PYRIDONE COMPOUND AS C-MET INHIBITOR

Abstract

Disclosed in the present invention is a type of pyridone compounds as c-met inhibitors, and specifically disclosed is a compound as shown in formula (I) or a pharmaceutically acceptable salt thereof.

##STR00001##

Claims

1. A compound represented by formula (I) or a pharmaceutically acceptable salt, ##STR00026## R.sub.1 is selected from H or F; R.sub.2 is selected from H or CH.sub.3; while R.sub.2 is not H, the configuration of the carbon atom bonded to R.sub.2 is R or S; A is selected from the group consisting of phenyl, pyridyl, pyrazolyl, isoxazolyl, isothiazolyl and thiazolyl, each of which is optionally substituted by 1, 2 or 3 R.sub.3; R.sub.3 is selected from CN, halogen, C(O)NH.sub.2, or is selected from the group consisting of C.sub.1-6 alkyl, C.sub.1-6 heteroalkyl, and C.sub.3-6 cycloalkyl, each of which is optionally substituted by 1, 2 or 3 R.sub.0; R.sub.0 is selected from F, Cl, Br, I, OH, CN, NH.sub.2, C(O)NH.sub.2, or is selected from the group consisting of C.sub.1-3 alkyl and C.sub.1-3 heteroalkyl, each of which is optionally substituted by 1, 2 or 3 R; R is selected from F, Cl, Br, I, CN, OH, NH.sub.2, CH.sub.3, CH.sub.3CH.sub.2, CF.sub.3, CHF.sub.2 or CH.sub.2F; the hetero in the C.sub.1-3 heteroalkyl or C.sub.1-6 heteroalkyl is selected from the group consisting of O, C(O)NR, C(O)NH, NR, and NH; in any of the above cases, the number of the heteroatom or the heteroatomic group is independently selected from 1, 2 or 3.

2. The compound or the pharmaceutically acceptable salt as defined in claim 1, wherein, R.sub.0 is selected from F, Cl, Br, I, OH, CN, NH.sub.2, C(O)NH.sub.2, CH.sub.3, CH.sub.3CH.sub.2, CF.sub.3, CHF.sub.2, CH.sub.2F, NH.sub.2CH.sub.2, (NH.sub.2).sub.2CH, CH.sub.3O, CH.sub.3CH.sub.2O, CH.sub.3OCH.sub.2, CH.sub.3NH or (CH.sub.3).sub.2N.

3. The compound or the pharmaceutically acceptable salt as defined in claim 1, wherein, R.sub.1 is H.

4. The compound or the pharmaceutically acceptable salt as defined in claim 1, wherein, R.sub.1 is F.

5. The compound or the pharmaceutically acceptable salt as defined in claim 1, wherein, R.sub.2 is H.

6. The compound or the pharmaceutically acceptable salt as defined in claim 1, wherein, R.sub.2 is CH.sub.3.

7. The compound or the pharmaceutically acceptable salt as defined in claim 6, wherein, the configuration of the carbon atom bonded to R.sub.2 is R.

8. The compound or the pharmaceutically acceptable salt as defined in claim 6, wherein, the configuration of the carbon atom bonded to R.sub.2 is S.

9. The compound or the pharmaceutically acceptable salt as defined in claim 1, wherein, R.sub.3 is selected from CN, halogen, C(O)NH.sub.2, or is selected from the group consisting of C.sub.1-3 alkyl and C.sub.1-3 heteroalkyl, each of which is optionally substituted by 1, 2 or 3 R.sub.0.

10. The compound or the pharmaceutically acceptable salt as defined in claim 9, wherein, R.sub.3 is selected from CN, F, Cl, Br, CH.sub.3, CH.sub.3CH.sub.2, CF.sub.3, CHF.sub.2, CH.sub.2F, CH.sub.3O or C(O)NH.sub.2.

11. The compound or the pharmaceutically acceptable salt as defined in claim 1, wherein, A is selected from the group consisting of ##STR00027## each of which is optionally substituted by 1, 2 or 3 R.sub.3.

12. The compound or the pharmaceutically acceptable salt as defined in claim 11, wherein, A is selected from the group consisting of ##STR00028##

13. The compound or the pharmaceutically acceptable salt as defined in claim 12, wherein, A is selected from the group consisting of ##STR00029##

14. The compound or the pharmaceutically acceptable salt as defined in claim 10, wherein, A is selected from the group consisting of ##STR00030##

15. The compound as defined in claim 1 is selected from the group consisting of ##STR00031## ##STR00032##

16. A pharmaceutical composition comprising a therapeutically effective amount of the compound or the pharmaceutically acceptable salt thereof as defined in claim 1, as well as a pharmaceutically acceptable carrier.

17. A method for treating tumor, comprising administering to a subject in need thereof the pharmaceutical composition as defined in claim 16.

Description

DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENT

[0056] The following embodiments further illustrate the present invention, but by all means the invention is not limited thereto. While the present invention has been described in detail and with reference to specific embodiments thereof, it will be apparent to those skilled in the art that various changes and modifications can be made therein without departing from the spirit and scope thereof.

Embodiment 1 (1-1 and 1-2)

[0057] ##STR00010## ##STR00011##

[0058] Step A:

[0059] The solution of intermediate 7C (synthetic method see embodiment 7) (20.4 g, 50.88 mmol) and manganese dioxide (44.23 g, 508.7 mmol) in DCM (300 mL) was stirred at room temperature for 16 hours. After the reaction was complete, the mixture was filtered and concentrated to give the intermediate 1A (18.4 g) which was used directly for the next step. LCMS (ESI) m/z: 398(M+1).

[0060] Step B:

[0061] Methylmagnesium bromide (3 M, 38.58 mL) was added into a solution of intermediate 1A (23.0 g, 57.87 mmol) in THF (200 mL) at 0 C. The solution was stirred at room temperature for 1 hour. After the reaction was complete, the mixture was quenched by saturated sodium chloride solution (300 mL), extracted by ethyl acetate (200 mL*2), dried over anhydrous sodium sulfate, filtered and concentrated to give intermediate 1B (22.76 g, yield 95.11%). LCMS (ESI) m/z: 414(M+1). HNMR (400 MHz, CHLOROFORM-d) 8=8.46 (s, H), 8.38-8.33 (m, 1H), 8.26 (td, J=1.9, 6.9 Hz, 1H), 7.53-7.44 (m, 2H), 5.02 (q, J=6.4 Hz, 1H), 4.31-4.12 (m, 2H), 3.95 (d, J=6.4 Hz, 2H), 2.78 (hr t, J=12.1 Hz, 2H), 2.13 (br s, 1H), 2.08-1.96 (m, 1H), 1.86 (br d, J=12.9 Hz, 2H), 1.58 (d, J=6.5 Hz, 3H), 1.49 (s, 9H), 1.39-1.29 (m, 2H).

[0062] Step C:

[0063] Diisopropylethylamine (21.34 g, 165.12 mmol) and methanesulfonyl chloride (9.12 g, 79.62 mmol) were added into a solution of intermediate 1B (22.7 g, 55.04 mmol) in DCM (300 mL) at 0 C. The reaction solution was stirred at room temperature for 1 h. After the reaction was complete as monitored by TLC, the mixture was washed with saturated ammonium chloride solution (200 mL) twice, dried over anhydrous sodium sulfate, filtered and concentrated to give the intermediate 1C (30 g, crude product) which was used directly for the next step.

[0064] Step D:

[0065] Potassium carbonate (10.68 g, 77.30 mmol), potassium iodide (641.58 mg, 3.86 mmol) and 5-bromo-3-fluoro-1H-pyridin-2-one (11.13 g, 57.97 mmol) were added into a solution of intermediate 1C (19 g, 3.86 mmol) in DMF (100 mL) at room temperature. The reaction solution was stirred at 90 C. for 3 hours. After the reaction was complete, ethyl acetate (300 mL) was added into the solution and the solution was washed with brine (300 mL) three times. The organic phase was dried over anhydrous sodium sulfate, filtered and concentrated to give the intermediate 1D (5.8 g, yield 25.54%). HNMR (400 MHz, CHLOROFORM-d) S=8.47 (s, 2H), 8.41-8.32 (m, 2H), 7.55-7.47 (m, 1H), 7.39 (d, J=7.7 Hz, 1H), 7.15 (dd, J=2.4, 8.4 Hz, 1H), 7.11-7.07 (m, 1H), 6.52 (q, J=7.0 Hz, 1H), 4.31-4.12 (m, 2H), 4.01-3.93 (m, 2H), 2.87-2.72 (m, 2H), 2.09-1.98 (m, 1H), 1.89-1.80 (m, 5H), 1.49 (s, 9H), 1.39-1.30 (m, 2H).

[0066] Step E:

[0067] Under nitrogen atmosphere, intermediate 1D (2.0 g, 3.4 mmol), 4,4,5,5-tetramethyl-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1,3,2-dioxaborolane (1.04 g, 4.09 mmol), acetate potassium (668.21 mg, 6.81 mmol) and Pd(dppf)Cl.sub.2 (498.20 mg, 680.87 mol) were dissolved in dioxane (30 mL) at room temperature. The reaction solution was stirred at 90 C. for 2 hours. After the reaction was complete, a solution (30 mL) of intermediate 1E in dioxane was obtained and used directly for the next step.

[0068] Step F (1F-1, 1F-2):

[0069] Under nitrogen atmosphere, a solution (30 mL) of intermediate 1E (1.92 g, 3.03 mmol) in dioxane, sodium carbonate (642.30 mg, 6.06 mmol), 2-bromo-5-cyanopyridine (665.42 mg, 3.64 mmol) and Pd(dppf)Cl.sub.2 (443.43 mg, 606.0 mol) were dissolved in dioxane (40 mL) and water (6 mL) at room temperature. The reaction was stirred at 90 C. for 3 hours. After the reaction was complete, the mixture was filtered and water (100 mL) was added into the filtrate and extracted with ethyl acetate (60 mL*3). The organic phase was dried over anhydrous sodium sulfate and then filtered and concentrated. The crude product was purified by preparative plate, and the intermediate 1F-1 (t=2.819, 490 mg, 26.04% yield) and intermediate 1F-2 (t=3.933, 480 mg, 25.95% yield) were isolated by SFC (column type: AS (250 mm*30 mm, 10 um); mobile phase: [B: 0.1% NH.sub.3H.sub.2O EtOH]; B %: 55%-55%, 10 min; 200 minmin).

[0070] LCMS (ESI) m/z: 611 (M+1).

[0071] HNMR (intermediate 1F-1) (400 MHz, METHANOL-d4) =8.73 (dd, J=0.9, 5.0 Hz, 1H), 8.55 (s, 2H), 8.39 (s, 1H), 8.34-8.26 (m, 2H), 8.17-8.08 (m, 2H), 7.58-7.49 (m, 3H), 6.50 (q, J=7.2 Hz, 1H), 4.15 (br d, J=13.3 Hz, 2H), 4.06 (d, J=6.3 Hz, 2H), 2.84 (br s, 2H), 2.14-2.01 (m, 1H), 1.97 (d, J=7.3 Hz, 3H), 1.87 (br d, J=11.9 Hz, 2H), 1.48 (s, 9H), 1.35-1.28 (m, 2H).

[0072] HNMR (intermediate 1F-2) (400 MHz, METHANOL-d4) 8=8.73 (dd, J=0.8, 5.0 Hz, 1H), 8.55 (s, 2H), 8.39 (s, 1H), 8.34-8.26 (m, 2H), 8.16-8.09 (m, 2H), 7.61-7.49 (m, 3H), 6.50 (q, J=7.2 Hz, 1H), 4.15 (br d, J=13.2 Hz, 2H), 4.06 (d, J=6.3 Hz, 2H), 2.84 (br s, 2H), 2.12-2.01 (m, 1H), 1.99-1.95 (m, 3H), 1.87 (br d, J=10.9 Hz, 2H), 1.48 (s, 9H), 1.35-1.29 (m, 2H).

[0073] Step G (1G-1, 1G-2)

[0074] Trifluoroacetic acid (3 mL) was added into a solution of intermediate 1F-1 (490 mg, 786.01 mol) in DCM (10 mL) at 0 C. The reaction solution was stirred at room temperature for 1 hour. After the reaction was complete, the mixture was evaporated to dryness to give intermediate 1G-1 (502 mg, crude product) which was directly used for the next step. Intermediate 1G-2 (491 mg, crude product) was obtained with the same method as intermediate 1G-1.

[0075] Step H:

[0076] Formalin (326.27 mg, 4.02 mmol, 37% purity) and sodium triacetoxyborohydride (511.03 mg, 2.41 mmol) were added into a solution of intermediate 1G-1 (502.00 mg, 803.74 mmol) in DCM (10 mL) at 0 C. The reaction solution was stirred at room temperature for 2 hours. After the reaction was complete, the mixture was quenched with water (50 mL) and DCM (30 mL*2). The organic phase was dried over anhydrous sodium sulfate, filtered and concentrated. The crude product obtained was purified by preparative HPLC to give the embodiment 1-1 (150 mg, 35.41% yield).

[0077] Embodiment 1-2 (100.6 mg, 23.91% yield) was obtained with the same method as embodiment 1-1, started from intermediate 1G-2.

Embodiment 1-1

[0078] LCMS (ESI) m/z: 525 (M+1).

[0079] HNMR (400 MHz, METHANOL-d4) 8=8.73 (d, J=4.9 Hz, 1H), 8.56 (s, 2H), 8.49 (s, 1H), 8.39 (s, 1H), 8.34-8.26 (m, 2H), 8.18-8.09 (m, 2H), 7.61-7.49 (m, 3H), 6.50 (q, J=7.2 Hz, 1H), 4.13 (d, J=5.8 Hz, 2H), 3.53 (br d, J=12.4 Hz, 21H), 3.03 (br t, J=12.4 Hz, 2H), 2.87 (s, 3H), 2.27-2.08 (m, 3H), 1.97 (d, J=7.2 Hz, 3H), 1.81-1.63 (m, 2H).

Embodiment 1-2

[0080] LCMS (ESI) m/z: 525 (M+1).

[0081] HNMR (400 MHz, METHANOL-d4) =8.72 (dd, J=0.8, 5.0 Hz, 1H), 8.61-8.46 (m, 3H), 8.38 (s, 1H), 8.33-8.25 (m, 2H), 8.16-8.08 (m, 2H), 7.58-7.47 (m, 3H), 6.49 (q, J=7.1 Hz, 1H), 4.12 (d, J=5.9 Hz, 2H), 3.50 (br d, J=12.2 Hz, 21-1), 3.05-2.93 (m, 2H), 2.83 (s, 3H), 2.22-2.06 (m, 3H), 1.96 (d, J=7.2 Hz, 3H), 1.80-1.62 (m, 2H).

Embodiment 2 (2-1 and 2-2)

[0082] ##STR00012## ##STR00013##

[0083] Step A:

[0084] Under nitrogen atmosphere, intermediate 1D (1.0 g*2, 1.70 mmol), 3-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolane-2-yl)isothiazole (1.15 g, 5.10 mmol), potassium phosphate (1 M, 3.4 mL) and 1,1-(tert-butylphosphino)ferrocene palladium dichloride (110.80 mg, 170.00 mol) were dissolved in THF (10 mL) at room temperature. The reaction solution was stirred at 70 C. for 16 hours. The reaction solution was then filtered and water (50 mL) was added into. The mixture was extracted by ethyl acetate (30 mL*3). The organic phase was then dried over anhydrous sodium sulfate, filtered and concentrated. The crude product was then purified by preparative HPLC. The intermediate 2A-1 (t=2.529, 560 mg, 24.28% yield) and intermediate 2A-2 (t=3.494, 500 mg, 27.19% yield) were isolated by SFC (column type: AS (250 mm*30 mm, 10 um); mobile phase: [B: 0.1% NH.sub.3H.sub.2O EtOH]: B %: 35%-35%, 7.2 min; 200 minmin).

[0085] LCMS (ESI) m/z: 605 (M+1)

[0086] HNMR (intermediate 2A-1) (400 MHz, METHANOL-d4) =8.61-8.50 (m, 2H), 8.41-8.26 (m, 2H), 7.76 (d, J=2.1 Hz, 1H), 7.70 (dd, J=2.1, 10.0 Hz, 1H), 7.57-7.50 (m, 2H), 7.29 (s, 1H), 6.45 (q, J=7.1 Hz, 1H), 4.16 (br d, J=13.3 Hz, 2H), 4.07 (d, J=6.1 Hz, 2H), 2.85 (br s, 2H), 2.45 (s, 3H), 2.08 (br s, 1H), 1.96-1.84 (m, 5H), 1.48 (s, 9H), 1.37-1.29 (m, 2H).

[0087] HNMR (intermediate 2A-2) (400 MHz, METHANOL-d4) =8.59-8.53 (m, 2H), 8.41-8.27 (m, 2H), 7.76 (s, 1H), 7.73-7.66 (m, 1H), 7.58-7.49 (m, 2H), 7.28 (d, J=2.8 Hz, 1H), 6.45 (q, J=6.9 Hz, 1H), 4.16 (br d, J=13.6 Hz, 2H), 4.06 (dd, J=3.9, 6.1 Hz, 2H), 2.94-2.78 (m, 2H), 2.44 (d, J=2.1 Hz, 3H), 2.07 (td, J=3.7, 9.6 Hz, 1H), 1.96-1.84 (m, 5H), 1.48 (s, 9H), 1.36-1.27 (m, 2H).

[0088] Step B: intermediate 2B-1 and intermediate 2B-2 were prepared according to the preparation method of intermediate 1G-1.

[0089] Step C: embodiment 2-1 and 2-2 were prepared according to the preparation method of embodiment 1.

Embodiment 2-1

[0090] LCMS (ESI) m/z: 520 (M+1).

[0091] HNMR (400 MHz, METHANOL-d4) =8.73 (s, 2H), 8.35 (s, 1H), 8.29 (d, J=7.2 Hz, 1H), 7.86-7.81 (m, 1H), 7.72 (dd, J=2.3, 10.0 Hz, 1H), 7.64-7.58 (m, 2H), 7.36 (s, 1H), 6.45 (q, J=7.1 Hz, 1H), 4.21 (d, J=5.9 Hz, 2H), 3.63 (br d, J=12.4 Hz, 2H), 3.15 (br t, J=11.9 Hz, 2H), 2.92 (s, 3H), 2.47 (s, 3H), 2.33-2.06 (m, 3H), 1.99 (d, J=7.2 Hz, 3H), 1.86-1.73 (m, 2H).

Embodiment 2-2

[0092] LCMS (ESI) m/z: 520 (M+1).

[0093] HNMR (400 MHz, METHANOL-d4)=8.75 (s, 2H), 8.37 (s, 1H), 8.28 (d, J=7.2 Hz, 1H), 7.88-7.81 (m, 1H), 7.70 (dd, J=2.3, 10.0 Hz, 1H), 7.65-7.56 (m, 2H), 7.34 (s, 1H), 6.42 (q, J=7.1 Hz, 1H), 4.20 (d, J=5.9 Hz, 2H), 3.62 (br d, J=12.4 Hz, 2H), 3.12 (br t, J=11.9 Hz, 2H), 2.91 (s, 3H), 2.45 (s, 3H), 2.33-2.08 (m, 3H), 1.96 (d, J=7.2 Hz, 3H), 1.87-1.70 (m, 2H).

Embodiment 3

[0094] ##STR00014##

[0095] Step A:

[0096] Intermediate 3D was prepared according to the preparation method of intermediate 1D.

[0097] Step B:

[0098] Intermediate 3E was prepared according to the preparation method of intermediate 1F. The intermediate 3E-1 (t=2.805, 33 mg, 33.0% yield) and intermediate 3E-2 (t=3.255, 33 mg, 33% yield) were isolated by SFC (column type: AS (250 mm*30 mm, 10 um); mobile phase: [B: 0.1% NH.sub.3H.sub.2O EtOH]; B %: 40%-40%, 5 min; 80 minmin). LCMS (ESI) m/z: 588 (M+1).

[0099] Step C:

[0100] Intermediate 3F-1 (580 mg, crude product) and 3F-2 (520 mg, crude product) were prepared according to the preparation method of intermediate 1G.

[0101] Step D:

[0102] Embodiment 3-1 and 3-2 were prepared according to the preparation method of embodiment 1.

Embodiment 3-1

[0103] LCMS (ESI) m z: 502 (M+1).

[0104] HNMR (400 MHz, METHANOL-d4) =8.62-8.49 (m, 3H), 8.36 (s, 1H), 8.31 (br d, J=6.8 Hz, 1H), 7.91 (s, 1H), 7.77 (br d, J=9.4 Hz, 1H), 7.57-7.49 (m, 2H), 7.26 (s, 1H), 6.71 (d, J=9.4 Hz, 1H), 6.42 (q, J=6.6 Hz, 1H), 4.13 (br d, J=5.1 Hz, 2H), 3.50 (br d, J=11.9 Hz, 2H), 2.97 (br t, J=12.2 Hz, 2H), 2.83 (s, 3H), 2.44 (s, 3H), 2.24-2.06 (m, 3H), 1.91 (br d, J=7.1 Hz, 3H), 1.80-1.61 (m, 2H).

Embodiment 3-2

[0105] LCMS (ESI) m/z: 502 (M+1).

[0106] HNMR (400 MHz, METHANOL-d4) =8.56 (s, 2H), 8.49 (br s, 1H), 8.36 (s, 1H), 8.30 (br d, J=6.7 Hz, 1H), 7.91 (d, J=2.4 Hz, 1H), 7.77 (dd, J=2.4, 9.4 Hz, 1H), 7.56-7.49 (n, 2H), 7.26 (s, 1H), 6.70 (d, J=9.4 Hz, 1H), 6.41 (q, J=7.1 Hz, 1H), 4.13 (d, J=5.7 Hz, 2H), 3.54 (br d, J=12.3 Hz, 2H), 3.05 (br t, J=11.9 Hz, 2H), 2.87 (s, 3H), 2.44 (s, 3H), 2.21-2.08 (m, 3H), 1.91 (d, J=7.1 Hz, 3H), 1.79-1.67 (m, 2H).

Embodiment 4

[0107] ##STR00015##

[0108] Step A:

[0109] Intermediate 4A was prepared according to the preparation method of intermediate 1D.

[0110] Step B:

[0111] Intermediate 4B was prepared according to the preparation method of intermediate 1E.

[0112] Step C:

[0113] Intermediate 4C was prepared according to the preparation method of intermediate 1F.

[0114] Step D:

[0115] Intermediate 4D was prepared according to the preparation method of intermediate 1G.

[0116] Step E:

[0117] Embodiment 4 was prepared according to the preparation method of embodiment 1. LCMS (ESI) m/z: 510 (M+1). HNMR (400 MHz, METHANOL-d4).sup.=8.59-8.47 (m, 3H), 8.37 (s, 1H), 8.32-8.24 (m, 1H), 8.17 (d, J=2.5 Hz, 1H), 7.95 (dd, J=2.0, 7.3 Hz, 1H), 7.85-7.73 (m, 2H), 7.51-7.46 (m, 2H), 7.41 (dd, J=8.6, 10.5 Hz, 1H), 6.70 (d, J=9.5 Hz, 1H), 5.37 (s, 2H), 4.12 (d, J=5.8 Hz, 2H), 3.52 (br d, J=12.8 Hz, 2H), 3.08-2.96 (m, 2H), 2.85 (s, 3H), 2.26-2.09 (m, 3H), 1.79-1.63 (m, 2H).

Embodiment 5

[0118] ##STR00016##

[0119] Step A:

[0120] Intermediate 5A was prepared according to the preparation method of intermediate 1D.

[0121] Step B:

[0122] Intermediate 5B was prepared according to the preparation method of intermediate 1F.

[0123] Step C:

[0124] Intermediate 5C was prepared according to the preparation method of intermediate 1G.

[0125] Step D:

[0126] Embodiment 5 was prepared according to the preparation method of Embodiment 1. LCMS (ESI) m/z: 506 (M+1). HNMR (400 MHz, METHANOL-d4)=8.58-8.49 (m, 3H), 8.37-8.26 (m, 2H), 8.16 (dd, J=1.3, 2.1 Hz, 1H), 7.74 (dd, J=2.2, 10.2 Hz, 1H), 7.50 (d, J=5.3 Hz, 2H), 7.34 (s, 1H), 5.40 (s, 2H), 4.12 (d, J=5.8 Hz, 2H), 3.51 (br d, J=12.4 Hz, 2H), 3.06-2.94 (m, 2H), 2.84 (s, 3H), 2.47 (s, 3H), 2.23-2.07 (m, 3H), 1.80-1.62 (m, 2H).

Embodiment 6

[0127] ##STR00017##

[0128] Step A:

[0129] Intermediate 6A was prepared according to the preparation method of intermediate 1E.

[0130] Step B:

[0131] Intermediate 6B was prepared according to the preparation method of intermediate 1F.

[0132] Step C:

[0133] Intermediate 6C was prepared according to the preparation method of intermediate 1G.

[0134] Step D:

[0135] Embodiment 6 was prepared according to the preparation method of Embodiment 1. LCMS (ESI) m/z: 493 (M+1). HNMR (400 MHz. METHANOL-d4) =8.75 (d, J=5.0 Hz, 1H), 8.69 (d, J=2.4 Hz, 1H), 8.58-8.43 (m, 3H), 8.34 (s, 1H), 8.30-8.22 (m, 2H), 8.13 (s, 1H), 7.55 (dd, J=1.1, 5.0 Hz, 1H), 7.51-7.44 (m, 2H), 6.71 (d, J=9.5 Hz, 1H), 5.39 (s, 2H), 4.10 (d, J=5.9 Hz, 2H), 3.54 (br d, J=12.0 Hz, 2H), 3.04 (br t, J=12.0 Hz, 2H), 2.87 (s, 3H), 2.23-2.07 (m, 3H), 1.79-1.65 (m, 2H).

Embodiment 7

[0136] ##STR00018## ##STR00019##

[0137] Step A:

[0138] Under nitrogen atmosphere, methane disulfonyl chloride (45.15 g, 394.15 mmol) was added dropwise into a solution of tert-butyl-4-(hydroxymethyl)piperidine-1-carbomate (68.00 g, 315.85 mmol) and diisopropylethylamine (81.64 g, 631.71 mmol) in dichloromethane (800 mL) while stirring. After the dropwise addition was complete, the reaction solution was stirred at 25 C. for 2 hours. Thin layer chromatography was used to ensure the reaction was complete. The reaction solution was washed with saturated ammonium chloride solution (500 mL*2) and brine (300 mL*2) and dried over anhydrous sodium sulfate, filtered and concentrated to give intermediate 7A (red oily liquid, 95.00 g, 100% yield) which was used directly for the next step without further purification.

[0139] Step B

[0140] Under nitrogen atmosphere, potassium carbonate (74.12 g, 536.28 mmol) was added into a solution of intermediate 7A (94.40 g, 321.77 mmol) and 2-chloropyrimidin-5-ol (35.00 g, 268.14 mmol) in DMF (1.00 L). The reaction solution was left at 80 C. for 16 hours, and thin layer chromatography was used to detect the completion of the reaction. Then the reaction solution was cooled to room temperature and concentrated, then water (500 mL) was added into the residue and extracted with ethyl acetate (300 mL*3). The organic phase was washed with brine (400 mL*2) and dried over anhydrous sodium sulfate, then filtered and concentrated. Then the residue was purified by column chromatography to give the intermediate 7B (pale yellow solid, 84.00 g, 95.05% yield). LCMS (ESI) m/z: 327.7 (M+1). 1HNMR (400 MHz, DMSO-d6) ppm 1.08-1.25 (m, 2H) 1.40 (s, 9H) 1.69-1.78 (m, 2H) 1.88-2.03 (m, 1H) 2.58-2.88 (m, 2H) 3.89-4.05 (m, 4H) 8.50-8.57 (m, 2H)

[0141] Step C:

[0142] Under nitrogen atmosphere, a mixed solution of intermediate 7B (84.00 g, 254.85 mmol), [3-(hydroxymethyl)phenyl]boronic acid (42.60 g, 280.34 mmol), Pd(PPh.sub.3).sub.2Cl.sub.2 (17.89 g, 25.49 mmol) and potassium carbonate (70.45 g, 509.71 mmol) in 1.4-dioxane (1.00 L) and water (200.00 mL) was stirred at 80 C. for 16 hours. Then the reaction solution was cooled to room temperature then filtered, followed by extraction with dichloromethane (500 mL*3), then the organic layers were combined together, washed with brine (500 mL*2) and dried over anhydrous sodium sulfate, then filtered and concentrated. The residue was recrystallized with methanol to give intermediate 7C (white solid, 77.60 g, 76.22% yield). LCMS (ESI) m/z: 400.1 (M+1). 1HNMR (400 MHz, DMSO-d6) ppm 1.14-1.31 (m, 2H) 1.45 (s, 9H) 1.75-1.87 (m, 2H) 1.95-2.10 (m, 1H) 2.66-2.93 (m, 2H) 3.94-4.22 (m, 4H) 4.63 (d, J=5.62 Hz, 2H) 5.34 (t, J=5.81 Hz, 1H) 7.41-7.54 (m, 2H) 8.21 (d, J=7.46 Hz, 1H) 8.35 (s, 1H) 8.68 (s, 2H)

[0143] Step D:

[0144] Under nitrogen atmosphere, methane disulfonyl chloride (3.44 g, 30.04 mmol) was added dropwise into a solution of intermediate 7C (10.00 g, 25.03 mmol) and diisopropylethylamine (6.47 g, 50.06 mmol) in dichloromethane (100.00 mL) while stirring. After the addition was complete, the reaction solution was stirred at 25 C. for 2 hours. The thin layer chromatography was used to detect the completion of the reaction. The reaction solution was washed with saturated ammonium chloride solution (500 mL*2) and brine (300 mL*2), dried over anhydrous sodium chloride, filtered and concentrated to give intermediate 7D (gray solid, 14.00 g, 100% yield) which was used directly for the next step without further purification. LCMS (ESI) m/z: 478.1 (M+).

[0145] Step E:

[0146] Under nitrogen atmosphere, potassium carbonate (6.95 g, 50.26 mmol) was added into a solution of intermediate 7D (12.00 g, 25.13 mmol) and 5-bromo-3-fluoro-1-H-pyridin-2-one (5.79 g, 30.16 mmol) in DMF (100.00 mL) at 25 C. The reaction solution was left at 90 C. for 3 hours, then the reaction was complete as monitored by thin layer chromatography. Then the reaction solution was cooled to room temperature and concentrated. The residue was washed by water (100 mL), extracted with ethyl acetate (100 mL*3) and then the organic phase was washed by brine (200 mL*2) and dried over anhydrous sodium sulfate, then filtered and concentrated. The residue was purified by column chromatography to give intermediate 7E (yellow solid, 9.60 g 66.62% yield). LCMS (ESI) m/z: 574.9 (M+1). 1HNMR (400 MHz, DMSO-d6) ppm 1.09-1.27 (m, 2H) 1.41 (s, 9H) 1.77 (br d, J=11.13 Hz, 2H) 1.90-2.10 (m, 1H) 2.62-2.91 (m, 2H) 3.87-4.14 (m, 4H) 5.16-5.30 (m, 2H) 7.39-7.52 (m, 2H) 7.76 (dd, J=9.66, 2.45 Hz, 1H) 8.14-8.19 (m, 1H) 8.24 (d, J=7.58 Hz, 1H) 8.28 (s, 1H) 8.65 (s, 2H)

[0147] Step F:

[0148] Under nitrogen atmosphere, a mixed solution of intermediate 7F (200.00 mg, 348.77 mmol), 4,4,5,5-tetramethyl-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolane-2-yl)-1,3,2-dioxaborolane (92.99 mg, 366.21 mmol). Pd(dppf)Cl.sub.2 (25.52 mg, 34.88 mol) and potassium acetate (102.68 mg, 1.05 mmol) in 1,4-dioxane (10.00 mL) was stirred at 70 C. for 2 hours to give a solution of intermediate 7F in dioxane, which was used directly for the next step without further purification.

[0149] Step G:

[0150] Under nitrogen atmosphere, a mixed solution of intermediate 7F in dioxane solution (210.00 mg, 338.43 mol), 2-bromopyridin-4-carbonitrile (185.81 mg, 1.02 mmol), Pd(dppf)Cl.sub.2CH.sub.2Cl.sub.2 (55.28 mg, 67.69 mol) and potassium carbonate (93.55 mg, 676.86 mol) in 1.4-dioxane (10.00 mL) and water (2.00 mL) was stirred at 80 C. for 3 hours. The reaction solution was then cooled to room temperature, filtered and concentrated. The residue was dissolved by adding water (50 mL) and extracted with ethyl acetate (30 mL*3). Then organic phases were combined, washed with brine (30 ml*2), dried over anhydrous sodium sulfate, followed by filtration and concentration. The residue was purified by preparative thin layer chromatography to give intermediate 7G (yellow solid, 50.00 mg, 24.76% yield). LCMS (ESI) m/z: 619.2 (M+23).

[0151] Step H:

[0152] Under nitrogen atmosphere, trifluoroacetic acid (4.62 g, 40.52 mmol, 3.00 mL) was added into a solution of intermediate 7G (50.00 mg, 83.80 mol) in dichloromethane (10.00 mL) at 0 C. The reaction solution was stirred at 25 C. for 1 hour, then concentrated to obtain intermediate 7H (brownish black oily liquid, 60.00 mg, 100% yield, trifluoroacetate), which was used for the next step directly without further purification. LCMS (ESI) m/z: 497.2 (M+1).

[0153] Step I:

[0154] Under nitrogen atmosphere, formaldehyde (40.87 mg, 503.50 mol, 37.50 L, 37% aqueous solution) and sodium triacetoxyborohydride (64.03 mg, 302.10 mol) were added into a solution of intermediate 7H (50.00 mg, 100.70 mol) in dichloromethane (5.00 mL) at 0 C. The reaction solution was left at 25 C. for 16 hours, then concentrated. The residue was purified by preparative HPLC to obtain embodiment 7 (21.70 mg, 38.48% yield, formate). LCMS (ESI) m/z: 511.1 (M+1). 1HNMR (400 MHz, DMSO-d6) ppm 1.27-1.43 (m, 2H) 1.77 (br d, J=9.78 Hz, 3H) 1.99 (br t, J=11.43 Hz, 2H) 2.22 (s, 3H) 2.85 (br d, J=11.37 Hz, 2H) 4.05 (d, J=5.99 Hz, 2H) 5.39 (s, 2H) 7.50 (d, J=5.01 Hz, 2H) 7.75 (dd, J=5.01, 1.22 Hz, 1H) 8.18-8.26 (m, 2H) 8.28 (s, 1H) 8.33 (s, 1H) 8.40 (s, 1H) 8.64 (s, 2H) 8.78 (d, J=1.34 Hz, 1H) 8.82 (d, J=5.01 Hz, 1H)

Embodiment 8 (8-1 and 8-2)

[0155] ##STR00020## ##STR00021##

[0156] Step A:

[0157] Under nitrogen atmosphere, a solution of intermediate 1D (1.50 g, 2.55 mol), tributyl(1-ethoxyethylene)tin (1.14 g, 3.16 mmol, 1.07 mL) and Pd(dppf)Cl.sub.2(358.43 mg, 510.66 mol) in toluene (10.00 mL) was stirred at 100 C. for 3 hours. Hydrochloric acid (10.21 mL, 1 N aqueous solution) was added into the reaction solution after the solution was cooled to room temperature and then the solution was stirred at 25 C. for 1 hour, filtered and concentrated. The residue was purified by column chromatography to give intermediate 8A (yellow oily liquid, 1.13 g, 80.48% yield). LCMS (ESI) m/z: 573.1 (M+23). 1HNMR (400 MHz, CHLOROFORM-d) ppm 1.50 (s, 9H) 1.89 (d, J=7.03 Hz, 6H) 1.98-2.10 (m, 2H) 2.31 (s, 3H) 2.72-2.86 (m, 2H) 3.98 (d, J=6.27 Hz, 2H) 4.12-4.31 (m, 2H) 6.54 (q, J=7.28 Hz, 1H) 7.42 (br d, J=7.65 Hz, 1H) 7.61 (dd, J=9.66, 2.26 Hz, 1H) 7.65-7.74 (m, 1H) 7.84 (d, J=1.38 Hz, 1H) 8.38 (d, J=7.78 Hz, 1H) 8.42 (s, 1H) 8.47 (s, 2H)

[0158] Step B:

[0159] Under nitrogen atmosphere, a solution of intermediate 8A (1.13 g, 2.05 mmol) in 1,1-dimethoxy-N,N-dimethyl-ethane (5.00 mL) was stirred at 120 C. for 3 hours. Then the reaction solution was cooled to room temperature and concentrated to dryness to obtain the intermediate 8B (brownish black oily liquid, 1.27 g, 100% yield), which was used directly for next step without further purification. LCMS (ESI) m/z: 620.1 (M+1).

[0160] Step C:

[0161] Under nitrogen atmosphere, hydroxylamine (213.61 mg, 3.08 mmol, hydrochloride salt) was added into a solution of intermediate 8B (1.27 g, 2.05 mmol) in ethanol (20.00 mL). The mixture was left at 80 C. for 16 hours, then concentrated. The residue was purified by preparative HPLC, the racemates were separated by preparative SFC (column: AS (250 mm*30 mm, 10 um); phase mobile: [0.1% NH.sub.3H.sub.2O EtOH]: B %: 0%-55%, 5.2 min; 150 minmin) to intermediate 8C-1 (white solid, 380.00 mg, 31.44% yield, 100% ee value, Rt=2.431 min) and intermediate 8C-2 (white solid, 350.00 mg, 38.95% yield, 100% ee value, Rt=3.299 min). LCMS (ESI) m/z: 590.4 (M+1). 1HNMR (intermediate 8C-1) (400 MHz, CHLOROFORM-d) ppm 1.31-1.38 (m, 2H) 1.50 (s, 9H) 1.82-1.94 (m, 5H) 1.97-2.12 (m, 1H) 2.29 (s, 3H) 2.79 (br t, J=12.23 Hz, 2H) 3.98 (d, J=6.36 Hz, 2H) 4.21 (br s, 2H) 6.06 (s, 1H) 6.59 (d, J=6.97 Hz, 1H) 7.33 (dd, J=9.41, 2.20 Hz, 1H) 7.40-7.46 (m, 1H) 7.48-7.55 (m, 1H) 7.56-7.62 (m, 1H) 8.36 (d, J=7.70 Hz, 1H) 8.43 (s, 1H) 8.47 (s, 2H).

[0162] 1HNMR (intermediate 8C-2) (400 MHz, CHLOROFORM-d) ppm 1.30-1.37 (m, 2H) 1.49 (s, 9H) 1.81-1.94 (m, 5H) 1.96-2.10 (m, 1H) 2.29 (s, 3H) 2.79 (br t, J=12.10 Hz, 2H) 3.98 (d, J=6.24 Hz, 2H) 4.20 (br s, 2H) 6.06 (s, 1H) 6.59 (q, J=7.05 Hz, 1H) 7.33 (dd, J=9.29, 2.20 Hz, 1H) 7.41-7.46 (m, 1H) 7.48-7.54 (m, 1H) 7.59 (d, J=1.59 Hz, 1H) 8.36 (d, J=7.82 Hz, 1H) 8.42 (s, 1H) 8.47 (s, 2H)

[0163] Step D:

[0164] Intermediates 8D-1, 8D-2 were prepared according to the preparation method of intermediate 1G.

[0165] Step E:

[0166] Embodiments 8-1, 8-2 were prepared according to the preparation method of embodiment 1.

Embodiment 8-1

[0167] LCMS (ESI) m/z: 504.1 (M+1).

[0168] 1HNMR (400 MHz, DMSO-d6) ppm 1.54-1.72 (m, 2H) 1.85-2.13 (m, 6H) 2.24 (s, 3H) 2.69-2.80 (m, 3H) 2.86-3.16 (m, 2H) 3.19-3.52 (m, 2H) 4.09 (d, J=6.27 Hz, 2H) 6.29 (q, J=7.07 Hz, 1H) 6.78 (s, 1H) 7.47-7.60 (m, 2H) 7.92 (dd, J=10.42, 2.13 Hz, 1H) 8.08 (s, 1H) 8.21-8.35 (m, 2H) 8.62-8.75 (m, 2H) 10.37-10.80 (m, 1H)

Embodiments 8-2

[0169] LCMS (ESI) m/z: 504.1 (M+1).

[0170] 1HNMR (400 MHz, DMSO-d6) ppm 1.57-1.74 (m, 2H) 1.81-2.12 (m, 6H) 2.23 (s, 3H) 2.62-2.79 (m, 3H) 2.86-3.05 (m, 2H) 3.41 (br d, J=11.92 Hz, 2H) 4.09 (d, J=6.27 Hz, 2H) 6.29 (q, J=6.99 Hz, 1H) 6.79 (s, 1H) 7.53 (d, J=5.02 Hz, 2H) 7.92 (dd, J=10.48, 2.07 Hz, 1H) 8.08 (s, 1H) 8.20-8.34 (m, 2H) 8.61-8.73 (m, 2H) 10.75 (br s, 1H)

Embodiment 9

[0171] ##STR00022##

[0172] Step A:

[0173] Under nitrogen atmosphere, a mixture of intermediate 3D (1.00 g, 1.76 mmol), 4,4,5,5-tetramethyl-(4,4,5,5-tetramethyl-1,3,2-dioxaborolane-2-yl)-1,3,2-dioxaborolane (469.28 mg, 1.85 mmol), Pd(dppf)Cl.sub.2 (128.78 mg, 176.00 mol) and potassium acetate (518.17 mg, 5.28 mmol) in 1,4-dioxane (15.00 mL) was stirred at 80 C. for 2 hours, then intermediate 9A in dioxane was obtained and was used directly for the next step without further treatment.

[0174] Step B:

[0175] Under nitrogen atmosphere, a mixture of intermediate 9A (1.09 g, 1.77 mmol) in dioxane, 2-bromopyridine-4-carbonitrile (485.89 mg, 2.66 mmol), Pd(dppf)Cl.sub.2.CH.sub.2Cl.sub.2 (289.09 mg, 354.00 mol) and potassium carbonate (489.26 mg, 3.54 mmol) in 1,4-dioxane (20.00 mL) and water (4.00 mL) in solution was stirred at 80 C. for 3 hours. Then the reaction solution was cooled to room temperature, filtered and concentrated. The residue was purified by preparative thin layer chromatography, the racemates was separated by preparative SFC (column: AS (250 mm*30 mm, 10 um); phase mobile: [0.1% NH.sub.3H.sub.2O EtOH]; B %: 55%-55%, 8.2 min; 100 minmin) to intermediate 9B-1 (yellow oily liquid, 200.00 mg, 100% ee value, 19.06% yield, Rt=2.973 min) and intermediate 9B-2 (yellow oily liquid, 200.00 mg, 100% ee value, 19.06% yield, Rt=3.605 min). LCMS (ESI) m/z: 593.1 (M+1).

[0176] Step C

[0177] Intermediate 9C-1, 9C-2 was prepared according to the preparation method of 1G.

[0178] Step D:

[0179] Embodiment 9-1, 9-2 was prepared according to the preparation method of embodiment 1.

Embodiment 9-1

[0180] LCMS (ESI) m/z: 507.1 (M+1). 1HNMR (400 MHz, DMSO-d6) ppm 1.29-1.45 (m, 2H) 1.80 (br d, J=10.54 Hz, 3H) 1.88 (d, J=7.28 Hz, 3H) 2.14 (br t, J=11.17 Hz, 2H) 2.30 (s, 3H) 2.94 (br d, J=11.29 Hz, 2H) 4.05 (d, J=6.02 Hz, 2H) 6.32 (d, J=7.15 Hz, 1H) 6.62 (d, J=9.66 Hz, 1H) 7.46-7.55 (m, 2H) 7.69 (dd, J=5.02, 1.25 Hz, 1H) 8.19-8.26 (m, 3H) 8.27 (s, 1H) 8.43 (t, J=1.07 Hz, 1H) 8.49 (d, J=2.38 Hz, 1H) 8.64 (s, 2H) 8.77 (dd, J=5.02, 0.88 Hz, 1H)

Embodiment 9-2

[0181] LCMS (ESI) m/z: 507.1 (M+1). 1HNMR (400 MHz. DMSO-d6) ppm 1.27-1.46 (m, 2H) 1.81 (br d, J=10.54 Hz, 3H) 1.89 (d, J=7.28 Hz, 3H) 2.17 (br t, J=11.17 Hz, 2H) 2.31 (s, 3H) 2.96 (br d, J=11.29 Hz, 2H) 4.09 (d, J=6.02 Hz, 2H) 6.35 (d, J=7.15 Hz, 1H) 6.65 (d, J=9.66 Hz, 1H) 7.42-7.57 (m, 2H) 7.66 (dd, J=5.02, 1.25 Hz, 1H) 8.21-8.27 (m, 3H) 8.29 (s, 1H) 8.45 (t, J=1.07 Hz, 1H) 8.51 (d, J=2.38 Hz, 1H) 8.67 (s, 2H) 8.79 (dd, J=5.02, 0.88 Hz, 1H)

Embodiment 10

[0182] ##STR00023##

[0183] Step A:

[0184] Under nitrogen atmosphere, a mixture of intermediate 4A (200.00 mg, 346.53 mol), 1-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolane-2-yl)pyrazole (108.15 mg, 519.80 mol), Pd(dppf)Cl.sub.2 (25.36 mg, 34.65 mol) and sodium carbonate (110.19 mg, 1.04 mmol) in 1,4-dioxane (10.00 mL) was stirred at 80 C. for 2 hours, then the reaction solution was cooled to room temperature, filtered and concentrated. The residue was dissolved by adding water (60 mL) and then extracted with ethyl acetate (50 mL*3). Then organic phases were combined and washed with brine (80 mL*2), and dried over anhydrous sodium sulfate, filtered and concentrated. The residue was purified by preparative thin layer chromatography to give intermediate 10B (yellow oily liquid, 200.00 mg, 95.45% yield). LCMS (ESI) m/z: 557.3 (M+1).

[0185] Step B:

[0186] Intermediate 10C was prepared according to the preparation method of intermediate 1G.

[0187] Step C:

[0188] Embodiment 10 was prepared according to the preparation method of embodiment 1. LCMS (ESI) m/z: 471.2 (M+1). 1HNMR (400 MHz, METHANOL-d4): 1.63-1.80 (m, 2H) 2.09-2.25 (m, 3H) 2.88 (s, 3H) 3.05 (t, J=12.17 Hz, 2H) 3.55 (d, J=12.67 Hz, 2H) 3.91 (s, 3H) 4.12 (d, J=5.90 Hz, 2H) 5.34 (s, 2H) 6.67 (d, J=9.41 Hz, 1H) 7.42-7.51 (m, 2H) 7.75 (s, 1H) 7.81 (dd, J=9.35, 2.57 Hz, 1H) 7.88 (s, 1H) 8.05 (d, J=2.38 Hz, 1H) 8.25-8.29 (m, 1H) 8.33 (s, 1H) 8.47 (s, 1H) 8.55 (s, 2H).

Embodiment 11

[0189] ##STR00024##

[0190] Step A:

[0191] Under nitrogen atmosphere, a solution of sodium nitrite (2.52 g, 36.54 mmol) in water (50 mL) was added dropwise into a mixed solution of 3-methyisothiazol-5-amine (5.00 g, 33.19 mmol, hydrochloride salt) in water (14.00 mL) and sulfuric acid (10.00 mL, 98% purity) at 0 C. The reaction solution was stirred at 0 C. for 1 hour, then a solution of potassium iodide (6.06 g, 36.51 mmol) in water (35 mL) was added and the solution was left at 80 C. for 1 hour for reaction. The reaction solution was cooled to room temperature, diluted with water (100 mL) and extracted with dichloromethane (50 mL*2). Then the organic phases were combined and washed with brine (25 mL*2), dried over anhydrous sodium sulfate, filtered and concentrated. The residue was purified by column chromatography to give intermediate 11A (yellow solid, 4.00 g, 53.55% yield). LCMS (ESI) m/z: 225.9 (M+1). 1HNMR (400 MHz, CHLOROFORM-d) ppm 2.39-2.48 (m, 3H) 7.04-7.13 (m, 1H).

[0192] Step B:

[0193] Under nitrogen atmosphere, isopropylamagnesium chloride-lithium chloride complex (3.66 mL, 1.3 M tetrahydrofuran solution) was added dropwise into a solution of intermediate 11A (1.00 g, 4.44 mmol) and 2-isopropoxy-4,4,5,5-1,3,2-dioxaborolane (850 mg, 4.57 mmol) in tetrahydrofiran (5.00 mL) at 25 C. The reaction solution was stirred at 25 C. for 0.5 hour. After the reaction, the solution was quenched by dripping into a solution of acetic acid (0.24 mL) in tetrahydrofuran (0.67 mL), then petroleum ether (48 mL) and tert-butyl methyl ether (24 mL) were added into the reaction solution. After filtration, tert-butyl methyl ether (32 mL) was added into filtrate, then the filtrate was again filtered and concentrated to give intermediate 11B (yellow oily liquid, 512 mg, 51.22% yield)which was used for the next step directly without further purification. 1HNMR (400 MHz, CHLOROFORM-d) ppm 1.28 (s, 12H) 2.46-2.48 (m, 3H) 7.31 (s, 1H).

[0194] Step C:

[0195] Under nitrogen atmosphere, a mixture of intermediate 11B (283.69 mg, 1.26 mmol), intermediate 4A (500.00 mg, 900.15 mol), 1,1-di(tert-butylphosphino)ferrocene palladium chloride (58.67 mg, 90.02 mol) and potassium phosphate trihydrate (479.44 mg, 1.80 mmol) in tetrahydrofuran (5.00 mL) and water (1.00 mL) was stirred at 65 C. for 12 hours. Then the reaction solution was cooled to room temperature, filtered and concentrated. After the residue was dissolved in water (50 mL) and extracted with ethyl acetate (100 mL*2), the organic phases were combined and washed with brine (50 mL*2), dried over anhydrous sodium sulfate, filtered and concentrated. The residue was purified by preparative thin layer chromatography to give intermediate 11C (yellow solid, 266.00 mg, 51.51% yield). LCMS (ESI) m/z: 574.2 (M+1). 1HNMR (400 MHz, CHLOROFORM-d) ppm 1.27-1.34 (m, 6H) 1.60-1.64 (m, 10H) 1.60-1.65 (m, 10H) 1.83-1.91 (m, 2H) 1.95 (s, 1H) 2.46-2.52 (m, 3H) 3.95-4.01 (m, 2H) 5.28-5.31 (m, 2H) 6.71-6.77 (m, 1H) 6.94-6.97 (m, 1H) 7.39-7.56 (m, 3H) 7.63-7.68 (m, 1H) 8.37 (s, 2H) 8.47 (s, 2H).

[0196] Step D:

[0197] Intermediate 11D was prepared according to the preparation method of intermediate 1F.

[0198] LCMS (ESI) m/z: 474.2 (M+1).

[0199] Step E:

[0200] Embodiment 11 was prepared according to the preparation method of embodiment 1.

[0201] LCMS (ESI) m/z: 488.2 (M+1). 1HNMR (400 MHz, DMSO-d6) ppm 1.37 (br d, J=10.54 Hz, 2H) 1.79 (br d, J=10.04 Hz, 3H) 2.11 (br s, 2H) 2.26-2.31 (m, 3H) 2.40-2.44 (m, 3H) 2.89-2.97 (m, 2H) 4.01-4.09 (m, 2H) 5.25 (s, 2H) 6.57 (d, J=9.41 Hz, 1H) 7.45 (d, J=1.80 Hz, 3H) 7.79 (dd, J=9.41, 2.64 Hz, 1H) 8.20-8.26 (m, 2H) 8.29 (s, 1H) 8.53-8.56 (m, 1H) 8.62-8.66 (m, 2H).

Embodiment 12

[0202] ##STR00025##

[0203] Step A:

[0204] Triethylamine (32.08 mg, 317.00 mol, 43.94 L) was added into a solution of phenyl isocyanate (830.74 mg, 6.97 mmol) in nitroethane (261.77 mg, 3.49 mmol, 249.30 L) and the reaction solution was stirred at 50 C. for 30 minutes, then a solution of tributyl(ethynyl)stannane (1.00 g, 3.17 mmol) in toluene (8.00 mL) was added into the reaction solution, followed by stirring at 50 C. for 5 hours. Thin layer chromatography was used to detect the completion of the reaction. Then water (100 mL) was added into the solution, which then was extracted with ethyl acetate (100 mL). The organic phase was then washed with brine (50 mL) and dried over anhydrous sodium sulfate, filtered and concentrated with a rotary evaporator. The residue was purified by column chromatography to give intermediate 12A (yellow oily liquid, 700.00 mg, 42.13% yield). LCMS (ESI) m/z: 373.14 (M+1). 1H NMR (400 MHz, CHLOROFORM-d) ppm 0.82-0.85 (m, 9H) 0.97-1.11 (m, 6H) 1.20-1.34 (m, 12H) 1.49-1.52 (m, 3H) 7.18-7.20 (m, 1H).

[0205] Step B:

[0206] Intermediate 12A (200 mg, 348.77 mol) and Pd(PPh.sub.3).sub.2Cl.sub.2 (25.27 mg, 36.01 mol) were added into a solution of intermediate 4A (200.00 mg, 360.06 mol) in dioxane (4.00 mL) at 20 C., then heated to 100 C. and stirred for 12 hours under nitrogen atmosphere. Thin layer chromatography was used to detect the completion of the reaction. Then water (50 mL) was added into the reaction solution and the solution was extracted with ethyl acetate (50 mL*2). The organic phase was washed with brine (50 mL), dried over anhydrous sodium sulfate, filtered and concentrated with rotary evaporator. The residue was purified by column chromatography to give intermediate 12B (yellow solid, 110.00 mg, 42.18% yield). LCMS (ESI) m/z: 557.26 (M+1). 1H NMR (400 MHz, CHLOROFORM-d) ppm 1.21-1.31 (m, 4H) 1.40 (s, 9H) 1.72-1.81 (m, 2H) 1.89-1.98 (m, 1H) 2.22 (s, 3H) 2.70 (br s, 2H) 3.88 (d, J=6.36 Hz, 2H) 5.21 (s, 2H) 6.02 (s, 1H) 6.63 (d, J=9.54 Hz, 1H) 7.33-7.37 (m, 1H) 7.50 (dd, J=9.54, 2.57 Hz, 1H) 7.57-7.64 (m, 1H) 7.83 (d, J=2.32 Hz, 1H) 8.23-8.31 (m, 2H) 8.38 (s, 2H).

[0207] Step C:

[0208] Intermediate 12C was prepared according to the preparation method of intermediate 1G. LCMS (ESI) m/z: 457.21 (M+1).

[0209] Step D:

[0210] Embodiment 12 was prepared according to the preparation method of embodiment 1. LCMS (ESI) m % z: 471.23 (M+1). 1H NMR (400 MHz, DMSO-d6) ppm 1.14-1.21 (m, 2H) 1.49 (br s, 2H) 1.79-1.95 (m, 3H) 1.99 (s, 2H) 2.24 (s, 3H) 2.38-2.38 (m, 1H) 2.46 (s, 3H) 3.12 (br d, J=10.92 Hz, 2H) 5.29 (s, 2H) 6.65 (s, 1H) 7.47 (br s, 1H) 7.82-7.90 (m, 1H) 8.29 (br s, 2H) 8.63 (s, 2H)

Assay 1: Binding Activity of c-MET Enzyme Assay

[0211] Reagents and Consumables:

[0212] cMET (invitrogen PV3143)

[0213] Tracer 236 (Lot Number: 10815978)

[0214] Eu-Anti-His AB (MAb Anti 6HIS-K)

[0215] PerkinElmer corporation Envison detection 665 nm and 615 nm

[0216] 384-well plate_checkerboard (PerkinElmer #6007299)

[0217] Experimental Principle:

[0218] The present experiment utilized the LanthaScreen Eu Kinase Binding Assay, as shown in FIG. 1, detection of Alexa Fluor conjugates or kinase combines tracer agent was done by adding Eu labelled antibody. The binding of tracer agent and antibody and kinase leaded to high FRET standard, while using kinase inhibitor instead of tracer agent would lead to loss of FRET.

[0219] Experimental Method:

[0220] 1) The antibody Eu-Anti-His AB, enzyme cMET, tracer agent Tracer236 were diluted.

[0221] 2) Preparation of the compound: 10 mM test compound and reference compound were diluted by 100% DMSO to 0.667 mM, then fully automated microplate pretreatment system ECHO was used for a 3-time dilution with 8 concentration gradients. Double duplicate wells were set and each of them 75 nL.

[0222] 3) The mixture of 7.5 L antibody ( 1/375 nM) and kinase (10 nM) was added to the compound plate, followed by addition of 7.5 L Tracer (60 nM). Final concentration: cMET: 5 nM, Tracer 236: 30 nM, Eu-Anti-His AB (MAb Anti 6HIS-K): 1/750 nM.

[0223] 4) After 60 mins of incubation at 4 C., Envision readings were performed with a multi-labelled microplate reader (data analysis of 665 nm/615 mm signal values with Prism 5; Ex excitation light: Laser mirror 446, Em excitation light; 615 and 665 nM.

[0224] Experimental result: See Table 1.

[0225] Conclusion: the compounds of the present invention have a relatively strong inhibitory effect on the c-MET enzyme.

TABLE-US-00001 TABLE 1 Test compound c-MET IC.sub.50 (nM) Embodiment 1-2 1.09 Embodiment 2-2 9.33 Embodiment 4 6.16 Embodiment 5 2.90 Embodiment 6 4.37 Embodiment 7 15.50 Embodiment 8-2 3.79 Embodiment 10 69.50 Embodiment 11 5.00

Assay 2: Inhibitory Effect Assay on Proliferation

[0226] Reagents and Consumables:

[0227] 1) Cell culture: DMEM cell medium, fetal bovine serum, DPBS

[0228] 2) Cell line: MHCC97-H

[0229] 3) Detection reagent: live cell detection kit CellTiter-Glo

[0230] 4) Other major consumables and reagents: compound dilution plate, intermediate plate, test plate, DMSO

[0231] Experimental Principle:

[0232] The amount of ATP directly reflects the number of cells and the state of the cells, thus the number of living cells could be directly detected by quantitatively measuring ATP. The live cell assay kit contains luciferase and its substrate. With the presence of ATP, a stable optical signal would be emitted by the luciferase catalyzed substrate. Thus the amount of ATP in the cell could be determined by detecting the intensity of the signal. The light signal was proportional to the amount of ATP in the cell, while the ATP was positively correlated with the number of living cells, so that the proliferation in the cell could be detected. The assay plate used was analyzed by Envision from PE Corporation.

[0233] Experimental Method:

[0234] 1. Preparation of the cell plates

[0235] MHCC97-H cells were seeded separately into 384-well plates, each of the well contains 500 cells. The cell plates were placed and incubated in a carbon dioxide incubator overnight.

[0236] 2. Preparation of the compound.

[0237] Echo was used for 4-time dilution and 9 concentration was prepared, ready for double duplicate wells assay.

[0238] 3. Compound treatment of cells

[0239] The compounds were transferred to cell plates at a starting concentration of 10 M. The cell plates were incubated in a carbon dioxide incubator for 3 days.

[0240] 4. Detection

[0241] The Promegaer-Glo reagent was added into the cell plates and the plate was incubated at room temperature for 10 mins to stabilize the luminescence signal. PerkinElmer Envision multi-label analyzer was used for readings.

[0242] Experimental results: See Table 2:

[0243] Conclusion: the compounds of the present invention exhibit good inhibitory activity against MHCC97H cells.

TABLE-US-00002 TABLE 2 Test compound MHCC97H cell IC.sub.50 (nM) Embodiment 1 8.80 Embodiment 2-2 13.80 Embodiment 3-2 19.0 Embodiment 4 72.90 Embodiment 5 58.80 Embodiment 6 32.90 Embodiment 7 22.30 Embodiment 9-2 22.10 Embodiment 10 166.00 Embodiment 11 93.80 Embodiment 12 51.40

Assay 3: Pharmacodynamics Assay of MHCC97H Liver Cancer Cell Subcutaneous Xanograft Tumor Model

[0244] Cell Culture:

[0245] MHCC97H cells were cultured in a single layer in-vitro. The culturing condition was RPMI1640 medium supplemented with 10% heat-inactivated fetal bovine serum, 1% penicillin-streptomycin double antibody under 37 C., 5% carbon dioxide. Digestion and passage treatment with trypsin-EDTA was done twice a week. When the cells are in the exponential growing phase, the cells were collected, counted and inoculated.

[0246] Animal:

[0247] BALB/c nude mice, male. 6-8 weeks old, weighting 18-22 g.

[0248] Tumor Inoculation:

[0249] 0.2 mL of a cell suspension containing 510{circumflex over ()}6 MHCC97H was subcutaneously inoculated into the right back of each mouse. Drugs were administrated by group after the average tumor volume reached approximately 172 mm.sup.3. The experimental grouping and administrational schedule are shown in the table below.

[0250] Aim of the assay: investigation of whether the tumor growth was inhibited, delayed or cured. The diameters of the tumor was measured twice a week using vernier calipers. The formula for calculating the tumor volume is V=0.5ab2, and a and b represent the long and short diameters of the tumor respectively. The antitumor effect (TGI) of the compounds was evaluated by T-C(days) and T/C (%).

[0251] Experimental results: see in Table 3.

[0252] Conclusion: the compounds of the present invention exhibit better tumor inhibitory activity than Tepotinib in the pharmacodynamics assays of the subcutaneous xenograft tumor model of MHCC97H hepatoma cells.

TABLE-US-00003 TABLE 3 Evaluation of the anti-tumor efficacy of tested drugs on human liver cancer MHCC97H cell xenograft model (calculations based on the 24.sup.th day-tumor-volume after administration of drug) Tumor volume (mm.sup.3).sup.a T/C TGI group (24th day) (%) (%) p value .sup.b blank 2059 305 (Tepotinib) 255 5 12.4 95.6 <0.001 Embodiment 1-2 153 12 7.4 101.0 <0.001 Embodiment 8-2 161 6 7.8 100.6 <0.001 remarks: .sup.aaverage SEM. .sup.b p value was calculated based on the volume of the tumor.

[0253] The compounds of the present invention have better metabolic stability than tepotinib. For example, the t.sub.1/2 of liver particle metabolism in the three species of human, rat and mice of embodiment 1-2 are 62.1 min, 36.5 min and 49.1 min respectively. While under the same conditions for Tepotinib in the three species of human, rat and mice, the t.sub.1/2 of liver particle metabolism are 48.3 min, 10.5 min and 12.4 min respectively. The compounds of the present invention have an extended half-time and action time on the target, an enhanced metabolic stability and more excellent inhibitory activity. The prolongation of half-time would keep the concentration in the blood for a longer time. Thus comparing to other medicament in the tumor treatment, the compounds would reduce the dose and interval between doses so that the patient compliance would be significantly improved.

[0254] Since when c-MET combined with HGF, it activated the MAPK, PI3K/AKT. CDc42-Rac1 and other pathways, leading to tumor cells survival and proliferation, thereby accelerated the tumor growth rate. Thus the pyridone compound as c-Met inhibitor has great application prospects in targeted therapeutic drugs such as liver cancer, non-small cell lung cancer and gastric cancer. Especially in treating liver cancer, this compound has a precise therapeutic effect on liver cancer with high expression of c-Met. Therefore, the pyridone compound as c-Met inhibitor in the present invention is expected to be a more therapeutically effective new drug than other similar products in view of its remarkable inhibitory activity in vivo and in vitro, as well as its good metabolic stability.