Substituted benzyl-triazole compounds for Cbl-b inhibition, and further 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, or a pharmaceutically acceptable salt thereof, wherein
Z 1 is CH or nitrogen;
Z 2 is CH or nitrogen;
R 1 is —CF 3 or cyclopropyl;
R 2 is —CF 3 or cyclopropyl;
R 3 is hydrogen, C 1 -C 2 alkyl, or C 1 -C 2 haloalkyl;
R 4 is hydrogen, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, 4- to 8-membered heterocyclyl, or C 3 -C 6 cycloalkyl,
wherein the heterocyclyl or cycloalkyl groups are optionally substituted by one to five R 6 groups;
or R 3 and R 4 are taken together with the carbon atom to which they are attached to form a C 3 -C 5 cycloalkyl or 4- to 6-membered heterocyclyl, each of which is optionally substituted by one to five R 6 groups;
R 5 is hydrogen, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, or C 3 -C 6 cycloalkyl;
each R 6 is independently C 1 -C 6 alkyl, halo, hydroxy, —O(C 1 -C 6 alkyl), —CN, C 1 -C 6 alkyl-CN, C 1 -C 6 alkyl-OH, or C 1 -C 6 haloalkyl;
or two R 6 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 spiro 4- to 6-membered heterocyclyl;
X is hydrogen, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 alkyl-OH, C 1 -C 6 alkyl-CN, C 3 -C 6 cycloalkyl optionally substituted by one to five R 8 groups, or
is 4- to 7-membered heterocyclyl or 5- to 8-membered heteroaryl, wherein each heterocyclyl or heteroaryl optionally contains one to two additional heteroatoms selected from the group consisting of nitrogen, oxygen, and sulfur, and wherein each heterocyclyl or heteroaryl is optionally substituted by one to five R 8 groups;
each R 7 is independently hydrogen, C 1 -C 6 alkyl, C 1 -C 6 alkyl-OH, or C 1 -C 6 haloalkyl;
or two R 7 groups are taken together with the carbon atom to which they are attached to form a C 3 -C 5 cycloalkyl or 3- to 5-membered heterocyclyl; and
each R 8 is independently halo, C 1 -C 6 alkyl, C 1 -C 6 alkyl-CN, C 1 -C 6 alkyl-OH, C 1 -C 6 haloalkyl, —CN, oxo, or —O(C 1 -C 6 alkyl);
or two R 8 groups are taken together with the carbon atom or atoms to which they are attached to form a spiro or fused C 3 -C 5 cycloalkyl or 3- to 5-membered heterocyclyl.
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 N.
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 N.
11. The compound of claim 10 , wherein
12. The compound of claim 1 , wherein
R 3 is hydrogen, C 1 -C 2 alkyl, or C 1 -C 2 haloalkyl;
R 4 is hydrogen, C 1 -C 3 alkyl, C 1 -C 3 haloalkyl, 4- to 6-membered heterocyclyl, or C 4 -C 5 cycloalkyl,
wherein the heterocyclyl or cycloalkyl groups are optionally substituted by one to three R 6 groups;
or R 3 and R 4 are taken together with the carbon atom to which they are attached to form a C 4 -C 5 cycloalkyl or 4- to 6-membered heterocyclyl, each of which is optionally substituted by one to three R 6 groups.
13. The compound of claim 12 , wherein
R 3 is hydrogen, —CH 3 , or —CF 3 ; and
R 4 is hydrogen, —CH 3 , —CF 3 , cyclobutyl, or
or R 3 and R 4 are taken together with the carbon atom to which they are attached to form
each of which is optionally substituted by one to three R 6 groups.
14. The compound of claim 13 , wherein R 3 and R 4 are taken together with the carbon atom to which they are attached to form
15. The compound of claim 1 , wherein
each R 6 is, independently, C 1 -C 3 alkyl, halo, hydroxy, —O(C 1 -C 3 alkyl), —CN, C 1 -C 3 alkyl-CN, C 1 -C 3 alkyl-OH, or C 1 -C 3 haloalkyl;
or two R 6 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 spiro 4- to 5-membered heterocyclyl.
16. The compound of claim 15 , wherein
each R 6 is, independently, —CH 3 , fluoro, hydroxy, —OCH 3 , —CN, —CH 2 CN, —CH 2 OH, or —CF 3 ;
or two R 6 groups attached to the same carbon atom are taken together with the carbon atom to which they are attached to form a spiro cyclopropyl.
17. The compound of claim 1 , wherein R 5 is hydrogen, C 1 -C 3 alkyl, C 1 -C 3 haloalkyl, or C 3 -C 4 cycloalkyl.
18. The compound of claim 17 , wherein R 5 is hydrogen, —CH 3 , —CHF 2 , or cyclopropyl.
19. The compound of claim 1 , wherein
X is hydrogen, C 1 -C 3 alkyl, C 1 -C 3 haloalkyl, C 1 -C 3 alkyl-OH, C 1 -C 3 alkyl-CN, or C 3 -C 5 cycloalkyl optionally substituted by one to three R 8 groups.
20. The compound of claim 19 , wherein X is hydrogen or —CH 3 .
21. The compound of claim 1 , wherein X is
22. The compound of claim 21 , wherein
is a 4- to 6-membered heterocyclyl or 5- to 6-membered heteroaryl, wherein each heterocyclyl or heteroaryl optionally contains one to two additional heteroatoms selected from the group consisting of nitrogen, oxygen, and sulfur, and wherein each heterocyclyl or heteroaryl is optionally substituted by one to five R 8 groups.
23. The compound of claim 22 , wherein
is a 4- to 5-membered heterocyclyl or 5- to 6-membered heteroaryl, wherein each heterocyclyl or heteroaryl optionally contains one additional heteroatom selected from the group consisting of nitrogen and oxygen, and wherein each heterocyclyl or heteroaryl is optionally substituted by one to five R 8 groups.
24. The compound of claim 21 , wherein X is
and wherein Y is oxygen.
25. The compound of claim 24 , wherein Y is —CH 2 —, —CHR 8 —, or —C(R 8 ) 2 —.
26. The compound of claim 25 , wherein
each R 7 is, independently, hydrogen, C 1 -C 3 alkyl, C 1 -C 3 alkyl-OH, or C 1 -C 3 haloalkyl;
or two R 7 groups are taken together with the carbon atom to which they are attached to form a C 3 -C 5 cycloalkyl or 3- to 5-membered heterocyclyl.
27. The compound of claim 26 , wherein
each R 7 is, independently, hydrogen, —CH 3 , —CH 2 OH, or —CF 3 ;
or two R 7 groups are taken together with the carbon atom to which they are attached to form a cyclopropyl or oxetanyl.
28. The compound of claim 21 , wherein
each R 8 is, independently, halo, C 1 -C 3 alkyl, C 1 -C 3 alkyl-CN, C 1 -C 3 alkyl-OH, C 1 -C 3 haloalkyl, —CN, oxo, or —O(C 1 -C 3 alkyl);
or two R 8 groups are taken together with the carbon atom or atoms to which they are attached to form a spiro or fused C 3 -C 5 cycloalkyl or a spiro or fused 3- to 5-membered heterocyclyl.
29. The compound of claim 28 , wherein
each R 8 is, independently, fluoro, —CH 3 , —CH 2 CH 3 , —CH 2 CN, —CH 2 OH, —CF 3 , —CN, oxo, or —OCH 3 ;
or two R 8 groups are taken together with the carbon atom or atoms to which they are attached to form a spiro or fused cyclopropyl or oxetanyl.
30. The compound of claim 1 , selected from the compounds in Table 1, or a tautomer thereof, or a pharmaceutically acceptable salt thereof.
31. A pharmaceutical composition comprising the compound of claim 1 , and a pharmaceutically acceptable excipient.
32. A kit comprising the pharmaceutical composition of claim 31 .