NRF2 PROTEIN DEGRADERS

1 . A compound of Formula A-I:

or a pharmaceutically acceptable salt or solvate thereof, wherein:

R 1 is selected from the group consisting of optionally substituted C 1 -C 6 alkyl, optionally substituted C 3 -C 8 cycloalkyl, optionally substituted phenyl, and optionally substituted 5- to 9-membered heteroaryl;

R 2a , R 2b , and R 2c are independently selected from the group consisting of hydrogen, C 1 -C 4 alkyl, C 1 -C 4 haloalkyl, C 1 -C 4 alkoxy, C 1 -C 4 haloalkoxy, cyano, hydroxy, —S(═O) 2 CH 3 , and halo;

R 3 is selected from the group consisting of hydrogen, C 1 -C 4 alkyl, C 1 -C 4 haloalkyl, C 1 -C 4 alkoxy, C 1 -C 4 haloalkoxy, cyano, hydroxy, —S(═O) 2 CH 3 , and halo;

Y is selected from the group consisting of —{circumflex over ( )}N(H)C(═O)—, —{circumflex over ( )}N(H)C(═O)CH 2 —, —{circumflex over ( )}C(═O)N(H)—and —{circumflex over ( )}C(═O)N(H)CH 2 —;

wherein the bond marked with a “{circumflex over ( )}” is attached to the thiazole;

R 4a , R 4b , R 4c , and R 4d are independently selected from the group consisting of hydrogen, C 1 -C 4 alkyl, C 1 -C 4 haloalkyl, C 1 -C 4 alkoxy, C 1 -C 4 haloalkoxy, cyano, hydroxy, —S(═O) 2 CH 3 , and halo;

L is selected from the group consisting of —(CH 2 ) m —, —* (CH 2 ) n (OCH 2 CH 2 ) o —, and —(CH 2 ) p —Z—CH 2 ) q —;

wherein the carbon marked with an “*” is attached to X;

m is 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, or 12;

n is 2, 3, or 4;

o is 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, or 12;

p is 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, or 12;

q is 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, or 12;

Z is selected from the group consisting of —(CR 6a R 6b )— and —N(R 7 )—;

R 6a is selected from the group consisting of halo, hydroxyl, C 1 -C 6 alkyl, C 1 -C 4 haloalkyl, optionally substituted C 3 -C 8 cycloalkyl, substituted optionally C 4 -C 8 heterocyclo, optionally substituted phenyl, and optionally substituted 5- to 9-membered heteroaryl;

R 6b is selected from the group consisting of hydrogen and C 1 -C 6 alkyl;

R 7 is selected from the group consisting of hydrogen, C 1 -C 6 alkyl, and C 1 -C 4 haloalkyl;

X is selected from the group consisting of —O—, —NH—,

B 1 is selected from the group consisting of:

R 5a , R 5b , and R 5c are independently selected from the group consisting of hydrogen, C 1 -C 4 alkyl, C 1 -C 4 haloalkyl, C 1 -C 4 alkoxy, C 1 -C 4 haloalkoxy, cyano, hydroxy, —S(═O) 2 CH 3 , and halo.

2 . The compound of claim 1 having Formula I:

or a pharmaceutically acceptable salt or solvate thereof.

3 . The compound of claim 1 having Formula II:

or a pharmaceutically acceptable salt or solvate thereof.

4 - 18 . (canceled)

19 . The compound of claim 1 , or a pharmaceutically acceptable salt or solvate thereof, wherein L is selected from the group consisting of —(CH 2 ) m — and —*(CH 2 ) n (OCH 2 CH 2 ) o —.

20 - 24 . (canceled)

25 . The compound of claim 1 , or a pharmaceutically acceptable salt or solvate thereof, wherein X is —O— or —NH—.

26 - 28 . (canceled)

29 . The compound of claim 1 , or a pharmaceutically acceptable salt or solvate thereof, wherein B 1 is B-1, wherein R 5a , R 5b , and R 5c are hydrogen.

30 . The compound of claim 1 , or a pharmaceutically acceptable salt or solvate thereof, wherein B 1 is B-2, wherein R 5a , R 5b , and R 5c are hydrogen.

31 - 36 . (canceled)

37 . The compound of claim 1 , or a pharmaceutically acceptable salt or solvate thereof, selected from the group consisting of:

38 . A pharmaceutical composition comprising the compound of claim 1 , or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.

39 - 47 . (canceled)

48 . A kit comprising the compound of claim 1 , or a pharmaceutically acceptable salt thereof, and instructions for administering the compound, or a pharmaceutically acceptable salt thereof, to a subject having cancer.

49 . A compound having Formula III:

or a pharmaceutically acceptable salt thereof, wherein:

R 1′ is selected from the group consisting of optionally substituted C 1 -C 6 alkyl, optionally substituted C 3 -C 8 cycloalkyl, optionally substituted phenyl, and optionally substituted 5- to 9-membered heteroaryl;

R 2a′ , R 2b′ , and R 2c′ are independently selected from the group consisting of hydrogen, C 1 -C 4 alkyl, C 1 -C 4 haloalkyl, C 1 -C 4 alkoxy, C 1 -C 4 haloalkoxy, cyano, hydroxy, —S(═O) 2 CH 3 , and halo;

R 3′ is selected from the group consisting of hydrogen, C 1 -C 4 alkyl, C 1 -C 4 haloalkyl, C 1 -C 4 alkoxy, C 1 -C 4 haloalkoxy, cyano, hydroxy, —S(═O) 2 CH 3 , and halo;

Z 1 is —O—; and

R 8 is hydrogen, C 1 -C 6 alkyl, or aralkyl; or

Z 1 is —N(H)—; and

R 8 is:

R 4a′ , R 4b′ , R 4c′ , and R 4d′ are independently selected from the group consisting of hydrogen, C 1 -C 4 alkyl, C 1 -C 4 haloalkyl, C 1 -C 4 alkoxy, C 1 -C 4 haloalkoxy, cyano, hydroxy, —S(═O) 2 CH 3 , and halo;

R 9 is selected from the group consisting of hydrogen and -L 1 -X 1 ;

X 1 is selected from the group consisting of —OR 10 and —NR 11a R 11b ;

R 10 is hydrogen;

R 11a is selected from the group consisting of hydrogen and —C(═O)OtBu;

R 11b is selected from the group consisting of hydrogen and C 1 -C 4 alkyl;

L 1 is selected from the group consisting of —(CH 2 ) m′ —, —*(CH 2 ) n (OCH 2 CH 2 ) o′ —, and —(CH 2 ) p′ —Z 2 —(CH 2 ) q′ —;

wherein the carbon marked with an “*” is attached to X 1 ;

m′ is 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, or 12;

n′ is 2, 3, or 4;

o′ is 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, or 12;

p′ is 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, or 12;

q′ is 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, or 12;

Z 2 is selected from the group consisting of —(CR 6a′ R 6b′ )— and —N(R 7′ )—;

R 6a′ is selected from the group consisting of halo, hydroxyl, C 1 -C 6 alkyl, C 1 -C 4 haloalkyl, optionally substituted C 3 -C 8 cycloalkyl, substituted optionally C 4 -C 8 heterocyclo, optionally substituted phenyl, and optionally substituted 5- to 9-membered heteroaryl;

R 6b′ is selected from the group consisting of hydrogen and C 1 -C 6 alkyl; and

R 7 is selected from the group consisting of hydrogen, C 1 -C 6 alkyl, and C 1 -C 4 haloalkyl.

50 . A method of treating cancer in a subject comprising degrading nuclear factor erythroid 2-related factor 2 (Nrf2) in the subject in need thereof.

51 . The method of claim 50 , wherein degrading Nrf2 comprises administering a therapeutically effective amount of a Nrf2 degrader to the subject in need thereof.

52 . The method of claim 51 , wherein the Nrf2 degrader is a heterobifunctional small molecule comprising a ligand that binds to the Nrf2 protein and a ligand that binds to an E3 ligase.

53 . The method of claim 52 , wherein the Nrf2 degrader further comprises a linker that tethers the Nrf2 ligand and the E3 ligase ligand.

54 . The method of claim 53 , wherein the Nrf2 degrader is a compound of Formula A-I:

or a pharmaceutically acceptable salt or solvate thereof, wherein:

R 1 is selected from the group consisting of optionally substituted C 1 -C 6 alkyl, optionally substituted C 3 -C 5 cycloalkyl, optionally substituted phenyl, and optionally substituted 5- to 9-membered heteroaryl;

R 2a , R 2b , and R 2c are independently selected from the group consisting of hydrogen, C 1 -C 4 alkyl, C 1 -C 4 haloalkyl, C 1 -C 4 alkoxy, C 1 -C 4 haloalkoxy, cyano, hydroxy, —S(═O) 2 CH 3 , and halo;

R 3 is selected from the group consisting of hydrogen, C 1 -C 4 alkyl, C 1 -C 4 haloalkyl, C 1 -C 4 alkoxy, C 1 -C 4 haloalkoxy, cyano, hydroxy, —S(═O) 2 CH 3 , and halo;

Y is selected from the group consisting of —{circumflex over ( )}N(H)C(═O)—, —{circumflex over ( )}N(H)C(═O)CH 2 —, —{circumflex over ( )}C(═O)N(H)— and —{circumflex over ( )}C(═O)N(H)CH 2 —;

wherein the bond marked with a “{circumflex over ( )}” is attached to the thiazole;

R 4a , R 4b , R 4c , and R 4d are independently selected from the group consisting of hydrogen, C 1 -C 4 alkyl, C 1 -C 4 haloalkyl, C 1 -C 4 alkoxy, C 1 -C 4 haloalkoxy, cyano, hydroxy, —S(═O) 2 CH 3 , and halo;

L is selected from the group consisting of —(CH 2 ) m —, —*(CH 2 ) n (OCH 2 CH 2 ) o —, and —(CH 2 ) p —Z—CH 2 ) q —;

wherein the carbon marked with an “*” is attached to X;

n is 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, or 12;

n is 2, 3, or 4;

o is 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, or 12;

p is 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, or 12;

q is 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, or 12;

Z is selected from the group consisting of —(CR 6a R 6b )— and —N(R 7 )—;

R 6a is selected from the group consisting of halo, hydroxyl, C 1 -C 6 alkyl, C 1 -C 4 haloalkyl, optionally substituted C 3 -C 8 cycloalkyl, substituted optionally C 4 -C 8 heterocyclo, optionally substituted phenyl, and optionally substituted 5- to 9-membered heteroaryl;

R 6b is selected from the group consisting of hydrogen and C 1 -C 6 alkyl;

R 7 is selected from the group consisting of hydrogen, C 1 -C 6 alkyl, and C 1 -C 4 haloalkyl;

X is selected from the group consisting of —O—, —NH—,

B 1 is selected from the group consisting of

R 5a , R 5b , and R 5c are independently selected from the group consisting of hydrogen, C 1 -C 4 alkyl, C 1 -C 4 haloalkyl, C 1 -C 4 alkoxy, C 1 -C 4 haloalkoxy, cyano, hydroxy, —S(═O) 2 CH 3 , and halo.

55 . A method of reducing Nrf2 protein levels within a cell of a subject, the method comprising administering a Nrf2 degrader to the subject.

56 . The method of claim 55 , wherein the Nrf2 degrader is a heterobifunctional small molecule comprising a ligand that binds to the Nrf2 protein and a ligand that binds to an E3 ligase.

57 . The method of claim 56 , wherein the Nrf2 degrader further comprises a linker that tethers the Nrf2 ligand and the E3 ligase ligand.

58 . The method of claim 57 , wherein the Nrf2 degrader is a compound of Formula A-I:

or a pharmaceutically acceptable salt or solvate thereof, wherein:

R 1 is selected from the group consisting of optionally substituted C 1 -C 6 alkyl, optionally substituted C 3 -C 5 cycloalkyl, optionally substituted phenyl, and optionally substituted 5- to 9-membered heteroaryl;

R 2a , R 2b , and R 2c are independently selected from the group consisting of hydrogen, C 1 -C 4 alkyl, C 1 -C 4 haloalkyl, C 1 -C 4 alkoxy, C 1 -C 4 haloalkoxy, cyano, hydroxy, —S(═O) 2 CH 3 , and halo;

R 3 is selected from the group consisting of hydrogen, C 1 -C 4 alkyl, C 1 -C 4 haloalkyl, C 1 -C 4 alkoxy, C 1 -C 4 haloalkoxy, cyano, hydroxy, —S(═O) 2 CH 3 , and halo;

Y is selected from the group consisting of —{circumflex over ( )}N(H)C(═O)—, —{circumflex over ( )}N(H)C(═O)CH 2 —, —{circumflex over ( )}C(═O)N(H)— and —{circumflex over ( )}C(═O)N(H)CH 2 —;

wherein the bond marked with a “*” is attached to the thiazole;

R 4a , R 4b , R 4c , and R 4d are independently selected from the group consisting of hydrogen, C 1 -C 4 alkyl, C 1 -C 4 haloalkyl, C 1 -C 4 alkoxy, C 1 -C 4 haloalkoxy, cyano, hydroxy, —S(═O) 2 CH 3 , and halo;

L is selected from the group consisting of —(CH 2 ) m —, —*(CH 2 ) n (OCH 2 CH 2 ) o —, and —(CH 2 ) p —Z—CH 2 ) q —;

wherein the carbon marked with an “*” is attached to X;

m is 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, or 12;

n is 2, 3, or 4;

o is 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, or 12;

p is 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, or 12;

q is 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, or 12;

Z is selected from the group consisting of —(CR 6a R 6b )— and —N(R 7 )—;

R 6a is selected from the group consisting of halo, hydroxyl, C 1 -C 6 alkyl, C 1 -C 4 haloalkyl, optionally substituted C 3 -C 8 cycloalkyl, substituted optionally C 4 -C 8 heterocyclo, optionally substituted phenyl, and optionally substituted 5- to 9-membered heteroaryl;

R 6b is selected from the group consisting of hydrogen and C 1 -C 6 alkyl;

R 7 is selected from the group consisting of hydrogen, C 1 -C 6 alkyl, and C 1 -C 4 haloalkyl;

X is selected from the group consisting of —O—, —NH—,

B 1 is selected from the group consisting of:

 and

R 5a , R 5b , and R 5c are independently selected from the group consisting of hydrogen, C 1 -C 4 alkyl, C 1 -C 4 haloalkyl, C 1 -C 4 alkoxy, C 1 -C 4 haloalkoxy, cyano, hydroxy, —S(═O) 2 CH 3 , and halo