Methods to induce targeted protein degradation through bifunctional molecules
The present application provides bifunctional compounds which act as protein degradation inducing moieties. The present application also relates to methods for the targeted degradation of endogenous proteins through the use of the bifunctional compounds that link a cereblon-binding moiety to a ligand that is capable of binding to the targeted protein which can be utilized in the treatment of proliferative disorders. The present application also provides methods for making compounds of the application and intermediates thereof.
1. A compound selected from:
or an enantiomer, diastereomer, stereoisomer, or a pharmaceutically acceptable salt thereof, wherein:
Y is a bond, (CH 2 ) 1-6 , (CH 2 ) 0-6 —O, (CH 2 ) 0-6 —C(O)NR 2 ′, (CH 2 ) 0-6 —NR 2 ′C(O), (CH 2 ) 0-6 —NH, or (CH 2 ) 0-6 —NR 2 ;
X is C(O) or C(R 3 ) 2 ;
X 1 -X 2 is C(R 3 )═N or C(R 3 ) 2 —C(R 3 ) 2 ;
each R 1 is independently halogen, OH, C 1 —C 6 alkyl, or C 1 —C 6 alkoxy;
R 2 is C 1 —C 6 alkyl, C(O)—C 1 —C 6 alkyl, or C(O)—C 3 -C 6 cycloalkyl;
R 2 ′ is H or C 1 -C 6 alkyl;
each R 3 is independently H or C 1 —C 3 alkyl;
each R 3 ′ is independently C 1 —C 3 alkyl;
each R 4 is independently H or C 1 —C 3 alkyl and at least one R 4 is C 1 —C 3 alkyl; or two R 4 , together with the carbon atom to which they are attached, form a C 3 —C 6 carbocycle or a 4-, 5-, or 6-membered heterocycle comprising 1 or 2 heteroatoms selected from N and O;
R 5 is H, deuterium, C 1 —C 3 alkyl, F, or Cl;
m is 0, 1, 2 or 3;
n is 0, 1 or 2;
the Linker is
each W is independently absent, CH 2 , O, S, NH or NR 5 ;
Z is absent, CH 2 , O, NH or NR 5 ;
Q is absent or —CH 2 C(O)NH—;
p1 is selected from 0, 1, 2, 3, 4, 5, and 6;
p2 is selected from 0, 1, 2, 3, 4, 5, and 6;
p3 is selected from 1, 2, 3, 4, and 5;
the Targeting Ligand binds to a targeted protein selected from SMARCA2, and Ras;
wherein the Targeting Ligand is selected from:
R is the attachment point to the Linker;
o is 0, 1, 2, 3, 4, 5, 6, 7, or 8; and
A is N or CH.
2. The compound of claim 1 , wherein the targeted protein is SMARCA2.
3. The compound of claim 1 , wherein the targeted protein is Ras.
4. The compound of claim 1 , wherein one R 4 is C 1 -C 3 alkyl.
5. The compound of claim 4 , wherein one R 4 is methyl or ethyl.
6. The compound of claim 1 , wherein each R 4 is independently methyl or ethyl.
7. The compound of claim 1 , wherein two R 4 , together with the carbon to which they are attached, form a cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl.
8. The compound of claim 1 , wherein two R 4 , together with the carbon to which they are attached, form a 4-, 5-, or 6-membered heterocycle comprising 1 or 2 heteroatoms selected from N and O.
9. The compound of claim 8 , wherein the heterocycle is selected from azetidine, tetrahydrofuran, pyrrolidine, piperidine, piperazine, morpholine, and oxetane.
10. The compound of claim 8 , wherein the heterocycle is oxetane.
11. The compound of claim 8 , wherein the heterocycle is azetidine.
12. The compound of claim 8 , wherein the heterocycle is tetrahydrofuran.
13. The compound of claim 8 , wherein the heterocycle is pyrrolidine.
14. The compound of claim 8 , wherein the heterocycle is piperidine.
15. The compound of claim 8 , wherein the heterocycle is piperazine.
16. The compound of claim 8 , wherein the heterocycle is morpholine.
17. The compound of claim 1 , wherein the compound is Formula I.
18. The compound of claim 17 , wherein X is C(O).
19. The compound of claim 17 , wherein X is C(R 3 ) 2 .
20. The compound of claim 1 , wherein R 5 is H or deuterium.
21. The compound of claim 1 , wherein R 3 is H or methyl.
22. The compound of claim 1 , wherein each R 1 is independently selected from F, Cl, OH, methyl, ethyl, propyl, methoxy, ethoxy and propoxy.
23. The compound of claim 1 , wherein m is 0.
24. The compound of claim 1 , wherein m is 1.
25. The compound of claim 1 , wherein n is 0.
26. The compound of claim 1 , wherein n is 1.
27. The compound of claim 1 , wherein n is 2.
28. The compound of claim 1 , wherein the compound is Formula II.
29. The compound of claim 1 , wherein each R 1 is independently methyl, methoxy, ethoxy or propoxy.
30. The compound of claim 1 , wherein X is C(CH 3 ) 2.
31. The compound of claim 1 , wherein Y is (CH 2 ) 0-6 —O.
32. The compound of claim 1 , wherein Y is (CH 2 ) 0-6 —NH.
33. The compound of claim 1 , wherein Y is (CH 2 ) 0-6 —C(O)NR 2 ′.
34. The compound of claim 1 , wherein Y is (CH 2 ) 0-6 —NR 2 ′C(O).
35. The compound of claim 1 , wherein Y is (CH 2 ) 0-6 —NR 2 .
36. The compound of claim 1 , wherein the Linker has 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, or 16 chain atoms.
37. The compound of claim 1 , wherein W is independently CH 2 , O, S, NH, or NR 5 .
38. The compound of claim 1 , wherein at least one W is CH 2 .
39. The compound of claim 1 , wherein at least one W is O.
40. The compound of claim 1 , wherein at least one W is S.
41. The compound of claim 1 , wherein at least one W is NH.
42. The compound of claim 1 , wherein at least one W is NR 5 .
43. The compound of claim 42 , wherein R 5 is C 1 -C 3 alkyl selected from methyl, ethyl, and propyl.
44. The compound of claim 1 , wherein Q is absent.
45. The compound of claim 1 , wherein Q is —CH 2 C(O)NH—.
46. The compound of claim 1 , wherein W is absent.
47. The compound of claim 1 , wherein at least one of W is CH 2 and Z is NH or O.
48. The compound of claim 1 , wherein at least one of W is O and Z is NH or O.
49. The compound of claim 1 , wherein at least one of W is S and Z is NH or O.
50. The compound of claim 1 , wherein at least one of W is NH and Z is NH or O.
51. The compound of claim 1 , wherein at least one of W is NR 5 and Z is NH or O.
52. The compound of claim 1 , wherein Z is CH 2.
53. The compound of claim 1 , wherein Z is O.
54. The compound of claim 1 , wherein at least one of Z is NH.
55. The compound of claim 1 , wherein at least one of Z is NR 5 .
56. The compound of claim 1 , wherein the Linker is of Formula L1 or L2:
57. A compound selected from:
or an enantiomer, diastereomer, stereoisomer, or a pharmaceutically acceptable salt thereof, wherein:
Y is a bond, (CH 2 ) 1-6 , (CH 2 ) 0-6 —O, (CH 2 ) 0-6 —C(O)NR 2 ′, (CH 2 ) 0-6 —NR 2 ′C(O), (CH 2 ) 0-6 —NH, or (CH 2 ) 0-6 —NR 2 ;
X is C(O) or C(R 3 ) 2 ;
X 1 -X 2 is C(R 3 )═N or C(R 3 ) 2 —C(R 3 ) 2 ;
each R 1 is independently halogen, OH, C 1 —C 6 alkyl, or C 1 —C 6 alkoxy;
R 2 is C 1 —C 6 alkyl, C(O)—C 1 —C 6 alkyl, or C(O)—C 3 —C 6 cycloalkyl;
R 2 ′ is H or C 1 C 6 alkyl;
each R 3 is independently H or C 1 —C 3 alkyl;
each R 3 ′ is independently C 1 —C 3 alkyl;
each R 4 is independently H or C 1 —C 3 alkyl; or two R 4 , together with the carbon atom to which they are attached, form a C(O), C 3 —C 6 carbocycle, or a 4-, 5-, or 6-membered heterocycle comprising 1 or 2 heteroatoms selected from N and 0 ;
R 5 is H, deuterium, C 1 —C 3 alkyl, F, or Cl;
m is 0, 1, 2 or 3;
n is 1 or 2;
the Linker is
each W is independently absent, CH 2 , O, S, NH or NR 5 ;
Z is absent, CH 2 , O, NH or NR 5 ;
Q is absent or —CH 2 C(O)NH—;
p1 is selected from 0, 1, 2, 3, 4, 5, and 6;
p2 is selected from 0, 1, 2, 3, 4, 5, and 6;
p3 is selected from 1, 2, 3, 4, and 5;
the Targeting Ligand binds to a targeted protein selected from SMARCA2, and Ras;
wherein the Targeting Ligand is selected from:
R is the attachment point to the Linker;
o is 0, 1, 2, 3, 4, 5, 6, 7, or 8; and
A is N or CH.
58. The compound of claim 57 , wherein the targeted protein is SMARCA2.
59. The compound of claim 57 , wherein the targeted protein is Ras.
60. The compound of claim 57 , wherein one R 4 is C 1 —C 3 alkyl.
61. The compound of claim 57 , wherein one R 4 is methyl, ethyl, or propyl.
62. The compound of claim 57 , wherein R 4 is hydrogen.
63. The compound of claim 57 , wherein two R 4 , together with the carbon to which they are attached, form a cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl.
64. The compound of claim 57 , wherein two R 4 , together with the carbon to which they are attached, form a 4-, p5-, or 6-membered heterocycle comprising 1 or 2 heteroatoms selected from N and O.
65. The compound of claim 64 , wherein the heterocycle is selected from azetidine, tetrahydrofuran, pyrrolidine, piperidine, piperazine, morpholine, and oxetane.
66. The compound of claim 57 , wherein the compound is Formula I.
67. The compound of claim 66 , wherein Xis C(O).
68. The compound of claim 66 , wherein X is C(R 3 ) 2 .
69. The compound of claim 57 , wherein R 5 is H or deuterium.
70. The compound of claim 57 , wherein R 3 is H or methyl.
71. The compound of claim 57 , wherein each R 1 is independently selected from F, Cl, OH, methyl, ethyl, propyl, methoxy, ethoxy and propoxy.
72. The compound of claim 57 , wherein m is 0.
73. The compound of claim 57 , wherein m is 1.
74. The compound of claim 57 , wherein n is 1.
75. The compound of claim 57 , wherein n is 2.
76. The compound of claim 57 , wherein the compound is Formula II.
77. The compound of claim 57 , wherein each R 1 is independently methyl, methoxy, ethoxy or propoxy.
78. The compound of claim 57 , wherein Xis C(CH 3 ) 2 .
79. The compound of claim 1 , wherein the Targeting Ligand is a SMARCA2 Targeting Ligand selected from:
wherein:
R is the attachment point to the Linker;
o is 0, 1, 2, 3, 4, 5, 6, 7, or 8; and
A is N or CH.
80. The compound of claim 1 , wherein the Targeting Ligand is a Ras Targeting Ligand selected from:
wherein:
R is the attachment point to the Linker.
81. The compound of claim 1 , wherein the Targeting Ligand is a RasG12C Targeting Ligand selected from:
wherein:
R is the attachment point to the Linker.
82. The compound of claim 57 , wherein the Targeting Ligand is a SMARCA2 Targeting Ligand selected from:
wherein:
R is the attachment point to the Linker;
o is 0, 1, 2, 3, 4, 5, 6, 7, or 8; and
A is N or CH.
83. The compound of claim 57 , wherein the Targeting Ligand is a Ras Targeting Ligand selected from:
wherein:
R is the attachment point to the Linker.
84. The compound of claim 57 , wherein the Targeting Ligand is a RasG12C Targeting Ligand selected from:
wherein:
R is the attachment point to the Linker.