Substituted heterocycles as c-MYC targeting agents

Patent metadata

Field	Value
Publication number	US-12152007-B2
Application number	US-201817272346-A
Country	US
Kind code	B2
Filing date	Aug 31, 2018
Priority date	Aug 31, 2018
Publication date	Nov 26, 2024
Grant date	Nov 26, 2024

Abstract

Disclosed are substituted heterocycle compounds including substituted pyrazoles, substituted pyrimidines, and substitute triazoles. The substituted heterocycles disclosed herein are shown to be useful in inhibiting c-MYC and may be utilized as therapeutics for treating cancer and cell proliferative disorders.

First claim

We claim:

1. A compound having a formula I:

wherein
R 1 is hydrogen or R 1 is an alkyl group, an aryl group, a benzyl group, a heteroaryl group, a cycloalkyl group, a benzoyl group, or a cycloheteroalkyl group, optionally R 1 is substituted at one or more positions with one or more of alkyl, alkoxy, haloalkyl, haloalkoxy, aryl, heteroaryl, hydroxyl, halo, cyano, amido, hydrazonyl, carbonyl, carboxyl, —NH—C(O)—CH 2 —(OCH 2 ) y —N 3 , —NH—C(O)-alkylene-alkynyl optionally substituted with azido, —O-alkylene-alkynyl,

 amino, nitro, and alkoxycarbonyl;
n is 0, 1, or 2;
p is 0 or 1;
X is O or NH, or R 1 (CH 2 ) n (X) p — is N-piperazinyl optionally N-substituted with alkyl;
m is 0 or 1;
y is 3 or 4;
R 2 is hydrogen or halo, or R 2 is an alkyl group, an aryl group, a benzyl group, a heteroaryl group, a cycloalkyl group, or a cycloheteroalkyl group, optionally R 2 is substituted at one or more positions with one or more of alkyl, alkoxy, haloalkyl, haloalkoxy, hydroxyl, halo, cyano, amido, hydrazonyl, carbonyl, and carboxyl;
R 3 is hydrogen, alkyl, alkoxy, haloalkyl, haloalkoxy, aryl, benzyl, hydroxyl, halo, amido, hydrazonyl, carbonyl, carboxyl, cyano, and alkoxycarbonyl;
R 4 is not present, or R 4 is hydrogen, amino, alkyl, or R 4 is aryl or benzyl; R 4 optionally is substituted at one or more positions with one or more of alkyl, alkoxy, haloalkyl, haloalkoxy, aryl (e.g., phenyl), hydroxyl, halo, cyano, amido, hydrazonyl, carbonyl, carboxyl, alkoxycarbonyl, aryloxy, and alkylaryloxy;
R 5 is hydrogen, alkyl, alkoxy, haloalkyl, haloalkoxy, hydroxyl, cyano, amino, amido, —C(O)H, hydroxyalkyl, or halo;
R 6 is not present, or R 6 is hydrogen, amino, alkyl, or R 6 is aryl or benzyl; R 6 optionally is substituted at one or more positions with one or more of alkyl, alkoxy, haloalkyl, haloalkoxy, aryl, hydroxyl, halo, cyano, amido, hydrazonyl, carbonyl, carboxyl, alkoxycarbonyl, aryloxy, and alkylaryloxy, or R 6 and R 5 together form a ring structure having a formula

R 7 is hydrogen or halo, or R 7 is an alkyl group, an aryl group, a benzyl group, a 5-membered heteroaryl group containing one oxygen or sulfur, a 6-membered heteroaryl group containing one nitrogen, a cycloalkyl group, or a cycloheteroalkyl group, optionally R 7 is substituted at one or more positions with one or more of alkyl, alkoxy, haloalkyl, haloalkoxy, hydroxyl, halo, cyano, amido, hydrazonyl, carbonyl, carboxyl, sulfonyl-alkyl, and alkoxycarbonyl;
with the proviso that at least one of R 4 and R 6 is present;
with the proviso that if R 5 is hydrogen, then p is 1 and m is 1;
with the proviso that if R 1 (CH 2 ) n (X) p — is hydrogen, hydroxyl, or alkyl, and R 5 is hydroxyl, then m is 1, or at least one of R 2 and R 3 is not hydrogen; and
with the proviso that if (i) R 1 (CH 2 ) n (X) p — and R 5 are hydroxyl, (ii) R 3 , R 4 , and R 7 are hydrogen, and (iii) m is 1, then R 2 is a substituted aryl.

2. The compound of claim 1 , wherein at least one of R 2 and R 7 is an aryl group, a benzyl group, a heteroaryl group, a cycloalkyl group, or a cycloheteroalkyl group, and R 2 optionally is substituted at one or more positions with one or more of alkyl, alkoxy, haloalkyl, haloalkoxy, hydroxyl, halo, cyano, amido, hydrazonyl, carbonyl, and carboxyl, and R 7 optionally is substituted at one or more positions with one or more of alkyl, alkoxy, haloalkyl, haloalkoxy, hydroxyl, halo, cyano, amido, hydrazonyl, carbonyl, carboxyl, and alkoxycarbonyl.

3. The compound of claim 1 , wherein m is 0 and R 2 is hydrogen; or wherein R 7 is hydrogen.

4. The compound of claim 1 , wherein R 2 is an aryl group, a benzyl group, a heteroaryl group, a cycloalkyl group, or a cycloheteroalkyl group, and R 2 optionally is substituted at one or more positions with one or more of alkyl, alkoxy, haloalkyl, haloalkoxy, hydroxyl, halo, cyano, amido, hydrazonyl, carbonyl, carboxyl; and wherein R 7 is hydrogen.

5. The compound of claim 1 , wherein m is 0 and R 2 is hydrogen; and wherein R 7 is an aryl group, a benzyl group, a heteroaryl group, a cycloalkyl group, or a cycloheteroalkyl group, and R 7 optionally is substituted at one or more positions with one or more of alkyl, alkoxy, haloalkyl, haloalkoxy, hydroxyl, halo, cyano, amido, hydrazonyl, carbonyl, carboxyl, and alkoxycarbonyl.

6. The compound of claim 1 having a formula I(i) or I(ii):

7. The compound of claim 1 having a formula selected from Ia(i), Ia(ii), Ib(i), Ib(ii), Ic(i), and Ic(ii):

8. A pharmaceutical composition comprising a compound of claim 1 and a suitable pharmaceutical carrier, excipient, or diluent.

9. A method of treating cancer comprising administering the composition of claim 8 to a patient having cancer.

10. The compound of claim 1 , wherein
R 1 is hydrogen or R 1 is an alkyl group, an aryl group, a benzyl group, a heteroaryl group, a cycloalkyl group, a benzoyl group, or a cycloheteroalkyl group, optionally R 1 is substituted at one or more positions with one or more of alkyl, alkoxy, haloalkyl, haloalkoxy, aryl, heteroaryl, hydroxyl, halo, cyano, amido, hydrazonyl, carbonyl, carboxyl, —NH—C(O)—CH 2 —(OCH 2 ) y —N 3 , —NH—C(O)-alkylene-alkynyl optionally substituted with azido, —O-alkylene-alkynyl, amino, nitro, and alkoxycarbonyl.

11. The compound of claim 1 , wherein R 1 is

12. The method of claim 9 , wherein at least one of R 2 and R 7 is an aryl group, a benzyl group, a heteroaryl group, a cycloalkyl group, or a cycloheteroalkyl group, and R 2 optionally is substituted at one or more positions with one or more of alkyl, alkoxy, haloalkyl, haloalkoxy, hydroxyl, halo, cyano, amido, hydrazonyl, carbonyl, and carboxyl, and R 7 optionally is substituted at one or more positions with one or more of alkyl, alkoxy, haloalkyl, haloalkoxy, hydroxyl, halo, cyano, amido, hydrazonyl, carbonyl, carboxyl, and alkoxycarbonyl.

13. The method of claim 9 , wherein m is 0 and R 2 is hydrogen; or wherein R 7 is hydrogen.

14. The method of claim 9 , wherein R 2 is an aryl group, a benzyl group, a heteroaryl group, a cycloalkyl group, or a cycloheteroalkyl group, and R 2 optionally is substituted at one or more positions with one or more of alkyl, alkoxy, haloalkyl, haloalkoxy, hydroxyl, halo, cyano, amido, hydrazonyl, carbonyl, carboxyl; and wherein R 7 is hydrogen.

15. The method of claim 9 , wherein m is 0 and R 2 is hydrogen; and wherein R 7 is an aryl group, a benzyl group, a heteroaryl group, a cycloalkyl group, or a cycloheteroalkyl group, and R 7 optionally is substituted at one or more positions with one or more of alkyl, alkoxy, haloalkyl, haloalkoxy, hydroxyl, halo, cyano, amido, hydrazonyl, carbonyl, carboxyl, and alkoxycarbonyl.

16. The method of claim 9 , wherein the compound has a formula I(i) or I(ii):

Assignees

• Univ Northwestern

Inventors

• Schiltz Gary E
• Mishra Rama K
• Han Huiying
• Abdulkadir Sarki A
• Izquierdo-Ferrer Javier
• Jain Atul D

Classifications

• A61P35/02

  specific for leukemia · CPC title

• A61P35/00

  Antineoplastic agents · CPC title

• C07D239/42

  One nitrogen atom (nitro radicals C07D239/30) · CPC title

• C07D239/26

  with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to ring carbon atoms · CPC title

• C07D401/14

  containing three or more hetero rings · CPC title