US 12,168,663 B2
Inhibitors of cyclin-dependent kinase 7 (CDK7)
Nathanael S. Gray, Boston, MA (US); Yanke Liang, Belmont, MA (US); Tinghu Zhang, Brookline, MA (US); and Nicholas Paul Kwiatkowski, Brookline, MA (US)
Assigned to Dana-Farber Cancer Institute, Inc., Boston, MA (US)
Filed by Dana-Farber Cancer Institute, Inc., Boston, MA (US)
Filed on Sep. 28, 2020, as Appl. No. 17/034,822.
Application 17/034,822 is a division of application No. 15/538,763, granted, now 10,870,651, previously published as PCT/US2015/000297, filed on Dec. 23, 2015.
Claims priority of provisional application 62/096,040, filed on Dec. 23, 2014.
Prior Publication US 2021/0115051 A1, Apr. 22, 2021
Prior Publication US 2022/0024929 A9, Jan. 27, 2022
Int. Cl. C07D 487/04 (2006.01); A61K 31/4162 (2006.01); A61K 31/454 (2006.01); A61K 45/06 (2006.01); A61P 35/00 (2006.01); C07D 487/10 (2006.01)
CPC C07D 487/04 (2013.01) [A61K 31/4162 (2013.01); A61K 31/454 (2013.01); A61K 45/06 (2013.01); A61P 35/00 (2018.01); C07D 487/10 (2013.01)] 17 Claims
 
1. A method of inhibiting the activity of a cyclin-dependent kinase (CDK) in a biological sample or subject, the method comprising administering to the subject or contacting the biological sample with a therapeutically effective amount of a compound of Formula (I):

OG Complex Work Unit Chemistry
or a pharmaceutically acceptable salt, solvate, hydrate, tautomer, stereoisomer, isotopically labeled derivative, or prodrug thereof, or a pharmaceutical composition comprising a therapeutically effective amount of a compound of Formula (I) and a pharmaceutically acceptable excipient;
wherein:
R1 is —NRaRb, —CHRaRb or —ORa, wherein each of Ra and Rb is independently hydrogen, 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, or an oxygen protecting group when attached to an oxygen atom, or Ra and Rb are joined to form an optionally substituted carbocyclic, optionally substituted heterocyclic, optionally substituted aryl, or optionally substituted heteroaryl ring;
each of R3 and R4 is independently hydrogen, halogen, optionally substituted C1-C6 alkyl, or optionally substituted aryl, or R3 and R4 are joined to form an optionally substituted C3-C6 carbocyclyl ring;
R5 is independently hydrogen, optionally substituted C1-C6 alkyl, or a nitrogen protecting group;
L1 is —NRL1—, —NRL1C(═O)—, —C(═O)NRL1—, —O—, or —S—, wherein RL1 is hydrogen, optionally substituted C1-C6 alkyl, or a nitrogen protecting group;
Ring A is optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, or optionally substituted heteroaryl;
L2 is a bond, —C(═O)—, —NRL2—, —C(═O)NRL2—, —NRL2C(═O)—, —O—, or —S—, wherein RL2 is hydrogen, optionally substituted C1-C6 alkyl, or a nitrogen protection group;
Ring B is absent, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, or optionally substituted heteroaryl; and
R2 is any of Formulae (i-1)-(i-42):

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wherein:
L3 is a bond or an optionally substituted C1-4 hydrocarbon chain, optionally wherein one or more carbon units of the hydrocarbon chain are independently replaced with —C═O—, —O—, —S—, —NRL3a—, —RL3aC(═O)—, —C(═O)NRL3a—, —SC(═O)—, —C(═O)S—, —OC(═O)—, —C(═O)O—, —RL3aC(═S)—, —C(═S)NRL3a—, trans-CRL3b═CRL3b—, cis-CRL3b═CRL3b—, —C≡C—, —S(═O)—, —S(═O)O—, —OS(═O)—, —S(═O)NRL3a —, —NRL3aS(═O)—, —S(═O)2—, —S(═O)2O—, —OS(═O)2—, —S(═O)2NRL3a—, or —NRL3aS(═O)2—, wherein RL3a is hydrogen, substituted or unsubstituted C1-6 alkyl, or a nitrogen protecting group, and wherein each occurrence of RL3b is independently hydrogen, halogen, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, or optionally substituted heteroaryl, or two RL3b groups are joined to form an optionally substituted carbocyclic or optionally substituted heterocyclic ring;
L4 is a bond or an optionally substituted, branched or unbranched C1-6 hydrocarbon chain;
each of RE1, RE2, and RE3 is independently hydrogen, halogen, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, optionally substituted heteroaryl, —CN, —CH2OREE, —CH2N(REE)2, —CH2SREE, —OREE, —N(REE)2, —Si(REE)3, and —SREE, wherein each occurrence of REE is independently hydrogen, optionally substituted alkyl, optionally substituted alkoxy, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, or optionally substituted heteroaryl, or two REE groups are joined to form an optionally substituted heterocyclic ring;
or RE1 and RE3, or RE2 and RE3, or RE1 and RE2 are joined to form an optionally substituted carbocyclic or optionally substituted heterocyclic ring;
RE4 is a leaving group;
RE5 is halogen;
RE6 is hydrogen, substituted or unsubstituted C1-6 alkyl, or a nitrogen protecting group;
each instance of Y is independently O, S, or NRE7, wherein RE7 is hydrogen, substituted or unsubstituted C1-6 alkyl, or a nitrogen protecting group;
a is 1 or 2; and
each instance of z is independently 0, 1, 2, 3, 4, 5, or 6, as valency permits.