Compounds targeting proteins, compositions, methods, and uses thereof

1. A compound of Formula (II):

or a pharmaceutically acceptable salt or solvate thereof, wherein:

Q 1 , Q 2 , and Q 3 , are each independently CR 1 , CR 2 , or —S—, and at least one of Q 1 , Q 2 , and Q 3 , is CR 1 ;

each is independently selected from a carbon-carbon double bond, a carbon-carbon single bond, and a carbon-sulfur single bond;

R 1 and R 2 are each independently H, deuterium, hydroxyl, halogen, cyano, nitro, optionally substituted amino, optionally substituted C-amido, optionally substituted N-amido, optionally substituted ester, optionally substituted urea, optionally substituted C 1 -C 6 alkoxy, optionally substituted C 1 -C 6 alkyl, optionally substituted C 2 -C 6 alkenyl, optionally substituted C 2 -C 6 alkynyl, optionally substituted C 3 -C 8 cycloalkyl, optionally substituted C 6 -C 10 aryl, optionally substituted 3 to 10-membered heterocyclyl, optionally substituted 5 to 10-membered heteroaryl,

or L-Y;

wherein when one of R 1 or R 2 is

or

the other of R 1 or R 2 is not L-Y;

R 5 is H, deuterium, optionally substituted C 1 -C 6 alkyl, or optionally substituted C 2 -C 6 alkenyl;

X is C(R 5 ) 2 , CH(R 5 ), CH 2 , C═O, or C═S;

X 1 is selected from the group consisting of H, deuterium, halogen, and optionally substituted C 1 -C 6 alkyl;

X 2 is selected from the group consisting of (CH 2 ) a , (CD 2 ) a , (CF 2 ) a , C═O, NH, N-(optionally substituted C 1 -C 6 alkyl), and [(CH 2 ) p —O—(CH 2 ) q ] r ;

X 3 is selected from the group consisting of O, NH, and S;

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

n is 1, 2, or 3;

m is 1, 2, 3, 4, or 5;

p and q are independently 0, 1, 2, 3, 4, 5, or 6;

r is 0, 1, 2, 3, or 4;

Qa and Qb are each independently C═O or C═S;

wherein when n is 2, then Q 3 is —S—, or when n is 2, then R 1 is substituted C 1 -C 6 alkyl,

optionally substituted C 3 -C 8 cycloalkyl, optionally substituted 3 to 10-membered heterocyclyl, optionally substituted 5 to 10-membered heteroaryl, optionally substituted urea, or L-Y;

L is —Z 1 —(R 6 —O—R 6 ) t —Z 2 —; —Z 1 (R 6 —NH—R 6 ) t —Z 2 —; —Z 1 —(R 6 —S—R 6 ) t —Z 2 —; —Z 1 —(R 6 —(C═O)—R 6 ) t —Z 2 —; —Z 1 —(R 6 —(CO 2 )—R 6 ) t —Z 2 —; —Z 1 —(R 6 —(NHCO)—R 6 ) t —Z 2 —; —Z 1 —(R 6 —(CONH)—R 6 ) t —Z 2 —; —Z 1 —(R 6 —(SO)—R 6 ) t —Z 2 —; —Z 1 —(R 6 —(SO 2 )—R 6 ) t —Z 2 —; —Z 1 —(R 6 —NH(C═NH)NH—R 6 ) t —Z 2 —; —Z 1 —(R 6 —(NHSO 2 )—R 6 ) t —Z 2 —; —Z 1 —(R 6 —(SO 2 NH)—R 6 ) t —Z 2 —; —Z 1 —(R 6 —NH(C═O)NH—R 6 ) t —Z 2 —; —Z 1 —(R 6 —NH(C═S)NH—R 6 ) t —Z 2 —; or —Z 1 —(R 6 —R 7 —R 6 ) t —Z 2 —;

each t is independently 1, 2, 3, 4, 5, 6, 7, or 8;

Z 1 and Z 2 are each independently —CH 2 —; —O—; —S—; S═O; —SO 2 —; C═O; —CO 2 —; —NH—; —NH(CO)—; —(CO)NH—; —NH—SO 2 —; —SO 2 —NH—; —R 6 CH 2 —; —R 6 O—; —R 6 S—; —R 6 —S═O; —R 6 SO 2 —; —R 6 —C═O; —R 6 CO 2 —; —R 6 NH—; —R 6 NH(CO)—; —R 6 (CO)NH—; —R 6 NH—SO 2 —; —R 6 SO 2 —NH—; —CH 2 R 6 —; —OR 6 —; —SR 6 —; —S═O—R 6 ; —SO 2 R 6 —; —C═O—R 6 ; —CO 2 R 6 —; —NHR 6 —; —NH(CO)R 6 —; —(CO)NHR 6 —; —NH—SO 2 R 6 —; or —SO 2 —NHR 6 —;

each R 6 is absent, or independently C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 6 -C 10 aryl, 3 to 10-membered heterocyclyl, or 5 to 10-membered heteroaryl;

R 7 is optionally substituted C 3 -C 8 cycloalkyl, optionally substituted C 6 -C 10 aryl, optionally substituted 3 to 10-membered heterocyclyl, or optionally substituted 5 to 10-membered heteroaryl;

R 8 is selected from the group consisting of optionally substituted C 3 -C 10 cycloalkyl, optionally substituted C 6 -C 10 aryl, optionally substituted 5 to 10-membered heteroaryl, optionally substituted 3 to 10-membered heterocyclyl, optionally substituted C 1 -C 10 alkyl, R 8A and R 8B ;

R 8A is selected from the group consisting of hydroxyl, halogen, cyano, nitro, unsubstituted amino, mono-substituted amino, di-substituted amino, optionally substituted C-amido, optionally substituted N-amido, optionally substituted ester, optionally substituted sulfonyl, optionally substituted S-sulfonamido, optionally substituted N-sulfonamido, optionally substituted sulfonate, optionally substituted O-thiocarbamyl, optionally substituted N-thiocarbamyl, optionally substituted N-carbamyl, optionally substituted O-carbamyl, optionally substituted urea, optionally substituted thiourea, optionally substituted C 1 -C 6 alkoxy, optionally substituted C 1 -C 6 haloalkoxy, optionally substituted C 3 -C 10 cycloalkyl(C 1 -C 6 alkyl), optionally substituted C 6 -C 10 aryl(C 1 -C 6 alkyl), optionally substituted 5 to 10 membered heteroaryl(C 1 -C 6 alkyl), and optionally substituted 3 to 10 membered heterocyclyl(C 1 -C 6 alkyl);

R 8B is Y 1 ;

Y and Y 1 are independently selected from

and

wherein Y is derivatized to attach to L and Y 1 is derivatized to attach to X 2 .

2. The compound of claim 1 , wherein the compound of Formula (II) is selected from the group consisting of compounds of Formula (IIa)

Formula (IIb)

and Formula (IIc)

or a pharmaceutically acceptable salt of any of the foregoing.

3. The compound of claim 1 , wherein the compound of Formula (II) is selected from Formulae (IId), (IIe) and (IIf):

or a pharmaceutically acceptable salt thereof.

4. The compound of claim 2 , wherein Qa is C═O and Qb is C═O.

5. The compound of claim 2 , wherein n is 2.

6. The compound of claim 2 , wherein n is 3.

7. The compound of claim 2 , wherein R 5 is H.

8. The compound of claim 2 , wherein X is CH 2 .

9. The compound of claim 2 , wherein X 1 is selected from the group consisting of H, deuterium, and fluoro.

10. The compound of claim 2 , wherein R 1 is optionally substituted C 3 -C 6 cycloalkyl or optionally substituted C 1 -C 6 alkyl; or R 2 is optionally substituted C 3 -C 6 cycloalkyl or optionally substituted C 1 -C 6 alkyl.

11. The compound of claim 2 , wherein

L is —Z 1 —(R 6 —O—R 6 ) t —Z 2 —; —Z 1 (R 6 —NH—R 6 ) t —Z 2 —; —Z 1 —(R 6 —(NHCO)—R 6 ) t —Z 2 —; —Z 1 —(R 6 —NH(C═O)NH—R 6 ) t —Z 2 —; —Z 1 —(R 6 —NH(C═NH)NH—R 6 ) t —Z 2 —; —Z 1 —(R 6 —NH(C═S)NH—R 6 ) t —Z 2 —; or —Z 1 —(R 6 —(CONH)—R 6 ) t —Z 2 —;

t is 1, 2, 3, or 4; and

Z 1 and Z 2 are each independently —CH 2 —; —O—; —NH—; —NH(CO)—; or —(CO)NH—.

12. The compound of claim 2 , wherein one of R 1 and R 2 is an optionally substituted urea, and the other of R 1 and R 2 is H, fluoro, optionally substituted C 1 -C 6 alkyl or optionally substituted C 3 -C 6 cycloalkyl.

13. The compound of claim 2 , wherein one of R 1 and R 2 is selected from

and

14. The compound of claim 13 , wherein m is 1, 2, or 3.

15. The compound of claim 14 , wherein m is 1.

16. The compound of claim 13 , wherein X 3 is O or S.

17. The compound of claim 13 , wherein X 2 is (CH 2 ) a .

18. The compound of claim 17 , wherein a is 2 or 3.

19. The compound of claim 13 , wherein X 2 is NH.

20. The compound of claim 13 , wherein m is 1, 2, or 3; X 2 is NH; and X 3 is O or S.

21. The compound of claim 13 , wherein one of R 1 or R 2 is

or

and R 8 is selected from the group consisting of an optionally substituted C 3 -C 10 cycloalkyl, an optionally substituted C 6 -C 10 aryl, an optionally substituted 5 to 10-membered heteroaryl, and an optionally substituted 3 to 10-membered heterocyclyl.

22. The compound of claim 21 , wherein the optionally substituted C 6 -C 10 aryl is a mono-substituted phenyl group, a di-substituted phenyl group, or a tri-substituted phenyl group.

23. The compound of claim 22 , wherein the optionally substituted C 6 -C 10 aryl is a C 6 aryl group substituted with halogen, a C 6 aryl group substituted with an unsubstituted C 1 -C 6 alkyl, a C 6 aryl group substituted with an unsubstituted C 1 -C 6 alkyl and halogen, a C 6 aryl group substituted with an unsubstituted C 1 -C 6 alkyl and an unsubstituted C 1 -C 3 alkoxy, a C 6 aryl group substituted with an unsubstituted C 1 -C 3 alkoxy and halogen, a C 6 aryl group substituted with an unsubstituted C 1 -C 6 alkyl and an unsubstituted di(C 1 -C 3 alkyl)amino, or a C 6 aryl group substituted with an unsubstituted di(C 1 -C 3 alkyl)amino and halogen.

24. The compound of claim 21 , wherein R 8 is selected from the group consisting of a 5-6 membered heteroaryl group substituted with halogen, a 5-6 membered heteroaryl group substituted with an unsubstituted C 1 -C 6 alkyl, a 5-6 membered heteroaryl group substituted with an unsubstituted C 1 -C 6 alkyl and halogen, a 5-6 membered heteroaryl group substituted with an unsubstituted C 1 -C 6 alkyl and an unsubstituted C 1 -C 3 alkoxy, a 5-6 membered heteroaryl group substituted with an unsubstituted C 1 -C 3 alkoxy and halogen, a 5-6 membered heteroaryl group substituted with an unsubstituted C 1 -C 6 alkyl and an unsubstituted di(C 1 -C 3 alkyl)amino, or a 5-6 membered heteroaryl group substituted with an unsubstituted di(C 1 -C 3 alkyl)amino and halogen.

25. The compound of claim 1 , wherein one of R 1 or R 2 is

or

R 8 is R 8A ; and R 8A is selected from: optionally substituted C 3 -C 10 cycloalkyl(C 1 -C 6 alkyl), optionally substituted C 6 -C 10 aryl(C 1 -C 6 alkyl), optionally substituted 5 to 10 membered heteroaryl(C 1 -C 6 alkyl), and optionally substituted 3 to 10 membered heterocyclyl(C 1 -C 6 alkyl).

26. The compound of claim 1 , wherein one of R 1 or R 2 is

or

R 8 is R 8B ; R 8B is Y 1 ; and Y 1 is

or

wherein Y 1 is derivatized to attach to X 2 .

27. The compound of claim 1 , wherein the compound of Formula (II) is selected from the group consisting of:

or a pharmaceutically acceptable salt or solvates of any of the foregoing.

28. A pharmaceutical composition comprising a compound of claim 1 , or a pharmaceutically acceptable salt thereof, and at least one pharmaceutically acceptable carrier.

29. A method of treating or ameliorating a disease, disorder, or condition associated with a protein selected from a cytokine, aiolos, ikaros, helios, CK1α, GSPT1, and combinations of any of the foregoing, the method comprising administering a therapeutically effective amount of a compound of claim 1 , or a pharmaceutically acceptable salt thereof; wherein the disease, disorder, or condition is selected from the group consisting of inflammation, fibromyalgia, rheumatoid arthritis, osteoarthritis, ankylosing spondylitis, psoriasis, psoriatic arthritis, inflammatory bowel diseases, Crohn's disease, ulcerative colitis, uveitis, inflammatory lung diseases, chronic obstructive pulmonary disease, Alzheimer's disease, and cancer.

30. A method of inhibiting protein activity, comprising contacting a cell with a compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein the protein is aiolos, ikaros, helios, CK1α, GSPT1, a cytokine, or a combination of any of the foregoing.