Substituted heterocycles as c-MYC targeting agents

Patent metadata

Field	Value
Publication number	US-11420957-B2
Application number	US-202016903890-A
Country	US
Kind code	B2
Filing date	Jun 17, 2020
Priority date	Jun 17, 2019
Publication date	Aug 23, 2022
Grant date	Aug 23, 2022

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 Ia(i) or Ia(ii):

wherein
R 1 is hydrogen or R 1 is aryl, alkylaryl, alkyldiaryl, heteroaryl, alkylheteroaryl, cycloalkyl, or cycloheteroalkyl, optionally R 1 is substituted at one or more positions with one or more of alkyl, alkoxy, haloalkyl, haloalkoxy, aryl, hydroxyl, halo, cyano, carboxyamido, hydrazonyl, carbonyl, carboxyl, and alkoxycarbonyl;
Alk 1 is straight-chain or branched alkylenyl;
n is 0 or 1;
X is O, NH, N(R 8 ), N(R 8 )CH(O), or CH(O)N(R 8 );
p is 0 or 1;
Alk 2 is straight-chain or branched alkylenyl;
q is 0 or 1;
Y is CH, C-halo, C-haloalkyl, or N;
Z is CH, C-halo, C-haloalkyl, or N;
m is 0 or 1;
R 2 is hydrogen, halo, or R 2 is alkyl, aryl, alkylaryl, heteroaryl, cycloalkyl, or cycloheteroalkyl, optionally R 2 is substituted at one or more positions with one or more of alkyl, alkoxy, haloalkyl, haloalkoxy, hydroxyl, halo, cyano, carboxyamido, hydrazonyl, carbonyl, carboxyl, and alkoxycarbonyl;
R 3 is hydrogen, alkyl, alkoxy, haloalkyl, haloalkoxy, alkenyl, aryl, alkylaryl, hydroxyl, halo, carboxyamido optionally substituted with alkyl, hydrazonyl, carbonyl, carboxyl, and alkoxycarbonyl;
R 4 is hydrogen, alkyl, or R 4 is aryl or alkylaryl; R 4 optionally is substituted at one or more positions with one or more of alkyl, alkoxy, haloalkyl, haloalkoxy, aryl, hydroxyl, halo, cyano, carboxyamido, hydrazonyl, carbonyl, carboxyl, alkoxycarbonyl, aryloxy, and alkylaryloxy;
R 6 is hydrogen, alkyl, or R 4 is aryl or alkylaryl; 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;
r is 0 or 1;
R 7 is aryl, alkylaryl, heteroaryl, cycloalkyl, or cycloheteroalkyl, optionally R 7 is substituted at one or more positions with one or more of alkyl, alkoxy, haloalkyl, haloalkoxy, hydroxyl, halo, cyano, carboxyamido, hydrazonyl, carbonyl, carboxyl, alkoxycarbonyl, oxoaryl, and oxoheteroaryl; and
R 8 is hydrogen, alkyl, aryl, or alkylaryl optionally substituted with halo;
with the proviso that if R 1 (Alk 1 ) n (X) p (Alk 2 ) q - is hydrogen, hydroxyl, or alkyl, then m is 1, or at least one of R 2 and R 3 is not hydrogen.

2. The compound of claim 1 , wherein m is 0 and R 2 is hydrogen.

3. The compound of claim 1 , wherein R 2 is aryl, alkylaryl, heteroaryl, cycloalkyl, or cycloheteroalkyl, and R 2 optionally is substituted at one or more positions with one or more of alkyl, alkoxy, haloalkyl, haloalkoxy, hydroxyl, halo, cyano, carboxyamido, hydrazonyl, carbonyl, carboxyl, and alkoxycarbonyl.

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

5. A method of treating cancer comprising administering the composition of claim 4 to a subject having cancer.

6. A compound having a formula Ia(i) or Ia(ii):

wherein
R 1 is hydrogen, aryl, alkylaryl, alkyldiaryl, heteroaryl, alkylheteroaryl, cycloalkyl, or cycloheteroalkyl, optionally R 1 is substituted at one or more positions with one or more of alkyl, alkoxy, haloalkyl, haloalkoxy, aryl, hydroxyl, halo, cyano, carboxyamido, hydrazonyl, carbonyl, carboxyl, and alkoxycarbonyl;
Alk 1 is straight-chain or branched alkylenyl;
n is 0 or 1;
X is O, NH, N(R 8 ), N(R 8 )CH(O), or CH(O)N(R 8 );
p is 0 or 1;
Alk 2 is straight-chain or branched alkylenyl;
q is 0 or 1;
Y is CH, C-halo, C-haloalkyl, or N;
Z is CH, C-halo, C-haloalkyl, or N;
m is 0 or 1;
R 2 is hydrogen, halo, alkyl, aryl, alkylaryl, heteroaryl, cycloalkyl, or cycloheteroalkyl, optionally R 2 is substituted at one or more positions with one or more of alkyl, alkoxy, haloalkyl, haloalkoxy, hydroxyl, halo, cyano, carboxyamido, hydrazonyl, carbonyl, carboxyl, and alkoxycarbonyl;
R 3 is hydrogen, alkyl, alkoxy, haloalkyl, haloalkoxy, alkenyl, aryl, alkylaryl, hydroxyl, halo, carboxyamido optionally substituted with alkyl, hydrazonyl, carbonyl, carboxyl, and alkoxycarbonyl;
R 4 is alkyl, aryl, or alkylaryl, optionally R 4 is substituted at one or more positions with one or more of alkyl, alkoxy, haloalkyl, haloalkoxy, aryl, hydroxyl, halo, cyano, carboxyamido, hydrazonyl, carbonyl, carboxyl, alkoxycarbonyl, aryloxy, and alkylaryloxy;
R 6 is alkyl, aryl, or alkylaryl, R 6 optionally R 6 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;
r is 0 or 1;
R 7 is aryl, alkylaryl, heteroaryl, cycloalkyl, or cycloheteroalkyl, optionally R 7 is substituted at one or more positions with one or more of alkyl, alkoxy, haloalkyl, haloalkoxy, hydroxyl, halo, cyano, carboxyamido, hydrazonyl, carbonyl, carboxyl, alkoxycarbonyl, oxoaryl, and oxoheteroaryl; and
R 8 is hydrogen, alkyl, aryl, or alkylaryl optionally substituted with halo;
with the proviso that if R 1 (Alk 1 ) n (X) p (Alk 2 ) q - is hydrogen, hydroxyl, or alkyl, then m is 1, or at least one of R 2 and R 3 is not hydrogen.

7. The compound of claim 6 , wherein m is 0 and R 2 is hydrogen.

8. The compound of claim 6 , wherein R 2 is aryl, alkylaryl, heteroaryl, cycloalkyl, or cycloheteroalkyl, and R 2 optionally is substituted at one or more positions with one or more of alkyl, alkoxy, haloalkyl, haloalkoxy, hydroxyl, halo, cyano, carboxyamido, hydrazonyl, carbonyl, carboxyl, and alkoxycarbonyl.

9. A pharmaceutical composition comprising a compound of claim 6 and a suitable pharmaceutical carrier, excipient, or diluent.

10. A method of treating cancer comprising administering the composition of claim 9 to a subject having cancer.

Assignees

• Univ Northwestern

Inventors

• Schiltz Gary E
• Jain Atul
• Han Huiying
• Abdulkadir Sarki A

Classifications

• C07D413/12

  linked by a chain containing hetero atoms as chain links · CPC title

• C07D405/04

  directly linked by a ring-member-to-ring-member bond · CPC title

• C07D231/18 Primary

  One oxygen or sulfur atom · CPC title

• C07D401/04

  directly linked by a ring-member-to-ring-member bond · CPC title

• C07D231/12

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