WO2025252850A1 - Thiourea based derivatives are novel antimicrobials against a. baumannii - Google Patents

Thiourea based derivatives are novel antimicrobials against a. baumannii

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Publication number
WO2025252850A1
WO2025252850A1 PCT/EP2025/065567 EP2025065567W WO2025252850A1 WO 2025252850 A1 WO2025252850 A1 WO 2025252850A1 EP 2025065567 W EP2025065567 W EP 2025065567W WO 2025252850 A1 WO2025252850 A1 WO 2025252850A1
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Prior art keywords
group
halogen
optionally substituted
alkyl
formula
Prior art date
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PCT/EP2025/065567
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French (fr)
Inventor
Alexander TITZ
Marta CZEKANSKA
Sidharth Chopra
Sandeep Verma
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Helmholtz Centre for Infection Research
Council of Scientific and Industrial Research
Indian Institute of Technology Kanpur
Original Assignee
Helmholtz Centre for Infection Research
Council of Scientific and Industrial Research
Indian Institute of Technology Kanpur
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Application filed by Helmholtz Centre for Infection Research, Council of Scientific and Industrial Research, Indian Institute of Technology Kanpur filed Critical Helmholtz Centre for Infection Research
Publication of WO2025252850A1 publication Critical patent/WO2025252850A1/en
Pending legal-status Critical Current
Anticipated expiration legal-status Critical

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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
    • C07D209/10—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
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A61P31/04—Antibacterial agents
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
    • C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
    • C07D403/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings linked by a chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D409/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms
    • C07D409/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings
    • C07D409/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings linked by a chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D413/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings
    • C07D413/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings linked by a chain containing hetero atoms as chain links

Definitions

  • the present invention is directed to thiourea based compounds of formula (I), as well as pharmaceutically acceptable salts or prodrugs thereof.
  • the present invention further provides a method for the preparation of the compounds of formula (I), pharmaceutical compositions comprising the same and their use in medicine, and preferably in the prophylaxis or treatment of Acinetobacter baumannii infections.
  • Acinetobacter baumannii is a pleomorphic gram-negative coccobacillus and the most common cause of bacterial hospital-acquired infections in immunocompromised individuals.
  • the major problem in the treatment of such infections is the increasingly frequent occurrence of antimicrobial resistance (AMR) to established therapeutic agents such as carbapenems, minocycline, levofloxacin and polymyxin B.
  • AMR antimicrobial resistance
  • Cock carbapenem-resistant Acinetobacter baumannii
  • AMR-associated infections are a leading cause of death worldwide and are projected to cause approximately 1.27 million direct deaths and an additional 4.95 million associated deaths worldwide in 2019, surpassing deaths from HIV and malaria.
  • A. baumannii belongs to the so-called "ESKAPE” pathogens (Enterococcus faecium, Staphylococcus aureus, Klebsiella pneumoniae, Acinetobacter baumannii, Pseudomonas aeruginosa and Enterobacter species, and E. coll), which currently cause the majority of nosocomial infections and are effectively "evading" the action of antimicrobial agents.
  • ESKAPE Enterococcus faecium, Staphylococcus aureus, Klebsiella pneumoniae, Acinetobacter baumannii, Pseudomonas aeruginosa and Enterobacter species, and E. coll
  • A. baumannii is most commonly found in intensive care units and surgical wards, where extensive use of antibiotics has allowed selection for resistance to all known antimicrobials.
  • Healthcare-associated infections are often associated with the use of medical devices such as catheters and ventilators, surgical procedures, transmission between patients and healthcare workers, and overuse of antibiotics.
  • A. baumannii-caused HAI comprise bacteremia, pneumonia, e.g. ventilator-associated pneumonia, meningitis, urinary tract infections, e.g. catheter-associated urinary tract infection (CAUTI).
  • the present inventors developed a new series of small molecules starting from the known compound SRI-12742 (Shukla et al., 2018). These new small molecules showed increased antimicrobial activity against clinical strains of A. baumanni, including multidrug resistant strains, compared to SRI- 12742 (Table 2), while the cytotoxicity in Vero cells remained at the same level.
  • the present invention provides, inter alia', (i) novel small molecules for the prophylaxis and treatment of infections caused by Acinetobacter baumannii, including multi-drug resistant Acinetobacter baumannii, (ii) methods for preparing said new small molecules.
  • the present invention provides a compound of the general formula (I): wherein
  • R 1 is individually selected from the group consisting of halogen and C1-4 alkyl, which is optionally substituted by one or more halogen(s), and C1-4 alkoxy, which is optionally substituted by one or more halogen(s);
  • R 2 is individually selected from the group consisting of hydrogen, OH, NH2, NO2, SH, one or more halogen(s), COOR 8 , wherein R 8 is hydrogen or C1-4 alkyl, which is optionally substituted by one or more halogen(s), C1-4 acyl, which is optionally substituted by one or more halogen(s), C1-4 alkyl, which is optionally substituted by one or more halogen(s), and Ci-4 alkoxy, which is optionally substituted by one or more halogen(s); m is 0, 1, 2 or 3;
  • R 7 is selected from the group consisting of one or more halogen(s), — CN, — NO 2 , — R f , — CO 2 R d , — CONR d R e , — C(O)R d , — OC(O)NR d R e , — NR e C(O)R d , — NR e C(O) 2 R f , — NR d C(O)NR d R e , — NR d R e , — OR d , and — S(O) 2 NR d R e ; wherein each R d and R e is independently selected from hydrogen, C1-8 alkyl, and C1-8 haloalky
  • R 4 and R 5 are individually selected from the group consisting of hydrogen, one or more halogen(s), and C1-4 alkyl, and preferably are hydrogen; or a salt thereof, or a solvate thereof, or a prodrug thereof.
  • the present invention relates to a pharmaceutical composition
  • a pharmaceutical composition comprising or consisting of at least one compound of the first aspect, and, optionally, one or more constituents selected from the group consisting of a pharmaceutically acceptable carrier, a diluent, an excipient and a further anti-bacterial therapeutic agent.
  • the present invention relates to the compound of the first aspect or the pharmaceutical composition of the second aspect for use in medicine.
  • the present invention relates to the compound of the first aspect or the pharmaceutical composition of the second aspect, optionally in combination with one or more anti-bacterial therapeutic agent(s), for use in the prophylaxis or treatment of Acinetobacter baumannii infections in a patient, or for use in the prophylaxis or treatment of Acinetobacter baumannii-associated lung infections, catheter-associated infections, bacteremia, or sepsis in a patient, or for use in the prophylaxis or treatment of carbapenem resistant Acinetobacter baumannii or multidrug resistant Acinetobacter baumannii.
  • one or more anti-bacterial therapeutic agent(s) for use in the prophylaxis or treatment of Acinetobacter baumannii infections in a patient, or for use in the prophylaxis or treatment of Acinetobacter baumannii-associated lung infections, catheter-associated infections, bacteremia, or sepsis in a patient, or for use in the prophylaxis or treatment of carbapenem resistant Acinetobacter
  • the present invention relates to a method for the preparation of a compound of formula (I): wherein
  • R 1 is individually selected from the group consisting of halogen and C1-4 alkyl, which is optionally substituted by one or more halogens, and C1-4 alkoxy, which is optionally substituted by one or more halogen(s);
  • R 2 is individually selected from the group consisting of hydrogen, OH, NH2, NO2, SH, one or more halogen(s), COOR 8 , wherein R 8 is hydrogen or C1-4 alkyl, which is optionally substituted by one or more halogen(s),Ci-4 acyl, which is optionally substituted by halogen(s), C1-4 alkyl, which is optionally substituted by one or more halogen(s), or C1-4 alkoxy, which is optionally substituted by one or more halogens; m is 0, 1, 2 or 3;
  • PGi is a protecting group; or b) reacting a compound of formula (II) and a compound of formula (Illb) wherein R 1 , R 2 , R 3 , R 4 , R 5 , and m are as defined for formula (I), and wherein R 3 is preferably a residue of the formula (lb) wherein
  • R 6 is selected from the group consisting of hydrogen, Ci-6 alkyl, which is optionally substituted by one or more halogen(s), Ci-6 alkoxy, which is optionally substituted by one or more halogen(s), and a 5, 6, 7, or 10-membered carbo- or heterocycle, which is optionally substituted by 1 to 3 R 7 substituents, wherein R 7 is selected from the group consisting of one or more halogen(s), — CN, — N0 2 , — R f , — CO 2 R d , — CONR d R e , — C(O)R d , — OC(O)NR d R e , — NR e C(O)R d , — NR e C(O) 2 R f , — NR d C(O)NR d R e , — NR d R e , — 0R d , and — S(O) 2
  • the terms used herein are defined as described in "A multilingual glossary of biotechnological terms: (IUPAC Recommendations)", Leuenberger, H.G.W, Nagel, B. and Klbl, H. eds. (1995), Helvetica Chimica Acta, CH-4010 Basel, Switzerland).
  • halogen refers to a halogen residue selected from the group consisting of fluorine (F), chlorine (Cl), bromine (Br) and iodine (I).
  • alkoxy and “alkylamino” are used herein in their conventional sense, and refer to those alkyl groups attached to the remainder of the molecule via an oxygen atom or an amino group, respectively.
  • the carbon chain comprises from 1 to 6 carbon atoms.
  • alkyl refers to a saturated straight or branched carbon chain.
  • the chain comprises from 1 to 8 carbon atoms, i.e. 1, 2, 3, 4, 5, 6, 7, or 8, e.g.
  • Alkyl groups are optionally substituted.
  • heteroalkyl refers in the context of the present invention to a saturated straight or branched carbon chain.
  • the chain comprises from 1 to 8 carbon atoms, i.e. 1, 2, 3, 4, 5, 6, 7, or 8, e.g. methyl, ethyl, propyl (//-propyl or zso-propyl), butyl (rz-butyl, iso-butyl, sec-butyl, tert-butyl), pentyl, hexyl, heptyl, or octyl, which is interrupted one or more times, e.g. 1, 2, 3, 4, 5, with the same or different heteroatoms.
  • heteroalkyl refers to -O-CH3, -OC2H5, -CH2-O-CH3, -CH2-O-C2H5, -CH2-O- C3H7, -CH2-O-C4H9, -CH2-O-C5H11, -C2H4-O-CH3, -C2H4-O-C2H5, -C2H4-O-C3H7, -C2H4-O- C4H9 etc.
  • Heteroalkyl groups are optionally substituted.
  • haloalkyl refers in the context of the present invention to a saturated straight or branched carbon chain in which one or more hydrogen atoms are replaced by halogen atoms, e.g. by F, Br, I or Cl.
  • the chain comprises from 1 to 8 carbon atoms, i.e. 1, 2, 3, 4, 5, 6, 7, or 8.
  • haloalkyl refers to -CH2F, -CHF2, -CF3, -C2H4F, -C2H3F2, -C2H2F3, -C2HF4, -C 2 F 5 , -C 3 H 6 F, -C 3 H 5 F 2 , -C3H4F3, -C3H3F4, -C 3 H 2 F 5 , -C3HF6, -C3F7, -CH2CI, -CHC12, -CC13, -C2H4CI, -C2H3CI2, -C2H2CI3, -C2HCI4, -C2CI5, -C3H6CI, -C 3 H 5 C1 2 , -C3H4CI3, -C3H3CI4, -C3H2CI5, -C3HQ6, and -C3CI7.
  • Haloalkyl groups are optionally substituted.
  • heterocycle means an unsaturated or saturated, monocyclic or polycyclic non-aromatic ring system containing one or more heteroatoms.
  • Preferred heteroatoms include N, O and S, including N-oxides, sulfur oxides and dioxides.
  • the ring is 5to 10 members and is fully saturated or has one or more degrees of unsaturation. This definition includes multiple degrees of substitution, preferably 1, 2 or 3 degrees of substitution.
  • 5, 6, 7 or 10 membered carbocycle is used in the context of the present invention to refer to "5, 6, 7 or 10 membered cycloalkyl", “5, 6, 7 or 10 membered cycloalkenyl” or "5, 6, 7 or 10 membered aryl” with 5, 6, 7 or 10 carbon atoms forming a ring.
  • 5, 6, 7 or 10 membered heterocycle is used in the context of the present invention to refer to "5, 6, 7 or 10 membered heterocycloalkyl", “5, 6, 7 or 10 membered heterocycloalkenyl” or “5, 6, 7 or 10 membered heteroaryl” with 5, 6, 7 or 10 carbon atoms forming a ring.
  • the term “5 to 10 membered carbocycle” is used in the context of the present invention to refer to "5 to 10 membered cycloalkyl", “5 to 10 membered cycloalkenyl” or “5 to 10 membered aryl” with 5, 6, 7, 8, 9 or 10 carbon atoms forming a ring.
  • 5 to 10 membered heterocycle is used in the context of the present invention to refer to "5 to 10 membered heterocycloalkyl", “5 to 10 membered heterocycloalkenyl” or “5 to 10 membered heteroaryl” with 5 to 10 carbon atoms forming a ring.
  • cycloalkenyl as used in the context of the present invention includes cyclopentenyl, cyclohexenyl, and cycloheptenyl. Cycloalkenyl groups are optionally substituted.
  • cycloalkyl and “heterocycloalkyl”, by themselves or in combination with other terms, represent, as used in the context of the present invention, unless otherwise stated, cyclic versions of “alkyl” and “heteroalkyl”, respectively, with preferably 3, 4, 5, 6, 7, 8, 9 or 10 atoms forming a ring, e.g. cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl etc.
  • cycloalkyl and “heterocycloalkyl” are also meant to include bicyclic, tricyclic and polycyclic versions thereof.
  • heterocycloalkyl preferably refers to a saturated ring having five of which at least one member is a N, O or S atom and which optionally contains one additional O or one additional N; a saturated ring having six members of which at least one member is a N, O or S atom and which optionally contains one additional O or one additional N or two additional N atoms; or a saturated bicyclic ring having nine or ten members of which at least one member is a N, O or S atom and which optionally contains one, two or three additional N atoms.
  • Cycloalkyl and “heterocycloalkyl” groups are optionally substituted.
  • a heteroatom can occupy the position at which the heterocycle is attached to the remainder of the molecule.
  • cycloalkyl include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, 1 -cyclohexenyl, 3-cyclohexenyl, cycloheptyl, spiro[3,3]heptyl, spiro [3, 4] octyl, spiro[4,3]octyl, spiro[3,5]nonyl, spiro[5,3]nonyl, spiro [3, 6] decyl, spiro[6,3]decyl, spiro[4,5]decyl, spiro [5, 4] decyl, bicyclo[2.2.1]heptyl, bicyclo[2.2.2]octyl, adamantyl, and the like.
  • heterocycloalkyl examples include 1 -( 1,2, 5,6- tetrahydropyridyl), 1-piperidinyl, 2-piperidinyl, 3-piperidinyl, 4-morpholinyl, 3-morpholinyl, 1,8 diazo-spiro-[4,5] decyl, 1,7 diazo-spiro-[4,5] decyl, 1,6 diazo-spiro-[4,5] decyl, 2,8 diazo- spiro[4,5] decyl, 2,7 diazo-spiro[4,5] decyl, 2,6 diazo-spiro[4,5] decyl, 1,8 diazo- spiro- [5, 4] decyl, 1,7 diazo- spiro- [5, 4] decyl, 2,8 diazo- spiro- [5, 4] decyl, 2,7 diazo-spiro[5,4] decyl, 3,8 diazo- spiro [5, 4] decyl,
  • aryl as used in the context of the present invention means, unless otherwise stated, a polyunsaturated, typically aromatic, hydrocarbon group which can be a single ring or multiple rings (up to three rings) which are fused together or linked covalently.
  • heteroaryl refers to a 5, 6 or 7-membered aromatic monocyclic ring wherein at least one of the carbon atoms are replaced by 1, 2, or 3 (for the five membered ring) or 1, 2, 3, or 4 (for the six membered ring) of the same or different heteroatoms, preferably selected from O, N and S.
  • Preferred heteroaryl groups have from 1 to 3 heteroatoms as ring members selected from N, O and S.
  • heteroaryls examples include benzimidazolyl, benzodioxolyl, benzofuranyl, 1 -benzofuranyl, 2-benzofuranyl, 2,1-benzosoxazoyl, 1,2-benzisothiazolyl, 2,1-benzisothiazolyl, benzothiazolyl, benzothienyl, benzothiophenyl, 2-benzothiophenyl, 1,2,3-benzotriazinyl, 1 ,2,4-benzotriazinyl, benzotriazolyl, dihydrobenzodioxinyl, dihydrocyclopentathienyl, dihydroindolyl, dihydroisoindolyl, dihydropyrrolizinyl, dihydroquinoxalinyl, dihydrothienodioxinyl, furanyl, furyl, imidazopyridinyl, imidazolyl, IH-indazolyl, ind
  • heteroatom is meant to include oxygen (O), nitrogen (N), and sulfur (S).
  • aryl when used in combination with other terms (e.g.: aryloxy, arylthioxy, arylalkyl) includes both aryl and heteroaryl rings as defined above.
  • arylalkyl is meant to include those radicals in which an aryl group is attached to an alkyl group.
  • alkyl in some embodiments, will include both substituted and unsubstituted forms of the indicated radical. Preferred substituents for each type of radical are provided below.
  • aryl and heteroaryl will refer to substituted or unsubstituted versions as provided below, while the term “alkyl” and related aliphatic radicals is meant to refer to unsubstituted version, unless indicated to be substituted.
  • R', R" and R'" each independently refer to hydrogen, unsubstituted C1-6 alkyl, unsubstituted heteroalkyl, unsubstituted aryl, aryl substituted with 1-3 halogens, unsubstituted C1-6 alkyl, Cn 8 alkoxy or C1-6 thioalkoxy groups, or unsubstituted aryl-Ci-4 alkyl groups.
  • R' and R" are attached to the same nitrogen atom, they can be combined with the nitrogen atom to form a 3-, 4-, 5-, 6-, or 7-membered ring.
  • an acyl preferably comprises 1 to 4 carbon atoms.
  • carbon atoms or hydrogen atoms in alkyl, heteroalkyl, cycloalkyl, aryl, aralkyl, alkenyl, cycloalkenyl, alkynyl radicals may be substituted independently from each other with one or more elements selected from the group consisting of O, S, N or with groups containing one or more elements selected from the group consisting of O, S, N.
  • radicals can be selected independently from each other, then the term "independently" means that the radicals may be the same or may be different.
  • R' and R" is each independently selected from the group consisting of hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, aralkyl, and heteroaryl or together form a heteroaryl, or heterocycloalkyl;
  • R'" and R"" is each independently selected from the group consisting of hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, alkoxy, aryl, aralkyl, heteroaryl, and -NR'R";
  • E is selected from the group consisting of alkyl, alkenyl, alkynyl, cycloalkyl, alkoxy, alkoxyalkyl, heterocycloalkyl, an alicyclic system, aryl and heteroaryl; optionally substituted.
  • amide bioisostere refers to a moiety wherein an amide bond is replaced by a bioisostere having chemical and/or physical similarities, which produce broadly similar biological properties in the same chemical compound (see IUPAC, Compendium of Chemical Terminology, 2nd ed. (the "Gold Book”) (1997). Online corrected version: (1998) "bioisostere”. doi:10.1351/goldbook.BT06798).
  • Amide bioisosteres preferably comprise, but are not limited to, 1,2,3-triazole, oxadiazole, imidazole, tetrazole, pyrazole, indole, pyridine, pyrazine, retroinverted and reverse amide, urea, olefin, fluoroalkene, trifluoroethylamine, amidine, ester, sulfonamide, phosphonamidate, thioamide, and carbamate.
  • amide bioisostere as used herein preferably refers to a moiety represented by, but not limited to, the following examples: wherein R 6 is selected from the group consisting of hydrogen, Ci-6 alkyl, which is optionally substituted by one or more halogen(s), Ci-6 alkoxy, which is optionally substituted by halogen(s), and a 5, 6, 7, or 10-membered carbo- or heterocycle, which is optionally substituted by 1 to 3 R 7 substituents, wherein R 7 is selected from the group consisting of one or more halogen(s), — CN, — NO 2 , — R f , — CO 2 R d , — CONR d R e , — C(O)R d , — OC(O)NR d R e , — NR e C(O)R d , — NR e C(O) 2 R f , — NR d C(O)NR d R e
  • pharmaceutically acceptable means approved by a regulatory agency of the Federal or a state government or listed in the U.S. Pharmacopeia (United States Pharmacopeia-33/National Formulary-28 Reissue, published by the United States Pharmacopeia Convention, Inc., Rockville Md., publication date: April 2010) or other generally recognized pharmacopeia for use in animals, and more particularly in humans.
  • Suitable pharmaceutically acceptable salts of the compound of the present invention include acid addition salts which may, for example, be formed by mixing a solution of a compound described herein or a derivative thereof with a solution of a pharmaceutically acceptable acid such as hydrochloric acid, sulfuric acid, fumaric acid, maleic acid, succinic acid, acetic acid, benzoic acid, citric acid, tartaric acid, carbonic acid or phosphoric acid.
  • a pharmaceutically acceptable acid such as hydrochloric acid, sulfuric acid, fumaric acid, maleic acid, succinic acid, acetic acid, benzoic acid, citric acid, tartaric acid, carbonic acid or phosphoric acid.
  • suitable pharmaceutically acceptable salts thereof may include alkali metal salts (e.g., sodium or potassium salts); alkaline earth metal salts (e.g., calcium or magnesium salts); and salts formed with suitable organic ligands (e.g., ammonium, quaternary ammonium and amine cations formed using counteranions such as halide, hydroxide, carboxylate, sulfate, phosphate, nitrate, alkyl sulfonate and aryl sulfonate).
  • alkali metal salts e.g., sodium or potassium salts
  • alkaline earth metal salts e.g., calcium or magnesium salts
  • suitable organic ligands e.g., ammonium, quaternary ammonium and amine cations formed using counteranions such as halide, hydroxide, carboxylate, sulfate, phosphate, nitrate, alkyl sulfonate and aryl sul
  • compositions include but are not limited to: acetate, adipate, alginate, ascorbate, aspartate, benzene sulfonate, benzoate, bicarbonate, bisulfate, bitartrate, borate, bromide, butyrate, calcium edetate, camphorate, camphorsulfonate, camsylate, carbonate, chloride, citrate, clavulanate, cyclopentanepropionate, digluconate, dihydrochloride, dodecylsulfate, edetate, edisylate, estolate, esylate, ethanesulfonate, formate, fumarate, gluceptate, glucoheptonate, gluconate, glutamate, glycerophosphate, glycolylarsanilate, hemisulfate, heptanoate, hexanoate, hexylresorcinate
  • the neutral forms of the compounds may be regenerated by contacting the salt with a base or acid and isolating the parent compound in the conventional manner.
  • the parent form of the compound differs from the various salt forms in certain physical properties, such as solubility in polar solvents, but otherwise the salts are equivalent to the parent form of the compound for the purposes of the present invention.
  • the present invention provides compounds which are in a prodrug form.
  • Prodrugs of the compounds described herein are those compounds that readily undergo chemical changes under physiological conditions to provide a compound of formula (I) or (IV).
  • a prodrug is an active or inactive compound that is modified chemically through in vivo physiological action, such as hydrolysis, metabolism and the like, into a compound of this invention following administration of the prodrug to a patient.
  • prodrugs can be converted to the compounds of the present invention by chemical or biochemical methods in an ex vivo environment. For example, prodrugs can be slowly converted to the compounds of the present invention when placed in a transdermal patch reservoir with a suitable enzyme.
  • prodrugs are well known by those skilled in the art.
  • Examples of a masked carboxylate anion include a variety of esters, such as alkyl (for example, methyl, ethyl), cycloalkyl (for example, cyclohexyl), aralkyl (for example, benzyl, p-methoxybenzyl), and alkylcarbonyloxyalkyl (for example, pivaloyloxymethyl).
  • Amines have been masked as arylcarbonyloxymethyl substituted derivatives which are cleaved by esterases in vivo releasing the free drug and formaldehyde (Bundgaard H et al., 1989. J Med Chem 32(12): 2503-2507).
  • drugs containing an acidic NH group such as imidazole, imide, indole and the like, have been masked with N- acyloxymethyl groups (Bundgaard H, 1985). Hydroxy groups have been masked as esters and ethers.
  • EP 0039 051 A2 discloses Mannich-base hydroxamic acid prodrugs, their preparation and use.
  • substitution when referring to the substituent of an aryl means that the substituent occupies the position opposite to the position at which the aryl is linked to the backbone of the compound.
  • a "patient” means any mammal or bird that may benefit from a treatment with the compounds described herein.
  • a “patient” is selected from the group consisting of laboratory animals, domestic animals, or primates including chimpanzees and human beings. It is particularly preferred that the "patient” is a human being.
  • treat means accomplishing one or more of the following: (a) reducing the severity of the disorder; (b) limiting or preventing development of symptoms characteristic of the disorder(s) being treated; (c) inhibiting worsening of symptoms characteristic of the disorder(s) being treated; (d) limiting or preventing recurrence of the disorder(s) in patients that have previously had the disorder(s); and (e) limiting or preventing recurrence of symptoms in patients that were previously symptomatic for the disorder(s).
  • prevent means preventing that a disorder occurs in a subject for a certain amount of time.
  • a compound described herein is administered to a subject with the aim of preventing a disease or disorder, said disease or disorder is prevented from occurring at least on the day of administration and preferably also on one or more days (e.g. on 1 to 30 days; or on 2 to 28 days; or on 3 to 21 days; or on 4 to 14 days; or on 5 to 10 days) following the day of administration.
  • a "pharmaceutical composition” according to the invention may be present in the form of a composition, wherein the different active ingredients and diluents and/or carriers are admixed with each other, or may take the form of a combined preparation, where the active ingredients are present in partially or totally distinct form.
  • An example for such a combination or combined preparation is a kit-of-parts.
  • an "effective amount” as used in the context of the present invention refers to an amount of a therapeutic agent sufficient to achieve the intended purpose.
  • the effective amount of a given therapeutic agent will vary with factors such as the nature of the agent, the route of administration, the size and species of the animal to receive the therapeutic agent, and the purpose of the administration.
  • the effective amount in each individual case may be determined empirically by a skilled artisan according to established methods in the art.
  • carrier refers to a diluent, adjuvant, excipient, or vehicle with which the therapeutic agent is administered.
  • Such pharmaceutical carriers can be sterile liquids, such as saline solutions in water and oils, including those of petroleum, animal, vegetable or synthetic origin, such as peanut oil, soybean oil, mineral oil, sesame oil and the like.
  • a saline solution is a preferred carrier when the pharmaceutical composition is administered intravenously.
  • Saline solutions and aqueous dextrose and glycerol solutions can also be employed as liquid carriers, particularly for injectable solutions.
  • Suitable pharmaceutical excipients include starch, glucose, lactose, sucrose, gelatine, malt, rice flour, chalk, silica gel, sodium stearate, glycerol monostearate, talc, sodium chloride, dried skim milk, glycerol, propylene glycol, water, ethanol and the like.
  • the composition if desired, can also contain minor amounts of wetting or emulsifying agents, or pH buffering agents. These compositions can take the form of solutions, suspensions, emulsions, tablets, pills, capsules, powders, sustained-release formulations and the like.
  • the composition can be formulated as a suppository, with traditional binders and carriers such as triglycerides.
  • the compounds of the invention can be formulated as neutral or salt forms.
  • Pharmaceutically acceptable salts include those formed with free amino groups such as those derived from hydrochloric, phosphoric, acetic, oxalic, tartaric acids, etc., and those formed with free carboxyl groups such as those derived from sodium, potassium, ammonium, calcium, ferric hydroxides, isopropylamine, triethylamine, 2-ethylamino ethanol, histidine, procaine, etc.
  • suitable pharmaceutical carriers are described in Martin EW, Remington's Pharmaceutical Sciences, Mack Publishing, Easton, Pa.
  • compositions will contain a therapeutically effective amount of the compound, preferably in purified form, together with a suitable amount of carrier so as to provide the form for proper administration to the patient.
  • the formulation should suit the mode of administration.
  • for use in medicine refers in the context of the present invention to the use of the compounds disclosed herein in a method for manufacturing a medicament or a pharmaceutical composition or for diagnosis, therapy or prevention of a disease or disorder in a subject or individual.
  • Acinetobacter baumannii infections refers in the context of the present invention to infections with Acinetobacter baumannii or diseases resulting from such infections comprising, but not limited to, bacteremia, eye infection (corneal ulcers, endophthalmitis, periorbital cellulitis), pneumonia, meningitis, bloodstream infection, bone infection, skin infection, soft tissue infection, peritonitis, sinusitis, urinary tract infection, and wound infection.
  • 'Acinetobacter baumannii-associated lung infections refers in the context of the present invention to infections of one or both lungs, such as pneumonia, and in particular ventilator-associated pneumonia.
  • catheter-associated Acinetobacter baumannii infections refers in the context of the present invention to infections with Acinetobacter baumannii associated with the use of catheters, such as urinary tract infections.
  • Acinetobacter baumannii-associated bacteremia refers in the context of the present invention to the presence of Acinetobacter baumannii in the bloodstream.
  • the most common sources of bacteremia are intravascular catheters and the respiratory tract.
  • Acinetobacter baumannii-associated sepsis refers in the context of the present invention to an uncontrolled systemic inflammatory response to an infection from Acinetobacter baumannii that may rapidly progress to a life-threatening condition and can lead to shock and organ failure (i.e., septic shock and severe sepsis) if not treated immediately.
  • carbapenem resistant Acinetobacter baumannii refers in the context of the present invention to an Acinetobacter baumannii that is nonsusceptible to at least one antip seudomonal carbapenem.
  • multidrug resistant Acinetobacter baumannii refers in the context of the present invention to an Acinetobacter baumannii nonsusceptible to at least one agent in three or more antibiotic groups (i.e., third- or fourth-generation cephalosporins, fluoroquinolones, aminoglycosides, carbapenems, piperacillin-tazobactam, and ampicillin-sulbactam).
  • antibiotic groups i.e., third- or fourth-generation cephalosporins, fluoroquinolones, aminoglycosides, carbapenems, piperacillin-tazobactam, and ampicillin-sulbactam.
  • anti-bacterial therapeutic agent refers in the context of the present invention substances or biomolecules that selectively destroy bacteria by interfering with bacterial growth or survival, anti- virulence agents and host-directed therapeutics.
  • anti-bacterial therapeutic agent refers to antibiotics, peptides, carbohydrates, and nucleic acids.
  • Anti-bacterial nucleic acids are preferably antisense antimicrobial therapeutic agents, aptamers, and topoisomerase inhibitors.
  • Antimicrobial peptides are usually short biomolecules (15-50 amino acids) encoded by genes. Most of these short peptides contain basic amino acids and hydrophobic residues, which are arranged in three dimensions on the surface of the peptide. Thousands of AMPs have been extracted from single-celled microorganisms of plants, insects, and bacteria.
  • the antimicrobial peptide database contains more than 3000 AMPs (Wang, G, el al., 2016. APD3: the antimicrobial peptide database as a tool for research and education. Nucleic Acids Research, 44, DI, D1087-D1093). Also bacteria produce a variety of AMPs in order to limit the growth of other microorganisms.
  • AMPs can be ranked according to their physical properties, sequence properties, and conformation of antimicrobial peptides interacting with cell membranes.
  • Exemplary antimicrobial peptides comprise, but are not limited to, LL-37, Bactenecin, BMAP-27, CATH-2, PMAP-36, Protegrin, Abaecin, Cecropin, BhDefl-2, alfAFP, Vrd2, Snakin-1, nisin, triAl, pediocin, LMW, and garvicin KS.
  • anti-bacterial therapeutic agent refers to a carbapenem antibiotic (e.g. ertapenem, doripenem, imipenem/cilastatin, and meropenem), cephalosporin antibiotic (e.g. cephalexin, cefuroxime, cefadroxil, cefazolin, cephalothin, cefaclor, cefamandole, cefoxitin, cefprozil, and ceftobiprole), cyclic lipopeptide antibiotic, fluoroquinolone antibiotic (e.g.
  • ciprofloxacin levaquin, floxin, tequin, moxifloxacin, and norfloxacin
  • tetracycline antibiotic e.g. tetracycline, minocycline, oxytetracycline, and doxycycline
  • fusidic acid lantibiotic (e.g nisin, mersacidin, actagardine, deoxyactagardine B, and microbio sporin)
  • lincomycin antibiotic macrolide antibiotic (azithromycin, clarithromycin, erythromycin, telithromycin, quinorubicin, and solithromycin), meropenem antibiotic (e.g.
  • meropenem e.g. linezolid, terizolide and lefluide
  • penicillin antibiotic e.g. amoxicillin, ampicillin, penicillin v, dicloxacillin, carbenicillin, vancomycin, and methicillin
  • streptogramin antibiotic e.g. tigecycline antibiotic, omacycline (omadacycline), evericin (ovacycline), doxycycline and minocycline
  • vancomycin antibiotic e.g. vancomycin, teicoplanin, telavancin, dalbavancin, and oritavancin.
  • the term "anti-bacterial therapeutic agent” refers to amikacin, amoxicillin, ampicillin (e.g., pivampicillin, hetacillin, bacampicillin, metampicillin, talampicillin), apramycin, arbekacin, azidocillin, azithromycin, azlocillin, aztreonam, benzathine benzylpenicillin, benzathine phenoxymethylpenicillin, benzazole, benzylpenicillin (g), biapenem, carbenicillin (carindacillin), carumonam, cefacetrile, cefaclor, cefadroxil, cefalexin, cefaloglycin, cefalonium, cefaloridine, cefalotin, cefamandole, cefapirin, cefatrizine, cefazaflur, cefazedone, cefazolin, cefbuperazone, cefcapene, cefd
  • anti-virulence agent refers in the context of the present invention to an agent able to reduce expression of a virulence factor that is expressed in a bacterium- specific manner under infection conditions, and which is not essential for bacterial viability but is rather required for pathogenesis.
  • an anti-virulence agent can target quorum sensing, secretion systems, toxins, and biofilms.
  • an anti-virulence agent can be an anti-sense nucleotide that inhibits expression of a virulence factor.
  • host-directed therapeutics refers in the context of the present invention to small-molecule drugs and proteins to alter the host response to pathogen infection.
  • Preferred host-directed therapeutics are selected from the group comprising probiotics, immunomodulators, such as lysophosphatidylcholine and macrolide antibiotics such as clarithromycin.
  • protecting group refers to a functional group as known in the art, i.e. a protecting group or protective group introduced into a molecule by chemical modification of a functional group to obtain chemoselectivity in a subsequent chemical reaction.
  • Preferred examples are those protecting groups selected from, but not limited to, a benzyl group (Ph — CH2 — , abbreviation Bn, a benzhydryl group (Phi — CH — ), a benzyloxycarbonyl group (Ph — CH2O — CO — , abbreviation Cbz), a benzyloxymethyl group (Ph — CH2O — CH2 — , abbreviation Bom), /-butoxycarbonyl group (Boc), a fluorenylmethoxyl group (FMoc), and a trityl group (Ph? — C — , abbreviation Tr).
  • a benzyl group Ph — CH2 — , abbreviation Bn
  • a benzhydryl group Phi — CH —
  • a benzyloxycarbonyl group Ph — CH2O — CO —
  • the present invention provides a compound of the general formula (I): wherein
  • R 1 is individually selected from the group consisting of halogen and C1-4 alkyl, which is optionally substituted by one or more halogen(s), and C1-4 alkoxy, which is optionally substituted by one or more halogen(s);
  • R 2 is individually selected from the group consisting of hydrogen, OH, NH2, NO2, SH, one or more halogen(s), COOR 8 , wherein R 8 is hydrogen or C1-4 alkyl, which is optionally substituted by one or more halogen(s), C1-4 acyl, which is optionally substituted by one or more halogen(s), C1-4 alkyl, which is optionally substituted by one or more halogen(s), and C1-4 alkoxy, which is optionally substituted by one or more halogen(s); m is 0, 1, 2 or 3;
  • R 7 is selected from the group consisting of one or more halogen(s), — CN, — N0 2 , — R f , — CO 2 R d , — CONR d R e , — C(O)R d , — OC(O)NR d R e , — NR e C(O)R d , — NR e C(O) 2 R f , — NR d C(O)NR d R e , — NR d R e , — 0R d , and — S(O) 2 NR d R e ; wherein each R d and R e is independently selected from hydrogen, C1-8 alkyl, and C1-8 halogen(s), and a 5 to 10 membered carbo- or heterocycle, which is optionally substituted by 1 to 3 R 7 substituents, wherein R 7 is selected from the group consisting of one or more halogen(
  • R 4 and R 5 are individually selected from the group consisting of hydrogen, one or more halogen(s), and C1-4 alkyl, and preferably are hydrogen; or a salt thereof, or a solvate thereof, or a prodrug thereof.
  • R 3 is a residue of the formula (la) wherein
  • R 6 is selected from the group consisting of hydrogen, C1-6 alkyl, which is optionally substituted by one or more halogen(s), C1-6 alkoxy, which is optionally substituted by one or more halogen(s), and a 5, 6, 7, or 10-membered carbo- or heterocycle, which is optionally substituted by 1 to 3 R 7 substituents, wherein R 7 is selected from the group consisting of one or more halogen(s), — CN, — NO 2 , — R f , — CO 2 R d , — CONR d R e , — C(O)R d , — OC(O)NR d R e , — NR e C(O)R d , — NR e C(O) 2 R f , — NR d C(O)NR d R e , — NR d R e , — 0R d , and — S(0)2NR d R
  • R 3 is a residue of the formula (lb) wherein
  • R 6 is selected from the group consisting of hydrogen, C1-6 alkyl, which is optionally substituted by one or more halogen(s), C1-6 alkoxy, which is optionally substituted by one or more halogen(s), and a 5, 6, 7, or 10-membered carbo- or heterocycle, which is optionally substituted by 1 to 3 R 7 substituents, wherein R 7 is selected from the group consisting of one or more halogen(s), — CN, — NO2, — R f , — CO 2 R d , — CONR d R e , — C(O)R d , — OC(O)NR d R e , — NR e C(O)R d , — NR e C(O) 2 R f , — NR d C(O)NR d R e , — NR d R e , — OR d , and — S(O)2NR d R e
  • R 6 is selected from the group consisting of hydrogen, C1-6 alkyl, which is optionally substituted by one or more halogen(s), C1-6 alkoxy, which is optionally substituted by one or more halogen(s), and a 5, 6, 7, or 10-membered carbo- or heterocycle, which is optionally substituted by 1 to 3 R 7 substituents, wherein R 7 is selected from the group consisting of one or more halogen(s), — CN, — NO2, — R f , — C02R d , — CONR d R e , — C(O)R d , — OC(O)NR d R e , — NR e C(O)R d , — NR e C(O) 2 R f , — NR d C(O)NR d R e , — NR d R e , — OR d , and — S(O)2NR d R e
  • R 3 is a residue of the formula (Id) wherein
  • R 6 is selected from the group consisting of hydrogen, Ci-6 alkyl, which is optionally substituted by one or more halogen(s), Ci-6 alkoxy, which is optionally substituted by halogen(s), and a 5, 6, 7, or 10-membered carbo- or heterocycle, which is optionally substituted by 1 to 3 R 7 substituents, wherein R 7 is selected from the group consisting of one or more halogen(s), — CN, — NO2, — R f , — C02R d , — CONR d R e , — C(O)R d , — OC(O)NR d R e , — NR e C(O)R d , — NR e C(O) 2 R f , — NR d C(O)NR d R e , — NR d R e , — OR d , and — S(0)2NR d R e ; wherein each
  • R 3 is a residue of the formula (la).
  • R 6 is selected from the group consisting of C3-6 alkyl, which is optionally substituted by one or more halogen(s), C1-6 alkoxy, which is optionally substituted by one or more halogen(s), and a 5, 6, 7, or 10-membered carbo- or heterocycle, having 1 to 3 heteroatoms as ring members selected from N, O, and S, which 5, 6, 7, or 10-carbo- or heterocycle is optionally substituted by 1 to 3 R 7 substituents, wherein R 7 is selected from the group consisting of one or more halogen(s), — CN, — NO 2 , — R f , — CO 2 R d , — CONR d R e , — C(O)R d , — OC(O)NR d R e , — NR e C(O)R d , — NR e C(O) 2 R f , — NR
  • R d , R e and R f are optionally further substituted with from one to three halogen, hydroxy, methyl, amino, C 1-6 alkylamino and di C1-6 alkylamino groups.
  • R 6 is a 5, 6,
  • R 7 is selected from the group consisting of one or more halogen(s), — CN, — NO 2 , — R f , — CO 2 R d , — CONR d R e , — C(O)R d , — OC(O)NR d R e , — NR e C(O)R d , — NR e C(O) 2
  • R 1 is chlorine.
  • R 2 is hydrogen.
  • R 4 is hydrogen.
  • R 5 is hydrogen.
  • R 1 is chlorine and/or R 2 , R 4 and/or R 5 are hydrogen.
  • R 2 , R 4 and/or R 5 are hydrogen.
  • n is 0. In a further preferred embodiment of the first aspect of the present invention, m is 0. In a further preferred embodiment of the first aspect of the present invention, m is 0 and n is 0. In a further preferred embodiment of the first aspect of the present invention, m is 0 and n is 2. In a further preferred embodiment of the first aspect of the present invention, n is 0. In a further preferred embodiment of the first aspect of the present invention, n is 2.
  • R 1 is chlorine, and R 2 , R 4 and R 5 are hydrogen, m is 0, and n is 0.
  • R 1 is chlorine, and R 2 , R 4 and R 5 are hydrogen, m is 0, and n is 1.
  • R 1 is chlorine, and R 2 , R 4 and R 5 are hydrogen, m is 0, and n is 2.
  • R 1 is chlorine, and R 2 , R 4 and R 5 are hydrogen, m is 0, R 3 is a residue of the formula (la), and n is 0.
  • R 1 is chlorine, and R 2 , R 4 and R 5 are hydrogen, m is 0, R 3 is a residue of the formula (la), and n is 1.
  • R 1 is chlorine, and R 2 , R 4 and R 5 are hydrogen, m is 0, R 3 is a residue of the formula (la), and n is 2.
  • R 1 is chlorine, and R 2 , R 4 and R 5 are hydrogen, m is 0, R 3 is a residue of the formula (lb), and n is 0.
  • R 1 is chlorine, and R 2 , R 4 and R 5 are hydrogen, m is 0, R 3 is a residue of the formula (lb), and n is 1.
  • R 1 is chlorine, and R 2 , R 4 and R 5 are hydrogen, m is 0, R 3 is a residue of the formula (lb), and n is 2.
  • R 1 is chlorine, and R 2 , R 4 and R 5 are hydrogen, m is 0, R 3 is a residue of the formula (Ic), and n is 0.
  • R 1 is chlorine, and R 2 , R 4 and R 5 are hydrogen, m is 0, R 3 is a residue of the formula (Ic), and n is 1.
  • R 1 is chlorine, and R 2 , R 4 and R 5 are hydrogen, m is 0, R 3 is a residue of the formula (Ic), and n is 2.
  • R 1 is chlorine, and R 2 , R 4 and R 5 are hydrogen, m is 0, R 3 is a residue of the formula (Id), and n is 0.
  • R 1 is chlorine, and R 2 , R 4 and R 5 are hydrogen, m is 0, R 3 is a residue of the formula (Id), and n is 1.
  • R 1 is chlorine, and R 2 , R 4 and R 5 are hydrogen, m is 0, R 3 is a residue of the formula (Id), and n is 2.
  • R 6 is a hydrogen, a pentyl group, a cyclopropyl group, a cyclopentyl group, a cyclohexyl group, a phenyl group, a tert-butyl group, a O-tert-butyl group, a n-butyl group, a methyl group, a methyl-butyl group, a benzyl group, a adamantyl group, a pyridinyl group, a piperazinyl group, a hexahydropyrimidinyl group, a hexahydropyridazinyl group, a 3-thienyl group, a piperidinyl group, a pyrrolyl group, a 4-Boc-morpholinyl group, a N-Boc-piperidinyl group, or a 1-Boc- (4-Boc)
  • R 1 is chlorine
  • R 2 , R 4 and R 5 are hydrogen
  • m is 0,
  • R 3 is a residue of the formula (la),
  • R 6 is a hydrogen, a pentyl group, a cyclopropyl group, a cyclopentyl group, a cyclohexyl group, a phenyl group, a tert-butyl group, a O-tert-butyl group, a n-butyl group, a methyl group, a methyl-butyl group, a benzyl group, a adamantyl group, a pyridinyl group, a piperazinyl group, a hexahydropyrimidinyl group, a hexahydropyridazinyl group, a 3-thienyl group, a piperidinyl group, a pyrrolyl group,
  • R 1 is chlorine
  • R 2 , R 4 and R 5 are hydrogen
  • m is 0,
  • R 3 is a residue of the formula (lb), n 0 or 2
  • R 6 is a hydrogen, a pentyl group, a cyclopropyl group, a cyclopentyl group, a cyclohexyl group, a phenyl group, a tert-butyl group, a O-tert-butyl group, a n-butyl group, a methyl group, a methyl-butyl group, a benzyl group, a adamantyl group, a pyridinyl group, a piperazinyl group, a hexahydropyrimidinyl group, a hexahydropyridazinyl group, a 3-thienyl group, a piperidinyl group, a pyrrolyl group
  • R 1 is chlorine
  • R 2 , R 4 and R 5 are hydrogen
  • m is 0,
  • R 3 is a residue of the formula (Ic), n 0 or 2
  • R 6 is a hydrogen, a pentyl group, a cyclopropyl group, a cyclopentyl group, a cyclohexyl group, a phenyl group, a tert-butyl group, a O-tert-butyl group, a n-butyl group, a methyl group, a methyl-butyl group, a benzyl group, a adamantyl group, a pyridinyl group, a piperazinyl group, a hexahydropyrimidinyl group, a hexahydropyridazinyl group, a 3-thienyl group, a piperidinyl group, a pyrrolyl group
  • R 1 is chlorine
  • R 2 , R 4 and R 5 are hydrogen
  • m is 0,
  • R 3 is a residue of the formula (Id), n 0 or 2
  • R 6 is a hydrogen, a pentyl group, a cyclopropyl group, a cyclopentyl group, a cyclohexyl group, a phenyl group, a tert-butyl group, a O-tert-butyl group, a n-butyl group, a methyl group, a methyl-butyl group, a benzyl group, a adamantyl group, a pyridinyl group, a piperazinyl group, a hexahydropyrimidinyl group, a hexahydropyridazinyl group, a 3-thienyl group, a piperidinyl group, a pyrrolyl group
  • R 1 is chlorine, m is 0, n is 2, R 3 is a residue of the formula (la), R 4 and R 5 are hydrogen, and R 6 is a O-tert-butyl group.
  • R 3 is selected from the group consisting of:
  • the compound has the following formula (II): wherein R 3 is as defined above.
  • the compound has the following formula: wherein
  • the present invention relates to a pharmaceutical composition
  • a pharmaceutical composition comprising or consisting of at least one compound of the first aspect, and, optionally, one or more constituents selected from the group consisting of a pharmaceutically acceptable carrier, a diluent, an excipient and a further anti-bacterial therapeutic agent.
  • the present invention relates to a pharmaceutical composition comprising or consisting of at least one compound of the first aspect, and one or more constituents selected from the group consisting of a pharmaceutically acceptable carrier, a diluent, an excipient.
  • the present invention relates to a pharmaceutical composition
  • a pharmaceutical composition comprising or consisting of at least one compound of the first aspect, and one or more constituents selected from the group consisting of a pharmaceutically acceptable carrier, a diluent, an excipient and one or more further anti-bacterial therapeutic agent(s).
  • the one or more anti-bacterial therapeutic agent(s) is selected from the group consisting of a carbapenem antibiotic (e.g. ertapenem, doripenem, imipenem/cilastatin, and meropenem), cephalosporin antibiotic (e.g. cephalexin, cefuroxime, cefadroxil, cefazolin, cephalothin, cefaclor, cefamandole, cefoxitin, cefprozil, and ceftobiprole), cyclic lipopeptide antibiotic, fluoroquinolone antibiotic (e.g.
  • a carbapenem antibiotic e.g. ertapenem, doripenem, imipenem/cilastatin, and meropenem
  • cephalosporin antibiotic e.g. cephalexin, cefuroxime, cefadroxil, cefazolin, cephalothin, cefaclor, cefamandole, cefoxitin, cefprozi
  • ciprofloxacin levaquin, floxin, tequin, moxifloxacin, and norfloxacin
  • tetracycline antibiotic e.g. tetracycline, minocycline, oxytetracycline, and doxycycline
  • fusidic acid lantibiotic (e.g nisin, mersacidin, actagardine, deoxyactagardine B, and microbio sporin)
  • lincomycin antibiotic macrolide antibiotic (azithromycin, clarithromycin, erythromycin, telithromycin, quinorubicin, and solithromycin), meropenem antibiotic (e.g.
  • meropenem e.g. linezolid, terizolide and lefluide
  • penicillin antibiotic e.g. amoxicillin, ampicillin, penicillin v, dicloxacillin, carbenicillin, vancomycin, and methicillin
  • streptogramin antibiotic e.g. tigecycline antibiotic, omacycline (omadacycline), evericin (ovacycline), doxycycline and minocycline
  • vancomycin antibiotic e.g. vancomycin, teicoplanin, telavancin, dalbavancin, and oritavancin.
  • the one or more anti-bacterial therapeutic agent(s) is selected from the group consisting of amikacin, amoxicillin, ampicillin (e.g., pivampicillin, hetacillin, bacampicillin, metampicillin, talampicillin), apramycin, arbekacin, azidocillin, azithromycin, azlocillin, aztreonam, benzathine benzylpenicillin, benzathine phenoxymethylpenicillin, benzazole, benzylpenicillin (g), biapenem, carbenicillin (carindacillin), carumonam, cef acetrile, cefaclor, cefadroxil, cefalexin, cefaloglycin, cefalonium, cefaloridine, cefalotin, cefamandole, cefapirin, cefatrizine, cefazaflur, cefazedone, cefazolin, cefbu
  • the present invention relates to the compound of the first aspect for use in medicine. In a third aspect, the present invention relates to the pharmaceutical composition of the second aspect for use in medicine.
  • the present invention relates to the compound of the first aspect for use as a medicament. In a preferred embodiment, the present invention relates to the pharmaceutical composition of the second aspect for use as a medicament.
  • the present invention relates to the compound of the first aspect optionally in combination with one or more anti-bacterial therapeutic agent(s), for use in the prophylaxis or treatment of Acinetobacter baumannii infections in a patient.
  • the present invention relates to the compound of the first aspect optionally in combination with one or more anti-bacterial therapeutic agent(s), for use in the prophylaxis or treatment of Acinetobacter baumannii-associated lung infections, catheter-associated infections, bacteremia, or sepsis in a patient.
  • the present invention relates to the compound of the first aspect optionally in combination with one or more anti-bacterial therapeutic agent(s), for use in the prophylaxis or treatment of carbapenem resistant Acinetobacter baumannii or multidrug resistant Acinetobacter baumannii.
  • the present invention relates to the pharmaceutical composition of the second aspect, for use in the prophylaxis or treatment of Acinetobacter baumannii infections in a patient.
  • the present invention relates to the pharmaceutical composition of the second aspect, for use in the prophylaxis or treatment of Acinetobacter baumannii-associated lung infections, catheter-associated infections, bacteremia, or sepsis in a patient.
  • the present invention relates to the pharmaceutical composition of the second aspect, for use in the prophylaxis or treatment of carbapenem resistant Acinetobacter baumannii or multidrug resistant Acinetobacter baumannii.
  • the one or more anti-bacterial therapeutic agent(s) is selected from the group consisting of a carbapenem antibiotic (e.g. ertapenem, doripenem, imipenem/cilastatin, and meropenem), cephalosporin antibiotic (e.g. cephalexin, cefuroxime, cefadroxil, cefazolin, cephalothin, cefaclor, cefamandole, cefoxitin, cefprozil, and ceftobiprole), cyclic lipopeptide antibiotic, fluoroquinolone antibiotic (e.g.
  • a carbapenem antibiotic e.g. ertapenem, doripenem, imipenem/cilastatin, and meropenem
  • cephalosporin antibiotic e.g. cephalexin, cefuroxime, cefadroxil, cefazolin, cephalothin, cefaclor, cefamandole, cefoxitin, cefprozi
  • ciprofloxacin levaquin, floxin, tequin, moxifloxacin, and norfloxacin
  • tetracycline antibiotic e.g. tetracycline, minocycline, oxytetracycline, and doxycycline
  • fusidic acid lantibiotic (e.g nisin, mersacidin, actagardine, deoxyactagardine B, and microbio sporin)
  • lincomycin antibiotic macrolide antibiotic (azithromycin, clarithromycin, erythromycin, telithromycin, quinorubicin, and solithromycin), meropenem antibiotic (e.g.
  • meropenem e.g. linezolid, terizolide and lefluide
  • penicillin antibiotic e.g. amoxicillin, ampicillin, penicillin v, dicloxacillin, carbenicillin, vancomycin, and methicillin
  • streptogramin antibiotic e.g. tigecycline antibiotic, omacycline (omadacycline), evericin (ovacycline), doxycycline and minocycline
  • vancomycin antibiotic e.g. vancomycin, teicoplanin, telavancin, dalbavancin, and oritavancin.
  • the one or more anti-bacterial therapeutic agent(s) is selected from the group consisting of amikacin, amoxicillin, ampicillin (e.g., pivampicillin, hetacillin, bacampicillin, metampicillin, talampicillin), apramycin, arbekacin, azidocillin, azithromycin, azlocillin, aztreonam, benzathine benzylpenicillin, benzathine phenoxymethylpenicillin, benzazole, benzylpenicillin (g), biapenem, carbenicillin (carindacillin), carumonam, cef acetrile, cefaclor, cefadroxil, cefalexin, cefaloglycin, cefalonium, cefaloridine, cefalotin, cefamandole, cefapirin, cefatrizine, cefazaflur, cefazedone, cefazolin, cefbu
  • the present invention relates to a method for the preparation of a compound of formula (I): wherein
  • R 1 is individually selected from the group consisting of halogen and C1-4 alkyl, which is optionally substituted by one or more halogens, and C1-4 alkoxy, which is optionally substituted by one or more halogen(s);
  • R 2 is individually selected from the group consisting of hydrogen, OH, NH2, NO2, SH, one or more halogen(s), COOR 8 , wherein R 8 is hydrogen or C1-4 alkyl, which is optionally substituted by one or more halogen(s),Ci-4 acyl, which is optionally substituted by halogen(s), C1-4 alkyl, which is optionally substituted by one or more halogen(s), or C1-4 alkoxy, which is optionally substituted by one or more halogens; m is 0, 1, 2 or 3;
  • R 4 and R 5 are individually selected from the group consisting of hydrogen, one or more halogen(s), and C1-4 alkyl, and preferably are hydrogen; or a salt thereof, or a solvate thereof, or a prodrug thereof, comprising reacting a compound of formula (II) and a compound of formula (Illa) wherein R 1 , R 2 , and m are as defined for formula (I), p is 1 or 2 or 3, and
  • PGi is a protecting group, and preferably is a t-butoxycarbonyl group (Boe).
  • the present invention relates to a method for the preparation of a compound of formula (I): wherein
  • R 1 is individually selected from the group consisting of halogen and Ci-4 alkyl, which is optionally substituted by one or more halogens, and Ci-4 alkoxy, which is optionally substituted by one or more halogen(s);
  • R 2 is individually selected from the group consisting of hydrogen, OH, NH2, NO2, SH, one or more halogen(s), COOR 8 , wherein R 8 is hydrogen or C1-4 alkyl, which is optionally substituted by one or more halogen(s),Ci-4 acyl, which is optionally substituted by halogen(s), C1-4 alkyl, which is optionally substituted by one or more halogen(s), or C1-4 alkoxy, which is optionally substituted by one or more halogens; m is 0, 1, 2 or 3;
  • R 4 and R 5 are individually selected from the group consisting of hydrogen, one or more halogen(s), and C1-4 alkyl, and preferably are hydrogen; or a salt thereof, or a solvate thereof, or a prodrug thereof, comprising reacting a compound of formula (II) and a compound of formula (Illb) wherein R 1 , R 2 , R 3 , R 4 , R 5 , and m are as defined for formula (I), and wherein R 3 is preferably a residue of the formula (lb) wherein
  • R 6 is selected from the group consisting of hydrogen, Ci-6 alkyl, which is optionally substituted by one or more halogen(s), Ci-6 alkoxy, which is optionally substituted by one or more halogen(s), and a 5, 6, 7, or 10-membered carbo- or heterocycle, which is optionally substituted by 1 to 3 R 7 substituents, wherein R 7 is selected from the group consisting of one or more halogen(s), — CN, — NO 2 , — R f , — CO 2 R d , — CONR d R e , — C(O)R d , — OC(O)NR d R e , — NR e C(O)R d , — NR e C(O) 2 R f , — NR d C(O)NR d R e , — NR d R e , — OR d , and — S(O) 2 NR d
  • the present invention relates to a method for the preparation of a compound of formula (I): wherein
  • R 1 is individually selected from the group consisting of halogen and C1-4 alkyl, which is optionally substituted by one or more halogens, and C1-4 alkoxy, which is optionally substituted by one or more halogen(s);
  • R 2 is individually selected from the group consisting of hydrogen, OH, NH 2 , NO 2 , SH, one or more halogen(s), COOR 8 , wherein R 8 is hydrogen or C1-4 alkyl, which is optionally substituted by one or more halogen(s),Ci-4 acyl, which is optionally substituted by halogen(s), C1-4 alkyl, which is optionally substituted by one or more halogen(s), or C1-4 alkoxy, which is optionally substituted by one or more halogens; m is 0, 1, 2 or 3;
  • R 3 is a residue of the formula (lb) wherein
  • R 6 is selected from the group consisting of hydrogen, Ci-6 alkyl, which is optionally substituted by one or more halogen(s), Ci-6 alkoxy, which is optionally substituted by one or more halogen(s), and a 5, 6, 7, or 10-membered carbo- or heterocycle, which is optionally substituted by 1 to 3 R 7 substituents, wherein R 7 is selected from the group consisting of one or more halogen(s), — CN, — NO 2 , — R f , — CO 2 R d , — CONR d R e , — C(O)R d , — OC(O)NR d R e , — NR e C(O)R d , — NR e C(O) 2 R f , — NR d C(O)NR d R e , — NR d R e , — OR d , and — S(O) 2 NR d
  • R 4 and R 5 are individually selected from the group consisting of hydrogen, one or more halogen(s), and C1-4 alkyl, and preferably are hydrogen; or a salt thereof, or a solvate thereof, or a prodrug thereof, comprising reacting a compound of formula (II) and a compound of formula (Illb) wherein R 1 , R 2 , R 4 , R 5 , and m are as defined for formula (I), and wherein R 3 is a residue of the formula (lb) wherein
  • R 6 is selected from the group consisting of hydrogen, Ci-6 alkyl, which is optionally substituted by one or more halogen(s), Ci-6 alkoxy, which is optionally substituted by one or more halogen(s), and a 5, 6, 7, or 10-membered carbo- or heterocycle, which is optionally substituted by 1 to 3 R 7 substituents, wherein R 7 is selected from the group consisting of one or more halogen(s), — CN, — NO 2 , — R f , — CO 2 R d , — CONR d R e , — C(O)R d , — OC(O)NR d R e , — NR e C(O)R d , — NR e C(O) 2 R f , — NR d C(O)NR d R e , — NR d R e , — OR d , and — S(O) 2 NR d
  • the present invention relates to a method for the preparation of a compound of formula (I): wherein
  • R 1 is chlorine
  • R 2 , R 4 and R 5 are hydrogen; m is 0,
  • R 3 is selected from the group consisting of a residue of the formula (la), a residue of the formula (lb), a residue of the formula (Ic), a residue of the formula (Id), n 0 or 2; and
  • R 6 is a hydrogen, a pentyl group, a cyclopropyl group, a cyclopentyl group, a cyclohexyl group, a phenyl group, a tert-butyl group, a O-tert-butyl group, a n-butyl group, a methyl group, a methyl-butyl group, a benzyl group, a adamantyl group, a pyridinyl group, a piperazinyl group, a hexahydropyrimidinyl group, a hexahydropyridazinyl group, a 3-thienyl group, a piperidinyl group, a pyrrolyl group, a 4-Boc-morpholinyl group, a N-Boc- piperidinyl group, or a l-Boc-(4-Boc)piperazinyl group; or a
  • PGi is a protecting group; or b) reacting a compound of formula (II) and a compound of formula (Illb) wherein R 1 , R 2 , R 3 , R 4 , R 5 , and m are as defined for formula (I), and wherein R 3 is preferably a residue of the formula (lb) wherein
  • R 6 is selected from the group consisting of hydrogen, Ci-6 alkyl, which is optionally substituted by one or more halogen(s), Ci-6 alkoxy, which is optionally substituted by one or more halogen(s), and a 5, 6, 7, or 10-membered carbo- or heterocycle, which is optionally substituted by 1 to 3 R 7 substituents, wherein R 7 is selected from the group consisting of one or more halogen(s), — CN, — NO 2 , — R f , — CO 2 R d , — CONR d R e , — C(O)R d , — OC(O)NR d R e , — NR e C(O)R d , — NR e C(O) 2 R f , — NR d C(O)NR d R e , — NR d R e , — OR d , and — S(O) 2 NR d
  • the present invention relates to a method for the preparation of a compound of formula (I): wherein
  • R 1 is chlorine, m is 0, n is 2, R 3 is a residue of the formula (la), R 4 and R 5 are hydrogen, and R 6 is a O-tert-butyl group; or a salt thereof, or a solvate thereof, or a prodrug thereof, comprising: a) reacting a compound of formula (II) and a compound of formula (Illa) wherein R 1 , R 2 , and m are as defined for formula (I), p is 1 or 2 or 3, and
  • PGi is a protecting group, and preferably is a t-butoxycarbonyl group (Boe).
  • residues R 1 to R 5 are preferably those as defined above, in particular for the first aspect of the invention.
  • PGi is an amino protecting group as known in the art, preferably a Fmoc, Boc (t-Butyl carbamate), Cbz (benzyl carbamate), Ac (acetyl), trifluoroacetyl, phthalimide, Bn (benzyl), Tr (trityl), benzylidene, or Ts (Tosyl) group.
  • the reaction of the amine compound of formula (II) with the isothiocyanate compounds of formula (Illa) or (Illb) to obtain a thiourea compound can be conducted under conditions known in the art.
  • the compounds are dissolved in a suitable solvent, such as DCM, and reacted by combining and mixing, typically at room temperature.
  • the reaction time can be from 2 h to 24 h.
  • the product are typically purified by chromatographic methods as known in the art.
  • the conditions for the addition and/or removal of protecting group, such as PGi are known in the art.
  • the most preferred protecting group Boc is removed under acidic conditions, e.g. by addition of TFA at 0°C.
  • PGi is removed, and preferably the resulting free amine group is reacted to obtain a compound of formula (I), e.g. by reacting with a suitable compound, such as an acid chloride, activated acid, sulfonic acid chloride, or by reactive deamination.
  • a suitable compound such as an acid chloride, activated acid, sulfonic acid chloride, or by reactive deamination.
  • Example 1 Materials and methods for chemical synthesis. Dry solvents were stored under an inert gas atmosphere and over molecular sieves. All chemicals were purchased from Sigma-Aldrich, TCI Chemicals, Alfa-Aesar or BLD Pharm. Aluminium-based 6OF254 silica gel plates from Merck were used for thin-layer chromatography. Detection was carried out by UV light at 254 nm.
  • HPLC-MS analyses were performed on a combination of Thermo Scientific Dionex UltiMate 3000 UHPLC+ and a Bruker amaZon SL. Samples were prepared in 1 mL of a 1:1 water/acetonitrile mixture.
  • Preparative HPLC was performed on a Waters 2545 Binary Gradient Module with a Waters 2489 UV/Vis Detector.
  • a RP-18 column 250/21 Nucleodur C18 Gravity SB, 5 pm (Macherey- Nagel) was used as the stationary phase.
  • HPLC-grade MeCN and MilliQ water were used as the mobile phase.
  • the compounds were also dissolved in an acetonitrile- water mixture.
  • NMR spectra were recorded either with a Bruker Ultrashield 500 Plus or a Bruker AV 500 UltraShield Plus.
  • the spectra were analyzed with MestReNova (MestreLab Research S. L., Version 14.2.1 or 14.2.2) and calibrated at the residual solvent peak of DMSO ( 1 H-NMR 2.50 ppm; 13 C-NMR 39.52 ppm) or chloroform ( ’ H-NMR 7.26 ppm; 13 C-NMR 77.16 ppm).
  • Multiplicity ’ H-NMR signals are as follows: s (singlet), d (doublet), t (triplet), q (quartet), br s (broad signal), m (multiplet).
  • the starting material was dissolved in anhydrous DCM (same volume as TFA) and cooled down to 0°C.
  • TFA 100 eq.
  • the reaction mixture was allowed to warm to r.t. and stirring was continued for further 30 min until completion.
  • the reaction mixture was diluted with DCM and saturated aqueous NaHCOa was added until pH 7 - 8.
  • the aqueous phase was washed twice with DCM and the combined organic layers were dried over anhydrous NaiSCE, filtered and evaporated in vacuo.
  • the crude product was directly used for next step or purified by reverse-phase column chromatography (McCN/HiO, 10 - 95%) if necessary.
  • Ketone/aldehyde (1.0 eq.) was dissolved in MeOH (0.01 M) with a drop of acetic acid. Subsequently, NaBH 3 CN (1.0 eq.) was added and the mixture was stirred for 5 min at r.t., followed by addition of the amine (1 eq.). The reaction mixture was stirred overnight, concentrated on a rotary evaporator without further processing and purified by column chromatography ((DCM/PE 6:4)/MeOH, 1 - 10%). Further purification was carried out using reverse-phase column chromatography or preparative HPLC (MeCN + 0.1% FA/H2O + 0.1% FA, 30 - 50%).
  • Step 1 L1AIH4, THF, 0 - reflux; Step 2: BociO, DCM, r.t.; Step 3: thiophosgene, NaHCO 3 , H 2 O, DCM, 0°C - r.t.; Step 4: tryptamine, DCM, r.t.; Step 5: TFA, DCM, 0°C - r.t.; Step 6: various conditions as indicated in Table 1.
  • Step 1 2-(aminomethyl)-4-chloroaniline (2) (Dong, Z. et al., 2015)
  • Step 3 tert-butyl [A-(5-chloro-2-isothiocyanatobenzyl)] carbamate (4)
  • Step 4 tert-butyl [A-(2-(3-(2-( 177-indol-3-yl)ethyl)thioureido)-5-chlorobenzyl)] carbamate (5)
  • Step 1 1) 0.5 M 9-BBN in THF, tert-butyl N-allylcarbamate, K3PO4, THF, r.t.; 2) 8, PdCh(dppf), r.t.; Step 2: thiophosgene, NaHCCF, H2O, DCM, 0°C - r.t.; Step 3: tryptamine, DCM, r.t.; Step 4: TFA, DCM, 0°C - r.t.; Step 5: cyclohexanecarboxylic acid, HATU, EtsN, DCM, r.t..
  • Step 1 tert-butyl [ A-(3-(2-amino-5-chlorophenyl)propyl)] carbamate (9) (Kennedy et al., Antimicrob. Agents Chemother. 2016)
  • Step 3 tert-butyl [A ⁇ -(3-(2-(3-(2-(177-indol-3-yl)ethyl)thioureido)-5-chlorophenyl)propyl)] carbamate (11) tert-butyl [ A A -(3-(5-chloro-2-isothiocyanatophcnyl)propyl)
  • Step 4 l-(2-(177-indol-3-yl)ethyl)-3-(2-(3-aminopropyl)-4-chlorophenyl)thiourea (12) tert-butyl [7V-(3-(2-(3-(2-( 177-indol-3-yl)ethyl)thioureido)-5-chlorophenyl)propyl) ] carbamate (11, 100 mg, 0.21 mmol) was deprotected according to general procedure C to give the product 12 as a beige foam (82 mg, crude).
  • Steps 1 - 4 see Scheme 2.; Step 5a: RCO2H and HATU, NEt 3 or RCOC1, NEt 3 , DCM, r.t.; Step 5b: RSO2CI, NEt 3 , r.t.; Step 5c: RNCO, NEt 3 or RNH 2 , CDI, NEt 3 , DCM, r.t.; Step 5d: CbzCl, NEt 3 , DCM, r.t.; Step 5e: TfN 3 , CuSO 4 , NaHCO 3 , toluene, MeOH, H 2 O; Step 6: phenylacetylene, CuSO 4 , sodium ascorbate, DMF, H2O, r.t..
  • Step 5a A- (3 -(2- (3- (2- ( l//-Indol-3-yl)ethyl)thioureido)-5-chlorophenyl)propyl)pivalamide
  • Step 5a A ⁇ -(3-(2-(3-(2-(177-Indol-3-yl)ethyl)thioureido)-5-chlorophenyl)propyl)-3,3- dimethylbutanamide (DH614)
  • Step 5a 7V-(3-(2-(3-(2-( 177-Indol-3-yl)ethyl)thioureido)-5-chlorophenyl)propyl)benzamide
  • Step 5a A ⁇ -(3-(2-(3-(2-(177-Indol-3-yl)ethyl)thioureido)-5- chlorophenyl)propyl)isonicotinamide (DH616)
  • Step 5a 7V-(3-(2-(3-(2-( 177-Indol-3-yl)ethyl)thioureido)-5-chlorophenyl)propyl)picolinamide
  • Step 5a 7V-(3-(2-(3-(2-( 177-Indol-3-yl)ethyl)thioureido)-5-chlorophenyl)propyl)nicotinamide
  • Step 5b A-(3-(2-(3-(2-(177-Indol-3-yl)ethyl)thioureido)-5- chlorophenyl)propyl)methanesulfonamide (DH619)
  • Step 5c l-(3-(2-(3-(2-(177-Indol-3-yl)ethyl)thioureido)-5-chlorophenyl)propyl)-3-phenylurea
  • TK461 l-(2-(177-Indol-3-yl)ethyl)-3-(2-(3-aminopropyl)-4-chlorophenyl)thioureatrifluoroacetic acid salt (TK391, 81.0 mg, 162 pmol, 1.0 eq.) was dissolved in anhydrous DCM (0.15 M) and NEt3 (45.0 pL, 323 pmol, 2.0 eq.) followed by phenyl isocyanate (19.0 pL, 178 pmol, 1.1 eq.) were added at 0 °C. The mixture was stirred at r.t. until completion (2 h), the solvent was evaporated and the residue was purified by column chromatography (DCM/EtiO). Compound TK461 (79.0 mg, 156 pmol, 96%) was obtained as a white solid.
  • Step 5c l-(3-(2-(3-(2-(177-Indol-3-yl)ethyl)thioureido)-5-chlorophenyl)propyl)-3-(tert- butyl)urea (TK462) l-(2-(177-Indol-3-yl)ethyl)-3-(2-(3-aminopropyl)-4-chlorophenyl)thioureatrifluoroacetic acid salt (TK391, 84.0 mg, 168 pmol, 1.0 eq.) was dissolved in anhydrous DCM (0.15 M) and NEt3 (70.0 pL, 503 pmol, 2.0 eq.) followed by l,l'-Carbonyldiimidazole (CDI, 29.9 mg, 184 pmol, 1.1 eq.) were added at 0 °C.
  • TK462 l-(2-(3-(2-(177-Ind
  • Step 5c l-(3-(2-(3-(2-(177-Indol-3-yl)ethyl)thioureido)-5-chlorophenyl)propyl)-3-benzylurea
  • TK463 l -(2-( 1 /7- Indol-3-yl )cthyl )-3-(2-(3-ami nopropyl )-4-chlorophcnyl)thiourcatrifluoroacctic acid salt (TK391, 84.0 mg, 168 pmol, 1.0 eq.) was dissolved in anhydrous DCM (0.15 M) and NEt3 (70.0 pL, 503 pmol, 2.0 eq.) followed by l,l'-Carbonyldiimidazole (CDI, 29.9 mg, 184 pmol, 1.1 eq.) were added at 0 °C. The mixture was stirred at r.t.
  • Step 5d Benzyl (3-(2-(3-(2-(177-Indol-3-yl)ethyl)thioureido)-5- chlorophenyl)propyl)carbamate (TK396) l-(2-(177-Indol-3-yl)ethyl)-3-(2-(3-aminopropyl)-4-chlorophenyl)thioureatrifluoroacetic acid salt (TK391, 75.0 mg, 150 pmol, 1.0 eq.) was dissolved in anhydrous DCM (0.1 M) and NEt3 (48.0 pL, 344 pmol, 2.3 eq.) followed by benzyl chloroformate (24.0 pL, 169 pmol, 1.13 eq.) were added at 0 °C. The mixture was stirred at r.t. until completion (90 min), the solvent was evaporated and the residue was purified by reverse-phase column chromatography (ACN/H2O
  • Step 5e l-(2-(177-Indol-3-yl)ethyl)-3-(2-(3-azidopropyl)-4-chlorophenyl)thiourea (TK460)
  • TK460 l-(2-(177-Indol-3-yl)ethyl)-3-(2-(3-aminopropyl)-4-chlorophenyl)thioureatrifluoroacetic acid salt (TK391, 350 mg, 699 pmol, 1.0 eq.), NaHCOa (264 mg, 3.14 mmol, 4.5 eq.) and CuS04- 5HiO (8.7 mg, 35 pmol, 0.05 eq.) were dissolved in H2O (0.93 mL) and MeOH (6.35 mL).
  • a triflic azide stock solution (1.61 mL, 2.09 mmol, 3.0 eq.) prepared according to the procedure of Titz el al.
  • Step 6 l-(2-(177-Indol-3-yl)ethyl)-3-(4-chloro-2-(3-(4-phenyl-177-l,2,3-triazol-l- yl)propyl)phenyl) thiourea (TK470)
  • TK470 l-(2-(177-Indol-3-yl)ethyl)-3-(2-(3-azidopropyl)-4-chlorophenyl)thiourea (TK460, 11.0 mg, 27 pmol, 1.0 eq.), phenylacetylene (8.8 pL, 80 pmol, 3.0 eq.) and sodium ascorbate (1.1 mg, 5 pmol, 0.2 eq.) were dissolved in DMF (0.22 mL) and CuSC -SHiO (1.3 mg, 5 pmol, 0.2 eq.) in H2O (0.07 mL) was added. The mixture was stirred at r.t. for 30 min, the solvent was evaporated and the residue was purified by reverse phase column chromatography (ACN/H2O). Compound TK470 (5.0 mg, 10 pmol, 36%) was obtained as a white solid.
  • Step 1 4 M NaOH( aq ), reflux; Step 2: BociO, THF, 4 M NaOH( aq ), reflux; Step 3: n- butylamine, HBTU, DCM, rt; Step 4: TFA, DCM, 0°C; Step 5: thiophosgene, NaHCCE, H2O, DCM, 0°C - rt; Step 6: tryptamine, DCM, rt.
  • Step 1 2-(2-amino-5-chlorophenyl)acetic acid (15) (Urgin, M, et al., 2017)
  • Step 2 2-(2-((tert-butoxycarbonyl)amino)-5-chlorophenyl)acetic acid (16) (Yang, Z, et al., 2018)
  • the reaction mixture for the synthesis of 15 (3.6 mL, 1.0 eq.) was diluted with 21.0 mL THE, and BOC2O (703 mg, 3.57 mmol, 2.0 eq.) was added. Subsequently, the solution was heated to reflux for 4 h. THE was removed in vacuo, and the aqueous layer was gently acidified with IM NH4Cl( aq ), followed by IN HCl( aq ) until reaching a pH of 5. The aqueous solution was then extracted three times with DCM, and the combined organic phases were dried over Na2SO4 and filtered. After concentration under reduced pressure, the crude product was purified by column chromatography (PE + 1% FA/EtOAc + 1% FA, 5 - 20%). Compound 16 was obtained as a colourless solid (404 mg, 79% over two steps).
  • tert-butyl [A-(2-(2-(butylamino)-2-oxoethyl)-4-chlorophenyl)] carbamate 17.8 mL of anhydrous DCM (0.08 M). After cooling to 0°C, TFA (3.70 mL, 48.3 mmol, 100.0 eq.) was slowly added. After stirring for 1 h at 0°C, the solution was washed three times with saturated aqueous NaHCO ,, dried over Na2SO4, filtered and concentrated under reduced pressure. Crude 18 (105 mg) was directly used in the next step without further purification.
  • Step 6 2-(2-(3-(2-(177-indol-3-yl)ethyl)thioureido)-5-chlorophenyl)-A-butylacetamide (20) Crude A-butyl-2-(5-chloro-2-isothiocyanatophenyl)acetamide (19, 109 mg, 0.388 mmol, 1.0 eq.) was dissolved in 7.5 mL of DCM (0.05 M). Subsequently, tryptamine (62.1 mg, 0.388 mmol, 1.0 eq.) was added, and the mixture was stirred for 1.5 h at r.t.. The reaction mixture was concentrated in vacuo and purified by column chromatography (PE/EtOAc, 30 - 80%). A total of 158 mg (0.357 mmol, 74% yield over three steps) of 20 as a colourless solid was obtained.
  • MHBII Mueller-Hinton cation supplemented broth II
  • MHA Mueller-Hinton agar
  • TTB Tryptic soy broth
  • All other chemicals and antibiotics were procured from Sigma- Aldrich (St. Louis, MO, USA). Roswell Park Memorial Institute Medium (RPMI) and Fetal Bovine Serum (FBS) were purchased from Lonza (Lonza, USA). All methods were performed in accordance with the relevant guidelines and regulations.
  • Molecules were screened against Acinetobacter baumannii (BAA- 1605).
  • the panel was further expanded to include drug-resistant clinical Acinetobacter baumannii strains including those resistant to meropenem and other clinically-utilized antibiotics. These strains were procured from Biodefense and Emerging Infections Research Resources Repository/ American Type Culture Collection (BEI/ATCC, USA) and routinely cultivated on MHA and MHBII. Before starting the experiment, a single colony was picked from MHA plate, inoculated in MHBII and incubated overnight at 37 °C with shaking for 18-24 h to get the starter culture.
  • Antibiotics Antibiotics
  • Antibiotic susceptibility testing of hits was conducted according to the CLSI guidelines using the broth microdilution assay. 10 mg/mL stock solutions of test compounds were prepared in DMSO. Bacterial cultures were inoculated in MHBII and optical density (OD) was measured at 600 nm, followed by dilution to achieve ⁇ 10 6 CFU/mL. The compounds were tested from 64-0.5 mg/L in two-fold serial diluted fashion with 2.5 pL of each concentration added to well of a 96-well round bottom microtiter plate. Later, 97.5 pL of bacterial suspension was added to each well containing either test compound or appropriate controls. The plates were incubated at 37°C for 18-24 h following which the MIC was determined. The MIC is defined as the lowest concentration of the compound at which there is absence of visible growth. For each test compound, MIC determinations were carried out independently three times using duplicate samples.
  • CC50 Cell toxicity was performed against Vero cells using the MTT assay. ⁇ 10 3 cells/well were seeded in 96 well plate and incubated at 37°C in an 5% CO2 atmosphere. After 24 h, compound was added ranging from 100-12.5 pg/mL concentration and incubated for 72 h. After the incubation was over, MTT was added to each well, incubated at 37 °C for further 4 h, residual medium was discarded, 0.1 mL of DMSO was added to solubilise the formazan crystals and OD was taken at 540 nm for the calculation of CC50. CC50 is defined as the lowest concentration of compound which leads to a 50% reduction in cell viability. Doxorubicin was used as positive control and each experiment was repeated in triplicate.
  • the tested small molecules showed strong antimicrobial activity (Table 2).
  • the compounds showing the highest activity were 7i, 7q, 11, and 13 showing MIC ⁇ 0.5 pg/ml.
  • Step 1 1) 0.5 M 9-BBN in THF, tert-butyl (V-vinylcarbamate, THF, 2) 3 M K3PO4, 4-chloro-2-iodoaniline, Pd(dppf)Ch, 65 °C.; Step 2: thiophosgene, NaHCCh, H2O, DCM, 0°C - r.t.; Step 3: tryptamine, DCM, r.t.; Step 4: TFA, DCM, 0°C: Step 5: benzyl chloroformate or pivaloyl chloride, NEt3, DCM, r.t..
  • Step 1.1 tert-Butyl (2-amino-5-chlorophenethyl)carbamate (TK420) (Kennedy el al.,
  • Step 1.2 /e/7- Butyl (5-chloro-2-isothiocyanatophenethyl)carbamate (TK425)
  • Step 3 l-(2-(777-indol-3-yl)ethyl)-3-(2-(2-aminoethyl)-4-chlorophenyl)thiourea trifluoroacetic acid salt (TK432)
  • TK432 tert-Butyl (2-(3-(2-(177-indol-3-yl)ethyl)thioureido)-5-chlorophenethyl)carbamate (TK427, 1.85 g, 3.91 mmol) was deprotected according to general procedure C to give the product TK432 as a beige foam (1.90 g, quant., crude), which was used in the next step without further purification.
  • Step 4 Benzyl (2-(3-(2-(177-indol-3-yl)ethyl)thioureido)-5-chlorophenethyl)carbamate
  • TK440 l-(2-(777-indol-3-yl)ethyl)-3-(2-(2-aminoethyl)-4-chlorophenyl)thiourea trifluoroacetic acid salt (TK432, 56.4 mg, 116 pmol, 1.0 eq.) was dissolved in anhydrous DCM (0.1 M) and NEt3 (44.0 pL, 316 pmol, 2.7 eq.) followed by benzyl chloroformate (25.0 pL, 174 pmol, 1.5 eq.) were added at 0 °C. The mixture was stirred at r.t. until completion (1 h), the solvent was evaporated and the residue was purified by reverse-phase column chromatography (ACN/H2O). Compound TK440 (40.0 mg, 79 pmol, 68%) was obtained as a white solid.
  • Step 5 A-(2-(3-(2-(177-Indol-3-yl)ethyl)thioureido)-5-chlorophenethyl)pivalamide (TK441)
  • TK441 l-(2-(777-indol-3-yl)ethyl)-3-(2-(2-aminoethyl)-4-chlorophenyl)thiourea trifluoroacetic acid salt (TK432, 56.4 mg, 116 pl-(2-(7H-indol-3-yl)ethyl)-3-(2-(2-aminoethyl)-4- chlorophenyl)thiourea trifluoroacetic acid salt (TK432, 56.4 mg, 116 pl-(2-(777-indol-3- yl)ethyl)-3-(2-(2-aminoethyl)-4-chlorophenyl)thiourea trifluoroacetic acid salt (TK432, 56.4 mg, 116 pmol, 1.0 eq.) was dissolved in anhydrous DCM (0.1 M) and NEt3 (40.0 pL, 290 pmol, 2.5 eq.) followed by pi
  • Example 8 Antimicrobial activity of compounds of Example 7 and Example 4-Part 2.

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Abstract

The present invention is directed to thiourea based compounds of formula (I), as well as pharmaceutically acceptable salts or prodrugs thereof. Further the present invention provides a method for the preparation of the compounds of formula (I), pharmaceutical compositions comprising the same and their use in medicine, and preferably in the prophylaxis or treatment of Acinetobacter baumannii infections.

Description

THIOUREA BASED DERIVATIVES ARE NOVEL ANTIMICROBIALS AGAINST A. BAUMANNII
Field of the invention
The present invention is directed to thiourea based compounds of formula (I), as well as pharmaceutically acceptable salts or prodrugs thereof. The present invention further provides a method for the preparation of the compounds of formula (I), pharmaceutical compositions comprising the same and their use in medicine, and preferably in the prophylaxis or treatment of Acinetobacter baumannii infections.
Background of the Invention
Acinetobacter baumannii is a pleomorphic gram-negative coccobacillus and the most common cause of bacterial hospital-acquired infections in immunocompromised individuals. The major problem in the treatment of such infections is the increasingly frequent occurrence of antimicrobial resistance (AMR) to established therapeutic agents such as carbapenems, minocycline, levofloxacin and polymyxin B. According to the WHO, carbapenem-resistant Acinetobacter baumannii (CRAB) is the pathogen of greatest concern (priority I pathogen). AMR-associated infections are a leading cause of death worldwide and are projected to cause approximately 1.27 million direct deaths and an additional 4.95 million associated deaths worldwide in 2019, surpassing deaths from HIV and malaria.
A. baumannii belongs to the so-called "ESKAPE" pathogens (Enterococcus faecium, Staphylococcus aureus, Klebsiella pneumoniae, Acinetobacter baumannii, Pseudomonas aeruginosa and Enterobacter species, and E. coll), which currently cause the majority of nosocomial infections and are effectively "evading" the action of antimicrobial agents.
A. baumannii is most commonly found in intensive care units and surgical wards, where extensive use of antibiotics has allowed selection for resistance to all known antimicrobials. Healthcare-associated infections (HAI) are often associated with the use of medical devices such as catheters and ventilators, surgical procedures, transmission between patients and healthcare workers, and overuse of antibiotics. A. baumannii-caused HAI comprise bacteremia, pneumonia, e.g. ventilator-associated pneumonia, meningitis, urinary tract infections, e.g. catheter-associated urinary tract infection (CAUTI).
Often, the only antibiotic available for the treatment of infections caused by multidrug-resistant (MDR) A. baumannii is polymyxin B, which suffers from severe side effects, including renal and irreversible neurotoxicity. Therefore, there is a need for new chemical molecules suitable for the development of new drugs against A. baumannii.
The present inventors developed a new series of small molecules starting from the known compound SRI-12742 (Shukla et al., 2018). These new small molecules showed increased antimicrobial activity against clinical strains of A. baumanni, including multidrug resistant strains, compared to SRI- 12742 (Table 2), while the cytotoxicity in Vero cells remained at the same level.
Thus, the present invention provides, inter alia', (i) novel small molecules for the prophylaxis and treatment of infections caused by Acinetobacter baumannii, including multi-drug resistant Acinetobacter baumannii, (ii) methods for preparing said new small molecules.
Summary of the invention
In a first aspect, the present invention provides a compound of the general formula (I): wherein
R1 is individually selected from the group consisting of halogen and C1-4 alkyl, which is optionally substituted by one or more halogen(s), and C1-4 alkoxy, which is optionally substituted by one or more halogen(s);
R2 is individually selected from the group consisting of hydrogen, OH, NH2, NO2, SH, one or more halogen(s), COOR8, wherein R8 is hydrogen or C1-4 alkyl, which is optionally substituted by one or more halogen(s), C1-4 acyl, which is optionally substituted by one or more halogen(s), C1-4 alkyl, which is optionally substituted by one or more halogen(s), and Ci-4 alkoxy, which is optionally substituted by one or more halogen(s); m is 0, 1, 2 or 3;
R3 is a Ci-8 alkyl chain wherein 1, 2 or 3 chain carbon atoms are individually replaced by NH, -O-, C=O, or S(=O) x, wherein X is 0, 1, or 2, and which chain is optionally substituted by 1 to 3 substituents individually selected from the group consisting of: one or more halogen(s), N3,
C1-6 alkyl, which is optionally substituted by one or more halogen(s),
C1-6 alkoxy, which is optionally substituted by one or more halogen(s), and a 5 to 10 membered carbo- or heterocycle, which is optionally substituted by 1 to 3 R7 substituents, wherein R7 is selected from the group consisting of one or more halogen(s), — CN, — NO2, — Rf, — CO2Rd, — CONRdRe, — C(O)Rd, — OC(O)NRdRe, — NReC(O)Rd, — NReC(O)2Rf, — NRdC(O)NRdRe, — NRdRe, — ORd, and — S(O)2NRdRe; wherein each Rd and Re is independently selected from hydrogen, C1-8 alkyl, and C1-8 haloalkyl; each Rf is independently selected from the group consisting of C1-8 alkyl or heteroalkyl, C1-8 haloalkyl, C3-6 cycloalkyl, heterocycloalkyl, aryl and heteroaryl, and wherein the aliphatic and/or cyclic portions of Rd, Re and Rf are optionally further substituted with from one to three halogen, hydroxy, methyl, amino, C 1-6 alkylamino and di C1-6 alkylamino groups;
R4 and R5 are individually selected from the group consisting of hydrogen, one or more halogen(s), and C1-4 alkyl, and preferably are hydrogen; or a salt thereof, or a solvate thereof, or a prodrug thereof.
In a second aspect, the present invention relates to a pharmaceutical composition comprising or consisting of at least one compound of the first aspect, and, optionally, one or more constituents selected from the group consisting of a pharmaceutically acceptable carrier, a diluent, an excipient and a further anti-bacterial therapeutic agent.
In a third aspect, the present invention relates to the compound of the first aspect or the pharmaceutical composition of the second aspect for use in medicine.
In a fourth aspect, the present invention relates to the compound of the first aspect or the pharmaceutical composition of the second aspect, optionally in combination with one or more anti-bacterial therapeutic agent(s), for use in the prophylaxis or treatment of Acinetobacter baumannii infections in a patient, or for use in the prophylaxis or treatment of Acinetobacter baumannii-associated lung infections, catheter-associated infections, bacteremia, or sepsis in a patient, or for use in the prophylaxis or treatment of carbapenem resistant Acinetobacter baumannii or multidrug resistant Acinetobacter baumannii.
In a fifth aspect, the present invention relates to a method for the preparation of a compound of formula (I): wherein
R1 is individually selected from the group consisting of halogen and C1-4 alkyl, which is optionally substituted by one or more halogens, and C1-4 alkoxy, which is optionally substituted by one or more halogen(s);
R2 is individually selected from the group consisting of hydrogen, OH, NH2, NO2, SH, one or more halogen(s), COOR8, wherein R8 is hydrogen or C1-4 alkyl, which is optionally substituted by one or more halogen(s),Ci-4 acyl, which is optionally substituted by halogen(s), C1-4 alkyl, which is optionally substituted by one or more halogen(s), or C1-4 alkoxy, which is optionally substituted by one or more halogens; m is 0, 1, 2 or 3;
R3 is a C1-8 alkyl chain wherein 1, 2 or 3 chain carbon atoms are individually replaced by NH, -O-, C=O, or S(=O)X , wherein X is 0, 1, or 2, and which chain is optionally substituted by 1 to 3 substituents individually selected from the group consisting of: one or more halogen(s), N3, C1-6 alkyl, which is optionally substituted by one or more halogen(s), C1-6 alkoxy, which is optionally substituted by one or more halogen(s), and a 5 to 10 membered carbo- or heterocycle, which is optionally substituted by 1 to 3 R7 substituents, wherein R7 is selected from the group consisting of one or more halogen(s), — CN, — NO2, — Rf, — CO2Rd, — CONRdRe, — C(O)Rd, — OC(O)NRdRe, — NReC(O)Rd, — NReC(O)2Rf, — NRdC(O)NRdRe, — NRdRe, — ORd, and — S(O)2NRdRe; wherein each Rd and Re is independently selected from hydrogen, C1-8 alkyl, and C1-8 haloalkyl; each Rf is independently selected from the group consisting of C1-8 alkyl or heteroalkyl, C1-8 haloalkyl, C3-6 cycloalkyl, heterocycloalkyl, aryl and heteroaryl, and wherein the aliphatic and/or cyclic portions of Rd, Re and Rf are optionally further substituted with from one to three halogen, hydroxy, methyl, amino, C1-6 alkylamino and di C1-6 alkylamino groups ; R4 and R5 are individually selected from the group consisting of hydrogen, one or more halogen(s), and Ci-4 alkyl, and preferably are hydrogen; or a salt thereof, or a solvate thereof, or a prodrug thereof, comprising: a) reacting a compound of formula (II) and a compound of formula (Illa) wherein R1, R2, and m are as defined for formula (I), p is 1 or 2 or 3, and
PGi is a protecting group; or b) reacting a compound of formula (II) and a compound of formula (Illb) wherein R1, R2, R3, R4, R5, and m are as defined for formula (I), and wherein R3 is preferably a residue of the formula (lb) wherein
R6 is selected from the group consisting of hydrogen, Ci-6 alkyl, which is optionally substituted by one or more halogen(s), Ci-6 alkoxy, which is optionally substituted by one or more halogen(s), and a 5, 6, 7, or 10-membered carbo- or heterocycle, which is optionally substituted by 1 to 3 R7 substituents, wherein R7 is selected from the group consisting of one or more halogen(s), — CN, — N02, — Rf, — CO2Rd, — CONRdRe, — C(O)Rd, — OC(O)NRdRe, — NReC(O)Rd, — NReC(O)2Rf, — NRdC(O)NRdRe, — NRdRe, — 0Rd, and — S(O)2NRdRe; wherein each Rd and Re is independently selected from hydrogen, C1-8 alkyl, and C1-8 haloalkyl; each Rf is independently selected from the group consisting of C1-8 alkyl or heteroalkyl, C1-8 haloalkyl, C3-6 cycloalkyl, heterocycloalkyl, aryl and heteroaryl, and wherein the aliphatic and/or cyclic portions of Rd, Re and Rf are optionally further substituted with from one to three halogen, hydroxy, methyl, amino, C1-6 alkylamino and di C1-6 alkylamino groups, and wherein n is 0, 1, or 2; or a residue of the formula (lb), wherein the amide is replaced by an amide bioisostere and R6 and n are as defined above; to obtain a compound of Formula (I).
Detailed Description of the Invention
Before the present invention is described in detail below, it is to be understood that this invention is not limited to the particular methodology, protocols and reagents described herein as these may vary. It is also to be understood that the terminology used herein is for the purpose of describing particular embodiments only, and is not intended to limit the scope of the present invention which will be limited only by the appended claims. Unless defined otherwise, all technical and scientific terms used herein have the same meanings as commonly understood by one of ordinary skill in the art.
Preferably, the terms used herein are defined as described in "A multilingual glossary of biotechnological terms: (IUPAC Recommendations)", Leuenberger, H.G.W, Nagel, B. and Klbl, H. eds. (1995), Helvetica Chimica Acta, CH-4010 Basel, Switzerland).
Throughout this specification and the claims, which follow, unless the context requires otherwise, the word "comprise", and variations such as "comprises" and "comprising", will be understood to imply the inclusion of a stated integer or step or group of integers or steps but not the exclusion of any other integer or step or group of integers or steps. In the following passages, different aspects of the invention are defined in more detail. Each aspect so defined may be combined with any other aspect or aspects unless clearly indicated to the contrary. In particular, any feature indicated as being optional, preferred or advantageous may be combined with any other feature or features indicated as being optional, preferred or advantageous. Several documents are cited throughout the text of this specification. Each of the documents cited herein (including all patents, patent applications, scientific publications, manufacturer's specifications, instructions etc.), whether supra or infra, is hereby incorporated by reference in its entirety. Nothing herein is to be construed as an admission that the invention is not entitled to antedate such disclosure by virtue of prior invention. Some of the documents cited herein are characterized as being "incorporated by reference" . In the event of a conflict between the definitions or teachings of such incorporated references and definitions or teachings recited in the present specification, the text of the present specification takes precedence.
In the following, the elements of the present invention will be described. These elements are listed with specific embodiments; however, it should be understood that they may be combined in any manner and in any number to create additional embodiments. The variously described examples and preferred embodiments should not be construed to limit the present invention to only the explicitly described embodiments. This description should be understood to support and encompass embodiments which combine the explicitly described embodiments with any number of the disclosed and/or preferred elements. Furthermore, any permutations and combinations of all described elements in this application should be considered disclosed by the description of the present application unless the context indicates otherwise.
Definitions
To practice the present invention, unless otherwise indicated, conventional methods of chemistry, biochemistry, and recombinant DNA techniques are employed which are explained in the literature in the field (cf., e.g., Molecular Cloning: A Laboratory Manual, 2nd Edition, J. Sambrook et al. eds., Cold Spring Harbor Laboratory Press, Cold Spring Harbor 1989).
In the following, some definitions of terms frequently used in this specification are provided. These terms will, in each instance of its use, in the remainder of the specification have the respectively defined meaning and preferred meanings.
As used in this specification and the appended claims, the singular forms "a", "an", and "the" include plural referents, unless the content clearly dictates otherwise.
The term "halogen" as used herein refers to a halogen residue selected from the group consisting of fluorine (F), chlorine (Cl), bromine (Br) and iodine (I).
The terms "alkoxy" and "alkylamino" are used herein in their conventional sense, and refer to those alkyl groups attached to the remainder of the molecule via an oxygen atom or an amino group, respectively. Preferably, the carbon chain comprises from 1 to 6 carbon atoms. The term "alkyl" refers to a saturated straight or branched carbon chain. Preferably, the chain comprises from 1 to 8 carbon atoms, i.e. 1, 2, 3, 4, 5, 6, 7, or 8, e.g. methyl, ethyl, propyl (n- ropyl or iso- ropyl), butyl (//-butyl , iso-butyl, sec-butyl, tert-butyl), pentyl, hexyl, heptyl, or octyl. Alkyl groups are optionally substituted.
The term "heteroalkyl" refers in the context of the present invention to a saturated straight or branched carbon chain. Preferably, the chain comprises from 1 to 8 carbon atoms, i.e. 1, 2, 3, 4, 5, 6, 7, or 8, e.g. methyl, ethyl, propyl (//-propyl or zso-propyl), butyl (rz-butyl, iso-butyl, sec-butyl, tert-butyl), pentyl, hexyl, heptyl, or octyl, which is interrupted one or more times, e.g. 1, 2, 3, 4, 5, with the same or different heteroatoms. Preferably, the heteroatoms are selected from O, S, and N, e.g. -(CH2)y-X-(CH2)zCH3, with y = 0, 1, 2, 3, 4, 5, 6, 7, 8, or 9, z = 0, 1, 2, 3, 4, 5, 6, 7, 8, or 9 and X = S, O or NR' with R' = H or hydrocarbon (e.g. Ci to C<> alkyl). In particular "heteroalkyl" refers to -O-CH3, -OC2H5, -CH2-O-CH3, -CH2-O-C2H5, -CH2-O- C3H7, -CH2-O-C4H9, -CH2-O-C5H11, -C2H4-O-CH3, -C2H4-O-C2H5, -C2H4-O-C3H7, -C2H4-O- C4H9 etc. Heteroalkyl groups are optionally substituted.
The term "haloalkyl" refers in the context of the present invention to a saturated straight or branched carbon chain in which one or more hydrogen atoms are replaced by halogen atoms, e.g. by F, Br, I or Cl. Preferably, the chain comprises from 1 to 8 carbon atoms, i.e. 1, 2, 3, 4, 5, 6, 7, or 8. In particular, "haloalkyl" refers to -CH2F, -CHF2, -CF3, -C2H4F, -C2H3F2, -C2H2F3, -C2HF4, -C2F5, -C3H6F, -C3H5F2, -C3H4F3, -C3H3F4, -C3H2F5, -C3HF6, -C3F7, -CH2CI, -CHC12, -CC13, -C2H4CI, -C2H3CI2, -C2H2CI3, -C2HCI4, -C2CI5, -C3H6CI, -C3H5C12, -C3H4CI3, -C3H3CI4, -C3H2CI5, -C3HQ6, and -C3CI7. Haloalkyl groups are optionally substituted.
The term "heterocycle", as used herein, unless otherwise indicated, means an unsaturated or saturated, monocyclic or polycyclic non-aromatic ring system containing one or more heteroatoms. Preferred heteroatoms include N, O and S, including N-oxides, sulfur oxides and dioxides. Preferably, the ring is 5to 10 members and is fully saturated or has one or more degrees of unsaturation. This definition includes multiple degrees of substitution, preferably 1, 2 or 3 degrees of substitution.
The term "5, 6, 7 or 10 membered carbocycle" is used in the context of the present invention to refer to "5, 6, 7 or 10 membered cycloalkyl", "5, 6, 7 or 10 membered cycloalkenyl" or "5, 6, 7 or 10 membered aryl" with 5, 6, 7 or 10 carbon atoms forming a ring.
The term "5, 6, 7 or 10 membered heterocycle" is used in the context of the present invention to refer to "5, 6, 7 or 10 membered heterocycloalkyl", "5, 6, 7 or 10 membered heterocycloalkenyl" or "5, 6, 7 or 10 membered heteroaryl" with 5, 6, 7 or 10 carbon atoms forming a ring. The term "5 to 10 membered carbocycle" is used in the context of the present invention to refer to "5 to 10 membered cycloalkyl", "5 to 10 membered cycloalkenyl" or "5 to 10 membered aryl" with 5, 6, 7, 8, 9 or 10 carbon atoms forming a ring.
The term "5 to 10 membered heterocycle" is used in the context of the present invention to refer to "5 to 10 membered heterocycloalkyl", "5 to 10 membered heterocycloalkenyl" or "5 to 10 membered heteroaryl" with 5 to 10 carbon atoms forming a ring.
The term "cycloalkenyl" as used in the context of the present invention includes cyclopentenyl, cyclohexenyl, and cycloheptenyl. Cycloalkenyl groups are optionally substituted.
The terms "cycloalkyl" and "heterocycloalkyl", by themselves or in combination with other terms, represent, as used in the context of the present invention, unless otherwise stated, cyclic versions of "alkyl" and "heteroalkyl", respectively, with preferably 3, 4, 5, 6, 7, 8, 9 or 10 atoms forming a ring, e.g. cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl etc. The terms "cycloalkyl" and "heterocycloalkyl" are also meant to include bicyclic, tricyclic and polycyclic versions thereof. The term "heterocycloalkyl" preferably refers to a saturated ring having five of which at least one member is a N, O or S atom and which optionally contains one additional O or one additional N; a saturated ring having six members of which at least one member is a N, O or S atom and which optionally contains one additional O or one additional N or two additional N atoms; or a saturated bicyclic ring having nine or ten members of which at least one member is a N, O or S atom and which optionally contains one, two or three additional N atoms. "Cycloalkyl" and "heterocycloalkyl" groups are optionally substituted. Additionally, for heterocycloalkyl, a heteroatom can occupy the position at which the heterocycle is attached to the remainder of the molecule. Examples of cycloalkyl include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, 1 -cyclohexenyl, 3-cyclohexenyl, cycloheptyl, spiro[3,3]heptyl, spiro [3, 4] octyl, spiro[4,3]octyl, spiro[3,5]nonyl, spiro[5,3]nonyl, spiro [3, 6] decyl, spiro[6,3]decyl, spiro[4,5]decyl, spiro [5, 4] decyl, bicyclo[2.2.1]heptyl, bicyclo[2.2.2]octyl, adamantyl, and the like. Examples of heterocycloalkyl include 1 -( 1,2, 5,6- tetrahydropyridyl), 1-piperidinyl, 2-piperidinyl, 3-piperidinyl, 4-morpholinyl, 3-morpholinyl, 1,8 diazo-spiro-[4,5] decyl, 1,7 diazo-spiro-[4,5] decyl, 1,6 diazo-spiro-[4,5] decyl, 2,8 diazo- spiro[4,5] decyl, 2,7 diazo-spiro[4,5] decyl, 2,6 diazo-spiro[4,5] decyl, 1,8 diazo- spiro- [5, 4] decyl, 1,7 diazo- spiro- [5, 4] decyl, 2,8 diazo- spiro- [5, 4] decyl, 2,7 diazo-spiro[5,4] decyl, 3,8 diazo- spiro [5, 4] decyl, 3,7 diazo-spiro[5,4] decyl, l-azo-7,l l-dioxo-spiro[5,5] undecyl, 1,4- diazabicyclo[2.2.2]oct-2-yl, tetrahydrofuran-2-yl, tetrahydrofuran-3-yl, tetrahydrothien-2-yl, tetrahydrothien-3-yl, 1-piperazinyl, 2-piperazinyl, and the like. The term "aryl" as used in the context of the present invention means, unless otherwise stated, a polyunsaturated, typically aromatic, hydrocarbon group which can be a single ring or multiple rings (up to three rings) which are fused together or linked covalently.
The term "heteroaryl" as used in the context of the present invention refers to a 5, 6 or 7-membered aromatic monocyclic ring wherein at least one of the carbon atoms are replaced by 1, 2, or 3 (for the five membered ring) or 1, 2, 3, or 4 (for the six membered ring) of the same or different heteroatoms, preferably selected from O, N and S. Preferred heteroaryl groups have from 1 to 3 heteroatoms as ring members selected from N, O and S. Examples of preferred heteroaryls are benzimidazolyl, benzodioxolyl, benzofuranyl, 1 -benzofuranyl, 2-benzofuranyl, 2,1-benzosoxazoyl, 1,2-benzisothiazolyl, 2,1-benzisothiazolyl, benzothiazolyl, benzothienyl, benzothiophenyl, 2-benzothiophenyl, 1,2,3-benzotriazinyl, 1 ,2,4-benzotriazinyl, benzotriazolyl, dihydrobenzodioxinyl, dihydrocyclopentathienyl, dihydroindolyl, dihydroisoindolyl, dihydropyrrolizinyl, dihydroquinoxalinyl, dihydrothienodioxinyl, furanyl, furyl, imidazopyridinyl, imidazolyl, IH-indazolyl, indazolyl, indolyl, indoyl, indoxazinyl, isoindoyl, isoquinolinyl, isothiazolyl, isoxazolyl, oxazolyl, 1,2,5-oxadiazolyl, 1,2,3- oxadiazolyl, pyridazinyl, pyrazinyl, pyrazolyl, pyridinonyl, pyrimidinyl, pyridinyl, pyrrolopyridazinyl, pyrrolyl, quinazolinonyl, quinolinyl, quinoxalinyl tetrahydrobenzothienyl, tetrahydroindolizinyl, tetrahydroisoquinolinyl, tetrahydroquinolinyl, 1,2,3-triazolyl, thiazolyl, 1,2,3,-thiadiazolyl, 1,2,5-thiadiazolyl, thienyl, 1,2,3-triazinyl, 1,2,4-triazinyl, 1,3,5-triazinyl. Heteroaryls groups are optionally substituted.
As used herein, the term "heteroatom" is meant to include oxygen (O), nitrogen (N), and sulfur (S).
Substituents for each of the above noted aryl and heteroaryl ring systems are selected from the group of acceptable substituents described below.
For brevity, the term "aryl" when used in combination with other terms (e.g.: aryloxy, arylthioxy, arylalkyl) includes both aryl and heteroaryl rings as defined above. Thus, the term "arylalkyl" is meant to include those radicals in which an aryl group is attached to an alkyl group.
The above terms (e.g., "alkyl," "aryl" and "heteroaryl"), in some embodiments, will include both substituted and unsubstituted forms of the indicated radical. Preferred substituents for each type of radical are provided below. For brevity, the terms aryl and heteroaryl will refer to substituted or unsubstituted versions as provided below, while the term "alkyl" and related aliphatic radicals is meant to refer to unsubstituted version, unless indicated to be substituted. Substituents for the alkyl radicals, if not further specified, (including those groups often referred to as alkylene, alkenyl, alkynyl and cycloalkyl) can be a variety of groups selected from: -halogen, -OR', -NR'R", -SR', -OC(O)R', -C(O)R', -CO2R', -CONR'R", -OC(O)NR'R", - NR"C(O)R', -NR'-C(O)NR"R'", -NR"C(O)2R', -NH-C(NH2)=NH, -NR'C(NH2)=NH, -NH- C(NH2)=NR', -S(O)R', -S(O)2R', -S(O)2NR’R", -NR’S(O)2R", -CN and -NO2 in a number ranging from zero to (2 m'+l), where m' is the total number of carbon atoms in such radical. R', R" and R'" each independently refer to hydrogen, unsubstituted C1-6 alkyl, unsubstituted heteroalkyl, unsubstituted aryl, aryl substituted with 1-3 halogens, unsubstituted C1-6 alkyl, Cn 8 alkoxy or C1-6 thioalkoxy groups, or unsubstituted aryl-Ci-4 alkyl groups. When R' and R" are attached to the same nitrogen atom, they can be combined with the nitrogen atom to form a 3-, 4-, 5-, 6-, or 7-membered ring. The term "acyl" as used by itself or as part of another group refers to an alkyl radical wherein two substituents on the carbon that is closest to the point of attachment for the radical is replaced with the substituent =0. As used herein, an acyl preferably comprises 1 to 4 carbon atoms.
Similarly, substituents for the aryl and heteroaryl groups are varied and are generally selected from: -halogen, -OR', -0C(0)R', -NR'R", -SR', -R', -CN, -N02, -C02R', -CONR'R", - C(0)R', -0C(0)NR'R", -NR"C(0)R', -NR"C(0)2R', ,-NR'-C(0)NR"R"', -NH-C(NH2)=NH, - NR'C(NH2)=NH, -NH-C(NH2)=NR', -S(O)R', -S(O)2R', -S(0)2NR’R", -NR’S(0)2R", -N3, perfluoro(Ci-C4)alkoxy, and perfluoro(Ci-C4)alkyl, in a number ranging from zero to the total number of open valences on the aromatic ring system; and where R', R" and R'" are independently selected from hydrogen, C1-6 alkyl, C3-6 cycloalkyl, C2-6 alkenyl, C2-8 alkynyl, unsubstituted aryl and heteroaryl, (unsubstituted aryl)-Ci-4 alkyl, and unsubstituted aryloxy-Ci- 4 alkyl. Other suitable substituents include each of the above aryl substituents attached to a ring atom by an alkylene tether of from 1-4 carbon atoms.
In one embodiment, carbon atoms or hydrogen atoms in alkyl, heteroalkyl, cycloalkyl, aryl, aralkyl, alkenyl, cycloalkenyl, alkynyl radicals may be substituted independently from each other with one or more elements selected from the group consisting of O, S, N or with groups containing one or more elements selected from the group consisting of O, S, N.
If two or more radicals can be selected independently from each other, then the term "independently" means that the radicals may be the same or may be different.
The term "optionally substituted" as used in the context of the present invention in each instance, if not further specified, refers to halogen (in particular F, Cl, Br, or I), -N02, N3, -CN, -OR'", NR'R", -COOR'", -CONR'R", -NR'COR", -NR"COR"', -NR'CONR'R", -NR'SO2E, -COR'"; - SO2NR'R", -OOCR'", -CR"'R""OH, -R"'OH, and -E;
R' and R" is each independently selected from the group consisting of hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, aralkyl, and heteroaryl or together form a heteroaryl, or heterocycloalkyl;
R'" and R"" is each independently selected from the group consisting of hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, alkoxy, aryl, aralkyl, heteroaryl, and -NR'R";
E is selected from the group consisting of alkyl, alkenyl, alkynyl, cycloalkyl, alkoxy, alkoxyalkyl, heterocycloalkyl, an alicyclic system, aryl and heteroaryl; optionally substituted. The term "amide bioisostere" as used herein refers to a moiety wherein an amide bond is replaced by a bioisostere having chemical and/or physical similarities, which produce broadly similar biological properties in the same chemical compound (see IUPAC, Compendium of Chemical Terminology, 2nd ed. (the "Gold Book") (1997). Online corrected version: (1998) "bioisostere". doi:10.1351/goldbook.BT06798). Amide bioisosteres preferably comprise, but are not limited to, 1,2,3-triazole, oxadiazole, imidazole, tetrazole, pyrazole, indole, pyridine, pyrazine, retroinverted and reverse amide, urea, olefin, fluoroalkene, trifluoroethylamine, amidine, ester, sulfonamide, phosphonamidate, thioamide, and carbamate. An "amide bioisostere" as used herein preferably refers to a moiety represented by, but not limited to, the following examples: wherein R6 is selected from the group consisting of hydrogen, Ci-6 alkyl, which is optionally substituted by one or more halogen(s), Ci-6 alkoxy, which is optionally substituted by halogen(s), and a 5, 6, 7, or 10-membered carbo- or heterocycle, which is optionally substituted by 1 to 3 R7 substituents, wherein R7 is selected from the group consisting of one or more halogen(s), — CN, — NO2, — Rf, — CO2Rd, — CONRdRe, — C(O)Rd, — OC(O)NRdRe, — NReC(O)Rd, — NReC(O)2Rf, — NRdC(O)NRdRe, — NRdRe, — ORd, and — S(O)2NRdRe; wherein each Rd and Re is independently selected from hydrogen, Cns alkyl, and Cns haloalkyl; each Rf is independently selected from the group consisting of Cns alkyl or heteroalkyl, Cns haloalkyl, C3-6 cycloalkyl, heterocycloalkyl, aryl and heteroaryl, and wherein the aliphatic and/or cyclic portions of Rd, Re and Rf are optionally further substituted with from one to three halogen, hydroxy, methyl, amino, C 1-6 alkylamino, and di C1-6 alkylamino groups.
The term "pharmaceutically acceptable" as used in the context of the present invention means approved by a regulatory agency of the Federal or a state government or listed in the U.S. Pharmacopeia (United States Pharmacopeia-33/National Formulary-28 Reissue, published by the United States Pharmacopeia Convention, Inc., Rockville Md., publication date: April 2010) or other generally recognized pharmacopeia for use in animals, and more particularly in humans.
The term "pharmaceutically acceptable salt" as used in the context of the present invention refers to a salt of a compound of the present invention. Suitable pharmaceutically acceptable salts of the compound of the present invention include acid addition salts which may, for example, be formed by mixing a solution of a compound described herein or a derivative thereof with a solution of a pharmaceutically acceptable acid such as hydrochloric acid, sulfuric acid, fumaric acid, maleic acid, succinic acid, acetic acid, benzoic acid, citric acid, tartaric acid, carbonic acid or phosphoric acid. Furthermore, where the compound of the invention carries an acidic moiety, suitable pharmaceutically acceptable salts thereof may include alkali metal salts (e.g., sodium or potassium salts); alkaline earth metal salts (e.g., calcium or magnesium salts); and salts formed with suitable organic ligands (e.g., ammonium, quaternary ammonium and amine cations formed using counteranions such as halide, hydroxide, carboxylate, sulfate, phosphate, nitrate, alkyl sulfonate and aryl sulfonate). Illustrative examples of pharmaceutically acceptable salts include but are not limited to: acetate, adipate, alginate, ascorbate, aspartate, benzene sulfonate, benzoate, bicarbonate, bisulfate, bitartrate, borate, bromide, butyrate, calcium edetate, camphorate, camphorsulfonate, camsylate, carbonate, chloride, citrate, clavulanate, cyclopentanepropionate, digluconate, dihydrochloride, dodecylsulfate, edetate, edisylate, estolate, esylate, ethanesulfonate, formate, fumarate, gluceptate, glucoheptonate, gluconate, glutamate, glycerophosphate, glycolylarsanilate, hemisulfate, heptanoate, hexanoate, hexylresorcinate, hydrabamine, hydrobromide, hydrochloride, hydroiodide, 2-hydroxyethanesulfonate, hydroxynaphthoate, iodide, isothionate, lactate, lactobionate, laurate, lauryl sulfate, malate, maleate, malonate, mandelate, mesylate, methanesulfonate, methylsulfate, mucate, 2-naphthalenesulfonate, napsylate, nicotinate, nitrate, N-methylglucamine ammonium salt, oleate, oxalate, pamoate (embonate), palmitate, pantothenate, pectinate, persulfate, 3-phenylpropionate, phosphate/diphosphate, picrate, pivalate, polygalacturonate, propionate, salicylate, stearate, sulfate, subacetate, succinate, tannate, tartrate, teoclate, tosylate, trifluoroacetate, triethiodide, undecanoate, valerate, and the like (see, for example, Berge, S. M., et al, "Pharmaceutical Salts", Journal of Pharmaceutical Science, 1977, 66, 1-19). Certain specific compounds of the present invention contain both basic and acidic functionalities that allow the compounds to be converted into either base or acid addition salts.
The neutral forms of the compounds may be regenerated by contacting the salt with a base or acid and isolating the parent compound in the conventional manner. The parent form of the compound differs from the various salt forms in certain physical properties, such as solubility in polar solvents, but otherwise the salts are equivalent to the parent form of the compound for the purposes of the present invention.
In addition to salt forms, the present invention provides compounds which are in a prodrug form. Prodrugs of the compounds described herein are those compounds that readily undergo chemical changes under physiological conditions to provide a compound of formula (I) or (IV). A prodrug is an active or inactive compound that is modified chemically through in vivo physiological action, such as hydrolysis, metabolism and the like, into a compound of this invention following administration of the prodrug to a patient. Additionally, prodrugs can be converted to the compounds of the present invention by chemical or biochemical methods in an ex vivo environment. For example, prodrugs can be slowly converted to the compounds of the present invention when placed in a transdermal patch reservoir with a suitable enzyme. The suitability and techniques involved in making and using prodrugs are well known by those skilled in the art. For a general discussion of prodrugs involving esters, see Svensson LA and Tunek A, 1988. Drug Metabolism Reviews 19(2): 165-194 and Bundgaard H, 1985. Design of Prodrugs, Elsevier Science Ltd. Examples of a masked carboxylate anion include a variety of esters, such as alkyl (for example, methyl, ethyl), cycloalkyl (for example, cyclohexyl), aralkyl (for example, benzyl, p-methoxybenzyl), and alkylcarbonyloxyalkyl (for example, pivaloyloxymethyl). Amines have been masked as arylcarbonyloxymethyl substituted derivatives which are cleaved by esterases in vivo releasing the free drug and formaldehyde (Bundgaard H et al., 1989. J Med Chem 32(12): 2503-2507). Also, drugs containing an acidic NH group, such as imidazole, imide, indole and the like, have been masked with N- acyloxymethyl groups (Bundgaard H, 1985). Hydroxy groups have been masked as esters and ethers. EP 0039 051 A2 discloses Mannich-base hydroxamic acid prodrugs, their preparation and use.
As used herein, "paraposition" when referring to the substituent of an aryl means that the substituent occupies the position opposite to the position at which the aryl is linked to the backbone of the compound.
As used herein, a "patient" means any mammal or bird that may benefit from a treatment with the compounds described herein. Preferably, a "patient" is selected from the group consisting of laboratory animals, domestic animals, or primates including chimpanzees and human beings. It is particularly preferred that the "patient" is a human being.
As used herein, "treat", "treating" or "treatment" of a disease or disorder means accomplishing one or more of the following: (a) reducing the severity of the disorder; (b) limiting or preventing development of symptoms characteristic of the disorder(s) being treated; (c) inhibiting worsening of symptoms characteristic of the disorder(s) being treated; (d) limiting or preventing recurrence of the disorder(s) in patients that have previously had the disorder(s); and (e) limiting or preventing recurrence of symptoms in patients that were previously symptomatic for the disorder(s).
As used herein, "prevent", "preventing", "prevention", or "prophylaxis" of a disease or disorder means preventing that a disorder occurs in a subject for a certain amount of time. For example, if a compound described herein is administered to a subject with the aim of preventing a disease or disorder, said disease or disorder is prevented from occurring at least on the day of administration and preferably also on one or more days (e.g. on 1 to 30 days; or on 2 to 28 days; or on 3 to 21 days; or on 4 to 14 days; or on 5 to 10 days) following the day of administration.
A "pharmaceutical composition" according to the invention may be present in the form of a composition, wherein the different active ingredients and diluents and/or carriers are admixed with each other, or may take the form of a combined preparation, where the active ingredients are present in partially or totally distinct form. An example for such a combination or combined preparation is a kit-of-parts.
An "effective amount" as used in the context of the present invention refers to an amount of a therapeutic agent sufficient to achieve the intended purpose. The effective amount of a given therapeutic agent will vary with factors such as the nature of the agent, the route of administration, the size and species of the animal to receive the therapeutic agent, and the purpose of the administration. The effective amount in each individual case may be determined empirically by a skilled artisan according to established methods in the art.
The term "carrier", as used herein, refers to a diluent, adjuvant, excipient, or vehicle with which the therapeutic agent is administered. Such pharmaceutical carriers can be sterile liquids, such as saline solutions in water and oils, including those of petroleum, animal, vegetable or synthetic origin, such as peanut oil, soybean oil, mineral oil, sesame oil and the like. A saline solution is a preferred carrier when the pharmaceutical composition is administered intravenously. Saline solutions and aqueous dextrose and glycerol solutions can also be employed as liquid carriers, particularly for injectable solutions. Suitable pharmaceutical excipients include starch, glucose, lactose, sucrose, gelatine, malt, rice flour, chalk, silica gel, sodium stearate, glycerol monostearate, talc, sodium chloride, dried skim milk, glycerol, propylene glycol, water, ethanol and the like. The composition, if desired, can also contain minor amounts of wetting or emulsifying agents, or pH buffering agents. These compositions can take the form of solutions, suspensions, emulsions, tablets, pills, capsules, powders, sustained-release formulations and the like. The composition can be formulated as a suppository, with traditional binders and carriers such as triglycerides. The compounds of the invention can be formulated as neutral or salt forms. Pharmaceutically acceptable salts include those formed with free amino groups such as those derived from hydrochloric, phosphoric, acetic, oxalic, tartaric acids, etc., and those formed with free carboxyl groups such as those derived from sodium, potassium, ammonium, calcium, ferric hydroxides, isopropylamine, triethylamine, 2-ethylamino ethanol, histidine, procaine, etc. Examples of suitable pharmaceutical carriers are described in Martin EW, Remington's Pharmaceutical Sciences, Mack Publishing, Easton, Pa. Such compositions will contain a therapeutically effective amount of the compound, preferably in purified form, together with a suitable amount of carrier so as to provide the form for proper administration to the patient. The formulation should suit the mode of administration. The term "for use in medicine" refers in the context of the present invention to the use of the compounds disclosed herein in a method for manufacturing a medicament or a pharmaceutical composition or for diagnosis, therapy or prevention of a disease or disorder in a subject or individual.
The term " Acinetobacter baumannii infections" refers in the context of the present invention to infections with Acinetobacter baumannii or diseases resulting from such infections comprising, but not limited to, bacteremia, eye infection (corneal ulcers, endophthalmitis, periorbital cellulitis), pneumonia, meningitis, bloodstream infection, bone infection, skin infection, soft tissue infection, peritonitis, sinusitis, urinary tract infection, and wound infection.
The term 'Acinetobacter baumannii-associated lung infections" refers in the context of the present invention to infections of one or both lungs, such as pneumonia, and in particular ventilator-associated pneumonia.
The term "catheter-associated Acinetobacter baumannii infections" refers in the context of the present invention to infections with Acinetobacter baumannii associated with the use of catheters, such as urinary tract infections.
The term "Acinetobacter baumannii-associated bacteremia" refers in the context of the present invention to the presence of Acinetobacter baumannii in the bloodstream. The most common sources of bacteremia are intravascular catheters and the respiratory tract.
The term "Acinetobacter baumannii-associated sepsis" refers in the context of the present invention to an uncontrolled systemic inflammatory response to an infection from Acinetobacter baumannii that may rapidly progress to a life-threatening condition and can lead to shock and organ failure (i.e., septic shock and severe sepsis) if not treated immediately.
The term "carbapenem resistant Acinetobacter baumannii" refers in the context of the present invention to an Acinetobacter baumannii that is nonsusceptible to at least one antip seudomonal carbapenem.
The term "multidrug resistant Acinetobacter baumannii" refers in the context of the present invention to an Acinetobacter baumannii nonsusceptible to at least one agent in three or more antibiotic groups (i.e., third- or fourth-generation cephalosporins, fluoroquinolones, aminoglycosides, carbapenems, piperacillin-tazobactam, and ampicillin-sulbactam).
The term "anti-bacterial therapeutic agent" refers in the context of the present invention substances or biomolecules that selectively destroy bacteria by interfering with bacterial growth or survival, anti- virulence agents and host-directed therapeutics. In some embodiments, the term "anti-bacterial therapeutic agent" refers to antibiotics, peptides, carbohydrates, and nucleic acids. Anti-bacterial nucleic acids are preferably antisense antimicrobial therapeutic agents, aptamers, and topoisomerase inhibitors.
Antimicrobial peptides (AMPs) are usually short biomolecules (15-50 amino acids) encoded by genes. Most of these short peptides contain basic amino acids and hydrophobic residues, which are arranged in three dimensions on the surface of the peptide. Thousands of AMPs have been extracted from single-celled microorganisms of plants, insects, and bacteria. The antimicrobial peptide database (APD3) contains more than 3000 AMPs (Wang, G, el al., 2016. APD3: the antimicrobial peptide database as a tool for research and education. Nucleic Acids Research, 44, DI, D1087-D1093). Also bacteria produce a variety of AMPs in order to limit the growth of other microorganisms. AMPs can be ranked according to their physical properties, sequence properties, and conformation of antimicrobial peptides interacting with cell membranes. Exemplary antimicrobial peptides comprise, but are not limited to, LL-37, Bactenecin, BMAP-27, CATH-2, PMAP-36, Protegrin, Abaecin, Cecropin, BhDefl-2, alfAFP, Vrd2, Snakin-1, nisin, triAl, pediocin, LMW, and garvicin KS.
In preferred embodiments, the term "anti-bacterial therapeutic agent" refers to a carbapenem antibiotic (e.g. ertapenem, doripenem, imipenem/cilastatin, and meropenem), cephalosporin antibiotic (e.g. cephalexin, cefuroxime, cefadroxil, cefazolin, cephalothin, cefaclor, cefamandole, cefoxitin, cefprozil, and ceftobiprole), cyclic lipopeptide antibiotic, fluoroquinolone antibiotic (e.g. ciprofloxacin, levaquin, floxin, tequin, moxifloxacin, and norfloxacin), tetracycline antibiotic (e.g. tetracycline, minocycline, oxytetracycline, and doxycycline), fusidic acid, lantibiotic (e.g nisin, mersacidin, actagardine, deoxyactagardine B, and microbio sporin), lincomycin antibiotic, macrolide antibiotic (azithromycin, clarithromycin, erythromycin, telithromycin, quinorubicin, and solithromycin), meropenem antibiotic (e.g. meropenem, doripenem, imipenem, ertapenem, biapenem, cephalopenem, and panipenem), novobiocin, oxazolidinone antibiotic (e.g. linezolid, terizolide and lefluide), penicillin antibiotic (e.g. amoxicillin, ampicillin, penicillin v, dicloxacillin, carbenicillin, vancomycin, and methicillin), streptogramin antibiotic, tigecycline antibiotic (e.g. tigecycline, omacycline (omadacycline), evericin (ovacycline), doxycycline and minocycline), vancomycin antibiotic (e.g. vancomycin, teicoplanin, telavancin, dalbavancin, and oritavancin).
In preferred embodiments, the term "anti-bacterial therapeutic agent" refers to amikacin, amoxicillin, ampicillin (e.g., pivampicillin, hetacillin, bacampicillin, metampicillin, talampicillin), apramycin, arbekacin, azidocillin, azithromycin, azlocillin, aztreonam, benzathine benzylpenicillin, benzathine phenoxymethylpenicillin, benzazole, benzylpenicillin (g), biapenem, carbenicillin (carindacillin), carumonam, cefacetrile, cefaclor, cefadroxil, cefalexin, cefaloglycin, cefalonium, cefaloridine, cefalotin, cefamandole, cefapirin, cefatrizine, cefazaflur, cefazedone, cefazolin, cefbuperazone, cefcapene, cefdaloxime, cefdinir, cefditoren, cefepime, cefetamet, cefixime, cefmenoxime, cefmetazole, cefminox, cefodizime, cefonicid, cefoperazone, ceforanide, cefotaxime, cefotetan, cefotiam, cefovecin, cefoxitin, cefozopran, cefpimizole, cefpiramide, cefpirome, cefpodoxime, cefprozil, cefquinome, cefradine, cefroxadine, cefsulodin, ceftaroline, ceftazidime, cefteram, ceftezole, ceftibuten, ceftiofur, ceftiolene, ceftizoxime, ceftobiprole, ceftriaxone, cefuroxime, cefuzonam, ciprofloxacin, clarithromycin, clometocillin, cioxacillin (e.g. dicloxacillin, flucioxacillin), dalfopristin, daptomycin, doripenem, epicillin, ertapenem, erythromycin, etimicin, faropenem, flomoxef, fusidic acid, gentamicin, kanamycin, imipenem, latamoxef, loracarbef, mecillinam (pivmecillinam), meropenem, methicillin, mezlocillin, mupirocin, nafcillin, neomycin, netilmicin, novobiocin, oxacillin, panipenem, paromomycin, penamecillin, pheneticillin, phenoxymethylpenicillin (v), piperacillin, plazamicin, procaine benzylpenicillin, propicillin, razupenem, rifabutin, rifalazil, rifampin (rifampicin), rifapentine, rifaximin, streptomycin, sulbenicillin, temocillin, ticarcillin, tigecycline, tigemonam, tobramycin, tomopenem, vancomycin.
The term "anti-virulence agent" refers in the context of the present invention to an agent able to reduce expression of a virulence factor that is expressed in a bacterium- specific manner under infection conditions, and which is not essential for bacterial viability but is rather required for pathogenesis. For example, an anti-virulence agent can target quorum sensing, secretion systems, toxins, and biofilms. For example, an anti-virulence agent can be an anti-sense nucleotide that inhibits expression of a virulence factor.
The term "host-directed therapeutics" refers in the context of the present invention to small-molecule drugs and proteins to alter the host response to pathogen infection. Preferred host-directed therapeutics are selected from the group comprising probiotics, immunomodulators, such as lysophosphatidylcholine and macrolide antibiotics such as clarithromycin.
The term "protecting group" as used in the context of the present invention refers to a functional group as known in the art, i.e. a protecting group or protective group introduced into a molecule by chemical modification of a functional group to obtain chemoselectivity in a subsequent chemical reaction. Preferred examples are those protecting groups selected from, but not limited to, a benzyl group (Ph — CH2 — , abbreviation Bn, a benzhydryl group (Phi — CH — ), a benzyloxycarbonyl group (Ph — CH2O — CO — , abbreviation Cbz), a benzyloxymethyl group (Ph — CH2O — CH2 — , abbreviation Bom), /-butoxycarbonyl group (Boc), a fluorenylmethoxyl group (FMoc), and a trityl group (Ph? — C — , abbreviation Tr).
Embodiments
In the following, different aspects of the invention are defined in more detail. Each aspect so defined may be combined with any other aspect or aspects unless clearly indicated to the contrary. In particular, any feature indicated as being preferred or advantageous may be combined with any other feature or features indicated as being preferred or advantageous.
In a first aspect, the present invention provides a compound of the general formula (I): wherein
R1 is individually selected from the group consisting of halogen and C1-4 alkyl, which is optionally substituted by one or more halogen(s), and C1-4 alkoxy, which is optionally substituted by one or more halogen(s);
R2 is individually selected from the group consisting of hydrogen, OH, NH2, NO2, SH, one or more halogen(s), COOR8, wherein R8 is hydrogen or C1-4 alkyl, which is optionally substituted by one or more halogen(s), C1-4 acyl, which is optionally substituted by one or more halogen(s), C1-4 alkyl, which is optionally substituted by one or more halogen(s), and C1-4 alkoxy, which is optionally substituted by one or more halogen(s); m is 0, 1, 2 or 3;
R3 is a C1-8 alkyl chain wherein 1, 2 or 3 chain carbon atoms are individually replaced by NH, -O-, C=O, or S(=O) x, wherein X is 0, 1, or 2, and which chain is optionally substituted by 1 to 3 substituents individually selected from the group consisting of: one or more halogen(s), N3,
C1-6 alkyl, which is optionally substituted by one or more halogen(s),
C1-6 alkoxy, which is optionally substituted by one or more halogen(s), and a 5 to 10 membered carbo- or heterocycle, which is optionally substituted by 1 to 3 R7 substituents, wherein R7 is selected from the group consisting of one or more halogen(s), — CN, — N02, — Rf, — CO2Rd, — CONRdRe, — C(O)Rd, — OC(O)NRdRe, — NReC(O)Rd, — NReC(O)2Rf, — NRdC(O)NRdRe, — NRdRe, — 0Rd, and — S(O)2NRdRe; wherein each Rd and Re is independently selected from hydrogen, C1-8 alkyl, and C1-8 haloalkyl; each Rf is independently selected from the group consisting of C1-8 alkyl or heteroalkyl, C1-8 haloalkyl, C3-6 cycloalkyl, heterocycloalkyl, aryl and heteroaryl, and wherein the aliphatic and/or cyclic portions of Rd, Re and Rf are optionally further substituted with from one to three halogen, hydroxy, methyl, amino, C 1-6 alkylamino and di C1-6 alkylamino groups;
R4 and R5 are individually selected from the group consisting of hydrogen, one or more halogen(s), and C1-4 alkyl, and preferably are hydrogen; or a salt thereof, or a solvate thereof, or a prodrug thereof.
In a preferred embodiment of the first aspect of the present invention, R3 is a C1-8 alkyl chain wherein 1, 2 or 3 of the chain carbon atoms are individually replaced by NH, -O-, C=O, and/or S(=O)2, and which chain is optionally substituted by 1, 2 or 3 substituents selected from the group consisting of N3, C1-6 alkyl, C1-6 alkoxy, and a 5, 6, or 10-membered carbo- or heterocycle, which is optionally substituted by 1 to 3 R7substituents, wherein R7 is selected from the group consisting of one or more halogen(s), — CN, — NO2, — Rf, — CO2Rd, — CONRdRe, — C(O)Rd, — OC(O)NRdRe, — NReC(O)Rd, — NReC(O)2Rf, — NRdC(O)NRdRe, — NRdRe, — ORd, and — S(O)2NRdRe; wherein each Rd and Re is independently selected from hydrogen, C1-8 alkyl, and C1-8 haloalkyl; each Rf is independently selected from the group consisting of C1-8 alkyl or heteroalkyl, C 1-8 haloalkyl, C3-6 cycloalkyl, heterocycloalkyl, aryl and heteroaryl, and wherein the aliphatic and/or cyclic portions of Rd, Re and Rf are optionally further substituted with from one to three halogen, hydroxy, methyl, amino, C1-6 alkylamino and di Ci -6 alkylamino groups.
In a further preferred embodiment of the first aspect of the present invention, R3 is a residue of the formula (la) wherein
R6 is selected from the group consisting of hydrogen, C1-6 alkyl, which is optionally substituted by one or more halogen(s), C1-6 alkoxy, which is optionally substituted by one or more halogen(s), and a 5, 6, 7, or 10-membered carbo- or heterocycle, which is optionally substituted by 1 to 3 R7substituents, wherein R7 is selected from the group consisting of one or more halogen(s), — CN, — NO2, — Rf, — CO2Rd, — CONRdRe, — C(O)Rd, — OC(O)NRdRe, — NReC(O)Rd, — NReC(O)2Rf, — NRdC(O)NRdRe, — NRdRe, — 0Rd, and — S(0)2NRdRe; wherein each Rd and Re is independently selected from hydrogen, Ci-s alkyl, and Ci-s haloalkyl; each Rfis independently selected from the group consisting of Ci-s alkyl or heteroalkyl, Ci-s haloalkyl, C3-6 cycloalkyl, heterocycloalkyl, aryl and heteroaryl, and wherein the aliphatic and/or cyclic portions of Rd, Re and Rf are optionally further substituted with from one to three halogen, hydroxy, methyl, amino, C1-6 alkylamino and di C1-6 alkylamino groups, and wherein n is 0, 1, or 2; or a residue of the formula (la), wherein the amide is replaced by an amide bioisostere and R6 and n are as defined above.
In a further preferred embodiment of the first aspect of the present invention, R3 is a residue of the formula (lb) wherein
R6 is selected from the group consisting of hydrogen, C1-6 alkyl, which is optionally substituted by one or more halogen(s), C1-6 alkoxy, which is optionally substituted by one or more halogen(s), and a 5, 6, 7, or 10-membered carbo- or heterocycle, which is optionally substituted by 1 to 3 R7substituents, wherein R7 is selected from the group consisting of one or more halogen(s), — CN, — NO2, — Rf, — CO2Rd, — CONRdRe, — C(O)Rd, — OC(O)NRdRe, — NReC(O)Rd, — NReC(O)2Rf, — NRdC(O)NRdRe, — NRdRe, — ORd, and — S(O)2NRdRe; wherein each Rd and Re is independently selected from hydrogen, Ci-s alkyl, and C 1-8 haloalkyl; each Rfis independently selected from the group consisting of Ci-s alkyl or heteroalkyl, Ci-s haloalkyl, C3-6 cycloalkyl, heterocycloalkyl, aryl and heteroaryl, and wherein the aliphatic and/or cyclic portions of Rd, Re and Rf are optionally further substituted with from one to three halogen, hydroxy, methyl, amino, C1-6 alkylamino and di C1-6 alkylamino groups, and wherein n is 0, 1, or 2; or a residue of the formula (lb), wherein the amide is replaced by an amide bioisostere and R6 and n are as defined above. In a further preferred embodiment of the first aspect of the present invention, R3 is a residue of the formula (Ic) wherein
R6 is selected from the group consisting of hydrogen, C1-6 alkyl, which is optionally substituted by one or more halogen(s), C1-6 alkoxy, which is optionally substituted by one or more halogen(s), and a 5, 6, 7, or 10-membered carbo- or heterocycle, which is optionally substituted by 1 to 3 R7 substituents, wherein R7 is selected from the group consisting of one or more halogen(s), — CN, — NO2, — Rf, — C02Rd, — CONRdRe, — C(O)Rd, — OC(O)NRdRe, — NReC(O)Rd, — NReC(O)2Rf, — NRdC(O)NRdRe, — NRdRe, — ORd, and — S(O)2NRdRe; wherein each Rd and Re is independently selected from hydrogen, C1-8 alkyl, and Ci-shaloalkyl; each Rfis independently selected from the group consisting of C1-8 alkyl or heteroalkyl, C1-8 haloalkyl, C3-6 cycloalkyl, heterocycloalkyl, aryl and heteroaryl, and wherein the aliphatic and/or cyclic portions of Rd, Re and Rf are optionally further substituted with from one to three halogen, hydroxy, methyl, amino, C1-6 alkylamino and di C1-6 alkylamino groups, and wherein n is 0, 1, or 2.
In a further preferred embodiment of the first aspect of the present invention, R3 is a residue of the formula (Id) wherein
R6 is selected from the group consisting of hydrogen, Ci-6 alkyl, which is optionally substituted by one or more halogen(s), Ci-6 alkoxy, which is optionally substituted by halogen(s), and a 5, 6, 7, or 10-membered carbo- or heterocycle, which is optionally substituted by 1 to 3 R7 substituents, wherein R7 is selected from the group consisting of one or more halogen(s), — CN, — NO2, — Rf, — C02Rd, — CONRdRe, — C(O)Rd, — OC(O)NRdRe, — NReC(O)Rd, — NReC(O)2Rf, — NRdC(O)NRdRe, — NRdRe, — ORd, and — S(0)2NRdRe; wherein each Rd and Re is independently selected from hydrogen, C1-8 alkyl, and Ci-8 haloalkyl; each Rfis independently selected from the group consisting of Ci-8 alkyl or heteroalkyl, Ci-8 haloalkyl, C3-6 cycloalkyl, heterocycloalkyl, aryl and heteroaryl, and wherein the aliphatic and/or cyclic portions of Rd, Reand Rfare optionally further substituted with from one to three halogen, hydroxy, methyl, amino, C1-6 alkylamino and di C 1-6 alkylamino groups, and wherein n is 0, 1, or 2.
In a further preferred embodiment of the first aspect of the present invention, R3 is a residue of the formula (la).
In a further preferred embodiment of the first aspect of the present invention, R6 is selected from the group consisting of C3-6 alkyl, which is optionally substituted by one or more halogen(s), C1-6 alkoxy, which is optionally substituted by one or more halogen(s), and a 5, 6, 7, or 10-membered carbo- or heterocycle, having 1 to 3 heteroatoms as ring members selected from N, O, and S, which 5, 6, 7, or 10-carbo- or heterocycle is optionally substituted by 1 to 3 R7 substituents, wherein R7 is selected from the group consisting of one or more halogen(s), — CN, — NO2, — Rf, — CO2Rd, — CONRdRe, — C(O)Rd, — OC(O)NRdRe, — NReC(O)Rd, — NReC(O)2Rf, — NRdC(O)NRdRe, — NRdRe, — ORd, and — S(O)2NRdRe; wherein each Rd and Re is independently selected from hydrogen, C1-8 alkyl, and C1-8 haloalkyl; each Rf is independently selected from the group consisting of C1-8 alkyl or heteroalkyl, C1-8 haloalkyl, C3-
6 cycloalkyl, heterocycloalkyl, aryl and heteroaryl, and wherein the aliphatic and/or cyclic portions of Rd, Re and Rf are optionally further substituted with from one to three halogen, hydroxy, methyl, amino, C 1-6 alkylamino and di C1-6 alkylamino groups.
In a further preferred embodiment of the first aspect of the present invention, R6 is a 5, 6,
7 or 10-membered carbo- or heterocycle, and the 5, 6, 7 or 10-membered carbo- or heterocycle is selected from the group consisting of a C5-10 cycloalkyl group, a heterocycloalkyl group having 1 to 3 heteroatoms as ring members selected from N, O, and S; a Ce aryl group, and a heteroaryl group having from 1 to 3 heteroatoms as ring members selected from N, O and S; which 5, 6, 7, or 10-membered carbo- or heterocycle is optionally substituted by 1 to 3 R7 substituents, wherein R7 is selected from the group consisting of one or more halogen(s), — CN, — NO2, — Rf, — CO2Rd, — CONRdRe, — C(O)Rd, — OC(O)NRdRe, — NReC(O)Rd, — NReC(O)2Rf, — NRdC(O)NRdRe, — NRdRe, — ORd, and — S(O)2NRdRe; wherein each Rd and Re is independently selected from hydrogen, C1-8 alkyl, and C1-8 haloalkyl; each Rf is independently selected from the group consisting of C1-8 alkyl or heteroalkyl, C1-8 haloalkyl, C3- 6 cycloalkyl, heterocycloalkyl, aryl and heteroaryl, and wherein the aliphatic and/or cyclic portions of Rd, Re and Rf are optionally further substituted with from one to three halogen, hydroxy, methyl, amino, Ci -6 alkylamino and di Ci-6 alkylamino groups.
In a further preferred embodiment of the first aspect of the present invention, R1 is chlorine. In a further preferred embodiment of the first aspect of the present invention, R2 is hydrogen. In a further preferred embodiment of the first aspect of the present invention, R4 is hydrogen. In a further preferred embodiment of the first aspect of the present invention, R5 is hydrogen. In a further preferred embodiment of the first aspect of the present invention, R1 is chlorine and/or R2, R4 and/or R5 are hydrogen. In a further preferred embodiment of the first aspect of the present invention, R2, R4 and/or R5 are hydrogen.
In a further preferred embodiment of the first aspect of the present invention, m is 0. In a further preferred embodiment of the first aspect of the present invention, m is 0 and n is 0. In a further preferred embodiment of the first aspect of the present invention, m is 0 and n is 2. In a further preferred embodiment of the first aspect of the present invention, n is 0. In a further preferred embodiment of the first aspect of the present invention, n is 2.
In a further preferred embodiment of the first aspect of the present invention, R1 is chlorine, and R2, R4 and R5 are hydrogen, m is 0, and n is 0. In a further preferred embodiment of the first aspect of the present invention, R1 is chlorine, and R2, R4 and R5 are hydrogen, m is 0, and n is 1. In a further preferred embodiment of the first aspect of the present invention, R1 is chlorine, and R2, R4 and R5 are hydrogen, m is 0, and n is 2.
In a further preferred embodiment of the first aspect of the present invention, R1 is chlorine, and R2, R4 and R5 are hydrogen, m is 0, R3 is a residue of the formula (la), and n is 0. In a further preferred embodiment of the first aspect of the present invention, R1 is chlorine, and R2, R4 and R5 are hydrogen, m is 0, R3 is a residue of the formula (la), and n is 1. In a further preferred embodiment of the first aspect of the present invention, R1 is chlorine, and R2, R4 and R5 are hydrogen, m is 0, R3 is a residue of the formula (la), and n is 2. In a further preferred embodiment of the first aspect of the present invention, R1 is chlorine, and R2, R4 and R5 are hydrogen, m is 0, R3 is a residue of the formula (lb), and n is 0. In a further preferred embodiment of the first aspect of the present invention, R1 is chlorine, and R2, R4 and R5 are hydrogen, m is 0, R3 is a residue of the formula (lb), and n is 1. In a further preferred embodiment of the first aspect of the present invention, R1 is chlorine, and R2, R4 and R5 are hydrogen, m is 0, R3 is a residue of the formula (lb), and n is 2. In a further preferred embodiment of the first aspect of the present invention, R1 is chlorine, and R2, R4 and R5 are hydrogen, m is 0, R3 is a residue of the formula (Ic), and n is 0. In a further preferred embodiment of the first aspect of the present invention, R1 is chlorine, and R2, R4 and R5 are hydrogen, m is 0, R3 is a residue of the formula (Ic), and n is 1. In a further preferred embodiment of the first aspect of the present invention, R1 is chlorine, and R2, R4 and R5 are hydrogen, m is 0, R3 is a residue of the formula (Ic), and n is 2. In a further preferred embodiment of the first aspect of the present invention, R1 is chlorine, and R2, R4 and R5 are hydrogen, m is 0, R3 is a residue of the formula (Id), and n is 0. In a further preferred embodiment of the first aspect of the present invention, R1 is chlorine, and R2, R4 and R5 are hydrogen, m is 0, R3 is a residue of the formula (Id), and n is 1. In a further preferred embodiment of the first aspect of the present invention, R1 is chlorine, and R2, R4 and R5 are hydrogen, m is 0, R3 is a residue of the formula (Id), and n is 2.
In a further preferred embodiment of the first aspect of the present invention, R6 is a hydrogen, a pentyl group, a cyclopropyl group, a cyclopentyl group, a cyclohexyl group, a phenyl group, a tert-butyl group, a O-tert-butyl group, a n-butyl group, a methyl group, a methyl-butyl group, a benzyl group, a adamantyl group, a pyridinyl group, a piperazinyl group, a hexahydropyrimidinyl group, a hexahydropyridazinyl group, a 3-thienyl group, a piperidinyl group, a pyrrolyl group, a 4-Boc-morpholinyl group, a N-Boc-piperidinyl group, or a 1-Boc- (4-Boc)piperazinyl group.
In a further preferred embodiment of the first aspect of the present invention, R1 is chlorine, and R2, R4 and R5 are hydrogen, m is 0, R3 is a residue of the formula (la), n 0 or 2, and R6 is a hydrogen, a pentyl group, a cyclopropyl group, a cyclopentyl group, a cyclohexyl group, a phenyl group, a tert-butyl group, a O-tert-butyl group, a n-butyl group, a methyl group, a methyl-butyl group, a benzyl group, a adamantyl group, a pyridinyl group, a piperazinyl group, a hexahydropyrimidinyl group, a hexahydropyridazinyl group, a 3-thienyl group, a piperidinyl group, a pyrrolyl group, a 4-Boc-morpholinyl group, a N-Boc-piperidinyl group, or a l-Boc-(4-Boc)piperazinyl group.
In a further preferred embodiment of the first aspect of the present invention, R1 is chlorine, and R2, R4 and R5 are hydrogen, m is 0, R3 is a residue of the formula (lb), n 0 or 2, and R6 is a hydrogen, a pentyl group, a cyclopropyl group, a cyclopentyl group, a cyclohexyl group, a phenyl group, a tert-butyl group, a O-tert-butyl group, a n-butyl group, a methyl group, a methyl-butyl group, a benzyl group, a adamantyl group, a pyridinyl group, a piperazinyl group, a hexahydropyrimidinyl group, a hexahydropyridazinyl group, a 3-thienyl group, a piperidinyl group, a pyrrolyl group, a 4-Boc-morpholinyl group, a N-Boc-piperidinyl group, or a l-Boc-(4-Boc)piperazinyl group.
In a further preferred embodiment of the first aspect of the present invention, R1 is chlorine, and R2, R4 and R5 are hydrogen, m is 0, R3 is a residue of the formula (Ic), n 0 or 2, and R6 is a hydrogen, a pentyl group, a cyclopropyl group, a cyclopentyl group, a cyclohexyl group, a phenyl group, a tert-butyl group, a O-tert-butyl group, a n-butyl group, a methyl group, a methyl-butyl group, a benzyl group, a adamantyl group, a pyridinyl group, a piperazinyl group, a hexahydropyrimidinyl group, a hexahydropyridazinyl group, a 3-thienyl group, a piperidinyl group, a pyrrolyl group, a 4-Boc-morpholinyl group, a N-Boc-piperidinyl group, or a l-Boc-(4-Boc)piperazinyl group.
In a further preferred embodiment of the first aspect of the present invention, R1 is chlorine, and R2, R4 and R5 are hydrogen, m is 0, R3 is a residue of the formula (Id), n 0 or 2, and R6 is a hydrogen, a pentyl group, a cyclopropyl group, a cyclopentyl group, a cyclohexyl group, a phenyl group, a tert-butyl group, a O-tert-butyl group, a n-butyl group, a methyl group, a methyl-butyl group, a benzyl group, a adamantyl group, a pyridinyl group, a piperazinyl group, a hexahydropyrimidinyl group, a hexahydropyridazinyl group, a 3-thienyl group, a piperidinyl group, a pyrrolyl group, a 4-Boc-morpholinyl group, a N-Boc-piperidinyl group, or a l-Boc-(4-Boc)piperazinyl group.
In a further preferred embodiment of the first aspect of the present invention, R1 is chlorine, m is 0, n is 2, R3 is a residue of the formula (la), R4 and R5 are hydrogen, and R6 is a O-tert-butyl group.
In a further preferred embodiment of the first aspect of the present invention,
R3 is selected from the group consisting of:
In a further preferred embodiment of the first aspect of the present invention, the compound has the following formula (II): wherein R3 is as defined above.
In a further preferred embodiment of the first aspect of the present invention, the compound has the following formula: wherein
In a second aspect, the present invention relates to a pharmaceutical composition comprising or consisting of at least one compound of the first aspect, and, optionally, one or more constituents selected from the group consisting of a pharmaceutically acceptable carrier, a diluent, an excipient and a further anti-bacterial therapeutic agent. In a preferred embodiment of the second aspect, the present invention relates to a pharmaceutical composition comprising or consisting of at least one compound of the first aspect, and one or more constituents selected from the group consisting of a pharmaceutically acceptable carrier, a diluent, an excipient. In a preferred embodiment of the second aspect, the present invention relates to a pharmaceutical composition comprising or consisting of at least one compound of the first aspect, and one or more constituents selected from the group consisting of a pharmaceutically acceptable carrier, a diluent, an excipient and one or more further anti-bacterial therapeutic agent(s).
In one embodiment of the second aspect, the one or more anti-bacterial therapeutic agent(s) is selected from the group consisting of a carbapenem antibiotic (e.g. ertapenem, doripenem, imipenem/cilastatin, and meropenem), cephalosporin antibiotic (e.g. cephalexin, cefuroxime, cefadroxil, cefazolin, cephalothin, cefaclor, cefamandole, cefoxitin, cefprozil, and ceftobiprole), cyclic lipopeptide antibiotic, fluoroquinolone antibiotic (e.g. ciprofloxacin, levaquin, floxin, tequin, moxifloxacin, and norfloxacin), tetracycline antibiotic (e.g. tetracycline, minocycline, oxytetracycline, and doxycycline), fusidic acid, lantibiotic (e.g nisin, mersacidin, actagardine, deoxyactagardine B, and microbio sporin), lincomycin antibiotic, macrolide antibiotic (azithromycin, clarithromycin, erythromycin, telithromycin, quinorubicin, and solithromycin), meropenem antibiotic (e.g. meropenem, doripenem, imipenem, ertapenem, biapenem, cephalopenem, and panipenem), novobiocin, oxazolidinone antibiotic (e.g. linezolid, terizolide and lefluide), penicillin antibiotic (e.g. amoxicillin, ampicillin, penicillin v, dicloxacillin, carbenicillin, vancomycin, and methicillin), streptogramin antibiotic, tigecycline antibiotic (e.g. tigecycline, omacycline (omadacycline), evericin (ovacycline), doxycycline and minocycline), and vancomycin antibiotic (e.g. vancomycin, teicoplanin, telavancin, dalbavancin, and oritavancin).
In one embodiment of the second aspect, the one or more anti-bacterial therapeutic agent(s) is selected from the group consisting of amikacin, amoxicillin, ampicillin (e.g., pivampicillin, hetacillin, bacampicillin, metampicillin, talampicillin), apramycin, arbekacin, azidocillin, azithromycin, azlocillin, aztreonam, benzathine benzylpenicillin, benzathine phenoxymethylpenicillin, benzazole, benzylpenicillin (g), biapenem, carbenicillin (carindacillin), carumonam, cef acetrile, cefaclor, cefadroxil, cefalexin, cefaloglycin, cefalonium, cefaloridine, cefalotin, cefamandole, cefapirin, cefatrizine, cefazaflur, cefazedone, cefazolin, cefbuperazone, cefcapene, cefdaloxime, cefdinir, cefditoren, cefepime, cefetamet, cefixime, cefmenoxime, cefmetazole, cefminox, cefodizime, cefonicid, cefoperazone, ceforanide, cefotaxime, cefotetan, cefotiam, cefovecin, cefoxitin, cefozopran, cefpimizole, cefpiramide, cefpirome, cefpodoxime, cefprozil, cefquinome, cefradine, cefroxadine, cefsulodin, ceftaroline, ceftazidime, cefteram, ceftezole, ceftibuten, ceftiofur, ceftiolene, ceftizoxime, ceftobiprole, ceftriaxone, cefuroxime, cefuzonam, ciprofloxacin, clarithromycin, clometocillin, cioxacillin (e.g. dicloxacillin, flucioxacillin), dalfopristin, daptomycin, doripenem, epicillin, ertapenem, erythromycin, etimicin, faropenem, flomoxef, fusidic acid, gentamicin, kanamycin, imipenem, latamoxef, loracarbef, mecillinam (pivmecillinam), meropenem, methicillin, mezlocillin, mupirocin, nafcillin, neomycin, netilmicin, novobiocin, oxacillin, panipenem, paromomycin, penamecillin, pheneticillin, phenoxymethylpenicillin (v), piperacillin, plazamicin, procaine benzylpenicillin, propicillin, razupenem, rifabutin, rifalazil, rifampin (rifampicin), rifapentine, rifaximin, streptomycin, sulbenicillin, temocillin, ticarcillin, tigecycline, tigemonam, tobramycin, tomopenem, and vancomycin.
In a third aspect, the present invention relates to the compound of the first aspect for use in medicine. In a third aspect, the present invention relates to the pharmaceutical composition of the second aspect for use in medicine.
In a preferred embodiment, the present invention relates to the compound of the first aspect for use as a medicament. In a preferred embodiment, the present invention relates to the pharmaceutical composition of the second aspect for use as a medicament.
In a preferred embodiment of the fourth aspect, the present invention relates to the compound of the first aspect optionally in combination with one or more anti-bacterial therapeutic agent(s), for use in the prophylaxis or treatment of Acinetobacter baumannii infections in a patient.
In a further preferred embodiment of the fourth aspect, the present invention relates to the compound of the first aspect optionally in combination with one or more anti-bacterial therapeutic agent(s), for use in the prophylaxis or treatment of Acinetobacter baumannii-associated lung infections, catheter-associated infections, bacteremia, or sepsis in a patient.
In a further preferred embodiment of the fourth aspect, the present invention relates to the compound of the first aspect optionally in combination with one or more anti-bacterial therapeutic agent(s), for use in the prophylaxis or treatment of carbapenem resistant Acinetobacter baumannii or multidrug resistant Acinetobacter baumannii.
In a further preferred embodiment of the fourth aspect, the present invention relates to the pharmaceutical composition of the second aspect, for use in the prophylaxis or treatment of Acinetobacter baumannii infections in a patient.
In a further preferred embodiment of the fourth aspect, the present invention relates to the pharmaceutical composition of the second aspect, for use in the prophylaxis or treatment of Acinetobacter baumannii-associated lung infections, catheter-associated infections, bacteremia, or sepsis in a patient.
In a further preferred embodiment of the fourth aspect, the present invention relates to the pharmaceutical composition of the second aspect, for use in the prophylaxis or treatment of carbapenem resistant Acinetobacter baumannii or multidrug resistant Acinetobacter baumannii.
In one embodiment of the fourth aspect, the one or more anti-bacterial therapeutic agent(s) is selected from the group consisting of a carbapenem antibiotic (e.g. ertapenem, doripenem, imipenem/cilastatin, and meropenem), cephalosporin antibiotic (e.g. cephalexin, cefuroxime, cefadroxil, cefazolin, cephalothin, cefaclor, cefamandole, cefoxitin, cefprozil, and ceftobiprole), cyclic lipopeptide antibiotic, fluoroquinolone antibiotic (e.g. ciprofloxacin, levaquin, floxin, tequin, moxifloxacin, and norfloxacin), tetracycline antibiotic (e.g. tetracycline, minocycline, oxytetracycline, and doxycycline), fusidic acid, lantibiotic (e.g nisin, mersacidin, actagardine, deoxyactagardine B, and microbio sporin), lincomycin antibiotic, macrolide antibiotic (azithromycin, clarithromycin, erythromycin, telithromycin, quinorubicin, and solithromycin), meropenem antibiotic (e.g. meropenem, doripenem, imipenem, ertapenem, biapenem, cephalopenem, and panipenem), novobiocin, oxazolidinone antibiotic (e.g. linezolid, terizolide and lefluide), penicillin antibiotic (e.g. amoxicillin, ampicillin, penicillin v, dicloxacillin, carbenicillin, vancomycin, and methicillin), streptogramin antibiotic, tigecycline antibiotic (e.g. tigecycline, omacycline (omadacycline), evericin (ovacycline), doxycycline and minocycline), and vancomycin antibiotic (e.g. vancomycin, teicoplanin, telavancin, dalbavancin, and oritavancin).
In one embodiment of the fourth aspect, the one or more anti-bacterial therapeutic agent(s) is selected from the group consisting of amikacin, amoxicillin, ampicillin (e.g., pivampicillin, hetacillin, bacampicillin, metampicillin, talampicillin), apramycin, arbekacin, azidocillin, azithromycin, azlocillin, aztreonam, benzathine benzylpenicillin, benzathine phenoxymethylpenicillin, benzazole, benzylpenicillin (g), biapenem, carbenicillin (carindacillin), carumonam, cef acetrile, cefaclor, cefadroxil, cefalexin, cefaloglycin, cefalonium, cefaloridine, cefalotin, cefamandole, cefapirin, cefatrizine, cefazaflur, cefazedone, cefazolin, cefbuperazone, cefcapene, cefdaloxime, cefdinir, cefditoren, cefepime, cefetamet, cefixime, cefmenoxime, cefmetazole, cefminox, cefodizime, cefonicid, cefoperazone, ceforanide, cefotaxime, cefotetan, cefotiam, cefovecin, cefoxitin, cefozopran, cefpimizole, cefpiramide, cefpirome, cefpodoxime, cefprozil, cefquinome, cefradine, cefroxadine, cefsulodin, ceftaroline, ceftazidime, cefteram, ceftezole, ceftibuten, ceftiofur, ceftiolene, ceftizoxime, ceftobiprole, ceftriaxone, cefuroxime, cefuzonam, ciprofloxacin, clarithromycin, clometocillin, cioxacillin (e.g. dicloxacillin, flucioxacillin), dalfopristin, daptomycin, doripenem, epicillin, ertapenem, erythromycin, etimicin, faropenem, flomoxef, fusidic acid, gentamicin, kanamycin, imipenem, latamoxef, loracarbef, mecillinam (pivmecillinam), meropenem, methicillin, mezlocillin, mupirocin, nafcillin, neomycin, netilmicin, novobiocin, oxacillin, panipenem, paromomycin, penamecillin, pheneticillin, phenoxymethylpenicillin (v), piperacillin, plazamicin, procaine benzylpenicillin, propicillin, razupenem, rifabutin, rifalazil, rifampin (rifampicin), rifapentine, rifaximin, streptomycin, sulbenicillin, temocillin, ticarcillin, tigecycline, tigemonam, tobramycin, tomopenem, and vancomycin.
In a fifth aspect, the present invention relates to a method for the preparation of a compound of formula (I): wherein
R1 is individually selected from the group consisting of halogen and C1-4 alkyl, which is optionally substituted by one or more halogens, and C1-4 alkoxy, which is optionally substituted by one or more halogen(s);
R2 is individually selected from the group consisting of hydrogen, OH, NH2, NO2, SH, one or more halogen(s), COOR8, wherein R8 is hydrogen or C1-4 alkyl, which is optionally substituted by one or more halogen(s),Ci-4 acyl, which is optionally substituted by halogen(s), C1-4 alkyl, which is optionally substituted by one or more halogen(s), or C1-4 alkoxy, which is optionally substituted by one or more halogens; m is 0, 1, 2 or 3;
R3 is a C1-8 alkyl chain wherein 1, 2 or 3 chain carbon atoms are individually replaced by NH, -O-, C=O, or S(=O)X , wherein X is 0, 1, or 2, and which chain is optionally substituted by 1, to 3 substituents individually selected from the group consisting of: one or more halogen(s), N3, C1-6 alkyl, which is optionally substituted by one or more halogen(s), C1-6 alkoxy, which is optionally substituted by one or more halogen(s), and a 5 to 10 membered carbo- or heterocycle, which is optionally substituted by 1 to 3 R7 substituents, wherein R7 is selected from the group consisting of one or more halogen(s), — CN, — NO2, — Rf, — CO2Rd, — CONRdRe, — C(O)Rd, — OC(O)NRdRe, — NReC(O)Rd, — NReC(O)2Rf, — NRdC(O)NRdRe, — NRdRe, — ORd, and — S(O)2NRdRe; wherein each Rd and Re is independently selected from hydrogen, Cns alkyl, and Cns haloalkyl; each Rf is independently selected from the group consisting of Cns alkyl or heteroalkyl, Cns haloalkyl, C3-6 cycloalkyl, heterocycloalkyl, aryl and heteroaryl, and wherein the aliphatic and/or cyclic portions of Rd, Re and Rf are optionally further substituted with from one to three halogen, hydroxy, methyl, amino, C1-6 alkylamino and di C1-6 alkylamino groups ;
R4 and R5 are individually selected from the group consisting of hydrogen, one or more halogen(s), and C1-4 alkyl, and preferably are hydrogen; or a salt thereof, or a solvate thereof, or a prodrug thereof, comprising reacting a compound of formula (II) and a compound of formula (Illa) wherein R1, R2, and m are as defined for formula (I), p is 1 or 2 or 3, and
PGi is a protecting group, and preferably is a t-butoxycarbonyl group (Boe).
In a fifth aspect, the present invention relates to a method for the preparation of a compound of formula (I): wherein
R1 is individually selected from the group consisting of halogen and Ci-4 alkyl, which is optionally substituted by one or more halogens, and Ci-4 alkoxy, which is optionally substituted by one or more halogen(s); R2 is individually selected from the group consisting of hydrogen, OH, NH2, NO2, SH, one or more halogen(s), COOR8, wherein R8 is hydrogen or C1-4 alkyl, which is optionally substituted by one or more halogen(s),Ci-4 acyl, which is optionally substituted by halogen(s), C1-4 alkyl, which is optionally substituted by one or more halogen(s), or C1-4 alkoxy, which is optionally substituted by one or more halogens; m is 0, 1, 2 or 3;
R3 is a C1-8 alkyl chain wherein 1, 2 or 3 chain carbon atoms are individually replaced by NH, -O-, C=O, or S(=O)X , wherein X is 0, 1, or 2, and which chain is optionally substituted by 1, to 3 substituents individually selected from the group consisting of: one or more halogen(s), N3, C1-6 alkyl, which is optionally substituted by one or more halogen(s), C1-6 alkoxy, which is optionally substituted by one or more halogen(s), and a 5 to 10 membered carbo- or heterocycle, which is optionally substituted by 1 to 3 R7 substituents, wherein R7 is selected from the group consisting of one or more halogen(s), — CN, — NO2, — Rf, — CO2Rd, — CONRdRe, — C(O)Rd, — OC(O)NRdRe, — NReC(O)Rd, — NReC(O)2Rf, — NRdC(O)NRdRe, — NRdRe, — ORd, and — S(O)2NRdRe; wherein each Rd and Re is independently selected from hydrogen, C1-8 alkyl, and C1-8 haloalkyl; each Rf is independently selected from the group consisting of C1-8 alkyl or heteroalkyl, C1-8 haloalkyl, C3-6 cycloalkyl, heterocycloalkyl, aryl and heteroaryl, and wherein the aliphatic and/or cyclic portions of Rd, Re and Rf are optionally further substituted with from one to three halogen, hydroxy, methyl, amino, C1-6 alkylamino and di C1-6 alkylamino groups ;
R4 and R5 are individually selected from the group consisting of hydrogen, one or more halogen(s), and C1-4 alkyl, and preferably are hydrogen; or a salt thereof, or a solvate thereof, or a prodrug thereof, comprising reacting a compound of formula (II) and a compound of formula (Illb) wherein R1, R2, R3, R4, R5, and m are as defined for formula (I), and wherein R3 is preferably a residue of the formula (lb) wherein
R6 is selected from the group consisting of hydrogen, Ci-6 alkyl, which is optionally substituted by one or more halogen(s), Ci-6 alkoxy, which is optionally substituted by one or more halogen(s), and a 5, 6, 7, or 10-membered carbo- or heterocycle, which is optionally substituted by 1 to 3 R7substituents, wherein R7 is selected from the group consisting of one or more halogen(s), — CN, — NO2, — Rf, — CO2Rd, — CONRdRe, — C(O)Rd, — OC(O)NRdRe, — NReC(O)Rd, — NReC(O)2Rf, — NRdC(O)NRdRe, — NRdRe, — ORd, and — S(O)2NRdRe; wherein each Rd and Re is independently selected from hydrogen, Ci-8 alkyl, and Ci-8 haloalkyl; each Rf is independently selected from the group consisting of Ci-8 alkyl or heteroalkyl, Ci-8 haloalkyl, C3-6 cycloalkyl, heterocycloalkyl, aryl and heteroaryl, and wherein the aliphatic and/or cyclic portions of Rd, Re and Rf are optionally further substituted with from one to three halogen, hydroxy, methyl, amino, C1-6 alkylamino and di C1-6 alkylamino groups, and wherein n is 0, 1, or 2; or a residue of the formula (lb), wherein the amide is replaced by an amide bioisostere and R6 and n are as defined above; to obtain a compound of Formula (I).
In a fifth aspect, the present invention relates to a method for the preparation of a compound of formula (I): wherein
R1 is individually selected from the group consisting of halogen and C1-4 alkyl, which is optionally substituted by one or more halogens, and C1-4 alkoxy, which is optionally substituted by one or more halogen(s);
R2 is individually selected from the group consisting of hydrogen, OH, NH2, NO2, SH, one or more halogen(s), COOR8, wherein R8 is hydrogen or C1-4 alkyl, which is optionally substituted by one or more halogen(s),Ci-4 acyl, which is optionally substituted by halogen(s), C1-4 alkyl, which is optionally substituted by one or more halogen(s), or C1-4 alkoxy, which is optionally substituted by one or more halogens; m is 0, 1, 2 or 3;
R3 is a residue of the formula (lb) wherein
R6 is selected from the group consisting of hydrogen, Ci-6 alkyl, which is optionally substituted by one or more halogen(s), Ci-6 alkoxy, which is optionally substituted by one or more halogen(s), and a 5, 6, 7, or 10-membered carbo- or heterocycle, which is optionally substituted by 1 to 3 R7 substituents, wherein R7 is selected from the group consisting of one or more halogen(s), — CN, — NO2, — Rf, — CO2Rd, — CONRdRe, — C(O)Rd, — OC(O)NRdRe, — NReC(O)Rd, — NReC(O)2Rf, — NRdC(O)NRdRe, — NRdRe, — ORd, and — S(O)2NRdRe; wherein each Rd and Re is independently selected from hydrogen, Ci-8 alkyl, and Ci-8 haloalkyl; each Rf is independently selected from the group consisting of Ci-8 alkyl or heteroalkyl, Ci-8 haloalkyl, C3-6 cycloalkyl, heterocycloalkyl, aryl and heteroaryl, and wherein the aliphatic and/or cyclic portions of Rd, Re and Rf are optionally further substituted with from one to three halogen, hydroxy, methyl, amino, C1-6 alkylamino and di C1-6 alkylamino groups, and wherein n is 0, 1, or 2; or a residue of the formula (lb), wherein the amide is replaced by an amide bioisostere and R6 and n are as defined above;
R4 and R5 are individually selected from the group consisting of hydrogen, one or more halogen(s), and C1-4 alkyl, and preferably are hydrogen; or a salt thereof, or a solvate thereof, or a prodrug thereof, comprising reacting a compound of formula (II) and a compound of formula (Illb) wherein R1, R2, R4, R5, and m are as defined for formula (I), and wherein R3 is a residue of the formula (lb) wherein
R6 is selected from the group consisting of hydrogen, Ci-6 alkyl, which is optionally substituted by one or more halogen(s), Ci-6 alkoxy, which is optionally substituted by one or more halogen(s), and a 5, 6, 7, or 10-membered carbo- or heterocycle, which is optionally substituted by 1 to 3 R7substituents, wherein R7 is selected from the group consisting of one or more halogen(s), — CN, — NO2, — Rf, — CO2Rd, — CONRdRe, — C(O)Rd, — OC(O)NRdRe, — NReC(O)Rd, — NReC(O)2Rf, — NRdC(O)NRdRe, — NRdRe, — ORd, and — S(O)2NRdRe; wherein each Rd and Re is independently selected from hydrogen, Ci-8 alkyl, and Ci-8 haloalkyl; each Rf is independently selected from the group consisting of Ci-8 alkyl or heteroalkyl, Ci-8 haloalkyl, C3-6 cycloalkyl, heterocycloalkyl, aryl and heteroaryl, and wherein the aliphatic and/or cyclic portions of Rd, Re and Rf are optionally further substituted with from one to three halogen, hydroxy, methyl, amino, C1-6 alkylamino and di C1-6 alkylamino groups, and wherein n is 0, 1, or 2; or a residue of the formula (lb), wherein the amide is replaced by an amide bioisostere and R6 and n are as defined above; to obtain a compound of Formula (I).
In a preferred embodiment of the fifth aspect, the present invention relates to a method for the preparation of a compound of formula (I): wherein
R1 is chlorine;
R2, R4 and R5 are hydrogen; m is 0,
R3 is selected from the group consisting of a residue of the formula (la), a residue of the formula (lb), a residue of the formula (Ic), a residue of the formula (Id), n 0 or 2; and
R6 is a hydrogen, a pentyl group, a cyclopropyl group, a cyclopentyl group, a cyclohexyl group, a phenyl group, a tert-butyl group, a O-tert-butyl group, a n-butyl group, a methyl group, a methyl-butyl group, a benzyl group, a adamantyl group, a pyridinyl group, a piperazinyl group, a hexahydropyrimidinyl group, a hexahydropyridazinyl group, a 3-thienyl group, a piperidinyl group, a pyrrolyl group, a 4-Boc-morpholinyl group, a N-Boc- piperidinyl group, or a l-Boc-(4-Boc)piperazinyl group; or a salt thereof, or a solvate thereof, or a prodrug thereof, comprising: a) reacting a compound of formula (II) and a compound of formula (Illa) wherein R1, R2, and m are as defined for formula (I), p is 1 or 2 or 3, and
PGi is a protecting group; or b) reacting a compound of formula (II) and a compound of formula (Illb) wherein R1, R2, R3, R4, R5, and m are as defined for formula (I), and wherein R3 is preferably a residue of the formula (lb) wherein
R6 is selected from the group consisting of hydrogen, Ci-6 alkyl, which is optionally substituted by one or more halogen(s), Ci-6 alkoxy, which is optionally substituted by one or more halogen(s), and a 5, 6, 7, or 10-membered carbo- or heterocycle, which is optionally substituted by 1 to 3 R7substituents, wherein R7 is selected from the group consisting of one or more halogen(s), — CN, — NO2, — Rf, — CO2Rd, — CONRdRe, — C(O)Rd, — OC(O)NRdRe, — NReC(O)Rd, — NReC(O)2Rf, — NRdC(O)NRdRe, — NRdRe, — ORd, and — S(O)2NRdRe; wherein each Rd and Re is independently selected from hydrogen, Ci-8 alkyl, and Ci-8 haloalkyl; each Rf is independently selected from the group consisting of Ci-8 alkyl or heteroalkyl, Ci-8 haloalkyl, C3-6 cycloalkyl, heterocycloalkyl, aryl and heteroaryl, and wherein the aliphatic and/or cyclic portions of Rd, Re and Rf are optionally further substituted with from one to three halogen, hydroxy, methyl, amino, C1-6 alkylamino and di C1-6 alkylamino groups, and wherein n is 0, 1, or 2; or a residue of the formula (lb), wherein the amide is replaced by an amide bioisostere and R6 and n are as defined above; to obtain a compound of Formula (I).
In a preferred embodiment of the fifth aspect, the present invention relates to a method for the preparation of a compound of formula (I): wherein
R1 is chlorine, m is 0, n is 2, R3 is a residue of the formula (la), R4 and R5 are hydrogen, and R6 is a O-tert-butyl group; or a salt thereof, or a solvate thereof, or a prodrug thereof, comprising: a) reacting a compound of formula (II) and a compound of formula (Illa) wherein R1, R2, and m are as defined for formula (I), p is 1 or 2 or 3, and
PGi is a protecting group, and preferably is a t-butoxycarbonyl group (Boe).
In the fifth aspect, the definitions of residues R1 to R5 are preferably those as defined above, in particular for the first aspect of the invention.
In the fifth aspect, PGi is an amino protecting group as known in the art, preferably a Fmoc, Boc (t-Butyl carbamate), Cbz (benzyl carbamate), Ac (acetyl), trifluoroacetyl, phthalimide, Bn (benzyl), Tr (trityl), benzylidene, or Ts (Tosyl) group.
In the fifth aspect, the reaction of the amine compound of formula (II) with the isothiocyanate compounds of formula (Illa) or (Illb) to obtain a thiourea compound can be conducted under conditions known in the art. Typically, the compounds are dissolved in a suitable solvent, such as DCM, and reacted by combining and mixing, typically at room temperature. The reaction time can be from 2 h to 24 h. The product are typically purified by chromatographic methods as known in the art. In the fifth aspect, the conditions for the addition and/or removal of protecting group, such as PGi, are known in the art. For example, the most preferred protecting group Boc is removed under acidic conditions, e.g. by addition of TFA at 0°C.
In the fifth aspect, after the reaction of the amine compound of formula (II) with the isothiocyanate compounds of formula (Illa) or (Illb), typically PGi is removed, and preferably the resulting free amine group is reacted to obtain a compound of formula (I), e.g. by reacting with a suitable compound, such as an acid chloride, activated acid, sulfonic acid chloride, or by reactive deamination. Suitable conditions and compounds are exemplified in the general procedure below.
Examples
Abbreviations
Ac acetyl
9-BBN 9-borabicyclo(3.3.1)nonane
Boc tert-butyloxycarbonyl br broad
CDI 1 , 1’ -carbonyldiimidazole d doublet
DCM dichloromethane
DIPEA A,A-diisopropylethylamine
DMF A,A-dimethylformamide
DMSO dimethylsulfoxide dppf 1 , 1 '-bis(diphenylphosphino)ferrocene
Et ethyl
FA formic acid
HATU O-(7-azabcnzotriazol- 1 -yl)-A, N, N', A'-tetramethyluronium hexafluorophosphate
HBTU O-(bcnzotriazol - 1 -yl)-A, N, N', A'-tctramcthyluron ium hexafluorophosphate
HPLC high performance liquid chromatography m multiplet
PE petroleum ether q quartet
RP reverse-phase r.t. room temperature t triplet
TFA trifluoroacetic acid
Calcd. calculated
Example 1: Materials and methods for chemical synthesis. Dry solvents were stored under an inert gas atmosphere and over molecular sieves. All chemicals were purchased from Sigma-Aldrich, TCI Chemicals, Alfa-Aesar or BLD Pharm. Aluminium-based 6OF254 silica gel plates from Merck were used for thin-layer chromatography. Detection was carried out by UV light at 254 nm.
For column chromatography, either a Pure C-810 Flash from Biichi or a Teledyne ISCO Combi Flash Nextgen 300+ device was used. The silica gel used was Merck silica gel 60 with a particle size of 43-60 pm.
HPLC-MS analyses were performed on a combination of Thermo Scientific Dionex UltiMate 3000 UHPLC+ and a Bruker amaZon SL. Samples were prepared in 1 mL of a 1:1 water/acetonitrile mixture.
For NMR measurements, all synthesized products were dissolved in deuterated DMSO or chloroform.
Preparative HPLC was performed on a Waters 2545 Binary Gradient Module with a Waters 2489 UV/Vis Detector. A RP-18 column (250/21 Nucleodur C18 Gravity SB, 5 pm (Macherey- Nagel)) was used as the stationary phase. HPLC-grade MeCN and MilliQ water (each + 0.1% FA) were used as the mobile phase. The compounds were also dissolved in an acetonitrile- water mixture.
NMR spectra were recorded either with a Bruker Ultrashield 500 Plus or a Bruker AV 500 UltraShield Plus. The spectra were analyzed with MestReNova (MestreLab Research S. L., Version 14.2.1 or 14.2.2) and calibrated at the residual solvent peak of DMSO ( 1 H-NMR 2.50 ppm; 13C-NMR 39.52 ppm) or chloroform ( ’ H-NMR 7.26 ppm; 13C-NMR 77.16 ppm). Multiplicity ’ H-NMR signals are as follows: s (singlet), d (doublet), t (triplet), q (quartet), br s (broad signal), m (multiplet).
Example 2: General procedures for compound synthesis
A. Isothiocyanate formation (Khatik et al., 2011)
Sodium bicarbonate (4 eq.) was dissolved in water (3.1 M). The aniline was dissolved in DCM (0.4 M), added to the sodium bicarbonate solution and cooled down to 0°C. Then, 1.5 eq. of thiophosgene were slowly added by syringe under vigorous stirring. After 30 min, the reaction was allowed to warm to r.t. and stirred for 2 h until completion. The reaction mixture was diluted with DCM and washed with water. The aqueous phase was extracted two times with DCM. The combined organic layers were dried over anhydrous Na2SO4, filtered and evaporated in vacuo. The crude product was directly used for next step or purified by column chromatography (PE/DCM, 10 - 100%) if necessary. B. Thiourea formation (Kumbhare RM, et al., 2013)
To the isothiocyanate dissolved in DCM (1.0 M) was added tryptamine (1 eq.) and the reaction mixture was stirred at r.t. overnight. The reaction mixture was directly purified by column chromatography (PE/EtOAc, 5 - 60%).
C. Boc-group deprotection
Under inert gas atmosphere, the starting material was dissolved in anhydrous DCM (same volume as TFA) and cooled down to 0°C. TFA (100 eq.) was added slowly and stirring was continued for 30 min at 0°C. Afterwards, the reaction mixture was allowed to warm to r.t. and stirring was continued for further 30 min until completion. The reaction mixture was diluted with DCM and saturated aqueous NaHCOa was added until pH 7 - 8. The aqueous phase was washed twice with DCM and the combined organic layers were dried over anhydrous NaiSCE, filtered and evaporated in vacuo. The crude product was directly used for next step or purified by reverse-phase column chromatography (McCN/HiO, 10 - 95%) if necessary.
D. Amide coupling
1. From acid chlorides
The amine (1.0 eq.) was added to a solution of EtaN (1.3 eq.) in DCM (0.2 M) and cooled to 0°C. Then, the acid chloride (1.1 eq.) that was separately dissolved in DCM (0.2 M) was added dropwise. The reaction mixture was warmed to r.t. and stirred for additional 30 min. The reaction mixture was concentrated and purified by column chromatography ((DCM/PE 6:4)/MeOH, 0 - 10% or PE/EtOAc, gradient of 20 - 70%). If necessary, the product was further purified by reverse-phase flash chromatography or preparative HPEC.
2. From acids
The corresponding carboxylic acid (1.1 eq.) was added to a mixture of EhN (3.0 eq.) in DCM (0.1 M) at r.t.. Then, HBTU (1.1 eq.) or HATU (1.25 eq.) was added to the reaction mixture, and it was stirred for 15 min. After that, the amine (1.0 eq.) was added to the reaction, and it was stirred at r.t. for about 45 min until full conversion. The reaction mixture was concentrated and purified by column chromatography ((DCM/PE 6:4)/MeOH, 0 - 10% or PE/EtOAc, 20 - 70%). If necessary, material was further purified by reverse-phase flash chromatography or preparative HPEC.
E. Sulfonamide formation The amine (1.0 eq.) was added to a solution of Et3N (1.1 eq.) in ACN (0.15 M). Then, the sulfonyl chloride (1.1 eq.) was added. The reaction mixture was stirred at r.t. for 45 min. The reaction mixture was concentrated and purified by column chromatography ((DCM/PE 6:4)/MeOH, 0 - 10% or PE/EtOAc, 20 - 70%). If necessary, the product was further purified by reverse-phase flash chromatography or preparative HPLC.
F. Reductive amination (Golime, G, et al., 2018)
Ketone/aldehyde (1.0 eq.) was dissolved in MeOH (0.01 M) with a drop of acetic acid. Subsequently, NaBH3CN (1.0 eq.) was added and the mixture was stirred for 5 min at r.t., followed by addition of the amine (1 eq.). The reaction mixture was stirred overnight, concentrated on a rotary evaporator without further processing and purified by column chromatography ((DCM/PE 6:4)/MeOH, 1 - 10%). Further purification was carried out using reverse-phase column chromatography or preparative HPLC (MeCN + 0.1% FA/H2O + 0.1% FA, 30 - 50%).
Example 3: Synthesis of derivatives based on benzylamine
Scheme 1. Step 1: L1AIH4, THF, 0 - reflux; Step 2: BociO, DCM, r.t.; Step 3: thiophosgene, NaHCO3, H2O, DCM, 0°C - r.t.; Step 4: tryptamine, DCM, r.t.; Step 5: TFA, DCM, 0°C - r.t.; Step 6: various conditions as indicated in Table 1. Step 1: 2-(aminomethyl)-4-chloroaniline (2) (Dong, Z. et al., 2015)
2-Amino-5-chlorobenzonitrile (1, 3.00 g, 19.7 mmol) was dissolved in anhydrous THF (98 mL, 0.2 M) under nitrogen atmosphere and cooled down to 0°C in an ice bath. Lithium aluminium hydride (2 eq., 1 M solution in anhydrous THF) was added very slowly by syringe under vigorous stirring. After gas evolution stopped, the ice bath was removed and reaction mixture was heated at reflux for 3 h. The reaction was quenched with isopropanol and filtered. The filtrate was then concentrated in vacuo to give the crude product (2.41 g) which was directly used for next step without further purification.
Step 2: tert-butyl [A-(2-amino-5-chlorobenzyl)] carbamate (3)
To crude 2 in DCM (197 mL, 0.1 M) BociO (4.29 g, 19.7 mmol, 1.0 eq.) was added and the reaction was stirred at r.t. overnight. The reaction mixture was then directly purified by column chromatography (PE/EtOAc, 5 - 60%) to give the product as a slightly yellow solid (3.96 g, 15.4 mmol, 78% yield over two steps).
MS (ESI): calcd for [C8H9CIN2O2 + H]+: 201.04, found 200.93.
XH-NMR (500 MHz, DMSO-d6, 3 in ppm): 1.39 (s, 10H), 3.92 (d, J = 6.2 Hz, 2H), 5.16 (s, 2H), 6.60 (d, J = 8.5 Hz, 1H), 6.90 (d, J = 2.6 Hz, 1H), 6.96 (dd, J = 8.5, 2.5 Hz, 1H), 7.29 (t, J = 6.3 Hz, 1H).
13C-NMR (126 MHz, DMSO-d6, 3 in ppm): 28.20, 78.06, 115.86, 118.85, 124.64, 127.04, 127.44, 144.89, 156.03.
Step 3 : tert-butyl [A-(5-chloro-2-isothiocyanatobenzyl)] carbamate (4)
The reaction was performed according to general procedure A starting from carbamate 3 (3.92 g, 15.3 mmol, 1.0 eq.). Crude product was obtained as a yellow solid (4.73 g) and used in the next step without purification.
MS (ESI): calcd for [C8H7CIN2S + H]+: 199.01, found 198.90.
Step 4: tert-butyl [A-(2-(3-(2-( 177-indol-3-yl)ethyl)thioureido)-5-chlorobenzyl)] carbamate (5)
Crude isothiocyanate 4 (3.91 g, 13.1 mmol, 1.0 eq.) was reacted with tryptamine according to general procedure B. Pure product was obtained as a slightly yellow solid (5.40 g, 11.8 mmol, 76% yield over two steps). MS (ESI): calcd for [C23H27CIN4O2S + H]+: 459.16, found 459.22.
XH-NMR (500 MHz, DMSO-d6, 3 in ppm): 1.40 (s, 9H), 2.95 (t, J = 7.5 Hz, 2H), 3.72 (br s, 2H), 4.09 (d, J = 6.0 Hz, 2H), 6.94 - 7.01 (m, 1H), 7.06 (t, J = 7.5 Hz, 1H), 7.15 (s, 1H), 7.20 (d, J = 8.4 Hz, 1H), 7.22 - 7.30 (m, 2H), 7.34 (d, J = 7.8 Hz, 2H), 7.63 (d, J = 7.9 Hz, 1H), 7.68 (s, 1H), 9.13 (s, 1H), 10.81 - 10.84 (m, 1H).
13C-NMR (126 MHz, DMSO-d6, 3 in ppm): 13.97, 22.11, 24.64, 28.18, 28.38, 31.26, 45.00, 78.21, 111.35, 111.61, 118.22, 118.52, 120.95, 122.74, 126.80, 126.92, 127.29, 129.77, 130.65, 136.25, 155.88, 181.38. Step 5: l-(2-(177-indol-3-yl)ethyl)-3-(2-(aminomethyl)-4-chlorophenyl)thiourea (6)
Carbamate 5 (1.73 g, 3.77 mmol, 1.0 eq.) was deprotected according to the general procedure C to afford amine 6 as a slightly orange solid (1.35 g, 3.77 mmol, quant, yield) which was used for derivatization without purification.
MS (ESI): calcd for [C18H19CIN4S + H]+: 359.11, found 359.12.
Step 6:
Table 1. Examples for derivatization of compound 6
Example 4: Synthesis of derivatives based on phenylpropylamine
Scheme 2. Step 1: 1) 0.5 M 9-BBN in THF, tert-butyl N-allylcarbamate, K3PO4, THF, r.t.; 2) 8, PdCh(dppf), r.t.; Step 2: thiophosgene, NaHCCF, H2O, DCM, 0°C - r.t.; Step 3: tryptamine, DCM, r.t.; Step 4: TFA, DCM, 0°C - r.t.; Step 5: cyclohexanecarboxylic acid, HATU, EtsN, DCM, r.t..
Step 1 : tert-butyl [ A-(3-(2-amino-5-chlorophenyl)propyl)] carbamate (9) (Kennedy et al., Antimicrob. Agents Chemother. 2016)
A 0.5 M solution of 9-BBN in THF (12.3 mL, 6.16 mmol, 2.6 eq.) was added to tert-butyl N- allyl carbamate (8a, 484 mg, 3.08 mmol, 1.3 eq.) at r.t. under N2 atmosphere and the reaction was stirred for 3.5 h until completion. K3PO4 (1.98 g, 6.16 mmol, 2.6 eq.) was added and the reaction was diluted with THF (0.2 M relative to 4-chloro-2-iodoaniline). Then, 4-chloro-2- iodoaniline (8c, 600 mg, 2.37, 1 eq.) and PdCh(dppf) (97 mg, 0.12 mmol, 0.05 eq.) were added sequentially and the reaction was stirred overnight, diluted with EtOAc and washed with 1 N HC1. The aqueous phase was extracted two more times with EtOAc, the organic layers were combined, dried over anhydrous Na2SO4, filtered and evaporated in vacuo. The crude was purified by column chromatography (DCM/PE 6:4)/MeOH, 0 - 10%) to give the impure product (1.0 g) which was directly used for next step.
MS (ESI): calcd for [C10H13CIN2O2 + H]+: 229.07, found 228.95.
Step 2: tert-butyl [A-(3-(5-chloro-2-isothiocyanatophenyl)propyl)] carbamate (10)
The reaction was performed according to the general procedure A using tert-butyl [A-(3-(2- amino-5-chlorophenyl)propyl)] carbamate (9, 0.84 g) and purified by column chromatography (PE/DCM, 10 - 100%) to give the title compound 10 (360 mg, 1.10 mmol, 55% yield over two steps) as a yellow oil.
MS (ESI): calcd for [C10H11CIN2S + H]+: 227.04, found 226.92. XH-NMR (500 MHz, DMSO-d6, 3 in ppm): 1.38 (s, 9H), 1.62 - 1.71 (m, 2H), 2.64 (t, J = 7.6 Hz, 2H), 2.91 - 2.98 (m, 2H), 6.89 (t, J = 5.7 Hz, 1H), 7.35 (dd, J = 8.5, 2.4 Hz, 1H), 7.44 (d, J = 8.5 Hz, 1H), 7.47 (d, J = 2.5 Hz, 1H).
13C-NMR (126 MHz, DMSO-d6, 3 in ppm): 28.26, 28.65, 29.48, 39.14, 77.49, 127.47, 127.95, 128.17, 129.90, 132.10, 134.88, 140.53, 155.58.
Step 3: tert-butyl [A^-(3-(2-(3-(2-(177-indol-3-yl)ethyl)thioureido)-5-chlorophenyl)propyl)] carbamate (11) tert-butyl [ AA-(3-(5-chloro-2-isothiocyanatophcnyl)propyl)| carbamate (10, 360 mg, 1.10 mmol) was used according to general procedure B and purified by column chromatography ((DCM/PE 6:4)/MeOH, 1 - 10%). The product was obtained as a white foam (500 mg, 1.03 mmol, 93% yield).
MS (ESI): calcd for [C25H31CIN4O2S + H]+: 487.19, found 487.22.
XH-NMR (500 MHz, DMSO-d6, 3 in ppm): 1.36 (s, 9H), 1.57 - 1.66 (m, 2H), 2.45 - 2.50 (m, 2H), 2.86 - 2.96 (m, 4H), 3.66 - 3.75 (m, 2H), 6.80 (t, J = 5.6 Hz, 1H), 6.97 (t, J = 7.4 Hz, 1H), 7.06 (t, J = 7.5 Hz, 1H), 7.13 (s, 1H), 7.17 (d, J = 8.5 Hz, 1H), 7.22 (dd, J = 8.4, 2.4 Hz, 1H), 7.29 - 7.36 (m, 2H), 7.52 (br s, 1H), 7.63 (d, J = 7.9 Hz, 1H), 9.07 (br s, 1H), 10.81 (s, 1H).
13C-NMR (126 MHz, DMSO-d6, 3 in ppm): 24.71, 28.01, 28.27, 29.43, 44.89, 77.44, 111.34, 111.63, 118.20, 118.53, 120.93, 122.70, 126.29, 127.28, 129.19, 130.42, 130.75, 135.71, 136.25, 141.08, 155.58, 181.37.
Step 4: l-(2-(177-indol-3-yl)ethyl)-3-(2-(3-aminopropyl)-4-chlorophenyl)thiourea (12) tert-butyl [7V-(3-(2-(3-(2-( 177-indol-3-yl)ethyl)thioureido)-5-chlorophenyl)propyl) ] carbamate (11, 100 mg, 0.21 mmol) was deprotected according to general procedure C to give the product 12 as a beige foam (82 mg, crude). Part of the material was purified by reverse-phase column chromatography (MeCN/HiO, 10 - 95%) to give pure 12 (19.7 mg, 0.05 mmol, quant, yield) as a colourless solid. Crude product was used for the next step without further purification.
MS (ESI): calcd for [C20H23CIN4S + H]+: 387.14, found 387.14.
XH-NMR (500 MHz, DMSO-d6, 3 in ppm): 1.72 - 1.82 (m, 2H), 2.57 (t, J = 7.6 Hz, 2H), 2.71 (t, J = 7.4 Hz, 2H), 2.95 (t, J = 7.6 Hz, 2H), 3.72 (br s, 2H), 6.97 (t, J = 7.4 Hz, 1H), 7.06 (t, J = 7.5 Hz, 1H), 7.16 (s, 1H), 7.23 (dd, J = 8.4, 2.4 Hz, 1H), 7.27 (d, J = 8.7 Hz, 1H), 7.30 - 7.37 (m, 2H), 7.63 (d, J = 7.9 Hz, 1H), 8.22 (br s, 1H), 8.43 (s, 1H), 10.85 (s, 1H). 13C-NMR (126 MHz, DMS0-d6, 3 in ppm): 24.77, 27.50, 28.13, 38.69, 44.94, 111.42, 111.72, 118.26, 118.56, 120.99, 122.80, 126.33, 127.33, 128.99, 130.35, 130.52, 136.31, 136.44,
139.83, 166.23, 181.78. Step 5: l-(2-(lH-indol-3-yl)ethyl)-3-(2-(3-aminopropyl)-4-chlorophenyl)thiourea (13)
Crude 12 (30 mg, 0.08 mmol, 1.0 eq.) was subjected to amide coupling according to the general procedure D2 using HATU to afford the product 13 as a colourless solid (26 mg, 0.05 mmol, 67% yield).
MS (ESI): calcd for [C27H33CIN4OS + H]+: 497.21, found 497.25. XH-NMR (500 MHz, DMSO-d6, 3 in ppm): 1.04 - 1.25 (m, 3H), 1.25 - 1.36 (m, 2H), 1.54 - 1.70 (m, 7H), 2.01 - 2.11 (m, 1H), 2.45 - 2.50 (m, 2H), 2.93 (t, J = 7.6 Hz, 2H), 2.97 - 3.04 (m, 2H), 3.67 - 3.75 (m, 2H), 6.97 (t, J = 7.4 Hz, 1H), 7.06 (t, J = 7.5 Hz, 1H), 7.13 (s, 1H), 7.17 (d, J = 8.5 Hz, 1H), 7.22 (dd, J = 8.4, 2.5 Hz, 1H), 7.31 (d, J = 2.4 Hz, 1H), 7.33 (d, J = 8.1 Hz, 1H), 7.55 (s, 1H), 7.59 - 7.66 (m, 2H), 9.09 (s, 1H), 10.81 (s, 1H). 13C-NMR (126 MHz, DMSO-d6, 3 in ppm): 24.75, 25.33, 25.49, 25.65, 28.07, 29.28, 38.00, 44.08, 44.92, 111.36, 111.64, 118.22, 118.54, 120.96, 122.71, 126.33, 127.29, 129.23, 130.51,
130.83, 135.74, 136.27, 141.20, 175.16, 181.41.
Part 2: Synthesis of further derivatives based on phenylpropylamine
TK470 (36%)
Scheme 2-b. Steps 1 - 4: see Scheme 2.; Step 5a: RCO2H and HATU, NEt3 or RCOC1, NEt3, DCM, r.t.; Step 5b: RSO2CI, NEt3, r.t.; Step 5c: RNCO, NEt3 or RNH2, CDI, NEt3, DCM, r.t.; Step 5d: CbzCl, NEt3, DCM, r.t.; Step 5e: TfN3, CuSO4, NaHCO3, toluene, MeOH, H2O; Step 6: phenylacetylene, CuSO4, sodium ascorbate, DMF, H2O, r.t..
Step 5a: A- (3 -(2- (3- (2- ( l//-Indol-3-yl)ethyl)thioureido)-5-chlorophenyl)propyl)pivalamide
(DH613)
Crude l -(2-( 1 /7- indol-3-yl )cthyl)-3-(2-(3-ami nopropyl )-4-chlorophcnyl)thiourca trifluoroacetic acid salt (DH612, 60 mg, 0.12 mmol, 1.0 eq.) was subjected to amide coupling according to the general procedure DI to afford the product DH613 (46.0 mg, 104 pmol, 87%) as a white solid.
MS (ESI): calcd. for [C25H31CIN4OS + H]+: 471.20, found 471.24.
'H NMR (500 MHz, acetone-d6, 5 in ppm): 1.15 (s, 9H), 1.77 (quint, J = 7.1 Hz, 2H), 2.57 (t, J = 7.5 Hz, 2H), 3.08 (t, J = 7.1 Hz, 2H), 3.17 (q, J = 6.5 Hz, 2H), 3.87-3.93 (m, 2H), 6.90— 7.05 (m, 3H), 7.09 (t, J = 7.6 Hz, 1H), 7.13-7.18 (m, 2H), 7.23 (d, J = 8.4 Hz, 1H), 7.28 (d, J = 2.3 Hz, 1H), 7.37 (d, J = 8.1 Hz, 1H), 7.66 (d, J = 7.8 Hz, 1H), 8.61 (s, 1H), 10.08 (s, 1H).
13C NMR (125 MHz, acetone-d6, 5 in ppm): 25.63, 28.04, 29.01, 31.02, 39.20, 39.52, 46.21, 112.22, 113.22, 119.52, 119.59, 122.21, 123.46, 123.62, 127.52, 128.71, 130.57, 131.39, 132.93, 136.37, 137.83, 142.66, 179.01, 183.34.
Step 5a: A^-(3-(2-(3-(2-(177-Indol-3-yl)ethyl)thioureido)-5-chlorophenyl)propyl)-3,3- dimethylbutanamide (DH614)
Crude l -(2-( 177- indol-3-yl )cthyl)-3-(2-(3-ami nopropyl )-4-chlorophcnyl)thiourca trifluoroacetic acid salt (DH612, 50 mg, 0.10 mmol, 1.0 eq.) was subjected to amide coupling according to the general procedure D2 to afford the product DH614 (35.0 mg, 72 pmol, 72%) as a white solid.
MS (ESI): calcd. for [C26H33CIN4OS + H]+: 485.21, found 485.27. 'H NMR (500 MHz, acetone-d6, 5 in ppm): 0.99 (s, 9H), 1.76 (quint, J = 7.0 Hz, 2H), 2.04 (bs, 2H), 2.60 (t, J = 7.5 Hz, 2H), 3.08 (t, J = 7.2 Hz, 2H), 3.16 (q, J = 6.4 Hz, 2H), 3.87-3.93 (m, 2H), 6.98-7.12 (m, 3H), 7.13-7.18 (m, 2H), 7.22-7.26 (m, 1H), 7.29 (d, J = 2.4 Hz, 1H), 7.38 (d, J = 8.1 Hz, 1H), 7.65 (d, J = 7.9 Hz, 1H), 8.62 (s, 1H), 10.08 (s, 1H).
13C NMR (125 MHz, acetone-d6, 5 in ppm): 25.62, 29.08, 31.05, 31.32, 39.07, 46.24, 50.31, 112.22, 113.23, 119.52, 119.60, 122.21, 123.62, 127.59, 128.71, 130.67, 131.41, 132.96, 137.82, 142.54, 172.44, 183.33.
Step 5a: 7V-(3-(2-(3-(2-( 177-Indol-3-yl)ethyl)thioureido)-5-chlorophenyl)propyl)benzamide
(DH615)
Crude l -(2-( 1 /7- indol-3-yl )cthyl)-3-(2-(3-ami nopropyl )-4-chlorophcnyl)thiourca trifluoroacetic acid salt (DH612, 50 mg, 0.10 mmol, 1.0 eq.) was subjected to amide coupling according to the general procedure DI to afford the product DH615 (9.0 mg, 18 pmol, 18%) as a white solid.
MS (ESI): calcd. for [C27H27CIN4OS + H]+: 491.17, found 491.21.
'H NMR (500 MHz, aceton-d6, 5 in ppm): 1.90 (quint, J = 7.1 Hz, 2H), 2.67 (t, J = 7.6 Hz, 2H), 3.06 (t, J = 7.2 Hz, 2H), 3.40 (q, J = 6.5 Hz, 2H), 3.89 (q, J = 6.7 Hz, 2H), 6.97-7.11 (m, 3H), 7.12-7.22 (m, 3H), 7.34 (d, J = 2.3 Hz, 1H), 7.37 (d, J = 8.2 Hz, 1H), 7.39-7.44 (m, 2H), 7.47-7.54 (m, 1H), 7.65 (d, J = 7.9 Hz, 1H), 7.78 (bs, 1H), 7.87-7.91 (m, 2H), 8.57 (s, 1H), 10.05 (s, 1H).
13C NMR (125 MHz, aceton-d6, 5 in ppm): 25.61, 29.21, 30.70, 40.00, 46.24, 112.22, 113.23, 119.52, 119.60, 122.21, 123.60, 127.65, 128.17, 128.69, 129.17, 130.65, 131.49, 131.95, 133.10, 135.99, 137.81, 142.77, 167.79, 183.39.
Step 5a: A^-(3-(2-(3-(2-(177-Indol-3-yl)ethyl)thioureido)-5- chlorophenyl)propyl)isonicotinamide (DH616)
Crude l-(2-(177-indol-3-yl)ethyl)-3-(2-(3-aminopropyl)-4-chlorophenyl)thiourea trifluoroacetic acid salt (DH612, 50 mg, 0.10 mmol, 1.0 eq.) was subjected to amide coupling according to the general procedure D2 to afford the product DH616 (19.0 mg, 39 pmol, 39%) as a slightly yellow solid.
MS (ESI): calcd. for [C26H27CIN5OS + H]+: 492.16, found 492.21.
'H NMR (500 MHz, aceton-d6, 5 in ppm): 1.92 (quint, J = 7.1 Hz, 2H), 2.68 (t, J = 7.6 Hz, 2H), 3.06 (t, J = 7.2 Hz, 2H), 3.42 (q, J = 6.4 Hz, 2H), 3.88 (q, J = 6.9 Hz, 2H), 6.97-7.02 (m, 1H), 7.06-7.17 (m, 4H), 7.18-7.22 (m, 1H), 7.33 (d, J = 2.3 Hz, 1H), 7.37 (d, J = 8.1 Hz, 1H), 7.65 (d, J = 7.8 Hz, 1H), 7.82 (d, J = 5.2 Hz, 2H), 8.10 (bs, 1H), 8.61 (s, 1H), 8.69 (d, J = 5.6 Hz, 2H), 10.03 (s, 1H).
13C NMR (125 MHz, aceton-d6, 5 in ppm): 25.66, 29.33, 40.22, 46.29, 112.22, 113.24, 119.54, 119.60, 122.23, 122.50, 123.59, 127.70, 128.70, 130.67, 131.56, 133.12, 137.80, 142.70, 143.40, 150.57, 165.86, 183.39.
Step 5a: 7V-(3-(2-(3-(2-( 177-Indol-3-yl)ethyl)thioureido)-5-chlorophenyl)propyl)picolinamide
(DH617)
Crude l -(2-( 1 /7- indol-3-yl )cthyl)-3-(2-(3-ami nopropyl )-4-chlorophcnyl)thiourca trifluoroacetic acid salt (DH612, 50 mg, 0.10 mmol, 1.0 eq.) was subjected to amide coupling according to the general procedure D2 to afford the product DH617 (39.0 mg, 79 pmol, 79%) as a white solid. MS (ESI): calcd. for IC26H27CIN5OS + H]+: 492.16, found 492.23.
'H NMR (500 MHz, aceton-d6, 5 in ppm): 1.93 (quint, J = 7.2 Hz, 2H), 2.67 (t, J = 7.5 Hz, 2H), 3.06 (t, J = 7.2 Hz, 2H), 3.44 (q, J = 6.7 Hz, 2H), 3.89 (q, J = 6.9 Hz, 2H), 6.91-7.02 (m, 2H), 7.06-7.11 (m, 1H), 7.12-7.21 (m, 3H), 7.32-7.39 (m, 2H), 7.52 (ddd, J = 7.5, 4.8, 1.1 Hz, 1H), 7.64 (d, J = 7.8 Hz, 1H), 7.92 (td, J = 7.7, 1.8 Hz, 1H), 8.08 (d, J = 7.8 Hz, 1H), 8.44 (bs, 1H), 8.50-8.57 (m, 2H), 10.04 (s, 1H).
13C NMR (125 MHz, aceton-d6, 5 in ppm): 25.59, 39.54, 46.22, 112.21, 113.29, 119.52, 119.61, 122.21, 122.80, 123.61, 127.16, 127.63, 128.71, 130.65, 131.49, 133.09, 137.81, 138.39, 142.67, 149.23, 151.26, 165.07, 183.41.
Step 5a: 7V-(3-(2-(3-(2-( 177-Indol-3-yl)ethyl)thioureido)-5-chlorophenyl)propyl)nicotinamide
(DH618)
Crude l -(2-( 1 /7- indol-3-yl )cthyl)-3-(2-(3-ami nopropyl )-4-chlorophcnyl)thiourca trifluoroacetic acid salt (DH612, 50 mg, 0.10 mmol, 1.0 eq.) was subjected to amide coupling according to the general procedure D2 to afford the product DH618 (26.0 mg, 53 pmol, 53%) as a white solid.
MS (ESI): calcd. for [C26H27C1N5OS + H]+: 492.16, found 492.23.
'H NMR (500 MHz, aceton-d6, 5 in ppm): 1.91 (quint, J = 7.1 Hz, 2H), 2.68 (t, J = 7.6 Hz, 2H), 3.06 (t, J = 7.2 Hz, 2H), 3.42 (q, J = 6.4 Hz, 2H), 3.89 (q, J = 6.9 Hz, 2H), 6.96-7.11 (m, 3H), 7.12-7.20 (m, 3H), 7.34 (d, J = 2.3 Hz, 1H), 7.37 (d, J = 8.1 Hz, 1H), 7.42 (dd, J = 7.9, 4.8 Hz, 1H), 7.64 (d, J = 7.9 Hz, 1H), 7.95 (bs, 1H), 8.22 (d, J = 8.2 Hz, 1H), 8.56 (s, 1H), 8.64- 8.69 (m, 1H), 9.07 (s, 1H), 10.03 (s, 1H).
13C NMR (125 MHz, aceton-d6, 5 in ppm): 25.62, 29.28, 40.07, 46.29, 112.21, 113.23, 119.54, 119.61, 122.22, 123.60, 124.16, 127.71, 128.69, 130.68, 131.38, 131.54, 133.17, 135.86, 137.80, 142.80, 149.45, 152.63, 166.20, 183.37. Step 5b: A-(3-(2-(3-(2-(177-Indol-3-yl)ethyl)thioureido)-5- chlorophenyl)propyl)methanesulfonamide (DH619)
Crude l -(2-( 1 /7- indol-3-yl )cthyl)-3-(2-(3-ami nopropyl )-4-chlorophcnyl)thiourca trifluoroacetic acid salt (DH612, 50 mg, 0.10 mmol, 1.0 eq.) was subjected to amide coupling according to the general procedure E to afford the product DH619 (9.4 mg, 20 pmol, 20%) as a white solid.
MS (ESI): calcd. for [C21H25CIN4O2S2+ H]+: 465.12, found 465.15.
'H NMR (500 MHz, dmso-d6, 5 in ppm): 1.83 (quint, J = 7.3 Hz, 2H), 2.64-2.69 (m, 2H), 2.90 (s, 3H), 3.04-3.13 (m, 4H), 3.90 (q, J = 6.9 Hz, 2H), 6.93-7.04 (m, 2H), 7.10 (t, J = 7.3 Hz, 1H), 7.14-7.19 (m, 3H), 7.33 (s, 1H), 7.38 (d, J = 8.1 Hz, 1H), 7.66 (d, J = 7.8 Hz, 1H), 8.46 (s, 1H), 9.99 (s, 1H).
13C NMR (125 MHz, dmso-d6, 5 in ppm): 15.69, 19.14, 21.16, 30.03, 33.57, 36.37, 102.30, 103.32, 109.63, 109.70, 112.32, 113.68, 117.89, 118.79, 120.84, 121.62, 123.23, 127.88, 132.63, 173.41. N-(3-(2-(3-(2-(lH-Indol-3-yl)ethyl)thioureido)-5- chlorophenyl)propyl)benzenesulfonamide (DH620)
Crude l -(2-( 1 /7- indol-3-yl )cthyl)-3-(2-(3-ami nopropyl )-4-chlorophcnyl)thiourca trifluoroacetic acid salt (DH612, 50 mg, 0.10 mmol, 1.0 eq.) was subjected to amide coupling according to the general procedure E to afford the product DH620 (28.0 mg, 53 pmol, 53%) as a white solid. MS (ESI): calcd. for [C26H27CIN4O2S2+ H]+: 527.13, found 527.17.
'H NMR (500 MHz, acetone-d6, 5 in ppm): 1.74 (quint, J = 7.3 Hz, 2H), 2.54-2.62 (m, 2H), 2.90 (q, J = 6.6 Hz, 2H), 3.06 (t, J = 7.2 Hz, 2H), 3.84-3.92 (m, 2H), 6.50 (t, J = 5.8 Hz, 1H), 6.88-7.02 (m, 2H), 7.05-7.18 (m, 3H), 7.23 (d, J = 1.8 Hz, 1H), 7.37 (d, J = 8.1 Hz, 1H), 7.55- 7.67 (m, 4H), 7.82-7.89 (m, 2H), 8.38 (s, 1H), 9.99 (s, 1H).
13C NMR (125 MHz, acetone-d6, 5 in ppm): 25.61, 28.90, 30.56, 43.49, 46.31, 112.22, 113.24, 119.55, 119.62, 122.24, 123.58, 127.82, 128.70, 130.05, 130.67, 131.46, 133.16, 133.23, 137.80, 141.98, 142.45, 183.27.
Step 5c: l-(3-(2-(3-(2-(177-Indol-3-yl)ethyl)thioureido)-5-chlorophenyl)propyl)-3-phenylurea
(TK461) l-(2-(177-Indol-3-yl)ethyl)-3-(2-(3-aminopropyl)-4-chlorophenyl)thioureatrifluoroacetic acid salt (TK391, 81.0 mg, 162 pmol, 1.0 eq.) was dissolved in anhydrous DCM (0.15 M) and NEt3 (45.0 pL, 323 pmol, 2.0 eq.) followed by phenyl isocyanate (19.0 pL, 178 pmol, 1.1 eq.) were added at 0 °C. The mixture was stirred at r.t. until completion (2 h), the solvent was evaporated and the residue was purified by column chromatography (DCM/EtiO). Compound TK461 (79.0 mg, 156 pmol, 96%) was obtained as a white solid.
MS (ESI): calcd. for [C27H28CIN5OS + H]+: 506.18, found 506.21.
'H NMR (500 MHz, dmso-d6, 5 in ppm): 1.68 (quint, J = 7.3 Hz, 2H), 2.53 (t, J = 7.6 Hz, 2H), 2.94 (t, J = 7.3 Hz, 2H), 3.07 (q, J = 6.9 Hz, 2H), 3.71 (bs, 2H), 6.14 (t, J = 5.6 Hz, 1H), 6.84- 6.90 (m, 1H), 7.04-7.08 (m, 1H), 7.12 (s, 1H), 7.17-7.25 (m, 4H), 7.32-7.39 (m, 4H), 7.54 (bs, 1H), 7.63 (d, J = 7.8 Hz, 1H), 8.39 (s, 1H), 9.11 (s, 1H), 10.81 (s, 1H).
13C NMR (125 MHz, dmso-d6, 5 in ppm): 24.70, 28.18, 29.82, 44.88, 54.91, 111.32, 111.61, 117.62, 118.19, 118.52, 120.93, 122.70, 126.34, 127.27, 128.60, 129.17, 130.49, 130.79, 135.75, 136.24, 140.51, 141.07, 155.21, 181.39. Step 5c: l-(3-(2-(3-(2-(177-Indol-3-yl)ethyl)thioureido)-5-chlorophenyl)propyl)-3-(tert- butyl)urea (TK462) l-(2-(177-Indol-3-yl)ethyl)-3-(2-(3-aminopropyl)-4-chlorophenyl)thioureatrifluoroacetic acid salt (TK391, 84.0 mg, 168 pmol, 1.0 eq.) was dissolved in anhydrous DCM (0.15 M) and NEt3 (70.0 pL, 503 pmol, 2.0 eq.) followed by l,l'-Carbonyldiimidazole (CDI, 29.9 mg, 184 pmol, 1.1 eq.) were added at 0 °C. The mixture was stirred at r.t. for 90 min before tert-butyl amine (21.0 pL, 201 pmol, 1.2 eq.) was added and stirring was continued at r.t. over night. The solvent was evaporated and the residue was purified by column chromatography (DCM/Et O). Compound TK462 (73.0 mg, 150 pmol, 90%) was obtained as a white solid.
MS (ESI): calcd. for [C25H32CIN5OS + H]+: 486.21, found 486.24.
'H NMR (500 MHz, dmso-d6, 5 in ppm): 1.20 (s, 9H), 1.58 (quint, J = 7.3 Hz, 2H), 2.46-2.49 (m, 2H), 2.88-2.97 (m, 4H), 3.71 (bs, 2H), 5.56 (s, 1H), 5.63 (t, J = 5.6 Hz, 1H), 6.95-6.70 (m, 1H), 7.04-7.09 (m, 1H), 7.13 (s, 1H), 7.16-7.24 (m, 2H), 7.30 (d, J = 2.3 Hz, 1H), 7.34 (d, J = 8.1 Hz, 1H), 7.54 (bs, 1H), 7.63 (d, J = 7.8 Hz, 1H), 9.09 (s, 1H), 10.83 (s, 1H).
13C NMR (125 MHz, dmso-d6, 5 in ppm): 24.69, 28.20, 29.32, 44.86, 54.91, 111.32, 111.61, 118.19, 118.52, 120.92, 122.71, 126.27, 127.27, 129.17, 130.45, 130.74, 135.70, 136.24, 141.13, 157.41, 181.35.
Step 5c: l-(3-(2-(3-(2-(177-Indol-3-yl)ethyl)thioureido)-5-chlorophenyl)propyl)-3-benzylurea
(TK463) l -(2-( 1 /7- Indol-3-yl )cthyl )-3-(2-(3-ami nopropyl )-4-chlorophcnyl)thiourcatrifluoroacctic acid salt (TK391, 84.0 mg, 168 pmol, 1.0 eq.) was dissolved in anhydrous DCM (0.15 M) and NEt3 (70.0 pL, 503 pmol, 2.0 eq.) followed by l,l'-Carbonyldiimidazole (CDI, 29.9 mg, 184 pmol, 1.1 eq.) were added at 0 °C. The mixture was stirred at r.t. for 90 min before tert-butyl amine (21.0 pL, 201 pmol, 1.2 eq.) was added and stirring was continued at r.t. over night. The solvent was evaporated and the residue was purified by reverse-phase column chromatography (ACN/H2O). Compound TK463 (76.0 mg, 146 pmol, 87%) was obtained as a white solid.
MS (ESI): calcd. for [C28H30CIN5OS + H]+: 520.19, found 520.24.
'H NMR (500 MHz, dmso-d6, 5 in ppm): 1.62 (quint, J = 7.3 Hz, 2H), 2.93 (t, J = 7.3 Hz, 2H), 3.00 (q, J = 6.8 Hz, 2H), 3.71 (bs, 2H), 4.19 (d, J = 6.0 Hz, 2H), 5.97 (t, J = 5.7 Hz, 1H), 6.31 (t, J = 6.0 Hz, 1H), 6.95-6.99 (m, 1H), 7.04-7.08 (m, 1H), 7.13 (bs, 1H), 7.17-7.25 (m, 4H), 7.26-7.35 (m, 4H), 7.54 (bs, 1H), 7.63 (d, J = 7.6 Hz, 1H), 9.11 (s, 1H), 10.83 (s, 1H).
13C NMR (125 MHz, dmso-d6, 5 in ppm): 25.68, 28.11, 30.13, 42.91, 45.96, 54.27, 111.35, 118.21, 120.95, 126.52, 126.98, 128.19, 130.05, 130.77, 136.25, 140.96, 158.10, 162.11.
Step 5d: Benzyl (3-(2-(3-(2-(177-Indol-3-yl)ethyl)thioureido)-5- chlorophenyl)propyl)carbamate (TK396) l-(2-(177-Indol-3-yl)ethyl)-3-(2-(3-aminopropyl)-4-chlorophenyl)thioureatrifluoroacetic acid salt (TK391, 75.0 mg, 150 pmol, 1.0 eq.) was dissolved in anhydrous DCM (0.1 M) and NEt3 (48.0 pL, 344 pmol, 2.3 eq.) followed by benzyl chloroformate (24.0 pL, 169 pmol, 1.13 eq.) were added at 0 °C. The mixture was stirred at r.t. until completion (90 min), the solvent was evaporated and the residue was purified by reverse-phase column chromatography (ACN/H2O).
Compound TK396 (59.0 mg, 113 pmol, 76%) was obtained as a white solid.
MS (ESI): calcd. for [C28H30CIN4O2S + H]+: 521.18, found 521.18.
'H NMR (500 MHz, dmso-d6, 5 in ppm): 1.65 (quint, J = 7.1 Hz, 2H), 2.93 (t, J = 6.9 Hz, 2H), 2.99 (q, J = 6.4 Hz, 2H), 3.71 (bs, 2H), 5.00 (s, 2H), 6.94-7.01 (m, 1H), 7.03-7.09 (m, 1H), 7.11-7.37 (m, 10H), 7.54 (bs, 1H), 7.63 (d, J = 7.6 Hz, 1H), 9.08 (s, 1H), 10.81 (s, 1H).
13C NMR (125 MHz, dmso-d6, 5 in ppm): 24.71, 27.96, 29.40, 44.89, 65.17, 111.34, 111.64, 118.20, 118.53, 120.94, 122.71, 126.34, 127.28, 127.73, 128.34, 129.20, 130.45, 130.78, 135.72, 136.25, 137.23, 141.00, 156.10, 181.39.
Step 5e: l-(2-(177-Indol-3-yl)ethyl)-3-(2-(3-azidopropyl)-4-chlorophenyl)thiourea (TK460)
TK460 l-(2-(177-Indol-3-yl)ethyl)-3-(2-(3-aminopropyl)-4-chlorophenyl)thioureatrifluoroacetic acid salt (TK391, 350 mg, 699 pmol, 1.0 eq.), NaHCOa (264 mg, 3.14 mmol, 4.5 eq.) and CuS04- 5HiO (8.7 mg, 35 pmol, 0.05 eq.) were dissolved in H2O (0.93 mL) and MeOH (6.35 mL). A triflic azide stock solution (1.61 mL, 2.09 mmol, 3.0 eq.) prepared according to the procedure of Titz el al. (Tetrahedron Lett. 2006) was added under vigorous stirring at r.t.. After full conversion was indicated by TLC (2 h), the solvents were removed in vacuo with a rotary evaporator keeping the temperature strictly below 25 °C. The residue was purified by column chromatography (DCM/EtiO) to yield the product TK460 (104 mg, 252 pmol, 36%) as a brown solid. Further purification by reverse phase colum chromatography (ACN/H2O) resulted in 15.0 mg (36 pmol, 5%) of the pure compound.
MS (ESI): calcd. for [C20H21CIN6OS + H]+: 413.13, found 413.17. 'H NMR (500 MHz, MeOD, 5 in ppm): 1.63-1.74 (m, 2H), 2.48 (t, J = 7.4 Hz, 2H), 3.04 (t, J = 6.9 Hz, 2H), 3.17 (t, J = 6.8 Hz, 2H), 3.84 (bs, 2H), 6.95-7.04 (m, 3H), 7.07-7.15 (m, 2H), 7.22 (d, J = 2.3 Hz, 1H), 7.34 (d, J = 8.1 Hz, 1H), 7.59 (d, J = 7.9 Hz, 1H).
13C NMR (125 MHz, MeOD, 5 in ppm): 25.72, 29.55, 30.24, 46.74, 51.95, 112.41, 113.04, 119.61, 119.89, 122.58, 123.78, 128.53, 128.95, 131.29, 131.53, 134.50, 135.77, 138.34, 142.57, 182.88.
Step 6: l-(2-(177-Indol-3-yl)ethyl)-3-(4-chloro-2-(3-(4-phenyl-177-l,2,3-triazol-l- yl)propyl)phenyl) thiourea (TK470)
TK470 l-(2-(177-Indol-3-yl)ethyl)-3-(2-(3-azidopropyl)-4-chlorophenyl)thiourea (TK460, 11.0 mg, 27 pmol, 1.0 eq.), phenylacetylene (8.8 pL, 80 pmol, 3.0 eq.) and sodium ascorbate (1.1 mg, 5 pmol, 0.2 eq.) were dissolved in DMF (0.22 mL) and CuSC -SHiO (1.3 mg, 5 pmol, 0.2 eq.) in H2O (0.07 mL) was added. The mixture was stirred at r.t. for 30 min, the solvent was evaporated and the residue was purified by reverse phase column chromatography (ACN/H2O). Compound TK470 (5.0 mg, 10 pmol, 36%) was obtained as a white solid.
MS (ESI): calcd. for [C28H27CIN6S + H]+: 515.18, found 515.24.
'H NMR (500 MHz, dmso-d6, 5 in ppm): 2.13 (dt, J = 14.8, 7.4 Hz, 2H), 2.56 (t, J = 7.6 Hz, 2H), 2.91 (t, J = 7.4 Hz, 2H), 3.69 (bs, 2H), 4.36 (t, J = 7.1 Hz, 2H), 6.94-6.99 (m, 1H), 7.03- 7.08 (m, 1H), 7.08-7.22 (m, 2H), 7.23-7.27 (m, 1H), 7.28-7.44 (m, 5 H), 7.58-7.69 (m, 2H), 7.79-7.85 (m, 2H), 8.53 (s, 1H), 9.25 (bs, 1H), 10.82 (s, 1H).
13C NMR (125 MHz, dmso-d6, 5 in ppm): 27.81, 28.84, 29.60, 49.20, 58.47, 111.35, 114.90, 118.21, 120.95, 121.12, 122.96, 125.15, 127.79, 128.87, 129.51, 130.85, 130.96, 136.25, 146.37, 187.15. Example 5: Synthesis of derivatives with a reverse amide
Scheme 3. Step 1: 4 M NaOH(aq), reflux; Step 2: BociO, THF, 4 M NaOH(aq), reflux; Step 3: n- butylamine, HBTU, DCM, rt; Step 4: TFA, DCM, 0°C; Step 5: thiophosgene, NaHCCE, H2O, DCM, 0°C - rt; Step 6: tryptamine, DCM, rt.
Step 1: 2-(2-amino-5-chlorophenyl)acetic acid (15) (Urgin, M, et al., 2017)
5 -Chloroxindole (14, 350 mg, 2.09 mmol, 1.0 eq.) was added to an aqueous NaOH solution (4.2 mL, 4 M). The reaction was refluxed overnight. Subsequently, it was cooled to r.t. and used directly for the next step.
MS (ESI): calcd for [C8H8C1NO2 + H]+: 186.03, found 186.20.
Step 2: 2-(2-((tert-butoxycarbonyl)amino)-5-chlorophenyl)acetic acid (16) (Yang, Z, et al., 2018)
The reaction mixture for the synthesis of 15 (3.6 mL, 1.0 eq.) was diluted with 21.0 mL THE, and BOC2O (703 mg, 3.57 mmol, 2.0 eq.) was added. Subsequently, the solution was heated to reflux for 4 h. THE was removed in vacuo, and the aqueous layer was gently acidified with IM NH4Cl(aq), followed by IN HCl(aq) until reaching a pH of 5. The aqueous solution was then extracted three times with DCM, and the combined organic phases were dried over Na2SO4 and filtered. After concentration under reduced pressure, the crude product was purified by column chromatography (PE + 1% FA/EtOAc + 1% FA, 5 - 20%). Compound 16 was obtained as a colourless solid (404 mg, 79% over two steps).
MS (ESI): calcd for [C13H16CINO4 + H]+: 286.08, found 286.03.
'H-NMR (500 MHz, CDCE, 6 in ppm): 1.49 (s, 9H); 3.62 (s, 2H); 7.10 - 7.30 (m, 3H); 7.57 (br s, 1H).
13C-NMR (126 MHz, CDCE, 6 in ppm): 28.41, 37.96, 128.48, 130.67, 135.37. Step 3 : tert-butyl [A-(2-(2-(butylamino)-2-oxoethyl)-4-chlorophenyl)] carbamate (17) 2-(2-((tert-butoxycarbonyl)amino)-5-chlorophenyl)acetic acid (16, 304 mg, 1.20 mmol, 1.0 eq.) was subjected to amide coupling according to general procedure D2 with HBTU (500 mg, 1.32 mmol, 1.1 eq.), EtaN (363 mg, 498 pL, 3.59 mmol, 3.0 eq.), n-butylamine (97.0 mg, 131 pL, 1.32 mmol, 1.1 eq.) in 7.8 mL DCM (0.14 M). The solvent was removed using a rotary evaporator, and the resulting solid was purified by column chromatography (PE/EtOAc, 2 - 30%). 170 mg of the product 17 were obtained as a colourless solid (42% yield).
MS (ESI): calcd for [C17H25CIN2O3 + H]+: 341.16, found 341.14.
'H-NMR (500 MHz, CDCh, 6 in ppm): 0.91 (t, J = 7.3 Hz, 3H), 1.25 (s, 4H), 1.22 - 1.40 (m, 3H), 1.43 - 1.50 (m, 2H), 1.51 (s, 9H), 3.23 (td, J = 7.3, 5.7 Hz, 2H), 3.45 (s, 2H), 5.82 (s, 1H), 7.10 (d, J = 2.5 Hz, 1H), 7.22 (dd, J = 8.7, 2.4 Hz, 1H), 7.77 (d, J = 8.8 Hz, 1H), 8.66 (s, 1H).
13C-NMR (126 MHz, CDCh, 5 in ppm): 13.82, 20.15, 28.50, 29.85, 31.50, 39.97, 41.10, 80.60, 124.76, 128.08, 128.25, 128.85, 129.88, 136.58, 153.98, 171.17.
Step 4: 2-(2-amino-5-chlorophenyl)-A-butylacetamide (18)
Under an inert gas atmosphere, tert-butyl [A-(2-(2-(butylamino)-2-oxoethyl)-4-chlorophenyl)] carbamate (17, 165 mg, 0.483 mmol, 1.0 eq.) was dissolved in 5.8 mL of anhydrous DCM (0.08 M). After cooling to 0°C, TFA (3.70 mL, 48.3 mmol, 100.0 eq.) was slowly added. After stirring for 1 h at 0°C, the solution was washed three times with saturated aqueous NaHCO ,, dried over Na2SO4, filtered and concentrated under reduced pressure. Crude 18 (105 mg) was directly used in the next step without further purification.
MS (ESI): calcd for [C12H17CIN2O + H]+: 241.11, found 241.18.
Step 5: A-butyl-2-(5-chloro-2-isothiocyanatophenyl)acetamide (19)
2-(2-amino-5-chlorophenyl)-A-butylacetamide (18, 105 mg, 0.446 mmol, 1.0 eq.) was transformed into isothiocyanate 19 according to general procedure A. Crude 19 (109 mg) was directly used for the next step.
MS (ESI): calcd for [C13H15CIN2OS + H]+: 283.07, found 283.15.
Step 6: 2-(2-(3-(2-(177-indol-3-yl)ethyl)thioureido)-5-chlorophenyl)-A-butylacetamide (20) Crude A-butyl-2-(5-chloro-2-isothiocyanatophenyl)acetamide (19, 109 mg, 0.388 mmol, 1.0 eq.) was dissolved in 7.5 mL of DCM (0.05 M). Subsequently, tryptamine (62.1 mg, 0.388 mmol, 1.0 eq.) was added, and the mixture was stirred for 1.5 h at r.t.. The reaction mixture was concentrated in vacuo and purified by column chromatography (PE/EtOAc, 30 - 80%). A total of 158 mg (0.357 mmol, 74% yield over three steps) of 20 as a colourless solid was obtained.
MS (ESI): calcd for [C23H27CIN4OS + H]+: 443.17, found 443.21.
'H-NMR (500 MHz, DMSO-d6, 5 in ppm): 0.85 (t, J = 7.3 Hz, 3H), 1.20 - 1.31 (m, 3H), 1.32 - 1.43 (m, 2H), 2.96 (t, J = 7.6 Hz, 2H), 3.01 - 3.08 (m, 2H), 3.42 (s, 2H), 3.67 - 3.75 (m, 2H), 6.94 - 7.01 (m, 1H), 7.03 - 7.10 (m, 1H), 7.15 (s, 1H), 7.22 - 7.38 (m, 4H), 7.62 (d, J = 7.9 Hz, 1H), 7.96 (br s, 1H), 8.07 (br s, 1H), 9.34 (s, 1H), 10.82 (s, 1H).
13C-NMR (126 MHz, DMSO-d6, 5 in ppm): 13.65, 19.55, 24.54, 31.04, 38.22, 38.49, 45.12, 111.37, 111.68, 118.23, 118.49, 120.95, 122.76, 126.94, 127.31, 129.37, 129.68, 134.47, 136.26, 136.93, 169.83, 181.12.
Example 6: Antimicrobial activity and cell toxicity
Growth media and reagents
All bacterial media and supplements including Mueller-Hinton cation supplemented broth II (MHBII), Mueller-Hinton agar (MHA) and Tryptic soy broth (TSB) were purchased from Becton-Dickinson (Franklin Lakes, NJ, USA). All other chemicals and antibiotics were procured from Sigma- Aldrich (St. Louis, MO, USA). Roswell Park Memorial Institute Medium (RPMI) and Fetal Bovine Serum (FBS) were purchased from Lonza (Lonza, USA). All methods were performed in accordance with the relevant guidelines and regulations.
Bacterial strains
Molecules were screened against Acinetobacter baumannii (BAA- 1605). The panel was further expanded to include drug-resistant clinical Acinetobacter baumannii strains including those resistant to meropenem and other clinically-utilized antibiotics. These strains were procured from Biodefense and Emerging Infections Research Resources Repository/ American Type Culture Collection (BEI/ATCC, USA) and routinely cultivated on MHA and MHBII. Before starting the experiment, a single colony was picked from MHA plate, inoculated in MHBII and incubated overnight at 37 °C with shaking for 18-24 h to get the starter culture. Antibiotic
Antibiotic susceptibility testing of hits was conducted according to the CLSI guidelines using the broth microdilution assay. 10 mg/mL stock solutions of test compounds were prepared in DMSO. Bacterial cultures were inoculated in MHBII and optical density (OD) was measured at 600 nm, followed by dilution to achieve ~106 CFU/mL. The compounds were tested from 64-0.5 mg/L in two-fold serial diluted fashion with 2.5 pL of each concentration added to well of a 96-well round bottom microtiter plate. Later, 97.5 pL of bacterial suspension was added to each well containing either test compound or appropriate controls. The plates were incubated at 37°C for 18-24 h following which the MIC was determined. The MIC is defined as the lowest concentration of the compound at which there is absence of visible growth. For each test compound, MIC determinations were carried out independently three times using duplicate samples.
Cell cytotoxicity against Vero cells
Cell toxicity was performed against Vero cells using the MTT assay. ~103 cells/well were seeded in 96 well plate and incubated at 37°C in an 5% CO2 atmosphere. After 24 h, compound was added ranging from 100-12.5 pg/mL concentration and incubated for 72 h. After the incubation was over, MTT was added to each well, incubated at 37 °C for further 4 h, residual medium was discarded, 0.1 mL of DMSO was added to solubilise the formazan crystals and OD was taken at 540 nm for the calculation of CC50. CC50 is defined as the lowest concentration of compound which leads to a 50% reduction in cell viability. Doxorubicin was used as positive control and each experiment was repeated in triplicate.
Results
The tested small molecules showed strong antimicrobial activity (Table 2). The compounds showing the highest activity were 7i, 7q, 11, and 13 showing MIC < 0.5 pg/ml.
The compound 11 was further tested for activity against a panel of clinical isolates of A. baumannii and the results listed in Table 3 below. The results showed that compound 11 is active against all clinical isolates and multi-drug resistant strains tested. Compound 11 showed an anti-microbial activity comparable to polymyxin B and was active even in meropenem, minocycline and/or levofloxacin resistant strains (MIC90 < 0.5 pg/ml). In addition, the inventors were unable to observe any cross-resistance with known antibiotics in compound 11, meaning that the compounds presented here could potentially have a novel mechanism of action, e.g. new target or known target with new site. Table 2. Antimicrobial activity evaluation against three Acinetobacter baumannii strains and cytotoxicity (n.d. = not determined). Table 3. Antimicrobial activity of compound 11 and approved antibiotics against A. baitmannii clinical isolates.
Example 7: Synthesis of derivatives based on phenylethylamine
TK410
TK432 (quant.) TK440 (68%)
TK441 (60%)
Scheme 4. Step 1: 1) 0.5 M 9-BBN in THF, tert-butyl (V-vinylcarbamate, THF, 2) 3 M K3PO4, 4-chloro-2-iodoaniline, Pd(dppf)Ch, 65 °C.; Step 2: thiophosgene, NaHCCh, H2O, DCM, 0°C - r.t.; Step 3: tryptamine, DCM, r.t.; Step 4: TFA, DCM, 0°C: Step 5: benzyl chloroformate or pivaloyl chloride, NEt3, DCM, r.t..
Step 1.1 : tert-Butyl (2-amino-5-chlorophenethyl)carbamate (TK420) (Kennedy el al.,
Antimicrob. Agents Chemother. 2016)
TK420
A 0.5 M solution of 9-BBN in THF (99.5 mL, 49.7 mmol, 3.5 eq.) was added to tert-butyl N- vinylcarbamate (2.64 g, 18.5 mmol, 1.3 eq.) at r.t. under N2 atmosphere and the reaction was stirred for 9 h until completion. K3PO4 (10.6 g, 49.7 mmol, 3.5 eq., 3 M in H2O) was added and the reaction was stirred for 10 min. Then, 4-chloro-2-iodoaniline (3.60 g, 14.2, 1.0 eq.) and Pd(dppf)Ch (520 mg, 0.71 mmol, 0.05 eq.) were added sequentially and the reaction was stirred overnight at 65 °C. The mixture was concentrated under reduced pressure, diluted with EtOAc and washed with 1 N HC1. The aqueous phase was extracted two more times with EtOAc, the organic layers were combined, dried over anhydrous Na2SO4, filtered and evaporated in vacuo. The crude was purified by column chromatography (DCM/Et2O) to give the impure product TK420 (5.35 g) which was directly used for next step.
MS (ESI): calcd. for [C13H19CIN2O2+ H]+: 271.12, found 271.07.
Step 1.2 : /e/7- Butyl (5-chloro-2-isothiocyanatophenethyl)carbamate (TK425)
TK425
The reaction was performed according to the general procedure A using tert-butyl (2-amino-5- chlorophenethyl)carbamate (TK420, 4.20 g) and purified by column chromatography (pentane/DCM) to give the title compound TK425 (1.71 g, 5.48 mmol, 50% yield over two steps) as a yellow solid.
MS (ESI): calcd. for [C14H17CIN2O2S + Na]+: 335.06, found 335.10.
'H NMR (500 MHz, dmso-d6, 5 in ppm): 1.32 (s, 9H), 2.77 (t, J = 6.5 Hz, 2H), 3.21 (q, J = 6.3 Hz, 2H), 6.9 (t, J = 5.7 Hz, 1H), 7.33-7.39 (m, 2H), 7.42-7.48 (m, 1H).
13C NMR (125 MHz, dmso-d6, 5 in ppm): 27.15, 37.76, 77.61, 127.64, 128.32, 128.42, 130.39, 131.84, 138.10, 155.51. Step 2: tert-Butyl (2-(3-(2-( 177-indol-3-yl )ethyl)thioureido)-5-chlorophenethyl )carbamate
(TK427)
TK427
The reaction was performed according to the general procedure B using tert-butyl (5-chloro-2- isothiocyanatophenethyl)carbamate (TK425, 1.48 g) and purified by column chromatography (DCM/EtOAc) to give the title compound TK427 (2.10 g, 4.44 mmol, 94%) as a white solid.
MS (ESI): calcd. for [C24H29CIN4O2S + H]+: 473.18, found 473.20.
'H NMR (500 MHz, dmso-d6, 5 in ppm): 1.33 (s, 9H), 2.65 (t, J = 6.8 Hz, 2H), 2.93 (t, J = 7.2 Hz, 2H), 3.13 (q, J = 6.6 Hz, 2H), 3.70 (q, J = 5.3 Hz, 2H), 6.82 (t, J = 5.6 Hz, 2H), 6.95-6.70 (m, 1H), 7.04-7.09 (m, 1H), 7.09-7.18 (m, 2H), 7.21-7.28 (m, 2H), 7.34 (d, J = 8.1 Hz, 2H), 7.51 (bs, 1H), 7.62 (d, J = 7.9 Hz, 1H), 9.13 (s, 1H), 10.82 (s, 1H).
13C NMR (125 MHz, dmso-d6, 5 in ppm): 24.61, 28.17, 31.19, 45.01, 77.65, 111.34, 111.61, 118.20, 118.50, 122.71, 126.73, 127.26, 129.91, 130.34, 130, 77, 135.98, 136.25, 139.04, 155.67, 181.49.
Step 3: l-(2-(777-indol-3-yl)ethyl)-3-(2-(2-aminoethyl)-4-chlorophenyl)thiourea trifluoroacetic acid salt (TK432)
TK432 tert-Butyl (2-(3-(2-(177-indol-3-yl)ethyl)thioureido)-5-chlorophenethyl)carbamate (TK427, 1.85 g, 3.91 mmol) was deprotected according to general procedure C to give the product TK432 as a beige foam (1.90 g, quant., crude), which was used in the next step without further purification. MS (ESI): calcd. for [C19H21CIN4S + H]+: 373.12, found 373.18.
Step 4: Benzyl (2-(3-(2-(177-indol-3-yl)ethyl)thioureido)-5-chlorophenethyl)carbamate
(TK440) l-(2-(777-indol-3-yl)ethyl)-3-(2-(2-aminoethyl)-4-chlorophenyl)thiourea trifluoroacetic acid salt (TK432, 56.4 mg, 116 pmol, 1.0 eq.) was dissolved in anhydrous DCM (0.1 M) and NEt3 (44.0 pL, 316 pmol, 2.7 eq.) followed by benzyl chloroformate (25.0 pL, 174 pmol, 1.5 eq.) were added at 0 °C. The mixture was stirred at r.t. until completion (1 h), the solvent was evaporated and the residue was purified by reverse-phase column chromatography (ACN/H2O). Compound TK440 (40.0 mg, 79 pmol, 68%) was obtained as a white solid.
MS (ESI): calcd. for [C27H27CIN4O2S + H]+: 507.16, found 507.20.
'H NMR (500 MHz, dmso-d6, 5 in ppm): 2.68 (t, J = 6.9 Hz, 2H), 2.93 (bs, 2H), 3.22 (q, J = 6.6 Hz, 2H), 3.70 (bs, 2H), 4.99 (s, 2H), 6.94-6.99 (m, 1H), 7.06 (t, J = 7.4 Hz, 1H), 7.11-7-16 (m, 2H), 7.23-7.36 (m, 8H), 7.53 (bs, 1H), 7.62 (d, J = 7.8 Hz, 1H), 9.16 (s, 1H), 10.81 (s, 1H).
13C NMR (125 MHz, dmso-d6, 5 in ppm): 24.67, 31.01, 44.96, 54.91, 65.17, 111.34, 111.61, 118.19, 118.50, 120.92, 122.73, 126.79, 127.27, 127.63, 128.33, 129.71, 130.44, 130.80, 136.24, 137.19, 138.82, 156.09, 181.46.
Step 5: A-(2-(3-(2-(177-Indol-3-yl)ethyl)thioureido)-5-chlorophenethyl)pivalamide (TK441)
TK441 l-(2-(777-indol-3-yl)ethyl)-3-(2-(2-aminoethyl)-4-chlorophenyl)thiourea trifluoroacetic acid salt (TK432, 56.4 mg, 116 pl-(2-(7H-indol-3-yl)ethyl)-3-(2-(2-aminoethyl)-4- chlorophenyl)thiourea trifluoroacetic acid salt (TK432, 56.4 mg, 116 pl-(2-(777-indol-3- yl)ethyl)-3-(2-(2-aminoethyl)-4-chlorophenyl)thiourea trifluoroacetic acid salt (TK432, 56.4 mg, 116 pmol, 1.0 eq.) was dissolved in anhydrous DCM (0.1 M) and NEt3 (40.0 pL, 290 pmol, 2.5 eq.) followed by pivaloyl chloride (19.0 pL, 151 pmol, 1.3 eq.) were added at 0 °C. The mixture was stirred at r.t. until completion (30 min), the solvent was evaporated and the residue was purified by reverse-phase column chromatography (ACN/H2O). Compound TK441 (32.0 mg, 70 pmol, 60%) was obtained as a white solid.
MS (ESI): calcd. for [C24H29CIN4OS + H]+: 457.18, found 457.21.
'H NMR (500 MHz, dmso-d6, 5 in ppm): 1.03 (s, 9H), 2.68 (t, J = 6.8 Hz, 2H), 2.94 (t, J = 7.3 Hz, 2H), 3.23-3.28 (m, 2H), 3.71 (bs, 2H), 6.94-6.99 (m, 1H), 7.03-7.08 (m, 1H), 7.11-7.25 (m, 4H), 7.34 (d, J = 8.1 Hz, 1H), 7.51 (bs, 1H), 7.62 (d, J = 7.8 Hz, 1H), 7.73 (s, 1H), 9.19 (s, 1H), 10.82 (s, 1H).
13C NMR (125 MHz, dmso-d6, 5 in ppm): 24.59, 27.36, 30.93, 37.95, 38.38, 45.00, 111.34, 111.61, 118.19, 118.47, 120.92, 122.73, 126.59, 127.26, 129.97, 130.16, 130.41, 136.15, 136.24, 138.81, 177.52, 181.63.
Example 8: Antimicrobial activity of compounds of Example 7 and Example 4-Part 2.
Table 4. Antimicrobial activity evaluation against Acinetobacter baumannii ATCC 19606 (DSM 30007).
List of references
1. Khatik, L, et al., 2011. Aldol derivatives of Thioxoimidazolidinones as potential anti- prostate cancer agents. Eur J Med Chem, 46, 3291-3301.
2. Kumbhare RM, et al., 2013. Synthesis and Study the Antimicrobial Activity of Novel 2- (lH-indol-3-yl)- N-(3, 4-diphenylthiazol-2(3H)-ylidene) Ethanamine Derivatives. Med Chem 9(2):287-93.
3. Golime, G, et al., 2018. Biomimetic Oxidative Deamination Catalysis via ortho- Naphthoquinone-Catalyzed Aerobic Oxidation Strategy. ACS Catal, 8, 4986-4990.
4. Dong, Z. et al., 2015. Rhodium(III) -Catalyzed Direct Cyanation of Aromatic C-H Bond to Form 2-(Alkylamino)benzonitriles Using N-Nitroso As Directing Group. J Org Chem, 80, 12588-12593.
5. Kennedy, AJ, et al., 2016. Synthesis and Antimicrobial Evaluation of Amixicile-Based Inhibitors of the Pyruvate-Ferredoxin Oxidoreductases of Anaerobic Bacteria and
Epsilonproteobacteria. Antimicrob. Agents Chemother., 60, 3980-3987. Urgin, M, et al., 2017. Pharmacomodulation of the Antimalarial Plasmodione: Synthesis of Biaryl- and N-Arylalkylamine Analogues, Antimalarial Activities and Physicochemical Properties. Molecules, 22, 161. Yang, Z, et al., 2018. Design and synthesis of (aza)indolyl maleimide -based covalent inhibitors of glycogen synthase kinase 3p. Org Biomol Chem, 16, 4127-4140. Titz, A.; Radic, Z.; Schwardt, O.; Ernst, B. A safe and convenient method for the preparation of triflyl azide, and its use in diazo transfer reactions to primary amines Tetrahedron Lett. 2006, 47, 2383 - 2385

Claims

Claims
1. A compound of the general formula (I): wherein
R1 is individually selected from the group consisting of halogen and C1-4 alkyl, which is optionally substituted by one or more halogen(s), and C1-4 alkoxy, which is optionally substituted by one or more halogen(s);
R2 is individually selected from the group consisting of hydrogen, OH, NH2, NO2, SH, one or more halogen(s), COOR8, wherein R8 is hydrogen or C1-4 alkyl, which is optionally substituted by one or more halogen(s), C1-4 acyl, which is optionally substituted by one or more halogen(s), C1-4 alkyl, which is optionally substituted by one or more halogen(s), and C1-4 alkoxy, which is optionally substituted by one or more halogen(s); m is 0, 1, 2 or 3;
R3 is a C1-8 alkyl chain wherein 1, 2 or 3 chain carbon atoms are individually replaced by NH, -O-, C=O, or S(=O) x, wherein X is 0, 1, or 2, and which chain is optionally substituted by 1 to 3 substituents individually selected from the group consisting of: one or more halogen(s), N3,
C1-6 alkyl, which is optionally substituted by one or more halogen(s),
C1-6 alkoxy, which is optionally substituted by one or more halogen(s), and a 5 to 10 membered carbo- or heterocycle, which is optionally substituted by 1 to 3 R7 substituents, wherein R7 is selected from the group consisting of one or more halogen(s), — CN, — NO2, — Rf, — CO2Rd, — CONRdRe, — C(O)Rd, — OC(O)NRdRe, — NReC(O)Rd, — NReC(O)2Rf, — NRdC(O)NRdRe, — NRdRe, — ORd, and — S(O)2NRdRe; wherein each Rd and Re is independently selected from hydrogen, Ci-s alkyl, and Ci-s haloalkyl; each Rf is independently selected from the group consisting of Ci-s alkyl or heteroalkyl, Ci-s haloalkyl, C3-6 cycloalkyl, heterocycloalkyl, aryl and heteroaryl, and wherein the aliphatic and/or cyclic portions of Rd, Re and Rf are optionally further substituted with from one to three halogen, hydroxy, methyl, amino, C1-6 alkylamino and di C1-6 alkylamino groups;
R4 andR5 are individually selected from the group consisting of hydrogen, one or more halogen(s), and C1-4 alkyl, and preferably are hydrogen; or a salt thereof, or a solvate thereof, or a prodrug thereof.
2. The compound according to claim 1, wherein R3 is a C1-8 alkyl chain wherein 1, 2 or 3 of the chain carbon atoms are individually replaced by NH, -O-, C=O, and/or S(=O)2, and which chain is optionally substituted by 1, 2 or 3 substituents selected from the group consisting of N3, C1-6 alkyl, C1-6 alkoxy, and a 5, 6, 7, or 10-membered carbo- or heterocycle, which is optionally substituted by 1 to 3 R7 substituents, wherein R7 is as defined in claim 1.
3. The compound according to claim 1, wherein R3 is selected from the group consisting of a) a residue of the formula (la) wherein
R6 is selected from the group consisting of hydrogen, C1-6 alkyl, which is optionally substituted by one or more halogen(s), C1-6 alkoxy, which is optionally substituted by one or more halogen(s), and a 5, 6, 7, or 10-membered carbo- or heterocycle, which is optionally substituted by 1 to 3 R7substituents, wherein R7 is as defined in claim 1, and wherein n is 0, 1, or 2; or a residue of the formula (la), wherein the amide is replaced by an amide bioisostere and R6 and n are as defined above; b) a residue of the formula (lb) wherein
R6 is selected from the group consisting of hydrogen, Ci-6 alkyl, which is optionally substituted by one or more halogen(s), Ci-6 alkoxy, which is optionally substituted by one or more halogen(s), and a 5, 6, 7, or 10-membered carbo- or heterocycle, which is optionally substituted by 1 to 3 R7substituents, wherein R7 is as defined in claim 1, and wherein n is 0, 1, or 2; or a residue of the formula (lb), wherein the amide is replaced by an amide bioisostere and R6 and n are as defined above; c) a residue of the formula (Ic) wherein
R6 is selected from the group consisting of hydrogen, Ci-6 alkyl, which is optionally substituted by one or more halogen(s), Ci-6 alkoxy, which is optionally substituted by one or more halogen(s), and a 5, 6, 7, or 10-membered carbo- or heterocycle, which is optionally substituted by 1 to 3 R7 substituents, wherein R7 is as defined in claim 1, and wherein n is 0, 1, or 2; or d) a residue of the formula (Id) wherein
R6 is selected from the group consisting of hydrogen, Ci-6 alkyl, which is optionally substituted by one or more halogen(s) or -N3, C1-6 alkoxy, which is optionally substituted by halogen(s), and a 5, 6, 7, or 10-membered carbo- or heterocycle, which is optionally substituted by 1 to 3 R7 substituents, wherein R7 is as defined in claim 1, and wherein n is 0, 1, or 2.
4. The compound according to claim 3, wherein R3 is a residue of the formula (la)
The compound according to claim 3 or 4, wherein R6 is selected from the group consisting of C3-6 alkyl, which is optionally substituted by one or more halogen(s), C1-6 alkoxy, which is optionally substituted by one or more halogen(s), and a 5, 6, 7, or 10- membered carbo- or heterocycle, having 1 to 3 heteroatoms as ring members selected from N, O, and S, which 5, 6, 7, or 10-carbo- or heterocycle is optionally substituted by 1 to 3 R7 substituents, wherein R7 is as defined in claim 1.
6. The compound according to claim 5, wherein in R6 the 5, 6, 7 or 10-membered carboor heterocycle is selected from the group consisting of a C5-10 cycloalkyl group, a heterocycloalkyl group having 1 to 3 heteroatoms as ring members selected from N, O, and S; a Ce aryl group, and a heteroaryl group having from 1 to 3 heteroatoms as ring members selected from N, O and S; which 5, 6, 7, or 10-membered carbo- or heterocycle is optionally substituted by 1 to 3 R7 substituents, wherein R7 is as defined in claim 1 .
7. The compound according to any one of the preceding claims, wherein R1 is chlorine, and/or wherein R2, R4 and R5 are hydrogen.
8. The compound according to any one of the preceding claims, wherein m is 0, and/or wherein R3 is a residue of the formula (la), (lb) or (Ic), and n is 0 or 2.
9. The compound according to any one of claims 3 to 8, wherein R6 is a hydrogen, a pentyl group, a cyclopropyl group, a cyclopentyl group, a cyclohexyl group, a phenyl group, a tert-butyl group, a O-tert-butyl group, a n-butyl group, a methyl group, a methyl-butyl group, a benzyl group, a adamantyl group, a pyridinyl group, a piperazinyl group, a hexahydropyrimidinyl group, a hexahydropyridazinyl group, a 3-thienyl group, a piperidinyl group, a pyrrolyl group, a 4-Boc-morpholinyl group, a N-Boc-piperidinyl group, or a l-Boc-(4-Boc)piperazinyl group.
10. The compound according to any one of claims 3 to 9, wherein R1 is chlorine, m is 0, n is 2, R3 is a residue of the formula (la), R2, R4 and R5 are hydrogen, and R6 is a O-tert- butyl group.
11. The compound according to any one of claims 3 to 10, wherein the compound has the following formula: wherein R3 is as defined in claims 1, 2, 3, or 4.
12. A pharmaceutical composition comprising the compound according to any one of claims 1 to 11, and optionally comprising one or more constituents selected from the group consisting of a pharmaceutically acceptable carrier, a diluent, an excipient and a further anti-bacterial therapeutic agent.
13. A compound according to any one of claims 1 to 11 or a pharmaceutical composition according to claim 12 for use in medicine.
14. A compound according to any one of claims 1 to 11 or a pharmaceutical composition according to claim 12, optionally in combination with one or more anti-bacterial therapeutic agent(s), for use in the prophylaxis or treatment of Acinetobacter baumannii infections in a patient, or for use in the prophylaxis or treatment of Acinetobacter baumannii-associated lung infections, catheter-associated infections, bacteremia, or sepsis in a patient, or for use in the prophylaxis or treatment of carbapenem resistant Acinetobacter baumannii or multidrug resistant Acinetobacter baumannii.
15. A method for the preparation of a compound of formula (I): wherein R1 is individually selected from the group consisting of halogen and C1-4 alkyl, which is optionally substituted by one or more halogens, and C1-4 alkoxy, which is optionally substituted by one or more halogen(s);
R2 is individually selected from the group consisting of hydrogen, OH, NH2, NO2, SH, one or more halogen(s), COOR8, wherein R8 is hydrogen or C1-4 alkyl, which is optionally substituted by one or more halogen(s),Ci-4 acyl, which is optionally substituted by halogen(s), C1-4 alkyl, which is optionally substituted by one or more halogen(s), or C1-4 alkoxy, which is optionally substituted by one or more halogens; m is 0, 1, 2 or 3;
R3 is a C1-8 alkyl chain wherein 1, 2 or 3 chain carbon atoms are individually replaced by NH, -O-, C=O, or S(=O)X , wherein X is 0, 1, or 2, and which chain is optionally substituted by 1, to 3 substituents individually selected from the group consisting of: one or more halogen(s), C1-6 alkyl, which is optionally substituted by one or more halogen(s), C1-6 alkoxy, which is optionally substituted by one or more halogen(s), and a 5 to 10 membered carbo- or heterocycle, which is optionally substituted by 1 to 3 R7 substituents, wherein R7 is selected from the group consisting of one or more halogen(s), — CN, — NO2, — Rf, — CO2Rd, — CONRdRe, — C(O)Rd, — OC(O)NRdRe, — NReC(O)Rd, — NReC(O)2Rf, — NRdC(O)NRdRe, — NRdRe, — ORd, and — S(O)2NRdRe; wherein each Rd and Re is independently selected from hydrogen, C1-8 alkyl, and C1-8 haloalkyl; each Rf is independently selected from the group consisting of C1-8 alkyl or heteroalkyl, C1-8 haloalkyl, C3-6 cycloalkyl, heterocycloalkyl, aryl and heteroaryl, and wherein the aliphatic and/or cyclic portions of Rd, Re and Rf are optionally further substituted with from one to three halogen, hydroxy, methyl, amino, C1-6 alkylamino and di C 1-6 alkylamino groups ;
R4 andR5 are individually selected from the group consisting of hydrogen, one or more halogen(s), and C1-4 alkyl, and preferably are hydrogen; or a salt thereof, or a solvate thereof, or a prodrug thereof, comprising: a) reacting a compound of formula (II) and a compound of formula (Illa)
wherein R1, R2, and m are as defined for formula (I), p is 1 or 2 or 3, and
PGi is a protecting group or b) reacting a compound of formula (II) and a compound of formula (Illb) wherein R1, R2, R3, R4, R5, and m are as defined for formula (I), and wherein R3 is preferably a residue of the formula (lb) as defined in claim 3; to obtain a compound of Formula (I).
PCT/EP2025/065567 2024-06-06 2025-06-04 Thiourea based derivatives are novel antimicrobials against a. baumannii Pending WO2025252850A1 (en)

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Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0039051A2 (en) 1980-04-24 1981-11-04 Merck & Co. Inc. Mannich-base hydroxamic acid prodrugs for the improved bioavailability of non-steroidal anti-inflammatory agents, a process for preparing and a pharmaceutical composition containing them
WO2015157618A1 (en) * 2014-04-11 2015-10-15 The Texas A&M University System Novel inhibitors of the new delhi metallo beta lactamase (ndm-1)
WO2018227178A1 (en) * 2017-06-09 2018-12-13 Fob Synthesis, Inc. Carbapenem compounds and compositions for the treatment of bacterial infections

Patent Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0039051A2 (en) 1980-04-24 1981-11-04 Merck & Co. Inc. Mannich-base hydroxamic acid prodrugs for the improved bioavailability of non-steroidal anti-inflammatory agents, a process for preparing and a pharmaceutical composition containing them
WO2015157618A1 (en) * 2014-04-11 2015-10-15 The Texas A&M University System Novel inhibitors of the new delhi metallo beta lactamase (ndm-1)
WO2018227178A1 (en) * 2017-06-09 2018-12-13 Fob Synthesis, Inc. Carbapenem compounds and compositions for the treatment of bacterial infections

Non-Patent Citations (18)

* Cited by examiner, † Cited by third party
Title
"Gold Book", 1997, article "Compendium of Chemical Terminology"
"Helvetica Chimica Acta", 1995, CH-4010 BASEL, article "A multilingual glossary of biotechnological terms: (IUPAC Recommendations"
"U.S. Pharmacopeia", April 2010, UNITED STATES PHARMACOPEIA CONVENTION, INC.
BERGE, S. M. ET AL.: "Pharmaceutical Salts", JOURNAL OF PHARMACEUTICAL SCIENCE, vol. 66, 1977, pages 1 - 19, XP002675560, DOI: 10.1002/jps.2600660104
BLASCO BENJAMIN ET AL: "High-throughput screening of small-molecules libraries identified antibacterials against clinically relevant multidrug-resistant A. baumannii and K. pneumoniae", vol. 102, 1 April 2024 (2024-04-01), NL, XP093214284, ISSN: 2352-3964, Retrieved from the Internet <URL:https://www.thelancet.com/action/showPdf?pii=S2352-3964(24)00108-7> DOI: 10.1016/j.ebiom.2024.105073 *
BUNDGAARD H ET AL., J MED CHEM, vol. 32, no. 12, 1989, pages 2503 - 2507
BUNDGAARD H: "Design of Prodrugs", 1985, ELSEVIER SCIENCE LTD.
DONG, Z. ET AL.: "Rhodium(III)-Catalyzed Direct Cyanation of Aromatic C-H Bond to Form 2-(Alkylamino)benzonitriles Using N-Nitroso As Directing Group", J ORG CHEM, vol. 80, 2015, pages 12588 - 12593
GOLIME, G ET AL.: "Biomimetic Oxidative Deamination Catalysis via ortho-Naphthoquinone-Catalyzed Aerobic Oxidation Strategy", ACS CATAL, vol. 8, 2018, pages 4986 - 4990
KENNEDY, AJ ET AL.: "Synthesis and Antimicrobial Evaluation of Amixicile-Based Inhibitors of the Pyruvate-Ferredoxin Oxidoreductases of Anaerobic Bacteria and Epsilonproteobacteria", ANTIMICROB. AGENTS CHEMOTHER., vol. 60, 2016, pages 3980 - 3987
KHATIK, L ET AL.: "Aldol derivatives of Thioxoimidazolidinones as potential anti-prostate cancer agents", EUR J MED CHEM, vol. 46, 2011, pages 3291 - 3301, XP028377950, DOI: 10.1016/j.ejmech.2011.04.050
KUMBHARE RM ET AL.: "Synthesis and Study the Antimicrobial Activity of Novel 2-(1H-indol-3-yl)- N-(3, 4-diphenylthiazol-2(3H)-ylidene) Ethanamine Derivatives", MED, vol. 9, no. 2, 2013, pages 287 - 93, XP093208136, DOI: 10.2174/1573406411309020011
SHUKLA MANJULIKA ET AL: "Identification and bioevaluation of SRI-12742 as an antimicrobial agent against multidrug-resistant Acinetobacter baumannii", vol. 52, no. 1, 1 July 2018 (2018-07-01), AMSTERDAM, NL, pages 22 - 27, XP093208148, ISSN: 0924-8579, Retrieved from the Internet <URL:https://pdf.sciencedirectassets.com/271247/1-s2.0-S0924857918X00077/1-s2.0-S0924857918300566/main.pdf?X-Amz-Security-Token=IQoJb3JpZ2luX2VjEJz//////////wEaCXVzLWVhc3QtMSJHMEUCIQDjwyDzFYIcmYgVQh03S5Bs0cNpxAt4dV4KPafpjVvu4gIgMc0h/FpsAUMsfaQMc+ySZu7QTFFg5Vb+qH+um1jNFngqvAUI1f//////////ARAFGgwwNTkwMDM1N> DOI: 10.1016/j.ijantimicag.2018.02.018 *
SVENSSON LATUNEK A, DRUG METABOLISM REVIEWS, vol. 19, no. 2, 1988, pages 165 - 194
TITZ, A.RADIC, Z.SCHWARDT, O.ERNST, B.: "A safe and convenient method for the preparation of triflyl azide, and its use in diazo transfer reactions to primary amines", TETRAHEDRON LETT, vol. 47, 2006, pages 2383 - 2385, XP025003844, DOI: 10.1016/j.tetlet.2006.01.157
URGIN, M: "Pharmacomodulation of the Antimalarial Plasmodione: Synthesis of Biaryl- and N-Arylalkylamine Analogues, Antimalarial Activities and Physicochemical Properties. ", MOLECULES, vol. 22, 2017, pages 161
WANG, G ET AL.: "APD3: the antimicrobial peptide database as a tool for research and education", NUCLEIC ACIDS RESEARCH, vol. 44, no. 1, 2016, pages 1087 - 1093
YANG, Z ET AL.: "Design and synthesis of (aza)indolyl maleimide-based covalent inhibitors of glycogen synthase kinase 3β", ORG BIOMOL CHEM, vol. 16, 2018, pages 4127 - 4140, XP055836237, DOI: 10.1039/C8OB00642C

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