Modulators of programmed death-ligand-1 and/or programmed death-ligand-2

Patent metadata

Field	Value
Publication number	US-12098216-B2
Application number	US-202017778823-A
Country	US
Kind code	B2
Filing date	Dec 3, 2020
Priority date	Dec 4, 2019
Publication date	Sep 24, 2024
Grant date	Sep 24, 2024

Abstract

The present disclosure is concerned with dipeptide compounds for the treatment of various cancers such as, for example, sarcomas, carcinomas, hematological cancers, solid tumors, breast cancer, cervical cancer, gastrointestinal cancer, colorectal cancer, brain cancer, skin cancer, prostate cancer, ovarian cancer, bladder cancer, thyroid cancer, testicular cancer, pancreatic cancer, endometrial cancer, melanomas, gliomas, leukemias, lymphomas, chronic myeloproliferative disorders, myelodysplastic syndromes, myeloproliferative neoplasms, and plasma cell neoplasms (myelomas). 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 0 or 1;
wherein each of R 1a and R 1b , when present, is independently selected from hydrogen, halogen, and unsubstituted C1-C4 alkyl;
or wherein each of R 1a and R 1b , when present, are covalently bonded and, together with the intermediate atoms, comprise an unsubstituted cyclopropyl group;
wherein each of R 2 and R 4 is independently selected from hydrogen and unsubstituted C1-C4 alkyl;
wherein R 3 is selected from —(C1-C8 alkyl)NR 10a R 10b , —(C1-C8 alkyl)C(O)NR 10a R 10b , unsubstituted C2-C8 alkyl, and —(C1-C4)Ar 2 ;
wherein each of R 10a and R 10b is independently selected from hydrogen and unsubstituted C1-C4 alkyl;
wherein Ar 2 is C6 aryl para-substituted with a —(CH 2 ) m NR 20a R 20b group, and substituted with 0, 1, 2, or 3 groups independently selected from halogen, —CN, —NH 2 , —OH, —NO 2 , unsubstituted C1-C4 alkyl, unsubstituted C2-C4 alkenyl, C1-C4 haloalkyl, C1-C4 cyanoalkyl, C1-C4 hydroxyalkyl, C1-C4 haloalkoxy, C1-C4 alkoxy, C1-C4 alkylamino, (C1-C4)(C1-C4) dialkylamino, and C1-C4 aminoalkyl;
wherein m is 1, 2, 3, or 4; and
wherein each of R 20a and R 20b is independently selected from hydrogen and unsubstituted C1-C4 alkyl;

wherein each of R 5a and R 5b is hydrogen;
or wherein each of R 5a and R 5b is independently unsubstituted C1-C4 alkyl;
or wherein each of R 5a and R 5b are covalently bonded and, together with the intermediate atom, comprise an unsubstituted C3-C6 group; and
wherein R 6 is hydrogen;
or wherein each of R 5a and R 5b together are covalently bonded to R 6 and, together with the intermediate atom, comprise a C3-C5 heteroaryl group substituted with 0, 1, 2, or 3 groups independently selected from halogen, —CN, —NH 2 , —OH, —NO 2 , unsubstituted C1-C4 alkyl, unsubstituted C2-C4 alkenyl, C1-C4 haloalkyl, C1-C4 cyanoalkyl, C1-C4 hydroxyalkyl, C1-C4 haloalkoxy, C1-C4 alkoxy, C1-C4 alkylamino, (C1-C4)(C1-C4) dialkylamino, and C1-C4 aminoalkyl; and
wherein Ar 1 is selected from C6 aryl, indolyl, pyridinyl, benzo[d]oxazole, and benzo[d]thiazole, and is substituted with 0, 1, 2, or 3 groups independently selected from halogen, —CN, —NH 2 , —OH, —NO 2 , unsubstituted C1-C4 alkyl, unsubstituted C2-C4 alkenyl, C1-C4 haloalkyl, C1-C4 cyanoalkyl, C1-C4 hydroxyalkyl, C1-C4 haloalkoxy, C1-C4 alkoxy, C1-C4 alkylamino, (C1-C4)(C1-C4) dialkylamino, and C1-C4 aminoalkyl,
or a pharmaceutically acceptable salt thereof,
provided that when each of R 5a and R 5b is hydrogen, then R 3 is not unsubstituted C2-C8 alkyl,
provided that when n is 0, then each of R 5a and R 5b is independently unsubstituted C1-C4 alkyl or each of R 5a and R 5b are covalently bonded and, together with the intermediate atom, comprise an unsubstituted C3-C6 group, and R 6 is hydrogen, and
provided that the compound is not:

2. The compound of claim 1 , wherein n is 0.

3. The compound of claim 1 , wherein n is 1.

4. The compound of claim 1 , wherein each of R 1a and R 1b , when present, is hydrogen, or wherein each of R 1a and R 1b , when present, are covalently bonded and, together with the intermediate atom, comprise an unsubstituted cyclopropyl group.

5. The compound of claim 1 , wherein each of R 2 and R 4 is hydrogen.

6. The compound of claim 1 , wherein R 3 is —(C1-C8 alkyl)NR 10a R 10b .

7. The compound of claim 1 , wherein R 3 is unsubstituted C2-C8 alkyl.

8. The compound of claim 1 , wherein R 3 is —(C1-C4)Ar 2 .

9. The compound of claim 1 , wherein the compound has a structure represented by a formula:

10. The compound of claim 1 , wherein the compound has a structure represented by a formula:

11. The compound of claim 1 , wherein the compound has a structure represented by a formula:

12. The compound of claim 1 , wherein the compound has a structure represented by a formula:

13. The compound of claim 1 , wherein the compound has a structure represented by a formula:

wherein each of R 21a , R 21b , R 21c , R 21d , and R 21e are independently selected from hydrogen, halogen, —CN, —NH 2 , —OH, —NO 2 , unsubstituted C1-C4 alkyl, unsubstituted C2-C4 alkenyl, C1-C4 haloalkyl, C1-C4 cyanoalkyl, C1-C4 hydroxyalkyl, C1-C4 haloalkoxy, C1-C4 alkoxy, C1-C4 alkylamino, (C1-C4)(C1-C4) dialkylamino, and C1-C4 aminoalkyl, provided that at least two of R 21a , R 21b , R 21c , R 21d , and R 21e are hydrogen.

14. The compound of claim 1 , wherein the compound has a structure represented by a formula:

15. A compound selected from:

or a pharmaceutically acceptable salt thereof.

16. A pharmaceutical composition comprising an effective amount of the compound of claim 1 , and a pharmaceutically acceptable carrier.

17. A pharmaceutical composition comprising an effective amount of the compound of claim 15 , and a pharmaceutically acceptable carrier.

Assignees

• Southern Res Inst

Inventors

• Suto Mark J
• Mathew Bini
• Boohaker Rebecca

Classifications

• C07K5/06034

  the side chain containing 2 to 4 carbon atoms · CPC title

• A61P35/00

  Antineoplastic agents · CPC title

• 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

• C07K5/06104

  with the first amino acid being acidic · CPC title

• A61P35/02

  specific for leukemia · CPC title