J = 8.0, 2.4 Hz, 1H), 3.72 (s, 2H), 3.64 (s, 2H), 2.72 (d, J = 7.1 Hz, 2H), 1.92 - 1.80 (m, 5H), 1.74 (d, J = 13.7 Hz, 3H), 1.52 (d, J = 11.7 Hz, 2H).
[00182]
Figure imgf000060_0003
1H NMR (400 MHz, DMSO-d6) d 8.13 (s,
OH), 6.96 (d, J = 7.9 Hz, 1H), 6.64 (d, J = 7.8 Hz, 1H), 2.87 (t, J = 7.9 Hz, 1H), 2.78 (dd, J = 15.8, 7.6 Hz, 2H), 1.91 (d, J = 12.0 Hz, 1H), 1.83 (d, J = 11.5 Hz, 4H), 1.74 (d, J = 16.6 Hz, 3H), 1.52 (d, J = 12.2 Hz, 1H).
Figure imgf000060_0005
6.30 (d, J = 2.7 Hz, 1H), 3.77 (s, 2H), 2.65 (d, J = 7. l Hz, 2H), 1.89 (s, 1H), 1.86 - 1.73 (m, 11H), 1.71 (s, 2H), 1.48 (d, J = 11.8 Hz, 2H).
Figure imgf000060_0006
6.35 (s, 1H), 3.77 (s, 2H), 2.61 - 2.52 (m, 2H), 1.86 (s, 1H), 1.79 (d, J = 12.1 Hz, 5H), 1.69 (d, J = 17.9 Hz, 8H), 1.44 (d, J = 12.1 Hz, 2H).
[00185]
Figure imgf000060_0004
7.70 (s, 1H),
7.47 (d, J = 10.1 Hz, 2H), 7.16 (d, J = 7.9 Hz, 1H), 6.76 (s, 1H), 3.83 (s, 2H), 3.00 (s, 4H), 2.63 (d, J = 7.2 Hz, 2H), 2.50 (s, 3H), 1.89 (s, 1H), 1.86 - 1.74 (m, 10H), 1.71 (s, 2H), 1.48 (d, J = 12.4 Hz, 3H).
[00186]
Figure imgf000061_0001
1H NMR (400 MHz, Chloroform-d) d 7.19
(t, J = 7.9 Hz, 1H), 6.74 - 6.67 (m, 2H), 6.57 (s, 1H), 5.39 (s, 2H), 2.96 (t, J = 6.5 Hz, 2H), 2.79 (t, J = 6.4 Hz, 2H), 2.74 (d, J = 7.2 Hz, 2H), 1.83 (d, J = 6.0 Hz, 2H), 1.76 (d, J = 10.4 Hz, 5H), 1.48 (d, J = 12.4 Hz, 2H).
[00187]
Figure imgf000061_0002
7.24 (d, J =
8.0 Hz, 1H), 7.17 (d, J = 7.8 Hz, 1H), 3.01 (s, 2H), 2.60 (d, J = 7.2 Hz, 1H), 1.83 - 1.72 (m, 5H), 1.71 (s, 1H), 1.48 (d, J = 11.9 Hz, 1H), 1.30 (s, 4H).
[00188]
Figure imgf000061_0003
7.15 (d, J
= 7.8 Hz, 2H), 7.09 (d, J = 7.7 Hz, 2H), 3.66 (s, 2H), 2.94 (t, J = 8.9 Hz, 1H), 2.60 (d, J = 7.2 Hz, 2H), 2.03 (s, 2H), 1.89 (s, 1H), 1.83 - 1.68 (m, 17H), 1.56 (s, 2H), 1.48 (d, J = 11.9 Hz, 2H), 1.25 (s, 1H).
[00189]
Figure imgf000061_0004
7.11 (s, 1H),
7.06 (d, J = 7.6 Hz, 1H), 6.99 (d, J = 7.6 Hz, 1H), 3.65 (s, 2H), 2.85 (td, J = 7.3, 3.4 Hz, 4H), 2.59 (d, J = 7.2 Hz, 2H), 2.50 (s, 1H), 2.05 (p, J = 7.4 Hz, 2H), 1.89 (s, 1H), 1.79 (d, J = 14.7 Hz, 7H), 1.71 (s, 3H), 1.48 (d, J = 11.5 Hz, 2H), 1.24 (s, 1H).
[00190]
Figure imgf000061_0005
Chloroform-d) d 8.65
(d, J = 5.2 Hz, 1H), 7.61 (d, J = 7.8 Hz, 1H), 7.51 (d, J = 5.2 Hz, 1H), 7.46 (d, J = 7.8 Hz, 1H), 3.87 (s, 1H), 2.74 (d, J = 7. l Hz, 1H), 1.81 (td, J = 26. l, 12.4 Hz, 7H).
[00191]
Figure imgf000061_0006
309.31
Figure imgf000062_0001
J = 7.0 Hz, 1H), 7.18 (d, J = 7.7 Hz, 1H), 3.78 (s, 1H), 2.72 (d, J = 7.1 Hz, 1H), 2.33 (ddt, J = 11.0, 8.3, 3.9 Hz, 1H), 2.19 - 2.07 (m, 1H), 1.81 (td, J = 28.7, 27.0, 13.3 Hz, 7H), 1.52 (d, J = 11.7 Hz, 1H). [00197]
Figure imgf000063_0001
1H NMR (400 MHz, DMSO-d6) d 7.23 (dd, J
= 8.4, 5.6 Hz, 1H), 7.07 (t, J = 8.8 Hz, 1H), 2.76 - 2.63 (m, J = 4.1 Hz, 2H), 2.59 (d, J = 7.1 Hz, 1H), 1.88 - 1.63 (m, 7H), 1.45 (d, J = 11.9 Hz, 1H).
Figure imgf000063_0004
Hz, 1H), 3.01 (s, 2H), 2.62 (d, J = 7.1 Hz, 2H), 1.92 - 1.86 (m, 1H), 1.86 - 1.79 (m, 6H), 1.79 - 1.69 (m, 9H), 1.48 (d, J = 12.0 Hz, 3H).
[00201]
Figure imgf000063_0002
322.25
[00202]
Figure imgf000063_0003
[00203] Compounds A12, A19, A21, A30, A36, A37, A40, A41, A43, A44, A45, A46,
A47, and A49 were made according to the following procedure: C R
Figure imgf000064_0001
[00204] To a solution of the corresponding aldehyde (10 mmol) in methanol (20 mL), (adamantan-2-yl)methanamine (10 mmol) was added. Reaction mixture was stirred at room temperature for 3-4 h, and then NaBH(OAc)3 (5.0 mmol) was added in batches and the mixture was further stirred for another 6 h. The reaction was then quenched by the addition of water (10 mL), and washed with diethyl ether (20 mLx 3). The combined organic phases were washed with saturated aqueous NaCl (30 mL), dried over Na2S04, and filtered. The solvent was evaporated to dryness under reduced pressure. The residue was purified using HPLC. Yields were 28- 64 %.
Example 2: Specific Compound Syntheses
[00205]
Figure imgf000064_0002
-(chloromethyl)-4-fluorobenzene (24 mmol) was slowly added dropwise to a mixture of adamantan-2-ylmethanamine (20 mmol) and Et3N (24 mmol, 3.3 mL) in anhydrous CH2CI2 (20 mL) at 0 °C. The reaction mixture was warmed to room temperature and stirred for an additional 20 h. After the solvent was removed under reduced pressure, the residue was washed with ice water (3.x. 20 mL) and the precipitate was separated by filtration. The crude product was purified using HPLC. Yield: 27 %. Yellow oil.
[00206]
Figure imgf000064_0003
A2. l-(chloromethyl)-benzene (24 mmol) was slowly added dropwise to a mixture of adamantan-2-amine (20 mmol) and Et3N (24 mmol, 3.3 mL) in anhydrous CH2C12 (20 mL) at 0 °C. The reaction mixture was warmed to room temperature and stirred for an additional 20 h. After the solvent was removed under reduced pressure, the residue was washed with ice water (3.x. 20 mL) and the precipitate was separated by filtration. The crude product was purified using HPLC. Yield: 27 %. White solid.
[00207]
Figure imgf000064_0004
Bromobenzene (24 mmol) was slowly added dropwise to a mixture of (adamantan-2-yl)methanamine (20 mmol) and Et3N (24 mmol, 3.3 mL) in anhydrous CH2CI2 (20 mL) at 0 °C. The reaction mixture was warmed to room temperature and stirred for an additional 20 h. After the solvent was removed under reduced pressure, the residue was washed with ice water (3.x. 20 mL) and the precipitate was separated by filtration. The crude product was purified using HPLC. Yield: 35 %. Yellow oil.
[00208]
Figure imgf000065_0001
-(chloromethyl)-benzene (24 mmol) was slowly added dropwise to a mixture of 3-(adamantan-l-yl)-3-aminopropan-l-ol (20 mmol) and Et3N (24 mmol, 3.3 mL) in anhydrous CH2CI2 (20 mL) at 0 °C. The reaction mixture was warmed to room temperature and stirred for an additional 20 h. After the solvent was removed under reduced pressure, the residue was washed with ice water (3.x. 20 mL) and the precipitate was separated by filtration. The crude product 3 was purified using HPLC. Yield: 32 %. Yellow solid.
[00209]
Figure imgf000065_0002
A5: l-(chloromethyl)-benzene (24 mmol) was slowly added dropwise to a mixture of (R)-l-(adamantan-l-yl)ethan-l -amine (20 mmol) and Et3N (24 mmol, 3.3 mL) in anhydrous CH2CI2 (20 mL) at 0 °C. The reaction mixture was warmed to room temperature and stirred for an additional 20 h. After the solvent was removed under reduced pressure, the residue was washed with ice water (3.x. 20 mL) and the precipitate was separated by filtration. The crude product was purified using HPLC. Yield: 41 %. Yellow oil.
[00210]
Figure imgf000065_0003
A6. To a stirring solution of benzylamine (10.0 mmol) in
DCM (20 mL) was added l-(adamantan-l-yl)ethan-l-one (10.0 mmol) and NaBH(OAc)3 (15 mmol) at room temperature. The reaction mixture was heated at 30 °C for 12 hours. After being cooled to room temperature and concentrated, the residue was purified using HPLC. Yield: 28%. Yellow liquid. [00211]
Figure imgf000066_0001
-(chloromethyl)-benzene (24 mmol) was slowly added dropwise to a mixture of (3-(trifluoromethyl)adamantan-l-yl)methanamine (20 mmol) and Et3N (24 mmol, 3.3 mL) in anhydrous CH2CI2 (20 mL) at 0 °C. The reaction mixture was warmed to room temperature and stirred for an additional 20 h. After the solvent was removed under reduced pressure, the residue was washed with ice water (3.x. 20 mL) and the precipitate was separated by filtration. The crude product was purified using HPLC. Yield:
38 %. Yellow oil.
[00212]
Figure imgf000066_0002
-(chloromethyl)-benzene (24 mmol) was slowly added dropwise to a mixture of 2-aminoadamantan-l-yl acetate (20 mmol) and Et3N (24 mmol, 3.3 mL) in anhydrous CH2CI2 (20 mL) at 0 °C. The reaction mixture was warmed to room temperature and stirred for an additional 20 h. After the solvent was removed under reduced pressure, the residue was washed with ice water (3.x. 20 mL) and the precipitate was separated by filtration. The crude product was purified using HPLC. Yield: 32 %. White solid.
[00213]
Figure imgf000066_0003
-(chloromethyl)-benzene (24 mmol) was slowly added dropwise to a mixture of (4-aminoadamantan-l-yl)methanol (20 mmol) and Et3N (24 mmol, 3.3 mL) in anhydrous CH2CI2 (20 mL) at 0 °C. The reaction mixture was warmed to room temperature and stirred for an additional 20 h. After the solvent was removed under reduced pressure, the residue was washed with ice water (3.x. 20 mL) and the precipitate was separated by filtration. The crude product was purified using HPLC. Yield: 45 %. Yellow oil.
[00214]
Figure imgf000066_0004
-(chloromethyl)-benzene (24 mmol) was slowly added dropwise to a mixture of 5-fluoroadamantan-2-amine (20 mmol) and Et3N (24 mmol, 3.3 mL) in anhydrous CH2CI2 (20 mL) at 0 °C. The reaction mixture was warmed to room temperature and stirred for an additional 20 h. After the solvent was removed under reduced pressure, the residue was washed with ice water (3.x. 20 mL) and the precipitate was separated by filtration. The crude product was purified using HPLC. Yield: 32 %. White solid.
[00215]
Figure imgf000067_0001
solution of 2-adamantylacetic acid (1.2 mmol) in DMF (8 mL) was added benzylamine (2.4 mmol), followed by triethylamine (0.5 mL, 3.6 mmol). The reaction mixture was stirred for 3 h after which the mixture was added to cold water (50 mL) and stirred for 1 h. The obtained N-benzyladamantane-2-carboxamide was filtered and washed with water, purified using HPLC. Yield: 38%. Yellow solid.
[00216]
Figure imgf000067_0002
-(chloromethyl)-2-flourbenzene (24 mmol) was slowly added dropwise to a mixture of adamantan-2-ylmethanamine (20 mmol) and Et3N (24 mmol, 3.3 mL) in anhydrous CH2CI2 (20 mL) at 0 °C. The reaction mixture was warmed to room temperature and stirred for an additional 20 h. After the solvent was removed under reduced pressure, the residue was washed with ice water (3.x. 20 mL) and the precipitate was separated by filtration. The crude product was purified using HPLC. Yield: 41%. Yellow oil.
[00217]
Figure imgf000067_0003
-(chloromethyl)-benzene (24 mmol) was slowly added dropwise to a mixture of (3-methyladamantan-l-yl)methanamine (20 mmol) and Et3N (24 mmol, 3.3 mL) in anhydrous CH2CI2 (20 mL) at 0 °C. The reaction mixture was warmed to room temperature and stirred for an additional 20 h. After the solvent was removed under reduced pressure, the residue was washed with ice water (3.x. 20 mL) and the precipitate was separated by filtration. The crude product was purified using HPLC. Yield: 56 %. Yellow oil. [00218]
Figure imgf000068_0001
bromoethyl)benzene (24 mmol) was slowly added dropwise to a mixture of adamantan-2-ylmethanamine (20 mmol) and Et3N (24 mmol, 3.3 mL) in anhydrous CH2CI2 (20 mL) at 0 °C. The reaction mixture was warmed to room temperature and stirred for an additional 20 h. After the solvent was removed under reduced pressure, the residue was washed with ice water (3.x. 20 mL) and the precipitate was separated by filtration. The crude product was purified using HPLC. Yield: 45 %. Yellow oil.
[00219]
Figure imgf000068_0002
l-(chloromethyl)-benzene (24 mmol) was slowly added dropwise to a mixture of 2-(adamantan-2-yl)ethan-l -amine (20 mmol) and Et3N (24 mmol, 3.3 mL) in anhydrous CH2CI2 (20 mL) at 0 °C. The reaction mixture was warmed to room temperature and stirred for an additional 20 h. After the solvent was removed under reduced pressure, the residue was washed with ice water (3.x. 20 mL) and the precipitate was separated by filtration. The crude product was purified using HPLC. Yield: 27 %. White solid.
[00220]
Figure imgf000068_0003
mixture of benzaldehyde (10 mmol) in methanol (20 mL), 2-(adamantan-l-yl)ethan-l -amine (10 mmol) was added. The reaction mixture was stirred at room temperature for 3-4 h, and then NaBH(OAc)3 (5.0 mmol) was added in batches and the mixture was further stirred for another period of 6 h. The reaction was then quenched by the addition of water (10 mL), and washed with diethyl ether (20 mLx 3). The combined organic phases were washed with saturated aqueous NaCl (30 mL), dried over Na2S04, and filtered. The solvent was evaporated to dryness under reduced pressure. The residue was purified using HPLC. Yield: 28%. Yellow oil.
[00221]
Figure imgf000068_0004
the solution of spiro[adamantane-2,2'-oxirane]
(3.20 mmol) in dry MeCN (43 mL), LiClCL (2.82 mmol) and the benzylamine (6.4 mmol) were added. The reaction mixture was kept at reflux temperature for 8-48 h, and after completion (monitored by means of TLC) the solvent was evaporated. The crude product was then dissolved in water (20 mL) and extracted with CH2CI2 (3x30 mL). The combined organic phase was washed with brine (30 mL), dried (Na2S04) and evaporated to dryness.
[00222]
Figure imgf000069_0001
stirring solution of benzylamine (10.0 mmol) in DCM (20 mL) was added l-(adamantan-l-yl)propan-2-one (10.0 mmol) and NaBH(OAc)3 (15 mmol) at room temperature. The reaction mixture was heated at 30 °C for 12 hours. After being cooled to room temperature and concentrated, the residue was purified using HPLC. Yield: 32%. Yellow liquid.
[00223]
Figure imgf000069_0002
-(chloromethyl)-2-methylbenzene (24 mmol) was slowly added dropwise to a mixture of adamantan-2-ylmethanamine (20 mmol) and Et3N (24 mmol, 3.3 mL) in anhydrous CH2CI2 (20 mL) at 0 °C. The reaction mixture was warmed to room temperature and stirred for an additional 20 h. After the solvent was removed under reduced pressure, the residue was washed with ice water (3.x. 20 mL) and the precipitate was separated by filtration. The crude product was purified using HPLC. Yield: 38 %. Colorless oil.
[00224]
Figure imgf000069_0003
mixture of benzaldehyde (10 mmol) in methanol (20 mL), (adamantan-2-yl)methanamine (10 mmol) was added. The reaction mixture was stirred at room temperature for 3-4 h, and then NaBH(OAc)3 (5.0 mmol) was added in batches and the mixture was further stirred for another period of 6 h. The reaction was then quenched by the addition of water (10 mL), and washed with diethyl ether (20 mLx 3). The combined organic phases were washed with saturated aqueous NaCl (30 mL), dried over Na2S04, and filtered. The solvent was evaporated to dryness under reduced pressure. The residue was purified using HPLC. Yield: 29%. colorless oil. [00225]
Figure imgf000070_0001
A32. l-(chloromethyl)-benzene (24 mmol) was slowly added dropwise to a mixture of (S)-l-(adamantan-l-yl)ethan-l -amine (20 mmol) and Et3N (24 mmol, 3.3 mL) in anhydrous CH2CI2 (20 mL) at 0 °C. The reaction mixture was warmed to room temperature and stirred for an additional 20 h. After the solvent was removed under reduced pressure, the residue was washed with ice water (3.x. 20 mL) and the precipitate was separated by filtration. The crude product was purified using HPLC. Yield: 57 %. Yellow oil.
[00226]
Figure imgf000070_0002
-(chloromethyl)-3-fluorobenzene (24 mmol) was slowly added dropwise to a mixture of adamantan-2-ylmethanamine (20 mmol) and Et3N (24 mmol, 3.3 mL) in anhydrous CH2CI2 (20 mL) at 0 °C. The reaction mixture was warmed to room temperature and stirred for an additional 20 h. After the solvent was removed under reduced pressure, the residue was washed with ice water (3.x. 20 mL) and the precipitate was separated by filtration. The crude product was purified using HPLC. Yield:
27 %. Yellow oil.
[00227]
Figure imgf000070_0003
-(chloromethyl)-3-m ethylbenzene (24 mmol) was slowly added dropwise to a mixture of adamantan-2-ylmethanamine (20 mmol) and Et3N (24 mmol, 3.3 mL) in anhydrous CH2CI2 (20 mL) at 0 °C. The reaction mixture was warmed to room temperature and stirred for an additional 20 h. After the solvent was removed under reduced pressure, the residue was washed with ice water (3.x. 20 mL) and the precipitate was separated by filtration. The crude product was purified using HPLC. Yield:
38 %. Yellow oil.
[00228]
Figure imgf000070_0004
mixture of [l,l'-biphenyl]-4- carbaldehyde (10 mmol) in methanol (20 mL), (adamantan-2-yl)methanamine (10 mmol) was added. The reaction mixture was stirred at room temperature for 3-4 h, and then NaBH(OAc)3 (5.0 mmol) was added in batches and the mixture was further stirred for another 6 h. The reaction was then quenched by the addition of water (10 mL), and washed with diethyl ether (20 mLx 3). The combined organic phases were washed with saturated aqueous NaCl (30 mL), dried over Na2S04, and filtered. The solvent was evaporated to dryness under reduced pressure. The residue was purified using HPLC. Yield: 54 %. Yellow solid.
[00229]
Figure imgf000071_0001
mixture of adamantane-2-carbaldehyde (10 mmol) in methanol (20 mL), 2-phenylethan-l -amine (10 mmol) was added. The reaction mixture was stirred at room temperature for 3-4 h, and then NaBH(OAc)3 (5.0 mmol) was added in batches and the mixture was further stirred for another 6 h. The reaction was then quenched by the addition of water (10 mL), and washed with diethyl ether (20 mLx 3). The combined organic phases were washed with saturated aqueous NaCl (30 mL), dried over Na2S04, and filtered. The solvent was evaporated to dryness under reduced pressure. The residue was purified using HPLC. Yield: 24%. Yellow oil.
[00230]
Figure imgf000071_0002
the solution of 4-isopropylbenzaldehyde
(10 mmol) in methanol (20 mL), (adamantan-2-yl)methanamine (10 mmol) was added. The reaction mixture was stirred at room temperature for 3-4 h, and then NaBH(OAc)3 (5.0 mmol) was added in batches and the mixture was further stirred for another 6 h. The reaction was then quenched by the addition of water (10 mL), and washed with diethyl ether (20 mLx 3). The combined organic phases were washed with saturated aqueous NaCl (30 mL), dried over Na2S04, and filtered. The solvent was evaporated to dryness under reduced pressure. The residue was purified using HPLC. Yield: 37 %. Yellow solid.
[00231]
Figure imgf000071_0003
A56. Benzylamine (0.25 mmol) and l-(adamantan-2- yl)ethan-l-one (0.3 mmol) were dissolved in 0.3 ml MeOH, heated at 100° C for 2 hours, then mixture was cooled, NaBLL (0.25 mmol) was added and stirred for 4 hours. The mixture was heated for 2 hours at 60° C, 3 ml of methanol and 0.1 g of C-18 chromatographic phase were added, stirred for 2 hours, filtered, evaporated and dissolved in 0.25 ml of DMSO. The residue was purified using HPLC. Yield: 34%. Cream solid. 1H NMR (400 MHz, DMSO-d6) d 9.42 (s, 1H), 8.54 (s, 1H), 7.68 - 7.58 (m, 2H), 7.43 (q, J = 5.8 Hz, 3H), 4.20 (q, J = 8.6, 7.2 Hz, 1H), 4.13 (s, 1H), 3.22 (s, 1H), 2.49 (s, 1H), 2.06 (s, 1H), 1.86 - 1.75 (m, 5H), 1.66 (d, J = 11.0 Hz, 4H), 1.43 (s, 2H), 1.36 (s, 2H), 1.28 (d, J = 6.5 Hz, 2H).
[00232]
Figure imgf000072_0001
(Chloromethyl)benzene (24 mmol) was slowly added dropwise to a mixture of 3-fluoroadamantan-l-amine (20 mmol) and Et3N (24 mmol, 3.3 mL) in anhydrous CH2CI2 (20 mL) at 0 °C. The reaction mixture was warmed to room temperature and stirred for an additional 20 h. After the solvent was removed under reduced pressure, the residue was washed with ice water (3.x. 20 mL) and the precipitate was separated by filtration. The crude product 3 was purified using HPLC. Yield: 33 %. Yellow gum. 1H NMR (400 MHz, DMSO-d6) d 7.33 (d, J = 7.7 Hz, 2H), 7.28 (t, J = 7.4 Hz, 2H), 7.19 (t, J = 7.2 Hz, 1H), 3.68 (s, 2H), 2.26 (s, 2H), 1.84 (s, 1H), 1.76 (d, J = 5.8 Hz, 5H), 1.56 (s, 3H), 1.47 (s, 2H).
[00233]
Figure imgf000072_0002
\82. adamantan-2-ylmethanamine (0.5 mmol) and 4- methylbenzaldehyde (0.55 mmol) were dissolved in 0.6 ml MeOH, heated at 100° C for 2 hours, then mixture was cooled, NaBH4 (0.5 mmol) was added and stirred for 4 hours. The mixture was heated for 2 hours at 60° C, 3 ml of methanol and 0.2 g of C-18
chromatographic phase were added, stirred for 2 hours, filtered, evaporated. The residue was purified using HPLC. Yield: 41%. Yellow gum. m/z: 269.27.
[00234]
Figure imgf000072_0003
isopropylphenyl)-N-methylmethanamine
(0.5 mmol), aldehyde 2 (0.55 mmol) were dissolved in 0.6 ml CHCb, NaBH(OAc)3 (1.5 mmol) was added and stirred for 4 hours. The mixture was heated for 12 hours at 60° C, 3 ml of methanol and 0.2 g of C-18 chromatographic phase were added, stirred for 2 hours, filtered, evaporated and dissolved in 0.5 ml of DMSO. The residue was purified using HPLC. Yield: 36 %. Blue gum. 1H NMR (400 MHz, DMSO-d6) d 7.17 (s, 6H), 2.85 (p, J = 7.0 Hz, 1H), 2.54 (s, 1H), 2.35 (d, J = 7.6 Hz, 3H), 2.09 (s, 4H), 1.85 (s, 3H), 1.78 (d, J =
12.7 Hz, 1H), 1.75 (s, 4H), 1.70 (s, 1H), 1.66 (s, 9H), 1.60 (s, 1H), 1.39 (d, J = 12.4 Hz, 3H), 1.18 (d, J = 6.9 Hz, 8H).
Figure imgf000073_0001
1 2
[00236] Amine 1 (0.5 mmol), benzaldehyde 2 (0.55 mmol) were dissolved in 0.6 ml MeOH, heated at 100° C for 2 hours, then mixture was cooled, NaBH4 (0.5 mmol) was added and stirred for 4 hours. The mixture was heated for 2 hours at 60° C, 3 ml of methanol and 0.2 g of C-18 chromatographic phase were added, stirred for 2 hours, filtered, evaporated and dissolved in 0.5 ml of DMSO. The residue was purified using HPLC. Yield: 34-42 % A100. 1H NMR (400 MHz, DMSO-d6) d 7.12 (dt, J = 10.6, 4.6 Hz, 3H), 2.76 - 2.65 (m, 4H), 2.62 - 2.52 (m, 2H), 1.87 (s, 2H), 1.80 (d, J = 13.4 Hz, 6H), 1.69 (s, 3H), 1.52 (dt, J = 23.8, 9.8 Hz, 3H), 0.93 (t, J = 7.3 Hz, 2H).
[00237]
Figure imgf000073_0002
Step A: methyl 2-(2-aminoethyl)benzoate (0.5 mmol) and adamantane-2-carbaldehyde (0.55 mmol) were dissolved in 0.6 ml MeOH, heated at 100° C for 2 hours, then mixture was cooled, NaBH4 (0.5 mmol) was added and stirred for 4 hours. The mixture was heated for 2 hours at 60° C, 3 ml of methanol and 0.2 g of C-18 chromatographic phase were added, stirred for 2 hours, filtered, evaporated and dissolved in 0.5 ml of DMSO. The residue was purified using HPLC. Yield: 41%. Step B: Under nitrogen atmosphere, at 0 °C, to a suspension of LiAiH4 (0.2 M in THF, 11 mL, 2.2 mmol) in dry THF (5 mL), a solution of methyl 2-(2-((adamantan-2-ylmethyl)amino)ethyl)benzoate (0.55 mmol,) in dry THF (0.5 mL) was added dropwise. The resulting mixture was stirred at r.t. for 3h, then cooled to 0 °C and H20 (1 mL) was slowly added, followed by a 0.3 M KOH solution (1 mL) and additional H2O (1.5 mL). The mixture was stirred at 0 °C for 1 h, filtered and the organic phase dried over Na2S04, concentrated to dryness giving the product. The residue was purified using HPLC. Yield: 27%. Broun solid. 1H NMR (400 MHz, DMSO-d6) d 7.16 (d, J = 3.2 Hz, 1H), 4.51 (d, J = 2.5 Hz, 1H), 2.63 - 2.52 (m, 1H), 2.52 - 2.47 (m, 2H), 1.78 (d, J = 15.0 Hz, 3H), 1.68 (s, 2H), 1.45 (d, J = 12.0 Hz, 1H).
[00238]
Figure imgf000074_0001
Synthesized according to the procedure outlined for A100. 1H NMR (400 MHz, DMSO-d6) d 7.11 (dtt, J = 14.3, 7.4, 3.9 Hz, 3H), 2.70 (q, J = 4.6 Hz, 3H), 2.66 - 2.56 (m, 3H), 1.84 (d, J = 17.7 Hz, 1H), 1.77 (s, 6H), 1.69 (s, 4H), 1.46 (d, J = 12.0 Hz, 2H), 1.15 (t, J = 7.6 Hz, 2H).
[00239]
Figure imgf000074_0002
Adamantan-2-ylmethanamine (0.5 mmol) and 4-cyclopropyl-3-methylbenzaldehyde (0.55 mmol) were dissolved in 0.6 ml MeOH, heated at 100° C for 2 hours, then mixture was cooled, NaBH4 (0.5 mmol) was added and stirred for 4 hours. The mixture was heated for 2 hours at 60° C, 3 ml of methanol and 0.2 g of C-18 chromatographic phase were added, stirred for 2 hours, filtered, evaporated and dissolved in 0.5 ml of DMSO. The residue was purified using HPLC. Yield: 32 %. Yellow gum. 1H MR (400 MHz, DMSO-d6) d 7.07 (s, 1H), 7.01 (d, J = 7.8 Hz, 1H), 6.84 (d, J = 7.9 Hz, 1H), 3.60 (s, 2H), 2.54 (d, J = 7.0 Hz, 3H), 2.34 (s, 3H), 1.85 (q, J = 5.0, 4.3 Hz, 2H), 1.81 - 1.72 (m, 8H), 1.69 (d, J = 19.8 Hz, 6H), 1.44 (d, J = 11.8 Hz, 2H), 0.87 (d, J = 7.9 Hz, 2H), 0.54 (d, J = 5.4 Hz, 2H).
[00240]
Figure imgf000074_0003
A105. Adamantan-2-ylmethanamine (0.5 mmol) and 3-cyclopropyl-4-methylbenzaldehyde (0.55 mmol) were dissolved in 0.6 ml MeOH, heated at 100° C for 2 hours, then mixture was cooled, NaBH4 (0.5 mmol) was added and stirred for 4 hours. The mixture was heated for 2 hours at 60° C, 3 ml of methanol and 0.2 g of C-18 chromatographic phase were added, stirred for 2 hours, filtered, evaporated and dissolved in 0.5 ml of DMSO. The residue was purified using HPLC. Yield: 36 %. Yellow gum. 1H MR (400 MHz, DMSO-d6) d 7.08 - 6.93 (m, 1H), 6.90 (s, 1H), 3.62 (s, 1H), 2.53 (d, J = 7.1 Hz, 2H), 2.43 (s, 1H), 2.33 (s, 2H), 1.87 (dd, J = 9.8, 4.6 Hz, 1H), 1.78 (d, J = 7.1 Hz, 3H), 1.74 - 1.65 (m, 4H), 1.43 (d, J = 11.9 Hz, 1H), 0.93 - 0.84 (m, 1H), 0.60 - 0.52 (m, 1H).
[00241]
Figure imgf000075_0001
Adamantan-2-ylmethanamine (0.5 mmol) and 3,4-dicyclopropylbenzaldehyde (0.55 mmol) were dissolved in 0.6 ml MeOH, heated at 100° C for 2 hours, then mixture was cooled, NaBH4 (0.5 mmol) was added and stirred for 4 hours. The mixture was heated for 2 hours at 60° C, 3 ml of methanol and 0.2 g of C-18 chromatographic phase were added, stirred for 2 hours, filtered, evaporated and dissolved in 0.5 ml of DMSO. The residue was purified using HPLC. Yield: 24 %. Yellow gum. 1H NMR (400 MHz, DMSO-d6) d 7.00 (d, J = 7.8 Hz, 1H), 6.89 (s, 1H), 6.84 (d, J = 7.9 Hz, 1H), 3.63 (s, 2H), 2.55 (d, J = 6.5 Hz, 3H), 2.23 - 2.10 (m, 2H), 1.85 (s, 1H), 1.78 (d, J = 8.2 Hz, 5H), 1.75 - 1.64 (m, 7H), 1.43 (d, J = 11.5 Hz, 2H), 0.93 (td, J = 8.0, 6.8, 4.4 Hz, 3H), 0.60 (t, J = 6.1 Hz, 3H).
[00242]
Figure imgf000075_0002
A107. (R)-l-(adamantan-2-yl)ethan-l -amine (0.5 mmol) and benzaldehyde (0.55 mmol) were dissolved in 0.6 ml MeOH, heated at 100° C for 2 hours, then mixture was cooled, NaBH4 (0.5 mmol) was added and stirred for 4 hours. The mixture was heated for 2 hours at 60° C, 3 ml of methanol and 0.2 g of C-18
chromatographic phase were added, stirred for 2 hours, filtered, evaporated and dissolved in 0.5 ml of DMSO. The residue was purified using HPLC. Yield: 29 %. 1H NMR (400 MHz, DMSO-d6) d 9.38 (s, 1H), 8.51 (s, 1H), 7.64 - 7.57 (m, 2H), 7.43 (d, J = 7.1 Hz, 3H), 4.22 (d, J = 12.6 Hz, 1H), 4.14 (s, 1H), 3.22 (s, 1H), 2.05 (s, 1H), 1.83 (s, 2H), 1.78 (d, J = 9.4 Hz, 3H), 1.66 (d, J = 11.1 Hz, 5H), 1.43 (s, 2H), 1.36 (s, 2H), 1.28 (d, J = 6.5 Hz, 3H). [00243]
Figure imgf000076_0001
(S)-l-(adamantan-2-yl)ethan-l -amine (0.5 mmol) and benzaldehyde (0.55 mmol) were dissolved in 0.6 ml MeOH, heated at 100° C for 2 hours, then mixture was cooled, NaBH4 (0.5 mmol) was added and stirred for 4 hours. The mixture was heated for 2 hours at 60° C, 3 ml of methanol and 0.2 g of C-18
chromatographic phase were added, stirred for 2 hours, filtered, evaporated and dissolved in 0.5 ml of DMSO. The residue was purified using HPLC. Yield: 37 %. 1H NMR (400 MHz, DMSO-d6) d 9.46 (s, 1H), 8.56 (s, 1H), 7.65 - 7.58 (m, 2H), 7.48 - 7.37 (m, 3H), 4.22 (d, J = 11.9 Hz, 1H), 4.14 (s, 1H), 3.21 (s, 1H), 2.07 (s, 1H), 1.83 (s, 2H), 1.78 (d, J = 9.6 Hz, 3H), 1.66 (d, J = 10.8 Hz, 5H), 1.43 (s, 2H), 1.36 (s, 2H), 1.28 (d, J = 6.5 Hz, 3H).
[00244]
Figure imgf000076_0002
12. l-(adamantan-2-yl)-N-methylmethanamine
(0.5 mmol) and 5,6,7,8-tetrahydronaphthalene-2-carbaldehyde (0.55 mmol) were dissolved in 0.6 ml CHCb, NaBH(OAc)3 (1.5 mmol) was added and stirred for 4 hours. The mixture was heated for 12 hours at 60°C, 3 ml of methanol and 0.2 g of C-18 chromatographic phase were added, stirred for 2 hours, filtered, evaporated. The residue was purified using HPLC. Yellow gum. Yield: 31%. 1H NMR (400 MHz, Chloroform-d) d 7.01 (d, J = 3.3 Hz, 3H), 3.47 (s, 2H), 2.75 (d, J = 12.0 Hz, 1H), 2.75 (s, 4H), 2.45 (d, J = 7.1 Hz, 2H), 2.22 (s, 3H), 1.89 (dd, J = 18.7, 9.4 Hz, 3H), 1.84 - 1.74 (m, 9H), 1.49 (d, J = 12.5 Hz, 2H).
[00245]
Figure imgf000076_0003
A113. N-(adamantan-2-ylmethyl)ethanamine (0.5 mmol) and 5,6,7,8-tetrahydronaphthalene-2-carbaldehyde (0.55 mmol) were dissolved in 0.6 ml CHCb, NaBH(OAc)3 (1.5 mmol) was added and stirred for 4 hours. The mixture was heated for 12 hours at 60°C, 3 ml of methanol and 0.2 g of C-18 chromatographic phase were added, stirred for 2 hours, filtered, evaporated. The residue was purified using HPLC.
Yellow gum. Yield: 41 %. 1H NMR (400 MHz, DMSO-d6) d 6.95 (d, J = 7.3 Hz, 3H), 2.67 (s, 4H), 2.38 (t, J = 7.2 Hz, 4H), 1.84 (s, 2H), 1.78 (d, J = 12.8 Hz, 4H), 1.74 - 1.60 (m,
12H), 1.41 (d, J = 12.4 Hz, 2H), 0.95 (t, J = 7.0 Hz, 3H). [00246]
Figure imgf000077_0001
A114. Step 1 : Adamantan-2-ylmethanamine (0.5 mmol), 2,3,6-trimethylbenzoic acid (0.55 mmol), 3H-[l,2,3]triazolo[4,5-b]pyridin-3-ol (0.75 mmol) and EDC (0.55 mmol) were dissolved in 0.6 mL of DMF, were stirred for 24 hours, then 3 mL of methanol, 0.2 g of C-18 chromatographic phase were added, were stirred for 2 hours, filtered, evaporated. The residue was purified using HPLC. Yield: 43%. Step 2: To borane tetrahydrofuran complex (1.6 ml, 1.6 mmol) was slowly added at 0°C compound N- (adamantan-2-ylmethyl)-2,3,6-trimethylbenzamide (0.89 mmol) in tetrahydrofuran (3 ml). The reaction mixture was then stirred at 60 °C for 3 hours, cooled to room temperature and quenched with 6N aqueous hydrochloric acid. The solvent was removed by distillation and water (10 ml) 5 was added. The residue was purified using HPLC. Yellow solid. Yield: 23%. 1H NMR (400 MHz, DMSO-d6) d 6.91 (d, J = 7.6 Hz, 1H), 6.84 (d, J = 7.8 Hz, 1H), 3.64 (s, 2H), 2.70 (d, J = 7.0 Hz, 2H), 2.53 - 2.48 (m, 6H), 2.28 (s, 3H), 2.19 (d, J = 13.7 Hz, 5H), 1.89 - 1.83 (m, 1H), 1.80 (d, J = 10.4 Hz, 8H), 1.69 (s, 4H), 1.46 (d, J = 11.9 Hz, 2H), 1.30
(s, 1H).
[00247]
Figure imgf000077_0002
Step 1 : Adamantan-2-ylmethanamine (0.5 mmol) and 5,6,7,8-tetrahydronaphthalene-2-carbaldehyde (0.55 mmol) were dissolved in 0.6 ml MeOH, heated at 100° C for 2 hours, then mixture was cooled, NaBH4 (0.5 mmol) was added and stirred for 4 hours. The mixture was heated for 2 hours at 60° C, 3 ml of methanol and 0.2 g of C-18 chromatographic phase were added, stirred for 2 hours, filtered, evaporated. The residue was purified using HPLC. Yield: 31%. Step 2: l-(adamantan-2-yl)- N-((5,6,7,8-tetrahydronaphthalen-2-yl)methyl)methanamine (0.5 mmol) and cyclobutanone (0.55 mmol) were dissolved in 0.6 ml CHCb, NaBH(OAc)3 (1.5 mmol) was added and stirred for 4 hours. The mixture was heated for 12 hours at 60°C, 3 ml of methanol and 0.2 g of C-18 chromatographic phase were added, stirred for 2 hours, filtered, evaporated. The residue was purified using HPLC. Yellow gum. Yield: 38%. 1H NMR (500 MHz, DMSO- d6) d 7.26 (s, 1H), 6.97 (d, J = 9.6 Hz, 3H), 3.09 (s, 1H), 2.75 (d, J = 13.1 Hz, 2H), 2.36 (d, J = 7.2 Hz, 2H), 1.98 (s, 2H), 1.86 (s, 4H), 1.84 - 1.76 (m, 9H), 1.74 (s, 1H), 1.69 (s, 9H), 1.55 (d, J = 9.9 Hz, 1H), 1.46 (d, J = 12.1 Hz, 2H). [00248]
Figure imgf000078_0001
Step A: Adamantan-2-ylmethanamine (1 mmol) and CDI (2 mmol) were dissolved in 0.6 ml CH3CN, the mixture was kept at a temperature of 70°C for 1 hour, then 2,3,6-trimethylbenzoic acid (1 mmol) was added. The mixture was heated for 2 hours at 70°C, then filtered, evaporated. The residue was purified by HPLC. Step B: N-(adamantan-2-ylmethyl)-2,3,6-trimethylbenzamide (0.5 mmol) was dissolved in anhydrous THF (5 mL); subsequently a suspension of LiAlH4 in THF (2N solution, 2 mmol) was added dropwise under argon. The reaction mixture was warmed to reflux for 3-6 h. Excess reactants were decomposed by addition of few drops of AcOEt, NaOH (1N water solution, 1 equiv), and water. After filtration of the salts over Celite, the clear solution was dried over Na2S04 and concentrated in vacuo. Residue was purified by HPLC. Yield: 28%. Yellow solid. 1H MR (400 MHz, DMSO-d6) d 6.91 (d, J = 7.6 Hz, 1H), 6.84 (d, J = 7.8 Hz, 1H), 3.64 (s, 2H), 2.70 (d, J = 7.0 Hz, 2H), 2.53 - 2.48 (m, 6H), 2.28 (s, 3H), 2.19 (d, J = 13.7 Hz, 5H), 1.89 - 1.83 (m, 1H), 1.80 (d, J = 10.4 Hz, 8H), 1.69 (s, 4H), 1.46 (d, J = 11.9 Hz, 2H), 1.30 (s, 1H). m/z=298.2
[00249]
Figure imgf000078_0002
A117. Step A: Adamantan-2-ylmethanamine (1 mmol) and CDI (2 mmol) were dissolved in 0.6 ml CH3CN, the mixture was kept at a temperature of 70°C for 1 hour, then 2-(5,6,7,8-tetrahydronaphthalen-2-yl)acetic acid (1 mmol) was added. The mixture was heated for 2 hours at 70°C, then filtered, evaporated. The residue was purified by HPLC. Step B: N-(adamantan-2-ylmethyl)-2-(5, 6,7,8- tetrahydronaphthalen-2-yl)acetamide (0.5 mmol) was dissolved in anhydrous THF (5 mL); subsequently a suspension of LiAlH4 in THF (2N solution, 2 mmol) was added dropwise under argon. The reaction mixture was warmed to reflux for 3-6 h. Excess reactants were decomposed by addition of few drops of AcOEt, NaOH (1N water solution, 1 equiv), and water. After filtration of the salts over Celite, the clear solution was dried over Na2S04 and concentrated in vacuo. Residue was purified by HPLC. Yield: 41%. Yellow solid. 1H NMR (400 MHz, DMSO-d6) d 8.34 (s, 1H), 6.96 (d, J = 7.6 Hz, 1H), 6.90 (d, J = 11.1 Hz, 2H), 2.84 (d, J = 8.3 Hz, 2H), 2.80 - 2.69 (m, 2H), 2.69 (d, J = 7.6 Hz, 1H), 2.67 (s, 6H), 2.54 (s, 2H), 1.85 (s, 1H), 1.80 (d, J = 12.2 Hz, 8H), 1.71 (d, J = 3.5 Hz, 2H), 1.69 (s, 9H), 1.47 (d, J = 11.7 Hz, 2H). m/z=324.2 [00250]
Figure imgf000079_0001
Step A: Adamantan-2-ylmethanamine (1 mmol) and 5,6,7,8-tetrahydronaphthalene-2-carbaldehyde (1 mmol) were dissolved in 0.9 ml MeOH, heated at l00°C for 2 hours, then mixture was cooled; NaBH4 (1 mmol) was added and stirred for 4 hours. The mixture was heated for 2 hours at 60°C, 5 ml of methanol and 0.4 g of C-18 chromatographic phase were added, stirred for 2 hours, filtered, evaporated. Step B: l-(adamantan-2-yl)-N-((5,6,7,8-tetrahydronaphthalen-2-yl)methyl)methanamine (0.5 mmol) and acetone (0.55 mmol) were dissolved in 0.6 ml CHCb; NaBH(OAc)3 (1.5 mmol) was added and stirred for 4 hours. The mixture was heated for 12 hours at 60°C, 3 ml of methanol and 0.2 g of C-18 chromatographic phase were added, stirred for 2 hours, filtered, evaporated and dissolved in 0.5 ml of DMSO. The residue was purified by HPLC. Yield: 32%. Yellow solid. 1H NMR (400 MHz, Chloroform-d) d 7.02 (s, 1H), 3.50 (s, 1H), 2.74 (s, 2H), 2.43 (s, 1H), 1.79 (s, 6H), 1.69 (s, 3H), 0.98 (s, 2H). m/z=352.3
[00251]
Figure imgf000079_0002
Step A: Adamantan-2-ylmethanamine (1 mmol) and 5,6,7,8-tetrahydronaphthalene-2-carbaldehyde (1 mmol) were dissolved in 0.9 ml MeOH and heated at lOO°C for 2 hours; then the mixture was cooled, NaBH4 (1 mmol) was added and stirred for 4 hours. The mixture was heated for 2 hours at 60 °C; 5 ml of methanol and 0.4 g of C-18 chromatographic phase were added, stirred for 2 hours, filtered, evaporated. Step B: l-(adamantan-2-yl)-N-((5,6,7,8-tetrahydronaphthalen-2- yl)methyl)methanamine (0.5 mmol) and cyclohexanone (0.55 mmol) were dissolved in 0.6 ml CHCb; NaBH(OAc)3 (1.5 mmol) was added and stirred for 4 hours. The mixture was heated for 12 hours at 60 °C; 3 ml of methanol and 0.2 g of C-18 chromatographic phase were added, stirred for 2 hours, filtered, evaporated and dissolved in 0.5 ml of DMSO. The residue was purified by HPLC. Yield: 41%. Light brown solid. 1H NMR (400 MHz, DMSO- d6) d 3.48 (s, 1H), 2.67 (s, 5H), 2.54 (s, 10H), 1.75 (s, 2H), 1.70 (s, 3H), 1.64 (s, 2H).
m/z=392.4
Figure imgf000080_0001
[00252] H A121. Adamantan-2-ylmethanamine (0.5 mmol) and
3,4-dihydronaphthalen-2(lH)-one (0.4 mmol) were dissolved in 2 ml MeOH, heated at l00°C for 10 hours, then mixture was cooled, NaBH4 (0.5 mmol) was added and stirred for 4 hours. The mixture was heated for 2 hours at 60°C, 3 ml of methanol and 0.2 g of C-18 chromatographic phase were added, stirred for 2 hours, filtered, evaporated. The residue was purified by HPLC. Yield: 41 %. Brown gum. 1H NMR (400 MHz, DMSO-d6) d 6.99 (s, 4H), 2.96 (d, J = 17.3 Hz, 1H), 2.86 (s, 2H), 2.82 (t, J = 5.1 Hz, 1H), 2.78 - 2.70 (m, 4H), 1.99 (s, 1H), 1.89 (s, 1H), 1.82 (d, J = 6.5 Hz, 8H), 1.73 (d, J = 9.4 Hz, 6H), 1.51 (d, J = 12.1 Hz, 3H). m/z=296.2
[00253]
Figure imgf000080_0002
fluoroadamantan-2-yl)methanamine
(0.5 mmol) and 5,6,7,8-tetrahydronaphthalene-2-carbaldehyde (0.5 mmol) were dissolved in 0.6 ml MeOH, heated at 100° C for 3 hours, then mixture was cooled; NaBH4 (0.5 mmol) was added and stirred for 5 hours. The mixture was heated for 2 hours at 60° C, 3 ml of methanol and 0.2 g of C-18 chromatographic phase were added, stirred for 2 hours, filtered. The residue was purified by HPLC. Purple solid. Yield: 31%. 1H NMR (400 MHz, DMSO- d6) d 8.23 (s, 1H), 7.06 (d, J = 9.5 Hz, 2H), 7.00 (d, J = 7.6 Hz, 1H), 3.74 (s, 2H), 2.67 (d, J = 7.5 Hz, 7H), 2.09 (s, 3H), 1.81 (d, J = 15.8 Hz, 8H), 1.72 (p, J = 3.1 Hz, 4H), 1.63 (d, J = 13.1 Hz, 2H), 1.32 (d, J = 12.9 Hz, 2H). m/z=328.2
Figure imgf000080_0003
[00254] H A123. Chroman-3 -amine (0.5 mmol) and adamantane-
2-carbaldehyde (0.5 mmol) were dissolved in 0.6 ml MeOH, heated at 100° C for 2 hours, then mixture was cooled; NaBH4 (0.5 mmol) was added and stirred for 4 hours. The mixture was heated for 2 hours at 60 C, 3 ml of methanol and 0.2 g of C-18 chromatographic phase were added, stirred for 2 hours, filtered. The residue was purified by HPLC. Brown gum. Yield: 41%. 1H NMR (400 MHz, Chloroform-d) d 7.10 (t, J = 7.7 Hz, 1H), 7.05 (d, J = 7.5 Hz, 1H), 6.90 - 6.78 (m, 2H), 4.22 (dt, J = 10.4, 2.1 Hz, 1H), 3.88 (dd, J = 10.6, 7.5 Hz, 1H), 3.12 (dq, J = 7.8, 3.9, 3.0 Hz, 1H), 3.02 (dd, J = 15.9, 5.2 Hz, 1H), 2.82 (d, J = 6.9 Hz, 2H), 2.67 (dd, J = 15.9, 7.7 Hz, 1H), 1.90 (t, J = 3.2 Hz, 1H), 1.82 (dt, J = 13.3, 8.7 Hz, 9H), 1.75 (s, 1H), 1.59 - 1.51 (m, 2H), 1.13 (s, 1H). m/z=298.2
[00255]
Figure imgf000081_0001
-fluoro-2-phenylethan-l -amine (0.5 mmol) and adamantane-2-carbaldehyde (0.5 mmol) were dissolved in 0.6 ml MeOH, heated at 100° C for 2 hours; then the mixture was cooled, and NaBH4 (0.5 mmol) was added and stirred for 4 hours. The mixture was heated for 2 hours at 60° C, 3 ml of methanol and 0.2 g of C-18 chromatographic phase were added, stirred for 2 hours, filtered, evaporated and the residue was purified by HPLC. Yield: 21 %. m/z=288.2
[00256]
Figure imgf000081_0002
stirred solution of 2-phenyloxirane (1 mmol) in anhydrous tetrahydrofuran were added adamantan-2-ylmethanamine (1 mmol) and N,N-diisopropylethylamine (0.5 mmol) at 0-5 °C. The resultant mixture was allowed to warm to 25 °C and stirred for 20 h, by which time the reaction was completed as indicated by TLC. To the reaction mixture water was added (2.5 mL) and stirred for 5 h. The solvent was removed under reduced pressure bringing the total volume to one-fourth. The content of the reaction mixture was extracted with dichlorom ethane (2 x 10 mL). The organic layer was dried over anhydrous Na2S04 and concentrated under reduced pressure to give the crude product. The crude product was purified by HPLC to obtain the pure product as brown gum. Yield: 34 %. 1H NMR (400 MHz, DMSO-d6) d 7.34 - 7.22 (m, 8H), 7.22 (d, J = 5.5 Hz, OH), 7.19 (s, 2H), 4.68 (s, 2H), 2.71 (s, 1H), 1.82 (s, 9H), 1.70 (d, J = 13.7 Hz, 9H), 1.51 (d,
J = 11.9 Hz, 3H), 1.44 (s, 2H), 1.24 (s, 1H). m/z=286.2
[00257]
Figure imgf000081_0003
tetrahydronaphthalen-l-yl)ethan-l- amine (0.5 mmol) and adamantane-2-carbaldehyde (0.5 mmol) were dissolved in 0.6 ml MeOH, heated at 100° C for 2 hours; then the mixture was cooled, and NaBH4 (0.5 mmol) was added and stirred for 4 hours. The mixture was heated for 2 hours at 60° C; 3 ml of methanol and 0.2 g of C-18 chromatographic phase were added, stirred for 2 hours, filtered, evaporated, and the residue was purified by HPLC. Yield: 28 %. 1H NMR (400 MHz, Chloroform-d) d 7.09 - 6.92 (m, 1H), 2.89 - 2.69 (m, 4H), 1.86 (s, 1H), 1.84 - 1.73 (m, 5H), 1.54 (d, J = 12.0 Hz, 1H). m/z=324.2
[00258]
Figure imgf000082_0001
tetrahydronaphthalen-2- yl)methyl)amino)ethan-l-ol (0.5 mmol) and adamantane-2-carbaldehyde (0.55 mmol) were dissolved in 0.6 ml CHCh; NaBH(OAc)3 (1.5 mmol) was added and stirred for 4 hours. The mixture was heated for 12 hours at 60°C; 3 ml of methanol and 0.2 g of C-18
chromatographic phase were added, stirred for 2 hours, filtered, evaporated. The residue was purified by HPLC. Yellow gum. Yield: 41 %. 1H NMR (400 MHz, DMSO-d6) d 6.99 (s, 1H), 3.46 (s, 2H), 2.69 (s, 2H), 1.84 (s, 1H), 1.76 (s, 1H), 1.72 (s, 4H), 1.66 (s, 1H), 1.43 (s, OH). m/z=354.2
[00259]
Figure imgf000082_0002
A122. Step A: 2-(3-fluorophenyl)ethan-l -amine (1 mmol) and adamantane-2-carbaldehyde (1.1 mmol) were dissolved in 0.6 ml MeOH, heated at 100° C for 2 hours; then the mixture was cooled, NaBH4 (0.5 mmol) was added and stirred for 4 hours. The mixture was heated for 2 hours at 60° C; 3 ml of methanol and 0.4 g of C-18 chromatographic phase were added, stirred for 2 hours, filtered, evaporated, and the residue was purified by HPLC. Step B: N-(adamantan-2-ylmethyl)-2-(3-fluorophenyl)ethan-l -amine (0.5 mmol), CH3I (0.75 mmol), and NaOH (0.5 mmol) were dissolved in 30 mL of ethanol. The mixture was stirred and refluxed for 5 h and then washed 3 times with 30 mL of distilled water. The aqueous phase was extracted by CHCh (30mL><3). The organic phases were combined and dried by Na2S04. After the solvent had been removed under reduced pressure, the residue was purified by HPLC. Yield: 37%. Yellow gum. 1H NMR (400 MHz,
Chloroform-d) d 7.23 (dd, J = 16.1, 9.0 Hz, 1H), 6.97 (d, J = 7.6 Hz, 1H), 6.95 - 6.83 (m, 2H), 2.77 (dd, J = 9.6, 6.1 Hz, 2H), 2.60 (dd, J = 9.6, 6.1 Hz, 2H), 2.43 (d, J = 7.1 Hz, 2H), 2.28 (s, 3H), 1.91 - 1.77 (m, 8H), 1.73 (d, J = 9.3 Hz, 6H), 1.53 (d, J = 12.3 Hz, 2H).
m/z=302.3 [00260]
Figure imgf000083_0001
Step A: Adamantan-2-ylmethanamine (2 mmol) and CDI (4 mmol) were dissolved in 1.2 ml CH3CN; the mixture was kept at a temperature of 70 °C for 1 hour, then 5-methyl-5,6,7,8-tetrahydronaphthalene-2-carboxylic acid (2 mmol) was added. The mixture was heated for 2 hours at 70 °C, then filtered and evaporated. The residue was purified by LC. Yield: 36 %. Step B: N-(adamantan-2- ylmethyl)-5-methyl-5,6,7,8-tetrahydronaphthalene-2-carboxamide (0.5 mmol) was dissolved in anhydrous THF (5 mL); subsequently a suspension of LiAlH4 in THF (2N solution, 2 mmol) was added dropwise under argon. The reaction mixture was warmed to reflux for 3-6 h. Excess reactants were decomposed by addition of few drops of AcOEt, NaOH (1N water solution, 1 equiv), and water. After filtration of the salts over Celite, the clear solution was dried over Na2S04 and concentrated in vacuo. Residue was purified by HPLC. Yield: 28%. 1H NMR (500 MHz, DMSO-d6) d 7.10 (d, J = 7.8 Hz, 1H), 7.04 (d, J = 7.8 Hz, 1H), 6.97 (s, 1H), 3.60 (d, J = 4.5 Hz, 2H), 2.82 (q, J = 6.6 Hz, 1H), 2.66 (q, J = 6.7 Hz, 2H), 2.56 (d, J = 7.0 Hz, 1H), 1.85 (q, J = 11.1, 7.6 Hz, 2H), 1.81 - 1.71 (m, 10H), 1.67 (s, 4H), 1.63 (s, 2H), 1.49 - 1.41 (m, 3H), 1.21 (d, J = 6.9 Hz, 3H). m/z=324.2
[00261]
Figure imgf000083_0002
Adamantan-2-ylmethanamine (1 mmol) and
8-methyl-5,6,7,8-tetrahydronaphthalene-2-carbaldehyde (1 mmol) were dissolved in 0.6 ml of MeOH and heated at 100° C for 2 hours; then the mixture was cooled, NaBH4 (1 mmol) was added and stirred for 4 hours. The mixture was heated for 2 hours at 60° C; 3 ml of methanol and 0.2 g of C-18 chromatographic phase were added, stirred for 2 hours, filtered, evaporated. The residue was purified by HPLC. Yield: 31%. 1H NMR (400 MHz,
Chloroform-d) d 7.13 (s, 1H), 7.06 - 6.96 (m, 2H), 3.73 (s, 2H), 2.88 (q, J = 6.5 Hz, 1H), 2.71 (p, J = 5.5 Hz, 4H), 1.94 - 1.63 (m, 18H), 1.50 (d, J = 11.8 Hz, 2H), 1.27 (d, J = 7.0 Hz, 3H), 1.24 (s, 1H). m/z=324.2 [00262]
Figure imgf000084_0001
Adamantan-2-ylmethanamine (1 mmol) and
8-fluoro-5,6,7,8-tetrahydronaphthalene-2-carbaldehyde (1 mmol) were dissolved in 0.6 ml MeOH, heated at 100° C for 2 hours; then the mixture was cooled, NaBH4 (1 mmol) was added and stirred for 4 hours. The mixture was heated for 2 hours at 60° C, 3 ml of methanol and 0.2 g of C-18 chromatographic phase were added, stirred for 2 hours, filtered, evaporated. The residue was purified by HPLC. Yield: 41 %. 1H NMR (400 MHz, DMSO- d6) d 9.06 (s, 2H), 7.52 (d, J = 1.9 Hz, 1H), 7.44 (dd, J = 8.0, 1.9 Hz, 1H), 7.18 (d, J = 7.9 Hz, 1H), 5.50 (t, J = 3.8 Hz, 1H), 4.09 (s, 2H), 3.01 - 2.95 (m, 2H), 2.86 (dd, J = 17.9, 5.5 Hz, 1H), 2.73 (ddd, J = 17.3, 10.8, 5.8 Hz, 1H), 2.17 (dt, J = 8.0, 3.9 Hz, 2H), 2.08 (s, 2H), 2.03 - 1.93 (m, 1H), 1.81 (d, J = 28.3 Hz, 9H), 1.69 (d, J = 10.7 Hz, 6H), 1.48 (d, J = 12.6 Hz, 2H). m/z=326.2
[00263]
Figure imgf000084_0002
Step A: Adamantan-2-ylmethanamine (10 mmol) and CDI (20 mmol) were dissolved in 10 ml CH3CN; the mixture was kept at a temperature of 70 °C for 1 hour, then 5-oxo-5,6,7,8-tetrahydronaphthalene-2-carboxylic acid (10 mmol) was added. The mixture was heated for 2 hours at 70 °C, then evaporated, and the residue was purified by LC. Yield: 62 %. Step B: N-(adamantan-2-ylmethyl)-5-oxo-5, 6,7,8- tetrahydronaphthalene-2-carboxamide (6 mmol) was dissolved in EtOH; then NaBH4 (6.6 mmol) was added and stirred for 5 hours at room temperature. The mixture was poured into the water, the organic layer was extracted with EtOAc, evaporated. The residue was purified by LC. Yield: 58 %. Step C: N-(adamantan-2-ylmethyl)-5-hydroxy-5, 6,7,8- tetrahydronaphthalene-2-carboxamide (3 mmol) was dissolved in anhydrous THF (10 mL); subsequently a suspension of LiAlH4 in THF (2 N solution, 3 mmol) was added dropwise under argon. The reaction mixture was warmed to reflux for 3-6 h. Excess reactants were decomposed by addition of few drops of AcOEt, NaOH (1 N water solution, 1 equiv), and water. After filtration of the salts over Celite, the clear solution was dried over Na2S04 and concentrated in vacuo. The residue was purified by HPLC. Yield: 61 %. Step D: To a solution of 6-(((adamantan-2-ylmethyl)amino)methyl)-l,2,3,4-tetrahydronaphthalen-l-ol (2 mmol) in CH2CI2 (30 mL) was added (BOC)20 (2 mmol). The resulting solution was stirred at room temperature overnight. The reaction was quenched by the addition of saturated NaElCCh and separated. The organic layer was washed with brine, dried over Na2S04, filtered, and concentrated under reduced pressure. The crude product was purified by flash chromatography using 10% EtOAc in hexanes as eluent. Yield: 49 %. Step F:
(Diethylamino)sulfur trifluoride (2 mmol) was added to a solution of tert-butyl (adamantan- 2-ylmethyl)((5-hydroxy-5,6,7,8-tetrahydronaphthalen-2-yl)methyl)carbamate (1 mmol) in CH2CI2 (6 mL) at 0C. After stirring at 25 °C for 15 h, the reaction was cooled to 0 °C and quenched by MeOH (10 mL) and EtiN (5 mL). The reaction mixture was diluted with EtOAc and washed with H2O, saturated aq. NaHC03, and saturated aq. NaCl. The organic layer was dried over anhydrous MgS04, filtered and concentrated. Yield: 32 %. Step J: To a solution of tert-butyl (adamantan-2-ylmethyl)((5-fluoro-5,6,7,8-tetrahydronaphthalen-2- yl)methyl)carbamate (0.5 mmol) in dichloromethane (2mL) was slowly added trifluoroacetic acid (3 mmol) at 0 °C. The reaction solution was stirred at room temperature for 5 h, and then 1N NaOH was added. The mixture was extracted with dichloromethane, and the organic layer was washed with brine, dried (Na2S04), and filtered. The solvent was evaporated under reduced pressure to give the final compound. Yield: 34 %. 1H NMR (400 MHz, DMSO-d6) d 9.05 (s, 2H), 7.38 (s, 2H), 7.32 (s, 1H), 5.55 (t, J = 3.8 Hz, 1H), 4.08 (t, J = 5.7 Hz, 2H), 3.00 (q, J = 6.4 Hz, 2H), 2.78 (dtt, J = 27.9, 10.8, 5.3 Hz, 2H), 2.21 - 2.04 (m, 3H), 2.00 (s, 1H), 1.83 (d, J = 15.5 Hz, 5H), 1.80 - 1.68 (m, 5H), 1.68 (s, 4H), 1.49 (d, J = 12.4 Hz, 2H). m/z=326.2
[00264]
Figure imgf000085_0001
Step A: Adamantan-2-ylmethanamine (2 mmol), and CDI (4 mmol) were dissolved in 1.2 ml CH3CN; the mixture was kept at a temperature of 70 °C for 1 hour, then 6,7,8,9-tetrahydro-5H-benzo[7]annulene-2-carboxylic acid (2 mmol) was added. The mixture was heated for 2 hours at 70 °C, then evaporated, and the residue was purified by LC. Yield: 36 %. Step B: N-(adamantan-2-ylmethyl)-6,7,8,9- tetrahydro-5H-benzo[7]annulene-2-carboxamide (0.5 mmol) were dissolved in anhydrous THF (5 mL); subsequently a suspension of LiAlH4 in THF (2N solution, 2 mmol) was added dropwise under argon atmosphere. The reaction mixture was warmed to reflux for 3-6 h. Excess reactants were decomposed by addition of few drops of AcOEt, NaOH (1N water solution, 1 equiv), and water. After filtration of the salts over Celite, the clear solution was dried over Na2S04 and concentrated in vacuo. Residue was purified by HPLC. Yield: 28%.
[00265] 1H NMR (500 MHz, DMSO-d6) d 7.03 (s, 1H), 7.02 - 6.95 (m, 2H), 3.60 (s, 2H), 2.71 (dt, J = 7.0, 2.8 Hz, 4H), 2.55 (d, J = 7.2 Hz, 2H), 1.87 - 1.82 (m, 1H), 1.81 - 1.65 (m, 16H), 1.54 (h, J = 5.3 Hz, 4H), 1.47 - 1.40 (m, 2H). m/z=324.2.
Figure imgf000086_0001
Step A: 5-oxo-5, 6,7,8- tetrahydronaphthalene-2-carboxylic acid (2 mmol), and CDI (2 mmol) were dissolved in 2 ml CH3CN; the mixture was heated at 70 °C for 1 hour, then adamantan-2-ylmethanamine (2 mmol) was added. The mixture was heated for 2 hours at 70 °C. Water (25 ml) were added; the organic layer was extracted with EtOAc (3* 15ml) and concentrated in vacuo. The crude product was purified by LC. Yield: 48 %. Step B: N-(adamantan-2-ylmethyl)-5-oxo-5, 6,7,8- tetrahydronaphthalene-2-carboxamide (0.5 mmol) was dissolved in anhydrous THF (5 mL); subsequently a suspension of LiAlHi in THF (2N solution, 3 mmol) was added dropwise under argon. The reaction mixture was warmed to reflux for 3-6 h. Excess reactants were decomposed by addition of few drops of AcOEt, NaOH (1N water solution, 1 equiv), and water. After filtration of the salts over Celite, the clear solution was dried over Na2S04 and concentrated in vacuo. Residue was purified by HPLC. Yield: 39%. 1H NMR (400 MHz, DMSO-d6) d 9.03 (s, 2H), 7.43 (d, J = 7.9 Hz, 1H), 7.36 - 7.29 (m, 1H), 7.24 (s, 1H), 5.20 (s, 1H), 4.57 (s, 1H), 4.05 (d, J = 5.5 Hz, 2H), 2.98 (q, J = 6.4 Hz, 2H), 2.71 (s, 1H), 2.66 (q, J = 12.1, 9.0 Hz, 1H), 2.54 (s, 1H), 2.08 (s, 1H), 1.90 (dd, J = 9.6, 4.3 Hz, 1H), 1.85 (s, 3H), 1.74 (dd, J = 22.0, 7.5 Hz, 4H), 1.68 (s, 6H), 1.49 (d, J = 12.5 Hz, 2H). m/z=326.2.
[00267]
Figure imgf000086_0002
Adamantan-2-ylmethanamine (1 mmol) and
8-hydroxy-5,6,7,8-tetrahydronaphthalene-2-carbaldehyde (1 mmol) were dissolved in 0.6 ml MeOH, heated at 100° C for 2 hours; then the mixture was cooled, NaBH4 (1 mmol) was added and stirred for 4 hours. The mixture was heated for 2 hours at 60° C; 3 ml of methanol and 0.2 g of C-18 chromatographic phase were added, stirred for 2 hours, filtered, the solvent was evaporated. The residue was purified by HPLC. Yield: 48%. 1H NMR (400 MHz, DMSO-d6) d 8.99 (s, 2H), 7.55 (d, J = 2.0 Hz, 1H), 7.34 (dd, J = 7.9, 2.0 Hz, 1H), 7.10 (d, J = 7.8 Hz, 1H), 5.19 (s, 1H), 4.56 (s, 1H), 4.06 (d, J = 5.7 Hz, 2H), 3.16 (s, OH), 2.99 (d, J = 6.7 Hz, 2H), 2.72 (s, 1H), 2.70 - 2.61 (m, 1H), 2.54 (s, 1H), 2.08 (s, 1H), 1.90 (s, 1H), 1.91 - 1.75 (m, 7H), 1.71 (d, J = 10.2 Hz, 1H), 1.68 (s, 6H), 1.49 (d, J = 12.5 Hz, 2H). m/z=326.2
[00268]
Figure imgf000087_0001
-fluoroadamantan-2-yl)methanamine (1.1 mmol) was dissolved in 0.6 ml CH3CN, thereafter Nal (5 mg) and l-(2-chloroethyl)-3- fluorobenzene (1 mmol) were added. The mixture was heated at 80° C for 2 hours; then the mixture was cooled, and the solvent was evaporated. The residue was purified by HPLC. Yield: 34 %. 1H NMR (400 MHz, DMSO-d6) d 8.30 (s, 1H), 7.13 (t, J = 9.7 Hz, 1H), 3.20 (s, 1H), 3.07 (s, 1H), 2.95 (t, J = 8.3 Hz, 1H), 2.17 (s, 2H), 1.90 (s, 2H), 1.82 (s, 1H), 1.68 (s, 2H), 1.60 (s, 1H). m/z=306.2
[00269]
Figure imgf000087_0002
Step A: 2-(2-aminoethyl)phenol (5 mmol) and adamantane-2-carbaldehyde (5 mmol) were dissolved in 1 ml MeOH, heated at 100° C for 2 hours; then the mixture was cooled, NaBH4 (5 mmol) was added and stirred for 4 hours. The mixture was heated for 2 hours at 60° C; 3 ml of methanol and 0.8 g of C- 18
chromatographic phase were added, stirred for 2 hours, filtered, solvent was evaporated. The residue was purified by HPLC. Yield: 68 %. Step B: To a solution of 2-(2-((adamantan-2- ylmethyl)amino)ethyl)phenol (3 mmol) in CH2CI2 (20 mL) was added (BOC)20 (3 mmol).
The resulting solution was stirred at room temperature overnight. The reaction was quenched by the addition of saturated NaHCCh and separated. The organic layer was washed with brine, dried over Na2S04, filtered, and concentrated under reduced pressure. The crude product was purified by flash chromatography using 10% EtOAc in hexanes as eluent.
Yield: 54 %. Step C: To a solution of Succinic acid tert-butyl pentafluorophenyl ester (2 mmol) HATU (2mmol) and DIPEA (3mmol) were added. The mixture was stirred at 50 °C for 5 h, then tert-butyl (adamantan-2-ylmethyl)(2-hydroxyphenethyl)carbamate (1.5 mmol) in THF was added. The resulting solution was refluxed for 2 h. The solvent was evaporated, and the crude product was purified by HPLC. Yield: 22 %. Step D: To a solution of 2-(2- ((adamantan-2-ylmethyl)(tert-butoxycarbonyl)amino)ethyl)phenyl tert-butyl succinate (0.5 mmol) in dichloromethane (2mL) trifluoroacetic acid (3 mmol)was slowly added at 0°C. The reaction was stirred at room temperature for 5 h, and then 1N NaOH was added. The mixture was extracted with dichloromethane, and the organic layer was washed with brine, dried (Na2S04), and filtered. The solvent was evaporated under reduced pressure to give the final compound. Yield: 12 %. 1H NMR (500 MHz, DMSO-d6) d 8.50 (s, 1H), 7.34 (q, J = 7.6 Hz, 2H), 7.09 (d, J = 8.0 Hz, 1H), 3.06 (s, 2H), 2.88 (q, J = 8.6, 7.0 Hz, 4H), 2.64 (t, J = 6.6 Hz, 2H), 2.48 (s, 12H), 2.02 (s, 1H), 1.86 - 1.78 (m, 6H), 1.70 (s, 3H), 1.51 (d, J = 12.1 Hz, 2H). m/z=386.2
[00270]
Figure imgf000088_0001
Step A: 2-(2-aminoethyl)phenol (5 mmol) and adamantane-2-carbaldehyde (5 mmol) were dissolved in 1 ml MeOH, heated at 100° C for 2 hours; then mixture was cooled, NaBH4 (5 mmol) was added and stirred for 4 hours. The mixture was heated for 2 hours at 60° C; 3 ml of methanol and 0.8 g of C- 18
chromatographic phase were added, stirred for 2 hours, filtered, solvent was evaporated. The residue was purified by HPLC. Yield: 68 %. Step B: To a solution of 2-(2-((adamantan-2- ylmethyl)amino)ethyl)phenol (3 mmol) in CH2CI2 (20 mL) was added (BOC)20 (3 mmol). The resulting solution was stirred at room temperature overnight. The reaction was quenched by the addition of saturated NaHCCb and separated. The organic layer was washed with brine, dried over Na2S04, filtered, and concentrated under reduced pressure. The crude product was purified by flash chromatography using 10% EtOAc in hexanes as eluent. Yield: 52%. Step C: To a solution of the nicotinic acid (2 mmol) in THF (5 ml) were added HATU (2mmol) and DIPEA (3mmol). The mixture was stirred at 50 °C for 5h, then tert-butyl (adamantan-2-ylmethyl)(2-hydroxyphenethyl)carbamate (1.5 mmol) in THF was added. The resulting solution was refluxed for 2 h. The solvent was evaporated and the crude product was purified by HPLC. Yield: 31 %. Step D: To a solution of 2-(2-((adamantan-2- ylmethyl)(tert-butoxycarbonyl)amino)ethyl)phenyl nicotinate (0.5 mmol) in dichloromethane (2mL) trifluoroacetic acid (3 mmol) was slowly added at 0°C. The reaction was stirred at room temperature for 5 h, and then 1N NaOH was added. The mixture was extracted with dichloromethane, and the organic layer was washed with brine, dried (Na2S04), and filtered. The solvent was evaporated under reduced pressure to give the final compound. Yield: 17 %. 1H MR (400 MHz, DMSO-d6) d 9.40 (s, 1H), 9.06 (s, 2H), 9.00 (d, J = 5.1 Hz, 1H), 8.73 (dt, J = 8.1, 1.9 Hz, 1H), 7.84 (dd, J = 8.1, 5.1 Hz, 1H), 7.45 (d, J = 8.2 Hz, 1H), 7.39 (dd, J = 8.6, 6.1 Hz, 1H), 7.33 (dt, J = 7.8, 3.3 Hz, 2H), 3.06 (d, J = 7.7 Hz, 4H), 2.98 (q, J = 6.8 Hz, 2H), 2.02 (s, 1H), 1.82 (s, 3H), 1.74 (s, 4H), 1.73 - 1.69 (m, 1H), 1.64 (d, J = 11.9 Hz, 4H), 1.44 (d, J = 12.4 Hz, 2H). m/z=39l.2
[00271]
Figure imgf000089_0001
Step A: 2-(2-aminoethyl)phenol (5 mmol) and adamantane-2-carbaldehyde (5 mmol) were dissolved in 1 ml of MeOH, heated at 100° C for 2 hours; then the mixture was cooled, NaBH4 (5 mmol) was added and stirred for 4 hours. The mixture was heated for 2 hours at 60° C; 3 ml of methanol and 0.8 g of C-18
chromatographic phase were added, stirred for 2 hours, filtered, solvent was evaporated. The residue was purified by HPLC. Yield: 68 %. Step B: To a solution of 2-(2-((adamantan-2- ylmethyl)amino)ethyl)phenol (3 mmol) in CH2CI2 (20 mL) was added (BOC)20 (3 mmol). The resulting solution was stirred at room temperature overnight. The reaction was quenched by the addition of saturated NaHCCb and separated. The organic layer was washed with brine, dried over Na2S04, filtered, and concentrated under reduced pressure. The crude product was purified by flash chromatography using 10% EtOAc in hexanes as eluent.
Yield: 52%. Step C: To a solution of the dimethylglycine (2 mmol) in THF (5 ml) were added HATU (2mmol) and DIPEA (3mmol). The mixture was stirred at 50 °C for 5 h, then tert-butyl (adamantan-2-ylmethyl)(2-hydroxyphenethyl)carbamate (1.5 mmol) in THF was added. The resulting solution was refluxed for 2 h. The solvent was evaporated, and the crude product was purified by HPLC. Yield: 28 %. Step D: To a solution of 2-(2- ((adamantan-2-ylmethyl)(tert-butoxycarbonyl)amino)ethyl)phenyl dimethylglycinate (0.5 mmol) in dichloromethane (2mL) was slowly added trifluoroacetic acid (3 mmol) at 0°C.
The reaction solution was stirred at room temperature for 5 h, and then 1N NaOH was added. The mixture was extracted with dichloromethane, and the organic layer was washed with brine, dried (Na2S04), and filtered. The solvent was evaporated under reduced pressure to give the final compound. Yield: 15 %. 1H NMR (500 MHz, DMSO-d6) d 10.52 (s, 1H), 9.17
(s, 2H), 7.39 (dd, J = 11.5, 7.2 Hz, 2H), 7.32 (t, J = 7.4 Hz, 1H), 7.25 (d, J = 7.9 Hz, 1H), 4.89 (s, 2H), 3.56 (d, J = 1.5 Hz, 1H), 3.02 (d, J = 8.9 Hz, 6H), 2.96 (s, 5H), 2.50 (d, J = 5.8 Hz, 3H), 2.11 (s, 1H), 1.90 (s, 2H), 1.86 (s, 1H), 1.81 (d, J = 13.8 Hz, 5H), 1.70 (d, J = 10.4 Hz, 4H), 1.49 (d, J = 12.6 Hz, 2H). m/z=37l.4
Figure imgf000090_0001
Step A:
[00272] 6-hydroxy-5,6,7,8-tetrahydronaphthalene-2-carboxylic acid (21 mmol) and CDI (21 mmol) were dissolved in 10 ml CH3CN, the mixture was heated at 70C for 1 hour, then adamantan-2-ylmethanamine (21 mmol) was added. The mixture was heated for 2 hours at 70°C. Water (100 ml) was added, the organic layer was extracted with EtOAc (3x40ml), and concentrated in vacuo. The crude product was purified using LC. Yield: 47 %.
Step B:
[00273] N-(adamantan-2-ylmethyl)-6-hydroxy-5,6,7,8-tetrahydronaphthalene-2- carboxamide (10 mmol) was dissolved in anhydrous THF (12 mL); subsequently a suspension of L1AIH4 in THF (2N solution, 10 mmol) was added dropwise under argon atmosphere. The reaction mixture was warmed to reflux for 3-6 h. The excess of reactants was decomposed by addition of a few drops of AcOEt, NaOH (1N water solution, 1 equiv), and water. After filtration of the salts over Celite, a clear solution was dried over Na2S04 and concentrated in vacuo. Residue was purified using HPLC. Yield: 61%.
Step C:
[00274] To a solution of 6-(((adamantan-2-ylmethyl)amino)methyl)-l, 2,3,4- tetrahydronaphthalen-2-ol (6 mmol) in CH2CI2 (20 mL) was added (BOC)20 (6 mmol). The resulting solution was stirred at room temperature overnight. The reaction was quenched by the addition of saturated NaHCCh and separated. The organic layer was washed with brine, dried over Na2S04, filtered, and concentrated under reduced pressure. The crude product was purified by flash chromatography using a 10% EtOAc in hexanes solution as eluent. Yield:
45 %. Step D:
[00275] (Diethylamino)sulfur trifluoride (2 mmol) was added to a solution of tert-butyl (adamantan-2-ylmethyl)((6-hydroxy-5,6,7,8-tetrahydronaphthalen-2-yl)methyl)carbamate (1 mmol) in THF (3 mL) at 0°C. After stirring at r.t. for 10 h, the reaction was cooled to 0°C and quenched by MeOH (2 mL) and Et3N (0.1 mL). The reaction mixture was diluted with EtOAc and washed with ELO, saturated aq.NaHCCh, and saturated aq. NaCl. The organic layer was dried over anhydrous MgSCri, filtered and concentrated. The residue was purified by LC. Yield: 54 %.
Step F:
[00276] To a solution of tert-butyl (adamantan-2-ylmethyl)((6-fluoro-5, 6,7,8- tetrahydronaphthalen-2-yl)methyl)carbamate (1 mmol) in dichloromethane (2mL) was slowly added trifluoroacetic acid (5 mmol) at 0°C. The reaction solution was stirred at room temperature for 5 h, and then 1N NaOH was added. The mixture was extracted with dichloromethane, and organic layer was washed with brine, dried (Na2S04), and filtered. The solvent was evaporated under reduced pressure to give the final compound. Yield: 58 %. 1H NMR (400 MHz, DMSO-d6) d 8.73 (s, 2H), 7.26 (d, J = 2.9 Hz, 2H), 7.16 (s, 1H), 5.21 (s, 1H), 5.08 (s, 1H), 4.07 (s, 2H), 3.01 (s, 3H), 2.84 (s, 2H), 2.78 (s, 1H), 2.03 (s, 3H), 1.82 (s, 6H), 1.79 - 1.66 (m, 10H), 1.49 (d, J = 12.7 Hz, 2H).
Example 3: Tuberculosis Assay
[00277] A luminescence assay was carried out via the following steps. The strain used in the luminescence assay was H37RvMA with the LuxCDABE operon integrated at the L5 site on a Kanamycin marked plasmid (pMV306hsp+LuxGl3):
1. Inoculate -80 stock into 7H9 OADC + Kan (25ug/mL)
2. When bacteria reach mid-log phase, passage cells in 7H9 OADC + Kan25
3. When cells reach mid log phase dilute to OD=0.05 in 7H9 OADC
4. Add lOOuL of cells to each well of the plate
5. Seal the plate with an optical film and read luminescence using the following
protocol:
a. Plate reader: Biotek Synergy Hl
b. Double orbital shaking (lOs); frequency: 282 cpm (3mm) c. Luminescence endpoint parameters: ls integration time, gain 200, read height lmm
6. Remove optical film, seal with a breathable film, and incubate shaking at 37C
7. Read luminescence at day 0, 1, 4, and 7
[00278] An Alamar Blue/Resazurin assay was carried out via the following steps. The strain used in the Alamar Blue/Resazurin assay was H37RvMA:
1. Inoculate -80 stocks into 7H9 OADC
2. When cells reach mid-log phase passage in 7H9 OADC
3. When cells reach mid log phase, dilute to OD=0.006
4. Add lOOuL of cells (diluted to OD=0.006) to the plate (making final OD in plate 0.003)
5. Seal the plate with breathable film, place in a ziplock, and put the plate in a box
a. Incubate shaking at 37°C for 4 days
6. After incubation, add 20uL of Resazurin/alamar blue (0.02%) to every well (not including water wells
7. Re-seal the plates and incubate at 37°C, check the plates after 24 and 48 hours
a. Purple = no growth, pink = growth
b. MIC recorded as the well with the lowest concentration of drug that there is killing (purple color).
[00279] The anti-tuberculosis activity of the compounds of the invention is shown in Table 3.
Example 4: Mutation Mapping
[00280] In order to select for mutations resistant to A51 (para-isopropyl compound), liquid culture of Mycobacterium smegmatis me2155 grown for 3 days in Middlebrook 7H9-
ADC was plated on LB-agar plates containing A51 at 5 mM, 9 pM, and 14 pM. A total of 8 resistant mutants were obtained from 3 mL of culture (approx. 3xl0 9 frequency of resistance). 20-mL cultures of each of the resistant mutants as well as of the parent strain were grown in Middlebrook 7H9-ADC, and cells were harvested by centrifugation at 4,000
RPM for 10 min at 4°C. The supernatant was discarded, and the pellet resuspended in 400 pL TBS-E (10 mM Tris pH 8, 25 mM NaCl, 1 mM EDTA). An equal volume of a 2: 1 mixture of chloroforrmmethanol was added and mixed thoroughly for 5 min. Tubes were centrifuged at 4,000 RPM for 20 min at 4°C. The top layer (aqueous phase) and bottom layer
(organic phase) were removed. The middle (cellular) layer was preserved and dried under a gentle nitrogen stream, then resuspended in 400 pL of TBS-E. Lysozyme was added to the final concentration of 100 pg/mL, and samples were incubated at 37°C overnight. RNAse A was added to the final concentration of 25 pg/mL, and the samples were incubated for 1 hour at 37°C. SDS was added to the final concentration of 1% and proteinase K to the final concentration of 100 pg/mL. The samples were incubated for 3 hours at 50°C and then mixed with an equal volume of phenol:chloroform:isoamyl alcohol (25:24: 1). The samples were incubated for 30 min at room temperature, rocked for 30 min at room temperature, and centrifuged for 15 min at l0,000xg at 4°C. The top layer (aqueous phase) was transferred into new tubes and mixed with ½ volume of chloroform; the tubes were centrifuged for 15 min at l0,000xg at 4°C. The top layer (aqueous phase) was transferred into new tubes, and DNA was precipitated with 1/10 volume of 3M NaOAc pH 5.2 and 1 volume of IPA. The tubes were incubated overnight at -20 °C. Each of DNA samples was picked up with an inoculating loop, washed with lmL of 70% ethanol by dropwise pipetting and dropped off into a new tube with 1 mL of 70% ethanol. The tubes were centrifuged at l0,000xg for 5 min, and the supernatant was removed; residual ethanol was allowed to evaporate. DNA was resuspended in 150 pL of water. Resulting DNA was used for an Illumina Nextera dual- indexed library, which was prepared and sequenced according to the manufacturer’ s instructions. A comparison of the sequence of the Mycobacterium smegmatis mc2l55 with those of the resistant mutants revealed that all of the resistant mutants had missense mutations in MmpL3.
Example 5: Toxicity Testing
The compounds of the invention gave favorable results in toxicity testing relative to three known inhibitors of the target (SQ109, BM212, and SQ609). To test the toxicity of the anti -tuberculosis compounds, the cells were cultured in media (MEM+O.OlmM
NEAA+10%FBS) at 37 C. 5% ( 02 and 95% humidity.
1. Harvested cells during logarithmic growth period and counted cell number using Count- star.
2. Adjusted cell concentrations to 3.33xl04 cells/mL with culture medium.
3. Added 90 pL cell suspensions to 96-well plates with the final cell density of 3>< l03 cells/well.
4. Prepared 10X compound gradients (The highest final concentration was 50pM in media with 3.16-fold serial dilutions to achieve 9 dose levels ).
5. Dispensed 10 pL of 10X drug solution of both compounds and DMSO controls in each plate (triplicate for each drug concentration. Final DMSO concentration in culture medium was 0.5% [v/v]).
6. Incubated the plate for 72 hrs in a humidified incubator at 37°C with 5% CO2, and then performed a CellTiter-Glo assay.
7. Equilibrated the plate and its contents at room temperature for approximately 30 mins.
8. Added 100 pL CellTiter-Glo to each well.
9. Mixed contents for 2 mins on an orbital shaker to induce cell lysis.
10. Allowed the plate to incubate at room temperature for 10 mins to stabilize luminescent signal.
11. Recorded luminescence.
12. In order to calculate absolute IC50 (EC50), a dose-response curve was fitted using nonlinear regression model with a sigmoidal dose response. The IC50 (EC50) was calculated according to the dose-response curve generated by GraphPad Prism 5.0.
[00281] Results from the toxicity testing are summarized in Table 4 below:
Table4:
IC50 IC50
Pat ID HEK293 HepG2
Figure imgf000094_0001
>50 NA
A31
Figure imgf000094_0004
A38
Figure imgf000094_0002
>50 >50
A42
Figure imgf000094_0005
A49
Figure imgf000094_0003
>50 >50
A50
Figure imgf000095_0002
A51
>50 >50
Figure imgf000095_0001
A71
Cisplatin 1.8837 8.431
Cisplatin 2.1134 5.0953
SQ109 33.3949 40.6236
BM212 7.9121 8.5659
SQ609 24.6062 20.9006
Figure imgf000095_0003
A84
REFERENCES
[00282] Koh W. 2017. Nontuberculous mycobacteria— overview microbiolspec 5(1): doi: 10.1 l28/microbiolspec.TNMI7-0024-20l6.
[00283] The teachings of all patents, published applications and references cited herein are incorporated by reference in their entirety.
[00284] While this invention has been particularly shown and described with references to example embodiments thereof, it will be understood by those skilled in the art that various changes in form and details may be made therein without departing from the scope of the invention encompassed by the appended claims.

Claims

What is claimed is:
1 A compound according to formula (I):
Figure imgf000096_0001
or a pharmaceutically acceptable salt thereof;
wherein:
L5 is (Ci-C2)alkylene, optionally substituted with (Ci-Ce)alkyl, hydroxyl, hydroxyl(Ci-C6)alkyl, (C3-C6)cycloalkyl, phenyl, halo(Ci-C6)alkyl, (Ci-C6)alkoxyl(Ci- Ce)alkyl, -C(0)0H, or -C(0)0-(Ci-C6)alkyl;
L6 is (Ci-C2)alkylene, optionally substituted with (Ci-Ce)alkyl, hydroxyl, hydroxyl(Ci-C6)alkyl, (C3-C6)cycloalkyl, phenyl, halo(Ci-C6)alkyl, (Ci-C6)alkoxyl(Ci- Ce)alkyl, -C(0)0H, or -C(0)0-(Ci-C6)alkyl;
Figure imgf000096_0002
is unsubstituted adamantyl;
R6 is optionally substituted phenyl;
R7 is H, alkyl, hydroxyalkyl, cycloalkyl, (cycloalkyl)alkyl, aralkyl, or heteroaralkyl; wherein when (a) L5 and L6 are both optionally substituted (Ci)alkylene, or (b) when
L5 is optionally substituted (C2)alkylene and L6 is optionally substituted (Ci)alkylene, then
R6 is phenyl substituted with one or more substituents, wherein the one or more substituents are selected from the group consisting of (C2-C6)alkyl, cycloalkyl, aryl, heteroaryl, halo, haloalkyl, hydroxyalkyl, alkoxy, (cycloalkyl)alkyl, and aralkyl, or wherein two adjacent substituents on phenyl, taken together with the intervening atoms, form a heteroaryl, aryl, cycloalkyl, or heterocycloalkyl ring.
2 A compound according to formula (G):
Figure imgf000096_0003
or a pharmaceutically acceptable salt thereof;
wherein: L5 is (Ci-C2)alkylene, optionally substituted with (C i-CTjalkyl, hydroxyl, hydroxyl(Ci-C6)alkyl, (C3-C6)cycloalkyl, phenyl, halo(Ci-C6)alkyl, (Ci-C6)alkoxyl(Ci- Cejalkyl, -C(0)0H, or -C(0)0-(Ci-C6)alkyl;
L6 is (Ci-C2)alkylene, optionally substituted with (C i-CTjalkyl, hydroxyl, hydroxyl(Ci-C6)alkyl, (C3-C6)cycloalkyl, phenyl, halo(Ci-C6)alkyl, (Ci-C6)alkoxyl(Ci- Cejalkyl, -C(0)0H, or -C(0)0-(Ci-C6)alkyl;
Figure imgf000097_0001
is unsubstituted adamantyl;
R6 is phenyl substituted with one or more substituents, wherein the one or more substituents are selected from the group consisting of (C2-C6)alkyl, cycloalkyl, aryl, heteroaryl, halo, haloalkyl, hydroxyalkyl, alkoxy, (cycloalkyl)alkyl, and aralkyl, or wherein two adjacent substituents on phenyl, taken together with the intervening atoms, form a heteroaryl, aryl, cycloalkyl, or heterocycloalkyl ring; and
R7 is H, alkyl, hydroxyalkyl, cycloalkyl, (cycloalkyl)alkyl, aralkyl, or heteroaralkyl.
3. The compound of claim 1 or 2, wherein L5 is unsubstituted methylene.
4. The compound of claim 1 or 2, wherein L5 is unsubstituted ethylene.
5. The compound of claim 1 or 2, wherein L5 is methylene substituted with (Ci-
C6)alkyl.
6 The compound of claim 1 or 2, wherein L5 is methylene substituted with methyl.
7. The compound of claim 1 or 2, wherein L5 is ethylene substituted with (Ci-C6)alkyl.
8 The compound of claim 1 or 2, wherein L5 is ethylene substituted with methyl.
9. The compound of any one of claims 1-8, wherein ring
Figure imgf000097_0002
is unsubstituted 1- adamantyl.
10 The compound of any one of claims 1-8, wherein ring
Figure imgf000097_0003
is unsubstituted 2- adamantyl.
11. The compound of any one of claims 1-10, wherein L6 is unsubstituted methylene.
12. The compound of any one of claims 1-10, wherein L6 is unsubstituted ethylene.
13. The compound of any one of claims 1-10, wherein L6 is methylene substituted with
(Ci-C6)alkyl.
14. The compound of any one of claims 1-10, wherein L6 is methylene substituted with methyl.
15. The compound of any one of claims 1-10, wherein L6 is ethylene substituted with (Ci-C6)alkyl.
16. The compound of any one of claims 1-10, wherein L6 is ethylene substituted with methyl.
17. The compound of claim 1 or 2, wherein R6 is unsubstituted phenyl.
18. The compound of any one of claims 1-17, wherein R6 is represented by
Figure imgf000098_0001
wherein:
R is a substituent selected from the group consisting of (C2-C6)alkyl, cycloalkyl, aryl, heteroaryl, halo, haloalkyl, hydroxylalkyl, alkoxy, (cycloalkyl)alkyl, and aralkyl; and n is an integer from 0 to 5.
19. The compound of claim 18, wherein R is represented
Figure imgf000098_0002
20 The compound of claim 18, wherein R6 is represented by
Figure imgf000098_0003
21. The compound of claim 18, wherein R6 is represented by
Figure imgf000098_0004
22. The compound of claim 18, wherein R6 is represented
Figure imgf000099_0001
23. The compound of claim 18, wherein R6 is represented
Figure imgf000099_0002
24. The compound of claim 18, wherein R6 is represented
Figure imgf000099_0003
25. The compound of claim 18, wherein R6 is represented
Figure imgf000099_0004
26. The compound of claim 18, wherein R6 is represented by
Figure imgf000099_0005
27. The compound of claim 18, wherein R6 is represented
Figure imgf000099_0006
28. The compound of any one of claims 19-27, wherein each occurrence of R is
independently selected from the group consisting of (C2-C6)alkyl, alkoxy, and halo.
29. The compound of claim 28, wherein R is alkyl.
30. The compound of claim 28 wherein R is alkoxy.
31. The compound of claim 28, wherein R is halo.
32. The compound of claim 31, wherein R is fluoro.
33. The compound of any one of claims 1-17, wherein R6 is phenyl substituted with two or more substituents, wherein two adjacent substituents on phenyl, taken together with the intervening atoms, form a heteroaryl, aryl, cycloalkyl, or heterocycloalkyl ring.
34. The compound of claim 33, wherein R6 is represented by
Figure imgf000100_0001
, wherein ring
Figure imgf000100_0002
represents an optionally substituted heteroaryl, aryl, cycloalkyl, or heterocycloalkyl ring.
35. The compound of claim 34, wherein
Figure imgf000100_0003
represents an optionally substituted heteroaryl ring such as thiophene.
36. The compound of claim 34, wherein
Figure imgf000100_0004
represents an optionally substituted cycloalkyl ring such as cyclohexane.
37. The compound of claim 34, wherein
Figure imgf000100_0005
represents an optionally substituted heterocycloalkyl ring such as tetrahydropyran.
38. The compound of any one of claims 1-37, wherein R7 represents H or alkyl.
39. The compound of claim 38, wherein R7 is H.
40. The compound of claim 1 or 2, having the structure of formula (la):
Figure imgf000100_0006
41. The compound of claim 1 or 2, having the structure of formula (lb):
Figure imgf000101_0001
42. The compound of claim 1 or 2, having the structure of formula (Ic):
Figure imgf000101_0002
43. The compound of claim 1 or 2, having the structure of formula (Id):
Figure imgf000101_0003
44. The compound of claim 1 or 2, having the structure of formula (Ie):
Figure imgf000101_0004
45. The compound of claim 1 or 2, having the structure of formula (If):
Figure imgf000101_0005
46. The compound of claim 1 or 2, having the structure of formula (Ig):
Figure imgf000101_0006
47. The compound of claim 1 or 2, having the structure of formula (Ih):
Figure imgf000101_0007
wherein R is a substituent selected from the group consisting of (C2-C6)alkyl, cycloalkyl, aryl, heteroaryl, halo, haloalkyl, hydroxyalkyl, alkoxy, (cycloalkyl)alkyl, and aralkyl; and n is an integer from 0 to 5.
48. The compound of claim 1 or 2, having the structure of formula (Ii):
Figure imgf000102_0001
wherein R is a substituent selected from the group consisting of (C2-C6)alkyl, cycloalkyl, aryl, heteroaryl, halo, haloalkyl, hydroxyalkyl, alkoxy, (cycloalkyl)alkyl, and aralkyl; and n is an integer from 0 to 5.
49. The compound of claim 1 or 2, having the structure of formula (Ij):
Figure imgf000102_0002
wherein R is a substituent selected from the group consisting of (C2-C6)alkyl, cycloalkyl, aryl, heteroaryl, halo, haloalkyl, hydroxyalkyl, alkoxy, (cycloalkyl)alkyl, and aralkyl; and n is an integer from 1 to 5.
50. The compound of claim 1 or 2, having the structure of formula (Ik):
Figure imgf000102_0003
wherein R is a substituent selected from the group consisting of (C2-C6)alkyl, cycloalkyl, aryl, heteroaryl, halo, haloalkyl, hydroxyalkyl, alkoxy, (cycloalkyl)alkyl, and aralkyl; and n is an integer from 0 to 5.
51. The compound of claim 1 or 2, having the structure of formula (II):
Figure imgf000103_0001
wherein R is a substituent selected from the group consisting of (C2-C6)alkyl, cycloalkyl, aryl, heteroaryl, halo, haloalkyl, hydroxyalkyl, alkoxy, (cycloalkyl)alkyl, and aralkyl; and n is an integer from 0 to 5.
52. The compound of claim 1 or 2, having the structure of formula (Im):
Figure imgf000103_0002
wherein R is a substituent selected from the group consisting of (C2-C6)alkyl, cycloalkyl, aryl, heteroaryl, halo, haloalkyl, hydroxyalkyl, alkoxy, (cycloalkyl)alkyl, and aralkyl; and n is an integer from 0 to 5.
53. The compound of claim 1 or 2, having the structure of formula (In):
Figure imgf000103_0003
wherein R is a substituent selected from the group consisting of (C2-C6)alkyl, cycloalkyl, aryl, heteroaryl, halo, haloalkyl, hydroxyalkyl, alkoxy, (cycloalkyl)alkyl, and aralkyl; and n is an integer from 0 to 5.
54. A compound, or a pharmaceutically acceptable salt thereof, selected from the
following table:
Figure imgf000103_0004
Figure imgf000104_0001
Figure imgf000105_0001
104
Figure imgf000106_0001
Figure imgf000107_0003
55. A method for treating tuberculosis, comprising administering to a subject in need thereof a therapeutically effective amount of a compound of formula (II):
Figure imgf000107_0001
or a pharmaceutically acceptable salt thereof;
wherein:
L1 is absent or is optionally substituted alkylene;
L2 is absent or is optionally substituted alkylene; ring
Figure imgf000107_0002
is optionally substituted adamantyl;
R2 is optionally substituted phenyl; and
R3 is H, alkyl, hydroxyalkyl, cycloalkyl, (cycloalkyl)alkyl, aralkyl, or heteroaralkyl.
56. The method of claim 55, wherein L1 is optionally substituted alkylene.
57. The method of claim 56, wherein L1 is optionally substituted (Ci-C2)alkylene.
58. The method of claim 57, wherein L1 is unsubstituted methylene
59. The method of claim 57, wherein L1 is unsubstituted ethylene
60. The method of claim 57, wherein L1 is methylene, substituted with alkyl
61. The method of claim 60, wherein L1 is methylene, substituted with methyl
62. The method of claim 57, wherein L1 is ethylene, substituted with alkyl
63. The method of any one of claims 55-62, wherein L2 is optionally substituted alkylene.
64. The method of claim 63, wherein L2 is optionally substituted (Ci-C2)alkylene.
65. The method of claim 64, wherein L2 is unsubstituted methylene
66. The method of claim 64, wherein L2 is unsubstituted ethylene
67. The method of claim 63, wherein L2 is methylene, substituted with alkyl
68. The method of claim 67, wherein L2 is methylene, substituted with methyl
69. The method of claim 63, wherein L2 is ethylene, substituted with alkyl.
70. The method of any one of claims 55-69, wherein ring
Figure imgf000108_0001
is optionally
substituted l-adamantyl.
71. The method of claim 70, wherein ring
Figure imgf000108_0002
is l-adamantyl, substituted with one or more substituents selected from the group consisting of alkyl, hydroxyl, hydroxyalkyl, halo, and haloalkyl.
72. The method of claim 71, wherein ring
Figure imgf000109_0001
is l-adamantyl, substituted with methyl or hydroxyl.
73. The method of claim 70, wherein ring
Figure imgf000109_0002
is unsubstituted l-adamantyl.
74. The method of any one of claims 55-69, wherein ring
Figure imgf000109_0003
is optionally
substituted 2-adamantyl.
75. The method of claim 74, wherein ring
Figure imgf000109_0004
is 2-adamantyl, substituted with one or more substituents selected from the group consisting of alkyl, hydroxyl, hydroxyalkyl, halo, and haloalkyl.
76. The method of claim 75, wherein ring
Figure imgf000109_0005
is 2-adamantyl, substituted with methyl or hydroxyl.
77. The method of claim 74, wherein ring
Figure imgf000109_0006
is unsubstituted 2-adamantyl.
78. The method of any one of claims 55-77, wherein R2 is represented by
Figure imgf000109_0007
wherein R is a substituent and n is an integer from 0 to 5.
79. The method of claim 78, wherein each R is independently selected from the group consisting of alkyl, cycloalkyl, aryl, heteroaryl, (cycloalkyl)alkyl, aralkyl, hydroxyl, hydroxyalkyl, alkoxy, halo, and haloalkyl.
80. The method of claim 78 or 79, wherein R2 is represented
Figure imgf000109_0008
81. The method of claim 78 or 79, wherein R2 is represented by
Figure imgf000110_0001
82. The method of claim 78 or 79, wherein R2 is represented by
Figure imgf000110_0002
83. The method of claim 78 or 79, wherein R2 is represented
Figure imgf000110_0003
84. The method of claim 78 or 79, wherein R2 is represented
Figure imgf000110_0004
85. The method of claim 78 or 79, wherein R2 is represented
Figure imgf000110_0005
86. The method of claim 78 or 79, wherein R2 is represented
Figure imgf000110_0006
87. The method of claim 78 or 79, wherein R2 is represented by
Figure imgf000110_0007
88. The method of claim 78 or 79, wherein R2 is represented
Figure imgf000110_0008
89. The method of any one of claims 79-88, wherein R represents alkyl, e.g., methyl.
90. The method of any one of claims 79-88, wherein R represents fluoro.
91. The method of claim 78, wherein n is 0.
92. The method of any one of claims 55-77, wherein R2 is phenyl substituted with two or more substituents, wherein two adjacent substituents on phenyl, taken together with the intervening atoms, form a heteroaryl, aryl, cycloalkyl, or heterocycloalkyl ring.
93. The method of claim 92, wherein R2 is represented by
Figure imgf000111_0001
, wherein ring
Figure imgf000111_0002
represents an optionally substituted heteroaryl, aryl, cycloalkyl, or heterocycloalkyl ring.
94. The method of claim 93, wherein
Figure imgf000111_0003
represents an optionally substituted
heteroaryl ring such as thiophene.
95. The method of claim 93, wherein
Figure imgf000111_0004
represents an optionally substituted
cycloalkyl ring such as cyclohexane.
96. The method of claim 93, wherein
Figure imgf000111_0005
represents an optionally substituted
heterocycloalkyl ring such as tetrahydropyran.
97. The method of any one of claims 55-96, wherein R3 is H.
98. The method of claim 55, wherein:
L1 is (Ci-C2)alkylene, optionally substituted with (Ci-Ce)alkyl, hydroxyl, hydroxyl(Ci-C6)alkyl, (C3-C6)cycloalkyl, phenyl, halo(Ci-C6)alkyl, (Ci-C6)alkoxyl(Ci- Ce)alkyl, -C(0)0H, or -C(0)0-(Ci-C6)alkyl;
L2 is (Ci-C2)alkylene, optionally substituted with (Ci-Ce)alkyl, hydroxyl, hydroxyl(Ci-C6)alkyl, (C3-C6)cycloalkyl, phenyl, halo(Ci-C6)alkyl, (Ci-C6)alkoxyl(Ci- Ce)alkyl, -C(0)0H, or -C(0)0-(Ci-C6)alkyl; ring
Figure imgf000111_0006
is unsubstituted adamantyl;
R2 is optionally substituted phenyl; R3 is H, alkyl, hydroxyalkyl, cycloalkyl, (cycloalkyl)alkyl, aralkyl, or heteroaralkyl; wherein when (a) L1 and L2 are both optionally substituted (Ci)alkylene, or (b) when L1 is optionally substituted (C2)alkylene and L2 is optionally substituted (Ci)alkylene, then R2 is phenyl substituted with one or more substituents, wherein the one or more substituents are selected from the group consisting of (C2-C6)alkyl, cycloalkyl, aryl, heteroaryl, halo, haloalkyl, hydroxyalkyl, alkoxy, (cycloalkyl)alkyl, and aralkyl, or wherein two adjacent substituents on phenyl, taken together with the intervening atoms, form a heteroaryl, aryl, cycloalkyl, or heterocycloalkyl ring.
99. The method of claim 55, wherein:
L1 is (Ci-C2)alkylene, optionally substituted with (Ci-Ce)alkyl, hydroxyl,
hydroxyl(Ci-C6)alkyl, (C3-C6)cycloalkyl, phenyl, halo(Ci-C6)alkyl, (Ci-C6)alkoxyl(Ci- Cejalkyl, -C(0)0H, or -C(0)0-(Ci-C6)alkyl;
L2 is (Ci-C2)alkylene, optionally substituted with (Ci-Ce)alkyl, hydroxyl,
hydroxyl(Ci-C6)alkyl, (C3-C6)cycloalkyl, phenyl, halo(Ci-C6)alkyl, (Ci-C6)alkoxyl(Ci- Cejalkyl, -C(0)0H, or -C(0)0-(Ci-C6)alkyl;
Figure imgf000112_0001
is unsubstituted adamantyl;
R2 is phenyl substituted with one or more substituents, wherein the one or more substituents are selected from the group consisting of (C2-C6)alkyl, cycloalkyl, aryl, heteroaryl, halo, haloalkyl, hydroxyalkyl, alkoxy, (cycloalkyl)alkyl, and aralkyl, or wherein two adjacent substituents on phenyl, taken together with the intervening atoms, form a heteroaryl, aryl, cycloalkyl, or heterocycloalkyl ring; and
R3 is H, alkyl, hydroxyalkyl, cycloalkyl, (cycloalkyl)alkyl, aralkyl, or heteroaralkyl.
100. The method of claim 55, wherein the compound has the structure of formula (Ha):
Figure imgf000112_0002
101. The method of claim 55, wherein the compound has the structure of formula (lib):
Figure imgf000113_0001
102. The method of claim 55, wherein the compound has the structure of formula (He):
Figure imgf000113_0002
103. The method of claim 55, wherein the compound has the structure of formula (lid):
Figure imgf000113_0003
(lid).
104. The method of claim 55, wherein the compound has the structure of formula (He):
Figure imgf000113_0004
105. The method of claim 55, wherein the compound has the structure of formula (Ilf):
Figure imgf000113_0005
106. The method of claim 55, wherein the compound has the structure of formula (Ilg):
Figure imgf000113_0006
107. The method of claim 55, wherein the compound has the structure of formula (Ilh):
Figure imgf000113_0007
wherein R is a substituent selected from the group consisting of alkyl, cycloalkyl, aryl, heteroaryl, (cycloalkyl)alkyl, aralkyl, hydroxyl, hydroxyalkyl, alkoxy, halo, and haloalkyl; and n is an integer from 0 to 5.
108. The method of claim 55, wherein the compound has the structure of formula (Hi):
Figure imgf000114_0001
wherein R is a substituent selected from the group consisting of alkyl, cycloalkyl, aryl, heteroaryl, (cycloalkyl)alkyl, aralkyl, hydroxyl, hydroxyalkyl, alkoxy, halo, and haloalkyl; and n is an integer from 0 to 5.
109. The method of claim 55, wherein the compound has the structure of formula (Ilj):
Figure imgf000114_0002
wherein R is a substituent selected from the group consisting of alkyl, cycloalkyl, aryl, heteroaryl, (cycloalkyl)alkyl, aralkyl, hydroxyl, hydroxyalkyl, alkoxy, halo, and haloalkyl; and n is an integer from 0 to 5.
110. The method of claim 55, wherein the compound has the structure of formula (Ilk):
Figure imgf000114_0003
wherein R is a substituent selected from the group consisting of alkyl, cycloalkyl, aryl, heteroaryl, (cycloalkyl)alkyl, aralkyl, hydroxyl, hydroxyalkyl, alkoxy, halo, and haloalkyl; and n is an integer from 0 to 5.
111. The method of claim 55, wherein the compound has the structure of formula (III):
Figure imgf000115_0001
wherein R is a substituent selected from the group consisting of alkyl, cycloalkyl, aryl, heteroaryl, (cycloalkyl)alkyl, aralkyl, hydroxyl, hydroxyalkyl, alkoxy, halo, and haloalkyl; and n is an integer from 0 to 5.
112. The method of claim 55, wherein the compound has the structure of formula (Ilm):
Figure imgf000115_0002
wherein R is a substituent selected from the group consisting of alkyl, cycloalkyl, aryl, heteroaryl, (cycloalkyl)alkyl, aralkyl, hydroxyl, hydroxyalkyl, alkoxy, halo, and haloalkyl; and n is an integer from 0 to 5.
113. The method of claim 55, wherein the compound has the structure of formula (Iln):
Figure imgf000115_0003
wherein R is a substituent selected from the group consisting of alkyl, cycloalkyl, aryl, heteroaryl, (cycloalkyl)alkyl, aralkyl, hydroxyl, hydroxyalkyl, alkoxy, halo, and haloalkyl; and n is an integer from 0 to 5.
114. The method of any one of claims 55-113, wherein the subject is a mammal.
115. The method of claim 114, wherein the subject is a human.
116. The method of claim 55, wherein the compound is selected from the following table:
Figure imgf000116_0001
Figure imgf000117_0001
116
Figure imgf000118_0001
117
Figure imgf000119_0001
118
Figure imgf000120_0001
119
Figure imgf000121_0003
117. A compound according to formula (X):
Figure imgf000121_0001
or a pharmaceutically acceptable salt thereof;
wherein:
X is -0-, -CH2-, or -C(R20)2-;
each R20 is independently selected from the group consisting of H and alkyl; L25 is absent or is optionally substituted alkylene; ring
Figure imgf000121_0002
is optionally adamantyl; R21 is a substituent selected from the group consisting of alkyl, cycloalkyl, aryl, heteroaryl, (cycloalkyl)alkyl, aralkyl, hydroxyl, hydroxyalkyl, alkoxy, halo, and haloalkyl; and m is an integer from 0 to 4; and
R27 is H, alkyl, hydroxyalkyl, cycloalkyl, (cycloalkyl)alkyl, aralkyl, or heteroaralkyl.
118. The compound of claim 117, wherein the compound
Figure imgf000122_0001
Figure imgf000122_0002
pharmaceutically acceptable salt thereof.
119. A method for treating tuberculosis, comprising administering to a subject in need thereof a therapeutically effective amount of a compound of claim 117 or 118.
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