Proteolysis targeting chimeric molecules (PROTACs) with functional handles and uses thereof

1. A compound of the formula:

or a salt thereof, wherein:

each instance of R A1 is hydrogen;

a is an integer between 1 and 20, inclusive;

each instance of R B1 is hydrogen;

b is an integer between 1 and 20, inclusive;

each instance of R 1 and R 2 is hydrogen, or two instances of R 1 attached to the same carbon atom are taken together to form oxo, or two instances of R 2 attached to the same carbon atom are taken together to form oxo;

R L is of the formula:

e is 1;

X 1 is —C(═O)OR C or —C(═O)N(R C ) 2 ;

each instance of R C is independently hydrogen or

 wherein each instance of n is independently an integer from 30 to 100, inclusive, and each instance of R F is independently hydrogen or unsubstituted C 1-6 alkyl, provided that at least one instance of R C is

L J is unsubstituted C 1 -C 6 alkylene or unsubstituted C 1 -C 6 heteroalkylene, wherein the C 1 -C 6 heteroalkylene is C 1 -C 6 alkylene that further comprises one oxygen atom inserted between adjacent carbon atoms or placed at one terminal position of the parent chain;

E is triazole, a bond, —O—, —C(═O)NR A —, or —NR A C(═O)—, wherein R A is hydrogen or methyl;

L K is of the formula:

wherein:

q is an integer from 1 to 12, inclusive;

g is 0 or an integer from 1 to 12, inclusive;

s is 0 or 1;

t is 0 or an integer from 1 to 10, inclusive;

-L B -L A - is —C(═O)O— or —OC(═O)O—;

r is 0 or an integer from 1 to 12, inclusive;

“**” is attached to E; and

“***” is attached to V;

V is CH;

each instance of L E is independently of the formula:

wherein:

each instance of A is independently a single bond or —CH 2 —;

each instance of o is independently an integer between 1 and 30, inclusive;

each instance of x is independently an integer between 1 and 30, inclusive;

“**” is attached to V; and

“***” is attached to M A or M B ;

M A is of the formula:

wherein:

A 1 is S;

A 2 is NRa 5 or O;

nn1 is 0, 1, or 2;

each Ra 1 is independently C 1 -C 3 alkyl, (CH 2 ) 0-3 —CN, (CH 2 ) 0-3 -halogen, (CH 2 ) 0-3 —OH, (CH 2 ) 0-3 —C 1 -C 3 alkoxy, C(O)NRa 5 L, OL, NRa 5 L, or L;

Ra 2 is H, C 1 -C 6 alkyl, (CH 2 ) 0-3 -heterocyclyl, (CH 2 ) 0-3 -phenyl, or L, wherein the heterocyclyl comprises one saturated 5- or 6-membered ring and 1-2 heteroatoms selected from N, O, and S and is optionally substituted with C 1 -C 3 alkyl, L, or C(O)L, and wherein the phenyl is optionally substituted with C 1 -C 3 alkyl, CN, halogen, OH, C 1 -C 3 alkoxy, or L;

nn2 is 0, 1, 2, or 3;

each Ra 3 is independently C 1 -C 3 alkyl, (CH 2 ) 0-3 —CN, (CH 2 ) 0-3 -halogen, L, or C(O)NRa 5 L;

Ra 4 is C 1 -C 3 alkyl or hydrogen;

Ra 5 is H or C 1 -C 3 alkyl; and

L is a Linker of Formula L0:

p1 is an integer selected from 0 to 12;

p2 is an integer selected from 0 to 12;

p3 is an integer selected from 1 to 6;

each W is independently absent, CH 2 , O, S, NH, or NR 19 ;

Z 1 is absent, CH 2 C(O)NH, OCH 2 C(O)NH, OCH 2 C(O)NR 1 g, C(O)NH, C(O)NR 19 , NHC(O), NR 19 C(O), CH 2 , O, NH, or NR 19 ;

each R 19 is independently C 1 -C 3 alkyl;

Q is absent or NHC(O)CH 2 ; and

the Linker of Formula L0 is covalently bonded to an instance of L E via the

 next to Q;

provided that Formula TL-I comprises only one L; and

M B is of the formula:

wherein:

Y′ is a single bond, —NH—, —O—, or —CH 2 —; and

is substituted or unsubstituted carbocyclylene, substituted or unsubstituted heterocyclylene, substituted or unsubstituted arylene, or substituted or unsubstituted heteroarylene.

2. A kit comprising:

a compound of claim 1 , or a salt thereof; and

instructions for using the compound, or a salt thereof.

3. The compound of claim 1 , or a salt thereof, wherein a is 2, 3, 4, 5, or 6.

4. The compound of claim 1 , or a salt thereof, wherein two instances of R 1 attached to the same carbon atom are taken together to form oxo.

5. The compound of claim 1 , or a salt thereof, wherein L J is unsubstituted C 1 -C 6 alkylene.

6. The compound of claim 1 , or a salt thereof, wherein E is triazole.

7. The compound of claim 1 , or a salt thereof, wherein L K is of the formula:

8. The compound of claim 1 , or a salt thereof, wherein -L J -E-L K - is of the formula:

wherein:

p is an integer from 1 to 12, inclusive.

9. The compound of claim 8 , or a salt thereof, wherein -L J -E-L K - is of the formula:

10. The compound of claim 1 , or a salt thereof, wherein

11. The compound of claim 1 , or a salt thereof, wherein M A is of Formula TL-I.

12. The compound of claim 1 , or salt thereof, wherein M B is of the formula:

13. The compound of claim 1 , or a salt thereof, wherein each instance of R 2 is hydrogen.

14. The compound of claim 1 , or a salt thereof, wherein b is 1, 2, 3, 4, 5, or 6.

15. The compound of claim 1 , or a salt thereof, wherein X 1 is —C(═O)N(R C ) 2 .

16. The compound of claim 15 , or a salt thereof, wherein:

one instance of R C is of the formula:

17. The compound of claim 1 , or a salt thereof, wherein the compound is of the formula:

18. The compound of claim 1 , or a salt thereof, wherein the compound is of the formula:

19. The compound of claim 1 , or a salt thereof, wherein M A is of the formula:

20. The compound of claim 1 , or a salt thereof, wherein M B is of the formula:

21. The compound of claim 1 , or a salt thereof, wherein the compound is of the formula:

22. The compound of claim 1 , or a salt thereof, wherein the compound is of the formula:

23. The compound of claim 1 , or a salt thereof, wherein E is a bond, —O—, —C(═O)NR A —, or —NR A C(═O)—.

24. The compound of claim 11 , or a salt thereof, wherein M A is of Formula TL-I1: