Dipeptide analogs as TGF-beta inhibitors

Patent metadata

Field	Value
Publication number	US-11046729-B2
Application number	US-201816172261-A
Country	US
Kind code	B2
Filing date	Oct 26, 2018
Priority date	Oct 26, 2017
Publication date	Jun 29, 2021
Grant date	Jun 29, 2021

Abstract

The present disclosure is concerned with dipeptide analogs that are capable of inhibiting TGF-β and methods of treating cancers such as, for example, multiple myeloma and a hematologic malignancy, methods for immunotherapy, 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.

First claim

What is claimed is:

1. A compound having a structure represented by a formula:

wherein n is selected from the group consisting of 0, 1, 2, 3, and 4;
wherein R 1 is selected from the group consisting of C1-C8 alkyl and (CH 2 ) q Cy 1 ;
wherein q is selected from the group consisting of 0 and 1;
wherein Cy 1 , when present, is selected from the group consisting of C3-C8 cycloalkyl and aryl and is substituted with 0-4 non-hydrogen groups independently selected from the group consisting of halogen, —(CH 2 ) r NH 2 , C1-C4 alkyl, C1-C4 haloalkyl, C1-C4 hydroxyalkyl, C1-C4 alkoxy, —(CH 2 ) r C1-C4 alkylamino, and —(CH 2 ) r (C1-C4)(C1-C4) dialkylamino;
wherein r is selected from the group consisting of 0 and 1;

wherein R 2 is selected from the group consisting of NR 20a R 20b , NHCOR 22 , and Ar 1 ;
wherein each of R 20a and R 20b , when present, is independently selected from the group consisting of hydrogen, C1-C4 alkyl, Cy 2 , and amine protecting group;
wherein Cy 2 , when present, is selected from the group consisting of C3-C8 cycloalkyl and aryl and is substituted with 0-4 non-hydrogen groups independently selected from the group consisting of halogen, —NH 2 , C1-C4 alkyl, C1-C4 haloalkyl, C1-C4 hydroxyalkyl, C1-C4 alkoxy, C1-C4 alkylamino, and (C1-C4)(C1-C4) dialkylamino;

wherein R 22 , when present, is selected from the group consisting of C1-C4 alkyl, cycloalkyl, and heterocycloalkyl and is substituted with 0-4 non-hydrogen groups independently selected from the group consisting of halogen, —NH 2 , C1-C4 alkyl, C1-C4 haloalkyl, C1-C4 hydroxyalkyl, C1-C4 alkoxy, C1-C4 alkylamino, and (C1-C4)(C1-C4) dialkylamino;
wherein Ar 1 , when present, is selected from the group consisting of aryl and heteroaryl and is monosubstituted with a non-hydrogen group selected from the group consisting of —(CH 2 ) m NH 2 , —(CH 2 ) m (C1-C4 alkylamino), and —(CH 2 ) m [(C1-C4)(C1-C4) dialkylamino];
wherein m is selected from the group consisting of 0 and 1;

wherein each of R 3a and R 3b is independently selected from the group consisting of C1-C4 alkyl and —(CH 2 ) s NR 21a R 21b ;
wherein s is selected from the group consisting of 0, 1, 2, 3, and 4;
wherein each of R 21a and R 21b , when present, is independently selected from the group consisting of hydrogen, C1-C4 alkyl, Cy 2 , and amine protecting group;

or wherein each of R 3a and R 3b 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 the group consisting of 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 R 4 is selected from the group consisting of hydrogen, C1-C4 alkyl, and Cy 3 ;
wherein Cy 3 , when present, is selected from the group consisting of C3-C8 cycloalkyl and aryl and is substituted with 0-4 non-hydrogen groups independently selected from the group consisting of halogen, —NH 2 , 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.

2. The compound of claim 1 , wherein R 2 is —NH 2 .

3. The compound of claim 1 , wherein R 2 is Ar 1 .

4. The compound of claim 1 , wherein each of R 3a and R 3b is methyl.

5. The compound of claim 1 , wherein each of R 3a and R 3b are optionally covalently bonded together and, together with the intermediate atoms, comprise an unsubstituted cyclopropyl.

6. The compound of claim 1 , wherein each of q and r is 0;
wherein R 2 is selected from the group consisting of NR 20a R 20b and Ar 1 ;
wherein each of R 3a and R 3b is independently C1-C4 alkyl;
or wherein each of R 3a and R 3b 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 the group consisting of 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 R 4 is selected from the group consisting of hydrogen, C1-C4 alkyl, and Cy 3 ,
or a pharmaceutically acceptable salt thereof.

7. The compound of claim 1 , having a structure represented by a formula:

8. The compound of claim 1 , having a structure represented by a formula:

9. The compound of claim 1 , having a structure represented by a formula:

wherein n is selected from the group consisting of 1, 2, 3, and 4.

10. The compound of claim 1 , wherein the compound is selected from the group consisting of:

or a pharmaceutically acceptable salt thereof.

11. A pharmaceutical composition comprising a therapeutically effective amount of at least one compound of claim 1 , and a pharmaceutically acceptable carrier.

12. A method for treating a disorder associated with TGF-β activity in a subject, the method comprising the step of administering to the subject an effective amount of the compound of claim 1 , thereby treating the disorder associated with TGF-β activity in the subject, wherein the disorder is multiple myeloma or liver fibrosis.

13. The method of claim 12 , wherein the disorder is multiple myeloma.

14. The method of claim 12 , wherein the disorder is liver fibrosis.

15. The method of claim 12 , wherein the subject has been diagnosed with a need for treatment of the disorder prior to the administering step.

16. The method of claim 12 , further comprising the step of identifying a subject in need of treatment of the disorder.

17. The compound of claim 9 , wherein R 1 is methyl.

18. The compound of claim 9 , wherein each of R 3a and R 3b is methyl.

19. The compound of claim 9 , wherein R 4 is hydrogen.

Assignees

• Southern Res Inst
• Uab Research Foundation

Inventors

• Suto Mark J
• Gupta Vandana
• Mathew Bini
• Murphy-Ullrich Joanne

Classifications

• A61K38/00

  Medicinal preparations containing peptides (peptides containing beta-lactam rings A61K31/00; cyclic dipeptides not having in their molecule any other peptide link than those which form their ring, e.g. piperazine-2,5-diones, A61K31/00; ergot alkaloids of the cyclic peptide type A61K31/48; containing macromolecular compounds having statistically distributed amino acid units A61K31/74; medicinal preparations containing antigens or antibodies A61K39/00; medicinal preparations characterised by the non-active ingredients, e.g. peptides as drug carriers, A61K47/00) · CPC title

• C07K5/06052

  Val-amino acid · CPC title

• C07K5/06086 Primary

  with the first amino acid being basic · CPC title

• C07K5/06078

  and aromatic or cycloaliphatic · CPC title

• A61P37/00

  Drugs for immunological or allergic disorders · CPC title