Monofunctional intermediates for ligand-dependent target protein degradation
The present disclosure provides compounds represented by Formula I: and the salts or solvates thereof, wherein X, L, Y, and B are as defined in the specification. Compounds having Formula I are immunomodulators and/or monofunctional synthetic intermediates that can be used to prepare small-molecule drug conjugates.
1. A compound having Formula I:
and the salts thereof,
wherein:
X is selected from the group consisting of —N(R 2a )—, —OC(═O)—,
wherein the —N(R 2b )— of
is attached to L; the —C(═O)— of —OC(═O)— is attached to L;
and the carbon atom of
is attached to L;
L is alkylenyl;
Y is —C≡C—;
R 2a and R 2b are each independently selected from the group consisting of hydrogen and C 1-4 alkyl;
B is:
A 1 is —C(R 16a )═;
A 2 is —C(R 16b )═;
A 3 is —C(R 16c )═;
Z is selected from the group consisting of —CH 2 and —C(═O)—;
R 5 is selected from the group consisting of hydrogen, methyl, and fluoro;
R 16a is selected from the group consisting of hydrogen, halo, and C 1-4 alkyl;
R 16b is selected from the group consisting of hydrogen, halo, and C 1-4 alkyl and
R 16c is selected from the group consisting of hydrogen, halo, and C 1-4 alkyl.
2. The compound of claim 1 , and the salts thereof, wherein:
X is selected from the group consisting of —N(R 2a )—, and wherein the —N(R 2b )— of
is attached to L.
3. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, having Formula II:
4. The compound of claim 3 , or a pharmaceutically acceptable salt thereof, wherein L is C 1-12 alkylenyl.
5. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, selected from the group consisting of:
3-(4-(3-aminoprop-1-yn-1-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione;
3-(4-(5-aminopent-1-yn-1-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione;
3-(4-(4-aminobut-1-yn-1-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione;
3-(1-oxo-4-(piperidin-4-ylethynyl)isoindolin-2-yl)piperidine-2,6-dione; and
3-(4-(5-aminopent-1-yn-1-yl)-7-fluoro-1-oxoisoindolin-2-yl)piperidine-2,6-dione.
6. The compound of claim 1 , wherein X is —OC(═O)—.
7. The compound of claim 1 , wherein X is —N(H)—.
8. The compound of claim 1 , wherein X is selected from the group consisting of
wherein the carbon atom of
is attached to L.
9. The compound of claim 1 , wherein L is C 1-12 alkylenyl.
10. The compound of claim 1 , wherein L is selected from the group consisting of —CH 2 —, —CH 2 CH 2 —, —CH 2 CH 2 CH 2 —, —CH 2 (CH 2 ) 2 CH 2 —, —CH 2 (CH 2 ) 3 CH 2 —, —CH 2 (CH 2 ) 4 CH 2 —, —CH 2 (CH 2 ) 5 CH 2 —, and —CH 2 (CH 2 ) 6 CH 2 —.
11. The compound of claim 1 , wherein R 16a is selected from the group consisting of hydrogen and halo.
12. The compound of claim 1 , wherein R 16b is selected from the group consisting of hydrogen and halo.
13. The compound of claim 1 , wherein R 16c is selected from the group consisting of hydrogen and halo.
14. The compound of claim 1 , wherein Z is —CH 2 —.
15. The compound of claim 1 , wherein Z is —C(═O)—.
16. The compound of claim 1 , wherein R 5 is hydrogen.
17. The compound of claim 1 , wherein B is:
18. The compound of claim 3 , wherein R 5 is hydrogen.
19. The compound of claim 3 , wherein Z is —CH 2 —.
20. The compound of claim 3 , wherein Z is —C(═O)—.