Degraders of cyclin-dependent kinase 12 (CDK12) and uses thereof

1 . A compound of Formula (I):

or a pharmaceutically acceptable salt, co-crystal, tautomer, stereoisomer, solvate, hydrate, polymorph, isotopically enriched derivative, or prodrug thereof, wherein:

each instance of R 1 is independently halogen, acyl, alkyl, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl, heteroaryl, —CN, —OR D1 , —N(R D1a ) 2 , or —SR D1 , wherein R D1 is hydrogen, acyl, alkyl, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl, or heteroaryl;

wherein each occurrence of R D1a is hydrogen, acyl, alkyl, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl, or heteroaryl; or two instances of R D1a are taken together with their intervening atoms to form a heteroaryl ring;

each instance of R 2 is independently halogen, acyl, alkyl, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl, heteroaryl, —CN, —OR D1 , —N(R D1a ) 2 , or —SR D1 ;

R 3 is hydrogen, acyl, alkyl, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl, or heteroaryl;

Ring A is of formula:

R Y is —SO 2 R Y1 , —P(═O)(R Y2 ) 2 , or —C(═O)N(R y3 )= 2 ;

R Y1 is C 1 -C 6 alkyl;

each instance of R Y2 is C 1 -C 6 alkyl;

each instance of R y3 is independently hydrogen or alkyl;

w1 is 1;

x is 0 or 1;

y is 0 or 1;

L1 is —NR A —; wherein R A is hydrogen;

L2 is an unsubstituted C 1-24 hydrocarbon chain, optionally wherein one or more chain atoms of the hydrocarbon chain are independently replaced with —C(═O)—, —O—, or —NR b —, wherein R b is hydrogen, or

l 4 indicates the point of attachment to D, and l R indicates the point of attachment to the moiety of formula

n1 is 1, 2, 3, 4, 5, or 6;

n2 is 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10;

and

D is of the formula:

wherein:

X A is C(O) or C(R 3A ) 2 ;

R 1A is halogen, —OH, C 1 -C 6 alkyl, or C 1 -C 6 alkoxy;

each R 3A is independently H or C 1 -C 3 alkyl;

R 3 ′ is C 1 -C 3 alkyl;

each R 4A is independently H or C 1 -C 3 alkyl; or two R 4A , together with the carbon atom to which they are attached, form C(O);

R 5A is H, C 1 -C 3 alkyl, or halogen;

m is 0 or 1;

n is 0 or 1; and

a1 is 0 or 1,

or

wherein:

R 2 ′ is halogen, —OH, C 1 -C 6 alkyl, or C 1 -C 6 alkoxy;

R 4 ′ is halogen, —OH, C 1 -C 6 alkyl, or C 1 -C 6 alkoxy;

R 5 ′ is halogen, —OH, C 1 -C 6 alkyl, or C 1 -C 6 alkoxy;

n1 is 0 or 1;

n2 is 0 or 1; and

n3 is 0 or 1.

2 . The compound of claim 1 , wherein the compound is of formula:

or a pharmaceutically acceptable salt, co-crystal, tautomer, stereoisomer, solvate, hydrate, polymorph, isotopically enriched derivative, or prodrug thereof, wherein at least one instance of R Y is —SO 2 R Y1 wherein R Y1 is C 1 -C 6 alkyl, —C(═O)N(R y3 ) 2 wherein each instance of R y3 is independently hydrogen or alkyl, or —P(═O)(R Y2 ) 2 wherein each instance of R Y2 is C 1 -C 6 alkyl.

3 . The compound of claim 1 , or a pharmaceutically acceptable salt, co-crystal, tautomer, stereoisomer, solvate, hydrate, polymorph, isotopically enriched derivative, or prodrug thereof, wherein D is of the formula:

wherein:

X A is C(O) or C(R 3A ) 2 ;

each R 3A is H;

two R 4A , together with the carbon atom to which they are attached, form C(O);

R 5A is H;

m is 0;

n is 0; and

a1 is 1.

4 . The compound of claim 1 , or a pharmaceutically acceptable salt, co-crystal, tautomer, stereoisomer, solvate, hydrate, polymorph, isotopically enriched derivative, or prodrug thereof, wherein D is of the formula:

5 . The compound of claim 1 , or a pharmaceutically acceptable salt, co-crystal, tautomer, stereoisomer, solvate, hydrate, polymorph, isotopically enriched derivative, or prodrug thereof, wherein D is of the formula:

wherein:

R 2 ′ is —OH;

R 5 ′ is C 1 -C 6 alkyl;

n1 is 1;

n2 is 0; and

n3 is 1.

6 . The compound of claim 1 , or a pharmaceutically acceptable salt, co-crystal, tautomer, stereoisomer, solvate, hydrate, polymorph, isotopically enriched derivative, or prodrug thereof, wherein D is of the formula:

7 . The compound of claim 1 , wherein the compound is of formula:

or a pharmaceutically acceptable salt, co-crystal, tautomer, stereoisomer, solvate, hydrate, polymorph, isotopically enriched derivative, or prodrug thereof, wherein at least one instance of R 1 is halogen, optionally substituted C 1-6 alkyl, —CF 3 , or —CN.

8 . The compound of claim 1 , or a pharmaceutically acceptable salt, co-crystal, tautomer, stereoisomer, solvate, hydrate, polymorph, isotopically enriched derivative, or prodrug thereof, wherein L2 is:

l A indicates the point of attachment to D, and/R indicates the point of attachment to the moiety of formula

n1 is 1, 2, 3, 4, 5, or 6;

n2 is 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10;

n3 is 1, 2, 3, 4, 5, or 6; and

g is 1, 2, 3, 4, 5, or 6.

9 . The compound of claim 1 , or a pharmaceutically acceptable salt, co-crystal, tautomer, stereoisomer, solvate, hydrate, polymorph, isotopically enriched derivative, or prodrug thereof, wherein L2 is of the formula:

10 . The compound of claim 1 , wherein the compound is of the formula:

or a pharmaceutically acceptable salt, co-crystal, tautomer, stereoisomer, solvate, hydrate, polymorph, isotopically enriched derivative, or prodrug thereof.

11 . A pharmaceutical composition comprising a compound of claim 1 , or a pharmaceutically acceptable salt, co-crystal, tautomer, stereoisomer, solvate, hydrate, polymorph, isotopically enriched derivative, or prodrug thereof, and optionally a pharmaceutically acceptable excipient,

wherein R 3A is H when D is of formula IA.

12 . A method of inducing the degradation of CDK9 and/or CDK12 in a cell, tissue, or biological sample, the method comprising:

contacting the cell, tissue, or biological sample with a therapeutically effective amount of a compound of claim 1 , or a pharmaceutically acceptable salt, co-crystal, tautomer, stereoisomer, solvate, hydrate, polymorph, isotopically enriched derivative, or prodrug thereof,

wherein R 3A is H when D is of formula IA.