Disubstituted and trisubstituted 1,2,3-triazoles as Wnt inhibitors

Patent metadata

Field	Value
Publication number	US-10793544-B2
Application number	US-201716330050-A
Country	US
Kind code	B2
Filing date	Aug 31, 2017
Priority date	Sep 1, 2016
Publication date	Oct 6, 2020
Grant date	Oct 6, 2020

Abstract

The present disclosure provides compounds that may be useful for inhibiting Wnt pathway comprising compounds of the formula: (Ia) or (Ib) wherein the variables are as defined herein. In some aspects, the compounds may be used to inhibit the Wnt pathway and used to treat cancer, myocardial infarction, osteopetrosis, or used in the maturation of a precursor cell to a mature cell. Also provided herein in are pharmaceutical compositions of the compounds described herein.

First claim

What is claimed is:

1. A compound of the formula:

wherein:
R 1 and R 1 ′ are each independently aryl (C≤18) , heteroaryl (C≤18) , or a substituted version of either group;
R 2 is aryl (C≤18) , substituted aryl (C≤18) , heteroaryl (C≤18) , or substituted heteroaryl (C≤18) ;

R 2 ′ is hydrogen, aryl (c≤18) , substituted aryl (c≤18) , heteroaryl (c≤18) , or substituted heteroaryl (c≤18) ;
R 3 and R 3 ′ are each independently —X—Y;
wherein:
X is arenediyl (C≤18) , substituted arenediyl (C≤18) , heteroarenediyl (C≤18) , or substituted heteroarenediyl (C≤18) ;
Y is aryl (C≤12) , heteroaryl (C≤12) , heterocycloalkyl (C≤12) , or a substituted version of these three groups;

R 4 and R 4 ′ are each independently hydrogen, alkyl (C≤12) , or substituted alkyl (C≤12) ; and
R 5 and R 5 ′ are each independently hydrogen, alkyl (C≤12) , or substituted alkyl (C≤12) ;

or a pharmaceutically acceptable salt thereof.

2. The compound of claim 1 , wherein the compound is a compound of formula Ia.

3. The compound of claim 1 , wherein the compound is a compound of formula Ib.

4. The compound of claim 1 further defined as a compound of formula Ib, wherein:
R 4 ′ is hydrogen, alkyl (C≤8) , or substituted alkyl (C≤8) ; and
R 5 ′ is hydrogen, alkyl (C≤8) , or substituted alkyl (C≤8) ;
or a pharmaceutically acceptable salt thereof.

5. The compound according to claim 1 , wherein R 1 or R 1 ′ is heteroaryl (C≤12) or substituted heteroaryl (C≤12) .

6. The compound according to claim 1 , wherein R 1 or R 1 ′ is aryl (C≤12) or substituted aryl (C≤12) .

7. The compound according to claim 1 , wherein R 2 or R 2 ′ is aryl (C≤12) or substituted aryl (C≤12) .

8. The compound according to claim 1 , wherein X is arenediyl (C≤18) or substituted arenediyl (C≤18) .

9. The compound according to claim 1 , wherein X is heteroarenediyl (C≤18) or substituted heteroarenediyl (C≤18) .

10. The compound according to claim 1 , wherein Y is aryl (C≤12) or substituted aryl (C≤12) .

11. The compound according to claim 1 , wherein Y is heteroaryl (C≤12) or substituted heteroaryl (C≤12) .

12. The compound according to claim 1 , wherein Y is heterocycloalkyl (C≤12) or substituted heterocycloalkyl (C≤12) .

13. The compound according to claim 1 , wherein
the compound is further defined as:

or a pharmaceutically acceptable salt thereof.

14. The compound according to claim 1 , wherein the compound is further defined as:

or a pharmaceutically acceptable salt thereof.

15. A pharmaceutical composition:
(A) a compound according to claim 1 ; and
(B) an excipient.

16. The pharmaceutical composition of claim 15 , wherein the pharmaceutical composition is formulated for administration: orally, intraadiposally, intraarterially, intraarticularly, intracranially, intradermally, intralesionally, intramuscularly, intracardially, intranasally, intraocularly, intrapericardially, intraperitoneally, intrapleurally, intraprostatically, intrarectally, intrathecally, intratracheally, intratumorally, intraumbilically, intravaginally, intravenously, intravesicularlly, intravitreally, liposomally, locally, mucosally, parenterally, rectally, subconjunctivally, subcutaneously, sublingually, topically, transbuccally, transdermally, vaginally, in crèmes, in lipid compositions, via a catheter, via a lavage, via continuous infusion, via infusion, via inhalation, via injection, via local delivery, or via localized perfusion.

17. A method of treating cancer in a patient comprising administering to the patient in need thereof a therapeutically effective amount of a compound or a pharmaceutically acceptable salt thereof according to claim 1 .

18. A method of inducing differentiation of a precursor cell into a mature cell comprising administering to the precursor cell an effective amount of a compound or composition according to claim 1 .

19. A method of inhibiting a Wnt protein comprising contacting the Wnt protein with an effective amount of a compound or composition according to claim 1 .

Assignees

• Univ Texas

Inventors

• Yarravarapu Nageswari
• Chen Chuo
• Lum Lawrence
• You Lin
• Zhang Chengwei
• Wang Xiaolei
• Zhang Lishu

Classifications

• A61K31/4192

  1,2,3-Triazoles · CPC title

• C07D409/14

  containing three or more hetero rings · CPC title

• A61K31/506

  not condensed and containing further heterocyclic rings · CPC title

• A61K31/4439

  containing a five-membered ring with nitrogen as a ring hetero atom, e.g. omeprazole (nicotine A61K31/465) · CPC title

• C07D405/14

  containing three or more hetero rings · CPC title