Macrocyclic compounds that inhibit MCL-1 protein

Patent metadata

Field	Value
Publication number	US-11279712-B2
Application number	US-201816642441-A
Country	US
Kind code	B2
Filing date	Aug 27, 2018
Priority date	Aug 29, 2017
Publication date	Mar 22, 2022
Grant date	Mar 22, 2022

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, or a stenoisomer thereof; 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

The invention claimed is:

1. A compound of Formula IA:

a stereoisomer thereof, a pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable salt of the stereoisomer thereof,
wherein:
Z is C or N;
b, represented by the symbol , is a single or double chemical bond which may be cis or trans;
R 1 is selected from H, halo, or C 1-6 alkyl;
R 2 is selected from H, halo, or C 1-6 alkyl;
R 3 is selected from H or —C 1-6 alkyl;
each of R 4 , R 5 , R 6 , R 7 , and R 8 is independently selected from H, —C 1-6 alkyl, or —C 1-6 alkyl-O—C 1-6 alkyl;
each of R 4A , R 5A , R 6A , R 7A , and R 8A is independently selected from H, or —C 1-6 alkyl;
R 7A and R 8A are absent when b is a double chemical bond;
R 9 is —C 1-6 alkyl, unsubstituted or substituted with 1, 2, 3 or 4 R 10 substituents independently selected from halo, —OH, —NR a R b ; —(═O), —OC 1-6 alkyl, —SO 2 R a , a 5- to 12-membered spirocycloalkyl or spiroheterocycloalkyl, or a 3- to 12-membered monocyclic or bicyclic heterocycloalkyl group, wherein the heteroaryl, spiroheterocycloalkyl and heterocycloalkyl groups have 1, 2, 3 or 4 heteroatoms independently selected from O, N or S,
wherein the aryl, heteroaryl, cycloalkyl, heterocycloalkyl, spirocycloalkyl and spiroheterocycloalkyl groups of any of the R 10 substituents can be unsubstituted or substituted with 1, 2, 3 or 4 R 2 substituents independently selected from halo, —NR a R b , —C 1-6 alkyl, —(═O), —C 1-6 alkyl-O—C 1-6 alkyl, —SO 2 R a , —C(═O)R a , and —C(═O)OR a ;
wherein R a and R b are each independently H, —C 1-6 alkyl, or —(CH 2 CH 2 O) n CH 3 , and
wherein n is 1.

2. The compound of claim 1 , wherein the compound has the Formula IIa:

a stereoisomer thereof, a pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable salt of the stereoisomer thereof.

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

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

5. The compound of claim 1 , wherein R 4 is independently selected from H, —C 1-6 alkyl, or —C 1-6 alkyl-O—C 1-6 alkyl.

6. The compound of claim 1 , wherein R 5 is selected from H or —C 1-6 alkyl.

7. The compound of claim 1 , wherein R 6 is selected from H or —C 1-6 haloalkyl.

8. The compound of claim 1 , wherein R 9 is —C 1-6 haloalkyl unsubstituted or substituted with 1, 2, or 3 R 10 substituents.

9. The compound of claim 1 , wherein R 10 is independently selected from halo, —OH, —NR a R b ; —(═O), —OC 1-6 alkyl, —SO 2 R a , a 5- to 12-membered spirocycloalkyl or spiroheterocycloalkyl, or a 3- to 12-membered monocyclic or bicyclic heterocycloalkyl group, wherein the heteroaryl, spiroheterocycloalkyl and heterocycloalkyl groups have 1, 2, 3 or 4 heteroatoms independently selected from O, N or S.

10. The compound of claim 9 , wherein R 10 is a 3- to 12-membered monocyclic or bicyclic heterocycloalkyl group, wherein the heterocycloalkyl group has 1, 2, 3 or 4 heteroatoms independently selected from O, S, or N.

11. The compound of claim 1 , wherein R 9 is independently selected from —CH 3 , —CH 2 OH, CH(OH)CF 3 , —C(═O), —C(═O)OH, —CHCH 2 (OH), —CH(OH)CH 3 , —CH 2 (O)CH 3 , —C(═O)CH 3 , —CH 2 S(O) 2 CH 3 , —C(═O)NH(CH 2 ) 2 OCH 3 ,

12. The compound of claim 1 , wherein the compound has the Formula Ma:

or a stereoisomer thereof, a pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable salt of the stereoisomer thereof.

13. The compound of claim 12 , wherein R 1 is halo.

14. The compound of claim 12 , wherein R 4 is —C 1-6 alkyl.

15. The compound of claim 12 , wherein R 5 is —C 1-6 alkyl.

16. The compound of claim 12 , wherein R 6 is H.

17. The compound of claim 12 , wherein R 9 is —CH 2 OH, —CH(OH)CH 2 CH 3 ,

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

or a stereoisomer thereof; a pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable salt of the stereoisomer thereof.

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

or a pharmaceutically acceptable salt thereof.

20. A pharmaceutical composition

Assignees

• Amgen Inc

Inventors

• Brown Sean P
• Li Yunxiao
• Harrington Paul E
• Lanman Brian Alan
• Low Jonathan D
• Minatti Ana Elena
• Ma Vu Van
• Li Kexue

Classifications

• C07D513/04 Primary

  Ortho-condensed systems · CPC title

• C07D513/08 Primary

  Bridged systems · CPC title

• C07D519/00

  Heterocyclic compounds containing more than one system of two or more relevant hetero rings condensed among themselves or condensed with a common carbocyclic ring system not provided for in groups C07D453/00 or C07D455/00 · CPC title

• A61P35/00

  Antineoplastic agents · CPC title

• A61K31/496

  Non-condensed piperazines containing further heterocyclic rings, e.g. rifampin, thiothixene or sparfloxacin · CPC title