US 11,932,625 B2
Inhibitors of cyclin-dependent kinase 12 (CDK12) and uses thereof
Nathanael S. Gray, Stanford, CA (US); Tinghu Zhang, Brookline, MA (US); Baishan Jiang, 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 Mar. 7, 2022, as Appl. No. 17/688,822.
Application 17/688,822 is a continuation of application No. 16/462,892, granted, now 11,306,070, previously published as PCT/US2017/063132, filed on Nov. 22, 2017.
Claims priority of provisional application 62/425,519, filed on Nov. 22, 2016.
Prior Publication US 2022/0213067 A1, Jul. 7, 2022
Prior Publication US 2023/0227433 A9, Jul. 20, 2023
Int. Cl. C07D 403/04 (2006.01); C07D 401/14 (2006.01)
CPC C07D 403/04 (2013.01) [C07D 401/14 (2013.01)] 30 Claims
 
1. A compound of Formula (I′):

OG Complex Work Unit Chemistry
or a pharmaceutically acceptable salt, solvate, hydrate, tautomer, or stereoisomer thereof, wherein:
Ring A is an optionally substituted indole ring;
Z is —CH— and R4 is —O—; or Z is —N— and R4 is —C(═O)— or a bond;
R1b is independently selected from hydrogen, 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, —ORB1a, —N(RB1b)2, and SRB1a, RB1a is selected from 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, an oxygen protecting group when attached to an oxygen atom, and a sulfur protecting group when attached to a sulfur atom,
wherein each occurrence of RB1b 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, optionally substituted heteroaryl, and a nitrogen protecting group, or optionally two instances of RB1b are taken together with their intervening atoms to form a substituted or unsubstituted heterocyclic or substituted or unsubstituted heteroaryl ring;
R2 is —N(R6);
each instance of R3, if present, is independently selected from 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, —ORCl,) —N(RC1a)2, and —SRCl, wherein each occurrence of RC1 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, optionally substituted heteroaryl, an oxygen protecting group when attached to an oxygen atom, and a sulfur protecting group when attached to a sulfur atom;
wherein each occurrence of RC1a 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, optionally substituted heteroaryl, and a nitrogen protecting group, or optionally two instances of RC1a are taken together with their intervening atoms to form a substituted or unsubstituted heterocyclic or substituted or unsubstituted heteroaryl ring; or
two R3 groups bound to the same ring carbon atom are taken together to form ═O, or
two R3 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;
each R6 is independently selected from hydrogen and —C1-C6 alkyl;
R7 is a warhead of formula:

OG Complex Work Unit Chemistry
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—, —NRL3aC(═O)—, —C(═O)NRL3a—, —SC(═O)—, —C(═O)S—, —OC(═O)—, —C(═O)O—, —NRL3aC(═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)2—, —OS(═O)2—, —S(═O)2NRL3a—, or NRL3aS(═O)2, wherein each instance of RL3a is independently 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;
each instance 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, or —SREE, wherein each instance 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;
each instance of Y is independently O, S, or NRE7, wherein each instance of RE7 is independently hydrogen, substituted or unsubstituted C1-6 alkyl, or a nitrogen protecting group;
a is 1 or 2;
and
W is —N═;
each instance of R8, if present, is independently selected from hydrogen, 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, —ORD1, —N(RD1a)2, and —SRD1, wherein each occurrence of RD1 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, optionally substituted heteroaryl, an oxygen protecting group when attached to an oxygen atom, and a sulfur protecting group when attached to a sulfur atom,
wherein each occurrence of RD1a 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, optionally substituted heteroaryl, and a nitrogen protecting group, or optionally two instances of RD1a are taken together with their intervening atoms to form a substituted or unsubstituted heterocyclic or substituted or unsubstituted heteroaryl ring; or
two R8 groups are joined to form an optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, or optionally substituted heteroaryl ring;
m is 0, 1, 2, or 3; and
n is 0, 1, 2, 3, 4, 5 or 6.