Compounds that inhibit Mcl-1 protein

Patent metadata

Field	Value
Publication number	US-10100063-B2
Application number	US-201615376456-A
Country	US
Kind code	B2
Filing date	Dec 12, 2016
Priority date	Aug 29, 2014
Publication date	Oct 16, 2018
Grant date	Oct 16, 2018

Abstract

Provided herein are myeloid cell leukemia 1 protein (Mcl-1) inhibitors, methods of their preparation, related pharmaceutical compositions, and methods of using the same. For example, provided herein are compounds of Formula I,

and pharmaceutically acceptable salts thereof and pharmaceutical compositions containing the compounds. The compounds and compositions provided herein may be used, for example, in the treatment of diseases or conditions, such as cancer.

First claim

What is claimed is:

1. A compound of Formula I:

or a pharmaceutically acceptable salt thereof,
wherein:
wherein b, represented by the symbol is a single or double chemical bond which may be cis or trans;
R is a halo;
R 1 is H, C 1-6 alkyl, or —(CH 2 CH 2 O) n CH 3 , wherein n is an integer from 1 to 4;
R 2 is H or C 1-6 alkyl;
R 2A is H or C 1-6 alkyl;
R 3 is H or C 1-6 alkyl; and
R 3A is H, C 1-6 alkyl, C 3-6 cycloalkyl, or (CH 2 ) m —C 3-6 cycloalkyl, wherein m is an integer from 1 to 4.

2. The compound of claim 1 , wherein b indicates a double bond.

3. The compound of claim 1 , wherein R is Cl.

4. The compound of claim 1 , wherein R 1 is C 1-6 alkyl.

5. The compound of claim 4 , wherein R 1 is CH 3 .

6. The compound of claim 1 , wherein R 2 is H and R 2A is C 1-6 alkyl.

7. The compound of claim 1 , wherein R 3 is H and R 3A is C 1-6 alkyl.

8. The compound of claim 1 , wherein the compound of Formula I has the Formula II:

or a pharmaceutically acceptable salt thereof,
wherein:
R 1 , R 2 , R 2A , R 3 and R 3A are defined above.

9. A compound, wherein the compound has a structure selected from:

or
a pharmaceutically acceptable salt thereof.

10. A pharmaceutical composition comprising the compound of claim 1 , or the pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient.

11. A compound, wherein the compound has a structure selected from:

or a pharmaceutically acceptable salt thereof.

12. A pharmaceutical composition comprising the compound of claim 11 or the pharmaceutically acceptable salt thereof and a pharmaceutically acceptable excipient.

Assignees

• Amgen Inc

Inventors

• Brown Sean P
• Li Yunxiao
• Lizarzaburu Mike Elias
• Lucas Brian S
• Paras Nick A
• Taygerly Joshua
• Vimolratana Marc
• Wang Xianghong
• Yu Ming
• Zancanella Manuel
• Zhu Liusheng
• Gonzalez Buenrostro Ana
• Li Zhihong

Classifications

• A61P35/02

  specific for leukemia · CPC title

• A61P35/00

  Antineoplastic agents · CPC title

• C07D513/08 Primary

  Bridged systems · CPC title

• C07D513/10 Primary

  Spiro-condensed systems · CPC title

• C07D498/00

  Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and oxygen atoms as the only ring hetero atoms (4-oxa-1-azabicyclo [3.2.0] heptanes, e.g. oxapenicillins C07D503/00; 5-oxa-1-azabicyclo [4.2.0] octanes, e.g. oxacephalosporins C07D505/00; analogues thereof having ring oxygen atoms in other position C07D507/00) · CPC title