WO2017206947A1 - 新型β-内酰胺酶抑制剂 - Google Patents

新型β-内酰胺酶抑制剂 Download PDF

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WO2017206947A1
WO2017206947A1 PCT/CN2017/086999 CN2017086999W WO2017206947A1 WO 2017206947 A1 WO2017206947 A1 WO 2017206947A1 CN 2017086999 W CN2017086999 W CN 2017086999W WO 2017206947 A1 WO2017206947 A1 WO 2017206947A1
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group
acid
compound
pharmaceutically acceptable
ring
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PCT/CN2017/086999
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English (en)
French (fr)
Inventor
胡伯羽
丁照中
黄志刚
林锐彬
肖敏亮
谢金生
陈曙辉
李程
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南京明德新药研发股份有限公司
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Priority to JP2018562934A priority Critical patent/JP6929881B2/ja
Application filed by 南京明德新药研发股份有限公司 filed Critical 南京明德新药研发股份有限公司
Priority to CN201780034023.6A priority patent/CN109311881B/zh
Priority to RU2018146128A priority patent/RU2741963C2/ru
Priority to KR1020187037429A priority patent/KR102392350B1/ko
Priority to EP17805892.1A priority patent/EP3466950B1/en
Priority to CA3026322A priority patent/CA3026322C/en
Priority to AU2017274131A priority patent/AU2017274131B2/en
Priority to US16/305,414 priority patent/US10738051B2/en
Priority to MYPI2018002269A priority patent/MY193239A/en
Priority to ES17805892T priority patent/ES2863725T3/es
Priority to SG11201810725WA priority patent/SG11201810725WA/en
Publication of WO2017206947A1 publication Critical patent/WO2017206947A1/zh
Priority to ZA2018/08552A priority patent/ZA201808552B/en

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    • 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
    • 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
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A61P31/04—Antibacterial agents
    • Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
    • Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
    • Y02A—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE
    • Y02A50/00—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE in human health protection, e.g. against extreme weather
    • Y02A50/30—Against vector-borne diseases, e.g. mosquito-borne, fly-borne, tick-borne or waterborne diseases whose impact is exacerbated by climate change

Definitions

  • the present invention relates to a novel class of beta-lactamase inhibitors, in particular to a compound of formula (I) or a pharmaceutically acceptable salt thereof.
  • Beta-lactam antibiotics have been used for more than 70 years and are the main varieties of clinical treatment of various infections.
  • bacterial resistance is also rapidly increasing.
  • the situation facing physicians has become worse and worse, that is, the incidence and mortality of bacterial infections are rising rapidly in both communities and hospitals.
  • MDR multidrug-resistant strains
  • XDR extremely drug-resistant strains
  • ESKAPE includes Enterococcus faecium, Staphylococcus aureus, Klebsiella pneumoniae, Acinetobacter baumannii, Pseudomonas aeruginosa, and intestines. 6 pathogenic bacteria such as Enterobacterspecies. These six strains cover most MDR and XDR strains, greatly limiting the choice of treatment options for physicians.
  • bacteria can be resistant to ⁇ -lactam antibiotics. The most important thing is that bacteria can produce enzymes that hydrolyze the ⁇ -lactam ring, causing antibiotics to lose their antibacterial activity. Bacteria can also selectively alter the target of antibiotic action. For example, multi-drug resistance of methicillin-resistant Staphylococcus aureus is associated with the production of new PBP 2a , increased synthesis of PBPs, and decreased drug affinity. The ⁇ -lactamase can rapidly bind to certain enzyme-resistant ⁇ -lactam antibiotics, allowing the drug to stay in the extracellular space of the cytoplasm, failing to reach the target site to exert an antibacterial effect.
  • the outer membrane of G-bacteria is not easily permeable to certain ⁇ -lactam antibiotics, resulting in non-specific low-level resistance.
  • Bacteria can produce various types of ⁇ -lactamases, which can be classified into four categories A, B, C, and D according to their amino acid and nucleotide sequences. Class A, B, and D enzymes catalyze hydrolysis with serine as the active site, and class B enzymes cleave the ring by one or more metal atoms at its active site.
  • the first well-known high-activity beta-lactamase inhibitor is potassium clavulanate, and its combination with amoxicillin has so far been popular in the market.
  • Two other important beta-lactamase inhibitors on the market are sulbactam and tazobactam. What these three drugs have in common is that the structure has a highly active ⁇ -lactam ring, which is the active site of the inhibitor. Although the three drugs are hot in the market, their antibacterial spectrum is very narrow. They have only an effect on the A- and D-class ⁇ -lactamases, but are completely ineffective against the K-type enzymes of the C-type enzymes and the A-class.
  • Diazabicyclic inhibitors will be a new direction in the development of ⁇ -lactamase inhibitors, especially for drugs that can achieve better inhibition of both Class A and Class C.
  • the present invention provides a compound of the formula (I) or a pharmaceutically acceptable salt thereof,
  • X is selected from O or N(R 1 );
  • R 1 is selected from a C 1-6 alkyl group optionally substituted by 1, 2 or 3 R, a C 1-6 heteroalkyl group, a C 3-6 cycloalkyl group, a 3 to 6-membered heterocycloalkyl group, 5 to 6-membered aryl or heteroaryl;
  • R is selected from F, Cl, Br, I, CN, OH, NH 2 , COOH, or a C 1-6 alkyl, C 1-6 heteroalkyl group optionally substituted by 1, 2 or 3 R' , C 3-6 cycloalkyl, 3- to 6-membered heterocycloalkyl, phenyl, 5- to 6-membered heteroaryl;
  • R' is selected from the group consisting of F, Cl, Br, I, OH, CN, NH 2 , COOH, Me, Et, CF 3 , CHF 2 , CH 2 F, NHCH 3 , N(CH 3 ) 2 ;
  • the number of heteroatoms or heteroatoms is independently selected from 1, 2 or 3.
  • R is selected from the group consisting of F, Cl, Br, I, CN, OH, NH 2 , COOH, Me, Et, CF 3 , CHF 2 , CH 2 F, NHCH 3 , N (CH 3 ) 2 and methoxy.
  • the above X is selected from the group consisting of O.
  • R is selected from the group consisting of F, Cl, Br, I, CN, OH, NH 2 , COOH, Me, Et, CF 3 , CHF 2 , CH 2 F, NHCH 3 , N (CH 3 ) 2 and methoxy, other variables are as defined above.
  • the above X is selected from O, and other variables are as defined above.
  • the above compound, or a pharmaceutically acceptable salt thereof is selected from
  • the invention also provides a pharmaceutical composition
  • a pharmaceutical composition comprising a therapeutically effective amount of a compound according to the above claims, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.
  • the present invention also provides the use of the above compound or a pharmaceutically acceptable salt thereof or the above pharmaceutical composition for the preparation of a ⁇ -lactamase inhibitor for treating a bacterial infection.
  • the mother nucleus of the present invention introduces a novel oxonium group side chain on the basis of the diazabicyclo ring.
  • test data in the in vitro and in vivo activity experiments also showed that the introduction of the oxonium group enables the compound of the present invention to inhibit various ⁇ -lactamases and significantly enhance the bacteriostatic activity.
  • the compounds of the present invention are a promising and developable drug for solving this problem, and exhibit better clinical effects in the clinic.
  • pharmaceutically acceptable salt refers to a salt of a compound of the invention prepared from a compound having a particular substituent found in the present invention and a relatively non-toxic acid or base.
  • a base addition salt can be obtained by contacting a neutral amount of such a compound with a sufficient amount of a base in a neat solution or a suitable inert solvent.
  • Pharmaceutically acceptable base addition salts include sodium, potassium, calcium, ammonium, organic ammonia or magnesium salts or similar salts.
  • an acid addition salt can be obtained by contacting a neutral form of such a compound with a sufficient amount of an acid in a neat solution or a suitable inert solvent.
  • pharmaceutically acceptable acid addition salts include inorganic acid salts including, for example, hydrochloric acid, hydrobromic acid, nitric acid, carbonic acid, hydrogencarbonate, phosphoric acid, monohydrogen phosphate, dihydrogen phosphate, sulfuric acid, Hydrogen sulfate, hydroiodic acid, phosphorous acid, etc.; and an organic acid salt, such as acetic acid, propionic acid, isobutyric acid, maleic acid, malonic acid, benzoic acid, succinic acid, suberic acid, Similar acids such as fumaric acid, lactic acid, mandelic acid, phthalic acid, benzenesulfonic acid, p-toluenesulfonic acid, citric acid, tartaric acid, and me
  • the salt is contacted with a base or acid in a conventional manner, and the parent compound is separated, thereby regenerating the neutral form of the compound.
  • the parent form of the compound differs from the form of its various salts by certain physical properties, such as differences in solubility in polar solvents.
  • a "pharmaceutically acceptable salt” is a derivative of a compound of the invention wherein the parent compound is modified by salt formation with an acid or with a base.
  • pharmaceutically acceptable salts include, but are not limited to, inorganic or organic acid salts of bases such as amines, alkali metal or organic salts of acid groups such as carboxylic acids, and the like.
  • Pharmaceutically acceptable salts include the conventional non-toxic salts or quaternary ammonium salts of the parent compound, for example salts formed from non-toxic inorganic or organic acids.
  • non-toxic salts include, but are not limited to, those derived from inorganic acids and organic acids selected from the group consisting of 2-acetoxybenzoic acid, 2-hydroxyethanesulfonic acid, acetic acid, ascorbic acid, Benzenesulfonic acid, benzoic acid, hydrogencarbonate, carbonic acid, citric acid, edetic acid, ethane disulfonic acid, ethanesulfonic acid, fumaric acid, glucoheptose, gluconic acid, glutamic acid, glycolic acid, Hydrobromic acid, hydrochloric acid, hydroiodide, hydroxyl, hydroxynaphthalene, isethionethane, lactic acid, lactose, dodecylsulfonic acid, maleic acid, malic acid, mandelic acid, methanesulfonic acid, nitric acid, oxalic acid, Pamoic acid, pantothenic acid, phenylacetic acid, phen
  • the pharmaceutically acceptable salts of the present invention can be synthesized from the parent compound containing an acid group or a base by conventional chemical methods.
  • such salts are prepared by reacting these compounds in water or an organic solvent or a mixture of the two via a free acid or base form with a stoichiometric amount of a suitable base or acid.
  • a nonaqueous medium such as ether, ethyl acetate, ethanol, isopropanol or acetonitrile is preferred.
  • the compounds provided herein also exist in the form of prodrugs.
  • Prodrugs of the compounds described herein are readily chemically altered under physiological conditions to convert to the compounds of the invention.
  • prodrugs can be converted to the compounds of the invention by chemical or biochemical methods in an in vivo setting.
  • Certain compounds of the invention may exist in unsolvated or solvated forms, including hydrated forms.
  • the solvated forms are equivalent to the unsolvated forms and are included within the scope of the invention.
  • Certain compounds of the invention may have asymmetric carbon atoms (optical centers) or double bonds. Racemates, diastereomers, geometric isomers and individual isomers are included within the scope of the invention.
  • wedged solid keys are used unless otherwise stated
  • wedge-shaped dashed keys Represents the absolute configuration of a stereocenter, using wavy lines Indicates a wedge solid key Or wedge-shaped dotted key
  • straight dashed keys Indicates the relative configuration of the stereocenter.
  • the compounds described herein contain olefinic double bonds or other centers of geometric asymmetry, they include the E and Z geometric isomers unless otherwise specified.
  • all tautomeric forms are included within the scope of the invention.
  • the compounds of the invention may exist in specific geometric or stereoisomeric forms.
  • the present invention contemplates all such compounds, including the cis and trans isomers, the (-)- and (+)-p-enantiomers, the (R)- and (S)-enantiomers, and the diastereomeric a conformation, a (D)-isomer, a (L)-isomer, and a racemic mixture thereof, and other mixtures, such as enantiomerically or diastereomeric enriched mixtures, all of which belong to It is within the scope of the invention.
  • Additional asymmetric carbon atoms may be present in the substituents such as alkyl groups. All such isomers, as well as mixtures thereof, are included within the scope of the invention.
  • optically active (R)- and (S)-isomers as well as the D and L isomers can be prepared by chiral synthesis or chiral reagents or other conventional techniques. If an enantiomer of a compound of the invention is desired, it can be prepared by asymmetric synthesis or by derivatization with a chiral auxiliary wherein the resulting mixture of diastereomers is separated and the auxiliary group cleaved to provide pure The desired enantiomer.
  • a diastereomeric salt is formed with a suitable optically active acid or base, followed by conventional methods well known in the art.
  • the diastereomers are resolved and the pure enantiomer is recovered.
  • Separation of enantiomers and diastereomers is generally accomplished by the use of chromatography using a chiral stationary phase, optionally in combination with chemical derivatization (eg, formation of carbamate from an amine) salt).
  • the compounds of the present invention may contain unnatural proportions of atomic isotopes on one or more of the atoms that make up the compound.
  • radiolabeled compounds can be used, such as tritium (3 H), iodine -125 (125 I) or C-14 (14 C). Alterations of all isotopic compositions of the compounds of the invention, whether radioactive or not, are included within the scope of the invention.
  • pharmaceutically acceptable carrier refers to any formulation or carrier medium that is capable of delivering an effective amount of an active substance of the present invention, does not interfere with the biological activity of the active substance, and has no toxic side effects to the host or patient, including water, oil, Vegetables and minerals, cream bases, lotion bases, ointment bases, etc. These bases include suspending agents, tackifiers, transdermal enhancers and the like. Their formulations are well known to those skilled in the cosmetic or topical pharmaceutical arts. For additional information on vectors, reference is made to Remington: The Science and Practice of Pharmacy, 21st Ed., Lippincott, Williams & Wilkins (2005), the contents of which are hereby incorporated by reference.
  • excipient generally refers to the carrier, diluent and/or vehicle required to formulate an effective pharmaceutical composition.
  • an "effective amount” or “therapeutically effective amount” with respect to a pharmaceutical or pharmacologically active agent refers to a sufficient amount of a drug or agent that is non-toxic but that achieves the desired effect.
  • an "effective amount” of an active substance in a composition refers to the amount required to achieve the desired effect when used in combination with another active substance in the composition. The determination of the effective amount will vary from person to person, depending on the age and general condition of the recipient, and also on the particular active substance, and a suitable effective amount in a case can be determined by one skilled in the art based on routine experimentation.
  • active ingredient refers to a chemical entity that is effective in treating a target disorder, disease or condition.
  • substituted means that any one or more hydrogen atoms on a particular atom are replaced by a substituent, and may include variants of heavy hydrogen and hydrogen, as long as the valence of the particular atom is normal and the substituted compound is stable. of.
  • Oxygen substitution does not occur on the aromatic group.
  • optionally substituted means that it may or may not be substituted, and unless otherwise specified, the kind and number of substituents may be arbitrary on the basis of chemically achievable.
  • any variable eg, R
  • its definition in each case is independent.
  • the group may optionally be substituted with at most two R, and each case has an independent option.
  • combinations of substituents and/or variants thereof are permissible only if such combinations result in stable compounds.
  • linking group When the number of one linking group is 0, such as -(CRR) 0 -, it indicates that the linking group is a single bond.
  • one of the variables When one of the variables is selected from a single bond, it means that the two groups to which it is attached are directly linked. For example, when L represents a single bond in A-L-Z, the structure is actually A-Z.
  • a substituent When a substituent is vacant, it means that the substituent is absent. For example, when X is vacant in AX, the structure is actually A.
  • the substituent can be attached to more than one atom on a ring, the substituent can be bonded to any atom on the ring, for example, a structural unit. or It is indicated that the substituent R can be substituted at any position on the cyclohexyl group or cyclohexadiene.
  • substituents When the listed substituents are not indicated by which atom is attached to the substituted group, such a substituent may be bonded through any atom thereof, for example, a pyridyl group as a substituent may be passed through any one of the pyridine rings.
  • a carbon atom is attached to the substituted group.
  • the listed linking group does not indicate its direction of attachment, its connection direction is arbitrary, for example,
  • the medium linking group L is -MW-, and at this time, -MW- can be connected in the same direction as the reading order from left to right to form ring A and ring B. It is also possible to connect the ring A and the ring B in a direction opposite to the reading order from left to right.
  • Combinations of the linking groups, substituents and/or variants thereof are permissible only if such combinations result in stable compounds.
  • hetero denotes a hetero atom or a hetero atomic group (ie, a radical containing a hetero atom), including atoms other than carbon (C) and hydrogen (H), and radicals containing such heteroatoms, including, for example, oxygen (O).
  • ring means substituted or unsubstituted cycloalkyl, heterocycloalkyl, cycloalkenyl, heterocycloalkenyl, cycloalkynyl, heterocycloalkynyl, aryl or heteroaryl. So-called rings include single rings, interlocking rings, spiral rings, parallel rings or bridge rings. The number of atoms on the ring is usually defined as the number of elements of the ring. For example, "5 to 7-membered ring” means 5 to 7 atoms arranged in a circle. Unless otherwise specified, the ring optionally contains from 1 to 3 heteroatoms.
  • 5- to 7-membered ring includes, for example, phenyl, pyridine, and piperidinyl; on the other hand, the term “5- to 7-membered heterocycloalkyl ring” includes pyridyl and piperidinyl, but does not include phenyl.
  • ring also includes ring systems containing at least one ring, each of which "ring” independently conforms to the above definition.
  • heterocycle or “heterocyclyl” means a stable monocyclic, bicyclic or tricyclic ring containing a hetero atom or a heteroatom group which may be saturated, partially unsaturated or unsaturated ( Aromatic) which comprise a carbon atom and 1, 2, 3 or 4 ring heteroatoms independently selected from N, O and S, wherein any of the above heterocycles may be fused to a phenyl ring to form a bicyclic ring.
  • the nitrogen and sulfur heteroatoms can be optionally oxidized (i.e., NO and S(O)p, p is 1 or 2).
  • the nitrogen atom can be substituted or unsubstituted (i.e., N or NR, wherein R is H or other substituents as already defined herein).
  • the heterocyclic ring can be attached to the side groups of any hetero atom or carbon atom to form a stable structure. If the resulting compound is stable, the heterocycles described herein can undergo substitutions at the carbon or nitrogen sites.
  • the nitrogen atom in the heterocycle is optionally quaternized.
  • a preferred embodiment is that when the total number of S and O atoms in the heterocycle exceeds 1, these heteroatoms are not adjacent to each other. Another preferred embodiment is that the total number of S and O atoms in the heterocycle does not exceed one.
  • aromatic heterocyclic group or "heteroaryl” as used herein means a stable 5, 6, or 7 membered monocyclic or bicyclic or aromatic ring of a 7, 8, 9 or 10 membered bicyclic heterocyclic group, It contains carbon atoms and 1, 2, 3 or 4 ring heteroatoms independently selected from N, O and S.
  • the nitrogen atom can be substituted or unsubstituted (i.e., N or NR, wherein R is H or other substituents as already defined herein).
  • the nitrogen and sulfur heteroatoms can be optionally oxidized (i.e., NO and S(O)p, p is 1 or 2).
  • bridged rings are also included in the definition of heterocycles.
  • a bridged ring is formed when one or more atoms (ie, C, O, N, or S) join two non-adjacent carbon or nitrogen atoms.
  • Preferred bridged rings include, but are not limited to, one carbon atom, two carbon atoms, one nitrogen atom, two nitrogen atoms, and one carbon-nitrogen group. It is worth noting that a bridge always converts a single ring into a three ring. In the bridged ring, a substituent on the ring can also be present on the bridge.
  • heterocyclic compounds include, but are not limited to, acridinyl, octanoyl, benzimidazolyl, benzofuranyl, benzofuranylfuranyl, benzindenylphenyl, benzoxazolyl, benzimidin Oxazolinyl, benzothiazolyl, benzotriazolyl, benzotetrazolyl, benzisoxazolyl, benzisothiazolyl, benzimidazolyl, oxazolyl, 4aH-carbazolyl, Porphyrin, chroman, chromene, porphyrin-decahydroquinolinyl, 2H, 6H-1,5,2-dithiazinyl, dihydrofuro[2,3-b] Tetrahydrofuranyl, furyl, furfuryl, imidazolidinyl, imidazolinyl, imidazolyl, 1H-carbazolyl, nonenyl,
  • hydrocarbyl or its subordinate concept (such as alkyl, alkenyl, alkynyl, aryl, etc.), by itself or as part of another substituent, is meant to be straight-chain, branched or cyclic.
  • the hydrocarbon atom group or a combination thereof may be fully saturated (such as an alkyl group), a unit or a polyunsaturated (such as an alkenyl group, an alkynyl group, an aryl group), may be monosubstituted or polysubstituted, and may be monovalent (such as Methyl), divalent (such as methylene) or polyvalent (such as methine), may include divalent or polyvalent radicals with a specified number of carbon atoms (eg, C 1 -C 12 represents 1 to 12 carbons) , C 1-12 is selected from C 1 , C 2 , C 3 , C 4 , C 5 , C 6 , C 7 , C 8 , C 9 , C 10 , C 11 and C 12 ; C 3-12 is selected from C 3 , C 4 , C 5 , C 6 , C 7 , C 8 , C 9 , C 10 , C 11 and C 12 .).
  • C 1-12 is selected from C 1
  • Hydrocarbyl includes, but is not limited to, aliphatic hydrocarbyl groups including chain and cyclic, including but not limited to alkyl, alkenyl, alkynyl groups including, but not limited to, 6-12 members.
  • An aromatic hydrocarbon group such as benzene, naphthalene or the like.
  • hydrocarbyl means a straight or branched chain radical or a combination thereof, which may be fully saturated, unitary or polyunsaturated, and may include divalent and multivalent radicals.
  • saturated hydrocarbon radicals include, but are not limited to, methyl, ethyl, n-propyl, isopropyl, n-butyl, t-butyl, isobutyl, sec-butyl, isobutyl, cyclohexyl, (cyclohexyl).
  • a homolog or isomer of a methyl group, a cyclopropylmethyl group, and an atomic group such as n-pentyl, n-hexyl, n-heptyl, n-octyl.
  • the unsaturated hydrocarbon group has one or more double or triple bonds, and examples thereof include, but are not limited to, a vinyl group, a 2-propenyl group, a butenyl group, a crotyl group, a 2-isopentenyl group, and a 2-(butadienyl group). , 2,4-pentadienyl, 3-(1,4-pentadienyl), ethynyl, 1- and 3-propynyl, 3-butynyl, and higher homologs and isomers body.
  • heterohydrocarbyl or its subordinate concept (such as heteroalkyl, heteroalkenyl, heteroalkynyl, heteroaryl, etc.), by itself or in combination with another term, means a stable straight chain, branched chain. Or a cyclic hydrocarbon radical or a combination thereof having a number of carbon atoms and at least one heteroatom.
  • heteroalkyl by itself or in conjunction with another term refers to a stable straight chain, branched hydrocarbon radical or combination thereof, having a number of carbon atoms and at least one heteroatom.
  • the heteroatoms are selected from the group consisting of B, O, N, and S, wherein the nitrogen and sulfur atoms are optionally oxidized, and the nitrogen heteroatoms are optionally quaternized.
  • the hetero atom or heteroatom group may be located at any internal position of the heterohydrocarbyl group, including where the hydrocarbyl group is attached to the rest of the molecule, but the terms "alkoxy”, “alkylamino” and “alkylthio” (or thioalkoxy). By customary expression, those alkyl groups which are attached to the remainder of the molecule through an oxygen atom, an amino group or a sulfur atom, respectively.
  • Up to two heteroatoms may be consecutive, for example, -CH 2 -NH-OCH 3.
  • cycloalkyl refers to any heterocyclic alkynyl group, etc., by itself or in combination with other terms, denotes a cyclized “hydrocarbyl group” or “heterohydrocarbyl group”, respectively.
  • a hetero atom may occupy a position at which the hetero ring is attached to the rest of the molecule.
  • cycloalkyl groups include, but are not limited to, cyclopentyl, cyclohexyl, 1-cyclohexenyl, 3-cyclohexenyl, cycloheptyl, and the like.
  • heterocyclic groups include 1-(1,2,5,6-tetrahydropyridyl), 1-piperidinyl, 2-piperidinyl, 3-piperidinyl, 4-morpholinyl, 3-morpholinyl, tetrahydrofuran-2-yl, tetrahydrofuran-3-yl, tetrahydrothiophen-2-yl, tetrahydrothiophen-3-yl, 1-piperazinyl and 2-piperazinyl.
  • alkyl is used to denote a straight or branched saturated hydrocarbon group, which may be monosubstituted (eg, -CH 2 F) or polysubstituted (eg, -CF 3 ), and may be monovalent (eg, Methyl), divalent (such as methylene) or polyvalent (such as methine).
  • alkyl group include methyl (Me), ethyl (Et), propyl (e.g., n-propyl and isopropyl), butyl (e.g., n-butyl, isobutyl, s-butyl). , t-butyl), pentyl (eg, n-pentyl, isopentyl, neopentyl) and the like.
  • alkenyl refers to an alkyl group having one or more carbon-carbon double bonds at any position of the chain, which may be mono- or poly-substituted, and may be monovalent, divalent or multivalent.
  • alkenyl group include a vinyl group, a propenyl group, a butenyl group, a pentenyl group, a hexenyl group, a butadienyl group, a pentadienyl group, a hexadienyl group and the like.
  • alkynyl refers to an alkyl group having one or more carbon-carbon triple bonds at any position of the chain, which may be mono- or poly-substituted, and may be monovalent, divalent or multivalent.
  • alkynyl groups include ethynyl, propynyl, butynyl, pentynyl and the like.
  • a cycloalkyl group includes any stable cyclic or polycyclic hydrocarbon group, any carbon atom which is saturated, may be monosubstituted or polysubstituted, and may be monovalent, divalent or multivalent.
  • Examples of such cycloalkyl groups include, but are not limited to, cyclopropyl, norbornyl, [2.2.2]bicyclooctane, [4.4.0]bicyclononane, and the like.
  • a cycloalkenyl group includes any stable cyclic or polycyclic hydrocarbon group which contains one or more unsaturated carbon-carbon double bonds at any position of the ring, and may be monosubstituted or polysubstituted, It can be one price, two price or multiple price.
  • Examples of such cycloalkenyl groups include, but are not limited to, cyclopentenyl, cyclohexenyl, and the like.
  • a cycloalkynyl group includes any stable cyclic or polycyclic hydrocarbon group which contains one or more carbon-carbon triple bonds at any position of the ring, which may be monosubstituted or polysubstituted, and may be one Price, price or price.
  • halo or “halogen”, by itself or as part of another substituent, denotes a fluorine, chlorine, bromine or iodine atom.
  • haloalkyl is intended to include both monohaloalkyl and polyhaloalkyl.
  • halo(C 1 -C 4 )alkyl is intended to include, but is not limited to, trifluoromethyl, 2,2,2-trifluoroethyl, 4-chlorobutyl, 3-bromopropyl, and the like. Wait.
  • examples of haloalkyl include, but are not limited to, trifluoromethyl, trichloromethyl, pentafluoroethyl, and pentachloroethyl.
  • alkoxy represents attached through an oxygen bridge
  • C 1-6 alkoxy groups include C 1, C 2, C 3 , C 4, C 5 , and C 6 alkoxy groups.
  • alkoxy groups include, but are not limited to, methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, sec-butoxy, tert-butoxy, n-pentyloxy and S- Pentyloxy.
  • aryl denotes a polyunsaturated, aromatic hydrocarbon substituent which may be monosubstituted or polysubstituted, which may be monovalent, divalent or polyvalent, which may be monocyclic or polycyclic ( For example, 1 to 3 rings; at least one of which is aromatic), they are fused together Or covalently connected.
  • heteroaryl refers to an aryl (or ring) containing one to four heteroatoms. In an illustrative example, the heteroatoms are selected from the group consisting of B, N, O, and S, wherein the nitrogen and sulfur atoms are optionally oxidized, and the nitrogen atom is optionally quaternized.
  • a heteroaryl group can be attached to the remainder of the molecule through a heteroatom.
  • aryl or heteroaryl groups include phenyl, naphthyl, biphenyl, pyrrolyl, pyrazolyl, imidazolyl, pyrazinyl, oxazolyl, phenyl-oxazolyl, isomerism Azyl, thiazolyl, furyl, thienyl, pyridyl, pyrimidinyl, benzothiazolyl, indolyl, benzimidazolyl, indolyl, isoquinolyl, quinoxalinyl, quinolinyl, 1 -naphthyl, 2-naphthyl, 4-biphenylyl, 1-pyrrolyl, 2-pyrrolyl, 3-pyrrolyl, 3-pyrazolyl, 2-imidazolyl, 4-imidazolyl, pyrazinyl, 2-oxazolyl
  • aryl groups when used in conjunction with other terms (e.g., aryloxy, arylthio, aralkyl), include aryl and heteroaryl rings as defined above.
  • aralkyl is intended to include those radicals to which an aryl group is attached to an alkyl group (eg, benzyl, phenethyl, pyridylmethyl, and the like), including wherein the carbon atom (eg, methylene) has been, for example, oxygen.
  • alkyl groups substituted by an atom such as phenoxymethyl, 2-pyridyloxymethyl 3-(1-naphthyloxy)propyl and the like.
  • leaving group refers to a functional group or atom which may be substituted by another functional group or atom by a substitution reaction (for example, an affinity substitution reaction).
  • substituent groups include triflate; chlorine, bromine, iodine; sulfonate groups such as mesylate, tosylate, p-bromobenzenesulfonate, p-toluenesulfonic acid Esters and the like; acyloxy groups such as acetoxy, trifluoroacetoxy and the like.
  • protecting group includes, but is not limited to, "amino protecting group", “hydroxy protecting group” or “thiol protecting group”.
  • amino protecting group refers to a protecting group suitable for preventing side reactions at the amino nitrogen position.
  • Representative amino protecting groups include, but are not limited to, formyl; acyl, such as alkanoyl (e.g., acetyl, trichloroacetyl or trifluoroacetyl); alkoxycarbonyl, e.g., tert-butoxycarbonyl (Boc) Arylmethoxycarbonyl, such as benzyloxycarbonyl (Cbz) and 9-fluorenylmethoxycarbonyl (Fmoc); arylmethyl, such as benzyl (Bn), trityl (Tr), 1, 1-di -(4'-methoxyphenyl)methyl; silyl groups such as trimethylsilyl (TMS) and tert-
  • hydroxy protecting group refers to a protecting group suitable for use in preventing hydroxy side reactions.
  • Representative hydroxy protecting groups include, but are not limited to, alkyl groups such as methyl, ethyl and t-butyl groups; acyl groups such as alkanoyl groups (e.g., acetyl); arylmethyl groups such as benzyl (Bn), Oxybenzyl (PMB), 9-fluorenylmethyl (Fm) and diphenylmethyl (diphenylmethyl, DPM); silyl groups such as trimethylsilyl (TMS) and tert-butyl Dimethylsilyl (TBS) and the like.
  • alkyl groups such as methyl, ethyl and t-butyl groups
  • acyl groups such as alkanoyl groups (e.g., acetyl)
  • arylmethyl groups such as benzyl (Bn), Oxybenzyl (PMB), 9-fluoreny
  • the solvent used in the present invention is commercially available.
  • the present invention employs the following abbreviations: aq for water; HATU for O-(7-azabenzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate ; EDC stands for N-(3-dimethylaminopropyl)-N'-ethylcarbodiimide hydrochloride; m-CPBA stands for 3-chloroperoxybenzoic acid; eq stands for equivalent, equivalent; CDI stands for Carbonyldiimidazole; DCM stands for dichloromethane; PE stands for petroleum ether; DIAD stands for diisopropyl azodicarboxylate; DMF stands for N,N-dimethylformamide; DMSO stands for dimethyl sulfoxide; EtOAc stands for acetic acid Esters; EtOH for ethanol; MeOH for methanol; CBz for benzyloxycarbonyl, an amine protecting group; BOC for
  • Figure 1 shows the results of Klebsiella pneumoniae strains producing KPC-type ⁇ -lactamase.
  • the synergistic inhibition concentration test was established based on the Clinical Laboratory Standardization Association (CLSI) method M7, with a combined initial concentration of antibiotics of 128 ⁇ g/ml for continuous dilution, for a total of 11 serial dilutions, active ⁇ -lactam
  • CLSI Clinical Laboratory Standardization Association
  • the enzyme inhibitor test concentration was fixed at 4 ⁇ g/ml.
  • test compound is dissolved (if it is not dissolved, it can be suspended) diluted in dimethyl sulfoxide to a concentration of 12.8 mg/ml as a stock solution, and ceftazidime (CAZ) is dissolved in water and diluted to 25.6 mg/ml, erectem ( ETP) was diluted in phosphate buffered saline (PBS) to 25.6 mg/ml.
  • CAZ ceftazidime
  • ETP erectem
  • PBS phosphate buffered saline
  • test compound After diluting the test compound at a concentration of 12.8 mg/ml with DMSO to 0.8 mg/ml, 30 ⁇ L was added to one column of the mother plate. Mix the liquid in the mother board with a lance.
  • 96-U type plate as a test plate.
  • the experimental plate was incubated at 37 ° C for 20 hours.
  • the minimum inhibitory concentration of ceftazidime is the lowest concentration that can completely or significantly inhibit bacterial growth.
  • Table 1 is the specific information of the ⁇ -lactamase-producing bacterial strain used in the experiment:
  • This test was designed to evaluate the advantage of the compound of the example compared to the inhibitory activity of OP-0595 on ⁇ -lactamase.
  • Enzyme Final concentration of enzyme Substrate uses final concentration Reaction buffer TEM-1 0.11nM 0.1mM 1 ⁇ PBS, pH 7.4, 0.1 mg/mL BSA AmpC-EC 1.98uM 0.1mM 1 ⁇ PBS, pH 7.4, 0.1 mg/mL BSA SHV-8 67.64nM 0.1mM 1 ⁇ PBS, pH 7.4, 0.1 mg/mL BSA CTX-M-44 0.68nM 0.1mM 1 ⁇ PBS, pH 7.4, 0.1 mg/mL BSA AmpC-PA 1.18nM 0.1mM 1 ⁇ PBS, pH 7.4, 0.1 mg/mL BSA OXA-2 68.40nM 0.1mM 1 ⁇ PBS, pH 7.4, 0.1 mg/mL BSA OXA-9 1.00nM 0.1mM 1 ⁇ PBS, pH 7.4, 0.1 mg/mL BSA
  • the microplate reader can give a curve of OD490 growth over time.
  • the slopes of the curves (Abs2-Abs1)/(T2-T1) were calculated by taking two data points Abs1 and Abs2 within the linear range of the curve.
  • Slope (EC) is the slope in the absence of inhibitor and Slop (S) is the slope at a certain inhibitor concentration.
  • PBS refers to phosphate buffer solution
  • BSA bovine serum albumin
  • Enzyme half inhibition concentration (IC 50 , nM) OP-0595 Avabatan Compound 1 TEM-1 (Class A) 157.20 12.39 38.94 KPC (Class A) 239.10 13.6 43.13
  • AmpC-EC (C class) 22.73 107.00 20.17 CTX-M-44 (Class C) 194.80 66.98 31.92 AmpC-PA (C class) 343.00 213.70 98.63 OXA-2 (Class D) 3451 1489 1547 OXA-9 (Class D) 51711 3129 4995
  • BLI ⁇ -lactamase inhibitor
  • the broth microdilution method was used to determine the minimum inhibitory concentration (MIC) of clinical isolates of carbapenemase-producing strains of antibacterial agents (with and without BLI lead compounds).
  • Susceptibility test According to the method of antimicrobial susceptibility test described in the 2016 edition of the Clinical and Laboratory Standards Institute (CLSI) document in the United States, the microscopic broth dilution method was used to determine the MIC of commonly used antibacterial drugs against clinically isolated bacteria.
  • strains of KPC-2 carbapenemase and NDM-1 metalloenzyme were produced, and 6 strains of OXA-181 carbapenemase were produced. All strains were clinically isolated Klebsiella pneumoniae.
  • Antibiotic concentration range 0.06 ⁇ g/mL-128 ⁇ g/mL, a total of 12 concentrations; enzyme inhibitor concentration: fixed at 4 ⁇ g/mL.
  • Drug susceptibility test quality control strains include Escherichia coli ATCC 25922 and ATCC 35218.
  • mice Female CD-1 mice of about 7 weeks old, weighing 26-28 grams; 150 mg/kg 4 days before cyclophosphamide infection, 100 mg/kg 1 day before; infected bacteria are Klebsiella pneumoniae (ATCC BAA-1705, KPC-2).
  • Compound 1, the reference compound OP-0595 was synthesized in the laboratory.
  • mice Female CD-1 mice were infected with Klebsiella pneumoniae by intranasal drip, and each mouse was instilled with 50 ul of bacteria through the nasal cavity at a dose of 3.14E+07 CFU per mouse, 2 h, 4 h, 6 h and 8 h after infection. Each group of mice was treated with a corresponding compound or a combination compound by intraperitoneal injection.
  • mice in groups 1, 2 and 3 were euthanized, and the lungs were placed in a 50 ml centrifuge tube containing 10 ml of sterile physiological saline, placed on wet ice and transferred to BSL-2 laboratory for CFU counting.
  • mice in groups 4, 5 and 6 were euthanized and the procedure was the same as before.
  • the lungs were ground using an IKA T10 homogenizer (maximum speed 20S, repeated once).
  • the homogenate was diluted in a gradient and placed on a tryptone soy agar plate.
  • the cells were placed in a 37-degree incubator for bacterial culture. After 24 hours, the plates were removed and counted on a plate. The number of single colonies grown in each dilution gradient homogenate was calculated, and the amount of bacteria in the lungs of each mouse was calculated therefrom.

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Abstract

本发明公开了一类新型β-内酰胺酶抑制剂，具体公开了式(I)所示化合物或其药学上可接受的盐。

Description

新型β-内酰胺酶抑制剂 发明领域
本发明涉及一类新型β-内酰胺酶抑制剂，具体公开了式(Ⅰ)所示化合物或其药学上可接受的盐。
技术背景
β-内酰胺类抗生素使用至今已有70多年，是临床上治疗各种感染的主力品种。但是，随着这类药物的大量使用和滥用，细菌耐药性也在快速增加。过去的20年间，内科医生面临的境况越来越糟，那就是无论是在社区还是医院，细菌性感染的发病率和死亡率都在迅速攀升。临床上耐受抗生素能力强且亟需新治疗药物的致病菌株主要有两种：一种是多重耐药菌(multidrug-resistant strains，MDR)，是指细菌对常用抗菌药物主要分类的3类或以上耐药；另一种是广泛耐药菌(extremely drug-resistant strains，XDR)，是指细菌对常用抗菌药物几乎全部耐药。院内感染的30-50％是ESKAPE导致的。ESKAPE包括屎肠球菌(Enterococcus faecium)、金黄色葡萄球菌(Staphylococcus aureus)、肺炎克雷伯菌(Klebsiella pneumoniae)、鲍氏不动杆菌(Acinetobacter baumannii)、铜绿假单胞菌(Pseudomonas aeruginosa)及肠杆菌属(Enterobacterspecies)等6类致病菌。这六类菌涵盖了大多数的MDR和XDR菌株，极大地限制了医生对于治疗方案的选择。
细菌对β-内酰胺类抗生素产生耐药的机制有几种，最主要的是细菌能产生使β-内酰胺环水解开裂的酶，从而导致抗生素失去抗菌活性。细菌还可以选择性改变抗生素的作用靶标。如耐甲氧西林金黄色葡萄球菌具有多重耐药性就与产生新的PBP2a、使PBPs合成增加、与药物亲和力下降有关。β-内酰胺酶可与某些耐酶β-内酰胺类抗生素迅速结合，使药物停留在胞质膜外间隙中，不能达到作用靶位发挥抗菌作用。另外，G-菌的外膜对某些β-内酰胺类抗生素不易透过，产生非特异性低水平耐药。还有些细菌的胞质膜上存在主动外排系统，细菌由此主动外排药物。因此，将β-内酰胺类抗生素和β-内酰胺酶抑制剂联合使用是临床上最有效的方法。细菌可以产生多种类型的β-内酰胺酶，按照其氨基酸和核苷酸序列可以分为A、B、C、D四类。A、B和D类酶以丝氨酸为活性位点来催化水解，B类酶通过其活性位点上的一个或多个金属原子使环开裂。
Figure PCTCN2017086999-appb-000001
第一个广为人知的高活性β-内酰胺酶抑制剂是克拉维酸钾，迄今为止，它与阿莫西林的组合在市场上仍然畅销。市场上另外两个重要的β-内酰胺酶抑制剂是舒巴坦和他唑巴坦。这三个药物的共同之处是结构中都有高活性的β-内酰胺环，是抑制剂的活性位点。虽然这三个药物在市场销售情况火热，但是其本身的抗菌谱很窄。它们只对A和D类β-内酰胺酶有作用效果，而对C类酶和A类中极为重要的KPC酶则完全无效。
2015年2月，FDA批准了一种新的β-内酰胺酶抑制剂，名叫阿维巴坦(NXL-104)。该药物的结构 中含有一个新型的二氮杂二环，具有比上述三个老一代的β-内酰胺酶抑制剂更广的抗菌谱。但是，阿维巴坦对A类具有较好的抑制活性，对C类酶抑制活性相对较弱。
二氮杂二环类抑制剂将会是β-内酰胺酶抑制剂开发的一个新的方向，尤其是同时对A类和C类均能达到较好抑制作用的药物仍未市场所需求。
Figure PCTCN2017086999-appb-000002
目前，抗生素耐药已经成为一个世界性的卫生问题，世界范围内新的耐药菌不断出现。伴随当下抗生素研发步伐放缓,临床上面临的抗菌治疗日趋严峻,甚至出现"无药可用"的情况.鉴于此种情况，开发新的安全、高效的β-内酰胺酶抑制剂是刻不容缓、势在必行的。
发明内容
本发明提供式(I)所示化合物或其药学上可接受的盐，
Figure PCTCN2017086999-appb-000003
其中，
X选自O或N(R1)；
R1选自任选被1、2或3个R取代的C1-6烷基、C1-6杂烷基、C3-6环烷基、3～6元杂环烷基、5～6元芳基或杂芳基；
R选自F、Cl、Br、I、CN、OH、NH2、COOH，或选自任选被1、2或3个R’取代的C1-6烷基、C1-6杂烷基、C3-6环烷基、3～6元杂环烷基、苯基、5～6元杂芳基；
R’选自F、Cl、Br、I、OH、CN、NH2、COOH、Me、Et、CF3、CHF2、CH2F、NHCH3、N(CH3)2；
“杂”表示杂原子或杂原子团，选自-C(＝O)N(R)-、-N(R)-、-C(＝NR)-、-S(＝O)2N(R)-、-S(＝O)N(R)-、-O-、-S-、＝O、＝S、-O-N＝、-C(＝O)O-、-C(＝O)-、-C(＝S)-、-S(＝O)-、-S(＝O)2-、-N(R)C(＝O)N(R)-；
以上任何一种情况下，杂原子或杂原子团的数目分别独立地选自1、2或3。
在本发明的一些方案中，上述R选自F、Cl、Br、I、CN、OH、NH2、COOH、Me、Et、CF3、CHF2、CH2F、NHCH3、N(CH3)2和甲氧基。
在本发明的一些方案中，上述X选自O。
在本发明的一些方案中，上述R选自F、Cl、Br、I、CN、OH、NH2、COOH、Me、Et、CF3、CHF2、CH2F、NHCH3、N(CH3)2和甲氧基，其他变量如上述所定义。
在本发明的一些方案中，上述X选自O，其他变量如上述所定义。
本发明还有一些方案是由上述变量任意组合而来。
在本发明的一些方案中，上述化合物或其药学上可接受的盐，选自
Figure PCTCN2017086999-appb-000004
本发明还提供一种药物组合物，其含有治疗有效量根据权利要求上述的化合物或其药学上可接受的盐和药学上可接受的载体。
本发明还提供上述的化合物或其药学上可接受的盐或上述的药物组合物在制备用于治疗细菌感染的β-内酰胺酶抑制剂中的应用。
技术效果
本发明化合物母核在二氮杂二环的基础上，引入了一个全新的氧胍基团侧链。该基团相较于现有技术，具有更多的氢键结合位点，因而有更好的水溶性等物化性质；另一方面，该氧胍基团的引入，使得pKa＝8.83与氨基的pKa较为接近(如赖氨酸中末端侧链的氨基pKa＝8.95)，远小于胍基(如精氨酸的pKa＝12.48),因而化合物可以保持很好的化学稳定性。体内外活性实验中测试数据也表明，氧胍基团的引入使得本发明化合物能够对多种β-内酰胺酶都产生抑制作用、抑菌活性显著增强。在目前急需临床新药来对抗日益严重的耐药菌感染的情况下，本发明化合物是解决这一问题的一类极具潜力的可开发药物，在临床中显现出其更优的临床效果。
定义和说明
除非另有说明，本文所用的下列术语和短语旨在具有下列含义。一个特定的术语或短语在没有特别定义的情况下不应该被认为是不确定的或不清楚的，而应该按照普通的含义去理解。当本文中出现商品名时，意在指代其对应的商品或其活性成分。这里所采用的术语“药学上可接受的”，是针对那些化合物、材料、组合物和/或剂型而言，它们在可靠的医学判断的范围之内，适用于与人类和动物的组织接触使用，而没有过多的毒性、刺激性、过敏性反应或其它问题或并发症，与合理的利益/风险比相称。
术语“药学上可接受的盐”是指本发明化合物的盐，由本发明发现的具有特定取代基的化合物与相对无毒的酸或碱制备。当本发明的化合物中含有相对酸性的功能团时，可以通过在纯的溶液或合适的惰性溶剂中用足够量的碱与这类化合物的中性形式接触的方式获得碱加成盐。药学上可接受的碱加成盐包括钠、钾、钙、铵、有机氨或镁盐或类似的盐。当本发明的化合物中含有相对碱性的官能团时，可以通过在纯的溶液或合适的惰性溶剂中用足够量的酸与这类化合物的中性形式接触的方式获得酸加成盐。药学上可接受的酸加成盐的实例包括无机酸盐，所述无机酸包括例如盐酸、氢溴酸、硝酸、碳酸，碳酸氢根，磷酸、磷酸一氢根、磷酸二氢根、硫酸、硫酸氢根、氢碘酸、亚磷酸等；以及有机酸盐，所述有机酸包括如乙酸、丙酸、异丁酸、马来酸、丙二酸、苯甲酸、琥珀酸、辛二酸、反丁烯二酸、乳酸、扁桃酸、邻苯二甲酸、苯磺酸、对甲苯磺酸、柠檬酸、酒石酸和甲磺酸等类似的酸；还包括氨基酸(如精氨酸等)的盐，以及如葡糖醛酸等有机酸的盐(参见Berge et al.,"Pharmaceutical Salts",Journal of Pharmaceutical Science 66:1-19(1977))。本发明的某些特定的化合物含有碱性和酸性的官能团，从而可以被转换成任一碱或酸加成盐。
优选地，以常规方式使盐与碱或酸接触，再分离母体化合物，由此再生化合物的中性形式。化合物的母体形式与其各种盐的形式的不同之处在于某些物理性质，例如在极性溶剂中的溶解度不同。
本文所用的“药学上可接受的盐”属于本发明化合物的衍生物，其中，通过与酸成盐或与碱成盐的方式修饰所述母体化合物。药学上可接受的盐的实例包括但不限于：碱基比如胺的无机酸或有机酸盐、酸根比如羧酸的碱金属或有机盐等等。药学上可接受的盐包括常规的无毒性的盐或母体化合物的季铵盐，例如无毒的无机酸或有机酸所形成的盐。常规的无毒性的盐包括但不限于那些衍生自无机酸和有机酸的盐，所述的无机酸或有机酸选自2-乙酰氧基苯甲酸、2-羟基乙磺酸、乙酸、抗坏血酸、苯磺酸、苯甲酸、碳酸氢根、碳酸、柠檬酸、依地酸、乙烷二磺酸、乙烷磺酸、富马酸、葡庚糖、葡糖酸、谷氨酸、乙醇酸、氢溴酸、盐酸、氢碘酸盐、羟基、羟萘、羟乙磺酸、乳酸、乳糖、十二烷基磺酸、马来酸、苹果酸、扁桃酸、甲烷磺酸、硝酸、草酸、双羟萘酸、泛酸、苯乙酸、磷酸、多聚半乳糖醛、丙酸、水杨酸、硬脂酸、亚乙酸、琥珀酸、氨基磺酸、对氨基苯磺酸、硫酸、单宁、酒石酸和对甲苯磺酸。
本发明的药学上可接受的盐可由含有酸根或碱基的母体化合物通过常规化学方法合成。一般情况下，这样的盐的制备方法是：在水或有机溶剂或两者的混合物中，经由游离酸或碱形式的这些化合物与化学计量的适当的碱或酸反应来制备。一般地，优选醚、乙酸乙酯、乙醇、异丙醇或乙腈等非水介质。
除了盐的形式，本发明所提供的化合物还存在前药形式。本文所描述的化合物的前药容易地在生理条件下发生化学变化从而转化成本发明的化合物。此外，前体药物可以在体内环境中通过化学或生化方法被转换到本发明的化合物。
本发明的某些化合物可以以非溶剂化形式或者溶剂化形式存在，包括水合物形式。一般而言，溶剂化形式与非溶剂化的形式相当，都包含在本发明的范围之内。
本发明的某些化合物可以具有不对称碳原子(光学中心)或双键。外消旋体、非对映异构体、几何异构体和单个的异构体都包括在本发明的范围之内。
除非另有说明，除非另有说明，用楔形实线键
Figure PCTCN2017086999-appb-000005
和楔形虚线键
Figure PCTCN2017086999-appb-000006
表示一个立体中心的绝对构型，用波浪线
Figure PCTCN2017086999-appb-000007
表示楔形实线键
Figure PCTCN2017086999-appb-000008
或楔形虚线键
Figure PCTCN2017086999-appb-000009
用直形实线键
Figure PCTCN2017086999-appb-000010
和直形虚线键
Figure PCTCN2017086999-appb-000011
表示立体中心的相对构型。当本文所述化合物含有烯属双键或其它几何不对称中心，除非另有规定，它们包括E、Z几何异构体。同样地，所有的互变异构形式均包括在本发明的范围之内。
本发明的化合物可以存在特定的几何或立体异构体形式。本发明设想所有的这类化合物，包括顺式和反式异构体、(-)-和(+)-对对映体、(R)-和(S)-对映体、非对映异构体、(D)-异构体、(L)-异构体，及其外消旋混合物和其他混合物，例如对映异构体或非对映体富集的混合物，所有这些混合物都属于本发明的范围之内。烷基等取代基中可存在另外的不对称碳原子。所有这些异构体以及它们的混合物，均包括在本发明的范围之内。
可以通过的手性合成或手性试剂或者其他常规技术制备光学活性的(R)-和(S)-异构体以及D和L异构体。如果想得到本发明某化合物的一种对映体，可以通过不对称合成或者具有手性助剂的衍生作用来制备，其中将所得非对映体混合物分离，并且辅助基团裂开以提供纯的所需对映异构体。或者，当分子中含有碱性官能团(如氨基)或酸性官能团(如羧基)时，与适当的光学活性的酸或碱形成非对映异构体的盐，然后通过本领域所公知的常规方法进行非对映异构体拆分，然后回收得到纯的对映体。此外， 对映异构体和非对映异构体的分离通常是通过使用色谱法完成的，所述色谱法采用手性固定相，并任选地与化学衍生法相结合(例如由胺生成氨基甲酸盐)。
本发明的化合物可以在一个或多个构成该化合物的原子上包含非天然比例的原子同位素。例如，可用放射性同位素标记化合物，比如氚(3H)，碘-125(125I)或C-14(14C)。本发明的化合物的所有同位素组成的变换，无论放射性与否，都包括在本发明的范围之内。
术语“药学上可接受的载体”是指能够递送本发明有效量活性物质、不干扰活性物质的生物活性并且对宿主或者患者无毒副作用的任何制剂或载体介质代表性的载体包括水、油、蔬菜和矿物质、膏基、洗剂基质、软膏基质等。这些基质包括悬浮剂、增粘剂、透皮促进剂等。它们的制剂为化妆品领域或局部药物领域的技术人员所周知。关于载体的其他信息，可以参考Remington:The Science and Practice of Pharmacy,21st Ed.,Lippincott,Williams&Wilkins(2005)，该文献的内容通过引用的方式并入本文。
术语“赋形剂”通常是指配制有效的药物组合物所需要载体、稀释剂和/或介质。
针对药物或药理学活性剂而言，术语“有效量”或“治疗有效量”是指无毒的但能达到预期效果的药物或药剂的足够用量。对于本发明中的口服剂型，组合物中一种活性物质的“有效量”是指与该组合物中另一种活性物质联用时为了达到预期效果所需要的用量。有效量的确定因人而异，取决于受体的年龄和一般情况，也取决于具体的活性物质，个案中合适的有效量可以由本领域技术人员根据常规试验确定。
术语“活性成分”、“治疗剂”，“活性物质”或“活性剂”是指一种化学实体，它可以有效地治疗目标紊乱、疾病或病症。
“任选”或“任选地”指的是随后描述的事件或状况可能但不是必需出现的，并且该描述包括其中所述事件或状况发生的情况以及所述事件或状况不发生的情况。
术语“被取代的”是指特定原子上的任意一个或多个氢原子被取代基取代，可以包括重氢和氢的变体，只要特定原子的价态是正常的并且取代后的化合物是稳定的。当取代基为氧(即＝O)时，意味着两个氢原子被取代。氧取代不会发生在芳香基上。术语“任选被取代的”是指可以被取代，也可以不被取代，除非另有规定，取代基的种类和数目在化学上可以实现的基础上可以是任意的。
当任何变量(例如R)在化合物的组成或结构中出现一次以上时，其在每一种情况下的定义都是独立的。因此，例如，如果一个基团被0-2个R所取代，则所述基团可以任选地至多被两个R所取代，并且每种情况下的R都有独立的选项。此外，取代基和/或其变体的组合只有在这样的组合会产生稳定的化合物的情况下才是被允许的。
当一个连接基团的数量为0时，比如-(CRR)0-，表示该连接基团为单键。
当其中一个变量选自单键时，表示其连接的两个基团直接相连，比如A-L-Z中L代表单键时表示该结构实际上是A-Z。
当一个取代基为空缺时，表示该取代基是不存在的，比如A-X中X为空缺时表示该结构实际上是A。当一个取代基可以连接到一个环上的一个以上原子时，这种取代基可以与这个环上的任意原子相键合，例如，结构单元
Figure PCTCN2017086999-appb-000012
或
Figure PCTCN2017086999-appb-000013
表示取代基R可在环己基或者环己二烯上的任意一个位置发生取代。当所列举的取代基中没有指明其通过哪一个原子连接到被取代的基团上时，这种取 代基可以通过其任何原子相键合，例如，吡啶基作为取代基可以通过吡啶环上任意一个碳原子连接到被取代的基团上。当所列举的连接基团没有指明其连接方向，其连接方向是任意的，例如，
Figure PCTCN2017086999-appb-000014
中连接基团L为-M-W-，此时-M-W-既可以按与从左往右的读取顺序相同的方向连接环A和环B构成也可以按照与从左往右的读取顺序相反的方向连接环A和环B构成
Figure PCTCN2017086999-appb-000016
所述连接基团、取代基和/或其变体的组合只有在这样的组合会产生稳定的化合物的情况下才是被允许的。
除非另有规定，术语“杂”表示杂原子或杂原子团(即含有杂原子的原子团)，包括碳(C)和氢(H)以外的原子以及含有这些杂原子的原子团，例如包括氧(O)、氮(N)、硫(S)、硅(Si)、锗(Ge)、铝(Al)、硼(B)、-O-、-S-、＝O、＝S、-C(＝O)O-、-C(＝O)-、-C(＝S)-、-S(＝O)、-S(＝O)2-，以及任选被取代的-C(＝O)N(H)-、-N(H)-、-C(＝NH)-、-S(＝O)2N(H)-或-S(＝O)N(H)-。
除非另有规定，“环”表示被取代或未被取代的环烷基、杂环烷基、环烯基、杂环烯基、环炔基、杂环炔基、芳基或杂芳基。所谓的环包括单环、联环、螺环、并环或桥环。环上原子的数目通常被定义为环的元数，例如，“5～7元环”是指环绕排列5～7个原子。除非另有规定，该环任选地包含1～3个杂原子。因此，“5～7元环”包括例如苯基、吡啶和哌啶基；另一方面，术语“5～7元杂环烷基环”包括吡啶基和哌啶基，但不包括苯基。术语“环”还包括含有至少一个环的环系，其中的每一个“环”均独立地符合上述定义。
除非另有规定，术语“杂环”或“杂环基”意指稳定的含杂原子或杂原子团的单环、双环或三环，它们可以是饱和的、部分不饱和的或不饱和的(芳族的)，它们包含碳原子和1、2、3或4个独立地选自N、O和S的环杂原子，其中上述任意杂环可以稠合到一个苯环上形成双环。氮和硫杂原子可任选被氧化(即NO和S(O)p，p是1或2)。氮原子可以是被取代的或未取代的(即N或NR，其中R是H或本文已经定义过的其他取代基)。该杂环可以附着到任何杂原子或碳原子的侧基上从而形成稳定的结构。如果产生的化合物是稳定的，本文所述的杂环可以发生碳位或氮位上的取代。杂环中的氮原子任选地被季铵化。一个优选方案是，当杂环中S及O原子的总数超过1时，这些杂原子彼此不相邻。另一个优选方案是，杂环中S及O原子的总数不超过1。如本文所用，术语“芳族杂环基团”或“杂芳基”意指稳定的5、6、7元单环或双环或7、8、9或10元双环杂环基的芳香环，它包含碳原子和1、2、3或4个独立地选自N、O和S的环杂原子。氮原子可以是被取代的或未取代的(即N或NR，其中R是H或本文已经定义过的其他取代基)。氮和硫杂原子可任选被氧化(即NO和S(O)p，p是1或2)。值得注意的是，芳香杂环上S和O原子的总数不超过1。桥环也包含在杂环的定义中。当一个或多个原子(即C、O、N或S)连接两个不相邻的碳原子或氮原子时形成桥环。优选的桥环包括但不限于：一个碳原子、两个碳原子、一个氮原子、两个氮原子和一个碳-氮基。值得注意的是，一个桥总是将单环转换成三环。桥环中，环上的取代基也可以出现在桥上。
杂环化合物的实例包括但不限于：吖啶基、吖辛因基、苯并咪唑基、苯并呋喃基、苯并巯基呋喃基、苯并巯基苯基、苯并恶唑基、苯并恶唑啉基、苯并噻唑基、苯并三唑基、苯并四唑基、苯并异恶唑基、苯并异噻唑基、苯并咪唑啉基、咔唑基、4aH-咔唑基、咔啉基、苯并二氢吡喃基、色烯、噌啉基十氢喹啉基、2H,6H-1,5,2-二噻嗪基、二氢呋喃并[2,3-b]四氢呋喃基、呋喃基、呋咱基、咪唑烷基、咪唑啉基、咪唑基、1H-吲唑基、吲哚烯基、二氢吲哚基、中氮茚基、吲哚基、3H-吲哚基、异苯并呋喃基、异吲哚基、异二氢吲哚基、异喹啉基、异噻唑基、异恶唑基、亚甲二氧基苯基、吗啉基、萘啶基，八氢异喹啉基、恶二唑基、1,2,3-恶二唑基、1,2,4-恶二唑基、1,2,5-恶二唑基、1,3,4-恶二唑基、恶唑烷基、恶唑基、羟吲哚基、嘧啶基、菲啶基、菲咯啉基、吩嗪、吩噻嗪、苯并黄嘌呤基、酚恶嗪基、酞嗪基、哌嗪基、哌啶基、哌啶酮基、4-哌啶酮基、胡椒基、蝶啶基、嘌呤基、吡喃基、吡嗪基、吡唑烷基、吡唑啉基、吡唑基、哒嗪基、吡啶并恶唑、吡啶并咪唑、吡啶并噻唑、吡啶基、吡咯烷基、吡咯啉基、2H-吡咯基、吡咯基、喹唑啉基、喹啉基、4H-喹嗪基、喹喔啉基、奎宁环基、四氢呋喃基、四氢异喹啉基、四氢喹啉基、四唑基，6H-1,2,5-噻二嗪基、1,2,3-噻二唑基、1,2,4-噻二唑基、1,2,5-噻二唑基、1,3,4-噻二唑基、噻蒽基、噻唑基、异噻唑基噻吩基、噻吩并恶唑基、噻吩并噻唑基、噻吩并咪唑基、噻吩基、三嗪基、1H-1,2,3-三唑基、2H-1,2,3-三唑基、1H-1,2,4-三唑基、4H-1,2,4-三唑基和呫吨基。还包括稠环和螺环化合物。
除非另有规定，术语“烃基”或者其下位概念(比如烷基、烯基、炔基、芳基等等)本身或者作为另一取代基的一部分表示直链的、支链的或环状的烃原子团或其组合，可以是完全饱和的(如烷基)、单元或多元不饱和的(如烯基、炔基、芳基)，可以是单取代或多取代的，可以是一价(如甲基)、二价(如亚甲基)或者多价(如次甲基)，可以包括二价或多价原子团，具有指定数量的碳原子(如C1-C12表示1至12个碳，C1-12选自C1、C2、C3、C4、C5、C6、C7、C8、C9、C10、C11和C12；C3-12选自C3、C4、C5、C6、C7、C8、C9、C10、C11和C12。)。“烃基”包括但不限于脂肪烃基和芳香烃基，所述脂肪烃基包括链状和环状，具体包括但不限于烷基、烯基、炔基，所述芳香烃基包括但不限于6-12元的芳香烃基，例如苯、萘等。在一些实施例中，术语“烃基”表示直链的或支链的原子团或它们的组合，可以是完全饱和的、单元或多元不饱和的，可以包括二价和多价原子团。饱和烃原子团的实例包括但不限于甲基、乙基、正丙基、异丙基、正丁基、叔丁基、异丁基、仲丁基、异丁基、环己基、(环己基)甲基、环丙基甲基，以及正戊基、正己基、正庚基、正辛基等原子团的同系物或异构体。不饱和烃基具有一个或多个双键或三键，其实例包括但不限于乙烯基、2-丙烯基、丁烯基、巴豆基、2-异戊烯基、2-(丁二烯基)、2,4-戊二烯基、3-(1,4-戊二烯基)、乙炔基、1-和3-丙炔基，3-丁炔基，以及更高级的同系物和异构体。
除非另有规定，术语“杂烃基”或者其下位概念(比如杂烷基、杂烯基、杂炔基、杂芳基等等)本身或者与另一术语联合表示稳定的直链的、支链的或环状的烃原子团或其组合，有一定数目的碳原子和至少一个杂原子组成。在一些实施例中，术语“杂烷基”本身或者与另一术语联合表示稳定的直链的、支链的烃原子团或其组合物，有一定数目的碳原子和至少一个杂原子组成。在一个典型实施例中，杂原子选自B、O、N和S，其中氮和硫原子任选地被氧化，氮杂原子任选地被季铵化。杂原子或杂原子团可以位于杂烃基的任何内部位置，包括该烃基附着于分子其余部分的位置，但术语“烷氧基”、“烷氨基”和“烷硫基”(或硫代烷氧基)属于惯用表达，是指分别通过一个氧原子、氨基或硫原子连接到分子的其余部 分的那些烷基基团。实例包括但不限于-CH2-CH2-O-CH3、-CH2-CH2-NH-CH3、-CH2-CH2-N(CH3)-CH3、-CH2-S-CH2-CH3、-CH2-CH2、-S(O)-CH3、-CH2-CH2-S(O)2-CH3、-CH＝CH-O-CH3、-CH2-CH＝N-OCH3和–CH＝CH-N(CH3)-CH3。至多两个杂原子可以是连续的，例如-CH2-NH-OCH3。
除非另有规定，术语“环烃基”、“杂环烃基”或者其下位概念(比如芳基、杂芳基、环烷基、杂环烷基、环烯基、杂环烯基、环炔基、杂环炔基等等)本身或与其他术语联合分别表示环化的“烃基”、“杂烃基”。此外，就杂烃基或杂环烃基(比如杂烷基、杂环烷基)而言，杂原子可以占据该杂环附着于分子其余部分的位置。环烃基的实例包括但不限于环戊基、环己基、1-环己烯基、3-环己烯基、环庚基等。杂环基的非限制性实例包括1-(1,2,5,6-四氢吡啶基)、1-哌啶基、2-哌啶基，3-哌啶基、4-吗啉基、3-吗啉基、四氢呋喃-2-基、四氢呋喃吲哚-3-基、四氢噻吩-2-基、四氢噻吩-3-基，1-哌嗪基和2-哌嗪基。
除非另有规定，术语“烷基”用于表示直链或支链的饱和烃基,可以是单取代(如-CH2F)或多取代的(如-CF3)，可以是一价(如甲基)、二价(如亚甲基)或者多价(如次甲基)。烷基的例子包括甲基(Me)，乙基(Et)，丙基(如，n-丙基和异丙基)，丁基(如，n-丁基，异丁基，s-丁基，t-丁基)，戊基(如，n-戊基，异戊基，新戊基)等。
除非另有规定，“烯基”指在链的任何位点上具有一个或多个碳碳双键的烷基,可以是单取代或多取代的，可以是一价、二价或者多价。烯基的例子包括乙烯基，丙烯基，丁烯基，戊烯基，己烯基，丁间二烯基，戊间二烯基，己间二烯基等。
除非另有规定，“炔基”指在链的任何位点上具有一个或多个碳碳三键的烷基，可以是单取代或多取代的，可以是一价、二价或者多价。炔基的例子包括乙炔基，丙炔基，丁炔基，戊炔基等。
除非另有规定，环烷基包括任何稳定的环状或多环烃基，任何碳原子都是饱和的，可以是单取代或多取代的，可以是一价、二价或者多价。这些环烷基的实例包括，但不限于，环丙基、降冰片烷基、[2.2.2]二环辛烷、[4.4.0]二环癸烷等。
除非另有规定，环烯基包括任何稳定的环状或多环烃基，该烃基在环的任何位点含有一个或多个不饱和的碳-碳双键，可以是单取代或多取代的，可以是一价、二价或者多价。这些环烯基的实例包括，但不限于，环戊烯基、环己烯基等。
除非另有规定，环炔基包括任何稳定的环状或多环烃基，该烃基在环的任何位点含有一个或多个碳-碳三键，可以是单取代或多取代的，可以是一价、二价或者多价。
除非另有规定，术语“卤代素”或“卤素”本身或作为另一取代基的一部分表示氟、氯、溴或碘原子。此外，术语“卤代烷基”意在包括单卤代烷基和多卤代烷基。例如，术语“卤代(C1-C4)烷基”意在包括但不仅限于三氟甲基、2,2,2-三氟乙基、4-氯丁基和3-溴丙基等等。除非另有规定，卤代烷基的实例包括但不仅限于：三氟甲基、三氯甲基、五氟乙基，和五氯乙基。
“烷氧基”代表通过氧桥连接的具有特定数目碳原子的上述烷基，除非另有规定，C1-6烷氧基包括C1、C2、C3、C4、C5和C6的烷氧基。烷氧基的例子包括但不限于：甲氧基、乙氧基、正丙氧基、异丙氧基、正丁氧基、仲丁氧基、叔丁氧基、正戊氧基和S-戊氧基。
除非另有规定，术语“芳基”表示多不饱和的芳族烃取代基，可以是单取代或多取代的，可以是一价、二价或者多价，它可以是单环或多环(比如1至3个环；其中至少一个环是芳族的)，它们稠合在一起 或共价连接。术语“杂芳基”是指含有一至四个杂原子的芳基(或环)。在一个示范性实例中，杂原子选自B、N、O和S，其中氮和硫原子任选地被氧化，氮原子任选地被季铵化。杂芳基可通过杂原子连接到分子的其余部分。芳基或杂芳基的非限制性实施例包括苯基、萘基、联苯基、吡咯基、吡唑基、咪唑基、吡嗪基、恶唑基、苯基-恶唑基、异恶唑基、噻唑基、呋喃基、噻吩基、吡啶基、嘧啶基、苯并噻唑基、嘌呤基、苯并咪唑基、吲哚基、异喹啉基、喹喔啉基、喹啉基、1-萘基、2-萘基、4-联苯基、1-吡咯基、2-吡咯基、3-吡咯基、3-吡唑基、2-咪唑基、4-咪唑基、吡嗪基、2-恶唑基、4-恶唑基、2-苯基-4-恶唑基、5-恶唑基、3-异恶唑基、4-异恶唑基、5-异恶唑基、2-噻唑基、4-噻唑基、5-噻唑基、2-呋喃基、3-呋喃基、2-噻吩基、3-噻吩基、2-吡啶基、3-吡啶基、4-吡啶基、2-嘧啶基、4-嘧啶基、5-苯并噻唑基、嘌呤基、2-苯并咪唑基、5-吲哚基、1-异喹啉基、5-异喹啉基、2-喹喔啉基、5-喹喔啉基、3-喹啉基和6-喹啉基。上述任意一个芳基和杂芳基环系的取代基选自下文所述的可接受的取代基。
除非另有规定，芳基在与其他术语联合使用时(例如芳氧基、芳硫基、芳烷基)包括如上定义的芳基和杂芳基环。因此，术语“芳烷基”意在包括芳基附着于烷基的那些原子团(例如苄基、苯乙基、吡啶基甲基等)，包括其中碳原子(如亚甲基)已经被例如氧原子代替的那些烷基，例如苯氧基甲基、2-吡啶氧甲基3-(1-萘氧基)丙基等。
术语“离去基团”是指可以被另一种官能团或原子通过取代反应(例如亲和取代反应)所取代的官能团或原子。例如，代表性的离去基团包括三氟甲磺酸酯；氯、溴、碘；磺酸酯基，如甲磺酸酯、甲苯磺酸酯、对溴苯磺酸酯、对甲苯磺酸酯等；酰氧基，如乙酰氧基、三氟乙酰氧基等等。
术语“保护基”包括但不限于“氨基保护基”、“羟基保护基”或“巯基保护基”。术语“氨基保护基”是指适合用于阻止氨基氮位上副反应的保护基团。代表性的氨基保护基包括但不限于：甲酰基；酰基，例如链烷酰基(如乙酰基、三氯乙酰基或三氟乙酰基)；烷氧基羰基，如叔丁氧基羰基(Boc)；芳基甲氧羰基，如苄氧羰基(Cbz)和9-芴甲氧羰基(Fmoc)；芳基甲基，如苄基(Bn)、三苯甲基(Tr)、1,1-二-(4'-甲氧基苯基)甲基；甲硅烷基，如三甲基甲硅烷基(TMS)和叔丁基二甲基甲硅烷基(TBS)等等。术语“羟基保护基”是指适合用于阻止羟基副反应的保护基。代表性羟基保护基包括但不限于：烷基，如甲基、乙基和叔丁基；酰基，例如链烷酰基(如乙酰基)；芳基甲基，如苄基(Bn)，对甲氧基苄基(PMB)、9-芴基甲基(Fm)和二苯基甲基(二苯甲基，DPM)；甲硅烷基，如三甲基甲硅烷基(TMS)和叔丁基二甲基甲硅烷基(TBS)等等。
本发明所使用的溶剂可经市售获得。
本发明采用下述缩略词：aq代表水；HATU代表O-(7-氮杂苯并三唑-1-基)-N，N，N'，N'-四甲基脲六氟磷酸盐；EDC代表N-(3-二甲基氨基丙基)-N'-乙基碳二亚胺盐酸盐；m-CPBA代表3-氯过氧苯甲酸；eq代表当量、等量；CDI代表羰基二咪唑；DCM代表二氯甲烷；PE代表石油醚；DIAD代表偶氮二羧酸二异丙酯；DMF代表N，N-二甲基甲酰胺；DMSO代表二甲亚砜；EtOAc代表乙酸乙酯；EtOH代表乙醇；MeOH代表甲醇；CBz代表苄氧羰基，是一种胺保护基团；BOC代表叔丁基羰基是一种胺保护基团；HOAc代表乙酸；NaCNBH3代表氰基硼氢化钠；r.t.代表室温；O/N代表过夜；THF代表四氢呋喃；Boc2O代表二-叔丁基二碳酸酯；TFA代表三氟乙酸；DIPEA代表二异丙基乙基胺；SOCl2代表氯化亚砜；CS2代表二硫化碳；TsOH代表对甲苯磺酸；NFSI代表N-氟-N-(苯磺酰基)苯磺酰胺； NCS代表1-氯吡咯烷-2,5-二酮；n-Bu4NF代表氟化四丁基铵；iPrOH代表2-丙醇；mp代表熔点；LDA代表二异丙基胺基锂。
化合物经手工或者
Figure PCTCN2017086999-appb-000017
软件命名，市售化合物采用供应商目录名称。
附图说明
图1为产KPC型β-内酰胺酶的克雷伯肺炎杆菌实验结果。
具体实施方式
下面通过实施例对本发明进行详细描述，但并不意味着对本发明任何不利限制。本文已经详细地描述了本发明，其中也公开了其具体实施例方式，对本领域的技术人员而言，在不脱离本发明精神和范围的情况下针对本发明具体实施方式进行各种变化和改进将是显而易见的。
实施例1:化合物1
Figure PCTCN2017086999-appb-000018
步骤一：
将原料1-A(50克，26.62毫摩尔)，N-羟基邻苯二甲酰亚胺(8.69克，53.24毫摩尔)和三乙胺(6.73克，66.55毫摩尔)溶于100毫升N,N-二甲基甲酰胺中，加热到50℃，搅拌16小时。反应液冷却到室温，搅拌下倒入100毫升冰水中，抽滤，固体用10毫升冷水洗涤三次，干燥得化合物1-B(9.3克，收率97％)。
步骤二：
将化合物1-B(6.0克，17.03毫摩尔)悬浮于400毫升二氯甲烷和150毫升甲醇中，向其中加入85％水合肼(1.71克，34.06毫摩尔，1.66毫升)。反应液在25℃下搅拌18小时，过滤，滤饼用50毫升乙酸乙酯洗涤，滤液浓缩至干，剩余物用40毫升石油醚/乙酸乙酸(3:1)打浆，过滤，重复打浆两次，滤液合并浓缩得化合物1-C(980毫克，收率62％)。
步骤三：
将化合物1-C(980毫克，10.64毫摩尔)溶于50毫升二氯甲烷中，冷却到-10℃，用注射器加入三乙胺(1.08克,10.64毫摩尔,1.47毫升)，然后滴入二碳酸二叔丁酯(2.32克,10.64毫摩尔)的30毫升二氯甲烷溶液。反应液缓慢升到室温(25℃)，搅拌20小时。浓缩，剩余物经硅胶柱纯化(乙酸乙酯/石油醚混合液，梯度30％～50％)得化合物1-D(700毫克,收率34％)。
步骤四：
将化合物1-D(300毫克,1.56毫摩尔)，(2S,5R)-6-苄氧基-7-氧-1,6-二氮杂二环[3.2.1]辛-2-羧酸(431.23毫克,1.56毫摩尔)(合成方法参考专利WO2012172368A1)，EDCI(388.77毫克,2.03毫摩尔),HOBt(274.02毫克,2.03毫摩尔)和二异丙基乙胺(201.62毫克,1.56毫摩尔,272.46微升)依次加入20毫升二氯甲烷中。反应液于室温(25℃)下搅拌20小时后加入30毫升二氯甲烷稀释，用15毫升水洗两次，15毫升盐水洗一次，有机相用无水硫酸钠干燥后过滤，滤液浓缩至干，粗品经硅胶柱纯化(乙酸乙酯/石油醚混合液，梯度30％～50％)得化合物1-E(262毫克，收率67％)。
步骤五：
化合物1-E(760.00毫克,1.69毫摩尔)溶解在二氯甲烷(7.00毫升)中，20℃下加入三氟乙酸(3.08克,27.01毫摩尔,2.00毫升)并搅拌3小时，将反应混合物浓缩，用乙酸乙酯(50毫升)稀释并用饱和碳酸氢钠(50毫升)洗涤，再用饱和食盐水(50毫升)洗涤一次，有机相用无水硫酸钠干燥，过滤浓缩得到化合物1-F(410.00毫克,收率65.68％)。
步骤六：
化合物1-F(200.00毫克,570.83微摩尔)和(E)-叔丁基(叔丁氧基羰基)氨基(亚甲基)氨基甲酸酯(177.16毫克,570.83微摩尔)溶解在乙腈(2毫升)中并在20℃搅拌16小时，反应完毕浓缩，将剩余物进行硅胶柱层析(乙酸乙酯/石油醚＝0～2/1梯度洗脱)得到化合物1-G(300.00毫克,收率86.91％)。
步骤七：
化合物1-G(300.00毫克,506.21微摩尔)溶解在异丙醇(3.00毫升)/水(3.00毫升)中，加入湿钯炭(50.00毫克,10％)，混合物在氢气氛围下于18-28℃搅拌2小时，过滤，得化合物1-H的异丙醇/水滤液，直接用于下一步反应。
步骤八：
在化合物1-H(250.00毫克,497.49微摩尔)的异丙醇(3.00毫升)/水(3.00毫升)中加入三氧化硫三甲胺配合物(69.24毫克,497.49微摩尔)和三乙胺(10.07毫克,99.50微摩尔,13.79微升)，将此混合物在18-28℃下搅拌16小时。反应完毕用乙酸乙酯/石油醚(2/1,6毫升，两次)洗涤，收集水相并加入四丁基硫酸氢胺(168.43毫克,496.07微摩尔)在室温下搅拌0.5小时，然后用乙酸乙酯(15毫升，两次)萃取，萃取液用饱和食盐水(10毫升)洗涤，无水硫酸钠干燥，过滤，浓缩得化合物1-I(400.00毫克,475.71微摩尔,收率95.89％)。
步骤九：
化合物1-I(200.00毫克,242.71微摩尔)溶解在无水二氯甲烷(2.00毫升)中，氮气氛围保护下冷却到0℃并加入三氟乙酸(1.54克,13.51毫摩尔,1.00毫升)搅拌2小时，再在25℃搅拌4小时，然后在空气中浓缩，剩余物用乙腈(2毫升)打浆三次得粗品用高效液相色谱分离得到化合物1(35.00毫克,收率18.91％)。1H NMR(400MHz,D2O)4.15(s,1H),4.10～4.08(m,2H),4.03-3.99(m,3H),3.26(d,J＝12Hz,1H),3.09(d,J＝12Hz,1H),2.13-1.99(m,2H),1.94–1.74(m,2H)；LCMS(ESI)m/z:383.1(M+1)。
实验例1：体外协同抑制浓度(SIC)测试方法
协同抑制浓度测试的建立基于临床实验室标准化协会(CLSI)方法M7，联用的抗生素起始浓度为128微克/毫升，进行连续的稀释，总共是11个系列稀释浓度，活性的β-内酰胺酶抑制剂测试浓度固定在4微克/毫升。
实验目的：
本实验旨在评估实施例中的化合物在体外活性中对比参照化合物OP-0595是否具有优势，本系列实验会从两个角度来考察：一方面是实施例中的化合物恢复抗生素的抗菌活性或者对抗生素产生增效作用；另一方面化合物自身相对于抗生素的抗菌能力。
实验方法：
1)待测化合物溶解(如果不溶解可以悬浮)在二甲基亚砜中稀释到浓度为12.8毫克/毫升作为原液，头孢他啶(CAZ)溶解在水中稀释到25.6毫克/毫升，厄它培南(ETP)溶解在磷酸缓冲溶液(PBS)中稀释到25.6毫克/毫升。
2)向96-V孔板的第2-12列内加入30微升二甲基亚砜。将60微升配制好的头孢他啶加到第1列内。从第1列取30微升头孢他啶到第2列，用排枪混匀。同样的操作直到第11列，将第11列的混合物弃去30微升。这是化合物母板。
3)将浓度为12.8毫克/毫升待测化合物的用DMSO稀释为0.8毫克/毫升后取30微升加入到母板的一列中。用排枪混匀母板内的液体。
4)在实验前一天，将保存在-80℃冰箱内的甘油菌取一环划线在胰酶大豆琼脂平板(TSA)上，将该平板放于37℃培养箱过夜培养。在实验当天，将细菌单克隆悬浮在生理盐水内并将浊度调为0.5标准麦氏浊度，相当于1×108CFU/毫升。将此悬浮液用阳离子调节米勒-辛顿肉汤(CAMHB)稀释100倍至1×106CFU/毫升，此为接种液。。
5)96-U型板作为实验板。先往实验板的所有孔内加入98微升CAMHB.将母板内的溶液转移2微 升到实验板内。取100微升接种液加到实验板的所有孔内。实验板的每一行包括头孢他啶/待测化合物或厄他培南/待测化合物的浓度分别为128/4,64/4,32/4,16/4,8/4,4/4,2/4,1/4,0.5/4,0.25/4,0.125/4,0/4微克/毫升。
6)实验板放在37℃培养20小时。头孢他啶的最低抑菌浓度为可以完全或明显抑制细菌生长的最低浓℃。
待测化合物或者抗生素单独的抗菌活性的测定同样采用上述的方法，表1是本实验所用的产β-内酰胺酶的细菌菌株的具体信息：
表1 产β-内酰胺酶的细菌菌株的种类以及来源
Figure PCTCN2017086999-appb-000019
注1:表1中细菌菌株产β-内酰胺酶的种类来源于供应商的公开网络信息；
注2：“ATCC”是“American Type Culture Colletcion”的缩写，“CCUG”是“Culture Collection University of Goteborg”的缩写，“NCTC”是“NCTC–National Collection of Type Culture”的缩写。
实验结果：见表2～3。
表2 化合物1与头孢他啶的对细菌的协同抑制作用(单位:μg/mL)
Figure PCTCN2017086999-appb-000020
表3 化合物1与厄他培南的对细菌的协同抑制作用(单位:μg/mL)
Figure PCTCN2017086999-appb-000021
结论：化合物1对恢复头孢他啶的抗菌活性的能力非常高，表现出了对抗生素头孢他啶很好的协同抗菌作用。化合物1联用抗生素厄他培南，使厄他培南的活性提高了显著提高，表现出了很好的协同抗菌作用。
实验例2：体外酶学实验方法
实验目的：
本试验旨在评估实施例化合物相比OP-0595对β-内酰胺酶的抑制活性的优势。
实验方法：
表4 酶学实验100微升反应体系
酶 酶使用终浓度 底物(Nitrocefin)使用终浓度 反应缓冲液
TEM-1 0.11nM 0.1mM 1×PBS,pH 7.4,0.1mg/mL BSA
AmpC-EC 1.98uM 0.1mM 1×PBS,pH 7.4,0.1mg/mL BSA
SHV-8 67.64nM 0.1mM 1×PBS,pH 7.4,0.1mg/mL BSA
CTX-M-44 0.68nM 0.1mM 1×PBS,pH 7.4,0.1mg/mL BSA
AmpC-PA 1.18nM 0.1mM 1×PBS,pH 7.4,0.1mg/mL BSA
OXA-2 68.40nM 0.1mM 1×PBS,pH 7.4,0.1mg/mL BSA
OXA-9 1.00nM 0.1mM 1×PBS,pH 7.4,0.1mg/mL BSA
1)化合物溶于DMSO中制备储存母液(12.8毫克/毫升,按照实验例1的方法)；
2)制备缓冲溶液A(1×PBS,pH 7.4,0.1毫克/毫升BSA)供酶测试用；
3)在一96孔尖底板中，将化合物母液于DMSO中进行11次4倍的梯度稀释，此为工作液。使用96孔平底板为测试孔板，每孔中预先加入对应的反应缓冲液，随后每孔加相应体积的工作液(100μM-0.095nM和0nM)。其中，EDTA-Na2作为NDM-1测试的对照起始终浓度为20mM；
4)加入对应的β-内酰胺酶，将测试孔板于37℃孵育5分钟；
5)加入5μl Nitrocefin(终反应体积为100微升)；使用酶标仪对平板内反应溶液的吸光度OD490进行跟踪记录，每分钟读取一次吸光度，跟踪30分钟；
6)酶标仪可以给出OD490随时间增长的曲线。于曲线的线性范围内选取两个数据点Abs1和Abs2计算曲线斜率(Abs2-Abs1)/(T2-T1)。
7)相对抑制率的计算公式如下：Slope(EC)为在没有抑制剂时的斜率，Slop(S)为在某一抑制剂浓度时的斜率。
Figure PCTCN2017086999-appb-000022
相对抑制率和对应的抑制剂浓度用于计算该抑制剂对β-内酰胺酶的IC50值。本实验使用GraphPad Prism 5.0自带的公式，log(inhibitor)vs.normalized response—Variable slope,计算IC50。
备注：PBS指的是磷酸盐缓冲溶液；BSA指的是牛血清白蛋白
实验结果：见表5。
表5 化合物对β-内酰胺酶抑制试验结果
酶半数抑制浓度(IC50,nM) OP-0595 阿维巴坦 化合物1
TEM-1(A类) 157.20 12.39 38.94
KPC(A类) 239.10 13.6 43.13
AmpC-EC(C类) 22.73 107.00 20.17
CTX-M-44(C类) 194.80 66.98 31.92
AmpC-PA(C类) 343.00 213.70 98.63
OXA-2(D类) 3451 1489 1547
OXA-9(D类) 51711 3129 4995
结论：化合物1对A类和C类β-内酰胺酶均有较好的抑制效果。
实验例3：中国临床分离菌体外协同抑制浓度(SIC)测试方法
实验目的：
考察BLI(β-内酰胺酶抑制剂)化合物1对主要碳青霉烯酶活性的抑制作用。
实验方法：
肉汤微量稀释法测定抗菌药(含与不含BLI先导化合物)对临床分离产碳青霉烯酶菌株的最低抑菌浓度(MIC)。
1.药敏试验：按2016年版美国Clinical and Laboratory Standards Institute(CLSI)文件描述的抗微生物药药敏试验的方法进行，采用微量肉汤稀释法测定常用抗菌药对临床分离细菌的MIC。
2.菌株：产KPC-2型碳青霉烯酶和NDM-1金属酶菌株各8株，产OXA-181型碳青霉烯酶菌株6株。所有菌株均为临床分离的肺炎克雷伯菌。
3.浓度：抗菌药物浓度范围：0.06μg/mL-128μg/mL，共12个浓度；酶抑制剂浓度：固定为4μg/mL。
4.质控菌株：药敏试验质控菌株包括大肠埃希菌ATCC 25922和ATCC 35218。
实验结果：见表6。
表6 化合物1对中国分离菌抑制试验结果
Figure PCTCN2017086999-appb-000023
Figure PCTCN2017086999-appb-000024
结论：化合物1和抗生素的组合无论对产KPC-2,NDM-1或OXA-181型碳青霉烯酶的临床分离克雷伯菌均具有强大的抑菌作用。尤其是在对NDM-1型碳青霉烯酶的细菌，化合物1的抑制作用明显优于阿维巴坦。
实验例4：小鼠肺部感染模型
实验目的：
本试验旨在考察实施例中的化合物在小鼠肺部感染模型中的是否具有药效，并进一步评估其药效对比参照化合物OP-0595是否具有显著优势。
实验材料：
7周左右大小的雌性CD-1小鼠，体重26～28克左右；环磷酰胺感染前4天注射150毫克/千克，1天前再注射100毫克/千克；感染细菌为肺炎克雷伯细菌(ATCC BAA-1705，KPC-2)。化合物1，参照化合物OP-0595均为实验室合成。
实验流程：
雌性CD-1小鼠通过滴鼻感染肺炎克雷伯菌，每只小鼠通过鼻腔滴入50ul菌液，剂量为每只小鼠3.14E+07CFU，在感染后2h，4h，6h和8h，各组小鼠通过腹腔注射分别给予对应的化合物或联用化合物治疗。
感染后10h，第1，2和3组的小鼠安乐死后，取肺置入盛有10ml无菌生理盐水的50ml离心管中，放在湿冰上转移至BSL-2实验室进行CFU计数，感染后20h，第4，5和6组的小鼠被安乐死，处置程序同前。
肺脏使用IKA T10匀浆机研磨(最高转速20S，重复一次)，匀浆液梯度稀释后点于胰蛋白胨大豆琼脂平板，置入37度培养箱进行细菌培养，24h后，取出平板，数出平板上各稀释梯度匀浆液长出的单菌落数，并由此计算每只小鼠肺部的荷菌量。
实验方案：
表7 化合物1和参照化合物OP-0595在小鼠大腿肌肉感染模型的药效评价方案
Figure PCTCN2017086999-appb-000025
实验结果：见附图1。
结论：从药效结果可以看出，两个不同剂量下，化合物1组在小鼠模型中的体内药效比参照化合物OP-0595组，荷菌量降低了0.5-1.5个log。化合物1药效明显优于参照化合物OP-0595。

Claims (6)

  1. 式(I)所示化合物或其药学上可接受的盐，
    Figure PCTCN2017086999-appb-100001
    其中，
    X选自O或N(R1)；
    R1选自任选被1、2或3个R取代的C1-6烷基、C1-6杂烷基、C3-6环烷基、3～6元杂环烷基、5～6元芳基或杂芳基；
    R选自F、Cl、Br、I、CN、OH、NH2、COOH，或选自任选被1、2或3个R’取代的C1-6烷基、C1-6杂烷基、C3-6环烷基、3～6元杂环烷基、苯基、5～6元杂芳基；
    R’选自F、Cl、Br、I、OH、CN、NH2、COOH、Me、Et、CF3、CHF2、CH2F、NHCH3、N(CH3)2；
    “杂”表示杂原子或杂原子团，选自-C(＝O)N(R)-、-N(R)-、-C(＝NR)-、-S(＝O)2N(R)-、-S(＝O)N(R)-、-O-、-S-、＝O、＝S、-O-N＝、-C(＝O)O-、-C(＝O)-、-C(＝S)-、-S(＝O)-、-S(＝O)2-、-N(R)C(＝O)N(R)-；
    以上任何一种情况下，杂原子或杂原子团的数目分别独立地选自1、2或3。
  2. 根据权利要求1所述化合物或其药学上可接受的盐，其中，R选自F、Cl、Br、I、CN、OH、NH2、COOH、Me、Et、CF3、CHF2、CH2F、NHCH3、N(CH3)2或甲氧基。
  3. 根据权利要求1或2所述化合物或其药学上可接受的盐，其中，X选自O。
  4. 根据权利要求1或2所述化合物或其药学上可接受的盐，选自
    Figure PCTCN2017086999-appb-100002
  5. 一种药物组合物，其含有治疗有效量的根据权利要求1～4任意一项所述的化合物或其药学上可接受的盐和药学上可接受的载体。
  6. 根据权利要求1～4任意一项所述的化合物或其药学上可接受的盐或根据权利要求5所述的药物组合物在制备用于治疗细菌感染的β-内酰胺酶抑制剂中的应用。
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