WO2018210229A1 - α-7尼古丁乙酰胆碱受体激动剂及应用 - Google Patents

α-7尼古丁乙酰胆碱受体激动剂及应用 Download PDF

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WO2018210229A1
WO2018210229A1 PCT/CN2018/086865 CN2018086865W WO2018210229A1 WO 2018210229 A1 WO2018210229 A1 WO 2018210229A1 CN 2018086865 W CN2018086865 W CN 2018086865W WO 2018210229 A1 WO2018210229 A1 WO 2018210229A1
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acid
mmol
nmr
pharmaceutically acceptable
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French (fr)
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吴凌云
张丽
张鹏
陈兆国
陈曙辉
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南京明德新药研发股份有限公司
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/439—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom the ring forming part of a bridged ring system, e.g. quinuclidine
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D453/00—Heterocyclic compounds containing quinuclidine or iso-quinuclidine ring systems, e.g. quinine alkaloids
    • C07D453/02—Heterocyclic compounds containing quinuclidine or iso-quinuclidine ring systems, e.g. quinine alkaloids containing not further condensed quinuclidine ring systems
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D491/00—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00
    • C07D491/02—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00 in which the condensed system contains two hetero rings
    • C07D491/04—Ortho-condensed systems

Definitions

  • the present invention relates to a series of alpha-7 nicotine acetylcholine receptor agonists, in particular to a compound of formula (I), a pharmaceutically acceptable salt thereof, or a tautomer thereof, and its medical use.
  • Nicotine acetylcholine receptors belong to the family of ligand-gated cation channels and are regulated by the endogenous agonist acetylcholine. Each receptor is a 5-mer composed of 5 sub-organisms. The homologous or heterologous subunits combine to form different nicotine acetylcholine receptor subtypes, but each subtype has the same basic structural features, and the five subtypes form a water-filled pore structure around a center [Masatomo Ishikawa and Kenji Hashimoto, current Pharmaceutical Design, 2011, 17, 121-129, Caulfield MP. Pharmacol Ther. 1993, 58, 319-79, Jones S, Sudweeks S, Yakel JL. Trends Neurosci. 1999, 22, 555-61]. They display three main functional states when they are affected by agonists: the "shutdown” state, the "channel open” state, and the "shutdown desensitization” state.
  • the a7 nicotine acetylcholine receptor is a homologous subtype and is a well-received target, mainly distributed in the cerebral cortex and hippocampus, which are related to learning, memory and cognition [Seguela P, Wadiche J, Dineley-Miller K, J Neurosci. 1993, 13, 596-604].
  • a7 nicotine acetylcholine receptors have been found around the synapses, where they are responsible for regulating other inputs to neurons and activating various downstream signaling pathways [Berg DK, Conroy WG.J Neurobiol. 2002, 53, 512–23, Shoop RD , Martone ME, Yamada N, et al. J Neurosci.
  • the a7 nicotine acetylcholine receptor not only participates in the process of learning, memory, but also plays an important role in regulating neurotransmitters.
  • the a7 nicotine acetylcholine receptor is highly permeable to calcium ions, is rapidly activated by agonists, and is rapidly desensitized. These characteristics make the a7 nicotine acetylcholine receptors the most potential targets for the repair and improvement of cognitive impairment, such as Alzheimer's disease, psychosis, Parkinson's disease, senile memory loss, and neuropathy. Pain and so on.
  • the present invention provides a compound of the formula (I), a pharmaceutically acceptable salt thereof and a tautomer thereof,
  • T 1 or T 2 is selected from NH and the other is selected from CH 2 ;
  • R 1 is selected from H or is selected from R 2 -L-;
  • R 2 is selected from C 1-6 alkyl, C 1-6 heteroalkyl, C 3-6 cycloalkyl, 3-6 -membered heterocycloalkyl optionally substituted by 1, 2 or 3 R, 6 ⁇ 10-membered aryl, 4-6-membered heteroaryl;
  • L is selected from a single bond, or selected from optionally substituted with 1 or 2 R is: -CH 2 -, or
  • R is selected from halogen, CN, OH, NH 2 , NO 2 , COOH, or C 1-6 alkyl, C 1-6 heteroalkyl optionally substituted by 1, 2 or 3 R';R' Selected from 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 above R is selected from the group consisting of F, Cl, Br, I, NH 2 , NO 2 , COOH, or a C 1-3 alkyl group optionally substituted by 1, 2 or 3 R', C 1-3 heteroalkyl.
  • R is selected from the group consisting of F, Cl, Br, I, NH 2 , NO 2 , COOH, Me, Et, CF 3 .
  • the above R 2 is selected from C 1-3 alkyl, C 1-3 heteroalkyl, C 3-6 cycloalkyl, or butyl butyl optionally substituted by 1, 2 or 3 R , azetidinyl, tetrahydropyranyl, phenyl, pyridyl, pyrazolyl, thiazolyl, oxazolyl, imidazolyl, thienyl, triazolyl, pyrazinyl, pyrimidinyl, pyrrolyl, 2, 3-Dihydrobenzofuranyl.
  • R 2 is selected from the group consisting of
  • the above L is selected from the group consisting of a single bond and -CH 2 -.
  • R 1 is selected from the group consisting of Me,
  • the above compounds, pharmaceutically acceptable salts thereof, and tautomers thereof are selected from the group consisting of:
  • R 1 is as defined above.
  • the above R is selected from the group consisting of F, Cl, Br, I, NH 2 , NO 2 , COOH, or a C 1-3 alkyl group optionally substituted by 1, 2 or 3 R', C 1-3 heteroalkyl, other variables are as defined above.
  • the above R is selected from the group consisting of F, Cl, Br, I, NH 2 , NO 2 , COOH, Me, Et, CF 3 , and other variables are as defined above.
  • the above R 2 is selected from C 1-3 alkyl, C 1-3 heteroalkyl, C 3-6 cycloalkyl, or butyl butyl optionally substituted by 1, 2 or 3 R , azetidinyl, tetrahydropyranyl, phenyl, pyridyl, pyrazolyl, thiazolyl, oxazolyl, imidazolyl, thienyl, triazolyl, pyrazinyl, pyrimidinyl, pyrrolyl, 2, 3-Dihydrobenzofuranyl, other variables are as defined above.
  • R 2 is selected from the group consisting of Other variables are as defined above.
  • the above L is selected from the group consisting of a single bond and -CH 2 -, and other variables are as defined above.
  • R 1 is selected from the group consisting of Me, Other variables are as defined above.
  • 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 treating diseases such as schizophrenia or senile dementia.
  • novel series of compounds in the present invention have good activity and drug-like properties and have potential as candidate compounds for further clinical studies.
  • C 1-6 is selected from 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 .
  • C 1-6 alkyl or C 1-6 heteroalkyl, C 3-6 cyclic or 3- to 6-membered heterocycloalkyl includes, but is not limited to:
  • pharmaceutically acceptable as used herein is intended to mean that those compounds, materials, compositions and/or dosage forms are within the scope of sound medical judgment and are suitable for use in contact with human and animal tissues. 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.
  • 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.
  • a diastereomeric salt is formed with a suitable optically active acid or base, and then carried out by methods known in the art.
  • the diastereomers are resolved and then recovered to give the pure enantiomer.
  • 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.
  • 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.
  • 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.
  • halo or halogen
  • 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.
  • 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.
  • 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).
  • N nitrogen
  • S sulfur
  • Si silicon
  • Ge germanium
  • Al aluminum
  • heterocycloalkyl means a stable monocyclic, bicyclic or tricyclic ring containing a hetero atom or a hetero atom group, which contains a carbon atom and 1, 2, 3 or 4 independently selected from N, Ring heteroatoms of O and S.
  • 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). If the resulting compound is stable, the heterocycloalkyl groups described herein can undergo substitutions at the carbon or nitrogen position.
  • the nitrogen atom in the heterocycloalkyl group 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 heterocycloalkyl group does not exceed one.
  • Bridged rings are also included in the definition of heterocycloalkyl.
  • a bridged ring is formed when one or more atoms (ie, C, O, N, or S) join two non-adjacent carbon or nitrogen atoms.
  • Preferred bridged rings include, but are not limited to, one carbon atom, two carbon atoms, one nitrogen atom, two nitrogen atoms, and one carbon-nitrogen group. It is worth noting that a bridge always converts a single ring into a three ring. In the bridged ring, a substituent on the ring can also be present on the bridge.
  • 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 groups include, but are not limited to, cyclopentyl, cyclohexyl, 1-cyclohexenyl, 3-cyclohexenyl, cycloheptyl, and the like.
  • aryl denotes a polyunsaturated, aromatic hydrocarbon substituent which may be monosubstituted, disubstituted or polysubstituted, may be monovalent, divalent or polyvalent, it may be monocyclic or Polycyclic (such as 1 to 3 rings; at least one of which is aromatic), which are fused together or covalently linked.
  • heteroaryl refers to an aryl (or ring) containing one to four heteroatoms.
  • 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
  • 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 water; HATU for O-(7-azabenzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate ; EDC stands for N-(3-dimethylaminopropyl)-N'-ethylcarbodiimide hydrochloride; m-CPBA stands for 3-chloroperoxybenzoic acid; eq stands for equivalent, equivalent; CDI stands for Carbonyldiimidazole; DCM stands for dichloromethane; PE stands for petroleum ether; DIAD stands for diisopropyl azodicarboxylate; DMF stands for N,N-dimethylformamide; DMSO stands for dimethyl sulfoxide; EtOAc stands for acetic acid Esters; EtOH for ethanol; MeOH for methanol; CBz for benzyl
  • Identification index (d2) The ratio of the time difference between the exploration time of the new and old objects (exploring new things time – exploring old things) and the total exploration time (the total exploration time of new and old things) in each group of rats in the test phase.
  • Figure 1 Comparison of the recognition indices of new and old things in each group of rats 15 minutes after training.
  • A-2A (2.00 g, 13.0 mmol) solution of phosphorus oxychloride (21 mL) was stirred at 80 ° C for 5 hours.
  • the reaction mixture was slowly added to water (50 mL), and the mixture was evaporated, evaporated, evaporated, evaporated, evaporated. Filtration and concentration of the filtrate under reduced pressure afforded A-2B (2.10 g).
  • MS-ESI calcd for [M+H] + 173.
  • Iron powder (3.24 g, 57.9 mmol) was added to a solution of A-2C (1.32 g, 5.80 mmol) in acetic acid (40 mL) and stirred at 70 ° C for 3 hr.
  • the reaction mixture was concentrated under reduced vacuolululululululululululululululululululululululululululululu X 1) Washing, drying with anhydrous sodium sulfate, filtration, EtOAc (EtOAc) ).
  • MS-ESI calcd for [M+H] + 153.
  • A-1 (500 mg, 2.54 mmol) and 37B (518 mg, 2.54 mmol) were dissolved in anhydrous dioxane (10 mL), and anhydrous potassium phosphate (1.80 g, 5.08 mmol), (1R) 2R)-cyclohexane-1,2-diamine (29.0 mg, 0.254 mmol) and cuprous iodide (4.8 mg, 0.0250 mmol).
  • the reaction solution was stirred at 110 ° C for 12 hours.
  • the in vitro activity of the compound against the cloned human nicotine acetylcholine receptor was tested.
  • the human nicotine acetylcholine receptor (AChR) ⁇ 7 (encoded by the CHRNA7 gene) and the human chaperone protein RIC-3 (encoded by the RIC3 gene) are stably co-expressed in CHO cells using the Fluo-8 calcium kit or fluorescent imaging plate. The reader reads the information.
  • Test board quality control results are shown in Table 2 (highest value. response; lowest value. response; Z-mass and signal window). The data shows that the test data obtained by this test method is reliable.
  • the test substance defaulted to the positive control acetylcholine (ACh) in the activity assay.
  • ACh positive control acetylcholine
  • the default allosteric modulator PNU-120596 the nicotine acetylcholine ⁇ 7 receptor is rapidly desensitized, it is difficult to observe the agonistic effect of any agonist. Therefore, 1 ⁇ M PNU-120596 was added to the agonist acetylcholine or test article to be tested.
  • the signal caused by the positive control and allosteric modulator PNU-120596 (30 ⁇ M acetylcholine + 1 ⁇ M PNU-120596) was set to an activation rate of 100%.
  • the signal caused by the negative control (1 ⁇ M PNU-120596) was set to an activation rate of 0%.
  • the test compound was classified into the nicotine acetylcholine ⁇ 7 receptor agonistic percentage as follows: + activation rate ⁇ 10%, ++ activation rate 10%-40%, +++ activation rate 40%-70%, ++++ activation rate 70%- 100%, the results are shown in Table 1.
  • Example 37 In vivo activity assay was detected by a NOR (New Object Recognition Memory Experiment) model. Male Wistar rats of 6-8 weeks were used and divided into 3 groups, respectively, a blank control group, Example 37 (1 mpk), and Example 37 (3 mpk), 8-10 rats per group, administered 2 hours before the test.
  • NOR New Object Recognition Memory Experiment
  • ⁇ Train (Trial1): Put the rat in the bucket and explore for 3 minutes.
  • Trial 2 15 minutes and 24 hours after training, replace one of the toys with a new toy and place the rat in the bucket for free to explore for 3 minutes.
  • Example 37 has obvious in vivo effects and can improve or improve the cognitive ability and memory of Wistar rats.
  • the compounds of the invention are effective in vitro and in vivo.
  • Example 37 1mpk group significantly delayed amnesia compared with the control group, the recognition index d2 was higher than the control group, with a significant difference p ⁇ 0.05;
  • Example 37 3mpk group can delay forgetting and recognition compared with the control group The index d2 was higher than the control group, but there was no significant difference, as shown in Figure 1-2.
  • *p ⁇ 0.05 identification index (d2) (exploring new things time – exploring old things time)/new and old The total exploration time of things.

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Abstract

公开了一系列α-7尼古丁乙酰胆碱受体激动剂，具体公开了式(Ⅰ)所示化合物、其药学上可接受的盐、或其互变异构体及其医药用途。

Description

α-7尼古丁乙酰胆碱受体激动剂及应用
相关申请的引用
本申请要求于2017年05月18日向中华人民共和国国家知识产权局提交的第201710354103.1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
本发明涉及一系列α-7尼古丁乙酰胆碱受体激动剂，具体涉及式(Ⅰ)所示化合物、其药学上可接受的盐、或其互变异构体及其医药用途。
技术背景
尼古丁乙酰胆碱受体(nAChRs)属于配体-门控阳离子通道家族，受内源性激动剂乙酰胆碱调控。每个受体都是由5个亚体组成的一个5聚体。同源或异源亚体相互组合构成不同的尼古丁乙酰胆碱受体亚型，但各亚型又具有相同的基本结构特征，5个亚体围绕一个中心形成一个充满水的孔状结构[Masatomo Ishikawa and Kenji Hashimoto,current Pharmaceutical Design,2011,17,121-129,Caulfield MP.Pharmacol Ther.1993,58,319–79,Jones S,Sudweeks S,Yakel JL.Trends Neurosci.1999,22,555–61]。他们在受激动剂作用的时候都会显示三种主要的功能状态，即：“关闭休眠”状态，“通道开放”状态和“关闭脱敏”状态。
a7尼古丁乙酰胆碱受体是一种同源亚型，也是备受关注的一个靶点，主要分布在大脑皮层和海马体中，而这些区域与学习，记忆以及认知相关[Seguela P,Wadiche J,Dineley-Miller K,J Neurosci.1993,13,596–604]。另外，突触周围也发现了a7尼古丁乙酰胆碱受体，在这里他们负责调节其他输入到神经元，并且激活各种下游信号通路[Berg DK,Conroy WG.J Neurobiol.2002,53,512–23,Shoop RD,Martone ME,Yamada N,etal.J Neurosci.1999,19,692–704]。因此，a7尼古丁乙酰胆碱受体不仅参与学习，记忆等过程，还在调节神经递质方面起到重要作用。a7尼古丁乙酰胆碱受体对钙离子有较高渗透性，被激动剂快速激活，然后快速脱敏。这些特点使得a7尼古丁乙酰胆碱受体作为最具潜力的靶点被广泛应用在修复和改善认知损伤的疾病领域，比如阿尔兹海默症，精神病，帕金森病，老年性记忆减退，以及神经性疼痛等。
近些年，一大批结构各异的化合物被开发出来作为选择性a7尼古丁乙酰胆碱受体激动剂，部分激动剂和正向变构调节剂。其中一些已经进入人体临床试验阶段，然而，这些化合物在临床试验中呈现的某些不利副作用和药代动力学问题阻碍了他们的进一步发展，因此，目前还没有药物被批准进入市场。
发明内容
本发明提供式(Ⅰ)所示化合物、其药学上可接受的盐及其互变异构体，
Figure PCTCN2018086865-appb-000001
其中，
T 1或T 2中的一个选自NH，另一个选自CH 2；
R 1选自H，或选自R 2-L-；
R 2选自任选被1、2或3个R取代的C 1-6烷基、C 1-6杂烷基、C 3-6环烷基、3～6元杂环烷基、6～10元芳基、4～6元杂芳基；
L选自单键，或选自任选被1或2个R取代的：-CH 2-、
Figure PCTCN2018086865-appb-000002
或
Figure PCTCN2018086865-appb-000003
R选自卤素、CN、OH、NH 2、NO 2、COOH，或选自任选被1、2或3个R’取代的C 1-6烷基、C 1-6杂烷基；R’选自F、Cl、Br、I、OH、CN、NH 2、COOH、Me、Et、CF 3、CHF 2、CH 2F、NHCH 3、N(CH 3) 2；
“杂”表示杂原子或杂原子团，选自-C(＝O)N(R)-、-N(R)-、-C(＝NR)-、-S(＝O) 2N(R)-、-S(＝O)N(R)-、-O-、-S-、＝O、＝S、-O-N＝、-C(＝O)O-、-C(＝O)-、-C(＝S)-、-S(＝O)-、-S(＝O) 2-和-N(R)C(＝O)N(R)-；
以上任何一种情况下，杂原子或杂原子团的数目分别独立地选自1、2或3。
本发明的一些方案中，上述R选自F、Cl、Br、I、NH 2、NO 2、COOH，或选自任选被1、2或3个R’取代的C 1-3烷基、C 1-3杂烷基。
本发明的一些方案中，上述R选自F、Cl、Br、I、NH 2、NO 2、COOH、Me、Et、CF 3。
本发明的一些方案中，上述R 2选自任选被1、2或3个R取代的C 1-3烷基、C 1-3杂烷基、C 3-6环烷基、恶丁环基、吖丁啶基、四氢吡喃基、苯基、吡啶基、吡唑基、噻唑基、恶唑基、咪唑基、噻吩基、***基、吡嗪基、嘧啶基、吡咯基、2,3-二氢苯并呋喃基。
本发明的一些方案中，上述R 2选自：
Figure PCTCN2018086865-appb-000004
Figure PCTCN2018086865-appb-000005
Figure PCTCN2018086865-appb-000006
本发明的一些方案中，上述L选自单键和-CH 2-。
本发明的一些方案中，上述R 1选自、Me、
Figure PCTCN2018086865-appb-000007
Figure PCTCN2018086865-appb-000008
Figure PCTCN2018086865-appb-000009
本发明的一些方案中，上述结构单元
Figure PCTCN2018086865-appb-000010
选自
Figure PCTCN2018086865-appb-000011
和
Figure PCTCN2018086865-appb-000012
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 PCTCN2018086865-appb-000013
其中，R 1如上述所定义。
本发明的一些方案中，上述R选自F、Cl、Br、I、NH 2、NO 2、COOH，或选自任选被1、2或3个R’取代的C 1-3烷基、C 1-3杂烷基，其他变量如上述所定义。
本发明的一些方案中，上述R选自F、Cl、Br、I、NH 2、NO 2、COOH、Me、Et、CF 3，其他变量如上述所定义。
本发明的一些方案中，上述R 2选自任选被1、2或3个R取代的C 1-3烷基、C 1-3杂烷基、C 3-6环烷基、恶丁环基、吖丁啶基、四氢吡喃基、苯基、吡啶基、吡唑基、噻唑基、恶唑基、咪唑基、噻吩基、***基、吡嗪基、嘧啶基、吡咯基、2,3-二氢苯并呋喃基，其他变量如上述所定义。
本发明的一些方案中，上述R 2选自：
Figure PCTCN2018086865-appb-000014
Figure PCTCN2018086865-appb-000015
Figure PCTCN2018086865-appb-000016
其他变量如上述所定义。
本发明的一些方案中，上述L选自单键和-CH 2-，其他变量如上述所定义。
本发明的一些方案中，上述R 1选自、Me、
Figure PCTCN2018086865-appb-000017
Figure PCTCN2018086865-appb-000018
Figure PCTCN2018086865-appb-000019
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 PCTCN2018086865-appb-000020
选自
Figure PCTCN2018086865-appb-000021
和
Figure PCTCN2018086865-appb-000022
本发明还有一些方案是由上述变量任意组合而来。
本发明的一些化合物选自：
Figure PCTCN2018086865-appb-000023
Figure PCTCN2018086865-appb-000024
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治疗精神***或老年痴呆等疾病药物中的应用。
技术效果：
本发明中的系列新化合物具有良好的活性和类药性，有潜力作为候选化合物用于进一步的临床研究。
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。
C 1-6选自C 1、C 2、C 3、C 4、C 5和C 6；C 3-6选自C 3、C 4、C 5和C 6。
C 1-6烷基或C 1-6杂烷基、C 3-6环基或3～6元杂环烷基包括但不限于：
C 1-6烷基、C 1-6烷氨基、N,N-二(C 1-3烷基)氨基、C 1-6烷氧基、C 1-6烷酰基、C 1-6烷氧羰基、C 1-6烷基磺酰基、C 1-6烷基亚磺酰基、C 3-6环烷基、3～6元环烷氨基、3～6元杂环烷氨基、3～6元环烷氧基、3～6元环烷基酰基、3～6元环烷基氧羰基、3～6元环烷基磺酰基、3～6元环烷基亚磺酰基；
甲基、乙基、正丙基、异丙基、-CH 2C(CH 3)(CH 3)(OH)、环丙基、环丁基、丙基亚甲基、环丙酰基、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、乙氧基、乙酰基、乙磺酰基、乙氧羰基、二甲基氨基、二乙基氨基、二甲基氨基羰基、二乙基氨基羰基；
N(CH 3) 2,NH(CH 3),-CH 2CF 3,-CH2CH 2CF 3,-CH 2CH 2F,-CH 2CH 2S(＝O) 2CH 3,-CH 2CH 2CN,-CH 2CH(OH)(CH 3) 2,-CH 2CH(F)(CH 3) 2,-CH 2CH 2F,-CH 2CF 3,-CH 2CH 2CF 3,-CH 2CH 2NH 2,-CH 2CH 2OH,- CH 2CH 2OCH 3,-CH 2CH 2CH 2OCH 3,-CH 2CH 2N(CH 3) 2,-S(＝O) 2CH 3,-CH 2CH 2S(＝O) 2CH 3。
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。
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的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( 125 I)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“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。
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(C 1-C 4)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。C 1-6烷氧基包括C 1、C 2、C 3、C 4、C 5和C 6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C 3、C 4、C 5、C 6和C 7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。
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，术语“杂环烷基”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)。如果产生的化合物是稳定的，本文所述的杂环烷基可以发生碳位或氮位上的取代。杂环烷基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，杂环烷基中S及O原子的总数不超过1。桥环也包含在杂环烷基的定义中。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。
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。
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。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，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。
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；HATU代表O-(7-氮杂苯并***-1-基)-N，N，N'，N'-四甲基脲六氟磷酸盐；EDC代表N-(3-二甲基氨基丙基)-N'-乙基碳二亚胺盐酸盐；m-CPBA代表3-氯过氧苯甲酸；eq代表当量、等量；CDI代表羰基二咪唑；DCM代表二氯甲烷；PE代表石油醚；DIAD代表偶氮二羧酸二异丙酯；DMF代表N，N-二甲基甲酰胺；DMSO代表二甲亚砜；EtOAc代表乙酸乙酯；EtOH代表乙醇；MeOH代表甲醇；CBz代表苄氧羰基，是一种胺保护基团；BOC代表叔丁基羰基是一种胺保护基团；HOAc代表乙酸；NaCNBH3代表氰基硼氢化钠；r.t.代表室温；O/N代表过夜；THF代表四氢呋喃；Boc 2O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；SOCl 2代表氯化亚砜；CS 2代表二硫化碳；TsOH代表对甲苯磺酸；NFSI代表N-氟-N-(苯磺酰基)苯磺酰胺；NCS代表1-氯吡咯烷-2,5-二酮；n-Bu 4NF代表氟化四丁基铵；iPrOH代表2-丙醇；mp代表熔点；LDA代表二异丙基胺基锂。
化合物经手工或者
Figure PCTCN2018086865-appb-000025
软件命名，市售化合物采用供应商目录名称。
附图说明：
识别指数(d2)：测试阶段各组大鼠对新旧两个物体的探索时间差(探索新事物时间–探索旧事物时间)与总探索时间(新旧事物总的探索时间)的比值。
图1：训练后15分钟，各组大鼠对新旧事物探索的识别指数对比。
图2：训练后24小时，各组大鼠对新旧事物探索的识别指数对比。图中数据表达为平均值±SEM，n＝8-10.采用一维组间方差分析t-test,*p＜0.05。
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
Figure PCTCN2018086865-appb-000026
合成路线：
Figure PCTCN2018086865-appb-000027
第一步
将A-2A(2.00g,13.0mmol)的三氯氧磷(21mL)溶液在80℃下搅拌5个小时。反应液缓慢加入水中(50mL)淬灭,用碳酸钠固体将pH调值7～8,用乙酸乙酯(150mL x 3)萃取,有机相用饱和食盐水(200mL)洗涤,无水硫酸钠干燥,过滤,滤液减压浓缩,得到A-2B(2.10g)。MS-ESI计算值[M+H] +173,实测值173。
第二步
向A-2B(1.00g,5.79mmol)的N,N-二甲基甲酰胺(20mL)溶液中加入N,N-二甲基甲酰胺二甲缩醛(759mg,6.37mmol),并在100℃下搅拌1小时。反应液减压浓缩,得到A-2C(1.40g)。 1H NMR:(400MHz,METHANOL-d4)δ8.68(s,1H),7.87(d,J＝13.2Hz,1H),7.63(s,1H),5.95(d,J＝13.2Hz,1H),3.09(s,6H)。
第三步
向A-2C(1.32g,5.80mmol)的乙酸(40mL)溶液中加入铁粉(3.24g,57.9mmol)并在70℃下搅拌3小时。反应液减压浓缩,溶于二氯甲烷(50mL)中,用5％碳酸钠溶液(150mL)洗涤,水相用二氯甲烷(50mL x 3)萃取,得到的有机相用饱和食盐水(150mL x 1)洗涤,用无水硫酸钠干燥,过滤,减压浓缩,得到的粗品用薄层层析法分离纯化(1:1石油醚/乙酸乙酯,Rf＝0.4)得到A-2(450mg)。MS-ESI计算值[M+H] +153,实测值153。
实施例1
Figure PCTCN2018086865-appb-000028
合成路线：
Figure PCTCN2018086865-appb-000029
第一步
向A-1(200mg,1.02mmol)和B-1(277mg,1.02mmol)的1,4-二氧六环(5mL)溶液中加入碘化亚铜(19.4mg,1.02umol),膦酸钾(433mg,2.04mmol)和(1R,2R)-环己烷-1,2-二胺(11.6mg,1.02umol),反应液在110℃下搅拌16个小时。将反应液过滤,滤液减压浓缩,得到的粗品用薄层层析法分离纯化(4:1石油醚/乙酸乙酯,Rf＝0.8)得到1C(210mg)。 1H NMR(400MHz,CHLOROFORM-d)δ8.42(d,J＝2.4Hz,1H),8.13(d,J＝2.4Hz,1H),8.03(s,2H),7.73-7.65(m,2H),7.58(d,J＝3.6Hz,1H),6.65(d,J＝3.6Hz,1H).MS-ESI计算值[M+H] +341 and 343,实测值341 and 343.
第二步
向1C(110mg,0.332 mmol),化合物D-1(128mg,0.645mmol)和叔丁醇钠(186mg,1.93mmol)的四氢呋喃(5mL)溶液中加入氯代[2-(二环己基膦)-3,6-二甲氧基-2',4',6'-,三异丙基-1,1'-二苯][2-(2-氨乙基)苯基]钯(II)(12.9mg,16.1umol),反应液在60℃下搅拌4个小时。将反应液过滤,滤液减压浓缩,得到的粗品用制备高效液相色谱分离纯化得到1(20.0mg)。 1H NMR(400MHz,METHANOL-d 4)δ8.11(s,1H),8.08(d,J＝2.4Hz,1H),8.01-7.95(m,2H),7.93-7.87(m,2H),7.85(d,J＝3.6Hz,1H),6.91(d,J＝3.6Hz,1H),4.21-4.13(m,1H),3.95-3.85(m,1H),3.53-3.37(m,4H),3.25-3.15(m,1H),2.47-2.29(m,2H),2.22-2.12(m,2H),2.02-1.88(m,1H).MS-ESI计算值[M+H] +387,实测值387.
实施例2
Figure PCTCN2018086865-appb-000030
合成路线：
Figure PCTCN2018086865-appb-000031
第一步
参照实施例1第一步，得到2C(130mg)。 1H NMR(400MHz,CHLOROFORM-d)δ8.28(d,J＝1.6Hz,1H),8.00(d,J＝2.0Hz,1H),7.40(s,1H),7.34(d,J＝3.6Hz,1H),7.22(dd,J＝2.0,8.4Hz,1H),6.82(d,J＝8.4Hz,1H),6.46(d,J＝3.6Hz,1H),4.58(t,J＝8.8Hz,2H),3.24(t,J＝8.8Hz,2H).MS-ESI计算值[M+H] +315 and 317,实测值315 and 317.
第二步
参照实施例1第二步，得到2(50.0mg)。 1H NMR(400MHz,METHANOL-d 4)δ8.16(d,J＝2.0Hz,1H),7.88(d,J＝2.0Hz,1H),7.71(d,J＝3.6Hz,1H),7.47(s,1H),7.37-7.29(m,1H),6.98(d,J＝8.4Hz,1H),6.87(d,J＝3.6Hz,1H),4.71(t,J＝8.8Hz,2H),4.23-4.11(m,1H),4.00-3.90(m,1H),3.52-3.35(m,6H),3.23-3.16(m,1H),2.40-2.25(m,2H),2.16(br.s,2H),2.01-1.89(m,1H).MS-ESI计算值[M+H] +361,实测值361.
实施例3
Figure PCTCN2018086865-appb-000032
合成路线：
Figure PCTCN2018086865-appb-000033
第一步
参照实施例1第一步，得到3C(20.0mg)。MS-ESI计算值[M+H] +301 and 303,实测值301 and 303.
第二步
参照实施例1第二步，得到3(4.0mg)。 1H NMR(400MHz,METHANOL-d 4)δ8.14(d,J＝2.4Hz,1H),7.83(d,J＝2.4Hz,1H),7.64(d,J＝3.6Hz,1H),7.41-7.27(m,3H),6.90(d,J＝3.6Hz,1H),4.17-4.10(m,1H),3.97-3.89(m,1H),3.52-3.36(m,4H),3.20-3.15(m,1H),2.47(s,3H),2.43-2.40(m,1H),2.31(br.s,1H),2.20-2.11(m,2H),2.04(s,3H),1.95(br.s,1H).MS-ESI计算值[M+H] +347,实测值347.
实施例4
Figure PCTCN2018086865-appb-000034
合成路线：
Figure PCTCN2018086865-appb-000035
第一步
参照实施例1第一步，得到4C(190mg)。 1H NMR(400MHz,CHLOROFORM-d)δ8.38(d,J＝2.4Hz,1H),8.09(d,J＝2.4Hz,1H),7.53-7.49(m,3H),7.41(t,J＝8.0Hz,1H),7.18(d,J＝8.0Hz,1H),6.57(d,J＝3.6Hz,1H),2.46(s,3H).MS-ESI计算值[M+H] +287 and 289,实测值287 and 289.
第二步
参照实施例1第二步，得到4(76.0mg)。 1H NMR(400MHz,METHANOL-d 4)δ7.86(s,2H),7.73(br.s,1H),7.57-7.48(m,2H),7.48-7.42(m,1H),7.37(d,J＝6.4Hz,1H),6.78(br.s,1H),4.11(br.s,1H),3.95-3.85(m,1H),3.51-3.39(m,4H),3.20-3.10(m,1H),2.49(s,3H),2.44-2.38(m,1H),2.33(br.s,1H),2.19-2.12(m,2H),1.95(br.s,1H).MS-ESI计算值[M+H] +333,实测值333.
实施例5
Figure PCTCN2018086865-appb-000036
合成路线：
Figure PCTCN2018086865-appb-000037
第一步
参照实施1第一步，得到5C(160mg)。MS-ESI计算值[M+H] +291 and 293,实测值291 and 293.
第二步
参照实施例1第二步，得到5(50.0mg)。 1H NMR(400MHz,METHANOL-d 4)δ8.20(d,J＝2.4Hz,1H),7.98(d,J＝2.0Hz,1H),7.90-7.78(m,1H),7.77-7.64(m,1H),7.61-7.48(m,2H),7.42-7.35(m,1H),6.93(d,J＝4.0Hz,1H),4.25-4.16(m,1H),3.95(m,1H),3.60-3.35(m,4H),3.29-3.18(m,1H),2.47-2.27(m,2H),2.24-2.09(m,2H),2.05-1.88(m,1H).MS-ESI计算值[M+H] +337,实测值337.
实施例6
Figure PCTCN2018086865-appb-000038
合成路线：
Figure PCTCN2018086865-appb-000039
第一步
参照实施例1第一步，得到6C(220mg)。 1HNMR(400MHz,CHLOROFORM-d)δ8.97(br.s,1H),8.61(d,J＝4.4Hz,1H),8.40(d,J＝4.4Hz,1H),8.26-8.18(m,1H),8.15-8.04(m,1H),7.56(d,J＝3.6Hz,1H),7.52-7.43(m,1H),6.65(d,J＝3.6Hz,1H).MS-ESI计算值[M+H] +274 and 276,实测值274 and 276.
第二步
参照实施例1第二步，得到6(90.0mg)。 1H NMR(400MHz,METHANOL-d 4)δ10.04(d,J＝2.4Hz,1H),9.26(dd,J＝1.2,8.4Hz,1H),8.70(d,J＝5.6Hz,1H),8.22(dd,J＝5.6,8.4Hz,1H),8.06(d,J＝2.8Hz,1H),8.01(d,J＝4.0Hz,1H),7.41(d,J＝2.4Hz,1H),6.79(d,J＝4.0Hz,1H),4.16-4.13(m,1H),3.96-3.81(m,1H),3.55-3.36(m,4H),3.20-3.07(m,1H),2.49-2.25(m,2H),2.21-2.03(m,2H),2.00-1.80(m,1H).MS-ESI计算值[M+H] +320,实测值320.
实施例7
Figure PCTCN2018086865-appb-000040
合成路线：
Figure PCTCN2018086865-appb-000041
第一步
参照实施例1第一步,得到7C(120mg)。 1H NMR(400MHz,CHLOROFORM-d)δ8.40(d,J＝2.0Hz,1H),8.06 (d,J＝2.0Hz,1H),7.91-7.80(m,1H),7.43(d,J＝2.4Hz,1H),6.98(d,J＝2.4Hz,1H),6.54(d,J＝3.6Hz,1H),3.94(s,3H).MS-ESI计算值[M+H] +277 and 279,实测值277 and 279.
第二步
参照实施例1第二步,得到7(50.0mg)。 1H NMR(400MHz,METHANOL-d 4)δ8.20(d,J＝2.4Hz,1H),8.10(d,J＝2.4Hz,1H),8.06(d,J＝3.6Hz,1H),7.80(d,J＝2.0Hz,1H),6.93(d,J＝3.6Hz,1H),6.63(d,J＝2.0Hz,1H),4.28-4.15(m,1H),4.06(s,3H),3.96(m,1H),3.61-3.38(m,4H),3.25-3.15(m,1H),2.50-2.29(m,2H),2.26-2.10(m,2H),2.04-1.88(m,1H).MS-ESI计算值[M+H] +323,实测值323.
实施例8
Figure PCTCN2018086865-appb-000042
合成路线：
Figure PCTCN2018086865-appb-000043
第一步
参照实施例1第一步,得到8C(210mg)。MS-ESI计算值[M+H] +298 and 300,实测值298 and 300。
第二步
参照实施例1第二步,得到8(15.0mg)。 1H NMR(400MHz,METHANOL-d 4)δ8.23(s,1H),8.09-7.96(m,3H),7.94-7.89(m,1H),7.88-7.79(m,2H),6.89(d,J＝3.6Hz,1H),4.20-4.14(m,1H),4.00-3.85(m,1H),3.56-3.37(m,4H),3.26-3.18(m,1H),2.46-2.29(m,2H),2.23-2.11(m,2H),2.00-1.90(m,1H).MS-ESI计算值[M+H] +344,实测值344.
实施例9
Figure PCTCN2018086865-appb-000044
合成路线：
Figure PCTCN2018086865-appb-000045
第一步
向A-1(200mg,1.02mmol)和B-9(197mg,1.22mmol)的甲苯(5mL)溶液中加入碘化亚铜(19.4mg,102umol),膦酸钾(433mg,2.04mmol)和N,N'-二甲基乙烷-1,2-二胺(8.9mg,102umol),并在120℃下搅拌16个小时。将反应液过滤,滤液减压浓缩,得到的粗品用薄层层析法分离纯化(4:1石油醚/乙酸乙酯,Rf＝0.9)得到9C(170mg)。 1H NMR(400MHz,CHLOROFORM-d)δ8.41(d,J＝2.0Hz,1H),8.13-8.08(m,2H),7.80(s,1H),7.46(d,J＝3.6Hz,1H),6.57(d,J＝3.6Hz,1H),4.02(s,3H).MS-ESI计算值[M+H] +277 and 279,实测值277 and 279.
第二步
参照实施例1第二步,得到9(40.0mg)。 1H NMR(400MHz,METHANOL-d 4)δ8.16(s,1H),8.11(d,J＝2.4Hz,1H),7.92-7.81(m,2H),7.64(d,J＝3.6Hz,1H),6.84(d,J＝3.6Hz,1H),4.20-4.10(m,1H),4.03(s,3H),3.97-3.87(m,1H),3.54-3.36(m,4H),3.25-3.12(m,1H),2.42-2.25(m,2H),2.21-2.07(m,2H),1.94(br.s,1H)。MS-ESI计算值[M+H] +323,实测值323.
实施例10
Figure PCTCN2018086865-appb-000046
合成路线：
Figure PCTCN2018086865-appb-000047
第一步
在0℃下向A-1(300mg,1.52mmol)的N,N-二甲基甲酰胺(3mL)溶液中加入钠氢(60％煤油,73.0mg,1.82mmol),并搅拌15分钟,然后加入B-10(1.29g,7.60mmol)并在15℃下搅拌16个小时。向反应液中加入15ml水,并用乙酸乙酯(20mL x 2)萃取,合并有机相,用无水硫酸钠干燥,过滤,滤液减压浓缩,得到的粗品用薄层层析法分离纯化(4:1石油醚/乙酸乙酯,Rf＝0.8)得到10C(290mg)。 1H NMR(400MHz,CHLOROFORM-d)δ8.35(d,J＝2.0Hz,1H),8.03(d,J＝2.4Hz,1H),7.24(d,J＝3.6Hz,1H),6.41(d,J＝3.6Hz,1H),4.35-4.10(m,2H), 2.01-1.80(m,2H),1.03-0.85(m,3H).MS-ESI计算值[M+H] +239 and 241,实测值239 and 241.
第二步
向10C(80.0mg,0.335mmol),D-1(200mg,1.00mmol)和三(二亚苄基丙酮)二钯(15.3mg,16.7umol)的四氢呋喃(5.00mL)溶液中加入叔丁醇钠(257mg,2.68mmol)和4,5-双二苯基膦-9,9-二甲基氧杂基氧杂蒽杂蒽(15.9mg,33.6umol)在80℃下搅拌16个小时。反应液过滤,滤液减压浓缩,得到的粗品用制备高效液相色谱分离纯化得到10(9.00mg)。 1H NMR(400MHz,METHANOL-d 4)δ8.10(s,1H),7.94(s,1H),7.64(d,J＝3.6Hz,1H),6.70(d,J＝3.6Hz,1H),4.30(t,J＝7.2Hz,2H),4.13(d,J＝3.6Hz,1H),3.91(t,J＝11.4Hz,1H),3.55-3.34(m,4H),3.20-3.10(m,1H),2.48-2.26(m,2H),2.21-2.07(m,2H),2.01-1.81(m,3H),0.96(t,J＝7.6Hz,3H).MS-ESI计算值[M+H] +285,实测值285.
实施例11
Figure PCTCN2018086865-appb-000048
合成路线：
Figure PCTCN2018086865-appb-000049
第一步
参照实施例10第一步,得到11C(180mg)。 1H NMR(400MHz,CHLOROFORM-d)δ8.25(d,J＝2.0Hz,1H),7.93(d,J＝2.0Hz,1H),7.25(d,J＝3.6Hz,1H),6.34(d,J＝3.6Hz,1H),5.06(spt,J＝6.8Hz,1H),1.44(d,J＝6.8Hz,6H).MS-ESI计算值[M+H] +239 and 241,实测值239 and 241.
第二步
参照实施例1第二步,得到11(60.0mg)。 1H NMR(400MHz,METHANOL-d 4)δ8.12(d,J＝2.4Hz,1H),7.96(d,J＝2.4Hz,1H),7.82(d,J＝3.6Hz,1H),6.79-6.73(m,1H),4.95-4.88(m,1H),4.21-4.11(m,1H),4.00-3.89(m,1H),3.57-3.36(m,4H),3.25-3.15(m,1H),2.44-2.28(m,2H),2.24-2.07(m,2H),2.01-1.86(m,1H),1.61(s,3H),1.59(s,3H).MS-ESI计算值[M+H] +285,实测值285
实施例12
Figure PCTCN2018086865-appb-000050
合成路线：
Figure PCTCN2018086865-appb-000051
第一步
参照实施例10第一步,得到12C(110mg)。 1H NMR(400MHz,CHLOROFORM-d)δ8.34(d,J＝2.0Hz,1H),8.06(d,J＝2.0Hz,1H),7.71(d,J＝3.6Hz,1H),6.57(d,J＝3.6Hz,1H),6.18-5.96(m,1H),5.21(t,J＝7.2Hz,2H),5.09-4.95(m,2H).MS-ESI计算值[M+H] +253 and 255,实测值253 and 255.
第二步
参照实施例1第二步,得到12(70.0mg)。 1H NMR(400MHz,METHANOL-d 4)δ8.12(d,J＝2.0Hz,1H),7.97(d,J＝2.0Hz,1H),7.86(d,J＝3.6Hz,1H),6.81(d,J＝3.6Hz,1H),5.06-4.96(m,1H),4.22-4.04(m,5H),3.98-3.86(m,1H),3.58-3.36(m,4H),3.25-3.15(m,1H),2.46-2.27(m,2H),2.22-2.10(m,2H),2.02-1.85(m,1H).MS-ESI计算值[M+H] +299,实测值299.
实施例13
Figure PCTCN2018086865-appb-000052
合成路线：
Figure PCTCN2018086865-appb-000053
第一步
参照实施例10第一步,得到13C(150mg)。 1H NMR(400MHz,CHLOROFORM-d)δ8.25(d,J＝2.0Hz,1H),7.94(d,J＝2.0Hz,1H),7.12(d,J＝3.2Hz,1H),6.31(d,J＝3.2Hz,1H),4.01(d,J＝7.2Hz,2H),1.66-1.56(m,4H),1.55-1.45(m,2H),1.15-1.04(m,3H),1.01-0.85(m,2H).MS-ESI计算值[M+H] +293 and 295,实测值293 and 295.
第二步
参照实施例1第二步,得到13(100mg)。 1H NMR(400MHz,METHANOL-d 4)δ8.12(d,J＝2.4Hz,1H),7.95(d,J＝1.6Hz,1H),7.67-7.58(m,1H),6.72(d,J＝3.6Hz,1H),4.24-4.09(m,3H),4.00-3.87(m,1H),3.58-3.35(m,4H),3.25-3.15(m,1H),2.48-2.28(m,2H),2.20-2.10(m,2H),2.01-1.84(m,2H),1.81-1.66(m,3H),1.60-1.50(m,2H),1.39-1.20(m,3H),1.15-1.01(m,2H).MS-ESI计算值[M+H] +339,实测值339.
实施例14
Figure PCTCN2018086865-appb-000054
合成路线：
Figure PCTCN2018086865-appb-000055
第一步
参照实施例10第一步,得到14C(90.0mg)。 1H NMR(400MHz,CHLOROFORM-d)δ8.31(d,J＝2.0Hz,1H),8.07-8.00(m,1H),7.51(d,J＝3.6Hz,1H),6.51(d,J＝3.6Hz,1H),5.69-5.55(m,1H),4.49(t,J＝8.8Hz,2H),4.33-4.21(m,2H),1.54-1.46(m,9H).MS-ESI计算值[M+H-56] +296 and 298,实测值296 and 298.
第二步
向14C(90.0mg,0.256mmol),D-1(153mg,0.767mmol)和叔丁醇钠(196mg,2.04mmol)的四氢呋喃(7mL)溶液中加入氯代[2-(二环己基膦)-3,6-二甲氧基-2',4',6'-,三异丙基-1,1'-二苯][2-(2-氨乙基)苯基]钯(II)(10.2mg,12.8umol),反应液在65℃下搅拌2小时。将反应液过滤,滤液减压浓缩得到14E(102mg)。MS-ESI计算值[M+H] +398,实测值398.
第三步
14E(102mg,0.256mmol)溶于盐酸乙酸乙酯(4M,10.0mL,40.0mmol)中并在16℃下搅拌半小时。将反应液减压浓缩,粗品用制备高效液相色谱分离纯化得到14(24.0mg)。 1H NMR(400MHz,METHANOL-d 4)δ8.13(d,J＝2.4Hz,1H),8.03(d,J＝2.4Hz,1H),7.97(d,J＝3.6Hz,1H),6.79(d,J＝3.6Hz,1H),5.90-5.80(m,1H),4.75-4.60(m,4H),4.20-4.10(m,1H),3.95-3.85(m,1H),3.60-3.49(m,1H),3.48-3.35(m,3H),3.31-3.23(m,1H), 2.45-2.35(m,2H),2.19-2.10(m,2H),2.0-1.85(m,1H).MS-ESI计算值[M+H] +298,实测值298.
实施例15
Figure PCTCN2018086865-appb-000056
合成路线：
Figure PCTCN2018086865-appb-000057
第一步
向A-1(150mg,0.671mmol)和B-15(124.9mg,0.761mmol)的N-甲基吡咯烷酮(5mL)溶液中加入碳酸铯(496mg,1.52mmol),反应液在130℃搅拌16个小时。向反应液中加入15mL水,并用乙酸乙酯(20mL x 2)萃取。合并有机相,用无水硫酸钠干燥,过滤,滤液减压浓缩,得到的粗品用用薄层层析法分离纯化(5:1石油醚/乙酸乙酯,Rf＝0.7)得到15C(110mg)。 1H NMR(400MHz,CHLOROFORM-d)δ8.50(d,J＝2.0Hz,1H),8.27(d,J＝4.0Hz,1H),8.10(d,J＝2.0Hz,1H),7.59(d,J＝3.6Hz,1H),7.19(d,J＝3.6Hz,1H),6.64(d,J＝4.0Hz,1H).MS-ESI计算值[M+H] +280 and 282,实测值280 and 282.
第二步
参照实施例1第二步,得到15(34.0mg)。 1H NMR(400MHz,METHANOL-d 4)δ8.13(d,J＝4.0Hz,1H),8.08(d,J＝2.4Hz,1H),7.76(d,J＝2.4Hz,1H),7.73(d,J＝3.6Hz,1H),7.47(d,J＝4.0Hz,1H),6.86(d,J＝3.6Hz,1H),4.20-4.09(m,1H),3.98-3.88(m,1H),3.51-3.38(m,4H),3.23-3.14(m,1H),2.46-2.29(m,2H),2.20-2.10(m,2H),1.95(br.s,1H).MS-ESI计算值[M+H] +326,实测值326.
实施例16
合成路线：
Figure PCTCN2018086865-appb-000059
第一步
在0℃下向A-1(50.0mg,0.250mmol),三丁基膦(103mg,0.508mmol)和B-16(18.3mg,0.254mol)的四氢呋喃(5mL)溶液中加入四甲基偶氮二甲酰胺(48.1mg,0.279mmol),反应液在80℃下搅拌3小时。反应液过滤蒸干得到16C(170mg)。MS-ESI计算值[M+H] +251 and 253,实测值251 and 253.
第二步
参照实施例1第二步,得到16(49.0mg)。 1H NMR(400MHz,METHANOL-d 4)δ8.08(d,J＝2.4Hz,1H),7.93(dd,J＝2.8,10.8Hz,2H),6.76(d,J＝3.6Hz,1H),5.13(t,J＝8.4Hz,1H),4.22-4.06(m,1H),3.99-3.82(m,1H),3.54-3.35(m,4H),3.25-3.11(m,1H),2.70-2.49(m,4H),2.44-2.24(m,2H),2.20-2.10(m,2H),2.07-1.84(m,3H).MS-ESI计算值[M+H] +297,实测值297.
实施例17
Figure PCTCN2018086865-appb-000060
合成路线：
Figure PCTCN2018086865-appb-000061
第一步
向A-1(200mg,1.02mmol),B-17(131mg,1.53mmol)和N-氧化吡啶(291mg,3.06mmol)的二氯甲烷(3mL)溶液中加入吡啶(242mg,3.06mmol)和醋酸铜(370mg,2.04mmol),反应液在30℃和氧气环境下搅拌16个小时,然后升温至60℃搅拌32小时。将反应液过滤,滤液减压浓缩,得到的粗品用薄层层析法分离纯化(4:1石油醚/乙酸乙酯,Rf＝0.7)得到17C(150mg)。 1H NMR(400MHz,METHANOL-d 4)δ8.30(d,J＝2.0Hz,1H),8.14(d,J＝2.0Hz,1H),7.43(d,J＝4.0Hz,1H),6.44(d,J＝4.0Hz,1H),3.56-3.48(m,1H),1.21-1.11(m,2H),1.08-0.99(m,2H).MS-ESI计算值[M+H] +237 and 239,实测值237 and 239.
第二步
参照实施例1第二步,得到17(60.0mg)。 1H NMR(400MHz,METHANOL-d 4)δ8.11(d,J＝2.4Hz,1H),7.99(d,J＝2.4Hz,1H),7.64-7.60(m,1H),6.67(d,J＝3.6Hz,1H),4.21-4.10(m,1H),4.00-3.88(m,1H),3.62-3.36(m, 5H),3.24-3.12(m,1H),2.44-2.28(m,2H),2.20-2.10(m,2H),2.02-1.87(m,1H),1.33-1.24(m,2H),1.18-1.09(m,2H).MS-ESI计算值[M+H] +283,实测值283.
实施例18
Figure PCTCN2018086865-appb-000062
合成路线：
Figure PCTCN2018086865-appb-000063
第一步
参照实施例1第一步,得到18C(270mg)。 1H NMR(400MHz,CHLOROFORM-d)δ8.66(s,1H),7.81-7.68(m,4H),7.62(s,1H),7.54(d,J＝3.2Hz,1H),6.70(d,J＝3.2Hz,1H).MS-ESI计算值[M+H] +297,实测值297.
第二步
向18C(50.0mg,0.169mmol),D-1(67.1mg,0.337mmol)和叔丁醇钠(97.2mg,1.01mmol)的四氢呋喃(4mL)溶液中加入甲烷磺酸(2-二-叔丁基膦基-2',4',6'-三异丙基-1,1'-联苯)(2'-氨基-1,1'-联苯-2-基)钯(II)(6.69mg,8.43umol),反应液在60℃下搅拌2小时。将反应液过滤,滤液减压浓缩,得到的粗品用制备高效液相色谱分离纯化得到18(20.0mg)。 1H NMR(400MHz,METHANOL-d 4)δ8.51(s,1H),8.34-8.20(m,1H),8.02-7.92(m,2H),7.91-7.80(m,2H),7.35(s,1H),6.89(d,J＝3.2Hz,1H),4.44-4.33(m,1H),4.07-3.94(m,1H),3.61-3.34(m,5H),2.50-2.40(m,1H),2.41-2.29(m,1H),2.28-2.11(m,2H),2.07-1.97(m,1H).MS-ESI计算值[M+H] +387,实测值387.
实施例19
Figure PCTCN2018086865-appb-000064
合成路线：
Figure PCTCN2018086865-appb-000065
第一步
参照实施例1第一步,得到19C(110mg)。 1H NMR(400MHz,CHLOROFORM-d)δ8.57(s,1H),7.51(s,1H),7.42(d,J＝3.2Hz,1H),7.33(s,4H),6.55(d,J＝3.2Hz,1H),3.04-2.87(m,1H),1.26(s,3H),1.25(s,3H).MS-ESI计算值[M+H] +271,实测值271.
第二步
参照实施例18第二步,得到19(70.0mg)。 1H NMR(400MHz,METHANOL-d 4)δ8.46(s,1H),8.18(d,J＝3.2Hz,1H),7.53(s,4H),7.29(s,1H),6.83(d,J＝3.2Hz,1H),4.38-4.30(m,1H),4.00-3.90(m,1H),3.60-3.37(m,4H),3.30(br.s,1H),3.10-3.00(m,1H),2.50-2.40(m,1H),2.33(br.s,1H),2.26-2.11(m,2H),2.01(br.s,1H),1.34(s,3H),1.33(s,3H).MS-ESI计算值[M+H] +361实测值361.
实施例20
Figure PCTCN2018086865-appb-000066
合成路线：
Figure PCTCN2018086865-appb-000067
第一步
参照实施例1第一步,得到20C(330mg)。MS-ESI计算值[M+H] +254,实测值254.
第二步
参照实施例18第二步,得到20(5.00mg)。 1H NMR(400MHz,METHANOL-d 4)δ8.58(s,1H),8.26(d,J＝3.2Hz,1H),8.10(s,1H),7.99(d,J＝8.2Hz,1H),7.93-7.81(m,2H),7.34(s,1H),6.89(d,J＝2.8Hz,1H),4.37(br.s,1H),3.99(br.s,1H),3.61-3.34(m,5H),2.46(br.s,1H),2.40-2.11(m,3H),2.01(br.s,1H).MS-ESI计算值[M+H] +344,实测值344.
实施例21
Figure PCTCN2018086865-appb-000068
合成路线：
Figure PCTCN2018086865-appb-000069
第一步
参照实施例1第一步,得到21C(76.0mg)。 1H NMR(400MHz,CHLOROFORM-d)δ8.65(s,1H),7.58(s,1H),7.51(d,J＝3.2Hz,1H),7.47-7.41(m,1H),7.31-7.26(m,3H),6.63(d,J＝3.2Hz,1H),2.46(s,3H).MS-ESI计算值[M+H] +243,实测值243.
第二步
参照实施例18第二步,得到21(44.0mg)。 1H NMR(400MHz,METHANOL-d 4)δ8.48(s,1H),8.20(d,J＝3.2Hz,1H),7.59-7.50(m,1H),7.45(s,1H),7.39(dd,J＝7.8,17.2Hz,2H),7.28(s,1H),6.84(d,J＝3.2Hz,1H),4.38-4.27(m,1H),4.03-3.93(m,1H),3.60-3.35(m,5H),2.50(s,4H),2.33(br.s,1H),2.19(br.s,2H),2.01(br.s,1H).MS-ESI计算值[M+H] +333,实测值333.
实施例22
Figure PCTCN2018086865-appb-000070
合成路线：
Figure PCTCN2018086865-appb-000071
第一步
参照实施例1第一步,得到22C(230mg)。 1H NMR(400MHz,CHLOROFORM-d)δ8.69(s,1H),7.71-7.48(m,3H),7.32(d,J＝8.4Hz,1H),7.23(d,J＝9.2Hz,1H),7.15(t,J＝8.4Hz,1H),6.67(d,J＝3.2Hz,1H).MS-ESI计算值[M+H] +247,实测值247.
第二步
参照实施例18第二步,得到22(90.0mg)。 1H NMR(400MHz,METHANOL-d 4)δ8.55(s,1H),8.23(d,J＝3.2Hz,1H),7.74-7.62(m,1H),7.56-7.44(m,2H),7.36-7.23(m,2H),6.87(d,J＝3.2Hz,1H),4.43-4.31(m,1H),4.05-3.95(m,1H),3.61-3.34(m,5H),2.50-2.42(m,1H),2.40-1.88(m,4H).MS-ESI计算值[M+H] +337,实测值337.
实施例23
Figure PCTCN2018086865-appb-000072
合成路线：
Figure PCTCN2018086865-appb-000073
第一步
参照实施例1第一步,得到23C(340mg)。MS-ESI计算值[M+H] +233,实测值233.
第二步
参照实施例18第二步,得到23(26.0mg)。 1H NMR(400MHz,METHANOL-d 4)δ9.10(s,1H),8.34(d,J＝3.2Hz,1H),7.73(d,J＝2.4Hz,1H),7.27(s,1H),6.81(d,J＝3.2Hz,1H),6.57(d,J＝2.4Hz,1H),4.33(br.s,1H),4.05-3.92(m,4H),3.56-3.37(m,5H),2.50-2.42(m,1H),2.33(br.s,1H),2.19(br.s,2H),2.02(br.s,1H).MS-ESI计算值[M+H] +323,实测值323.
实施例24
Figure PCTCN2018086865-appb-000074
合成路线：
Figure PCTCN2018086865-appb-000075
第一步
参照实施例1第一步,得到24C(15.0mg)。MS-ESI计算值[M+H] +220,实测值220.
第二步
参照实施例18第二步,得到24(8.0mg)。 1H NMR(400MHz,METHANOL-d 4)δ9.10(s,1H),8.42(d,J＝3.6Hz,1H),7.93(s,1H),7.34(d,J＝18.4Hz,2H),6.92(d,J＝3.6Hz,1H),4.41-4.35(m,1H),4.02-3.94(m,1H),3.64-3.37(m,5H),2.48-2.42(m,1H),2.31(br.s,1H),2.24-2.16(m,2H),2.01(br.s,1H).MS-ESI计算值[M+H] +310,实测值310.
实施例25
Figure PCTCN2018086865-appb-000076
合成路线：
Figure PCTCN2018086865-appb-000077
第一步
参照实施例1第一步,得到25C(270mg)。MS-ESI计算值[M+H] +230,实测值230.
第二步
参照实施例18第二步,得到25(54.0mg)。 1H NMR(400MHz,METHANOL-d 4)δ9.42(s,1H),8.97(d,J＝6.0Hz,2H),8.77(s,1H),8.41-8.29(m,2H),7.41(s,1H),7.01(d,J＝3.2Hz,1H),4.49-4.38(m,1H),4.05-3.94(m,1H),3.61-3.35(m,5H),2.50-2.40(m,1H),2.40-2.13(m,3H),2.05-1.95(m,1H).MS-ESI计算值[M+H] +320,实测值320.
实施例26
Figure PCTCN2018086865-appb-000078
合成路线：
Figure PCTCN2018086865-appb-000079
第一步
参照实施例1第一步,得到26C(170mg)。 1H NMR(400MHz,CHLOROFORM-d)δ8.52(s,1H),7.77-7.65(m,2H),7.62-7.55(m,1H),7.37(d,J＝3.2Hz,1H),6.61(d,J＝2.8Hz,1H),4.05(s,3H).MS-ESI计算值[M+H] +233,实测值233.
第二步
参照实施例18第二步,得到26(57.0mg)。 1H NMR(400MHz,METHANOL-d 4)δ8.42(s,1H),8.17(s,1H),8.06(d,J＝3.2Hz,1H),7.87(s,1H),7.27(s,1H),6.79(d,J＝3.2Hz,1H),4.38-4.28(m,1H),4.08-3.91(m,4H),3.60-3.37(m,4H),3.35-3.20(m1H),2.52-2.41(m,1H),2.40-2.28(m,1H),2.27-2.10(m,2H),2.07-1.90(m,1H).MS-ESI计算值[M+H] +323,实测值323.
实施例27
Figure PCTCN2018086865-appb-000080
合成路线：
Figure PCTCN2018086865-appb-000081
第一步
参照实施例15第一步,得到27C(180mg)。 1H NMR(400MHz,CHLOROFORM-d)δ9.47(s,1H),7.81(d,J＝3.6Hz,1H),7.66(d,J＝3.6Hz,1H),7.59(s,1H),7.15(d,J＝3.6Hz,1H),6.70(d,J＝3.6Hz,1H).MS-ESI计算值[M+H] +236,实测值236.
第二步
参照实施例18第二步,得到27(100mg)。 1H NMR(400MHz,METHANOL-d 4)δ9.33(s,1H),8.39(d,J＝3.2Hz,1H),7.71(d,J＝3.2Hz,1H),7.44(d,J＝3.6Hz,1H),7.34(s,1H),6.91(d,J＝3.6Hz,1H),4.41-4.33(m,1H),4.06-3.93(m,1H),3.59-3.34(m,5H),2.50-2.43(m,1H),2.38-2.12(m,3H),2.09-1.94(m,1H).MS-ESI计算值[M+H] +326,实测值326.
实施例28
Figure PCTCN2018086865-appb-000082
合成路线：
Figure PCTCN2018086865-appb-000083
第一步
在0℃下向A-1(200mg,1.02mmol)的N,N-二甲基甲酰胺(5mL)溶液中加入钠氢(48.9mg,1.22mmol)并搅拌15分钟,然后加入B-28(109mg,1.12mmol)在100℃下搅拌16个小时。向反应液中加入15mL水,并用乙酸乙酯(20mL x 2)萃取。合并有机相,用无水硫酸钠干燥,过滤,滤液减压浓缩,得到的粗品用用薄层层析法分离纯化(4:1石油醚/乙酸乙酯,Rf＝0.8)得到28C(200mg)。MS-ESI计算值[M+H] +274 and 276,实测值274 and 276.
第二步
向28C(100mg,0.365mmol),D-1(218mg,1.09mmol)和叔丁醇钠(70.1mg,0.729mmol)的1,4-二氧六环(5mL)溶液中加入氯代[2-(二环己基膦)-3,6-二甲氧基-2',4',6'-,三异丙基-1,1'-二苯][2-(2-氨乙基)苯基]钯(II)(14.6mg,18.2umol),反应液在80℃下搅拌2小时。将反应液过滤,滤液减压浓缩,得到的粗品用制备高效液相色谱分离纯化得到28(20.0mg)。 1H NMR(400MHz,METHANOL-d 4)δ8.69(d,J＝4.4Hz,1H),8.40(d,J＝4.0Hz,1H),8.22-8.05(m,3H),7.94(d,J＝8.4Hz,1H),7.52-7.45(m,1H),7.00(d,J＝4.0Hz,1H),4.30-4.15(m,1H),4.02-3.90(m,1H),3.55-3.37(m,4H),3.26-3.17(m,1H),2.50-2.40(m,1H),2.34(br.s,1H),2.25-2.10(m,2H),1.97(br.s,1H).MS-ESI计算值[M+H] +320,实测值320.
实施例29
Figure PCTCN2018086865-appb-000084
合成路线：
Figure PCTCN2018086865-appb-000085
第一步
参照实施例28第一步,得到29C(80.0mg)。 1H NMR(400MHz,CHLOROFORM-d)δ8.80-8.71(m,2H),8.46(d,J＝2.0Hz,1H),8.13(d,J＝2.0Hz,1H),8.00-7.88(m,2H),7.68(d,J＝3.6Hz,1H),6.69(d,J＝3.6Hz,1H).MS-ESI计算值[M+H] +274 and 276,实测值274 and 276.
第二步
参照实施例28第二步,得到29(45.0mg)。 1H NMR(400MHz,METHANOL-d 4)δ9.05(d,J＝7.4Hz,2H),8.75(d,J＝7.4Hz,2H),8.13(d,J＝4.0Hz,1H),8.08(d,J＝3.2Hz,1H),7.36(d,J＝3.2Hz,1H),6.87(d,J＝4.0Hz,1H),4.13-4.05(m,1H),3.97-3.85(m,1H),3.53-3.37(m,4H),3.21-3.11(m,1H),2.44-2.27(m,2H),2.20-2.11(m,2H),2.05-1.90(m,1H).MS-ESI计算值[M+H] +320,实测值320.
实施例30
Figure PCTCN2018086865-appb-000086
合成路线：
Figure PCTCN2018086865-appb-000087
第一步
参照实施例28第一步,得到30C(130mg)。 1H NMR(400MHz,CHLOROFORM-d)δ9.45(s,1H),8.61(d,J＝4.0Hz,1H),7.94-7.85(m,2H),7.58(s,1H),7.47(d,J＝8.0Hz,1H),7.27-7.16(m,1H),6.69(d,J＝3.6Hz,1H).MS-ESI计算值[M+H] +230,实测值230.
第二步
参照实施例18第二步,得到30(112mg)。 1H NMR(400MHz,METHANOL-d 4)δ9.53(s,1H),8.67-8.56(m,2H),8.07-7.97(m,1H),7.78(d,J＝8.4Hz,1H),7.40-7.27(m,2H),6.88(d,J＝3.6Hz,1H),4.46-4.32(m,1H),4.09-3.94(m,1H),3.61-3.34(m,5H),2.54-2.43(m,1H),2.41-2.11(m,3H),2.09-1.95(m,1H).MS-ESI计算值[M+H] +320,实测值320.
实施例31
Figure PCTCN2018086865-appb-000088
合成路线：
Figure PCTCN2018086865-appb-000089
第一步
参照实施例28第一步,得到31C(130mg)。MS-ESI计算值[M+H] +230,实测值230.
第二步
参照实施例18第二步,得到31(14.0mg)。 1H NMR(400MHz,METHANOL-d 4)δ8.99(d,J＝7.2Hz,2H),8.94(s,1H),8.59(d,J＝3.6Hz,1H),8.40(d,J＝7.2Hz,2H),7.48(s,1H),7.12(d,J＝3.6Hz,1H),4.56-4.44(m,1H),4.08-3.96(m,1H),3.66-3.35(m,5H),2.50-2.40(m,1H),2.42-2.11(m,3H),2.10-1.95(m,1H).MS-ESI计算值[M+H] +320,实测值320.
实施例32
Figure PCTCN2018086865-appb-000090
合成路线：
Figure PCTCN2018086865-appb-000091
第一步
参照实施例10第一步,得到32C(190mg)。MS-ESI计算值[M+H] +195,实测值195.
第二步
参照实施例18第二步,得到32(140mg)。 1H NMR(400MHz,METHANOL-d 4)δ8.61(s,1H),7.99(d,J＝3.2Hz,1H),7.17(s,1H),6.61(d,J＝3.2Hz,1H),4.30-4.20(m,3H),3.99-3.90(m,1H),3.55-3.37(m,4H),3.31-3.24(m,1H),2.49-2.40(m,1H),2.35-2.25(m,1H),2.22-2.14(m,2H),2.04-1.86(m,3H),0.95(t,J＝7.6Hz,3H).MS-ESI计算值[M+H] +285,实测值285.
实施例33
Figure PCTCN2018086865-appb-000092
合成路线：
Figure PCTCN2018086865-appb-000093
第一步
参照实施例10第一步,得到33C(120mg)。MS-ESI计算值[M+H] +209,实测值209.
第二步
参照实施例18第二步,得到33(80.0mg)。 1H NMR(400MHz,METHANOL-d 4)δ8.73-8.63(m,1H),8.17(d,J＝3.2Hz,1H),7.26-7.18(m,1H),6.70(d,J＝3.2Hz,1H),4.91-4.83(m,1H),4.37-4.28(m,1H),4.17-3.91(m,5H),3.61-3.36(m,4H),3.30-3.10(m,1H),2.45-2.25(m,1H),2.40-2.28(m,1H),2.26-2.10(m,2H),2.05-1.93(m,1H).MS-ESI计算值[M+H] +299,实测值299.
实施例34
Figure PCTCN2018086865-appb-000094
合成路线：
Figure PCTCN2018086865-appb-000095
第一步
参照实施例10第一步,得到34C(180mg)。MS-ESI计算值[M+H] +308,实测值308.
第二步
参照实施例18第二步,得到34E(232mg)。MS-ESI计算值[M+H] +398,实测值398.
第三步
将34E(232mg)的盐酸乙酸乙酯(4M,5.0mL,20.0mmol)溶液在15℃下搅拌2.5小时。反应液蒸干用制备高效液相色谱分离纯化得到34(40.0mg)。 1H NMR(400MHz,METHANOL-d 4)δ8.60(s,1H),8.40(d,J＝3.6Hz,1H),7.17(s,1H),6.77(d,J＝3.6Hz,1H),5.80-5.70(m,1H),4.75-4.54(m,4H),4.37-4.16(m,1H),4.03-3.82(m,1H),3.57-3.35(m,4H),3.30-3.20(m,1H),2.50-2.40(m,1H),2.35-2.10(m,3H),2.03-1.88(m,1H).MS-ESI计算值[M+H] +298,实测值298.
实施例35
Figure PCTCN2018086865-appb-000096
合成路线：
Figure PCTCN2018086865-appb-000097
第一步
参照实施例10第一步,得到35C(170mg)。 1H NMR(400MHz,CHLOROFORM-d)δ8.48(s,1H),7.45(s,1H),7.33(d,J＝3.2Hz,1H),6.39(d,J＝3.2Hz,1H),4.75-4.55(m,1H),1.51(s,3H),1.49(s,3H).MS-ESI计算值[M+H] +195,实测值195.
第二步
参照实施例18第二步,得到35(110mg)。 1H NMR(400MHz,METHANOL-d 4)δ8.61(s,1H),8.11(d,J＝2.8Hz, 1H),7.15(s,1H),6.62(d,J＝2.8Hz,1H),4.81(td,J＝6.4,13.2Hz,1H),4.30-4.21(m,1H),3.99-3.88(m,1H),3.58-3.35(m,4H),3.29-3.21(m,1H),2.48-2.37(m,1H),2.36-2.24(m,1H),2.23-2.09(m,2H),2.02-1.90(m,1H),1.58(s,3H),1.56(s,3H).MS-ESI计算值[M+H] +285,实测值285.
实施例36
Figure PCTCN2018086865-appb-000098
合成路线：
Figure PCTCN2018086865-appb-000099
第一步
参照实施例10第一步,得到36C(170mg)。 1H NMR(400MHz,CHLOROFORM-d)δ8.44(s,1H),7.46(s,1H),7.18(d,J＝3.2Hz,1H),6.39(d,J＝3.2Hz,1H),4.00(d,J＝7.6Hz,2H),3.90(dd,J＝3.2,11.6Hz,2H),3.30-3.20(m,2H),2.04(br.s,1H),1.51-1.25(m,4H).MS-ESI计算值[M+H] +251,实测值251.
第二步
参照实施例18第二步,得到36(50.0mg)。 1H NMR(400MHz,METHANOL-d 4)δ8.67(s,1H),7.98(d,J＝3.2Hz,1H),7.19(s,1H),6.66-6.58(m,1H),4.38-4.27(m,1H),4.20(d,J＝7.6Hz,2H),4.01-3.89(m,3H),3.59-3.36(m,6H),3.30-3.20(m,1H),2.50-2.40(m,1H),2.40-2.28(m,1H),2.27-2.10(m,3H),2.05-1.92(m,1H),1.46(br.s,4H).MS-ESI计算值[M+H] +341,实测值341.
实施例37
Figure PCTCN2018086865-appb-000100
合成路线：
Figure PCTCN2018086865-appb-000101
第一步
将A-1(500mg,2.54mmol)和37B(518mg,2.54mmol)溶于无水二氧六环(10mL)中,氮气保护下,加入无水磷酸钾(1.80g,5.08mmol),(1R,2R)-环己烷-1,2-二胺(29.0mg,0.254mmol)和碘化亚铜(4.8mg,0.0250mmol)。反应液在110℃,搅拌反应12小时。反应液冷至室温,加入水(30mL),用乙酸乙酯(30mL x 3)萃取,合并有机相,用无水硫酸钠干燥,过滤,滤液减压浓缩,得到的粗品用硅胶色谱柱分离纯化(5:1石油醚/乙酸乙酯,Rf＝0.5)得到37C(250mg)。 1H NMR:(400MHz,METHANOL-d 4)δ8.31(s,1H),8.23(s,1H),7.78-7.75(m,3H),7.57-7.54(m,2H),7.42-7.38(m,1H),6.69-6.68(m,1H)。MS-ESI计算值[M+H] +272,实测值272。
第二步
将37C(68.4mg,0.251mmol),D-1(50.0mg,0.251mmol),碳酸铯(327mg,1.00mmol)和二环己基-[2-(2,4,6-三异丙基)苯基]膦(7.2mg,0.0150mmol)溶解于叔丁醇(5mL)中。氮气保护下,加入三(二亚苄基丙酮)二钯(4.6mg,0.0500mmol)。反应液加热到80℃,搅拌12小时。反应液冷至室温,用制备高效液相色谱分离纯化得到37(10.0mg)。 1H NMR:(400MHz,METHANOL-d 4)δ7.88-7.87(m,1H),7.74-7.72(m,2H),7.60-7.59(m,1H),7.54-7.52(m,2H),7.34-7.33(m,2H),6.55-6.54(m,1H),4.03-4.01(m,1H),3.88-3.87(m,1H),3.40-3.32(m,4H),3.11-3.01(m,1H),2.39-2.37(m,2H),2.14-2.10(m,2H),1.91-1.90(m,1H)。MS-ESI计算值[M+H] +319,实测值319。
实施例38
Figure PCTCN2018086865-appb-000102
合成路线：
Figure PCTCN2018086865-appb-000103
第一步
参照实施例37第一步,得到38C(250mg)。 1H NMR:(400 MHz,DMSO-d 6)δ8.43-8.42(m,1H),8.37-8.36(m,1H),8.11-8.08(m,2H),7.89-7.88(m,1H),7.59-7.57(m,1H),7.45-7.44(m,1H),6.76-6.75(m,1H)。MS-ESI计算值[M+H] +307,实测值307。
第二步
将38C(100mg,0.325mmol),D-1,叔丁醇钠(69.5mg,0.650mmol)和1,1'-双(二叔丁基膦)二茂铁二氯化钯(15.4mg,0.0325mmol)溶解于无水四氢呋喃(5mL)中。氮气保护下,加入三(二亚苄基丙酮)二钯(14.9mg,0.162mmol)。反应液加热到80℃,搅拌6小时。反应液冷至室温,用制备高效液相色谱分离纯化得到38(10.0mg)。 1H NMR:(400MHz,METHANOL-d 4)δ7.98-7.97(m,1H),7.92-7.91(m,1H),7.73-7.71(m,2H),7.67-7.66(m,1H),7.35-7.32(m,2H),6.58-6.57(m,1H),4.02-4.01(m,1H),3.89-3.84(m,1H),3.39-3.33(m,4H),3.11-3.09(m,1H),2.39-2.33(m,2H),2.14-2.12(m,2H),1.91-1.90(m,1H)。MS-ESI计算值[M+H] +353,实测值353。
实施例39
Figure PCTCN2018086865-appb-000104
合成路线：
Figure PCTCN2018086865-appb-000105
第一步
参照实施例37第一步,得到39C(140mg)。 1H NMR:(400MHz,METHANOL-d 4)δ8.63(s,1H),7.91-7.83(d,J＝2.8Hz,1H),7.73(s,1H),7.70(s,1H),7.66-7.58(m,2H),7.55-7.48(m,1H),6.80(d,J＝2.8Hz,1H)。
第二步
向39C(80.0mg,0.304mmol)和D-1(38.0mg,0.304mmol)的四氢呋喃(4mL)溶液中加入三(二亚苄基丙酮)二钯(14.0mg,0.0152mmol),叔丁醇钠(58.0mg,0.608mmol)和二叔丁基膦二茂铁(14.0mg,0.0304mmol),并在80℃下搅拌16个小时。冷却至室温,将反应液过滤,滤液减压浓缩,得到的粗品用制备高效液相色谱分离纯化得到39(25.0mg)。 1H NMR:(400MHz,METHANOL-d 4)δ8.51(s,1H),8.26-8.16(d,J＝2.4Hz,1H),7.72(s,1H),7.67-7.47(m,3H),7.30(s,1H),6.84(d,J＝2.4Hz,1H),4.34(br,1H),3.97(t,J＝10.8Hz,1H),3.63-3.32(m,5H),2.44(br,1H),2.32(br,1H),2.18(br,2H),1.90(br,1H)。MS-ESI计算值[M+H] +353,实测值353。
实施例40
Figure PCTCN2018086865-appb-000106
合成路线：
Figure PCTCN2018086865-appb-000107
第一步
参照实施例10第一步,得到40C(200mg)。 1H NMR:(400 MHz,METHANOL-d4)δ8.55(s,1H),7.59(s,1H),7.53(d,J＝2.4Hz,1H),6.52(d,J＝2.4Hz,1H),3.94(s,3H)。MS-ESI计算值[M+H] +153,实测值153。
第二步
在氮气保护下,向40C(100mg,0.600mmol)和(3R)-奎宁环-3-胺(75.8mg,0.600mmol)的四氢呋喃(4mL)溶液中加入三(二亚苄基丙酮)二钯(27.5mg,0.0300mmol),叔丁醇钠(115mg,1.20mmol)和二叔丁基膦二茂铁(28.5mg,0.0600mmol),并在80℃下搅拌16个小时。冷却至室温,将反应液过滤,滤液浓缩,得到的粗品用制备高效液相色谱分离纯化得到40(40.0mg)。 1H NMR:(400MHz,METHANOL-d4)δ8.55(s,1H),7.90(d,J＝3.2Hz,1H),7.18(s,1H),6.59(d,J＝3.2Hz,1H),4.37-4.26(m,1H),4.02-3.95(m,1H),3.93(s,3H),3.60-3.36(m,4H),3.29(d,J＝3.2Hz,1H),2.48-2.29(m,2H),2.26-2.07(m,2H),2.05-1.90(m,1H)。MS-ESI计算值[M+H] +257,实测值257。
实施例41
Figure PCTCN2018086865-appb-000108
合成路线：
Figure PCTCN2018086865-appb-000109
第一步
参照实施例10第一步,得到41C(300mg)。 1H NMR:(400MHz,METHANOL-d4)δ8.26-8.25(m,1H),8.10-8.09(m,1H),7.39(d,J＝3.6Hz,1H),6.45(d,J＝3.6Hz,1H),3.85(s,3H)。MS-ESI计算值[M+H] +210,实测值210。
第二步
将41C(31.8mg,0.151mmol),D-1(30.0mg,0.151mmol),叔丁醇钠(57.9mg,0.602mmol)和1,1'-双(二叔丁基膦)二茂铁二氯化钯(7.2mg,0.0150mmol)溶解于无水四氢呋喃(5mL)中。氮气保护下,加入三(二亚苄基丙酮)二钯(6.9mg,0.0750mmol)。反应液加热到80℃,搅拌6小时。反应液冷至室温,加入水(30mL),用乙酸乙酯(30mL x 3)萃取,合并有机相,用无水硫酸钠干燥,过滤,滤液减压浓缩,得到的粗品用制备高效液相色谱分离纯化得到41(15.0mg)。 1H NMR:(400MHz,METHANOL-d4)δ7.88-7.87(m,1H),7.29-7.26(m,2H),6.33-6.32(m,1H),3.98-3.97(m,1H),3.86-3.81(m,4H),3.40-3.32(m,5H),3.10-3.07(m,1H),2.36-2.35(m,1H),2.11-2.10(m,2H),1.90-1.88(m,1H)。MS-ESI计算值[M+H] +257,实测值257。
生物化学检测：
体外评价
检测化合物对克隆人体尼古丁乙酰胆碱受体的体外活性。人体尼古丁乙酰胆碱受体(AChR)α7(由CHRNA7基因编码)和人伴侣蛋白RIC-3(由RIC3基因编码)稳定的共表达在CHO细胞中，用Fluo-8钙试剂盒或者荧光成像板
Figure PCTCN2018086865-appb-000110
读取器读取信息。
测定2个浓度下，每个试验品的激动效应，n＝2-3孔/浓度。具体条件如表1所示。结果表达为标准化的活化百分比(％)。在试验品的激动性能评价中，如果测试品的平均值超过对照品平均值三个或三个以上的标准偏差，认定为效果显著。3×SD的检测阈值附表1下。
测试板质量控制结果如表2所示(最高值.响应；最低值.响应；Z-质数和信号窗口)。数据表明，通过本试验方法得到的检测数据可靠。
测试品对nAChRα7受体激动作用的测试
测试品作为尼古丁乙酰胆碱α7受体激动剂，在活性检测中缺省阳性对照乙酰胆碱(ACh)。缺省变构调节剂PNU-120596时，尼古丁乙酰胆碱α7受体迅速脱敏，难以观察到任何激动剂的激动效应。因此，在待测激动剂乙酰胆碱或测试品中加入1μM PNU-120596。阳性对照剂和变构调节剂PNU-120596(30μM乙酰胆碱+1μM PNU-120596)引起的信号被设置为激活率100％。阴性对照(1μM PNU-120596)引起的信号被设置为激活率0％。测试化合物对尼古丁乙酰胆碱α7受体激动百分比分类为：+激活率＜10％,++激活率10％-40％，+++激活率40％-70％，++++激活率70％-100％，结果如表1所示。
表1：本发明化合物体外筛选试验结果
Figure PCTCN2018086865-appb-000111
Figure PCTCN2018086865-appb-000112
Figure PCTCN2018086865-appb-000113
3x SD阴性对照(1μM PNU-120596；n＝16)＝6.36；活性值大于6.36表示差异显著.
表2.阳性对照板质控对检测的影响
Figure PCTCN2018086865-appb-000114
Figure PCTCN2018086865-appb-000115
*RLU:最大相对发光度单位(Max)
结论：表1结果显示在低浓度1uM时，测试品对尼古丁乙酰胆碱α7的激动活性明显，最高可以达到100％。
体内评价
实施例37体内活性试验通过NOR(新物体识别记忆实验)模型检测。 选用6-8周雄性Wistar大鼠，分3组，分别为空白对照组，实施例37(1mpk)，实施例37(3mpk)每组8-10只鼠，测试前2小时给药。
实验步骤(NOR):
·适应:：大鼠连续适应3天，每天两次
·训练(Trial1)：将大鼠放入桶中自由探索3分钟
·测试(Trial2)：训练后15分钟和24小时，将其中一个玩具换成新玩具，将大鼠放入桶中让其自由探索3分钟。
视频录入及数据分析：
·使用Anymaze视频跟踪分析***进行视频记录；采用双人盲法对大鼠对不同玩具的探索时间进行记录及评分分析。
试验结果如图1-1，图1-2所示：结果显示实施例37在1mpk给药组，24小时新旧事物探索时间识别指数与对照组相比差异化显著，具有统计学意义。说明实施例37体内药效明显，能够提高或改善Wistar鼠的认知能力和记忆力。
结论：
本发明化合物体外和体内药效明显。
训练后15分钟，各组大鼠对新物体探索时间高于旧物体，各组新旧物体的识别指数无显著性差异。
训练后24小时，实施例37 1mpk组与对照组相比显著延迟遗忘，识别指数d2高于对照组，具有显著性差异p＜0.05；实施例37 3mpk组与对照组相比能够延迟遗忘，识别指数d2高于对照组，但无显著性差异，见图1-2。图中数据表达为平均值±SEM，n＝8-10.采用一维组间方差分析t-test,*p＜0.05识别指数(d2)＝(探索新事物时间–探索旧事物时间)/新旧事物总的探索时间。

Claims (11)

  1. 式(Ⅰ)所示化合物、其药学上可接受的盐及其互变异构体，
    Figure PCTCN2018086865-appb-100001
    其中，
    T 1或T 2中的一个选自NH，另一个选自CH 2；
    R 1选自H，或选自R 2-L-；
    R 2选自任选被1、2或3个R取代的C 1-6烷基、C 1-6杂烷基、C 3-6环烷基、3～6元杂环烷基、6～10元芳基、4～6元杂芳基；
    L选自单键，或选自任选被1或2个R取代的：-CH 2-、
    Figure PCTCN2018086865-appb-100002
    R选自卤素、CN、OH、NH 2、NO 2、COOH，或选自任选被1、2或3个R’取代的C 1-6烷基、C 1-6杂烷基；
    R’选自F、Cl、Br、I、OH、CN、NH 2、COOH、Me、Et、CF 3、CHF 2、CH 2F、NHCH 3、N(CH 3) 2；
    “杂”表示杂原子或杂原子团，选自-C(＝O)N(R)-、-N(R)-、-C(＝NR)-、-S(＝O) 2N(R)-、-S(＝O)N(R)-、-O-、-S-、＝O、＝S、-O-N＝、-C(＝O)O-、-C(＝O)-、-C(＝S)-、-S(＝O)-、-S(＝O) 2-和-N(R)C(＝O)N(R)-；
    以上任何一种情况下，杂原子或杂原子团的数目分别独立地选自1、2或3。
  2. 根据权利要求1所述化合物、其药学上可接受的盐及其互变异构体，其中，R选自F、Cl、Br、I、NH 2、NO 2、COOH，或选自任选被1、2或3个R’取代的C 1-3烷基、C 1-3杂烷基。
  3. 根据求权利要求2所属化合物、其药学上可接受的盐及其互变异构体，其中，R选自F、Cl、Br、I、NH 2、NO 2、COOH、Me、Et、CF 3。
  4. 根据权利要求1～3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，R 2选自任选被1、2或3个R取代的C 1-3烷基、C 1-3杂烷基、C 3-6环烷基、恶丁环基、吖丁啶基、四氢吡喃基、苯基、吡啶基、吡唑基、噻唑基、恶唑基、咪唑基、噻吩基、***基、吡嗪基、嘧啶基、吡咯基、2,3-二氢苯并呋喃基。
  5. 根据权利要求4所述化合物、其药学上可接受的盐及其互变异构体，其中，R 2选自：
    Figure PCTCN2018086865-appb-100003
    Figure PCTCN2018086865-appb-100004
  6. 根据权利要求1～3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，L选自单键和-CH 2-。
  7. 根据权利要求1～3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，R 1选自、Me、
    Figure PCTCN2018086865-appb-100005
    Figure PCTCN2018086865-appb-100006
  8. 根据权利要求1～3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，结构单元
    Figure PCTCN2018086865-appb-100007
    选自
    Figure PCTCN2018086865-appb-100008
  9. 根据权利要求1～8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，其选自：
    Figure PCTCN2018086865-appb-100009
    其中，R 1如权利要求1～8任意一项所定义。
  10. 下式所示化合物，其选自：
    Figure PCTCN2018086865-appb-100010
    Figure PCTCN2018086865-appb-100011
  11. 根据权利要求1～10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治疗精神***或老年痴呆等疾病药物中的应用。
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