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

Patent metadata

Field	Value
Publication number	US-11345670-B2
Application number	US-202016864479-A
Country	US
Kind code	B2
Filing date	May 1, 2020
Priority date	Jan 13, 2015
Publication date	May 31, 2022
Grant date	May 31, 2022

Abstract

Compounds having a structure of Formula I:or a pharmaceutically acceptable salt, tautomer or stereoisomer thereof, wherein R1, R2, R3, R11a, R11b, R11c, R11d, X, n1, n2, and n3 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:

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 )—, —C(═N—NHR 5 )—;
R 1 and R 2 are each independently H, hydroxyl, —O-heterocyclyl, or —OC(═O)R 13 ;
R 3 is a 4-7 membered heterocyclyl which 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, 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 is 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 ;
R 9 is 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 an 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 5-7 membered heterocylyl, wherein said heterocyclyl comprises at least one N atom in the ring.

6. The compound of claim 1 , wherein R 3 is selected from a group consisting of oxazine, azepine, pyrrolidine, pyrroline, imidazoline, imidazolidine, pyrazoline, pyrazolidine, piperidine, dioxane, morpholine, dithiane, thiomorpholine, piperazine, and tetrazine.

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

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

9. 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.

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

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

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

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

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

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

14. A pharmaceutical composition, comprising: a pharmaceutically acceptable carrier and a compound of formula (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 )—, —C(═N—NHR 5 )—;
R 1 and R 2 are each independently H, hydroxyl, —O-heterocyclyl, or —OC(═O)R 13 ;
R 3 is a 4-7 membered heterocyclyl which 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, 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 is 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 ;
R 9 is 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 an 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.

15. The pharmaceutical composition of claim 14 , further comprising an additional therapeutic agent.

16. The pharmaceutical composition of claim 15 , wherein the additional therapeutic agent is for treating prostate cancer, breast cancer, ovarian cancer, endometrial cancer, salivary gland carcinoma, hair loss, acne, hirsutism, ovarian cysts, polycystic ovary disease, precocious puberty, spinal and bulbar muscular atrophy, or age-related macular degeneration.

17. The pharmaceutical composition of claim 15 , wherein the additional therapeutic agent is enzalutamide, Galeterone, ARN-509, abiraterone, bicalutamide, nilutamide, flutamide, cyproterone acetate, docetaxel, Bevacizumab (Avastin), OSU-HDAC42, VITAXIN, sunitumib, ZD-4054, Cabazitaxel (XRP-6258), MDX-010 (Ipilimumab), OGX 427, OGX 011, finasteride, dutasteride, turosteride, bexlosteride, izonsteride, FCE 28260, SKF105,111, ODM-201, or radium 233.

18. A m

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

• C07D249/04 Primary

  1,2,3-Triazoles; Hydrogenated 1,2,3-triazoles · CPC title

• C07D295/084

  with the ring nitrogen atoms and the oxygen or sulfur atoms attached to the same carbon chain, which is not interrupted by carbocyclic rings · CPC title

• C07B59/002

  Heterocyclic compounds · CPC title

• A61K51/0459

  having six-membered rings with two nitrogen atoms as the only ring hetero atoms, e.g. piperazine · CPC title

• C07D233/60

  with hydrocarbon radicals, substituted by oxygen or sulfur atoms, attached to ring nitrogen atoms · CPC title