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WO2019162911A1 - Fnew activators of sirt1 enzyme for the treatment of cardiovascular and cardiometabolic pathologies - Google Patents

Fnew activators of sirt1 enzyme for the treatment of cardiovascular and cardiometabolic pathologies Download PDF

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WO2019162911A1
WO2019162911A1 PCT/IB2019/051489 IB2019051489W WO2019162911A1 WO 2019162911 A1 WO2019162911 A1 WO 2019162911A1 IB 2019051489 W IB2019051489 W IB 2019051489W WO 2019162911 A1 WO2019162911 A1 WO 2019162911A1
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WO2019162911A8 (en
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Vincenzo Calderone
Filippo Minutolo
Tiziano Tuccinardi
Lara TESTAI
Carlotta Granchi
Alma MARTELLI
Valentina CITI
Virginia DE LORENZO GARDINAL
Giulia LENZI
Francesca LEO
Giulia MALLOGGI
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Universita di Pisa
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D263/00—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings
    • C07D263/02—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings not condensed with other rings
    • C07D263/30—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
    • C07D263/34—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D263/48—Nitrogen atoms not forming part of a nitro radical
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
    • A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism
    • A61P3/08—Drugs for disorders of the metabolism for glucose homeostasis
    • A61P3/10—Drugs for disorders of the metabolism for glucose homeostasis for hyperglycaemia, e.g. antidiabetics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A61P9/04—Inotropic agents, i.e. stimulants of cardiac contraction; Drugs for heart failure
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A61P9/10—Drugs for disorders of the cardiovascular system for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C215/00—Compounds containing amino and hydroxy groups bound to the same carbon skeleton
    • C07C215/74—Compounds containing amino and hydroxy groups bound to the same carbon skeleton having hydroxy groups and amino groups bound to carbon atoms of six-membered aromatic rings of the same carbon skeleton
    • C07C215/76—Compounds containing amino and hydroxy groups bound to the same carbon skeleton having hydroxy groups and amino groups bound to carbon atoms of six-membered aromatic rings of the same carbon skeleton of the same non-condensed six-membered aromatic ring
    • C07C215/82—Compounds containing amino and hydroxy groups bound to the same carbon skeleton having hydroxy groups and amino groups bound to carbon atoms of six-membered aromatic rings of the same carbon skeleton of the same non-condensed six-membered aromatic ring having the nitrogen atom of at least one of the amino groups further bound to a carbon atom of another six-membered aromatic ring
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C323/00—Thiols, sulfides, hydropolysulfides or polysulfides substituted by halogen, oxygen or nitrogen atoms, or by sulfur atoms not being part of thio groups
    • C07C323/01—Thiols, sulfides, hydropolysulfides or polysulfides substituted by halogen, oxygen or nitrogen atoms, or by sulfur atoms not being part of thio groups containing thio groups and halogen atoms, or nitro or nitroso groups bound to the same carbon skeleton
    • C07C323/09—Thiols, sulfides, hydropolysulfides or polysulfides substituted by halogen, oxygen or nitrogen atoms, or by sulfur atoms not being part of thio groups containing thio groups and halogen atoms, or nitro or nitroso groups bound to the same carbon skeleton having sulfur atoms of thio groups bound to carbon atoms of six-membered aromatic rings of the carbon skeleton
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C43/00—Ethers; Compounds having groups, groups or groups
    • C07C43/02—Ethers
    • C07C43/257—Ethers having an ether-oxygen atom bound to carbon atoms both belonging to six-membered aromatic rings
    • C07C43/295—Ethers having an ether-oxygen atom bound to carbon atoms both belonging to six-membered aromatic rings containing hydroxy or O-metal groups
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
    • C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
    • C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D213/60—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D213/72—Nitrogen atoms
    • C07D213/74—Amino or imino radicals substituted by hydrocarbon or substituted hydrocarbon radicals
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D217/00—Heterocyclic compounds containing isoquinoline or hydrogenated isoquinoline ring systems
    • C07D217/22—Heterocyclic compounds containing isoquinoline or hydrogenated isoquinoline ring systems with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to carbon atoms of the nitrogen-containing ring

Definitions

  • This invention describes a class of compounds able to activate the human SIRT1 enzyme and regulate many metabolic functions.
  • This invention relates to compounds that can be employed in medical applications, specifically for the treatment or prevention of cardiometabolic diseases, such as diabetes, and of cardiovascular disorders, such as coronaropathy, heart failure and atherosclerosis.
  • Sirtuins are a conserved family of deacetylase enzymes deeply involved in cellular physiological processes. To date, seven types of enzymes have been described, classified from SIRT1 to SIRT7 on the basis of their different cellular localization. SIRT1 is biosynthesized in the nucleus and - on the basis of cellular needs - transferred into the cytosol through a shuttling system. In the cytosol SIRT1 , influences mitochondrial activity and the metabolism of the whole cell through the modulation of different transcription cofactors which are essential for the maintenance of cellular homeostasis.
  • SIRT1 was first described in the yeast Saccharomyces cerevisiae and then in worms and flies, where it modulates the lifespan.
  • the reduction of SIRT 1 expression / activity due to physiological aging and also observed in mammals, may explain the worsening of age-related cellular functions and may be linked to cardiovascular and non-cardiovascular pathologies.
  • Recent studies have shown that SIRT 1 is less effective in patients with heart failure and coronary heart disease; furthermore, pre-clinical studies have demonstrated that SIRT1 activity is reduced after ischemia-reperfusion injury.
  • SIRT1 is also involved in insulin resistance, suggesting that it may represent a novel and interesting target in the management of type II diabetes mellitus.
  • Cardiovascular diseases are still today the main cause of morbidity and mortality in Western countries and aging represents one of the main risk factors.
  • resveratrol represents the reference activator of SIRT1 .
  • SRT501 polyphenol microemulsion formulations
  • SRT1720 is one of the most studied compounds: it has shown to be able to prolong life expectancy, control glucose homeostasis in different animal models of diabetes and protect the myocardium from ischemia / reperfusion injury.
  • SRT2104 is a very promising SIRT1 activator, as it showed high tolerability when administered for 28 days to elderly volunteers; moreover, an assessment of its pharmacodynamic profile in humans gave promising results in respect of lipid parameters.
  • the compound SRT2104 is well tolerated by diabetic patients and promotes a reduction in body weight; however, it exerts no significant cardiometabolic and vascular effect.
  • the compound SRT3025 another SIRT1 activator, has also been included in a phase I clinical trial; however, the prolongation of the QT interval (time of depolarization and repolarization of the ventricular cells) that was observed discouraged the researchers and no further study was conducted.
  • SIRT1 plays a key role in the regulation of cellular physiological processes, there is a great interest in identifying and developing novel SIRT1 activators to be employed in the treatment/prevention of cardiovascular diseases. Such compounds may provide novel ways to treat age-related diseases.
  • the compounds covered by this patent have been developed with the aim of improving the activity, selectivity and bioavailability of the SIRT1 activators discovered so far, and our preliminary data confirm their potential usefulness as SIRT1 activators. Indeed, novel molecules have been synthetized and they have shown SIRT1 activating properties; some of these compounds have been found to be more potent than resveratrol. Furthermore, they have shown interesting cardioprotective properties in an experimental model of acute myocardial infarction.
  • This invention relates to a compound having the structural formula (I):
  • R1 , R2, R3 e R4 are independently selected from -OFI and -H;
  • X is selected from: -NH, O, S;
  • R5 is selected from among the following groups:
  • R6 is selected from -H or a non-substituted phenyl group
  • R2 and R3 are never simultaneously -OH.
  • the compound of this invention is used as a medicament for the treatment or prevention of ischemic pathologies, cardio-metabolic pathologies, including diabetes, and cardiovascular pathologies, including coronary pathologies, heart failure, acute myocardial infarction and atherosclerosis.
  • Figure 1 shows the effects of compounds 1 -36 on SIRT1 ; data are expressed as a % vs resveratrol.
  • Figure 2 shows the effects of different concentrations of compounds 14-17 on SIRT1 ; data are expressed as a % vs resveratrol.
  • Figure 3 shows the effects of compounds 14 and 15 in reducing the ischemic area after an ischemia/reperfusion injury. Ischemic areas are expressed as a % of the whole left ventricle area.
  • This invention relates to a compound having the structural formula (I):
  • R1 , R2, R3 e R4 are independently selected from -OH and -H;
  • X is selected from: -NH, O, S;
  • R5 is selected from among the following groups:
  • R6 is selected from -H or a non-substituted phenyl group
  • R2 and R3 are never simultaneously -OH.
  • X is selected from -NH and -O.
  • X is -NH
  • R1 , R2, R3 and R4 are independently selected from -OH and -H, X is selected from -NH and -O and R5 is
  • R1 , R2, R3 and R4 are independently selected from -OH and -H, X is -NH and R5 is
  • R1 , R2, R3 and R4 are independently selected from -OH and -H, X is -NH and R5 is selected from the groups: In one embodiment of the invention, R1 , R2, R3 and R4 are independently selected from -OH and -H, X is selected from -O and -NH and R5 is
  • R1 , R2, R3 and R4 are independently selected from -OH and -H, X is -NH and R5 is
  • R1 , R2, R3 and R4 are independently
  • R1 , R2, R3 and R4 are independently selected from -OH and -H, X is -S and R5 is
  • R1 , R2, R3 and R4 are independently
  • R1 , R2, R3 and R4 are independently
  • the compound according to this invention is selected from:
  • the compounds of the invention activate the SIRT1 enzyme and regulate cell metabolism and the transcription of numerous factors that are important for cell survival.
  • the compounds are capable of activating the SIRT1 enzyme and favoring cell survival following an insult, for example following an ischemic insult.
  • a further aspect of this invention relates to a pharmaceutical composition
  • a pharmaceutical composition comprising the compound according to the invention and pharmaceutically acceptable excipients, adjuvants and/or carriers.
  • the pharmaceutical composition is formulated for enteral use, preferably oral or sublingual; for example, the composition is prepared in the form of pills, capsules, tablets, granular powder, hard-shelled capsules, orally dissolving granules, sachets or lozenges.
  • the pharmaceutical composition is formulated for parenteral use, for example intravenous, subcutaneous or intramuscular, preferably intravenous.
  • parenteral use for example intravenous, subcutaneous or intramuscular, preferably intravenous.
  • a further aspect of this invention relates to the compound as described above or the pharmaceutical composition comprising the compound for use as a medicament, preferably for use in the treatment or in the prevention of cardiovascular pathologies, including coronary pathologies, heart failure, acute myocardial infarction and atherosclerosis.
  • a further aspect of this invention relates to the compound as described above or the pharmaceutical composition comprising the compound used in association or in combination with other molecules.
  • Said molecules are selected from: ACE inhibitors, statins, sartans, calcium channel blockers, beta-blockers, vasodilators, digitalin, antianginal, anti-ischemic, antiarrhythmic, antihypertensive and hypocholesterolemic drugs and combinations thereof.
  • a further aspect of this invention relates to a method for the treatment or prevention of cardio-metabolic pathologies, including diabetes, and cardiovascular pathologies, including coronary pathologies, heart failure, acute myocardial infarction and atherosclerosis.
  • Said method comprises at least a step of administering an effective dose of the compound of this invention or of the pharmaceutical composition comprising said compound to a patient who has a need for said compound.
  • the process for preparing the compound according to this invention is exemplified in the experimental part.
  • Azide B1 or B2 (0.523 mmol, 100 mg) was dissolved in anhydrous 1 ,4- dioxane (2 ml_) and commercially available 3- or 4-methoxyphenyl isothiocyanate (0.436 mmol) was added, followed by PPh3 (0.523 mmol). The mixture was stirred at 100 °C for 30 min. The cooled solution was concentrated and the resulting crude product was purified by column chromatography over silica gel using n- hexane/EtOAc mixtures as the eluent, to yield intermediate C1 (83% yield); C2 (57% yield); C3 (35% yield) or C4 (74% yield).
  • a vial was loaded with K3PO4 (1.62 mmol) and intermediate F1 or F2 (1.62 mmol, 324 mg). Then, in an inert atmosphere, copper (I) iodide (0.081 mmol) in DMSO (0.6 ml_) and commercially available 4-bromoanisole (0.81 mmol) were added. The vial was sealed, and the reaction mixture was stirred at 130 °C. After the reaction mixture was heated for 24 h, it was cooled to rt and the workup consisted of filtration of the reaction mixture through a Celite pad and washing with EtOAc.
  • N8 (22% yield), N9 (2% yield), N10 (57% yield) or N1 1 (63% yield).
  • a commercially available enzyme kit was used to perform a preliminary screening of the original compounds developed and synthetized as SIRT1 activators. The enzyme activity was monitored through a spectrofluorimetric approach.
  • the enzyme substrate (comprising a polypeptide conjugated with a fluorophore through an acetyl bond (Arg-His-Lys-Lys (e-acetyl)- AMC)) is incubated with the SIRT1 enzyme and NAD+ as a cofactor.
  • the deacetylation of the polypeptide leads to the formation of the acetylated fluorophore (acetyl-AMC), which releases the fluorophore and emits fluorescence, after the addition of a developer.
  • the fluorescence which is directly proportional to the enzyme’s activity, was analyzed using a spectrofluorimetric plate (Aex 350-360 nm, Aem 450-465 nm) and the data obtained were expressed as a % of the fluorescence evoked by 100 mM resveratrol, used as the reference activator of SIRT1.
  • Many of the tested compounds showed higher activity when compared with the reference compound.
  • compounds 14, 15, 16 and 17 showed a markedly higher effectiveness in activating the purified enzyme than resveratrol 100 mM ( Figures 1 and 2, table 2).
  • all the pyridine derivatives showed concentration-dependent SIRT 1 activation.
  • Table 2 the table shows the effects of the synthetized compounds on SIRT1 (expressed as a % vs the reference compound resveratrol 100 mM). Negative values indicate that the compound reduced the activity of the enzyme.
  • SIRT1 activators were selected for the purpose of evaluating their cardioprotection properties in an in vivo rat model of ischemia / reperfusion injury.
  • Wistar albino rats males, 300-350 g
  • the rats were anesthetized with pentobarbital sodium (70mg / kg i.p.) and connected to an electrocardiograph to monitor cardiac activity. Following tracheotomy, respiratory activity was kept constant by means of an artificial respirator (70 breaths / min, 1 ml of air blown / 10Og) for the whole duration of the experimental procedure. After partial thoracotomy, the heart was exposed and reversible occlusion of the left coronary artery was performed for 30 minutes by means of a ligature with a surgical needle (13mm, C1 , 3/8 circular, 6-0). After the removal of the occlusion, reperfusion was maintained for 120 min. The animals were then sacrificed by administration of an anesthetic overdose and a morphometric evaluation of the heart was performed.
  • the left ventricle was transversally cut into slices about 2 mm thick and each slice was incubated for 20 min at 37 ° C in triphenyl-tetrazolium chloride in order to distinguish the ischemic areas, which appeared pale pink or white, from the vital areas, which appeared red in colour.

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Abstract

This invention describes a class of compounds able to activate the human SIRT1 enzyme and regulate many metabolic functions. This invention relates to compounds that can be employed in medical applications, specifically for the treatment or prevention of cardiometabolic diseases, such as diabetes, and of cardiovascular disorders, such as coronaropathy, heart failure and atherosclerosis.

Description

DESCRIPTION
FNEW ACTIVATORS OF SIRT1 ENZYME FOR THE TREATMENT OF
CARDIOVASCULAR AND CARDIOMETABOLIC PATHOLOGIES
FIELD OF THE INVENTION
This invention describes a class of compounds able to activate the human SIRT1 enzyme and regulate many metabolic functions. This invention relates to compounds that can be employed in medical applications, specifically for the treatment or prevention of cardiometabolic diseases, such as diabetes, and of cardiovascular disorders, such as coronaropathy, heart failure and atherosclerosis.
BACKGROUND OF THE INVENTION
Sirtuins are a conserved family of deacetylase enzymes deeply involved in cellular physiological processes. To date, seven types of enzymes have been described, classified from SIRT1 to SIRT7 on the basis of their different cellular localization. SIRT1 is biosynthesized in the nucleus and - on the basis of cellular needs - transferred into the cytosol through a shuttling system. In the cytosol SIRT1 , influences mitochondrial activity and the metabolism of the whole cell through the modulation of different transcription cofactors which are essential for the maintenance of cellular homeostasis.
SIRT1 was first described in the yeast Saccharomyces cerevisiae and then in worms and flies, where it modulates the lifespan. The reduction of SIRT 1 expression / activity, due to physiological aging and also observed in mammals, may explain the worsening of age-related cellular functions and may be linked to cardiovascular and non-cardiovascular pathologies. Recent studies have shown that SIRT 1 is less effective in patients with heart failure and coronary heart disease; furthermore, pre-clinical studies have demonstrated that SIRT1 activity is reduced after ischemia-reperfusion injury. SIRT1 is also involved in insulin resistance, suggesting that it may represent a novel and interesting target in the management of type II diabetes mellitus.
Cardiovascular diseases are still today the main cause of morbidity and mortality in Western countries and aging represents one of the main risk factors.
At present, resveratrol represents the reference activator of SIRT1 . Many pharmacological effects exhibited by resveratrol in the cardiovascular system, such as vascular and myocardial protection, increased bioavailability of NO and positive effects on lipid parameters, are probably mediated through the activation of SIRT1 . In spite of the numerous preclinical and clinical findings, there are great limitations on the therapeutic use of resveratrol because of its low bioavailability and metabolic issues. Although many attempts have been made to overcome problems related to its absorption by using polyphenol microemulsion formulations (SRT501 ), no significant improvements have been achieved. Therefore, research on and the development of new molecules activators of SIRT1 are currently considered as truly innovative strategies for the treatment of age-related diseases.
In 2007 Sinclair et al. were the first to develop synthetic derivatives starting from the resveratrol structure; other non-stilbene compounds have since been developed and are currently in advanced experimental phases. The compound SRT1720 is one of the most studied compounds: it has shown to be able to prolong life expectancy, control glucose homeostasis in different animal models of diabetes and protect the myocardium from ischemia / reperfusion injury. Furthermore, SRT2104 is a very promising SIRT1 activator, as it showed high tolerability when administered for 28 days to elderly volunteers; moreover, an assessment of its pharmacodynamic profile in humans gave promising results in respect of lipid parameters. Very recently, the results of a clinical trial in type II diabetes mellitus patients were published: the compound SRT2104 is well tolerated by diabetic patients and promotes a reduction in body weight; however, it exerts no significant cardiometabolic and vascular effect. The compound SRT3025, another SIRT1 activator, has also been included in a phase I clinical trial; however, the prolongation of the QT interval (time of depolarization and repolarization of the ventricular cells) that was observed discouraged the researchers and no further study was conducted.
Since SIRT1 plays a key role in the regulation of cellular physiological processes, there is a great interest in identifying and developing novel SIRT1 activators to be employed in the treatment/prevention of cardiovascular diseases. Such compounds may provide novel ways to treat age-related diseases.
The compounds covered by this patent have been developed with the aim of improving the activity, selectivity and bioavailability of the SIRT1 activators discovered so far, and our preliminary data confirm their potential usefulness as SIRT1 activators. Indeed, novel molecules have been synthetized and they have shown SIRT1 activating properties; some of these compounds have been found to be more potent than resveratrol. Furthermore, they have shown interesting cardioprotective properties in an experimental model of acute myocardial infarction.
SUMMARY OF THE INVENTION
This invention relates to a compound having the structural formula (I):
Figure imgf000005_0001
wherein
R1 , R2, R3 e R4 are independently selected from -OFI and -H;
X is selected from: -NH, O, S;
R5 is selected from among the following groups:
Figure imgf000006_0001
R6 is selected from -H or a non-substituted phenyl group,
Figure imgf000006_0002
with the condition that when R5 is
R2 and R3 are never simultaneously -OH.
The compound of this invention, or a pharmaceutical composition comprising said compound, is used as a medicament for the treatment or prevention of ischemic pathologies, cardio-metabolic pathologies, including diabetes, and cardiovascular pathologies, including coronary pathologies, heart failure, acute myocardial infarction and atherosclerosis.
BRIEF DESCRIPTION OF THE FIGURES
Figure 1 shows the effects of compounds 1 -36 on SIRT1 ; data are expressed as a % vs resveratrol.
Figure 2 shows the effects of different concentrations of compounds 14-17 on SIRT1 ; data are expressed as a % vs resveratrol.
Figure 3 shows the effects of compounds 14 and 15 in reducing the ischemic area after an ischemia/reperfusion injury. Ischemic areas are expressed as a % of the whole left ventricle area. DETAILED DESCRIPTION OF THE INVENTION
This invention relates to a compound having the structural formula (I):
Figure imgf000007_0001
wherein
R1 , R2, R3 e R4 are independently selected from -OH and -H;
X is selected from: -NH, O, S;
R5 is selected from among the following groups:
Figure imgf000007_0002
R6 is selected from -H or a non-substituted phenyl group,
Figure imgf000007_0003
with the condition that when R5 is
R2 and R3 are never simultaneously -OH.
In one embodiment of the invention, X is selected from -NH and -O.
In one embodiment of the invention, X is -NH.
In one embodiment of the invention, R1 , R2, R3 and R4 are independently selected from -OH and -H, X is selected from -NH and -O and R5 is
Figure imgf000008_0001
selected from the groups
Figure imgf000008_0002
In a preferred embodiment of the invention, R1 , R2, R3 and R4 are independently selected from -OH and -H, X is -NH and R5 is
Figure imgf000008_0003
In one embodiment of the invention, R1 , R2, R3 and R4 are independently selected from -OH and -H, X is -NH and R5 is selected from the groups:
Figure imgf000008_0004
In one embodiment of the invention, R1 , R2, R3 and R4 are independently selected from -OH and -H, X is selected from -O and -NH and R5 is
Figure imgf000008_0005
In one embodiment of the invention, R1 , R2, R3 and R4 are independently selected from -OH and -H, X is -NH and R5 is
Figure imgf000008_0006
In one embodiment of the invention R1 , R3 = H and R2, R4 = OH; or R2, R3 = H and R1 , R4 = OH; or R2, R4 = H and R1 , R3 = OH, X is -NH and
Figure imgf000009_0001
R5 is
In one embodiment of the invention R1 , R2, R3 and R4 are independently
Figure imgf000009_0002
selected from -OH and -H, X is -NH and R5 is
In one embodiment of the invention R1 , R2, R3 and R4 are independently selected from -OH and -H, X is -S and R5 is
Figure imgf000009_0003
In one embodiment of the invention R1 , R2, R3 and R4 are independently
selected from -OH and -H, X is -NH and R5 is
Figure imgf000009_0004
a non-substituted phenyl group.
In one embodiment of the invention R1 , R2, R3 and R4 are independently
Figure imgf000009_0005
selected from -OH and -H, X is -NH and R5 is
The compound according to this invention is selected from:
(1)
Figure imgf000009_0006
Figure imgf000010_0001
Figure imgf000011_0001
10
Figure imgf000012_0001
11
Figure imgf000013_0001
Figure imgf000014_0001
The compounds of the invention activate the SIRT1 enzyme and regulate cell metabolism and the transcription of numerous factors that are important for cell survival. In particular, the compounds are capable of activating the SIRT1 enzyme and favoring cell survival following an insult, for example following an ischemic insult.
A further aspect of this invention relates to a pharmaceutical composition comprising the compound according to the invention and pharmaceutically acceptable excipients, adjuvants and/or carriers.
In one embodiment of this invention, the pharmaceutical composition is formulated for enteral use, preferably oral or sublingual; for example, the composition is prepared in the form of pills, capsules, tablets, granular powder, hard-shelled capsules, orally dissolving granules, sachets or lozenges.
In one embodiment of this invention, the pharmaceutical composition is formulated for parenteral use, for example intravenous, subcutaneous or intramuscular, preferably intravenous. A further aspect of this invention relates to the compound as described above or the pharmaceutical composition comprising the compound for use as a medicament, preferably for use in the treatment or in the prevention of cardiovascular pathologies, including coronary pathologies, heart failure, acute myocardial infarction and atherosclerosis.
A further aspect of this invention relates to the compound as described above or the pharmaceutical composition comprising the compound used in association or in combination with other molecules. Said molecules are selected from: ACE inhibitors, statins, sartans, calcium channel blockers, beta-blockers, vasodilators, digitalin, antianginal, anti-ischemic, antiarrhythmic, antihypertensive and hypocholesterolemic drugs and combinations thereof.
A further aspect of this invention relates to a method for the treatment or prevention of cardio-metabolic pathologies, including diabetes, and cardiovascular pathologies, including coronary pathologies, heart failure, acute myocardial infarction and atherosclerosis.
Said method comprises at least a step of administering an effective dose of the compound of this invention or of the pharmaceutical composition comprising said compound to a patient who has a need for said compound. The process for preparing the compound according to this invention is exemplified in the experimental part.
Examples
Synthesis of compounds
The compounds of this invention (examples 1 -36) can be prepared according to the procedures described in the following schemes (schemes 1 -8), specific for each series of examples.
In the procedures described below all temperatures are expressed in degrees Celsius. The following abbreviations or reagents are explained as follows: room temperature, 20-25 °C (rt), hours (h), minutes (min.), aqueous solution (aq.), potassium carbonate (K2CO3), sodium bicarbonate (NaHC03), sodium carbonate (Na2C03), potassium phosphate (K3PO4), dichloromethane (DCM), chloroform (CHCI3), methanol (MeOH), ethyl acetate (EtOAc), dimethyl sulfoxide (DMSO), ethanol (EtOH), tetrahydrofuran (THF), triethylamine (Et3N), trifluoroacetic acid (TFA), di- tert-butyl dicarbonate ((Boc)20) isopropanol (/PrOH), N,N- dimethylformamide (DMF), molar concentration (M), volume/volume ratio (v/v), millimoles (mmol), millilitres (ml_), thin layer chromatography (TLC), nuclear magnetic resonance (NMR), palladium acetate (Pd(OAc)2), ris(dibenzylideneacetone)dipalladium(0) (Pd2dba3), 2- dicyclohexylphosphino-2',4',6'-triisopropylbiphenyl (XPhos), (2-di-tert- butylphosphino-3,4,5,6-tetramethyl-2',4',6'-triisopropyl-1 ,1 -biphenyl) (Me4/BuXPhos), triphenylphosphine (PPh3), cupric bromide (CuBr2), sodium azide (NaN3), cuprous iodide (Cul), boron tribromide (BBr3), sodium cyanate (NaOCN), acetic acid (AcOH).
Figure imgf000017_0001
Scheme 1. Synthesis of oxazole derivatives: examples 1 -4.
Figure imgf000017_0002
OH
Example 5 Scheme 2. Synthesis of oxazole derivative: example 5.
Figure imgf000018_0001
Scheme 3. Synthesis of diaryl ether derivatives: examples 6-9.
Figure imgf000019_0001
Scheme 4. Synthesis of aniline derivatives: examples 10-13.
Figure imgf000020_0001
Scheme 5. Synthesis of pyridine derivatives: examples 14-17 and 22-28.
Figure imgf000021_0001
Examples 18-21
18: R1, R3 = H, R2, R4 = OH;
19: R1, R4 = OH, R2, R3 = H;
20: R1, R4 = H, R2, R3 = OH;
21: R1, R3 = OH, R2, R4 = H.
Scheme 6. Synthesis of pyridine derivatives: examples 18-21.
Figure imgf000022_0001
Scheme 7. Synthesis of diaryl thioether derivatives: examples 29-32.
Figure imgf000023_0001
Scheme 8. Synthesis of isoquinoline derivatives: examples 34 and 36; and triaryl-substituted pyridine derivatives: examples 33 and 35.
Procedures for the preparation of compounds 1 -36 Scheme 1.
Step 1.
In a round-bottomed flask, commercially available 3- or 4-methoxy- substituted acetophenone (3.33 mmol, 500 mg) was dissolved in chloroform (7.6 ml_) and ethyl acetate (7.6 ml_) (1 :1 v/v) to give a clear solution. Then copper (II) bromide (6.66 mmol) was added and the reaction was stirred at 85 °C for 3 h. The reaction mass was then filtered through a Celite bed, which was washed repeatedly with EtOAc. The filtrate was concentrated under vacuum. The resulting crude product was purified by column chromatography over silica gel, using n- hexane/EtOAc mixtures as the eluent, in order to get pure substituted phenacyl bromides A1 (72% yield) or A2 (78% yield). [A1 : 1H-NMR (CDCIa) d (ppm): 3.87 (s, 3H), 4.45 (s, 2H), 7.16 (ddd, 1 H, J = 8.3, 2.7, 0.9 Hz), 7.40 (t, 1 H, J = 7.9 Hz), 7.51 (t, 1 H, J = 2.1 Hz), 7.56 (dt, 1 H, J = 7.9, 1.2 Hz). A2: 1H-NMR (CDC ) d (ppm): 3.89 (s, 3H), 4.40 (s, 2H), 6.96 (AA’XX’, 2H, JAX = 9.0 Hz, JAAVXX· = 2.5 Hz), 7.97
(AA’XX’, 2H, JAX = 9.0 Hz, JAAVXX· = 2.5 Hz).]
Step 2.
Intermediate A1 or A2 (1.20 mmol, 275 mg) was dissolved in acetone (19.7 ml_) and a single portion of sodium azide (2.40 mmol) was added to the stirred mixture, which was allowed to stir at rt overnight. The mixture was concentrated and then the residue was partitioned between EtOAc and H2O and the aqueous layer extracted several times with EtOAc. The combined organic phases were dried over Na2S04 and concentrated to yield pure intermediate azides B1 (92% yield) or B2 (95% yield). [B1 : 1H-NMR (CDC ) d (ppm): 3.86 (s, 3H), 4.55 (s, 2H), 7.17 (ddd, 1 H , J= 8.0, 2.4, 1.2 Hz), 7.37- 7.47 (m, 3H). B2: 1H-NMR (CDCIs) d (ppm): 3.89 (s, 3H), 4.51 (s, 2H), 6.93- 6.99 (m, 2H), 7.86-7.92 (m, 2H).]
Step 3.
Azide B1 or B2 (0.523 mmol, 100 mg) was dissolved in anhydrous 1 ,4- dioxane (2 ml_) and commercially available 3- or 4-methoxyphenyl isothiocyanate (0.436 mmol) was added, followed by PPh3 (0.523 mmol). The mixture was stirred at 100 °C for 30 min. The cooled solution was concentrated and the resulting crude product was purified by column chromatography over silica gel using n- hexane/EtOAc mixtures as the eluent, to yield intermediate C1 (83% yield); C2 (57% yield); C3 (35% yield) or C4 (74% yield). [C1 : 1H-NMR (CDCIs) d (ppm): 3.84 (s, 6H), 6.63 (dd, 1 H, J= 8.1 , 2.0 Hz), 6.94 (AA’XX’, 2H, JAX = 8.9 Hz, JAAYXX = 2.5 Hz), 7.00-7.05 (m, 2H), 7.17 (t, 1 H, J= 2.3 Hz), 7.26 (t, 1 H, J = 8.2 Hz), 7.47 (AA’XX’, 2H,
JAX = 8.9 Hz, JAAVXX· = 2.5 Hz). C2: 1H-NMR (CDCIs) d (ppm): 3.81 (s, 3H), 3.84 (s, 3H), 6.88-6.95 (m, 4H), 6.99 (s, 1 H), 7.40 (AA’XX’, 2H, JAX = 9.0 Hz, JAAYXX = 2.9 Hz), 7.45 (AA’XX’, 2H, JAX = 8.9 Hz, JAAVXX· = 2.4 Hz). C3: 1H-NMR (CDCIs) d (ppm): 3.84 (s, 3H), 3.85 (s, 3H), 6.63 (ddd, 1 H, J = 8.3, 2.3, 0.6 Hz), 6.83 (ddd, 1 H, J = 8.2, 2.5, 0.8 Hz), 7.03 (ddd, 1 H, J= 8.1 , 2.1 ,
0.7 Hz), 7.07 (t, 1 H, J= 2.0 Hz), 7.1 1 -7.20 (m, 3H), 7.26 (t, 1 H, J= 8.2 Hz), 7.31 (t, 1 H, J= 8.0 Hz). C4: 1H-NMR (CDCIs) d (ppm): 3.81 (s, 3H), 3.85 (s, 3H), 6.81 (ddd, 1 H, J = 8.3, 2.5, 0.7 Hz), 6.92 (AA’XX’, 2H, JAX = 9.0 Hz, JAAYXX’ = 2.9 Hz), 7.05 (t, 1 H, J= 1.0 Hz), 7.10-7.15 (m, 2H), 7.23 (t, 1 H, J = 8.0 Hz), 7.41 (AA’XX’, 2H, JAX = 9.0 Hz, JAAVXX’ = 2.9 Hz).]
Step 4.
A solution of methoxylated intermediate C1 , C2, C3 or C4 (0.337 mmol, 100 mg) in anhydrous DCM (5.5 ml_) was cooled to -15 °C and treated dropwise with a 1 M solution of BBr3 in dichloromethane (3.4 ml_), and the resulting solution was stirred at 0 °C for 1 h and at rt until the reaction was complete (disappearance of the starting material as verified by TLC analysis). The mixture was then diluted with water and extracted with ethyl acetate. The organic phase was washed with brine, dried and concentrated. The crude product was purified by flash chromatography (n-hexane/ethyl acetate mixtures) to yield pure phenolic compounds examples 1 -4 (example 1 : yield 92%, example 2: yield 20%, example 3: yield 21 %, example 4: yield 98%). Scheme 2.
Step 1.
A solution of sodium cyanate (6.05 mmol) in H2O (2.7 ml_) was added slowly to the mixture of commercially available 3-aminophenol (5.50 mmol, 600 mg) in glacial acetic acid (0.6 ml_) and H2O (5.4 ml_) at room temperature. Upon the completion of the addition, the reaction mixture was stirred at rt overnight. The reaction mixture was diluted with H2O, and extracted several times with EtOAc. The combined organic phases were dried over anhydrous sodium sulphate and concentrated under vacuum. The resulting crude product was purified by column chromatography over silica gel using DCM/MeOH mixture 8:2 as the eluent in order to obtain pure phenylurea D (yield 85%). [D: 1H-NMR (DMSO-de) d (ppm): 5.76 (bs, 2H), 6.28 (ddd, 1 H, J= 8.0, 2.4, 0.9 Hz), 6.69 (ddd, 1 H, J= 8.1 , 2.0, 0.9 Hz), 6.96 (t, 1 H, J= 8.0 Hz), 7.01 (t, 1 H, J = 2.2 Hz), 8.37 (bs, 1 H), 9.18 (s, 1 H).]
Step 2.
In a sealed vial, an equimolar mixture of compound D (1.45 mmol, 220 mg) and compound A2 (Scheme 1 , 1.45 mmol) in ethanol (2.9 ml_) was refluxed in the presence of DMF (0.22 ml_) for about 7 h. The progress of the reaction was monitored by TLC. Upon the disappearance of the starting materials, the reaction mixture was cooled and concentrated under vacuum. The crude residue was purified by column chromatography over silica gel (n- hexane/EtOAc 3:7) to afford intermediate E (yield 26%). [E: 1H-NMR (acetone- e) d (ppm): 3.83 (s, 3H), 6.68-6.72 (m, 1 H), 6.98 (AA’XX’, 2H, JAX = 9.0 Hz, JAAVXX’ = 2.6 Hz), 7.20-7.26 (m, 3H), 7.46-7.49 (m, 1 H), 7.62 (AA’XX’, 2H, JAX = 9.0 Hz, JAAVXX· = 2.6 Hz), 8.50 (s, 1 H), 9.83 (bs, 1 H).] Step 3.
A solution of methoxylated intermediate E (0.365 mmol, 103 mg) in anhydrous DCM (6 ml_) was cooled to -15 °C and treated dropwise with a 1 M solution of BBr3 in dichloromethane (1.8 ml_), and the resulting solution was stirred at 0 °C for 1 h and at rt until the reaction was complete (disappearance of the starting material as verified by TLC analysis). The mixture was then diluted with water and extracted with ethyl acetate. The organic phase was washed with brine, dried and concentrated. The crude product was purified by flash chromatography (n-hexane/ethyl acetate 3:7) to yield the pure phenolic compound, example 5 (yield 33%).
Scheme 3.
Step 1.
A solution of Pd(OAc)2 (0.0435 mmol) and triphenylphosphine (0.218 mmol) in ethanol (3.3 ml_) and toluene (3.3 ml_) was stirred at rt under inert atmosphere for 10 min. After that period, commercially available 3- bromophenol (1.45 mmol, 250 mg), a 2 M aqueous solution of Na2C03 (3.3 ml_), and commercially available 3- or 4-methoxybenzeneboronic acid (2.32 mmol) were sequentially added. The resulting mixture was heated at 100 °C in a sealed vial overnight. After being cooled to rt, the mixture was diluted with water and extracted with EtOAc. The combined organic phases were dried over anhydrous sodium sulphate and concentrated under vacuum. The crude product was purified by flash column chromatography; eluting with n- hexane/EtOAc mixtures as eluents afforded the biaryl intermediates F1 (99% yield) or F2 (99% yield). [F1 : 1H-NMR (CDCIa) d (ppm): 3.87 (s, 3H), 6.83 (ddd, 1 H, J= 8.0, 2.6, 1.0 Hz), 6.90 (ddd, 1 H, J= 8.2, 2.6, 0.9 Hz), 7.06 (t, 1 H, J = 2.0 Hz), 7.1 1 (t, 1 H, J = 2.1 Hz), 7.14-7.16 (m, 1 H), 7.16- 7.18 (m, 1 H), 7.31 (t, 1 H, J = 7.9 Hz), 7.35 (t, 1 H, J = 8.0 Hz). F2: 1H-NMR
(CDCIs) d (ppm): 3.85 (s, 3H), 4.73-4.93 (bs, 1 H), 6.78 (ddd, 1 H, J = 8.1 , 2.5, 0.9 Hz), 6.97 (AA’XX’, 2H, JAX = 8.9 Hz, JAAVXX’ = 2.6 Hz), 7.02 (dd, 1 H, J= 2.2, 1.7 Hz), 7.13 (ddd, 1 H, J= 7.7, 1.7, 1.0 Hz), 7.29 (t, 1 H, J= 8.0 Hz), 7.51 (AA’XX’, 2H, JAX = 8.9 Hz, JAAVXX = 2.6 Hz).] Step 2.
A vial was loaded with K3PO4 (1.62 mmol) and intermediate F1 or F2 (1.62 mmol, 324 mg). Then, in an inert atmosphere, copper (I) iodide (0.081 mmol) in DMSO (0.6 ml_) and commercially available 4-bromoanisole (0.81 mmol) were added. The vial was sealed, and the reaction mixture was stirred at 130 °C. After the reaction mixture was heated for 24 h, it was cooled to rt and the workup consisted of filtration of the reaction mixture through a Celite pad and washing with EtOAc. The filtrate was concentrated under vacuum to give a crude residue, which was then purified by flash chromatography, using mixtures of n- hexane/EtOAc as the eluent to give intermediates G1 (28% yield) or G2 (46% yield). [G1 : 1H-NMR (CDCI3) d (ppm): 3.81 (s, 3H), 3.85 (s, 3H), 6.87-6.94 (m, 4H), 7.03 (AA’XX’, 2H, JAX = 9.1 Hz, JAA’/XX’ = 3.0 Hz), 7.08 (t, 1 H, J = 2.1 Hz), 7.13 (ddd, 1 H, J = 7.6, 1.6, 0.9 Hz), 7.18 (t, 1 H, J = 2.0 Hz), 7.28 (t, 1 H, J = 1.3 Hz), 7.30-7.38 (m, 2H). F2: 1H-NMR (CDCI3) d (ppm): 3.81 (s, 3H), 3.84 (s, 3H), 6.85-6.88 (m,
1 H), 6.89 (AA’XX’, 2H, JAX = 9.1 Hz, JAAVXX· = 2.8 Hz), 6.95 (AA’XX’, 2H, JAX = 8.9 Hz, JAAVXX’ = 2.6 Hz), 7.02 (AA’XX’, 2H, JAX = 9.0 Hz, JAAVXX = 3.0 Hz), 7.14 (t, 1 H, J = 2.1 Hz), 7.23 (dt, 1 H, J = 8.2, 1.3 Hz), 7.33 (t, 1 H, J = 7.9 Hz), 7.48 (AA’XX’, 2H, JAX = 8.8 Hz, JAAVXX· = 2.6 Hz).]
Step 3.
A sealed vial was charged with Me4/BuXPhos (0.0125 mmol), Pd(OAc)2 (0.00832 mmol), K3PO4 (0.832 mmol), intermediate F1 or F2 (0.499 mmol, 100 mg), commercially available 3-bromoanisole (0.416 mmol) and toluene (0.8 mL) under a positive pressure of argon. The resulting mixture was heated at 100 °C overnight. The mixture was allowed to cool to room temperature and then filtered through a small pad of Celite and washed several times with ethyl acetate; the filtrate was concentrated under reduced pressure. The crude product was purified by flash chromatography over silica gel (n- hexane/EtOAc mixtures) to afford diaryl ether derivatives H1 (58% yield) or H2 (71 % yield). [H1 : 1H-NMR (CDCIs) d (ppm): 3.79 (s, 3H), 3.85 (s, 3H), 6.60-6.70 (m, 3H), 6.90 (dd, 1 H, J= 8.2, 1.8 Hz), 6.97-7.03 (m, 1 H), 7.09 (t, 1 H, J = 1.9 Hz), 7.12-7.18 (m, 1 H), 7.19-7.28 (m, 2H), 7.30- 7.43 (m, 3H). H2: 1H-NMR (CDCIs) d (ppm): 3.79 (s, 3H), 3.85 (s, 3H), 6.60-
6.69 (m, 3H), 6.93-6.99 (m, 3H), 7.20-7.27 (m, 2H), 7.30 (ddd, 1 H, J = 7.6, 1.6, 1.2 Hz), 7.37 (t, 1 H, J= 8.0 Hz), 7.50 (AA’XX’, 2H, JAX = 8.9 Hz, JAAYXX = 2.6 Hz).]
Step 4.
A solution of methoxylated intermediate G1 , G2, H1 or H2 (0.349 mmol, 107 mg) in anhydrous DCM (4.1 mL) was cooled to -15 °C and treated dropwise with a 1 M solution of BBr3 in dichloromethane (2.2 mL), and the resulting solution was stirred at 0 °C for 1 h and at rt until the reaction was complete (disappearance of the starting material as verified by TLC analysis). The mixture was then diluted with water and extracted with ethyl acetate. The organic phase was washed with brine, dried and concentrated. The crude product was purified by chromatography over silica gel (n-hexane/ethyl acetate mixtures) to yield pure phenolic compounds, examples 6-9 (example 6: yield 76%, example 7: yield 77%, example 8: yield 71 %, example 9: yield 95%).
Scheme 4.
Step 1.
Et3N (2.4 ml_) and di-te/t-butyl dicarbonate (10.5 mmol) were added to a solution of commercially available 3-bromoaniline (8.72 mmol, 1.50 g) in anhydrous THF (22.2 ml_) at 0 °C, and the reaction mixture was stirred for 24 h at room temperature. The solvent was removed under reduced pressure; then the residue was diluted with EtOAc and sequentially washed with a saturated solution of sodium bicarbonate, water and brine. The organic phase was dried with Na2S04 and concentrated. The residue was purified by column chromatography with a mixture of n- hexane/EtOAc 95:5 as the eluent to afford intermediate I (62% yield). [I: 1H-NMR (CDC ) d (ppm): 1.52 (s, 9H), 6.47 (bs, 1 H), 7.10-7.18 (m, 2H), 7.20 (dt, 1 H, J = 7.2, 2.0 Hz), 7.67 (s, 1 H).]
Step 2.
A solution of Pd(OAc)2 (0.0495 mmol) and triphenylphosphine (0.248 mmol) in ethanol (3.7 ml_) and toluene (3.7 ml_) was stirred at rt under an inert atmosphere for 10 min. After that period, intermediate I (1.65 mmol, 450 mg), a 2 M aqueous solution of Na2C03 (3.7 ml_), and commercially available 3- or 4-methoxybenzeneboronic acid (2.64 mmol) were sequentially added. The resulting mixture was heated at 100 °C in a sealed vial under an inert atmosphere overnight. After being cooled to rt, the mixture was diluted with water and extracted with EtOAc. The combined organic phases were dried over anhydrous sodium sulphate and concentrated under vacuum. The crude residue was purified by flash column chromatography, eluting with n- hexane/EtOAc mixtures as eluents to afford intermediates J1 (89% yield) or J2 (89% yield). [J1 : 1H-NMR (CDCIs) d (ppm): 1.53 (s, 9H), 3.86 (s, 3H), 6.53 (bs, 1 H), 6.89 (ddd, 1 H, J = 8.2, 2.6, 0.9 Hz), 7.11 (t, 1 H, J = 2.1 Hz), 7.17 (ddd, 1 H, J = 7.7, 1.6, 1.0 Hz), 7.23-7.28 (m, 1 H), 7.31 -7.28 (m, 3H), 7.59 (s, 1 H). J2: 1H-NMR (CDCIa) d (ppm): 1.53 (s, 9H), 3.85 (s, 3H), 6.51 (bs, 1 H), 6.96 (AA’XX’, 2H, JAX = 8.9 Hz, JAAVXX’ = 2.6 Hz), 7.22 (dt, 1 H, J = 7.4, 1.5 Hz), 7.27-7.35 (m, 2H),
7.52 (AA’XX’, 2H, JAX = 8.9 Hz, JAAVXX = 2.6 Hz), 7.59 (s, 1 H).]
Step 3.
Compounds J1 -J2 (2.18 mmol, 653 mg) were dissolved in DCM (9.8 ml_), cooled to 0 °C, treated with trifluoroacetic acid (3.0 ml_), and stirred at rt until complete consumption of the starting material (as verified by TLC). The mixture was concentrated to dryness under reduced pressure, diluted with EtOAc, and washed with a 1 M NaHC03 aqueous solution. The organic layer was dried over Na2S04 and concentrated to give the title compounds K1 (85% yield) or K2 (94% yield). [K1 : 1H-NMR (CDCIa) d (ppm): 3.86 (s, 3H), 6.70 (ddd, 1 H, J= 7.9, 2.3, 0.9 Hz), 6.89 (ddd, 1 H, J= 8.2, 2.6, 0.9 Hz),
6.92 (t, 1 H, J = 1.9 Hz), 7.00 (ddd, 1 H, J = 7.6, 1.6, 1.0 Hz), 7.10 (t, 1 H, J = 2.0 Hz), 7.15 (ddd, 1 H, J= 7.6, 1.6, 1.0 Hz), 7.23 (t, 1 H, J= 7.8 Hz), 7.33 (t, 1 H, J = 7.9 Hz). K2: 1H-NMR (CDCIa) d (ppm): 3.84 (s, 3H), 6.64 (ddd, 1 H, J = 7.9, 2.3, 0.9 Hz), 6.87 (t, 1 H, J = 1.9 Hz), 6.93-6.98 (m, 3H), 7.20 (t, 1 H, J = 7.8 Hz), 7.50 (AA’XX’, 2H, JAX = 8.9 Hz, JAAVXX = 2.6 Hz).]
Step 4.
A solution of Pd2dba3 (0.0125 mmol), XPhos (0.0502 mmol), K3PO4 (0.878 mmol), commercially available 3- or 4-bromoanisole (0.627 mmol) and aniline intermediate K1 or K2 (0.753 mmol, 150 mg) in toluene (1.3 ml_) was stirred at 100 °C under an inert atmosphere in a sealed vial for 20 h. The reaction mixture was allowed to cool to room temperature, then filtered through a small Celite pad, washed with ethyl acetate and concentrated under vacuum. The crude residue obtained was purified by flash column chromatography (eluent mixtures of n- hexane/EtOAc) to give intermediates L1 (86% yield); L2 (91% yield); L3 (54% yield) or L4 (39% yield). [L1 : 1H- NMR (CDC ) d (ppm): 3.79 (s, 3H), 3.85 (s, 3H), 6.50 (ddd, 1 H, J= 8.2, 2.4, 0.8 Hz), 6.67-6.73 (m, 2H), 6.96 (AA’XX’, 2H, JAX = 8.9 Hz, JAAVXX· = 2.6 Hz), 7.05 (ddd, 1 H, J= 8.0, 2.3, 1.0 Hz), 7.14 (ddd, 1 H, J= 7.7, 1.7, 1.0 Hz), 7.18
(t, 1 H, J = 8.1 Hz), 7.28 (t, 1 H, J = 1.9 Hz), 7.31 (t, 1 H, J = 7.9 Hz), 7.50 (AA’XX’, 2H, JAX = 8.9 Hz, JAAVXX = 2.6 Hz). L2: 1H-NMR (acetone-de) d (ppm): 3.77 (s, 3H), 3.82 (s, 3H), 6.85-7.03 (m, 6H), 7.08-7.27 (m, 5H), 7.48- 7.56 (m, 2H). L3: 1H-NMR (CDC ) d (ppm): 3.79 (s, 3H), 3.86 (s, 3H), 6.51 (ddd, 1 H, J = 8.2, 2.4, 0.8 Hz), 6.67-6.74 (m, 2H), 6.90 (ddd, 1 H, J = 8.2, 2.6, 0.9 Hz), 7.07-7.13 (m, 2H), 7.13-7.21 (m, 3H), 7.29-7.37 (m, 3H). L4: 1H-NMR (acetone-de) d (ppm): 3.77 (s, 3H), 3.85 (s, 3H), 6.87-6.93 (m, 3H), 6.96 (ddd, 1 H, J = 8.1 , 2.4, 0.9 Hz), 7.02 (ddd, 1 H, J = 7.6, 1.7, 1.0 Hz), 7.10-7.13 (m, 1 H), 7.13-7.18 (m, 3H), 7.19 (bs, 1 H), 7.21 -7.24 (m, 1 H), 7.25 (t, 1 H, J = 7.9 Hz), 7.34 (t, 1 H, J = 7.9 Hz).]
Step 5.
A solution of methoxylated intermediate L1 , L2, L3 or L4 (0.426 mmol, 130 mg) in anhydrous DCM (5.0 ml_) was cooled to -15 °C and treated dropwise with a 1 M solution of BBr3 in dichloromethane (2.7 ml_), and the resulting solution was stirred at 0 °C for 1 h and at rt until the reaction was complete (disappearance of starting material as verified by TLC analysis). The mixture was then diluted with water and extracted with ethyl acetate. The organic phase was washed with brine, dried and concentrated. The crude product was purified by chromatography over silica gel (n-hexane/ethyl acetate mixtures) to yield pure phenolic compounds, examples 10-13 (example 10: yield 72%, example 1 1 : yield 83%, example 12: yield 98%, example 13: yield 86%).
Scheme 5.
Step 1.
A solution of Pd(OAc)2 (0.0607 mmol) and triphenylphosphine (0.303 mmol) in toluene (19.6 ml_) was stirred at rt under an inert atmosphere for 10 min. After that period, commercially available 2-amino-6-bromopyridine (X = CH, Y = N, Scheme 5) or 2-amino-4-bromopyirdine (X = N, Y = CH, Scheme 5) or 3-amino-5-bromopyridine (X = CH, Y = CH, Z = N, Scheme 5)(2.02 mmol, 350 mg), anhydrous K2CO3 (3.03 mmol), and commercially available 3- or 4-methoxybenzeneboronic acid (4.04 mmol) were sequentially added. The resulting mixture was heated at 100 °C in a sealed vial under an inert atmosphere overnight. After being cooled to rt, the mixture was diluted with water and extracted with EtOAc. The combined organic phases were dried over anhydrous sodium sulphate and concentrated under vacuum. The crude residue was purified by flash column chromatography, eluting with n- hexane/EtOAc mixtures as eluents to afford the biaryl intermediates M1 (99% yield); M2 (91 % yield); M3 (97% yield), M4 (98% yield), M5 (99% yield) or M6 (94% yield). [M1 : 1H-NMR (CDCIs) d (ppm): 3.89 (s, 3H), 4.67 (bs, 2H), 6.48 (dd, 1 H, J= 8.1 , 0.6 Hz), 6.93 (ddd, 1 H, J= 8.2, 2.6, 1.0 Hz), 7.08 (dd, 1 H, J= 7.5, 0.7 Hz), 7.34 (t, 1 H, J= 7.9 Hz), 7.46-7.55 (m, 3H). M2: 1H- NMR (CDCIs) d (ppm): 3.85 (s, 3H), 4.67 (bs, 2H), 6.42 (dd, 1 H, J= 8.1 , 0.7 Hz), 6.97 (AA’XX’, 2H, JAX = 9.0 Hz, JAAVXX’ = 2.6 Hz), 7.03 (dd, 1 H, J= 7.6, 0.7 Hz), 7.49 (dd, 1 H, J= 8.1 , 7.6 Hz), 7.90 (AA’XX’, 2H, JAX = 9.0 Hz, JAAVXX· = 2.6 Hz). M3: 1H-NMR (CDCIs) d (ppm): 3.86 (s, 3H), 4.64 (bs, 2H), 6.70 (dd, 1 H, J = 1.5, 0.7 Hz), 6.88 (dd, 1 H, J = 5.5, 1.6 Hz), 6.96 (ddd, 1 H, J =
8.3, 2.6, 0.9 Hz), 7.10 (t, 1 H, J = 2.1 Hz), 7.17 (ddd, 1 H, J = 7.7, 1.6, 0.9 Hz), 7.37 (t, 1 H, J = 7.9 Hz), 8.14 (dd, 1 H, J = 5.4, 0.5 Hz). M4: 1H-NMR (CDCIs) d (ppm): 3.86 (s, 3H), 4.45-4.55 (bs, 2H), 6.68 (dd, 1 H, J= 1.5, 0.7 Hz), 6.86 (dd, 1 H, J= 5.4, 1.6 Hz), 6.98 (AA’XX’, 2H, JAX = 8.9 Hz, JAAVXX = 2.6 Hz), 7.54 (AA’XX’, 2H, JAX = 8.9 Hz, JAAVXX’ = 2.6 Hz), 8.08 (dd, 1 H, J =
5.4, 0.6 Hz). M5: 1H-NMR (CDC ) d (ppm): 3.86 (s, 3H), 6.93 (ddd, 1 H, J = 8.2, 2.6, 0.8 Hz), 7.07 (t, 1 H, J= 2.0 Hz), 7.10-7.15 (m, 1 H), 7.16 (t, 1 H, J = 2.3 Hz), 7.37 (t, 1 H, J = 8.0 Hz), 8.09 (d, 1 H, J = 2.5 Hz), 8.25 (d, 1 H, J = 1.5 Hz). M6: 1H-NMR (CDCb) d (ppm): 3.50-3.90 (bs, 2H), 3.85 (s, 3H), 6.98 (AA’XX’, 2H, JAX = 8.8 Hz, JAAVXX’ = 2.6 Hz), 7.12 (dd, 1 H, J = 2.5, 2.0 Hz), 7.48 (AA’XX’, 2H, JAX = 8.8 Hz, JAAVXX = 2.6 Hz), 8.04 (d, 1 H, J = 2.6 Hz), 8.23 (d, 1 H, J = 1.9 Hz).]
Step 2.
A solution of Pd2dba3 (0.0108 mmol), XPhos (0.0433 mmol), K3PO4 (0.757 mmol), commercially available 3- or 4-bromoanisole (0.541 mmol) and aniline intermediate M1 , M2, M3, M4, M5 or M6 (0.649 mmol, 130 mg) in toluene (1.1 mL) was stirred at 100 °C under an inert atmosphere in a sealed vial for 20 h. The reaction mixture was allowed to cool to room temperature, then filtered through a small Celite pad and washed with ethyl acetate; the filtrate was concentrated under vacuum. The crude residue obtained was purified by flash column chromatography (eluent mixtures of n- hexane/EtOAc) to give intermediates N1 (64% yield), N2 (48% yield), N3 (99% yield), N4 (83% yield), N5 (42% yield), N6 (23% yield), N7 (40% yield),
N8 (22% yield), N9 (2% yield), N10 (57% yield) or N1 1 (63% yield). [N1 : 1H- NMR (CDC ) d (ppm): 3.83 (s, 3H), 3.91 (s, 3H), 6.62 (ddd, 1 H, J= 8.3, 2.5, 0.7 Hz), 6.83 (d, 1 H, J= 7.8 Hz), 6.91 -6.98 (m, 2H), 7.18-7.25 (m, 3H), 7.37 (t, 1 H, J = 7.9 Hz), 7.53-7.62 (m, 2H), 7.64 (t, 1 H, J = 2.1 Hz). N2: 1H-NMR (CDC ) d (ppm): 3.82 (s, 3H), 3.90 (s, 3H), 6.64 (dd, 1 H, J = 8.3, 0.6 Hz), 6.91 (AA’XX’, 2H, JAX = 8.9 Hz, JAAVXX· = 2.9 Hz), 6.95 (ddd, 1 H, J= 8.2, 2.6, 0.9 Hz), 7.13 (dd, 1 H, J = 7.5, 0.7 Hz), 7.32 (AA’XX’, 2H, JAX = 8.8 Hz, JAAVXX· = 2.7 Hz), 7.36 (t, 1 H, J= 8.0 Hz), 7.49-7.56 (m, 2H), 7.58-7.61 (m, 1 H). N3: 1H-NMR (CDC ) d (ppm): 3.83 (s, 3H), 3.87 (s, 3H), 6.60 (ddd, 1 H, J = 8.1 , 2.5, 0.8 Hz), 6.60-6.67 (bs, 1 H), 6.78 (d, 1 H, J= 8.2 Hz), 6.92 (ddd, 1 H, J = 8.0, 2.0, 0.7 Hz), 7.98 (AA’XX’, 2H, JAX = 9.0 HZ, JAAVXX’ = 2.6 Hz), 7.13-7.18 (m, 2H), 7.24 (t, 1 H, J= 8.1 Hz), 7.55 (t, 1 H, J = 7.9 Hz), 7.97 (AA’XX’, 2H, JAX = 9.0 Hz, JAAVXX = 2.5 Hz). N4: 1H-NMR (aceton e-de) d (ppm): 3.78 (s, 3H), 3.86 (s, 3H), 6.65 (dd, 1 H, J= 8.3, 0.6 Hz), 6.91 (AA’XX’, 2H, JAX = 9.0 Hz, JAAVXX = 2.9 Hz), 7.01 (AA’XX’, 2H, JAX = 9.0 Hz, JAAVXX = 2.6 Hz), 7.19 (dd, 1 H, J = 7.5, 0.6 Hz), 7.54 (dd, 1 H, J = 8.2, 7.6 Hz), 7.66 (AA’XX’, 2H, JAX = 9.0 Hz, JAAVXX· = 2.9 Hz), 8.01 (bs, 1 H), 8.05 (AA’XX’, 2H, JAX = 9.0 Hz, JAAVXX’ = 2.6 Hz). N5: 1H-NMR (CDCb) d (ppm): 3.82 (s, 3H), 3.86 (s, 3H), 6.62 (ddd, 1 H, J = 8.4, 2.4, 0.8 Hz), 6.73 (bs, 1 H), 6.91 -6.99 (m, 3H), 7.00 (t, 1 H, J = 2.2 Hz), 7.07-7.12 (m, 2H), 7.16 (ddd, 1 H, J = 7.6, 1.6, 1.0 Hz), 7.25 (t, 1 H, J = 8.1 Hz), 7.37 (t, 1 H, J = 7.9 Hz), 8.25 (d, 1 H, J = 5.6 Hz). N6: 1H-NMR (CDCb) d (ppm): 3.82 (s, 3H), 3.85 (s, 3H), 6.57 (bs, 1 H), 6.84-6.96 (m, 5H), 7.07 (t, 1 H, J = 2.0 Hz), 7.13 (ddd, 1 H, J = 7.6, 1.7, 1.0
Hz), 7.24-7.30 (m, 2H), 7.35 (t, 1 H, J = 7.9 Hz), 8.18 (dd, 1 H, J = 5.3, 0.6 Hz). N7: 1H-NMR (CDCb) d (ppm): 3.82 (s, 3H), 3.85 (s, 3H), 6.62 (ddd, 1 H, J = 8.2, 2.4, 0.8 Hz), 6.90-7.01 (m, 5H), 7.06-7.10 (m, 1 H), 7.25 (t, 1 H, J = 8.1 Hz), 7.54 (AA’XX’, 2H, JAX = 8.9 Hz, JAAVXX’ = 2.6 Hz), 8.21 (dd, 1 H, J = 5.4, 0.5 Hz). N8: 1H-NMR (CDCb) d (ppm): 3.82 (s, 3H), 3.84 (s, 3H), 6.51
(bs, 1 H), 6.83-6.85 (m, 1 H), 6.88 (dd, 1 H, J= 5.4, 1.6 Hz), 6.91 (AA’XX’, 2H, JAX = 8.9 Hz, JAAVXX = 2.9 Hz), 6.95 (AA’XX’, 2H, JAX = 8.9 Hz, JAAVXX’ = 2.5 Hz), 7.24-7.30 (m, 2H), 7.50 (AA’XX’, 2H, JAX = 8.9 Hz, JAAVXX· = 2.8 Hz), 8.16 (d, 1 H, J = 5.3 Hz). N9: 1H-NMR (acetone-de) d (ppm): 3.79 (s, 3H), 3.84 (s, 3H), 6.91 -6.96 (m, 2H), 7.00-7.06 (m, 2H), 7.16-7.22 (m, 2H), 7.34 (s, 1 H), 7.45 (s, 1 H), 7.53-7.58 (m, 2H), 8.21 (bs, 1 H). N10: 1H-NMR (CDCIs) d (ppm): 3.82 (s, 3H), 3.85 (s, 3H), 5.69 (bs, 1 H), 6.90 (AA’XX’, 2H, JAX = 9.0 Hz, JAAYXX’ = 2.5 Hz), 6.93 (ddd, 1 H, J = 8.2, 2.6, 0.9 Hz), 7.05 (t, 1 H, J
= 2.1 Hz), 7.09-7.16 (m, 3H), 7.33-7.39 (m, 2H), 8.23 (d, 1 H, J = 2.6 Hz), 8.28 (d, 1 H, J = 1.8 Hz). N1 1 : 1H-NMR (CDCIs) d (ppm): 3.80 (s, 3H), 3.86 (s, 3H), 5.88 (bs, 1 H), 6.57 (dd, 1 H, J= 8.0, 2.1 Hz), 6.67 (t, 1 H, J= 2.2 Hz), 6.72 (dd, 1 H, J = 8.0, 1.5 Hz), 6.94 (ddd, 1 H, J = 8.2, 2.5, 0.7 Hz), 7.08 (t, 1 H, J = 2.1 Hz), 7.10-7.16 (m, 1 H), 7.22 (t, 1 H, J = 8.1 Hz), 7.38 (t, 1 H, J =
8.0 Hz), 7.60 (t, 1 H, J = 2.3 Hz), 8.37 (d, 1 H, J = 2.5 Hz), 8.39 (d, 1 H, J = 1.8 Hz).]
Step 3.
A solution of methoxylated intermediate N1 , N2, N3, N4, N5, N6, N7, N8, N9, N10 or N1 1 (0.653 mmol, 200 mg) in anhydrous DCM (7.6 ml_) was cooled to -15 °C and treated dropwise with a 1 M solution of BBr3 in dichloromethane (4.2 ml_), and the resulting solution was stirred at 0 °C for 1 h and at rt until the reaction was complete (disappearance of the starting material as verified by TLC analysis). The mixture was diluted with water, treated with a 1 M aqueous solution of NaHC03 and extracted with ethyl acetate. The organic phase was washed with brine, dried and concentrated. The crude product was purified by chromatography over silica gel (n- hexane/ethyl acetate mixtures) to yield pure phenolic compounds, examples 14-17 and 22-28 (example 14: 92% yield, example 15: 78% yield, example 16: 81 % yield, example 17: 99% yield, example 22: 6% yield, example 23: 31 % yield, example 24: 32% yield, example 25: 74% yield, example 26: 63% yield, example 27: 44% yield, example 28: 63% yield).
Scheme 6.
Step 1.
Et3N (0.64 ml_) and di-te/7-butyl dicarbonate (4.62 mmol) at 0 °C were added to a solution of commercially available 4-amino-2-bromopyirdine (2.31 mmol, 400 mg) in anhydrous THF (5.9 ml_), and the reaction mixture was stirred overnight at room temperature. The solvent was removed under reduced pressure; then the residue was diluted with EtOAc and sequentially washed with a saturated solution of sodium bicarbonate, water and brine. The organic phase was dried with Na2S04 and concentrated. The crude reaction product was purified by column chromatography over silica gel with a mixture of n- hexane/EtOAc 8:2 as the eluent to afford intermediate O (72% yield). [1H-NMR (CDCIs) d (ppm): 1.52 (s, 9H), 6.68 (bs, 1 H), 7.18 (dd, 1 H, J = 5.6, 2.0 Hz), 7.64 (d, 1 H, J = 1.9 Hz), 8.17 (d, 1 H, J = 5.7 Hz).]
Step 2.
A solution of Pd(OAc)2 (0.0520 mmol) and triphenylphosphine (0.260 mmol) in toluene (16.8 ml_) was stirred at rt under an inert atmosphere for 10 min. After that period, commercially available 4-amino-2-bromopyirdine (for the synthesis of intermediate R, Scheme 6) or intermediate O (for the synthesis of intermediate P, Scheme 6)(1.73 mmol, 300 mg), anhydrous K2CO3 (2.60 mmol), and commercially available 3- or 4-methoxybenzeneboronic acid (3.47 mmol, 3-methoxybenzeneboronic acid for the synthesis of intermediate P and 4-methoxybenzeneboronic acid for the synthesis of intermediate R, Scheme 6 ) were sequentially added. The resulting mixture was heated at 100 °C in a sealed vial under an inert atmosphere overnight. After being cooled to rt, the mixture was diluted with water and extracted with EtOAc. The combined organic phases were dried over anhydrous sodium sulphate and concentrated under vacuum. The crude residue was purified by flash column chromatography, eluting with n-hexane/EtOAc mixtures (for intermediate P) or EtOAc/MeOH (for intermediate R) as eluents to afford the biaryl intermediates P (96% yield) or R (84% yield). [P: 1H-NMR (CDCIs) d (ppm): 1.55 (s, 9H), 3.89 (s, 3H), 6.77 (bs, 1 H), 6.96 (ddd, 1 H, J = 8.2, 2.6, 0.8 Hz), 7.24 (dd, 1 H, J = 5.6, 2.1 Hz), 7.36 (t, 1 H, J = 8.0 Hz), 7.49-7.54 (m, 1 H), 7.57 (t, 1 H, J = 2.0 Hz), 111 (d, 1 H, J = 1.8 Hz), 8.51 (d, 1 H, J= 5.5 Hz). R: 1H-NMR (CDCIa) d (ppm): 3.85 (s, 3H), 4.20 (bs, 2H), 6.46 (dd, 1 H, J = 5.6, 2.3 Hz), 6.90 (d, 1 H, J = 2.2 Hz), 6.96 (AA’XX’, 2H, JAX = 9.0 Hz, JAAVXX’ = 2.6 Hz), 7.87 (AA’XX’, 2H, JAX = 9.0 Hz, JAAYXX = 2.6 Hz), 8.28 (d, 1 H, J = 5.6 Hz).]
Step 3.
Compound P (1.77 mmol, 532 mg) was dissolved in DCM (8 ml_), cooled to 0 °C, treated with trifluoroacetic acid (2.4 ml_), and stirred at rt until complete consumption of the starting material (TLC). The mixture was concentrated to dryness under reduced pressure, diluted with EtOAc, and washed with a 1 M solution of NaHC03. The organic layer was dried over Na2S04 and concentrated to give the pure compound P which was used in the next step without further purification (99% yield). [1H-NMR (CDC ) d (ppm): 3.88 (s, 3H), 4.25 (bs, 2H), 6.50 (dd, 1 H, J= 5.6, 2.3 Hz), 6.91 -6.98 (m, 2H), 7.90 (t, 1 H, J= 7.9 Hz), 7.46 (ddd, 1 H, J= 7.7, 1.5, 1.0 Hz), 7.48-7.53 (m, 1 H), 8.31
(d, 1 H, J = 5.6 Hz).]
Step 4.
A solution of Pd2dba3 (0.0120 mmol), XPhos (0.0483 mmol), K3PO4 (0.844 mmol), commercially available 3- or 4-bromoanisole (0.603 mmol) and aniline intermediate R or Q (0.724 mmol, 145 mg) in toluene (1.2 ml_) was stirred at 100 °C under an inert atmosphere in a sealed vial for 20 h. If the starting material with a stoichiometric defect (bromoanisole) was still visible by TLC, further aliquots of Pd2dba3 and XPhos were added and the reaction was heated for a further 6 h. The reaction mixture was allowed to cool to room temperature, then filtered through a small Celite pad, washed with ethyl acetate and concentrated under vacuum. The crude residue obtained was purified by flash column chromatography (eluent mixtures of n- hexane/EtOAc) to give intermediates S1 (57% yield), S2 (51 % yield), S3 (83% yield), S4 (33% yield). [S1 : 1H-NMR (CDCIs) d (ppm): 3.83 (s, 3H), 3.84 (s, 3H), 6.09 (bs, 1 H), 6.59 (dd, 1 H, J= 5.8, 2.2 Hz), 6.89-6.99 (m, 4H),
7.03 (d, 1 H, J = 2.0 Hz), 7.17 (AA’XX’, 2H, JAX = 8.8 Hz, JAAYXX = 2.7 Hz), 7.84 (AA’XX’, 2H, JAX = 9.0 Hz, JAAYXX = 2.5 Hz), 8.28 (d, 1 H, J = 5.8 Hz). S2: 1H-NMR (CDCIs) d (ppm): 3.84 (s, 3H), 3.87 (s, 3H), 5.99 (bs, 1 H), 6.63 (dd, 1 H, J = 5.7, 2.3 Hz), 6.90-6.97 (m, 3H), 7.07 (d, 1 H, J = 2.2 Hz), 7.17 (AA’XX’, 2H, JAX = 8.8 Hz, JAA’/XX = 2.8 Hz), 7.33 (t, 1 H, J = 7.9 Hz), 7.42 (dt, 1 H, J = 7.7, 1.3 Hz), 7.49 (t, 1 H, J = 2.0 Hz), 8.32 (d, 1 H, J = 5.7 Hz). S3: 1H-NMR (CDCIs) d (ppm): 3.82 (s, 3H), 3.85 (s, 3H), 6.24 (bs, 1 H), 6.69 (dd, 1 H, J= 7.8, 2.2 Hz), 6.75-6.85 (m, 3H), 6.97 (AA’XX’, 2H, JAX = 8.9 Hz, JAAYXX = 2.5 Hz), 7.22 (d, 1 H, J = 2.0 Hz), 7.29 (d, 1 H, J = 8.0 Hz), 7.87 (AA’XX’, 2H, JAX = 8.8 Hz, JAAVXX· = 2.5 Hz), 8.35 (d, 1 H, J= 5.7 Hz). S4: 1H- NMR (CDCIs) d (ppm): 3.82 (s, 3H), 3.88 (s, 3H), 6.21 (bs, 1 H), 6.69 (dd, 1 H, J = 8.1 , 2.4 Hz), 6.77 (t, 1 H, J = 2.2 Hz), 6.79-6.85 (m, 2H), 6.95 (ddd, 1 H, J = 8.1 , 2.6, 0.9 Hz), 7.25 (d, 1 H, J = 2.2 Hz), 7.28 (t, 1 H, J = 8.1 Hz),
7.34 (t, 1 H, J = 7.9 Hz), 7.42-7.46 (m, 1 H), 7.51 (t, 1 H, J = 2.1 Hz), 8.38 (d, 1 H, J = 5.7 Hz).]
Step 5.
A solution of methoxylated intermediate S1 , S2, S3 or S4 (0.421 mmol, 129 mg) in anhydrous DCM (4.9 ml_) was cooled to -15 °C and treated dropwise with a 1 M solution of BBr3 in dichloromethane (2.7 ml_), and the resulting solution was stirred at 0 °C for 1 h and at rt until the reaction was complete (disappearance of the starting material as verified by TLC analysis). The mixture was diluted with water, treated with a 1 M aqueous solution of NaHC03 and extracted with ethyl acetate. The organic phase was washed with brine, dried and concentrated. The residue was purified by flash chromatography (ethyl acetate or EtOAc/MeOH mixtures) to yield pure phenolic compounds, examples 18-21 (example 18: 45% yield, example 19: 78% yield, example 20: 62% yield, example 21 : 76% yield).
Scheme 7.
Step 1.
Cu(l) iodide (0.0795 mmol), potassium carbonate (3.18 mmol), commercially available 3- or 4-iodoanisoloe (1.59 mmol) and 3- bromothiophenol (1.59 mmol, 300 mg) were dissolved in a mixture of /- propanol (1.1 ml_) and ethylene glycol (0.2 ml_) in a screw-capped test tube under an inert atmosphere. The reaction was heated to 80 °C and stirred for 18 h. After cooling to room temperature, the mixture was diluted with water and extracted several times with EtOAc. The combined organic phases were washed with brine, dried over anhydrous sodium sulphate and concentrated under vacuum. The crude product was purified by flash column chromatography over silica gel using petroleum ether as the eluent to afford the desired thioether derivatives T 1 (83% yield) or T2 (46% yield). [T1 : 1H-NMR (CDCIs) d (ppm): 3.78 (s, 3H), 6.84 (ddd, 1 H, J = 8.3, 2.5, 0.8 Hz), 6.92 (t, 1 H, J= 2.1 Hz), 6.97 (ddd, 1 H, J= 7.7, 1.5, 0.9 Hz), 7.15 (t, 1 H, J = 7.9 Hz), 7.20-7.28 (m, 2H), 7.34 (ddd, 1 H, J = 7.9, 1.8, 1.1 Hz), 7.44 (t, 1 H, J = 1.8 Hz). T2: 1H-NMR (CDC ) d (ppm): 3.84 (s, 3H), 6.93 (AA’XX’, 2H, JAX = 8.9 Hz, JAAVXX’ = 2.6 Hz), 7.02-7.1 1 (m, 2H), 7.21 -7.26 (m, 2H),
7.43 (AA’XX’, 2H, JAX = 8.9 Hz, JAAVXX = 2.6 Hz).]
Step 2.
A solution of Pd(OAc)2 (0.0204 mmol) and triphenylphosphine (0.102 mmol) in ethanol (1.5 ml_) and toluene (1.5 ml_) was stirred at rt under an inert atmosphere for 10 min. After that period, intermediate T1 or T2 (0.676 mmol, 200 mg), a 2 M aqueous solution of Na2C03 (1.5 ml_), and commercially available 3- or 4-methoxybenzeneboronic acid (1.08 mmol) were sequentially added. The resulting mixture was heated at 100 °C in a sealed vial under an inert atmosphere overnight. After being cooled to rt, the mixture was diluted with water and extracted with EtOAc. The combined organic phases were washed with brine, dried over anhydrous sodium sulphate and concentrated under vacuum. The crude residue was purified by flash column chromatography, eluting with petroleum ether/EtOAc mixtures as eluents to afford intermediates U1 (91 % yield), U2 (67% yield), U3 (71 % yield) or U4 (61 % yield). [U1 : 1H-NMR (CDCIa) d (ppm): 3.83 (s, 3H), 3.84 (s, 3H), 6.91 (AA’XX’, 2H, JAX = 8.9 Hz, JAAYXX = 2.6 Hz), 6.95 (AA’XX’, 2H, JAX = 8.9 Hz, JAAVXX· = 2.6 Hz), 7.09 (ddd, 1 H, J= 7.6, 1.8, 1.3 Hz), 7.27 (t, 1 H, J = 7.6 Hz), 7.32 (dt, 1 H, J = 7.8, 1.5 Hz), 7.39 (t, 1 H, J = 1.6 Hz), 7.42-7.48 (m, 4H). U2: 1H-NMR (CDCIa) d (ppm): 3.83 (s, 3H), 3.84
(s, 3H), 6.88 (ddd, 1 H, J= 8.3, 2.6, 0.9 Hz), 6.91 (AA’XX’, 2H, JAX = 8.9 Hz, JAAYXX = 2.6 Hz), 7.03 (t, 1 H, J = 2.1 Hz), 7.09 (ddd, 1 H, J = 7.6, 1.6, 1.0 Hz), 7.13 (ddd, 1 H, J = 7.7, 1.8, 1.2 Hz), 7.26-7.33 (m, 2H), 7.35 (dt, 1 H, J = 8.2, 1.7 Hz), 7.41 (t, 1 H, J= 1.8 Hz), 7.45 (AA’XX’, 2H, JAX = 8.9 Hz, JAAYXX = 2.6 Hz). U3: 1H-NMR (CDC ) d (ppm): 3.76 (s, 3H), 3.84 (s, 3H), 6.79
(ddd, 1 H, J = 8.3, 2.5, 0.9 Hz), 6.91 (t, 1 H, J = 2.1 Hz), 6.93-6.98 (m, 3H), 7.21 (t, 1 H, J = 8.0 Hz), 7.29 (dt, 1 H, J = 8.0, 1.5 Hz), 7.35 (t, 1 H, J = 7.7 Hz), 7.44 (dt, 1 H, J = 8.0, 1.5 Hz), 7.48 (AA’XX’, 2H, JAX = 8.9 Hz, JAAYXX = 2.6 Hz), 7.58 (t, 1 H, J = 1.6 Hz). U4: 1H-NMR (CDCIs) d (ppm): 3.77 (s, 3H), 3.85 (s, 3H), 6.79 (ddd, 1 H, J = 8.3, 2.5, 0.9 Hz), 6.88-6.93 (m, 2H), 6.96 (ddd, 1 H, J = 7.7, 1.7, 1.0 Hz), 7.07 (t, 1 H, J = 2.1 Hz), 7.13 (ddd, 1 H, J = 7.6, 1.6, 1.0 Hz), 7.22 (t, 1 H, J= 8.0 Hz), 7.31 -7.36 (m, 2H), 7.37 (t, 1 H, J = 7.6 Hz), 7.47 (dt, 1 H, J = 7.4 Hz), 7.61 (t, 1 H, J = 1.6 Hz).]
Step 3.
A solution of methoxylated intermediate U1 , U2, U3 or U4 (0.372 mmol, 120 mg) in anhydrous DCM (4.3 ml_) was cooled to -15 °C and treated dropwise with a 1 M solution of BBr3 in dichloromethane (2.4 ml_), and the resulting solution was stirred at 0 °C for 1 h and at rt until the reaction was complete (disappearance of the starting material as verified by TLC analysis). The mixture was then diluted with water and extracted with ethyl acetate. The organic phase was washed with brine, dried and concentrated. The crude residue was purified by chromatography over silica gel (n-hexane/ethyl acetate mixtures) to yield pure phenolic compounds, examples 29-32 (example 29: yield 78%, example 30: yield 92%, example 31 : yield 99%, example 32: yield 99%).
Scheme 8.
Step 1.
A solution of Pd(OAc)2 (0.0403 mmol) and triphenylphosphine (0.201 mmol) in toluene (13.0 ml_) was stirred at rt under an inert atmosphere for 10 min. After that period, commercially available 3-amino-1 -bromoisoquinoline (1.34 mmol, 300 mg), anhydrous K2CO3 (2.02 mmol), and commercially available 4-methoxybenzeneboronic acid (2.69 mmol) were sequentially added. The resulting mixture was heated at 100 °C in a sealed vial under an inert atmosphere overnight. After being cooled to rt, the mixture was diluted with water and extracted with EtOAc. The combined organic phases were dried over anhydrous sodium sulphate and concentrated under vacuum. The crude residue was purified by flash column chromatography over silica gel, eluting with a 7:3 petroleum ether/EtOAc mixture as the eluent to afford intermediate V (97% yield). [1H-NMR (CDC ) d (ppm): 3.89 (s, 3H), 4.48 (bs, 2H), 6.72 (s, 1 H), 7.04 (AA’XX’, 2H, JAX = 8.8 Hz, JAAVXX’ = 2.5 Hz), 7.17 (ddd, 1 H, J = 8.6, 6.7, 1.2 Hz), 7.47 (ddd, 1 H, J= 8.4, 6.7, 1.2
Hz), 7.57 (d, 1 H, J = 8.4 Hz), 7.62 (AA’XX’, 2H, JAX = 8.8 Hz, JAAVXX = 2.5 Hz), 7.90 (dd, 1 H, J= 8.5, 0.8 Hz).]
Step 2.
1 ) Synthesis of W1 and W2. A solution of Pd2dba3 (0.0162 mmol), XPhos (0.0650 mmol), K3PO4 (1.29 mmol), commercially available 3- or 4-bromoanisole (0.812 mmol) and intermediate V (0.975 mmol, 244 mg) in toluene (1.6 ml_) was stirred at 100 °C under argon in a sealed vial for 20 h. The reaction mixture was allowed to cool to room temperature, then filtered through a small Celite pad and washed with ethyl acetate; the filtrate was concentrated under vacuum. The crude residue obtained was purified by column chromatography over silica gel (eluent mixtures of petroleum ether/EtOAc) to give intermediates W1 (96% yield) or W2 (63% yield). [W1 : 1H-NMR (CDC ) d (ppm): 3.83 (s, 3H), 3.90 (s, 3H), 6.61 (ddd, 1 H, J = 8.2, 2.4, 0.7 Hz), 6.72 (bs, 1 H), 6.91 (dd, 1 H, J= 7.9, 1.4 Hz), 6.96 (t, 1 H, J = 2.2 Hz), 7.06 (AA’XX’, 2H, JAX = 8.8 Hz, JAAVXX = 2.5 Hz), 7.20- 7.30 (m, 3H), 7.51 (ddd, 1 H, J= 8.3, 6.8, 1.2 Hz), 7.60-7.69 (m, 3H), 7.95 (dd, 1 H, J= 8.5, 0.8 Hz). W2: 1H-NMR (CDC ) d (ppm): 3.84 (s,
3H), 3.90 (s, 3H), 6.52 (bs, 1 H), 6.92 (s, 1 H), 6.95 (AA’XX’, 2H, JAX = 8.9 Hz, JAA’/XX = 2.9 Hz), 7.06 (AA’XX’, 2H, JAX = 8.8 Hz, JAAVXX· = 2.5 Hz), 7.17 (ddd, 1 H, J = 8.5, 6.7, 1.3 Hz), 7.28 (AA’XX’, 2H, JAX = 8.8 Hz, JAAVXX’ = 2.9 Hz), 7.46 (ddd, 1 H, J= 8.3, 6.7, 1.2 Hz), 7.54 (d, 1 H, J = 8.4 Hz), 7.64 (AA’XX’, 2H, JAX = 8.8 Hz, JAAVXX = 2.5 Hz), 7.91
(dd, 1 H, J= 8.4, 0.8 Hz).]
) Synthesis of Z1 and Z2. A solution of Pd2dba3 (0.0186 mmol), XPhos (0.0744 mmol), K3PO4 (0.930 mmol), commercially available 3- or 4- bromoanisole (0.990 mmol) and intermediate Y (0.619 mmol, 171 mg) in toluene (1.1 ml_) was stirred at 100 °C under argon in a sealed vial for 20 h. As the starting material with a stoichiometric defect (aniline derivative) was still visible by TLC, further aliquots of Pd2dba3 and XPhos were added and the reaction was heated for a further 20 h. The reaction mixture was allowed to cool to room temperature, then filtered through a small Celite pad and washed with ethyl acetate; the filtrate was concentrated under vacuum. The crude residue obtained was purified by column chromatography over silica gel (eluent mixtures of petroleum ether/EtOAc) to give intermediates Z1 (64% yield) or Z2 (65% yield). [Z1 : 1H-NMR (CDCIa) d (ppm): 3.78 (s, 3H), 3.82 (s, 3H), 6.60 (dd, 1 H, J = 8.3, 2.4 Hz), 6.70 (bs, 1 H), 6.76 (AA’XX’, 2H, JAX = 8.9 Hz, JAAYXX = 2.4 Hz), 6.89 (dd, 1 H, J = 8.1 , 1.4 Hz), 6.94 (d, 1 H, J = 8.4 Hz), 7.12-7.20 (m, 3H), 7.20-7.29 (m, 4H), 7.33 (AA’XX’, 2H, JAX = 8.9 Hz, JAAYXX = 2.5 Hz), 7.55 (d,
1 H, J = 8.4 Hz). Z2: 1H-NMR (CDCIs) d (ppm): 3.78 (s, 3H), 3.82 (s, 3H), 6.52 (bs, 1 H), 6.71 (d, 1 H, J = 8.4 Hz), 6.76 (AA’XX’, 2H, JAX = 8.9 Hz, JAAYXX = 2.5 Hz), 6.92 (AA’XX’, 2H, JAX = 8.9 Hz, JAAVXX· = 2.8 Hz), 7.1 1 -7.18 (m, 2H), 7.19-7.33 (m, 7H), 7.49 (d, 1 H, J = 8.5 Hz).] Step 3.
A solution of Pd(OAc)2 (0.0360 mmol) and triphenylphosphine (0.180 mmol) in toluene (5.7 ml_) and MeOH (0.57 ml_) was stirred at rt under an inert atmosphere for 10 min. After that period, commercially available 5,6- dibromopyridin-2-amine (1.20 mmol, 300 mg), Na2C03 (2.40 mmol), water (1.4 ml_) and commercially available 4-methoxybenzeneboronic acid (1.20 mmol) were sequentially added. The resulting mixture was heated at 1 10 °C in a sealed vial overnight. After being cooled to rt, the mixture was diluted with water and extracted several times with EtOAc. The combined organic phases were dried and concentrated. The crude product was purified by flash column chromatography over silica gel. Elution with a 75:25 petroleum ether/EtOAc mixture as the eluent afforded intermediate X (73% yield). [1H- NMR (CDCIs) d (ppm): 3.85 (s, 3H), 4.50 (bs, 2H), 6.34 (d, 1 H, J = 8.6 Hz), 6.96 (AA’XX’, 2H, JAX = 8.9 Hz, JAA’/XX’ = 2.5 Hz), 7.61 (AA’XX’, 2H, JAX = 8.9 Hz, JAAVXX· = 2.5 Hz), 7.64 (d, 1 H, J = 8.6 Hz).]
Step 4.
A solution of Pd(OAc)2 (0.0234 mmol) and triphenylphosphine (0.1 17 mmol) in ethanol (1.8 ml_) and toluene (1.8 ml_) was stirred at rt under an inert atmosphere for 10 min. After that period, intermediate X (0.780 mmol, 217 mg), a 2 M aqueous solution of Na2C03 (1.8 ml_), and commercially available benzeneboronic acid (1.24 mmol) were sequentially added. The resulting mixture was heated at 100 °C in a sealed vial overnight. After being cooled to rt, the mixture was diluted with water and extracted with EtOAc. The combined organic phases were washed with brine, dried and concentrated. The crude product was purified by flash column chromatography over silica gel. Elution with a 7:3 petroleum ether/EtOAc mixture as the eluent afforded the intermediates Y (98% yield). [1H-NMR (CDCIs) d (ppm): 3.77 (s, 3H), 4.52 (bs, 2H), 6.52 (d, 1 H, J = 8.3 Hz), 6.75 (AA’XX’, 2H, JAX = 8.9 Hz, JAAVXX· = 2.5 Hz), 7.10-7.15 (m, 2H), 7.16-7.29 (m, 5H), 7.48 (d, 1 H, J= 8.3 Hz).]
Step 5.
A solution of methoxylated intermediate W1 , W2, Z1 or Z2 (0.370 mmol, 132 mg) in anhydrous DCM (4.3 ml_) was cooled to -15 °C and treated dropwise with a 1 M solution of BBr3 in dichloromethane (2.3 ml_), and the resulting solution was stirred at 0 °C for 1 h and at rt until the reaction was complete (disappearance of the starting material as verified by TLC analysis). The mixture was diluted with water, treated with a 1 M aqueous solution of NaHC03 and extracted with ethyl acetate. The organic phase was washed with brine, dried and concentrated. The residue was purified by chromatography over silica gel (CHC /MeOH mixtures) to yield pure phenolic compounds, examples 34 and 36 (from W1 and W2) and examples 33 and 35 (from Z1 and Z2) (example 33: 46% yield, example 34: 82% yield, example 35: 64% yield, example 36: 48% yield).
The obtained compounds 1 -36 are exemplified in table 1.
Table 1
Figure imgf000051_0001
Figure imgf000052_0001
Figure imgf000053_0001
Figure imgf000054_0001
Characterization of compounds 1 -36
Compound 1. 1H-NMR (acetone-cfc) d (ppm): 6.43-6.48 (m, 1 H), 6.89 (AA’XX’, 2H, JAX = 8.7 Hz, JAAVXX’ = 2.5 Hz), 7.07-7.14 (m, 3H), 7.40-7.47 (m, 3H), 8.29 (s, 1H), 8.51 (s, 1H), 9.04 (bs, 1H).13C-NMR (aceton e- fe) d (ppm): 104.83, 109.07, 109.34, 116.64, 120.65, 121.31, 125.42 (2C), 130.47 (2C), 141.85, 145.79, 156.86, 157.77, 159.03.
Compound 2.1H-NMR (acetone-de) d (ppm): 6.81 (AA’XX’, 2H, JAX = 9.0 Hz, JAAYXX’ = 2.8 Hz), 6.88 (AA’XX’, 2H, JAX = 8.8 Hz, JAAYXX = 2.4 Hz), 7.07 (s, 1 H), 7.42 (AA’XX’, 2H, JAX = 8.7 Hz, JAAYXX = 2.4 Hz), 7.56 (AA’XX’, 2H, JAX = 9.0 Hz, JAAVXX· = 2.8 Hz), 7.97 (s, 1 H), 8.48 (s, 1 H), 8.81 (bs, 1 H).13C- NMR (acetone-de) d (ppm): 116.28 (2C), 116.61 (2C), 119.37 (2C), 120.65, 121.49, 125.26 (2C), 133.11, 145.49, 153.13, 157.57, 157.63.
Compound 3.1H-NMR (acetone-c/6) d (ppm): 6.48 (dt, 1 H, J= 6.4, 2.4 Hz), 6.75 (ddd, 1H, J= 8.1, 2.4, 0.8 Hz), 7.02-7.16 (m, 4H), 7.22 (t, 1H, J= 7.9 Hz), 7.28 (s, 1 H), 7.41 -7.45 (m, 1 H).13C-NMR (acetone-de) d (ppm): 104.98,
109.20, 109.55, 110.48, 115.11, 115.13, 123.15, 130.52, 130.75, 130.90, 141.67, 145.43, 157.46, 158.73, 159.06.
Compound 4.1H-NMR (acetone-de) d (ppm): 6.73 (ddd, 1H, J= 8.1, 2.5, 0.9 Hz), 6.82 (AA’XX’, 2H, JAX = 9.0 Hz, JAAVXX· = 2.9 Hz), 7.03 (t, 1H, J = 1.9 Hz), 7.06 (ddd, 1H, J= 7.7, 1.5, 1.0 Hz), 7.21 (t, 1H, J= 7.8 Hz), 7.23 (s, 1 H), 7.56 (AA’XX’, 2H, JAX = 9.0 Hz, JAAVXX· = 2.9 Hz), 8.01 (bs, 1 H), 8.42 (bs, 1 H), 8.90 (bs, 1H). 13C-NMR (acetone-de) d (ppm): 110.28, 114.90, 114.96, 116.32 (3C), 119.66 (2C), 123.11 , 130.84, 132.81 , 145.13, 153.31,
158.20, 158.66.
Compound 5. 1H-NMR (acetone-de) d (ppm): 6.67-6.71 (m, 1H), 6.89 (AA’XX’, 2H, JAX = 8.8 Hz, JAAYXX = 2.5 Hz), 7.18 (d, 1H, J= 2.4 Hz), 7.21- 7.25 (m, 2H), 7.46-7.50 (m, 1H), 7.54 (AA’XX’, 2H, JAX = 8.8 Hz, JAAYXX = 2.5 Hz), 8.51 (bs, 1 H), 9.82 (bs, 1 H).13C-NMR (acetone-de) d (ppm): 105.29, 108.75, 112.14, 112.80, 116.61 , 121.85, 124.02, 126.05 (2C), 130.57 (2C), 139.89, 153.99, 157.92, 158.89.
Compound 6.1H-NMR (acetone-d6) d (ppm): 6.50-6.54 (m, 2H), 6.62 (ddd, 1 H, J = 8.1 , 2.3, 0.9 Hz), 6.90-6.95 (m, 3H), 7.16-7.22 (m, 1 H), 7.23 (t, 1 H, J= 1.9 Hz), 7.37 (dt, 1H, J= 8.2, 1.5 Hz), 7.42 (t, 1H, J= 7.8 Hz), 7.50 (AA’XX’, 2H, JAX = 8.9 Hz, JAATXX = 2.6 Hz), 8.49 (s, 1 H).13C-NMR (acetone- d6) d (ppm): 106.64, 110.45, 111.26, 116.58 (2C), 117.67, 117.78, 122.18, 128.90 (2C), 130.98, 131.19, 132.32, 143.74, 158.31, 158.45, 159.51, 159.74.
Compound 7.1H-NMR (acetone-c/6) d (ppm): 6.82 (ddd, 1H, J= 8.1, 2.5, 1.0 Hz), 6.88 (AA’XX’, 2H, JAX = 9.1 Hz, JAA’/XX’ = 2.9 Hz), 6.91 (AA’XX’, 2H, JAX = 8.8 Hz, JAATXX· = 2.6 Hz), 6.95 (AA’XX’, 2H, JAX = 9.1 Hz, JAATXX· = 2.9 Hz), 7.12 (t, 1 H, J= 2.0 Hz), 7.26 (ddd, 1 H, J= 7.7, 1.7, 1.1 Hz), 7.35 (t, 1 H, J= 7.9 Hz), 7.46 (AA’XX’, 2H, JAX = 8.8 Hz, JAATXX = 2.6 Hz), 8.28 (s, 1H), 8.47 (s, 1 H). 13C-NMR (acetone-de) d (ppm): 115.90, 115.99, 116.57, 117.13, 121.91 (4C), 128.83 (2C), 130.83 (2C), 132.60, 143.60, 149.92, 154.79, 158.25, 160.32.
Compound 8.1H-NMR (aceton e-de) d (ppm): 6.51-6.55 (m, 2H), 6.63 (ddd, 1 H, J= 8.1 , 2.3, 0.9 Hz), 6.85 (ddd, 1 H, J= 8.1 , 2.4, 1.0 Hz), 7.01 (ddd, 1 H, J= 8.0, 2.4, 1.1 Hz), 7.07-7.12 (m, 2H), 7.20 (t, 1H, J=8.4Hz), 7.24 (t, 1H, J= 2.0 Hz), 7.28 (t, 1 H, J= 7.8 Hz), 7.39 (dt, 1H, J= 8.2, 1.4 Hz), 7.46 (t, 1 H, J= 7.9 Hz), 8.42-8.56 (bm, 2H).13C-NMR (acetone-de) d (ppm): 106.81 , 110.61, 111.43, 114.58, 115.57, 118.10, 118.67, 118.98, 122.71, 130.84, 131.10, 131.26, 142.60, 143.82, 158.54, 158.78, 159.39, 159.79.
Compound 9.1H-NMR (acetone-d6) d (ppm): 6.83 (ddd, 1H, J= 8.1, 2.5, 0.9 Hz), 6.86-6.91 (m, 3H), 6.97 (AA’XX’, 2H, JAX = 9.0 Hz, JAATXX· = 2.9 Hz), 7.03-7.08 (m, 2H), 7.13 (t, 1H, J= 2.0 Hz), 7.23-7.31 (m, 2H), 7.39 (t, 1H, J = 7.9 Hz), 8.30 (s, 1 H), 8.43 (s, 1 H).13C-NMR (acetone-de) d (ppm): 114.56, 115.49, 116.28, 116.89, 117.17 (2C), 118.97 (2C), 121.60, 122.03, 130.80, 130.93, 142.83, 143.66, 149.77, 154.89, 158.75, 160.36.
Compound 10.1H-NMR (acetone-de) d (ppm): 6.36 (ddd, 1H, J= 8.0, 2.3, 0.8 Hz), 6.61-6.66 (m, 1H), 6.71 (t, 1H, J= 2.2 Hz), 6.91 (AA’XX’, 2H, JAX = 8.7 Hz, JAATXX· = 2.5 Hz), 7.03-7.09 (m, 3H), 7.28 (t, 1 H, J= 7.8 Hz), 7.34 (t, 1 H, J= 1.9 Hz), 7.37 (bs, 1 H), 7.47 (AA’XX’, 2H, JAX = 8.6 Hz, JAATXX· = 2.5 Hz), 8.15 (s, 1 H), 8.42 (s, 1H). 13C-NMR (acetone-de) d (ppm): 104.83, 108.26, 109.64, 116.40, 116.49 (2C), 116.60, 119.22, 128.75 (2C), 130.34, 130.79, 133.44, 142.86, 145.04, 146.04, 158.02, 159.28.
Compound 11.1H-NMR (acetone-cfc) d (ppm): 6.81 (AA’XX’, 2H, JAX = 8.8 Hz, JAAVXX’ = 2.8 Hz), 6.85 (ddd, 1H, J = 8.1, 2.3, 0.9 Hz), 6.89 (AA’XX’, 2H, JAX = 8.7 Hz, JAAVXX· = 2.5 Hz), 6.93 (ddd, 1 H, J= 7.6, 1.7, 1.0 Hz), 7.02 (bs, 1 H), 7.07 (AA’XX’, 2H, JAX = 8.8 Hz, JAAVXX = 2.8 Hz), 7.13 (t, 1H, J= 2.0 Hz), 7.19 (t, 1 H, J= 7.8 Hz), 7.42 (AA’XX’, 2H, JAX = 8.7 Hz, JAAVXX· = 2.5 Hz), 8.38 (s, 1 H), 8.01 (s, 1H). 13C-NMR (acetone-de) d (ppm): 113.69, 113.91, 116.43 (2C), 116.71 (2C), 117.50, 123.17 (2C), 128.72 (2C), 130.30, 133.77, 136.04, 142.83, 147.57, 153.58, 157.91.
Compound 12.1H-NMR (aceton e-de) d (ppm): 6.77-6.85 (m, 3H), 6.87-6.93 (m, 1 H), 6.93-6.98 (m, 1 H), 7.01 -7.10 (m, 5H), 7.16 (t, 1 H, J= 1.9 Hz), 7.18- 7.26 (m, 2H), 8.04 (s, 1H), 8.36 (s, 1H). 13C-NMR (acetone-de) d (ppm):
113.95, 114.53, 114.66, 115.01, 116.71 (2C), 117.83, 118.92, 123.33, 130.33 (2C), 130.58, 135.86, 142.88, 143.97, 147.64, 153.67, 158.62.
Compound 13.1H-NMR (acetone-de) d (ppm): 6.37 (ddd, 1H, J= 8.1, 2.3, 0.9 Hz), 6.64 (ddd, 1H, J = 8.1 , 2.1 , 0.8 Hz), 6.72 (t, 1H, J= 2.2 Hz), 6.82 (ddd, 1 H, J = 8.1 , 2.4, 1.0 Hz), 7.04-7.12 (m, 5H), 7.26 (t, 1 H, J = 8.1 Hz), 7.31 (t, 1 H, J= 7.9 Hz), 7.37 (t, 1H, J=1.8 Hz), 7.42 (bs, 1 H), 8.18 (s, 1H), 8.40 (s, 1 H). 13C-NMR (acetone-de) d (ppm): 104.97, 108.43, 109.79, 114.61, 115.20, 116.70, 117.38, 118.98, 119.62, 130.44, 130.70, 130.87,
142.96, 143.70, 145.15, 145.91 , 158.73, 159.31.
Compound 14.1H-NMR (acetone-de) d (ppm): 6.44 (ddd, 1H, J= 7.9, 2.4, 1.0 Hz), 6.73 (d, 1H, J= 8.1 Hz), 6.93 (AA’XX’, 2H, JAX = 8.7 Hz, JAAVXX· = 2.4 Hz), 7.10 (t, 1 H, J= 8.0 Hz), 7.15-7.19 (m, 1H), 7.21 (d, 1H, J= 7.5 Hz), 7.46 (t, 1 H, J = 2.2 Hz), 7.56 (t, 1 H, J = 7.9 Hz), 8.00 (AA’XX’, 2H, JAX = 8.8 Hz, JAAVXX = 2.5 Hz), 8.15 (bs, 1H), 8.18 (s, 1H), 8.54 (s, 1H). 13C-NMR (acetone-de) d (ppm): 106.49, 108.82, 108.89, 110.46, 110.83, 116.17 (2C), 128.90 (2C), 130.19, 132.15, 138.75, 144.09, 155.99, 156.72, 158.78, 159.12. Compound 15.1H-NMR (acetone-cfc) d (ppm): 6.60 (dd, 1H, J = 8.2, 0.5 Hz), 6.82 (AA’XX’, 2H, JAX = 8.8 Hz, JAAVXX = 2.8 Hz), 6.91 (AA’XX’, 2H, JAX = 8.8 Hz, JAA’/XX’ = 2.5 Hz), 7.14 (dd, 1 H, J= 7.5, 0.5 Hz), 7.46-7.56 (m, 3H), 7.86 (bs, 1 H), 7.93-8.01 (m, 3H), 8.53 (s, 1H). 13C-NMR (acetone-de) d (ppm): 107.42, 109.60, 116.10 (2C), 116.15 (2C), 122.48 (2C), 128.77 (2C), 132.25, 134.80, 138.64, 153.27, 155.88, 157.54, 159.03.
Compound 16.1H-NMR (aceton e-de) d (ppm): 6.68 (dd, 1H, J = 8.4, 0.6 Hz), 6.82 (AA’XX’, 2H, JAX = 8.9 Hz, JAAVXX· = 2.8 Hz), 6.86 (ddd, 1 H, J= 8.0, 2.5, 0.9 Hz), 7.18 (dd, 1H, J= 7.5, 0.6 Hz), 7.27 (t, 1H, J= 7.9 Hz), 7.50- 7.58 (m, 4H), 7.62 (t, 1H, J= 2.0 Hz), 7.94 (bs, 1H), 7.99 (s, 1H), 8.40 (s, 1 H).13C-NMR (acetone-de) d (ppm): 108.64, 110.70, 114.38, 116.18 (2C), 116.38, 118.64, 122.39 (2C), 130.28, 134.71, 138.68, 142.27, 153.27,
155.77, 157.55, 158.54.
Compound 17.1H-NMR (acetone-de) d (ppm): 6.44 (ddd, 1H, J= 8.0, 2.4, 1.0 Hz), 6.81 (dd, 1H, J= 8.3, 0.6 Hz), 6.88 (ddd, 1H, J= 8.0, 2.5, 0.9 Hz), 7.10 (t, 1 H, J= 8.1 Hz), 7.21-7.31 (m, 3H), 7.40 (t, 1H, J= 2.2 Hz), 7.54- 7.64 (m, 3H), 8.18 (s, 1H), 8.20 (bs, 1H), 8.41 (s, 1H).13C-NMR (acetone- d6) d (ppm): 106.46, 108.99, 109.96, 110.85, 111.60, 114.47, 116.49, 118.75, 130.25, 130.36, 138.80, 142.19, 143.98, 155.93, 156.80, 158.61,
158.77.
Compound 18.1H-NMR (DMSO-de) d (ppm): 6.58 (dd, 1 H, J= 5.7, 2.2 Hz),
6.74-6.84 (m, 4H), 7.01-7.07 (m, 3H), 7.72 (AA’XX’, 2H, JAX = 8.8 Hz, JAAVXX· = 2.4 Hz), 8.12 (d, 1 H, J= 5.7 Hz), 8.39 (s, 1 H), 9.31 (bs, 1 H), 9.58 (bs, 1 H). 13C-NMR (DMSO-de) d (ppm): 103.15, 106.21, 115.27 (2C), 115.91 (2C), 124.01 (2C), 127.60 (2C), 130.43, 131.45, 149.53, 152.64, 153.84, 156.62, 158.10.
Compound 19.1H-NMR (DMSO-de) d (ppm): 6.64 (dd, 1 H, J= 5.7, 2.2 Hz),
6.74-6.82 (m, 3H), 7.05 (AA’XX’, 2H, JAX = 8.7 Hz, JAAVXX· = 2.7 Hz), 7.09 (d, 1 H, J = 2.0 Hz), 7.19 (t, 1H, J= 7.8 Hz), 7.29 (dt, 1H, J= 7.8, 1.4 Hz), 7.33 (t, 1 H, J = 2.0 Hz), 8.16 (d, 1H, J= 5.6 Hz), 8.46 (s, 1H), 9.32 (s, 1H), 9.46 (s, 1 H). 13C-NMR (DMSO -d6) d (ppm): 104.23, 106.91, 113.17, 115.57 115.93 (2C), 116.98, 124.15 (2C), 129.50, 131.33, 140.99, 149.76, 152.71, 153.95, 156.60, 157.53.
Compound 20.1H-NMR (DMSO -d6) d (ppm): 6.43 (ddd, 1H, J= 8.1, 2.1, 1.0 Hz), 6.62-6.68 (m, 2H), 6.80 (dd, 1 H, J= 5.6, 2.2 Hz), 6.83 (AA’XX’, 2H, JAX = 8.8 Hz, JAA’/XX’ = 2.5 Hz), 7.13 (t, 1H, J=8.0 Hz), 7.26 (d, 1H, J=2.1 Hz), 7.77 (AA’XX’, 2H, JAX = 8.7 Hz, JAAVXX· = 2.5 Hz), 8.21 (d, 1H, J= 5.7 Hz), 8.72 (s, 1 H), 9.43 (s, 1H), 9.65 (s, 1H).13C-NMR (DMSO-de) d (ppm): 104.53, 106.55, 107.52, 109.57, 110.59, 115.30 (2C), 127.65 (2C), 129.37, 130.06, 130.31, 141.77, 149.78, 150.82, 156.86, 158.19.
Compound 21.1H-NMR (DMSO-de) d (ppm): 6.42-6.48 (m, 1H), 6.62-6.69 (m, 2H), 6.77-6.82 (m, 1H), 6.86 (dd, 1H, J= 5.6, 2.2 Hz), 7.14 (t, 1H, J = 8.3 Hz), 7.25 (t, 1 H, J= 7.8 Hz), 7.29-7.35 (m, 2H), 7.37 (t, 1 H, J= 1.9 Hz), 8.26 (d, 1 H, J = 5.6 Hz), 8.76 (s, 1 H), 9.46 (s, 1 H), 9.50 (s, 1 H).13C-NMR (DMSO-de) d (ppm): 105.62, 106.72, 108.22, 109.76, 110.73, 113.23, 115.71, 117.03, 129.57, 130.12, 140.83, 141.65, 149.98, 150.94, 156.81, 157.59, 158.25.
Compound 22.1H-NMR (acetone-de) d (ppm): 6.95 (AA’XX’, 2H, JAX = 8.8 Hz, JAAVXX = 2.8 Hz), 7.03 (AA’XX’, 2H, JAX = 8.8 Hz, JAAVXX = 2.6 Hz), 7.26 (AA’XX’, 2H, JAX = 8.9 Hz, JAAVXX· = 2.8 Hz), 7.65 (AA’XX’, 2H, JAX = 8.9 Hz, JAAVXX = 2.6 Hz), 8.13 (dd, 1H, J= 2.4, 1.7 Hz), 8.18 (d, 1H, J= 2.4 Hz), 8.30 (s, 1 H). 13C-NMR (acetone-de) d (ppm): 117.13, 117.26, 117.30, 123.44, 124.94, 125.86 (2C), 126.80, 129.19, 129.33, 129.47, 129.59, 131.39, 147.44, 154.19, 156.19, 160.10.
Compound 23.1H-NMR (DMSO-de) d (ppm): 6.75 (AA’XX’, 2H, JAX = 8.8 Hz, JAAVXX’ = 2.9 Hz), 6.78 (ddd, 1 H, J= 8.1 , 2.4, 0.8 Hz), 6.93 (t, 1 H, J= 2.0 Hz), 6.98-7.03 (m, 3H), 7.25 (t, 1 H, J= 7.9 Hz), 7.29 (t, 1 H, J= 2.2 Hz), 8.01 (s, 1 H), 8.05 (d, 1 H, J= 1.2 Hz), 8.14 (d, 1 H, J= 2.3 Hz), 9.16 (s, 1 H), 9.57 (s, 1 H).13C-NMR (DMSO-de) d (ppm): 113.42, 114.96, 115.70, 115.96 (2C), 117.01, 117.45, 122.35 (2C), 130.12, 132.91, 135.95, 136.68, 139.09, 142.45, 152.95, 157.85.
Compound 24.1H-NMR (DMSO -ofe) d (ppm): 6.51 (ddd, 1H, J = 8.0, 2.2, 0.8 Hz), 6.73-6.81 (m, 2H), 7.00 (ddd, 1H, J= 8.1, 2.4, 0.9 Hz), 7.19 (t, 1H, J = 3.0 Hz), 7.22-7.29 (m, 2H), 7.48 (t, 1 H, J = 7.9 Hz), 7.76 (t, 1 H, J = 2.2 Hz), 8.43 (d, 1 H, J= 1.9 Hz), 8.48 (d, 1 H, J= 2.5 Hz), 8.56 (s, 1 H), 9.52 (s, 1 H), 9.81 (s, 1 H).13C-NMR (DMSO-de) d (ppm): 104.03, 108.11, 108.38, 113.53, 115.09, 117.55, 119.94, 130.12, 130.17, 135.93, 138.06, 138.35, 138.82, 140.16, 143.45, 157.92, 158.31.
Compound 25.1H-NMR (DMSO-de) d (ppm): 6.69 (AA’XX’, 2H, JAX = 8.9 Hz, JAAYXX’ = 2.8 Hz), 6.84-6.90 (m, 4H), 7.40 (AA’XX’, 2H, JAX = 8.9 Hz, JAAYXX = 2.7 Hz), 7.50 (AA’XX’, 2H, JAX = 8.7 Hz, JAAVXX· = 2.5 Hz), 8.03-8.07 (m, 1 H), 8.62 (s, 1H), 8.96 (s, 1H), 9.75 (bs, 1H).13C-NMR (DMSO-de) d (ppm): 105.43, 110.89, 115.17 (2C), 115.86 (2C), 120.85 (2C), 127.66 (2C), 128.64, 133.35, 147.89, 147.98, 151.84, 157.28, 158.33.
Compound 26.1H-NMR (DMSO-de) d (ppm): 6.70 (AA’XX’, 2H, JAX = 8.8 Hz, JAAYXX = 2.7 Hz), 6.80-6.90 (m, 3H), 7.01 (t, 1H, J= 2.0 Hz), 7.03-7.09 (m, 1 H), 7.28 (t, 1H, J= 7.9 Hz), 7.40 (AA’XX’, 2H, JAX = 8.9 Hz, JAAYXX = 2.7 Hz), 8.09 (d, 1 H, J= 5.5 Hz), 8.68 (s, 1 H), 8.98 (bs, 1 H), 9.63 (bs, 1 H). 13C-NMR (DMSO-de) d (ppm): 106.31 ,111.34, 113.15, 115.20 (2C), 115.82, 117.17, 121.03 (2C), 130.13, 133.17, 139.61, 148.03, 148.29, 151.98, 157.29, 157.90.
Compound 27.1H-NMR (DMSO-de) d (ppm): 6.25-6.33 (m, 1H), 6.84-6.92 (m, 2H), 6.93-7.05 (m, 4H), 7.28 (s, 1 H), 7.49-7.57 (m, 2H), 8.13 (d, 1 H, J = 5.4 Hz), 8.90 (s, 1 H), 9.19 (bs, 1H), 9.79 (bs, 1H).13C-NMR (DMSO-de) d (ppm): 105.11, 106.78, 107.67, 109.17, 111.75, 115.93 (2C), 127.74 (2C), 128.47, 129.21, 142.92, 147.82, 148.12, 156.64, 157.68, 158.45.
Compound 28.1H-NMR (DMSO-de) d (ppm): 6.27-6.34 (m, 1 H), 6.85 (ddd, 1 H, J= 8.0, 2.4, 0.9 Hz), 6.95 (dd, 1H, J= 5.4, 1.5 Hz), 6.99-7.06 (m, 4H), 7.10 (ddd, 1 H, J= 7.7, 1.7, 1.0 Hz), 7.27-7.33 (m, 2H), 8.18 (d, 1H, J= 5.3 Hz), 8.96 (s, 1 H), 9.20 (s, 1H), 9.66 (s, 1H).13C-NMR (DMSO-de) d (ppm): 105.18, 107.70, 107.79, 109.21, 112.20, 113.22, 115.94, 117.22, 129.21,
130.18, 139.43, 142.77, 147.94, 148.40, 156.62, 157.68, 157.95.
Compound 29.1H-NMR (acetone-de) d (ppm): 6.90 (AA’XX’, 2H, JAX = 8.8 Hz, JAAYXX’ = 2.6 Hz), 6.93 (AA’XX’, 2H, JAX = 8.8 Hz, JAAYXX = 2.6 Hz), 7.04 (ddd, 1 H, J = 7.7, 1.8, 1.3 Hz), 7.30 (td, 1 H, J = 7.6, 0.7 Hz), 7.34-7.38 (m, 2H), 7.38-7.44 (m, 4H), 8.48 (bs, 1H), 8.69 (bs, 1H).13C-NMR (acetone-de) d (ppm): 116.61 , 117.56 (2C), 123.02, 124.64, 126.23, 126.47, 128.83 (4C), 130.23, 132.51, 136.88, 140.55, 142.69, 158.29, 159.15.
Compound 30.1H-NMR (aceton e-de) d (ppm): 6.83 (ddd, 1H, J= 8.1, 2.4, 1.0 Hz), 6.93 (AA’XX’, 2H, JAX = 8.8 Hz, JAAVXX· = 2.6 Hz), 7.00-7.04 (m, 2H), 7.11 (ddd, 1 H, J = 7.6, 1.9, 1.3 Hz), 7.25 (t, 1 H, J = 8.1 Hz), 7.31 -7.40 (m, 3H), 7.42 (AA’XX’, 2H, JAX = 8.8 Hz, JAAVXX· = 2.6 Hz), 8.58 (bs, 2H).13C- NMR (acetone-de) d (ppm): 114.61, 115.52, 117.62 (2C), 118.96, 122.77, 125.14, 126.62, 127.24, 130.28, 130.81, 137.01 (2C), 140.76, 142.78, 142.82, 158.78, 159.25.
Compound 31.1H-NMR (acetone-de) d (ppm): 6.76 (ddd, 1H, J= 8.1, 2.4, 0.9 Hz), 6.83 (t, 1H, J= 1.8 Hz), 6.86 (ddd, 1H, J= 7.7, 1.7, 0.9 Hz), 6.92 (AA’XX’, 2H, JAX = 8.8 Hz, JAAVXX· = 2.6 Hz), 7.19 (t, 1H, J= 7.8 Hz), 7.28 (ddd, 1 H, J= 7.7, 1.8, 1.1 Hz), 7.42 (td, 1H, J= 7.7, 0.4 Hz), 7.48 (AA’XX’, 2H, JAX = 8.8 Hz, JAAVXX· = 2.6 Hz), 7.53 (ddd, 1 H, J= 7.8, 1.8, 1.1 Hz), 7.59 (td, 1H, J= 1.8, 0.4 Hz), 8.49 (bs, 2H). 13C-NMR (acetone-de) d (ppm): 115.28, 116.60 (2C), 118.11 , 122.54, 126.27, 128.91 (2C), 129.91 , 130.12, 130.62, 131.11, 132.21, 136.73, 137.72, 143.07, 158.43, 159.05.
Compound 32.1H-NMR (acetone-de) d (ppm): 6.77 (ddd, 1H, J= 8.1, 2.4, 0.9 Hz), 6.82-6.90 (m, 3H), 7.05-7.11 (m, 2H), 7.20 (t, 1 H, J= 7.8 Hz), 7.27 (t, 1 H, J= 8.1 Hz), 7.34 (ddd, 1H, J= 7.7, 1.7, 1.1 Hz), 7.44 (t, 1H, J= 7.7 Hz), 7.55 (ddd, 1 H, J = 7.7, 1.7, 1.1 Hz), 7.59 (t, 1 H, J = 1.6 Hz), 8.49 (bs, 2H). 13C-NMR (acetone-de) d (ppm): 114.62, 115.40, 115.65, 118.26, 119.00, 122.70, 126.76, 130.27, 130.66, 130.86, 130.89, 131.41, 136.97, 137.45, 142.45, 143.13, 158.82, 159.05. Compound 33.1H-NMR (acetone-de) d (ppm): 6.69 (AA’XX’, 2H, JAX = 8.8 Hz, JAAYXX’ = 2.4 Hz), 6.74 (d, 1H, J= 8.5 Hz), 6.80 (AA’XX’, 2H, JAX = 8.9 Hz, JAAYXX = 2.8 Hz), 7.14-7.29 (m, 7H), 7.49 (d, 1H, J = 8.4 Hz), 7.54 (AA’XX’, 2H, JAX = 8.9 Hz, JAAVXX· = 2.7 Hz), 7.94 (s, 1 H), 7.98 (bs, 1 H), 8.36 (bs, 1H).13C-NMR (acetone-de) d (ppm): 107.57, 115.26 (2C), 116.22 (2C), 122.45 (2C), 126.24, 126.92, 129.02 (2C), 130.37 (2C), 132.19 (2C), 133.26, 134.78, 140.93, 142.28, 153.38, 155.32, 156.58, 157.89.
Compound 34.1H-NMR (acetone-de) d (ppm): 6.85 (AA’XX’, 2H, JAX = 8.8 Hz, JAAYXX’ = 2.8 Hz), 6.95 (s, 1 H), 7.02 (AA’XX’, 2H, JAX = 8.7 Hz, JAAYXX =
2.4 Hz), 7.18 (ddd, 1H, J=8.3, 6.7, 1.2 Hz), 7.37 (AA’XX’, 2H, JAX = 8.7 Hz, JAAYXX = 2.8 Hz), 7.47 (ddd, 1 H, J= 8.4, 6.7, 1.2 Hz), 7.58 (AA’XX’, 2H, JAX = 8.7 Hz, JAAYXX’ = 2.4 Hz), 7.62 (d, 1 H, J= 8.4 Hz), 7.67 (bs, 1 H), 7.93 (dd, 1 H, J = 8.6, 0.9 Hz), 8.11 (bs, 1H), 8.66 (bs, 1H).13C-NMR (acetone-de) d (ppm): 97.41, 115.77 (2C), 116.50 (2C), 116.56, 122.36, 123.37, 123.56 (2C), 126.39, 128.24, 130.55, 131.90, 132.17 (2C), 134.56, 141.11 , 153.89, 153.95, 158.84, 160.43.
Compound 35.1H-NMR (acetone-de) d (ppm): 6.43 (ddd, 1H, J= 8.0, 2.4, 1.0 Hz), 6.70 (AA’XX’, 2H, JAX = 8.8 Hz, JAAVXX· = 2.5 Hz), 6.87 (d, 1H, J =
8.4 Hz), 7.08 (t, 1 H, J = 8.0 Hz), 7.16-7.25 (m, 4H), 7.25-7.30 (m, 4H), 7.43 (t, 1H, J = 2.2 Hz), 7.55 (d, 1H, J=8.4 Hz), 8.17 (bs, 1H), 8.24 (s, 1H), 8.39 (bs, 1 H).13C-NMR (acetone-de) d (ppm): 106.52, 108.94, 108.99, 110.84, 115.32 (2C), 126.99, 127.05, 129.05 (2C), 130.22, 130.36 (2C), 132.25 (2C), 133.08, 140.98, 142.10, 144.03, 155.30, 155.68, 157.93, 158.79.
Compound 36.1H-NMR (acetone-de) d (ppm): 6.46 (ddd, 1H, J= 7.9, 2.4,
1.1 Hz), 7.00-7.08 (m, 3H), 7.12 (t, 1H, J=8.0 Hz), 7.17 (t, 1H, J= 2.2 Hz), 7.21 (s, 1 H), 7.25 (ddd, 1 H, J= 8.5, 6.8, 1.2 Hz), 7.53 (ddd, 1 H, J= 9.5, 6.7,
1.2 Hz), 7.61 (AA’XX’, 2H, JAX = 8.7 Hz, JAAVXX· = 2.4 Hz), 7.71 (d, 1H, J =
8.4 Hz), 7.98 (dd, 1H, J= 8.6, 0.9 Hz), 8.01 (s, 1H), 8.23 (s, 1H), 8.67 (s, 1 H).13C-NMR (acetone-de) d (ppm): 99.86, 106.49, 109.16, 110.93, 115.84 (2C), 122.76, 124.06, 126.65, 128.24, 130.53, 130.68, 131.91 , 132.29 (2C), 140.92, 144.28, 152.17, 158.85, 159.01, 160.38. In vitro screening for the evaluation of SIRT1 enzyme activity.
A commercially available enzyme kit was used to perform a preliminary screening of the original compounds developed and synthetized as SIRT1 activators. The enzyme activity was monitored through a spectrofluorimetric approach.
In particular, the enzyme substrate (comprising a polypeptide conjugated with a fluorophore through an acetyl bond (Arg-His-Lys-Lys (e-acetyl)- AMC)) is incubated with the SIRT1 enzyme and NAD+ as a cofactor. The deacetylation of the polypeptide leads to the formation of the acetylated fluorophore (acetyl-AMC), which releases the fluorophore and emits fluorescence, after the addition of a developer.
The fluorescence, which is directly proportional to the enzyme’s activity, was analyzed using a spectrofluorimetric plate (Aex 350-360 nm, Aem 450-465 nm) and the data obtained were expressed as a % of the fluorescence evoked by 100 mM resveratrol, used as the reference activator of SIRT1. Many of the tested compounds showed higher activity when compared with the reference compound. In particular, at a concentration of 100 mM, compounds 14, 15, 16 and 17 (pyridine derivatives) showed a markedly higher effectiveness in activating the purified enzyme than resveratrol 100 mM (Figures 1 and 2, table 2). Moreover, all the pyridine derivatives showed concentration-dependent SIRT 1 activation. The incubation of compounds 1 , 2, 3, 4, 5 (oxazolidine derivatives), 6 (diaryl-ether derivative), 10, 1 1 , 12 and 13 (aniline derivatives) at 100 mM resulted in a clearly lower SIRT1 activation than was induced by resveratrol 100 mM.
Table 2 - the table shows the effects of the synthetized compounds on SIRT1 (expressed as a % vs the reference compound resveratrol 100 mM). Negative values indicate that the compound reduced the activity of the enzyme.
Figure imgf000064_0001
Evaluation of the cardioprotection properties in an in vivo model of ischemia / reperfusion injury.
The most active SIRT1 activators were selected for the purpose of evaluating their cardioprotection properties in an in vivo rat model of ischemia / reperfusion injury. Wistar albino rats (males, 300-350 g) were treated i.p. with the compounds 120 min before proceeding with the experimental model of acute myocardial infarct.
The rats were anesthetized with pentobarbital sodium (70mg / kg i.p.) and connected to an electrocardiograph to monitor cardiac activity. Following tracheotomy, respiratory activity was kept constant by means of an artificial respirator (70 breaths / min, 1 ml of air blown / 10Og) for the whole duration of the experimental procedure. After partial thoracotomy, the heart was exposed and reversible occlusion of the left coronary artery was performed for 30 minutes by means of a ligature with a surgical needle (13mm, C1 , 3/8 circular, 6-0). After the removal of the occlusion, reperfusion was maintained for 120 min. The animals were then sacrificed by administration of an anesthetic overdose and a morphometric evaluation of the heart was performed.
The left ventricle was transversally cut into slices about 2 mm thick and each slice was incubated for 20 min at 37 ° C in triphenyl-tetrazolium chloride in order to distinguish the ischemic areas, which appeared pale pink or white, from the vital areas, which appeared red in colour.
On the basis of the in vitro results obtained for the purified enzyme, compounds 14 and 15 were selected in order to evaluate their cardioprotective activity in an in vivo model of acute myocardial infarction, since at all tested concentrations (from 3 to 100 mM) they showed an activation equivalent to or higher than resveratrol 100 mM. Both compounds significantly reduced the ischemic area vs the vehicle (DMSO 1 % p/v), and thus showed a significant protective effect against myocardial injury. In particular, compound 14 at 1 mg/kg (i.p.) proved to be even more effective than diazoxide 40mg/kg (i.p.), selected as a reference cardioprotective drug. Compound 15, at a dose of 1 mg/kg, was less effective than compound 14. However, it significantly reduced the ischemic area (Figure 3, Table 3). The cardioprotective effect was dose-dependent, since at a dose of 10 mg/Kg compound 15 showed a significant improvement in effectiveness. Table 3 - Percentage of ischemic area (Ai) vs left ventricle area (Alv).
Figure imgf000066_0001

Claims

1. A compound of formula (I):
Figure imgf000067_0001
wherein
R1 , R2, R3 and R4 are independently selected from -OH and -H;
X is selected from: -NH, -O, -S,
R5 is selected from among the following groups:
Figure imgf000067_0002
R6 is selected from -H or a non-substituted phenyl group,
Figure imgf000067_0003
with the condition that when R5 is
R2 and R3 are never -OH.
2. The compound according to claim 1 , wherein X is selected from: -NH and
-O.
3. The compound according to claim 1 or 2, wherein X is -NH.
4. The compound according to any one of claims 1
Figure imgf000068_0001
, wherein R5 is selected
Figure imgf000068_0002
from among the following groups:
Figure imgf000068_0003
5. The compound according to claim 4, wherein R5 is
Figure imgf000068_0004
6. The compound according to any one of claims 1 to 3, wherein R5 is selected from among the following groups:
Figure imgf000068_0005
7. The compound according to any one of claims 1 to 3, wherein R5 is
Figure imgf000068_0006
8. The compound according to any one of claims 1 to 3, wherein R5 is
Figure imgf000068_0007
9. The compound according to any one of claims 1 to 3, wherein R5 is
Figure imgf000069_0001
10. The compound according to any one of claims 1 to 3, wherein R5 is
Figure imgf000069_0002
1 1. The compound according to claim 1 , wherein X is S and R5 is
Figure imgf000069_0003
12. The compound according to any one of claims 1 to 3, wherein R5 is
Figure imgf000069_0004
14. The compound according to any one of the preceding claims selected from: 
Figure imgf000070_0001
PCT/IB2019/051489
Figure imgf000071_0001
70
Figure imgf000072_0001
71
Figure imgf000073_0001
Figure imgf000074_0001
15. A pharmaceutical composition comprising the compound according to any one of the preceding claims and pharmaceutically acceptable excipients, adjuvants and/or carriers.
16. The pharmaceutical composition according to claim 15 or the compound according to any one of claims 1 to 14 for use as a medicament.
17. The pharmaceutical composition according to claim 15 or the compound according to any one of claims 1 to 14, for use in the treatment or in the prevention of cardio-metabolic pathologies, preferably diabetes, and cardiovascular pathologies, preferably coronary pathologies, heart failure, acute myocardial infarction and atherosclerosis.
18. The pharmaceutical composition according to claim 15 or the compound according to any one of claims 1 to 14 for use in association or in combination with other molecules selected from: ACE inhibitors, statins, sartans, calcium channel blockers, beta-blockers, vasodilators, digitalin, antianginal, anti-ischemic, antiarrhythmic, antihypertensive and hypocholesterolemic drugs and combinations thereof.
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