PCNA inhibitors

Patent metadata

Field	Value
Publication number	US-11345656-B2
Application number	US-202017108739-A
Country	US
Kind code	B2
Filing date	Dec 1, 2020
Priority date	Sep 17, 2015
Publication date	May 31, 2022
Grant date	May 31, 2022

Abstract

Described herein, inter alia, are compositions of PCNA modulators and methods for treating or preventing cancer.

First claim

What is claimed is:

1. A compound having the formula:

wherein
Ring A is phenyl or 5 to 6 membered heteroaryl;
Ring B is quinolinyl;
R 1 is independently halogen, —CX 1 3 , —CHX 1 2 , —CH 2 X 1 , —CN, —SO n1 R 10 , —SO v1 NR 7 R 8 , —NHNH 2 , —ONR 7 R 8 , —NHC═(O)NHNH 2 , —NHC═(O)NR 7 R 8 , —N(O) m1 , —NR 7 R 8 , —C(O)R 9 , —C(O)—OR 9 , —C(O)NR 7 R 8 , —OR 10 , —NR 7 SO 2 R 10 , —NR 7 C═(O)R 9 , —NR 7 C(O)—OR 9 , —NR 7 OR 9 , —OCX 1 3 , —OCHX 1 2 , —OCH 2 X 1 , substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl; or two adjacent R 1 substituents may optionally be joined to form a substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl;
R 2 is hydrogen, halogen, —CX 2 3 , —CHX 2 2 , —CH 2 X 2 , —CN, —COOH, —CONH 2 , substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl;
R 3 is hydrogen, halogen, —CX 3 3 , —CHX 3 2 , —CH 2 X 3 , —CN, —COOH, —CONH 2 , substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl;
R 4 is independently halogen, —CX 4 3 , —CHX 4 2 , —CH 2 X 4 , —CN, —SO n4 R 14 , —SO v4 NR 11 R 12 , —NHNR 11 R 12 , —ONR 11 R 12 , —NHC═(O)NHNR 11 R 12 , —NHC═(O)NR 11 R 12 , —N(O) m4 , —NR 11 R 12 , —C(O)R 13 , —C(O)—OR 13 , —C(O)NR 11 R 12 , —OR 14 , —NR 11 SO 2 R 14 , —NR 11 C═(O)R 13 , —NR 11 C(O)—OR 13 , —NR 11 OR 13 , —OCX 4 3 , —OCHX 4 2 , —OCH 2 X 4 , substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl; or two adjacent R 4 substituents may optionally be joined to form a substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl;
R 5 is independently halogen, —CX 5 3 , —CHX 5 2 , —CH 2 X 5 , —CN, —SO n5 R 18 , —SO v5 NR 15 R 16 , —NHNR 15 R 16 , —ONR 15 R 16 , —NHC═(O)NHNR 15 R 16 , —NHC═(O)NR 15 R 16 , —N(O) m5 , —NR 15 R 16 , —C(O)R 17 , —C(O)—OR 17 , —C(O)NR 15 R 16 , —OR 18 , —NR 15 SO 2 R 18 , —NR 15 C═(O)R 17 , —NR 15 C(O)—OR 17 , —NR 15 OR 17 , —OCX 5 3 , —OCHX 5 2 , —OCH 2 X 5 , substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl; or two adjacent R 5 substituents may optionally be joined to form a substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl;
R 7 , R 8 , R 9 , and R 10 are independently hydrogen, halogen, —CX A 3 , —CHX A 2 , —CH 2 X A , —CN, —COOH, —CONH 2 , substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl; or R 7 and R 8 substituents bonded to the same nitrogen atom may optionally be joined to form a substituted or unsubstituted heterocycloalkyl or substituted or unsubstituted heteroaryl;
R 11 , R 12 , R 13 , and R 14 and are independently hydrogen, halogen, —CX B 3 , —CHX B 2 , —CH 2 X B , —CN, —COOH, —CONH 2 , substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl; or R 11 and R 12 substituents bonded to the same nitrogen atom may optionally be joined to form a substituted or unsubstituted heterocycloalkyl or substituted or unsubstituted heteroaryl;
R 15 , R 16 , R 17 , and R 18 are independently hydrogen, halogen, —CX C 3 , —CHX C 2 , —CH 2 X C , —CN, —COOH, —CONH 2 , substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl; or R 15 and R 16 substituents bonded to the same nitrogen atom may optionally be joined to form a substituted or unsubstituted heterocycloalkyl or substituted or unsubstituted heteroaryl;
z1 is an integer from 0 to 4;
z2 is an integer from 0 to 5;
z3 is an integer from 0 to 6;
m1, m4, m5, v1, v4, and v5 are independently 1 or 2;
n1, n4, and n5 are independently an integer from 0 to 4; and
X 1 , X 2 , X 3 , X 4 , X 5 , X A , X B , and X C are independently —Cl, —Br, —I, or —F.

2. The compound of claim 1 , wherein R 1 is independently halogen, —CF 3 , —OH, —NH 2 , —SH, substituted or unsubstituted C 1 -C 4 alkyl, substituted or unsubstituted 2 to 4 membered heteroalkyl, substituted or unsubstituted C 3 -C 6 cycloalkyl, substituted or unsubstituted 3 to 6 membered heterocycloalkyl, substituted or unsubstituted phenyl, or substituted or unsubstituted 5 to 6 membered heteroaryl.

3. The compound of claim 1 , wherein R 4 is independently halogen, —CF 3 , —OH, —NH 2 , —SH, substituted or unsubstituted C 1 -C 4 alkyl, substituted or unsubstituted 2 to 4 membered heteroalkyl, substituted or unsubstituted C 3 -C 6 cycloalkyl, substituted or unsubstituted 3 to 6 membered heterocycloalkyl, substituted or unsubstituted phenyl, or substituted or unsubstituted 5 to 6 membered heteroaryl.

4. The compound of claim 1 , wherein R 4 is independently —OR 14 , and R 14 is hydrogen or unsubstituted C 1 -C 5 alkyl.

5. The compound of claim 1 , wherein R 5 is independently halogen, —CF 3 , —OH, —NH 2 , —SH, substituted or unsubstituted C 1 -C 4 alkyl, substituted or unsubstituted 2 to 4 membered heteroalkyl, substituted or unsubstituted C 3 -C 6 cycloalkyl, substituted or unsubstituted 3 to 6 membered heterocycloalkyl, substituted or unsubstituted phenyl, or substituted or unsubstituted 5 to 6 membered heteroaryl.

6. The compound of claim 1 , wherein R 2 is hydrogen, unsubstituted methyl, unsubstituted ethyl, or unsubstituted isopropyl.

7. The compound of claim 1 , wherein R 3 is hydrogen, unsubstituted methyl, unsubstituted ethyl, or unsubstituted isopropyl.

8. The compound of claim 1 , wherein Ring A is phenyl.

9. The compound of claim 1 , wherein Ring A is a 2-thienyl, 3-thienyl, 2-pyridyl, 3-pyridyl, or 4-pyridyl.

10. A pharmaceutical composition comprising a compound of claim 1 , or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient.

11. The pharmaceutical composition of claim 10 , further comprising an anti-cancer agent.

12. The pharmaceutical composition of claim 11 , wherein the anti-cancer agent is a platinum-based compound or a topoisomerase inhibitor.

13.

Assignees

• Hope City

Inventors

• Malkas Linda H
• Horne David
• Hickey Robert J
• Gu Long

Classifications

• A61K31/4409

  only substituted in position 4, e.g. isoniazid, iproniazid · CPC title

• A61K33/243

  Platinum; Compounds thereof · CPC title

• A61K2300/00

  Mixtures or combinations of active ingredients, wherein at least one active ingredient is fully defined in groups A61K31/00 - A61K41/00 · CPC title

• C07D401/12 Primary

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

• C07D213/68

  attached in position 4 · CPC title