Classifications

• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
  • C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
  • C07D471/08—Bridged systems
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
  • C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
  • C07D471/10—Spiro-condensed systems
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K31/00—Medicinal preparations containing organic active ingredients
  • A61K31/33—Heterocyclic compounds
  • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
  • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
  • A61K31/425—Thiazoles
  • A61K31/429—Thiazoles condensed with heterocyclic ring systems
  • A61K31/43—Compounds containing 4-thia-1-azabicyclo [3.2.0] heptane ring systems, i.e. compounds containing a ring system of the formula, e.g. penicillins, penems
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K31/00—Medicinal preparations containing organic active ingredients
  • A61K31/33—Heterocyclic compounds
  • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
  • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
  • A61K31/439—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom the ring forming part of a bridged ring system, e.g. quinuclidine
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K31/00—Medicinal preparations containing organic active ingredients
  • A61K31/33—Heterocyclic compounds
  • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
  • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
  • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
  • A61K31/4427—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems
  • A61K31/444—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems containing a six-membered ring with nitrogen as a ring heteroatom, e.g. amrinone
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K31/00—Medicinal preparations containing organic active ingredients
  • A61K31/33—Heterocyclic compounds
  • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
  • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
  • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
  • A61K31/445—Non condensed piperidines, e.g. piperocaine
  • A61K31/4523—Non condensed piperidines, e.g. piperocaine containing further heterocyclic ring systems
  • A61K31/4545—Non condensed piperidines, e.g. piperocaine containing further heterocyclic ring systems containing a six-membered ring with nitrogen as a ring hetero atom, e.g. pipamperone, anabasine
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K31/00—Medicinal preparations containing organic active ingredients
  • A61K31/33—Heterocyclic compounds
  • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
  • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
  • A61K31/46—8-Azabicyclo [3.2.1] octane; Derivatives thereof, e.g. atropine, cocaine
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K31/00—Medicinal preparations containing organic active ingredients
  • A61K31/33—Heterocyclic compounds
  • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
  • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
  • A61K31/496—Non-condensed piperazines containing further heterocyclic rings, e.g. rifampin, thiothixene or sparfloxacin
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K31/00—Medicinal preparations containing organic active ingredients
  • A61K31/33—Heterocyclic compounds
  • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
  • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
  • A61K31/4995—Pyrazines or piperazines forming part of bridged ring systems
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
  • A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
• • 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
  • C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
  • C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
  • C07D487/08—Bridged systems

Definitions

• the present invention relates to a beta-lactamase inhibitor and a process for the preparation thereof.
• the invention further relates to a pharmaceutical composition comprising a beta-lactamase inhibitor and to the use thereof.
• Beta-lactam antibiotics are the first antibiotics cited in the clinic. Since the successful application of penicillin G as the first ⁇ -lactam antibiotic to the clinic, ⁇ -lactam antibiotics have developed rapidly. Different structure types of ⁇ -lactam antibiotics have been developed and applied in a large number of clinical applications, and have achieved good results. However, since bacterial cells can produce ⁇ -lactamase, the antibiotics are inactivated, causing the bacteria to develop resistance to ⁇ -lactam antibiotics.
• the ⁇ -lactamase is an enzyme that catalyzes the hydrolysis of the ⁇ -lactam ring, which inactivates the antibacterial activity of the ⁇ -lactam antibiotic and allows the bacteria to be resistant to the ⁇ -lactam antibiotic.
• the ⁇ -lactamase can be classified into A, B, C, and D depending on the amino acid sequence difference in the molecular structure.
• Class A ⁇ -lactamases preferably hydrolyze penicillin antibiotics
• Class B ⁇ -lactamases can hydrolyze various ⁇ -lactam antibiotics, including carbapenems
• Class C ⁇ -lactamases are more effective.
• Hydrolyzed cephalosporin antibiotics while D-type ⁇ -lactamases are more prone to hydrolyzing oxacillin and o-chloropenicillin.
• the resistance of bacteria, especially Gram-negative bacteria, to ⁇ -lactam antibiotics is usually mediated by ⁇ -lactamase.
• Inhibition of ⁇ -lactamase can delay or inhibit the degradation of ⁇ -lactam antibiotics and restore the sensitivity of bacteria producing ⁇ -lactam antibiotic resistance to ⁇ -lactam antibiotics.
• ⁇ -lactamase can inactivate the hydrolysis activity of ⁇ -lactam antibiotics, thereby enhancing the bacteria against ⁇ -lactam.
• the sensitivity of antibiotics reduces or overcomes the problem of drug resistance.
• bacteriostatic beta-lactamase inhibitors such as those disclosed in WO2013149121A1, WO2014141132A1, US20130296290A1, WO2013030735A1, WO2015110963A1, WO2015150890A1, WO2015159265A1, WO2015173663, WO2015173665A1, WO2017055922A1 [bicyclo[3.2.1] ] Octane compounds.
• beta-lactamase inhibitors available on the market, such as clavulanic acid, tazobactam, abivudan, Relebactam, and the like.
• the present invention provides a compound of the formula (I) or an ester thereof, a stereoisomer thereof, and a pharmaceutically acceptable salt thereof:
• W 1 is selected from the group consisting of an optionally substituted five- or six-membered heteroaryl ring containing O, N and/or S or -C(O)-; and, (i) when W 1 is selected from the group consisting of optionally substituted When a 5- or 6-membered heteroaryl ring of O, N and/or S is substituted, W 1 is optionally substituted by C 1 -C 12 alkyl,
• W 2 is selected from:
• R 1 is selected from Wherein R 2 , R 3 , R 4 , R 4 ', R 5 or R 6 are each independently selected from H, C 1 -C 12 alkyl, amino C 1 -C 12 alkyl, C 1 -C 12 alkylamine Base C 1 -C 12 alkyl, Ra and Rb are each independently selected from H, C 1 -C 12 alkyl, OH, -OC 1 -C 12 alkyl, -NH 2 , -NHC 1 -C 12 alkyl, -N(C 1 -C 12 Alkyl) 2 , -SH, -SC 1 -C 12 alkyl, -S(O)C 1 -C 12 alkyl, -S(O 2 )C 1 -C 12 alkyl, -SO 3 H;R 7 and R 7 ' are each independently selected from -NH 2 , -NHC 1 -C 12 alkyl, -N(C 1 -C 12 alkyl
• R 1 ' is selected from H, C 1 -C 12 alkyl, C 3 -C 8 cycloalkyl, OH, -OC 1 -C 12 alkyl, -NH 2 , -NHC 1 -C 12 alkyl, -N (C 1 -C 12 alkyl) 2 , -SH, -SC 1 -C 12 alkyl, -S(O)C 1 -C 12 alkyl, -S(O 2 )C 1 -C 12 alkyl, -SO 3 H;
• Z 2 is selected from CR 18 R 19 or NR 20 , and R 18 , R 19 and R 20 are each independently selected from H, NH 2 or
• R 21 is selected from the group consisting of -NH 2 , -NHC 1 -C 12 alkyl, -N(C 1 -C 12 alkyl) 2 , -O C 1 -C 12 alkyl, -S C 1 -C 12 alkyl;
• R 22 is selected from the group consisting of NH, -NHC 1 -C 12 alkyl, O, S;
• t, u and w are each independently selected from 1, 2, 3, 4, 5 or 6, provided that t and u are not 0 at the same time;
• W 1 when W 1 is selected from -C(O)-, W 2 is selected from -OR 26 , -NHR 27 , wherein R 26 and R 27 are each independently selected from H, C 1 -C 12 alkyl or Wherein Z 5 is selected from CR 28 R 29 or NR 30 , and R 28 , R 29 and R 30 are each independently selected from H, NH 2 or Wherein R 31 is selected from the group consisting of -NH 2 , -NHC 1 -C 12 alkyl, -N(C 1 -C 12 alkyl) 2 , -O C 1 -C 12 alkyl, -S C 1 -C 12 alkyl; R 32 is selected from the group consisting of NH, NC 1 -C 12 alkyl, O, S; x, y and z are each independently selected from 1, 2, 3, 4, 5 or 6, provided that x and y are not simultaneously 0;
• W 3 is selected from the group consisting of -SO 3 M, -OSO 3 M, -OSO 2 NH 2 , -OPO 3 M, -OCR 33 R 34 CO 2 M, -OCR 35 R 36 SO 3 M, -OCR 37 R 38 PO 3 M; wherein M is selected from H or a pharmaceutically acceptable cation; and R 33 , R 34 , R 35 , R 36 , R 37 and R 38 are each independently selected from H, C 1 -C 12 alkyl, halogen.
• the present invention provides a process for the preparation of a compound of the formula (I) or a pharmaceutically acceptable salt thereof.
• the present invention provides a pharmaceutical composition
• a pharmaceutical composition comprising a compound of the formula (I) or a pharmaceutically acceptable salt thereof and one or more ⁇ -lactam antibiotics.
• the present invention provides a method of treating a disease caused by a bacterial infection comprising administering a compound of the formula (I) as described herein in combination with one or more ⁇ -lactam antibiotics A patient or subject in need.
• alkyl refers to a straight or branched saturated hydrocarbon group having from 1 to 20 carbon atoms.
• the alkyl group is an alkyl group having from 1 to 12 carbon atoms. More preferably, the alkyl group is an alkyl group having 1 to 6 carbon atoms. Most preferably, the alkyl group is an alkyl group having from 1 to 4 carbon atoms.
• alkyl groups include, but are not limited to, methyl, ethyl, 1-propyl (n-propyl), 2-propyl (isopropyl), 1-butyl (n-butyl), 2-methyl 1-propyl (isobutyl), 2-butyl (sec-butyl), 2-methyl-2-propyl (tert-butyl), 1-pentyl (n-pentyl), 2-pentyl , 3-pentyl, 2-methyl-2-butyl, 3-methyl-2-butyl, 3-methyl-1-butyl, 2-methyl-1-butyl, 1-hexyl, 2-hexyl, 3-hexyl, 2-methyl-2-pentyl, 3-methyl-2-pentyl, 4-methyl-2-pentyl, 3-methyl-3-pentyl, 2- Methyl-3-pentyl, 2,3-dimethyl-2-butyl, 3,3-dimethyl-2-butyl, 1-heptyl, 1-octyl
• amino refers to -NH 2.
• halogen refers to fluoro, chloro, bromo, iodo.
• aminoalkyl refers to an alkyl group in which one or more hydrogens are replaced by an amino group.
• cycloalkyl refers to a monovalent saturated carbocyclic group.
• the cycloalkyl group is a 3 to 8 membered monocyclic group. More preferably, the cycloalkyl group is a 3- to 6-membered monocyclic group.
• Examples of cycloalkyl groups include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, and the like.
• heteroaryl refers to a 5- or 6-membered, monovalent aromatic radical containing 1-3 heteroatoms independently selected from the group consisting of nitrogen, oxygen, and sulfur.
• heteroaryl groups include: furan ring, pyrrole ring, pyrazole ring, imidazole ring, triazole ring, thiophene ring, thiazole ring, isothiazole ring, oxazole ring, isoxazole ring, 1,2,4-oxine Diazole ring, 1,3,4-oxadiazole ring; pyridine ring, pyrimidinyl group, triazine ring, pyrazine ring, tetrazole ring, pyridazine ring, thiadiazole ring.
• the heteroaryl group is optionally substituted independently with one or more substituents as described herein.
• the term "optionally substituted” means that the given structure or group is unsubstituted or that the given structure or group is substituted with one or more specific substituents. Unless otherwise stated, the optional substitution can be substituted at any position of the substituted group.
• ester refers to an ester of -OSO 3 - or COOH (if present) in the compound of formula (I) which can be esterified with an alcohol; as shown in formula (I) When a hydroxyl group is present in the compound, it can be esterified with an organic acid, an inorganic acid or the like to form an ester. The ester can be hydrolyzed under acidic or basic conditions to form the corresponding acid or alcohol.
• stereoisomer refers to a compound that has the same chemical composition and connectivity, but whose atoms have different orientations in space, which orientation cannot be interchanged by single bond rotation.
• Stepoisomers include “diastereomers” and “enantiomers.”
• Diastereomer refers to a stereoisomer that has two or more centers of chirality and whose molecules are not mirror images of each other. Diastereomers have different physical properties such as melting point, boiling point, spectral properties and reactivity. The mixture of diastereomers can be separated under high resolution analytical procedures such as crystallization, electrophoresis and chromatography.
• Enantiomer refers to two stereoisomers that are non-overlapping mirror images of each other.
• salts refers to a pharmaceutically acceptable organic or inorganic salt of a compound of the invention.
• exemplary salts include, but are not limited to, sulfates, citrates, acetates, oxalates, chlorides, bromides, iodides, nitrates, hydrogen sulfates, phosphates, acid phosphates, isoniazids Acid salt, lactate, salicylate, acid citrate, tartrate, oleate, citrate, pantothenate, hydrogen tartrate, ascorbate, succinate, maleate, dragon Cholate, fumarate, gluconate, glucuronate, saccharate, formate, benzoate, glutamate, methanesulfonate (methanesulfonate), B Alkane sulfonate, besylate, p-toluenesulfonate, and pamoate; or ammonium (eg, primary
• the term "pharmaceutically acceptable” means that the substance or composition must be chemically and/or toxicologically compatible with the other ingredients of the mammal comprising the formulation and/or treatment therewith.
• treatment refers to both therapeutic and prophylactic or preventative or preventive measures, wherein the goal is to prevent or slow (reduce) undesired pathological changes or conditions.
• beneficial or desirable clinical outcomes include, but are not limited to, alleviation of symptoms, reduction in disease severity, delay or slowing of disease progression, improvement or mitigation of disease states, and relief (either in part or in whole), regardless of Is detectable or undetectable.
• the term "therapeutically effective amount” means that the amount of a compound of the invention may be: (i) treating or preventing a disease or condition described herein, (ii) ameliorating or eliminating one or more diseases or conditions described herein. Or (iii) preventing or delaying the onset of one or more symptoms of the disease or condition described herein.
• the invention claims a compound of formula (Ia) or an ester, solvate, stereoisomer thereof, and pharmaceutically acceptable salts thereof:
• W 1 , W 2 and W 3 are as defined in the formula (I).
• W 1 is selected from the group consisting of an optionally substituted five- or six-membered heteroaryl ring containing O, N and/or S;
• W 2 is selected from:
• R 1 is selected from Wherein R 2 , R 3 , R 4 , R 4 ', R 5 or R 6 are each independently selected from H, C 1 -C 12 alkyl, amino C 1 -C 12 alkyl, C 1 -C 12 alkylamine Base C 1 -C 12 alkyl, Ra and Rb are each independently selected from H, C 1 -C 12 alkyl, OH, -OC 1 -C 12 alkyl, -NH 2 , -NHC 1 -C 12 alkyl, -N(C 1 -C 12 Alkyl) 2 , -SH, -SC 1 -C 12 alkyl, -S(O)C 1 -C 12 alkyl, -S(O 2 )C 1 -C 12 alkyl, -SO 3 H;R 7 and R 7 ' are each independently selected from -NH 2 , -NHC 1 -C 12 alkyl, -N(C 1 -C 12 alkyl
• R 1 ' is selected from H, C 1 -C 12 alkyl, C 3 -C 8 cycloalkyl, OH, -OC 1 -C 12 alkyl, -NH 2 , -NHC 1 -C 12 alkyl, -N (C 1 -C 12 alkyl) 2 , -SH, -SC 1 -C 12 alkyl, -S(O)C 1 -C 12 alkyl, -S(O 2 )C 1 -C 12 alkyl, -SO 3 H;
• Z 2 is selected from CR 18 R 19 or NR 20 , and R 18 , R 19 and R 20 are each independently selected from H, NH 2 or
• R 21 is selected from the group consisting of -NH 2 , -NHC 1 -C 12 alkyl, -N(C 1 -C 12 alkyl) 2 , -O C 1 -C 12 alkyl, -S C 1 -C 12 alkyl;
• R 22 is selected from the group consisting of NH, -NHC 1 -C 12 alkyl, O, S;
• t, u and w are each independently selected from 1, 2, 3, 4, 5 or 6, provided that t and u are not 0 at the same time;
• Or NH;
• R 25 is selected from H, amino C 1 -C 12 alkyl or C 1 -C 12 alkylamino C 1 -C 12 alkyl.
• W 1 is selected from Wherein X is selected from O, S or NH, and Y and Z are each independently selected from CH or N, and W 1 is optionally substituted by C 1 -C 12 alkyl.
• W 1 is selected from the group consisting of a furan ring, a pyrrole ring, a pyrazole ring, an imidazole ring, a triazole ring, a thiophene ring, a thiazole ring, an isothiazole ring, an oxazole ring, an isoxazole ring, 1,2,4- Oxadiazole ring, 1,3,4-oxadiazole ring; pyridine ring, pyrimidinyl group, triazine ring, pyrazine ring, tetrazole ring, pyridazine ring, thiadiazole ring.
• W 1 is selected from the group consisting of
• M is selected from the group consisting of H, sodium ion, potassium ion, calcium ion, magnesium ion, NH 4 + , N(C 1 -C 12 alkyl) 4 + .
• W 1 is selected from the group consisting of -C(O)-;
• W 2 is selected from the group consisting of -OR 26 , -NHR 27 , wherein R 26 and R 27 are each independently selected from H, C 1 -C 12 alkyl or Wherein Z 5 is selected from CR 28 R 29 or NR 30 , and R 28 , R 29 and R 30 are each independently selected from H, NH 2 or Wherein R 31 is selected from the group consisting of -NH 2 , -NHC 1 -C 12 alkyl, -N(C 1 -C 12 alkyl) 2 , -O C 1 -C 12 alkyl, -S C 1 -C 12 alkyl; R 32 is selected from the group consisting of NH, NC 1 -C 12 alkyl, O, S; x, y and z are each independently selected from 1, 2, 3, 4, 5 or 6, provided that x and y are not simultaneously 0.
• Preferred compounds of the invention are as follows:
• the invention provides a process for the preparation of a compound of formula (I) of the invention:
• Step 1 The intermediate 1 is reacted with an alkyne under basic conditions to obtain an intermediate 2;
• Step 2 Selective removal of the intermediate 2 to the protecting group P to obtain the intermediate 3;
• Step 3 Intermediate 3 is reacted with SO 3 under basic conditions to obtain Intermediate 4;
• Step 4 The protecting group P' in the intermediate 4 is removed to give the product 5.
• P is a hydroxy protecting group which is common in the art
• P' is a hydroxy or amino protecting group which is common in the art
• B is as defined in the formula (I).
• Hydroxy or amino protecting groups include, but are not limited to, benzyl, silane protecting groups, ester protecting groups, alkyl ether protecting groups, Boc, Fmoc, Cbz, etc. See, for example, Greene, TW and Wuts, PGM, Greene's Protective Groups in Organic Synthesis, 4th edition, John Wiley and Sons.
• the base used in the reaction may be an inorganic base or an organic base, wherein the inorganic base may be selected from alkali metal or alkaline earth metal hydroxides (for example, sodium hydroxide, potassium hydroxide, barium hydroxide, lithium hydroxide).
• alkali metal or alkaline earth metal hydroxides for example, sodium hydroxide, potassium hydroxide, barium hydroxide, lithium hydroxide.
• alkali metal or alkaline earth metal carbonate or hydrogencarbonate such as potassium carbonate, sodium carbonate, lithium carbonate, calcium carbonate, magnesium carbonate, sodium hydrogencarbonate
• alkali metal or alkaline earth metal Alkoxide such as sodium methoxide, sodium ethoxide, sodium t-butoxide, potassium t-butoxide, etc.
• alkali metal or alkaline earth metal amide such as sodium amide, sodium hexamethyldisilazide
• ammonia organic base can Selected from organic amines commonly found in the art, such as triethylamine, trimethylamine, pyridine, piperidine, 4-N,N-dimethylaminopyridine, morpholine, N-methylmorpholine, tetramethylethylenediamine , DBU, DBN, DABCO, etc.
• the deprotection operation is a routine experimental operation in the art, see, for example, Greene, T. W. and Wuts, P. G. M., Greene's Protective Groups in Organic Synthesis, 4th edition, John Wiley and Sons.
• step 3 the base used in the reaction is as defined in step 1.
• P is a hydroxy protecting group which is common in the art
• P' is a hydroxy or amino protecting group which is common in the art
• B is as defined in the formula (I).
• Hydroxy or amino protecting groups include, but are not limited to, benzyl, silane protecting groups, ester protecting groups, alkyl ether protecting groups, Boc, Fmoc, Cbz, etc. See, for example, Greene, TW and Wuts, PGM, Greene's Protective Groups in Organic Synthesis, 4th edition, John Wiley and Sons.
• Step 1 Intermediate 1 is condensed with a hydrazide under basic conditions to obtain Intermediate 2; wherein the base used in the reaction may be an inorganic base or an organic base, which is defined as the base in step 1 of Scheme 1.
• the condensing agent may be a condensing agent commonly used in the art for the condensation reaction between a carboxylic acid and an amine, such as a carbodiimide condensing agent (CDI, DCC, DIC, EDCI and DMAP, HOBt, HOAt, HOSu, NHPI).
• the reaction temperature may be in the range of 0-100 ° C, preferably in The reaction is in the range of 0-70 ° C, more preferably 0-50 ° C, most preferably at room temperature.
• Step 2 Intermediate 2 is obtained by a ring closure reaction to obtain Intermediate 3; wherein the ring closure reaction is carried out in the presence of a condensing agent, and the condensing agent used is preferably Burgess reagent; the reaction temperature may be in the range of 0-100 ° C, It is preferably in the range of 0 to 70 ° C, more preferably 0 to 50 ° C, most preferably at room temperature.
• a condensing agent preferably Burgess reagent
• the reaction temperature may be in the range of 0-100 ° C, It is preferably in the range of 0 to 70 ° C, more preferably 0 to 50 ° C, most preferably at room temperature.
• Step 3 Selective removal of the intermediate 3 to the protecting group P to obtain the intermediate 4;
• Step 4 Intermediate 4 is reacted with SO 3 under basic conditions to obtain Intermediate 5;
• Step 5 removing the protecting group P' in the intermediate 5 to obtain the product 6;
• the deprotection operation is a routine experimental operation in the art, see, for example, Greene, T. W. and Wuts, P. G. M., Greene's Protective Groups in Organic Synthesis, 4th edition, John Wiley and Sons.
• step 4 the base used in the reaction is as defined in step 1 of Scheme 1.
• the present invention provides a pharmaceutical composition of the compound of the formula (I) or a pharmaceutically acceptable salt thereof as an active ingredient.
• the composition comprises a compound of the invention, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.
• the pharmaceutically acceptable carrier can be either solid or liquid. Wherein the solid carrier can be one or more of those used as excipients, diluents, sweeteners, solubilizers, lubricants, binders, tablet disintegrating agents, stabilizers, preservatives or encapsulating materials. substance.
• the liquid carrier can be a solvent or a liquid dispersion medium.
• Suitable solid carriers include, but are not limited to, for example, cellulose, glucose, lactose, mannitol, magnesium stearate, magnesium carbonate, sodium carbonate, sodium saccharin, sucrose, dextrin, talc, starch, pectin, gelatin, tragacanth, Acacia gum, sodium alginate, parabens, methylcellulose, sodium carboxymethylcellulose, a low melting wax, cocoa butter, and the like.
• Suitable liquid carriers include, but are not limited to, water, ethanol, polyols (eg, glycerol, propylene glycol, liquid polyethylene glycol, and the like), vegetable oils (eg, peanut oil, cottonseed oil, safflower oil, sesame oil, olive oil, corn oil, and soybean oil). ), glycerides, agar, pyrogen-free water, isotonic saline, Ringer's solution, and mixtures thereof.
• polyols eg, glycerol, propylene glycol, liquid polyethylene glycol, and the like
• vegetable oils eg, peanut oil, cottonseed oil, safflower oil, sesame oil, olive oil, corn oil, and soybean oil.
• glycerides eg, agar, pyrogen-free water, isotonic saline, Ringer's solution, and mixtures thereof.
• compositions of the invention are generally known.
• the preparation of the pharmaceutical compositions of the present invention in a known manner includes conventional methods of mixing, granulating, tableting, coating, dissolving or lyophilizing.
• the therapeutically effective amount of the compound of the present invention or a pharmaceutical composition comprising the same can be easily determined by routine experimentation, and the most effective and convenient route of administration can be determined by routine experimentation.
• the pharmaceutical composition of the present invention can be administered to a patient or a subject in need of treatment by any suitable administration, including oral administration, parenteral (including subcutaneous, intramuscular, intravenous, and intradermal) administration.
• parenteral including subcutaneous, intramuscular, intravenous, and intradermal
• Inhalation spray administration topical administration, rectal administration, nasal administration, buccal administration, vaginal administration or administration via an implantable reservoir.
• the provided pharmaceutical compositions are administered intravenously and/or intraperitoneally.
• parenteral includes subcutaneous, intravenous, intramuscular, intraocular, intravitreal, intra-articular, intrasynovial, intrasternal, intrathecal, intrahepatic. , intraperitoneal, intralesional, and intracranial injection or infusion techniques.
• these pharmaceutical compositions are administered orally, subcutaneously, intraperitoneally or intravenously. .
• compositions suitable for oral administration for use in the present invention include solid forms such as pills, tablets, caplets, capsules (including immediate release formulations, time release formulations and sustained release formulations, respectively), granules and powders; and liquids Forms such as solutions, syrups, elixirs, emulsions and suspensions.
• forms for ocular administration include sterile solutions or ocular delivery devices.
• Forms useful for parenteral administration include sterile solutions, emulsions and suspensions.
• the pharmaceutical composition of the present invention may additionally comprise one or more ⁇ -lactam antibiotics.
• the ⁇ -lactam antibiotic may include a penicillin antibiotic, a cephalosporin antibiotic, a monolactam cyclic antibiotic, a carbapenem antibiotic, and a penemase inhibitor.
• the ⁇ -lactam antibiotic may include penicillin, oxacillin, cloxacillin, dicloxacillin, flucloxacillin, ampicillin, piroxicillin, amoxicillin, carbenicillin, furazocillin, sulfonate.
• a compound of the present invention or an ester thereof, a stereoisomer or a pharmaceutically acceptable salt thereof, and a pharmaceutical composition comprising the compound of the present invention or an ester thereof, a stereoisomer thereof or a pharmaceutically acceptable salt thereof, can be used for treatment and / or prevent diseases caused by bacterial infections. Therefore, in the use of the compound of the formula (I) of the present invention, an ester thereof, a stereoisomer thereof or a pharmaceutically acceptable salt thereof for the preparation of a medicament for the treatment and/or prevention of bacteria The disease caused by infection.
• the present invention relates to a method of inhibiting bacteria or treating and/or preventing a disease caused by a bacterial infection, comprising administering to a patient or subject in need thereof a therapeutically and/or prophylactically effective amount of the formula (I) of the present invention.
• the bacteria in the disease caused by bacterial interference are selected from the group consisting of Gram-positive bacteria and Gram-negative bacteria, wherein the Gram-positive bacteria are selected from the group consisting of: Staphylococcus aureus, Staphylococcus epidermidis, and lactose-free chains One or more of cocci, S. pneumoniae, Streptococcus pyogenes, Enterococcus or C.
• Gram-negative bacteria selected from the group consisting of: Citrobacter faecalis, Citrobacter freundii, Enterobacter cloacae, pneumonia Lei Bojun, Escherichia coli, Proteus vulgaris, Salmonella, Serratia marcescens, Shigella, Pseudomonas aeruginosa, Moraxella muforma, Neisseria gonorrhoeae, Neisseria meningitidis, immobile Bacillus, Burkholder, Campylobacter, Helicobacter pylori, Vibrio cholerae, Klebsiella, Haemophilus influenzae, Mycobacterium avium, Mycobacterium abscessus, Mycobacterium kansii, Mycobacterium ulcerum, Chlamydia pneumoniae, Trachoma One or more of Chlamydia, ⁇ -hemolytic streptococcus, Acinetobacter baumannii,
• the bacterium causes a disease selected from the group consisting of: respiratory tract infection (upper respiratory tract infection, lower respiratory tract infection, bronchitis, bronchitis, pneumonia, tuberculosis, pharyngitis), urinary tract infection (complex urinary tract infection, complicated urethra) Infection, non-concurrent urinary tract infection, cystitis, pyelonephritis), central nervous system infection (encephalitis, meningitis, brain abscess), ear infection (otitis, otitis media), pleural lung and bronchial infection, intra-abdominal infection , cardiovascular infection (blood infections such as sepsis or bacteremia, endocarditis, myocarditis, pericarditis), skin or soft tissue infections, bone and joint infections (arthritis, osteomyelitis), genital infections (genital ulcers, vaginitis) , cervicitis), one or more of eye infections (conjunctivitis,
• the compounds or pharmaceutical compositions of the invention may be provided in a pack or dispenser device containing one or more unit dosage forms.
• the package may comprise a metal or plastic foil or glass and a rubber stopper (eg, in a vial).
• the package or dispensing device can be accompanied by a instructions for use of the drug.
• the dosage will depend on various factors including the age, weight and condition of the patient as well as the route of administration. The precise dose administered is determined based on the judgment of the treating physician.
• the actual dosage level and time course of administration of the active ingredient in the pharmaceutical compositions of the present invention can be varied to achieve the following amounts of active ingredient which are effective to achieve the desired condition for the particular patient, composition and mode of administration.
• the response is treated without toxicity to the patient.
• the agents or pharmaceutical compositions of the invention are administered in an amount sufficient to reduce or eliminate the symptoms associated with bacterial infection.
• the preferred dosage of the agent is the maximum amount that the patient can withstand and does not produce serious or unacceptable side effects.
• Exemplary dosage ranges include 0.01 mg to 250 mg/day, 0.01 mg to 100 mg/day, 1 mg to 100 mg/day, 10 mg to 100 mg/day, 1 mg to 10 mg/day, and 0.01 mg to 10 mg/day.
• the preferred dosage of the agent is the maximum amount that the patient can withstand and does not produce serious or unacceptable side effects.
• the agent is administered at a concentration of from about 10 micrograms to about 100 mg/kg body weight per day, from about 0.1 to about 10 mg/kg/day, or from about 1.0 mg to about 10 mg/kg body weight per day.
• the therapeutically effective dose produces a serum concentration of the agent from about 0.1 ng/ml to about 50-100 mg/ml.
• These pharmaceutical compositions should typically provide a dosage of from about 0.001 mg to about 2000 mg of compound per kilogram of body weight per day.
• the dose for systemic administration to a human patient may range from 1-10 mg/kg, 20-80 mg/kg, 5-50 mg/kg, 75-150 mg/kg, 100-500 mg/kg, 250-750 mg/kg.
• the pharmaceutical unit dosage form is prepared to provide a compound or combination of essential ingredients from about 1 mg to about 5000 mg (e.g., from about 100 mg to about 2500 mg) per unit dosage form.
• Preferred unit dosage formulations are those containing the daily dose or unit, daily sub-dose, or suitable fraction thereof as discussed herein.
• Steps 1-4 follow steps 2-5 in the synthesis of Compound D.
• Step 1-6 Steps 1-6 in the synthesis of Compound D
• Step 1-6 Steps 1-6 in the synthesis of Compound E
• the crude product was purified by Prep-HPLC using the following conditions: column: XBridge Prep OBD C18 column 19*250 mm, 5 um; mobile phase A: water (0.1% FA), mobile phase B: ACN; flow rate: 20 mL/min; gradient: From 12% B to 23% B in 7 minutes; 220, 254 nm; Rt: 6.2 min; 8 mg (12%) of compound E was obtained.
• ESI-MS (EI + , m/z): 402, 0.418 min.
• Step 1-6 Steps 1-6 in the synthesis of Compound D
• Step 1-6 Steps 1-6 in the synthesis of Compound D
• Step 1-5 follow steps 1-6 in the synthesis of Compound I
• Step 6 follow step 8 in the synthesis of Compound I
• Step 7-8 follow steps 1-2 in the synthesis of Compound E
• ESI-MS EI + , m/z
• Steps 10-12 Steps 3-5 in the synthesis of Compound E
• Step 1-6 Steps 1-6 in the synthesis of Compound E
• Step 1-6 Steps 1-6 in the synthesis of Compound E
• Step 1-6 Steps 1-6 in the synthesis of Compound E
• Step 1-3 follow steps 1-3 in the synthesis of Compound D
• Step 4-8 Steps 1-5 in the synthesis of Compound E
• Step 3-8 Steps 1-6 in the synthesis of Compound D
• Step 1-6 Steps 1-6 in the synthesis of Compound D
• Step 1-6 Steps 1-6 in the synthesis of Compound D
• Step 1-6 Steps 1-6 in the synthesis of Compound D
• Step 1-6 Steps 1-6 in the synthesis of Compound D
• Step 3-8 Steps 1-6 in the synthesis of Compound D
• Step 1-3 follow steps 4-6 in the synthesis of Compound D
• Step 1-6 Steps 1-6 in the synthesis of Compound D
• Step 1-6 Steps 1-6 in the synthesis of Compound D
• Step 1-6 Steps 1-6 in the synthesis of Compound D
• Step 1-6 Steps 1-6 in the synthesis of Compound D
• Steps 1-5 follow steps 2-6 in the synthesis of compound FF
• Steps 1-5 follow steps 2-6 in the synthesis of compound FF
• Steps 1-4 Steps 2, 4-6 in the synthesis of Compound D
• Steps 1-4 Steps 2, 4-6 in the synthesis of Compound D
• Steps 1-4 Steps 2, 4-6 in the synthesis of Compound D
• Steps 5-9 Steps 1-5 in accordance with the synthesis of Compound D
• Steps 10-11 Steps 8-9 in the synthesis of Compound I
• Step 1-4 Steps 1-4 in the synthesis of compound DD
• Steps 5-9 Steps 1-5 in the synthesis of Compound D
• Steps 10-11 Steps 8-9 in the synthesis of Compound I
• Step 2-5 follow steps 3-6 in the synthesis of compound FF
• Step 1-5 Steps 1-5 in the synthesis of compound GG
• Steps 1-4 follow steps 3-6 in the synthesis of compound FF
• Step 1 Step 1 in the synthesis of compound GG
• Step 2-5 follow steps 3-6 in the synthesis of compound FF
• Step 1-5 Steps 1-5 in the synthesis of compound GG
• Step 1 follow step 1 in the synthesis of compound UU
• Step 2 follow step 1 in the synthesis of compound GG
• Step 5-7 follow steps 3-5 in the synthesis of compound FF
• TEA ⁇ HF (0.068 g, 0.56 mmol) was added to (1R,4S)-4-(5-((E)-8-((tert-butoxycarbonyl)amino)-2,2,3,3, 12,12-hexamethyl-10-oxo-4,11-dioxa-7,9-diaza-3-silatridec-8-8-en-5-yl)isoxazole-3- 6-oxo-5,7-diazaspiro[bicyclo[3.2.1]octane-2,1'-cyclopropane]-7-yl hydrogensulfate (0.102 g, 0.14 mmol) In a THF solution (2.000 mL).
• Step 9 follow step 6 in the synthesis of compound LL
• Steps 1-4 follow steps 6-9 in the synthesis of Compound I
• Steps 1-4 follow steps 6-9 in the synthesis of Compound I
• Step 1-5 Steps 1-5 in the synthesis of compound FF
• Step 2-4 follow steps 4-6 in the synthesis of compound FF
• Steps 1-4 follow steps 2-5 in the synthesis of compound FF
• Steps 1-4 follow steps 2-5 in the synthesis of compound FF
• Steps 1-4 follow steps 2-5 in the synthesis of compound FF
• Step 3-6 follow steps 2-5 in the synthesis of compound FF
• Step 2 follow step 2 in the synthesis of compound GG
• Step 3-4 follow steps 1-2 in the synthesis of compound TT
• Step 5-8 follow steps 2-5 in the synthesis of compound FF
• Step 1 follow step 2 in the synthesis of compound TT
• Step 3-6 Steps 1-4 in the synthesis of the compound PP
• Step 4-7 Steps 1-4 in the synthesis of the compound PP
• Step 2-6 follow steps 2-6 in the synthesis of compound VV
• Step 1 Step 1 in the synthesis of compound GG
• Step 2-3 follow steps 1-2 in the synthesis of compound TT
• Step 4-7 Steps 1-4 in the synthesis of the compound PP
• step 1
• Step 2-7 Steps 2-7 in the synthesis of the compound WW
• step 1
• Step 3 follow step 2 in the synthesis of compound TT
• Step 6 in accordance with step 1 in the synthesis of compound GG
• Step 7-10 Steps 1-4 in the synthesis of the compound PP
• Compound 5 was prepared according to steps 1-5 in Example 60.
• Phenyl-I3-iodanediyl-bis(2,2,2-trifluoroacetate) (3.6 g, 8.37 mmol, 1.5 eq.) was added portionwise to compound 3 (1.48 g, 5.58 mmol, 1 eq.) And a solution of ter-2-butyl prop-2-yn-1-ylcarbamate (0.86 g, 5.58 mmol, 1 eq.) in methanol (20 mL) and water (4 mL). The resulting mixture was stirred at room temperature for 4 hours. The solvent was removed under reduced pressure.
• DIPEA N,N-Diisopropylethylamine
• TSA Trypticase soy agar
• the bacterial strain used for the minimum inhibitory concentration (MIC) test was stored frozen in a -80 ° C low temperature refrigerator, and the use required to recover 2 days earlier. A small amount of frozen bacterial strain was scraped off with a sterile inoculating loop and streaked on a TSA solid medium plate, and placed in a normal atmospheric culture environment at 35 ⁇ 2 ° C for 20-24 hours.
• the liquid medium was taken out from the refrigerator at 4 ° C and left to heat at room temperature.
• the bacteria were diluted 300-fold with 1.1x CAMHB.
• Test compound for line A-H highest final test concentration of 64 ⁇ g/ml or 32 ⁇ g/ml, diluted 2 times.
• GC Growth control
• SC Sterile control
• Test compound dilution All test compounds were dissolved and diluted with dimethyl sulfoxide (DMSO). 170 ⁇ l of 3.2 mg/ml (50 ⁇ x 64 ⁇ g/ml) of the compound was transferred to the wells of column 1 of the dilution mother plate (A1-H1), and then 85 ⁇ l of DMSO was transferred to the wells of the other columns. Each compound was serially diluted 2 times (ie, 85 ⁇ l of the compound was aspirated from the wells of column 1 into the wells of column 2 and mixed, and 85 ⁇ l of the compound was aspirated from the wells of column 2 to column 3. Mix wells in the wells, then pipet 85 ⁇ l of the compound from the wells in column 3 into the wells of column 4 and mix, and so on to the wells in column 11).
• DMSO dimethyl sulfoxide
• Imipenem and ceftazidime were dissolved in 10 mM MOPS buffer. Transfer 110 ⁇ l of 50 ⁇ g/ml (12.5 ⁇ x 4 ⁇ g/ml) of imipenem or 110 ⁇ l of 100 ⁇ g/ml (12.5 ⁇ x 8 ⁇ g/ml) of ceftazidime to columns 1-11 of the addition plate, and then transfer 110 ⁇ l of MOPS buffer to Column 12.
• cover 6 test plates with a sterile cover, centrifuge in a centrifuge at 1000 rpm for 30 seconds, mix at 800 rpm on a vibrating plate for 1 minute, and place in a normal incubator at 35 ⁇ 2 ° C for 16-20 hours. .
• the inoculated bacteria were diluted from 10 -1 to 10 -7 with a liquid medium (such as 100 ⁇ l of bacterial inoculum + 900 ⁇ l of 1.1xCAMHB).
• test plates were placed on a plate reading device, and the mirrors were adjusted to observe the growth of bacteria in each well. At the same time, each test board was photographed with QCount software.
• the number of colonies of the bacterial inoculum at different dilutions on the TSA plates was counted and the bacterial inoculum was calculated.
• test compound When the test compound was tested in combination with imipenem, ceftazidime and ampicillin, imipenem was fixed at a concentration of 4 ⁇ g/ml, ceftazidime was fixed at a concentration of 8 ⁇ g/ml, and ampicillin was fixed at a concentration of 8 ⁇ g/ml.
• the bacterial inoculum in the assay plate was resuscitated from TSA and diluted in CAMHB, while a growth control (GC well) and a sterile control (SC well) were placed in the assay plate.
• the test plates were observed and cultured at 35 ⁇ 2 ° C for 16-20 hours in a conventional incubator to observe and record the minimum inhibitory concentration of each compound combination against different bacteria. See Table 1-3 for the results.
• A ⁇ 8 ⁇ g/ml
• B 8-16 ⁇ g/ml
• C 16-128 ⁇ g/ml
• A ⁇ 8 ⁇ g/ml
• B 8-16 ⁇ g/ml
• C 16-128 ⁇ g/ml
• A ⁇ 8 ⁇ g/ml
• B 8-16 ⁇ g/ml
• C 16-128 ⁇ g/ml

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