Polycyclic inhibitors of cyclin-dependent kinase 7 (CDK7)

Patent metadata

Field	Value
Publication number	US-10906889-B2
Application number	US-201816051896-A
Country	US
Kind code	B2
Filing date	Aug 1, 2018
Priority date	Oct 18, 2013
Publication date	Feb 2, 2021
Grant date	Feb 2, 2021

Abstract

The present invention provides novel compounds of Formula (I), and pharmaceutically acceptable salts, solvates, hydrates, polymorphs, co-crystals, tautomers, stereoisomers, isotopically labeled derivatives, prodrugs, and compositions thereof. Also provided are methods and kits involving the inventive compounds or compositions for treating or preventing proliferative diseases (e.g., cancers (e.g., leukemia, lymphoma, melanoma, multiple myeloma, breast cancer, Ewing's sarcoma, osteosarcoma, brain cancer, neuroblastoma, lung cancer), 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), cyclin-dependent kinase 12 (CDK12), or cyclin-dependent kinase 13 (CDK13)), and therefore, induce cellular apoptosis and/or inhibit transcription in the subject.

First claim

What is claimed is:

1. A method of treating a proliferative disease in a subject in need thereof, the method comprising administering to the subject a therapeutically effective amount of a pharmaceutical composition comprising a compound having Formula (Ia):

or a pharmaceutically acceptable salt thereof, wherein:
the proliferative disease is leukemia, breast cancer, or bone cancer;
Ring A is selected from the group consisting of

wherein Ring A may be substituted with a substituent selected from the group consisting of halogen, optionally substituted C 1 -C 3 alkyl, optionally substituted C 3 -C 10 carbocyclyl, optionally substituted 3- to 10-membered heterocyclyl, optionally substituted C 6 , C 10 , or C 14 aryl, and optionally substituted 5- to 10-membered monocyclic or bicyclic heteroaryl;
W B is CR B2 , wherein R B2 is selected from the group consisting of halogen, substituted or unsubstituted C 3 -C 10 carbocyclyl, unsubstituted C 1-6 alkyl, C 1-6 alkyl substituted with one or more halogen, and —CN;
R B1 is hydrogen or halogen;
L 1 is —N(R L1 )—, wherein R L1 is hydrogen or unsubstituted C 1-6 alkyl;
each instance of R C is independently selected from the group consisting of halogen, —OR C1 , and substituted or unsubstituted C 1-6 alkyl, wherein each instance of R C1 is independently hydrogen or substituted or unsubstituted C 1-6 alkyl, or two R C are taken together to form an optionally substituted 3- to 10-membered heterocyclyl or C 3 -C 8 carbocyclyl fused to the ring to which the RC are bound;
L 2 is selected from the group consisting of —N(R L2 )C(═O)—, —C(═O)N(R L2 )—, —N(R L2 )—(C 1-2 alkylene)-, —N(R L2 )—, —NH—S(O) 2 —, and —S(O) 2 —NH—, wherein each instance of R L2 is independently hydrogen, or substituted or unsubstituted C 1-6 alkyl;
each instance of R D is independently halogen or optionally substituted C 1 -C 4 alkyl;
R E is selected from:

R E1 is selected from the group consisting of hydrogen, halogen, optionally substituted C 1-6 alkyl, optionally substituted C 2-6 alkenyl, optionally substituted C 2-6 alkynyl, optionally substituted C 3 -C 10 carbocyclyl, optionally substituted 3- to 10-membered heterocyclyl, optionally substituted C 6 , C 10 , or C 14 aryl, optionally substituted 3- to 10-membered 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 C 1-6 alkyl, optionally substituted C 2-6 alkenyl, optionally substituted C 2-6 alkynyl, optionally substituted C 3 -C 10 carbocyclyl, optionally substituted 3- to 10-membered heterocyclyl, optionally substituted C 6 , C 10 , or C 14 aryl, and optionally substituted 3- to 10-membered heteroaryl, or two R E1a groups are joined to form an optionally substituted 3- to 10-membered heterocyclic ring;
R E2 is selected from the group consisting of hydrogen, halogen, optionally substituted C 1-6 alkyl, optionally substituted C 2-6 alkenyl, optionally substituted C 2-6 alkynyl, optionally substituted C 3 -C 10 carbocyclyl, optionally substituted 3- to 10-membered heterocyclyl, optionally substituted C 6 , C 10 , or C 14 aryl, optionally substituted 3- to 10-membered 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 C 1-6 alkyl, optionally substituted C 2-6 alkenyl, optionally substituted C 2-6 alkynyl, optionally substituted C 3 -C 10 carbocyclyl, optionally substituted 3- to 10-membered heterocyclyl, optionally substituted C 6 , C 10 , or C 14 aryl, and optionally substituted 3- to 10-membered heteroaryl, or two R E2 a groups are joined to form an optionally substituted 3- to 10-membered heterocyclic ring;
R E3 is selected from the group consisting of hydrogen, halogen, optionally substituted C 1-6 alkyl, optionally substituted C 2-6 alkenyl, optionally substituted C 2-6 alkynyl, optionally substituted C 3 -C 10 carbocyclyl, optionally substituted 3- to 10-membered heterocyclyl, optionally substituted C 6 , C 10 , or C 14 aryl, optionally substituted 3- to 10-membered 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 C 1-6 alkyl, optionally substituted C 2-6 alkenyl, optionally substituted C 2-6 alkynyl, optionally substituted C 3 -C 10 carbocyclyl, optionally substituted 3- to 10-membered heterocyclyl, optionally substituted C 6 , C 10 , or C 14 aryl, and optionally substituted 3- to 10-membered heteroaryl, or two R E3a groups are joined to form an optionally substituted 3- to 10-membered 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 C 3 -C 10 carbocyclic or optionally substituted 3- to 10-membered heterocyclic ring;
n is 0, 1, or 2; and
p is 0 or 1.

2. The method of claim 1 , wherein R B2 is chloro, cyclopropyl, or —CN.

3. The method of claim 1 , wherein L 1 is —NH—.

4. The method of claim 1 , wherein each instance of R C is independently fluoro, —OH, or methyl, or Ring C and all instances of R C are taken together to form a ring:

wherein “2” represents a portion of the ring bound to L 1 , and “3” represents a portion of the ring bound to L 2 .

5. The method of claim 1 , wherein n is 1.

6. The method of claim 1 , wherein L 2 is —NHC(═O)—, —C(═O)NH—, —NH—(C 1-2 alkylene)-, or —NH—.

7. The method of claim 1 , wherein p is 0.

8. The method of claim 1 , wherein R E is selected from:

9. The method of claim 1 , wherein ring A is

10. The method of claim 1 , wherein ring C is

wherein “2” represents a portion of ring C bound to L 1 , and “3” represents a portion of ring C bound to L 2 .

11. The method of claim 1 , wherein L 2 is *—NH—C(O)—, “*” represents a point of attachment to ring C, and L 1 and L 2 are positioned 1,3 relative to one another on ring C.

12. The method of claim 1 , wherein R E is

13. The method of claim 1 , wherein the compound is

14. The method of claim 1 , wherein the compound is

15. The method of claim 1 , wherein the compound is

16.

Assignees

• Dana Farber Cancer Inst Inc

Inventors

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

Classifications

• A61P37/06

  Immunosuppressants, e.g. drugs for graft rejection · CPC title

• C07D471/04

  Ortho-condensed systems · CPC title

• A61P43/00

  Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00 · CPC title

• A61P35/02

  specific for leukemia · CPC title

• C07F7/0812

  comprising a heterocyclic ring · CPC title