Compounds and methods of use

Abstract

This disclosure provides compounds and compositions and methods of using those compounds and compositions to treat diseases and disorders associated with excessive transforming growth factor-beta (TGFβ) activity. This disclosure also provides methods of using the compounds in combination with one or more cancer immunotherapies.

Claims

1. A method of treating a tumor in an individual diagnosed with cancer, comprising administering to the individual an effective amount of ##STR00258## 4-(2-(5-chloro-2-fluorophenyl)-5-isopropylpyridin-4-ylamino)-N-(1,3-dihydroxypropan-2-yl)nicotinamide or a pharmaceutically acceptable salt thereof, wherein the cancer is selected from the group consisting of colon cancer, liver cancer, thyroid cancer, endometroid cancer, gallbladder cancer, kidney cancer, adrenocortical cancer, skin cancer, head and neck cancer and sarcoma.

2. The method of claim 1, wherein the individual is diagnosed with colon cancer.

3. The method of claim 2, wherein the colon cancer is selected from the group consisting of colon adenocarcinoma, colon adenocarcinoma from a metastatic site lymph node, metastatic colorectal cancer, and colon carcinoma.

4. The method of claim 1, wherein the individual is diagnosed with liver cancer.

5. The method of claim 4, wherein the liver cancer is selected from the group consisting of hepatocellular carcinoma, hepatoblastoma and cholangiocarcinoma.

6. The method of claim 1, wherein the individual is diagnosed with thyroid cancer.

7. The method of claim 6, wherein the thyroid cancer is selected from the group consisting of papillary thyroid carcinoma, follicular thyroid cancer and medullary thyroid cancer.

8. The method of claim 1, wherein the cancer is endometroid cancer.

9. The method of claim 8, wherein the endometrial cancer is selected from the group consisting of high grade endometroid cancer, uterine papillary serous carcinoma and uterine clear cell carcinoma.

10. The method of claim 1, wherein the cancer is gallbladder cancer.

11. The method of claim 10, wherein the gallbladder cancer is gallbladder adenocarcinoma or squamous cell gallbladder carcinoma.

12. The method of claim 1, wherein the cancer is kidney cancer.

13. The method of claim 12, wherein the kidney cancer is renal cell carcinoma or urothelial cell carcinoma.

14. The method of claim 1, wherein the cancer is adrenocortical cancer.

15. The method of claim 14, wherein the adrenocortical cancer is adrenal cortical carcinoma.

16. The method of claim 1, wherein the cancer is skin cancer.

17. The method of claim 16, wherein the skin cancer is selected from the group consisting of basal cell carcinoma, squamous carcinoma and melanoma.

18. The method of claim 1, wherein the cancer is head and neck cancer.

19. The method of claim 18, wherein the head and neck cancer is selected from the group consisting of oropharyngeal cancer, nasopharyngeal cancer, laryngeal cancer and cancer of the trachea.

20. The method of claim 1, wherein the cancer is sarcoma.

21. The method of claim 20, wherein the sarcoma is selected from the group consisting of synovial sarcoma, osteosarcoma, rhabdomiosarcoma, fibrosarcoma and Ewing's sarcoma.

22. The method of claim 1, wherein the pharmaceutically acceptable salt is a hydrochloride salt.

23. The method of claim 1, further comprising administering to the individual a second cancer therapy.

24. The method of claim 23, wherein the second cancer therapy comprises a therapy selected from the group consisting of surgery, radiation, and chemotherapy.

25. A compound: ##STR00259##

26. A compound: ##STR00260##

Description

EXAMPLES

Comparative Example 1

Synthesis of 4-[[6-(5-chloro-2-fluoro-phenyl)-3-isopropyl-2-pyridyl]amino]-N-(2-hydroxy propyl)pyridine-3-carboxamide

(1) ##STR00197## ##STR00198##

Step 1: Synthesis of 2-(6-bromo-3-pyridyl)propan-2-ol

(2) To a stirred solution of 2,5-dibromopyridine (20 g, 84.4 mmol) in diethyl ether (300 mL) was added a 2.5M solution of n-BuLi in hexane (8.8 mL, 22.16 mmol) at −78° C. and the reaction mixture was stirred at the same temperature for 1 h. To this stirred reaction mixture was added acetone (8 mL, 109.7 mmol) dropwise and the reaction mixture was stirred at −78° C. for 45 min. The progress of reaction was monitored by TLC. After completion of reaction, the mixture was quenched with an aqueous solution of ammonium chloride (100 mL) and extracted by adding more diethyl ether (1000 mL). The organic layer was dried over sodium sulfate, and concentrated under reduced pressure to give a crude product. The crude product was purified by column chromatography on silica gel (100-200 mesh) using 8% EtOAc-hexane system as eluent to afford 2-(6-bromo-3-pyridyl)propan-2-ol (9.9 g).

Step 2: Synthesis of (5-chloro-2-fluoro-phenyl)boronic acid

(3) To a solution of 2-bromo-4-chloro-1-fluoro-benzene (5 g, 0.0238 mot) in anhydrous diethyl ether (30 mL) was added a 2M solution of n-BuLi in n-hexane (13 mL, 0.0262 mol) at −70° C. under nitrogen atmosphere. The reaction mixture was stirred at the same temperature for 30 min. Then, to this reaction mixture was added triisopropyl borate (4.93 g, 0.0262 mol) dropwise. The reaction mixture turned into a white slurry, which was further stirred at −70° C. for 30 min and then warmed to RT and stirred for 1 h. The progress of reaction was monitored by TLC and .sup.1H NMR. After completion of the reaction, the mixture was hydrolyzed with 6 N HCl, stirred for 1 h and the product was extracted with EtOAc (50 mL). The organic layer was washed with brine and concentrated under reduced pressure to obtain a sticky compound which was triturated with n-pentane to afford (5-chloro-2-fluoro-phenyl)boronic acid (2.2 g) as an off white solid.

Step 3: Synthesis of 2-[6-(5-chloro-2-fluoro-phenyl)-3-pyridyl]propan-2-ol

(4) To a solution 2-(6-bromo-3-pyridyl)propan-2-ol (1.5 g, 6.94 mmol) and (5-chloro-2-fluoro-phenyl)boronic acid (1.81 g, 10.41 mmol) in DMF (20 mL) and water (20 mL) was added NaHCO.sub.3 (1.16 g, 0.013 mmol). The reaction mixture was purged with nitrogen for 30 min. To this reaction mixture was added tetrakis(triphenylphosphine)palladium(0) (401 mg, 0.347 mmol) and then the reaction mixture was heated at 100° C. overnight. The progress of reaction was monitored by LCMS. After completion of the reaction, to the reaction mixture was added water (75 mL) and the product was extracted with EtOAc (2×250 mL). The combined organic layer was washed with water (4×100 mL), dried over sodium sulfate and concentrated under reduced pressure to give a crude product. The crude product was purified by column chromatography on silica gel (100-200 mesh) using 20-60% EtOAc-hexane to afford 2-[6-(5-chloro-2-fluoro-phenyl)-3-pyridyl]propan-2-ol (1.1 g).

Step 4: Synthesis of 2-[6-(5-chloro-2-fluoro-phenyl)-3-pyridyl]propan-2-ol

(5) To a stirred solution of 2-[6-(5-chloro-2-fluoro-phenyl)-3-pyridyl]propan-2-ol (2 g, 7.54 mmol) in DCM (12 mL) was added mCPBA (1.95 g, 11.32 mmol) in portions at 0° C. The reaction mixture was stirred at RT overnight. The progress of reaction was monitored by TLC and LCMS. After completion of the reaction, the DCM layer was washed with 1 N HCl (2×100 mL). The aqueous layer was then concentrated under reduced pressure to give N-oxide of 2-[6-(5-chloro-2-fluoro-phenyl)-3-pyridyl]propan-2-ol as HCl salt (1.9 g) as an off white solid.

Step 5: Synthesis of 2-chloro-6-(5-chloro-2-fluoro-phenyl)-3-isopropenyl-pyridine

(6) A mixture of the N-oxide of 2-[6-(5-chloro-2-fluoro-phenyl)-3-pyridyl]propan-2-ol (1.9 g, 6.76 mmol) and POCl.sub.3 (9.7 mL, 101.4 mmol) was heated to reflux at 80° C. for 2 h. The progress of reaction was monitored by LCMS. After completion of the reaction, the POCl.sub.3 was evaporated under reduced pressure. An aqueous solution of NaHCO.sub.3 was added to the residue, and the product was extracted with EtOAc (2×250 mL). The combined organic layer was dried over sodium sulfate and concentrated under reduced pressure to give a pale yellow liquid compound that was purified by column chromatography on silica gel (100-200 mesh) using 0.5% EtOAc-hexane system as eluent to afford 2-chloro-6-(5-chloro-2-fluoro-phenyl)-3-isopropenyl-pyridine (600 mg) as a yellow oily liquid.

Step 6: Synthesis of 2-chloro-6-(5-chloro-2-fluoro-phenyl)-3-isopropyl-pyridine

(7) To a stirred solution of 2-chloro-6-(5-chloro-2-fluoro-phenyl)-3-isopropenyl-pyridine (600 mg, 2.13 mmol) in ethanol (5 mL) was added PtO.sub.2 (100 mg). The reaction mixture was hydrogenated using hydrogen bladder for 4 h. The progress of reaction was monitored by NMR. After completion of the reaction, the mixture was filtered through a celite bed and the celite bed washed with MeOH (200 mL). The filtrate was concentrated under reduced pressure to obtain 2-chloro-6-(5-chloro-2-fluoro-phenyl)-3-isopropyl-pyridine (570 mg) as a pale yellow liquid.

Step 7: Synthesis of 4-[[6-(5-chloro-2-fluoro-phenyl)-3-isopropyl-2-pyridyl]amino]pyridine-3-carboxylate acid

(8) To a solution of 2-chloro-6-(5-chloro-2-fluoro-phenyl)-3-isopropyl-pyridine (570 mg, 2.01 mmol) and methyl 4-aminopyridine-3-carboxylate (306 mg, 2.01 mmol) in dioxane (3 mL) was added Cs.sub.2CO.sub.3 (918 mg, 2.8 mmol). The reaction mixture was purged with nitrogen for 1 h. Then, to this reaction mixture was added BINAP (175 mg, 0.281 mmol) and Pd(OAc).sub.2. The reaction mixture was heated at 90° C. overnight. The progress of reaction was monitored by LCMS and TLC. After completion of the reaction, the product was extracted with EtOAc (2×200 mL). The combined organic layer was concentrated under reduced pressure to give a crude product. The crude product was purified by column chromatography on silica gel (100-200 mesh) using 20% EtOAc-hexane system as eluent to afford methyl 4-[[6-(5-chloro-2-fluoro-phenyl)-3-isopropyl-2-pyridyl]amino]pyridine-3-carboxylate acid (360 mg) as a white solid compound.

Step 8: Synthesis of 4-[[6-(5-chloro-2-fluoro-phenyl)-3-isopropyl-2-pyridyl]amino]pyridine-3-carboxylic acid

(9) To a solution of methyl 4-[[6-(5-chloro-2-fluoro-phenyl)-3-isopropyl-2-pyridyl]amino]pyridine-3-carboxylate (360 mg, 0.90 mmol) in MeOH (6 mL) was added sodium hydroxide (72 mg, 1.30 mmol) in water (1 mL). The reaction mixture was heated at reflux for 1 h. The progress of reaction was monitored by TLC and NMR. After completion of the reaction, the mixture was concentrated and toluene was added to give 4-[[6-(5-chloro-2-fluoro-phenyl)-3-isopropyl-2-pyridyl]amino]pyridine-3-carboxylic acid (350 mg) as sodium salt as an off white solid.

Step 9: Synthesis of 4-[[6-(5-chloro-2-fluoro-phenyl)-3-isopropyl-2-pyridyl]amino]-N-(2-hydroxypropyl) pyridine-3-carboxamide

(10) To a solution of 4-[[6-(5-chloro-2-fluoro-phenyl)-3-isopropyl-2-pyridyl]amino]pyridine-3-carboxylic acid (50 mg, 0.123 mmol) in DMF (1.5 mL) was added DIPEA (0.06 mL, 0.369 mmol) followed by addition of HATU (93 mg, 0.246 mmol). After 15 min, to this reaction mixture was added (S)-1-aminopropan-2-ol (18 mg, 0.23 mmol). The reaction mixture was heated at 100° C. overnight. The progress of reaction was monitored by LCMS. After completion of the reaction, the mixture was quenched by addition of water (5 mL) and the product was extracted with EtOAc (2×50 mL). The combined organic layer was dried over sodium sulfate and concentrated under reduced pressure to give a crude product. The crude product was purified by reverse phase preparative HPLC to afford 4-[[6-(5-chloro-2-fluoro-phenyl)-3-isopropyl-2-pyridyl]amino]-N-(2-hydroxy propyl)pyridine-3-carboxamide (11.89 mg) as an off white solid.

(11) NMR: .sup.1H NMR (400 MHz, CD.sub.3OD) δ (ppm): 8.84-8.69 (m, 2H), 8.34 (d, J=6.1 Hz, 1H), 8.00 (dd, J=6.8, 2.7 Hz, 1H), 7.79 (d, J=8.0 Hz, 1H), 7.57-7.49 (m, 1H), 7.42 (m, 1H), 7.25 (dd, J=10.9, 8.9 Hz, 1H), 4.01 (q, J=6.1 Hz, 1H), 3.45 (d, J=4.7 Hz, 2H), 3.37 (dd, J=13.3, 6.9 Hz, 2H), 3.23 (dd, J=13.7, 6.8 Hz, 1H), 1.37 (d, J=6.8 Hz, 6H), 1.24 (d, J=6.3 Hz, 3H).

Example 1. Preparation of Compound Nos. 1, 1a and 1b

Synthesis of 4-[[5-bromo-2-(5-chloro-2-fluoro-phenyl)-4-pyridyl]amino]-N-(2-hydroxypropyl) pyridine-3-carboxamide

(12) ##STR00199## ##STR00200##

Step 1: Synthesis of 2,5-dibromo-4-iodo-pyridine

(13) To a solution of diisopropylamine (3.24 mL, 0.023 mol) in anhydrous THF (50 mL) was added a 2M solution of n-BuLi in n-hexane (11.6 mL, 0.023 mol) at −70° C. under nitrogen atmosphere. The reaction mixture was stirred at −70° C. for 30 min. To this reaction mixture was added 2,5-dibromopyridine (5 g, 0.021 mol) in THF (30 mL) dropwise. The reaction mixture was stirred at −70° C. for 4 h. To the reaction mixture, then was added a solution of iodine (6.96 g, 0.0274 mol) in THF (20 mL) and stirred for 30 min at the same temperature. The progress of reaction was monitored by TLC & .sup.1H NMR. After completion of reaction, the mixture was quenched using aqueous Sodium thiosulfate solution and the product was extracted with EtOAc. The organic layer was washed with aqueous sodium thiosulfate solution and brine solution. The organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure to afford 2,5-dibromo-4-iodo-pyridine (7.3 g) as a yellow solid pure compound.

Step 2: Synthesis of methyl 4-[(2,5-dibromo-4-pyridyl)amino]pyridine-3-carboxylate

(14) To a suspension of 2,5-dibromo-4-iodo-pyridine (3.5 g, 0.0096 mol) methyl 4-aminopyridine-3-carboxylate (1.615 g, 0.0106 mot) and potassium phosphate tribasic (4.095 g, 0.0193 mol) in dioxane (20 mL) was purged with nitrogen for 45 min at RT. Then, to this reaction mixture was added Xantphos (0.837 g, 0.00144 mol) and Pd.sub.2(dba).sub.3 (1.397 g, 0.00144 mol) and purging with nitrogen was continued for 10 min. The reaction mixture was heated at 110° C. overnight. The progress of reaction was monitored by TLC and LCMS. After completion of reaction, the mixture was filtered through a celite bed and the celite bed was washed with EtOAc. The filtrate was concentrated under reduced pressure to obtain crude compound that was purified by column chromatography on silica (100:200 mesh) using 40% EtOAc-hexane system as eluent to afford methyl 4-[(2,5-dibromo-4-pyridyl)amino]pyridine-3-carboxylate pure compound (1.510 g) as a yellow solid.

Step 3: Synthesis of methyl 4-[[5-bromo-2-(5-chloro-2-fluoro-phenyl)-4-pyridyl]amino]pyridine-3-carboxylate

(15) To a suspension of methyl 4-[(2,5-dibromo-4-pyridyl)amino]pyridine-3-carboxylate (1.5 g, 0.0038 mol), (5-chloro-2-fluoro-phenyl) boronic acid (1.014 g, 0.0058 mol) and sodium carbonate (0.823 g, 0.0077 mol) in toluene (20 mL) was purged with nitrogen for 45 min at RT. To this reaction mixture was added Pd(PPh.sub.3).sub.4 (0.224 g, 0.00019 mol) and purging with nitrogen was continued for a further 10 min. The reaction mixture was heated at 100° C. overnight. After completion of reaction, the mixture was diluted with water and the product was extracted with EtOAc. The organic layer was washed with water and brine solution, dried over anhydrous sodium sulfate and concentrated under reduced pressure to obtain crude compound that was purified by column chromatography on silica (100:200 mesh) using 35-40% EtOAc-hexane system as eluent to afford methyl 4-[[5-bromo-2-(5-chloro-2-fluoro-phenyl)-4-pyridyl]amino]pyridine-3-carboxylate (1.07 g) in pure form.

Step 4: Synthesis of 4-[[5-bromo-2-(5-chloro-2-fluoro-phenyl)-4-pyridyl]amino]pyridine-3-carboxylic acid

(16) To a suspension of methyl 4-[[5-bromo-2-(5-chloro-2-fluoro-phenyl)-4-pyridyl]amino]pyridine-3-carboxylate (665 mg, 1.522 mmol) in MeOH (5 mL) was added a solution of NaOH (91 mg, 2.284 mmol) in water (1 mL). The reaction mixture was heated at 80° C. for 1 h. The progress of reaction was monitored by TLC. After completion of reaction, the mixture was concentrated under reduced pressure to obtain a sticky compound. To this reaction mixture was added toluene (3×10 mL) to obtain a solid compound which was triturated with diethyl ether (10 mL) to afford 4-[[5-bromo-2-(5-chloro-2-fluoro-phenyl)-4-pyridyl]amino]pyridine-3-carboxylic acid (550 mg) as a light yellow solid.

Step 5: Synthesis of (5-chloro-2-fluoro-phenyl)boronic acid

(17) To a solution of 2-bromo-4-chloro-1-fluoro-benzene (5 g, 0.0238 mot) in anhydrous diethyl ether (30 mL) was added a 2M solution of n-BuLi in n-hexane (13 mL, 0.0262 mole) at −70° C. under nitrogen atmosphere. The solution was stirred for 30 min at the same temperature, and then triisopropyl borate (4.93 g, 0.0262 mol) was added dropwise in to the solution. The white slurry that formed was stirred for 30 min at −70° C. and then warmed to RT and stirred for 1 h. The reaction was monitored by TLC and .sup.1H NMR. After completion of reaction, the reaction mixture was hydrolyzed with 6 N NaOH and stirred for 1 h. The reaction mixture was extracted with EtOAc. The organic layer was washed with brine and concentrated under reduced pressure to obtain a sticky compound that was triturated with n-Pentane and dried to afford (5-chloro-2-fluoro-phenyl)boronic acid (2.2 g) as an off white solid.

Step 6: Synthesis of 4-[[5-bromo-2-(5-chloro-2-fluoro-phenyl)-4-pyridyl]amino]-N-(2-hydroxypropyl)pyridine-3-carboxamide

(18) To a solution of 4-[[5-bromo-2-(5-chloro-2-fluoro-phenyl)-4-pyridyl]amino]pyridine-3-carboxylic acid (550 mg, 1.241 mmol) in DMF (5 mL) was added N,N-diisopropylethyl amine (0.65 mL, 3.725 mmol) and HATU (755 mg, 1.986 mmol). The reaction mixture was stirred at RT for 15 min under nitrogen atmosphere. Then, to this reaction mixture was added (S)-1-aminopropan-2-ol (233 mg, 3.104 mmol) and the reaction mixture was stirred at 35° C. overnight. The progress of reaction was monitored by TLC. After completion of reaction, the mixture was diluted with water and extracted with EtOAc (100 mL). The organic layer was washed with water (100 mL) and brine solution (100 mL), dried over anhydrous sodium sulfate and concentrated under reduced pressure to obtain crude product. The crude product was purified by reverse phase HPLC to afford 4-[[5-bromo-2-(5-chloro-2-fluoro-phenyl)-4-pyridyl]amino]-N-(2-hydroxypropyl) pyridine-3-carboxamide (11 mg) as a white solid. The (R) enantiomer can be synthesized utilizing (R)-1-aminopropan-2-ol in this step.

(19) NMR: .sup.1H NMR (400 MHz, CDCl.sub.3) δ (ppm): 10.62 (s, 1H), 8.75 (d, J=5.7 Hz, 2H), 8.50 (d, J=5.9 Hz, 1H), 8.03 (dd, J=6.8, 2.7 Hz, 1H), 7.88 (s, 1H), 7.47 (d, J=5.8 Hz, 1H), 7.35 (m, 1H), 7.11 (dd, J=10.8, 8.7 Hz, 1H), 6.76 (s, 1H), 4.09 (m, 1H), 3.76 (m, 1H), 3.31 (m, 1H), 1.34-1.23 (d, 3H).

Example 2. Preparation of Compound Nos. 2, 2a and 2b

Synthesis of (S)-4-[[2-(5-chloro-2-fluoro-phenyl)-5-isopropyl-4-pyridyl]amino]-N-(2-hydroxy propyl)pyridine-3-carboxamide

(20) ##STR00201##

Step 1: Synthesis of 2-(4,6-dichloro-3-pyridyl)propan-2-ol

(21) To a solution of (5 g, 0.0243 mol) in dry THF (60 mL) was added a 3M solution of methylmagnesium bromide in diethyl ether (28.3 mL, 0.0848 mol) dropwise under nitrogen at −60° C. The reaction mixture was stirred at −60° C. to 0° C. for 2 h. The progress of reaction was monitored by TLC & .sup.1H NMR. After completion of the reaction, the mixture was quenched with a saturated aqueous solution of ammonium chloride and extracted with EtOAc. The organic layer was washed water and brine solution, dried over anhydrous sodium sulfate and concentrated under reduced pressure to afford 2-(4,6-dichloro-3-pyridyl)propan-2-ol (4.96 g) in pure form as a yellow oily substance.

Step 2: Synthesis of 2-[4-chloro-6-(5-chloro-2-fluoro-phenyl)-3-pyridyl]propan-2-ol

(22) A suspension of 2-(4,6-dichloro-3-pyridyl)propan-2-ol (4.96 g, 0.024 mole), (5-chloro-2-fluoro-phenyl)boronic acid (6.284 g, 0.036 mol) and sodium bicarbonate (4.045 g, 0.048 mol) in a 2:1 mixture of DMF:H.sub.2O (60 mL) was purged with nitrogen for 45 min. Then, to this reaction mixture was added Pd(PPh.sub.3).sub.4 (500 mg) and purging continued with nitrogen for 10 min. The reaction mixture was heated at 80° C. overnight. After completion of reaction, the reaction mixture was diluted with water, and the product was extracted with EtOAc. The organic layer was washed with water and brine solution, then dried over anhydrous sodium sulfate and concentrated under reduced pressure to obtain crude product. The crude product was purified by column chromatography on silica gel (100:200 mesh) using 7% EtOAc-hexane system as eluent to afford 2-[4-chloro-6-(5-chloro-2-fluoro-phenyl)-3-pyridyl]propan-2-ol (4.931 g) pure compound as an off white solid.

Step 3: Synthesis of 4-chloro-2-(5-chloro-2-fluoro-phenyl)-5-isopropenyl-pyridine

(23) To a solution of 2-[4-chloro-6-(5-chloro-2-fluoro-phenyl)-3-pyridyl]propan-2-ol (4.931 g, 0.0165 mol) in O-xylene (60 mL) was added PTSA.H.sub.2O (0.313 g, 0.00165 mol) and hydroquinone (0.181 g, 0.00165 mol) and heated at 160° C. in Dean Stark apparatus overnight. The progress of reaction was monitored by TLC and .sup.1H NMR. After completion of reaction, the mixture was concentrated under reduced pressure to obtain crude product. The crude product was purified by column chromatography on silica gel (100:200 mesh) using 10% EtOAc-hexane to afford 4-chloro-2-(5-chloro-2-fluoro-phenyl)-5-isopropenyl-pyridine (4 g) pure compound.

Step 4: Synthesis of 4-[[2-(5-chloro-2-fluoro-phenyl)-5-isopropenyl-4-pyridyl]amino]pyridine-3-carboxylate

(24) To a suspension of 4-chloro-2-(5-chloro-2-fluoro-phenyl)-5-isopropenyl-pyridine (1 g, 3.55 mmol), methyl 4-aminopyridine-3-carboxylate (0.595 g, 0.0039 mol) and potassium phosphate tribasic (1.510 g, 0.0071 mol) in dioxane (20 mL) was purged with nitrogen for 45 min. To this reaction mixture was added Xantphos (0.308 g, 0.0053 mol) and Pd.sub.2(dba).sub.3 (0.552 g, 0.0053 mol) and purging continued with nitrogen for 10 min. The reaction mixture was heated at 100° C. for 16 h. The progress of reaction was monitored by TLC and LCMS. After completion of reaction, the reaction mixture was filter through a celite bed, and the celite bed was washed with EtOAc. The filtrate was concentrated under reduced pressure to obtain the crude product. The crude product was purified by column chromatography on silica gel (100:200 mesh) using 30-35% EtOAc-hexane as eluent to afford methyl 4-[[2-(5-chloro-2-fluoro-phenyl)-5-isopropenyl-4-pyridyl]amino]pyridine-3-carboxylate (0.7 g) pure compound as a yellow solid.

Step 5: Synthesis of methyl 4-[[2-(5-chloro-2-fluoro-phenyl)-5-isopropyl-4-pyridyl]amino]pyridine-3-carboxylate

(25) To a stirred solution of methyl 4-[[2-(5-chloro-2-fluoro-phenyl)-5-isopropenyl-4-pyridyl]amino]pyridine-3-carboxylate (360 mg, 0.906 mmol) in ethanol (5 mL) was added PtO.sub.2 (80 mg). The reaction mixture was stirred at RT for 18 h under hydrogen atmosphere using a hydrogen bladder. The progress of reaction was monitored by .sup.1H NMR. After completion of reaction, the mixture was filtered through a celite bed, and the celite bed was washed with EtOAc (2×50 mL). The filtrate was collected and concentrated under reduced pressure to afford methyl 4-[[2-(5-chloro-2-fluoro-phenyl)-5-isopropyl-4-pyridyl]amino]pyridine-3-carboxylate (350 mg) as a sticky oily substance.

Step 6: Synthesis of (S)-4-[[2-(5-chloro-2-fluoro-phenyl)-5-isopropyl-4-pyridyl]amino]-N-(2-hydroxypropyl)pyridine-3-carboxamide

(26) To a stirred solution of (S)-1-aminopropan-2-ol (86 mg, 1.14 mmol) in DCM (10 mL) was added potassium tert-butoxide (128 mg, 1.14 mmol). The reaction mixture was stirred at RT for 10 min under nitrogen atmosphere. Then, to this reaction mixture was added a solution of methyl 4-[[2-(5-chloro-2-fluoro-phenyl)-5-isopropyl-4-pyridyl]amino]pyridine-3-carboxylate (350 mg, 0.877 mmol) in DCM (10 mL) dropwise. The reaction mixture was heated at 55° C. for 1 h. The progress of reaction was monitored by TLC and LCMS. After completion of reaction, the mixture was diluted with DCM (50 mL) and washed with water (30 mL) and brine solution (20 mL). The organic layer was dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain the crude product. The crude product was purified by reverse phase HPLC to afford (S)-4-[[2-(5-chloro-2-fluoro-phenyl)-5-isopropyl-4-pyridyl]amino]-N-(2-hydroxypropyl)pyridine-3-carboxamide (13 mg) as the TFA salt. The (R) enantiomer can be synthesized utilizing (R)-1-aminopropan-2-ol in this step.

(27) NMR: .sup.1H NMR (400 MHz, CD.sub.3OD) δ (ppm): 8.92 (s, 1H), 8.77 (s, 1H), 8.37 (d, J=7.1 Hz, 1H), 7.99-7.90 (m, 2H), 7.54 (m, 1H), 7.46 (d, J=7.0 Hz, 1H), 7.31 (t, J=9.7 Hz, 1H), 4.07-3.94 (m, 1H), 3.49 (m, 1H), 3.37 (m, 1H), 3.32-3.21 (m, 1H), 1.40 (d, J=6.9 Hz, 6H), 1.24 (d, J=6.3 Hz, 3H).

Example 3. Preparation of Compound Nos. 3, 3a and 3b

Synthesis of (S)-4-(2-(5-chloro-2-fluorophenyl)-5-(prop-1-en-2-yl)pyridin-4-ylamino)-N-(2-hydroxypropyl)pyridine-5-carboxamide

(28) ##STR00202##

(29) Steps 1 to 4 are the same as in Example 2.

Step 5: Synthesis of (S)-4-(2-(5-chloro-2-fluorophenyl)-5-(prop-1-en-2-yl)pyridin-4-ylamino)-N-(2-hydroxypropyl)pyridine-5-carboxamide

(30) To a stirred solution of (S)-1-aminopropan-2-ol (92 mg, 1.227 mmol) in DCM (10 mL) was added potassium tertiary butoxide (138 mg, 1.227 mmol). The reaction mixture was stirred at RT for 10 min under nitrogen atmosphere. Then, to this stirred reaction mixture was added a solution of methyl 4-[[2-(5-chloro-2-fluoro-phenyl)-5-isopropenyl-4-pyridyl]amino]pyridine-3-carboxylate (375 mg, 0.944 mmol) in DCM (10 mL) dropwise. The reaction mixture was heated at 55° C. for 1 h. The progress of reaction was monitored by TLC and LCMS. After completion of reaction, the mixture was diluted with DCM (60 mL), washed with water (40 mL) and brine solution (20 mL). The organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure to obtain the crude product. The crude product was purified by reverse phase HPLC to afford (S)-4-(2-(5-chloro-2-fluorophenyl)-5-(prop-1-en-2-yl)pyridin-4-ylamino)-N-(2-hydroxypropyl)pyridine-5-carboxamide (31 mg) as a white solid. The (R) enantiomer can be synthesized utilizing (R)-1-aminopropan-2-ol in this step.

(31) NMR: .sup.1H NMR (400 MHz, CDCl.sub.3) δ (ppm): 10.21 (s, 1H), 8.68 (s, 1H), 8.50 (s, 1H), 8.44-8.37 (m, 1H), 8.03 (dd, J=6.8, 2.8 Hz, 1H), 7.81 (d, J=1.8 Hz, 1H), 7.43-7.24 (m, 2H), 7.10 (t, J=9.7 Hz, 1H), 6.76 (s, 1H), 5.51 (s, 1H), 5.23 (s, 1H), 4.13-4.00 (m, 1H), 3.70 (m, 1H), 3.29 (m, 1H), 2.14 (d, J=1.4 Hz, 3H), 1.29 (d, J=6.3 Hz, 3H).

Example 4. Preparation of Compound Nos. 4, 4a and 4b

Synthesis of (S)-4-(2-(5-chloro-2-fluorophenyl)-5-(prop-1-en-2-yl)pyridin-4-ylamino)-N-(2-hydroxypropyl)pyrimidine-5-carboxamide

(32) ##STR00203##

(33) Steps 1 to 3 are the same as in Example 2.

Step 4: Synthesis of 4-aminopyrimidine-5-carboxylic acid

(34) To a stirred solution of 4-aminopyrimidine-5-carboxylic acid (1 g, 7.188 mmol) in MeOH (20 mL) was added concentrated sulfuric acid (4 mL) dropwise at 0° C. The reaction mixture was heated to reflux at 85° C. in a reagent bottle overnight. The progress of reaction was monitored by .sup.1H NMR. After completion of reaction, the mixture was concentrated under reduced pressure to remove MeOH. To the residue was added ice-water (10 mL) and the pH of the aqueous mixture was made neutral by the addition of a saturated solution of sodium bicarbonate. The product was extracted with EtOAc (2×50 mL). The organic layer was again washed with brine solution (40 mL). The organic layer was separated, dried over anhydrous sodium sulfate and concentrated under reduced pressure to afford 4-aminopyrimidine-5-carboxylic acid (780 mg) as an off-white solid.

Step 5: Synthesis of methyl 4-[[2-(5-chloro-2-fluoro-phenyl)-5-isopropenyl-4-pyridyl]amino]pyrimidine-5-carboxylate

(35) A solution of 4-chloro-2-(5-chloro-2-fluoro-phenyl)-5-isopropenyl-pyridine (440 mg, 1.559 mmol), methyl 4-aminopyrimidine-5-carboxylate (263 mg, 1.715 mmol) and potassium phosphate (tribasic) (662 mg, 3.118 mmol) in 1,4-dioxane (20 mL) was purged with nitrogen for 30 min. Then, to this reaction mixture was added tris(dibenzylidineacetone)dipalladium(0) (143 mg, 0.156 mmol) and Xantphos (135 mg, 0.233 mmol). Then, to this reaction mixture was purged with nitrogen gas for another 5 min. The reaction mixture was heated at 100° C. overnight. The progress of reaction was monitored by TLC and LCMS. After completion of reaction, the mixture was diluted with EtOAc (50 mL) and filtered through a celite bed. The filtrate was washed with water (20 mL) and finally with brine solution (20 mL). The organic layer was separated, dried over anhydrous sodium sulfate and concentrated under reduced pressure to afford crude product which was purified by CombiFlash® chromatography using 20% EtOAc-hexane system as eluent to afford methyl 4-[[2-(5-chloro-2-fluoro-phenyl)-5-isopropenyl-4-pyridyl]amino]pyrimidine-5-carboxylate (325 mg) as a light yellow solid.

Step 6: Synthesis of (S)-4-(2-(5-chloro-2-fluorophenyl)-5-(prop-1-en-2-yl)pyridin-4-ylamino)-N-(2-hydroxypropyl)pyrimidine-5-carboxamide

(36) To a stirred solution of methyl 4-[[2-(5-chloro-2-fluoro-phenyl)-5-isopropenyl-4-pyridyl]amino]pyrimidine-5-carboxylate (100 mg, 0.250 mmol) and (S)-1-amino-propan-2-ol (28 mg, 0.376 mmol) in toluene (8 mL) was added a 1 M solution of trimethylaluminium in heptane (1 mL, 1.00 mmol) at RT. The reaction mixture was heated at reflux for 2 h. The progress of reaction was monitored by TLC. After completion of reaction, the mixture was diluted with EtOAc (30 mL) and washed with saturated solution of sodium bicarbonate (15 mL), water (15 mL) and brine (15 mL). The organic layer was separated, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to afford crude product. The crude product was purified by precipitating in DCM-Pentane system and dried to afford (S)-4-(2-(5-chloro-2-fluorophenyl)-5-(prop-1-en-2-yl)pyridin-4-ylamino)-N-(2-hydroxypropyl)pyrimidine-5-carboxamide (90 mg) as an off-white solid. The (R) enantiomer can be synthesized utilizing (R)-1-aminopropan-2-ol in this step.

(37) NMR: .sup.1H NMR (400 MHz, CD.sub.3OD) δ (ppm): 9.56 (s, 1H), 9.15 (d, J=9.8 Hz, 2H), 8.63 (s, 1H), 7.88 (dd, J=6.3, 2.7 Hz, 1H), 7.75 (ddd, J=9.1, 4.5, 2.7 Hz, 1H), 7.48 (t, J=9.5 Hz, 1H), 5.88-5.64 (s, 1H), 5.45 (s, 1H), 3.99 (td, J=6.8, 4.6 Hz, 1H), 3.52-3.34 (m, 2H), 2.72 (s, 9H), 2.25 (s, 3H), 1.23 (d, J=6.3 Hz, 3H). LCMS: 442.2 (M+1).

Example 5. Preparation of Compound Nos. 5, 5a and 5b

Synthesis of (S)-1-((4-(2-(5-chloro-2-fluorophenyl)-5-isopropylpyridin-4-ylamino)pyridin-3-yl)methylamino)propan-2-ol

(38) ##STR00204##

(39) Steps 1 to 7 are the same as in Comparative Example 1

Step 8: Synthesis of (S)-1-((4-(2-(5-chloro-2-fluorophenyl)-5-isopropylpyridin-4-ylamino)pyridin-3-yl)methylamino)propan-2-ol

(40) To a solution of methyl 4-[[2-(5-chloro-2-fluoro-phenyl)-5-isopropyl-4-pyridyl]amino]pyridine-3-carboxylate (100 mg, 0.25 mmol) in THF (10 mL) was added a 1 M solution of DIBAL-H (1.25 mL, 1.25 mmol) in toluene at 0° C. The reaction mixture was stirred at RT overnight. The progress of reaction was monitored by TLC and LCMS. After completion of reaction, the mixture was quenched with an aqueous solution of NH.sub.4Cl and extracted with EtOAc (50 mL). The combined organic layer was washed with water (20 mL), dried over anhydrous sodium sulfate and concentrated under reduced pressure to obtain [4-[[2-(5-chloro-2-fluoro-phenyl)-5-isopropyl-4-pyridyl]amino]-3-pyridyl]methanol (70 mg).

Step 9: Synthesis of [4-[[2-(5-chloro-2-fluoro-phenyl)-5-isopropyl-4-pyridyl]amino]-3-pyridyl]methyl methanesulfonate

(41) To a solution of [4-[[2-(5-chloro-2-fluoro-phenyl)-5-isopropyl-4-pyridyl]amino]-3-pyridyl]methanol (70 mg, 0.188 mmol) in DCM (5 mL) was added triethylamine (0.13 mL, 0.94 mmol) at 0° C. After 10 min, to this reaction mixture was added methane sulfonyl chloride (0.03 mL, 0.376 mmol). The reaction mixture was stirred at the same temperature for 2 h. The progress of reaction was monitored by TLC and LCMS. After completion of the reaction, the mixture was diluted with DCM (15 mL) and washed with water (10 mL). The organic layer was separated and further washed with water (20 mL). The organic layer was dried over anhydrous sodium sulfate, and concentrated under reduced pressure to give [4-[[2-(5-chloro-2-fluoro-phenyl)-5-isopropyl-4-pyridyl]amino]-3-pyridyl]methyl methanesulfonate (40 mg).

Step 10: Synthesis of 1-[[4-[[2-(5-chloro-2-fluoro-phenyl)-5-isopropyl-4-pyridyl]amino]-3-pyridyl] methylamino]propan-2-ol

(42) To a solution of (2S)-1-aminopropan-2-ol (33 mg, 0.444 mmol) in DMF (3 mL) was added NaH (10 mg, 0.22 mmol) at 0° C. The reaction mixture was stirred for 30 min at the same temperature. To this stirred reaction mixture was added a solution of [4-[[2-(5-chloro-2-fluoro-phenyl)-5-isopropyl-4-pyridyl]amino]-3-pyridyl]methyl methanesulfonate (100 mg, 0.22 mmol) in DMF (2 mL). Then, the reaction mixture was stirred at 0° C. for 2 h. The progress of reaction was monitored by LCMS. After completion of the reaction, the mixture was quenched with ice-cold water (10 mL) and extracted with EtOAc (50 mL). The organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure to obtain the crude product. The crude product was purified by reverse phase HPLC to give 1-[[4-[[2-(5-chloro-2-fluoro-phenyl)-5-isopropyl-4-pyridyl]amino]-3-pyridyl]methylamino]propan-2-ol (8.9 mg). The (R) enantiomer can be synthesized utilizing (R)-1-aminopropan-2-ol in this step.

(43) NMR: .sup.1H NMR (400 MHz, CDCl.sub.3) δ (ppm): 8.83 (s, 1H), 8.75 (s, 1H), 8.09-7.91 (m, 2H), 7.61 (s, 1H), 7.42-7.29 (m, 1H), 7.11-6.95 (m, 2H), 6.71 (d, J=6.7 Hz, 1H), 4.52 (s, 2H), 4.25 (s, 1H), 3.23 (m, 1H), 3.11 (m, 1H), 2.40 (m, 1H), 1.35 (m, 3H), 1.28 (m, 6H).

Example 6. Preparation of Compound Nos. 6, 6a and 6b

Synthesis of (S)-4-(2-(5-chloro-2-fluorophenyl)-5-isopropylpyridin-4-ylamino)-N-(1-hydroxypropan-2-yl)nicotinamide

(44) ##STR00205##

(45) Steps 1 to 7 are the same as in Comparative Example 1

Step 8: Synthesis of (S)-4-(2-(5-chloro-2-fluorophenyl)-5-isopropylpyridin-4-ylamino)-N-(1-hydroxypropan-2-yl)nicotinamide

(46) A suspension of (S)-2-aminopropan-1-ol (45 mg, 0.601 mmol), potassium tert-butoxide (68 mg, 0.601 mmol) in DCM (5 mL) was stirred for 5 min. The reaction mixture turned yellow. To this reaction mixture was added a solution of methyl 4-[[2-(5-chloro-2-fluoro-phenyl)-5-isopropyl-4-pyridyl]amino]pyridine-3-carboxylate (200 mg, 0.503 mmol) in DCM (5 mL). Then, this reaction mixture was heated in a closed reagent bottle at 55° C. for 1 h. The progress of reaction was monitored by TLC and LCMS. After completion of the reaction, the reaction mixture was diluted with DCM (15 mL) and water (5 mL). The DCM layer was separated. The aqueous layer was again extracted with DCM (15 mL). The combined organic layer was dried over anhydrous sodium sulfate, and concentrated under reduced pressure to afford a crude product which was purified by reverse phase HPLC to afford (S)-4-(2-(5-chloro-2-fluorophenyl)-5-isopropylpyridin-4-ylamino)-N-(1-hydroxypropan-2-yl)nicotinamide (42.12 mg) as a white solid. The (R) enantiomer can be synthesized utilizing (R)-2-aminopropan-1-ol in this step.

(47) NMR: .sup.1H NMR (400 MHz, CD.sub.3OD) δ (ppm): 8.76 (s, 1H), 8.59 (s, 1H), 8.32 (d, J=6.0 Hz, 1H), 7.89 (dd, J=6.7, 2.7 Hz, 1H), 7.80 (s, 1H), 7.45 (t, J=5.2 Hz, 1H), 7.37 (d, J=6.1 Hz, 1H), 7.25 (t, J=9.75 Hz, 1H), 4.24 (h, J=6.4 Hz, 1H), 3.62 (m, 2H), 3.25 (m, 1H), 1.40 (dd, J=7.0, 1.6 Hz, 6H), 1.26 (d, J=6.8 Hz, 3H).

Example 7a. Preparation of Compound No. 7a

Synthesis of (S)-4-(2-(5-chloro-2-fluorophenyl)-5-(prop-1-en-2-yl)pyridin-4-ylamino)-N-(1-hydroxypropan-2-yl)nicotinamide

(48) ##STR00206##

(49) Steps 1 to 4 are the same as in Example 2

Step 5: Synthesis of (S)-4-(2-(5-chloro-2-fluorophenyl)-5-(prop-1-en-2-yl)pyridin-4-ylamino)-N-(1-hydroxypropan-2-yl)nicotinamide

(50) A suspension of (S)-2-aminopropan-1-ol (45 mg, 0.601 mmol) and tert-butoxide (68 mg, 0.601 mmol) in DCM (5 mL) was stirred for 5 min. The reaction mixture turned yellow. To this reaction mixture was added a solution of methyl 4-[[2-(5-chloro-2-fluoro-phenyl)-5-isopropenyl-4-pyridyl]amino]pyridine-3-carboxylate (200 mg, 0.501 mmol) in DCM (5 mL). Then, the reaction mixture was heated in a closed reagent bottle at 55° C. for 1 h. The progress of reaction was monitored by TLC and LCMS. After completion of the reaction, the mixture was diluted with DCM (15 mL) and water (5 mL). The DCM layer was separated. The aqueous layer was again extracted with DCM (15 mL). The combined organic layer was dried over anhydrous sodium sulfate. Removal of DCM under reduced pressure afforded a crude product which was purified by reverse phase HPLC to afford (S)-4-(2-(5-chloro-2-fluorophenyl)-5-(prop-1-en-2-yl)pyridin-4-ylamino)-N-(1-hydroxypropan-2-yl)nicotinamide (66 mg) as a white solid.

(51) NMR: .sup.1H NMR (400 MHz, DMSO-d6) δ (ppm): 10.78 (s, 1H), 8.84 (s, 1H), 8.66 (d, J=7.9 Hz, 1H), 8.56 (s, 1H), 8.40 (d, J=6.2 Hz, 1H), 8.00 (dd, J=6.8, 2.8 Hz, 1H), 7.85 (s, 1H), 7.57 (dt, J=8.7, 3.6 Hz, 1H), 7.47-7.37 (m, 2H), 5.47 (s, 1H), 5.22 (s, 1H), 4.84-4.74 (m, 1H), 4.03 (m, 1H), 3.50-3.35 (m, 1H), 2.08 (s, 3H), 1.13 (d, J=6.7 Hz, 3H).

Example 7b. Preparation of Compound No. 7b

Synthesis of 4-[[2-(5-chloro-2-fluoro-phenyl)-5-isopropenyl-4-pyridyl]amino]-N-(2-hydroxy-1-methyl-ethyl)pyridine-3-carboxamide

(52) ##STR00207##

(53) Steps 1 to 4 are the same as in Example 2

Step 5: Synthesis of (2R)-4-[[2-(5-chloro-2-fluoro-phenyl)-5-isopropenyl-4-pyridyl]amino]-N-(2-hydroxy-1-methyl-ethyl)pyridine-3-carboxamide

(54) To methyl 4-[[2-(5-chloro-2-fluoro-phenyl)-5-isopropenyl-4-pyridyl]amino]pyridine-3-carboxylate (100 mg, 0.25 mmol) and (2R)-2-aminopropan-1-ol (37 mg, 0.5 mmol) in toluene (4 mL) was added Mc.sub.3Al (1.0 mL, 1.00 mmol). The reaction mixture was heated at 140° C. for 4 h. The progress of reaction was monitored by LCMS. After completion reaction, the mixture was quenched with a saturated aqueous solution of NaHCO.sub.3 (20 mL) and the product was extracted with EtOAc (2×70 mL). The combined organic layer was washed with brine (30 mL), dried over sodium sulfate and concentrated under reduced pressure to give a crude product. The crude product was purified by preparative HPLC to afford (2R)-4-[[2-(5-chloro-2-fluoro-phenyl)-5-isopropenyl-4-pyridyl]amino]-N-(2-hydroxy-1-methyl-ethyl)pyridine-3-carboxamide (13.25 mg).

(55) NMR: .sup.1H NMR (400 MHz, CDCl.sub.3) δ (ppm): 10.55 (s, 1H), 8.94 (s, 1H), 8.54 (s, 1H), 8.32 (d, J=6.4 Hz, 1H), 8.03 (dd, J=6.7, 2.7 Hz, 1H), 7.79 (d, J=1.7 Hz, 1H), 7.39-7.25 (m, 3H), 7.09 (dd, J=10.7, 8.7 Hz, 1H), 5.50 (d, J=2.2 Hz, 1H), 5.23 (s, 1H), 4.28 (m, 1H), 3.82 (dd, J=11.4, 3.5 Hz, 1H), 3.70 (dd, J=11.3, 5.6 Hz, 1H), 2.13 (s, 3H), 1.32 (d, J=6.7 Hz, 3H). LCMS: 441.2 (M+1).

Example 8. Preparation of Compound No. 8

Synthesis of 4-[[2-(5-chloro-2-fluoro-phenyl)-5-isopropenyl-4-pyridyl]amino]-N-(2-hydroxy-1,1-dimethyl-ethyl)pyridine-3-carboxamide

(56) ##STR00208##

(57) Steps 1 to 4 are the same as in Example 2

Step 5: Synthesis of 4-[[2-(5-chloro-2-fluoro-phenyl)-5-isopropenyl-4-pyridyl]amino]-N-(2-hydroxy-1,1-dimethyl-ethyl)pyridine-3-carboxamide

(58) To a solution of 2-amino-2-methyl-propan-1-ol (24 mg, 0.27 mmol) in DCM (3 mL) was added potassium tertiary butoxide (33 mg, 0.30 mmol). The reaction mixture was stirred at RT for 20 min. To the stirred reaction mixture was added a solution of methyl 4-[[2-(5-chloro-2-fluoro-phenyl)-5-isopropenyl-4-pyridyl]amino]pyridine-3-carboxylate (100 mg, 0.25 mmol) in DCM (5 mL) dropwise at RT. The reaction mixture was heated at 50° C. for 1 h. After completion of reaction, water (50 mL) was added and the mixture was diluted with DCM (50 mL). The organic layer was washed with brine (20 mL) and concentrated under reduced pressure to give a crude product which was purified by reverse phase HPLC to give of 4-[[2-(5-chloro-2-fluoro-phenyl)-5-isopropenyl-4-pyridyl]amino]-N-(2-hydroxy-1,1-dimethyl-ethyl)pyridine-3-carboxamide (17.96 mg) as a white solid.

(59) NMR: .sup.1H NMR (400 MHz, CD.sub.3OD) δ (ppm): 8.65 (s, 1H), 8.42 (s, 1H), 8.35 (d, J=5.9 Hz, 1H), 7.90 (dd, J=6.7, 2.7 Hz, 1H), 7.82 (s, 1H), 7.46 (m, 2H), 7.26 (m, 1H), 5.53 (s, 1H), 5.23 (s, 1H), 3.72 (s, 2H), 2.15 (s, 3H), 1.40 (s, 6H).

Example 9. Preparation of Compound No. 9

Synthesis of [4-[[2-(5-chloro-2-fluoro-phenyl)-5-isopropyl-4-pyridyl]amino]-3-pyridyl]-(4-hydroxy-1-piperidyl)methanone

(60) ##STR00209##

(61) Steps 1 to 8 are the same as in Comparative Example 1

Step 9: Synthesis of [4-[[2-(5-chloro-2-fluoro-phenyl)-5-isopropyl-4-pyridyl]amino]-3-pyridyl]-(4-hydroxy-1-piperidyl)methanone

(62) To a solution of 4-[[2-(5-chloro-2-fluoro-phenyl)-5-isopropyl-4-pyridyl]amino]pyridine-3-carboxylic acid (140 mg, 0.343 mmol) in DMF (4 mL) was added N,N-diisopropylethyl amine (0.23 mL, 1.37 mmol) and HATU (254 mg, 0.686 mmol). The reaction mixture was stirred at RT for 15 min under nitrogen atmosphere. To this stirred reaction mixture was added piperidin-4-ol (41 mg, 0.411 mmol) in DMF (1 mL) and the reaction mixture was stirred at RT overnight. The progress of reaction was monitored by TLC. After completion of the reaction, the mixture was diluted with water and extracted with EtOAc (50 mL). The organic layer was washed with water (2×10 mL) and brine solution (10 mL). The combined organic layer was dried over anhydrous sodium sulfate and evaporated under reduced pressure to obtain oily crude compound that was purified by reverse phase HPLC to afford [4-[[2-(5-chloro-2-fluoro-phenyl)-5-isopropyl-4-pyridyl]amino]-3-pyridyl]-(4-hydroxy-1-piperidyl)methanone (9 mg).

(63) NMR: .sup.1H NMR (400 MHz, CDCl.sub.3) δ (ppm): 8.76 (s, 1H), 8.60 (s, 1H), 8.40 (d, J=14.5 Hz, 2H), 8.02 (dd, J=6.8, 2.7 Hz, 1H), 7.76 (s, 1H), 7.39-7.27 (m, 2H), 7.09 (dd, J=10.7, 8.8 Hz, 1H), 4.10-4.01 (m, 3H), 3.51 (m, 2H), 3.13 (p, J=6.9 Hz, 1H), 1.99 (m, 2H), 1.7 (m, 2H), 1.38 (d, J=6.8 Hz, 6H).

Example 10. Preparation of Compound Nos. 10, 10a and 10b

Synthesis of (S)-4-(2-(5-chloro-2-fluorophenyl)-5-vinylpyridin-4-ylamino)-N-(2-hydroxypropyl)nicotinamide

(64) ##STR00210##

Step 1: Synthesis of (4,6-dichloro-3-pyridyl)methanol

(65) To a solution of methyl 4,6-dichloropyridine-3-carboxylate (1 g, 4.854 mmol) in anhydrous THF (25 mL) was added a 1 M solution of diisobutylaluminium hydride in toluene (14.5 mL, 14.5 mmol) dropwise under nitrogen atmosphere at −78° C. The reaction mixture was stirred for 2 h during which reaction mixture slowly warmed to 0° C. The progress of reaction was monitored by TLC. After completion of reaction, the mixture was quenched with saturated ammonium chloride solution (20 mL). EtOAc (100 mL) was added to the reaction mixture which was filtered. The filtrate was washed with water (30 mL) followed by brine wash (30 mL). The organic layer was separated, dried over anhydrous sodium sulfate and concentrated under reduced pressure to afford (4,6-dichloro-3-pyridyl)methanol (820 mg) as a white solid.

Step 2: Synthesis of 4,6-dichloropyridine-3-carbaldehyde

(66) A solution of oxalyl chloride (2.32 mL, 26.963 mmol) in DCM (30 mL) was cooled down to −78° C. To this solution was added DMSO (3.83 mL, 53.922 mmol) dropwise under nitrogen atmosphere. The reaction mixture was stirred at the same temperature for another 30 min. To this reaction mixture was added a solution of (4,6-dichloro-3-pyridyl)methanol (1.6 g, 8.987 mmol) in DCM (10 mL), and then the reaction mixture was stirred for 30 min. Then, to this stirred reaction mixture was added triethylamine (11.2 mL, 80.883 mmol). The reaction mixture was stirred at the same temperature for another 30 min. The progress of reaction was monitored by TLC. After completion of reaction, the mixture was quenched with saturated sodium bicarbonate solution (30 mL). The product was extracted using DCM (2×50 mL). The combined organic layer was again washed with water (3×30 mL) and finally with brine solution (30 mL). The organic layer was separated, dried over anhydrous sodium sulfate and concentrated under reduced pressure to afford 4,6-dichloropyridine-3-carbaldehyde (1.53 g) as a light yellow solid.

Step 3: Synthesis of 1-(4,6-dichloro-3-pyridyl)ethanol

(67) To a solution of 4,6-dichloropyridine-3-carbaldehyde (1.53 g, 8.693 mmol) in anhydrous THF (15 mL) was added a 3M solution of methylmagnesium bromide in diethyl ether (5.8 mL, 17.386 mmol) dropwise under nitrogen atmosphere at −78° C. The reaction mixture was stirred for 1 h during which the reaction mixture slowly warmed to 0° C. The progress of reaction was monitored by TLC. After completion of reaction, the mixture was quenched with saturated ammonium chloride solution (15 mL). The product was extracted using EtOAc (2×25 mL). The combined organic layer was again washed with water (20 mL) and finally with brine solution (20 mL). The organic layer was separated, dried over anhydrous sodium sulfate and concentrated under reduced pressure to afford 1-(4,6-dichloro-3-pyridyl)ethanol (1.56 g) as a light brown liquid.

Step 4: Synthesis of 1-[4-chloro-6-(5-chloro-2-fluoro-phenyl)-3-pyridyl]ethanol

(68) A mixture of 1-(4,6-dichloro-3-pyridyl)ethanol (1.56 g, 8.123 mmol), (5-chloro-2-fluoro-phenyl)boronic acid (2.12 g, 12.184 mmol) and sodium bicarbonate (1.36 g, 16.246 mmol) in a 2:1 mixture of DMF:H.sub.2O (21 mL) was purged with nitrogen gas for 40 min. To this reaction mixture was added bis(triphenylphosphine)palladium(II) dichloride (285 mg, 0.406 mmol) and then was purged with nitrogen gas for another 5 min. The reaction mixture was heated at 100° C. overnight. The progress of reaction was monitored by TLC and LCMS. After completion of reaction, water (20 mL) was added to the reaction mixture and product was extracted with EtOAc (2×25 mL). The combined organic layer was washed with water (3×25 mL) and finally with brine solution (25 mL). The organic layer was separated, dried over anhydrous sodium sulfate and concentrated under reduced pressure to afford crude product which was purified by column chromatography on silica gel (100-200 mesh) using 6% EtOAc:Hexane system as eluent to afford 1-[4-chloro-6-(5-chloro-2-fluoro-phenyl)-3-pyridyl]ethanol (1.2 g) as a light brown liquid.

Step 5: Synthesis of 4-chloro-2-(5-chloro-2-fluoro-phenyl)-5-vinyl-pyridine

(69) To a stirred solution of 1-[4-chloro-6-(5-chloro-2-fluoro-phenyl)-3-pyridyl]ethanol (1.2 g, 4.193 mmol) in o-Xylene (10 mL) was added p-toluenesulfonic acid monohydrate (80 mg, 0.419 mmol) and hydroquinone (46 mg, 0.419 mmol). The reaction mixture was heated at 160° C. in a Dean-Stark apparatus for 48 h. The progress of reaction was monitored by TLC. After completion of the reaction, the mixture was concentrated under reduced pressure to remove o-Xylene. To the residue was added water (50 mL) and product was extracted with EtOAc (2×50 mL). The combined organic layer was again washed with water (40 mL) and brine solution (40 mL). The organic layer was separated, dried over anhydrous sodium sulfate and concentrated under reduced pressure to afford crude product which was purified by CombiFlash® chromatography using 0.5% EtOAc-hexane system as eluent to afford 4-chloro-2-(5-chloro-2-fluoro-phenyl)-5-vinyl-pyridine (270 mg) as a light yellow solid.

Step 6: Synthesis of methyl 4-[[2-(5-chloro-2-fluoro-phenyl)-5-vinyl-4-pyridyl]amino]pyridine-3-carboxylate

(70) To a mixture of 4-chloro-2-(5-chloro-2-fluoro-phenyl)-5-vinyl-pyridine (270 mg, 1.007 mmol), methyl 4-aminopyridine-3-carboxylate (169 mg, 1.107 mmol) and potassium phosphate (tribasic) (428 mg, 2.014 mmol) in 1,4-dioxane (10 mL) was purged with nitrogen gas for 30 min. To this reaction mixture was added tris(dibenzylidineacetone)dipalladium(0) (92 mg, 0.100 mmol) and Xantphos (87 mg, 0.151 mmol) and then the reaction mixture was purged with nitrogen for another 5 min. Then, the reaction mixture was heated at 100° C. overnight. The progress of reaction was monitored by TLC and LCMS. After completion of reaction, reaction mixture was diluted with EtOAc (50 mL) and filtered through a celite bed. The filtrate was washed with water (20 mL) and finally with brine solution (20 mL). The organic layer was separated, dried over anhydrous sodium sulfate and concentrated under reduced pressure to afford crude product which was purified by CombiFlash® chromatography using 20% EtOAc-hexane system as eluent to afford methyl 4-[[2-(5-chloro-2-fluoro-phenyl)-5-vinyl-4-pyridyl]amino]pyridine-3-carboxylate (100 mg) as an off-white solid.

Step 7: Synthesis of (S)-4-(2-(5-chloro-2-fluorophenyl)-5-vinylpyridin-4-ylamino)-N-(2-hydroxypropyl) nicotinamide

(71) To a stirred solution of (S)-1-amino-propan-2-ol (14 mg, 0.187 mmol) in DCM (2 mL) was added potassium tert-butoxide (21 mg, 0.187 mmol) under nitrogen atmosphere at 0° C. The reaction mixture was stirred at RT for 15 min. Then, to this reaction mixture was added a solution of methyl 4-[[2-(5-chloro-2-fluoro-phenyl)-5-vinyl-4-pyridyl]amino]pyridine-3-carboxylate (60 mg, 0.156 mmol) in DCM (3 mL) dropwise. The reaction mixture was heated at 55° C. for 1 h. The progress of reaction was monitored by TLC. After completion of reaction, the mixture was diluted with DCM (15 mL). The organic layer washed with saturated solution of sodium bicarbonate solution (10 mL), water (10 mL) and finally with brine solution (10 mL). The organic layer was separated, dried over anhydrous sodium sulfate and concentrated under reduced pressure to obtain the crude product which was purified by reverse phase preparative HPLC to afford (S)-4-(2-(5-chloro-2-fluorophenyl)-5-vinylpyridin-4-ylamino)-N-(2-hydroxy propyl)nicotinamide (2 mg) as an off-white solid. The (R) enantiomer can be synthesized utilizing (R)-1-aminopropan-2-ol in this step.

(72) NMR: .sup.1H NMR (400 MHz, CD.sub.3OD) δ (ppm): 8.76 (d, J=6.6 Hz, 2H), 8.35 (s, 1H), 7.94 (dd, J=6.7, 2.8 Hz, 1H), 7.84 (s, 1H), 7.51-7.37 (m, 2H), 7.26 (dd, J=10.7, 8.8 Hz, 1H), 6.92 (dd, J=17.6, 11.2 Hz, 2H), 5.98 (d, J=17.5 Hz, 1H), 5.60 (d, J=11.3 Hz, 1H), 3.97 (p, J=6.5 Hz, 1H), 3.56 (dd, J=10.7, 5.5 Hz, 1H), 3.44 (dd, J=13.6, 4.6 Hz, 1H), 1.22 (d, J=6.4 Hz, 3H). LCMS: 427.0 (M+1).

Example 11. Preparation of Compound Nos. 11, 11a and 11b

Synthesis of (S)-4-(2-(5-chloro-2-fluorophenyl)-5-ethylpyridin-4-ylamino)-N-(2-hydroxy propyl)nicotinamide

(73) ##STR00211##

Step 1: Synthesis of (4,6-dichloro-3-pyridyl)methanol

(74) To a solution of methyl 4,6-dichloropyridine-3-carboxylate (1 g, 4.854 mmol) in anhydrous THF (25 mL) was added a 1 M solution of diisobutylaluminium hydride in toluene (14.5 mL, 14.5 mmol) dropwise under nitrogen atmosphere at −78° C. The reaction mixture was stirred for 2 h during which the reaction mixture slowly warmed to 0° C. The progress of reaction was monitored by TLC. After completion of reaction, the mixture was quenched with saturated ammonium chloride solution (20 mL). EtOAc (100 mL) was added to the reaction mixture and filtered. The filtrate was washed with water (30 mL) followed by brine wash (30 mL). The organic layer was separated, dried over anhydrous sodium sulfate and concentrated under reduced pressure to afford (4,6-dichloro-3-pyridyl)methanol (820 mg) as a white solid.

Step 2: Synthesis of 4,6-dichloropyridine-3-carbaldehyde

(75) A solution of oxalyl chloride (2.32 mL, 26.963 mmol) in DCM (30 mL) was cooled to −78° C. To this solution was added DMSO (3.83 mL, 53.922 mmol) dropwise under nitrogen atmosphere. The reaction mixture was stirred at the same temperature for another 30 min. To this reaction mixture was added a solution of (4,6-dichloro-3-pyridyl)methanol (1.6 g, 8.987 mmol) in DCM (10 mL) and then the reaction mixture was stirred for 30 min. Then, to this stirred reaction mixture was added triethylamine (11.2 mL, 80.883 mmol). The reaction mixture was stirred at the same temperature for another 30 min. The progress of reaction was monitored by TLC. After completion of reaction, the mixture was quenched with saturated sodium bicarbonate solution (30 mL). The product was extracted using DCM (2×50 mL). The combined organic layer was washed with water (3×30 mL) and finally with brine solution (30 mL). The organic layer was separated, dried over anhydrous sodium sulfate and concentrated under reduced pressure to afford 4,6-dichloropyridine-3-carbaldehyde (1.53 g) as a light yellow solid.

Step 3: Synthesis of 1-(4,6-dichloro-3-pyridyl)ethanol

(76) To a solution of 4,6-dichloropyridine-3-carbaldehyde (1.53 g, 8.693 mmol) in anhydrous THF (15 mL) was added a 3M solution of methylmagnesium bromide in diethyl ether (5.8 mL, 17.386 mmol) dropwise under nitrogen atmosphere at −78° C. The reaction mixture was stirred for 1 h during which the reaction mixture slowly warmed to 0° C. The progress of reaction was monitored by TLC. After completion of reaction, the mixture was quenched with saturated ammonium chloride solution (15 mL). The product was extracted using EtOAc (2×25 mL). The combined organic layer was washed with water (20 mL) and finally with brine solution (20 mL). The organic layer was separated, dried over anhydrous sodium sulfate and concentrated under reduced pressure to afford 1-(4,6-dichloro-3-pyridyl)ethanol (1.56 g) as a light brown liquid.

Step 4: Synthesis of 1-[4-chloro-6-(5-chloro-2-fluoro-phenyl)-3-pyridyl]ethanol

(77) To a mixture of 1-(4,6-dichloro-3-pyridyl)ethanol (1.56 g, 8.123 mmol), (5-chloro-2-fluoro-phenyl)boronic acid (2.12 g, 12.184 mmol) and sodium bicarbonate (1.36 g, 16.246 mmol) in 2:1 mixture of DMF:H.sub.2O (21 mL) was purged with nitrogen gas for 40 min. To this reaction mixture was added bis(triphenylphosphine)palladium(II) dichloride (285 mg, 0.406 mmol) and to the reaction mixture was purged with nitrogen gas for another 5 min. The reaction mixture was then heated at 100° C. overnight. The progress of reaction was monitored by TLC and LCMS. After completion of reaction, water (20 mL) was added to the reaction mixture and product was extracted with EtOAc (2×25 mL). The combined organic layer was washed with water (3×25 mL) and finally with brine solution (25 mL). The organic layer was separated, dried over anhydrous sodium sulfate and concentrated under reduced pressure to afford crude product which was purified by column chromatography on silica gel (100-200 mesh) using 6% EtOAc:Hexane system as eluent to afford 1-[4-chloro-6-(5-chloro-2-fluoro-phenyl)-3-pyridyl]ethanol (1.2 g) as a light brown liquid.

Step 5: Synthesis of 4-chloro-2-(5-chloro-2-fluoro-phenyl)-5-vinyl-pyridine

(78) To a stirred solution of 1-[4-chloro-6-(5-chloro-2-fluoro-phenyl)-3-pyridyl]ethanol (1.2 g, 4.193 mmol) in o-Xylene (10 mL) was added p-toluenesulfonic acid monohydrate (80 mg, 0.419 mmol) and hydroquinone (46 mg, 0.419 mmol). The reaction mixture was heated at 160° C. in a Dean-Stark apparatus for 48 h. The progress of reaction was monitored by TLC. After completion of reaction, the mixture was concentrated under reduced pressure to remove o-Xylene. To the residue was added water (50 mL) and product was extracted with EtOAc (2×50 mL). The combined organic layer was washed with water (40 mL) and brine solution (40 mL). The organic layer was separated, dried over anhydrous sodium sulfate and concentrated under reduced pressure to afford crude product which was purified by CombiFlash® chromatography using 0.5% EtOAc-hexane system as eluent to afford 4-chloro-2-(5-chloro-2-fluoro-phenyl)-5-vinyl-pyridine (270 mg) as a light yellow solid.

Step 6: Synthesis of methyl 4-[[2-(5-chloro-2-fluoro-phenyl)-5-vinyl-4-pyridyl]amino]pyridine-3-carboxylate

(79) To a mixture of 4-chloro-2-(5-chloro-2-fluoro-phenyl)-5-vinyl-pyridine (270 mg, 1.007 mmol), methyl 4-aminopyridine-3-carboxylate (169 mg, 1.107 mmol) and potassium phosphate (tribasic) (428 mg, 2.014 mmol) in 1,4-dioxane (10 mL) was purged with nitrogen gas for 30 min. To this reaction mixture was added tris(dibenzylidineacetone)dipalladium(0) (92 mg, 0.100 mmol) and Xantphos (87 mg, 0.151 mmol) and the reaction mixture was purged with nitrogen gas for another 5 min. The reaction mixture was then heated at 100° C. overnight. The progress of reaction was monitored by TLC and LCMS. After completion of reaction, the mixture was diluted with EtOAc (50 mL) and filtered through a celite bed. The filtrate was washed with water (20 mL) and finally with brine solution (20 mL). The organic layer was separated, dried over anhydrous sodium sulfate and concentrated under reduced pressure to afford crude product which was purified by CombiFlash® chromatography using 20% EtOAc-hexane system as eluent to afford methyl 4-[[2-(5-chloro-2-fluoro-phenyl)-5-vinyl-4-pyridyl]amino]pyridine-3-carboxylate (100 mg) as an off-white solid.

Step 7: Synthesis of methyl 4-[[2-(5-chloro-2-fluoro-phenyl)-5-ethyl-4-pyridyl]amino]pyridine-3-carboxylate

(80) To a stirred solution of 4-[[2-(5-chloro-2-fluoro-phenyl)-5-vinyl-4-pyridyl]amino]pyridine-3-carboxylate (70 mg, 0.182 mmol) in a 1:1 mixture of EtOAc:EtOH (6 mL) was added platinum dioxide (30 mg). The reaction mixture was agitated under hydrogen atmosphere using hydrogen bladder at RT overnight. The progress of reaction was monitored by .sup.1H NMR. After completion of reaction, reaction mixture was filtered through a celite bed and filtrate was concentrated under reduced pressure to afford methyl 4-[[2-(5-chloro-2-fluoro-phenyl)-5-ethyl-4-pyridyl]amino]pyridine-3-carboxylate (65 mg) as an off-white solid.

Step 8: Synthesis of (S)-4-(2-(5-chloro-2-fluorophenyl)-5-ethylpyridin-4-ylamino)-N-(2-hydroxypropyl)nicotinamide

(81) To a stirred solution of methyl 4-[[2-(5-chloro-2-fluoro-phenyl)-5-ethyl-4-pyridyl]amino]pyridine-3-carboxylate (65 mg, 0.168 mmol) and (S)-1-amino-propan-2-ol (19 mg, 0.252 mmol) in toluene (6 mL) was added a 1 M solution of trimethylaluminium in heptane (0.67 mL, 0.67 mmol) at RT. The reaction mixture was heated at reflux for 2 h. The progress of reaction was monitored by TLC. After completion of reaction, reaction mixture was diluted with EtOAc (20 mL) and washed with saturated solution of sodium bicarbonate (15 mL), water (10 mL) followed by brine wash (10 mL). The organic layer was separated, dried over anhydrous sodium sulfate and concentrated under reduced pressure to obtain the crude product which was purified by reverse phase preparative HPLC to afford (S)-4-(2-(5-chloro-2-fluorophenyl)-5-ethylpyridin-4-ylamino)-N-(2-hydroxy propyl)nicotinamide (12 mg) as an off-white solid. The (R) enantiomer can be synthesized utilizing (R)-1-aminopropan-2-ol in this step.

(82) NMR: .sup.1H NMR (400 MHz, CD.sub.3OD) δ (ppm): 8.76 (s, 1H), 8.46 (s, 1H), 8.37-8.25 (m, 1H), 7.84 (dd, J=6.7, 2.8 Hz, 1H), 7.76 (s, 1H), 7.52-7.35 (m, 2H), 7.23 (dd, J=10.7, 8.8 Hz, 1H), 4.00 (td, J=6.8, 4.7 Hz, 1H), 3.50-3.33 (m, 2H), 2.77 (q, J=7.5 Hz, 2H), 1.32 (t, J=7.5 Hz, 3H), 1.22 (d, J=6.3 Hz, 3H). LCMS: 429.3 (M+1).

Example 12. Preparation of Compound Nos. 12, 12a and 12b

Synthesis of (S)-4-(2-(5-chloro-2-fluorophenyl)-5-isopropylpyridin-4-ylamino)-N-(2-hydroxypropyl)pyrimidine-5-carboxamide

(83) ##STR00212##

(84) Steps 1 to 6 are the same as in Example 4.

Step 7: Synthesis of (S)-4-(2-(5-chloro-2-fluorophenyl)-5-isopropylpyridin-4-ylamino)-N-(2-hydroxypropyl)pyrimidine-5-carboxamide

(85) To a stirred solution of (S)-4-(2-(5-chloro-2-fluorophenyl)-5-(prop-1-en-2-yl)pyridin-4-ylamino)-N-(2-hydroxypropyl)pyrimidine-5-carboxamide (120 mg, 0.271 mmol) in EtOAc (4 mL) was added platinum oxide (20 mg). The reaction mixture was stirred under hydrogen atmosphere using hydrogen bladder at RT for 3 h. The progress of reaction was monitored by LCMS. After completion of the reaction, the mixture was diluted with EtOAc (20 mL) and filtered through a celite bed. The filtrate was concentrated under reduced pressure to obtain the crude product which was purified by reverse phase preparative HPLC to afford (S)-4-(2-(5-chloro-2-fluorophenyl)-5-isopropylpyridin-4-ylamino)-N-(2-hydroxypropyl)pyrimidine-5-carboxamide (36 mg) TFA salt as a white solid. The (R) enantiomer can be synthesized utilizing (R)-1-aminopropan-2-ol in this step.

(86) NMR: .sup.1H NMR (400 MHz, CD.sub.3OD) δ (ppm): 9.64 (s, 1H), 9.13 (s, 1H), 9.04 (s, 1H), 8.52 (s, 1H), 7.86 (dd, J=6.3, 2.7 Hz, 1H), 7.73 (ddd, J=8.9, 4.3, 2.6 Hz, 1H), 7.46 (t, J=9.5 Hz, 1H), 4.02 (td, J=6.8, 4.6 Hz, 1H), 3.47 (m, 3H), 1.59-1.48 (d, J=8.0 Hz, 6H), 1.24 (d, J=6.3 Hz, 3H). LCMS: 443.8 (M+1).

Example 13. Preparation of Compound Nos. 13, 13a and 13b

Synthesis of 4-[[2-(5-chloro-2-fluoro-phenyl)-5-methoxy-4-pyridyl]amino]-N-[(2S)-2-hydroxypropyl]pyridine-3-carboxamide

(87) ##STR00213##

Step 1: Synthesis of 2-chloro-5-(methoxymethoxy)pyridine

(88) To a solution of 6-chloropyridin-3-ol (2 g, 15.439 mmol) in DMF (10 mL) was added NaH (0.960 g, 23.200 mmol) under nitrogen atmosphere at 0° C. The reaction mixture was stirred at 0° C. for 30 min. Then, to this reaction mixture was added a solution of chloro(methoxy)methane (1.62 g, 20.121 mmol) in DMF (2 mL) dropwise. This reaction mixture was stirred at 0° C. for 30 min. The progress of reaction was monitored by TLC. After completion reaction, the mixture was quenched with ice-cold water (20 mL), extracted with EtOAc (2×50 mL). The combined organic layer was washed with water (2×75 mL) and brine (75 mL), dried over anhydrous sodium sulfate and concentrated under reduced pressure to afford 2-chloro-5-(methoxymethoxy)pyridine (2.8 g) as a brown liquid.

Step 2: Synthesis of 2-chloro-4-iodo-5-(methoxymethoxy)pyridine

(89) To a solution of 2-chloro-5-(methoxymethoxy)pyridine (2.1 g, 12.096 mmol) in THF (20 mL) was added a 1.6 M solution of n-BuLi in hexane (8.3 mL) under nitrogen atmosphere at −78° C. dropwise. The reaction mixture was stirred at −78° C. for 1 h. Then, to this reaction mixture was added a solution of iodine (3.6 g, 14.184 mmol) in THF (5 mL) dropwise. The reaction mixture was stirred at −78° C. for 15 min. The progress of reaction was monitored by TLC. After completion of the reaction, the mixture was quenched with a saturated aqueous solution of NH.sub.4Cl (50 mL) and saturated aqueous solution of Na.sub.2S.sub.2O.sub.3 (50 mL), and the product was extracted with EtOAc (2×150 mL). The combined organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure to afford 2-chloro-4-iodo-5-(methoxymethoxy)pyridine (4 g) as a yellow solid.

Step 3: Synthesis of 6-chloro-4-iodo-pyridin-3-ol

(90) A mixture of solution of 2-chloro-4-iodo-5-(methoxymethoxy)pyridine (4.4 g, 14.691 mmol) in THF (50 mL) and 3 N aqueous HCl (50 mL) was heated at 60° C. for 2 h. The progress of reaction was monitored by TLC. After completion of the reaction, the mixture was basified using saturated aqueous solution of NaHCO.sub.3 (200 mL) and extracted with EtOAc (3×200 mL). The combined organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure to afford 6-chloro-4-iodo-pyridin-3-ol (3.7 g) as a yellow solid.

Step 4: Synthesis of 2-chloro-4-iodo-5-methoxy-pyridine

(91) To a solution of 6-chloro-4-iodo-pyridin-3-ol (300 mg, 1.174 mmol) in DMF (5 mL) was added methyl iodide (0.1 mL, 1.606 mmol) and K.sub.2CO.sub.3 (325 mg, 2.351 mmol). The reaction mixture was stirred at RT for 2 h. The progress of reaction was monitored by TLC. After completion of the reaction, the mixture was diluted with water (20 mL) and extracted with EtOAc (2×50 mL). The combined organic layer was washed with water (2×75 mL) and brine (50 mL), dried over anhydrous sodium sulfate and concentrated under reduced pressure to afford 2-chloro-4-iodo-5-methoxy-pyridine (250 mg) as a white solid.

Step 5: Synthesis of 4-aminopyridine-3-carboxylic acid

(92) A solution of 4-chloropyridine-3-carboxylic acid (15 g, 0.095 mol) in aqueous NH.sub.3 (600 mL) was heated in a pressure vessel at 150° C. overnight. The progress of reaction was monitored by TLC. After completion of reaction, the mixture was concentrated under reduced pressure. To this reaction mixture was added toluene (2×100 mL) to obtain 4-aminopyridine-3-carboxylic acid (17 g) as a white solid.

Step 6: Synthesis of methyl 4-aminopyridine-3-carboxylate

(93) To a solution of 4-aminopyridine-3-carboxylic acid (17 g, 0.123 mol) in MeOH (300 mL) was added H.sub.2SO.sub.4 (45 mL) dropwise at 0° C. The reaction mixture was heated to reflux at 85° C. overnight. The progress of reaction was monitored by TLC. After completion of the reaction, the mixture was concentrated under reduced pressure to remove MeOH, residue was basified with a saturated aqueous solution of Na.sub.2CO.sub.3 (400 mL), extracted with EtOAc (3×500 mL). The combined organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure to afford methyl 4-aminopyridine-3-carboxylate (10.3 g) as a white solid.

Step 7: Synthesis of methyl 4-aminopyridine-3-carboxylate

(94) To a mixture of 2-chloro-4-iodo-5-methoxy-pyridine (5 g, 0.0185 mol), methyl 4-aminopyridine-3-carboxylate (2.26 g, 0.0148 mol) and K.sub.3PO.sub.4 (7.88 g, 0.0371 mol) in dioxane (200 mL) was purged with nitrogen for 20 min. To this reaction mixture was added Pd.sub.2(dba).sub.3 (1.7 g, 0.0018 mot) and Xantphos (2.15 G, 0.0037 mot) and the reaction mixture was purged with nitrogen gas for 5 min. The reaction mixture was heated at reflux overnight at 110° C. The progress of reaction was monitored by TLC. After completion of reaction, the mixture was diluted with water (250 mL) and extracted with EtOAc (3×400 mL). The combined organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure to afford crude product. The crude product was purified by column chromatography on silica gel (100-200 mesh) using 70% EtOAc-hexane system as eluent to obtain methyl 4-aminopyridine-3-carboxylate (400 mg) as a yellow solid.

Step 8: Synthesis of 2(5-chloro-2-fluoro-phenyl)boronic acid

(95) To a solution of 2-bromo-4-chloro-1-fluoro-benzene (25 g, 0.122 mol) in dry diethyl ether (250 mL) was added n-BuLi (2.5 M in hexane, 53 mL) was added dropwise at −70° C. under nitrogen atmosphere. The reaction mixture was stirred at the same temperature for 30 min, followed by slow addition of triisopropyl borate (30.3 mL, 0.134 mol). The reaction mixture turned to a white slurry, which was further stirred for 30 min at the same temperature. Then, the reaction mixture was warmed to RT sand stirred for 1 h. The progress of reaction was monitored by TLC. After completion of reaction, the mixture was cooled to 0° C., quenched with aqueous 6 N HCl (400 mL), stirred at RT for 1 h and extracted with EtOAc (2×500 mL). The combined organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure to obtain the crude product. The crude product was purified by washing with pentane to afford 2(5-chloro-2-fluoro-phenyl)boronic acid (19.5 g) as a white solid.

Step 9: Synthesis of methyl 4-[[2-(5-chloro-2-fluoro-phenyl)-5-methoxy-4-pyridyl]amino]pyridine-3-carboxylate

(96) A solution of methyl 4-[(2-chloro-5-methoxy-4-pyridyl)amino]pyridine-3-carboxylate (360 mg, 1.225 mmol), (5-chloro-2-fluoro-phenyl)boronic acid (853 mg, 4.902 mmol) and triethylamine (0.85 mL, 6.106 mmol) in toluene (25 mL) was purged with nitrogen for 20 min. To this reaction mixture was added tetrakis (142 mg, 0.122 mmol) and then again the reaction mixture was purged for 5 min with nitrogen. The reaction mixture was heated at 100° C. for 12 h. The progress of reaction was monitored by TLC. After completion of reaction, the mixture was diluted with water (50 mL) and extracted with EtOAc (2×100 mL). The combined organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure to afford a crude product. The crude product was purified by column chromatography on silica gel (230-400 mesh) using 40% acetone-hexane system as eluent to obtain methyl 4-[[2-(5-chloro-2-fluoro-phenyl)-5-methoxy-4-pyridyl]amino]pyridine-3-carboxylate (100 mg) as a brown solid.

Step 10: Synthesis of 4-[[2-(5-chloro-2-fluoro-phenyl)-5-methoxy-4-pyridyl]amino]-N-[(2S)-2-hydroxypropyl]pyridine-3-carboxamide

(97) A solution of (S)-1-aminopropan-2-ol (48 mg, 0.639 mmol) and potassium tert-butoxide (46 mg, 0.410 mmol) in DCM (3 mL) was stirred at RT for 30 min. To this stirred reaction mixture was added a solution of methyl 4-[[2-(5-chloro-2-fluoro-phenyl)-5-methoxy-4-pyridyl]amino]pyridine-3-carboxylate (100 mg, 0.258 mmol) in DCM (3 mL). The reaction mixture was heated at 50° C. for 2 h. The progress of reaction was monitored by TLC. After completion of reaction, reaction mixture was diluted with water (25 mL) and extracted with EtOAc (3×100 mL). The combined organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure to afford a crude product. The crude product was purified by reverse phase CombiFlash® using 50% MeOH in 0.05% aqueous TFA as eluent to obtain 4-[[2-(5-chloro-2-fluoro-phenyl)-5-methoxy-4-pyridyl]amino]-N-[(2S)-2-hydroxypropyl]pyridine-3-carboxamide (20 mg) TFA salt as a white solid. The (R) enantiomer can be synthesized utilizing (R)-1-aminopropan-2-ol in this step.

(98) NMR: .sup.1H NMR (400 MHz, CD.sub.3OD) δ (ppm): 8.90 (s, 1H), 8.58 (s, 1H), 8.41 (s, 1H), 8.03-7.86 (m, 2H), 7.55 (d, J=6.7 Hz, 1H), 7.47 (ddd, J=8.8, 4.2, 2.6 Hz, 1H), 7.27 (dd, J=10.7, 8.8 Hz, 1H), 4.12 (s, 3H), 4.00 (pd, J=6.4, 4.2 Hz, 1H), 3.48 (m, 2H), 3.40-3.33 (m, 1H), 1.24 (d, J=6.2 Hz, 3H).

Example 14. Preparation of Compound No. 14

Synthesis of N-(2-acetamidoethyl)-4-[[2-(5-chloro-2-fluoro-phenyl)-5-isopropyl-4-pyridyl]amino]pyridine-3-carboxamide

(99) ##STR00214##

(100) Steps 1 to 8 are the same as in Comparative Example 1

Step 9: Synthesis of N-(2-acetamidoethyl)-4-[[2-(5-chloro-2-fluoro-phenyl)-5-isopropyl-4-pyridyl]amino]pyridine-3-carboxamide

(101) To a solution of 4-[[2-(5-chloro-2-fluoro-phenyl)-5-isopropyl-4-pyridyl]amino]pyridine-3-carboxylic acid (200 mg, 0.518 mmol) in DMF (7 mL) was added N,N-diisopropylethyl amine (0.45 mL, 2.59 mmol) and HATU (317 mg, 0.829 mmol) and the reaction mixture was stirred at RT for 15 min under nitrogen atmosphere. To the reaction mixture was added a solution of N-(2-aminoethyl)acetamide (132 mg, 1.295 mmol) in DMF (3 mL) and the reaction mixture was stirred at RT overnight. The progress of reaction was monitored by TLC. After completion of the reaction, the mixture was diluted with water and extracted with EtOAc (50 mL). The organic layer was washed with water (2×10 mL) and brine solution (10 mL), dried over anhydrous sodium sulfate and concentrated under reduced pressure to obtain the crude product. The crude product was purified by reverse phase HPLC to afford N-(2-acetamidoethyl)-4-[[2-(5-chloro-2-fluoro-phenyl)-5-isopropyl-4-pyridyl]amino]pyridine-3-carboxamide (19 mg).

(102) NMR: .sup.1H NMR (400 MHz, CD.sub.3OD) δ (ppm): 8.72 (s, 1H), 8.59 (s, 1H), 8.32 (d, J=6.0 Hz, 1H), 7.89 (dd, J=6.7, 2.7 Hz, 1H), 7.80 (s, 1H), 7.45 (ddd, J=8.8, 4.3, 2.8 Hz, 1H), 7.37 (d, J=6.0 Hz, 1H), 7.25 (dd, J=10.7, 8.8 Hz, 1H), 3.52 (dd, J=6.7, 5.1 Hz, 2H), 3.42 (t, J=5.9 Hz, 2H), 3.30-3.18 (m, 1H), 1.94 (s, 3H), 1.41 (d, J=6.9 Hz, 6H).

Example 15. Preparation of Compound No. 15

Synthesis of N-(2-amino-2-oxo-ethyl)-4-[[2-(5-chloro-2-fluoro-phenyl)-5-isopropyl-4-pyridyl]amino]pyridine-3-carboxamide

(103) ##STR00215##

(104) Steps 1 to 8 are the same as in Comparative Example 1

Step 9: Synthesis of N-(2-amino-2-oxo-ethyl)-4-[[2-(5-chloro-2-fluoro-phenyl)-5-isopropyl-4-pyridyl]amino]pyridine-3-carboxamide

(105) To a solution of 4-[[2-(5-chloro-2-fluoro-phenyl)-5-isopropyl-4-pyridyl]amino]pyridine-3-carboxylic acid (200 mg, 0.518 mmol) in a 10:1 mixture of DCM:DMF (10 mL) was added N,N-diisopropylethyl amine (0.45 mL, 2.59 mmol) and HATU (317 mg, 0.829 mmol) and the reaction mixture was stirred at RT for 15 min under nitrogen atmosphere. To this stirred reaction mixture was added 2-aminoacetamide hydrochloride (143 mg, 1.295 mmol) the reaction mixture was again stirred at RT overnight. The progress of reaction was monitored by TLC. After completion of reaction, the mixture was diluted with water and extracted with EtOAc (50 mL). The organic layer was washed with water (2×10 mL) and brine solution (10 mL), dried over anhydrous sodium sulfate and concentrated under reduced pressure to obtain the crude product. The crude product was purified by reverse phase HPLC to afford N-(2-amino-2-oxo-ethyl)-4-[[2-(5-chloro-2-fluoro-phenyl)-5-isopropyl-4-pyridyl]amino]pyridine-3-carboxamide (115 mg) as a white solid.

(106) NMR: .sup.1H NMR (400 MHz, DMSO-d6) δ (ppm): 10.67 (s, 1H), 9.14 (t, J=5.9 Hz, 1H), 8.87 (s, 1H), 8.64 (s, 1H), 8.36 (d, J=5.9 Hz, 1H), 7.99 (dd, J=6.7, 2.8 Hz, 1H), 7.78 (d, J=1.4 Hz, 1H), 7.58-7.45 (m, 2H), 7.45-7.26 (m, 2H), 7.09 (s, 1H), 3.85 (d, J=5.9 Hz, 2H), 3.14 (m, 1H), 1.32 (d, J=6.8 Hz, 6H).

Example 16. Preparation of Compound Nos. 16, 16a and 16b

Synthesis of (S)-4-(2-(5-chloro-2-fluorophenyl)-5-(dimethylamino)pyridin-4-ylamino)-N-(2-hydroxypropyl)nicotinamide

(107) ##STR00216##

Step 1: Synthesis of 4,6-dichloropyridine-3-carboxylic acid

(108) To a stirred solution of methyl 4,6-dichloropyridine-3-carboxylate (3.5 g, 16.990 mmol) in THF (30 mL) was added a solution of lithium hydroxide monohydrate (3.56 g, 84.951 mmol) in water (15 mL). The reaction mixture was stirred at RT for 1.5 h. The progress of reaction was monitored by TLC. After completion of reaction, the pH of the aqueous layer was adjusted to 2 by the addition of 2 N HCl (aq.) and the product was extracted with EtOAc (2×50 mL). The organic layer was separated, dried over anhydrous sodium sulfate and concentrated under reduced pressure to afford 4,6-dichloropyridine-3-carboxylic acid (3.2 g) as a white solid.

Step 2: Synthesis of tert-butyl N-(4,6-dichloro-3-pyridyl)carbamate

(109) To a solution of 4,6-dichloropyridine-3-carboxylic acid (2.8 g, 14.58 mmol) in dry DMF (10 mL) was added triethylamine (2.24 mL, 16.04 mmol) at 0° C. followed by addition of diphenylphosphoryl azide (3.45 mL, 16.04 mmol). The reaction mixture was stirred at RT for 1 h and poured onto a mixture of ice-water-EtOAc. The product was extracted with EtOAc (2×50 mL). The combined extracts were washed with water (50 mL), saturated solution of sodium bicarbonate (50 mL) and finally with brine solution (50 mL). The organic layer was separated, dried over anhydrous sodium sulfate and concentrated under reduced pressure to afford light yellow solid which was dissolved in dry toluene (30 mL) and heated to reflux for 2 h. Then the reaction mixture was cooled to RT and t-butanol (8.36 mL, 87.48 mmol) was added. The reaction mixture was heated at 90° C. for 4 h. The reaction was monitored by TLC. After completion, the reaction mixture was concentrated under reduced pressure, water was added to the residue and product was extracted with EtOAc (2×100 mL). Removal of EtOAc under reduced pressure afforded an oily residue that was purified by column chromatography on silica gel (100-200 mesh) using 1% EtOAc-hexane system as eluent to afford tert-butyl N-(4,6-dichloro-3-pyridyl)carbamate (3.8 g) as a light yellow liquid.

Step 3: Synthesis of 4,6-dichloropyridin-3-amine

(110) To a stirred solution of tert-butyl N-(4,6-dichloro-3-pyridyl)carbamate (3.8 g, 14.44 mmol) in DCM (15 mL) was added trifluoroacetic acid (5 mL) dropwise at 0° C. The reaction mixture was slowly warmed to RT and stirred for 3 h. The progress of reaction was monitored by TLC. After completion of reaction, the mixture was concentrated under reduced pressure. To the residue was added saturated solution of sodium bicarbonate (30 mL) and product was extracted with EtOAc (100 mL). The organic layer was again washed with water (30 mL) and brine solution (30 mL). The organic layer was separated, dried over anhydrous sodium sulfate. Removal of EtOAc under reduced pressure afforded product which was again washed with n-pentane and dried to afford 4,6-dichloropyridin-3-amine (1.9 g) as a light brown solid.

Step 4: Synthesis of 4,6-dichloro-N-methyl-pyridin-3-amine

(111) To a stirred solution of 4,6-dichloropyridin-3-amine (1.42 g, 8.712 mmol) in dry DMF (8 mL) was added a 60% suspension of sodium hydride in mineral oil (767 mg, 19.166 mmol) under nitrogen atmosphere at 0° C. The reaction mixture was stirred at this temperature for 5-10 min. To this stirred reaction mixture was added a solution of methyl iodide (1.2 mL, 19.166 mmol) in dry DMF (2 mL) dropwise. Then, the reaction mixture was stirred at RT for 20 min. The progress of reaction was monitored by TLC. After completion of the reaction, the mixture was quenched by addition of ice-water and product was extracted with EtOAc (50 mL). The organic layer was again washed with water (2×20 mL) and brine solution (20 mL). The organic layer was separated, dried over anhydrous sodium sulfate and concentrated under reduced pressure to afford 4,6-dichloro-N-methyl-pyridin-3-amine (1.6 g) as a light brown solid.

Step 5: Synthesis of 4-chloro-6-(5-chloro-2-fluoro-phenyl)-N,N-dimethyl-pyridin-3-amine

(112) A mixture of 4,6-dichloro-N-methyl-pyridin-3-amine (1.6 g, 8.374 mmol), (5-chloro-2-fluoro-phenyl)boronic acid (2.19 g, 12.561 mmol) and sodium bicarbonate (1.4 g, 16.748 mmol) in a 2:1 mixture DMF:H.sub.2O (21 mL) was purged with nitrogen gas for 40 min. To this reaction mixture was added bis(triphenylphosphine)palladium(II) dichloride (294 mg, 0.418 mmol) and the reaction mixture was purged with nitrogen gas for another 5 min. Then, the reaction mixture was heated at 100° C. overnight. The progress of reaction was monitored by TLC and LCMS. After completion of reaction, water (20 mL) was added to the reaction mixture and product was extracted with EtOAc (2×25 mL). The combined organic layer was washed with water (3×25 mL) and finally with brine solution (25 mL). The organic layer was separated, dried over anhydrous sodium sulfate and concentrated under reduced pressure to afford 4-chloro-6-(5-chloro-2-fluoro-phenyl)-N,N-dimethyl-pyridin-3-amine (1.2 g) as an off-white solid.

Step 6: Synthesis of methyl 4-[[2-(5-chloro-2-fluoro-phenyl)-5-(dimethylamino)-4-pyridyl]amino]pyridine-3-carboxylate

(113) A mixture of 4-chloro-6-(5-chloro-2-fluoro-phenyl)-N,N-dimethyl-pyridin-3-amine (980 mg, 3.436 mmol), methyl 4-aminopyridine-3-carboxylate (272 mg, 1.787 mmol) and potassium phosphate (tribasic) (693 mg, 3.264 mmol) in 1,4-dioxane (20 mL) was purged with nitrogen gas for 30 min. To this reaction mixture was added tris(dibenzylidineacetone)dipalladium(0) (151 mg, 0.165 mmol) and Xantphos (139 mg, 0.240 mmol) and the reaction mixture was purged with nitrogen gas for another 5 min. The reaction mixture was then heated at 100° C. overnight. The progress of reaction was monitored by TLC and LCMS. After completion of the reaction, the mixture was diluted with EtOAc (50 mL) and filtered through a celite bed. The filtrate was washed with water (20 mL) and finally with brine solution (20 mL). The organic layer was separated, dried over anhydrous sodium sulfate and concentrated under reduced pressure to afford a crude product which was purified by CombiFlash® chromatography using 25% EtOAc-hexane system as eluent to afford methyl 4-[[2-(5-chloro-2-fluoro-phenyl)-5-(dimethylamino)-4-pyridyl]amino]pyridine-3-carboxylate (98 mg) as an off-white solid.

Step 7: Synthesis of (S)-4-(2-(5-chloro-2-fluorophenyl)-5-(dimethylamino)pyridin-4-ylamino)-N-(2-hydroxypropyl)nicotinamide

(114) To a stirred solution of methyl 4-[[2-(5-chloro-2-fluoro-phenyl)-5-(dimethylamino)-4-pyridyl]amino]pyridine-3-carboxylate (98 mg, 0.244 mmol) and (S)-1-amino-propan-2-ol (28 mg, 0.366 mmol) in toluene (6 mL) was added a 1 M solution of trimethylaluminium in heptane (0.98 mL, 0.98 mmol) at RT. The reaction mixture was heated at reflux for 4 h. The progress of reaction was monitored by TLC. After completion of the reaction, the mixture was diluted with EtOAc (30 mL) and washed with saturated solution of sodium bicarbonate (15 mL), water (15 mL) followed by brine wash (15 mL). The organic layer was separated, dried over anhydrous sodium sulfate and concentrated under reduced pressure to obtain the crude product which was purified by CombiFlash® chromatography using 6% MeOH-DCM system as eluent to afford (S)-4-(2-(5-chloro-2-fluorophenyl)-5-(dimethylamino)pyridin-4-ylamino)-N-(2-hydroxypropyl)nicotinamide (30 mg) as an off-white solid. The (R) enantiomer can be synthesized utilizing (R)-1-aminopropan-2-ol in this step.

(115) NMR: .sup.1H NMR (400 MHz, CDCl.sub.3) δ (ppm): 10.21 (s, 1H), 8.71 (s, 1H), 8.41 (d, J=9.0 Hz, 2H), 7.99 (dd, J=6.8, 2.8 Hz, 1H), 7.78 (d, J=1.9 Hz, 1H), 7.43 (d, J=5.9 Hz, 1H), 7.29 (ddd, J=8.5, 4.1, 2.6 Hz, 1H), 7.08 (dd, J=10.7, 8.7 Hz, 1H), 6.88 (bs, 1H), 4.14-4.02 (m, 1H), 3.72 (ddd, J=14.0, 6.7, 3.1 Hz, 1H), 3.30 (ddd, J=13.4, 8.0, 4.7 Hz, 1H), 2.85 (s, 6H), 1.29 (d, J=6.3 Hz, 3H). LCMS: 444.2 (M+1).

Example 17. Preparation of Compound Nos. 17, 17a and 17b

Synthesis of 4-[[2-(5-chloro-2-fluoro-phenyl)-5-(1-methoxy-1-methyl-ethyl)-4-pyridyl]amino]-N-(2-hydroxypropyl)pyridine-3-carboxamide

(116) ##STR00217##

Step 1: Synthesis of 2-(4,6-dichloro-3-pyridyl)propan-2-ol

(117) A solution of methyl 4,6-dichloropyridine-3-carboxylate (5 g, 0.0243 mol) in dry THF (60 mL) was cooled to −60° C. under nitrogen atmosphere. To this reaction mixture was added methylmagnesium bromide (3 M in THF, 28.3 mL). The reaction mixture was warmed to RT and stirred for 2 h. The progress of reaction was monitored by TLC. After completion of reaction, the mixture was cooled to 0° C. and quenched with saturated aqueous ammonium chloride solution (200 mL) and extracted with EtOAc (2×300 mL). The organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure to afford 2-(4,6-dichloro-3-pyridyl)propan-2-ol (4.91 g) as a yellow liquid.

Step 2: Synthesis of 2(5-chloro-2-fluoro-phenyl)boronic acid

(118) To a solution of 2-bromo-4-chloro-1-fluoro-benzene (25 G, 0.122 mol) in dry diethyl ether (250 mL) was added n-BuLi (2.5 M in hexane, 53 mL) dropwise at −70° C. under nitrogen atmosphere. The reaction mixture was stirred at the same temperature for 30 min, followed by slow addition of triisopropyl borate (30.3 mL, 0.134 mol). Formation of a white slurry was observed, which was stirred for 30 min at the same temperature. Then, the reaction mixture was warmed to RT and stirred for 1 h. The progress of reaction was monitored by TLC. After the completion of the reaction, the mixture was cooled to 0° C. and quenched with aqueous 6 N HCl (400 mL), stirred at RT for 1 h and then extracted with EtOAc (2×500 mL). The organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure to obtain the crude product. The crude product was purified by washing with pentane to afford 2(5-chloro-2-fluoro-phenyl)boronic acid (19.5 g) as a white solid.

Step 3: Synthesis of 2-[4-chloro-6-(5-chloro-2-fluoro-phenyl)-3-pyridyl]propan-2-ol

(119) A solution of methyl 2-(4,6-dichloro-3-pyridyl)propan-2-ol (800 mg, 3.882 mmol), (5-chloro-2-fluoro-phenyl)boronic acid (1.150 g, 6.595 mmol) in DMF (18 mL) was mixed with solution of NaHCO.sub.3 (625 mg, 7.761 mmol) in water (9 mL). The reaction mixture was purged with nitrogen for 15 min followed by addition of palladium dichloro diphenyl phosphine (136 mg, 0.193 mmol). The reaction mixture was again purged for 5 min and heated at 100° C. overnight. The progress of reaction was monitored by TLC. After completion of reaction, the mixture was diluted with water (60 mL) and extracted with EtOAc (3×125 mL). The organic layers were washed with water (2×300 mL) and brine (150 mL), dried over anhydrous sodium sulfate and concentrated under reduced pressure to afford a crude product. The crude product was purified by CombiFlash® using 10% EtOAc-hexane system as eluent to obtain 2-[4-chloro-6-(5-chloro-2-fluoro-phenyl)-3-pyridyl]propan-2-ol (750 mg) as a pale yellow sticky material.

Step 4: Synthesis of 4-chloro-2-(5-chloro-2-fluoro-phenyl)-5-(1-methoxy-1-methyl-ethyl)pyridine

(120) To a solution of 2-[4-chloro-6-(5-chloro-2-fluoro-phenyl)-3-pyridyl]propan-2-ol (110 mg, 0.366 mmol) in THF (5 mL) was added NaH (33 mg, 0.797 mmol) and Mel (0.03 mL, 0.481 mmol) at 0° C. under nitrogen atmosphere. The reaction mixture was warmed to RT and stirred overnight. The progress of reaction was monitored by TLC. After completion of reaction, the mixture was quenched with ice-cold water (10 mL) and extracted with EtOAc (2×15 mL). The organic layers were dried over anhydrous sodium sulfate and concentrated under reduced pressure to afford 4-chloro-2-(5-chloro-2-fluoro-phenyl)-5-(1-methoxy-1-methyl-ethyl)pyridine (100 mg) as a brown semisolid.

Step 5: Synthesis of 4-aminopyridine-3-carboxylic acid

(121) A solution of 4-chloropyridine-3-carboxylic acid (15 g, 0.095 mol) in aqueous NH.sub.3 (600 mL) was heated in a pressure vessel at 150° C. overnight. The progress of reaction was monitored by TLC. After completion of reaction, the mixture was concentrated under reduced pressure. To this reaction mixture was added toluene (2×100 mL) to obtain 4-aminopyridine-3-carboxylic acid (17 g) as a white solid.

Step 6: Synthesis of methyl 4-aminopyridine-3-carboxylate

(122) To a solution of 4-aminopyridine-3-carboxylic acid (17 g, 0.123 mol) in MeOH (300 mL) was added H.sub.2SO.sub.4 (45 mL) dropwise at 0° C. The reaction mixture was heated to reflux at 85° C. overnight. The progress of reaction was monitored by TLC. After completion of the reaction, the mixture was concentrated under reduced pressure. The residue was basified with saturated aqueous Na.sub.2CO.sub.3 solution (400 mL), and extracted with EtOAc (3×500 mL). The organic layers were dried over anhydrous sodium sulfate and concentrated under reduced pressure to afford methyl 4-aminopyridine-3-carboxylate (10.3 g) as a white solid.

Step 7: Synthesis of methyl 4-[[2-(5-chloro-2-fluoro-phenyl)-5-(1-methoxy-1-methyl-ethyl)-4-pyridyl]amino]pyridine-3-carboxylate

(123) A mixture of 4-chloro-2-(5-chloro-2-fluoro-phenyl)-5-(1-methoxy-1-methyl-ethyl)pyridine (200 mg, 0.636 mmol), methyl 4-aminopyridine-3-carboxylate (107 mg, 0.703 mmol) and K.sub.3PO.sub.4 (270 mg, 1.271 mmol) in dioxane (1.5 mL) was purged with nitrogen for 10 min, followed by addition of Pd.sub.2(dba).sub.3 (58 mg, 0.063 m mol) and Xantphos (74 mg, 0.127 mmol) and again purged for 2 min. The reaction mixture was heated in a microwave at 100° C. for 2 h. The progress of reaction was monitored by TLC and LCMS. After completion of reaction, the mixture was diluted with EtOAc (15 mL) and washed with water (2×10 mL). The organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure to afford a crude product. The crude product was purified by CombiFlash® using 25% EtOAc-hexane as eluent to obtain methyl 4-[[2-(5-chloro-2-fluoro-phenyl)-5-(1-methoxy-1-methyl-ethyl)-4-pyridyl]amino]pyridine-3-carboxylate (42 mg).

Step 8: Synthesis of 4-[[2-(5-chloro-2-fluoro-phenyl)-5-(1-methoxy-1-methyl-ethyl)-4-pyridyl]amino]pyridine-3-carboxylic acid

(124) To a stirred solution of potassium tert-butoxide (21 mg, 0.197 mmol) in DCM (2 mL) was added a solution of methyl 4-[[2-(5-chloro-2-fluoro-phenyl)-5-(1-methoxy-1-methyl-ethyl)-4-pyridyl]amino]pyridine-3-carboxylate (50 mg, 0.116 mmol) in DCM (2 mL). The reaction mixture was heated at 50° C. for 4 h. The progress of reaction was monitored by TLC and LCMS. After completion of the reaction, the mixture was diluted with DCM (20 mL) and washed with water (2×10 mL). The organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure to obtain 4-[[2-(5-chloro-2-fluoro-phenyl)-5-(1-methoxy-1-methyl-ethyl)-4-pyridyl]amino]pyridine-3-carboxylic acid (50 mg) as a yellow solid.

Step 9: Synthesis of 4-[[2-(5-chloro-2-fluoro-phenyl)-5-(1-methoxy-1-methyl-ethyl)-4-pyridyl]amino]-N-(2-hydroxypropyl)pyridine-3-carboxamide

(125) To a solution of 4-[[2-(5-chloro-2-fluoro-phenyl)-5-(1-methoxy-1-methyl-ethyl)-4-pyridyl]amino]pyridine-3-carboxylic acid (50 mg, 0.120 mmol) in DMF (2 mL) was added HATU (91 mg, 0.289 mmol) and DIPEA (0.13 mL, 0.746 mmol) at 0° C. under nitrogen atmosphere. The reaction mixture was stirred at 0° C. for 15 min followed by addition of (S)-1-aminopropan-2-ol (18 mg, 0.239 mmol) in DMF (1 mL). Then, the reaction mixture was warmed to RT and stirred overnight. The progress of reaction was monitored by TLC. After completion of the reaction, the mixture was diluted with EtOAc (25 mL) and washed with water (2×15 mL), saturated aqueous NaHCO.sub.3 solution (15 mL), saturated aqueous NH.sub.4Cl solution (15 mL) and brine (15 mL). The organic layers were dried over anhydrous sodium sulfate and concentrated under reduced pressure to obtain the crude product. The crude product was purified by reverse phase preparative HPLC to obtain 4-[[2-(5-chloro-2-fluoro-phenyl)-5-(1-methoxy-1-methyl-ethyl)-4-pyridyl]amino]-N-(2-hydroxypropyl)pyridine-3-carboxamide (19.8 mg) as a white solid. The (R) enantiomer can be synthesized utilizing (R)-1-aminopropan-2-ol in this step.

(126) NMR: .sup.1H NMR (400 MHz, CD.sub.3OD) δ (ppm): 8.70 (s, 1H), 8.52 (s, 1H), 8.36 (d, J=6.0 Hz, 1H), 7.89 (dd, J=6.7, 2.8 Hz, 1H), 7.83 (d, J=1.8 Hz, 1H), 7.53 (d, J=6.0 Hz, 1H), 7.46 (ddd, J=8.8, 4.3, 2.8 Hz, 1H), 7.25 (dd, J=10.7, 8.8 Hz, 1H), 3.98 (td, J=6.7, 4.8 Hz, 1H), 3.44 (m, 2H), 3.23 (s, 3H), 1.70 (s, 6H), 1.25 (d, J=6.2, 3H).

Example 18. Preparation of Compound No. 18

Synthesis of 4-[[2-(5-chloro-2-fluoro-phenyl)-5-isopropyl-4-pyridyl]amino]-N-[2-(methane sulfonamido)ethyl]pyridine-3-carboxamide

(127) ##STR00218##

(128) Steps 1 to 8 are the same as in Comparative Example 1

Step 9: Synthesis of 4-[[2-(5-chloro-2-fluoro-phenyl)-5-isopropyl-4-pyridyl]amino]-N-[2-(methanesulfonamido)ethyl]pyridine-3-carboxamide

(129) To a solution of 4-[[2-(5-chloro-2-fluoro-phenyl)-5-isopropyl-4-pyridyl]amino]pyridine-3-carboxylic acid (100 mg, 0.245 mmol) in DMF (4 mL) was added N,N-diisopropylethyl amine (0.17 mL, 0.98 mmol) and HATU (149 mg, 0.39 mmol) and stirred at RT for 15 min under nitrogen atmosphere. Then, to this reaction mixture was added N-(2-aminoethyl)methanesulfonamide hydrochloride (107 mg, 0.613 mmol) and the reaction mixture was stirred at RT overnight. The progress of reaction was monitored by TLC. After completion of reaction, the mixture was diluted with water and extracted with EtOAc (50 mL). The organic layer was washed with water (2×10 mL) and brine solution (10 mL), dried over anhydrous sodium sulfate and concentrated under reduced pressure to obtain the crude product. The crude product was purified by reverse phase HPLC to afford 4-[[2-(5-chloro-2-fluoro-phenyl)-5-isopropyl-4-pyridyl]amino]-N-[2-(methane sulfonamido)ethyl]pyridine-3-carboxamide (25 mg) as a white solid.

(130) NMR: .sup.1H NMR (400 MHz, CD.sub.3OD) δ (ppm): 8.76 (s, 1H), 8.57 (s, 1H), 8.31 (d, J=5.9 Hz, 1H), 7.88 (dd, J=6.7, 2.7 Hz, 1H), 7.78 (s, 1H), 7.45 (ddd, J=8.8, 4.2, 2.7 Hz, 1H), 7.36 (d, J=5.3 Hz, 1H), 7.25 (dd, J=10.7, 8.8 Hz, 1H), 3.55 (d, J=6.0 Hz, 2H), 3.37-3.17 (m, 3H), 2.96 (s, 3H), 1.40 (d, J=6.9 Hz, 6H).

Example 19. Preparation of Compound No. 19

Synthesis of N-(2-aminoethyl)-4-[[2-(5-chloro-2-fluoro-phenyl)-5-isopropyl-4-pyridyl]amino]pyridine-3-carboxamide

(131) ##STR00219##

(132) Steps 1 to 8 are the same as in Comparative Example 1

Step 9: Synthesis of tert-butyl N-[2-[[4-[[2-(5-chloro-2-fluoro-phenyl)-5-isopropyl-4-pyridyl]amino]pyridine-3-carbonyl]amino]ethyl]carbamate

(133) To a solution of 4-[[2-(5-chloro-2-fluoro-phenyl)-5-isopropyl-4-pyridyl]amino]pyridine-3-carboxylic acid (150 mg, 0.367 mmol) in DMF (4 mL) was add N,N-diisopropylethyl amine (0.26 mL, 1.47 mmol) and HATU (224 mg, 0.588 mmol) and stirred at RT for 15 min under nitrogen atmosphere. Then, to this reaction mixture was added tert-butyl N-(2-aminoethyl)carbamate hydrochloride (147 mg, 0.919 mmol) and the reaction mixture was stirred at RT overnight. The progress of reaction was monitored by TLC. After completion of reaction, the mixture was diluted with water and extracted with EtOAc (50 mL). The organic layer was washed with water (2×10 mL) and brine solution (10 mL), dried over anhydrous sodium sulfate and concentrated under reduced pressure to obtain the crude product. The crude product was purified by column chromatography on silica gel (100:200 mesh) using 80% EtOAc-hexane system as eluent to afford tert-butyl N-[2-[[4-[[2-(5-chloro-2-fluoro-phenyl)-5-isopropyl-4-pyridyl]amino]pyridine-3-carbonyl]amino]ethyl]carbamate (75 mg).

Step 10: Synthesis of N-(2-aminoethyl)-4-[[2-(5-chloro-2-fluoro-phenyl)-5-isopropyl-4-pyridyl]amino]pyridine-3-carboxamide

(134) To a stirred solution of tert-butyl N-[2-[[4-[[2-(5-chloro-2-fluoro-phenyl)-5-isopropyl-4-pyridyl]amino]pyridine-3-carbonyl]amino]ethyl]carbamate (75 mg, 0.142 mmol) in DCM (4 mL) was added TFA (1.5 mL) and stirred at RT for 1 h. The progress of reaction was monitored by TLC and NMR. After completion of reaction, the mixture was concentrated under reduced pressure to obtain the crude product. The crude product was triturated with diethyl ether and dried to obtain a crude residue, which was purified by reverse phase HPLC to afford N-(2-aminoethyl)-4-[[2-(5-chloro-2-fluoro-phenyl)-5-isopropyl-4-pyridyl]amino]pyridine-3-carboxamide (6 mg) as an off white solid.

(135) NMR: .sup.1H NMR (400 MHz, CD.sub.3OD) δ (ppm): 8.77 (s, 1H), 8.60 (s, 1H), 8.32 (d, J=6.0 Hz, 1H), 7.90 (dt, J=6.7, 3.3 Hz, 1H), 7.80 (d, J=1.9 Hz, 1H), 7.46 (ddd, J=8.8, 4.3, 2.6 Hz, 1H), 7.36 (d, J=6.1 Hz, 1H), 7.25 (t, J=9.75 Hz, 1H), 3.65 (t, J=6.0 Hz, 2H), 3.12 (t, J=6.0 Hz, 2H), 1.40 (d, J=6.9 Hz, 6H).

Example 20. Preparation of Compound Nos. 20, 20a and 20b

Synthesis of 3-[[2-(5-chloro-2-fluoro-phenyl)-5-isopropenyl-4-pyridyl]amino]-N-(2-hydroxypropyl)-1H-pyrazole-4-carboxamide

(136) ##STR00220##

(137) To a solution of 3-[[2-(5-chloro-2-fluoro-phenyl)-5-isopropenyl-4-pyridyl]amino]-1H-pyrazole-4-carboxylic acid (160 mg, 0.42 mmol) in DMF (4 mL) was added EDC.HCl (164 mg, 0.85 mmol), HOBT (115 mg, 0.85 mmol) and followed by the addition of DIPEA (0.37 mL, 2.14 mmol). The reaction mixture was stirred at RT for 15 min. Then, to this reaction mixture was added a solution of (S)-1-aminopropan-2-ol (96 mg 1.28 mmol) in DMF (1 mL) and the reaction mixture was stirred at RT overnight. The progress of reaction was monitored by LCMS. After completion of the reaction, the mixture was diluted with water (15 mL) and the product was extracted with EtOAc (2×100 mL). The organic layers were washed with water (2×40 mL), dried over sodium sulfate and concentrated under reduced pressure to get the crude product. The crude product was purified by preparative HPLC to afford (S)-3-[[2-(5-chloro-2-fluoro-phenyl)-5-isopropenyl-4-pyridyl]amino]-N-(2-hydroxypropyl)-1H-pyrazole-4-carboxamide (7.08 mg). The (R) enantiomer can be synthesized utilizing (R)-1-aminopropan-2-ol in this step.

(138) NMR: .sup.1H NMR (400 MHz, CD.sub.3OD) δ (ppm): 8.79 (s, 1H), 8.15 (d, J=15.8 Hz, 2H), 7.75 (dd, J=6.5, 2.7 Hz, 1H), 7.44 (m, 1H), 7.24 (dd, J=10.2, 8.8 Hz, 1H), 5.64 (s, 1H), 5.25 (s, 1H), 3.92 (m, 1H), 3.46-3.32 (m, 2H), 2.20 (s, 3H), 1.20 (d, J=6.2 Hz, 3H). LCMS: 430.6 (M+1).

Example 21. Preparation of Compound Nos. 21, 21a and 21b

Synthesis of 3-[[2-(5-chloro-2-fluoro-phenyl)-5-isopropyl-4-pyridyl]amino]-N-(2-hydroxy propyl)-1H-pyrazole-4-carboxamide

(139) ##STR00221##

(140) To (S)-3-[[2-(5-chloro-2-fluoro-phenyl)-5-isopropenyl-4-pyridyl]amino]-N-(2-hydroxy propyl)-1H-pyrazole-4-carboxamide (10 mg, 0.023 mmol) in MeOH (1.5 mL) was added PtO.sub.2 (2 mg) and conc. HCl (1 drop), and the reaction mixture was hydrogenated using a hydrogen bladder for 90 min. The progress of reaction was monitored by NMR. After completion the reaction, the mixture was filtered through a celite bed. The filtrate was washed with MeOH and concentrated under reduced pressure to get crude product. The crude product was purified by preparative HPLC giving 3-[[2-(5-chloro-2-fluoro-phenyl)-5-isopropyl-4-pyridyl]amino]-N-(2-hydroxypropyl)-1H-pyrazole-4-carboxamide (2.1 mg). The (R) enantiomer can be synthesized utilizing the (R)-enantiomeric starting material.

(141) NMR: .sup.1H NMR (400 MHz, CD.sub.3OD) δ (ppm): 8.75 (s, 1H), 8.30 (s, 1H), 8.16 (s, 1H), 7.73 (dd, J=6.5, 2.7 Hz, 1H), 7.43 (m, 1H), 7.23 (dd, J=10.2, 8.8 Hz, 1H), 3.95 (td, J=6.8, 4.8 Hz, 1H), 3.42 (dd, J=13.7, 4.6 Hz, 2H), 3.31-3.15 (m, 2H), 1.44 (d, J=6.8 Hz, 6H), 1.21 (d, J=6.3 Hz, 4H). LCMS: 432.5 (M+1).

Example 22. Preparation of Compound No. 22

Synthesis of 4-[[2-(5-chloro-2-fluoro-phenyl)-5-isopropyl-4-pyridyl]amino]-N-[2-hydroxy-1-(hydroxymethyl)ethyl]pyridine-3-carboxamide

(142) ##STR00222##

(143) Steps 1 to 8 are the same as in Comparative Example 1

Step 9: Synthesis of 4-[[2-(5-chloro-2-fluoro-phenyl)-5-isopropyl-4-pyridyl]amino]-N-[2-hydroxy-1-(hydroxymethyl)ethyl]pyridine-3-carboxamide

(144) To a solution of 4-[[2-(5-chloro-2-fluoro-phenyl)-5-isopropyl-4-pyridyl]amino]pyridine-3-carboxylic acid (100 mg, 0.245 mmol) in DMF (4 mL) was added N,N-diisopropylethyl amine (0.17 mL, 0.98 mmol) and PYBOP (254 mg, 0.829 mmol) and the reaction mixture was stirred at RT for 15 min under nitrogen atmosphere. Then, to this reaction mixture was added a solution of 2-aminopropane-1,3-diol (33 mg, 0.367 mmol) in DMF (1 mL) and the reaction mixture was stirred at RT overnight. The progress of reaction was monitored by TLC. After completion of reaction, the mixture was diluted with water and extracted with EtOAc (50 mL). The organic layer was washed with water (2×10 mL) and brine solution (10 mL). The combined organic layer was dried over anhydrous sodium sulfate and evaporated under reduced pressure to obtain oily crude compound which was purified by reverse phase HPLC to afford 4-[[2-(5-chloro-2-fluoro-phenyl)-5-isopropyl-4-pyridyl]amino]-N-[2-hydroxy-1-(hydroxymethyl)ethyl]pyridine-3-carboxamide (10 mg).

(145) NMR: .sup.1H NMR (400 MHz, CD.sub.3OD) δ (ppm): 8.80 (s, 1H), 8.58 (s, 1H), 8.32 (d, J=6.0 Hz, 1H), 7.89 (dd, J=6.6, 2.8 Hz, 1H), 7.80 (d, J=1.8 Hz, 1H), 7.50-7.34 (m, 2H), 7.25 (dd, J=10.7, 8.8 Hz, 1H), 4.24 (p, J=5.7 Hz, 1H), 3.82-3.68 (m, 4H), 3.30-3.18 (m, 1H), 1.40 (d, J=6.9 Hz, 6H).

Example 23. Preparation of Compound Nos. 23, 23a and 23b

Synthesis of 4-[[2-amino-6-(5-chloro-2-fluoro-phenyl)-3-isopropenyl-4-pyridyl]amino]-N-[(2S)-2-hydroxypropyl]pyridine-3-carboxamide

(146) ##STR00223##

Step 1: Synthesis of methyl 2-amino-4,6-dihydroxy-pyridine-3-carboxylate

(147) A mixture of dimethyl 1,3-acetonedicarboxylate (50 g, 0.287 mol), cyanamide (36.17 g, 0.861 mol) and nickel(II) acetylacetonate (7.376 g, 0.0287 mol) in 1,4-dioxane (300 mL) was heated to reflux for 16 h. Then, the reaction mixture was cooled to RT and stirred for 1 h. The reaction mixture was filtered and the resulting residue was filtered. The residue was mixed with MeOH (100 mL) and stirred for 1 h and filtered to afford methyl 2-amino-4,6-dihydroxy-pyridine-3-carboxylate (44 g) as a yellow solid.

Step 2: Synthesis of methyl 2-amino-4,6-dichloro-pyridine-3-carboxylate

(148) Phosphorous oxychloride (225 mL) was added to methyl 2-amino-4,6-dihydroxy-pyridine-3-carboxylate (44 g, 0.239 mol) at 0° C. under nitrogen atmosphere. To this reaction mixture was added N,N-diisopropylethyl amine (44 mL) at the same temperature and the reaction mixture was stirred at RT for 3 d. The progress of reaction monitored by TLC and LCMS. After completion of reaction, the reaction mixture was concentrated under reduced pressure to obtain a sticky compound which was cooled to 0° C. and MeOH (40 mL) and water (200 mL) were added. The reaction mixture was stirred at RT for 1 h. The resulting solid was filtered off and purified by column chromatography on silica (100:200 mesh) using 10% EtOAc-hexane system as eluent to afford methyl 2-amino-4,6-dichloro-pyridine-3-carboxylate (20 g).

Step 3: Synthesis of 2-(2-amino-4,6-dichloro-3-pyridyl)propan-2-ol

(149) To a solution of methyl 2-amino-4,6-dichloro-pyridine-3-carboxylate (300 mg, 1.357 mmol) in dry THF (7 mL) was added a 3M solution of methylmagnesium bromide in diethyl ether (1.58 mL, 4.75 mmol) dropwise under nitrogen at −60° C. The reaction mixture was stirred at −60° C. to 0° C. for 1 h. The progress of reaction was monitored by TLC & .sup.1H NMR. After completion of reaction, the mixture was quenched using aqueous saturated solution of ammonium chloride and extracted with EtOAc. The organic layer was washed with water and brine, dried over anhydrous sodium sulfate and concentrated under reduced pressure to obtain the crude product. The crude product was purified by column chromatography on silica (100:200 mesh) using 10% EtOAc-hexane system as eluent to afford 2-(2-amino-4,6-dichloro-3-pyridyl)propan-2-ol (263 mg).

Step 4: Synthesis of 2-[2-amino-4-chloro-6-(5-chloro-2-fluoro-phenyl)-3-pyridyl]propan-2-ol

(150) A suspension of 2-(2-amino-4,6-dichloro-3-pyridyl)propan-2-ol (3.5 g, 0.0158 mole); (5-chloro-2-fluoro-phenyl) boronic acid (4.409 g, 0.0253 mol) and cesium carbonate (10.32 g, 0.0316 mol) in 2:1 mixture of DMF:H.sub.2O (50 mL). This mixture was purged with nitrogen for 45 min. Then, to this reaction mixture was added Pd(PPh.sub.3).sub.4 (1.829 g, 0.00158 mol) and purging continued with nitrogen for further 10 min. The resulting reaction mixture was heated at 95° C. overnight. After completion of reaction, the reaction mixture was diluted with water, extracted with EtOAc. The organic layer was washed with water and brine solution, dried over anhydrous sodium sulfate and concentrated under reduced pressure to obtain the crude product. The crude product was purified by column chromatography on silica (100:200 mesh) using 8% EtOAc-hexane system as eluent to afford 2-[2-amino-4-chloro-6-(5-chloro-2-fluoro-phenyl)-3-pyridyl]propan-2-ol (1.38 g) pure compound as a sticky yellow solid.

Step 5: Synthesis of 4-chloro-6-(5-chloro-2-fluoro-phenyl)-3-isopropenyl-pyridin-2-amine

(151) 2-[2-amino-4-chloro-6-(5-chloro-2-fluoro-phenyl)-3-pyridyl]propan-2-ol (1.04 g, 0.0033 mol) in polyphosphoric acid (10 g) was heated at 120° C. for 2 h. The progress of reaction was monitored by TLC and LCMS. After completion of reaction, the mixture was cooled to 0° C., diluted with water, basified with a saturated aqueous solution of sodium hydroxide (pH 10-12) and extracted with EtOAc. The organic layer was washed with water and brine solution, dried over anhydrous sodium sulfate and concentrated under reduced pressure to afford 4-chloro-6-(5-chloro-2-fluoro-phenyl)-3-isopropenyl-pyridin-2-amine (850 mg) as a pure compound.

Step 6: Synthesis of tert-butyl N-[4-chloro-6-(5-chloro-2-fluoro-phenyl)-3-isopropenyl-2-pyridyl]carbamate

(152) To a solution of 4-chloro-6-(5-chloro-2-fluoro-phenyl)-3-isopropenyl-pyridin-2-amine (3.25 g, 0.019 mol) in DCM (30 mL) was added TEA (3 mL) followed by DMAP (0.267 g, 0.00218 mol) under nitrogen atmosphere and stirred at RT for 15 min. To this reaction mixture was added (BOC).sub.2O (3.104 g, 0.01425 mol) and stirred overnight at RT. The progress of reaction was monitored by TLC and LCMS. After completion of reaction, the mixture was diluted with DCM and washed with water and brine solution. The organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure to obtain the crude which was purified by column chromatography on silica gel (100:200 mesh) using 1% EtOAc-hexane system as eluent to afford tert-butyl N-[4-chloro-6-(5-chloro-2-fluoro-phenyl)-3-isopropenyl-2-pyridyl]carbamate (3.2 g).

Step 7: Synthesis of methyl 4-[[2-(tert-butoxycarbonylamino)-6-(5-chloro-2-fluoro-phenyl)-3-isopropenyl-4-pyridyl]amino]pyridine-3-carboxylate

(153) A suspension of tert-butyl N-[4-chloro-6-(5-chloro-2-fluoro-phenyl)-3-isopropenyl-2-pyridyl]carbamate (3.2 g, 0.0062 mol), methyl 4-aminopyridine-3-carboxylate (1.137 g, 0.0074 mol) and potassium phosphate tribasic (2.64 g, 0.01247 mol) in dioxane (40 mL) was purged with nitrogen for 45 min. To this reaction mixture was added Xantphos (0.721 g, 0.001247 mot) and Pd.sub.2(dba).sub.3 (0.856 g, 0.00093 mol) and purging continued with nitrogen for 10 min. The resulting mixture was heated at 100° C. for 18 h. The progress of reaction was monitored by TLC and LCMS. After completion of reaction, the mixture was filtered through a celite bed. The filtrate was concentrated under reduced pressure to obtain oily crude compound that was purified by column chromatography on silica gel (100:200 mesh) using 25-30% EtOAc-hexane system as eluent to afford methyl 4-[[2-(tert-butoxycarbonylamino)-6-(5-chloro-2-fluoro-phenyl)-3-isopropenyl-4-pyridyl]amino]pyridine-3-carboxylate (0.84 g) pure compound as a yellow solid.

Step 8: Synthesis of 4-[[2-(tert-butoxycarbonylamino)-6-(5-chloro-2-fluoro-phenyl)-3-isopropenyl-4-pyridyl]amino]pyridine-3-carboxylic acid

(154) To a suspension of methyl 4-[[2-(tert-butoxycarbonylamino)-6-(5-chloro-2-fluoro-phenyl)-3-isopropenyl-4-pyridyl]amino]pyridine-3-carboxylate (500 mg, 0.814 mmol) in MeOH (10 mL) was added NaOH (52 mg, 1.3 mmol) in water (1 mL) and heated at 80° C. for 2 h. The progress of reaction was monitored by TLC. After completion of reaction, the mixture was concentrated under reduced pressure to obtain a sticky compound. To this was added toluene (3×10 mL) to obtain a solid compound which was triturated with diethyl ether (10 mL) to afford 4-[[2-(tert-butoxycarbonylamino)-6-(5-chloro-2-fluoro-phenyl)-3-isopropenyl-4-pyridyl]amino]pyridine-3-carboxylic acid (500 mg) as a light yellow solid.

Step 9: Synthesis of afforded 4-[[2-amino-6-(5-chloro-2-fluoro-phenyl)-3-isopropenyl-4-pyridyl]amino]pyridine-3-carboxylic acid

(155) To a suspension of 4-[[2-(tert-butoxycarbonylamino)-6-(5-chloro-2-fluoro-phenyl)-3-isopropenyl-4-pyridyl]amino]pyridine-3-carboxylic acid (100 mg, 0.16 mmol) in 10:1 mixture of DCM:DMF (10 mL) was added TFA (1 mL) and stirred for 2 h. The progress of reaction was monitored by TLC and LCMS. After completion of reaction, the mixture was concentrated under reduced pressure to obtain the crude product. The crude product was triturated with diethylether and dried in vacuo to afford 4-[[2-amino-6-(5-chloro-2-fluoro-phenyl)-3-isopropenyl-4-pyridyl]amino]pyridine-3-carboxylic acid (80 mg).

Step 10: Synthesis of 4-[[2-amino-6-(5-chloro-2-fluoro-phenyl)-3-isopropenyl-4-pyridyl]amino]-N-[(2S)-2-hydroxypropyl]pyridine-3-carboxamide

(156) To a stirred solution of 4-[[2-amino-6-(5-chloro-2-fluoro-phenyl)-3-isopropenyl-4-pyridyl]amino]pyridine-3-carboxylic acid (80 mg, 0.127 mmol) in DMF (4 mL) added N,N-diisopropylethyl amine (0.09 mL, 0.51 mmol) and HATU (78 mg, 0.204 mmol) and stirred for 15 min at RT under nitrogen atmosphere. To this reaction mixture was added (S)-1-aminopropan-2-ol (24 mg, 0.318 mmol) and the reaction mixture was stirred at RT for 4 h. The progress of reaction was monitored by TLC and LCMS. After completion of reaction, the mixture was diluted with water and extracted with EtOAc. The organic layer was washed with brine and water, dried over anhydrous sodium sulfate and concentrated under reduced pressure to obtain the crude product. The crude product was purified by reverse phase HPLC to afford 4-[[2-amino-6-(5-chloro-2-fluoro-phenyl)-3-isopropenyl-4-pyridyl]amino]-N-[(2S)-2-hydroxypropyl]pyridine-3-carboxamide (6.5 mg) as a white solid. The (R) enantiomer can be synthesized utilizing (R)-1-aminopropan-2-ol in this step.

(157) NMR: .sup.1H NMR (400 MHz, CDCl.sub.3) δ (ppm): 10.12 (s, 1H), 8.73 (s, 1H), 8.34 (s, 1H), 7.97 (dd, J=6.7, 2.8 Hz, 1H), 7.36 (s, 1H), 7.33-7.22 (m, 2H), 7.06 (dd, J=10.6, 8.7 Hz, 1H), 6.96 (s, 1H), 5.64 (d, J=2.2 Hz, 1H), 5.22 (s, 1H), 4.69 (s, 2H), 4.06 (m, 1H), 3.67 (d, J=13.8 Hz, 1H), 3.34-3.24 (m, 1H), 2.05 (s, 3H), 1.27 (t, J=6.2 Hz, 3H).

Example 24. Preparation of Compound Nos. 24, 24a and 24b

Synthesis of 4-[[2-(5-chloro-2-fluoro-phenyl)-5-isopropenyl-4-pyridyl]amino]-N-[(1S)-1-(hydroxymethyl)propyl]pyridine-3-carboxamide

(158) ##STR00224##

(159) To a solution of methyl 4-[[2-(5-chloro-2-fluoro-phenyl)-5-isopropenyl-4-pyridyl]amino]pyridine-3-carboxylate (100 mg, 0.25 mmol) and (2S)-2-aminobutan-1-ol (45 mg, 0.5 mmol) in toluene (5 mL) was added a 1 M solution of trimethylaluminium) in heptane (1 mL, 1.005 mmol) and heated at 120° C. for 4 h. The progress of reaction was monitored by TLC and LCMS. After completion of reaction, the mixture was cooled to RT and diluted with water and EtOAc. The organic layer was washed with water and brine solution, dried over anhydrous sodium sulfate and concentrated under reduced pressure to obtain the crude product. The crude product was purified by CombiFlash® chromatography to afford a residue which was triturated with n-pentane and dried under vacuum to afford 4-[[2-(5-chloro-2-fluoro-phenyl)-5-isopropenyl-4-pyridyl]amino]-N-[(1S)-1-(hydroxymethyl)propyl]pyridine-3-carboxamide (43 mg). The (R) enantiomer can be synthesized utilizing (2R)-2-aminobutan-1-ol in this step.

(160) NMR: .sup.1H NMR (400 MHz, DMSO-d6) δ (ppm): 10.42 (s, 1H), 8.81 (s, 1H), 8.46 (d, J=9.3 Hz, 2H), 8.39 (d, J=5.8 Hz, 1H), 7.99 (dd, J=6.7, 2.8 Hz, 1H), 7.84 (s, 1H), 7.60-7.49 (m, 1H), 7.41 (dd, J=11.9, 7.4 Hz, 2H), 5.48 (s, 1H), 5.20 (s, 1H), 4.70 (t, J=5.8 Hz, 1H), 3.88 (td, J=8.6, 4.5 Hz, 1H), 3.43 (m, 2H), 2.09 (s, 3H), 1.65 (m, 1H), 1.53-1.37 (m, 1H), 0.88 (t, J=7.5 Hz, 3H).

Example 25a. Preparation of Compound No. 25a

Synthesis of 4-[[2-(5-chloro-2-fluoro-phenyl)-5-vinyl-4-pyridyl]amino]-N-[(1R)-1-(hydroxy methyl)-2-methyl-propyl]pyridine-3-carboxamide

(161) ##STR00225##

(162) To a solution of methyl 4-[[2-(5-chloro-2-fluoro-phenyl)-5-isopropenyl-4-pyridyl]amino]pyridine-3-carboxylate (100 mg, 0.25 mmol) and ((2R)-2-amino-3-methyl-butan-1-ol (52 mg, 0.502 mmol) in toluene (5 mL) was added a 1 M solution of trimethylaluminium in heptane (1 mL, 1.005 mmol) and heated at 120° C. for 4 h. The progress of reaction was monitored by TLC and LCMS. After completion of reaction, the mixture was cooled to RT and diluted with water and EtOAc. The organic layer was washed with water and brine solution, dried over anhydrous sodium sulfate and concentrated under reduced pressure to obtain the crude product. The crude product was purified by reverse phase HPLC to afford 4-[[2-(5-chloro-2-fluoro-phenyl)-5-vinyl-4-pyridyl]amino]-N-[(1R)-1-(hydroxymethyl)-2-methyl-propyl]pyridine-3-carboxamide (13.8 mg).

(163) NMR: .sup.1H NMR (400 MHz, CDCl.sub.3) δ (ppm): 10.13 (s, 1H), 8.68 (s, 1H), 8.50 (s, 1H), 8.39 (d, J=5.9 Hz, 1H), 8.02 (dd, J=6.8, 2.7 Hz, 1H), 7.84-7.78 (m, 1H), 7.41-7.21 (m, 2H), 7.10 (dd, J=10.7, 8.7 Hz, 1H), 6.57 (d, J=8.8 Hz, 1H), 5.47 (s, 1H), 5.21 (s, 1H), 3.96 (m, 1H), 3.82 (d, J=4.3 Hz, 2H), 2.15-1.97 (m, 4H), 1.04 (t, J=6.9 Hz, 6H).

Example 25b. Preparation of Compound No. 25b

Synthesis of 4-[[2-(5-chloro-2-fluoro-phenyl)-5-vinyl-4-pyridyl]amino]-N-[(1S)-1-(hydroxy methyl)-2-methyl-propyl]pyridine-3-carboxamide

(164) ##STR00226##

(165) To a solution of methyl 4-[[2-(5-chloro-2-fluoro-phenyl)-5-isopropenyl-4-pyridyl]amino]pyridine-3-carboxylate (100 mg, 0.25 mmol) and ((2R)-2-amino-3-methyl-butan-1-ol (52 mg, 0.502 mmol) in toluene (5 mL) was added a 1 M solution of trimethylaluminium in heptane (1 mL, 1.005 mmol) and heated at 120° C. for 4 h. The progress of reaction was monitored by TLC and LCMS. After completion of reaction, the mixture was cooled to RT and diluted with water and EtOAc. The organic layer was separated, washed with water and brine solution, dried over anhydrous sodium sulfate and concentrated under reduced pressure to obtain the crude product. The crude product was purified by reverse phase HPLC to afford 4-[[2-(5-chloro-2-fluoro-phenyl)-5-vinyl-4-pyridyl]amino]-N-[(1S)-1-(hydroxymethyl)-2-methyl-propyl]pyridine-3-carboxamide (14.58 mg).

(166) NMR: .sup.1H NMR (400 MHz, CDCl.sub.3) δ (ppm): 10.13 (s, 1H), 8.68 (s, 1H), 8.50 (s, 1H), 8.40 (d, J=5.9 Hz, 1H), 8.02 (dd, J=6.8, 2.7 Hz, 1H), 7.81 (d, J=1.7 Hz, 1H), 7.41-7.27 (m, 2H), 7.10 (dd, J=10.7, 8.7 Hz, 1H), 6.57 (d, J=8.7 Hz, 1H), 5.47 (s, 1H), 5.21 (s, 1H), 3.97 (m, 1H), 3.82 (d, J=4.3 Hz, 2H), 2.15-1.97 (m, 4H), 1.04 (t, J=6.9 Hz, 6H).

Example 26. Preparation of Compound No. 26

Synthesis of 4-[[2-(5-chloro-2-fluoro-phenyl)-5-isopropenyl-4-pyridyl]amino]-N-(2-hydroxy ethyl)pyridine-3-carboxamide

(167) ##STR00227##

(168) Steps 1 to 4 are the same as in Example 2

Step 5: Synthesis of 4-[[2-(5-chloro-2-fluoro-phenyl)-5-isopropenyl-4-pyridyl]amino]-N-(2-hydroxyethyl)pyridine-3-carboxamide

(169) To 2-aminoethanol (30 mg, 0.5 mmol) in toluene (4 mL) was added sodium methoxide (13 mg, 0.25 mmol). The reaction mixture was stirred at RT for 5 min. Then, to this reaction mixture was added methyl 4-[[2-(5-chloro-2-fluoro-phenyl)-5-isopropenyl-4-pyridyl]amino]pyridine-3-carboxylate (100 mg, 0.25 mmol) and the reaction mixture was heated at 50° C. for 5 h. The progress of reaction was monitored by LCMS. After completion of the reaction, the mixture was quenched with ice-cold water (15 mL) and the product was extracted with EtOAc (2×250 mL). The combined organic layer was washed with brine (50 mL), dried over sodium sulfate and concentrated under reduced pressure to give a crude product. The crude product was purified by preparative HPLC to afford 4-[[2-(5-chloro-2-fluoro-phenyl)-5-isopropenyl-4-pyridyl]amino]-N-(2-hydroxy ethyl)pyridine-3-carboxamide (29.28 mg) as the TFA salt.

(170) NMR: .sup.1H NMR (400 MHz, CD.sub.3OD) δ (ppm): 8.88 (s, 1H), 8.68 (s, 1H), 8.36 (d, J=7.2 Hz, 1H), 8.02-7.91 (m, 2H), 7.56-7.44 (m, 2H), 7.29 (dd, J=10.7, 8.8 Hz, 1H), 5.53-5.45 (m, 1H), 5.29 (s, 1H), 3.75 (t, J=5.6 Hz, 2H), 3.55 (t, J=5.5 Hz, 2H), 2.13 (s, 3H) LCMS: 425.4 (m−1).

Example 27. Preparation of Compound No. 27

Synthesis of 4-[[2-(5-chloro-2-fluoro-phenyl)-5-isopropenyl-4-pyridyl]amino]-N-cyclopropyl-pyridine-3-carboxamide

(171) ##STR00228##

(172) Steps 1 to 4 are the same as in Example 2

Step 5: Synthesis of 4-[[2-(5-chloro-2-fluoro-phenyl)-5-isopropenyl-4-pyridyl]amino]-N-cyclopropyl-pyridine-3-carboxamide

(173) To methyl 4-[[2-(5-chloro-2-fluoro-phenyl)-5-isopropenyl-4-pyridyl]amino]pyridine-3-carboxylate (100 mg, 0.25 mmol) and cyclopropanamine (28 mg, 0.5 mmol) in toluene (4 mL) was added Mc.sub.3Al (1.0 mL, 1.00 mmol) and the reaction was heated at 140° C. for 4 h. The progress of reaction was monitored by LCMS. After completion of reaction, the mixture was quenched with a saturated aqueous solution of NaHCO.sub.3 (20 mL) and the product was extracted with EtOAc (2×70 mL). The combined organic layer was washed with brine (30 mL), dried over sodium sulfate and concentrated under reduced pressure to give a crude product. The crude compound was purified by preparative HPLC to afford 4-[[2-(5-chloro-2-fluoro-phenyl)-5-isopropenyl-4-pyridyl]amino]-N-cyclopropyl-pyridine-3-carboxamide (34.85 mg).

(174) NMR: .sup.1H NMR (400 MHz, CD.sub.3OD) δ (ppm): 8.79 (s, 1H), 8.68 (s, 1H), 8.34 (d, J=7.2 Hz, 1H), 7.99 (dd, J=6.7, 2.8 Hz, 1H), 7.92 (s, 1H), 7.56-7.36 (m, 2H), 7.29 (dd, J=10.8, 8.8 Hz, 1H), 5.54-5.48 (m, 1H), 5.29 (s, 1H), 2.92 (tt, J=7.4, 3.9 Hz, 1H), 2.14 (s, 3H), 0.86 (m, 2H), 0.80-0.65 (m, 2H). LCMS: 423.4 (M+1).

Example 28. Preparation of Compound Nos. 28, 28a and 28b

Synthesis of N-[(2S)-2-hydroxypropyl]-4-{[2-phenyl-5-(propan-2-yl)pyridin-4-yl]amino}pyridine-3-carboxamide

(175) ##STR00229##

Step 1: Synthesis of 2-(4,6-dichloro-3-pyridyl)propan-2-ol

(176) To a solution of methyl 4,6-dichloropyridine-3-carboxylate (5 g, 0.0243 mol) in dry THF (60 mL) was added McMgBr (3 M in THF, 28.3 mL) dropwise at −60° C. under nitrogen atmosphere. The resultant reaction mixture was allowed to warm to RT and stirred for 2 h. The progress of reaction was monitored over TLC. After completion of reaction, the reaction mixture was cooled to 0° C. and quenched with saturated aqueous solution of ammonium chloride solution (200 mL) and extracted with EtOAc (2×300 mL). The combined organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure to afford 2-(4,6-dichloro-3-pyridyl)propan-2-ol (4.91 g) as a yellow liquid.

Step 2: Synthesis of 2-(4-chloro-6-phenyl-3-pyridyl)propan-2-ol

(177) To a solution of methyl 2-(4,6-dichloro-3-pyridyl)propan-2-ol (1.5 g, 7.279 mmol), phenylboronic acid (1.150 g, 9.431 mmol) in DMF (24 mL) was added a solution of Na.sub.2CO.sub.3 (1.54 g, 14.529 mmol) in water (12 mL). The resultant reaction mixture was purged with nitrogen for 30 min, followed by addition of tetrakis (673 mg, 0.582 mmol). The reaction mixture was again purged for 10 min and heated at 80° C. for 10 h. The progress of reaction was monitored over TLC & LCMS. After completion of reaction, the reaction mixture was diluted with water (300 mL) and extracted with EtOAc (2×300 mL), dried over anhydrous sodium sulfate and concentrated under reduced pressure to afford a crude product, which was purified by column chromatography on silica gel (100-200 mesh) using 11% EtOAc-hexane as eluent to obtain 2-(4-chloro-6-phenyl-3-pyridyl)propan-2-ol (3.2 g) as an off white semi-solid.

Step 3: Synthesis of 4-chloro-5-isopropenyl-2-phenyl-pyridine

(178) A mixture of 2-(4-chloro-6-phenyl-3-pyridyl)propan-2-ol (100 mg, 0.403 mmol) and poly phosphoric acid (PPA, 1 g) was heated at 110° C. for 1 h. The progress of reaction was monitored by TLC. After the completion of reaction, the reaction mixture was basified with aqueous KOH solution and extracted with EtOAc (2×20 mL). The combined organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure to afford 4-chloro-5-isopropenyl-2-phenyl-pyridine (75 mg) as an off white sticky solid.

Step 4: Synthesis of 4-aminopyridine-3-carboxylic acid

(179) A solution of 4-chloropyridine-3-carboxylic acid (15 g, 0.095 mol) in aqueous NH.sub.3 (600 mL) was heated in a pressure vessel at 150° C. overnight. The progress of reaction was monitored by TLC. After completion of the reaction, the reaction mixture was concentrated under reduced pressure. To this concentrated reaction mixture was added toluene to (2×100 mL) to obtain 4-aminopyridine-3-carboxylic acid (17 g) as a white solid.

Step 5: Synthesis of methyl 4-aminopyridine-3-carboxylate

(180) To a solution 4-aminopyridine-3-carboxylic acid (17 g, 0.123 mol) in methanol (300 mL) was added sulfuric acid (45 mL) dropwise at 0° C. The resultant reaction mixture was heated to reflux at 85° C. overnight. The progress of reaction was monitored by TLC. After the completion of the reaction, the reaction mixture was concentrated under reduced pressure to remove methanol, the residue was basified with saturated aqueous solution of sodium carbonate (400 mL), and extracted with EtOAc (3×500 mL). The combined organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure to afford of methyl 4-aminopyridine-3-carboxylate (10.3 g) as a white solid.

Step 6: Synthesis of methyl 4-[(5-isopropenyl-2-phenyl-4-pyridyl)amino]pyridine-3-carboxylate

(181) A mixture of 4-chloro-5-isopropenyl-2-phenyl-pyridine (1.2 g, 5.24 mmol), methyl 4-aminopyridine-3-carboxylate (795 mg, 5.225 mmol) and Cs2CO3 (3.40 g, 10.435 mmol) in dioxane (30 mL) was purged with nitrogen for 30 min, followed by addition of Pd.sub.2(dba).sub.3 (478 mg, 0.521 mmol) and xantphos (604 mg, 1.043 mmol) and again purged with nitrogen for 5 min. The reaction mixture was heated at 100° C. overnight. The progress of reaction was monitored over LCMS. After completion of the reaction, the reaction mixture was diluted with water (100 mL) and extracted with EtOAc (2×150 mL). The combined organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure to afford a crude product, which was purified by column chromatography on silica gel (100-200 mesh) using 20% EtOAc-hexane as eluent to obtain methyl 4-[(5-isopropenyl-2-phenyl-4-pyridyl)amino]pyridine-3-carboxylate (500 mg) as a yellow sticky semi-solid.

Step 7: Synthesis of methyl 4-[(5-isopropyl-2-phenyl-4-pyridyl)amino]pyridine-3-carboxylate

(182) To a solution of methyl 4-[(5-isopropenyl-2-phenyl-4-pyridyl)amino]pyridine-3-carboxylate (1 g, 2.895 mmol) in ethanol (30 mL) was added PtO.sub.2 (225 mg). The resultant reaction mixture was allowed to stir at RT under hydrogen atmosphere (using a hydrogen bladder) for 7 h. The progress of reaction was monitored over .sup.1HNMR. After completion of reaction, the reaction mixture was filtered through a celite bed. The organic layer was concentrated under reduced pressure to afford methyl 4-[(5-isopropyl-2-phenyl-4-pyridyl)amino]pyridine-3-carboxylate (890 mg) as a brown semi-solid.

Step 8: Synthesis of N-(2-hydroxypropyl)-4-[(5-isopropyl-2-phenyl-4-pyridyl)amino]pyridine-3-carboxamide

(183) A solution of (S)-1-aminopropan-2-ol (162 mg, 2.156 mmol) and (155 mg, 1.381 mmol) in DCM (8 mL) was allowed to stir at RT for 30 min. To this reaction mixture was added a solution of methyl 4-[(5-isopropyl-2-phenyl-4-pyridyl)amino]pyridine-3-carboxylate (300 mg, 0.863 mmol) in DCM (2 mL). The reaction mixture was heated at 50° C. for 90 min. The progress of reaction was monitored over LCMS. After completion of the reaction, the reaction mixture was diluted with water (50 mL) and extracted with EtOAc (2×100 mL). The organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure to afford a crude product, which was purified by reverse phase preparative HPLC to obtain N-(2-hydroxypropyl)-4-[(5-isopropyl-2-phenyl-4-pyridyl)amino]pyridine-3-carboxamide (57 mg) as a white solid. The (R) enantiomer can be synthesized utilizing (R)-1-aminopropan-2-ol in this step.

(184) .sup.1H NMR: (400 MHz, DMSO-d6) δ (ppm): 10.59 (s, 1H), 8.84 (m, 2H), 8.59 (s, 1H), 8.34 (d, J=5.9 Hz, 1H), 8.13-7.87 (m, 2H), 7.81 (s, 1H), 7.45 (m, 2H), 7.33-7.15 (m, 1H), 3.82 (h, J=6.2 Hz, 1H), 3.11 (m, 3H), 1.31 (d, J=6.8 Hz, 6H), 1.09 (d, J=6.2 Hz, 3H).

Example 29. Preparation of Compound No. 29

Synthesis of 2-(3-fluoropyridin-2-yl)-5-(propan-2-yl)-N-{1H-pyrrolo[2,3-b]pyridin-4-yl}pyridin-4-amine

(185) ##STR00230##

Step-1: Synthesis of 2-(4, 6-dichloro-3-pyridyl)propan-2-ol

(186) To a solution of methyl 4,6-dichloropyridine-3-carboxylate (5 g, 0.0243 mol) in dry THF (60 mL) was added 3M solution of methyl magnesium bromide in diethyl ether (28.3 mL, 0.0848 mol) dropwise under nitrogen atmosphere at −60° C. The resultant mixture was stirred at −60° C. to 0° C. for 2 h. The reaction was monitored by TLC & NMR. After completion of reaction, the reaction mixture was quenched using aq. saturated ammonium chloride solution and extracted with EtOAc. The organic layer washed with water and brine solution, dried over anhydrous sodium sulfate and concentrated under reduced pressure afforded 2-(4,6-dichloro-3-pyridyl)propan-2-ol (4.96 g) as a yellow oil.

Step-2: Synthesis of 2,4-dichloro-5-isopropenyl-pyridine

(187) To 2-(4,6-dichloro-3-pyridyl)propan-2-ol (200 mg, 0.97 mmol) was added PPA (2 g) and heated at 120° C. for 90 min. The reaction was monitored by TLC & LCMS. After completion of reaction, the reaction mixture was cooled to RT, basified with a saturated solution of NaOH solution up to pH 12-14 and extracted with EtOAc (2×50 mL). The organic layer washed with water (100 mL) and brine, dried over anhydrous sodium sulfate and concentrated under reduced pressure to obtain the crude compound which was purified by column chromatography using silica 100:200 mesh and eluent 1% EtOAc in Hexane to afford 2,4-dichloro-5-isopropenyl-pyridine (150 mg).

Step-3: Synthesis of 4-chloro-2-(3-fluoro-2-pyridyl)-5-isopropenyl-pyridine

(188) 2,4-Dichloro-5-isopropenyl-pyridine (900 mg, 4.787 mmol) and (3-fluoro-2-pyridyl) boronic acid (1.011 g, 7.180 mmol) were dissolved in DMF (15 mL). To the stirred solution were added CsCO.sub.3 (3.12 g, 9.574 mmol), CuCl (236 mg, 2.393 mmol) and Pd(dppf) (26.87 mg, 0.1196 mmol) slowly at RT for 5 min. Then Pd(OAc).sub.2 (132.6 mg, 0.239 mmol) was added and the resultant reaction mixture was kept at 100° C. overnight. The progress of the reaction was monitored by LCMS. On completion of reaction, the reaction mixture was diluted with water (150 mL) and the reaction mixture was extracted with EtOAc (2×200 mL). The combined organic layer was washed with water (2×100 mL), brine solution (200 mL), dried over anhydrous sodium sulfate and concentrated under reduced pressure to obtain the crude compound, which was further purified by column chromatography using silica gel 100:200 mesh, compound eluting with 40% EtOAc:hexane to give pure 4-chloro-2-(3-fluoro-2-pyridyl)-5-isopropenyl-pyridine (700 mg).

Step-4: Synthesis of 4-chloro-1-[(4-methoxyphenyl)methyl]pyrrolo[2,3-b]pyridine

(189) To a solution of 4-chloro-1H-pyrrolo[2,3-b]pyridine (7 g, 0.026 mmol) in DMF (5 mL) was added sodium hydride (55-60%) (1.56 g, 0.039 mmol) portionwise at 0° C. The reaction mixture was stirred at 0° C. to 10° C. for 30 min, followed by the slow addition of Para-methoxybenzyl chloride (5.319 g, 0.0338 mmol) in DMF (5 mL). The reaction mixture was allowed to stir at 0° C. to 10° C. for 2 h. The reaction was monitored by TLC and LCMS. After completion of reaction, ice cold water (100 mL) was added to the reaction mixture and product was extracted with EtOAc (2×200 mL). The combined organic layer was again washed with water (3×100 mL) and finally with brine solution (2×75 mL). The organic layer was separated, dried over anhydrous sodium sulfate and concentrated under reduced pressure to afford a crude product which was purified by column chromatography with silica gel 100:200 mesh in EtOAc:hexane product elutes at 5% to give 4-chloro-1-[(4-methoxyphenyl)methyl]pyrrolo[2,3-b]pyridine as an off-white solid (7 g).

Step 5: Synthesis of N-[1-[(4-methoxyphenyl)methyl]pyrrolo[2,3-b]pyridin-4-yl]-2-methyl-propane-2-sulfinamide

(190) To a solution of 4-chloro-1-[(4-methoxyphenyl)methyl]pyrrolo[2,3-b]pyridine (5 g, 0.0183 mmol) was added cesium carbonate (2.66 g, 0.0219 mmol) in dioxane (40 mL) then purged with nitrogen for 5 min. To this was added xantphos (0.634 g, 0.0010 mmol) and palladium acetate (12 mg, 0.0005 mmol). The reaction mixture was heated in a reagent bottle at 100° C. overnight. The reaction was monitored by TLC and LCMS. After completion of reaction, the reaction mixture was filtered through celite, the celite bed was washed with EtOAc (2×100 mL). The filtrate obtained was concentrated under reduced pressure. The crude product obtained was purified by column chromatography on silica gel 100:200 mesh. The product elutes at 20% EtOAc:Hexane to give N-[1-[(4-methoxyphenyl)methyl]pyrrolo[2,3-b]pyridin-4-yl]-2-methyl-propane-2-sulfinamide (2 g).

Step-6: Synthesis of 1-[(4-methoxyphenyl)methyl]pyrrolo[2,3-b]pyridin-4-amine

(191) To a solution of N-[1-[(4-methoxyphenyl)methyl]pyrrolo[2,3-b]pyridin-4-yl]-2-methyl-was added 4M HCl in dioxane (15 mL) dropwise at 0° C. under nitrogen atmosphere. The reaction mixture was kept at RT for 1 h. The reaction was monitored by TLC and LCMS. After completion of reaction, the reaction mixture was neutralized by NaHCO.sub.3 to pH 6-7. Then the product was extracted with EtOAc (2×100 mL). The combined organic layer was again washed with water (100 mL) and finally with brine solution (2×75 mL). The organic layer was separated, dried over anhydrous sodium sulfate and concentrated under reduced pressure to afford crude 1-[(4-methoxyphenyl)methyl]pyrrolo[2,3-b]pyridin-4-amine (2.5 g).

Step-7: Synthesis of N-[2-(3-fluoro-2-pyridyl)-5-isopropenyl-4-pyridyl]-1-[(4-methoxyphenyl) methyl]pyrrolo[2,3-b]pyridin-4-amine

(192) A suspension of 1-[(4-methoxyphenyl) methyl]pyrrolo[2,3-b]pyridin-4-amine (430 mg, 1.699 mmol), 4-chloro-2-(3-fluoro-2-pyridyl)-5-isopropenyl-pyridine (424 mg, 1.699 mmol) and cesium carbonate (1.104 g, 3.398 mmol) in dioxane (15 mL) was purged for 20 min and xantphos (147.303 mg; 0.2548 moles), Pd.sub.2(dba).sub.3 (311.18 mg, 0.339 mmol) were added and the mixture purged for 5 min. The reaction mixture was heated in a reagent bottle at 100° C. overnight. The reaction was monitored by TLC and LCMS. After completion of reaction mixture was filtered through celite, the celite bed was washed with EtOAc (2×100 mL). The filtrate obtained was concentrated under reduced pressure. The crude product was purified by column chromatography on silica gel 100:200 mesh. The product elutes at 55% EtOAc:hexane to give N-[2-(3-fluoro-2-pyridyl)-5-isopropenyl-4-pyridyl]-1-[(4-methoxyphenyl) methyl]pyrrolo[2,3-b]pyridin-4-amine (490 mg).

Step-8: Synthesis of N-[2-(3-fluoro-2-pyridyl)-5-isopropyl-4-pyridyl]-1-[(4-methoxyphenyl) methyl]pyrrolo[2,3-b]pyridin-4-amine

(193) To a stirred solution of N-[2-(3-fluoro-2-pyridyl)-5-isopropenyl-4-pyridyl]-1-[(4-methoxyphenyl)methyl]pyrrolo[2,3-b]pyridin-4-amine (480 mg, 0.953 mmol) in ethanol (5 mL) and EtOAc (0.4 mL), PtO.sub.2 (100 mg) was added at RT under H.sub.2 atmosphere using a hydrogen bladder. The reaction was kept on continuous stirring overnight. Completion of reaction was monitored by LCMS and NMR. On completion of reaction, the reaction mixture was filtered through a celite bed. The filtrate obtained was concentrated under reduced pressure to obtain N-[2-(3-fluoro-2-pyridyl)-5-isopropyl-4-pyridyl]-1-[(4-methoxyphenyl)methyl]pyrrolo[2,3-b]pyridin-4-amine was obtained (450 mg).

Step-9: Synthesis of N-[2-(3-fluoro-2-pyridyl)-5-isopropyl-4-pyridyl]-1H-pyrrolo[2,3-b]pyridin-4-amine

(194) N-[2-(3-Fluoro-2-pyridyl)-5-isopropyl-4-pyridyl]-1-[(4-methoxyphenyl)methyl]pyrrolo[2,3-b]pyridin-4-amine (450 mg, 0.963 mmol) in TFA (8 mL) was added triflic acid (3 mL) and the reaction was heated at 60° C. for 1 h. Completion of reaction was monitored by TLC and LCMS. On completion of reaction, the reaction mixture was concentrated under reduced pressure to obtain an oily compound which was neutralized by aq. saturated NaHCO.sub.3 and extracted with EtOAc (2×100 mL). The organic layer was again washed with brine, dried over anhydrous sodium sulfate and concentrated under reduced pressure to afford a crude product which was purified by reverse phase HPLC to obtain N-[2-(3-fluoro-2-pyridyl)-5-isopropyl-4-pyridyl]-1H-pyrrolo[2,3-b]pyridin-4-amine (95 mg) as an off-white solid. This was dissolved in ethanolic HCl (10 mL) and concentrated under reduced pressure to give N-[2-(3-fluoro-2-pyridyl)-5-isopropyl-4-pyridyl]-1H-pyrrolo[2,3-b]pyridin-4-amine hydrochloride salt (96 mg) as an off-white solid.

(195) .sup.1H NMR: (400 MHz, Methanol-d4) δ (ppm): 8.96 (s, 1H), 8.84 (s, 1H), 8.77 (d, J=5.3 Hz, 1H), 8.29 (d, J=6.7 Hz, 1H), 8.20 (t, J=6.1 Hz, 1H), 7.96 (s, 1H), 7.57 (d, J=3.5 Hz, 1H), 7.27 (d, J=6.7 Hz, 1H), 6.76 (d, J=3.7 Hz, 1H), 3.56 (h, J=6.8 Hz, 1H), 1.46 (d, J=6.8 Hz, 6H). LCMS: 348 (M+1).

Example 30. Preparation of Compound No. 30

Synthesis of 2-(3-fluoropyridin-2-yl)-5-(propan-2-yl)-N-{7H-pyrrolo[2,3-d]pyrimidin-4-yl}pyridin-4-amine

(196) ##STR00231##

Steps 1-8: Synthesis of N-[2-(3-fluoro-2-pyridyl)-5-isopropyl-4-pyridyl]-7-[(4-methoxyphenyl) methyl]pyrrolo[2,3-d]pyrimidin-4-amine

(197) See Example 29.

Step 9: Synthesis of N-[2-(3-fluoro-2-pyridyl)-5-isopropyl-4-pyridyl]-7H-pyrrolo[2,3-d]pyrimidin-4-amine

(198) A solution of N-[2-(3-fluoro-2-pyridyl)-5-isopropyl-4-pyridyl]-7-[(4-methoxyphenyl) methyl]pyrrolo[2,3-d]pyrimidin-4-amine (290 mg, 0.618 mmol) in TFA (5 mL) and triflic acid (2.5 mL) was heated at 70° C. for 5 h. Progress of the reaction was monitored by TLC & LCMS. After completion of reaction, the reaction mixture was cooled to RT and concentrated under reduced pressure to obtain an oily compound which was neutralized using aq. saturated sodium bicarbonate and extracted with EtOAc (2×100 mL). The combined organic layer was washed with brine solution (50 mL) and dried over anhydrous sodium sulfate and concentrate under reduced pressure to obtain the crude compound, which was purified by reverse phase HPLC to obtain N-[2-(3-fluoro-2-pyridyl)-5-isopropyl-4-pyridyl]-7H-pyrrolo[2,3-d]pyrimidin-4-amine (15 mg).

(199) .sup.1H NMR: (400 MHz, Methanol-d4) δ (ppm): 8.70 (s, 1H), 8.56 (d, J=3.1 Hz, 1H), 8.51 (d, J=5.1 Hz, 1H), 8.25 (d, J=5.1 Hz, 2H), 7.99 (dd, J=6.8, 5.1 Hz, 1H), 7.25 (d, J=3.6 Hz, 1H), 6.66 (d, J=3.6 Hz, 1H), 3.43 (p, J=6.9 Hz, 1H), 1.38 (d, J=6.9 Hz, 6H). LCMS: 349 (M+1).

Example 31. Preparation of Compound Nos. 31, 31a and 31b

Synthesis of 4-{[2-(5-chloro-2-fluorophenyl)-5-cyclopropylpyridin-4-yl]amino}-N-[(2S)-2-hydroxypropyl]pyridine-3-carboxamide

(200) ##STR00232##

STEP-1: Synthesis of 2,4-dichloro-5-cyclopropyl-pyridine

(201) 5-Bromo-2,4-dichloro-pyridine (1.5 g, 6.60 mmol), cyclopropyl boronic acid (1.14 g, 13.2 mmol) and sodium carbonate (2.1 g, 19.82 mmol) were dissolved in 1,4-dioxane:Water (20:5 mL). Nitrogen gas was purged for 10 min. Then Pd(dppf)Cl.sub.2.DCM (270 mg, 0.330 mmol) was added and the resulting mixture was heated at 100° C. for 3 h. Product formation was confirmed by TLC and LCMS. Then the reaction mixture was diluted with water (50 mL) and extracted with EtOAc (2×100 mL). The combined organic layer was dried over anhydrous sodium sulfate and concentrated. The crude product was passed through the CombiFlash® chromatography to afford 700 mg of 2,4-dichloro-5-cyclopropyl-pyridine.

STEP-2: Synthesis of 4-chloro-2-(5-chloro-2-fluoro-phenyl)-5-cyclopropyl-pyridine

(202) 2,4-Dichloro-5-cyclopropyl-pyridine (700 mg, 3.72 mmol), (5-chloro-2-fluoro-phenyl)boronic acid (1.3 g, 7.44 mmol) and sodium bicarbonate (626 mg, 7.44 mmol) were dissolved in DMF:Water (10:5 mL) and nitrogen was purged for 10 min. Then Pd(PPh.sub.3).sub.2.Cl.sub.2 and heated at 90° C. for 12 h. Product formation was confirmed by TLC and LCMS. Then the reaction mixture was diluted with water (50 mL) and extracted with EtOAc (2×100 mL). The combined organic layer was washed with water (5×50 mL) and dried over anhydrous sodium sulfate, and concentrated. The crude product was passed through CombiFlash®chromatography to afford 400 mg of 4-chloro-2-(5-chloro-2-fluoro-phenyl)-5-cyclopropyl-pyridine.

STEP-3: Synthesis of 4-[[2-(5-chloro-2-fluoro-phenyl)-5-cyclopropyl-4-pyridyl]amino]pyridine-3-carboxylate

(203) 4-Chloro-2-(5-chloro-2-fluoro-phenyl)-5-cyclopropyl-pyridine (300 mg, 1.06 mmol), methyl 4-aminopyridine-3-carboxylate (244 mg, 1.60 mmol) and potassium phosphate tribasic (566 mg, 2.66 mmol) were dissolved in 1,4-dioxane (5 mL). Nitrogen gas was purged for 10 min. Then Pd.sub.2(dba).sub.3 (49 mg, 0.053 mmol) and xantphos (31 mg, 0.053 mmol) were added and the resulting mixture was heated at 180° C. in a microwave reactor for 30 min. Product formation was confirmed by TLC and LCMS. Then the reaction mixture was diluted with water (50 mL) and extracted with EtOAc (2×100 mL). The combined organic layer was dried over anhydrous sodium sulfate and concentrated. The crude product was passed through the CombiFlash®chromatography to afford 200 mg of methyl 4-[[2-(5-chloro-2-fluoro-phenyl)-5-cyclopropyl-4-pyridyl]amino]pyridine-3-carboxylate.

STEP-4: Synthesis of 4-[[2-(5-chloro-2-fluoro-phenyl)-5-cyclopropyl-4-pyridyl]amino]-N-[(2S)-2-hydroxypropyl]pyridine-3-carboxamide

(204) Methyl 4-[[2-(5-chloro-2-fluoro-phenyl)-5-cyclopropyl-4-pyridyl]amino]pyridine-3-carboxylate (200 mg, 0.503 mmol) and (S)-1-aminopropan-2-ol (227 mg, 3.00 mmol) were dissolved in 2 mL of DMSO and heated at 120° C. for 4 h. Product formation was confirmed by LCMS. Then the reaction mixture was diluted with water (50 mL) and extracted with EtOAc (2×50 mL). The combined organic layer was washed with water (5×20 mL) and dried over anhydrous sodium sulfate, and concentrated. The crude product was passed over reverse phase HPLC to afford 45 mg of 4-[[2-(5-chloro-2-fluoro-phenyl)-5-cyclopropyl-4-pyridyl]amino]-N-[(2S)-2-hydroxypropyl]pyridine-3-carboxamide. The (R) enantiomer can be synthesized utilizing (R)-1-aminopropan-2-ol in this step.

(205) .sup.1H NMR: (400 MHz, CDCl.sub.3): δ (ppm): 10.58 (bs, 1H), 8.75 (s, 1H), 8.42 (m, 2H), 7.99 (m, 1H), 7.78 (s, 1H), 7.42 (d, 1H), 7.30 (m, 1H), 7.08 (t, 1H), 6.92 (bs, 1H), 4.08 (m, 1H), 3.70 (m, 1H), 3.32 (m, 1H), 1.88 (m, 1H), 1.30 (d, 3H), 1.18 (m, 2H), 0.75 (m, 2H).

Example 32. Preparation of Compound No. 32

Synthesis of 2-(5-chloro-2-fluorophenyl)-5-cyclopropyl-N-{1H-pyrrolo[2,3-b]pyridin-4-yl}pyridin-4-amine

(206) ##STR00233##

(207) 4-Chloro-2-(5-chloro-2-fluoro-phenyl)-5-cyclopropyl-pyridine (200 mg, 0.709 mmol), 1H-pyrrolo[2,3-b]pyridin-4-amine (189 mg, 1.41 mmol) and potassium phosphate tribasic (376 mg, 1.77 mmol) were dissolved in 1,4-dioxane (5 mL). Nitrogen gas was purged for 10 min. Then Pd.sub.2(dba).sub.3 (33 mg, 0.035 mmol) and xantphos (21 mg, 0.035 mmol) were added and the resulting mixture was heated at 180° C. in microwave reactor for 30 min. Product formation was confirmed by LCMS. Then the reaction mixture was diluted with water (50 mL) and extracted with EtOAc (2×50 mL). The combined organic layer was dried over anhydrous sodium sulfate and concentrated. The crude product was passed through reverse phase HPLC to afford 50 mg of N-[2-(5-chloro-2-fluoro-phenyl)-5-cyclopropyl-4-pyridyl]-1H-pyrrolo[2,3-b]pyridin-4-amine.

(208) .sup.1H NMR: (400 MHz, CDCl.sub.3): δ (ppm): 10.58 (bs, 1H), 8.75 (s, 1H), 8.42 (m, 2H), 7.99 (m, 1H), 7.78 (s, 1H), 7.42 (d, 1H), 7.30 (m, 1H), 7.08 (t, 1H), 6.92 (bs, 1H), 4.08 (m, 1H), 3.70 (m, 1H), 3.32 (m, 1H), 1.88 (m, 1H), 1.30 (d, 3H), 1.18 (m, 2H), 0.75 (m, 2H).

Example 33. Preparation of Compound No. 33

Synthesis of 4-{[2-(5-chloro-2-fluorophenyl)-5-(pyrrolidin-1-yl)pyridin-4-yl]amino}-N-(1,3-dihydroxypropan-2-yl)pyridine-3-carboxamide

(209) ##STR00234##

Step-1: Synthesis of 4,6-dichloropyridine-3-carboxylic acid

(210) To a stirred solution of methyl 4,6-dichloropyridine-3-carboxylate (15 g, 0.0728 mol) in THF (100 mL) was added a solution of lithium hydroxide monohydrate (8.737 g, 0.364 mol) in water (50 mL). The resultant reaction mixture was stirred at RT for 1.5 h. The reaction was monitored by TLC. After completion of reaction, the pH of the aqueous layer was adjusted to 2 by the addition of 2 N HCl (aq.) and product was extracted with EtOAc (2×500 mL). The organic layer was separated, dried over anhydrous sodium sulfate and concentrated under reduced pressure to afford 4,6-dichloropyridine-3-carboxylic acid (13.5 g) as a white solid.

Step-2: Synthesis of tert-butyl N-(4,6-dichloro-3-pyridyl)carbamate

(211) To a solution of 4,6-dichloropyridine-3-carboxylic acid (8.4 g, 43.75 mmol) in dry DMF (30 mL) was added triethylamine (6.5 mL, 48.12 mmol) at 0° C. followed by diphenylphosphoryl azide (10.37 mL, 48.12 mmol). The resultant reaction mixture was stirred at RT for 1 h and poured onto a mixture of ice-water-EtOAc. The product was extracted with EtOAc (2×200 mL). The combined extracts were washed with water (2×100 mL), a saturated solution of sodium bicarbonate (50 mL) and finally with brine solution (50 mL). The organic layer was separated, dried over anhydrous sodium sulfate and concentrated under reduced pressure to afford a light yellow solid which was dissolved in 80 mL of dry toluene and heated to reflux for 2 h. Then the reaction mixture was cooled to RT and t-butanol (25.1 mL, 262.5 mmol) was added. The resultant reaction mixture was heated at 90° C. for 4 h. The reaction was monitored by TLC. After completion, the reaction mixture was concentrated under reduced pressure, water was added to the residue and the product was extracted with EtOAc (2×250 mL). Removal of EtOAc under reduced pressure afforded an oily residue that was purified by column chromatography on silica gel (100-200 mesh) using 1% EtOAc-hexane system as eluent to afford tert-butyl N-(4,6-dichloro-3-pyridyl)carbamate (6.9 g) as a light yellow liquid.

Step-3: Synthesis of 4,6-dichloropyridin-3-amine

(212) To a stirred solution of tert-butyl N-(4,6-dichloro-3-pyridyl)carbamate (6.9 g, 0.0262 mol) in DCM (20 mL) was added trifluoroacetic acid (8 mL) dropwise at 0° C. The reaction mixture was slowly warmed to RT and stirred for 90 min. The reaction was monitored by TLC. After completion of reaction, reaction mixture was concentrated under reduced pressure. To the residue was added saturated solution of sodium bicarbonate (30 mL) and product was extracted with EtOAc (2×200 mL). The organic layer was again washed with water (30 mL) and brine solution (30 mL). The organic layer was separated, dried over anhydrous sodium sulfate. Removal of EtOAc under reduced pressure afforded product which was again washed with n-pentane and dried to afford 4,6-dichloropyridin-3-amine (3.8 g) as a light brown solid.

Step-4: Synthesis of 2,4-di chloro-5-pyrrolidin-1-yl-pyridine

(213) To a stirred solution of 4,6-dichloropyridin-3-amine (3.9 g, 0.0239 mol) in dry DMF (35 mL) was added sodium hydride (1.914 g, 0.0478 mol, 60% suspension in mineral oil) under nitrogen atmosphere at 0° C. The reaction mixture was stirred at this temperature for 30 min. Then 1,4-dibromobutane (4.134 g, 0.0191 mol) was added dropwise. The reaction mixture was stirred at RT overnight. The reaction was monitored by TLC and LCMS. After completion of reaction, the reaction was quenched by addition of ice-water (50 mL) and the product was extracted with EtOAc (2×150 mL). The organic layer was again washed with water (2×50 mL) and brine solution (50 mL). The organic layer was separated, dried over anhydrous sodium sulfate and concentrated under reduced pressure to afforded an oily residue that was purified by column chromatography on silica gel (100-200 mesh) using 0.5-1% EtOAc-hexane to afford 2,4-dichloro-5-pyrrolidin-1-yl-pyridine (3.711 g) as an off-white solid.

Step-5: Synthesis of 4-chloro-2-(5-chloro-2-fluoro-phenyl)-5-pyrrolidin-1-yl-pyridine

(214) To a stirred solution of 2,4-dichloro-5-pyrrolidin-1-yl-pyridine (3.5 g, 0.0161 mot), (5-chloro-2-fluoro-phenyl)boronic acid (3.36 g, 0.01963 mol) in DMF (15 mL) was added a suspension of sodium bicarbonate (2.7 g, 0.0322 mol) in water (15 mL) was purged nitrogen for 30 min. Then bis(triphenylphosphine)palladium(II) dichloride (566 mg, 0.000806 mmol) was added to the reaction mixture and nitrogen gas was purged through it for another 5 min. The reaction mixture was then heated at 80° C. overnight. The reaction was monitored by TLC and LCMS. After completion of reaction, the reaction mixture was cooled to RT and water (50 mL) was added to the reaction mixture and product was extracted with EtOAc (2×100 mL). The combined organic layer was washed with water (3×50 mL) and finally with brine solution (50 mL). The organic layer was separated, dried over anhydrous sodium sulfate and concentrated under reduced pressure to obtain the crude compound which was purified by combi flash chromatography using 5% EtOAc in hexane elute to afford 4-chloro-2-(5-chloro-2-fluoro-phenyl)-5-pyrrolidin-1-yl-pyridine (1.615 g) as an off-white solid and also recover unreacted starting material (2,4-dichloro-5-pyrrolidin-1-yl-pyridine, 1.8 g).

Step-6: Synthesis of methyl 4-[[2-(5-chloro-2-fluoro-phenyl)-5-pyrrolidin-1-yl-4-pyridyl]amino]pyridine-3-carboxylate

(215) A stirred solution of 4-chloro-2-(5-chloro-2-fluoro-phenyl)-5-pyrrolidin-1-yl-pyridine (1.2 g, 3.85 mmol), methyl 4-aminopyridine-3-carboxylate (645 mg, 4.24 mmol) and potassium phosphate (tribasic) (1.635 g, 7.712 mmol) in 1,4-dioxane (20 mL) was purged with nitrogen for 30 min. Then tris(dibenzylidineacetone)dipalladium(0) (353 mg, 0.385 mmol) and xantphos (335 mg, 0.578 mmol) were added to the reaction mixture. Nitrogen gas was purged through it for another 5 min. The resulting reaction mixture was then heated at 100° C. overnight. The reaction was monitored by TLC and LCMS. After completion of reaction, reaction mixture was filtered through a celite bed. The celite bed was washed with EtOAc (2×100 mL). The filtrate was concentrated under reduced pressure to afford a crude product which was purified by combi-flash chromatography using 25% EtOAc-hexane system as eluent to afford methyl 4-[[2-(5-chloro-2-fluoro-phenyl)-5-pyrrolidin-1-yl-4-pyridyl]amino]pyridine-3-carboxylate (1.056 g) as a light yellow solid.

Step-7: Synthesis of obtain 4-[[2-(5-chloro-2-fluoro-phenyl)-5-pyrrolidin-1-yl-4-pyridyl]amino]-N-[2-hydroxy-1-(hydroxymethyl)ethyl]pyridine-3-carboxamide

(216) To a stirred suspension of methyl 4-[[2-(5-chloro-2-fluoro-phenyl)-5-pyrrolidin-1-yl-4-pyridyl]amino]pyridine-3-carboxylate (120 mg, 0.281 mmol) and 2-aminopropane-1,3-diol (128 mg, 1.405 mmol) in DMF (3 mL) The resulting reaction mixture was heated at 90° C. for 5 h. The reaction was monitored by TLC and LCMS. After completion of reaction, reaction mixture was cooled to RT and diluted with water (10 mL) and extracted with EtOAc (2×50 mL), and the organic layer washed with water (15 mL). The organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure to obtain the crude product which was purified by reverse phase HPLC to afford 4-[[2-(5-chloro-2-fluoro-phenyl)-5-pyrrolidin-1-yl-4-pyridyl]amino]-N-[2-hydroxy-1-(hydroxy methyl)ethyl]pyridine-3-carboxamide (75 mg) as an off-white solid, which was dissolved in ethanolic HCl (10 mL) and concentrated under reduced pressure to obtain 4-[[2-(5-chloro-2-fluoro-phenyl)-5-pyrrolidin-1-yl-4-pyridyl]amino]-N-[2-hydroxy-1-(hydroxy methyl)ethyl]pyridine-3-carboxamide (76 mg) as the HCl salt.

(217) .sup.1H NMR: (400 MHz, Methanol-d4) δ (ppm): 8.90 (s, 1H), 8.33 (d, J=8.3 Hz, 2H), 7.88 (d, J=11.0 Hz, 2H), 7.51 (m, 1H), 7.30 (t, J=9.7 Hz, 1H), 7.19 (d, J=7.1 Hz, 1H), 4.26 (d, J=6.1 Hz, 1H), 3.76 (qd, J=11.2, 5.7 Hz, 4H), 3.47 (m, 4H), 1.99 (m, 4H). LCMS: 486 (M+1).

Example 34. Preparation of Compound No. 34

Synthesis of 2-(5-chloro-2-fluorophenyl)-5-(prop-1-en-2-yl)-N-[3-(pyrrolidine-1-carbonyl)pyridin-4-yl]pyridin-4-amine

(218) ##STR00235##

(219) To a solution of methyl 4-[[2-(5-chloro-2-fluoro-phenyl)-5-isopropenyl-4-pyridyl]amino]pyridine-3-carboxylate (700 mg, 1.763 m mol) and added pyrrolidine (1.25 g, 17.63 mmol) and heated at 100° C. for 1 h in a microwave reactor. The progress of the reaction was monitored by TLC and LCMS. After completion of reaction, the mixture was diluted with water (20 mL) extracted with EtOAc (2×100 mL) and washed with water (5×100 mL). The combined organic layer was dried with anhydrous sodium sulfate and concentrated under reduced pressure to afford a crude product, which was purified by reverse phase purification to afford 200 mg 2-(5-chloro-2-fluorophenyl)-5-(prop-1-en-2-yl)-N-[3-(pyrrolidine-1-carbonyl)pyridin-4-yl]pyridin-4-amine.

(220) .sup.1HNMR: (Free Base, DMSO-d6): δ (ppm): 9.15 (bs, 1H) 8.58 (s, 1H), 8.42 (s, 1H), 8.38 (d, 1H), 7.98 (m, 1H), 7.75 (s, 1H), 7.58 (m, 1H), 7.41 (m, 2H), 5.42 (s, 1H) 5.18 (s, 1H), 3.52 (m, 2H), 3.42 (m, 2H), 2.15 (s, 3H), 1.88 (m, 2H), 1.78 (m, 2H).

Example 35. Preparation of Compound No. 35

Synthesis of 2-(5-chloro-2-fluorophenyl)-5-(propan-2-yl)-N-{7H-pyrrolo[2,3-d]pyrimidin-4-yl}pyridin-4-amine

(221) ##STR00236## ##STR00237##

Step-1: Synthesis of N-[2-(5-chloro-2-fluoro-phenyl)-5-isopropenyl-4-pyridyl]-7-[(4-methoxyphenyl)methyl]pyrrolo[2,3-d]pyrimidin-4-amine

(222) 4-Chloro-2-(5-chloro-2-fluoro-phenyl)-5-isopropenyl-pyridine (1.0 g, 3.5 mmol), 7-[(4-methoxyphenyl)methyl]pyrrolo[2,3-d]pyrimidin-4-amine (1.35 g, 5.3 mmol) potassium phosphate (2.25 g, 10.52 mmol) was dissolved in 1,4-dioxane (20 ml)nitrogen gas was purged for 20 min. To it was added tris(dibenzylideneacetone)dipalladium(0) (324 mg, 0.35 mmol) and xantphos (418 mg, 0.72 mmol) and again degassed with nitrogen for 20 min and the reaction mass was heated to reflux overnight. The reaction was monitored by TLC and LCMS. The reaction mass was filtered through a small bed of celite and concentrated under reduced pressure to get the crude product that was purified by chromatography (eluent: 20-40% EtOAc in hexane) to obtain the pure N-[2-(5-chloro-2-fluoro-phenyl)-5-isopropenyl-4-pyridyl]-7-[(4-methoxyphenyl)methyl]pyrrolo[2,3-d]pyrimidin-4-amine (530 mg).

Step-2: Synthesis of N-[2-(5-chloro-2-fluoro-phenyl)-5-isopropyl-4-pyridyl]-7-[(4-methoxyphenyl)methyl]pyrrolo[2,3-d]pyrimidin-4-amine

(223) N-[2-(5-Chloro-2-fluoro-phenyl)-5-isopropenyl-4-pyridyl]-7-[(4-methoxyphenyl)methyl]pyrrolo[2,3-d]pyrimidin-4-amine (502 mg, 1 mmol) was dissolved in a solution of ethanol and EtOAc (1:1) (10 mL), and to it was added platinum oxide (45 mg, 0.20 mmol) and the reaction mass was purged by Hydrogen, with Hydrogen gas bladder for 3 h and kept under a hydrogen atmosphere overnight. The reaction was monitored by NMR. The reaction mass was filtered through a small bed of celite and concentrated under reduced pressure to obtain the product that was purified by chromatography (eluent: 50% EtOAc in hexane) to obtain the pure N-[2-(5-chloro-2-fluoro-phenyl)-5-isopropyl-4-pyridyl]-7-[(4-methoxyphenyl)methyl]pyrrolo[2,3-d]pyrimidin-4-amine (340 mg).

Step-3: Synthesis of 2-(5-chloro-2-fluorophenyl)-5-(propan-2-yl)-N-{7H-pyrrolo[2,3-d]pyrimidin-4-yl}pyridin-4-amine

(224) N-[2-(5-Chloro-2-fluoro-phenyl)-5-isopropyl-4-pyridyl]-7-[(4-methoxyphenyl)methyl]pyrrolo[2,3-d]pyrimidin-4-amine (250 mg, 0.5 mmol) was dissolved in trifluoroacetic acid (0.8 mL), and to it was added trifluoromethanesulfonic acid (0.2 mL) and the reaction mass was heated in a microwave at 120° C. for 50 min. The reaction was monitored by LCMS. The reaction mass was basified with ice cold saturated sodium hydrogen carbonate (20 mL) and extracted with DCM (2×20 mL). The combined organics were dried over sodium sulfate and concentrated under reduced pressure to obtain the product that was purified by chromatography (mobile phase (0-5% methanol in DCM) to obtain the product (120 mg). This product was again purified with reverse phase HPLC to obtain the pure product 2-(5-chloro-2-fluorophenyl)-5-(propan-2-yl)-N-{7H-pyrrolo[2,3-d]pyrimidin-4-yl}pyridin-4-amine as free base (15 mg).

(225) .sup.1HNMR: (400 MHz; DMSO-d6) δ (ppm): 11.8 (bs 1H), 9.02 (s, 1H), 8.82 (s, 1H), 8.2 (s, 1H), 8.04 (s, 1H), 8.0 (d, 1H), 7.44 (m, 1H), 7.40 (m, 1H), 7.22 (s, 1H), 6.6 (s, 1H), 3.4 (m, 1H), 1.2 (d, 6H).

Example 36. Preparation of Compound No. 36

Synthesis of 2-(5-chloro-2-fluorophenyl)-5-(propan-2-yl)-N-{1H-pyrazolo[3,4-d]pyrimidin-4-yl}pyridin-4-amine

(226) ##STR00238## ##STR00239##

Step-1: Synthesis of N-[2-(5-chloro-2-fluoro-phenyl)-5-isopropenyl-4-pyridyl]-1-[(4-methoxyphenyl)methyl]pyrazolo[3,4-d]pyrimidin-4-amine

(227) 4-Chloro-2-(5-chloro-2-fluoro-phenyl)-5-isopropenyl-pyridine (2.0 g, 7.09 mmol), 1-[(4-methoxyphenyl)methyl]pyrazolo[3,4-d]pyrimidin-4-amine (2.7 g, 10.6 mmol) and potassium phosphate (4.5 g, 21.2 mmol) were dissolved in 1,4-dioxane (40 mL), and the mixture purged with nitrogen gas for 20 min. To this was added tris(dibenzylidene acetone)dipalladium(0) (324 mg, 0.35 mmol,) and xantphos (418 mg, 0.72 mmol) and again degassed with nitrogen for 20 min and the reaction mass was heated to reflux overnight. The reaction was monitored by TLC and LCMS. The reaction mass was filtered through a small bed of celite and concentrated under reduced pressure to get the crude product that was purified by chromatography (eluent: 20-40% EtOAc in hexane) to obtain the pure N-[2-(5-chloro-2-fluoro-phenyl)-5-isopropenyl-4-pyridyl]-1-[(4-methoxyphenyl)methyl]pyrazolo[3,4-d]pyrimidin-4-amine (1.1 g).

Step-2: Synthesis of N-[2-(5-chloro-2-fluoro-phenyl)-5-isopropyl-4-pyridyl]-1-[(4-methoxyphenyl)methyl]pyrazolo[3,4-d]pyrimidin-4-amine

(228) N-[2-(5-Chloro-2-fluoro-phenyl)-5-isopropenyl-4-pyridyl]-1-[(4-methoxyphenyl)methyl]pyrazolo[3,4-d]pyrimidin-4-amine (1.0 g, 2.0 mmol) was dissolved in a solution of ethanol and EtOAc (1:1) (20 mL), and to it was added platinum oxide (90 mg, 0.39 mmol) and the reaction mass was purged with hydrogen gas, by bladder, for 3 h and kept under a hydrogen atmosphere overnight. The reaction was monitored by NMR. The reaction mass was filtered through a small bed of celite and concentrated under reduced pressure to obtain the product which was purified by chromatography (eluent: 50% EtOAc in hexane) to obtain the pure form of N-[2-(5-chloro-2-fluoro-phenyl)-5-isopropyl-4-pyridyl]-1-[(4-methoxyphenyl)methyl]pyrazolo[3,4-d]pyrimidin-4-amine (650 mg).

Step-3: Synthesis of 2-(5-chloro-2-fluorophenyl)-5-(propan-2-yl)-N-{1H-pyrazolo[3,4-d]pyrimidin-4-yl}pyridin-4-amine

(229) N-[2-(5-Chloro-2-fluoro-phenyl)-5-isopropyl-4-pyridyl]-1-[(4-methoxyphenyl)methyl]pyrazolo[3,4-d]pyrimidin-4-amine (503 mg, 1.0 mmol) was dissolved in trifluoroacetic acid (0.8 mL), and to it was added trifluoromethanesulfonic acid (0.2 mL) and the reaction mass was heated in a microwave at 120° C. for 50 min. The reaction was monitored by LCMS. The reaction mass was basified with ice cold saturated sodium hydrogen carbonate (20 mL) and extracted with DCM (2×20 mL). The combined organics were dried over sodium sulfate and concentrated under reduced pressure to obtain the product that was purified by chromatography (mobile phase (0-5% methanol in DCM) to obtain the product (270 mg). that was again purified with reverse phase HPLC to obtain the pure product 2-(5-chloro-2-fluorophenyl)-5-(propan-2-yl)-N-{1H-pyrazolo[3,4-d]pyrimidin-4-yl}pyridin-4-amine as formate salt (52 mg).

(230) .sup.1HNMR: (400 MHz; DMSO-d6) δ (ppm): 13.8-13.6 (bs, 1H) 10.0-9.8 (bs, 1H) 8.8 (s, 1H), 8.2 (s, 1H), 8.14-8.0 (bs, 1H), 8.0 (d, 1H), 7.98 (s, 1H), 7.6 (m, 1H), 7.4 (m, 1H), 3.2 (m, 1H), 1.2 (d, 6H).

Example 37. Preparation of Compound Nos. 37, 37a and 37b

Synthesis of 4-{[2-(2-fluorophenyl)-5-(prop-1-en-2-yl)pyridin-4-yl]amino}-N-[(2S)-2-hydroxypropyl]pyridine-3-carboxamide

(231) ##STR00240##

Step-1: Synthesis of 4-amino-N-[(2S)-2-hydroxypropyl]pyridine-3-carboxamide

(232) (S)-1-Amino-2-propanol (2.0 g, 13.1 mmol) was added to methyl-4-aminonicotinate (3.0 g, 39.9 mmol) in a microwave tube and the resulting mixture was heated in a microwave reactor at 120° C. for 1.5 h. The product formation was confirmed by TLC and LCMS. The crude product was purified by chromatography to afford 1.03 g of the product 4-amino-N-[(2S)-2-hydroxypropyl]pyridine-3-carboxamide as white crystals.

Step-2: Synthesis of 4-chloro-2-(2-fluorophenyl)-5-isopropenyl-pyridine

(233) A 100 mL screw cap bottle was charged with 2,4-dichloro-5-isopropenyl-pyridine (2.0 g, 10.6 mmol), 2-fluorophenylboronic acid (1.1 g, 8.0 mmol) and sodium carbonate (3.4 g, 31.8 mmol) DME (20 ml) and water (5 mL) and degassed with nitrogen for 15 min. To it was added Pd(PPh.sub.3).sub.2.Cl.sub.2 (364 mg, 0.52 mmol) and degassed with nitrogen for another 10 min. The resulting mixture was heated at 100° C. for 3 h. The reaction was monitored by TLC and LCMS. Then the reaction mixture was passed through a celite bed, diluted with water (25 mL) and EtOAc (25 mL). The layers were separated, and the aqueous layer was again extracted with EtOAc (50 mL). The combined organics were dried over anhydrous sodium sulfate and concentrated under reduced pressure to obtain the product, which was purified by chromatography (eluent: hexane) to afford 1.24 g of product 4-chloro-2-(2-fluorophenyl)-5-isopropenyl-pyridine as white crystals.

Step-3: Synthesis of 4-[[2-(2-fluorophenyl)-5-isopropenyl-4-pyridyl]amino]-N-[(2S)-2-hydroxypropyl]pyridine-3-carboxamide

(234) A 25 mL screw cap bottle was charged with 4-chloro-2-(2-fluorophenyl)-5-isopropenyl-pyridine (500 mg, 2.0 mmol), 4-amino-N-[(2S)-2-hydroxypropyl]pyridine-3-carboxamide (433 mg, 2.2 mmol), K.sub.3PO.sub.4 (849 mg, 4.0 mmol) and 1,4-dioxane (10 mL) and degassed with nitrogen for 20 min. Then Xantphos (174 mg, 0.3 mmol) and Pd.sub.2(dba).sub.3 (183 mg, 0.2 mmol) were added and again degassed with nitrogen for a further 15 min. The resulting mixture was heated at 100° C. overnight. The product formation was confirmed by LCMS. Then the reaction mixture was passed through a celite bed and concentrated under reduced pressure to obtain the product, which was purified with reverse phase HPLC to afford 85 mg of product 4-[[2-(2-fluorophenyl)-5-isopropenyl-4-pyridyl]amino]-N-[(2S)-2-hydroxypropyl]pyridine-3-carboxamide as a white solid. The (R) enantiomer can be synthesized utilizing (R)-1-aminopropan-2-ol in Step-1.

(235) .sup.1HNMR: (400 MHz, DMSO): δ (ppm): 10.43 (bs, 1H), 8.83-8.81 (m, 2H), 8.47 (m, 1H), 7.99 (m, 1H), 7.78 (s, 1H), 7.42 (d, 1H), 7.30 (m, 1H), 7.08 (t, 1H), 6.92 (bs, 1H), 4.08 (m, 1H), 3.70 (m, 1H), 3.32 (m, 1H), 1.88 (m, 1H), 1.30 (d, 3H), 1.18 (m, 2H), 0.75 (m, 2H).

Example 38. Preparation of Compound Nos. 38, 38a and 38b

Synthesis of 4-{[2-(4-fluorophenyl)-5-(prop-1-en-2-yl)pyridin-4-yl]amino}-N-[(2S)-2-hydroxypropyl]pyridine-3-carboxamide

(236) ##STR00241##

Step-1: Synthesis of 4-amino-N-[(2S)-2-hydroxypropyl]pyridine-3-carboxamide

(237) See Example 37.

Step-2: Synthesis of 4-chloro-2-(4-fluorophenyl)-5-isopropenyl-pyridine

(238) A 100 mL screw cap bottle was charged with 2,4-dichloro-5-isopropenyl-pyridine (2.0 g, 10.6 mmol), 2-fluorophenylboronic acid (1.1 g, 8.0 mmol) and sodium carbonate (3.4 g, 31.8 mmol) in a mixture of DME (20 mL) and water (5 mL) and degassed with nitrogen for 15 min. Then Pd(PPh.sub.3).sub.2.Cl.sub.2 (364 mg, 0.52 mmol) was added and again degassed with nitrogen for a another 10 min. The resulting mixture was heated at 100° C. for 3 h. The reaction was monitored by LCMS formation TLC and LCMS. Then the reaction mixture was passed through a celite bed, diluted with water (25 mL) and extracted with EtOAc (2×50 mL). The combined organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The crude product was passed through the CombiFlash® chromatography to afford 1.41 g of product 4-chloro-2-(4-fluorophenyl)-5-isopropenyl-pyridine as white crystals.

Step-3: Synthesis of 4-{[2-(4-fluorophenyl)-5-(prop-1-en-2-yl)pyridin-4-yl]amino}-N-[(2S)-2-hydroxypropyl]pyridine-3-carboxamide

(239) A 25 mL screw cap bottle was charged with 4-chloro-2-(4-fluorophenyl)-5-isopropenyl-pyridine (500 mg, 2.0 mmol) and 4-amino-N-[(2S)-2-hydroxypropyl]pyridine-3-carboxamide (433 mg, 2.2 mmol) and K.sub.3PO.sub.4 (849 mg, 4.0 mmol) and 1,4-dioxane (10 mL) and degassed with nitrogen for 30 min. Then Xantphos (174 mg, 0.3 mmol) and Pd.sub.2(dba).sub.3 (183 mg, 0.2 mmol) were added and nitrogen was purged for further 15 min. The resulting mixture was heated at 100° C. overnight. The reaction was monitored by LCMS. Then the reaction mixture was passed through a celite bed and extracted with EtOAc (2×50 mL) and concentrated under reduced pressure to obtain the product, which was purified with reverse phase HPLC to afford 169 mg of product 4-[[2-(2-fluorophenyl)-5-isopropenyl-4-pyridyl]amino]-N-[(2S)-2-hydroxypropyl]pyridine-3-carboxamide as a white solid. The (R) enantiomer can be synthesized utilizing (R)-1-aminopropan-2-ol in Step-1.

(240) .sup.1HNMR: (400 MHz, CDCl.sub.3): δ (ppm): 10.58 (bs, 1H), 8.75 (s, 1H), 8.42 (m, 2H), 7.99 (m, 1H), 7.78 (s, 1H), 7.42 (d, 1H), 7.30 (m, 1H), 7.08 (t, 1H), 6.92 (bs, 1H), 4.08 (m, 1H), 3.70 (m, 1H), 3.32 (m, 1H), 1.88 (m, 1H), 1.30 (d, 3H), 1.18 (m, 2H), 0.75 (m, 2H).

Example 39. Preparation of Compound Nos. 39, 39a and 39b

Synthesis of 4-{[2-(3-chlorophenyl)-5-(prop-1-en-2-yl)pyridin-4-yl]amino}-N-[(2S)-2-hydroxypropyl]pyridine-3-carboxamide

(241) ##STR00242##

Step-1: Synthesis of 4-amino-N-[(2S)-2-hydroxypropyl]pyridine-3-carboxamide

(242) See Example 37.

Step-2: Synthesis of 4-chloro-2-(3-chlorophenyl)-5-isopropenyl-pyridine

(243) A 100 mL screw cap bottle was charged with 2,4-dichloro-5-isopropenyl-pyridine (1.5 g, 8.0 mmol), 2-fluorophenylboronic acid (837 mg, 6.0 mmol) and sodium carbonate (2.5 g, 24.0 mmol) in a mixture of DME (20 mL) and water (5 mL) and degassed with nitrogen for 15 min. Then Pd(PPh.sub.3).sub.2.Cl.sub.2 (280 mg, 0.40 mmol) and again degassed with nitrogen for another 10 min. The resulting mixture was heated at 100° C. for 3 h. The reaction was monitored by LCMS. Then the reaction mixture was passed through a celite bed, diluted with water (25 mL) and extracted with EtOAc (2×50 mL). The combined organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The crude product was passed through the CombiFlash® chromatography to afford 935 mg of product 4-chloro-2-(3-chlorophenyl)-5-isopropenyl-pyridine as a colorless thick liquid.

Step-3: Synthesis of 4-{[2-(3-chlorophenyl)-5-(prop-1-en-2-yl)pyridin-4-yl]amino}-N-[(2S)-2-hydroxypropyl]pyridine-3-carboxamide

(244) A 25 mL screw cap bottle was charged with 4-chloro-2-(3-chlorophenyl)-5-isopropenyl-pyridine (500 mg, 2.0 mmol) and 4-amino-N-[(2S)-2-hydroxypropyl]pyridine-3-carboxamide (433 mg, 2.2 mmol) and K.sub.3PO.sub.4 (849 mg, 4.0 mmol) and 1,4-dioxane (10 mL) and degassed with nitrogen for 15 min. Then xantphos (174 mg, 0.3 mmol) and Pd.sub.2(dba).sub.3 (183 mg, 0.2 mmol) were added and degassed with nitrogen for a further 15 min. The resulting mixture was heated at 100° C. overnight. The product formation was confirmed by LCMS. Then the reaction mixture was passed through a celite bed and extracted with EtOAc (2×50 mL) extracted with EtOAc (2×50 mL) and concentrated under reduced pressure to obtain the product, which was purified with reverse phase HPLC to obtain 52 mg of 4-[[2-(3-chlorophenyl)-5-isopropenyl-4-pyridyl]amino]-N-[(2S)-2-hydroxypropyl]pyridine-3-carboxamide as a white solid. The (R) enantiomer can be synthesized utilizing (R)-1-aminopropan-2-ol in Step-1.

(245) .sup.1HNMR: (400 MHz, CDCl.sub.3): δ (ppm): 10.58 (bs, 1H), 8.75 (s, 1H), 8.42 (m, 2H), 7.99 (m, 1H), 7.78 (s, 1H), 7.42 (d, 1H), 7.30 (m, 1H), 7.08 (t, 1H), 6.92 (bs, 1H), 4.08 (m, 1H), 3.70 (m, 1H), 3.32 (m, 1H), 1.88 (m, 1H), 1.30 (d, 3H), 1.18 (m, 2H), 0.75 (m, 2H).

Example 40. Preparation of Compound Nos. 40, 40a and 40b

Synthesis of N-[(2S)-2-hydroxypropyl]-4-{[5-(prop-1-en-2-yl)-2-[3-(trifluoromethyl)phenyl]pyridin-4-yl]amino}pyridine-3-carboxamide

(246) ##STR00243##

Step-1: Synthesis of 4-amino-N-[(2S)-2-hydroxypropyl]pyridine-3-carboxamide

(247) See Example 37.

Step-2: Synthesis of 4-chloro-5-isopropenyl-2-[3-(trifluoromethyl)phenyl]pyridine

(248) A 100 mL screw cap bottle was charged with 2,4-dichloro-5-isopropenyl-pyridine (800 mg, 4.26 mmol), [3-(trifluoromethyl)phenyl]boronic acid (606 mg, 3.19 mmol) and sodium carbonate (1.3 g, 12.8 mmol) in a mixture of DME (5 mL) and water (2.5 mL) and degassed with nitrogen for 15 min. Then Pd(PPh.sub.3).sub.2.Cl.sub.2 (147 mg, 0.21 mmol) and again degassed with nitrogen for another 10 min. The resulting mixture was heated at 100° C. for 3 h. The reaction was monitored by LCMS. Then the reaction mixture was passed through a celite bed, diluted with water (25 mL) and extracted with EtOAc (2×50 mL). The combined organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure to obtain the product, which was purified by chromatography to obtain the product (250 mg) as an oil.

Step-3: Synthesis of N-[(2S)-2-hydroxypropyl]-4-{[5-(prop-1-en-2-yl)-2-[3-(trifluoromethyl)phenyl]pyridin-4-yl]amino}pyridine-3-carboxamide

(249) A 25 mL screw cap bottle was charged with 4-chloro-5-isopropenyl-2-[3-(trifluoro methyl)phenyl]pyridine (250 mg, 0.84 mmol) and 4-amino-N-[(2S)-2-hydroxypropyl]pyridine-3-carboxamide (180 mg, 0.92 mmol) and K.sub.3PO.sub.4 (356 mg, 1.7 mmol) and 1,4-dioxane (10 mL) and degassed with nitrogen for 15 min. Then xantphos (73 mg, 0.13 mmol) and Pd.sub.2(dba).sub.3 (77 mg, 0.08 mmol) were added and degassed with nitrogen for a further 15 min. The resulting mixture was heated at 100° C. overnight. The product formation was confirmed by LCMS. Then the reaction mixture was passed through a celite bed and extracted with EtOAc (2×50 mL) and concentrated under reduced pressure to obtain the product that was purified with reverse phase HPLC to obtain the product 4-[[2-(3-chlorophenyl)-5-isopropenyl-4-pyridyl]amino]-N-[(2S)-2-hydroxypropyl]pyridine-3-carboxamide as a white solid (40 mg). The (R) enantiomer can be synthesized utilizing (R)-1-aminopropan-2-ol in Step-1.

(250) .sup.1HNMR: (400 MHz, DMSO-d6): δ (ppm): 10.47 (bs, 1H), 8.86 (s, 1H), 8.48 (m, 2H), 8.4-8.3 (m, 2H), 8.0 (s, 1H), 7.79 (d, 1H), 7.74-7.720 (m, 1H), 7.44 (d, 1H), 5.44 (s, 1H), 5.18 (s, 1H) 4.78 (d, 1H), 3.80 (m, 1H), 3.32 (m, 1H), 2.06 (s, 3H), 1.07 (d, 3H).

Example 41. Preparation of Compound No. 41

Synthesis of N-[2-(5-chloro-2-fluorophenyl)-5-(prop-1-en-2-yl)pyridin-4-yl]quinolin-4-amine

(251) ##STR00244##

(252) Quinolin-4-amine (500 mg, 3.47 mmol) and 4-chloro-2-(5-chloro-2-fluoro-phenyl)-5-isopropenyl-pyridine (1.1 g, 3.82 mmol) were dissolved in 5 mL dioxane. N.sub.2 gas was purged for 10 min. Palladium acetate (78 mg, 0.347 mmol), xantphos (200 mg, 0.347 mmol), K.sub.3PO.sub.4 (2.2 g, 10.41 mmol) were added. Again N.sub.2 gas was purged for 10 min. The reaction was irradiated at 180° C. temperature for 30 min. The progress of reaction was monitored by LCMS. After completion of reaction, the solvent was removed under reduced pressure. The residue was diluted with 30 mL of water and extracted with DCM (3×50 mL). The combined organic layer was washed with water (2×20 mL), dried over anhydrous sodium sulfate and concentrated under reduced pressure. The crude product was purified by reverse phase HPLC to obtain 150 mg of the free base of N-[2-(5-chloro-2-fluoro-phenyl)-5-isopropenyl-4-pyridyl]quinolin-4-amine.

(253) .sup.1HNMR: (Free Base, CD.sub.3OD): δ (ppm): 8.50 (m, 2H), 8.20 (d, 1H), 7.95 (d, 1H), 7.90 (d, 1H), 7.80 (t, 1H), 7.60 (m, 2H), 7.42 (m, 1H), 7.20 (m, 1H), 6.95 (bs, 1H), 5.30 (s, 2H), 2.05 (s, 3H).

Example 42. Preparation of Compound No. 42

Synthesis of N-[2-(5-chloro-2-fluorophenyl)-5-(prop-1-en-2-yl)pyridin-4-yl]quinolin-5-amine

(254) ##STR00245##

(255) Quinolin-5-amine (300 mg, 2.10 mmol) and 4-chloro-2-(5-chloro-2-fluoro-phenyl)-5-isopropenyl-pyridine (644 mg, 2.30 mmol) were dissolved in 5 mL of dioxane. N.sub.2 gas was purged for 10 min. Palladium acetate (47 mg, 0.21 mmol), xantphos (127 mg, 0.21 mmol), K.sub.3PO.sub.4 (1.34 g, 6.30 mmol) were added. Again N.sub.2 gas was purged for 10 min. The reaction was irradiated at 180° C. temperature for 30 min. Progress of reaction was monitored by LCMS. After completion of reaction, solvent was removed under reduced pressure. The residue was diluted with 30 mL of water and extracted with DCM (3×50 mL). The combined organic layer was washed with water (2×20 mL), dried over anhydrous sodium sulfate and concentrated under reduce pressure. The crude product was purified by reverse phase HPLC to obtain 25 mg free base of N-[2-(5-chloro-2-fluoro-phenyl)-5-isopropenyl-4-pyridyl]quinolin-5-amine.

(256) .sup.1HNMR: (Free Base, CD.sub.3OD): δ (ppm): 8.95 (s, 1H), 8.30 (m, 3H), 7.90 (m, 2H), 7.75 (t, 1H), 7.55 (m, 1H), 7.42 (m, 2H), 7.20 (t, 1H), 6.80 (s, 1H), 5.40 (s, 1H), 5.30 (s, 1H), 2.15 (s, 3H).

Example 43. Preparation of Compound Nos. 43, 43a and 43b

Synthesis of 4-{[2-(5-chloro-2-fluorophenyl)-5-(propan-2-yl)pyridin-4-yl]amino}-N-[(2S)-1-hydroxybutan-2-yl]pyridine-3-carboxamide

(257) ##STR00246##

Step-1: Synthesis of methyl 2-[[2-(5-chloro-2-fluoro-phenyl)-5-isopropenyl-4-pyridyl]amino]pyridine-3-carboxylate

(258) A 250 mL screw cap bottle was charged 4-chloro-2-(5-chloro-2-fluoro-phenyl)-5-isopropenyl-pyridine (5 g, 17.7 mmol), methyl 2-aminopyridine-3-carboxylate (4.0 g, 26.5 mmol), potassium phosphate tribasic (11.2 g, 53.1 mmol) and 1,4-dioxane (60 mL). The resultant mixture was degassed with nitrogen for 15 min. To it was added Pd.sub.2dba.sub.3(811 mg, 0.88 mmol) and xantphos (1.02 g, 1.77 mmol) and again degassed with nitrogen for 15 min. The reaction mass was heated at 100° C. for 12 h. The reaction was monitored by LCMS. The reaction mass was cooled to RT, diluted with DCM (20 mL) filtered through a small celite bed and concentrated under reduced pressure to obtain the product, which was purified by chromatography (eluent: 30% EtOAc in hexane) to obtain the pure methyl 2-[[2-(5-chloro-2-fluoro-phenyl)-5-isopropenyl-4-pyridyl]amino]pyridine-3-carboxylate (2.1 g).

Step-2: Synthesis of 2-[[2-(5-chloro-2-fluoro-phenyl)-5-isopropenyl-4-pyridyl]amino]-N-[(1S)-1-(hydroxymethyl)propyl]pyridine-3-carboxamide

(259) A heterogeneous mixture of methyl 2-[[2-(5-chloro-2-fluoro-phenyl)-5-isopropenyl-4-pyridyl]amino]pyridine-3-carboxylate (1 g, 2.5 mmol) and (S)-2-aminobutan-1-ol was irradiated by microwave at 120° C. for 1 h. The reaction mass became a homogenous solution. The reaction was monitored by LCMS and TLC. The reaction mass was purified by chromatography using combi flash (eluent: 5% methanol in DCM) to obtain 2-[[2-(5-chloro-2-fluoro-phenyl)-5-isopropenyl-4-pyridyl]amino]-N-[(1S)-1-(hydroxymethyl) propyl]pyridine-3-carboxamide (500 mg).

Step-3: Synthesis of 4-{[2-(5-chloro-2-fluorophenyl)-5-(propan-2-yl)pyridin-4-yl]amino}-N-[(2S)-1-hydroxybutan-2-yl]pyridine-3-carboxamide

(260) To a solution of 2-[[2-(5-chloro-2-fluoro-phenyl)-5-isopropenyl-4-pyridyl]amino]-N-[1-(hydroxymethyl)propyl]pyridine-3-carboxamide (500 mg, 1.09 mmol) in EtOAc (10 mL) and ethanol (5 mL) was added platinum oxide (90 mg 0.3 mmol) and bubbled with hydrogen gas for 3 h at RT. The reaction was monitored by .sup.1H NMR and TLC. The reaction mass was filtered through a celite bed and concentrated under reduced pressure to obtain the product, which was purified by chromatography two times (eluent: 3% methanol in DCM) to obtain pure 4-{[2-(5-chloro-2-fluorophenyl)-5-(propan-2-yl)pyridin-4-yl]amino}-N-[(2S)-1-hydroxybutan-2-yl]pyridine-3-carboxamide (50 mg). This compound was converted to the HCl salt (46 mg). The (R) enantiomer can be synthesized utilizing (R)-2-aminobutan-1-ol in Step-2.

(261) .sup.1HNMR: (400 MHz, DMSO-d6): δ (ppm): 11.5 (bs, 1H), 9.0 (s, 1H), 8.9 (d, 1H), 8.8 (s 1H,) 8.38 (d, 1H), 8.0 (d, 1H), 7.78 (s, 1H), 7.76 (m, 1H), 7.42 (t, 1H), 7.24 (d, 1H), 3.90 (m, 1H), 3.32 (m, 1H), 1.7 (m, 1H), 1.5 (m, 1H), 1.30 (d, 6H), 0.9 (t, 3H).

Example 44. Preparation of Compound Nos. 44, 44a and 44b

Synthesis of 4-{[2-(5-chloro-2-fluorophenyl)-5-(trifluoromethyl)pyridin-4-yl]amino}-N-[(2S)-2-hydroxypropyl]pyridine-3-carboxamide

(262) ##STR00247##

Step-1: Synthesis of 4-chloro-2-(5-chloro-2-fluoro-phenyl)-5-(trifluoromethyl)pyridine

(263) A two neck round bottom flask (100 mL) was charged with 2,4-dichloro-5-(trifluoromethyl)pyridine (2.16 g, 10 mmol), (5-chloro-2-fluoro-phenyl)boronic acid (1.04 g, 6.0 mmol), sodium carbonate (3.18 g, 30 mmol), 1,2-dimethoxy ethane (20 mL) and water (4 mL) degassed with nitrogen for 15 min. To it was added bis(triphenylphosphine)palladium(II) dichloride (140 mg, 0.2 mmol) again degassed with nitrogen for 10 min. The reaction mass was heated at 90° C. for 90 min. The reaction was monitored by LCMS. The reaction mass was cooled to RT, filtered through a small bed of celite, and diluted with EtOAc (50 mL) and water (50 mL). The layers were separated, aqueous layer was again extracted with EtOAc (50 mL), the combined organics were dried over sodium sulfate and concentrated under reduced pressure to obtain the product, which was purified by chromatography (eluent: hexane) to obtain 1.2 g pure 4-chloro-2-(5-chloro-2-fluoro-phenyl)-5-(trifluoromethyl)pyridine.

Step-2: Synthesis of 4-{[2-(5-chloro-2-fluorophenyl)-5-(trifluoromethyl)pyridin-4-yl]amino}-N-[(2S)-2-hydroxypropyl]pyridine-3-carboxamide

(264) A 25 mL screw cap bottle was charged with 4-chloro-2-(5-chloro-2-fluoro-phenyl)-5-(trifluoromethyl)pyridine (500 mg, 1.60 mmol), (S)-2-amino-N-(2-hydroxypropyl)benzamide (469 mg, 2.4 mmol), potassium phosphate tribasic (1.02 g, 4.89 mmol) and 1,4-dioxane (20 mL). The resultant mixture was degassed with nitrogen for 15 min. To it was added Pd.sub.2dba.sub.3 (74 mg, 0.08 mmol) and xantphos (93 mg, 0.160 mmol) and again degassed with nitrogen for 15 min. The reaction mass was heated at 100° C. for 12 h. The reaction was monitored by LCMS. The reaction mass was cooled to room temperature, diluted with DCM (20 mL), filtered through a small celite bed and concentrated under reduced pressure to obtain the product, which was purified by chromatography and with reverse phase HPLC to obtain the pure 4-{[2-(5-chloro-2-fluorophenyl)-5-(trifluoromethyl)pyridin-4-yl]amino}-N-[(2S)-2-hydroxypropyl]pyridine-3-carboxamide (50 mg). The (R) enantiomer can be synthesized utilizing the (R)-2-amino-N-(2-hydroxypropyl)benzamide in this step.

(265) .sup.1HNMR: (400 MHz, CD.sub.3OD): δ (ppm): 8.86-8.84 (d, 1H), 8.4 (d, 1H), 8.0 (s, 2H), 7.56 (d, 1H), 7.50 (bs, 1H), 7.28 (t, 1H), 3.98 (m, 1H), 3.43-3.41 (m, 2H), 1.25 (d, 3H).

Example 45. Preparation of Compound Nos. 45

Synthesis of 4-{[2-(5-chloro-2-fluorophenyl)-5-(prop-1-en-2-yl)pyridin-4-yl]amino}-N-(oxetan-3-yl)pyridine-3-carboxamide

(266) ##STR00248##

(267) A heterogeneous mixture of methyl 2-[[2-(5-chloro-2-fluoro-phenyl)-5-isopropenyl-4-pyridyl]amino]pyridine-3-carboxylate (500 mg, 1.25 mmol) and 3-oxetane amine (1 mL) was irradiated by microwave at 120° C. for 1 h. The reaction mass became a homogenous solution. The reaction was monitored by LCMS and TLC. The reaction mass was purified by chromatography using combi flash (eluent: 5% methanol in DCM) to obtain the product, which was triturated with EtOAc to obtain pure 4-{[2-(5-chloro-2-fluorophenyl)-5-(prop-1-en-2-yl)pyridin-4-yl]amino}-N-(oxetan-3-yl)pyridine-3-carboxamide (35 mg).

(268) .sup.1HNMR: (400 MHz, DMSO-d6): δ (ppm): 10.3 (s, 1H), 9.47 (d, 1H), 8.9 (s, 1H), 8.46 (s, 1H), 8.41 (d, 1H), 8.0 (d, 1H,) 7.8 (s, 1H), 7.55 (m, 1H), 7.40 (m, 2H), 5.46 (s, 1H), 5.19 (s, 1H), 5.0 (m, 1H), 4.7 (m, 2H), 4.6 (m, 2H), 2.0 (s, 3H).

Example 46. Preparation of Compound Nos. 46, 46a and 46b

Synthesis of 4-{[2-(5-chloro-2-fluorophenyl)-5-(prop-1-en-2-yl)pyridin-4-yl]amino}-N-(oxolan-3-yl)pyridine-3-carboxamide

(269) ##STR00249##

(270) A heterogeneous mixture of methyl 2-[[2-(5-chloro-2-fluoro-phenyl)-5-isopropenyl-4-pyridyl]amino]pyridine-3-carboxylate (250 mg, 0.62 mmol) and tetrahydrofuran-3-amine) was irradiated by microwave at 120° C. for 1 h. The reaction mass became a homogenous solution. The reaction was monitored by LCMS and TLC. The reaction mass was purified by chromatography using combi flash (eluent: 5% methanol in DCM) to obtain product, which was triturated with EtOAc to obtain pure 4-{[2-(5-chloro-2-fluorophenyl)-5-(prop-1-en-2-yl)pyridin-4-yl]amino}-N-(oxolan-3-yl)pyridine-3-carboxamide (17 mg) as a racemate. Chiral HPLC will resolve the enantiomers into the individual (R) and (S) forms.

(271) .sup.1HNMR: (400 MHz, DMSO-d6): δ (ppm): 10.3 (s, 1H), 8.96 (d, 1H), 8.79 (s, 1H), 8.44 (s, 1H), 8.40 (d, 1H), 8.0 (d, 1H,) 7.8 (s, 1H), 7.5 (m, 1H), 7.4 (m, 2H), 5.48 (s, 1H), 5.2 (s, 1H), 4.46 (bs, 1H), 3.86-3.84 (m, 2H), 3.7 (m, 1H), 3.6 (m, 1H), 2.1 (m, 1H), 2.0 (s, 3H), 1.9 (m, 1H).

Example 47. Preparation of Compound Nos. 47, 47a and 47b

Synthesis of 4-({2-[2-fluoro-5-(trifluoromethoxy)phenyl]-5-(prop-1-en-2-yl)pyridin-4-yl}amino)-N-[(2S)-2-hydroxypropyl]pyridine-3-carboxamide

(272) ##STR00250##

Step-1: Synthesis of 4-chloro-2-[2-fluoro-5-(trifluoromethoxy)phenyl]-5-isopropenyl-pyridine

(273) A 100 mL screw cap bottle was charged with 2,4-dichloro-5-isopropenyl-pyridine (800 mg, 4.26 mmol [4-fluoro-3-(trifluoromethoxy)phenyl]boronic acid (606 mg, 3.1 mmol) and sodium carbonate (1.3 g, 12.8 mmol) in a mixture of DME (5 mL) and water (2.5 mL) and degassed with nitrogen for 15 min. Then Pd(PPh.sub.3).sub.2.Cl.sub.2 (147 mg, 0.21 mmol) and again degassed with nitrogen for another 10 min. The resulting mixture was heated at 100° C. for 3 h. The reaction was monitored by LCMS. Then the reaction mixture was passed through a celite bed, diluted with water (25 mL) and extracted with EtOAc (2×50 mL). The combined organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure to obtain the product, which was purified by chromatography to obtain 4-chloro-2-[2-fluoro-5-(trifluoromethoxy)phenyl]-5-isopropenyl-pyridine (250 mg) as an oil.

Step-2: Synthesis of 4-({2-[2-fluoro-5-(trifluoromethoxy)phenyl]-5-(prop-1-en-2-yl)pyridin-4-yl}amino)-N-[(2S)-2-hydroxypropyl]pyridine-3-carboxamide

(274) A 25 mL screw cap bottle was charged with 4-chloro-2-[2-fluoro-5-(trifluoro methoxy)phenyl]-5-isopropenyl-pyridine (250 mg, 0.84 mmol), 4-amino-N-[(2S)-2-hydroxypropyl]pyridine-3-carboxamide (180 mg, 0.92 mmol), K.sub.3PO.sub.4 (356 mg, 1.7 mmol) and 1,4-dioxane (10 mL) and degassed with nitrogen for 15 min. Then Xantphos (73 mg, 0.13 mmol) and Pd.sub.2(dba).sub.3 (77 mg, 0.08 mmol) were added and the mixture degassed with nitrogen for 15 min. The resulting mixture was heated at 100° C. overnight. Product formation was confirmed by LCMS. The reaction mixture was passed through a celite bed and extracted with EtOAc (2×50 mL) and concentrated under reduced pressure to obtain the product that was purified with reverse phase HPLC to obtain 4-({2-[2-fluoro-5-(trifluoromethoxy)phenyl]-5-(prop-1-en-2-yl)pyridin-4-yl}amino)-N-[(2S)-2-hydroxypropyl]pyridine-3-carboxamide as a free base (15 mg). The (R) enantiomer can be synthesized utilizing (R)-2-aminobutan-1-ol in this step.

(275) .sup.1H NMR: (400 MHz, DMSO-D6): δ (ppm): 10.42 (bs, 1H), 8.86 (m, 2H), 8.5 (s, 1H), 8.4 (d, 2H), 8.0 (d, 1H), 7.90 (s, 1H), 7.58 (m, 2H), 7.40 (d, 1H), 5.44 (s, 1H), 5.20 (s, 1H) 4.78 (d, 1H), 3.80 (m, 1H), 3.18 (m, 1H), 2.06 (s, 3H), 1.07 (d, 3H).

Example 48. Preparation of Compound No. 48

Synthesis of 4-{[2-(5-chloro-2-fluorophenyl)-5-(propan-2-yl)pyridin-4-yl]amino}-N-(oxetan-3-yl)pyridine-3-carboxamide

(276) ##STR00251##

Step-1: Synthesis of methyl 4-[[2-(5-chloro-2-fluoro-phenyl)-5-isopropyl-4-pyridyl]amino]pyridine-3-carboxylate

(277) To a solution of methyl 4-[[2-(5-chloro-2-fluoro-phenyl)-5-isopropenyl-4-pyridyl]amino]pyridine-3-carboxylate (398 mg, 1.0 mmol) in EtOAc (10 mL) and ethanol (5 mL) was added platinum oxide (60 mg, 0.2 mmol) and bubbled with hydrogen gas for 3 h at RT. The reaction was monitored by .sup.1H NMR and TLC. The reaction mass was filtered through a celite bed and concentrated under reduced pressure to obtain the product, which was purified by chromatography (5% MeOH in DCM) to obtain methyl 4-[[2-(5-chloro-2-fluoro-phenyl)-5-isopropyl-4-pyridyl]amino]pyridine-3-carboxylate (180 mg).

Step-2: Synthesis of 4-{[2-(5-chloro-2-fluorophenyl)-5-(propan-2-yl)pyridin-4-yl]amino}-N-(oxetan-3-yl)pyridine-3-carboxamide

(278) A heterogeneous mixture of methyl 4-[[2-(5-chloro-2-fluoro-phenyl)-5-isopropyl-4-pyridyl]amino]pyridine-3-carboxylate (180 mg, 0.45 mmol) and 3-oxitane amine (1 mL) was irradiated by microwave at 120° C. for 1 h. The reaction mass became a homogenous solution. The reaction was monitored by LCMS and TLC. The reaction mass purified by chromatography (eluent: 5% MeOH in DCM) to obtain the product, which was triturated with EtOAc to obtain 4-{[2-(5-chloro-2-fluorophenyl)-5-(propan-2-yl)pyridin-4-yl]amino}-N-(oxetan-3-yl)pyridine-3-carboxamide (10 mg).

(279) .sup.1H NMR: (400 MHz, DMSO-D6): δ (ppm): 10.5 (s, 1H), 9.47 (d, 1H), 8.9 (s, 1H), 8.62 (s, 1H), 8.38 (d, 1H), 8.0 (d, 1H,) 7.8 (s, 1H), 7.55 (m, 1H), 7.40 (m, 2H), 7.30 (d, 1H), 5.0 (m, 1H), 4.8 (t, 2H), 4.60 (t, 2H), 3.10 (m, 1H), 1.24 (d, 6H).

Example 49. Preparation of Compound No. 49

Synthesis of N-[2-(5-chloro-2-fluorophenyl)-5-(propan-2-yl)pyridin-4-yl]quinolin-4-amine

(280) ##STR00252##

(281) N-[2-(5-Chloro-2-fluoro-phenyl)-5-isopropenyl-4-pyridyl]quinolin-4-amine (100 mg, 0.257 mmol) was dissolved in EtOAc:EtOH (10 mL), and purged with N.sub.2 gas for 10 min. PtO.sub.2 (20 mg) was added, and the mixture now purged with H.sub.2 gas for 10 min. The reaction was stirred at RT for 5 h. The progress of reaction was monitored by LCMS. After completion of reaction, the PtO.sub.2 was removed by filtration, and the solvent removed under reduced pressure. The residue was purified by flash chromatography using MeOH:DCM to obtain 70 mg free base of N-[2-(5-chloro-2-fluoro-phenyl)-5-isopropyl-4-pyridyl]quinolin-4-amine.

(282) .sup.1H NMR: (Free Base, CD.sub.3OD): δ (ppm): 8.65 (m, 1H), 8.50 (s, 1H), 8.25 (d, 1H), 7.95 (m, 1H), 7.85 (d, 1H), 7.75 (t, 1H), 7.60 (t, 1H), 7.50 (s, 1H), 7.40 (m, 1H), 7.20 (t, 1H), 6.80 (s, 1H), 3.45 (m, 1H), 1.19 (m, 6H).

Example 50. Preparation of Compound No. 50

Synthesis of 2-N-[2-(5-chloro-2-fluorophenyl)-5-(prop-1-en-2-yl)pyridin-4-yl]-2-N-methyl pyridine-2,4-diamine

(283) ##STR00253##

(284) Nitrogen gas was purged in a mixture of 4-chloro-2-(5-chloro-2-fluoro-phenyl)-5-isopropenyl-pyridine (300 mg, 1.06 mmol), N-2-methylpyridine-2,4-diamine (157 mg, 1.27 mmol) and potassium phosphate (tribasic) (449 mg, 2.12 mmol) in 1,4-dioxane (15 mL) for 15 min. Then tris(dibenzylidineacetone) dipalladium(O) (97 mg, 0.12 mmol) and Xantphos (92 mg, 0.16 mmol) were added to the reaction mixture. Nitrogen gas was purged through it for another 5 min. The reaction mixture was irradiated by microwave at 180° C. for 1 h. The reaction was monitored by TLC and LCMS. After completion of reaction, the mixture was diluted with EtOAc (100 mL) and filtered through a celite bed. The filtrate was washed with water (25 mL), and the organic layer was separated, dried over anhydrous sodium sulfate and concentrated under reduced pressure to afford a crude product which was purified by reverse phase purification to get N-2-[2-(5-chloro-2-fluoro-phenyl)-5-isopropenyl-4-pyridyl]-N-2-methyl-pyridine-2,4-diamine (Peak 1) as a semi-solid (26 mg) and N4-[2-(5-chloro-2-fluoro-phenyl)-5-isopropenyl-4-pyridyl]-N2-methyl-pyridine-2,4-diamine (Peak 2) (44 mg) as a white solid.

(285) .sup.1H NMR: (400 MHz, DMSO-d6): δ (ppm): 8.59 (s, 1H), 7.99 (s, 1H), 7.62 (m, 2H), 7.59 (s, 1H), 7.38 (m, 1H), 6.00 (d, 1H), 5.70 (m, 3H), 5.15 (m, 2H), 3.23 (s, 3H), 1.90 (s, 3H).

Example 51. Preparation of Compound Nos. 51, 51a and 51b

Synthesis of 4-{[2-(2,5-difluorophenyl)-5-(prop-1-en-2-yl)pyridin-4-yl]amino}-N-[(2S)-2-hydroxypropyl]pyridine-3-carboxamide

(286) ##STR00254##

Step-1: Synthesis of 2-(2,5-difluorophenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane

(287) A 250 mL screw cap bottle was charged with 2-bromo-1,4-difluoro-benzene (1.0 g, 5.18 mmol), bis(pinacolato)diboroncarbonate and potassium acetate (1.52 g, 15.54 mmol) in 1,4-dioxane (20 mL) and degassed with nitrogen for 20 min. Then Pd(dppf)Cl.sub.2.DCM (634 mg, 0.77 mmol) was added, and the mixture again degassed with nitrogen for another 10 min. The resulting mixture was heated at 100° C. overnight. The reaction was monitored by TLC and LCMS. The reaction mixture was passed through a celite bed, diluted with water (100 mL) and extracted with EtOAc (3×50 mL) and washed with water (2×50 mL). The combined organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure to obtain the product, which was purified by chromatography to obtain 2-(2,5-difluorophenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (500 mg) as a semisolid.

Step-2: Synthesis of 4-chloro-2-(2,5-difluorophenyl)-5-isopropenyl-pyridine

(288) A 100 mL screw cap bottle was charged with 2,4-dichloro-5-isopropenyl-pyridine (1.5 g, 7.97 mmol) and to is was added 2-(2,5-difluorophenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (2.29 mg, 9.57 mmol) and sodium carbonate (2.53 g, 23.91 mmol) in a mixture of DME (15 mL) and water (7 mL), and the mixture degassed with nitrogen for 20 min. Then Pd(PPh.sub.3).sub.2.Cl.sub.2 (279 mg, 0.398 mmol) was added and the mixture again degassed with nitrogen for another 10 min. The resulting mixture was heated at 100° C. for 3 h. The reaction was monitored by TLC and LCMS. Then the reaction mixture was passed through a celite bed, diluted with water (50 mL) and extracted with EtOAc (4×150 mL). The combined organic layer was washed with water (2×150 mL), dried over anhydrous sodium sulfate and concentrated under reduced pressure to obtain the product, which was purified with combiflash chromatography to obtain 4-chloro-2-(2,5-difluoro phenyl)-5-isopropenyl-pyridine (1.0 g) as a semi solid.

Step-3: Synthesis of 4-{[2-(2,5-difluorophenyl)-5-(prop-1-en-2-yl)pyridin-4-yl]amino}-N-[(2S)-2-hydroxypropyl]pyridine-3-carboxamide

(289) A 30 mL microwave vial was charged with 4-chloro-2-(2,5-difluorophenyl)-5-isopropenyl-pyridine (500 mg, 1.886 mmol), 4-amino-N-[(2S)-2-hydroxypropyl]pyridine-3-carboxamide (400 mg, 2.07 mmol), K.sub.3PO.sub.4 (797 mg, 3.76 mmol) and 1,4-dioxane (10 mL) and the mixture degassed with nitrogen for 20 min. Then Xantphos (163 mg, 0.28 mmol) and Pd.sub.2(dba).sub.3 (172 mg, 0.188 mmol) were added and degassed with nitrogen for a further 10 min. The resulting mixture was heated at 140° C. in a microwave. Product formation was confirmed by TLC and LCMS. The reaction mixture was passed through a celite bed, diluted with water (50 mL), extracted with EtOAc (2×100 mL) and washed with water (2×50 mL). The organic layer was dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain the product that was purified by reverse phase HPLC to obtain 4-{[2-(2,5-difluorophenyl)-5-(prop-1-en-2-yl)pyridin-4-yl]amino}-N-[(2S)-2-hydroxypropyl]pyridine-3-carboxamide as the free base (70 mg). The (R) enantiomer can be synthesized utilizing the (R)-enantiomeric reagent in this step.

(290) .sup.1H NMR: (400 MHz, DMSO-D6): δ (ppm): 10.45 (bs, 1H), 8.82 (m, 2H), 8.45 (s, 1H), 8.39 (d, 1H), 7.82 (s, 1H), 7.78 (bs, 1H), 7.42 (m, 2H), 7.39 (m, 1H), 5.43 (s, 1H), 5.20 (s, 1H), 4.78 (d, 1H), 3.78 (m, 1H), 3.19 (m, 2H), 2.06 (s, 3H), 1.12 (d, 3H).

Example 52. Preparation of Compound Nos. 52, 52a and 52b

Synthesis of 4-{[2-(2,5-difluorophenyl)-5-(propan-2-yl)pyridin-4-yl]amino}-N-[(2S)-2-hydroxypropyl]pyridine-3-carboxamide

(291) ##STR00255##

(292) To a solution of 4-[[2-(2,5-difluorophenyl)-5-isopropenyl-4-pyridyl]amino]-N-[(2S)-2-hydroxypropyl]pyridine-3-carboxamide (50 mg, 0.117 mmol) in EtOAc (5 mL) and ethanol (5 mL) was added platinum oxide (20 mg, 0.2 mmol) and bubbled with hydrogen gas for 4 h at RT. The reaction was monitored by .sup.1H NMR and TLC. The reaction mass was filtered through a celite bed and concentrated under reduced pressure to obtain the product, which was purified by chromatography (5% MeOH in DCM) to obtain 4-[[2-(2,5-difluorophenyl)-5-isopropyl-4-pyridyl]amino]-N-[(2S)-2-hydroxy propyl]pyridine-3-carboxamide (20 mg). The (R) enantiomer can be synthesized utilizing (R)-2-aminobutan-1-ol in this step.

(293) .sup.1H NMR: (400 MHz, CDCl.sub.3): δ (ppm): 10.39 (s, 1H), 8.70 (s, 1H), 8.62 (s, 1H), 8.39 (d, 1H), 7.79 (m, 2H), 7.28 (d, 1H,) 7.15 (m, 2H), 6.98 (bs, 11H), 4.15 (m, 1H), 3.71 (m, 1H), 3.31 (m, 1H), 3.21 (m, 1H), 1.40 (d, 6H), 1.21 (d, 3H).

Example 53. Preparation of Compound Nos. 53, 53a and 53b

Synthesis of 4-({2-[2-fluoro-5-(trifluoromethyl)phenyl]-5-(prop-1-en-2-yl)pyridin-4-yl}amino)-N-[(2S)-2-hydroxypropyl]pyridine-3-carboxamide

(294) ##STR00256##

Step-1: Synthesis of 4-chloro-2-[2-fluoro-5-(trifluoromethyl)phenyl]-5-isopropenyl-pyridine

(295) A 100 mL screw cap bottle was charged with 2,4-dichloro-5-isopropenyl-pyridine (1.0 g, 5.31 mmol), [2-fluoro-5-(trifluoromethyl)phenyl]boronic acid (1.65 g, 7.97 mmol) and sodium carbonate (1.68 g, 15.93 mmol) in a mixture of DME (10 mL) and water (5 mL), and the mixture degassed with nitrogen for 20 min. Then Pd(PPh.sub.3).sub.2.Cl.sub.2 (186 mg, 0.265 mmol) and again degassed with nitrogen for another 10 min. The resulting mixture was heated at 100° C. for 3 h. The reaction was monitored by TLC and LCMS. Then the reaction mixture was passed through a celite bed, diluted with water (50 mL) and extracted with EtOAc (3×100 mL). The combined organic layer was washed with water (2×150 mL) dried over anhydrous sodium sulfate and concentrated under reduced pressure to obtain the product that was purified by chromatography to obtain 4-chloro-2-[2-fluoro-5-(trifluoromethyl)phenyl]-5-isopropenyl-pyridine (500 mg) as a semi solid. Step-2: Synthesis of 4-({2-[2-fluoro-5-(trifluoromethyl)phenyl]-5-(prop-1-en-2-yl)pyridin-4-yl}amino)-N-[(2S)-2-hydroxypropyl]pyridine-3-carboxamide

(296) A 30 mL microwave vial was charged with 4-chloro-2-[2-fluoro-5-(trifluoromethyl) phenyl]-5-isopropenyl-pyridine (500 mg, 1.58 mmol) and 4-amino-N-[(2S)-2-hydroxy propyl]pyridine-3-carboxamide (340 mg, 1.74 mmol) and K.sub.3PO.sub.4 (669 mg, 3.16 mmol) and 1,4-dioxane (5 mL) and degassed with nitrogen for 20 min. Then Xantphos (137 mg, 0.237 mmol) and Pd.sub.2(dba).sub.3 (144 mg, 0.158 mmol) were added and degassed with nitrogen for a further 10 min. The resulting mixture was heated at 140° C. by microwave. Product formation was confirmed by TLC and LCMS. Then the reaction mixture was passed through a celite bed and diluted with water (50 mL), extracted with EtOAc (2×100 mL) and washed with water (2×50 mL). The organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure to obtain the product that was purified by HPLC to obtain 4-({2-[2-fluoro-5-(trifluoromethyl)phenyl]-5-(prop-1-en-2-yl)pyridin-4-yl}amino)-N-[(2S)-2-hydroxypropyl]pyridine-3-carboxamide as free base (30 mg). The (R) enantiomer can be synthesized utilizing (R)-2-aminobutan-1-ol in this step.

(297) .sup.1H NMR: (400 MHz, DMSO-D6): δ (ppm): 10.45 (bs, 1H), 8.82 (m, 2H), 8.45 (s, 1H), 8.39 (d, 1H), 8.32 (d, 1H), 7.82 (bs, 2H), 7.61 (t, 1H), 7.41 (d, 1H), 5.42 (s, 1H), 5.20 (s, 1H), 4.78 (d, 1H), 3.79 (m, 1H), 3.19 (m, 2H), 2.06 (s, 3H), 1.12 (d, 3H).

Example 54. Preparation of Compound No. 54

Synthesis of 4-{[2-(5-chloro-2-fluorophenyl)-5-cyclopropylpyridin-4-yl]amino}-N-(1,3-dihydroxypropan-2-yl)pyridine-3-carboxamide

(298) ##STR00257##

(299) Methyl 4-[[2-(5-chloro-2-fluoro-phenyl)-5-cyclopropyl-4-pyridyl]amino]pyridine-3-carboxylate (100 mg, 0.251 mmol) and 2-aminopropane-1,3-diol (92 mg, 1.00 mmol) were dissolved in 1 mL of DMSO and heated at 120° C. in a microwave for 1.5 h. Product formation was confirmed by LCMS. Then the reaction mixture was diluted with water (50 mL), and the resultant precipitate filtered and dried. This crude product was purified by chromatography to obtain 20 mg of 4-[[2-(5-chloro-2-fluoro-phenyl)-5-cyclopropyl-4-pyridyl]amino]-N-[2-hydroxy-1-(hydroxymethyl)ethyl]pyridine-3-carboxamide.

(300) .sup.1H NMR: (400 MHz, DMSO-d6): δ (ppm): 10.78 (bs, 1H), 8.85 (s, 1H), 8.48 (s, 1H), 8.40 (m, 2H), 7.98 (d, 1H), 7.80 (s, 1H), 7.55-7.42 (m, 2H), 7.40 (t, 1H), 4.70 (t, 2H), 4.00 (m, 1H), 3.58 (m, 4H), 1.80 (m, 1H), 1.05 (m, 2H), 0.75 (m, 2H).

Example P1. Preparation of Compound Nos. 2.1 to 2.35

(301) Compound nos. 2.1 to 2.35 can be prepared according to the methods presented herein using appropriately functionalized starting materials and reagents.

Example B1: p-SMAD2 Inhibition

(302) Compounds of the invention were screened for inhibition of p-SMAD2, using Western Blot Analysis, using the following protocol. On Day 1, MDA-MB-231 cells were seeded at 150,000 cells/well in a 12-well plate using DMEM plus antibiotics (Pen/Strepto) plus FBS 10%. On Day 2, the medium was changed to a serum-free version (DMEM plus Ab) and left overnight. On Day 3, the cells were treated with Compounds of the invention for 30 min (pre-treatment) at two concentrations of 0.1 μM and 0.5 μM (prepared with serum-free medium). Then, TGFβ was added to a final concentration of 2 ng/mL for 1.5 h.

(303) Western Blot Analysis: Lysis buffer plus proteases and phosphatise inhibitors were added to the cells (100 μL), then the cells were collected with a cell scraper and placed into an Eppendorf tube. The sample was sonicated for 3 min, then centrifuged for 15 min at 13,000 rpm at 4° C. The proteins were quantified with the BCA Protein Assay Kit (Pierce, #23225), and SDS-PAGE electrophoresis with 10% acrylamide gel was used to separate the samples (20 μg of protein loaded). The proteins were transferred in a PDVF membrane overnight at 50 mA and 4° C., then the membrane was blocked with 5% milk solution for 1 h. The primary antibody was added (p-SMAD2, cell signalling #3108; SMAD2, cell signalling #3103; or β-Actin, Sigma #A5441) at 4° C. overnight, or for 2 h at RT. The membrane was washed with TBS-TWEEN® (0.1%) three times over 10 min. The second antibody was added for 1 h at RT, and then the membrane washed again with TBS-TWEEN® (0.1%) for 10 min. Signal development was performed using an ECL Western Blotting Substrate (Pierce #32106), and the image acquired using the Gel Logic 6000 Pro. Quantification was performed using ImageJ software, and the average % inhibition was obtained and presented in Table B1.

(304) TABLE-US-00005 TABLE B1 Inhibition of p-SMAD (samples run in triplicate) Average p-SMAD2 Average p-SMAD2 Compound inhibition @ 0.1 inhibition @ 0.5 Number μM (% Inh) μM (% Inh) CE-1 15.67 17.00  1a 31.33 64.33  2a 26.33 77.67  3a 45.67 78.00  4a 72.67 99.67  5a 14.33 41.33  6a 53.67 98.33  7a 74.33 99.33  7b 36.33 78.67  8 58.67 94.33  9 6.00 12.67 10a 0 64.33 11a 44.67 96.00 12a 64.33 93.00 13a 59.00 93.67 14 45.00 92.33 15 80.33 97.33 16a 58.33 88.00 17a 25.33 81.67 18 31.33 82.67 19 74.67 93.00 20a 0 3.67 21a 4.67 7.67 22 50.00 93.67 23a 46.33 93.67 24a 17.00 68.33 25a 15.33 18.67 25b 14.33 12.67 26 64.00 89.00 27 29.33 81.33 28 2.33 51.33 29 58.00 67.67 30 59.67 70.33

Example B2: In Vitro Kinase Assay—Inhibition of ALK1/2/3/4/5/6 Kinases

(305) Compound of the invention were screened in an in vitro kinase assay against several members of the TGFβ3 family of Ser/Thr kinases. The kinases tested were ALK1 (ACVRL1), ALK2 (ACVR1), ALK3 (BMPR1A), ALK4 (ACVR1B), ALK5 (TGFBR1), and ALK6 (BMPR1B). Standard kinase testing conditions and techniques were employed. For each case, specific kinase/substrate pairs along with required cofactors were prepared in reaction buffer. Compound of the invention were delivered into the reaction, followed 15-20 min later by addition of a mixture of ATP and .sup.33P ATP to a final concentration of 10 μM. Reactions were carried out at RT for 120 min, followed by spotting of the reactions onto P81 ion exchange filter paper. Unbound phosphate was removed by extensive washing of filters in 0.75% phosphoric acid. Kinase activity data was expressed as the percent of remaining kinase activity in test samples compared to vehicle. IC.sub.50 values were generated from activity values performed at multiple concentrations, and the results are presented in Table B2.

(306) TABLE-US-00006 TABLE B2 In vitro Kinase Assay Inhibition Inhibition Inhibition Inhibition Inhibition Inhibition of ALK1 of ALK2 of ALK3 of ALK4 of ALK5 of ALK6 Compound (IC.sub.50 (IC.sub.50 (IC.sub.50 (IC.sub.50 (IC.sub.50 (IC.sub.50 Number μM) μM) μM) μM) μM) μM) CE-1 >100 >100 >100 >100 >100 >100  1a >100 >100 >100 93.2 0.25 >100  2a 10 >100 >100 0.0325 0.0204 >100  3a 8.41 >100 >100 0.0315 0.0452 >100  4a 3.44 10.6 >100 0.0424 0.0281 —  6a 5.01 10.4 >100 0.0086 0.0157 —  7a 6.57 10.9 >100 0.0130 0.0162 —  7b 16.50 >100 >100 0.1710 0.0539 >100  8 >100 >100 >100 0.5020 0.0992 — 11a 6.75 >100 >100 0.0868 0.0335 — 12a 1.53 9.97 >100 0.0304 0.0175 — 13a 9.12 >100 >100 0.0235 0.0715 — 14 5.85 >100 >100 0.0451 0.0239 — 15 4.59 11.4 15.4 0.0117 0.0155 — 16a 7.3 >1000 >1000 0.1140 0.0422 >1000 17a 4.67 >1000 >1000 0.0401 0.0508 >1000 18 6.92 >1000 >1000 0.1050 0.0345 >1000 19 2.13 >1000 >1000 0.0110 0.0068 >1000 20a >100 >1000 >1000 >1000 >100 >1000 21a >100 >1000 >1000 >1000 >100 >1000 22 7.29 >1000 >1000 0.0567 0.0247 >1000 23a 5.67 >100 >100 0.0331 0.0169 >100 24a >100 >100 >100 0.2300 0.0653 >100 25a >100 >100 >100 >100 2.8000 >100 25b >100 >100 >100 5.02 0.9880 >100 26 5.20 >100 >100 0.0115 0.0103 >100 27 13.10 >100 >100 0.0402 0.0281 >100 28 >100 >1000 >1000 1.1000 0.5510 >1000 29 8.20 60.60 >10 0.0105 0.0164 15.30 30 5.90 73.00 >10 0.0237 0.0264 13.50 31 >10 >10 >10 0.0048 0.0105 >10 32 2.54 5.84 3.33 0.0027 0.0061 >10 33 >10 >10 >10 0.0896 0.0788 >10 34 >10 >10 >10 0.1490 0.0773 >10 35 1.94 5.45 8.71 0.0037 0.0082 9.62 36 3.7 8.93 >10 0.0037 0.0177 >10

Example B3: Pharmacokinetics and Bioavailability for Compounds of the Invention

(307) The pharmacokinetics and bioavailability of compounds in male mice were determined after a single dose, administered either intravenously (2 mg/kg) or orally (10 mg/kg). Compounds were formulated at 1 mg/mL in 50% PEG-400 or 20% HPβCD. Parameters were generated using WinNonlin non-compartment analysis with no weighting, and are presented in Tables B3a and B3b.

(308) TABLE-US-00007 TABLE B3a Intravenous Administration, 2 mg/kg, n = 3 mice/timepoint. Compound C.sub.max AUC.sub.last Terminal t.sub.1/2 CL V No. (μM) (μM*h) (h) (L/h/kg) (L/kg)  2a 0.544 1.19 1.80 1.60 4.14  3a 0.602 2.56 3.86 0.77 1.29  8 1.24 0.709 1.68 6.15 14.9 11a 3.61 3.15 1.02 1.48 2.17 12a 2.15 3.69 1.63 1.19 2.80 13a 1.42 1.56 2.09 1.24 3.72 14 3.01 1.57 0.987 2.71 3.86 16a 3.40 4.41 0.655 1.02 0.967 19 0.52 1.19 6.12 2.39 21.1 22 2.46 3.77 1.53 1.10 2.43 23a 2.56 1.11 0.607 3.96 3.47 26 3.00 1.76 1.62 2.66 6.21

(309) TABLE-US-00008 TABLE B3b Oral Administration, 10 mg/kg Compound C.sub.max T.sub.max AUC.sub.last Terminal t.sub.1/2 No. (μM) (h) (μM*h) (h) Bioavailability  2a 1.57 0.5 5.25 2.57 .sup. 88%  3a 1.65 0.25 10.5 3.85 .sup. 82%  8 1.06 0.25 1.31 1.26 36.9% 11a 3.48 0.25 9.79 1.65 62.2% 12a 4.28 0.5 14.5 1.72 78.3% 13a 1.60 0.25 5.64 2.85 72.3% 14 1.88 0.5 2.54 1.60 32.5% 16a 3.42 0.5 7.50 2.36 34.1% 19 0.198 1 0.927 4.19 15.5% 22 7.07 0.5 16.2 2.09 86.6% 23a 0.612 0.25 0.907 0.822 16.4% 26 1.29 0.5 2.36 1.66 26.9%

(310) Plasma and brain concentrations of compounds at 0.5 and 1 h were also analyzed and are presented in Tables B3c and B3d.

(311) TABLE-US-00009 TABLE B3c Plasma and brain concentrations (ng/mL) Compound Time IV (2 mg/kg) PO (10 mg/kg) No. (h) Plasma Brain % Brain Plasma Brain % Brain 2a 0.5 310 73.2 24 1570 202 13 1 366 82.4 23 905 114 13 0.5 432 173 40 1280 305 24 3a 1 365 168 46 1250 406 32

(312) TABLE-US-00010 TABLE B3d Plasma and brain concentrations (μM). Brain Plasma Compound Time Concentration Concentration % of No. Route (h) (μM) μM) Plasma 16a IV 0.5 0.048 3.04 1.58% 1 0.019 1.23 1.52% PO 0.5 0.048 3.42 1.40% 1 0.025 1.69 1.50% 19 IV 0.5 0.004 0.280 1.49% 1 0.003 0.183 1.80% PO 0.5 BLQ 0.164 na 1 BLQ 0.198 na 22 IV 0.5 0.007 1.69 0.41% 1 0.005 0.967 0.48% PO 0.5 0.020 7.07 0.29% 1 0.015 3.53 0.43%

(313) It is understood that the foregoing examples and embodiments described above are for illustrative purposes only and that various modifications or changes in light thereof will be suggested to persons skilled in the art and are to be included within the spirit and purview of this application and the scope of the appended claims.