Patent Application
20230416258
The present application claims priority to the Patent Application for Invention with the application No. 202011237945.7 and entitled “NEW BENZODIAZEPINE COMPOUNDS, AND PREPARATION METHOD THEREFOR AND USE THEREOF” filed with China National Intellectual Property Administration on Nov. 9, 2020, which is incorporated herein by reference in its entirety.
The present disclosure relates to a benzodiazepine derivative of formula (I) as a short-acting anaesthetic, a pharmaceutical composition comprising the same, a kit comprising the same, a preparation method therefor, a method of sedation and anaesthesia using the same, and use thereof for manufacturing a medicament for sedation and anaesthesia.
Anesthetic drugs can cause temporary and reversible loss of consciousness and pain in the body or part of the body and help patients reduce pain and other uncomfortable symptoms, and are essential auxiliary drugs for clinical surgery.
Benzodiazepines are activators of a GABAA receptor (also known as γ-aminobutyric acid type A receptor). The GABAA receptor is a gated receptor for a chloride ion channel which is composed of two α and two β subunits (α2β2). There is a GABA receptor site on the R subunit, and when GABA binds to the GABA receptor site, the chloride ion channel is opened to allow chloride ions to flow in, so that the nerve cells are hyperpolarized, and an inhibition effect is generated. There is a benzodiazepine receptor on the a subunit, and when a benzodiazepine binds to the benzodiazepine receptor, the binding of GABA to the GABAA receptor can be promoted to enable an increased opening frequency of the chloride channel (rather than an increased opening time of the chloride channel or an increased chloride ion flow), thereby allowing more chloride ions to flow in. This enables benzodiazepine derivatives to enhance GABA neurotransmission function and synapse inhibitory effect, thereby exerting various therapeutic effects of anesthesia induction, hypnosis, anxiolysis, and alleviation of central nervous system disorder or epileptic spasm, and the like in clinical practice.
Benzodiazepine drugs, which are drugs for sedation and anesthesia that have been rapidly developed in recent years, have good pharmaceutical effects such as oblivion, anxiolysis, and sedation, and thus are widely used in the fields of sedation and anesthesia. The first benzodiazepine drug, chlordiazepoxide (Librium), was marketed in 1960. Since then, an increasing number of novel benzodiazepine drugs have emerged, including ultrashort-acting drugs (remimazolam), short-acting drugs (triazolam/midazolam), medium-acting drugs (lorazepam/estazolam), long-acting (diazepam), and the like. There are more than 20 benzodiazepine derivatives commonly used in clinical practice, which have similar structures but different clinical indications. The reason is that the binding sites and actions of GABA and GABA receptors are heterogeneous. GABA-gated chloride channels of different nerves are composed of different kinds of subunits, and the composition of the different subunits can cause subtle changes in the interaction of these channels with allosteric modulators, resulting in different sedative and anesthetic effects. Midazolam was introduced to the market in the early 1980s as the first benzodiazepine compound with water solubility and was used as an intravenous injection to provide sedative and anesthetic means for short-term surgery or intensive care units. However, midazolam produces active metabolites in vivo, resulting in a relatively long time required for patients to regain consciousness from the midazolam-induced sedative and anesthetic state. In addition, since the metabolism of midazolam depends on the hepatic enzyme cytochrome P4503A4, after it is administered to patients with impaired liver function, the problem of drug-drug interaction may occur. Remimazolam was approved for marketing in December 2019 as a novel ultrashort-acting GABAA receptor agonist by introducing a methyl propionate side chain that can be metabolized rapidly on the benzodiazepine parent nucleus structure. Since the side chain of methyl propionate can be rapidly metabolized by esterase, and the main metabolite remimazolam propionate has almost no sedative and anesthetic activity, it has a very short duration of efficacy and belongs to the ultrashort-acting benzodiazepine drugs. However, long-term infusion of remimazolam still causes problems such as wake-up delay and drug accumulation, and is only approved for sedation for gastroscopy and general anesthesia procedures.
In conclusion, benzodiazepine anaesthetic drugs are often used with dependence and addiction, and most of the drug metabolites still have certain drug effects and cannot rapidly return patients to a normal state, and long-term use of the drugs tends to result in drug accumulation, which hinders further development of the drugs. Therefore, the development of a benzodiazepine drug with fast onset of action, short recovery time, and no accumulation is a problem to be solved.
In view of the problem described above, the present disclosure provides a novel benzodiazepine compound, and a preparation method therefor and use thereof.
The technical solutions of the present disclosure are as follows: provided is a novel benzodiazepine compound, comprising a compound represented by general formula (I), and a pharmaceutically acceptable salt, a stereoisomer, a tautomer, a polymorph, a solvate, a metabolite, or a prodrug thereof:
wherein:
Further, provided is a novel benzodiazepine compound, and a pharmaceutically acceptable salt, a stereoisomer, a tautomer, a polymorph, a solvate, a metabolite, or a prodrug thereof, wherein, X is C; R2 and R3 are halogen; R5 is selected from hydrogen, C1-20 alkyl, C1-20 acyl, C2-20 alkenyl, C2-20 alkynyl, C1-10 alkylene-phosphate group, P(O)(OH)2-C1-10 alkylene, 3- to 10-membered cycloalkyl or C1-10 alkylene-3- to 10-membered cycloalkyl, R6R7N—(CH2)n—, (R6)(R7)N—(CH2)n—, 3- to 10-membered heterocyclyl or C1-10 alkylene-3- to 10-membered heterocyclyl, 6- to 14-membered aryl or C1-10 alkylene-6- to 14-membered aryl, and 5- to 14-membered heteroaryl or C1-10 alkylene-5- to 14-membered heteroaryl;
Further, provided is a novel benzodiazepine compound, and a pharmaceutically acceptable salt, a stereoisomer, a tautomer, a polymorph, a solvate, a metabolite, or a prodrug thereof, wherein, X is N; R5 is selected from hydrogen, C1-20 alkyl, C1-20 acyl, C2-20 alkenyl, C2-20 alkynyl, C1-10 alkylene-phosphate group, P(O)(OH)2-C1-10 alkylene, 3- to 10-membered cycloalkyl or C1-10 alkylene-3- to 10-membered cycloalkyl, R6R7N—(CH2)n—, (R6)(R7)N—(CH2)n—, 3- to 10-membered heterocyclyl or C1-10 alkylene-3- to 10-membered heterocyclyl, 6- to 14-membered aryl or C1-10 alkylene-6- to 14-membered aryl, and 5- to 14-membered heteroaryl or C1-10 alkylene-5- to 14-membered heteroaryl; the C1-20 alkyl, C1-20 acyl, C2-20 alkenyl, C2-20 alkynyl, 3- to 10-membered cycloalkyl or C1-10 alkylene-3- to 10-membered cycloalkyl, R6R7N—(CH2)n—, (R6)(R7)N—(CH2)n—, 3- to 10-membered heterocyclyl or C1-10 alkylene-3- to 10-membered heterocyclyl, 6- to 14-membered aryl or C1-10 alkylene-6- to 14-membered aryl, or 5- to 14-membered heteroaryl or C1-10 alkylene-5- to 14-membered heteroaryl is each optionally substituted with one or more (e.g., 1, 2, 3, or 4) substituents independently selected from halogen, C1-10 alkylene-halogen, hydroxy, C1-10 alkylene-hydroxy, R6R7N—(CH2)n—, (R6)(R7)N—(CH2)n—, cyano, C1-10 alkylene-cyano, nitro, C1-10 alkylene-nitro, amino, C1-20 alkyl, C1-20 alkoxy, C2-20 alkenyl, C2-20 alkynyl, 3- to 10-membered cycloalkyl or C1-10 alkylene-3- to 10-membered cycloalkyl, 3- to 10-membered heterocyclyl or C1-10 alkylene-3- to 10-membered heterocyclyl, 6- to 14-membered aryl or C1-10 alkylene-6- to 14-membered aryl, and 5- to 14-membered heteroaryl or C1-10 alkylene-5- to 14-membered heteroaryl; preferably, R5 is selected from hydrogen and C1-10 alkyl, C1-10 alkylene-phosphate group, 3- to 10-membered cycloalkyl or C1-10 alkylene-3- to 10-membered cycloalkyl, R6R7N—(CH2)n—, (R6)(R7)N—(CH2)n—, and 3- to 10-membered heterocyclyl or C1-10 alkylene-3- to 10-membered heterocyclyl; more preferably, R5 is selected from hydrogen, methyl, ethyl, methylene-phosphate group, C1-10 alkylene-morpholinyl, C1-10 alkylene-pyrrolyl group, C1-10 alkylene-imidazoliyl, 2-(4-hydroxypiperidin-1-yl)ethyl, C1-10 alkylene-pyridyl, C1-10 alkylene-piperazinyl, 2-(4-methylpiperazin-1-yl)ethyl, 3-(4-(2-hydroxyethyl)piperazin-1-yl)propyl, 2-(4-methylpiperazin-1-yl)2-oxyethyl, 2-(4-methylpiperazin)-1-carbonyl, (4-phenylpiperazin-1-yl)methyl, 2-hydroxyethyl, 2-aminoethyl, acetyl, propan-2-yn-1-yl, dimethylaminomethyl, dimethylaminoethyl, dimethylamino-n-propyl, dimethylamino-isopropyl, dimethylamino-n-butyl, dimethylamino-isobutyl, dimethylamino-tert-butyl, dimethylamino-n-pentyl, dimethylamino-isopentyl, dimethylamino-neopentyl, cyclopropylmethyl, cyclopropylethyl, cyclopropyl n-propyl, cyclopropylisopropyl, 1-methylpiperidin-4-yl, 1-ethyl-carbamoyl, 1-methyl-carbamoyl, (dimethylamino)-3-oxopropyl, and (4,5-dihydro-1H-imidazol-2-yl)methyl; further, wherein the compound is selected from:
Further, the compounds of the present disclosure may be present in the pharmaceutical composition in a content or an amount of about 10 mg to about 3000 mg, suitably 25-3000 mg, preferably 60-2700 mg, more preferably 60-1500 mg, particularly preferably 60-1000 mg, e.g., 60 mg, 80 mg, 100 mg, 150 mg, 200 mg, 300 mg, or 500 mg.
The pharmaceutically acceptable carrier is selected from water, oil, and other injectable solvents.
The pharmaceutical additive is selected from starch, glucose, lactose, brown sugar, gelatin, maltose, chalk, silica gel, sodium stearate, glyceryl monostearate, talc, sodium oxide, skimmed milk powder, glycerol, propylene glycol, ethanol, lecithin, glycine, mannitol, Tween 80, polysorbate, sodium carboxymethylcellulose, gelatin, pectin, albumin, trehalose, and dextran.
Further, the pharmaceutically acceptable salt thereof is selected from acetate, adipate, aspartate, benzoate, benzenesulfonate, bicarbonate/carbonate, bisulfate/sulfate, borate, camphorsulfonate, citrate, cyclamate, edisylate, ethanesulfonate, formate, fumarate, glucoheptonate, gluconate, glucuronate, hexafluorophosphate, hydrochloride/oxide, hydrobromide/bromide, hydroiodide/iodide, isethionate, lactate, malate, maleate, malonate, methanesulfonate, methylsulfate, naphthoate, 2-naphthalenesulfonate, nicotinate, nitrate, orotate, oxalate, palmitate, dihydronaphthoate, phosphate/hydrophosphate/dihydrophosphate, pyroglutamate, saccharate, stearate, succinate, tannate, tartrate, tosylate, trifluoroacetate and xinafoate, aluminum salt, arginine, benzathine, calcium salt, choline, diethylamine salt, diethanolamine salt, glycinate, lysinate, magnesium salt, meglumine salt, ethanolamine salt, sodium salt, potassium salt, ammonium salt, tromethamine salt, and zinc salt.
Further, provided is a preparation method for the compound according to a reaction route as follows:
wherein R1, R2, R3, R4, R5, and W are as defined in any one of claims 1 and 3, and the method comprises the following steps:
Further, provided is use of the compound or the composition for manufacturing a medicament for sedation and anesthesia, including use in conscious sedation during short-term diagnostic, surgical or endoscopic procedures, induction and maintenance of general anesthesia, and ICU sedation.
Further, provided is a method of sedation and anesthesia comprising administering an effective amount of the compound according to any one of claims 1 to 7 or the pharmaceutical composition according to claim 8 by an intravenous, intra-arterial, subcutaneous, intraperitoneal, intramuscular, or transdermal route.
Further, provided is a pharmaceutical formulation comprising a compound represented by general formula (I) or a pharmaceutically acceptable salt thereof as an active agent and a pharmaceutically acceptable carrier. The pharmaceutically acceptable carrier refers to one or more inert and non-toxic solid or liquid fillers, diluents, adjuvants, and the like, which do not adversely affect the active compound or the patient.
Further, the dosage form may be a suspension, an emulsion, an injection, a lyophilized powder injection, or other pharmaceutically common dosage form.
Further, the dosing regimen may be adjusted to provide the best desired response. For example, a single bolus may be given, several separate doses may be administered over time, or the dose may be proportionally reduced or increased as indicated by the exigency of the treatment situation. It is noted that dose values may vary with the type and severity of the condition to be alleviated, and may include single or multiple doses. It is further understood that for any particular individual, the specific dosage regimen will be adjusted over time according to the individual need and the professional judgment of the person administering the composition or supervising the administration of the composition.
It is an object of the present disclosure to provide a pharmaceutical composition comprising an effective amount of the compound of the present disclosure and one or more pharmaceutically acceptable carriers.
The pharmaceutically acceptable carriers that can be used in the pharmaceutical composition of the present disclosure include, but are not limited to, a sterile liquid, e.g., water, oil, and other injectable solvents, including those of petroleum, animal, vegetable, or synthetic source, e.g., peanut oil, soybean oil, mineral oil, sesame oil, and the like; water is an exemplary carrier when the pharmaceutical composition is administered intravenously; normal saline, glucose, aqueous glycerol solution, ethanol, propylene glycol, polyethylene glycol, or glycerol may also be used as a liquid carrier, particularly for an injectable liquid or an emulsion. Suitable pharmaceutical additives include starch, glucose, lactose, brown sugar, gelatin, maltose, chalk, silica gel, sodium stearate, glyceryl monostearate, talc, sodium oxide, skimmed milk powder, glycerol, propylene glycol, ethanol, lecithin, glycine, mannitol, Tween 80, polysorbate, sodium carboxymethylcellulose, gelatin, pectin, albumin, trehalose, dextran, and the like. The composition may further optionally contain a small amount of wetting agent, emulsifier, or pH buffer.
The pharmaceutical composition of the present disclosure may be administered by a suitable route.
Preferably, the pharmaceutical composition of the present disclosure is administered by an intravenous, intra-arterial, subcutaneous, intraperitoneal, intramuscular, or transdermal route.
It is another object of the present disclosure to provide a kit comprising the compound or the pharmaceutical composition of the present disclosure.
It is a further object of the present disclosure to provide a method of sedation and anesthesia, comprising administering, preferably by an intravenous, intra-arterial, subcutaneous, intraperitoneal, intramuscular, or transdermal route, an effective amount of the compound or the pharmaceutical composition of the present disclosure, preferably for use in the following clinical treatment regimens: preoperative sedation during surgery; conscious sedation during short-term diagnosis, surgery, or an endoscopic procedure; induction and maintenance of general anesthesia prior to and/or concurrently with administration of other anesthetics and analgesics; ICU sedation; use for manufacturing a medicament for sedation and anesthesia and an anxiolytic medicament, including use in sedation, hypnosis, anxiolysis, and oblivion for early-wake insomnia due to dysfunction of excitation and inhibition of the brain.
It is a further object of the present disclosure to provide the compounds of the present disclosure for use as a medicament for sedation and anesthesia, preferably for intravenous administration in the following clinical treatment regimens: preoperative sedation during surgery; conscious sedation during short-term diagnosis, surgery, or an endoscopic procedure; induction and maintenance of general anesthesia prior to and/or concurrently with administration of other anesthetics and analgesics; ICU sedation; use for manufacturing a medicament for sedation and anesthesia and an anxiolytic medicament, including use in sedation, hypnosis, anxiolysis, and oblivion for early-wake insomnia due to dysfunction of excitation and inhibition of the brain.
It is a further object of the present disclosure to provide use of the compound or pharmaceutical composition of the present disclosure for manufacturing a medicament for sedation and anesthesia, preferably for intravenous administration in the following clinical treatment regimens: preoperative sedation during surgery; conscious sedation during short-term diagnosis, surgery, or an endoscopic procedure; induction and maintenance of general anesthesia prior to and/or concurrently with administration of other anesthetics and analgesics; ICU sedation; use for manufacturing a medicament for sedation and anesthesia and an anxiolytic medicament, including use in sedation, hypnosis, anxiolysis, and oblivion for early-wake insomnia due to dysfunction of excitation and inhibition of the brain.
The amount of the compound of the present disclosure administered will depend on the individual being treated, the rate of administration, the disposition of the compound, and the judgment of the prescribing physician. Generally, an effective dose is about 0.0001 mg to about 50 mg/kg/day, e.g., about 0.01 to about 10 mg/kg/day (single or separate administration). For a person weighing 70 kg, this would total about 0.007 mg/day to about 3500 mg/day, for example, about 0.7 mg/day to about 700 mg/day. In some cases, dosage levels below the lower limit of the above range may be sufficient, while in other cases, a larger dosage may still be employed without causing any harmful side effects, provided that the larger dosage is first divided into several smaller dosages for administration throughout the day.
The beneficial effects of the present disclosure are as follows: the short-acting benzodiazepine derivatives of the present disclosure have the characteristics of fast onset of action, short acting time, strong depth, fast metabolism, and fast wake-up. In anesthesia experiments on mice and rats, the short-acting benzodiazepine derivatives of the present disclosure have comparable onset of action to remimazolam, but have significantly shortened acting time and wake-up time, and some of the compounds have significantly enhanced depth of action and have characteristics such as faster onset of action, shorter action time, greater action strength, faster metabolism, faster wake-up, and the like; in a long-term infusion anesthesia experiment on rats, compared to remimazolam, the short-acting benzodiazepine derivatives of the present disclosure have significantly shortened wake-up time and recovery time and have characteristics such as faster wake-up, faster recovery and the like; the benzodiazepine compounds of the present disclosure not only retain high affinity and selectivity for the GABAA receptor, but also have the following advantages by structural modification of benzodiazepine and modulation of the carboxylate group: predictable fast onset time for achieving sedation and anesthesia, short effective action time, strong depth of action, and short wake-up time, thereby reducing adverse inhibitory reactions on the cardiovascular system and the respiratory system and reducing the side effects on the nervous system of a patient, including problems such as sleepiness, dizziness, and the like.
Unless otherwise stated, the definitions of groups and terms described in the specification and claims of the present application, including definitions thereof as examples, exemplary definitions, preferred definitions, definitions documented in tables, definitions of specific compounds in the examples, and the like, may be arbitrarily combined and incorporated with each other. The definitions of groups and the structures of the compounds in such combinations and incorporations should be construed as being within the scope of the present specification and/or the claims.
Unless otherwise stated, a numerical range set forth in the description and claims shall be construed as at least including each specific integer value within the range. For example, the numerical range “1-20” shall be construed as at least including each integer value in the numerical range “1-10”, i.e., 1, 2, 3, 4, 5, 6, 7, 8, 9, and 10, and each integer value in the numerical range “11-20”, i.e., 11, 12, 13, 14, 15, 16, 17, 18, 19 and 20.
The term “halogen” refers to fluorine, chlorine, bromine, and iodine.
The term “C1-20 alkyl” should be understood to represent a linear or branched saturated monovalent hydrocarbyl group having 1-20 carbon atoms. For example, “C1-10 alkyl” represents linear and branched chain alkyl groups having 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10 carbon atoms, “C1-8 alkyl” represents linear and branched chain alkyl groups having 1, 2, 3, 4, 5, 6, 7, or 8 carbon atoms, and “C1-6 alkyl” represents linear and branched chain alkyl groups having 1, 2, 3, 4, 5, or 6 carbon atoms. The alkyl is, for example, methyl, ethyl, propyl, butyl, pentyl, hexyl, isopropyl, isobutyl, sec-butyl, tert-butyl, isopentyl, 2-methylbutyl, 1-methylbutyl, 1-ethylpropyl, 1,2-dimethylpropyl, neopentyl, 1,1-dimethylpropyl, 4-methylpentyl, 3-methylpentyl, 2-methylpentyl, 1-methylpentyl, 2-ethylbutyl, 1-ethylbutyl, 3,3-dimethylbutyl, 2,2-dimethylbutyl, 1,1-dimethylbutyl, 2,3-dimethylbutyl, 1,3-dimethylbutyl, 1,2-dimethylbutyl, etc., or isomers thereof.
The term “C2-20 alkenyl” should be understood to represent a linear or branched monovalent hydrocarbyl group containing one or more double bonds and having 2-20 carbon atoms, preferably “C2-10 alkenyl”. “C2-10 alkenyl” should be understood to preferably represent a linear or branched monovalent hydrocarbyl group containing one or more double bonds and having 2, 3, 4, 5, 6, 7, 8, 9, or 10 carbon atoms, more preferably “C2-8 alkenyl”. “C2-10 alkenyl” should be understood to preferably represent a linear or branched monovalent hydrocarbyl group containing one or more double bonds and having 2, 3, 4, 5, 6, 7, or 8 carbon atoms, for example, having 2, 3, 4, 5, or 6 carbon atoms (i.e., C2-6 alkenyl) or having 2 or 3 carbon atoms (i.e., C2-3 alkenyl). It should be understood that in the case that the alkenyl comprises more than one double bond, the double bonds can be separated from one another or conjugated. The alkenyl is, for example, vinyl, allyl, (E)-2-methylvinyl, (Z)-2-methylvinyl, (E)-but-2-enyl, (Z)-but-2-enyl, (E)-but-1-enyl, (Z)-but-1-enyl, pent-4-enyl, (E)-pent-3-enyl, (Z)-pent-3-enyl, (E)-pent-2-enyl, (Z)-pent-2-enyl, (E)-pent-1-enyl, (Z)-pent-1-enyl, hex-5-enyl, (E)-hex-4-enyl, (Z)-hex-4-enyl, (E)-hex-3-enyl, (Z)-hex-3-enyl, (E)-hex-2-enyl, (Z)-hex-2-enyl, (E)-hex-1-enyl, (Z)-hex-1-enyl, isopropenyl, 2-methylprop-2-enyl, 1-methylprop-2-enyl, 2-methylprop-1-enyl, (E)-1-methylprop-1-enyl, (Z)-1-methylprop-1-enyl, 3-methylbut-3-enyl, 2-methylbut-3-enyl, 1-methylbut-3-enyl, 3-methylbut-2-enyl, (E)-2-methylbut-2-enyl, (Z)-2-methylbut-2-enyl, (E)-1-methylbut-2-enyl, (Z)-1-methylbut-2-enyl, (E)-3-methylbut-1-enyl, (Z)-3-methylbut-1-enyl, (E)-2-methylbut-1-enyl, (Z)-2-methylbut-1-enyl, (E)-1-methylbut-1-enyl, (Z)-1-methylbut-1-enyl, 1,1-dimethylprop-2-enyl, 1-ethylprop-1-enyl, 1-propylvinyl or 1-isopropylvinyl.
The term “C2-20 alkynyl” should be understood to represent a linear or branched monovalent hydrocarbyl group containing one or more triple bonds and having 2-20 carbon atoms, preferably “C2-10 alkynyl”. The term “C2-10 alkynyl” should be understood to preferably represent a linear or branched monovalent hydrocarbyl group containing one or more triple bonds and having 2, 3, 4, 5, 6, 7, 8, 9, or 10 carbon atoms, for example, having 2, 3, 4, 5, 6, 7, or 8 carbon atoms (i.e., “C2-8 alkynyl”), having 2, 3, 4, 5, or 6 carbon atoms (i.e., “C2-6 alkynyl”), or having 2 or 3 carbon atoms (“C2-3 alkynyl”). The alkynyl is, for example, ethynyl, prop-1-ynyl, prop-2-ynyl, but-1-ynyl, but-2-ynyl, but-3-ynyl, pent-1-ynyl, pent-2-ynyl, pent-3-ynyl, pent-4-ynyl, hex-1-ynyl, hex-2-ynyl, hex-3-ynyl, hex-4-ynyl, hex-5-ynyl, 1-methylprop-2-ynyl, 2-methylbut-3-ynyl, 1-methylbut-3-ynyl, 1-methylbut-2-ynyl, 3-methylbut-1-ynyl, 1-ethylprop-2-ynyl, 3-methylpent-4-ynyl, 2-methylpent-4-ynyl, 1-methylpent-4-ynyl, 2-methylpent-3-ynyl, 1-methylpent-3-ynyl, 4-methylpent-2-ynyl, 1-methylpent-2-ynyl, 4-methylpent-1-ynyl, 3-methylpent-1-ynyl, 2-ethylbut-3-ynyl, 1-ethylbut-3-ynyl, 1-ethylbut-2-ynyl, 1-propylprop-2-ynyl, 1-isopropylprop-2-ynyl, 2,2-dimethylbut-3-ynyl, 1,1-dimethylbut-3-ynyl, 1,1-dimethylbut-2-ynyl or 3,3-dimethylbut-1-ynyl. In particular, the alkynyl is ethynyl, prop-1-ynyl or prop-2-ynyl.
The term “C3-10 cycloalkyl” should be understood to represent a saturated monovalent monocyclic or bicyclic (such as bridged or spiro) hydrocarbon ring or tricyclic alkane having 3, 4, 5, 6, 7, 8, 9 or 10 carbon atoms. The C3-10 cycloalkyl may be monocyclic hydrocarbyl such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, cyclononyl or cyclodecyl, or bicyclic hydrocarbyl such as bornyl, indolyl, hexahydroindolyl, tetrahydronaphthyl, decahydronaphthyl, bicyclo[2.1.1]hexyl, bicyclo[2.2.1]heptyl, bicyclo[2.2.1]heptenyl, 6,6-dimethylbicyclo[3.1.1]heptyl, 2,6,6-trimethylbicyclo[3.1.1]heptyl, bicyclo[2.2.2]octyl, 2,7-diazaspiro[3,5]nonyl, 2,6-diazaspiro[3,4]octyl, or tricyclic hydrocarbyl such as adamantyl.
The term “3- to 10-membered heterocyclyl” refers to a saturated or unsaturated non-aromatic ring or ring system and contains at least one heteroatom selected from O, S and N. The heterocyclyl may be connected to the rest of the molecule through any one of the carbon atoms or the nitrogen atom (if present). The heterocyclyl may include fused or bridged rings as well as spiro rings. In particular, the heterocyclyl may include, but is not limited to: 4-membered rings such as azetidinyl and oxetanyl; 5-membered rings such as tetrahydrofuranyl, dioxolyl, pyrrolidinyl, imidazolidinyl, pyrazolidinyl and pyrrolinyl; 6-membered rings such as tetrahydropyranyl, piperidyl, morpholinyl, dithianyl, thiomorpholinyl, piperazinyl and trithianyl; or 7-membered rings such as diazepanyl. Optionally, the heterocyclyl may be benzo-fused. The heterocyclyl may be bicyclic, for example, but not limited to, a 5,5-membered ring such as a hexahydrocyclopenta[c]pyrrol-2(1H)-yl ring, or a 5,6-membered bicyclic ring such as a hexahydropyrrolo[1,2-a]pyrazin-2(1H)-yl ring. The heterocyclyl may be partially unsaturated, i.e., it may contain one or more double bonds, for example, but not limited to, dihydrofuranyl, dihydropyranyl, 2,5-dihydro-1H-pyrrolyl, 4H-[1,3,4]thiadiazinyl, 1,2,3,5-tetrahydrooxazyl, or 4H-[1,4]thiazinyl, or it may be benzo-fused, for example, but not limited to, dihydroisoquinolyl. When the 3- to 10-membered heterocyclyl is connected to another group to form the compound of the present disclosure, the group may be connected to the carbon atom on the 3- to 10-membered heterocyclyl, or may be connected to the heteroatom on the 3- to 10-membered heterocyclyl. For example, when the 3- to 10-membered heterocyclyl is selected from piperazinyl, the group may be connected to the nitrogen atom on the piperazinyl. Alternatively, when the 3- to 10-membered heterocyclyl is selected from piperidyl, the group may be connected to the nitrogen atom on the piperidyl ring or the carbon atom in the para position.
The term “C6-14 aryl” should be understood to preferably represent an aromatic or partially aromatic monovalent monocyclic, bicyclic or tricyclic hydrocarbon ring having 6, 7, 8, 9, 10, 11, 12, 13 or 14 carbon atoms (“C6-14 aryl”), in particular a ring having 6 carbon atoms (“C6 aryl”), e.g., phenyl; biphenyl; a ring having 9 carbon atoms (“C9 aryl”), e.g., indanyl or indenyl; a ring having 10 carbon atoms (“C10 aryl”), e.g., tetrahydronaphthyl, dihydronaphthyl, or naphthyl; a ring having 13 carbon atoms (“C13 aryl”), e.g., fluorenyl; or a ring having 14 carbon atoms (“C14 aryl”), e.g., anthryl. When the C6-14 aryl is substituted, it may be monosubstituted or polysubstituted. In addition, the substitution site is not limited, and may be, for example, ortho-substitution, para-substitution, or meta-substitution.
The term “5- to 14-membered heteroaryl” should be understood to represent a monovalent monocyclic, bicyclic (e.g., fused, bridged or spiro) or tricyclic aromatic ring system that has 5-14 ring atoms and contains one or more (e.g., 1-5) heteroatoms independently selected from N, O, and S, e.g., “5- to 14-membered heteroaryl”. The term “5- to 14-membered heteroaryl” should be understood to represent a monovalent monocyclic, bicyclic or tricyclic aromatic ring system that has 5, 6, 7, 8, 9, 10, 11, 12, 13 or 14 ring atoms, in particular 5, 6, 9 or 10 carbon atoms, contains 1-5, preferably 1-3 heteroatoms independently selected from N, O and S, and may be benzo-fused in each case. “Heteroaryl” also refers to a group in which a heteroaromatic ring is fused to one or more aryl, alicyclic or heterocyclyl rings, wherein the radical or site of attachment is on the heteroaromatic ring. When the 5- to 14-membered heteroaryl is connected to another group to form the compound of the present disclosure, the group may be connected to the carbon atom on the 5- to 14-membered heteroaryl ring, or may be connected to the heteroatom on the 5- to 14-membered heteroaryl ring. When the 5- to 14-membered heteroaryl is substituted, it may be monosubstituted or polysubstituted. In addition, the substitution site is not limited. For example, hydrogen connected to the carbon atom on the heteroaryl ring may be substituted, or hydrogen connected to the heteroatom on the heteroaryl ring may be substituted.
The term “spiro rings” refers to a ring system in which two rings share 1 ring-forming atom.
The term “fused rings” refers to a ring system in which two rings share 2 ring-forming atoms.
The term “bridged rings” refers to a ring system in which two rings share 3 or more ring-forming atoms.
The term “oxo” means that the carbon atom, nitrogen atom or sulfur atom in the substituent is substituted with an oxy group formed after oxidation (═O).
In order to make the objects and technical solutions of the present disclosure clearer, the present disclosure is further illustrated below with reference to specific examples. It should be understood that these examples are merely intended to illustrate the present disclosure rather than limit the scope of the present disclosure. Moreover, specific experimental methods not mentioned in the following examples are performed according to the conventional experimental methods.
The abbreviations herein have the following meanings:
2-amino-5-chloro-2′-fluorobenzophenone (compound 1a, 11.48 g, 0.046 mol) and the compound N-tert-butoxycarbonyl-L-glutamic acid--methyl ester (compound 1b, 10 g, 0.038 mol) were dissolved in DCM (300 mL). The mixture was cooled to 0° C., and DCC (9.49 g, 0.046 mmol) was added. The mixture was stirred for 24 h. After the reaction was completed as detected by LCMS, the reaction solution was filtered in vacuum. The filtrate was collected and concentrated under reduced pressure to evaporate the solvent. The residue was purified by column chromatography (petroleum ether/ethyl acetate, 4:1, v/v) to give methyl (S)-5-((2-fluoro-benzoyl-4-chlorophenyl)amino)-4-((tert-butoxycarbonyl)amino)-5-oxopentanoate as a white solid (compound ac, 10.56 g, yield: 56.4%).
Methyl (S)-5-((2-fluoro-benzoyl-4-chlorophenyl)amino)-4-((tert-butoxycarbonyl)amino)-5-oxopentanoate (compound 1c, 10.56 g) was dissolved in DCM (50 mL). TFA(50 mL) was added, and the mixture was stirred for 20 m until LCMS showed that the reaction was completed. The reaction solution was concentrated to give a residue, crude methyl (S)-4-amino-5-((2-fluorobenzoyl-4-chlorophenyl)amino)-5-oxopentanoate (compound 1d, 8.4 g), which was used directly in the next step.
Methyl (S)-4-amino-5-((2-fluorobenzoyl-4-chlorophenyl)amino)-5-oxopentanoate (compound 1d, 8.4 g) was dissolved in MeOH (100 mL) and adjusted to about pH 10 by the addition of NaHCO3. The mixture was stirred for 24 h. After the reaction was completed as detected by LCMS, the reaction solution was filtered. The filtrate was poured into ice water and extracted with ethyl acetate. The organic phase was washed 3 times with water, dried, and concentrated, and the residue was purified by column chromatography (petroleum ether/ethyl acetate, 2:1, v/v) to obtain white methyl (S)-3-(7-chloro-2-oxo-5-(2-fluorophenyl)-2,3-dihydro-1H-benzo[e][1,4]diazepin-3-yl)propionate (compound 1e, 7.5 g).
Methyl (S)-3-(7-chloro-2-oxo-5-(2-fluorophenyl)-2,3-dihydro-1H-benzo[e][1,4]diazepin-3-yl)propionate (compound 1e, 7.5 g) was dissolved in toluene (200 mL), and Lawesson reagent (4.86 g, 0.012 mol) was added. The compound was heated to 100° C. and stirred for 1.5 h until LCMS showed that the reaction was completed. A saturated sodium bicarbonate solution was added to remove excessive Lawesson reagent, and the mixture was extracted with ethyl acetate (20 mL×3). The organic layers were combined, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to evaporate the reaction solvent. The residue was purified by column chromatography (petroleum ether/ethyl acetate, 7:1, v/v) to obtain methyl (S)-3-(7-chloro-5-(2-fluorophenyl)-2-thio-2-3,3-dihydro-1H-benzo[e][1,4]diazepin-3-yl)propionate as alight yellow solid (compound 1f, 4.07 g, yield: 52.1%).
Methyl (S)-3-(7-chloro-5-(2-fluorophenyl)-2-thio-2-3,3-dihydro-1H-benzo[e][1,4]diazepin-3-yl)propionate (compound 1f, 4.07 g) was dissolved in 50 mL of THF, and the mixture was cooled to 0° C. 80% hydrazine hydrate (1.56 g, 0.031 mol) was added, and the mixture was stirred for 30 min until LCMS showed that the reaction was completed. Saturated NaCl was added to remove excess hydrazine hydrate, the mixture was extracted with DCM. The organic phases were combined, dried, and concentrated to obtain crude methyl (S)-3-(7-chloro-5-(2-fluorophenyl)-2-hydrazino-2,3-dihydro-1H-benzo[e][1,4]diazepin-3-yl)propionate (compound 1g, 3.1 g), which was used directly in the next step.
Methyl (S)-3-(7-chloro-5-(2-fluorophenyl)-2-hydrazino-2,3-dihydro-1H-benzo[e][1,4]diazepin-3-yl)propionate (compound 1g, 3.1 g) was dissolved in 80 mL of THF, followed by the addition of TEA (1.77 g, 0.018 mol), and the mixture was cooled to 0° C. Thiophosgene (1.0 g, 0.009 mol) was added, and the mixture was stirred for 2 h until LCMS showed that the reaction was completed. The reaction solution was filtered in vacuum. The filtrate was collected and concentrated under reduced pressure to evaporate the reaction solvent. The residue was purified by column chromatography (petroleum ether/ethyl acetate, 4:1, v/v) to give methyl (S)-3-(8-bromo-6-(pyridin-2-yl)-1-thio-2-2,4-dihydro-1H-benzo[f][1,2,4]triazolo[4,3-a][1,4]diazepin-4-yl)propionate as a white solid (Tautomer of Compound 1, 1.46 g, yield: 42.5%).
1H NMR (300 MHz, DMSO-d6) δ: 14.17 (s, 1H), 8.46 (d, J=8.7 Hz, 1H), 7.90-7.28 (m, 6H), 4.26 (t, J=6.1 Hz, 1H), 3.62 (s, 3H), 2.70-2.45 (m, 4H); 13C NMR (75 MHz, DMSO-d6) δ: 173.58, 166.94, 164.32, 161.78, 158.47, 153.86, 133.56, 132.55, 132.23, 131.91, 131.18, 129.03, 127.87, 127.02, 125.27, 116.78, 55.15, 51.85, 30.19, 26.26; LC-MS (ESI) m/z: 430.5 [M+H]+.
Examples 2-7 were synthesized according to the methods as described in the above example, with the specific NMR, MS, and C NMR characterization data shown as follows:
1H NMR (300 MHz, DMSO-d6) δ: 14.15 (s, 1H), 8.46 (d, J=8.8 Hz, 1H), 7.87 (d, J=7.4 Hz, 1H), 7.66-7.50 (m, 4H), 7.16 (s, 1H), 4.34 (t, J=5.8 Hz, 1H), 3.62 (s, 3H), 2.70-2.45 (m, 4H); 13C NMR (75 MHz, DMSO-d6) δ: 173.54, 167.16, 167.00, 153.68, 138.23, 132.42, 132.28, 132.12, 131.94, 131.73, 131.64, 131.07, 130.21, 128.52, 127.99, 127.96, 55.30, 51.85, 30.22, 26.16; LC-MS (ESI) m/z: 447.2 [M+H]+.
1H NMR (300 MHz, DMSO-d6) δ: 14.17 (s, 1H), 8.59 (d, J=4.3 Hz, 1H), 8.37 (d, J=8.8 Hz, 1H), 8.13 (d, J=7.9 Hz, 1H), 8.03-7.98 (m, 2H), 7.60-7.54 (m, 2H), 4.34 (t, J=5.8 Hz, 1H), 3.65 (s, 3H), 2.70-2.45 (m, 4H); 13C NMR (75 MHz, CDCl3-d1) δ: 173.70, 167.81, 166.51, 157.68, 155.34, 149.03, 136.91, 134.69, 134.01, 132.24, 130.18, 126.91, 125.28, 124.90, 123.99, 55.09, 51.71, 30.17, 26.18; LC-MS (ESI) m/z: 457.8 [M+H]+.
1H NMR (300 MHz, DMSO-d6) δ: 11.14 (s, 1H), 8.38 (d, J=9.1 Hz, 1H), 7.97 (d, J=8.9 Hz, 1H), 7.66-7.54 (m, 2H), 7.43 (s, 1H), 7.36 (t, J=7.5 Hz, 1H), 7.24 (t, J=9.8 Hz, 1H), 4.27 (t, J=6.7 Hz, 1H), 3.60 (s, 3H), 2.70-2.45 (m, 4H); 13C NMR (75 MHz, DMSO-d6) δ: 173.60, 166.91, 164.26, 161.78, 158.48, 153.87, 134.09, 133.46, 132.45, 131.93, 131.60, 128.02, 127.05, 125.28, 120.85, 116.80, 55.14, 51.87, 30.20, 26.27; LC-MS (ESI) m/z: 475.1 [M+H]+.
1H NMR (400 MHz, DMSO-d6) δ: 14.06 (s, 1H), 8.43 (d, J=8.0 Hz, 1H), 7.80 (t, J=7.3 Hz, 1H), 7.60-7.40 (m, 7H), 4.17 (t, J=5.7 Hz, 1H), 3.62 (s, 3H), 2.70-2.40 (m, 4H); 13C NMR (75 MHz, CDCl3-d1) δ: 173.89, 169.62, 167.15, 154.17, 138.77, 133.17, 131.38, 131.10, 131.00, 129.80 (2C), 129.57, 128.35 (2C), 127.88, 125.67, 54.78, 51.87, 30.25, 26.21; LC-MS (ESI) m/z: 379.5[M+H]+.
1H NMR (400 MHz, DMSO-d6) δ: 14.06 (s, 1H), 8.43 (d, J=8.3 Hz, 1H), 7.81 (t, J=8.8 Hz, 1H), 7.60-7.55 (m, 3H), 7.43 (d, J=9.0 Hz, 1H), 7.28 (t, J=7.7 Hz, 2H), 4.17 (t, J=7.6 Hz, 1H), 3.62 (s, 3H), 2.70-2.40 (m, 4H); 13C NMR (75 MHz, CDCl3-d1) δ: 173.84, 168.39, 167.18, 166.24, 162.90, 154.14, 134.90, 133.16, 131.98, 131.18, 129.31, 127.98, 125.80, 115.58, 115.29, 54.77, 51.88, 30.22, 26.17; LC-MS (ESI) m/z: 397.3 [M+H]+.
1H NMR (300 MHz, CDCl3-d1) δ: 11.34 (s, 1H), 8.57 (d, J=8.8 Hz, 1H), 7.71-7.41 (m, 7H), 4.17 (t, J=5.8 Hz, 1H), 3.73 (s, 3H), 2.81-2.60 (m, 4H); 13C NMR (75 MHz, DMSO-d6) δ: 173.62, 167.25, 166.82, 154.07, 138.40, 132.31, 132.24, 131.44, 131.20, 130.96, 130.45, 129.54, 128.91, 127.86, 55.36, 51.84, 30.23, 26.34; LC-MS (ESI) m/z: 412.7 [M+H]+.
Methyl (S)-3-(8-chloro-6-(2-fluorophenyl)-1-mercapto-4H-benzo[ ][1,2,4]triazolo[4,3-a][1,4]diazepin-4-yl)propionate (Compound 1, 0.1 g) was dissolved in 8 mL of THF, and the mixture was cooled in an ice bath. A solution of 20% sodium isopropoxide in tetrahydrofuran was added dropwise, and the mixture was stirred at room temperature for 30 min after the dropwise addition was completed. The reaction solution was concentrated by rotary evaporation to remove the solvent to obtain a corresponding sodium salt. Iodomethane (0.049 g, 0.35 mmol) was added, and the mixture was heated and refluxed at 68° C. for 8 h. The reaction solution was concentrated under reduced pressure, and the residue was purified by column chromatography (PE:EA=1:1) to obtain methyl (S)-3-(8-chloro-6-(2-fluorophenyl)-1-(methylthio)-4H-benzo[f][1,2,4]triazolo[4,3-a][1,4]diazepin-4-yl)propionate as a white solid (compound 8, 0.075 g, yield: 72.8%).
1H NMR (300 MHz, CDCl3-d1) δ: 7.78-7.61 (m, 3H), 7.48 (q, J=6.1 Hz, 1H), 7.34-7.24 (m, 2H), 7.05 (t, J=9.6 Hz, 1H), 4.23 (t, J=5.7 Hz, 1H), 3.68 (s, 3H), 2.90-2.72 (m, 7H); 13C NMR (75 MHz, CDCl3-d1) δ 173.88, 163.67, 161.96, 158.65, 157.58, 151.07, 133.73, 132.71, 132.60, 131.62, 131.27, 130.35, 129.78, 127.05, 124.63, 116.46, 55.06, 51.63, 30.18, 26.55, 15.28; LC-MS (ESI) m/z: 445.3 [M+H]+. Examples 9-144 (compounds 9-144) were synthesized according to the methods as described in the above example, with the specific NMR, MS, and C NMR characterization data shown as follows:
1H NMR (300 MHz, CDCl3-d1) δ 7.67 (dd, J=7.3, 2.2 Hz, 1H), 7.59 (d, J=2.0 Hz, 1H), 7.55-7.31 (m, 5H), 7.22 (dd, J=7.2, 2.2 Hz, 1H), 5.22 (s, 1H), 3.68 (s, 3H), 2.53 (d, J=28.9 Hz, 4H), 2.45-2.26 (m, 2H), 2.25 (d, J=12.4 Hz, 1H); 13C NMR (75 MHz, CDCl3-d1) δ 173.78, 160.03, 150.29, 147.02, 140.17, 138.02, 131.75, 129.62, 129.44, 129.40, 125.51, 125.40, 122.44, 118.85, 117.15, 115.82, 54.38, 51.46, 32.25, 27.63, 14.05; LC-MS (ESI) m/z: 490.3 [M+H]+.
1H NMR (300 MHz, CDCl3-d1) δ 8.30 (dd, J=7.5, 2.0 Hz, 1H), 8.15 (d, J=2.0 Hz, 1H), 7.75 (d, J=7.5 Hz, 1H), 7.64 (dd, J=7.2, 2.3 Hz, 1H), 7.50-7.31 (m, 2H), 7.27 (dd, J=7.2, 2.4 Hz, 1H), 5.15 (s, 1H), 3.68 (s, 3H), 2.56 (s, 3H), 2.53 (d, J=12.4 Hz, 1H), 2.40 (d, J=12.4 Hz, 1H), 2.24 (d, J=1.5 Hz, 2H); 13C NMR (75 MHz, CDCl3-d1) δ 173.68, 160.03, 150.29, 148.47, 146.96, 143.52, 141.28, 129.83, 129.75, 128.39, 124.87, 124.15, 123.29, 122.44, 120.52, 115.88, 57.87, 51.40, 32.25, 27.60, 14.05; LC-MS (ESI) m/z: 456.4 [M+H]+.
1H NMR (300 MHz, CDCl3-d1) δ: 7.78-7.61 (m, 5H), 7.48 (q, J=5.4 Hz, 1H), 7.34-7.24 (m, 2H), 7.05 (t, J=9.4 Hz, 1H), 4.23 (t, J=5.7 Hz, 1H), 3.68 (s, 3H), 3.25 (q, J=7.2 Hz, 2H), 2.90-2.72 (m, 4H), 1.39 (t, J=7.2 Hz, 3H); 13C NMR (75 MHz, CDCl3-d1) δ: 173.88, 163.70, 162.02, 158.68, 157.41, 150.20, 133.69, 132.71, 131.51, 131.26, 130.40, 129.65, 127.06, 125.08, 124.56, 116.45, 55.10, 51.63, 30.20, 27.81, 26.54, 14.66; LC-MS (ESI) m/z: 458.9 [M+H]+.
1H NMR (300 MHz, CDCl3-d1) δ 7.67 (dd, J=7.1, 2.4 Hz, 1H), 7.59 (d, J=2.0 Hz, 1H), 7.55-7.29 (m, 4H), 7.22 (dd, J=7.0, 2.5 Hz, 1H), 5.22 (s, 1H), 3.68 (s, 3H), 3.18 (s, 2H), 2.50 (d, J=12.4 Hz, 1H), 2.39 (d, J=12.4 Hz, 1H), 2.37-2.19 (m, 2H), 1.39 (s, 3H); 13C NMR (75 MHz, CDCl3-d1) δ 173.78, 160.03, 147.02, 144.40, 140.17, 138.02, 131.75, 129.69, 129.44, 129.40, 127.05, 124.20, 122.44, 119.90, 116.44, 115.82, 54.38, 51.46, 32.25, 28.40, 27.60, 14.23; LC-MS (ESI) m/z: 504.4 [M+H]+.
1H NMR (300 MHz, CDCl3-d1) δ 8.30 (dd, J=7.5, 2.0 Hz, 1H), 8.17 (d, J=2.0 Hz, 1H), 7.75 (d, J=7.5 Hz, 1H), 7.66-7.56 (m, 1H), 7.47-7.31 (m, 2H), 7.32-7.22 (m, 1H), 5.15 (s, 1H), 3.68 (s, 3H), 3.18 (s, 2H), 2.53 (d, J=12.4 Hz, 1H), 2.45-2.33 (m, 2H), 2.23 (d, J=12.4 Hz, 1H), 1.40 (s, 3H); 13C NMR (75 MHz, CDCl3-d1) δ 173.90, 160.03, 148.47, 146.96, 144.00, 143.52, 141.28, 129.50, 129.44, 128.71, 124.87, 124.15, 122.86, 122.44, 120.52, 115.88, 54.38, 51.43, 32.25, 28.40, 27.60, 14.23; LC-MS (ESI) m/z: 470.5 [M+H]+.
1H NMR (300 MHz, CDCl3-d1) δ: 7.78-7.61 (m, 3H), 7.48 (q, J=8.3 Hz, 1H), 7.34-7.24 (m, 2H), 7.05 (t, J=9.0 Hz, 1H), 4.23 (t, J=6.2 Hz, 1H), 3.68 (s, 3H), 3.22 (t, J=7.0 Hz, 2H), 2.90-2.72 (m, 4H), 1.77 (q, J=7.1 Hz, 2H), 1.01 (t, J=7.2 Hz, 3H); 13C NMR (75 MHz, CDCl3-d1) δ: 173.89, 163.69, 162.02, 158.68, 157.40, 150.42, 133.67, 132.70, 131.50, 131.27, 130.42, 129.65, 127.06, 125.11, 124.57, 116.45, 55.11, 51.63, 35.33, 30.21, 26.54, 22.68, 13.17; LC-MS (ESI) m/z: 473.1 [M+H]+.
1H NMR (300 MHz, CDCl3-d1) δ 7.67 (dd, J=7.0, 2.4 Hz, 1H), 7.62-7.29 (m, 6H), 7.21 (dd, J=6.9, 2.5 Hz, 1H), 5.17 (s, 1H), 3.68 (s, 3H), 3.24 (s, 2H), 2.50 (d, J=12.4 Hz, 1H), 2.452.19 (m, 3H), 1.80 (d, J=0.4 Hz, 3H), 1.01 (s, 3H); 13C NMR (75 MHz, CDCl3-d1) δ 173.78, 160.03, 147.02, 145.70, 140.80, 138.02, 131.75, 129.84, 129.69, 129.44, 127.05, 124.20, 122.44, 121.80, 116.44, 115.82, 54.38, 51.45, 32.86, 32.25, 27.67, 27.60, 14.10; LC-MS (ESI) m/z: 518.4 [M+H]+.
1H NMR (300 MHz, CDCl3-d1) δ 8.28 (dd, J=7.5, 2.0 Hz, 1H), 8.17 (d, J=1.9 Hz, 1H), 7.75 (d, J=7.5 Hz, 1H), 7.64 (dd, J=5.7, 3.8 Hz, 1H), 7.40 (dd, J=5.6, 3.9 Hz, 2H), 7.28 (dd, J=5.6, 3.9 Hz, 1H), 5.15 (s, 1H), 3.68 (s, 3H), 3.28 (s, 2H), 2.53 (d, J=12.4 Hz, 1H), 2.40 (d, J=12.4 Hz, 1H), 2.24 (d, J=1.5 Hz, 2H), 1.79 (s, 2H), 1.03 (s, 3H); 13C NMR (75 MHz, CDCl3-d1) δ 173.90, 160.03, 148.47, 145.70, 144.82, 143.03, 142.03, 129.44, 128.90, 128.71, 124.87, 124.15, 122.86, 122.44, 120.52, 115.82, 54.33, 51.46, 33.02, 32.86, 27.67, 27.60, 14.09; LC-MS (ESI) m/z: 484.5 [M+H]+.
1H NMR (300 MHz, CDCl3-d1) δ: 7.78-7.61 (m, 3H), 7.48 (q, J=7.3 Hz, 1H), 7.34-7.24 (m, 2H), 7.05 (t, J=10.0 Hz, 1H), 4.25-4.13 (m, 2H), 3.99 (q, J=5.6 Hz, 2H), 3.68 (s, 3H), 3.49-3.35 (m, 2H), 2.90-2.72 (m, 4H); 13C NMR (75 MHz, CDCl3-d1) δ: 173.81, 163.79, 162.01, 158.67, 157.51, 150.84, 133.95, 132.78, 131.69, 131.27, 130.17, 129.77, 126.92, 125.06, 124.58, 116.50, 61.90, 54.99, 51.66, 36.08, 30.13, 26.46; LC-MS (ESI) m/z: 475.1 [M+H]+.
1H NMR (300 MHz, CDCl3-d1) δ 7.67 (dd, J=7.0, 2.4 Hz, 1H), 7.62-7.46 (m, 2H), 7.47-7.29 (m, 2H), 7.21 (dd, J=6.9, 2.5 Hz, 1H), 7.11 (d, J=7.5 Hz, 1H), 5.15 (s, 1H), 4.58 (t, J=5.5 Hz, 1H), 3.71-3.49 (m, 6H), 3.43 (d, J=12.4 Hz, 1H), 2.50 (d, J=12.4 Hz, 1H), 2.39 (d, J=12.4 Hz, 1H), 2.24 (d, J=1.6 Hz, 2H); 13C NMR (75 MHz, CDCl3-d1) δ 173.78, 160.03, 147.02, 145.12, 140.80, 138.02, 131.75, 129.84, 129.65, 129.44, 127.05, 124.20, 122.44, 121.80, 116.44, 115.82, 61.40, 54.38, 51.45, 34.93, 32.03, 27.60; LC-MS (ESI) m/z: 520.4 [M+H]+.
1H NMR (300 MHz, CDCl3-d1) δ 8.28 (dd, J=7.5, 2.0 Hz, 1H), 8.17 (d, J=2.0 Hz, 1H), 7.75 (d, J=7.5 Hz, 1H), 7.64 (dd, J=5.7, 3.8 Hz, 1H), 7.40 (dd, J=5.6, 3.9 Hz, 2H), 7.41-7.23 (m, 1H), 5.15 (s, 1H), 4.27 (t, J=5.5 Hz, 1H), 3.71-3.54 (m, 6H), 3.51 (d, J=12.4 Hz, 1H), 2.53 (d, J=12.4 Hz, 1H), 2.40 (d, J=12.4 Hz, 1H), 2.24 (d, J=1.6 Hz, 2H); 13C NMR (75 MHz, CDCl3-d1) δ 173.90, 160.03, 148.47, 145.70, 144.82, 143.03, 142.03, 129.44, 128.90, 128.71, 124.87, 124.15, 122.86, 122.44, 121.02, 115.82, 61.63, 54.33, 51.46, 35.01, 33.02, 27.60; LC-MS (ESI) m/z: 486.5 [M+H]+.
1H NMR (300 MHz, CDCl3-d1) δ: 7.78-7.61 (m, 3H), 7.48 (q, J=5.4 Hz, 1H), 7.34-7.24 (m, 2H), 7.05 (t, J=9.0 Hz, 1H), 4.38-4.21 (m, 3H), 3.68 (s, 3H), 3.46-3.22 (m, 4H), 2.90-2.72 (m, 4H); 13C NMR (75 MHz, CDCl3-d1) δ: 173.84, 163.79, 162.00, 158.65, 157.61, 150.05, 133.93, 132.74, 131.74, 131.24, 130.09, 129.69, 126.95, 125.11, 124.56, 116.48, 54.98, 51.65, 40.72, 31.58, 30.15, 26.45; LC-MS (ESI) m/z: 474.0 [M+H]+.
1H NMR (300 MHz, CDCl3-d1) δ 7.67 (dd, J=7.0, 2.5 Hz, 1H), 7.62-7.46 (m, 2H), 7.47-7.29 (m, 2H), 7.21 (dd, J=6.9, 2.5 Hz, 1H), 7.04 (d, J=7.5 Hz, 1H), 5.15 (s, 1H), 4.49 (d, J=0.7 Hz, 1H), 4.37 (d, J=0.7 Hz, 1H), 3.71-3.51 (m, 5H), 2.95 (s, 2H), 2.50 (d, J=12.4 Hz, 1H), 2.39 (d, J=12.4 Hz, 1H), 2.24 (d, J=1.5 Hz, 2H); 13C NMR (75 MHz, CDCl3-d1) δ 173.78, 160.03, 147.02, 145.12, 140.80, 138.02, 131.75, 129.84, 129.69, 129.44, 127.05, 124.20, 122.44, 121.80, 116.44, 115.82, 54.38, 51.45, 39.99, 34.13, 32.03, 27.60; LC-MS (ESI) m/z: 519.4 [M+H]+.
1H NMR (300 MHz, CDCl3-d1) δ 8.29 (dd, J=7.5, 2.0 Hz, 1H), 8.17 (d, J=2.0 Hz, 1H), 7.75 (d, J=7.5 Hz, 1H), 7.64 (dd, J=5.7, 3.8 Hz, 1H), 7.40 (dd, J=5.6, 3.9 Hz, 2H), 7.41-7.23 (m, 1H), 5.15 (s, 1H), 4.49 (d, J=0.7 Hz, 1H), 4.37 (d, J=0.7 Hz, 1H), 3.65 (d, J=17.9 Hz, 5H), 3.00-2.82 (m, 2H), 2.53 (d, J=12.4 Hz, 1H), 2.40 (d, J=12.4 Hz, 1H), 2.24 (d, J=1.6 Hz, 2H); 13C NMR (75 MHz, CDCl3-d1) δ 173.90, 160.03, 148.47, 145.70, 144.82, 143.03, 142.03, 129.44, 128.90, 128.71, 124.87, 124.15, 122.86, 122.44, 120.52, 115.82, 54.33, 51.46, 39.99, 34.37, 33.02, 27.60; LC-MS (ESI) m/z: 485.5 [M+H]+.
1H NMR (300 MHz, CDCl3-d1) δ: 7.74 (d, J=8.6 Hz, 1H), 7.64-7.54 (m, 2H), 7.43-7.33 (m, 3H), 7.19 (s, 1H), 4.28 (t, J=6.4 Hz, 1H), 3.68 (s, 3H), 2.90-2.76 (m, 7H); 13C NMR (75 MHz, CDCl3-d1) δ: 173.83, 166.45, 157.49, 151.12, 138.02, 133.68, 132.84, 131.57, 131.35, 131.30, 131.00, 130.94, 130.25, 129.49, 127.19, 124.62, 55.10, 51.63, 30.18, 26.50, 15.25; LC-MS (ESI) m/z: 461.1 [M+H]+.
1H NMR (300 MHz, CDCl3-d1) δ 7.66 (dd, J=7.4, 1.9 Hz, 1H), 7.62-7.44 (m, 3H), 7.51-7.27 (m, 3H), 7.34-7.24 (m, 1H), 5.32 (s, 1H), 3.68 (s, 3H), 2.53 (d, J=28.9 Hz, 4H), 2.45-2.26 (m, 2H), 2.25 (d, J=12.4 Hz, 1H); 13C NMR (75 MHz, CDCl3-d1) δ 173.78, 150.29, 149.26, 147.02, 140.80, 133.13, 132.57, 131.75, 130.86, 129.62, 128.97, 128.62, 125.51, 124.07, 118.85, 118.19, 54.38, 51.46, 32.25, 27.63, 14.05; LC-MS (ESI) m/z: 506.8 [M+H]+.
1H NMR (300 MHz, CDCl3-d1) δ 8.33 (dd, J=7.5, 2.0 Hz, 1H), 8.17 (d, J=2.1 Hz, 1H), 7.68-7.54 (m, 2H), 7.54-7.31 (m, 3H), 5.22 (s, 1H), 3.68 (s, 3H), 2.56 (s, 3H), 2.53 (d, J=12.4 Hz, 1H), 2.40 (d, J=12.4 Hz, 1H), 2.35-2.17 (m, 2H); 13C NMR (75 MHz, CDCl3-d1) δ 173.78, 150.96, 150.29, 148.47, 143.37, 141.28, 134.20, 130.98, 130.35, 129.35, 128.71, 128.62, 124.17, 123.83, 122.86, 121.02, 54.38, 51.43, 32.25, 27.60, 14.05; LC-MS (ESI) m/z: 472.9 [M+H]+.
1H NMR (300 MHz, CDCl3-d1) δ: 7.74 (d, J=8.5 Hz, 1H), 7.64-7.54 (m, 2H), 7.43-7.33 (m, 3H), 7.19 (s, 1H), 4.28 (t, J=6.2 Hz, 1H), 3.68 (s, 3H), 3.34 (q, J=7.6 Hz, 2H), 2.90-2.72 (m, 4H), 1.42 (t, J=7.1 Hz, 3H); 13C NMR (75 MHz, CDCl3-d1) δ: 173.83, 166.46, 157.23, 150.27, 138.05, 133.63, 132.82, 131.46, 131.32, 131.30, 130.98, 130.95, 130.21, 129.36, 127.19, 125.04, 55.14, 51.63, 30.20, 27.68, 26.49, 14.77; LC-MS (ESI) m/z: 475.1[M+H]+.
1H NMR (300 MHz, CDCl3-d1) δ 7.71-7.61 (m, 1H), 7.60 (d, J=2.0 Hz, 1H), 7.57-7.25 (m, 6H), 5.32 (s, 1H), 3.68 (s, 3H), 3.18 (s, 2H), 2.50 (d, J=12.4 Hz, 1H), 2.45-2.26 (m, 2H), 2.25 (d, J=12.4 Hz, 1H), 1.39 (s, 3H); 13C NMR (75 MHz, CDCl3-d1) δ 173.78, 149.26, 147.02, 144.40, 140.17, 133.47, 132.57, 131.75, 130.98, 129.65, 128.97, 128.62, 127.05, 124.07, 122.26, 116.44, 54.38, 51.48, 32.03, 29.80, 28.40, 14.23; LC-MS (ESI) m/z: 520.8[M+H]+.
1H NMR (300 MHz, CDCl3-d1) δ 8.30 (dd, J=7.5, 2.0 Hz, 1H), 8.19 (d, J=2.0 Hz, 1H), 7.75 (d, J=7.5 Hz, 1H), 7.61 (dd, J=7.4, 2.0 Hz, 1H), 7.54-7.31 (m, 3H), 5.22 (s, 1H), 3.68 (s, 3H), 3.18 (s, 2H), 2.53 (d, J=12.4 Hz, 1H), 2.40 (d, J=12.4 Hz, 1H), 2.24 (d, J=1.5 Hz, 2H), 1.40 (s, 3H); 13C NMR (75 MHz, CDCl3-d1) δ 173.90, 150.96, 147.02, 144.00, 143.37, 141.28, 133.92, 130.98, 130.35, 129.31, 128.71, 128.54, 124.07, 123.83, 122.86, 121.02, 54.38, 51.46, 32.25, 28.40, 27.60, 14.23; LC-MS (ESI) m/z: 486.9[M+H]+.
1H NMR (300 MHz, CDCl3-d1) δ: 7.76-7.19 (m, 7H), 4.28 (t, J=5.7 Hz, 1H), 3.68 (s, 3H), 3.30 (t, J=13.8 Hz, 2H), 2.90-2.72 (m, 4H), 1.81 (q, J=6.7 Hz, 2H), 1.04 (t, J=6.9 Hz, 3H); 13C NMR (75 MHz, CDCl3-d1) δ: 173.85, 166.46, 157.22, 150.50, 138.06, 133.61, 132.84, 131.47, 131.35, 131.29, 130.99, 130.95, 130.22, 129.35, 127.18, 125.09, 55.19, 51.64, 35.17, 30.23, 26.52, 22.73, 13.23; LC-MS (ESI) m/z: 488.9 [M+H]+.
1H NMR (300 MHz, CDCl3-d1) δ 7.99-7.88 (m, 2H), 7.79 (dd, J=8.4, 2.5 Hz, 1H), 7.59-7.49 (m, 1H), 7.51-7.39 (m, 2H), 7.41-7.27 (m, 1H), 6.06-5.90 (m, 1H), 3.62 (s, 2H), 3.32 (dt, J=14.5, 6.4 Hz, 1H), 3.17 (dt, J=14.5, 6.4 Hz, 1H), 2.79-2.62 (m, 1H), 2.58-2.40 (m, 2H), 2.44-2.24 (m, 1H), 1.93-1.58 (m, 2H), 1.02 (t, J=7.6 Hz, 3H); 13C NMR (75 MHz, CDCl3-d1) δ 173.45, 162.53, 154.57, 153.88, 138.65, 136.35, 134.47, 133.31, 132.86, 130.41, 129.64, 129.59, 128.37, 126.63, 122.44, 119.72, 55.11, 51.90, 34.69, 29.81, 29.59, 22.63, 13.16; LC-MS (ESI) m/z: 532.03 [M+H]+.
1H NMR (300 MHz, CDCl3-d1) δ 8.46 (dd, J=8.5, 2.1 Hz, 1H), 8.36 (d, J=2.1 Hz, 1H), 8.25 (d, J=8.5 Hz, 1H), 7.57 (dd, J=7.8, 1.5 Hz, 1H), 7.54-7.36 (m, 2H), 7.35 (td, J=7.6, 1.5 Hz, 1H), 5.12-4.94 (m, 1H), 3.61 (s, 2H), 3.38-3.13 (m, 2H), 2.70-2.46 (m, 3H), 2.35-2.17 (m, 1H), 1.92-1.58 (m, 2H), 1.03 (t, J=7.6 Hz, 3H); 13C NMR (75 MHz, CDCl3-d1) δ 173.50, 162.06, 154.57, 153.88, 146.01, 138.70, 137.82, 134.63, 130.41, 129.65, 128.42, 128.36, 128.20, 126.67, 125.98, 123.39, 55.11, 51.90, 34.69, 29.70, 29.62, 22.63, 13.16; LC-MS (ESI) m/z: 499.11 [M+H]+.
1H NMR (300 MHz, CDCl3-d1) δ: 7.75 (d, J=8.6 Hz, 1H), 7.64-7.55 (m, 2H), 7.45-7.33 (m, 3H), 7.19 (s, 1H), 4.28 (t, J=5.3 Hz, 1H), 4.11-3.96 (m, 3H), 3.68 (s, 3H), 3.51-3.42 (m, 2H), 2.90-2.72 (m, 4H); 13C NMR (75 MHz, CDCl3-d1) δ: 173.79, 166.57, 157.42, 150.92, 137.91, 133.98, 132.83, 131.65, 131.39, 131.29, 130.98, 130.71, 130.27, 129.48, 127.22, 125.07, 62.20, 55.08, 51.68, 36.05, 30.15, 26.42; LC-MS (ESI) m/z: 491.4 [M+H]+.
1H NMR (300 MHz, CDCl3-d1) δ 7.99-7.88 (m, 2H), 7.81 (dd, J=8.4, 2.5 Hz, 1H), 7.59-7.48 (m, 1H), 7.51-7.39 (m, 2H), 7.39-7.27 (m, 1H), 6.07-5.90 (m, 1H), 4.40 (t, J=7.2 Hz, 1H), 3.75 (q, J=7.0 Hz, 2H), 3.62 (s, 3H), 3.67-3.51 (m, 1H), 3.39 (dt, J=15.0, 6.8 Hz, 1H), 2.78-2.60 (m, 1H), 2.60-2.38 (m, 2H), 2.41-2.22 (m, 1H); 13C NMR (75 MHz, CDCl3-d1) δ 173.42, 162.52, 154.54, 153.87, 138.65, 136.35, 134.89, 133.44, 132.85, 130.33, 129.69, 129.62, 128.28, 126.66, 122.43, 119.94, 60.25, 55.10, 51.89, 35.35, 29.70, 29.59; LC-MS (ESI) m/z: 534.01 [M+H]+.
1H NMR (300 MHz, CDCl3-d1) δ 8.49-8.35 (m, 2H), 8.26 (d, J=8.4 Hz, 1H), 7.57 (dd, J=7.8, 1.4 Hz, 1H), 7.54-7.38 (m, 2H), 7.34 (td, J=7.5, 1.5 Hz, 1H), 5.09-4.93 (m, 1H), 4.40 (t, J=7.2 Hz, 1H), 3.82-3.63 (m, 2H), 3.61 (s, 3H), 3.68-3.40 (m, 2H), 2.77-2.60 (m, 1H), 2.61-2.42 (m, 2H), 2.35-2.16 (m, 1H); 13C NMR (75 MHz, CDCl3-d1) δ 173.40, 162.06, 154.59, 153.87, 146.02, 138.70, 137.80, 134.47, 130.33, 129.69, 128.29, 128.18, 127.85, 126.71, 125.90, 123.39, 60.27, 55.10, 51.90, 35.34, 29.65, 29.60; LC-MS (ESI) m/z: 501.09 [M+H]+.
1H NMR (300 MHz, CDCl3-d1) δ: 7.79 (d, J=8.7 Hz, 1H), 7.62-7.51 (m, 2H), 7.41-7.31 (m, 3H), 7.15 (s, 1H), 6.46 (s, 2H), 4.24 (t, J=7.8 Hz, 1H), 3.77-3.52 (m, 7H), 2.82-2.73 (m, 4H); 13C NMR (75 MHz, CDCl3-d1) δ: 173.80, 166.72, 157.62, 150.17, 137.84, 134.11, 132.82, 131.95, 131.37, 131.23, 130.93, 130.39, 130.27, 129.39, 127.18, 125.15, 54.93, 51.71, 40.16, 31.60, 30.15, 26.31; LC-MS (ESI) m/z: 490.2 [M+H]+.
1H NMR (300 MHz, CDCl3-d1) δ 7.98-7.88 (m, 2H), 7.81 (dd, J=8.3, 2.5 Hz, 1H), 7.59-7.49 (m, 1H), 7.51-7.39 (m, 2H), 7.39-7.27 (m, 1H), 6.06-5.89 (m, 1H), 3.74 (t, J=6.1 Hz, 2H), 3.62 (s, 2H), 3.48 (dt, J=15.6, 5.8 Hz, 1H), 3.34 (dt, J=15.6, 5.9 Hz, 1H), 3.18-2.88 (m, 2H), 2.79-2.61 (m, 1H), 2.59-2.37 (m, 2H), 2.41-2.22 (m, 1H); 13C NMR (75 MHz, CDCl3-d1) δ 173.42, 162.53, 154.45, 153.86, 138.65, 136.35, 134.80, 133.38, 132.85, 130.33, 129.69, 129.62, 128.28, 126.66, 122.43, 119.94, 55.10, 51.89, 40.95, 35.18, 29.70, 29.59; LC-MS (ESI) m/z: 533.03 [M+H]+.
1H NMR (300 MHz, CDCl3-d1) δ 8.47 (dd, J=8.5, 2.1 Hz, 1H), 8.37 (d, J=2.1 Hz, 1H), 8.27 (d, J=8.4 Hz, 1H), 7.56 (dd, J=7.7, 1.5 Hz, 1H), 7.56-7.38 (m, 2H), 7.34 (td, J=7.5, 1.5 Hz, 1H), 5.08-4.90 (m, 1H), 3.74 (t, J=6.1 Hz, 2H), 3.64-3.33 (m, 4H), 3.14 (dp, J=14.6, 6.0 Hz, 1H), 2.98 (dp, J=14.6, 5.9 Hz, 1H), 2.74-2.57 (m, 1H), 2.62-2.42 (m, 2H), 2.26 (dtd, J=11.0, 8.4, 7.7 Hz, 1H); I3C NMR (75 MHz, CDCl3-d1) δ 173.39, 162.06, 154.50, 153.88, 146.02, 138.70, 137.80, 134.48, 130.33, 129.69, 128.29, 128.17, 127.79, 126.71, 125.90, 123.39, 55.10, 51.90, 40.95, 35.19, 29.65, 29.60; LC-MS (ESI) m/z: 500.10 [M+H]+.
1H NMR (300 MHz, CDCl3-d1) δ: 8.49 (d, J=8.8 Hz, 1H), 7.64 (d, J=9.5 Hz, 1H), 7.51-7.39 (m, 4H), 7.15 (d, J=3.2 Hz, 1H), 4.28 (t, J=5.8 Hz, 1H), 3.68 (s, 3H), 2.80-2.62 (m, 4H), 2.30 (s, 3H); 13C NMR (75 MHz, CDCl3-d1) δ: 173.46, 168.18, 167.82, 166.20, 151.61, 141.72, 137.59, 134.00, 133.16, 132.08, 131.51, 131.07, 130.85, 130.49, 129.00, 127.37, 127.07, 54.77, 51.81, 29.81, 25.73, 20.63; LC-MS (ESI) m/z: 489.4 [M+H]+.
1H NMR (300 MHz, CDCl3-d1) δ 8.10 (d, J=8.3 Hz, 1H), 7.96 (d, J=2.5 Hz, 1H), 7.79 (dd, J=8.4, 2.5 Hz, 1H), 7.57-7.27 (m, 4H), 6.06-5.93 (m, 1H), 3.62 (s, 3H), 2.71-2.44 (m, 3H), 2.45-2.22 (m, 4H); 13C NMR (75 MHz, CDCl3-d1) δ 185.25, 173.42, 162.53, 154.37, 148.67, 138.65, 136.35, 134.79, 133.71, 132.84, 130.33, 129.63, 129.62, 128.28, 126.66, 122.42, 119.94, 55.10, 51.89, 30.14, 29.65, 29.59; LC-MS (ESI) m/z: 532.00 [M+H]+.
1H NMR (300 MHz, CDCl3-d1) δ 8.54-8.36 (m, 2H), 8.34 (d, J=2.0 Hz, 1H), 7.55 (ddd, J=7.7, 6.0, 1.8 Hz, 2H), 7.53-7.32 (m, 2H), 5.99 (ddd, J=8.2, 7.4, 0.8 Hz, 1H), 3.61 (s, 2H), 2.71-2.40 (m, 3H), 2.42 (s, 3H), 2.44-2.25 (m, 1H); 13C NMR (75 MHz, CDCl3-d1) δ 185.25, 173.39, 162.06, 154.37, 148.19, 146.02, 138.70, 138.07, 134.47, 130.33, 129.69, 128.29, 128.21, 128.17, 126.71, 125.90, 123.40, 55.10, 51.90, 30.14, 29.65, 29.60; LC-MS (ESI) m/z: 499.07 [M+H]+.
1H NMR (300 MHz, CDCl3-d1) δ: 12.39 (s, 1H), 8.52 (d, J=8.7 Hz, 1H), 7.62 (d, J=8.6 Hz, 1H), 7.64-7.38 (m, 4H), 7.14 (s, 1H), 4.28 (t, J=6.3 Hz, 1H), 4.14 (q, J=7.0 Hz, 2H), 2.76-2.57 (m, 4H), 1.23 (t, J=7.1 Hz, 3H); 13C NMR (75 MHz, CDCl3-d1) δ: 173.32, 168.00, 167.13, 153.25, 137.67, 133.88, 133.07, 131.81, 131.39, 131.17, 130.91, 130.82, 130.40, 129.14, 127.01, 60.70, 54.92, 30.18, 25.84, 14.19; LC-MS (ESI) m/z: 461.0 [M+H]+.
1H NMR (300 MHz, CDCl3-d1) δ: 7.75 (d, J=8.5 Hz, 1H), 7.64-7.56 (m, 2H), 7.43-7.31 (m, 3H), 7.19 (s, 1H), 4.28 (t, J=5.6 Hz, 1H), 4.14 (q, J=7.0 Hz, 2H), 2.90-2.76 (m, 7H) 1.24 (t, J=6.6 Hz, 3H); 13C NMR (75 MHz, CDCl3-d1) δ: 173.44, 166.45, 157.55, 151.14, 138.05, 133.70, 132.88, 131.60, 131.38, 131.02, 130.28, 129.51, 127.22, 124.63, 60.43, 55.14, 30.46, 26.54, 15.27, 14.24; LC-MS (ESI) m/z: 475.1 [M+H]+.
1H NMR (300 MHz, CDCl3-d1) δ 7.99-7.87 (m, 2H), 7.80 (dd, J=8.4, 2.5 Hz, 1H), 7.53 (dd, J=8.0, 1.6 Hz, 1H), 7.51-7.39 (m, 2H), 7.39-7.27 (m, 1H), 5.02 (ddd, J=8.3, 7.6, 0.7 Hz, 1H), 4.21-3.97 (m, 2H), 2.64 (s, 3H), 2.73-2.26 (m, 4H), 1.18 (t, J=6.9 Hz, 3H); 13C NMR (75 MHz, CDCl3-d1) δ 172.72, 162.53, 154.47, 153.45, 138.65, 136.35, 134.56, 133.15, 132.85, 130.33, 129.69, 129.62, 128.28, 126.67, 122.44, 119.73, 60.67, 55.10, 30.27, 29.68, 16.53, 14.18; LC-MS (ESI) m/z: 518.02 [M+H]+.
1H NMR (300 MHz, CDCl3-d1) δ 8.52-8.35 (m, 2H), 8.25 (d, J=8.4 Hz, 1H), 7.56 (dd, J=7.7, 1.5 Hz, 1H), 7.53-7.39 (m, 2H), 7.33 (td, J=7.5, 1.5 Hz, 1H), 5.02-4.87 (m, 1H), 4.21-3.97 (m, 2H), 2.75-2.58 (m, 1H), 2.64 (s, 3H), 2.61-2.39 (m, 2H), 2.33-2.15 (m, 1H), 1.18 (t, J=6.9 Hz, 3H); 13C NMR (75 MHz, CDCl3-d1) δ 172.77, 161.98, 154.47, 153.47, 146.09, 138.70, 137.56, 134.51, 130.33, 129.67, 128.29, 128.17, 127.79, 126.66, 125.92, 123.39, 60.68, 55.10, 30.29, 29.68, 16.53, 14.17; LC-MS (ESI) m/z: 485.09 [M+H]+.
1H NMR (300 MHz, CDCl3-d1) δ: 7.90 (s, 2H), 7.62 (dt, J=25.3, 7.0 Hz, 2H), 7.37 (d, J=14.2 Hz, 2H), 7.22 (t, J=9.6 Hz, 1H), 4.28 (t, J=6.4 Hz, 1H), 3.62 (s, 3H), 3.07 (d, J=7.2 Hz, 2H), 2.77-2.57 (m, 4H), 1.05 (s, 1H), 0.45 (d, J=7.9 Hz, 2H), 0.24-0.12 (m, 2H); 13C NMR (75 MHz, CDCl3-d1) δ: 173.57, 163.45, 161.94, 161.87, 161.44, 156.52, 153.90, 134.08, 133.03, 132.44, 132.38, 131.36, 130.59, 130.53, 129.90, 127.85, 127.79, 127.77, 127.69, 124.73, 124.71, 122.90, 116.37, 116.21, 55.18, 51.94, 38.04, 29.44, 29.28, 11.77, 6.27; LC-MS (ESI) m/z: 486.1 [M+H]+.
1H NMR (300 MHz, CDCl3-d1) δ 7.97-7.83 (m, 2H), 7.80 (dd, J=8.4, 2.5 Hz, 1H), 7.53 (dddd, J=15.6, 7.6, 5.0, 1.6 Hz, 2H), 7.28 (dtd, J=16.5, 7.7, 1.4 Hz, 2H), 4.70-4.53 (m, 1H), 3.61 (s, 2H), 3.36-3.21 (m, 1H), 3.09-2.96 (m, 1H), 2.71-2.53 (m, 1H), 2.58-2.42 (m, 2H), 2.36 (dtd, J=10.9, 8.4, 7.6 Hz, 1H), 1.40-1.20 (m, 5H); 13C NMR (75 MHz, CDCl3-d1) δ 173.43, 163.16, 162.00, 161.89, 159.80, 154.35, 153.86, 136.35, 133.54, 132.91, 131.57, 131.46, 130.46, 130.36, 128.86, 128.82, 126.92, 126.66, 124.26, 124.22, 122.43, 119.98, 115.98, 115.71, 55.26, 51.89, 37.41, 29.65, 29.60, 13.37, 6.76; LC-MS (ESI) m/z: 528.06 [M+H]+.
1H NMR (300 MHz, CDCl3-d1) δ 8.46 (dd, J=8.5, 2.1 Hz, 1H), 8.35-8.19 (m, 2H), 7.63-7.44 (m, 2H), 7.30 (dtd, J=13.2, 7.7, 1.4 Hz, 2H), 4.93 (t, J=8.1 Hz, 1H), 3.61 (s, 2H), 3.42-3.29 (m, 1H), 3.05-2.91 (m, 1H), 2.71-2.50 (m, 2H), 2.55-2.27 (m, 2H), 1.39-1.20 (m, 5H); 13C NMR (75 MHz, CDCl3-d1) δ 173.39, 163.12, 161.47, 161.36, 159.76, 154.35, 153.88, 146.14, 137.98, 131.60, 131.49, 130.48, 130.37, 128.16, 127.31, 127.25, 127.07, 126.81, 126.00, 124.32, 124.28, 123.39, 115.95, 115.68, 55.26, 51.90, 37.41, 29.65, 29.61, 13.37, 6.76; LC-MS (ESI) m/z: 495.14 [M+H]+.
1H NMR (400 MHz, CDCl3-d1) δ: 7.95-7.85 (m, 2H), 7.68-7.53 (m, 2H), 7.42-7.30 (m, 2H), 7.28-7.18 (m, 1H), 4.30 (dd, J=8.0, 5.5 Hz, 1H), 3.98 (qd, J=16.4, 2.6 Hz, 2H), 3.62 (s, 3H), 3.17 (t, J=2.6 Hz, 1H), 2.80-2.54 (m, 4H); 13C NMR (75 MHz, CDCl3-d1) δ:173.35, 163.77, 161.57, 161.23, 161.14, 156.64, 153.26, 134.21, 133.16, 132.95, 132.63, 131.36, 130.71, 130.55, 129.34, 127.76, 127.65, 127.58, 127.39, 124.83, 124.53, 123.25, 116.64, 116.33, 79.82, 72.44, 55.37, 51.62, 29.43, 29.30, 20.68; LC-MS (ESI) m/z: 469.2 [M+H]+.
1H NMR (300 MHz, CDCl3-d1) δ 7.91 (d, J=8.4 Hz, 1H), 7.88-7.74 (m, 2H), 7.63-7.44 (m, 2H), 7.37-7.19 (m, 2H), 4.90 (t, J=8.0 Hz, 1H), 4.07 (dd, J=12.4, 3.0 Hz, 1H), 3.85 (dd, J=12.4, 3.0 Hz, 1H), 3.62 (s, 2H), 2.71-2.27 (m, 5H); 13C NMR (75 MHz, CDCl3-d1) δ 173.39, 163.17, 162.00, 161.89, 159.80, 154.01, 153.86, 136.35, 133.51, 132.85, 131.57, 131.46, 130.43, 130.33, 128.86, 128.82, 126.93, 126.66, 124.29, 124.25, 122.43, 119.81, 115.98, 115.71, 79.08, 72.66, 55.26, 51.89, 29.65, 29.59, 20.39; LC-MS (ESI) m/z:512.03 [M+H]+.
1H NMR (300 MHz, CDCl3-d1) δ 8.48 (dd, J=8.5, 2.1 Hz, 1H), 8.33 (d, J=2.1 Hz, 1H), 8.22 (d, J=8.5 Hz, 1H), 7.63-7.45 (m, 2H), 7.29 (dtd, J=16.4, 7.7, 1.4 Hz, 2H), 4.90 (t, J=8.1 Hz, 1H), 4.08 (dd, J=12.3, 3.0 Hz, 1H), 3.87 (dd, J=12.3, 3.0 Hz, 1H), 3.61 (s, 2H), 2.73-2.26 (m, 5H); 13C NMR (75 MHz, CDCl3-d1) δ 173.41, 163.13, 161.47, 161.36, 159.77, 154.02, 153.88, 146.14, 137.89, 131.58, 131.46, 130.43, 130.33, 128.17, 127.36, 127.32, 127.07, 126.81, 126.05, 124.33, 124.29, 123.39, 115.98, 115.71, 79.07, 72.67, 55.26, 51.90, 29.65, 29.61, 20.39; LC-MS (ESI) m/z: 479.11 [M+H]+.
1H NMR (300 MHz, CDCl3-d1) δ: 7.93 (s, 2H), 7.75-7.52 (m, 2H), 7.45-7.31 (m, 2H), 7.30-7.18 (m, 1H), 4.31 (d, J=5.9 Hz, 1H), 3.63 (s, 3H), 3.55-3.45 (m, 4H), 3.35 (d, J=6.7 Hz, 2H), 2.86-2.55 (m, 6H), 2.36 (s, 4H); 13C NMR (75 MHz, CDCl3-d1) δ: 173.54, 163.45, 161.75, 161.42, 161.17, 156.34, 153.67, 134.62, 133.22, 132.15, 132.07, 131.46, 130.36, 130.22, 129.77, 127.83, 127.72, 127.68, 127.61, 124.84, 124.71, 122.83, 116.41, 116.33, 66.57, 55.24, 53.94, 53.56, 51.78, 30.26, 29.56, 29.35; LC-MS (ESI) m/z: 547.1 [M+H]+.
1H NMR (300 MHz, CDCl3-d1) δ: 8.06 (dd, J=8.7, 2.2 Hz, 1H), 7.85 (d, J=8.7 Hz, 1H), 7.74-7.47 (m, 3H), 7.37 (t, J=7.5 Hz, 1H), 7.25 (dd, J=10.6, 8.6 Hz, 1H), 4.30 (t, J=6.6 Hz, 1H), 3.64 (s, 3H), 3.53-3.46 (m, 4H), 3.35 (d, J=6.8 Hz, 2H), 2.89-2.56 (m, 6H), 2.36 (s, 4H); 13C NMR (75 MHz, CDCl3-d1) δ 173.40, 163.21, 162.00, 161.89, 159.85, 154.56, 153.86, 136.19, 133.51, 132.95, 131.61, 131.50, 130.38, 130.28, 128.98, 128.94, 126.92, 126.66, 124.32, 124.28, 122.44, 119.83, 115.98, 115.71, 65.42, 55.26, 53.50, 52.67, 51.93, 30.41, 29.65, 29.61; LC-MS (ESI) m/z: 591.90 [M+H]+.
1H NMR (300 MHz, CDCl3-d1) δ 8.52 (dd, J=8.5, 2.1 Hz, 1H), 8.38 (d, J=2.1 Hz, 1H), 8.22 (d, J=8.4 Hz, 1H), 7.64-7.46 (m, 2H), 7.37-7.20 (m, 2H), 6.05-5.91 (m, 1H), 3.66-3.50 (m, 7H), 3.37 (dt, J=14.3, 5.2 Hz, 1H), 2.81 (dt, J=12.0, 5.2 Hz, 1H), 2.71-2.40 (m, 6H), 2.42-2.22 (m, 3H). 13C NMR (75 MHz, CDCl3-d1) δ 173.37, 163.30, 161.48, 161.38, 159.94, 154.57, 153.88, 146.17, 137.95, 131.60, 131.49, 130.54, 130.43, 128.17, 127.60, 127.56, 127.08, 126.81, 125.94, 124.26, 124.22, 123.35, 115.98, 115.71, 65.46, 55.26, 53.55, 52.62, 51.89, 30.41, 29.67, 29.61; LC-MS (ESI) m/z: 555.60 [M+H]+.
1H NMR (300 MHz, CDCl3-d1) δ: 7.90 (d, J=1.8 Hz, 2H), 7.69-7.53 (m, 2H), 7.41-7.31 (m, 2H), 7.29-7.17 (m, 1H), 4.27 (dd, J=7.7, 5.5 Hz, 1H), 3.61 (s, 3H), 3.30-3.22 (m, 2H), 2.80-2.68 (m, 3H), 2.68-2.52 (m, 4H), 2.45 (q, J=7.1 Hz, 6H), 0.90 (t, J=7.1 Hz, 6H); 13C NMR (75 MHz, CDCl3-d1) δ: 173.49, 163.48, 161.84, 161.77, 161.52, 156.36, 153.37, 134.73, 133.25, 132.58, 132.39, 131.41, 130.67, 130.46, 129.73, 127.74, 127.62, 127.58, 127.39, 124.68, 124.51, 122.76, 116.45, 116.26, 55.22, 51.83, 51.53, 47.82, 30.37, 29.51, 29.33, 11.51; LC-MS (ESI) m/z: 531.6 [M+H]+.
1H NMR (300 MHz, CDCl3-d1) δ 7.96-7.84 (m, 2H), 7.79 (dd, J=8.4, 2.5 Hz, 1H), 7.53 (dddd, J=16.9, 7.6, 5.0, 1.6 Hz, 2H), 7.28 (dtd, J=16.4, 7.7, 1.4 Hz, 2H), 6.05-5.89 (m, 1H), 3.62 (s, 2H), 3.51 (dt, J=14.1, 5.2 Hz, 1H), 3.35 (dt, J=14.1, 5.2 Hz, 1H), 2.84 (dt, J=12.2, 5.2 Hz, 1H), 2.77-2.60 (m, 2H), 2.66-2.47 (m, 4H), 2.53-2.40 (m, 2H), 2.43-2.24 (m, 1H), 1.01 (t, J=7.2 Hz, 6H); 13C NMR (75 MHz, CDCl3-d1) δ 173.41, 163.21, 162.00, 161.89, 159.85, 154.56, 153.86, 136.19, 133.43, 132.95, 131.62, 131.52, 130.53, 130.42, 128.86, 128.82, 126.92, 126.66, 124.26, 124.22, 122.42, 119.83, 115.98, 115.71, 55.26, 51.93, 50.88, 47.11, 30.42, 29.65, 29.61, 11.17; LC-MS (ESI) m/z: 575.51 [M+H]+.
1H NMR (300 MHz, CDCl3-d1) δ 8.49 (dd, J=8.5, 2.1 Hz, 1H), 8.32 (d, J=2.1 Hz, 1H), 8.21 (d, J=8.5 Hz, 1H), 7.54 (dddd, J=20.4, 7.6, 5.0, 1.7 Hz, 2H), 7.37-7.20 (m, 2H), 4.89 (ddd, J=8.2, 7.5, 0.6 Hz, 1H), 3.62 (s, 2H), 3.47 (dt, J=14.1, 5.2 Hz, 1H), 3.33 (dt, J=14.1, 5.2 Hz, 1H), 2.87 (dt, J=12.1, 5.2 Hz, 1H), 2.79-2.26 (m, 9H), 1.01 (t, J=7.2 Hz, 6H); 13C NMR (75 MHz, DMSO-d6) δ 173.42, 163.09, 161.48, 161.38, 159.73, 154.51, 153.88, 146.17, 137.95, 131.60, 131.49, 130.49, 130.38, 128.17, 127.60, 127.56, 127.08, 126.81, 126.00, 124.26, 124.22, 123.37, 115.98, 115.71, 55.26, 51.91, 50.88, 47.11, 30.42, 29.67, 29.61, 11.17; LC-MS (ESI) m/z: 541.61 [M+H]+.
1H NMR (300 MHz, CDCl3-d1) δ: 7.92-7.84 (m, 2H), 7.65 (td, J=7.6, 1.8 Hz, 1H), 7.58 (tdd, J=7.5, 5.2, 1.8 Hz, 1H), 7.42-7.31 (m, 2H), 7.22 (dd, J=10.9, 8.3 Hz, 1H), 4.28 (dd, J=7.7, 5.5 Hz, 1H), 3.61 (s, 3H), 3.24-3.06 (m, 2H), 2.78-2.52 (m, 4H), 2.39 (tt, J=6.9, 4.3 Hz, 2H), 2.18 (s, 6H), 1.79 (q, J=7.1 Hz, 2H); 13C NMR (75 MHz, CDCl3-d1) δ: 173.72, 163.68, 161.90, 161.82, 161.54, 156.38, 153.73, 134.21, 133.12, 132.51, 132.36, 131.73, 130.66, 130.48, 129.41, 127.88, 127.60, 127.47, 127.39, 124.63, 124.49, 122.88, 116.47, 116.28, 58.73, 55.48, 51.63, 45.28, 31.91, 29.53, 29.33, 26.74; LC-MS (ESI) m/z: 517.14 [M+H]+.
1H NMR (300 MHz, CDCl3-d1) δ 7.97-7.83 (m, 2H), 7.79 (dd, J=8.4, 2.5 Hz, 1H), 7.53 (dddd, J=16.9, 7.6, 4.9, 1.6 Hz, 2H), 7.28 (dtd, J=13.1, 7.7, 1.4 Hz, 2H), 6.06-5.91 (m, 1H), 3.62 (s, 3H), 3.37-3.12 (m, 2H), 2.70-2.53 (m, 2H), 2.58-2.40 (m, 2H), 2.45-2.24 (m, 2H), 2.21 (s, 5H), 1.94 (ddq, J=21.9, 13.0, 6.5 Hz, 2H), 13C NMR (75 MHz, CDCl3-d1) δ 173.41, 163.21, 162.00, 161.89, 159.85, 154.56, 153.86, 136.19, 133.43, 132.95, 131.57, 131.46, 130.53, 130.42, 128.86, 128.82, 126.92, 126.66, 124.26, 124.22, 122.42, 119.83, 115.98, 115.72, 57.69, 55.26, 51.89, 44.74, 30.52, 29.65, 29.61, 27.44; LC-MS (ESI) m/z: 560.49 [M+H]+.
1H NMR (300 MHz, CDCl3-d1) δ 8.48 (dd, J=8.5, 2.1 Hz, 1H), 8.31 (d, J=2.1 Hz, 1H), 8.22 (d, J=8.5 Hz, 1H), 7.63-7.45 (m, 2H), 7.37-7.20 (m, 2H), 4.95 (t, J=8.1 Hz, 1H), 3.62 (s, 3H), 3.30 (dt, J=14.4, 6.4 Hz, 1H), 3.15 (dt, J=14.4, 6.4 Hz, 1H), 2.71-2.26 (m, 6H), 2.21 (s, 5H), 1.91 (ddq, J=20.6, 13.0, 6.5 Hz, 2H); 13C NMR (75 MHz, CDCl3-d1) δ 173.43, 163.12, 161.48, 161.38, 159.76, 154.59, 153.88, 146.17, 137.96, 131.60, 131.49, 130.51, 130.41, 128.17, 127.29, 127.25, 127.08, 126.81, 126.00, 124.26, 124.22, 123.37, 115.95, 115.68, 57.69, 55.26, 51.91, 44.74, 30.52, 29.65, 29.61, 27.43; LC-MS (ESI) m/z: 527.59 [M+H]+.
1H NMR (300 MHz, CDCl3-d1) δ: 7.96-7.83 (m, 3H), 7.71-7.55 (m, 3H), 7.43-7.32 (m, 3H), 7.23 (dd, J=11.0, 8.3 Hz, 2H), 4.28 (dd, J=7.7, 5.5 Hz, 2H), 3.62 (s, 3H), 2.78-2.56 (m, 11H); 13C NMR (75 MHz, CDCl3-d1) δ: 173.69, 163.57, 161.84, 161.73, 161.56, 156.48, 153.38, 134.67, 133.55, 132.47, 132.34, 131.73, 130.35, 130.13, 129.57, 127.65, 127.58, 127.37, 127.29, 124.67, 124.61, 122.48, 116.37, 116.24, 55.32, 53.46, 52.78, 52.55, 51.78, 45.84, 30.26, 29.74, 29.36; LC-MS (ESI) m/z: 557.18 [M+H]+.
1H NMR (300 MHz, CDCl3-d1) δ 7.96-7.84 (m, 2H), 7.80 (dd, J=8.3, 2.4 Hz, 1H), 7.54 (dddd, J=15.2, 7.6, 5.0, 1.6 Hz, 2H), 7.28 (dtd, J=17.6, 7.7, 1.4 Hz, 2H), 6.06-5.90 (m, 1H), 3.66-3.50 (m, 4H), 3.31 (dt, J=14.1, 5.2 Hz, 1H), 2.93 (dt, J=12.1, 5.2 Hz, 1H), 2.72-2.60 (m, 2H), 2.65-2.49 (m, 4H), 2.55-2.40 (m, 2H), 2.43-2.21 (m, 7H). 13C NMR (75 MHz, CDCl3-d1) δ 173.36, 163.19, 162.00, 161.89, 159.83, 154.56, 153.86, 136.38, 133.51, 132.95, 131.61, 131.50, 130.38, 130.28, 128.98, 128.94, 126.92, 126.66, 124.32, 124.28, 122.44, 119.83, 115.98, 115.71, 55.26, 53.62, 52.88, 52.57, 51.93, 45.16, 30.41, 29.67, 29.59; LC-MS (ESI) m/z: 602.54 [M+H]+.
1H NMR (300 MHz, CDCl3-d1) δ 8.52 (dd, J=8.4, 2.1 Hz, 1H), 8.37 (d, J=2.1 Hz, 1H), 8.20 (d, J=8.5 Hz, 1H), 7.64-7.46 (m, 2H), 7.28 (dtd, J=18.3, 7.7, 1.4 Hz, 2H), 5.98 (ddd, J=8.2, 7.5, 0.6 Hz, 1H), 3.66-3.49 (m, 4H), 3.29 (dt, J=14.1, 5.2 Hz, 1H), 2.84 (dt, J=12.1, 5.2 Hz, 1H), 2.80-2.45 (m, 8H), 2.52-2.29 (m, 5H), 2.25 (s, 3H); 13C NMR (75 MHz, CDCl3-d1) δ 173.36, 163.30, 161.48, 161.38, 159.94, 154.51, 153.88, 146.17, 138.11, 131.60, 131.49, 130.54, 130.43, 128.17, 127.60, 127.56, 127.08, 126.81, 125.94, 124.26, 124.22, 123.35, 115.98, 115.71, 55.26, 53.62, 52.88, 52.57, 51.93, 45.16, 30.41, 29.67, 29.61; LC-MS (ESI) m/z: 568.64 [M+H]+.
1H NMR (300 MHz, CDCl3-d1) δ: 7.94-7.71 (m, 3H), 7.62 (tdd, J=7.6, 5.3, 1.9 Hz, 1H), 7.50-7.25 (m, 3H), 2.63 (dt, J=17.0, 8.0 Hz, 2H), 2.15-2.09 (m, 3H), 1.94 (d, J=15.2 Hz, 6H), 1.86-1.74 (m, 1H), 1.61-1.42 (m, 2H), 1.26 (p, J=4.6, 3.6 Hz, 2H); 13C NMR (75 MHz, CDCl3-d1) δ:173.62, 163.43, 161.72, 161.63, 161.53, 154.68, 153.31, 133.68, 133.10, 132.42, 132.23, 131.41, 130.63, 130.48, 129.88, 127.82, 127.79, 127.73, 127.45, 124.68, 124.56, 123.36, 116.38, 116.23, 55.16, 53.81, 51.92, 45.91, 39.48, 31.55, 29.39, 29.25; LC-MS (ESI) m/z: 528.63 [M+H]+.
1H NMR (300 MHz, CDCl3-d1) δ 7.95-7.85 (m, 2H), 7.80 (dd, J=8.4, 1.9 Hz, 1H), 7.64-7.45 (m, 2H), 7.28 (dtd, J=16.4, 7.7, 1.3 Hz, 2H), 6.05-5.91 (m, 1H), 3.62 (s, 2H), 3.27 (p, J=5.8 Hz, 1H), 2.74 (ddd, J=12.2, 7.8, 5.9 Hz, 2H), 2.68-2.51 (m, 1H), 2.58-2.42 (m, 3H), 2.48-2.32 (m, 2H), 2.37-2.29 (m, OH), 2.29 (s, 3H), 2.04-1.79 (m, 4H). 13C NMR (75 MHz, CDCl3-d1) δ 173.41, 163.21, 162.00, 161.89, 159.85, 153.44, 153.01, 136.19, 133.07, 132.95, 131.60, 131.49, 130.53, 130.42, 128.86, 128.82, 126.92, 126.66, 124.26, 124.22, 122.42, 119.83, 115.98, 115.71, 55.26, 54.28, 51.93, 45.68, 34.94, 31.76, 29.65, 29.61; LC-MS (ESI) m/z: 573.50 [M+H]+.
1H NMR (300 MHz, CDCl3-d1) δ 8.51 (dd, J=8.4, 1.9 Hz, 1H), 8.40 (d, J=1.9 Hz, 1H), 8.22 (d, J=8.5 Hz, 1H), 7.55 (dddd, J=17.0, 7.6, 5.0, 1.7 Hz, 2H), 7.29 (dtd, J=14.3, 7.7, 1.4 Hz, 2H), 6.06-5.90 (m, 1H), 3.62 (s, 2H), 3.28 (p, J=5.8 Hz, 1H), 2.77 (ddd, J=12.2, 7.8, 5.8 Hz, 2H), 2.71-2.24 (m, 6H), 2.29 (s, 3H), 2.06-1.80 (m, 4H). 13C NMR (75 MHz, CDCl3-d1) δ 173.37, 163.09, 161.48, 161.38, 159.73, 153.42, 153.03, 146.17, 137.52, 131.60, 131.49, 130.51, 130.41, 128.17, 127.60, 127.56, 127.08, 126.81, 126.05, 124.26, 124.22, 123.35, 115.98, 115.71, 55.26, 54.28, 51.91, 45.68, 34.92, 31.67, 29.67, 29.61; LC-MS (ESI) m/z: 539.60 [M+H]+.
1H NMR (300 MHz, CDCl3-d1) δ: 7.89 (s, 2H), 7.70-7.53 (m, 2H), 7.42-7.31 (m, 2H), 7.22 (dd, J=10.9, 8.3 Hz, 1H), 4.35 (s, 1H), 4.27 (dd, J=7.8, 5.5 Hz, 1H), 3.45 (q, J=6.0 Hz, 2H), 3.33 (s, 4H), 3.21-3.03 (m, 2H), 2.80-2.57 (m, 4H), 2.41-2.21 (m, 10H), 1.74 (q, J=6.9 Hz, 2H); 13C NMR (75 MHz, CDCl3-d1) δ: 173.51, 163.39, 161.74, 161.67, 161.24, 156.51, 153.86, 134.09, 133.33, 132.18, 132.28, 131.50, 130.54, 130.47, 129.88, 127.75, 127.58, 127.72, 127.61, 124.72, 124.66, 122.55, 116.36, 116.02, 59.79, 57.51, 55.23, 55.12, 52.68, 52.08, 51.89, 31.15, 29.43, 29.18, 27.65; LC-MS (ESI) m/z: 602.3 [M+H]+.
1H NMR (300 MHz, CDCl3-d1) δ 7.94-7.77 (m, 3H), 7.54 (dddd, J=8.5, 7.5, 5.0, 1.4 Hz, 2H), 7.37-7.18 (m, 2H), 6.07-5.90 (m, 1H), 4.26 (t, J=7.3 Hz, 1H), 3.66-3.45 (m, 4H), 3.36-3.12 (m, 2H), 2.87 (t, J=5.3 Hz, 3H), 2.72-2.53 (m, 7H), 2.54 (dt, J=3.6, 1.8 Hz, 1H), 2.56-2.42 (m, 2H), 2.49-2.31 (m, 1H), 2.36-2.22 (m, 1H), 1.88 (pd, J=6.5, 4.1 Hz, 2H). 13C NMR (75 MHz, CDCl3-d1) δ 173.40, 163.37, 162.00, 161.89, 160.00, 154.56, 153.86, 136.38, 133.59, 132.95, 131.61, 131.50, 130.39, 130.28, 128.98, 128.94, 126.93, 126.66, 124.21, 124.17, 122.44, 119.76, 115.91, 115.64, 59.24, 58.71, 55.29, 55.11, 52.38, 52.36, 51.93, 30.47, 29.67, 29.59, 27.31; LC-MS (ESI) m/z: 645.59 [M+H]+.
1H NMR (300 MHz, CDCl3-d1) δ 8.52 (dd, J=8.4, 1.9 Hz, 1H), 8.41 (d, J=1.8 Hz, 1H), 8.22 (d, J=8.3 Hz, 1H), 7.63-7.48 (m, 2H), 7.28 (dtd, J=21.6, 7.7, 1.4 Hz, 2H), 6.04-5.89 (m, 1H), 4.27 (t, J=7.3 Hz, 1H), 3.66-3.49 (m, 4H), 3.35 (dt, J=14.4, 6.4 Hz, 1H), 3.19 (dt, J=14.4, 6.4 Hz, 1H), 2.87 (t, J=5.3 Hz, 3H), 2.72-2.58 (m, 4H), 2.64-2.44 (m, 6H), 2.47-2.23 (m, 2H), 1.85 (ddq, J=29.5, 13.0, 6.5 Hz, 2H). 13C NMR (75 MHz, CDCl3-d1) δ 173.36, 163.30, 161.56, 161.45, 159.94, 154.60, 153.88, 146.16, 138.12, 131.61, 131.50, 130.46, 130.35, 128.16, 127.78, 127.74, 127.08, 126.81, 125.94, 124.35, 124.31, 123.35, 115.91, 115.64, 59.24, 58.71, 55.26, 55.11, 52.44, 52.41, 51.94, 30.45, 29.67, 29.59, 27.31; LC-MS (ESI) m/z: 612.69 [M+H]+.
1H NMR (300 MHz, CDCl3-d1) δ: 8.47 (d, J=8.9 Hz, 1H), 7.87 (dd, J=8.9, 2.5 Hz, 1H), 7.69-7.42 (m, 3H), 7.41-7.31 (m, 2H), 7.25 (dd, J=10.8, 8.3 Hz, 1H), 5.19 (d, J=13.4 Hz, 1H), 5.03 (d, J=13.4 Hz, 1H), 4.33 (dd, J=8.7, 5.1 Hz, 1H), 3.32 (s, 1H), 2.88-2.54 (m, 7H), 2.49-2.39 (m, 1H), 1.24 (s, 1H); 13C NMR (75 MHz, CDCl3-d1) δ: 173.44, 163.43, 161.90, 161.83, 161.34, 153.79, 153.74, 134.22, 133.01, 132.43, 132.37, 131.35, 130.53, 130.46, 129.92, 127.75, 127.65, 127.51, 127.49, 124.71, 124.61, 123.02, 116.42, 116.01, 66.71, 58.33, 55.58, 51.74, 43.81, 29.41, 29.17; LC-MS (ESI) m/z: 531.2 [M+H]+.
1H NMR (300 MHz, CDCl3-d1) δ: 7.97-7.83 (m, 2H), 7.81 (dd, J=8.4, 2.5 Hz, 1H), 7.53 (dddd, J=16.9, 7.6, 5.0, 1.6 Hz, 2H), 7.36-7.19 (m, 2H), 6.04-5.90 (m, 1H), 4.24 (d, J=13.4 Hz, 1H), 3.99 (d, J=13.4 Hz, 1H), 3.75-3.56 (m, 7H), 2.93 (ddd, J=12.7, 6.5, 5.5 Hz, 2H), 2.80-2.40 (m, 5H), 2.41-2.23 (m, 1H). 13C NMR (75 MHz, CDCl3-d1) δ 173.41, 163.21, 162.00, 161.89, 159.85, 153.86, 149.17, 136.19, 133.62, 132.95, 131.62, 131.52, 130.53, 130.42, 128.86, 128.82, 126.92, 126.66, 124.26, 124.22, 122.42, 119.83, 115.98, 115.71, 66.31, 58.28, 55.26, 52.38, 51.93, 29.65, 29.61; LC-MS (ESI) m/z: 575.47 [M+H]+.
1H NMR (300 MHz, CDCl3-d1) δ 8.50 (dd, J=8.4, 2.1 Hz, 1H), 8.33 (d, J=2.1 Hz, 1H), 8.23 (d, J=8.5 Hz, 1H), 7.65-7.46 (m, 2H), 7.29 (dtd, J=14.4, 7.7, 1.4 Hz, 2H), 4.75 (t, J=8.2 Hz, 1H), 4.20 (d, J=13.4 Hz, 1H), 4.06 (d, J=13.4 Hz, 1H), 3.74-3.54 (m, 7H), 2.93 (ddd, J=12.7, 6.8, 5.3 Hz, 2H), 2.73 (ddd, J=12.7, 6.9, 5.2 Hz, 2H), 2.72-2.48 (m, 2H), 2.53-2.27 (m, 2H). 13C NMR (75 MHz, CDCl3-d1) δ 173.37, 163.09, 161.48, 161.38, 159.73, 153.86, 149.17, 146.17, 137.95, 131.60, 131.49, 130.51, 130.41, 128.17, 127.65, 127.61, 127.08, 126.81, 126.05, 124.26, 124.22, 123.35, 115.98, 115.71, 66.32, 58.28, 55.26, 52.43, 51.91, 29.67, 29.61; LC-MS (ESI) m/z: 541.57 [M+H]+.
1H NMR (300 MHz, CDCl3-d1) δ: 8.47 (d, J=8.9 Hz, 1H), 7.92-7.83 (m, 1H), 7.68-7.51 (m, 2H), 7.40-7.30 (m, 2H), 7.29-7.14 (m, 3H), 6.93 (t, J=9.3 Hz, 2H), 6.76 (t, J=7.2 Hz, 1H), 5.28 (d, J=13.4 Hz, 1H), 5.10 (d, J=13.4 Hz, 1H), 4.37-4.23 (m, 1H), 3.33 (s, 2H), 3.13 (t, J=4.9 Hz, 3H), 3.02-2.85 (m, 4H), 2.82-2.56 (m, 4H), 2.45 (dd, J=10.1, 6.7 Hz, 1H); 13C NMR (75 MHz, CDCl3-d1) δ: 173.46, 163.40, 161.84, 161.81, 161.33, 153.79, 153.34, 150.64, 134.18, 133.22, 132.16, 132.12, 131.39, 130.49, 130.33, 129.94, 129.11, 127.75, 127.63, 127.53, 127.49, 124.63, 124.45, 123.18, 118.61, 116.59, 116.44, 116.31, 58.36, 55.28, 51.91, 51.72, 48.41, 29.39, 29.19; LC-MS (ESI) m/z: 605.22 [M+H]+.
1H NMR (300 MHz, CDCl3-d1) δ: 7.87 (d, J=2.4 Hz, 1H), 7.80-7.62 (m, 2H), 7.57 (dddd, J=7.6, 6.7, 3.9, 1.4 Hz, 2H), 7.29 (td, J=7.5, 1.4 Hz, 1H), 7.23-7.11 (m, 3H), 6.90-6.81 (m, 3H), 6.02-5.87 (m, 1H), 4.34-4.09 (m, 2H), 3.76 (s, 2H), 3.34 (ddd, J=11.8, 6.4, 4.2 Hz, 2H), 3.22 (ddd, J=11.8, 6.5, 4.2 Hz, 2H), 2.76 (ddd, J=11.7, 6.4, 4.2 Hz, 2H), 2.61-2.52 (m, 1H), 2.60-2.32 (m, 4H), 2.41-2.15 (m, 1H); 13C NMR (75 MHz, CDCl3-d1) δ: 173.34, 163.22, 162.45, 161.76, 160.45, 153.56, 151.31, 149.21, 136.45, 133.70, 132.32, 131.37, 131.67, 130.78, 130.43, 129.23, 128.68, 128.45, 126.57, 126.34, 124.23, 124.12, 122.45, 119.56, 118.50, 116.12, 115.91, 115.64, 58.79, 55.33, 51.53, 51.74, 48.44, 29.32, 29.52; LC-MS (ESI) m/z: 649.58 [M+H]+.
1H NMR (300 MHz, CDCl3-d1) δ: 8.48-8.37 (m, 2H), 8.00 (d, J=8.2 Hz, 1H), 7.56-7.38 (m, 2H), 7.23 (td, J=7.6, 1.3 Hz, 1H), 7.14-7.01 (m, 3H), 6.88-6.73 (m, 3H), 4.56 (ddd, J=8.2, 7.2, 0.7 Hz, 1H), 4.13 (d, J=13.4 Hz, 1H), 4.01 (d, J=13.3 Hz, 1H), 3.43 (s, 2H), 3.21 (ddd, J=11.8, 6.3, 4.2 Hz, 2H), 3.01 (ddd, J=11.8, 6.5, 4.2 Hz, 2H), 2.74 (ddd, J=11.8, 6.4, 4.2 Hz, 2H), 2.65-2.54 (m, 1H), 2.60-2.47 (m, 2H), 2.53-2.42 (m, 1H), 2.48-2.33 (m, 1H), 2.34-2.16 (m, 1H); 13C NMR (75 MHz, CDCl3-d1) δ: 173.34, 163.54, 161.56, 161.36, 160.78, 153.98, 151.45, 149.54, 146.16, 137.22, 131.51, 131.65, 130.54, 130.76, 129.17, 128.20, 127.55, 127.12, 127.01, 126.71, 126.02, 124.43, 124.23, 123.45, 118.08, 116.11, 115.87, 115.45, 58.56, 55.68, 51.45, 51.67, 48.44, 29.78, 29.68; LC-MS (ESI) m/z: 615.68 [M+H]+.
1H NMR (300 MHz, CDCl3-d1) δ: 7.93-7.81 (m, 2H), 7.66 (dd, J=6.0, 3.3 Hz, 1H), 7.53 (dq, J=6.1, 4.0, 3.4 Hz, 2H), 7.51-7.42 (m, 1H), 7.19 (d, J=2.3 Hz, 1H), 4.31 (dd, J=7.9, 5.5 Hz, 1H), 3.26-3.07 (m, 2H), 2.79-2.57 (m, 3H), 1.11 (ddt, J=10.7, 7.5, 3.7 Hz, 1H), 0.58-0.45 (m, 2H), 0.34-0.21 (m, 2H); 13C NMR (75 MHz, CDCl3-d1) δ: 173.43, 162.78, 156.44, 153.88, 137.85, 134.75, 133.44, 133.26, 131.45, 131.39, 129.69, 129.45, 128.57, 128.38, 127.21, 122.56, 54.73, 51.82, 38.13, 29.58, 29.14, 11.63, 6.31; LC-MS (ESI) m/z: 503.0[M+H]+.
1H NMR (300 MHz, CDCl3-d1) δ: 7.81 (d, J=2.4 Hz, 1H), 7.74 (d, J=8.4 Hz, 1H), 7.70-7.55 (m, 2H), 7.53-7.41 (m, 2H), 7.32 (ddd, J=7.8, 5.1, 3.8 Hz, 1H), 4.79-4.50 (m, 1H), 3.70 (s, 2H), 3.43 (dd, J=13.5, 4.8 Hz, 1H), 3.13 (dd, J=13.6, 4.8 Hz, 1H), 2.71-2.43 (m, 3H), 2.53-2.28 (m, 1H), 1.50-1.33 (m, 1H), 1.42-1.14 (m, 4H); 13C NMR (75 MHz, CDCl3-d1) δ: 173.45, 162.31, 154.35, 153.57, 138.87, 136.17, 134.12, 133.45, 132.28, 130.98, 129.34, 129.47, 128.38, 126.68, 122.44, 119.76, 55.43, 51.67, 37.43, 29.81, 29.62, 13.54, 6.60; LC-MS (ESI) m/z: 545.88 [M+H]+.
1H NMR (300 MHz, CDCl3-d1) δ: 8.49 (d, J=2.1 Hz, 1H), 8.37 (dd, J=8.5, 2.1 Hz, 1H), 8.02 (d, J=8.5 Hz, 1H), 7.67-7.48 (m, 3H), 7.30 (ddd, J=8.0, 6.9, 1.7 Hz, 1H), 4.67-4.43 (m, 1H), 3.34 (s, 2H), 3.10-3.01 (m, 1H), 2.90-2.85 (m, 1H), 2.59-2.33 (m, 2H), 2.39-2.23 (m, 1H), 2.20-2.05 (m, 1H), 1.46-1.21 (m, 5H); 13C NMR (75 MHz, CDCl3-d1) δ: 173.50, 162.65, 154.76, 153.55, 146.81, 138.09, 137.32, 134.46, 130.71, 129.98, 128.12, 128.23, 128.46, 126.87, 125.67, 123.75, 55.43, 51.56, 37.56, 29.65, 29.23, 13.45, 6.76; LC-MS (ESI) m/z: 511.98 [M+H]+.
1H NMR (300 MHz, CDCl3-d1) δ: 7.94-7.80 (m, 2H), 7.69-7.60 (m, 1H), 7.58-7.48 (m, 2H), 7.45 (qd, J=5.5, 2.5 Hz, 1H), 7.20 (d, J=2.4 Hz, 1H), 4.33 (dd, J=7.9, 5.4 Hz, 1H), 4.15-3.96 (m, 2H), 3.60 (s, 3H), 3.21 (t, J=2.5 Hz, 1H), 2.78-2.54 (m, 4H); 13C NMR (75 MHz, CDCl3-d1) δ: 173.25, 162.95, 156.03, 153.88, 137.76, 134.79, 133.90, 133.06, 131.54, 131.29, 129.88, 129.65, 128.82, 128.67, 127.31, 123.03, 79.13, 72.19, 54.94 51.94, 29.57, 29.24, 20.22; LC-MS (ESI) m/z: 485.1 [M+H]+.
1H NMR (300 MHz, CDCl3-d1) δ: 7.97 (d, J=2.5 Hz, 1H), 7.76 (d, J=8.4 Hz, 1H), 7.55 (dd, J=8.5, 2.4 Hz, 1H), 7.48-7.31 (m, 3H), 7.18 (ddd, J=7.8, 5.7, 3.2 Hz, 1H), 4.67-4.52 (m, 1H), 4.01 (dd, J=12.3, 3.0 Hz, 1H), 3.89 (dd, J=12.4, 3.0 Hz, 1H), 3.71 (s, 2H), 2.65-2.32 (m, 3H), 2.29-2.05 (m, 2H); 13C NMR (75 MHz, CDCl3-d1) δ: 173.12, 162.65, 154.30, 153.09, 138.23, 136.76, 134.09, 133.19, 132.65, 130.65, 129.45, 129.76, 128.78, 126.13, 122.56, 119.73, 79.01, 72.66, 55.11, 51.70, 29.57, 29.76, 20.41; LC-MS (ESI) m/z: 529.87 [M+H]+.
1H NMR (300 MHz, CDCl3-d1) δ: 8.49-8.34 (m, 2H), 8.09 (d, J=8.4 Hz, 1H), 7.55-7.40 (m, 3H), 7.30 (ddd, J=7.7, 7.2, 1.7 Hz, 1H), 4.89 (t, J=8.0 Hz, 1H), 4.12 (dd, J=12.4, 3.0 Hz, 1H), 3.89 (dd, J=12.4, 3.0 Hz, 1H), 3.60 (s, 2H), 2.87-2.63 (m, 2H), 2.49-2.33 (m, 1H), 2.37-2.29 (m, 1H), 2.21 (t, J=3.0 Hz, 1H); 13C NMR (75 MHz, CDCl3-d1) δ: 173.50, 162.06, 154.02, 153.88, 146.01, 138.70, 137.82, 134.63, 130.41, 129.65, 128.39, 128.36, 128.20, 126.67, 125.98, 123.39, 79.06, 72.67, 55.11, 51.90, 29.70, 29.62, 20.40; LC-MS (ESI) m/z: 495.97 [M+H]+.
1H NMR (300 MHz, CDCl3-d1) δ: 7.92 (d, J=1.8 Hz, 2H), 7.72-7.64 (m, 1H), 7.58-7.46 (m, 3H), 7.27-7.16 (m, 1H), 4.34 (t, J=6.6 Hz, 1H), 3.62 (s, 3H), 3.55 (t, J=4.5 Hz, 4H), 3.43 (s, 2H), 2.81-2.67 (m, 2H), 2.63 (t, J=6.6 Hz, 4H), 2.40 (s, 4H); 13C NMR (75 MHz, CDCl3-d1) δ:173.34, 162.85, 156.47, 153.39, 137.34, 134.56, 133.33, 133.10, 131.49, 131.36, 129.24, 129.11, 128.87, 128.59, 127.39, 122.55, 66.23, 54.88, 53.99, 53.54, 51.78, 30.35, 29.88, 29.68; LC-MS (ESI) m/z: 564.1 [M+H]+.
1H NMR (300 MHz, CDCl3-d1) δ: 8.04 (dd, J=8.7, 2.3 Hz, 1H), 7.83 (d, J=8.7 Hz, 1H), 7.68 (dd, J=6.0, 3.3 Hz, 1H), 7.60-7.45 (m, 3H), 7.33 (d, J=2.2 Hz, 1H), 4.33 (t, J=6.6 Hz, 1H), 3.62 (s, 3H), 3.56-3.51 (m, 4H), 3.39 (d, J=6.2 Hz, 2H), 2.82-2.66 (m, 2H), 2.62 (t, J=6.7 Hz, 4H), 2.45-2.32 (m, 4H); 13C NMR (75 MHz, CDCl3-d1) δ: 173.54, 162.56, 154.86, 153.45, 138.96, 136.11, 134.57, 133.69, 132.98, 130.01, 129.24, 129.30, 128.45, 126.35, 122.57, 119.97, 65.12, 55.45, 53.55, 52.57, 51.98, 30.65, 29.80, 29.89; LC-MS (ESI) m/z: 606.7 [M+H]+.
1H NMR (300 MHz, CDCl3-d1) δ: 8.56-8.43 (m, 2H), 8.13 (d, J=8.3 Hz, 1H), 7.59-7.47 (m, 1H), 7.52-7.38 (m, 2H), 7.37-7.25 (m, 1H), 5.11-4.96 (m, 1H), 3.54-3.33 (m, 8H), 3.19 (dt, J=14.1, 5.2 Hz, 1H), 2.89-2.65 (m, 3H), 2.57-2.32 (m, 6H), 2.20-2.11 (m, 1H); 13C NMR (75 MHz, CDCl3-d1) δ: 173.11, 162.45, 154.44, 153.90, 146.22, 138.67, 137.48, 135.92, 130.33, 129.68, 128.45, 128.85, 128.68, 126.15, 125.68, 123.42, 65.82, 55.15, 53.47, 52.98, 51.75, 30.09, 29.61, 29.01; LC-MS (ESI) m/z: 571.05 [M+H]+.
1H NMR (300 MHz, CDCl3-d1) δ: 8.06-7.74 (m, 2H), 7.66 (s, 1H), 7.49 (d, J=27.1 Hz, 3H), 7.19 (s, 1H), 3.60 (s, 3H), 3.32 (s, 2H), 2.69 (s, 5H), 0.93 (s, 6H); 13C NMR (75 MHz, CDCl3-d1) δ: 173.45, 162.23, 156.68, 153.44, 137.88, 134.21, 133.45, 133.88, 131.73, 131.46, 129.96, 129.78, 128.75, 128.53, 127.38, 122.45, 54.59, 51.83, 51.67, 47.65, 30.57, 29.99, 29.43, 11.87; LC-MS (ESI) m/z: 548.1 [M+H]+.
1H NMR (300 MHz, CDCl3-d1) δ: 7.95 (d, J=2.4 Hz, 1H), 7.79-7.61 (m, 2H), 7.55-7.40 (m, 3H), 7.28 (ddd, J=7.7, 6.4, 2.4 Hz, 1H), 4.76-4.62 (m, 1H), 3.68-3.51 (m, 3H), 3.43 (dt, J=14.2, 5.2 Hz, 1H), 2.87 (dt, J=12.1, 5.2 Hz, 1H), 2.79-2.56 (m, 3H), 2.63-2.46 (m, 4H), 2.52-2.39 (m, 1H), 2.43-2.24 (m, 1H), 1.03 (t, J=7.2 Hz, 6H); 13C NMR (75 MHz, CDCl3-d1) δ: 173.47, 162.55, 154.56, 153.88, 138.65, 136.19, 134.57, 133.30, 132.51, 130.41, 129.80, 129.31, 128.32, 126.70, 122.48, 119.74, 55.12, 51.92, 50.90, 47.11, 30.42, 29.81, 29.62, 11.17; LC-MS (ESI) m/z: 590.97 [M+H]+.
1H NMR (300 MHz, CDCl3-d1) δ: 8.54 (dd, J=8.5, 2.1 Hz, 1H), 8.41 (d, J=2.1 Hz, 1H), 8.29 (d, J=8.3 Hz, 1H), 7.60 (dd, J=7.7, 1.5 Hz, 1H), 7.56-7.39 (m, 2H), 7.31 (td, J=7.5, 1.4 Hz, 1H), 5.98 (ddd, J=8.2, 7.3, 0.7 Hz, 1H), 3.76-3.56 (m, 4H), 3.33 (dt, J=14.3, 5.2 Hz, 1H), 2.81 (dt, J=12.1, 5.2 Hz, 1H), 2.63-2.49 (m, 8H), 2.32-2.14 (m, 1H), 1.01 (t, J=7.3 Hz, 6H); 13C NMR (75 MHz, CDCl3-d1) δ:173.23, 162.11, 154.63, 153.23, 146.87, 138.86, 137.98, 134.58, 130.23, 129.96, 128.42, 128.18, 128.49, 126.26, 125.86, 123.14, 55.75, 51.87, 50.97, 47.31, 30.65, 29.43, 29.61, 11.32; LC-MS (ESI) m/z: 557.07 [M+H]+.
1H NMR (300 MHz, CDCl3-d1) δ: 7.93-7.80 (m, 2H), 7.66 (dd, J=5.9, 3.4 Hz, 1H), 7.53 (dq, J=6.1, 3.9, 3.5 Hz, 2H), 7.50-7.42 (m, 1H), 7.19 (d, J=2.3 Hz, 1H), 4.31 (dd, J=7.9, 5.5 Hz, 1H), 3.60 (s, 3H), 3.31-3.23 (m, 1H), 3.16 (dt, J=13.4, 7.2 Hz, 1H), 2.78-2.57 (m, 4H), 2.36 (s, 2H), 2.17 (s, 6H), 1.86-1.73 (m, 2H); 13C NMR (75 MHz, CDCl3-d1) δ: 173.98, 162.36, 156.78, 153.43, 137.67, 134.84, 133.56, 133.42, 131.86, 131.46, 129.86, 129.08, 128.68, 128.49, 127.17, 122.98, 58.03, 54.10, 51.27, 45.55, 31.36, 29.71, 29.59, 26.59; LC-MS (ESI) m/z: 534.07 [M+H]+.
1H NMR (300 MHz, CDCl3-d1) δ: 7.99 (d, J=8.4 Hz, 1H), 7.87-7.70 (m, 2H), 7.67 (dd, J=7.6, 1.8 Hz, 1H), 7.56 (dd, J=7.6, 1.6 Hz, 1H), 7.39 (dtd, J=23.1, 7.4, 1.7 Hz, 2H), 6.01-5.91 (m, 1H), 3.65 (s, 3H), 3.38 (dt, J=14.4, 6.4 Hz, 1H), 3.10 (dt, J=14.4, 6.5 Hz, 1H), 2.67-2.34 (m, 6H), 2.22 (s, 5H), 2.01 (dp, J=12.9, 6.4 Hz, 1H), 1.88 (dp, J=12.8, 6.4 Hz, 1H); 13C NMR (75 MHz, CDCl3-d1) δ: 173.14, 162.23, 154.50, 153.43, 138.22, 136.18, 134.79, 133.26, 132.96, 130.16, 129.09, 129.34, 128.98, 126.12, 122.43, 119.21, 57.64, 55.86, 51.43, 44.53, 30.15, 29.70, 29.34, 27.78; LC-MS (ESI) m/z: 576.92 [M+H]+.
1H NMR (300 MHz, CDCl3-d1) δ: 8.58 (dd, J=8.5, 2.1 Hz, 1H), 8.43 (d, J=2.1 Hz, 1H), 8.34 (d, J=8.5 Hz, 1H), 7.55 (dd, J=7.7, 1.4 Hz, 1H), 7.50-7.38 (m, 2H), 7.32 (td, J=7.5, 1.5 Hz, 1H), 4.99 (t, J=8.1 Hz, 1H), 3.61 (s, 3H), 3.26-3.04 (m, 2H), 2.83-2.37 (m, 6H), 2.31 (s, 5H), 1.95 (ddt, J=17.5, 12.8, 6.3 Hz, 2H); 13C NMR (75 MHz, CDCl3-d1) δ: 173.14, 162.40, 154.60, 153.77, 146.41, 138.33, 137.69, 134.87, 130.44, 129.82, 128.58, 128.69, 127.77, 126.86, 125.93, 123.39, 57.73, 55.26, 51.98, 44.99, 30.58, 29.88, 29.09, 27.54; LC-MS (ESI) m/z: 543.09 [M+H]+.
1H NMR (300 MHz, CDCl3-d1) δ: 7.91 (dd, J=8.7, 2.4 Hz, 1H), 7.84 (d, J=8.7 Hz, 1H), 7.71-7.63 (m, 1H), 7.59-7.50 (m, 2H), 7.50-7.41 (m, 1H), 7.21 (d, J=2.4 Hz, 1H), 4.32 (dd, J=7.9, 5.5 Hz, 1H), 3.60 (s, 3H), 2.92-2.56 (m, 10H); 13C NMR (75 MHz, CDCl3-d1) δ: 173.76, 162.91, 156.09, 153.49, 137.91, 134.24, 133.76, 133.42, 131.90, 131.11, 129.46, 129.36, 128.87, 128.71, 127.90, 122.23, 54.29, 53.70, 52.40, 52.22, 51.53, 45.66, 30.98, 29.56, 29.29; LC-MS (ESI) m/z: 573.19 [M+H]+.
1H NMR (300 MHz, CDCl3-d1) δ: 8.03-7.87 (m, 2H), 7.86 (dd, J=8.3, 2.4 Hz, 1H), 7.60 (ddd, J=7.7, 5.3, 1.6 Hz, 2H), 7.42 (td, J=7.5, 1.7 Hz, 1H), 7.32 (td, J=7.6, 1.5 Hz, 1H), 6.10-5.98 (m, 1H), 3.69-3.56 (m, 4H), 3.33 (dt, J=14.2, 5.2 Hz, 1H), 2.90 (dt, J=12.1, 5.2 Hz, 1H), 2.78-2.33 (m, 13H), 2.36-2.26 (s, 3H); 13C NMR (75 MHz, CDCl3-d1) δ: 173.23, 162.76, 154.34, 153.67, 138.98, 136.34, 134.59, 133.16, 132.90, 130.46, 129.51, 129.33, 128.40, 126.10, 122.21, 119.70, 55.37, 53.48, 52.69, 52.16, 51.95, 45.17, 30.34, 29.11, 29.60; LC-MS (ESI) m/z: 617.99 [M+H]+.
1H NMR (300 MHz, CDCl3-d1) δ: 8.56 (dd, J=7.2, 1.5 Hz, 1H), 8.33 (d, J=1.5 Hz, 1H), 7.87 (d, J=7.7 Hz, 1H), 7.69-7.59 (m, 1H), 7.56-7.33 (m, 3H), 5.95-5.83 (m, 1H), 3.56 (s, 3H), 3.50-3.28 (m, 2H), 2.88-2.60 (m, 2H), 2.67-2.49 (m, 7H), 2.55-2.45 (m, 4H), 2.50-2.42 (m, 1H), 2.42-2.29 (m, OH), 2.30 (s, 3H); 13C NMR (75 MHz, CDCl3-d1) δ:173.36, 162.07, 154.51, 153.88, 146.14, 138.72, 137.95, 134.98, 130.33, 129.65, 128.27, 128.25, 128.17, 126.71, 125.83, 123.35, 55.10, 53.62, 52.88, 52.57, 51.93, 45.16, 30.41, 29.67, 29.61; LC-MS (ESI) m/z: 584.19 [M+H]+.
1H NMR (300 MHz, CDCl3-d1) δ: 7.92-7.78 (m, 2H), 7.70-7.60 (m, 1H), 7.58-7.41 (m, 3H), 7.18 (d, J=2.4 Hz, 1H), 4.31 (dd, J=7.8, 5.5 Hz, 1H), 3.36 (d, J=18.0 Hz, 4H), 2.79-2.54 (m, 5H), 2.13 (s, 3H), 2.10-1.92 (m, 3H), 1.90-1.79 (m, 1H), 1.66 (dtd, J=13.2, 10.2, 9.7, 3.5 Hz, 1H), 1.51 (dtd, J=13.8, 10.3, 3.8 Hz, 1H), 1.24 (s, 1H), 1.19-0.97 (m, 1H); 13C NMR (75 MHz, CDCl3-d1) δ: 173.56, 162.78, 154.34, 153.98, 137.09, 134.34, 133.39, 133.14, 131.98, 131.01, 129.84, 129.37, 128.81, 128.58, 127.23, 123.67, 54.45, 53.76, 51.43, 45.98, 39.09, 31.34, 29.71, 29.01; LC-MS (ESI) m/z: 544.17 [M+H]+.
1H NMR (300 MHz, CDCl3-d1) δ 8.02-7.93 (m, 1H), 7.87-7.74 (m, 2H), 7.68-7.57 (m, 1H), 7.53-7.37 (m, 3H), 5.75 (t, J=8.3 Hz, 1H), 3.74 (p, J=4.3 Hz, 1H), 2.95 (ddd, J=12.6, 7.7, 5.0 Hz, 2H), 2.81-2.69 (m, 2H), 2.72-2.64 (m, 1H), 2.67-2.52 (m, 1H), 2.38-2.22 (m, 2H), 2.25 (s, 2H), 2.11-1.94 (m, 2H), 1.76-1.60 (m, 2H); 13C NMR (75 MHz, CDCl3-d1) δ 173.44, 162.92, 154.83, 153.07, 136.68, 136.32, 134.54, 132.69, 130.92, 129.67, 129.29, 128.62, 126.95, 122.39, 118.51, 55.15, 52.59, 51.85, 45.28, 39.32, 30.13, 29.31, 29.03; LC-MS (ESI) m/z: 589.07 [M+H]+.
1H NMR (300 MHz, CDCl3-d1) δ 8.65 (dd, J=8.9, 2.0 Hz, 1H), 8.44 (d, J=2.0 Hz, 1H), 8.20 (d, J=8.9 Hz, 1H), 7.68-7.52 (m, 1H), 7.53-7.35 (m, 3H), 5.75 (t, J=8.3 Hz, 1H), 3.76 (p, J=4.3 Hz, 1H), 2.92 (ddd, J=12.6, 7.7, 5.0 Hz, 2H), 2.82-2.63 (m, 2H), 2.73-2.64 (m, 1H), 2.67-2.52 (m, 1H), 2.41-2.32 (m, 2H), 2.24 (s, 2H), 2.11-1.95 (m, 2H), 1.76-1.60 (m, 2H). 13C NMR (75 MHz, CDCl3-d1) δ 173.44, 162.54, 154.39, 153.21, 145.72, 137.91, 137.16, 134.54, 130.92, 129.44, 129.27, 128.61, 128.47, 126.86, 125.17, 123.04, 55.05, 52.59, 51.85, 45.22, 39.42, 30.26, 29.38, 29.04; LC-MS (ESI) m/z: 556.15 [M+H]+.
1H NMR (300 MHz, CDCl3-d1) δ: 7.93-7.84 (m, 2H), 7.74-7.65 (m, 1H), 7.58-7.50 (m, 2H), 7.50-7.47 (m, 1H), 7.15 (d, J=2.3 Hz, 1H), 4.33-4.26 (m, 2H), 3.47 (q, J=5.9 Hz, 2H), 3.43-3.35 (m, OH), 3.31 (s, 2H), 3.26 (dt, J=13.8, 7.0 Hz, 1H), 3.12 (dt, J=13.4, 7.2 Hz, 1H), 2.78-2.57 (m, 3H), 2.32 (s, 10H), 1.90-1.71 (m, 2H); 13C NMR (75 MHz, CDCl3-d1) δ: 173.23, 162.34, 156.65, 153.22, 137.74, 134.46, 133.56, 133.06, 131.88, 131.72, 129.74, 129.36, 128.80, 128.55, 127.38, 122.21, 59.43, 57.76, 55.63, 54.52, 52.37, 52.27, 51.28, 31.15, 29.36, 29.27, 27.46; LC-MS (ESI) m/z: 617.23 [M+H]+.
1H NMR (300 MHz, CDCl3-d1) δ 8.02-7.92 (m, 1H), 7.87-7.73 (m, 2H), 7.68-7.57 (m, 1H), 7.53-7.37 (m, 3H), 5.75 (t, J=8.3 Hz, 1H), 4.11 (t, J=6.3 Hz, 1H), 3.62 (s, 2H), 3.60-3.45 (m, 2H), 3.24 (td, J=6.9, 1.9 Hz, 2H), 2.78-2.54 (m, 2H), 2.60-2.52 (m, 1H), 2.56-2.43 (m, 2H), 2.52-2.45 (m, 1H), 2.29-2.35 (m, 6H), 2.40-2.21 (m, 2H), 1.85 (tt, J=6.9, 5.8 Hz, 2H); 13C NMR (75 MHz, CDCl3-d1) δ 173.41, 162.97, 156.25, 153.66, 136.68, 136.32, 134.34, 134.42, 132.59, 130.92, 129.67, 129.26, 128.51, 126.45, 122.37, 118.53, 59.43, 57.28, 55.15, 54.51, 52.52, 51.92, 51.75, 30.28, 29.37, 29.07, 27.65; LC-MS (ESI) m/z: 662.13 [M+H]+.
1H NMR (300 MHz, CDCl3-d1) δ 8.65 (dd, J=8.9, 2.0 Hz, 1H), 8.46 (d, J=2.0 Hz, 1H), 8.20 (d, J=8.9 Hz, 1H), 7.67-7.66 (m, 1H), 7.53-7.34 (m, 3H), 5.75 (t, J=8.3 Hz, 1H), 4.11 (t, J=6.3 Hz, 1H), 3.65 (s, 2H), 3.63-3.55 (m, 2H), 3.24 (td, J=6.9, 1.9 Hz, 2H), 2.78-2.56 (m, 2H), 2.60-2.51 (m, 1H), 2.56-2.42 (m, 3H), 2.49-2.34 (m, 7H), 2.44-2.35 (m, 1H), 2.39-2.18 (m, 2H), 1.81 (tt, J=6.9, 5.8 Hz, 2H); 13C NMR (75 MHz, CDCl3-d1) δ 173.44, 162.54, 156.32, 153.82, 145.72, 138.32, 137.06, 134.54, 130.92, 129.41, 129.27, 128.61, 128.42, 126.96, 125.17, 123.04, 59.43, 57.27, 55.05, 54.51, 52.52, 51.92, 51.85, 30.28, 29.37, 29.07, 27.55; LC-MS (ESI) m/z: 629.20 [M+H]+.
1H NMR (300 MHz, CDCl3-d1) δ: 8.42 (d, J=8.8 Hz, 1H), 7.86 (dd, J=8.8, 2.5 Hz, 1H), 7.70-7.60 (m, 1H), 7.58-7.51 (m, 2H), 7.51-7.42 (m, 1H), 7.16 (d, J=2.4 Hz, 1H), 5.21-5.08 (m, 2H), 4.38 (dd, J=8.6, 5.2 Hz, 1H), 3.60 (s, 3H), 3.32 (s, 1H), 2.88-2.54 (m, 7H), 2.48-2.38 (m, 1H); 13C NMR (75 MHz, CDCl3-d1) δ: 173.36, 162.28, 153.47, 153.28, 137.19, 134.03, 133.47, 133.19, 131.63, 131.57, 129.72, 129.56, 128.86, 128.55, 127.05, 123.53, 66.32, 58.17, 54.59, 51.73, 43.82, 29.47, 29.18; LC-MS (ESI) m/z: 547.34 [M+H]+.
1H NMR (300 MHz, CDCl3-d1) δ 7.93 (dd, J=1.9, 0.7 Hz, 1H), 7.87-7.74 (m, 2H), 7.64-7.51 (m, 1H), 7.53-7.37 (m, 3H), 5.75 (t, J=8.3 Hz, 1H), 4.08 (d, J=3.6 Hz, 2H), 3.53 (s, 3H), 3.69-3.52 (m, 4H), 2.68-2.52 (m, 2H), 2.48-2.46 (m, 4H), 2.38-2.29 (m, 1H), 2.33-2.21 (m, 1H). 13C NMR (75 MHz, CDCl3-d1) δ 173.44, 162.92, 153.77, 153.55, 137.68, 136.38, 134.61, 134.54, 132.69, 130.92, 129.73, 129.21, 128.61, 126.95, 122.30, 118.53, 66.63, 56.98, 55.05, 51.65, 46.16, 29.48, 29.27; LC-MS (ESI) m/z: 591.01 [M+H]+.
1H NMR (300 MHz, CDCl3-d1) δ 8.65 (dd, J=9.0, 2.1 Hz, 1H), 8.46 (d, J=2.2 Hz, 1H), 8.20 (d, J=8.9 Hz, 1H), 7.67-7.56 (m, 1H), 7.53-7.37 (m, 3H), 5.72 (t, J=8.3 Hz, 1H), 4.08 (d, J=3.6 Hz, 2H), 3.63 (s, 3H), 3.69-3.54 (m, 4H), 2.72-2.57 (m, 2H), 2.58-2.42 (m, 4H), 2.38-2.25 (m, 1H), 2.33-2.18 (m, 1H); 13C NMR (75 MHz, CDCl3-d1) δ 173.44, 162.54, 153.83, 153.78, 145.72, 138.23, 137.06, 134.57, 130.82, 129.44, 129.37, 128.64, 128.47, 126.96, 125.17, 123.04, 66.63, 56.91, 55.05, 51.82, 46.16, 29.38, 29.06; LC-MS (ESI) m/z: 558.13 [M+H]+.
1H NMR (300 MHz, CDCl3-d1) δ: 7.97-7.83 (m, 2H), 7.57-7.40 (m, 6H), 4.23 (dd, J=7.6, 5.5 Hz, 1H), 3.63 (s, 3H), 2.82-2.53 (m, 7H); 13C NMR (75 MHz, CDCl3-d1) δ: 173.47, 166.48, 153.48, 153.37, 139.58, 133.75, 133.42, 132.62, 130.46, 130.27, 128.69, 128.43, 128.12, 122.65, 55.63, 51.73, 29.83, 29.07, 16.74; LC-MS (ESI) m/z: 427.06 [M+H]+.
1H NMR (300 MHz, CDCl3-d1) δ 7.82-7.70 (m, 2H), 7.66-7.54 (m, 2H), 7.53 (d, J=8.1 Hz, 1H), 7.52-7.43 (m, 2H), 7.48-7.39 (m, 1H), 5.64 (t, J=8.3 Hz, 1H), 2.72 (s, 3H), 2.74-2.51 (m, 2H), 2.38-2.24 (m, 1H), 2.33-2.18 (m, 1H); 13C NMR (75 MHz, CDCl3-d1) δ: 173.44, 166.20, 153.33, 152.80, 138.56, 136.32, 133.69, 133.29, 129.80, 129.08, 128.49, 128.41, 122.38, 118.45, 55.26, 51.82, 29.38, 29.06, 16.60; LC-MS (ESI) m/z: 472.04 [M+H]+.
1H NMR (300 MHz, CDCl3-d1) δ 8.61 (dd, J=8.9, 2.1 Hz, 1H), 8.59 (d, J=2.2 Hz, 1H), 8.12 (d, J=9.0 Hz, 1H), 7.69-7.66 (m, 2H), 7.55-7.43 (m, 2H), 7.48-7.34 (m, 1H), 5.64 (t, J=8.3 Hz, 1H), 2.72 (s, 3H), 2.78-2.52 (m, 2H), 2.38-2.23 (m, 1H), 2.33-2.18 (m, 1H); 13C NMR (75 MHz, CDCl3-d1) δ: 173.44, 166.07, 153.35, 153.07, 145.66, 138.78, 137.34, 129.81, 128.93, 128.42, 128.42, 128.42, 125.72, 123.07, 55.32, 51.81, 29.34, 29.16, 16.62; LC-MS (ESI) m/z: 438.12 [M+H]+.
1H NMR (300 MHz, CDCl3-d1) δ: 7.92 (d, J=2.5 Hz, 2H), 7.52-7.42 (m, 6H), 4.23 (t, J=6.4 Hz, 1H), 3.63 (s, 3H), 3.43 (t, J=4.6 Hz, 4H), 2.75-2.53 (m, 6H), 2.33-2.27 (m, 3H), 2.09 (s, 1H); 13C NMR (75 MHz, CDCl3-d1) δ: 172.36, 166.71, 156.82, 153.23, 139.62, 133.81, 133.53, 132.55, 130.71, 130.52, 128.64, 128.37, 128.10, 122.51, 66.73, 55.87, 53.44, 53.31, 51.34, 30.36, 29.52, 29.37; LC-MS (ESI) m/z: 526.19 [M+H]+.
1H NMR (300 MHz, CDCl3-d1) δ: 8.09 (d, J=10.9 Hz, 1H), 7.87 (d, J=8.7 Hz, 1H), 7.61-7.48 (m, 6H), 4.25 (t, J=6.5 Hz, 1H), 3.65 (s, 3H), 3.56-3.39 (m, 6H), 2.81-2.58 (m, 6H), 2.34 (s, 4H); 13C NMR (75 MHz, CDCl3-d1) δ 173.34, 165.99, 155.26, 153.74, 138.36, 136.51, 134.19, 133.09, 129.84, 129.04, 128.59, 128.40, 122.38, 118.45, 66.51, 55.23, 54.17, 52.82, 51.81, 30.47, 29.32, 29.08; LC-MS (ESI) m/z: 572.00 [M+H]+.
1H NMR (300 MHz, CDCl3-d1) δ 8.61 (dd, J=8.9, 2.1 Hz, 1H), 8.49 (d, J=2.2 Hz, 1H), 8.12 (d, J=9.0 Hz, 1H), 7.69-7.56 (m, 2H), 7.55-7.43 (m, 2H), 7.48-7.39 (m, 1H), 5.61 (t, J=8.3 Hz, 1H), 3.64-3.43 (m, 7H), 3.35 (td, J=6.3, 0.8 Hz, 2H), 2.73-2.76 (m, 3H), 2.61-2.41 (m, 4H), 2.41-2.14 (m, 2H); 13C NMR (75 MHz, CDCl3-d1) δ: 173.44, 166.04, 155.51, 153.77, 145.66, 138.78, 137.67, 129.60, 128.98, 128.49, 128.46, 128.42, 125.71, 123.07, 66.23, 55.42, 54.12, 52.79, 51.85, 30.47, 29.35, 29.07; LC-MS (ESI) m/z: 537.19 [M+H]+.
1H NMR (300 MHz, CDCl3-d1) δ: 7.97-7.85 (m, 2H), 7.57-7.40 (m, 6H), 4.23 (dd, J=7.6, 5.5 Hz, 1H), 3.61 (s, 2H), 3.11 (td, J=7.2, 2.7 Hz, 2H), 2.82-2.54 (m, 4H), 2.24-2.16 (m, 2H), 2.02 (s, 6H), 1.69 (dq, J=14.5, 7.1 Hz, 2H), 1.27-1.11 (m, 1H); 13C NMR (75 MHz, CDCl3-d1) δ:173.57, 166.82, 156.35, 153.86, 139.08, 133.50, 133.02, 132.63, 130.71, 130.21, 128.66, 128.68, 128.42, 122.91, 58.46, 55.26, 51.91, 45.36, 31.13, 29.46, 29.28, 26.47; LC-MS (ESI) m/z: 499.56 [M+H]+.
1H NMR (300 MHz, CDCl3-d1) δ 7.82-7.70 (m, 2H), 7.66-7.39 (m, 7H), 5.64 (t, J=8.3 Hz, 1H), 3.62 (s, 3H), 3.23 (d, J=12.4 Hz, 1H), 2.78-2.61 (m, 1H), 2.67-2.57 (m, 1H), 2.57 (t, J=5.7 Hz, 2H), 2.38-2.29 (m, 1H), 2.33-2.14 (m, 1H), 1.92-1.74 (m, 2H); 13C NMR (75 MHz, CDCl3-d1) δ 173.44, 165.99, 156.25, 153.75, 138.56, 136.31, 134.08, 133.09, 129.80, 129.05, 128.49, 128.40, 122.32, 118.45, 58.21, 55.26, 51.85, 44.82, 30.04, 29.35, 29.08, 26.61; LC-MS (ESI) m/z: 543.11 [M+H]+.
1H NMR (300 MHz, CDCl3-d1) δ 8.63 (dd, J=8.9, 2.1 Hz, 1H), 8.49 (d, J=2.2 Hz, 1H), 8.11 (d, J=9.0 Hz, 1H), 7.69-7.56 (m, 2H), 7.55-7.39 (m, 3H), 5.64 (t, J=8.3 Hz, 1H), 3.63 (s, 3H), 3.23 (d, J=12.4 Hz, 1H), 2.78-2.64 (m, 1H), 2.67-2.55 (m, 1H), 2.57 (t, J=5.7 Hz, 2H), 2.38-2.23 (m, 1H), 2.33-2.28 (m, 1H), 1.92-1.74 (m, 2H); 13C NMR (75 MHz, CDCl3-d1) δ 173.44, 166.04, 156.33, 153.75, 145.66, 138.78, 137.81, 129.81, 128.98, 128.49, 128.43, 128.42, 125.61, 123.07, 58.21, 55.42, 51.85, 44.72, 30.08, 29.33, 29.07, 26.61; LC-MS (ESI) m/z: 509.19 [M+H]+.
1H NMR (300 MHz, CDCl3-d1) δ: 7.82 (d, J=8.2 Hz, 1H), 7.87 (s, 2H), 7.67-7.60 (m, 2H), 7.51-7.40 (m, 4H), 5.83 (d, J=8.5 Hz, 2H), 5.75 (t, J=8.3 Hz, 1H), 2.74-2.56 (m, 2H), 2.39-2.23 (m, 2H); 13C NMR (75 MHz, CDCl3-d1) S: 173.42, 161.14, 157.56, 157.13, 154.10, 137.57, 134.72, 134.19, 132.66, 131.29, 131.26, 129.70, 129.62, 128.68, 128.46, 127.31, 123.05, 66.32, 66.28, 58.25, 51.94, 29.93, 29.01; LC-MS (ESI) m/z: 557.34 [M+H]+.
1H NMR (300 MHz, CDCl3-d1) δ 7.99 (dd, J=1.9, 0.7 Hz, 1H), 7.87 (s, 2H), 7.84-7.64 (m, 2H), 7.67-7.53 (m, 1H), 7.53-7.35 (m, 3H), 5.83 (d, J=8.4 Hz, 2H), 5.75 (t, J=8.3 Hz, 1H), 2.78-2.51 (m, 2H), 2.38-2.29 (m, 1H), 2.33-2.21 (m, 1H); 13C NMR (75 MHz, CDCl3-d1) δ 173.30, 161.23, 157.01, 156.93, 153.98, 136.52, 136.24, 135.16, 133.90, 132.76, 130.92, 129.32, 128.64, 128.61, 126.95, 122.23, 118.29, 66.01, 65.93, 58.26, 51.55, 29.53, 29.22; LC-MS (ESI) m/z: 601.96 [M+H]+.
1H NMR (300 MHz, CDCl3-d1) δ 8.65 (dd, J=9.0, 2.1 Hz, 1H), 8.41 (d, J=2.2 Hz, 1H), 8.29 (d, J=8.9 Hz, 1H), 7.87 (s, 2H), 7.67-7.57 (m, 1H), 7.53-7.37 (m, 3H), 5.81 (d, J=8.4 Hz, 2H), 5.75 (t, J=8.3 Hz, 1H), 2.77-2.52 (m, 2H), 2.38-2.18 (m, 2H). 13C NMR (75 MHz, CDCl3-d1) δ:173.30, 160.78, 157.01, 157.04, 154.03, 145.72, 137.80, 136.97, 133.90, 130.72, 129.30, 128.61, 128.46, 128.44, 126.75, 124.61, 123.23, 66.11, 65.82, 58.24, 51.72, 29.53, 29.52; LC-MS (ESI) m/z: 567.04 [M+H]+.
1H NMR (300 MHz, CDCl3-d1) S: 8.79 (dd, J=3.5, 1.2 Hz, 1H), 7.86-7.75 (m, 3H), 7.70-7.65 (m, 1H), 7.54 (dd, J=7.8, 1.5 Hz, 1H), 7.33-7.30 (m, 1H), 6.13 (t, J=5.3 Hz, 1H), 3.66 (s, 2H), 2.72 (s, 3H), 2.66 (td, J=7.8, 1.2 Hz, 3H), 2.62-2.51 (m, 2H). 13C NMR (75 MHz, CDCl3-d1) δ 173.38, 162.32, 155.83, 153.99, 150.80, 147.41, 137.47, 136.64, 136.60, 134.48, 127.86, 125.25, 122.80, 122.65, 120.45, 57.05, 52.01, 29.61, 29.27, 16.69. LC-MS (ESI) m/z:472.3[M+H]+.
1H NMR (300 MHz, CDCl3-d1) δ: 8.78 (dd, J=3.5, 1.3 Hz, 1H), 7.85-7.74 (m, 3H), 7.67 (t, J=1.3 Hz, 1H), 7.54 (dd, J=7.9, 1.3 Hz, 1H), 7.33-7.30 (m, 1H), 6.13 (t, J=5.2 Hz, 1H), 3.65 (s, 3H), 3.29-3.18 (m, 2H), 2.70-2.52 (m, 4H), 1.40 (t, J=7.2 Hz, 3H). 13C NMR (75 MHz, CDCl3-d1) δ 173.72, 160.73, 157.51, 153.83, 151.63, 147.12, 137.61, 137.47, 136.40, 134.75, 125.25, 124.56, 123.44, 122.65, 120.39, 66.22, 57.42, 52.01, 29.61, 29.23, 14.70. LC-MS (ESI) m/z:486.1 [M+H]+.
1H NMR (300 MHz, CDCl3-d1) δ: 8.79 (dd, J=3.6, 1.3 Hz, 1H), 7.82 (td, J=7.6, 1.2 Hz, 1H), 7.80-7.71 (m, 2H), 7.67 (d, J=2.2 Hz, 1H), 7.56 (dd, J=7.9, 1.4 Hz, 1H), 7.33-7.31 (m, 1H), 6.13 (t, J=5.2 Hz, 1H), 3.66 (s, 3H), 3.02 (d, J=4.8 Hz, 2H), 2.70-2.51 (m, 4H), 1.40-1.24 (m, 5H). 13C NMR (75 MHz, CDCl3-d1) δ 173.58, 162.37, 156.38, 154.59, 149.57, 147.13, 137.57, 137.28, 136.60, 134.78, 127.93, 125.30, 122.76, 122.64, 120.55, 59.05, 51.80, 39.41, 29.45, 29.28, 10.89, 6.19. LC-MS (ESI) m/z: 512.4[M+H]+.
1H NMR (300 MHz, CDCl3-d1) δ: 8.58 (d, J=4.2 Hz, 1H), 8.18 (d, J=7.9 Hz, 1H), 7.85 (dd, J=7.2, 1.3 Hz, 1H), 7.79 (dd, J=6.5, 4.2 Hz, 1H), 7.66 (d, J=8.8 Hz, 2H), 7.41-7.37 (m, 1H), 4.27 (t, J=5.1 Hz, 1H), 3.69 (s, 3H), 3.64 (t, J=4.8 Hz, 4H), 3.52-3.41 (m, 2H), 2.91-2.82 (m, 4H), 2.74 (t, J=6.7 Hz, 2H), 2.46 (t, J=4.5 Hz, 4H). 13C NMR (75 MHz, CDCl3-d1) δ 173.62, 162.11, 156.69, 154.59, 148.12, 147.31, 137.47, 137.09, 136.60, 135.16, 128.24, 125.26, 122.73, 122.59, 120.96, 65.69, 58.05, 54.45, 53.31, 51.93, 32.18, 29.54, 29.28. LC-MS (ESI) m/z: 571.1 [M+H]+.
1H NMR (300 MHz, CDCl3-d1) δ: 8.79 (dd, J=3.6, 1.2 Hz, 1H), 7.81 (td, J=7.6, 1.2 Hz, 1H), 7.78-7.72 (m, 2H), 7.67 (dd, J=1.7, 0.9 Hz, 1H), 7.56 (dd, J=7.9, 1.4 Hz, 1H), 7.33-7.30 (m, 1H), 6.13 (t, J=5.4 Hz, 1H), 3.65 (s, 3H), 3.27 (t, J=6.4 Hz, 2H), 2.73-2.62 (m, 2H), 2.60-2.48 (m, 4H), 2.25 (s, 6H), 1.93 (pd, J=6.5, 1.1 Hz, 2H). 13C NMR (75 MHz, CDCl3-d1) δ 173.33, 162.11, 156.72, 154.49, 147.89, 146.31, 137.30, 137.09, 136.67, 135.32, 128.24, 125.26, 122.74, 122.32, 120.94, 58.49, 58.05, 51.96, 44.90, 32.55, 29.54, 29.28, 26.44. LC-MS (ESI) m/z:543.2 [M+H]+.
1H NMR (300 MHz, CDCl3-d1) δ: 7.91 (d, J=2.0 Hz, 1H), 7.61 (dd, J=7.1, 2.2 Hz, 1H), 7.51-7.37 (m, 4H), 7.29 (d, J=7.5 Hz, 1H), 5.22 (s, 1H), 3.68 (s, 3H), 3.48 (d, J=0.9 Hz, 2H), 2.68-2.58 (m, 4H), 2.49 (s, 2H), 2.44-2.31 (m, 2H), 2.30-2.19 (m, 2H), 1.80 (d, J=12.5 Hz, 4H). 13C NMR (75 MHz, CDCl3-d1) δ 173.30, 160.77, 154.13, 148.12, 138.12, 135.83, 134.71, 132.61, 130.82, 130.51, 130.43, 129.29, 129.04, 128.19, 126.36, 122.81, 57.76, 55.23, 54.02, 51.98, 32.51, 29.56, 29.39, 23.39.
LC-MS (ESI) m/z:544.1 [M+H]+.
1H NMR (300 MHz, CDCl3-d1) δ: 7.72 (dd, J=8.4, 2.6 Hz, 1H), 7.61-7.56 (m, 2H), 7.55-7.43 (m, 2H), 7.28 (td, J=7.5, 1.5 Hz, 1H), 7.21 (dd, J=7.8, 1.5 Hz, 1H), 6.10 (t, J=5.2 Hz, 1H), 3.64 (s, 3H), 3.45 (t, J=5.1 Hz, 2H), 2.74 (t, J=4.9 Hz, 4H), 2.65-2.51 (m, 6H), 1.89-182 (m, 4H). 13C NMR (75 MHz, CDCl3-d1) δ 173.65, 163.32, 159.17, 154.22, 147.98, 136.64, 136.54, 132.59, 131.54, 130.23, 128.57, 127.70, 124.00, 121.79, 120.47, 115.76, 58.29, 55.23, 54.02, 51.93, 32.18, 29.54, 29.30, 23.40. LC-MS (ESI) m/z:572.1 [M+H]+.
1H NMR (300 MHz, CDCl3-d1) δ: 7.75 (dd, J=8.4, 2.6 Hz, 1H), 7.68-7.58 (m, 2H), 7.55 (dd, J=7.7, 1.6 Hz, 1H), 7.49 (dd, J=7.8, 1.6 Hz, 1H), 7.40 (td, J=7.6, 1.6 Hz, 1H), 7.33 (td, J=7.5, 1.5 Hz, 1H), 6.11 (t, J=5.2 Hz, 1H), 3.64 (s, 3H), 3.45 (t, J=5.1 Hz, 2H), 2.74 (t, J=4.9 Hz, 4H), 2.65-2.51 (m, 6H), 1.86 (td, J=4.9, 2.7 Hz, 4H). 13C NMR (75 MHz, CDCl3-d1) δ 173.57, 160.33, 154.78, 149.12, 137.49, 136.40, 136.44, 134.71, 133.11, 131.17, 130.63, 129.36, 128.19, 126.09, 121.84, 120.47, 57.87, 55.33, 54.02, 51.93, 32.14, 29.54, 29.39, 23.33. LC-MS (ESI) m/z:588.0 [M+H]+.
1H NMR (300 MHz, CDCl3-d1) δ: 7.77 (d, J=8.7 Hz, 1H), 7.61 (dd, J=2.4 Hz, 8.7 Hz, 1H), 7.57-7.53 (m, 1H), 7.41 (dd, J=5.6, 3.0 Hz, 2H), 7.37 (d, J=3.6 Hz, 1H), 7.17 (d, J=2.4 Hz, 1H), 4.26 (t, J=6.9 Hz, 1H), 3.67 (s, 3H), 3.50 (t, J=7.1 Hz, 2H), 2.83 (t, J=3.7 Hz, 4H), 2.74 (t, J=7.1 Hz, 2H), 2.47 (s, 4H), 1.62-1.56 (m, 4H), 1.45 (s, 2H). 13C NMR (75 MHz, CDCl3-d1) δ 173.63, 160.77, 154.20, 148.15, 138.23, 135.93, 134.66, 132.61, 130.83, 130.54, 130.43, 129.22, 129.10, 128.13, 126.35, 122.71, 57.76, 54.95, 54.06, 51.97, 32.18, 29.54, 29.39, 26.64, 23.96. LC-MS (ESI) m/z: 558.2[M+H]+.
1H NMR (300 MHz, CDCl3-d1) δ: 7.73 (dd, J=8.4, 2.6 Hz, 1H), 7.62-7.56 (m, 2H), 7.53-7.43 (m, 2H), 7.29 (td, J=7.5, 1.5 Hz, 1H), 7.17 (dd, J=7.9, 1.5 Hz, 1H), 6.10 (t, J=5.2 Hz, 1H), 3.64 (s, 3H), 3.45 (t, J=5.1 Hz, 2H), 2.68-2.51 (m, 10H), 1.58-1.54 (m, 4H), 1.48-1.37 (m, 2H). 13C NMR (75 MHz, CDCl3-d1) δ 173.60, 163.21, 159.19, 154.15, 148.12, 136.35, 136.54, 132.44, 131.52, 130.23, 128.53, 127.70, 124.00, 121.85, 120.25, 115.78, 58.29, 54.90, 54.06, 51.93, 32.18, 29.54, 29.30, 26.83, 24.03. LC-MS (ESI) m/z: 586.1[M+H]+.
1H NMR (300 MHz, CDCl3-d1) δ: 8.47 (d, J=5.2 Hz, 2H), 7.93-7.83 (m, 1H), 7.78 (d, J=8.7 Hz, 1H), 7.67-7.56 (m, 1H), 7.56-7.47 (m, 2H), 7.46-7.34 (m, 3H), 7.23-7.09 (m, 1H), 4.64-4.43 (m, 2H), 4.30 (t, J=6.2 Hz, 1H), 3.59 (s, 3H), 2.67-2.57 (m, 4H). 13C NMR (75 MHz, CDCl3-d1) δ 173.65, 161.70, 154.16, 149.79, 147.48, 146.26, 138.07, 135.66, 134.71, 132.61, 130.82, 130.51, 130.43, 129.36, 129.04, 128.19, 126.36, 124.08, 122.76, 57.76, 51.96, 39.84, 29.54, 29.39. LC-MS (ESI) m/z: 538.1[M+H]>.
1H NMR (300 MHz, CDCl3-d1) δ: 8.62-8.57 (m, 2H), 7.73 (dd, J=8.4, 2.6 Hz, 1H), 7.59 (d, J=2.5 Hz, 1H), 7.58-7.51 (m, 2H), 7.47 (td, J=7.7, 1.6 Hz, 1H), 7.33-7.26 (m, 3H), 7.26-7.20 (m, 1H), 6.10 (t, J=5.2 Hz, 1H), 4.53 (s, 2H), 3.64 (s, 3H), 2.67-2.57 (m, 2H), 2.57-2.51 (m, 2H). 13C NMR (75 MHz, CDCl3-d1) δ 173.62, 163.35, 159.17, 154.16, 149.79, 147.48, 146.26, 136.60, 136.54, 132.67, 131.51, 130.23, 128.53, 127.70, 124.09, 124.00, 121.79, 120.47, 115.76, 58.29, 51.92, 39.84, 29.54, 29.30. LC-MS (ESI) m/z:566.4 [M+H]+.
1H NMR (300 MHz, CDCl3-d1) δ: 8.62-8.58 (m, 1H), 8.53-8.46 (m, 2H), 8.18 (d, J=7.9 Hz, 1H), 7.84 (td, J=7.8, 1.7 Hz, 1H), 7.75 (dd, J=8.7, 2.2 Hz, 1H), 7.67 (d, J=2.2 Hz, 1H), 7.54 (d, J=8.7 Hz, 1H), 7.42-7.38 (m, 1H), 7.36-7.32 (m, 2H), 4.55-4.37 (m, 2H), 4.30-4.21 (m, 1H), 3.69 (s, 3H), 2.93-2.77 (m, 4H). 13C NMR (75 MHz, CDCl3-d1) δ 173.41, 161.93, 156.42, 154.52, 149.59, 147.48, 147.33, 146.06, 137.37, 137.19, 136.60, 135.48, 128.31, 125.25, 124.08, 122.76, 122.61, 120.94, 58.05, 51.96, 39.84, 29.54, 29.34. LC-MS (ESI) m/z: 549.4[M+H]+.
1H NMR (300 MHz, CDCl3-d1) δ: 7.68-7.59 (m, 2H), 7.62-7.52 (m, 2H), 7.53-7.45 (m, 1H), 7.41-7.32 (m, 2H), 6.11 (t, J=5.2 Hz, 1H), 3.66 (s, 3H), 3.46 (t, J=5.2 Hz, 2H), 2.74-2.62 (m, 6H), 2.65-2.51 (m, 4H), 2.25-2.12 (m, 4H). 13C NMR (75 MHz, CDCl3-d1) δ 172.98, 160.92, 154.16, 148.12, 137.98, 135.93, 134.65, 132.65, 131.03, 130.83, 130.56, 129.18, 129.10, 128.07, 126.30, 122.69, 118.58, 57.87, 54.60, 51.78, 48.83, 32.57, 31.95, 9.54, 29.49. LC-MS (ESI) m/z: 594.4[M+H]+.
1H NMR (300 MHz, CDCl3-d1) δ: 7.74 (dd, J=8.4, 2.4 Hz, 1H), 7.62-7.54 (m, 2H), 7.54-7.44 (m, 2H), 7.33-7.21 (m, 2H), 4.32 (t, J=5.3, 6.8 Hz, 1H), 3.66 (s, 3H), 3.46 (t, J=5.2, 7.4 Hz, 2H), 2.74-2.68 (m, 3H), 2.68-2.62 (m, 4H), 2.61 (dd, J=1.9, 1.2 Hz, 1H), 2.61-2.51 (m, 2H), 2.25-2.12 (m, 4H). 13C NMR (75 MHz, CDCl3-d1) δ 173.33, 163.02, 159.33, 154.16, 148.12, 136.55, 136.54, 132.67, 131.53, 130.23, 128.58, 127.70, 123.91, 121.85, 120.45, 118.58, 115.77, 58.29, 54.60, 51.94, 48.71, 32.61, 32.23, 29.34, 29.63. LC-MS (ESI) m/z: 622.5[M+H]+.
1H NMR (300 MHz, CDCl3-d1) δ: 7.72 (d, J=8.4 Hz, 1H), 7.64-7.57 (m, 2H), 7.55 (d, J=2.4 Hz, 1H), 7.53-7.45 (m, 1H), 7.41-7.32 (m, 2H), 6.11 (t, J=5.2 Hz, 1H), 4.08 (d, J=2.7 Hz, 2H), 3.66 (s, 3H), 3.49 (t, J=5.3 Hz, 4H), 2.65-2.50 (m, 8H), 2.23 (s, 3H). 13C NMR (75 MHz, CDCl3-d1) δ 173.37, 171.54, 160.92, 154.17, 147.98, 137.98, 136.05, 134.72, 132.65, 131.16, 130.83, 130.56, 129.18, 129.10, 128.33, 126.44, 122.74, 56.97, 54.43, 51.80, 46.07, 45.25, 35.71, 29.47, 29.78. LC-MS (ESI) m/z: 587.5[M+H]+.
1H NMR (300 MHz, CDCl3-d1) δ: 7.69 (d, J=8.3 Hz, 1H), 7.61-7.54 (m, 2H), 7.54-7.45 (m, 2H), 7.41-7.30 (m, 2H), 6.12 (t, J=5.4 Hz, 1H), 3.77-3.62 (m, 7H), 2.74-2.63 (m, 2H), 2.60-2.45 (m, 6H), 2.29 (s, 3H). 13C NMR (75 MHz, CDCl3-d1) δ 173.22, 164.87, 160.77, 154.72, 143.84, 137.98, 136.55, 134.71, 132.60, 130.83, 130.54, 130.43, 129.20, 129.10, 128.16, 126.36, 122.85, 57.81, 54.27, 52.08, 47.39, 45.36, 29.54, 29.57. LC-MS (ESI) m/z: 573.1[M+H]+.
1H NMR (300 MHz, CDCl3-d1) δ: 7.75 (dd, J=8.4, 2.6 Hz, 1H), 7.59 (d, J=2.5 Hz, 1H), 7.56-7.44 (m, 3H), 7.28 (td, J=7.6, 1.4 Hz, 1H), 7.22 (dd, J=7.7, 1.3 Hz, 1H), 6.12 (t, J=5.4 Hz, 1H), 3.77-3.68 (m, 2H), 3.68-3.63 (m, 5H), 2.74-2.63 (m, 2H), 2.57 (ddd, J=7.9, 5.5, 1.0 Hz, 2H), 2.55-2.45 (m, 4H), 2.29 (s, 3H). 13C NMR (75 MHz, CDCl3-d1) δ: 173.61, 167.58, 160.70, 148.74, 143.80, 143.14, 132.49, 131.38, 131.10, 129.83, 129.44, 129.40, 124.54, 124.20, 121.80, 115.88, 115.73, 54.33, 54.18, 51.71, 51.50, 44.98, 33.02, 31.91. LC-MS (ESI) m/z: 601.10 [M+H]+.
1H NMR (300 MHz, CDCl3-d1) δ: 7.91 (d, J=1.6 Hz, 1H), 7.62 (dd, J=7.2, 2.2 Hz, 1H), 7.51-7.37 (m, 5H), 5.32 (s, 1H), 3.68 (s, 3H), 3.25 (d, J=2.5 Hz, 2H), 2.65-2.49 (m, 6H), 2.44-2.28 (m, 4H), 1.99 (d, J=2.2 Hz, 2H), 0.99 (s, 6H). 13C NMR (75 MHz, CDCl3-d1) δ: 173.62, 145.70, 144.01, 141.27, 138.92, 132.79, 130.73, 130.17, 129.99, 129.43, 129.37, 128.94, 128.72, 128.62, 124.77, 120.33, 54.20, 53.56, 51.40, 47.08, 33.51, 33.02, 31.91, 30.11, 11.83. LC-MS (ESI) m/z: 560.16 [M+H]+.
1H NMR (300 MHz, CDCl3-d1) δ: 7.75 (d, J=8.7 Hz, 1H), 7.59 (dd, J=8.7, 2.4 Hz, 1H), 7.55 (dd, J=5.8, 3.4 Hz, 1H), 7.45-7.39 (m, 2H), 7.37-7.32 (m, 1H), 7.17 (d, J=2.3 Hz, 1H), 4.26 (t, J=6.0 Hz, 1H), 3.67 (s, 3H), 3.62-3.40 (m, 2H), 2.91-2.78 (m, 4H), 2.72 (h, J=6.1 Hz, 2H), 2.30 (s, 6H). 13C NMR (75 MHz, CDCl3-d1) δ: 173.88, 145.68, 144.42, 143.87, 138.88, 133.17, 130.68, 130.54, 129.82, 129.72, 129.46, 129.41, 128.74, 124.66, 122.11, 54.20, 52.83, 51.40, 42.92, 37.46, 33.02, 31.93. LC-MS (ESI) m/z: 518.11 [M+H]+.
1H NMR (300 MHz, CDCl3-d1) δ: 7.73 (dd, J=8.5, 2.5 Hz, 1H), 7.61-7.55 (m, 2H), 7.54-7.43 (m, 2H), 7.29 (td, J=7.7, 1.5 Hz, 1H), 7.23 (dd, J=7.9, 1.5 Hz, 1H), 4.30 (t, J=5.2 Hz, 1H), 3.64 (s, 3H), 3.46 (t, J=5.2 Hz, 2H), 2.71 (dt, J=12.4, 5.2 Hz, 1H), 2.69-2.57 (m, 3H), 2.60-2.51 (m, 2H), 2.29 (s, 6H). 13C NMR (75 MHz, CDCl3-d1) δ: 173.78, 160.38, 145.61, 144.39, 143.49, 134.16, 131.97, 130.87, 130.41, 130.05, 129.44, 124.54, 124.20, 122.40, 115.82, 115.55, 54.33, 52.69, 51.40, 42.92, 37.46, 33.02, 30.26. LC-MS (ESI) m/z: 546.09 [M+H]+.
1H NMR (300 MHz, CDCl3-d1) δ: 7.91 (d, J=2.0 Hz, 1H), 7.66 (dd, J=7.0, 2.4 Hz, 1H), 7.50-7.35 (m, 4H), 7.29 (d, J=7.5 Hz, 1H), 5.25 (s, 1H), 3.68 (s, 3H), 3.63-3.51 (m, 2H), 3.48 (d, J=0.9 Hz, 2H), 2.62 (d, J=2.4 Hz, 4H), 2.55 (s, 2H), 2.44-2.32 (m, 2H), 2.33 (d, J=7.0 Hz, 1H), 2.25 (d, J=12.5 Hz, 1H), 1.79 (d, J=7.5 Hz, 4H). 13C NMR (75 MHz, CDCl3-d1) δ:173.61, 145.63, 145.00, 143.04, 138.86, 132.79, 130.72, 130.15, 129.99, 129.37, 128.72, 128.60, 128.19, 124.67, 119.77, 67.85, 54.33, 51.50, 50.74, 50.54, 33.99, 33.02, 32.94, 31.92. LC-MS (ESI) m/z: 574.14 [M+H]+.
1H NMR (300 MHz, CDCl3-d1) δ: 7.98 (d, J=2.0 Hz, 1H), 7.66-7.59 (m, 1H), 7.50-7.44 (m, 1H), 7.46-7.33 (m, 3H), 7.29 (d, J=7.5 Hz, 1H), 5.25 (s, 1H), 4.42 (s, 1H), 3.68 (s, 3H), 2.62 (d, J=10.6 Hz, 2H), 2.49 (d, J=12.3 Hz, 1H), 2.41-2.30 (m, 5H), 2.25 (d, J=12.5 Hz, 1H), 2.02 (d, J=21.1 Hz, 2H), 1.65 (s, 1H), 1.59 (d, J=4.6 Hz, 2H), 1.53 (s, 1H). 13C NMR (75 MHz, CDCl3-d1) δ:175.67, 173.61, 148.74, 145.69, 143.49, 138.91, 132.79, 130.71, 130.16, 129.99, 129.84, 129.37, 128.72, 128.60, 128.19, 124.68, 122.11, 62.34, 54.53, 54.33, 51.45, 41.64, 33.02, 31.91, 28.57, 26.60, 22.95.
LC-MS (ESI) m/z:571.12[M+H]+.
1H NMR (300 MHz, CDCl3-d1) δ: 13.8 (s, 1H), 7.80 (d, J=8.5 Hz, 1H), 7.58-7.50 (m, 2H), 7.50-7.45 (m, 1H), 7.45-7.36 (m, 2H), 7.34 (d, J=2.4 Hz, 1H), 4.56 (t, J=6.0 Hz, 1H), 4.22 (t, J=6.5 Hz, 2H), 3.60-3.48 (m, 4H), 2.85 (t, J=6.4, 8.2 Hz, 2H), 2.72-2.57 (m, 4H), 2.53-2.45 (m, 2H), 2.43-2.28 (m, 2H). 13C NMR (75 MHz, CDCl3-d1) δ: 173.82, 172.99, 145.29, 143.07, 143.02, 132.79, 130.64, 130.52, 129.38, 129.37, 129.30, 128.94, 128.72, 128.62, 124.74, 122.85, 66.04, 65.90, 55.35, 54.26, 53.77, 30.86, 30.56. LC-MS (ESI) m/z: 546.11 [M+H]+.
1H NMR (300 MHz, CDCl3-d1) δ: 7.85 (s, 1H), 7.63 (d, J=8.3 Hz, 1H), 7.59-7.51 (m, 3H), 7.47 (dd, J=7.7, 1.7 Hz, 1H), 7.38 (td, J=23.6, 7.4, 1.6 Hz, 2H), 7.03 (s, 2H), 6.10 (t, J=5.2 Hz, 1H), 4.27 (td, J=5.0, 1.6 Hz, 2H), 3.66-3.60 (m, 5H), 2.66-2.51 (m, 4H). 13C NMR (75 MHz, CDCl3-d1) δ:173.87, 145.66, 145.05, 143.04, 139.39, 138.93, 133.92, 132.79, 130.68, 130.55, 129.71, 129.46, 129.44, 129.37, 129.31, 128.94, 128.62, 124.73, 120.33, 54.20, 51.40, 49.21, 36.04, 33.07, 31.90. LC-MS (ESI) m/z: 541.09 [M+H]+.
1H NMR (300 MHz, CDCl3-d1) δ: 7.85 (s, 1H), 7.72 (dd, J=8.4, 2.6 Hz, 1H), 7.61-7.54 (m, 2H), 7.52 (dd, J=7.9, 1.5 Hz, 1H), 7.47 (td, J=7.7, 1.6 Hz, 1H), 7.28 (td, J=7.5, 1.5 Hz, 1H), 7.21 (dd, J=7.8, 1.5 Hz, 1H), 7.03 (s, 2H), 6.10 (t, J=5.2 Hz, 1H), 4.27 (td, J=5.0, 1.7 Hz, 2H), 3.66-3.60 (m, 5H), 2.67-2.51 (m, 4H). 13C NMR (75 MHz, CDCl3-d1) δ 172.39, 160.89, 154.16, 148.42, 137.37, 136.33, 136.43, 134.20, 132.08, 131.13, 130.83, 129.13, 128.19, 126.39, 121.84, 120.47, 57.37, 55.24, 54.02, 51.93, 32.18, 28.94, 29.34, 23.27. LC-MS (ESI) m/z:569.1[M+H]+.
1H NMR (300 MHz, CDCl3-d1) δ: 7.87 (dd, J=8.7, 2.4 Hz, 1H), 7.78 (d, J=8.7 Hz, 1H), 7.65 (dd, J=5.9, 3.3 Hz, 1H), 7.55-7.49 (m, 2H), 7.49-7.42 (m, 1H), 7.18 (d, J=2.3 Hz, 1H), 6.76 (t, J=2.1 Hz, 2H), 5.99 (t, J=2.1 Hz, 2H), 4.32 (t, J=6.4 Hz, 1H), 4.24 (t, J=6.5 Hz, 2H), 3.60 (s, 3H), 2.68 (t, J=6.4 Hz, 2H), 2.52-2.50 (m, 4H). 13C NMR (75 MHz, CDCl3-d1) δ:173.90, 145.62, 145.01, 143.04, 138.89, 132.79, 130.67, 130.54, 129.72, 129.46, 129.44, 129.37, 128.94, 128.62, 125.93, 124.70, 120.33, 119.18, 54.20, 53.61, 51.39, 36.04, 33.00, 31.89. LC-MS (ESI) m/z: 540.09 [M+H]+.
1H NMR (300 MHz, CDCl3-d1) δ: 8.03 (s, 1H), 7.97-7.90 (m, 2H), 7.61 (dd, J=7.5, 2.0 Hz, 1H), 7.53-7.34 (m, 5H), 5.17 (s, 1H), 3.68 (s, 6H), 2.56-2.45 (m, 2H), 2.30-2.19 (m, 2H). 13C NMR (75 MHz, CDCl3-d1) δ:173.94, 156.53, 145.64, 145.36, 144.40, 138.85, 137.66, 133.15, 132.20, 130.65, 130.54, 129.82, 129.70, 129.46, 129.44, 128.94, 128.70, 124.72, 122.11, 54.20, 51.40, 33.80, 33.05, 30.26; LC-MS (ESI) m/z: 527.07 [M+H]+.
1H NMR (300 MHz, CDCl3-d1) δ 7.75 (d, J=8.4 Hz, 1H), 7.60-7.51 (m, 3H), 7.50 (dd, J=7.8, 1.4 Hz, 1H), 7.41 (td, J=7.7, 1.8 Hz, 1H), 7.34 (td, J=7.5, 1.4 Hz, 1H), 4.30 (t, J=8.2 Hz, 1H), 3.64 (s, 3H), 3.45 (q, J=7.2 Hz, 2H), 3.02 (s, 3H), 2.75-2.59 (m, 2H), 2.59-2.53 (m, 2H), 1.22 (t, J=7.2 Hz, 3H). 13C NMR (75 MHz, CDCl3-d1) δ:173.90, 162.05, 148.74, 146.39, 143.80, 138.87, 133.16, 130.61, 130.53, 129.82, 129.75, 129.46, 129.45, 129.25, 128.74, 124.69, 124.25, 54.19, 51.41, 43.61, 34.27, 32.98, 30.26, 12.47. LC-MS (ESI) m/z: 532.09 [M+H]+.
1H NMR (300 MHz, CDCl3-d1) δ: 7.89 (d, J=1.9 Hz, 1H), 7.61 (dd, J=7.1, 2.2 Hz, 1H), 7.54-7.37 (m, 6H), 5.32 (s, 1H), 3.68 (s, 3H), 3.39 (s, 2H), 2.86 (s, 5H), 2.80-2.69 (m, 2H), 2.44-2.28 (m, 3H), 2.25 (d, J=12.5 Hz, 1H). 13C NMR (75 MHz, CDCl3-d1) δ: 173.78, 172.42, 145.67, 144.02, 143.04, 138.84, 132.79, 130.60, 130.55, 129.74, 129.46, 129.37, 129.02, 128.93, 128.62, 124.74, 120.33, 54.22, 51.42, 36.42, 35.74, 33.03, 31.88, 31.67. LC-MS (ESI) m/z:546.1[M+H]+.
1H NMR (300 MHz, CDCl3-d1) δ: 7.91 (d, J=2.0 Hz, 1H), 7.61 (dd, J=7.2, 2.3 Hz, 1H), 7.54-7.37 (m, 4H), 7.31 (d, J=7.5 Hz, 1H), 6.83 (s, 1H), 5.17 (s, 1H), 4.32 (s, 2H), 3.68 (s, 3H), 3.59-3.50 (m, 4H), 2.49 (d, J=12.5 Hz, 1H), 2.40 (d, J=12.5 Hz, 1H), 2.30-2.19 (m, 2H). 13C NMR (75 MHz, CDCl3-d1) S: 173.87, 159.44, 145.60, 143.90, 141.65, 138.93, 133.18, 130.69, 130.56, 129.82, 129.73, 129.46, 129.44, 128.91, 128.70, 124.73, 122.11, 54.18, 51.38, 44.30, 44.27, 41.81, 33.04, 31.95. LC-MS (ESI) m/z: 529.1 [M+H]+.
In anesthetic drug experiments, latency generally refers to the time from the start of administration to the loss of consciousness of the subject. The shorter latency is preferred, indicating a rapid onset of action after administration. The duration of anesthesia generally refers to the duration of time from the loss of consciousness to the restoration of consciousness of the subject. The duration of the drug will vary from animal model to animal species. Too long anesthesia may produce adverse cardiovascular and respiratory responses, such as adverse neurological effects to the subject, including sleepiness and dizziness; meanwhile, too short duration of anesthesia may affect the anesthesia effect, causing problems such as increase of anesthesia dosage during the operation.
KM mice (female, 18-25 g) were randomly grouped and subjected to a single administration by rapid bolus via the tail vein. The latency and duration of disappearance of righting reflex in the mice were recorded. The experimental results are shown in Table 1 below.
As shown in Table 1, the compounds of the present disclosure had the anesthetic effect of fast onset of action and faster wake-up in a mouse experiment.
SD rats (male, 200-280 g) were randomly grouped and subjected to a single administration by rapid bolus via the tail vein. The latency and duration of righting reflex in the rats were recorded.
As shown in Table 2 above, the compounds of the present disclosure had the anesthetic effect of fast onset of action and fast wake-up in a rat experiment.
SD rats (male, 200-280 g) were randomly grouped and subjected to administration of an initial dose by rapid bolus via the tail vein, followed by a continuous infusion with a maintenance dose for 20 min.
After the infusion was completed, the duration of the righting reflex and the time from wake-up to recovery in rats were recorded.
As shown in Table 3 above, the compounds of the present disclosure could maintain anesthesia in animals under continuous infusion, and faster wake-up and faster recovery were observed after completion of the continuous infusion.
Test compounds were dissolved at various concentrations in an extracellular buffer (140 mM NaCl, 4.7 mM KCl, 10 mM HEPES, 2 mM CaCl2), 10 mM glucose, 1 mM MgCl2, pH 7.4). HEK 293T cells were seeded on glass coverslips and cultured in DMEM media at 37° C. with 5% CO2 for 24 h. GABA Cl− current was subjected to whole cell recording using an HEKA EPC 10USB patch clamp amplifier. 2 μM GABA was used for exciting Cl− current, with the membrane potential clamped at −60 mV. The cells were treated with the test compound and 2 μM GABA simultaneously, and the induction effect on and Emax of Cl− current in the same cell were recorded.
Maximum enhancement percentage Emax for 2 μM GABA current and corresponding concentration (μM): 100% for normal humans. The greater the percentage, the lower the corresponding concentration, and the greater the depth of anesthesia.
As shown in Tables 4 and 5 above, the compounds of the present disclosure had a suitable depth of anesthesia, indicating that the compounds of the present disclosure have an excellent anesthetic effect.
A Transwell device (pore size: 5.0 μm) was placed in a 24-well cell culture well; then hCMEC/D3 cells at 1×105 cells/mL were transferred to the upper microwells of Transwell at 150 μL/well, and cell culture medium was added to the lower microwells. After the bottom was covered by a single layer of the cells, the medium in the wells was replaced with EBM-2 complete medium containing 1% FBS, and the cells were cultured in a CO2 incubator for 10 days until a fully dense single layer of the cells was formed. When a fully dense single layer of the cells was formed, the compound at 0.1 mg/mL was added to the lower medium, and after 5 min, the concentration of the compound in the upper medium was measured to calculate the permeability:
P
compound%=Cupper compound/Clower compound×100%
As shown in Table 6 above, the compounds had the function of rapidly passing through the blood-brain barrier.
Preparation of plasma: after the SD rats were fasted and kept with water for 12 h, blood was collected through orbital venous plexus. The freshly collected blood was added into a centrifuge tube containing heparin sodium and centrifuged at 5000 rpm for 10 min at 4° C. The supernatant was slowly pipetted and subpackaged. Finally, the collected SD rat plasma was sealed, marked, and stored at −20° C. for later use.
Preparation of target compound sample: the target compound was precisely weighed by an analytical balance and prepared into a stock solution at a concentration of 2 mg/mL (solvent: Vacetone:VTween 80:Vnormal saline=1:1:3) for later use.
Determination of in vitro half-life of target compound sample: 20 μL of test compound stock solution and 80 μL of rat plasma were mixed uniformly. Nine parallel ep tubes were taken, marked as corresponding test tubes of 0 min, 1 min, 2 min, 3 min, 5 min, 10 min, 15 min, 20 min, and 30 min, respectively, and placed in a water bath at 37° C. for incubation for 0 min, 1 min, 2 min, 3 min, 5 min, 10 min, 15 min, 20 min, and 30 min, respectively. 50 μL of mixed solution were taken from the corresponding ep tube at each time point, and 100 mL of acetonitrile was added for precipitating protein. The mixture was vortexed for 10 min using a mixer and centrifuged at 12000 rpm for 15 min. Then, the supernatant was centrifuged at 12000 rpm for 10 min. The optimal detection method for the target compound in the MRM mode was determined using Intellistat software in UPLC-MS/MS, the peak area of the corresponding mass spectrum was integrated, and the plasma half-life of the compound was calculated.
As shown in Table 7 above, the compounds had the function of rapidly passing through the blood-brain barrier.
In this experiment, IC50 was calculated by detecting the effect of compounds at 8 concentrations on the current of the hERG channel. The procedures were performed exactly as for Predictor™ hERG fluorescence polarization assay kit. Before measuring fluorescence polarization, the assay plate was covered to protect the reagents from light and evaporation, and after incubation at room temperature for 2-4 h, the sample plate was centrifuged to read the fluorescence polarization value, with the excitation light at 540 nm and the emission light at 573 nm. The data showed that the cardiotoxicity of the compounds of the present disclosure was significantly lower than that of the marketed drug midazolam.
The above pharmacological data showed that the compounds of general formula (I) had the characteristics of fast onset of action, strong action depth, and fast wake-up, and the preferred compound had almost no accumulation.
Compound 32 (10 g) and glycine (100 g) were added to a flask, water for injection was added to 1 L, and the pH of the solution was adjusted to 3.5. The solution was subpackaged into 1000 vials, and prepared into lyophilized powder for injection by a conventional lyophilization method.
It should be understood that various modifications or changes may be made by those skilled in the art after reading the above teachings of the present disclosure, and these equivalent forms also fall within the scope defined by the claims appended hereto.
| Number | Date | Country | Kind |
|---|---|---|---|
| 202011237945.7 | Nov 2020 | CN | national |
| Filing Document | Filing Date | Country | Kind |
|---|---|---|---|
| PCT/CN2021/129655 | 11/9/2021 | WO |
