Heterocyclic compounds for cancer imaging and treatment and methods for their use

Patent metadata

Field	Value
Publication number	US-10654811-B2
Application number	US-201615543389-A
Country	US
Kind code	B2
Filing date	Jan 13, 2016
Priority date	Jan 13, 2015
Publication date	May 19, 2020
Grant date	May 19, 2020

Abstract

Compounds having a structure of Formula I: or a pharmaceutically acceptable salt, tautomer or stereoisomer thereof, wherein R 1 , R 2 , R 3 , R 11a , R 11b , R 11c , R 11d , X, n 1 , n 2 , and n 3 are as defined herein, are provided. Uses of such compounds for modulating androgen receptor activity, imaging diagnostics in cancer and therapeutics, and methods for treatment of subjects in need thereof, including prostate cancer are also provided.

First claim

What is claimed is:

1. A compound having the following structure (I):

or a pharmaceutically acceptable salt, tautomer or stereoisomer thereof, wherein:
X is —O—, —S(O) 0-2 —, —C(═O)—, —C(OR 5 ) 2 —, —C(OR 5 )(OC(═O)R 13 )—, —C(R 8 R 9 )—, C(═CR 8 R 9 )—, —N(R 9 )—, —N(COR 9 )—, —CHNR 8 R 9 —, —C(═NR 9 )—, —C(═NOR 5 )—, or —C(═N—NHR 5 )—;
R 1 is H, hydroxyl, —O-heterocyclyl, or —OC(═O)R 13 ;
R 2 is hydroxyl, —O-heterocyclyl, or —OC(═O)R 13 ;
R 3 is —N 3 or heteroaryl, each R 3 is optionally substituted with one or more R 6 ;
R 5 is each independently H, C 1 -C 6 alkyl, C 2 -C 6 alkenyl, or C 2 -C 6 alkynyl;
R 6 is each independently selected from the group consisting of H, F, Cl, Br, I, 123 I, hydroxyl, C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 1 -C 6 alkoxy, and C 6 -C 12 aryl, wherein each R 6 is optionally substituted with one or more of halogen, 123 I, 18 F, hydroxyl, —OS(O) 2 -aryl, C 1 -C 6 alkyl, C 2 -C 6 alkenyl, or C 2 -C 6 alkynyl;
R 8 and R 9 are each independently H, halogen, —S(O) 0-2 R 5 , C 1 -C 10 alkyl, C 2 -C 10 alkenyl, C 2 -C 10 alkynyl, aryl, aralkyl, C 1 -C 10 acyl, or —NR 5 R 5 , or R 8 and R 9 can join to form a unsubstituted or substituted mono-, bi-, or tri-cyclic carbocycle or heterocycle containing from 3 to 20 carbon atoms;
R 11a , R 11b , R 11c , and R 11d are each independently H, F, Cl, Br, I, 123 I, hydroxyl, C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, —OR 5 , —OC(═O)R 13 , C 1 -C 10 acyl, —S(O) 0-2 R 5 , —NO 2 , —CN, —NH 2 , —NHR 5 , or —N(R 5 ) 2 ;
R 13 is each independently C 1 -C 6 alkyl, C 2 -C 6 alkenyl, or C 2 -C 6 alkynyl;
n 1 and n 2 are each independently 0, 1, or 2; and
n 3 is 0, 1, 2, 3, 4, or 5.

2. The compound of claim 1 , wherein X is —C(R 8 R 9 )—.

3. The compound of claim 1 , wherein R 8 and R 9 are C 1 -C 10 alkyl.

4. The compound of claim 1 , wherein R 8 and R 9 are methyl.

5. The compound of claim 1 , wherein R 3 is 5-6 membered heteroaryl, wherein the heteroaryl comprises at least one N atom in the ring.

6. The compound of claim 1 , wherein R 3 is selected from the group consisting of pyrrole, furan, thiophene, pyrazole, pyridine, pyridazine, pyrimidine, imidazole, thiazole, isoxazole, oxadiazole, thiadiazole, oxazole, triazole, isothiazole, triazine, azepine, and tetrazine.

7. The compound of claim 1 , wherein R 3 is substituted with at least one 123 I or I.

8. The compound of claim 1 , wherein R 3 is substituted with at least one R 6 , wherein at least one R 6 is further substituted with at least one of 123 I, I, or 18 F.

9. The compound of claim 1 , wherein at least one R 6 is C 1 -C 6 alkyl, wherein at least one R 6 is further substituted with at least one of 123 I, I, or 18 F.

10. The compound of claim 1 , wherein each R 13 is independently methyl, ethyl or propyl.

11. The compound of claim 1 , wherein each R 13 is methyl.

12. The compound of claim 1 , wherein at least one of R 11a , R 11b , R 11c and R 11d is Cl, Br, I or 123 I.

13. The compound of claim 1 , wherein at least one of R 6 , R 11a R 11b , R 11c and R 11d is I; and at least one of R 6 , R 11a , R 11b , R 11c and R 11d is 123 I.

14. The compound of claim 1 , wherein n 3 is 0, 1, or 2.

15. The compound of claim 1 , wherein the compound has one of the following structures:

or a pharmaceutically acceptable salt, tautomer, or stereoisomer thereof.

16. The compound of claim 1 , wherein the compound has one of the following structures:

Assignees

• Univ British Columbia
• British Columbia Cancer Agency Branch

Inventors

• Andersen Raymond John
• Fernandez Javier Garcia
• Jian Kunzhong
• Sadar Marianne Dorothy
• Mawji Nasrin R
• Banuelos Carmen Adriana

Classifications

• C07D265/30

  not condensed with other rings · CPC title

• C07D295/088

  to an acyclic saturated chain · CPC title

• A61K31/4192

  1,2,3-Triazoles · CPC title

• A61K31/5375

  1,4-Oxazines, e.g. morpholine · CPC title

• A61K31/4164

  1,3-Diazoles · CPC title