NEW BENZAMIDE DERIVATIVES AS PPAR-GAMMA MODULATORS

Abstract

The present invention relates to novel benzamides derivatives of formula (I)

##STR00001##

as modulators of PPAR-gamma receptor, to processes for their preparation, to pharmaceutical compositions comprising said compounds and to said compound for use in the treatment of pathological conditions, disorders or diseases that can improve by modulation of PPAR-gamma receptor, such as cancer; metabolic diseases, inflammatory diseases, respiratory disorders, autoimmune diseases, neurodegenerative diseases, cardiovascular diseases and renal diseases.

Claims

1. A compound of formula (I): ##STR00062## wherein: R.sup.2 is Cl or F atoms, R.sup.1 represents a cyano group, G.sup.1 and G.sup.2 independently represent N atom or —CR.sup.9, wherein G.sup.1 and G.sup.2 are not simultaneously CR.sup.9, R.sup.9 is independently selected from the group consisting of: a) five or a six-membered heteroaryl ring optionally substituted by one or more substituents selected from the group consisting of halogen atom, cyano group, —COOH group, linear or branched C.sub.1-C.sub.3 alkyl group, linear or branched C.sub.1-C.sub.3 alkoxy, linear or branched C.sub.1-C.sub.3 haloalkyl group, C.sub.3-C.sub.4 cycloalkyl, and C.sub.3-C.sub.4 cycloalkoxy, b) phenyl group optionally substituted by one or more substituents selected from the group consisting of halogen atom, cyano group, —COOH group, linear or branched C.sub.1-C.sub.3 alkyl group, linear or branched C.sub.1-C.sub.3 alkoxy, linear or branched C.sub.1-C.sub.3 haloalkyl group, C.sub.3-C.sub.4 cycloalkyl, and C.sub.3-C.sub.4 cycloalkoxy, c) a five or six-membered saturated heterocyclic ring comprising one or two heteroatoms selected from N and O as part of the cycle, which heterocycle is optionally substituted by a C.sub.1-C.sub.3 alkyl group or C.sub.3-C.sub.4 cycloalkyl group, and d) —C.sub.3-C.sub.6 cycloalkyl group, and R.sup.3, R.sup.4 and R.sup.5 are independently selected from the group consisting of hydrogen atom, halogen atom, linear or branched C.sub.1-C.sub.3 alkyl group, C.sub.3-C.sub.4 cycloalkyl group and cyano group, or pharmaceutically acceptable salts thereof.

2. The compound according to claim 1, wherein R.sup.3, R.sup.4 and R.sup.5 are independently selected from the group consisting of hydrogen atom and halogen atom.

3. The compound according to claim 1, wherein R.sup.3, R.sup.4 and R.sup.5 are hydrogen atoms.

4. The compound according to claim 1, wherein G.sup.1 represents a N atom and G.sup.2 represents a —CR.sup.9 group, wherein R.sup.9 is selected from the group consisting of: a) phenyl group optionally substituted by one or more substituents selected from the group consisting of halogen atom, and —COOH group, b) a pyridyl ring optionally substituted by one or more substituents selected from the group consisting of halogen atom and cyano group, and c) a morpholinyl and piperazinyl group optionally substituted by a C.sub.1-C.sub.3 alkyl group or C.sub.3-C.sub.6 cycloalkyl group.

5. The compound according to claim 1, wherein G.sup.2 represents a N atom and G.sup.1 represents a —CR.sup.9 group, wherein R.sup.9 is selected from the group consisting of: a)phenyl group optionally substituted by one or more substituents selected from the group consisting of halogen atom and —COOH group, b)pyridinyl ring optionally substituted by one or more substituents selected from the group consisting of halogen atom and cyano group, and c) a morpholinyl and piperazinyl groups optionally substituted by a group selected from of C.sub.1-C.sub.3 alkyl group and C.sub.3-C.sub.6 cycloalkyl group.

6. The compound according to claim 1 wherein R.sup.1 represents a cyano group, R.sup.3, R.sup.4 and R.sup.5 represent hydrogen atoms, G.sup.1 represents a N atom and G.sup.2 represents a —CR.sup.9 group, wherein R.sup.9 represents a phenyl group optionally substituted by one or more substituents selected from the group consisting of halogen atom, —COOH group and cyano group.

7. The compound according to claim 1 wherein R.sup.1 represents a cyano group, R.sup.3, R.sup.4 and R.sup.5 independently represent a hydrogen atom, G.sup.1 represents a N atom and G.sup.2 represents a —CR.sup.9 group, wherein R.sup.9 represents pyridyl ring optionally substituted by one or more substituents selected from the group consisting of halogen atom, and cyano group.

8. The compound according to claim 1 wherein R.sup.1 represents a cyano group, R.sup.3, R.sup.4 and R.sup.5 independently represent a hydrogen atom, G.sup.2 represents a N atom and G.sup.1 represents a —CR.sup.9 group, wherein R.sup.9 is selected from: a) a phenyl group optionally substituted by one or more substituents selected from the group consisting of halogen atom, —COOH group and cyano group, and b) pyridyl ring optionally substituted by one or more substituents selected from the group consisting of halogen atom, and cyano group.

9. The compound according to claim 1 which is ene e: 2-chloro-5-cyano-N-(2-phenylpyridin-4-yl)benzamide 2-chloro-5-cyano-N-(6-phenylpyridin-3-yl)benzamide 2-chloro-5-cyano-N-(2-(4-fluorophenyl)pyridin-4-yl)benzamide 2-chloro-5-cyano-N-(6-(4-fluorophenyl)pyridin-3-yl)benzamide N-([2,3′-bipyridin]-5-yl)-2-chloro-5-cyanobenzamide N-([2,3′-bipyridin]-4-yl)-2-chloro-5-cyanobenzamide N-([2,4′-bipyridin]-5-yl)-2-chloro-5-cyanobenzamide N-([2,4′-bipyridin]-4-yl)-2-chloro-5-cyanobenzamide N-([2,3′-bipyridin]-5-yl)-5-cyano-2-fluorobenzamide 5-cyano-2-fluoro-N-(6-(4-fluorophenyl)pyridin-3-yl)benzamide 5-cyano-2-fluoro-N-(2-(4-fluorophenyl)pyridin-4-yl)benzamide N-([2,3′-bipyridin]-4-yl)-5-cyano-2-fluorobenzamide N-([2,2′-bipyridin]-5-yl)-2-chloro-5-cyanobenzamide 2-chloro-5-cyano-N-(6-(4-methylpiperazin-1-yl)pyridin-3-yl)benzamide 2-chloro-5-cyano-N-(2-(4-methylpiperazin-1-yl)pyridin-4-yl)benzamide 2-chloro-5-cyano-N-(2-morpholinopyridin-4-yl)benzamide 2-chloro-5-cyano-N-(6-morpholinopyridin-3-yl)benzamide N-([2,4′-bipyridin]-4-yl)-5-cyano-2-fluorobenzamide N-([2,4′-bipyridin]-5-yl)-5-cyano-2-fluorobenzamide 2-chloro-5-cyano-N-(pyridazin-4-yl)benzamide 5-cyano-2-fluoro-N-(pyridazin-4-yl)benzamide 2-chloro-5-cyano-N-(6-cyclopropylpyridin-3-yl)benzamide 3-(5-(2-chloro-5-cyanobenzamido)pyridin-2-yl)benzoic acid, or 4-(5-(2-chloro-5-cyanobenzamido)pyridin-2-yl)benzoic acid, or pharmaceutically acceptable salts thereof.

10. (canceled)

11. A pharmaceutical composition comprising a compound as defined in claim 1, a pharmaceutically acceptable diluent or carrier and optionally a therapeutically effective amount of further chemotherapeutics agents, anti-inflammatory agents, steroids, immunotherapeutic agent, or and other agents such as therapeutic antibodies.

12. A combination product comprising a compound as defined in claim 1 or a pharmaceutically acceptable salt thereof and at least a therapeutic agent selected from the group consisting of chemotherapeutics agents, anti-inflammatory agents, steroids, immunosuppressants, immunotherapeutic agents, therapeutic antibodies and PPAR modulators, in particular those selected from the group consisting of antibodies anti-CTLA4, selected from Ipilimumab and tremelimumab, antibodies anti-PD1 selected from the group consisting of MDX-1106 (nivolumab), MK3475 (pembrolizumab), CT-011 (pidilizumab) and AMP-224, antibodies anti-PDL1 selected from the group consisting of MPDL3280A, MEDI4736 and MDX-1105; Carboplatin, Carmustine (BCNU), Cisplatin, Cyclophosphamide, Etoposide, Irinotecan, Lomustine (CCNU), Methotrexate, Procarbazine, Temozolomide, or Vincristine.

13. (canceled)

14. A method of treating or preventing diseases or pathological conditions that can be ameliorated by modulation of PPAR-gamma receptor comprising the administration to a patient in need thereof of a compound as defined in claim 1, wherein said disease or pathological condition is selected from the group consisting of cancer selected from breast cancer, pancreatic cancer, ovarian cancer, prostate cancer, renal cancer, bladder cancer, testicular cancer, urothelial cancer skin cancer, melanoma, colon cancer, kidney cancer, brain cancer or a hematopoietic cancer selected from lymphoma, multiple myeloma and leukemia; metabolic diseases selected from osteoporosis, rachitis, arthrosis, obesity, type I and type II diabetes mellitus, lipid metabolism disorder, pancreatitis, glucose metabolism disorder, diabetic neuropathy, diabetic complications, hyperuricemia, inflammatory diseases selected from psoriasis, atopic dermatitis, eczema, acne vulgaris, other dermatitides and pruritu, pulmonary disorders selected from asthma, and chronic obstructive pulmonary disease, autoimmune disease, neurodegenerative disease selected from multiple sclerosis, Alzheimer's disease, Parkinson's disease, cardiovascular diseases selected from atherosclerosis, venous and arterial occlusive diseases, restenosis after invasive procedures, cardiomyopathy, myocardial fibrosis, congestive heart failure, angiogenesis and neovascularization in neoplastic diseases and renal diseases.

15. The compound according to claim 2, wherein G.sup.1 represents a N atom and G.sup.2 represents a —CR.sup.9 group, wherein R.sup.9 is selected from the group consisting of: a) phenyl group optionally substituted by one or more substituents selected from the group consisting of halogen atom and —COOH group, b) a pyridyl ring optionally substituted by one or more substituents selected from the group consisting of halogen atom and cyano group, and c) a morpholinyl and piperazinyl group optionally substituted by a C.sub.1-C.sub.3 alkyl group or C.sub.3-C.sub.6 cycloalkyl group.

16. The compound according to claim 3, wherein G.sup.1 represents a N atom and G.sup.2 represents a —CR.sup.9 group, wherein R.sup.9 is selected from the group consisting of: a) phenyl group optionally substituted by one or more substituents selected from the group consisting of halogen atom and —COOH group, b) a pyridyl ring optionally substituted by one or more substituents selected from the group consisting of halogen atom and cyano group, and c) a morpholinyl and piperazinyl group optionally substituted by a C.sub.1-C.sub.3 alkyl group or C.sub.3-C.sub.6 cycloalkyl group.

17. The compound according to claim 2, wherein G.sup.2 represents a N atom and G.sup.1 represents a —CR.sup.9 group, wherein R.sup.9 is selected from the group consisting of: a) phenyl group optionally substituted by one or more substituents selected from the group consisting of halogen atom and —COOH group, b) pyridinyl ring optionally substituted by one or more substituents selected from the group consisting of halogen atom and cyano group, and c) a morpholinyl and piperazinyl groups optionally substituted by a group selected from of C.sub.1-C.sub.3 alkyl group and C.sub.3-C.sub.6 cycloalkyl group.

18. The compound according to claim 3, wherein G.sup.2 represents a N atom and G.sup.1 represents a —CR.sup.9 group, wherein R.sup.9 is selected from the group consisting of: a) phenyl group optionally substituted by one or more substituents selected from the group consisting of halogen atom and —COOH group, b) pyridinyl ring optionally substituted by one or more substituents selected from the group consisting of halogen atom and cyano group, and c) a morpholinyl and piperazinyl groups optionally substituted by a group selected from of C.sub.1-C.sub.3 alkyl group and C.sub.3-C.sub.6 cycloalkyl group.

Description

EXAMPLES

[0160] General. Reagents, solvents and starting products were acquired from commercial sources. The term “concentration” refers to the vacuum evaporation using a Buchi rotavapor. When indicated, the reaction products were purified by “flash” chromatography on silica gel (40-63 μm) with the indicated solvent system. The spectroscopic data were measured in a Varian Mercury 400 spectrometer. The melting points were measured in a Buchi 535 instrument. The HPLC-MS were performed on a Gilson instrument equipped with a Gilson 321 piston pump, a Gilson 864 vacuum degasser, a Gilson 189 injection module, a 1/1000 Gilson splitter, a Gilson 307 pump, a Gilson 170 detector, and a Thermoquest Fennigan aQa detector.

Intermediate 1: 2-chloro-5-cyanobenzoyl chloride

[0161] ##STR00007##

[0162] 2-chloro-5-cyanobenzoic acid (100 mg, 0.55 mmol) was suspended in 1 mL of thionyl chloride and the reaction mixture was stirred at reflux overnight. The reaction was cooled to room temperature and the solvent was remove under vacuum. The solid was used in the next reaction step without further purification.

[0163] The following intermediate was synthesized using the procedure described for the intermediate 1 starting from the 5-cyano-2-fluorobenzoic acid.

Intermediate 2: 5-cyano-2-fluorobenzoyl chloride

[0164] ##STR00008##

[0165] The chloride of the carboxylic acid was also used in the next reaction step without further purification

Intermediate 3:2-phenylpyridin-4-amine

[0166] ##STR00009##

[0167] Bromopyridin-4-amine (150 mg, 0.86 mmol), phenylboronic acid (211.4 mg, 1.73 mmol) and [1,1′-Bis(diphenylphosphino)ferrocene]dichloropalladium(II) (42.46 mg, 0.054 mmol) were suspended in a mixture of Cs.sub.2CO.sub.3 2M in water (1.3 mL, 2.60 mmol) and 6.5 mL of 1,4-Dioxane. The reaction mixture was degassed and the vial was sealed and heated at 110° C. overnight. The reaction was quenched with NaOH 1M and extracted two times with ethyl acetate. The organic layer was washed (NaHCO.sub.3 saturated and Brine), dried with sodium sulphate and concentrated under vacuum. The crude was purified by CombiFlash column chromatography (Cyclohexane: Ethyl Acetate) to obtain the amine derivative (91.2 mg, 61.8%).

[0168] .sup.1H-NMR (400 MHz, DMSO-d.sub.6): δ=8.08 (d, 1H), 7.90 (d, 2H), 7.44 (t, 2H), 7.37 (t, 1H), 6.99 (d, 1H), 6.45 (dd, 1H), 6.07 (s, 2H).

[0169] HPLC-MS: Rt 3.014; m/z 170.9 (MH.sup.+).

[0170] The following intermediates were synthesized using the procedure described for the intermediate 3 starting from the corresponding pyridinyl halide and boronic acid derivatives.

Intermediate 4: 2-(4-fluorophenyl)pyridin-4-amin

[0171] ##STR00010##

[0172] .sup.1H-NMR (400 MHz, DMSO-d.sub.6): δ=8.07 (d, 1H), 7.95 (dd, 2H), 7.25 (t, 2H), 6.96 (d, 1H), 6.44 (dd, 1H), 6.06 (s, 2H).

[0173] HPLC-MS: Rt 3.328; m/z 189.1 (MH.sup.+).

Intermediate 5: 6-phenylpyridin-3-amine

[0174] ##STR00011##

[0175] .sup.1H-NMR (400 MHz, DMSO-d.sub.6): δ=8.02 (d, 1H), 7.91 (d, 2H), 7.62 (d, 1H), 7.38 (t, 2H), 7.26 (t, 1H), 6.99 (dd, 1H), 5.45 (s, 2H).

[0176] HPLC-MS: Rt 3.442; m/z 170.9 (MH.sup.+).

Intermediate 6: 6-(4-fluorophenyl)pyridin-3-amine

[0177] ##STR00012##

[0178] .sup.1H-NMR (400 MHz, DMSO-d.sub.6): δ=8.01 (d, 1H), 7.93 (dd, 2H), 7.60 (d, 1H), 7.20 (t, 2H), 6.99 (dd, 1H), 5.45 (s, 2H).

[0179] HPLC-MS: Rt 3.670; m/z 188.9 (MH.sup.+).

Intermediate 7: [2,4′-bipyridin]-4-amine

[0180] ##STR00013##

[0181] .sup.1H-NMR (400 MHz, DMSO-d.sub.6): δ=8.64 (d, 2H), 8.13 (d, 1H), 7.86 (d, 2H), 7.11 (d, 1H), 6.54 (dd, 1H), 6.21 (s, 2H).

[0182] HPLC-MS: Rt 2.326; m/z 172.0 (MH.sup.+).

Intermediate 8: [2,4′-bipyridin]-5-amine

[0183] ##STR00014##

[0184] .sup.1H-NMR (400 MHz, DMSO-d.sub.6): δ=8.54 (d, 2H), 8.07 (d, 1H), 7.87 (d, 2H), 7.79 (d, 1H), 7.01 (dd, 1H), 5.76 (s, 2H).

[0185] HPLC-MS: Rt 2.479; m/z 171.9 (MH.sup.+).

Intermediate 9: [2,3′-bipyridin]-4-amine

[0186] ##STR00015##

[0187] .sup.1H-NMR (400 MHz, DMSO-d.sub.6): =9.02 (d, 1H), 8.69 (dd, 1H), 8.23 (d, 1H), 8.15 (d, 1H), 7.57 (dd, 2H), 7.28 (s, 1H), 7.08 (d, 1H), 6.70 (dd, 1H).

[0188] HPLC-MS: Rt 2.303; m/z 172.0 (MH.sup.+).

Intermediate 10: [2,3′-bipyridin]-5-amine

[0189] ##STR00016##

[0190] .sup.1H-NMR (400 MHz, DMSO-d.sub.6): δ=9.10 (d, 1H), 8.46 (dd, 1H), 8.24 (m, 1H), 8.05 (d, 1H), 7.71 (d, 1H), 7.40 (dd, 1H), 7.01 (dd, 1H), 5.58 (s, 2H).

[0191] HPLC-MS: Rt 2.471; m/z 172.0 (MH.sup.+).

Intermediate 11: tert-butyl 3-(5-aminopyridin-2-yl)benzoate

[0192] ##STR00017##

[0193] .sup.1H-NMR (400 MHz, DMSO-d.sub.6): =8.45 (s, 1H), 8.12 (d, 1H), 8.05 (d, 1H), 7.79 (d, 1H), 7.67 (d, 1H), 7.50 (t, 1H), 7.02 (dd, 1H), 5.55 (s, 2H), 1.57 (s, 9H).

[0194] HPLC-MS: Rt 4.808; m/z 271.1 (MH.sup.+)

Intermediate 12: methyl 3-(5-aminopyridin-2-yl)benzoate

[0195] ##STR00018##

[0196] .sup.1H-NMR (400 MHz, DMSO-d.sub.6): =8.55 (s, 1H), 8.16 (d, 1H), 8.05 (d, 1H), 7.85 (d, 1H), 7.70 (d, 1H), 7.54 (t, 1H), 7.01 (dd, 1H), 5.56 (s, 2H), 3.88 (s, 3H).

[0197] HPLC-MS: Rt 3.731; m/z 229.1 (MH.sup.+) Intermediate 13: tert-butyl 4-(5-aminopyridin-2-yl)benzoate

##STR00019##

[0198] .sup.1H-NMR (400 MHz, DMSO-d.sub.6): δ=8.04 (d, 3H), 7.90 (d, 2H), 7.73 (d, 1H), 7.00 (dd, 1H), 5.66 (s, 2H), 1.55 (s, 9H).

[0199] HPLC-MS: Rt 4.589; m/z 271.1 (MH.sup.+) Intermediate 14: methyl 4-(5-aminopyridin-2-yl)benzoate

##STR00020##

[0200] .sup.1H-NMR (400 MHz, DMSO-d.sub.6): δ=8.07 (d, 3H), 7.97 (d, 2H), 7.74 (d, 1H), 7.01 (dd, 1H), 5.66 (s, 2H), 3.85 (s, 3H).

[0201] HPLC-MS: Rt 3.724; m/z 229.1 (MH.sup.+)

Intermediate 15: 2-morpholinopyridin-4-amine

[0202] ##STR00021##

[0203] In a sealed flask were solved 2-bromopyridin-4-amine (100 mg, 0.58 mmol) and morpholine (0.25 mL, 2.9 mmol) in 0.8 mL of dry DMSO. Potassium carbonate (239.6 mg, 1.73 mmol) was added to the mixture and the reaction was stirred at 190° C. for 16 hours. The mixture was quenched with NaHCO.sub.3 saturated and extracted with ethyl acetate. The organic layer was dried and concentrated. The crude was purified by CombiFlash column chromatography (DCM/MeOH) to afford the desired product (25 mg, 24.1%).

[0204] .sup.1H-NMR (400 MHz, DMSO-d.sub.6): δ=7.63 (d, 1H), 5.98 (dd, 1H), 5.85 (s, 3H), 3.66 (m, 4H), 3.27 (m, 4H).

[0205] HPLC-MS: Rt 1.661; m/z 180.0 (MH.sup.+).

[0206] The following intermediate was synthesized using the procedure described for the intermediate 15 starting from the corresponding pyridinyl halide and amine.

Intermediate 16:6-morpholinopyridin-3-amine

[0207] ##STR00022##

[0208] .sup.1H-NMR (400 MHz, DMSO-de): δ=7.61 (s, 1H), 6.93 (d, 1H), 6.62 (d, 1H), 4.66 (s, 2H), 3.68 (s, 4H), 3.17 (s, 4H).

[0209] HPLC-MS: Rt 1.730; m/z 179.9 (MH.sup.+).

Intermediate 17:2-(4-methylpiperazin-1-yl)pyridin-4-amine

[0210] ##STR00023##

[0211] 2-bromopyridin-4-amine (100 mg, 0.58 mmol) in 1-metilpiperazine (0.64 mL, 5.8 mmol) were heated in a sealed vial at 135° C. for 16 hours. The reaction was solved in a mixture of diethyl ether and methanol and concentrated. Purification of the solid was carried out by CombiFlash chromatography column (DCM/MeOH) obtained 2-(4-methylpiperazin-1-yl)pyridin-4-amine (84.2 mg, 75.7%).

[0212] .sup.1H-NMR (400 MHz, DMSO-de): δ=7.61 (d, 1H), 5.95 (dd, 1H), 5.86 (s, 1H), 5.82 (s, 2H), 3.33 (m, 4H), 3.04 (m, 4H), 2.23 (s, 3H).

[0213] HPLC-MS: Rt 1.995; m/z 193.0 (MH.sup.+).

[0214] The following intermediate was synthesized using the procedure described for the intermediate 17 starting from the corresponding pyridinyl halide and amine.

Intermediate 18: 6-(4-methylpiperazin-1-yl)pyridin-3-amine

[0215] ##STR00024##

[0216] .sup.1H-NMR (400 MHz, DMSO-de): δ=7.59 (s, 1H), 6.90 (d, 1H), 6.62 (d, 1H), 4.61 (s, 2H), 3.23 (s. 4H), 2.46 (s. 4H), 2.25 (s. 3H).

[0217] HPLC-MS: Rt 1.903; m/z 192.9 (MH.sup.+).

Intermediate 19: 2-bromo-5-(2,5-dimethyl-1H-pyrrol-1-yl)pyridine

[0218] ##STR00025##

[0219] In a settled tube with molecular sieves, were added 6-bromopyridin-3-amine (100 mg, 0.58 mmol), hexane-2,5-dione (0.075 mL, 0.64 mmol) and p-toluensulphonic acid (1.5 mg, 0.008 mmol) in 2 mL of anhydride Toluene. The mixture was stirred for 4 hours at reflux. The reaction mixture was quenched with NaHCO.sub.3 saturated and extracted with toluene (×2). The organic layer was dried, concentrated under vacuum and was purified by CombiFlash chromatography column (cyclohexane/ethyl acetate) to obtain the desired intermediate (83.2 mg, 57.3%).

[0220] .sup.1H-NMR (400 MHz, DMSO-d.sub.6): δ=8.39 (d, 1H), 7.79 (m, 2H), 5.85 (s, 2H), 1.99 (s, 6H).

[0221] HPLC-MS: Rt 4.958; m/z 251.8 (MH.sup.+).

[0222] The following intermediate was synthesized using the procedure described for the intermediate 19 starting from the corresponding amine.

Intermediate 20: 2-bromo-4-(2,5-dimethyl-1H-pyrrol-1-yl)pyridine

[0223] ##STR00026##

[0224] .sup.1H-NMR (400 MHz, DMSO-d.sub.6): δ=8.51 (d, 1H), 7.72 (s, 1H), 7.45 (d, 1H), 5.88 (s, 2H), 2.06 (s, 6H).

[0225] HPLC-MS: Rt 4.892; m/z 251.8 (MH.sup.+).

Intermediate 21: 5-(2,5-dimethyl-1H-pyrrol-1-yl)-2,2′-bipyridine

[0226] ##STR00027##

[0227] To a solution of 2-bromo-5-(2,5-dimethyl-1H-pyrrol-1-yl)pyridine (73.2 mg, 0.29 mmol) in 1.5 mL of dry toluene at room temperature, was added 2-(tributylstannyl)pyridine (0.02 mL, 0.44 mmol) dropwise under N.sub.2 atmosphere following by the addition of tetrakis(triphenylphosphine)palladium (10.1 mg, 0.009 mmol). The reaction mixture was degassed with nitrogen and was stirred at 130° C. overnight. The reaction was cooled to room temperature. Next, the mixture was taken up with NaOH 2M and separated with ethyl acetate (×2). The organic layer was washed with brine, was dried with Na.sub.2SO.sub.4 and the solvent was removed under vacuum. The crude was purified by CombiFlash chromatography column (cyclohexane/ethyl acetate) to afford the desired compound (60.2 mg, 82.9%).

[0228] .sup.1H-NMR (400 MHz, DMSO-d.sub.6): δ=8.77 (d, 1H), 8.68 (d, 1H), 8.55 (d, 1H), 8.51 (d, 1H), 8.12 (t, 1H), 7.98 (dd, 1H), 7.60 (m, 1H), 5.89 (s, 2H), 2.04 (s, 6H).

[0229] HPLC-MS: Rt 5.044; m/z 249.9 (MH.sup.+).

[0230] The following intermediate was synthesized using the procedure described for the intermediate 21 starting from the corresponding (2,5-dimethyl-1H-pyrrol-1-yl)pyridine derivative.

Intermediate 22: 4-(2,5-dimethyl-1H-pyrrol-1-yl)-2,2′-bipyridine

[0231] ##STR00028##

[0232] .sup.1H-NMR (400 MHz, DMSO-d.sub.6): δ=8.82 (d, 1H), 8.70 (d, 1H), 8.45 (d, 1H), 8.19 (d, 1H), 8.00 (t, 1H), 7.48 (m, 2H), 5.91 (s, 2H), 2.08 (s, 6H).

[0233] HPLC-MS: Rt 5.056; m/z 249.9 (MH.sup.+).

Intermediate 23: [2,2′-bipyridin]-5-amine

[0234] ##STR00029##

[0235] Method A: The mixture of 5-(2,5-dimethyl-1H-pyrrol-1-yl)-2,2′-bipyridine (75.6 mg, 0.3 mmol), hydroxylamine hydrochloride (210.7 mg, 3.0 mmol) and triethylamine (0.084 mL, 0.6 mmol) in 1.4 mL ethanol and 0.6 mL of H.sub.2O was stirred at 80° C. for 20 hours. The mixture was poured over HCl 1M and was washed with diethyl ether. The aqueous layer was neutralized and basified with NaOH 5M and NaOH 2M until obtained pH=9-10 and was extracted with dichloromethane (×3). The different organic layers were collected and were dried. The crude was purified by CombiFlash chromatography column (dichloromethane/dichloromethane:methanol 20%) to afforded the amine derivative (19.6 mg, 37.8%).

##STR00030##

[0236] Method B: To a solution of 6-bromopyridin-3-amine (50 mg, 0.29 mmol) in 1.5 mL of dry toluene at room temperature, was added 2-(tributylstannyl)pyridine (0.013 mL, 0.35 mmol) dropwise under N.sub.2 atmosphere following by the addition of tetrakis(triphenylphosphine)palladium (40.2 mg, 0.03 mmol). The reaction mixture was degassed with nitrogen and was stirred at 130° C. for two days. The reaction was cooled to room temperature. Next, the mixture was taken up with NaOH 2M and separated with ethyl acetate (×2). The organic layer was washed with brine, was dried with Na.sub.2SO.sub.4 and the solvent was removed under vacuum. The crude was purified by CombiFlash chromatography column (DCM/DCM:MeOH 20%) to afforded the desired compound (21.6 mg, 43.5%).

[0237] .sup.1H-NMR (400 MHz, DMSO-d.sub.6): δ=8.54 (d, 1H), 8.17 (d, 1H), 8.08 (d, 1H), 8.01 (d, 1H), 7.80 (td, 1H), 7.25 (m, 1H), 7.01 (dd, 1H), 5.65 (s, 2H).

[0238] HPLC-MS: Rt 2.746; m/z 172.0 (MH.sup.+).

[0239] The following intermediate was synthesized using the procedure described for the intermediate 23 starting from the corresponding derivatives.

Intermediate 24: [2,2′-bipyridin]-4-amine

[0240] ##STR00031##

[0241] .sup.1H-NMR (400 MHz, DMSO-d.sub.6): δ=8.62 (d, 1H), 8.29 (d, 1H), 8.09 (d, 1H), 7.88 (td, 1H), 7.61 (d, 1H), 7.39 (dd, 1H), 6.53 (dd, 1H), 6.27 (s, 2H).

[0242] HPLC-MS: Rt 2.851; m/z 171.9 (MH.sup.+).

Intermediate 25: 6-cyclopropylpyridin-3-amine

[0243] ##STR00032##

[0244] In a sealed tube were mixed 300 mg (1.73 mmol) of 6-bromopyridin-3-amine, 297.9 mg (3.47 mmol) of cyclopropylboronic acid, 97.25 mg (0.35 mmol) of tricyclohexylphosphine, 38.92 mg (0.17 mmol) of Palladium acetate and 1104 mg (5.20 mmol) of potassium phosphate in 12 mL of toluene and 0.6 mL of H.sub.2O. The reaction mixture was degassed with N.sub.2 and was stirred at 100° C. for two days. The mixture was taken up with ethyl acetate and was extracted with NaOH 1M (×2). The organic layer was dried under vacuum and the crude was purified by chromatography column (Combi-Flash hexane:ethyl acetate) to obtain 28 mg (0.21 mmol, 12.03%) of 6-cyclopropylpyridin-3-amine.

[0245] .sup.1H-NMR (400 MHz, DMSO-d.sub.6): δ=7.77 (d, 1H), 6.89 (d, 1H), 6.81 (dd, 1H), 4.96 (s, 2H), 1.85 (m, 1H), 0.75 (m, 2H), 0.70 (m, 2H).

[0246] HPLC-MS: Rt 2.589; m/z 135.1 (MH.sup.+)

Intermediate 26: N-(2-bromopyridin-4-yl)-2-chloro-5-cyanobenzamide

[0247] ##STR00033##

[0248] The mixture of 2-chloro-5-cyanobenzoic acid (50 mg, 0.27 mmol), 2-bromopyridin-4-amine (47.6 mg, 0.27 mmol) and EDC (116.2 mg, 0.60 mmol) in 0.5 mL of pyridine was stirred at 60° for 48 hours. The pyridine was removed under vacuum and the resulting crude was purified by CombiFlash chromatography column (Hexane/ethyl acetate) to obtain the desired product (6.2 mg, 6.7%).

[0249] .sup.1H-NMR (400 MHz, DMSO-d.sub.6): δ=11.23 (s, 1H), 8.33 (d, 1H), 8.27 (d, 1H), 8.05 (dd, 1H), 7.98 (s, 1H), 7.86 (d, 1H), 7.60 (dd, 1H).

[0250] HPLC-MS: Rt 4.289; m/z 337.9 (MH.sup.+).

[0251] The following intermediates were synthesized using the procedure described for the intermediate 26 starting from the corresponding derivatives.

Intermediate 27: N-(6-bromopyridin-3-yl)-2-chloro-5-cyanobenzamide

[0252] ##STR00034##

[0253] .sup.1H-NMR (400 MHz, DMSO-d.sub.6): δ=11.01 (s, 1H), 8.68 (s, 1H), 8.25 (d, 1H), 8.09 (dd, 1H), 8.03 (dd, 1H), 7.85 (d, 1H), 7.68 (d, 1H).

[0254] HPLC-MS: Rt 4.243; m/z 337.9 (MH.sup.+).

Intermediate 28: tert-butyl 3-(5-(2-chloro-5-cyanobenzamido)pyridin-2-yl)benzoate

[0255] ##STR00035##

[0256] .sup.1H-NMR (400 MHz, DMSO-d.sub.6): δ=11.01 (s, 1H), 8.94 (d, 1H), 8.59 (s, 1H), 8.30 (m, 3H), 8.08 (d, 1H), 8.04 (dd, 1H), 7.94 (d, 1H), 7.86 (d, 1H), 7.62 (t, 1H), 1.59 (s, 9H).

[0257] HPLC-MS: Rt 5.584; m/z 434.1 (MH.sup.+)

Intermediate 29: tert-butyl 4-(5-(2-chloro-5-cyanobenzamido)pyridin-2-yl)benzoate

[0258] ##STR00036##

[0259] .sup.1H-NMR (400 MHz, DMSO-d.sub.6): δ=11.05 (s, 1H), 8.95 (d, 1H), 8.30 (m, 2H), 8.20 (d, 2H), 8.11 (d, 1H), 8.04 (dd, 1H), 8.00 (d, 2H), 7.86 (d, 1H), 1.57 (s, 9H).

[0260] HPLC-MS: Rt 5.610; m/z 434.1 (MH.sup.+)

Intermediate 30: pyridazin-4-ylamine

[0261] ##STR00037##

[0262] This product is commercially available and can also be obtained as described in Hara, H. and Van Der Plas, H. C. (1982), On the amination of azaheterocycles. A new procedure for the introduction of an amino group. Journal of Heterocyclic Chemistry, 19: 1285-1287. doi:10.1002/jhet.5570190605.

Final Products

Example 1: 2-chloro-5-cyano-N-(2-phenylpyridin-4-yl)benzamide

[0263] ##STR00038##

[0264] 2-chloro-5-cyanobenzoyl chloride (intermediate 1) (55.1 mg, 0.27 mmol) in dry DCM was added dropwise in a cooling mixture of 2-phenylpyridin-4-amine (intermediate 3) (42.5 mg, 0.25 mmol), triethylamine (0.05 mL, 0.37 mmol) in 1 mL of dry DCM. The reaction mixture was stirred at 40° C. overnight. The mixture was extracted with DCM and NaHCO.sub.3 saturated. The organic layer was dried (Na.sub.2SO.sub.4) and concentrated. The crude was purified by CombiFlash column chromatography (Cyclohexane/ethyl acetate) to afford the amide derivative (54.2, 59.1%).

[0265] .sup.1H-NMR (400 MHz, DMSO-d.sub.6): δ=11.11 (s, 1H), 8.61 (d, 1H), 8.29 (d, 1H), 8.20 (s, 1H), 8.05 (dd, 1H), 7.99 (d, 2H), 7.86 (d, 1H), 7.64 (d, 1H), 7.52 (t, 2H), 7.46 (t, 1H).

[0266] HPLC-MS: Rt 4.737; m/z 333.8 (MH.sup.+).

[0267] The following examples were synthesized using the procedure described for example 1 starting from the corresponding substituted benzoic acid chlorides and amines.

Example 2: 2-chloro-5-cyano-N-(6-phenylpyridin-3-yl)benzamide

[0268] (Using Intermediates 1 and 5)

##STR00039##

[0269] .sup.1H-NMR (400 MHz, DMSO-d.sub.6): δ=10.96 (s, 1H), 8.91 (d, 1H), 8.27 (t, 1H), 8.24 (d, 1H), 8.04 (m, 4H), 7.85 (d, 1H), 7.49 (t, 2H), 7.42 (t, 1H).

[0270] HPLC-MS: Rt 4.785; m/z 333.8 (MH.sup.+).

Example 3: 2-chloro-5-cyano-N-(2-(4-fluorophenyl)pyridin-4-yl)benzamide

[0271] ##STR00040##

[0272] .sup.1H-NMR (400 MHz, DMSO-d.sub.6): δ=11.11 (s, 1H), 8.60 (d, 1H), 8.28 (s, 1H), 8.19 (s, 1H), 8.04 (t, 3H), 7.86 (d, 1H), 7.62 (d, 1H), 7.35 (t, 2H).

[0273] HPLC-MS: Rt 4.838; m/z 351.8 (MH.sup.+).

Example 4: 2-chloro-5-cyano-N-(6-(4-fluorophenyl)pyridin-3-yl)benzamide

[0274] (Using Intermediates 1 and 6)

##STR00041##

[0275] .sup.1H-NMR (400 MHz, DMSO-d.sub.6): δ=10.96 (s, 1H), 8.90 (s, 1H), 8.25 (d, 2H), 8.12 (m, 2H), 8.02 (t, 2H), 7.85 (d, 1H), 7.31 (t, 2H).

[0276] HPLC-MS: Rt 4.870; m/z 351.8 (MH.sup.+).

Example 5: N-([2,3′-bipyridin]-5-yl)-2-chloro-5-cyanobenzamide

[0277] (Using Intermediates 1 and 10)

##STR00042##

[0278] .sup.1H-NMR (400 MHz, DMSO-d.sub.6): δ=11.02 (s, 1H), 9.25 (d, 1H), 8.95 (d, 1H), 8.62 (dd, 1H), 8.42 (d, 1H), 8.29 (dd, 2H), 8.11 (d, 1H), 8.04 (dd, 1H), 7.86 (d, 1H), 7.52 (dd, 1H).

[0279] HPLC-MS: Rt 3.897; m/z 334.8 (MH.sup.+).

Example 6: N-([2,3′-bipyridin]-4-yl)-2-chloro-5-cyanobenzamide

[0280] (Using Intermediates 1 and 9)

##STR00043##

[0281] .sup.1H-NMR (400 MHz, DMSO-d.sub.6): =11.17 (s, 1H), 9.16 (d, 1H), 8.66 (d, 2H), 8.33 (d, 1H), 8.28 (d, 1H), 8.22 (s, 1H), 8.05 (dd, 1H), 7.87 (d, 1H), 7.71 (d, 1H), 7.55 (dd, 1H).

[0282] HPLC-MS: Rt 3.908; m/z 334.8 (MH.sup.+).

Example 7: N-([2,4′-bipyridin]-5-yl)-2-chloro-5-cyanobenzamide

[0283] ##STR00044##

[0284] 2-chloro-5-cyanobenzoyl chloride (intermediate 1) (64.3 mg, 0.32 mmol) in dry acetonitrile was added dropwise in a solution of [2,4′-bipyridin]-5-amine (intermediate 8) (50 mg, 0.29 mmol), triethylamine (0.05 mL, 0.37 mmol) and 4-DMAP (0.36 mg, 0.0029 mmol) in 3 mL of dry acetonitrile. The reaction mixture was stirred at 50° C. overnight. The mixture was quenched with water and was extracted three times with ethyl acetate. The organic layer was dried (Na.sub.2SO.sub.4) and concentrated. The crude was purified by CombiFlash column chromatography (DCM/Methanol) to afford the amide derivative (21.7, 22.2%).

[0285] .sup.1H-NMR (400 MHz, DMSO-d.sub.6): δ=11.09 (s, 1H), 8.97 (d, 1H), 8.69 (d, 2H), 8.33 (dd, 1H), 8.29 (d, 1H), 8.19 (d, 1H), 8.05 (dd, 3H), 7.86 (d, 1H).

[0286] HPLC-MS: Rt 3.874; m/z 334.8 (MH.sup.+).

[0287] The following examples were synthesized using the procedure described for the example 7 starting from the corresponding substituted benzoic acid chlorides and amines.

Example 8: N-([2,4′-bipyridin]-4-yl)-2-chloro-5-cyanobenzamide

[0288] (Using Intermediates 1 and 7)

##STR00045##

[0289] .sup.1H-NMR (400 MHz, DMSO-d.sub.6): δ=11.21 (s, 1H), 8.70 (m, 3H), 8.30 (d, 2H), 8.06 (d, 1H), 7.94 (s, 2H), 7.87 (d, 1H), 7.75 (s, 1H).

[0290] HPLC-MS: Rt 3.902; m/z 334.8 (MH.sup.+).

Example 9: N-([2,3′-bipyridin]-5-yl)-5-cyano-2-fluorobenzamide

[0291] (Using Intermediates 2 and 10)

##STR00046##

[0292] 15 .sup.1H-NMR (400 MHz, DMSO-d.sub.6): δ=10.96 (s, 1H), 9.25 (d, 1H), 8.97 (d, 1H), 8.61 (d, 1H), 8.42 (d, 1H), 8.30 (m, 2H), 8.13 (dd, 2H), 7.66 (t, 1H), 7.52 (dd, 1H).

[0293] HPLC-MS: Rt 3.759; m/z 318.8 (MH.sup.+).

Example 10: 5-cyano-2-fluoro-N-(6-(4-fluorophenyl)pyridin-3-yl)benzamide

[0294] (Using Intermediates 2 and 6)

##STR00047##

[0295] .sup.1H-NMR (400 MHz, DMSO-d.sub.6): δ=10.90 (s, 1H), 8.92 (d, 1H), 8.31 (dd, 1H), 8.24 (dd, 1H), 8.14 (td, 3H), 8.01 (d, 1H), 7.66 (t, 1H), 7.31 (t, 2H).

[0296] HPLC-MS: Rt 4.816; m/z 335.8 (MH.sup.+).

Example 11: 5-cyano-2-fluoro-N-(2-(4-fluorophenyl)pyridin-4-yl)benzamide

[0297] (Using Intermediates 2 and 4)

##STR00048##

[0298] .sup.1H-NMR (400 MHz, DMSO-d.sub.6): δ=11.04 (s, 1H), 8.60 (d, 1H), 8.31 (dd, 1H), 8.19 (d, 1H), 8.16 (dd, 1H), 8.04 (dd, 2H), 7.68 (d, 1H), 7.64 (m, 1H), 7.35 (t, 2H).

[0299] HPLC-MS: Rt 4.724; m/z 335.8 (MH.sup.+).

Example 12: N-([2,3′-bipyridin]-4-yl)-5-cyano-2-fluorobenzamide

[0300] (Using Intermediates 2 and 9)

##STR00049##

[0301] .sup.1H-NMR (400 MHz, DMSO-d.sub.6): δ=11.10 (s, 1H), 9.16 (d, 1H), 8.66 (d, 2H), 8.32 (t, 2H), 8.24 (d, 1H), 8.16 (m, 1H), 7.72 (dd, 1H), 7.67 (t, 1H), 7.55 (dd, 1H).

[0302] HPLC-MS: Rt 3.756; m/z 318.9 (MH.sup.+).

Example 13: N-([2,2′-bipyridin]-5-yl)-2-chloro-5-cyanobenzamide

[0303] (Using Intermediates 1 and 23)

##STR00050##

[0304] .sup.1H-NMR (400 MHz, DMSO-d.sub.6): δ=11.04 (s, 1H), 8.93 (d, 1H), 8.67 (d, 1H), 8.43 (d, 1H), 8.35 (d, 2H), 8.30 (dd, 1H), 8.04 (dd, 1H), 7.94 (td, 1H), 7.86 (d, 1H), 7.43 (dd, 1H).

[0305] HPLC-MS: Rt 4.229; m/z 334.8 (MH.sup.+).

Example 14: 2-chloro-5-cyano-N-(6-(4-methylpiperazin-1-yl)pyridin-3-yl)benzamide

[0306] (Using Intermediates 1 and 18)

##STR00051##

[0307] .sup.1H-NMR (400 MHz, DMSO-d.sub.6): δ=10.47 (s, 1H), 8.38 (d, 1H), 8.18 (d, 1H), 7.99 (dd, 1H), 7.86 (dd, 1H), 7.81 (d, 1H), 6.87 (d, 1H), 3.44 (m, 4H), 2.40 (m, 4H), 2.21 (s, 3H).

[0308] HPLC-MS: Rt 3.618; m/z 355.9 (MH.sup.+).

Example 15: 2-chloro-5-cyano-N-(2-(4-methylpiperazin-1-yl)pyridin-4-yl)benzamide

[0309] (Using Intermediates 1 and 17)

##STR00052##

[0310] .sup.1H-NMR (400 MHz, DMSO-d.sub.6): δ=10.74 (s, 1H), 8.20 (d, 1H), 8.04 (d, 1H), 8.01 (dd, 1H), 7.83 (d, 1H), 7.19 (s, 1H), 6.90 (d, 1H), 3.44 (d, 4H), 2.40 (m, 4H), 2.22 (s, 3H).

[0311] HPLC-MS: Rt 3.776; m/z 355.8 (MH.sup.+).

Example 16: 2-chloro-5-cyano-N-(2-morpholinopyridin-4-yl)benzamide

[0312] (Using Intermediates 1 and 15)

##STR00053##

[0313] .sup.1H-NMR (400 MHz, DMSO-d.sub.6): δ=10.93 (s, 1H), 8.22 (d, 1H), 8.07 (d, 1H), 8.03 (dd, 1H), 7.84 (d, 1H), 7.28 (s, 1H), 6.98 (d, 1H), 3.72 (s, 4H), 3.43 (s, 4H).

[0314] HPLC-MS: Rt 3.938; m/z 342.8 (MH.sup.+).

Example 17: 2-chloro-5-cyano-N-(6-morpholinopyridin-3-yl)benzamide

[0315] (Using Intermediates 1 and 16)

##STR00054##

[0316] .sup.1H-NMR (400 MHz, DMSO-d.sub.6): δ=10.50 (s, 1H), 8.41 (d, 1H), 8.19 (d, 1H), 7.99 (dd, 1H), 7.90 (dd, 1H), 7.81 (d, 1H), 6.88 (d, 1H), 3.70 (m, 4H), 3.40 (m, 4H).

[0317] HPLC-MS: Rt 3.774; m/z 342.8 (MH.sup.+).

Example 18: N-([2,4′-bipyridin]-4-yl)-5-cyano-2-fluorobenzamide

[0318] (Using Intermediates 2 and 7)

##STR00055##

[0319] H.sup.1-RMN (400 MHz, DMSO-d.sub.6): 11.14 (s, 1H), 8.71 (dd, 3H), 8.33 (s, 2H), 8.18 (d, 1H), 7.95 (d, 2H), 7.76 (d, 1H), 7.67 (t, 1H).

[0320] HPLC-MS: 3.811; m/z 319.0 (MH.sup.+)

Example 19: N-([2,4′-bipyridin]-5-yl)-5-cyano-2-fluorobenzamide

[0321] (Using Intermediates 2 and 8)

##STR00056##

[0322] .sup.1H-NMR (400 MHz, DMSO-d.sub.6): δ=11.02 (s, 1H), 8.99 (s, 1H), 8.69 (d, 2H), 8.33 (dd, 2H), 8.19 (d, 1H), 8.15 (m, 1H), 8.04 (d, 2H), 7.66 (t, 1H).

[0323] HPLC-MS: Rt 3.829; m/z 319.0 (MH.sup.+).

Example 20: 2-chloro-5-cyano-N-(pyridazin-4-yl)benzamide

[0324] (Using Intermediates 1 and 30)

##STR00057##

[0325] .sup.1H-NMR (400 MHz, DMSO-d.sub.6): δ=11.31 (s, 1H), 9.36 (d, 1H), 9.13 (d, 1H), 8.30 (d, 1H), 8.06 (dd, 1H), 8.03 (dd, 1H), 7.87 (d, 1H).

[0326] HPLC-MS: Rt 3.149; m/z 259.0 (MH.sup.+).

Example 21: 5-cyano-2-fluoro-N-(pyridazin-4-yl)benzamide

[0327] (Using Intermediates 2 and 30)

##STR00058##

[0328] .sup.1H-NMR (400 MHz, DMSO-d.sub.6): δ=11.23 (s, 1H), 9.39 (m, 1H), 9.13 (d, 1H), 8.32 (dd, 1H), 8.18 (m, 1H), 8.03 (dd, 1H), 7.67 (m, 1H).

[0329] HPLC-MS: Rt 2.958; m/z 243.0 (MH.sup.+).

Example 22: 2-chloro-5-cyano-N-(6-cyclopropylpyridin-3-yl)benzamide

[0330] (Using Intermediates 1 and 25)

##STR00059##

[0331] .sup.1H-NMR (400 MHz, DMSO-d.sub.6): δ=10.73 (s, 1H), 8.63 (d, 1H), 8.21 (d, 1H), 8.00 (m, 2H), 7.82 (d, 1H), 7.30 (d, 1H), 2.08 (m, 1H), 0.92 (m, 2H), 0.88 (m, 2H).

[0332] HPLC-MS: Rt 4.239; m/z 296.1 (MH.sup.+)

Example 23: 3-(5-(2-chloro-5-cyanobenzamido)pyridin-2-yl)benzoic Acid

[0333] ##STR00060##

[0334] To a solution of 76 mg (0.175 mmol) of tert-butyl 3-(5-(2-chloro-5-cyanobenzamido)pyridin-2-yl)benzoate (intermediate 28) in 2 mL of dry DCM, were added 0.3 mL (3.5 mmol) of trifluoroacetic acid. The reaction was stirred at room temperature for 8 hours. The solvent was remove under reduce pressure. The obtained solid was washed with THF and Methanol and was filtrated. The filtrate was purified by Combi-Flash column chromatography (DCM/MeOH) to afford the desired carboxyl acid derivative (22.3 mg, 33.7%)

[0335] .sup.1H-NMR (400 MHz, DMSO-d.sub.6): δ=13.11 (s, 1H), 11.01 (s, 1H), 8.94 (d, 1H), 8.66 (s, 1H), 8.30 (m, 3H), 8.09 (d, 1H), 8.04 (dd, 1H), 7.98 (d, 1H), 7.86 (d, 1H), 7.62 (t, 1H).

[0336] HPLC-MS: Rt 2.991; m/z 378.0 (MH.sup.+)

[0337] The following example was synthesized using the procedure described for the example 23 starting from the corresponding substituted benzoic acid chlorides and amines.

Example 24: 4-(5-(2-chloro-5-cyanobenzamido)pyridin-2-yl)benzoic Acid (Using Intermediate 29)

[0338] ##STR00061##

[0339] .sup.1H-NMR (400 MHz, DMSO-d.sub.6): δ=13.05 (s, 1H), 11.05 (s, 1H), 8.95 (d, 1H), 8.30 (dd, 2H), 8.20 (d, 2H), 8.12 (d, 1H), 8.05 (d, 3H), 7.86 (d, 1H).

[0340] HPLC-MS: Rt 2.899; m/z 378.0 (MH.sup.+)