PARP inhibitors for treating cancer and asthma

Patent metadata

Field	Value
Publication number	US-12030858-B2
Application number	US-201917272015-A
Country	US
Kind code	B2
Filing date	Aug 23, 2019
Priority date	Aug 27, 2018
Publication date	Jul 9, 2024
Grant date	Jul 9, 2024

Abstract

Provided are substituted 8-methylquinazolin-4(3H)-one compounds useful as PARP inhibitors for the treatment of cancer and asthma, as well as pharmaceutical compositions comprising them and methods for their synthesis.

First claim

What is claimed:

1. A compound of Formula I, or a pharmaceutically acceptable salt thereof:

wherein R 1 is selected from C 1 -C 3 alkyl, C 2 -C 3 alkenyl, and C 2 -C 3 alkynyl; and
R 2 is selected from a phenyl ring and a 3-membered to 10-membered aromatic, partially unsaturated, or unsaturated heterocycle containing 1, 2, 3, or 4 ring nitrogen atoms, with the phenyl ring and the 5- to 10-membered aromatic, partially unsaturated, or unsaturated heterocycle being substituted by 0, 1, 2 or 3 substituents selected from the group of Cl, F, Br, I, OH, C 1 -C 6 alkyl, —O-C 1 -C 6 alkyl, —NH 2 , —NH(C 1 -C 6 alkyl), —N(C 1 -C 6 alkyl) 2 , —CO 2 H, —CO 2 (C 1 -C 6 alkyl), —CO 2 -phenyl, and —CO 2 -benzyl;
wherein the phenyl and benzyl rings of the R 2 —CO 2 -phenyl, —CO 2 -benzyl groups are substituted by 0, 1, 2, or 3 substituents selected from the group of Cl, F, Br, I, OH, C 1 -C 6 alkyl, —O-C 1 -C 6 alkyl, —NH 2 , —NH(C 1 -C 6 alkyl), and —N(C 1 -C 6 alkyl) 2 .

2. A compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein R 1 is selected from the group of C 1 -C 3 alkyl, C 2 -C 3 alkenyl, and C 2 -C 3 alkynyl; and
R 2 is selected from the group of a phenyl ring and a 5- to 10-membered aromatic or partially unsaturated heterocycle containing 1, 2, 3, or 4 ring nitrogen atoms, wherein the phenyl ring and the 5- to 10-membered aromatic, partially unsaturated, or unsaturated heterocycle are each independently substituted by 0, 1, 2, or 3 substituents selected from the group of Cl, F, Br, I, OH, C 1 -C 6 alkyl, —O-C 1 -C 6 alkyl, —NH 2 , —NH(C 1 -C 6 alkyl), —N(C 1 -C 6 alkyl) 2 , —CO 2 H, —CO 2 (C 1 -C 6 alkyl), —CO 2 -phenyl, and —CO 2 -benzyl;
wherein the phenyl and benzyl rings of the R 2 —CO 2 -phenyl, —CO 2 -benzyl groups are substituted by 0, 1, 2, or 3 substituents selected from the group of Cl, F, Br, I, OH, C 1 -C 6 alkyl, —O-C 1 -C 6 alkyl, —NH 2 , —NH(C 1 -C 6 alkyl), and —N(C 1 -C 6 alkyl) 2 .

3. A compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein R 1 is selected from the group of C 1 -C 3 alkyl, C 2 -C 3 alkenyl, and C 2 -C 3 alkynyl; and
R 2 is selected from the group of a phenyl ring and a 5- to 10-membered aromatic or partially unsaturated heterocycle containing 1, 2, 3, or 4 ring nitrogen atoms, wherein the phenyl ring and the 5- to 10-membered aromatic, partially unsaturated, or unsaturated heterocycle are each independently substituted by 0, 1, 2, or 3 substituents selected from the group of OH, C 1 -C 6 alkyl, —O-C 1 -C 6 alkyl, —NH 2 , —NH(C 1 -C 6 alkyl), —N(C 1 -C 6 alkyl) 2 , —CO 2 H, —CO 2 (C 1 -C 6 alkyl), —CO 2 -phenyl, and —CO 2 -benzyl;
wherein the phenyl and benzyl rings of the R 2 —CO 2 -phenyl, —CO 2 -benzyl groups are substituted by 0, 1, 2, or 3 substituents selected from the group of Cl, F, Br, I, OH, C 1 -C 6 alkyl, —O-C 1 -C 6 alkyl, —NH 2 , —NH(C 1 -C 6 alkyl), and —N(C 1 -C 6 alkyl) 2 .

4. A compound of claim 1 of Formula II, or a pharmaceutically acceptable salt thereof:

wherein R 1 is selected from the group of C 1 -C 3 alkyl, C 2 -C 3 alkenyl, and C 2 -C 3 alkynyl; and
R 3 , R 4 , and R 5 are each independently selected from the group of OH, C 1 -C 6 alkyl, —O—C 1 -C 6 alkyl, —NH 2 , —NH(C 1 -C 6 alkyl), —N(C 1 -C 6 alkyl) 2 , —CO 2 H, —CO 2 (C 1 -C 6 alkyl), —CO 2 -phenyl, and —CO 2 -benzyl;
wherein the phenyl and benzyl rings of the R 3 , R 4 , and R 5 —CO 2 -phenyl and —CO 2 -benzyl groups are substituted by 0, 1, 2, or 3 substituents selected from the group of Cl, F, Br, I, OH, C 1 -C 6 alkyl, —O-C 1 -C 6 alkyl, —NH 2 , —NH(C 1 -C 6 alkyl), and —N(C 1 -C 6 alkyl) 2 .

5. A compound of claim 1 of Formula III, or a pharmaceutically acceptable salt thereof:

wherein R 1 is selected from the group of C 1 -C 3 alkyl, C 2 -C 3 alkenyl, and C 2 -C 3 alkynyl; and
R 3 and R 4 are each independently selected from the group of OH, C 1 -C 6 alkyl, —O-C 1 -C 6 alkyl, —NH 2 , —NH(C 1 -C 6 alkyl), —N(C 1 -C 6 alkyl) 2 , —CO 2 H, —CO 2 (C 1 -C 6 alkyl), —CO 2 -phenyl, and —CO 2 -benzyl;
wherein the R 6 is selected from the group of C 1 -C 6 alkyl, phenyl, and benzyl, wherein the rings of the phenyl and benzyl groups are substituted by 0, 1, 2, or 3, substituents selected from the group of Cl, F, Br, I, OH, C 1 -C 6 alkyl, —O-C 1 -C 6 alkyl, —NH 2 , —NH(C 1 -C 6 alkyl), and —N(C 1 -C 6 alkyl) 2 .

6. A compound of claim 1 of Formula IV, or a pharmaceutically acceptable salt thereof:

wherein R 1 is selected from the group of C 1 -C 3 alkyl, C 2 -C 3 alkenyl, and C 2 -C 3 alkynyl.

7. A compound of claim 1 of Formula V, or a pharmaceutically acceptable salt thereof:

wherein R 1 is selected from the group of C 1 -C 3 alkyl, C 2 -C 3 alkenyl, and C 2 -C 3 alkynyl.

8. A compound of claim 1 of Formula VI, or a pharmaceutically acceptable salt

wherein R 1 is selected from the group of C 1 -C 3 alkyl, C 2 -C 3 alkenyl, and C 2 -C 3 alkynyl.

9. A compound of claim 1 of Formula VII, or a pharmaceutically acceptable salt

wherein R 1 is selected from the group of C 1 -C 3 alkyl, C 2 -C 3 alkenyl, and C 2 -C 3 alkynyl; and R 7 is selected from the group of H, —CH 3 , —NH 2 , —NH(C 1 -C 6 alkyl), and —N(C 1 -C 6 alkyl) 2 .

10. The compound of claim 1 , wherein R 1 is C 1 -C 3 alkyl, or a pharmaceutically acceptable salt thereof.

11. The compound of claim 1 , wherein R 1 is —CH 3 , or a pharmaceutically acceptable salt thereof.

12. The compound of claim 1 , wherein R 1 is C 2 -C 3 alkenyl, or a pharmaceutically acceptable salt thereof.

13. The compound of claim 1 , wherein R 1 is C 2 -C 3 alkynyl, or a pharmaceutically acceptable salt thereof.

14. A compound of claim 1 selected from the group of:

or a pharmaceutically acceptable salt thereof.

15. A pharmaceutical composition comprising a pharmaceutically effective amount of the compound of claim 1 , or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier or excipient.

16. A method of sensitizing a cell to a DNA-damaging agent, the method comprising administering to a human in need thereof a pharmaceutically effective amount of the compound of claim 1 , or a pharmaceutically acceptable salt thereof.

17. The method of claim 16 wherein the DNA-damaging agent is selected from the group of cisplatin, carboplatin, oxaliplatin, picoplatin, dicycloplatin, eptaplatin, lobaplatin, miriplatin, nedaplatin, satraplatin, triplatin tetranitrate, doxorubicin, daunorubicin, epirubicin, idarubicin, procarbazine, altretamine, bleomycin, carmustine, lomustine, streptozocin, semustine, temozolomide, 5-fluorouracil, capecitabine, floxuridine, gemcitabine, 6-mercaptopurine, 8-a

Assignees

• Univ Oregon Health & Science

Inventors

• Cohen Michael
• Kirby Ilsa

Classifications

• C07D473/38

  attached in position 6 · CPC title

• C07D403/12

  linked by a chain containing hetero atoms as chain links · CPC title

• C07D239/90 Primary

  with acyclic radicals attached in position 2 or 3 · CPC title

• A61P35/00 Primary

  Antineoplastic agents · CPC title