Compounds that inhibit Mcl-1 protein

Patent metadata

Field	Value
Publication number	US-10632128-B2
Application number	US-201916547747-A
Country	US
Kind code	B2
Filing date	Aug 22, 2019
Priority date	Mar 30, 2017
Publication date	Apr 28, 2020
Grant date	Apr 28, 2020

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 stereoisomer 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 I′:

or a stereoisomer thereof, a pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable salt of the stereoisomer thereof,
wherein:
Z is C or N;
Q is O or S;
W is CR WA R WB or C═O;
R WA and R WB are independently selected from H, C 1-3 alkyl, halo, —OH, or —O—C 1-3 alkyl;
b, represented by the symbol is a single or double chemical bond which may be cis or trans;
R 1 is independently selected from H, halo, C 1-6 alkylhalo, C 1-6 alkyl, —(CH 2 CH 2 O) n R a , —SO 2 R a , —C(═O)R a , —C(═O)OR a , or —C(═O)NR a R b ;
R 2 is selected from H, halo, —C 1-6 haloalkyl, —C 1-6 alkyl, —O—C 1-6 alkyl, —C 2-6 alkenyl, —C 1-6 alkyl-O—C 1-6 alkyl, —(CH 2 CH 2 O) n R a , —SO 2 R a , —C(═O)R a , —C(═O)OR a , —OC(═O)R a , or —C(═O)NR a R b ,
R 3 is independently selected from H, —C 1-6 alkylhalo, —C 1-6 alkyl, —C 2-6 alkenyl, —(CH 2 CH 2 O) n R a , —C(═O)R a , —C(═O)OR a , or —C(═O)NR a R b ;
each of R 4 , R 5 , R 6 , R 7 , and R 8 is independently selected from H, halo, —C 1-6 haloalkyl, —C 1-6 alkyl, —O—C 1-6 alkyl, —C 2-6 alkenyl, —C 1-6 alkyl-O—C 1-6 alkyl, —(CH 2 CH 2 O) n R a , —SO 2 R a , —C(═O)R a ,—C(═O)OR a , —OC(═O)R a , —C(═O)NR a R b , a 6- to 12-membered aryl or heteroaryl, a 5- to 12-membered spirocycloalkyl or spiroheterocycloalkyl, a 3- to 12-membered cycloalkenyl, a 3- to 12-membered monocyclic or bicyclic cycloalkyl, 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 cycloalkyl, spirocycloalkyl, spiroheterocycloalkyl, and heterocycloalkyl groups may include a C═O group, and further wherein the spiroheterocycloalkyl and heterocycloalkyl groups may include a S═O or SO 2 ;
alternatively R 3 and R 4 together with the atoms to which they are bonded may form a 5- to 12-membered ring, optionally containing a heteroatom selected from a N, O or S atom, in addition to the S and N atoms present in the ring, wherein the ring may optionally contain at least one double bond; and the ring may be substituted with 0, 1, 2, or 3 R 3A substituents;
R 3A is independently selected from H, halo, —OH, C 1-6 haloalkyl, C 1-6 alkyl, O—C 1-6 alkyl, C 2-6 alkenyl, —C 1-6 alkyl-O—C 1-6 alkyl, —(CH 2 CH 2 O) n R a , —SO 2 R a , —C(═O)R a , —C(═O)OR a , —OC(═O)R a , —C(═O)NR a R b ;
each of R 4A , R 5A , R 6A , R 7A , and R 8A is independently selected from H, OH, halo, or —C 1-6 alkyl;
R 7A and R 8A are absent when b is a double chemical bond;
R 9 is independently selected from H, —C 1-6 haloalkyl, —C 1-6 alkyl, —C 2-6 alkenyl, —C 2-6 alkynyl, —(CH 2 CH 2 O) n R a , —C(═O)R a , —C(═O)OR a , —C(═O)NR a R b , —C 1-6 alkyl-O—C 1-6 alkyl, a 6- to 12-membered aryl or heteroaryl, a 5- to 12-membered spirocycloalkyl or spiroheterocycloalkyl, a 3- to 12-membered cycloalkenyl, a 3- to 12-membered monocyclic or bicyclic cycloalkyl, 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 cycloalkyl, spirocycloalkyl, spiroheterocycloalkyl, and heterocycloalkyl groups may include a C═O group, and further wherein the spiroheterocycloalkyl and heterocycloalkyl groups may include a S═O or SO 2 ;
R 9A is independently selected from H, C 1-6 haloalkyl, C 1-6 alkyl, —C 2-6 alkenyl, —C 2-6 alkynyl, —(CH 2 CH 2 O) n R a , —SO 2 R a , —C(═O)R a , —C(═O)OR a , —C(═O)NR a R b , —NR a R b , —N═N═N, —C 1-6 alkyl-O—C 1-6 alkyl, a 6- to 12-membered aryl, a 6- to 12-membered heteroaryl, a 5- to 12-membered spirocycloalkyl or spiroheterocycloalkyl, a 3- to 12-membered cycloalkenyl, a 3- to 12-membered monocyclic or bicyclic cycloalkyl, 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 cycloalkyl, spirocycloalkyl, spiroheterocycloalkyl, and heterocycloalkyl groups may include a C═O group, and further wherein the spiroheterocycloalkyl and heterocycloalkyl groups may include a S═O or SO 2 ;
wherein the aryl, heteroaryl, cycloalkyl, heterocycloalkyl, spirocycloalkyl and spiroheterocycloalkyl groups of the R 9A substituent can be unsubstituted or substituted with 1, 2, 3 or 4 R 10 substituents independently selected from OH, halo, —NR c R d , —C 1-6 alkyl, —C 2 -C 6 alkenyl, —C 2 -C 6 alkynyl, —OC 1-6 alkyl, —C 1-6 alkyl-OH, —C 1-6 alkyl-O—C 1-6 alkyl, C 1-6 haloalkyl, —O-haloC 1-6 alkyl, —SO 2 R c , —CN, —C(═O)NR c R d , —C(═O)R c , —OC(═O)R a , —C(═O)OR c , a 6- to 12-membered aryl, a 6- to 12-membered heteroaryl, a 5- to 12-membered spirocycloalkyl or spiroheterocycloalkyl, a 3- to 12-membered cycloalkenyl, a 3- to 12-membered monocyclic or bicyclic cycloalkyl, or a 3- to 12-membered monocyclic or bicyclic heterocycloalkyl group, wherein the heteroaryl, spiroheterocycloalkyl, and heterocycloalkyl groups have 0, 1, 2, 3 or 4 heteroatoms independently selected from O, N or S, wherein the cycloalkyl, spirocycloalkyl, spiroheterocycloalkyl, and heterocycloalkyl groups may include a C═O group, and further wherein the spiroheterocycloalkyl and heterocycloalkyl groups may include a S═O or SO 2 ;
alternatively R 9 and R 9A together with Q, W, and the C to which W and Q are bonded, may form a 3- to 12-membered monocyclic or bicyclic ring, optionally containing a heteroatom in addition to Q that is selected from N, O or S, wherein the ring may contain a double bond, wherein the ring may optionally include a C═O group, and further wherein the ring optionally may be substituted by 1, 2, or 3 R 11 substituents;
R 11 is independently selected from OH, halo, —NR c R d , —C 1-6 alkyl, —OC 1-6 alkyl, —C 1-6 alkyl-OH, —C 1-6 alkyl-O—C 1-6 alkyl, C 1-6 haloalkyl, —O-haloC 1-6 alkyl, —SO 2 R c , —CN, —C(═O)NR c R d , —C(═O)R c , —OC(═O)R a , —C(═O)OR c , a 6- to 12-membered aryl or heteroaryl, a 5- to 12-membered spirocycloalkyl or spiroheterocycloalkyl, a 3- to 12-membered cycloalkenyl, a 3- to 12-membered monocyclic or bicyclic cycloalkyl, or a 3- to 12-membered monocyclic or bicyclic heterocycloalkyl group, wherein the heteroaryl, spiroheterocycloalkyl, and heterocycloalkyl group have 1, 2, 3, or 4 heteroatoms independently selected from O, N or S, wherein the cycloalkyl, spirocycloalkyl, spiroheterocycloalkyl, and heterocycloalkyl groups may include a C═O group, and further wherein the spiroheterocycloalkyl and heterocycloalkyl groups may include a S═O or SO 2 ;
wherein the —C 1-6 alkyl of any of the R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , R 8 , R 9 , R 10 , R 11 , R 4A , R 5A , R 6A , R 7A , R 8A , and R 9A substituents is unsubstituted or substituted by 1, 2 or 3 R 12 substituents independently selected from OH, —OC 1-6 alkyl, —C 1-6 alkyl-O—C 1-6 alkyl, halo, —O-haloC 1-6 alkyl, —CN, —NR a R b , —(NR a R b R c ) n , —SO 2 R a , —(CH 2 CH 2 O) n CH 3 , (═O), —C(═O), —C(═O)R a , —OC(═O)R a , —C(═O)OR a , —C(═O)NR a R b , —O—SiR a R b R c , —O-(3- to 12-membered heterocycloakyl), phenyl, a 6- to 12-membered aryl or heteroaryl, a 5- to 12-membered spirocycloalkyl or spiroheterocycloalkyl, a 3- to 12-membered cycloalkenyl, a 3- to 12-membered monocyclic or bicyclic cycloalkyl, 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 cycloalkyl, spirocycloalkyl, spiroheterocycloalkyl, and heterocycloalkyl groups may include a C═O group, and further wherein the spiroheterocycloalkyl

Assignees

• Amgen Inc

Inventors

• Harrington Paul E
• Ashton Kate
• Brown Sean P
• Kaller Matthew R
• Kohn Todd J
• Lanman Brian Alan
• Li Kexue
• Li Yunxiao
• Low Jonathan D
• Minatti Ana Elena
• Pickrell Alexander J
• Stec Markian M
• Taygerly Joshua

Classifications

• C07D498/08 Primary

  Bridged systems · CPC title

• A61P35/00

  Antineoplastic agents · CPC title

• A61K31/553 Primary

  having at least one nitrogen and one oxygen as ring hetero atoms, e.g. loxapine, staurosporine · CPC title

• A61P35/02

  specific for leukemia · CPC title