Compound having ERK kinase inhibitory activity and use thereof

1. A compound of Formula (Ie), or a stereoisomer, racemate, geometric isomer, tautomer, hydrate, solvate or pharmaceutically acceptable salt thereof,

wherein,

X 1 is selected from the group consisting of CH, CD, and N;

R 1 is selected from the group consisting of H and D;

R 2 is selected from the group consisting of C 1-6 alkyl optionally substituted with one or more hydroxyl, C 3-8 cycloalkyl optionally substituted with one or more hydroxyl, 3-8 membered heterocyclyl, and 5-7 membered heteroaryl optionally substituted with one or more substituents selected from —CD 3 , C 1-6 alkyl and hydroxylC 1-6 alkyl;

R 3 is selected from the group consisting of halo and C 1-6 alkyl;

R 4 is —CO(CR 10 R 11 ) m R 12 ; wherein m is 0, 1, 2 or 3, and wherein

R 10 and R 11 are each independently selected from the group consisting of H, D, and C 1-4 alkyl optionally substituted with hydroxyl; and

R 12 is each independently selected from optionally substituted phenyl and optionally substituted pyridinyl, wherein the optional substituent is one or more substituents independently selected from the group consisting of D, halo, C 1-4 alkyl, cyano, and C 3-8 heterocyclyl-(CH 2 ) 0-4 —; and

R 5 , R 6 , R 7 and R 8 are each independently selected from the group consisting of —H, and C 1-6 alkyl optionally substituted with hydroxyl or —OC 1 -C 6 alkyl,

provided that the compound is not

2-(2-chloropyridin-3-yl)-1-(7-fluoro-2-(hydroxylmethyl)-5-(2-(isopropylamino)pyrimidin-4-yl)indolin-1-yl)ethan-1-one.

2. The compound according to claim 1 , wherein

R 2 is selected from the group consisting of C 1-4 alkyl optionally substituted with one or more hydroxyl;

 which are optionally substituted with one or more hydroxyl;

 which are optionally substituted with one or more substituents independently selected from the group consisting of C 1-4 alkyl, —CD 3 and hydroxylC 1-4 alkyl.

3. The compound according to claim 1 , wherein R 3 is selected from the group consisting of fluoro, chloro, bromo, iodo, —CH 3 , —CH 2 CH 3 , —CH(CH 3 ) 2 , and —CH 2 CH 2 CH 3 .

4. The compound according to claim 1 , wherein

R 12 is selected from the group consisting of

wherein Rc is selected from the group consisting of halo, C 1-4 alkyl,

wherein R d is selected from the group consisting of H, C 1-4 alkyl, and

wherein R e is selected from the group consisting of halo, and p is 1 or 2; and

wherein R f is selected from the group consisting of

5. The compound according to claim 1 , wherein R 4 is selected from the group consisting of —CO(CR 10 R 11 ) m R 12 , wherein m is 0, 1, 2 or 3, and wherein

R 10 and R 11 are each independently H; and

R 12 is selected from the group consisting of

6. The compound according to claim 1 , wherein R 4 is selected from the group consisting of —CO(CR 10 R 11 ) m R 12 , wherein m is 0, 1, 2 or 3, and wherein R 10 and R 11 are each independently H; R 12 is selected from the group consisting of 2-cyanophenyl, 5-chloro-2-fluorophenyl, 2-chloro-3-fluorophenyl, 2-chloro-4-fluorophenyl, 2-chloro-5-fluorophenyl, 2,5-difluorophenyl, 3-chloropyridin-2-yl, 6-chloropyridin-2-yl, 3-chloropyridin-4-yl, or 4-chloropyridin-3-yl.

7. The compound according to claim 1 , wherein

R 5 and R 6 are each independently selected from the group consisting of H and C 1-6 alkyl; and R 7 and R 8 are each independently selected from the group consisting of H and C 1-6 alkyl optionally substituted with hydroxyl or —OC 1 -C 6 alkyl.

8. A compound selected from the group consisting of Examples P1-P20, P23-P25, P28-51, P53-P64, or a pharmaceutically acceptable salt thereof,

P1 

P2 

P3 

P4 

P5 

P6 

P7 

P8 

P9 

P10

P11

P12

P12

P13

P13

P14

P14

P15

P16

P17

P17

P18

P18

P19

P19

P20

P23

P24

P25

P28

P29

P30

P31

P32

P33

P34

P35

P35

P36

P37

P38

P39

P40 and P41

P42 and P43

P44

P45

P46

P47

P48

P49

P50

P51

P53

P54

P55

P56

P57

P58

P59

P60

P 60

P61

P62 and P63

P64

9. A compound t-butyl

(4-(7-fluoroindolin-5-yl)pyridin-2-yl)(1-methyl-1H-pyrazol-5-yl)carbamate represented by the formula:

or a stereoisomer, racemate, geometric isomer, tautomer, hydrate, solvate, or pharmaceutically acceptable salt thereof.

10. The compound according to claim 1 , wherein R 2 is selected from the group consisting of isopropyl,

11. The compound according to claim 1 , wherein R 3 is selected from the group consisting of fluoro, chloro and —CH 3 .

12. The compound according to claim 1 , wherein R 3 is selected from the group consisting of fluoro.

13. The compound according to claim 1 , wherein R 5 , R 6 , R 7 and R 8 are each independently selected from the group consisting of —H, —CH 3 , and —CH 2 OH.

14. A pharmaceutical composition, comprising the compound according to claim 1 or a pharmaceutically acceptable salt thereof, and optionally a pharmaceutically acceptable carrier.

15. A non-therapeutic method of inhibiting ERK kinase activity, comprising contacting an effective amount of the compound according to claim 1 or a pharmaceutically acceptable salt thereof, with an ERK kinase, thereby inhibiting the ERK kinase.

16. A method for preparing the compound of formula (Ie) according to claim 1 , wherein said compound of formula (Ie) is the compound of formula C3:

wherein X 1 , R 2 , R 3 , R 10 , R 11 , R 12 and m are as defined in claim 1 ,

comprising the steps of:

(a) subjecting the compound of formula C1

and the compound

 to amide coupling reaction, to give the compound of formula C2,

 and

(b) When the compound of C2 is Boc-protected, deprotecting it, to give the compound of formula C3,

17. The method according to claim 16 , wherein the amide coupling reaction is carried out in the presence of a condensing agent and a base in an inert solvent.

18. The method according to claim 16 , wherein the deprotection is carried out in the presence of an acid in an inert solvent.

19. The method according to claim 17 , wherein the inert solvent is selected from the group consisting of ethyl acetate, tetrahydrofuran, methyltetrahydrofuran, acetonitrile, dimethyl sulfoxide, N,N-dimethylformamide, dichloromethane, 1,2-dichloroethane, N-methyl-2-pyrolidone, or a combination thereof.

20. The method according to claim 17 , wherein the condensing agent is one or more selected from the group consisting of 1-hydroxylbenzotriazole (HOBT), 1-hydroxyl-7-azobenzotriazole (HOAT), benzotriazol-1-yl-oxytripyrrolidino-phosphonium hexafluorophosphate (PyBOP), benzotriazol-1-yloxytris(dimethylamino)phosphonium hexafluorophosphate (BOP), 1,1-carbonyldiimidazole (CDI), 1-propylphosphonic anhydride (T 3 P), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (EDC.HCl), N,N-dicyclohexylcarbodiimide (DCC), acetic anhydride, acetyl chloride, oxalyl chloride, O-(7-azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate (HATU), and O-(benzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate (HBTU).

21. The method according to claim 17 , wherein the base is one or more selected from the group consisting of triethylamine, DIPEA, pyridine, 2,4-dimethylpyridine, NaOH, KOH, LiOH, Na 2 CO 3 , K 2 CO 3 , NaHCO 3 , Cs 2 CO 3 , Na 3 PO 4 , or K 3 PO 4 .

22. The method according to claim 16 , wherein the amide coupling reaction is carried out at a temperature from room temperature to reflux for 0.5-24 h.

23. The method according to claim 18 , wherein the acid is one or more selected from the group consisting of hydrochloric acid, sulfuric acid, trifluoroacetic acid, acetic acid, formic acid, and phosphoric acid.

24. The method according to claim 16 , wherein the deprotection is carried out at a temperature from −10° C. to 80° C. for 0.5-24 h.

25. The method according to claim 18 , wherein the inert solvent is selected from the group consisting of ethyl acetate, tetrahydrofuran, methyltetrahydrofuran, acetonitrile, dimethyl sulfoxide, N,N-dimethylformamide, dichloromethane, 1,2-dichloroethane, N-methyl-2-pyrolidone, or a combination thereof.