Fused 1,4-oxazepines as BET protein degraders

Patent metadata

Field	Value
Publication number	US-11466028-B2
Application number	US-201716332533-A
Country	US
Kind code	B2
Filing date	Sep 13, 2017
Priority date	Sep 13, 2016
Publication date	Oct 11, 2022
Grant date	Oct 11, 2022

Abstract

The present disclosure provides compounds represented by Formula I and the pharmaceutically acceptable salts, hydrates, and solvates thereof, wherein R1, R2a, R2b, R3a, R3b, R4, Ar, L, X, Y, and B are as defined as set forth in the specification. The present disclosure also provides compounds of Formula I for use to treat a condition or disorder responsive to 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 each independently selected from the group consisting of hydrogen, optionally substituted C 1-4 alkyl, and (alkoxycarbonyl)alkyl, or
R 2a and R 2b together with the carbon atom to which they are attached form a 3- to 6-membered cycloalkyl;
R 3a and R 3b are each independently selected from the group consisting of hydrogen and optionally substituted C 1-4 alkyl; or
R 3a and R 3b together with the carbon atom to which they are attached form an optionally substituted 3- to 6-membered cycloalkyl;
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, alkylsulfonyl, arylsulfonyl, 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 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, optionally substituted 5- to 14-membered heteroaryl, and amino;
R 9 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;
Y is selected from the group consisting of —O—, —S—, and —NR 10 —;
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 selected from the group consisting of alkylenyl, heteroalkylenyl, -A-(CH 2 ) m —W—(CH 2 ) n —, —(CH 2 ) m —W—(CH 2 ) u —O—(CH 2 ) v —, and —(CH 2 ) m —W—[(CH 2 ) w —O] x —(CH 2 ) v —; or
L is absent;
A is selected from the group consisting of 5-membered heteroarylenyl and 6-membered heteroarylenyl; or
A is absent;
W is selected from the group consisting of phenylenyl, 5-membered heteroarylenyl, 6-membered heteroarylenyl, heterocyclenyl, and cycloalkylenyl;
m is 0, 1, 2, 3, 4, 5, 6, or 7;
n is 0, 1, 2, 3, 4, 5, 6, 7, or 8;
u is 0, 1, 2, or 3;
v is 1, 2, 3, or 4;
each w is independently 2, 3, or 4;
x is 2, 3, or 4;
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—, and —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 )—, and the carbon atom of —C(═O)N(R 2d )— is attached to L;
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; and
R 16c is selected from the group consisting of hydrogen, halo, and C 1-4 alkyl.

2. The compound of claim 1 having Formula V:

Assignees

• Univ Michigan Regents

Inventors

• Wang Shaomeng
• Hu Yang
• Qin Chong
• Xu Fuming
• Hu Jiantao
• Zhou Bing
• Chen Zhuo
• Fernandez-Salas Ester
• Bai Longchuan
• Mceachern Donna

Classifications

• A61P35/02

  specific for leukemia · CPC title

• A61P35/00

  Antineoplastic agents · CPC title

• C07D498/14 Primary

  Ortho-condensed systems · CPC title

• A61P37/00

  Drugs for immunological or allergic disorders · CPC title

• A61P35/04

  specific for metastasis · CPC title