Inhibition of MCL-1 and/or BFL-1/A1

Patent metadata

Field	Value
Publication number	US-9926306-B2
Application number	US-201314386747-A
Country	US
Kind code	B2
Filing date	Mar 14, 2013
Priority date	Mar 20, 2012
Publication date	Mar 27, 2018
Grant date	Mar 27, 2018

Abstract

This disclosure features compounds and pharmaceutically acceptable salts thereof that inhibit MCL-1 and/or BFL-1/A1 and compositions containing the same. This disclosure also features combinations that include one or more of the MCL-1/BFL-1/A1 inhibitor compounds described herein, or a pharmaceutically acceptable salt thereof; and one or more additional therapeutic agents (e.g., one or more chemotherapeutic agents (including small molecule and/or anti-body based chemotherapy and/or radiation); e.g., one or more therapeutic agents that modulate apoptosis; e.g., one or more therapeutic agents that bind to and inhibit anti-apoptotic proteins or modulate them indirectly; e.g., one or more therapeutic agents that bind to and inhibit, or indirectly modulate, anti-apoptotic BCL-2, BCL-XL, BCL-w, MCL-1, and/or BFL-1/A1; e.g., one or more therapeutic agents that directly bind to and inhibit anti-apoptotic BCL-2/BCL-XL; e.g., agents such as ABT-199, ABT-263 and ABT-737; e.g., ABT-737), or (where applicable) a pharmaceutically acceptable salt of the one or more therapeutic agents (as well as compositions containing the same). Also featured are methods of using such compounds, salts, combinations, and compositions, e.g., for the treatment or prevention of diseases, disorders, and conditions associated with deregulated apoptosis of cells (e.g., diseased or damaged cells; e.g., insufficient apoptosis of diseased or damaged cells or reduced apoptosis of diseased or damaged cells).

First claim

What is claimed is:

1. A pharmaceutical combination comprising a compound of formula (II), or a pharmaceutically acceptable salt thereof; and one or more additional therapeutic agents selected from the group consisting of chemotherapeutic agents and therapeutic agents that modulate apoptosis, or a pharmaceutically acceptable salt of the agent:

wherein:
R 22 is:
(i) C 6 -C 10 aryl, which is optionally substituted with from 1-5 independently selected R a ;
(ii) heteroaryl, which contains from 5-10 ring atoms, wherein from 1-4 of the ring atoms is independently selected from the group consisting of N, NH, N(C 1 -C 3 alkyl), O, and S; and wherein said heteroaryl ring is optionally substituted with from 1-4 independently selected R a ; or
(iii) phenyl fused to C 1 -C 3 alkylenedioxy, wherein the phenyl portion is optionally substituted with from 1-2 independently selected R a ;
R 23 is:
(i) C 3 -C 8 branched alkyl or C 1 -C 8 haloalkyl, each of which is optionally substituted with from 1-2 independently selected R b ; or
(ii) C 3 -C 6 cycloalkyl or C 3 -C 6 cycloalkenyl, each of which is optionally substituted with from 1-4 independently selected R d ;
R 25 is:
(i) hydrogen;
(ii) C 1 -C 8 alkyl or C 1 -C 8 haloalkyl, each of which is optionally substituted with from 1-2 independently selected R b ;
(iii) C 3 -C 6 cycloalkyl or C 3 -C 6 cycloalkenyl, each of which is optionally substituted with from 1-4 independently selected R d ; or
(iv) —C(O)O(C 1 -C 6 alkyl);
or
R 23 and R 25 , together with the carbon atoms to which each is attached, form:
(i) a 5-6 membered saturated or unsaturated carbocyclic ring, which is optionally substituted with from 1-4 independently selected R d ; or
(ii) a 5-6 membered saturated or unsaturated hetrocyclic ring, which is optionally substituted with from 1-4 independently selected R d , and wherein from 1-2 of the ring atoms (other than the two ring atoms attached to R 23 and R 24 ) is independently selected from the group consisting of N, NH, N(C 1 -C 3 alkyl), NC(O)(C 1 -C 6 alkyl), O, and S;
R 26 and R 27 together are a bond (form a second or double bond between the carbon atoms to which each is attached); or
each of R 26 and R 27 is independently selected from the group consisting of hydrogen, halo, and hydroxyl;
R 24 is:
(i) C 3 -C 10 cycloalkyl or C 3 -C 10 cycloalkenyl, each of which is optionally substituted with from 1-4 independently selected R d ;
(ii) C 6 -C 10 aryl, which is optionally substituted with from 1-5 independently selected R c ;
(iii) heteroaryl, which contains from 5-10 ring atoms, wherein from 1-4 of the ring atoms is independently selected from the group consisting of N, NH, N(C 1 -C 3 alkyl), O, and S; and wherein said heteroaryl ring is optionally substituted with from 1-4 independently selected R c ;
(iv) unsubstituted C 1 -C 8 alkyl or unsubstituted C 1 -C 8 haloalkyl;
(v) heterocyclyl containing from 3-6 ring atoms, wherein from 1-2 of the ring atoms is independently selected from the group consisting of N, NH, N(C 1 -C 3 alkyl), NC(O)(C 1 -C 6 alkyl), O, and S; and wherein said heterocyclyl is optionally substituted with from 1-3 independently selected R d ;
(vi) (C 1 -C 6 alkyl)-(C 3 -C 8 cycloalkyl), wherein the cycloalkyl portion is optionally substituted with from 1-4 independently selected R d ; or
(vii) dihydronaphthyl, tetrahydronaphthyl, indanyl, or indenyl;
R a at each occurrence is, independently, selected from the group consisting of halo, hydroxyl, C 1 -C 6 alkoxy; C 1 -C 6 haloalkoxy; C 1 -C 6 thiohaloalkoxy; —NHC(O)(C 1 -C 6 alkyl); cyano; —C(O)H; —C(O)(C 1 -C 6 alkyl); —C(O)(C 1 -C 6 haloalkyl); C(O)OH; —C(O)O(C 1 -C 6 alkyl); —C(O)NH 2 ; —C(O)NH(C 1 -C 6 alkyl); C(O)N(C 1 -C 6 alkyl) 2 ; —SO 2 (C 1 -C 6 alkyl); —SO 2 NH 2 ; —SO 2 NH(C 1 -C 6 alkyl); and —SO 2 N(C 1 -C 6 alkyl) 2 ;
R b at each occurrence is, independently, selected from the group consisting of hydroxyl, C 1 -C 6 alkoxy; C 1 -C 6 thioalkoxy; C 1 -C 6 haloalkoxy; C 1 -C 6 thiohaloalkoxy; —NH 2 ; —NH(C 1 -C 6 alkyl); N(C 1 -C 6 alkyl) 2 ; —NHC(O)(C 1 -C 6 alkyl); cyano; —C(O)H; —C(O)(C 1 -C 6 alkyl); —C(O)(C 1 -C 6 haloalkyl); C(O)OH; —C(O)O(C 1 -C 6 alkyl); —C(O)NH 2 ; —C(O)NH(C 1 -C 6 alkyl); C(O)N(C 1 -C 6 alkyl) 2 ; —SO 2 (C 1 -C 6 alkyl); —SO 2 NH 2 ; —SO 2 NH(C 1 -C 6 alkyl); and —SO 2 N(C 1 -C 6 alkyl) 2 ;
R c at each occurrence is, independently, any one of the substituents delineated collectively in (a), (b), (c), and (d) below:
(a) C 1 -C 6 alkoxy; C 1 -C 6 haloalkoxy; C 1 -C 6 thioalkoxy; C 1 -C 6 thiohaloalkoxy; C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, —NH(C 1 -C 6 alkyl), N(C 1 -C 6 alkyl) 2 , or —NHC(O)(C 1 -C 6 alkyl), each of which is optionally substituted with —OH, C 1 -C 6 alkoxy, —NH 2 , or —SH;
(b) halo; —OH; —CN; nitro; —NH 2 ; azido; C 2 -C 4 alkenyl; C 2 -C 4 alkynyl; —C(O)H; —C(O)(C 1 -C 6 alkyl); C(O)OH; —C(O)O(C 1 -C 6 alkyl); —OC(O)(C 1 -C 6 alkyl); —SO 2 (C 1 -C 6 alkyl); —SO 2 (C 1 -C 6 haloalkyl); —C(O)NH 2 ; —C(O)NH(C 1 -C 6 alkyl); C(O)N(C 1 -C 6 alkyl) 2 ; —SO 2 (C 1 -C 6 alkyl); —SO 2 NH 2 ; —SO 2 NH(C 1 -C 6 alkyl); —SO 2 N(C 1 -C 6 alkyl) 2 ; —NHCO(C 1 -C 6 alkyl), —NHSO 2 (C 1 -C 6 alkyl); or —C(O)O—(CH 2 ) 1-3 —C(O)-(phenyl optionally substituted as defined in (d) below;
(c) L-C 3 -C 8 cycloalkyl, C 3 -C 6 cycloalkoxy, or L-heterocyclyl containing from 5-7 ring atoms, wherein from 1-2 of the ring atoms of the heterocyclyl is independently selected from the group consisting of N, NH, N(C 1 -C 6 alkyl), NC(O)(C 1 -C 6 alkyl), NC(O)O(C 1 -C 6 alkyl), O, and S; and each of said ring systems is optionally substituted with from 1-3 independently selected C 1 -C 4 alkyl groups; and wherein L is a bond or C 1 -C 6 alkylene; and
(d) phenyl, —O-(phenyl), or heteroaryl containing from 5-6 ring atoms, wherein from 1-2 of the ring atoms of the heteroaryl is independently selected from the group consisting of N, NH, N(C 1 -C 3 alkyl), O, and S; wherein each of said phenyl and heteroaryl is optionally substituted with from 1-3 substituents independently selected from the group consisting of halo; hydroxyl; cyano; —C(O)(C 1 -C 6 alkyl); C(O)OH; —C(O)O(C 1 -C 6 alkyl); nitro; —NH 2 ; —NH(C 1 -C 6 alkyl), N(C 1 -C 6 alkyl) 2 , —NHC(O)(C 1 -C 6 alkyl), C 1 -C 6 alkoxy; C 1 -C 6 haloalkoxy; C 1 -C 6 thioalkoxy; C 1 -C 6 thiohaloalkoxy; C 1 -C 6 alkyl, and C 1 -C 6 haloalkyl, wherein said alkyl or alkyl portion is optionally substituted with —OH, —NH 2 , or —SH;
R d at each occurrence is, independently, any one of the substituents delineated collectively in (a) and (b) below:
(a) C 1 -C 6 alkoxy; C 1 -C 6 haloalkoxy; C 1 -C 6 thioalkoxy; C 1 -C 6 thiohaloalkoxy; C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, —NH(C 1 -C 6 alkyl), N(C 1 -C 6 alkyl) 2 , or —NHC(O)(C 1 -C 6 alkyl), each of which is optionally substituted with —OH, C 1 -C 6 alkoxy, —NH 2 , or —SH; or
(b) halo; —OH; —CN; nitro; —NH 2 ; azido; C 2 -C 4 alkenyl; C 2 -C 4 alkynyl; —C(O)H; —C(O)(C 1 -C 6 alkyl); C(O)OH; —C(O)O(C 1 -C 6 alkyl); —OC(O)(C 1 -C 6 alkyl); —SO 2 (C 1 -C 6 alkyl); —SO 2 (C 1 -C 6 haloalkyl); —C(O)NH 2 ; —C(O)NH(C 1 -C 6 alkyl); C(O)N(C 1 -C 6 alkyl) 2 ; —SO 2 (C 1 -C 6 alkyl); —SO 2 NH 2 ; —SO 2 NH(C 1 -C 6 alkyl); —SO 2 N(C 1 -C 6 alkyl) 2 ; —NHCO(C 1 -C 6 alkyl), or —NHSO 2 (C 1 -C 6 alkyl).

2. The composition of claim 1 , wherein R 26 and R 27 together are a bond.

3. The composition of claim 1 , wherein R 22 is C 6 -C 10 aryl, which is optionally substituted with from 1-5 independently selected R a .

4. The composition of claim 1 , wherein each R a is independently selected from the group consisting of halo, hydroxyl, C 1 -C 6 alkox

Assignees

• Dana Farber Cancer Inst Inc

Inventors

• Walensky Loren D

Classifications

• A61K45/06

  Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca · CPC title

• C07D417/12 Primary

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

• A61K31/428

  condensed with carbocyclic rings · CPC title

• C07D277/56

  Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen · CPC title

• A61K31/427

  not condensed and containing further heterocyclic rings · CPC title