Compositions and methods for adjuvant cancer therapeutics

Patent metadata

Field	Value
Publication number	US-11801242-B2
Application number	US-201917283461-A
Country	US
Kind code	B2
Filing date	Oct 9, 2019
Priority date	Oct 9, 2018
Publication date	Oct 31, 2023
Grant date	Oct 31, 2023

Abstract

This invention relates to compounds, pharmaceutical compositions comprising them, and methods of using the compounds and compositions for treating diseases related to translesion synthesis (TLS) pathway. More particularly, this disclosure relates to small molecule inhibitors of TLS, methods of inhibiting TLS pathway with these compounds, and methods of treating diseases related to the TLS pathway.

First claim

What is claimed is:

1. A method of treating cancer, comprising administering to a subject in need thereof (i) one or more secondary therapeutic agents and (ii) one or more compounds of formula (I),

or a pharmaceutically acceptable salt thereof, wherein
X and Y are independently selected from NR, O, or S,
where R is hydrogen or C 1 -C 4 alkyl;

R 1 , R 2 , R 3 , and R 4 are independently selected from the group consisting of hydrogen, halogen, —NO 2 , —CN, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, —NH 2 , —NH(C 1 -C 6 alkyl), —N(C 1 -C 6 alkyl) 2 , —OH, C 1 -C 6 alkoxy, C 1 -C 6 haloalkoxy, —SH, hydroxy(C 1 -C 6 alkyl), alkoxy(C 1 -C 6 alkyl), amino(C 1 -C 6 alkyl), —CONH 2 , —CONH(C 1 -C 6 alkyl), —CON(C 1 -C 6 alkyl) 2 , —CO 2 H, —CO 2 (C 1 -C 6 alkyl), —CHO, —CO(C 1 -C 6 alkyl), and —S(O) 0-2 (C 1 -C 6 alkyl);
R 5 , R 6 , and R 7 are independently selected from the group consisting of hydrogen, halogen, —NO 2 , —CN, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, —NH 2 , —NH(C 1 -C 6 alkyl), —N(C 1 -C 6 alkyl) 2 , —OH, C 1 -C 6 alkoxy, C 1 -C 6 haloalkoxy, —SH, —CONH 2 , —CONH(C 1 -C 6 alkyl), —CON(C 1 -C 6 alkyl) 2 , —CO 2 H, —CO 2 (C 1 -C 6 alkyl), —CHO, —CO(C 1 -C 6 alkyl), and —S(O) 0-2 (C 1 -C 6 alkyl),
or R 5 and R 6 , together with the atoms to which they are attached, form a 5 or 6 membered aryl, heteroaryl, or heterocyclyl;

R 8 is C 1 -C 8 alkyl optionally substituted with one or more R 10 , C 2 -C 8 alkenyl optionally substituted with one or more R 10 , or C 2 -C 8 alkynyl optionally substituted with one or more R 10 ,
wherein each R 10 is independently selected from the group consisting of halogen, —NO 2 , —CN, —NH 2 , —NH(C 1 -C 6 alkyl), —N(C 1 -C 6 alkyl) 2 , —OH, C 1 -C 6 alkoxy, C 1 -C 6 haloalkoxy, —CONH 2 , —CONH(C 1 -C 6 alkyl), —CON(C 1 -C 6 alkyl) 2 , —CO 2 H, —CO 2 (C 1 -C 6 alkyl), —CHO, —CO(C 1 -C 6 alkyl), and —S(O) 0-2 (C 1 -C 6 alkyl), or two R 10 groups when attached to the same carbon atom form ═O, ═NR, or ═N—OH; and

R 9 is hydrogen or C 1 -C 4 alkyl.

2. The method of claim 1 , wherein the cancer is selected from the group consisting of breast cancer, prostate cancer, colon cancer, squamous cell cancer, small-cell lung cancer, non-small cell lung cancer, ovarian cancer, cervical cancer, gastrointestinal cancer, pancreatic cancer, glioblastoma, liver cancer, bladder cancer, hepatoma, colorectal cancer, uterine cervical cancer, endometrial carcinoma, salivary gland carcinoma, mesothelioma, kidney cancer, vulval cancer, pancreatic cancer, thyroid cancer, hepatic carcinoma, skin cancer, melanoma, brain cancer, neuroblastoma, myeloma, various types of head and neck cancer, acute lymphoblastic leukemia, acute myeloid leukemia, Ewing sarcoma, fibrosarcoma, and peripheral neuroepithelioma.

3. The method of claim 1 , wherein the secondary therapeutic agent is a chemotherapeutic reagent.

4. The method of claim 3 , wherein the chemotherapeutic reagent is an alkylating antineoplastic agent.

5. The method of claim 3 , wherein the chemotherapeutic reagent is a platinum-based antineoplastic agent.

6. The method of claim 1 , wherein the one or more secondary therapeutic agents is cisplatin.

7. The method of claim 1 , wherein the one or more secondary therapeutic agents is administered prior to the one or more compounds of formula (I).

8. The method of claim 1 , wherein the one or more secondary therapeutic agents is administered concurrently with the one or more compounds of formula (I).

9. The method of claim 1 , wherein the one or more secondary therapeutic agents is administered after the one or more compounds of formula (I).

10. The method of claim 1 , wherein X is NR or O.

11. The method of claim 1 , wherein Y is NR or O.

12. The method of claim 1 , wherein the compound of formula (I) is:

13. The method of claim 1 , wherein the compound of formula (I) is:

14. The method of claim 13 , wherein R 5 and R 6 are independently hydrogen, halogen, —NO 2 , —CN, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, —OH, C 1 -C 6 alkoxy, C 1 -C 6 haloalkoxy, —CO 2 H, or —CO 2 (C 1 -C 6 alkyl).

15. The method of claim 13 , wherein R 5 and R 6 are independently —F, —Cl, —Br, —NO 2 , —CH 3 , —CF 3 , —OH, —OCH 3 , —OCF 3 , —CO 2 H, or —CO 2 CH 3 .

16. The method of claim 13 , wherein R 7 is —F, —Cl, —Br, —NO 2 , —CH 3 , —CF 3 , —OH, —OCH 3 , —OCF 3 , —CO 2 H, or —CO 2 CH 3 .

17. The method of claim 1 , wherein the compound of formula (I) is:

18. The method of claim 1 , wherein the compound of formula (I) is selected from Table 1.

19. The method of claim 1 , wherein the one or more compounds of formula (I) is provided as a pharmaceutical composition comprising the one or more compounds and a pharmaceutically acceptable carrier, an excipient, a diluent, or a combination thereof.

20. The method of claim 1 , wherein the compound of formula (I) is selected from Table 2.

Assignees

• Univ Duke

Inventors

• Zhou Pei
• Hong Jiyong

Classifications

• A61K31/4706 Primary

  4-Aminoquinolines; 8-Aminoquinolines, e.g. chloroquine, primaquine · CPC title

• A61K33/243

  Platinum; Compounds thereof · CPC title

• A61P35/00

  Antineoplastic agents · CPC title

• A61P35/04

  specific for metastasis · CPC title

• C07D215/38 Primary

  Nitrogen atoms (nitro radicals C07D215/18) · CPC title