3-substituted piperidine compounds for Cbl-b inhibition, and use thereof
Compounds, compositions, and methods for use in inhibiting the E3 enzyme Cbl-b in the ubiquitin proteasome pathway are disclosed. The compounds, compositions, and methods can be used to modulate the immune system, to treat diseases amenable to immune system modulation, and for treatment of cells in vivo, in vitro, or ex vivo. Also disclosed are pharmaceutical compositions comprising a Cbl-b inhibitor and a cancer vaccine, as well as methods for treating cancer using a Cbl-b inhibitor and a cancer vaccine; and pharmaceutical compositions comprising a Cbl-b inhibitor and an oncolytic virus, as well as methods for treating cancer using a Cbl-b inhibitor and an oncolytic virus.
1. A compound of Formula (I):
or a tautomer thereof, stereoisomer thereof, or a pharmaceutically acceptable salt thereof,
wherein
X is CH or nitrogen;
Z 1 is CH or nitrogen;
Z 2 is CH or nitrogen;
R 1a and R 1b are independently hydrogen, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, or C 1 -C 6 alkyl-OH;
R 2a is —CN, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 alkyl-OH, C 1 -C 6 alkyl-CN, or —(C 1 -C 6 alkylene)-O—(C 1 -C 6 alkyl);
R 2a is hydrogen, halo, or C 1 -C 6 alkyl;
or R 2a and R 2b are taken together with the carbon atom to which they are attached to form a Spiro 3- to 6-membered heterocyclyl or a spiro C 3 -C 6 cycloalkyl,
wherein at least one of the atoms of the Spiro heterocyclyl which is adjacent to the connecting piperidinyl ring is carbon;
R 3a and R 3b are independently hydrogen, halo, or C 1 -C 6 alkyl;
or R 3a and R 3b are taken together with the carbon atom to which they are attached to form C 3 -C 4 cycloalkyl;
R 4 is hydrogen, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, or C 1 -C 6 alkyl-OH;
and Y is CR 5a R 5b or sulfur;
and Y is a bond;
W is oxygen or a bond;
R 5a and R 5b are independently hydrogen, halo, or C 1 -C 6 alkyl;
or R 5a and R 5b are taken together with the carbon atom to which they are attached to form a C 3 -C 6 cycloalkyl;
R 6 is C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, or C 3 -C 6 cycloalkyl;
R 7 is hydrogen, halo, C 3 -C 6 cycloalkyl, —NH-(3- to 6-membered heterocyclyl), —NH—(C 1 -C 6 alkyl), —NH—(C 3 -C 6 cycloalkyl), —O-(3- to 6-membered heterocyclyl), —O—(C 1 -C 6 alkyl), or —O—(C 3 -C 6 cycloalkyl);
R 8 is C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, or C 3 -C 6 cycloalkyl;
R 9 is hydrogen, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, or C 1 -C 6 alkyl-OH; and
R 10 is —CF 3 or cyclopropyl.
2. The compound of claim 1 , wherein
3. The compound of claim 2 , wherein V is CH.
4. The compound of claim 3 , wherein
5. The compound of claim 2 , wherein Z 1 is nitrogen.
6. The compound of claim 5 , wherein
7. The compound of claim 1 , wherein
8. The compound of claim 7 wherein Z 2 is CH.
9. The compound of claim 8 , wherein
10. The compound of claim 7 , wherein Z 2 is nitrogen.
11. The compound of claim 10 , wherein
12. The compound of claim 1 , wherein
and Y is CR 5a R 5b or sulfur.
13. The compound of claim 12 , wherein W is a bond.
14. The compound of claim 12 , wherein W is oxygen.
15. The compound of claim 1 , wherein
and Y is a bond.
16. The compound of claim 15 , wherein R 8 is C 1 -C 3 alkyl, C 1 -C 3 haloalkyl, or C 3 -C 4 cycloalkyl.
17. The compound of claim 16 , wherein R 8 is —CH 3 , —CF 3 , or cyclopropyl.
18. The compound of claim 1 , wherein X is CH.
19. The compound of claim 1 , wherein X is nitrogen.
20. The compound of claim 1 , wherein Y is a bond.
21. The compound of claim 1 , wherein Y is CR 5a R 5b .
22. The compound of claim 21 , wherein R 5a and R 5b are independently hydrogen, halo, or C 1 -C 3 alkyl, or R 5a and R 5b are taken together with the carbon atom to which they are attached to form a C 3 -C 4 cycloalkyl.
23. The compound of claim 22 , wherein R 5a and R 5b are independently hydrogen, fluorine, or —CH 3 ; or
R 5a and R 5b are taken together with the carbon atom to which they are attached to form cyclopropyl.
24. The compound of claim 23 , wherein R 5a and R 5b are independently hydrogen or fluorine.
25. The compound of claim 1 , wherein Y is sulfur.
26. The compound of claim 1 , wherein R 1a and R 1b are independently hydrogen, C 1 -C 3 alkyl, C 1 -C 3 haloalkyl, or C 1 -C 3 alkyl-OH.
27. The compound of claim 26 , wherein R 1a and R 1b are independently hydrogen, —CH 3 , —CF 3 , or —CH 2 OH.
28. The compound of claim 1 , wherein R 1b is hydrogen.
29. The compound of claim 1 , wherein R 2a is —CN, C 1 -C 3 alkyl, C 1 -C 3 haloalkyl, C 1 -C 3 alkyl-OH, C 1 -C 3 alkyl-CN, or —(C 1 -C 3 alkylene)-O—(C 1 -C 3 alkyl).
30. The compound of claim 29 , wherein R 2a is —CN, —CH 3 , —CF 3 , —CH 2 OH, —CH 2 CN, or —CH 2 —O—CH 3 .
31. The compound of claim 1 , wherein R 2b is hydrogen, halo, or C 1 -C 3 alkyl.
32. The compound of claim 31 , wherein R 2b is hydrogen, fluorine, or —CH 3 .
33. The compound of claim 1 , wherein R 2a and R 2b are taken together with the carbon atom to which they are attached to form a spiro 4- to 5-membered heterocyclyl or a spiro C 3 -C 4 cycloalkyl.
34. The compound of claim 33 , wherein R 2a and R 2b are taken together with the carbon atom to which they are attached to form spiro cyclopropyl,
35. The compound of claim 1 , wherein R 3a and R 3b are independently hydrogen, halo, or C 1 -C 3 alkyl;
or R 3a and R 3b are taken together with the carbon atom to which they are attached to form C 3 -C 4 cycloalkyl.
36. The compound of claim 35 , wherein R 3a and R 3b are independently hydrogen, fluorine, or —CH 3 ;
or R 3a and R 3b are taken together with the carbon atom to which they are attached to form cyclopropyl.
37. The compound of claim 1 , wherein R 4 is hydrogen, C 1 -C 3 alkyl, C 1 -C 3 haloalkyl, or C 1 -C 3 alkyl-OH.
38. The compound of claim 37 , wherein R 4 is hydrogen, —CH 3 , —CF 3 , or —CH 2 OH.
39. The compound of claim 1 , wherein R 6 is C 1 -C 3 alkyl, C 1 -C 3 haloalkyl, or C 3 -C 4 cycloalkyl.
40. The compound of claim 39 , wherein R 6 is —CH 3 , —CHF 2 , or cyclopropyl.
41. The compound of claim 1 , wherein R 7 is hydrogen, halo, C 3 -C 4 cycloalkyl, —NH(4- to 5-membered heterocyclyl), —NH(C 1 -C 3 alkyl), —NH(C 3 -C 5 cycloalkyl), —O(C 1 -C 3 alkyl), —O(4- to 5-membered heterocyclyl), or —O(C 3 -C 5 cycloalkyl).
42. The compound of claim 41 , wherein R 7 is hydrogen, chlorine, cyclopropyl, —NH(CH 2 CH 3 ), —NH(cyclopropyl), —OCH 2 CH 3 , —O(cyclopropyl),
43. The compound of claim 1 , wherein R 9 is hydrogen, C 1 -C 3 alkyl, C 1 -C 3 haloalkyl, or C 1 -C 3 alkyl-OH.
44. The compound of claim 43 , wherein R 9 is hydrogen, —CH 3 , —CF 3 , or —CH 2 OH.
45. The compound of claim 1 , wherein the compound is a compound of Formula (I-a):
or a tautomer thereof, stereoisomer thereof, or a pharmaceutically acceptable salt thereof, wherein:
X is CH or nitrogen;
Z 1 is CH or nitrogen;
Z 2 is CH or nitrogen;
R 1a and R 1b are independently hydrogen, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, or C 1 -C 6 alkyl-OH;
R 2a is —CN, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 alkyl-OH, C 1 -C 6 alkyl-CN, or —(C 1 -C 6 alkylene)-O—(C 1 -C 6 alkyl);
R 2b is hydrogen, halo, or C 1 -C 6 alkyl;
or R 2a and R 2b are taken together with the carbon atom to which they are attached to form a spiro 3- to 6-membered heterocyclyl or a spiro C 3 -C 6 cycloalkyl,
wherein at least one of the atoms of the spiro heterocyclyl which is adjacent to the connecting piperidinyl ring is carbon;
R 3a and R 3b are independently hydrogen, halo, or C 1 -C 6 alkyl;
or R 3a and R 3b are taken together with the carbon atom to which they are attached to form C 3 -C 4 cycloalkyl;
R 4 is hydrogen, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, or C 1 -C 6 alkyl-OH;
and Y is CR 5a R 5b or sulfur;
or
and Y is a bond;
W is oxygen or a bond;
R 5a and R 5b are independently hydrogen, halo, or C 1 -C 6 alkyl;
or R 5a and R 5b are taken together with the carbon atom to which they are attached to form a C 3 -C 6 cycloalkyl;
R 6 is C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, or C 3 -C 6 cycloalkyl;
R 7 is hydrogen, C 3 -C 6 cycloalkyl, —NH-(3- to 6-membered heterocyclyl), —NH—(C 1 -C 6 alkyl), —NH—(C 3 -C 6 cycloalkyl), —O-(3- to 6-membered heterocyclyl), —O—(C 1 -C 6 alkyl), or —O—(C 3 -C 6 cycloalkyl);
R 8 is C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, or C 3 -C 6 cycloalkyl;
R 9 is hydrogen, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, or C 1 -C 6 alkyl-OH; and
R 10 is —CF 3 or cyclopropyl.
46. The compound of claim 1 , selected from Compound Nos. 1-45 or 47-52 in Table 1.
47. The compound of claim 1 , selected from the group consisting of
48. A pharmaceutical composition comprising the compound of claim 1 , and a pharmaceutically acceptable excipient.
49. A cell culture composition comprising a cell population containing an immune cell and a Cbl-b inhibitor, wherein the Cbl-b inhibitor is a compound of claim 1 .
50. A pharmaceutical composition comprising a Cbl-b inhibitor and one or both of an adjuvant and an antigen, wherein the Cbl-b inhibitor is a compound of claim 1 .
51. An article of manufacture comprising the cell culture composition of claim 49 .
52. A kit for treating cancer, the kit comprising:
(a) a small molecule Cbl-b inhibitor of claim 1 ;
(b) a therapeutic cancer vaccine;
(c) instructions for administration of an effective amount of the Cbl-b inhibitor and the therapeutic cancer vaccine to treat cancer in an individual.
53. A kit for treating cancer, the kit comprising:
(a) a pharmaceutical composition comprising a small molecule Cbl-b inhibitor of claim 1 and a therapeutic cancer vaccine; and
(b) instructions for administration of an effective amount of the pharmaceutical composition comprising the Cbl-b inhibitor and the therapeutic cancer vaccine to treat cancer in an individual.