IP Library › Granted Patent US 8,778,977

Granted Patent B2

US 8,778,977 · App. 12/307,104 · Granted Jul 15, 2014

Pyridinonyl PDK1 inhibitors

View Patent ↗

Loading inventors, assignments & file history…

Monitor This Case

Get email alerts when status or documents change.

Order Certified Copies

Most orders are placed with the USPTO same day — all within 24 business hours.

Order via The Patent Place →

Pre-filled with this patent's details

Quick Facts

Patent No.: US 8,778,977
App. No.: 12/307,104
Granted: Jul 15, 2014
Kind: B2

External Links

USPTO Patent Center↗ Full Patent PDF↗

Abstract

The present invention provides pyridinonyl PDK1 inhibitors and methods of treating cancer using the same.

Claims (71)

1. A compound of the formula:

wherein

n is an integer from 2 to 3;

L 1 and L 2 are independently absent, —O—, —NH—, —S—, —S(O)—, S(O) 2 —, substituted or unsubstituted alkylene, or substituted or unsubstituted heteroalkylene;

X is absent, substituted or unsubstituted cycloalkylene, substituted or unsubstituted heterocycloalkylene, substituted or unsubstituted arylene, or substituted or unsubstituted heteroarylene,

wherein if X is substituted or unsubstituted phenylene and L 1 is absent, then R 1 is not substituted or unsubstituted pyridinyl, substituted or unsubstituted benzo-oxazolyl, substituted or unsubstituted phenyl, or substituted or unsubstituted quinazolinyl, and

wherein if X is substituted or unsubstituted phenylene, then R 1 is not substituted or unsubstituted cyclohexyl;

R 1 is substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl,

wherein if R 1 is substituted or unsubstituted phenyl and X absent, then L 1 is not absent, and wherein if R 1 is substituted or unsubstituted phenyl, then X is not substituted or unsubstituted pyridinonyl, or substituted or unsubstituted imidazolyl;

each R 2 is fluorine;

R 4 , R 5 , and R 6 are hydrogen;

R 7 , and R 8 are independently hydrogen, halogen, —OH, —CF 3 , —NO 2 , —OR 10 , —C(O)R 12 , —NR 13 R 14 , 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, —OH, —CF 3 , —OR 10 , —C(O)R 12 , 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, wherein R 3 is optionally attached to X thereby forming a substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl;

each instance of R 10 is independently —C(O)R 15 , 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;

each instance of R 12 and R 15 is independently hydrogen, —NR 19 R 20 , —OR 21 , 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;

each instance of R 13 is independently hydrogen, —C(O)R 15 , —S(O) 2 R 16 , 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;

each instance of R 14 , R 19 , R 20 and R 21 is independently hydrogen, 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; and

each instance of R 16 is independently hydrogen, —NR 19 R 20 , 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.

2. The compound of claim 1 , wherein R 1 is substituted or unsubstituted imidazopyridinyl, substituted or unsubstituted triazolopyridinyl, substituted or unsubstituted pyrrolopyridinyl, substituted or unsubstituted pyrrolopyrimidinyl, substituted or unsubstituted pyrrolopyrazinyl, substituted or unsubstituted pyrazolopyridyl, substituted or unsubstituted pyrazolopyrimidinyl, substituted or unsubstituted pyrazolopyrazinyl, substituted or unsubstituted amino-benzimidazolyl, substituted or unsubstituted 2-indolinonyl, substituted or unsubstituted 2-benzimidazolinonyl, substituted or unsubstituted 2-pyrrolidinonyl, substituted or unsubstituted benzimidazolyl, substituted or unsubstituted tetrazolyl, substituted or unsubstituted pyridinonyl, substituted or unsubstituted pyrazolyl, substituted or unsubstituted 5,8-dihydro-6H-pyrido-pyrimidin-7-one-yl, substituted or unsubstituted indazolyl, substituted or unsubstituted dihydro-imidazopyridinon-2-yl, substituted or unsubstituted indolyl, substituted or unsubstituted benzothiadiazolyl, substituted or unsubstituted benzo-oxodiazolyl, substituted or unsubstituted imidazopyridinyl, substituted or unsubstituted triazolopyridinonyl, substituted or unsubstituted dihydro-pyrazolone, substituted or unsubstituted triazolopyridinyl, or substituted or unsubstituted pyrimidinyl.

3. The compound of claim 1 , wherein R 1 is substituted or unsubstituted pyrimidinyl and L 1 is —NH-L 1A - thereby forming a substituent with the formula R 1 —NH-L 1A , wherein L 1A is absent, substituted or unsubstituted alkylene, or substituted or unsubstituted heteroalkylene.

4. The compound of claim 1 , wherein

R 7 , and R 8 are independently hydrogen, halogen, —OH, —CF 3 , —NO 2 , —OR 10 , —C(O)R 12 , —NR 13 R 14 , substituted or unsubstituted C 1 -C 10 alkyl, substituted or unsubstituted 2 to 10 membered heteroalkyl, substituted or unsubstituted C 3 -C 6 cycloalkyl, substituted or unsubstituted 3 to 6 membered heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl;

R 3 is hydrogen, —OH, —CF 3 , —OR 10 , —C(O)R 12 , substituted or unsubstituted C 1 -C 10 alkyl, substituted or unsubstituted 2 to 10 membered heteroalkyl, substituted or unsubstituted C 3 -C 6 cycloalkyl, substituted or unsubstituted 3 to 6 membered heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl;

each instance of R 10 is independently —C(O)R 15 , substituted or unsubstituted C 1 -C 10 alkyl, substituted or unsubstituted 2 to 10 membered heteroalkyl, substituted or unsubstituted C 3 -C 6 cycloalkyl, substituted or unsubstituted 3 to 6 membered heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl;

each instance of R 12 and R 15 is independently hydrogen, —NR 19 R 20 , —OR 21 , substituted or unsubstituted C 1 -C 10 alkyl, substituted or unsubstituted 2 to 10 membered heteroalkyl, substituted or unsubstituted C 3 -C 6 cycloalkyl, substituted or unsubstituted 3 to 6 membered heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl;

each instance of R 13 is independently hydrogen, —C(O)R 15 , —S(O) 2 R 16 , substituted or unsubstituted C 1 -C 10 alkyl, substituted or unsubstituted 2 to 10 membered heteroalkyl, substituted or unsubstituted C 3 -C 6 cycloalkyl, substituted or unsubstituted 3 to 6 membered heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl;

each instance of R 14 , R 19 , R 20 and R 21 is independently hydrogen, substituted or unsubstituted C 1 -C 10 alkyl, substituted or unsubstituted 2 to 10 membered heteroalkyl, substituted or unsubstituted C 3 -C 6 cycloalkyl, substituted or unsubstituted 3 to 6 membered heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl.

5. The compound of claim 1 , wherein X is absent, substituted or unsubstituted C 3 -C 6 cycloalkylene, substituted or unsubstituted 3 to 6 membered heterocycloalkylene, or substituted or unsubstituted heteroarylene.

6. The compound of claim 5 , wherein L 2 is unsubstituted C 1 -C 5 alkylene.

7. The compound of claim 5 , wherein L 1 is unsubstituted C 1 -C 5 alkylene.

8. The compound of claim 1 of the formula:

wherein

Z 1 , Z 2 , and Z 3 are independently —N═, —NH—, —O—, —S—, or —CH═; and

R 23 is hydrogen, halogen, —OH, —CF 3 , —NO 2 , —OR 10 , —C(O)R 12 , —NR 13 R 14 , 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.

9. The compound of claim 8 , wherein L 1 is —C(R 24 )(R 25 )—, wherein R 24 and R 25 are independently hydrogen, halogen, —OH, —CF 3 , —NO 2 , —OR 10 , —C(O)R 12 , —NR 13 R 14 , 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.

10. The compound of claim 1 of the formula:

wherein

t is an integer from 1 to 4;

each instance of R 22 is hydrogen, halogen, —OH, —CF 3 , —NO 2 , —OR 10 , —C(O)R 12 , —NR 13 R 14 , 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;

11. The compound of claim 10 , wherein X is of the formula:

wherein

Z 1 , Z 2 , and Z 3 are independently —N═, —NH—, —O—, —S—, or —CH═; and

12. The compound of claim 10 , wherein L 1 is —C(R 24 )(R 25 )—, and wherein R 24 and R 25 are independently hydrogen, halogen, —OH, —CF 3 , —NO 2 , —OR 10 , —C(O)R 12 , —NR 13 R 14 , 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.

13. The compound of claim 1 of the formula:

wherein

v is an integer from 1 to 3;

Z 4 is —N(R 28 )—, —C(R 29 )(R 30 )—, or

each instance of R 26 , R 27 , R 28 , R 29 , R 30 , R 31 , and R 32 is independently selected from hydrogen, halogen, —OH, —CF 3 , —NO 2 , —OR 10 , —C(O)R 12 , —NR 13 R 14 , 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 10 is independently —C(O)R 15 , 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;

each instance of R 16 is independently hydrogen, —NR 19 R 20 , or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl.

14. The compound of claim 1 of the formula:

wherein

Z 5 and Z 6 are independently ═N— and ═C(R 23 )—;

each instance of R 23 and R 33 is independently hydrogen, halogen, —OH, —CF 3 , —NO 2 , —OR 10 , —C(O)R 12 , —NR 13 R 14 , 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;

15. The compound of claim 1 of the formula:

wherein

w is 0 or 1; and

R 2 is fluorine.

Assignments (5)

CHANGE OF NAME Recorded Dec 9, 2021

From: SUNESIS PHARMACEUTICALS, INC.

To: VIRACTA THERAPEUTICS, INC.

Reel/Frame 058741/0187 →

ASSIGNMENT OF ASSIGNOR'S INTEREST Recorded Feb 24, 2012

From: BIOGEN IDEC MA INC.

To: MILLENNIUM PHARMACEUTICALS, INC.