Piperazine-2,5-diones as TGF-beta inhibitors
The present disclosure is concerned with piperazine-2,5-diones that are capable of inhibiting TGF-β and methods of treating cancers such as, for example, multiple myeloma and a hematologic malignancy, and methods of treating fibrotic conditions using these compounds. This abstract is intended as a scanning tool for purposes of searching in the particular art and is not intended to be limiting of the present invention.
1. A compound having a structure represented by a formula:
wherein n is selected from 1, 2, 3, and 4;
wherein each of R 1a and R 1b is independently C1-C4 alkyl;
or wherein each of R 1a and R 1b are optionally covalently bonded together and, together with the intermediate atoms, comprise a 3- to 7-membered cycloalkyl substituted with 0-4 non-hydrogen groups independently selected from halogen, —NH 2 , C1-C4 alkyl, C1-C4 haloalkyl, C1-C4 hydroxyalkyl, C1-C4 alkoxy, C1-C4 alkylamino, and (C1-C4)(C1-C4) dialkylamino; and
wherein each of R 2 and R 3 is independently selected from hydrogen and C1-C4 alkyl; and
wherein R 4 is selected from —NR 20a R 20b and Cy 1 ;
wherein each of R 20a and R 20b , when present, is independently selected from hydrogen, C1-C4 alkyl, C1-C4 haloalkyl, cycloalkyl, and heteroaryl;
wherein Cy 1 , when present, is selected from C5-C6 cycloalkyl, monocyclic heteroaryl, and —C 6 H 4 R 21 and is substituted with 0-4 non-hydrogen groups independently selected from halogen, —NH 2 , C1-C4 alkyl, C1-C4 haloalkylh, C1-C4 hydroxyalkyl, C1-C4 alkoxy, C1-C4 alkylamino, and (C1-C4)(C1-C4) dialkylamino; and
wherein R 21 , when present, is selected from —(CH 2 ) q NR 31a R 31b and —C(O)NR 32a R 32b ;
wherein q, when present, is selected from 0 and 1;
wherein each of R 31a , R 31b , R 32a , and R 32b , when present, is independently selected from hydrogen and C1-C4 alkyl;
or wherein each of R 1a and R 1b is hydrogen and R 4 is —C 6 H 4 C(O)NR 32a R 32b ;
or wherein R 1a is hydrogen, R 1b is —CH 2 Cy 2 , and R 4 is —C 6 H 4 R 21 ;
wherein Cy 2 is selected from C3-C6 cycloalkyl substituted with 0-4 non-hydrogen groups independently selected from halogen, —NH 2 , C1-C4 alkyl, C1-C4 haloalkyl, C1-C4 hydroxyalkyl, C1-C4 alkoxy, C1-C4 alkylamino, and (C1-C4)(C1-C4) dialkylamino;
provided that when n is 1 and each of R 1a and R 1b together comprise a 3-membered cycloalkyl then Cy 1 , when present, is not monocyclic heteroaryl, and
provided that when R 4 is NR 20a R 20b then each of R 1a and R 1b is independently C1-C4 alkyl,
or a pharmaceutically acceptable salt thereof.
2. The compound of claim 1 , wherein n is 1.
3. The compound of claim 1 , wherein each of R 2 and R 3 is hydrogen.
4. The compound of claim 1 , wherein R 4 is NHR 20a .
5. The compound of claim 1 , wherein each of R 20a and R 20b is hydrogen.
6. The compound of claim 1 , wherein R 4 is Cy 1 .
7. The compound of claim 1 , having a structure represented by a formula:
wherein Z is selected from O, S, and NR 40 ;
wherein R 40 , when present, is selected from hydrogen and C1-C4 alkyl;
wherein each of Q 1 and Q 2 is independently selected from CH and N; and
wherein R 33 is selected from hydrogen and C1-C4 alkyl.
8. The compound of claim 1 , having a structure represented by a formula:
wherein R 33 is selected from hydrogen and C1-C4 alkyl.
9. The compound of claim 1 , having a structure represented by a formula:
wherein Q 1 is selected from CH and N; and
wherein R 33 is selected from hydrogen and C1-C4 alkyl.
10. The compound of claim 1 , having a structure selected from:
11. The compound of claim 1 , having a structure selected from:
12. A pharmaceutical composition comprising a therapeutically effective amount of at least one compound of claim 1 and a pharmaceutically acceptable carrier.