Heteroaromatic compounds useful for the treatment of proliferative diseases

Patent metadata

Field	Value
Publication number	US-11040957-B2
Application number	US-201816210264-A
Country	US
Kind code	B2
Filing date	Dec 5, 2018
Priority date	Oct 18, 2013
Publication date	Jun 22, 2021
Grant date	Jun 22, 2021

Abstract

The present invention provides novel compounds of Formula (I), and pharmaceutically acceptable salts, solvates, hydrates, tautomers, stereoisomers, isotopically labeled derivatives, and compositions thereof. Also provided are methods and kits involving the compounds or compositions for treating or preventing proliferative diseases (e.g., cancers (e.g., leukemia, melanoma, multiple myeloma), benign neoplasms, angiogenesis, inflammatory diseases, autoinflammatory diseases, and autoimmune diseases) in a subject. Treatment of a subject with a proliferative disease using a compound or composition of the invention may inhibit the aberrant activity of a kinase, such as a cyclin-dependent kinase (CDK) (e.g., cyclin-dependent kinase 7 (CDK7)), and therefore, induce cellular apoptosis and/or inhibit transcription in the subject.

First claim

What is claimed is:

1. A compound having the structural formula I:

or a pharmaceutically acceptable salt, solvate, tautomer, or stereoisomer thereof, wherein:
ring A is of Formula:

wherein:
R A1 is selected from hydrogen, deuterium, optionally substituted acyl, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, and optionally substituted heteroaryl;
each instance of R A2 is independently selected from hydrogen, deuterium, halogen, —CN, optionally substituted acyl, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, optionally substituted heteroaryl, —OR A2a , —N(R A2a ) 2 , and —SR A2a , wherein each occurrence of R A2a is independently selected from hydrogen, optionally substituted acyl, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, and optionally substituted heteroaryl;
each X is independently selected from N and CH, wherein at least one X is N;
W is C(R 1a );
R 1a , if present, is selected from hydrogen, deuterium, halogen, optionally substituted acyl, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, optionally substituted heteroaryl, —CN, —OR B1a , —N(R B1a ) 2 , and —SR B1a , wherein each occurrence of R B1a is independently selected from hydrogen, optionally substituted acyl, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, and optionally substituted heteroaryl;
R 1b is selected from hydrogen, deuterium, and halogen;
R 2 is an optionally substituted C 1 -C 4 alkylene, an optionally substituted C 2 -C 4 alkenylene, or an optionally substituted C 2 -C 4 alkynylene, wherein one or more methylene units of the alkylene, alkenylene, or alkynylene are optionally and independently replaced with —O—, —S—, or —N(R 6 )—;
R 4 is selected from a bond, an optionally substituted C 1 -C 4 alkylene, an optionally substituted C 2 -C 4 alkenylene, and an optionally substituted C 2 -C 4 alkynylene, wherein:
one or more methylene units of the alkylene, alkenylene, or alkynylene other than a methylene unit bound to a nitrogen atom is optionally and independently replaced with —O—, —S—, —N(R 6 )—, or —S(═O) 2 —, and
two substituents on either the same or adjacent carbon atoms in the alkylene, alkenylene, or alkynylene are optionally taken together to form an optionally substituted carbocyclic or optionally substituted heterocyclic ring;
each R 6 is independently selected from hydrogen and —C 1 -C 6 alkyl;
R 7 is of Formula (ii-1):

wherein:
L 3 is a bond, an optionally substituted C 1 -C 4 alkylene, an optionally substituted C 2 -C 4 alkenylene, or an optionally substituted C 2 -C 4 alkynylene, wherein one or more methylene units of the alkylene, alkenylene, or alkynylene are optionally and independently replaced with —O—, —S—, or —N(R 6 )—;
R E1 is selected from the group consisting of hydrogen, halogen, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, optionally substituted heteroaryl, —CN, —CH 2 OR E1a , —CH 2 N(R E1a ) 2 , —CH 2 SR E1a , —OR E1a , —N(R E1a ) 2 , —Si(R E1a ) 3 , and —SR E1a , wherein each occurrence of R E1a is independently selected from the group consisting of hydrogen, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, and optionally substituted heteroaryl, or two R E1a groups are joined to form an optionally substituted heterocyclic ring;
R E2 is selected from the group consisting of hydrogen, halogen, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, optionally substituted heteroaryl, —CN, —CH 2 OR E2a , —CH 2 N(R E2a ) 2 , —CH 2 SR E2a , —OR E2a , —N(R E2a ) 2 , and —SR E2a , wherein each occurrence of R E2a is independently selected from the group consisting of hydrogen, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, and optionally substituted heteroaryl, or two R E2a groups are joined to form an optionally substituted heterocyclic ring;
R E3 is selected from the group consisting of hydrogen, halogen, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, optionally substituted heteroaryl, —CN, —CH 2 OR E3a , —CH 2 N(R E3a ) 2 , —CH 2 SR E3a , —OR E3a , —N(R E3a ) 2 , and —SR E3a , wherein each occurrence of R E3a is independently selected from the group consisting of hydrogen, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, and optionally substituted heteroaryl, or two R E3a groups are joined to form an optionally substituted heterocyclic ring;
optionally R E1 and R E3 , or R E2 and R E3 , or R E1 and R E2 are joined to form an optionally substituted carbocyclic or optionally substituted heterocyclic ring;
Y is O;
each instance of R 8 , if present, is independently selected from deuterium, halogen, optionally substituted acyl, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, optionally substituted heteroaryl, —OR D1 , —N(R D1 ) 2 , and —SR D1 , wherein each occurrence of R D1 is independently selected from hydrogen, optionally substituted acyl, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, and optionally substituted heteroaryl, or
two R 8 groups are joined to form an optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, or optionally substituted heteroaryl ring;
m is 0, 1, 2, 3 or 4; and
n is 0.

2. The compound of claim 1 , or the pharmaceutically acceptable salt, tautomer, stereoisomer, or solvate thereof, wherein ring A is

3. The compound of claim 1 , or the pharmaceutically acceptable sal

Assignees

• Syros Pharmaceuticals Inc
• Dana Farber Cancer Inst Inc

Inventors

• Ciblat Stephane
• Deroy Patrick
• Gray Nathanael
• Leblanc Melissa
• Marineau Jason J
• Moore Joel
• Sprott Kevin
• Zhang Tinghu
• Siddiqui M Arshad
• Kabro Anzhelika
• Leger Serge
• Roy Stephanie
• Schmidt Darby
• Winter Dana K
• Bradley Michael
• Miller Tom

Classifications

• A61K45/06

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

• A61P35/02

  specific for leukemia · CPC title

• A61K31/506

  not condensed and containing further heterocyclic rings · CPC title

• C07D401/14 Primary

  containing three or more hetero rings · CPC title