Heteromaromatic compounds useful for the treatment of prolferative diseases

Patent metadata

Field	Value
Publication number	US-2016264552-A1
Application number	US-201415030265-A
Country	US
Kind code	A1
Filing date	Oct 17, 2014
Priority date	Oct 18, 2013
Publication date	Sep 15, 2016
Grant date	—

Abstract

The present invention provides novel compounds of Formula (I) and Formula (II), 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. (I)

First claim

1 . A compound having the structural formula I:

or a pharmaceutically acceptable salt, solvate, hydrate, tautomer, or stereoisomer thereof, wherein:
ring A is an optionally substituted heteroaryl ring of any one of the Formulae (i-1)-(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 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, 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 selected from N and CH, wherein at least one X is N;
W is selected from N and C(R 1a );
each of R 1a , if present, and R 1b is independently 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, 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 6 )—;
Q is selected from: R 5 ,

 and a 4-14 membered, divalent, fused or spirofused bicyclic ring system comprising a total of 0 to 4 ring heteroatoms independently selected from N, O and S, and optionally substituted with 1 to 6 independently selected R 3 , wherein:
each ring in the bicyclic ring system is independently selected from heterocyclyl, carbocyclyl, aromatic or heteroaromatic,
one atom in each ring of the bicyclic ring system is attached to the rest of the compound, and
t is 0, 1, 2, 3, or 4;

wherein each represents a portion of Q bound to the rest of the compound; and “*” represents a portion of Q bound to R 2 ;
each instance of R 3 , 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 C1 , —N(R C1 ) 2 , and —SR C1 , wherein each occurrence of R C1 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 3 groups bound to the same ring carbon atom are taken together to form ═O, or
two R 3 groups bound to the same or different ring carbon atoms are joined to form an optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, or optionally substituted heteroaryl ring;
R 4 is selected from a bond, an optionally substituted C 1 -C 4 alkylene, and an optionally substituted C 2 -C 4 alkenylene or 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 taken together to form an optionally substituted carbocyclic or optionally substituted heterocyclic ring;

R 5 is selected from a bond, an optionally substituted C 1 -C 4 alkylene, and 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 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 any one of the Formulae (ii-1)-(ii-20):

wherein:
R 7 and Q are para or meta to each other;
L 3 is a bond, an optionally substituted C 1 -C 7 alkylene, or an optionally substituted C 2 -C 5 alkenylene or alkynylene, wherein one or more methylene units of the alkylene, alkenylene or alkynylene are optionally and independently replaced with —O—, —S—, —S(O)—, —S(O) 2 , or —N(R 6 )—;
L 4 is a bond, an optionally substituted C 1 -C 4 alkylene, or an optionally substituted C 2 -C 4 alkenylene or alkynylene;
each of R E1 , R E2 and R E3 is independently selected from hydrogen, deuterium, halogen, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, optionally substituted heteroaryl, —CH 2 OR 9 , —CH 2 N(R 9 ) 2 , —CH 2 SR 9 , —CN, —OR 9 , —N(R 9 ) 2 , and —SR 9 , wherein each occurrence of R 9 is independently selected from hydrogen, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, and optionally substituted heteroaryl, or
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;
R E4 is a leaving group;
R E5 is selected fro

Assignees

• Syros Pharmaceuticals Inc

Inventors

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

Classifications

• A61P35/02

  specific for leukemia · CPC title

• 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

• A61K31/437

  the heterocyclic ring system containing a five-membered ring having nitrogen as a ring hetero atom, e.g. indolizine, beta-carboline · CPC title

• A61K31/4155

  non condensed and containing further heterocyclic rings · CPC title