Substituted benzofuran, benzothiophene and indole MCL-1 inhibitors

Patent metadata

Field	Value
Publication number	US-10093640-B2
Application number	US-201314429799-A
Country	US
Kind code	B2
Filing date	Sep 20, 2013
Priority date	Sep 21, 2012
Publication date	Oct 9, 2018
Grant date	Oct 9, 2018

Abstract

The present invention provides for compounds that inhibit the activity of an anti-apoptotic Bcl-2 family member Myeloid cell leukemia-1 (Mcl-1) protein. The present invention also provides for pharmaceutical compositions as well as methods for using compounds for treatment of diseases and conditions (e.g., cancer) characterized by the over-expression or dysregulation of Mcl-1 protein.

First claim

What is claimed is:

1. A compound of Formula II:

or a pharmaceutically acceptable salt or solvate thereof, wherein:
A 2 is C(O)R 7 ;
R 1B is selected from

R 2 , R 3 , R 4 and R 5 are independently selected from hydrogen (H), alkyl, alkenyl, alkynyl, cycloalkyl, aryl, heteroaryl, heterocyclyl, halo, —NH 2 , —CN, —NO 2 , —C(O)OH, —C(O)OR 9 , —OCF 3 , —OR 9 , —OH, —SH, —SR 9 , —S(O) 3 H, —P(O) 3 H 2 , —C(O)NH 2 , —C(O)NHR 9 , —C(O)NR 9 R 9 , —NHR 9 , —NR 9 R 9 , —S(O) 2 NHR 9 , —S(O) 2 NR 9 R 9 , —NHS(O) 2 CF 3 , —NR 9 S(O) 2 CF 3 , —C(O)NHS(O) 2 R 9 , —C(O)NR 9 S(O)R 9 , —S(O) 2 NHC(O)OR 9 , —S(O) 2 NR 9 C(O)OR 9 , —S(O) 2 NHC(O)NHR 9 , —S(O) 2 NHC(O)NR 9 R 9 , —S(O) 2 NR 9 C(O)NHR 9 , —C(O)H, —S(O) 2 NR 9 C(O)NR 9 R 9 , —C(O)NHS(O) 2 CF 3 , —C(O)NR 9 S(O) 2 CF 3 , —C(O)R 9 , —NR 9 C(O)H, —NHC(O)R 9 , —NR 9 C(O)R, —OC(O)R 9 , —OC(O)NH 2 , —OC(O)NHR 9 , —OC(O)NR 9 R 9 , —C(NH)NH 2 , —C(NH)NHR 9 , —C(NH)NR 9 R 9 , —C(NR 9 )NH 2 , —C(NR 9 )NHR 9 , —NHC(NR)NR 9 R 9 , —S(O)R 9 , —S(O) 2 R 9 , —NHC(O)OR 9 , —NR 9 C(O)OR 9 , —NHS(O)R 9 and —NR 9 S(O)R 9 , wherein said alkyl, alkenyl, alkynyl, cycloalkyl, aryl, heteroaryl, and heterocyclyl groups are each optionally substituted with one, two, three, four, or five substituents independently selected from R 10 ;
optionally one of R 2 and R 3 , R 3 and R 4 or R 4 and R 5 may be taken together to form a 5-10 membered carbocyclyl, a 5-10 membered heterocyclyl, an aryl or a 5-7 membered heteroaryl ring, each of which may optionally be substituted by one two, three, four, or five of alkyl, alkenyl, alkynyl, cycloalkyl, aryl, heteroaryl, heterocyclyl, halo, —NH 2 , —CN, —NO 2 , —C(O)OH, —C(O)OR 9 , —OCF 3 , —OR 9 , —OH, —SH, —SR 9 , —S(O) 3 H, —P(O) 3 H 2 , —C(O)NH 2 , —C(O)NHR 9 , —C(O)NR 9 R 9 , —NHR 9 , —NR 9 R 9 , —S(O) 2 NHR 9 , —S(O) 2 NR 9 R 9 , —NHS(O) 2 CF 3 , —NR 9 S(O) 2 CF 3 , —C(O)NHS(O) 2 R 9 , —C(O)NR 9 S(O) 2 R 9 , —S(O) 2 NHC(O)OR 9 , —S(O) 2 NR 9 C(O)OR 9 , —S(O) 2 NHC(O)NHR 9 , —S(O) 2 NHC(O)NR 9 R 9 , —S(O) 2 NR 9 C(O)NHR 9 , —C(O)H, —S(O) 2 NR 9 C(O)NR 9 R 9 , —C(O)NHS(O) 2 CF 3 , —C(O)NR 9 S(O) 2 CF 3 , —C(O)R 9 , —NR 9 C(O)H, —NHC(O)R 9 , —NR 9 C(O)R 9 , —OC(O)R 9 , —OC(O)NH 2 , —OC(O)NHR 9 , —OC(O)NR 9 R 9 , —C(NH)NH 2 , —C(NH)NHR 9 , —C(NH)NR 9 R 9 , —C(NR 9 )NH 2 , —C(NR 9 )NHR 9 , —NHC(NR)NR 9 R 9 , —S(O)R 9 , —S(O)R, —NHC(O)OR 9 , —NR 9 C(O)OR 9 , —NHS(O)R 9 and —NR 9 S(O)R 9 , wherein said alkyl, alkenyl, alkynyl, cycloalkyl, aryl, heteroaryl, and heterocyclyl groups are each optionally substituted with one, two, three, four, or five substituents independently selected from R 10 ;
R 6 is selected from R 6A , hydrogen (H), alkyl, cycloalkyl, heterocyclyl, alkenyl, alkynyl, aryl, heteroaryl, heterocyclyl, —C(O)OR 9 , —C(O)NHR 9 , —C(O)NR 9 R 9 , —S(O) 2 NHR 9 , —S(O) 2 NR 9 R 9 , —S(O) 2 R 9 , —C(O)NH 2 , —C(O)NHS(O) 2 R 9 , —C(O)NR 9 S(O) 2 R 9 , —S(O) 2 NHC(O)OR 9 , —S(O) 2 NR 9 C(O)OR 9 , —S(O) 2 NHC(O)NHR 9 , —S(O) 2 NHC(O)NR 9 R 9 , —S(O) 2 NR 9 C(O)NHR 9 , —C(O)H, —S(O) 2 NR 9 C(O)NR 9 R 9 , —C(O)NHS(O) 2 CF 3 , —C(O)NR 9 S(O) 2 CF 3 , —C(O)R 9 , —C(NH)NH 2 , —C(NH)NHR 9 , —C(NH)NR 9 R 9 , —C(NR 9 )NH 2 , —C(NR 9 )NHR 9 , —S(O)R 9 , and —S(O) 2 R 9 , wherein said alkyl, alkenyl, alkynyl, cycloalkyl, aryl, heteroaryl, and heterocyclyl groups are each optionally substituted one, two, three, four, or five substituents independently selected from R 10 ;
R 6A is selected from R 6A1 ,
C 1-6 alkyl substituted with 1-3 R 8 ,
C 2-6 alkenyl substituted with 1-2 R 8 ,
C 2-6 alkynyl substituted with 1-2 R 8 ,
C 3-8 cycloalkyl substituted with 1-2 R 8 ,
5-6 membered heterocyclic ring system containing from 1-4 heteroatoms selected from the group consisting of N, O, and S substituted with 1-2 R 8 ;

R 6A1 is C 2-6 alkyl, C 3-6 alkenyl, or C 3-8 cycloalkyl wherein: (a) each of which has at least one CH 2 moiety replaced with O, S, S(O), S(O) 2 , S(O) 2 NH, S(O) 2 NR 9 , C(O), C(O)NH, C(O)NR 9A , NH, or NR 9A ; and (b) remaining CH 2 or CH substituted with 1-2 R 8 ;
R 7 is selected from —COOH, —COOR 9 , —NHS(O) 2 CF 3 , —NR 12 S(O) 2 CF 3 , —NHC(O)H, —NR 12 C(O)H, —NHC(O)R 9 , —NR 12 C(O)R 9 , —NHC(O)OR 9 , —NR 12 C(O)OR 9 , —NHS(O)R 9 and —NR 12 S(O)R;
R 8 is selected from cycloalkyl, heterocyclyl, aryl, heteroaryl, each of which may optionally be substituted by one or more of R 11 , halo, —NH 2 , —CN, —NO 2 , —C(O)OH, —C(O)OR 11 , —OCF 3 , —OR 11 , —OH, —SH, —SR 11 , —C(O)NH 2 , —C(O)NHR 11 , —C(O)NR 11 R 12 , —NHR 11 , —NR 11 R 12 , —S(O) 2 NHR 11 , —S(O) 2 NR 1 R 2 , —NHS(O) 2 CF 3 , —NR 12 S(O) 2 CF 3 , —C(O)NHS(O) 2 R 1 , —C(O)NR 12 S(O) 2 R 11 , —S(O) 2 NHC(O)OR 11 , —S(O) 2 NR 12 C(O)OR 11 , —S(O) 2 NHC(O)NHR 11 , —S(O) 2 NHC(O)NR 11 R 12 , —S(O) 2 NR 12 C(O)NHR 11 , —C(O)H, —S(O) 2 NR 12 C(O)NR 11 R 12 , —C(O)NHS(O) 2 CF 3 , —C(O)NR 12 S(O) 2 CF 3 , —C(O)R 11 , —NR 12 C(O)H, —NHC(O)R 11 , —NR 12 C(O)R 11 , —OC(O)R 11 , —OC(O)NH 2 , —OC(O)NHR 11 , —OC(O)NR 11 R 12 , —C(NH)NH 2 , —C(NH)NHR 11 , —C(NH)NR 11 R 12 , —C(NR 12 )NH 2 , —C(NR 12 )NHR 11 , —NHC(NR 12 )NR 11 R 12 , —S(O)R 11 , —S(O) 2 R 11 , —NHC(O)OR 11 , —NR 12 C(O)OR 11 , —NHS(O 2 )R 11 and —NR 12 S(O 2 )R 11 ;
R 9 is selected from alkyl, cycloalkyl, heterocyclyl, alkenyl, alkynyl, aryl, heteroaryl, each of which may optionally be substituted by one or more of R 11 , halo, —NH 2 , —CN, —NO 2 , —C(O)OH, —C(O)OR 12 , —OCF 3 , —OR 12 , —OH, —SH, —SR 12 , —C(O)NH 2 , —C(O)NHR 12 , —C(O)NR 12 R 12 , —NHR 12 , —NR 12 R 12 , —S(O) 2 NHR 12 , —S(O) 2 NR 12 R 12 , —NHS(O) 2 CF 3 , —NR 12 S(O) 2 CF 3 , —C(O)H, —C(O)R 12 , —NHC(O)H, —NR 12 C(O)H, —NHC(O)R 12 , —NR 12 C(O)R 12 , —S(O)R 12 , —S(O) 2 R 12 , —NHC(O)OR 12 , —NR 12 C(O)OR 12 , —NHS(O 2 )R 12 and —NR 12 S(O 2 )R 12 ;
R 9A is C 1-4 alkyl;
R 10 is selected from alkyl, cycloalkyl, heterocyclyl, alkenyl, alkynyl, aryl, heteroaryl, halo, —NH 2 , —CN, —NO 2 , —C(O)OH, —OCF 3 , —OR 13 , —OH, —SH, —SR 13 , —C(O)NH 2 , —C(O)NHR 13 , —C(O)NR 9A R 13 , —NHR 13 , —NR 9A R 13 , —S(O) 2 NHR 13 , —S(O) 2 NR 9A R 13 , —NHS(O) 2 CF 3 , —C(O)H, —C(O)R 13 , —NHC(O)R 13 , —NR 9A C(O)R 13 , —S(O)R 13 , —S(O) 2 R 13 , —NHC(O)OR 13 , —NR 9A C(O)OR 13 , —NHS(O 2 )R 11 and —NR 9A S(O 2 )R 3 , wherein said alkyl, cycloalkyl, heterocyclyl, alkenyl, alkynyl, aryl, and heterocyclyl groups are each optionally substituted with one or more R 14 ;
R 12 is selected from C 1-4 alkyl, C 1-4 alkyloxy, C 1-4 haloalkyl, 3-6 membered cycloalkyl, 3-6 membered heterocyclyl, aryl, heteroaryl, each of which may optionally be substituted by one or more of R 9A , NH 2 , —CN, —NO 2 , —C(O)OH, —OCF 3 , —OR 13 , —OH, —SH, —SR 13 , —C(O)NH 2 , —C(O)NHR 9A , —NHR 9A , —S(O) 2 NHR 9A , —NHS(O) 2 CF 3 , —C(O)H, —C(O)R 9A , —S(O)R 9A , —S(O) 2 R 9A , —NHC(O)R 9A , —NHC(O)OR 9A , and —NHS(O 2 )R 13 ;
R 12 is selected from C 1-4 alkyl, C 1-4 alkyloxy, C 1-4 haloalkyl, 3-6 membered cycloalkyl, 3-6 membered heterocyclyl, aryl, and heteroaryl, wherein when R 12 is aryl, the aryl may be optionally substituted with 1, 2 or 3 substituents selected from halo, haloalkyl, alkyl, alkoxy, haloalkoxy, alkenyl, alkynyl, cycloalkyl-alkyl, cycloheteroalkyl, cycloheteroalkylalkyl, aryl, heteroaryl, arylalkyl, aryloxy, aryloxyalkyl, arylalkoxy, arylthio, arylazo, heteroarylalkyl, heteroarylalkenyl, heteroarylheteroaryl, heteroaryloxy, hydroxy, nitro, cyano, amino, thiol, alkylthio, arylthio, heteroarylthio, arylthioalkyl, alkoxyarylthio, alkylcarbonyl, arylcarbonyl, alkylaminocarbonyl, aryl

Assignees

• Univ Vanderbilt

Inventors

• Lee Taekyu
• Pelz Nicholas F
• Belmar Johannes
• Bian Zhiguo
• Olejniczak Edward T
• Fesik Stephen W
• Chauder Brian A

Classifications

• C07D333/70

  attached in position 2 · CPC title

• C07D401/14

  containing three or more hetero rings · CPC title

• A61K31/381

  having five-membered rings · CPC title

• C07D403/12

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

• C07D405/14

  containing three or more hetero rings · CPC title