WO2019046465A2 - Indoles thérapeutiques - Google Patents

Indoles thérapeutiques Download PDF

Info

Publication number
WO2019046465A2
WO2019046465A2 PCT/US2018/048607 US2018048607W WO2019046465A2 WO 2019046465 A2 WO2019046465 A2 WO 2019046465A2 US 2018048607 W US2018048607 W US 2018048607W WO 2019046465 A2 WO2019046465 A2 WO 2019046465A2
Authority
WO
WIPO (PCT)
Prior art keywords
compound
alkyl
aryl
cycloalkyl
alkanoyl
Prior art date
Application number
PCT/US2018/048607
Other languages
English (en)
Other versions
WO2019046465A3 (fr
Inventor
Joel S. Freundlich
David Alland
Matthew B. NEIDITCH
Daigo Inoyama
Glenn CAPODAGLI
Pradeep Kumar
Original Assignee
Rutgers, The State University Of New Jersey
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Rutgers, The State University Of New Jersey filed Critical Rutgers, The State University Of New Jersey
Publication of WO2019046465A2 publication Critical patent/WO2019046465A2/fr
Publication of WO2019046465A3 publication Critical patent/WO2019046465A3/fr

Links

Classifications

    • 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
    • C07D209/30—Indoles; Hydrogenated indoles with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, directly attached to carbon atoms of the hetero ring
    • C07D209/42—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/40—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil
    • A61K31/403—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil condensed with carbocyclic rings, e.g. carbazole
    • A61K31/404—Indoles, e.g. pindolol
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/4409—Non condensed pyridines; Hydrogenated derivatives thereof only substituted in position 4, e.g. isoniazid, iproniazid
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
    • A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
    • 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
    • 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
    • C07D209/10—Indoles; Hydrogenated indoles with substituted hydrocarbon radicals attached to carbon atoms of the hetero ring
    • C07D209/14—Radicals substituted by nitrogen atoms, not forming part of a nitro radical
    • 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
    • C07D209/30—Indoles; Hydrogenated indoles with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, directly attached to carbon atoms of the hetero ring
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
    • C07D405/02—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings
    • C07D405/12—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings linked by a chain containing hetero atoms as chain links

Definitions

  • Tuberculosis is an ongoing global health threat, made worse by an increase in drug- resistant Mycobacterium tuberculosis (TB) (Lin, J., et al., Int J Tuber c Lung Dis, 2004, 8, 568-573).
  • TB Mycobacterium tuberculosis
  • Clinical drug-resistance has been identified among even the most recently approved drugs bedaquiline (BDQ) and delamanid (Bloemberg, G.V., et al., Engl J Med, 2015, 373, 1986-1988), prompting concerns that TB may become untreatable.
  • BDQ bedaquiline
  • delamanid Billloemberg, G.V., et al., Engl J Med, 2015, 373, 1986-1988
  • TB regimens require lengthy treatment - six months for drug susceptible TB and >18 months for drug-resistance TB.
  • a lengthy treatment duration provides ample opportunity for partial non-compliance that can lead to both treatment failure and the emergence of new drug-resistance (Gelmanova, I.Y., et al., Bull World Health Organ, 2007, 85, 703-711; Pablos-Mendez, A., et al., Am J Med, 1997, 102, 164-170; and Saunders, N.J., et al., J Infect, 2011, 62, 212-217).
  • new TB therapies are needed to both counter emerging drug-resistance and to enable shortened TB treatments (Global tuberculosis report 2016 (Geneva: World Health Organization)).
  • Inhibitors of cell-wall biosynthesis disrupt the outer cell-envelope causing rapid cell death, and a number of drugs that target the cell-wall such as isoniazid (INH), ethambutol (EMB), ethionamide (ETH), carbapenems and delamanid are effective at treating clinical TB. Furthermore, many of the enzymes involved in biosynthesis of theM tuberculosis cell-wall do not have close homologues in humans, suggesting that specific inhibitors of this pathway would be less toxic.
  • the mycobacterial cell-wall is adorned with essential my colic acids, which are synthesized by a fatty acid synthase-II (FAS-II) system that is absent in humans.
  • the FAS-II complex consists of five enzymes encoded in two operons: one operon encoding three enzymes ⁇ -ketoacyl-ACP synthases KasA and KasB, an acyl-carrier protein (AcpM) and the second operon encoding the ketoreductase (MabA) and the enoyl reductase (InhA) (Banerjee, A., et al., Science, 1994, 263, 227-230; and Banerjee, A., et al., Microbiology, 1998, 144 (Pt 10),
  • This complex carries out cyclic elongation of short-chain fatty acids to produce long-chain meromycolic acids (C48-C64) (Bhatt, A., et al., J Bacteriol, 2005, 757, 7596-7606) that are condensed with C26 fatty acids to yield branched my colic acids by Pksl3 (Portevin, D., et al., Proc Natl Acad Sci USA, 2004, 101, 314-319; and Wilson, R., et al., Nat Chem Biol, 2013, 9, 499-506).
  • Mycolic acid variants are not only critical for pathogenesis, virulence, and persistence (Bhatt, A., et al., Mol Microbiol, 2007, 64, 1442-1454; Dubnau, E., et al., Mol Microbiol, 2000, 36, 630-637; and Glickman, M.S., et al., Mo/ Cell, 2000, 5, 717-727), but they are also effective targets for anti-TB drugs.
  • INH one of the most effective first- line antitubercular drugs, targets InhA. KasA has also been shown to be essential and a vulnerable target in mycobacteria (Bhatt, A., et al., Mol Microbiol, 2007, 64, 1442-1454).
  • Kapilashrami K., et al., JBiol Chem, 2013, 288, 6045-6052; Lee, W., et al., Biochemistry, 2011, 50, 5743-5756; Machutta, C.A., et al., JBiol Chem, 2010, 285, 6161-6169; and Schiebel, J., et al., J Biol Chem , 2013,255, 34190-34204) and platensimycin (Brown, A.K., et al., PLoS One, 2009, 4, e6306) have very poor whole-cell activity in M tuberculosis of 142 and 27 ⁇ , respectively.
  • Small molecule indole sulfonamides have been synthesized and demonstrated to be potent inhibitors of Mycobacterium tuberculosis in culture and more specifically to be inhibitors of the M. tuberculosis enzyme KasA.
  • Representative molecules in these classes exhibit acceptable physiochemical, in vitro ADME, and mouse PK profiles.
  • Select molecules have been crystallized with KasA and their binding modes to the target protein have been elucidated.
  • Select molecules have exhibited in vivo activity in a mouse model of acute M. tuberculosis infection.
  • the invention provides inhibitors of Mycobacterium tuberculosis of compound of formula I:
  • R 2 is (Ci-C 6 )alkyl or halo
  • R 3 is H and R 4 is nitro or - R a R b ; or R 3 is nitro or - R a R b and R 4 is H;
  • R a is H or (Ci-Ce)alkyl
  • R a and R b together with the nitrogen to which they are attached form a azetidino, pyrrolidino, piperidino, piperazin-l-yl, morpholino, or thiomorpholino ring, which azetidino, pyrrolidino, piperidino, piperazin-l-yl, morpholino, or thiomorpholino ring is optionally substituted with one or more groups independently selected from the group consisting of halo and (Ci-C 6 )alkyl;
  • R g is (C3-C6)cycloalkyl, aryl, or (Ci-C 6 )alkyl that is optionally substituted with one or more R e groups independently selected from the group consist
  • R m is H or (Ci-C 6 )alkyl
  • R m and R n together with the nitrogen to which they are attached form a azetidino, pyrrolidino, piperidino, piperazin-l-yl, morpholino, azepanyl, or thiomorpholino ring, which azetidino, pyrrolidino, piperidino, piperazin-l-yl, morpholino, azepanyl, or thiomorpholino ring is optionally substituted with one or more groups independently selected from the group consisting of halo, (Ci-C 6 )alkyl;
  • R p is hydroxy, (Ci-C 6 )alkoxy, (Ci-C 6 )alkanoyl, (Ci-Ce)alkoxycarbonyl, (C3- C 6 )cycloalkyl, or RTt 5 ;
  • R u and R v together with the nitrogen to which they are attached form a azetidino, pyrrolidino, piperidino, piperazin-l-yl, morpholino, or thiomorpholino ring, which azetidino, pyrrolidino, piperidino, piperazin-l-yl, morpholino, or thiomorpholino ring is optionally substituted with one or more groups independently selected from the group consisting of halo, (Ci-C 6 )alkyl.
  • the invention also provides a pharmaceutical composition
  • a pharmaceutical composition comprising a compound of formula I or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient.
  • the invention also provides a method for treating a bacterial infection in an animal (e.g., a mammal such as a human) comprising administering a compound of formula I or a
  • the invention also provides a compound of formula I or a pharmaceutically acceptable salt thereof for use in medical therapy.
  • the invention also provides a compound of formula I or a pharmaceutically acceptable salt thereof for the prophylactic or therapeutic treatment of a bacterial infection.
  • the invention also provides the use of a compound of formula I or a pharmaceutically acceptable salt thereof to prepare a medicament for treating a bacterial infection in an animal (e.g. a mammal such as a human).
  • an animal e.g. a mammal such as a human.
  • the invention also provides processes and intermediates disclosed herein that are useful for preparing a compound of formula I or a salt thereof.
  • Figure 1 illustrates the synthesis of representative compounds of the invention.
  • a respective sulfonylating agent can be used to give 5-alkylsulfonamide analogs.
  • FIGS. 2A-2D show a plot of plasma concentration (Cpiasma) as a function of time for compounds in a single 25 mg/kg oral dose study in mice showing the pharmacokinetic profile of (FIG. 2A) compound 3, (FIG. 2B) compound 7, (FIG. 2C) compound 9, and (FIG. 2D) compound 32.
  • the dotted line in each graph represents the MIC of each compound.
  • FIG. 4 Pharmacokinetic profile of compound 32 in mice at a (a) 5 mg/kg IV and (b) 25 mg/kg PO dosing. Red dotted line represents the MIC of the compound.
  • Figure 5 Kill curves showing the bactericidal activity of the compounds against M. tuberculosis at lOx MIC.
  • Figure 6 Plot of absorption as a function of concentrations of compounds tested against an SSI 8b non-replicating M. tuberculosis. Isoniazid (INH), 9, and 32 showed no activity against the non-replicating model.
  • Figure 7 shows efficacy studies of (a) compound 9 at 100 mg/kg and (b) compound 32 at two levels of dosing. The treatment with each compound was started at two weeks post inoculation.
  • Figure 8 shows the reduction of M. tuberculosis colony-forming units in the lungs of infected mice (PMID: 25421483) treated with compound 32 as compared to INH treatment and vehicle only.
  • halo or halogen is fluoro, chloro, bromo, or iodo.
  • Alkyl, alkoxy, etc. denote both straight and branched groups; but reference to an individual radical such as propyl embraces only the straight chain radical, a branched chain isomer such as isopropyl being specifically referred to.
  • alkyl by itself or as part of another substituent, means, unless otherwise stated, a straight or branched chain hydrocarbon radical, having the number of carbon atoms designated (i.e., Ci- 8 means one to eight carbons). Examples include (Ci-Cs)alkyl, (C 2 -C 8 )alkyl, Ci-C 6 )alkyl, (C2-C 6 )alkyl and (C3-C 6 )alkyl.
  • alkyl groups include methyl, ethyl, n- propyl, iso-propyl, n-butyl, t-butyl, iso-butyl, sec-butyl, n-pentyl, n-hexyl, n-heptyl, n-octyl, and and higher homologs and isomers.
  • alkoxy refers to an alkyl groups attached to the remainder of the molecule via an oxygen atom (“oxy").
  • cycloalkyl refers to a saturated or partially unsaturated (non-aromatic) all carbon ring having 3 to 8 carbon atoms (i.e., (C3-C 8 )carbocycle).
  • the term also includes multiple condensed, saturated all carbon ring systems (e.g., ring systems comprising 2, 3 or 4 carbocyclic rings).
  • carbocycle includes multi cyclic carbocyles such as a bicyclic carbocycles (e.g., bicyclic carbocycles having about 3 to 15 carbon atoms , about 6 to 15 carbon atoms, or 6 to 12 carbon atoms such as bicyclo[3.1.0]hexane and bicyclo[2.1.1]hexane), and polycyclic carbocycles (e.g tricyclic and tetracyclic carbocycles with up to about 20 carbon atoms).
  • the rings of the multiple condensed ring system can be connected to each other via fused, spiro and bridged bonds when allowed by valency requirements.
  • multicyclic carbocyles can be connected to each other via a single carbon atom to form a spiro connection (e.g., spiropentane, spiro[4,5]decane, etc), via two adjacent carbon atoms to form a fused connection (e.g., carbocycles such as decahydronaphthalene, norsabinane, norcarane) or via two non-adjacent carbon atoms to form a bridged connection (e.g., norbornane,
  • cycloalkyls include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, bicyclo[2.2.1]heptane, pinane, and adamantane.
  • aryl refers to a single all carbon aromatic ring or a multiple condensed all carbon ring system wherein at least one of the rings is aromatic.
  • an aryl group has 6 to 20 carbon atoms, 6 to 14 carbon atoms, 6 to 12 carbon atoms, or 6 to 10 carbon atoms.
  • Aryl includes a phenyl radical.
  • Aryl also includes multiple condensed carbon ring systems (e.g., ring systems comprising 2, 3 or 4 rings) having about 9 to 20 carbon atoms in which at least one ring is aromatic and wherein the other rings may be aromatic or not aromatic (i.e., cycloalkyl.
  • the rings of the multiple condensed ring system can be connected to each other via fused, spiro and bridged bonds when allowed by valency requirements. It is to be understood that the point of attachment of a multiple condensed ring system, as defined above, can be at any position of the ring system including an aromatic or a carbocycle portion of the ring.
  • aryl groups include, but are not limited to, phenyl, indenyl, indanyl, naphthyl, 1, 2, 3, 4-tetrahydronaphthyl, anthracenyl, and the like.
  • heterocycle refers to a single saturated or partially unsaturated ring that has at least one atom other than carbon in the ring, wherein the atom is selected from the group consisting of oxygen, nitrogen and sulfur; the term also includes multiple condensed ring systems that have at least one such saturated or partially unsaturated ring, which multiple condensed ring systems are further described below.
  • the term includes single saturated or partially unsaturated rings (e.g., 3, 4, 5, 6 or 7-membered rings) from about 1 to 6 carbon atoms and from about 1 to 3 heteroatoms selected from the group consisting of oxygen, nitrogen and sulfur in the ring.
  • the sulfur and nitrogen atoms may also be present in their oxidized forms.
  • heterocycles include but are not limited to azetidinyl, tetrahydrofuranyl and piperidinyl.
  • heterocycle also includes multiple condensed ring systems (e.g., ring systems comprising 2, 3 or 4 rings) wherein a single heterocycle ring (as defined above) can be condensed with one or more groups selected from cycloalkyl, aryl, and heterocycle to form the multiple condensed ring system.
  • the rings of the multiple condensed ring system can be connected to each other via fused, spiro and bridged bonds when allowed by valency
  • heterocycle includes a 3-15 membered heterocycle.
  • heterocycle includes a 3-10 membered heterocycle.
  • heterocycle includes a 3-8 membered heterocycle.
  • heterocycle includes a 3-7 membered heterocycle.
  • heterocycle includes a 3-6 membered heterocycle. In one embodiment the term heterocycle includes a 4-6 membered heterocycle. In one embodiment the term
  • heterocycle includes a 3-10 membered monocyclic or bicyclic heterocycle comprising 1 to 4 heteroatoms. In one embodiment the term heterocycle includes a 3-8 membered monocyclic or bicyclic heterocycle heterocycle comprising 1 to 3 heteroatoms. In one embodiment the term heterocycle includes a 3-6 membered monocyclic heterocycle comprising 1 to 2 heteroatoms. In one embodiment the term heterocycle includes a 4-6 membered monocyclic heterocycle comprising 1 to 2 heteroatoms.
  • heterocycles include, but are not limited to aziridinyl, azetidinyl, pyrrolidinyl, piperidinyl, homopiperidinyl, morpholinyl, thiomorpholinyl, piperazinyl, tetrahydrofuranyl, dihydrooxazolyl, tetrahydropyranyl, tetrahydrothiopyranyl, 1,2,3,4- tetrahydroquinolyl, benzoxazinyl, dihydrooxazolyl, chromanyl, 1,2-dihydropyridinyl, 2,3-dihydrobenzofuranyl, 1,3-benzodioxolyl, 1,4-benzodioxanyl, spiro[cyclopropane-l, l'- isoindolinyl]-3'-one, isoindolinyl-l-one, 2-oxa-6-azaspiro[3.3]heptany
  • heteroaryl refers to a single aromatic ring that has at least one atom other than carbon in the ring, wherein the atom is selected from the group consisting of oxygen, nitrogen and sulfur; "heteroaryl” also includes multiple condensed ring systems that have at least one such aromatic ring, which multiple condensed ring systems are further described below.
  • heteroaryl includes single aromatic rings of from about 1 to 6 carbon atoms and about 1-4 heteroatoms selected from the group consisting of oxygen, nitrogen and sulfur. The sulfur and nitrogen atoms may also be present in an oxidized form provided the ring is aromatic.
  • heteroaryl ring systems include but are not limited to pyridyl, pyrimidinyl, oxazolyl or furyl.
  • Heteroaryl also includes multiple condensed ring systems (e.g., ring systems comprising 2, 3 or 4 rings) wherein a heteroaryl group, as defined above, is condensed with one or more rings selected from cycloalkyl, aryl, heterocycle, and heteroaryl. It is to be understood that the point of attachment for a heteroaryl or heteroaryl multiple condensed ring system can be at any suitable atom of the heteroaryl or heteroaryl multiple condensed ring system including a carbon atom and a heteroatom (e.g., a nitrogen).
  • heteroaryls include but are not limited to pyridyl, pyrrolyl, pyrazinyl, pyrimidinyl, pyridazinyl, pyrazolyl, thienyl, indolyl, imidazolyl, triazolyl, tetrazolyl, oxazolyl, isoxazolyl, thiazolyl, furyl, oxadiazolyl, thiadiazolyl, quinolyl, isoquinolyl, benzothiazolyl, benzoxazolyl, indazolyl, quinoxalyl, and quinazolyl.
  • a wavy line " " that intersects a bond in a chemical structure indicates the point of attachment of the bond that the wavy bond intersects in the chemical structure to the remainder of a molecule.
  • the terms “treat”, “treatment”, or “treating” to the extent it relates to a disease or condition includes inhibiting the disease or condition, eliminating the disease or condition, and/or relieving one or more symptoms of the disease or condition.
  • treatment also refer to both therapeutic treatment and/or prophylactic treatment or preventative measures, wherein the object is to prevent or slow down (lessen) an undesired physiological change or disorder, such as, for example, the development or spread of cancer.
  • beneficial or desired clinical results include, but are not limited to, alleviation of symptoms, diminishment of extent of disease or disorder, stabilized (i.e., not worsening) state of disease or disorder, delay or slowing of disease progression, amelioration or palliation of the disease state or disorder, and remission (whether partial or total), whether detectable or undetectable.
  • Treatment can also mean prolonging survival as compared to expected survival if not receiving treatment.
  • Those in need of treatment include those already with the disease or disorder as well as those prone to have the disease or disorder or those in which the disease or disorder is to be prevented.
  • "treat", “treatment”, or “treating” does not include preventing or prevention
  • terapéuticaally effective amount includes but is not limited to an amount of a compound of the that (i) treats or prevents the particular disease, condition, or disorder, (ii) attenuates, ameliorates, or eliminates one or more symptoms of the particular disease, condition, or disorder, or (iii) prevents or delays the onset of one or more symptoms of the particular disease, condition, or disorder described herein.
  • mammal refers to humans, higher non-human primates, rodents, domestic, cows, horses, pigs, sheep, dogs and cats. In one embodiment, the mammal is a human.
  • patient refers to any animal including mammals. In one embodiment, the patient is a mammalian patientln one embodiment, the patient is a human patient.
  • this invention also includes any compound claimed that may be enriched at any or all atoms above naturally occurring isotopic ratios with one or more isotopes such as, but not limited to, deuterium ( 2 H or D).
  • a -CH 3 group may be substituted with -CD 3 .
  • the compound is enriched in that isotope above the natural abundance of that isotope.
  • the compound may be enriched by at least 2-times the natural abundance of that isotope.
  • the compound may be enriched by at least 10-times the natural abundance of that isotope.
  • the compound may be enriched by at least 100-times the natural abundance of that isotope.
  • the compound may be enriched by at least 1000-times the natural abundance of that isotope.
  • compositions of the invention can comprise one or more excipients.
  • excipients refers generally to an additional ingredient that is combined with the compound of formula (I) or the pharmaceutically acceptable salt thereof to provide a corresponding composition.
  • excipients includes, but is not limited to: carriers, binders,
  • disintegrating agents lubricants, sweetening agents, flavoring agents, coatings, preservatives, and dyes.
  • stereoisomeric forms of the compounds of the invention including but not limited to, diastereomers, enantiomers and atropisomers, as well as mixtures thereof such as racemic mixtures, form part of the present invention.
  • Many organic compounds exist in optically active forms, i.e., they have the ability to rotate the plane of plane-polarized light.
  • the prefixes D and L, or R and S are used to denote the absolute configuration of the molecule about its chiral center(s).
  • the prefixes d and 1 or (+) and (-) are employed to designate the sign of rotation of plane-polarized light by the compound, with (-) or 1 meaning that the compound is levorotatory.
  • a compound prefixed with (+) or d is
  • dextrorotatory For a given chemical structure, these stereoisomers are identical except that they are mirror images of one another.
  • a specific stereoisomer can also be referred to as an enantiomer, and a mixture of such isomers is often called an enantiomeric mixture.
  • a 50:50 mixture of enantiomers is referred to as a racemic mixture or a racemate, which can occur where there has been no stereoselection or stereospecificity in a chemical reaction or process.
  • racemic mixture and “racemate” refer to an equimolar mixture of two enantiomeric species, devoid of optical activity.
  • the present invention encompasses any racemic, optically-active, polymorphic, or stereoisomeric form, or mixtures thereof, of a compound of the invention, which possess the useful properties described herein, it being well known in the art how to prepare optically active forms (for example, by resolution of the racemic form by recrystallization techniques, by synthesis from optically-active starting materials, by chiral synthesis, or by chromatographic separation using a chiral stationary phase.
  • the atom to which the bond is attached includes all stereochemical possibilities.
  • a bond in a compound formula herein is drawn in a defined stereochemical manner (e.g. bold, bold-wedge, dashed or dashed-wedge)
  • a bond in a compound formula herein is drawn in a defined stereochemical manner (e.g. bold, bold-wedge, dashed or dashed-wedge)
  • the atom to which the stereochemical bond is attached is enriched in the absolute stereoisomer depicted unless otherwise noted.
  • the compound may be at least 51% the absolute stereoisomer depicted.
  • the compound may be at least 60% the absolute stereoisomer depicted.
  • the compound may be at least 80% the absolute stereoisomer depicted.
  • the compound may be at least 90% the absolute stereoisomer depicted. In another embodiment, the compound may be at least 95% the absolute stereoisomer depicted. In another embodiment, the compound may be at least 99% the absolute stereoisomer depicted.
  • the term "residue” as it applies to the residue of a compound refers to a compound that has been modified in any manner which results in the creation of an open valence wherein the site of the open valence.
  • the open valence can also be created by the chemical conversion of a first function group of the compound to a second functional group of the compound (e.g., reduction of a carbonyl group, replacement of a carbonyl group with an amine, ) followed by the removal of 1 or more atoms from the second functional group to create the open valence.
  • radicals, substituents, and ranges are for illustration only; they do not exclude other defined values or other values within defined ranges for the radicals and substituents. It is to be understood that two or more values or embodiments may be combined. It is also to be understood that the values or embodiments listed herein below (or subsets thereof) can be excluded.
  • (Ci-C8)alkyl can be methyl, ethyl, propyl, isopropyl, butyl, iso-butyl, sec- butyl, pentyl, 3-pentyl, or hexyl;
  • (C3-C 8 )cycloalkyl can be cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl;
  • (Ci-C 8 )alkoxy can be methoxy, ethoxy, propoxy, isopropoxy, butoxy, iso-butoxy, sec-butoxy, pentoxy, 3-pentoxy, or hexyloxy;
  • (Ci-C 8 )alkanoyl can be acetyl, propanoyl or butanoyl;
  • (Ci-C 8 )alkoxycarbonyl can be methoxy carbonyl, ethoxycarbonyl, propoxycarbonyl, isopropoxycarbon
  • R 1 is -(Ci-C6)alkoxycarbonyl.
  • R 1 is H, bromo, ethoxycarbonyl, carboxy, hydroxymethyl, aminocarbonyl, cyano, aminomethyl, acetylaminomethyl, methylsulfonylaminomethyl, methylaminocarbonyl, phenylcarbonylaminocarbonyl, benzylaminomethyl, ethylaminocarbonyl, 4-tert-butoxycarbonylpiperizin- 1 -ylcarbonyl, morpholinocarbonyl, butylaminocarbonyl, cyclopropylaminocarbonyl, cyclobutylaminocarbonyl, cyclopentylaminocarbonyl, 4- methylpiperizin-1 -ylcarbonyl, 1-azetidinylcarbonyl, cyclohexylaminocarbonyl, iso- propylaminocarbonyl, ⁇ , ⁇ -dimethylbenzylaminocarbonyl, 4-fluorobenzylaminocarbon
  • R 2 is methyl
  • R 3 is H and R 4 is - R a R b .
  • R 3 is - R a R b and R 4 is H.
  • R a is H.
  • R b is -SC R 0 .
  • the c (I) is a compound of formula (la): (la).
  • the compound of formula (I) is a compound of formula (lb):
  • R 4 is amino, nitro, tert-butoxycarbonylamino, «-butylsulfonylamino, «-pentylsulfonylamino, pyrrolidin-l-yl, 4-fluorobutylsulfonylamino, 4,4,4- trifluorobutylsulfonylamino, or 4-methylphenylsulfonylamino.
  • the invention provides a compound of any one of Examples 1-85 or a salt thereof.
  • a salt of a compound of formula I can be useful as an intermediate for isolating or purifying a compound of formula I.
  • administration of a compound of formula I as a pharmaceutically acceptable acid or base salt may be appropriate.
  • pharmaceutically acceptable salts are organic acid addition salts formed with acids which form a physiological acceptable anion, for example, tosylate, methanesulfonate, acetate, citrate, malonate, tartarate, succinate, benzoate, ascorbate, a-ketoglutarate, and a-glycerophosphate.
  • Suitable inorganic salts may also be formed, including hydrochloride, sulfate, nitrate, bicarbonate, and carbonate salts.
  • Salts may be obtained using standard procedures well known in the art, for example by reacting a sufficiently basic compound such as an amine with a suitable acid affording a physiologically acceptable anion.
  • a sufficiently basic compound such as an amine
  • a suitable acid affording a physiologically acceptable anion.
  • Alkali metal (for example, sodium, potassium or lithium) or alkaline earth metal (for example calcium) salts of carboxylic acids can also be made.
  • the compounds of formula I can be formulated as pharmaceutical compositions and administered to a mammalian host, such as a human patient in a variety of forms adapted to the chosen route of administration, i.e., orally or parenterally, by intravenous, intramuscular, topical or subcutaneous routes.
  • the present compounds may be systemically administered, e.g., orally, in combination with a pharmaceutically acceptable vehicle such as an inert diluent or an assimilable edible carrier. They may be enclosed in hard or soft shell gelatin capsules, may be compressed into tablets, or may be incorporated directly with the food of the patient's diet.
  • a pharmaceutically acceptable vehicle such as an inert diluent or an assimilable edible carrier.
  • the active compound may be combined with one or more excipients and used in the form of ingestible tablets, buccal tablets, troches, capsules, elixirs, suspensions, syrups, wafers, and the like.
  • Such compositions and preparations should contain at least 0.1% of active compound.
  • compositions and preparations may, of course, be varied and may conveniently be between about 2 to about 60% of the weight of a given unit dosage form.
  • the amount of active compound in such therapeutically useful compositions is such that an effective dosage level will be obtained.
  • the tablets, troches, pills, capsules, and the like may also contain the following: binders such as gum tragacanth, acacia, corn starch or gelatin; excipients such as dicalcium phosphate; a disintegrating agent such as corn starch, potato starch, alginic acid and the like; a lubricant such as magnesium stearate; and a sweetening agent such as sucrose, fructose, lactose or aspartame or a flavoring agent such as peppermint, oil of wintergreen, or cherry flavoring may be added.
  • binders such as gum tragacanth, acacia, corn starch or gelatin
  • excipients such as dicalcium phosphate
  • a disintegrating agent such as
  • the unit dosage form When the unit dosage form is a capsule, it may contain, in addition to materials of the above type, a liquid carrier, such as a vegetable oil or a polyethylene glycol. Various other materials may be present as coatings or to otherwise modify the physical form of the solid unit dosage form. For instance, tablets, pills, or capsules may be coated with gelatin, wax, shellac or sugar and the like.
  • a syrup or elixir may contain the active compound, sucrose or fructose as a sweetening agent, methyl and
  • propylparabens as preservatives, a dye and flavoring such as cherry or orange flavor.
  • any material used in preparing any unit dosage form should be pharmaceutically acceptable and substantially non-toxic in the amounts employed.
  • the active compound may be incorporated into sustained-release preparations and devices.
  • the active compound may also be administered intravenously or intraperitoneally by infusion or injection.
  • Solutions of the active compound or its salts can be prepared in water, optionally mixed with a nontoxic surfactant.
  • Dispersions can also be prepared in glycerol, liquid polyethylene glycols, triacetin, and mixtures thereof and in oils. Under ordinary conditions of storage and use, these preparations contain a preservative to prevent the growth of microorganisms.
  • the pharmaceutical dosage forms suitable for injection or infusion can include sterile aqueous solutions or dispersions or sterile powders comprising the active ingredient which are adapted for the extemporaneous preparation of sterile injectable or infusible solutions or dispersions, optionally encapsulated in liposomes.
  • the ultimate dosage form should be sterile, fluid and stable under the conditions of manufacture and storage.
  • the liquid carrier or vehicle can be a solvent or liquid dispersion medium comprising, for example, water, ethanol, a polyol (for example, glycerol, propylene glycol, liquid polyethylene glycols, and the like), vegetable oils, nontoxic glyceryl esters, and suitable mixtures thereof.
  • the proper fluidity can be maintained, for example, by the formation of liposomes, by the maintenance of the required particle size in the case of dispersions or by the use of surfactants.
  • the prevention of the action of microorganisms can be brought about by various antibacterial and antifungal agents, for example, parabens, chlorobutanol, phenol, sorbic acid, thimerosal, and the like. In many cases, it will be preferable to include isotonic agents, for example, sugars, buffers or sodium chloride. Prolonged absorption of the injectable compositions can be brought about by the use in the compositions of agents delaying absorption, for example, aluminum monostearate and gelatin.
  • Sterile injectable solutions are prepared by incorporating the active compound in the required amount in the appropriate solvent with various of the other ingredients enumerated above, as required, followed by filter sterilization.
  • the preferred methods of preparation are vacuum drying and the freeze drying techniques, which yield a powder of the active ingredient plus any additional desired ingredient present in the previously sterile-filtered solutions.
  • the present compounds may be applied in pure form, i.e., when they are liquids. However, it will generally be desirable to administer them to the skin as compositions or formulations, in combination with a dermatologically acceptable carrier, which may be a solid or a liquid.
  • Useful solid carriers include finely divided solids such as talc, clay, microcrystalline cellulose, silica, alumina and the like.
  • Useful liquid carriers include water, alcohols or glycols or water-alcohol/glycol blends, in which the present compounds can be dissolved or dispersed at effective levels, optionally with the aid of non-toxic surfactants.
  • Adjuvants such as fragrances and additional antimicrobial agents can be added to optimize the properties for a given use.
  • the resultant liquid compositions can be applied from absorbent pads, used to impregnate bandages and other dressings, or sprayed onto the affected area using pump-type or aerosol sprayers.
  • Thickeners such as synthetic polymers, fatty acids, fatty acid salts and esters, fatty alcohols, modified celluloses or modified mineral materials can also be employed with liquid carriers to form spreadable pastes, gels, ointments, soaps, and the like, for application directly to the skin of the user.
  • Examples of useful dermatological compositions which can be used to deliver the compounds of formula I to the skin are known to the art; for example, see Jacquet et al. (U.S. Pat. No. 4,608,392), Geria (U.S. Pat. No. 4,992,478), Smith et al. (U.S. Pat. No. 4,559, 157) and Wortzman (U.S. Pat. No. 4,820,508).
  • Useful dosages of the compounds of formula I can be determined by comparing their in vitro activity, and in vivo activity in animal models. Methods for the extrapolation of effective dosages in mice, and other animals, to humans are known to the art; for example, see U.S. Pat. No. 4,938,949.
  • the amount of the compound, or an active salt or derivative thereof, required for use in treatment will vary not only with the particular salt selected but also with the route of administration, the nature of the condition being treated and the age and condition of the patient and will be ultimately at the discretion of the attendant physician or clinician.
  • the desired dose may conveniently be presented in a single dose or as divided doses administered at appropriate intervals, for example, as two, three, four or more sub-doses per day.
  • the sub-dose itself may be further divided, e.g., into a number of discrete loosely spaced administrations; such as multiple inhalations from an insufflator or by application of a plurality of drops into the eye.
  • the invention can also be administered in combination with other therapeutic agents, for example, other antibacterial agents.
  • examples of such agents include isoniazid.
  • the invention also provides a composition comprising a compound of formula I, or a pharmaceutically acceptable salt thereof, at least one other therapeutic agent, and a pharmaceutically acceptableexcipient.
  • the invention also provides a kit comprising a compound of formula I, or a pharmaceutically acceptable salt thereof, at least one other therapeutic agent, packaging material, and instructions for
  • Chromolith SpeedRod RP-18e column 50 x 4.6 mm.
  • a 10 - 100% gradient of acetonitrile containing 0.1% formic acid was used for the analysis of the samples.
  • All compounds were purified to >95% peak area (i.e., purity) as observed by an HPLC UV trace at 220 nm or 250 nm and observed a low-resolution MS m/z consistent with each compound.
  • Purification of samples by flash chromatography was performed on a Teledyne ISCO
  • Trifluoroacetic acid (5 mL) was added dropwise to a vigorously stirring solution of compound 1 (2.85 g, 8.99 mmol) in 45 mL dichloromethane. The reaction was stirred at room temperature for 3 hours and no starting material was remaining based on LCMS analysis. The reaction was neutralized with saturated aqueous NaHCCb solution until the pH of the aqueous layer was approximately 8. The DCM layer was collected and the remaining aqueous phase was extracted with twice with EtOAc. The organic fractions were pooled and washed with brine. The organic phase was dried over Na 2 S04 and concentrated to give the desired product as off-white solid (1.88 g, 97%).
  • Example 6 Preparation of ethyl 3-methyl-5-(pentylsulfonamido)-lH-indole-2- carboxylate (6) Using a procedure similar to that described in Example 3, except replacing the 1- butanesulfonyl chloride used therein with 1-pentanesulfonyl chloride, the title compound was prepared.
  • the intermediate 3-methyl-lH-indol-5-amine was prepared as follows. a. 3-Methyl-lH-indol-5-amin A flask containing solution of 3-methyl-5-nitro-lH-indole (1.07 g, 6.1 mmol) in ethanol was purged with N2 and 10% Pd/C (107 mg) was added in one portion. The flask was charged with H2 and the reaction was stirred at room temperature for 12 hours. The mixture was filtered through a pad of celite and concentrated. The product was purified by silica gel flash column chromatography using 10 - 60 EtOAc in hexanes to give 741 mg light yellow solid (83%).
  • N-bromosuccinimide (56.8 mg, 0.319 mmol) in portions over 1 hour.
  • the reaction diluted with 5-fold with EtOAc and washed 3 times with saturated NaHCCb, followed by a wash with brine.
  • the organic phase was dried over Na 2 S04, concentrated, and purified by silica gel flash column chromatography using 0 - 35% EtOAc in hexanes to give product as 62 mg white solid (56%).
  • the starting material for the reaction was synthesized following general procedure for the amides using Boc-ethylenediamine.
  • the Boc-protected intermediate (50 mg, 0.11 mmol) was treated with 2 mL 10% trifluoroacetic acid in dichloromethane for 3 hours at room temperature.
  • the product was obtained as a TFA-salt after concentration.
  • the crude TFA-salt was taken in 2 mL anhydrous DMF and trimethyl amine (2.0 eq) was added to the solution, followed by 5-nitro-2-furoyl chloride (1.1 eq). The resulting mixture was stirred at room temperature overnight.
  • M. tuberculosis strains were obtained from laboratory stocks. Clinical strains were obtained from a collection of clinical isolates for Research and Training in Tropical Diseases (TDR) established by UNICEF/UNDPAVorld BankAVHO Special Programs. All M. tuberculosis strains were grown at 37 °C in Middlebrook medium 7H9 (Becton Dickinson, Sparks, MD) enriched with 10% oleic acid-albumin-dextrose-catalase (OADC-Becton Dickinson) or lx ADS (albumin (0.5 g/L)-dextrose(0.2 g/L)-sodium chloride (0.081 g/L)) and Tween 80 0.05% (wt/v) or tyloxapol (0.05%) (wt/v) in liquid media. Middlebrook 7H10 agar (Becton Dickinson) supplemented with 10%) OADC and 0.5%> glycerol (v/v) was used to grow strains on
  • MABA microdilution alamar blue
  • M. tuberculosis cells (-107 CFU/mL) were treated with compounds, incubated at 37 °C under shaking, the samples were drawn at specific time points and total viable counts determined by dilution plating on 7H10-OADC-agar plates and counting colony forming units after 4 week incubation at 37 °C.
  • mice Female BALB/c mice were weighed (23-29 g) and treated via oral gavage with a single dose of compound (60, 100, or 200 mg/kg) formulated in 0.5% CMC / 0.5% Tween 80. Sequential bleeds were collected at 0.25, 0.5, 1, 3, 5 and 8 h post-dose via tail snip method. Blood (50 ⁇ ) was collected in capillary microvette EDTA blood tubes and kept on ice prior to centrifugation at 1,500 g for 5 min. The supernatant (plasma) was transferred into a 96-well plate and stored at -80 °C. In a dose escalation study, mice were dosed with 50, 100, 250 or 500 mg/kg compound and blood was similarly sampled and processed.
  • MRM Multiple-reaction monitoring of parent/daughter transitions in electrospray positive-ionization mode
  • ESI+ electrospray positive-ionization mode
  • a DMSO stock solution was serial diluted in blank K2EDTA plasma (Bioreclammation) to create standard curves and quality control samples.
  • Compounds were extracted by combining 20 ⁇ of spiked plasma or study samples and 200 ⁇ . of acetonitrile/methanol (50/50) protein precipitation solvent containing 20 ng/mL verapamil internal standard (IS). Extracts were vortexed for 5 minutes and centrifuged at 4000 RPM for 5 minutes. The supernatants were analyzed by LC-MS.
  • Verapamil IS was sourced from Sigma- Aldrich. The following MRM transitions were used for verapamil (455.4/165.2). Sample analysis was accepted if the concentrations of the quality control samples were within 20% of the nominal concentration. Drug Tolerability
  • mice Five mice were dosed orally daily for 5 days with compound 9 or compound 32 (50, 100, 250, and 500 mg/kg) formulated in 0.5 % CMC/ 0.5% Tween 80 and INH (25 mg/kg) in water. The mice were weighed and observed daily. Their behavior, drinking and feeding patterns, and feces were monitored and recorded. Upon necropsy, liver, gall bladder, kidney and spleen pathology were observed as well.
  • mice Nine week-old female B ALB/c mice (weight range 18-20 g) were infected with an inoculum ofM tuberculosis H37Rv in 5 mL of PBS (3 x 10 6 CFU/mL) using a Glas-Col whole body aerosol unit. This resulted in lung implantation of 1.09 logio CFU per mouse. Groups of 5 mice were sacrificed by cervical dislocation at the start of treatment (2 week post-infection), and after receiving compound 9 (100 mg/kg) or compound 32 (60 and 200 mg/kg), INH at 25 mg/kg, or the vehicle only for 2 week, or 4 weeks daily. Whole lungs were homogenized in 5 mL of PBS containing 0.05% Tween 80. CFU were determined by plating serial dilutions of homogenates onto Middlebrook 7H11 agar with OADC. Colonies were counted after at least 21 days of incubation at 37 °C. Docking Experiments
  • the MIC minimum concentration of compound resulting in 90% growth inhibition of the bacteria
  • CC50 minimum concentration of compound resulting in 50% growth inhibition of this model mammalian cell line
  • SI selectivity index
  • the parent 3-methyl-lH-indole 14 demonstrated whole-cell efficacy with an MIC of 1.6 ⁇ and little toxicity to Vero cells (CCso > 190 ⁇ ; SI > 119).
  • the indole 2-ethyl ester 3 exhibited an MIC of 0.20 ⁇ and a Vero cell CC50 > 150 ⁇ (SI > 750).
  • its carboxylic acid analog 4 was inactive with an MIC > ⁇ .
  • the 2-hydroxymethyl indole 5 was also inactive with an observed MIC > 100 ⁇ .
  • the primary amide 7 demonstrated an MIC of 3.1 ⁇ .
  • the physiochemical properties of selected 2-substituted 3 -methyl- lH-indoles based on MIC and CC50 were profiled.
  • the ethyl ester 3 showed poor aqueous solubility as the kinetic solubility in PBS pH 7.4 was determined to be 0.895 ⁇ .
  • the MIC of 2-nitrile analog 9 was slightly higher than the ethyl ester, the compound displayed significant improvement in aqueous solubility.
  • the kinetic solubility of the nitrile analog 9 in pH 7.4 PBS was determined to be 133 ⁇ ; a 150-fold increase in aqueous solubility over the more potent ethyl ester 3.
  • the primary amide 7 showed improved aqueous solubility over the ester analog, but in comparison to the nitrile the aqueous solubility was moderate (45.5 ⁇ ). While a 4-fold improvement in MIC over compound 3 was achieved by replacing the butanesulfonamide with a
  • the compounds were also profiled for their stability in mouse liver microsomes. All of the compounds assayed had relatively short half-life in MLM.
  • the ethyl esters 3 and 6 showed the shortest half-life of the 3 -methyl- lH-indole series with an MLM ti/2 of less than 0.5 min in presence of NADPH.
  • the metabolite identification showed that the esters were hydrolyzed in the mouse liver microsomes. This was expected as esters are generally considered to be metabolically labile.
  • the MLM ti/2 of compound 9 and 32 were similar to compound 7 with half-lives of 6.51 and 4.08 min, respectively, showing the similar oxidation at the 3 -methyl- lH-indole scaffold as the amide in MLM metabolite identification.
  • nitrile indole 9 exhibited even better exposure than the amide with a plasma concentration that was maintained above the MIC during the entire 5 hour duration of the PK study at the same dosing level (Figure 2C).
  • the Cpiasma of the compound was maintained even higher above the MIC for the entire duration of the PK study ( Figure 2D).
  • compounds 9 and 32 were selected for further profiling to facilitate an in vivo efficacy study.
  • each of the two compounds was dosed into mice by intravenous (IV) and PO route at a single 5 mg/kg and 25 mg/kg, respectively, and Cpiasma for each compound was followed for 8 hours.
  • IV intravenous
  • compound 9 showed an average half-life of 1.08 h in mice and Cpiasma was maintained above the MIC for at least 3.5 h ( Figure 3).
  • compound 9 was administered by PO, the Cpiasma stayed above the MIC for the entire 8 hour duration of the PK study with an oral bioavailability (%F) of 65.3%.
  • Compound 32 showed 1.3 h half-life in mice and Cpiasma above the MIC for the 8 hour duration of the study by IV route ( Figure 4).
  • compound 32 is a more potent antitubercular agent and, therefore, it exhibited an improvement over compound 9 and DG167 in the efficacy study with a greater reduction in CFU over the vehicle-treated control.
  • the overall trend for compound 32 shows a decrease in bacterial burden as compared to the inoculum after 4 weeks of treatment.
  • the in vivo efficacy data demonstrates the potential of these compounds as antitubercular agents targeting a novel mechanism of action.
  • Example 87 The following illustrate representative pharmaceutical dosage forms, containing a compound of formula I ('Compound X'), for therapeutic or prophylactic use in humans.

Landscapes

  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Health & Medical Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Epidemiology (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

La présente invention concerne des composés de formule (I) et leurs sels, R1-R4 ayant l'une quelconque des valeurs définies dans la description. Ces composés sont utiles dans le traitement d'infections bactériennes (par ex., la tuberculose).
PCT/US2018/048607 2017-08-29 2018-08-29 Indoles thérapeutiques WO2019046465A2 (fr)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
US201762551482P 2017-08-29 2017-08-29
US62/551,482 2017-08-29

Publications (2)

Publication Number Publication Date
WO2019046465A2 true WO2019046465A2 (fr) 2019-03-07
WO2019046465A3 WO2019046465A3 (fr) 2019-04-04

Family

ID=65527861

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/US2018/048607 WO2019046465A2 (fr) 2017-08-29 2018-08-29 Indoles thérapeutiques

Country Status (1)

Country Link
WO (1) WO2019046465A2 (fr)

Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US11186549B2 (en) 2017-08-29 2021-11-30 Rutgers, The State University Of New Jersey Therapeutic indazoles

Family Cites Families (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
MX2007003287A (es) * 2004-09-24 2007-10-11 Bayer Schering Pharma Ag Derivados de indol como inhibidores de la adenilato ciclasa soluble.
GB0428173D0 (en) * 2004-12-23 2005-01-26 Astrazeneca Ab Compounds
JP5959537B2 (ja) * 2011-01-28 2016-08-02 ベーリンガー インゲルハイム インターナショナル ゲゼルシャフト ミット ベシュレンクテル ハフツング 置換ピリジニル−ピリミジン及び医薬としてのその使用
WO2015107724A1 (fr) * 2014-01-14 2015-07-23 大日本住友製薬株式会社 Dérivé condensé de 5-oxazolidinone

Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US11186549B2 (en) 2017-08-29 2021-11-30 Rutgers, The State University Of New Jersey Therapeutic indazoles
US12060330B2 (en) 2017-08-29 2024-08-13 Rutgers, The State University Of New Jersey Therapeutic indazoles

Also Published As

Publication number Publication date
WO2019046465A3 (fr) 2019-04-04

Similar Documents

Publication Publication Date Title
JP6500024B2 (ja) Ｌｔａ４ｈ阻害剤としてのヘテロアリールブタン酸誘導体
EP3677584A1 (fr) Composé ayant une activité d'inhibition et de dégradation de la tyrosine kinase de bruton (btk)
JP5897566B2 (ja) 環式ｎ，ｎ’−ジアリールチオ尿素及びｎ，ｎ’−ジアリール尿素−アンドロゲン受容体アンタゴニスト、抗癌剤、その調製のための方法及び使用
KR20170053686A (ko) Raf 키나제 억제제로서의 화합물 및 조성물
WO2014165090A1 (fr) Composés pour le traitement de la tuberculose
CN112638866B (zh) 索拉非尼衍生物的共晶体及其制备方法
EP3753926A1 (fr) Composé spiro utilisé en tant qu'inhibiteur de l'indoléamine-2,3-dioxygénase
CN114375193A (zh) 甲状腺激素受体β激动剂化合物
WO2020254562A1 (fr) Inhibiteur d'egfr pour le traitement du cancer
US9862678B2 (en) 3,4-diaminobenzenesulfonamide derivatives for inhibiting cell death
EA030374B1 (ru) Производные нафтиридиндиона
US12060330B2 (en) Therapeutic indazoles
JP6880166B2 (ja) スルタム化合物及びその使用方法
WO2019046465A2 (fr) Indoles thérapeutiques
WO2017175185A1 (fr) Dérivés d'acide hétéroaryl butanoïque utilisés en tant qu'inhibiteurs de la lta4h
KR20240051146A (ko) 방향족 헤테로고리 화합물, 이를 함유한 약물 조성물 및 이의 응용
US11760751B2 (en) Benzo 2-azaspiro[4.4]nonane compound and use thereof
CN115557949A (zh) 四环类衍生物、其制备方法及其在医药上的应用
JP2020502283A (ja) インドールアミン−２，３−ジオキシゲナーゼ阻害剤としてのスルホニルアミディーン及びその製造方法と用途
WO2021214080A1 (fr) Composés de 1,3-di-oxo-indène antiviraux
US11702425B2 (en) Bicyclic compounds as kinase modulators, methods and uses thereof
US20200399224A1 (en) Cyclopentaimidazolones for the treatment of cancer
WO2024059333A1 (fr) Composés pour le traitement d'infections par des protozoaires parasites
EP4406962A1 (fr) Inhibiteur de protéase peptidomimétique macrocyclique et son utilisation
CA3239097A1 (fr) Promedicaments de composes de bore et leur utilisation dans le traitement d'infections bacteriennes

Legal Events

Date Code Title Description
121 Ep: the epo has been informed by wipo that ep was designated in this application

Ref document number: 18852531

Country of ref document: EP

Kind code of ref document: A2

NENP Non-entry into the national phase

Ref country code: DE

122 Ep: pct application non-entry in european phase

Ref document number: 18852531

Country of ref document: EP

Kind code of ref document: A2