Benzylamino substituted pyridopyrimidinones and derivatives as SOS1 inhibitors
The present invention encompasses compounds of formula (I) wherein the groups R 1 to R 4 , A and p have the meanings given in the claims and specification, their use as inhibitors of SOS1, pharmaceutical compositions which contain compounds of this kind and their use as medicaments/medical uses, especially as agents for treatment and/or prevention of oncological diseases.
1. A compound of formula (I)
wherein
R 1 is R a1 ;
R a1 is selected from the group consisting of C 1-6 alkyl, C 1-6 haloalkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-10 cycloalkyl, C 4-10 cycloalkenyl, 3-10 membered heterocyclyl, C 6-10 aryl and 5-10 membered heteroaryl, wherein the C 1-6 alkyl, C 1-6 haloalkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-10 cycloalkyl, C 4-10 cycloalkenyl, 3-10 membered heterocyclyl, C 6-10 aryl and 5-10 membered heteroaryl are all optionally substituted by one or more, identical or different R b1 and/or R c1 ;
each R b1 is independently selected from the group consisting of —OR c1 , —NR c1 R c1 , halogen, —CN, —C(O)R c1 , —C(O)OR c1 , —C(O)NR c1 R c1 , —S(O) 2 R c1 , —S(O) 2 NR c1 R c1 , —NHC(O)R c1 , —N(C 1-4 alkyl)C(O)R c1 , —NHC(O)OR c1 and —N(C 1-4 alkyl)C(O)OR c1 ;
each R c1 is independently selected from the group consisting of hydrogen, C 1-6 alkyl, C 1-6 haloalkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-10 cycloalkyl, C 4-10 cycloalkenyl, 3-10 membered heterocyclyl, C 6-10 aryl and 5-10 membered heteroaryl, wherein the C 1-6 alkyl, C 1-6 haloalkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-10 cycloalkyl, C 4-10 cycloalkenyl, 3-10 membered heterocyclyl, C 6-10 aryl and 5-10 membered heteroaryl are all optionally substituted by one or more, identical or different R d1 and/or R e1 ;
each R d1 is independently selected from the group consisting of —OR e1 , —NR e1 R e1 , halogen, —CN, —C(O)R e1 , —C(O)OR e1 , —C(O)NR e1 R e1 , —S(O) 2 R e1 , —S(O) 2 NR e1 R e1 , —NHC(O)R e1 , —N(C 1-4 alkyl)C(O)R e1 , —NHC(O)OR e1 and —N(C 1-4 alkyl)C(O)OR e1 ;
each R e1 is independently selected from the group consisting of hydrogen, C 1-6 alkyl, C 1-6 haloalkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-10 cycloalkyl, C 4-10 cycloalkenyl, 3-10 membered heterocyclyl, C 6-10 aryl and 5-10 membered heteroaryl;
R 2 is selected from the group consisting of hydrogen, C 1-4 alkyl, C 3-6 cycloalkyl, 3-6 membered heterocyclyl and halogen;
R 3 is selected from the group consisting of hydrogen, C 1-4 alkyl and C 1-4 haloalkyl;
ring system A is selected from the group consisting of C 6-10 aryl, 5-10 membered heteroaryl and 9-10 membered bicyclic heterocyclyl;
p denotes 1, 2 or 3;
each R 4 is independently selected from the group consisting of C 1-4 alkyl, C 2-4 alkenyl, C 2-4 alkinyl, C 1-4 haloalkyl, hydroxy-C 1-4 alkyl, hydroxy-C 1-4 haloalkyl, C 3-6 cycloalkyl, 3-6 membered heterocyclyl, hydroxy-C 3-6 cycloalkyl, C 1-4 haloalkyl substituted with a 3-6 membered heterocyclyl, 3-6 membered heterocyclyl substituted with hydroxy, halogen, —NH 2 , —SO 2 —C 1-4 alkyl and the bivalent substituent ═O, while ═O may only be a substituent in a non-aromatic ring;
or a salt thereof.
2. A compound or salt according to claim 1 , wherein
R 1 is R a1 ;
R a1 is selected from the group consisting of C 1-6 alkyl, C 1-6 haloalkyl, C 3-10 cycloalkyl, C 4-10 cycloalkenyl, 3-10 membered heterocyclyl, C 6-10 aryl and 5-10 membered heteroaryl, wherein the C 1-6 alkyl, C 1-6 haloalkyl, C 3-10 cycloalkyl, C 4-10 cycloalkenyl, 3-10 membered heterocyclyl, C 6-10 aryl and 5-10 membered heteroaryl are all optionally substituted by one or more, identical or different R b1 and/or R c1 ;
each R b1 is independently selected from the group consisting of —OR c1 , —NR c1 R c1 , halogen, —CN, —C(O)R c1 , —C(O)OR c1 and —C(O)NR c1 R c1 ;
each R c1 is independently selected from the group consisting of hydrogen, C 1-6 alkyl, C 1-6 haloalkyl, C 3-10 cycloalkyl, C 4-10 cycloalkenyl, 3-10 membered heterocyclyl, C 6-10 aryl and 5-10 membered heteroaryl, wherein the C 1-6 alkyl, C 1-6 haloalkyl, C 3-10 cycloalkyl, C 4-10 cycloalkenyl, 3-10 membered heterocyclyl, C 6-10 aryl and 5-10 membered heteroaryl are all optionally substituted by one or more, identical or different R d1 and/or R e1 ;
each R d1 is independently selected from the group consisting of —OR e1 , —NR e1 R e1 , halogen, —CN, —C(O)R e1 , —C(O)OR e1 and —C(O)NR e1 R e1 ;
each R e1 is independently selected from the group consisting of hydrogen, C 1-6 alkyl, C 1-6 haloalkyl, C 3-10 cycloalkyl, C 4-10 cycloalkenyl, 3-10 membered heterocyclyl, C 6-10 aryl and 5-10 membered heteroaryl.
3. A compound or salt according to claim 2 , wherein
R 1 is R a1 ;
R a1 is selected from the group consisting of C 1-6 alkyl, C 1-6 haloalkyl, C 3-10 cycloalkyl, C 4-10 cycloalkenyl, 3-10 membered heterocyclyl and 5-10 membered heteroaryl, wherein the C 1-6 alkyl, C 1-6 haloalkyl, C 3-10 cycloalkyl, C 4-10 cycloalkenyl, 3-10 membered heterocyclyl and 5-10 membered heteroaryl are all optionally substituted by one or more, identical or different R b1 and/or R c1 ;
each R b1 is independently selected from the group consisting of —OR c1 , halogen and —C(O)NR c1 R c1 ;
each R c1 is independently selected from the group consisting of hydrogen, C 1-6 alkyl, C 1-6 haloalkyl, 3-10 membered heterocyclyl, C 6-10 aryl and 5-10 membered heteroaryl, wherein the C 1-6 alkyl, C 1-6 haloalkyl, 3-10 membered heterocyclyl, C 6-10 aryl and 5-10 membered heteroaryl are all optionally substituted by one or more, identical or different R d1 and/or R e1 ;
each R d1 is independently selected from the group consisting of —OR e1 and halogen;
each R e1 is independently selected from the group consisting of hydrogen and C 1-6 alkyl.
4. A compound or salt according to claim 1 , wherein
R 1 is R a1 ;
R a1 is selected from the group consisting of C 3-10 cycloalkyl and C 4-10 cycloalkenyl, wherein the C 3-10 cycloalkyl and C 4-10 cycloalkenyl are both optionally substituted by one or more, identical or different R b1 and/or R c1 ;
each R b1 is independently selected from the group consisting of —OR c1 , —NR c1 R c1 , halogen, —CN, —C(O)R c1 , —C(O)OR c1 and —C(O)NR c1 R c1 ;
each R c1 is independently selected from the group consisting of hydrogen, C 1-6 alkyl, C 1-6 haloalkyl, C 3-10 cycloalkyl, C 4-10 cycloalkenyl, 3-10 membered heterocyclyl, C 6-10 aryl and 5-10 membered heteroaryl, wherein the C 1-6 alkyl, C 1-6 haloalkyl, C 3-10 cycloalkyl, C 4-10 cycloalkenyl, 3-10 membered heterocyclyl, C 6-10 aryl and 5-10 membered heteroaryl are all optionally substituted by one or more, identical or different R d1 and/or R e1 ;
each R d1 is independently selected from the group consisting of —OR e1 , —NR e1 R e1 , halogen, —CN, —C(O)R e1 , —C(O)OR e1 , —C(O)NR e1 R e1 ;
each R e1 is independently selected from the group consisting of hydrogen, C 1-6 alkyl, C 1-6 haloalkyl, C 3-10 cycloalkyl, C 4-10 cycloalkenyl, 3-10 membered heterocyclyl, C 6-10 aryl and 5-10 membered heteroaryl.
5. A compound or salt according to claim 4 , wherein
R 1 is C 3-8 cycloalkyl optionally substituted by one or more, identical or different R b1 and/or R c1 ;
each R b1 is independently selected from the group consisting of —OR c1 , halogen and —C(O)NR c1 R c1 ;
each R c1 is independently selected from the group consisting of hydrogen, C 1-6 alkyl, C 1-6 haloalkyl, 3-8 membered heterocyclyl, phenyl and 5-6 membered heteroaryl, wherein the C 1-6 alkyl, C 1-6 haloalkyl, 3-8 membered heterocyclyl, phenyl and 5-6 membered heteroaryl are all optionally substituted by one or more, identical or different R d1 and/or R e1 ;
each R d1 is independently selected from the group consisting of —OR e1 and halogen;
each R e1 is independently selected from the group consisting of hydrogen and C 1-6 alkyl.
6. A compound or salt according to claim 5 , wherein
R 1 is C 3-8 cycloalkyl optionally substituted by one or more, identical or different substituent(s) selected from the group consisting of C 1-4 alkyl, C 1-4 haloalkyl, C 1-4 alkoxy-C 1-4 alkyl, 5-6 membered heteroaryl, phenyl, halophenyl, halogen, 3-6 membered heterocyclyl, —C(O)N(C 1-4 alkyl) 2 and hydroxy.
7. A compound or salt according to claim 1 , wherein
R 1 is selected from the group consisting of C 1-6 alkyl and C 1-6 haloalkyl.
8. A compound or salt according to claim 1 , wherein
R 1 is 3-10 membered heterocyclyl optionally substituted by one or more, identical or different R b1 and/or R c1 ;
each R b1 is independently selected from the group consisting of —OR c1 , —NR c1 R c1 , halogen, —CN, —C(O)R c1 , —C(O)OR c1 and —C(O)NR c1 R c1 ;
each R c1 is independently selected from the group consisting of hydrogen, C 1-6 alkyl, C 1-6 haloalkyl, C 3-10 cycloalkyl, C 4-10 cycloalkenyl, 3-10 membered heterocyclyl, C 6-10 aryl and 5-10 membered heteroaryl, wherein the C 1-6 alkyl, C 1-6 haloalkyl, C 3-10 cycloalkyl, C 4-10 cycloalkenyl, 3-10 membered heterocyclyl, C 6-10 aryl and 5-10 membered heteroaryl are all optionally substituted by one or more, identical or different R d1 and/or R;
each R d1 is independently selected from the group consisting of —OR e1 , —NR e1 R e1 , halogen, —CN, —C(O)R e1 , —C(O)OR e1 and —C(O)NR e1 R e1 ;
each R e1 is independently selected from the group consisting of hydrogen, C 1-6 alkyl, C 1-6 haloalkyl, C 3-10 cycloalkyl, C 4-10 cycloalkenyl, 3-10 membered heterocyclyl, C 6-10 aryl and 5-10 membered heteroaryl.
9. A compound or salt according to claim 8 , wherein
R 1 is 3-10 membered heterocyclyl optionally substituted by one or more, identical or different substituent(s) selected from the group consisting of C 1-6 alkyl, C 1-6 haloalkyl and C 6-10 aryl.
10. A compound or salt according to claim 9 , wherein
R 1 is 3-8 membered heterocyclyl optionally substituted by one substituent selected from the group consisting of C 1-6 alkyl, C 1-6 haloalkyl and C 6-10 aryl.
11. A compound or salt according to claim 1 , wherein
R 1 is 5-6 membered heteoraryl optionally substituted with C 1-4 alkyl.
12. A compound or salt according to claim 1 , wherein
ring system A is selected from the group consisting of C 6-10 aryl, 5-10 membered heteroaryl and 9-10 membered bicyclic heterocyclyl;
p denotes 1 or 2;
each R 4 is independently selected from the group consisting of C 1-4 alkyl, C 2-4 alkinyl, C 1-4 haloalkyl, hydroxy-C 1-4 haloalkyl, C 1-4 haloalkyl substituted with a 3-6 membered heterocyclyl, halogen and the bivalent substituent ═O, while ═O may only be a substituent in a non-aromatic ring.
13. A compound or salt according to claim 1 , wherein
A together with the p substituents R 4 has substructure
R A is selected from the group consisting of C 1-4 alkyl, C 1-4 haloalkyl, hydroxy-C 1-4 alkyl, hydroxy-C 1-4 haloalkyl, C 1-4 haloalkyl substituted with a 3-6 membered heterocyclyl, C 3-6 cycloalkyl, hydroxy-C 3-6 cycloalkyl, 3-6 membered heterocyclyl, 3-6 membered hydroxy-heterocyclyl, halogen and —SO 2 —C 1-4 alkyl;
R B is selected from the group consisting of hydrogen and —NH 2 ;
R C is selected from the group consisting of hydrogen, C 1-4 alkyl and halogen;
or
R A and R C together with the carbon atoms they are attached form a 5-6 membered non-aromatic carbocycle, a 5-6 membered non-aromatic heterocycle or a 5-6 membered heteroaryl, wherein the 5-6 membered non-aromatic carbocycle, 5-6 membered non-aromatic heterocycle and 5-6 membered heteroaryl are all optionally substituted by one or more halogen or by an oxo group.
14. A compound or salt according to claim 13 , wherein
A together with the p substituents R 4 has substructure
R A is selected from the group consisting of C 1-4 haloalkyl, hydroxy-C 1-4 haloalkyl and C 1-4 haloalkyl substituted with a 3-6 membered heterocyclyl;
R B is hydrogen;
R C is selected from the group consisting of hydrogen, C 1-4 alkyl and fluorine;
or
R A and R C together with the carbon atoms they are attached form a 5-6 membered non-aromatic carbocycle, a 5-6 membered non-aromatic heterocycle or a 5-6 membered heteroaryl, wherein the 5-6 membered non-aromatic carbocycle, 5-6 membered non-aromatic heterocycle and 5-6 membered heteroaryl are all optionally substituted by one or more fluorine or by an oxo group.
15. A compound having the following structure:
or a pharmaceutically acceptable salt thereof.
16. A compound having the following structure:
or a pharmaceutically acceptable salt thereof.
17. A compound having the following structure:
or a pharmaceutically acceptable salt thereof.
18. A compound having the following structure:
or a pharmaceutically acceptable salt thereof.
19. A compound having the following structure:
or a pharmaceutically acceptable salt thereof.
20. A compound having the following structure:
or a pharmaceutically acceptable salt thereof.
21. A compound having the following structure:
or a pharmaceutically acceptable salt thereof.
22. A compound having the following structure:
or a pharmaceutically acceptable salt thereof.
23. A compound having the following structure:
or a pharmaceutically acceptable salt thereof.
24. A compound having the following structure:
or a pharmaceutically acceptable salt thereof.
25. A compound having the following structure:
or a pharmaceutically acceptable salt thereof.
26. A compound having the following structure:
or a pharmaceutically acceptable salt thereof.
27. A compound having the following structure:
or a pharmaceutically acceptable salt thereof.
28. A compound having the following structure:
or a pharmaceutically acceptable salt thereof.
29. A compound having the following structure:
or a pharmaceutically acceptable salt thereof.
30. A compound having the following structure:
or a pharmaceutically acceptable salt thereof.
31. A compound having the following structure:
or a pharmaceutically acceptable salt thereof.
32. A compound having the following structure:
or a pharmaceutically acceptable salt thereof.
33. A compound having the following structure:
or a pharmaceutically acceptable salt thereof.
34. A compound having the following structure:
or a pharmaceutically acceptable salt thereof.
35. A compound having the following structure:
or a pharmaceutically acceptable salt thereof.
36. A compound having the following structure:
or a pharmaceutically acceptable salt thereof.
37. A compound having the following structure:
or a pharmaceutically acceptable salt thereof.
38. A compound having the following structure:
or a pharmaceutically acceptable salt thereof.
39. A compound having the following structure:
40. A compound having the following structure:
41. A compound having the following structure:
42. A compound having the following structure:
43. A compound having the following structure:
44. A compound having the following structure:
45. A compound having the following structure:
46. A compound having the following structure:
47. A compound having the following structure:
48. A compound having the following structure:
49. A compound having the following structure:
50. A compound having the following structure:
51. A compound having the following structure:
52. A compound having the following structure:
53. A compound having the following structure:
54. A compound having the following structure:
55. A compound having the following structure:
56. A compound having the following structure:
57. A compound having the following structure:
58. A compound having the following structure:
59. A compound having the following structure:
60. A compound having the following structure:
61. A compound having the following structure:
62. A compound having the following structure:
63. A pharmaceutical composition comprising a compound according to claim 1 —or a pharmaceutically acceptable salt thereof—and one or more pharmaceutically acceptable excipient(s).
64. A pharmaceutical preparation comprising a compound according to claim 1 —or a pharmaceutically acceptable salt thereof—and at least one other pharmacologically active substance.
65. A pharmaceutical preparation according to claim 64 comprising one other pharmacologically active substance.