WO2016169514A1 - 咪唑类化合物 - Google Patents

咪唑类化合物 Download PDF

Info

Publication number
WO2016169514A1
WO2016169514A1 PCT/CN2016/079992 CN2016079992W WO2016169514A1 WO 2016169514 A1 WO2016169514 A1 WO 2016169514A1 CN 2016079992 W CN2016079992 W CN 2016079992W WO 2016169514 A1 WO2016169514 A1 WO 2016169514A1
Authority
WO
WIPO (PCT)
Prior art keywords
compound
group
mmol
tautomer
pharmaceutically acceptable
Prior art date
Application number
PCT/CN2016/079992
Other languages
English (en)
French (fr)
Inventor
龙超峰
陈曙辉
陈小新
罗云富
刘卓伟
潘剑峰
Original Assignee
广东众生药业股份有限公司
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 广东众生药业股份有限公司 filed Critical 广东众生药业股份有限公司
Priority to EP16782661.9A priority Critical patent/EP3287453A4/en
Priority to JP2017555623A priority patent/JP2018513199A/ja
Priority to US15/568,828 priority patent/US20180104220A1/en
Publication of WO2016169514A1 publication Critical patent/WO2016169514A1/zh

Links

Classifications

    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
    • A61K31/4164—1,3-Diazoles
    • A61K31/4174—Arylalkylimidazoles, e.g. oxymetazolin, naphazoline, miconazole
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D413/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings
    • C07D413/10—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings linked by a carbon chain containing aromatic rings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A61P9/10—Drugs for disorders of the cardiovascular system for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D233/00—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings
    • C07D233/54—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having two double bonds between ring members or between ring members and non-ring members
    • C07D233/56—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having two double bonds between ring members or between ring members and non-ring members with only hydrogen atoms or radicals containing only hydrogen and carbon atoms, attached to ring carbon atoms
    • C07D233/60—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having two double bonds between ring members or between ring members and non-ring members with only hydrogen atoms or radicals containing only hydrogen and carbon atoms, attached to ring carbon atoms with hydrocarbon radicals, substituted by oxygen or sulfur atoms, attached to ring nitrogen atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/08—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a carbon chain containing alicyclic rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/10—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a carbon chain containing aromatic rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
    • C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
    • C07D403/10—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings linked by a carbon chain containing aromatic rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D413/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings
    • C07D413/06—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings linked by a carbon chain containing only aliphatic carbon atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D413/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings
    • C07D413/08—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings linked by a carbon chain containing alicyclic rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D413/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing three or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
    • C07D417/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings
    • C07D417/10—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings linked by a carbon chain containing aromatic rings

Definitions

  • the present invention relates to an imidazole compound, and in particular to a compound of the formula (I), a pharmaceutically acceptable salt thereof or a tautomer thereof.
  • Ischemic cerebral vascular disease is caused by the temporary or permanent decrease of blood flow in an arterial blood supply area due to embolism or hemorrhage.
  • the pathological process involves complex time and spatial cascades, and its mechanism and Ca 2+ overload, free radical damage and other factors are related.
  • Ozagrel Sodium has a specific inhibitory effect on thromboxane A synthetase, and its pharmacological effects include anti-platelet aggregation and dilation of blood vessels.
  • Ozagrel also inhibits lipid peroxidation, reduces free radical production, and directly scavenges free radicals, improving brain tissue tolerance to anoxic conditions. It is widely used in clinical treatment of ischemic cerebrovascular disease, including the treatment of acute cerebral infarction and has achieved good results.
  • Ozagrel is a new type of anti-platelet aggregation drug. It was the first specific thromboxane synthetase A2 (TXA2) inhibitor introduced by Japan Ono Pharmaceutical Co., Ltd. under the trade name Cataclot in 1989, which can block prostaglandin H2 ( PGH2) produces thromboxane A2 (TXA2), which causes platelet-derived PGH2 to turn to endothelial cells. Endothelial cells are used to synthesize PGI2, thereby improving the balance abnormality of TXA2 and prostaglandin PGI2, and achieving the effect of treating ischemic cerebrovascular disease.
  • TXA2 thromboxane synthetase A2
  • PGH2 prostaglandin H2
  • TXA2 thromboxane A2
  • n is an integer from 0 to 3, preferably 0 or 1;
  • L is selected from a 5- to 6-membered cycloalkyl or heterocycloalkyl group optionally substituted by R or -(CH 2 ) 1-6 -;
  • Ring A is selected from a 5- to 6-membered unsaturated cyclic hydrocarbon group or a heterocyclic group optionally substituted with R;
  • R 01 The number of R 01 , hetero atom or hetero atomic group is independently selected from 0, 1, 2 or 3;
  • R 1 , R 2 , and R are each independently selected from the group consisting of H, F, Cl, Br, I, CH 3 , C 2 H 5 -, CH 3 O- or
  • the L is selected from the group consisting of a 5- to 6-membered aryl or heteroaryl group, a 5- to 6-membered aliphatic ring group, and -(CH 2 ) 1-6 -.
  • the above L is selected from Or -(CH 2 ) 1-6 - optionally substituted by R, wherein
  • T 21-24 0 or 1 of T 21-24 is selected from N, and the remainder is selected from C(R);
  • T 25 is selected from N or C(R);
  • the above L is selected from
  • the above A is selected from a 5- to 6-membered aryl or heteroaryl group.
  • the above A is selected from the group consisting of
  • T 31-34 are each independently selected from N or C(R),
  • the above A is selected from the group consisting of
  • the structural unit Selected from Its tautomer is selected from
  • the structural unit Selected from Its tautomer is selected from
  • the above compound, a pharmaceutically acceptable salt thereof or a tautomer thereof is selected from the group consisting of:
  • the above compound, a pharmaceutically acceptable salt thereof or a tautomer thereof is selected from the group consisting of:
  • C 1-6 is selected from the group consisting of C 1 , C 2 , C 3 , C 4 , C 5 and C 6
  • C 3-6 is selected from C 3 , C 4 , C 5 , and C 6
  • the group consisting of numbers indicates the number of carbon atoms.
  • the 5- to 6-membered cyclic hydrocarbon group includes both saturated or unsaturated, and includes both aromatic and aliphatic; the 5- to 6-membered unsaturated cyclic hydrocarbon or heterocyclic group includes an aryl group, a heteroaryl group, and an aliphatic group.
  • pharmaceutically acceptable is for those compounds, materials, compositions and/or dosage forms that are within the scope of sound medical judgment and are applicable to humans and animals.
  • the tissue is used in contact without excessive toxicity, irritation, allergic reactions or other problems or complications, commensurate with a reasonable benefit/risk ratio.
  • 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.
  • the prodrug can be converted to the present invention by chemical or biochemical methods in an in vivo environment. compound of.
  • 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 non-pair The mixture of the phantoms is separated and the auxiliary groups are cleaved to provide the pure desired enantiomer.
  • a diastereomeric salt is formed with a suitable optically active acid or base, and then resolved by a method known in the art.
  • the diastereomers are resolved and the pure enantiomer is recovered.
  • 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, including variants of heavy hydrogen and hydrogen, as long as the valence of the particular atom is normal and the substituted compound is stable.
  • it means that two hydrogen atoms are substituted.
  • 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.
  • substituents 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.
  • 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 only in such combinations It is allowed in the case of a stable compound.
  • alkyl and heteroalkyl radicals (including what are commonly referred to as alkylene, alkenyl, heteroalkyl, heteroalkenyl, alkynyl, cycloalkyl, heterocycloalkyl, cycloalkenyl and heterocycloalkenyl)
  • R', R", R"', R"" and R""' are each independently preferably hydrogen, a substituted or unsubstituted heteroalkyl group, a substituted or unsubstituted aryl group (for example, an aryl group substituted by 1 to 3 halogens), a substituted or unsubstituted alkyl group, an alkoxy group, or a thioalkyl group Oxyl a group or an aralkyl group.
  • each R group is independently selected, as when more than one R', R", R"' Each of these groups, R"" and R""' groups.
  • R' and R" When R' and R" are attached to the same nitrogen atom, they can form a 5-, 6- or 7-member with the nitrogen atom. ring.
  • -NR'R is intended to include, but is not limited to, 1-pyrrolidinyl and 4-morpholinyl.
  • alkyl is intended to include carbon.
  • a group bonded to a non-hydrogen group such as a haloalkyl group (e.g., -CF 3 , -CH 2 CF 3 ) and an acyl group (e.g., -C(O)CH 3 , -C(O)CF 3 ,- C(O)CH 2 OCH 3 , etc..
  • a non-hydrogen group such as a haloalkyl group (e.g., -CF 3 , -CH 2 CF 3 ) and an acyl group (e.g., -C(O)CH 3 , -C(O)CF 3 ,- C(O)CH 2 OCH 3 , etc.
  • Two substituents on adjacent atoms of the aryl or heteroaryl ring may be optionally substituted with a substituent of the formula -TC(O)-(CRR')qU-, wherein T and U are independently selected From -NR-, -O-, CRR'- or a single bond, q is an integer from 0 to 3.
  • two substituents on adjacent atoms of the aryl or heteroaryl ring may be optionally substituted with a substituent of the formula -A(CH2)r B-, wherein A and B are independently selected From -CRR'-, -O-, -NR-, -S-, -S(O)-, S(O) 2 -, -S(O) 2 NR'- or a single bond, r is 1 to 4 The integer.
  • a single bond on the new ring thus formed can be replaced with a double bond.
  • two substituents on adjacent atoms of the aryl or heteroaryl ring may be optionally substituted with a substituent of the formula -A(CH2)r B-, wherein s and d are each independently An integer selected from 0 to 3, X is -O-, -NR', -S-, -S(O)-, -S(O) 2 - or -S(O) 2 NR'-.
  • the substituents R, R', R" and R"' are each independently preferably selected from hydrogen and substituted or unsubstituted (C 1 -C 6 )alkyl.
  • halo or halogen
  • haloalkyl is intended to include 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.
  • haloalkyl groups include, but are not limited to, trifluoromethyl, trichloromethyl, pentafluoroethyl, and pentachloroethyl.
  • Alkoxy represents the above alkyl group having a specified number of carbon atoms attached through an oxygen bridge.
  • the C 1-6 alkoxy group includes a 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.
  • Cycloalkyl includes saturated cyclic groups such as cyclopropyl, cyclobutyl or cyclopentyl.
  • the 3-7 cycloalkyl group includes C 3 , C 4 , C 5 , C 6 and C 7 cycloalkyl groups.
  • Alkenyl includes hydrocarbon chains in a straight or branched configuration wherein one or more carbon-carbon double bonds, such as vinyl and propylene groups, are present at any stable site on the chain.
  • halo or halogen refers to fluoro, chloro, bromo and iodo.
  • heteroatom as used herein includes atoms other than carbon (C) and hydrogen (H), including, for example, oxygen (O), nitrogen (N), sulfur (S), silicon (Si), germanium (Ge), aluminum ( Al) and boron (B) and the like.
  • hetero a radical containing a hetero atom
  • C carbon
  • hydrogen hydrogen
  • Ring means a substituted or unsubstituted cycloalkyl group, a substituted or unsubstituted heterocycloalkyl group, a substituted or unsubstituted aryl group or a substituted or unsubstituted heteroaryl group.
  • the so-called ring includes a fused ring.
  • 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" refers to the surrounding row. Columns 5-7 atoms. Unless otherwise specified, the ring optionally contains from 1 to 3 heteroatoms.
  • 5- to 7-membered ring includes, for example, phenylpyridine 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 or bicyclic or bicyclic heterocycle which may be saturated, partially unsaturated or unsaturated (aromatic) which contain a carbon atom and 2, 3 or 4 ring heteroatoms independently selected from N, O and S, wherein any of the above heterocyclic rings 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).
  • 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). It is worth noting that the total number of S and O atoms on the aromatic heterocycle does not exceed one.
  • 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 bridge rings include, but are not limited to, one carbon atom, two carbon atoms, A nitrogen atom, two nitrogen atoms and a 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, phenyl, etc.) by itself or as part of another substituent means straight-chain, branched or cyclic
  • the hydrocarbon radical or a combination thereof may be fully saturated, mono- or polyunsaturated, may be monosubstituted, disubstituted or polysubstituted, and may be monovalent (such as methyl), divalent (such as methylene) or polyvalent (methine), may include a divalent or polyvalent radical having the specified number of carbon atoms (e.g., C 1 -C 10 represents 1 to 10 carbons).
  • 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.
  • alkyl refers to a straight or branched chain of atoms 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 alkyl 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 Structure.
  • 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 heteroatoms B, O, N and S may be located at any internal position of the heterohydrocarbyl group (except where the hydrocarbyl group is attached to the rest of the molecule).
  • Up to two heteroatoms may be consecutive, for example, -CH 2 -NH-OCH 3.
  • alkoxy alkylamino and “alkylthio” (or thioalkoxy) are customary expressions and refer to those alkane which are attached to the remainder of the molecule through an oxygen atom, an amino group or a sulfur atom, respectively.
  • Base group alkoxy
  • cycloalkyl Unless otherwise specified, the terms “cycloalkyl”, “heterocycloalkyl”, “cyclohetero” or subordinates thereof (such as aryl, heteroaryl, aryl, cycloalkyl, heterocycloalkyl, ring) Alkyl, cycloalkenyl, heterocycloalkenyl, cycloalkenyl, cycloalkynyl, heterocycloalkynyl, cycloalkynyl, and the like, by themselves or in combination with other terms, respectively denote a cyclized “hydrocarbyl group", Heterohydrocarbyl” or “hydrocarbyl”.
  • 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.
  • aryl denotes a polyunsaturated, aromatic hydrocarbon substituent which may be monosubstituted, disubstituted or polysubstituted, which may be monocyclic or polycyclic (preferably 1 to 3 rings), 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.
  • Non-limiting examples of 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, indolyl, 2-benzimidazolyl, 5-indenyl
  • aryl groups when used in conjunction with other terms (eg, 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).
  • representative leaving groups include triflate; chlorine, bromine, iodine; sulfonate groups such as mesylate, tosylate, p-bromobenzenesulfonate, P-toluenesulfonate or the like; acyloxy group such as acetoxy group, trifluoroacetoxy group or 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 invention is now further described by way of examples.
  • the examples given below are for illustrative purposes only and are not intended to be limited to the scope of the invention.
  • the compounds of the present invention can be prepared by a number of methods known in the art of organic synthesis.
  • Embodiments of the present invention can be synthesized using the methods described below, as well as synthetic methods known in the art of organic synthetic chemistry, or by improved methods based thereon.
  • Preferred methods include, but are not limited to, the methods described below.
  • the present invention employs the following abbreviations: aq for water; DCM for methylene chloride; PE for petroleum ether; DMF for N,N-dimethylformamide; DMSO for dimethyl sulfoxide; EtOAc for ethyl acetate; EtOH stands for ethanol; MeOH stands for methanol; Cbz stands for benzyloxycarbonyl, an amine protecting group; Boc stands for t-butyloxycarbonyl, an amine protecting group; HOAc stands for acetic acid; and NaBH(OAc) 3 stands for triacetoxyborohydride Sodium; rt stands for room temperature; THF stands for tetrahydrofuran; Boc 2 O stands for di-tert-butyldicarbonate; TFA stands for trifluoroacetic acid; DIPEA stands for diisopropylethylamine; Pd(dppf)Cl 2 stands for [1,1'- Bis(diphenylphosphino)ferrocen
  • Example 1B (37 g, 161 mmol), imidazole (22 g, 322 mmol), a mixture of potassium iodide (22 g, 322 mmol) and potassium carbonate (44.7 g, 323 mmol) in acetone (370 ml) Stir at 50 to 60 ° C for 3 hours. The filtrate was filtered, and the filtrate was poured into water (1. The combined organic layers were dried with EtOAc EtOAc.
  • Triethylamine (125 mg, 1.24) was added dropwise to a solution of compound 15B (170 mg, 0.62 mmol) and p-toluenesulfonyl chloride (177 mg, 0.93 mmol) in dichloromethane (5 mL). Millimoles). The mixture was stirred at 20 ° C for 2 hr, diluted with water (10 mL) andEtOAc. The combined organic layers were dried with EtOAc EtOAc EtOAc. LCMS (ESI) m/z: 294 (M+H + )
  • TXA2 thromboxane A2 pathway
  • TXB2 thromboxane B2
  • the key enzyme of this pathway is thromboxane synthase, which is a specific inhibitor of the enzyme (test compound) in the in vitro coagulation process, which can inhibit the formation of TXA2 and reduce the content of TXB2.
  • the IC50 that inhibits the production of TXB2 reflects the activity of the test compound.
  • SD Male Sprague-Dawley (SD) rat purchased from Shanghai Slack Laboratory Animal Center
  • physiological saline solution 100M sodium hydroxide solution (solvent), 100uM thromboxane synthase inhibitor solution, isoflurane
  • TXB2 The content of TXB2 was detected using LC-MS/MS-AG (API 4000).
  • Control% (test tube TXB2 content-negative tube TXB2 content)/control tube TXB2 content ⁇ 100
  • Negative tube high concentration (100uM) thromboxane synthase inhibitor

Landscapes

  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Health & Medical Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Bioinformatics & Cheminformatics (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)
  • Epidemiology (AREA)
  • Urology & Nephrology (AREA)
  • Vascular Medicine (AREA)
  • Cardiology (AREA)
  • Heart & Thoracic Surgery (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • General Chemical & Material Sciences (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Plural Heterocyclic Compounds (AREA)

Abstract

本发明公开了一种咪唑类化合物，具体公开了式(I)所示的化合物、其药学上可接受的盐或其互变异构体。

Description

咪唑类化合物
相关申请的交叉引用
本申请要求2015年4月24日递交的申请号为201510200711.8的中国专利申请的权益，在此将其全部内容引入作为参考。
技术领域
本发明涉及一种咪唑类化合物，具体涉及式(I)示化合物、其药学上可接受的盐或其互变异构体。
背景技术
缺血性脑血管疾病(ischemic stroke)是由于某动脉供血区的血流因栓塞或出血而暂时或永久地减少所致，其病理过程涉及复杂的时间和空间级联反应，其发生机制与Ca2+超载、自由基损伤等多种因素有关。奥扎格雷钠(Ozagrel Sodium)具有特异性的抑制血栓素A合成酶的作用，其药理作用主要有：抗血小板聚集、扩张血管。此外，奥扎格雷还具有抑制脂质过氧化作用，能减少自由基的生成，并可直接清除自由基，提高脑组织对缺氧条件的耐受力。在临床上广泛应用于缺血性脑血管病，包括急性脑梗死的治疗并取得较好的疗效。
奥扎格雷是一种新型抗血小板聚集药，是日本小野药品工业株式会社于1989年以商品名Cataclot投放市场的首个特异性血栓素合成酶A2(TXA2)抑制剂，能阻碍前列腺素H2(PGH2)生成血栓烷A2(TXA2)，促使血小板所衍生的PGH2转向内皮细胞。内皮细胞用以合成PGI2，从而改善TXA2与前列腺素PGI2的平衡异常，达到治疗缺血性脑血管病之功效。
奥扎格雷的结构式如下:
Figure PCTCN2016079992-appb-000001
发明内容
本发明的目的在于提供式(Ⅰ)所示化合物、其药学上可接受的盐或其互变异构体，
Figure PCTCN2016079992-appb-000002
其中，n为0-3的整数，优选为0或1；L选自任选R取代的5～6元环烃基或杂环烃基或-(CH2)1-6-；
环A选自任选R取代的5～6元不饱和环烃基或杂环基；
R1、R2、R分别独立地选自H、F、Cl、Br、I、CN、OH、SH、NH2、CHO、COOH，或选自任选被R01取代的：C(＝O)NH2、S(＝O)NH2、S(＝O)2NH2、C1-6烷基或杂烷基、C3-6环烷基或杂环烷基；
“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-、-C(＝O)O-、-C(＝O)-、-C(＝S)-、-S(＝O)-、-S(＝O)2-或-N(R)C(＝O)N(R)-；
R01、杂原子或杂原子团的数目分别独立地选自0、1、2或3；和
R01选自H、F、Cl、Br、I、CN、OH、C1-3烷基、N(CH3)2、NH(CH3)、NH2、CHO、COOH、C(＝O)NH2、S(＝O)NH2、S(＝O)2NH2、三氟甲基、氨甲基、羟甲基、甲氧基、甲酰基、甲氧羰基、甲磺酰基、甲基亚磺酰基。
本发明的一个方案中，上述R1、R2、R分别独立地选自H、F、Cl、Br、I、C1-3烷基、C1-3烷氧基、N(CH3)2、NH(CH3)、NH2、CHO、COOH、C(＝O)NH2、S(＝O)NH2、S(＝O)2NH2、三氟甲基、氨甲基、羟甲基、甲酰基、甲氧羰基、甲磺酰基、甲基亚磺酰基、环丙基。
本发明的一个方案中，上述R1、R2、R分别独立地选自H、F、Cl、Br、I、CH3、C2H5-、CH3O-或
Figure PCTCN2016079992-appb-000003
本发明的一个方案中，上述L选自任选被R取代的：5～6元芳基或杂 芳基、5～6元脂肪环基、-(CH2)1-6-。
本发明的一个方案中，上述L选自
Figure PCTCN2016079992-appb-000004
Figure PCTCN2016079992-appb-000005
或任选被R取代的-(CH2)1-6-，其中，
T21-24中的0或1个选自N，其余选自C(R)；
D21-24中的0～3个选自-C(＝O)N(R)-、-N(R)-、-C(＝NR)-、-S(＝O)2N(R)-、-S(＝O)N(R)-、-O-、-S-、-C(＝O)O-、-C(＝O)-、-C(＝S)-、-S(＝O)-、-S(＝O)2-或-N(R)C(＝O)N(R)-，其余选自C(R)(R)；
T25选自N或者C(R)；
D25-27中的0～3个选自-C(＝O)N(R)-、-N(R)-、-C(＝NR)-、-S(＝O)2N(R)-、-S(＝O)N(R)-、-O-、-S-、-C(＝O)O-、-C(＝O)-、-C(＝S)-、-S(＝O)-、-S(＝O)2-或-N(R)C(＝O)N(R)-，其余选自C(R)(R)。
本发明的一个方案中，上述L选自
Figure PCTCN2016079992-appb-000006
Figure PCTCN2016079992-appb-000007
本发明的一个方案中，上述A选自5～6元芳基或杂芳基。
本发明的一个方案中，上述A选自
Figure PCTCN2016079992-appb-000008
T31-34分别独立地选自N或C(R)，
D31选自-C(R)(R)-、-C(＝O)N(R)-、-N(R)-、-C(＝NR)-、-S(＝O)2N(R)-、-S(＝O)N(R)-、-O-、-S-、-C(＝O)O-、-C(＝O)-、-C(＝S)-、-S(＝O)-、-S(＝O)2-或-N(R)C(＝O)N(R)-。
本发明的一个方案中，上述A选自
Figure PCTCN2016079992-appb-000009
Figure PCTCN2016079992-appb-000010
本发明的一个方案中，上述结构单元
Figure PCTCN2016079992-appb-000011
选自
Figure PCTCN2016079992-appb-000012
Figure PCTCN2016079992-appb-000013
其互变异构体选自
Figure PCTCN2016079992-appb-000014
本发明的一个方案中，上述结构单元
Figure PCTCN2016079992-appb-000016
选自
Figure PCTCN2016079992-appb-000017
Figure PCTCN2016079992-appb-000018
其互变异构体选自
Figure PCTCN2016079992-appb-000019
本发明的一个方案中，上述化合物、其药学上可接受的盐或其互变异构体，其选自：
Figure PCTCN2016079992-appb-000020
Figure PCTCN2016079992-appb-000021
本发明的一个方案中，上述化合物、其药学上可接受的盐或其互变异构体，其选自：
Figure PCTCN2016079992-appb-000022
定义和说明：
C1-6选自于由C1，C2，C3，C4，C5和C6组成的基团，C3-6选自于由C3，C4，C5，和C6组成的基团，数字表示碳原子数。
5～6元环烃基包括饱和或不饱和两种情况，也包括芳香族或脂肪族两种情况；5～6元不饱和环烃基或杂环基包括芳基、杂芳基和脂肪族三种情况。
C1-6烷基，C1-6杂烷基，C3-6环烷基，C3-6杂环烷基，C1-6烷基被C3-6环烷基或C3-6杂环烷基取代，和C1-6杂烷基被C3-6环烷基或C3-6杂环烷基取代，包括但不限于：甲基，乙基，正丙基，异丙基，-CH2C(CH3)(CH3)(OH)，环丙基，环丁基，丙基亚甲基，环丙基酰基，苄氧基，环丙基烯基，三氟甲基，氨基甲基，羟甲基，甲氧基，甲基酰基，甲氧酰基，甲基磺酰基，甲基亚磺酰基，乙氧基，乙酰基，乙基磺酰基，乙氧酰基，二甲基氨基，二乙基氨基，二甲基氨基，和二乙基氨基；N(CH3)2,NH(CH3),-CH2CF3,-CH2CH2CF3,-CH2CH2F,-CH2CH2S(＝O)2CH3,-CH2CH2CN,
Figure PCTCN2016079992-appb-000023
Figure PCTCN2016079992-appb-000024
-CH2CH(OH)(CH3)2,-CH2CH(F)(CH3)2,-CH2CH2F,-CH2CF3,-CH2CH2CF3,-CH2CH2NH2,-CH2CH2OH,-CH2CH2OCH3,-CH2CH2CH2OCH3,-CH2CH2N(CH3)2,-S(＝O)2CH3,-CH2CH2S(＝O)2CH3,
Figure PCTCN2016079992-appb-000025
Figure PCTCN2016079992-appb-000026
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。
本文中消旋体、ambiscalemic and scalemic或者对映体纯的化合物的图示法来自Maehr,J.Chem.Ed.1985,62:114-120。1985年，62：114-120。除非另有说明，用楔形键和虚线键表示一个立体中心的绝对构型。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拆分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。
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，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。
烷基和杂烷基原子团(包括通常被称为亚烷基、链烯基、亚杂烷基、杂烯基、炔基、环烷基、杂环烷基、环烯基和杂环烯基的那些基团)的取代基一般被称为“烷基取代基”，它们可以选自但不限于下列基团中的一个或多个：-R’、-OR’、＝O、＝NR’、＝N-OR’、-NR’R”、-SR’、卤素、-SiR’R”R”’、OC(O)R’、-C(O)R’、-CO2R’、-CONR’R”、-OC(O)NR’R”、-NR”C(O)R’、NR’C(O)NR”R”’、-NR”C(O)2R’、-NR””’-C(NR’R”R’”)＝NR””、NR””C(NR’R”)＝NR’”、-S(O)R’、-S(O)2R’、-S(O)2NR’R”、NR”SO2R’、-CN、–NO2、-N3、-CH(Ph)2和氟代(C1-C4)烷基,取代基的数目为0～(2m’+1),其中m’是这类原子团中碳原子的总数。R'、R”、R”'、R””和R””’各自独立地优选氢、被取代或未被取代的杂烷基、被取代或未被取代的芳基(例如被1～3个卤素取代芳基)、被取代或未被取代的烷基、烷氧基、硫代烷氧基基团或芳烷基。当本发明的化合物包括一个以上的R基团时，例如，每一个R基团是独立地加以选择的，如同当存在一个以上的R'、R”、R”'、R””和R””’基团时的每个这些基团。当R'和R”附着于同一个氮原子时，它们可与该氮原子结合形成5-，6-或7-元环。例如，-NR'R“意在包括但不仅限于1-吡咯烷基和4-吗啉基。根据上述关于取代基的讨论中，本领域技术人员可以理解，术语“烷基”意在包括碳原子键合于非氢基团所构成的基团，如卤代烷基(例如-CF3、-CH2CF3)和酰基(例如-C(O)CH3、-C(O)CF3、-C(O)CH2OCH3等)。与烷基原子团所述取代基相似，芳基和杂芳基取代基一般统称为“芳基取代基”，选自例如-R’、-OR’、-NR’R”、-SR’、-卤素,-SiR’R”R”’、OC(O)R’、-C(O)R’、 -CO2R’、-CONR’R”、-OC(O)NR’R”、-NR”C(O)R’、NR’C(O)NR”R”’、-NR”C(O)2R’、-NR””’-C(NR’R”R’”)＝NR””、NR””C(NR’R”)＝NR’”、-S(O)R’、-S(O)2R’、-S(O)2NR’R”、NR”SO2R’、-CN、–NO2、-N3、-CH(Ph)2、氟(C1-C4)烷氧基和氟(C1-C4)烷基等，取代基的数量为0到芳香环上开放化合价的总数之间；其中R’、R”、R”’、R””和R””’独立地优选自氢、被取代或未被取代的烷基、被取代或未被取代的杂烷基、被取代或未被取代的芳基和被取代或未被取代的杂芳基。当本发明的化合物包括一个以上的R基团时，例如，每个R基团是独立地加以选择的，如同当存在一个以上R’、R”、R”’、R””和R””’基团时的每个这些基团。
芳基或杂芳基环的相邻原子上的两个取代基可以任选地被通式为–T-C(O)-(CRR’)q-U-的取代基所取代，其中T和U独立地选自-NR-、-O-、CRR'-或单键，q是0到3的整数。作为替代选择，芳基或杂芳基环的相邻原子上的两个取代基可以任选地被通式为–A(CH2)r B-的取代基所取代，其中A和B独立的选自–CRR’-、-O-、-NR-、-S-、-S(O)-、S(O)2-、-S(O)2NR’-或单键，r是1～4的整数。任选地，由此形成的新环上的一个单键可以替换为双键。作为替代选择，芳基或杂芳基环的相邻原子上的两个取代基可以任选地被通式为–A(CH2)r B-的取代基所取代，其中s和d分别独立的选自0～3的整数，X是–O-、-NR’、-S-、-S(O)-、-S(O)2-或–S(O)2NR’-。取代基R、R’、R”和R”’分别独立地优选自氢和被取代或未被取代的(C1-C6)烷基。
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。
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。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。“环烷基”包括饱和环基，如环丙基、环丁基或环戊基。3-7环烷基包括C3、C4、C5、C6和C7环烷基。“链烯基”包括直链或支链构型的烃链，其中该链上任何的稳定位点上存在一个或多个碳-碳双键，例如乙烯基和丙烯基。
术语“卤”或“卤素”是指氟、氯、溴和碘。
本文所用术语“杂原子”包括碳(C)和氢(H)以外的原子，例如包括氧(O)、氮(N)、硫(S)、硅(Si)、锗(Ge)、铝(Al)和硼(B)等。
除非另有说明，术语“杂”，“杂原子”或“杂自由基”(即自由基含杂原子)，包括除碳(C)和氢(H)外的原子，也包含上述杂原子的自由基。例如包括氧(O)、氮(N)、硫(S)、硅(Si)、锗(Ge)、铝(Al)和硼(B)等，还包括任意取代的-C(＝O)N(H)-、-N(H)-、-C(＝NH)-、-S(＝O)2N(H)-,or-S(＝O)N(H)-。
“环”表示被取代或未被取代的环烷基、被取代或未被取代的杂环烷基、被取代或未被取代的芳基或被取代或未被取代的杂芳基。所谓的环包括稠环。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。
术语“杂环”或“杂环基”意指稳定的单环或双环或双环杂环，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)。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)。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、isatino基、异苯并呋喃基、吡喃、异吲哚基、异二氢吲哚基、异吲哚基、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、异恶唑基、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、嘧啶基、吡咯烷基、吡咯啉基、2H-吡咯基、吡咯基、吡唑基、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、苯基等等)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、单元或多元不饱和的，可以是单取代、二取代或多取代的，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-C10表示1至10个碳)。“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“烷基”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。不饱和烷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B、O、N和S可以位于杂烃基的任何内部位置(除该烃基基附着于分子其余部分的位置之外)。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。
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。
除非另有规定，术语“环烃基”、“杂环烃基”、“环烃杂基”或者其下位概念(比如芳基、杂芳基、芳杂基、环烷基、杂环烷基、环烷杂基、环烯基、杂环烯基、环烯杂基、环炔基、杂环炔基、环炔杂基等等)本身或与其他术语联合分别表示环化的“烃基”、“杂烃基”或“烃杂基”。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。环烷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“芳基”表示多不饱和的芳族烃取代基，可以是单取代、二取代或多取代的，它可以是单环或多环(优选1至3个环)，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。
为简便起见，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。
本发明现在进一步通过实施例描述。下面给出的实施例仅用于说明目的，而不是仅限于此发明的范围。本发明的化合物可以用有机合成领域中许多已知的方法来制备。本发明的实施例可以使用下面描述的方法来合成，以及有机合成化学领域中已知的合成方法，或在其基础上通过改进的方法。优选的方法包括，但不限于以下描述方法。
本发明所使用的所有溶剂是市售的，无需进一步纯化即可使用。反应一般是在惰性氮气下、无水溶剂中进行的。质子核磁共振数据记录在Bruker Avance III 400(400MHz)分光仪上，化学位移以四甲基硅烷低场处的(ppm) 表示。质谱是在安捷伦1200系列加6110(&1956A)上测定。LC/MS或Shimadzu MS包含一个DAD：SPD-M20A(LC)和Shimadzu Micromass 2020检测器。质谱仪配备有一个正或负模式下操作的电喷雾离子源(ESI)。
本发明采用下述缩略词：aq代表水；DCM代表二氯甲烷；PE代表石油醚；DMF代表N,N-二甲基甲酰胺；DMSO代表二甲基亚砜；EtOAc代表乙酸乙酯；EtOH代表乙醇；MeOH代表甲醇；Cbz代表苄氧羰基，一种胺保护基；Boc代表叔丁基氧羰基，一种胺保护基；HOAc代表乙酸；NaBH(OAc)3代表三乙酰氧基硼氢化钠；r.t代表室温；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代表二异丙基乙胺；Pd(dppf)Cl2代表[1,1'-双(二苯基膦基)二茂铁]二氯化钯(II)；POCl3代表三氯氧磷；NaH代表氢化钠；LAH代表氢化铝锂；Pd(OAc)2代表钯(II)乙酸盐；Pd2(dba)3代表三(二亚苄基丙酮)二钯；Pd(PPh3)4代表四(三苯基膦)钯；Et3SiH代表三乙基硅烷；PPh3代表三苯基膦；Xantphos代表4,5-双(二苯基膦基)-9,9-二甲基；MeSO3H代表甲磺酸；Xphos代表2-二环己基膦基-2'，4'，6'-三异丙基联苯；劳森试剂代表2,4-二(4-甲氧基苯基)-1,3-二硫杂-2,4-二磷烷-2,4-二硫化物；NBS代表N-溴代丁二酰亚胺；t-BuOK代表叔丁醇钾。
化合物经手工或者
Figure PCTCN2016079992-appb-000027
软件命名，市售化合物采用供应商目录名称。
具体实施方式
为了更详细地说明本发明，给出下列实例，但本发明的范围并非限定于此。
流程A
Figure PCTCN2016079992-appb-000028
实施例1
5-(4-((1H-咪唑-1-基)甲基)苯基)异噁唑-3-酚
Figure PCTCN2016079992-appb-000029
化合物1A
3-(4-(羟甲基)苯基)丙炔酸乙酯
Figure PCTCN2016079992-appb-000030
氮气保护下，4-碘苯甲醇(73克，311毫摩尔)，丙炔酸乙酯(91.4克，933毫摩尔)和氧化亚铜(44.6克，311毫摩尔)的DMF(700毫升)混合物在110℃下搅拌8小时。冷却过滤，滤液减压浓缩除去大部分DMF，残余物加入水(400毫升)，用乙酸乙酯(300毫升×3)萃取。将合并的有机层用无水硫酸钠干燥，过滤并蒸发，粗品通过柱色谱纯化得到化合物1A(浅灰色固体，45克，70％产率)。LCMS(ESI)m/z:205(M+H+)
化合物1B
3-(4-(氯甲基)苯基)丙炔酸乙酯
Figure PCTCN2016079992-appb-000031
0℃下，往实施例1A(45克，225毫摩尔)和DMF(0.5毫升)的二氯甲烷(200毫升)溶液中滴加氯化亚砜(104克，881毫摩尔)，滴加完毕后，混合物在20℃下搅拌1小时。减压蒸除大部分溶剂和剩余的氯化亚砜，残余物通过硅胶色谱法纯化得到化合物1B(无色液体，37.5克，76.4％产率)。1H NMR(400MHz,CDCl3):δ7.58(d,J＝8.4Hz,2H),7.41(d,J＝8.4Hz,2H),4.59(s,2H),4.31(q,J＝7.2Hz,2H),1.36(t,J＝7.2Hz,3H)。LCMS(ESI)m/z:223(M+H+)。
化合物1C
3-(4-((1H-咪唑-1-基)甲基)苯基)丙炔酸乙酯
Figure PCTCN2016079992-appb-000032
实施例1B(37克，161毫摩尔)，咪唑(22克，322毫摩尔)，碘化钾(22克，322毫摩尔)和碳酸钾(44.7克，323毫摩尔)的丙酮(370毫升)混合物在50～60℃搅拌3小时。冷却过滤，滤液倒入水(1.2升)中，用乙酸乙酯(600毫升×3)萃取。将合并的有机层用无水硫酸钠干燥，过滤并蒸发，残余物通过硅胶色谱法纯化得到化合物1C(白色固体，18克，32.2％产率)。1H NMR(400MHz,CDCl3):δ7.50-7.63(m,3H),7.07-7.18(m,3H),6.90(s,1H),5.16(s,2H),4.30(q,J＝7.2Hz,2H),1.35(t,J＝7.2Hz,3H)。LCMS(ESI)m/z:255(M+H+)。
化合物1
5-(4-((1H-咪唑-1-基)甲基)苯基)异噁唑-3-酚
Figure PCTCN2016079992-appb-000033
0℃下，固体NaOH(14.2克,350毫摩尔)溶解于水(60毫升)中， 分批加入羟胺盐酸盐(14.8克，350毫摩尔)，搅拌10分钟后，将此溶液分批加入实施例1C(18克，70.8毫摩尔)的甲醇(60毫升)溶液。混合物在30～40℃搅拌3小时。减压蒸除大部分溶剂，残余物用4N氯化氢甲醇溶液(200毫升)酸化，过滤并蒸发，粗品用乙醇(100毫升)打浆1小时后，过滤干燥得到实施例1的盐酸盐(6.5克，36％产率)。1H NMR(400MHz,CD3OD):δ9.12(s,1H),7.86(d,J＝8.28Hz,2H),7.69(s,1H),7.63(s,1H),7.55(d,J＝8.28Hz,2H),6.41(s,1H),5.55(s,2H)。LCMS(ESI)m/z:242(M+H+)。
实施例2
5-(4-((1H-咪唑-1-基)甲基)-3-氟苯基)异噁唑-3-酚
Figure PCTCN2016079992-appb-000034
化合物2
该实施例如实施例1中描述的方法制备。1H NMR(400MHz,CD3OD):δ9.06(s,1H),7.49-7.73(m,5H),6.45(s,1H),5.57(s,2H)。LCMS(ESI)m/z:260(M+H+)。
实施例3
5-(4-((1H-咪唑-1-基)甲基)-2-氟苯基)异噁唑-3-酚
Figure PCTCN2016079992-appb-000035
化合物3
该实施例如实施例1中描述的方法制备。1H NMR(400MHz,CD3OD):δ9.14(s,1H),7.97(t,J＝7.78Hz,1H),7.72(s,1H),7.65(s,1H),7.17-7.49 (m,2H),6.38(d,J＝3.51Hz,1H),5.57(s,2H)。LCMS(ESI)m/z:260(M+H+)。
实施例4
5-(4-((1H-咪唑-1-基)甲基)-2,5-二氟苯基)异噁唑-3-酚
Figure PCTCN2016079992-appb-000036
化合物4
该实施例如实施例1中描述的方法制备。1H NMR(400MHz,CD3OD):δ8.86(s,1H),7.78(dd,J＝5.73,9.92Hz,1H),7.62(s,1H),7.55(s,1H),7.50(dd,J＝5.84,10.25Hz,1H),6.54(d,J＝3.53Hz,1H),5.62(s,2H)。LCMS(ESI)m/z:278(M+H+)。
实施例5
5-(4-((1H-咪唑-1-基)甲基)-2,6-二氟苯基)异噁唑-3-酚
Figure PCTCN2016079992-appb-000037
化合物5
该实施例如实施例1中描述的方法制备。1H NMR(400MHz,CD3OD):δ9.15(s,1H),7.74(s,1H),7.67(s,1H),7.26(d,J＝9.0Hz,2H),6.39(s,1H),5.57(s,2H)。LCMS(ESI)m/z:278(M+H+)。
实施例6
5-(4-((1H-咪唑-1-基)甲基)-3-氯-5-氟苯基)异噁唑-3-酚
Figure PCTCN2016079992-appb-000038
化合物6
该实施例如实施例1中描述的方法制备。1H NMR(400MHz,CD3OD):δ9.07(s,1H),7.87(s,1H),7.73(d,J＝10.0Hz,1H),7.67-7.54(m,2H),6.58(s,1H),5.71(s,2H)。LCMS(ESI)m/z:294(M+H+)。
实施例7
5-(4-((1H-咪唑-1-基)甲基)-2-氯苯基)异噁唑-3-酚
Figure PCTCN2016079992-appb-000039
化合物7
该实施例如实施例1中描述的方法制备。1H NMR(400MHz,CD3OD):δ9.15(s,1H),7.96(d,J＝8.2Hz,1H),7.73(s,1H),7.69(s,1H),7.65(s,1H),7.50(dd,J＝1.6,8.0Hz,1H),6.62(s,1H),5.56(s,2H)。LCMS(ESI)m/z:276(M+H+)。
实施例8
5-(4-((1H-咪唑-1-基)甲基)-2-甲基苯基)异噁唑-3-酚
Figure PCTCN2016079992-appb-000040
化合物8
该实施例如实施例1中描述的方法制备。1H NMR(400MHz,CDCl3):δ9.12(br.s.,1H),7.77-7.56(m,3H),7.46-7.30(m,2H),6.22(s,1H),5.50(s,2H),2.49(br.s.,3H)。LCMS(ESI)m/z:256(M+H+)。
实施例9
5-(4-((1H-咪唑-1-基)甲基)-2-甲氧基苯基)异噁唑-3-酚
Figure PCTCN2016079992-appb-000041
化合物9
该实施例如实施例1中描述的方法制备。1H NMR(400MHz,CD3OD):δ9.16(s,1H),7.87(d,J＝8.0Hz,1H),7.78-7.58(m,2H),7.31(s,1H),7.11(d,J＝8.0Hz,1H),6.44(s,1H),5.54(s,2H),4.02(s,3H)。LCMS(ESI)m/z:272(M+H+)。
实施例10
5-(4-((1H-咪唑-1-基)甲基)-3-甲氧基苯基)异噁唑-3-酚
Figure PCTCN2016079992-appb-000042
化合物10
该实施例如实施例1中描述的方法制备。1H NMR(400MHz,CD3OD):δ8.73(s,1H),7.39-7.35(m,3H),7.33-7.29(m,1H),7.28-7.24(m,1H),6.06(s,1H),5.37(s,2H)。LCMS(ESI)m/z:272(M+H+)。
实施例11
5-(4-((1H-咪唑-1-基)甲基)-3-氯苯基)异噁唑-3-酚
Figure PCTCN2016079992-appb-000043
化合物11
该实施例如实施例1中描述的方法制备。1H NMR(400MHz,D2O):δ8.64(s,1H),7.31(d,J＝17.1Hz,2H),7.24(d,J＝7.8Hz,1H),7.03(d,J＝7.8Hz, 1H),6.95(s,1H),6.08(s,1H),5.20(s,2H)。LCMS(ESI)m/z:276(M+H+)。
实施例12
5-(4-((1H-咪唑-1-基)甲基)-3-甲基苯基)异噁唑-3-酚
Figure PCTCN2016079992-appb-000044
化合物12
该实施例如实施例1中描述的方法制备。1H NMR(400MHz,D2O):δ8.59(s,1H),7.37(s,1H),7.27(s,1H),7.22-7.10(m,2H),7.01(d,J＝7.8Hz,1H),5.94(s,1H),5.26(s,2H),2.04(s,3H)。LCMS(ESI)m/z:256(M+H+)。
实施例13
5-(4-((1H-咪唑-1-基)甲基)-3-溴苯基)异噁唑-3-酚
Figure PCTCN2016079992-appb-000045
化合物13
该实施例如实施例1中描述的方法制备。1H NMR(400MHz,D2O):δ8.99(s,1H),8.14(s,1H),7.88(d,J＝8.0Hz,1H),7.61(d,J＝13.1Hz,2H),7.53(d,J＝8.0Hz,1H),6.50(s,1H),5.63(s,2H)。LCMS(ESI)m/z:321(M+H+)。
实施例14
5-(6-((1H-咪唑-1-基)甲基)-吡啶-3-基)异噁唑-3-酚
Figure PCTCN2016079992-appb-000046
化合物14
该实施例如实施例1中描述的方法制备。1H NMR(400MHz,CD3OD): δ9.13(s,1H),8.93(d,J＝1.76Hz,1H),8.22(dd,J＝2.21,8.16Hz,1H),7.70(s,1H),7.57-7.65(m,2H),6.51(s,1H),5.65(s,2H)。LCMS(ESI)m/z:243(M+H+)。
流程B
Figure PCTCN2016079992-appb-000047
实施例15
5-(4-((1H-咪唑-1-基)甲基)-3-环丙基苯基)异噁唑-3-酚
Figure PCTCN2016079992-appb-000048
化合物15A
(2-溴-4-(3-(甲氧甲氧基)异噁唑-5-基)苯甲醇
Figure PCTCN2016079992-appb-000049
0℃下氮气保护下，将氯甲基甲醚(313毫克，3.89毫摩尔)滴加到5-(4-((1H-咪唑-1-基)甲基)-3-溴苯基)异噁唑-3-酚(14.8克，350毫摩尔)和三乙胺(0.8毫升，5.54毫摩尔)的DMSO(8毫升)溶液。混合物在0℃搅拌1小时，加水(40毫升)淬灭，然后用乙酸乙酯(40毫升×3)萃取。将合并的有机层用无水硫酸钠干燥，过滤并蒸发，残余物通过制备型HPLC纯化得到化合物15A(黄色油状物，520毫克，63.9％产率)。LCMS(ESI)m/z:314(M+H+)
化合物15B
(2-环丙基-4-(3-(甲氧甲氧基)异噁唑-5-基)苯甲醇
Figure PCTCN2016079992-appb-000050
氮气保护下，化合物15A(230毫克，0.73毫摩尔)，环丙基频那醇硼酸酯(369毫克，2.20毫摩尔)，碳酸钾(201毫克，1.46毫摩尔)和Pd(dppf)Cl2(54毫克，0.074毫摩尔)的1,4-二氧六环(3毫升)和水(0.5毫升)的混合物在90℃搅拌2小时，冷却后加水(10毫升)稀释，用乙酸乙酯(15毫升×3)萃取。将合并的有机层用无水硫酸钠干燥，过滤并蒸发，残余物通过制备型TLC纯化得到化合物15B(黄色油状物，170毫克，84.3％产率)。LCMS(ESI)m/z:276(M+H+)
化合物15C
5-(4-(氯甲基)-3-环丙基苯基)-3-(甲氧甲氧基)异噁唑
Figure PCTCN2016079992-appb-000051
0℃氮气保护下，向化合物15B(170毫克，0.62毫摩尔)和对甲苯磺酰氯(177毫克，0.93毫摩尔)的二氯甲烷溶液(5毫升)中滴加三乙胺(125毫克，1.24毫摩尔)。混合物在20℃搅拌2小时，加水(10毫升)稀释，用乙酸乙酯(15毫升×3)萃取。将合并的有机层用无水硫酸钠干燥，过滤并蒸发，残余物通过制备型TLC纯化得到化合物15C(浅黄色固体，45毫克，17％产率)。LCMS(ESI)m/z:294(M+H+)
化合物15D
5-(4-((1H-咪唑-1-基)甲基)-3-环丙基苯基)-3-(甲氧甲氧基)异噁唑
Figure PCTCN2016079992-appb-000052
化合物15C(40毫克，0.16毫摩尔)，咪唑(10.9毫克，0.16毫摩尔)和碳酸钾(44.3毫克，0.32毫摩尔)的丙酮(5毫升)混合物在50～60℃搅拌3小时。冷却过滤，滤液倒入水(10毫升)中，用乙酸乙酯(15毫升×3)萃取。将合并的有机层用无水硫酸钠干燥，过滤并蒸发，残余物通过硅胶色谱法纯化得到化合物15D(浅黄色固体，45毫克，86.3％产率)。LCMS(ESI)m/z:326(M+H+)
化合物15
5-(4-((1H-咪唑-1-基)甲基)-3-环丙基苯基)异噁唑-3-酚
Figure PCTCN2016079992-appb-000053
0℃下，向化合物15D(45毫克，0.14毫摩尔)的甲醇(5毫升)溶液中滴加4N的盐酸甲醇(1毫升)。混合物在20℃搅拌0.5小时，减压浓缩，残余物通过制备型HPLC纯化得到实施例15的盐酸盐(8毫克，21％产率)。1H NMR(400MHz,CD3OD):δ9.04(s,1H),7.70(d,J＝7.8Hz,1H),7.64(s,2H),7.55(s,1H),7.39(d,J＝8.0Hz,1H),6.42(s,1H),5.74(s,2H),2.04-1.93(m,1H),1.07-0.98(m,2H),0.79-0.71(m,2H)。LCMS(ESI)m/z:282(M+H+)。
实施例16
5-(4-((1H-咪唑-1-基)甲基)-3-乙基苯基)异噁唑-3-酚
Figure PCTCN2016079992-appb-000054
化合物16
该实施例如实施例15中描述的方法制备。1H NMR(400MHz,CD3OD): δ9.03(s,1H),7.77(s,1H),7.74-7.68(m,1H),7.63(d,J＝7.5Hz,2H),7.34(d,J＝8.0Hz,1H),6.42(s,1H),5.60(s,2H),2.79(q,J＝7.7Hz,2H),1.23(t,J＝7.7Hz,3H)。LCMS(ESI)m/z:270(M+H+)。
流程C
Figure PCTCN2016079992-appb-000055
实施例17
5-(4-((1H-咪唑-1-基)甲基)-3,5-二氟苯基)异噁唑-3-酚
Figure PCTCN2016079992-appb-000056
化合物17A
((4-溴-2,6-二氟苄氧基)(叔丁基)二甲基硅烷
Figure PCTCN2016079992-appb-000057
氮气保护下，4-溴-2,6-二氟苯甲醇(7.5克，33.5毫摩尔)，叔丁基二甲基氯硅烷(10.8克，67.0毫摩尔)和咪唑(3.0克，40.2毫摩尔)的DMF(70毫升)混合物在20℃搅拌2小时，加水(350毫升)淬灭，然后用乙酸乙酯(200毫升×3)萃取。将合并的有机层用无水硫酸钠干燥，过滤并蒸发， 残余物通过硅胶色谱柱纯化得到化合物17A(无色油状物，10.2克，90％产率)。LCMS(ESI)m/z:338(M+H+)
化合物17B
叔丁基((2,6-二氟-4-((三甲基硅)乙炔基)苄氧基)二甲基硅烷
Figure PCTCN2016079992-appb-000058
氮气保护下，化合物17A(10.0克，29.6毫摩尔)，三甲基硅乙炔(14.5克，89.0毫摩尔)，三乙胺(9.0克，89.0毫摩尔)，三苯基膦(777毫克，2.96毫摩尔)，碘化亚铜(564毫克，2.96毫摩尔)和Pd(PPh3)Cl2(1.0克，1.48毫摩尔)的四氢呋喃(100毫升)混合物在80℃搅拌12个小时，冷却后过滤，滤液倒入水(500毫升)中，用乙酸乙酯(200毫升×5)萃取。将合并的有机层用无水硫酸钠干燥，过滤并蒸发，残余物通过硅胶色谱柱纯化得到化合物17B(黄色油状物，8.0克，77％产率)。LCMS(ESI)m/z:355(M+H+)
化合物17C
叔丁基((2,6-二氟-4-(乙炔基)苄氧基)二甲基硅烷
Figure PCTCN2016079992-appb-000059
氮气保护下，向化合物17B(8.0克，22.5毫摩尔)的甲醇溶液(80毫升)中加入碳酸钾(9.3克，67.5毫摩尔)。混合物在20℃搅拌1小时，过滤，滤液到入水(300毫升)中，用乙酸乙酯(100毫升×6)萃取。将合并的有机层用无水硫酸钠干燥，过滤并蒸发，残余物通过硅胶色谱柱纯化得到化合物17C(浅黄色固体，6.0克，95％产率)。LCMS(ESI)m/z:283(M+H+)
化合物17D
3-(4-(((叔丁基二甲基硅氧基)甲基)-3,5-二氟苯)丙炔酸乙酯
Figure PCTCN2016079992-appb-000060
-78℃氮气保护下，往化合物17C(6.0克，21.2毫摩尔)的四氢呋喃(50毫升)溶液中滴加2.5M的正丁基锂(12.7毫升，31.9毫摩尔)，搅拌1小时后，再滴加氯甲酸乙酯(4.5克，42.4毫摩尔)的四氢呋喃(10毫升)溶液。混合物自然升温到20℃搅拌2小时，加入饱和氯化铵水溶液(50毫升)淬灭，然后用乙酸乙酯(100毫升×5)萃取。将合并的有机层用无水硫酸钠干燥，过滤并蒸发，残余物通过硅胶色谱法纯化得到化合物17D(黄色油状物，5.8克，77％产率)。LCMS(ESI)m/z:355(M+H+)
实施例17E
3-(3,5-二氟-4-(羟甲基)苯丙炔酸乙酯
Figure PCTCN2016079992-appb-000061
0℃下，向化合物17D(5.8克，16.4毫摩尔)的四氢呋喃(50毫升)溶液中滴加浓盐酸(6毫升)。混合物在20℃搅拌12个小时，倒入水(250毫升)中，然后用乙酸乙酯(100毫升×3)萃取。将合并的有机层用无水硫酸钠干燥，减压浓缩，残余物通过硅胶色谱法纯化得到化合物17E(白色固体，3.9克，95％产率)。LCMS(ESI)m/z:241(M+H+)
实施例17F
3-(3,5-二氟-4-(氯甲基)苯丙炔酸乙酯
Figure PCTCN2016079992-appb-000062
0℃下，向化合物17E(3.9克，16.2毫摩尔)和DMF(2.4克)的二氯甲烷(20毫升)溶液中滴加氯化亚砜(3.8克，32.4毫摩尔)。滴加完毕后，混合物在20℃下搅拌2小时，倒入水(50毫升)中，然后用二氯甲烷(50毫升×3)萃取。将合并的有机层用无水硫酸钠干燥，减压浓缩，残余物通过硅胶色谱法纯化得到化合物17F(白色固体，3.0克，72％产率)。LCMS(ESI)m/z:259(M+H+)
实施例17G
3-(4-((1H-咪唑-1-基)甲基)-3,5-二氟苯丙炔酸乙酯
Figure PCTCN2016079992-appb-000063
化合物17F(3.0克，11.6毫摩尔)，咪唑(1.6克，23.2毫摩尔)，碘化钾(0.96克，5.8毫摩尔)和碳酸钾(2.4克，17.4毫摩尔)的丙酮(10毫升)混合物在50～60℃搅拌0.5小时。冷却过滤，滤液倒入水(50毫升)中，用乙酸乙酯(50毫升×5)萃取。将合并的有机层用无水硫酸钠干燥，过滤并蒸发，残余物通过硅胶色谱法纯化得到化合物17G(浅褐色固体，2.0克，60％产率)。LCMS(ESI)m/z:291(M+H+)
化合物17
5-(4-((1H-咪唑-1-基)甲基)-3,5-二氟苯基)异噁唑-3-酚
Figure PCTCN2016079992-appb-000064
0℃下，固体NaOH(1.7克,41.4毫摩尔)溶解于水(8毫升)中，分批加入羟胺盐酸盐(1.4克，20.3毫摩尔)，搅拌10分钟后，滴加入化合物17G(2.0克，6.8毫摩尔)的甲醇(15毫升)溶液。混合物在20℃搅拌12小时，用2N的稀盐酸调节pH值到8，减压蒸除大部分甲醇，有淡黄色固体析出。过滤，滤饼用4N的盐酸甲醇(50毫升)成盐，减压浓缩，残余物用甲醇/乙酸乙酯混和溶液重结晶得到实施例17的盐酸盐(0.3克，16％产率)。1H NMR(400MHz,CD3OD):δ9.18(br.s.,1H),7.75-7.54(m,4H),6.57(s,1H),5.67(s,2H)。LCMS(ESI)m/z:278(M+H+)。
实施例18
5-(4-((1H-咪唑-1-基)甲基)-3,5-二甲基苯基)异噁唑-3-酚
化合物18
该实施例如实施例17中描述的方法制备。1H NMR(400MHz,CD3OD):δ8.82(s,1H),7.66-7.59(m,3H),7.50(s,1H),6.41(s,1H),5.60(s,2H),2.43(s,6H)。LCMS(ESI)m/z:270(M+H+)。
实施例19
5-(4-((1H-咪唑-1-基)甲基)-吡啶-2-基)异噁唑-3-酚
Figure PCTCN2016079992-appb-000066
化合物19
该实施例如实施例17中描述的方法制备。1H NMR(400MHz,CD3OD):δ9.18(s,1H),8.78(d,J＝1.5Hz,1H),8.10-8.04(m,1H),8.03-7.98(m,1H),7.76(s,1H),7.66(s,1H),6.65(s,1H),5.64(s,2H)。LCMS(ESI)m/z:243 (M+H+)。
流程D
Figure PCTCN2016079992-appb-000067
实施例20
5-(4-(1-(1H-咪唑-1-基)乙基)苯基)异噁唑-3-酚
Figure PCTCN2016079992-appb-000068
化合物20A
3-(4-(1-羟乙基)苯丙炔酸乙酯
Figure PCTCN2016079992-appb-000069
氮气保护下，往1-(4-碘苯)乙醇(10克，40.3毫摩尔)，碘化亚铜(383毫克，2.02毫摩尔)和Pd(PPh3)2C12(100毫克，10％wt)的1,4-二氧六环(17毫升)溶液中加入丙炔酸乙酯(5.93克，60.4毫摩尔)的1,4-二氧六环(6毫升)溶液，再加入碳酸钠(6.41克，60.5毫摩尔)水(20毫升)溶液。加料完毕后，混合物在氮气氛围下80℃搅拌20分钟，倒入水(100毫升)中，用乙酸乙酯(100毫升×3)萃取。将合并的有机层用无水硫酸钠干燥，过滤并蒸发，残余物通过硅胶色谱柱纯化得到化合物20A(无色油状物，4.1克，46.6％产率)。LCMS(ESI)m/z:219(M+H+)
化合物20B
3-(4-(1-(1H-咪唑-1-基)乙基)苯丙炔酸乙酯
Figure PCTCN2016079992-appb-000070
0℃氮气保护下，往化合物20A(270毫克，1.24毫摩尔)，咪唑(101毫克，1.48毫摩尔)和三苯基膦(389毫克，1.48毫摩尔)的四氢呋喃(5毫升)溶液中滴加偶氮二甲酸二叔丁酯(428毫克，1.86毫摩尔)。滴加完毕后，混合物在20℃搅拌12小时，减压浓缩，残余物通过制备型TLC纯化得到化合物20B(棕色油状物，120毫克，36.2％产率)。LCMS(ESI)m/z:269(M+H+)
化合物20
5-(4-(1-(1H-咪唑-1-基)乙基)苯基)异噁唑-3-酚
Figure PCTCN2016079992-appb-000071
0℃下，固体NaOH(208毫克,5.22毫摩尔)溶解于水(1.5毫升)中，慢慢加入羟胺盐酸盐(108毫克，1.57毫摩尔)，搅拌10分钟后，滴加实施例20B(140毫克，0.52毫摩尔)的甲醇(1.5毫升)溶液。混合物在20℃搅拌12小时，用2N的稀盐酸调节pH值到8，减压蒸除大部分甲醇，残余物通过制备型HPLC纯化得到实施例20(55毫克，41.3％产率)。1H NMR(400MHz,CD3OD):δ7.81(s,1H),7.69(d,J＝8.16Hz,2H),7.31(d,J＝8.38Hz,2H),7.18(s,1H),6.99(s,1H),6.13(s,1H),5.56(q,J＝7.06Hz,1H),1.86(d,J＝7.06Hz,3H)。LCMS(ESI)m/z:256(M+H+)。
实施例21和22
R-5-(4-(1-(1H-咪唑-1-基)乙基)苯基)异噁唑-3-酚和S-5-(4-(1-(1H-咪唑-1-
基)乙基)苯基)异噁唑-3-酚
Figure PCTCN2016079992-appb-000072
化合物21和22
该实施例由实施例20通过SFC方法拆分而得到，化合物21保留时间为5.198min，化合物22保留时间为8.972min。LCMS(ESI)m/z:256(M+H+)
实施例23
5-(4-(2-(1H-咪唑-1-基)-2-丙基)苯基)异噁唑-3-酚
Figure PCTCN2016079992-appb-000073
化合物23
该实施例如实施例20中描述的方法制备。1H NMR(400MHz,CD3OD):δ9.22(s,1H),7.84(d,J＝8.0Hz,2H),7.66(br s,2H),7.43(d,J＝8.0Hz,2H),6.40(s,1H),2.12(s,6H)。LCMS(ESI)m/z:270(M+H+)。
流程E
Figure PCTCN2016079992-appb-000074
实施例24
5-(3-((1H-咪唑-1-基)甲基)苯基)异噁唑-3-酚
Figure PCTCN2016079992-appb-000075
化合物24A
3-(3-(羟甲基)苯基)丙炔酸乙酯
Figure PCTCN2016079992-appb-000076
氮气保护下，3-碘苯甲醇(5.9克，25.2毫摩尔)，丙炔酸乙酯(5.0克，50.4毫摩尔)和氧化亚铜(3.6克，25.2毫摩尔)的DMF(100毫升)混合物在110℃下搅拌16小时。冷却过滤，滤液减压浓缩除去大部分DMF，残余物加入水(100毫升)，用乙酸乙酯(100毫升×3)萃取。将合并的有机层用无水硫酸钠干燥，过滤并蒸发，粗品通过柱色谱纯化得到化合物24A(棕色油状体，3.2克，62％产率)。1H NMR(400MHz,CDCl3):δ7.58(s,1H),7.49(d,J＝7.50Hz,1H),7.40-7.46(m,1H),7.30-7.39(m,1H),4.68(s,2H),4.28(q,J＝7.20Hz,2H),1.34(t,J＝7.20Hz,3H)。LCMS(ESI)m/z:205(M+H+)。
实施例24B
3-(3-(氯甲基)苯基)丙炔酸乙酯
Figure PCTCN2016079992-appb-000077
0℃下，往化合物24A(1.5克，7.3毫摩尔)和DMF(0.2毫升)的二氯甲烷(20毫升)溶液中滴加氯化亚砜(2.6克，22毫摩尔)，滴加完毕后，混合物在20℃下搅拌1小时。减压蒸除大部分溶剂和剩余的氯化亚砜得到化合物24B(无色液体，1.6克，98％产率)，可直接用于下一步骤而无需进 一步纯化。LCMS(ESI)m/z:223(M+H+)
化合物24C
3-(3-((1H-咪唑-1-基)甲基)苯基)丙炔酸乙酯
Figure PCTCN2016079992-appb-000078
化合物24B(1.6克，7.2毫摩尔)，咪唑(0.98克，14.4毫摩尔)，碘化钾(1.8克，10.8毫摩尔)和碳酸钾(2.0克，14.4毫摩尔)的丙酮(50毫升)混合物在50～60℃搅拌3小时。冷却过滤，滤液倒入水(250毫升)中，用乙酸乙酯(200毫升×3)萃取。将合并的有机层用无水硫酸钠干燥，过滤并蒸发，残余物通过硅胶色谱法纯化得到化合物24C(棕色油状体，1.1克，59％产率)。1H NMR(400MHz,CD3OD):δ7.77(s,1H),7.54(d,J＝7.50Hz,1H),7.39-7.48(m,2H),7.28-7.39(m,1H),7.13(s,1H),7.00(s,1H),5.25(s,2H),4.25(q,J＝7.06Hz,2H),1.30(t,J＝7.06Hz,3H)。LCMS(ESI)m/z:255(M+H+)。
化合物24
5-(3-((1H-咪唑-1-基)甲基)苯基)异噁唑-3-酚
Figure PCTCN2016079992-appb-000079
0℃下，固体NaOH(314毫克,7.9毫摩尔)溶解于水(3毫升)中，加入羟胺盐酸盐(164毫克，2.4毫摩尔)，搅拌10分钟后，将此溶液加入到化合物24C(200毫克，0.79毫摩尔)的甲醇(3毫升)溶液。混合物在20℃搅拌3小时。减压蒸除大部分溶剂，残余物通过制备型HPLC纯化得到实施例24的盐酸盐(70毫克，37％产率)。1H NMR(400MHz,CD3OD):δ9.17(s, 1H),7.91(s,1H),7.83(s,1H),7.72(s,1H),7.50-7.66(m,3H),6.44(s,1H),5.58(s,2H)。LCMS(ESI)m/z:242(M+H+)。
流程F
Figure PCTCN2016079992-appb-000080
实施例25
5-(4-(2-(1H-咪唑-1-基)甲基)苄基)异噁唑-3-酚
Figure PCTCN2016079992-appb-000081
化合物25A
4-(4-(羟甲基)苯基)丁-2-炔酸乙酯
Figure PCTCN2016079992-appb-000082
15℃氮气保护下，往4-氯甲基苯甲醇(4.50克，28.7毫摩尔)的乙腈(100毫升)溶液中依次加入丙炔酸乙酯(5.64克，57.5毫摩尔)，碘化亚铜(5.47克，28.7毫摩尔)，碳酸钾(3.97克，28.7毫摩尔)和四正丁基碘化铵(10.6克，28.7毫摩尔)。加料完毕后，混合物在50℃氮气氛围下搅拌 12小时，加水(300毫升)稀释，用乙酸乙酯(200毫升×3)萃取。将合并的有机层用无水硫酸钠干燥，过滤并浓缩，残余物通过硅胶柱色谱纯化得到化合物25A(无色油状物，4.7克，75.0％产率)。LCMS(ESI)m/z:219(M+H+)
化合物25B
5-(4-(羟甲基)苄基)异噁唑-3-酚
Figure PCTCN2016079992-appb-000083
0℃下，固体NaOH(4.31克,107.7毫摩尔)溶解于水(25毫升)中，滴加羟胺盐酸盐(4.49克，64.6毫摩尔)的甲醇(50毫升)溶液，搅拌10分钟后，再滴加化合物25A(4.70克，21.5毫摩尔)的甲醇(50毫升)溶液。混合物在20℃搅拌12小时。减压蒸除大部分甲醇，用3M盐酸调节pH＝2，乙酸乙酯(100毫升×3)萃取。将合并的有机层用无水硫酸钠干燥，过滤并浓缩，残余物通过硅胶柱色谱纯化得到化合物25B(2.2克，49.8％产率)。LCMS(ESI)m/z:206(M+H+)
实施例25C
4-甲基苯磺酸-5-(4-(羟甲基)苄基)异噁唑-3-酯
Figure PCTCN2016079992-appb-000084
15℃氮气保护下，往化合物25B(100毫克，0.49毫摩尔)的二氯甲烷(3毫升)溶液中依次加入对甲苯磺酰氯(557毫克，2.92毫摩尔)，三乙胺(394毫克，3.90毫摩尔)和DMAP(6.0毫克，0.05毫摩尔)。加料完毕后，混合物在15℃氮气氛围下搅拌5小时，减压浓缩，残余物通过硅胶柱色谱纯化得到化合物25C(黄色油状物，100毫克，57.1％产率)。LCMS(ESI)m/z: 360(M+H+)
实施例25D
4-甲基苯磺酸-5-(4-(氯甲基)苄基)异噁唑-3-酯
Figure PCTCN2016079992-appb-000085
15℃下，往化合物25C(100毫克，0.28毫摩尔)的二氯甲烷(3毫升)溶液中加入氯化亚砜(66毫克，0.56毫摩尔)。混合物在15℃搅拌3小时，加入饱和碳酸氢钠(15毫升)淬灭，再用乙酸乙酯(15毫升×3)萃取。将合并的有机层用无水硫酸钠干燥，过滤并浓缩得到化合物25D(黄色固体，100毫克，95.1％产率)。LCMS(ESI)m/z:378(M+H+)
化合物25E
4-甲基苯磺酸-5-(4-(氯甲基)苄基)异噁唑-3-酯
Figure PCTCN2016079992-appb-000086
化合物25D(100毫克，0.26毫摩尔)，咪唑(36毫克，0.53毫摩尔)，碘化钾(44毫克，0.26毫摩尔)和碳酸钾(73毫克，0.53毫摩尔)的丙酮(2毫升)混合物在50～60℃搅拌3小时。冷却过滤，滤液倒入水(20毫升)中，用乙酸乙酯(15毫升×3)萃取。将合并的有机层用无水硫酸钠干燥，过滤并浓缩得到粗品化合物25E(黄色固体，100毫克)。LCMS(ESI)m/z:410(M+H+)
化合物25
5-(4-(2-(1H-咪唑-1-基)甲基)苄基)异噁唑-3-酚
Figure PCTCN2016079992-appb-000087
15℃下，向化合物25E(100毫克，0.24毫摩尔)的水(2毫升)和甲醇(2毫升)混合溶液中加入1M氢氧化钠水溶液(1毫升，1.0毫摩尔)。混合物在15℃搅拌12小时，减压浓缩，残余物通过制备型HPLC纯化得到实施例25的盐酸盐(20毫克，32.1％产率)。1H NMR(400MHz,CD3OD):δ9.07(s,1H),7.63(s,1H),7.58(s,1H),7.32-7.44(m,4H),5.70(s,1H),5.45(s,2H),4.01(s,2H)。LCMS(ESI)m/z:256(M+H+)。
实施例26
5-(3-((1H-咪唑-1-基)甲基)苄基)异噁唑-3-酚
Figure PCTCN2016079992-appb-000088
化合物26
该实施例如实施例25中描述的方法制备。1H NMR(400MHz,CD3OD):δ9.06(s,1H),7.63(s,1H),7.58(s,1H),7.38-7.46(m,1H),7.29-7.38(m,3H),5.69(s,1H),5.45(s,2H),4.02(s,2H)。LCMS(ESI)m/z:256(M+H+)。
流程G
Figure PCTCN2016079992-appb-000089
实施例27
4-(4-((1H-咪唑-1-基)甲基)苯基)-3-氟吡啶-2-酚
Figure PCTCN2016079992-appb-000090
化合物27A
4-(4-羟甲基)苯基)-3-氟吡啶-2-酚
Figure PCTCN2016079992-appb-000091
氮气保护下，3-氟-4-碘-2-甲氧基吡啶(2.5克，9.8毫摩尔)，(4-(羟甲基苯硼酸(3.0克，19.6毫摩尔)，磷酸钾(6.0克，29.6毫摩尔)和Pd(dppf)Cl2(0.5克，0.98毫摩尔)的1,4-二氧六环(18毫升)和水(3毫升)混合物在90℃下搅拌下12小时。冷却至室温后，用水(60毫升)稀释，乙酸乙酯(50毫升×4)萃取。有机层用无水硫酸钠干燥，过滤并浓缩，残余物用硅胶柱色谱纯化得到化合物27A(褐色固体，2.0克，87％产率)。LCMS(ESI)m/z:234(M+H+)
化合物27B
4-(4-氯甲基)苯基)-3-氟-2-甲氧基吡啶
Figure PCTCN2016079992-appb-000092
0℃氮气保护下，向化合物27A(500毫克，2.1毫摩尔)的二氯甲烷(5毫升)溶液依次加入氯化亚砜(765毫克，6.3毫摩尔)和DMF(450毫克，6.3毫摩尔)。混合物在20℃下搅拌2小时，倒入水(25毫升)中，用乙酸乙酯(50毫升×3)萃取。有机层用无水硫酸钠干燥，过滤并浓缩，残余物通过柱色谱法纯化得到化合物27B(白色固体，200毫克，37％产率)。LCMS(ESI)m/z:252(M+H+)
化合物27C
4-(4-((1H-咪唑-1-基)甲基)苯基)-3-氟-2-甲氧基吡啶
Figure PCTCN2016079992-appb-000093
化合物27B(800毫克，3.2毫摩尔)，咪唑(432毫克，6.4毫摩尔)，碘化钾(105毫克，0.64毫摩尔)和碳酸钾(870毫克，6.4毫摩尔)的丙酮(10毫升)混合物在50～60℃搅拌0.5小时。冷却过滤，滤液倒入水(40毫升)中，用乙酸乙酯(50毫升×3)萃取。将合并的有机层用无水硫酸钠干燥，过滤并浓缩，残余物通过硅胶柱色谱法纯化得到化合物27C(白色固体，700毫克，77％产率)。LCMS(ESI)m/z:284(M+H+)
化合物27
4-(4-((1H-咪唑-1-基)甲基)苯基)-3-氟吡啶-2-酚
Figure PCTCN2016079992-appb-000094
氮气保护下，向化合物27C(400毫克，1.4毫摩尔)的甲醇(5毫升) 溶液加入4M氯化氢甲醇溶液(20毫升)。混合物在20℃下搅拌12小时，减压浓缩，加入水(2毫升)和甲醇(3毫升)，搅拌10分钟后，过滤，滤饼通过制备型HPLC纯化得到实施例27的盐酸盐(100毫克，26％产率)。1H NMR(400MHz,CD3OD):δ9.13(s,1H),7.74-7.66(m,3H),7.64-7.51(m,3H),7.34(d,J＝6.5Hz,1H),6.50(t,J＝6.5Hz,1H),5.55(s,2H)。LCMS(ESI)m/z:270(M+H+)。
实施例28
4'-((1H-咪唑-1-基)甲基)-2,4-二氟-[1,1'-二苯基]-3-酚
Figure PCTCN2016079992-appb-000095
化合物28
该实施例如实施例27中描述的方法制备。1H NMR(400MHz,CD3OD):δ9.11(br.s.,1H),7.69(t,J＝1.8Hz,1H),7.57-7.64(m,3H),7.48-7.54(m,2H),6.97-7.05(m,1H),6.90(td,J＝8.4,5.8Hz,1H),5.53(s,2H)。LCMS(ESI)m/z:287(M+H+)。
实施例29
5-(4-((1H-咪唑-1-基)甲基)苯基)异噻唑-3-酚
Figure PCTCN2016079992-appb-000096
化合物29
该实施例如实施例27中描述的方法制备。1H NMR(400MHz,CD3OD):δ79.14(s,1H),7.77-7.67(m,3H),7.63(s,1H),7.54(d,J＝8.0Hz,2H),6.91(s,1H),5.55(s,2H)。LCMS(ESI)m/z:258(M+H+)。
流程H
Figure PCTCN2016079992-appb-000097
实施例30
5-(4-((1H-咪唑-1-基)甲基)苯基)-4-甲基异噁唑-3-酚
Figure PCTCN2016079992-appb-000098
化合物30A
1-(4-(叔丁基二甲基硅氧甲基)苯基)丙-1-酮
Figure PCTCN2016079992-appb-000099
0℃氮气保护下，往1-(4-(羟甲基)苯基)丙-1-酮(3.2克，19.5毫摩尔)和咪唑(2.65克，39.0毫摩尔)的DMF(50毫升)溶液中加入叔丁基二甲基氯硅烷(4.4克，29.2毫摩尔)。混合物在20℃下搅拌9小时，加入乙酸乙酯(200毫升)稀释，再用水(200毫升×2)洗涤，有机层用无水硫酸钠干燥，过滤并浓缩，残余物通过硅胶柱色谱法纯化得到化合物30A(黄色油状物，4.9克，84％产率)。LCMS(ESI)m/z:279(M+H+)
化合物30B
3-(4-(叔丁基二甲基硅氧甲基)苯基)-2-甲基-3-酮丙酸甲酯
Figure PCTCN2016079992-appb-000100
0℃氮气保护下，往化合物30A(4.9克，16.4毫摩尔)的碳酸二甲酯(70毫升)混合物分批加入钠氢(1.3克，32.8毫摩尔，60％在矿物油中)。混合物在90℃下搅拌3小时。冷却至室温，反应物用饱和氯化铵水溶液(100毫升)淬灭，再用乙酸乙酯(60毫升×3)萃取，将合并的有机层用硫酸钠干燥，过滤并蒸发，得到化合物30B(黄色油状物，4.4克，80％产率)可直接用于下一步骤而无需进一步纯化。LCMS(ESI)m/z:337(M+H+)
化合物30C
3-(4-(羟甲基)苯基)-2-甲基-3-酮丙酸甲酯
Figure PCTCN2016079992-appb-000101
氮气保护下，向化合物30B(4.4克，13.1毫摩尔)的四氢呋喃(30毫升)溶液中加入1M的盐酸(30毫升)。混合物在25℃下搅拌3小时。过滤，滤液减压浓缩，残余物通过硅胶柱色谱法纯化得到化合物30C(黄色油状物，2.1克，72.4％产率)。LCMS(ESI)m/z:223(M+H+)
化合物30D
3-(4-((1H-咪唑-1-基)甲基)苯基)-2-甲基-3-酮丙酸甲酯
Figure PCTCN2016079992-appb-000102
0℃氮气保护下，向化合物30C(1.5克，6.75毫摩尔)，咪唑(559毫克，8.10毫摩尔)和三正丁基膦(2.69克，13.5毫摩尔)的无水四氢呋喃(15毫升)溶液中滴加偶氮二羧酸二叔丁酯(3.1克，13.5毫摩尔)。滴加完毕后，反应混合物在20℃搅拌9小时，加入乙酸乙酯(200毫升)稀释后，用水(80毫升x 2)洗涤。有机层用无水硫酸钠干燥，过滤并蒸发，残余物通过制备型HPLC纯化得到化合物30D(黄色油状物，150毫克，8.1％产率)。LCMS(ESI)m/z:273(M+H+)
化合物30
5-(4-((1H-咪唑-1-基)甲基)苯基)-4-甲基异噁唑-3-酚
Figure PCTCN2016079992-appb-000103
-30℃下，往化合物30D(112毫克，0.4毫摩尔)的甲醇(3毫升)溶液中加入氢氧化钠(64毫克，1.6毫摩尔)的水(1毫升)溶液。搅拌10分钟后，滴加羟胺盐酸盐(56.0毫克，0.8毫摩尔)的甲醇(2毫升)溶液。滴加完毕后，混合物在20℃搅拌2小时，减压浓缩，残余物通过制备型HPLC纯化得到实施例30的盐酸盐(50毫克，50.1％产率)。1H NMR(400MHz,CD3OD):δ9.09(s,1H),7.63-7.73(m,3H),7.58(t,J＝7.83Hz,3H),5.54(s,2H),1.91-1.99(m,3H)。LCMS(ESI)m/z:256(M+H+)。
实施例31
5-(4-((1H-咪唑-1-基)甲基)苯基)-1H-吡唑-3-酚
Figure PCTCN2016079992-appb-000104
化合物31
该实施例如实施例30中所述制备，用水合肼替换羟胺盐酸盐。1H NMR(400MHz,CDCl3):δ9.18(s,1H),7.86-7.88(m,3H),7.64-7.71(m,3H),6.35(s,1H),5.60(s,2H)。LCMS(ESI)m/z:241(M+H+)。
流程I
Figure PCTCN2016079992-appb-000105
实施例32
5-(4-(1H-咪唑-1-基)丁基)异噁唑-3-酚
Figure PCTCN2016079992-appb-000106
化合物32A
叔丁基(5-己炔-1-氧基)二苯基硅烷
Figure PCTCN2016079992-appb-000107
本化合物如化合物17A中描述的方法制备，用叔丁基二苯基氯硅烷替换叔丁基二甲基氯硅烷。LCMS(ESI)m/z:337(M+H+)
化合物32B
7-(叔丁基二苯基硅氧基)庚-2-炔酸甲酯
Figure PCTCN2016079992-appb-000108
本化合物如化合物17D中描述的方法制备，用氯甲酸甲酯替换氯甲酸乙酯。LCMS(ESI)m/z:395(M+H+)
化合物32C
7-羟基庚-2-炔酸甲酯
Figure PCTCN2016079992-appb-000109
氮气保护下，往化合物32B(5.0克，12.6毫摩尔)的四氢呋喃(50毫升)溶液加入TBAF(4.0克，12.6毫摩尔)。混合物在20℃搅拌3小时，倒入水(60毫升)中，用乙酸乙酯(100毫升x 3)萃取。合并后的有机层用无水硫酸钠干燥，过滤并蒸发，残余物通过硅胶柱色谱法纯化得到化合物32C(无色油状物，1.2克，61％产率)。LCMS(ESI)m/z:157(M+H+)
化合物32D
7-对甲苯磺酰氧基庚-2-炔酸甲酯
Figure PCTCN2016079992-appb-000110
0℃氮气保护下，往化合物32C(0.8克，5.12毫摩尔)，三乙胺(1.13克，10.24毫摩尔)和DMAP(80毫克)的二氯甲烷(50毫升)溶液分批加入对甲苯磺酰氯(1.07克，5.63毫摩尔)。混合物在20℃搅拌1.5小时，加入二氯甲烷(30毫升)稀释，用水(50毫升x 2)洗涤。有机层用无水硫酸钠干燥，过滤并蒸发，残余物通过硅胶柱色谱法纯化得到化合物32D(黄色油状物，0.82克，78％产率)。LCMS(ESI)m/z:311(M+H+)
化合物32E
7-(1H-咪唑-1-基)庚-2-炔酸甲酯
Figure PCTCN2016079992-appb-000111
0℃氮气保护下，往咪唑(280毫克，4.0毫摩尔)的DMF(5毫升)溶液中加入钠氢(240毫克，6.0毫摩尔，60％在矿物油中)，搅拌10分钟后，再加入化合物32D(620毫克，2.0毫摩尔)。混合物在15℃搅拌5小时，加 入饱和氯化铵水溶液(30毫升)淬灭，乙酸乙酯(50毫升x 3)萃取。合并后的有机层用无水硫酸钠干燥，过滤并蒸发，残余物通过制备型HPLC纯化得到化合物32E(黄色油状物，150毫克，36％产率)。LCMS(ESI)m/z:207(M+H+)
化合物32
5-(4-(1H-咪唑-1-基)丁基)异噁唑-3-酚
Figure PCTCN2016079992-appb-000112
该实施例如化合物25B中描述的方法制备。1H NMR(400MHz,CD3OD):δ9.04(s,1H),7.72(s,1H),7.65(s,1H),3.60(s,1H),2.10-2.40(m,2H),2.20-2.50(m,2H),1.70-2.00(m,4H)。LCMS(ESI)m/z:208(M+H+)。
实施例33
5-(5-(1H-咪唑-1-基)戊基)异噁唑-3-酚
Figure PCTCN2016079992-appb-000113
化合物33
该实施例中如实施例32中描述的方法制备。1H NMR(400MHz,CD3OD):δ9.01(s,1H),7.70(s,1H),7.60(s,1H),5.75(s,1H),4.30(t,J＝7.3Hz,2H),2.70(t,J＝7.3Hz,2H),2.09-1.88(m,2H),1.76(q,J＝7.7Hz,2H),1.51-1.33(m,2H)。LCMS(ESI)m/z:222(M+H+)。
流程J
Figure PCTCN2016079992-appb-000114
实施例34和35
5-(trans-4-((1H-咪唑-1-基)甲基)环)异噁唑-3-酚和5-(cis-4-((1H-咪唑-1-基)甲基)环)异噁唑-3-酚
Figure PCTCN2016079992-appb-000115
化合物34A和35A
(4-(((叔丁基二甲基硅氧)甲基)环己基)甲醇
Figure PCTCN2016079992-appb-000116
该化合物如化合物17A中描述的方法制备。LCMS(ESI)m/z:259(M+H+)
实施例34B和35B
(4-(((叔丁基二甲基硅氧)甲基)环己基)甲醛
Figure PCTCN2016079992-appb-000117
0℃氮气保护下，往化合物34A和35A(12.9克，50.0毫摩尔)的二氯甲烷(350毫升)溶液中加入Dess-Martin试剂(21.5克，50.0毫摩尔)。混合物在25℃搅拌3小时，过滤，滤液加入二氯甲烷(200毫升)稀释，依次用饱和碳酸钠溶液(50毫升)和水(50毫升)洗涤。然后有机层用无水硫酸钠干燥，过滤并蒸发，残余物通过硅胶柱色谱法纯化得到化合物34&35B(黄色固体，6.45克，50％产率)。LCMS(ESI)m/z:257(M+H+)
化合物34C和35C
叔丁基((4-乙炔基环己基)甲氧基)二甲基硅烷
Figure PCTCN2016079992-appb-000118
0℃氮气保护下，往化合物34B和35B(6.4克，25毫摩尔)和碳酸钾(6.98克，25毫摩尔)的甲醇(300毫升)混合物中加入(1-重氮-2-酮丙基)磷酸二甲酯(4.78克，25毫摩尔)。反应混合物在25℃搅拌9小时，加入乙酸乙酯(200毫升)稀释，用水(100毫升x 2)洗涤。有机层用无水硫酸钠干燥，过滤并蒸发，残余物通过硅胶柱色谱法纯化得到化合物34&35C(黄色油状物，2.7克，42％产率)。LCMS(ESI)m/z:253(M+H+)
化合物34D和35D
3-(4-(叔丁基二甲基硅氧甲基)环己基)丙炔酸乙酯
Figure PCTCN2016079992-appb-000119
本化合物如化合物17D中描述的方法制备。LCMS(ESI)m/z:325(M+H+)
化合物34E和35E
5-(4-(叔丁基二甲基硅氧甲基)环己基)异噁唑-3-酚
Figure PCTCN2016079992-appb-000120
本化合物如化合物25B中描述的方法制备。LCMS(ESI)m/z:312(M+H+)
化合物34F和35F
5-(4-(叔丁基二甲基硅氧甲基)环己基)-3-(4-甲氧基苄氧基)异噁唑和5-(4-(叔丁基二甲基硅氧甲基)环己基)-2-(4-甲氧基苄基)异噁唑-3(2H)-酮
Figure PCTCN2016079992-appb-000121
氮气保护下，向化合物34E和35E(15.0克，48.2毫摩尔)和碳酸钾(13.3克，96.3毫摩尔)的DMF(8毫升)混合物中滴加对甲氧基苄氯(9.8克，62.6毫摩尔)。混合物在25℃搅拌5小时，倒入水(150毫升)中，用乙酸乙酯(200毫升x 3)洗涤。有机层用无水硫酸钠干燥，过滤并蒸发，残余物通过硅胶柱色谱法纯化分别得到化合物5-(4-(叔丁基二甲基硅氧甲基)环己基)-3-(4-甲氧基苄氧基)异噁唑(5.0克，24.1％产率)和5-(4-(叔丁基二甲基硅氧甲基)环己基)-2-(4-甲氧基苄基)异噁唑-3(2H)-酮(12.0克，57.7％产率)，均为黄色固体。LCMS(ESI)m/z:432(M+H+)
化合物34G和35G
5-(4-(羟甲基)环己基)-3-(4-甲氧基苄氧基)异噁唑和5-(4-(羟甲基)环己基)-2-(4-甲氧基苄基)异噁唑-3(2H)-酮
Figure PCTCN2016079992-appb-000122
本化合物如化合物17E中描述的方法制备。LCMS(ESI)m/z:318(M+H+)
化合物34H和35H
5-(4-(对甲苯磺酰氧甲基)环己基)-3-(4-甲氧基苄氧基)异噁唑和5-(4-(对甲苯磺酰氧甲基)环己基)-2-(4-甲氧基苄基)异噁唑-3(2H)-酮
Figure PCTCN2016079992-appb-000123
本化合物如化合物32D中描述的方法制备。LCMS(ESI)m/z:471(M+H+)
化合物34I和35I
5-(4-((1H-咪唑-1-基)甲基)环己基)-3-(4-甲氧基苄氧基)异噁唑和5-(4-((1H-咪唑-1-基)甲基)环己基)-2-(4-甲氧基苄基)异噁唑-3(2H)-酮
Figure PCTCN2016079992-appb-000124
本化合物如化合物17G中描述的方法制备。LCMS(ESI)m/z:368(M+H+)
化合物34和35
5-(trans-4-((1H-咪唑-1-基)甲基)环)异噁唑-3-酚和5-(cis-4-((1H-咪唑-1-基)甲基)环)异噁唑-3-酚
Figure PCTCN2016079992-appb-000125
氮气保护下，化合物34I和35I(5-(4-((1H-咪唑-1-基)甲基)环己基)-3-(4-甲氧基苄氧基)异噁唑，2.0克，5.44毫摩尔；5-(4-((1H-咪唑-1-基)甲基)环己基)-2-(4-甲氧基苄基)异噁唑-3(2H)-酮，4.0克，10.8毫摩尔)溶于三氟乙酸(48毫升)和甲磺酸(6毫升)中。混合物在100℃搅拌12小时，倒入水(150 毫升)中，用饱和碳酸钠溶剂调节pH值到6-7，有固体析出，过滤，滤饼进一步通过制备型HPLC分离纯化分别得到化合物34，5-(反式-4-((1H-咪唑-1-基)甲基)环)异噁唑-3-酚的盐酸盐(400毫克)和化合物35，5-(顺式-4-((1H-咪唑-1-基)甲基)环)异噁唑-3-酚的盐酸盐(300毫克)，总产率17.5％。化合物34：1H NMR(400MHz,CD3OD):δ9.01(s,1H),7.69(s,1H),7.62(s,1H),5.69(s,1H),4.18(d,J＝7.3Hz,2H),2.76-2.61(m,1H),2.12(d,J＝11.0Hz,2H),1.97(ttd,J＝3.8,7.7,15.2Hz,1H),1.77(d,J＝11.5Hz,2H),1.48(dq,J＝3.0,12.9Hz,2H),1.33-1.14(m,2H)。LCMS(ESI)m/z:248(M+H+)化合物35：1H NMR(400MHz,CD3OD):δ9.00(s,1H),7.68(s,1H),7.60(s,1H),5.82(s,1H),4.20(d,J＝7.5Hz,2H),3.02(t,J＝4.8Hz,1H),2.14-1.99(m,3H),1.86-1.75(m,2H),1.66-1.53(m,2H),1.40-1.25(m,2H)。LCMS(ESI)m/z:248(M+H+)。
流程K
Figure PCTCN2016079992-appb-000126
实施例36
4-(4-((1H-咪唑-1-基)甲基)环己-1-烯-1-基)-3-氟吡啶-2-酚
Figure PCTCN2016079992-appb-000127
化合物36A
4-(3-氟-2-甲氧基吡啶-4-基)环己-3-烯甲酸乙酯
Figure PCTCN2016079992-appb-000128
本化合物如化合物27A中描述的方法制备。LCMS(ESI)m/z:280(M+H+)
化合物36B
(4-(3-氟-2-甲氧基吡啶-4-基)环己-3-烯-1-基)甲醇
Figure PCTCN2016079992-appb-000129
氮气保护下，向化合物36A(600毫克，2.15毫摩尔)的四氢呋喃(5毫升)溶液中加入硼氢化锂(234毫克，10.7毫摩尔)。混合物在25℃搅拌12小时，加入水(10毫升)淬灭，再用乙酸乙酯(30毫升x 3)洗涤。有机层用无水硫酸钠干燥，过滤并蒸发，残余物通过硅胶柱色谱法纯化得到化合物36B(白色固体，450毫克，88.2％产率)。LCMS(ESI)m/z:238(M+H+)
化合物36C
3-氟-2-甲氧基-4-(4-(对甲苯磺酰氧甲基)环己-1-烯-1-基)吡啶
Figure PCTCN2016079992-appb-000130
本化合物如化合物32D中描述的方法制备。LCMS(ESI)m/z:376(M+H+)
实施例36D
4-(4-((1H-咪唑-1-基)甲基)环己-1-烯-1-基)-3-氟-2-甲氧基吡啶
Figure PCTCN2016079992-appb-000131
本化合物如化合物17G中描述的方法制备。LCMS(ESI)m/z:288(M+H+)
化合物36
4-(4-((1H-咪唑-1-基)甲基)环己-1-烯-1-基)-3-氟吡啶-2-酚
Figure PCTCN2016079992-appb-000132
本化合物如实施例27中描述的方法制备。1H NMR(400MHz,CD3OD):δ9.06(s,1H),7.98-7.51(m,2H),7.20(d,J＝6.5Hz,1H),6.31(t,J＝6.1Hz,1H),6.16(br.s.,1H),4.29(d,J＝7.0Hz,2H),2.66-2.19(m,4H),2.12-1.77(m,2H),1.59-1.42(m,1H)。LCMS(ESI)m/z:274(M+H+)。
实验例1.大鼠体外全血凝血过程中TXB2水平的释放的实验
实验原理：
体外凝血过程中，血栓素A2(TXA2)通路被激活，大量TXA2生成并迅速代谢转化为稳定形态即血栓素B2(TXB2)。
该通路的关键酶为血栓素合成酶，在体外凝血过程加入该酶的特异抑制剂(待测化合物)，能够抑制TXA2的生成，从而减少TXB2的含量。
以抑制TXB2生成的IC50反映待测化合物的活性。
实验动物：
雄性Sprague-Dawley(SD)大鼠，购买自上海斯莱克实验动物中心
实验试剂：
0.9％生理盐水溶液，100M氢氧化钠溶液(溶媒)，100uM血栓素合成酶抑制剂溶液，异氟烷
实验步骤和方法：
1、将生理盐水溶解的化合物溶液梯度稀释至所需浓度，于离心管中加入167uL化合物溶液。
2、雄性SD大鼠异氟烷麻醉，心脏取血，迅速加入离心管中至0.5mL，摇匀，放入37℃恒温水浴中孵育30分钟至血液全凝。
3、取出离心管，6000g,4℃离心5分钟，取血清。
4、使用LC-MS/MS-AG(API 4000)检测TXB2的含量。
数据分析：
以溶媒组为对照，根据以下公式，将每个样品的TXB2含量归一化为对照组％(Control％)：
Control％＝(测试管TXB2含量-阴性管TXB2含量)/对照管TXB2含量×100
注：测试管：不同浓度化合物
阴性管：高浓度(100uM)血栓素合酶抑制剂
对照管：溶媒
使用GraphPad Prism，以化合物浓度为横坐标，Control％为纵坐标，将数据进行拟合，并计算IC50值。
实验结果见表1：
表1大鼠体外全血凝血过程中TXB2水平的释放检测IC50测试结果
Figure PCTCN2016079992-appb-000133
注：A≤25nM；25nM＜B≤50nM；50nM＜C≤100nM；100nM＜D≤250nM；E>250nM

Claims (12)

  1. 式(Ⅰ)所示的化合物、其药学上可接受的盐或其互变异构体，
    Figure PCTCN2016079992-appb-100001
    其中，
    n为0-3的整数，优选为0或1；
    L选自任选R取代的5～6元环烃基或杂环烃基或-(CH2)1-6-；
    环A选自任选R取代的5～6元不饱和环烃基或杂环基；
    R1、R2、R分别独立地选自H、F、Cl、Br、I、CN、OH、SH、NH2、CHO、COOH，或选自任选被R01取代的：C(＝O)NH2、S(＝O)NH2、S(＝O)2NH2、C1-6烷基或杂烷基、C3-6环烷基或杂环烷基；
    “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-、-C(＝O)O-、-C(＝O)-、-C(＝S)-、-S(＝O)-、-S(＝O)2-或-N(R)C(＝O)N(R)-；
    R01、杂原子或杂原子团的数目分别独立地选自0、1、2或3；和
    R01选自H、F、Cl、Br、I、CN、OH、C1-3烷基、N(CH3)2、NH(CH3)、NH2、CHO、COOH、C(＝O)NH2、S(＝O)NH2、S(＝O)2NH2、三氟甲基、氨甲基、羟甲基、甲氧基、甲酰基、甲氧羰基、甲磺酰基、甲基亚磺酰基。
  2. 根据权利要求1所述的化合物、其药学上可接受的盐或其互变异构体，其中R1、R2、R分别独立地选自H、F、Cl、Br、I、C1-3烷基、C1-3烷 氧基、N(CH3)2、NH(CH3)、NH2、CHO、COOH、C(＝O)NH2、S(＝O)NH2、S(＝O)2NH2、三氟甲基、氨甲基、羟甲基、甲酰基、甲氧羰基、甲磺酰基、甲基亚磺酰基、环丙基；
    优选地，R1、R2、R分别独立地选自H、F、Cl、Br、I、CH3、C2H5-、CH3O-或
    Figure PCTCN2016079992-appb-100002
  3. 根据权利要求1或2所述的化合物、其药学上可接受的盐或其互变异构体，其中L选自任选被R取代的：5～6元芳基或杂芳基、5～6元脂肪环基、-(CH2)1-6-；
    优选地，L选自
    Figure PCTCN2016079992-appb-100003
    或任选被R取代的-(CH2)1-6-，其中，
    T21-24中的0或1个选自N，其余选自C(R)；
    D21-24中的0～3个选自-C(＝O)N(R)-、-N(R)-、-C(＝NR)-、-S(＝O)2N(R)-、-S(＝O)N(R)-、-O-、-S-、-C(＝O)O-、-C(＝O)-、-C(＝S)-、-S(＝O)-、-S(＝O)2-或-N(R)C(＝O)N(R)-，其余选自C(R)(R)；
    T25选自N或者C(R)；
    D25-27中的0～3个选自-C(＝O)N(R)-、-N(R)-、-C(＝NR)-、-S(＝O)2N(R)-、-S(＝O)N(R)-、-O-、-S-、-C(＝O)O-、-C(＝O)-、-C(＝S)-、-S(＝O)-、-S(＝O)2-或-N(R)C(＝O)N(R)-，其余选自C(R)(R)。
  4. 根据权利要求3所述的化合物、其药学上可接受的盐或其互变异构 体，其中L选自
    Figure PCTCN2016079992-appb-100004
    Figure PCTCN2016079992-appb-100005
  5. 根据权利要求1或2所述的化合物、其药学上可接受的盐或其互变异构体，其中A选自5～6元芳基或杂芳基；
    优选地，A选自
    Figure PCTCN2016079992-appb-100006
    T31-34分别独立地选自N或C(R)，
    D31选自-C(R)(R)-、-C(＝O)N(R)-、-N(R)-、-C(＝NR)-、-S(＝O)2N(R)-、-S(＝O)N(R)-、-O-、-S-、-C(＝O)O-、-C(＝O)-、-C(＝S)-、-S(＝O)-、-S(＝O)2-或-N(R)C(＝O)N(R)-。
  6. 根据权利要求5所述的化合物、其药学上可接受的盐或其互变异构体，其中A选自
    Figure PCTCN2016079992-appb-100007
    Figure PCTCN2016079992-appb-100008
  7. 根据权利要求5所述的化合物、其药学上可接受的盐或其互变异构 体，其中结构单元
    Figure PCTCN2016079992-appb-100009
    选自
    Figure PCTCN2016079992-appb-100010
    Figure PCTCN2016079992-appb-100011
    其互变异构体选自
    Figure PCTCN2016079992-appb-100012
  8. 根据权利要求6或7所述的化合物、其药学上可接受的盐或其互变异构体，其中结构单元
    Figure PCTCN2016079992-appb-100013
    选自
    Figure PCTCN2016079992-appb-100014
    Figure PCTCN2016079992-appb-100015
    其互变异构体选自
    Figure PCTCN2016079992-appb-100016
    Figure PCTCN2016079992-appb-100017
  9. 根据权利要求1所述的化合物、其药学上可接受的盐或其互变异构体，其特征在于，式Ⅰ所示化合物选自：
    Figure PCTCN2016079992-appb-100018
    Figure PCTCN2016079992-appb-100019
    Figure PCTCN2016079992-appb-100020
  10. 根据权利要求1所述的化合物、其药学上可接受的盐或其互变异构体，其特征在于，式Ⅰ所示化合物的互变异构体选自：
    Figure PCTCN2016079992-appb-100021
  11. 一种抗血小板聚集的方法，该方法包括给有需要的患者施用治疗有效量的权利要求1至10中任一项所述的化合物、其药学上可接受的盐或其互变异构体。
  12. 一种治疗缺血性脑血管病的方法，该方法包括给有需要的患者施用治疗有效量的权利要求1至10中任一项所述的化合物、其药学上可接受的盐或其互变异构体；其中，优选地，所述缺血性脑血管病包括急性脑梗死。
PCT/CN2016/079992 2015-04-24 2016-04-22 咪唑类化合物 WO2016169514A1 (zh)

Priority Applications (3)

Application Number Priority Date Filing Date Title
EP16782661.9A EP3287453A4 (en) 2015-04-24 2016-04-22 Imidazole compound
JP2017555623A JP2018513199A (ja) 2015-04-24 2016-04-22 イミダゾール系化合物
US15/568,828 US20180104220A1 (en) 2015-04-24 2016-04-22 Imidazole compound

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
CN201510200711 2015-04-24
CN201510200711.8 2015-04-24

Publications (1)

Publication Number Publication Date
WO2016169514A1 true WO2016169514A1 (zh) 2016-10-27

Family

ID=57142811

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/CN2016/079992 WO2016169514A1 (zh) 2015-04-24 2016-04-22 咪唑类化合物

Country Status (5)

Country Link
US (1) US20180104220A1 (zh)
EP (1) EP3287453A4 (zh)
JP (1) JP2018513199A (zh)
CN (1) CN106065012A (zh)
WO (1) WO2016169514A1 (zh)

Families Citing this family (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2018072702A1 (zh) * 2016-10-20 2018-04-26 南京明德新药研发股份有限公司 一种咪唑类化合物的晶型、盐型及其制备方法
CN111269120A (zh) * 2020-02-29 2020-06-12 深圳市祥根生物科技有限公司 一种奥扎格雷杂质ⅱ的环保型制备方法

Citations (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4353905A (en) * 1981-09-17 1982-10-12 Warner-Lambert Company Substituted 4,5-dihydro-6-[4-(1H-imidazol-1-yl)phenyl]-3(2H)-pyridazinones and 6-[4-(1H-imidazol-1-yl)phenyl]-3(2H)-pyridazinones
US4504479A (en) * 1981-07-31 1985-03-12 A. Nattermann & Cie Gmbh 6-{5-[ω-(1-Imidazolyl)-alkyl]-thien-2-yl}-3-oxo-2,3,4,5-tetrahydro-pyridazines and acid addition salts thereof and a process for the treatment of inflammatory atherosclerotic and thrombo-embolic, illnesses in humans
US4507298A (en) * 1981-07-31 1985-03-26 A. Nattermann & Cie Gmbh 6-{4-(ω-(1-imidazolyl)-alkyl-phenyl}-3-oxo-2,3,4,5-tetrahydro-pyridazines and acid addition salts thereof, and a process for the treatment of inflammatory, atherosclerotic and thromboembolic illnesses in humans
US4643998A (en) * 1982-11-06 1987-02-17 A. Natterman & Cie Gmbh Imidazolylalkylthienyl tetrahydropyridazines and processes for their use
US20090269301A1 (en) * 2006-11-09 2009-10-29 Probiodrug Ag Novel Inhibitors of Glutaminyl Cyclase
WO2013049565A1 (en) * 2011-09-30 2013-04-04 Endo Pharmaceuticals Inc. Imidazole derivatives as cyp17 inhibitors for the treatment of cancer

Family Cites Families (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0293500A1 (en) * 1987-06-01 1988-12-07 American Cyanamid Company 3-heteroalkyl-2,4.quinzaoline-diones

Patent Citations (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4504479A (en) * 1981-07-31 1985-03-12 A. Nattermann & Cie Gmbh 6-{5-[ω-(1-Imidazolyl)-alkyl]-thien-2-yl}-3-oxo-2,3,4,5-tetrahydro-pyridazines and acid addition salts thereof and a process for the treatment of inflammatory atherosclerotic and thrombo-embolic, illnesses in humans
US4507298A (en) * 1981-07-31 1985-03-26 A. Nattermann & Cie Gmbh 6-{4-(ω-(1-imidazolyl)-alkyl-phenyl}-3-oxo-2,3,4,5-tetrahydro-pyridazines and acid addition salts thereof, and a process for the treatment of inflammatory, atherosclerotic and thromboembolic illnesses in humans
US4353905A (en) * 1981-09-17 1982-10-12 Warner-Lambert Company Substituted 4,5-dihydro-6-[4-(1H-imidazol-1-yl)phenyl]-3(2H)-pyridazinones and 6-[4-(1H-imidazol-1-yl)phenyl]-3(2H)-pyridazinones
US4643998A (en) * 1982-11-06 1987-02-17 A. Natterman & Cie Gmbh Imidazolylalkylthienyl tetrahydropyridazines and processes for their use
US20090269301A1 (en) * 2006-11-09 2009-10-29 Probiodrug Ag Novel Inhibitors of Glutaminyl Cyclase
WO2013049565A1 (en) * 2011-09-30 2013-04-04 Endo Pharmaceuticals Inc. Imidazole derivatives as cyp17 inhibitors for the treatment of cancer

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
See also references of EP3287453A4 *

Also Published As

Publication number Publication date
US20180104220A1 (en) 2018-04-19
JP2018513199A (ja) 2018-05-24
EP3287453A1 (en) 2018-02-28
CN106065012A (zh) 2016-11-02
EP3287453A4 (en) 2018-02-28

Similar Documents

Publication Publication Date Title
JP6754505B2 (ja) Ａｓｋ１阻害剤、その調製方法および使用
EP3555070B1 (en) Amine-substituted heterocyclic compounds as ehmt2 inhibitors and methods of use thereof
WO2018108064A1 (zh) 作为第四代egfr激酶抑制剂的螺环芳基磷氧化合物
CA3133753A1 (en) Novel small molecule inhibitors of tead transcription factors
WO2016112637A1 (zh) Btk抑制剂
WO2016173438A1 (zh) 稠环或三环芳基嘧啶化合物用作激酶抑制剂
JP2020516606A (ja) Ａ２Ａ受容体阻害剤としての［１，２，４］トリアゾロ［１，５−ｃ］ピリミジン誘導体
WO2016161952A1 (zh) 酪氨酸激酶抑制剂及包含该酪氨酸激酶抑制剂的药物组合物
WO2016192563A1 (zh) Janus激酶抑制剂
WO2017024968A1 (zh) 作为fgfr和vegfr抑制剂的乙烯基化合物
JP6836693B2 (ja) Ａ２ａ受容体アンタゴニストとしての縮合環誘導体
CA3054324C (en) Tri-cycle compound and applications thereof
CA2550717A1 (en) Bicycloheteroarylamine compounds as ion channel ligands and uses thereof
TWI650315B (zh) 異喹啉磺胺衍生物及其藥物組合物和製藥用途
JP2011525924A (ja) プロリルヒドロキシラーゼ阻害剤
JP2020533328A (ja) ベンゼン縮合複素環誘導体およびその医薬組成物
TW201311678A (zh) 二苯并氧呯衍生物
WO2016169514A1 (zh) 咪唑类化合物
WO2016124129A1 (zh) 二氮杂-苯并荧蒽类化合物
AU2017298256B2 (en) Indole derivative used as CRTH2 inhibitor
WO2019134662A1 (zh) 作为csf-1r抑制剂的杂环化合物及其应用
WO2018090973A1 (zh) Fgfr4抑制剂及其制备方法和应用
WO2017215588A1 (zh) 作为Akt抑制剂的二氢吡唑氮杂卓类化合物
TW201544504A (zh) 作為凝血因子Ｘa抑制劑的醯肼類化合物
JP7381170B2 (ja) 受容体阻害剤、同阻害剤を含む医薬組成物及びその使用

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: 16782661

Country of ref document: EP

Kind code of ref document: A1

ENP Entry into the national phase

Ref document number: 2017555623

Country of ref document: JP

Kind code of ref document: A

WWE Wipo information: entry into national phase

Ref document number: 15568828

Country of ref document: US

NENP Non-entry into the national phase

Ref country code: DE