RS604A - New compounds,which are potent inhibitors of na+/ca2+ exchange mechanism and are useful in the treatment of arrhythmais - Google Patents

Abstract

Therapeutically active compounds of formula (1): wherein X is: -O-, -CH2- or -C (O) -; Z is -CHR9- or a valence bond; Y is -CH2-, -C (O), CH (OR10) -, -CH (NR11R12) -, -O-, -S-, -S (O) -, or -S (O2) -, provided that if Z is in a valence bond, Y is not C (O); the dashed line represents a possible double bond in which case Z is -CR9-a Y is -CH-, C (OR10) - or -C (NR11R12) -; R 1 is - (CH 2) n NR 4 R 7 or one of the following groups: n = 1 -4, R 2 and R 3 are independently H, lower alkyl, lower alkoxy, -NO 2, halogen, -CF 3, -OH, -NHR 8 or -COOH, R 4 and R7 is independently H, lower alkyl, or lower hydroxyalkyl, R5 is H, lower alkoxy, -CF3, -NH2 or -CN, R6 is -NO2, -NR14R19, -CF3 or R8 and R16 are independently H or acyl, H is or lower alkyl, R10 is H, alkylsulfonyl or acyl, R11 and R12 are independently H, lower alkyl or acyl, R13 and R18 are independently H or -OR20, R14 and R19 are independently H, acyl, alkylsulfonyl, C (S ) NHR17 or C (O) NHR17, R15 is H or NH2, R17 is H or lower alkyl, R20 is H or acyl, and pharmaceutically acceptable salts and esters thereof. These compounds are potent inhibitors of the mechanism of Na + / Ca2 + ion exchange.

Description

NEW COMPOUNDS, STRONG CHANGE MECHANISM INHIBITORS

Na /Ca2+ IONS USED IN ARRHYTHMIA THERAPY

Technical area

This invention relates to novel therapeutically active compounds as well as pharmaceutically acceptable salts and esters. The invention also relates to pharmaceutical compositions that have the mentioned compound as an active component. The compounds that are the subject of the invention show a strong inhibitory effect on the Na<+>/Ca<2+> ion exchange mechanism.

Basis of the invention

The Na/Ca ion exchange mechanism is one of the ion transport mechanisms that regulate the concentrations of Na<+> and Ca<2+> ions in the cell. Compounds that selectively inhibit the mechanism of Na<+>/Ca<2+> ion exchange can therefore prevent the excessive accumulation of Ca<2+> ions in the cell, i.e. represent protection against possible heart muscle damage during and after ischemia as well as during normalization of flow. Such compounds are very useful for use in the treatment of ischemic heart disease, ischemic cerebral damage, ischemic kidney diseases, then in the protection of cells during thrombolytic therapy (thrombus dissolution), operations on blood vessels, bypass operations on coronary arteries, or in organ transplants, as well as finally in arrhythmias.

Compounds capable of inhibiting the Na<+>/Ca<2+> ion exchange mechanism have already been described earlier, e.g. in patent publication WO 97/09306, EP 0978506, EP 1031556, JP 1049752 and JP 11302235.

Brief description of the invention

So far, it has been determined that the compounds of the basic formula (I) are individually strong inhibitors of the Na+/Ca2+ ion exchange mechanism and as such are particularly useful in the treatment of arrhythmias.

The basic compound representing the invention has the structural formula (I):

where are the substituents

X is -O-, -CH2- or -C(O)-;

Z is -CHR9- or a valence bond;

Y is -CH2-, -C(O)-, CH(OR,o)-, -CH(NRnR12)-, -O-, -S-, -S(O)- or -S(O2)- Provided that in the case of valence-bonded Z, the substituent for Y is not C(O);

dotted lines represent such an example of a double bond where Z is -CR9- and Y is -CH-, C(OR,0)- or -C(NRuR12)-;

R 1 is -{CH 2 ) n NR 4 R 7 or one of the following groups:

1 - 4

R 2 and R 3 are independently H, lower alkyl radical, lower alkoxy, -NO 2 , halogen, -CF 3 , -OH, -NHR 8 or -COOH,

R4 and R7 are independently H, lower alkyl or lower hydroxy alkyl radical,

R 5 is H, lower alkoxy radical, -CF 3 , -NH 2 or -CN group

R6 is -NO2, -NR14R19, or

R§ and R16 are independently H or an acyl radical CF3 or a group

R 9 is H or a lower alkyl radical

R io is H, an alkylsulfonyl or an acyl radical;

Rj 1 and R 12 are independently H, lower alkyl or acyl radical,

R13 and R18 are independently H or -OR20,

RM and R19 are independently H, acyl, alkylsulfonyl, C(S)NHRn or C(0)NHR17, RisjeH or NH2,

R17 is H or a lower alkyl radical,

R20 is H or an acyl radical

as well as their pharmaceutically acceptable salts or esters.

In one class of the most favorable compounds and their pharmaceutically acceptable salts and esters are compounds having the following formula:

where R 1 , R 2 , R 3 , X, Y and Z are as defined above. In another class of advantageous compounds and their pharmaceutically acceptable salts and esters with the basic formula (I), they have for X the substituent O and for Z and Y the substituent -CH2-. Another class of such very convenient compounds and their pharmaceutically acceptable salts and esters with the general formula (1) has for X the substituent O, for Z -CH2- while for Y it is CHOH.

A subclass of very suitable compounds and their pharmaceutically acceptable salts and esters also has the general formula (I) wherein R is one of the following groups:

In another subclass of very suitable compounds are those in which the substituents for R6 are -NO2 or NR14R19. In one group of those subclasses R, 4 and R 19 are independently H, acyl or alkylsulfonyl radicals, while R 5 and R 6 are primarily hydrogen, and R 5 is hydrogen or a lower alkoxy radical.

A further subclass of very suitable compounds are compounds where R 2 and R 3 are independently H or halogen. Of the halogens, the most suitable would be fluorine (F).

Another subclass of very suitable compounds are those where n=2, while for R4 and R7 the most suitable substituent is a methyl group.

The present invention also provides a pharmaceutical composition comprising a compound of formula (I) with a pharmaceutically acceptable carrier.

The present invention further provides a method of inhibiting the Na<+>/Ca<2+> exchange mechanism in a cell, comprising administering to a subject in need thereof a therapeutically effective amount of a compound of formula (I).

The present invention further provides a method of preventing the accumulation of calcium (Ca<2+>) ions within a cell, comprising administering to a subject in need thereof a therapeutically effective amount of a compound of formula (I).

The present invention further provides a method of treating arrhythmias, comprising administering to a subject in need thereof a therapeutically effective amount of a compound of formula (I).

Brief description of the drawing

Figure 1 shows the antiarrhythmic effects of the compound of Example 27 on ouabain-induced aftercontractions of papillary muscles isolated from guinea pig tissue.

Figure 2 shows the antiarrhythmic effects of the compound of Example 67 on ouabain-induced aftercontractions of papillary muscles isolated from guinea pig tissue.

Detailed description of the invention

The compounds of this pronalsk can be synthesized from the corresponding phenolic derivatives (II) if R.2, R3, X, Z and Y are substituted in the manner previously defined.

The syntheses are shown in scheme 1 where the formula (II) is abbreviated as Ar-OH(II) and R4, R5, Rf,, R7, R15 and Ribs are defined as before, while Hal denotes halogen.

Compounds of the basic formula (II) can react with l-chloro-2-nitrobenzene derivatives to give nitrophenoxy compounds (10), which undergo hydrogenation to give phenylamine derivatives (11). 5-nitropyridin-2-yloxy derivatives (12) are obtained by reaction with 2-chloro-5-nitropyridine.

2-oxymethylimidazoline derivatives (14) can be synthesized from phenolic derivatives (II) via cyanomethyl ether (13) which is transformed into imidazoline (14) using known methods (e.g. J. Med. Chem. 1994, 37(12), 1874). Alkoxyazide derivatives (16) are obtained via the corresponding haloalkoxy derivatives (15) by reaction with sodium azide. Azides (16) are transformed to amines (17) by reaction with triphenylamine. 2-(dimethylamino)ethoxy derivatives (18) are obtained by direct reaction of the phenolic compound of formula (II) with 2-(dimethylamino)ethyl chloride.

Reduction of nitropyridine (22) followed by acylation, mesylation, etc. produces compounds of formula (24) as shown in Scheme 2.

As shown in the following scheme 3 where R 2 and R 3 are the same as stated above, the 6- and 7-hydroxyflavone derivatives (2) were obtained from the corresponding flavanones (1) via the Clemmensen reaction. The compounds 6- and 7-hydroxyflavanones (1) are commercially available or can be synthesized using methods described in the literature, e. Mr. C. Org Chem. 1960, 25, 1247-9 and J. Org Chem., 1958, 23, 1159-61 or as shown later in Scheme 5.

The following Scheme 4 where R 2 and R 3 are the same as previously defined, describes the synthesis of 2-phenyl indan-5-ol (9). Condensation of p-anisaldehyde (3) with substituted phenylacetic acid (4) produces a mixture of the cis-i/trans-isomer of the corresponding acrylic acid (5). After hydrogenation and intramolecular Friedel-Crafts reaction, the carbonyl functionality in 1-indanone (7) can be reduced by Clemmensen reduction. Finally, methoxy indane (8) is subjected to reflux in hydrobromic acid and 2-phenyl indan-5-ols (9) are obtained.

6-Hydroxyflavanone derivatives can be synthesized as shown in Scheme 5. Compound 2',5'-Dihydroxyacetophenone or the corresponding propiophenone is condensed with the corresponding benzaldehyde to give a mixture of the desired 6-hydroxyflavanones (36) and the corresponding chalcones (35). Chalcones can then be cyclized to flavanones. 2-Phenylchroman-4,6-diol derivatives (37) are obtained from the corresponding 6-hydroxyfavanone (36) by reduction as shown in Scheme 6. These diol derivatives can be further reduced to 6-hydroxyflavans. (38).

As shown in Scheme 7, 4-amino-2-phenylchromanol derivatives (19) can be synthesized from the corresponding flavanones (1) via hydroxy-2-phenylchroman-4-one oxime (20). By reducing the oxime derivative, 4-amino-2-phenylchromanols (21) are obtained, which can be alkylated or acylated by general methods. The 4-hydroxy-2-phenylchromanol derivative can be treated by simple methods.

From Scheme 8 where R2 and R3 are as previously defined, the synthesis of 7-hydroxyisoflavanone (29) and 7-hydroxyisoflavan (30) can be followed. By acylation of 3-methoxyphenol with substituted phenylacetic acid, the corresponding 2-hydroxydeoxybenzoins (27) are obtained, which can be cyclized with triethylorthoformate to yield isoflavane (28). Reaction with hydrobromic acid and catalytic hydrogenation give 7-hydroxyisoflavans.

(30).

The following Scheme 9 describes the synthesis of 2-phenyl-2, 3-dihydrobenzo (1,4) oxatin-6-ol (34). The reaction of 2-mercaptobenzene-1,4-diol with styrene epoxide in the presence of a base gives sulfides (33). Ring closure with cyanoic acid enables the formation of 2-phenyl-2,3-dihydrobenzo (1,4)oxatin-6-ol (34).

From Scheme 10, the synthesis of 6-phenyl-5, 6, 7, 8-tetrahydronaphthalene-2ol (41) and 6-hydroxy-2-phenyl-3,4-dihydro-2H-naphthalene-1-one (40) can be followed. Palladium Pd-catalyzed alpha-arylation was applied to 6-methoxy-l-tetralone to give 6-methoxy-2-phenyl-3,4-dihydro-2H-naphthalen-l-one (39) which after demethylation gave phenolic compounds (40).

From Scheme 11 where R2 and R3 are the substituents as previously defined, the synthesis of 2,3-dihydro-2-phenylbenzo (1,4) dioxin-6-ol (45) is described. After protection of the hydroxyl groups from 2,5-dihydroxyacetophenone, this ketone was subjected to peracid rearrangement (internal change) to give phenol after hydrolysis. Phenol was then subjected to a condensation reaction with haloketone and after reduction and deprotection, hydroxyphenol (44) was cyclized to 2,3dihydro-2-phenyl-benzo (1,4)-dioxin-6-ol (45).

Salts and esters of compounds according to the invention can be synthesized by known methods. Physiologically acceptable salts are useful as active drugs. Examples include salts with inorganic acids such as hydrochloric, hydrobromic or nitric acid as well as salts of compounds with organic acids such as methylsulfonic, citric or tartaric acid. And physiologically acceptable esters are also used as active drugs. Such are esters with aliphatic or aromatic acids, such as acetic acid, or with aliphatic or aromatic alcohols.

The term "alkyl" as used herein either alone or as part of another group includes open-chain, branched or ring radicals of up to 18 carbon atoms, generally from 1 to 7, and most preferably radicals from 1 to 4 carbon atoms. The term "lower alkyl" as used herein alone or as part of another group includes an open chain, branched chain or ring radical of 1 to 7 carbon atoms, preferably 1 to 4, most preferably 1 to 2 carbon atoms. Specific examples of the term "alkyl" and "lower alkyl" radical are methyl, ethyl, propyl, isopropyl, butyl, tertiary butyl, pentyl, cyclopentyl, hexyl, cyclohexyl, octyl, decyl and dodecyl groups including their branched chain isomers.

The term "alkoxy" as used herein either alone or as part of another group includes an alkyl group as defined above attached through an oxygen atom.

The term "acyl" as used herein alone or as part of another group refers to an alkylcarbonyl or alkenylcarbonyl group, and alkyl and alkenyl groups are as defined above.

The compounds of this invention can be administered to patients in therapeutically effective amounts. These dosages generally range from about 0.05-200 mg., preferably from about 0.1-100 mg., and the most favorable from about 0.5-50 mg., per day and depends on the age, body weight and condition of the patient and the method of administration and the type of Na<+>/Ca<2+> exchange inhibitor used. The compounds of the present invention can be prepared in dosage forms using principles known in the art. They can be administered to patients as such or in combination with a suitable pharmaceutical carrier in the form of tablets, granules, capsules, suppositories, emulsions, suspensions or solutions. The selection of suitable ingredients to form a composition is a routine job for experts. It is to be understood that suitable carriers, solvents, gelling agents, spray dispersants, antioxidants, colors, sweeteners, moisture correctors and similar other ingredients normally employed in this art can be used. Compositions containing the active compound can be administered enterally or parenterally, with the oral route being preferred. The content of the active compound in the composition ranges between 0.5-100%, and preferably from 0.5-20%, calculated according to the mass of the total composition.

EXPERIMENTS

The effects of the compounds on pronalsk were investigated on ouabain-induced arrhythmias in guinea pig papillary muscles.

Procedures

Guinea pig tissue papillary muscles were loaded into a horizontal muscle cuvette. A hook connected to the force transducer is attached to the other end of the muscle. Muscle preparations were exposed to 1 Hz pulses with stimulation via platinum electrodes. Modified Tyrode's solution was used for superfusion of muscle preparations. Tyrode's solution consisted of (Mm): NaCl 135, MgCl2x 6H20 1, KC1 5, CaCl2x 2H20 2, NaHC0315, Na2HP04x 2H20 1, and glucose 10. Gases were passed through the Tyrode solution, in the form of a combination of carbogen (95%02, 5%C02) to stabilize the pH at 7.4. The experiment was performed at 37 °C. The course and analysis of the intensity of muscle tremors were performed with the Action Potential and Force Measurement System (ACFOvl.O, Fision Ltd., Finland).

Inhibition of ouabain-induced arrhythmias

By blocking Na-K-ATP (adenosine triphosphatase), ouabain increases the intracellular level of sodium that is exchanged for calcium via NCX. An increase in intracellular calcium levels leads to overloading of the sarcoplasmic reticulum (SR) and spontaneous release of calcium from the SR causing delayed polarizations (DADs). Proportional to the strength of the DADs signal, subsequent contractions (ACs) occur, which are manifested as spontaneous flickering after rhythmically controlled flickering.

The compounds according to the invention delayed the onset and reduced the amplitude of subsequent contractions. As shown in Figure 1, the title compound of Example 27 at concentrations of 30 micromolar delays the onset (38 ± 7.5 min vs vehicle: 25 ± 8.9 min (mean ± SD), p=0.013, n=5) and reduces the peak amplitude of aftercontractions #1 (74 ± 16mg vs vehicle: 143 ± 54mg, p=0.008, one-way ANOVA followed by LSD; n=5). As shown in Figure 2, the title compound of Example 67, at a concentration of 10 micromolar, decreased the peak amplitude of aftercontractions #1 (88 ± 22mg vs vehicle: 143 ± 54 mg, p=0.027, n=5).

EXAMPLES

Example1:

5- Nitro-2-(2-phenylchroman-6-yloxy)pyridine

a) 2-phenylchroman-6-ol.

Zinc (5.4 g, 83.2 mmol), mercury (II) chloride (340 mg), concentrated hydrogen chloride

acid (0.2ml) and water were mixed at room temperature for 15 minutes and the mixture was then decanted (poured off). The compound 6-hydroxyflavanone (1.0g)) was added as a suspension in a mixture of acetic acid (25ml), concentrated hydrochloric acid (5.2ml) and water (2ml). The reaction mixture was subjected to reflux. After cooling to room temperature, the reaction mixture was filtered and the filtrate was extracted with ethyl acetate. The combined organic layers were washed with saturated (NaHCO 3 )-sodium bicarbonate solution, then the water was extracted with Na 2 SO 4 . The 2-phenylchroman-6-ol compound was then purified by column chromatography using heptane-ethyl acetate (2:1) as eluent. HNMR (400MHz, d6-DMSO) δ: 8.78 (s,lH),7.43-7.31 (m,5H), 6.63 (d,lH,J 8.6 Hz) 6.51 (dd,lH,J 8.6, 2.9 Hz), 6.48 (d,lH,J 2.9 Hz), 4.98 (dd,lH,J, 9.9, 2.2 Hz), 2.89 (ddd, IH. J -16.7, 11.3, 6.1 Hz), 2.63 (ddd, IH, J -16.7, 5.5, 3.3 Hz) 2.10 (m, IH), 1.94 (m,lH).

b) 5-nitro-2-(2-phenyllyroman-6-yloxy)pyridine

Potassium umfluoride (225mg) was added to a solution of 2-phenylchroman 6-ol (300mg) in dry

DMF (3ml). After mixing, 2-chloro-5-nitropyridine (195 mg) was added to the solution obtained at 120 °C for 30 min. The reaction mixture was stirred for 6 1/2 hours at 120 °C. After cooling to room temperature, a 1-M solution of hydrochloric acid was added and the mixture was then extracted with ethyl acetate. The combined organic layers were then washed with water and saturated NaCl solution and finally dried with Na2SO4. The 5-nitro-2-(2-phenylchroman-6-yloxy)-pyridine compound was recrystallized from an acetone-2-propanol (1:5) solution.

1H NMR (400 MHz, d6-DMSO) δ: 9.00(d, 1H, J 2.9 Hz), 8.60 (dd, 1H, J 9.2, 2.9 Hz), 7.47-7.32 (m, 5H), 7.20 (d, 1H, J 9.2 Hz), 7.00-6.89 (m, 3H), 5.15 (dd, IH, J 10.1, 2.2 Hz), 2.99 (ddd, IH, J-16.8, 11.3, 6.2 Hz), 2.75 (ddd, IH, J -16.8, 5.4, 3.3 Hz) 2.18 (m, IH), 2.02 (m,

IH).

Example 2:

Dimethyl r2-(2-phenylchroman-6-yloxy)ethylamine.

Cesium carbonate (230mg) and an excess of 2-(dimethylamino)ethyl chloride in ethylacetate were added to a solution of 2-phenylichroman-6-ol (150mg) in acetonitrile (5ml). The reaction mixture was refluxed for 30 minutes. After removing the solvent, the residue is transferred to water and extracted with ethyl acetate. The combined organic layers were washed with water, then with saturated NaCl solution and dried with Na2SO4. The compound dimethyl(2-(2-phenylchroman-6-yloxy)-ethyl amine was then recrystallized from heptane.<*>H NMR (400 MHz, d6-DMSO) δ: 7.43-7.30 (m, 5H) 6.75-6.67 (m, 3H), 5.03 (dd, IH, J 10.0, 2.2 Hz), 3.95 (t, 2H, J 5.9 Hz), 2.94 (ddd, IH, J -16.7, 10.9, 5.8 Hz), 2.69 (ddd, IH, J -16.7, 5.2, 3.3 Hz), 2.58 (t, 2H, J 5.9 Hz) 2.13 (m, IH), 1.96 (m, IH).

Example 3:

5- methoxy- 2-( 2- phenyl- chroman- 6- yloxy) phenylamine hydrochloride

a) 6-(4-methoxy-2-nitrophenoxy)-2-phenylchroman

The compounds 2-phenylchroman-6-ol (500mg) and l-chloro-4-methoxy-2-nitrobenzene (390mg) are

dissolved in DMSO (1Oml). Then, potassium hydroxide (230 mg) and potassium iodide (520 mg) were added, and the reaction mixture was stirred at 90 °C for 1 hour. After cooling, 20 ml of 1 M HCl solution was poured into it, and extraction was performed with dichloromethane. After evaporation of the organic solvent, the compound 6-(-4-methoxy-2-nitrophenoxy)-2-phenylchroman was obtained by trituration-crushing in methanol. 1 H NMR (400 MHz, d6-DMSO) δ: 7.58 (d, IH, J 3.1 Hz), 7.45-7.33 (m, 6H), 7.28 (dd, IH, J 9.2 Hz, 3.1 Hz) 7.10 (d, IH, J 9.2 Hz), 6.86-6.78 (m, 3H), 5.10 (dd, IH, J 10.0, 1.9 Hz), 3.83 (s, 3H) 2.92 (ddd, IH J-16.9, 11.2, 5.9 Hz), 2.75 (ddd, IH, J-16.9, 7.9, 4.2 Hz) 2.15 (m, IH), 1.97 (m, IH).

b) 5-methoxy-2-(-2-phenyl-chroman-6-yloxy) phenylamine hydrochloride Compound 6-(4-methoxy-2-nitrophenoxy)-2-phenylchroman in the amount of 360mg dissolved

is in ethyl acetate, to which carbon sal 0% palladium (90mg) was added. The reaction mixture was subjected to hydrogenation for 2 hours at normal pressure and room temperature.

The mixture was then passed through Celite and washed with ethyl acetate. The compound 5-methoxy-2-(2-phenyl-chroman-6-yloxy)phenylamine was isolated as the hydrochloride salt. 1H NMR (400 MHz, d^-DMSO) δ: 7.44-7.33 (m, 5H) 6.83-6.72 (m, 4H), 6.68 (d, IH, J 2.9 Hz), 6.48 (dd, IH, J 8.9, 2.8 Hz) 5.07 (dd, IH, J 10.0, 2.2 Hz), 3.70 (s, 3H) 2.93 (ddd, IH, J-17.0, 11.1,6.1 Hz), 2.68 (ddd, IH, J-17.0, 8.3, 4.5 Hz) 2.15 (m, IH), 1.97 (m, IH).

Example 4:

2-(2-phenylchroman-6-yloxy)ethylamine methylsulfonate

a) 6-(2-azidoethoxy)-2-phenylchroman

2-phenylchroman-6-ol in the amount of 340 mg, then 1-bromo-2-chloroethane (1.25 ml) and cesium

carbonate in the amount of 977mg were dissolved in acetonitrile (4ml). The reaction mixture was refluxed for 4 hours. After cooling to room temperature, the mixture was poured into a solution of 1 M HCl and extracted with dichloromethane. The combined dichloromethane extracts were first washed with water and then dried with Na2SO4. The mixture was passed through a silica gel column using ethyl acetate and hexane (1:7), the eluent yielding 190 mg of the haloethane derivative. It was then dissolved in DMF (5 ml) with the addition of 214 mg of sodium azide. The reaction mixture was refluxed for 2 hours. The mixture was then filtered, ethyl acetate was added to the filtrate and then washed once with 1M HCl solution, several times with water and dried with Na 2 SO 4 . The solvents were then removed under reduced pressure, and finally the compound 6-(2-azidoethoxy)-2-phenylchroman was obtained. ]H NMR (400 MHz, d6-DMSO) δ: 7.44-7.32 (m, 5H) 6.78-6.71 (m, 3H), 5.04 (dd, 1H, J 10.1, 2.3 Hz), 4.10 (t, 2H, J 4.8 Hz), 3.60 (t, 2H, J 4.8 Hz), 2.95 (ddd, 1H,J- 16.8, 11.1, 6.0 Hz), 2.70 (ddd, IH, J-16.8, 5.3, 3.3 Hz), 2.14 (m, IH), 1.97 (m, IH).

b) 2-(2-phenylchroman-6-yloxy) ethylamine methylsulfonate

Triphenylphosphine in the amount of 165 mg in 40 microliters of water was added to the solution

prepared from 6-(2-azidoethoxy)-2-phenylchroman (155mg) in tetrahydrofuran. The resulting mixture was stirred for 2 hours at room temperature. The compound 2-(-2-phenylchroman-6-yloxy)-ethylamine was isolated as its methylsulfonate salt. 1H NMR (400 MHz, d6-DMSO) δ: 7.91 (bs, 3H), 7.44-7.32 (m, 5H), 6.81-6.75 (m, 3H), 5.05 (dd, 1H, J 9.9, 2.3 Hz), 4.08 (t, 2H, J 5.1 Hz), 3.19 (m, 2H), 2.95 (ddd, IH, J-16.8, 11.0, 5.9 Hz), 2.71 (ddd, IH, J 16.8,5.2,3.4 Hz), 2.30 (s, 3H) 2.15 (m, IH), 1.97 (m, IH).

Example 5:

2-(2-phenylchroman-6-yloxymethyl)-4,5-dihydro-1H-imidazole hydrochloride.

a) (2-phenylchroman-6-yloxy)acetonitrile

Cesium carbonate (310 mg) and chloroacetonitrile (62 microliters) were added to the solution

2-phenylchroman-6-ol (200mg) in acetonitrile (3ml). The resulting mixture was kept under reflux for 6 hours, then cooled to room temperature. IM of HC1 solution was added to her and she was performed

extraction with ethyl acetate. The collected organic layers were washed with water, then saturated NaCl solution and dried with Na2SO4. The solvent was removed under reduced pressure to give (2-phenylchroman-6-yloxy)acetonitrile, 1H NMR (400 MHz, d6-DMSO) δ: 7.44-7.30 (m, 5H), 6.86-6.81(m, 3H), 5.08(dd,1H, J 9.8, 2.2 Hz), 5.07 (s, 2H), 2.97 (ddd, IH, J -16.9, 10.9, 6.0 Hz), 2.71 (ddd, IH, J - 16.9, 5.0, 3.4 Hz), 2.15 (m, IH), 1.97 (m, IH).

b) 2-(2-phenylchroman-6-yloxymethyl)-4,5-dihydro-1H-imidazole hydrochloride Dry gas HCl was passed through a solution of (2-phenylchroman-6-yloxy)acetonitrile (270mg) in

diethylether with the addition of 90 microliters of absolute ethanol while cooling in an ice bath. The reaction mixture was evaporated to dryness as the intermediate imidate was formed. The precipitate was dissolved in absolute ethanol with the addition of 252 microliters of ethylenediamine, which was poured into the cooled solution. The reaction mixture was then allowed to warm to room temperature, evaporated to dryness, dissolved in dichloromethane and washed with water. The combined organic layers were dried and treated with activated carbon. The compound 2-(2-phenylchroman-6-yloxymethyl)-4,5-dihydro-1H-imidazole was isolated as its HCl salt. 'H NMR (d4-

MeOH) 8: 7.5-7.2 (m, 5H), 6.85-6.75 (m, 3H), 5.01 (d, IH, J 8.8 Hz), 4.97 (s, 2H) 4.00 (s, 4H), 3.02-2.90 (m, IH), 2.80-2.70 (m, IH), 2.21-2.12 (m, IH), 2.05-1.90 (m, IH). (M)<+>=308

(100%)

Example 6:

6-(5-nitropyridin-2-yloxy)-2-phenylchroman-4-one

Compound 6-(5-nitropyridin-2-yloxy)-2-phenylchroman-4-one was prepared as described for compound 5-nitro-2-(2-phenylchroman-6-yloxy pyridine in Example 1(b) using 200 mg of 6-hydroxyflavan.<*>H NMR (400 MHz, d6-DMSO) 8: 9.03 (bs, IH), 8.64 (d, IH, J) 9.0 Hz), 7.59-7.41 (m, 7H), 7.31 (d, IH, J 9.0 Hz), 7.23 (d, IH, 8.8 Hz), 5.75 (dd, IH, J 12.3, 2.9 Hz), 3.30 (dd, IH, -16.3, 12.3 Hz), 2.87 (dd, IH, -16.3, 2.9 Hz).

Example 7:

7-(5-nitropyridin-2-yloxy)-2-phenylchroman

The compound 7-(5-nitropyridin-2-yloxy)-2-phenylchroman-4-one was prepared as described for 5-nitro-2-(2-phenylchroman-6-yloxy)pyridine in Example 1(b) using 150 mg of 7-hydroxyflavanone. 1H NMR (400 MHz, d6-DMSO) §: 9.07(d,lH, J 2.8 Hz) 8.67(dd, IH, J 9.0, 2.8 Hz), 7.89 (d, IH, 8.6 Hz), 7.60-7.35 (m, 6H), 7.04 (d, IH, 2.1 Hz), 6.97 (dd, 1 H, 8.6, 2.1 Hz), 5.75 (dd, IH, J 13.0, 2.7 Hz), 3.32 (dd, IH, 16.9, 13.0 Hz), 2.85 (d, -16.9, 2.7 Hz).

Example 8:

6-(5-nitropyridin-2-yloxy)-2-phenylchroman-4-ol

a) 2-phenylchroman-4,6-diol

To a suspension of the compound 6-hydroxyflavanone (l.Og.) in dry THF (1 l.5ml) addition

dropwise a solution of Boron-THF complex (12.5 ml, 1.0 M in THF) in a stream of nitrogen. The reaction took place under reflux for 1 hour. After cooling to room temperature, pour ice-cold 2 M HCl solution. The compound 2-phenylchroman-4,6-diol was then filtered off. 1H NMR (400 MHz, dć-DMSO) δ: 8.83 (s, IH), 7.45-7.38 (m, 4H), 7.35 (m, IH), 6.89 (d, IH, J 2.8 Hz), 6.59 (d, IH, J 8.7 Hz), 6.54 (dd, IH, J 8.7, 2.8 Hz), 5.41 (d, IH, J 7.0 Hz), 5.11 (dd, IH, J 11.7, 1.2 Hz), 4.87 (m, IH), 2.26 (m, IH), 1.90 (m, IH).

b) 6-(-5-nitropyridin-2-yloxy)-2-phenylchroman-4-ol

The compound 6-(5-nitropyridin-2-yloxy)-2-phenylchroman-4-ol was prepared as follows

described for 5-nitro-2-(2-phenylchroman-6-yloxy)pyridine in Example 1(b) starting from 1.5 g of 2-phenylchroman-4,6 diol. The product was passed through a silica gel column using toluene and ethyl acetate (4:1) as eluent. Crystallization performed from 2-propanol. 1H NMR (400 MHz, d6-DMSO) δ: 9.04 (d, IH, j 2.7 Hz), 8.61 (dd, IH, J 9.1, 2.7 Hz), 7.50-7.36 (m, 5H), 7.25 (d, IH, J 2.7 Hz), 7.22 (d, IH, 9.1 Hz), 7.00 (dd, IH J 8.7, 2.7 Hz), 6.88 (d, IH, J 8.7 Hz), 5.65 (d, IH, J 6.3 Hz), 5.30 (dd, IH, J 11.9, 1.3 Hz), 4.99 (m, IH) 2.33 (m, IH), 1.98 (m, IH).

Example 9:

2-[ 2-(3-fluorophenyl)chroman-6-yloxyl-5-nitropyridine

a) 2-(3-fluorophenyl)-6-hydroxychroman-4-one

The compound 2',5'-dihydroxyacetophenone (1.50 gr.) was dissolved in warm glacial

acetic acid (26ml) and then (1.35g) 3-fluorobenzaldehyde and (0.98g) ammonium acetate were added. The reaction mixture was refluxed for 2 hours. It was left to cool to room temperature and poured over ice. Precipitation and filtration yielded 2.2 g of a mixture of

2-(3-fluorophenyl)-6-hydroxychroman-4-one and 1-(2,5-dihydroxyphenyl)-3-(3-fluorophenyl)-propenone. The resulting mixture was dissolved in ethanol (90 ml) and sodium acetate in the amount of (1.75 g) was also added. The reaction mixture was reacted under reflux for 5 hours. After it was cooled to room temperature and diluted with water, it was filtered. The resulting 2-(3-fluorophenyl)-6-hydroxychroman-4-one was recrystallized from acetic acid. 1H NMR (400 MHz, d6-DMSO) δ: 9.45 (s, 1H), 7.47 (m, 1H), 7.40-7.37 (m, 2H), 7.22(m, 1H), 7.12 (d, 1H, J 3.0 Hz), 7.05 (dd, 1H, J 8.8, 3.0 Hz), 6.98 (d, 1H, J). 8.8 Hz), 5.59 DD,1H,J 13.0, 2.9 Hz), 3.21 (dd, IH, J - 16.9, 13.0 Hz), 2.82 (dd, IH, J- 16.9, 2.9 Hz).

b) 2-(3-fluorophenyl)chroman-4,6-diol

The compound 2-(3-fluorophenyl)chroman-4,6-diol was prepared as described for

2-phenylchroman-4,6-diol in Example 8(a), starting from 220 mg of 2-(3-fluorophenyl)-6-hydroxychroman-4-one. 1H NMR (400 MHz, d6-DMSO) δ: 8.85 (s, 1H), 7.45(m, 1H), 7.30-7.25 (m, 2H),

7.15 (m, IH), 6.88 (d, IH, J 2.8 Hz), 6.62 (d,lH, J 8.7 Hz), 6.55 (dd, IH, J 8.7, 2.8 Hz), 5.44 (d, IH, J 7.0 Hz), 5.15 (d, IH, J 10.7 Hz), 4.86 (m, IH), 2.29 (m, IH), 1.86 (m, IH).

c) 2-(3-fluorophenyl)chroman-6-ol

Triethylsilane (960 microliters) was poured slowly into a solution of 2-(3-fluorophenyl)chroman-4,6-diol (195mg) in dichloromethane solvent (4ml). (1.9 ml) of trifluoroacetic acid was then added to the reaction mixture in drops, and then the mixture was kept on a stirrer at room temperature for another 5 hours. After that, the reaction mixture was poured into ice water and extracted with dichloromethane. The residue was evaporated under reduced pressure in the presence of toluene to give 2-(3-fluorophenyl)chroman-6-ol. 1 H NMR (400 MHz, d6-DMSO) δ: 8.78 (s, IH), 7.43 (m, IH), 7.28-7.25 (m, 2H), 7.14 (m, IH), 6.66 (d, IH, J 8.5 Hz), 6.52

(dd, IH, J 8.5, 2.7 Hz), 6.49 (d, IH, J 2.7 Hz), 5.03 (dd, IH, J 9.9, 2.1 Hz), 2.86 (m, IH), 2.63 (m, IH), 2.13 (m, IH), 1.93 (m, IH).

d) 2-[2-(3-fluorophenyl)chroman-6-yloxy]-5-nitropyridine

The compound 2-[2-(3-fluorophenyl)lyroman-6-yloxy]-5-nitropyridine was prepared in the same way

as well as in the procedure described for 5-nitro-2-(-2-phenylchroman-6-yloxy)pyridine, in Example 1(b) starting from 210 mg of 2-(3-fluorophenyl)chroman-6-ol. The product was then recrystallized from 2-propanol. <]>H NMR (400 MHz, CDCl 3 ) δ: 9.07 (d,1H,J 2.8 Hz), 8.46 (dd, IH, J 9.0, 2.8 Hz), 7.36 (m, IH), 7.21-7.15 (m, 2H), 7.03 (m, IH), 7.01 (d, IH, J 9.0 Hz), 6.98 (d, IH, J 8.6 Hz), 6.92 (dd, IH, J 8.6, 2.7 Hz), 6.90 (d, IH, J 2.7 Hz), 5.09 (dd, IH, J 10.3, 2.4 Hz), 3.01 (ddd, IH, J-16.9, 11.4, 6.0 Hz), 2.82 (ddd, IH, J-16.9, 5.1, 3.2 Hz) 2.24 (m, IH), 2.09 (m, IH).

Example 10:

5-nitro-2-(2-phenylchroman-7-yloxy)pyridine

a) 2-phenylchroman-7-ol

The compound 2-phenyl-chroman-7-ol was prepared according to the procedure described for 5-nitro-2-(2-phenylchroman-yloxy)pyridine in Example 1(a) starting from 1.0 g of 7-hydroxy flavanone. The product was purified on a chromatography column, using the solvent heptane-ethyl acetate in the ratio (2:1) as eluent. 1H NMR (400 MHz, CD3OD) δ: 7.41-7.28 (m, 5H), 6.86 (d, IH, J 8.2 Hz), 6.32 (dd, IH, J 8.2, 2.4 Hz), 6.29 (d, IH, J 2.4 Hz), 5.00 (dd, IH J 9.9, 2.4 Hz), 2.84 (m, IH), 2.64 9m, IH), 2.15 (m, IH), 1.99 (m, IH).

b) 5-nitro-2(2-phenylchroman-7-yloxy)pyridine

The compound 5-nitro-2-(2-phenylchroman-7-yloxy)pyridine was prepared as described

for 5-nitro-2-(2-phenylchroman-6-yloxy)pyridine in Example 1(b) starting from 115 mg of 2-phenylchroman-7-ol. The product was purified on a thin layer by preparative chromatography, over silica gel and using the eluent toluene-ethyl acetate in the ratio (15:1). <!>H NMR (400 MHz, dć-DMSO) δ: 9.04 (d,lH, J 2.8 Hz), 8.60 (dd, IH, J 9.1, 2.8 Hz), 7.46-7.32 (m, 5H), 7.22 (d, IH, J 9.1 Hz), 7.20 (d, IH, J 8.9 Hz), 6.72 (dd, IH, 8.9, 2.3 Hz), 6.72 (d, IH, J 2.3 Hz), 5.16 (dd, IH, J 10.1, 2.1 Hz), 2.97 (ddd, IH, J-16.7, 11.3, 5.9 Hz), 2.77 (ddd, IH, J-16.7, 8.1, 4.5 Hz) 2.20 (m, IH), 2.02 (m, IH).

Example 11:

2-[ 2-( 2, 4- dichlorophenyl) chroman- 6- yloxyl- 5- nitropyridine

a) 2-(2,4-dichlorophenyl)-6-hydroxychroman-4-one

The compound 2-(2,4-dichlorophenyl)-6-hydroxychroman-4-one was prepared as

described for 2-(3-fluorophenyl)-6-hydroxychroman-4-one in Example 9(a) starting from 1.Og. 2',5'-dihydroxyacetophenone and 1,4g 2-(2,4-dichlorobenzaldehyde. The product was recrystallized from acetic acid. 1H NMR (400 MHz, d6-DMSO) δ: 9.49 (s, IH), 7.78 (d, IH, J 8.5 Hz), 7.71 (d, IH, J 2.0 Hz), 7.57 (dd, IH, J 8.5, 2.0 Hz), 7.14 (d, IH, J 3.0 Hz), 7.06 (dd, IH, J 8.8, 3.0 Hz), 6.97 (d, IH, J 8.8 Hz), 5.77 (dd, IH, J 13.5, 2.7 Hz), 3.18 (dd, IH, J-16.9, 13.5 Hz), 2.78 (dd, IH, J-16.9, 2.7 Hz).

b) 2-(2,4-dichlorophenyl)chroman-4,6-diol

The compound 2-(2,4-dichlorophenyl)chroman-4,6-diol was prepared as described for

2-Phenylchroman-4,6-diol in Example 8(a) starting from 1.2g. 2-(2,4-dichlorophenyl)-6-hydroxychroman-4-one. The product was purified by column chromatography using heptane - ethyl acetate in the ratio (2:1) as eluent. 1H NMR (400 MHz, d6-DMSO) δ: 8.89 (s, IH), 7.66 (d, IH, J 2.1 Hz), 7.64 (d, IH, J 8.5 Hz), 7.51 (dd, IH, J 2.1, 8.5 Hz), 6.89 (d, IH, J

2.7 Hz), 6.63 (d, IH, J 8.7 Hz), 6.56 (dd, IH, J 2.7, 8.7 Hz), 5.50 (d, IH, J 6.8 Hz), 5.37 (d, IH J 10.4 Hz), 4.90 (m, IH), 2.32 (m, IH), 1.80 (m, IH).

c) 2-(2-4-dichlorophenyl)chroman-6-ol

The compound 2-(2,4-dichlorophenyl)chroman-6-ol was synthesized according to the procedure described for

2-(3-Fluorophenyl)chroman-6-ol in Example 9(c), starting from 625 mg of 2-(2,4-dichlorophenylphenyl)chroman-4,6-diol. <!>H NMR (400MHz, d6-DMSO) 5 : 8.85 (s,lH), 7.65 (d, IH, J 2.2 Hz), 7.57 (d, IH, J 8.4 Hz). 7.49 (dd, IH, J 8.4, 2.2 Hz), 6.67-6.51 (m, 3H), 5.21 (dd, IH J 10.3, 2.1 Hz), 2.91 (m, IH), 2.69 (m, IH), 2.16 (m, IH), 1.85 (m, IH).

d) 2-[2-(2,4-dichlorophenyl)chroman-6-yloxy]-5-nitropyridine

The compound 2-[2-(2,4-dichlorophenyl)chroman-6-yloxy]-5 nitropyridine was synthesized by

by the procedure described for 5-nitro-2-(2-phenylchroman-6-yloxy)pyridine in Example 1(b) starting from 530mg. 2-(2,4 dichlorophenyl)chroman-6-ol. The product was preparatively purified on plates

with silica gel using a combination of heptane - ethyl acetate in the ratio (3:1) as eluent. 1 H NMR (400 MHz, CDCl 3 ) δ: 9.06 (d, IH, J 2.7 Hz), 8.47 (dd, IH, J 9.0, 2.7 Hz), 7.56 (d, IH, J 8.4 Hz), 7.41 (d, IH, J 2.0 Hz), 7.33 (dd, IH, J 8.4, 2.0 Hz), 7.02 (d, IH, J 9.0 Hz) 6.99-6.92 (m, 3H), 5.39 (dd, IH, J 10.4,2.2 Hz), 3.06 (ddd, IH, J-16.9, 11.9, 6.0 Hz), 2.83 (ddd, IH, J-16.9, 5.3, 2.7 Hz) 2.34 (m, IH) 1.89 (m, IH).

Example 12:

2-[2-(3-chlorophenyl)chroman-6-yloxy1-5-nitropyridine

a) 2-(3-chlorophenyl)-6-hydroxychroman-4-one

The compound 2-(3-chlorophenyl)-6-hydroxychroman-4-one was synthesized according to the synthesis procedure

of 2-(3-fluorophenyl)-6-hydroxychroman-4-one in Example 9(a) starting from 2.0 g of 2',5' dihydroxyacetophenone and 1.85 g. 3-chlorobenzaldehyde. The product was recrystallized from acetic acid solution. HNMR (400 MHz, d6-DMSO) δ: 9.47 (s,1H), 7.62 (s,1H), 7.51-7.45 (m, 3H), 7.12 (d, IH, J 3.0 Hz), 7.05 (dd, IH, J, 8.8, 3.0 Hz), 6.98 (d, IH, J 8.8 Hz), 5.58 (dd, IH, J 13.1, 2.9 Hz), 3.18 (dd, IH, J-16.9, 13.1 Hz), 2.81 (dd, IH, J-16.9, 2.9 Hz).

b) 2-(3-chlorophenyl)chroman-4,6-diol

Compound 2-(3-chlorophenyl)chroman-4,6-diol was prepared as described in the synthesis of 2-phenylchroman-4,6-diol in Example 8(a), starting from 730 mg of 2-(3-chlorophenyl)-6-hydroxychroman-4-one. 1H NMR (400 MHz, d6-DMSO) δ: 8.85 (s, IH), 7.50 (d, IH, J 1.7 Hz), 7.46-7.38 (m, 3H), 6.88 (d, IH, J 2.5 Hz), 6.62 (d, IH, J 8.6 Hz), 6.55 (dd,lH, J 8.6 Hz), 5.44 (d, IH, J 6.6 HZ), 5.15 (dd, IH, J 11.8, 1.4 Hz), 4.87 (m, IH), 2.29 (m, IH), 1.85 (m, IH).

c) 2-(3-chlorophenyl)chroman-6-ol

The compound 2-(3-chlorophenyl)chroman-6-ol was synthesized in the same manner as in the synthesis of 2-(3-chlorophenyl)chroman-6-ol in Example 9(c), starting from 635 mg of 2-(3-chlorophenyl)chroman-4,6-diol.

1H NMR (300MHz, d6-DMSO) δ: 8.79 (s, IH), 7.48 (d, IH, J 0.7 Hz), 7.42-7.37 (m, 3H), 6.71-6.49 (m, 3H), 5.04 (m, IH), 2.91 (m, IH), 2.65 (m, IH), 2.12 (m, IH), 1.93 (m, IH).

d) 2-[2-(3-chlorophenyl)chroman-6-yloxy]-5-nitropyridine

The compound 2-[2-(3-chlorophenyl)chroman-6-yloxy]-5-nitropyridine was synthesized according to

to the description for the synthesis of 5-nitro-2-(2-phenylchroman-6-yloxy)pyridine in Example 1(b) starting from 590 mg

2-(3-chlorophenyl)chroman-6-ol. The product was recrystallized from a mixture (3:1) of 2-propanol and ethyl acetate. 1H NMR (400 MHz, CDCl3) δ: 9.04 (d, IH, J 2.9 Hz), 8.60 (dd, IH, 9.0, 2.9 Hz), 7.53 (s, IH), 7.46-7.42 (m, 3H), 7.20 (d, IH J 9.0 Hz), 7.00 (dd, IH, J 8.7, 2.7 Hz), 6.97 (d, III, J 2.7 Hz), 6.94 (d, IH J 8.7 Hz), 5.18 (dd, IH, J 10.2, 2.2 Hz), 2.97 (ddd, IH, J-17.0, 11.5. 5.9 Hz), 2.83 (ddd, IH, J-17.0, 8.1, 4.5 Hz), 2.21 (m, IH), 2.00 (m, 1H).

Example 13:

2-[2-(315-difluorophenyl)chroman-6-yloxy]-5-nitropyridine

a) 2-(3,5-difluorophenyl)-6-hydroxychroman-4-one

The compound 2-(3,5-difluorophenyl)-6-hydroxyliroman-4-one was synthesized according to the description of the synthesis

2-(3-fluorophenyl)-6-hydroxychroman-4-one in Example 9(a), starting from 1.0 g of 2',5'-hydroxy-acetophenone and 1.12 g of 3,5-difluorobenzaldehyde. The resulting product was recrystallized from acetic acid.<*>H NMR (400 MHz, d6-DMSO) δ: 9.47 (s, IH), 7.30-7.23 (m, 3H), 7.12 (d, IH, J 2.9 Hz), 7.06 (dd, IH, J 8.8, 2.9 Hz), 7.00 (d, IH, J 8.8 Hz), 5.60 (dd, IH, J 13.1, 2.8 Hz), 3.15 (dd, IH, J-16.8, 13.1 Hz), 2.85 (dd, IH, J-16.8, 2.8 Hz).

b) 2-(3,5 difluorophenyl)chroman-4,6-diol

The compound 2-(3,5 difluorophenyl)chroman-4,6-diol was synthesized as described for

synthesis of 2-phenylchroman-4,6-diol as in Example 8(a), starting from 800 mg of 2-(3,5-difluorophenyl)-6-hydroxychroman-4-one. 1H NMR (400 MHz, d6-DMSO) δ: 8.87 (s, IH), 7.21-7.17 (m, 3H), 6.88 (d, IH, J 2.4 Hz), 6.64 (d, IH, J 8.7 Hz), 6.55 (dd, IH, J 2.4, 8.7 Hz), 5.47 (d, IH, J 7.0 Hz), 5.17 (d, IH, J 10.5 Hz), 4.86 (m, IH), 2.32 (m, IH), 1.85 (m, IH).

c) 2-(3,5-difluorophenyl)chroman-6-ol

The compound 2-(3,5-dichlorophenyl)chroman-6-ol was synthesized as 2-(3-fluorophenyl)chroman-6-ol in Example 9(c) starting from 500 mg of 2-(3,5-difluorophenyl)chroman-4,6-diol. 1H NMR (300 MHz, d6-DMSO) δ: 8.82 (s, IH), 7.20-7.14 (m, 3H), 6.68 (d, IH, J 8.6 Hz), 6.53 (d, IH, J 2.9 Hz), 6.50 (dd, IH, J 8.6, 2.9 Hz), 5.05 (dd, IH, J 9.8, 2.2 Hz), 2.88 (ddd, IH, J-16.7, 10.8, 5.9 Hz), 2.62 (ddd, IH, J-16.7, 8.9, 5.0 Hz), 2.15 (m, IH), 1.93 (m,

IH).

d) 2-[2-(3,5-difluorophenyl)chroman-6-yloxy]-5-nitropyridine The compound 2-[2-(3,5-difluorophenyl)chroman-6-yloxy]-5-nitropyridine was synthesized according to the description

for 5-nitro-2-(2-phenylchroman-6-yloxy)pyridine in Example 1(b), starting from 340 mg of 2-(3,5-difluorophenyl)chroman-6-ol. Purification of the product was carried out preparatively on TCL plates coated with silica gel and using a mixture of toluene ethyl acetate for eluent and 2-propanol for crystallization. 1H NMR (400 MHz, d6-DMSO) δ: 9.04 (d, IH, J 2.9 Hz), 8.60 (dd, IH, J 9.1 2.9 Hz), 7.23-7.19 (m, 4H), 7.01-6.95 (m, 3H), 5.18 (dd, IH, J 10.0, 2.1 Hz), 2.97 (ddd, IH, J-16.9, 10.9, 5.7 Hz), 2.76 (ddd, IH, J-16.9, 8.4, 4.7 Hz), 2.22 (m, IH), 1.99 (m, IH).

Example 14:

2-[ 2-(2, 5- difluorophenyl) chroman-6- yloxy]- 5- nitropyridine

a) 2-(2,5-difluorophenyl)-6-hydroxychroman-4-one

The compound 2-(2,5-difluorophenyl)-6-hydroxychroman-4-one was synthesized as 2-(3-fluorophenyl)-6-hydroxychroman-4-one in Example 9(a), starting from 3.0 g of 2',5' dihydroxyacetophenone and 2.57 ml of 2,5 difluorobenzaldehyde. The resulting product was recrystallized from acetic acid.<*>H NMR (300 MHz, oVDMSO) δ: 9.46 (s, IH), 7.53 (m, IH), 7.36-7.30 (m, 2H), 7.14 (d, IH, J 3.0 Hz), 7.05 (dd, IH, J 8.8, 3.0 Hz), 6.97 (d, IH, J 8.8 Hz), 5.76 (dd, IH, J 13.6, 2.7 Hz), 3.26 (dd, IH, J-16.8, 13.6 Hz), 2.76 (dd, IH, J-16.8, 2.7 Hz).

b) 2-(2,5-difluorophenyl)chroman-4,6-diol

The compound 2-(2,5-difluorophenyl)chroman-4,6-diol was synthesized according to the description for 2-phenylchroman-4,6-diol of Example 8(a), starting from 1.0g.-2-(2,5-difluorophenyl)-6-hydroxychroman-4-one-a. 1H NMR (400 MHz, d6-DMSO) δ: 8.87 (s, 1H), 7.39-7.22 (m, 3H), 6.89 (d, 1H, J 6.8 Hz), 6.63 (d, 1H, J 8.7 Hz), 6.56 (dd, 1H, J 8.7, 2.8 Hz), 5.50 (d, 1H, J 6.8 Hz), 5.35 (d, IH, J 11.2 Hz), 4.89 (m, IH), 2.28 (m, IH), 1.95 (m, IH).

c) 2-(2,5-difluorophenyl)chroman-6-ol

The compound 2-(2,5-difluorophenyl)chroman-6-ol was synthesized as described for 2-(3-fluorophenyl)chroman-6-ol in Example 9(c) starting from 420 mg of 2-(2,5-difluorophenyl)chroman-4,6-diol. ]H NMR (300 MHz, d6-DMSO) δ: 8.82 (s, 1H), 7.34-7.22 (m, 3H), 6.71-6.51 (m, 3H), 5.20 (m, 1H), 2.93 (m, 1H), 2.68 (m, 1H), 2.11 (m, 1H), 1.98 (m, 1H).

d) 2-[2-(2,5-difluorophenyl)chloronan-6-yloxy]-5-nitropyridine

The compound 2-[2-(2,5-difluorophenyl)chroman-6-yloxy]-5-nitropyridine was synthesized

as described for 5-nitro-2-(2-phenylchroman-6-yloxy)pyridine in Example 1 (b), starting from 100mg of 2-(2,5-difluorophenyl)chroman-6-ol. The product was recrystallized from 2-propanol.<*>H NMR (400 MHz, CDCl3) δ: 9.07 (dd, IH, J 2.8, 0.4 Hz), 8.47 (dd, IH, J 9.1, 2.8 Hz), 7.26 (m, IH), 7.05-6.91 (m, 6H), 5.35 (dd, 1H,J) 10.3, 1.5 Hz), 3.04 (ddd, IH, J-16.9, 11.7, 6.0 Hz), 2.82 (ddd, IH, J-16.9, 5.2, 3.0 Hz), 2.29 (m, IH), 2.01 (m, IH).

Example 15:

2-[2-(3-bromophenyl)chroman-6-yloxy1-5-nitropyridine

a) 2-(3-bromophenyl)-6-hydroxychroman-4-one

The compound 2-(3-bromophenyl)-6-hydroxychroman-4-one was synthesized as described

for 2-(3-fluorophenyl)-6-hydroxychroman-4-one from Example 9(a) starting from 3.0 g of 2',5'-dihydroxyacetophenone and 2.3 ml of 3-bromobenzaldehyde. The resulting product was recrystallized from acetic acid. 1H NMR (300MHz, oVDMSO) δ: 9.41 (s, IH), 7.50 (m, IH), 7.59-7.53 (m, 2H), 7.39 (m, IH), 7.12 (d, IH, J 2.9 Hz), 7.05 (dd, IH, J 8.8, 2.9 Hz), 6.98 (d, IH, J 8.8 Hz), 5.57 (dd, IH, J 13.0, 2.9 Hz), 3.12 (dd, IH, J-16.9, 13.0 Hz), 2.81 (dd, IH, J-16.9, 2.9 Hz).

b) 2-(3-bromophenyl)chroman-4,6-diol

The compound 2-(3-bromophenyl)chromane-4,6-diol was synthesized as well as 2-phenylchromane-4,6-diol

from Example 8(a) starting from 1.0 g of 2-(3-bromophenyl)-6-hydroxychroman-4-one.<*>H NMR (300 MHz, d6-DMSO) δ: 8.83 (s,lH), 7.63 (m, IH), 7.53 (m, IH) 7.46 (m, IH) 7.37 (m, IH), 6.88 (d, IH, J) 2.9 Hz), 6.62 (d, IH, J 8.7 Hz), 6.55 (dd, IH, J 8.7, 2.9 Hz), 5.42 (d, IH, J 7.0 Hz), 5.14 (d, IH, J 10.5 Hz), 4.86 (m, IH), 2.29 (m, IH), 1.84 (m, IH).

c) 2-(3-bromophenyl)chroman-6-ol

Compound 2-(3-bromophenyl)chroman-6-ol was synthesized as described for 2-(3-fluorophenyl)chroman-6-ol of Example 9(c), starting from 700 mg of 2-(3-bromophenyl)chroman-4,6-diol. <!>H NMR (400 MHz, d6-DMSO) 8: 8.81 (s, 1H), 7.61 (m, 1H). 7.51 (m, IH), 7.43 (m, IH), 7.35 (m, IH), 6.67-6.48 (m, 3H), 5.01 (m, IH), 2.87 (m, IH), 2.63 (m, IH), 2.12 (m, IH), 1.92 (m, IH).

d) 2-[2-(3-bromophenyl)chroman-6-yloxy]-5-nitropyridine

The compound 2-[2-(3-bromophenyl)chroman-6-yloxy]-5-nitropyridine was prepared as described

for 5-nitro-2-(2-phenylchroman-6-yloxy)pyridine from Example 1(b) starting from 339 mg of 2-(3-bromophenyl)chroman-6-ol. The product was filtered through a silica gel column and eluted with a toluene-ethyl acetate mixture. Crystallization was from 2-propanol.<*>H NMR (400 MHz, CDCl3) δ: 9.04 (d, IH, J 2.9 Hz), 8.60 (dd, IH, J 9.2, 2.9 Hz), 7.66 (bs, IH), 7.55 (m, IH), 7.48 (m, IH), 7.39 (m, IH), 7.20 (d, IH, J 9.2 Hz) 7.01-6.93 (m, 3H), 5.17 (dd, IH, J 10.1, 2.2 Hz), 2.97 (m, IH,), 2.72 (m, IH) 2.20 (m, IH), 2.00 (m, IH).

Example 16:

2-[ 2-(4-ethylphenyl)chroman-6-yloxyl-5-nitropyridine

a) 2-(4-ethylphenyl)-6-hydroxychroman-4-one

The compound 2-(4-ethylphenyl)-6-hydroxychroman-4-one was synthesized as described for 2-(3-fluorophenyl)-6-hydroxychroman-4-one of Example 9(a), starting from 1.0 g of 2',5'-dihydroxyacetophenone and 0.8 ml of 4-ethylbenzaldehyde. The obtained product was recrystallized from acetic acid. *H NMR (400 MHz, d6-DMSO) δ: 7.43 (d, 2H, J 8.1 Hz), 7.25 (d, 2H, J 8.1 Hz), 7.11 (d, IH, J 3.1 Hz), 7.03 (dd, IH, J 8.9, 3.1 Hz), 6.93 (d, IH, J 8.9 Hz), 5.51 (dd, IH, J 13.0, 2.9 Hz), 3.15 (dd, IH, J-16.9, 13.0 Hz), 2.75 (dd, IH, J-16.9, 2.9 Hz), 2.62 (q, 2H, J 7.5 Hz), 1.18 (t, 3H, J 7.5 Hz).

b) 2-(4-ethylphenyl)chroman-4,6-diol

The compound 2-(4-ethylphenyl)chroman-4,6-diol was synthesized according to the description for 2-phenylchroman-4,6-diol in Example 8(a) starting from 474 mg of 2-(4-ethylphenyl)-6-hydroxychroman-4-one.

1H NMR (400 MHz, d6-DMSO) δ: 8.81 (s,1H), 7.34 (d, 2H, J 8.0 Hz) 7.22 (d, 2H, J 8.0 Hz) 6.88 (d, IH, J 2.8 Hz), 6.57 (d, IH, J 8.6 Hz), 6.53 (dd, IH, J 8.6 Hz) 2.8 Hz), 5.39 (d, IH, J 7.1 Hz), 5.06 (d, IH, J 10.7 Hz), 4.86 (m, IH), 2.61 (q, 2H, J 7.6 Hz), 2.29 (m, IH), 1.84 (m, IH), 1.19 (t, 3H, J 7.6 Hz).

c) 2-(4-ethylphenyl)chroman-6-ol

The compound 2-(4-ethylphenyl)chroman-6-ol was synthesized according to the procedure described for 2-(3-fluorophenyl)chroman-6-ol of Example 9(c), starting from 425 mg of 2-(4-ethylphenyl)chroman-4,6-diol. The product was purified using heptane and ethyl acetate in the ratio (3:1) as eluent. 1H NMR (400 MHz, CD3OD) δ: 7.26 (d,2H, J 8.2 Hz) 7.13 (d, 2H, J 8.2 Hz), 6.65 (d, IH, J 8.6 Hz), 6.65 (d, IH, J 8.6 Hz), 6.55 (dd, IH, J 8.6 2.8 Hz), 6.51 (d, IH, J 2.8 Hz), 4.83 (dd, IH, J 10.1, 2.3 Hz), 2.84 (m, IH), 2.62 (m, IH), 2.59 (q, 2H, J 7.6 Hz), 2.03 (m, IH), 1.93(m, IH), 1.19 (t, 3H, J 7.6 Hz).

d) 2-[2-(4-ethylphenyl)chroman-6-yloxy]-5-nitropyridine

The compound 2-[2-(4-ethylphenyl)chroman-6-yloxy]-5-nitropyridine was synthesized as

described for -5-nitro-2-(2-phenylchroman-6-yloxy)pyridine from Example 1(b) starting from 205 mg of 2-(4-ethylphenyl)chroman-6-ol. The product was recrystallized from a mixture of 2-propanyl and acetone.<*>H NMR (400 MHz, CDCl3) δ: 9.04 (d, IH J 2.8 Hz), 8.60 (dd, IH, J 9.1, 2.8 Hz), 7.36 (d, 2H, J 8.1 Hz), 7.24 (d, 2H, J 8.1 Hz), 7.20 (d, IH, J 9.1 Hz), 7.00 (d, IH, J 2.7 Hz), 6.96 (dd, IH, J 8.8, 2.7 Hz), 6.89 (d, IH, J 2.7 Hz), 5.11 (dd, IH, J 10.1, 2.2 Hz), 2.98 (m, IH), 2.75 (m, IH), 2.62 (q, 2H, J 7.5 Hz), 2.16 (m, IH), 2.01 (m, IH), 1.19 (t, 3H, J 7.5 Hz).

Example 17:

2-(3-methyl-2-phenylchroman-6-yloxy)-5-nitropyridine

a) 6-hydroxy-3-methyl-2-phenylchroman-4-one

The synthesized compound 6-hydroxy-3-methyl-2-phenylchroman-4-one was obtained by

the procedure described for 2-(3-fluorophenyl)-6-hydroxychroman-4-one, in Example 9(a) starting from 2.0 g of 2,5-dihydroxypropiophenone and 1.63 ml of benzaldehyde. The product was purified on a column chromatography with an eluent composed of heptane and ethyl acetate (3:1).<*>H NMR (300 MHz, d(,-DMSO) 5: 9.37 (s, IH), 7.53 (m, 2H), 7.47-7.39 (m, 3H), 7.13 (d, IH, J 3.1 Hz), 7.02 (dd, IH, J 8.9, 3.1 Hz), 6.89 (d, IH, J 8.9 Hz), 5.17 (d, IH, J 12.3), 3.18 (dq, IH, J 12.3, 6.9 Hz), 0.84 (d, 3H, J 6.9 Hz).

b) 3-methyl-2-phenylchroman-4,6-diol

The compound 3-methyl-2-phenylchroman-4,6-diol was synthesized as described in the procedure

for 2-phenylchroman-4,6-diol in Example 8(a) starting from 474 mg of 6-hydroxy-3-methyl-2-phenylchroman-4-one. <]>H NMR (300 MHz, d6-DMSO) 8: 8.79 (s, 1H), 7.42-7.33 (m, 5H), 6.88 (bs, 1H), 6.53 (m, 2H). 5.37 (d, IH, J 8.0 Hz), 4.70 (d, IH, J 10.6 Hz), 1.94 (m, IH), 0.73 (d, 3H, J 6.7 Hz).

c) 3-methyl-2-phenylchroman-6-ol

The compound 3-methyl-2-phenylchroman-6-ol was synthesized for 2-(3-fluorophenyl)chroman-6-ol in

Example 9(c), starting from 605 mg of 3-methyl-2-phenylchroman-4,6-diol. 1H NMR (400 MHz, CD3OD) δ: 8.77 (s, IH), 7.41-7.33 (m, 5H), 6.59-6.48 (m, 3H), 4.56 (d, IH J 9.2 Hz), 2.73 (dd, IH, J-16.5, 5.0 Hz), 2.54 (dd, IH, J-16.5, 5.8 Hz), 2.11 (m, IH), 0.72 (d, 3H, J 6.6 Hz).

d) 2-(3-methyl-2-phenylchroman-6-yloxy)-5-nitropyridine

The compound 2-(3-methyl-2-phenylchroman-6-yloxy)-5-nitropyridine was synthesized as follows

described for 5-nitro-2-(2-phenylchroman-6-yloxy)pyridine in Example 1(b), starting from 600 mg of 3-methyl-2-phenylchroman-6-ol. The product was purified on column chromatography using heptane - 2-propanol (20:1) as eluent.<*>H NMR (400 MHz, d6-DMSO) δ: 9.04 (d, IH, J 2.8 Hz), 8.59 (dd, IH, J 9.1, 2.8 Hz), 7.43-7.36 (m, 5H), 7.19 (d, IH, J). 9.1 Hz), 7.00 (d, IH, J 2.6 Hz), 6.95 (dd, IH, J 8.7, 2.6 Hz), 6.86 (d, IH, J 8.7 Hz), 4.73 (d, IH, J 9.3 Hz), 2.85 (dd, IH, J-16.7, 5.0 Hz), 2.64 (dd, IH, J-16.7, 5.0 Hz) J-16.5, 10.9 Hz), 2.18 (m, IH), 0.77 (d, 3H, J 6.7 Hz).

Example 18:

3- methyl- 6-( 5- nitropyridin- 2- yloxy)- 2- phenylchroman- 4- one

The compound 3-methyl-6-(5-nitropyridin-2-yloxy)-2-phenylchroman-4-one was synthesized as described for 5-nitro-2-(2-phenylchroman-6-yloxy)pyridine in Example 1(b) starting from 200 mg of the compound 6-hydroxy-3-methyl-2-phenylchroman-4-one. The product was purified on a chromatographic column using the eluent heptane - ethyl acetate in the ratio (2:1). Crystallization was then carried out from a mixture of 2-propanol and acetone. 1H NMR (400 MHz, d6-DMSO) δ: 9.03 (d, IH, J 2.9 Hz), 8.64 (dd, IH, J 9.1, 2.9 Hz), 7.59-7.56 (m, 3H), 7.50-7.32 (m, 4H), 7.30 (d, IH, J 9.1 Hz), 7.18 (d, IH, J 8.9 Hz), 5.38 (d, IH, J 12.5 Hz), 3.36 (dd, IH, J 12.5, 6.9 Hz), 0.86 (d, 3H, J 6.9 Hz).

Example 19:

2- r2-(2-fluorophenyl)chroman-6-yloxy1-5-nitropyridine

a) 2-(2-fluorophenyl)-6-hydroxychroman-4-one

The compound 2-(2-fluorophenyl)-6-hydroxychroman-4-one was synthesized according to the description for 2-(3-fluorophenyl)-6-hydroxychroman-4-one in Example 9(a) starting from 2.0 g of the compound 2', 5'-dihydroxyacetophenone and 1.4 ml of 2-fluorobenzaldehyde. The resulting product was recrystallized from acetic acid. ]H NMR (400 MHz, d6-DMSO) δ: 9.45 (s, IH), 7.67 (m, IH), 7.47 (m, IH), 7.32-7.25 (m, 2H), 7.14 (d, IH, J 3.0 Hz), 7.04 (dd, IH, J 8.9, 3.0 Hz), 6.95 (d, IH, J 8.9 Hz), 5.77 (dd, IH, J 13.5, 2.8 Hz), 3.26 (dd, IH, J-16.9, 13.5 Hz), 2.76 (dd, IH, J-16.9, 2.8 Hz).

b) 2-(2-fluorophenyl)chroman-4,6-diol

The 2-(2-fluorophenyl)chroman-4,6-diol compound was synthesized as described for 2-phenylchroman-4,6-diol in Example 8(a) starting from 1.19g of 2-(2-fluorophenyl)6-hydroxychroman-4-one. 1H NMR (400 MHz, d6-DMSO) δ: 8.85 (s, IH), 7.56 (m, IH), 7.40 (m, IH), 7.28-7.21 (m, 2H), 6.89 (d, IH, J 2.9 Hz), 6.60 (d, IH, J 8.7 Hz), 6.54 (dd, IH, J 8.7 Hz). 2.8 Hz), 5.46 (d, IH, J 6.9 Hz), 5.35 (d, IH, J 10.6 Hz), 4.89 (m, IH), 2.26 (m, IH), 1.98 (m, IH).

c) 2-(2-fluorophenyl)chroman-6-ol

The compound 2-(2-fluorophenyl)chroman-6-ol was synthesized according to the description for 2-(3-fluorophenyl)chroman-6-ol from Example 9(c), starting from 800 mg of 2-(2-fluorophenyl)chroman-4,6-diol.

1H NMR (300 MHz, d6-DMSO) δ: 7.50 (m, IH), 7.39 (m, IH), 7.26-7.19 (m, 2H), 6.63 (m, IH) 6.53-6.50 (m, 2H), 5.21 (dd, IH, J 10.2, 2.3 Hz), 2.98 (ddd, IH, J-16.9, 11.2,6.0 Hz), 2.66 (ddd, IH, J-16.9, 5.0, 2.9 Hz), 2.11 (m, IH), 1.99 (m, IH).

d) 2-[2-(2-fluorophenyl)chroman-6-yloxy]-5-nitropyridine

The compound 2-[2-(2-fluorophenyl)chroman-6-yloxy]-5-nitropyridine was synthesized as

described for 5-nitro-2-(2-phenylchroman-6-yloxy)pyridine in Example 1(b) starting from 390 mg of the compound 2-(2-fluorophenyl)chroman-6-ol. The resulting product was purified by column chromatography using heptane - ethyl acetate in the ratio (4:1) as eluent.<*>H NMR (400 MHz, CDCl3) δ: 9.04 (d, IH, J 2.8 Hz), 8.60 (dd, IH, J 9.1, 2.8 Hz), 7.56 (m, IH), 7.43 (m, IH), 7.30-7.22 (m, 2H), 7.20 (d, IH, J 9.1 Hz), 7.02 (d, IH, J 2.8.Hz), 6.98 (dd, IH, J 8.7 Hz), 6.91 (d, IH, J 8.7 Hz), 5.37 (dd, IH, J 10.6,2.3 Hz), 3.04 (ddd, IH, J-17.0, 11.5, 6.0 Hz), 2.82 (ddd, IH, J-17.0, 5.1 2.8 Hz) 2.18 (m, IH), 2.08 (m, IH).

Example 20:

2-( 2, 3- dihydro- 2- phenyl- benzori, 41- doxin- 6- yloxy)- 5- nitropyridine

a) 1-[2,5-Bis(benzyloxy)phenyl]ethanone

A combination composed of 1-(2,5-dihydroxyphenyl)ethanone (3.16g), benzyl chloride

(7.04g), potassium carbonate (12.4g) and 18-Crown-6 (30mg) in 2-butanone (50ml) was heated under reflux for 5 hours. After cooling, the resulting precipitate was filtered. The filtrate was evaporated to dryness under reduced pressure, and then 50 ml of ether was added to the dry residue. The solution was then washed twice with dilute sodium hydroxide (NaOH) solution, and then twice with dilute hydrochloric acid. After that, the solution was dried over sodium sulfate, and only then was it evaporated to dryness under reduced pressure. The residue was then triturated with cold n-heptane (30 ml) and the precipitate was filtered off under vacuum, yielding after drying 2.85 g of 1-[2,5-Bis(benzyloxy)phenyl]ethanone. 1H NMR (400 MHz, DMSO-d6) δ = 2.50 (s, 3H), 5.08 (s, 2H), 5.18 (s, 2H), 7.20-7.50 (m, 13H).

b) 2,5-bis (benzyloxy)phenyl acetic acid ester

A mixture that includes (2.25g) 1-[2,5-bis(benzyloxy)phenyl]ethanone, then (1.63ml) 40%

of peracetic acid and (5.4 ml) of acetic acid, is stirred for 1 hour at 60°C. After cooling to room temperature, the precipitated product is collected by filtration, washed with cold ether and dried under reduced pressure. The product 2,5-bis(benzyloxy)phenyl acetic acid ester is recrystallized from 2-propanol. The yield is 1.87g. <*>H NMR (DMSO-d6) 5 = 2.23 (s, 1H), 5.03 (s, 2H), 5.05 (s, 2H), 6.84-7.44 (m, 13H).

c) 2,5-Bis(benzyloxy)phenol

A solution containing 1.85g of 2,5-bis(benzyloxy)phenyl acetic acid ester and (10.6ml)

A 5M solution of sodium hydroxide in (1 lml) ethanol was heated under reflux for 6.5 hours. After the ethanol was removed under reduced pressure, the clear solution was acidified with dilute hydrochloric acid. The resulting product was then filtered, washed with cold water and dried under vacuum. The yield was 0.56g. 1H NMR (DMSO-d6) δ = 4.97 (s, 2H), 5.01 (s, 2H), 6.34 (dd, J=3.1, 8.8 Hz, IH), 6.49 (d, J=3.1 Hz, IH), 6.85 (d, J=8.8 Hz, IH), 7.28-7.46 (m, 10H), 9.1 (br with IH).

d) 2-[2,5-bis (benzyloxy)phenoxy]-1-phenylethanone

A mixture of 2,5-bis(benzyloxy)phenol (0.28g), 2-bromoacetophenone (0.22g), potassium bicarbonate (0.25g) and 18-Crown-6 (3mg) in acetonitrile (4.2ml) was allowed to stir at 22°C for one week. The reaction mass was filtered and evaporated to dryness under reduced pressure. The residue was triturated with a mixture of ether (8:2 ml) and water (1:4 ml) at ice bath temperature. The resulting product was then collected by filtration, washed with cold ether and dried under reduced pressure. The yield was 0.14 g.<l>H NMR (DMSO-d6) δ: 4.98 (s, 2H), 5.06 (s, 2H), 5.58 (s, 2H), 6.51 (dd, J=8.9, 2.3 Hz, IH), 6.68 (d, J=2.3 Hz, IH), 6.94 (d, J=8.9 Hz, IH), 7.28-8.03 (m, 15H).

e) 2-[2,5-bis(benzyloxy)phenoxy]-1-phenylethanol

To a solution of 2-[2,5-bis(benzyloxy)phenoxy]-1-phenylethanone (0.14g) in (0.5ml) methanol, and

(1.9ml) of tetrahydrofuran was added sodium borohydride in the amount of (6.5mg) and at a temperature of 0°C. The reaction mixture was stirred for 15 minutes at 0°C, and for 2 hours at a temperature of 22°C. After adding 5 ml of water, methanol and tetrahydrofuran were evaporated. The residue was then stirred at 22°C for 0.5 hours and the resulting product was filtered, washed with cold water and dried under reduced pressure. The yield was 0.09g. 1H NMR (DMSO-d6) δ: 4.05 (m, 2H), 4.91 (m, IH), 4.95 (s, 2H), 5.01 (s, 2H), 5.59 (d, J=4.7 Hz, IH), 6.47 (dd, J=2.8, 8.8 Hz, IH), 6.68 (d, J=2.8 Hz, IH), 6.89 (d, J=8.8 Hz, 1H), 7.24-7.45 (m, 15H).

f) 2-(2-hydroxy-2-phenylethoxy)benzene-1,4diol

A solution obtained from 2-[2,5-bis(benzyloxy)phenoxy]-1-phenylethanol (3.9g) in (175ml)

ethanol was hydrogenated in the presence of 10% palladium on carbon (1 OOmg) and at 30psi. The catalyst was removed by filtration and the solvent was evaporated under reduced pressure. The residue was recrystallized from a mixture of toluene - ethyl acetate in the ratio (8:1) (15 ml). The yield of 2-(2-hydroxy-2-phenylethoxy)-benzene-1,4-diol was 1,2g.<*>H NMR (DMSO-d6) 5 = 3.79 (dd, J=9.6, 8.3 Hz, IH), 4.00 (dd, J=9.6, 3.6 Hz, IH), 4.94 (ddd, J=3.6, 8.3, 3.9 Hz, IH). IH), 5.66 (d, J=3.9 Hz, IH), 6.18 (dd, J =8.5, 2.3 Hz, IH), 6.34 (d, J=2.3, IH), 6.57 (d, J=8.5, IH), 7.26-7.47 (m, 5H), 7.97 (s, IH), 8.66 (s,lH).

g) 2,3-dihydro-phenyl-benzo(1,4)dioxin-6-ol

A solution of the composition (1,2g) 2-(2-hydroxy-2-phenylethoxy)benzene-1,4-diol in 75ml of totuol, was

was heated with amberlyst-15 catalyst in the amount of (0.5g) under reflux for 7 hours. After filtration, the solvent was evaporated under reduced pressure. The residue was purified on a silica gel chromatography column while the eluent was toluene/ethyl acetate/acetic acid (8:1:1). The yield was 0.5 g of 2,3-dihydro-2-phenyl-benzo-(1,4)-dioxin-6-ol.<*>H NMR (DMSO-d6) δ: 4.02 (dd, J=8.5, 11.4 Hz, IH), 4.35 (dd, J=2.3, 11.4 Hz, IH), 5.11 (dd, J=8.5, 2.3 Hz, IH). IH), 6.29 (dd, J=2.8, 8.5 Hz, IH), 6.32 (d, J=2.8 Hz, IH), 6.75 (d, J=8.5 Hz, IH), 7.36-7.47 (m, 5H), 8.99 (s, IH).

h) 2-(2,3-dihydro-2-phenyl-benzo[1,4]dioxin-6-yloxy)5-nitropyridine

A solution of the composition 2,3 dihydro-2-phenyl-benzo(1,4)dioxin-6-ol (80mg), 2-chloro 5

of nitropyridine (56mg) as well as potassium carbonate (52mg) in dimethylformamide (1.0ml) was stirred at 120°C for 2 hours. After cooling to room temperature, 10 ml of water was added to the reaction mixture, and the resulting precipitate was filtered, washed with water and 2-propanol, and then dried under reduced pressure. Yield was 60mg mp 163-170°C. <!>H NMR (DMSO-d6)5: 4.16 (dd, J = 8.5, 11.6 Hz, IH), 4.47 (dd, J = 11.6, 2.6 Hz, IH), 5.28 (dd, J = 2.6, 8.5 Hz, IH), 6.75 (dd, J=2.6, 8.8 Hz, IH), 6.88 (d, J=2.6 Hz, IH), 7.05 (d, J=8.8 Hz, IH), 7.21 (d, J=9.1 Hz, IH), 7.39-7.52 (m, 5H), 8.60 (dd, J=2.8, 9.1 Hz, IH), 9.05 (d, J=2.8 Hz, IH).

Example 21:

2-(2,3-dihydro-2-phenyl-benzofl,41-dioxin-6-yloxy)-3-nitropyridine

The compound 2-(2,3-dihydro-2-phenyl-benzo[1,4]dioxin-6-yloxy)-3-nitropyridine was synthesized in the same way as 2-(2,3-dihydro-2-phenyl-benzo[1,4]dioxin-6-yloxy)-5-nitropyridine previously mentioned from 2,3-dihydro-2-phenyl-benzo(1,4)dioxin-6-ol (80 mg) and 2-chloro-3-nitropyridine (56mg). The yield was 30mg and the melting point <60°C.<*>H NMR (DMSO-d6) δ: 4.16 (dd, J=8.6, 11.4 Hz, IH), 4.46 (dd, J=l 1.4, 2.5 Hz, IH), 5.27 (dd, J=2.5, 8.6 Hz, IH), 6.73 (dd, J=2.5, 8.6 Hz, IH), 6.85 (d, J=2.5 Hz, IH), 7.03 (d, J=8.6 Hz, IH), 7.34-7.52 (m, 6H), 8.43 (dd, J=1.9, 4.8 Hz, IH), 8.55 (dd, J=7.8, 1.9 Hz, lH).

Example 22:

2-(23-dihydro-2-phenylbenzo[1,41dioxin-6-yloxy)-5-thyrfluoromethylpyridine

The compound 2-(2,3-dihydro-2-phenylbenzo[l14]dioxin-6-yloxy)-5-trifluoromethylpyridine was prepared in the same way as the above-described compound -2-(2,3-dihydro-2-phenyl-benzo[l14Jdioxin-6-yloxy)-5-nitropyridine from 2,3-dihydro-2-phenyl-benzo(1,4)dioxin-6-ol (80mg) and 2-Chloro-5-(trifluoromethyl)pyridine (64mg). The yield was 50mg, melting point 104-110°C. 1H NMR (DMSO-d6)5 = 4.15 (dd, J=8.3, 11.4 Hz, IH), 4.46 (dd, J=2.3, 11.4 Hz, IH), 5.27 (dd, J=2.3, 8.3 Hz, IH), 6.72 (dd, J=2.8, 8.8 Hz, IH), 6.84 (d, J=2.8 Hz, IH), 7.03 (d, J=8.8 Hz, IH), 7.19 (d, J=8.8 Hz, IH), 7.39-7.52 (m, 5H), 8.20 (dd, J=8.8, 2.6 Hz, IH), 8.58 (d, J=2.6 Hz, IH).

Example23:

5-nitro-2-(6-phenyl-5,6,7,8-tetrahydro-naphthalene-2-yloxy)-pyridine

a) 6-methoxy-2-phenyl-3,4-dihydro-2H-naphthalen-1-one

A mixture consisting of palladium(II) acetate (0.57g), racemic-2,2'-bis(diphenyl-phosphino)-1,1'-binaphthyl (1.91g) and potassium tertiary butoxide (4.15g) in dry toluene was stirred under a stream of argon for 10 minutes. The compound bromobenzene (5.34g) and 6-methoxy-1-tetralone (3.0g) was dissolved in dry toluene and then added to the basic mixture and stirred at a temperature of 100°C for 2 hours. The reaction mixture was cooled to room temperature and poured into a saturated aqueous solution of ammonium chloride and then extracted with ethyl ether. The organic extract was washed with brine, dried and evaporated, and the solid product was purified by flash chromatography on silica gel using a combination of toluene and toluene acetate (9:1) as eluent. HNMR (400MHz, d6-DMSO) δ: 7.87 (d,lH, J 7.8 Hz), 7.16-7.33 (m, 5H), 6.91-6.94 (m, 2H), 3.85 (s, 3H), 3.82-3.88 (m,lH), 3.06-3.14 (m,lH), 2.92-2.98 (m, 1H), 2.23-2.38 (m, 2H).

b) 6-hydroxy-2-phenyl-3,4-dihydro-2H-naphthalene-l-one

The compound 6-methoxy-2-phenyl-3,4-dihydro-2H-naphthalen-1-one (1.0g) was subjected to

reflux with 47%HBr (20ml) until the starting materials disappear. The mixture was poured into water and extracted with ethyl acetate. The ethyl acetate was dried and evaporated. The product was recrystallized from toluene. <]>H NMR (400 MHz, d6-DMSO) δ: 10.35 (s,1H), 7.79 (d,1H, J 8.6 Hz), 7.15-7.33 (m, 5H), 6.75

(dd,lH, J 8.6, 2.4 Hz), 6.68 (d, IH J 2.3 Hz), 3.79-3.85 (m,lH), 2.99-3.06 (m,lH), 2.83-2.90 (m,lH), 2.19-2.33 (m, 2H).

c) 6-phenyl-5,6,7,8-tetrahydro-naphthalen-2-ol

A solution of 6-hydroxy-2-phenyl-3,4-dihydro-2H-naphthalen-1-one (50 mg) in trifluoroacetic

acid, triethylsilane (98mg) was added. The mixture was heated to 60°C for 3 hours. The solvent was evaporated, water was added to the residue and the mixture was extracted with ethyl acetate. The organic extract was then dried and evaporated. <]>H NMR (400 MHz, d6-DMSO) δ: 9.02 (s,H), 7.18-7.32 (m, 5H), 6.87 (d, 1H, J 7.9), 6.50-6.53 (m, 2H), 2.68-2.92 (m, 5H), 1.94-1.99 (m, IH), 1.81-1.89 (m, IH).

d) 5-nitro-2-(6-phenyl-5,6,7,8-tetrahydro-naphthalen-2-yloxy)-pyridine

A mixture of 6-phenyl-5,6,7,8-tetrahydro-naphthalen-2-ol (30ml), -2-chloro-5-nitropyridine (21mg) and potassium fluoride (23mg) in dry dimethylformamide was heated to 120°C until the polar material disappeared. Then water and 1N HCl were added, and then the entire mass was extracted with ethyl acetate. Ethyl acetate was washed with brine and water, then dried and evaporated. The product was recrystallized from toluene. 1H NMR (400 MHz, d6-DMSO) δ: 9.04 (d,1H, J 2.4 Hz), 8.61 (dd, IH, J 9.0, 2.5), 7.18-7.35 (m, 7H), 6.95-6.99 (m, 2H), 2.83-3.01 (m, 5H), 1.87-2.04 (m, 2H).

Example 24:

6-(5-nitro-pyridin-2-yloxy)-2-phenyl-3,4-dihydro-2H-naphthalene-1-one

Compound 6-(5-nitropyridin-2-yloxy)-2-phenyl-3,4-dihydro-2H-naphthalen-l-one was synthesized as described for compound 5-nitro-2-(6-phenyl-5,6,7,8-tetrahydro-naphthalen-2-yloxy)-pyridine in Example 23(d) using 50 mg of 6-hydroxy-2-phenyl-3,4-one. dihydro-2H-naphthalene-l-one, 33mg 2-chloro-5-nitropyridine and 37mg potassium fluoride.<*>H NMR (400 MHz, d6-DMSO) δ: 9.07 (d, IH, J 2.8 Hz), 8.68 (dd, IH, J 9.0, 2.9), 8.01 (d, IH, J 8.5), 7.37 (d, IH, J 9.1 Hz), 7.21-7.38 (m, 7H), 3.96-4.04 (m, IH), 3.15-3.23 (m, IH), 2.98-3.04 (m, IH), 2.39-2.48 (m, IH), 2.25-2.31 (m, IH).

Example25:

3- N-acetylamino-4-(2-ferrylchroman-6-yloxy)-anisole

The compound 3-amino-4-(2-phenylchroman-6-yloxy)-anisole from Example 3 (0.174g) was dissolved in 2ml of dry pyridine under a stream of nitrogen. After that, acetic anhydride (0.15 ml) and a 10 mol% solution of 4-(N,N-dimethylamino)pyridine (DMAP) were added to the reaction mixture, and then the reaction solution was stirred for 2.5 hours, at room temperature, and then the reaction was suppressed by adding lml H2O. Toluene was added to the reaction mass, and then everything was evaporated to dryness. Evaporation with toluene was repeated, and the resulting product was purified on a chromatographic column using (CH2Cl2:EtOAc/98:2). 1H NMR (400 MHz; d6-DMSO) 6:9.38 (s, IH), 7.68 (s, IH), 7.47-7.25 (m, 5H), 6.85-6.66 (m, 4H), 6.63 (dd, IH, J=8.8 Hz, J=3.0 Hz), 5.07 (dd, IH, J=9.9 Hz, J=1.9 Hz), 3.71 (s, 3H), 3.0-2.85 (m, IH), 2.75-2.62 (s, IH), 2.20-2.10 (m, IH), 2.05 (s, 3H), 2.08-1.90 (m, IH).

Example26:

5-amino-2-(2-phenylchroman-6-yloxy)-pyridine

The compound 5-nitro-2-(2-phenylchroman-6-yloxy)-pyridine from Example 1, (2.26g) was dissolved in 350ml of glacial acetic acid. Zn powder (8.48g) was then added in small portions to ensure an exothermic reaction. The mixture was then stirred at room temperature for 2 hours and then filtered. Zn was eluted using glacial acetic acid. The acid was evaporated and then toluene was added and evaporated again. The product was then dissolved in dichloromethane (CH 2 Cl 2 ) and washed with 1M NaOH. The aqueous phase was further washed with dichloromethane. Both organic fractions were combined and dried over Na2SO4. The product was purified by column chromatography. *H NMR (400 MHz; d6-DMSO) δ: 7.52 (d, IH, J=2.8 Hz), 7.46-7.30 (m, 5H), 7.05 (dd, IH, J=8.6 Hz, J=3.0 Hz), 6.82-6.72 (m, 3H), 6.69 (d, IH, J=8.6 Hz), 5.08 (dd, IH, J=10.0 Hz; J=2.1 Hz), 5.00 (s, 2H), 3.00-2.87 (m, IH), 2.74-2.64 (m, IH), 2.19-2.10 (m, IH), 2.05-1.91 (m, IH).

Example27:

5-N-acetylamino-2-(2-phenylchroman-6-yloxy)-pyridine

The compound 5-amino-2-(2-phenylchroman-6-yloxy)-pyridine from Example 26 (0.955g) was dissolved in 8ml of dry pyridine under a stream of nitrogen. DMAP (0.03 8g) was then added, followed by AcCl (0.26ml) at room temperature dropwise since it was a strongly exothermic reaction. The reaction mixture was stirred for 90 min at room temperature. The reaction subsided after the addition of lml water. Toluene (50 mL) was added and the mixture evaporated to dryness. Evaporation with toluene was repeated twice. The brownish product was purified on a chromatographic column, and the combination (EtOAc:CH2Cl2/60:40) was used for elution, giving a crystalline yellowish product. The product was further purified by recrystallization from MeOH:H 2 O (71:29). The precipitate was filtered off and washed twice with 10 ml of ice-cold methanol/water (1:1). <!>H NMR (400 MHz; d6-DMSO) δ: 10.04 (s,lH), 8.27 (d,lH, J=2.4 Hz), 8.01 (dd, IH, J=8.9 Hz; J=2.8 Hz), 7.47-7.31 (m, 5H), 6.93 (d, IH, J=8.9 Hz), 6.85 (d, 2H, J=6.8 Hz), 6.84 (s, IH), 5.11 (dd, IH, J=10.1 Hz; J=2.2 Hz), 3.02-2.90 (m, IH), 2.71 (ddd, IH, J=16.8 Hz); J=5.1, J=1.8 Hz), 2.22-2.11 (m, IH), 2.08-1.92 (m, IH).

Example 28:

5- Af1A^- diacetylamino- 2-( 2- phenylchroman- 6- yloxy)- pyridine

The compound 5-amino-2-(2-phenylchroman-6-yloxy)-pyridine from Example 26, (0.40g) was dissolved in 1.5ml of dry pyridine under nitrogen, then DMAP (10mol% Ni) and Ac2O (1.0ml) were added and then the solution was stirred at room temperature for 2.5h. After that, toluene was added and evaporated to dryness. Evaporation of toluene was repeated twice. The product was then purified by column chromatography. Eluting solvents were (EtOAc:CH2Cl2/60:40).<*>H NMR (400MHz; d6-DMSO) δ: 8.05 (d, IH, J=2.6 Hz), 7.78 (dd, IH, J=8.7 Hz; J=2.6 Hz), 7.48-7.31 (m, 5H), 7.07 (d, IH, J=8.9 Hz), 6.99-6.85 (m, 3H), 5.13 (dd, IH, J=10.1 Hz; J=1.9 Hz), 3.05-2.92(m, IH), 2.78-2.70 (m, IH), 2.21 (s, 6H), 2.25-2.12 (m, IH), 2.08-1.94 (m, IH).

Example 29:

2-(2-phenylchroman-6-yloxy)aniline

a) 2-nitro-1-(2-phenylchroman-6-yloxy)benzene

The compound 6-hydroxyflavan (0.150g) was dissolved in dry DMSO (5ml) and in

nitrogen stream. 0.166g KJ and 0.074g KOH were added, and the solution was stirred at room temperature for 15 minutes. After that, the 2-chloro-1-nitrobenzene compound (0.104g) was added and the solution was stirred at 90°C for 2.5 hours. The cooled solution was extracted with dichloromethane. All organic phases were combined and washed with 1M HCl followed by water (to pH~7) and brine. The solution was dried over Na2SO4 and purified by filtration through small columns

silakagel a eluted with a combination of dichloromethane CH2Cl2:n-heptane (60:40). <]>H NMR (300 MHz; d6-DMSO) δ: 8.01 (dd, IH, J=8.1 Hz, J=1.7 Hz), 7.69 (m, IH), 7.50-7.31 (m, 5H), 7.31-7.24 (m, IH), 7.04 (dd, IH, J=8.5 Hz; J=1.2 Hz), 6.92 (s, IH), 6.90 (s, 2H), 5.12 (dd, IH, J-10.1 Hz; J=2.3 Hz), 2.95 (ddd, IH, J=16.9 Hz; J=l 1.2 Hz, J =5.8 Hz), 2.73 (ddd, IH, J=16.9 Hz; J=3.2 Hz, J=1.7 Hz), 2.25-2.10 (m, IH), 2.08-1.90 (m, IH).

b) 2-(2-phenylchroman-6-yloxy)-aniline

The compound 2-nitro-1-(2-phenylchroman-6-yloxy)-benzene (0.160g) was mostly dissolved

in 30ml of glacial acetic acid, Zn powder (1.190g) added in small portions to the mixture which was mixed for 90 min. at room temperature. Zn was filtered and washed with glacial acetic acid and then evaporated. The residue after evaporation was dissolved in toluene and evaporated again. The dry residue was dissolved in dichloromethane and washed with 1M NaOH. The NaOH solution was further washed with dichloromethane. Both organic fractions were collected together and dried over Na 2 SO 4 , and purification of the crude product was carried out by elution with dichloromethane through small silica gel columns. (dd, IH, J=8.0 Hz; J=1.7 Hz), 6.73-6.67 (m, 3H), 6.54-6.48 (m, IH), 5.06 (dd, IH, J=10.1 Hz; J=2.3 Hz), 4.85 (s, 2H), 2.99-2.87 (m, IH), 2.73-2.61 (m, IH), 2.19-2.09 (m, 1H), 2.03-1.90 (m, 1H).

Example 30:

5- Trifluoromethyl-2-(2-phenylchroman-6-yloxy)-aniline

a) 2-nitro-1-(2-phenylchroman-6-yloxy)-4-trifluoromethylbenzene The compound 2-nitro-1-(2-phenylchroman-6-yloxy)-4-trifluorobenzene was synthesized as

as described for 2-nitro-1-(2-phenylchroman-6-yloxy)-benzene of Example 29(a), except that 6-hydroxyflavan (0.339 g) was dissolved in 7 ml of dry DMSO under a stream of nitrogen. Also KJ (0.374g) and KOH (0.168g) as well as 4-chloro-3-nitro-1-trifluoromethylbenzene were added (0.24ml) in the same manner. The product was purified on column chromatography, the eluent being a combination of (CH2Cl2:n-heptane (60:40).<]>H NMR (300 MHz; d6-DMSO) δ: 8.44 (d, IH, J=2.1 Hz), 7.99 (dd, IH, J=9.0 Hz; J=2.2 Hz), 7.51-7.29 (m, 5H), 7.15 (d, IH, J=8.7 Hz), 7.09-6.91 (m, 3H), 5.15 (dd, IH, J=10.1 Hz; J=2.3 Hz), 3.08-2.90 (m, IH), 2.83-2.68 (m, IH), 2.25-2.11 (m, IH), 2.09-1.91 (m, IH).

b) 5-trifluoromethyl-2-(2-phenylchroman-6-yloxy)-aniline

The compound 2-nitro-1-(2-phenylchroman-6-yloxy)-4-trifluoromethylbenzene (0.31 lg) was

reduced in 25 ml of glacial acetic acid with Zn (1.48 g) as described for 2-(2-phenylchroman-6-yloxy)aniline in Example 29. The product was purified by column chromatography with (CH 2 Cl 2 : n-heptane/70:30) as eluent.<*>H NMR (300 MHz; d^-DMSO) 5: 7.48-7.28 (m, 5H), 7.06 (d, IH, J=2.2 Hz), 6.86 (dd, IH, J=7.8 Hz, J=1.5 Hz) 6.85-6.56 (m, 3H), 6.72 (d, IH, J=8.4 Hz), 5.40 (s, 2H), 5.10 (dd, IH, J=10.0 Hz; J=2.3 Hz), 3.04-2.87 (m, 1H), 2.87-2.65 (m, 1H), 2.24-2.10 (m, 1H), 2.08-1.89 (m, 1H).

Example 31:

5-amino-2-(2-phenylchroman-6-yloxy)-aniline

a) 2,4-dinitro-1-(2-phenylchroman-6-yloxy)-benzene

The compound 2,4-dinitro-1-(2-phenylchroman-6-yloxy)-benzene was prepared according to

to the description for 2-nitro-1-(2-phenylchroman-6-yloxy)-benzene in Example 29(a) except that 6-hydroxyflavan (0.226g) was dissolved in 5 ml of dry DMSO under a stream of nitrogen, and that KJ (0.249g) and KOH (0.112g) and 2,4-dinitrochlorobenzene (0.210mg) were added in the same manner. The product was purified by column chromatography with (CH2Cl2:n-heptane/in the ratio 75:25) as eluent. 1H NMR (400 MHz; d6-DMSO) δ: 8.88 (d, IH, J=2.8 Hz), 8.45 (dd, IH, J=9.4 Hz, J=2.9 Hz), 7.48-7.30 (m, 5H), 7.14 (d, IH, J=9.3 Hz), 7.10 (d, IH, J=2.8 Hz), 7.05 (dd, IH, J=8.8 Hz, J=2.9 Hz), 6.98 (d, IH, J=8.7 Hz), 5.16 (dd, IH, J=10.2 J=2.1 Hz), 3.08-2.93 (m, IH), 2.83-2.71 (m, IH), 2.25-2.13 (m, IH), 2.08-1.94 (m, IH).

b) 5-amino-2-(2-phenylchroman-6-yloxy)aniline

The compound 2,4-dinitro-1-(2-phenylchroman-6-yloxy)benzene (0.04g) was dissolved in 12 ml

of glacial acetic acid, so (0.13 lg) Zn was added to the reaction mixture. All this was mixed at room temperature for 30 min. The process was further carried out as described for 2-(2-phenylchroman-6-yloxy)aniline in Example 29. Purification was carried out on column chromatography (with CH2Cl2:Et3N/96:4 as eluents).<*>H NMR (300 MHz; d6-DMSO) δ: 7.48-7.28 (m, 5H), 6.74 (d, IH, J=8.8). Hz), 6.63 (dd,lH, J=8.8 Hz, J=2.9 Hz), 6.57 (d,lH, J=2.8 Hz) 6.49 (d, IH, J=8.4 Hz), 6.02 (d, IH, J=2.6 Hz), 5.81 (dd, IH, J=8.4 Hz, J=2.6 Hz), 5.03 (dd, IH, J=2.6 Hz) J=10.0 Hz, J=2.3 Hz), 4.62 (s, 2H), 4.48 (s, 2H), 2.99-2.82 (m, IH), 2.71-2.57 (m, IH), ? 90-? n^. Cm11-n ? rn.1 8f> fm mi

Example 32:

5- Cyano-2-(2-phenylchroman-6-yloxy)-aniline

a) 4-cyano-2-nitro-1-(2-phenylchroman-6-yloxy)-benzene

The compound 4-cyano-2-nitro-1-(2-phenylchroman-6-yloxy)-benzene was prepared

as described for 2-nitro-1-(2-phenylchroman-6-yloxy)-benzene in Example 29(a) except that for 6-hydroxyflavan (0.453g) the compound was dissolved in 1Oml of dry DMSO under a stream of nitrogen, and also KJ (0.498g) and (0.224g) KOH as well as (0.365mg) 4-chloro-3-nitrobenzonitrile were added in the same way. Purification on a chromatography column was performed using a combination of solvents CH2C12 and n-heptane (90:10) as eluents. 1H NMR (400 MHz; d6-DMSO) δ: 8.64 (d,1H, J=2.0 Hz), 8.06 (dd, IH, J=8.8 Hz, J=2.1 Hz), 7.08 (d,1H, J=8.8 Hz), 7.07-6.93 (m, 3H), 5.15 (dd, IH, J=10.1 Hz, J=2.1 Hz), 3.05-2.91 (m, IH), 2.82-2.70 (m, IH), 2.24-2.12 (m, IH), 2.08-1.92 (m, IH).

b) 5-cyano-2-(2-phenylchroman-6-yloxy)-aniline

Compound 4-cyano-2-nitro-1-(2-phenylchroman-6-yloxy)-benzene (0.155g; 0.4mmol)

was reduced to the corresponding aniline as described for 2-(2-phenylchroman-6-yloxy)-aniline in Example 29 except that 40 ml of glacial acetic acid and 0.93 g of powdered Zn were used. The product was purified on a chromatographic column and the eluent was 100% methylene chloride.<*>H NMR (300 Mhz; d6-DMSO) δ: 7.57-7.28 (m, 5H), 7.06 (d, 1H, J=2.0 Hz), 6.95-6.78 (m, 4H), 6.65 (d, 1H, J=8.3 Hz), 5.46 (s, 2H), 5.11 (dd, IH, J=10.0 Hz, J=2.1 Hz), 3.03-2.88 (m,lH), 2.78-2.66 (m, IH), 2.23-2.10 (m, IH), 2.08-1.89 (m,lH).

Example33:

Af-Acetyl-2-(2-phenylchroman-6-yloxy)-aniline

2-(2-Phenylchroman-6-yloxy)-aniline (0.093 g) was dissolved in 1 ml of dry pyridine under a stream of nitrogen. Then (10 mol%) DMAP and acetic anhydride (0.1 ml) were added to the solution, which was then stirred at room temperature for 4 hours and the reaction was quenched by adding 0.5 ml of H20. The solution was then evaporated to dryness and toluene was added twice and evaporated again. The resulting product was then purified on a column chromatography with an eluent consisting of CH2Cl2:i-PrOH/98:2. Recrystallization was carried out by measuring 0.5 ml of absolute ethanol, which was first heated, then cooled and added to the basic solution. 6.89-6.74 (m,

4H), 5.10(dd, 1H, J=9.9, J=2.0), 3.03-2.88 (m, IH), 2.76-2.65 (m, IH), 2.21-2.1 l(m, IH), 2.10-1.91 (m, IH), 2.06 (s, 3H).

Example 34:

3-nitro-2-(2-phenylchroman-6-yloxy)-pyridine

0.15 g of the 6-hydroxyflavan compound was dissolved in 3 ml of dry DMF under a stream of nitrogen. After that, KF (0.117g) was added, and the solution was stirred for 30 minutes at +120°C. The solution was then cooled a little and 2-chloro-3-nitropyridine (0.212g) was added to it and stirred for 7 hours at +120°C and then overnight at room temperature. EtOAc and 1MHCl and water were then added to this mass to separate the phases. The organic phase was washed with water and the pH adjusted with 1M NaOH to 7. This phase was further washed with water and brine and then dried over. Na2S04. The product was purified by column chromatography using eluents (CH2CI2:n-heptane/80:20). 1H-NMR (400 MHz; d6-DMSO) δ: 8.55 (dd, IH, J=7.9 Hz, J=1.7 Hz), 8.42 (dd, IH, J=4.9 Hz, J=1.7 Hz), 7.51-7.29 (m, 6H), 7.02-6.92 (m, 2H), 6.88 (d, IH, J=8.7 Hz), 5.14 (dd, IH, J=10.0 Hz, J=2.1 Hz), 3.05-2.92 (m, IH), 2.78-2.68 (m, IH), 2.22-2.13 (m, IH), 2.07-1.95 (m,lH).

Example 35:

3-amino-5-(trifluoromethyl)-2-(2-phenylchroman-6-yloxy)aniline

a) 2,6-dinitro-1-(2-phenylchroman-6-yloxy)-4-trifluoromethylbenzene The synthesis of the compound 2,6-dinitro-1-(2-phenylchroman-6-yloxy)-4-trifluoromethylbenzene was

performed as described for 2-nitro-1-(2-phenylchroman-6-yloxy)-benzene in Example 29(a) except that 6-hydroxyflavan (0.453g). was dissolved in 10 ml of dry DMSO in a stream of N. Compounds KJ (0.498g) KOH (0.224g) and 4-chloro-3,5-dinitrobenzotrifluoride (0.54lg) were added to the reaction mixture in the same manner. 1H-NMR (400 MHz; d6-DMSO) δ: 8.87 (s, 2H), 7.46-7.29 (m, 5H), 6.89-6.75 (m, 4H), 5.09 (dd, IH, J=10.3 Hz, J=2.1 Hz), 2.98-2.85 (m, IH), 2.75-2.62 (m, IH), 2.19-2.08 (m, IH), 2.03-1.88 (m, IH).

b) 3-amino-5-(trifluoromethyl)-2-(2-phenylchroman-6-yloxy)-aniline 2,6-dinitro-1-(2-phenylchroman-6-yloxy)-4-trifluoromethylbenzene (0.198g; 0.43 mmol)

was reduced to the corresponding diamino compound as described for 2-(2-phenylchroman-6-yloxy)-aniline in Example 29 except that 25 ml of glacial acetic acid and 1.525 g of metallic zinc powder were also used. The product was purified by column chromatography

graphy with 100% CH2C12 as eluent. 1H-NMR (400 MHz; d6-DMSO) δ: 7.45-7.28 (m, 5H), 6.76 (d, IH, J=8.8 Hz), 6.65 (dd, IH, J=8.7 Hz, J=3.0 Hz), 6.62 (d, IH, J=2.8 Hz), 5.04 (dd, IH, J=10.0 Hz, J=2.1 Hz), 4.98 (s, 4H), 2.98-2.86 (m IH), 2.70-2.60 (m, IH), 2.18-2.09 (m, IH), 2.00-1.88 (m, IH).

Example36:

5-succinimido-2-(2-phenylchroman-6-yloxy)-pyridine

The compound 5-amino-2-(2-phenylchroman-6-yloxy)-pyridine from Example 26 (0.16g) was dissolved in 7.5 ml of glacial acetic acid in a stream of N. Succinic anhydride (0.0563g) was added, the reaction mixture was subjected to reflux for 60 min., and the solution was cooled and evaporated to dryness. Toluene (25ml) was added to the dry residue and evaporated again to dryness. The resulting product was purified by column chromatography eluted with solvents (CH2Cl2: i-PrOH/95:5).<*>H-NMR (400 Mhz; d6-DMSO) δ: 8.03 (d, IH, J=2.6 Hz), 7.73 (dd, IH, J=8.7 Hz, J=2.6 Hz), 7.48-7.31 (m, 5H), 7.10 (d, IH, J=8.7 Hz), 6.95 (d, IH, J=2.6 Hz), 6.92 (dd, IH, J=8.7 Hz, J=2.7 Hz), 6.88 (d, IH, J=8.6 Hz), 5.13 (dd, IH, J=10.2 Hz, J=2.2 Hz), 3.05-2.92 (m, IH), 2.84-6.68 (m, 1H), 2.79 (s, 4H), 2.22-2.12 (m, 1H), 2.08-1.93 (m, 1H).

Example37:

5-(0,0,-diacetyl-L-imidotartrate)-2-(2-phenylchroman-6-yloxy)-pyridine

The compound 5-(0,0'-diacetyl-L-imidotartrate-2-(2-phenylchroman-6-yloxy)-pyridine was synthesized as described in Example 36 for 5-succinimido-2-(2-phenylchroman-6-yloxy)-pyridine, except that 5-amino-2-(2-phenylchroman-6-yloxy)-pyridine (0.318g) and (+)-diacetyl-L-tartrate anhydride (0.227g) was subjected to reflux in 15ml of glacial acetic acid, and in the course of 60 min.'H-NMR (400 MHz; d6-DMSO) δ: 8.10 (d, IH, J=2.6 Hz), 7.79 (dd, IH, J=8.7 Hz, J=2.6 Hz). 7.49-7.30 (m, 5H), 7.13 (d, IH, J 8.8 Hz), 6.97 (d, IH, J=2.5 Hz), 6.93 (dd, IH, J=8.7 Hz, J=2.7 Hz), 6.88 (d, IH, J=8.7 Hz), 6.08 (s, 2H), 5.13 (dd, IH, J=10.1 Hz, J=1.9 Hz), 3.06-2.92 (m, IH), 2.80-2.69 (m, IH), 2.23-2.12 (m, IH), 2.18 (s, 6H), 2.08-1.93 (m, IH).

Example 38:

5-nitro-2-(2-phenylindan-5-yloxy)pyridine

a) 3-(4-methoxyphenyl)-2-phenylacrylic acid

Triethylamine was added to a solution of p-anisaldehyde (lOg) and phenyl acetic acid (lOg) in

acetic anhydride (25ml) The reaction mixture is stirred at 90°C for 8 hours, and

then cooled, and 600 ml of water and 8 lgr of potassium carbonate were added to it. After the addition, the reaction mixture was heated to 60°C for 1 hour. Before neutralization with concentrated hydrochloric acid, the reaction mixture was cooled to below 10°C. The precipitate was filtered and washed with water. <!>H -NMR (400 MHz, d6-DMSO) δ: 12.6 (bs, IH), 7.67 (s, IH), 7.4-7.3 (m, 3H), 7.2-7.1 (m, 2H), 7.0-6.9 (m, 2H), 6.8-6.7 (m, 2H), 3.70 (s, 3H). (M)+ = 254(100%).

b) 3-(4-methoxyphenyl)-2-phenylpropionic acid

13 g of the compound 3-(4-methoxyphenyl)-2-phenylacrylic acid was dissolved in 600ml

of ethyl acetate and 2.6 g of 10% palladium on carbon were added in an inert atmosphere. The starting material was hydrogenated at room temperature to give a quantitative yield of 3-(4-methoxyphenyl)-2-phenylpropionic acid. 'H -MMR (400 MHz; d6-DMSO) 6: 12.3 (bs, IH), 7.32-7.20 (m, 5H), 7.1-7.0 (m, 2H), 6.8-6.7 (m, 2H), 3.79 (dd, IH, J 6.9, 8.7 Hz), 3.70 (s, 3H), 3.22 (dd, IH, J 8.7, 13.7 Hz), 2.87 (dd, IH, J 6.9, 13.7 (Hz).

c) 6-methoxy-2-phenylindan-1-one

To a solution of 3-(4-methoxyphenyl)-2-phenylpropionic acid (4.60g) in 26ml of dry

of methylene chloride, two drops of dry DMF were added. After adding 3 ml of thionyl chloride to the reaction mixture, it was placed under a stirrer at 40°C for 4 hours. The solvent was then evaporated under vacuum. The precipitated part (precipitate) was dissolved in methylene chloride. The solution was then cooled to a temperature of 0-3°C, and then the solution, with the addition of (2.5g) aluminum chloride, was stirred gently for over 4 hours while maintaining the temperature at 4°C. The reaction mixture was then stirred at room temperature for another 2 hours. The reaction was quenched by pouring ice-cold dilute hydrochloric acid. The layers were then separated and the aqueous solution was extracted with methylene chloride. The combined organic layers were washed with water, dried and evaporated. The crude product was crushed with a yield of 2.9 g. 6-Methoxy-2-phenylindan-l-one.<!>H - NMR (400 MHz; d6-DMSO) δ: 7.56 (d, IH), 7.35-7.23 (m, 4H), 7.18-7.13(m, 3H), 4.02 (dd, IH, J 3.9, 8.0 Hz), 3.82 (s, 3H), 3.61 (dd, IH, J.80, 17.2 Hz), 3.11 (dd, IH, J 3.9, 17.2 Hz).

d) 5-methoxy-2-phenylindane

The compound 5-methoxy-2-phenylindan was synthesized as described for 2-phenylchroman-6-ol in Example 1(a) using 600 mg of 6-methoxy-2-phenylindan-1-one. 1H-NMR (400 MHz, oVDMSO) δ: 7.32-7.27 (m, 4H), 7.21-7.18 (m, IH), 7.13 (d, IH, J 8.2 Hz), 6.83 (d,lH, J 2.4 Hz), 6.72 (dd, IH, J 2.4, 8.2 Hz), 3.72 (s, 3H), 3.64 (k, 1H, J 8.5 Hz), 3.23 (dt, 2H, J 8.5, 15.9 Hz), 2.92 (m, 2H).

e) 2-phenylindan-5-ol

A mixture of 200 mg of 5-methoxy-2-phenylindane and 4 ml of concentrated HBr was placed under

reflux for 5.5 hours. The reaction mixture was then cooled to room temperature, 20 ml of ice water was added to it, and the extraction was then carried out using methylene chloride. The combined organic layers were washed with brine and then dried with Na2SO4. The solvents were evaporated and the residue was the yield of 2-phenylindan-5-ol. 1 H -NMR (400 MHz; d6-DMSO) δ: 9.05 (bs,1H), 7.3-7.28 (m, 4H), 7.26-7.15 (m, IH), 7.0 (d, IH, J 8.1 Hz), 6.64 (d, IH, J 1.9 Hz), 6.55 (dd, IH, J 1.9, 8.1 Hz), 3.60 (k, IH, J 8.6 Hz), 3.18 (m, 2H), 2.86 (dt, 2H, J 8.6, 16 Hz).

f) 5-nitro-2-(2-phenylindan-5-yloxy)pyridine

The compound 5-nitro-2-(2-phenylindan-5-yloxy)pyridine was prepared as described

for 2-phenylchroman-6-yloxy)pyridine in Example 1(b) from 107 mg of the compound 2-phenylindan-5-ol. *H - NMR (400 MHz, d6-DMSO): 9.04 (d, IH, J 2.9 Hz), 8.61 (dd, IH, J 2.9, 9.1 Hz), 7.38-7.28 (m, 5H), 7.24-7.20 (m, 2H), 7.11 (d, IH, J 2.2 Hz), 7.00 (dd, IH, J) 2.2, 8.0 Hz), 3.72 (k, IH, J 8.9 Hz), 3.36-3.28 (m, 2H), 3.01 (dd, 2H, J 8.9, 15.3 Hz).

Example 39:

5-Methoxy-2-(2-phenylindan-5-yloxy)phenylamine

a) 5-(4-methoxy-2-(nitrophenoxy)-2-phenylindane

The compound 5-(4-methoxy-2-nitrophenoxy)-2-phenylindane was synthesized as

described for 6-(4-methoxy-2-nitrophenoxy)-2-phenylchroman in Example 3(a) starting from 575 mg of the compound 2-phenylindan-5-ol. 1 H -NMR (400 MHz; d6-DMSO) δ: 7.60 (d,1H, J 3.1 Hz), 7.35-7.28 (m, 5H), 7.25-7.16 (m, 3H), 6.86 (d, IH, J 2.3 Hz), 6.78 (dd, IH, J 2.3, 8.2 Hz), 3.84 (s, 3H), 3.67 (k, 1H, J 8.3 Hz), 3.25 (dd, 2H, J 8.3, 15.7 Hz), 2.95 (m, 2H). (M)<+>=361 (60%), 209(100%).

b) 5-methoxy-2-(2-phenylindan-5-yloxy)phenylamine

The compound -5-methoxy-2(2-phenylindan-5-yloxy)phenylamine was prepared as described for

5-Methoxy-2-(2-phenylchroman-6-yloxy)phenylamine in Example 3(b) starting from 200mg of the compound 5-(4-methoxy-2-nitrophenoxy)-2-phenylindane. <1>H -NMR (400 MHz, d6-DMSO) δ: 7.33-7.27 (m, 4H), 7.23-7.18 (m, 2H). 6.82 (d, IH, J 8.4 Hz), 6.81 (s, IH), 6.77 (dd, IH, J 2.3, 8.4 Hz), 6.69 (d, IH, J 2.3 Hz), 6.48 (bd, IH, J 6.4 Hz), 3.71 (s, 3H), 3.66 (k, IH, J 8.3 Hz), 3.24 (dd, 2H, J 8.3, 15.6 Hz), 2.93 (m, 2H). (M)<+>= 331 (100%).

Example 40:

2-( 2-( 3- fluorophenyl)- indan- 5- yloxy)- 5- methoxyphenylamine

a) 2-(3-fluorophenyl)indan-5-ol

The compound 2-(3-fluorophenyl)indan-5-ol was synthesized according to the description for 2-phenylindan-5-ol in

Example 25 (a-e) using 5 g of the compound 3-fluorophenylacetic acid.<*>H-NMR (400 MHz, d6-DMSO) δ: 9.09 (s, IH), 7.37-7.29 (m, IH), 7.14-7.09 (m, 2H), 7.02-6.98 (m, 2H), 6.64 (d, IH, J 1.7 Hz), 6.55 (dd, IH, J 2.3, 8.1 Hz), 3.63 (k, IH, J 8.3 Hz), 3.24-3.12 (m, 2H), 2.94-2.79 (m, 2H).

b) 5-methoxy-2-[(2-(3-fluorophenyl)indan-5-yloxy]phenylamine

The compound 5-methoxy-2-[2-(3-fluorophenyl)indan-5-yloxy] phenylamine was synthesized

according to the procedure described for 5-methoxy-2-(2-phenylchroman-6-yloxy)phenylamine in Example 3(a-b) using 500 mg of 2-(3-fluorophenyl)indan-5-ol. 1H NMR (400 MHz, CDCl 3 ) δ: 7.26-7.21 (m, IH), 7.16 (d, IH, J 2.9 Hz), 7.09 (d, IH, J 8.2 Hz), 7.02 (d, IH, J 7.7 Hz), 6.96-6.88 (m, 4H), 6.83 (d, IH, J 9.1 Hz), 6.72 (dd, IH, J 2.9, 9.1 Hz), 3.69 (s, 3H), 3.65 (k, IH, J 8.8 Hz), 3.26-3.19 (m, 2H), 2.94 (dd, 2H, J 8.8, 15.1 Hz).

Example 41:

2-(2-phenylindan-5-yloxy)phenylamine

a) 5-(2-nitrophenoxy)-2-phenylindane

The compound 5-(2-nitrophenoxy)-2-phenylindane was synthesized as described for

compound 6-(4-methoxy-2-nitrophenoxy)-2-phenylchroman in Example 3(a) using 200 mg of the compound 2-phenylindan-5-ol and 150 mg. compounds l-chloro-2-nitrobenzene. 'H NMR (400 MHz,

oVDMSO) 8: 8.04 (dd, IH, J 1.6, 8.3 Hz), 7.68 (ddd, IH, J 1.6, 7.4, 8.3 Hz), 7.36-7.27 (m, 6H), 7.24-7.17 (m, IH), 7.11 (dd, IH, J 1.1, 8.4 Hz), 6.98 (bd, IH, J 2.3 Hz), 6.89 (dd, IH, J 2.3, 8.1 Hz), 3.69 (k, IH, J 8.5 Hz), 3.28 (dd, 2H, J 8.5, 15.8 Hz), 3.05-2.95 (m, 2H).

b) 2-(2-phenylindan-5-yloxy)phenylamine

The compound 2-(2-phenylindan-5-yloxy)phenylamine was synthesized as previously described

for the compound 2-(2-phenylchroman-6-yloxy)-phenylamine in Example 29(b) using 170 mg of the compound 5-(2-nitrophenoxy)-2-phenylindane. 1H NMR (400 MHz, d6-DMSO) δ: 7.32-7.27 (m, 4H), 7.23-7.16 (m, 2H), 6.92-6.87 (m, 1H), 6.81-6.71 (m, 4H), 6.56-6.53 (m, 1H), 4.85 (bs, 2H), 3.65 (k, 1H, J 8.3 Hz), 3.23 (dd, 2H, J 8.3, 15.5 Hz), 2.97-2.88 (m, 2H).

Example 42:

2-(2-phenylindan-5-yloxy)-5-trifluoromethylbenzol-1,3-diamine

a) 5-(2,6-dinitro-4-trifluoromethylphenoxy)-2-phenylindane

117mg of potassium t-butoxide was added to a solution prepared from 200mg of 2-phenylindan-5-ol in dry DMF (3ml). After stirring this reaction mixture for 30 min. at room temperature, more (275 mg) of 4-chloro-3,5-dinitrobenzotrifluoride was added. The reaction mixture was stirred for another three hours at a temperature of 150°C. After cooling to room temperature, water and ethyl acetate were added to the mixture. 1M hydrochloric acid was added to the aqueous layer and the solution was extracted with ethyl acetate. The combined organic layers were washed first with water, then with brine, then dried with Na 2 SO 4 and evaporated. The product 5-(2,6-dinitro-4-trifluoromethylphenoxy)-2-phenylindane was then recrystallized from ethanol.<*>H NMR (400 MHz, d(,-DMSO) 5 : 8.89 (s,2H), 7.33-7.27 (m, 4H), 7.23-7.18 (m, 2H), 6.96 (d, IH, J 2.5 Hz), 6.83 (dd, IH, J 2.5, 8.2 Hz), 3.67 (k, IH, J 8.6 Hz), 3.27-3.19 (m, 2H), 2.97-2.89 (m, 2H).

b) 2-(2-phenylindan-5-yloxy)-5-trifluoromethylbenzene-1,3-diamine The compound 2-(2-phenylindan-5-yloxy)-5-trifluoromethylbenzene-1,3-diamine was

synthesized as described for 2-(2-phenylchroman-6-yloxy)-5-trifluoromethylbenzene 1,3-diamine of Example 35 (b) using 230 mg of 5-(2,6-dinitro-4-trifluoromethylphenoxy)-2-phenylindane.<*>H NMR (300 MHz, d6-DMSO) 5: 7.33-7.27 (m, 4H). 7.22-7.18 (m, IH), 7.14 (d, IH, J 8.1 Hz), 6.73-6.69 (m, 2H), 6.31 (s, 2H), 4.98 (s, 4H), 3.64 (k, IH, J 8.5 Hz), 3.26-3.18 (m, 2H), 2.96-2.86 (m, 2H).

Example 43:

6-(5-nitropyridin-2-yloxy)-2-phenylchroman-4-ylamine

a) 6-hydroxy-2-phenylchroman-4-one oxime

122mg of sodium hydroxide was added to a cold solution of 6-hydroxyflavanone (2g) as well as

hydroxylamine hydrochloride (900mg) dissolved in ethanol (5ml) and water (2ml). The resulting mixture was then refluxed for 6 hours, and every 45 min. (450 mg) of hydroxylamine hydrochloride and (61 mg) of sodium hydroxide were added. After cooling to room temperature, 23 ml of water and (5.6 ml) of concentrated hydrochloric acid were added to the mixture. The resulting precipitate was drained, washed with water and dried under vacuum.<*>H -NMR (400 MHz, d6-DMSO) 5: 11.3 (s,lH), 9.11 (s, 1H<+>), 7.50-7.48 (m, 2H), 7.43-7.33 (m, 3H), 7.21 (d, IH, J 2.9 Hz), 6.80 (d, IH, J 8.8 Hz), 6.72 (dd, IH, J 2.9, 8.8 Hz), 5.07 (dd, IH, J 3.2, 11.9 Hz), 3.28 (dd, IH, J 3.2, 17.1 Hz), 2.64 (dd, IH, J 11.9, 17.1 Hz).

b) b) 4-amino-2-phenylchroman-6-ol

A solution (2.07g) of 6-hydroxy-2-phenylchroman-4-one oxime in 20ml of 1,2 dimethoxyethane

was added to cooled titanium(IV) chloride (1.9ml) and a solution of sodium borohydride (1.29g) in 20ml of 1,2 dimethoxyethane. The resulting mixture was stirred for 4 hours at room temperature. The reaction was then quenched by adding ice and the pH-value adjusted to 2-3, then the whole mixture was extracted with toluene. The aqueous layer was adjusted to an alkaline reaction using sodium hydroxide solution. The dark colored precipitate was filtered off and washed with methanol. Methanol after washing was evaporated to dryness, dissolved in water and neutralized and finally the precipitate was filtered. The resulting mixture of diastereomers of 4-amino-2-phenylchroman-6-ol was isolated in the form of the hydrochloride salt (M)<+>= 241 (4.4%) 224, (10%), 137 (100%).

c) 6-(5-nitropyridin-2-yloxy)-2-phenylchroman-4-ylamine

The compound 6-(5-nitropyridin-2-yloxy)-phenylchroman-4-ylamine was synthesized as

was described for 2-phenylchroman-6-yloxy)pyridine in Example 1(b) using 100 mg of the hydrochloride salt of 4-amino-2-phenylchroman-6-ol. A mixture of the resulting diastereomers of 6-(5-nitropyridin-2-yloxy)-2-phenylchroman-4-ylamine was isolated as the hydrochloride salts (M)<+>= 363 (22%), 259 (100%), 242 (70%), 224 (64%) and 223 (62%).

Example 44:

N-[ 6-(5-nitropyridin-2-yloxy)-2-phenylchroman-4-yl-acetaniide

Acetic anhydride (60 microliters) was added to a cooled solution of 6-(5-nitropyridin-2-yloxy)-2-phenylchroman-4-ylamine hydrochloride (100mg) and pyridine (41 microliters) in dry DMF. The resulting mixture was stirred for 20 hours at 0° C. The reaction was quenched with ice water and then neutralized. The mixture was extracted with dichloromethane, then dried over N 2 SO 4 and evaporated. The resulting mixture of diastereomers of N-[6-(5-nitropyridin-2-yloxy)-2-phenylchroman-4-yl]-acetamide was recrystallized from dichloromethane. (M)<+>= 405 (24%), 301 (14%), 259(100%), 242 (55%), 224 (96%).

Example 45:

Dimethyl-r6-(5-nitropyridin-2-yloxy)-2-phenylchroman-4-in-amine

a) 4-N,N-dimethylamino-2-phenylchroman-6-ol

274mg of sodium cyanoborohydride was added to 263mg of a solution of the free base 4-amino-2-phenylchroman-6-ol and 37% formaldehyde (1.4ml) in 15ml of acetonitrile. After 30 minutes, the pH was adjusted to the level of pH 6-7 using acetic acid. The resulting reaction mixture was stirred at room temperature overnight. It was then evaporated to dryness, and the precipitated part was then dissolved in a 10% solution of potassium hydroxide and extracted with methylene chloride. The combined organic layers were dried and then evaporated to remove the organic solvent and then the dry residue yielded 4-N,N-dimethylamino-2-phenylchroman-6-ol as a mixture of diastereomers. 1 H -NMR (400 MHz, d6-DMSO) δ: 8.79 (bs, IH, highest and lowest), 7.5-7.3 (m, 5H, highest and lowest), 6.96 (d, IH, J 2.8 Hz, highest), 6.75 (d, IH, J 2.9 Hz, lowest), 6.69 (d, IH, 8.7 Hz, lowest), 6.63-6.60 (m, IH, highest and lowest), 6.53 (dd, IH, J 2.8, 8.7 Hz, highest) 5.17 (dd, IH, J 2.7, 9.7 Hz, highest), 5.04 (d, IH, J 10.7 Hz, highest), 4.17 (dd, IH, J 5.7, 11.4 Hz, highest), 3.35 (m, IH, lowest), 2.24 (s, 3H, lowest), 2.21 (s, 3H, highest), 2.2-1.7 (m, 2H, highest and lowest).

b) Dimethyl-[6-(5-nitropyridin-2-yloxy)-2-phenylchroman-4-yl]-amine

The compound N,N-dimethyl-[6-(5-nitropyridin-2-yloxy)-2-phenylchroman-4-yl]-amine

was synthesized as described for the compound 2-phenylchroman-6-yloxy)pyridine in Example 1(b) using 220 mg of 4-N,N-dimethylamino-2-phenylchroman-6-ol. N,N-dimethyl-[6-(5-nitro-

pyridin-2-yloxy)-2-phenylchroman-4-yl]-amine was isolated as a mixture of diastereomers (M)+ = 391(8%), 347 (8%), 346 (8%), 287 (68%), 147 (100%).

Example 46:

N-r6-(2-phenylchroman-6-yloxy)pyridin-3-yl]methylsulfonamide

Pyridine (77 microliters) and methylsulfonyl chloride (32 microliters) were added to a cooled solution of 6-(2-phenylchroman-6-yloxy)pyridin-3-ylamine (121mg) in 2ml dry THF. After stirring the reaction mixture at 0°C for 2 hours, 1M hydrochloric acid was added. The solution was then extracted with ethyl acetate. The collected organic layers were dried over Na 2 SO 4 , removed by evaporation. N-[6-(2-Phenylchroman-6-yloxy)pyridin-3-ylmethanesulfonamide was recrystallized from diethyl ether.<*>H NMR (300 MHz, d6-DMSO) 6: 9.64 (s, IH), 7.99 (d, IH, J 2.8 Hz), 7.67 (dd, IH, J 2.8, 8.8 Hz), 7.47-7.31 (m, 5H), 6.97 (d, IH, J 8.8 Hz), 6.89-6.82 (m, 3H), 5.12 (dd, IH J 2.2, 10.1 Hz), 3.0-2.9 (m, IH), 2.98 (s, 3H), 2.77-2.69 (m, IH), 2.20-2.13 (m, IH), 2.04-1.96 (m, IH).

Example 47:

l-methyl-3-[6-2-phenylchroman-6-yloxy)pyridin-3-yl]thiourea

A solution of 6-(2-phenylchroman-6-yloxy)pyridin-3-ylamine (150 mg) and methyl isothiocyanate (94 microliters) in ethanol was maintained at reflux for 10 hours. After cooling, the solvents were evaporated and the crude residue of 1-methyl-3-[6-2-phenylchroman-6-yloxy)pyridin-3-yl]thiourea was purified by column chromatography (5% methanol in dichloromethane). 1H NMR (400 MHz, de-DMSO) δ: 9.45 (bs, IH), 8.02 (d, IH, J 2.7 Hz), 7.81 (dd, IH, J 2.7, 8.8 Hz), 7.70 (bs, IH), 7.47-7.38 (m, 4H), 7.36-7.32 (m, IH), 6.94-6.86 (m, 4H), 5.12 (dd, IH, J 2.3, 10.1 Hz), 2.98-2.93 (m, IH), 2.90 (d, 3H, J 4.3 Hz), 2.76-2.71 (m, IH), 2.19-2.15 (m, IH), 2.15-1.99 (m, IH).

Example 48:

3-[6-(5-nitropyridin-2-yloxy)chroman-2-yl]phenol

a) 6-hydroxy-2-(3-hydroxyphenyl)chroman-4-one

The compound 6-hydroxy-2-(3-hydroxyphenyl)chroman-4-one was synthesized as described

for 6-hydroxy-2-(3-fluorophenyl)chroman-4-one in Example 9(a). The resulting product was

recrystallized from ethanol. 1H NMR (400 MHz, d6-DMSO) δ: 9.50 (bs, IH), 9.41 (bs, 1H), 7.22-7.17 (m, IH), 7.11 (d, IH, J 3.0 Hz), 7.03 (dd, IH, J 3.0, 8.9 Hz), 6.64 (d, IH, J 8.9 Hz), 6.92-6.90 (m, 2H), 6.76-6.73 (m, IH), 5.46 (dd, IH, J 2.9, 12.7 Hz), 3.09 (dd, IH, J 12.7, 16.9 Hz), 2.75 (dd, IH, J 2.9, 16.9 Hz).

b) 2-(3-Hydroxyphenyl)chroman-4,6-diol

The compound 2-(3-hydroxyphenyl)chroman-4,6-diol was prepared as described for

synthesis of the compound 2-phenylchroman-4,6-diol in Example 8(a) starting from 6-hydroxy-2-(3-hydroxyphenyl)chroman-4-one. 1H NMR (400 MHz, d6-DMSO) δ: 9.43 (bs, IH), 8.88 (bs, IH), 7.19-7.15 (m, IH), 6.87 (d, IH, J 2.7 Hz), 6.84-6.82 (m, 2H), 6.72-6.69 (m, IH), 6.58 (d, IH, J 8.7 Hz), 6.53 (dd, IH, J 2.7, 8.7), 5.01 (d, IH, J 11.3 Hz), 4.86 (dd, IH, J 6.2, 10.8 Hz), 2.25-2.19 (m, IH), 1.88-1.75 (m, IH).

c) 2-(3-hydroxyphenyl)chroman-6-ol

The compound 2-(3-hydroxyphenyl)chroman-6-ol was prepared as described for 2-(3-fluorophenyl)-chroman-6-ol in Example 9(c) starting from 2-(3-hydroxyphenyl)-chroman-4,6-diol. 1H NMR (400 MHz, d6-DMSO) δ: 9.38 (s,1H), 8.77 (s, IH), 7.17-7.13 (m, IH), 6.82-6.79 (m, 2H), 6.70-6.67 (m,1H), 6.62 (d, IH, J 8.6 Hz), 6.52-6.47 (m, 2H), 4.89 (dd, IH, J 2.1, 9.9 Hz), 2.86-2.82 (m, IH), 2.65-2.59 (m, IH), 2.09-2.04 (m, IH), 1.91-1.85 (m, 1H).

d) 3-[6-(5-nitropyridin-2-yloxy)chroman-2-yl]phenol

The compound 3-[6-(5-nitropyridin-2-yloxy)chroman-2-yl]phenol was synthesized as

is described for 5-nitro-2-(2-phenylchroman-6-yloxy)pyridine of Example 1(b) starting from 2-(3-hydroxyphenyl)chroman-6-ol.<*>H NMR (400 MHz, d6-DMSO) S: 9.44 (s,1H), 9.04 (d, IH, J 2.8 Hz), 8.60 (dd, IH, J 2.8, 9.1 Hz). 7.21-7.16 (m, 2H), 7.00-6.94 (m, 2H), 6.91-6.84 (m, 3H), 6.73-6.70 (m, IH), 5.06 (dd, IH, J 2.1, 9.9 Hz), 2.99-2.92 (m, IH), 2.75-2.69 (m, IH), 2.17-2.01 (m, IH), 2.00-1.93 (m, IH).

Example49:

6-[2-(2,5-difluorophenyl)chroman-6-yloxy]pyridin-3-ylamine

The compound 6-[2-(2,5-difluorophenyl)chroman-6-yloxy]pyridin-3-ylamine was synthesized according to the description for 5-amino-2-(2-phenylchroman-6-yloxy)pyridine in Example 26, starting from 830 mg of the compound 2-[2-(2,5-difluorophenyl)chroman-6-yloxy]-5-nitropyridine (in Example 14(d)). 1H NMR (300 MHz, d6-DMSO) δ: 7.51 (d, IH, J 2.9 Hz), 7.36-7.25 (m, 3H), 7.05 (dd, IH, J 8.6, 2.9 Hz), 6.84-6.68 (m, 4H), 5.29 (d, IH, J 8.6), 4.99 (s, 2H), 2.96 (m, 1H), 2.72 (m, 1H), 2.14 (m, 1H), 2.01 (m, 1H).

Example50:

N-{6-r2-(2,5-difluorophenyl)chroman-6-yloxy1pyridin-3-yl}acetamide

The compound N-{6-[2-(2,5-difluorophenyl)chroman-6-yloxy]pyridin-3-yl}acetamide was synthesized according to the description for the synthesis of 5-N'-acetylamino-2-(2-phenylchroman-6-yloxy)pyridine in Example 27, starting from 370 mg of 6-[2-(2,5-difluorophenyl)chroman-6-yloxy]-pyridin-3-ylamine (Example 49). The product was purified by thin layer chromatography (TCL), preparative on silica gel, using a combination of ethyl acetate-heptane (4:1) as eluent.<*>H NMR (400 MHz, CD3OD) δ: 8.27 (d, IH, J 2.7 Hz), 8.01 (dd, IH, J 8.9, 2.7 Hz), 7.26 (m, IH), 7.13 (m, IH), 7.08 (m, IH), 6.92-6.84 (m, 4H), 5.32 (dd, IH, J 10.1, 1.6 Hz), 2.99 (ddd, IH, J-16.9, 11.4, 5.9 Hz), 2.78 (ddd, IH, J-16.9, 8.4, 5.1 Hz), 2.26 (m, IH), 2.13 (s, 3H), 1.97 (m, 1H).

Example 51:

6-[2-(2-fluorophenyl)chroman-6-yloxy]-pyridin-3-ylamine

The compound 6-[2-(2-fluorophenyl)chroman-6-yloxy]-pyridin-3-ylamine was synthesized according to the description for the synthesis of 5-amino-2-(2-phenylchroman-6-yloxy)pyridine in Example 26 starting from 240 mg of the compound 2-[2-(2-fluorophenyl)chroman-6-yloxy]-5-nitropyridine, Example 19(d). 'HNMR (400 MHz, d6-DMSO) δ: 7.52 (m, IH), 7.51 (d, IH, J 3.0 Hz), 7.41 (m, IH), 7.28-7.24 (m, 2H), 7.05 (dd, IH, J 8.6, 3.0 Hz), 6.81-6.73 (m, 3H), 6.70 (d,lH, J 8.6 Hz), 5.31 (dd, IH, J 10.3, 2.2 Hz), 5.00 (s, 2H), 2.98 (m, IH), 2.72 (m, IH), 2.15 (m, IH), 2.06 (m, IH).

Example 52:

N-{6-["2-(2-fluorophenyl)chroman-6-yloxy1pyridin-3-yl}acetamide

The compound N- {6-[2-(2-fluorophenyl)chroman-6-yloxy]pyridin-3-yl} acetamide was synthesized as described in the synthesis of 5-N'-acetylamino-2-(2-phenylchroman-6-yloxy)pyridine in Example 27 starting from 220 mg of 6-[2-(-fluorophenyl)chroman-6-yloxy]pyridin-3-ylamine (Example 51). The product was recrystallized from a mixture of methanol and diethyl ether. 1H NMR (400 MHz, d6-DMSO) δ: 10.6 (s, IH), 8.27 (d, IH, J 2.7 Hz), 8.01 (dd, IH, J 8.8, 2.7 Hz), 7.55 (m, IH), 7.42 (m, IH), 7.29-7.23 (m, 2H), 6.93 (d, IH, J) 8.8 Hz), 6.89-6.85 (m, 3H), 5.34 (dd, IH, J 10.2, 2.2 Hz), 3.01 (m, IH), 2.75 (m, IH), 2.17 (m, IH), 2.05 (m, IH), 2.04 (s, 3H).

Example53:

N- 6-( 2- r2- fluorophenyl) chroman- 6- yloxy1pyridin- 3- yl) methylsulfonamide

The compound N-6-{2-[2-fluorophenyl)chroman-6-yloxy]pyridin-3-yl} methylsulfonamide was synthesized according to the description for N-[6-(2-phenylchroman-6-yloxy)pyridin-3-yl]methylsulfonamide in Example 46 starting from 400 mg of 6-[2-(2-fluorophenyl)chroman-6-yloxy]pyridin-3-ylamine (Example 51). The product was crystallized from a mixture of methanol and diethyl ether. 1H NMR (400 MHz, d6-DMSO) δ: 9.67 (s, IH), 7.99 (d, IH, J 2.8 Hz), 7.67 (dd, IH, J 8.8, 2.8 Hz), 7.55 (m, IH), 7.42 (m, IH), 7.29-7.23 (m, 2H), 6.98 (dd, IH, J 8.8 Hz), 6.92-6.94 (m, 3H), 5.35 (dd, IH, J 10.4, 2.3 Hz), 3.01 (m, IH), 2.99 (s, 3H), 2.76 (m, IH), 2.16 (m, IH), 2.04 (m, IH).

Example54:

6- r2-(3-fluorophenyl)chroman-6-yloxylpyridin-3-ylamine

The compound 6-[2-(3-fluorophenyl)chroman-6-yloxy]pyridin-3-ylamine was synthesized as described for 5-amino-2-(2-phenylchroman-6-yloxy)pyridine in Example 26 starting from 2.34 g of the compound 2-[2-(3-fluorophenyl)chroman-6-yloxy]-5-nitropyridine (Example 9(d).<*>H NMR (400 MHz, d6-DMSO) 5: 7.51 (d, IH, J 3.0 Hz), 7.44 (m, IH), 7.30-7.25 (m, 2H), 7.16 (m, IH), 7.05 (dd, IH, J 8.6, 3.0 Hz), 6.83-6.73 (m, 3H), 6.69 (d, IH, J 8.6 Hz), 5.13 (dd, IH, J 10.0, 3.0 Hz), 5.00 (s, 2H), 2.93 (ddd, IH, -16.8, 10.5, 5.3 Hz), 2.68 (ddd, IH, J - 16.8, 8.0, 4.4 Hz), 2.18 (m, IH), 1.96 (m, IH).

Example55:

N-{6-[2-(3-fluorophenyl)chroman-6-yloxy]pyridin-3-yl} acetamide

The compound N-{6-[2-(3-fluorophenyl)chroman-6-yloxy]pyridin-3-yl}acetamide was synthesized according to the description for 5-N'-acetylamino-2-(2-phenylchroman-6-yloxy)pyridine in Example 27 starting from 3OOmg of the compound 6-[2-(3-fluorophenyl)chroman-6-yloxy]pyridin-3-ylamine (Example 54). The resulting product was recrystallized from a mixture of methanol and diethyl ether.<*>H NMR (400 MHz, d6-DMSO) δ: 10.09 (s, IH), 8.28 (d, IH, J 2.7 Hz), 8.02 (dd, IH, J 8.8, 2.7 Hz), 7.46 (m, IH), 7.31-7.27 (m, 2H), 7.17 (m, IH), 6.93 (d, IH, J 8.8 Hz), 6.89-6.83 (m, 3H), 5.16 (dd, IH, J 10.1, 2.1 Hz), 2.95 (ddd, IH, J-16.5, 11.0, 6.5 Hz), 2.71 (ddd, IH, J - 16.5, 8.7, 4.4 Hz), 2.19 (m, 1H), 2.04 (s, 3H), 1.96 (m, 1H).

Example 56:

6-(5-aminopyridin-2-yloxy)-2-phenylchroman-4-one

Compound 6-(5-aminopyridin-2-yloxy)-2-phenylchroman-4-one was synthesized as described for 5-amino2-(2-phenyltroman-6-yloxy)pyridine in Example 26, starting from 100mg of compound 6-(5-nitropyridin-2-yloxy)-2-phenylchroman-4-one. (Example 6) *H NMR (400 MHz, CD3OD) δ: 7.62 (d, IH, J 3.0 Hz), 7.51-7.49 (m, 2H), 7.42-7.33 (m, 3H), 7.25-7.18 (m, 3H), 7.06 (d, IH, J 8.8 Hz), 6.76 (d, IH, J 8.6 Hz), 5.50 (dd, IH, J 13.0, 2.9 Hz), 3.08 (dd, IH, - 17.0, 13.0 Hz), 2.82 (dd, IH, J - 17.0, 2.9 Hz).

Example 57:

6-(5-nitropyridin-2-yloxy)-2-phenylchroman-4-yl acetic acid ester

0.26ml of acetic anhydride was added dropwise to a solution of (100mg) 6-(5-nitropyridin-2-yloxy)-2 phenylchroman-4-ol (Example 8(b)) in dry pyridine. The reaction mixture was kept under reflux for 1-2 hours. After that, it is introduced into cold water and extracted with ethyl acetate. The organic phase was washed with 1M hydrochloric acid, water, and saturated NaCl solution. The solution was then dried over MgSO 4 , and evaporated to dryness. 1H NMR (400 MHz, d6-DMSO) δ: 9.05 (d, III, J 2.8 Hz), 8.61 (dd, IH, J 9.1, 2.8 Hz), 7.52-7.35 (m, 5H), 7.23 (d, IH, J 9.1 Hz), 7.14-7.10 (m, 2H), 6.98 (d, IH, J 8.5 Hz), 6.18 (dd, IH, J 10.1,6.4 Hz), 5.44 (dd, IH, J 11.4, 1.4 Hz), 2.51 (m, IH), 2.15 (m, IH), 2.05 (s, 3H).

Example 58:

6-(2-aminoethoxy)-2-phenylchroman-4-one-methyl sulfonate

a) 6-2-azidoethoxy)-2-phenylchroman-4-one

The synthesis of the compound 6-(2-azidoethoxy)-2-phenylchroman-4-one was carried out according to the description for

6-(2-azidoethoxy)-2-phenylchroman in Example 4(a) starting from 1.0 g of 6-hydroxy-flavanone. 1H NMR (400 MHz, CD3OD) δ: 7.53-7.51 (m, 2H), 7.44-7.35 (m, 4H), 7.22 (dd, IH, J 9.0, 3.1 Hz), 7.04 (d, IH, J 9.0 Hz), 5.51 (dd, IH, J 13.1, 3.0 Hz), 4.17 (t, 2H, J 4.9 Hz), 3.60 (t, 2H, J 4.9 Hz), 3.11 (dd, IH, J-16.9, 13.1 Hz), 2.85 (dd, IH, J-16.9, 3.0 Hz).

b) 6-(2-aminoethoxy)-2-phenylchroman-4-one methylsulfonate

The synthesis of 6-(2-aminoethoxy)-2-phenylchroman-4-one methylsulfonate was performed as

is described for 2-(2-phenylchroman-6-yloxy)ethylamine methylsulfonate in Example 4 (b) starting from 6-(2-azidoethoxy)-2-phenylchroman-4-one-a.<*>H NMR (400 MHz, dć-DMSO) δ: 7.91 (bs, 3H), 7.55-7.54 (m, 2H), 7.46-7.37 (m, 3H), 7.31 (d,lH, J 3.1 Hz), 7.28 (dd, IH, 8.8, 3.1 Hz), 7.12 (d, IH, 8.8 Hz), 5.63 (dd, IH, J 13.0, 3.0 Hz), 4.17 (t, 2H, J 5.1 Hz), 3.25 (dd, IH, J - 16.9, 13.0 Hz), 3.23 (m, 2H), 2.86 (dd, 1H, J-16.9, 3.0 Hz), 2.29 (s, 3H).

Example 59:

2-(3-bromophenyl)-6-(5-nitropyridin-2-yloxy)chroman-4-ol

The compound 2-(3-bromophenyl)-6-(5-nitropyridin-2-yloxy)chroman-4-ol was synthesized in the manner described for the synthesis of 5-nitro-2-(2-phenylchroman-6-yloxy)pyridine in Example 1(b) starting from 215 mg of 2-(3-bromophenyl)chroman-4,6-diol (Example 15(b)). The product was recrystallized from a mixture of 2-propanol and acetone. 1H NMR (300 MHz, d6-DMSO) δ: 9.04 (d, IH, J 2.8 Hz), 8.61 (dd, IH, J 9.1, 2.8 Hz), 7.69 (m, IH), 7.58-7.50 (m, 2H), 7.40 (m, IH), 7.25 (d, IH, J 2.7 Hz), 7.22 (d, IH, 9.1 Hz), 7.02 (dd, IH, J 8.8, 2.7 Hz), 6.91 (d, IH, J 8.8 Hz), 5.65 (d, IH, J 6.4 Hz), 5.33 (d, IH, J 10.8 Hz), 4.97 (m, IH), 2.36 (m, IH), 1.94 (m, IH).

Example60:

2-(2-fluorophenyl)-6-(5-nitropyridin-2-yloxy)chroman-4-ol

The compound 2-(2-fluorophenyl)-6-(5-nitropyridin-2-yloxy)chroman-4-ol was synthesized

according to the description for 5-nitro-2-(2-phenylchroman-6-yloxy)pyridine in Example 1(b) starting from 315 mg of compound 2-(2-fluorophenylchroman-4,6-diol-a. (Example 19(b)). The product was recrystallized from a mixture of 2-propanol and acetone.<*>H NMR (400 MHz, d6-DMSO) 5: 9.04 (d, IH, J 2.9 Hz), 8.61 (dd, IH, J 9.1, 2.9 Hz), 7.61 (m, IH), 7.43 (m, IH), 7.31-7.24 (m, 3H), 7.23 (d, IH, J 9.1 Hz), 7.02 (dd, IH, J 8.7, 3.1 Hz), 6.89 (d, IH, J 8.7 Hz), 5.69 (d, IH, J 6.3 Hz), 5.55 (d, 1H, J 11.9 Hz), 5.00 (m, IH), 2.33 (m, IH), 2.07 (m, IH).

Example 61:

2-(2,5-difluorophenyl)-6-(5-nitropyridin-2-yloxy)chroman-4-ol

The compound 2-(2,5-difluorophenyl)-6-(5-nitropyridin-2-yloxy)chroman-4-ol was synthesized as described in the synthesis of the compound 5-nitro-2-(2-phenylchroman-6-yloxy)pyridine in Example 1(b) starting from 200 mg of the compound 2-(2,5-difluorophenyl)chroman-4,6-diol (Example 14(b)). purified preparatively on a thin layer of silica gel (TCL) using toluene - ethyl acetate (4:1) as eluent. 1H NMR (400 MHz, CDCl3) δ: 9.03 (d, IH, J 2.8 Hz), 8.50 (dd, IH, J 9.1, 2.8 Hz), 7.36-7.33 (m, 2H), 7.08-6.95 (m, 5H), 5.50 (d, IH, J 11.1 Hz), 5.09 (m, IH), 2.53 (m, IH), 2.05 (m, IH).

Example 62:

2-(3-fluorophenyl)-6-(5-nitropyridin-2-yloxy)chroman-4-ol

The synthesis of the compound 2-(3-fluorophenyl)-6-(5-nitropyridin-2-yloxy)chroman-4-ol was performed as described in the synthesis of the compound 5-nitro-2-(2-phenylchroman-6-yloxy)pyridine in Example 1(b) starting from 890 mg of the compound 2-(3-fluorophenyl)chroman-4,6-diol from Example 9(b). The product was purified by column chromatography using a split gradient with ethyl acetate : heptane (20%->33%) as eluent followed by recrystallization from a mixture of 2-propanol and acetone.<*>H NMR (400 MHz, d6-DMSO) δ: 9.04 (d, IH, J 2.9 Hz), 8.61 (dd, IH, J 9.1, 2.9 Hz), 7.48 (m, IH), 7.35-7.31 (m, 2H), 7.26-7.19 (m,3H), 7.02 (dd, IH, J 8.8, 2.9 Hz), 6.91 (d, IH, J 8.8 Hz), 5.67 (d, IH, J 6.4 Hz), 5.34 (d, IH, J 10.4 Hz), 4.98 (m, IH), 2.36 (m, 1H), 1.99 (m, 1H).

Example63:

2-( 2-( 2, 5- difluorophenyl) chroman- 6- yloxy)- 5- ethoxyphenylamine hydrochloride

a) 1-chloro-4-ethoxy-2-nitrobenzene

The compound 4-chloro-3-nitrobenzene (5.0g) was dissolved in acetone and (2.5ml) ethyl iodide and

(4.4 grams) of potassium carbonate. The reaction mixture was stirred at 40°C for 4/2 hours. After cooling to room temperature, the mixture was filtered and the filtrate was evaporated to dryness. 1H NMR (400 MHz, d 6 -DMSO) δ: 7.64 (m, 2H), 7.27 (dd, 1H, J 9.0, 3.1 Hz), 4.12 (q, 2H, J 7.0 Hz), 1.34 (t, 3H, 7.0 Hz).

b) 2-(2,5-difluorophenyl)-6-(4-ethoxy-2-nitrophenoxy)chroman 320 mg of the compound 2-(2,5-difluorophenyl)chroman-6-ol (Example 14(c)) was dissolved in

with dry DMF and then 150 mg of potassium tert-butoxide was added. The resulting reaction mixture was stirred for 30 minutes with the addition of another 250 mg of 1-chloro-4-ethoxy-2-nitrobenzene. The reaction mixture was then kept under reflux for another 8 hours. After cooling to room temperature, a saturated HCl solution was added to the reaction mixture, and the entire mixture was extracted with ethyl acetate. The collected organic solvent layers were first washed with water and then with saturated NaCl solution. The product was purified by column chromatography using heptane-ethyl acetate (3:1) as the eluent.<*>H NMR (300 MHz, CDCl3) 5: 7.43 (d, IH, J 2.9Hz), 7.25 (m, IH), 7.08-6.97 (m, 4H), 6.89-6.75 (m, 3H), 5.31 (d, IH, J 9.1 Hz), 4.06 (q, 2H, J 7.0 Hz), 2.97 (m, IH), 2.74 (m, IH), 2.26 (m, IH), 1.98 (m, IH), 1.44 (t, 3H, 7.0 Hz).

c) 2-[2-(2,5-difluorophenyl)chroman-6-yloxy]-ethoxyphenylamine hydrochloride The compound 2-[2-(2,5-difluorophenyl)chroman-6-yloxy]-ethoxyphenylamine hydrochloride was

synthesized as described for 5-methoxy-2-(2-phenylchroman-6-yloxy)phenylamine hydrochloride in Example 3(b) starting from 150 mg of the compound 2-(2,5-difluorophenyl)-6-(4-ethoxy-2-nitrophenoxy)chromane.<*>H NMR (400 MHz, CDCl3) 5: 7.26-7.22 (m, 2H). 7.01-6.74 (m, 7H), 5.22 (d, IH, J 9.1 Hz), 3.90 (q, 2H, J 6.9 Hz), 2.90 (m, IH), 2.68 (m, IH), 2.19 (m, IH), 1.90 (m, IH), 1.34 (t, 3H, 6.9 Hz).

Example 64:

5-nitro-2-["2-(4-trifluoromethylphenyl)chloronan-6-yloxy]pyridine

a) 6-hydroxy-2-(4-trifluoromethylphenyl)chroman-4-one

The compound 6-hydroxy-2-(4-trifluoromethylphenyl)chroman-4-one was synthesized as

described in the synthesis of 2-(3-fluorophenyl)-6-hydroxy chroman-4-one from Example 9(a) starting from the compound 2',5'-dihydroxy acetophenone (2.0 g) and 2.1 ml of the compound 4-trifluoromethylbenzaldehyde. The resulting product was purified by column chromatography while n-heptane-ethyl acetate (2:1) was used as the eluent. The continuation of the purification was also carried out by column chromatography, but with the eluent toluene-ethyl acetate (4:1). The final product was obtained by recrystallization from ethanol. *H NMR (400 MHz, d6-DMSO) δ: 9.47 (s, IH), 7.82-7.76 (m, 4H), 7.13 (d, IH, J 3.0 Hz), 7.06 (dd, IH, J 8.8, 3.0 Hz), 6.99 (d, IH, J 8.8 Hz), 5.70 (dd, IH, J 12.9, 2.9 Hz), 3.16 (dd, IH, J -16.9, 12.9 Hz), 2.86 (dd, IH, J - 16.9, 2.9 Hz).

b) 2-(4-trifluoromethylphenyl)chroman-4,6-diol

The compound 2-(4-trifluoromethylphenyl)chroman-4,6-diol was synthesized as described for

2-phenylchroman-4,6-diol in Example 8(a) starting from 860 mg of the compound 2-(4-trifluoromethylphenyl)-6-hydroxy chroman-4-one.<*>H NMR (400 MHz, d6-DMSO) 8: 8.86 (s, 1H), 7.77 (d, 2H, J 8.3), 7.68 (d, 2H, J 8.3 Hz). Hz), 6.89 (d, IH, J 2.9 Hz), 6.63 (d, IH, J 8.7 Hz), 6.56 (dd, IH, J 8.7, 2.9 Hz), 5.45 (d, IH, J 7.0 Hz), 5.26 (d, IH, J 11.2 Hz), 4.90 (m, IH), 2.32 (m, IH), 1.85 (m,

IH).

c) 2-(4-trifluoromethylphenyl)chroman-6-ol

The synthesis of 2-(4-trifluoromethylphenyl)chroman-6-ol was carried out as described for 2-(3-fluorophenyl)chroman-6-ol in Example 9(c) starting from 730 mg of the compound 2-(4-trifluoromethyl-phenyl)chroman-4,6-diol. 1H NMR (400 MHz, d6-DMSO) δ: 8.82 (s, IH), 7.75 (d, 2H, J 8.3 Hz), 7.65 (d, 2H, J 8.3 Hz), 6.67 (d, IH, J 8.6 Hz), 6.53 (d, IH, J 2.9 Hz) 6.51 (dd, IH, J 8.6 Hz). 2.9 Hz), 5.12 (d, IH, J 8.3 Hz), 2.90 (m, lH), 2.63 (m, IH), 2.16 (m, IH), 1.92 (m, IH).

d) 2-[2-(4-Trifluoromethylphenyl)chroman-6-yloxy]-5-nitropyridine The compound 2-[2-(4-trifluoromethylphenyl)chroman-yloxy]-5-nitropyridine was synthesized

as described for 5-nitro-2-(2-phenylchroman-6-yloxy)pyridine in Example 1(b) starting from

605mg of 2-(4-trifluoromethylphenyl)chroman-ol. The product was purified by column chromatography, using 1.5% ethyl acetate in toluene as eluent, and then recrystallized from a mixture of -2-propanol and acetone.<*>H NMR (400 MHz, d6-DMSO) δ: 9.04 (d, IH, J 2.9 Hz), 8.60 (dd, IH, J 9.1, 2.9 Hz), 7.79 (d, 2H, J 8.2 Hz), 7.70 (d, IH, J 8.2 Hz), 7.21 (d, IH, J 9.1 Hz), 7.01 (dd, IH, J 8.7, 2.7 Hz), 6.98 (d, IH, J 2.7 Hz), 6.95 (d, IH, 8.7 Hz), 5.29 (dd, IH, J 10.1, 2.0 Hz), 3.00 (ddd, IH, J -16.9, 10.1, 5.8 Hz), 2.4 (ddd, IH, J-16.9, 8.4, 4.5 Hz), 2.24 (m, IH), I. 99 (m, IH).

Example65:

6- f2-(4-trifluoromethylphenyl)chroman-6-yloxylpyridin-3-ylamine

The compound 6-[2-(4-trifluoromethylphenyl)chroman-6-yloxy]pyridin-3-ylamine was synthesized like the compound 5-amino-2-(2-phenylchroman-6-yloxy)pyridine in Example 26 starting from 275 mg of the compound 2-[2-(4-trifluoromethylphenyl)chroman-6-yloxy]-5-nitropyridine (Example 64 (d)). 1H NMR (400 MHz, d6-DMSO) δ: 7.78 (d, 2H, J 8.4 Hz), 7.68 (d, 2H, J 8.4 Hz), 7.52 (dd, IH, J 2.9, 0.5 Hz), 7.06 (dd, IH, 8.6, 2.9 Hz), 6.84 (m, IH), 6.77-6.75 (m, 2H), 6.70 (dd, IH, J 8.6, 0.5 Hz), 5.23 (dd, IH, J 10.0, 2.0 Hz), 5.01 (s, 2H), 2.95 (ddd, IH, - 16.8, II. 1, 5.9 Hz), 2.69 (ddd, IH, J-16.8, 8.5, 4.8 Hz), 2.21 (m, 1H), 1.97 (m, 1H).

Example66:

N-{6-[2-(4-trifluoromethylphenyl)chroman-6-yloxy1pyridin-3-yl| acetamide

The compound N-{6-[2-(4-trifluoromethylphenyl)chroman-6-yloxy]pyridin-3-yl}acetamide was synthesized according to the description for 5-N'-acetylamino-2-(2-phenylchroman-6-yloxy)pyridine in Example 27, starting from 140 mg of the compound 6-[2-(4-trifluoromethylphenyl)chroman-6-yloxy]pyridin-3-ylamine (Example 65). 1H NMR (400 MHz, d6-DMSO) δ: 10.11 (s, IH), 8.29 (d, IH, J 2.7 Hz), 8.02 (dd, IH, J 8.9, 2.7 Hz), 7.78 (d, 2H, J 8.3 Hz), 7.69 (d, 2H, J 8.3 Hz), 7.17 (m, IH), 6.94-6.86 (m, 3H), 5.66 (d, IH, J 8.2 Hz), 2.98 (m, IH), 2.72 (m, IH), 2.23 (m, IH), 2.04 (s, 3H), 1.97 (m, IH).

Example67:

N-{6-r2-(3-fluorophenyl)chroman-6-yloxy1pyridin-3-yl}methylsulfonamide

The compound N-{6-[2-(3-fluorophenyl)chroman-6-yloxy]pyridin-3-yl}methylsulfonamide was synthesized as in the synthesis of N-[6-(2-phenylchroman-6-yloxy)pyridin-3-yl] methylsulfonamide in Example 46 starting from 300 mg of 6-(2-(3-fluorophenyl)chroman-6-yloxy)-pyridin-3-ylamine (Example 54). The product was purified over silica gel using ethyl acetate-heptane (5:1) as eluent. 1H NMR (400 MHz, d6-DMSO) δ: 9.67 (s, IH), 7.99 (dd, IH, J 2.8, 0.6 Hz), 7.67 (dd, IH, J 8.8, 2.8 Hz), 7.46 (m, IH), 7.31-7.27 (m, 2H), 7.17 (m, IH), 6.98 (dd, IH, J 8.8, 0.6 Hz), 6.90-6.88 (m, 3H), 5.16 (dd, IH, J 10.0, 2.2 Hz), 2.99 (s, 3H), 2.96 (m, IH), 2.72 (m, IH), 2.20 (m, IH), 1.99 (m,lH).

Example68:

2-(4-chlorophenyl)-6-(5-nitropyridin-2-yloxy)chroman-4-ol

a) 6-hydroxy-2-(4-chlorophenyl)chroman-4-one

The compound 6-hydroxy-2-(4-chlorophenyl)chroman-4-one was synthesized as

described for 2-(3-fluorophenyl)-6-hydroxychroman-4-one in Example 9(a) starting from 3.0 g of the compound 2',5'-dihydroxyacetophenone and 2.8 g of 4-chlorobenzaldehyde. The product was extracted from ethanol. <!>H NMR (400 MHz, d6-DMSO) δ: 9.46 (s, IH), 7.56 (d, 2H, J 8.5 Hz), 7.45 (d, 2H, J 8.5 Hz), 7.11 (d,lH, J 2.8 Hz), 7.04 (dd, IH, J 8.9, 2.8 Hz), 6.96 (d, IH, J 8.9 Hz), 5.58 (dd, IH, J 13.1, 2.9 Hz), 3.15 (dd, IH, J-16.8, 13.1 Hz), 2.79 (dd, IH, J-16.8, 2.9 Hz).

b) 2-(4-chlorophenyl)chroman-4,6-diol

The compound 2-(4-chlorophenyl)chroman-4,6-diol was synthesized according to the description for 2-phenylchroman-4,6-diol in Example 8(a) starting from 375 mg of the compound 2-(4-chlorophenyl)-6-hydroxychroman-4-one.<*>H NMR (400 MHz, d6-DMSO) 5: 8.84 (s,1H). 7.49-7.44 (m, 4H), 6.88 (d,lH, J 2.8 Hz), 6.60 (d, IH, J 8.6 Hz), 6.55 (dd, IH, J 8.6, 2.8 Hz), 5.43 (bs, IH), 5.14 (dd, IH, J 11.9, 1.6 Hz), 4.87 (m, IH), 2.26 (m, IH), 1.85 (m, 1H).

c) 2-(4-chlorophenyl)-6-(5-nitropyridin-2-yloxy)chroman-4-ol The compound 2-(4-chlorophenyl)-6-(5-nitropyridin-2-yloxy)chroman-4-ol was synthesized

according to the description for 5-nitro-2-(2-phenylchroman-6-yloxy)pyridine in Example 1(b) starting from 330 mg of the compound 2-(4-chlorophenyl)chroman-4,6-diol. The resulting product was purified by column chromatography using n-heptane and ethyl acetate (2:1) as eluent. <]>H NMR (300 MHz, d6-DMSO) δ: 9.04 (d, IH, J 2.9 Hz), 8.61 (dd, III, J 9.1, 2.9 Hz), 7.54-7.47 (m, 4H), 7.25 (d, IH, J 2.8 Hz), 7.22 (d, IH, 9.1 Hz), 7.02 (dd, IH, J 8.8, 2.8 Hz), 6.89 (d, IH, J 8.8 Hz), 5.65 (d, IH, J 6.4 Hz), 5.33 (d, IH, J 10.6 Hz), 4.98 (m, IH), 2.34 (m, IH), 1.94 (m, IH).

Example69:

2- r2-(2, 4- dilfluorophenyl) chroman- 6- yloxyl- 5- nitropyridine

a) 2-(2,4-difluorophenyl)-6-hydroxychroman-4-one

The compound 2-(2,4-dinitrophenyl)-6-hydroxychroman-4-one was synthesized as described

at 2-(3-fluorophenyl)-6-hydroxychroman-4-one in Example 9(a) starting from 3.0 g of the compound 2',5'-dihydroxyacetophenone and 1.6 ml of 2-4-difluorobenzaldehyde. 1H NMR (400 MHz, d6-DMSO) δ: 9.46 (s, IH), 7.73 (m, IH), 7.34 (m, IH), 7.19 (m, IH), 7.13 (d, IH, J 2.9 Hz), 7.04 (dd, IH, J 8.8, 2.9 Hz), 6.95 (d, IH, J 8.8 Hz), 5.74 (dd, IH, J 13.5, 2.8 Hz), 3.28 (dd, IH, J -16.9, 13.5 Hz), 2.74 (dd, IH, J-16.9, 2.8 Hz).

b) 2-(2,4-difluorophenyl)chroman-4,6-diol

The compound 2-(2,4-difluorophenyl)chroman-4,6 diol was synthesized as described for 2-phenylchroman-4,6-diol, in Example 8(a) starting from 1.47 g of 2-(2,4-difluorophenyl)-6-hydroxychroman-4-one-a. <1>H NMR (400 MHz, d6-DMSO) 5: 8.86 (s,1H). 7.61 (m, IH), 7.28 (m,lH), 7.14 (m, IH), 6.88 (d,lH, J 2.7 Hz), 6.59 (d,lH, J 8.9 Hz), 6.54 (dd, IH, J 8.9, 2.7 Hz), 5.46 (s, IH), 5.32 (dd, IH, J 11.9, 1.4 Hz), 4.88 (m, IH), 2.24 (m, IH), 1.99 (m, IH).

c) 2-(2,4-difluorophenyl)chroman-6-ol

The compound 2-(2,4-difluorophenyl)chroman-6-ol) was obtained according to the procedure described in

of obtaining 2-(3-fluorophenyl)chroman-6-ol in Example 9(c) starting from 800 mg of the compound 2-(2,4-difluorophenyl)chroman-4,6-diol. 1 h NMR (400 MHz, d6-DMSO) δ: 8.83 (s, III), 7.56 (m, III), 7.28 (m, IH), 7.13 (m, IH), 6.63 (m, IH), 6.53-6.50 (m, 2H), 5.17 (dd, IH, J 10.3, 2.3 Hz), 2.92 (ddd, IH, J-17.0, 11.5, 5.8 Hz), 2.66 (ddd, IH, J-17.0, 5.0, 2.7 Hz), 2.09 (m, IH), 1.98 (m,lH).

d) 2-[2-(2,4-difluorophenyl)chroman-6-yloxy]-5-nitropyridine

The compound 2-[2-(2,4-difluorophenyl)chroman-6-yloxy]-5-nitropyridine was synthesized according to

to the description for 5-nitro-2-(2-phenylchroman-6-yloxy)pyridine from Example 1(b) starting from 720 mg of the compound 2-(2,4-difluorophenyl)chroman-6-ol. *H NMR (400 MHz, d6-DMSO) δ: 9.04 (d,lH, J 3.0 Hz), 8.60 (dd, IH, J 9.0 3.0 Hz), 7.61 (m, IH), 7.31 (m, IH), 7.21 (d,lH, 9.0 Hz), 7.17 (m,

IH), 7.02 (d,lH, J 2.9 Hz), 6.97 (dd, IH, J 8.9, 2.9 Hz), 6.91 (d, IH, 8.9 Hz), 5.34 (dd, IH, J 9.9, 2.0 Hz), 3.03 (m, IH), 2.78 (m,lH), 2.17 (m, IH), 2.07 (m, IH).

Example70:

6-[2-(2,4-difluorophenyl)chroman-6-yloxy1pyridin-3-ylamine

The compound 6-[2-(2,4-difluorophenyl)chroman-6-yloxy]pyridin-3-ylamine was synthesized according to the description for 5-amino-2-(2-phenylchroman-6-yloxy)pyridine in Example 26 starting from 845 mg of the compound 2-[2-(2,4-difluorophenyl)chroman-6-yloxy]-5-nitropyridine (Example 69(d)). 1H NMR (400 MHz, d6-DMSO) δ: 7.58 (m, IH), 7.51 (d, IH, J 3.3 Hz), 7.30 (m, IH), 7.15 (m, IH), 7.05 (dd, IH, J 8.3, 3.3 Hz), 6.84-6.73 (m, 3H), 6.70 (d, IH, J) 8.3 Hz), 5.27 (dd, IH, J 10.3, 2.3 Hz), 5.01 (s, 2H), 2.97 (m, IH), 2.73 (m, IH), 2.13 (m, IH), 2.03 (m, 1H).

Example 71:

N-{6-[2-(2,4-difluorophenyl)chroman-6-yloxy]pyridin-3-yl| methylsulfonamide

The compound N-{6-[2-(2,4-difluorophenyl)chroman-6-yloxy]pyridin-3-yl}methylsulfonamide was prepared as described for N-[6-(2-phenylchroman-6-yloxy)pyridin-3-yl]methylsulfonamide in Example 46 starting from 100 mg of 6-[2-(2,4-difluorophenyl)chroman-6-yloxy]pyridin-3-ylamine (Example 70). The product was recrystallized from a mixture of methanol and diethyl ether. 1H NMR (400 MHz, d6-DMSO) δ: 9.67 (s, IH), 7.99 (d, IH, J 2.8 Hz), 7.67 (dd, IH, J 8.8, 2.8 Hz), 7.60 (m, IH), 7.30 (m, IH), 7.16 (m, IH), 6.98 (d, IH, J 8.8 Hz), 6.92-6.86 (m, 3H), 5.31 (dd, IH, J 10.3, 2.3 Hz), 3.01 (m, IH), 2.98 (s, 3H), 2.76 (m, IH), 2.06 (m, IH).

Example 72:

2-(2,4-difluorophenyl)-6-(5-nitropyridin-2-yloxy)chroman-4-ol

The compound 2-(2,4-difluorophenyl)-6-(5-nitropyridin-2-yloxy)chroman-4-ol was synthesized according to the description for 5-nitro-2-(2-phenylchroman-6-yloxy)pyridine in Example 1(b) starting from 520 mg of the compound 2-(2,4-difluorophenyl)chroman-4,6-diol (Example 69(b)). The resulting product was recrystallized from a mixture of 2-propanol and diethylether.<*>H NMR (400 MHz, d6-DMSO) 6: 9.04 (d, IH, J 2.8 Hz), 8.61 (dd, IH, J 9.1, 2.8 Hz), 7.66 (m, IH), 7.32 (m, IH), 7.26 (d, IH, J 2.9 Hz), 7.23 (d, IH, 9.1 Hz), 7.17 (m, IH), 7.02 (dd, IH, J 8.9, 2.9 Hz), 6.88 (d, IH, J 8.9 Hz), 5.70 (bs, IH), 5.52 (dd, IH, J 11.9, 1.5 Hz), 5.00 (m, IH), 2.31 (m, IH), 2.09 (m, IH).

Example73:

2-(2-(2-chlorophenyl)chroman-6-yloxy)-5-nitropyridine

a) 2-(2-chlorophenyl)-6-hydroxychroman-4-one

The compound 2-(2-chlorophenyl)-6-hydroxychroman-4-one was synthesized as described for

2-(3-fluorophenyl)-6-hydroxychroman-4-one in Example 9(a) starting from 3.0 g of the compound 2',5'-dihydroxyacetophenone and 2.8 g of the compound 2-chlorobenzaldehyde. The product was passed through silica gel, and heptane-ethyl acetate was used as an eluent, and then the resulting product was washed with ethanol. 1H NMR (400 MHz, d6-DMSO) δ: 9.49 (s, IH), 7.77 (dd, IH, J 7.7, 2.0 Hz), 7.53 (dd, IH, J 7.6, 1.8 Hz), 7.49-7.41 (m, 2H), 7.14 (d, IH, J 2.9 Hz), 7.06 (dd, IH, J 8.8, 2.9 Hz), 6.93 (d, IH, J 8.8 Hz), 5.78 (dd, IH, J 13.6, 2.6 Hz), 3.19 (dd, IH, J-16.9, 13.6 Hz), 2.78 (dd, IH, J-16.9, 2.6 Hz).

b) 2-(2-chlorophenyl)chroman-4,6-diol

The compound 2-(2-chlorophenyl)chroman-4,6-diol was synthesized as described for 2-phenyl-chroman-4,6-diol in Example 8(a) starting from 1.12 g of the compound 2-(2-chlorophenyl)-6-hydroxy-chroman-4-one. 1H NMR (400 MHz, d6-DMSO) δ: 7.63 (dd, IH, J 7.7, 1.8 Hz), 7.49 (dd, IH, J 7.8, 1.4 Hz), 7.45-7.36 (m, 2H), 6.89 (d, IH, J 2.9 Hz), 6.63 (d, IH, J 8.8 Hz), 6.56 (dd, IH, J 8.9, 2.9 Hz), 5.39 (dd, IH, JI 1.7, 1.5 Hz), 4.90 (m, IH), 2.33 (m, IH), 1.82 (m, IH).

c) 2-(2-chlorophenyl)chroman-6-ol

Compound 2-(2-chlorophenyl)chroman-6-ol was synthesized as described for compound 2-(3-fluorophenyl)chroman-6-ol in Example 9(c) starting from 500 mg of 2-(2-chlorophenyl)-chroman-4,6-diol.

1H NMR (300 MHz, d6-DMSO) δ: 7.58-7.36 (m, 4H), 6.66 (m, IH), 6.55-6.51 (m, 2H), 5.23 (dd, IH, J 10.1 2.1 Hz), 2.92 (m, IH), 2.68 (m, IH), 2.17 (m, IH), 1.87 (m, IH)

d) 2-[2-(2-chlorophenyl)chroman-6-yloxy]-5-nitropyridine

The compound 2-[2-(2-chlorophenyl)chroman-6-yloxy]-5-nitropyridine was synthesized as described for

5-nitro-2-(2-phenylchroman-6-yloxy)pyridine in Example 1(b) starting from 485 mg, 2-(2-chlorophenyl)-chroman-6-ol. 1H NMR (400 MHz, d6-DMSO) δ: 9.04 (d, IH, J 2.9,0.5 Hz), 8.60 (dd, IH, J 9.1, 2.9 Hz), 7.62 (dd, IH, J 7.5, 1.8 Hz), 7.51 (dd, IH, J 7.6, 1.7 Hz), 7.45-7.40 (m, 2H), 7.21

(dd, IH, J 9.1, 0.5 Hz), 7.04 (d, IH, J 2.7 Hz), 6.99 (dd, IH, J 8.8, 2.7 Hz), 6.94 (d, IH, 8.8 Hz), 5.40 (dd, IH, J 10.4, 2.1 Hz), 3.04 (m, IH), 2.80 (m, IH), 2.24 (m, IH), 1.95 (m, IH).

Example 74:

2-(2-chlorophenyl)-6-(5-nitropyridin-2-yloxy)chroman-4-ol

The compound 2-(2-chlorophenyl)-6-(5-nitropyridin-2-yloxy)chroman-4-ol was synthesized according to the description for 5-nitro-2-(2-phenylchroman-6-yloxy)pyridine in Example 1(b) starting from 520 mg of the compound 2-(2-chlorophenyl)chroman-4,6-diol (Example 68(b). The resulting product was recrystallized from 2-propanol.<]>H NMR (300MHz, d6-DMSO) S: 9.04 (d, IH, J 2.9 Hz), 8.61 (dd, IH, J 9.1, 2.9 Hz), 7.68 (dd, IH, J 7.6, 1.8 Hz), 7.51-7.40 (m, 3H), 7.27 (d, IH, J 2.9 Hz), 7.23 (d, IH, J 9.1 Hz), 7.04 (dd, IH, J 8.8, 2.9 Hz), 6.92 (d, IH, J 8.8 Hz), 5.59 (d, IH, J 10.6 Hz), 5.02 (m,lH), 2.40 (m, IH), 1.93 (m, IH).

Example 75:

5-nitro-2-r2-(4-fluorophenyl)chroman-6-yloxy]pyridine

a) 6-hydroxy-2-(4-fluorophenyl)chroman-4-one

The synthesis of the compound 6-hydroxy-2-(4-fluorophenyl)chroman-4-one was carried out according to the description for 2-(3-fluorophenyl)-6-hydroxychroman-4-one in Example 9(a) starting from 2.0 g of the compound 2',5'-dihydroacetophenone and 1.6 ml of the compound 4-fluorobenzaldehyde. The product was recrystallized from acetic acid. <]>H NMR (400MHz, d6-DMSO) δ: 7.59 (m, 2H), 7.27 (m, 2H), 7.14 (d, IH, J 3.1 Hz), 7.05 (dd, IH, J 8.9, 3.1 Hz), 6.96 (d, IH, J 8.9 Hz), 5.56 (dd, IH, J 13.2, 2.8 Hz), 3.18 (dd, IH, J-16.9, 13.2 Hz), 2.77 (dd, IH, J-16.9, 2.8 Hz).

b) 2-(4-fluorophenyl)chroman-4,6-diol

The compound 2-(4-fluorophenyl)chroman-4,6-diol was synthesized according to the procedure described

for 2-phenylchroman-4,6-diol in Example 8(a) starting from 1.5 g of 2-(4-fluorophenyl)-6-hydroxy-chroman-4-one. 1H NMR (400MHz, d6-DMSO) δ: 8.84 (s,1H), 7.48 (m, 2H), 7.21 (m, 2H), 6.89 (d, IH, J 2.7 Hz), 6.59 (d, IH, J 8.7 Hz), 6.54 (dd, IH, J 8.7, 2.7 Hz), 5.42 (bs,lH), 5.12 (d,lH, J 10.7 Hz), 4.87 (m, IH), 2.25 (m, IH), 1.89 (m, IH).

c) 2-(4-fluorophenyl)chroman-6-ol

The compound 2-(4-fluorophenyl)chroman-6-ol was synthesized according to the description for 2-(3-fluorophenyl)chroman-6-ol in Example 9(c) starting from 480 mg of the compound 2-(4-fluorophenyl)chroman-4,6-diol. 1H NMR (400 MHz, CDCl3) δ: 7.38 (m, 2H), 7.06 (m, 2H), 6.77 (d, IH, J 8.6 Hz), 6.61 (dd, IH, J 8.6, 2.9 Hz), 6.57 (d, IH, 8.6 Hz), 4.97 (dd, IH, J 10.2, 2.4 Hz), 2.95 (ddd, IH, J-16.8, 11.4, 6.2 Hz), 2.74 (ddd, IH, J-16.8, 5.3, 3.1 Hz), 2.15 (m, IH), 2.05 (m, IH).

d) 2-[2-(4-fluorophenyl)chroman-6-yloxy]-5-nitropyridine

The compound 2-[2-(4-fluorophenyl)chroman-6-yloxy]-5-nitropyridine was synthesized like 5-nitro-2-(2-phenylchroman-6-yloxy)pyridine in Example 1(b) starting from 160 mg of the compound 2-(4-fluorophenyl)hyoman-6-ol. The product was purified by preparative (TCL) silica gel thin layer chromatography using n-heptane-ethyl acetate (4:1) as eluent.<*>H NMR (400 MHz, d6-DMSO) 8: 9.04 (dd, IH, J 2.9,0.4 Hz), 8.60 (dd, IH, J 9.1, 2.9 Hz), 7.51 (m, 2H), 7.24 (m, IH), 7.20 (dd, IH, J 9.1, 0.4 Hz), 7.01 (d,lH, J 2.8 Hz), 6.96 (dd, IH, J 8.7, 2.8 Hz), 6.91 (d, IH, 8.7 Hz), 5.15 (dd, IH, J 10.3, 2.2 Hz), 2.94 (m, IH), 2.76 (m, IH), 2.17 (m, IH), 2.01 (m, IH).

Example76:

6- r2-(4-fluorophenyl)chroman-6-yloxylpyridin-3-ylamine

The compound 6-[2-(4-fluorophenyl)chroman-6-yloxy]pyridin-3-ylamine was synthesized as 5-amino-2-(2-phenylchroman-6-yloxy)pyridine in Example 26 starting from 3.04 g of the compound 2-[2-(4-fluorophenyl)chroman-6-yloxy]-5-nitropyridine (Example 75(d)).<!>H NMR (400 MHz, d6-DMSO) 8: 7.52-7.47 (m, 3H), 7.24 (m, 2H), 7.05 (dd, IH, J 8.6, 3.0 Hz), 6.84-6.68 (m, 4H), 5.09 (dd, IH, J 10.2, 2.1 Hz), 5.00 (bs, 2H), 2.93 (m,lH), 2.69 (m, IH), 2.13 (m, IH), 1.98 (m, IH).

Example77:

N-{6-r2-(4-fluorophenyl)chroman-6-yloxylpyridin-3-yl}methylsulfonamide

The synthesis of the compound N-{6-[2-(4-fluorophenyl)chroman-6-yloxy]pyridin-3-yl} methylsulfonamide was carried out according to the description for N-[6-(2-phenylchroman-6-yloxy)pyridin-3-yl]methylsulfonamide in Example 46 starting from 442 mg of the compound 6-[2-(4-fluorophenyl)chroman-6-yloxy]pyridin-3-ylamine (Example 76). The product was passed through a silica gel column, elution was performed using ethyl acetate-n-heptane (10:3) and crystallization was performed from diethyl ether. <]>H NMR (400 MHz, CDCl3) δ: 8.09 (d, IH, J 2.8 Hz), 7.72 (dd, IH, J 8.9, 2.8 Hz), 7.40 (m, 2H), 7.08 (m, 2H), 6.92-6.87 (m, 4H), 6.74 (s, IH), 5.03 (dd, IH, J 10.4, 2.3 Hz), 3.01 (m, IH), 3.00 (s, 3H), 2.80 (m, IH), 2.19/m, IH), 2.07 (m, IH).

Example78:

2-[ 2-( 2, 3- dilfluorophenyl) chroman- 6- yloxyl- 5- nitropyridine

a) 2-(2,3-difluorophenyl)-6-hydroxychroman-4-one

The compound 2-(2,3-difluorophenyl)-6-hydroxychroman-4-one was obtained as

described for 2-(3-fluorophenyl)-6-hydroxychroman-4-one in Example 9(a) starting from 3.0 g of the compound 2',5'-dihydroxyacetophenone and 2.6 ml of 2,3-difluorobenzaldehyde. ]H NMR (400 MHz, d6-DMSO) δ: 9.51 (s,1H), 7.53-7.46 (m, 2H), 7.31 (m, IH), 7.14 (d, IH, J 3.0 Hz), 7.05 (dd, IH, J 8.8, 3.0 Hz), 6.96 (d, IH, J 8.8 Hz), 5.82 (dd, IH, J 13.4, 2.8 Hz), 3.26 (dd, IH, J-16.9, 13.4 Hz), 2.79 (dd, IH, J-16.9, 2.8 Hz).

b) 2-(2,3-difluorophenyl)chroman-4,6-diol

The compound 2-(2,3-difluorophenyl)chroman-4,6-diol was synthesized as described for

compound 2-phenylchroman-4,6-diol in Example 8(a) starting from 2.9 lg of the compound 2-(2,3-difluorophenyl)-6-hydroxychroman-4-one. 1H NMR (400 MHz, d6-DMSO) δ: 8.88 (s,1H), 7.45-7.36 (m, 2H), 7.28 (m, IH), 6.89 (d, IH, J 2.8 Hz), 6.61 (d, IH, J 8.7 Hz), 6.55 (dd, IH, J 8.7, 2.8 Hz), 5.49 (bs, IH), 5.40 (dd, IH, J 11.8, 1.4 Hz), 4.90 (m, IH), 2.28 (m, IH), 1.99 (m, IH).

c) 2-(2,3-difluorophenyl)chroman-6-ol

The compound 2-(2,3-difluorophenyl)chroman-6-ol was synthesized according to the description for the compound 2-(3-fluorophenyl)chroman-6-ol from Example 9(c) starting from 1.5 g of the compound 2-(2,3-difluorophenyl)-chroman-4,6-diol. 1H NMR (400 MHz, d6-DMSO) δ: 8.85 (s, IH), 7.41 (m, IH), 7.33 (m, IH), 7.26 (m, IH), 6.64 (dd, IH, 9.0, 2.8 Hz), 6.54-6.51 (m, 2H), 5.25 (dd, IH, J 10.2, 2.2 Hz), 2.93 (m, IH), 2.66 (m, IH), 2.14 (m, IH), 2.01 (m, IH).

d) 2-[2-(2,3-difluorophenyl)chroman-6-yloxy]-5-nitropyridine

The compound 2-[2-(2,3-difluorophenyl)chroman-6-yloxy]-5-nitropyridine was synthesized by

to the description for 5-nitro-2-(2-phenylchroman-6-yloxy)pyridine in Example 1(b) starting from 1.88g of the compound

2-(2,3-difluorophenyl)chroman-6-ol. 1H NMR (400 MHz, d6-DMSO) δ: 9.04 (d, IH, J 3.0 Hz), 8.60 (dd, IH, J 9.1, 3.0 Hz), 7.45 (m, IH), 7.38 (m, IH), 7.30 (m, IH), 7.21 (d, IH, 9.1 Hz), 7.03 (d, IH, J) 2.7 Hz), 6.98 (dd, IH, J 8.8, 2.7 Hz), 6.92 (d,lH, 8.8 Hz), 5.42 (dd, IH, J 10.4, 2.3 Hz), 3.04 (m, IH), 2.79 (m, IH), 2.21 (m,lH), 2.08 (m,lH).

Example79:

2-(2,6-difluorophenyl)-6-(5-nitropyridin-2-yloxy)chroman-4-ol

a) 6-hydroxy-2-(2,6-difluorophenyl)chroman-4-one

The synthesis of 6-hydroxy-2-(2,6-dichlorophenyl)chroman-4-one was carried out as described for 2-(3-fluorophenyl)-6-hydroxy chroman-4-one in Example 9(a) starting from 3.0 g of the compound 2',5'-dihydroxyacetophenone and 2.6 ml of the compound 2,6-difluorobenzaldehyde. The product is distilled from ethanol. *H NMR (400 MHz, d6-DMSO) δ: 7.55 (m,1H) 7.22-7.18 (m, 2H), 7.14 (d, IH, J 3.0 Hz), 7.03 (dd, IH, J 8.9, 3.0 Hz), 6.93 (d, IH, J 8.9 Hz), 5.84 (dd, IH, J 14.0, 3.0 Hz), 3.38 (dd, IH, J-17.0, 14.0 Hz), 2.80 (dd, IH, J-17.0, 3.0 Hz).

b) 2-(2,6-difluorophenyl)chroman-4,6-diol

The compound 2-(2,6-difluorophenyl)chromane-4,6-diol was synthesized as

described for 2-phenylchroman-4,6-diol in Example 8(a) starting from 4.45 g of the compound 2-(2,6-difluorophenyl)-6-hydroxychroman-4-one. 1H NMR (400 MHz, d6-DMSO) δ: 8.87 (s, 1H), 7.48 (m, IH), 7.17-7.13 (m, 2H), 6.90 (d, IH, J 2.9 Hz), 6.55-6.54 (m, 2H), 5.46 (dd, IH, J 12.2, 1.8 Hz), 4.87 (m, 1H), 2.37 (m, 1H), 2.23 (m, 1H).

c) 2-(2,6-difluorophenyl)-6-(5-nitropyridin-2-yloxy)chroman-4-ol The compound 2-(2,6-difluorophenyl)-6-(5-nitropyridin-2-yloxy)chroman-4-ol was synthesized

according to the procedure already used for the synthesis of 5-nitro-2-(2-phenylchroman-6-yloxy)pyridine from Example 1(b) starting from 1.9g of the compound 2-(2,6-difluorophenyl)chroman-4,6-diol. ]H NMR (300 MHz, d6-DMSO) δ: 9.03 (d, IH, J 2.9 Hz), 8.61 (dd, IH, J 9.1, 2.9 Hz), 7.52 (m, IH), 7.26-7.16 (m, 4H), 7.01 (dd, IH, J 8.8, 2.9 Hz), 6.83 (d, IH, 8.8 Hz), 5.69-5.64 (m, 2H), 4.98 (m, IH), 2.37 (m, IH), 2.29 (m, IH).

Example80:

6-(5-nitropyridin-2-yloxy)-2-(24rifluoromethylphenyl)chlororian-4-ol

a) 6-hydroxy-2-(2-trifluoromethylphenyl)chroman-4-one

The compound 6-hydroxy-2-(2-trifluoromethylphenyl)chroman-4-one was synthesized according to

to the description for 2-(3-fluorophenyl)-6-hydroxychroman-4-one from Example 9(a) starting from the 3,Og compound of 2',5'-dihydroxyacetophenone and the 3,Omi compound of 2-trifluoromethylbenzaldehyde. The product was extracted from ethanol. 1H NMR (300 MHz, d6-DMSO) δ: 9.48 (s, IH), 8.07 (m, IH), 7.86-7.79 (m, 2H), 7.66 (m, IH), 7.15 (d, IH, J 3.0 Hz), 7.06 (dd, IH, J 8.8, 3.0 Hz), 6.95 (d, IH, J 8.8 Hz), 5.70 (dd, IH, J 13.8, 2.4 Hz), 3.38 (dd, IH, J-16.9, 13.8 Hz), 2.66 (dd, IH, J-16.9, 3.0 Hz).

b) 2-(2-trifluoromethylphenyl)chroman-4,6-diol

The synthesis of 2-(2-trifluoromethylphenyl)chroman-4,6-diol was performed according to the description for 2-phenylchroman-4,6-diol from Example 8(a) starting from 1.43 g of the compound 2-(2-trifluoromethylphenyl)-6-hydroxychroman-4-one. 1H NMR (300 MHz, d6-DMSO) δ: 8.89 (s, IH), 7.83 (m, IH), 7.79-7.74 ), 2H), 7.58 )m, IH), 6.90 (d, IH, J 2.7 Hz), 6.61 (d, IH, J 8.9 Hz), 6.56 (dd, IH, J 8.7, 2.7 Hz), 5.51 (d, IH, J 6.5 Hz), 5.34 (d, IH, J 11.6 Hz), 4.88 (m, IH), 2.21 (m, IH), 1.95 (m,

IH).

c) 6-(5-nitropyridin-2-yloxy)-2-(2-trifluoromethylphenyl)chroman-4-ol Compound 6-(5-nitropyridin-2-yloxy)-2-(2-trifluoromethylphenyl)chroman-4-ol synthesized

is the same as the compound 5-nitro-2-(2-phenylchroman-6-yloxy)pyridine from Example 1(b) starting from

350 mg of the compound 2-(2-trifluoromethylphenyl)chroman-4,6-diol. 1H NMR (400 MHz, d6-DMSO) δ: 9.04, (d, IH, J 2.8 Hz), 8.62 (dd, IH, J 9.1, 2.8 Hz), 7.89 (m, IH), 7.82-7.78 (m, 2H), 7.62 (m, IH), 7.28 (d, IH, J 2.7 Hz), 7.24 (d,lH, 9.1 Hz), 7.04 (dd, IH, J 8.7, 2.7 Hz), 6.90 (d, IH, J 8.7 Hz), 5.7 (bs, IH), 5.38 (d, IH, J 11.6 Hz), 5.01 (m, IH), 2.29 (m, IH), 2.05 (m, IH).

Example 81:

2-(3-(3-fluorophenyl)chroman-7-yloxy)-5-nitropyridine

a) 2-(3-fluorophenyl)-1-(2-hydroxy-4-methoxyphenyl)ethanone

3.7g of (3-fluorophenyl)acetic acid and (3.0g) of 3-methoxyphenol were dissolved in BF3Et20

(60ml, 20eq) in a stream of argon. The mixture was stirred at 60-70°C until the starting substances disappeared (9 hours) and then poured into a large volume of ice water. After extraction with ethyl acetate, the total organic layers were washed with water, dried and removed by evaporation. The crude product was purified by column chromatography, using CH 2 Cl 2 as eluent. 1H NMR (400 MHz, d6-DMSO) δ: 12.41 (br s, IH), 8.02 (d, IH, J 9.0 Hz), 7.34-7.38 (m, IH), 7.09-7.13 (m, 3H), 6.56 (dd, IH, J 9.0, 2.5 Hz), 6.49 (d, IH, J 2.5 Hz), 4.41 (s, 2H), 3.83 (s, 3H).

b) 3-(3-fluorophenyl)-7-methoxychromen-4-one

1.76 g of the compound 2-(3-fluorophenyl)-1-(2-hydroxy-4-methoxyphenyl)ethanone was dissolved in

(88 ml) of pyridine. Then (8.8 ml) of piperidine and 88 ml of triethyl orthoformate were added, and the mixture was stirred at 120°C for 3 hours. Since the mixture was poured into water and acidified with conc. HC1, the resulting crude product was filtered. Purification by column chromatography using n-heptane-ethyl acetate (7:3) as eluent gave 3-(3-fluorophenyl)-7-methoxychromen-4-one. <!>H NMR (400 MHz, d6-DMSO) δ: 8.57 (s, IH), 8.06 (d, IH, J 8.9 Hz), 7.45-7.50 (m, 3H), 7.21-7.25 (m, IH), 7.20 (d, IH, J 2.4 Hz), 7.12 (dd, IH, J 8.9, 2.4 Hz), 3.92 (s, 3H).

c) 3-(3-fluorophenyl)-7-hydroxychromen-4-one

The compound 3-(3-fluorophenyl)-7-methoxychromen-4-one (320mg) was kept under

by reflux together with 18 ml of 47% HBr until the disappearance of the starting substances. The resulting mixture was poured into water, and the precipitate was filtered and dried. The yield was 3-(3-fluorophenyl)-7-hydroxychromen-4-one. 1H NMR (400 MHz, dfi-DMSO) δ: 10.87 (s, IH), 8.49 (s, IH), 7.99 (d, IH, J 8.7 Hz), 7.43-7.49 (m, 3H), 7.20-7.24 (m, IH), 6.97 (dd, IH, J 8.7, 2.2 Hz), 6.90 (d, IH, J 2.2 Hz).

d) 3-(3-fluorophenyl)chroman-7-ol

160mg of the compound 3-(3-fluorophenyl)-7-hydroxychromen-4-one was dissolved in 40ml

of ethanol and added 400 mg of carbon rod coated with 10% palladium. Hydrogenation of the reaction mixture was carried out for 6 hours at room temperature and normal pressure. The reaction mixture was then filtered through Celite and washed with ethanol. After removal of the solvent, the product 3-(3-fluorophenyl)chroman-7-ol was formed under reduced pressure. 1H NMR (400 MHz, d6-DMSO) δ: 9.19 (br s, IH), 7.38 (m, IH), 7.17-7.21 (m, 2H), 7.08 (m, IH), 6.88 (d, IH, J 8.2 Hz), 6.30 (dd, IH, J 8.2, 2.4 Hz), 6.20 (d, IH, J) 2.4 Hz), 4.22 (dd, IH, J 10.3, 3.6 Hz), 4.02 (t, IH, 10.3 Hz), 3.20 (m, IH), 2.90 (m, 2H).

e) 2-[3-(3-fluorophenyl)chroman-7-yloxy]-5-nitropyridine

The synthesis of the compound 2-[3-(3-fluorophenyl)chroman-7-yloxy]-5-nitropyridine was carried out as

which is described in the synthesis of the compound 5-nitro-2-(2-phenylchroman-6-yloxy)pyridine of Example 1(b) using 125 mg of 3-(3-fluorophenyl)chroman-7-ol. The resulting product was recrystallized from ethanol.

1H NMR (400 MHz, CDCl 3 ) δ: 9.07 (d, IH, J 2.8 Hz), 8.47 (dd, IH, J 9.0, 2.8 Hz), 7.33 (m, IH), 7.16 (d, IH, J 8.9 Hz), 6.95-7.06 (m, 4H), 6.69-6.71 (m, 2H), 4.38 (dd, IH, J 10.6, 4.3 Hz), 4.06 (t, IH, 10.6 Hz), 3.30 (m, IH), 3.06 (m, 2H).

Example 82:

5-nitro-2-(3-phenylchroman-7-yloxy)pyridine

a) 7-hydroxy-3-phenylchromen-4-one

The compound 7-hydroxy-3-phenylchromen-4-one is commercially available or can

be synthesized by the methods described for 3-(3-fluorophenyl)-7-hydroxychromen-4-one of Example 81(a-c). The ]H NMR spectrum is as reported in the literature (Synth. Commun., 2000, 30(3), 469-484).

b) 3-phenylchroman-7-ol

The compound 3-phenylchroman-7-ol was synthesized according to the description for the synthesis of 3-(3-fluorophenyl)-chroman-7-ol of Example 81 (d) using 0.5 g of the compound 7-hydroxy-3-phenylchromen-4-one *H NMR (400 MHz, d6-DMSO) δ: 8.18 (br s, 1H), 7.31-7.34 (m, 4H). 7.25-7.27 (m, IH), 6.88 (d, IH, J 8.2 Hz), 6.30 (dd, IH, J 8.2, 2.4 Hz), 6.20 (d, IH, J 2.4 Hz), 4.21 (dd, IH, J 10.3, 3.6 Hz), 4.00 (t,lH, 10.3 Hz), 3.13 (m, IH), 2.84-2.87 (m, 2H).

c) 5-nitro-2-(3-phenylchroman-7-yloxy)pyridine

The compound 5-nitro-2-(3-phenylchroman-7-yloxy)pyridine was synthesized as described for

synthesis of 5-nitro-2-(2-phenylchroman-6-yloxy)pyridine in Example 1(b) using 200 mg of the compound 3-phenylchroman-7-ol. <!>H NMR (400 MHz, d6-DMSO) δ: 9.05 (d, IH, J 2.9 Hz), 8.61 (dd, IH, J 9.1, 2.9 Hz), 7.34-7.38 (m, 4H), 7.27-7.30 (m, IH), 7.22 (m, 2H), 6.70-6.74 (m, 2H), 4.31 (dd, IH, J 10.4, 3.5 Hz), 4.12 (t, IH, 10.4 Hz), 3.24 (m, IH). 3.01-3.11 (m, 2H).

Example 83:

5- methoxy- 2-( 3- phenylchroman- 7- yloxy) phenylamine hydrochloride

a) 7-(4-methoxy-2-nitrophenoxy)-3-phenylchroman

The compound 7(4-methoxy-2-nitrophenoxy)-3-phenylchroman was synthesized according to

to the description for 6-(4-methoxy-2-nitrophenoxy)-2-phenylchroman of Example 3(a) using 0.5 g of the compound 3-phenylchroman-7-ol. 1H NMR (400MHz, d6-DMSO) δ: 7.60 (d, IH, J 3.1 Hz), 7.35 (m, 4H), 7.32 (dd, IH, J 9.1, 3.1 Hz), 7.27-7.29 (m, IH), 7.21 (d,lH, J 9.1 Hz), 7.12 (d, IH, J 8.3 Hz), 6.48 (dd, IH, J 8.3, 2.5 Hz), 6.38 (d, IH, J 2.5 Hz), 4.26 (dd, IH, J 10.4, 3.5 Hz), 4.08 (t,lH, J 10.4 Hz), 3.85 (s, 3H), 3.20 (m, IH), 2.90-3.04 (m, 2H).

b) 5-methoxy-2-(3-phenylchroman-7-yloxy)phenylamine hydrochloride The compound 5-methoxy-2-(3-phenylchroman-7-yloxy)phenylamine hydrochloride was synthesized by

to the description for the compound 5-methoxy-2-(2-phenylchroman-6-yloxy)phenylamine hydrochloride in Example 3 (b) using 3 10 mg of the compound 7-(4-methoxy-2-nitrophenoxy)-3-phenylchromane. 1H NMR (400 MHz, d6-DMSO) δ: 7.32-7.35 (m, 4H), 7.23-7.29 (m, IH), 7.05 (d, IH, J 8.4 Hz), 6.76 (d, IH, J 8.8 Hz), 6.46 (d, IH, J 2.8 Hz), 6.43 (dd, IH, J 8.4 Hz). 2.5 Hz), 6.28 (d, IH, J 2.5 Hz), 6.24 (dd, IH, J 8.8, 2.8 Hz), 4.24 (dd, IH, J 10.4, 3.4 Hz), 4.05 (t, IH, J 10.4 Hz), 3.18 (m, IH), 2.88-3.01 (m, 2H).

Example 84:

5- nitro- 2-( 2- phenyl- 2, 3- dihydrobenzori, 41oxatin- 6- yloxy) pyridine

a) 2-(2-hydroxy-1-phenylsulfanyl)benzene-1,4-diol

Into a solution of (0.5g) 2-mercaptobenzo-1,4-diol and (0.49g) potassium carbonate in 5ml of water

(0.40 ml) of 2-phenyloxirane was added with stirring under a stream of argon. After stirring for 2.5 hours at room temperature, the mixture was treated with 2M HCl and then extracted with ethyl acetate. The total organic layers were washed with water and brine, dried and evaporated. The crude product was purified by column chromatography, using a mixture of heptane-ethyl acetate (1:1) for elution. 1H NMR (400 MHz, d6-DMSO) δ: 8.94 (br s, IH), 8.72 (br s, IH), 7.24-7.37 (m, 5H), 6.62-6.65 (m, 2H), 6.47 (dd, IH, J 8.6, 2.8 Hz), 4.97 (br s, IH), 4.34 (m, IH), 3.72 (m, 2H).

b) 2-phenyl-2,3-dihydrobenzo[1,4]oxatin-6-ol

0.83g of the compound 2-(2-hydroxy-1-phenylethylsulfanyl)benzene-1,4-diol dissolved in 60ml

of dry toluene and with the addition (0.5g) of Amberlist 15, it was mixed at 60°C until the original substances disappeared. After stirring, the mixture was filtered, the solvent was evaporated and the crude product was purified by column chromatography, eluting with heptane-ethyl acetate (1:1). 1H NMR (400 MHz, CDCl3) δ: 7.41 (m, 4H), 7.33-7.40 (m, IH), 6.81 (d, IH, J 8.7 Hz), 6.61 (d, IH, J3.0Hz), 6.51 (dd,lH, J8.7,J8.7, 3.0 Hz), 5.10 (dd, IH, J 9.6, 1.9 Hz), 3.28 (dd, IH, J 13.0, 9.6 Hz), 3.06 (dd, IH, J 13.0, 1.9 Hz).

c) 5-nitro-2-(2-phenyl-2,3-dihydrobenzo[1,4]oxatin-6-yloxy)pyridine

The synthesis of 5-nitro-2-(2-phenyl-2,3-dihydrobenzo[1,4]oxatin-6-yloxy)pyridine was performed

according to the description for 5-nitro-2-(2-phenylchroman-6-yloxy)pyridine from Example 1(b) using 269 mg of 2-phenyl-2,3-dihydrobenzo[1,4]oxatin-6-ol. The resulting product was recrystallized from ethanol.

1H NMR (400Mhz, CDCl3) δ: 9.07 (d, IH, J 2.8 Hz), 8.47 (dd, IH, J 9.1, 2.8 Hz), 7.43 (m, 4H), 7.37-7.41 (m,lH), 7.02 (d, IH, J 9.1 Hz), 6.99 (d, IH, J 8.9 Hz), 6.95 (d, IH, J 2.8 Hz), 6.82 (dd, IH, J 8.9, 2.8 Hz), 5.21 (dd, IH, J 9.7, 1.9 Hz), 3.31 (dd, IH, 13.2, 9.7 Hz), 3.11 (dd, IH, 13.2, 1.9 Hz).

Example 85:

5-Nitro-2-(4-ox:iso-2-phenyl-3,4-dihydrobenzo[l,41oxathyn-6-yloxy)pyridine

To 214 mg of the compound 5-nitro-2-(2-phenyl-2,3-dihydrobenzo[1,4]oxatin-6-yloxy)pyridine in 80 ml of methanol, in very small portions, NaO 4 (total 2.5 eq) was added at 60°C, until the starting substances had completely disappeared. The mixture was then poured into water, and the resulting precipitate was filtered and washed with water. The crude product was then purified by column chromatography, eluting with heptane-ethyl acetate (1:1).<*>H NMR (400 MHz, CDCl 3 ) δ: 9.02 (d, IH, J 2.8 Hz), 8.51 (dd, IH, J 9.1, 2.8 Hz), 7.45-7.56 /m, 6H, 7.32 (dd, IH, J 9.0, 2.8 Hz), 7.21 (d, IH, J 9.0 Hz), 7.10 (d, IH, J 9.1 Hz), 5.77 (dd, IH, J 12.0, 1.5 Hz), 3.34 (dd, IH, 14.4, 1.5 Hz), 3.13 (dd, IH, 14.4, 12.0 Hz).

Example86:

2-(4,4-dioxo-2-phenyl-3,4-dihydro-2-benzori,41oxatin-6-yloxy)-5-nitropyridine

With stirring, 125 mg of KMn04 was added to 150 mg of the compound 5-nitro-2-(2-phenyl-2,3-dihydrobenzo[1,4]oxatin-6-yloxy)pyridine dissolved in (3.7 ml) of AcOH and 1.2 ml of water, in an ice/water bath. The mixture was stirred at room temperature for 1.5 hours, and then another 5 ml of water and 30% H2O2 were added until the excess potassium permanganate decomposed. The mixture was then diluted by adding another 20ml of water. The resulting white precipitate was filtered off, washed with water and dried to give 2-(4,4-dioxo-2-phenyl-3,4-dihydro-2-benzo[1,4]oxatin-6-yloxy)-5-nitropyridine.<]>H NMR (400 MHz, CDCl 3 ) 8: 9.03 (d, IH, J 2.8 Hz), 8.52 (dd, IH, J 9.0, 2.8 Hz), 7.68 (d, IH, J 2.8 Hz), 7.46-7.52 (m, 5H), 7.33 (dd, IH, J 9.1, 2.8 Hz), 7.17 (d, IH, J 9.1 Hz), 7.11 (d, IH, J 9.0 Hz), 5.87 (dd, IH, J 12.2, 1.6 Hz), 3.76 (dd, IH, 14.1, 12.2 Hz), 3.55 (dd, IH, 14.1, 1.6 Hz).

Example87:

5-nitro-2-(2-(4-nitrophenyl)chroman-6-yloxy)pyridine

a) 6-hydroxy-2-(4-nitrophenyl)chroman-4-one

The compound 6-hydroxy-2-(4-nitrophenyl)chroman-4-one was synthesized as described

for 6-hydroxy-2-(3-fluorophenylchroman-4-one in Example 9(a). The product was recrystallized from ethanol.

1H NMR (400 MHz, d6-DMSO) δ: 9.48 (s, IH), 8.29 (d, 2H, J 6.9 Hz), 7.83 (d, 2H, J 6.9 Hz), 7.13 (d, IH, J 2.9 Hz), 7.06 (dd, IH, J 8.8, 2.9 Hz), 7.01 (d, IH, J 8.8, Hz), 5.77 (dd, IH, J 13.0, 3.0 Hz), 3.15 (dd, 1H,J 16.8, 13.0 Hz), 2.89 (dd, IH, J 16.8, 3.0 Hz).

b) 2-(4-nitrophenyl)chroman-4,6-diol

The compound 2-(4-nitrophenyl)chroman-4,6-diol was synthesized according to the description for 2-phenylchroman-4,6-diol of Example 8(a) starting from 6-hydroxy-2-(4-nitrophenyl)-chroman-4-one. 1H NMR (300 MHz, d6-DMSO) δ: 8.86 (s, IH), 8.26 (d, 2H, J 6.9 Hz), 7.74 (d, 2H, J 6.9 Hz), 6.89 (d, IH, J 2.8 Hz), 6.65 (d, IH, J 8.6 Hz), 6.56 (dd, IH, J 8.6 Hz). 2.8 Hz), 5.46 (d, IH, J 6.9 Hz), 5.32 (d, IH, J 10.5 Hz), 4.86-4.94 (m, IH), 2.31-2.38 (m, IH), 1.78-1.89 (m, IH).

c) 2-(4-nitrophenyl)chroman-6-ol

The compound 2-(4-nitrophenyl)chroman-6-ol was synthesized as described for 2-(3-fluorophenyl)chroman-6-ol of Example 9 (c) starting from 2-(4-nitrophenyl)chroman-4,6-diol. <]>H NMR (400MHz, d6-DMSO) 8: 8.84 (s, 1H), 8.26 (d, 2H, J 6.9 Hz), 7.71 (d, 2H, J 6.9 Hz), 6.69 (d, IH, J 8.6 Hz), 6.53 (dd, IH, J 8.6, 2.8 Hz), 6.50 (d, IH, J 2.8 Hz), 5.19 (dd, IH, J 9.9, 2.2 Hz), 2.87-2.91 (m, IH), 2.61-2.66 (m, IH), 2.16-2.21 (m, IH), 1.89-1.93 (m, IH).

d) 5-nitro-2-[2-(4-nitrophenyl)chroman-6-yloxy]pyridine

The compound 5-nitro-2-[2-(4-nitrophenyl)chroman-6-yloxy]pyridine was synthesized at

method as described for the synthesis of 5-nitro-2-(2-phenylchroman-6-yloxy)pyridine of Example 1(b) starting from 2-(4-nitrophenyl)chroman-6-ol.<*>H NMR (300 MHz, d6-DMSO) 8: 9.04 (d, IH, J 2.9 Hz), 8.60 (dd, IH, J 9.1, 2.9 Hz), 8.29 (d, 2H, J 6.9 Hz), 7.76 (d, 2H, J 6.9 Hz), 7.21 (d, IH, J 9.1 Hz), 6.98-7.02 (m, 3H), 5.35 (dd, IH, J 9.9, 2.2 Hz), 2.96-3.05 (m, IH), 2.73-2.78 (m, IH), 2.24-2.29 (m, IH), 1.96-2.04 (m, IH).

Example88:

6-[2-(4-aminophenyl)chroman-6-yloxyl-pyridin-3-ylamine

Compound 6-[2-(4-aminophenyl)chroman-6-yloxy]-pyridin-3-ylamine was synthesized as described in the synthesis of compound 5 amino-2-(2-phenylchroman-6-yloxy)pyridine in Example 26, using 100mg of 5-nitro-2-[2-(4-nitrophenyl)chroman-6-yloxy]pyridine (Example 87(d)) and 665mg of Zn.'H NMR 400 MHz, d6-DMSO) 7.50 (d, IH. J 2.9 Hz), 7.07 (d, 2H, 8.4 Hz), 7.04 (dd, IH, J 8.6, 2.9 Hz), 6.71 (s, 3H), 6.68 (d, IH, J 8.6 Hz), 6.56 (d, 2H, J 8.4 Hz), 5.07 (s, 2H), 4.99 (s, 2H), 4.84 (dd, IH, J 9.7, 2.3 Hz), 2.86-2.95 (m, IH), 2.66-2.71 (m, IH), 1.95-2.05 (m, 2H).

Example 89:

5-nitro-2-[2-(2-nitrophenyl)chroman-6-yloxylpyridine

a) 6-hydroxy-2-(2-nitrophenyl)chroman-4-one

The compound 6-hydroxy-2-(2-nitrophenyl)chroman-4-one was synthesized as described in

synthesis of the compound 6-hydroxy-2-(3-fluorophenyl)chroman-4-one in Example 9 (a). 1H NMR (400 MHz, d6-DMSO) δ: 9.49 (s, IH), 8.05-8.06 (m, IH), 7.96-7.98 (m, IH), 7.83-7.87 (m, IH), 7.65-7.69 (m, IH), 7.14 (d, IH, J), 7.05 (dd, IH, J) 3.1 Hz 8.8, 3.1 Hz), 6.91 (d, IH, J 8.8 Hz), 5.69 (dd, IH, J 13.0, 2.6 Hz), 3.22 (dd, IH, J 16.8, 13.0 Hz), 2.98 (dd, IH, J 16.8, 2.6 Hz).

b) 2-(2-nitrophenyl)chroman-4,6-diol

The compound 2-(2-nitrophenyl)chroman-4,6-diol was synthesized the same as the compound 2-phenyl-chroman-4,6-diol of Example 8(a) starting from 6-hydroxy-2-(2-nitrophenyl)-chroman-4-one. <]>H NMR (300 MHz, d6-DMSO) 5: 8.87 (s, 1H), 7.99-8.02 (m, 1H). 7.77-7.86 (m, 2H), 7.59-7.64 (m, IH), 6.89 (d, IH, J 2.4 Hz), 6.56-6.57 (m, 2H), 5.51-5.55 (m, 2H), 4.85-4.92 (m, IH), 2.42-2.47 (m, IH), 1.85-1.96 (m, IH).

c) 2-(2-nitrophenyl)chroman-6-ol

The compound 2-(2-nitrophenyl)chroman-6-ol was synthesized according to the description for 2-(3-fluorophenyl)chroman-6-ol of Example 9 (c) starting from 2-(2-nitrophenyl)chroman-4,6-diol. 1H NMR (400 MHz, d6-DMSO) δ: 8.85 (s, IH), 8.00 (d, IH, J 8.0 Hz), 7.79-7.80 (m, 2H), 7.59-7.63 (m, IH), 6.59-6.62 (m, IH), 6.50-6.53 (m, 2H), 5.36 (dd, IH, J 10.2, 2.0 Hz), 2.89-2.93 (m, IH), 2.67-2.73 (m, IH), 2.26-2.31 (m, IH), 1.90-1.95 (m, IH).

d) 5-nitro-2-[2-(2-nitrophenyl)chroman-6-yloxy]pyridine

The compound 5-nitro-2-[2-(2-nitrophenyl)chroman-6-yloxy]pyridine was synthesized as

compound 5-nitro-2-(2-phenylchroman-6-yloxy)pyridine from Example 1(b) starting from 2-(2-nitrophenyl)chroman-6-ol. 11 NMR (400 MHz, d6-DMSO) δ: 9.04 (d, IH, J 2.9 Hz), 8.60 (dd, IH, J 9.1, 2.9 Hz), 8.03 (d, IH, J 7.9 Hz), 7.80-7.85 (m, 2H), 7.62-7.66 (m, IH), 7.22 (d, IH, J) 9.1 Hz), 7.04 (d, IH, J 2.8 Hz), 6.98 (dd, IH, J 8.8 , 2.8 Hz), 6.88 (d, IH, J 8.8 Hz), 5.52 (dd, IH, J 10.3, 2.0 Hz), 2.99-3.31 (m, IH), 2.80-2.85 (m, IH), 2.35-2.40 (m, 1H), 1.99-2.04 (m, 1H).

Example 90:

6- r2-(2-aminophenyl)chroman-6-yloxyl-pyridin-3-ylamine

Compound 6-[2-(2-aminophenyl)chroman-6-yloxy]-pyridin-3-ylamine was synthesized as described for 5-amino-2-(2-phenylchroman-6-yloxy)pyridine of Example 26 using 100 mg of 5-nitro-2-[2-(2-nitrophenyl)chroman-6-yloxy]pyridine (Example 89(d)) and 700 mg of Zn<*>H NMR (300 MHz, d6-DMSO) 5: 7.51 (d, IH, J 2.9 Hz), 7.15-7.18 (m, IH), 7.05 (dd, IH, J 8.6, 2.9 Hz), 6.98-7.00 (m, IH), 6.77 (d, IH, J 8.6 Hz), 6.73-6.75 (m, 2H), 6.66-6.71 (m, 2H), 6.56-6.61 (m, IH), 5.11 (dd, IH, J 10.4, 2.0 Hz), 5.01 (s, 2H ), 4.99 (s, 2H), 2.94-2.99 (m, IH), 2.66-2.74 (m, IH), 2.06-2.13 (m, IH), 1.88-1.95 (m, IH).

Example 91:

N-(6-[2-(2-Acetylaminophenyl)chroman-6-yloxylpyridin-3-yl|acetamide

The compound N-{6-[2-(2-acetylaminophenyl)chroman-6-yloxy]pyridin-3-yl}acetamide was synthesized according to the description for 5-N'-acetylamino-2-(2-phenylchroman-6-yloxy)pyridine from Example 27, starting from the compound 6-[2-(2-aminophenyl)chroman-6-yloxy]-pyridin-3-ylamine (Example 90).

1H NMR (300 MHz, d6-DMSO) δ: 10.02 (s, IH), 9.44 (s, IH), 8.27 (d, IH, J 2.7 Hz), 8.00 (dd, IH J 8.8, 2.7 Hz), 7.49 (d, IH, J 8.8 Hz), 7.25-7.38 (m, 3H), 6.92 (d, IH, J 8.9 Hz), 6.88 (s, IH), 6.83 (s, 2H), 5.22 (d, IH, J 8.7 Hz), 2.90-2.99 (m, IH), 2.72-2.79 (m, IH), 2.12-2.18 (m, IH), 2.04 (s, 6H), 1.86-1.94 (m, IH).

Example 92:

5-Nitro-2-[2-(3-nitrophenyl)chroman-6-yloxylpyridine

a) 6-hydroxy-2-(3-nitrophenyl)chroman-4-one

Compound 6-hydroxy-2-(3-nitrophenyl)chroman-4-one was synthesized as described

synthesis of the compound 6-hydroxy-2-(3-fluorophenyl)chroman-4-one in Example 9(a). The resulting product was recrystallized from ethanol. 1H NMR (300 MHz, d6-DMSO) δ: 8.40 (s, IH), 8.24 (dd, IH, J 8.2, 2.3 Hz), 8.01 (d, IH, J 7.9 Hz), 7.74 (t, IH, J 15.9, 7.9 Hz), 7.13 (d, IH, J 2.9 Hz), 7.07 (dd, IH, J 8.8, 2.9 Hz), 7.00 (d, IH, 8.8 Hz), 5.75 (dd, IH, J 13.1, 2.9 Hz), 3.21 (dd, IH, J 16.8, 13.1 Hz), 2.88 (dd, IH, J 16.8, 2.9 Hz).

b) 2-(3-nitrophenyl)chroman-4,6-diol

The compound 2-(3-nitrophenyl)chroman-4,6-diol was synthesized as described for 2-phenylchroman-4,6-diol in Example 8(a) starting from 6-hydroxy-2-(3-nitrophenyl)chroman-4-one. 1H NMR (400 MHz, d6-DMSO) δ: 8.89 (br s, IH), 8.29(s,lH), 8.20 (dd, IH, J 8.2, 2.3 Hz), 7.93 (d, IH, J 7.9 Hz), 7.71 (t, IH, J 15.9, 7.9 Hz), 6.89 (d, IH, J 2.8 Hz), 6.66 (d, IH, J 8.7 Hz), 6.57 (dd, IH, J 8.7, 2.9 Hz), 5.47 (br s, IH), 5.33 (d, IH, J 10.7 Hz), 4.88-4.92 (m, IH), 2.33-2.39 (m, IH), 1.83-1.92 (m, IH).

c) 2-(3-nitrophenyl)chroman-6-ol

The compound 2-(3-nitrophenyl)chroman-6-ol was synthesized as described for

compound 2-(3-fluorophenyl)chroman-6-ol of Example 9(c) starting from the compound 2-(3-nitrophenyl)chroman-4,6-diol. <!>H NMR (300 MHz, d6-DMSO) δ: 8.80 (s, IH), 8.26 (s, IH), 8.19 (dd, IH, J 8.1, 2.3 Hz), 7.90 (d, IH, J 7.9 Hz), 7.70 (t, IH, J 15.9, 7.9 Hz), 6.70 (d, IH, J 8.4 Hz), 6.51-6.55 (m, 2H), 5.19 (dd, IH, J 10.0, 2.0), 2.86-2.91 (m, IH), 2.61-2.68 (m, IH), 2.17-2.23 (m, 1H), 1.91-1.97 (m, 1H).

d) 5-Nitro-2-[2-(3-nitrophenyl)chroman-6-yloxy]pyridine

The compound 5-Nitro-2-[2-(3-nitrophenyl)chroman-6-yloxy]pyridine was synthesized as

which is described in the synthesis of 5-nitro-2-(2-phenylchroman-6-yloxy)-pyridine from Example 1(b) starting from the compound 2-(3-nitrophenyl)chroman-6-ol. 1H NMR (400 MHz, d6-DMSO) δ: 9.04(d, IH, J 2.9 Hz), 8.60 (dd, IH, J 9.0, 2.9 Hz), 8.32 (s, IH), 8.23 (d, IH, J 8.3 Hz), 7.95 (d, IH, J 7.9 Hz), 7.74 (t, IH, J) 15.8, 7.9 Hz), 7.21 (d, IH, J 9.0 Hz), 6.96-7.03 (m, 3H), 5.35 (d, IH, J 8.7 Hz), 2.98-3.06 (m, IH), 2.72-2.79 (m, IH), 2.26-2.33 (m, IH), 1.99-2.06 (m, IH).

Example93:

6-[2-(3-aminophenyl)chroman-6-yloxylpyridin-3-ylamine

The synthesis of the compound 6-[2-(3-aminophenyl)chroman-6-yloxy]pyridin-3-ylamine was performed as described for 5-amino-2-(2-phenylchroman-6-yloxy)pyridine from Example 26, using 150mg of 5-nitro-2-[2-(3-nitrophenyl)chroman-6-yloxy]pyridine (Example 92 (d)) and 997mg of Zn<!>H NMR. (300 MHz, d6-DMSO) 5: 7.51 (d, IH, J 2.8 Hz), 7.05 (dd, IH, J 8.6, 2.8 Hz), 7.01 (t, IH, J 15.4, 7.7 Hz), 6.70-6.78 (m, 3H), 6.68 (d, IH, J 8.6 Hz), 6.63 (s, IH), 6.54 (d, IH, J 7.7 Hz), 6.50 (d, IH, J 8.6 Hz), 5.06 (s, 2H), 4.98 (s, 2H), 4.90 (dd, IH, J 10.0, 2.2 Hz), 2.85-2.96 (m, IH), 2.62-2.74 (m, IH), 2.05-2.11 (m, IH), 1.89-1.95 (m, IH).

Example 94:

2-(4-methoxyphenyl)-6-(5-nitropyridin-2-yloxy)chloronan-4-ol

a) 6-hydroxy-2-(4-methoxyphenyl)chroman-4-one

The compound 6-hydroxy-2-(4-methoxyphenyl)chroman-4-one was synthesized as

described for 6-hydroxy-2-(3-fluorophenyl)chroman-4-one of Example 9(a). The resulting product was recrystallized from ethanol. <]>H NMR (400 MHz, d5-DMSO) δ: 9.40 (s, IH), 7.45 (d, 2H, J 8.7 Hz), 7.11 (d, IH, J 3.0 Hz), 7.02 (dd, IH, J 8.9, 3.0 Hz), 6.97 (d, 2H, J 8.7 Hz), 6.93 (d, IH, J 8.9 Hz), 5.47 (dd, IH, J 13.1, 2.8 Hz), 3.77 (s, 3H), 3.19 (dd, IH, J 16.8, 13.1 Hz), 2.72 (dd, IH, J 16.8, 2.8 Hz).

b) 2-(4-Methoxyphenyl)chroman-4,6-diol

Synthesizing the compound 2-(4-methoxyphenyl)chroman-4,6-diol was performed as for

the 2-phenylchroman-4,6-diol compound of Example 8(a) starting from 6-hydroxy-2-(4-methoxyphenyl)chroman-4-one. ]H NMR (300 MHz, d6-DMSO) δ: 8.78 (s, IH), 7.35 (d, 2H, J 8.7 Hz), 6.94 (d, 2H, J 8.7 Hz), 6.88 (d, IH, J 2.5 Hz), 6.56 (d, IH, J 8.7 Hz), 6.52 (dd, IH, J 8.7 Hz). 2.5 Hz), 5.37 (br s, IH), 5.04 (d, IH, J 10.9 Hz), 4.83-4.89 (m, IH), 3.76 (s, 3H), 2.18-2.25 (m, IH), 1.85-1.97 (m, IH).

c) 2-(4-methoxyphenyl)-6-(5-nitropyridin-2-yloxy)chroman-4-ol The synthesis of the compound 2-(4-methoxyphenyl)-6-(5-nitropyridin-2-yloxy)chroman-4-ol was

performed according to the description for 5-nitro-2-(2-phenylchroman-6-yloxy)pyridine from Example 1(b) starting from the compound 2-(4-methoxyphenyl)chroman-4,6-diol.<*>H NMR (400 MHz, d6-DMSO) 9.04 (d, IH, J 2.9 Hz), 8.61 (dd, IH, J 9.1, 2.9 Hz), 7.40 (d, 2H, J 8.7 Hz), 7.24 (d, IH, J 2.8 Hz), 7.22 (d,

IH, J 9.1 Hz), 7.00 (dd, IH, J 8.7, 2.8 Hz), 6.97 (d, 2H, J 8.7 Hz), 6.84 (d, IH, J 8.7 Hz), 5.63 (d, IH, J 6.4 Hz), 5.23 (d, IH, J 10.8 Hz), 4.95-5.02 (m, IH), 3.78 (s, 3H), 2.25-2.29 (m, 1H), 1.98-2.04 (m, 1H).

Example 95:

6-(5-aminopyridin-2-yloxy)-2-(4-methoxyphenyl)chroman-4-ol

The compound 6-(5-aminopyridin-2-yloxy)-2-(4-methoxyphenyl)chroman-4-ol was synthesized as described in the synthesis of 5-amino-2-(2-phenylchroman-6-yloxy)pyridine in Example 26, using 105 mg of 2-(4-methoxyphenyl)-6-(5-nitropyridin-2-yloxy)chroman-4-ol (Example 94(c)) and 348mg Zn.

1H NMR (400 MHz, d6-DMSO) δ: 7.52 (d, 1H, J 3.0 Hz), 7.38 (d, 2H, J 8.8 Hz), 7.06 (dd,

IH, J 8.7, 3.0 Hz), 7.04 (d, IH, J 2.9 Hz), 6.96 (d, 2H, J 8.8 Hz), 6.77 (dd, IH, J 8.7, 2.9 Hz), 6.72 (d, IH, J 8.7 Hz), 6.70 (d, IH, J 8.6 Hz), 5.52 (d, IH, J 6.6 Hz), 5.15 (d, IH, J 10.7 Hz), 5.01 (s, 2H), 4.87-4.93 (m, IH), 3.77 (s, 3H), 2.22-2.26 (m, IH), 1.90-1.99 (m, IH).

Example 96: N-{6-[4-hydroxy-2-(4-methoxyphenyl)chroman-6-yloxylpyridin-3-yl}acetamide

The compound N-{6-[4-hydroxy-2-(4-methoxyphenyl)chroman-6-yloxy]pyridin-3-yl} acetamide was synthesized as described for 5-N'-acetylamino-2-(2-phenylchroman-6-yloxy)pyridine of Example 27 starting from 6-(5-aminopyridin-2-yloxy-2-(4-methoxyphenyl)chroman-4-ol (Example 95). (400 MHz, d6-DMSO) 5: 10.05 (s, IH), 8.28 (d, IH, J 2.7 Hz), 8.01 (dd, IH, J 8.8, 2.7 Hz), 7.39 (d, 2H, J 8.7 Hz), 7.14 (d, IH, J 2.7 Hz), 6.97 (d, 2H, J 8.7 Hz), 6.94 ( d, IH, J 8.8 Hz), 6.88 (dd, IH, J 8.8, 2.7 Hz), 6.77 (d, IH, J 8.8 Hz), 5.57 (d, IH, J 6.5 Hz), 5.19 (d, IH, J 10.6 Hz), 4.90-4.97 (m, IH), 3.77 (s, 3H), 2.24-2.27 (m, 1H), 2.04 (s, 3H), 1.93-2.01 (m, 1H).

Example97:

2-(2-methoxyphenyl)-6-(5-nitropyridin-2-yloxy)chroman-4-ol

a) 6-hydroxy-2-(2-methoxyphenyl)chroman-4-one

The compound 6-hydroxy-2-(2-methoxyphenyl)chroman-4-one was synthesized as

described for the compound 6-hydroxy-2-(3-fluorophenyl)chroman-4-one of Example 9(a). The product was recrystallized from ethanol. <]>H NMR (400 MHz, d6-DMSO) δ: 9.40 (s, IH), 7.56 (dd, IH, J 7.6, 1.6 Hz), 7.37 (dt, IH, J 8.6, 7.0, 1.6 Hz), 7.12 (d, IH, J 2.9 Hz), 7.07 (d, IH, J). 8.6 Hz), 7.03 (d, IH, J 8.9 Hz), 7.02 (d, IH, J 7.0 Hz), 6.95 (d, IH, J 8.9 Hz), 5.70 (dd, IH, J 13.3, 2.7 Hz), 3.82 (s, 3H), 3.09 (dd, IH, J 16.8, 13.3 Hz), 2.71 (dd, IH, J 16.8, 2.7 Hz).

b) 2-(2-methoxyphenyl)chroman-4,6-diol

The synthesis of the compound 2-(2-methoxyphenyl)chroman-4,6-diol was carried out according to the description for

synthesis of 2-phenylchroman-4,6-diol from Example 8(a) starting from 6-hydroxy-2-(2-(methoxyphenyl)-chroman-4-one-a. HNMR (300 MHz, d6-DMSO) 5 : 8.79 (s, 1H), 7.45 (dd, IH, J 7.6, 1.6 Hz), 7.31 (dt, IH, J 8.5, 7.3, 1.6 Hz), 7.04 (d, IH, J 8.5 Hz), 6.99 (d, IH, J 7.3 Hz), 6.88 (d, IH, J 2.7 Hz), 6.59 (d, IH, J 8.7 Hz), 6.54 (dd, IH, J 8.7, 2.7 Hz), 5.38 (s, IH), 5.34 (d, IH, J 11.4 Hz), 4.80-4.88 (m, 1H), 3.81 (s, 3H), 2.24-2.28 (m, 1H), 1.74-1.86 (m, 1H).

c) 2-(2-methoxyphenyl)-6-(5-nitropyridin-2-yloxy)chroman-4-ol

The compound 2-(2-methoxyphenyl)-6-(5-nitropyridin-2-yloxy)chroman-4-ol was

synthesized as described for the synthesis of 5-nitro-2-(2-phenylchroman-6-yloxy)pyridine in Example 1(b) starting from 2-(2-methoxyphenyl)chroman-4,6-diol.<*>H NMR 400 MHz, d6-DMSO) δ: 9.04 (d, IH, J 2.9 Hz), 8.61 (dd, IH, J 9.1, 2.9 Hz), 7.49 (dd, IH, J 7.6, 1.7 Hz), 7.34 (dt, IH, J 8.3, 7.5, 1.7 Hz), 7.24 (d, IH, J 2.8 Hz), 7.22 (d, IH, J 9.1 Hz), 7.07 (d, IH, J 8.3 Hz), 7.03 (d, IH, J 7.5 Hz), 7.01 (dd, IH, J 8.7, 2.8 Hz), 6.88 (d, IH, J 8.7 Hz), 5.62 (d, IH, J 6.3 Hz), 5.52 (d, IH, J 10.4 Hz), 4.93-4.99 (m, IH), 3.84 (s, 3H), 2.30-2.35 (m, IH), 1.85-1.94 (m, IH).

Example98:

6-(5-aminopyridin-2-yloxy)-2-(2-methoxyphenyl)chroman-4-ol

Compound 6-(5-aminopyridin-2-yloxy)-2-(2-methoxyphenyl)chroman-4-ol was synthesized as described for 5-amino-2-(2-phenylchroman-6-yloxy)pyridine in Example 26

using 79 mg of 2-(2-methoxyphenyl)-6-(5-nitropyridin-2-yloxy)chroman-4-ol (Example 97(c)) and 262 mg of Zn. 1H NMR (400 MHz, d6-DMSO) δ: 7.52 (d, IH, J 2.9 Hz), 7.47 (dd, IH, J 7.5, 1.6 Hz), 7.33 (dt, IH, J 8.5, 7.4, 1.6 Hz), 7.06 (d, IH, J 2.8 Hz), 7.03-7.05 (m, 2H), 7.01 (d, IH, J 7.4 Hz), 6.79 (dd, IH, J 8.6, 2.8 Hz), 6.75 (d, IH, J 8.7 Hz), 6.71 (d, IH, J 8.6 Hz), 5.52 (d, IH, J 6.5 Hz), 5.44 (d, IH, J 10.5 Hz), 5.01 (s, 2H), 4.86-4.92 (m, 1H), 3.83 (s, 3H), 2.27-2.32 (m, 1H), 1.80-1.88 (m, 1H).

Example 99:

2-[ 2-(3-Methoxyphenyl)chroman-6-yloxyl-5-nitropyridine

a) 6-hydroxy-2-(3-methoxyphenyl)chroman-4-one

The synthesis of compound 6-hydroxy-2-(3-methoxyphenyl)chroman-4-one was performed as described for 6-hydroxy-2-(3-fluorophenyl)chroman-4-one in Example 9(a). The resulting product was recrystallized from elanol. 1H NMR 400 MHz, d6-DMSO) δ: 9.42 (s, IH), 7.33 (t, IH, J 15.8, 8.3 Hz), 7.12 (d, IH, J 3.0 Hz), 7.10 (s, IH), 7.09 (d, IH, J 8.3 Hz), 7.04 (dd, IH, J 8.8, 3.0 Hz), 6.96 (d, IH, 8.8 Hz), 6.93 (dd, IH, J 8.0, 2.5 Hz), 5.52 (dd, IH, J 12.9, 2.9 Hz), 3.77 (s, 3H), 3.17 (dd, IH, J 16.9, 12.9 Hz), 2.77 (dd, IH, J 16.9, 2.9 Hz).

b) 2-(3-methoxyphenyl)chroman-4,6-diol

The compound 2-(3-methoxyphenyl)chroman-4,6-diol was synthesized as described for

synthesis of 2-phenylchroman-4,6-diol from Example 8(a) starting from 6-hydroxy-2-(3-methoxyphenyl)chroman-4-one. *H NMR (400 MHz, oVDMSO) δ: 8.82 (s, IH), 7.31 (t, IH, J 15.7, 7.9 Hz), 6.99-7.02 (m, 2H), 6.88-6.90 (m, 2H), 6.59 (d, IH, J 8.7 Hz), 6.54 (dd, IH, J 8.7, 2.8 Hz), 5.40 (d, IH, 7.0 Hz), 5.08 (d, IH, J 11.5 Hz), 4.83-4.89 (m, IH), 3.77 (s, 3H), 2.23-2.28 (m, IH), 1.83-1.92 (m, IH).

c) 2-(3-methoxyphenyl)chroman-6-ol

The compound 2-(3-methoxyphenyl)chroman-6-ol was synthesized according to the description for 2-(3-fluorophenyl)chroman-6-ol of Example 9(c) starting from the compound 2-(3-methoxyphenyl)chroman-4,6-diol. *H NMR (300 MHz, d6-DMSO) δ: 8.75 (s, IH), 7.28 (t, IH, J 15.7, 7.9 Hz), 6.96-6.99 (m, 2H), 6.87 (dd, IH, J 7.9, 2.5 Hz), 6.63 (d, IH, J 8.3 Hz), 6.52 (d, IH, J 2.9 Hz), 6.48(s, IH), 4.95 (dd, IH, J 9.8, 2.2 Hz), 3.75 (s, 3H), 2.82-2.89 (m, IH), 2.57-2.66 (m, IH), 2.06-2.13 (m, IH), 1.89-1.97 (m, IH).

d) 2-[2-(3-methoxyphenyl)chroman-6-yloxy]-5-nitropyridine

The synthesis of the compound 2-[2-(3-methoxyphenyl)chroman-6-yloxy]-5-nitropyridine was

performed according to the description for 5-nitro-2-(2-phenylchroman-6-yloxy)pyridine from Example 1(b) starting from the compound 2-(3-methoxyphenyl)chroman-6-ol. ]H NMR (400 MHz, d6-DMSO) δ: 9.04 (d, IH, J 2.9 Hz), 8.60 (dd, IH, .1 9.1, 2.9 Hz), 7.32 (t, IH, JI 5.7, 7.9 Hz), 7.20 (d, 1H, J 9.1 Hz), 7.03 (d, IH, J 8.4 Hz), 7.01 (s, IH), 7.00 (d, IH, J 2.8 Hz), 6.96 (dd, IH, J 8.7, 2.8 Hz), 6.92 (d, IH, J 8.7 Hz), 6.90 (dd, IH, J 8.4, 2.6 Hz), 5.12 (dd, IH, J 10.0, 2.3 Hz), 3.77 (s, 3H), 2.93-2.97 (m, IH), 2.71-2.77 (m, IH), 2.15-2.20 (m, IH), 1.99-2.05 (m, IH).

Example100:

6-[2-(3-Methoxyphenyl)chroman-6-yloxylpyridin-3-ylamine

The compound 6-[2-(3-methoxyphenyl)chroman-6-yloxy]pyridin-3-ylamine was synthesized according to the description for 5-amino-2-(2-phenylchroman-6-yloxy)pyridine of Example 26 using 300 mg of the compound 2-[2-(3-methoxyphenyl)chroman-6-yloxy]-5-nitropyridine (Example 99(d)) and 1.0 g.Zn.'H NMR (400MHz, d6-DMSO) 5: 7.51 (d, IH, J 3.0 Hz), 7.31 (t, IH, J 15.8, 7.9 Hz), 7.04 (dd, IH, J 8.7, 3.0 Hz), 6.99-7.02 (m, IH), 6.99 (d, IH, J 2.6 Hz), 6.90 (dd, IH, J 8.9, 2.6 Hz)), 6.79-6.81 (m, IH), 6.72-6.74 (m, 2H), 6.69 (d, IH, J 8.9 Hz), 5.06 (dd, IH, J 9.9, 2.2 Hz), 4.50 (s, 2H), 3.77 (s, 3H), 2.88-2.95 (m, IH)), 2.66-2.71 (m, IH)), 2.12-2.17 (m, IH), 1.94-2.00 (m, IH).

Example 101:

N-{ 6-[ 2-( 3- methoxyphenyl) chroman- 6- yloxylpyridin- 3- iU acetamide

The compound N-{6-[2-(3-methoxyphenyl)chroman-6-yloxy]pyridin-3-yl}acetamide was synthesized according to the description for 5-N'-acetylamino-2-(2-phenylchroman-6-yloxy)pyridine from Example 27 starting from the compound 6-[2-(3-methoxyphenyl)chroman-6-yloxy]pyridin-3-ylamine (Example 100).

1H NMR (400 MHz, d6-DMSO) δ: 10.04 (s, IH), 8.27 (d, IH, J 2.7 Hz), 8.01 (dd, IH, J 8.9, 2.7 Hz), 7.32 (t, IH, J 15.7, 7.8 Hz), 7.02 (d, IH, J 8.8 Hz), 7.00 (d, IH, J 2.5 Hz), 6.92 (d, IH, J 8.9 Hz), 6.90 (dd, IH, J 8.2, 2.5 Hz), 6.84-6.86 (m, 3H), 5.09 (dd, IH, J 9.9, 2.1 hz), 3.77 (s, 3H), 2.91-2.95 (m, IH), 2.68-2.74 (m, IH), 2.14-2.18 (m, IH), 2.04 (s, 3H), 1.97-2.02 (m, IH).

Example 102:

2-(3-methoxyphenyl)-6-(5-nitropyridin-2-yloxy)chroman-4-ol

The compound 2-(3-methoxyphenyl)-6-(5-nitropyridin-2-yloxy)chroman-4-ol was synthesized like the compound 5-nitro-2-(2-phenylchroman-6-yloxy)pyridine from Example 1(b) starting from 2-(3-methoxyphenyl)chroman-4,6-diol (Example 99(b)). 1H NMR (400 MHz, d6-DMSO) δ: 9.04 (d, IH, J 2.9 Hz), 8.61 (dd, IH, 9.1, 2.9 Hz), 7.34 (t, IH, J 15.7, 7.8 Hz), 7.25 (d, IH, J 2.4 Hz), 7.22 (d, IH, 9.1 Hz), 7.00-7.06 (m, 3H), 6.92 (dd, IH, J 8.8, 2.4 Hz), 6.88 (d, IH, J 8.8 Hz), 5.64 (d, IH, J 6.4 Hz), 5.27 (d, IH, J 10.7 Hz), 4.95-5.00 (m, IH), 3.79 (s, 3H), 2.30-2.35 (m, IH), 1.92-2.01 (m, 1H).

Example 103

6-(5-aminopyridin-2-yloxy)-2-(3-methoxyphenyl)chloronan-4-ol

The compound 6-(5-aminopyridin-2-yloxy)-2-(3-methylphenyl)chroman-4-ol was synthesized like the compound 5-amino-2-(2-phenylchroman-6-yloxy)pyridine of Example 26 using 138mg of 2-(3-methoxyphenyl)-6-(5-nitropyridin-2-yloxy)chroman-4-ol (Example 102) and 457mg of Zn<!>H. NMR (400 MHz, d6-DMSO) δ: 7.52 (d, IH, J 3.0 Hz), 7.32 (t, IH, J 15.7, 7.8Hz), 7.06 (dd, IH, 8.7, 3.0 Hz), 7.01-7.04 (m, 3H), 6.91 (dd, IH, J 8.6, 2.4 Hz), 6.78-6.80 (m, IH), 6.76 (d, IH, J 8.7 Hz), 6.71 (d, IH, J 8.6 Hz), 5.54 (d, IH, J 6.5 Hz), 5.19 (d, IH, J 10.6 Hz), 5.01 (s, 2H), 4.88-4.94 (m, IH), 3.78 (s, 3H), 2.27-2.32 (m, 1H), 1.87-1.96 (m, 1H).

Example 104:

6-(2-phenyl-2,3-dihydrobenzo[1,41oxathyn-6-yloxy)pyridin-3-ylamine hydrochloride

The synthesis of the compound 6-(2-phenyl-2,3-dihydrobenzo[1,4]oxatin-6-yloxy)pyridin-3-ylamine was performed according to the description for 5-amino-2-(2-phenylchroman-6-yloxy)pyridine from Example 26, starting from 5-nitro-2-(2-phenyl-2,3-dihydrobenzo[1,4]oxatin-6-yloxy)pyridine (Example 84). The compound 6-(2-phenyl-2,3-dihydrobenzo[1,4]oxathyn-6-yloxy)pyridin-3-ylamine was isolated as its dihydrochloride salt. <!>H NMR (400 MHz, CDCl3) δ: 8.20 (d, IH, J 2.1 Hz), 7.87 (dd, IH, J 8.9, 2.1 Hz). 7.41-7.44 (m, 4H), 7.37-7.40 (m, IH), 6.98 (d, IH, J 8.9 Hz), 6.97 (d, IH, J 8.8 Hz), 6.93 (d, IH, J 2.7 Hz), 6.80 (dd, IH, J 8.8, 2.7 Hz), 5.20 (dd, IH, J 9.6, 1.9 Hz), 3.30 (dd, IH, 13.2, 9.6 Hz), 3.12 (dd, IH, 13.2, 1.9 Hz).

Example 105: N-["6-(2-phenyl-2,3-dihydrobenzo[1,41oxathyn-6-yloxy)pyridin-3-yl1acetamide

The compound N-[6-(2-phenyl-2,3-dihydrobenzo[1,4]oxatin-6-yloxy)pyridin-3-yl]acetamide was synthesized as described for 5-N'acetamino-2-(2-phenylchroman-6-yloxy)pyridine in Example 27 starting from 6-(2-Phenyl-2,3-dihydrobenzo[1,4]oxathyn-6-yloxy)pyridin-3-ylamine.<*>H NMR (400 MHz, CDCl 3 ) δ: 8.07-8.11 (m, 2H), 7.40-7.42 (m, 4H), 7.36-7.39 (m, IH), 7.15 (br s, IH), 6.94 (d, IH, J 8.8 Hz), 6.90 (d, IH, J 2.8 Hz), 6.88 (d, IH, J 9.1 Hz), 6.78 (dd, IH, J 8.8, 2.8 Hz), 5.17 (dd, IH, J 9.6, 1.9 Hz), 3.28 (dd, IH, 13.2, 9.6 Hz), 3.08 (dd, IH, 13.2, 1.9 Hz), 2.19 (s, 3H).

Claims (16)

1. Compound of formula (1) where X is -O-, -CH2-or -C(O)-; Z is -CHR9- or a valence bond; Y is -CH2-, -C(O)-, CH(ORio)-, -CH(NR,,R12)-, -O-, -S-, -S(O)-, or -S(O2)- provided that if Z is in a valence bond, Y is not C(0); the dashed line represents a possible double bond in which case Z is -CR9 and Y is -CH-, C(ORiO)-or -C(NR, ,Ri2)-; Rije -(CH2)nNR4R7 or one of the following groups: n=l - 4, R2 and R3 are independently H, lower alkyl, lower alkoxy, -NO2, halogen, -CF3, -OH, -NHR8 or -COOH, R4 and R7 are independently H, lower alkyl, or lower hydroxyalkyl, R5 is H, lower alkoxy, -CF3, -NH2 or -CN, R 6 is -NO 2 , -NR 14 R 19 , -CF 3 or R 1 R 16 are independently H or acyl, R 9 is H or lower alkyl, Rio is H, alkylsulfonyl or acyl, R 1 R 12 are independently H, lower alkyl or acyl, Rn and Rig are independently H or -OR20, RM and R19 are independently H, acyl, alkylsulfonyl, C(S)NHR,7 or C(0)NHR,7, Risje H or NH2, Rnje H or lower alkyl, R20 is H or acyl, and their pharmaceutically acceptable salts and esters. 2. A compound according to claim 1, characterized in that it has the structure where R2, R3, X, Y and Rikao are as defined above. 3. A compound according to claim 1 or 2, characterized in that X: -O- and Z and Y are -CH2-. 4. A compound according to any one of claims 1 or 2, characterized in that X is O, Z is -CH2- and Y is CHOH. 5. A compound according to any one of claims 1 to 4, characterized in that Ri is one of the following groups: 6. A compound according to any one of claims 1 to 5, characterized in that R<> NO 2 or -NR 14 R 19 . 7. A compound according to claim 6, characterized in that R14 and R19 are independently H, acyl, or alkylsulfonyl radical. 8. A compound according to any one of claims 1 to 7, characterized in that R 15 and R 16 are H. 9. A compound according to any one of claims 1 to 8, characterized in that R 5 H is lower alkoxy. 10. A compound according to any one of claims 1 to 9, characterized in that R 2 and R 3 are independently H or halogen. 11. The compound according to claim 10, characterized in that the halogen is fluorine. 12. A compound according to any one of claims 1 to 11, characterized in that n=2. 13. A compound according to any one of claims 1 to 12, characterized in that R4 and R7 are a methyl group. 14. Pharmaceutical composition, characterized in that it comprises the compound of claim 1, together with a pharmaceutically acceptable carrier. 15. A method of inhibiting the Na<+>/Ca<2+> exchange mechanism in a cell, which consists of administering to a subject in need of it a therapeutically effective amount of a compound from claim 1. 16. A method of treating an arrhythmia condition, which consists of administering to a subject in need of it a therapeutically effective amount of a compound from claim 1.