Modulators of the adenosine A3 receptors

Abstract

Modulators of adenosin A.sub.3 receptors of formula (I): ##STR00001##
And procedure for preparing these compounds. Other objectives of the present invention are to provide pharmaceutical compositions comprising an effective amount of these compounds and the use of the compounds for manufacturing a medicament for the treatment of pathological conditions or diseases that can improve by modulation of the adenosine A.sub.3 receptor.

Claims

1. A compound of formula (I) ##STR00016## wherein: R.sup.1 represents a five or six membered aryl or heteroaryl group optionally substituted by one or more substituents selected from the group consisting of halogen atom, C.sub.1-C.sub.6 alkyl linear or branched, C.sub.3-C.sub.12 cycloalkyl, hydroxyl, C.sub.1-C.sub.6 alkoxy linear or branched and cyano group, R.sup.2 is selected from the group consisting of halogen atom and cyano group, R.sup.3 represents a five or six membered aryl or heteroaryl group optionally substituted by one or more substituents selected from the group consisting of halogen atom, cyano group, C.sub.3-C.sub.12 cycloalkyl, hydroxyl, C.sub.1-C.sub.6 alkoxy linear or branched, optionally substituted by one, two or three halogen atoms, C.sub.1-C.sub.6 alkylthio, amino, mono or dialkylamino, C.sub.1-C.sub.6 alcoxyalkyl, hydroxycarbonyl and C.sub.2-C.sub.6 alcoxycarbonyl, and R.sup.4 represents independently: a) a hydroxyl group, b) N(R.sup.5)(R.sup.6) group, wherein: i) R.sup.5 and R.sup.6 represent independently a C.sub.3-C.sub.12 cycloalkyl group or C.sub.3-C.sub.4 alkyl linear or branched, substituted by a carboxyl group (COOH); or ii) R.sup.5 and R.sup.6 form together with the nitrogen atom to which they are bound a five or six membered saturated cycle comprising optionally a heteroatom selected from N and O, which is substituted by a carboxylic group (COOH), and pharmaceutically acceptable salts thereof.

2. A compound according to claim 1 wherein R.sup.3 represents a phenyl group optionally substituted by one, two or three halogen atoms or by a C.sub.1-C.sub.6 alkoxy group optionally substituted by one, two or three halogen atoms.

3. A compound according to claim 2 wherein R is selected from a group consisting of phenyl group and thienyl group optionally substituted by one, two or three halogen atoms.

4. A compound according to claim 3 wherein R.sup.2 represents a cyano group.

5. A compound according to claim 4 wherein R.sup.4 represents a hydroxyl group.

6. A compound according to claim 4 wherein R.sup.4 represents a N(R.sup.5)(R.sup.6) group wherein: i) R.sup.5 and R.sup.6 represent independently a C.sub.3-C.sub.12 cycloalkyl group or C.sub.3-C.sub.4 alkyl linear or branched, substituted by a carboxyl group (COOH); or ii) R.sup.5 and R.sup.6 form together with the nitrogen atom to which they are bound a five or six membered saturated cycle comprising optionally a heteroatom selected from N and O, which is substituted by a carboxylic group (COOH).

7. A compound according to claim 6 wherein R.sup.5 and R.sup.6 form together with the nitrogen atom to which they are attached a five or six membered saturated cycle substituted by a carboxylic group (COOH).

8. A compound according to claim 1 wherein R.sup.1 represents a phenyl group optionally substituted by one, two or three halogen atoms, R.sup.2 represents a cyano group, R.sup.3 represents a phenyl group optionally substituted by one, two or three halogen atoms or by a methoxyl group, and R.sup.4 represents a hydroxyl group.

9. A compound according to claim 1 wherein R.sup.1 represents a thienyl group optionally substituted by one, two or three halogen atoms, R.sup.2 represents a cyano group, R.sup.3 represents a phenyl group optionally substituted by one, two or three halogen atoms or by a methoxyl group, and R.sup.4 represents a hydroxyl group.

10. A compound according to claim 1 which is one of: 3-[5-cyano-4-(3,4-dimethoxyphenyl)thiazol-2-ylcarbamoyl]benzoic acid; 4-[5-cyano-4-(4-methoxyphenyl)thiazol-2-ylcarbamoyl]benzoic acid; 4-(5-cyano-4-phenylthiazol-2-ylcarbamoyl)benzoic acid; 3-(5-cyano-4-phenylthiazol-2-ylcarbamoyl)benzoic acid; 6-(5-cyano-4-phenylthiazol-2-ylcarbamoyl)pyridine-2-carboxylic acid; 3-(5-cyano-4-(4-methoxyphenyl)thiazol-2-ylcarbamoyl)benzoic acid; 2-[5-cyano-4-(4-methoxyphenyl)thiazol-2-ylcarbamoyl]benzoic acid; 5-(5-cyano-4-(4-methoxyphenyl)thiazol-2-ylcarbamoyl)thiophene-2-carboxylic acid; 6-[5-cyano-4-(4-methoxyphenyl)thiazol-2-ylcarbamoyl]pyridine-2-carboxylic acid; 3-{5-cyano-4-[4-(trifluoromethoxy)phenyl]thiazol-2-ylcarbamoyl}benzoic acid; 5-{5-cyano-4-[4-(trifluoromethoxy)phenyl]thiazol-2-ylcarbamoyl}thiophene-2-carboxylic acid; 3-[5-cyano-4-(4-fluorophenyl)thiazol-2-ylcarbamoyl]benzoic acid; 5-(5-cyano-4-(4-fluorophenyl)thiazol-2-ylcarbamoyl)thiophene-2-carboxylic acid; 5-[5-cyano-4-(3-fluorophenyl)thiazol-2-ylcarbamoyl]thiophene-2-carboxylic acid; 5-(5-cyano-4-(2-fluorophenyl)thiazol-2-ylcarbamoyl)thiophene-2-carboxylic acid; 3-[5-cyano-4-(pyridin-4-yl)thiazol-2-ylcarbamoyl]benzoic acid; 3-[5-cyano-4-(pyridin-2-yl)thiazol-2-ylcarbamoyl]benzoic acid; 3-[5-cyano-4-(6-methylpyridin-2-yl)thiazol-2-ylcarbamoyl]benzoic acid; 5-(5-cyano-4-(pyridin-3-yl)thiazol-2-ylcarbamoyl)thiophene-2-carboxylic acid; 5-(5-cyano-4-(3-cyanophenyl)thiazol-2-ylcarbamoyl)thiophene-2-carboxylic acid; 5-(5-cyano-4-(4-cyanophenyl)thiazol-2-ylcarbamoyl)thiophene-2-carboxylic acid; 5-(5-cyano-4-phenylthiazol-2-ylcarbamoyl)thiophene-2-carboxylic acid; 5-(5-cyano-4-(6-methoxypyridin-3-yl)thiazol-2-ylcarbamoyl)thiophene-2-carboxylic acid; 5-((5-cyano-4-(furan-2-yl)thiazol-2-yl)carbamoyl)thiophene-2-carboxylic acid; 5-((5-cyano-4-(thiophen-2-yl)thiazol-2-yl)carbamoyl)thiophene-2-carboxylic acid; 5-((4-(4-chlorothiophen-2-yl)-5-cyanothiazol-2-yl)carbamoyl)thiophene-2-carboxylic acid; 5-((5-cyano-[2,4-bithiazol]-2-yl)carbamoyl)thiophene-2-carboxylic acid; 3-((5-cyano-[2,4-bithiazol]-2-yl)carbamoyl)benzoic acid; 4-((5-cyano-[2,4-bithiazol]-2-yl)carbamoyl)benzoic acid; 4-((5-cyano-4-(thiophen-2-yl)thiazol-2-yl)carbamoyl)benzoic acid; 3-((5-cyano-4-(thiophen-2-yl)thiazol-2-yl)carbamoyl)benzoic acid; 3-((5-cyano-4-(furan-2-yl)thiazol-2-yl)carbamoyl)benzoic acid; 4-((5-cyano-4-(furan-2-yl)thiazol-2-yl)carbamoyl)benzoic acid; 3-((4-(4-chlorothiophen-2-yl)-5-cyanothiazol-2-yl)carbamoyl)benzoic acid; 4-((4-(4-chlorothiophen-2-yl)-5-cyanothiazol-2-yl)carbamoyl)benzoic acid; 5-((5-cyano-4-(3-methoxyphenyl)thiazol-2-yl)carbamoyl)thiophene-2-carboxylic acid; 3-(5-cyano-4-(6-methoxypyridin-3-yl)thiazol-2-ylcarbamoyl)benzoic acid; 5-(5-chloro-4-phenylthiazole-2-ylcarbamoyl)thiophene-2-carboxylic acid; 3-(5-chloro-4-phenylthiazole-2-ylcarbamoyl)benzoic acid; 5-(5-bromo-4-phenylthiazol-2-ylcarbamoyl)thiophene-2-carboxylic acid; 5-(5-fluoro-4-phenylthiazol-2-ylcarbamoyl)thiophene-2-carboxylic acid; 3-(5-bromo-4-phenylthiazol-2-ylcarbamoyl)benzoic acid; 3-(5-fluoro-4-phenylthiazole-2-ylcarbamoyl)benzoic acid; 5-(5-chloro-4-(4-methoxyphenyl)thiazol-2-ylcarbamoyl)thiophene-2-carboxylic acid; 5-[5-cyano-4-(4-methoxyphenyl)thiazol-2-ylcarbamoyl]-1H-pyrazole-3-carboxylic acid; 1-(3-{[5-cyano-4-(4-methoxyphenyl)thiazol-2-yl]carbamoyl}benzoyl)piperidine-4-carboxylic acid; 1-{4-[(5-cyano-4-phenyl-thiazol-2-yl)carbamoyl]benzoyl}piperidine-4-carboxylic acid; 1-{3-[(5-cyano-4-phenyl-thiazol-2-yl)carbamoyl]benzoyl}piperidine-4-carboxylic acid; 1-(5-((5-cyano-4-phenylthiazol-2-yl)carbamoyl)thiophene-2-carbonyl)piperidine-4-carboxylic acid; 1-(4-((5-cyano-4-(thiophen-2-yl)thiazol-2-yl)carbamoyl)benzoyl)piperidine-4-carboxylic acid; 1-(5-((5-cyano-4-(thiophen-2-yl)thiazol-2-yl)carbamoyl)thiophene-2-carbonyl)piperidine-4-carboxylic acid; and 1-(3-((5-cyano-4-(thiophen-2-yl)thiazol-2-yl)carbamoyl)benzoyl)piperidine-4-carboxylic acid.

11. A pharmaceutical composition comprising a compound of claim 1 or pharmaceutically acceptable salt thereof and a pharmaceutically acceptable diluent or carrier.

12. Method for the treatment of a disease or pathological condition susceptible of amelioration by modulation of the adenosine A.sub.3 receptor, said method comprising administering to a subject in need thereof an effective amount of a compound according to claim 1, wherein the disease or pathological condition susceptible of amelioration by modulation of the adenosine A.sub.3 receptor is selected from the group consisting of: atherosclerosis; asthma; autoimmune diseases selected from rheumatoid arthritis and psoriasis, diseases of the gastrointestinal system selected from ulcerative colitis, Crohn's disease, and inflammatory bowel disease; and ophthalmologic diseases selected from glaucoma and uveitis.

13. A combination comprising a compound of claim 1 and a therapeutic agent used for the treatment of diseases selected from the group consisting of neurological disorders, cardiovascular diseases, respiratory diseases, renal diseases, cancer, autoimmune diseases, diseases of the gastrointestinal system, and phthalmologic diseases or conditions.

14. A combination comprising a compound of claim 1 and a therapeutic agent selected from the group consisting of Montelukast, Bicalutamide, Flutamide, Tofacitinib, and a diuretic selected from Hydrochlorothiazide and Lubiprostone for the treatment of a disease selected from glaucoma, asthma, prostate cancer, rheumatoid arthritis, acute renal failure and irritable bowel syndrome.

Description

EXAMPLES

(1) The synthesis of compounds and intermediates of the invention for use herein are illustrated by the following Examples (1 to 52), including the preparation of the intermediates, which do not limit in any way the scope of the present invention.

(2) General.

(3) Reagents, solvents and starting materials were purchased from commercial suppliers. Concentration refers to evaporation under vacuum using a B?chi rotatory evaporator. Reaction products were purified when necessary, by flash chromatography on silica gel (40-63 ?m) with the solvent system indicated. Spectroscopic data were recorded on a Varian Gemeni 300 spectrometer. Melting points were recorded on a B?chi 535 apparatus. HPLC-MS were performed on a Gilson instrument equipped with a Gilson piston pump 321, a Gilson 864 vacuum degasser, a Gilson 189 injection module, a 1/1000 splitter, a Gilson 307 make-up pump, a Gilson 170 diode array detector, and a Thermoquest Fennigan aQa detector.

(4) General Method for the Synthesis of Acid Chlorides

(5) Acid chlorides of formula (VII) are synthesized from the corresponding commercial carboxylic acids using the synthesis method described in the literature. (Burdett, K. A., Sintesis, 1991, 441-42).

Intermediate 1: 2-amino-4-(pyridin-2-yl)thiazole-5-carbonitrile

(6) ##STR00008##

(7) A suspension of sodium hydride in mineral oil (60%) (0.81 g, 16.52 mmol) was added to a solution of 0.95 ml (18.02 mmol) of acetonitrile in 10 ml of THF, and stirred for 15 min. To this suspension, a solution of 2.27 g (15.02 mmol) of ethyl picolinate in 5 ml of THF is dropped slowly. After about 10 min of stirring a white precipitate is formed. The reaction mixture is stirred at room temperature overnight, and then 30 ml of pyridine, 2.28 g (30 mmol) of thiourea and 3.81 g (15 mmol) of iodine were added, and the mixture stirred 90? C. for 6 h. The reaction was then allowed to reach room temperature and poured into cold water. The precipitate formed is filtered, washed several times with cold water and dried. 1.85 g (61%) of a black solid are obtained.

(8) .sup.1H-NMR (400 MHz, DMSO-d.sub.6): ?=7.46 (m, 1H), 7.93 (m, 2H), 8.21 (s, 2H), 8.66 (d, 1H).

(9) Intermediates 2 to 8 were synthesized using the procedure described for Intermediate 1 using the corresponding esters: 6-methyl-2-pyridinecarboxylate, methyl nicotinate, methyl 2-methoxypyridin-5-carboxylate, methyl 4-cyanobenzoate, methyl 3-cyanobenzoate, methyl 4-chlorothiophene-2-carboxylate, and methyl thiazole-2-carboxylate through intermediates: 3-(6-methylpyridin-2-yl)-3-oxopropanonitrile, 3-oxo-3-(pyridin-3-yl)propanonitrile, 3-(6-methoxy-3-yl)-3-oxopropanonitrile, 4-(2-cyanoacetyl)benzonitrile, 3-(2-cyanoacetyl) benzonitrile, 3-(4-chlorothiophen-2-yl)-3-oxopropanenitrile and 3-oxo-3-(thiazol-2-yl)propanenitrile respectively, to finally obtain the corresponding thiazole.

Intermediate 2: 2-amino-4-(6-methylpyridin-2-yl)thiazole-5-carbonitrile

(10) .sup.1H-NMR (400 MHz, DMSO-d.sub.6): ?=2.51 (s, 3H), 7.31 (d, 1H), 7.71 (d, 1H), 7.81 (t, 1H), 8.17 (d, 2H).

Intermediate 3: 2-amino-4-(pyridin-3-yl)thiazole-5-carbonitrile

(11) .sup.1H-NMR (400 MHz, DMSO-d.sub.6): ?=7.56 (dd, 1H), 8.25 (d, 1H), 8.33 (s, 2H), 8.67 (dd, 1H), 9.07 (d, 1H).

(12) HPLC-MS: Rt 2.249 m/z 203.0 (MH.sup.+).

Intermediate 4: 2-amino-4-(6-methoxypyridin-3-yl)thiazole-5-carbonitrile

(13) .sup.1H-NMR (400 MHz, DMSO-d.sub.6): ?=3.91 (s, 3H), 6.97 (d, 1H), 8.17 (dd, 1H), 8.27 (s, 2H), 8.71 (d, 1H).

(14) HPLC-MS: Rt 2.949 m/z 233.0 (MH.sup.+).

Intermediate 5: 2-amino-4-(4-cyanophenyl)thiazole-5-carbonitrile

(15) .sup.1H-NMR (400 MHz, DMSO-d.sub.6): ?=7.99 (d, 2H), 8.07 (d, 2H), 8.33 (s, 2H).

(16) HPLC-MS: Rt 3.077 m/z 227.0 (MH.sup.+).

Intermediate 6: 2-amino-4-(3-cyanophenyl)thiazole-5-carbonitrile

(17) .sup.1H-NMR (400 MHz, DMSO-d.sub.6): ?=7.76 (t, 1H), 7.97 (d, 1H), 8.23 (m, 2H), 8.34 (s, 2H).

(18) HPLC-MS: Rt 3.169 m/z 227.0 (MH.sup.+).

Intermediate 7: 2-amino-4-(4-chlorothiophen-2-yl)thiazole-5-carbonitrile

(19) .sup.1H-NMR (400 MHz, DMSO-d.sub.6): ?=8.36 (s, 2H), 7.79 (d, 1H), 7.63 (d, 1H).

(20) HPLC-MS: Rt 3.639, m/z 241.9 (M.sup.+).

Intermediate 8: 2-amino-[2,4-bithiazole]-5-carbonitrile

(21) .sup.1H-NMR (400 MHz, DMSO-d.sub.6): ?=8.39 (5, 2H), 8.04 (d, 1H), 7.94 (d, 1H)

(22) HPLC-MS: Rt 3.639, m/z 241.9 (M.sup.+)

Intermediate 9: 2-amino-4-(4-methoxyphenyl)thiazole-5-carbonitrile

(23) ##STR00009##

(24) 5.07 g (28.94 mmol) of 3-(4-methoxyphenyl)-3-oxopropanonitrile were dissolved in pyridine (30 ml) and 3.08 g (40.5 mmol) of thiourea and 7.35 g (28.94 mmol) of iodine were added. The solution was heated for 6 hours at 90? C. The solution was then cooled to room temperature and poured into ice water (500 ml). The resulting solid was filtered, washed with water several times to obtain 5.11 g (76.35%) of a light brown solid.

(25) .sup.1H-NMR (400 MHz, DMSO-d.sub.6): ?=3.84 (s, 3H), 7.09 (d, 2H), 8.08 (d, 2H), 8.38 (d, 2H).

(26) The following intermediates have been synthesized using the procedure described for Intermediate 9 using the corresponding oxonitriles.

Intermediate 10: 2-amino-4-(3,4-dimethoxyphenyl)thiazole-5-carbonitrile

(27) .sup.1H-NMR (400 MHz, DMSO-d.sub.6): ?=3.77 (s, 3H), 3.80 (s, 3H), 7.06 (d, 1H), 7.48 (s, 1H), 7.53 (d, 1H), 8.18 (s, 2H).

Intermediate 11: 2-amino-4-phenylthiazole-5-carbonitrile

(28) .sup.1H-NMR (400 MHz, DMSO-d.sub.6): ?=7.47 (t, 1H), 7.55 (t, 2H), 8.09 (d, 2H), 8.39 (d, 2H).

Intermediate 12: 2-amino-4-[4-(trifluoromethoxy)phenyl]thiazole-5-carbonitrile

(29) .sup.1H-NMR (400 MHz, DMSO-d.sub.6): ?=7.54 (d, 2H), 8.02 (d, 2H), 8.29 (s, 2H).

Intermediate 13: 2-amino-4-(4-fluorophenyl)thiazole-5-carbonitrile

(30) .sup.1H-NMR (400 MHz, DMSO-d.sub.6): ?=7.36 (t, 2H), 7.97 (dd, 2H), 8.25 (s, 2H).

(31) HPLC-MS: Rt 3.316 m/z 220.0 (MH.sup.+).

Intermediate 14: 2-amino-4-(3-fluorophenyl)thiazole-5-carbonitrile

(32) .sup.1H-NMR (400 MHz, DMSO-d.sub.6): ?=7.34 (td, 1H), 7.60-7.53 (m, 1H), 7.64 (ddd, 1H), 7.80-7.74 (m, 1H), 8.28 (s, 2H).

(33) HPLC-MS: Rt 3.373 m/z 220.0 (MH.sup.+).

Intermediate 15: 2-amino-4-(2-fluorophenyl)thiazole-5-carbonitrile

(34) .sup.1H-NMR (400 MHz, DMSO-d.sub.6): ?=7.32 (m, 2H), 7.54 (d, 1H), 7.64 (m, 1H), 8.26 (s, 2H).

(35) HPLC-MS: Rt 2.950 m/z 219.4 (MH.sup.+).

Intermediate 16: 2-amino-4-(pyridin-4-yl)thiazole-5-carbonitrile

(36) .sup.1H-NMR (400 MHz, DMSO-d.sub.6): ?=7.83 (d, 2H), 8.35 (s, 2H), 8.74 (d, 2H).

Intermediate 17: 2-amino-4-(3-methoxyphenyl)thiazole-5-carbonitrile

(37) .sup.1H-NMR (400 MHz, DMSO-d.sub.6): ?=3.80 (s, 3H), 7.06 (dd, 1H), 7.42 (d, 1H), 7.45 (dd, 1H), 7.51 (dd, 1H), 8.26 (s, 2H).

(38) HPLC-MS: Rt 3.530, m/z 232.0 (MH.sup.+).

Intermediate 18: 2-amino-4-(furan-2-yl)thiazole-5-carbonitrile

(39) .sup.1H-NMR (400 MHz, DMSO-d.sub.6): ?=8.22 (s, 2H), 7.89 (d, 1H), 6.93 (d, 1H), 6.68 (dd, 1H).

(40) HPLC-MS: Rt 2.615, m/z 192.0 (MH.sup.+)

Intermediate 19: 2-amino-4-(thiophen-2-yl)thiazole-5-carbonitrile

(41) .sup.1H-NMR (400 MHz, DMSO-d.sub.6): ?=7.21 (dd, 1H), 7.74 (s, 1H), 737-7.80 (m, 1H), 8.31 (s, 2H).

(42) HPLC-MS: Rt 3.141, m/z 208.0 (MH.sup.+)

Intermediate 20: 5-fluoro-4-phenylthiazol-2-amine

(43) ##STR00010##

(44) 1.1 g (3.12 mmol) of Selectfluor? were dissolved in 4-phenylthiazole-2-amina (0.5 g, 2.83 mmol) in 10 ml of acetonitrile cooled in an ice bath, was stirred for 15 min at this temperature, then cooled to room temperature and stirred for 12 hours. The solvent was removed by rotoevaporation, and the solution was filtered through gel silica using a mixture ethyl acetate/cyclohexane.

(45) .sup.1H-NMR (400 MHz, DMSO-d.sub.6): ?=6.97 (s, 2H), 7.28 (t, 1H), 7.41 (t, 2H), 7.70 (t, 2H).

(46) HPLC-MS: Rt 3.568 m/z 195.0 (MH.sup.+).

Intermediate 21: 5-chloro-4-phenylthiazol-2-amine

(47) 0.378 g (2.83 mmol) of N-chlorosuccinimide were added to 0.5 g (2.83 mmol) of 4-phenylthiazol-2-amine in 1.5 ml DMF. The reaction mixture was stirred for 12 h, and then poured into brine. The precipitate formed, filtered, washed several times with cold water and dried to obtain the desired compound.

(48) .sup.1H-NMR (400 MHz, DMSO-d.sub.6): ?=7.32 (dd, 3H), 7.42 (t, 2H), 7.81 (m, 2H).

(49) HPLC-MS: Rt 3.768 m/z 211.0 (MH.sup.+).

(50) The following intermediates were synthesized using the procedure described for Intermediate 21 with N-chloro- or N-bromosuccinimide and the corresponding thiazole.

Intermediate 22: 5-chloro-4-(4-methoxyphenyl)thiazol-2-amine

(51) .sup.1H-NMR (400 MHz, DMSO-d.sub.6): ?=3.78 (s, 3H), 6.98 (d, 2H), 7.22 (s, 2H), 7.77 (d, 2H).

(52) HPLC-MS: Rt 3.776 m/z 241.0 (MH.sup.+).

Intermediate 23: 5-bromo-4-phenylthiazol-2-amine

(53) .sup.1H-NMR (400 MHz, DMSO-d.sub.6): ?=7.30 (s, 2H), 7.36 (m, 1H), 7.42 (m, 2H), 7.80 (m, 2H).

(54) HPLC-MS: Rt 3.781 m/z 254.9 (M.sup.+).

Intermediate 24: 5-bromo-4-(4-methoxyphenyl)thiazol-2-amine

(55) .sup.1H-NMR (400 MHz, DMSO-d.sub.6): ?=3.78 (s, 3H), 6.98 (d, 2H), 7.29 (s, 2H), 7.76 (d, 2H).

(56) HPLC-MS: Rt 3.78 m/z 286.1 (MH.sup.+).

Intermediate 25: Methyl 5-((5-cyano-4-phenylthiazol-2-yl)carbamoyl)thiophene-2-carboxylate

(57) ##STR00011##

(58) 13.5 g (64.6 mmol) of thiophene-2,5-dicarbonyl dichloride were dissolved in dry acetonitrile (ACN) (250 mL) and the solution was cooled in an ice water bath. Then 2.62 ml (64.6 mmol) of dry methanol and 20.8 ml (149.07 mmol) of triethylamine were added. The resulting suspension was allowed to reach room temperature and stirred at this temperature for 1 h. The obtained acylchloride has been used in the next step without further purification.

(59) 10 g (49.69 mmol) of 2-amino-4-phenylthiazole-5-carbonitrile, 10 mg of DMAP and additional 20 ml of ACN were added to the above described suspension of the acylchloride. The reaction mixture was stirred 2 h at 40? C. The complete consumption of the starting material was followed by TLC. Triethylamine hydrochloride was removed by filtration and the resulting solution was poured into a cooled NaHCO.sub.3 solution (1.5 L). The resulting solid was filtered, washed with water and 2 times additionally with water at 60? C. The brown solid was re-suspended in 500 ml of ACN and poured again into a NaHCO.sub.3 solution (1.5 L). The precipitate was filtered, washed with water at room temperature, the washed two times additionally with water at 60? C., and dried. The resulting brown solid was washed shortly with cold diethyl ether to obtain the desired compound

(60) .sup.1H-NMR (400 MHz, DMSO-d.sub.6): ?=3.86 (s, 3H), 7.57 (m, 3H), 7.88 (d, 1H), 8.03 (d, 2H), 8.20 (s, 1H), 13.89 (s, 1H).

(61) The following intermediates were synthesized using the procedure described for Intermediate 25 employing the corresponding ethyl or methyl (chlorocarbonyl)-R.sup.1-carboxylate derivatives and 2-amino thiazole.

Intermediate 26: Methyl 5-(5-cyano-4-(6-methoxypyridin-3-yl)thiazol-2-ylcarbamoyl)thiophene-2-carboxylate

(62) .sup.1H-NMR (400 MHz, DMSO-d.sub.6): ?=3.86 (d, 3H), 3.94 (s, 3H), 7.01 (d, 1H), 7.82 (m, 1H), 7.95 (d, 1H), 8.28 (dd, 1H), 8.82 (dd, 1H), 13.84 (s, 1H).

Intermediate 27: Methyl 5-((5-cyano-4-(furan-2-yl)thiazol-2-yl)carbamoyl)thiophene-2-carboxylate

(63) .sup.1H-NMR (400 MHz, DMSO-d.sub.6): ?=3.87 (s, 3H), 6.75 (dd, 1H), 7.09 (dd, 1H), 7.88 (d, 1H), 7.99 (dd, 1H), 8.29 (d, 1H), 13.96 (s, 1H).

Intermediate 28: Methyl 5-((5-cyano-4-(thiophen-2-yl)thiazol-2-yl)carbamoyl)thiophene-2-carboxylate

(64) .sup.1H-NMR (400 MHz, DMSO-d.sub.6): ?=3.87 (s, 3H), 7.28 (dd, 1H), 7.84 (dd, 1H), 7.89-7.93 (m, 2H), 8.32 (d, 1H), 13.94 (s, 1H).

Intermediate 29: Methyl 5-((4-(4-chlorothiophen-2-yl)-5-cyanothiazol-2-yl)carbamoyl)thiophene-2-carboxylate

(65) .sup.1H-NMR (400 MHz, DMSO-d.sub.6): ?=3.87 (s, 3H), 7.73 (s, 1H), 7.89 (s, 2H), 8.30 (s, 1H), 13.97 (s, 1H).

Intermediate 30: Methyl 5-((5-cyano-[2,4-bithiazol]-2-yl)carbamoyl)thiophene-2-carboxylate

(66) .sup.1H-NMR (400 MHz, DMSO-d.sub.6): ?=3.87 (s, 1H), 7.89 (d, 1H), 8.04 (d, 1H), 8.13 (d, 1H), 8.32 (d, 1H), 14.02 (s, 1H).

Intermediate 31: Methyl 3-((5-cyano-[2,4-bithiazol]-2-yl)carbamoyl)benzoate

(67) .sup.1H-NMR (400 MHz, DMSO-d.sub.6): ?=3.92 (s, 3H), 7.74 (t, 1H), 8.04 (d, 1H), 8.13 (d, 1H), 8.23 (d, 1H), 8.40 (d, 1H), 8.75 (s, 1H), 13.94 (s, 1H).

Intermediate 32: Methyl 4-((5-cyano-[2,4-bithiazol]-2-yl)carbamoyl)benzoate

(68) .sup.1H-NMR (400 MHz, DMSO-d.sub.6): ?=3.90 (s, 3H), 8.04 (d, 1H), 8.12 (dd, 3H), 8.26 (d, 2H), 13.89 (s, 1H).

(69) HPLC-MS: Rt 3.263, m/z 371.0 (MH.sup.+).

Intermediate 33: Methyl 4-((5-cyano-4-(thiophen-2-yl)thiazol-2-yl)carbamoyl)benzoate

(70) .sup.1H-NMR (400 MHz, DMSO-d.sub.6): ?=3.90 (s, 3H), 7.29 (dd, J=5.0, 3.8 Hz, 1H), 7.86-7.80 (m, 1H), 7.95-7.89 (m, 1H), 8.14-8.08 (m, 2H), 8.25 (d, J=8.5 Hz, 2H), 13.80 (s, 1H).

(71) HPLC-MS: Rt 3.767, m/z 371.0 (MH.sup.+)

Intermediate 34: Methyl 3-((5-cyano-4-(thiophen-2-yl)thiazol-2-yl)carbamoyl)benzoate

(72) .sup.1H-NMR (400 MHz, DMSO-d.sub.6): ?=3.92 (s, 3H), 7.28 (dd, 1H), 7.73 (t, 1H), 7.84 (dd, 1H), 7.92 (dd, 1H), 8.20-8.25 (m, 1H), 8.39 (dd, 1H), 8.73 (t, 1H), 13.83 (s, 1H).

(73) HPLC-MS: Rt 3.867, m/z 370.0 (MH.sup.+)

Intermediate 35: Methyl 3-((5-cyano-4-(furan-2-yl)thiazol-2-yl)carbamoyl)benzoate

(74) .sup.1H-NMR (400 MHz, DMSO-d.sub.6): ?=3.92 (s, 3H), 6.76 (dd 1H), 7.11 (dd, 1H), 7.74 (t, 1H), 8.00 (dd, 1H), 8.21-8.25 (m, 1H), 8.37-8.42 (m, 1H), 8.73 (t, 1H), 13.87 (s, 1H).

(75) HPLC-MS: Rt 3.515, m/z 354.0 (MH.sup.+)

Intermediate 36: Methyl 4-((5-cyano-4-(furan-2-yl)thiazol-2-yl)carbamoyl)benzoate

(76) .sup.1H-NMR (400 MHz, DMSO-d.sub.6): ?=4.00 (s, 3H) 7.24 (m, 1H), 7.65 (m, 1H), 8.11 (d, 2H), 8.17 (d, 1H), 8.26 (d, 2H).

(77) HPLC-MS: Rt 3.435, m/z 354.0 (MH.sup.+)

Intermediate 37: Methyl 3-((4-(4-chlorothiophen-2-yl)-5-cyanothiazol-2-yl)carbamoyl)benzoate

(78) .sup.1H-NMR (400 MHz, DMSO-d.sub.6): ?=3.91 (s, 3H), 7.72 (t, 2H), 7.87 (s, 1H), 8.21 (d, 1H), 8.38 (d, 1H), 8.72 (s, 1H), 13.84 (s, 1H).

Intermediate 38: Methyl 4-((4-(4-chlorothiophen-2-yl)-5-cyanothiazol-2-yl)carbamoyl)benzoate

(79) .sup.1H-NMR (400 MHz, DMSO-d.sub.6): ?=3.89 (s, 3H), 7.72 (s, 1H), 7.87 (s, 1H), 8.08 (d, 2H), 8.23 (d, 2H), 13.80 (s, 1H).

Intermediate 39: Methyl 5-((5-cyano-4-(3-methoxyphenyl)thiazol-2-yl)carbamoyl)thiophene-2-carboxylate

(80) .sup.1H-NMR (400 MHz, DMSO-d.sub.6): ?=3.92 (s, 3H), 3.97 (s, 3H), 7.21 (m, 1H), 7.52 (d, 1H), 7.57 (m, 1H), 7.64 (m, 1H), 7.86 (d, 1H), 8.17 (d, 1H).

Intermediate 40: Methyl 3-(5-cyano-4-(6-methoxypyridin-3-yl)thiazol-2-ylcarbamoyl)benzoate

(81) .sup.1H-NMR (400 MHz, DMSO-d.sub.6): ?=3.92 (s, 3H), 3.94 (s, 3H), 7.03 (d, 1H), 7.71 (t, 1H), 8.19 (d, 1H), 8.29 (dd, 1H), 8.39 (d, 1H), 8.75 (s, 1H), 8.84 (d, 1H), 13.78 (s, 1H).

Intermediate 41: Methyl 5-(5-chloro-4-phenylthiazol-2-ylcarbamoyl)thiophene-2-carboxylate

(82) .sup.1H-NMR (400 MHz, DMSO-d.sub.6): ?=3.87 (s, 3H), 7.42 (t, 1H), 7.50 (t, 2H), 7.86 (d, 1H), 7.91 (d, 2H), 8.17 (d, 1H), 13.35 (s, 1H).

Intermediate 42: Methyl 3-(5-chloro-4-phenylthiazol-2-ylcarbamoyl)benzoate

(83) .sup.1H-NMR (400 MHz, DMSO-d.sub.6): ?=3.91 (d, 3H), 7.42 (t, 1H), 7.51 (t, 2H), 7.72 (dt, 1H), 7.93 (d, 2H), 8.21 (d, 1H), 8.36 (dd, 1H), 8.72 (s, 1H), 13.06 (s, 1H).

Intermediate 43: Methyl 5-(5-bromo-4-phenylthiazol-2-ylcarbamoyl)thiophene-2-carboxylate

(84) .sup.1H-NMR (400 MHz, DMSO-d.sub.6): ?=3.87 (s, 3H), 7.43 (t, 1H), 7.50 (t, 2H), 7.88 (dd, 3H), 8.23 (d, 1H), 13.41 (s, 1H).

Intermediate 44: Methyl 5-(5-fluoro-4-phenylthiazol-2-ylcarbamoyl)thiophene-2-carboxylate

(85) .sup.1H-NMR (400 MHz, DMSO-d.sub.6): ?=3.86 (s, 3H), 7.37 (d, 1H), 7.49 (t, 3H), 7.85 (d, 2H), 8.24 (d, 1H), 13.15 (s, 1H).

Intermediate 45: Methyl 5-(5-cyano-4-(pyridin-3-yl)thiazol-2-ylcarbamoyl)thiophene-2-carboxylate

(86) .sup.1H-NMR (400 MHz, DMSO-d.sub.6): ?=3.84 (s, 3H), 7.56 (dd, 1H), 7.68 (d, 1H), 7.75 (d, 1H), 8.35 (d, 1H), 8.64 (d, 1H), 9.19 (s, 1H).

Intermediate 46: Methyl 3-(5-bromo-4-phenylthiazol-2-ylcarbamoyl)benzoate

(87) .sup.1H-NMR (400 MHz, DMSO-d.sub.6): ?=3.92 (s, 3H), 7.44 (d, 1H), 7.51 (t, 2H), 7.70 (t, 1H), 7.91 (d, 2H), 8.18 (dd, 1H), 8.36 (m, 1H), 12.91 (s, 1H).

Intermediate 47: Methyl 3-(5-fluoro-4-phenylthiazol-2-ylcarbamoyl)benzoate

(88) .sup.1H-NMR (400 MHz, DMSO-d.sub.6): ?=7.38 (d, 1H), 7.50 (t, 2H), 7.70 (t, 2H), 7.86 (d, 2H), 8.18 (d, 1H), 8.36 (d, 1H), 8.71 (s, 1H), 12.99 (s, 1H).

Intermediate 48: Methyl 5-(5-chloro-4-(4-methoxyphenyl)thiazol-2-ylcarbamoyl)thiophene-2-carboxylate

(89) .sup.1H-NMR (400 MHz, DMSO-d.sub.6): ?=3.81 (s, 3H), 3.86 (s, 3H), 7.05 (d, 2H), 7.85 (dd, 3H), 8.13 (d, 1H), 13.39 (s, 1H).

EXAMPLES

Example 1: 3-[5-cyano-4-(3,4-dimethoxyphenyl)thiazol-2-ylcarbamoyl]benzoic Acid

(90) ##STR00012##

(91) To a solution of 0.20 g (0.77 mmol) of 2-amino-4-(3,4-dimethoxyphenyl)thiazole-5-carbonitrile (Intermediate 10) in THF (4 ml), 0.2 ml of pyridine was added followed by a slow addition of 0.19 g (0.92 mmol) of isophthaloyl dichloride. The reaction mixture was stirred for 12 hours at room temperature. Then, 2 ml of water were added and the reaction was stirred an additional hour at room temperature. 5 ml of a solution of NaOH (1 M) were then added. The resulting solution is then stirred at room temperature for 2 hours and washed 3 times with DCM in a separating funnel. The desired acid precipitates by adding dropwise a solution of 4 M HCl until pH<3. The precipitate formed was filtered, washed with cold water and dried. 0.22 g (71.4%) of the desired product were obtained as a light brown solid.

(92) .sup.1H-NMR (400 MHz, DMSO-d.sub.6): ?=3.84 (s, 3H), 3.86 (s, 3H), 7.19 (d, 1H), 7.61 (s, 1H), 7.66 (d, 1H), 7.71 (t, 1H), 8.21 (d, 1H), 8.36 (d, 1H), 8.72 (s, 1H), 13.73 (s, 1H).

(93) The following examples were synthesized using the procedure described for Example 1, starting from the corresponding intermediate and acid chlorides in each case.

Example 2: 4-[5-cyano-4-(4-methoxyphenyl)thiazol-2-ylcarbamoyl]benzoic Acid

(94) .sup.1H-NMR (400 MHz, DMSO-d.sub.6): ?=3.82 (s, 3H), 7.12 (d, 2H), 8.00 (m, 3H), 8.07 (d, 2H), 8.21 (d, 2H), 13.71 (s, 1H).

Example 3: 4-[5-cyano-4-phenylthiazol-2-ylcarbamoyl]benzoic Acid

(95) .sup.1H-NMR (400 MHz, DMSO-d.sub.6): ?=7.58 (m, 3H), 8.05 (m, 3H), 8.11 (d, 2H), 8.24 (d, 2H), 13.76 (s, 1H).

Example 4: 3-(5-cyano-4-phenylthiazol-2-ylcarbamoyl)benzoic Acid

(96) .sup.1H-NMR (400 MHz, DMSO-d.sub.6): ?=7.59 (m, 4H), 7.73 (t, 1H), 8.05 (m, 2H), 8.22 (d, 1H), 8.38 (d, 1H), 8.74 (s, 1H), 13.80 (s, 1H).

Example 5: 6-(5-cyano-4-phenylthiazol-2-ylcarbamoyl)pyridine-2-carboxylic Acid

(97) .sup.1H-NMR (400 MHz, DMSO-d.sub.6): ?=7.59 (m, 3H), 8.06 (d, 2H), 8.36 (d, 1H), 8.39 (t, 1H), 8.47 (d, 1H), 13.28 (s, 1H), 13.79 (s, 1H).

Example 6: 3-(5-cyano-4-(4-methoxyphenyl)thiazol-2-ylcarbamoyl)benzoic Acid

(98) .sup.1H-NMR (400 MHz, DMSO-d.sub.6): ?=3.85 (s, 3H), 7.16 (d, 2H), 7.72 (t, 1H), 8.03 (d, 2H), 8.21 (d, 1H), 8.37 (d, 1H), 8.73 (s, 1H), 13.74 (s, 1H).

Example 7: 2-[5-cyano-4-(4-methoxyphenyl)thiazol-2-ylcarbamoyl]benzoic Acid

(99) .sup.1H-NMR (400 MHz, DMSO-d.sub.6): ?=3.82 (s, 3H), 7.11 (d, 2H), 7.66 (m, 3H), 7.96 (m, 3H), 8.46 (s, 1H), 13.45 (s, 1H).

Example 8: 5-(5-cyano-4-(4-methoxyphenyl)thiazol-2-ylcarbamoyl)thiophene-2-carboxylic Acid

(100) .sup.1H-NMR (400 MHz, DMSO-d.sub.6): ?=3.83 (s, 3H), 7.12 (d, 2H), 7.69 (d, 2H), 7.79 (d, 1H), 7.99 (d, 1H), 8.25 (s, 1H), 13.61 (s, 1H).

Example 9: 6-[5-cyano-4-(4-methoxyphenyl)thiazol-2-ylcarbamoyl]pyridine-2-carboxylic Acid

(101) .sup.1H-NMR (400 MHz, DMSO-d.sub.6): ?=3.85 (s, 3H), 7.14 (d, 2H), 8.03 (d, 2H), 8.35 (d, 1H), 8.38 (t, 1H), 8.46 (d, 1H), 13.28 (s, 1H), 13.73 (s, 1H).

Example 10: 3-{5-cyano-4-[4-(trifluoromethoxy)phenyl]thiazol-2-ylcarbamoyl}benzoic Acid

(102) .sup.1H-NMR (400 MHz, DMSO-d.sub.6): ?=7.59 (d, 2H), 7.70 (t, 1H), 8.14 (d, 2H), 8.19 (d, 1H), 8.37 (d, 1H), 8.71 (s, 1H), 13.49 (s, 1H).

Example 11: 5-{5-cyano-4-[4-(trifluoromethoxy)phenyl]thiazol-2-ylcarbamoyl}thiophene-2-carboxylic Acid

(103) .sup.1H-NMR (400 MHz, DMSO-d.sub.6): ?=7.58 (d, 2H), 7.79 (d, 1H), 8.12 (d, 2H), 8.26 (d, 1H), 8.24 (s, 1H), 13.60 (s, 1H).

Example 12: 3-[5-cyano-4-(4-fluorophenyl)thiazol-2-ylcarbamoyl]benzoic Acid

(104) .sup.1H-NMR (400 MHz, DMSO-d.sub.6): ?=7.44 (t, 2H), 732 (t, 1H), 8.09 (dd, 2H), 8.22 (d, 1H), 8.37 (d, 1H), 8.72 (s, 1H), 13.27 (s, 1H), 13.79 (s, 1H).

Example 13: 5-(5-cyano-4-(4-fluorophenyl)thiazol-2-ylcarbamoyl)thiophene-2-carboxylic Acid

(105) .sup.1H-NMR (400 MHz, DMSO-d.sub.6): ?=7.44 (t, 2H), 7.81 (d, 1H), 8.08 (dd, 2H), 8.30 (d, 1H), 13.81 (s, 2H).

(106) HPLC-MS: Rt 3.073 m/z 374.1 (MH.sup.+).

Example 14: 5-[5-cyano-4-(3-fluorophenyl)thiazol-2-ylcarbamoyl]thiophene-2-carboxylic Acid

(107) .sup.1H-NMR (400 MHz, DMSO-d.sub.6): ?=7.42 (s, 1H), 7.77 (m, 4H), 8.29 (s, 1H), 13.88 (s, 2H).

(108) HPLC-MS: Rt 2.577 m/z 374.0 (MH.sup.+).

Example 15: 5-(5-cyano-4-(2-fluorophenyl)thiazol-2-ylcarbamoyl)thiophene-2-carboxylic Acid

(109) .sup.1H-NMR (400 MHz, DMSO-d.sub.6): ?=7.43 (m, 2H), 7.63 (s, 1H), 7.79 (d, 2H), 8.28 (s, 1H), 13.85 (s, 2H).

(110) HPLC-MS: Rt 2.265 m/z 374.0 (MH.sup.+).

Example 16: 3-[5-cyano-4-(pyridin-4-yl)thiazol-2-ylcarbamoyl]benzoic Acid

(111) .sup.1H-NMR (400 MHz, DMSO-d.sub.6): ?=7.73 (t, 1H), 7.98 (d, 2H), 8.23 (d, 1H), 8.38 (d, 1H), 8.73 (s, 1H), 8.83 (d, 2H), 13.26 (s, 1H), 13.90 (s, 1H).

Example 17: 3-[5-cyano-4-(pyridin-2-yl)thiazol-2-ylcarbamoyl]benzoic Acid

(112) .sup.1H-NMR (400 MHz, DMSO-d.sub.6): ?=7.52 (t, 1H), 7.70 (t, 1H), 8.01 (t, 1H), 8.08 (d, 1H), 8.19 (d, 1H), 8.36 (d, 1H), 8.72 (s, 1H), 8.74 (d, 1H), 13.24 (s, 1H), 13.77 (s, 1H).

Example 18: 3-[5-cyano-4-(6-methylpyridin-2-yl)thiazol-2-ylcarbamoyl]benzoic Acid

(113) .sup.1H-NMR (400 MHz, DMSO-d.sub.6): ?=2.56 (s, 3H), 7.37 (d, 1H), 7.70 (t, 1H), 7.88 (m, 2H), 8.20 (d, 1H), 8.36 (d, 1H), 8.71 (s, 1H), 13.24 (s, 1H), 13.73 (s, 1H).

Example 19: 5-(5-cyano-4-(pyridin-3-yl)thiazol-2-ylcarbamoyl)thiophene-2-carboxylic Acid

(114) .sup.1H-NMR (400 MHz, DMSO-d.sub.6): ?=7.65 (dd, 1H), 7.81 (d, 1H), 8.30 (d, 1H), 8.37 (m, 1H), 8.74 (dd, 1H), 9.19 (d, 1H), 13.94 (s, 2H).

(115) HPLC-MS: Rt 1.836 m/z 357.0 (MH.sup.+).

Example 20: 5-(5-cyano-4-(3-cyanophenyl)thiazol-2-ylcarbamoyl)thiophene-2-carboxylic Acid

(116) .sup.1H-NMR (400 MHz, DMSO-d.sub.6): ?=7.82 (d, 1H), 7.86 (t, 1H), 8.08 (d, 1H), 8.22 (d, 1H), 8.31 (d, 1H), 8.35 (s, 1H), 13.80 (s, 2H).

Example 21: 5-(5-cyano-4-(4-cyanophenyl)thiazol-2-ylcarbamoyl)thiophene-2-carboxylic Acid

(117) .sup.1H-NMR (400 MHz, DMSO-d.sub.6): ?=7.80 (s, 1H), 8.08 (s, 2H), 8.21 (m, 3H), 13.82 (s, 2H).

Example 22: 5-(5-cyano-4-phenylthiazol-2-ylcarbamoyl)thiophene-2-carboxylic Acid

(118) ##STR00013##

(119) In a 50 mL vessel equipped with a stopcock at the bottom and a mechanical stirrer, 0.2 g of the corresponding methyl ester (Intermediate 25 in this case) were suspended in 3 mL of THF. To this suspension was then added slowly 5 mL of sodium hydroxide (1M). The dark solution obtained was stirred at room temperature until TLC indicates the disappearance of the starting material. Water (15 mL) and chloroform (30 mL) were then added and the biphasic system was stirred for 20 min. The phases were then separated and the aqueous phase was washed successively with chloroform (30 mL) and dichloromethane (30 mL). The aqueous phase was filtered to remove insoluble impurities.

(120) Under a strong mechanical stirring, the resulting aqueous phase (initial pH of about 12) was acidified with hydrochloric acid 4 M to reach a pH<3. Already at pH=6, a brownish solid starts to precipitate. The suspension was stirred 30 min at room temperature and filtered. The solid was washed with 50 mL of water, and then 2 times more with 20 ml water at 60? C., and dried to obtain the title compound

(121) .sup.1H-NMR (400 MHz, DMSO-d.sub.6): ?=7.59 (m, 3H), 7.71 (s, 1H), 7.82 (d, 1H), 8.03 (d, 2H), 8.29 (d, 1H), 13.88 (s, 1H).

(122) The following examples were synthesized using the procedure described for Example 22, starting from the corresponding intermediates and carbonyl chlorides in each case.

Example 23: 5-(5-cyano-4-(6-methoxypyridin-3-yl)thiazol-2-ylcarbamoyl)thiophene-2-carboxylic Acid

(123) .sup.1H-NMR (400 MHz, DMSO-d.sub.6): ?=3.93 (s, 3H), 7.02 (d, 1H), 7.78 (d, 1H), 8.26 (dd, 2H), 8.80 (d, 1H), 13.85 (s, 2H).

(124) HPLC-MS: Rt 2.189 m/z 387.0 (MH.sup.+).

Example 24: 5-((5-cyano-4-(furan-2-yl)thiazol-2-yl)carbamoyl)thiophene-2-carboxylic Acid

(125) .sup.1H-NMR (400 MHz, DMSO-d.sub.6): ?=6.76 (dd, 1H), 7.11 (dd, 1H), 7.81 (d, 1H), 7.99-8.02 (m, 1H), 8.29 (d, 1H), 13.94 (s, 2H).

(126) HPLC-MS: Rt 2.083, m/z 346.0 (MH.sup.+).

Example 25: 5-((5-cyano-4-(thiophen-2-yl)thiazol-2-yl)carbamoyl)thiophene-2-carboxylic Acid

(127) .sup.1H-NMR (400 MHz, DMSO-d.sub.6): ?=7.28 (dd, 1H), 7.80 (d, 1H), 7.83 (dd, 1H) 7.91 (dd, 1H), 8.29 (d, 1H), 13.87 (s, 2H).

(128) HPLC-MS: Rt 2.362, m/z 362.0 (MH.sup.+).

Example 26: 5-((4-(4-chlorothiophen-2-yl)-5-cyanothiazol-2-yl)carbamoyl)thiophene-2-carboxylic Acid

(129) .sup.1H-NMR (400 MHz, DMSO-d.sub.6): ?=7.71 (s, 1H), 7.78 (d, 1H), 7.86 (s, 1H), 8.24 (d, 1H), 13.80 (s, 2H).

Example 27: 5-((5-cyano-[2,4-bithiazol]-2-yl)carbamoyl)thiophene-2-carboxylic Acid

(130) .sup.1H-NMR (400 MHz, DMSO-d.sub.6): ?=7.81 (d, 1H), 8.03 (d, 1H), 8.12 (d, 1H), 8.29 (d, 1H), 13.95 (s, 2H).

(131) HPLC-MS: Rt 1.916, m/z 363.0 (MH.sup.+).

Example 28: 3-((5-cyano[2,4-bithiazol]-2-yl)carbamoyl)benzoic Acid

(132) .sup.1H-NMR (400 MHz, DMSO-d.sub.6): ?=7.72 (t, 1H), 8.04 (d, 1H), 8.13 (d, 1H), 8.22 (d, 1H), 8.37 (d, 1H), 8.73 (s, 1H), 13.36 (s, 1H), 13.91 (s, 1H).

(133) HPLC-MS: Rt 2.129, m/z 357.0 (MH.sup.+).

Example 29: 4-((5-cyano[2,4-bithiazol]-2-yl)carbamoyl)benzoic Acid

(134) .sup.1H-NMR (400 MHz, DMSO-d.sub.6): ?=8.04 (d, 1H), 8.09 (d, 2H), 8.13 (d, 1H), 8.24 (d, 2H), 13.41 (s, 1H), 13.88 (s, 1H).

(135) HPLC-MS: Rt 2.049, m/z 357.0 (MH.sup.+).

Example 30: 4-((5-cyano-4-(thiophen-2-yl)thiazol-2-yl)carbamoyl)benzoic Acid

(136) .sup.1H-NMR (400 MHz, DMSO-d.sub.6): ?=7.29 (dd, J=5.0, 3.8 Hz, 1H), 7.88-7.82 (m, 1H), 7.92 (dd, J=3.7, 1.0 Hz, 1H), 8.09 (d, J=8.5 Hz, 2H), 8.24 (d, J=8.5 Hz, 2H), 13.44 (s, 1H), 13.80 (s, 1H).

(137) HPLC-MS: Rt 2.589, m/z 356.0 (MH.sup.+).

Example 31: 3-((5-cyano-4-(thiophen-2-yl)thiazol-2-yl)carbamoyl)benzoic Acid

(138) .sup.1H-NMR (400 MHz, DMSO-d.sub.6): ?=7.29 (dd, 1H), 7.72 (t, 1H), 7.85 (dd, 1H), 7.93 (dd, 1H), 8.20-8.24 (m, 1H), 8.35-8.40 (m, 1H), 8.72 (t, 1H), 13.32 (s, 2H), 13.81 (s, 1H).

Example 32: 3-((5-cyano-4-(furan-2-yl)thiazol-2-yl)carbamoyl)benzoic Acid

(139) .sup.1H-NMR (400 MHz, DMSO-d.sub.6): ?=6.76 (dd, 1H), 7.11 (dd, 1H), 7.71 (t, 1H), 8.00 (dd, 1H), 8.21 (dt 1H), 8.34-8.39 (m, 1H), 8.71 (t, 1H), 13.35 (s, 1H) 13.84 (s, 1H).

Example 33: 4-((5-cyano-4-(furan-2-yl)thiazol-2-yl)carbamoyl)benzoic Acid

(140) .sup.1H-NMR (400 MHz, DMSO-d.sub.6): ?=6.76 (ddd, 1H), 7.10 (dt, 1H), 7.99 (dd, 1H), 8.12-8.05 (2, 1H), 8.25-8.20 (m, 2H), 13.64 (m, 2H).

Example 34: 3-((4-(4-chlorothiophen-2-yl)-5-cyanothiazol-2-yl)carbamoyl)benzoic Acid

(141) .sup.1H-NMR (400 MHz, DMSO-d.sub.6): ?=7.71 (dd, 2H), 7.88 (s, 1H), 8.21 (d, 1H), 8.35 (d, 1H), 8.71 (s, 1H), 13.36 (s, 1H), 13.83 (s, 1H).

Example 35: 4-((4-(4-chlorothiophen-2-yl)-5-cyanothiazol-2-yl)carbamoyl)benzoic Acid

(142) .sup.1H-NMR (400 MHz, DMSO-d.sub.6): ?=7.74 (s, 1H), 7.88 (s, 1H), 8.08 (d, 2H), 8.22 (d, 2H), 13.40 (s, 1H), 13.80 (s, 1H).

Example 36: 5-((5-cyano-4-(3-methoxyphenyl)thiazol-2-yl)carbamoyl)thiophene-2-carboxylic Acid

(143) .sup.1H-NMR (400 MHz, DMSO-d.sub.6): ?=3.83 (s, 3H), 7.13 (m, 2H), 7.51 (t, 1H), 7.58 (d, Hz, 1H), 7.63 (d, Hz, 1H), 7.81 (d, 1H), 13.90 (s, 2H).

Example 37: 3-(5-cyano-4-(6-methoxypyridin-3-yl)thiazol-2-ylcarbamoyl)benzoic Acid

(144) .sup.1H-NMR (400 MHz, DMSO-d.sub.6): ?=3.94 (s, 3H), 7.04 (d, 1H), 7.71 (t, 1H), 8.21 (d, 1H), 8.29 (dd, 1H), 8.36 (d, 1H), 8.72 (s, 1H), 8.84 (d, 1H), 13.34 (s, 1H), 13.80 (s, 1H).

(145) HPLC-MS: Rt 2.419 m/z 381.0 (MH.sup.+).

Example 38: 5-(5-chloro-4-phenylthiazole-2-ylcarbamoyl)thiophene-2-carboxylic Acid

(146) .sup.1H-NMR (400 MHz, DMSO-d.sub.6): ?=7.43 (m, 1H), 7.51 (t, 2H), 7.79 (d, 1H), 7.91 (d, 2H), 8.25 (d, 1H), 13.38 (s, 1H), 13.64 (s, 1H).

(147) HPLC-MS: Rt 3.088 m/z 364.9 (M.sup.+).

Example 39: 3-(5-chloro-4-phenylthiazole-2-ylcarbamoyl)benzoic Acid

(148) .sup.1H-NMR (400 MHz, DMSO-d.sub.6): ?=7.43 (t, 1H), 7.52 (t, 2H), 7.70 (t, 1H), 7.93 (d, 2H), 8.19 (d, 1H), 8.35 (d, 1H), 8.69 (s, 1H), 13.27 (s, 2H).

(149) HPLC-MS: Rt 3.178 m/z 359.0 (MH.sup.+).

Example 40: 5-(5-bromo-4-phenylthiazol-2-ylcarbamoyl)thiophene-2-carboxylic Acid

(150) .sup.1H-NMR (400 MHz, DMSO-d.sub.6): ?=7.44 (d, 1H), 7.50 (t, 2H), 7.79 (d, 1H), 7.90 (d, 2H), 8.25 (d, 1H), 13.40 (s, 1H), 13.64 (s, 1H).

(151) HPLC-MS: Rt 3.118 m/z 410.9 (MH.sup.+).

Example 41: 5-(5-fluoro-4-phenylthiazol-2-ylcarbamoyl)thiophene-2-carboxylic Acid

(152) .sup.1H-NMR (400 MHz, DMSO-d.sub.6): ?=7.39 (d, 1H), 7.51 (t, 2H), 7.79 (d, 1H), 7.84 (d, 2H), 8.24 (d, 1H), 13.18 (s, 1H), 13.63 (s, 1H).

(153) HPLC-MS: Rt 3.012 m/z 349.0 (MH.sup.+).

Example 42: 3-(5-bromo-4-phenylthiazol-2-ylcarbamoyl)benzoic Acid

(154) .sup.1H-NMR (400 MHz, DMSO-d.sub.6): ?=7.44 (d, 1H), 7.51 (t, 2H), 7.70 (t, 1H), 7.91 (d, 2H), 8.18 (dd, 1H), 8.35 (d, 1H), 8.69 (s, 1H), 13.29 (s, 2H).

(155) HPLC-MS: Rt 3.221 m/z 405.0 (MH.sup.+).

Example 43: 3-(5-fluoro-4-phenylthiazole-2-ylcarbamoyl)benzoic Acid

(156) .sup.1H-NMR (400 MHz, DMSO-d.sub.6): b=7.39 (d, 1H), 7.51 (t, 2H), 7.70 (t, 1H), 7.86 (d, 2H), 8.18 (dd, 1H), 8.33 (d, 1H), 8.68 (s, 1H), 13.06 (s, 1H), 13.25 (s, 1H).

(157) HPLC-MS: Rt 3.093 m/z 343.0 (MH.sup.+).

Example 44: 5-(5-chloro-4-(4-methoxyphenyl)thiazol-2-ylcarbamoyl)thiophene-2-carboxylic Acid

(158) .sup.1H-NMR (400 MHz, DMSO-d.sub.6): ?=3.81 (s, 3H), 7.07 (d, 2H), 7.79 (d, 1H), 7.87 (d, 2H), 8.24 (d, 1H), 13.33 (s, 1H), 13.65 (s, 1H).

(159) HPLC-MS: Rt 3.110 m/z 395.0 (MH.sup.+).

Example 45: 5-[5-cyano-4-(4-methoxyphenyl)thiazol-2-ylcarbamoyl]-1H-pyrazole-3-carboxylic Acid

(160) ##STR00014##

(161) 0.2 g (0.86 mmol) of 2-amino-4-(4-methoxyphenyl)thiazole-5-carbonitrile (Intermediate 9), 0.2 g (1.12 mmol) of 1H-pyrazole 3,5-dicarboxylic acid, 0.5 g (1.3 mmol) of HATU and 300 ?l (1.7 mmol) of ethyldiisopropylamine were mixed in 20 ml of acetonitrile and stirred for 6 h at 90? C. After this time the solvent was removed under reduced pressure, and 5 ml of a solution of 1M sodium hydroxide were added and the organic impurities were filtered. The aqueous phase was extracted 3 times with DCM in a separating funnel and added 4M HCl dropwise until pH<3. The precipitate formed was filtered, washed with cold water and dried. 0.19 g (61.2%) of the desired product is obtained.

(162) .sup.1H-NMR (400 MHz, DMSO-d.sub.6): ?=3.84 (s, 3H), 7.15 (d, 2H), 7.61 (s, 1H), 8.02 (d, 2H), 13.45 (s, 1H), 14.73 (s, 1H).

Example 46: 1-{3-[(5-cyano-4-phenyl-thiazol-2-yl)carbamoyl]benzoyl}piperidine-4-carboxylic Acid

(163) ##STR00015##

(164) A mixture of 0.11 g (0.29 mmol) of 3-[5-cyano-4-(4-methoxyphenyl)thiazol-2-ylcarbamoyl) benzoic acid (Example 6), 49 ?l (0.32 mmol) of ethyl piperidine-4-carboxylate, 0.13 g (0.34 mmol) of HATU and 60 ?l (0.43 mmol) of TEA in 4 ml acetonitrile was allowed to react 24 h at room temperature. Then poured into cold water, the precipitate formed was filtered, washed several times with cold water and dried. Then the solid obtained was suspended in a solution of NaOH (5 mL, 1M) and stirred at room temperature following the reaction by thin layer chromatography (TLC) until the ester was completely hydrolyzed. The aqueous phase was then washed 3 times with DCM in a separating funnel. The phases were separated, and to the aqueous layers 4 M HCl was added until reaching pH<3. The precipitate formed was filtered, washed with cold water and dried. 0.083 g (58.4%) of the desired product is obtained as a light brown solid.

(165) .sup.1H-NMR (400 MHz, DMSO-d.sub.6): ?=1.55 (m, 2H), 1.87 (m, 2H), 2.54 (m, 1H), 3.08 (m, 2H), 3.45 (m, 1H), 3.82 (s, 3H), 4.36 (m, 1H), 7.12 (d, 2H), 7.65 (m, 2H), 8.00 (d, 2H), 8.16 (m, 2H), 13.70 (s, 1H).

(166) The following examples were synthesized using the procedure described for Example 46 from their corresponding starting materials:

Example 47: 1-{4-[(5-cyano-4-phenylthiazol-2-yl)carbamoyl]benzoyl}piperidine-4-carboxylic Acid

(167) .sup.1H-NMR (400 MHz, DMSO-d.sub.6): ?=1.56 (m, 2H), 1.87 (m, 2H), 2.55 (m, 1H), 3.08 (m, 2H), 3.45 (m, 1H), 4.37 (m, 1H), 7.54 (m, 3H), 7.98 (m, 2H), 8.18 (d, 2H), 8.37 (d, 2H), 8.45 (s, 1H), 13.51 (s, 1H).

Example 48: 1-{3-[(5-cyano-4-phenylthiazol-2-yl)carbamoyl]benzoyl}piperidine-4-carboxylic Acid

(168) .sup.1H-NMR (400 MHz, DMSO-d.sub.6): ?=1.55 (m, 2H), 1.88 (m, 2H), 2.54 (m, 1H), 3.08 (m, 2H), 3.45 (m, 1H), 4.36 (m, 1H), 7.54 (m, 3H), 7.69 (t, 1H), 7.99 (m, 2H), 8.31 (d, 1H), 8.40 (d, 1H), 8.45 (s, 1H), 8.86 (s, 1H), 13.51 (s, 1H).

Example 49: 1-(5-((5-cyano-4-phenylthiazol-2-yl)carbamoyl)thiophene-2-carbonyl)piperidine-4-carboxylic Acid

(169) .sup.1H-NMR (400 MHz, DMSO-d.sub.6): ?=1.55 (q, 2H), 1.89 (m, 2H), 2.55 (m, 1H), 3.16 (m, 2H), 3.17 (m, 2H), 4.10 (m, 1H), 7.51 (d, 1H), 7.55 (m, 3H), 7.99 (m, 2H), 8.29 (d, 1H), 12.33 (s, 1H), 13.79 (s, 1H).

(170) HPLC-MS: Rt 2.394, m/z 467.1 (MH.sup.+)

Example 50: 1-(4-((5-cyano-4-(thiophen-2-yl)thiazol-2-yl)carbamoyl)benzoyl)piperidine-4-carboxylic Acid

(171) .sup.1H-NMR (400 MHz, DMSO-d.sub.6): ?=1.77 (s, 1H), 1.92 (s, 1H), 1.53 (s, 2H), 2.50 (s, 1H), 2.97 (s, 1H), 3.12 (s, 1H), 3.45 (s, 1H), 4.34 (d, 1H), 7.29 (dd, 1H), 7.57 (d, 2H), 7.84 (dd, 1H), 7.92 (dd, 1H), 8.20 (m, 2H), 12.35 (2, 1H), 13.76 (s, 1H).

(172) HPLC-MS: Rt 2.579, m/z 467.0 (MH.sup.+).

Example 51: 1-(5-((5-cyano-4-(thiophen-2-yl)thiazol-2-yl)carbamoyl)thiophene-2-carbonyl)piperidine-4-carboxylic Acid

(173) .sup.1H-NMR (400 MHz, DMSO-d.sub.6): ?=1.56 (q, 2H), 1.90 (d, 2H), 2.58 (m, 1H), 3.17 (m, 2H), 4.09 (m, 2H), 7.33-7.26 (m, 1H), 7.50 (d, 1H), 7.84 (dd, 1H), 7.92 (dd, 1H), 8.28 (d, 1H), 12.35 (s, 1H), 13.81 (s, 1H).

Example 52: 1-(3-((5-cyano-4-(thiophen-2-yl)thiazol-2-yl)carbamoyl)benzoyl)piperidine-4-carboxylic Acid

(174) .sup.1H-NMR (400 MHz, DMSO-d.sub.6): ?=1.55 (d, 2H), 1.78 (s, 1H), 1.93 (s, 1H), 2.53-2.62 (m, 1H), 2.99 (s, 1H), 4.35 (s, 1H), 3.15 (s, 1H), 3.54 (s, 1H), 7.29 (dd, 1H), 7.62-7.72 (m, 2H), 7.84 (dd, 1H), 7.92 (dd, 1H), 8.19 (d, 2H), 12.35 (s, 1H), 13.69 (s, 1H).