Benzylamide Derivatives as Inhibitors of Transforming Growth Factor-Beta Receptor I/Alk5

Abstract

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

##STR00001##

to processes for the preparation of said compounds; to pharmaceutical compositions comprising said compounds and to said compounds for use in the treatment of pathological conditions or diseases that can improve by inhibition of transforming growth factor-β receptor I (TGFβRI)/ALK5, such as diseases and disorders associated to fibrotic conditions of gastrointestinal system, skin and eyes, to methods for the treatment and/or prevention of said diseases or pathological conditions and to combinations comprising said compounds and further comprising therapeutically effective amounts of other therapeutic agents useful for the treatment of said diseases or pathological conditions.

Claims

1. A compound of formula (I): ##STR00009## wherein: R.sup.i is 1 or 2 groups independently selected from: a) halogen atom, b) linear or branched C.sub.1-C.sub.6 alkyl optionally substituted by 1, 2 or 3 halogen atoms, c) cyano group, d) C.sub.1-C.sub.3alkoxy, and e) —COOH, R.sup.2 is a group selected from: a) hydrogen atom, and b) C.sub.1-C3 alkyl, R.sup.3 is a group selected from: a) hydrogen atom, b) C.sub.1-C.sub.3 alkyl optionally substituted by 1, 2 or 3 halogen atoms, and c) halogen atom, R.sup.4 and R.sup.5 independently are selected from: a) hydrogen atom, b) C.sub.1-C.sub.3 alkyl optionally substituted by 1, 2 or 3 halogen atoms, and c) halogen atoms, n has a value of 0, 1 or 2.sub.1 or a pharmaceutically acceptable salt thereof.

2. The compound or salt of claim 1 wherein each of R.sup.2, R.sup.4, and R.sup.5 are hydrogen atoms.

3. The compound or salt of claim 1 wherein n is 0 or n is 1 or 2 and each R.sup.1 independently is a halogen atom.

4. The compound or salt according to of claim 3, wherein n is 1 or 2 and each R.sup.1 independently is a halogen atom.

5. The compound or salt of claim 4, wherein each R.sup.1 is selected from the group consisting of a fluorine atom and a chlorine atom.

6. The compound or salt according to any one claims 1 to 2 of claim 1 wherein R.sup.3 is a group selected from a hydrogen atom, an ethyl group and a methyl group.

7. The compound or salt of claim 6. wherein R.sup.3 is a methyl group.

8. The compound or salt of claim 1, wherein R.sup.2, R.sup.4, and R.sup.5 independently represent are hydrogen atoms, n is 0 or n is 1 or 2 and each R.sup.1 independently represents is a halogen atom, and R.sup.3 represents is a group selected from a hydrogen atom, an ethyl group, and a methyl group.

9. The compound or salt according to of claim wherein n is 1 or 2, each R.sup.l is independently selected from the group consisting of a fluorine atom and a chlorine atom, and R.sup.3 represents is a methyl group.

10. The compound or salt according to claim 1, wherein the compound is selected from the group consisting of: N-benzyl-2-(3 -(pyridin-2-yl)-4-(quinolin-4-yl)-1H-pyrazol- 1 -yl)acetamide; N-(4-fluorobenzyl)-2-(3 -(pyridin-2-yl)-4-(quinolin-4-yl)-1H-pyrazol-1-yl)acetamide; N-(4-chlorobenzyl)-2-(3 -(pyridin-2-yl)-4-(quinolin-4-yl)-1H-pyrazol-1-yl)acetamide; N-(4-bromobenzyl)-2-(3 -(pyridin-2-yl)-4-(quinolin-4-yl)-1H-pyrazol-1-yl)acetamide; N-(4-cyanobenzyl)-2-(3 -(pyridin-2-yl)-4-(quinolin-4-yl)-1H-pyrazol-1-yl)acetamide; N-(4-methoxyb enzyl)-2-(3 -(pyri din-2-yl)-4-(quinolin-4-yl)-1H-pyrazol-1-yl)acetamide; N-(4-methylbenzyl)-2-(3 -(pyridin-2-yl)-4-(quinolin-4-yl)-1H-pyrazol-1-yl)acetamide; N-(4-(tert-butyl)benzyl)-2-(3 -(pyridin-2-yl)-4-(quinolin-4-yl)-1H-pyrazol-1-yl)acetamide; N-benzyl-2-(3-(6-methyl pyridin-2-yl)-4-(quinolin-4-yl)-1H-pyrazol-1-yl)acetamide; N-(3-methylbenzyl)-2-(3-(pyridin-2-yl)-4-(quinolin-4-yl)-1H-pyrazol-1-yl)acetamide; N-(3-fluorobenzyl)-2-(3-(pyridin-2-yl)-4-(quinolin-4-yl)-1H-pyrazol-1-yl)acetamide; N-(3-chlorobenzyl)-2-(3-(pyridin-2-yl)-4-(quinolin-4-yl)-1H-pyrazol-1-yl)acetamide; N-(3-cyanobenzyl)-2-(3-(pyridin-2-yl)-4-(quinolin-4-yl)-1H-pyrazol-1-yl)acetamide; N-(2-methylbenzyl)-2-(3-(pyridin-2-yl)-4-(quinolin-4-yl)-1H-pyrazol -1-yl)acetamide; N-(2-methylbenzyl)-2-(3-(6-methylpyridin-2-yl)-4-(quinolin-4-yl)-1H-pyrazol-1-yl)acetamide; N-(2-fluorobenzyl)-2-(3-(pyridin-2-yl)-4-(quinolin-4-yl)-1H-pyrazol-1-yl)acetamide; N-(2-fluorobenzyl)-2-(3-(6-methylpyridin-2-yl)-4-(quinolin-4-yl)-1H-pyrazol-1-yl)acetamide; N-benzyl-2-(3-(6-ethylpyridin-2-yl)-4-(quinolin-4-yl)-1H-pyrazol-1-yl)acetamide; 2-(3-(6-ethylpyridin-2-yl)-4-(quinolin-4-yl)-1H-pyrazol-1-yl)-N-(2-methylbenzyl)acetamide; N-(4-methylbenzyl)-2-(3-(6-methylpyridin-2-yl)-4-(quinolin-4-yl)-1H-pyrazol-1-yl)acetamide; N-(2-chlorobenzyl)-2-(3-(pyridin-2-yl)-4-(quinolin-4-yl)-1H-pyrazol-1-yl)acetamide; N-(2-chlorobenzyl)-2-(3-(6-methylpyridin-2-yl)-4-(quinolin-4-yl)-1H-pyrazol-1-y1)acetamide; N-(2,6-difluorobenzyl)-2-(3-(pyridin-2-yl)-4-(quinolin-4-yl)-1H-pyrazol-1-yl)acetamide; N-(2,6-difluorobenzyl)-2-(3-(6-methylpyridin-2-yl)-4-(quinolin-4-yl)-1H-pyrazol-1-yl)acetamide; N-(2,6-dimethylbenzyl)-2-(3-(pyridin-2-yl)-4-(quinolin-4-yl)-1H-pyrazol-1-yl)acetamide; N-(2,6-dimethylbenzyl)-2-(3-(6-methylpyridin-2-yl)-4-(quinolin-4-yl)-1H-pyrazol-1-yl)acetamide; N-(2-ethylbenzyl)-2-(3-(6-methylpyridin-2-yl)-4-(quinolin-4-yl)-1H-pyrazol-1-yl)acetamide; N-(2,6-dichlorobenzyl)-2-(3-(6-methylpyridin-2-yl)-4-(quinolin-4-yl)-1H-pyrazol-1-yl)acetamide; 4-((2-(3-(pyridin-2-yl)-4-(quinolin-4-yl)-1H-pyrazol-1-yl)acetamido)methyl)benzoic acid and a pharmaceutically acceptable salt of any one thereof.

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

12. A method of inhibiting transforming growth factor-β receptor I (TGFβRI/ALK5) in a subject, the method comprising: administering to the subject the compound or salt of claim 1.

13. The method according to claim 12 wherein the subject suffers from a disease or pathological condition selected from the group consisting of gastrointestinal diseases hepatic fibrosis, cancer, fibrotic skin diseases, and fibrotic eye diseases.

14. The composition of claim 11, the composition further comprising a therapeutic agent used for the treatment and/or prevention of a disease selected from the group consisting of gastrointestinal diseases, hepatic fibrosis, cancer, fibrotic skin diseases, and fibrotic eye diseases.

15. (canceled)

16. (canceled)

17. A method for the treatment of a disease pathological condition susceptible to amelioration by inhibition of transforming growth factor-β receptor I (TGFβRI/ALK5) in a subject in need thereof, the method comprising: administering to the subject the compound or salt of claim 1.

18. The method according to claim 17 wherein the disease or pathological condition is selected from the group consisting of gastrointestinal diseases hepatic fibrosis, cancer, fibrotic skin diseases, fibrotic eye diseases.

19. T The method according to claim 17 wherein the disease or pathological condition is selected from the group consisting of Crohn' s disease, ulcerative colitis, gastric cancer, esophageal cancer, colorectal cancer, scleroderma, nephrogenic fibrosing dermopathy, mixed connective tissue disease, scleromyxedema, eosinophilic fasciitis, dry eyes, age-related macular degeneration, scarring in the cornea, scarring in the conjunctiva, post-cataract fibrosis, proliferative vitreoretinopathy and proliferative diabetic retinopathy.

20. T The composition of claim 11, the composition further comprising a therapeutic agent used for the treatment and/or prevention of a disease selected from the group consisting of Crohn' s disease, ulcerative colitis, gastric cancer, esophageal cancer, colorectal cancer, scleroderma, nephrogenic fibrosing dermopathy, mixed connective tissue disease, scleromyxedema, eosinophilic fasciitis, dry eyes, age-related macular degeneration, scarring in the cornea, scarring in the conjunctiva, post-cataract fibrosis, proliferative vitreoretinopathy and proliferative diabetic retinopathy.

21. The compound of claim 1 not in the form of a pharmaceutically acceptable salt.

22. The compound of claim 1 in the form of a pharmaceutically acceptable salt.

Description

EXAMPLES

Example 1: N-benzyl-2-(3-(pyridin-2-yl)-4-(quinolin-4-yl)-1H-pyrazol-1-yl)acetamide

[0254] To a solution of N-benzyl-2-bromoacetamide(0.100 g, 0.441 mmol) in acetonitrile (2 mL), K.sub.2CO.sub.3 (0.076 g, 0.550 mmol) and 4-(3-(pyridin-2-yl)-1H-pyrazol-4-yl)quinoline (0.100 g, 0.367 mmol) were added and the reaction mixture was refluxed for 6 h. N-benzyl-2-bromoacetamide (0.017 g, 0.073 mmol) was added and the mixture was refluxed other 1 h and allowed to reach room temperature. H.sub.2O (10 mL) was added and extracted with EtOAc (3×5 mL). The organic extracts combined were dried over sodium sulfate and concentrated under reduced pressure. The residue was purified by C18 chromatography with a Combiflash system (5.fwdarw.100% H.sub.2O/MeOH:MeCN 1:1) and by flash chromatography on silice gel (3% MeOH/CH.sub.2Cl.sub.2) to give a white solid (0.080 g, 52%).

[0255] .sup.1H-NMR (500 MHz, CDC13): δ=8.89 (d, J=4.4 Hz, 1H), 8.42 (d, J=4.4, Hz, 1H), 8.16 (d, J=8.4 Hz, 1H), 7.74 (s, 1H), 7.72-7.66 (m, 2H), 7.45 (td, J =7.8, 1.8 Hz, 1H), 7.37-7.34 (m, 1H), 7.32-7.21 (m, 7H), 7.10 (ddd, J =7.8, 4.4, 1.8 Hz, 1H), 6.87 (br a, 1H), 5.05 (s, 2H), 4.52 (d, J=5.8 Hz, 2H).

[0256] HPLC-MS: Rt 16.753 m/z 420.2 [M+H].sup.+.

[0257] The following examples 2-4 were synthesized using the procedure described for the example 1 from the corresponding 4-(3-(pyridin-2-yl)-1H-pyrazol-4-yl)quinoline derivatives.

Example 2: N-(4-fluorobenzyl)-2-(3-(pyridin-2-yl)-4-(quinolin-4-yl)-1H-pyrazol-1-yl)acetamide

[0258] .sup.1H-NMR (300 MHz, DMSO-d.sub.6 ): 8.98-8.65 (m, 2H), 8.19-7.95 (m, 3H), 7.87-7.58 (m, 4H), 7.51-7.25 (m, 4H), 7.26-7.05 (m, 3H), 5.06 (s, 2H), 4.36 (d, J =5.8 Hz, 2H).

[0259] HPLC-MS: Rt 16.989 m/z 438.2 [M+H].sup.+.

Example 3: N-(4-chlorobenzyl)-2-(3-(pyridin-2-yl)-4-(quinolin-4-yl)-1H-pyrazol-1-yl)acetamide

[0260] .sup.1H-NMR (300 MHz, DMSO-d.sub.6 ): 6 =8.99-8.62 (m, 2H), 8.22-7.89 (m, 3H), 7.88-7.50 (m, 4H), 7.53-7.22 (m, 6H), 7-17-7.13 (m, 1H), 5.06 (s, 2H), 4.36 (d, J=5.8 Hz, 2H).

[0261] HPLC-MS: Rt 17.839 m/z 454.2 [M+H]+.

Example 4: N-(4-bromobenzyl)-2-(3-(pyridin-2-yl)-4-(quinolin-4-yl)-1H-pyrazol-1-yl)acetamide

[0262] .sup.1H-NMR (300 MHz, DMSO-d.sub.6 ): δ=8.84-8.80 (m, 2H), 8.18-7.93 (m, 3H), 7.88-7.60 (m, 4H), 7.60-7.20 (m, 6H), 7.18-7.14 (m, 1H), 5.06 (s, 2H), 4.34 (d, J =5.9 Hz, 2H).

[0263] HPLC-MS: Rt 18.057 m/z 498.0-500.0 [M+H].sup.+.

Example 5: N-(4-cyanobenzyl)-2-(3-(pyridin-2-yl)-4-(quinolin-4-yl)-1H-pyrazol-1-yl)acetamide

[0264] To a suspension of 4-(3-(pyridin-2-yl)-1H-pyrazol-4-yhquinoline (0.060 g, 0.220 mmol) in tetrahydrofuran (3 mL), cooled down to 5° C. with the aid of an external ice/water bath, 60% sodium hydride (0.012 g, 0.308 mmol) was added and the mixture was stirred at the same temperature for 30 min.. A solution of N-(4-cyanobenzyl)-2-bromoacetamide(0.078 g, 0.308 mmol) in a mixture of tetrahydrofuran (1 mL) and dimethylformamide (0.3 mL) was added dropwise and the mixture was stirred for 40 min. Other portion of N-(4-cyanobenzyI)-2-bromoacetamide(0.011 g, 0.048 mmol) was added stirring for 1.5 h additional. The reaction mixture was diluted with water (10 mL) and extracted with EtOAc (3×10 mL). The organic layers combined were dried over sodium sulfate and concentrated under reduced pressure. The residue was purified by flash chromatography on silica gel (2.fwdarw.4.fwdarw.5% MeOH/CH.sub.2Cl.sub.2) and by C18 chromatography with a Combiflash system (5.fwdarw.100% H.sub.2O/ MeCN) to give a white solid (0.016 g, 16%).

[0265] .sup.1H-NMR (500 MHz, DMSO-d.sub.6 ): δ=8.89 (t, J=6.0 Hz, 1H), 8.83 (dd, J=4.4, 1.1 Hz, 1H), 8.16-8.07 (m, 2H), 8.03 (d, J=8.4 Hz, 1H), 7.85-7.61 (m, 5H), 7.53 (d, J=7.9 Hz, 2H), 7.44-7.36 (m, 1H), 7.32 (dd, J=4.4, 1.0 Hz, 1H), 7.20-7.12 (m, 1H), 5.10 (s, 2H), 4.47 (d, J=6.0 Hz, 2H).

[0266] HPLC-MS: Rt 16.091 m/z 445.1 [M+H].sup.+.

[0267] The following examples 6-29 were synthesized using the procedure described for the example 5.

Example 6: N-(4-methoxybenzyl)-2-(3-(pyridin-2-yl)-4-(quinolin-4-yl)-1H-pyrazol-1-yl)acetamide

[0268] .sup.1H-NMR (500 MHz, DMSO-d.sub.6 ): δ=8.84 (d, J=4.5 Hz, 1H), 8.73 (t, J=5.9 Hz, 1H), 8.15-8.06 (m, 2H), 8.03 (d, J=8.6 Hz, 1H), 7.82-7.65 (m, 4H), 7.41-7.12 (m, 5H), 6.93-6.87 (m, 2H), 5.04 (s, 2H), 4.30 (d, J=5.8 Hz, 2H), 3.73 (s, 3H).

[0269] HPLC-MS: Rt 17.709 m/z 450.1[M+H].sup.+.

Example 7: N-(4-methylbenzyl)-2-(3-(pyridin-2-yl)-4-(quinolin-4-yl)-1H-pyrazol-1-yl)acetamide

[0270] .sup.1H-NMR (500 MHz, DMSO-d.sub.6 ): δ=8.84 (d, J=4.4 Hz, 1H), 8.74 (t, J=5.9 Hz, 1H), 8.13-8.07 (m, 2H), 8.03 (d, J=9.1 Hz, 1H), 7.83-7.65 (m, 4H), 7.41 (ddd, J=8.2, 6.8, 1.3 Hz, 1H), 7.33 (d, J=4.4 Hz, 1H), 7.24-7.10 (m, 5H), 5.05 (s, 2H), 4.33 (d, J=5.8 Hz, 2H), 2.28 (s, 3H).

[0271] HPLC-MS: Rt 17.574 m/z 434.1 [M+H].sup.+.

Example 8: N-(4-(tert-butyl)benzyl)-2-(3-(pyridin-2-yl)-4-(quinolin-4-yl)-1H-pyrazol-1-yl)acetamide

[0272] .sup.1H-NMR (500 MHz, DMSO-d.sub.6 ): δ=8.83 (d, J=4.4 Hz, 1H), 8.74 (t, J=5.8 Hz, 1H), 8.10-8.07 (m, 2H), 8.03 (d, J=8.4 Hz, 1H), 7.84-7.61 (m, 4H), 7.40 (t, J=7.6 Hz, 1H), 7.38-7.29 (m, 3H), 7.25 (d, J=8.2 Hz, 2H), 7.20-7.10 (m, 1H), 5.04 (s, 2H), 4.32 (d, J=5.8 Hz, 2H), 1.26 (s, 9H).

[0273] HPLC-MS: Rt 19.625 m/z 476.2 [M+H].sup.+.

Example 9: N-benzyl-2-(3-(6-methylpyridin-2-yl)-4-(quinolin-4-yl)-1H-pyrazol-1-yl)acetamide

[0274] .sup.1H-NMR (300 MHz, DMSO-d.sub.6 ): δ=8.84 (d, J=4.5 Hz, 1H), 8.81-8.75 (m, 1H), 8.11 (d, J=1.2 Hz, 1H), 8.03 (d, J=8.1 Hz, 1H), 7.79-7.45 (m, 4H), 7.45-7.21 (m, 7H), 6.98 (d, J=7.5 Hz, 1H), 5.06 (s, 2H), 4.39 (d, J=5.7 Hz, 2H), 1.83 (s, 3H).

[0275] HPLC-MS: Rt 17.541 m/z 434.1 [M+H].sup.+.

Example 10: N-(3-methylbenzyl)-2-(3-(pyridin-2-yl)-4-(quinolin-4-yl)-1H-pyrazol-1-yl)acetamide

[0276] .sup.1H-NMR (300 MHz, DMSO-d.sub.6): δ=8.90-8.62 (m, 2H), 8.19-7.89 (m, 3H), 7.88-7.53 (m, 4H), 7.51-6.90 (m, 7H), 5.06 (s, 2H), 4.34 (d, J=5.7 Hz, 2H), 2.27 (s, 3H).

[0277] HPLC-MS: Rt 17.625 m/z 433.9 [M+H].sup.+.

Example 11: N-(3-fluorobenzyl)-2-(3-(pyridin-2-yl)-4-(quinolin-4-yl)-1H-pyrazol-1-yl)acetamide

[0278] .sup.1H-NMR (300 MHz, DMSO-de): 6 =8.83 (d, J=4.3 Hz, 2H), 8.13 (s, 1H), 8.10 (d, J=5.2 Hz, 1H), 8.03 (d, J=8.4 Hz, 1H), 7.84-7.65 (m, 4H), 7.48-7.27 (m, 3H), 7.22-7.02 (m, 4H), 5.08 (s, 2H), 4.40 (d, J=5.9 Hz, 2H).

[0279] HPLC-MS: Rt 16.970 m/z 438.0 [M+H].sup.+.

Example 12: N-(3-chlorobenzyl)-2-(3-(pyridin-2-yl)-4-(quinolin-4-yl)-1H-pyrazol-1-yl)acetamide

[0280] .sup.1H-NMR (300 MHz, DMSO-de): 6 =8.86-8.82 (m, 2H), 8.12 (s, 1H), 8.09 (d, J =5.1 Hz, 1H), 8.03 (d, J=8.4 Hz, 1H), 7.88-7.61 (m, 4H), 7.48-7.23 (m, 6H), 7.18-7.12 (m, 1H), 5.08 (s, 2H), 4.39 (d, J=5.8 Hz, 2H).

[0281] HPLC-MS: Rt 17.747 m/z 454.1 [M+H].sup.+.

Example 13: N-(3-cyanobenzyl)-2-(3-(pyridin-2-yl)-4-(quinolin-4-yl)-1H-pyrazol-1-yl)acetamide

[0282] .sup.1H-NMR (300 MHz, DMSO-de): 6 =9.03-8.70 (m, 2H), 8.14 (d, J=1.7 Hz, 1H), 8.09 (d, J=4.9 Hz, 1H), 8.04 (d, J=8.3 Hz, 1H), 7.86-7.63 (m, 7H), 7.56 (t, J=7.6 Hz, 1H), 7.42 (t, J=7.6 Hz, 1H), 7.35 (dd, J=4.9, 1.7 Hz, 1H), 7.16 (dd, J=6.9, 5.0 Hz, 1H), 5.10 (s, 2H), 4.44 (d, J=5.9 Hz, 2H).

[0283] HPLC-MS: Rt 16.152 m/z 445.1 [M+H].sup.+.

Example 14: N-(2-methylbenzyl)-2-(3-(pyridin-2-yl)-4-(quinolin-4-yl)-1H-pyrazol-1-yl)acetamide

[0284] .sup.1H-NMR (300 MHz, DMSO-d.sub.6 ): δ=8.85-8.82 (m, 1H), 8.68 (br s, 1H), 8.18-7.95 (m, 3H), 7.88-7.60 (m, 4H), 7.49-7.08 (m, 7H), 5.06 (s, 2H), 4.35 (d, J=5.4 Hz, 2H), 2.30 (s, 3H).

[0285] HPLC-MS: Rt 17.417 m/z 434.1 [M+H].sup.+.

Example 15: N-(2-methylbenzyl)-2-(3-(6-methylpyridin-2-yl)-4-(quinolin-4-yl)-1H-pyrazol-1-yl)acetamide

[0286] .sup.1H-NMR (300 MHz, DMSO-d.sub.6 ): δ=8.84 (d, J=4.5 Hz, 1H), 8.68 (br s, 1H), 8.12 (s, 1H), 8.03 (d, J =8.4 Hz, 1H), 7.78-7.23 (m, 7H), 7.19 (br s, 3H), 6.98 (d, J =7.5 Hz, 1H), 5.06 (s, 2H), 4.35 (d, J=5.6 Hz, 2H), 2.31 (s, 3H), 1.82 (s, 3H).

[0287] HPLC-MS: Rt 18.202 m/z 448.1 [M+H].sup.+.

Example 16: N-(2-fluorobenzyl)-2-(3-(pyridin-2-yl)-4-(quinolin-4-yl)-1H-pyrazol-1-yl)acetamide

[0288] .sup.1H-NMR (300 MHz, DMSO-de): 6 =8.93-8.70 (m, 2H), 8.24-7.91 (m, 3H), 7.91-7.60 (m, 4H), 7.55-7.02 (m, 7H), 5.07 (s, 2H), 4.41 (d, J=5.5 Hz, 2H).

[0289] HPLC-MS: Rt 16.941 m/z 438.1 [M+H].sup.+.

Example 17: N-(2-fluorobenzyl)-2-(3-(6-methylpyridin-2-yl)-4-(quinolin-4-yl)-1H-pyrazol-1-yl)acetamide

[0290] .sup.1H-NMR (300 MHz, DMSO-de): 6 =8.85-8.80 (m, 2H), 8.11 (s, 1H), 8.03 (d, J=8.4 Hz, 1H), 7.78-7.11 (m, 10H), 6.98 (d, J=7.5 Hz, 1H), 5.07 (s, 2H), 4.42 (d, J=5.6 Hz, 2H), 1.83 (s, 3H).

[0291] HPLC-MS: Rt 17.628 m/z 452.0 [M+H].sup.+.

Example 18: N-benzyl-2-(3-(6-ethylpyridin-2-yl)-4-(quinolin-4-yl)-1H-pyrazol-1-yl)acetamide

[0292] .sup.1H-NMR (300 MHz, DMSO-d.sub.6 ): δ=8.85 (d, J=4.4 Hz, 1H), 8.78 (t, J=5.9 Hz, 1H), 8.09 (s, 1H), 8.02 (d, J=9.3 Hz, 1H), 7.72-7.62 (m, 4H), 7.42-7.16 (m, 7H), 6.95 (dd, J=6.7, 2.0 Hz, 1H), 5.07 (s, 2H), 4.39 (d, J =5.8 Hz, 2H), 2.10 (q, J =7.5 Hz, 2H), 0.28 (t, J=7.5 Hz, 3H).

[0293] HPLC-MS: Rt 18.386 m/z 448.1 [M+H].sup.+.

Example 19: 2-(3-(6-ethylpyridin-2-yl)-4-(quinolin-4-yl)-1H-pyrazol-1-yl)-N-(2-methylbenzyl)acetamide

[0294] .sup.1H-NMR (300 MHz, DMSO-d.sub.6 ): δ=9.04 (d, J=4.4 Hz, 1H), 8.86 (t, J=5.7 Hz, 1H), 8.28 (s, 1H), 8.21 (d, J=8.4 Hz, 1H), 7.92-7.77 (m, 4H), 7.62 — 7.45 (m, 3H), 7.38 (m, 3H), 7.14 (dd, J=6.4, 2.4 Hz, 1H), 5.25 (s, 2H), 4.55 (d, J=5.6 Hz, 2H), 2.50 (s, 3H), 2.29 (q, J=7.5 Hz, 2H), 0.46 (t, J=7.5 Hz, 3H).

[0295] HPLC-MS: Rt 19.102 m/z 462.1 [M+H].sup.+.

Example 20: N-(4-methylbenzyl)-2-(3-(6-methylpyridin-2-yl)-4-(quinolin-4-yl)-1 H-pyrazol-1-yl)acetamide

[0296] .sup.1H-NMR (300 MHz, DMSO-d.sub.6 ): δ=8.84 (d, J=4.4 Hz, 1H), 8.75 (t, J=5.9 Hz, 1H), 8.11 (s, 1H), 8.03 (d, J=8.3 Hz, 1H), 7.75-7.47 (m, 4H), 7.44-7.31 (m, 2H), 7.26-7.10 (m, 4H), 6.98 (d, J=7.5 Hz, 1H), 5.05 (s, 2H), 4.33 (d, J=5.8 Hz, 2H), 2.28 (s, 3H), 1.83 (s, 3H).

[0297] HPLC-MS: Rt 16.848 m/z 448.1 [M+H].sup.+.

Example 21: N-(2-chlorobenzyl)-2-(3-(pyridin-2-yl)-4-(quinolin-4-yl)-1H-pyrazol-1-yl)acetamide

[0298] .sup.1H-NMR (300 MHz, DMSO-de): 6 =8.85-8.79 (m, 1H), 8.18-8.06 (m, 2H), 8.03 (d, J=8.5 Hz, 1H), 7.88-7.62 (m, 4H), 7.57-7.23 (m, 6H), 7.24-7.06 (m, 1H), 5.10 (s, 2H), 4.44 (d, J=5.7 Hz, 2H).

[0299] HPLC-MS: Rt 17.627 m/z 454.0 [M+H].sup.+.

Example 22: N-(2-chlorobenzyl)-2-(3-(6-methylpyridin-2-yl)-4-(quinolin-4-yl)-1H-pyrazol-1-yl)acetamide

[0300] .sup.1H-NMR (300 MHz, DMSO-d.sub.6 ): δ=8.89-8.73 (m, 2H), 8.13 (s, 1H), 8.03 (d, J=8.3 Hz, 1H), 7.77-7.26 (m, 10H), 6.98 (d, J=7.4 Hz, 1H), 5.11 (s, 2H), 4.45 (d, J=5.7 Hz, 2H), 1.83 (s, 3H).

[0301] HPLC-MS: Rt 18.273 m/z 468.0 [M+H].sup.+.

Example 23: N-(2,6-difluorobenzyl)-2-(3-(pyridin-2-yl)-4-(quinolin-4-yl)-1H-pyrazol-1-yl)acetamide

[0302] .sup.1H-NMR (300 MHz, DMSO-d.sub.6 ): δ=8.83 (d, J=4.5 Hz, 1H), 8.77 (t, J=5.4 Hz, 1H), 8.15-7.96 (m, 3H), 7.82-7.63 (m, 4H), 7.50-7.34 (m, 2H), 7.31 (d, J=4.5 Hz, 1H), 7.22-7.04 (m, 3H), 4.99 (s, 2H), 4.42 (d, J=5.1 Hz, 2H).

[0303] HPLC-MS: Rt 16.731 m/z 455.9 [M+H].sup.+.

Example 24: N-(2,6-difluorobenzyl)-2-(3-(6-methylpyridin-2-yl)-4-(quinolin-4-yl)-1 H-pyrazol-1-yl)acetamide

[0304] .sup.1H-NMR (300 MHz, DMSO-d.sub.6 ): δ=8.84 (d, J=4.4 Hz, 1H), 8.76 (t, J=5.3 Hz, 1H), 8.11-7.97 (m, 2H), 7.75-7.28 (m, 7H), 7.13 (t, J=7.8 Hz, 2H), 6.97 (d, J=7.5 Hz, 1H), 4.99 (s, 2H), 4.43 (d, J=5.3 Hz, 2H), 1.83 (s, 3H).

[0305] HPLC-MS: Rt 17.513 m/z 470.0 [M+H].sup.+.

Example 25: N-(2,6-dimethylbenzyl)-2-(3-(pyridin-2-yl)-4-(quinolin-4-yl)-1H-pyrazol-1-yl)acetamide

[0306] .sup.1H-NMR (300 MHz, DMSO-d.sub.6): δ=8.83 (d, J=4.4 Hz, 1H), 8.43-8.39 (m, 2H), 8.16-8.06 (m, 2H), 8.03 (d, J=8.4 Hz, 1H), 7.81-7.63 (m, 4H), 7.48-7.35 (m, 1H), 7.32 (d, J=4.5 Hz, 1H), 7.21-6.97 (m, 4H), 4.99 (s, 2H), 4.37 (d, J =4.8 Hz, 2H), 2.35 (s, 6H).

[0307] HPLC-MS: Rt 18.188 m/z 448.1 [M+H].sup.+.

Example 26: N-(2,6-dimethylbenzyl)-2-(3-(6-methylpyridin-2-yl)-4-(quinolin-4-yl)-1H-pyrazol-1-yl)acetamide

[0308] .sup.1H-NMR (300 MHz, DMSO-d.sub.6 ): δ=8.83 (d, J=4.4 Hz, 1H), 8.40 (t, J=4.9 Hz, 1H), 8.08 (s, 1H), 8.02 (dd, J=8.9, 1.3 Hz, 1H), 7.77-7.27 (m, 6H), 7.18-6.92 (m, 4H), 4.98 (s, 2H), 4.37 (d, J=4.8 Hz, 2H), 2.35 (s, 6H), 1.82 (s, 3H).

[0309] HPLC-MS: Rt 18.911 m/z 462.1 [M+H].sup.+.

Example 27: N-(2-ethylbenzyl)-2-(3-(6-methylpyridin-2-yl)-4-(quinolin-4-yl)-1 H-pyrazol-1-yl)acetamide

[0310] .sup.1H-NMR (300 MHz, DMSO-d.sub.6 ): δ=8.84 (d, J=4.5 Hz, 1H), 8.69 (t, J=5.6 Hz, 1H), 8.11 (s, 1H), 8.03 (d, J=8.3 Hz, 1H), 7.77-7.13 (m, 10H), 6.98 (d, J=7.5 Hz, 1H), 5.05 (s, 2H), 4.39 (d, J=5.6 Hz, 2H), 2.66 (q, J=7.5 Hz, 2H), 1.17 (t, J=7.5 Hz, 3H).

[0311] HPLC-MS: Rt 18.940 m/z 462.1 [M+H].sup.+.

Example 28: N-(2,6-dichlorobenzyI)-2-(3-(6-methylpyridin-2-yl)-4-(quinolin-4-yl)-1H-pyrazol-1-yl)acetamide

[0312] .sup.1H-NMR (300 MHz, DMSO-d.sub.6 ): δ=8.84 (d, J=4.5 Hz, 1H), 8.61 (m, 1H), 8.09 (s, 1H), 8.03 (d, J=8.6 Hz, 1H), 7.75-7.28 (m, 9H), 6.98 (d, J=7.5 Hz, 1H), 5.01 (s, 2H), 4.61 (d, J=4.6 Hz, 2H), 1.83 (s, 3H).

[0313] HPLC-MS: Rt 18.877 m/z 502.1 [M+H].sup.+.

Example 29: 4-((2-(3-(pyridin-2-yl)-4-(quinolin-4-yl)-1H-pyrazol-1-yl)acetamido)methyl)benzoic acid hydrochloride

[0314] A suspension of tent-butyl 44(2-(3-(pyridin-2-yl)-4-(quinolin-4-yl)-1H-pyrazol-1-yl)acetamido)methyl)benzoate (0.106 g, 0.204 mmol) in hydrochloroic acid (9 mL. Disolution 4M in dioxane) was heated at 80 ° C. for 1 hour. The reaction was cooled and concentrated in vacuo. The residue was purified by C18 chromatography with a Combiflash system (5.fwdarw.100% H.sub.2O: MeCN) to afford a white solid (0.033 g, 33%).

[0315] .sup.1H-NMR (300 MHz, DMSO-d.sub.6 ): δ=9.04 (d, J=5.3 Hz, 1H), 8.95 (m, 1H), 8.27 (s, 1H), 8.21 (d, J=8.2 Hz, 1H), 8.09 (d, J=4.1 Hz, 1H), 7.92-7.79 (m, 5 H), 7.63-7.57 (m, 2H), 7.45 (d, J=7.6 Hz, 2H), 7.21 (m, 1H), 5.13 (s, 2H), 4.45 (d, J=5.3 Hz, 2H).

[0316] HPLC-MS: Rt 13.067 m/z 464.2 [M+H].sup.+.