Cyano cyclobutyl compounds for CBL-B inhibition and uses 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
Z 1 is CH or nitrogen;
Z 2 is CH or nitrogen;
R 1 is hydrogen, C 1 -C 6 alkyl, or C 1 -C 6 haloalkyl;
R 2 is hydrogen, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, or C 3 -C 6 cycloalkyl;
R 3 is —CF 3 or cyclopropyl;
R 4 is —CF 3 or cyclopropyl;
X is hydrogen, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, or
R 5 is hydrogen, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 alkyl-OH, or C 1 -C 6 alkyl-CN;
R 6 is monocyclic C 3 -C 6 cycloalkyl, fused bicyclic C 4 -C 8 cycloalkyl, bridged bicyclic C 4 -C 8 cycloalkyl, spiro bicyclic C 5 -C 8 cycloalkyl, or 5- to 6-membered heterocyclyl, each of which is optionally substituted by one to five R 7 groups;
or R 5 and R 6 are taken together with the nitrogen atom to which they are attached to form a 5- to 10-membered monocyclic, fused bicyclic, or bridged heterocyclyl, or a 5- to 10-membered monocyclic or bicyclic heteroaryl, each of which heterocyclyl or heteroaryl optionally contains one to two additional heteroatoms selected from the group consisting of nitrogen and oxygen, and each of which heterocyclyl or heteroaryl is optionally substituted by one to five R 8 groups;
each R 7 is independently halo, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 alkyl-OH, or C 1 -C 6 alkyl-CN;
each R 8 is independently C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 alkyl-OH, —CN, C 1 -C 6 alkyl-CN, —(C 1 -C 6 alkylene)-O—(C 1 -C 6 alkyl), hydroxy, or halo,
or two R 8 groups attached to the same carbon atom are taken together with the carbon atom to which they are attached to form a spiro C 3 -C 6 cycloalkyl or a spiro 5- to 6-membered heterocyclyl;
each R 9 is independently hydrogen, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, or C 1 -C 6 alkyl-OH; and
n is zero or one.
2. The compound of claim 1 , wherein
3. The compound of claim 2 , wherein Z 1 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 R 1 is hydrogen, C 1 -C 3 alkyl, or C 1 -C 3 haloalkyl.
13. The compound of claim 12 , wherein R 1 is hydrogen, —CH 3 , or —CF 3 .
14. The compound of claim 1 , wherein R 2 is hydrogen, C 1 -C 3 alkyl, C 1 -C 3 haloalkyl, or C 3 -C 4 cycloalkyl.
15. The compound of claim 14 , wherein R 2 is hydrogen, —CH 3 , —CF 3 , —CHF 2 , —CH 2 F, or cyclopropyl.
16. The compound of claim 1 , wherein n is zero.
17. The compound of claim 1 , wherein n is one.
18. The compound of claim 1 , wherein X is hydrogen.
19. The compound of claim 1 , wherein X is C 1 -C 3 alkyl or C 1 -C 3 haloalkyl.
20. The compound of claim 19 , wherein X is —CH 3 or —CF 3 .
21. The compound of claim 1 , wherein X is
22. The compound of claim 21 , wherein R 5 is hydrogen, C 1 -C 3 alkyl, or C 1 -C 3 haloalkyl.
23. The compound of claim 22 , wherein R 5 is hydrogen, —CH 3 , —CF 3 , —CH 2 CN, or —CH 2 OH.
24. The compound of claim 21 , wherein R 6 is monocyclic C 3 -C 6 cycloalkyl, fused bicyclic C 4 -C 8 cycloalkyl, bridged bicyclic C 4 -C 8 cycloalkyl, spiro bicyclic C 5 -C 8 cycloalkyl, or 5- to 6-membered heterocyclyl, each of which is optionally substituted by one to five R 7 groups.
25. The compound of claim 24 , wherein R 6 is selected from the group consisting of
26. The compound of claim 24 , wherein each R 7 , when present, is independently halo, C 1 -C 3 alkyl, C 1 -C 3 haloalkyl, C 1 -C 3 alkyl-OH, or C 1 -C 3 alkyl-CN.
27. The compound of claim 26 , wherein each R 7 , when present, is independently fluoro, —CH 3 , —CF 3 , —CH 2 OH, or —CH 2 CN.
28. The compound of claim 21 , wherein R 5 and R 6 are taken together with the nitrogen atom to which they are attached to form a 5- to 10-membered monocyclic, fused bicyclic, or bridged heterocyclyl, or a 5- to 10-membered monocyclic or bicyclic heteroaryl, each of which heterocyclyl or heteroaryl optionally contains one to two additional heteroatoms selected from the group consisting of nitrogen and oxygen, and each of which heterocyclyl or heteroaryl is optionally substituted by one to five R 8 groups.
29. The compound of claim 28 , wherein R 5 and R 6 are taken together with the nitrogen atom to which they are attached to form a moiety selected from the group consisting of
30. The compound of claim 28 , wherein
each R 8 , when present, is independently C 1 -C 3 alkyl, C 1 -C 3 haloalkyl, C 1 -C 3 alkyl-OH, —CN, C 1 -C 3 alkyl-CN, —(C 1 -C 3 alkylene)-O—(C 1 -C 3 alkyl), hydroxy, or halo, or
two R 8 groups attached to the same carbon atom are taken together with the carbon atom to which they are attached to form a spiro C 3 -C 4 cycloalkyl or a spiro 5- to 6-membered heterocyclyl.
31. The compound of claim 30 , wherein
each R 8 , when present, is independently —CH 3 , —CH 2 CH 3 , —CF 3 , —CH 2 OH, —CN, —CH 2 CN, —CH 2 —O—CH 3 , hydroxy, or fluorine, or
two R 8 groups attached to the same carbon atom are taken together with the carbon atom to which they are attached to form a spiro cyclopropyl.
32. The compound of claim 1 , wherein each R 9 is independently hydrogen, C 1 -C 3 alkyl, C 1 -C 3 haloalkyl, or C 1 -C 3 alkyl-OH.
33. The compound of claim 32 , wherein each R 9 is independently hydrogen, —CH 3 , —CF 3 , or —CH 2 OH.
34. The compound of claim 1 , selected from the following compounds, and tautomers thereof, stereoisomers thereof, and pharmaceutically acceptable salts thereof:
35. A pharmaceutical composition comprising the compound of claim 1 , and a pharmaceutically acceptable excipient.
36. A method of modulating activity of an immune cell, the method comprising contacting the immune cell with an effective amount of a Cbl-b inhibitor to modulate activity of the immune cell, wherein the Cbl-b inhibitor is a compound of claim 1 .
37. A method of producing a modified immune cell, comprising culturing a cell population containing an immune cell in the presence of an effective amount of a Cbl-b inhibitor to modulate activity of the immune cell, thereby producing the modified immune cell, wherein the Cbl-b inhibitor is a compound of claim 1 .
38. A modified immune cell produced by the method of claim 37 .
39. A modified immune cell comprising a Cbl-b inhibitor, wherein the Cbl-b inhibitor is a compound of claim 1 .
40. An isolated modified immune cell, wherein the immune cell has been contacted or is in contact with a Cbl-b inhibitor, wherein the Cbl-b inhibitor is a compound of claim 1 .
41. A composition comprising a cell population containing the modified immune cell of claim 38 .
42. A method of modulating the immune response, the method comprising administering an effective amount of the composition of claim 41 to an individual in need thereof.
43. A method of treating a colon or lung cancer responsive to inhibition of Cbl-b activity, the method comprising administering an effective amount of the composition of claim 41 to an individual having the cancer responsive to inhibition of Cbl-b activity.
44. A method of inhibiting abnormal colon or lung cell proliferation, the method comprising administering an effective amount of the composition of claim 41 to an individual in need thereof.
45. A method of modulating the immune response, the method comprising administering an effective amount of a Cbl-b inhibitor to an individual to modulate the immune response in the individual, wherein the Cbl-b inhibitor is a compound of claim 1 .
46. A method of inhibiting Cbl-b activity, the method comprising administering an effective amount of a Cbl-b inhibitor to an individual to inhibit Cbl-b activity in the individual, wherein the Cbl-b inhibitor is a compound of claim 1 .
47. A method of treating a colon or lung cancer responsive to inhibition of Cbl-b activity, the method comprising administering an effective amount of a Cbl-b inhibitor to an individual to treat the cancer responsive to inhibition of Cbl-b activity, wherein the Cbl-b inhibitor is a compound of claim 1 .
48. A method of inhibiting abnormal colon or lung cell proliferation, the method comprising administering an effective amount of a Cbl-b inhibitor to an individual to inhibit abnormal cell proliferation in the individual, wherein the Cbl-b inhibitor is a compound of claim 1 .
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 comprising the composition of claim 41 .
53. A kit comprising the pharmaceutical composition of claim 35 .
54. A kit comprising the cell culture composition of claim 49 .
55. A method of treating colon or lung cancer, the method comprising
administering to an individual with cancer an effective amount of a Cbl-b inhibitor, wherein the Cbl-b inhibitor is a compound of claim 1 , and
administering to the individual an effective amount of an additional therapeutic agent.
56. A method of treating colon or lung cancer, the method comprising
administering to an individual with cancer an effective amount of a Cbl-b inhibitor, wherein the Cbl-b inhibitor is a compound of claim 1 , and
administering to the individual an effective amount of radiation therapy.
57. A method of producing an expanded population of tumor infiltrating lymphocytes (TILs), the method comprising
(a) obtaining a biological sample comprising TILs from the individual treated according to the method of claim 49 , and
(b) culturing the TILs in cell culture medium comprising at least one T-cell growth factor to produce an expanded population of TILs.
58. A composition comprising the expanded population of TILs produced by the method of claim 57 , and a physiologically acceptable buffer.
59. A method of treating colon or lung cancer, the method comprising administering an effective amount of the composition of claim 58 to the individual with cancer.
60. A method of producing an expanded population of tumor infiltrating lymphocytes (TILs), the method comprising
(a) obtaining a biological sample comprising TILs from an individual having cancer who has received or is receiving an effective amount of a Cbl-b inhibitor, wherein the Cbl-b inhibitor is a compound of claim 1 ; and
(b) culturing the TILs in cell culture medium comprising at least one T-cell growth factor to produce an expanded population of TILs.
61. A composition comprising the expanded population of TILs produced by the method of claim 60 , and a physiologically acceptable buffer.
62. A method of treating colon or lung cancer, the method comprising administering an effective amount of the composition of claim 61 to the individual with cancer.
63. A method of immunizing, the method comprising
administering to an individual in need thereof an effective amount of a small molecule Cbl-b inhibitor, wherein the Cbl-inhibitor is a compound of claim 1 , and
administering to the individual an effective amount of a vaccine.
64. A method of treating colon or lung cancer, the method comprising
administering to an individual with cancer an effective amount of a small molecule Cbl-b inhibitor, wherein the Cbl-inhibitor is a compound of claim 1 ; and
administering to the individual an effective amount of an oncolytic virus.
65. A method of treating colon or lung or adenocarcinoma cancer, the method comprising
administering to an individual with cancer an effective amount of the compound of claim 1 , and
administering to the individual an effective amount of a therapeutic cancer vaccine; or
administering to the individual an effective amount of an oncolytic virus.
66. A pharmaceutical composition comprising a cancer vaccine and a small molecule Cbl-b inhibitor of claim 1 , optionally wherein the composition further comprises a pharmaceutically acceptable excipient.
67. 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.
68. 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.
69. A pharmaceutical composition comprising an oncolytic virus and a small molecule Cbl-b inhibitor of claim 1 , optionally wherein the composition further comprises a pharmaceutically acceptable excipient.
70. A kit for treating cancer, the kit comprising
(a) a small molecule Cbl-b inhibitor of claim 1 ;
(b) an oncolytic virus;
(c) instructions for administration of an effective amount of the Cbl-b inhibitor and the oncolytic virus to treat cancer in an individual.
71. A kit for treating cancer, the kit comprising
(a) a pharmaceutical composition comprising a small molecule Cbl-b inhibitor of claim 1 and an oncolytic virus; and
(b) instructions for administration of an effective amount of the pharmaceutical composition comprising the small molecule Cbl-b inhibitor and the oncolytic virus to treat cancer in an individual.