Inhibitors of cyclin-dependent kinase 7 (CDK7)

Patent metadata

Field	Value
Publication number	US-10308648-B2
Application number	US-201515519484-A
Country	US
Kind code	B2
Filing date	Oct 15, 2015
Priority date	Oct 16, 2014
Publication date	Jun 4, 2019
Grant date	Jun 4, 2019

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 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 the group consisting of 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 the group consisting of 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 the group consisting of 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 the group consisting of N and CH, wherein at least one X is N;
W is selected from the group consisting of N and C(R 1a );
each of R 1a , if present, and R 1b is independently selected from the group consisting of 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 7 )—;
R 3 is selected from the group consisting of 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 7 )—, or —S(O) 2 —;
R 4 is selected from the group consisting of —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 , and —NH—C(O)—C(O)—NH 2 ;
each R 5 , if present, is independently selected from the group consisting of 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, and optionally substituted aryl, optionally substituted heteroaryl;
each R 6 , if present, is independently selected from the group consisting of 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, ═O, CN, OR C1 , —N(R C1 ) 2 , and —SR C1 , wherein each occurrence of R C1 is independently selected from the group consisting of hydrogen, optionally substituted acyl, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, optionally substituted heteroaryl, a nitrogen protecting group when attached to a nitrogen atom, an oxygen protecting group when attached to an oxygen atom, and a sulfur protecting group when attached to a sulfur atom, or two R C1 groups are joined to form an optionally substituted heterocyclic ring; or
two R 6 are taken together to form a first 5-7 membered optionally substituted, heterocyclyl or carbocyclyl ring fused to the ring to which the R 6 are bound; wherein two substituents on the substituted heterocyclyl or carbocyclyl ring, or one substituent on the substituted heterocyclyl or carbocyclyl ring and a third R 6 may be taken together with the atoms to which they are bound to form a second optionally substituted, heterocyclyl or carbocyclyl ring fused to the ring to the first optionally substituted, heterocyclyl or carbocyclyl ring and/or the ring to which the third R 6 is bound;
each R 7 is independently selected from the group consisting of hydrogen and optionally substituted —C 1 -C 6 alkyl;
n is 0, 1, 2, 3, 4, 5 or 6; and
p is 0, 1, 2 or 3,

wherein the compound is other than

and stereoisomers and enantiomers thereof.

2. The compound of claim 1 , wherein ring A is selected from the group consisting of:

3. The compound of claim 2 , wherein, ring A is selected from the group consisting of:

4. The compound of claim 1 , wherein each X is N.

5. The compound of claim 1 , wherein W is C(R 1a ).

6. The compound of claim 5 , wherein R 1a is selected from the group consisting of hydrogen, halo, —OH, —C 1 -C 3 alkyl, halo-substituted —C 1 -C 3 alkyl, —O—C 1 -C 3 alkyl, halo-substituted —O—C 1 -C 3 alkyl, —CN, —NH 2 , —NH(C 1 -C 3 alkyl), —N(C 1 -C 3 alkyl) 2 , and C 3 -C 6 cycloalkyl.

7. The compound of claim 6 , wherein R 1a is selected from the group consisting of hydrogen, chloro, fluoro, —CN, —CF 3 , and cyclopropyl.

8. The compound of claim 1 , wherein R 1b is hydrogen.

9. The compound of claim 1 , wherein R 2 is selected from the group consisting of —NH—; —N(C 1 -C 3 alkyl)-; —NH—CH 2 -*; and C 1 -C 2 alkylene optionally substituted w

Assignees

• Syros Pharmaceuticals Inc

Inventors

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

Classifications

• A61P37/00

  Drugs for immunological or allergic disorders · CPC title

• A61P35/04

  specific for metastasis · CPC title

• A61P35/00

  Antineoplastic agents · CPC title

• A61P31/00

  Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics · CPC title

• A61P29/00

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