MCL-1 antagonists

Patent metadata

Field	Value
Publication number	US-10544131-B2
Application number	US-201816027029-A
Country	US
Kind code	B2
Filing date	Jul 3, 2018
Priority date	Mar 3, 2014
Publication date	Jan 28, 2020
Grant date	Jan 28, 2020

Abstract

Provided herein are Mcl-1 antagonist compositions and methods of treating cancer using the compositions described herein.

First claim

What is claimed is:

1. A method of treating cancer mediated by MCL-1 activity in a subject in need thereof, wherein said cancer is leukemia, lymphoma, breast, or lung cancer, said method comprising administering to the subject an effective amount of a compound having the formula:

wherein,
L 1 , L 2 , L 3 , L 4 , L 5 , and L 6 are independently a bond, —C(O)—, —C(O)O—, —C(O)NR 7 —, —O—, —S(O) n —, —S(O)NR 7 —, —C(O)NR 7 S(O) 2 —, —NR′—, substituted or unsubstituted alkylene, or substituted or unsubstituted heteroalkylene, substituted or unsubstituted cycloalkylene, substituted or unsubstituted heterocycloalkylene, substituted or unsubstituted arylene, or substituted or unsubstituted heteroarylene;
R 7 is independently hydrogen, halogen, —N 3 , —NO 2 , —CF 3 , —CCl 3 , —CBr 3 , —CI 3 , —CN, —OH, —NH 2 , —COOH, —CONH 2 , —NO 2 , —SH, —SO 2 Cl, —SO 3 H, —SO 2 Ph, —SO 2 NH 2 , —NHNH 2 , —ONH 2 , —OCH 3 , —NHCNHNH 2 , substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl;
n is 0, 1, or 2;
R 1 is halogen, —N 3 , —CF 3 , —CCl 3 , —CBr 3 , —CI 3 , —CN, —CHO, ═O, —OR 1A , —NR 1B R 1C , —COOR 1A , —CONR 1B R 1C , —NO 2 , —SR 1D , —SO n1 R 1B , —S(O) n1 OR 1B , —S(O) n1 NR 1B R 1C , —NHNR 1B R 1C , —ONR 1B R 1C , —NHC(O)NHNR 1B R 1C , substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl, wherein R 1 and R 2 are optionally joined together to form a substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl;
R 2 is hydrogen, halogen, —N 3 , —CF 3 , —CCl 3 , —CBr 3 , —CI 3 , —CN, —CHO, ═O, —OR 2A , —NR 2B R 2C , —COOR 2A , —CONR 2B R 2C , NO 2 , SR 2D , —SO n2 R 2B , —SO n2 OR 2B , —SO n2 NR 2B R 2C , —NHNR 2B R 2C , —ONR 2B R 2C , —NHC(O)NHNR 2B R 2C , substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl, wherein R 2 and R 3 are optionally joined together to form a substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl;
R 3 is hydrogen, halogen, —N 3 , —CF 3 , —CCl 3 , —CBr 3 , —CI 3 , —CN, —CHO, ═O, —OR 3A , —NR 3B R 3C , —COOR 3A , —CONR 3B R 3C , NO 2 , SR 3D , —SO n3 R 3B , —SO n3 OR 3B , —SO n3 NR 3B R 3C , —NHNR 3B R 3C , —ONR 3B R 3C , —NHC(O)NHNR 3B R 3C , substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl, wherein R 3 and R 4 are optionally joined together to form a substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl;
R 4 is hydrogen, halogen, —N 3 , —CF 3 , —CCl 3 , —CBr 3 , —CI 3 , —CN, —CHO, ═O, —OR 4A , —NR 4B R 4C , —COOR 4A , —CONR 4B R 4C , NO 2 , SR 4D , —SO n4 R 4B , —SO n4 OR 4B , —SO n4 NR 4B R 4C , —NHNR 4B R 4C , —ONR 4B R 4C , —NHC(O)NHNR 4B R 4C , substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl;
R 5 is independently hydrogen, halogen, —N 3 , —CF 3 , —CCl 3 , —CBr 3 , —CI 3 , —CN, —CHO, ═O, —OR 5A , —NR 5B R 5C , —COOR 5A , —CONR 5B R 5C , NO 2 , SR 5D , —SO n5 R 5B , —SO n5 OR 5B , —SO n5 NR 5B R 5C , —NHNR 5B R 5C , —ONR 5B R 5C , —NHC(O)NHNR 5B R 5C , substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl, wherein R 5 and R 6 are optionally joined together to form a substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl;
R 6 is hydrogen, halogen, —N 3 , —CF 3 , —CCl 3 , —CBr 3 , —CI 3 , —CN, —CHO, ═O, —OR 6A , —NR 6B R 6C , —COOR 6A , —CONR 6B R 6C , NO 2 , SR 6D , —SO n6 R 6B , —SO n6 OR 6B , —SO n6 NR 6B R 6C , —NHNR 6B R 6C , —ONR 6B R 6C , —NHC(O)NHNR 6B R 6c , substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl;
R 1A , R 2A , R 3A , R 4A , R 5A , R 6A , R 1B , R 2B , R 3B , R 4B , R 5B , R 6B , R 1C , R 2C , R 3C , R 4C , R 5C , R 6C , R 1D , R 2D , R 3D , R 4D , R 5D , and R 6D are independently hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl, wherein R 6B and R 6C , are optionally joined together to form a substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl;
n1, n2, n3, n4, n5, and n6 are independently 1 or 2; and
z is 1 or 2.

2. A method of antagonizing Mcl-1, said method comprising contacting the Mcl-1 with the compound of claim 1 thereby antagonizing said Mcl-1.

3. The method of claim 1 , wherein said leukemia is myeloid leukemia.

4. The method of claim 1 , further comprising administering to said patient a chemotherapy drug.

5. The method of claim 4 , wherein said chemotherapy drug is doxorubicin.

6. The method of claim 1 , wherein L 1 and L 4 are independently a bond, or —S(O) 2 — and L 2 and L 3 are independently a bond or substituted or unsubstituted alkylene.

7. The method of claim 6 , wherein L 5 is a bond, —O—, or substituted or unsubstituted alkylene and L 6 is a bond or —C(O)—.

8. The method of claim 7 , wherein R 4 is halogen, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted aryl or joined together with R 3 to form a substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, or substituted or unsubstituted aryl.

9. The method of claim 8 , wherein:
R 4 is R 11 -substituted or unsubstituted alkyl or R 11 -substituted or unsubstituted aryl, wherein R 11 is halogen, oxo, —OH, substituted or unsubstituted alkyl or substituted or unsubstituted aryl;
R 2 is hydrogen, joined together with R 1 to form a substituted or unsubstituted cycloalkyl or substituted or unsubstituted heterocycloalkyl, or joined together with R 3 to form substituted or unsubstituted heterocycloalkyl or substituted or unsubstituted aryl; and
R 3 is hydrogen.

10. The method of claim 1 , wherein the compound is of the formula:

wherein
R 5 is —OR 5A , wherein R 5A is R 13 -substituted or unsubstituted alkyl, R 13 -substi

Assignees

• Univ California
• The Royal Institute For The Advancement Of Learning/Mcgill Univ
• The Royal Institution For The Advancement Of Learning/Mcgill Univ

Inventors

• Harran Patrick
• Frederich James H
• Shore Gordon
• Nguyen Mai

Classifications

• C07D413/04

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

• C07D471/04

  Ortho-condensed systems · CPC title

• C07D405/12

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

• C07D401/04

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

• C07D405/04 Primary

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