WO2019013789A1 - Composés antimicrobiens - Google Patents

Composés antimicrobiens Download PDF

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Publication number
WO2019013789A1
WO2019013789A1 PCT/US2017/041790 US2017041790W WO2019013789A1 WO 2019013789 A1 WO2019013789 A1 WO 2019013789A1 US 2017041790 W US2017041790 W US 2017041790W WO 2019013789 A1 WO2019013789 A1 WO 2019013789A1
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Prior art keywords
compound
optionally substituted
formula
group
butyl
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PCT/US2017/041790
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English (en)
Inventor
Hariprasada R. Kanna REDDY
Paul R. Sebahar
Catherine M. SERRANO
Ryan E. LOOPER
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Curza Global, Llc
The University Of Utah Research Foundation
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Priority to PCT/US2017/041790 priority Critical patent/WO2019013789A1/fr
Publication of WO2019013789A1 publication Critical patent/WO2019013789A1/fr

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D239/00—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings
    • C07D239/02—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings
    • C07D239/24—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members
    • C07D239/28—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, directly attached to ring carbon atoms
    • C07D239/32—One oxygen, sulfur or nitrogen atom
    • C07D239/34—One oxygen atom
    • C07D239/36—One oxygen atom as doubly bound oxygen atom or as unsubstituted hydroxy radical
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D239/00—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings
    • C07D239/02—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings
    • C07D239/06—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having one double bond between ring members or between a ring member and a non-ring member
    • C07D239/08—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having one double bond between ring members or between a ring member and a non-ring member with hetero atoms directly attached in position 2
    • C07D239/10—Oxygen or sulfur atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D239/00—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings
    • C07D239/02—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings
    • C07D239/20—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having two double bonds between ring members or between ring members and non-ring members
    • C07D239/22—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having two double bonds between ring members or between ring members and non-ring members with hetero atoms directly attached to ring carbon atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D239/00—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings
    • C07D239/02—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings
    • C07D239/24—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members
    • C07D239/28—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, directly attached to ring carbon atoms
    • C07D239/46—Two or more oxygen, sulphur or nitrogen atoms
    • C07D239/47—One nitrogen atom and one oxygen or sulfur atom, e.g. cytosine

Definitions

  • Tuberculosis remains one of the world's leading causes of death from a single infectious agent, second only to Human Immunodeficiency Virus (HIV). About one third of the world's population is infected with latent TB, with over 9 million active TB cases and 1.3 million TB-related deaths in 2012. Recent years have seen an increase in the number of deadly strains of TB. As of 2012, extensively drug resistant TB (XDR-TB) has been reported in over 91 countries, as well as totally drug resistant strains in Italy, Iran, and India.
  • XDR-TB extensively drug resistant TB
  • TB is the most common illness among people with HIV.
  • the World Health Organization estimated that 12 million people living with HIV are co-infected with TB. It is the leading cause of death among people with HIV infection with about 320,000 HIV- associated TB deaths reported in 2012.
  • TB-HIV co-infection is aggravated by the activation of hepatic cytochromes (CYP2C9 and CYP3A4) by the current TB drugs (e.g. rifampin).
  • CYP2C9 and CYP3A4 are liver proteins that degrade drugs including the anti-retrovirals, especially HIV-protease inhibitors and NNRTls used in treating HIV. Activation of these proteins renders the plasma levels of the anti-retrovirals subtherapeutic, which concomitantly accelerates the progression of TB due to increased weakening of the immune system. Further, an ineffective regimen of TB therapeutics leads to increased resistance in organisms.
  • A is phenylene optionally substituted with one or two halo
  • Yi is selected from the group consisting of CH2 or optionally substituted phenylene
  • Ri is selected from the group consisting of H, halo, NRpRr, and heterocycloalkyl optionally substituted with NH 2 or Me; wherein Rv and Rr are each independently selected from H and Me;
  • Z 2 is absent or is selected from the group consisting of optionally substituted Ci-Cio alkylene, and optionally substituted heterocycloalkylene;
  • R 2 is selected from H, OH, NH 2 , NH(Ci -6 alkyl), N(G- 6 alkyl) 2 , NH(cycloalkyl), N(cycloalkyl) 2 .
  • Compounds of formula 1 are structurally related to amicetin, a ribosomal antibiotic isolated from Streptomyces vinaceusdrappus.
  • Amicetin is a known inhibitor of protein synthesis that is active against a number of acid-fast gram-positive bacteria including Mycobacterium tuberculosis (Mtb).
  • Amicetin exhibits an IC50 of 0.24 ⁇ (0.15 ⁇ g/mL) against Mtb H37Ra and an EC50 of 4.4 ⁇ (2.8 ⁇ g/mL) against CEM/TART T-Cell leukemia lineage, respectively, corresponding to almost 20-fold selectivity index.
  • Amicetin was also found to be a poor inducer of CYP2C9 and CYP3A4 ( ⁇ 2 fold induction as measured by qPCR in the HepG2 cell line), making it potentially compatible with ART. However, due to its chemical complexity and instability it remains a poor drug candidate. Most notably the cytosine-glycal linkage is labile and hydrolysis produces two fragments (amicetamine and cytimidine) which are not active against MTb.
  • the invention provides methods of using compounds of formula I for the treatment of bacterial infections.
  • the invention provides processes for making compounds of formula I as depicted in the synthetic schemes.
  • FIG. 1 provides IC50 curves for selected compounds of formula I compared to amicetin.
  • FIG. 2 provides protein synthesis inhibition curves for selected compounds of formula I compared to amicetin.
  • acyl as used herein includes an alkanoyl, aroyl, heterocycloyl, or heteroaroyl group as defined herein.
  • acyl groups include, but are not limited to, acetyl, benzoyl, and nicotinoyl.
  • alkanoyl as used herein includes an alkyl-C(O)- group wherein the alkyl group is as defined herein.
  • alkanoyl groups include, but are not limited to, acetyl and propanoyl.
  • agent includes a compound or mixture of compounds that, when added to a composition, tend to produce a particular effect on the composition's properties.
  • a composition comprising a thickening agent is likely to be more viscous than an otherwise identical comparative composition that lacks the thickening agent.
  • alkenyl as used herein includes a straight or branched chain
  • the chain may contain an indicated number of carbon atoms.
  • “Ci-Cn alkenyl” indicates that the group may have from 1 to 12 (inclusive) carbon atoms and at least one carbon-carbon double bond. When the indicated number of carbon atoms is 1 , then the C alkenyl is double bonded to a carbon (i.e., a carbon equivalent to an oxo group).
  • the chain includes 1 to 12, about 2 to 15, about 2 to 12, about 2 to 8, or about 2 to 6 carbon atoms.
  • An alkenyl group can be preferably one stereoisomer (i.e., cis- or, alternatively, trans-).
  • alkenyl group may include, but are not limited to, ethenyl (i.e., vinyl), allyl, propenyl, butenyl, crotyl, pentenyl, hexenyl, heptenyl, octenyl, nonenyl, decenyl, dodecenyl, cyclopentenyl, cyclohexenyl, 2-isopentenyl, allenyl, butadienyl, pentadienyl, 3-(l,4- pentadienyl), and hexadienyl.
  • ethenyl i.e., vinyl
  • propenyl i.e., butenyl
  • crotyl pentenyl
  • hexenyl hexenyl
  • heptenyl octenyl
  • octenyl nonenyl
  • decenyl dodecenyl
  • An alkenyl group can be unsubstituted or optionally substituted.
  • one or more hydrogen atoms of the alkenyl group e.g., from 1 to 4, from 1 to 2, or 1
  • the alkenyl group is unsubstituted or not optionally substituted.
  • Alkenylene as used herein includes an alkenyl group that is substituted at two points.
  • alkyl as used herein includes an aliphatic hydrocarbon chain that may be straight chain or branched.
  • the chain may contain an indicated number of carbon atoms: For example, O-Oo indicates that the group may have from 1 to 10 (inclusive) carbon atoms in it. If not otherwise indicated, an alkyl group contains from 1 to about 20 carbon atoms. In some aspects, alkyl groups have 1 to about 10 carbon atoms. In some aspects, alkyl groups (“lower alkyl”) have 1 to 8, 1 to 6, or 1 to 3 carbon atoms in the chain.
  • Examples may include, but are not limited to, methyl, ethyl, propyl, isopropyl (iPr), 1 -butyl, 2-butyl, isobutyl (iBu), tert-butyl, pentyl, 2-methylbutyl, 1 ,1-dimethylpropyl, hexyl, heptyl, octyl, nonyl, decyl, docecyl, cyclopentyl, or cyclohexyl.
  • An alkyl group can be unsubstituted or optionally substituted.
  • one or more hydrogen atoms of the alkyl group e.g., from 1 to 4, from 1 to 2, or 1 may be replaced with a moiety independently selected from the group consisting of fluoro, hydroxy, haloalkyl, alkoxy, amino, alkylamino, acylamino, thio, and alkylthio.
  • the alkyl group is unsubstituted or not optionally substituted.
  • Alkylene as used herein includes an alkyl group that is substituted at two points.
  • An example is methylene (-CH 2 -), propylene (-CH 2 CH 2 CH 2 -), and the like.
  • An alkylene group can be unsubstituted or optionally substituted.
  • one or more hydrogen atoms of the alkyl group e.g., from 1 to 4, from 1 to 2, or 1
  • the alkylene group is unsubstituted or not optionally substituted.
  • alkoxy as used herein includes a straight or branched chain saturated or unsaturated hydrocarbon containing at least one oxygen atom in an ether group (e.g., EtO-).
  • the chain may contain an indicated number of carbon atoms.
  • Ci-Ci 2 alkoxy indicates that the group may have from 1 to 12 (inclusive) carbon atoms and at least one oxygen atom.
  • Examples of a Ci-Cn alkoxy group include, but are not limited to, methoxy, ethoxy, isopropoxy, butoxy, n-pentoxy, isopentoxy, neopentoxy, and hexoxy.
  • An alkoxy group can be unsubstituted or optionally substituted.
  • one or more hydrogen atoms of the alkoxy group e.g., from 1 to 4, from 1 to 2, or 1 may be replaced with a moiety independently selected from the group consisting of fluoro, hydroxy, alkoxy, amino, alkylamino, acylamino, thio, and alkylthio, with the proviso that no hydrogen atom alpha to the ether oxygen is replaced by a hydroxy, amino, or thio group.
  • the alkoxy group is unsubstituted or not optionally substituted.
  • alkynyl as used herein includes a straight, branched, or cyclic hydrocarbon containing at least one carbon-carbon triple bond. Examples may include, but are not limited to, ethynyl, propargyl, propynyl, butynyl, pentynyl, hexynyl, heptynyl, octynyl, nonynyl, decynyl, or decynyl.
  • Alkynylene as used herein includes an alkynyl group that is substituted at two points.
  • An example is 2-butynylene (-CH 2 CCCH 2 -) and the like.
  • An alkynyl group can be unsubstituted or optionally substituted.
  • one or more hydrogen atoms of the alkynyl group e.g., from 1 to 4, from 1 to 2, or 1
  • the alkynyl group is unsubstituted or not optionally substituted.
  • aryl as used herein includes cyclic aromatic carbon ring systems containing from 6 to 18 carbons. Examples of an aryl group include, but are not limited to, phenyl, naphthyl, anthracenyl, tetracenyl, biphenyl and phenanthrenyl.
  • Arylene as used herein includes an aryl group that is substituted at two points.
  • An example is phenylene.
  • An aryl group can be unsubstituted or optionally substituted.
  • one or more hydrogen atoms of the aryl group e.g., from 1 to 5, from 1 to 2, or 1
  • the alkoxy group is unsubstituted or not optionally substituted.
  • arylalkyl or "aralkyl” as used herein includes an alkyl group as defined herein where at least one hydrogen substituent has been replaced with an aryl group as defined herein. Examples include, but are not limited to, benzyl, 1-phenylethyl, 4- methylbenzyl, and 1 , 1 , -dimethyl- 1 -phenylmethyl.
  • An arylalkyl or aralkyl group can be unsubstituted or optionally substituted as per its component groups.
  • the aryl group of an arylalkyl group can be substituted, such as in 4-methylbenzyl.
  • the group is unsubstituted or not optionally substituted, especially if including a defined substituent, such as a hydroxyalkyl or alkylaminoalkoxy group.
  • cycloalkyl as used herein includes a cyclic hydrocarbon group that may contain an indicated number of carbon atoms: For example, C3-C12 indicates that the group may have from 3 to 12 (inclusive) carbon atoms in it.
  • a cycloalkyl group includes about 3 to about 20 carbon atoms. In some aspects, cyclo alkyl groups have 3 to about 12 carbon atoms in the group. In some aspects, cycloalkyl groups have 3 to about 7 carbon atoms in the group. Examples may include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, 4,4-dimethylcyclohexyl, and cycloheptyl.
  • a cycloalkyl group can be unsubstituted or optionally substituted.
  • one or more hydrogen atoms of the cycloalkyl group e.g., from I to 4, from 1 to 2, or 1 may be replaced with a moiety independently selected from the group consisting of fluoro, hydroxy, alkoxy, amino, alkylamino, acylamino, thio, and alkylthio.
  • a substituted cycloalkyl group can incorporate an exo- or endocyclic alkene (e.g., cyclohex-2- en-l -yl).
  • a cycloalkyl group is unsubstituted or not optionally substituted.
  • disorder is a disturbance or derangement that affects the normal function of the body of a subject.
  • a disease is a pathological condition of an organ, a body part, or a system resulting from various causes, such as infection, genetic defect, or environmental stress that is characterized by an identifiable group of symptoms.
  • a disorder or disease can refer to a biofilm-related disorder or disorder caused by a planktonic bacterial phenotype that is characterized by a disease-related growth of bacteria.
  • fluoroalkyl includes an alkyl group wherein the alkyl group includes one or more fluoro- substituents. Examples include, but are not limited to, trifluoromethyl.
  • geometric substitution includes two or more substituents that are directly attached to the same atom.
  • An example is 3,3-dimethyl substitution on a cyclohexyl or spirocyclohexyl ring.
  • halo or halogen includes fluoro, chloro, bromo, or iodo.
  • heteroaryl includes mono and bicyclic aromatic groups of about 4 to about 14 ring atoms (e.g., 4 to 10 or 5 to 10 atoms) containing at least one heteroatom.
  • Heteroatom as used in the term heteroaryl refers to oxygen, sulfur and nitrogen.
  • a nitrogen atom of a heteroaryl is optionally oxidized to the corresponding N-oxide.
  • Examples include, but are not limited to, pyrazinyl, furanyl, thienyl, pyridyl, pyrimidinyl, isoxazolyl, isothiazolyl, oxazolyl, thiazolyl, pyrazolyl, furazanyl, pyrrolyl, pyrazolyl, triazolyl, 1 ,2,4- thiadiazolyl, pyrazinyl, pyridazinyl, quinoxalinyl, phthalazinyl, imidazo[l ,2-a]pyridine, imidazo[2, l -b]thiazolyl, benzofurazanyl, indolyl, azaindolyl, benzimidazolyl, benzothienyl
  • An heteroaryl group can be unsubstituted or optionally substituted.
  • one or more hydrogen atoms of the heteroaryl group e.g., from 1 to 5, from 1 to 2, or 1 may be replaced with a moiety independently selected from the group consisting of alkyl, cyano, acyl, halo, hydroxy, alkoxy, amino, alkylamino, acylamino, thio, and alkylthio.
  • the heteroaryl group is unsubstituted or not optionally substituted.
  • heteroaroyl as used herein includes a heteroaryl-C(O)- group wherein heteroaryl is as defined herein.
  • Heteroaroyl groups include, but are not limited to, thiophenoyl, nicotinoyl, pyrrol-2-ylcarbonyl, and pyridinoyl.
  • heterocycloyl as used herein includes a heterocyclyl-C(O)- group wherein heterocyclyl is as defined herein. Examples include, but are not limited to, N-methyl prolinoyl and tetrahydrofuranoyl.
  • heterocyclyl or “heterocycloalkyl” (which may be used interchangeably) includes a non-aromatic saturated monocyclic or multicyclic ring system of about 3 to about 10 ring atoms (e.g., 5 to about 10 ring atoms, or 3 to about 6 ring atoms), in which one or more of the atoms in the ring system is an element or elements other than carbon, e.g., nitrogen, oxygen or sulfur.
  • a heterocyclyl group optionally comprises at least one sp 2 -hybridized atom (e.g., a ring incorporating an carbonyl, endocyclic olefin, or exocyclic olefin).
  • a nitrogen or sulfur atom of the heterocyclyl is optionally oxidized to the corresponding N-oxide, S-oxide or S,S-dioxide.
  • monocycylic heterocyclyl rings include, but are not limited to, piperidyl, pyrrolidinyl, piperazinyl, morpholinyl, thiomorpholinyl, thiazolidinyl, 1 ,3-dioxolanyl, 1 ,4-dioxanyl, tetrahydrofuranyl, tetrahydrothiophenyl, tetrahydrothiopyranyl, azetidyl, and
  • Heterocycloalkyene as used herein includes an alkynyl group that is substituted at two points.
  • a heterocycyl group can be unsubstituted or optionally substituted.
  • one or more hydrogen atoms of the group e.g., from 1 to 4, from 1 to 2, or 1
  • one or more hydrogen atoms of the group may be replaced with a moiety independently selected from the group consisting of fluoro, hydroxy, alkoxy, amino, alkylamino, acylamino, thio, and alkylthio.
  • a substituted heterocycyl group can incorporate an exo- or endocyclic alkene (e.g., cyclohex- 2-en-l -yl).
  • the heterocycyl group is unsubstituted or not optionally substituted.
  • hydrophilic moiety or “hydrophilic group” includes a moiety or a functional group that has a strong affinity to water. Examples may include, but are not limited to, a charged moiety, such as a cationic moiety or an anionic moiety, or a polar uncharged moiety, such as an alkoxy group or an amine group.
  • hydroxyalkyl includes an alkyl group where at least one hydrogen substituent has been replaced with an alcohol (-OH) group.
  • the hydroxyalkyl group has one alcohol group.
  • the hydroxyalkyl group has one or two alcohol groups, each on a different carbon atom.
  • the hydroxyalkyl group has 1 , 2, 3, 4, 5, or 6 alcohol groups. Examples may include, but are not limited to, hydroxymethyl, 2-hydroxyeth l, and 1 -hydroxyethyl.
  • any two substituent groups or any two instances of the same substituent group are "independently selected" from a list of alternatives, the groups may be the same or different.
  • R a and R b are independently selected from the group consisting of alkyl, fluoro, amino, and hydroxyalkyl, then a molecule with two R a groups and two R b groups could have all groups be an alkyl group (e.g., four different alkyl groups).
  • the first R a could be alkyl
  • the second R a could be fluoro
  • the first R b could be hydroxyalkyl
  • the second R b could be amino (or any other substituents taken from the group).
  • both R a and the first R b could be fluoro
  • the second R b could be alkyl (i.e., some pairs of substituent groups may be the same, while other pairs may be different).
  • “Pharmaceutically acceptable acid addition salt” refers to those salts that retain the biological effectiveness of the free bases and that are not biologically or otherwise undesirable, formed with inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, and the like, as well as organic acids such as acetic acid, trifluoroacetic acid, propionic acid, glycolic acid, pyruvic acid, oxalic acid, maleic acid, malonic acid, succinic acid, fumaric acid, tartaric acid, citric acid, benzoic acid, cinnamic acid, mandelic acid, orotic acid, methanesulfonic acid, ethanesulfonic acid, p-toluenesulfonic acid, salicylic acid and the like.
  • inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, and the like
  • organic acids such as acetic acid,
  • “Pharmaceutically acceptable base addition salts” include those derived from inorganic bases such as sodium, potassium, lithium, ammonium, calcium, magnesium, iron, zinc, copper, manganese, aluminum salts and the like. Exemplary salts are the ammonium, potassium, sodium, calcium, and magnesium salts. Salts derived from pharmaceutically acceptable organic non-toxic bases include, but are not limited to, salts of primary, secondary, and tertiary amines, substituted amines including naturally occurring substituted amines, cyclic amines and basic ion exchange resins, such as isopropylamine,
  • Exemplary organic bases are isopropylamine, diethylamine,
  • compositions comprising A or B would typically present an aspect with a composition comprising both A and B, and an embodiment of "a method to disperse or kill biofilms” could disperse, kill, or a combination of both.
  • Or should, however, be construed to exclude those aspects presented that cannot be combined without contradiction (e.g., a composition pH that is between 9 and 10 or between 7 and 8).
  • spirocycloalkyl includes a cycloalkyl in which geminal substituents on a carbon atom are replaced to join in forming a 1 ,1 -substituted ring.
  • geminal substituents on a carbon atom are replaced to join in forming a 1 ,1 -substituted ring.
  • R 1 and R 2 joined to form a cyclopropyl ring incorporating the carbon to which R' and R 2 were bonded, this would be a spirocycloalkyl group (i.e., spirocyclopropyl).
  • spiroheterocyclyl includes a heterocycloalkyl in which geminal substituents on a carbon atom are replaced to join in forming a 1 , 1 -substituted ring.
  • a heterocycloalkyl in which geminal substituents on a carbon atom are replaced to join in forming a 1 , 1 -substituted ring.
  • R 1 and R 2 joined to form a pyrrolidine ring incorporating the carbon to which R 1 and R 2 were bonded, this would be a spiroheterocyclyl group.
  • molecular fragments such as and the like are bound to two other groups in either orientation. For example, unless otherwise indicated, can be bound to A and B to provide both
  • the term “treat,” “treating,” or “treatment” includes administering or applying a composition (e.g., a composition described herein) in an amount, manner ⁇ e.g., schedule of administration), and mode ⁇ e.g., route of administration) that is effective to improve a disorder or a symptom thereof, or to prevent, to retard, or to slow the progression of a disorder or a symptom thereof.
  • a composition e.g., a composition described herein
  • mode e.g., route of administration
  • Such improvements can include, but are not limited to, alleviation or amelioration of one or more symptoms or conditions, diminishment of the extent of a disease, stabilizing ⁇ i.e., not worsening) the state of disease, prevention of a disease's transmission or spread, delaying or slowing of disease progression, amelioration or palliation of the disease state, diminishment of the reoccurrence of disease, and remission, whether partial or total and whether detectable or undetectable.
  • Treating” and “treatment” as used herein also include prophylactic treatment.
  • treatment methods comprise administering to a subject a
  • the administering step may consist of a single administration or may comprise a series of administrations.
  • the length of the treatment period depends on a variety of factors, such as the severity of the condition, the age of the patient, the concentration of active agent in the composition, the activity of the compositions used in the treatment, or a combination thereof.
  • the effective dosage of an agent used for the treatment or prophylaxis may increase or decrease over the course of a particular treatment or prophylaxis regime. Changes in dosage may result and become apparent by standard diagnostic assays known in the art.
  • chronic administration may be required.
  • the compositions are administered to the subject in an amount, and for a duration, sufficient to treat the patient.
  • the invention provides a compound of formula I: or a pharmaceutically acceptable salt thereof, wherein:
  • A is phenylene optionally substituted with one or two halo
  • Yi is selected from the group consisting of CH 2 or optionally substituted phenylene
  • Ri is selected from the group consisting of H, halo, NRi -Rr, and heterocycloalkyl optionally substituted with NH 2 or Me; wherein Ri- and Rr are each independently selected from H and Me;
  • Z 2 is absent or is selected from the group consisting of optionally substituted CI-CIO alkylene, and optionally substituted heterocycloalkylene;
  • R 2 is selected from H, OH, NH 2 , NH(d- 6 alkyl), N(Ci-6 alkyl) 2 , NH(cycloalkyl), N(cycloalkyl) 2 .
  • X is absent.
  • A is phenylene substituted with one or two halo.
  • Yi is CH 2 .
  • Yi is optionally substituted aryl. In another embodiment, Yi is optionally substituted phenyl.
  • Y 2 is absent.
  • Y 2 is optionally substituted Ci-
  • Cio alkenylene wherein up to three carbon atoms are independently replaced by O, NH, N-
  • Ci-Cio alkynylene wherein up to three carbon atoms are independently replaced by O, NH,
  • Ri is H.
  • Ri is halo
  • Ri is NRi-Rr- wherein Rp and
  • Ri - are each independently selected from H and Me.
  • Ri is heterocycloalkyl optionally substituted with NH 2 or Me.
  • Zi is absent.
  • Zi is CH 2 .
  • Zi is -CH 2 0-.
  • Zi is -CH 2 NH-.
  • Zi is -CH 2 N(Ci-6 alkyl)-.
  • Z 2 is absent.
  • Z 2 is optionally substituted Ci-
  • Z 2 optionally substituted heterocycloalkyl.
  • R 2 is H.
  • R 2 is OH.
  • R 2 is NH 2 .
  • R 2 is NH(Ci-6 alkyl).
  • R 2 is N(Ci- 6 alkyl) 2 .
  • R 2 is NH(cycloalkyl).
  • R 2 is N(cycloalkyl) 2 .
  • R 2 -Z 2 -Z1 is ? wherein R2 a is selected from the group consisting of hydrogen and (Ci-C 6 alkyl) and R2b is selected from the group consisting of hydrogen, (Ci-C 6 alkyl), (C2-C6 alkenyl), aryl, and arylalkyl.
  • R2-Z2-Z1 is wherein R2a and R2b are defined as previously.
  • the compound of formula I is a compound of formula IA:
  • Yi is selected from the group consisting of CH 2 or optionally substituted phenylene
  • Ri is selected from the group consisting of H, halo, NRpRr, and heterocycloalkyl optionally substituted with NH2 or Me; wherein Rr and Rr are each independently selected from H and Me.
  • the compound of formula IA is a compound of formula
  • Yi is selected from the group consisting of CH 2 or optionally substituted phenylene
  • Ri is selected from the group consisting of H, halo, NRrRr, and heterocycloalkyl optionally substituted with NH 2 or Me; wherein Rr and Rr are each independently selected from H and Me.
  • the compound of formula IAi and thus of formula IA and thus of formula I is a compound of formula IA-1 :
  • the compound of formula IAi and thus of formula IA and thus of formula I is a compound of formula IA-2:
  • the compound of formula IA-1 and thus of formula IA and thus of formula I is a compound of formula IA-3:
  • Ri is selected from the group consisting of NRpRr, and heterocycloalkyl optionally substituted with NH 2 or Me; wherein Rr and Rr are each independently selected from H and Me.
  • Ri is halo.
  • Ri is chloro.
  • Ri is N(Me) 2 .
  • the compound of formula IA-I and thus of formula IA and thus of formula I is a compound of formula IA-4:
  • R x is H or methyl; and Ri is heterocycloalkyl.
  • the compound of formula IA-I and thus of formula IA and thus of formula I is a compound of formula IA-5:
  • R x is H or methyl
  • Ri is selected from the group consisting of H, halo, NRi Ri ', and heterocycloalkyl optionally substituted with NH 2 or Me; wherein Rr and Rr are each independently selected from H and Me.
  • Ri is NH 2 .
  • the compound of formula IA-I and thus of formula IA and thus of formula I is a compound of formula IA-6:
  • Ri is selected from the group consisting of H, halo, NRi-Rr, and heterocycloalkyl optionally substituted with NH 2 or Me; wherein Rr and Rr are each independently selected from H and Me.
  • Ri is heterocycloalkyl optionally substituted with NH 2 or Me.
  • the compound of formula IA-I and thus of formula IA and thus of formula I is a compound of formula IA-7a or IA-7b:
  • Ri is heterocycloalkyl optionally substituted with NH 2 or Me.
  • the compound of formula IA-1 and thus of formula IA and thus of formula I is a compound of formula IA-8:
  • R x is H or methyl and Ri is selected from the group consisting of H, NRpRr, and heterocycloalkyl optionally substituted with NH 2 or Me; wherein Rr and Rr are each independently selected from H and Me.
  • Ri is heterocycloalkyl optionally substituted with NH 2 or Me.
  • the compound of formula IA-I and thus of formula IA and thus of formula I is a compound of formula IA-9:
  • R x is H or methyl and Ri is selected from the group consisting of H, NRrRr, and heterocycloalkyl optionally substituted with NH 2 or Me; wherein Rr and Rr are each independently selected from H and Me.
  • Ri is heterocycloalkyl optionally substituted with NH 2 or Me.
  • the compound of formula IA-I and thus of formula IA and thus of formula I is a compound of formula IA- 10:
  • R x is H or methyl and Ri is selected from the group consisting of H, NRrRr, and heterocycloalkyl optionally substituted with NH 2 or Me; wherein Rr and Rr are each independently selected from H and Me.
  • Ri is heterocycloalkyl optionally substituted with NH2 or Me.
  • the compound of formula IA-I and thus of formula IA and thus of formula I is a compound of formula IA- 1 1 a or IA-I I B:
  • R x is H or methyl and Rj is selected from the group consisting of NRrRr, and heterocycloalkyl optionally substituted with NH 2 or Me; wherein Rr and Rr are each independently selected from H and Me.
  • Ri is heterocycloalkyl optionally substituted with NH 2 or Me.
  • the compound of formula IA-I and thus of formula IA and thus of formula I is a compound of formula IA-12:
  • Ri is selected from the group consisting of H, halo, NRrRr, and heterocycloalkyl optionally substituted with NH 2 or Me; wherein Rr and Rr are each independently selected from H and Me.
  • Ri is heterocycloalkyl optionally substituted with NH 2 or Me.
  • the compound of formula I is a compound of formula IB: harmaceutically acceptable salt thereof.
  • the phenylene ring in the compound of formula IB is optionally substituted with one or two halo selected from the group consisting of F and CI.
  • the compound of formula IB and thus of formula I is a compound of formula IB-1 or 1B-2:
  • the phenylene ring in the compound of formula IB is optionally substituted with one or two halo selected from the group consisting of F and CI. In one embodiment, when one halo group is present,
  • is selected from the group consisting of:
  • rein indicates a point of attachment.
  • the invention provides a compound which is:
  • the invention provides a compound which is:
  • the present invention provides pharmaceutical compositions comprising a compound of the present invention and a pharmaceutically acceptable excipient.
  • the compound of the present invention is provided in an effective amount in the pharmaceutical composition.
  • the effective amount is a therapeutically effective amount.
  • the effective amount is a prophylactically effective amount.
  • compositions agents include any and all solvents, diluents, or other liquid vehicles, dispersions, suspension aids, surface active agents, isotonic agents, thickening or emulsifying agents, preservatives, solid binders, lubricants and the like, as suited to the particular dosage form desired.
  • solvents diluents, or other liquid vehicles, dispersions, suspension aids, surface active agents, isotonic agents, thickening or emulsifying agents, preservatives, solid binders, lubricants and the like.
  • compositions described herein can be prepared by any method known in the art of pharmacology. In general, such preparatory methods include the steps of bringing the compound of the present invention (the "active ingredient") into association with a carrier and/or one or more other accessory ingredients, and then, if necessary and/or desirable, shaping and/or packaging the product into a desired single- or multi-dose unit.
  • compositions can be prepared, packaged, and/or sold in bulk, as a single unit dose, and/or as a plurality of single unit doses.
  • a "unit dose" is discrete amount of the pharmaceutical composition comprising a predetermined amount of the active ingredient.
  • the amount of the active ingredient is generally equal to the dosage of the active ingredient which would be administered to a subject and/or a convenient fraction of such a dosage such as, for example, one-half or one-third of such a dosage.
  • Relative amounts of the active ingredient, the pharmaceutically acceptable excipient, and/or any additional ingredients in a pharmaceutical composition of the invention will vary, depending upon the identity, size, and/or condition of the subject treated and further depending upon the route by which the composition is to be administered.
  • the composition may comprise between 0.1 % and 100% (w/w) active ingredient.
  • compositions used in the manufacture of provided pharmaceutical compositions include inert diluents, dispersing and/or granulating agents, surface active agents and/or emulsifiers, disintegrating agents, binding agents, preservatives, buffering agents, lubricating agents, and/or oils. Excipients such as cocoa butter and suppository waxes, coloring agents, coating agents, sweetening, flavoring, and perfuming agents may also be present in the composition.
  • Exemplary diluents include calcium carbonate, sodium carbonate, calcium phosphate, dicalcium phosphate, calcium sulfate, calcium hydrogen phosphate, sodium phosphate lactose, sucrose, cellulose, microcrystalline cellulose, kaolin, mannitol, sorbitol, inositol, sodium chloride, dry starch, cornstarch, powdered sugar, and mixtures thereof.
  • Exemplary granulating and/or dispersing agents include potato starch, corn starch, tapioca starch, sodium starch glycolate, clays, alginic acid, guar gum, citrus pulp, agar, bentonite, cellulose and wood products, natural sponge, cation-exchange resins, calcium carbonate, silicates, sodium carbonate, cross-linked poly(vinyl-pyrrolidone) (crospovidone), sodium carboxymethyl starch (sodium starch glycolate), carboxymethyl cellulose, cross- linked sodium carboxymethyl cellulose (croscarmellose), methylcellulose, pregelatinized starch (starch 1500), microcrystalline starch, water insoluble starch, calcium carboxymethyl cellulose, magnesium aluminum silicate (Veegum), sodium lauryl sulfate, quaternary ammonium compounds, and mixtures thereof.
  • crospovidone cross-linked poly(vinyl-pyrrolidone)
  • sodium carboxymethyl starch sodium starch glycolate
  • Exemplary surface active agents and/or emulsifiers include natural emulsifiers (e.g. acacia, agar, alginic acid, sodium alginate, tragacanth, chondrux, cholesterol, xanthan, pectin, gelatin, egg yolk, casein, wool fat, cholesterol, wax, and lecithin), colloidal clays (e.g.
  • natural emulsifiers e.g. acacia, agar, alginic acid, sodium alginate, tragacanth, chondrux, cholesterol, xanthan, pectin, gelatin, egg yolk, casein, wool fat, cholesterol, wax, and lecithin
  • colloidal clays e.g.
  • sorbitan fatty acid esters e.g. polyoxyethylene sorbitan monolaurate [Tween 20], polyoxyethylene sorbitan [Tween 60], polyoxyethylene sorbitan monooleate [Tween 80], sorbitan monopalmitate [Span 40], sorbitan monostearate [Span 60], sorbitan tristearate [Span 65], glyceryl monooleate, sorbitan monooleate [Span 80]
  • polyoxyethylene esters e.g. polyoxyethylene sorbitan monolaurate [Tween 20], polyoxyethylene sorbitan [Tween 60], polyoxyethylene sorbitan monooleate [Tween 80], sorbitan monopalmitate [Span 40], sorbitan monostearate [Span 60], sorbitan tristearate [Span 65], glyceryl monooleate, sorbitan monooleate [Span 80]
  • polyoxyethylene esters e.g.
  • polyoxyethylene monostearate [Myrj 45], polyoxyethylene hydrogenated castor oil, polyethoxylated castor oil, polyoxymethylene stearate, and Solutol), sucrose fatty acid esters, polyethylene glycol fatty acid esters (e.g. Cremophor), polyoxyethylene ethers, (e.g.
  • polyoxyethylene lauryl ether [Brij 30]), poly(vinyl-pyrrolidone), diethylene glycol monolaurate, triethanolamine oleate, sodium oleate, potassium oleate, ethyl oleate, oleic acid, ethyl laurate, sodium lauryl sulfate, Pluronic F 68, Poloxamer 188, cetrimonium bromide, cetylpyridinium chloride, benzalkonium chloride, docusate sodium, and/or mixtures thereof.
  • Exemplary binding agents include starch (e.g. cornstarch and starch paste), gelatin, sugars (e.g. sucrose, glucose, dextrose, dextrin, molasses, lactose, lactitol, mannitol, etc.), natural and synthetic gums (e.g. acacia, sodium alginate, extract of Irish moss, panwar gum, ghatti gum, mucilage of isapol husks, carboxymethylcellulose, methylcellulose,
  • starch e.g. cornstarch and starch paste
  • gelatin e.g. cornstarch and starch paste
  • sugars e.g. sucrose, glucose, dextrose, dextrin, molasses, lactose, lactitol, mannitol, etc.
  • natural and synthetic gums e.g. acacia, sodium alginate, extract of Irish moss, panwar gum, ghatti gum, mucilage
  • methylcellulose methylcellulose, microcrystalline cellulose, cellulose acetate, poly(vinyl-pyrrolidone), magnesium aluminum silicate (Veegum), and larch arabogalactan), alginates, polyethylene oxide, polyethylene glycol, inorganic calcium salts, silicic acid, polymethacrylates, waxes, water, alcohol, and/or mixtures thereof.
  • Exemplary preservatives include antioxidants, chelating agents, antimicrobial preservatives, antifungal preservatives, alcohol preservatives, acidic preservatives, and other preservatives.
  • antioxidants include alpha tocopherol, ascorbic acid, acorbyl palmitate, butylated hydroxyanisole, butylated hydroxytoluene, monothioglycerol, potassium metabisulfite, propionic acid, propyl gallate, sodium ascorbate, sodium bisulfite, sodium metabisulfite, and sodium sulfite.
  • Exemplary chelating agents include ethylenediaminetetraacetic acid (EDTA) and salts and hydrates thereof (e.g., sodium edetate, disodium edetate, trisodium edetate, calcium disodium edetate, dipotassium edetate, and the like), citric acid and salts and hydrates thereof (e.g., citric acid monohydrate), fumaric acid and salts and hydrates thereof, malic acid and salts and hydrates thereof, phosphoric acid and salts and hydrates thereof, and tartaric acid and salts and hydrates thereof.
  • EDTA ethylenediaminetetraacetic acid
  • salts and hydrates thereof e.g., sodium edetate, disodium edetate, trisodium edetate, calcium disodium edetate, dipotassium edetate, and the like
  • citric acid and salts and hydrates thereof e.g., citric acid mono
  • antimicrobial preservatives include benzalkonium chloride, benzethonium chloride, benzyl alcohol, bronopol, cetrimide, cetylpyridinium chloride, chlorhexidine, chlorobutanol, chlorocresol, chloroxylenol, cresol, ethyl alcohol, glycerin, hexetidine, imidurea, phenol, phenoxyethanol, phenylethyl alcohol, phenylmercuric nitrate, propylene glycol, and thimerosal.
  • Exemplary antifungal preservatives include butyl paraben, methyl paraben, ethyl paraben, propyl paraben, benzoic acid, hydroxybenzoic acid, potassium benzoate, potassium sorbate, sodium benzoate, sodium propionate, and sorbic acid.
  • Exemplary alcohol preservatives include ethanol, polyethylene glycol, phenol, phenolic compounds, bisphenol, chlorobutanol, hydroxybenzoate, and phenylethyl alcohol.
  • Exemplary acidic preservatives include vitamin A, vitamin C, vitamin E, beta- carotene, citric acid, acetic acid, dehydroacetic acid, ascorbic acid, sorbic acid, and phytic acid.
  • preservatives include tocopherol, tocopherol acetate, deteroxime mesylate, cetrimide, butylated hydroxyanisol (BHA), butylated hydroxytoluened (BHT),
  • the preservative is an anti-oxidant. In other embodiments, the preservative is a chelating agent.
  • Exemplary buffering agents include citrate buffer solutions, acetate buffer solutions, phosphate buffer solutions, ammonium chloride, calcium carbonate, calcium chloride, calcium citrate, calcium glubionate, calcium gluceptate, calcium gluconate, D-gluconic acid, calcium glycerophosphate, calcium lactate, propanoic acid, calcium levulinate, pentanoic acid, dibasic calcium phosphate, phosphoric acid, tribasic calcium phosphate, calcium hydroxide phosphate, potassium acetate, potassium chloride, potassium gluconate, potassium mixtures, dibasic potassium phosphate, monobasic potassium phosphate, potassium phosphate mixtures, sodium acetate, sodium bicarbonate, sodium chloride, sodium citrate, sodium lactate, dibasic sodium phosphate, monobasic sodium phosphate, sodium phosphate mixtures, tromethamine, magnesium hydroxide, aluminum hydroxide, alginic acid, pyrogen- free water, isotonic saline
  • Exemplary lubricating agents include magnesium stearate, calcium stearate, stearic acid, silica, talc, malt, glyceryl behanate, hydrogenated vegetable oils, polyethylene glycol, sodium benzoate, sodium acetate, sodium chloride, leucine, magnesium lauryl sulfate, sodium lauryl sulfate, and mixtures thereof.
  • Exemplary natural oils include almond, apricot kernel, avocado, babassu, bergamot, black current seed, borage, cade, camomile, canola, caraway, carnauba, castor, cinnamon, cocoa butter, coconut, cod liver, coffee, corn, cotton seed, emu, eucalyptus, evening primrose, fish, flaxseed, geraniol, gourd, grape seed, hazel nut, hyssop, isopropyl myristate, jojoba, kukui nut, lavandin, lavender, lemon, litsea cubeba, macademia nut, mallow, mango seed, meadowfoam seed, mink, nutmeg, olive, orange, orange roughy, palm, palm kernel, peach kernel, peanut, poppy seed, pumpkin seed, rapeseed, rice bran, rosemary, safflower, sandalwood, sasquana, savoury, sea
  • Exemplary synthetic oils include, but are not limited to, butyl stearate, caprylic triglyceride, capric triglyceride, cyclomethicone, diethyl sebacate, dimethicone 360, isopropyl myristate, mineral oil, octyldodecanol, oleyl alcohol, silicone oil, and mixtures thereof.
  • Liquid dosage forms for oral and parenteral administration include pharmaceutically acceptable emulsions, microemulsions, solutions, suspensions, syrups and elixirs.
  • the liquid dosage forms may comprise inert diluents commonly used in the art such as, for example, water or other solvents, solubilizing agents and emulsifiers such as ethyl alcohol, isopropyl alcohol, ethyl carbonate, ethyl acetate, benzyl alcohol, benzyl benzoate, propylene glycol, 1 ,3-butylene glycol, dimethylformamide, oils (e.g., cottonseed, groundnut, corn, germ, olive, castor, and sesame oils), glycerol, tetrahydrofurfuryl alcohol, polyethylene glycols and fatty acid esters of sorbitan, and mixtures thereof.
  • inert diluents commonly used in the art such as, for example, water or other solvents
  • the oral compositions can include adjuvants such as wetting agents, emulsifying and suspending agents, sweetening, flavoring, and perfuming agents.
  • adjuvants such as wetting agents, emulsifying and suspending agents, sweetening, flavoring, and perfuming agents.
  • the conjugates of the invention are mixed with solubilizing agents such as Cremophor, alcohols, oils, modified oils, glycols, polysorbates, cyclodextrins, polymers, and mixtures thereof.
  • Injectable preparations for example, sterile injectable aqueous or oleaginous suspensions can be formulated according to the known art using suitable dispersing or wetting agents and suspending agents.
  • the sterile injectable preparation can be a sterile injectable solution, suspension or emulsion in a nontoxic parenterally acceptable diluent or solvent, for example, as a solution in 1 ,3-butanediol.
  • acceptable vehicles and solvents that can be employed are water, Ringer's solution, U.S. P. and isotonic sodium chloride solution.
  • sterile, fixed oils are conventionally employed as a solvent or suspending medium.
  • any bland fixed oil can be employed including synthetic mono- or diglycerides.
  • fatty acids such as oleic acid are used in the preparation of injectables.
  • the injectable formulations can be sterilized, for example, by filtration through a bacterial-retaining filter, or by incorporating sterilizing agents in the form of sterile solid compositions which can be dissolved or dispersed in sterile water or other sterile injectable medium prior to use.
  • a sterile injectable composition e.g., a sterile injectable aqueous or oleaginous suspension
  • a sterile injectable preparation can be formulated according to techniques known in the art using suitable dispersing or wetting agents (such as Tween 80) and suspending agents.
  • the sterile injectable preparation can also be a sterile injectable solution or suspension in a non-toxic parenterally acceptable diluent or solvent, for example, as a solution in 1 ,3-butanediol.
  • suitable vehicles and solvents that can be employed are mannitol, water, Ringer's solution and isotonic sodium chloride solution.
  • sterile, fixed oils are conventionally employed as a solvent or suspending medium (e.g., synthetic mono- or diglycerides).
  • Fatty acids such as oleic acid and its glyceride derivatives are useful in the preparation of injectables, as are natural pharmaceutically-acceptable oils, such as olive oil or castor oil, especially in their polyoxyethylated versions.
  • These oil solutions or suspensions can also contain a long-chain alcohol diluent or dispersant, or carboxymethyl cellulose or similar dispersing agents.
  • Other commonly used surfactants such as Tweens or Spans or other similar emulsifying agents or bioavailability enhancers which are commonly used in the manufacture of pharmaceutically acceptable solid, liquid, or other dosage forms can also be used for the purposes of formulation.
  • compositions for rectal or vaginal administration are typically suppositories which can be prepared by mixing the conjugates of this invention with suitable non-irritating excipients or carriers such as cocoa butter, polyethylene glycol or a suppository wax which are solid at ambient temperature but liquid at body temperature and therefore melt in the rectum or vaginal cavity and release the active ingredient.
  • suitable non-irritating excipients or carriers such as cocoa butter, polyethylene glycol or a suppository wax which are solid at ambient temperature but liquid at body temperature and therefore melt in the rectum or vaginal cavity and release the active ingredient.
  • Solid dosage forms for oral administration include capsules, tablets, pills, powders, and granules.
  • the active ingredient is mixed with at least one inert, pharmaceutically acceptable excipient or carrier such as sodium citrate or dicalcium phosphate and/or a) fillers or extenders such as starches, lactose, sucrose, glucose, mannitol, and silicic acid, b) binders such as, for example, carboxymethylcellulose, alginates, gelatin, polyvinylpyrrolidinone, sucrose, and acacia, c) humectants such as glycerol, d) disintegrating agents such as agar, calcium carbonate, potato or tapioca starch, alginic acid, certain silicates, and sodium carbonate, e) solution retarding agents such as paraffin, absorption accelerators such as quaternary ammonium compounds, g) wetting agents such as, for example, cetyl alcohol and glycerol
  • Solid compositions of a similar type can be employed as fillers in soft and hard- filled gelatin capsules using such excipients as lactose or milk sugar as well as high molecular weight polyethylene glycols and the like.
  • the solid dosage forms of tablets, dragees, capsules, pills, and granules can be prepared with coatings and shells such as enteric coatings and other coatings well known in the pharmaceutical formulating art. They may optionally comprise opacifying agents and can be of a composition that they release the active ingredient(s) only, or preferentially, in a certain part of the intestinal tract, optionally, in a delayed manner
  • Examples of embedding compositions which can be used include polymeric substances and waxes.
  • Solid compositions of a similar type can be employed as fillers in soft and hard-filled gelatin capsules using such excipients as lactose or milk sugar as well as high molecular weight polyethylene glycols and the like.
  • the active ingredient can be in micro-encapsulated form with one or more excipients as noted above.
  • the solid dosage forms of tablets, dragees, capsules, pills, and granules can be prepared with coatings and shells such as enteric coatings, release controlling coatings and other coatings well known in the pharmaceutical formulating art.
  • the active ingredient can be admixed with at least one inert diluent such as sucrose, lactose or starch.
  • Such dosage forms may comprise, as is normal practice, additional substances other than inert diluents, e.g., tableting lubricants and other tableting aids such a magnesium stearate and microcrystalline cellulose.
  • the dosage forms may comprise buffering agents. They may optionally comprise opacifying agents and can be of a composition that they release the active ingredient(s) only, or preferentially, in a certain part of the intestinal tract, optionally, in a delayed manner
  • opacifying agents include polymeric substances and waxes.
  • Dosage forms for topical and/or transdermal administration of a compound of this invention may include ointments, pastes, creams, lotions, gels, powders, solutions, sprays, inhalants and/or patches.
  • the active ingredient is admixed under sterile conditions with a pharmaceutically acceptable carrier and/or any needed preservatives and/or buffers as can be required.
  • the present invention contemplates the use of transdermal patches, which often have the added advantage of providing controlled delivery of an active ingredient to the body.
  • Such dosage forms can be prepared, for example, by dissolving and/or dispensing the active ingredient in the proper medium.
  • the rate can be controlled by either providing a rate controlling membrane and/or by dispersing the active ingredient in a polymer matrix and/or gel.
  • Suitable devices for use in delivering intradermal pharmaceutical compositions described herein include short needle devices such as those described in U.S. Pat. Nos.
  • Intradermal compositions can be administered by devices which limit the effective penetration length of a needle into the skin, such as those described in PCT publication WO 99/34850 and functional equivalents thereof. Jet injection devices which deliver liquid vaccines to the dermis via a liquid jet injector and/or via a needle which pierces the stratum corneum and produces a jet which reaches the dermis are suitable. Jet injection devices are described, for example, in U.S. Pat. Nos. 5,480,381 ; 5,599,302; 5,334, 144; 5,993,412;
  • Ballistic powder/particle delivery devices which use compressed gas to accelerate vaccine in powder form through the outer layers of the skin to the dermis are suitable.
  • conventional syringes can be used in the classical mantoux method of intradermal administration.
  • a pharmaceutical composition of the invention can be prepared, packaged, and/or sold in a formulation suitable for pulmonary administration via the buccal cavity.
  • a formulation may comprise dry particles which comprise the active ingredient and which have a diameter in the range from about 0.5 to about 7 nanometers or from about 1 to about 6 nanometers.
  • Such compositions are conveniently in the form of dry powders for
  • a device comprising a dry powder reservoir to which a stream of propellant can be directed to disperse the powder and/or using a self-propelling
  • solvent/powder dispensing container such as a device comprising the active ingredient dissolved and/or suspended in a low-boiling propellant in a sealed container.
  • Such powders comprise particles wherein at least 98% of the particles by weight have a diameter greater than 0.5 nanometers and at least 95% of the particles by number have a diameter less than 7 nanometers. Alternatively, at least 95% of the particles by weight have a diameter greater than 1 nanometer and at least 90% of the particles by number have a diameter less than 6 nanometers.
  • Dry powder compositions may include a solid fine powder diluent such as sugar and are conveniently provided in a unit dose form.
  • Low boiling propellants generally include liquid propellants having a boiling point of below 65 °F at atmospheric pressure.
  • the propellant may constitute 50 to 99.9% (w/w) of the composition, and the active ingredient may constitute 0.1 to 20% (w/w) of the composition.
  • the propellant may further comprise additional ingredients such as a liquid non-ionic and/or solid anionic surfactant and/or a solid diluent (which may have a particle size of the same order as particles comprising the active ingredient).
  • compositions of the invention formulated for pulmonary delivery may provide the active ingredient in the form of droplets of a solution and/or suspension.
  • Such formulations can be prepared, packaged, and/or sold as aqueous and/or dilute alcoholic solutions and/or suspensions, optionally sterile, comprising the active ingredient, and may conveniently be administered using any nebulization and/or atomization device.
  • Such formulations may further comprise one or more additional ingredients including, but not limited to, a flavoring agent such as saccharin sodium, a volatile oil, a buffering agent, a surface active agent, and/or a preservative such as methylhydroxybenzoate.
  • the droplets provided by this route of administration may have an average diameter in the range from about 0.1 to about 200 nanometers.
  • Formulations described herein as being useful for pulmonary delivery are useful for intranasal delivery of a pharmaceutical composition of the invention.
  • Another formulation suitable for intranasal administration is a coarse powder comprising the active ingredient and having an average particle from about 0.2 to 500 micrometers. Such a formulation is administered by rapid inhalation through the nasal passage from a container of the powder held close to the nares.
  • Formulations for nasal administration may, for example, comprise from about as little as 0.1% (w/w) and as much as 100% (w/w) of the active ingredient, and may comprise one or more of the additional ingredients described herein.
  • a pharmaceutical composition of the invention can be prepared, packaged, and/or sold in a formulation for buccal
  • formulations may, for example, be in the form of tablets and/or lozenges made using conventional methods, and may contain, for example, 0.1 to 20% (w/w) active ingredient, the balance comprising an orally dissolvable and/or degradable composition and, optionally, one or more of the additional ingredients described herein.
  • formulations for buccal administration may comprise a powder and/or an aerosolized and/or atomized solution and/or suspension comprising the active ingredient.
  • Such powdered, aerosolized, and/or aerosolized formulations when dispersed, may have an average particle and/or droplet size in the range from about 0.1 to about 200 nanometers, and may further comprise one or more of the additional ingredients described herein.
  • compositions are principally directed to pharmaceutical compositions which are suitable for administration to humans, it will be understood by the skilled artisan that such compositions are generally suitable for administration to animals of all sorts. Modification of pharmaceutical compositions suitable for administration to humans in order to render the compositions suitable for administration to various animals is well understood, and the ordinarily skilled veterinary pharmacologist can design and/or perform such modification with ordinary experimentation.
  • compositions of the present invention are typically formulated in dosage unit form for ease of administration and uniformity of dosage. It will be understood, however, that the total daily usage of the compositions of the present invention will be decided by the attending physician within the scope of sound medical judgment.
  • the specific therapeutically effective dose level for any particular subject or organism will depend upon a variety of factors including the disease, disorder, or condition being treated and the severity of the disorder; the activity of the specific active ingredient employed; the specific composition employed; the age, body weight, general health, sex and diet of the subject; the time of administration, route of administration, and rate of excretion of the specific active ingredient employed; the duration of the treatment; drugs used in combination or coincidental with the specific active ingredient employed; and like factors well known in the medical arts.
  • the above-described compound or its pharmaceutical composition can be administered orally, parenterally, by inhalation spray, topically, rectally, nasally, buccally, vaginally, rectally, or via an implanted reservoir.
  • parenteral as used herein includes subcutaneous, intracutaneous, intravenous, intramuscular, intraarticular, intraarterial, intrasynovial, intrasternal, intrathecal, intralesional, and intracranial injection or infusion techniques.
  • the most appropriate route of administration will depend upon a variety of factors including the nature of the agent (e.g., its stability in the environment of the gastrointestinal tract), and/or the condition of the subject (e.g., whether the subject is able to tolerate oral administration).
  • the exact amount of a compound required to achieve an effective amount will vary from subject to subject, depending, for example, on species, age, and general condition of a subject, severity of the side effects or disorder, identity of the particular compound(s), mode of administration, and the like.
  • the desired dosage can be delivered three times a day, two times a day, once a day, every other day, every third day, every week, every two weeks, every three weeks, or every four weeks.
  • the desired dosage can be delivered using multiple administrations (e.g., two, three, four, five, six, seven, eight, nine, ten, eleven, twelve, thirteen, fourteen, or more administrations).
  • an effective amount of a compound for administration one or more times a day to a 70 kg adult human may comprise about 0.0001 mg to about 3000 mg, about 0.0001 mg to about 2000 mg, about 0.0001 mg to about 1000 mg, about 0.001 mg to about 1000 mg, about 0.01 mg to about 1000 mg, about 0.1 mg to about 1000 mg, about 1 mg to about 1000 mg, about 1 mg to about 100 mg, about 10 mg to about 1000 mg, or about 100 mg to about 1000 mg, of a compound per unit dosage form.
  • the compounds of the invention may be administered orally or parenterally at dosage levels sufficient to deliver from about 0.001 mg/kg to about 100 mg kg, from about 0.01 mg/kg to about 50 mg/kg, preferably from about 0.1 mg/kg to about 40 mg/kg, preferably from about 0.5 mg/kg to about 30 mg/kg, from about 0.01 mg/kg to about 10 mg/kg, from about 0.1 mg/kg to about 10 mg/kg, and more preferably from about 1 mg/kg to about 25 mg/kg, of subject body weight per day, one or more times a day, to obtain the desired therapeutic effect.
  • dose ranges as described herein provide guidance for the administration of provided pharmaceutical compositions to an adult.
  • the amount to be administered to, for example, a child or an adolescent can be determined by a medical practitioner or person skilled in the art and can be lower or the same as that administered to an adult.
  • a compound or composition, as described herein can be administered in combination with one or more additional therapeutically active agents.
  • the compounds or compositions can be administered in combination with additional therapeutically active agents that improve their bioavailability, reduce and/or modify their metabolism, inhibit their excretion, and/or modify their distribution within the body.
  • the therapy employed may achieve a desired effect for the same disorder, and/or it may achieve different effects.
  • the compound or composition can be administered concurrently with, prior to, or subsequent to, one or more additional therapeutically active agents.
  • each agent will be administered at a dose and/or on a time schedule determined for that agent.
  • the additional therapeutically active agent utilized in this combination can be administered together in a single composition or administered separately in different compositions.
  • the particular combination to employ in a regimen will take into account compatibility of the inventive compound with the additional therapeutically active agent and/or the desired therapeutic effect to be achieved.
  • additional therapeutically active agents utilized in combination be utilized at levels that do not exceed the levels at which they are utilized individually. In some embodiments, the levels utilized in combination will be lower than those utilized individually.
  • antibiotic agents e.g., antibiotics useful for treating tuberculosis.
  • antibiotics include, but are not limited to, isoniazid, rifampin, pyrazinamide, ethambutol, and streptomycin.
  • kits e.g., pharmaceutical packs
  • the kits provided may comprise an inventive pharmaceutical composition or compound and a container (e.g., a vial, ampule, bottle, syringe, and/or dispenser package, or other suitable container).
  • a container e.g., a vial, ampule, bottle, syringe, and/or dispenser package, or other suitable container.
  • provided kits may optionally further include a second container comprising a pharmaceutical excipient for dilution or suspension of an inventive pharmaceutical composition or compound.
  • the inventive kits may optionally further include a second container comprising a pharmaceutical excipient for dilution or suspension of an inventive pharmaceutical composition or compound.
  • compositions or compound provided in the container and the second container are combined to form one unit dosage form.
  • the invention provides a method of treating a bacterial infection in a patient in need of such treatment, comprising administering an effective amount of a compound of formula I or a composition comprising a compound of formula I.
  • the effective amount is a therapeutically effective amount.
  • the effective amount is a prophylactically effective amount.
  • the bacterial infection is tuberculosis.
  • the tuberculosis infection is a Mycobacterium tuberculosis infection.
  • the tuberculosis infection is multi-drug-resistant tuberculosis (MDR-TB) infection, e.g., resistant to first-line TB drugs rifampicin and/or isoniazid.
  • MDR-TB multi-drug-resistant tuberculosis
  • XDR-TB extensively-drug-resistant tuberculosis
  • the compounds of the invention can be active against a wide range of both Gram-positive and Gram-negative organisms.
  • the compounds of the invention can be used to treat infections and to inhibit microbial growth.
  • the compounds of the invention can be used to treat humans and animals having a broad spectrum of bacterial infections such as impetigo, pneumonia, bronchitis, pharyngitis, endocarditis, urinary tract infections, diabetes foot ulcers, gastro-intestinal infections and bacteremia.
  • bacterial infections could be caused by any of the following bacteria-Staphylococcus aureus, coagulase negative staphylococci, methicillin-resistant Staphylococcus aureus, methicillin-resistant coagulase negative staphylococci, enterococci, beta-haemolytic streptococci, viridans group of streptococci, Bacillus mycobacterial infections due to multi-drug resistant M. tuberculosis and other atypical mycobacteria such as M. intracellulare and M.
  • Gram-negative pathogens such as Chryseobacterium meningosepticum, Chryseobacterium indologense and other Gram- negative pathogens such as E. coli, Klebsiella, Proteus, Serratia, Citrobacter, Pseudomonas, Burkholderia, Brucella, Yersinia, Francisella, Coxiella, Chlamydia, Salmonella, Rickettsia, Shigella and Campylobacter.
  • Gram-negative pathogens such as Chryseobacterium meningosepticum, Chryseobacterium indologense and other Gram- negative pathogens such as E. coli, Klebsiella, Proteus, Serratia, Citrobacter, Pseudomonas, Burkholderia, Brucella, Yersinia, Francisella, Coxiella, Chlamydia, Salmonella, Rickettsia, Shig
  • the invention provides processes for preparing compounds of formula I.
  • the process is depicted in the synthetic schemes in the following section.
  • Triethylamine (Et 3 N) and N,N-diisopropylethylamine (DIPEA) were stored over 4 A molecular sieves or distilled over 4 A molecular sieves prior to usage. Microwave reactions were done in CEM Discover System Model 908005.
  • Reactions were monitored by TLC and visualized by a dual short wave/long wave UV lamp and stained with ethanolic solutions of either KMn0 4 or 12-phosphomolybdic acid. Flash chromatography was performed on Merck silica gel ieselgel 60 (230-400 mesh) from EM Science with the indicated HPLC grade solvent. Reverse phase HPLC was conducted on a Gilson 322 using a Vydac CI 8 column eluting with H 2 0 (0.1 % TFA) and 10%H 2 O:90 CH3CN (0.1 % TFA).
  • Melting points were determined using Mel-Temp® Capillary Melting Point Apparatus. Infrared spectra were obtained using Nicoiet 380-FT IR spectrometer fitted with a Smart Orbit sample system. Optical rotations were obtained at ambient temperature on a Perkin Elmer Model 343 polarimeter (Na D line) using a microcell with a 1 decimeter path length.
  • Mass spectra were determined on a Micromass Quattro II (ESI/APCI-TOF) for HRMS at the University of Utah Mass Spectrometry Facility or LCMS were collected on Thermo ScientificTM UltiMateTM 3000 UHPLC with electrochemical detector with a fluorescence detector monitored at either 214 or 254 nm.
  • l H NMR spectra were recorded at 500 MHz, 400 MHz, and 300 MHz, and 13 C at 125 MHz.
  • Example 1 was prepared according to Synthetic Scheme 1 .
  • Reagents Step 1) Cs 2 C0 3 , Nal (cat.), CH 3 CN, reflux, 2h (2) K 2 C0 3 , CH 3 CN,70 °C, 2h (3)
  • Step 1 4-Amino-l-(2-f2-f2-chIoroethoxy)ethoxy)ethyl)pyrimidin-2(lH)-one
  • Step 2 4-Amino-l-(2-r2-(dimethylamino)ethoxy)ethyl)pyrimidin-2(lH)-one
  • Step 3 f2 ⁇ ,4 ⁇ -/gr Butyl-2-(/gr ⁇ butvn-4-(f4-ffl-(2-f2-fdimethylamino)ethoxy)ethyl)-2- oxo-l ⁇ 2-dihvdropyrimidin-4-vncarbamovhphenvncarbamoyl)-4-methyloxazolidine-3- carboxylate
  • the reaction mixture was concentrated under reduced pressure, dissolved in water, and washed with ether (2x2 mL) to remove the organic impurities.
  • the aqueous layer was basified with NaHCCh to pH 10 and was extracted with dichloromethane (2x4 mL), dried over anhydrous Na 2 S04, filtered, and concentrated under reduced pressure, to leave a residue.
  • the residue was stirred in 30% TFA in dichloromethane for 0.5h, the solvent was evaporated, and the remaining solid was triturated with diethyl ether.
  • Example 2 was prepared in a similar fashion to Example 1 from (2/?,4,/?)-/er/-butyl- 2-(/e ⁇ /-butyl)-4-((4-(methoxycarbonyl)phenyl)carbamoyl)-4-methyloxazolidine-3- carboxylate and 4-amino-l -(2-(2-(dimethylamino)ethoxy)ethyl)pyrimidin-2( l H)-one to afford the desired product as a yellow solid.
  • Example 3 was prepared in a similar fashion to Example 1 from (27?,4 ?)-1 ⁇ 2r/-butyl- 2-(teri-butyl)-4-((4-(methoxycarbonyl)phenyl)carbamoyl)-4-methyloxazolidine-3- carboxylate and 4-Amino-l-(2-(2-(chloro)ethoxy)ethyl)pyrimidin-2(l H)-one as a white solid.
  • Example 4 was prepared in a similar fashion to Example 1 from (2 ?,4/?)-/e /-butyl- 2-(ier/-butyl)-4-((4-(methoxycarbonyl)phenyl)carbamoyl)-4-methyloxazolidine-3- carboxylate and 4-amino-l -(2-(2-chloroethoxy)ethyl)pyrimidin-2( l H)-one to afford the desired product as a white solid ⁇ NMR (400 MHz, D 2 0) ⁇ ppm 8.04 (d, I H), 7.91 (d, 2H), 7.66 (d, 2H), 7.44 (d, I H), 4.18 (d, I H), 4.12 (br s, 2H), 3.96 (d, I H), 3.89 (br s, 2H), 3.80 (br s, 2H), 3.69 (br s, 2H), 1.72 (s, 3H).
  • Example S Example S
  • Example 5 was prepared in a similar fashion to Example 1 from (2R,4R)-tert-buty ⁇ - 2-(/er/-buty l)-4-((4-(methoxycarbony l)pheny l)carbamoyl)-4-methy loxazol idine-3 - carboxylate and 4-amino-l -(2-(2-dimethylamino)ethyl)pyrimidin-2(l H)-one to afford the desired product as a white solid.
  • Example 6 was prepared according to Synthetic Scheme 2.
  • Reagents Step 1) NaH, THF, 0 °C to 50 °C, 16h (2) C0 2 CI 2 , Et 3 N, CH 2 CI 2 , 0 °C to rt, 0.5h then, KHMDS in toluene, 0 °C to 50 °C (3) K 2 C0 3 , Cul (Cat ), N.N'-dimethylethylenediamine (Cat ). 1 ,4-dioxane, 110 °C, 24 h (4) 10% Pd/C, H 2 , MeOH, rt, 20min
  • Step 1 2-( " Benzyloxy)pyrimidiii-4-aiiiine
  • Benzyl alcohol (4.0 mL, 39.0 mmol) was added drop wise to a stirring mixture of NaH (0.36 g, 1 5.0 mmol) in dry THF (12 mL) at 0 °C, under nitrogen atmosphere. The mixture was stirred for another 30 minutes until it forms a clear solution followed by the addition of 4-Amino-2-chloropyrimidine (0.33 g, 2.55 mmol) at 0 °C and then heated at 80 °C for 12 h. The reaction mixture was concentrated under reduced pressure. The crude mixture was purified using column chromatography (60% EtOAc/Hexanes) to afford the desired product as a white solid. M.P. 76-78 °C (lit.
  • KHMDS 0.5M solution in toluene (5.95 mL, 2.98 mmol)
  • 2-(benzyloxy)pyrimidin-4-amine 0.50 g, 2.48 mmol
  • toluene 15 mL
  • 4- iodobenzoic acid 1.85 g, 7.44 mmol
  • CH 2 CI 20 mL
  • oxalylchloride 0.65 mL, 5.16 mmol
  • Step 4 (2RAS)-tert- ut ⁇ -2Atert >u ⁇ )-A-meth ⁇ (4-((2-o ⁇
  • Step 5 (2R ⁇ 4-y)-fert-Butyl-2-(fe/-r-burvn-4-methyl-4-f(4-((2-oxo-l-(prop-2-vn-l-vn-l,2- dihvdropyri-midin-4-vncarbaniovnphenvncarbamoyl)oxazolidine-3-carboxylate:
  • Example 7 was prepared in a similar fashion to Example 1 from (2 ?,45)- eri-butyl- 2-(/e/"/-butyl)-4-methyl-4-((4-((2-oxo- l ,2-dihydropyrimidin-4-yl)carbamoyl) phenyl) carba- moyl)oxazolidine-3-carboxylate and methyl iodide to afford the desired product as a white solid.
  • Example 8 was prepared according to Synthetic Scheme 3.
  • Reagents Step 1) Cu(OAc) 2 , (HCHO)n, 1.4-dioxane, 80 °C, W, 200W, 20Min (2) 30% TFA in CH 2 CI 2 . rt. 12h
  • Step 1 (2RAS)-fert- ut ⁇ l 2-(/g/-/-butvn-4-g4-((l- 4-((2- fdimethylamino)ethyl methyl)amino)but-2-vn-l-vn-2-oxo-1.2-dihvdropyrimidin-4- vncarbamov0phenyl)carbamoyl)-4-methyloxazolidine-3-carboxylate:
  • Step 2 (.in-4-(2-Amino-3-hvdroxy-2-methylpropanamido)-N-(l-(4-((2-(dimethylaniino) ethyl) (methyl) amino)but-2-vn-l-vn-2-oxo-l,2-dihvdropyrimidin-4-vnbenzamide trifluoroacetate salt:
  • the aqueous layer was basified with NaHC03 to pH 10 and the compound was extracted with dichloromethane (2 X 4 mL), dried over anhydrous Na 2 S04, filtered, and concentrated under reduced pressure. The residue was stirred in 30% TFA in dichloromethane for 0.5h, and then the solvent was evaporated and triturated with diethyl ether.
  • Example 9 was prepared in a similar fashion to Example 5 from 4-amino-l-(prop-2- yn-l -yl)pyrimidin-2(l H)-one, paraformaldehyde and N l , l ,N2-trimethylethane-l ,2-diamine to afford the desired product as a brick red solid.
  • Example 10 was prepared in a similar fashion to Example 5 from 4-nitro-N-(2-oxo- l ,2-dihydropyrimidin-4-yl)benzamide, paraformaldehyde and l ,N l ,N2-trimethylethane- 1,2-diamine to afford the desired product as a brick red solid.
  • Example 1 1 was prepared in a similar fashion to Example 5 from (2R,4S)-teri-b ty ⁇ - 2-(terf-butyl)-4-methyl-4-((4-((2-oxo- 1 ,2-dihydropyrimidin-4-yl) carba-moyl)
  • Example 12 was prepared in a similar fashion to Example 5 from (2/?,45)-/er/-butyl- 2-(tert-butyl)-4-methyl-4-((4-((2-oxo-l ,2-dihydropyrimidin-4-yl) carbamoyl)
  • Example 13 was prepared as provided in Synthetic Scheme 4. 7 041790
  • Reagents Step 1) Ethylchloroformate. N-Methylmorpholine, THF:DMF (5:1 ), -20 °C to rt, 12 h (2) CH 3 CN, Cs 2 C0 3 , reflux. 2h (3) EDC CI, HOBt, Et 3 N, CH 2 CI 2 , rt, 24h (4) 30% TFA in CH 2 CI 2 , rt, 12h.
  • Step 1 fert-Butyl (R)-2-((3-bromopropyl)carbamovnpyrrolidine-l-carboxylate:
  • Step 3 fert-Butyl (2R ⁇ 4S)-4-(r4-((l-(3-((S)-l-(/g ⁇ -butoxycarbonvnpyrrolidine-2- carboxamido) propyn-2-oxo-l,2-dihYdropyrimidin-4-vncarbamovnphenyl)carbamovn- 2-(/g/ , ?-butyl)-4-methyloxazolidine-3-carboxylate;
  • Step 4 (S)- V-(3-(4-(4-((S -2-Amino-3-hvdroxy-2-methylpropanamido)benzaniido)-2-oxo pyrimidin-l(2H)-v0propyl)pyrrolidine-2-carboxamide trifluoroacetate salt;
  • reaction mixture was concentrated under reduced pressure, dissolved in water washed with ether (2 X 2 mL) to remove the organic impurities.
  • ether 2 X 2 mL
  • the aqueous layer was basified with NaHC0 to pH 10 and the compound was extracted with dichloromethane (2 X 4 mL) dried over anhydrous Na 2 S0 4 , filtered and concentrated under reduced pressure.
  • the residue was stirred in 30% TFA in dichloromethane for 0.5h.
  • Example 14 was prepared in a similar fashion to Example 13 from Q.R, S)-tert- butyl-2-(iert-butyl)-4-methyl-4-((4-((2-oxo- 1 ,2-dihydropyrimidin-4-yl) carba-moyl) phenyl)carbamoyl) oxazolidine-3-carboxylate, and 4-((27?,45)-3-(ierr-butoxycarbonyl)-2- (1 ⁇ 2ri-butyl)-4-methyloxazo-lidine-4-carboxamido)benzoic acid to afford the desired product as a brown solid.
  • Example 15 was prepared as provided in Synthetic Scheme 5.
  • Step 1 10% Pd/C. H 2 . rt, MeOH, 6h ⁇ 2) 30% CF 3 COOH in CH 2 Clj. rt, 6h Step 1: (/erf-Butyl (2j?,4-?)-4-((4-((l-(4-(4-((/grr-butoxycarbonvnainino)piperidin-l- yl)butvn-2-oxo-l,2-dihvdropyrimid!n-4-yl)carbamovnphenyl)carbamoyl)-2-(/ g r/-butyl)-
  • Step 2 (S)-4-(2-amino-3-hvdroxy-2-methylpropanamido)-iV " -(l-(4-(4-aminopiperidin-l- vnbutvn-2-oxo-l,2-dihvdropyrimidin-4-yl)benzamide hydrochloride salt;
  • Reagents Step 1) Cs 2 C0 3 , CH 3 CN, reflux, 2h (2) K 2 C0 3 , CH 3 CN,70 °C, 2h (3) NH 4 OH, MeOH, 12h
  • Step 1 N-fl-(4-Bromobutyl)-2-oxo-l,2-dihvdropyrimidin-4-yl)acetaniide:
  • Step 2 fert-Butyl (l-(4-(4-acetamido-2-oxopyrimidin-l(2 /)-yl)butvhpiperidin-4- vDcarbamate:
  • Step 3 fe -Butyl (l-(4-(4-amino-2-oxopyrimidin-l(2HVyl)butvnpiperidin-4- ylkarbamate:
  • Step 4 (fe -Butyl (2R,4S)-4-((4-((l-(4-(4-((/gr/-butoxycarbonyl)amino)niperidin-l- yl)butvn-2-oxo-l,2-dihvdropyrimidin-4-vI)carbamovnphenvI)carbatnoyl)-2-(feA , /-butyl)-
  • Step 5 t y)-4-(2-Atnino-3-hvdroxy-2-methylpropanamido)-N-(l-(4-(4-aminopiperidin-l- yl)butyl)-2-oxo-l,2-dihvdropyrimidin-4-v0benzamide:
  • Example 16 was prepared in a similar fashion to Scheme 6 from 4-amino-l-(4-(4- (dimethylamino)piperidin-l -yl)butyl)pyrimidin-2( l H)-one and 4-((2R,4S)-3-(tert- butoxycarbonyI)-2-(tert-butyl)-4-methyloxazolidine-4-carboxamido)benzoic acid to afford the desired product as a brown solid. %).
  • Example 17 was prepared in a similar fashion to Scheme 6 from tert-butyl (S)-2-((4- (3-(4-amino-2-oxopyrimidin- 1 (2H)-yl)propyl)phenyl)carbamoyl)pyrroIidine- 1 -carboxylate and 4-((2R,4S)-3-(tert-butoxycarbonyl)-2-(tert-butyl)-4-methyloxazolidine-4- carboxamido)benzoic acid.to afford the desired product as a brown solid.
  • Example 18 was prepared in a similar fashion to Scheme 6 from tert-butyl ( l -(4-(4- amino-2-oxopyrimidin- 1 (2H)-yl)butyl)piperidin-4-yl)(methyl)carbamate and 4-((2/?,45)-3- (/ert-butoxycarbonyl)-2-(/e ⁇ -butyl)-4-methyloxazolidine-4-carboxamido)benzoic acid.
  • Example 19 was prepared in a similar fashion to Scheme 6 from tert-butyl (4-(4- amino-2-oxopyrimidin-l(2H)-yl)benzyl)(3-((tert-butoxycarbonyl)amino) propyl)carbamate and 4-((2/?,45 -3-(/e /-butoxycarbonyl)-2-(1 ⁇ 2 -/-butyl)-4-methyloxazolidine-4- carboxamido)benzoic acid.
  • Example 20 was prepared in a similar fashion to Scheme 6 from tert-butyl (l-(4-(4- amino-2-oxopyrimidin-l (2H)-yl)butyl)piperidin-4-yl)carbamate and 4-(3-((tert- butoxycarbonyl)amino)-3-methylbutanamido)benzoic acid.
  • Example 21 was prepared in a similar fashion to Scheme 6 from tert-butyl ( l-(4-(4- amino-2-oxopyrimidin-l (2H)-yl)butyl)piperidin-4-yl)carbamate and 4-(2-((tert- butoxycarbonyl)amino)-2-methylpropanamido)benzoic acid.
  • Example 22 was prepared as provided in Synthetic Scheme 7.
  • Raagents Step 1) CsjCO,, CH 3 CN, 50 "C, 0.5h (2) LIOH. H 2 0:THF (1:1), 6h (3) EDC CI, HOBt. Et j N, CH 2 Cl j , rt, 24h
  • Step 1 fer/-Butyl j g ⁇ - ⁇ grf-butyl -f ⁇ -ra-g-methoxy ⁇ -oxoethyn ⁇ -oxo-l ⁇ - dihvdropyrimidin-4-ylkarbamoyl)phenyl)carbamovn-4-methyloxazolidine-3- carboxylate:
  • Step 3 fert-Butyl qR ⁇ 4S)-2-f/er/-butyl)-4-ff4-((l-(2-((3-
  • N, N'.N'-Trimethylethylenediamine (1.80 mg, 18.0 ⁇ ) was added to a solution of 2-(4-(4-((2 «,45)-3-(/e /-butoxycarbonyl)-2-(/er/-butyl)-4-methyloxazolidine-4- carboxamido)benzamido)-2-oxopyrimidin-l(2H)-yl)acetic acid (10.0 mg, 18.0 ⁇ ), Et3N (8 ⁇ , 54.0 ⁇ ), EDCI (4.12 mg, 21.6 ⁇ ), and HOBt (3.00 mg, 21 .6 ⁇ ) in dichloromethane ( I mL).
  • Step 4 (.y)-4-(2-Amino-3-hvdroxy-2-methylpropananiido)-N-(l-(2-(( ' 2- (dimethylamino)ethyl) (methvnamino)-2-oxoethyl)-2-oxo-l,2-dihydroDyriniidin-4- vDbenzamide trifluoroacetate salt: [00223] /ert-But l (2 ,4S)-2-(1 ⁇ 2r/-butyl)-4-((4-(( l -(2-((3- (dimethylamino)propyl)(methyl)amino)-2-oxoethyl)-2-oxo-l ,2-dihydropyrimidin
  • Example 23 was prepared in a similar fashion to Example 18 from 2-(4-(4-((2R,4S)- 3-(ter/-butoxycarbony l)-2-(/er/-buty l)-4-methy loxazol id ine-4-carboxam ido)benzam ido)-2- oxopyri-midin- l (2H)-yl)acetic acid and 1 ⁇ 2r/-butyl 3-(aminomethyl)piperidine- l -carboxylate.
  • Example 24 was prepared as provided in Synthetic Scheme 8.
  • Reagents Step 1) C0 2 CI 2 , OMF (cat), CH 2 CI 2 . 0 °C to rt, 2h then Et 3 N (2) Pd(PPh) 2 CI 2 , Cul, Et 3 N, 70 °C. 3h (3) MeS0 2 CI,
  • Step 1 tgrt-Butyl (l-(4-iodobenzoyl)piperidin-4-yl)carbamate:
  • Step 3 3-(4-(4-((rgrt-Butoxycarbonyl)amino)piperidine-l-carbonvnphenyl)prop-2-yn-l- yl meth-anesulfonate;
  • Step 4 (2RAS)-tert-Butyl 4-((4-((l-(3-(4-(4-(f/gr/-butoxycarbonyl)aminQ)piperidine-l- carbonyl)phenyl)prop-2-vn-l-yl)-2-oxo-l,2-dihydropyrimidin-4- yl)carbamoynphenvncarbamovn-2-f/g/' ⁇ -butyl)-4-methyloxazolidine-3-carboxylate:
  • Step 5 (.9 -4-(2-amino-3-hvdroxy-2-methvtpropanamido)-N-(l-(3-(4-(4- aminopiperidine-l-carbonvnphenyl prop-2-vn-l-vn-2-oxo-l,2-dihvdropyrimidin-4- vDbenzamide trifluoroacetate salt:
  • Example 25 was prepared in a similar fashion to Example 20 from (2R,4S)-/er - butyl 2-(/er/-butyl)-4-methyl-4-((4-((2-oxo- l ,2-dihydropyrimidin-4- yl)carbamoyl)phenyl)carbamoyl) oxazolidine-3-carboxylate and (S)-terl-butyl 2-((4-(3- ((methylsulfonyl)oxy)prop- 1 -yn- 1 -y l)pheny l)carbamoyl)pyrrolidine- 1 -carboxylate to afford the desired product as a yellow solid.
  • Example 26 was prepared as provided in Synthetic Scheme 9.
  • Step 1 fert-Butyl (l-(4-(4-((4-((3-((tert-butoxycarbonyl)amino)propylkarbamovn phenyl)amino)-2-oxopyriniidin-l(2H)-yl)buryl)Diperidin-4-ylkarbamate:
  • reaction mixture was degassed and purged with nitrogen 3 times and stirred at 1 10 °C for 16h. After which the reaction mixture is diluted with CHCb (25 mL) and filtered through a pad of celite and concentrated under reduced pressure. Purification on silica gel using flash chromatography afforded tert-butyl ( 1 -(4-(4-((4-((3-((tert-butoxycarbonyl)amino)propyl)carbamoyl) phenyl)amino)-2-oxopyrimidin-l (2H)-yl)butyl) piperidin-4-yl)carbamate as an yellow solid.
  • Step 2 4-((l-(4-(4-Aminopiperidin-l-vnburvn-2-oxo-l,2-dihvdropyrimidin-4-yl)amino)- N-(3-aminopropyl)benzamide:
  • Example 27 was prepared in a similar fashion to Synthetic Scheme 9 from tert- butyl (3-(3-bromobenzamido)propyl)carbamate and tert-butyl ( l-(4-(4-amino-2- oxopyrimidin-l (2H)-yl)butyl)piperidin-4-yl)carbamate to afford the desired product.
  • Example 28 was prepared in a similar fashion to Synthetic Scheme 9 from tert- butyl (3-bromobenzyl)(3-((tert-butoxycarbonyl)amino)propyl)carbamate and tert-butyl (l -(4- (4-amino-2-oxopyrimidin- l (2H)-yl)butyl)piperidin-4-yI)carbamate to afford the desired product.
  • Example 29 was prepared in a similar fashion to Synthetic Scheme 9 from tert-butyl (4-bromobenzyl)(3-((tert-butoxycarbonyl)amino)propyl)carbamate and tert-butyl (l -(4-(4- amino-2-oxopyrimidin-l (2H)-yl)butyl)piperidin-4-yl)carbamate to afford the desired product.
  • Example 30 was prepared in a similar fashion to Synthetic Scheme 9 from ethyl 4- bromobenzoate and tert-butyl (l -(4-(4-amino-2-oxopyrimidin- l (2H)-yl)butyl)piperidin-4- yl)carbamate to afford the desired product.
  • Example 31 was prepared in a similar fashion to Synthetic Scheme 9 from tert- butyl (3-(3-bromobenzamido)propyl)carbamate and tert-butyl (l-(4-(4-amino-2- oxopyrimidin-l(2H)-yl)butyl)piperidin-4-yl)carbamate to afford the desired product.
  • Example 32 was prepared in a similar fashion to Synthetic Scheme 9 from tert-butyl (3-(3-chloro-4-fluoro-5-iodobenzamido)propyl)carbamate and tert-butyl (l-(4-(4-amino-2- oxopyrimidin-l(2H)-yl)butyl)piperidin-4-yl)carbamate to afford the desired product.
  • Example 33 was prepared in a similar fashion to Synthetic Scheme 9 from tert-butyl (3-((tert-butoxycarbonyl)amino)propyl)(3-chloro-4-fluoro-5-iodobenzyl)carbamate and tert- butyl (l-(4-(4-amino-2-oxopyrimidin-l(2H)-yl)butyl)piperidin-4-yl)carbamate to afford the desired product.
  • 'H NMR 500 MHz, D 2 0) ⁇ 7.95 (d, IH), 7.76 (br s, IH), 7.65 (br s, IH), 6.26 (brs, 1H),4.29 (s, 2H),3.91 (brs, 2H),3.71 (d, 2H), 3.58-3.53 (m, 1 H), 3.32-3.17 (m, 4H), 3.09 (t, 4H), 2.34 (d, 2H), 2.15-2.
  • Example 34 was prepared in a similar fashion to Synthetic Scheme 9 from tert-butyl (l-(4-(4-bromo-3-fluorophenyl)butyI)piperidin-4-yl)carbamate and tert-butyl (l-(4-(4-amino- 2-oxopyrimidin-l(2H)-yl)butyl)piperidin-4-yl)carbamate to afford the desired product.
  • 'H NMR 500 MHz, CD 3 OD
  • Example 35 was prepared in a similar fashion to Synthetic Scheme 9 from tert-butyl ((4'-bromo-3'-fluoro-[l , 1 '-biphenyl]-4-yl)methyl)(3-((tert- butoxycarbonyl)amino)propyl)carbamate and tert-butyl (l-(4-(4-amino-2-oxopyrimidin- l(2H)-yl)butyl)piperidin-4-yl)carbamate to afford the desired product.
  • 'H NMR 500 MHz, CD 3 OD)58.19(brs, IH), 7.72 (d, IH), 7.60 (d, 2H), 7.45-7.36 (m, 4H), 6.18 (d, IH), 3.83 (t, 2H), 3.80 (s, 2H), 2.93 (d, 2H), 2.89 (t, 2H), 2.80 (p, 1 H), 2.72 (t, 2H
  • Example 36 was prepared in a similar fashion to Synthetic Scheme 9 tert-butyl 4-(4- bromo-3-fluorobenzyl)piperidine-l -carboxylate and tert-butyl ( l-(4-(4-amino-2- oxopyrimidin- l (2H)-yl)butyl)piperidin-4-yl)carbamate to afford the desired product.
  • Example 37 was prepared in a similar fashion to Synthetic Scheme 9 from tert-butyl ((4'-bromo-[l , 1 '-bipheny l]-4-y l)methy l)(3-((tert-butoxycarbonyl)amino)propy l)carbamate and tert-butyl (l-(4-(4-amino-2-oxopyrimidin-l(2H)-yl)butyl)piperidin-4-yl)carbamate to afford the desired product as a yellow solid.
  • Example 38 was prepared as provided in Synthetic Scheme 10.
  • Step 1 tert-Butyl (l-(4-(4-(f4-iodophenvnsulfonamido)-2-oxopyrimidin-lt2H>-yl)butvn piperidin-4-vQcarbamate ;
  • MIC microdilution minimum inhibitory concentration
  • MBC minimum bactericidal concentration
  • E. coli S30 Inhibition of bacterial protein synthesis was determined using the E. coli S30 Extract System for Circular DNA (Promega catalog #L-2010) and Luciferase Assay Reagent (Promega catalog #E1500) with slight modifications to a published protocol. Fyfe, C, Sutcliffe, J.A. and Grossman, T.H. (2012) "Development and characterization of a Pseudomonas aeruginosa in vitro coupled transcription-translation assay system for evaluation of translation inhibitors" J. Microbiol. Methods 90(3), 256-261.
  • luciferase synthesis mixture 18 ⁇ ; see below was added to wells with compounds or water mixture and incubated at 37 °C for 1 hour. Reactions were stopped by transferring to 4 °C refrigerator for 5 minutes then 25 ⁇ L ⁇ of luciferase activity mix was added. Luminescence was measured using a BioTek Synergy HTX plate reader. %
  • Inhibition of eukaryotic protein synthesis was determined using the Rabbit Reticulocyte Lysate System, Nuclease-Treated from Promega (catalog #L-4960) with slight modifications to the manufacturer's protocol. Compounds were serial diluted in 0.5 mL microcentrifuge tubes by mixing and transferring 50 ⁇ , from the highest concentration to 50 ⁇ . of water, mixing and transferring 50 ⁇ L ⁇ of this 2-fold dilution to 50 ⁇ . of water. This mixing and transferring was repeated so that there are a total of 8 tubes with serial dilutions of compound at l Ox the desired screening concentration that are ultimately diluted to l x by the addition of rabbit reticulocyte luciferase synthesis mixture.
  • Rabbit reticulocyte luciferase synthesis mixture Rabbit reticulocyte luciferase synthesis mixture:
  • MIC Minimum Inhibitory Concentration
  • MICs were determined using the Clinical Laboratory and Standards Institute (CLSI) Broth Microdilution Method with slight modification. Clinical and Laboratory Standards Institute (2012). "Methods for dilution antimicrobial susceptibility tests for bacteria that grow aerobically; approved standard, 9th ed. M07-A9. Clinical and Laboratory Standards Institute, Wayne, PA.” Serial two-fold dilutions of compounds are prepared in sterile clear round- bottom 96-well plates.
  • microdilution trays two-fold dilutions of antimicrobial agent are prepared by adding 200 ⁇ L ⁇ of the highest concentration, prepared in Cation-Adjusted Mueller-Hinton Broth (CAMHB), to be tested (64 ⁇ g/mL, for example) in row A, mixing and transferring 100 ⁇ L ⁇ from row A to 100 ⁇ L ⁇ CAMHB in row B, then repeating the mixing and transferring through row H of the 96-well plate, discarding the excess 100 ⁇ L ⁇ remaining.
  • CAMHB Cation-Adjusted Mueller-Hinton Broth
  • Bacterial suspensions are added to a final concentration of 5 ⁇ 104 CFU/well by adding 5 ⁇ of a 1 : 10 dilution of a 0.5 McFarland suspension (1 ⁇ 108 CFU/mL) for each bacterium evaluated.
  • Bacterial suspensions were prepared using the growth method described by CLSI.
  • Well-isolated colonies (3-5 from an agar plate) were selected using a sterile loop and used to inoculate a tube containing 4 mL of tryptic soy broth. The cultures are incubated at 35 ⁇ 2°C until it achieves or exceeds the turbidity of the 0.5 McFarland standard, determined by measuring A600nm (usually two to six hours). When growth exceeds a 0.5 McFarland standard, the turbidity is adjusted with broth to be equivalent to a 0.5 McFarland standard.
  • Data for compounds is provided in Table 1 .
  • An IC50 value that is 1 ⁇ or greater is designated by a "+”.
  • An IC50 value that is 0.5 ⁇ or greater and less than 1 ⁇ is designated by a "++”.
  • An IC50 value that is less than 0.5 ⁇ is designated by "+++”.
  • An MIC value that is 32 ⁇ g/mL or greater and less than 128 ⁇ g/mL is designated by a "+”.
  • An MIC value that is 8 ⁇ g/mL or greater and less than 32 ⁇ g/mL is designated by a "++”.
  • An MIC value that is less than 8 ⁇ / ⁇ _, is designated by "+++”.

Abstract

L'invention concerne des composés de formule I ou leurs sels pharmaceutiquement acceptables. Les composés de formule I sont des agents antimicrobiens qui inhibent, par exemple, le Mycobacterium tuberculosis (Mtb) H37Ra. Les composés de formule I ont également une activité anti-tuberculeuse, présentent une cytotoxicité limitée et inhibent la synthèse des protéines. L'invention concerne également des procédés de fabrication de composés de formule I, ainsi que des méthodes d'utilisation des composés de formule I pour le traitement d'infections bactériennes, en particulier de la tuberculose.
PCT/US2017/041790 2017-07-12 2017-07-12 Composés antimicrobiens WO2019013789A1 (fr)

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Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2021097061A1 (fr) * 2019-11-13 2021-05-20 Curza Global, Llc Composés antimicrobiens et procédés

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Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2021097061A1 (fr) * 2019-11-13 2021-05-20 Curza Global, Llc Composés antimicrobiens et procédés
CN115297930A (zh) * 2019-11-13 2022-11-04 库扎环球有限责任公司 抗微生物化合物和方法

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