WO2019175464A1

WO2019175464A1 - Compounds useful as inhibitors of sodium-calcium exchanger (ncx)

Info

Publication number: WO2019175464A1
Application number: PCT/FI2018/050188
Authority: WO
Inventors: Leena Otsomaa; Arto Karjalainen; Jouko Levijoki; Tuula Koskelainen; Kaisa SYRJÄNEN; Gerd Wohlfahrt
Original assignee: Orion Corporation
Priority date: 2018-03-14
Filing date: 2018-03-14
Publication date: 2019-09-19

Abstract

The present invention related to compounds of formula (I) wherein R₁, R₂, ring A and ring Bare as defined in the claims. The compounds are potent inhibitors of the sodium-calcium exchanger (NCX) and are useful in the treatment or prevention of various clinical conditions in which intracellular calcium homeostasis is disturbed, including ischemic diseases and arrhythmias. In particular, the compounds of formula (I) are useful as inotropic agents in the treatment and 10 prevention of conditions in which inotropic support is required to maintain a sufficient level of blood supply, for example, in the treatment of heart failure or in the treatment of patients undergoing surgery.

Description

COMPOUNDS USEFUL AS INHIBITORS OF SODIUM-CALCIUM EXCHANGER (NCX)

Technical field

The present invention relates to compounds that are potent inhibitors of the sodium-calcium exchanger (NCX) and to the use thereof as NCX inhibitors, e.g. in the treatment or prevention of various clinical conditions in which intracellular calcium homeostasis is disturbed. The present invention also relates to pharmaceutical compositions comprising such compounds.

Background of the invention

Sodium-calcium exchanger (NCX) is a membrane protein that plays important roles in cardiac electrical activity and calcium homeostasis. It is one of the ion transport mechanisms that regulate the concentration of sodium and calcium ions in the cells. Compounds which selectively inhibit NCX and thereby prevent overload of calcium in cells are regarded useful in preventing cell injury mechanisms 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.

Sodium-calcium exchanger (NCX) changes three to four sodium ions to one calcium ion. The direction of the exchange of ions depends on sodium and calcium ion concentrations inside and outside of cardiomyocyte membrane, membrane potential as well as the phase of action potential. It is traditionally thought that intracellular calcium concentration increases inside cardiomyocyte and relaxation of cardiomyocyte impairs. Most probably inhibition of NCX modulates Ca²⁺ concentration in subcellular compartment and induces positive calcium balance in sarcoplasmic reticulum. This is seen as positive inotropic effect and improved relaxation of heart. In addition, inhibition of NCX is thought to be crucial for heart rate and maintenance of normal blood pressure. It turned to be that NCX inhibition has minimal effect on the heart rate or blood pressure. Using NCX inhibitor as positive inotropic compound has unique hemodynamic profile: positive inotropic effect with improved relaxation having no effect on heart rate or blood pressure. Such drugs would have significant potential in the treatment of surgical patients or heart failure patients who do not tolerate an increase in the heart rate or a drop in the blood pressure as currently used positive inotropic drugs do.

Compounds capable of inhibiting NCX have been described earlier e.g. in patent publications WO 97/09306, EP 0978506, EP 1031556, WO 2003/006452 and WO 2004/063191.

Summary of the invention

It has now been found that compounds of formula (I) are potent NCX inhibitors and are therefore useful in the treatment or prevention of clinical conditions in which intracellular calcium homeostasis is disturbed, including ischemic diseases and arrhythmias. In particular, the compounds of formula (I) are useful as inotropic agents in the treatment and prevention of conditions in which inotropic support is required to maintain a sufficient level of blood supply, for example, in the treatment of heart failure or in the treatment of patients undergoing surgery.

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

wherein

Ri is H, halogen, cyano or nitro;

R₂ is H or halogen;

wherein at least one of Ri and R_? is other than H;

ring A is a group of formula (1’), (2’) or (3’)

the asterisk denoting the point of attachment to the ring B;

ring B is a group of formula (4’), (5’), (6’) or (7’)

R₃, R_S R_V and R₉ are, independently, H, halogen, or methyl;

R₄, Rr,_. Rs and Rio are, independently, H, halogen, methyl, amino or

-NHC(0)CH₃;

or a pharmaceutically acceptable salt thereof;

with the proviso that the compound of formula (I) is not any of the following compounds:

/V-(4-Bromophcnyl)-5-(2-fluorophcnyl)-2-furanmcthanaminc (2);

/V-(3-Chloro-4-fluorophcnyl)-5-(2-chlorophcnyl)-2-furanmcthanaminc (13); 5-(3-Chlorophenyl)-/V-(3,4-dichlorophenyl)-2-furanmethanamine (14);

/V-(3-Chloro-4-fluorophcnyl)-5-(3-chlorophcnyl)-2-furanmcthanaminc (16); 5-(3-Chlorophcnyl)-/V-(4-fluorophcnyl)-2-furanmcthanaminc (18);

5-(3-Chlorophcnyl)-/V-(4-chlorophcnyl)-2-furanmcthanaminc (20);

/V-(4-Chlorophcnyl)-5-(2-fluorophcnyl)-2-furanmcthanaminc (21);

/V-(4-Bromophcnyl)-5-phcnyl-2-furanmcthanaminc (27);

/V-(3,4-Dichlorophcnyl)-5-phcnyl-2-furanmcthanaminc (38);

/V-(4-Chlorophcnyl)-5-phcnyl-2-furanmcthanaminc (44);

5-(2-Chlorophcnyl)-/V-(3,4-dichlorophcnyl)-2-furanmcthanaminc (51);

;_'V-(4-Bromophcnyl)-5-(2-chlorophcnyl)-2-furanmcthanaminc (66);

;_'V-(4-Bromophcnyl)-5-(3-chlorophcnyl)-2-furanmcthanaminc (67);

5-(3-Chloro-2-mcthylphcnyl)-_;'V-(4-fluorophcnyl)-2-furanmcthanaminc (71); 5-(2-Chlorophcnyl)-/V-(4-fluorophcnyl)-2-furanmcthanaminc (73);

;_'V-(4-Bromophcnyl)-5-(3-chloro-2-mcthylphcnyl)-2-furanmcthanaminc (74); /V-(3-Chloro-4-fluorophcnyl)-5-phcnyl-2-furanmcthanaminc (76); /V-(3-Chloro-4-fluorophcnyl)-5-(3-chloro-2-mcthylphcnyl)-2-furanmcthan- amine (78);

5-(3-Chloro-2-mcthylphcnyl)-/V-(3,4-dichlorophcnyl)-2-furanmcthanaminc

(82);

/V-(3-Chloro-4-fluorophcnyl)-5-(2-fluorophcnyl)-2-furanmcthanaminc (91);

N-( 3 ,4-Dichlorophenyl)-5 -(2-fluorophenyl)-2-furanmethanamine (100);

5-(2-Chlorophcnyl)-/V-(4-chlorophcnyl)-2-furanmcthanaminc (107);

5-(3-Chloro-2-mcthylphcnyl)-_;'V-(4-chlorophcnyl)-2-furanmcthanaminc ( 109); 5-(2-Fluorophcnyl)-/V-(4-fluorophcnyl)-2-furanmcthanaminc (111); or /V-(4-Fluorophcnyl)-5-phcnyl-2-furanmcthanaminc (116).

In one class of compounds are compounds of formula (I), wherein, in case ring A is a group of formula (1’),

R4 is methyl, amino or -NHC(0)CH₃ or,

in case R_? is hydrogen or R₃ is halogen, then R4 can also be halogen, or in case R₂ is hydrogen, then R4 can also be hydrogen.

In a subclass of any of the above classes are compounds of formula (I), wherein ring A is a group of formula (1’). In a subclass of this class are compounds of formula (I), wherein

R4 is methyl, amino or -NHC(0)CH₃ or,

in case R_? is hydrogen or R₃ is halogen, then R4 can also be halogen, or in case R₂ is hydrogen, then R4 can also be hydrogen. In another subclass of any of the above classes are compounds wherein ring B is a group of formula (4’) or (5’), particularly wherein ring B is a group of formula (4’)·

In another subclass of any of the above classes are compounds wherein R₂ is fluoro.

In another subclass of any of the above classes are compounds wherein Ri is hydrogen and R₂ is fluoro. In another subclass of any of the above classes are compounds wherein R4 is amino. In another subclass of any of the above classes are compounds wherein R₃ is hydrogen and R₄ is amino. In one class of compounds are compounds of formula (I), wherein ring A is a group of formula (2’). In a subclass of this class are compounds of formula (I), wherein ring B is a group of formula (4’) or (5’), particularly wherein ring B is a group of formula (4’). In another subclass of any of the above classes are compounds wherein Ri is chloro or fluoro.

In another subclass of any of the above classes are compounds wherein R₂ is fluoro or hydrogen.

In another subclass of any of the above classes are compounds wherein R₄ is methyl, fluoro or hydrogen.

In another subclass of any of the above classes are compounds wherein R₃ is hydrogen and R₄ is methyl.

In another class of compounds are compounds of formula (I) which are represented by formula (IA)

wherein R_ls R₂ and ring B are as defined above.

In another class of compounds are compounds of formula (I) which are represented by formula (IB)

wherein R_ls R₂ and ring B are as defined above. In another class of compounds are compounds of formula (I) which are represented by formula (IC)

wherein R_ls R₂ and ring B are as defined above.

The present invention also provides a pharmaceutical composition comprising a compound of formula (I) as defined above. The present invention also provides a method for the treatment of conditions in which NCX inhibition is desired, comprising administering to a subject in need thereof a therapeutically effective amount of a compound of formula (I) as defined above.

In particular, the above conditions in which NCX inhibition is desired are conditions in which inotropic support is required to maintain a sufficient level of blood supply, for example for the treatment of heart failure or for the treatment of patients undergoing surgery.

The present invention also provides a compound of formula (I) as defined above, for use in the treatment of conditions in which NCX inhibition is desired. In particular, the above conditions in which NCX inhibition is desired are conditions in which inotropic support is required to maintain a sufficient level of blood supply, for example for the treatment of heart failure or for the treatment of patients undergoing surgery.

The present invention also provides a pharmaceutical composition comprising a compound of formula (I)

wherein

Ri is H, halogen, cyano or nitro;

R₂ is H or halogen;

wherein at least one of Ri and R_? is other than H;

ring A is a group of formula (G), (2’) or (3’)

the asterisk denoting the point of attachment to the ring B;

ring B is a group of formula (4’), (5’), (6’) or (7’)

R₃, R_S R_V and R₉ are, independently, H, halogen, or methyl;

R₄, R_f>. Rs and Rio are, independently, H, halogen, methyl, amino or

-NHC(0)CH₃; or a pharmaceutically acceptable salt thereof;

together with a pharmaceutically acceptable carrier.

The present invention also provides a method for the treatment of conditions in which NCX inhibition is desired, comprising administering to a subject in need thereof a therapeutically effective amount of a compound of formula (I)

wherein

Ri is H, halogen, cyano or nitro;

R₂ is H or halogen;

wherein at least one of Ri and R_? is other than H;

ring A is a group of formula (G), (2’) or (3’)

the asterisk denoting the point of attachment to the ring B;

ring B is a group of formula (4’), (5’), (6’) or (7’)

R₃, R_S R_V and R₉ are, independently, H, halogen, or methyl;

R₄, R_f>. Rs and Rio are, independently, H, halogen, methyl, amino or

-NHC(0)CH₃;

or a pharmaceutically acceptable salt thereof In particular, the above conditions in which NCX inhibition is desired are conditions in which inotropic support is required to maintain a sufficient level of blood supply, for example for the treatment of heart failure or for the treatment of patients undergoing surgery.

The present invention also provides a compound of formula (I)

wherein

Ri is H, halogen, cyano or nitro;

R₂ is H or halogen;

wherein at least one of Ri and R_? is other than H;

ring A is a group of formula (G), (2’) or (3’)

the asterisk denoting the point of attachment to the ring B;

ring B is a group of formula (4’), (5’), (6’) or (7’)

R₃, R_S R_V and R₉ are, independently, H, halogen, or methyl;

R₄, R_f>. Rs and Rio are, independently, H, halogen, methyl, amino or

-NHC(0)CH₃;

or a pharmaceutically acceptable salt thereof, for use in the treatment of conditions in which NCX inhibition is desired.

Detailed description of the invention The compounds of formula (I) wherein ring A is a group of formula (2’) or

(3’) can be prepared by reacting aniline derivatives of formula (II) with halide derivatives of formula (III) according to Scheme 1, wherein R_ls R₂ and ring B are the same as defined above, and ring A is a group of formula (2’) or (3’) as defined above.

SCHEME 1

The reaction is suitably carried out in the presence of a base, such as potassium carbonate, in a suitable solvent such as water at elevated temperature, for example in refluxing temperature. The compound of formula (I) can be isolated from the reaction mixture for example by extraction with a suitable solvent such as ethyl acetate and by evaporation of the solvent.

Compounds of formula (I) wherein ring B is substituted with an amino group can be prepared from the corresponding compound substituted with a nitro group by reducing the nitro group for example by hydrogenating in the presence of suitable catalyst such as palladium catalyst.

Compounds of formula (I) wherein ring A is a group of formula (1’) or (2’) and ring B is a group of formula (4’) can be prepared by reacting aniline derivatives of formula (II) with carboxylic acid derivatives of formula (IV) such as to obtain a carboxamide derivative of formula (V). The carbonyl group of the compound of formula (V) can then be reduced to obtain compounds of formula (I) as shown in Scheme 2, wherein R_ls R₂ are the same as defined above, ring A is a group of formula (G) or (2’) as defined above, and ring B is a group of formula (4’) as defined above.

SCHEME 2

The condensation reaction between the aniline derivative of formula (II) and the carboxylic acid derivative of formula (IV) is suitably carried out in the presence of a suitable coupling reagent such as l-ethyl-3-(3-dimethylaminopropyl)carbodiimide in a suitable solvent such as dichloromethane. The obtained compound of formula (V) can be isolated for example by adding water to the reaction mixture and evaporating the organic phase. The reduction of the carbonyl group of the compound (V) can be carried out with suitable reducing agent such as BH₃ THF in a suitable solvent, for example tetrahydrofuran, at elevated temperature.

Compounds of formula (I) wherein ring A is a group of formula (1’) or (2’) and ring B is a group of formula (5’), (6’) or (7’) can be prepared according to Scheme 3, wherein R_ls R₂ are the same as defined above, ring A is a group of formula (G) or (2’) as defined above, ring B is a group of formula (5’), (6’) or (7’) as defined above and X is halogen, for example bromo.

SCHEME 3

The condensation reaction between the aniline derivative of formula (II) and the carboxylic acid derivative of formula (VI) can be carried out as in Scheme 2. The reaction between compound of formula (VII) and ring B is suitably carried out in the presence of «-butyllithium, zinc chloride and tetrakis(triphenylphosphine)palladium in a suitable solvent such as tetrahydrofuran.

Compounds of formula (I) wherein ring A is a group of formula (1’) can also be prepared according to Scheme 4, wherein R_ls R₂, and ring B are the same as defined above, and ring A is a group of formula (1’) as defined above.

SCHEME 4

The reaction between the aniline derivative of formula (II) and the carbaldehyde derivative of formula (VI) can be carried out in the presence a strong acid such as / -tolucncsulfonic acid in a suitable solvent such as toluene or ethanol at elevated temperature. The reduction of the compound of formula (VII) can be carried out using a suitable reduction agent such as NaBH₄ in a suitable solvent such as ethanol.

The starting materials used in the processes are either commercially available or can be prepared using synthetic routes known in the literature, for example WO 2000/064888; WO 2001/038332; Bioorg & Med. Chem Lett, 2010, 20(9), 2933; Org. Biomol. Chem, 2003, 1(9), 1447 and ChemMedChem 2012, 7(6), 1020.

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. Compounds of the invention may be administered to a patient in therapeutical ly 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 NCX 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 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. The compounds of the invention can be given to the subject as the sole active ingredient or in combination with one of more other active ingredients.

The present invention will be explained in more detail by the following experiments and examples. The experiments and examples are meant only for illustrating purposes and do not limit the scope of the invention defined in claims.

EXPERIMENTS NCX inhibitory activity

Methods

NCX activity was measured from Sf9 cells that were stably transfected with human 1.1 NCX. Briefly, reverse-mode NCX activity was evoked by 50 % dilution of extracellular Na⁺ level by internal pipettor of fluorescence imaging plate reader FLEXstation (Molecular Devices, Sunnyvale, CA, USA) in 96-well plates while intracellular calcium level was simultaneously monitored. Typically 150 - 200 000 cells were loaded to each well at a volume of 50 mΐ. Cells were preincubated with intracellular calcium dye Fluo-4 and test compounds for about for about 1 h at room temperature before experiments. Normal extracellular solution contained: 172 mM NaCl, 10 mM HEPES, 1 mM CaCl₂, 1.2 mM MgCfl, 0,33 mM NaH₂P0₄, 5 mM Glucose and 5 mM probencid. pH was adjusted to 7.4 with NaOH. Na⁺-free extracellular solution contained: 147 mM NMDG, 10 mM HEPES, 1 mM CaCl₂, 1.2 MgCfl, 0.33 NaH₂P0 and 5 mM Glucose. pH was adjusted to 7.4 with HC1.

Osmolarity of both solutions was adjusted to 340 - 355 mOsm in order to match Sf9 cell media osmolarity. Dilution of extracellular Na⁺ induced robust and reproducible intracellular calcium elevations in human NCX expressing Sf9 cells. In each plate, the IC₅o determination of test compounds was based on relative fluorescence changes in comparison to control and 5 mM nickel acetate-induced NCX inhibition.

Results

The effect of the compounds of the invention on NCX inhibition is shown in Table 1. Table 1. IC50 values for inhibition of NCX by example compounds

EXAMPLES:

The compounds of the invention were prepared using the following general procedures, which are referred to in the examples that will follow. General Procedure A (Scheme 1):

To a round bottom flask, the phenyl oxazole derivative (1 equivalent), the aniline derivative (1 - 1.5 eq), the potassium carbonate (0.5 - 1 equivalent) and distilled water (0.13-0.39 M) were added. The reaction mixture was refluxed until completion of the reaction. The reaction mixture was then allowed to cool to room temperature and extracted with ethyl acetate. The combined organic phase was washed with brine and dried over Na₂S0 . Solvents were evaporated. General procedure B (Scheme 2 or 3):

Step 1

To a round bottom flask under an argon atmosphere, the phenyl oxazole carboxylic acid derivative or the phenyl furan carboxylic acid derivative (1 equivalent), the aniline derivative (1.1 - 1.5 equivalent) and dichloromethane (0.03 - 0.04 M) were added. 1 -Ethyl-3 -(3 -dimethylaminopropyl)carbodiimide (1.1 - 1.5 equivalent) was added to the mixture in portions and the reaction mixture was stirred at room temperature until completion of the reaction. Water was added to the reaction mixture and the resulting phases were separated. The organic phase was dried with Na₂S0 and solvents were evaporated.

Step 2

Under argon atmosphere, the oxazole carboxamide derivative or the furan carboxamide derivative (1 equivalent) was dissolved in dry tetrahydrofuran (0.04 M).

1 M BH₃-THF (4 equivalent) was added dropwise, and the reaction mixture was refluxed until completion of the reaction. The reaction mixture was then cooled to room temperature before placing in an ice bath. The reaction mixture was made acidic by dropwise addition of 3 M hydrochloric acid and subsequently stirred at room temperature until the reaction was complete. The reaction mixture was made neutral by the addition of diluted sodium hydroxide solution and then extracted with ethyl acetate. The combined organic phases were washed with brine and dried over Na₂S0 . Solvents were evaporated.

General procedure C (Scheme 4):

In a round bottom flask, the furan carbaldehyde derivative (1 equivalent), the aniline derivative (1 equivalent), / -tolucncsulfonic acid (5 mol-%) and toluene (0.018 - 0.072 M) were added. The reaction mixture was refluxed using a Dean-Stark apparatus until the reaction was complete. Solvents were evaporated, and dry ethanol (0.024 - 0.09 M) and NaBH₄ (2 equivalent) were subsequently added to the flask. The reaction mixture was stirred at room temperature until completion of the reaction.

The pH of the reaction mixture was made acidic using 1 M hydrochloric acid solution. The acidic reaction mixture was extracted with ethyl acetate, and the combined organic phases were dried with Na₂S0 and solvents were evaporated.

General procedure D:

The nitrophenyl derivative (1 equivalent) was dissolved in acetic acid (0.014 M). Zinc (20 equivalent) was added in small portions to the solution and the reaction mixture was stirred at room temperature until completion of the reaction. The reaction mixture was filtered through a pad of Celite®, which was washed with acetic acid and methanol. The filtrate was evaporated. The evaporation residue was dissolved in ethyl acetate and washed with 1 M sodium hydroxide. General procedure E:

The nitrophenyl derivative was dissolved in ethyl acetate and 10 % palladium on carbon (25 w-%) was added. The reaction mixture was hydrogenated until completion of the reaction. It was filtered through a pad of Celite® and the solvents were evaporated.

Example 1 : N-((2-(3-aminophenyl)oxazol-4-yl)methyl)-3-chloro-4-fluoro- aniline a) 3-Chloro-4-fluoro-N-((2-(3-nitrophenyl)oxazol-4-yl)methyl)aniline

The title compound was prepared according to the general procedure A using 4-(chloromethyl)-2-(3-nitrophenyl)oxazole (0.84 g, 3.53 mmol), 3-chloro-4-fluoro- aniline (0.77 g, 5.28 mmol), K₂C0₃ (0.49 g, 3.52 mmol) and water (15 ml). The product was purified by flash column chromatography using ethyl acetate and heptane as eluent and converted to HC1 salt. Isolated yield 270 mg. ¹ H NMR (DMSO-d₆) d: 8.65-8.67 (m, 1H), 8.35-8.39 (m, 2H), 8.19 (s, 1H), 7.82-7.87 (m, 1H), 7.09-7.15 (m, 1H), 6.78-6.82 (m, 1H), 6.62-6.66 (m, 1H), 4.24 (s, 2H). b) N-((2-(3-aminophenyl)oxazol-4-yl)methyl)-3-chloro-4-fluoroaniline The title compound was prepared according to the general procedure E using

3-chloro-4-fluoro-/V-((2-(3-nitrophcnyl)oxazol-4-yl)mcthyl)anilinc (220 mg, 0.63 mmol), 10 % palladium on carbon (55 mg) and ethyl acetate (20 ml). Isolated yield 196 mg. 1H NMR (DMSO-d₆) d: 8.11 (s, 1H), 7.81-7.86 (m, 2H), 7.55-7.60 (m, 1H), 7.37-7.41 (m, 1H), 7.09-7.14 (m, 1H), 6.78-6.81 (m, 1H), 6.61-6.68 (m, 1H), 4.21 (s,

2H).

Example 2: 3-Chloro-4-fluoro-N-((2-phenyloxazol-4-yl)methyl)aniline The title compound was prepared according to the general procedure A using

4-(chloromethyl)-2-phenyloxazole (22 g, 114 mmol), 3-chloro-4-fluoroaniline (16.5 g, 114 mmol), K₂C0₃ (7.85 g, 57 mmol) and water (500 ml). The product was purified by flash column chromatography using ethyl acetate and heptane as eluent. The product was further purified by recrystallization from ether/heptane and converted to HC1 salt. Isolated yield 5.4 g. 1H NMR (DMSO-d₆) d: 8.07 (s, 1H), 7.94-7.99 (m,

2H), 7.51-7.56 (m, 3H), 7.08-7.15 (m, 1H), 6.78-6.82 (m, 1H), 6.61-6.66 (m, 1H), 4.20 (s, 2H).

Example 3: 3-Chloro-4-fluoro-N-((2-(o-tolyl)oxazol-4-yl)methyl)aniline

The title compound was prepared according to the general procedure A using 4-(chloromethyl)-2-(o-tolyl)oxazole (1 g, 4.82 mmol), 3-chloro-4-fluoroaniline (1.05 g, 7.22 mmol), K₂C0₃ (0.33 g, 2.41 mmol) and water (25 ml). The crude product was made into a hydrochloride salt and triturated with ethyl acetate. The crude product was then released from the salt form and crystallized with ether/heptane. The product was made into a hydrochloride salt. Isolated yield 209 mg. ¹ H NMR (DMSO-dr,) d: 8.08 (s, 1H), 7.87-7.92 (m, 1H), 7.31-7.44 (m, 4H), 7.08-7.16 (m, 1H), 6.81-6.87 (m, 1H), 6.62-6.69 (m, 1H), 4.22 (s, 2H), 2.62 (s, 3H) (1H +). Example 4: 3-Chloro-4-fluoro-N-((2-(m-tolyl)oxazol-4-yl)methyl)aniline

The title compound was prepared according to the general procedure A using 4-(chloromethyl)-2-(m-tolyl)oxazole (2 g, 9.63 mmol), 3-chloro-4-fluoroaniline (2.1 g, 14.44 mmol), K₂C0₃ (0.66 g, 4.82 mmol) and water (40 ml). The product was recrystallized from ether/heptane and converted to HC1 salt. Isolated yield 457 mg. ¹ H NMR (DMSO-de) d: 8.05 (s, 1H), 7.73-7.80 (m, 2H), 7.38-7.45 (m, 1H), 7.31-7.36 (m, 1H), 7.09-7.15 (m, 1H), 6.78-6.83 (m, 1H), 6.62-6.67 (m, 1H), 4.20 (s, 2H), 2.38 (s, 3H).

Example 5: 3-Chloro-4-fluoro-N-((2-(2-fluorophenyl)oxazol-4-yl)methyl)- aniline

The title compound was prepared according to the general procedure A using 4-(chloromethyl)-2-(2-fluorophenyl)oxazole (0.7 g, 3.31 mmol), 3-chloro-4-fluoro- aniline (0.6 g, 3.97 mmol), K₂C0₃ (0.23 g, 1.65 mmol) and water (25 ml). The product was triturated with ether/heptane and converted to HC1 salt. Isolated yield 255 mg. 1H NMR (DMSO-de) d: 8.13 (s, 1H), 7.98-8.02 (m, 1H), 7.55-7.61 (m, 1H), 7.35-7.43 (m, 2H), 7.08-7.14 (m, 1H), 6.77-6.80 (m, 1H), 6.60-6.65 (m, 1H), 6.29- 6.33 (m, 1H), 4.22 (d, 2H). Example 6: 3,4-Difluoro-N-((2-phenyloxazol-4-yl)methyl)aniline

The title compound was prepared according to the general procedure A using 4-(chloromethyl)-2-phenyloxazole (1 g, 5.16 mmol), 3,4-difluoroaniline (768 mΐ, 7.75 mmol), K₂C0₃ (357 mg, 2.58 mmol) and water (35 ml). The product was purified by gel filtration using ethyl acetate and heptane (1 : 1) as the eluent. The compound was further purified by recrystallization from ether/heptane and converted to HC1 salt. Isolated yield 434 mg. 1H NMR (DMSO-d₆) d: 8.07 (s, 1H), 7.93-7.99 (m, 2H), 7.49- 7.57 (m, 3H), 7.07-7.15 (m, 1H), 6.62-6.68 (m, 1H), 6.42-6.47 (m, 1H), 4.19 (s, 2H). Example 7: 3,4-Dichloro-N-((2-phenyloxazol-4-yl)methyl)aniline

The title compound was prepared according to the general procedure A using 4-(chloromethyl)-2-phenyloxazole (250 mg, 1.29 mmol), 3,4-dichloroaniline (209 mg, 1.29 mmol), K₂C0₃ (89 mg, 0.65 mmol) and water (8.1 ml). The product was purified by flash column chromatography using ethyl acetate and heptane as eluent followed by heptane and 2-propanol as eluent. The product was further purified by

recrystallization from ether/heptane and converted to HC1 salt. Isolated yield 11 mg.

1H NMR (DMSO-de) d: 8.07 (s, 1H), 7.94-8.01 (m, 2H), 7.51-7.57 (m, 3H), 7.26 (d, 1H), 6.84-6.88 (m, 1H), 6.63-6.69 (m, 1H), 4.22 (s, 2H). Example 8: 3-Chloro-N-((2-(3-chlorophenyl)oxazol-4-yl)methyl)-4-fluoro- aniline

The title compound was prepared according to the general procedure A using 4-(chloromethyl)-2-(3-chlorophenyl)oxazole (300 mg, 1.26 mmol), 3-chloro-4-fluoro- aniline (220 mg, 1.51 mmol), K2CO3 (87 mg, 0.63 mmol) and water (10 ml). The product was converted to HC1 salt. Isolated yield 157 mg. ¹ H NMR (DMSO-d₆) d: 8.11 (s, 1H), 7.90-7.95 (m, 2H), 7.57-7.62 (m, 2H), 7.08-7.14 (m, 1H), 6.76-6.80 (m, 1H), 6.60-6.65 (m, 1H), 4.20 (s, 2H).

Example 9: 3,4-Difluoro-N-((2-(m-tolyl)oxazol-4-yl)methyl)aniline

The title compound was prepared according to the general procedure A using 4-(chloromethyl)-2-(m-tolyl)oxazole (500 mg, 2.41 mmol), 3,4-difluoroaniline (358 mΐ, 3.61 mmol), K₂C0₃ (166 mg, 1.20 mmol) and water (15 ml). The product was triturated with ether/heptane and converted to HC1 salt. Isolated yield 65 mg. ¹ H NMR (DMSO-d₆) d: 8.05 (s, 1H), 7.73-7.81 (m, 2H), 7.39-7.45 (m, 1H), 7.31-7.36 (m, 1H), 7.06-7.16 (m, 1H), 6.59-6.68 (m, 1H), 6.40-6.47 (m, 1H), 4.18 (s, 2H), 2.37-2.40 (m, 3H).

Example 10: 3-Fluoro-N-((2-phenyloxazol-4-yl)methyl)aniline

The title compound was prepared according to the general procedure A using 4-(chloromethyl)-2-phenyloxazole (200 mg, 1.03 mmol), 3-fluoroaniline (126 mg,

1.14 mmol), K2CO3 (114 mg, 0.82 mmol) and water (3 ml). The product was converted to HC1 salt. Isolated yield 55 mg. 1H NMR (DMSO-d₆) d: 8.07 (s, 1H), 7.93-8.00 (m, 2H), 7.49-7.57 (m, 3H), 7.04-7.11 (m, 1H), 6.41-6.52 (m, 2H), 6.28- 6.35 (m, 1H), 4.21 (s, 2H).

Example 11: 3-(((2-Phenyloxazol-4-yl)methyl)amino)benzonitrile

To a round bottom flask, 4-(chloromethyl)-2-phenyloxazole (1.50 g, 7.75 mmol), 3-aminobenzonitrile (1.37 g, 11.62 mmol), K₂C0₃ (1.07 g, 7.75 mmol) and water (20 ml) were added. The mixture was refluxed until completion. The mixture was allowed to cool to room temperature and 1 ml of 1 M hydrochloric acid was added. The solid product was filtered and converted to HC1 salt and further purified by flash column chromatography using heptane and isopropanol as eluent. Isolated yield 380 mg. 1H NMR (DMSO-d₆) d: 8.10 (s, 1H), 7.94-7.99 (m, 2H), 7.51-7.56 (m, 3H), 7.23-7.28 (m, 1H), 6.92-7.02 (m, 3H), 4.26 (s, 2H). Example 12: 3-Chloro-N-((2-phenyloxazol-4-yl)methyl)aniline

The title compound was prepared according to the general procedure A using 4-(chloromethyl)-2-phenyloxazole (1.0 g, 5.16 mmol), 3-chloroaniline (0.82 ml, 7.75 mmol), K₂C0₃ (0.71 g, 5.16 mmol) and water (15 ml). The product was recrystallized from ether/heptane and converted to HC1 salt. Isolated yield 62 mg. ¹ H NMR

(DMSO-de) d: 8.07 (s, 1H), 7.94-7.99 (m, 2H), 7.50-7.56 (m, 3H), 7.05-7.10 (m,

1H), 6.67-6.71 (m, 1H), 6.60-6.64 (m, 1H), 6.54-6.57 (m, 1H), 4.20-4.24 (m, 2H).

Example 13: 3-(((2-(m-Tolyl)oxazol-4-yl)methyl)amino)benzonitrile

The title compound was prepared according to the general procedure A using 4-(chloromethyl)-2-(m-tolyl)oxazole (915 mg, 4.41 mmol), 3-aminobenzonitrile (781 mg, 6.61 mmol), K₂C0₃ (304 mg, 2.20 mmol) and water (25 ml). The product was converted to HC1 salt and purified further by gel filtration. Isolated yield 92 mg. ¹ H NMR (DMSO-de) d: 8.08 (s, 1H), 7.73-7.80 (m, 2H), 7.39-7.44 (m, 1H), 7.32-7.36 (m, 1H), 7.23-7.28 (m, 1H), 6.96-7.01 (m, 2H), 6.92-6.96 (m, 1H), 6.61-6.67 (m,

1H), 4.25 (d, 2H), 2.38 (s, 3H).

Example 14: 3-Nitro-N-((2-phenyloxazol-4-yl)methyl)aniline

The title compound was prepared according to the general procedure A using 4-(chloromethyl)-2-phenyloxazole (200 mg, 1.03 mmol), 3-nitroaniline (157 mg, 1.14 mmol), K₂CO₃ (114 mg, 0.82 mmol) and water (3 ml). The product was recrystallized from ether/heptane and converted to HC1 salt. Isolated yield 20 mg. 1H NMR

(DMSO-de) d: 8.10 (s, 1H), 7.91-8.00 (m, 2H), 7.51-7.56 (m, 3H), 7.46-7.49 (m,

1H), 7.31-7.38 (m, 2H), 7.07-7.12 (m, 1H), 4.31 (s, 2H).

Example 15: 3-Chloro-4-fluoro-N-((2-(3-fluorophenyl)oxazol-4-yl)methyl)- aniline The title compound was prepared according to the general procedure A using 4-(chloromethyl)-2-(3-fluorophenyl)oxazole (200 mg, 0.95 mmol), 3-chloro-4-fluoro- aniline (138 mg, 0.95 mmol), K₂C0₃ (131 mg, 0.95 mmol) and water (3 ml). The product was recrystallized from ether/heptane and converted to HC1 salt. Isolated yield 30 mg. 1H NMR (DMSO-d₆) d: 8.11 (s, 1H), 7.78-7.83 (m, 1H), 7.68-7.72 (m, 1H), 7.56-7.63 (m, 1H), 7.36-7.41 (m, 1H), 7.08-7.14 (m, 1H), 6.76-6.80 (m, 1H), 6.60-6.65 (m, 1H), 4.20 (s, 2H).

Example 16: 4-Fluoro-N-((2-(m-tolyl)oxazol-4-yl)methyl)aniline

The title compound was prepared according to the general procedure A using 4-(chloromethyl)-2-(m-tolyl)oxazole (1.48 g, 7.13 mmol), 4-fluoroaniline (1 ml, 10.69 mmol), K₂C0₃ (493 mg, 3.56 mmol) and water (40 ml). The product was purified by gel filtration and converted to HC1 salt. Isolated yield 63 mg. ¹ H NMR (DMSO-dr,) d: 8.02 (s, 1H), 7.73-7.80 (m, 2H), 7.38-7.44 (m, 1H), 7.32-7.36 (m, 1H), 6.90-6.98 (m,

2H), 6.67-6.72 (m, 2H), 4.19 (s, 2H), 2.38 (s, 3H).

Example 17: 3,4-Difluoro-N-((4-phenyloxazol-2-yl)methyl)aniline The title compound was prepared according to the general procedure A using

2-(chloromethyl)-4-phenyloxazole (0.15 g, 0.77 mmol), 3,4-difluoroaniline (0.12 ml, 1.16 mmol), K₂C0₃ (0.05 g, 0.39 mmol) and water (5ml). The product was converted to HC1 salt and further purified by preparative thin layer chromatography using heptane and ethyl acetate as eluent. Isolated yield 12 mg. 1H NMR (DMSO-dr,) d: 8.54 (s, 1H), 7.73-7.77 (m, 2H), 7.40-7.44 (m, 2H), 7.29-7.34 (m, 1H), 7.11-7.17 (m,

1H), 6.63-6.71 (m, 1H), 6.43-6.48 (m, 1H), 4.45 (s, 2H).

Example 18: 3,4-Difluoro-N-((2-(furan-2-yl)oxazol-4-yl)methyl)aniline The title compound was prepared according to the general procedure A using

4-(chloromethyl)-2-(furan-2-yl)oxazole (300 mg, 1.63 mmol), 3,4-difluoroaniline (141 mg, 1.09 mmol), K₂C0₃ (151 mg, 1.09 mmol) and water (5 ml). The product purified by flash column chromatography using heptane and ethyl acetate as eluent and converted to HC1 salt. Isolated yield 33 mg. 1H NMR (DMSO-d₆) d: 8.03 (s, 1H), 7.90-7.92 (m, 1H), 7.07-7.14 (m, 2H), 6.69-6.72 (m, 1H), 6.60-6.66 (m, 1H), 6.40- 6.45 (m, 1H), 4.16 (s, 2H). Example 19: 3-Chloro-N-((2-(2-chlorophenyl)oxazol-4-yl)methyl)-4-fluoro- aniline a) N-(3-chloro-4-fluorophenyl)-2-(2-chlorophenyl)oxazole-4-carboxamide

The title compound was prepared according to the general procedure B, step

1, using 2-(2-chlorophenyl)oxazole-4-carboxylic acid (0.50 g, 2.24 mmol), 3-chloro- 4-fluoroaniline (0.49 g, 3.35 mmol), 1 -ethyl-3 -(3 -dimethylaminopropyl)carbodiimide (0.64 g, 3.35 mmol) and dichloromethane (50 ml). The product was purified by trituration with heptane and ethyl acetate. Isolated yield 0.55 g. 1H NMR (DMSO-dr,) d: 10.43 (s, 1H), 9.00 (s, 1H), 8.09-8.13 (m, 1H), 8.04-8.09 (m, 1H), 7.79-7.84 (m, 1H), 7.68-7.72 (m, 1H), 7.54-7.66 (m, 2H), 7.40-7.46 (m, 1H). b) 3-Chloro-N-((2-(2-chlorophenyl)oxazol-4-yl)methyl)-4-fluoroaniline

The title compound was prepared according to the general procedure B, step

2, using 'V-(3-chloro-4-fluorophcnyl)-2-(2-chlorophcnyl)oxazolc-4-carboxamidc (0.55 g, 1.57 mmol), 1M BH₃ THF (6.3 ml) and tetrahydrofuran (40 ml). The product was purified by flash column chromatography using ethyl acetate and heptane as eluent and converted to HC1 salt. Isolated yield 246 mg. 1H NMR (DMSO-d₆) d: 8.16 (s, 1H), 7.94-7.98 (m, 1H), 7.62-7.66 (m, 1H), 7.48-7.57 (m, 2H), 7.09-7.15 (m, 1H), 6.80-6.84 (m, 1H), 6.62-6.67 (m, 1H), 4.22 (s, 2H).

Example 20: N-((5-(2,3-dichlorophenyl)furan-2-yl)methyl)-4-fluoroaniline a) 5-(2,3-Dichlorophenyl)-N-(4-fluorophenyl)furan-2-carboxamide

The title compound was prepared according to the general procedure B, step 1, using 5-(2,3-dichlorophenyl)furan-2-carboxylic acid (0.2 g, 0.78 mmol), 4-fluoro- aniline (0.07 ml, 0.71 mmol), 1 -ethyl-3 -(3 -dimethylaminopropyl)carbodiimide (0.149 g, 0.78 mmol) and dichloromethane (20 ml). The product was purified by column chromatography using ethyl acetate and heptane as eluent. Isolated yield 100 mg. ¹ H NMR (DMSO-de) d: 10.32 (s, 1H), 8.14-8.18 (m, 1H), 7.71-7.79 (m, 3H), 7.53-7.58 (m, 1H), 7.46-7.49 (m, 1H), 7.39-7.42 (m, 1H), 7.19-7.26 (m, 2H). b) N-((5-(2,3-dichlorophenyl)furan-2-yl)methyl)-4-fluoroaniline

The title compound was prepared according to the general procedure B, step 2, using 5-(2,3-dichlorophcnyl)-/V-(4-fluorophcnyl)furan-2-carboxamidc (0.1 g, 0.28 mmol), 1M BH₃-THF (2 ml,) and tetrahydrofuran (5 ml). The product was purified by flash column chromatography using ethyl acetate and heptane (1 :2) as eluent and converted to HC1 salt. Isolated yield 30 mg. 1H NMR (DMSO-d₆) d: 7.76-7.80 (m, 1H), 7.57-7.62 (m, 1H), 7.42-7.48 (m, 1H), 7.12-7.15 (m, 1H), 6.93-7.00 (m, 2H), 6.72-6.79 (m, 2H), 6.48-6.53 (m, 1H), 4.36 (s, 2H).

Example 21: 4-Fluoro-/V-((5-(m-tolyl)furan-2-yl)methyl)aniline a) N-(4-fluorophenyl)-5-(m-tolyl)furan-2-carboxamide The title compound was prepared according to the general procedure B, stepl, using 5-(m-tolyl)furan-2-carboxylic acid (340 mg, 1.68 mmol), 4-fluoroaniline (239 mΐ, 2.52 mmol), 1 -ethyl-3 -(3 -dimethylaminopropyl)carbodiimide (482 mg, 2.52 mmol) and dichloromethane (50 ml). The product was purified by gel filtration using ethyl acetate and heptane as eluent. Isolated yield 306 mg. 1H NMR (DMSO-dr,) d: 10.20 (s, 1H), 7.74-7.80 (m, 4H), 7.35-7.41 (m, 2H), 7.18-7.26 (m, 3H), 7.15 (d, 1H), 2.39

(s, 3H). b) 4-Fluoro-N-((5-(m-tolyl)furan-2-yl)methyl)aniline The title compound was prepared according to the general procedure B, step

2, using /V-(4-fluorophenyl)-5-(m-tolyl)furan-2-carboxamide (305 mg, 1.03 mmol), 1 M BH₃-THF (7.2 ml,) and tetrahydrofuran (10 ml). The product was converted to HC1 salt and triturated with ether. Isolated yield 239 mg. 1H NMR (DMSO-dr,) d: 7.42-7.49 (m, 2H), 7.26-7.32 (m, 1H), 7.07-7.11 (m, 1H), 6.96-7.04 (m, 2H), 6.78- 6.85 (m, 3H), 6.42 (d, 1H), 4.34 (s, 2H), 2.33 (s, 3H).

Example 22: 3,4-Difluoro-N-((5-(oxazol-2-yl)furan-2-yl)methyl)aniline a) N-((5-bromofuran-2-yl)methyl)-3,4-difluoroaniline The title compound was prepared according to the general procedure B, step 2, using 5-bromo-/V-(3,4-difluorophcnyl)furan-2-carboxamidc (1.47 g, 4.87 mmol), 1M BH₃-THF (19 ml) and tetrahydrofuran (5 ml). The product was purified by flash column chromatography. Isolated yield 0.96 g. 1H NMR (DMSO-d₆) d: 7.06-7.15 (m, 1H), 6.57-6.65 (m, 1H), 6.48 (d, 1H), 6.40-6.44 (m, 1H), 6.39 (d, 1H), 6.31-6.37 (m,

1H), 4.18-4.24 (m, 2H). b) 3,4-Difluoro-N-((5-(oxazol-2-yl)furan-2-yl)methyl)aniline Oxazole (217 mΐ, 3.30 mmol) was dissolved in dry tetrahydrofuran under argon atmosphere. The solution was cooled to -78 °C and 1.6 M «-butyllithium in hexane (1.77 ml) was added keeping the temperature under -60 °C. The mixture was stirred vigorously before the portion wise addition of dry zinc chloride (1.3 g, 9.44 mmol). The mixture was allowed to warm to room temperature and tetrakis(triphenyl- phosphine)palladium (136 mg, 0.12 mmol) was added, followed by the addition of N- ((5-bromofuran-2-yl)methyl)-3,4-difluoroaniline (680 mg, 2.36 mmol). The mixture was stirred vigorously at 60 °C until completion of the reaction. The solvents were evaporated and the residue was dissolved in saturated ammonium chloride and ethyl acetate. The aqueous phase was extracted with ethyl acetate. The combined organic phases were dried with Na₂S0 and solvents were evaporated. The product was purified by flash column chromatography using ethyl acetate and heptane as eluents and converted to HC1 salt. Isolated yield 121 mg. 1H NMR (DMSO-d₆) d: 8.16 (s, 1H), 7.35 (s, 1H), 7.07-7.15 (m, 1H), 7.05 (d, 1H), 6.63-6.69 (m, 1H), 6.54 (d, 1H), 6.43-6.48 (m, 1H), 4.34 (s, 2H).

Example 23: N-((5-(3-aminophenyl)furan-2-yl)methyl)-4-fluoroaniline a) 4-Fluoro-N-((5-(3-nitrophenyl)furan-2-yl)methyl)aniline The title compound was prepared according to the general procedure C using

5-(3-nitrophenyl)furan-2-carbaldehyde (5 g, 23 mmol), 4-fluoroaniline (2,18, 23 mmol), /?-toluenesulfonic acid (219 mg, 1.1 mmol) and toluene (150 ml). The amine reduction was performed using dry ethanol (100 ml) and NaBH₄ (1.74 g, 46 mmol). The product was purified by triturating with heptane. Isolated yield 7.18 g. 1H NMR (DMSO-de) d: 8.41-8.40 (m, 1H), 8.10-8.08 (m, 2H), 7.72-7.68 (m, 1H), 7.16 (d, 1H), 6.95-6.91 (m, 2H), 6.70-6.67 (m, 2H), 6.47 (d, 1H), 6.13-6.11 (m, 1H), 4.32 (d, 2H). b) N-((5-(3-aminophenyl)furan-2-yl)methyl)-4-fluoroaniline

The title compound was prepared according to the general procedure D using 4-fluoro-/V-((5-(3-nitrophcnyl)furan-2-yl)mcthyl)anilinc (0.66 g, 2.1 mmol), zinc (2.75 g, 42 mmol) and acetic acid (150 ml). The product was purified by flash column chromatography using ethyl acetate and toluene as eluent. Isolated yield 440 mg. ¹ H NMR (DMSO-d₆) d: 7.65-7.71 (m, 1H), 7.60 (s, 1H), 7.47-7.55 (m, 1H), 7.25-7.30 (m, 1H), 7.01-7.08 (m, 2H), 6.87-6.97 (m, 3H), 6.50 (d, 1H), 4.40 (s, 2H).

Example 24: N-((5-(3-aminophenyl)furan-2-yl)methyl)-3-chloro-4-fluoro- aniline a) 3-Chloro-4-fluoro-N-((5-(3-nitrophenyl)furan-2-yl)methyl)aniline

The title compound was prepared according to the general procedure C using 5-(3-nitrophenyl)furan-2-carbaldehyde (746 mg, 3.43 mmol), 3-chloro-4-fluoroaniline (500 mg, 3.43 mmol), /?-toluenesulfonic acid (33 mg, 0.17 mmol) and toluene (60 ml). The amine reduction was performed using dry ethanol (30 ml) and NaBH₄ (260 mg, 6.87 mmol). The product was purified by gel filtration chromatography using ethyl acetate and heptane as eluent. Isolated yield 1.16 g. ¹ H NMR (DMSO-dr,) d: 8.41- 8.40 (m, 1H), 8.11-8.08 (m, 2H), 7.72-7.68 (m, 1H), 7.16-7.10 (m, 2H), 6.84-6.82 (m, 1H), 6.68-6.65 (m, 1H), 6.50 (d, 1H), 6.43-6.40 (m, 1H), 4.36 (d, 2H). b) N-((5-(3-aminophenyl)furan-2-yl)methyl)-3-chloro-4-fluoroaniline

The title compound was prepared according to the general procedure E using 3-chloro-4-fluoro-/V-((5-(3-nitrophcnyl)furan-2-yl)mcthyl)anilinc (1.16 g, 3.35 mmol), 10 % palladium on carbon (350 mg, 30 w-%) and ethyl acetate (60 ml). The product was purified by flash column chromatography using ethyl acetate and heptane as eluent and further purified by recrystallization from methanol/ether. Isolated yield 149 mg. 1H NMR (DMSO-de) d: 7.60-7.63 (m, 1H), 7.45-7.54 (m, 2H), 7.10-7.21 (m, 2H), 6.93 (d, 1H), 6.78-6.82 (m, 1H), 6.62-6.68 (m, 1H), 6.46 (d, 1H), 4.32 (s, 2H). Example 25 : N-((5 -(3 -aminophenyl)furan-2-yl)methyl)-3 -chloroaniline a) 3-Chloro-N-((5-(3-nitrophenyl)furan-2-yl)methyl)aniline The title compound was prepared according to the general procedure C using

5-(3-nitrophenyl)furan-2-carbaldehyde (0.5 g, 2.3 mmol), 3-chloroaniline (0.29 g, 2.3 mmol), / -tolucncsulfonic acid (20 mg, 0.11 mmol) and toluene (60 ml). The amine reduction was performed using dry ethanol (40 ml) and NaBH₄ (174 mg, 4.6 mmol). The product was purified by gel filtration chromatography using ethyl acetate as eluent. Isolated yield 0.87 g. 1H NMR (DMSO-d₆) d: 8.42-8.41 (m, 1H), 8.11-8.09 (m, 2H), 7.73-7.69 (m, 1H), 7.17 (d, 1H), 7.11- 7.06 (m, 1H), 6.73-6.72 (m,lH), 6.66-6.63 (m, 1H), 6.58-6.55 (m, 1H), 6.50 (d, 1H), 4.37 (s, 2H). b) N-((5 -(3 -aminophenyl)furan-2-yl)methyl)-3 -chloroaniline

The title compound was prepared according to the general procedure D using 3-chloro-/V-((5-(3-nitrophcnyl)furan-2-yl)mcthyl)anilinc (0.7 g, 2.12 mmol), zinc (2.7 g, 42 mmol) and acetic acid (150 ml). The product was converted to HC1 salt and triturated with ethyl acetate. Isolated yield 650 mg (91 %). ¹ H NMR (DMSO-d₆) d: 7.53-7.57 (m, 1H), 7.41-7.48 (m, 2H), 7.05-7.15 (m, 2H), 6.89 (d, 1H), 6.68-6.72

(m, 1H), 6.61-6.66 (m, 1H), 6.54-6.59 (m, 1H), 6.44 (d, 1H), 4.33 (s, 2H).

Example 26 : N-(3 -(5 -(((4-fluorophenyl)amino)methyl)furan-2-yl)phenyl)- acetamide

Under argon atmosphere .V-((5-(3-aminophcnyl)furan-2-yl)mcthyl)-4- fluoroaniline (1 g, 3.54 mmol) was dissolved in dichloromethane (50 ml). The solution was cooled in an ice bath before the addition of triethylamine (1.48 ml, 10.63 mmol) and acetyl chloride (277 mΐ, 3.90 mmol). The mixture was allowed to warm to room temperature and was stirred until completion of the reaction. Water was added to the mixture and the pH was adjusted to pH 5-6. The organic phase was separated and evaporated. The product was purified by gel filtration chromatography using ethyl acetate and heptane as eluent. The product was converted to HC1 salt and triturated with dichloromethane. Isolated yield 630 mg. ¹ H NMR (DMSO-d₆) d: 9.99-10.06 (m, 1H), 7.87-7.93 (m, 1H), 7.44-7.51 (m, 1H), 7.29-7.35 (m, 2H), 6.89-7.01 (m, 2H), 6.69-6.80 (m, 3H), 6.39-6.44 (m, 1H), 4.30 (s, 2H), 2.00-2.09 (s, 3H). Example 27: 3,4-Difluoro-N-((5-(pyridin-4-yl)furan-2-yl)methyl)aniline

The title compound was prepared according to the general procedure C using 5-(pyridin-4-yl)furan-2-carbaldehyde (78 mg, 0.45 mmol), 3,4-difluoroaniline (45 mΐ, 0.45 mmol), p-toluenesulfonic acid (5 mg, 0.02 mmol) and toluene (20 ml). The amine reduction was performed using dry ethanol (10 ml) and NaBH₄ (34 mg, 0.90 mmol). The crude product was purified by flash column chromatography using ethyl acetate and heptane as eluent. The product was converted to HC1 salt. Isolated yield 30 mg. 1H NMR (DMSO-de) d: 8.81-8.84 (m, 2H), 8.11-8.14 (m, 2H), 7.75 (d, 1H),

7.09-7.17 (m, 1H), 6.65-6.71 (m, 2H), 6.45-6.49 (m, 1H), 4.42 (s, 2H).

Example 28: 4-Fluoro-N-((5-(pyridin-2-yl)furan-2-yl)methyl)aniline a) (E)-4-fluoro-N-((5-(pyridin-2-yl)furan-2-yl)methylene)aniline

The title compound was prepared a adding 5-(pyridin-2-yl)furan-2- carbaldehyde (1.54 g, 8.89 mmol), 4-fluoroaniline (0.99 g, 8.89 mmol) and ethanol (6 ml) to a suitable round bottomed flask. The mixture was refluxed until completion of the reaction. The product was crystallized by addition of water to the still warm ethanol. The isolated yield 2.01 g. 1H NMR (DMSO-d₆) d: 8.63-8.68 (m, 1H), 8.52 (s, 1H), 7.87-7.96 (m, 2H), 7.24-7.41 (m, 7H). b) 4-Fluoro-N-((5-(pyridin-2-yl)furan-2-yl)methyl)aniline

The title compound was prepared by adding (E)-4-fluoro-N-((5-(pyridin-2-yl)- furan-2-yl)methylene)aniline (2.0 g, 7.51 mmol) and methanol (16 ml) to a suitable round bottomed flask. The solution was heated to 40 °C and NaBH₄ (0.28 g, 7.51 mmol) was added portion wise. The mixture was refluxed until completion of the reaction. The product was crystallized from the reaction mixture by addition of water. The product was purified by flash chromatography using dichloromethane and methanol as eluent and converted to HC1 salt. Isolated yield 1.95 g. 1H NMR

(DMSO-de) d: 8.59-8.63 (m, 1H), 8.03-8.11 (m, 1H), 7.83-7.90 (m, 1H), 7.42-7.49 (m, 1H), 7.26-7.33 (m, 1H), 6.96-7.03 (m, 2H), 6.75-6.85 (m, 2H), 6.55 (d, 1H),

4.40 (s, 2H). Example 29: 3,4-Difluoro-N-((5-(pyridin-3-yl)furan-2-yl)methyl)aniline

The title compound was prepared according to the general procedure C using 5-(pyridin-3-yl)furan-2-carbaldehyde (511 mg, 2.95 mmol), 3,4-difluoroaniline (293 mΐ, 2.95 mmol), / -tolucncsulfonic acid (28 mg, 0.15 mmol) and toluene (60 ml). The amine reduction was performed using dry ethanol (40 ml) and NaBH₄ (223 mg, 5.90 mmol). The product was purified by flash column chromatography using ethyl acetate and heptane as eluent. Isolated yield 324 mg. 1H NMR (DMSO-d₆) d: 8.89-8.92 (m, 1H), 8.44-8.48 (m, 1H), 7.98-8.03 (m, 1H), 7.41-7.46 (m, 1H), 7.08-7.16 (m, 1H), 7.03 (d, 1H), 6.63-6.71 (m, 1H), 6.45-6.50 (m, 2H), 6.32-6.42 (m, 1H), 4.30-4.34

(m, 2H).

Example 30: 3,4-Difluoro-N-((5-(pyridin-2-yl)furan-2-yl)methyl)aniline The title compound was prepared according to the general procedure C using

5-(pyridin-2-yl)furan-2-carbaldehyde (1.24 g, 7.16 mmol), 3,4-difluoroaniline (710 mΐ, 7.16 mmol), ), / -tolucncsulfonic acid (68 mg, 0.36 mmol) and toluene (100 ml). The amine reduction was performed using dry ethanol (80 ml) and NaBH₄ (542 mg, 14.32 mmol). The product was purified by flash column chromatography using ethyl acetate and heptane as eluent. Isolated yield 1.365 g. 1H NMR (DMSO-d₆) d: 8.52-8.57 (m, 1H), 7.80-7.87 (m, 1H), 7.64-7.69 (m, 1H), 7.23-7.29 (m, 1H), 7.07-7.16 (m, 1H), 7.03 (d, 1H), 6.62-6.70 (m, 1H), 6.43-6.51 (m, 2H), 6.37-6.43 (m, 1H), 4.33 (d, 2H).

Example 31: N-((5-(2-chlorophenyl)furan-2-yl)methyl)-3-nitroaniline

The title compound was prepared according to the general procedure C using 5-(2-chlorophenyl)furan-2-carbaldehyde (0.3 g, 1.45 mmol), 3-nitroaniline (0.2 g,

1.45 mmol), / -tolucncsulfonic acid (13 mg, 0.07 mmol) and toluene (40 ml). The amine reduction was performed using dry ethanol (30 ml) and NaBH (109 mg, 2.9 mmol). Isolated yield 480 mg. 1H NMR (DMSO-d₆) d: 7.78-7.85 (m, 1H), 7.49-7.56 (m, 2H), 7.29-7.46 (m, 4H), 7.09-7.16 (m, 1H), 7.05-7.08 (m, 1H), 6.50-6.54 (m, 1H), 4.45 (s, 2H).

Example 32: 3-Chloro-N-((5-(2-chlorophenyl)furan-2-yl)methyl)aniline The title compound was prepared according to the general procedure C using 5-(2-chlorophenyl)furan-2-carbaldehyde (0.15 g, 0.73 mmol), 3-chloroaniline (0.07 ml, 0.73 mmol), / -tolucncsulfonic acid (7 mg, 0.04 mmol) and toluene (40 ml). The amine reduction was performed using dry ethanol (30 ml) and NaBH₄ (55 mg, 1.46 mmol). The product was purified by flash column chromatography using ethyl acetate and heptane (1 :5) as eluent. The product was converted to HC1 salt. Isolated yield 130 mg. 1H NMR (DMSO-d₆) d: 7.79-7.83 (m, 1H), 7.52-7.57 (m, 1H), 7.40-7.46 (m, 1H), 7.29-7.35 (m, 1H), 7.03-7.13 (m, 2H), 6.71-6.76 (m, 1H), 6.62-6.67 (m, 1H), 6.55-6.59 (m, 1H), 6.49 (d, 1H), 4.36 (s, 2H).

Claims

1. A compound of formula (I)

wherein

Ri is hydrogen, halogen, cyano or nitro;

R₂ is hydrogen or halogen;

wherein at least one of Ri and R_? is other than hydrogen;

ring A is a group of formula (G), (2’) or (3’)

the asterisk denoting the point of attachment to the ring B;

ring B is a group of formula (4’), (5’), (6’) or (7’)

R₃, R_S R_V and R₉ are, independently, hydrogen, halogen, or methyl;

R₄, R_f>. Rs and Rio are, independently, hydrogen, halogen, methyl, amino or -NHC(0)CH₃;

or a pharmaceutically acceptable salt thereof;

/V-(4-Bromophcnyl)-5-(2-fluorophcnyl)-2-furanmcthanaminc (2); /V-(3-Chloro-4-fluorophcnyl)-5-(2-chlorophcnyl)-2-furanmcthanaminc (13); 5-(3-Chlorophcnyl)-/V-(3 ,4-dichlorophenyl)-2-furanmethanamine (14);

5-(3-Chlorophcnyl)-/V-(4-chlorophcnyl)-2-furanmcthanaminc (20);

/V-(4-Chlorophcnyl)-5-(2-fluorophcnyl)-2-furanmcthanaminc (21);

/V-(4-Bromophcnyl)-5-phcnyl-2-furanmcthanaminc (27);

N-( 3 ,4-Dichlorophenyl)-5 -phenyl-2-furanmethanamine (38);

/V-(4-Chlorophcnyl)-5-phcnyl-2-furanmcthanaminc (44);

5-(2-Chlorophcnyl)-/V-(3 ,4-dichlorophenyl)-2-furanmethanamine (51);

/V-(4-Bromophcnyl)-5-(2-chlorophcnyl)-2-furanmcthanaminc (66);

/V-(4-Bromophcnyl)-5-(3-chlorophcnyl)-2-furanmcthanaminc (67);

;_'V-(4-Bromophcnyl)-5-(3-chloro-2-mcthylphcnyl)-2-furanmcthanaminc (74);

/V-(3-Chloro-4-fluorophcnyl)-5-phcnyl-2-furanmcthanaminc (76);

/V-(3-Chloro-4-fluorophcnyl)-5-(3-chloro-2-mcthylphcnyl)-2-furanmcthan- amine (78);

5-(3-Chloro-2-methylphenyl)-/V-(3,4-dichlorophenyl)-2-furanmethanamine (82);

/V-(3-Chloro-4-fluorophcnyl)-5-(2-fluorophcnyl)-2-furanmcthanaminc (91); N-( 3 ,4-Dichlorophenyl)-5 -(2-fluorophenyl)-2-furanmethanamine ( 100);

5-(2-Chlorophcnyl)-/V-(4-chlorophcnyl)-2-furanmcthanaminc (107);

5-(3-Chloro-2-mcthylphcnyl)-_;'V-(4-chlorophcnyl)-2-furanmcthanaminc (109); 5-(2-Fluorophcnyl)-/V-(4-fluorophcnyl)-2-furanmcthanaminc (111); or

/V-(4-Fluorophcnyl)-5-phcnyl-2-furanmcthanaminc (116).

2. A compound according to claim 1, wherein, in case ring A is a group of formula ( ),

R is methyl, amino or -NHC(0)CH or,

in case R_? is hydrogen or R is halogen, then R can also be halogen, or in case R is hydrogen, then R can also be hydrogen.

3. A compound according to claim 1, wherein ring A is a group of formula (G).

4. A compound according to claim 3, wherein

R₄ is methyl, amino or -NHC(0)CH₃ or,

in case R₂ is hydrogen or R₃ is halogen, then R₄ can also be halogen, or in case R₂ is hydrogen, then R₄ can also be hydrogen.

5. A compound according to claim 4, wherein ring B is a group of formula (4’) or (5’).

6. A compound according to claim 5, wherein ring B is a group of formula (4’).

7. A compound according to claim 6, wherein R₂ is fluoro.

8. A compound according to claim 7, wherein Ri is hydrogen and R₂ is fluoro.

9. A compound according to claim 6, 7 or 8, wherein R₄ is amino.

10. A compound according to claim 9, wherein R₃ is hydrogen and R₄ is amino.

11. A compound according to claim 1 or 2, wherein ring A is a group of formula (2’).

12. A compound according to claim 11, wherein ring B is a group of formula (4’) or (5’).

13. A compound according to claim 12, wherein ring B is a group of formula

(4’)· 14. A compound according to claim 13, wherein Ri is chloro or fluoro.

15. A compound according to claim 12 or 13, wherein R₂ is fluoro or hydrogen.

16. A compound according to claim 15, wherein R₄ is methyl, fluoro or hydrogen.

17. A compound according to claim 15, wherein R₃ is hydrogen and R4 is methyl.

18. A pharmaceutical composition comprising a compound according to formula (I)

wherein

Ri is hydrogen, halogen, cyano or nitro;

R₂ is hydrogen or halogen;

wherein at least one of Ri and R_? is other than hydrogen;

ring A is a group of formula (G), (2’) or (3’)

the asterisk denoting the point of attachment to the ring B;

ring B is a group of formula (4’), (5’), (6’) or (7’)

R₃, R_5, R₇ and R₉ are, independently, hydrogen, halogen, or methyl;

R4, Rr,_. Re and Rio are, independently, hydrogen, halogen, methyl, amino or -NHC(0)CH₃;

or a pharmaceutically acceptable salt thereof;

together with a pharmaceutically acceptable carrier.

19. A method for the treatment of conditions in which NCX inhibition is desired, comprising administering to a subject in need thereof a therapeutically effective amount of a compound according to formula (I)

wherein

Ri is hydrogen, halogen, cyano or nitro;

R₂ is hydrogen or halogen;

wherein at least one of Ri and R_? is other than hydrogen;

ring A is a group of formula (G), (2’) or (3’)

the asterisk denoting the point of attachment to the ring B;

ring B is a group of formula (4’), (5’), (6’) or (7’)

R₃, R_S R_V and R₉ are, independently, hydrogen, halogen, or methyl;

or a pharmaceutically acceptable salt thereof.

20. A method according to claim 19, for the treatment of conditions in which inotropic support is required to maintain a sufficient level of blood supply.

21. A method according to claim 20, for the treatment of heart failure or for the treatment of patients undergoing surgery.

22. A compound of formula (I)

wherein

Ri is H, halogen, cyano or nitro;

R₂ is H or halogen;

wherein at least one of Ri and R_? is other than H;

ring A is a group of formula (1’), (2’) or (3’)

the asterisk denoting the point of attachment to the ring B;

ring B is a group of formula (4’), (5’), (6’) or (7’)

R₃, R_S R_V and R₉ are, independently, H, halogen, or methyl;

R₄, R_f>. Rs and Rio are, independently, H, halogen, methyl, amino or -NHC(0)CH₃;

or a pharmaceutically acceptable salt thereof,

for use in the treatment of conditions in which NCX inhibition is desired.

23. A compound for use according to claim 22, for the treatment of a condition in which inotropic support is required to maintain a sufficient level of blood supply.

24. A compound for use according to claim 23, for the treatment of heart failure or for the treatment of patients undergoing surgery.