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WO2022220725A1 - Inhibiteurs de lpxh en tant qu'agents anti-infectieux - Google Patents

Inhibiteurs de lpxh en tant qu'agents anti-infectieux Download PDF

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Publication number
WO2022220725A1
WO2022220725A1 PCT/SE2022/050360 SE2022050360W WO2022220725A1 WO 2022220725 A1 WO2022220725 A1 WO 2022220725A1 SE 2022050360 W SE2022050360 W SE 2022050360W WO 2022220725 A1 WO2022220725 A1 WO 2022220725A1
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Prior art keywords
piperazin
phenyl
dichlorophenyl
mmol
sulfonyl
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PCT/SE2022/050360
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Inventor
Edouard Zamaratski
Dmitry Antonov
Vivekananda R. KONDA
Stefan LINDSTRÖM
Gustav OLANDERS
Anders KARLÉN
T. Alwyn JONES
Sherry L. MOWBRAY
Diarmaid HUGHES
Peter Brandt
Einars Loza
Olga BOBILEVA
Martins Ikaunieks
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D211/00—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings
    • C07D211/92—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with a hetero atom directly attached to the ring nitrogen atom
    • C07D211/96—Sulfur atom
    • 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
    • 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
    • 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
    • C07D403/04—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 directly linked by a ring-member-to-ring-member bond
    • 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
    • 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
    • C07D403/14—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 three or more hetero rings

Definitions

  • the present invention relates to compounds suitable for use as anti-infectives, particularly as antibiotics, as well as the use of such compounds in therapeutic applications.
  • Antibiotics are an essential pillar of modern medicine.
  • MDR multidrug resistant
  • pan-drug resistant bacterial pathogens are becoming increasingly frequent and threaten to undermine the effectiveness of antibiotic therapy.
  • WHO World Health Organization
  • researchers most notably the World Health Organization (WHO) have issued lists prioritizing pathogens for which there is an urgent need to discover and develop new antibiotics.
  • WHO World Health Organization
  • carbapenem-resistant Gram-negative bacterial species the Enterobacteriaceae, Pseudomonas aeruginosa and Acinetobacter baumannii.
  • the object of the invention is thus to provide compounds useful for the treatment or prevention of infection, particularly bacterial infection.
  • a further object is to provide a method of treating such an infection.
  • the compounds have a formula Ilia:
  • X 1 is N or CH.
  • X 2 is selected from the group consisting of CH, N, and N(O)
  • Y is selected from the group consisting of C 3 -C 10 alkyl optionally substituted with 1, 2 or 3 substituents each independently selected from F, Cl, CFs and OH,
  • C 3 -C 8 cycloalkyl optionally substituted with 1, 2 or 3 substituents each independently selected from F, Cl, CH 3 , CF 3 , OH and CN,
  • 6-membered heteroaryl comprising carbon atoms and 1, 2 or three N-atoms and being optionally substituted with one or more R 7 groups.
  • X 2 is C
  • Y is selected from the group consisting of C 3 -C 10 alkylidene optionally substituted with 1, 2 or 3 substituents each independently selected from F, Cl, CF3 and OH, and
  • C 3 -C 8 cycloalkylidene optionally substituted with 1, 2 or 3 substituents each independently selected from F, Cl, CH 3 , CF 3 , OH and CN.
  • E is CH, C-OMe or N.
  • Each instance of Z 2 is independently selected from CH, CF and N.
  • Each R 1 group is independently selected from H, C 1-6 alkyl and C3-6 cycloalkyl.
  • Each R 2 group is independently selected from NR 1 S0 2 R 8 , S0 2 NR 9 R 10 and monocyclic unsaturated heterocyclyl optionally substituted with one or more R 7 groups
  • Ci_ 6 alkyl is optionally substituted with one or more groups independently selected from azetidine, trimethylammonium, C 3-4 cycloalkyl, OH, oxo, NH2, NHMe, and N(Me)2, wherein C 3-4 cycloalkyl is optionally substituted with NH2,
  • R 15 and R 16 are each independently selected from H, and C 1-6 alkyl optionally substituted with OH, NH2, NHMe, and N(Me)2,
  • W is C 1-6 alkoxy optionally substituted with one or more groups independently selected from OH, oxo, and NH2,
  • CH 2 NH-C(0)NH-C 1-6 alkyl optionally substituted with one or more groups independently selected from OH, oxo, and NH2,
  • X s is O or NH
  • X 6 is OH, NH2, NHMe or NMe 2 .
  • Each R 5 group is independently selected from H, F, C 1-6 alkyl, C 3-6 cycloalkyl and OR 1 .
  • Each R 8 group is independently selected from OH, and C 1-6 alkyl optionally substituted with one or two groups selected from OH, NH2, CO2R 1 and NH-C(NH)-NH2.
  • m is from 1 to 6.
  • n is 0, 1 or 2.
  • Compounds, or salts thereof, as defined by Formula Ilia may be used in the treatment or prevention of infection, especially bacterial infection.
  • Lipid A is the membrane-anchoring moiety of lipopolysaccharides (LPS), and a major component of the outer membrane of Gram-negative bacteria.
  • LPS lipopolysaccharides
  • Gram-negative bacteria need to produce Lipid A.
  • the Lipid A synthesis pathway is a potential target for antibacterial agents.
  • the enzyme LpxH hydrolyzes the pyrophosphate bond of UDP-2,3- diacylglucosamine to yield 2,3-diacylglucosamine 1-phosphate (Lipid X) and UMP, by catalyzing the attack of water at the alpha-P atom.
  • Approximately 70% of Gram-negative bacteria utilize LpxH, and the enzyme is, for example, essential for E. coli growth.
  • believing choir may be a single bond
  • Y may be phenyl optionally substituted with one or more R 7 groups
  • one Z 2 may be CH and the other may independently be N or CH. That is to say that in such embodiments, the central ring moiety may
  • the compounds may have a formula IVa:
  • Y may be C 3 -C 8 cycloalkyl optionally substituted with 1, 2 or 3 substituents each independently selected from F, Cl, CF 3 and OH.
  • Y may be C 3 -C 10 alkyl optionally substituted with 1, 2 or 3 substituents each independently selected from F, Cl, CF 3 and OH.
  • the compounds of formula Ilia may have a formula III wherein each instance of Z 1 is independently selected from CR 14 and N; each R 7 group is independently selected from H, F, Cl, CF3, CHF2, oxo, C 1-6 alkyl, C3-6 cycloalkyl, OR 1 , CO2R 1 , Ci-6alkyl-C02R 1 , cyano, NH2, Ci-6 alkyl-NH2, C3-6cycloalkyl-Ci-6 alkyl-NH 2 , O-Ci-6 alkyl-OR 1 , 0-C 1-6 alkyl-NH 2 , and CoC-CH2-NH2, and at least one instance of R 7 is a substituent other than H; each R 14 is independently selected from the group consisting of H, Me and F; or may be a pharmaceutically acceptable salt thereof.
  • the compounds of formula I la may have a formula IV
  • each R 7 group is independently selected from H, F, Cl, CF3, CHF2, oxo, C 1-6 alkyl, C3-6 cycloalkyl, OR 1 , CO2R 1 , Ci-6alkyl-C02R 1 , cyano, NH2, Ci-6 alkyl-NH 2 , C3-6cycloalkyl-Ci-6 alkyl-NH2, O-Ci-6 alkyl-OR 1 , 0-C 1-6 alkyl-NH 2 , and CoC-CH2-NH2, and at least one instance of R 7 is a substituent other than H; each instance of Z 1 is independently selected from CR 14 and N; each R 14 is independently selected from the group consisting of H, Me and F; or may be a pharmaceutically acceptable salt thereof.
  • R 2 may be NR 1 S0 2 R 8 and R 3 may not be H.
  • R 2 may be selected from 3H-l,2,3,5-oxathiadiazole 2-oxide-4-yl, imidazolyl, 4H-l,2,4-triazol-3-yl, and lH-l,2,3-triazol-5-yl, wherein R 2 is optionally substituted with an NH2 group, R 3 may be H, and Z 1 and Z 2 may be CH.
  • R 2 may be SO2NHR 10
  • R 3 may be H
  • Z 1 and Z 2 may be CH.
  • the compounds of formula Ilia may have a formula V wherein each R 7 group is independently selected from H, F, Cl, CF3, CHF2, oxo, C 1-6 alkyl, C3-6 cycloalkyl, OR 1 , CO2R 1 , Ci-6alkyl-C02R 1 , cyano, NH2, Ci-6 alkyl-NH2, C3-6cycloalkyl-Ci-6 alkyl-NH 2 , O-Ci-6 alkyl-OR 1 , 0-C 1-6 alkyl-NH 2 , and CoC-CH2-NH2, and at least one instance of R 7 is a substituent other than H; each instance of Z 1 is independently selected from CR 14 and N; and each R 14 is independently selected from the group consisting of H, Me and F; or may be a pharmaceutically acceptable salt thereof.
  • the compounds as disclosed herein may be used in a method of treatment of the human or animal body by therapy.
  • the therapy may be treatment or prevention of an infection.
  • the infection may be a bacterial, fungal, or parasitic infection.
  • the bacterial infection may be caused or complicated by bacteria of a genus that expresses LpxH protein selected from the group including:
  • Acinetobacter Bordetella, Campylobacter, Chlamydia, Citrobacter, Coxiella, Enterobacter, Escherichia, Haemophilus, Helicobacter, Klebsiella, Kluyvera, Legionella, Moraxella, Morganella, Neisseria, Photorhabdus, Proteus, Providencia, Pseudomonas, Ralstonia, Salmonella, Serratia, Shigella, Stenotrophomonas, Vibrio, Yersinia.
  • the bacterial infection may be caused or complicated by a bacterial species that expresses LpxH protein selected from the group including:
  • Acinetobacter baumannii Acinetobacter Iwojfi, Bordetella petrussiis, Campylobacter jejuni, Campylobacter pylori, Campylobacter upsaliensis, Campylobacter coli, Chlamydia trachomatis, Chlamydia pneumoniae, Chlamydia psittacosis, Citrobacter freundii, Citrobacter koseri,
  • the objects of the invention are attained by a method of treating an infection as defined in the appended independent claims.
  • the method comprises administering to a patient in need thereof a therapeutically effective amount of a compound as disclosed herein.
  • the infection may be a bacterial, fungal, or parasitic infection.
  • the bacterial infection may be caused or complicated by bacteria of a genus that expresses LpxH protein selected from the group including:
  • Acinetobacter Bordetella, Campylobacter, Chlamydia, Citrobacter, Coxiella, Enterobacter, Escherichia, Haemophilus, Helicobacter, Klebsiella, Kluyvera, Legionella, Moraxella, Morganella, Neisseria, Photorhabdus, Proteus, Providencia, Pseudomonas, Ralstonia, Salmonella, Serratia, Shigella, Stenotrophomonas, Vibrio, Yersinia.
  • the bacterial infection may be caused or complicated by a bacterial species that expresses LpxH protein selected from the group including:
  • Acinetobacter baumannii Acinetobacter Iwoffi, Bordetella petrussiis, Campylobacter jejuni, Campylobacter pylori, Campylobacter upsaliensis, Campylobacter coli, Chlamydia trachomatis, Chlamydia pneumoniae, Chlamydia psittacosis, Citrobacter freundii, Citrobacter koseri,
  • the objects of the invention are attained by use of a compound as disclosed herein, or a salt thereof, in inhibition of bacterial LpxH activity, or as a bactericide.
  • the objects of the invention are attained by a pharmaceutical composition comprising a compound as disclosed herein, or a pharmaceutically acceptable salt thereof, in association with a pharmaceutically acceptable excipient, adjuvant, diluent and/or carrier.
  • the compounds as disclosed herein may be used in the treatment or prevention of infection, especially bacterial infection. Without wishing to be bound by theory, it is thought that the antibacterial/antibiotic effect of the disclosed compounds is due to them acting as inhibitors of the enzyme LpxH in the Lipid A biosynthesis pathway.
  • Lipid A is the membrane-anchoring moiety of lipopolysaccharides (LPS), and a major component of the outer membrane of Gram-negative bacteria.
  • LPS lipopolysaccharides
  • Gram-negative bacteria need to produce Lipid A.
  • the Lipid A biosynthesis pathway is a potential target for antibacterial agents.
  • the enzyme LpxH hydrolyzes the pyrophosphate bond of UDP-2,3-diacylglucosamine to yield 2,3- diacylglucosamine 1-phosphate (Lipid X) and UMP, by catalyzing the attack of water at the alpha-P atom.
  • Approximately 70% of Gram-negative bacteria utilize LpxH, and the enzyme is, for example, essential for E. coli growth.
  • alkyl means a linear, branched, saturated hydrocarbon radical possessing the defined number of carbon atoms.
  • alkyl encompasses all isomers including primary, secondary, iso and tertiary groups. If not otherwise specified, the alkyl moiety may possess from 1 to 6 carbon atoms. Examples of alkyl moieties include, but are not limited to, methyl, ethyl, n-propyl, iso-propyl, n-butyl, sec-butyl, tert-butyl, n-pentyl, iso-pentyl, sec-pentyl, n- hexyl, etc.
  • alkoxy is defined as an -OR radical, where R is an alkyl moiety as defined above.
  • C 1-6 alkyl-NH 2 means a C 1-6 alkyl radical which is substituted with NH 2
  • C 1-6 alkyl-OH means a C 1-6 alkyl radical which is substituted with OH.
  • the substituent can be at any position of the alkyl moiety.
  • Me means methyl
  • cycloalkyl means a cyclic alkyl radical possessing the defined number of carbon atoms.
  • C 3 cycloalkyl means cyclopropyl
  • C4 cycloalkyl means cyclobutyl C 5 cycloalkyl cyclopentyl, etc.
  • heteroaryl means an aromatic monovalent radical comprising 1, 2, 3 or 4 heteroatoms each independently selected from N, O and S.
  • the heteroaryl may be monocyclic, in which case it may be a single 5- or 6-membered ring, or it may be bicyclic, in which case two aromatic rings are fused.
  • a bicyclic heteroaryl group may comprise two heteroaryl rings fused together, or may comprise a heteroaryl ring fused to a homoaryl ring, such as a benzo-fused heteroaryl ring.
  • heteroaryl moieties include, but are not limited to, pyrrolyl, thienyl, thiazolyl, imidazolyl, furanyl, indolyl, isoindolyl, oxazolyl, isoxazolyl, benzothiazolyl, benzoxazolyl, quinolinyl, isoquinolinyl, pyridinyl, pyrimidinyl, pyrazinyl, pyridazinyl, triazolyl, tetrazolyl, etc.
  • heterocyclyl means a partially or fully saturated monovalent ring possessing the defined number of ring atoms.
  • the heterocyclyl moiety may comprise 1, 2, 3 or 4 heteroatoms each independently selected from N, O and S. If not otherwise specified, the heterocyclyl moiety may be 3-, 4-, 5-, 6- or 7-membered.
  • the heterocycyl group may be fused to a further ring to form a system termed a bicyclic heterocyclyl moiety, regardless of whether the further ring is saturated or unsaturated, heterocyclic or carbocyclic.
  • oxo means a double bonded oxygen, i.e. forming a keto, aldehyde, carboxylic acid, ester or amide function when bound to a carbon atom, and a sulfoxide or sulfone when one or two such groups respectively are bound to a sulfur atom.
  • substituted refers to, wherein in a molecule or part of a molecule, at least one hydrogen atom is replaced with a substituent.
  • alkyl group optionally substituted with one or more substituents means that the alkyl group is substituted by zero, one or more substituents.
  • radical position(s) on any molecular moiety may be anywhere on such a moiety as long as it is chemically permitted and stable.
  • pharmaceutically acceptable salt means a salt that possesses the desired pharmacological activity of the parent compound, and where the compound forming the salt with the parent compound is non-toxic.
  • Such salts include the acid addition salts to a basic moiety in the parent compound, e.g. hydrochloride, hydrobromide, formate and acetate salts, or the alkali or alkali earth salts of acidic moieties of the parent compound, e.g. sodium, potassium, magnesium and calcium salts. Additional information regarding pharmaceutically acceptable salts can be found in Remington: The Science and Practice of Pharmacy, 23 rd ed., Academic Press, 2020.
  • treating or “method of treatment” it is meant preventing, inhibiting, alleviating or curing a disease.
  • a therapeutically effective amount it is meant an amount that when administered to a human or animal is sufficient to provide the therapeutic effect.
  • reaction mixture was stirred at RT until completion of the reaction (usually 2 h), diluted with EtOAc (30 ml), washed successively with saturated NaHCC>3 solution, water, brine, and dried (Na 2 S0 4 ). The solvent was evaporated and the residue was purified by appropriate method to give desired amide.
  • reaction mixture was diluted with EtOAc (30 ml), washed successively with 0.1N aqueous solution of HCI, saturated NaHC0 3 solution, water, brine, dried (Na 2 S0 4 ) and evaporated. The residue was purified by appropriate method to give desired amide.
  • Reagents and conditions a) MeS0 2 CI, TEA, DCM, 0 °C, 3h; b) Mel, CS 2 CO 3 , DMF, RT, 16h; c) NaOH, THF/MeOH, reflux, 16h.
  • Reagents and conditions a) cat. Pd(OAc)2/BINAP, tBuONa, 110 °C, 16h; b) TFA, DCM, RT; c) 4- nitrobenzenesulfonyl chloride, DCM, RT; d) Zn, AcOH, MeOH, 60 °C, 4h.
  • Reagents and conditions cat. Pd2(dba)3/ RuPhos, 2 eq CS2CO3, 1,4-dioxane, 90 °C, 3h.
  • Reagents and conditions EtOH/FhO, 80 °C, 48 h.
  • Reagents and conditions a) DIPEA, DCM, RT, 18 h; b) H , Pd/C, MeOH/EtOAc, RT; c) Method A; d) TFA, DCM, RT.
  • Reagents and conditions cat. Pd(OAc) 2 , Xantphos, K3PO4, CO(gas).
  • a flame-dried septum-sealed flask containing N-[4-[4-(3,5-dichlorophenyl)piperazin-l- yl]sulfonyl- phenyl]-5-iodo-2-[methyl(methylsulfonyl)amino]benzamide (INTERMEDIATE 4, 79 mg, 0.109 mmol), Pd(OAc)2 (1.23 mg, 0.00546 mmol), Xantphos (6.32 mg, 0.0109 mmol), K3PO4 (93 mg, 0.437 mmol) was evacuated and backfilled with CO(gas).
  • Reagents and conditions 1. SOCI2, DCM, reflux, 3.0 h 2. DIPEA, DCM, RT, 24 h.
  • N-(4-((4-(3,5-dichlorophenyl)piperazin-l-yl)sulfonyl)phenyl)-5-formyl-2-(N-methylmethyl- sulfonamido)benzamide (22 mg) was dissolved in methanol/THF (total volume about 2 ml), 1,3- diaminopropan-2-ol (7 mg, 2 eq) was added and stirred overnight at r.t., then sodium borohydride (5 mg, 3 eq) was added. Reaction mixture was stirred for about 24h at r.t., concentrated by rotary evaporation, mixed with water and extracted in ethyl acetate. Dried organic extracts were concentrated and purified by prep HPLC (flowrate 10 ml/min; 15 min gradient of acetonitrile/water with 0,05% of formic acid) to give about 12 mg of desired product as white fluffy powder after freeze drying.
  • Triphenylphosphine (218 mg) was dissolved in about 3 ml of toluene in 8 ml vial and iodine powder (211 mg) was added to the reaction mixture and stirred at r.t. for approx 30 min (yellow precipitate formed with some residual iodine on the bottom).
  • N-(4-((4-(3,5- dichlorophenyl)piperazin-l-yl)sulfonyl)phenyl)-5-iodo-2-(N- methylmethylsulfonamido)benzamide (INTERMEDIATE 4, 300 mg) and palladium (II) acetate (7 mg) was added to the reaction mixture followed with triethylamine (1,2 ml).
  • Reaction mixture was closed with the seal and formic acid (0,2 ml) was added in one portion via syringe (gas evolution starts during the addition). Reaction mixture was heated in a closed vial at 80°C for about lh (full conversion according to LC-MS: two main product peaks corresponds to carboxylated product M + 641; 25-40% by UV and formylated product M + 625; 75-60% by UV). Reaction mixture was filtered via Celite, concentrated and distributed between ethyl acetate and water. Organic extract was washed with water and brine, dried over magnesium sulphate and concentrated. Purified by short pad of neutral aluminium oxide (removal of acid M + 641).
  • Reagents and conditions a) Zn(CN)2 (0.6 equiv.), Pd(PPh 3 )4 (0.04 equiv.), DMF, 80 °C, 4 h. b) NaBH 4 , NiCI 2 , Boc 2 0, MeOH-THF (5:2), 0 °C, then RT, 2 h. c) DCM-TFA (4:1), RT, 6 h.
  • Et3N (0.08 ml, mmol) was added to a suspension of (2/?)-l-(3,5-dichlorophenyl)-2-methyl- piperazine dihydrochloride (66 mg, 0.208 mmol), the mixture was cooled to 0 °C and a solution of 4-[[2-[methyl(methylsulfonyl)amino]benzoyl]amino]benzenesulfonyl chloride (70 mg, 0.174 mmol) in DCM (2 ml) was slowly added dropwise.
  • reaction mixture was stirred at RT for 1.5 h, diluted with EtOAc (20 ml), washed with saturated NaHCC> 3 solution, water, brine, dried (Na 2 S0 4 ), and concentrated.
  • the residue was purified by column chromatography on silica gel (eluent 30-100% EtOAc in hexanes) to give white foam which was crystallized from a mixture of CHCI 3 and n-heptane. After drying in vacuo, desired compound was obtained as a white solid. Yield: 75 mg, 71%.
  • Oxalyl chloride (0.98 ml, 11.6 mmol) was added dropwise to a suspension of 2- [methyl(methylsulfonyl)amino]benzoic acid (1060 mg, 4.64 mmol) in DCM (5ml) followed by a small drop of DMF. The solution was stirred at RT for 1 h and the volatiles were evaporated in vacuo. The residue was redissolved in DCM (2 mL) and added dropwise to a solution of aniline (360 mg, 3.87 mmol) and DIPEA (1250 mg, 9.66 mmol) in DCM (5 mL) at ice bath temperature.
  • Reagents and conditions a) DIPEA, DCM, RT, 1 h b) Mel, CS2CO3, DMF, RT, 1,5 h c) TFA, DCM,
  • Reaction mixture was deluted with water and extracted into ethylacetate (4x25 ml), washed with brine and dried over magnesium sulfate. Concentration (followed by coevaporation with DCM and drying for about lh in high vacuum) gave 305 mg of desired product as yellowish powder.
  • N-(4-((4-(3,5-dichlorophenyl)piperazin-l-yl)sulfonyl)phenyl)-2-((2-(l,3-dioxoisoindolin-2-yl)-N- methylethyl)sulfonamido)benzamide (240 mg) was dissolved in ethanol and THF and hydrazine hydrate (50% solution in ethanol, 0.2 ml) was added to the reaction mixture and stirred at r.t. for about 30 min (LC-MS: full conversion). Reaction mixture was concentrated by rotary evaporation to dryness and kept overnight under high vacuum (LC-MS shows almost full hydrolysis).
  • Reagents and conditions a) DIPEA, DCM, RT, 20 h b) Mel, CS2CO3, DMF, RT, 20 h c) TFA, DCM, RT, 20 h d) Method C e) LiCI, DMF, MW heating 160°C, 30 min.
  • Product was synthesized according to Method C from 2-((3-methoxy-N-methyl-3- oxopropyl)sulfonamido)benzoic acid (90 mg) and 4-((4-(3,5-dichlorophenyl)piperazin-l- yl)sulfonyl)aniline (110 mg) to give 154 mg of desired product as white powder.
  • Reagents and conditions a) MeCN, 60°C, 12 h b) SOCl 2 , reflux c) Me 3 AI, toluene, RT, 12 h d) AD- mix-beta, water/tert-butanol, 0 °C, 48 h.
  • AD-Mix-Beta 120 mg were dissolved in water (0.5 ml) and tert-butanol (0.5 ml) at 0°C.
  • 2-(N- (but-3-en-l-yl)sulfamoyl)-N-(4-((4-(3,5-dichlorophenyl)piperazin-l- yl)sulfonyl)phenyl)benzamide 40 mg, 0.06 mmol
  • N-[4-[4-(3,5-Dichlorophenyl)piperazin-l-yl]sulfonylphenyl]-3-iodo-pyridine-4-carboxamide Prepared according to Method C from 3-iodopyridine-4-carboxylic acid (100 mg) and 4-[4-(3,5- dichlorophenyl)piperazin-l-yl]sulfonyl aniline. Purified by column chromatography (30% EtOAc in hexanes) to provide the product and a foam). Yield: 150 mg (60%).
  • N-[4-([4-[3-(3-Aminoprop-l-yn-l-yl)-5-fluorophenyl]piperazin-l-yl]sulfonyl)phenyl]-2-(N- methylmethanesulfonamido)benzamide has been sunthesized from lOOmg of Intermediate 3 by General Method D utilizing 2-(3-(3-bromo-5-fluorophenyl)prop-2-yn-l-yl)isoindoline-l,3- dione followed by standard hydrazine deprotection yielding llmg of title compound.
  • N-[4-([4-[3-Chloro-5-(trifluoromethyl)phenyl]piperazin-l-yl]sulfonyl)phenyl]-2-(N- methylmethane-sulfonamido)benzamide was prepared using general method D from 48mg of 2-(N-methylmethyl-sulfonamido)-N-(4-(piperazin-l-ylsulfonyl)phenyl)benzamide and 97 mI of 1- bromo-3-chloro-5-(trifluoromethyl)benzene. Yield 12mg.
  • N-[4-([4-[3-Cyano-5-(trifluoromethyl)phenyl]piperazin-l-yl]sulfonyl)phenyl]-2-(N- methylmethane-sulfonamido)benzamide was prepared using general method D from 49 mg of
  • N-[4-([4-[3-(3-Aminoprop-l-yn-l-yl)phenyl]piperazin-l-yl]sulfonyl)phenyl]-2-(N-methyl- methanesulfonamido)benzamide was prepared by general method D using 90 mg of 2-(N- methylmethylsulfonamido)-N-(4-(piperazin-l-ylsulfonyl)phenyl)benzamide and 270 mg of 2-[3- (3-bromophenyl)prop-2-ynyl]isoindoline-l,3-dione followed by standard hydrazine deprotection. Yield 29 mg.
  • N-(4-[[4-(3-Ethylphenyl)piperazin-l-yl]sulfonyl]phenyl)-2-(N-methylmethanesulfonamido)- benzamide was prepared using general method D from 53 mg of 2-(N-methylmethylsulfon- amido)-N-(4-(piperazin-l-ylsulfonyl)phenyl)benzamide and 96 mI of l-bromo-3-ethyl-benzene. Yield 48 mg.
  • N-(4-[[4-(4-Cyanophenyl)piperazin-l-yl]sulfonyl]phenyl)-2-(N-methylmethanesulfonamido)- benzamide was prepared using general method D from 50 mg of 2-(N- methylmethylsulfonamido)-N-(4-(piperazin-l-ylsulfonyl)phenyl)benzamide and 160 mg of 4- bromobenzonitrile. Yield 45 mg.
  • N-(4-[[4-(3-Cyanophenyl)piperazin-l-yl]sulfonyl]phenyl)-2-(N-methylmethanesulfonamido)- benzamide was prepared using general method D from 30 mg of 2-(N- methylmethylsulfonamido)-N-(4-(piperazin-l-ylsulfonyl)phenyl)benzamide and 97 mg of 3- bromobenzonitrile. Yield 11 mg.
  • Reagents and conditions a) l-fluoro-4-nitro-benzene, K 2 CO 3 DMAc, 80 °C, 5 h. b) Zn/AcOH, MeOH, 80 °C, 1 h.
  • Acetyl chloride (0.6 ml) was added to dry methanol (5 ml) and stirred for about 20 min to form HCI solution in methanol. Solution obtained was added to N-[4-([4-[3- (ethoxymethoxy)phenyl]piperazin-l-yl]sulfonyl)phenyl]-2-(N-methylmethanesulfonamido) benzamide (20 mg) and stirred for about lh.
  • Reaction mixture was concentrated by rotary evaporation, kept in high vacuum for about lh and then dissolved in water/acetonitrile and purified by prep HPLC (flow rate 10 ml/min; gradient 25-95% acetonitrile/water with 0.05% of formic acid, collection at 272 nm). Obtained 24 mg of desired product as white powder by concentration of correct fractions by rotary evaporation, dried in high vacuum over phosphorus pentoxide overnight.
  • EOM was removed from from from N-(4-((4-(4-(ethoxymethoxy)phenyl)piperazin-l- yl)sulfonyl)phenyl)-2-(N-methylmethylsulfonamido)benzamide (17 mg) by HCI in MeOH, generated from acetyl chloride to give 10 mg of pure material as fluffy white powder after freeze drying.
  • Desired product (16 mg) was obtained as fluffy white powder after lyophilisation.
  • Reaction mixture was concentrated by rotary evaporation, re-dissolved in acetonitrile/water and purified by prep HPLC (flowrate 10 ml/min, 10 min, acetonitrile/water with 0,05% of formic acid). Pure fractions were combined, concentrated and freeze dried to give about 15 mg of desired material as white fluffy powder.
  • N-(4-((4-(3,5-Dichlorophenyl)piperazin-l-yl)sulfonyl)phenyl)-5-(((2-((2-hydroxyethyl)amino)- ethyl)amino)methyl)-2-(N-methylmethylsulfonamido)benzamide Prepared according to Method H from N-(4-((4-(3,5-dichlorophenyl)piperazin-l- yl)sulfonyl)phenyl)-5-formyl-2-(N-methylmethylsulfonamido)- benzamide (40 mg), N,N"- bis(tert-butyloxycarbonyl)di-ethylenetriamine (10 mg) and sodium cyanoborohydride (17 mg) as reducing agent to pure product (15 mg) as fluffy white powder after freeze drying.
  • Reagents and conditions a) KOCN, 1M HCI, MeCN, 60 °C 4 h, then RT 16 h. b) tert-Butyl N-(2- aminoethyl)carbamate hydrochloride, CDI, DIPEA, MeCN, RT, 18 h. c) TFA-DCM 1:15, RT, 2 h.
  • Reagents and conditions a) Goodman's reagent, DIPEA, DCM, RT, 18 h. b) DCM-TFA 15:2, RT, 16 h.
  • the reaction mixture was stirred at RT for 48 h. According to LC/MS analysis, the Fmoc protection of the amine group was removed as well. The mixture was diluted with DCM, washed with water, brine, dried (Na 2 S0 4 ), and concentrated in vacuo. The residue was purified by column chromatoraphy on silica gel (eluent 8% MeOH in DCM, containing 1% of Et 3 N) to give compound as a white foam. Yield: 72 mg, 76%.
  • Reagents and conditions a) tert-Butyl prop-2-enoate, cat. Pd(Oac)2, Et3N, MeCN, 55-70 °C, 3 h. b) H 2 , Pt0 2 , RT, 2 h. c) DCM, TFA (10:1), RT, 2 h.
  • Reagents and conditions a) DCM or DMF, diisopropylethyl amine; b) Fe/HOAc/MeOH c) Method A. l-(3,5-Dichlorophenyl)-4-((3-methoxy-4-nitrophenyl)sulfonyl)piperazine A mixture of 3-methoxy-4-nitrobenzenesulfonyl chloride (150 mg), l-(3,5- dichlorophenyl)piperazine (150 mg), diisopropylethylamine of dry DCM was stirred at room temperature overnight. The mixture was then quenched with water. The organic phase was washed with sat.
  • Reagents and conditions a) 1.3 M iPrMgCI x LiCI in THF, l,3-dichloro-5-bromo-benzene, -55 °C lh, then RT 15 h. b) HCI, dioxane, RT, 16 h. c) 4-nitrobenzenesulfonyl chloride, TEA, DCM, RT, 2 h. d) SnCl 2 , MeOH-THF (6:1), reflux, 3 h. e) 2-[methyl(methylsulfonyl)amino]benzoic acid, (COOCI)2, cat.
  • Oxalyl chloride (0.107 ml, 1.24 mmol) was added dropwise to a suspension of 2- [methyl(methyl-sulfonyl)amino]benzoic acid (105 mg, 0.458 mmol) in DCM (2 ml) followed by a small drop of DMF. The solution was stirred at RT for 1 h and the volatiles were evaporated in vacuo.
  • KHSO 5 MeOH-water (2:1), 30 °c, 21 H.
  • HCI dioxane, RT, 16 h.
  • Oxalyl chloride (0.08 ml, 0.906 mmol) was added dropwise to a suspension of 2- [methyl(methyl-sulfonyl)amino]benzoic acid (90 mg, 0.393 mmol) in DCM (5 ml) followed by a small drop of DMF. The reaction mixture was stirred at RT for 1 h and the volatiles were evaporated in vacuo.
  • Reagents and conditions a) t-butyl 4-aminopiperidine-l-carboxylate, TEA, DCM, RT, 3.0 h and TFA, RT, 3.0 h. b) benzyl 4-chlorosulfonylpiperidine-l-carboxylate, TEA, DCM, RT, 12.0 h. c) Pd/C, Methanol, 6.0 h; RT. D) Pd2(dba) 3 / RuPhos, C£ 2 C0 3 , 1,4-dioxane, 90 °C, 3.0 h.
  • Reagents and conditions a) TEA, DCM, RT, 3.0 h. b) Ammonium acetate, NaBH 3 CN, Methanol, RT, 3.0 h. c) 2-(N-methylmethylsulfonamido)benzoic acid, SOCl 2 , DCM, Reflux, 3 h; TEA, RT, 18 h.

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Abstract

La présente invention concerne des composés de formule (IIIa), qui sont appropriés pour une utilisation en tant qu'agents anti-infectieux, en particulier en tant qu'antibiotiques. X1 représente N ou CH. …. est une liaison simple ou double. Lorsque .... représente une liaison simple, alors X2 est choisi dans le groupe constitué par CH, N et N(O), et Y est choisi dans le groupe constitué par les groupes alkyle C3-C10 éventuellement substitués, cycloalkyle C3-C8 éventuellement substitués, phényle éventuellement substitué et hétéroaryle à 6 chaînons éventuellement substitué. Lorsque .... représente une liaison double, alors X2 représente C, et Y est choisi dans le groupe constitué par C3-C10 alkylidène éventuellement substitué, et C3-C8 cycloalkylidène éventuellement substitué. E représente CH, C-OMe ou N. Chaque instance de Z2 est indépendamment choisie parmi CH, CF et N. L'invention concerne en outre l'utilisation de ces composés dans des applications thérapeutiques, ainsi que des compositions pharmaceutiques comprenant ces composés.
PCT/SE2022/050360 2021-04-16 2022-04-11 Inhibiteurs de lpxh en tant qu'agents anti-infectieux Ceased WO2022220725A1 (fr)

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Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2025085848A1 (fr) * 2023-10-20 2025-04-24 Arrepath, Inc. Composés antibactériens
WO2025231269A1 (fr) * 2024-05-02 2025-11-06 Arrepath, Inc. Composés antibactériens

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WO2003055876A1 (fr) 2001-12-21 2003-07-10 Anormed Inc. Composes heterocycliques a efficacite accrue se fixant sur les recepteurs de la chimiokine
EP2771324A1 (fr) * 2011-10-24 2014-09-03 Emory University Thérapeutique des myxovirus, composés et utilisations s'y rapportant

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Publication number Priority date Publication date Assignee Title
WO2003055876A1 (fr) 2001-12-21 2003-07-10 Anormed Inc. Composes heterocycliques a efficacite accrue se fixant sur les recepteurs de la chimiokine
EP2771324A1 (fr) * 2011-10-24 2014-09-03 Emory University Thérapeutique des myxovirus, composés et utilisations s'y rapportant

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AIMING SUN ET AL: "Potent Non-Nucleoside Inhibitors of the Measles Virus RNA-Dependent RNA Polymerase Complex", JOURNAL OF MEDICINAL CHEMISTRY, vol. 51, no. 13, 1 July 2008 (2008-07-01), pages 3731 - 3741, XP055016282, ISSN: 0022-2623, DOI: 10.1021/jm701239a *
KWAK SEUNG-HWA ET AL: "Synthesis and evaluation of sulfonyl piperazine LpxH inhibitors", BIOORGANIC CHEMISTRY, vol. 102, 1 September 2020 (2020-09-01), US, pages 104055, XP055939708, ISSN: 0045-2068, DOI: 10.1016/j.bioorg.2020.104055 *
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WEI ZHI-LIANG ET AL: "Identification of orally-bioavailable antagonists of the TRPV4 ion-channel", BIOORGANIC & MEDICINAL CHEMISTRY LETTERS, vol. 25, no. 18, 1 September 2015 (2015-09-01), AMSTERDAM, NL, pages 4011 - 4015, XP055939571, ISSN: 0960-894X, DOI: 10.1016/j.bmcl.2015.06.098 *

Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2025085848A1 (fr) * 2023-10-20 2025-04-24 Arrepath, Inc. Composés antibactériens
WO2025231269A1 (fr) * 2024-05-02 2025-11-06 Arrepath, Inc. Composés antibactériens

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