Inhibitors of cyclin-dependent kinase 7 (CDK7)

Patent metadata

Field	Value
Publication number	US-10865206-B2
Application number	US-201916412726-A
Country	US
Kind code	B2
Filing date	May 15, 2019
Priority date	Oct 16, 2014
Publication date	Dec 15, 2020
Grant date	Dec 15, 2020

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 cyclin-dependent kinase (e.g., CDK7), and therefore induce cellular apoptosis and/or inhibit transcription in the subject.

First claim

What is claimed is:

1. A pharmaceutical composition comprising a pharmaceutically acceptable excipient and a therapeutically effective amount of a compound having the structural formula I:

or a pharmaceutically acceptable salt, isotopically labeled derivative, or stereoisomer thereof, wherein
ring A is an optionally substituted heteroaryl ring of Formula (i-1), (i-2), (i-3), (i-4), (i-5) or (i-6):

wherein
each instance of V 1 , V 2 , V 3 , V 4 , V 5 , V 6 , V 7 , V 8 , V 9 , V 10 , V 11 , V 12 , V 13 , V 14 and V 15 is, independently, O, S, N, N(R A1 ), C, or C(R A2 );
each instance of R A1 is, independently, hydrogen, deuterium, optionally substituted acyl, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, or optionally substituted heteroaryl;
each instance of R A2 is, independently, 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 , or —SR A2a , wherein each occurrence of R A2a is, independently, hydrogen, optionally substituted acyl, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, or optionally substituted heteroaryl, or
any two R A1 , any two R A2 , or one R A1 and one R A2 are joined to form an optionally substituted carbocyclic, optionally substituted heterocyclic, optionally substituted aryl, or optionally substituted heteroaryl ring;
each X is, independently, N or CH, wherein at least one X is N;
W is N or C(R 1a );
each of R 1a , if present, and R 1b is, independently, 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 , or —SR B1a , wherein each occurrence of R B1a is, independently, hydrogen, optionally substituted acyl, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, or optionally substituted heteroaryl, or
R 1a and R 1b are joined to form an optionally substituted carbocyclic, optionally substituted heterocyclic, optionally substituted aryl, or optionally substituted heteroaryl ring;
R 2 is an optionally substituted C 1 -C 4 alkylene or an optionally substituted C 2 -C 4 alkenylene or alkynylene, wherein one or more methylene units of the alkylene, alkenylene or alkynylene are optionally and independently replaced with —O—, —S—, or —N(R 7 )—;
R 3 is a bond, an optionally substituted C 1 -C 4 alkylene, or an optionally substituted C 2 -C 4 alkenylene or alkynylene, wherein one or more methylene units of the alkylene, alkenylene or alkynylene is optionally and independently replaced with —O—, —S—, —N(R 7 )—, or —S(O) 2 —;
R 4 is —NH 2 , —NH—C(O)—(CH 2 ) 3 —N(CH 3 ) 2 , —NH—C(O)—CH 2 —CH(OH)—CH 2 —N(CH 3 ) 2 , —NH—CH 3 , or —NH—C(O)—C(O)—NH 2 ;
p is 0, 1, 2 or 3,

wherein the compound is other than

or a pharmaceutically acceptable salt, isotopically labeled derivative or stereoisomer thereof.

2. The pharmaceutical composition of claim 1 , wherein, within the compound or the pharmaceutically acceptable salt, isotopically labeled derivative, or stereoisomer thereof, ring A is a heteroaryl ring of Formula (i-1), (i-2), (i-3), (i-4), (i-5) or (i-6) optionally substituted with methyl;
each instance of R A1 is, independently, hydrogen, deuterium, unsubstituted acyl, unsubstituted alkyl, unsubstituted alkenyl, unsubstituted alkynyl, unsubstituted carbocyclyl, unsubstituted heterocyclyl, unsubstituted aryl, or unsubstituted heteroaryl;
each instance of R A2 is, independently, hydrogen, deuterium, halogen, —CN, unsubstituted acyl, unsubstituted alkyl, unsubstituted alkenyl, unsubstituted alkynyl, unsubstituted carbocyclyl, unsubstituted heterocyclyl, unsubstituted aryl, unsubstituted heteroaryl, —OR A2a , —N(R A2a ) 2 , or —SR A2a , wherein each occurrence of R A2a is, independently, hydrogen, unsubstituted acyl, unsubstituted alkyl, unsubstituted alkenyl, unsubstituted alkynyl, unsubstituted carbocyclyl, unsubstituted heterocyclyl, unsubstituted aryl, or unsubstituted heteroaryl, or
any two R A1 , any two R A2 , or one R A1 and one R A2 are joined to form an unsubstituted carbocyclic, unsubstituted heterocyclic, unsubstituted aryl, or unsubstituted heteroaryl ring;
each X is, independently, N or CH, wherein at least one X is N;
W is N or C(R 1a );
each of R 1a , if present, and R 1b is, independently, hydrogen, deuterium, halogen, unsubstituted acyl, unsubstituted alkyl, unsubstituted alkenyl, unsubstituted alkynyl, unsubstituted carbocyclyl, unsubstituted heterocyclyl, unsubstituted aryl, unsubstituted heteroaryl, —CN, —OR B1a , —N(R B1a ) 2 , or —SR B1a , wherein each occurrence of R B1a is, independently, hydrogen, unsubstituted acyl, unsubstituted alkyl, unsubstituted alkenyl, unsubstituted alkynyl, unsubstituted carbocyclyl, unsubstituted heterocyclyl, unsubstituted aryl, or unsubstituted heteroaryl, or
R 1a and R 1b are joined to form an unsubstituted carbocyclic, unsubstituted heterocyclic, unsubstituted aryl, or unsubstituted heteroaryl ring;
R 2 is an unsubstituted C 1 -C 4 alkylene or an unsubstituted C 2 -C 4 alkenylene or alkynylene, wherein one or more methylene units of the alkylene, alkenylene or alkynylene are optionally and independently replaced with —O—, —S—, or —N(R 7 )—;
R 3 is a bond, a C 1 -C 4 alkylene optionally substituted with ═O or ═S, or an unsubstituted C 2 -C 4 alkenylene or alkynylene, wherein one or more methylene units of the alkylene, alkenylene or alkynylene is optionally and independently replaced with —O—, —S—, —N(R 7 )—, or —S(O) 2 —;
R 4 is —NH 2 , —NH—C(O)—(CH 2 ) 3 —N(CH 3 ) 2 , —NH—C(O)—CH 2 —CH(OH)—CH 2 —N(CH 3 ) 2 , —NH—CH 3 , or —NH—C(O)—C(O)—NH 2 ;
each R 5 , if present, is, independently, deuterium, halogen, unsubstituted acyl, unsubstituted alkyl, unsubstituted alkenyl, unsubstituted alkynyl, unsubstituted carbocyclyl, unsubstituted heterocyclyl, unsubstituted aryl, unsubstituted heteroaryl, —OR D1 , —N(R D1 ) 2 , or —SR D1 , wherein each occurrence of R D1 is, independently, hydrogen, unsubstituted acyl, unsubstituted alkyl, unsubstituted alkenyl, unsubstituted alkynyl, unsubstituted carbocyclyl, unsubstituted heterocyclyl, unsubstituted aryl, or unsubstituted heteroaryl;
each R 6 , if present, is, independently, deuterium, halogen, unsubstituted acyl, unsubstituted alkyl, unsubstituted alkenyl, unsubstituted alkynyl, unsubstituted carbocyclyl, unsubstituted heterocyclyl, unsubstituted aryl, unsubstituted heteroaryl, ═O, —CN, —OR C1 , —N(R C1 ) 2 , or —SR C1 , wherein each occurrence of R C1 is, independently, hydrogen, unsubstituted acyl, unsubstituted alkyl, unsubstituted alkenyl, unsubstituted alkynyl, unsubstituted carbocyclyl, unsubstituted heterocyclyl, unsubstituted aryl, unsubsti

Assignees

• Syros Pharmaceuticals Inc

Inventors

• Ciblat Stephane
• Kabro Anzhelika
• Leblanc Melissa
• Leger Serge
• Marineau Jason J
• Miller Tom
• Roy Stephanie
• Schmidt Darby
• Siddiqui M Arshad
• Sprott Kevin
• Winter Dana K
• Ripka Amy
• Li Dansu
• Zhang Guoli

Classifications

• C07D401/04

  directly linked by a ring-member-to-ring-member bond · CPC title

• C07D403/04

  directly linked by a ring-member-to-ring-member bond · CPC title

• A61P29/00

  Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID] · CPC title

• A61P35/04

  specific for metastasis · CPC title

• C07D401/14

  containing three or more hetero rings · CPC title