BET bromodomain protein degraders with cleavable linkers

Patent metadata

Field	Value
Publication number	US-11267822-B2
Application number	US-201816645953-A
Country	US
Kind code	B2
Filing date	Sep 12, 2018
Priority date	Sep 13, 2017
Publication date	Mar 8, 2022
Grant date	Mar 8, 2022

Abstract

The present disclosure provides compounds represented by Formula (I): Formula (I) and the pharmaceutically acceptable salts and solvates thereof, wherein R 1 , R 2a , R 2b , R 3a , R 3b , R 4 , Y, ═, Ar, W, L, and B are as defined as set forth in the specification. The present disclosure also provides compounds of Formula (I)I for use to treat a condition or disorder responsive to inhibition and/or degradation of BET bromodomains such as cancer.

First claim

What is claimed is:

1. A compound having Formula I:

or a pharmaceutically acceptable salt or hydrate thereof, wherein:
R 1 is selected from the group consisting of hydrogen and optionally substituted C 1-4 alkyl;
R 2a and R 2b are independently selected from the group consisting of hydrogen, optionally substituted C 1-4 alkyl, —CH 2 C(═O)OR 18 , and —CH 2 C(═O)NR 19a R 19b ; or
R 2a and R 2b together with the carbon atom to which they are attached form a 3- to 6-membered cycloalkyl;
is a single bond, R 3a and R 3b are independently selected from the group consisting of hydrogen and optionally substituted C 1-4 alkyl; and Y is selected from the group consisting of —O—, —S—, and —NR 10 —; or
is a double bond, R 3a is selected from the group consisting of optionally substituted C 6-14 aryl and optionally substituted 5- to 14-membered heteroaryl; R 3b is absent; and Y is —N═;
R 4 is selected from the group consisting of hydrogen, halogen, optionally substituted C 1-4 alkyl, optionally substituted C 2-4 alkenyl, optionally substituted C 2-4 alkynyl, aralkyl, optionally substituted C 6-14 aryl, optionally substituted C 3-12 cycloalkyl, optionally substituted 3- to 14-membered heterocyclo, optionally substituted 5- to 14-membered heteroaryl, —NR 6a R 6b , —OR 7 , —SR 8a , —S(═O)R 8b , —S(═O) 2 R 8c , —C(═O)R 9 , (heteroaryl)alkyl, and alkoxyalkyl;
R 6a and R 6b are each independently selected from the group consisting of hydrogen, optionally substituted C 1-6 alkyl, aralkyl, optionally substituted C 6-14 aryl, optionally substituted C 3-12 cycloalkyl, optionally substituted 3- to 14-membered heterocyclo, optionally substituted 5- to 14-membered heteroaryl, alkylcarbonyl, arylcarbonyl, alkoxycarbonyl, alkyl sulfonyl, aryl sulfonyl, and carboxamido; or
R 6a and R 6b taken together with the nitrogen atom to which they are attached form an optionally substituted 4- to 8-membered heterocyclo;
R 7 is selected from the group consisting of hydrogen, optionally substituted C 1-4 alkyl, aralkyl, optionally substituted C 6-14 aryl, optionally substituted C 3-12 cycloalkyl, optionally substituted 3- to 14-membered heterocyclo, optionally substituted 5- to 14-membered heteroaryl, alkylcarbonyl, and carboxamido;
R 8a is selected from the group consisting of optionally substituted C 1-4 alkyl, aralkyl, optionally substituted C 6-14 aryl, optionally substituted C 3-12 cycloalkyl, optionally substituted 3- to 14-membered heterocyclo, and optionally substituted 5- to 14-membered heteroaryl;
R 8b is selected from the group consisting of optionally substituted C 1-4 alkyl, aralkyl, optionally substituted C 6-14 aryl, optionally substituted C 3-12 cycloalkyl, optionally substituted 3- to 14-membered heterocyclo, and optionally substituted 5- to 14-membered heteroaryl;
R 8c is selected from the group consisting of optionally substituted C 1-4 alkyl, aralkyl, optionally substituted C 6-14 aryl, optionally substituted C 3-12 cycloalkyl, optionally substituted 3- to 14-membered heterocyclo, optionally substituted 5- to 14-membered heteroaryl, and amino;
R 9 is selected from the group consisting of hydrogen, optionally substituted C 1-4 alkyl, aralkyl, optionally substituted C 6-14 aryl, optionally substituted C 3-12 cycloalkyl, optionally substituted 3- to 14-membered heterocyclo, optionally substituted 5- to 14-membered heteroaryl, alkoxy, and amino;
R 10 is selected from the group consisting of hydrogen, optionally substituted C 1-6 alkyl, optionally substituted C 6-14 aryl, optionally substituted C 3-12 cycloalkyl, optionally substituted 3- to 14-membered heterocyclo, optionally substituted 5- to 14-membered heteroaryl, (C 3-6 cycloalkyl)C 1-4 alkyl, aralkyl, (alkoxycarbonyl)alkyl, —C(═O)R 11 , —SO 2 R 12 , —C(═O)—OR 13 , and —C(═O)—NR 14a R 14b ;
R 11 is selected from the group consisting of optionally substituted C 1-6 alkyl, optionally substituted C 6-14 aryl, optionally substituted C 3-12 cycloalkyl, optionally substituted 3- to 14-membered heterocyclo, optionally substituted 5- to 14-membered heteroaryl, and aralkyl;
R 12 is selected from the group consisting of optionally substituted C 1-6 alkyl, optionally substituted C 6-14 aryl, optionally substituted C 3-12 cycloalkyl, optionally substituted 3- to 14-membered heterocyclo, optionally substituted 5- to 14-membered heteroaryl, and aralkyl;
R 13 is selected from the group consisting of optionally substituted C 1-6 alkyl, optionally substituted C 6-14 aryl, optionally substituted C 3-12 cycloalkyl, optionally substituted 3- to 14-membered heterocyclo, optionally substituted 5- to 14-membered heteroaryl, and aralkyl;
R 14a and R 14b are each independently selected from the group consisting of hydrogen, optionally substituted C 1-6 alkyl, optionally substituted C 6-14 aryl, optionally substituted C 3-12 cycloalkyl, 3- to 14-membered heterocyclo, optionally substituted 5- to 14-membered heteroaryl, and aralkyl; or
R 14a and R 14b taken together with the nitrogen atom to which they are attached form an optionally substituted 4- to 8-membered heterocyclo;

is a fused thienyl or fused phenyl group, wherein the fused phenyl group is additionally substituted with R 15 ;
R 15 is selected from the group consisting of hydrogen, halogen, C 1-4 alkyl, and alkoxy;
B is selected from the group consisting of:

L is -L -E-L 2 -X—, wherein L 1 is attached to W;
L 1 is selected from the group consisting of alkylenyl and heteroalkylenyl;
E is —C(═O)—O—;
L 2 is selected from the group consisting of alkylenyl and heteroalkylenyl; or
L 2 is absent;
W is selected from the group consisting of phenylenyl, 5-membered heteroarylenyl, 6-membered heteroarylenyl, heterocyclenyl, and cycloalkylenyl;
X is selected from the group consisting of —C≡C—, —CH 2 —, —O—, —N(R 2c )—, —C(═O)N(R 2d )—, —N(R 2e )C(═O)CH 2 O—, —N(R 2f )C(═O)CH 2 N(R 2g )—,

or
X is absent;
wherein the carboxamide nitrogen atom of —N(R 2e )C(═O)CH 2 O—and —N(R 2f )C(═O)CH 2 N(R 2g )—, the carbon atom of —C(═O)N(R 2d )—, and the piperidine nitrogen atom of

is attached to L 2 ;
with the proviso that when L 2 is absent, X is selected from the group consisting of —C≡C—, —CH 2 —, and —O—;
R 2c , R 2d , R 2e , R 2f , and R 2g are each independently selected from the group consisting of hydrogen and C 1-4 alkyl;
Z is selected from the group consisting of —CH 2 and —C(═O)—;
R 5 is selected from the group consisting of hydrogen, methyl, and fluoro;
A 1 is selected from the group consisting of —C(R 16a )═ and —N═;
A 2 is selected from the group consisting of —C(R 16b )═ and —N═;
A 3 is selected from the group consisting of —C(R 16c )═ and —N═;
R 16a is selected from the group consisting of hydrogen, halo, and C 1-4 alkyl;
R 16b is selected from the group consisting of hydrogen, halo, and C 1-4 alkyl;
R 16c is selected from the group consisting of hydrogen, halo, and C 1-4 alkyl;
R 18 is

Assignees

• Univ Michigan Regents

Inventors

• Wang Shaomeng
• Xiang Weiguo
• Xu Fuming
• Bai Longchuan
• Fernandez-Salas Ester
• Mceachern Donna

Classifications

• A61P35/00

  Antineoplastic agents · CPC title

• C07D495/14

  Ortho-condensed systems · CPC title

• C07D498/14 Primary

  Ortho-condensed systems · CPC title