IP Library › Granted Patent US 9,359,299

Granted Patent B2

US 9,359,299 · App. 14/009,969 · Granted Jun 7, 2016

Small molecules for treating breast cancer

Inventors: Sivanesan Dakshanamurthy (Hernon, VA); Milton L. Brown (Brookeville, MD); Robert Clarke (Rockville, MD); Ayesha N. Shajahan-Haq (Haymarket, VA); Jacqueline Smith (Bowie, MD)

Assignee: Georgetown University

C07D213/32 A61K31/41 A61K31/426 A61K31/427 A61K31/444 A61K31/4439 A61K45/06 C07D401/04 C07D401/14 C07D405/14 C07D417/04 C07D417/14

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Quick Facts

Patent No.: US 9,359,299
App. No.: 14/009,969
Granted: Jun 7, 2016
Kind: B2

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USPTO Patent Center↗ Full Patent PDF↗

Abstract

Small molecule inhibitors of XBP1 splicing by IRE1 are provided, as well as methods for their use in treating or preventing cancer (e.g., endocrine resistant breast cancer), diabetes, and obesity.

Claims (103)

1. A compound selected from the group consisting of:

or a pharmaceutically acceptable salt or prodrug thereof, wherein:

L is —C(═O)NH—, —NHC(═O)—, —C(═O)O—, —C(═O)—CH 2 —,

R 1 , R 2 , R 3 , R 4 , R 6 , R 7 , R 8 , R 9 , and R 10 are each independently selected from hydrogen, halogen, hydroxyl, cyano, nitro, trifluoromethyl, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted amino, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted alkoxyl, substituted or unsubstituted aryloxyl, substituted or unsubstituted carbonyl, or substituted or unsubstituted carboxyl; and

X is substituted or unsubstituted heteroaryl,

or a pharmaceutically acceptable salt or prodrug thereof, wherein:

L is —C(═O)NH—, —NHC(═O)—, —C(═O)O—, —C(═O)—CH 2 —,

X is substituted or unsubstituted heteroaryl,

or a pharmaceutically acceptable salt or prodrug thereof, wherein:

A is S or NH;

L is —C(═O)NH—, —NHC(═O)—, —C(═O)O—, —C(═O)—CH 2 —,

X 1 and X 2 are each independently selected from hydrogen, halogen, trifluoromethyl, substituted or unsubstituted alkyl, or substituted or unsubstituted heteroaryl; and

Z is S or NH,

wherein one of X 1 or X 2 is substituted or unsubstituted heteroaryl,

or a pharmaceutically acceptable salt or prodrug thereof, wherein:

L is —C(═O)NH—, —NHC(═O)—, —C(═O)O—, —C(═O)—CH 2 —,

X is substituted or unsubstituted heteroaryl, and

or a pharmaceutically acceptable salt or prodrug thereof, wherein:

L is —C(═O)NH—, —NHC(═O)—, —C(═O)O—, —C(═O)—CH 2 —,

X is substituted or unsubstituted heteroaryl.

2. A compound of the following structure:

or a pharmaceutically acceptable salt or prodrug thereof, wherein:

L is —C(═O)NH—, —NHC(═O)—, —C(═O)O—, —C(═O)—CH 2 —,

R 1 , R 2 , R 3 , and R 4 are each independently selected from hydrogen, halogen, hydroxyl, cyano, nitro, trifluoromethyl, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted amino, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted alkoxyl, substituted or unsubstituted aryloxyl, substituted or unsubstituted carbonyl, or substituted or unsubstituted carboxyl;

R 5 is substituted or unsubstituted aryl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted alkynyl, or dansyl; and

X is substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted sulfonyl, or substituted or unsubstituted alkynyl,

wherein if L is —C(═O)NH—, R 5 is unsubstituted phenyl, and R 1 , R 2 , R 3 , and R 4 are each hydrogen, then X is not

3. The compound of claim 2 , wherein R 5 is substituted or unsubstituted phenyl.

4. The compound of claim 3 , wherein R 5 is fluoro-substituted phenyl.

5. The compound of claim 2 , wherein X is pyridyl.

6. The compound of claim 2 , wherein X is phenyl, cyclohexyl, alkynyl, or dansyl.

7. The compound of claim 2 , wherein L is —C(═O)NH—.

8. The compound of claim 1 , wherein the compound has the following structure:

or a pharmaceutically acceptable salt or prodrug thereof, wherein:

L is —C(═O)NH—, —NHC(═O)—, —C(═O)O—, —C(═O)—CH 2 —,

X is substituted or unsubstituted heteroaryl.

9. The compound of claim 1 , wherein the compound has the following structure:

or a pharmaceutically acceptable salt or prodrug thereof, wherein:

L is —C(═O)NH—, —NHC(═O)—, —C(═O)O—, —C(═O)—CH 2 —,

X is substituted or unsubstituted heteroaryl.

10. The compound of claim 1 , wherein the compound has the following structure:

or a pharmaceutically acceptable salt or prodrug thereof, wherein:

A is S or NH;

L is —C(═O)NH—, —NHC(═O)—, —C(═O)O—, —C(═O)—CH 2 —,

X 1 and X 2 are each independently selected from hydrogen, halogen, trifluoromethyl, substituted or unsubstituted alkyl, or substituted or unsubstituted heteroaryl; and

Z is S or NH,

wherein one of X 1 or X 2 is substituted or unsubstituted heteroaryl.

11. The compound of claim 1 , wherein the compound has the following structure:

or a pharmaceutically acceptable salt or prodrug thereof, wherein:

L is —C(═O)NH—, —NHC(═O)—, —C(═O)O—, —C(═O)—CH 2 —,

X is substituted or unsubstituted heteroaryl.

12. The compound of claim 1 , wherein the compound has the following structure:

or a pharmaceutically acceptable salt or prodrug thereof, wherein:

L is —C(═O)NH—, —NHC(═O)—, —C(═O)O—, —C(═O)—CH 2 —,

X is substituted or unsubstituted heteroaryl.

13. A compound of the following structure:

or a pharmaceutically acceptable salt or prodrug thereof, wherein:

X is substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted sulfonyl, substituted or unsubstituted alkynyl, or absent; and

Y is substituted or unsubstituted thiazole, substituted or unsubstituted triazole, substituted or unsubstituted imidazole, or —V—CH 2 —O—, wherein V is substituted or unsubstituted cyclohexyl, alkynyl, or substituted or unsubstituted pyridyl.

14. A compound of the following structure:

or a pharmaceutically acceptable salt or prodrug thereof, wherein:

n is 0, 1, or 2; and

R 6 , R 7 , R 8 , and R 9 are each independently selected from hydrogen, halogen, hydroxyl, cyano, nitro, trifluoromethyl, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted amino, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted alkoxyl, substituted or unsubstituted aryloxyl, substituted or unsubstituted carbonyl, or substituted or unsubstituted carboxyl.

15. The compound of claim 2 , wherein the compound is selected from the group consisting of:

wherein R 6 , R 7 , R 8 , R 9 , and R 10 are each independently selected from hydrogen, chloro, fluoro, trifluoromethyl, hydroxyl, methoxyl, and methyl and wherein R 6 , R 7 , R 8 , R 9 , and R 10 are not simultaneously hydrogen,

wherein X is phenyl, cyclohexyl, alkynyl, dansyl, or pyridyl, and

wherein R 5 is phenyl, cyclohexyl, alkynyl, dansyl, or pyridyl,

or a pharmaceutically acceptable salt or prodrug thereof.

16. The compound of claim 14 , wherein the compound is selected from the group consisting of:

or a pharmaceutically acceptable salt or prodrug thereof.

17. The compound of claim 13 , wherein the compound is selected from the group consisting of:

or a pharmaceutically acceptable salt or prodrug thereof,

wherein W is cyclohexyl, alkynyl, or pyridyl.

18. A composition comprising one or more compounds of claim 1 and a pharmaceutically acceptable carrier.

19. A method of treating breast cancer in a subject, comprising:

administering to the subject an effective amount of a compound selected from the group consisting of:

or a pharmaceutically acceptable salt or prodrug thereof

and a pharmaceutically acceptable carrier.

20. The method of claim 19 , wherein the cancer is breast cancer.

21. The method of claim 20 , wherein the breast cancer is endocrine resistant breast cancer.

22. The method of claim 19 , further comprising administering a second therapeutic agent to the subject.

23. The method of claim 22 , wherein the second therapeutic agent is an antiestrogen or an aromatase inhibitor.

24. A method of treating a subject with anti-estrogen resistant breast cancer, comprising:

1) selecting a subject with anti-estrogen resistant breast cancer;

2) administering to the subject one or more of the compounds of the following structure:

or a pharmaceutically acceptable salt or prodrug thereof, wherein:

L is —C(═O)NH—, —NHC(═O)—, —C(═O)O—, —C(═O)—CH 2 —,

R 5 is substituted or unsubstituted aryl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted alkynyl, or dansyl; and

3) administering to the subject an anti-estrogen compound.

25. The compound of claim 2 , wherein R 1 , R 2 , R 3 , and R 4 are each hydrogen; R 5 is substituted or unsubstituted phenyl, L is —C(═O)NH—, and X is phenyl or pyridyl.

26. The compound of claim 2 , wherein R 1 , R 2 , R 3 , and R 4 are each hydrogen; R 5 is unsubstituted phenyl, L is —C(═O)NH—, and X is unsubstituted phenyl.

27. The compound of claim 2 , wherein R 1 , R 2 , R 3 , and R 4 are each hydrogen; R 5 is substituted phenyl, L is —C(═O)NH—, and X is pyridyl.

Assignments (2)

CONFIRMATORY LICENSE Recorded Aug 17, 2016

From: GEORGETOWN UNIVERSITY

To: US ARMY, SECRETARY OF THE ARMY

Reel/Frame 039708/0170 →

ASSIGNMENT OF ASSIGNOR'S INTEREST Recorded Apr 21, 2014

From: DAKSHANAMURTHY, SIVANESAN; BROWN, MILTON L.; CLARKE, ROBERT; SHAJAHAN-HAQ, AYESHA N.; SMITH, JACQUELINE

To: GEORGETOWN UNIVERSITY

Reel/Frame 032716/0009 →

Continuity (2)

Provisional Application 61471479 · Apr 4, 2011

Related Publication 20140088148A1 · Mar 27, 2014