Piperazine-2,5-diones as tgf-beta inhibitors
AssigneeThe UAB Research Foundation
InventorsMark J. Suto, Vandana V. Gupta, Wei Zhang, Joanne Murphy-Ullrich
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Abstract
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.
Claims26
A compound having a structure represented by a formula:
- wherein n is selected from 1, 2, 3, and 4;
- wherein each of R1a and R1b is independently C1-C4 alkyl;
- or wherein each of R1a and R1b 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, —NH2, 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 R2 and R3 is independently selected from hydrogen and C1-C4 alkyl;
- and
- wherein R4 is selected from —NR20aR20b and Cy1;
- wherein each of R20a and R20b, when present, is independently selected from hydrogen, C1-C4 alkyl, C1-C4 haloalkyl, cycloalkyl, and heteroaryl;
- wherein Cy1, when present, is selected from C5-C6 cycloalkyl, monocyclic heteroaryl, and —C6H4R21 and is substituted with 0-4 non-hydrogen groups independently selected from halogen, —NH2, C1-C4 alkyl, C1-C4 haloalkyl, C1-C4 hydroxyalkyl, C1-C4 alkoxy, C1-C4 alkylamino, and (C1-C4)(C1-C4) dialkylamino;
- and
- wherein R21, when present, is selected from —(CH2)qNR31aR31b and —C(O)NR32aR32b;
- wherein q, when present, is selected from 0 and 1;
- wherein each of R31a, R31b, R32a, and R32b, when present, is independently selected from hydrogen and C1-C4 alkyl;
- or wherein each of R1a and R1b is hydrogen and R4 is —C6H4C(O)NR32aR32b,
- or wherein R1a is hydrogen, R1b is —CH2Cy2, and R4 is —C6H4R21;
- wherein Cy2 is selected from C3-C6 cycloalkyl substituted with 0-4 non-hydrogen groups independently selected from halogen, —NH2, 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 R1a and R1b together comprise a 3-membered cycloalkyl then Cy1, when present, is not monocyclic heteroaryl, and
- provided that when R4 is —NR20aR20b then each of R1a and R1b is independently C1-C4 alkyl,
- or a pharmaceutically acceptable salt thereof.
3-5. (canceled)
10-14. (canceled)
16-17. (canceled)
A method for inhibiting TGF-β activity in a subject, the method comprising the step of administering to the subject an effective amount of at least one compound having a structure represented by a formula:
- wherein n is selected from 1, 2, 3, and 4;
- wherein each of R1a and R1b is independently C1-C4 alkyl;
- or wherein each of R1a and R1b 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, —NH2, 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 R2 and R3 is independently selected from hydrogen and C1-C4 alkyl;
- and
- wherein R4 is selected from —NHR20 and Cy1;
- wherein R20, when present, is selected from hydrogen and C1-C4 alkyl;
- wherein Cy1, when present, is selected from C5-C6 cycloalkyl, monocyclic heteroaryl, and —C6H4R21 and is substituted with 0-4 non-hydrogen groups independently selected from halogen, —NH2, C1-C4 alkyl, C1-C4 haloalkyl, C1-C4 hydroxyalkyl, C1-C4 alkoxy, C1-C4 alkylamino, and (C1-C4)(C1-C4) dialkylamino;
- and
- wherein R21, when present, is selected from —(CH2)qNR31aR31b and —C(O)NR32aR32b;
- wherein q, when present, is selected from 0 and 1;
- wherein each of R31a, R31b, R32a, and R32b, when present, is independently selected from hydrogen and C1-C4 alkyl;
- or wherein each of R1a and R1b is hydrogen and R4 is —C6H4C(O)NR32aR32b;
- or wherein R1a is hydrogen, R1b is —CH2Cy3 and R4 is —C6H4R21;
- wherein Cy3 is selected from C3-C6 cycloalkyl, monocyclic heteroaryl, and aryl and is substituted with 0-4 non-hydrogen groups independently selected from halogen, —NH2, C1-C4 alkyl, C1-C4 haloalkyl, C1-C4 hydroxyalkyl, C1-C4 alkoxy, C1-C4 alkylamino, and (C1-C4)(C1-C4) dialkylamino;
- or a pharmaceutically acceptable salt thereof, thereby inhibiting TGF-β activity in the subject.
The method of claim 0, provided that when n is 1 and each of R1a and R1b together comprise a 3-membered cycloalkyl then Cy1, when present, is not monocyclic heteroaryl, and provided that when R4 is —NR20aR20b then each of R1a and R1b is independently C1-C4 alkyl.
The method of claim 0, wherein inhibiting TGF-β is inhibiting cancer.
The method of claim 0, wherein the cancer is selected from multiple myeloma or a hematologic malignancy.
27-28. (canceled)
The method of claim 0, wherein inhibiting TGF-β is inhibiting a fibrotic disorder.
The method of claim 0, wherein the fibrotic disorder is found in the liver, the lung, the cardiac muscle, the kidney, the skin, or the eye.
The method of claim 0, wherein the fibrotic disorder is glaucoma, amyotropic lateral sclerosis, muscular dystrophy, or liver fibrosis.
32-34. (canceled)
The method of claim 0, wherein inhibiting TGF-β is associated with immunotherapy.
36-79. (canceled)
Dependencies are inferred from the claim text.