WO2018028556A1 - 抗hcmv病毒化合物 - Google Patents

抗hcmv病毒化合物 Download PDF

Info

Publication number
WO2018028556A1
WO2018028556A1 PCT/CN2017/096366 CN2017096366W WO2018028556A1 WO 2018028556 A1 WO2018028556 A1 WO 2018028556A1 CN 2017096366 W CN2017096366 W CN 2017096366W WO 2018028556 A1 WO2018028556 A1 WO 2018028556A1
Authority
WO
WIPO (PCT)
Prior art keywords
group
pharmaceutically acceptable
acceptable salt
compound according
tautomer
Prior art date
Application number
PCT/CN2017/096366
Other languages
English (en)
French (fr)
Inventor
熊剑
王晶晶
伍文韬
谭海忠
彭宣嘉
张杨
陈新海
黎健
陈曙辉
Original Assignee
南京明德新药研发股份有限公司
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by 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 ES17838686T priority Critical patent/ES2882531T3/es
Priority to EP17838686.8A priority patent/EP3498715B1/en
Priority to JP2019507208A priority patent/JP6951418B2/ja
Priority to US16/323,074 priority patent/US10851112B2/en
Priority to CN201780045987.0A priority patent/CN109476677B/zh
Publication of WO2018028556A1 publication Critical patent/WO2018028556A1/zh

Links

Classifications

    • CCHEMISTRY; METALLURGY
    • C07ORGANIC CHEMISTRY
    • C07DHETEROCYCLIC COMPOUNDS
    • C07D495/00Heterocyclic compounds containing in the condensed system at least one hetero ring having sulfur atoms as the only ring hetero atoms
    • C07D495/02Heterocyclic compounds containing in the condensed system at least one hetero ring having sulfur atoms as the only ring hetero atoms in which the condensed system contains two hetero rings
    • C07D495/04Ortho-condensed systems
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61KPREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00Medicinal preparations containing organic active ingredients
    • A61K31/33Heterocyclic compounds
    • A61K31/395Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495Heterocyclic 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
    • A61K31/505Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
    • A61K31/519Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim ortho- or peri-condensed with heterocyclic rings
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61PSPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A61P31/12Antivirals
    • A61P31/20Antivirals for DNA viruses
    • A61P31/22Antivirals for DNA viruses for herpes viruses

Definitions

  • the present invention relates to a class of paracyclic compounds which are resistant to HCMV viruses and their use in the preparation of a medicament for the treatment of diseases associated with HCMV viruses. Specifically, it relates to a compound of the formula (I) and formula (II) and a pharmaceutically acceptable salt thereof.
  • HCMV Human cytomegalovirus
  • GCV ganciclovir
  • VGCV valganciclovir
  • FOS sodium foscarnet
  • CDV cidofovir
  • ganciclovir against cytomegalovirus
  • Sodium foscarnet and cidofovir are the two most common alternatives, but both have nephrotoxicity. Mutations in viral DNA polymerase targeted by these agents may lead to drug resistance, so there is still a largely unmet clinical need in the clinic, and we urgently need new and safer anti-human cytomegalovirus drugs.
  • the present invention provides a compound of the formula (II), a pharmaceutically acceptable salt thereof and a tautomer thereof,
  • Ring A is selected from a 5-membered heteroaryl ring
  • R 1 is selected from H, halogen, or selected from C 1 1-6 alkyl, C 1-6 heteroalkyl optionally substituted by 1, 2 or 3 R;
  • R 2 is selected from H, or is selected from C 1-6 alkoxy optionally substituted or 1, 2 or 3 R;
  • R 3 is selected from H or is selected from optionally substituted by 1, 2 or 3 R: C 1-6 alkyl, C 1-6 heteroalkyl;
  • T is selected from N or C(R);
  • n is selected from 1 or 2;
  • Ar is selected from phenyl, 6-membered heteroaryl optionally substituted by 1, 2 or 3 R;
  • 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.
  • the present invention provides a compound of the formula (I), a pharmaceutically acceptable salt thereof and a tautomer thereof,
  • Ring A is selected from a 5-membered heteroaryl ring
  • R 1 is selected from H, halogen, or selected from C 1 1-6 alkyl, C 1-6 heteroalkyl optionally substituted by 1, 2 or 3 R;
  • R 2 is selected from H, or is selected from C 1-6 alkoxy optionally substituted or 1, 2 or 3 R;
  • R 3 is selected from H or is selected from optionally substituted by 1, 2 or 3 R: C 1-6 alkyl, C 1-6 heteroalkyl;
  • T is selected from N or C(R);
  • Ar is selected from phenyl, 6-membered heteroaryl optionally substituted by 1, 2 or 3 R;
  • 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.
  • the ring A is selected from the group consisting of a thienyl group, a furyl group, an oxazolyl group, an isothiazolyl group, and an isoxazolyl group.
  • the structural unit From:
  • R 1 is selected from the group consisting of H, F, Cl, Br, I, or selected from the group consisting of: 1 , 2 or 3 R: C 1-3 alkyl, C 1-3 alkane Base-O-, C 1-3 alkyl-S-.
  • said R 1 is selected from the group consisting of H, F, Cl, Br, I, or selected from the group consisting of: 1, 2 or 3 R: Me, Et.
  • R 1 is selected from the group consisting of H, F, Cl, Br, I, Me, Et.
  • R 2 is selected from H or is selected from C 1-3 alkyl-O- which is optionally substituted by 1, 2 or 3 R.
  • R 2 is selected from H or is selected from the group consisting of optionally substituted by 1, 2 or 3 R
  • R 2 is selected from the group consisting of H
  • R 3 is selected from H or is selected from the group consisting of 1, 2 or 3 R substituted: C 1-3 alkyl, C 1-3 alkyl-O-, C 1- 3- alkyl-S-.
  • R 3 is selected from H or is selected from the group consisting of: 1, 2 or 3 R: Me, Et,
  • R 3 is selected from the group consisting of H, Me, Et, CF 3 ,
  • the T is selected from the group consisting of N, CH, C(F), C(Cl), C(Br), and C(I).
  • the Ar is optionally substituted with 1, 2 or 3 R: phenyl, pyridyl, pyrimidinyl, pyrazinyl, pyridazinyl.
  • the Ar is selected from the group consisting of: 1, 2 or 3, R:
  • the Ar is selected from the group consisting of:
  • the structural unit From:
  • the ring A is selected from the group consisting of a thienyl group, a furyl group, an oxazolyl group, an isothiazolyl group, and an isoxazolyl group.
  • the structural unit From:
  • R 1 is selected from the group consisting of H, F, Cl, Br, I, or selected from the group consisting of: 1 , 2 or 3 R: C 1-3 alkyl, C 1-3 alkane
  • the base -O-, C 1-3 alkyl-S-, R is as defined in the present invention.
  • R 1 is selected from H, F, Cl, Br, I, or selected from the group consisting of 1, 2 or 3 R: Me, Et, R are as defined herein.
  • R 1 is selected from the group consisting of H, F, Cl, Br, I, Me, Et.
  • R 2 is selected from H or is selected from C 1-3 alkyl-O-, optionally substituted by 1, 2 or 3 R, as defined in the present invention.
  • R 2 is selected from H or is selected from the group consisting of optionally substituted by 1, 2 or 3 R R is as defined by the present invention.
  • R 2 is selected from the group consisting of H
  • R 3 is selected from H or is selected from the group consisting of 1, 2 or 3 R substituted: C 1-3 alkyl, C 1-3 alkyl-O-, C 1- 3- Alkyl-S-, R is as defined in the invention.
  • R 3 is selected from H or is selected from the group consisting of: 1, 2 or 3 R: Me, Et, R is as defined by the present invention.
  • R 3 is selected from the group consisting of H, Me, Et, CF 3 ,
  • the T is selected from the group consisting of N, CH, C(F), C(Cl), C(Br), and C(I).
  • the above Ar is optionally substituted with 1, 2 or 3 R: phenyl, pyridyl, pyrimidinyl, pyrazinyl, pyridazinyl, and R is as defined herein.
  • the Ar is selected from the group consisting of: 1, 2 or 3, R: R is as defined by the present invention.
  • the Ar is selected from the group consisting of:
  • the structural unit From:
  • the structural unit From:
  • the ring A is selected from the group consisting of thienyl, furyl, oxazolyl, isothiazolyl, isoxazolyl, and other variables are as defined above.
  • R 1 is selected from the group consisting of H, F, Cl, Br, I, or selected from the group consisting of: 1 , 2 or 3 R: C 1-3 alkyl, C 1-3 alkane Base-O-, C 1-3 alkyl-S-, other variables are as defined above.
  • R 1 is selected from H, F, Cl, Br, I, or selected from the group consisting of: 1, 2 or 3 R: Me, Et, other variables are as defined above.
  • R 1 is selected from the group consisting of H, F, Cl, Br, I, Me, Et, and other variables are as defined above.
  • R 2 is selected from H or is selected from C 1-3 alkyl-O- which is optionally substituted by 1, 2 or 3 R, and other variables are as defined above.
  • R 2 is selected from H or is selected from the group consisting of optionally substituted by 1, 2 or 3 R Other variables are as defined above.
  • R 2 is selected from the group consisting of H, Other variables are as defined above.
  • R 3 is selected from H or is selected from the group consisting of 1, 2 or 3 R substituted: C 1-3 alkyl, C 1-3 alkyl-O-, C 1- 3 alkyl-S-, other variables are as defined above.
  • R 3 is selected from H or is selected from the group consisting of: 1, 2 or 3 R: Me, Et, Other variables are as defined above.
  • R 3 is selected from the group consisting of H, Me, Et, CF 3 , Other variables are as defined above.
  • the T is selected from the group consisting of N, CH, C(F), C(Cl), C(Br), and C(I), and other variables are as defined above.
  • the above Ar is optionally substituted with 1, 2 or 3 R: phenyl, pyridyl, pyrimidinyl, pyrazinyl, pyridazinyl, and other variables are as defined above.
  • the Ar is selected from the group consisting of: 1, 2 or 3, R: Other variables are as defined above.
  • the Ar is selected from the group consisting of: Other variables are as defined above.
  • R 3 is selected from the group consisting of H, Me, Et, CF 3 , Other variables are as defined above.
  • the Ar is selected from the group consisting of: Other variables are as defined above.
  • the above compounds, pharmaceutically acceptable salts thereof, and tautomers thereof are selected from the group consisting of:
  • R 1 , R 3 , R are as defined above,
  • T 1 is selected from N or CH.
  • the above compounds, pharmaceutically acceptable salts thereof, and tautomers thereof are selected from the group consisting of:
  • R 1 , R 3 , R are as defined above,
  • T 1 is selected from N or CH.
  • the present invention provides a compound of the formula, a pharmaceutically acceptable salt thereof, and tautomers thereof, which are selected from the group consisting of:
  • the above compounds, pharmaceutically acceptable salts thereof, and tautomers thereof are selected from the group consisting of:
  • the present invention also provides the use of the above compound, a pharmaceutically acceptable salt thereof and tautomer thereof for the preparation of a medicament for anti-HCMV virus.
  • the drug is mainly used to prevent human cytomegalovirus infection in patients undergoing allogeneic hematopoietic stem cell transplantation, kidney transplantation, lung transplantation and pancreas transplantation. Compared with existing clinical drugs, it has less toxic side effects, better oral bioavailability, and lower risk of drug resistance.
  • 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.
  • 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. Alternatively, when the molecule contains a basic functional group (such as an amino group) or an acidic functional group (such as a carboxyl group), it forms a diastereomer with an appropriate optically active acid or base.
  • a basic functional group such as an amino group
  • an acidic functional group such as a carboxyl group
  • the salt of the construct is then subjected to diastereomeric resolution by conventional methods well known in the art and then recovered to yield the pure enantiomer. Furthermore, the 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 an amino group from an amine). Formate).
  • 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.
  • Ketone substitution does not occur on the aryl 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.
  • 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. When a bond of a substituent can be cross-linked to two atoms on a ring, the substituent can be bonded to any atom on the ring. When the recited substituents do not indicate which atom is attached to a compound included in the chemical structural formula including but not specifically mentioned, such a substituent may be bonded through any atomic phase thereof. Combinations of substituents and/or variants thereof are permissible only if such combinations result in stable compounds. For example, a structural unit It is indicated that it can be substituted at any position on the cyclohexyl or cyclohexadiene.
  • 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. Bridge In the ring, a substituent on the ring may 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 linked.
  • 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, 1-naphthyl, 2-naphthyl, 4-biphenyl, 1-pyrrolyl, 2-pyrrolyl, 3-pyrrolyl, 3-pyridyl Azyl, 2-imidazolyl, 4-imidazolyl, pyrazinyl, 2-oxazolyl, 4-oxazolyl, 2-phenyl-4-oxazolyl, 5-oxazolyl, 3-isoxan Azyl, 4-isoxazolyl, 5-isoxazolyl, 2-thiazolyl, 4-thiazolyl, 5-thiazolyl, 2-furyl, 3-furyl, 2-thienyl, 3-thiophene , 2-pyridyl, 3-pyridyl, 4-pyridyl, 2-pyrimidinyl, 4-pyrimidinyl, 5-benzothiazolyl, 5-
  • 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-butyldimethylsilyl (TBS) )and many more.
  • 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-flu
  • the compounds of the present invention can be prepared by a variety of synthetic methods well known to those skilled in the art, including the specific embodiments set forth below, combinations thereof with other chemical synthetic methods, and those well known to those skilled in the art. Equivalent alternatives, preferred embodiments include, but are not limited to, embodiments of the invention.
  • the solvent used in the present invention is commercially available.
  • the present invention employs the following abbreviations: aq for an aqueous solution; 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; DBU stands for 1,8-diazabicyclo[5.4.0]undec-7-ene; DCM stands for dichloromethane; PE stands for petroleum ether; DIAD stands for diisopropyl azodicarboxylate DMF stands for N,N-dimethylformamide; DPPA stands for diphenylphosphoryl azide; DMSO
  • Reference Example 1 Fragment BB-1, BB-2, BB-3, BB-4, BB-5, BB-6, BB-7, BB-8, BB-9, BB-10, BB-12, BB -13, BB-14, BB-15, BB-16.
  • Step 1 Synthesis of Compound BB-1-3
  • Trifluoroacetic acid (1.54 g, 13.51 mmol, 1.00 mL, 10.31 eq) was added to a solution of BB-1-3 (400.00 mg, 1.31 mmol, 1.00 eq) in dichloromethane (5.00 mL). Stir for 3 hours. The reaction mixture was concentrated to give a crude compound BB-1 (400.00 mg, TFA). MS (ESI) m/z: 207.1.
  • Methyl acrylate (8.71 g, 101.20 mmol, 8.00 eq) was added to a solution of compound 1-2 (5.00 g, 12.65 mmol, 1.00 eq) in N,N-dimethylacetamide (60.00 mL).
  • Diacetonitrile palladium dichloride (164.12 mg, 632.50 umol, 0.05 eq), tris(o-methylphenyl) Phosphorus (385.09 mg, 1.27 mmol, 0.10 eq) and triethylamine (6.40 g, 63.25 mmol, 5.00 eq).
  • the reaction solution was replaced with nitrogen three times, and the mixture was stirred at 100 ° C for 12 hours under nitrogen atmosphere.
  • Compound 1-8 (18.00 mg, 31.11 umol, 1.00 eq) by SFC preparation method: [column model (OD (250 mm * 30 mm, 5 um), flow The mobile phase (A: carbon dioxide, B: 0.1 ammonia methanol, gradient: B 40%-40%)] gave compound WX-075 (3.00 mg, 5.03 umol, yield 16.17%, retention time: first peak) and Compound WX-076 (3.00 mg, 5.19 umol, yield 16.67%, retention time: second peak).
  • Step 7 Target compounds WX-106 and WX-107
  • reaction system was heated to 50 ° C for 2 hours, and the reaction mixture was poured into water (150 mL), and the aqueous layer was extracted with toluene (100 mL), and the organic phase was washed with saturated brine (200 mL) Drying gave crude compound 4-1 directly to ⁇ 250 mL of toluene.
  • Step 4 Target compounds WX-203 and WX-204
  • Compound 4-3 (2g, 3.20mmol, 1.00eq) was prepared by SFC [column model (IC-H (250mm*30mm, 5um), mobile phase (A: carbon dioxide, B: 0.1 ammonia methanol, gradient: B 30%- 30%)] Preparation of WX-203 (600 mg, yield 29.40%, retention time: first peak) and WX-204 (900 mg, yield 44.10%, second peak). MS (ESI) m/z :575.2[M+1].
  • Step 4 Target compounds WX-200 and WX-201
  • Compound 5-3 (0.5 g, 0.75 mmol, 1.00 eq) was prepared by SFC [column model [AS-H (250mm*30mm, 5um), mobile phase (A: carbon dioxide, B: 0.1 ammonia methanol, gradient: B 25%) -25%)], obtained WX-200 (130 mg, yield 26.00%, retention time: first peak) and WX-201 (129 mg, yield 25.00%, retention time: second peak). MS (ESI) m/z: 59:21.
  • Step 7 Target compounds WX-173 and WX-174
  • the WX-153 in the following table was synthesized by referring to the synthesis methods of the steps 1 to 8 in Example 6.
  • HCMV human cytomegalovirus
  • EC50 EC 50
  • the HCMV used in this experiment was inserted into the reporter-enhanced green fluorescent protein (EGFP) by gene recombination, and the intracellular replication of the virus can be reflected by the expression level of GFP.
  • the inhibitory activity of the compounds on HCMV GFP expression was evaluated by measuring the fluorescence intensity in the wells of different concentrations of the compounds using the high-content cell analysis platform Acumen eX3.
  • MRC5 cells were seeded into black 96-well cell culture plates at a density of 20,000 cells per well, and then cultured overnight at 37 ° C in a 5% CO 2 incubator.
  • the US3-6-EGFP-HCMV-AD169 virus was added to the cell culture well at a certain MOI (0.003-0.1) and cultured for 3 hours at 37 ° C in a 5% CO 2 incubator.
  • the virus-containing medium was aspirated and 200 ⁇ l of cell culture medium containing different concentrations of compound (4 fold dilution, 6 test concentration points) was added. The final concentration of DMSO in the medium was 1%.
  • Virus control wells (with DMSO added, no compound added) and control wells (high concentration of control compound added) were set up.
  • the cell plates were incubated at 37 ° C in a 5% CO 2 incubator for 10 days, and the cells were changed on days 4 and 7. After 10 days of culture, the fluorescence intensity was measured using a high content cell analysis platform Acumen eX3 (TTP LabTech). Raw data was used for compound antiviral activity calculations.
  • the percent inhibition were introduced into GraphPad Prism software for data processing corresponding to the dose of the compound obtained - response curves and derived EC 50 values of the test compound.
  • the protein binding rate of the test compound in CD-1 mice, SD rats, and human plasma was evaluated by equilibrium dialysis.
  • the test compounds were separately diluted into the plasma of the above three species to prepare a sample having a final concentration of 2 ⁇ M, and then the sample was added to a 96-well equilibrium dialysis apparatus, and dialyzed against a phosphate buffer solution at 37 ° C for 4 hours. Warfarin was used as a control compound in the experiment.
  • the concentration of the test compound and warfarin in plasma and buffer was determined by LC-MS/MS.
  • H stands for human
  • R stands for rat
  • M stands for mouse
  • HCMV Human cytomegalovirus
  • a gelatin sponge containing HCMV was transplanted into mice, and after 9 days of continuous administration, a gelatin sponge was collected for plaque detection.
  • the anti-HCMV effect of the compounds in this model was evaluated by measuring the amount of HCMV in the gelatin sponge.
  • the animals selected for the experiment were NOD SCID mice (purchased from Shanghai Slack Laboratory Animal Co., Ltd.), 5 weeks, male. 5 animals per group.
  • the day when the mice were subjected to gelatin sponge transplantation was set to day 0.
  • the animals were anesthetized by intraperitoneal injection of pentobarbital sodium at 75 mg/kg (10 ml/kg). After the animals entered the deep anesthesia state, the treated gelatin sponge was subcutaneously transplanted into the back of the mice.

Landscapes

  • Health & Medical Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Virology (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Medicinal Chemistry (AREA)
  • Engineering & Computer Science (AREA)
  • Biotechnology (AREA)
  • Molecular Biology (AREA)
  • Communicable Diseases (AREA)
  • Oncology (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • General Chemical & Material Sciences (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Epidemiology (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Heterocyclic Carbon Compounds Containing A Hetero Ring Having Oxygen Or Sulfur (AREA)

Abstract

一类抗HCMV病毒的并环类化合物,及其在制备治疗与HCMV病毒相关疾病的药物中的应用。具体为式(Ⅱ)所示化合物及其药学上可接受的盐。

Description

抗HCMV病毒化合物
相关申请的引用
本申请要求于2016年08月8日向中华人民共和国国家知识产权局提交的第201610644091.1号中国发明专利申请的权益,在此将其全部内容以援引的方式整体并入本文中。
技术领域
本发明涉及一类抗HCMV病毒的并环类化合物,及其在制备治疗与HCMV病毒相关疾病的药物中的应用。具体涉及式(Ⅰ)和式(Ⅱ)所示化合物及其药学上可接受的盐。
背景技术
人类巨细胞病毒(HCMV)是人类8类疱疹病毒之一,它有着世界范围的分布和较高的临床发现。尽管诊断和治疗在进步,但是在孕期和免疫低下相关的临床情况:如器官或骨髓移植,癌症和艾滋病,人类巨细胞病毒感染依然有着显著的并发症。目前批准的抗病毒的药品包括更昔洛韦(GCV),其前药缬更昔洛韦(VGCV)膦甲酸钠(FOS)和西多福韦(CDV),这些药物的靶标都是病毒DNA聚合酶抑制剂。虽然有效,但是这些药品因为严重的毒副作用、低口服生物利用度(VGCV除外),以及发生耐药性而受到限制。更昔洛韦抗巨细胞病毒的疗效有限,并且存在毒性。膦甲酸钠和西多福韦是两个最常见的替代品,但两者都有肾毒性。这些试剂靶向的病毒DNA聚合酶的突变可能导致耐药性,因此临床上仍然存在着极大未被满足的临床需求,我们迫切需要全新的、更为安全的抗人巨细胞病毒药物。
WO2004096778报道了化合物A:
Figure PCTCN2017096366-appb-000001
发明内容
本发明提供了式(Ⅱ)所示化合物、其药学上可接受的盐及其互变异构体,
Figure PCTCN2017096366-appb-000002
其中,
环A选自5元杂芳环;
R1选自H、卤素,或选自任选被1、2或3个R取代的:C1-6烷基、C1-6杂烷基;
R2选自H,或选自任选或1、2或3个R取代的C1-6烷氧基;
R3选自H,或选自任选或1、2或3个R取代的:C1-6烷基、C1-6杂烷基;
T选自N或C(R);
n选自1或2;
Ar选自任选被1、2或3个R取代的:苯基、6元杂芳基;
R选自H、F、Cl、Br、I、OH、CN、NH2、C(=O)NH2,或选自任选被1、2或3个R’取代的:C1-6烷基、C1-6杂烷基;
R’选自F、Cl、Br、I、OH、CN、NH2、COOH、Me、Et、CF3、CHF2、CH2F、NHCH3、N(CH3)2
所述5元杂芳环、6元杂芳基、C1-6杂烷基之杂原子或杂原子团,选自-C(=O)NH-、-NH-、-S(=O)2NH-、-S(=O)NH、-O-、-S-、N、-C(=O)O-、-C(=O)-、-S(=O)-和-S(=O)2-;
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。
本发明提供了式(Ⅰ)所示化合物、其药学上可接受的盐及其互变异构体,
Figure PCTCN2017096366-appb-000003
其中,
环A选自5元杂芳环;
R1选自H、卤素,或选自任选被1、2或3个R取代的:C1-6烷基、C1-6杂烷基;
R2选自H,或选自任选或1、2或3个R取代的C1-6烷氧基;
R3选自H,或选自任选或1、2或3个R取代的:C1-6烷基、C1-6杂烷基;
T选自N或C(R);
Ar选自任选被1、2或3个R取代的:苯基、6元杂芳基;
R选自H、F、Cl、Br、I、OH、CN、NH2、C(=O)NH2,或选自任选被1、2或3个R’取代的:C1-6烷基、C1-6杂烷基;
R’选自F、Cl、Br、I、OH、CN、NH2、COOH、Me、Et、CF3、CHF2、CH2F、NHCH3、N(CH3)2
所述5元杂芳环、6元杂芳基、C1-6杂烷基之杂原子或杂原子团,选自-C(=O)NH-、-NH-、-S(=O)2NH-、-S(=O)NH、-O-、-S-、N、-C(=O)O-、-C(=O)-、-S(=O)-和-S(=O)2-;
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。
本发明的一些方案中,上述R选自H、F、Cl、Br、I、OH、CN、NH2、C(=O)NH2,或选自任选被1、2或3个R’取代的:C1-3烷基、C1-3烷基-O-、C1-3烷基-S-、C1-3烷基-NH-、N,N’-二(C1-3烷基)氨基。
本发明的一些方案中,上述R选自H、F、Cl、Br、I、OH、CN、NH2、C(=O)NH2、Me、Et、
Figure PCTCN2017096366-appb-000004
Figure PCTCN2017096366-appb-000005
本发明的一些方案中,上述环A选自噻吩基、呋喃基、恶唑基、异噻唑基、异恶唑基。
本发明的一些方案中,上述其中结构单元
Figure PCTCN2017096366-appb-000006
选自:
Figure PCTCN2017096366-appb-000007
本发明的一些方案中,上述R1选自H、F、Cl、Br、I,或选自任选被1、2或3个R取代的:C1-3烷基、C1-3烷基-O-、C1-3烷基-S-。
本发明的一些方案中,上述R1选自H、F、Cl、Br、I,或选自任选被1、2或3个R取代的:Me、Et。
本发明的一些方案中,上述R1选自H、F、Cl、Br、I、Me、Et。
本发明的一些方案中,上述R2选自H,或选自任选被1、2或3个R取代的C1-3烷基-O-。
本发明的一些方案中,上述R2选自H,或选自任选被1、2或3个R取代的
Figure PCTCN2017096366-appb-000008
本发明的一些方案中,上述R2选自H、
Figure PCTCN2017096366-appb-000009
本发明的一些方案中,上述R3选自H,或选自任选被1、2或3个R取代的:C1-3烷基、C1-3烷基-O-、C1-3烷基-S-。
本发明的一些方案中,上述R3选自H,或选自任选被1、2或3个R取代的:Me、Et、
Figure PCTCN2017096366-appb-000010
本发明的一些方案中,上述R3选自H、Me、Et、CF3
Figure PCTCN2017096366-appb-000011
本发明的一些方案中,上述T选自N、CH、C(F)、C(Cl)、C(Br)和C(I)。
本发明的一些方案中,上述Ar选任被1、2或3个R取代的:苯基、吡啶基、嘧啶基、吡嗪基、哒嗪基。
本发明的一些方案中,上述Ar选自任选被1、2或3个R取代的:
Figure PCTCN2017096366-appb-000012
Figure PCTCN2017096366-appb-000013
本发明的一些方案中,上述Ar选自:
Figure PCTCN2017096366-appb-000014
Figure PCTCN2017096366-appb-000015
本发明的一些方案中,上述结构单元
Figure PCTCN2017096366-appb-000016
选自:
Figure PCTCN2017096366-appb-000017
本发明的一些方案中,上述R选自H、F、Cl、Br、I、OH、CN、NH2、C(=O)NH2,或选自任选被1、2或3个R’取代的:C1-3烷基、C1-3烷基-O-、C1-3烷基-S-、C1-3烷基-NH-、N,N’-二(C1-3烷基)氨基,R’如本发明所定义。
本发明的一些方案中,上述R选自H、F、Cl、Br、I、OH、CN、NH2、C(=O)NH2、Me、Et、
Figure PCTCN2017096366-appb-000018
Figure PCTCN2017096366-appb-000019
本发明的一些方案中,上述环A选自噻吩基、呋喃基、恶唑基、异噻唑基、异恶唑基。
本发明的一些方案中,上述结构单元
Figure PCTCN2017096366-appb-000020
选自:
Figure PCTCN2017096366-appb-000021
本发明的一些方案中,上述R1选自H、F、Cl、Br、I,或选自任选被1、2或3个R取代的:C1-3烷基、C1-3烷基-O-、C1-3烷基-S-,R如本发明所定义。
本发明的一些方案中,上述R1选自H、F、Cl、Br、I,或选自任选被1、2或3个R取代的:Me、Et,R如本发明所定义。
本发明的一些方案中,上述R1选自H、F、Cl、Br、I、Me、Et。
本发明的一些方案中,上述R2选自H,或选自任选被1、2或3个R取代的C1-3烷基-O-,R如本发明所定义。
本发明的一些方案中,上述R2选自H,或选自任选被1、2或3个R取代的
Figure PCTCN2017096366-appb-000022
R如本发明所定义。
本发明的一些方案中,上述R2选自H、
Figure PCTCN2017096366-appb-000023
本发明的一些方案中,上述R3选自H,或选自任选被1、2或3个R取代的:C1-3烷基、C1-3烷基-O-、C1-3烷基-S-,R如本发明所定义。
本发明的一些方案中,上述R3选自H,或选自任选被1、2或3个R取代的:Me、Et、
Figure PCTCN2017096366-appb-000024
R如本发明所定义。
本发明的一些方案中,上述R3选自H、Me、Et、CF3
Figure PCTCN2017096366-appb-000025
本发明的一些方案中,上述T选自N、CH、C(F)、C(Cl)、C(Br)和C(I)。
本发明的一些方案中,上述Ar选任选被1、2或3个R取代的:苯基、吡啶基、嘧啶基、吡嗪基、哒嗪基,R如本发明所定义。
本发明的一些方案中,上述Ar选自任选被1、2或3个R取代的:
Figure PCTCN2017096366-appb-000026
Figure PCTCN2017096366-appb-000027
R如本发明所定义。
本发明的一些方案中,上述Ar选自:
Figure PCTCN2017096366-appb-000028
Figure PCTCN2017096366-appb-000029
本发明的一些方案中,上述结构单元
Figure PCTCN2017096366-appb-000030
选自:
Figure PCTCN2017096366-appb-000031
Figure PCTCN2017096366-appb-000032
本发明的一些方案中,上述结构单元
Figure PCTCN2017096366-appb-000033
选自:
Figure PCTCN2017096366-appb-000034
Figure PCTCN2017096366-appb-000035
本发明的一些方案中,上述R选自H、F、Cl、Br、I、OH、CN、NH2、C(=O)NH2,或选自任选被1、2或3个R’取代的:C1-3烷基、C1-3烷基-O-、C1-3烷基-S-、C1-3烷基-NH-、N,N’-二(C1-3烷基)氨基,其他变量如上述所定义。
本发明的一些方案中,上述R选自H、F、Cl、Br、I、OH、CN、NH2、C(=O)NH2、Me、Et、
Figure PCTCN2017096366-appb-000036
Figure PCTCN2017096366-appb-000037
其他变量如上述所定义。
本发明的一些方案中,上述环A选自噻吩基、呋喃基、恶唑基、异噻唑基、异恶唑基,其他变量如上述所定义。
本发明的一些方案中,上述结构单元
Figure PCTCN2017096366-appb-000038
选自:
Figure PCTCN2017096366-appb-000039
其他变量如上述所定义。
本发明的一些方案中,上述R1选自H、F、Cl、Br、I,或选自任选被1、2或3个R取代的:C1-3烷基、C1-3烷基-O-、C1-3烷基-S-,其他变量如上述所定义。
本发明的一些方案中,上述R1选自H、F、Cl、Br、I,或选自任选被1、2或3个R取代的:Me、Et,其他变量如上述所定义。
本发明的一些方案中,上述R1选自H、F、Cl、Br、I、Me、Et,其他变量如上述所定义。
本发明的一些方案中,上述R2选自H,或选自任选被1、2或3个R取代的C1-3烷基-O-,其他变量如上述所定义。
本发明的一些方案中,上述R2选自H,或选自任选被1、2或3个R取代的
Figure PCTCN2017096366-appb-000040
其他变量如上述所定义。
本发明的一些方案中,上述R2选自H、
Figure PCTCN2017096366-appb-000041
其他变量如上述所定义。
本发明的一些方案中,上述R3选自H,或选自任选被1、2或3个R取代的:C1-3烷基、C1-3烷基-O-、C1-3烷基-S-,其他变量如上述所定义。
本发明的一些方案中,上述R3选自H,或选自任选被1、2或3个R取代的:Me、Et、
Figure PCTCN2017096366-appb-000042
其他变量如上述所定义。
本发明的一些方案中,上述R3选自H、Me、Et、CF3
Figure PCTCN2017096366-appb-000043
其他变量如上述所定义。
本发明的一些方案中,上述T选自N、CH、C(F)、C(Cl)、C(Br)和C(I),其他变量如上述所定义。
本发明的一些方案中,上述Ar选任选被1、2或3个R取代的:苯基、吡啶基、嘧啶基、吡嗪基、哒嗪基,其他变量如上述所定义。
本发明的一些方案中,上述Ar选自任选被1、2或3个R取代的:
Figure PCTCN2017096366-appb-000044
Figure PCTCN2017096366-appb-000045
其他变量如上述所定义。
本发明的一些方案中,上述Ar选自:
Figure PCTCN2017096366-appb-000046
Figure PCTCN2017096366-appb-000047
其他变量如上述所定义。
本发明的一些方案中,上述结构单元
Figure PCTCN2017096366-appb-000048
选自:
Figure PCTCN2017096366-appb-000049
其他变量如上述所定义。
本发明的一些方案中,上述R3选自H、Me、Et、CF3
Figure PCTCN2017096366-appb-000050
其他变量如上述所定义。
本发明的一些方案中,上述Ar选自:
Figure PCTCN2017096366-appb-000051
Figure PCTCN2017096366-appb-000052
其他变量如上述所定义。
本发明的一些方案中,上述结构单元
Figure PCTCN2017096366-appb-000053
选自:
Figure PCTCN2017096366-appb-000054
Figure PCTCN2017096366-appb-000055
其他变量如上述所定义。
本发明的一些方案中,上述结构单元
Figure PCTCN2017096366-appb-000056
选自:
Figure PCTCN2017096366-appb-000057
Figure PCTCN2017096366-appb-000058
其他变量如上述所定义。
本发明的一些方案中,上述化合物、其药学上可接受的盐及其互变异构体,其中选自:
Figure PCTCN2017096366-appb-000059
其中,
R1、R3、R如上述所定义,
T1选自N或CH。
本发明的一些方案中,上述化合物、其药学上可接受的盐及其互变异构体,其选自:
Figure PCTCN2017096366-appb-000060
其中,
R1、R3、R如上述所定义,
T1选自N或CH。
本发明还有一些方案是由上述变量任意组合而来。
本发明提供了下式所示化合物、其药学上可接受的盐及其互变异构体,其选自:
Figure PCTCN2017096366-appb-000061
Figure PCTCN2017096366-appb-000062
Figure PCTCN2017096366-appb-000063
本发明的一些方案中,上述化合物、其药学上可接受的盐及其互变异构体,其选自:
Figure PCTCN2017096366-appb-000064
Figure PCTCN2017096366-appb-000065
Figure PCTCN2017096366-appb-000066
Figure PCTCN2017096366-appb-000067
本发明还提供了上述化合物、其药学上可接受的盐及其互变异构体在制备抗HCMV病毒药物中的应用。
技术效果:
该药物主要用于预防异体造血干细胞移植、肾移植、肺移植及胰腺移植接受患者所出现的人巨细胞病毒感染。和现有临床用药相比,具有毒副作用更小、具有更佳的口服生物利用度,以及更低发生药物耐药的风险。
相关定义
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,用楔形键和虚线键
Figure PCTCN2017096366-appb-000068
表示一个立体中心的绝对构型,用
Figure PCTCN2017096366-appb-000069
表示一个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。当取代基为酮基(即=O)时,意味着两个氢原子被取代。酮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。当一个取代基的键可以交叉连接到一个环上的两个原子时,这种取代基可以与这个环上的任意原子相键合。当所列举的取代基中没有指明其通过哪一个原子连接到化学结构通式中包括但未具体提及的化合物时,这种取代基可以通过其任何原子相键合。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。例如,结构单元
Figure PCTCN2017096366-appb-000070
表示其可在环己基或者环己二烯上的任意一个位置发生取代。
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、1,2,3-三唑基、1,2,4-三唑基、1,2,5-三唑基、1,3,4-三唑基和呫吨基。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、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。
本发明的化合物可以通过本领域技术人员所熟知的多种合成方法来制备,包括下面列举的具体实施方式、其与其他化学合成方法的结合所形成的实施方式以及本领域技术上人员所熟知的等同替换方式,优选的实施方式包括但不限于本发明的实施例。
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代表水溶液;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;DBU代表1,8-二氮杂二环[5.4.0]十一烷-7-烯;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;DPPA代表叠氮磷酸二苯酯;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;MTBE代表甲基叔丁基醚;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;NFth代表1-氟-4-羟基-1,4-二氮杂二环辛烷二(四氟硼酸盐);NCS代表N-氯代丁二酰亚胺-;NBS代表N-溴代丁二酰亚胺;n-Bu4NF代表四丁基氟化铵;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 PCTCN2017096366-appb-000071
软件命名,市售化合物采用供应商目录名称。
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。
参考例1:片段BB-1,BB-2,BB-3,BB-4,BB-5,BB-6,BB-7,BB-8,BB-9,BB-10,BB-12,BB-13,BB-14,BB-15,BB-16.
Figure PCTCN2017096366-appb-000072
合成路线:
Figure PCTCN2017096366-appb-000073
步骤1:化合物BB-1-3的合成
在室温下向化合物BB-1-1(3.50g,17.48mmol,1.00eq)和化合物BB-1-2(4.90g,26.22mmol,3.31mL, 1.50eq)的甲苯(50.00mL)中加入三叔丁基膦(1M甲苯溶液,174.80uL,0.01eq),Pd2(dba)3(160.03mg,174.80umol,0.01eq)和叔丁醇钾(2.94g,26.22mmol,1.50eq),反应液在氮气保护下100℃搅拌12小时。化合物浓缩旋干,粗产品经硅胶柱(PE/EtOAc=2/1)纯化得到BB-1-3(2.80g,收率39.42%)。
步骤2:化合物BB-1的合成
向BB-1-3(400.00mg,1.31mmol,1.00eq)的二氯甲烷(5.00mL)溶液中加入三氟乙酸(1.54g,13.51mmol,1.00mL,10.31eq),反应液在15℃下搅拌3小时。反应液浓缩旋干得粗品化合物BB-1(400.00mg,TFA)。MS(ESI)m/z:207.1[M+1]。
参照参考例1中步骤1~2的合成方法,合成下表中各参考实例。
Figure PCTCN2017096366-appb-000074
Figure PCTCN2017096366-appb-000075
参考例2:片段BB-11
Figure PCTCN2017096366-appb-000076
在0℃下向氯化亚铜(353.28mg,3.57mmol,85.33uL,0.03eq)和Xantphos(2.06g,3.57mmol,0.03eq)的四氢呋喃(150mL)中加入叔丁醇钠(685.87mg,7.14mmol,0.06eq),反应液在0℃下搅拌一小时,
BB-11-1(30.21g,118.95mmol,1.00eq)的四氢呋喃溶液(50mL)加入到该反应液中,然后20℃在氮气保护下反应一小时。将丙炔酸甲酯(10.00g,118.95mmol,9.90mL,1.00eq)和甲醇(7.62g,237.90mmol,2.00eq)加入反应液,反应液在20℃反应12小时。将反应液旋干,加入水(200mL),用乙酸乙酯(150mL)萃取两次。有机相用饱和碳酸氢钠溶液(150mL)和饱和食盐水(100mL)分别洗涤,硫酸钠干燥,减压浓缩,所得物经硅胶柱(PE/EtOAc=20/1)纯化得BB-11(18.00g,84.89mmol,收率71.36%)。
1HNMR(400MHz,CHLOROFORM-d)δ6.75–6.86(m,1H),6.62(d,J=18Hz,1H),3.71–3.79(m,3H)1.28-1.30(m,12H)
实施例1
Figure PCTCN2017096366-appb-000077
合成路线:
Figure PCTCN2017096366-appb-000078
步骤1:化合物1-2的合成:
在冰浴下,向化合物1-1(10.00g,48.30mmol,1.00eq)的甲苯(100.00mL)溶液中加入叠氮磷酸二苯酯(19.94g,72.45mmol,1.50eq),随后滴加三乙胺(14.66g,144.90mmol,3.00eq)。混合物升至室温并搅拌1小时后,升温至80℃并搅拌1小时,化合物2-甲氧基-5-三氟甲基苯胺(12.93g,67.62mmol,1.4eq)加入反应液中并80℃搅拌过夜。反应液冷却至室温,减压浓缩,剩余物加入水(50mL)中,用乙酸乙酯(100mL)萃取三次,有机相用盐水洗涤,无水硫酸钠干燥,过滤,浓缩得到粗产品,用(石油醚:乙酸乙酯=3:1)(50mL)重结晶得到化合物1-2(12.00g,30.37mmol,收率62.87%)。1H NMR(400MHz,DMSO-d6)δ9.28(s,1H),9.07-9.17(m,1H),8.56(d,J=2.0Hz,1H),7.63-7.72(m,2H),7.33(dd,J=1.6,8.4Hz,1H),7.20(d,J=8.4Hz,1H),3.97(s,3H).
步骤2:化合物1-3的合成
在室温下,向化合物1-2(5.00g,12.65mmol,1.00eq)的N,N-二甲基乙酰胺(60.00mL)溶液中加入丙烯酸甲酯(8.71g,101.20mmol,8.00eq),双乙腈二氯化钯(164.12mg,632.50umol,0.05eq),三(邻甲基苯基) 磷(385.09mg,1.27mmol,0.10eq)和三乙胺(6.40g,63.25mmol,5.00eq)。反应液用氮气置换三次,混合物在氮气保护下100℃搅拌12小时。反应液用水(20mL)稀释,用乙酸乙酯(50mL)萃取三次,有机相用盐水洗涤,无水硫酸钠干燥,过滤,浓缩得到粗产品,经用硅胶柱层析(石油醚:乙酸乙酯=5:1至4:1)纯化得到化合物1-3(4.00g,5.99mmol,收率47.39%)。MS(ESI)m/z:400.9[M+1]。
步骤3:化合物1-4的合成:
在室温下,向化合物1-3(2.00g,5.00mmol,1.00eq)的四氢呋喃(10.00mL)溶液中加入氢氧化钠溶液(1M,500.00uL,0.10eq)。随后,混合物在50℃下搅拌12小时。粗品减压浓缩,剩余物经用硅胶层析柱(PE:EtOAc=4:1至2:1)纯化得到化合物1-4(800.00mg,2.00mmol,收率39.96%)。MS(ESI)m/z:401.1[M+1]。
步骤4:化合物1-5的合成:
在室温下,向化合物1-4(1.00g,2.50mmol,1.00eq)的乙腈溶液(30.00mL)中加入化合物NFth(2.41g,7.50mmol,3.00eq)和无水碳酸钠(397.10mg,3.75mmol,156.96uL,1.50eq)。随后,混合物在70℃下搅拌12小时。粗品减压浓缩,经用硅胶柱层析(石油醚:乙酸乙酯=10:1至5:1)纯化得到化合物1-5(220.00mg,525.86umol,收率21.03%)。MS(ESI)m/z:419.1[M+1]。
步骤5:化合物1-6的合成:
化合物1-5(50.00mg,119.51umol,1.00eq)的三氯氧磷(7.16g,46.70mmol,390.73eq)溶液在100℃下搅拌12小时。粗品减压浓缩并用冰水(10mL)淬灭,用乙酸乙酯(20mL)萃取两次,合并有机相用盐水洗涤,无水硫酸钠干燥,过滤,浓缩得到粗品化合物1-6(52.20mg),直接用于下一步反应。
步骤6:化合物1-7的合成:
在室温下,向化合物1-6(52.20mg,119.50umol,1.00eq)的乙腈(4.00mL)溶液中加入化合物BB-2(68.93mg,358.50umol,3.00eq)和无水碳酸钾(330.32mg,2.39mmol,20.00eq),混合物在80℃下搅拌12小时。粗品减压浓缩并用水(10mL)稀释,用乙酸乙酯(20mL)萃取两次,合并有机相用盐水洗涤,无水硫酸钠干燥,过滤、浓缩得到粗产品,经用硅胶层析柱(石油醚:乙酸乙酯=5:1至3:1)纯化得到化合物1-7(50.00mg,88.88umol,收率74.37%)。MS(ESI)m/z:593.2[M+1]。
步骤7:化合物1-8的合成:
在室温下,向化合物1-7(50.00mg,84.37umol,1.00eq)的甲醇(2.00mL),四氢呋喃(2.00mL)和水(1.00mL)的溶液中加入氢氧化钠(16.87mg,421.85umol,5.00eq),混合物在25℃下搅拌12小时。粗品减压浓缩,所得物用HPLC制备得到化合物1-8(20.00mg,32.52umol,收率38.54%)。MS(ESI)m/z:579.1[M+1].
步骤8:化合物WX-075和WX-076的合成
化合物1-8(18.00mg,31.11umol,1.00eq)通过SFC制备方法:[柱子型号(OD(250mm*30mm,5um),流 动相(A:二氧化碳,B:0.1氨水甲醇,梯度:B 40%-40%)]制备得到化合物WX-075(3.00mg,5.03umol,收率16.17%,保留时间:第一个峰)和化合物WX-076(3.00mg,5.19umol,收率16.67%,保留时间:第二个峰).
参照实施例1中步骤1~8的合成方法,合成下表中各实施例。
Figure PCTCN2017096366-appb-000079
Figure PCTCN2017096366-appb-000080
Figure PCTCN2017096366-appb-000081
Figure PCTCN2017096366-appb-000082
Figure PCTCN2017096366-appb-000083
Figure PCTCN2017096366-appb-000084
Figure PCTCN2017096366-appb-000085
实施例2
Figure PCTCN2017096366-appb-000086
合成路线:
Figure PCTCN2017096366-appb-000087
步骤1:化合物2-2的合成
在15℃下,向化合物2-1(10.00g,78.03mmol,1.00eq)和叠氮磷酸二苯酯(25.77g,93.64mmol,20.29mL,1.20eq)的甲苯(150.00mL)溶液中加入三乙胺(23.69g,234.09mmol,32.45mL,3.00eq)。反应液在氮气保护下15℃反应1.5小时,然后加热到80℃反应7小时。2-甲氧基-5-三氟甲基苯胺(15.66g,81.93mmol,1.05eq)加入到反应液中继续反应12小时。反应液减压浓缩,所得物倒入HCl(1N,300mL),用乙酸乙酯(200mL)萃取二次,合并有机相用饱和食盐水洗涤,无水硫酸钠干燥,减压浓缩,所得物用PE:EtOAc(2:1)洗涤得2-2(10.00g,24.41mmol,收率31.28%)。1H NMR(400MHz,DMSO-d6)δ9.72(s,1H),8.58 (s,1H),8.47(s,1H),7.47–7.48(m,1H),7.33–7.35(m,2H),7.20(d,J=8.4Hz,2H),7.02(d,J=5.2Hz,1H),3.92(s,3H)。
步骤2:化合物2-3的合成
在0℃下,向化合物2-2(10.00g,31.62mmol,1.00eq)的二氯甲烷(150.00mL)溶液中加入化合物NBS(5.63g,31.62mmol,1.00eq)。混合物在0℃搅拌2小时后。反应液过滤,滤饼干燥后得到2-3(6.80g,14.80mmol,收率46.80%)。MS(ESI)m/z:397.0[M+1]。
步骤3:化合物2-4的合成
在室温下,向化合物2-3(6.80g,17.21mmol,1.00eq)和BB-11(7.30g,34.42mmol,2.00eq)的四氢呋喃(80.00mL)和水(10.00mL)溶液中加入化合物Pd(dppf)Cl2(1.26g,1.72mmol,0.10eq)和碳酸钾(7.14g,51.63mmol,3.00eq)。混合物在氮气保护下55℃搅拌12小时。反应旋干过柱(PE/EtOAc=5/1)得2-4(2.60g,4.68mmol,收率27.17%)。MS(ESI)m/z:401.1[M+1]。
步骤4:化合物2-5的合成
在室温下,向化合物2-4(2.65g,6.62mmol,1.00eq)的四氢呋喃(15.00mL)溶液中加入氢氧化锂(1M,6.62mL,1.00eq)水溶液。混合物在40℃搅拌12小时。反应旋干得粗产品2-5(2.80g)。
步骤5:化合物2-6的合成
在0℃下,向化合物2-5(6.80g,17.21mmol,1.00eq)的甲醇(60.00mL)溶液中加入氯化亚砜(2.40g,20.19mmol,1.46mL,3.00eq)。混合物在氮气保护下70℃搅拌3小时。反应旋干过柱(PE/EtOAc=3/1至3/2)得化合物2-6(800.00mg,1.58mmol,收率23.54%)。1H NMR:(400MHz,CHLOROFORM-d)δ7.59(d,J=7.2Hz,1H),7.16(d,J=5.2Hz,1H),7.05(d,J=8.8Hz,1H),6.57(d,J=5.2Hz,1H),5.40–5.43(m,1H),.3.89(s,3H),3.57(s,3H),2.75–2.81(m,2H)。
步骤6:化合物2-7的合成
在室温下,向化合物2-6(6.80g,17.21mmol,1.00eq)的三氯氧磷(15.70g,102.39mmol,9.57mL,136.65eq)溶液中慢慢加入N,N-二异丙基乙基胺(484.20mg,3.75mmol,654.33uL,5.00eq)。混合物在氮气保护下110℃搅拌12小时。五氯化磷(468.11mg,2.25mmol,3.00eq)加入到该反应中并继续氮气保护下110℃搅拌2小时。反应液减压浓缩,所得物加入水中,用碳酸氢钠调至中性,乙酸乙酯(100mL)萃取三次,合并有机相用饱和食盐水洗涤,无水硫酸钠干燥,过滤,减压浓缩得粗品化合物2-7(250.00mg)。MS(ESI)m/z:419.1[M+1]。
步骤7:化合物2-8的合成
在室温下,向化合物2-7(200.00mg,477.53umol,1.00eq)和BB-1(98.51mg,477.53umol,1.00eq)的乙腈(5.00mL)溶液中加入碳酸钾(659.99mg,4.78mmol,10.00eq)。混合物在80℃搅拌12小时。反应过滤,滤饼干燥得粗品化合物2-8(300.00mg)。MS(ESI)m/z:589.2[M+1]。
步骤8:化合物2-9的合成
在室温下,向化合物2-8(300.00mg,509.65umol,1.00eq)的甲醇(5.00mL),四氢呋喃(5.00mL)和水(3.00mL)溶液中加入氢氧化钠(61.16mg,1.53mmol,3.00eq)。混合物在15℃搅拌12小时。反应液旋干,所得物HPLC制备得化合物2-9(50.00mg,66.85umol,收率13.12%)。MS(ESI)m/z:575.2[M+1]。
步骤9:化合物WX-135和WX-136的合成
化合物2-9(50.00mg,81.82umol,1.00eq)经过SFC制备方法:[柱子型号(OD(250mm*30mm,10um),流动相(A:二氧化碳,B:0.1氨水甲醇,梯度:B 40%-40%)]得WX-135(11.00mg,收率21.76%,保留时间:第一个峰)和WX-136(6.00mg,收率12.76%,保留时间:第二个峰)。
参照实施例2中步骤1~9的合成方法,合成下表中各实施例。
Figure PCTCN2017096366-appb-000088
Figure PCTCN2017096366-appb-000089
Figure PCTCN2017096366-appb-000090
Figure PCTCN2017096366-appb-000091
Figure PCTCN2017096366-appb-000092
实施例3
Figure PCTCN2017096366-appb-000093
合成路线:
Figure PCTCN2017096366-appb-000094
步骤1:化合物3-2的合成
在0℃下,向化合物3-1(2.00g,5.06mmol,1.00eq)的四氢呋喃(30.00mL)溶液中加入化合物NCS(1.01g,7.59mmol,1.50eq)。反应液旋干并加入50mL水中,乙酸乙酯(50mL)萃取三次,合并有机相,用饱和食盐水洗涤和无水硫酸钠干燥,过滤,滤液旋干得3-2(2.00g,4.66mmol,92.00%收率)。
1H NMR:(400MHz,DMSO-d6)δ9.02-9.40(m,2H),8.49(t,J=10.2Hz,1H),7.58-7.66(m,1H),7.31-7.34(m,2H),7.19(d,J=8.8Hz,1H),3.89-4.00(m,3H).
步骤2:化合物3-3的合成
在室温下,向化合物3-2(1.00g,2.33mmol,1.00eq)和BB-11(988.15mg,4.66mmol,2.00eq)的四氢呋喃(15.00mL)和水(5.00mL)溶液中加入化合物三水合磷酸钾(1.86g,6.99mmol,3.00eq)和Pd(dppf)Cl2(170.49mg,233.00umol,0.10eq)。混合物在氮气保护下55℃搅拌12小时。反应旋干过柱((PE/EtOAc=5/1)得化合物3-3(300.00mg,收率17.47%)。MS(ESI)m/z:435.0[M+1]。
步骤3:化合物3-4的合成
在室温下,向化合物3-3(800.00mg,1.84mmol,1.00eq)的四氢呋喃(10.00mL)溶液中加入一水合氢氧化锂(1M,1.29mL,0.70eq)水溶液。混合物在40℃搅拌12小时后继续加入一水合氢氧化锂(1M,5.52mL,3.00eq)到反应液并在40℃搅拌4小时。反应旋干得粗品化合物3-4(800.00mg)。MS(ESI)m/z:421.0[M+1]。
步骤4:化合物3-5的合成
在0℃下,向化合物3-4(800.00mg,1.90mmol,1.00eq)的甲醇(10.00mL)溶液中加入氯化亚砜(678.55mg,5.70mmol,3.00eq)。混合物在氮气保护下60℃搅拌3小时。反应液减压浓缩,所得物经HPLC制备得化合物3-5(100.00mg,收率11.62%)。MS(ESI)m/z:435.0[M+1]。
步骤5:化合物3-6的合成
在室温下,化合物3-5(50.00mg,114.99umol,1.00eq)分批加入到三氯氧磷(12.46g,81.26mmol,706.69eq)中,再缓慢加入N,N-二异丙基乙基胺(44.58mg,344.97umol,3.00eq)。混合物在氮气保护下100℃搅拌12小时。反应旋干得到粗产品,粗产品投入水中(40mL)并用饱和碳酸氢钠溶液调至中性,用乙酸乙酯(40mL)萃取二次,合并有机相用饱和食盐水洗涤,无水硫酸钠干燥,减压浓缩得粗品化合物3-6(50.00mg)。MS(ESI)m/z:453.0[M+1]。
步骤5:化合物3-7的合成
在室温下,向化合物3-6(50.00mg,110.31umol,1.00eq)和BB-2(63.63mg,330.94umol,3.00eq)的乙腈(3.00mL)溶液中加入碳酸钾(152.46mg,1.10mmol,10.00eq)。混合物在80℃搅拌12小时。反应液减压浓缩得粗品化合物3-7(150.00mg),直接用于下一步反应。MS(ESI)m/z:609.1[M+1]。
步骤6:化合物3-8的合成
在室温下,向化合物3-7(100.00mg,164.19umol,1.00eq)的甲醇(2.00mL),四氢呋喃(2.00mL)和水(1.00mL)溶液中加入氢氧化钠(19.70mg,492.57umol,3.00eq)。混合物在10℃搅拌2小时。反应液旋干,所得物HPLC制备得化合物3-8(10.00mg,收率10.24%)。MS(ESI)m/z:595.1[M+1]。
步骤7:目标化合物WX-106和WX-107
化合物3-8(40.00mg,67.22umol,1.00eq)经SFC制备[柱子型号(IC(250mm*30mm,10um),流动相(A:
二氧化碳,B:0.1氨水乙醇,梯度:B 40%-40%)]得WX-106(13.00mg,收率28.34%)和WX-107(10.00mg,收率21.48%)。
Figure PCTCN2017096366-appb-000095
实施例4
Figure PCTCN2017096366-appb-000096
合成路线:
Figure PCTCN2017096366-appb-000097
步骤1:化合物4-1的合成
在氮气保护,20℃下,向化合物1-3(5g,12.49mmol,1eq)和2,6-二甲基吡啶(8.03g,74.93mmol,8.73mL,6eq)的甲苯(150mL)溶液中分批加入五氯化磷(7.80g,37.47mmol,3eq),然后加热到50℃,反应2小时。将反应液降低至0℃,向反应液中加入2M氢氧化钾溶液,调节pH值到中性。分液,有机相分别用1M柠檬酸溶液(100mL)和饱和食盐水(100mL)洗涤。上述有机相中分别加入化合物BB-1(3.35g,13.81mmol,1.1eq,HCl),磷酸氢二钠(9.80g,69.05mmol,9.80mL,5.5eq),三乙胺(3.49g,34.52mmol,4.81mL,2.75eq)和水(50mL)。将反应体系加热到50℃反应2小时,将反应液倒入水(150mL)中,分液后水相用甲苯(100mL)萃取,合并有机相用饱和食盐水(200mL)洗涤,无水硫酸钠干燥,得到粗品化合物4-1在~250mL甲苯中直接用于下步反应。
MS(ESI)m/z:589.2[M+1]。
步骤2:化合物4-2的合成
在室温下,向步骤1中得到的化合物4-1在~250mL甲苯溶液中加入DBU(11.42g,74.99mmol,11.30mL,6.0eq),混合物在110℃搅拌12小时。将反应浓缩后通过硅胶柱分离(PE/EtOAc=10/1~2/1)得到化合物4-2(4.7g,7.98mmol,步骤1和2总收率为69.42%)。
MS(ESI)m/z:589.2[M+1]。
步骤3:化合物4-3的合成
在室温下,向化合物4-2(4.7g,7.98mmol,1eq)的MeOH(100mL)和水(20mL)溶液中加入氢氧化钠(3.19g,79.85mmol,10eq)。反应液在70℃搅拌3小时。将反应液浓缩,除去大部分甲醇后加入水(20mL),用MTBE(30mL)萃取两次,水相用1M盐酸溶液调节pH到6左右,用EtOAc(30mL)萃取两次,合并有机相,用饱和食盐水(50mL)洗涤,无水硫酸钠干燥,过滤浓缩得到化合物4-3(2 g,3.20mmol,收率40.10%,纯度92%)。MS(ESI)m/z:575.2[M+1]。
步骤4:目标化合物WX-203和WX-204
化合物4-3(2g,3.20mmol,1.00eq)经SFC制备[柱子型号(IC-H(250mm*30mm,5um),流动相(A:二氧化碳,B:0.1氨水甲醇,梯度:B 30%-30%)]制备得WX-203(600mg,收率29.40%,保留时间:第一个峰)和WX-204(900mg,收率44.10%,第二个峰)。MS(ESI)m/z:575.2[M+1]。
参照实施例4中步骤1~4的合成方法,合成下表中WX-198和WX-199。
Figure PCTCN2017096366-appb-000098
Figure PCTCN2017096366-appb-000099
实施例5
Figure PCTCN2017096366-appb-000100
合成路线:
Figure PCTCN2017096366-appb-000101
步骤1:化合物5-1的合成
在氮气保护,于20℃下,向化合物2-4(1g,2.50mmol,1eq)和2,6-二甲基吡啶(1.61g,14.99mmol,1.75mL,6eq)的甲苯(20mL)溶液中分批加入五氯化磷(1.56g,7.49mmol,3eq),加热到50℃反应1小时。将反应液降温至0℃,向反应液中加入2M氢氧化钾溶液,调节pH到中性。将反应液分液, 水相用甲苯(5mL)萃取两次,合并有机相,分别用柠檬酸溶液(1M,30mL)和饱和食盐水(30mL)洗涤。室温下向该溶液中分别加入化合物BB-13(749.61mg,2.88mmol,1.15eq,HCl),磷酸氢二钠(2.13g,15.00mmol,2.13mL,6eq),三乙胺(758.93mg,7.50mmol,1.04mL,3eq)和水(5mL)。反应体系加热到50℃反应1小时。将反应体系倒入水(20mL)中,分液,水相用甲苯(5mL)萃取两次,合并有机相,用饱和食盐水(5mL)洗涤两次,无水硫酸钠干燥,得到粗产品化合物5-1在~40mL甲苯溶液中直接用于下步反应。MS(ESI)m/z:607.2[M+1]。
步骤2:化合物5-2的合成
在20℃温度下,向步骤1中得到的化合物5-1在~40mL甲苯溶液中加入DBU(2.28g,15.00mmol,2.26mL,6eq),混合物在110℃搅拌2小时。将反应浓缩后通过硅胶柱分离(PE:EtOAc=10:1至2:1)得到混合化合物5-2(0.6g,865.44umol,纯度87.5%,步骤1和2总收率为34.62%)。
MS(ESI)m/z:607.3[M+1]。
步骤3:化合物5-3的合成
在室温下,向化合物5-2(0.6g,865.44umol,1eq)溶于的MeOH(12mL)和水(4mL)溶液中加入氢氧化钠(395.63mg,9.89mmol,11eq)。混合物在70℃搅拌2小时。将反应液浓缩除去大部分甲醇后加入水(20mL),用EtOAc(20mL)萃取,水相用1M盐酸溶液调节pH到7左右,用EtOAc萃取(30mL)两次,合并有机相用饱和食盐水(50mL)洗涤,无水硫酸钠干燥,过滤浓缩得到化合物5-3(0.5g,0.75mmol,收率86.8%,纯度89%)。1H NMR(400MHz,METHANOL-d4)δppm 7.55-7.47(m,1H)7.18-7.30(m,2H)6.86-6.91(m,2H)6.54-6.60(m,1H)6.31-6.48(m,1H)4.91-4.95(m,1H)3.90(br s,3H)3.80(s,3H)3.71(d,J=4.0Hz,3H)3.58(br s,1H)3.46(br s,1H)2.99-3.11(m,1H)2.63-2.94(m,3H)0.76(d,J=6.4Hz,1H)0.45(br s,1H).MS(ESI)m/z:593.3[M+1]。
步骤4:目标化合物WX-200和WX-201
化合物5-3(0.5g,0.75mmol,1.00eq)经SFC制备[柱子型号[AS-H(250mm*30mm,5um),流动相(A:二氧化碳,B:0.1氨水甲醇,梯度:B 25%-25%)],得WX-200(130mg,收率26.00%,保留时间:第一个峰)和WX-201(129mg,收率25.00%,保留时间:第二个峰)。MS(ESI)m/z:593.2[M+1]。
参照实施例5中步骤1~4的合成方法,合成下表中各实施例。
Figure PCTCN2017096366-appb-000102
Figure PCTCN2017096366-appb-000103
Figure PCTCN2017096366-appb-000104
Figure PCTCN2017096366-appb-000105
实施例6
Figure PCTCN2017096366-appb-000106
合成路线:
Figure PCTCN2017096366-appb-000107
步骤1:化合物6-2的合成
在15℃下,向化合物6-1(2g,14.07mmol,1eq)和DPPA(3.87g,14.07mmol,3.05mL,1eq)的甲苯(20mL)溶液中加入三乙胺(4.27g,42.20mmol,5.87mL,3eq)。反应液在氮气保护下15℃反应0.5小时,然后加热到80℃反应2小时。2-甲氧基-5-三氟甲基苯胺(2.55g,13.36mmol,0.95eq)加入到反应液中继续80℃反应12小时。反应液减压浓缩,所得物加入水(30mL),用EtOAc(20mL)萃取二次,合并有机相用饱和食盐水洗涤,无水硫酸钠干燥,减压浓缩,所得物用硅胶柱分离(洗脱剂为PE:EtOAc=1:0至10:1)得到化合物6-2(4g,12.11mmol,收率86.08%)。MS(ESI)m/z:331.1[M+1]。
步骤2:化合物6-3的合成
在氮气保护下于0-5℃下,向化合物6-2(4g,12.11mmol,1eq)的DCM(50mL)溶液中分批加入化合物NBS(2.26g,12.71mmol,1.05eq),混合物在0℃搅拌10mins。在0-5℃下加入饱和碳酸氢钠溶液(30mL)淬灭反应,用DCM(20mL)萃取二次,合并有机相用饱和食盐水(50mL)洗涤,无水硫酸钠干燥,减压浓缩,将反应浓缩后通过硅胶柱分离(PE:EtOAc=1:0至20:1)得到化合物6-3(2g,3.63mmol,纯度74.23%,收率29.96%)。MS(ESI)m/z:409.1[M+1]。
步骤3:化合物6-4的合成
在室温下,向化合物6-3(1.5g,3.67mmol,1eq)和BB-11(2.33g,11.00mmol,3eq)的乙二醇二甲醚(20mL)溶液中加入化合物Pd(dppf)Cl2(268.21mg,366.55umol,0.1eq)和磷酸钾(1.71g,8.06mmol,2.2eq),反应混合物在氮气保护下85℃搅拌12小时。将反应体系倒入20mL水中,用EtOAc(20mL)萃取 两次,合并有机相用饱和食盐水(40mL)洗涤,无水硫酸钠干燥,过滤浓缩得粗产物。用硅胶柱分离(PE:EtOAc=50:1至5:1)和中性prep-HPLC分离条件纯化,得到化合物6-4(170mg,410.23umol,收率11.2%)。MS(ESI)m/z:415.1[M+1]。
步骤4:化合物6-5的合成
在氮气保护下于15℃下,向化合物6-4(170mg,410.23umol,1eq)和2,6-二甲基吡啶(263.74mg,2.46mmol,286.67uL,6eq)的甲苯(5mL)溶液中分批加入PCl5(256.28mg,1.23mmol,3eq),然后加热到50℃反应1.5小时。在0℃下向反应液中加入2M氢氧化钾溶液将pH调节到中性。分液后有机相分别用1M柠檬酸溶液(10mL)和饱和食盐水(10mL)洗涤。15℃下向该溶液中分别加入化合物BB-5(129.91mg,533.00umol,1.3eq,HCl),磷酸氢二钠(349.22mg,2.46mmol,349.22uL,6eq),三乙胺(124.46mg,1.23mmol,171.20uL,3eq),甲苯(2mL)和水(1mL)。反应体系加热到50℃反应2小时。将反应体系倒入水(20mL)中,并用EtOAc(30mL)萃取两次,合并有机相用饱和食盐水(50mL)洗涤两次,无水硫酸钠干燥,过滤并浓缩得到粗产品化合物6-5(200mg,crude)并直接用于下步反应。MS(ESI)m/z:604.3[M+1]。
步骤5:化合物6-6的合成
在20℃温度下,将在步骤4中得到的粗品化合物6-5(200mg,331.32umol,1eq)溶解在甲苯溶液(2mL)中加入DBU(302.64mg,1.99mmol,299.64uL,6eq),混合物在110℃搅拌2小时。将反应浓缩后通过硅胶柱分离(PE:EtOAc=10:1至0:1)得到混合化合物5-2(120mg,198.79umol,步骤4和5总收率为48.5%)。MS(ESI)m/z:604.3[M+1]。
步骤6:化合物6-7的合成
在室温下,向化合物6-7(120mg,198.79umol,1eq)溶于的MeOH:水=3:1(10mL)溶液中加入氢氧化钠(79.52mg,1.99mmol,10eq)。混合物在70℃搅拌2小时。将反应液浓缩除去甲醇后加入水(20mL),使用EtOAc(20mL)提取水溶液中的杂质后,用1M盐酸溶液将水相pH调节到5左右,再用EtOAc萃取(30mL)两次,合并有机相用饱和食盐水(50mL)洗涤,无水硫酸钠干燥,过滤并浓缩得到粗产品,经prep-HPLC分离得到化合物6-7(90mg,135.91umol,收率68.4%,纯度90.4%)。MS(ESI)m/z:590.2[M+1]。
步骤7:目标化合物WX-173和WX-174
化合物6-7(90mg,135.91umol,1.00eq)经SFC制备[柱子型号(IC-H(250mm*30mm,5um),流动相(A:二氧化碳,B:0.1氨水甲醇,梯度:B 40%-40%)],得WX-173(32.1mg,纯度92.31%,收率37%,保留时间:第一个峰)和WX-174(40.1mg,纯度95.02%,收率47.5%,保留时间:第二个峰)。MS(ESI)m/z:590.2[M+1]。
参照实施例6中步骤1~8的合成方法,合成下表中WX-153。
Figure PCTCN2017096366-appb-000108
实验例1
抗人巨细胞病毒荧光衰减实验
通过测定化合物的半数有效浓度(EC50)值来评价化合物对人巨细胞病毒(HCMV)的抗病毒活性。本实验中使用的HCMV通过基因重组插入报告基因增强型绿色荧光蛋白(EGFP),病毒在细胞内的复制可以由GFP的表达水平来反映。使用高内涵细胞分析平台Acumen eX3测定不同浓度化合物孔中的荧光强度来评价化合物对HCMV GFP表达的抑制活性。
抗HCMV荧光衰减实验
将MRC5细胞以20,000细胞每孔的密度种入黑色96孔细胞培养板中,随后置于37℃,5%CO2培养箱中培养过夜。US3-6-EGFP-HCMV-AD169病毒以一定MOI(0.003-0.1)加入细胞培养孔中,于37℃,5%CO2培养箱中培养3小时。病毒吸附后将含有病毒的培养基吸出并加入200μl含有不同浓度化合物(4倍倍比稀释,6个测试浓度点)的细胞培养基。培养基中DMSO终浓度为1%。设置病毒对照孔(加入DMSO,不含化合物)和抑制对照孔(加入高浓度的对照化合物)。细胞板置于37℃,5%CO2培养箱中培养10天,第4天和第7天换液。培养10天后用高内涵细胞分析平台Acumen eX3(TTP LabTech)检测荧光强度。原始数据用于化合物抗病毒活性计算。
Figure PCTCN2017096366-appb-000109
将抑制百分数分别导入GraphPad Prism软件进行数据处理得出化合物对应的剂量-效应曲线并得出测试化合物的EC50值。
结果见表-1:
表-1
化合物 EC50(uM) 化合物 EC50(uM)
WX-075 0.295 WX-140 0.144
WX-076 0.001 WX-141 0.0002
WX-087 >1 WX-142 0.056
WX-088 0.002 WX-143 0.00089
WX-089 >1 WX-144 0.261
WX-090 0.079 WX-145 0.002
WX-097 0.001 WX-146 0.352
WX-098 0.031 WX-147 0.00017
WX-099 0.024 WX-148 0.012
WX-100 0.073 WX-149 0.00067
WX-106 >1 WX-150 0.020
WX-107 0.004 WX-151 0.000503
WX-108 0.340 WX-153 0.00026
WX-109 0.004 WX-160 0.0444
WX-112 0.001 WX-161 0.000317
WX-113 0.107 WX-169 >0.538
WX-127 0.830 WX-170 0.000264
WX-128 0.015 WX-171 >0.01
WX-129 0.014 WX-172 0.000099
WX-130 >0.1 WX-173 0.000849
WX-131 0.055 WX-174 >0.01
WX-132 0.00015 WX-196 0.001914
WX-133 0.017 WX-197 >0.01
WX-134 >1 WX-198 0.000713
WX-135 0.941 WX-199 >0.01
WX-136 0.00017 WX-200 >0.01
WX-137 0.031 WX-201 0.00053
WX-138 >1 WX-203 >0.01
WX-139 0.003 WX-204 0.000172
结论:本发明设计的化合物展示出良好的体外抑制人巨细胞病毒复制的抑制活性。
实验例2
化合物的血浆蛋白结合率测试
待测化合物在CD-1小鼠、SD大鼠和人血浆中的蛋白结合率采用平衡透析法进行了评估。将受试化合物分别稀释到上述三个物种的血浆中,配制成终浓度为2μM的样品,然后将样品加入到96孔平衡透析装置中,在37℃下用磷酸盐缓冲溶液透析4小时。实验采用华法林(warfarin)作为对照化合物。血浆和缓冲液中受试化合物与warfarin的浓度用LC-MS/MS法进行测定。
结果显示如表-2,本发明涉及的化合物在三个种属血浆中均具有合理的的血浆蛋白结合率,预示在上述三个种属的血浆中,受试化合物的游离态药物浓度比例适中,具有良好的成药性质。
表-2
Figure PCTCN2017096366-appb-000110
注:H代表人,R代表大鼠,M代表小鼠
实验例3
人巨细胞病毒(HCMV)小鼠移植模型
将含有HCMV的明胶海绵移植到小鼠体内,连续给药9天后,收集明胶海绵用于空斑检测。通过检测明胶海绵中的HCMV数量评价化合物在该模型中的抗HCMV作用。
实验选用的动物为NOD SCID小鼠(购自上海斯莱克实验动物有限公司),5周,雄性。每组5只动物。将小鼠进行明胶海绵移植当天设为第0天。事先用HCMV病毒(毒株:GFP-AD169)感染人包皮成纤维细胞(HFF,MOI=0.03),再将感染HCMV的HFF细胞加到1cm2大小的明胶海绵内孵育待用。动物经75mg/kg(10ml/kg)的戊巴比妥钠腹腔注射麻醉,待动物进入深麻状态后,将处理好的明胶海绵皮下移植到小鼠的背部。从第1天至第9天,每天口服给予8mg/kg(10ml/kg)的待测化合物,每天一次。第9天给药后4小时,将明胶海绵取出,消化后进行空斑检测。试验数据显示,化合物WX-136、WX-141和WX-151对HCMV病毒载量的下降分别为2.33log PFU/ml、2.38log PFU/ml和2.30log PFU/ml,展示出了优良的体内药效,在体内药效研究试验过程中,小鼠体重稳定,临床观察无异常,表明该系列化合物在给药剂量下对小鼠无明显副作用。

Claims (44)

  1. 式(Ⅱ)所示化合物、其药学上可接受的盐及其互变异构体,
    Figure PCTCN2017096366-appb-100001
    其中,
    环A选自5元杂芳环;
    R1选自H、卤素,或选自任选被1、2或3个R取代的:C1-6烷基、C1-6杂烷基;
    R2选自H,或选自任选或1、2或3个R取代的C1-6烷氧基;
    R3选自H,或选自任选或1、2或3个R取代的:C1-6烷基、C1-6杂烷基;
    T选自N或C(R);
    n选自1或2;
    Ar选自任选被1、2或3个R取代的:苯基、6元杂芳基;
    R选自H、F、Cl、Br、I、OH、CN、NH2、C(=O)NH2,或选自任选被1、2或3个R’取代的:C1-6烷基、C1-6杂烷基;
    R’选自F、Cl、Br、I、OH、CN、NH2、COOH、Me、Et、CF3、CHF2、CH2F、NHCH3、N(CH3)2
    所述5元杂芳环、6元杂芳基、C1-6杂烷基之杂原子或杂原子团,选自-C(=O)NH-、-NH-、-S(=O)2NH-、-S(=O)NH、-O-、-S-、N、-C(=O)O-、-C(=O)-、-S(=O)-和-S(=O)2-;
    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. 式(Ⅰ)所示化合物、其药学上可接受的盐及其互变异构体,
    Figure PCTCN2017096366-appb-100002
    其中,
    环A选自5元杂芳环;
    R1选自H、卤素,或选自任选被1、2或3个R取代的:C1-6烷基、C1-6杂烷基;
    R2选自H,或选自任选或1、2或3个R取代的C1-6烷氧基;
    R3选自H,或选自任选或1、2或3个R取代的:C1-6烷基、C1-6杂烷基;
    T选自N或C(R);
    Ar选自任选被1、2或3个R取代的:苯基、6元杂芳基;
    R选自H、F、Cl、Br、I、OH、CN、NH2、C(=O)NH2,或选自任选被1、2或3个R’取代的:C1-6烷基、C1-6杂烷基;
    R’选自F、Cl、Br、I、OH、CN、NH2、COOH、Me、Et、CF3、CHF2、CH2F、NHCH3、N(CH3)2
    所述5元杂芳环、6元杂芳基、C1-6杂烷基之杂原子或杂原子团,选自-C(=O)NH-、-NH-、-S(=O)2NH-、-S(=O)NH、-O-、-S-、N、-C(=O)O-、-C(=O)-、-S(=O)-和-S(=O)2-;
    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。
  3. 根据权利要求2所述化合物、其药学上可接受的盐及其互变异构,其中,R选自H、F、Cl、Br、I、OH、CN、NH2、C(=O)NH2,或选自任选被1、2或3个R’取代的:C1-3烷基、C1-3烷基-O-、C1-3烷基-S-、C1-3烷基-NH-、N,N’-二(C1-3烷基)氨基。
  4. 根据权利要求3所述化合物、其药学上可接受的盐及其互变异构体,其中,R选自H、F、Cl、Br、I、OH、CN、NH2、C(=O)NH2、Me、Et、
    Figure PCTCN2017096366-appb-100003
  5. 根据权利要求2~4任意一项所述化合物、其药学上可接受的盐及其互变异构体,其中,环A选自噻吩基、呋喃基、恶唑基、异噻唑基、异恶唑基。
  6. 根据权利要求5所述化合物、其药学上可接受的盐及其互变异构体,其中结构单元
    Figure PCTCN2017096366-appb-100004
    选自:
    Figure PCTCN2017096366-appb-100005
  7. 根据权利要求2~4任意一项所述化合物、其药学上可接受的盐及其互变异构体,其中,R1选自H、F、Cl、Br、I,或选自任选被1、2或3个R取代的:C1-3烷基、C1-3烷基-O-、C1-3烷基-S-。
  8. 根据权利要求7所述化合物、其药学上可接受的盐及其互变异构体,其中,R1选自H、F、Cl、Br、I,或选自任选被1、2或3个R取代的:Me、Et。
  9. 根据权利要求8所述化合物、其药学上可接受的盐及其互变异构体,其中,R1选自H、F、Cl、Br、I、Me、Et。
  10. 根据权利要求2~4任意一项所述化合物、其药学上可接受的盐及其互变异构体,其中,R2选自H,或选自任选被1、2或3个R取代的C1-3烷基-O-。
  11. 根据权利要求10所述化合物、其药学上可接受的盐及其互变异构体,其中,R2选自H,或选自任 选被1、2或3个R取代的
    Figure PCTCN2017096366-appb-100006
  12. 根据权利要求11所述化合物、其药学上可接受的盐及其互变异构体,其中,R2选自H、
    Figure PCTCN2017096366-appb-100007
    Figure PCTCN2017096366-appb-100008
  13. 根据权利要求2~4任意一项所述化合物、其药学上可接受的盐及其互变异构体,其中,R3选自H,或选自任选被1、2或3个R取代的:C1-3烷基、C1-3烷基-O-、C1-3烷基-S-。
  14. 根据权利要求13所述化合物、其药学上可接受的盐及其互变异构体,其中,R3选自H,或选自任选被1、2或3个R取代的:Me、Et、
    Figure PCTCN2017096366-appb-100009
  15. 根据权利要求14所述化合物、其药学上可接受的盐及其互变异构体,其中,R3选自H、Me、Et、CF3
    Figure PCTCN2017096366-appb-100010
  16. 根据权利要求2~4任意一项所述化合物、其药学上可接受的盐及其互变异构体,其中,T选自N、CH、C(F)、C(Cl)、C(Br)和C(I)。
  17. 根据权利要求2~4任意一项所述化合物、其药学上可接受的盐及其互变异构体,其中,Ar选任选被1、2或3个R取代的:苯基、吡啶基、嘧啶基、吡嗪基、哒嗪基。
  18. 根据权利要求17所述化合物、其药学上可接受的盐及其互变异构体,其中,Ar选自任选被1、2或3个R取代的:
    Figure PCTCN2017096366-appb-100011
  19. 根据权利要求18所述化合物、其药学上可接受的盐及其互变异构体,其中,Ar选自:
    Figure PCTCN2017096366-appb-100012
    Figure PCTCN2017096366-appb-100013
  20. 根据权利要求6或9所述化合物、其药学上可接受的盐及其互变异构体,其中,结构单元
    Figure PCTCN2017096366-appb-100014
    选自:
    Figure PCTCN2017096366-appb-100015
  21. 根据权利要求1所述化合物、其药学上可接受的盐及其互变异构,其中,R选自H、F、Cl、Br、I、OH、CN、NH2、C(=O)NH2,或选自任选被1、2或3个R’取代的:C1-3烷基、C1-3烷基-O-、C1-3烷基 -S-、C1-3烷基-NH-、N,N’-二(C1-3烷基)氨基。
  22. 根据权利要求21所述化合物、其药学上可接受的盐及其互变异构体,其中,R选自H、F、Cl、Br、I、OH、CN、NH2、C(=O)NH2、Me、Et、
    Figure PCTCN2017096366-appb-100016
  23. 根据权利要求1、21或22任意一项所述化合物、其药学上可接受的盐及其互变异构体,其中,环A选自噻吩基、呋喃基、恶唑基、异噻唑基、异恶唑基。
  24. 根据权利要求23所述化合物、其药学上可接受的盐及其互变异构体,其中结构单元
    Figure PCTCN2017096366-appb-100017
    选自:
    Figure PCTCN2017096366-appb-100018
  25. 根据权利要求1、21或22任意一项所述化合物、其药学上可接受的盐及其互变异构体,其中,R1选自H、F、Cl、Br、I,或选自任选被1、2或3个R取代的:C1-3烷基、C1-3烷基-O-、C1-3烷基-S-。
  26. 根据权利要求25所述化合物、其药学上可接受的盐及其互变异构体,其中,R1选自H、F、Cl、Br、I,或选自任选被1、2或3个R取代的:Me、Et。
  27. 根据权利要求26所述化合物、其药学上可接受的盐及其互变异构体,其中,R1选自H、F、Cl、Br、I、Me、Et。
  28. 根据权利要求1、21或22任意一项所述化合物、其药学上可接受的盐及其互变异构体,其中,R2选自H,或选自任选被1、2或3个R取代的C1-3烷基-O-。
  29. 根据权利要求28所述化合物、其药学上可接受的盐及其互变异构体,其中,R2选自H,或选自任选被1、2或3个R取代的
    Figure PCTCN2017096366-appb-100019
  30. 根据权利要求29所述化合物、其药学上可接受的盐及其互变异构体,其中,R2选自H、
    Figure PCTCN2017096366-appb-100020
    Figure PCTCN2017096366-appb-100021
  31. 根据权利要求1、21或22任意一项所述化合物、其药学上可接受的盐及其互变异构体,其中,R3选自H,或选自任选被1、2或3个R取代的:C1-3烷基、C1-3烷基-O-、C1-3烷基-S-。
  32. 根据权利要求31所述化合物、其药学上可接受的盐及其互变异构体,其中,R3选自H,或选自任选被1、2或3个R取代的:Me、Et、
    Figure PCTCN2017096366-appb-100022
  33. 根据权利要求32所述化合物、其药学上可接受的盐及其互变异构体,其中,R3选自H、Me、Et、 CF3
    Figure PCTCN2017096366-appb-100023
  34. 根据权利要求1、21或22任意一项所述化合物、其药学上可接受的盐及其互变异构体,其中,T选自N、CH、C(F)、C(Cl)、C(Br)和C(I)。
  35. 根据权利要求1、21或22任意一项所述化合物、其药学上可接受的盐及其互变异构体,其中,Ar选任选被1、2或3个R取代的:苯基、吡啶基、嘧啶基、吡嗪基、哒嗪基。
  36. 根据权利要求35所述化合物、其药学上可接受的盐及其互变异构体,其中,Ar选自任选被1、2或3个R取代的:
    Figure PCTCN2017096366-appb-100024
  37. 根据权利要求36所述化合物、其药学上可接受的盐及其互变异构体,其中,Ar选自:
    Figure PCTCN2017096366-appb-100025
    Figure PCTCN2017096366-appb-100026
  38. 根据权利要求24或27所述化合物、其药学上可接受的盐及其互变异构体,其中,结构单元
    Figure PCTCN2017096366-appb-100027
    选自:
    Figure PCTCN2017096366-appb-100028
  39. 根据权利要求1或33所述化合物、其药学上可接受的盐及其互变异构体,其中,结构单元
    Figure PCTCN2017096366-appb-100029
    选自:
    Figure PCTCN2017096366-appb-100030
  40. 根据权利要求1~4、7~15、21~22、25~33中任意一项所述化合物、其药学上可接受的盐及其互变异构体,其中选自:
    Figure PCTCN2017096366-appb-100031
    其中,
    R1、R3、R如权利要求1~4、7~15、21~22、25~33所定义;
    T1选自N或CH。
  41. 根据权利要求40所述化合物、其药学上可接受的盐及其互变异构体,其选自:
    Figure PCTCN2017096366-appb-100032
    其中,
    R1、R3、R如权利要求1~4、7~15、21~22、25~33所定义;
    T1选自N或CH。
  42. 下式所示化合物、其药学上可接受的盐及其互变异构体,其选自:
    Figure PCTCN2017096366-appb-100033
    Figure PCTCN2017096366-appb-100034
  43. 根据权利要求42所述化合物、其药学上可接受的盐及其互变异构体,其选自:
    Figure PCTCN2017096366-appb-100035
    Figure PCTCN2017096366-appb-100036
    Figure PCTCN2017096366-appb-100037
  44. 根据权利要求1~43任意一项所述化合物、其药学上可接受的盐及其互变异构体在制备抗HCMV病毒药物中的应用。
PCT/CN2017/096366 2016-08-08 2017-08-08 抗hcmv病毒化合物 WO2018028556A1 (zh)

Priority Applications (5)

Application Number Priority Date Filing Date Title
ES17838686T ES2882531T3 (es) 2016-08-08 2017-08-08 Compuesto anti-virus CMVH
EP17838686.8A EP3498715B1 (en) 2016-08-08 2017-08-08 Anti-hcmv virus compound
JP2019507208A JP6951418B2 (ja) 2016-08-08 2017-08-08 抗hcmvウイルス化合物
US16/323,074 US10851112B2 (en) 2016-08-08 2017-08-08 Anti-HCMV virus compound
CN201780045987.0A CN109476677B (zh) 2016-08-08 2017-08-08 抗hcmv病毒化合物

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
CN201610644091 2016-08-08
CN201610644091.1 2016-08-08

Publications (1)

Publication Number Publication Date
WO2018028556A1 true WO2018028556A1 (zh) 2018-02-15

Family

ID=61161770

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/CN2017/096366 WO2018028556A1 (zh) 2016-08-08 2017-08-08 抗hcmv病毒化合物

Country Status (6)

Country Link
US (1) US10851112B2 (zh)
EP (1) EP3498715B1 (zh)
JP (1) JP6951418B2 (zh)
CN (1) CN109476677B (zh)
ES (1) ES2882531T3 (zh)
WO (1) WO2018028556A1 (zh)

Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2019154192A1 (zh) * 2018-02-08 2019-08-15 南京明德新药研发股份有限公司 一种3,4-二氢噻吩并[3,2-d]嘧啶类化合物的晶型及其制备方法

Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2004096778A1 (de) * 2003-05-02 2004-11-11 Bayer Healthcare Ag Substituierte dihydrochinazoline mit antiviralen eigenschaften
WO2005113552A1 (de) * 2004-05-07 2005-12-01 Bayer Healthcare Ag Substituierte azachinazoline mit antiviraler wirkung
WO2016109360A1 (en) * 2014-12-29 2016-07-07 Auspex Pharmaceuticals, Inc. Dihydroquinazoline inhibitors of viral terminase

Family Cites Families (7)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
DE10305785A1 (de) * 2003-02-12 2004-08-26 Bayer Healthcare Ag Dihydrochinazoline
CA2848616A1 (en) * 2011-09-16 2013-03-21 Bayer Intellectual Property Gmbh Disubstituted 5-fluoro-pyrimidines
US9453034B2 (en) * 2013-03-15 2016-09-27 Merck Sharp & Dohme Corp. C2-azaspiro iminothiazine dioxides as BACE inhibitors, compositions, and their use
WO2015043364A1 (zh) * 2013-09-29 2015-04-02 华北制药集团新药研究开发有限责任公司 作为凝血因子Xa抑制剂的苯并恶唑并恶嗪酮类化合物
CN104693211A (zh) * 2013-12-10 2015-06-10 南京明德新药研发股份有限公司 作为抗病毒剂的咪唑衍生物及其制药用途
ES2757570T3 (es) * 2013-12-10 2020-04-29 Shandong Danhong Pharmaceutical Co Ltd Derivado de imidazol usado como agente antiviral y uso del mismo en la preparación de un medicamento
CN104860935A (zh) * 2014-02-21 2015-08-26 常州寅盛药业有限公司 作为丙肝病毒抑制剂的噻吩或其变体衍生物及其制药用途

Patent Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2004096778A1 (de) * 2003-05-02 2004-11-11 Bayer Healthcare Ag Substituierte dihydrochinazoline mit antiviralen eigenschaften
WO2005113552A1 (de) * 2004-05-07 2005-12-01 Bayer Healthcare Ag Substituierte azachinazoline mit antiviraler wirkung
WO2016109360A1 (en) * 2014-12-29 2016-07-07 Auspex Pharmaceuticals, Inc. Dihydroquinazoline inhibitors of viral terminase

Cited By (9)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2019154192A1 (zh) * 2018-02-08 2019-08-15 南京明德新药研发股份有限公司 一种3,4-二氢噻吩并[3,2-d]嘧啶类化合物的晶型及其制备方法
CN111741960A (zh) * 2018-02-08 2020-10-02 南京明德新药研发有限公司 一种3,4-二氢噻吩并[3,2-d]嘧啶类化合物的晶型及其制备方法
KR20200118161A (ko) * 2018-02-08 2020-10-14 메드샤인 디스커버리 아이엔씨. 3,4-디하이드로티에노[3,2-d]피리미딘 화합물의 결정형 및 이의 제조방법
JP2021512928A (ja) * 2018-02-08 2021-05-20 メッドシャイン ディスカバリー インコーポレイテッド 3,4−ジヒドロチエノ[3,2−d]ピリミジン系化合物の結晶形およびその調製方法
CN111741960B (zh) * 2018-02-08 2021-06-25 南京明德新药研发有限公司 一种3,4-二氢噻吩并[3,2-d]嘧啶类化合物的晶型及其制备方法
EP3753942A4 (en) * 2018-02-08 2021-10-27 Medshine Discovery Inc. CRYSTAL FORM OF 3,4-DIHYDROTHIENO [3,2-D] PYRIMIDINE COMPOUND AND MANUFACTURING METHOD FOR IT
US11174270B2 (en) 2018-02-08 2021-11-16 Phaeno Therapeutics Co., Ltd. Crystal form of 3,4-dihydrothieno[3,2-d]pyrimidine compound and preparation method thereof
JP7076845B2 (ja) 2018-02-08 2022-05-30 フェーノ・セラピューティクス・カンパニー・リミテッド 3,4-ジヒドロチエノ[3,2-d]ピリミジン系化合物の結晶形およびその調製方法
KR102423393B1 (ko) 2018-02-08 2022-07-21 파에노 테라퓨틱스 씨오., 엘티디. 3,4-디하이드로티에노[3,2-d]피리미딘 화합물의 결정형 및 이의 제조방법

Also Published As

Publication number Publication date
JP2019524810A (ja) 2019-09-05
EP3498715A1 (en) 2019-06-19
CN109476677B (zh) 2024-06-07
JP6951418B2 (ja) 2021-10-20
US10851112B2 (en) 2020-12-01
US20190202838A1 (en) 2019-07-04
CN109476677A (zh) 2019-03-15
EP3498715B1 (en) 2021-06-09
ES2882531T3 (es) 2021-12-02
EP3498715A4 (en) 2019-06-26

Similar Documents

Publication Publication Date Title
CN110446712B (zh) 作为A2A受体抑制剂的[1,2,4]三唑并[1,5-c]嘧啶衍生物
TWI568734B (zh) 作為hbv抑制劑的二氫嘧啶並環衍生物
CN106459009B (zh) 丙肝病毒抑制剂及其制药用途
CN110627784B (zh) 抗流感病毒嘧啶衍生物
JP6836693B2 (ja) A2a受容体アンタゴニストとしての縮合環誘導体
JP6724246B2 (ja) チオフェン化合物、その合成方法及び医療における応用
WO2019085933A1 (zh) 作为Wee1抑制剂的大环类化合物及其应用
WO2018130155A1 (zh) Hdac6选择性抑制剂及其制备方法和应用
JP7050054B2 (ja) Pde4阻害剤としての縮合環系化合物
WO2018233696A1 (zh) 作为mek抑制剂的类香豆素环类化合物及其应用
WO2018157820A1 (zh) 氮杂环丁烷衍生物
WO2018127207A1 (zh) 噻唑衍生物及其应用
WO2018028556A1 (zh) 抗hcmv病毒化合物
WO2019134662A1 (zh) 作为csf-1r抑制剂的杂环化合物及其应用
CN111205244B (zh) 噻唑并环类化合物、其制备方法、中间体和应用
WO2018028557A1 (zh) 三环类化合物及其应用
WO2018014869A1 (zh) 作为crth2抑制剂的吲哚衍生物
WO2016169514A1 (zh) 咪唑类化合物
WO2024067744A1 (zh) 杂环取代喹唑啉及其制备方法和应用

Legal Events

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

Ref document number: 17838686

Country of ref document: EP

Kind code of ref document: A1

ENP Entry into the national phase

Ref document number: 2019507208

Country of ref document: JP

Kind code of ref document: A

NENP Non-entry into the national phase

Ref country code: DE

ENP Entry into the national phase

Ref document number: 2017838686

Country of ref document: EP

Effective date: 20190311