Indian Patents
Title of Invention

PYRIDINE DERIVATIVES
Abstract Therapeutically active compounds of formula (I) or (II) wherein X is -O-, -CH2- or -C(O)-; Z is -CHR12- or a valence bond; Y is -CH2-, -C(O)-, CH(OR13)-, -O-, -S-; provided that in case Z is a valence bond, Y is not C(O); the dashed line representing an optional double bond in which case Z is -CR12- and Y is -CH2-, -C(O)- or -CH(OR10)- (in formula II) or -CH- (in formula I); R2 and R3 are independently H, lower alkyl, lower alkoxy, -NO2, halogen, -CF3, -OH, benzyloxy or a group of formula (IIIa). R1 is H, CN, halogen, -CONH2, -COOR15, CH2NR15R18, NHC(O)R5, NHCH2R5. NHR20, NR21R22. NHC(NH)NHCH3 or, in case the compound is of formula (II) wherein the optional double bond exists or in case R2 or R3 is benzyloxy or a group of formula (IIIa) or in case the pyridine ring of formula (I) or (II) is attached to the oxygen atom in 3-, 4- or 5-position, R1 can also be -NO2 or NR16R17; R4 is H, -NO2, CN, halogen, -CONH2, -COOR15, -CH2NR15R18, -NR16R17, NHC(O)R5 or -NHC(NH)NHCH3; R5 is alkyl substituted with 1-3 substituents selected from the group consisting of halogen, amino and hydroxy, or carboxyalkyl, in which the alkyl portion is optionally substituted with 1-3 substituents selected from the group consisting of halogen, amino and hydroxyl, -CHR6NR,R8 or one of the following groups: formula (IVa), (IVb), (IVc), (IVd), (IVe), and pharmaceutically acceptable salts and esters thereof. The compounds are potent inhibitors of Na+/Ca2+ exchange mechanism.
Full Text PYRIDINE DERIVATIVES USEFUL FOR INHIBITING SODIUM/CALCIUM EXCHANGE SYSTEM
Technical field
The present invention relates to new therapeutically active compounds and
pharmaceutically acceptable salts and esters thereof. The invention also relates to
pharmaceutical compositions containing these compounds as active ingredients. The
compounds of the invention are potent inhibitors of Na+/Ca2+ exchange mechanism.
Background of the invention
Na+/Ca2+ exchange mechanism is one of the ion transport mechanisms that re-
gulate the concentration of sodium and calcium ions in the cells. Compounds which
selectively inhibit Na+/Ca2+ exchange mechanism and thereby prevent overload of
Ca2+ in cells are regarded useful in preventing the cell injury mechanism of cardiac
muscle and the like after ischemia and reperfusion. Such compounds are useful e.g.
in the treatment of ischemic diseases such as heart diseases, ischemic cerebral
diseases, ischemic renal diseases and in the protection of cells during thrombolytic
therapy, angioplasty, bypass operation of coronary artery or organ transplantation and
arrhythmias.
Compounds capable of inhibiting Na+/Ca2+ exchange system have been
described earlier e.g. in patent publications WO 97/09306, EP 0978506, EP 1031556,
JP 11042752 and JP 11302235.
Summary of the invention
It has now been found that compounds of formula (I) or (II) are particularly
potent inhibitors of Na+/Ca2+ exchange mechanism and are particularly useful in the
treatment of arrhythmias.

The compounds of the present invention have a structure represented by
formula (I) or (II):

wherein
X is -O-, -CH2- or -C(O)-;
Z is -CHR12- or a valence bond;
Y is -CH2-, -C(O)-, CH(OR13)-, -O-, -S-;
provided that in case Z is a valence bond, Y is not C(O);
the dashed line represents an optional double bond in which case Z is -CR12-
and Y is
-CH2-, -C(O)- or CH(OR10)- (in formula II) or
-CH- (in formula I);
R2 and R3 are independently H, lower alkyl, lower alkoxy, -NO2, halogen,
-CF3, -OH, benzyloxy or a group of formula (IIIa)

R1 is H, CN, halogen, -CONH2, -COOR15, -CH2NR15R18, NHC(O)R5,
NHCH2R5, NHR20, NR21R22, NHC(NH)NHCH3 or, in case the compound is of
formula (II) wherein the optional double bond exists or in case R2 or R3 is benzyloxy
or a group of formula (IIIa) or in case the pyridine ring of formula (I) or (II) is
attached to the oxygen atom in 3-, 4- or 5-position, R1 can also be -NO2 or NR16R17;
R4 is H, -NO2, CN, halogen, -CONH2, -COOR15, -CH2NR15R18, -NR16R17,
-NHC(O)R5 or -NHC(NH)NHCH3;

R5 is alkyl substituted with 1-3 substituents selected from the group consisting
of halogen, amino and hydroxy, or carboxyalkyl, in which the alkyl portion is
optionally substituted with 1-3 substituents selected from the group consisting of
halogen, amino and hydroxyl, -CHR6NR7R8 or one of the following groups

W is N or CH;
Q is CHR14, NR9, S or O;
R6 is H or lower alkyl;
R7 and R8 are independently H, acyl, lower alkyl or lower hydroxyalkyl:
R9 is H, lower alkyl or phenyl;
R10 and R11 are independently H or lower alkyl;
R12 is H or lower alkyl;
R13 is H, alkylsulfonyl or acyl;
R14 is H, -OH, -COOR15;
R15 is H or lower alkyl;
R16 and R17 are independently H, acyl, alkylsulfonyl, -C(S)NHR18 or
-C(O)NHR18;
R18 is H or lower alkyl;
R19 is H or -OH;
R20 is a pyridinyl group optionally substituted with a -NO2 group;
R21 and R22 are lower alkyl;
and pharmaceutically acceptable salts and esters thereof.
In one class of preferred compounds and pharmaceutically acceptable salts
and esters thereof are compounds of formula (Ib) or (IIb), wherein R1, R2, R3, X, Y
and Z are as defined above.


In a subclass of preferred compounds and pharmaceutically acceptable salts and
esters thereof are compounds of formula (Ic) or (IIc), wherein R1, R2, R3, X, Y and Z
are as defined above.

In another class of preferred compounds and pharmaceutically acceptable
salts and esters thereof are compounds of formula (I) or (II) wherein R1 is
-NHC(O)R5, X is O, Y is CH2 and Z is CHR12. In one subclass of preferred
compounds and pharmaceutically acceptable salts and esters thereof are compounds
of formula (I) or (II) wherein R1 is -NHC(O)R5, X is O, Y is CH2, Z is CH2 and R5 is
alkyl substituted with 1-3 substituents selected from the group consisting of halogen,
ammo and hydroxy, or carboxyalkyl, in which the alkyl portion is optionally
substituted with 1-3 substituents selected from the group consisting of halogen,
amino and hydroxyl, -CHR6NR7R8 or one of the following groups:


In other class of preferred compounds and pharmaceutically acceptable salts
and esters thereof are compounds wherein R2 or R3 is a benzyloxy or a group of
formula (IIIa)

In one subclass of preferred compounds and pharmaceutically acceptable salts
and esters thereof are compounds wherein R4 and R1 are NO2.
The present invention also provides a pharmaceutical composition comprising
a compound of formula (I) or (II) together with a pharmaceutically acceptable carrier.
The present invention further provides a method for inhibiting Na+/Ca2+
exchange mechanism in a cell, comprising administering to a subject in need thereof
a therapeutically effective amount of a compound of formula (I) or (II).
The present invention further provides a method for preventing overload of
Ca2+ ions in cells, comprising administering to a subject in need thereof a
therapeutically effective amount of a compound of formula (I) or (II).
The present invention further provides a method for treating arrhythmias,
comprising administering to a subject in need thereof a therapeutically effective
amount of a compound of formula (I) or (II).
Brief description of the accompanying drawings
FIG. 1 shows the effects of the title compounds of Examples 13, 33, 14a and
14b on the start time of fast rise of ouabain-induced aftercontractions in guinea-pig
papillary muscles.
FIG. 2 shows the effects of the compounds of Examples 13, 33, 14a and 14b
on the maximum heights of ouabain-induced aftercontractions in guinea-pig papillary
muscles.
FIG. 3 shows the effects of the compounds of Examples 13, 33, 14a and 14b
on the time to maximum heights of ouabain-induced aftercontractions in guinea-pig
papillary muscles.

Detailed description of the invention
The compounds of the invention can be prepared from corresponding phenol
derivatives (IV), wherein R2, R3, X, Z and Y are the same as defined above.

The syntheses are shown in Scheme 1, wherein formula (IV) is abbreviated as
Ar-OH (IV). Pyridin-2-yloxy derivatives (1) are obtained by reactions with a suitable
halopyridines (2) where R1 can be hydrogen, nitro, cyano, halogen, or amide and X1
chlorine or bromine. The nitropyridine and nicotinamide derivatives can be reduced
to corresponding amines (3) and (4), respectively.


The reaction of 2-chloro-5-chlorome1hylpyridine (5) with diemethylamine
results in (6-chloropyridin-3-ylmethyl)dimethylamine (6), which in turn can be
reacted with phenol derivatives (IV), as shown in Scheme 2.

Nicotinic acid derivatives (12) and their esters (11) are obtained as shown in
Scheme 3. The esterification of 6-chloronicotinic acid and its reaction with phenol
derivatives (IV) gives nicotinic acid ester derivatives (11) (R can be lower alkyl).
Nicotinic acid derivatives (12) are obtained upon hydrolysis.

The aminopyridine derivatives (3) are reacted with suitable amino acids and
other carboxylic acid derivatives using 1-(dimethylaminopropyl)-3-ethylacarbodi-
imide hydrochloride as an coupling agent to result in amide derivatives (13) as shown
in the following Scheme 4 wherein R5 is as defined above. Optionally the amide

derivatives of (13) can be obtained by well-known acylation methods. Protecting
groups are removed if needed.

4-(4-methylpiperazin-1-ylmethyl)benzoic acid (17) is obtained as described in
the following Scheme 5. 4-Chloromethylbenzoic acid (14) is first esterified to a
methyl ester to protect an acid group in the following reaction. 4-Chloromethyl-
benzoic acid methyl ester (15) is then allowed to react with 1-methylpiperazine to
give 4-(4-methylpiperazin-1-yhnethyl)benzoic acid methyl ester (16). Methyl ester is
cleaved by heating with potassium hydroxide in methanol. 4-(4-methylpiperazin-1-
ylmethyl)benzoic acid is reacted as described above in Scheme 4 with aminopyridine
derivatives (3) to result in N-4-(4-methylpiperazin-1-ylmethyl)benzamide derivatives
of (13). By a similar manner other N-4-(piperazin-1-ylmethyl)benzamide derivatives
of (13) can be prepared.

The 2-chloroacetamide derivatives (13') where R5 is CH2C1 are reacted with
sodium azide to result in azide derivatives (18) which in turn are reduced to corres-
ponding 2-aminoacetamide derivatives (19) as shown in the following Scheme 6
wherein R7 and R8 are as defined above. The acetamide derivatives (20) are obtained
from 2-chloroacetamide derivatives (13') by reaction with various amines. The amide
moiety of acetamide derivatives (20) can be reduced in order to result in
corresponding amines (21).

As shown in the following Scheme 7, wherein R2 and R3 are the same as
defined above, 6- and 7-hydroxyflavane derivatives (23) are obtained from corres-
ponding fiavanones (22) by Clemmensen reduction. 6- and 7-hydroxyflavanones (22)
are commercially available or can be synthesised by methods described in the litera-
ture, e.g. J. Org Chem., 1960,25,1247-9 and J. Org. Chem., 1958, 23, 1159-61 or as
described later in Scheme 9.


The following Scheme 8, wherein R2 and R3 are the same as defined above,
describes the synthesis of 2-phenyl indan-5-ols (30). Condensation of p-anisaldehyde
(24) with substituted phenyl acetic acid (25) gives mixture of cis-and trans-isomers
of the corresponding acrylic acid (26). After hydrogenation and intramolecular
Friedel-Crafts reaction carbonyl functionality of 1-indanones (28) can be reduced by
Clemmensen reduction. Finally methoxy indane (29) is refluxed in concentrated
hydrobromic acid to obtain 2-phenyl indan-5-ols (30).


6-Hydroxyflavanone derivatives can be synthesised as shown in Scheme 9
wherein R2, R3 and R12 are as defined above. 2',5'-Dihydroxyacetophenone or
corresponding propiophenone (32) is condensed with appropriate benzaldehyde (31)
resulting in a mixture of desired 6-hydroxyflavanone (34) and the corresponding
chalcone (35). The chalcone can be cyclised to flavanone.

The benzaldehyde derivatives of (31) wherein R2 and R3 can contain pyridine
moiety are obtained by the reaction of hydroxybenzaldehydes (35) with pyridine
derivatives (36) (where X1 can be chlorine or bromine and R' hydrogen, nitro or
halogen) as shown in Scheme 10.

2-Phenylchroman-4,6-diol derivatives (39) are obtained from corresponding
6-hydroxyflavanones (38) by reduction as shown in Scheme 11 wherein R2, R3 and

R12 are as defined above. These diol derivatives can be reduced further into 6-
hydroxyflavanes (40).

The following Scheme 12, wherein R2 and R3 are the same as defined above,
describes the synthesis of 7-hydroxyisoflavones (45) and 7-hydroxyisoflavans (46),
Acylation of 3-methoxyphenol (41) with substituted phenyl acetic acids (42) gives
the corresponding 2-hydroxydeoxybenzoins (43) which can be cyclised with triethyl-
orthoformate to yield isoflavones (44). Deprotection with hydrobromic acid and
catalytic hydrogenation gives 7-hydroxyisoflavans (46).


The following Scheme 13 describes the synthesis of 2-phenyl-2,3-dihydro-
benzo[1,4]oxathiin-6-ol (50). The reaction of 2-mercaptobenzene-1,4-diol (47) with
styrene epoxide (48) in the presence of base gives sulphide (49). The ring closure
with an acid ion exchanger affords 2-phenyl-2,3-dihydrobenzo[1,4]oxathiin-6-ol
(50).


The following Scheme 14 describes the synthesis of 6-phenyl-5,6,7,8-tetra-
hydro-naphthalen-2-ol (55) and 6-hydroxy-2-phenyl-3,4-dihydro-2H-naphthalen-1-
one (54). Palladium catalyzed á-arylation of 6-methoxy-1-tetralone (51) gives 6-
methoxy-2-phenyl-3,4-dihydro-2H-naphthalen-1-one (53) which after demethylation
leads to the phenolic compound (54). Reduction with triethylsilane gives 6-phenyl-
5,6,7,8-tetrahydronaphthalen-2-ol (55).


The following Scheme 15, wherein R2 and R3 are as defined above and R" is
an appropriate protecting group, describes the synthesis of 2,3-dihydro-2-phenyl-
benzo[l,4]dioxin-6-ols (60). After the protecting hydroxyl groups of 2,5-dihydroxy-
acetophenone are removed, this ketone rearranges with peracids and gives a phenol
(56) after hydrolysis. The phenol (56) is condensed with a haloketone and after
reduction and removal of protection groups the hydroxyphenol (59) is cyclised to a
2,3-dihydro-2-phenyl-benzo[1,4]-dioxin-6-ol (60).


Dihydroxyflavane derivatives (61) can be reacted with pyridine derivatives in
a similar manner as described for compound (1) in Scheme 1. 4-Chromanol
derivative of (62), where R* is OH, can be reduced to corresponding flavane with
triethylsilane in acidic media. 5-nitropyridine derivatives (62) are reduced to corres-
ponding 2-aminoderivatives (63), which in turn can be acylated or mesylated or
reacted with various aminoacid- or carboxylic acid derivatives as described in
Scheme 4 for compound (13).


When the nitro group in the benzyloxy derivatives (65) is reduced by
hydrogenation using palladium as catalyst there are obtained [6-(5-aminopyridin-2-
yloxy)chroman-2-yl]phenol derivatives (68) which in turn can be acylated or
mesylated. These phenol derivatives (69) can then be reacted with pyridine
derivatives (2) to result in derivatives like (70) as shown in the following Scheme 17.
The reduction with zinc leads to amines like (66) which in turn can be acylated,
mesylated or reacted with various amino acid- or carboxylic acid derivatives as
described in Scheme 4 for compound (13).

Alkyl derivatives of aminopyridines (3) can be obtained by reductive
amination as shown in Scheme 18 for dimethylamine derivatives (71). In the course
of the reaction the amine moiety is partially rearranged from 5 to 4 position.


The following Scheme 19, describes the synthesis of l-methyl-3-
(pyridinyl)thiourea (73) and N-methyl-N-(pyridynyl)guanidine (74) derivatives.
Aminopyridine derivatives (3) were reacted with methyl isothiocyanate to result in
tioura derivatives (73), which in turn were treated first with methyl iodide and then
with methanolic solution of ammonia in order to obtain guanidine derivatives (74).

Salts and esters of the compounds, when applicable, may be prepared by
known methods. Physiologically acceptable salts are useful as active medicaments.
Examples are the salts with inorganic acids such as hydrochloric acid, hydrobromic
acid or nitric acid, and salts with organic acids such as methanesulfonic acid, citric
acid or tartaric acid. Physiologically acceptable esters are also useful as active
medicaments. Examples are the esters with aliphatic or aromatic acids such as acetic
acid or with aliphatic or aromatic alcohols such as ethanol.
The term "alkyl" as employed herein by itself or as part of another group
includes both straight, branched and cyclised chain radicals of up to 18 carbon atoms,
preferably 1 to 7 carbon atoms. The term "lower alkyl" as employed herein by itself
or as part of another group includes straight, branched and cyclized chain radicals of
1 to 7 carbon atoms. Specific examples for the alkyl and lower alkyl residues,
respectively, are methyl, ethyl, propyl, isopropyl, butyl, tert. butyl, pentyl,
cyclopentyl, hexyl, cyclohexyl, octyl, decyl and dodecyl including the various
branched chain isomers thereof.
The term "alkoxy" as employed herein by itself or as part of another group
includes an alkyl group as defined above linked to an oxygen atom.
The term "acyl" as employed herein by itself or as part of another group refers
to an alkylcarbonyl or alkenylcarbonyl group, the alkyl and alkenyl groups being
defined above.

Compounds of the invention may be administered to a patient in therapeuti-
cally effective amounts which range usually from about 0.05 to 200 mg, preferably
0.1 to 100 mg, more preferably 0.5 to 50, mg per day depending on the age, weight,
condition of the patient, administration route and the Na+/Ca2+ exchange inhibitor
used. The compounds of the invention can be formulated into dosage forms using the
principles known in the art. It can be given to a patient as such or in combination
with suitable pharmaceutical excipients in the form of tablets, granules, capsules,
suppositories, emulsions, suspensions or solutions. Choosing suitable ingredients for
the composition is a routine for those of ordinary skill in the art. It is evident that
suitable carriers, solvents, gel forming ingredients, dispersion forming ingredients,
antioxidants, colours, sweeteners, wetting compounds and other ingredients normally
used in this field of technology may be also used. The compositions containing the
active compound can be given enterally or parenterally, the oral route being the
preferred way. The contents of the active compound in the composition is from about
0.5 to 100 %, preferably from about 0.5 to about 20 %, per weight of the total
composition.
EXPERIMENTS
The effects of the compounds of the invention were tested on ouabain-induced
arrhythmias in guinea-pig papillary muscles.
Methods
Guinea-pig papillary muscles were mounted into horizontal muscle cuvette. A
hook connected to force transducer was attached to another end of the muscle.
Muscle preparations were electrically paced at 1 Hz with field stimulation via
platinum electrodes. Modified Tyrode solution was used for superfusion of muscle
preparations. The composition of the Tyrode solution was the following (mM): NaCl
135, MgCl2 x 6H2O 1, KCl5, CaCl2 x 2H2O 2, NaHCO3 15, Na2HPO4 x 2H2O 1, and
glucose 10. The Tyrode solution was gassed with carbogen (95% O2, 5% CO2) to set
pH at 7.4. Experiments were carried out at 37 °C. Acquisition and analysis of twitch
tensions with Action Potential and Force Measurement System (ACFO v1.0, Fision
Ltd, Finland).

Inhibition of ouabain-induced arrhythmias
Ouabain by blocking of sodium-potassium ATPase increases intracellular
sodium which is changed for calcium via NCX. Increased intracellular calcium is
leading to overload of sarcoplasmic reticulum (SR) and spontaneous calcium release
from SR inducing delayed afterpolarizations (DADs). Equivalence for DADs in force
signal is aftercontractions (ACs) which are seen as spontaneous twitches after the
pacing controlled twitch.
The antiarrhythmic effects of the title compounds of Examples 13, 33, 14a
and 14b were examined. The results are shown in Figures 1 to 3. Figure 1 shows the
effects of the compounds on the start time of fast rise of ouabain-induced after-
contractions. Figure 2 shows the effects of the compounds on the maximum heights
of ouabain-induced aftercontractions in guinea-pig papillary muscles. Figure 3 shows
the effects of the compounds on the time to maximum heights of ouabain-induced
aftercontractions in guinea-pig papillary muscles.
In general, the compounds of the invention delayed appearance and decreased
the amplitude of aftercontractions. The title compound of Example 33, at 10 µM
concentration, was able to inhibit completely the emergency of ouabain-induced
second aftercontraction.
EXAMPLES:
Examples 1 to 11 generally describe the preparation of intermediates of the
compounds of the invention. The preparation of the compounds of the invention is
generally described from Example 12 onwards.
Example 1. Intermediates
a) 2-phenylchromanol intermediates
2-phenylchroman-6-ol

Zinc (5,4 g, 83,2 mmol), mercury (II) chloride (340 mg), concentrated
hydrogen chloride (0,2 ml) and water were mixed at room temperature for 15 minutes
and the mixture was decanted. 6-Hydroxyflavanone (1,0 g) was added as a
suspension in a mixture of acetic acid (25 ml), concentrated hydrogen chloride (5,2
ml) and water (2 ml). The reaction mixture was refluxed for 1½ hours. After cooling
into room temperature, the reaction mixture was filtered and the filtrate was extracted
with ethyl acetate. The combined organic layers were washed with saturated
NaHCO3-solution, then with water and dried with Na2SO4. The 2-phenylchroman-6-
ol was purified by column chromatography using heptane-ethyl acetate (2:1) as an
eluant. lH NMR (400 MHz, d6-DMSO) ä: 8.78 (s, 1H), 7.43-7.31 (m, 5H), 6.63 (d,
1H, J 8.6 Hz) 6.51 (dd, 1H, J 8.6,2.9 Hz), 6.48 (d, 1H, J 2.9 Hz), 4.98 (dd, 1H, J, 9.9,
2.2 Hz), 2.89 (ddd, 1H, J -16.7, 11.3, 6.1 Hz), 2.63 (ddd, 1H, J -16.7, 5.5, 3.3 Hz)
2.10 (m, 1H), 1.94 (m, 1H).
Using the same procedure as described above for 2-phenylchroman-6-ol, but
replacing 6-hydroxyflavanone by 7-hydroxyflavanone, there was obtained:
2-Phenylchroman-7-ol
1H NMR (400 MHz, CD3OD) ä: 7.41-7.28 (m, 5H), 6.86 (d, 1H, J 8.2 Hz)
6.32 (dd, 1H, J 8.2,2.4 Hz), 6.29 (d, 1H, J 2.4 Hz), 5.00 (dd, 1H, J 9.9, 2.4 Hz), 2.84
(m, 1H), 2.64 (m, 1H) 2.15 (m, 1H), 1.99 (m, 1H).
b)5-Nitro-2-(2-(nonsubstituted)phenylchromanyloxy)pyridine intermediates
5-Nitro-2-(2-phenylchroman-6-yloxy)pyridine
Potassium fluoride (225 mg) was added into a solution of 2-phenylchroman-
6-ol (300 mg) in dry DMF (3 ml). After stirring the resulting mixture at 120°C for
30 minutes 2-chloro-5-nitropyridine (195 mg) was added. The reaction mixture was
stirred for a further 6½ hours at 120°C. After cooling into room temperature 1 M
HCl-solution was added and the mixture was extracted with ethyl acetate. The
combined organic layers were washed with water then with saturated NaCl-solution
and dried with Na2SO4. 5-Nitro-2-(2-phenylchroman-6-yloxy)-pyridine was
recrystallised from acetone- 2-propanol (1:5). 1H NMR (400 MHz, d6-DMSO)ä:
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, 1H, J 10.1, 2.2 Hz), 2.99 (ddd, 1H, J -16.8,
11.3, 6.2 Hz), 2.75 (ddd, 1H, J-16.8, 5.4, 3.3 Hz) 2.18 (m, 1H), 2.02 (m, 1H).
Using the same procedure as described above for 5-nitro-2-(2-phenyl-
chroman-6-yloxy)pyridine, but replacing 2-phenylchroman-6-ol by 2-phenylchroman-
7-ol, there was obtained:
5-Nitro-2-(2-phenylchroman-7-yloxy)pyridine
1H NMR (400 MHz, d6-DMSO) ä: 9.04 (d, 1H, J 2.8 Hz), 8.60 (dd, 1H, J 9.1,
2.8 Hz), 7.46-7.32 (m, 5H), 7.22 (d, 1H, J 9.1 Hz), 7.20 (d, 1H, J 8.9 Hz) 6.72 (dd,
1H, J 8.9,2.3 Hz), 6.72 (d, 1H, J 2.3 Hz), 5.16 (dd, 1H, J 10.1,2.1 Hz), 2.97 (ddd,
1H, J -16.7,11.3,5.9 Hz), 2.77 (ddd, 1H, J -16.7, 8.1,4.5 Hz) 2.20 (m, 1H), 2.02
(m, 1H).
Example 2. Intermediates
a) Chroman-4-none intermediates
6-Hydroxy-2-(4-fluorophenyl)chroman-4-one
2',5'-Dihydroxyacetophenone (3,0 g) was dissolved in warm glacial acetic
acid (40 ml). 4-Fluorobenzaldehyde (2,4 ml) and ammonium acetate (1,97 g) were
added. The reaction mixture was refluxed for 8 hours. It was allowed to cool to room
temperature and poured in ice. The precipitate formed was filtered resulting in 4,23 g
of a mixture of 2-(4-fluorophenyl)-6-hydroxychroman-4-one and 1-(2,5-dihydroxy-
phenyl)-3-(4-fluorophenyl)propenone. The obtained mixture was dissolved in ethanol
(75 ml) and sodium acetate (3,4 g) was added. The reaction mixture was refluxed for
5 hours. It was then allowed to cool to room temperature and diluted with water and
filtered. The 2-(4-fluorophenyl)-6-hydroxychroman-4-one was recrystallised from
acetic acid. 1H NMR (400 MHz, d6-DMSO) ä: 7.59 (m, 2H), 7.27 (m, 2H), 7.14 (d,
1H, J 3.1 Hz), 7.05 (dd, 1H, J 8.9, 3.1 Hz), 6.96 (d, 1H, J 8.9 Hz), 5.56 (dd, 1H, J
13.2, 2.8 Hz), 3.18 (dd, 1H, J -16.9, 13.2 Hz), 2.77 (dd, 1H, J -16.9, 2.8 Hz).
Using the same procedure as described above for 6-hydroxy-2-(4-
fluorophenyl)chroman-4-one, but replacing 4-fluorobenzaldehyde by an appropriate
benzaldehyde, there was obtained:

2-(3 -Fluorophenyl)-6-hydroxychroman-4-one
1H NMR (400 MHz, d6-DMSO) ä: 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, 1H, J -16.9, 13.0 Hz), 2.82 (dd, 1H,
J-16.9, 2.9Hz).
2-(2-Fluorophenyl)-6-hydroxychroman-4-one
1H NMR (400 MHz, d6-DMSO) ä: 9.45 (s, 1H), 7.67 (m, 1H), 7.47 (m, 1H),
7.32-7.25 (m, 2H), 7.14 (d, 1H, J 3.0 Hz), 7.04 (dd, 1H, J 8.9, 3.0 Hz), 6.95 (d, 1H, J
8.9 Hz), 5.77 (dd, 1H, J 13.5, 2.8 Hz), 3.26 (dd, 1H, J -16.9, 13.5 Hz), 2.76 (dd, 1H,
J-16.9,2.8 Hz).
2-(2,3-Difluorophenyl)-6-hydroxychroman-4-one
1H NMR (400 MHz, d6-DMSO) ä: 9.51 (s, 1H), 7.53-7.46 (m, 2H), 7.31 (m,
1H), 7.14 (d, 1H, J 3.0 Hz), 7.05 (dd, 1H, J 8.8, 3.0 Hz), 6.96 (d, 1H, J 8.8 Hz), 5.82
(dd, 1H, J 13.4,2.8 Hz), 3.26 (dd, 1H, J-16.9,13.4 Hz), 2.79 (dd, 1H, J-16.9, 2.8
Hz).
2-(2,4-Difluorophenyl)-6-hydroxychroman-4-one
1H NMR (400 MHz, d6-DMSO) ä: 9.46 (s, 1H), 7.73 (m, 1H), 7.34 (m, 1H),
7.19 (m, 1H), 7.13 (d, 1H, J 2.9 Hz), 7.04 (dd, 1H, J 8.8, 2.9 Hz), 6.95 (d, 1H, J 8.8
Hz), 5.74 (dd, 1H, J 13.5, 2.8 Hz), 3.28 (dd, 1H, J -16.9, 13.5 Hz), 2.74 (dd, 1H, J -
16.9, 2.8 Hz).
2-(2,5-Difluorophenyl)-6-hydroxychroman-4-one
1H NMR (300 MHz, d6-DMSO) ä: 9.46 (s, 1H), 7.53 (m, 1H), 7.36-7.30 (m,
2H), 7.14 (d, 1H, J 3.0 Hz), 7.05 (dd, 1H, J 8.8,3.0 Hz), 6.97 (d, 1H, J 8.8 Hz), 5.76
(dd, 1H, J 13.6,2.7 Hz), 3.26 (dd, 1H, J-16.8,13.6 Hz), 2.76 (dd, 1H, J-16.8, 2.7
Hz).
2-(2,6-Difluorophenyl)-6-hydroxychroman-4-one
1H NMR (400 MHz, d6-DMSO) ä: 7.55 (m, 1H) 7.22-7.18 (m, 2H), 7.14 (d,
1H, J 3.0 Hz), 7.03 (dd, 1H, J 8.9, 3.0 Hz), 6.93 (d, 1H, J 8.9 Hz), 5.84 (dd, 1H, J
14.0, 3.0 Hz), 3.38 (dd, 1H, J -17.0, 14.0 Hz), 2.80 (dd, 1H, J -17.0, 3.0 Hz).

2-(3,5-Difluorophenyl)-6-hydroxychroman-4-one
1H NMR (400 MHz, d6-DMSO) ä: 9.47 (s, 1H), 7.30-7.23 (m, 3H), 7.12 (d,
1H, J 2.9 Hz), 7.06 (dd, 1H, J 8.8,2.9 Hz), 7.00 (d, 1H, J 8.8 Hz), 5.60 (dd, 1H, J
13.1, 2.8 Hz), 3.15 (dd, 1H, J-16.8,13.1 Hz), 2.85 (dd, 1H, J-16.8, 2.8 Hz).
6-Hydroxy-2-(2-trifluoromethylphenyl)chroman-4-one
1H NMR (400 MHz, d6-DMSO) ä: 9.48 (s, 1H), 8.07 (m, 1H,) 7.86-7.79 (m,
2H), 7.66 (m, 1H), 7.15 (d, 1H, J 3.0 Hz), 7.06 (dd, 1H, J 8.8, 3.0 Hz), 6.95 (d, 1H, J
8.8 Hz), 5.70 (dd, 1H, J 13.8,2.4 Hz), 3.38 (dd, 1H, J-16.9, 13.8 Hz), 2.66 (dd, 1H,
J-16.9, 3.0 Hz).
6-Hydroxy-2-(4-trifluoromethylphenyl)chroman-4-one
1H NMR (400 MHz, d6-DMSO) ä: 9.47 (s, 1H), 7.82-7.76 (m, 4H), 7.13 (d,
1H, J 3.0 Hz), 7.06 (dd, 1H, J 8.8,3.0 Hz), 6.99 (d, 1H, J 8.8 Hz), 5.70 (dd, 1H, J
12.9, 2.9 Hz), 3.16 (dd, 1H, J -16.9, 12.9 Hz), 2.86 (dd, 1H, J -16.9, 2.9 Hz).
2-(3-Chloro-4-fluorophenyl)-6-hydroxychroman-4-one
1H NMR (400 MHz, d6-DMSO) ä: 9.45 (s, 1H), 7.53 (m, 1H), 7.36-7.31 (m,
2H), 7.13 (d, 1H, J 3.0 Hz), 7.05 (dd, 1H, J 8.9, 3.0 Hz), 6.96 (d, 1H, J 8.9 Hz), 5.76
(dd, 1H, J 13.5,2.7 Hz), 3.26 (dd, 1H, J -16.9,13.5 Hz), 2.75 (dd, 1H, J -16.9, 2.7
Hz).
2-(2-Chlorophenyl)-6-hydroxychroman-4-one
1H NMR (400 MHz, d6-DMSO) ä: 9.49 (s, 1H), 7.77 (dd, 1H, J 7.7, 2.0 Hz),
7.53 (dd, 1H, J 7.6,1.8 Hz), 7.49-7.41 (m, 2H), 7.14 (d, 1H, J 2.9 Hz), 7.06 (dd, 1H,
J 8.8, 2.9 Hz), 6.93 (d, 1H, J 8.8 Hz), 5.78 (dd, 1H, J 13.6,2.6 Hz), 3.19 (dd, 1H, J -
16.9,13.6 Hz), 2.78 (dd, 1H, J -16.9,2.6 Hz).
2-(3-Chlorophenyl)-6-hydroxychroman-4-one
1H NMR (400 MHz, d6-DMSO) ä: 9.47 (s, 1H), 7.62 (s, 1H), 7.51-7.45 (m,
3H), 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), 5.58
(dd, 1H, J 13.1,2.9 Hz), 3.18 (dd, 1H, J -16.9,13.1 Hz), 2.81 (dd, 1H, J -16.9,2.9
Hz).
2-(2,4-Dichlorophenyl)-6-hydroxychroman-4-one

1H NMR (400 MHz, d6-DMSO) ä: 9.49 (s, 1H), 7.78 (d, 1H, J 8.5 Hz),
7.71 (d, 1H, J 2.0 Hz)), 7.57 (dd, 1H, J 8.5,2.0 Hz), 7.14 (d, 1H, J 3.0 Hz), 7.06 (dd,
1H, J 8.8, 3.0 Hz), 6.97 (d, 1H, J 8.8 Hz), 5.77 (dd, 1H, J 13.5, 2.7 Hz), 3.18 (dd, 1H,
J -16.9, 13.5 Hz), 2.78 (dd, 1H, J-16.9,2.7 Hz).
2-(3-Bromophenyl)-6-hydroxychroman-4-one
1H NMR (400 MHz, d6-DMSO) ä: 9.41 (s, 1H), 7.50 (m, 1H), 7.59-7.53 (m,
2H), 7.39 (m, 1H) 7.12 (d, 1H, J 2.9 Hz), 7.05 (dd, 1H, J 8.8,2.9 Hz), 6.98 (d, 1H, J
8.8 Hz), 5.57 (dd, 1H, J 13.0, 2.9 Hz), 3.12 (dd, 1H, J-16.9, 13.0 Hz), 2.81 (dd, 1H,
J-16.9, 2.9 Hz).
2-(4-Ethylphenyl)-6-hydroxychroman-4-one
1H NMR (400 MHz, d6-DMSO) ä: 7.43 (d, 2H, J 8.1 Hz), 7.25 (d, 2H, J 8.1
Hz), 7.11 (d, 1H, J 3.1 Hz), 7.03 (dd, 1H, J 8.9, 3.1 Hz), 6.93 (d, 1H, J 8.9 Hz), 5.51
(dd, 1H, J 13.0, 2.9 Hz), 3.15 (dd, 1H, J-16.9,13.0Hz), 2.75 (dd, 1H, J-16.9,2.9
Hz), 2.62 (q, 2H, J 7.5 Hz), 1.18 (t, 3H, J 7.5 Hz).
6-Hydroxy-2-(2-nitrophenyl)chroman-4-one
1H NMR (400 MHz, d6-DMSO) ä: 9.49 (s, 1H), 8.05-8.06 (m, 1H), 7.96-7.98
(m, 1H), 7.83-7.87 (m, 1H), 7.65-7.69 (m, 1H), 7.14 (d, 1H, J 3.1 Hz), 7.05 (dd, 1H,
J 8.8, 3.1 Hz), 6.91 (d, 1H, J 8.8 Hz), 5.69 (dd, 1H, J 13.0,2.6 Hz), 3.22 (dd, 1H, J
16.8.13.0 Hz), 2.98 (dd, 1H, J 16.8,2.6 Hz).
6-Hydroxy-2-(3-nitrophenyl)chroman-4-one
1H NMR (400 MHz, d6-DMSO) ä: 8.40 (s, 1H), 8.24 (dd, 1H, J 8.2, 2.3 Hz),
8.01 (d, 1H, J 7.9 Hz), 7.74 (t, 1H, J 15.9,7.9 Hz), 7.13 (d, 1H, J 2.9 Hz), 7.07 (dd,
1H, J 8.8, 2.9 Hz), 7.00 (d, 1H, 8.8 Hz), 5.75 (dd, 1H, J 13.1, 2.9 Hz), 3.21 (dd, 1H, J
16.8.13.1 Hz), 2.88 (dd, 1H, J 16.8,2.9 Hz).
6-Hydroxy-2-(4-nitrophenyl)chroman-4-one
1H NMR (400 MHz, d6-DMSO) ä: 9.48 (s, 1H), 8.29 (d, 2H, J 6.9 Hz), 7.83
(d, 2H, J 6.9 Hz), 7.13 (d, 1H J 2.9 Hz), 7.06 (dd, 1H, J 8.8,2.9 Hz), 7.01 (d, 1H, J
8.8 Hz), 5.77 (dd, 1H, J 13.0, 3.0 Hz), 3.15 (dd, 1H, J 16.8,13.0 Hz), 2.89 (dd, 1H, J
16.8,3.0 Hz).
6-Hydroxy-2-(3-methoxyphenyl)chroman-4-one

1H NMR (400 MHz, d6-DMSO) ä: 9.42 (s, 1H), 7.33 (t, 1H, J 15.8, 8.3 Hz),
7.12 (d, 1H, J 3.0 Hz), 7.10 (s, 1H), 7.09 (d, 1H, J 8.3 Hz), 7.04 (dd, 1H, J 8.8, 3.0
Hz), 6.96 (d, 1H, 8.8 Hz), 6.93 (dd, 1H, J 8.0,2.5 Hz), 5.52 (dd, 1H, J 12.9,2.9 Hz),
3.77 (s, 3H), 3.17 (dd, 1H, J 16.9,12.9 Hz), 2.77 (dd, 1H, J 16.9,2.9 Hz).
6-Hydroxy-3-methyl-2-phenylchroman-4-one
1H NMR (300 MHz, d6-DMSO) ä; 9.37 (s, 1H), 7.53 (m, 2H), 7.47-7.39 (m,
3H), 7.13 (d, 1H, J 3.1 Hz), 7.02 (dd, 1H, J 8.9,3.1 Hz), 6.89(d, 1H, J 8.9 Hz), 5.17
(d, 1H, J 12.3), 3.18 (dq, 1H, J 12.3, 6.9 Hz), 0.84 (d, 3H, J 6.9 Hz).
b) Chroman-4,6-diol intermediates
2-(4-Fluorophenyl)chroman-4,6-diol
Into a suspension of 2-(4-fluorophenyl)-6-hydroxychroman-4-one (3,4 g) in
dry THF (34 ml) was added dropwise a solution of borane-THF complex (20 ml, 1.0
M in THF) under nitrogen. The reaction mixture was refluxed for 1 hour. After
cooling to the room temperature it was poured into an ice-2 M HCl-solution. 2-(4-
Fluorophenyl)chroman-4,6-diol was filtered. 1H NMR (400 MHz, d6-DMSO) ä: 8.84
(s, 1H), 7.48 (m, 2H), 7.21 (m, 2H), 6.89 (d, 1H, J 2.7 Hz), 6.59 (d, 1H, J 8.7 Hz),
6.54 (dd, 1H, J 8.7,2.7 Hz), 5.42 (bs, 1H), 5.12 (d, 1H, J 10.7 Hz), 4.87 (m, 1H),
2.25 (m, 1H), 1.89 (m, 1H).
Using the same procedure as described above for 2-(4-fluorophenyl)chroman-
4,6-diol, but replacing 2-(4-fluorophenyl)-6-hydroxychroman-4-one by an
appropriate 2-phenyl-6-hydroxychroman-4-one, there was obtained:
2-(3-Fluorophenyl)chroman-4,6-diol
1H NMR (400 MHz, d6-DMSO) ä: 8.85 (s, 1H), 7.45 (m, 1H), 7.30-7.25 (m,
2H), 7.15 (m, 1H), 6.88 (d, 1H, J 2.8 Hz), 6.62 (d, 1H, J 8.7 Hz), 6.55 (dd, 1H, J 8.7,
2.8 Hz), 5.44 (d, 1H, J 7.0 Hz), 5.15 (d, 1H, J 10.7 Hz), 4.86 (m, 1H), 2.29 (m, 1H),
1.86 (m,1H).
2-(2-Fluorophenyl)chroman-4,6-diol
1H NMR (400 MHz, d6-DMSO) ä: 8.85 (s, 1H), 7.56 (m, 1H), 7.40 (m, 1H),
7.28-7.21 (m, 2H), 6.89 (d, 1H, J 2.9 Hz), 6.60 (d, 1H, J 8.7 Hz), 6.54 (dd, 1H, J 8.7,

2.8 Hz), 5.46 (d, 1H, J 6.9 Hz), 5.35 (d, 1H, J 10.6 Hz), 4.89 (m, 1H), 2.26 (m, 1H),
1.98 (m, 1H).
2-(2,3-Difluorophenyl)chroman-4,6-diol
1H NMR (400 MHz, d6-DMSO) ä: 8.88 (s, 1H), 7.45-7.36 (m, 2H), 7.28 (m,
1H), 6.89 (d, 1H, J 2.8 Hz), 6.61 (d, 1H, J 8.7 Hz), 6.55 (dd, 1H, J 8.7, 2.8 Hz), 5.49
(bs, 1H), 5.40 (dd, 1H, J 11.8,1.4 Hz), 4.90 (m, 1H), 2.28 (m, 1H), 1.99 (m, 1H).
2-(2,4-Difluorophenyl)chroman-4,6-diol
1H NMR (400 MHz, d6-DMSO) ä: 8.86 (s, 1H), 7.61 (m, 1H), 7.28 (m, 1H),
7.14 (m, 1H), 6.88 (d, 1H, J 2.7 Hz), 6.59 (d, 1H, J 8.9 Hz), 6.54 (dd, 1H, J 8.9,2.7
Hz), 5.46 (s, 1H), 5.32 (dd, 1H, J 11.9,1.4 Hz), 4.88 (m, 1H), 2.24 (m, 1H), 1.99 (m,
1H).
2-(2,5-Difluorophenyl)chroman-4,6-diol
1H NMR (400 MHz, d6-DMSO) ä: 8.87 (s, 1H), 7.39-7.22 (m, 3H), 6.89 (d,
1H, J 2.8 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, 1H, J 11.2 Hz), 4.89 (m, 1H), 2.28 (m, 1H), 1.95 (m, 1H).
2-(2,6-Difluorophenyl)chroman-4,6-diol
1H NMR (400 MHz, d6-DMSO) ä: 8.87 (s, 1H), 7.48 (m, 1H), 7.17-7.13 (m,
2H), 6.90 (d, 1H, J 2.9 Hz), 6.55-6.54 (m, 2H), 5.46 (dd, 1H, J 12.2,1.8 Hz), 4.87
(m, 1H), 2.37 (m, 1H), 2.23 (m, 1H).
2-(3,5-Difluorophenyl)chroman-4,6-diol
1H NMR (400 MHz, d6-DMSO) ä: 8.87 (s, 1H), 7.21-7.17 (m, 3H), 6.88 (d,
1H, J 2.4 Hz), 6.64 (d, 1H, J 8.7 Hz), 6.55 (dd, 1H, J 2.4, 8.7 Hz), 5.47 (d, 1H, J 7.0
Hz), 5.17 (d, 1H, J 10.5 Hz), 4.86 (m, 1H), 2.32 (m, 1H), 1.85 (m, 1H).
2-(2-Trifluoromethylphenyl)chroman-4,6-diol
1H NMR (300 MHz, d6-DMSO) ä: 8.89 (s, 1H), 7.83 (m, 1H), 7.79-7.74 (m,
2H), 7.58 (m, 1H), 6.90 (d, 1H, J 2.7 Hz), 6.61 (d, 1H, J 8.9 Hz), 6.56 (dd, 1H, J 8.7,
2.7 Hz), 5.51 (d, 1H, J 6.5 Hz), 5.34 (d, 1H, J 11.6 Hz), 4.88 (m, 1H), 2.21 (m, 1H),
1.95 (m, 1H).
2-(4-Trifluoromethylphenyl)chroman-4,6-diol

1H NMR (400 MHz, d6-DMSO) ä: 8.86 (s, 1H), 7.77 (d, 2H, J 8.3 Hz), 7.68
(d, 2H, J 8.3 Hz), 6.89 (d, 1H, J 2.9 Hz), 6.63 (d, 1H, J 8.7 Hz), 6.56 (dd, 1H, J 8.7,
2.9 Hz), 5.45 (d, 1H, J 7.0 Hz), 5.26 (d, 1H, J 11.2 Hz), 4.90 (m, 1H), 2.32 (m, 1H),
1.85 (m, 1H).
2-(3-Chloro-4-fluorophenyl)chroman-4,6-diol
1H NMR (400 MHz, d6-DMSO) ä: 8.88 (s, 1H), 7.39-7.24 (m, 3H), 6.88 (d,
1H, J 2.8 Hz), 6.63 (d, 1H, J 8.7 Hz), 6.55 (dd, 1H, J 8.7, 2.8 Hz), 5.49 (d, 1H, J 6.8
Hz), 5.35 (d, 1H, J 11.3 Hz), 4.89 (m, 1H), 2.39 (m, 1H), 1.97 (m, 1H).
2-(2-Chlorophenyl)chroman-4,6-diol
1H NMR (400 MHz, d6-DMSO) ä: 7.63 (dd, 1H, J 7.7, 1.8 Hz), 7.49 (dd, 1H,
J 7.8,1.4 Hz), 7.45-7.36 (m, 2H), 6.89 (d, 1H, J 2.9 Hz), 6.63 (d, 1H, J 8.8 Hz), 6.56
(dd, 1H, J 8.9,2.9 Hz), 5.39 (dd, 1H, J 11.7, 1.5 Hz), 4.90 (m, 1H), 2.33 (m, 1H),
1.82 (m, 1H).
2-(3-Chlorophenyl)chroman-4,6-diol
1H NMR (400 MHz, d6-DMSO) ä: 8.85 (s, 1H), 7.50 (d, 1H, J 1.7 Hz), 7.46-
7.38 (m, 3H), 6.88 (d, 1H, J 2.5 Hz), 6.62 (d, 1H, J 8.6 Hz), 6.55 (dd, 1H, J 8.6,2.5
Hz), 5.44 (d, 1H, J 6.6 Hz), 5.15 (dd, 1H, J 11.8,1.4 Hz), 4.87 (m, 1H), 2.29 (m, 1H),
1.85 (m, 1H).
2-(2,4-Dichlorophenyl)chroman-4,6-diol
1H NMR (400 MHz, d6-DMSO) ä: 8.89 (s, 1H), 7.66 (d, 1H, J 2.1 Hz), 7.64
(d, 1H, J 8.5 Hz), 7.51 (dd, 1H, J 2.1, 8.5 Hz), 6.89 (d, 1H, J 2.7 Hz), 6.63 (d, 1H, J
8.7 Hz), 6.56 (dd, 1H, J 2.7, 8.7 Hz), 5.50 (d, 1H, J 6.8 Hz), 5.37 (d, 1H, J 10.4 Hz),
4.90 (m, 1H), 2.32 (m, 1H), 1.80 (m, 1H).
2-(3-Bromophenyl)-chroman-4,6-diol
1H NMR (300 MHz, d6-DMSO) ä: 8.83 (s, 1H), 7.63 (m, 1H) 7.53 (m, 1H)
7.46 (m, 1H) 7.37 (m, 1H), 6.88 (d, 1H, J 2.9 Hz), 6.62 (d, 1H, J 8.7 Hz), 6.55 (dd,
1H, J 8.7,2.9 Hz), 5.42 (d, 1H, J 7.0 Hz), 5.14 (d, 1H, J 10.5 Hz), 4.86 (m, 1H), 2.29
(m, 1H), 1.84 (m, 1H).
2-(4-Ethylphenyl)chroman-4,6-diol

1H NMR (400 MHz, d6-DMSO) ä: 8.81 (s, 1H), 7.34 (d, 2H, J 8.0 Hz) 7.22
(d, 2H, J 8.0 Hz), 6.88 (d, 1H, J 2.8 Hz), 6.57 (d, 1H, J 8.6 Hz), 6.53 (dd, 1H, J 8.6,
2.8 Hz), 5.39 (d, 1H, J 7.1 Hz), 5.06 (d, 1H, J 10.7 Hz), 4.86 (m, 1H), 2.61 (q, 2H, J
7.6 Hz), 2.29 (m, 1H), 1.84 (m, 1H), 1.19 (t, 3H, J 7.6 Hz).
2-(2-Nitrophenyl)chroman-4,6-diol
1H NMR (300 MHz, d6-DMSO) ä: 8.87 (s, 1H), 7.99-8.02 (m, 1H), 7.77-7.86
(m, 2H), 7.59-7.64 (m, 1H), 6.89 (d, 1H, J 2.4 Hz), 6.56-6.57 (m, 2H), 5.51-5.55 (m,
2H), 4.85-4.92 (m, 1H), 2.42-2.47 (m, 1H), 1.85-1.96 (m, 1H).
2-(3 -Nitrophenyl)chroman-4,6-diol
1H NMR (400 MHz, d6-DMSO) ä: 8.89 (br s, 1H), 8.29 (s, 1H), 8.20 (dd, 1H,
J 8.2, 2.3 Hz), 7.93 (d, 1H, J 7.9 Hz), 7.71 (t, 1H, J 15.9, 7.9 Hz), 6.89 (d, 1H, J 2.8
Hz), 6.66 (d, 1H, J 8.7 Hz), 6.57 (dd, 1H, J 8.7,2.9 Hz), 5.47 (br s, 1H), 5.33 (d, 1H,
J 10.7 Hz), 4.88-4.92 (m, 1H), 2.33-2.39 (m, 1H), 1.83-1.92 (m, 1H).
2-(4-Nitrophenyl)chroman-4,6-diol
1H NMR (300 MHz, d6-DMSO) ä: 8.86 (s, 1H), 8.26 (d, 2H, J 6.9 Hz), 7.74
(d, 2H, J 6.9 Hz), 6.89 (d, 1H J 2.8 Hz), 6.65 (d, 1H, J 8.6 Hz), 6.56 (dd, 1H, J 8.6,
2.8 Hz), 5.46 (d, 1H, J 6.9 Hz), 5.32 (d, 1H, J 10.5 Hz), 4.86-4.94 (m, 1H), 2.31-2.38
(m, 1H), 1.78-1.89 (m,lH).
2-(3 -methoxyphenyl)chroman-4,6-diol
]H NMR (400 MHz, d6-DMSO) ä: 8.82 (s, 1H), 7.31 (t, 1H, J 15.7, 7.9 Hz),
6.99-7.02 (m, 2H), 6.88-6.90 (m, 2H), 6.59 (d, 1H, J 8.7 Hz), 6.54 (dd, 1H, J 8.7,2.8
Hz), 5.40 (d, 1H, J 7.0 Hz), 5.08 (d, 1H, J 11.5 Hz), 4.83-4.89 (m, 1H), 3.77 (s, 3H),
2.23-2.28 (m, 1H), 1.83-1.92 (m, 1H).
3-Methyl-2-phenylchroman-4,6-diol
1H NMR (300 MHz, d6-DMSO) ä: 8.79 (s, 1H), 7.42-7.33 (m, 5H), 6.88 (bs,
1H,), 6.53 (m, 2H), 5.37 (d, 1H, J 8.0 Hz), 4.70 (d, 1H, J 10.6 Hz), 1.94 (m, 1H),
0.73 (d, 3H, J 6.7 Hz).
c) Chroman-6-ol intermediates
2-(4-Fluorophenyl)chroman-6-ol

Triethylsilane (14 ml) was added slowly into a solution of 2-(4-fluorophenyl)-
chroman-4,6-diol (2,9 g) in dichloromethane (58 ml). Trifluoroacetic acid (27 ml)
was then added dropwise into a reaction mixture and it was stirred at room
temperature for 1 hour. The reaction mixture was poured on ice-water and extracted
with dichloromethane. The residue was evaporated under reduced pressure with
toluene to obtain 2-(4-fluorophenyl)chroman-6-ol. 1H NMR (400 MHz, CDCL3) ä:
7.38 (m, 2H), 7.06 (m, 2H), 6.77 (d, 1H, J 8.6 Hz), 6.61 (dd, 1H, J 8.6,2.9 Hz) 6.57
(d, 1H, 8.6 Hz), 4.97 (dd, 1H, J 10.2,2.4 Hz), 2.95 (ddd, 1H, J -16.8,11.4,6.2 Hz),
2.74 (ddd, 1H, J-16.8, 5.3, 3.1 Hz), 2.15 (m, 1H), 2.05 (m, 1H).
Using the same procedure as described above for 2-(4-fluorophenyl)chroman-
6-0L, but replacing 2-(4-fluorophenyl)chroman-4,6-diol by an appropriate 2-phenyl-
chroman-4,6-diol, there was obtained:
2-(3-Fluorophenyl)chroman-6-ol
1H NMR (400 MHz, d6-DMSO) ä: 8.78 (s, 1H), 7.43 (m, 1H), 7.28-7.25 (m,
2H), 7.14 (m, 1H), 6.66 (d, 1H, J 8.5 Hz) 6.52 (dd, 1H, J 8.5,2.7 Hz), 6.49 (d, 1H, J
2.7 Hz), 5.03 (dd, 1H, J 9.9,2.1 Hz), 2.86 (m, 1H), 2.63 (m, 1H) 2.13 (m, 1H), 1.93
(m, 1H).
2-(2-Fluorophenyl)chroman-6-ol
1H NMR (300 MHz, d6-DMSO) ä: 7.50 (m, 1H), 7.39 (m, 1H), 7.26-7.19 (m,
2H), 6.63 (m, 1H) 6.53-6.50 (m, 2H), 5.21 (dd, 1H, J, 10.2, 2.3 Hz), 2.98 (ddd, 1H, J
-16.9,11.2, 6.0 Hz), 2.66 (ddd, 1H, J-16.9, 5.0, 2.9 Hz) 2.11 (m, 1H), 1.99 (m, 1H).
2-(2,3 -Difluorophenyl)chroman-6-ol
1H NMR (400 MHz, d6-DMSO) ä: 8.85 (s, 1H), 7.41 (m, 1H), 7.33 (m, 1H),
7.26 (m, 1H), 6.64 (dd, 1H, 9.0, 2.8 Hz), 6.54-6.51 (m, 2H), 5.25 (dd, 1H, J 10.2, 2.2
Hz), 2.93 (m, 1H), 2.66 (m, 1H), 2.14 (m, 1H), 2.01 (m, 1H).
2-(2,4-Difluorophenyl)chroman-6-ol
1H NMR (400 MHz, d6-DMSO) ä: 8.83 (s, 1H), 7.56 (m, 1H), 7.28 (m, 1H),
7.13 (m, 1H), 6.63 (m, 1H), 6.53-6.50 (m, 2H), 5.17 (dd, 1H, J 10.3,2.3 Hz), 2.92
(ddd, 1H, J -17.0,11.5, 5.8 Hz), 2.66 (ddd, 1H, J -17.0, 5.0, 2.7 Hz), 2.09 (m, 1H),

1.98 (m, 1H).
2-(2,5-Difluorophenyl)chroman-6-ol
1H NMR (300 MHz, d6-DMSO) ä: 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).
2-(2,6-Difluorophenyl)chroman-6-ol
1H NMR (300 MHz, d6-DMSO) ä: 8.85 (s, 1H), 7.41 (m, 1H), 7.33 (m, lh),
7.26 (m, 1H), 6.64 (dd, 1H, J 9.0,2.8 Hz), 6.54-6.51 (m, 2H), 5.25 (dd, 1H, J 10.2,
2.2 Hz), 2.93 (m, 1H,), 2.66 (m, 1H), 2.14 (m, 1H), 2.01 (m, 1H).
2-(3,5-Difluorophenyl)chroman-6-ol
1H NMR (300 MHz, d6-DMSO) ä: 8.82 (s, 1H), 7.20-7.14 (m, 3H), 6.68 (d,
1H, J 8.6 Hz), 6.53 (d, 1H, J 2.9 Hz), 6.50 (dd, 1H, J 8.6,2.9 Hz), 5.05 (dd, 1H, J 9.8,
2.2 Hz), 2.88 (ddd, 1H, J -16.7,10.8,5.9 Hz), 2.62 (ddd, 1H, J -16.7, 8.9, 5.0 Hz),
2.15 (m, 1H), 1.93 (m, 1H).
2-(2-Trifluoromethylphenyl)chroman-6-ol
1H NMR (400 MHz, d6-DMSO) ä: 8.86 (s, 1H), 7.81-7.75 (m, 3H), 7.57 (m,
1H), 6.674 (dd, 1H, J 7.1,2.1 Hz), 6.54-6.51 (m, 2H), 5.14 (d, 1H, J 10.5 Hz), 2.95
(m, 1H), 2.72 (m, 1H), 2.05 (m, 1H), 1.96 (m, 1H).
2-(4-Trifluoromethylphenyl)chroman-6-ol
1H NMR (400 MHz, d6-DMSO) ä: 8.82 (s, 1H), 7.75 (d, 2H, J 8.3 Hz), 7.65
(d, 2H, J 8.3 Hz), 6.67 (d, 1H, J 8.6 Hz), 6.53 (d, 1H, J 2.9 Hz) 6.51 (dd, 1H, 8.6,2.9
Hz), 5.12 (d, 1H, J 8.3 Hz), 2.90 (m, 1H), 2.63 (m, 1H), 2.16 (m, 1H), 1.92 (m, 1H).
2-(3-Chloro-4-fluorophenyl)chroman-6-ol
1H NMR (400 MHz, d6-DMSO) ä: 8.84 (s, 1H), 7.33-7.21 (m, 3H), 6.66 (d,
1H, J 8.3 Hz) 6.54-6.51 (m, 2H), 5.19 (d, 1H, J, 8.8 Hz), 2.92 (m, 1H), 2.66 (m, 1H)
2.12 (m, 1H), 1.96 (m, 1H).
2-(2-Chlorophenyl)chroman-6-ol
1H NMR (300 MHz, d6-DMSO) ä: 7.58-7.36 (m, 4H), 6.66 (m, 1H), 6.55-
6.51 (m, 2H), 5.23 (dd, 1H, J 10.1,2.1 Hz), 2.92 (m, 1H), 2.68 (m, 1H), 2.17 (m,

1H), 1.87 (m, 1H).
2-(3-Chlorophenyl)chroman-6-ol
1H NMR (300 MHz, d6-DMSO) ä: 8.79 (s, 1H), 7.48 (d, 1H, J 0.7 Hz), 7.42-
7.37 (m, 3H), 6.71-6.49 (m, 3H), 5.04 (m, 1H), 2.91 (m, 1H), 2.65 (m, 1H), 2.12 (m,
1H), 1.93 (m, 1H).
2-(2,4-Dichlorophenyl)chroman-6-ol
1H NMR (400 MHz, d6-DMSO) 8: 8.85 (s, 1H), 7.65 (d, 1H, J 2.2 Hz), 7.57
(d, 1H, J 8.4 Hz), 7.49 (dd, 1H, J 8.4,2.2 Hz), 6.67-6.51 (m, 3H), 5.21 (dd, 1H, J
10.3, 2.1 Hz), 2.91 (m, 1H), 2.69 (m, 1H), 2.16 (m, 1H), 1.85 (m, 1H).
2-(3-Bromophenyl)chroman-6-ol
1H NMR (400 MHz, d6-DMSO) ä: 8.81 (s, 1H), 7.61 (m, 1H), 7.51 (m, 1H),
7.43 (m, 1H), 7.35 (m, 1H) 6.67-6.48 (m, 3H), 5.01 (m, 1H), 2.87 (m, 1H,), 2.63 (m,
1H), 2.12 (m, 1H), 1.92 (m, 1H).
2-(4-Ethylphenyl)chroman-6-ol
1H NMR (400 MHz, CD3OD) ä: 7.26 (d, 2H, J 8.2 Hz) 7.13 (d, 2H, J 8.2
Hz), 6.65 (d, 1H, J 8.6 Hz), 6.55 (dd, 1H, J 8.6,2.8 Hz), 6.51 (d, 1H, J 2.8 Hz),, 4.83
(dd, 1H, J 10.1,2.3 Hz), 2.84 (m, 1H,), 2.62 (m, 1H), 2.59 (q, 2H, J 7.6 Hz) 2.03 (m,
1H), 1.93 (m, 1H), 1.19 (t, 3H, J 7.6 Hz).
2-(2-Nitrophenyl)chroman-6-ol
1H NMR (400 MHz, d6-DMSO) ä: 8.85 (s, 1H), 8.00 (d, 1H, J 8.0 Hz), 7.79-
7.80 (m, 2H), 7.59-7.63 (m, 1H), 6.59-6.62 (m, 1H), 6.50-6.53 (m, 2H), 5.36 (dd, 1H,
J 10.2, 2.0 Hz), 2.89-2.93 (m, 1H), 2.67-2.73 (m, 1H), 2.26-2.31 (m, 1H), 1.90-1.95
(m, 1H).
2-(3-Nitrophenyl)chroman-6-ol
1H NMR (300 MHz, d6-DMSO) ä: 8.80 (s, 1H), 8.26 (s, 1H), 8.19 (dd, 1H, J
8.1, 2.3 Hz), 7.90 (d, 1H, J 7.9 Hz), 7.70 (t, 1H, J 15.9, 7.9 Hz), 6.70 (d, 1H, J 8.4
Hz), 6.51-6.55 (m, 2H), 5.19 (dd, 1H, J 10.0, 2.0), 2.86-2.91 (m, 1H), 2.61-2.68 (m,
1H), 2.17-2.23 (m, 1H), 1.91-1.97 (m, 1H).
2-(4-Nitrophenyl)chroman-6-ol

1H NMR (400 MHz, d6-DMSO) ä: 8.84 (s, 1H), 8.26 (d, 2H, J 6.9 Hz), 7.71
(d, 2H, J 6.9 Hz), 6.69 (d, 1H, J 8.6 Hz), 6.53 (dd, 1H, J 8.6,2.8 Hz), 6.50 (d, 1H, J
2.8 Hz), 5.19 (dd, 1H, J 9.9,2.2 Hz), 2.87-2.91 (m, 1H), 2.61-2.66 (m, 1H), 2.16-
2.21 (m, 1H), 1.89-1.93 (m, 1H).
2-(3-Methoxyphenyl)chroman-6-ol
1H NMR (300 MHz, d6-DMSO) ä: 8.75 (s, 1H), 7.28 (t, 1H, J 15.7, 7.9 Hz),
6.96-6.99 (m, 2H), 6.87 (dd, 1H, J 7.9,2.5 Hz), 6.63 (d, 1H, J 8.3 Hz), 6.52 (d, 1H, J
2.9 Hz), 6.48 (s, 1H), 4.95 (dd, 1H, J 9.8,2.2 Hz), 3.75 (s, 3H), 2.82-2.89 (m, 1H),
2.57-2.66 (m, 1H), 2.06-2.13 (m, 1H), 1.89-1.97 (m, 1H).
3-Methyl-2-phenylchroman-6-ol
1H NMR (400 MHz, CD3OD) ä: 8.77 (s, 1H), 7.41-7.33 (m, 5H), 6.59-6.48
(m, 3H), 4.56 (d, 1H, J 9.2 Hz), 2.73 (dd, 1H, J -16.5, 5.0 Hz), 2.54 (dd, 1H, J -16.5,
5.8 Hz), 2.11 (m, 1H), 0.72 (d, 3H, J 6.6 Hz).
d) 2-[2-Phenylchroman-6-yloxy]-5-nitropyridine intermediates
2-[2-(4-Fluorophenyl)chroman-6-yloxy]-5-nitropyridine
2-[2-(4-Fluorophenyl)chroman-6-yloxy]-5-nitropyridine was prepared as
described for 5-nitro-2-(2-phenylchroman-6-yloxy)pyridine in Example l(b) starting
from 160 mg of 2-(4-fluorophenyl)chroman-6-ol. 1H NMR (400 MHz, d6-DMSO) ä:
9.04 (dd, 1H, J 2.9, 0.4 Hz), 8.60 (dd, 1H, J 9.1,2.9 Hz), 7.51 (m, 2H), 7.24 (m, 1H),
7.20 (dd, 1H, J 9.1,0.4 Hz), 7.01 (d, 1H, J 2.8 Hz), 6.96 (dd, 1H, J 8.7,2.8 Hz) 6.91
(d, 1H, 8.7 Hz), 5.15 (dd, 1H, J 10.3,2.2 Hz), 2.94 (m, 1H), 2.76 (m, 1H) 2.17 (m,
1H), 2.01 (m, 1H).
Using the same procedure as described above for 2-[2-(4-fluorophenyl)-
chroman-6-yloxy]-5-nitropyridine, but replacing 2-(4-fluorophenyl)chroman-6-ol by
an appropriate 2-phenylchroman-6-ol, there was obtained:
2-[2-(3-Fluorophenyl)chroman-6-yloxy]-5-nitropyridine
1H NMR (400 MHz, CDCl3) ä: 9.07 (d, 1H, J 2.8 Hz), 8.46 (dd, 1H, J 9.0,
2.8 Hz), 7.36 (m, 1H), 7.21-7.15 (m, 2H), 7.03 (m, 1H), 7.01 (d, 1H, J 9.0 Hz), 6.98
(d, 1H, J 8.6 Hz) 6.92 (dd, 1H, J 8.6,2.7 Hz), 6.90 (d, 1H, J 2.7 Hz), 5.09 (dd, 1H, J

10.3, 2.4 Hz), 3.01 (ddd, 1H, J-16.9,11.4, 6.0Hz), 2.82 (ddd, 1H, J-16.9, 5.1, 3.2
Hz) 2.24 (m, 1H), 2.09 (m, 1H).
2-[2-(2-Fluorophenyl)chroman-6-yloxy]-5-nitropyridine
1H NMR (400 MHz, CDCl3) ä: 9.04 (d, 1H, J 2.8 Hz), 8.60 (dd, 1H, J 9.1,
2.8 Hz), 7.56 (m, 1H), 7.43 (m, 1H), 730-7.22 (m, 2H), 7.20 (d, 1H, J 9.1 Hz), 7.02
(d, 1H, J 2.8 Hz) 6.98 (dd, 1H, J 8.7,2.8 Hz), 6.91 (d, 1H, J 8.7 Hz), 5.37 (dd, 1H, J
10.4,2.3 Hz), 3.04 (ddd, 1H, J-17.0,11.5, 6.0 Hz), 2.82 (ddd, 1H, J-17.0, 5.1, 2.8
Hz) 2.18 (m, 1H), 2.08 (m, 1H).
2-[2-(2,3-Difluorophenyl)chroman-6-yloxy]-5-nitropyridine
1H NMR (400 MHz, d6-DMSO) ä: 9.04 (d, 1H, J 3.0 Hz), 8.60 (dd, 1H, J 9.1,
3.0 Hz), 7.45 (m, 1H), 7.38 (m, 1H), 7.30 (m, 1H), 7.21 (d, 1H, 9.1Hz), 7.03 (d, 1H, J
2.7 Hz), 6.98 (dd, 1H, J 8.8, 2.7 Hz), 6.92 (d, 1H, 8.8 Hz), 5.42 (dd, 1H, J 10.4, 2.3
Hz), 3.04 (m, 1H), 2.79 (m, 1H) 2.21 (m, 1H), 2.08 (m, 1H).
2-[2-(2,4-Difluorophenyl)chroman-6-yloxy]-5-nitropyridine
1H NMR (400 MHz, d6 -DMSO) ä: 9.04 (d, 1H, J 3.0 Hz), 8.60 (dd, 1H, J
9.0,3.0 Hz), 7.61 (m, 1H), 7.31 (m, 1H), 7.21 (d, 1H, 9.0Hz), 7.17 (m, 1H) 7.02 (d,
1H, J 2.9 Hz), 6.97 (dd, 1H, J 8.9, 2.9 Hz), 6.91 (d, 1H, 8.9 Hz), 5.34 (dd, 1H, J 9.9,
2.0 Hz), 3.03 (m, 1H), 2.78 (m, 1H) 2.17 (m, 1H), 2.07 (m, 1H).
2-[2-(2,5-Difluorophenyl)chroman-6-yloxy]-5-nitropyridine
1H NMR (400 MHz, CDCl3) ä: 9.07 (dd, 1H, J 2.8,0.4 Hz), 8.47 (dd, 1H, J
9.1,2.8 Hz), 7.26 (m, 1H), 7.05-6.91 (m, 6H), 5.35 (dd, 1H, J 10.3,1.5 Hz), 3.04
(ddd, 1H, J -16.9,11.7, 6.0 Hz), 2.82 (ddd, 1H, J -16.9, 5.2,3.0 Hz) 2.29 (m, 1H),
2.01 (m, 1H).
2-[2-(2,6-Difluorophenyl)chroman-6-yloxy]-5-nitropyridine
1H NMR (400 MHz, CDCl3) ä: 9.04 (d, 1H, J 3.0 Hz), 8.60 (dd, 1H, J 9.1,
3.0 Hz), 7.45 (m, 1H), 7.38 (m, 1H), 7.30 (m, 1H), 7.21 (d, 1H, J 9.1 Hz), 7.03 (d,
1H, J 2.7 Hz), 6.98 (dd, 1H, J 8.8,2.7 Hz) 6.92 (d, 1H, J 8.8 Hz), 5.42 (dd, 1H, J
10.4, 2.3 Hz), 3.04 (m, 1H), 2.79 (m, 1H) 2.21 (m, 1H), 2.08 (m, 1H).
2-[2-(3,5-Difluorophenyl)chroman-6-yloxy]-5-nitropyridine

'H NMR (400 MHz, d6-DMSO) 8: 9.04 (d, 1H, J 2.9 Hz), 8.60 (dd, 1H, J 9.1,
2.9 Hz), 7.23-7.19 (m, 4H), 7.01-6.95 (m, 3H), 5.18 (dd, 1H, J 10.0,2.1 Hz), 2.97
(ddd, 1H, J -16.9,10.9, 5.7 Hz), 2.76 (ddd, 1H, J -16.9, 8.4,4.7 Hz) 2.22 (m, 1H),
1.99 (m, 1H).
2-[2-(2-Trifluoromethylphenyl)chroman-6-yloxy]-5-nitropyridine
1H NMR (300 MHz, d6-DMSO) 8: 9.04 (d, 1H, J 2.9 Hz), 8.60 (dd, 1H, J 9.2,
2.9 Hz), 7.86-7.76 (m, 3H), 7.60 (m, 1H), 7.22 (d, 1H, J 9.2 Hz) 7.05 (d, 1H, J 2.7
Hz), 6.99 (dd, 1H, J 8.7,2.7 Hz), 6.91 (d, 1H, 8.7 Hz), 5.30 (d, 1H, J 10.0, Hz), 3.05
(m, 1H), 2.84 (m, 1H) 2.16-2.00 (m, 2H).
2-[2-(4-Trifluoromethylphenyl)chroman-6-yIoxy]-5-nitropyridine
1H NMR (400 MHz, d6-DMSO) ä: 9.04 (d, 1H, J 2.9 Hz), 8.60 (dd, 1H, J 9.1,
2.9 Hz), 7.79 (d, 2H, J 8.2 Hz), 7.70 (d, 1H, J 8.2 Hz), 7.21 (d, 1H, J 9.1 Hz) 7.01
(dd, 1H, J 8.7,2.7 Hz) 6.98 (d, 1H, J 2.7 Hz), 6.95 (d, 1H, 8.7 Hz), 5.29 (dd, 1H, J
10.1,2.0 Hz), 3.00 (ddd, 1H, J-16.9,10.1, 5.8 Hz), 2.4 (ddd, 1H, J-16.9, 8.4,4.5
Hz) 2.24 (m, 1H), 1.99 (m, 1H).
2-[2-(3-Chloro-4-fluorophenyl)chroman-6-yloxy]-5-nitropyridine
1H NMR (400 MHz, d6-DMSO) ä: 9.04 (d, 1H, J 2.9 Hz), 8.60 (dd, 1H, J 9.1,
2.9 Hz), 7.40-7.27 (m, 3H), 7.21 (d, 1H, J 9.1 Hz), 7.03 (d, 1H, J 2.7 Hz) 6.98 (dd,
1H, J 8.8,2.7 Hz), 6.94 (d, 1H, J 8.8 Hz), 5.36 (dd, 1H, J 10.7,2.1 Hz), 3.04 (m, 1H),
2.80 (m, 1H) 2.18 (m, 1H), 1.99 (m, 1H).
2-[2-(2-Chlorophenyl)chroman-6-yloxy]-5-nitropyridine
1H NMR (400 MHz, d6-DMSO) ä: 9.04 (d, 1H, J 2.9,0.5 Hz), 8.60 (dd, 1H, J
9.1,2.9 Hz), 7.62 (dd, 1H, J 7.5,1.8 Hz), 7.51 (dd, 1H, J 7.6,1.7 Hz), 7.45-7.40 (m,
2H), 7.21 (dd, 1H, J 9.1,0.5 Hz), 7.04 (d, 1H, J 2.7 Hz), 6.99 (dd, 1H, J 8.8,2.7 Hz),
6.94 (d, 1H, 8.8 Hz), 5.40 (dd, 1H, J 10.4,2.1 Hz), 3.04 (m, 1H), 2.80 (m, 1H) 2.24
(m, 1H), 1.95 (m, 1H).
2-[2-(3-Chlorophenyl)chroman-6-yloxy]-5-nitropyridine
1H NMR (400 MHz, CDCl3) ä: 9.04 (d, 1H, J 2.9 Hz), 8.60 (dd, 1H, J 9.0,
2.9 Hz), 7.53 (s, 1H), 7.46-7.42 (m, 3H), 7.20 (d, 1H, J 9.0 Hz) 7.00 (dd, 1H, J 8.7,
2.7 Hz), 6.97 (d, 1H, J 2.7 Hz), 6.94 (d, 1H, J 8.7 Hz), 5.18 (dd, 1H, J 10.2,2.2 Hz),
2.97 (ddd, 1H, J -17.0,11.5,5.9 Hz), 2.83 (ddd, 1H, J -17.0, 8.1,4.5 Hz) 2.21 (m,

1H), 2.00 (m, 1H).
2-[2-(2,4-Dichlorophenyl)chroman-6-yloxy]-5-nitropyridine
1H NMR (400 MHz, CDCl3) ä: 9.06 (d, 1H, J 2.7 Hz), 8.47 (dd, 1H, J 9.0,
2.7 Hz), 7.56 (d, 1H, J 8.4 Hz), 7.41 (d, 1H, J 2.0 Hz), 7.33 (dd, 1H, J 8.4,2.0 Hz)
7.02 (d, 1H, J 9.0 Hz) 6.99-6.92 (m, 3H), 5.39 (dd, 1H, J 10.4,2.2 Hz), 3.06 (ddd,
1H, J -16.9,11.9, 6.0 Hz), 2.83 (ddd, 1H, J -16.9, 5.3,2.7 Hz) 2.34 (m, 1H), 1.89
(m, 1H).
2-[2-(3-Bromophenyl)chroman-6-yloxy]-5-nitropyridine
1H NMR (400 MHz, CDCl3) ä: 9.04 (d, 1H, J 2.9 Hz), 8.60 (dd, 1H, J 9.2,
2.9 Hz), 7.66 (bs, 1H), 7.55 (m, 1H), 7.48 (m, 1H), 7.39 (m, 1H) 7.20 (d, 1H, J 9.2
Hz) 7.01-6.93 (m, 3H), 5.17 (dd, 1H, J 10.1,2.2 Hz), 2.97 (m, 1H), 2.72 (m, 1H)
2.20 (m, 1H), 2.00 (m, 1H).
2-[2-(4-Ethylphenyl)clffoman-6-yloxy]-5-nitropyridine
1H NMR (400 MHz, CDCl3) ä: 9.04 (d, 1H, J 2.8 Hz), 8.60 (dd, 1H, 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, 1H, J 9.1 Hz), 7.00 (d,
1H, J 2.7 Hz) 6.96 (dd, 1H, J 8.8,2.7 Hz), 6.89 (d, 1H, J 2.7 Hz), 5.11 (dd, 1H, J
10.1,2.2 Hz), 2.98 (m, 1H), 2.75 (m, 1H), 2.62 (q, 2H, J 7.5 Hz) 2.16 (m, 1H), 2.01
(m, 1H), 1.19(t,3H,J 7.5Hz).
5-Nitro-2-[2-(2-mtrophenyl)chroman-6-yloxy]pyridine
1H NMR (400 MHz, d6-DMSO) ä: 9.04 (d, 1H, J 2.9 Hz), 8.60 (dd, 1H, J 9.1,
2.9 Hz), 8.03 (d, 1H, J 7.9 Hz), 7.80-7.85 (m, 2H), 7.62-7.66 (m, 1H), 7.22 (d, 1H, J
9.1 Hz), 7.04 (d, 1H, J 2.8 Hz), 6.98 (dd, 1H, J 8.8,2.8 Hz), 6.88 (d, 1H, J 8.8 Hz),
5.52 (dd, 1H, J 10.3, 2.0 Hz), 2.99-3.31 (m, 1H), 2.80-2.85 (m, 1H), 2.35-2.40 (m,
1H), 1.99-2.04 (m,1H).
5-Nitro-2-[2-(3-nitrophenyl)chroman-6-yloxy]pyridine
1H NMR (400 MHz, d6-DMSO) ä: 9.04 (d, 1H, J 2.9 Hz), 8.60 (dd, 1H, J 9.0,
2.9 Hz), 8.32 (s, 1H), 8.23 (d, 1H, J 8.3 Hz), 7.95 (d, 1H, J 7.9 Hz), 7.74 (t, 1H, J
15.8,7.9 Hz), 7.21 (d, 1H, J 9.0 Hz), 6.96-7.03 (m, 3H), 5.35 (d, 1H, J 8.7 Hz), 2.98-
3.06 (m, 1H), 2.72-2.79 (m, 1H), 2.26-2.33 (m, 1H), 1.99-2.06 (m, 1H).
5-Nitro-2-[2-(4-nitrophenyl)chroman-6-yloxy]pyridine

1H NMR (300 MHz, d6-DMSO) ä: 9.04 (d, 1H, J 2.9 Hz), 8.60 (dd, 1H, 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, 1H, J 9.1 Hz), 6.98-
7.02 (m, 3H),5.35 (dd, 1H, J 9.9,2.2 Hz), 2.96-3.05 (m, 1H), 2.73-2.78 (m, 1H),
2.24-2.29 (m, 1H), 1.96-2.04 (m, 1H).
2-[2-(3-Methoxyphenyl)chroman-6-yloxy]-5-nitropyridine
1H NMR (400 MHz, d6-DMSO) ä: 9.04 (d, 1H, J 2.9 Hz), 8.60 (dd, 1H, J 9.1,
2.9 Hz), 7.32 (t, 1H, J 15.7, 7.9 Hz), 7.20 (d, 1H, J 9.1 Hz), 7.03 (d, 1H, J 8.4 Hz),
7.01 (s, 1H), 7.00 (d, 1H, J 2.8 Hz), 6.96 (dd, 1H, J 8.7,2.8 Hz), 6.92 (d, 1H, J 8.7
Hz), 6.90 (dd, 1H, J 8.4,2.6 Hz), 5.12 (dd, 1H, J 10.0,2.3 Hz), 3.77 (s, 3H), 2.93-
2.97 (m, 1H), 2.71-2.77 (m, 1H), 2.15-2.20 (m, 1H), 1.99-2.05 (m, 1H).
2-(3-Methyl-2-phenylchroman-6-yloxy)-5-nitropyridine
1H NMR (400 MHz, d6-DMSO) ä: 9.04 (d, 1H, J 2.8 Hz), 8.59 (dd, 1H, J 9.1,
2.8 Hz), 7.43-7.36 (m, 5H), 7.19 (d, 1H, J 9.1 Hz), 7.00 (d, 1H, J 2.6 Hz) 6.95 (dd,
1H, J 8.7,2.6 Hz), 6.86 (d, 1H, J 8.7 Hz), 4.73 (d, 1H, J 9.3 Hz), 2.85 (dd, 1H, J -
16.7, 5.0 Hz), 2.64 (dd, 1H, J -16.5,10.9 Hz), 2.18 (m, 1H), 0.77 (d, 3H, J 6.7 Hz).
Example 3. Intermediates
(5-Nitropyridin-2-yloxy)-2-phenylchroman-4-one intermediates
6-(5-Nitropyridin-2-yloxy)-2-phenylchroman-4-one
6-(5-Nitropyridin-2-yloxy)-2-phenylchroman-4-one was prepared as described
for 5-Nitro-2-(2-phenylchroman-6-yloxy)pyridine in Example l(b) using 200 mg of
6-hydroxyflavanone. 1H NMR (400 MHz, d6-DMSO) ä: 9.03 (bs, 1H), 8.64 (d, 1H,
J 9.0 Hz), 7.59-7.41 (m, 7H), 7.31 (d, 1H, J 9.0 Hz), 7.23 (d, 1H, 8.8 Hz), 5.75 (dd,
1H, J 12.3,2.9 Hz), 3.30 (dd, 1H, -16.3,12.3 Hz), 2.87 (dd, 1H, -16.3,2.9 Hz).
Using the same procedure as described above for 6-(5-nitropyridin-2-yloxy)-
2-phenylchroman-4-one, but replacing 6-hydroxyflavanone by an appropriate 2-
phenylchromanone derivative, there was obtained:
7-(5-Nitropyridin-2-yloxy)-2-phenylchroman-4-one
1H NMR (400 MHz, d6-DMSO) ä: 9.07 (d, 1H, J 2.8 Hz), 8.67 (dd, 1H, J 9.0,
2.8 Hz), 7.89 (d, 1H, 8.6 Hz), 7.60-7.35 (m, 6H), 7.04 (d, 1H, 2.1 Hz), 6.97 (dd, 1 H,

8.6,2.1 HZ), 5.75 (dd, 1H, J 13.0,2.7 Hz), 3.32 (dd, 1H, 16.9,13.0 Hz), 2.85 (d, -
16.9, 2.7 Hz).
3-Methyl-6-(5-nitropyridin-2-yloxy)-2-phenyIchroman-4-one
1H NMR (400 MHz, d6-DMSO) ä: 9.03 (d, 1H, J 2.9 Hz), 8.64 (dd, 1H, J 9.1,
2.9 Hz), 7.59-7.56 (m, 3H), 7.50-7.32 (m, 4H) 7.30 (d, 1H, J 9.1 Hz), 7.18 (d, 1H, J
8.9 Hz), 5.38 (d, 1H, J 12.5 Hz), 3.36 (dd, 1H, J 12.5,6.9 Hz), 0.86 (d, 3H, J 6.9 Hz).
Example 4. Intermediate
2-(2,3-Dihydro-2-phenyl-benzo[l,4]dioxin-6-yloxy)-5-nitropyridine
a) 1-[2,5-Bis(benzyloxy)phenyl]ethanone
A mixture of l-(2,5-dihydroxyphenyl)ethanone (3.16 g), benzyl chloride (7.04
g), potassium carbonate (12.4 g) and 18-Crown-6 (30 mg) in 2-butanone (50 ml) was
heated under reflux for 5 hrs. After cooling the precipitate was filtered off. The
filtrate was evaporated to dryness under reduced pressure and ether (50 ml) was
added to it. The solution was washed twice with dilute sodium hydroxide solution,
twice with dilute hydrochloric acid, dried over sodium sulphate and substantially
evaporated to dryness under reduced pressure. The residue was triturated with cold n-
heptane (30 ml), and the precipitate was filtered off with suction filtration giving
after drying 2.85 g of l-[2,5-bis(benzyloxy)phenyl]ethanone. 1H NMR (400 MHz,
DMSO-d6) ä: 2.50 (s, 3H), 5.08 (s, 2H), 5.18 (s,2H), 7.20-7.50 (m, 13H).
b) Acetic acid 2,5-bis(benzyloxy)phenyl ester
A solution of l-[2,5-bis(benzyloxy)phenyl]ethanone (2.25 g) and peracetic
acid 40% (1.63 ml) in acetic acid (5.4 ml) was stirred at 60 °C for 1 h. After cooling
to room temperature the precipitated product was collected by filtration, washed with
cold ether and dried under reduced pressure. Acetic acid 2,5-bis(benzyloxy)phenyl
ester was recrystallized from 2-propanol. Yield is 1.87 g. 1H NMR (DMSO-d6) ä:
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 of acetic acid 2,5-bis(benzyloxy)phenyl ester (1.85 g) and 5M
sodium hydroxide solution (10.6ml) in ethanol (11 ml) was heated under reflux for
6.5 hrs. After ethanol was evaporated under reduced pressure the clear solution was
made acidic with diluted hydrochloric acid. The precipitated product was collected
by filtration, washed with cold water and dried under reduced pressure. Yield is 0.56
g. 1H NMR (DMSO-d6) ä: 4.97 (s, 2H), 5.01 (s, 2H), 6.34 (dd, J 3.1, 8.8 Hz, 1H),
6.49(d, J 3.1 Hz, 1H), 6.85 (d, J 8.8 Hz, 1H), 7.28-7.46 (m, 10H), 9.1 (br s, 1H).
d) 2-[2,5-Bis(benzyloxy)phenoxy]-1 -phenylethanone
A mixture of 2,5-bis(benzyloxy)phenol (0.28 g), 2-bromoacetophenone (0.22
g), potassium hydrogen-carbonate (0.25 g) and 18-Crown-6 (3 mg) in acetonitrile
(4.2 ml) was stirred at 22 °C for one week. The mixture was filtered and evaporated
to dryness under reduced pressure. The residue was triturated with the mixture of
ether (8.2 ml) and water (1.4 ml) at the ice bath temperature. The product was
collected by filtration, washed with cold ether and dried under reduced pressure.
Yield is 0.14 g. 1H NMR (DMSO-d6) ä:4.98 (s, 2H), 5.06 (s, 2H), 5.58 (s, 2H), 6.51
(dd, J 8.9,2.3 Hz, 1H), 6.68 (d, J 2.3 Hz, 1H), 6.94 (d, J 8.9 Hz, 1H), 7.28-8.03 (m,
15H).
e)2-[2,5-Bis(benzyloxy)phenoxy]-1-phenylethanol
To the solution of 2-[2,5-bis(benzyloxy)phenoxy]-1-phenylethanone (0.14 g)
in methanol (0.5 ml) and tetrahydrofuran (1.9 ml) was added at the 0 °C temperature
sodium borohydride (6.5 mg). The reaction was stirred 15 minutes at 0 °C and 2 hrs
at 22 °C temperature. After adding water (5 ml) methanol and tetrahydrofuran were
evaporated off. After the residue was stirred at 22 °C 0.5 hr the product was filtered,
washed with cold water and dried under reduced pressure. Yield is 0.09 g. 1H NMR
(DMSO-d6) ä: 4.05 (m, 2H), 4.91 (m, 1H), 4.95 (s, 2H), 5.01 (s, 2H), 5.59 (d, J 4.7
Hz, 1H), 6.47 (dd, J 2.8, 8.8 Hz, 1H), 6.68 (d, J 2.8 Hz, 1H), 6.89 (d, J 8.8 Hz, 1H),
7.24-7.45 (m, 15H).
f)2-(2-Hydroxy-2-phenylethoxy)benzene-l,4-diol
A solution of 2-[2,5-bis(benzyloxy)phenoxy]-1-phenylethanol (3.9 g) in
ethanol (175 ml) was hydrogenated in the presence of 10 % palladium on charcoal

(100 mg) at 30 psi. The catalyst was removed by filtration and the solvent was
evaporated under reduced pressure. The residue was recrystallized from the mixture
of toluene-ethyl acetate 8:1 (15 ml). The yield of 2-(2-Hydroxy-2-phenylethoxy)-
benzene-l,4-diol is 1.2 g. 1H NMR (DMSO-d6) ä: 3.79 (dd, J 9.6, 8.3 Hz, 1H), 4.00
(dd, J 9.6, 3.6 Hz, 1H), 4.94 (ddd, J 3.6, 8.3,3.9 Hz, 1H), 5.66 (d, J 3.9 Hz, 1H), 6.18
(dd, J 8.5, 2.3 Hz, 1H), 6.34 (d, J 2.3,1H), 6.57 (d, J 8.5,1H), 7.26-7.47 (m, 5H),
7.97 (s, 1H), 8.66 (s, 1H).
g) 2,3-Dihydro-2-phenyl-benzo[1,4]dioxin-6-ol
A solution of 2-(2-hydroxy-2-phenylethoxy)benzene-1,4-diol (1.2 g) in
toluene (75 ml) was heated with Amberlyst 15 catalyst (0.5 g) under reflux for 7 hrs.
After filtering the solvent was evaporated under reduced pressure. The residue was
purified by column chromatography on silica gel (toluene/ethyl acetate/acetic acid,
8:1:1). The yield of 2,3-dihydro-2-phenyl-benzo[l,4]dioxin-6-ol is 0.5 g. 1H NMR
(DMSO-d6) ä: 4.02 (dd, J 8.5,11.4 Hz, 1H), 4.35 (dd, J 2.3,11.4 Hz, 1H), 5.11 (dd, J
8.5, 2.3 Hz, 1H), 6.29 (dd, J 2.8, 8.5 Hz, 1H), 6.32 (d, J 2.8 Hz, 1H), 6.75 (d, J 8.5
Hz, 1H), 7.36-7.47 (m, 5H), 8.99 (s, 1H).
h) 2-(2,3-Dihydro-2-phenyl-benzo[1,4]dioxin-6-yloxy)-5-nitropyridine
A solution of 2,3-dihydro-2-phenyl-benzo[l,4]dioxin-6-ol (80 mg), 2-chloro-
5-nitropyridine (56 mg) and potassium carbonate (52 mg) in dimethylformarnide (1.0
ml) was stirred at 120 °C for 2 hrs. After cooling the mixture water (10 ml) was
added and the precipitated product was filtered, washed with water and 2-propanol
and dried under reduced pressure. Yield is 60 mg and mp 163-170 °C. 1H NMR
(DMSO-d6) ä 4.16(dd, J8.5,11.6Hz, lH),4.47(dd, J 11.6,2.6Hz, 1H), 5.28 (dd, J
2.6, 8.5 Hz, 1H), 6.75 (dd, J 2.6, 8.8 Hz, 1H), 6.88 (d, J 2.6 Hz, 1H), 7.05 (d, J 8.8
Hz, 1H), 7.21 (d, J 9.1 Hz, 1H), 7.39-7.52 (m, 5H), 8.60 (dd, J 2.8, 9.1 Hz, 1H), 9.05
(d, J 2.8 Hz, 1H).
Example 5. Intermediate
5-Nitro-2-(6-phenyl-5,6,7,8-tetrahydro-naphthalen-2-yloxy)-pyridine
a) 6-Methoxy-2-phenyl-3,4-dihydro-2H-naphthalen-1-one

A mixture of palladium(H) acetate (0.57 g), rac-2,2'-bis(diphenylphosphino)-
1,1'-binaphtyl (1.91 g) and potassium tert-butoxide (4.15 g) in dry toluene was
stirred under argon for 10 minutes. Bromobenzene (5.34 g) and 6-methoxy-1-tetralo-
ne (3.0 g) solvated in dry toluene were added and the mixture was stirred at 100 °C
for 2 h. The reaction mixture was cooled to room temperature and poured into
saturated aqueous ammonium chloride and extracted with ethyl ether. Organic extract
was washed with brine, dried and evaporated. The crude product was purified by
flash chromatography on silica gel using toluene and toluene-ethyl acetate (9:1) as an
eluant. 1H NMR (400 MHz, d6-DMSO) ä: 7.87 (d, 1H, 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, 1H), 3.06-3.14 (m, 1H), 2.92-2.98 (m,
1H), 2.23-2.38 (m, 2H).
b) 6-Hydroxy-2-phenyl-3,4-dmydro-2H-naphthalen-1 -one
6-Memoxy-2-phenyl-3,4-dmydro-2H-naphthalen-1-one (1.0 g) was refluxed
with 47 % HBr (20 ml) until disappearance of the starting material. The mixture was
poured into water and extracted with ethyl acetate. Ethyl acetate was dried and
evaporated. The product was recrystallised from toluene. 1H NMR (400 MHz, d6-
DMSO) ä: 10.35 (s, 1H), 7.79 (d, 1H, J 8.6 Hz), 7.15-7.33 (m, 5H), 6.75 (dd, 1H, J
8.6,2.4 Hz), 6.68 (d, 1H, J 2.3 Hz), 3.79-3.85 (m, 1H), 2.99-3.06 (m, 1H), 2.83-2.90
(m, 1H), 2.19-2.33 (m, 2H).
c) 6-Phenyl-5,6,7,8-tetrahydro-naphthalen-2-ol
To a solution of 6-hydroxy-2-phenyl-3,4-dihydro-2H-naphthalen-1-one (50
mg) in trifiuoroacetic acid was added triethylsilane (98 mg). The mixture was heated
at 60 °C for 3 h. Solvent was evaporated, water added to the residue and the mixture
extracted with ethyl acetate. Organic extract was dried and evaporated. 1H NMR (400
MHz, d6-DMSO) ä: 9.02 (s, 1H), 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, 1H), 1.81-1.89 (m, 1H).
d) 5-Nitro-2-(6-phenyl-5,637,8-tetrahydro-naphthalen-2-yloxy)-pyridine
6-Phenyl-5,6,7,8-tetrahydro-naphthalen-2-ol (30 mg), 2-chloro-5-nitropyridi-
ne (21 mg) and potassium fluoride (23 mg) in dry dimethylformamide were heated at
120 °C until disappearance of the starting material. Water and 1 N HC1 were added

and the mixture extracted with ethyl acetate. Ethyl acetate was washed with brine and
water, dried and evaporated. The product was recrystallised from toluene. 1H NMR
(400 MHz, d6-DMSO) ä: 9.04 (d, 1H, J 2.4 Hz), 8.61 (dd, 1H, 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 6. Intermediate
6-(5-Nitro-pyridin-2-yloxy)-2-phenyI-3,4-dihydro-2H-naphthalen-lone
6-(5-Nitro-pyridin-2-yloxy)-2-phenyl-3 ,4-dihydro-2H-naphthalen-1 -one was
prepared as described for 5-nitro-2-(6-phenyl-5,6,7,8-tetrahydro-naphthalen-2-
yloxy)-pyridine in Example 5(d) using 50 mg 6-hydroxy-2-phenyl-3,4-dihydro-2H-
naphthalen-1-one, 33 mg 2-chloro-5-nitropyridine and 37 mg potassium fluoride.
1H NMR (400 MHz, d6-DMSO) ä: 9.07 (d, 1H, J 2.8 Hz), 8.68 (dd, 1H, J 9.0,2.9), 8.01
(d, 1H, J 8.5), 7.37 (d, 1H, J 9.1 Hz), 7.21-7.38 (m, 7H), 3.96-4.04 (m, 1H), 3.15-
3.23 (m, 1H), 2.98-3.04 (m, 1H), 2.39-2.48 (m, 1H), 2.25-2.31 (m, 1H).
Example 7. Intermediates
2-[3-(phenyl)chroman-7-yloxy]-5-nitropyridine intermediates
a)2-(3-Fluorophenyl)-1-(2-hydroxy-4-methoxyphenyl)ethanone
(3-Fluorophenyl)acetic acid (3.7 g) and 3-methoxyphenol (3.0 g) were
dissolved into BF3Et2O (60 ml, 20 eq) under argon. The mixture was stirred at 60-
70°C until disappearance of the starting materials (9 h) and poured into large volume
of ice water. After extraction with ethyl acetate the combined organic layers were
washed with water, dried and evaporated. The crude product was purified by column
chromatography using CH2Cl2 as an eluant. 1H NMR (400 MHz, d6-DMSO) ä: 12.41
(br s, 1H), 8.02 (d, 1H, J 9.0 Hz), 7.34-7.38 (m, 1H), 7.09-7.13 (m, 3H), 6.56 (dd,
1H, J 9.0,2.5 Hz), 6.49 (d, 1H, J 2.5 Hz), 4.41 (s, 2H), 3.83 (s, 3H).
b)3-(3-Fluorophenyl)-7-methoxychromen-4-one
2-(3-Fluorophenyl)-1-(2-hydroxy-4-methoxyphenyl)ethanone (1.76 g) was
dissolved in pyridine (88 ml). Piperidine (8.8 ml) and triethylorthoformate (88 ml)
were added and the mixture was stirred at 120°C for 3.5 hours. After pouring the
mixture into water and acidification with cone. HCl the crude product was filtered.

Purification by column chromatography using heptane-ethyl acetate (7:3) as an eluant
afforded 3-(3-fluorophenyl)-7-methoxychromen-4-one. 1H NMR (400 MHz, d6-
DMSO) ä: 8.57 (s, 1H), 8.06 (d, 1H, J 8.9 Hz), 7.45-7.50 (m, 3H), 7.21-7.25 (m, 1H),
7.20 (d, 1H, J 2.4 Hz), 7.12 (dd, 1H, J 8.9,2.4 Hz), 3.92 (s, 3H).
c)3-(3-Fluorophenyl)-7-hydroxychromen-4-one
3-(3-Fluorophenyl)-7-methoxychromen-4-one (320 mg) was refluxed with 47
% HBr (18 ml) until disappearance of the starting material. The mixture was poured
into water and the precipitate was filtrated and dried yielding 3-(3-fluorophenyl)-7-
hydroxychromen-4-one. 1H NMR (400 MHz, d6-DMSO) ä: 10.87 (s, 1H), 8.49 (s,
1H), 7.99 (d, 1H, J 8.7 Hz), 7.43-7.49 (m, 3H), 7.20-7.24 (m, 1H), 6.97 (dd, 1H, J
8.7,2.2 Hz), 6.90 (d, 1H, J 2.2 Hz).
d) 3-(3-Fluorophenyl)chroman-7-ol
3-(3-Fluorophenyl)-7-hydroxychromen-4-one (160 mg) was dissolved in
. ethanol (40 ml) and 10 % palladium on carbon (400 mg) was added. The reaction
mixture was hydrogenated for 6 hours at normal pressure and room temperature. It
was then filtered through Celite and washed with ethanol. The solvent was evapo-
rated under reduced pressure to give 3-(3-fluorophenyl)chroman-7-ol. 1H NMR (400
MHz, d6-DMSO) ä: 9.19 (br s, 1H), 7.38 (m, 1H), 7.17-7.21 (m, 2H), 7.08 (m, 1H),
6.88 (d, 1H, J 8.2 Hz), 6.30 (dd, 1H, J 8.2,2.4 Hz), 6.20 (d, 1H, J 2.4 Hz), 4.22 (dd,
1H, J 10.3, 3.6 Hz), 4.02 (t, 1H, 10.3 Hz), 3.20 (m, 1H), 2.90 (m, 2H).'
e)2-[3-(3-Fluorophenyl)chroman-7-yloxy]-5-nitropyridine
2-[3-(3-Fluorophenyl)chroman-7-yloxy]-5-nitropyridine was prepared as
described for 5-nitro-2-(2-phenylchroman-6-yloxy)pyridine in Example l(b) using
125 mg of 3-(3-fluorophenyl)-chroman-7-ol. The product was recrystallised from
ethanol. 1H NMR (400 MHz, CDCl3) ä:9.07 (d, 1H, J 2.8 Hz), 8.47 (dd, 1H, J 9.0,
2.8 Hz), 7.33 (m, 1H), 7.16 (d, 1H J 8.9 Hz), 6.95-7.06 (m, 4H), 6.69-6.71 (m, 2H),
4.38 (dd, 1H, J 10.6,4.3 Hz), 4.06 (t, 1H, 10.6 Hz), 3.30 (m, 1H), 3.06 (m, 2H).
Using the same procedure as described above for 3-(3-fluorophenyl)chroman-
7-ol, but replacing 3-(3-fluorophenyl)-7-hydroxychromen-4-one by 7-hydroxy-3-

phenylchromen-4-one, there was obtained:
3-Phenylchroman-7-ol
1H NMR (400 MHz, d6-DMSO) ä: 8.18 (br s, 1H), 7.31-7.34 (m, 4H), 7.25-
7.27 (m, 1H), 6.88 (d, 1H, J 8.2 Hz), 6.30 (dd, 1H, J 8.2,2.4 Hz), 6.20 (d, 1H, J 2.4
Hz), 4.21 (dd, 1H, J 10.3, 3.6 Hz), 4.00 (t, 1H, 10.3 Hz), 3.13 (m, 1H), 2.84-2.87 (m,
2H).
Using the same procedure as described above for 2-[3-(3-fluorophenyl)-
chroman-7-yloxy]-5-nitropyridine, but replacing 3-(3-fluorophenyl)chroman-7-ol by
3-phenylchroman-7-ol, there was obtained:
5-Nitro-2-(3-phenylchroman-7-yloxy)pyridine
1H NMR (400 MHz, d6-DMSO) ä: 9.05 (d, 1H, J 2.9 Hz), 8.61 (dd, 1H, J 9.1,
2.9 Hz), 7.34-7.38 (m, 4H), 7.27-7.30 (m, 1H), 7.22 (m, 2H), 6.70-6.74 (m, 2H), 4.31
(dd, 1H, J 10.4,3.5 Hz), 4.12 (t, 1H, 10.4 Hz), 3.24 (m, 1H), 3.01-3.11 (m, 2H).
7-Hydroxy-3-phenylchromen-4-one is commercially available or can be
synthesised by methods described for 3-(3-fluorophenyl)-7-hydroxychromen-4-one.
Example 8. Intermediate
5-Nitro-2-(2-phenyl-2,3-dihydrobenzo[ 1,4]oxathiin-6-yloxy)pyridine
a)2-(2-Hydroxy-1-phenylethylsulfanyl)benzene-l,4-diol
To a stirred solution of 2-mercaptobenzene-l,4-diol (0.5 g) and potassium
carbonate (0.49 g) in water (5 ml) was added 2-phenyloxirane (0.40 ml) under argon.
The mixture was stirred at room temperature for 2.5 hours and then treated with 2 M
HC1 and extracted with ethyl acetate. The combined organic layers were washed with
water and brine, dried and evaporated. The crude product was purified by column
chromatography using heptane-ethyl acetate (1:1) as an eluant. 1H NMR (400 MHz,
d6-DMSO) ä: 8.94 (br s, 1H), 8.72 (br s, 1H), 7.24-7.37 (m, 5H), 6.62-6.65 (m, 2H),
6.47 (dd, 1H, J 8.6,2.8 Hz), 4.97 (br s, 1H), 4.34 (m, 1H), 3.72 (m, 2H).
b)2-Phenyl-2,3-dihydrobenzo[l,4]oxathiin-6-ol

A solution of 2-(2-hydroxy-1-phenylethylsulfanyl)benzene-l,4-diol (0.83 g) in
dry toluene (60 ml) was stiirred with Amberlyst 15 (0.5 g) at 60 °C until disappear-
ance of the starting material. After the mixture was filtered and solvent evaporated
the crude product was purified by column chromatography using heptane-ethyl ace-
tate (1:1) as an eluant. lH NMR (400 MHz, CDCl3) ä: 7.41 (m, 4H), 7.33-7.40 (m,
1H), 6.81 (d, 1H, J 8.7 Hz), 6.61 (d, 1H, J 3.0 Hz), 6.51 (dd, 1H, J 8.7,3.0 Hz), 5.10
(dd, 1H, J 9.6,1.9 Hz), 3.28 (dd, 1H, J 13.0,9.6 Hz), 3.06 (dd, 1H, J 13.0,1.9 Hz).
c) 5-Nitro-2-(2-phenyl-2,3-dihydrobenzo[ 1,4]oxathiin-6-yloxy)pyridine
5-Nitro-2-(2-phenyl-2,3-dihydrobenzo[l,4]oxathim-6-yloxy)pyridine was
prepared as described for 5-nitro-2-(2-phenylchroman-6-yloxy)pyridrne in Example
1(b) using 269 mg 2-phenyl-2,3-dihydrobenzo[1,4]oxathiin-6-ol. The product was
recrystallised from ethanol. 1H NMR (400 MHz, CDCl3) ä: 9.07 (d, 1H, J 2.8 Hz),
8.47 (dd, 1H, J 9.1,2.8 Hz), 7.43 (m, 4H), 7.37-7.41 (m, 1H), 7.02 (d, 1H, J 9.1 Hz),
6.99 (d, 1H, J 8.9 Hz), 6.95 (d, 1H, J 2.8 Hz), 6.82 (dd, 1H, J 8.9,2.8 Hz), 5.21 (dd,
1H, J 9.7, 1.9 Hz), 3.31 (dd, 1H, 13.2,9.7 Hz), 3.11 (dd, 1H, 13.2,1.9 Hz).
Example 9. Intermediate
5-Nitro-2-(2-phenylindan-5-yloxy)pyridine
a) 3-(4-Methoxyphenyl)-2-phenylacrylic acid
Triethylamine was added to solution of p-anisaldehyde (10 g) and phenyl-
acetic acid (10 g) in acetic anhydride (25 ml). Reaction mixture was stirred at 90°C
for 8 h. Reaction mixture was cooled and water (600ml) solution of potassium
carbonate (81 g) was added. After addition reaction mixture was heated at 60°C for
an hour. Before neutralising with concentrated hydrochloric acid the reaction mixture
was cooled below 10°C. Precipitate was filtered and washed with water. 1H-NMR
(400 MHz, d6-DMSO): 12.6 (bs, 1H), 7.67 (s, 1H), 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 3-(4-methoxyphenyl)-2-phenylacrylic acid was dissolved to 600 ml of
ethyl acetate and 2.6 g of 10% palladium on charcoal was added under inert atmos-

phere. Starting material was hydrogenated at room temperature to give quantitative
yield of 3-(4-methoxyphenyl)-2-phenylpropionic acid. 1H-NMR (400 MHz, d6-
DMSO): 12.3 (bs, 1H), 7.32-7.20 (m, 5H), 7.1-7.0 (m, 2H), 6.8-6.7 (m, 2H), 3.79
(dd, 1H, J 6.9, 8.7 Hz), 3.70 (s, 3H), 3.22 (dd, 1H, J 8.7,13.7 Hz), 2.87 (dd, 1H, J
6.9,13.7 Hz).
c) 6-Mehoxy-2-phenylindan-1-one
To solution of 3-(4-methoxyphenyl)-2-phenylpropionic acid (4.6 g) in dry
methylene chloride (26 mi) was added two drops of dry DMF. Thionylchloride (3 ml)
was added and reaction mixture was stirred at 40°C for 4 h. Solvent was evaporated
under vacuum. Precipitate was dissolved to methylene chloride. Solution was cooled
to 0-3°C. This solution and aluminium chloride (2.5g) were mixed slowly over 4
hours keeping temperature under 4°C. After mixing reaction mixture was stirred at
room temperature for 2 h. Reaction was quenched by pouring to dilute ice cold
hydrochloric acid. Layers were separated and water solution was extracted with
methylene chloride. Combined organic layers were washed with water, dried and
evaporated. Crude product was triturated to give 2.9 g of 6-Methoxy-2-phenylindan-
1-one. 1H-NMR (400 MHz, d6-DMSO): 7.56 (d, 1H), 7.35-7.23 (m, 4H), 7.18-7.13
(m, 3H), 4.02 (dd, 1H, J 3.9,8.0 Hz), 3.82 (s, 3H), 3,61 (dd, 1H, J 8.0,17.2 Hz), 3.11
(dd,1H,J3.9,17.2 Hz).
d) 5-Methoxy-2-phenylindane
5-Methoxy-2-phenylindane was prepared as described for 2-phenylchroman-
6-oI in Example 1(a) using 600 mg of 6-meftoxy~2-phenylindan~l-one, 1H-NMR
(400 MHz, d6-DMSO): 7.32-7.27 (m, 4H), 7.21-7.18 (m,1H), 7.13 (d, 1H, J 8.2 Hz),
6.83 (d, 1H, J 2.4 Hz), 6.72 (dd, 1H, J 2.4, 8.2 Hz), 3.72 (s, 3H), 3.64 (k, 1H, J 8.5
z), 3.23 (dt, 2H, J 8.5,15.9 Hz), 2.92 (m, 2H).
e) 2-Phenylindan-5-ol
Mixture of 5-methoxy-2-phenylindane (200 mg) and concentrated HBr (4 ml)
was refluxed for 5.5 h. Reaction mixture was allowed to cool to room temperature
and 20 ml of ice water and it was extracted with methylene chloride. The combined
organic layers were washed with brine and dried with Na2SO4. The solvents were

evaporated to give 2-phenylindan-5-ol. 1H-NMR (400 MHz, d6-DMSO): 9.05 (bs,
1H), 7.3-7.28 (m, 4H), 7.26-7.15 (m, 1H), 7.0 (d, 1H, J 8.1 Hz), 6.64 (d, 1H, J 1.9
Hz), 6.55 (dd, 1H, J 1.9, 8.1 Hz), 3.60 (k, 1H, 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
5-Nitro-2-(2-phenylindan-5-yloxy) pyridine was prepared as described for 2-
phenylchroman-6-yloxy)pyridine in Example l(b) using 107 mg of 2-phenylindan-5-
ol. 1H-NMR (400 MHz, d6-DMSO): 9.04 (d, 1H, J 2.9 Hz), 8.61 (dd, 1H, J 2.9, 9.1
Hz), 7.38-7.28 (m, 5H), 7.24-7.20 (m, 2H), 7.11 (d, 1H, J 2.2 Hz), 7.00 (dd, 1H, J
2.2, 8.0 Hz), 3.72 (k, 1H, J 8.9 Hz), 3.36-3.28 (m, 2H), 3.01 (dd, 2H, J 8.9,15.3 Hz).
Example 10. Intermediates
5-Aminopyridine intermediates
5-Amino-2-(2-phenylchroman-6-yloxy)pyridine
5-Nitro-2-(2-phenylchroman-6-yloxy)pyridine (2.26g) was dissolved in 350
ml of glacial acetic acid. Zinc powder (8.48g) was added in few portions due to
exothermic reaction. The mixture was stirred at room temperature for 2 hours and
filtered. The zinc was washed with glacial acetic acid. The acid was evaporated and
toluene was added and evaporated again. A product mixture was dissolved in CH2Cl2
and washed with 1M NaOH. Water phase was further washed with CH2Cl2. Both
organic fractions were combined and dried over Na2SO4. Product was purified by
column chromatography. 1H-NMR (400 MHz; d6-DMSO) ä: 7.52 (d, 1H, J 2.8 Hz),
7.46-7.30 (m, 5H), 7.05 (dd, 1H, J 8.6, 3.0 Hz), 6.82-6.72 (m, 3H), 6.69 (d, 1H, J 8.6
Hz), 5.08 (dd, 1H, J 10.0,2.1 Hz), 5.00 (s, 2H), 3.00-2.87 (m, 1H), 2.74-2.64 (m,
1H), 2.19-2.10 (m, 1H), 2.05-1.91 (m, 1H).
Using the same procedure as described above for 5-amino-2-(2-
phenylchroman-6-yloxy)pyridine, but replacing 5-nitro-2-(2-phenylchroman-6-
yloxy)pyridine by an appropriate nitropyridine intermediate, there was obtained:
6-[2-(4-Fluorophenyl)chroman-6-yloxy]pyridin-3-ylamine

1H NMR (400 MHz, d6-DMSO) ä: 7.52-7.47 (m, 3H), 7.24 (m, 2H), 7.05
(dd, 1H, J 8.6, 3.0 Hz), 6.84-6.68 (m, 4H), 5.09 (dd, 1H, J 10.2, 2.1 Hz), 5.00 (bs,
2H), 2.93 (m, 1H), 2.69 (m, 1H), 2.13 (m, 1H), 1.98 (m, 1H).
6-[2-(3-fluorophenyl)chroman-6-yloxy]-pyridin-3-ylamine
1H NMR (400 MHz, d6-DMSO) ä: 7.51 (d, 1H, J 3.0 Hz), 7.44 (m, 1H), 7.30-
7.25 (m, 2H), 7.16 (m, 1H), 7.05 (dd, 1H, J 8.6, 3.0 Hz), 6.83-6.73 (m, 3H), 6.69 (d,
1H, J 8.6 Hz), 5.13 (dd, 1H, J 10.0, 3.0 Hz), 5.00 (s, 2H), 2.93 (ddd, 1H, -16.8,10.5,
5.3 Hz), 2.68 (ddd, 1H, J-16.8, 8.0,4.4 Hz), 2.18 (m, 1H), 1.96 (m, 1H).
6-[2-(2-Fluorophenyl)chroman-6-yloxy]-pyridin-3-ylamine
1H NMR (400 MHz, d6-DMSO) ä: 7.52 (m, 1H), 7.51 (d, 1H, J 3.0 Hz), 7.41
(m, 1H), 7.28-7.24 (m, 2H), 7.05 (dd, 1H, J 8.6, 3.0 Hz), 6.81-6.73 (m, 3H), 6.70 (d,
1H, J 8.6 Hz), 5.31 (dd, 1H, J 10.3,2.2 Hz), 5.00 (s, 2H), 2.98 (m, 1H), 2.72 (m, 1H),
2.15 (m,1H), 2.06 (m,lH).
6-[2-(2,3-Difluorophenyl)chroman-6-yloxy]-pyridin-3-ylamine
1H NMR (400 MHz, d6-DMSO) ä: 7.52 (d, 1H, J 3.0 Hz), 7.45-7.27 (m, 3H),
7.06 (dd, 1H, J 8.6,3.0 Hz), 6.76-6.69 (m, 4H), 5.36 (dd, 1H, J 10.3,2.2 Hz), 5.01
(bs, 2H), 2.97 (m, 1H), 2.73 (m, 1H), 2.18 (m, 1H), 2.03 (m, 1H).
6-[2-(2,4-Difluorophenyl)chroman-6-yloxy]-pyridin-3-ylamine
1H NMR (400 MHz, d6-DMSO) ä: 7.58 (m, 1H), 7.51 (d, 1H, J 3.3 Hz), 7.30
(m, 1H), 7.15 (m, 1H), 7.05 (dd, 1H, J 8.3, 3.3 Hz), 6.84-6.73 (m, 3H), 6.70 (d, 1H, J
8.3 Hz), 5.27 (dd, 1H, J 10.3,2.3 Hz), 5.01 (bs, 2H), 2.97 (m, 1H), 2.73 (m, 1H),
2.13 (m, 1H), 2.03 (m, 1H).
6-[2-(2,5-Difluorophenyl)chroman-6-yloxy]-pyridin-3-ylamine
1H NMR (300 MHz, d6-DMSO) ä: 7.51 (d, 1H, J 2.9 Hz), 7.36-7.25 (m, 3H),
7.05 (dd, 1H, J 8.6, 2.9 Hz), 6.84-6.68 (m, 4H), 5.29 (d, 1H, J 8.6), 4.99 (bs, 2H),
2.96 (m, 1H), 2.72 (m, 1H), 2.14 (m, 1H), 2.01 (m, 1H).
6-[2-(2,6-Difluorophenyl)chroman-6-yloxy]-pyridin-3-ylamine
1H NMR (400 MHz, d6-DMSO) ä: 7.52-7.47 (m, 2H), 7.24 (m, 1H), 7.19-
7.14 (m, 3H), 7.07 (dd, 1H, J 8.6,2.9 Hz), 6.76-6.51 (m, 3H), 5.37 (dd, 1H, J 11.6,

2.0 Hz), 5.00 (bs, 2H), 3.00 (m, 1H), 2.78 (m, 1H), 2.32 (m, 1H), 2.11 (m, 1H).
6-[2-(3,5-Difluorophenyl)chroman-6-yloxy]-pyridin-3-ylamine
1H NMR (400 MHz, d6-DMSO) ä: 7.51 (d, 1H, J 2.9 Hz), 7.22-7.17 (m, 3H),
7.05 (dd, 1H, J 8.6,2.9 Hz), 6.84 (dd, 1H, J 7.9,2.0 Hz), 6.76-6.74 (m, 2H), 6.69 (d,
1H, J 8.6 Hz), 5.14 (dd, 1H, J 10.0,2.2 Hz), 5.01 (bs, 2H), 2.91 (m, 1H), 2.69 (m,
1H), 2.20 (m, 1H), 1.97 (m, 1H).
6-[2-(4-Trifluoromethylphenyl)chroman-6-yloxy]pyridin-3-ylamine
1H NMR (400 MHz, d6-DMSO) ä: 7.78 (d, 2H, J 8.4 Hz), 7.68 (d, 2H, J 8.4
Hz), 7.52 (dd, 1H, J 2.9, 0.5 Hz), 7.06 (dd, 1H, 8.6,2.9 Hz) 6.84 (m, 1H), 6.77-6.75
(m, 2H), 6.70 (dd, 1H, J 8.6,0.5 Hz), 5.23 (dd, 1H, J 10.0,2.0 Hz), 5.01 (bs, 2H),
2.95 (ddd, 1H, -16.8,11.1, 5.9 Hz), 2.69 (ddd, 1H, J-16.8, 8.5,4.8 Hz), 2.21 (m,
1H), 1.97 (m, 1H).
6-[2-(2-Chlorophenyl)cbxoman-6-yloxy]pyridin-3-ylamine
1H NMR (400 MHz, d6-DMSO) ä: 7.59 (m, 1H), 7.52-7.38 (m, 4H), 7.06
(dd, 1H, J 8.6,3.0 Hz), 6.87-6.70 (m, 4H), 5.33 (dd, 1H, J 10.3,2.1 Hz), 5.01 (bs,
2H), 2.97 (m, 1H), 2.74 (m, 1H), 2.20 (m, 1H), 1.93 (m, 1H).
6-[2-(2-Aminophenyl)chroman-6-yloxy]-pyridin-3-ylamine
1H NMR (300 MHz, d6-DMSO) ä: 7.51 (d, 1H, J 2.9 Hz), 7.15-7.18 (m, 1H),
7.05 (dd, 1H, J 8.6,2.9 Hz), 6.98-7.00 (m, 1H), 6.77 (d, 1H, J 8.6 Hz), 6.73-6.75 (m,
2H), 6.66-6.71 (m, 2H), 6.56-6.61 (m, 1H), 5.11 (dd, 1H, J 10.4,2.0 Hz), 5.01 (s,
2H), 4.99 (s, 2H), 2.94-2.99 (m, 1H), 2.66-2.74 (m, 1H), 2.06-2.13 (m, 1H), 1.88-
1.95 (m, 1H).
6-[2-(3-Aminophenyl)chroman-6-yloxy]-pyridin-3-ylamine
1H NMR (300 MHz, d6-DMSO) ä: 7.51 (d, 1H, J 2.8 Hz), 7.05 (dd, 1H, J 8.6,
2.8 Hz), 7.01 (t, 1H, J 15.4,7.7 Hz), 6.70-6.78 (m, 3H), 6.68 (d, 1H, J 8.6 Hz), 6.63
(s, 1H), 6.54 (d, 1H, J 7.7 Hz), 6.50 (d, 1H, J 8.6 Hz), 5.06 (s, 2H), 4.98 (s, 2H), 4.90
(dd, 1H, J 10.0,2.2 Hz), 2.85-2.96 (m, 1H), 2.62-2.74 (m, 1H), 2.05-2.11 (m, 1H),
1.89-1.95 (m,1H).
6-[2-(4-Aminophenyl)chroman-6-yloxy]-pyridin-3-ylamine

1H NMR (400 MHz, d6-DMSO) ä: 7.50 (d, 1H, J 2.9 Hz), 7.07 (d, 2H, 8.4
Hz), 7.04 (dd, 1H, J 8.6,2.9 Hz), 6.71 (s, 3H), 6.68 (d, 1H, J 8.6 Hz), 6.56 (d, 2H, J
8.4 Hz), 5.07 (s, 2H), 4.99 (s, 2H), 4.84 (dd, 1H, J 9.7,2.3 Hz), 2.86-2.95 (m, 1H),
2.66-2.71 (m, 1H), 1.95-2.05 (m, 2H).
6-[2-(3-Methoxyhenyl)chroman-6-yloxy]pyridin-3-ylamine ORM-10684
1H NMR (400 MHz, d6-DMSO) ä: 7.51 (d, 1H, J 3.0 Hz), 7.31 (t, 1H, J 15.8,
7.9 Hz), 7.04 (dd, 1H, J 8.7,3.0 Hz), 6.99-7.02 (m, 1H), 6.99 (d, 1H, J 2.6 Hz), 6.90
(dd, 1H, J 8.9,2.6 Hz), 6.79-6.81 (m, 1H), 6.72-6.74 (m, 2H), 6.69 (d, 1H, J 8.9 Hz),
5.06 (dd, 1H, J 9.9,2.2 Hz), 4.50 (s, 2H), 3.77 (s, 3H), 2.88-2.95 (m, 1H), 2.66-2.71
(m, 1H), 2.12-2.17 (m, 1H), 1.94-2.00 (m, 1H).
6-(5-Aminopyridin2-yloxy)-2-phenylchroman-4-one
1H NMR (400 MHz, CD3OD) ä: 7.62 (d, 1H, 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, 1H, J 8.8 Hz), 6.76 (d, 1H, J 8.6Hz),
5.50 (dd, 1H, J 13.0,2.9 Hz), 3.08 (dd, 1H, -17.0,13.0 Hz), 2.82 (dd, 1H, J-17.0,
2.9 Hz).
6-(2-Phenyl-2,3-dihydrobenzo[1,4]oxathiin-6-yloxy)pyridin-3-ylamine
hydrochloride
1H NMR (400 MHz, CDCl3) ä: 8.20 (d, 1H, J 2.1 Hz), 7.87 (dd, 1H, J 8.9,2.1
Hz), 7.41-7.44 (m, 4H), 7.37-7.40 (m, 1H), 6.98 (d, 1H, J 8.9 Hz), 6.97 (d, 1H, J 8.8
Hz), 6.93 (d, 1H, J 2.7 Hz), 6.80 (dd, 1H, J 8.8,2.7 Hz), 5.20 (dd, 1H, J 9.6,1.9 Hz),
3.30 (dd, 1H, 13.2,9.6 Hz), 3.12 (dd, 1H, 13.2,1.9 Hz).
6-(5-Aminopyridin-2-yloxy)-2-phenylchromen-4-one
1H-NMR (300 MHz; d6-DMSO) ä: 8.14-8.10 (m, 2H), 7.63-7.51 (m, 5H),
7.42 (d, 1H, J 2.9 Hz) 7.14 (dd, 1H, J 8.6,2.9 Hz), 7.03 (s, 1H), 6.89 (d, 1H, J 8.6
Hz),5.19(s,2H).
6-{2-[3-(Pyridin-2-yloxy)phenyl]chroman-6-yloxy}pyridin-3-ylamine
1H NMR (400 MHz, d6-DMSO) ä: 8.16 (dd, 1H, J 4.7,1.3 Hz), 7.86 (ddd,
1H, H 8.7,6.9,2.0 Hz), 7.51 (d, 1H, J 2.8 Hz), 7.44 (t, 1H, J 7.8 Hz), 7.29 (d, 1H, J
7.8 Hz), 7.19 (s, 1H), 7.13 (dd, 1H, J 6.9, 5.2 Hz), 7.09-7.03 (m, 3H), 6.81-6.71 (m,
3H), 6.69 (d, 1H, J 8.7 Hz), 5.11 (d, 1H, J 9.8 Hz), 4.99 (s, 2H), 2.89 (m, 1H), 2.68
(m, 1H), 2.17 (m, 1H), 1.97 (m, 1H).

Using the same procedure described for 5-amino-2-(2-phenylchroman-6-
yloxy)pyridine but replacing 5-nitro-2-(2-phenylchroman-6-yloxy)-pyridine by:
2-[2-(3,4-difluorophenyl)chroman-6-yloxy]-5-nitropyridine,
5-nitro-2-[2-(2-trifluoromethylphenyl)chroman-6-yloxy]pyridine,
2-[2-(3-chloro-4-fluorophenyl)chroman-6-yloxy]-5-nitropyridine,
2-[2-(3-chkorophenyl)chroman-6-yloxy]-5-nitropyridine,
2-[2-(2,4-dichlorophenyl)chroman-6-yloxy]-5-nitropyridine,
2-[2-(3-bromophenyl)chroman-6-yloxy]-5-nitropyridine,
2-[2-(4-ethylphenyl)chroman-6-yloxy]-5-nitropyridine,
2-(3-methyl-2-phenylchroman-6-yloxy)-5-nitropyridine,
5-nitro-2-(2-phenylchroman-7-yloxy)-pyridine,
7-(5-nitropyridin-2-yloxy)-2-phenylchroman-4-one,
3-methyl-6-(5-nitropyridin-2-yloxy)-2-phenylchroman-4-one,
2-(2,3-dihydro-2-phenyl-benzo[1,4]dioxin-6-yloxy)-5-nitropyridine,
5-nitro-2-(6-phenyl-5,6,7,8-tetrahydronaphthalen-2-yloxy)pyridine,
6-(5-nitropyridin-2-yloxy)-2-phenyl-3,4-dihydro-2H-naphthalen-lone,
2-[3-(3-fluorophenyl)chroman-7-yloxy]-5-nitropyridine,
2-(3-phenylchroman-7-yloxy)-5-nitropyridine,
5-nitro-2-(2-phenylindan-5-yloxy)pyridine,
5-Nitro-2-(2-phenylindan-5-yloxy)pyridine
there can be obtained:
6-[2-(3,4-Difluorophenyl)chrornan-6-yloxy]pyridin-3-ylamine,
6-[2-(2-Trifluoromethylphenyl)chroman-6-yloxy]pyridin-3-ylamine,
6-[2-(3-Chloro-4-fluorophenyl)chroman-6-yloxy]pyridin-3-ylamine,
6-[2-(3-Chlorophenyl)chroman-6-yloxy]pyridin-3-yiamine,
6-[2-(2,4-Dichlorophenyl)chroman-6-yloxy]pyridin-3-ylamine,
6-[2-(3-Bromophenyl)criroman-6-yloxy]pyridin-3-ylamine,
6-[2-(4-Ethylphenyl)chroman-6-yloxy]pyridin-3-ylarnine,
6-(3-Methyl-2-phenylchroman-6-yloxy)pyridin-3-ylamine,
5-Amino-2-(2-phenylchroman-7-yloxy)pyridine,
7-(5-Aminopyridin2-yloxy)-2-phenylchroman-4-one,
6-(5-Aminopyridin-2-yloxy)-3-methyl-2-phenylchroman-4-one,

6-(2-Phenyl-2,3-dihydrobenzo[ 1,4]dioxin-6-yloxy)pyridin-3-ylamine,
6-(6-Phenyl-5,6,7,8-tetraliydronaphthalen-2-yloxy)pyridin-3-ylamine,
6-(5-Aminopyridin-2-yloxy)-2-phenyl-3,4-dihydro-2H-naphthalen-1 -one,
6-[3-(3-Fluorophenyl)chroman-7-yloxy]pyridin-3-ylamine,
6-(3-Phenylchroman-7-yloxy)-pyridin-3-ylamine,
6-(2-Phenylindan-5-yloxy)-pyridin-3-ylamine, respectively.
Example 11. Intermediates
3-Pyridinyloxybenzaldehyde intermediates
3-(5-Chloropyridin-2-yloxy)benzaldehyde
3-Hydroxybenzaldehyde (3,0 g) was dissolved in dry DMF (30 ml) under
nitrogen. Potassium tert-butoxide (3,0 g) was added in to a solution and the resulting
mixture was stirred for 30 minutes. 2,5-Dichloropyridine (3,6 g) was added and the
mixture was stirred at 120°C for 1,5 hours. The reaction mixture was allowed to cool
to room temperature and 1 M HCl-solution was added and it was extracted with ethyl
acetate. The combined organic phases were washed with water and saturated NaCl-
solution and dried. The product was purified by column chromatography using
heptane- ethyl acetate (3:1) as an eluant. 1H NMR (400 MHz, d6-DMSO) ä: 10.01 (s,
1H), 8.22 (d, 1H, J 2.6 Hz), 8.01 (dd, 1H, J 8.7,2.6 Hz), 7.79 (d, 1H, J 7.6 Hz), 7.69-
7.65 (m, 2H), 7.52 (m, 1H), 7.20 (d, 1H, J 8.7 Hz).
Similarly starting from 2-chloropyridin there was obtained:
3-(pyridin-2-yloxy)benzaldehyde.
1H NMR (400 MHz, d6-DMSO) ä: 10.01 (s, 1H), 8.17 (dd, 1H, J 5.0,1.7 Hz),
7.90 (ddd, 1H, J 8.5, 6.8,1.9 Hz), 7.77 (d, 1H, J 7.8 Hz), 7.66, (t, 1H, J 7.8 Hz), 7.63
(m, 1H), 7.50 (m, 1H), 7.18 (dd, 1H, J 6.9, 5.0 Hz), 7.13 (d, 1H, 8.3 Hz).
Example 12.
6-(5-Nitropyridin-2-yloxy)-2-phenylchromen-4-one
6-(5-Nitropyridin-2-yloxy)-2-phenylchromen-4-one was prepared as described
for 5-nitro-2-(2-phenylchroman-6-yloxy)pyridine in Example l(b) starting from 500
mg of 6-hydroxyfiavone. The product was recrystallised from a mixture of 2-propa-
nol and acetone. 1H NMR (300 MHz, d6-DMSO) ä: 9.04 (d, 1H, J 2.9 Hz), 8.67 (dd,

1H, J 9.0, 2.9 Hz), 8.16-8.13 (m, 2H), 7.95 (d, 1H, J 9.0 Hz), 7.82 (d, 1H, J 2.9 Hz),
7.63 (dd, 1H, J 9.1,2.9 Hz), 7.64-7.61 (m, 3H), 7.38 (d, 1H, J 9.1 Hz), 7.09 (s, 1H).
Example 13.
2-[2-(3-(5-Nitropyridin-2-yloxy)phenyl)chroman-6-yloxy]-5-nitropyridine and
its derivatives
a) 6-Hydroxy-2-(3-hydroxyphenyl)chroman-4-one (intermediate)
6-Hydroxy-2-(3-hydroxyphenyl)chroman-4-one was prepared as described for
6-hydroxy-2-(4-fluorophenyl)chroman-4-one in Example 2(a) but starting from 3-
hydroxybenzaldehyde. The product was recrystallised from ethanol. 1H NMR (400
MHz, d6-DMSO) ä: 9.50 (bs, 1H), 9.41 (bs, 1H), 7.22-7.17 (m, 1H), 7.11 (d, 1H, J
3.0 Hz), 7.03 (dd, 1H J 3.0, 8.9 Hz), 6.64 (d, 1H, J 8.9 Hz), 6.92-6.90 (m, 2H), 6.76-
6.73 (m, 1H), 5.46 (dd, 1H J 2.9,12.7 Hz), 3.09 (dd, 1H, J 12.7,16.9 Hz), 2.75 (dd,
1H, J 2.9,16.9 Hz).
Similarly there were obtained:
6-Hydroxy-2-(4-hydroxyphenyl)chroman-4-one
1H NMR (400 MHz, d6-DMSO) ä: 9.54 (bs, 1H), 9.38 (bs, 1H), 7.34-7.31 (m,
2H), 7.10 (d, 1H, J 3.0 Hz), 7.02 (dd, 1H J 3.0, 8.8 Hz), 6.91 (d, 1H, J 8.8 Hz), 6.80-
6.77 (m, 2H), 5.40 (dd, 1H J 2.7,13.1 Hz), 3.17 (dd, 1H, J 13.2,16.9 Hz), 2.68 (dd,
1H, J2.7, 16.9 Hz).
6-Hydroxy-2-(3-benzyloxyphenyl)chroman-4-one
1H NMR (400 MHz, d6-DMSO) ä: 9.41 (bs, 1H), 7.50-7.30 (m, 6H), 7.20 (s,
1H), 7.12-7.08 (m, 2H), 7.05-7.00 (m, 2H), 6.95 (d, 1H, J 8.9 Hz), 5.52 (dd, 1H J 2.9,
12.9 Hz), 5.12 (s, 2H), 3.16 (dd, 1H, J 12.9,16.9 Hz), 2.78(dd, 1H, J 2.9,16.9 Hz).
2-[3-(5-Chloropyridin-2-yloxy)phenyl3-6-hydroxychroman-4-one
1H NMR (400 MHz, d6-DMSO) ä: 9.52 (bs, 1H), 8.22 (d, 1H, J 2.6 Hz), 7.97
(dd, 1H, J 8.8, 2.6 Hz), 7.47 (t, 1H, J 7.7 Hz), 7.39 (d, 1H, J 7.7 Hz), 7.32 (s, 1H),
7.16-7.10 (m, 3H), 7.04 (dd, 1H, J 8.8, 3.0 Hz), 6.96 (d, 1H, J 8.8 Hz), 5.57 (dd, 1H,
J 13.0,2.7 Hz), 3.17 (dd, 1H, J -16.8,13.0 Hz), 2.80 (dd, 1H, J -16.8,2.7 Hz).

6-Hydroxy-2-[3-(pyridin-2-yloxy)phenyl]chroman-4-one
1H NMR (300 MHz, d6-DMSO) ä: 8.16 (ddd, 1H, J 5.0, 2.0,1.8 Hz), 7.86 (m,
1H), 7.46 (t, 1H, J 7.8 Hz), 7.37 (d, 1H, J 7.8 Hz), 7.30 (d, 1H J 2.0 Hz), 7.16-7.10
(m, 3H), 7.06-7.02 (m, 2H), 6.94 (d, 1H, J 8.8 Hz), 5.57 (dd, 1H, J 12.9,2.9 Hz),
3.17 (dd, 1H, J -16.8,12.9 Hz), 2.80 (dd, 1H, J -16.8,2.9 Hz).
b) 2-(3-Hydroxyphenyl)chromaa-4,6-diol (intermediate)
2-(3-Hydroxyphenyl)chroman-4,6-diol was prepared as described for 2-(4-
fluorophenyl)chroman-4,6-diol in Example 2(b) but starting from 6-hydroxy-2-(3-
hydroxyphenyl)chroman-4-one. 1H NMR (400 MHz, d6-DMSO) ä: 9.43 (bs, 1H),
8.88 (bs, 1H), 7.19-7.15 (m, 1H), 6.87 (d, 1H, J 2.7 Hz), 6.84-6.82 (m, 2H), 6.72-
6.69 (m, 1H), 6.58 (d, 1H, J 8.7 Hz), 6.53 (dd, 1H, J 2.7, 8.7), 5.01 (d, 1H, J 11.3
Hz), 4.86 (dd, 1H, J 6.2,10.8 Hz), 2.25-2.19 (m, 1H), 1.88-1.75 (m, 1H).
Similarly there were obtained:
2-(4-Hydroxyphenyl)chroman-4,6-diol
1H NMR (400 MHz, d6-DMSO) ä: 9.41 (bs, 1H), 8.79 (bs, 1H), 7.23-7.21 (m,
2H), 6.87 (s, 1H), 6.77-6.74 (m, 2H), 6.53 (m, 2H), 5.37 (d, 1H, J 7.0 Hz), 4.97 (d,
1H, J 11.6 Hz), 4.85-4.82 (m, 1H), 2.20-2.15 (m, 1H), 1.95-1.85 (m, 1H).
2-(3-Benzyloxyphenyl)chrornan-4,6-diol
1H NMR (400 MHz, d6-DMSO) ä: 8.81 (bs, 1H), 7.47-7.28 (m, 6H), 7.09 (s,
1H), 7.02 (d, 1H, J 7.9 Hz), 6.97 (dd, 1H, J 2.4, 7.9 Hz), 6.88 (d, 1H, J 2.8 Hz), 6.59
(d, 1H, J 8.7 Hz), 6.54 (dd, 1H, J 2.8, 8.7 Hz), 5.40 (d, 1H, J 6.2 Hz), 5.12 (s, 2H),
5.08 (d, 1H, J 10.9 Hz), 4.88-4.85 (m, 1H), 2.28-2.23 (m, 1H), 1.92-1.77 (m, 1H).
2-[3-(5-Chloropyridin-2-yloxy)phenyl]chroman-4,6-diol
1H NMR (400 MHz, d6-DMSO) ä: 8.82 (s, 1H), 8.22 (d, 1H, J 2.6 Hz), 7.97
(dd, 1H, J 8.6,2.6 Hz), 7.45 (t, 1H, J 7.9 Hz), 7.31 (d, 1H, J 7.9 Hz), 7.20 (d, 1H, J
1.7 Hz), 7.12 (d, 1H, J 8.6 Hz), 7.11 (dd, 1H, J 7.9,1.7 Hz), 6.87 (d, 1H, J 2.6 Hz),
6.59 (d, 1H, J 8.6 Hz), 6.53 (dd, 1H, J 8.6,2.6 Hz), 5. 41 (bs, 1H), 5.14 (d, 1H, J 12.9
Hz), 4.86 (m, 1H) 2.29 (m, 1H), 1.87 (m, 1H).
2-[3-(Pyridin-2-yloxy)phenyl]chroman-4,6-diol

1H NMR (400 MHz, d6-DMSO) ä: 8.82 (s, 1H), 8.17 (m, 1H), 7.86 (m, 1H),
7.43 (t, 1H, J 7.8 Hz), 7.29 (d, 1H, J 7.8 Hz), 7.18 (s, 1H), 7.15-7.04 (m, 3H), 6.87
(d, 1H, J 2.7 Hz), 6.59 (d, 1H, J 8.7 Hz), 6.53 (dd, 1H, J 8.7,2.7 Hz), 5. 40 (d, 1H, J
7.0 Hz), 5.14 (d, 1H, J 11.6 Hz), 4.86 (m, 1H) 2.29 (m, 1H), 1.88 (m, 1H).
c) 2-(3-Hydroxyphenyl)chroman-6-ol (intermediate)
2-(3-Hydroxyphenyl)chroman-6-ol was prepared as described for 2-(4-
fluorophenyl)chroman-6-ol in Example 2(c) but starting from 2-(3-hydroxyphenyl)-
chroman-4,6-diol. XH NMR (400 MHz, d6-DMSO) ä: 9.38 (s, 1H), 8.77 (s, 1H), 7.17-
7.13 (m, 1H), 6.82-6.79 (m, 2H), 6.70-6.67 (m, 1H), 6.62 (d, 1H, J 8.6 Hz), 6.52-6.47
(m, 2H), 4.89 (dd, 1H, J 2.1, 9.9 Hz), 2.86-2.82 (m, 1H), 2.65-2.59 (m, 1H), 2.09-
2.04 (m, 1H), 1.91-1.85 (m, 1H).
Similarly there were obtained:
2-(3-Benzyloxyphenyl)chroman-6-ol
1H NMR (400 MHz, d6-DMSO) ä: 8.77 (s, 1H), 7.46-7.26 (m, 6H), 7.06 (s,
1H), 7.00-6.93 (m, 2H), 6.63 (d, 1H, J 8.5 Hz), 6.52-6.47 (m, 2H), 5.10 (s, 2H), 4.96
(dd, 1H, J 1.8,9.8 Hz), 2.91-2.82 (m, 1H), 2.67-2.59 (m, 1H), 2.12-2.07 (m, 1H),
1.99-1.87 (m, 1H).
2-[3-(5-Chloropyridin-2-yloxy)phenyl]chroman-6-ol
1H NMR (300 MHz, d6-DMSO) ä: 8.75 (s, 1H), 8.21 (d, 1H, J 2.6 Hz), 7.95
(dd, 1H, J 8.7,2.6 Hz), 7.43 (t, 1H, J 7.8 Hz), 7.28 (d, 1H, J 7.8 Hz), 7.18 (d, 1H, J
1.9 Hz), 7.11-7.07 (m, 2H), 6.61-6.48 (m, 3H), 5.01 (dd, 1H, J 9.8,2.0 Hz), 2.87 (m,
1H) 2.62 (m, 1H), 2.13 (m, 1H), 1.93 (m, 1H).
2-[3-(Pyridin-2-yloxy)phenyl]chroman-6-ol
1H NMR (400 MHz, d6-DMSO) ä: 8.81 (bs, 1H), 8.17 (m, 1H), 7.85 (m, 1H),
7.42 (t, 1H, J 7.9 Hz), 7.26 (d, 1H, J 7.9 Hz), 7.16-7.12 (m, 2H), 7.07-7.02 (m, 2H),
6.63 (d, 1H, J 8.2 Hz), 6.57-6.48 (m, 2H), 5.01 (d, 1H, J 8.5 Hz), 2.88 (m, 1H) 2.63
(m, 1H), 2.13 (m, 1H), 1.93 (m, 1H).
d)2-[2-(3-(5-Nitropyridin-2-yloxy)phenyl)cbxoman-6-yloxy]-5-nitropyridine

2-[2-(3-(5-Nitropyridin-2-yloxy)phenyl)chroman-6-yloxy]-5-nitropyridine
was prepared as described for 5-nitro-2-(2-phenylchroman-6-yloxy)pyridine in
Example 1 (b) but starting from 2-(3-hydroxyphenyl)chroman-6-ol and using 210
mol-% of 2-chloro-5-nitropyridine. 1H NMR (400 MHz, d6-DMSO) ä: 9.05 (d, 1H, J
2.9 Hz), 9.03 (d, 1H, J 2.9 Hz), 8.64 (dd, 1H, J 2.9, 9.1 Hz), 8.60 (dd, 1H, J 2.9, 9.1
Hz), 7.52 (t, 1H, J 7.8 Hz), 7.41 (d, 1H, J 7.8 Hz), 7.33-7.31 (m, 1H), 7.28 (d, 1H, J
7.8 Hz), 7.23-7.18 (m, 2H) 7.01-6.90 (m, 3H), 5.20 (dd, 1H, J 2.1,10.1 Hz), 3.07-
2.92 (m, 1H), 2.80-2.70 (m, 1H), 2.30-2.18 (m, 1H), 2.10-1.98 (m, 1H).
Using only 100 mol-% of 2-chloro-5-nitropyridine there were obtained:
5-Nitro-2-[2-(3-benzyloxyphenyl)cnroman-6-yloxy]pyridine
1H NMR (300 MHz, d6-DMSO) ä: 9.03 (d, 1H, J 2.9 Hz), 8.59 (dd, 1H, J 2.9,
9.1 Hz), 7.47-7.29 (m, 6H), 7.19 (d, 1H, J 9.1 Hz), 7.10 (s, 1H), 7.05-6.92 (m, 5H),
5.14-5.10 (m, 3H), 3.00-2.88 (m, 1H), 2.75-2.69 (m, 1H), 2.20-2.14 (m, 1H), 2.07-
1.95 (m, 1H).
5-Nitro-2-{2-[3-(5-chloropyridin-2-yloxy)phenyl]chroman-6-yloxy}pyridme
1H NMR (300 MHz, d6-DMSO) ä: 9.02 (d, 1H, J 2.9 Hz), 8.59 (dd, 1H, J 9.1,
2.9 Hz), 8.22 (d, 1H, J 2.8 Hz), 7.97 (dd, 1H, J 8.7,2.8 Hz), 7.46 (t, 1H, J 7.8 Hz),
7.33 (d, 1H, J 7.8 Hz), 7.23, (s, 1H), 7.19 (d, 1H, J 9.1 Hz), 7.13-7.10 (m, 2H), 6.99-
6.89 (m, 3H), 5.18 (d, 1H, J 8.0 Hz), 2.97 (m, 1H), 2.75 (m, 1H), 2.21 (m, 1H), 2.01
(m, 1H).
5-Nitro-2-{2-[3-(pyridin-2-yloxy)phenyl]chroman-6-yloxy}pyridine
1H NMR (400 MHz, d6-DMSO) ä: 9.04 (d, 1H, J 2.7 Hz), 8.59 (dd, 1H, J 9.1,
2.7 Hz), 8.17 (m, 1H), 7.86 (m, 1H), 7.45 (t, 1H, J 7.8 Hz), 7.31 (d, 1H, J 7.8 Hz),
7.21, (s, 1H), 7.20 (d, 1H, J 9.1 Hz), 7.13 (m, 1H), 7.09 (m, 1H), 7.06 (8.6 Hz), 7.04
(2.5 Hz), 6.96 (dd, 1H, J 8.6, 2.5 Hz), 5.18 (d, 1H, J 8.8 Hz), 2.98 (m, 1H), 2.72 (m,
1H), 2.21 (m, 1H), 2.02 (m, 1H).
Example 14.
6-(5-Nitropyridin-2-yloxy)-2-[3-(5-nitropyridin-2-yloxy)phenyl]chroman-4-ol
and its derivatives

a)6-(5-Nitropyridin-2-yloxy)-2-[3-(5-nitropyridin-2-yloxy)phenyl]chroman-4-
ol
6-(5-Nitropyridin-2-yloxy)-2-[3-(5-nitropyridin-2-yloxy)phenyl]chroman-4-ol
was prepared as described for 5-nitro-2-(2-phenylchroman-6-yloxy)pyridine in
Example 1 (b) but starting from 2-(3-hydroxyphenyl)chroman-4,6-diol and using 210
mol-% of 2-chloro-5-nitropyridine. 1H NMR (400 MHz, d6-DMSO) ä: 9.06 (d, 1H, J
2.8 Hz), 9.03 (d, 1H, J 2.8 Hz), 8.64 (dd, 1H, J 2.8, 9.1 Hz), 8.61 (dd, 1H, J 2.8, 9.1
Hz), 7.54 (t, 1H, J 7.9 Hz), 7.43 (d, 1H, J 7.9 Hz), 7.36 (s, 1H), 7.30 (d, 1H, J 9.1
Hz), 7.25-7.21 (m, 3H) 7.01 (dd, 1H, J 2.9, 8.7 Hz), 6.89 (d, 1H, J 8.7 Hz), 5.67 (d,
1H, J 6.4 Hz), 5.36 (d, 1H, J 10.8 Hz), 5.01-4.95 (m, 1H), 2.41-2.36 (m, 1H), 2.02-
1.92 (m, 1H).
Similarly there was obtained:
b)6-(5-Nitropyridin-2-yloxy)-2-[4-(5-nitropyridin-2-yloxy)phenyl]chroman-
4-ol
1H NMR (400 MHz, d6-DMSO) ä: 9.05-9.04 (m, 2H, major & minor), 8.66-
8.60 (m, 2H, major & minor), 7.61-7.58 (m, 2H, major & minor), 7.31-7.21 (m, 5H,
major & minor), 7.10 (dd, 1 H, J 2.9, 8.8 Hz, minor), 7.03 (dd, 1H, J 3, 8.8 Hz,
major), 6.97 (d, 1H, J 8.8 Hz, minor) 6.89 (d, 1H, J 8.8 Hz, major), 5.68 (d, 1H, J 6.4
Hz, major), 5.63 (d, 1H, J 4.7 Hz, minor), 5.37-5.30 (m, 1H, major & minor), 5.04-
4.97 (m, 1H, major), 4.69-4.65 (m, 1H, minor), 2.41-2.36 (m, 1H, major), 2.21-2.15
(m, 2H, major&minor), 2.07-1.98 (m, 1H, major).
Example 15.
2- {2-[4-(5-Nitropyridin-2-yloxy)phenyl]chroman-6-yloxy} -5-nitropyridine
2-{2-[4-(5-Nitropyridin-2-yloxy)-phenyl]-chroman-6-yloxy}-5-nitropyridine
was prepared as described for 2-(4-fluorophenyl)chroman-6-ol in Example 2(c) but
starting from 6-(5-nitropyridin-2-yloxy)-2-[4-(5-nitropyridin-2-yloxy) phenyl]-
cbroman-4-ol. 1H NMR (400 MHz, d6-DMSO) ä: 9.05 (d, 2H, J 2.9 Hz), 8.65-8.58
(m, 2H), 7.58-7.55 (m, 2H), 7.30-7.26 (m, 3H), 7.20 (d, 1H, J 9.1 Hz), 7.03-6.91 (m,
3H) 5.20 (dd, 1H, J 2.0,10.1 Hz), 3.06-2.97 (m, 1H), 2.81-2.75 (m, 1H), 2.26-2.21
(m, 1H), 2.11-2.02 (m, 1H).

Example 16.
6-[2-(3-(5-Aminopyridin-2-yloxy)phenyl)chroman-6-yloxy]-pyridin-3-
ylamine and derivatives thereof
6-[2-(3-(5-Aminopyridin-2-yloxy)phenyl)chroman-6-yloxy]-pyridin-3-yl-
amine was prepared as described for 5-amino-2-(2-phenylchroman-6-yloxy)pyridine
in Example 10 but starting from 2-[2-(3-(5-nitropyridin-2-yloxy)phenyl)chroman-6-
yloxy]-5-nitropyridine. Product was isolated as its dihydrochloride salt. 1H NMR
(300 MHz, d6-DMSO) ä: 8.12 (m, 2H), 7.78 (m, 1H), 7.45 (t, 1H, J 7.8 Hz), 7.31 (d,
1H, J 7.2 Hz), 7.21 (s, 1H), 7.13-7.04 (m, 3H), 6.91-6.87 (m, 3H), 5.15 (d, 1H, J 9.8
Hz), 3.02-2.91 (m, 1H), 2.76-2.70 (m, 1H), 2.23-2.17 (m, 1H), 2.05-1.93 (m, 1H).
Similarly there were obtained:
6-[2-(3-Benzyloxyphenyl)chroman-6-yloxy]pyridin-3-ylamine hydrochloride
1H NMR (400 MHz, d6-DMSO) ä: 7.85 (s, 1H), 7.47-7.29 (m, 6H), 7.09 (s,
1H), 7.02 (d, 1H, J 7.4 Hz), 6.98 (dd, 1H, J 2.3, 8.2 Hz), 6.91 (d, 1H, J 8.7 Hz), 6.85-
6.81 (m, 4H), 5.12 (s, 2H), 5.09 (d, 1H, J 9.5 Hz), 2.96-2.89 (m, 1H), 2.72-2.67 (m,
1H) 2.20-2.14 (m, 1H), 2.03-1.97 (m, 1H).
6-(5-Aminopyridin-2-yloxy)-2-[3-(5-aminopyridin-2-yloxy)phenyl]chroman-
4-ol dihydrochloride
1H NMR (400 MHz, d6-DMSO) ä: 8.15 (d, 2H, J 2.6 Hz), 7.82 (dd, 2H, J 2.6,
8.8 Hz), 7.47 (t, 1H, 7.9 Hz), 7.35 (d, 1H, J 7.9 Hz), 7.24 (s, 1H), 7.19-7.08 (m, 4H),
6.94 (dd, 1H, 2.8, 8.8 Hz), 6.84 (d, 1H, 8.8 Hz), 5.30 (d, 1H, J 10.9 Hz), 4.96 (dd,
1H, J 6.1,10.7 Hz), 2.38-2.32 (m, 1H), 1.98-1.88 (m, 1H).
Example 17.
3-[6-(5-Aminopyridin-2-yloxy)chroman-2-yl]phenol
2.15 g of 5-nitro-2-[2-(3-benzyloxyphenyl)chroman-6-yloxy]pyridine was
dissolved to 600 ml of ethanol and 430 mg g of 10% palladium on charcoal was
added under inert atmosphere. Starting material was hydrogenated at room
temperature to give quantitative yield of 3-[6-(5-aminopyridin-2-yloxy)chroman-2-
yljphenol 1H NMR (400 MHz, d6-DMSO) ä: 9.50 (bs, 1H), 7.52 (d, 1H, J 3.0 Hz),
7.17 (t, 1H, J 8.1 Hz), 7.05 (dd, 1H, J 3.0, 8.6 Hz), 6.84-6.68 (m, 7H), 5.01-4.99 (m,
3H), 2.91-2.86 (m, 1H), 2.70-2.63 (m, 1H), 2.14-2.08 (m, 1H), 1.96-1.89 (m, 1H).

Example 18.
2-Acetylamino-N:-[6-(2-phenylchroman-6-yloxy)-pyridin-3-yl]-acetamide
5-Airrino-2-(2-phenylchroman-6-yloxy)-pyridine (500 mg) and N-acetyl-
glycine (275 mg) was dissolved in 35 ml of methylene chloride. l-(3-dimethylamino-
propyl)-3-ethyIcarbodiimide hydrochloride (450 mg) was added. The mixture was
stirred at room temperature for 6 hours. Reaction was quenched with addition of
water and formed precipitate was filtered. 1H-NMR (400 MHz; d6-DMSO) ä: 10.1 (s,
1H), 8.30 (d, 1H, J 2.7 Hz), 8.21 (t, 1H, J 5.7 Hz), 8.00 (dd, 1H, J 2.7, 8.9 Hz), 7.47-
7.30 (m, 5H), 6.95 (d, 1H, J 8.9 Hz), 6.87-6.84 (m, 3H), 5.12 (dd, 1H, J 1.90,10.0
Hz), 3.86 (d, 2H, J 5.7 Hz), 3.00-2.92 (m, 1H), 2.75-2.70 (m, 1H), 2.19-2.14 (m, 1H),
2.03-1.97 (m, 1H).
Using the same procedure described for 2-acetylamino-N-[6-(2-phenyl-
chroman-6-yloxy)-pyridin-3-yl]-acetamide above but replacing 5-amino-2-(2-
phenylchroman-6-yloxy)pyridine by:
6-[2-(4-Fluorophenyl)chroman-6-yloxy]pyridin-3-ylamine,
6-[2-(3-fluorophenyl)chroman-6-yloxy]-pyridin-3-ylamine,
6-[2-(2-Fluorophenyl)chroman-6-yloxy]-pyridin-3-ylamine,
6-[2-(2,3-Difluorophenyl)chroman-6-yloxy]-pyridin-3-ylamine,
6-[2-(2,4-Difluorophenyl)chroman-6-yloxy]-pyridin-3-ylamine,
6-[2-(2,5-Difluorophenyl)chroman-6-yloxy]-pyridin-3-ylamine
6-[2-(2,6-Difluorophenyl)chroman-6-yloxy]-pyridin-3-ylamine,
6-[2-(3,4-Difluorophenyl)chroman-6-yloxy]pyridin-3-ylamine,
6-[2-(3,5-Difluorophenyl)chroman-6-yloxy]-pyridin-3-ylamine
6-[2-(2-Trifluoromethylphenyl)chroman-6-yloxy]pyridin-3-ylamine,
6-[2-(4-Trifluoromethylphenyl)chroman-6-yloxy]pyridin-3-ylamine,
6-[2-(3-Chloro-4-fluorophenyl)chroman-6-yloxy]pyridin-3-ylamine,
6-[2-(2-Chlorophenyl)chroman-6-yloxy]pyridin-3-ylamine,
6-[2-(3-Chlorophenyl)chroman-6-yloxy]pyridin-3-ylarnine,
6-[2-(2,4-Dichlorophenyl)chroman-6-yloxy]pyridin-3-ylamine,
6-[2-(3-Bromophenyl)chroman-6-yloxy]pyridin-3-ylamine,
6-[2-(4-Ethylphenyl)chroman-6-yloxy]pyridin-3-ylamine,
6-[2-(3-Methoxyphenyl)chroman-6-yloxy]pyridin-3-ylarnine

6-(3-Methyl-2-phenylchroman-6-yloxy)pyridin-3-ylamine,
5-Amino-2-(2-phenylchroman-7-yloxy)pyridine,
6-(5-Aminopyridin2-yloxy)-2-phenylchroman-4-one,
7-(5-Aminopyridin2-yloxy)-2-phenylchroman-4-one,
6-(5-Aminopyridin-2-yloxy)-3-methyl-2-phenylchroman-4-one,
6-(2-Phenyl-2,3-dihydroben2o[1,4]dioxin-6-yloxy)pyridin-3-ylamine
6-(6-Phenyl-5,6,7,8-tetrahydronaphthalen-2-yloxy)pyridin-3-ylamine,
6-(5-Aminopyridin-2-yloxy)-2-phenyl-3,4-dihydro-2H-naphthalen-1-one,
6-(2-Phenyl-2,3-dihydrobenzo[1,4]oxathiin-6-yloxy)pyridin-3-ylamine
6-[3-(3-Fluorophenyl)chroman-7-yloxy]pyridin-3-ylamine,
6-(3-Phenylchroman-7-yloxy)-pyridin-3-ylamine,
6-(5-Aminopyridin-2-yloxy)-2-phenylchromen-4-one,
6-(2-Phenylindan-5-yloxy)-pyridin-3-ylamine,
there is obtained:
2-Acetylamino-N-{6-[2-(4-fluorophenyl)chroman-6-yloxy]pyridin-3-
yl}acetamide,
2-Acetylamino-N-{6-[2-(3-fluorophenyl)chroman-6-yloxy]pyridin-3-
yl}acetamide,
2-Acetylamino-N-{6-[2-(2-fluorophenyl)chroman-6-yloxy]pyridin-3-
yl}acetamide,
2-Acetylamino-N-{6-[2-(2,3-difluorophenyl)chroman-6-yloxy]pyridin-3-
yl}acetamide,
2-Acetylamino-N-{6-[2-(2,4-difluorophenyl)chroman-6-yloxy]pyridin-3-
yl}acetamide,
2-Acetylamino-N-{6-[2-(2,5-difluorophenyl)chroman-6-yloxy]pyridin-3-
yl}acetamide,
2-Acetylamino-N-{6-[2-(2,6-difluorophenyl)chroman-6-yloxy]pyridin-3-
yl}acetamide,
2-Acetylamino-N-{6-[2-(3,4-difluorophenyl)chroman-6-yloxy]pyridin-3-
yl}acetamide
2-Acetylamino-N-{6-[2-(3,5-difluorophenyl)chroman-6-yloxy]pyridin-3-
yl}acetamide
2-Acetylamino-N-{6-[2-(2-trifluoromethyIphenyl)chroman-6-yloxy]pyridin-3-
yl}acetamide,

2-Acetylammo-N{6-[2-(4-trifluoromethylphenyl)chroman-6-yloxy]pyridin-3-
yl} acetamide,,
2-Acetylammo-N-{6-[2-(3-chloro-4-fluorophenyl)chroman-6-yloxy]pyridin-3-
yl} acetamide,
2-Acetylamino-N-{6-[2-(2-chlorophenyl)chroman-6-yloxy]pyridin-3-
yl} acetamide,
2-Acetylammo-N-{6-[2-(3-chlorophenyl)chroman-6-yloxy]pyridin-3-
yl} acetamide,
2-Acetylamino-N-{6-[2-(2,4-diclilorophenyl)chroman-6-yloxy]pyridin-3-
yl} acetamide,
2-Acetylamino-N-{6-[2-(3-bromophenyl)chroman-6-yloxy]pyridin-3-
yl} acetamide,
2-Acetylamino-N-{6-[2-(4-ethylphenyl)chroman-6-yloxy]pyridin-3-
yl} acetamide,
2-Acetylammo-N-{6-[2-(3-methoxyphenyl)chroman-6-yloxy]pyridin-3-
yl} acetamide,
2-Acetylamino-N-{6-(3-methyl-2-phenylchroman-6-yloxy)pyridin-3-
yl} acetamide,
2-Acetylamino-N-[6-(2-phenylchroman-7-yloxy)-pyridin-3-yl]-acetamide,
2-Acetylamino-N-[6-(4-oxo-2-phenylchroman-6-yloxy)pyridin-3-
yl] acetamide,
2-Acetylamino-N-[6-(4-oxo-2-phenylchroman-7-yloxy)pyridin-3-
yl] acetamide,
2-Acetylammo-N-[6-(3-methyl-4-oxo-2-phenylchroman-6-yloxy)pyridin-3-
yl]acetamide,
2-Acetylammo-N-[6-(2-phenyl-2,3-dihydrobenzo[1,4]dioxin-6-yloxy)pyridin-
3-yl]acetamide,
2-Acetylamino-N-[6-(6-phenyl-5,6,7,8-tetrahydronaphthalen-2-yloxy)-
pyridin-3-yl]acetamide,
2-Acetylamino-N-[6-(5-oxo-6-phenyl-5,6,7,8-tetrahydronaphthalen-2-
yloxy)pyridin-3-yl]acetamide,
2-Acetylamino-N-[6-(2-phenyl-2,3-dihydrobenzo[1,4]oxathiin-6-
yloxy)pyridin-3-yl3acetamide,
2-Acetylamino-N-{6-[3-(3-fluorophenyl)chroman-7-yloxy]pyridin-3-
yl} acetamide,
2-Acetylamino-N-[6-(3-phenylchroman-7-yloxy)pyridm-3-yl]acetamide,

2-Acetylamino-N-[6-(4-oxo-2-phenyl-4H-chromen-6-yloxy)pyridin-3-
yl]acetamide,
2-Acetylamino-N-[6-(2-phenylindan-5-yloxy)pyridin-3-yl]acetamide,
respectively.
Example 19.
Piperidine-4-carboxylic acid [6-(2-phenylchroman-6-yloxy)pyridin-3-
yl] amide
a) 4-[6-(2-Phenylchroman-6yloxy)pyridin-3-ylcarbamoyl]piperidine-1 -
carboxylic acid tert-butyl ester
5-Amino-2-(2-phenylchroman-6-yloxy)-pyridine (500 mg) and N-(tert-
butoxycarbonyl)isonipecotic acid (541 mg) was dissolved in 40 ml of THF. 1-(3-
dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (451 mg) was added. The
mixture was refluxed for few hours. Reaction was quenched with addition of water
and extracted with ethyl acetate. Combined organic layers were washed with water,
saturated sodium carbonate solution, dried with Na2SO4 and evaporated. 1H-NMR
(300 MHz; d6-DMSO) ä: 10.0 (s, 1H), 8.31 (d, 1H, J 2.7 Hz), 8.03 (dd, 1H, J 2.7, 8.8
Hz), 7.47-7.33 (m, 5H), 6.92 (d, 1H, J 8.8 Hz), 6.87-6.84 (m, 3H), 5.13 (dd, 1H, J
2.2,10.1 Hz), 4.04-3.96 (m, 2H), 2.99-2.91 (m, 1H), 2.81-2.69 (m, 3H), 2.20-2.12
(m, 2H), 2.08-1.98 (m, 1H), 1.79-1.74 (m, 3H), 1.50-1.35 (m, 11H).
b) Piperidine-4-carboxylic acid [6-(2-phenylchroman-6-yloxy)pyridin-3-
yl] amide
Mixture of 4-[6-(2-Phenyl-chroman-6-yloxy)-pyridin-3-ylcarbamoyl]-
piperidine-1-carboxylic acid tert-butyl ester (860 mg) and of 1 M HC1 in diethyl ether
(13 ml) was stirred at room temperature for 24 hours. Precipitate was filtered and
washed with ether. 1H-NMR (300 MHz; d6-DMSO) ä: 10.3 (s, 1H), 8.97 (bs, 1H),
8.65 (bs, 1H), 8.34 (d, 1H, J 2.7 Hz), 8.04 (dd, 1H, J 2.7, 8.8 Hz), 7.47-7.33 (m, 5H),
6.94 (d, 1H, J 8.8 Hz), 6.86-6.84 (m, 3H), 5.11 (dd, 1H, J 2.3,10.0 Hz), 3.35-3.29
(m, 2H), 2.97-2.89 (m, 3H), 2.74-2.66 (m, 2H), 2.19-2.13 (m, 1H), 2.00-1.74 (m,
5H), 1.50-1.35 (m, 11H).

Example 20.
2-Amino-N-[6-(2-phenylchroman-6-yloxy)-pyridin-3-yl]propionamide and
derivatives thereof
2-Amino-N-[6-(2-phenylchroman-6-yloxy)-pyridin-3-yl]propionamide and its
derivatives were prepared as described for piperidine-4-carboxylic acid [6-(2-phenyl-
chroman-6-yloxy)pyridine-3-yl]amine in Example 19 a) and b) but replacing N-(tert-
butoxycarbonyl)isonipecotic acid with (S), (R) or (S R)-2-tert-butoxycarbonylamino-
propionic acid.
a) {1-[6-(2-Phenylchroman-6-yloxy)pyridin-3-ylcarbamoyl]ethyl} carbamic
acid tert-butyl ester and its derivatives
{(S)-1-[6-(2-Phenylchroman-6-yloxy)pyridm-3-ylcarbamoyl]ethyl}carbamic
acid tert-butyl ester
1H-NMR (300 MHz; d6-DMSO) ä:10.0 (s, 1H), 8.31 (d, 1H, J 2.7 Hz), 8.03
(dd, 1H, J 2.7, 8.9 Hz), 7.47-7.33 (m, 5H), 6.94 (d, 1H, J 8.9 Hz), 6.87-6.84 (m, 3H),
5.11 (dd, 1H, J 2.0,10.0 Hz), 4.08 (t, 1H, J 7.1 Hz), 3.00-2.91 (m, 1H), 2.75-2.69 (m,
1H), 2.19-2.04 (m, 1H), 2.02-1.97 (m, 1H), 1.38 (s, 9H), 1.26 (d, 3H, J 7.1 Hz).
{(R)-1-[6-(2-Phenylchroman-6-yloxy)pyridin-3-ylcarbanioyl]ethyl}carbamic
acid tert-butyl ester
1H NMR (400 MHz, d6-DMSO) d: 10.05 (br s, 1H), 8.31 (d, 1H, J 2.4 Hz),
8.04 (dd, 1H, J 2.4, 8.9 Hz), 7.39-7.46 (m, 3H), 7.32-7.35 (m, 1H), 7.08 (m, 1H),
6.94 (d, 1H, J 8.9 Hz), 6.81-6.86 (m, 3H), 5.12 (d, 1H, J 10.1 Hz), 4.11 (m, 1H), 2.98
(m, 1H), 2.70 (m, 1H), 2.17 (m, 1H), 2.00 (m, 1H), 1.38 (s, 9H), 1.26 (d, 3H, J 7.1
Hz).
b) 2-Amino-N-[6-(2-phenylchroman-6-yloxy)pyridin-3-yl]propionamide and
derivatives thereof
(S)-2-Amino-N-[6-(2-phenylchroman-6-yloxy)pyridin-3-yl]propionamide
hydrochloride
1H-NMR (400 MHz; d6-DMSO) ä: 10.9 (s, 1H), 8.39 (d, 1H, J 2.5 Hz), 8.05
(dd, 1H, J 2.5, 8.8 Hz), 7.46-7.31 (m, 5H), 7.00 (d, 1H, J 8.8 Hz), 6.88-6.85 (m, 3H),
5.12 (d, 1H, J 8.6 Hz), 4.07 (m, 1H) 3.01-2.92 (m, 1H), 2.75-2.70 (m, 1H), 2.19-2.15

(m, 1H), 2.02-1.97 (m, 1H).
(R)-2-Amino-N-[6-(2-phenylchroman-6-yloxy)pyridin-3-yl]propionamide
hydrochloride
1H NMR (400 MHz, d6-DMSO) ä: 10.78 (br s, 1H), 8.37 (d, 1H, J 2.8 Hz),
8.27 (br s, 2H), 8.03 (dd, 1H, J 2.8, 8.8 Hz), 7.39-7.46 (m, 4H), 7.34-7.35 (m, 1H),
7.00 (d, 1H, J 8.8 Hz), 6.86-6.88 (m, 3H), 5.12 (d, 1H, J 10.5 Hz), 4.04 (m, 1H), 2.96
(m, 1H), 2.72 (m, 1H), 2.17 (m, 1H), 2.01 (m, 1H), 1.47 (d, 3H, J 6.9 Hz).
Example 21.
2-Amino-3-methyl-N-[6-(2-phenylchroman-6-yloxy)pyridin-3-yl]butyramide
and its derivatives
2-Amino-3-methyl-N-[6-(2-phenylchroman-6-yloxy)pyridin-3-yl]butyramide
and its derivatives were prepared as described for piperidine-4-carboxylic acid [6-(2-
phenylchroman-6-yloxy)pyridine-3-yl]amine in Example 19 a) and b) but replacing
N-(tert-butoxycarbonyl)isonipecotic acid with (S), (R) or (S,R)-2-tert-butoxy-
carbonylamino-3-methylbutyric acid.
a) {2-Methyl-1-[6-(2-phenylchroman-6-yloxy)pyridin-3 -ylcarbamoyl]propyl} -
carbamic acid tert-bntyl ester and its derivatives
{(S)-2-Methyl-1-[6-(2-phenylchroman-6-yloxy)pyridm-3-ylcarbamoyl]-
propyl} carbamic acid tert-butyl ester
1H-NMR (300 MHz; d6-DMSO) ä:10.1 (s, 1H), 8.32 (d, 1H, J 2.7 Hz), 8.04
(dd, 1H, J 2.7, 8.8 Hz), 7.47-7.33 (m, 5H), 6.94 (d, 1H, J 8.8 Hz), 6.89-6.84 (m, 3H),
5.11 (dd, 1H, J 2.2,10.0 Hz), 3.91 (t, 1H, J 6.7 Hz), 3.04-2.91 (m, 1H), 2.78-2.69 (m,
1H), 2.21-2.12 (m, 1H), 2.07-1.92 (m, 2H), 1.39 (s, 9H), 0.9 (d, 6H, J 6.7 Hz).
{(R)-2-Methyl-1-[6-(2-phenylchroman-6-yloxy)pyridin-3-ylcarbamoyl]-
propyl} carbamic acid tert-butyl ester
1H NMR (400 MHz, d6-DMSO) ä: 10.11 (br s, 1H), 8.32 (d, 1H, J 2.3 Hz),
8.04 (dd, 1H, J 2.6, 8.8 Hz), 7.39-7.46 (m, 4H), 7.32-7.35 (m, 1H), 6.95 (d, 1H, J 8.8
Hz), 6.85-6.S7(m, 4H), 5.11 (d, 1H, J 8.1 Hz), 3.91 (m, 1H), 2.94 (m, 1H), 2.72 (m,
1H), 2.16 (m, 1H), 1.96-2.03 (m, 2H), 1.39 (s, 9H), 0.90 (d, 6H, J 6.6 Hz).

b)2-Amino-3-methyl-N-[6-(2-phenylchroman-6-yloxy)pyridin-3-yl]butyr-
amide and its derivatives
(S)-2-Amino-3-methyl-N-[6-(2-phenylchroman-6-yloxy)-pyridin-3-yl]butyr-
amide
1H-NMR (300 MHz; d6-DMSO) S: 10.8 (s, 1H), 8.38 (d, 1H, J 2.7 Hz), 8.31
(bs, 3H), 8.05 (dd, 1H, J 2.7, 8.9 Hz), 7.47-7.33 (m, 5H), 7.00 (d, 1H, J 8.9 Hz), 6.98-
6.86 (m, 3H), 5.12 (dd, 1H, J 2.2,10.0 Hz), 3.82-3.78 (m, 1H), 3.08-2.90 (m, 1H),
2.78-2.68 (m, 1H), 2.30-2.10 (m, 2H), 2.07-1.92 (m, 1H), 1.02-0.98 (m, 6H).
(R)-2-Amino-3-methyl-7^-[6-(2-phenylchroman-6-yloxy)pyridin-3-
yl]butyramide hydrochloride
1H NMR (400 MHz, d6-DMSO) ä: 10.97 (br s, 1H), 8.43 (s, 1H), 8.35 (br s,
2H), 8.07 (dd, 1H, J 2.4, 8.7 Hz), 7.39-7.46 (m, 4H), 7.32-7.36 (m, 1H), 7.00 (d, 1H,
J 8.7 Hz), 6.86-6.89 (m, 3H), 5.12 (d, 1H, J 10.2 Hz), 3.83 (m, 1H), 2.97 (m, 1H),
2.73 (m, 1H), 2.17-2.23 (m, 2H), 1.99 (m, 1H), 1.00 (d, 6H, J 6.5 Hz).
Example 22.
(S)-2-Amino-3-methyl-N-(6-{2-[3-(5-nitropyridin-2-yloxyphenylchroman-6-
yloxy}pyridin-3-yl)butyramide hydrochloride
a) ((S)-1-{6-[2-(3-Hydroxyphenyl)chroman-6-yloxy]pyridin-3-ylcarbamoyl} -
2-methyl-propyl)carbamic acid tert-butyl ester
((S)-1-{6-[2-(3-Hydroxyphenyl)chroman-6-yloxy]pyridin-3-ylcarbamoyl}-2-
methyl-propyl)carbamic acid tert-butyl ester was obtained using the same procedure
as described in example 21 a) for {(S)-2-Methyl-1-[6-(2-phenylchroman-6-yloxy)-
pyridin-3-ylcarbamoyl]propyl}carbamic acid tert-butyl ester, but replacing 5-amino-
2-(2-phenylchroman-6-yloxy)pyridine by 3-[6-(5-aminopyridin-2-yloxy)chroman-2-
yl]phenol (described in Example 17). 1H NMR (400 MHz, d6-DMSO) ä: 10.11 (br s,
1H), 9.42 (br s, 1H), 8.32 (s, 1H); 8.04 (dd, 1H, J 2.2, 8.9 Hz), 7.18 (t, 1H, J 8.2 Hz),
6.95 (d, 1H, J 8.9 Hz), 6.90 (d, 1H, J 8.5 Hz), 6.84-6.86 (m, 6H), 6.71 (d, 1H, J 8.2
Hz), 5.03 (d, 1H, J 9.7 Hz), 3.91 (m, 1H), 2.94 (m, 1H), 2.70 (m, 1H), 2.14 (m, 1H),
1.95 (m, 1H), 1.39 (s, 9H), 0.90 (d, 6H, J 6.6 Hz).

b) [(S)-2-Methyl-1 -(6- {2-[3-(5-nitropyridin-2-yloxy)phenyl]chroman-6-
yloxy}pyridin-3-ylcarbamoyl)propyl]carbamic acid tert-butyl ester
[(S)-2-Methyl-1-(6-{2-[3-(5-nitropyridin-2-yloxy)phenyl]chroman-6-
yloxy}pyridin-3-ylcarbamoyl)propyl]carbamic acid tert-butyl ester was prepared as
described for 5-nitro-2-(2-phenylchroman-6-yloxy)pyridine in Example 1 b). 1H
NMR (400 MHz, d6-DMSO) ä:10.14 (br s, 1H), 9.05 (d, 1H, J 2.8 Hz), 8.63 (dd, 1H,
2.8, 9.0 Hz), 8.32 (s, 1H); 8.04 (dd, 1H, J 2.6, 8.7 Hz), 7.52 (t, 1H, J 8.0 Hz), 7.40 (d,
1H, J 7.6 Hz), 7.27-7.31 (m, 2H), 7.21 (dd, 1H, J 0.9, 8.0 Hz), 6.94 (d, 1H, J 8.7 Hz),
6.85-6.91 (m, 4H), 5.17 (d, 1H, J 9.8 Hz), 3.91 (m, 1H), 2.94 (m, 1H), 2.73 (m, 1H),
2.21 (m, 1H), 2.02 (m, 1H), 1.39 (s, 9H), 0.89 (d, 6H, J 6.6 Hz).
c) (S)-2-Amino-3-methyl-N-(6- {2-[3-(5-nitropyridin-2-yloxy)phenyl]-
chroman-6-yloxy}pyridin-3-yl)butyramide hydrochloride
(S)-2-Amino-3-methyl-N-(6-{2-[3-(5-nitropyridin-2-yloxy)phenyl]chroman-6-
yloxy}pyridin-3-yl)butyramide hydrochloride was obtained in the same manner as
described for (S)-2-Amino-3-methyl-N-[6-(2-phenylchroman-6-yloxy)-pyridin-3-
yl]butyramide in Example 21 b). 1H NMR (400 MHz, d6-DMSO) ä: 10.91 (br s,
1H), 9.05 (d, 1H, J 2.7 Hz), 8.64 (dd, 1H, 3.0,9.1 Hz), 8.38 (d, 1H, J 2.5 Hz), 8.32
(br s, 2H), 8.06 (dd, 1H, J 2.5, 8.8 Hz), 7.52 (t, 1H, J 7.9 Hz), 7.40 (d, 1H, J 7.6 Hz),
7.27-7.32 (m, 2H), 7.22 (d, 1H, J 8.1 Hz), 7.00 (d, 1H, J 8.8 Hz), 6.86-6.89 (m, 4H),
5.17 (d, 1H, J 8.8 Hz), 3.81 (m, 1H), 2.96 (m, 1H), 2.73 (m, 1H), 2.20 (m, 1H), 2.00
(m,lH), 0.99-1.01 (m,6H).
Example 23.
Pyrrolidine-2 -carboxylic acid [6-(2-phenylchroman-6-yloxy)pyridin-3-
yl]amide and its derivatives
Pyrrolidine-2 -carboxylic acid [6-(2-phenylchroman-6-yloxy)pyridin-3-
yl] amide and its derivatives were prepared as described for piperidine-4-carboxylic
acid [6-(2-phenylchroman-6-yloxy)pyridine-3-yl]amine in Example 19 a) and b) but
replacing N-(tert-butoxycarbonyl)isonipecotic acid with (S),(R) or (R,S)-pyrrolidine-
1,2-dicarboxylic acid 1-tert-butyl ester and 5-amino-2-(2-phenylchroman-6-yloxy)-
pyridine by an appropriate 5-aminopyridine derivatives.

a) 2-[6-(2-Phenylchroman-6-yloxy)pyridin-3-ylcarbamoyl] pyrrolidine-1-
carboxylic acid tert-butyl ester and its derivatives
2-[6-(2-Phejiylchroman-6-yloxy)pyridin-3-ylcarbamoyl]-(S)-pyrrolidine-1-
carboxylic acid tert-butyl ester
1H NMR (300 MHz, d6-DMSO) ä: 10.1 (s, 1H), 8.31 (d, 1H, J 2.4 Hz), 8.03
(dd, 1H, J 2.4, 8.8 Hz), 7.47-7.33 (m, 5H), 6.95 (d, 1H, J 8.8 Hz), 6.87-6.85 (m, 3H),
5.12 (dd, 1H, J 2.1, 9.9 Hz), 4.25 (m, 1H), 3.5-3.3 (m, 2H), 2.97 (m, 1H), 2.74 (m,
1H), 2.29-2.11 (m, 2H), 2.09-1.73 (m, 4H), 1.40 (s, 3H) 1.29 (m, 6H).
2-[6-(2-Phenylchroman-6-yloxy)pyridin-3-ylcarbanioyl]-(R)-pyrrolidine-1-
carboxylic acid tot-butyl ester.
1H NMR (400 MHz, d6-DMSO) ä: 10.09 (s, 1H), 8.31 (s, 1H), 8.03 (d, 1H, J
8.8 Hz), 7.46-7.33 (m, 5H), 6.95 (d, 1H, J 8.8 Hz), 6.88-6.85 (m, 3H), 5.12 (d, 1H, J
10,0 Hz), 4.18 (m, 1H), 3.42-3.31 (m, 2H), 2.97 (m, 1H), 2.75 (m, 1H), 2.22-2.17 (m,
2H), 2.01-1.80 (m, 4H), 1.40 (s, 3H) 1.29 (m, 6H).
2-[6-(2-(4-Fluorophenyl)chroman-6-yloxy)pyridin-3-ylcarbamoyl]-(S)-
pyrrolidine-1-carboxylic acid tert-butyl ester
1H NMR (400 MHz, d6-DMSO) ä: 10.09 (s, 1H), 8.31 (d, 1H, 2.5 Hz), 8.03
(dd, 1H, J 8.8,2.5 Hz), 7.50 (m, 2H), 7.23 (m, 2H), 6.95 (d, 1H, J 8.8 Hz), 6.88-6.85
(m, 3H), 5.12 (d, 1H, J 8.6 Hz), 4.26 (m, 1H), 3.41-3.34 (m, 2H), 2.96 (m, 1H), 2.73
(m, 1H), 2.22-2.13 (m, 2H), 1.90-1.80 (m, 4H), 1.40 (s, 3H) 1.29 (m, 6H).
2-[6-(2-(3-Fluorophenyl)chroman-6-yloxy)pyridin-3-ylcarbamoyl]-(S)-
pyrrolidine-1-carboxylic acid tert-butyl ester
1H NMR (400 MHz, d6-DMSO) ä: 10.09 (s, 1H), 8.31 (s, 1H), 8.03 (d, 1H, J
8.7 Hz), 7.46 (m, 1H), 7.31-7.27 (m, 2H), 7.17 (m, 1H), 6.95 (d, 1H, J 8.7 Hz), 6.87-
6.85 (m, 3H), 5.16 (d, 1H, J 8.6 Hz), 4.17 (m, 1H), 3.41-3.34 (m, 2H), 2.95 (m, 1H),
2.72 (m, 1H), 2.22-2.18 (m, 2H), 1.95-1.79 (m, 4H), 1.40 (s, 3H) 1.29 (m, 6H).
2-[6-(2-(2-Fluorophenyl)cbxoman-6-yloxy)pyridin-3-ylcarbamoyl]-(S)-
pyrrolidine-1-carboxylic acid tert-butyl ester
1H NMR (400 MHz, d6-DMSO) ä: 10.09 (s, 1H), 8.31 (s, 1H), 8.03 (d, 1H, J
8.7 Hz), 7.55 (m, 1H), 7.41 (m, 1H), 7.29-7.23 (m, 2H), 6.96 (d, 1H, J 8.7 Hz), 6.90-
6.85 (m, 3H), 5.34 (d, 1H, J 9.6 Hz), 4.17 (m, 1H), 3.44-3.35 (m, 2H), 3.00 (m, 1H),

2.75 (m, 1H), 2.17 (m, 1H) 2.05 (m, 1H), 1.90-1.77 (m, 4H), 1.40 (s, 3H) 1.29 (m,
6H).
b) Pyrrolidine-2-carboxylic acid [6-(2-phenylchroman-6-yloxy)pyridin-3-
yl]amide and its derivatives
(S)-Pyrrolidine-2- carboxylic acid [6-(2-phenylchroman-6-yloxy)pyridin-3-
yl]amide hydrochloride
1H NMR (300 MHz, d6-DMSO) ä:10.9 (s, 1H), 8.38 (d, 1H, J 2.7 Hz), 8.03
(dd, 1H, J 2.7, 8.8 Hz), 7.47-7.33 (m, 5H), 7.00 (d, 1H, J 8.8 Hz), 6.99-6.85 (m, 3H),
5.12 (dd, 1H, 2.2,10.1 Hz), 3.32-3.20 (m, 2H), 2.97 (m, 1H), 2.74 (m, 1H), 2.42 (m,
1H), 2.15 (m, 1H), 2.08-1.90 (m, 4H).
(R)-Pyrrolidine-2-carboxylic acid [6-(2-phenylchroman-6-yloxy)pyridin-3-
yl] amide hydrochloride
1HNMR(400 MHz, d6-DMSO) ä:11.11 (s, 1H), 10.03 (bs, 1H), 8.71 (bs,
1H), 8.40 (s, 1H), 8.06 (d, 1H, J 8.8 Hz), 7.46-7.32 (m, 5H), 7.00 (d, 1H, J 8.8 Hz),
6.88-6.86 (m, 3H), 5.12 (d, 1H, 9.9 Hz), 4.39 (m, 1H), 3.27-3.20 (m, 2H), 2.98 (m,
1H), 2.73 (m, 1H), 2.44 (m, 1H), 2.17 (m, 1H), 2.04-1.93 (m, 4H).
(S)-Pyrrolidine-2-carboxylic acid [6-(2-(4-fluoropheny)lchroman-6-
yloxy)pyridin-3-yl]amide hydrochloride
1H NMR (400 MHz, d6-DMSO) ä: 10.92 (s, 1H), 9.72 (bs, 1H), 8.70 (bs, 1H),
8.38 (d, 1H, J 2.5 Hz), 8.03 (dd, 1H, J 8.9,2.5 Hz), 7.50 (m, 2H), 7.23 (m, 2H), 7.00 -
(d, 1H, J 8.9 Hz), 6.89-6.86 (m, 3H), 5.12 (d, 1H, 10.1 Hz), 4.35 (m, 1H), 3.29-3.24
(m, 2H), 2.97 (m, 1H), 2.73 (m, 1H), 2.42 (m, 1H), 2.16 (m, 1H), 2.03-1.91 (in, 4H).
(S)-Pyrrolidine-2-carboxylic acid [6-(2-(3-fluoro)phenylchroman-6-
yloxy)pyridin-3-yl]amide hydrochloride
1H NMR (400 MHz, d6-DMSO) ä: 10.97 (s, 1H), 9.79 (bs, 1H), 8.70 (bs, 1H),
8.38 (d, 1H, J 2.6 Hz), 8.04 (dd, 1H, J 8.9,2.6 Hz), 7.46 (m, 1H), 7.31-7.27 (m, 2H),
7.17 (m, 1H), 7.01 (d, 1H, J 8.9 Hz), 6.90-6.85 (m, 3H), 5.16 (d, 1H, 8.4 Hz), 4.37
(m, 1H), 3.29-3.24 (m, 2H), 2.96 (m, 1H), 2.72 (m, 1H), 2.42 (m, 1H), 2.20 (m, 1H),
2.03-1.91 (m,4H).

(S)-Pyrrolidine-2-carboxylic acid [6-(2-(2-fluoropheny)lchroman-6-
yloxy)pyridin-3-yl] amide hydrochloride
1H NMR (400 MHz, d6-DMSO) ä:10.90 (s, 1H), 9.70 (bs, 1H), 8.71 (bs, 1H),
8.38 (d, 1H, J 2.7 Hz), 8.03 (dd, 1H, J 8.9,2.5 Hz), 7.55 (m, 1H), 7.42 (m, 1H), 7.29-
7.23 (m, 2H), 7.01 (d, 1H, J 8.9 Hz), 6.90-6.86 (m, 3H), 5.34 (d, 1H, 8.6 Hz), 4.37
(m, 1H), 3.29-3.24 (m, 2H), 2.99 (m, 1H), 2.76 (m, 1H), 2.40 (m, 1H), 2.17 (m, 1H),
2.07-1.91 (m,4H).
Example 24.
(S)-Pyrrolidine-2- carboxylic acid (6-{2-[3-(5-nitropyridin-2-yloxy)phenyl]-
chroman-6-yloxy}pyridin-3-yl)amide
(S)-Pyrrolidine-2-carboxylic acid (6-{2-[3-(5-nitropyridin-2-yloxy)phenyl]-
chroman-6-yloxy}pyridin-3-yl)amide was prepared as described for (S)-2-amino-3-
methyl-N-(6-{2-[3-(5-nitroopyridin-2-yloxy-phenyl-chroman-6-yloxy}pyridin-3-yl)-
butyramide in Example 22 steps a)-c) starting with (S)-pyrrolidine-l,2-dicarboxylic
acid 1-tert-butyl ester.
a) 2- {6-[2-(3-Hydroxyphenyl)cbroman-6-yloxy]pyridin-3-ylcarbamoyl} -(S)-
pyrrolidine-1-carboxylic acid tert-butyl ester
1H NMR (400 MHz, d6-DMSO) ä: 10.09 (s, 1H), 9.43 (s, 1H), 8.31 (s, 1H),
8.03 (d, 1H, J 8.9 Hz), 7.18 (t, 1H, J 8.0 Hz), 6.95 (d, 1H, J 8.9 Hz), 6.87-6.84 (m,
5H), 6.71, (d, 1H, J 7.2 Hz), 5.03 (d, 1H, J 8.2 Hz), 4.19 (m, 1H), 3.42-3.35 (m, 2H),
2.93 (m, 1H), 2.69 (m, 1H), 2.21-2.12 (m, 2H), 1.95-1.79 (m, 4H), 1.40 (s, 3H) 1.28
(m, 6H).
b)2-(6-{2-[3-(5-Nitropyridin-2-yloxy)phenyl]chroman-6-yloxy}pyridin-3-
ylcarbamoyl)-(S)-pyrrolidine-1-carboxylic acid tert-butyl ester
1H NMR (400 MHz, d6-DMSO) ä: 10.09 (s, 1H), 9.05 (d, 1H, J 2.9 Hz), 8.63
(dd, 1H, J 8.9,2.9 Hz), 8.31 (s, 1H), 8.03 (d, 1H, J 8.8 Hz), 7.52 (t, 1H, J 7.8 Hz),
7.40 (d, 1H, J 7.8 Hz), 7.31-7.27 (m, 2H) 7.21 (dd, 1H, J 7.8,1.7 Hz), 6.95 (d, 1H, J
8.9 Hz), 6.87-6.85 (m, 3H), 5.17 (d, 1H, J 9.3 Hz), 4.18 (m, 1H), 3.42-3.34 (m, 2H),
2.95 (m, 1H), 2.73 (m, 1H), 2.20 (m, 1H), 1.97 (m, 1H), 1.89-1.79 (m, 4H), 1.40 (s,
3H)1.28(m, 6H).

c) (S)-Pyrrolidine-2 -carboxylic acid (6-{2-[3-(5-nitropyridin-2-yloxy)-
phenyl]chroman-6-yloxy}pyridin-3-yl)amide hydrochloride
1H NMR (400 MHz, d6-DMSO) ä: 10.89 (s, 1H), 9.69 (bs, 1H), 9.05 (d, 1H, J
2.8 Hz), 8.71 (bs, 1H), 8.64 (dd, 1H, J 9.0,2.8 Hz), 8.37 (d, 1H, J 2.7 Hz), 8.04 (dd,
1H, J 8.8, 2.7 Hz), 7.52 (t, 1H, J 7.9 Hz), 7.40 (d, 1H, J 7.9 Hz), 7.31-7.27 (m, 2H),
7.21 (d, 1H, J 8.8 Hz), 7.00 (d, 1H, J 9.0 Hz), 6.88-6.83 (m, 3H), 5.17 (d, 1H, 8.4
Hz), 4.35 (m, 1H), 3.29-3.24 (m, 2H), 2.95 (m, 1H), 2.73 (m, 1H), 2.40 (m, 1H), 2.22
(m,lH), 2.04-1.91 (m,4H).
Example 25.
(S)-2-Amino-3-hydroxy-N-[6-(2-phenylchroman-6-yloxy)pyridin-3-
yl]propionamide hydrochloride
(S)-2-Amino-3-hydroxy-N-[6-(2-phenylcliroman-6-yloxy)pyridin-3-yl]-
propionamide hydrochloride was prepared as described for piperidine-4-carboxylic
acid [6-(2-phenylchroman-6-yloxy)pyridine-3-yl]amine in Example 19 a) and b) but
replacing N-(tert-butoxycarbonyl)isonipecotic acid with (S)-2-tert-butoxycarbonyl-
amino-3-hydroxypropionic acid.
a) {(S)-2-Hydroxy-1-[6-(2-phenylchroman-6-yloxy)pyridin-3-ylcarbamoyl]-
ethyl}carbamic acid tert-butyl ester
1H NMR (400 MHz, d6-DMSO) ä: 10.07 (br s, 1H), 8.33 (d, 1H, J 2.4 Hz),
8.05 (dd, 1H, J 2.4,9.0 Hz), 7.39-7.47 (m, 5H), 7.32-7.36 (m, 1H), 6.94 (d, 1H, J 9.0
Hz), 6.85-6.86 (m, 2H), 6.77 (br d, 1H, J 7.3 Hz), 5.12 (d, 1H, J 10.0 Hz), 4.95 (br s,
1H), 4.14 (m, 1H), 3.63 (br s, 2H), 2.95 (m, 1H), 2.70 (m, 1H), 2.18 (m, 1H), 2.01
(m, 1H), 1.39 (s,9H).
b) (S)-2-Amino-3-hydroxy-N-[6-(2-phenylchroman-6-yloxy)pyridin-3-
yl]propionamide hydrochloride
1H NMR (400 MHz, CD3OD) ä: 8.63 (d, 1H, J 2.4 Hz), 8.22 (dd, 1H, J 2.4,
9.1 Hz), 7.36-7.45 (m, 4H), 7.29-7.33 (m, 1H), 7.05 (d, 1H, J 9.1 Hz), 6.94-6.97 (m,
3H), 5.11 (d, 1H, J 10.0 Hz), 4.15 (m, 1H), 3.97-4.06 (m, 2H), 3.03 (m, 1H), 2.79 (m,
1H), 2.24 (m, 1H), 2.07 (m, 1H).
Example 26.

(S)-2-Amino-4-[6-(2-phenylchroman-6-yloxy)pyridin-3-ylcarbamoyl]butyric
acid
(S)-2-Amino-4-[6-(2-phenylchroman-6-yloxy)pyridin-3-ylcarbamoyl]butyric
acid was prepared as described for piperidine-4-carboxylic acid [6-(2-phenyl-
chroman-6-yloxy)pyridine-3-yl]amine in Example 19 a) and b) but replacing N-(tert-
butoxycarbonyl)isonipecotic acid with (S)-2-carboxyaminopentanedioic acid 1-tert-
butyl ester.
a) (S)-2-tert-Butoxycarbonylamino-4-[6-(2-phenylchroman-6-yloxy)-
pyridine-3-ylcarbamoyl]butyric acid tert-butyl ester
1H NMR (400 MHz, d6-DMSO) ä:10.01 (br s, 1H), 8.28 (d, 1H, J 2.4 Hz),
8.01 (dd, 1H, J 2.4, 8.8 Hz), 7.39-7.46 (m, 4H), 7.32-7.35 (m, 1H), 7.14 (br d, 1H, J
7.7 Hz), 6.93 (d, 1H, J 8.8 Hz), 6.84-6.86 (m, 3H), 5.12 (d, 1H, J 10.0 Hz), 3.84 (m,
1H), 2.97 (m, 1H), 2.71 (m, 1H), 2.38-2.42 (m, 2H), 2.16 (m, 1H), 1.96-2.04 (m,
2H), 1.81 (m, 1H), 1.40 (s, 9H), 1.38 (s, 9H).
b) (S)-2-Amino-4-[6-(2-phenylchroman-6-yloxy)pyridin-3-ylcarbamoyl]-
butyric acid hydrochloride
1H NMR (400 MHz, d6-DMSO) ä:10.28 (br s, 1H), 8.41 (br s, 2H), 8.33 (d,
1H, J 2.4 Hz), 8.03 (dd, 1H, J 2.4, 8.8 Hz), 7.39-7.46 (m, 4H), 7.32-7.36 (m, 1H),
6.94 (d, 1H, J 8.8 Hz), 6.85-6.86 (m, 3H), 5.12 (d, 1H, J 10.1 Hz), 3.96 (m, 1H), 2.97
(m, 1H), 2.72 (m, 1H), 2.50-2.65 (m, 2H), 2.12-2.19 (m, 3H), 2.00 (m, 1H).
Example 27.
(S)-4-Amino-4-[6-(2-phenylchroman-6-yloxy)pyridin-3-ylcarbamoyl]butyric
acid
(S)-4-Amino-4-[6-(2-phenylchroman-6-yloxy)pyridin-3-ylcarbamoyl]butyric
acid was prepared as described for piperidine-4-carboxylic acid [6-(2-phenyl-
chroman-6-yloxy)pyridine-3-yl]amine in Example 19 a) and b) but replacing N-(tert-
butoxycarbonyl)isonipecotic acid with (S)-2-carboxyaminopentanedioic acid 5-tert-
butyl ester.
a)(S)-4-tert-Butoxycarbonylamino-4-[6-(2-phenylchroman-6-yloxy)pyridin-
3-ylcarbamoyl]butyric acid tert-butyl ester

1H NMR (400 MHz, d6-DMSO) ä: 10.09 (br s, 1H), 8.32 (d, 1H, J 2.4 Hz),
8.04 (dd, 1H, J 2.4, 8.8 Hz), 7.39-7.47 (m, 4H), 7.32-7.35 (m, 1H), 7.06 (br d, 1H, J
7.7 Hz), 6.94 (d, 1H, J 8.8 Hz), 6.85-6.86 (m, 3H), 5.12 (d, 1H, J 10.0 Hz), 4.07 (m,
1H), 2.95 (m, 1H), 2.72 (m, 1H), 2.26-2.27 (m, 2H), 2.17 (m, 1H), 1.92-2.04 (m,
2H), 1.75 (m, 1H), 1.38 (br s, 18H).
b)(S)-4-Amino-4-[6-(2-phenylchroman-6-yloxy)pyridin-3-ylcarbamoyl]-
butyric acid hydrochloride
1H NMR (400 MHz, MeOD) 5: 8.54 (d, 1H, J 2.8 Hz), 8.15 (dd, 1H, J 2.8, 9.0
Hz), 7.43-7.45 (m, 2H), 7.36-7.40 (m, 2H), 7.29-7.33 (m, 1H), 7.01 (d, 1H, J 9.0 Hz),
6.93-6.94 (m, 3H), 5.11 (d, 1H, J 10.0 Hz), 4.11 (m, 1H), 3.01 (m, 1H), 2.79 (m, 1H),
2.56 (m, 2H), 2.22-2.30 (m, 3H), 2.03-2.09 (m, 1H).
Example 28.
(S)-3-Amino-N-[6-(2-phenylchroman-6-yloxy)pyridin-3-yl]succinamic acid
S)-3-Amino-N-[6-(2-phenylchroman-6-yloxy)pyridin-3-yl]succinamic acid
was prepared as described for piperidine-4-carboxylic acid [6-(2-phenylchroman-6-
yloxy)pyridine-3-yl]amine in Example 19 a) and b) but replacing N-(tert-butoxy-
carbonyl)isonipecotic acid with (S)-2-tert-butoxycarbonylaminosuccinic acid 4-tert-
butyl ester.
a)(S)-3-tert-Butoxycarbonylamino-N-[6-(2-phenylchroman-6-yloxy)pyridin-
3-yl]succinamic acid tert-butyl ester
1H-NMR (400 MHz; d6-0DMSO) ä: 10.12 (s, 1H), 8.31 (d, 1H, J 2.4 Hz), 8.02
(dd, 1H, J 8.9,2.4 Hz), 7.46-7.39 (m, 5H), 7.34 (d, 1H, J 7.1 Hz), 6.94 (d, 1H, J 8.9
Hz), 6.87-6.84 (m, 3H), 5.12 (d, 1H, J 10.0 Hz), 4.44 (m, 1H), 2.97 (m, 1H), 2.74-
2.65 (m, 2H), 2.50 (m, 1H), 2.16 (m, 1H), 2.00 (m, 1H), 1.38 (s, 18H).
b)(S)-3-Amino-N-[6-(2-phenylchroman-6-yloxy)pyridin-3-yl]succinamic acid
Hydrochloride
1H-NMR (400 MHz; d6-DMSO) ä: 10.83 (s, 1H), 8.41 (bs, 3H), 8.36 (d, 1H, J
2.4 Hz), 8.03 (dd, 1H, J 8.9,2.4 Hz), 7.47-7.32 (m, 5H), 7.00 (d, 1H, J 8.9 Hz), 6.88-
6.85 (m, 3H), 5.12 (d, 1H, J 10.1 Hz), 4.25 (m, 1H), 3.03-2.87 (m, 3H), 2.73 (m, 1H),
2.17 (m, 1H), 2.00 (m, 1H).

Example 29.
(S)-2-Amino-N-[6-(2-phenylchroman-6-yloxy)pyridin-3-yl]succinamic cacid
(S)-2-Amino-N-[6-(2-phenylchroman-6-yloxy)pyridin-3-yl]succinamic acid
Hydrochloride was prepared as described for piperidine-4-carboxylic acid [6-(2-
phenylchroman-6-yloxy)pyridine-3-yl]amine in Example 19 a) and b) but replacing
N-(tert-butoxycarbonyl)isonipecotic acid with (S)-2-tert butoxycarbonylamino-
succinic acid 1-tert-butyl ester.
a) (S)-2-tert-Butoxycarbonylarnino-N-[6-(2-phenylchroman-6-yloxy)pyridin-
3-yl]succinamic acid tert-butyl ester
1H-NMR (400 MHz; d6-DMSO) ä:10.10 (s, 1H), 8.29 (s, 1H), 8.15 (d, 1H, J
8.9 Hz), 7.47-7.39 (m, 5H), 7.34 (d, 1H, J 8.4 Hz), 6.94 (d, 1H, J 8.9 Hz), 6.86-6.84
(m, 3H), 5.12 (d, 1H, J 10.0 Hz), 4.29 (m, 1H), 2.97 (m, 1H), 2.82-2.76 (m, 2H), 2.61
(m, 1H), 2.17 (m, 1H), 2.01 (m, 1H), 1.38 (s, 12H), 1.36 (s, 6H).
b) (S)-2-Amino-N-[6-(2-phenylchroman-6-yloxy)pyridin-3-yl]succinamic acid
Hydrochloride
1H-NMR (400 MHz; d6-DMSO) ä:13.7 (bs, 1H), 10.52 (s, 1H), 8.36-8.32 (m,
4H), 8.01 (d, 1H, J 8.7Hz), 7.46-7.32 (m, 5H), 6.96 (d, 1H, J 8.7 Hz), 6.87-6.85 (m,
3H), 5.12 1H), 2.00 (m, 1H).
Example 30.
N- {6-[2-(4-fluorophenyl)chroman-6-yloxy]pyridin-3-yl} -4-(4-methyl-
piperazin-1-ylmethyl)benzamide
a) 4-Chloromethylbenzoic acid methyl ester
4-Chloromethylbenzoic acid (2.0 g) was dissolved in 300 ml of methanol and
0.5 ml concentrated sulphuric acid was added. The mixture was stirred at room
temperature for eight days. Methanol was evaporated and the residue was dissolved
in ethyl acetate. The organic layer was washed with saturated NaHCO3-solution,
dried with Na2SO4 and evaporated to yield 4-chloromethylbenzoic acid methyl ester.
1H NMR (300 MHz, d6-DMSO) ä: 3.86 (s, 3H), 4.84 (s, 2H), 7.59 (d, 2H, J
8.2 Hz), 7.97 (d, 2H, J 8.2 Hz).

b) 4-(4-Methylpiperazin-1-ylmethyl)benzoic acid methyl ester
4-Chloromethylbenzoic acid methyl ester (1.66 g), 1-methylpiperazine (1.8 g)
and sodium iodide (0.67 g) were added into acetone (50 ml). The reaction mixture
was stirred at 60 °C for 9 hours. More 1-methylpiperazine (0.9 g) and sodium iodide
(0.34 g) were added and after stirring additional 1 1/2 hours at 60 °C the reaction
mixture was allowed to cool into room temperature. The mixture was filtered and
acetone was evaporated. The residue was dissolved in ethyl acetate and washed with
water. The solvent was dried with NaSO4 and evaporated to yield 4-(4-methyl-
piperazin-1-yhnethyl)benzoic acid methyl ester. 1H NMR (300 MHz, d6-DMSO) ä:
2.18 (s, 3H), 2.37 (bs, 8H), 3.53 (s, 2H), 3.84 (s, 3H), 7.44 (d, 2H, J 8.1 Hz), 7.91 (d,
2H, J 8.2 Hz).
HCl-salt of 4-(4-Methylpiperazin-1-ylmethyl)benzoic acid methyl ester 4-(4-
Methylpiperazin-1-ylmethyl)benzoic acid methyl ester was dissolved in ethyl acetate
and 1 M HCl-diethyl ether solution was added. The mixture was stirred for 1 hour
and precipitated HCl-salt was filtered and washed with diethyl ether. 1H NMR (300
MHz, d6-DMSO) ä: 2.78 (s, 3H), 3.10-3.75 (m, 8H), 3.87 (s, 3H), 4.35 (bs, 2H), 7.77
(d, 2H, J 7.5 Hz), 8.00 (d, 2H, J 8.1 Hz).
c) 4-(4-Methylpiperazin-1-ylmethyl)benzoic acid
HCl-salt of 4-(4-methylpiperazin-1-ylmethyl)benzoic acid methyl ester (1.25
g) was dissolved in potassium hydroxide-methanol solution (0.93 g KOH in 15 ml
methanol). Water (0.75 ml) was added and the mixture was refluxed for 1 hour. The
reaction mixture was allowed to cool into room temperature and the pH was tuned to
6 with 2 M HC1. The solvent was evaporated and the residue was dried under
vacuum. The residue contained 4-(4-methylpiperazin-1-ylmethyl)benzoic acid and
inorganic salts. It was used further without purification and the yield of title
compound was assumed to be 100%. 1H NMR (400 MHz, d6-DMSO) ä: 2.27 (s, 3H),
2.44 (bs, 2H), 3.18-3.95 (m, 8H), 7.41 (d, 2H, J 8.0 Hz), 7.89 (d, 2H, J 8.1 Hz).
d) N- {6-[2-(4-fluorophenyl)chroman-6-yloxy]pyridin-3-yl}-4-(4-methyl-
piperazin-1-ylrnethyl)benzamide

4-(4-Methylpiperazin-1-ylmethyl)benzoic acid (ca 0.19 g), 6-[2-(4-fiuoro-
phenyl)-chroman-6-yloxy]pyridin-3-ylamine (0.18 g) and l-(3-dimethylamino-
propyl)-3-ethylcarbodiimide hydrochloride (0.12 g) were added into dichloromethane
(12 ml). The mixture was stirred at room temperature and after 4 hours more 4-(4-
methylpiperazin-1-ylmethyl)-benzoic acid (ca 0.11 g) and l-(3-dimethyl-amino-
propyl)-3-ethylcarbodiimide hydrochloride (0.0.46 g) were added. Stirring was
continued for additional 3 hours. Water and dichloromethane were added and organic
and water phases were separated. Water phase was extracted with dichloromethane.
The product was purified by column chromatography using dichloromethane -
methanol (9:1) as an eluent to give N-{6-[2-(4-fluorophenyl)chroman-6-yloxy]-
pyridin-3-yl}-4-(4-methylpiperazin-1-yhnethyl)benzamide. 1H NMR (300 MHz, d6-
DMSO) ä:1.90-2.08 (m, 1H), 2.11-2.21 (m, 1H), 2.18 (s, 3H), 2.38 (bs, 8H), 2.68-
2.79 (m, 1H), 2.91-3.05 (m, 1H), 3.54 (s, 2H), 5.13 (dd, 1H, J 2.0,10.1 Hz), 6.86 (d,
2H, J 1.2 Hz), 6.90 (s, 1H), 6.98 (d,1H, J 8.8 Hz), 7.19-7.27 (m, 2H), 7.43-7.54 (m,
4H), 7.92 (d, 2H, J 8.2 Hz), 8.18 (dd, 1H, J 2.7, 8.9 Hz), 8.48 (d, 1H, J 2.7 Hz), 10.31
(s, 1H).
Example 31.
N-[6-(2-Phenylchroman-6-yloxy)pyridin-3-yl]succinamic acid
6-(2-Phenylchroman-6-yloxy)pyridin-3-ylamine (example 35) (270 mg) and
succinic acid (151 mg) were dissolved in dichloromethane (16 ml). l-(3-Dimethyl-
aminopropyl)-3-ethylcarbodiimide hydrochloride (245 mg) was added into a reaction
mixture and it was stirred at room temperature for 3 hours. Water was added and the
mixture was filtered. The precipitate was collected and treated with methanol and
filtered again. The methanol-filtrate was evaborated to dryness to yield N-[6-(2-
phenylchroman-6-yloxy)pyridin-3-yl]succinamic acid. 1H NMR (400 MHz, d6-
DMSO) ä:12.0 (bs, 1H), 10.08 (s, 1H), 8.29 (d, 1H, J 2.4 Hz), 8.01 (dd, 1H, J 8.8,
2.4 Hz), 7.46-7.32 (m, 5H), 6.93 (d, 1H, J 8.8 Hz), 6.86-6.84 (m, 3H), 5.11 (d, 1H, J
8.6 Hz), 2.96 (m, 1H), 2.70 (m, 1H), 2.56-2.52 (m, 4H), 2.16 (m, 1H), 2.00 (m, 1H).
Example 32.
2-Chloro-N-[6-(2-phenylchroman-6-yloxy)pyridin-3-yl]acetarnide
To a cooled solution of 5-amino-2-(2-phenylchroman-6-yloxy)-pyridine (500
mg) in 7.5 ml of methylene chloride was added triethyl amine (437 ìl) and

chloracetyl chloride (163 ìl). The reaction mixture was stirred at room temperature
for 3 hours and quenched with addition of water. Water layer was acidified and
extracted with methylene chloride. The combined organic layers were dried with
Na2SO4 and evaporated. The 2-chloro-N-[6-(2-phenyl-chroman-6-yloxy)-pyridin-3-
yl]-acetamide was purified by column chromatography using 10% methanol in
methylene chloride as an eluant. 1H-NMR (400 MHz; d6-DMSO) ä: 10.4 (s, 1H),
8.30 (d, 1H, J 2.7 Hz), 8.03 (dd, 1H, J 2.7, 8.8 Hz), 7.47-7.32 (m, 5H), 6.97 (d, 1H, J
8.8 Hz), 6.88-6.85 (m, 3H), 5.12 (dd, 1H, J 2.10,10.1 Hz), 4.27 (s, 2H), 2.97-2.92
(m, 1H), 2.76-2.70 (m, 1H), 2.19-2.14 (m, 1H), 2.02-1.97 (m, 1H).
2-Chloro-N-{6-[2-(4-fluorophenyl)chroman-6-yloxy]pyridin-3-yl}acetamide
was obtained using the same procedure as described above for 2-chloro-N-[6-(2-
phenylchroman-6-yloxy)pyridin-3-yl]acetamide but replacing 5-amino-2-(2-
phenylchroman-6-yloxy)pyridine by 5-amino-2-(2-(4-fluorophenylchroman-6-
yloxy)pyridine.1H-NMR (400 MHz; d6-DMSO) ä: 10.4 (s, 1H), 8.29 (d, 1H, J 2.7
Hz), 8.02 (dd, 1H, J 2.7, 8.8 Hz), 7.52-7.48 (m, 2H), 7.25-7.20 (m, 2H), 6.97 (d, 1H,
J 8.8 Hz), 6.88-6.84 (m, 3H), 5.12 (dd, 1H, J 1.90,10.2 Hz), 4.27 (s, 2H), 2.98-2.92
(m, 1H), 2.76-2.69 (m, 1H), 2.18-2.13 (m, 1H), 2.01-1.96 (m, 1H),
Similarly using the same procedure as described above for 2-chloro-N-[6-(2-
phenylchroman-6-yloxy)pyridin-3-yl]acetamide but replacing 5-amino-2-(2-
phenylchroman-6-yloxy)pyridine by an appropriate pyridin-3-ylamine-derivative
listed in Example 18, there can be obtained:
2-chloro-N-{6-[2-(3-fluorophenyl)chroman-6-yloxy]-pyridin-3-yl}acetamide,
2-chloro-N-{6-[2-(2-fluorophenyl)chroman-6-yloxy]-pyridin-3-yl}acetamide,
2-chloro-N-{6-[2-(2,3-difluorophenyl)chroman-6-yloxy]-pyridin-3-
yl}acetamide,
2-chloro-N-{6-[2-(2,4-difluorophenyl)chroman-6-yloxy]-pyridin-3-
yl}acetamide,
2-chloro-N-{6-[2-(2,5-difluorophenyl)chroman-6-yloxy]-pyridin-3-
yl}acetamide,
2-chloro-N-{6-[2-(2,6-difluorophenyl)chroman-6-yloxy]-pyridin-3-
yl}acetamide,
2-chloro-N-{6-[2-(3,4-difluorophenyl)chroman-6-yloxy]-pyridin-3-
yl}acetamide,

2-chloro-N-{6-[2-(3,5-difluorophenyI)chroman-6-yloxy]-pyridin-3-
yl}acetamide,
2-chloro-N-{6-[2-(2-trifluoromethylphenyl)chroman-6-yloxy]-pyridin-3-
yl}acetamide,
2-chloro-N-{6-[2-(4-trifluoromethylphenyl)chroman-6-yloxy]-pyridin-3 -
yl}acetamide,
2-chloro-N-{6-[2-(3-chloro-4-fluorophenyl)chroman-6-yloxy]-pyridin-3-
yl}acetamide,
2-chloro-N-{6-[2-(2-chlorophenyl)chroman-6-yloxy]-pyridin-3-yl}acetamide,
2-chloro-N-{6-[2-(3-chlorophenyl)chroman-6-yloxy]-pyridin-3-yl}acetamide,
2-chloro-N-{6-[2-(2,4-dichlorophenyl)chroman-6-yloxy]-pyridin-3-
yl}acetamide,
2-chloro-N-{6-[2-(3-bromophenyl)chroman-6-yloxy]-pyridin-3-yl}acetamide,
2-chloro-N-{6-[2-(4-ethylphenyl)chroman-6-yloxy]-pyridin-3-yl}acetamide,
2-chloro-N-{6-t2-(3-methoxyphenyl)chroman-6-yloxy]-pyridin-3-
yl}acetamide,
2-chloro-N-[6-(3-methyl-2-phenylchroman-6-yloxy)-pyridin-3-yl]acetamide,
2-chloro-N-[6-(2-phenylchroman-7-yloxy)-pyridin-3-yl]acetamide,
2-chloro-N-[6-(4-oxo-2-phenylchroman-6-yIoxy)pyridin-3-yl]acetamide,
2-chloro-N-[6-(4-oxo-2-phenylchroman-7-yloxy)pyridin-3-yl]acetamide,
2-chloro-N-[6-(3-methyl-4-oxo-2-phenylchroman-6-yloxy)pyridin-3-
yl]acetamide,
2-chloro-N-[6-(2-phenyl-2,3-dihydrobenzo[1,4]dioxin-6-yloxy)pyridin-3-
yl]acetamide,
2-chloro-N-[6-(6-phenyl-5,6,7,8-tetrahydronaphthalen-2-yloxy)pyridin-3-
yl]acetamide,
2-chloro-N-[6-(5-oxo-6-phenyl-5,6,73-tetrahydronaphthalen-2-yloxy)pyridin-
3-yl]acetamide
2-chloro-N-[6-(2-phenyl-23-dihydrobenzo[1,4]oxathin-6-yloxy)pyridin-3-
yl]acetamide,
2-chloro-N-{6-[3-(3-fluorophenyl)chroman-7-yloxy]pyridin-3-yl}acetamide,
2-chloro-N-[6-(3-phenylchroman-7-yloxy)pyridin-3-yl]acetamide,
2-chloro-N-[6-(4-oxo-2-phenylchromen-6-yloxy)pyridin-3-yl]acetamide,
2-chloro-N-[6-(2-phenylindan-5-yloxy)pyridin-3-yl]acetamide,
respectively.

Example 33.
2-Amino-N-[6-(2-phenylchroman-6-yloxy)pyridin-3-yl]acetamide
a) 2-Azido-N-[6-(2-phenylchroman-6-yloxy)pyridin-3-yl]acetamide
2-Chloro-N-[6-(2-phenylchroman-6-yloxy)pyridin-3-yl]acetainide (500 mg),
sodium azide (445 mg) and acetonitrile were mixed. Reaction mixture was refluxed
for 3 hours. After cooling into room temperature, the reaction mixture was filtered
and the filtrate was evaporated to the dryness. 1H-NMR (400 MHz; d6-DMSO) ä:
10.3 (s, 1H), 8.29 (d, 1H, J 2.7 Hz), 8.03 (dd, 1H, J 2.7, 8.8 Hz), 7.47-7.33 (m, 5H),
6.96 (d, 1H, J 8.8 Hz), 6.88-6.85 (m, 3H), 5.12 (dd, 1H, J 2.20,10.1 Hz), 4.07 (s,
2H), 3.00-2.92 (m, 1H), 2.76-2.70 (m, 1H), 2.19-2.14 (m, 1H), 2.02-1.97 (m, 1H).
Similarly there was obtained:
2-azido-N-{6-[2-(4-fluorophenyl)chroman-6-yloxy]-pyridin-3-yl}-acetamide
1H-NMR (400 MHz; d6-DMSO) ä:10.3 (s, 1H), 8.30 (d, 1H, J 2.7 Hz), 8.03 (dd, 1H,
J 2.7, 8.8 Hz), 7.53-7.47 (m, 2H), 7.26-7.19 (m, 2H), 6.96 (d, 1H, J 8.8 Hz), 6.88-
6.84 (m, 3H), 5.12 (dd, 1H, J 2.1,10.1 Hz), 4.07 (s, 2H), 3.00-2.92 (m, 1H), 2.76-
2.70 (m, 1H), 2.19-2.14 (m, 1H), 2.02-1.97 (m, 1H).
b)2-Amino-N-[6-(2-phenylchroman-6-yloxy)pyridin-3-yl]acetamide
2-Azido-N-[6-(2-phenylchroman-6-yloxy)pyridin-3-yl]acetamide (500 mg)
was dissolved in methanol (100 ml) and 10 % palladium on charcoal (125 mg) was
added. Starting material was hydrogenated for 5 hours at room temperature to give 2-
amino-N-[6-(2-phenylchroman-6-yloxy)pyridin-3-yl]acetamide. The product was
isolated as its hydrochloride salt. 1H-NMR (400 MHz; d6-DMSO) ä: 10.7 (s, 1H),
8.35 (d, 1H, J 2.6 Hz), 8.17 (bs, 3H), 8.01 (dd, 1H, J 2.6, 8.9 Hz), 7.47-7.32 (m, 5H),
7.00 (d, 1H, J 8.9 Hz), 6.89-6.86 (m, 3H), 5.12 (dd, 1H, J 1.90,10.1 Hz), 3.79 (q, 2H,
J 5.6 Hz), 3.01-2.92 (m, 1H), 2.74-2.70 (m, 1H), 2.20-2.15 (m, 1H), 2.05-1.94 (m,
1H).
Similarly there was obtained:
2-Amino-//-{6-[2-(4-fluorophenyl)chroman-6-yloxy]-pyridin-3-yl}-acetamide

1H-NMR (400 MHz; d6-DMSO) ä:10.8 (s, 1H), 8.36 (d, 1H, J 2.7 Hz), 8.21
(bs, 3H), 8.02 (dd, 1H, J 2.7, 8.9 Hz), 7.52-7'.47 (m, 2H), 7.26-7.19 (m, 2H), 6.99 (d,
1H, J 8.9 Hz), 6.88-6.85 (m, 3H), 5.14 (dd, 1H, J 1.90,10.0 Hz), 3.79 (q, 2H, J 5.7
Hz), 2.97-2.91 (m, 1H), 2.74-2.69 (m, 1H), 2.19-2.12 (m, 1H), 2.01-1.91 (m, 1H).
Example 34.
N-[6-(2-Phenylchroman-6-yloxy)pyridin-3-yl]-2-(4-phenylpiperazin-1-
yl)acetamide
To a solution of 2-Chloro-N-[6-(2-phenylchroman-6-yloxy)-pyridin-3-yl]-
acetamide (500 mg) in acetonitrile was added potassium carbonate (333 mg) and 1-
phenylpiperazine (213 ìl). The mixture was stirred at room temperature. Water was
added to the reaction mixture. Solution was extracted with dichloromethane. Organic
extract was dried and evaporated. Product was purified by column chromatography
using 10% methanol in dichlomethane as an eluant. N-[6-(2-Phenylchroman-6-
yloxy)-pyridin-3-yl]-2-(4-phenylpiperazin-1-yl)acetamide was isolated as its
dihydrochloride salt 1H NMR (300 MHz, d6-MeOH) ä: 8.70 (bs, 1H), 8.25 (dd, 1H, J
2.1, 9.1 Hz), 7.46-7.28 (m, 7H), 7.09-6.96 (m, 7H), 5.12 (dd, 1H, J 2.3, 9.8 Hz), 4.32
(s, 2H), 3.73-3.40 (m, 8H), 3.10-2.95 (m, 1H), 2.90-2.76 (m, 1H), 2.33-2.20 (m, 1H),
2.13-2.00 (m, 1H).
Example 35.
2-(4-Methylpiperazin-1-yl)-N-[6-(2-phenylchroman-6-yloxy)pyridin-3-yl]-
acetamide
To a solution of 2-chloro-N-[6-(2-phenylchroman-6-yloxy)pyridin-3-yl]-
acetamide (200 mg) in acetonitrile was added potassium carbonate (133 mg) and 1-
methylpiperazine (62 ìl). The mixture was stirred at room temperature. Water was
added to the reaction mixture. Solution was extracted with dichloromethane. Organic
extract was dried and evaporated. N-[6-(2-Phenylchroman-6-yloxy)pyridin-3-yl]-2-
(4-methylpiperazin-1-yl)acetamide was isolated as its dihydrochloride salt. 1H-NMR
(300 MHz; d6-DMSO) ä: 10.7 (s, 1H), 8.38 (d, 1H, J 2.7 Hz), 8.04 (dd, 1H, J 2.7, 8.8
Hz), 7.47-7.31 (m, 5H), 6.99 (d, 1H, J 8.8 Hz), 6.88-6.85 (m, 3H), 5.12 (dd, 1H, J
2.0,10.0 Hz), 3.95 (s, 2H), 3.68-3.42 (m, 4H), 3.42-3.18 (m, 4H), 2.97-2.91 (m, 1H),
2.81 (s, 3H), 2.80-2.73 (m, 1H), 2.25-2.10 (m, 1H), 2.10-1.96 (m, 1H).

Example 36.
N-[6-(2-Phenylchroman-6-yloxy)pyridin-3-yl]-2-piperazin-1 -yl acetamide
To a solution of 2-Chloro-N-[6-(2-phenylchroman-6-yloxy)pyridin-3-
yl]acetamide (200 mg) in acetonitrile was added potassium carbonate (133 mg) and
1-methylpiperazine (262 ìl). The mixture was stirred at room temperature. Water
was added to the reaction mixture. Solution was extracted with dichloromethane.
Organic extract was dried and evaporated. N-[6-(2-Phenylchroman-6-yloxy)pyridin-
3-yl]-2-(4-piperazin-1-yl)acetamide was isolated as its dihydrochloride salt. 'H-NMR
(400 MHz; d6-DMSO) ä:10.7 (s, 1H), 8.38 (d, 1H, J 2.7 Hz), 8.03 (dd, 1H, J 2.7, 8.9
Hz), 7.47-7.33 (m, 5H), 6.99 (d, 1H, J 8.9 Hz), 6.88-6.85 (m, 3H), 5.12 (dd, 1H, J
2.1,10.1 Hz), 3.5-3.2 (m, 10H), 2.97-2.92 (m,. 1H), 2.74-2.70 (m, 1H), 2.20-2.15 (m,
1H), 2.03-1.97 (m, 1H).
Example 37.
2-Morpholin-4-yl-N-[6-(2-phenylchroman-6-yloxy)pyridin-3-yl]acetamide
To a solution of 2-chloro-N-[6-(2-phenylchroman-6-yloxy)-pyridin-3-yl]-
acetamide (200 mg) in acetonitrile was added potassium carbonate (133 mg) and
morpholine (53 mg). The mixture was stirred at room temperature. Water was added
to the reaction mixture. Solution was extracted with ethyl acetate. Organic extract
was dried and evaporated. 2-Morpholin-4-yl-N-[6-(2-phenylchroman-6-yloxy)-
pyridin-3-yl]-acetarnide was isolated as its hydrochloride salt. 1H-NMR (400 MHz;
d6-DMSO) ä: 11.1 (s, 1H), 8.38 (d, 1H, J 2.7 Hz), 8.03 (dd, 1H, J 2.7, 8.9 Hz), 7.47-
7.32 (m, 5H), 7.01 (d, 1H, J 8.9 Hz), 6.89-6.85 (m, 3H), 5.12 (dd, 1H, J 1.9,10.0
Hz), 4.23 (s, 2H), 4.02-3.76 (m, 4H), 3.55-3.20 (m, 4H), 3.00-2.92 (m, 1H), 2.75-
2.69 (m, 1H), 2.19-2.15 (m, 1H), 2.03-1.98 (m, 1H).
Example 38.
N-[6-(2-Phenylchroman-6-yloxy)pyridin-3-yl]-2-thiomorpholin-4-yl
acetamide
To a solution of 2-chloro-N-[6-(2-phenylchroman-6-yloxy)-pyridin-3-yl]-
acetamide (200 mg) in acetonitrile was added potassium carbonate (133 mg) and
thiomarpholine (63 mg). The mixture was stirred at room temperature. Water was
added to the reaction mixture. Solution was extracted with ethyl acetate. Organic

extract was dried and evaporated. N-[6-(2-Phenylchroman-6-yloxy)-pyridin-3-yl]-2-
thiomorpholin-4-yl-acetamide was isolated as its hydrochloride salt. 1H-NMR (400
MHz; d6-DMSO) ä:11.0 (s, 1H), 8.37 (d, 1H, J 2.6 Hz), 8.02 (dd, 1H, J 2.6, 8.9 Hz),
7.46-7.32 (m, 5H), 7.01 (d, 1H, J 8.9 Hz), 6.89-6.86 (m, 3H), 5.12 (dd, 1H, J 1.9,
10.1 Hz), 4.20 (bs, 2H), 3.85-2.65 (m, 10H), 2.20-2.15 (m, 1H), 2.05-1.95 (m, 1H).
Example 39.
N-[6-(2-Phenylchroman-6-yloxy)pyridin-3-yl]-2-pyrrolidin-1-yl acetamide
To a solution of 2-Chloro-N-[6-(2-phenylchroman-6-yloxy)-pyridin-3-yl]-
acetamide (200 mg) in acetonitrile was added potassium carbonate (133 mg) and
pyrrolidine (51 ìl). The mixture was stirred at room temperature. Water was added to
the reaction mixture. Solution was extracted with ethyl acetate. Organic extract was
dried and evaporated. N-[6-(2-Phenyl-chroman-6-yloxy) pyridin-3-yl]-2-pyrrolidin-1-
yl acetamide was isolated as its hydrochloride salt. 1H-NMR (400 MHz; d6-DMSO)
ä:10.8 (s, 1H), 8.35 (d, 1H, J 2.7 Hz), 8.02 (dd, 1H, J 2.7, 8.9 Hz), 7.47-7.32 (m,
5H), 7.00 (d, 1H, J 8.9 Hz), 6.89-6.85 (m, 3H), 5.12 (dd, 1H, J 1.9,10.0 Hz), 4.25 (d,
2H, 5.4 Hz), 3.67-3.55 (m, 2H), 3.20-3.06 (m, 2H), 3.06-2.90 (m, 1H), 2.80-2.65 (m,
1H), 2.23-2.12 (m, 1H), 2.10-1.85 (m, 5H).
Example 40.
2-(2,5-Dimethylpyrrolidin-1-yl)-N-[6-(2-phenylchroman-6-yloxy)pyridin-3-
yl] acetamide
To a solution of 2-Chloro-N-[6-(2-phenylchroman-6-yloxy)-pyridin-3-yl]-
acetamide (200 mg) in acetonitrile was added potassium carbonate (133 mg) and 2,5-
dimethylpyrrolidine (81 ìl). The mixture was stirred at room temperature. Water was
added to the reaction mixture. Solution was extracted with ethyl acetate. Organic
extract was dried and evaporated. The product was purified by column chromato-
graphy using gradient elution with methanol -dichloromethane (2 %-> 5 %). 1H-
NMR (300 MHz; d6-DMSO) ä: 9.66 (s, 1H), 8.35 (d, 1H, J 2.7 Hz), 8.06 (dd, 1H, J
2.7, 8.8 Hz), 7.47-7.32 (m, 5H), 6.93 (d, 1H, J 8.8 Hz), 6.88-6.84 (m, 3H), 5.12 (dd,
1H, J 2.1,9.9 Hz), 3.22 (s, 2H), 3.05-2.88 (m, 1H), 2.78-2.66 (m, 3H), 2.22-2.12 (m,
1H), 2.08-1.92 (m, 1H), 1.90-1.79 (m, 2H), 1.43-1.34 (m, 2H), 1.06 (d, 6H, J 6.1 Hz).

Example 41.
N-[6-(2-Phenylchroman-6-yloxy)pyridin-3-yl]-2-piperidin-l -yl acetamide
To a solution of 2-Chloro-N-[6-(2-phenylchroman-6-yloxy)-pyridin-3-yl]-
acetamide (200 mg) in acetonitrile was added potassium carbonate (133 mg)
piperidine (60 ìl). The mixture was stirred at room temperature. Water was added to
the reaction mixture. Solution was extracted with dichloromethane. Organic extract
was dried and evaporated. N-[6-(2-Phenylchroman-6-yloxy)-pyridin-3-yl]-2-(4-
piperin-1-yl)acetamide was isolated as its hydrochloride salt. 1H-NMR (400 MHz;
d6-DMSO) ä: 11.0 (s, 1H), 8.38 (d, 1H, J 2.7 Hz), 8.03 (dd, 1H, J 2.7, 8.8 Hz), 7.46-
7.32 (m, 5H), 7.00 (d, 1H, J 8.8 Hz), 6.89-6.85 (m, 3H), 5.12 (dd, 1H, J 1.9, 10.0
Hz), 4.13 (d, 2H, J 4.9 Hz), 3.52-3.41 (m, 2H), 3.15-2.90 (m, 3H), 2.79-2.67 (m, 1H),
2.24-2.12 (m, 1H), 2.07-1.92 (m, 1H), 1.85-1.33 (m, 6H).
Example 42.
2-(4-Hydroxypiperidin-1-yl)-N-[6-(2-phenylchroman-6-yloxy)pyridin-3-
yl] acetamide
To a solution of 2-Chloro-N-[6-(2-phenylchroman-6-yloxy)-pyridin-3-yl]-
acetamide (200 mg) in acetonitrile was added potassium carbonate (133 mg) and 4-
hydroxypiperidine (62 mg). The mixture was stirred at room temperature. Water was
added to the reaction mixture. Solution was extracted with ethyl acetate. Organic
extract was dried and evaporated. Product was purified by column chromatography
using 10% methanol in methylene chloride as eluant. 2-(4-Hydroxypiperidin-1-yl)-N-
[6-(2-phenyl-chroman-6-yloxy)-pyridin-3-yl]-acetamide was isolated as its hydro-
chloride salt. 1H-NMR (400 MHz; d4-MeOH) ä: 8.41 (s, 1H), 8.06 (dd, 1H, J 2.7, 9.0
Hz), 7.45-7.28 (m, 5H), 6.95-6.85 (m, 4H), 5.10 (dd, 1H, J 2.1,10.0 Hz), 4.13 (s,
2H), 3.72-3.68 (m, 1H), 3.48-3.43 (m, 3H), 3.25-3.10 (m, 1H), 3.02-2.97 (m, 1H),
2.81-2.75 (m, 1H), 2.26-1.76 (m, 6H). (M)+ = 459 (5.8%), 360 (7.4%), 114 (100%).
Example 43.
2-(3-Hydroxypiperidin-1-yl)-N-[6-(2-phenylchroman-6-yloxy)-pyridin-3-yl]-
acetamide hydrochloride
2-(3-Hydroxypiperidin-1-yl)-N-[6-(2-phenylchroman-6-yloxy)-pyridin-3-yl]-
acetamide hydrochloride was synthesized using the same procedure as described for

2-(4-Hydroxypiperidin-1-yl)-N-[6-(2-phenyl-chroman-6-yloxy)-pyridin-3-yl]-
acetamide in Example 41 but replacing 4-hydroxypiperidine with 3-
hydroxypiperidine. 1H-NMR (400 MHz; MeOD) ä: 1.47 (m, 1H), 1.62 (m, 1H), 1.75
(m, 1H), 1.87 (m, 1H), 2.05 (m, 1H), 2.22 (m, 1H), 2.37-2.57 (m, 3H), 2.68-2.72 (m,
2H), 3.01 (m, 1H), 3.08-3.22 (m, 2H), 3.80-3.88 (m, 1H), 5.08 (dd, 1H, J 1.8,10.0
Hz), 6.82-6.91 (m, 4H), 7.27-7.46 (m, 5H), 8.06 (m, 1H), 8.35 (d, 1H, J 2.1 Hz).
Example 44.
2-(3-Hydroxypyrrolidin-1-yl)-N-[6-(2-phenylchronian-6-yloxy)-pyridin-3-yl]-
acetamide hydrochloride
2-(3-Hydroxypyrrolidin-1-yl)-N-[6-(2-phenylchroman-6-yloxy)-pyridin-3-yl]-
acetamide hydrochloride was synthesized using the same procedure as described for
2-(4-hydroxypiperidin-1-yl)-N-[6-(2-phenyl-chroman-6-yloxy)-pyridin-3-yl]-
acetamide in Example 41 but replacing 4-hydroxypiperidine with pyrrolidin-3-ol.
1H-NMR (400 MHz; d6-DMSO) ä:1.81-2.31 (m, 4H), 2.68-2.77 (m, 1H), 2.91-3.02
(m, 1H), 3.05-3.57 (m, 2 H), 3.63-3.78 (m, 2H), 4.17-4.50 (m, 3H), 5.12 (d, 1H, J 8.5
Hz), 6.84-6.90 (m, 3H), 7.00 (dd, 1H, J 2.5, 8.8 Hz), 7.32-7.49 (m, 5H), 8.03 (dd, 1
H, J 2.7, 8.8 Hz), 8.36 (s, 1H), 10.40 (bd, 1H, J 30.3 Hz), 10.93 (d, 1H, J 3.2 Hz).
Example 45.
l-{[6-(2-Phenylchroman-6-yloxy)pyridin-3-ylcarbamoyl]methyl}piperidine-4-
carboxylic acid ethyl ester
To a solution of 2-chloro-N-[6-(2-phenylchroman-6-yloxy)-pyridin-3-
yl]acetamide (200 mg) in acetonitrile was added potassium carbonate (133 mg)
piperidine-4-carboxylic acid ethyl ester (94 ìl). The mixture was stirred at room
temperature. Water was added to the reaction mixture. Solution was extracted with
ethyl acetate. Organic extract was dried and evaporated. Product was purified by
column chromatography using 10% methanol in methylenechloride as eluant. 1-{[6-
(2-Phenylchroman-6-yloxy)pyridin-3-ylcarbamoyl]methyl}piperidine-4-carboxylic
acid ethyl ester was isolated as its hydrochloride salt. 1H-NMR (400 MHz; d4-
MeOH) ä: 8.48 (s, 1H), 8.10 (dd, 1H, J 2.2, 9.0 Hz), 7.45-7.29 (m, 5H), 6.99-6.88
(m, 4H), 5.10 (dd, 1H, J 2.0,10.0 Hz), 4.23-4.15 (m, 4H), 3.76-3.72 (m, 2H), 3.22-
3.15 (m, 2H), 3.05-2.98 (m, 1H), 2.82-2.75 (m, 2H), 2.27-1.97 (m, 6H), 1.27 (t, 3H, J
7.2 Hz). (M)+ = 515 (2.9%), 470 (4.3%), 360 (8.5%), 170 (100%).

Example 46.
2-Diethylamino-N-[6-(2-phenylchroman-6-yloxy)pyridin-3-yl]acetamide
To a solution of 2-chloro-N-[6-(2-phenylchroman-6-yloxy)pyridin-3-
yl]acetamide (200 mg) in acetonitrile was added potassium carbonate (133 mg) and
diethyl amine (63 ìl). The mixture was stirred at room temperature. Water was added
to the reaction mixture. Solution was extracted with ethyl acetate. Organic extract
was dried and evaporated. Product was purified by column chromatography using
10% methanol in methylenechloride as eluant. 2-Diemylamino-N-[6-(2-phenyl-
chroman-6-yloxy)pyridin-3-yl]acetamide was isolated as its hydrochloride salt. 1H-
NMR (400 MHz; d6-DMSO) ä:11.1 (s, 1H), 8.38 (d, 1H, J 2.7 Hz), 8.04 (dd, 1H, J
2.7, 8.9 Hz), 7.47-7.32 (m, 5H), 7.01 (d, 1H, J 8.9 Hz), 6.89-6.85 (m, 3H), 5.12 (dd,
1H, J 2.0,10.0 Hz), 4.14 (d, 2H, J 4.9 Hz), 3.24 (k, 4H, J 7.2 Hz), 3.01-2.92 (m, 1H),
2.76-2.70 (m, 1H), 2.19-2.15 (m, 1H), 2.04-1.94 (m, 1H), 1.24 (t, 6H, J 7.2 Hz).
Example 47.
2-Dimemylamino-N-[6-(2-phenylchroman-6-yloxy)pyridin-3-yl]acetarnide
To a solution of 2-chloro-N-[6-(2-phenylchroman-6-yloxy)-pyridin-3-yl]-
acetamide (177 mg) in acetonitrile was added potassium carbonate (118 mg) and 33
% dimethylamine in ethanol (480 ìl). The mixture was stirred at room temperature.
Water was added to the reaction mixture. Solution was extracted with ethyl acetate.
Organic extract was dried and evaporated. 2-Dmiemylamino-N-[6-(2-phenyl-
chroman-6-yloxy)-pyridin-3-yl]acetamide was isolated as its hydrochloride salt. 1H-
NMR (300 MHz; d6-DMSO) ä: 11.3 (s, 1H), 8.41 (d, 1H, J 2.3 Hz), 8.07 (dd, 1H, J
2.3, 8.8 Hz), 7.47-7.33 (m, 5H), 7.00 (d, 1H, J 8.8 Hz), 6.88-6.85 (m, 3H), 5.12 (d,
1H, J 8.5 Hz), 4.20 (s, 2H), 3.01-2.69 (m, 8H), 2.20-1.91 (m, 2H).
Example 48.
2-[Bis(-2-hydroxyemyl)arnmo]-N-[6-(2-phenylchroman-6-yloxy)pyridin-3-
yl]acetamide
To a solution of 2-chloro-N-[6-(2-phenylchroman-6-yloxy)-pyridin-3-
yl]acetamide (177 mg) in acetonitrile was added potassium carbonate (118 mg) and

diethanolamine (65 ìl). The mixture was stirred at room temperature. Water was
added to the reaction mixture. Solution was extracted with ethyl acetate. Organic
extract was dried and evaporated. 2-[Bis(2-hydroxyethyl)amino]-N-[6-(2-phenyl-
chroman-6-yloxy)pyridin-3-yl]acetamide was purified by column chromatography
using 10% methanol in methylenechloride as eluant. 1H-NMR (400 MHz; d6-DMSO)
ä: 10.1 (s, 1H), 8.31 (d, 1H, J 2.7 Hz), 8.07 (dd, 1H, J2.7, 8.8 Hz), 7.46-7.31 (m,
5H), 6.95 (d, 1H, J 8.8 Hz), 6.86-6.84 (m, 3H), 5.11 (dd, 1H, J 2.1,10.0 Hz), 4.71 (t,
2H, J 5.4 Hz), 3.50 (q, 4H, J 5.4 Hz), 2.97-2.92 (m, 1H), 2.74-2.70 (in, 1H), 2.67 (t,
4H, J 5.4 Hz), 2.18-2.14 (m, 1H), 2.02-1.97 (m, 1H).
Example 49.
[6-(2-Phenylchroman-6-yloxy)pyridin-3-yl](2-pyrrolidin-1-ylethyl)amine
[6-(2-Phenylchroman-6-yloxy)pyridin-3 -yl] -2-pyrrolidin-1 -yl acetamide 0.20
g was dissolved in dry THF (2 ml) and solution of borane-THF complex (3.3 ml, 1.0
M in THF) was added dropwise under nitrogen. The reaction mixture was refluxed
for 2 hours. Solvent was evaporated and the precipitate was diluted into methanol.
The solution was acidified with 6 N HC1 and stirred at 70 °C for an hour. After
cooling into room temperature 5 % NaOH solution was added and the mixture was
extracted with ethyl acetate. The solvent was dried over Na2SO4 and evaporated
under reduced pressure. [6-(2-Phenylchroman-6-yloxy)pyridin-3-yl](2-pyrrolidin-1-
ylethyl)amine was isolated as its hydrochloride salt. 1H NMR (400 MHz, d6-DMSO)
6: 10.24 (br s, 1H), 7.60 (d, 1H, J 2.9 Hz), 7.38-7.45 (m, 4H), 7.34 (m, 1H), 7.19 (dd,
1H, J 2.9, 8.7 Hz), 6.75-6.82 (m, 4H), 5.09 (d, 1H, J 9.9 Hz), 3.57 (m, 2H), 3.38-3.43
(m, 2H), 3.29 (m, 2H), 3.03 (m, 2H); 2.94 (m, 1H), 2.69 (m, 1H), 2.16 (m, 1H), 1.99
(m,3H), 1.89 (m,2H).
The following examples 50-53 were prepared as described for [6-(2-
phenylchroman-6-yloxy)pyridin-3-yl](2-pyrrolidin-1-ylethyl)amine in Example 49
replacing [6-(2-phenylchroman-6-yloxy)pyridin-3-yl]-2-pyrrolidin-1-yl acetamide
with an appropriate acetamide derivative.
Example 50.
N-Ethyl-N'-[6-(2-phenylchroman-6-yloxy)pyridin-3-yl]ethane-l,2-diamine
dihydrochloride

1H NMR (400 MHz, d6-DMSO) ä: 8.85 (br s, 2H), 7.60 (d, 1H, J 2.8 Hz),
7.38-7.45 (m, 4H), 7.34 (d, 1H, J 6.8 Hz), 7.21 (dd, 1H, J 3.0, 8.8 Hz), 6.76-6.83 (m,
4H), 5.10 (d, 1H, J 8.1 Hz), 3.36 (t, 2H, J 6.3 Hz), 3.06 (m, 2H), 2.92-2.97 (m, 3H),
2.69 (m, 1H), 2.16 (m, 1H), 2.01 (m, 1H), 1.21 (t, 3H, J 7.2 Hz).
Example 51.
N* 1 *-[6-(2-Phenylchroman-6-yloxy)pyridin-3-yl]ethane-l ,2-diamine
dihydrochloride
1H NMR (400 MHz, d6-DMSO) ä: 7.99 (br s, 2H), 7.58 (d, 1H, J 2.7 Hz),
7.38-7.45 (m, 4H), 7.34 (d, 1H, J 7.0 Hz), 7.17 (dd, 1H, J 3.0, 8.7 Hz), 6.75-6.82 (m,
4H), 5.10 (d, 1H, J 7.8 Hz), 3.27-3.30 (m, 2H), 2.93-2.97 (m, 3H), 2.69 (m, 1H), 2.16
(m, 1H), 1.99 (m, 1H).
Example 52.
N,N-Diethyl-N'-[6-(2-phenylchroman-6-yloxy)pyridin-3-yl]ethane-1,2-
diamine dihydrochloride
1H NMR (400 MHz, d6-DMSO) ä: 7.61 (d, 1H, J 2.8 Hz), 7.38-7.45 (m, 4H),
7.34 (m, 1H), 7.19 (dd, 1H, J 2.8, 8.8 Hz), 6.75-6.83 (m, 4H), 5.10 (d, 1H, J 7.8 Hz),
3.42-3.44 (m, 2H), 3.18-3.22 (m, 6H), 2.92 (m, 1H), 2.69 (m, 1H), 2.14 (m, 1H), 1.99
(m, 1H), 1.21 (t, 6H, J 7.2 Hz).
Example 53.
N,N-Dimethyl-N'-[6-(2-phenylchroman-6-yloxy)pyridin-3-yl]ethane-l,2-
diamine dihydrochloride
1H NMR (400 MHz, d6-DMSO) ä: 7.61 (d, 1H, J 2.8 Hz), 7.38-7.45 (m, 4H),
7.34 (m, 1H), 7.20 (dd, 1H, J 2.9, 8.8 Hz), 6.75-6.83 (m, 4H), 5.10 (d, 1H, J 8.0 Hz),
3.42 (t, 2H, J 6.2 Hz), 3.22 (t, 2H, J 6.2 Hz), 2.93 (m, 1H), 2.80 (s, 6H), 2.69 (m,
1H), 2.16 (m, 1H), 1.98 (m, 1H).
Example 54.
Methanesulfonamide derivatives
N-{6-[2-(3-(N-methanesulfonyl(5-aminopyridin-6-yloxy-))phenyl)chroman-6-
yloxy]-pyridin-3-yl}-methanesulfonamide

Pyridine (620 ìl) and methanesufonyl chloride (260 ìl) were added into a
cooled solution of 6-[2-(3-(5-aminopyridin-2-yloxy)phenyl)chroman-6-yloxy]-
pyridin-3-ylamine (650 mg) in dry THF (11 ml). After stirring resulting mixture at
room temperature for additional 2 hours 1 M hydrochloric acid was added. Solution
was extracted with ethyl acetate. Combined organic layers were washed with water,
dried with Na2SO4 and evaporated. N{6-[2-(3-(N-methanesulfonyl(5-aminopyridin-
6-yloxy-))phenyl)-chroman-6-yloxy]-pyridin-3-yl}methanesulfonamide was
recrystallised from mixture of methanol and diethyl ether. 1H NMR (300 MHz, d6-
DMSO) ä: 9.74 (s, 1H), 9.67 (s, 1H), 8.02 (d, 1H, 2.7 Hz), 7.98 (d, 1H, J 2.7 Hz),
7.72 (dd, 1H, J 2.7, 8.8 Hz), 7.67 (dd, 1H, J 2.7, 8.8 Hz), 7.44 (t, 1H, J 7.8 Hz), 7.30
(d, 1H, 7.8 Hz), 7.20 (s, 1H), 7.09-7.05 (m, 2H), 6.97 (d, 1H, J 8.8 Hz), 6.89-6.85 (m,
3H), 5.14 (d, 1H J 8.5 Hz), 3.00 (s, 3H), 2.98 (m, 3H), 2.98-2.91 (m, 1H), 2.75-2.70
(m, 1H), 2.21-2.17 (m, 1H), 2.02-1.97 (m, 1H).
6-[(N-methanesulfonyl(5-aminopyridin-6-yloxy-)]-2-{3-[N-methanesulfonyl-
(5-aminopyridin-6-yloxy-)]phenyl}chroman-4-ol
1H NMR (300 MHz, d6-DMSO) ä: 9.73 (s, 1H), 9.66 (s, 1H), 8.03 (d, 1H, J
2.6 Hz), 7.99 (d, 1H, J 2.6 Hz), 7.71-7.66 (m, 2H), 7.45 (t, 1H, J 7.8 Hz), 7.32 (d, 1H,
J 7.8 Hz), 7.22-6.80 (m, 7H), 5.29 (d, 1H J 11.5 Hz), 4.95 (dd, 1H, J 6.1,10.5 Hz),
3.00 (s, 3H), 2.99 (s, 3H), 2.38-2.31 (m, 1H), 1.99-1.91 (m, 1H).
N-{6-[2-(3-Benzyloxyphenyl)chroman-6-yloxy]pyridin-3-yl}methanesulfon-
amide
1H NMR (300 MHz, d6-DMSO) ä: 9.64 (s, 1H), 7.98 (d, 1H, J 2.8 Hz), 7.66
(dd, 1H, J 2.8, 8.9 Hz), 7.47-7.28 (m, 6H), 7.09 (s, 1H), 7.04-6.94 (m, 3H), 6.89-6.85
(m, 3H), 5.12 (s, 2H), 5.09 (dd, 1H, J 2.1,12.0 Hz), 2.98 (s, 3H), 2.98-2.89 (m, 1H),
2.73-2.67 (m, 1H) 2.20-2.14 (m, 1H), 2.02-1.96 (m, 1H).
N-{6-[2-(3-Hydroxyphenyl)chroman-6-yloxy]pyridin-3-yl}methanesulfon-
amide
1H NMR (400 MHz, d6-DMSO) ä: 9.42 (s, 1H), 7.98 (d, 1H, J 2.8 Hz), 7.66
(dd, 1H, J 2.8, 8.8 Hz), 7.18 (t, 1H, J 8.0 Hz), 6.97 (d, 1H, J 8.8 Hz), 6.88-6.83 (m,
5H), 6.73-6.69 (m, 1H), 5.03 (dd, 1H J 2.1, 9.9 Hz), 2.98 (s, 3H), 2.98-2.90 (m, 1H),
2.72-2.67 (m, 1H), 2.16-2.11 (m, 1H), 1.98-1.91 (m, 1H).

Example 55.
N-(6-{2-[3-(5-Nitropyridin-2-yloxy)phenyl]chroman-6-yloxy}pyridin-3-yl)-
methanesulfonamide
Potassium fluoride (42 mg) was added into a solution of N-{6-[2-(3-hydroxy-
phenyl)chroman-6-yloxy]pyridin-3-yl}methanesulfonainide (100 mg) in dry DMF (1
ml). After stirring the resulting mixture at 120°C for 30 minutes 2-chloro-5-nitro-
pyridine (40 mg) was added. The reaction mixture was stirred for a further 30
minutes at 120°C. After cooling into room temperature 1 M HCl-solution was added
and formed precipitate was filtered. iV-(6-{2-[3-(5-Nitropyridin-2-yloxy)phenyl]-
chroman-6-yloxy}pyridin-3-yl) methanesulfonamide was purified by column
chromatography using 1:1 mixture of ethyl acetate and heptane as eluant. 1H NMR
(300 MHz, d6-DMSO) ä: 9.64 (s, 1H), 9.04 (d, 1H, J 2.9 Hz), 8.63 (dd, 1H, J 2.9, 9.1
Hz), 7.98 (d, 1H, J 2.7 Hz), 7.66 (dd, 1H, J 2.7, 8.8 Hz), 7.52 (t, 1H, J 7.7 Hz), 7.39
(d, 1H, J 7.7 Hz), 7.31 (s, 1H), 7.27 (d, 1H, J 9.1 Hz), 7.22-7.19 (m, 1H), 6.96 (d, 1H,
J 8.8 Hz), 6.89-6.85 (m, 3H), 5.17 (d, 1H, J 7.8 Hz), 2.97 (s, 3H), 2.98-2.92 (m, 1H),
2.76-2.69 (m, 1H) 2.28-2.19 (m, 1H), 2.02-1.97 (m, 1H).
Example 56.
(5-Nitropyridin-2-yl)(6-{2-[3-(5-nitropyridin-2-yloxy)phenyl]chroman-6-
yloxy}pyridin-3-yl)amine
5-Nitropyridin-2-yl)(6-{2-[3-(5-nitropyridin-2-yloxy)phenyl]chroman-6-
yloxy}pyridin-3-yl)amine was prepared using the same procedure as described for 5-
nitro-2-(2-phenylchroman-6-yloxy)pyridine in Example l(b) starting from N-{6-[2-
(3-hydroxyphenyl)chroman-6-yloxy]pyridine-3-yl}methanesulfonamide. 1H NMR
(300 MHz, d6-DMSO) ä: 10.14 (s, 1H), 9.02 (m, 1H), 8.63 (dd, 1H, J 2.8, 8.8 Hz),
8.40 (d, 1H, J 2.8 Hz), 8.30 (dd, 1H, J 2.8, 9.2 Hz), 8.13 (dd, 1H, J 2.6, 8.6 Hz), 7.52
(t, 1H, J 7.9 Hz), 7.40 (d, 1H, J 7.8 Hz), 7.31 (s, 1H), 7.28 (d, 1H, J 9.2 Hz), 7.21 (dd,
1H, J 2.1, 7.9 Hz), 6.70 (d, 1H, J 8.8 Hz), 6.85-6.90 (m, 5H), 5.18 (d, 1H, J 8.1 Hz),
2.97 (m, 1H), 2.74 (m, 1H), 2.23 (m, 1H), 2.02 (m, 1H).
Example 57.
N-{6-[2-(3-(N-Acyl(5-aminopyridin-6-yloxy-))phenyl)chroman-6-
yloxy]pyridin-3 -yl} -acetamide

6-[2-(3-(5-Aminopyridin-2-yloxy)phenyl)chroman-6-yloxy]pyridin-3-ylamine
of Example 77 (289 mg) was dissolved in 3 ml of dry pyridine under nitrogen.
DMAP (16 mg) was added. AcCl (240 ìl) was added at room temperature into the
reaction solution dropwise because of vigorous and exothermic reaction. The reaction
was stirred for 4.5 hours at room temperature and quenched with slow addition of
few drops of H2O. 50 ml of toluene was added and evaporated to dryness. Toluene
evaporation was repeated twice. Brownish product mixture was purified with column
chromatography (10% methanol in dichloromethane) to give of crystalline slightly
yellowish product. The product was further purified with recrystallization from
methanol/diethyl ether 'H-NMR (400 MHz; CDCl3) ä: 8.12-8.03 (m, 4H), 7.42-736
(m, 2H), 7.26-7.21 (m, 2H), 7.15 (s, 1H), 7.06 (dd, 1H, J 1.7, 8.0 Hz), 6.91-6.82 (m,
5H), 5.08 (dd, 1H, J 9.6, 2.3 Hz), 3.02-2.90 (m, 1H), 2.80-2.70 (m, 1H), 2.28-2.14
(m, 7H), 2.14-2.01 (m, 1H).
Example 58.
N-(6-{2-[3-(5-Nitropyridin-2-yloxy)phenyl]chroman-6-yloxy}pyridin-3-
yl)acetamide
a) N-{6-[2-(3-Hydroxyphenyl)chroman-6-yloxy]pyridin-3-yl}acetamide was
prepared as described for N-(6-{2-[3-(5-acetylaminopyridin-2-yloxy)-phenyl]-
chroman-6-yloxy}pyridin-3-yl)acetamide in Example 57 starting from 3-[6-(5-
aminopyridin-2-yloxy)chroman-2-yl]phenol using 1.2 eq. AcCl. 1H NMR (400 MHz,
d6-DMSO) ä: 10.03 (s, 1H), 9.42 (s, 1H), 8.27 (d, 1H, J 2.6 Hz), 8.01 (dd, 1H, J 8.8,
2.6 Hz), 7.18 (t, 1H, J 8.0 Hz), 6.93 (d, 1H, J 8.8 Hz), 6.84-6.85 (m, 5H), 6.72 (d, 1H,
J 8.9 Hz), 5.03 (d, 1H, J 8.2 Hz), 2.94 (m, 1H), 2.70 (m, 1H), 2.14 (m, 1H), 2.04 (s,
3H), 1.94 (m, 1H).
b)N-(6-{2-[3-(5-Nitropyridin-2-yloxy)phenyl]chroman-6-yloxy}pyridin-3-
yl)acetamide was prepared as described for 5-nitro-2-(2-phenylchroman-6-
yloxy)pyridine in Example l(b) starting from N-{6-[2-(3-hydroxyphenyl)chroman-6-
yloxy]pyridin-3-yl}acetamide. 1H NMR (400 MHz, d6-DMSO) ä: 10.03 (s, 1H), 9.05
(d, 1H, J 2.1 Hz), 8.63 (d, 1H, J 8.9 Hz), 8.26 (s, 1H), 8.00 (m, 1H), 7.50 (m, 1H),
7.40 (m, 1H), 7.27-7.31 (m, 2H), 7.20 (m, 1H), 6.92 (d, 1H, J 8.9 Hz), 6.85-6.87 (m,
3H), 5.17 (d, 1H, J 10.4 Hz), 2.96 (m, 1H), 2.71 (m, 1H), 2.20 (m, 1H), 2.04 (s, 3H),
1.99 (m, 1H).

Example 59.
N-Methyl-N-[6-(2-phenylchroman-6-yloxy)pyridin-3-yl]guanidine
a) 1 -Methyl-3-[6-(2-phenylchroman-6-yloxy)pyridin-3-yl]thiourea
Solution of 6-(2-phenylchroman-6-yloxy)pyridin-3-ylamine (150 mg) and
methyl isothiocyanate (94 ìl) in ethanol was refluxed for 10 hours. After cooling
solvents were evaporated. Crude product of 1-methyl-3-[6-(2-phenylchroman-6-
yloxy)pyridin-3-yl]thiourea was purified by column chromatography (5% methanol
in dichloromethane). 1HNMR (400 MHz, d6-DMSO) ä: 9.45 (bs, 1H), 8.02 (d, 1H, J
2.7 Hz), 7.81 (dd, 1H, J 2.7, 8.8 Hz), 7.70 (bs, 1H), 7.47-7.38 (m, 4H), 7.36-7.32 (m,
1H), 6.94-6.86 (m, 4H), 5.12 (dd, 1H J 2.3,10.1 Hz), 2.98-2.93 (m, 1H), 2.90 (d, 3H,
J 4.3 Hz), 2.76-2.71 (m, 1H), 2.19-2.15 (m, 1H), 2.15-1.99 (m, 1H).
b)iV-Methyl-N'-[6-(2-phenylchroman-6-yloxy)pyridin-3-yl]guariidme
Solution of l-methyl-3-[6-(2-phenylchroman-6-yloxy)pyridin-3-yl]thiourea
(150 mg), methyliodide (36 ìl) and acetone (15 ml) was refluxed for 90 minutes.
Solvent was evaporated and residue was dissolved to 4 ml of methanol saturated with
NH3. Mixture was heated under preasure at 100°C for 16 hours. Solvent was
evaporated and residue was purified by column chromatography using 10% methanol
in dichloromethane as eluant. 1H NMR (400 MHz, d6-DMSO) ä: 9.35 (bs, 1H), 8.04
(d, 1H, J 2.7 Hz), 7.71 (dd, 1H, J 2.7, 8.8 Hz), 7.65 (bs, 1H), 7.47-7.34 (m, 5H), 7.05
(d, 1H, J 8.8 Hz), 6.90-6.88 (m, 3H), 5.13 (d, 1H J 7.9 Hz), 3.01-2.98 (m, 1H), 2.80
(d, 3H, J 4.4 Hz), 2.75-2.71 (m, 1H), 2.19-2.15 (m, 1H), 2.02-1.98 (m, 1H).
Example 60.
Dimethyl-[6-(2-phenylchroman-6-yloxy)pyridin-3-yl]-amine and dimethyl-[2-
(2-phenylchroman-6-yloxy)-pyridin-4-yl]-amine
5-Amino-2-(2-phenylchroman-6-yloxy)pyridine (ORM-10543) (0.20 g, 0.63
mmol) and 37% formaldehyde (0.73 ml, 0.80 mmol) were dissolved in acetonitrile
(12 ml). Sodiumcyanoborohydride (0.16 g, 2.51 mmol) was added and the mixture
was stirred for 30 minutes at the room temperature. The pH was adjusted to 6-7 with
acetic acid and the reaction mixture was stirred additional 30 minutes. The solvent
was evaporated. The residue was solvated to 10% potassiumhydroxide solution and

extracted with methylene chloride. Organic phase was dried and evaporated.
Recrystallization from diethylether yielded dimethyl-[6-(2-phenylchroman-6-
yloxy)pyridin-3-yl]-amine in 92% purity. Recrystalh'zation filtrate was evaporated.
The residue was solvated in methylene chloride and 1M HCl-diethylether was added.
Dimethyl-[2-(2-phenylchroman-6-yloxy)-pyridin-4-yl]-amine precipitated as a
hydrochloride in 95.3% purity.
Dimethyl-[6-(2-phenylchroman-6-yloxy)pyridin-3-yl]-amine
1H-NMR (400 MHz; d6-DMSO) ä: 2.01 (m, 1H), 2.18 (m, 1H), 2.76 (m, 1H),
2.95 (s, 6H), 2.95-3.04 (m, 1H), 5,14 (d, 1H, J 8.2 Hz), 6.91-6.99 (m, 4H), 7.35-7.48
(m, 5H), 7.63 (d, 1H, J 3.1 Hz), 7.72 (dd, 1H, 3.2, 9.4 Hz).
Dimethyl-[2-(2-phenylchroman-6-yloxy)-pyridin-4-yl]-arnine
1H-NMR (400 MHz; d6-DMSO) ä:1.99 (m, 1H), 2.16 (m, 1H), 2.69 (m, 1H),
2.86 (s, 6H), 2.94 (m, 1H), 5,10 (d, 1H, J 9.2 Hz), 6.75-6.86 (m, 4H), 7.27-7.35 (m,
2H), 7.37-7.48 (m, 4H), 7.65 (d, 1H, 2.9 Hz).
Example 61.
5-Chloropyridinyloxy derivatives
5-Chloro-2-(2-phenylchroman-6-yloxy)pyridine
2-Phenylchroman-6-ol (500 mg) was dissolved in dry DMF (5 ml) under
nitrogen. Potassium tert-butoxide (270 mg) was added in to a sloution and the
resulting mixture was stirred for 30 minutes. 2,5-Dichloropyridine was added and the
mixture was stirred at 120°C for 2,5 hours. The reaction mixture was allowed to cool
to room temperature and 1 M HCl-solution was added and it was extracted with ethyl
acetate. The combined organic phases were washed with water and saturated NaCl-
solution and dried. The raw product was passed silica gel column using heptane-
ethyl acetate (3:1) as an eluant and then recrystallised 2-propanol. 1H NMR (300
MHz, d6-DMSO) ä: 8.19 (d, 1H, J 2.6 Hz), 7.92 (dd, 1H, 8.8,2.6 Hz), 7.47-7.34 (m,
5H), 7.02 (d, 1H, J 8.8 Hz) 6.92-6.87 (m, 3H), 5.12 (dd, 1H, J 10.0,2.1 Hz), 2.97 (m,
1H), 2.73 (m, 1H), 2.17 (m, 1H), 2.01 (m, 1H).
2-[2-(3-(5-Chloropyridin-2-yloxy)phenyl)chroman-6-yloxy]-5-chloropyridine
was obtained in a same manner by using 200 mol-% of 2,5-dichloropyridine and

starting from 2-(3-hydroxyphenyl)chroman-6-ol 1H NMR (400 MHz, d6-DMSO) ä:
8.22 (d, 1H, J 2.6 Hz), 8.19 (d, 1H, J 2.9 Hz), 7.97 (dd, 1H, J 8.9,2.6 Hz), 7.92 (dd,
1H, J 9.0,2.9 Hz), 7.46 (t, 1H, J 7.9 Hz), 7.32 (d, 1H, J 7.8 Hz), 7.22, (s, 1H), 7.13-
7.10 (m, 2H), 7.02 (d, 1H, J 9.2 Hz) 6.91-6.87 (m, 2H), 5.15 (dd, 1H, J 10.0, 2.1 Hz),
2.96 (m, 1H), 2.74 (m, 1H), 2.18 (m, 1H), 1.99 (m, 1H)
Using the same procedure as described above for 5-Chloro-2-(2-phenyl-
chroman-6-yloxy)pyridme, but replacing 2-phenylchroman-6-ol by:
2-(4-Fluorophenyl)chroman-6-ol,
2-(3-fluorophenyl)chroman-6-ol,
2-(2-Fluorophenyl)chroman-6-ol,
2-(2,3-Difluorophenyl)chroman-6-ol,
2-(2,4-Difluorophenyl)chroman-6-ol,
2-(2,5-Difluorophenyl)chroman-6-ol,
2-(2,6-Difluorophenyl)chroman-6-ol,
2-(3,4-Difluorophenyl)cbxoman-6-ol,
2-(3,5-Difluorophenyl)chroman-6-ol,
2-(2-Trifluoromethylphenyl)chroman-6-ol,
2-(4-Trifluoromethylphenyl)chroman-6-ol,
2-(3-Chloro-4-fluorophenyl)chroman-6-ol,
2-(2-Chlorophenyl)chroman-6-ol,
2-(3-Chlorophenyl)chroman-6-ol,
2-(2,4-Dichlorophenyl)chroman-6-ol,
2-(3-Bromophenyl)chroman-6-ol,
2-(4-Ethylphenyl)chroman-6-ol,
2-(3-Methoxyphenyl)chroman-6-ol,
3-Methyl-2-phenylchroman-6-ol,
2-phenylchroman-7-ol,
6-hydroxyflavanone,
7-hydroxyflavanone,
6-Hydroxy-3-methyl-2-phenylchroman-4-one,
2-Phenyl-2,3-dihydrobenzo[1,4]dioxin-6-ol,
6-Phenyl-5,6,7,8-tetrahydronaphthalen-2-ol,
6-Hydroxy-2-phenyl-3,4-dihydro-2H-naphthalen-1-one,
2-Phenyl-2,3-dihydrobenzo[1,4]oxathiin-6-ol,
3-(3-Fluorophenyl)chroman-7-ol,

3-Phenylchlroman-7-ol,
6-Hydroxyflavone,
2-Phenylindan-5-oI,
there can be obtained:
5-Chloro-2-[2-(4-fluorophenyl)chroman-6-yloxy3pyridine,
5-Chloro-2-[2-(3-fluorophenyl)chroman-6-yloxy]pyridine,
5-chloro-2-[2-(2-fluorophenyl)chroman-6-yloxy]pyridine,
5-Chloro-2-[2-(2,3-difluorophenyl)chroman-6-yloxy]pyridine,
5-Chloro-2-[2-(2,4-difluorophenyl)chromaii-6-yloxy]pyridine,
5-Chloro-2-[2-(2,5-difluorophenyl)chroman-6-yioxy]pyridine,
5-Chloro-2-[2-(2,6-difluorophenyl)chroman-6-yloxy]pyridine,
5-Chloro-2-[2-(3,4-difluorophenyl)chroman-6-yloxy]pyridine,
5-Chloro-2-[2-(3,5-difluorophenyl)chroman-6-yloxy]pyridine,
5-Chloro-2-[2-(2-trifluoromethylphenyl)chroman-6-yloxy]pyridine,
5-Chloro-2-[2-(4-trifluoromethylphenyl)chroman-6-yloxy]pyridine,
5-Chloro-2-[2-(3-chloro-4-fluorophenyl)chroman-6-yloxy]pyridine,
5-Chloro-2-[2-(2-chlorophenyl)chroman-6-yloxy]pyridine,
5-Chloro-2-[2-(3-chlorophenyl)chroman-6-yloxy]pyridine,
5-Chloro-2-[2-(2,4-dichlorophenyl)chroman-6-yloxy]pyridine,
5-Chloro-2-[2-(3-bromophenyl)chroman-6-yloxy]pyridine,
5-Chloro-2-[2-(4-ethylphenyl)chroman-6-yloxy]pyridine,
5-Chloro-2-[2-(3-methoxyphenyl)chroman-6-yloxy]pyridine,
5-Chloro-2-(3-methyl-2-phenylchroman-6-yloxy)pyridine,
5-Chloro-2-(2-phenylchroman-7-yloxy)pyridine,
6-(5-Chloropyridin-2-yloxy)-2-phenylchroman-4-one,
7-(5-Chloropyridin-2-yloxy)-2-phenylchroman-4-one,
6-(5-Chloropyridin-2-yloxy)-3-methyl-2-phenylchroman-4-one,
5-Chloro-2-(2-phenyl-2,3-dihydrobenzo[1,43dioxin-6-yloxy)pyridme,
5-Chloro-2-(6-phenyl-5,6,7,8-tetrahydronaphthalen-2-yloxy)pyridine,
6-(5-Chloropyridin-2-yloxy)-2-phenyl-3,4-dihydro-2H-naphthalen-1 -one,
5-Chloro-2-(2-phenyl-2,3-dihydrobenzo[ 1,4]oxathiin-6-yloxy)pyridine,
5-Chloro-2-[3-(3-fluorophenyl)chroman-7-yloxy]pyridine,
5-Chloro-2-(3-phenylchroman-7-yloxy)pyridine,
6-(5-Chloropyridin-2-yloxy)-2-phenylchromen-4-one,
5-Chloro-2-(2-phenylindan-5-yloxy)pyridine, respectively.

Example 62.
2-Pyridine derivatives
2-(2-Phenylchroman-6-yloxy)pyridine
2-(2-Phenylchroman-6-yloxy)pyridine was obtained in a same manner than 5-
Chloro-2-(2-phenylchroman-6-yloxy)pyridine in Example 61, but replacing 2,5-
dichloropyridine with 2-chloropyridine. 1H NMR (400 MHz, d6-DMSO) ä: 8.13 (dd,
1H, J 5.1,1.9 Hz), 7.81 (ddd, 1H, 8.6,6.9,1.9 Hz), 7.47-7.32 (m, 5H), 7.08 (dd, 1H,
J 6.9, 5.1 Hz), 6.95 (d, 1H, J 8.6 Hz), 6.90-6.86 (m, 3H), 5.11 (dd, 1H, J 10.2, 2.2
Hz), 2.97 (m, 1H), 2.73 (m, 1H), 2.17 (m, 1H), 2.01 (m, 1H).
2-[2-(3-(pyridin-2-yloxy)phenyl)chroman-6-yloxy]pyridine was obtained in a
same manner by using 200 mol-% of 2-chloropyridine and starting from 2-(3-
hydroxyphenyl)chroman-6-ol. 1H NMR (400 MHz, d6-DMSO) 6: 8.17 (dd, 1H, J 4.1,
1.7 Hz), 8.13 (dd, 1H, J 4.1,1.0 Hz), 7.86 (ddd, 1H, J 8.6, 7.5,1.7 Hz), 7.81 (ddd,
1H, 8.5, 7.5, 1.0 Hz), 7.45 (t, 1H, J 7.9 Hz) 7.30 (d, 1H, J 7.5 Hz), 7.20 (s, 1H), 7.15-
7.06 (m, 3H), 7.04 (d, 1H, J 8.6 Hz), 6.95 (d, 1H, J 8.5 Hz), 6.89-6.86 (m, 3H), 5.15
(d, 1H, J 8.7 Hz), 2.95 (m, 1H), 2.73 (m, 1H), 2.21 (m, 1H), 2.00 (m, 1H).
Example 63.
4-(2-Phenyl-chroman-6-yloxy)-pyridine
4-(2-Phenyl-chroman-6-yloxy)-pyridine was obtained in a same manner than
5-Chloro-2-(2-phenylchroman-6-yloxy)pyridine in Example 61, but replacing 2,5-
dichloropyridine with 4-chloropyridine. 1H NMR (400 MHz, d6-DMSO) ä: 8.43 (dd,
2H, J 4.8,1.5 Hz), 7.47-7.33 (m, 5H), 6.98-6.93 (m, 3H), 6.88 (dd, 2H, J 4.8,1,5
Hz), 5.14 (dd, 1H, J 10.2,2.2 Hz), 2.99 (m, 1H), 2.75 (m, 1H), 2.18 (m, 1H), 2.01
(m, 1H).
Example 64.
6-Nicotinamide derivatives
6-(2-Phenylchroman-6-yloxy)nicotinamide

6-(2-Phenylchroman-6-yloxy) nicotinamide was obtained in a same manner
than 5-Chloro-2-(2-phenylchroman-6-yloxy)pyridine in Example 61, but replacing
2,5-dichloropyridine with 6-chloronicotinamide. 1H NMR (400 MHz, d6-DMSO) ä:
8.61 (d, 1H, J 2.4 Hz), 8.23 (dd, 1H, J 8.7,2.4 Hz), 8.00 (bs, 1H), 7.47-7.32 (m, 6H),
7.01 (d, 1H, J 8.7 Hz), 6.93-6.86 (m, 3H), 5.13 (dd, 1H, J 8.2,1.9 Hz), 3.00 (m, 1H),
2.73 (m, 1H), 2.17 (m, 1H), 2.02 (m, 1H).
6-(2-[3-(5-Carbamoylpyridin-2-yloxy)phenyl]phenylchroman-6-yloxy)
nicotinamide was obtained in a same manner by using 200 mol-% of 6-chloronicotin-
amide and starting from 2-(3-hydroxyphenyl)chroman-6-ol.
1H NMR (400 MHz, d6-DMSO) ä: 8.63 (d, 1H, J 2.4 Hz), 8.61 (d, 1H, J 2.4
Hz), 8.27 (dd, 1H, J 8.6,2.4 Hz), 8.23 (dd, 1H, J 8.7,2.4 Hz), 8.03 (bs, 1H), 8.00 (bs,
1H), 7.48 (t, 1H, J 7.9 Hz), 7.46 (bs, 1H), 7.44 (bs, 1H), 7.35 (d, 1H, J 7.7 Hz), 7.25,
(s, 1H), 7.14 (dd, 1H, 7.9,7.7 Hz), 7.11 (d, 1H, 8.7 Hz), 7.01 (d, 1H, 8.6 Hz), 6.93-
6.89 (m, 3H), 5.17 (d, 1H, J 8.7 Hz), 2.97 (m, 1H), 2.76 (m, 1H), 2.20 (m, 1H), 1.99
(m, 1H).
Example 65.
C-[6-(2-Phenylchroman-6-yloxy)pyridin-3-yl]methylamine hydrochloride
Into a solution of 6-(2-Phenylcnrornan-6-yloxy) nicotinamide (100 mg) in dry
THF (2.0 ml) was added dropwise a solution of borane-THF complex (0,6 ml, 1.0 M
in THF). The resulting mixture was refluxed for 4 hours. After cooling to the room
temperature 3 M HC1 solution was added and THF was evaporated in vacuum. The
mixture was made alkaline with 50 % NaOH-solution and extracted with ethyl
acetate and dried. The hydrochloride of C-[6-(2-phenylchroman-6-yloxy)pyridin-3-
yl]methylamine was obtained via treatment with HCL-ether solution. 1H NMR (400
MHz, d6-DMSO) ä: 8.29 (bs, 3H), 8.21 (s, 1H), 7.95 (d, 1H, J 8.5 Hz), 7.47-7.34 (m,
5H), 7.03 (d, 1H, J 8.5 Hz), 6.89-6.86 (m, 3H), 5.13 (d, 1H, J 8.4 Hz), 4.00 (m, 2H),
2.94 (m, 1H), 2.70 (m, 1H), 2.19 (m, 1H), 2.00 (m, 1H).
Example 66.
Dimethyl-[6-(2-phenylchroman-6-yloxy)pyridm-3-ylmethyl]amine
a) (6-Chloropyridin-3-ylmethyl)dimethylamine

2-Chloro-5-(chloromethyl)pyridine (500 mg) was dissolved in ethanol (7,0
ml), dimethylamine (0,83 ml, 33 % in ethanol) and potassium carbonate (641 mg)
were added and the resulting mixture was refluxed for 1,5 hours. After evaboration of
ethanol, water was added and the aqueous mixture was extracted with ethyl acetate.
1H NMR (400 MHz, d6-DMSO) ä: 8.31 (d, 1H, J 2.3 Hz), 7.77 (dd, 1H, J 8.2, 2.3
Hz), 7.47 (d, 1H, J 8.2 Hz), 3.41 (s, 2H), 2.14 (s, 6 H).
b) Dimethyl-[6-(2-phenylchroman-6-yloxy)pyridin-3 -ylmethyl] amine
Dimethyl-[6-(2-phenylchroman-6-yloxy)pyridin-3-ylmethyl]amine was
prepared as described for 5-Chloro-2-(2-phenylchroman-6-yloxy)pyridine in
Example 61, but replacing 2,5-dichloropyridine with (6-chloropyridin-3-
ylmethyl)dimethylamine. 1H NMR (400 MHz, CDCl3) ä: 8.03 (d, 1H, J 2.3 Hz), 7.65
(dd, 1H, J 8.4,2.3 Hz), 7.44-7.32 (m, 5H), 6.92-6.88 (m, 3H), 6.84 (d, 1H, J 8.4 Hz),
5.05 (dd, 1H, J 10.2,2.3 Hz), 3.36 (s, 2H), 3.02 (m, 1H), 2.80 (m, 1H), 2.23 (s, 1H),
2.19 (m, lH),2.10(m, 1H).
Example 67.
6-(2-Phenylchroman-6-yloxy)nicotinic acid methyl ester
a) 6-Chloronicotinic acid methyl ester
6-Chloronicotinic acid (2,0 g) was dissolved in methanol and concentrated
hydrochloric acid (3,0 ml) was added. The reaction mixture was refluxed for 5 hours
and methanol was removed in vacuum. Ethyl acetate was added and the resulting
solution was washed with saturated sodium bicarbonate solution, water and brine.
1H NMR (400 MHz,) 5: 8.92 (d, 1H, J 2.1 Hz), 8.32 (dd, 1H, J 8.4, 2.1 Hz), 7.70 (d, 1H,
J 8.4 Hz), 3.90 (s, 3H).
b) 6-(2-Phenylchroman-6-yloxy) nicotinic acid methyl ester
6-(2-Phenylchroman-6-yloxy) nicotinic acid methyl ester was prepared as
described for 5-Chloro-2-(2-phenylchroman-6-yloxy)pyridine in Example 61, but
replacing 2,5-dichloropyridine with 6-chloronicotinic acid methyl ester. 1H NMR
(400 MHz, CDCl3) ä: 8.70 (d, 1H, J 2.4 Hz), 8.29 (dd, 1H, J 8.6,2.4 Hz), 7.47-7.32

(m, 5H), 7.07 (d, 1H, J 8.6 Hz), 6.96-6.88 (m, 3H), 5.14 (d, 1H, J 10.0 Hz), 3.85 (s,
3H), 2.97 (m, 1H), 2.74 (m, 1H), 2.18 (m, 1H), 2.01 (m, 1H).
Example 68.
6-(2-Phenylchroman-6-yloxy) nicotinic acid
6-(2-Phenylchroman-6-yloxy) nicotinic acid (200 mg), water (10 ml), ethanol
(2 ml) and potassium hydroxide were placed in a flask. The resulting mixture was
refluxed for 2,5 hours. After cooling to room temperature the pH was adjusted to pH
1 with concentrated hydrochloric acid and the white precipitate was filtered. 1H
NMR (300 MHz, d6-DMSO) ä: 13.12 (s, 1H), 8.67 (d, 1H, J 2.4 Hz), 8.25 (dd, 1H, J
8.6,2.4 Hz), 7.48-7.34 (m, 5H), 7.04 (d, 1H, J 8.6 Hz), 6.95-6.86 (m, 3H), 5.14 (dd,
1H, J 10.0, 2.2 Hz), 2.99 (m, 1H), 2.74 (m, 1H), 2.17 (m, 1H), 2.01 (m, 1H).
Example 69.
6-Nicotinonitrile derivatives
6-(2-Phenylchroman-6-yloxy)nicotinonitrile
6-(2-Phenylchroman-6-yloxy)nicotinomtrile was prepared as described for 5-
m'tro-2-(2-phenylchroman-6-yloxy)pyridine in example 1 (b) using 500 mg of 2-
phenylchroman-6-ol and replacing 2-chloro-5-nitropyridine by 337 mg of 6-chloro-
nicotinonitrile. The product was purified by column chromatography using heptane-
ethyl acetate as an eluant and then crystallised from 2-propanol. 1H NMR (400 MHz,
d6-DMSO) ä: 8.65 (d, 1H, J 2.4 Hz), 8.28 (dd, 1H, 8.8, 2.4 Hz), 7.47-7.34 (m, 5H),
7.17 (d, 1H, J 8.8 Hz) 6.96-6.87 (m, 3H), 5.14 (dd, 1H, J 10.1,2.2 Hz), 2.99 (m, 1H),
2.73 (m, 1H), 2.18 (m, 1H), 2.00 (m, 1H).
6-{2-[3-(5-Cyanopyridin-2-yloxy)-phenyl]chroman-6-yloxy}nicotinonitrile
was obtained in a same manner by using 200 mol-% of 6-Chloronicotinonitrile and
starting from 2-(3-hydroxyphenyl)chroman-6-ol. 1H NMR (400 MHz, d6-DMSO) ä:
8.66 (d, 1H, J 2.2 Hz), 8.64 (d, 1H, J 2.3 Hz), 8.33 (dd, 1H, J 8.6, 2.3 Hz), 8.28 (dd,
1H, J 8.7, 2.2 Hz), 7.50 (t, 1H, J 7.8 Hz), 7.38 (d, 1H, J 7.8 Hz), 7.28, (s, 1H), 7.26
(d, 1H, 8.6 Hz), 7.19-7.16 (m, 2H), 6.97-6.88 (m, 2H), 5.18 (d, 1H, J 8.3 Hz), 2.97
(m, 1H), 2.74 (m, 1H), 2.22 (m, 1H), 2.01 (m, 1H).

Example 70.
3-(2-Phenylchroman-6-yloxy)pyridine
2-Phenylchroman-6-ol (598 mg), 3-bromopyridine (500 mg), potassium
hydroxide (322 mg) and potassium iodide were placed in a flask with dry DMSO (10
ml). The reaction mixture was stirred at 120°C for 3,5 hours. After cooling to room
temperature 1M HCl-solution was added and the mixture was extracted wit
dichloromethane. The combined organig extracts were washed with 1 M HCl-
solution, then with water and brine and dried. 3-(2-Phenylchroman-6-yloxy)pyridine
was purified by column chromatography using heptane -ethyl acetate as an eluant. 1H
NMR (400 MHz, d6-CDCl3 + MeOH) ä: 8.31 (s, 1H), 8.24 (dd, 1H, J 3.8,1.9 Hz),
7.45-7.25 (m, 7H), 6.87 (d, 1H, J 8.6 Hz), 6.83 (dd, 1H, J 8.6, 2.6 Hz), 6.81 (d, 1H, J
2.6 Hz), 5.07 (dd, 1H, J 10.1, 2.3 Hz), 2.98 (m, 1H), 2.78 (m, 1H), 2.23 (m, 1H), 2.12
(m, 1H).

WE CLAIM:
1. Pyridine derivatives of formula (I):

wherein
X is -O-;
Z is -CHR12-;
Y is -CH2-, -C(O)-, CH(OR13)-;
the dashed line represents an optional double bond in which case Z is -CR12-
and Y is -C(O)-;
R2 and R3 are independently H, halogen, -OH, benzyloxy or a group of
formula (Ilia)

R1 is H, CN, halogen, -CONH2, -COOR15, -CH2NR15R18, -NHC(O)R5,
-NHCH2R5, -NHR20, -NR21R22, -NHC(NH)NHCH3 or, in case the optional double
bond exists or in case R2 or R3 is benzyloxy or a group of formula (IIIa) or in case the
pyridine ring is attached to the oxygen atom in 3-, 4- or 5-position, R1 can also be
-NO2 or -NR16R17;
R4 is H, -NO2, CN, halogen, -CONH2, -NR16R17;
R5 is C1-7 alkyl substituted with 1-2 substituents selected from the group
consisting of halogen, amino and hydroxy, or carboxy C1-7 alkyl, -CHR6NR7R8 or
one of the following groups:


W is N;
Q is CHR14, NR9, S or O;
R6 is H;
R7 and R8 are independently H, C1-7 acyl, C1-7 alkyl or hydroxy C1-7 alkyl;
R9 is H, C1-7 alkyl or phenyl;
R10 and R11 are independently H or C1-7 alkyl;
R12 is H;
R13 is H;
R14 is H, -OH, -COOR15;
R15 is H or C1-7 alkyl;
R16 and R17 are independently H, C1-7 acyl, C1-7 alkylsulfonyl, or -C(S)NHR18;
R18 is H or C1-7 alkyl;
R19 is H or -OH;
R20 is a pyridinyl group substituted with -NO2;
R21 and R22 are independently C1-7 alkyl;
and pharmaceutically acceptable salts and esters thereof.
4. A compound as claimed in claim 1 wherein R2 or R3 is a benzyloxy or a
group of formula (IIIa)
2. A compound as claimed in claim 1 wherein R1 is -NHC(O)R5, X is O, Y is
CH2 and Z is CHR12.
3. A compound as claimed in claim 2 wherein Z is CH2 and R5 is C1-7 alkyl
substituted with 1-2 substituents selected from the group consisting of halogen,
amino and hydroxy, or carboxy C1-7 alkyl, -CHR6NR7R8 or one of the following
groups:



5. A compound as claimed in claim 4 wherein R4 is NO2.
6. A compound as claimed in claim 4 or 5 wherein R1 is NO2
Therapeutically
active compounds of formula (I)
or (II) wherein X is -O-, -CH2-
or -C(O)-; Z is -CHR12- or a
valence bond; Y is -CH2-, -C(O)-,
CH(OR13)-, -O-, -S-; provided that
in case Z is a valence bond, Y is not
C(O); the dashed line representing
an optional double bond in which
case Z is -CR12- and Y is -CH2-,
-C(O)- or -CH(OR10)- (in formula
II) or -CH- (in formula I); R2 and
R3 are independently H, lower
alkyl, lower alkoxy, -NO2, halogen,
-CF3, -OH, benzyloxy or a group of
formula (IIIa). R1 is H, CN, halogen,
-CONH2, -COOR15, CH2NR15R18,
NHC(O)R5, NHCH2R5. NHR20,
NR21R22. NHC(NH)NHCH3 or, in
case the compound is of formula
(II) wherein the optional double
bond exists or in case R2 or R3 is
benzyloxy or a group of formula
(IIIa) or in case the pyridine ring of
formula (I) or (II) is attached to the
oxygen atom in 3-, 4- or 5-position,
R1 can also be -NO2 or NR16R17; R4
is H, -NO2, CN, halogen, -CONH2, -COOR15, -CH2NR15R18, -NR16R17, NHC(O)R5 or -NHC(NH)NHCH3; R5 is alkyl substituted
with 1-3 substituents selected from the group consisting of halogen, amino and hydroxy, or carboxyalkyl, in which the alkyl portion
is optionally substituted with 1-3 substituents selected from the group consisting of halogen, amino and hydroxyl, -CHR6NR,R8 or
one of the following groups: formula (IVa), (IVb), (IVc), (IVd), (IVe), and pharmaceutically acceptable salts and esters thereof.
The compounds are potent inhibitors of Na+/Ca2+ exchange mechanism.

Documents:

1287-KOLNP-2005-CORRESPONDENCE.pdf

1287-KOLNP-2005-FORM 27.pdf

1287-kolnp-2005-granted-abstract.pdf

1287-kolnp-2005-granted-assignment.pdf

1287-kolnp-2005-granted-claims.pdf

1287-kolnp-2005-granted-correspondence.pdf

1287-kolnp-2005-granted-description (complete).pdf

1287-kolnp-2005-granted-drawings.pdf

1287-kolnp-2005-granted-examination report.pdf

1287-kolnp-2005-granted-form 1.pdf

1287-kolnp-2005-granted-form 18.pdf

1287-kolnp-2005-granted-form 3.pdf

1287-kolnp-2005-granted-form 5.pdf

1287-kolnp-2005-granted-gpa.pdf

1287-kolnp-2005-granted-reply to examination report.pdf

1287-kolnp-2005-granted-specification.pdf


« Previous Patent
Next Patent »
Patent Number 222873
Indian Patent Application Number 1287/KOLNP/2005
PG Journal Number 35/2008
Publication Date 29-Aug-2008
Grant Date 27-Aug-2008
Date of Filing 01-Jul-2005
Name of Patentee ORION CORPORATION
Applicant Address ORIONINTIE 1, FIN-02200 ESPOO
Inventors:
# Inventor's Name Inventor's Address
1 OTSOMMA, LEENA PIISPANTILANTIE 1B 6, FI-02240 ESPOO
2 KOSKELAINEN, TUULA HAKAJAAKOPINKUJA 5, FIN-08500 LOHJA AS
3 KARJALAINEN, ARTO ALBERGANESPLANADI 11 A 13, FIN-02600 ESPOO
4 RASKU, SIRPA KAVALJEERINTIE 14 B 10, FI-01520 VANTAA
5 POLLESELLO, PIERO MARIAVAGEN 1 A, fin-02700 grankulla
6 levijoki, jouko AIROTIE 5 A, FIN-00830 HELSINKI
PCT International Classification Number C07D 405/14, 405/12
PCT International Application Number PCT/FI2004/000011
PCT International Filing date 2004-01-09
PCT Conventions:
# PCT Application Number Date of Convention Priority Country
1 20030030 2003-01-09 Finland