Uracil derivatives as AXL and c-MET kinase inhibitors

1. A compound of Formula I,

wherein:

E and G are independently chosen from H, C 1-6 alkyl optionally substituted by 1-6 R 19 , C 2-6 alkenyl optionally substituted by 1-6 R 19 , C 2-6 alkynyl optionally substituted by 1-6 R 19 , C 6-11 aryl optionally substituted by 1-6 R 19 , C 3-11 cycloalkyl optionally substituted by 1-6 R 19 , 3-15 membered heterocyclyl optionally substituted by 1-6 R 19 , 5-15 membered heteroaryl optionally substituted by 1-6 R 19 , —C(═O)R 20 , —C(═O)OR 20 , —C(═O)NR 22 R 23 , —S(═O) 2 R 20 , and —S(═O) 2 NR 22 R 23 ;

X is N or C—R 4 ;

Y is N or C—R 1d ;

R 3 is H or C 1-6 alkyl;

D is —O—;

W is CH or N;

R a , R b , R c , R d , R 1a , R 1b , R 1c , R 1d , and R 4 are independently chosen from H, C 1-6 alkyl optionally substituted by 1-6 R 119 , C 2-6 alkenyl optionally substituted by 1-6 R 119 , C 2-6 alkynyl optionally substituted by 1-6 R 119 , C 6-11 aryl optionally substituted by 1-6 R 119 , C 3-11 cycloalkyl optionally substituted by 1-6 R 119 , 3-15 membered heterocyclyl optionally substituted by 1-6 R 119 , 5-15 membered heteroaryl optionally substituted by 1-6 R 119 , halogen, —CN, —C(═O)R 110 , —C(═O)OR 110 , —C(═O)NR 112 R 113 , —NC, —NO 2 , —NR 112 R 113 , —NR 114 C(═O)R 110 , —NR 114 C(O)OR 111 , —NR 114 C(O)NR 112 R 113 , —NR 114 S(═O) 2 R 111 , —NR 114 S(O) 2 NR 112 R 113 , —OR 110 , —OCN, —OC(═O)R 110 , —OC(═O)NR 112 R 113 , —OC(═O)OR 110 , —S(═O) n R 110 , and —S(═O) 2 NR 112 R 113 ;

or any of R a and R b , R a and R d , and R b and R c can, together with the atoms linking them, form a C 6-11 aryl optionally substituted by 1-6 R 119 , C 3-11 cycloalkyl optionally substituted by 1-6 R 119 , 3-15 membered heterocyclyl optionally substituted by 1-6 R 119 or a 5-15 membered heteroaryl optionally substituted by 1-6 R 119 ;

R 19 at each occurrence is independently chosen from C 1-6 alkyl optionally substituted by 1-6 R 39 , C 2-6 alkenyl optionally substituted by 1-6 R 39 , C 2-6 alkynyl optionally substituted by 1-6 R 39 , C 6-11 aryl optionally substituted by 1-6 R 39 , C 3-11 cycloalkyl optionally substituted by 1-6 R 39 , 3-15 membered heterocyclyl optionally substituted by 1-6 R 39 , 5-15 membered heteroaryl optionally substituted by 1-6 R 39 , halogen, —CN, —C(═O)R 30 , —C(═O)OR 30 , —C(═O)NR 32 R 33 , —NO 2 , —NR 32 R 33 , —NR 34 C(═O)R 30 , —NR 34 C(═O)OR 31 , —NR 34 C(═O)NR 32 R 33 , —NR 34 S(═O) 2 R 31 , —NR 34 S(═O) 2 NR 32 R 33 , —OR 30 , ═O, —OC(═O)R 30 , —OC(═O)NR 32 R 33 , —OC(═O)OR 30 , —S(═O) n R 30 , and —S(═O) 2 NR 32 R 33 ;

R 20 , R 30 , R 31 , and R 34 at each occurrence is independently chosen from H, C 1-6 alkyl optionally substituted by 1-6 R 49 , C 2-6 alkenyl optionally substituted by 1-6 R 49 , C 2-6 alkynyl optionally substituted by 1-6 R 49 , C 6-11 aryl optionally substituted by 1-6 R 49 , C 3-11 cycloalkyl optionally substituted by 1-6 R 49 , 3-15 membered heterocyclyl optionally substituted by 1-6 R 49 , and 5-15 membered heteroaryl optionally substituted by 1-6 R 49 ;

R 22 , R 23 , R 32 and R 33 at each occurrence is independently chosen from H, C 1-6 alkyl optionally substituted by 1-6 R 59 , C 2-6 alkenyl optionally substituted by 1-6 R 59 , C 2-6 alkynyl optionally substituted by 1-6 R 59 , C 6-11 aryl optionally substituted by 1-6 R 59 , C 3-11 cycloalkyl optionally substituted by 1-6 R 59 , 3-15 membered heterocyclyl optionally substituted by 1-6 R 59 , and 5-15 membered heteroaryl optionally substituted by 1-6 R 59 ;

or any R 22 and R 23 and/or R 32 and R 33 may form, together with the nitrogen atom to which they are attached, a 3-15 membered heterocyclyl optionally substituted by 1-6 R 69 or a 5-15 membered heteroaryl optionally substituted by 1-6 R 69 ;

R 39 , R 49 , R 59 and R 69 at each occurrence is independently chosen from C 1-6 alkyl optionally substituted by 1-6 R 79 , C 2-6 alkenyl optionally substituted by 1-6 R 79 , C 2-6 alkynyl optionally substituted by 1-6 R 79 , C 6-11 aryl optionally substituted by 1-6 R 79 , C 3-11 cycloalkyl optionally substituted by 1-6 R 79 , 3-15 membered heterocyclyl optionally substituted by 1-6 R 79 , 5-15 membered heteroaryl optionally substituted by 1-6 R 79 , halogen, —CN, —C(═O)R 70 , —C(═O)OR 70 , —C(═O)NR 72 R 73 , —NO 2 , —NR 72 R 73 , —NR 74 C(═O)R 70 , —NR 74 C(═O)OR 71 , —NR 74 C(═O)NR 72 R 73 , —NR 74 S(═O) 2 R 71 , —NR 74 S(═O) 2 NR 72 R 73 , —OR 70 , ═O, —OC(═O)R 70 , —OC(═O)NR 72 R 73 , —S(═O)—R 70 , and —S(═O) 2 NR 72 R 73 ;

R 70 , R 71 , R 72 , R 73 , and R 74 at each occurrence is independently chosen from H, C 1-6 alkyl and C 1-6 -haloalkyl;

R 79 at each occurrence is independently chosen from C 1-6 alkyl, C 1-6 -haloalkyl, benzyl, halogen, —CN, —C(═O)(C 1-6 alkyl), —C(═O)O(C 1-6 alkyl), —C(═O)N(C 1-6 alkyl) 2 , —C(═O)OH, —C(═O)NH 2 , —C(═O)NHC 1-6 alkyl, —NO 2 , —NH 2 , —NHC 1-6 alkyl, —N(C 1-6 alkyl) 2 , —NHC(═O)C 1-6 alkyl, —NHS(═O) 2 C 1-6 alkyl, —OH, —OC 1-6 alkyl, ═O, —OC(═O)C 1-6 alkyl, —OS(═O) 2 C 1-6 alkyl, —S(═O) 2 C 1-6 alkyl, and —S(═O) 2 N(C 1-6 alkyl) 2 ;

R 110 , R 111 , and R 114 at each occurrence is independently chosen from H, C 1-6 alkyl optionally substituted by 1-6 R 129 , C 2-6 alkenyl optionally substituted by 1-6 R 129 , C 2-6 alkynyl optionally substituted by 1-6 R 129 , C 6-11 aryl optionally substituted by 1-6 R 129 , C 3-11 cycloalkyl optionally substituted by 1-6 R 129 , 3-15 membered heterocyclyl optionally substituted by 1-6 R 129 , and 5-15 membered heteroaryl optionally substituted by 1-6 R 129 ;

R 112 and R 113 at each occurrence is independently chosen from H, C 1-6 alkyl optionally substituted by 1-6 R 139 , C 2-6 alkenyl optionally substituted by 1-6 R 139 , C 2-6 alkynyl optionally substituted by 1-6 R 139 , C 6-11 aryl optionally substituted by 1-6 R 139 , C 3-11 cycloalkyl optionally substituted by 1-6 R 139 , 3-15 membered heterocyclyl optionally substituted by 1-6 R 139 , and 5-15 membered heteroaryl optionally substituted by 1-6 R 139 ;

or any R 112 and R 113 may form, together with the nitrogen atom to which they are attached, a 3-15 membered heterocyclyl optionally substituted by 1-6 R 149 or a 5-15 membered heteroaryl optionally substituted by 1-6 R 149 ;

R 119 at each occurrence is independently chosen from C 1-6 alkyl optionally substituted by 1-6 R 159 , C 2-6 alkenyl optionally substituted by 1-6 R 159 , C 2-6 alkynyl optionally substituted by 1-6 R 159 , C 6-11 aryl optionally substituted by 1-6 R 159 , C 3-11 cycloalkyl optionally substituted by 1-6 R 159 , 3-15 membered heterocyclyl optionally substituted by 1-6 R 159 , 5-15 membered heteroaryl optionally substituted by 1-6 R 159 , halogen, —CN, —C(═O)R 150 , —C(═O)OR 150 , —C(═O)NR 152 R 153 , —NC, —NO 2 , —NR 152 R 153 , —NR 154 C(═O)R 150 , —NR 154 C(═O)OR 151 , —NR 154 C(═O)NR 152 R 153 , —NR 154 S(═O) 2 R 151 , —NR 154 S(═O) 2 NR 152 R 153 , —OR 150 , ═O, —OC(═O)R 150 , —OC(═O)NR 152 R 153 , —S(═O) n R 150 , and —S(═O) 2 NR 152 R 153 ;

R 150 , R 151 , R 152 , R 153 and R 154 at each occurrence is independently chosen from H, C 1-6 alkyl, benzyl, and C 1-6 -haloalkyl;

R 129 , R 139 , R 149 , and R 159 at each occurrence is independently chosen from C 1-6 alkyl, C 1-6 -haloalkyl, benzyl, halogen, —CN, —C(═O)(C 1-6 alkyl), —C(═O)O(C 1-6 alkyl), —C(═O)N(C 1-6 alkyl) 2 , —C(═O)OH, —C(═O)NH 2 , —C(═O)NHC 1-6 alkyl, —NO 2 , —NH 2 , —NHC 1-6 alkyl, —N(C 1-6 alkyl) 2 , —NHC(═O)C 1-6 alkyl, —NHS(═O) 2 C 1-6 alkyl, —OH, —OC 1-6 alkyl, ═O, —OC(═O)C 1-6 alkyl, —OS(═O) 2 C 1-6 alkyl, —S(═O) 2 C 1-6 alkyl, and —S(═O) 2 N(C 1-6 alkyl) 2 ; and

n at each occurrence is independently chosen from 0, 1, and 2;

or a pharmaceutically acceptable salt thereof.

2. The compound according to claim 1 , wherein E and G are independently chosen from H, C 1-6 alkyl optionally substituted by 1-6 R 19 , C 2-6 alkenyl optionally substituted by 1-6 R 19 , C 2-6 alkynyl optionally substituted by 1-6 R 19 , phenyl optionally substituted by 1-5 R 19 , C 3-6 cycloalkyl optionally substituted by 1-6 R 19 , 3-6 membered heterocyclyl optionally substituted by 1-5 R 19 , 5-6 membered heteroaryl optionally substituted by 1-3 R 19 , —C(═O)R 20 , —C(═O)OR 20 , —C(O)NR 22 R 23 , —S(═O) 2 R 20 , and —S(═O) 2 NR 22 R 23 ; or a pharmaceutically acceptable salt thereof.

3. The compound according to claim 1 , wherein E is chosen from H, C 1-6 alkyl optionally substituted by 1-3 R 19 , C 2-6 alkenyl, C 2-6 alkynyl optionally substituted by —OH, phenyl optionally substituted by halogen, and cyclohexyl; or a pharmaceutically acceptable salt thereof.

4. The compound according to claim 1 , wherein G is chosen from H, C 1-6 alkyl optionally substituted by 1-3 R 19 , C 3-6 alkenyl optionally substituted by 1-3 fluoro, C 3-6 alkynyl, phenyl optionally substituted by 1-3 fluoro, C 3-6 cycloalkyl, and 6 membered heterocyclyl; or a pharmaceutically acceptable salt thereof.

5. The compound according to claim 1 , wherein R 3 is H; or a pharmaceutically acceptable salt thereof.

6. The compound according to claim 1 , wherein W is CH, or a pharmaceutically acceptable salt thereof.

7. The compound according to claim 1 , wherein R a , R b , R c , and R d are independently chosen from H, C 1-6 alkyl optionally substituted by 1-6 R 119 , —CN, and —OR 110 , or R a and R b can, together with the atoms linking them, form a 5-6 membered heterocyclyl optionally substituted by 1-6 R 119 , or a pharmaceutically acceptable salt thereof.

8. The compound according to claim 1 , wherein R a is chosen from H and —OC 1-6 alkyl; R b is chosen from H and —OC 1-6 alkyl; R c is H; and R d is chosen from H and —OC 1-6 alkyl; or R a and R b together form

or a pharmaceutically acceptable salt thereof.

9. The compound according to claim 1 , wherein X is C—R 4 , and R 4 is chosen from H and C 1-6 alkyl, or a pharmaceutically acceptable salt thereof.

10. The compound according to claim 1 , wherein R 1a , R 1b , R 1c , and R 1d are independently chosen from H, C 1-6 alkyl optionally substituted by 1-6 R 119 , C 3-6 cycloalkyl optionally substituted by 1-6 R 119 , 3-6 membered heterocyclyl optionally substituted by 1-6 R 119 , halogen, —CN, —NR 112 R 113 , and —OR 110 , or a pharmaceutically acceptable salt thereof.

11. The compound according to claim 1 , wherein R 1a , R 1b , R 1c , and R 1d are independently chosen from H, C 1-6 alkyl, C 1-6 haloalkyl, C 3-6 cycloalkyl, halogen, —N(C 1-6 alkyl) 2 , —OC 1-6 alkyl, or a pharmaceutically acceptable salt thereof.

12. The compound according to claim 1 , wherein R 1a , R 1b , R 1c , and R 1d are independently chosen from H and fluoro, or a pharmaceutically acceptable salt thereof.

13. The compound according to claim 1 , wherein R 1a and R 1b are independently chosen from H, C 1-3 alkyl, C 1-3 haloalkyl, C 3-6 cycloalkyl, halogen, and —OC 1-3 alkyl; and R 1c and R 1d are independently chosen from H, C 1-3 alkyl, halogen, —N(C 1-3 alkyl) 2 , and —OC 1-3 alkyl, or a pharmaceutically acceptable salt thereof.

14. The compound according to claim 1 , wherein R 1a , R 1c , and R 1d are H and R 1b is chosen from H, halogen, and —OC 1-3 alkyl, or a pharmaceutically acceptable salt thereof.

15. The compound according to claim 1 , wherein R 19 at each occurrence is independently chosen from C 1-6 alkyl, phenyl optionally substituted by 1-3 halogen, C 3-6 cycloalkyl, 5-6 membered heterocyclyl, 5-6 membered heteroaryl optionally substituted by 1-3 C 1-6 alkyl, halogen, —CN, —C(═O)OH, —C(═O)OC 1-6 alkyl, —C(═O)N(C 1-6 alkyl) 2 , —C(═O)pyrrolidinyl, —C(═O)morpholinyl, —N(C 1-6 alkyl) 2 , —OH, —OC 1-6 alkyl, —Obenzyl, and ═O; R 20 , R 22 , and R 23 at each occurrence is independently chosen from H, C 1-6 alkyl, C 1-6 halolkyl, phenyl, benzyl, C 5-6 cycloalkyl, 5-6 membered heterocyclyl, and 5-6 membered heteroaryl; R 110 , R 112 , R 113 and R 114 at each occurrence is independently chosen from H, and C 1-6 alkyl optionally substituted by —OC 1-3 alkyl; and R 119 at each occurrence is independently chosen from C 1-6 alkyl, C 1-6 haloalkyl, 5-6 membered heterocyclyl, and halogen, or a pharmaceutically acceptable salt thereof.

16. The compound according to claim 1 , wherein:

E and G are independently chosen from H, C 1-6 alkyl optionally substituted by 1-6 R 19 , C 2-6 alkenyl optionally substituted by 1-6 R 19 , C 2-6 alkynyl optionally substituted by 1-6 R 19 , phenyl optionally substituted by 1-5 R 19 , C 3-6 cycloalkyl optionally substituted by 1-6 R 19 , 3-6 membered heterocyclyl optionally substituted by 1-5 R 19 , 5-6 membered heteroaryl optionally substituted) by 1-3 R 19 , —C(═O)R 20 , —C(═O)OR 20 , —C(═O)NR 22 R 23 , —S(═O) 2 R 20 , and —S(═O) 2 NR 22 R 23 ;

R 3 is H;

W is CH;

Y is C—R 1d ;

R 1a , R 1b , R 1c , and R 1d are independently chosen from H, C 1-6 alkyl optionally substituted by 1-6 R 119 , C 3-6 cycloalkyl optionally substituted by 1-6 R 119 , 3-6 membered heterocyclyl optionally substituted by 1-6 R 119 , halogen, —CN, —NR 112 R 113 , and —OR 110 ; and

R 19 at each occurrence is independently chosen from C 1-6 alkyl, phenyl optionally substituted by 1-3 halogen, C 3-6 cycloalkyl, 5-6 membered heterocyclyl, 5-6 membered heteroaryl optionally substituted by 1-3 C 1-6 alkyl, halogen, —CN, —C(═O)OH, —C(═O)OC 1-6 alkyl, —C(═O)N(C 1-6 alkyl) 2 , —C(═O)pyrrolidinyl, —C(═O)morpholinyl, —N(C 1-6 alkyl) 2 , —OH, —OC 1-6 alkyl, —Obenzyl, and ═O; R 20 , R 22 , and R 23 at each occurrence is independently chosen from H, C 1-6 alkyl, C 1-6 halolkyl, phenyl, benzyl, C 5-6 cycloalkyl, 5-6 membered heterocyclyl, and 5-6 membered heteroaryl; R 110 , R 112 , R 113 , and R 114 at each occurrence is independently chosen from H, and C 1-6 alkyl optionally substituted by —OC 1-3 alkyl; and R 119 at each occurrence is independently chosen from C 1-6 alkyl, C 1-6 haloalkyl, 5-6 membered heterocyclyl, and halogen;

or a pharmaceutically acceptable salt thereof.

17. The compound according to claim 16 , wherein:

E and G are independently chosen from C 1-6 alkyl optionally substituted by 1-6 R 19 , and phenyl optionally substituted by 1-5 R 19 ; and

R 1a , R 1b , R 1c , and R 1d are independently chosen from H and halogen;

or a pharmaceutically acceptable salt thereof.

18. The compound according to claim 17 , wherein E and G are independently chosen from C 1-6 alkyl, and phenyl substituted by 1-5 R 19 ; or a pharmaceutically acceptable salt thereof.

19. The compound according to claim 18 , wherein R 19 is halogen, or a pharmaceutically acceptable salt thereof.

20. The compound according to claim 18 , wherein E and G are independently chosen from C 1-6 alkyl, and phenyl substituted by 1 R 19 ; or a pharmaceutically acceptable salt thereof.

21. The compound according to claim 20 , wherein R 19 is halogen, or a pharmaceutically acceptable salt thereof.

22. The compound according to claim 21 , wherein E is phenyl substituted with halogen, or a pharmaceutically acceptable salt thereof.

23. The compound according to claim 22 , wherein E is phenyl substituted with fluorine, or a pharmaceutically acceptable salt thereof.

24. The compound according to claim 23 , wherein E is para-fluorophenyl, or a pharmaceutically acceptable salt thereof.

25. The compound according to claim 1 , wherein:

E is phenyl substituted with halogen;

G is C 1-6 alkyl;

X and Y are C—H;

R 3 , R 1b , R 1c , R c and R d are hydrogen;

R 1a is halogen;

W is CH;

R a and R b are —OR 110 ; and

R 110 is C 1-6 alkyl;

or a pharmaceutically acceptable salt thereof.

26. The compound according to claim 25 , wherein E is phenyl substituted with fluorine, or a pharmaceutically acceptable salt thereof.

27. The compound according to claim 26 , wherein E is para-fluorophenyl, or a pharmaceutically acceptable salt thereof.

28. The compound according to claim 25 , wherein G is iso-propyl, or a pharmaceutically acceptable salt thereof.

29. A pharmaceutical composition, comprising a therapeutically effective amount of the compound according to claim 1 , or a pharmaceutically acceptable salt thereof.