HU WANYI (US)
ZHANG PEIYI (US)
ZHENG GUANGRONG (US)
UNIV TEXAS (US)
ZHOU DAOHONG (US)
CLAIMS What is claimed is: 1. A compound of Formula (I), or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof: Formula (I); wherein: R1 is –O(substituted or unsubstituted alkyl) or –N(Ra)2, wherein each instance of Ra is independently substituted or unsubstituted alkyl or substituted or unsubstituted carbocyclyl, or two instances of Ra are joined with the nitrogen atom to which they are attached to form substituted or unsubstituted heterocyclyl; R2 is SO2CF3 or NO2; , wherein Rb is halogen or substituted or unsubstituted alkyl; each instance of R4 is independently F, Cl, –CN, –CFH2, –CF2H, –CF3, or –OCH3; n1 is 0, 1, 2, or 3; Z is a bond, CH2, or CO; Y is CO; , wherein R6 is F, Cl, –CN, –CFH2, –CF2H, –CF3, – OCH3, or H; and R7 is H or substituted or unsubstituted alkyl; L1 is substituted or unsubstituted, C1-11 alkylene, substituted or unsubstituted, C2-11 alkenylene, substituted or unsubstituted, C2-11 alkynylene, or substituted or unsubstituted heterocyclylene, optionally wherein one or more backbone carbon atoms in the substituted or unsubstituted, C1-11 alkylene, substituted or unsubstituted, C2-11 alkenylene, or substituted or unsubstituted, C2-11 alkynylene are independently replaced with –O–, –NR5–, =N–, –N=, –S–, – S(=O)–, –S(=O)2–, –C(=O)–, substituted or unsubstituted heterocyclylene, substituted or unsubstituted heteroarylene, substituted or unsubstituted carbocyclylene, or substituted or unsubstituted arylene; each instance of R5 is independently hydrogen, substituted or unsubstituted acyl, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted carbocyclyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl; L2 is substituted or unsubstituted, C1-12 alkylene, substituted or unsubstituted, C2-12 alkenylene, substituted or unsubstituted, C2-12 alkynylene, substituted or unsubstituted heterocyclylene, or substituted or unsubstituted carbocyclylene, optionally wherein one or more backbone carbon atoms in the substituted or unsubstituted, C1-12 alkylene, substituted or unsubstituted, C2-12 alkenylene, or substituted or unsubstituted, C2-12 alkynylene are independently replaced with –O–, –NR5–, =N–, –N=, –S–, –S(=O)–, –S(=O)2–, –C(=O)–, substituted or unsubstituted heterocyclylene, substituted or unsubstituted heteroarylene, substituted or unsubstituted carbocyclylene, or substituted or unsubstituted arylene; and L3 is a bond, substituted or unsubstituted, C1-13 alkylene, substituted or unsubstituted, C2- 13 alkenylene, substituted or unsubstituted, C2-13 alkynylene, or substituted or unsubstituted heterocyclylene, optionally wherein one or more backbone carbon atoms in the substituted or unsubstituted, C1-13 alkylene, substituted or unsubstituted, C2-13 alkenylene, or substituted or unsubstituted, C2-13 alkynylene are independently replaced with –O–, –NR5–, =N–, –N=, –S–, – S(=O)–, –S(=O)2–, –C(=O)–, substituted or unsubstituted heterocyclylene, substituted or unsubstituted heteroarylene, substituted or unsubstituted carbocyclylene, or substituted or unsubstituted arylene. 2. The compound of claim 1, or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof, wherein: R6 is F, Cl, –CN, –CFH2, –CF2H, –CF3, or –OCH3, and L3 is substituted or unsubstituted, C1-13 alkylene, substituted or unsubstituted, C2-13 alkenylene, substituted or unsubstituted, C2-13 alkynylene, or substituted or unsubstituted heterocyclylene, optionally wherein one or more backbone carbon atoms in the substituted or unsubstituted, C1-13 alkylene, substituted or unsubstituted, C2-13 alkenylene, or substituted or unsubstituted, C2-13 alkynylene are independently replaced with –O–, –NR5–, =N–, –N=, –S–, – S(=O)–, –S(=O)2–, –C(=O)–, substituted or unsubstituted heterocyclylene, substituted or unsubstituted heteroarylene, substituted or unsubstituted carbocyclylene, or substituted or unsubstituted arylene. 3. The compound of claim 1 or 2, or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof, wherein R1 is –O(substituted or unsubstituted alkyl). 4. The compound of any one of claims 1-2, or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof, wherein R1 is –O(alkyl substituted at least with substituted or unsubstituted heterocyclyl, wherein at least one heteroatom in the heterocyclic ring system is nitrogen). 5. The compound of any one of claims 1-2, or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof, wherein R1 is –N(Ra)2, wherein each instance of Ra is independently substituted or unsubstituted alkyl or substituted or unsubstituted carbocyclyl. 6. The compound of any one of claims 1-2, or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof, wherein R1 is –N(Ra)2, wherein two instances of Ra are joined with the nitrogen atom to which they are attached to form substituted or unsubstituted heterocyclyl. 7. The compound of any one of claims 1-2, or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof, wherein R1 is –N(Ra)2, wherein two instances of Ra are joined with the nitrogen atom to which they are attached to form substituted or unsubstituted, monocyclic heterocyclyl. 8. The compound of any one of claims 1-2, or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof, wherein R1 is –N(Ra)2, wherein two instances of Ra are joined with the nitrogen atom to which they are attached to form substituted or unsubstituted, fused bicyclic heterocyclyl. 9. The compound of any one of claims 1-2, or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof, wherein R1 is –N(Ra)2, wherein two instances of Ra are joined with the nitrogen atom to which they are attached to form substituted or unsubstituted, bridged bicyclic heterocyclyl. 10. The compound of any one of claims 1-2, or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof, wherein R1 is –N(Ra)2, wherein two instances of Ra are joined with the nitrogen atom to which they are attached to form substituted or unsubstituted, spiro bicyclic heterocyclyl. 11. The compound of any one of claims 1-2, or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof, wherein R1 is , , , , , , , wherein: each n is independently 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10; each p is independently 0, 1, 2, 3, or 4; each q is independently 1, 2, or 3; each r is independently 1 or 2; each s is independently 1, 2, 3, or 4; each t is independently 1, 2, 3, 4, or 5; and each u is independently 0, 1, 2, 3, 4, or 5. 12. The compound of any one of claims 1-2, or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof, wherein R 1 is of the formula: . 13. The compound of any one of claims 1-12, or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof, wherein R2 is NO2. 14. The compound of any one of claims 1-12, or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof, wherein R2 is SO2CF3. 15. The compound of any one of claims 1-14, or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof, wherein R3 is . 16. The compound of claim 15, or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof, wherein . 17. The compound of any one of claims 1-14, or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof, wherein R3 is . 18. The compound of any one of claims 1-15 and 17, or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof, wherein Rb is halogen. 19. The compound of claim 18, or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof, wherein Rb is Cl. 20. The compound of any one of claims 1-15 and 17, or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof, wherein Rb is substituted or unsubstituted alkyl. 21. The compound of claim 20, or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof, wherein Rb is alkyl substituted only with one or more instances of fluoro. 22. The compound of any one of claims 1-14, or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled compound, or , , , , 23. The compound of any one of claims 1-22, or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof, wherein n1 is 0. 24. The compound of any one of claims 1-22, or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof, wherein n1 is 1. 25. The compound of any one of claims 1-22 and 24, or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof, wherein at least one instance of R4 is F. 26. The compound of any one of claims 1-25, or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof, wherein Z is a bond. 27. The compound of any one of claims 1-25, or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof, wherein Z is CH2. 28. The compound of any one of claims 1-25, or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof, wherein Z is CO. 29. The compound of any one of claims 1-28, or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof, wherein Y is CO. 30. The compound of any one of claims 1-25, or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof, wherein , , . 31. The compound of any one of claims 1-28, or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof, wherein . 32. The compound of claim 31, or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof, wherein . 33. The compound of any one of claims 1-32, or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof, wherein L1 is substituted or unsubstituted, C1-11 alkylene. 34. The compound of any one of claims 1-32, or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof, wherein L1 is substituted or unsubstituted, C1-11 alkylene, wherein one or more backbone carbon atoms in the substituted or unsubstituted, C1-11 alkylene are independently replaced with –O–, –NR5–, –S(=O)–, –S(=O)2–, or –C(=O)–. 35. The compound of any one of claims 1-32, or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof, wherein L1 is substituted or unsubstituted, monocyclic heterocyclylene, substituted or unsubstituted, bicyclic heterocyclylene, or substituted or unsubstituted, monocyclic heteroarylene. 36. The compound of any one of claims 1-32, or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof, wherein L1 is –(substituted or unsubstituted, monocyclic heterocyclylene)– (substituted or unsubstituted, C1-2 alkylene)–, –(substituted or unsubstituted, bicyclic heterocyclylene)–(substituted or unsubstituted, C1-2 alkylene)–, –(substituted or unsubstituted, monocyclic heteroarylene)–(substituted or unsubstituted, C1-2 alkylene)–, –(substituted or unsubstituted, C1-2 alkylene)–(substituted or unsubstituted, monocyclic heterocyclylene)–, – (substituted or unsubstituted, C1-2 alkylene)–(substituted or unsubstituted, bicyclic heterocyclylene)–, or –(substituted or unsubstituted, C1-2 alkylene)–(substituted or unsubstituted, monocyclic heteroarylene)–, optionally wherein one or two backbone carbon atoms in the substituted or unsubstituted, C1-2 alkylene are independently replaced with –O–, –NR5–, –S(=O)– , –S(=O)2–, or –C(=O)–. 37. The compound of any one of claims 1-32, or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof, wherein L1 is –(substituted or unsubstituted, C1-2 alkylene)–(substituted or unsubstituted, monocyclic heterocyclylene)–(substituted or unsubstituted, C1-2 alkylene)–, – (substituted or unsubstituted, C1-2 alkylene)–(substituted or unsubstituted, bicyclic heterocyclylene)–(substituted or unsubstituted, C1-2 alkylene)–, or –(substituted or unsubstituted, C1-2 alkylene)–(substituted or unsubstituted, monocyclic heteroarylene)–(substituted or unsubstituted, C1-2 alkylene)–, optionally wherein one or two backbone carbon atoms in each instance of the substituted or unsubstituted, C1-2 alkylene are independently replaced with –O–, – NR5–, –S(=O)–, –S(=O)2–, or –C(=O)–. 38. The compound of any one of claims 1-32, or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof, wherein L1 is –(substituted or unsubstituted, monocyclic heterocyclylene)2– (substituted or unsubstituted, C1 alkylene)–, –(substituted or unsubstituted, C1 alkylene)– (substituted or unsubstituted, monocyclic heterocyclylene)2–, –(substituted or unsubstituted, C1 alkylene)–(substituted or unsubstituted, monocyclic heterocyclylene)2–(substituted or unsubstituted, C1 alkylene)–, –(substituted or unsubstituted, monocyclic heterocyclylene)– (substituted or unsubstituted, monocyclic carbocyclylene)–(substituted or unsubstituted, C1 alkylene)–, –(substituted or unsubstituted, monocyclic carbocyclylene)–(substituted or unsubstituted, monocyclic heterocyclylene)–(substituted or unsubstituted, C1 alkylene)–, – (substituted or unsubstituted, C1 alkylene)–(substituted or unsubstituted, monocyclic heterocyclylene) (substituted or unsubstituted monocyclic carbocyclylene) or (substituted or unsubstituted, C1 alkylene)–(substituted or unsubstituted, monocyclic carbocyclylene)– (substituted or unsubstituted, monocyclic heterocyclylene)–, optionally wherein the backbone carbon atom in each instance of the substituted or unsubstituted, C1 alkylene is independently replaced with –O–, –NR5–, –S(=O)–, –S(=O)2–, or –C(=O)–. 39. The compound of any one of claims 1-32, or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof, wherein L1 is , , , , , N N , , , O , N N O , , , , N N O , , , , , , wherein: each n is independently 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10; each p is independently 0 1 2 3 or 4; each q is independently 1, 2, or 3; each r is independently 1 or 2; each s is independently 1, 2, 3, or 4; each t is independently 1, 2, 3, 4, or 5; and each u is independently 0, 1, 2, 3, 4, or 5. 40. The compound of any one of claims 1-32, or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof, wherein . 41. The compound of any one of claims 1-32, or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof, wherein L1 is –CH2–. 42. The compound of any one of claims 1-41, or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof, wherein L2 is substituted or unsubstituted, C1-12 alkylene, substituted or unsubstituted, C2-12 alkenylene, or substituted or unsubstituted, C2-12 alkynylene. 43. The compound of any one of claims 1-41, or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof, wherein L2 is substituted or unsubstituted, C1-12 alkylene, substituted or unsubstituted, C2-12 alkenylene, or substituted or unsubstituted, C2-12 alkynylene, wherein one or more backbone carbon atoms in the substituted or unsubstituted, C1-12 alkylene, substituted or unsubstituted, C2-12 alkenylene, or substituted or unsubstituted, C2-12 alkynylene are independently replaced with –O–, –NR5–, –S(=O)–, –S(=O)2–, or –C(=O)–. 44. The compound of any one of claims 1-41, or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof, wherein L2 is substituted or unsubstituted heterocyclylene. 45. The compound of any one of claims 1-41, or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof, wherein L2 is substituted or unsubstituted, monocyclic heterocyclylene. 46. The compound of any one of claims 1-41, or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof, wherein L2 is –(substituted or unsubstituted, monocyclic heterocyclylene)– (substituted or unsubstituted, C1-8 alkylene, substituted or unsubstituted, C2-8 alkenylene, or substituted or unsubstituted, C2-8 alkynylene)–, –(substituted or unsubstituted, bicyclic heterocyclylene)–(substituted or unsubstituted, C1-8 alkylene, substituted or unsubstituted, C2-8 alkenylene, or substituted or unsubstituted, C2-8 alkynylene)–, –(substituted or unsubstituted, monocyclic heteroarylene)–(substituted or unsubstituted, C1-8 alkylene, substituted or unsubstituted, C2-8 alkenylene, or substituted or unsubstituted, C2-8 alkynylene)–, –(substituted or unsubstituted, monocyclic carbocyclylene)–(substituted or unsubstituted, C1-8 alkylene, substituted or unsubstituted, C2-8 alkenylene, or substituted or unsubstituted, C2-8 alkynylene)–, – (substituted or unsubstituted, bicyclic carbocyclylene)–(substituted or unsubstituted, C1-8 alkylene, substituted or unsubstituted, C2-8 alkenylene, or substituted or unsubstituted, C2-8 alkynylene)–, –(substituted or unsubstituted, C1-8 alkylene, substituted or unsubstituted, C2-8 alkenylene, or substituted or unsubstituted, C2-8 alkynylene)–(substituted or unsubstituted, monocyclic heterocyclylene)–, –(substituted or unsubstituted, C1-8 alkylene, substituted or unsubstituted, C2-8 alkenylene, or substituted or unsubstituted, C2-8 alkynylene)–(substituted or unsubstituted, bicyclic heterocyclylene)–, –(substituted or unsubstituted, C1-8 alkylene, substituted or unsubstituted, C2-8 alkenylene, or substituted or unsubstituted, C2-8 alkynylene)– (substituted or unsubstituted, monocyclic heteroarylene)–, –(substituted or unsubstituted, C1-8 alkylene, substituted or unsubstituted, C2-8 alkenylene, or substituted or unsubstituted, C2-8 alkynylene)–(substituted or unsubstituted, monocyclic carbocyclylene)–, or –(substituted or unsubstituted, C1-8 alkylene, substituted or unsubstituted, C2-8 alkenylene, or substituted or unsubstituted, C2-8 alkynylene)–(substituted or unsubstituted, bicyclic carbocyclylene)–, optionally wherein one or more backbone carbon atoms in the substituted or unsubstituted, C1-8 alkylene, substituted or unsubstituted, C2-8 alkenylene, or substituted or unsubstituted, C2-8 alkynylene are independently replaced with –O–, –NR5–, –S(=O)–, –S(=O)2–, or –C(=O)–. 47. The compound of any one of claims 1-41, or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof, wherein L2 is –(substituted or unsubstituted, C1-8 alkylene, substituted or unsubstituted C28 alkenylene or substituted or unsubstituted C28 alkynylene) (substituted or unsubstituted, monocyclic heterocyclylene)–(substituted or unsubstituted, C1-8 alkylene, substituted or unsubstituted, C2-8 alkenylene, or substituted or unsubstituted, C2-8 alkynylene)–, – (substituted or unsubstituted, C1-8 alkylene, substituted or unsubstituted, C2-8 alkenylene, or substituted or unsubstituted, C2-8 alkynylene)–(substituted or unsubstituted, bicyclic heterocyclylene)–(substituted or unsubstituted, C1-8 alkylene, substituted or unsubstituted, C2-8 alkenylene, or substituted or unsubstituted, C2-8 alkynylene)–, –(substituted or unsubstituted, C1-8 alkylene, substituted or unsubstituted, C2-8 alkenylene, or substituted or unsubstituted, C2-8 alkynylene)–(substituted or unsubstituted, monocyclic heteroarylene)–(substituted or unsubstituted, C1-8 alkylene, substituted or unsubstituted, C2-8 alkenylene, or substituted or unsubstituted, C2-8 alkynylene)–, –(substituted or unsubstituted, C1-8 alkylene, substituted or unsubstituted, C2-8 alkenylene, or substituted or unsubstituted, C2-8 alkynylene)–(substituted or unsubstituted, monocyclic carbocyclylene)–(substituted or unsubstituted, C1-8 alkylene, substituted or unsubstituted, C2-8 alkenylene, or substituted or unsubstituted, C2-8 alkynylene)–, or –(substituted or unsubstituted, C1-8 alkylene, substituted or unsubstituted, C2-8 alkenylene, or substituted or unsubstituted, C2-8 alkynylene)–(substituted or unsubstituted, bicyclic carbocyclylene)–(substituted or unsubstituted, C1-8 alkylene, substituted or unsubstituted, C2-8 alkenylene, or substituted or unsubstituted, C2-8 alkynylene)–, optionally wherein one or more backbone carbon atoms in each instance of the substituted or unsubstituted, C1-8 alkylene, substituted or unsubstituted, C2-8 alkenylene, or substituted or unsubstituted, C2-8 alkynylene are independently replaced with –O–, –NR5–, –S(=O)–, –S(=O)2–, or –C(=O)–. 48. The compound of any one of claims 1-41, or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof, wherein L2 is –(substituted or unsubstituted, monocyclic heterocyclylene)2– (substituted or unsubstituted, C1-2 alkylene)–, –(substituted or unsubstituted, C1-2 alkylene)– (substituted or unsubstituted, monocyclic heterocyclylene)2–, or –(substituted or unsubstituted, C1-2 alkylene)–(substituted or unsubstituted, monocyclic heterocyclylene)2–(substituted or unsubstituted, C1-2 alkylene)–, optionally wherein one or more of the backbone carbon atoms in each instance of the substituted or unsubstituted, C1-2 alkylene are independently replaced with – O–, –NR5–, –S(=O)–, –S(=O)2–, or –C(=O)–. 49. The compound of any one of claims 1-41, or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof, wherein L2 is H ( )rN , , , , , , , , , N X N , , , wherein: each n is independently 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10; each p is independently 0, 1, 2, 3, or 4; each q is independently 1, 2, or 3; each r is independently 1 or 2; each s is independently 1, 2, 3, or 4; each t is independently 1, 2, 3, 4, or 5; and each u is independently 0, 1, 2, 3, 4, or 5. 50. The compound of any one of claims 1-49, or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof, wherein L3 is a bond. 51. The compound of any one of claims 1-49, or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof, wherein L3 is substituted or unsubstituted, C1-13 alkylene, substituted or unsubstituted, C2-13 alkenylene, or substituted or unsubstituted, C2-13 alkynylene. 52. The compound of any one of claims 1-49, or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof, wherein L3 is substituted or unsubstituted, C1-13 alkylene, substituted or unsubstituted, C2-13 alkenylene, or substituted or unsubstituted, C2-13 alkynylene, wherein one or more backbone carbon atoms in the substituted or unsubstituted C113 alkylene substituted or unsubstituted, C2-13 alkenylene, or substituted or unsubstituted, C2-13 alkynylene are independently replaced with –O–, –NR5–, –S(=O)–, –S(=O)2–, or –C(=O)–. 53. The compound of any one of claims 1-49, or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof, wherein L3 is substituted or unsubstituted, monocyclic heterocyclylene or substituted or unsubstituted, bicyclic heterocyclylene. 54. The compound of any one of claims 1-49, or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof, wherein L3 is –(substituted or unsubstituted, monocyclic heterocyclylene)– (substituted or unsubstituted, C1 alkylene)–, –(substituted or unsubstituted, bicyclic heterocyclylene)–(substituted or unsubstituted, C1 alkylene)–, –(substituted or unsubstituted, C1 alkylene)–(substituted or unsubstituted, monocyclic heterocyclylene)–, –(substituted or unsubstituted, C1 alkylene)–(substituted or unsubstituted, bicyclic heterocyclylene)–, – (substituted or unsubstituted, C2 alkylene)–(substituted or unsubstituted, bicyclic carbocyclylene)–, –(substituted or unsubstituted, bicyclic carbocyclylene)–(substituted or unsubstituted, C2 alkylene)–, optionally wherein one backbone carbon atom in the substituted or unsubstituted, C1 alkylene or C2 alkylene is replaced with –O–, –NR5–, –S(=O)–, –S(=O)2–, or – C(=O)–. 55. The compound of any one of claims 1-49, or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof, wherein L3 is –(substituted or unsubstituted, C1 alkylene)–(substituted or unsubstituted, monocyclic heterocyclylene)–(substituted or unsubstituted, C1 alkylene)– or – (substituted or unsubstituted, C1 alkylene)–(substituted or unsubstituted, bicyclic heterocyclylene)–(substituted or unsubstituted, C1 alkylene)–, optionally wherein the backbone carbon atom in each instance of the substituted or unsubstituted, C1 alkylene is independently replaced with –O–, –NR5–, –S(=O)–, –S(=O)2–, or –C(=O)–. 56. The compound of any one of claims 1-49, or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof, wherein L3 is –(substituted or unsubstituted, monocyclic heterocyclylene)2–, – (substituted or unsubstituted, monocyclic heterocyclylene)2–(substituted or unsubstituted, C1 alkylene)–, –(substituted or unsubstituted, C1 alkylene)–(substituted or unsubstituted, monocyclic heterocyclylene)2 (substituted or unsubstituted C1 alkylene) (substituted or unsubstituted monocyclic heterocyclylene)2–(substituted or unsubstituted, C1 alkylene)–, –(substituted or unsubstituted, monocyclic heterocyclylene)–(substituted or unsubstituted, monocyclic carbocyclylene)–, or –(substituted or unsubstituted, monocyclic carbocyclylene)–(substituted or unsubstituted, monocyclic heterocyclylene)–, optionally wherein the backbone carbon atom in each instance of the substituted or unsubstituted, C1 alkylene is independently replaced with –O–, –NR5–, –S(=O)–, –S(=O)2–, or –C(=O)–. 57. The compound of any one of claims 1-49, or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof, wherein L3 is –(substituted or unsubstituted, C1 alkylene)–(substituted or unsubstituted, monocyclic heterocyclylene)– or –(substituted or unsubstituted, monocyclic heterocyclylene)–(substituted or unsubstituted, C1 alkylene)–. 58. The compound of any one of claims 1-49, or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof, wherein L3 is , , , , , wherein: each n is independently 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10; each p is independently 0, 1, 2, 3, or 4; each q is independently 1 2 or 3; each r is independently 1 or 2; each s is independently 1, 2, 3, or 4; each t is independently 1, 2, 3, 4, or 5; and each u is independently 0, 1, 2, 3, 4, or 5. 59. The compound of any one of claims 1-58, or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof, wherein at least one instance of R5 is hydrogen. 60. The compound of any one of claims 1-58, or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof, wherein at least one instance of R5 is substituted or unsubstituted alkyl or substituted or unsubstituted carbocyclyl. 61. The compound of any one of claims 1-60, or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof, wherein L3 is attached to the 2 or 3 position. 62. The compound of any one of claims 1-60, or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof, wherein L3 is attached to the 1 or 4 position. 63. The compound of claim 1, or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof, wherein the compound is of the formula: 64. The compound of claim 1, or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof, wherein the compound is of the formula: 65. The compound of any one of claims 1-64, or a pharmaceutically acceptable salt thereof. 66. A pharmaceutical composition comprising a compound of any one of claims 1-64, or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof, and a pharmaceutically acceptable carrier. 67. The pharmaceutical composition of claim 66 further comprising an additional pharmaceutical agent. 68. The pharmaceutical composition of claim 67, wherein the additional pharmaceutical agent is an anti-cancer agent. 69. The pharmaceutical composition of claim 68, wherein the anti-cancer agent is an alkylating agent, an anti-metabolite, an anti-tumor antibiotic, an anti-cytoskeletal agent, a topoisomerase inhibitor, an anti-hormonal agent, a targeted therapeutic agent, a photodynamic therapeutic agent, or a combination thereof. 70. A kit comprising: a compound of any one of claims 1-64, or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof, or a pharmaceutical composition of any one of claims 66-69; and instructions for using the compound, or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof, or the pharmaceutical composition. 71. A method of degrading a Bcl-2 protein in a cell, tissue, or biological sample, the method comprising contacting the cell, tissue, or biological sample with an effective amount of a compound of any one of claims 1-64, or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof, or a pharmaceutical composition of any one of claims 66-69. 72. A method of degrading a Bcl-xL protein in a cell, tissue, or biological sample, the method comprising contacting the cell, tissue, or biological sample with an effective amount of a compound of any one of claims 1-64, or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof, or a pharmaceutical composition of any one of claims 66-69. 73. The method of any one of claims 71-72, wherein the cell is a cancer cell. 74. A method of selectively killing one or more cancer cells in a tissue or biological sample comprising contacting the tissue or biological sample with an effective amount of a compound of any one of claims 1-64, or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co- crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof, or a pharmaceutical composition of any one of claims 66-69. 75. The method of any one of claims 71-74, wherein the cell, tissue, biological sample, or cancer cell is in vitro. 76. The method of any one of claims 71-74, wherein the cell, tissue, biological sample, or cancer cell is in a subject. 77. A method of treating a disease in a subject in need thereof, the method comprising administering to the subject an effective amount of a compound of any one of claims 1-64, or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof, or a pharmaceutical composition of any one of claims 66-69. 78. A method of preventing a disease in a subject in need thereof, the method comprising administering to the subject an effective amount of a compound of any one of claims 1-64, or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof, or a pharmaceutical composition of any one of claims 66-69. 79. The method of any one of claims 77-78, wherein the disease is an age-related disease. 80. The method of any one of claims 77-79, wherein the disease is an age-related cognitive dysfunction, age-related intervertebral disc disease, age-related muscle loss, Alzheimer’s disease, amyotrophic lateral sclerosis, ataxia, AV fistulae, bone marrow transplant complication, cardiac dysfunction, cataracts, chemotherapy complication, chronic obstructive, cirrhosis, COVID-19 complication, diabetes, frailty, glaucoma, hepatic steatosis, hyperoxic lung damage, idiopathic pulmonary fibrosis, macular degeneration, MGUS, myeloma, obesity, obesity-related neuropsychiatric dysfunction, organ transplantation complication, osteoarthritis, osteoporosis, Parkinson’s disease, pre-eclampsia, primary biliary cirrhosis, progerias, prostatic hypertrophy, psoriasis, pulmonary disease, radiation complication, renal dysfunction, urinary incontinence, vascular calcification, or vascular hyporeactivity. 81. The method of any one of claims 77-79, wherein the disease is cancer. 82. A method of selectively killing one or more cancer cells in a subject in need thereof comprising administering to the subject an effective amount of a compound of any one of claims 1-64, or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof, or a pharmaceutical composition of any one of claims 66-69. 83. The method of any one of claims 73-76 and 81-82, wherein the cancer is a Bcl-2- mediated cancer. 84. The method of any one of claims 73-76 and 81-83, wherein the cancer is a Bcl-xL- mediated cancer. 85. The method of any one of claims 73-76 and 81-84, wherein the cancer is a hematological malignancy. 86. The method of claim 85, wherein the cancer is leukemia. 87. The method of claim 85, wherein the cancer is acute myeloid leukemia, chronic lymphocytic leukemia, or acute lymphoblastic leukemia. 88. The method of claim 85, wherein the cancer is lymphoma. 89. The method of claim 85, wherein the cancer is T-cell lymphoma. 90. The method of any one of claims 73-76 and 81-84, wherein the cancer is a solid tumor. 91. The method of any one of claims 76-90, wherein the subject is a mammal. 92. The method of claim 91, wherein the subject is a human. |
, , , , , wherein: each n is independently 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10; each p is independently 0, 1, 2, 3, or 4; each q is independently 1, 2, or 3; each r is independently 1 or 2; each s is independently 1, 2, 3, or 4; each t is independently 1, 2, 3, 4, or 5; and each u is independently 0, 1, 2, 3, 4, or 5. In certain embodiments, R 1 is of the formula: . In certain embodiments, R1 is of the formula: . In certain embodiments, R 1 is of the formula: . In certain embodiments, R2 is NO2. In certain embodiments, R2 is SO2CF3. In certain embodiments, R3 is . In certain embodiments, R3 is . In certain embodiments, . In certain embodiments, R b is halogen. In certain embodiments, R b is Cl. In certain embodiments, R b is F. In certain embodiments, R b is substituted or unsubstituted alkyl. In certain embodiments, R b is unsubstituted C1-6 alkyl. In certain embodiments, R b is –CH3. In certain embodiments, R b is substituted C 1-6 alkyl. In certain embodiments, R b is substituted methyl. In certain embodiments, R b is methyl substituted at least with halogen. In certain embodiments, R b is alkyl substituted only with one or more (e.g., two or three) instances of fluoro. In certain embodiments, R b is –CFH 2 , –CF 2 H, or –CF 3 . . In certain embodiments, Z is a bond. In certain embodiments, Z is CH2. In certain embodiments, Z is CO. In certain embodiments, Y is CO. , , , . , . , . In certain embodiments, n1 is 0. In certain embodiments, n1 is 1. In certain embodiments, n1 is 1, 2, or 3, and each instance of R4 is independently F, Cl, –CN, –CFH2, –CF2H, –CF3, or – OCH3. In certain embodiments, at least one instance of R4 is F. In certain embodiments, L 1 is substituted or unsubstituted, C 1-11 alkylene. In certain embodiments, L1 is unsubstituted C1-2 alkylene. In certain embodiments, L1 is –CH2–. In certain embodiments, L1 is unsubstituted, C3-5 alkylene. In certain embodiments, L1 is unsubstituted C6-8 alkylene. In certain embodiments, L 1 is unsubstituted, C 9-11 alkylene. In certain embodiments, L 1 is substituted or unsubstituted, C 1-11 alkylene, wherein one or more (e.g., two or three) backbone carbon atoms in the substituted or unsubstituted, C1-11 alkylene are independently replaced with –O–, –NR5–, –S(=O)–, –S(=O)2–, or –C(=O)–. In certain embodiments, L 1 is substituted or unsubstituted, C 1-3 alkylene, wherein one or more (e.g., two or three) backbone carbon atoms in the substituted or unsubstituted, C1-3 alkylene are independently replaced with –O–, –NR5–, –S(=O)–, –S(=O)2–, or –C(=O)–. In certain embodiments, L 1 is substituted or unsubstituted, C 4-5 alkylene, wherein one or more (e.g., two or three) backbone carbon atoms in the substituted or unsubstituted, C4-5 alkylene are independently replaced with –O–, –NR5–, –S(=O)–, –S(=O)2–, or –C(=O)–. In certain embodiments, L1 is substituted or unsubstituted, C 6-7 alkylene, wherein one or more (e.g., two or three) backbone carbon atoms in the substituted or unsubstituted, C 6-7 alkylene are independently replaced with – O–, –NR5–, –S(=O)–, –S(=O)2–, or –C(=O)–. In certain embodiments, L1 is substituted or unsubstituted, C8-9 alkylene, wherein one or more (e.g., two or three) backbone carbon atoms in the substituted or unsubstituted, C 8-9 alkylene are independently replaced with –O–, –NR 5 –, – S(=O)–, –S(=O)2–, or –C(=O)–. In certain embodiments, L1 is substituted or unsubstituted, C10-11 alkylene, wherein one or more (e.g., two or three) backbone carbon atoms in the substituted or unsubstituted, C 10-11 alkylene are independently replaced with –O–, –NR 5 –, –S(=O)–, –S(=O) 2 –, or –C(=O)–. In certain embodiments, L1 is substituted or unsubstituted, C2 alkylene, wherein one or two backbone carbon atoms in the substituted or unsubstituted, C 2 alkylene are independently replaced with –O–, –NR5–, –S(=O)–, –S(=O)2–, or –C(=O)–. In certain embodiments, L1 is substituted or unsubstituted, C3 alkylene, wherein one, two, or three backbone carbon atoms in the substituted or unsubstituted, C 3 alkylene are independently replaced with –O–, –NR 5 –, – S(=O)–, –S(=O)2–, or –C(=O)–. In certain embodiments, L1 is substituted or unsubstituted, monocyclic heterocyclylene, substituted or unsubstituted, bicyclic heterocyclylene, or substituted or unsubstituted, monocyclic heteroarylene. In certain embodiments, L1 is –(substituted or unsubstituted, monocyclic heterocyclylene)–(substituted or unsubstituted, C 1-2 alkylene)–, –(substituted or unsubstituted, bicyclic heterocyclylene)–(substituted or unsubstituted, C 1-2 alkylene)–, –(substituted or unsubstituted, monocyclic heteroarylene)–(substituted or unsubstituted, C1-2 alkylene)–, – (substituted or unsubstituted, C1-2 alkylene)–(substituted or unsubstituted, monocyclic heterocyclylene)–, –(substituted or unsubstituted, C 1-2 alkylene)–(substituted or unsubstituted, bicyclic heterocyclylene)–, or –(substituted or unsubstituted, C1-2 alkylene)–(substituted or unsubstituted, monocyclic heteroarylene)–, optionally wherein one or two backbone carbon atoms in the substituted or unsubstituted, C 1-2 alkylene are independently replaced with –O–, – NR5–, –S(=O)–, –S(=O)2–, or –C(=O)–. In certain embodiments, L1 is –(substituted or unsubstituted, C1-2 alkylene)–(substituted or unsubstituted, monocyclic heterocyclylene)–(substituted or unsubstituted, C 1-2 alkylene)–, – (substituted or unsubstituted, C 1-2 alkylene)–(substituted or unsubstituted, bicyclic heterocyclylene)–(substituted or unsubstituted, C1-2 alkylene)–, or –(substituted or unsubstituted, C1-2 alkylene)–(substituted or unsubstituted, monocyclic heteroarylene)–(substituted or unsubstituted, C 1-2 alkylene)–, optionally wherein one or two backbone carbon atoms in each instance of the substituted or unsubstituted, C1-2 alkylene are independently replaced with –O–, – NR5–, –S(=O)–, –S(=O)2–, or –C(=O)–. In certain embodiments, L 1 is –(substituted or unsubstituted, monocyclic heterocyclylene)2–(substituted or unsubstituted, C1 alkylene)–, –(substituted or unsubstituted, C1 alkylene)–(substituted or unsubstituted, monocyclic heterocyclylene)2–, –(substituted or unsubstituted, C 1 alkylene)–(substituted or unsubstituted, monocyclic heterocyclylene) 2 – (substituted or unsubstituted, C 1 alkylene)–, –(substituted or unsubstituted, monocyclic heterocyclylene)–(substituted or unsubstituted, monocyclic carbocyclylene)–(substituted or unsubstituted, C1 alkylene)–, –(substituted or unsubstituted, monocyclic carbocyclylene)– (substituted or unsubstituted, monocyclic heterocyclylene)–(substituted or unsubstituted, C 1 alkylene)–, –(substituted or unsubstituted, C1 alkylene)–(substituted or unsubstituted, monocyclic heterocyclylene)–(substituted or unsubstituted, monocyclic carbocyclylene)–, or –(substituted or unsubstituted, C1 alkylene)–(substituted or unsubstituted, monocyclic carbocyclylene)– (substituted or unsubstituted, monocyclic heterocyclylene)–, optionally wherein the backbone carbon atom in each instance of the substituted or unsubstituted, C 1 alkylene is independently replaced with –O–, –NR5–, –S(=O)–, –S(=O)2–, or –C(=O)–. In certain embodiments, L1 is , , , , ,
N N N N O , O , , , , , , N N , O , , ,
, , ,
, Each n is independently 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10. Each p is independently 0, 1, 2, 3, or 4. Each q is independently 1, 2, or 3. Each r is independently 1 or 2. Each s is independently 1, 2, 3, or 4. Each t is independently 1, 2, 3, 4, or 5. Each u is independently 0, 1, 2, 3, 4, or 5. In certain embodiments, . In certain embodiments, at least one instance of R 5 is hydrogen. In certain embodiments, at least one instance of R5 is substituted or unsubstituted alkyl or substituted or unsubstituted carbocyclyl. In certain embodiments, each instance of R 5 is hydrogen. In certain embodiments, at least one instance of R 5 is not hydrogen. In certain embodiments, no instance of R 5 is hydrogen. In certain embodiments, at least one instance of R5 is substituted alkyl (e.g., alkyl substituted with one or more (e.g., two or three) instances of halogen (e.g., F)). In certain embodiments, at least one instance of R 5 is unsubstituted alkyl. In certain embodiments, at least one instance of R 5 is unsubstituted C1-6 alkyl. In certain embodiments, at least one instance of R5 is Me. In certain embodiments, at least one instance of R5 is Et, Pr, or Bu. In certain embodiments, at least one instance of R 5 is substituted C 1-6 alkyl. In certain embodiments, at least one instance of R 5 is substituted methyl (e.g., fluorinated methyl or Bn). In certain embodiments, at least one instance of R5 is substituted ethyl, substituted propyl, or substituted butyl. In certain embodiments, at least one instance of R 5 is substituted or unsubstituted alkenyl. In certain embodiments, at least one instance of R 5 is substituted or unsubstituted, C 2-6 alkenyl (e.g., substituted or unsubstituted vinyl or substituted or unsubstituted allyl). In certain embodiments, at least one instance of R5 is substituted or unsubstituted alkynyl. In certain embodiments, at least one instance of R5 is substituted or unsubstituted, C 2-6 alkynyl (e.g., substituted or unsubstituted ethynyl). In certain embodiments, at least one instance of R5 is substituted or unsubstituted carbocyclyl (e.g., substituted or unsubstituted, monocyclic, 3- to 7-membered carbocyclyl comprising 0, 1, or 2 double bonds in the carbocyclic ring system, as valency permits). In certain embodiments, at least one instance of R5 is substituted or unsubstituted cyclopropyl, substituted or unsubstituted cyclobutyl, substituted or unsubstituted cyclopentyl, substituted or unsubstituted cyclohexyl, or substituted or unsubstituted cycloheptyl. In certain embodiments, at least one instance of R 5 is substituted or unsubstituted heterocyclyl (e.g., substituted or unsubstituted, 3- to 7-membered, monocyclic heterocyclyl). In certain embodiments, at least one instance of R5 is substituted or unsubstituted oxetanyl, substituted or unsubstituted tetrahydrofuranyl, substituted or unsubstituted tetrahydropyranyl, substituted or unsubstituted azetidinyl, substituted or unsubstituted pyrrolidinyl, substituted or unsubstituted piperidinyl, substituted or unsubstituted morpholinyl, or substituted or unsubstituted piperazinyl. In certain embodiments, at least one instance of R 5 is substituted or unsubstituted aryl. In certain embodiments, at least one instance of R 5 is substituted or unsubstituted phenyl. In certain embodiments, at least one instance of R 5 is substituted or unsubstituted naphthyl. In certain embodiments, at least one instance of R5 is substituted or unsubstituted heteroaryl. In certain embodiments, at least one instance of R5 is substituted or unsubstituted, 5- to 6-membered, monocyclic heteroaryl. In certain embodiments, at least one instance of R5 is substituted or unsubstituted furanyl, substituted or unsubstituted thienyl, substituted or unsubstituted pyrrolyl, substituted or unsubstituted imidazolyl, substituted or unsubstituted oxazolyl, substituted or unsubstituted isoxazolyl, substituted or unsubstituted thiazolyl, or substituted or unsubstituted isothiazolyl. In certain embodiments, at least one instance of R5 is substituted or unsubstituted pyridinyl, substituted or unsubstituted pyrazinyl, substituted or unsubstituted pyrimidinyl, or substituted or unsubstituted pyridazinyl. In certain embodiments, at least one instance of R 5 is substituted or unsubstituted, 9- to 10-membered, bicyclic heteroaryl. In certain embodiments, L2 is substituted or unsubstituted, C1-12 alkylene, substituted or unsubstituted, C 2-12 alkenylene, or substituted or unsubstituted, C 2-12 alkynylene. In certain embodiments, L2 is unsubstituted, C1-2 alkylene. In certain embodiments, L2 is unsubstituted, C3-4 alkylene. In certain embodiments, L2 is unsubstituted, C5-6 alkylene. In certain embodiments, L2 is unsubstituted, C 7-9 alkylene. In certain embodiments, L 2 is unsubstituted, C 10-12 alkylene. In certain embodiments, L2 is unsubstituted C2-12 alkenylene comprising only one unsaturated CC bond in the backbone. In certain embodiments, L2 is unsubstituted C2-12 alkynylene comprising only one unsaturated CC bond in the backbone. In certain embodiments, L 2 is substituted or unsubstituted, C 1-12 alkylene, substituted or unsubstituted, C2-12 alkenylene, or substituted or unsubstituted, C2-12 alkynylene, wherein one or more (e.g., two or three) backbone carbon atoms in the substituted or unsubstituted, C1-12 alkylene, substituted or unsubstituted, C 2-12 alkenylene, or substituted or unsubstituted, C 2-12 alkynylene are independently replaced with –O–, –NR5–, –S(=O)–, –S(=O)2–, or –C(=O)–. In certain embodiments, L2 is –(substituted or unsubstituted, monocyclic heterocyclylene)–(substituted or unsubstituted, C 1-8 alkylene, substituted or unsubstituted, C 2-8 alkenylene, or substituted or unsubstituted, C2-8 alkynylene)–, –(substituted or unsubstituted, bicyclic heterocyclylene)–(substituted or unsubstituted, C1-8 alkylene, substituted or unsubstituted, C 2-8 alkenylene, or substituted or unsubstituted, C 2-8 alkynylene)–, –(substituted or unsubstituted, monocyclic heteroarylene)–(substituted or unsubstituted, C 1-8 alkylene, substituted or unsubstituted, C2-8 alkenylene, or substituted or unsubstituted, C2-8 alkynylene)–, –(substituted or unsubstituted, monocyclic carbocyclylene)–(substituted or unsubstituted, C1-8 alkylene, substituted or unsubstituted, C 2-8 alkenylene, or substituted or unsubstituted, C 2-8 alkynylene)–, – (substituted or unsubstituted, bicyclic carbocyclylene)–(substituted or unsubstituted, C1-8 alkylene, substituted or unsubstituted, C 2-8 alkenylene, or substituted or unsubstituted, C 2-8 alkynylene)–, –(substituted or unsubstituted, C1-8 alkylene, substituted or unsubstituted, C2-8 alkenylene, or substituted or unsubstituted, C2-8 alkynylene)–(substituted or unsubstituted, monocyclic heterocyclylene)–, –(substituted or unsubstituted, C 1-8 alkylene, substituted or unsubstituted, C2-8 alkenylene, or substituted or unsubstituted, C2-8 alkynylene)–(substituted or unsubstituted, bicyclic heterocyclylene)–, –(substituted or unsubstituted, C1-8 alkylene, substituted or unsubstituted, C 2-8 alkenylene, or substituted or unsubstituted, C 2-8 alkynylene)– (substituted or unsubstituted, monocyclic heteroarylene)–, –(substituted or unsubstituted, C1-8 alkylene, substituted or unsubstituted, C2-8 alkenylene, or substituted or unsubstituted, C2-8 alkynylene)–(substituted or unsubstituted, monocyclic carbocyclylene)–, or –(substituted or unsubstituted, C 1-8 alkylene, substituted or unsubstituted, C 2-8 alkenylene, or substituted or unsubstituted, C2-8 alkynylene)–(substituted or unsubstituted, bicyclic carbocyclylene)–, optionally wherein one or more (e.g., two or three) backbone carbon atoms in the substituted or unsubstituted, C 1-8 alkylene, substituted or unsubstituted, C 2-8 alkenylene, or substituted or unsubstituted, C2-8 alkynylene are independently replaced with –O–, –NR5–, –S(=O)–, –S(=O)2–, or –C(=O)–. In certain embodiments, L 2 is –(substituted or unsubstituted, C 1-8 alkylene, substituted or unsubstituted, C2-8 alkenylene, or substituted or unsubstituted, C2-8 alkynylene)–(substituted or unsubstituted, monocyclic heterocyclylene)–(substituted or unsubstituted, C1-8 alkylene, substituted or unsubstituted, C 2-8 alkenylene, or substituted or unsubstituted, C 2-8 alkynylene)–, – (substituted or unsubstituted, C 1-8 alkylene, substituted or unsubstituted, C 2-8 alkenylene, or substituted or unsubstituted, C2-8 alkynylene)–(substituted or unsubstituted, bicyclic heterocyclylene)–(substituted or unsubstituted, C1-8 alkylene, substituted or unsubstituted, C2-8 alkenylene, or substituted or unsubstituted, C 2-8 alkynylene)–, –(substituted or unsubstituted, C 1-8 alkylene, substituted or unsubstituted, C2-8 alkenylene, or substituted or unsubstituted, C2-8 alkynylene)–(substituted or unsubstituted, monocyclic heteroarylene)–(substituted or unsubstituted, C 1-8 alkylene, substituted or unsubstituted, C 2-8 alkenylene, or substituted or unsubstituted, C2-8 alkynylene)–, –(substituted or unsubstituted, C1-8 alkylene, substituted or unsubstituted, C2-8 alkenylene, or substituted or unsubstituted, C2-8 alkynylene)–(substituted or unsubstituted, monocyclic carbocyclylene)–(substituted or unsubstituted, C 1-8 alkylene, substituted or unsubstituted, C 2-8 alkenylene, or substituted or unsubstituted, C 2-8 alkynylene)–, or –(substituted or unsubstituted, C1-8 alkylene, substituted or unsubstituted, C2-8 alkenylene, or substituted or unsubstituted, C2-8 alkynylene)–(substituted or unsubstituted, bicyclic carbocyclylene)–(substituted or unsubstituted, C 1-8 alkylene, substituted or unsubstituted, C 2-8 alkenylene, or substituted or unsubstituted, C2-8 alkynylene)–, optionally wherein one or more (e.g., two or three) backbone carbon atoms in each instance of the substituted or unsubstituted, C1-8 alkylene, substituted or unsubstituted, C2-8 alkenylene, or substituted or unsubstituted, C2-8 alkynylene are independently replaced with –O–, –NR5–, –S(=O)–, –S(=O)2–, or –C(=O)–. In certain embodiments, L 2 is –(substituted or unsubstituted, monocyclic heterocyclylene)2–(substituted or unsubstituted, C1-2 alkylene)–, –(substituted or unsubstituted, C1-2 alkylene)–(substituted or unsubstituted, monocyclic heterocyclylene)2–, or –(substituted or unsubstituted, C 1-2 alkylene)–(substituted or unsubstituted, monocyclic heterocyclylene) 2 – (substituted or unsubstituted, C1-2 alkylene)–, optionally wherein one or more (e.g., two or three) of the backbone carbon atoms in each instance of the substituted or unsubstituted, C1-2 alkylene are independently replaced with –O–, –NR 5 –, –S(=O)–, –S(=O) 2 –, or –C(=O)–. In certain embodiments, L 2 is substituted or unsubstituted heterocyclylene. In certain embodiments, L2 is substituted or unsubstituted, monocyclic heterocyclylene. In certain embodiments, L2 is substituted or unsubstituted, monocyclic, 3- to 8-membered heterocyclylene. In certain embodiments, L 2 is substituted or unsubstituted, bicyclic heterocyclylene. In certain embodiments, L2 is substituted or unsubstituted, bicyclic, 5- to 14-membered heterocyclylene. In certain embodiments, L2 is , , , ,
, , , , , , , , , , , ,
. In certain embodiments, R 6 is F, Cl, –CN, –CFH 2 , –CF 2 H, –CF 3 , or –OCH 3 . In certain embodiments, R6 is H. In certain embodiments, L 3 is a bond. In certain embodiments, L 3 is substituted or unsubstituted, C 1-13 alkylene, substituted or unsubstituted, C 2-13 alkenylene, or substituted or unsubstituted, C2-13 alkynylene. In certain embodiments, L3 is unsubstituted, C1-2 alkylene. In certain embodiments, L3 is unsubstituted, C3-4 alkylene. In certain embodiments, L3 is unsubstituted, C 5-6 alkylene. In certain embodiments, L 3 is unsubstituted, C 7-10 alkylene. In certain embodiments, L 3 is unsubstituted, C 10-13 alkylene. In certain embodiments, L 3 is unsubstituted C 2- 13 alkenylene comprising only one unsaturated CC bond in the backbone. In certain embodiments, L 3 is unsubstituted C 2-13 alkynylene comprising only one unsaturated CC bond in the backbone. In certain embodiments, L 3 is substituted or unsubstituted, C 1-13 alkylene, wherein one or more (e.g., two or three) backbone carbon atoms in the substituted or unsubstituted, C1-13 alkylene are independently replaced with –O–, –NR5–, –S(=O)–, –S(=O)2–, or –C(=O)–. In certain embodiments, L 3 is substituted or unsubstituted, C 1-3 alkylene, wherein one or more (e.g., two or three) backbone carbon atoms in the substituted or unsubstituted, C1-3 alkylene are independently replaced with –O–, –NR5–, –S(=O)–, –S(=O)2–, or –C(=O)–. In certain embodiments, L 3 is substituted or unsubstituted, C 4-5 alkylene, wherein one or more (e.g., two or three) backbone carbon atoms in the substituted or unsubstituted, C4-5 alkylene are independently replaced with –O–, –NR5–, –S(=O)–, –S(=O)2–, or –C(=O)–. In certain embodiments, L3 is substituted or unsubstituted, C 6-7 alkylene, wherein one or more (e.g., two or three) backbone carbon atoms in the substituted or unsubstituted, C 6-7 alkylene are independently replaced with – O–, –NR5–, –S(=O)–, –S(=O)2–, or –C(=O)–. In certain embodiments, L3 is substituted or unsubstituted, C8-9 alkylene, wherein one or more (e.g., two or three) backbone carbon atoms in the substituted or unsubstituted, C 8-9 alkylene are independently replaced with –O–, –NR 5 –, – S(=O)–, –S(=O)2–, or –C(=O)–. In certain embodiments, L3 is substituted or unsubstituted, C10-13 alkylene, wherein one or more (e.g., two or three) backbone carbon atoms in the substituted or unsubstituted, C 10-13 alkylene are independently replaced with –O–, –NR 5 –, –S(=O)–, –S(=O) 2 –, or –C(=O)–. In certain embodiments, L3 is substituted or unsubstituted, C2 alkylene, wherein one or two backbone carbon atoms in the substituted or unsubstituted, C2 alkylene are independently replaced with –O–, –NR 5 –, –S(=O)–, –S(=O) 2 –, or –C(=O)–. In certain embodiments, L 3 is substituted or unsubstituted, C 3 alkylene, wherein one, two, or three backbone carbon atoms in the substituted or unsubstituted, C3 alkylene are independently replaced with –O–, –NR5–, – S(=O)–, –S(=O)2–, or –C(=O)–. In certain embodiments, L3 is substituted or unsubstituted, C4 alkylene, wherein one, two, or three backbone carbon atoms in the substituted or unsubstituted, C4 alkylene are independently replaced with –O–, –NR5–, –S(=O)–, –S(=O)2–, or –C(=O)–. In certain embodiments, L3 is substituted or unsubstituted, C5 alkylene, wherein one, two, or three backbone carbon atoms in the substituted or unsubstituted, C 5 alkylene are independently replaced with –O–, –NR5–, –S(=O)–, –S(=O)2–, or –C(=O)–. In certain embodiments, L3 is substituted or unsubstituted, C6 alkylene, wherein one, two, or three backbone carbon atoms in the substituted or unsubstituted, C 6 alkylene are independently replaced with –O–, –NR 5 –, – S(=O)–, –S(=O) 2 –, or –C(=O)–. In certain embodiments, L3 is substituted or unsubstituted, C1-13 alkylene, substituted or unsubstituted, C2-13 alkenylene, or substituted or unsubstituted, C2-13 alkynylene, wherein one or more (e.g., two or three) backbone carbon atoms in the substituted or unsubstituted, C 1-13 alkylene, substituted or unsubstituted, C 2-13 alkenylene, or substituted or unsubstituted, C 2-13 alkynylene are independently replaced with –O–, –NR5–, –S(=O)–, –S(=O)2–, or –C(=O)–. In certain embodiments, L3 is substituted or unsubstituted, monocyclic heterocyclylene or substituted or unsubstituted, bicyclic heterocyclylene. In certain embodiments, L3 is –(substituted or unsubstituted, monocyclic heterocyclylene)–(substituted or unsubstituted, C1 alkylene)–, –(substituted or unsubstituted, bicyclic heterocyclylene)–(substituted or unsubstituted, C 1 alkylene)–, –(substituted or unsubstituted, C1 alkylene)–(substituted or unsubstituted, monocyclic heterocyclylene)–, – (substituted or unsubstituted, C1 alkylene)–(substituted or unsubstituted, bicyclic heterocyclylene)–, –(substituted or unsubstituted, C 2 alkylene)–(substituted or unsubstituted, bicyclic carbocyclylene)–, –(substituted or unsubstituted, bicyclic carbocyclylene)–(substituted or unsubstituted, C2 alkylene)–, optionally wherein one backbone carbon atom in the substituted or unsubstituted, C1 alkylene or C2 alkylene is replaced with –O–, –NR5–, –S(=O)–, –S(=O)2–, or –C(=O)–. In certain embodiments, L3 is –(substituted or unsubstituted, C1 alkylene)–(substituted or unsubstituted, monocyclic heterocyclylene)–(substituted or unsubstituted, C1 alkylene)– or – (substituted or unsubstituted, C 1 alkylene)–(substituted or unsubstituted, bicyclic heterocyclylene)–(substituted or unsubstituted, C1 alkylene)–, optionally wherein the backbone carbon atom in each instance of the substituted or unsubstituted, C1 alkylene is independently replaced with –O–, –NR 5 –, –S(=O)–, –S(=O) 2 –, or –C(=O)–. In certain embodiments, L 3 is –(substituted or unsubstituted, C 1 alkylene)–(substituted or unsubstituted, monocyclic heterocyclylene)– or –(substituted or unsubstituted, monocyclic heterocyclylene)–(substituted or unsubstituted, C1 alkylene)–. In certain embodiments, L 3 is –(substituted or unsubstituted, monocyclic heterocyclylene)2–, –(substituted or unsubstituted, monocyclic heterocyclylene)2–(substituted or unsubstituted, C1 alkylene)–, –(substituted or unsubstituted, C1 alkylene)–(substituted or unsubstituted, monocyclic heterocyclylene) 2 –, –(substituted or unsubstituted, C 1 alkylene)– (substituted or unsubstituted, monocyclic heterocyclylene)2–(substituted or unsubstituted, C1 alkylene)–, –(substituted or unsubstituted, monocyclic heterocyclylene)–(substituted or unsubstituted, monocyclic carbocyclylene)–, or –(substituted or unsubstituted, monocyclic carbocyclylene)–(substituted or unsubstituted, monocyclic heterocyclylene)–, optionally wherein the backbone carbon atom in each instance of the substituted or unsubstituted, C1 alkylene is independently replaced with –O–, –NR5–, –S(=O)–, –S(=O)2–, or –C(=O)–. In certain embodiments, L 3 is
, , , , , ,
, , , , , , , In certain embodiments, L3 is attached to the 2 or 3 position. In certain embodiments, L3 is attached to the 1 or 4 position. In certain embodiments, the compound is of the formula: Compo Numb 1
or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof.
In certain embodiments, the compound is of the formula:
or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof. In certain embodiments, a provided compound (a compound of the present disclosure, a compound provided herein) is a compound of Formula (I), or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof. In certain embodiments, a provided compound is a compound of Formula (I), or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, or isotopically labeled compound thereof. In certain embodiments, a provided compound is a compound of Formula (I), or a pharmaceutically acceptable salt, tautomer, or stereoisomer thereof. In certain embodiments, a provided compound is a compound of Formula (I), or a pharmaceutically acceptable salt thereof. In certain embodiments, a provided compound is a mixture (e.g., a racemic mixture) of stereoisomers. In certain embodiments, a provided compound is any one of Compounds 1 to 20, or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled compound, or prodrug thereof. In certain embodiments, a provided compound is any one of Compounds 1 to 20, or a pharmaceutically acceptable salt thereof. Compounds provided herein can be obtained from natural sources or made or modified made by means known in the art of organic synthesis. Methods for optimizing reaction conditions, if necessary minimizing competing by-products, are known in the art. Reaction optimization and scale-up may advantageously utilize high-speed parallel synthesis equipment and computer-controlled microreactors (e.g. Design And Optimization in Organic Synthesis, 2 nd Edition, Carlson R, Ed, 2005; Elsevier Science Ltd.; Jähnisch, K et al, Angew. Chem. Int. Ed. Engl.200443: 406; and references therein). Additional reaction schemes and protocols may be determined by the skilled artesian by use of commercially available structure-searchable database software, for instance, SciFinder® (CAS division of the American Chemical Society) and CrossFire Beilstein® (Elsevier MDL), or by appropriate keyword searching using an internet search engine such as Google® or keyword databases such as the US Patent and Trademark Office text database. For example, compounds of formulae herein can be made using methodology known in the art, including Additionally, general principles of organic chemistry, as well as specific functional moieties and reactivity, are described in Thomas Sorrell, Organic Chemistry, University Science Books, Sausalito, 1999;Michael B. Smith, March’s Advanced Organic Chemistry, 7 th Edition, John Wiley & Sons, Inc., New York, 2013; Richard C. Larock, Comprehensive Organic Transformations, John Wiley & Sons, Inc., New York, 2018; and Carruthers, Some Modern Methods of Organic Synthesis, 3 rd Edition, Cambridge University Press, Cambridge, 1987. The compounds provided herein may also contain linkages (e.g., carbon-carbon bonds) wherein bond rotation is restricted about that particular linkage, e.g. restriction resulting from the presence of a ring or double bond. Accordingly, all cis/trans and E/Z isomers are expressly included in the present disclosure. The compounds herein may also be represented in multiple tautomeric forms, in such instances, the disclosure expressly includes all tautomeric forms of the compounds provided herein, even though only a single tautomeric form may be represented. All such isomeric forms of such compounds herein are expressly included in the present disclosure. All crystal forms and polymorphs of the compounds provided herein are expressly included in the present disclosure. All hydrate and solvate forms of the compounds provided herein are expressly included in the present disclosure. Also embodied are extracts and fractions comprising compounds provided herein. The term “isomers” is intended to include diastereoisomers, enantiomers, regioisomers, structural isomers, rotational isomers, tautomers, and the like. All such isomers of such compounds herein are expressly included in the present disclosure. For compounds which contain one or more stereogenic centers, e.g., chiral compounds, the methods provided herein may be carried out with an enantiomerically enriched compound, a racemate, or a mixture of diastereomers. Preferred enantiomerically enriched compounds have an enantiomeric excess of 50% or more, more preferably the compound has an enantiomeric excess of 60%, 70%, 80%, 90%, 95%, 98%, or 99% or more. In preferred embodiments, only one enantiomer or diastereomer of a chiral compound the present disclosure provides administered to cells or a subject. The compounds of the formulae herein can be synthesized using methodology similarly to that described in Chen, Q. Y.; Liu, Y.; Cai, W.; Luesch, H. Improved Total Synthesis and Biological Evaluation of Potent Apratoxin S4 Based Anticancer Agents with Differential Stability and Further Enhanced Activity. J. Med. Chem.2014, 57 (7):p.3011–302; and in WO2012/158933. The present disclosure provides compounds which are in a salt form. In some embodiments, the salt is a pharmaceutically acceptable salt. Certain specific compounds provided herein contain both basic and acidic functionalities that allow the compounds to be converted into either base or acid addition salts. The neutral forms of the compounds may be regenerated by contacting the salt with a base or acid and isolating the parent compound in the conventional manner. The parent form of the compound differs from the various salt forms in certain physical properties, such as solubility in polar solvents, but otherwise the salts are equivalent to the parent form of the compound for the purposes of the present disclosure. In addition to salt forms, provided herein are compounds which are in a prodrug form. Prodrugs of the compounds provided herein are those compounds that readily undergo chemical changes under physiological conditions to provide the compounds provided herein. Additionally, prodrugs can be converted to the compounds provided herein by chemical or biochemical methods in an ex vivo environment. For example, prodrugs can be slowly converted to the compounds provided herein when placed in a transdermal patch reservoir with a suitable enzyme or chemical reagent. Certain compounds provided herein can exist in unsolvated forms as well as solvated forms, including hydrated forms. In general, the solvated forms are equivalent to unsolvated forms and are intended to be encompassed within the scope of the present disclosure. Certain compounds provided herein may exist in multiple crystalline or amorphous forms. In general, all physical forms are equivalent for the uses contemplated by the present disclosure and are intended to be within the scope of the present disclosure. In certain embodiments, the provided compounds bind to Bcl-2 with a dissociation constant (K d ) of less than 1 pM, between 1 and 10 pM, between 10 and 100 pM, between 0.1 and 1 nM, between 1 and 10 nM, between 10 and 100 nM, between 0.1 and 1 µM, between 1 and 10 µM, between 10 and 30 µM, or between 30 and 100 µM. In certain embodiments, the provided compounds inhibit the activity of Bcl-2 with an IC 50 of less than 1 pM, between 1 and 10 pM, between 10 and 100 pM, between 0.1 and 1 nM, between 1 and 10 nM, between 10 and 100 nM, between 0.1 and 1 µM, between 1 and 10 µM, between 10 and 30 µM, or between 30 and 100 µM. In certain embodiments, the provided compounds inhibit the production of Bcl-2 with an IC50 of less than 1 pM, between 1 and 10 pM, between 10 and 100 pM, between 0.1 and 1 nM, between 1 and 10 nM, between 10 and 100 nM, between 0.1 and 1 µM, between 1 and 10 µM, between 10 and 30 µM, or between 30 and 100 µM. In certain embodiments, the provided compounds bind to Bcl-xL with a dissociation constant (Kd) of less than 1 pM, between 1 and 10 pM, between 10 and 100 pM, between 0.1 and 1 nM, between 1 and 10 nM, between 10 and 100 nM, between 0.1 and 1 µM, between 1 and 10 µM, between 10 and 30 µM, or between 30 and 100 µM. In certain embodiments, the provided compounds inhibit the activity of Bcl-xL with an IC50 of less than 1 pM, between 1 and 10 pM, between 10 and 100 pM, between 0.1 and 1 nM, between 1 and 10 nM, between 10 and 100 nM, between 0.1 and 1 µM, between 1 and 10 µM, between 10 and 30 µM, or between 30 and 100 µM. In certain embodiments, the provided compounds inhibit the production of Bcl-xL with an IC 50 of less than 1 pM, between 1 and 10 pM, between 10 and 100 pM, between 0.1 and 1 nM, between 1 and 10 nM, between 10 and 100 nM, between 0.1 and 1 µM, between 1 and 10 µM, between 10 and 30 µM, or between 30 and 100 µM. In certain embodiments, the provided compounds are able to bind to both Bcl-2 and Bcl- xL. In certain embodiments, the provided compounds inhibit the activity of both Bcl-2 and Bcl- xL. In certain embodiments, the provided compounds inhibit the production of both Bcl-2 and Bcl-xL. In certain embodiments, the selectivity (e.g., as determined by K d or IC 50 ) of the provided compounds for Bcl-2 over a different Bcl-2 family protein (e.g., Bcl-xL) is between 2 and 3, between 3 and 5, between 5 and 10, between 10 and 30, between 30 and 100, between 100 and 300, or between 300 and 1000 folds, or greater than 1000 folds. In certain embodiments, the selectivity (e.g., as determined by Kd or IC50) of the provided compounds for Bcl-xL over a different Bcl-2 family protein (e.g., Bcl-2) is between 2 and 3, between 3 and 5, between 5 and 10, between 10 and 30, between 30 and 100, between 100 and 300, or between 300 and 1000 folds, or greater than 1000 folds. In certain embodiments, a compound provided herein has reduced platelet toxicity relative to other Bcl-2 and/or Bcl-xL inhibitors. In certain embodiments, the ratio of human platelet toxicity (IC50) to anticancer activity (IC50) of the compound the present disclosure provides less than that of other Bcl-2 and/or Bcl-xL inhibitors (e.g., the another Bcl-2 inhibitor and the another Bcl-xL inhibitor described herein). The provided compounds may be prepared by methods known in the art, e.g., the methods described in U.S. Patent Application Publication No.2022-0169628. Pharmaceutical Compositions, Kits, and Administration In another aspect, the present disclosure provides a pharmaceutical composition comprising a compound of the present disclosure, and a pharmaceutically acceptable carrier. In certain embodiments, the pharmaceutical composition comprises an effective amount of the provided compound. In certain embodiments, the effective amount is a therapeutically effective amount. In certain embodiments, the effective amount is a prophylactically effective amount. In certain embodiments, the effective amount is an amount effective for treating a disease in a subject in need thereof. In certain embodiments, the effective amount is an amount effective for preventing a disease in a subject in need thereof. In certain embodiments, the effective amount is an amount effective for reducing the risk of developing a disease in a subject in need thereof. In certain embodiments, the effective amount is an amount effective for binding Bcl-xL and/or Bcl-2 (e.g., in a subject, tissue, biological sample, or cell). In certain embodiments, the effective amount is an amount effective for inhibiting the production of Bcl-xL and/or Bcl-2 (e.g., in a subject, tissue, biological sample, or cell). In certain embodiments, the effective amount is an amount effective for inhibiting the activity (e.g., aberrant activity, such as increased activity) of Bcl-xL and/or Bcl-2 (e.g., in a subject, tissue, biological sample, or cell). In certain embodiments, the effective amount is an amount effective for binding Bcl-xL and/or Bcl-2 by between 0.1% and 10%, between 10% and 20%, between 20% and 30%, between 30% and 40%, between 40% and 50%, between 50% and 60%, between 60% and 70%, between 70% and 80%, between 80% and 90%, between 90% and 95%, between 95% and 98%, between 98% and 99%, or greater than 99%. In certain embodiments, the effective amount is an amount effective for inhibiting the production of Bcl-xL and/or Bcl-2 by between 0.1% and 10%, between 10% and 20%, between 20% and 30%, between 30% and 40%, between 40% and 50%, between 50% and 60%, between 60% and 70%, between 70% and 80%, between 80% and 90%, between 90% and 95%, between 95% and 98%, between 98% and 99%, or greater than 99%. In certain embodiments, the effective amount is an amount effective for inhibiting the activity of Bcl-xL and/or Bcl-2 by between 0.1% and 10%, between 10% and 20%, between 20% and 30%, between 30% and 40%, between 40% and 50%, between 50% and 60%, between 60% and 70%, between 70% and 80%, between 80% and 90%, between 90% and 95%, between 95% and 98%, between 98% and 99%, or greater than 99%. In certain embodiments, the pharmaceutical composition is for use in treating a disease. In certain embodiments, the pharmaceutical composition is for use in preventing a disease. In certain embodiments, the pharmaceutical composition is for use in inhibiting the activity of Bcl- xL and/or Bcl-2. In certain embodiments, the pharmaceutical composition is for use in inhibiting the production of Bcl-xL and/or Bcl-2. In certain embodiments, the pharmaceutical composition is for use in inhibiting the activity of Bcl-xL and/or Bcl-2. A provided compound or pharmaceutical composition, as described herein, can be administered in combination with one or more additional pharmaceutical agents (e.g., therapeutically and/or prophylactically active agents). The provided compounds or pharmaceutical compositions can be administered in combination with additional pharmaceutical agents that improve their activity (e.g., activity (e.g., potency and/or efficacy) in treating a disease in a subject in need thereof, in preventing a disease in a subject in need thereof, and/or in reducing the risk of developing a disease in a subject in need thereof), improve bioavailability, improve safety, reduce drug resistance, reduce and/or modify metabolism, inhibit excretion, and/or modify distribution in a subject or cell. It will also be appreciated that the additional pharmaceutical agents employed may achieve a desired effect for the same disorder, and/or it may achieve different effects. In certain embodiments, a pharmaceutical composition described herein including a provided compound described herein and an additional pharmaceutical agent exhibit a synergistic effect that is absent in a pharmaceutical composition including one of the provided compounds and the additional pharmaceutical agent, but not both. In some embodiments, the additional pharmaceutical agent achieves a desired effect for the same disorder. In some embodiments, the additional pharmaceutical agent achieves different effects. The provided compound or pharmaceutical composition can be administered concurrently with, prior to, or subsequent to one or more additional pharmaceutical agents, which are different from the compound or pharmaceutical composition and may be useful as, e.g., combination therapies. Pharmaceutical agents include therapeutically active agents. Pharmaceutical agents also include prophylactically active agents. Pharmaceutical agents include small organic molecules such as drug compounds (e.g., compounds approved for human or veterinary use by the U.S. Food and Drug Administration as provided in the Code of Federal Regulations (CFR)), peptides, proteins, carbohydrates, monosaccharides, oligosaccharides, polysaccharides, nucleoproteins, mucoproteins, lipoproteins, synthetic polypeptides, synthetic proteins, small molecules linked to proteins, glycoproteins, steroids, nucleic acids, DNAs, RNAs, nucleotides, nucleosides, oligonucleotides, antisense oligonucleotides, lipids, hormones, vitamins, and cells. In certain embodiments, the additional pharmaceutical agent is a pharmaceutical agent useful for treating and/or preventing a disease. Each additional pharmaceutical agent may be administered at a dose and/or on a time schedule determined for that pharmaceutical agent. The additional pharmaceutical agents may also be administered together with each other and/or with the compound or pharmaceutical composition described herein in a single dose or administered separately in different doses. The particular combination to employ in a regimen will take into account compatibility of the compound described herein with the additional pharmaceutical agent(s) and/or the desired therapeutic and/or prophylactic effect to be achieved. In general, it is expected that the additional pharmaceutical agent(s) in combination be utilized at levels that do not exceed the levels at which they are utilized individually. In some embodiments, the levels utilized in combination will be lower than those utilized individually. The additional pharmaceutical agents include, but are not limited to, anti-proliferative agents, anti-cancer agents, cytotoxic agents, anti-angiogenesis agents, anti-inflammatory agents, and immunosuppressants. In certain embodiments, the additional pharmaceutical agent is an anti- inflammatory agent. In certain embodiments, the additional pharmaceutical agent is an immunotherapy. In certain embodiments, the additional pharmaceutical agent is an anti- proliferative agent. In certain embodiments, the additional pharmaceutical agent is an anti-cancer agent. In certain embodiments, the anti-cancer agents include, but are not limited to, epigenetic or transcriptional modulators (e.g., DNA methyltransferase inhibitors, HDAC inhibitors, lysine methyltransferase inhibitors), antimitotic drugs (e.g., taxanes and vinca alkaloids), cell signaling pathway inhibitors (e.g., tyrosine protein kinase inhibitors), modulators of protein stability (e.g., proteasome inhibitors), Hsp90 inhibitors, glucocorticoids, all-trans retinoic acids, anti-estrogens (e.g., tamoxifen, raloxifene, and megestrol), LHRH agonists (e.g., goscrclin and leuprolide), anti- androgens (e.g. flutamide and bicalutamide), photodynamic therapies (e.g., vertoporfin (BPD- MA), phthalocyanine, photosensitizer Pc4, and demethoxy-hypocrellin A (2BA-2-DMHA)), nitrogen mustards (e.g., cyclophosphamide, ifosfamide, trofosfamide, chlorambucil, estramustine, and melphalan), nitrosoureas (e.g., carmustine (BCNU) and lomustine (CCNU)), alkylsulphonates (e.g., busulfan and treosulfan), triazenes (e.g. dacarbazine, temozolomide), platinum containing compounds (e.g. cisplatin, carboplatin, oxaliplatin), vinca alkaloids (e.g. vincristine, vinblastine, vindesine, and vinorelbine), taxoids (e.g. paclitaxel or a paclitaxel equivalent such as nanoparticle albumin-bound paclitaxel (ABRAXANE), docosahexaenoic acid bound-paclitaxel (DHA-paclitaxel, Taxoprexin), polyglutamate bound-paclitaxel (PG-paclitaxel, paclitaxel poliglumex, CT-2103, XYOTAX), the tumor-activated prodrug (TAP) ANG1005 (Angiopep-2 bound to three molecules of paclitaxel), paclitaxel-EC-1 (paclitaxel bound to the erbB2-recognizing peptide EC-1), and glucose-conjugated paclitaxel, e.g., 2'-paclitaxel methyl 2- glucopyranosyl succinate; docetaxel, taxol), epipodophyllins (e.g. etoposide, etoposide phosphate, teniposide, topotecan, 9-aminocamptothecin, camptoirinotecan, irinotecan, crisnatol, mytomycin C), anti-metabolites, DHFR inhibitors (e.g., methotrexate, dichloromethotrexate, trimetrexate, edatrexate), IMP dehydrogenase inhibitors (e.g., mycophenolic acid, tiazofurin, ribavirin, and EICAR), ribonuclotide reductase inhibitors (e.g., hydroxyurea and deferoxamine), uracil analogs (e.g., 5-fluorouracil (5-FU), floxuridine, doxifluridine, ratitrexed, tegafur-uracil, capecitabine), cytosine analogs (e.g., cytarabine (ara C), cytosine arabinoside, and fludarabine), purine analogs (e.g., mercaptopurine and Thioguanine), Vitamin D3 analogs (e.g., EB 1089, CB 1093, and KH 1060), isoprenylation inhibitors (e.g., lovastatin), dopaminergic neurotoxins (e.g., 1-methyl-4-phenylpyridinium ion), cell cycle inhibitors (e.g., staurosporine), actinomycin (e.g., actinomycin D, dactinomycin), bleomycin (e.g., bleomycin A2, bleomycin B2, peplomycin), anthracycline (e.g., daunorubicin, doxorubicin, pegylated liposomal doxorubicin, idarubicin, epirubicin, pirarubicin, zorubicin, mitoxantrone), MDR inhibitors (e.g., verapamil), Ca 2+ ATPase inhibitors (e.g., thapsigargin), thalidomide, lenalidomide, pomalidomide, tyrosine kinase inhibitors (e.g., axitinib, bosutinib, cediranib (RECENTINTM), dasatinib (SPRYCEL ® ), erlotinib (TARCEVA ® ), gefitinib (IRESSA ® ), imatinib (Gleevec ® ), lapatinib (TYKERB ® , TYVERB ® ), lestaurtinib, neratinib, nilotinib (TASIGNA ® ), semaxanib, sunitinib (SUTENT ® ), toceranib (PALLADIA ® ), vandetanib (ZACTIMA®, ZD6474), vatalanib (PTK787), nilotinib (TASIGNA®), sorafenib (NEXAVAR®), everolimus (AFINITOR®), gemtuzumab ozogamicin (MYLOTARG®), temsirolimus (TORISEL®), ENMD-2076, PCI-32765, AC220, dovitinib lactate (TKI258, CHIR-258), BIBW 2992 (TOVOKTM), SGX523, PF-04217903, PF-02341066, PF-299804, BMS-777607, ABT-869, MP470, BIBF 1120 (VARGATEF®), AP24534, JNJ- 26483327, MGCD265, DCC-2036, BMS-690154, CEP-11981, tivozanib (AV-951), OSI-930, MM-121, XL-184, XL-647, and/or XL228), proteasome inhibitors (e.g., bortezomib (VELCADE)), mTOR inhibitors (e.g., rapamycin, temsirolimus (CCI-779), everolimus (RAD- 001), ridaforolimus, AP23573 (Ariad), AZD8055 (AstraZeneca), BEZ235 (Novartis), BGT226 (Norvartis), XL765 (Sanofi Aventis), PF-4691502 (Pfizer), GDC0980 (Genetech), SF1126 (Semafoe) and OSI-027 (OSI)), oblimersen, gemcitabine, carminomycin, leucovorin, pemetrexed, cyclophosphamide, dacarbazine, procarbizine, prednisolone, dexamethasone, camptothecin, plicamycin, asparaginase, aminopterin, methopterin, porfiromycin, melphalan, leurosidine, leurosine, chlorambucil, trabectedin, procarbazine, discodermolide, carminomycin, aminopterin, and hexamethyl melamine. In certain embodiments, the anti-cancer agent is alkylating agent, an anti-metabolite, an anti-tumor antibiotic, an anti-cytoskeletal agent, a topoisomerase inhibitor, an anti-hormonal agent, a targeted therapeutic agent, a photodynamic therapeutic agent, or a combination thereof. Non-limiting examples of suitable alkylating agents include altretamine, benzodopa, busulfan, carboplatin, carboquone, carmustine (BCNU), chlorambucil, chlornaphazine, cholophosphamide, chlorozotocin, cisplatin, cyclosphosphamide, dacarbazine (DTIC), estramustine, fotemustine, ifosfamide, improsulfan, lipoplatin, lomustine (CCNU), mafosfamide, mannosulfan, mechlorethamine, mechlorethamine oxide hydrochloride, melphalan, meturedopa, mustine (mechlorethamine), mitobronitol, nimustine, novembichin, oxaliplatin, phenesterine, piposulfan, prednimustine, ranimustine, satraplatin, semustine, temozolomide, thiotepa, treosulfan, triaziquone, triethylenemelamine, triethylenephosphoramide (TEPA), triethylenethiophosphaoramide (thiotepa), trimethylolomelamine, trofosfamide, uracil mustard and uredopa. Suitable anti-metabolites include, but are not limited to aminopterin, ancitabine, azacitidine, 8-azaguanine, 6-azauridine, capecitabine, carmofur (1-hexylcarbomoyl-5- fluorouracil), cladribine, clofarabine, cytarabine (cytosine arabinoside (Ara-C)), decitabine, denopterin, dideoxyuridine, doxifluridine, enocitabine, floxuridine, fludarabine, 5-fluorouracil, gemcetabine, hydroxyurea (hydroxycarbamide), leucovorin (folinic acid), 6-mercaptopurine, methotrexate, nafoxidine, nelarabine, oblimersen, pemetrexed, pteropterin, raltitrexed, tegofur, tiazofurin, thiamiprine, tioguanine (thioguanine), and trimetrexate. Non-limiting examples of suitable anti-tumor antibiotics include aclacinomysin, aclarubicin, actinomycins, adriamycin, aurostatin (for example, monomethyl auristatin E), authramycin, azaserine, bleomycins, cactinomycin, calicheamicin, carabicin, caminomycin, carzinophilin, chromomycins, dactinomycin, daunorubicin, detorubicin, 6-diazo-5-oxo-L- norleucine, doxorubicin, epirubicin, epoxomicin, esorubicin, idarubicin, marcellomycin, mitomycins, mithramycin, mycophenolic acid, nogalamycin, olivomycins, peplomycin, plicamycin, potfiromycin, puromycin, quelamycin, rodorubicin, sparsomycin, streptonigrin, streptozocin, tubercidin, valrubicin, ubenimex, zinostatin, and zorubicin. Non-limiting examples of suitable anti-cytoskeletal agents include cabazitaxel, colchicines, demecolcine, docetaxel, epothilones, ixabepilone, macromycin, omacetaxine mepesuccinate, ortataxel, paclitaxel (for example, DHA-paclitaxel), taxane, tesetaxel, vinblastine, vincristine, vindesine, and vinorelbine. Suitable topoisomerase inhibitors include, but are not limited to, amsacrine, etoposide (VP-16), irinotecan, mitoxantrone, RFS 2000, teniposide, and topotecan. Non-limiting examples of suitable anti-hormonal agents such as aminoglutethimide, antiestrogen, aromatase inhibiting 4(5)-imidazoles, bicalutamide, finasteride, flutamide, fluvestrant, goserelin, 4-hydroxytamoxifen, keoxifene, leuprolide, LY117018, mitotane, nilutamide, onapristone, raloxifene, tamoxifen, toremifene, and trilostane. Examples of targeted therapeutic agents include, without limit, monoclonal antibodies such as alemtuzumab, cartumaxomab, edrecolomab, epratuzumab, gemtuzumab, gemtuzumab ozogamicin, glembatumumab vedotin, ibritumomab tiuxetan, reditux, rituximab, tositumomab, and trastuzumab; protein kinase inhibitors such as bevacizumab, cetuximab, crizonib, dasatinib, erlotinib, gefitinib, imatinib, lapatinib, mubritinib, nilotinib, panitumumab, pazopanib, sorafenib, sunitinib, toceranib, and vandetanib; angiogeneisis inhibitors such as angiostatin, bevacizumab, denileukin diftitox, endostatin, everolimus, genistein, interferon alpha, interleukin-2, interleukin- 12, pazopanib, pegaptanib, ranibizumab, rapamycin (sirolimus), temsirolimus, and thalidomide; and growth inhibitory polypeptides such as bortazomib, erythropoietin, interleukins (e.g., IL-1, IL-2, IL-3, IL-6), leukemia inhibitory factor, interferons, romidepsin, thrombopoietin, TNF-α, CD30 ligand, 4-1BB ligand, and Apo-1 ligand. Non-limiting examples of photodynamic therapeutic agents include aminolevulinic acid, methyl aminolevulinate, retinoids (alitretinon, tamibarotene, tretinoin), and temoporfin. Other antineoplastic agents include anagrelide, arsenic trioxide, asparaginase, bexarotene, bropirimine, celecoxib, chemically linked Fab, efaproxiral, etoglucid, ferruginol, lonidamide, masoprocol, miltefosine, mitoguazone, talapanel, trabectedin, and vorinostat. In certain embodiments, the additional pharmaceutical agent is another Bcl-2 inhibitor. In certain embodiments, the another Bcl-2 inhibitor is ABT-737, navitoclax (ABT-263), venetoclax (ABT-199), obatoclax (GX 15-070), (-)-gossypol (AT-101), sabutoclax (BI-97C1), TW-37, BM- 1252 (APG-1252), or A-1155463. In certain embodiments, the other Bcl-2 inhibitor is venetoclax or ABT-263. In certain embodiments, the additional pharmaceutical agent is another Bcl-xL inhibitor. In certain embodiments, the another Bcl-xL inhibitor is ABT-263, ABT-737, A- 1155463, A-1331852, AZD4320, WEHI-539, (-)-gossypol, BH3I-1, berberine, flavokawain A, sabutoclax, TW-37, or gambogic acid. In certain embodiments, the additional pharmaceutical agent is an immunotherapy. In certain embodiments, the immunotherapy is useful in the treatment of a cancer. Exemplary immunotherapies include, but are not limited to, T-cell therapies, interferons, cytokines (e.g., tumor necrosis factor, interferon α, interferon γ), vaccines, hematopoietic growth factors, monoclonal serotherapy, immunostimulants and/or immunodulatory agents (e.g., IL-1, 2, 4, 6, or 12), immune cell growth factors (e.g., GM-CSF) and antibodies. In certain embodiments, the immunotherapy is a T-cell therapy. In certain embodiments, the T-cell therapy is chimeric antigen receptor T cells (CAR-T). In certain embodiments, the immunotherapy is an antibody. In certain embodiments, the antibody is an anti-PD-1 antibody, an anti-PD-L1 antibody, an anti- CTLA-4 antibody, an anti-TIM3 antibody, an anti-OX40 antibody, an anti-GITR antibody, an anti-LAG-3 antibody, an anti-CD137 antibody, an anti-CD27 antibody, an anti-CD28 antibody, an anti-CD28H antibody, an anti-CD30 antibody, an anti-CD39 antibody, an anti-CD40 antibody, an anti-CD47 antibody, an anti-CD48 antibody, an anti-CD70 antibody, an anti-CD73 antibody, an anti-CD96 antibody, an anti-CD160 antibody, an anti-CD200 antibody, an anti- CD244 antibody, an anti-ICOS antibody, an anti-TNFRSF25 antibody, an anti-TMIGD2 antibody, an anti-DNAM1 antibody, an anti-BTLA antibody, an anti-LIGHT antibody, an anti- TIGIT antibody, an anti-VISTA antibody, an anti-HVEM antibody, an anti-Siglec antibody, an anti-GAL1 antibody, an anti-GAL3 antibody, an anti-GAL9 antibody, an anti-BTNL2 (butrophylins) antibody, an anti-B7-H3 antibody, an anti-B7-H4 antibody, an anti-B7-H5 antibody, an anti-B7-H6 antibody, an anti-KIR antibody, an anti-LIR antibody, an anti-ILT antibody, an anti-MICA antibody, an anti-MICB antibody, an anti-NKG2D antibody, an anti- NKG2A antibody, an anti-TGFβ antibody, an anti-TGFβR antibody, an anti-CXCR4 antibody, an anti-CXCL12 antibody, an anti-CCL2 antibody, an anti-IL-10 antibody, an anti-IL-13 antibody, an anti-IL-23 antibody, an anti-phosphatidylserine antibody, an anti-neuropilin antibody, an anti- GalCer antibody, an anti-HER2 antibody, an anti-VEGFA antibody, an anti-VEGFR antibody, an anti-EGFR antibody, or an anti-Tie2 antibody. In certain embodiments, the antibody is pembrolizumab, nivolumab, pidilizumab, ipilimumab, tremelimumab, durvalumab, atezolizumab, avelumab, PF-06801591, utomilumab, PDR001, PBF-509, MGB453, LAG525, AMP-224, INCSHR1210, INCAGN1876, INCAGN1949, samalizumab, PF-05082566, urelumab, lirilumab, lulizumab, BMS-936559, BMS-936561, BMS-986004, BMS-986012, BMS-986016, BMS-986178, IMP321, IPH2101, IPH2201, varilumab, ulocuplumab, monalizumab, MEDI0562, MEDI0680, MEDI1873, MEDI6383, MEDI6469, MEDI9447, AMG228, AMG820, CC-90002, CDX-1127, CGEN15001T, CGEN15022, CGEN15029, CGEN15049, CGEN15027, CGEN15052, CGEN15092, CX-072, CX-2009, CP-870893, lucatumumab, dacetuzumab, Chi Lob 7/4, RG6058, RG7686, RG7876, RG7888, TRX518, MK- 4166, MGA271, IMC-CS4, emactuzumab, pertuzumab, obinutuzumab, cabiralizumab, margetuximab, enoblituzumab, mogamulizumab, carlumab, bevacizumab, trastuzumab (HERCEPTIN®), bevacizumab (AVASTIN®), rituximab (RITUXAN®), cetuximab (ERBITUX®), panitumumab (VECTIBIX®), alemtuzumab (CAMPATH®), or ranibizumab (Lucentis®). In certain embodiments, at least one of the additional pharmaceutical agents is a cytotoxic agent. In certain embodiments, at least one of the additional pharmaceutical agents is venetoclax, azacitidine, bortezomib, cladribine, cytarabine, doxorubicin, eribulin, etoposide, everolimus, ixabepilone, mitoxantrone, ixazomib, panobinostat, pemetrexed, SN-38, or topotecan. In certain embodiments, at least one of the additional pharmaceutical agents is nivolumab, pidilizumab, pembrolizumab, MEDI-0680, REGN2810, AMP-224, atezolizumab, durvalumab, BMS-936559, avelumab, CA-170, ipilimumab, or tremelimumab. In certain embodiments, at least one of the additional pharmaceutical agents is an immune check-point inhibitor. In certain embodiments, at least one of the additional pharmaceutical agents is a cytotoxic T-lymphocyte-associated protein 4 (CTLA-4) inhibitor. In certain embodiments, at least one of the additional pharmaceutical agents is a programmed cell death 1 protein (PD-1) inhibitor. In certain embodiments, at least one of the additional pharmaceutical agents is a programmed cell death 1 protein ligand 1 (PD-L1) inhibitor. In certain embodiments, at least one of the additional pharmaceutical agents is a stimulator of interferon genes (STING) agonist. In certain embodiments, the additional pharmaceutical agents include pharmaceutically acceptable salts, solvates, hydrates, polymorphs, co-crystals, tautomers, stereoisomers, isotopically labeled compounds, and prodrug thereof. In certain embodiments, the provided compounds or pharmaceutical compositions can be administered in combination with an anti-cancer therapy including, but not limited to, surgery, radiation therapy, transplantation (e.g., stem cell transplantation, bone marrow transplantation), immunotherapy, and chemotherapy. In certain embodiments, the provided compound or pharmaceutical composition is a solid. In certain embodiments, the provided compound or pharmaceutical composition is a powder. In certain embodiments, the provided compound or pharmaceutical composition can be dissolved in a liquid to make a solution. In certain embodiments, the provided compound or pharmaceutical composition is dissolved in water to make an aqueous solution. In certain embodiments, the pharmaceutical composition is a liquid for parental injection. In certain embodiments, the pharmaceutical composition is a liquid for oral administration (e.g., ingestion). In certain embodiments, the pharmaceutical composition is a liquid (e.g., aqueous solution) for intravenous injection. In certain embodiments, the pharmaceutical composition is a liquid (e.g., aqueous solution) for subcutaneous injection. Pharmaceutical compositions described herein can be prepared by any method known in the art of pharmacology. In general, such preparatory methods include the steps of bringing the composition comprising a provided compound (i.e., the “active ingredient”) into association with a carrier and/or one or more other accessory ingredients, and then, if necessary and/or desirable, shaping and/or packaging the product into a desired single- or multi-dose unit. Pharmaceutical compositions can be prepared, packaged, and/or sold in bulk, as a single unit dose, and/or as a plurality of single unit doses. A “unit dose” is a discrete amount of the pharmaceutical composition comprising a predetermined amount of the active ingredient. The amount of the active ingredient is generally equal to the dosage of the active ingredient which would be administered to a subject and/or a convenient fraction of such a dosage, such as one- half or one-third of such a dosage. Relative amounts of the provided compound, pharmaceutically acceptable excipient, agent, and/or any additional ingredients in a pharmaceutical composition described herein will vary, depending upon the identity, size, and/or condition of the subject treated and further depending upon the route by which the pharmaceutical composition is to be administered. The pharmaceutical composition may comprise between 0.1% and 100% (w/w) agent. Pharmaceutically acceptable excipients used in manufacture of provided pharmaceutical compositions include inert diluents, dispersing and/or granulating agents, surface active agents and/or emulsifiers, disintegrating agents, binding agents, preservatives, buffering agents, lubricating agents, and/or oils. Excipients and accessory ingredients, such as cocoa butter and suppository waxes, coloring agents, coating agents, sweetening, flavoring, and perfuming agents, may also be present in the pharmaceutical composition. Exemplary diluents include calcium carbonate, sodium carbonate, calcium phosphate, dicalcium phosphate, calcium sulfate, calcium hydrogen phosphate, sodium phosphate lactose, sucrose, cellulose, microcrystalline cellulose, kaolin, mannitol, sorbitol, inositol, sodium chloride, dry starch, cornstarch, powdered sugar, and mixtures thereof. Exemplary granulating and/or dispersing agents include potato starch, corn starch, tapioca starch, sodium starch glycolate, clays, alginic acid, guar gum, citrus pulp, agar, bentonite, cellulose, and wood products, natural sponge, cation-exchange resins, calcium carbonate, silicates, sodium carbonate, cross-linked poly(vinyl-pyrrolidone) (crospovidone), sodium carboxymethyl starch (sodium starch glycolate), carboxymethyl cellulose, cross-linked sodium carboxymethyl cellulose (croscarmellose), methylcellulose, pregelatinized starch (starch 1500), microcrystalline starch, water insoluble starch, calcium carboxymethyl cellulose, magnesium aluminum silicate (Veegum), sodium lauryl sulfate, quaternary ammonium compounds, and mixtures thereof. Exemplary surface active agents and/or emulsifiers include natural emulsifiers (e.g., acacia, agar, alginic acid, sodium alginate, tragacanth, chondrux, cholesterol, xanthan, pectin, gelatin, egg yolk, casein, wool fat, cholesterol, wax, and lecithin), colloidal clays (e.g., bentonite (aluminum silicate) and Veegum (magnesium aluminum silicate)), long chain amino acid derivatives, high molecular weight alcohols (e.g., stearyl alcohol, cetyl alcohol, oleyl alcohol, triacetin monostearate, ethylene glycol distearate, glyceryl monostearate, and propylene glycol monostearate, polyvinyl alcohol), carbomers (e.g., carboxy polymethylene, polyacrylic acid, acrylic acid polymer, and carboxyvinyl polymer), carrageenan, cellulosic derivatives (e.g., carboxymethylcellulose sodium, powdered cellulose, hydroxymethyl cellulose, hydroxypropyl cellulose, hydroxypropyl methylcellulose, methylcellulose), sorbitan fatty acid esters (e.g., polyoxyethylene sorbitan monolaurate (Tween ® 20), polyoxyethylene sorbitan monostearate (Tween ® 60), polyoxyethylene sorbitan monooleate (Tween ® 80), sorbitan monopalmitate (Span ® 40), sorbitan monostearate (Span ® 60), sorbitan tristearate (Span ® 65), glyceryl monooleate, sorbitan monooleate (Span ® 80), polyoxyethylene esters (e.g., polyoxyethylene monostearate (Myrj ® 45), polyoxyethylene hydrogenated castor oil, polyethoxylated castor oil, polyoxymethylene stearate, and Solutol ® ), sucrose fatty acid esters, polyethylene glycol fatty acid esters (e.g., Cremophor ® ), polyoxyethylene ethers, (e.g., polyoxyethylene lauryl ether (Brij ® 30)), poly(vinyl-pyrrolidone), diethylene glycol monolaurate, triethanolamine oleate, sodium oleate, potassium oleate, ethyl oleate, oleic acid, ethyl laurate, sodium lauryl sulfate, Pluronic ® F-68, poloxamer P-188, cetrimonium bromide, cetylpyridinium chloride, benzalkonium chloride, docusate sodium, and/or mixtures thereof. Exemplary binding agents include starch (e.g., cornstarch and starch paste), gelatin, sugars (e.g., sucrose, glucose, dextrose, dextrin, molasses, lactose, lactitol, mannitol, etc.), natural and synthetic gums (e.g., acacia, sodium alginate, extract of Irish moss, panwar gum, ghatti gum, mucilage of isapol husks, carboxymethylcellulose, methylcellulose, ethylcellulose, hydroxyethylcellulose, hydroxypropyl cellulose, hydroxypropyl methylcellulose, microcrystalline cellulose, cellulose acetate, poly(vinyl-pyrrolidone), magnesium aluminum silicate (Veegum ® ), and larch arabogalactan), alginates, polyethylene oxide, polyethylene glycol, inorganic calcium salts, silicic acid, polymethacrylates, waxes, water, alcohol, and/or mixtures thereof. Exemplary preservatives include antioxidants, chelating agents, antimicrobial preservatives, antifungal preservatives, antiprotozoan preservatives, alcohol preservatives, acidic preservatives, and other preservatives. In certain embodiments, the preservative is an antioxidant. In other embodiments, the preservative is a chelating agent. Exemplary antioxidants include alpha tocopherol, ascorbic acid, ascorbyl palmitate, butylated hydroxyanisole, butylated hydroxytoluene, monothioglycerol, potassium metabisulfite, propionic acid, propyl gallate, sodium ascorbate, sodium bisulfite, sodium metabisulfite, and sodium sulfite. Exemplary chelating agents include ethylenediaminetetraacetic acid (EDTA) and salts and hydrates thereof (e.g., sodium edetate, disodium edetate, trisodium edetate, calcium disodium edetate, dipotassium edetate, and the like), citric acid and salts and hydrates thereof (e.g., citric acid monohydrate), fumaric acid and salts and hydrates thereof, malic acid and salts and hydrates thereof, phosphoric acid and salts and hydrates thereof, and tartaric acid and salts and hydrates thereof. Exemplary antimicrobial preservatives include benzalkonium chloride, benzethonium chloride, benzyl alcohol, bronopol, cetrimide, cetylpyridinium chloride, chlorhexidine, chlorobutanol, chlorocresol, chloroxylenol, cresol, ethyl alcohol, glycerin, hexetidine, imidurea, phenol, phenoxyethanol, phenylethyl alcohol, phenylmercuric nitrate, propylene glycol, and thimerosal. Exemplary antifungal preservatives include butyl paraben, methyl paraben, ethyl paraben, propyl paraben, benzoic acid, hydroxybenzoic acid, potassium benzoate, potassium sorbate, sodium benzoate, sodium propionate, and sorbic acid. Exemplary alcohol preservatives include ethanol, polyethylene glycol, phenol, phenolic compounds, bisphenol, chlorobutanol, hydroxybenzoate, and phenylethyl alcohol. Exemplary acidic preservatives include vitamin A, vitamin C, vitamin E, beta-carotene, citric acid, acetic acid, dehydroacetic acid, ascorbic acid, sorbic acid, and phytic acid. Other preservatives include tocopherol, tocopherol acetate, deteroxime mesylate, cetrimide, butylated hydroxyanisol (BHA), butylated hydroxytoluened (BHT), ethylenediamine, sodium lauryl sulfate (SLS), sodium lauryl ether sulfate (SLES), sodium bisulfite, sodium metabisulfite, potassium sulfite, potassium metabisulfite, Glydant ® Plus, Phenonip ® , methylparaben, Germall ® 115, Germaben ® II, Neolone ® , Kathon ® , and Euxyl ® . Exemplary buffering agents include citrate buffer solutions, acetate buffer solutions, phosphate buffer solutions, ammonium chloride, calcium carbonate, calcium chloride, calcium citrate, calcium glubionate, calcium gluceptate, calcium gluconate, D-gluconic acid, calcium glycerophosphate, calcium lactate, propanoic acid, calcium levulinate, pentanoic acid, dibasic calcium phosphate, phosphoric acid, tribasic calcium phosphate, calcium hydroxide phosphate, potassium acetate, potassium chloride, potassium gluconate, potassium mixtures, dibasic potassium phosphate, monobasic potassium phosphate, potassium phosphate mixtures, sodium acetate, sodium bicarbonate, sodium chloride, sodium citrate, sodium lactate, dibasic sodium phosphate, monobasic sodium phosphate, sodium phosphate mixtures, tromethamine, magnesium hydroxide, aluminum hydroxide, alginic acid, pyrogen-free water, isotonic saline, Ringer’s solution, ethyl alcohol, and mixtures thereof. Exemplary lubricating agents include magnesium stearate, calcium stearate, stearic acid, silica, talc, malt, glyceryl behanate, hydrogenated vegetable oils, polyethylene glycol, sodium benzoate, sodium acetate, sodium chloride, leucine, magnesium lauryl sulfate, sodium lauryl sulfate, and mixtures thereof. Exemplary natural oils include almond, apricot kernel, avocado, babassu, bergamot, black current seed, borage, cade, camomile, canola, caraway, carnauba, castor, cinnamon, cocoa butter, coconut, cod liver, coffee, corn, cotton seed, emu, eucalyptus, evening primrose, fish, flaxseed, geraniol, gourd, grape seed, hazel nut, hyssop, isopropyl myristate, jojoba, kukui nut, lavandin, lavender, lemon, litsea cubeba, macademia nut, mallow, mango seed, meadowfoam seed, mink, nutmeg, olive, orange, orange roughy, palm, palm kernel, peach kernel, peanut, poppy seed, pumpkin seed, rapeseed, rice bran, rosemary, safflower, sandalwood, sasquana, savoury, sea buckthorn, sesame, shea butter, silicone, soybean, sunflower, tea tree, thistle, tsubaki, vetiver, walnut, and wheat germ oils. Exemplary synthetic oils include, but are not limited to, butyl stearate, caprylic triglyceride, capric triglyceride, cyclomethicone, diethyl sebacate, dimethicone 360, isopropyl myristate, mineral oil, octyldodecanol, oleyl alcohol, silicone oil, and mixtures thereof. Liquid dosage forms for oral and parenteral administration include pharmaceutically acceptable emulsions, microemulsions, solutions, suspensions, syrups and elixirs. In addition to the active ingredients, the liquid dosage forms may comprise inert diluents commonly used in the art such as, for example, water or other solvents, solubilizing agents and emulsifiers such as ethyl alcohol, isopropyl alcohol, ethyl carbonate, ethyl acetate, benzyl alcohol, benzyl benzoate, propylene glycol, 1,3-butylene glycol, dimethylformamide, oils (e.g., cottonseed, groundnut, corn, germ, olive, castor, and sesame oils), glycerol, tetrahydrofurfuryl alcohol, polyethylene glycols and fatty acid esters of sorbitan, and mixtures thereof. Besides inert diluents, the oral pharmaceutical compositions can include adjuvants such as wetting agents, emulsifying and suspending agents, sweetening, flavoring, and perfuming agents. In certain embodiments for parenteral administration, the conjugates described herein are mixed with solubilizing agents such as Cremophor®, alcohols, oils, modified oils, glycols, polysorbates, cyclodextrins, polymers, and mixtures thereof. Injectable preparations, for example, sterile injectable aqueous or oleaginous suspensions can be formulated according to the known art using suitable dispersing or wetting agents and suspending agents. The sterile injectable preparation can be a sterile injectable solution, suspension, or emulsion in a nontoxic parenterally acceptable diluent or solvent, for example, as a solution in 1,3-butanediol. Among the acceptable vehicles and solvents that can be employed are water, Ringer’s solution, U.S.P., and isotonic sodium chloride solution. In addition, sterile, fixed oils are conventionally employed as a solvent or suspending medium. For this purpose any bland fixed oil can be employed including synthetic mono- or di-glycerides. In addition, fatty acids such as oleic acid are used in the preparation of injectables. The injectable formulations can be sterilized, for example, by filtration through a bacterial-retaining filter, or by incorporating sterilizing agents in the form of sterile solid pharmaceutical compositions which can be dissolved or dispersed in sterile water or other sterile injectable medium prior to use. In order to prolong the effect of a drug, it is often desirable to slow the absorption of the drug from subcutaneous or intramuscular injection. This can be accomplished by the use of a liquid suspension of crystalline or amorphous material with poor water solubility. The rate of absorption of the drug then depends upon its rate of dissolution, which, in turn, may depend upon crystal size and crystalline form. Alternatively, delayed absorption of a parenterally administered drug form may be accomplished by dissolving or suspending the drug in an oil vehicle. Pharmaceutical compositions for rectal or vaginal administration are typically suppositories which can be prepared by mixing the conjugates described herein with suitable non-irritating excipients or carriers such as cocoa butter, polyethylene glycol, or a suppository wax which are solid at ambient temperature but liquid at body temperature and therefore melt in the rectum or vaginal cavity and release the active ingredient. Solid dosage forms for oral administration include capsules, tablets, pills, powders, and granules. In such solid dosage forms, the active ingredient is mixed with at least one inert, pharmaceutically acceptable excipient or carrier such as sodium citrate or dicalcium phosphate and/or (a) fillers or extenders such as starches, lactose, sucrose, glucose, mannitol, and silicic acid, (b) binders such as, for example, carboxymethylcellulose, alginates, gelatin, polyvinylpyrrolidinone, sucrose, and acacia, (c) humectants such as glycerol, (d) disintegrating agents such as agar, calcium carbonate, potato or tapioca starch, alginic acid, certain silicates, and sodium carbonate, (e) solution retarding agents such as paraffin, (f) absorption accelerators such as quaternary ammonium compounds, (g) wetting agents such as, for example, cetyl alcohol and glycerol monostearate, (h) absorbents such as kaolin and bentonite clay, and (i) lubricants such as talc, calcium stearate, magnesium stearate, solid polyethylene glycols, sodium lauryl sulfate, and mixtures thereof. In the case of capsules, tablets, and pills, the dosage form may include a buffering agent. Solid compositions of a similar type can be employed as fillers in soft and hard-filled gelatin capsules using such excipients as lactose or milk sugar as well as high molecular weight polyethylene glycols and the like. The solid dosage forms of tablets, dragees, capsules, pills, and granules can be prepared with coatings and shells such as enteric coatings and other coatings well known in the art of pharmacology. They may optionally comprise opacifying agents and can be of a composition that they release the active ingredient(s) only, or preferentially, in a certain part of the intestinal tract, optionally, in a delayed manner. Examples of encapsulating compositions which can be used include polymeric substances and waxes. The active ingredient can be in a micro-encapsulated form with one or more excipients as noted above. The solid dosage forms of tablets, dragees, capsules, pills, and granules can be prepared with coatings and shells such as enteric coatings, release controlling coatings, and other coatings well known in the pharmaceutical formulating art. In such solid dosage forms the active ingredient can be admixed with at least one inert diluent such as sucrose, lactose, or starch. Such dosage forms may comprise, as is normal practice, additional substances other than inert diluents, e.g., tableting lubricants and other tableting aids such a magnesium stearate and microcrystalline cellulose. In the case of capsules, tablets and pills, the dosage forms may comprise buffering agents. They may optionally comprise opacifying agents and can be of a composition that they release the active ingredient(s) only, or preferentially, in a certain part of the intestinal tract, optionally, in a delayed manner. Examples of encapsulating agents which can be used include polymeric substances and waxes. Dosage forms for topical and/or transdermal administration of a compound described herein may include ointments, pastes, creams, lotions, gels, powders, solutions, sprays, inhalants, and/or patches. Generally, the active ingredient is admixed under sterile conditions with a pharmaceutically acceptable carrier or excipient and/or any needed preservatives and/or buffers as can be required. Additionally, the present disclosure contemplates the use of transdermal patches, which often have the added advantage of providing controlled delivery of an active ingredient to the body. Such dosage forms can be prepared, for example, by dissolving and/or dispensing the active ingredient in the proper medium. Alternatively or additionally, the rate can be controlled by either providing a rate controlling membrane and/or by dispersing the active ingredient in a polymer matrix and/or gel. Formulations suitable for topical administration include, but are not limited to, liquid and/or semi-liquid preparations such as liniments, lotions, oil-in-water and/or water-in-oil emulsions such as creams, ointments, and/or pastes, and/or solutions and/or suspensions. Topically administrable formulations may, for example, comprise from about 1% to about 10% (w/w) active ingredient, although the concentration of the active ingredient can be as high as the solubility limit of the active ingredient in the solvent. Formulations for topical administration may further comprise one or more of the additional ingredients described herein. Suitable devices for use in delivering injectable pharmaceutical compositions described herein include short needle devices. Injectable pharmaceutical compositions can be administered by devices which limit the effective penetration length of a needle into the skin. Alternatively or additionally, conventional syringes can be used in the classical mantoux method of administration. Jet injection devices which deliver liquid formulations via a liquid jet injector and/or via a needle. Ballistic powder/particle delivery devices which use compressed gas to accelerate the compound in powder form are suitable. A pharmaceutical composition described herein can be prepared, packaged, and/or sold in a formulation suitable for pulmonary administration via the buccal cavity. Such a formulation may comprise dry particles which comprise the active ingredient and which have a diameter in the range from about 0.5 to about 7 nanometers, or from about 1 to about 6 nanometers. Such pharmaceutical compositions are conveniently in the form of dry powders for administration using a device comprising a dry powder reservoir to which a stream of propellant can be directed to disperse the powder and/or using a self-propelling solvent/powder dispensing container such as a device comprising the active ingredient dissolved and/or suspended in a low-boiling propellant in a sealed container. Such powders comprise particles wherein at least 98% of the particles by weight have a diameter greater than 0.5 nanometers and at least 95% of the particles by number have a diameter less than 7 nanometers. Alternatively, at least 95% of the particles by weight have a diameter greater than 1 nanometer and at least 90% of the particles by number have a diameter less than 6 nanometers. Dry powder pharmaceutical compositions may include a solid fine powder diluent such as sugar and are conveniently provided in a unit dose form. Low boiling propellants generally include liquid propellants having a boiling point of below 65 °F at atmospheric pressure. Generally, the propellant may constitute 50 to 99.9% (w/w) of the pharmaceutical composition, and the active ingredient may constitute 0.1 to 20% (w/w) of the pharmaceutical composition. The propellant may further comprise additional ingredients such as a liquid non-ionic and/or solid anionic surfactant and/or a solid diluent (which may have a particle size of the same order as particles comprising the active ingredient). Pharmaceutical compositions described herein formulated for pulmonary delivery may provide the active ingredient in the form of droplets of a solution and/or suspension. Such formulations can be prepared, packaged, and/or sold as aqueous and/or dilute alcoholic solutions and/or suspensions, optionally sterile, comprising the active ingredient, and may conveniently be administered using any nebulization and/or atomization device. Such formulations may further comprise one or more additional ingredients including a flavoring agent such as saccharin sodium, a volatile oil, a buffering agent, a surface active agent, and/or a preservative such as methylhydroxybenzoate. The droplets provided by this route of administration may have an average diameter in the range from about 0.1 to about 200 nanometers. Formulations described herein as being useful for pulmonary delivery are useful for intranasal delivery of a pharmaceutical composition described herein. Another formulation suitable for intranasal administration is a coarse powder comprising the active ingredient and having an average particle from about 0.2 to 500 micrometers. Such a formulation is administered by rapid inhalation through the nasal passage from a container of the powder held close to the nares. Formulations for nasal administration may, for example, comprise from about as little as 0.1% (w/w) to as much as 100% (w/w) of the active ingredient, and may comprise one or more of the additional ingredients described herein. A pharmaceutical composition described herein can be prepared, packaged, and/or sold in a formulation for buccal administration. Such formulations may, for example, be in the form of tablets and/or lozenges made using conventional methods, and may contain, for example, 0.1 to 20% (w/w) active ingredient, the balance comprising an orally dissolvable and/or degradable composition and, optionally, one or more of the additional ingredients described herein. Alternately, formulations for buccal administration may comprise a powder and/or an aerosolized and/or atomized solution and/or suspension comprising the active ingredient. Such powdered, aerosolized, and/or aerosolized formulations, when dispersed, may have an average particle and/or droplet size in the range from about 0.1 to about 200 nanometers, and may further comprise one or more of the additional ingredients described herein. A pharmaceutical composition described herein can be prepared, packaged, and/or sold in a formulation for ophthalmic administration. Such formulations may, for example, be in the form of eye drops including, for example, a 0.1-1.0% (w/w) solution and/or suspension of the active ingredient in an aqueous or oily liquid carrier or excipient. Such drops may further comprise buffering agents, salts, and/or one or more other of the additional ingredients described herein. Other opthalmically-administrable formulations which are useful include those which comprise the active ingredient in microcrystalline form and/or in a liposomal preparation. Ear drops and/or eye drops are also contemplated as being within the scope of this disclosure. Although the descriptions of pharmaceutical compositions provided herein are principally directed to pharmaceutical compositions which are suitable for administration to humans, it will be understood by the skilled artisan that such pharmaceutical compositions are generally suitable for administration to animals of all sorts. Modification of pharmaceutical compositions suitable for administration to humans in order to render the pharmaceutical compositions suitable for administration to various animals is well understood, and the ordinarily skilled veterinary pharmacologist can design and/or perform such modification with ordinary experimentation. Provided compounds are typically formulated in dosage unit form for ease of administration and uniformity of dosage. It will be understood, however, that the total daily usage of the pharmaceutical compositions described herein will be decided by a physician within the scope of sound medical judgment. The specific therapeutically effective dose level for any particular subject or organism will depend upon a variety of factors including the disease being treated and the severity of the disorder; the activity of the specific active ingredient employed; the specific composition employed; the age, body weight, general health, sex, and diet of the subject; the time of administration, route of administration, and rate of excretion of the specific active ingredient employed; the duration of the treatment; drugs used in combination or coincidental with the specific active ingredient employed; and like factors well known in the medical arts. The provided compounds and pharmaceutical compositions provided herein can be administered by any route, including enteral (e.g., oral), parenteral, intravenous, intramuscular, intraarticular, intra-arterial, intramedullary, intrathecal, subcutaneous, intraventricular, transdermal, interdermal, rectal, intravaginal, intraperitoneal, topical (as by powders, ointments, creams, and/or drops), mucosal, nasal, bucal, sublingual; by intratracheal instillation, bronchial instillation, and/or inhalation; and/or as an oral spray, nasal spray, and/or aerosol. Specifically, contemplated routes are intraarticular administration, oral administration, intravenous administration (e.g., systemic intravenous injection), regional administration via blood and/or lymph supply, and/or direct administration to an affected site. In general, the most appropriate route of administration will depend upon a variety of factors including the nature of the agent (e.g., its stability in the environment of the gastrointestinal tract), and/or the condition of the subject (e.g., whether the subject is able to tolerate oral administration). The exact amount of a provided compound required to achieve an effective amount will vary from subject to subject, depending, for example, on species, age, and general condition of a subject, severity of the side effects or disorder, identity of the particular compound of the disclosure, mode of administration, and the like. An effective amount may be included in a single dose (e.g., single oral dose) or multiple doses (e.g., multiple oral doses). In certain embodiments, when multiple doses are administered to a subject or applied to a biological sample, tissue, or cell, any two doses of the multiple doses include different or substantially the same amounts of an agent described herein. In certain embodiments, a pharmaceutical composition comprising a provided compound is administered, orally or parenterally, at dosage levels of each pharmaceutical composition sufficient to deliver from about 0.001 mg/kg to about 200 mg/kg in one or more dose administrations for one or several days (depending on the mode of administration). In certain embodiments, the effective amount per dose varies from about 0.001 mg/kg to about 200 mg/kg, about 0.001 mg/kg to about 100 mg/kg, about 0.01 mg/kg to about 100 mg/kg, from about 0.01 mg/kg to about 50 mg/kg, preferably from about 0.1 mg/kg to about 40 mg/kg, preferably from about 0.5 mg/kg to about 30 mg/kg, from about 0.01 mg/kg to about 10 mg/kg, from about 0.1 mg/kg to about 10 mg/kg, of subject body weight per day, one or more times a day, to obtain the desired therapeutic and/or prophylactic effect. In certain embodiments, the compounds described herein may be at dosage levels sufficient to deliver from about 0.001 mg/kg to about 200 mg/kg, from about 0.001 mg/kg to about 100 mg/kg, from about 0.01 mg/kg to about 100 mg/kg, from about 0.01 mg/kg to about 50 mg/kg, preferably from about 0.1 mg/kg to about 40 mg/kg, preferably from about 0.5 mg/kg to about 30 mg/kg, from about 0.01 mg/kg to about 10 mg/kg, from about 0.1 mg/kg to about 10 mg/kg, and more preferably from about 1 mg/kg to about 25 mg/kg, of subject body weight per day, one or more times a day, to obtain the desired therapeutic and/or prophylactic effect. The desired dosage may be delivered three times a day, two times a day, once a day, every other day, every third day, every week, every two weeks, every three weeks, or every four weeks. In certain embodiments, the desired dosage may be delivered using multiple administrations (e.g., two, three, four, five, six, seven, eight, nine, ten, eleven, twelve, thirteen, fourteen, or more administrations). In certain embodiments, the pharmaceutical composition described herein is administered at a dose that is below the dose at which the agent causes non-specific effects. In certain embodiments, the pharmaceutical composition is administered at a dose of about 0.001 mg to about 1000 mg per unit dose. In certain embodiments, the pharmaceutical composition is administered at a dose of about 0.01 mg to about 200 mg per unit dose. In certain embodiments, the pharmaceutical composition is administered at a dose of about 0.01 mg to about 100 mg per unit dose. In certain embodiments, pharmaceutical composition is administered at a dose of about 0.01 mg to about 50 mg per unit dose. In certain embodiments, the pharmaceutical composition is administered at a dose of about 0.01 mg to about 10 mg per unit dose. In certain embodiments, the pharmaceutical composition is administered at a dose of about 0.1 mg to about 10 mg per unit dose. Dose ranges as described herein provide guidance for the administration of provided compounds or pharmaceutical compositions to an adult. The amount to be administered to, for example, a child or an adolescent can be determined by a medical practitioner or person skilled in the art and can be lower or the same as that administered to an adult. In certain embodiments, a dose described herein is a dose to an adult human whose body weight is 70 kg. In certain embodiments, when multiple doses are administered to a subject or applied to a tissue or cell, the frequency of administering the multiple doses to the subject or applying the multiple doses to the tissue or cell may be, in non-limiting examples, three doses a day, two doses a day, one dose a day, one dose every other day, one dose every third day, one dose every week, one dose every two weeks, one dose every three weeks, or one dose every four weeks, or even slow dose controlled delivery over a selected period of time using a drug delivery device. In certain embodiments, when multiple doses are administered to a subject or applied to a biological sample, tissue, or cell, the duration between the first dose and last dose of the multiple doses is one day, two days, four days, one week, two weeks, three weeks, one month, two months, three months, four months, six months, nine months, one year, two years, three years, four years, five years, seven years, ten years, fifteen years, twenty years, or the lifetime of the subject, tissue, or cell. In certain embodiments, the duration between the first dose and last dose of the multiple doses is three months, six months, or one year. In certain embodiments, the duration between the first dose and last dose of the multiple doses is the lifetime of the subject, tissue, or cell. In another aspect, the present disclosure provide a kit comprising a provided compound or pharmaceutical composition, and instructions for using the compound or pharmaceutical composition. In certain embodiments, the kit comprises a first container, wherein the first container includes the compound or pharmaceutical composition. In some embodiments, the kit further comprises a second container. In certain embodiments, the second container includes an excipient (e.g., an excipient for dilution or suspension of the compound or pharmaceutical composition). In certain embodiments, the second container includes an additional pharmaceutical agent. In some embodiments, the kit further comprises a third container. In certain embodiments, the third container includes an additional pharmaceutical agent. In some embodiments, the provided compound or pharmaceutical composition included in the first container and the excipient or additional pharmaceutical agent included in the second container are combined to form one unit dosage form. In some embodiments, the provided compound or pharmaceutical composition included in the first container, the excipient included in the second container, and the additional pharmaceutical agent included in the third container are combined to form one unit dosage form. In certain embodiments, each of the first, second, and third containers is independently a vial, ampule, bottle, syringe, dispenser package, tube, or inhaler. In certain embodiments, the instructions are for administering the provided compound or pharmaceutical composition to a subject (e.g., a subject in need of treatment or prevention of a disease described herein). In certain embodiments, the instructions are for contacting a biological sample or cell with the provided compound or pharmaceutical composition. In certain embodiments, the instructions comprise information required by a regulatory agency, such as the U.S. Food and Drug Administration (FDA) or the European Agency for the Evaluation of Medicinal Products (EMA). In certain embodiments, the instructions comprise prescribing information. In certain embodiments, the kits and instructions provide for treating a disease in a subject in need thereof. In certain embodiments, the kits and instructions provide for preventing a disease in a subject in need thereof. In certain embodiments, the kits and instructions provide for reducing the risk of developing a disease in a subject in need thereof. In certain embodiments, the kits and instructions provide for inhibiting the activity (e.g., aberrant activity, such as increased activity) of Bcl-xL and/or Bcl-2in a subject or cell. A kit described herein may include one or more additional pharmaceutical agents described herein as a separate pharmaceutical composition. Methods of Treatment In another aspect, the present disclosure provides a method of degrading a Bcl-2 protein in a cell, tissue, or biological sample, the method comprising contacting the cell, tissue, or biological sample with an effective amount of a compound or pharmaceutical composition provided herein. In another aspect, the present disclosure provides a method of degrading a Bcl-xL protein in a cell, tissue, or biological sample, the method comprising contacting the cell, tissue, or biological sample with an effective amount of a compound or pharmaceutical composition provided herein. In another aspect, the present disclosure provides a method of treating a disease in a subject in need thereof, the method comprising administering to the subject an effective amount of a compound or pharmaceutical composition provided herein. In another aspect, the present disclosure provides a method of preventing a disease in a subject in need thereof, the method comprising administering to the subject an effective amount of a compound or pharmaceutical composition provided herein. In another aspect, the present disclosure provides a method of selectively killing one or more cancer cells in a tissue or biological sample, the method comprising contacting the tissue or biological sample with an effective amount of a compound or pharmaceutical composition of the present disclosure In another aspect, the present disclosure provides a method of selectively killing one or more cancer cells in a subject in need thereof, the method comprising administering to the subject an effective amount of a compound or pharmaceutical composition of the present disclosure. By “selectively killing one or more cancer cells,” it is meant that a composition provided herein does not appreciably kill non-cancer cells at the same concentration. In one embodiment, a composition provided herein has reduced platelet toxicity and retained or improved toxicity in cancer cells when compared to other Bcl-2 and/or Bcl-xL inhibitors. Accordingly, the median lethal dose or LD50 of the inhibitor in non-cancer cells may be about 5 to about 50 times higher than the LD 50 of the inhibitor in cancer cells. As used herein, the LD 50 is the concentration of inhibitor required to kill half the cells in the cell sample. For example, the LD50 of the inhibitor in non-cancer cells may be greater than about 5, about 6, about 7, about 8, about 9 or about 10 times higher than the LD 50 of the inhibitor in cancer cells. Alternatively, the LD 50 of the inhibitor in non-cancer cells may be greater than about 10, about 15, about 20, about 25, about 30, about 35, about 40, about 45, or about 50 times higher than the LD50 of the inhibitor in cancer cells. Additionally, the LD 50 of the inhibitor in non-cancer cells may be greater than 50 times higher than the LD 50 of the inhibitor in cancer cells. In a specific embodiment, the LD 50 of the inhibitor in non-cancer cells is greater than 10 times higher than the LD500 of the inhibitor in cancer cells. In another specific embodiment, the LD50 of the inhibitor in non-cancer cells is greater than 20 times higher than the LD 50 of the inhibitor in cancer cells. In certain embodiments, the cell, tissue, biological sample, or cancer cell is in vitro. In certain embodiments, the cell, tissue, biological sample, or cancer cell is in vivo. In certain embodiments, the cell, tissue, or biological sample is ex vivo. In certain embodiments, the cell is a cancer cell. In certain embodiments, the cell is a pre-cancer cell. In certain embodiments, the cell, tissue, or biological sample is in a subject. In certain embodiments, the disease is cancer. In certain embodiments, the cancer is a Bcl-2-mediated cancer. In certain embodiments, the cancer is a Bcl-xL-mediated cancer. In certain embodiments, the cancer is a hematological malignancy. In certain embodiments, the cancer is leukemia. In certain embodiments, the cancer is acute myeloid leukemia, chronic lymphocytic leukemia, or acute lymphoblastic leukemia. In certain embodiments, the cancer is lymphoma. In certain embodiments, the cancer is T-cell lymphoma. In certain embodiments, the cancer is a solid tumor. In certain embodiments, the anticancer activity is measured in MOLT-4 cells. In certain embodiments, the anticancer activity is measured in RS4 cells. In some embodiments, the anticancer activity is higher in MOLT-4 cells than in RS4 cells. In certain embodiments, the anticancer activity is higher in RS4 cells than in MOLT-4 cells. In certain embodiments, the ratio of the anticancer activity in MOLT-4 cells to the anticancer activity in RS4 cells is between 2:1 and 5:1, between 5:1 and 10:1, between 10:1 and 30:1, between 30:1 and 100:1, between 100:1 and 300:1, or between 300:1 and 1000:1, or greater than 1000:1. In certain embodiments, the ratio of the anticancer activity in RS4 cells to the anticancer activity in MOLT-4 cells is between 2:1 and 5:1, between 5:1 and 10:1, between 10:1 and 30:1, between 30:1 and 100:1, between 100:1 and 300:1, or between 300:1 and 1000:1, or greater than 1000:1. It has been reported that senolytics have the potential to prevent and treat a growing number of age-related diseases and extend healthspan, and that senolytics include inhibitors of the antiapoptotic Bcl-2 family proteins (He et al., Nat. Commun., 11, 1996 (2020); Kirkland et al., J. Intern. Med., 2020, 288: 518-536). In certain embodiments, the disease is an age-related disease. In certain embodiments, the disease is age-related cognitive dysfunction, age-related intervertebral disc disease, age-related muscle loss, Alzheimer’s disease, amyotrophic lateral sclerosis, ataxia, AV fistulae, bone marrow transplant complication, cardiac dysfunction, cataracts, chemotherapy complication, chronic obstructive, cirrhosis, COVID-19 complication, diabetes, frailty, glaucoma, hepatic steatosis, hyperoxic lung damage, idiopathic pulmonary fibrosis, macular degeneration, MGUS, myeloma, obesity, obesity-related neuropsychiatric dysfunction, organ transplantation complication, osteoarthritis, osteoporosis, Parkinson’s disease, pre-eclampsia, primary biliary cirrhosis, progerias, prostatic hypertrophy, psoriasis, pulmonary disease, radiation complication, renal dysfunction, urinary incontinence, vascular calcification, or vascular hyporeactivity. In certain embodiments, the subject is an animal. In certain embodiments, the subject is a human. In certain embodiments, the subject is a human aged 18 years or older. In certain embodiments, the subject is a human aged 12-18 years, exclusive. In certain embodiments, the subject is a human aged 2-12 years. In certain embodiments, the subject is a human younger than 2 years. In certain embodiments, the subject is a non-human animal. In certain embodiments, the subject is a mammal. In certain embodiments, the subject is a non-human mammal. EXAMPLES The present disclosure will now be demonstrated using specific examples that are not to be construed as limiting. Preparation of Intermediate A
Step 1: Synthesis of tert-butyl (R)-(4-hydroxy-1-(phenylthio)butan-2-yl)carbamate (A-2). To a solution of A-1 (2.7 g, 6.72 mmol) in THF/MeOH (50 mL/5 mL) was added NaBH4 (1.49 g, 40.35 mmol) in portions over a period of 6 hours. The reaction mixture was added sat. aq. NH 4 Cl and extracted with DCM. The combined organic layers were washed with sat. aq. NH4Cl, then dried over Na2SO4, filtered and concentrated. The residue was purified by flash column chromatography (0% to 70% of EtOAc in hexanes) to afford A-2 (1.6 g, 80% yield) as a white solid. 1 H NMR (600 MHz, Chloroform-d) δ (ppm): 7.43 – 7.40 (m, 2H), 7.32 (t, J = 7.8 Hz, 2H), 7.26 – 7.21 (m, 1H), 4.84 (d, J = 8.4 Hz, 1H), 4.07 (s, 1H), 3.67 (s, 2H), 3.22 – 2.98 (m, 3H), 1.98 – 1.82 (m, 1H), 1.67 – 1.49 (m, 1H), 1.46 (s, 9H). LC/MS (ESI) m/z 320.2 [M+Na] + ; [M+H] + calcd for C 15 H 24 NO 3 S + : 298.15. Step 2: Synthesis of tert-butyl (R)-(4-oxo-1-(phenylthio)butan-2-yl)carbamate (A-3). DMP (2.08 g, 4.90 mmol) was added to a solution of A-2 (1.08 g, 3.63 mmol) in EtOAc (25 mL) and stirred at room temperature for 3 hours. The resulting mixture was filtered and the filtrate was concentrated. The residue was purified by flash column chromatography (0% to 45% of EtOAc in hexanes) to afford A-3 (1.0 g, 93% yield) as a colorless oil. 1 H NMR (600 MHz, Chloroform- d) δ 9.71 (s, 1H), 7.43 – 7.40 (m, 2H), 7.35 – 7.30 (m, 2H), 7.26 – 7.21 (m, 1H), 5.00 (s, 1H), 4.22 (s, 1H), 3.33 – 3.21 (m, 1H), 3.17 – 3.07 (m, 1H), 2.90 – 2.72 (m, 2H), 1.44 (s, 9H). LC/MS (ESI) m/z 296.2; [M+H] + calcd for C 15 H 22 NO 3 S + : 296.13. Step 3: Synthesis of tert-butyl (R)-(4-(1,4-oxazepan-4-yl)-1-(phenylthio)butan-2- yl)carbamate (A-4). NaBH(OAc)3 (632 mg, 2.98 mmol) was added to a solution of 1,4- oxazepane hydrochloride (410 mg, 2.98 mmol), TEA (565 µL, 4.06 mmol) and A-3 (800 mg, 2.71 mmol) in DCM (15 mL), then stirred at room temperature overnight. The reaction mixture was washed with sat. aq. NH 4 Cl. The organic layers were dried over Na 2 SO 4 , filtered and concentrated. The residue was purified by flash column chromatography (50% to 100% of EtOAc in hexanes, then 0% to 10% of MeOH in DCM) to afford A-4 (920 mg, 89% yield) as a white solid. 1 H NMR (600 MHz, Chloroform-d) δ 7.42 (d, J = 7.6 Hz, 2H), 7.33 – 7.29 (m, 2H), 7.19 (t, J = 7.4 Hz, 1H), 3.91 (s, 1H), 3.82 (t, J = 6.1 Hz, 2H), 3.73 (t, 2H), 3.30 (d, J = 13.5 Hz, 1H), 3.07 – 2.95 (m, 1H), 2.77 – 2.60 (m, 4H), 2.59 – 2.52 (m, 1H), 1.95 – 1.82 (m, 3H), 1.74 – 1.66 (m, 1H), 1.45 (s, 9H). LC/MS (ESI) m/z 381.4; [M+H] + calcd for C 20 H 33 N 2 O 3 S + : 381.22. Step 4: Synthesis of (R)-4-(1,4-oxazepan-4-yl)-1-(phenylthio)butan-2-amine hydrochloride (A-5).4 N HCl in dioxane (10 mL) was added to a stirring solution of A-4 (730 mg, 1.92 mmol) in DCM (10 mL). After stirring at room temperature for 1 hour, the reaction mixture was concentrated to afford A-5 (850 mg, quantitative yield), which was directly used in the next step. LC/MS (ESI) m/z 281.1; [M+H] + calcd for C15H25N2OS + : 281.17. Step 5: Synthesis of (R)-4-((4-(1,4-oxazepan-4-yl)-1-(phenylthio)butan-2-yl)amino )-3- ((trifluoromethyl)sulfonyl)benzenesulfonamide (intermediate A). A-6 (600 mg, 1.95 mmol) was added to a stirring solution of A-5 (850 mg, HCl salt) and DIPEA (2.72 mL, 15.64 mmol) in DMSO (25 mL), then stirred at room temperature overnight. The resulting mixture was diluted with EtOAc and washed with sat. aq. NH4Cl. The organic layer was dried over Na2SO4, filtered, and concentrated. The residue was purified by flash column chromatography (50% to 100% of EtOAc in hexanes, then 0% to 10% of MeOH in DCM) to afford Intermediate A (900 mg, 82% yield for two steps) as a yellow solid. 1 H NMR (600 MHz, Chloroform-d) δ 8.27 (d, J = 2.2 Hz, 1H), 7.83 (dd, J = 9.2, 2.3 Hz, 1H), 7.44 – 7.40 (m, 2H), 7.37 – 7.33 (m, 2H), 7.33 – 7.27 (m, 1H), 7.19 (d, J = 8.5 Hz, 1H), 6.65 (d, J = 9.2 Hz, 1H), 5.06 (s, 2H), 4.01 – 3.91 (m, 1H), 3.77 (t, J = 6.0 Hz, 2H), 3.73 – 3.63 (m, 2H), 3.17 – 3.03 (m, 2H), 2.75 – 2.69 (m, 2H), 2.68 – 2.52 (m, 4H), 2.14 – 2.04 (m, 1H), 1.90 – 1.82 (m, 2H), 1.76 – 1.67 (m, 1H). LC/MS (ESI) m/z 568.1; [M+H] + calcd for C 22 H 29 F 3 N 3 O 5 S 3 + : 568.12. Preparation of Intermediate B
Step 1: Synthesis of ethyl (R)-4-(4-((4'-chloro-4-formyl-4-methyl-3,4,5,6-tetrahydro-[1 ,1'- biphenyl]-2-yl)methyl)piperazin-1-yl)benzoate (B-2). Under an argon atmosphere, to a solution of DMSO (1.76 mL, 24.84 mmol) in DCM (30 mL) was added oxalyl chloride (1.3 mL, 15.53 mmol) dropwise at -78 °C with stirring. The resulting mixture was stirred at -78 °C for an additional 15 min. Then a solution of B-1 (4 g, 6.21 mmol) in DCM/DMSO (20 mL/5 mL) was added dropwise. The mixture was stirred at -78 °C for an extra 30 min after completing the addition. TEA (6.9 mL, 49.69 mmol) was added to the mixture at -78 °C, then dry-ice/acetone bath was removed. The reaction mixture was warmed up to room temperature and stirred for an additional 30 min. Water was added to the reaction mixture, then extracted with DCM. The combined organic layers were washed with 10% aq. Na 2 S 2 O 3 and sat. aq. NH 4 Cl, dried over Na2SO4, filtered, and concentrated. The residue was purified by flash column chromatography (0% to 40% of EtOAc in hexanes) to afford B-2 (2.82 g, 71%) as an off-white solid. 1 H NMR (600 MHz, Chloroform-d) δ (ppm): 9.56 (s, 1H), 7.95 – 7.89 (m, 2H), 7.33 – 7.27 (m, 2H), 7.01 – 6.95 (m, 2H), 6.87 – 6.81 (m, 2H), 4.34 (q, J = 7.1 Hz, 2H), 3.30 (t, J = 5.1 Hz, 4H), 2.86 (q, J = 12.7 Hz, 2H), 2.73 – 2.66 (m, 1H), 2.48 – 2.41 (m, 2H), 2.40 – 2.26 (m, 4H), 2.12 – 2.04 (m, 1H), 2.05 – 1.99 (m, 1H), 1.69 – 1.60 (m, 1H), 1.38 (t, J = 7.1 Hz, 3H), 1.18 (s, 3H). LC/MS (ESI) m/z 481.2; [M+H] + calcd for C28H34ClN2O3 + : 481.23. Step 2: Synthesis of (R)-4-(4-((4'-chloro-4-formyl-4-methyl-3,4,5,6-tetrahydro-[1 ,1'- biphenyl]-2-yl)methyl)piperazin-1-yl)benzoic acid (B-3). To a solution of B-2 (2.3 g, 4.78 mmol) in MeOH/THF (25 mL/25 mL) was added a solution of LiOH·H2O (602 mg, 14.35 mmol) in water (6 mL), then stirred at 40 °C overnight. The reaction mixture was concentrated to remove the organic solvents, then adjusted to pH = 6 with 10% aq. citric acid. The precipitate was collected via filtration and washed with water. The filtered cake was dried under vacuum to afford B-3 (2.0 g, 92% yield) as a white solid. 1 H NMR (600 MHz, Methanol-d4) δ 9.56 (s, 1H), 7.91 (d, J = 9.0 Hz, 2H), 7.39 (d, J = 8.4 Hz, 2H), 7.10 (d, J = 8.5 Hz, 2H), 6.98 (d, J = 9.0 Hz, 2H), 3.52 – 3.42 (m, 5H), 2.97 (s, 4H), 2.68 (dd, J = 17.5, 1.9 Hz, 1H), 2.44 – 2.33 (m, 3H), 2.14 – 2.06 (m, 2H), 1.77 – 1.69 (m, 1H), 1.21 (s, 3H). LC/MS (ESI) m/z 453.2; [M+H] + calcd for C26H30ClN2O3 + : 453.19. Step 3: Synthesis of N-((4-(((R)-4-(1,4-Oxazepan-4-yl)-1-(phenylthio)butan-2-yl)a mino)-3- ((trifluoromethyl)sulfonyl)phenyl)sulfonyl)-4-(4-(((R)-4'-ch loro-4-formyl-4-methyl-3,4,5,6- tetrahydro-[1,1'-biphenyl]-2-yl)methyl)piperazin-1-yl)benzam ide (intermediate B). Intermediate A (853 mg, 1.5 mmol) was added to a solution of B-3 (680 mg, 1.5 mmol), DMAP (916 mg, 7.51 mmol) and EDC (1.49 g, 7.51 mmol) in DCM (15 mL). The resulting mixture was stirred at room temperature overnight. The reaction mixture was washed with water and sat. aq. NH 4 Cl, dried over Na 2 SO 4 , filtered, and concentrated. The residue was purified by flash column chromatography (0% to 10% of MeOH in EtOAc) to afford Intermediate B (840 mg, 56% yield). 1 H NMR (600 MHz, DMSO-d6) δ 9.52 (s, 1H), 8.09 (d, J = 2.2 Hz, 1H), 7.94 (dd, J = 9.0, 2.2 Hz, 1H), 7.71 (d, J = 8.6 Hz, 2H), 7.37 (d, J = 8.2 Hz, 2H), 7.34 (d, J = 7.7 Hz, 2H), 7.29 (t, J = 7.6 Hz, 2H), 7.22 – 7.17 (m, 1H), 7.08 (d, J = 8.2 Hz, 2H), 6.89 (d, J = 9.3 Hz, 1H), 6.79 (dd, J = 18.3, 8.6 Hz, 3H), 4.05 – 3.96 (m, 1H), 3.63 (t, J = 6.1 Hz, 4H), 3.39 – 3.29 (m, 7H), 3.26 (dd, J = 13.9, 6.7 Hz, 1H), 3.20 – 3.11 (m, 4H), 2.85 – 2.71 (m, 3H), 2.55 (d, J = 17.6 Hz, 1H), 2.35 – 2.17 (m, 6H), 2.06 – 1.95 (m, 2H), 1.92 – 1.74 (m, 4H), 1.57 (dt, J = 13.5, 6.9 Hz, 1H), 1.08 (s, 3H). LC/MS (ESI) m/z 1002.4; [M+H] + calcd for C48H56ClF3N5O7S3 + : 1002.3. Preparation of Intermediate C Step 1: Synthesis of tert-butyl 4-(1-oxo-1,3-dihydroisobenzofuran-5-yl)piperazine-1- carboxylate (C-2). Under an argon atmosphere a mixture of C-1 (4 g 1878 mmol) 4-Boc- piperazine (5.24 g, 28.17 mmol), Pd 2 (dba) 3 (860 mg, 0.94 mmol), BINAP (1.17 g, 1.88 mmol), and K3PO4 (11.9 g, 56.34 mmol) in toluene (100 mL) was stirred at 90 °C overnight. After cooling to room temperature, the reaction mixture was washed with water and sat. aq. NH4Cl. The organic layers were dried over Na 2 SO 4 , filtered and concentrated. The residue was purified by flash column chromatography (0% to 10% of MeOH in DCM) to afford C-2 (2.2 g, 37% yield). 1 H NMR (600 MHz, Chloroform-d) δ 7.78 (d, J = 8.6 Hz, 1H), 7.01 (dd, J = 8.6, 2.2 Hz, 1H), 6.82 (d, J = 2.2 Hz, 1H), 5.23 (s, 2H), 3.63 (t, 4H), 3.38 (t, J = 5.3 Hz, 4H), 1.51 (s, 8H). LC/MS (ESI) m/z 319.1; [M+H] + calcd for C17H23N2O4 + : 319.17. Step 2: Synthesis of 4-(4-(tert-butoxycarbonyl)piperazin-1-yl)-2-(hydroxymethyl)b enzoic acid (C-3). To a solution of B-2 (2.2 g, 6.92 mmol) in MeOH/THF (10 mL/10 mL) was added a solution of LiOH·H2O (553 mg, 13.84 mmol) in water (5 mL). The resulting mixture was stirred at room temperature for 2.5 hours. The reaction mixture was concentrated to remove the organic solvents, then extracted with EtOAc. The water phase was adjusted to pH = 3-4 with 5% aq. citric acid. The precipitate was collected via filtration and washed with water. The filtered cake was dried under vacuum to afford C-3 (2.2 g, 96% yield) as a light-yellow solid. 1 H NMR (600 MHz, Chloroform-d) δ 8.07 (d, J = 8.8 Hz, 1H), 6.91 (d, J = 2.7 Hz, 1H), 6.81 (dd, J = 8.9, 2.7 Hz, 1H), 4.81 (s, 2H), 3.61 (t, J = 5.3 Hz, 4H), 3.40 (t, J = 5.3 Hz, 4H), 1.51 (s, 9H). LC/MS (ESI) m/z 337.2; [M+H] + calcd for C17H25N2O5 + : 337.18. Step 3: Synthesis of tert-butyl 4-(3-(hydroxymethyl)-4- (methoxycarbonyl)phenyl)piperazine-1-carboxylate (C-4). (Trimethylsilyl)diazomethane (10% in hexanes, 22.4 g, 19.64 mmol) was added dropwise to a stirring solution of C-3 (2.2 g, 6.55 mmol) in MeOH/EtOAc (50 mL/50 mL) at room temperature. After completing the addition, the resulting mixture was stirred at room temperature for an extra 30 min. The reaction mixture was concentrated and the residue was purified by flash column chromatography (0% to 60% of EtOAc in hexanes) to afford C-4 (2.2 g, 96% yield). 1 H NMR (600 MHz, Chloroform-d) δ 7.97 (dd, J = 8.8, 1.3 Hz, 1H), 6.88 (d, J = 2.7 Hz, 1H), 6.81 – 6.77 (m, 1H), 4.75 (d, J = 7.5 Hz, 2H), 3.91 (s, 3H), 3.60 (t, J = 5.2 Hz, 4H), 3.36 (t, J = 5.4 Hz, 4H), 1.51 (s, 9H). LC/MS (ESI) m/z 351.2; [M+H] + calcd for C 18 H 27 N 2 O 5 + : 351.19. Step 4: Synthesis of tert-butyl 4-(3-(bromomethyl)-4-(methoxycarbonyl)phenyl)piperazine- 1-carboxylate (C-5). Under argon atmosphere, to a solution of C-4 (2.2 g, 6.29 mmol) in THF (60 mL) were added triphenylphosphine (2.5 g, 9.43 mmol) and carbon tetrabromide (3.1 g, 9.43 mmol). The resulting mixture was stirred at room temperature for 1 hour, then washed with water and brine. The organic layers were dried over Na 2 SO 4 , filtered, and concentrated. The residue was purified by flash column chromatography (0% to 50% of EtOAc in hexanes) to afford C-5 (2.24 g, 86% yield) as an off-white solid. 1 H NMR (600 MHz, Chloroform-d) δ 7.96 (d, J = 8.8 Hz, 1H), 6.91 (d, J = 2.7 Hz, 1H), 6.80 (dd, J = 8.9, 2.7 Hz, 1H), 4.99 (s, 2H), 3.91 (s, 3H), 3.61 (t, 4H), 3.34 (t, J = 5.3 Hz, 4H), 1.51 (s, 9H). LC/MS (ESI) m/z 313.1, 315.1 (M-Boc); [M+H] + calcd for C18H25BrN2O4 + : 413.11. Step 5: Synthesis of tert-butyl 4-(2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5- yl)piperazine-1-carboxylate (C-6). A solution of C-5 (2.2 g, 5.33 mmol), 3-aminopiperidine- 2,6-dione hydrochloride (1.31 g, 8.0 mmol), and DIPEA (4.6 mL, 26.63mmol) in acetonitrile (30 mL) was stirred at 70 °C overnight. After cooling to room temperature, the reaction mixture was concentrated. Water was added to the residue, then collected the precipitate via filtration. The filtered cake was washed with water, DCM and DCM/Et2O (v/v=1/1), then dried under vacuum to afford C-6 (1.43 g, 63% yield). 1 H NMR (600 MHz, Chloroform-d) δ 8.07 (s, 1H), 7.77 (d, J = 8.5 Hz, 1H), 7.01 (dd, J = 8.6, 2.2 Hz, 1H), 6.90 (d, J = 2.2 Hz, 1H), 5.22 (dd, J = 13.3, 5.1 Hz, 1H), 4.44 (d, J = 15.6 Hz, 1H), 4.28 (d, J = 15.6 Hz, 1H), 3.62 (t, J = 5.3 Hz, 4H), 3.30 (t, J = 5.2 Hz, 4H), 2.98 – 2.77 (m, 2H), 2.35 (qd, J = 13.2, 4.8 Hz, 1H), 2.26 – 2.17 (m, 1H), 1.51 (s, 9H). LC/MS (ESI) m/z 429.2; [M+H] + calcd for C22H29N2O5 + : 429.21. Step 6: Synthesis of 3-(1-oxo-5-(piperazin-1-yl)isoindolin-2-yl)piperidine-2,6-di one hydrochloride (Intermediate C). HCl (10 mL, 4 N in dioxane) was added to a stirring solution of C-6 (1 g, 2.34 mmol) in DCM (10 mL) at room temperature. The resulting mixture was stirred at room temperature for 2 hours, the reaction mixture was concentrated and the residue was triturated with diethyl ether. The precipitate was collected via filtration and dried under vacuum to afford Intermediate C (1.04 g, quantitative yield), which was directly used in the next step. LC/MS (ESI) m/z 329.2; [M+H] + calcd for C17H21N4O3 + : 329.16. Preparation of Intermediate D
Intermediates D was synthesized according to the procedure described in WO 2023107606. Preparation of Intermediate E Synthesis of 3-(5-bromo-1-oxoisoindolin-2-yl)piperidine-2,6-dione (Intermediate E). A solution of E-1 (6.7 g, 21.89 mmol), 3-aminopiperidine-2,6-dione hydrochloride (3.6 g, 21.89 mmol), and DIPEA (11.4 mL, 65.69 mmol) in acetonitrile (120 mL) was stirred at 70 °C overnight. After cooling to room temperature, the reaction mixture was concentrated. The residue was triturated with water and DCM, then the precipitate was collected via filtration and dried under vacuum to afford Intermediate E (5.1 g, 72% yield). 1 H NMR (600 MHz, DMSO-d6) δ 11.01 (s, 1H), 7.90 (d, J = 1.6 Hz, 1H), 7.72 (dd, J = 8.1, 1.7 Hz, 1H), 7.68 (d, J = 8.0 Hz, 1H), 5.12 (dd, J = 13.3, 5.2 Hz, 1H), 4.47 (d, J = 17.6 Hz, 1H), 4.35 (d, J = 17.5 Hz, 1H), 2.91 (ddd, J = 17.4, 13.6, 5.4 Hz, 1H), 2.61 (ddd, J = 17.4, 4.5, 2.2 Hz, 1H), 2.40 (qd, J = 13.3, 4.5 Hz, 1H), 2.05 – 1.97 (m, 1H). LC/MS (ESI) m/z 323.1, 325.1; [M+H] + calcd for C13H12BrN2O3 + : 323.00. Preparation of Intermediates F and G
Step 1: Synthesis of 4-(4-((4'-chloro-4-((4-(2-chloroacetyl)piperazin-1-yl)methyl )-4-methyl- 3,4,5,6-tetrahydro-[1,1'-biphenyl]-2-yl)methyl)piperazin-1-y l)-N-((4-(((R)-4-morpholino-1- (phenylthio)butan-2-yl)amino)-3-((trifluoromethyl)sulfonyl)p henyl)sulfonyl)benzamide (G- 1). To a solution of 2-chloroacetic acid (8.6 mg, 0.091 mmol) and HATU (43 mg, 0.11 mmol) in (1 mL) was added a solution of Intermediate F (100 mg, 0.091 mmol. Intermediate F was synthesized according to WO 2023107606), and DIPEA (25 µL, 0.14 mmol) in DCM (0.5 mL). The resulting mixture was stirred at room temperature for 2 hours, then washed with water and sat. aq. NH4Cl. The organic layers were dried over Na2SO4, filtered and concentrated. The residue was purified by flash column chromatography (0% to 5% of DCM in MeOH) to afford G-1 (75 mg, 72% yield). 1 H NMR (600 MHz, Chloroform-d) δ 8.35 (d, J = 2.3 Hz, 1H), 8.09 (d, J = 9.1 Hz, 1H), 7.66 (d, J = 8.5 Hz, 2H), 7.40 – 7.34 (m, 2H), 7.34 – 7.22 (m, 6H), 7.04 (d, J = 8.6 Hz, 1H), 6.99 (d, J = 8.0 Hz, 2H), 6.75 (s, 2H), 6.61 (d, J = 9.3 Hz, 1H), 4.04 (s, 2H), 3.90 (d, J = 9.9 Hz, 1H), 3.72 – 3.55 (m, 6H), 3.50 (s, 2H), 3.27 (s, 4H), 3.10 (dd, J = 13.9, 5.1 Hz, 1H), 3.02 (dd, J = 13.9, 7.2 Hz, 1H), 2.96 – 2.82 (m, 2H), 2.69 – 2.49 (m, 4H), 2.49 – 2.18 (m, 14H), 2.17 – 2.07 (m, 2H), 2.02 – 1.93 (m, 1H), 1.73 – 1.52 (m, 2H), 1.51 – 1.42 (m, 1H), 0.96 (s, 3H). LC/MS (ESI) m/z 1134.4; [M+H] + calcd for C 53 H 65 Cl 2 F 3 N 7 O 7 S 3 + : 1134.34. Step 2: Synthesis of tert-butyl 4-(2-(4-((4'-chloro-4-methyl-6-((4-(4-(((4-(((R)-4-morpholin o- 1-(phenylthio)butan-2-yl)amino)-3- ((trifluoromethyl)sulfonyl)phenyl)sulfonyl)carbamoyl)phenyl) piperazin-1-yl)methyl)- 2,3,4,5-tetrahydro-[1,1'-biphenyl]-4-yl)methyl)piperazin-1-y l)-2-oxoethyl)piperazine-1- carboxylate (G-2). A mixture of G-1 (72 mg, 0.063 mmol), N-Boc-piperazine (15.3 mg, 0.082 mmol), and K 2 CO 3 (26.3 mg, 0.19 mmol) in DMF (1.0 mL) was stirred at room temperature overnight. The reaction mixture was diluted with EtOAc and washed with water and sat. aq. NH4Cl. The organic layers were dried over Na2SO4, filtered, and concentrated. The residue was purified by flash column chromatography (0% to 10% of DCM in MeOH) to afford G-2 (69 mg, 85% yield). 1 H NMR (600 MHz, Chloroform-d) δ 8.35 (s, 1H), 8.11 (d, J = 9.1 Hz, 1H), 7.64 (d, J = 8.4 Hz, 2H), 7.41 – 7.34 (m, 2H), 7.34 – 7.21 (m, 5H), 7.06 (d, J = 8.5 Hz, 1H), 6.99 (d, J = 7.9 Hz, 2H), 6.76 (d, J = 8.6 Hz, 2H), 6.61 (d, J = 9.3 Hz, 1H), 3.95 – 3.83 (m, 1H), 3.71 – 3.49 (m, 8H), 3.45 – 3.30 (m, 5H), 3.30 – 3.20 (m, 4H), 3.20 – 3.13 (m, 2H), 3.10 (dd, J = 13.9, 5.0 Hz, 1H), 3.02 (dd, J = 13.9, 7.2 Hz, 1H), 2.89 – 2.75 (m, 2H), 2.61 – 2.47 (m, 5H), 2.47 – 2.07 (m, 19H), 1.92 (d, J = 17.2 Hz, 1H), 1.71 – 1.56 (m, 2H), 1.52 – 1.39 (m, 10H), 0.95 (s, 3H). LC/MS (ESI) m/z 1284.4; [M+H] + calcd for C62H82ClF3N9O9S3 + : 1284.50. Step 3: Synthesis of 4-(4-((4'-chloro-4-methyl-4-((4-(2-(piperazin-1-yl)acetyl)pi perazin-1- yl)methyl)-3,4,5,6-tetrahydro-[1,1'-biphenyl]-2-yl)methyl)pi perazin-1-yl)-N-((4-(((R)-4- morpholino-1-(phenylthio)butan-2-yl)amino)-3- ((trifluoromethyl)sulfonyl)phenyl)sulfonyl)benzamide hydrochloride (Intermediate G). HCl (1 mL, 4 N HCl in dioxane) was added to a stirring solution of G-2 (69 mg, 0.054 mmol) in DCM (1 mL) at room temperature. Then the resulting mixture was stirred at room temperature for 2 hours, then concentrated and dried under vacuum to afford Intermediate G (71 mg, quantitative yield), which was directly used in the next step. LC/MS (ESI) m/z 1184.5; [M+H] + calcd for C57H74ClF3N9O7S3 + : 1184.45. Preparation of Intermediates H, I, and J General synthetic procedure: A mixture of phthalic anhydride (1.0 equiv.), 3-aminopiperidine- 2,6-dione hydrochloride (1.1 equiv.) and KOAc (1.3 equiv.) in acetic acid was stirred at 90 °C overnight. The resulting mixture was cooled to room temperature and concentrated. The residue was triturated with DCM and water, then collected the precipitate via filtration and dried under vacuum to afford Intermediates H, I and J. 2-(2,6-dioxopiperidin-3-yl)-4-fluoroisoindoline-1,3-dione (Intermediate H) (37.5 g, 90% yield): 1 H NMR (600 MHz, DMSO-d6) δ 11.15 (s, 1H), 7.99 – 7.92 (m, 1H), 7.80 (d, J = 7.3 Hz, 1H), 7.74 (t, J = 8.8 Hz, 1H), 5.17 (dd, J = 12.9, 5.5 Hz, 1H), 2.90 (ddd, J = 17.2, 13.9, 5.4 Hz, 1H), 2.62 (ddd, J = 17.2, 4.7, 2.4 Hz, 1H), 2.58 – 2.47 (m, 1H), 2.13 – 2.03 (m, 1H). LC/MS (ESI) m/z 277.1; [M+H] + calcd for C13H10FN2O4 + : 277.06.2-(2,6-dioxopiperidin-3-yl)-4- hydroxyisoindoline-1,3-dione (Intermediate I) (13.2 g, 79% yield): 1 H NMR (600 MHz, DMSO-d 6 ) δ 11.17 (s, 1H), 11.08 (s, 1H), 7.65 (dd, J = 8.4, 7.2 Hz, 1H), 7.32 (d, J = 7.1 Hz, 1H), 7.25 (d, J = 8.3 Hz, 1H), 5.07 (dd, J = 12.9, 5.4 Hz, 1H), 2.88 (ddd, J = 17.0, 13.9, 5.4 Hz, 1H), 2.63 – 2.56 (m, 1H), 2.57 – 2.46 (m, 1H), 2.02 (dtd, J = 13.1, 5.4, 2.3 Hz, 1H). LC/MS (ESI) m/z 275.1; [M+H] + calcd for C 13 H 11 N 2 O 5 + : 275.07.2-(2,6-dioxopiperidin-3-yl)-5-fluoroisoindoline- 1,3-dione (Intermediate J) (27.6 g, 83% yield): 1 H NMR (600 MHz, DMSO-d 6 ) δ 11.14 (s, 1H), 8.01 (dd, J = 8.3, 4.4 Hz, 1H), 7.85 (dd, J = 7.4, 2.3 Hz, 1H), 7.72 (ddd, J = 9.4, 8.3, 2.3 Hz, 1H), 5.16 (dd, J = 13.0, 5.4 Hz, 1H), 2.89 (ddd, J = 17.2, 13.9, 5.4 Hz, 1H), 2.64 – 2.57 (m, 1H), 2.58 – 2.46 (m, 1H), 2.12 – 2.02 (m, 1H). LC/MS (ESI) m/z 277.2; [M+H] + calcd for C 13 H 10 FN 2 O 4 + : 277.06. Preparation of Intermediate K Step 1: Synthesis of tert-butyl 4-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4- yl)piperazine-1-carboxylate (K-1). A mixture of Intermediate H (300 mg, 1.09 mmol), N-Boc- piperazine (263 mg, 1.41 mmol), and DIPEA (567 µL, 3.26 mmol) in DMSO (5 mL) was stirred at 90 °C overnight. The reaction mixture was cooled to room temperature and diluted with EtOAc, then washed with water and sat. aq. NH 4 Cl. The organic layers were dried over Na 2 SO 4 , filtered and concentrated. The residue was purified by flash column chromatography (30% to 100% of EtOAc in hexanes) to afford K-1 (320 mg, 63% yield). 1 H NMR (600 MHz, Chloroform-d) δ 8.05 (s, 1H), 7.63 (dd, J = 8.4, 7.2 Hz, 1H), 7.46 (dd, J = 7.2, 0.8 Hz, 1H), 7.19 (dd, J = 8.5, 0.8 Hz, 1H), 4.99 (dd, J = 12.6, 5.3 Hz, 1H), 3.68 (t, J = 5.0 Hz, 4H), 3.36 – 3.25 (m, 4H), 2.99 – 2.68 (m, 3H), 2.18 – 2.11 (m, 1H), 1.51 (s, 9H). LC/MS (ESI) m/z 443.2; [M+H] + calcd for C 22 H 27 N 4 O 5 + : 443.19. Step 2: Synthesis of 2-(2,6-dioxopiperidin-3-yl)-4-(piperazin-1-yl)isoindoline-1, 3-dione (Intermediate K): HCl (2 mL, 4 N HCl in dioxane) was added to a stirring solution of K-1 (150 mg, 3.39 mmol) in DCM (4 mL), then stirred at room temperature for 2 hours. The resulting mixture was concentrated and dried under vacuum to afford Intermediate K (151 mg, quantitative yield), which was directly used in the next step. LC/MS (ESI) m/z 343.1; [M+H] + calcd for C 17 H 19 N 4 O 4 + : 343.14. Preparation of Intermediates L, M, N and P Step 1: General procedure for the synthesis of tert-butyl 4-(3-cyano-4- (methoxycarbonyl)phenyl)-1,4-diazepane-1-carboxylate (L-1), tert-butyl 4-(3-cyano-4- (methoxycarbonyl)phenyl)-1,4-diazepane-1-carboxylate (M-1), tert-butyl 5-(3-cyano-4- (methoxycarbonyl)phenyl)-2,5-diazabicyclo[2.2.1]heptane-2-ca rboxylate (N-1) and tert- butyl 4-(4-cyano-3-(methoxycarbonyl)phenyl)piperazine-1-carboxylat e (P-1). A mixture of fluoride (1.0 equiv.), amine (1.1 equiv.), and DIPEA (3.0 equiv.) in DMSO was stirred at 110 °C for 2 hours. The resulting mixture was cooled to room temperature and diluted with EtOAc, then washed with water and sat. aq. NH 4 Cl. The organic layers were dried over Na 2 SO 4 , filtered and concentrated. The residue was purified by flash column chromatography (0% to 60% of EtOAc in hexanes) to afford L-1, M-1, N-1, and P-1. L-1 (960 mg, 67% yield): 1 H NMR (600 MHz, Chloroform-d) δ 7.96 (d, J = 9.0 Hz, 1H), 6.98 (d, J = 2.7 Hz, 1H), 6.83 (dd, J = 9.0, 2.6 Hz, 1H), 3.92 (s, 3H), 3.67 – 3.56 (m, 6H), 3.35 (t, J = 5.8 Hz, 1H), 3.25 (t, J = 6.1 Hz, 1H), 2.00 – 1.91 (m, 2H), 1.38 (d, J = 32.5 Hz, 9H). LC/MS (ESI) m/z 360.3; [M+H] + calcd for C 19 H 26 N 3 O 4 + : 360.19. M-1 (610 mg, 64% yield): 1 H NMR (600 MHz, Chloroform-d) δ 7.99 (d, J = 9.0 Hz, 1H), 7.13 (d, J = 2.8 Hz, 1H), 6.98 (dd, J = 9.0, 2.8 Hz, 1H), 4.34 – 4.26 (m, 2H), 3.94 (s, 3H), 3.65 – 3.57 (m, 2H), 3.16 (dd, J = 12.7, 4.5 Hz, 2H), 1.49 (s, 9H), 1.30 (s, 3H), 1.29 (s, 3H). LC/MS (ESI) m/z 374.2; [M+H] + calcd for C 20 H 28 N 3 O 4 + : 374.21. N-1: (700 mg, 70% yield): 1 H NMR (600 MHz, Chloroform-d) δ 7.96 (d, J = 8.9 Hz, 1H), 6.83 (d, J = 8.6 Hz, 1H), 6.67 (dd, J = 8.8, 2.6 Hz, 1H), 4.64 (d, J = 80.9 Hz, 1H), 4.52 – 4.43 (m, 1H), 3.93 (s, 3H), 3.62 – 3.52 (m, 1H), 3.50 – 3.18 (m, 3H), 2.08 – 1.95 (m, 2H), 1.44 (d, J = 29.7 Hz, 9H). LC/MS (ESI) m/z 358.2; [M+H] + calcd for C 19 H 24 N 3 O 4 + : 358.18. P-1 (520 mg, 54% yield): 1 H NMR (599 MHz, Chloroform-d) δ 7.62 (d, J = 8.7 Hz, 1H), 7.53 (d, J = 2.8 Hz, 1H), 6.98 (dd, J = 8.7, 2.8 Hz, 1H), 3.99 (s, 3H), 3.60 (t, J = 5.3 Hz, 4H), 3.37 (t, J = 5.2 Hz, 4H), 1.49 (s, 9H). LC/MS (ESI) m/z 346.1; [M+H] + calcd for C 18 H 24 N 3 O 4 + : 346.18. Step 2: General procedure for the synthesis of tert-butyl 4-(3-formyl-4- (methoxycarbonyl)phenyl)-1,4-diazepane-1-carboxylate (L-2), tert-butyl 4-(3-formyl-4- (methoxycarbonyl)phenyl)-2,6-dimethylpiperazine-1-carboxylat e (M-2), tert-butyl 5-(3- formyl-4-(methoxycarbonyl)phenyl)-2,5-diazabicyclo[2.2.1]hep tane-2-carboxylate (N-2) and tert-butyl 4-(4-formyl-3-(methoxycarbonyl)phenyl)piperazine-1-carboxyla te (P-2). A mixture of L-1, M-1, N-1, or P-1 (1.0 equiv.), pyridine (30.0 equiv.), acetate acid (20.0 equiv.), Raney-Ni (2.0 equiv.) and NaH2PO2•H2O (10.0 equiv.) in water was stirred at 85 °C overnight. The resulting mixture was cooled to room temperature and filtered through celite. The filtration was extracted with EtOAc. The combined organic layers were washed with water and sat. aq. NH4Cl, dried over Na2SO4, then filtered and concentrated. The residue was purified by flash column chromatography (0% to 60% of EtOAc in hexanes) to afford L-2, M-2, N-2, and P-2. L-2 (567 mg, 59% yield): 1 H NMR (600 MHz, Chloroform-d) δ 10.75 (s, 1H), 7.91 (d, J = 8.8 Hz, 1H), 7.15 (d, J = 2.8 Hz, 1H), 6.82 (dd, J = 8.9, 2.6 Hz, 1H), 3.90 (s, 3H), 3.72 – 3.55 (m, 6H), 3.33 (t, J = 6.0 Hz, 1H), 3.22 (t, J = 6.1 Hz, 1H), 2.02 – 1.93 (m, 2H), 1.38 (d, J = 43.1 Hz, 9H). LC/MS (ESI) m/z 363.2; [M+H] + calcd for C 19 H 27 N 2 O 5 + : 363.19. M-2 (345 mg, 56% yield): 1 H NMR (600 MHz, Chloroform-d) δ 10.74 (s, 1H), 7.93 (d, J = 8.8 Hz, 1H), 7.31 (d, J = 2.8 Hz, 1H), 6.99 (dd, J = 8.8, 2.8 Hz, 1H), 4.33 – 4.24 (m, 2H), 3.92 (s, 3H), 3.71 – 3.62 (m, 2H), 3.13 (dd, J = 12.6, 4.5 Hz, 2H), 1.49 (s, 9H), 1.30 (s, 3H), 1.29 (s, 3H). LC/MS (ESI) m/z 377.2; [M+H] + calcd for C 20 H 29 N 2 O 5 + : 377.21. N-2 (270 mg, 54% yield): 1 H NMR (600 MHz, Chloroform-d) δ 10.74 (s, 1H), 7.92 (dd, J = 8.8, 3.3 Hz, 1H), 6.98 (d, J = 10.8 Hz, 1H), 6.65 (d, J = 9.0 Hz, 1H), 4.75 – 4.46 (m, 2H), 3.91 (s, 3H), 3.59 (t, J = 7.2 Hz, 1H), 3.48 – 3.21 (m, 3H), 2.03 – 1.93 (m, 2H), 1.43 (d, J = 32.3 Hz, 9H). LC/MS (ESI) m/z 361.1; [M+H] + calcd for C19H25N2O5 + : 361.18. P-2 (198 mg, 44% yield): 1 H NMR (600 MHz, Chloroform-d) δ 10.35 (s, 1H), 7.92 (d, J = 8.8 Hz, 1H), 7.27 (d, J = 2.7 Hz, 1H), 7.00 (dd, J = 9.0, 2.6 Hz, 1H), 3.96 (s, 3H), 3.59 (t, J = 5.3 Hz, 4H), 3.40 (t, J = 5.3 Hz, 4H), 1.49 (s, 9H). LC/MS (ESI) m/z 349.2; [M+H] + calcd for C18H25N2O5 + : 349.18. Step 3: General procedure for the synthesis of tert-butyl 4-(2-(2,6-dioxopiperidin-3-yl)-1- oxoisoindolin-5-yl)-1,4-diazepane-1-carboxylate (L-3), tert-butyl 4-(2-(2,6-dioxopiperidin-3- yl)-1-oxoisoindolin-5-yl)-2,6-dimethylpiperazine-1-carboxyla te (M-3), tert-butyl 5-(2-(2,6- dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)-2,5-diazabicyclo[ 2.2.1]heptane-2-carboxylate (N- 3) and tert-butyl 4-(2-(2,6-dioxopiperidin-3-yl)-3-oxoisoindolin-5-yl)piperazi ne-1- carboxylate (P-3). A mixture of L-2, M-2, N-2, or P-2 (1.0 equiv.), 3-aminopiperidine-2,6-dione hydrochloride (1.3 equiv.), acetate acid (1.2 equiv.) and NaBH(OAc) 3 (3.0 equiv.) in EtOH was stirred at 40 °C overnight. The resulting mixture was concentrated and the residue was purified by flash column chromatography (0% to 5% of MeOH in DCM) to afford L-3, M-3, N-3 and P- 3. L-3 (370 mg, 54% yield): 1 H NMR (600 MHz, Chloroform-d) δ 8.16 (s, 1H), 7.70 (d, J = 8.6 Hz, 1H), 6.78 (dd, J = 8.7, 2.2 Hz, 1H), 6.70 – 6.62 (m, 1H), 5.21 (dd, J = 13.3, 5.1 Hz, 1H), 4.39 (d, J = 15.5 Hz, 1H), 4.26 – 4.21 (m, 1H), 3.71 – 3.52 (m, 6H), 3.40 – 3.27 (m, 1H), 3.23 (q, J = 5.9 Hz, 1H), 2.95 – 2.87 (m, 1H), 2.83 (ddd, J = 17.9, 13.2, 5.3 Hz, 1H), 2.35 – 2.27 (m, 1H), 2.21 – 2.16 (m, 1H), 2.03 – 1.91 (m, 2H), 1.39 (d, J = 42.7 Hz, 9H). LC/MS (ESI) m/z 443.3; [M+H] + calcd for C23H31N4O5 + : 443.23. M-3 (72 mg, 56% yield): 1 H NMR (600 MHz, DMSO-d6) δ 10.95 (s, 1H), 7.54 (d, J = 8.5 Hz, 1H), 7.10 (d, J = 2.1 Hz, 1H), 7.07 (dd, J = 8.6, 2.2 Hz, 1H), 5.05 (dd, J = 13.4, 5.1 Hz, 1H), 4.34 (d, J = 16.7 Hz, 1H), 4.22 (d, J = 16.8 Hz, 1H), 4.15 – 4.09 (m, 2H), 3.73 (d, J = 12.7 Hz, 2H), 2.99 (dd, J = 12.7, 4.4 Hz, 2H), 2.91 (ddd, J = 17.3, 13.6, 5.4 Hz, 1H), 2.63 – 2.54 (m, 1H), 2.37 (qd, J = 13.2, 4.5 Hz, 1H), 1.99 – 1.93 (m, 1H), 1.44 (s, 9H), 1.23 (s, 3H), 1.22 (s, 3H). LC/MS (ESI) m/z 457.2; [M+H] + calcd for C24H33N4O5 + : 457.24. M-3 (103 mg, 65% yield): 1 H NMR (600 MHz, Chloroform-d) δ 8.07 (s, 1H), 7.74 – 7.67 (m, 1H), 6.67 – 6.57 (m, 1H), 6.55 – 6.47 (m, 1H), 5.25 – 5.16 (m, 1H), 4.71 – 4.43 (m, 2H), 4.39 (dd, J = 15.5, 4.8 Hz, 1H), 4.28 – 4.19 (m, 1H), 3.65 – 3.56 (m, 1H), 3.50 – 3.35 (m, 2H), 3.24 (dd, J = 50.7, 8.9 Hz, 1H), 2.94 – 2.87 (m, 1H), 2.87 – 2.78 (m, 1H), 2.31 (qd, J = 13.2, 4.8 Hz, 1H), 2.23 – 2.16 (m, 1H), 2.04 – 1.93 (m, 2H), 1.43 (d, J = 27.6 Hz, 9H). LC/MS (ESI) m/z 441.1; [M+H] + calcd for C 23 H 29 N 4 O 5 + : 441.21. P-3 (70 mg, 33% yield): 1 H NMR (600 MHz, Chloroform-d) δ 8.06 (s, 1H), 7.38 (d, J = 2.4 Hz, 1H), 7.35 (d, J = 8.4 Hz, 1H), 7.17 (dd, J = 8.4, 2.4 Hz, 1H), 5.21 (dd, J = 13.3, 5.1 Hz, 1H), 4.41 (d, J = 15.5 Hz, 1H), 4.27 (d, J = 15.7 Hz, 1H), 3.59 (t, J = 5.2 Hz, 4H), 3.19 (t, J = 5.2 Hz, 4H), 2.96 – 2.88 (m, 1H), 2.83 (ddd, J = 18.0, 13.4, 5.4 Hz, 1H), 2.42 – 2.29 (m, 1H), 2.25 – 2.18 (m, 1H), 1.49 (s, 9H). LC/MS (ESI) m/z 429.2; [M+H] + calcd for C C 22 H 29 N 4 O 5 + : 429.21. Step 4: General procedure for the synthesis of 3-(5-(1,4-diazepan-1-yl)-1-oxoisoindolin-2- yl)piperidine-2,6-dione hydrochloride (intermediate L), 3-(5-(3,5-dimethylpiperazin-1-yl)-1- oxoisoindolin-2-yl)piperidine-2,6-dione hydrochloride (intermediate M), 3-(5-(2,5- diazabicyclo[2.2.1]heptan-2-yl)-1-oxoisoindolin-2-yl)piperid ine-2,6-dione hydrochloride (intermediate N) and 3-(1-oxo-6-(piperazin-1-yl)isoindolin-2-yl)piperidine-2,6-di one hydrochloride (intermediate P). HCl (4 N HCl in dioxane) was added to a solution of L-3, M- 3, N-3, or P-3 (1.0 equiv.) in DCM, then stirred at room temperature for 2 hours. The resulting mixture was concentrated to afford Intermediates L, M, N and P, which were directly used in the next step. Intermediate L (362 mg, quantitative yield): LC/MS (ESI) m/z 343.1; [M+H] + calcd for C18H23N4O3 + : 343.18. Intermediate M (70 mg, quantitative yield): LC/MS (ESI) m/z 357.3; [M+H] + calcd for C 19 H 25 N 4 O 3 + : 357.29. Intermediate N (100 mg, quantitative yield): LC/MS (ESI) m/z 341.2; [M+H] + calcd for C18H21N4O3 + : 341.16. Intermediate P (67 mg, quantitative yield): LC/MS (ESI) m/z 329.1; [M+H] + calcd for C17H21N4O3 + : 329.16. PREPARATION OF COMPOUNDS IN TABLE 1 General Procedure A: Step 1: A reaction mixture of Intermediate C (1.0 equiv.), Bromide (2.0 equiv.) and TEA (4.0 equiv.) in DCM were stirred at room temperature overnight. The mixture was washed with sat. aq. NHCl4 and dried over Na2SO4, filtered and concentrated. The residue was purified by flash column chromatography (hexanes/EtOAc or DCM/MeOH) to afford a tert-butyl ester intermediate. Step 2: To a solution of the tert-butyl ester intermediate from Step 1 (1.0 equiv.) in DCM was added HCl (4 N HCl in dioxane), then stirred at room temperature overnight. The reaction mixture was concentrated to afford a carboxylic acid intermediate, which was directly used in the next step. Step 3: To a solution of the carboxylic acid intermediate from step 2 (1.2 equiv.) and HATU (1.5 equiv.) in DCM was added a solution of Intermediate D (1.0 equiv.) and TEA (6.0 equiv.) in DCM. The resulting mixture was stirred at room temperature for 2 hours, then washed with water and sat. aq. NH4Cl. The organic layers were dried over Na2SO4, filtered and concentrated. The residue was purified by preparative TLC (DCM/MeOH) to afford the desired compound. General Procedure B: Step 1: Under an argon atmosphere, a mixture of Intermediate E (1.0 equiv.), alkyne (1.5 equiv.), Pd(Ph 3 P) 2 Cl 2 (0.15 equiv.) and CuI (0.3 equiv.) in TEA and DMSO were irradiated at 110 °C for 3 hours. The resulting mixture was diluted with EtOAc and washed with water and sat. aq. NHCl4. The organic layers were dried over Na2SO4, filtered and concentrated. The residue was purified by flash column chromatography (hexanes/EtOAc or DCM/MeOH) to afford a Boc-protected amine. Step 2: HCl (4 N HCl in dioxane) or TFA was added to a stirring solution of the Boc-protected amine from step 1(1.0 equiv.) in DCM. Then the resulting mixture was stirred at room temperature for 1 hour. The reaction mixture was concentrated to afford the corresponding amine, which was directly used in the next step. Step 3: Intermediate B (1.0 equiv.) and NaBH(OAc)3 (1.2 equiv.) were added to a solution of the amine from step 2 (2.0 equiv.) and TEA (8.0 equiv.) in DCM, then stirred at room temperature overnight. The resulting mixture was washed with sat. aq. NH 4 Cl. The organic layers were dried over Na 2 SO 4 , filtered and concentrated. The residue was purified by preparative TLC (DCM/MeOH) to afford the desired compound. General Procedure C: Step 1: Aldehyde (1.2 equiv.) and NaBH(OAc)3 (1.5 equiv.) were added to a solution of amine (1.0 equiv.) and TEA (6.0 equiv.) in DCM. The resulting mixture was stirred at room temperature overnight, then washed with water and sat. aq. NH 4 Cl. The organic layers were dried over Na2SO4, filtered and concentrated. The residue was purified by flash column chromatography (hexanes/EtOAc or DCM/MeOH) to afford the reductive amination product. Step 2: 4 N HCl in dioxane or TFA was added to a stirring solution of the product from Step 1 (1.0 equiv.) in DCM and stirred at room temperature for 1 hour. The reaction mixture was concentrated to afford the corresponding de-Boc product, which was directly used in the next step. Step 3: Intermediate B (1.0 equiv.) and NaBH(OAc) 3 (1.2 equiv.) were added to a solution of the product from Step 2 (2.0 equiv.) and TEA (8.0 equiv.) in DCM, then stirred at room temperature overnight. The resulting mixture was washed with sat. aq. NH4Cl. The organic layers were dried over Na 2 SO 4 , filtered and concentrated. The residue was purified by preparative TLC (DCM/MeOH) to afford the desired compound. General Procedure D: Step 1: A stirring mixture of alkyne (1.0 equiv.) and 10% palladium on carbon (20%, w/w) in EtOAc/MeOH (v/v=1/1) was hydrogenated overnight with a hydrogen balloon. The resulting mixture was filtered through celite and the filtration was concentrated. The residue was purified by flash column chromatography (hexanes/EtOAc or DCM/MeOH) to afford the corresponding coupling product. Step 2: To a solution of the product from Step 1 (1.2 equiv.) and HATU (1.5 equiv.) in DCM was added a solution of Intermediate D (1.0 equiv.) and TEA (6.0 equiv.) in DCM. The resulting mixture was stirred at room temperature for 2 hours, then washed with water and sat. aq. NH 4 Cl. The organic layers were dried over Na 2 SO 4 , filtered and concentrated. The residue was purified by preparative TLC (DCM/MeOH) to afford the desired compound. General Procedure E: Step 1: A stirring mixture of alkyne (1.0 equiv.) and 10% palladium on carbon (20%, w/w) in EtOAc/MeOH (v/v=1/1) was hydrogenated overnight with a hydrogen balloon. The resulting mixture was filtered through celite and the filtration was concentrated. The residue was purified by flash column chromatography (hexanes/EtOAc or DCM/MeOH) to afford the corresponding coupling product. Step 2: 4 N HCl in dioxane or TFA was added to a stirring solution of the product from Step 1 (1.0 equiv.) in DCM and stirred at room temperature for 1 hour. The reaction mixture was concentrated to afford the corresponding de-Boc product, which was directly used in the next step. Step 3: Intermediate B (1.0 equiv.) and NaBH(OAc)3 (1.2 equiv.) were added to a solution of the product from Step 2 (2.0 equiv.) and TEA (8.0 equiv.) in DCM, then stirred at room temperature overnight. The resulting mixture was washed with sat. aq. NH 4 Cl and dried over Na 2 SO 4 , filtered and concentrated. The residue was purified by preparative TLC (DCM/MeOH) to afford the desired compound. General Procedure F: Step 1: A reaction mixture of Intermediate H (1.0 equiv.), amine (1.5 equiv.) and DIPEA (3.0 equiv.) in DMSO were stirred at 80 °C overnight. The resulting mixture was cooled to room temperature and diluted with EtOAc, then washed with water and sat. aq. NHCl 4 . The organic layers were dried over Na2SO4, filtered and concentrated. The residue was purified by flash column chromatography (hexanes/EtOAc or DCM/MeOH) to afford a carboxylic acid intermediate. Step 2: To a solution of the carboxylic acid intermediate from Step 1 (1.2 equiv.) and HATU (1.5 equiv.) in DCM was added a solution of Intermediate G (1.0 equiv.) and TEA (6.0 equiv.) in DCM. The resulting mixture was stirred at room temperature for 2 hours, then washed with water and sat. aq. NH4Cl. The organic layers were dried over Na2SO4, filtered and concentrated. The residue was purified by preparative TLC (DCM/MeOH) to afford the desired compound. General Procedure G: Step 1: A reaction mixture of Intermediate H or I (1.0 equiv.), amine or bromide (1.2 equiv.) and DIPEA (3.0 equiv.) in NMP were irradiated at 110 °C for 3 hours. The resulting mixture was diluted with EtOAc and washed with water and sat. aq. NHCl 4 . The organic layers were dried over Na2SO4, filtered and concentrated. The residue was purified by flash column chromatography (hexanes/EtOAc or DCM/MeOH) to afford the corresponding product. Step 2: To a solution of the product from Step 1 (1.0 equiv.) in DCM was added HCl (4 N HCl in dioxane), then stirred at room temperature overnight. The reaction mixture was concentrated to afford a carboxylic acid intermediate, which was directly used in the next step. Step 3: To a solution of 19-3 or the carboxylic acid intermediate from Step 2 (1.2 equiv.) and HATU (1.5 equiv.) in DCM was added a solution of Intermediate G, 19-2, 20-2, or 21-2 (1.0 equiv.) and TEA (6.0 equiv.) in DCM. The resulting mixture was stirred at room temperature for 2 hours, then washed with water and sat. aq. NH4Cl. The organic layers were dried over Na2SO4, filtered and concentrated. The residue was purified by preparative TLC (DCM/MeOH) to afford the desired compound. General Procedure H: Intermediate B (1.0 equiv.) and NaBH(OAc)3 (1.2 equiv.) were added to a solution of an appropriate amine (2.0 equiv.) and TEA (8.0 equiv.) in DCM, then stirred at room temperature overnight. The resulting mixture was washed with sat. aq. NH 4 Cl. The organic layers were dried over Na2SO4, filtered and concentrated. The residue was purified by preparative TLC (DCM/MeOH) to afford the desired compound. Example 1: Preparation of Compound #11 Step 1: Synthesis of tert-butyl 4-((4-(2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5- yl)piperazin-1-yl)methyl)piperidine-1-carboxylate (11-1).1-Boc-piperidine-4-carboxaldehyde (93 mg, 0.44 mmol) and NaBH(OAc)3 (92 mg, 0.44 mmol) were added to a solution of Intermediate C (106 mg, 0.29 mmol) and TEA (242 µL, 1.74 mmol) in DCM (5 mL). The resulting mixture was stirred at room temperature overnight, then washed with water and sat. aq. NH4Cl. The organic layers were dried over Na2SO4, filtered and concentrated. The residue was purified by flash column chromatography (0% to 15% of MeOH in DCM) to afford 11-1 (112 mg, 74% yield) as an off-white solid. 1 H NMR (600 MHz, Chloroform-d) δ 8.04 (s, 1H), 7.75 (d, J = 8.6 Hz, 1H), 7.01 (dd, J = 8.6, 2.2 Hz, 1H), 6.89 (d, J = 2.2 Hz, 1H), 5.22 (dd, J = 13.3, 5.1 Hz, 1H), 4.43 (d, J = 15.6 Hz, 1H), 4.27 (d, J = 15.6 Hz, 1H), 4.20 – 4.02 (m, 2H), 3.37 – 3.28 (m, 4H), 2.98 – 2.79 (m, 2H), 2.78 – 2.65 (m, 2H), 2.58 (t, J = 5.1 Hz, 4H), 2.34 (qd, J = 13.2, 4.8 Hz, 1H), 2.25 (d, J = 7.2 Hz, 2H), 2.24 – 2.19 (m, 1H), 1.78 (d, J = 13.2 Hz, 2H), 1.73 – 1.66 (m, 1H), 1.48 (s, 9H), 1.12 (qd, J = 12.3, 4.3 Hz, 2H). LC/MS (ESI) m/z 526.1; [M+H] + calcd for C28H40N5O5 + : 526.3. Step 2: Synthesis of 3-(1-oxo-5-(4-(piperidin-4-ylmethyl)piperazin-1-yl)isoindoli n-2- l) i idi 26 di (112) HCl (1 L 4 N HCl i di ) dd d t ti i l ti of 11-1 (70 mg, 0.13 mmol) in DCM (1 mL) at room temperature. Then the resulting mixture was stirred at room temperature for 1 hour, the reaction mixture was concentrated to afford 11-2 (72 mg, quantitative yield) as HCl salt, which was used in the next step directly. LC/MS (ESI) m/z 426.2; [M+H] + calcd for C 23 H 32 N 5 O 3 + : 426.25. Step 3: Synthesis of N-((4-(((R)-4-(1,4-oxazepan-4-yl)-1-(phenylthio)butan-2-yl)a mino)-3- ((trifluoromethyl)sulfonyl)phenyl)sulfonyl)-4-(4-(((4R)-4'-c hloro-4-((4-((4-(2-(2,6- dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)piperazin-1-yl)met hyl)piperidin-1-yl)methyl)-4- methyl-3,4,5,6-tetrahydro-[1,1'-biphenyl]-2-yl)methyl)pipera zin-1-yl)benzamide (compound #11). Intermediate B (15 mg, 0.015 mmol) and NaBH(OAc) 3 (3 mg, 0.023 mmol) were added to a solution of 11-2 (9 mg, 0.0195 mmol) and TEA (13 µL, 0.09 mmol) in DCM (1 mL), then stirred at room temperature overnight. The resulting mixture was washed with sat. aq. NH4Cl. The organic layers were dried over Na2SO4, filtered and concentrated. The residue was purified by preparative TLC (DCM/MeOH = 10/1) to afford compound #11 (5.37 mg, 25% yield) as an off-white solid. 1 H NMR (600 MHz, Chloroform-d) δ 8.32 (d, J = 2.3 Hz, 1H), 8.01 (d, 1H), 7.84 (d, J = 8.5 Hz, 2H), 7.71 (d, J = 8.6 Hz, 1H), 7.36 (d, J = 7.6 Hz, 2H), 7.32 – 7.25 (m, 4H), 7.23 (t, J = 7.5 Hz, 1H), 6.97 (t, J = 8.8 Hz, 3H), 6.86 (s, 1H), 6.74 (d, J = 8.6 Hz, 2H), 6.47 (d, J = 9.2 Hz, 1H), 5.16 (dd, J = 13.4, 5.0 Hz, 1H), 4.40 (d, J = 15.8 Hz, 1H), 4.26 (d, J = 15.8 Hz, 1H), 3.85 – 3.67 (m, 5H), 3.28 (t, J = 5.0 Hz, 4H), 3.25 – 3.14 (m, 5H), 3.09 (dd, J = 13.8, 5.0 Hz, 2H), 3.02 (dd, J = 13.9, 6.9 Hz, 1H), 2.92 – 2.64 (m, 7H), 2.63 – 2.42 (m, 7H), 2.41 – 2.21 (m, 9H), 2.21 – 2.14 (m, 1H), 2.14 – 2.01 (m, 2H), 1.90 (p, J = 6.0 Hz, 2H), 1.85 – 1.53 (m, 14H), 1.53 – 1.41 (m, 1H), 1.02 (s, 3H).. LC/MS (ESI) m/z 1411.7; [M+H] + calcd for C71H87ClF3N10O3S3 + : 1411.55. Example 2: Preparation of compounds #1-3
Compounds #1-3 were prepared by following General Procedure A: tert-butyl 2-(4-(2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)piper azin-1-yl)acetate (1-1) (59 mg, 81% yield). 1 H NMR (600 MHz, Chloroform-d) δ 8.04 (s, 1H), 7.75 (d, J = 8.6 Hz, 1H), 7.02 (dd, J = 8.6, 2.2 Hz, 1H), 6.90 (s, 1H), 5.22 (dd, J = 13.3, 5.1 Hz, 1H), 4.43 (d, J = 15.6 Hz, 1H), 4.28 (d, J = 15.6 Hz, 1H), 3.42 – 3.37 (m, 4H), 3.21 (s, 2H), 2.97 – 2.89 (m, 1H), 2.88 – 2.80 (m, 1H), 2.80 – 2.74 (m, 4H), 2.37 – 2.29 (m, 1H), 2.26 – 2.18 (m, 1H), 1.50 (s, 9H). LC/MS (ESI) m/z 443.4; [M+H] + calcd for C 23 H 31 N 4 O 5 + : 443.52. tert-butyl 4-(4-(2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)piper azin-1-yl)butanoate (2-1) (66 mg, 61% yield). 1 H NMR (600 MHz, Chloroform-d) δ 8.11 (s, 1H), 7.75 (d, J = 8.6 Hz, 1H), 7.01 (dd, J = 8.6, 2.2 Hz, 1H), 6.90 (d, J = 2.1 Hz, 1H), 5.22 (dd, J = 13.3, 5.1 Hz, 1H), 4.43 (d, J = 15.6 Hz, 1H), 4.28 (d, J = 15.6 Hz, 1H), 3.35 (t, J = 5.1 Hz, 4H), 2.92 (ddd, J = 17.8, 4.8, 2.6 Hz, 1H), 2.84 (ddd, J = 18.0, 13.3, 5.3 Hz, 1H), 2.64 (t, J = 5.0 Hz, 4H), 2.45 (t, J = 7.5 Hz, 2H), 2.39 – 2.28 (m, 3H), 2.25 – 2.18 (m, 1H), 1.84 (p, J = 7.5 Hz, 2H), 1.47 (s, 9H). LC/MS (ESI) m/z 471.2; [M+H] + calcd for C25H35N4O5 + : 471.26. tert-butyl 6-(4-(2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)piper azin-1-yl)hexanoate (3-1) (84 mg, 68% yield). 1 H NMR (600 MHz, Chloroform-d) δ 8.08 (s, 1H), 7.75 (d, J = 8.6 Hz, 1H), 7.01 (dd, J = 8.6, 2.2 Hz, 1H), 6.90 (d, J = 2.1 Hz, 1H), 5.22 (dd, J = 13.3, 5.1 Hz, 1H), 4.43 (d, J = 15.6 Hz, 1H), 4.28 (d, J = 15.6 Hz, 1H), 3.35 (t, J = 5.1 Hz, 4H), 2.96 – 2.88 (m, 1H), 2.88 – 2.79 (m, 1H), 2.62 (t, J = 4.9 Hz, 4H), 2.42 (t, J = 7.7 Hz, 2H), 2.38 – 2.29 (m, 1H), 2.28 – 2.17 (m, 3H), 1.64 (p, J = 7.5 Hz, 2H), 1.60 – 1.53 (m, 2H), 1.47 (s, 9H), 1.43 – 1.34 (m, 2H). LC/MS (ESI) m/z 499.2; [M+H] + calcd for C 27 H 39 N 4 O 5 + : 499.29. 2-(4-(2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)piper azin-1-yl)acetic acid (1-2) (11 mg, quantitative yield). LC/MS (ESI) m/z 387.1; [M+H] + calcd for C19H23N4O5 + : 387.17. 4-(4-(2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)piper azin-1-yl)butanoic acid (2-2) ( 13 mg, quantitative yield). LC/MS (ESI) m/z 415.1; [M+H] + calcd for C21H27N4O5 + : 415.20. 6-(4-(2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)piper azin-1-yl)hexanoic acid (3-2) (13 mg, quantitative yield). LC/MS (ESI) m/z 443.1; [M+H] + calcd for C23H31N4O5 + : 443.23. N-((4-(((R)-4-(1,4-oxazepan-4-yl)-1-(phenylthio)butan-2-yl)a mino)-3- ((trifluoromethyl)sulfonyl)phenyl)sulfonyl)-4-(4-(((4R)-4'-c hloro-4-((4-(2-(4-(2-(2,6- dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)piperazin-1-yl)ace tyl)piperazin-1-yl)methyl)-4- methyl-3,4,5,6-tetrahydro-[1,1'-biphenyl]-2-yl)methyl)pipera zin-1-yl)benzamide (compound #1) (2.83 mg, 15% yield). 1 H NMR (600 MHz, Chloroform-d) δ 8.31 (s, 1H), 8.07 (d, J = 9.1 Hz, 1H), 7.74 (d, J = 8.4 Hz, 2H), 7.70 (d, J = 8.7 Hz, 1H), 7.40 – 7.35 (m, 3H), 7.34 – 7.21 (m, 5H), 7.02 – 6.94 (m, 3H), 6.88 (s, 1H), 6.75 (d, J = 8.4 Hz, 2H), 6.59 (d, J = 9.3 Hz, 1H), 5.18 (d, J = 13.1 Hz, 1H), 4.43 – 4.36 (m, 1H), 4.27 (d, J = 15.8 Hz, 1H), 3.89 (s, 1H), 3.76 (t, J = 6.1 Hz, 2H), 3.74 – 3.66 (m, 2H), 3.65 – 3.54 (m, 4H), 3.30 (s, 4H), 3.28 – 3.16 (m, 6H), 3.11 (dd, J = 14.1, 5.0 Hz, 1H), 3.04 (dd, J = 14.0, 6.8 Hz, 1H), 2.97 – 2.79 (m, 4H), 2.78 – 2.50 (m, 13H), 2.43 – 2.14 (m, 12H), 2.12 – 2.01 (m, 1H), 1.96 – 1.85 (m, 3H), 1.76 – 1.68 (m, 1H), 1.66 – 1.58 (m, 1H), 1.49 – 1.43 (m, 1H), 0.97 (s, 3H). LC/MS (ESI) m/z 1440.5; [M+H] + calcd for C71H86ClF3N11O10S3 + : 1440.54. N-((4-(((R)-4-(1,4-oxazepan-4-yl)-1-(phenylthio)butan-2-yl)a mino)-3- ((trifluoromethyl)sulfonyl)phenyl)sulfonyl)-4-(4-(((4R)-4'-c hloro-4-((4-(4-(4-(2-(2,6- dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)piperazin-1-yl)but anoyl)piperazin-1-yl)methyl)-4- methyl-3,4,5,6-tetrahydro-[1,1'-biphenyl]-2-yl)methyl)pipera zin-1-yl)benzamide (compound #2) (2.79 mg, 14% yield). 1 H NMR (600 MHz, Chloroform-d) δ 8.38 (d, J = 3.0 Hz, 1H), 8.05 (d, J = 8.5 Hz, 1H), 7.84 (d, J = 8.5 Hz, 2H), 7.77 – 7.69 (m, 1H), 7.39 (d, J = 7.3 Hz, 2H), 7.34 – 7.23 (m, 6H), 7.08 – 6.97 (m, 4H), 6.93 (s, 1H), 6.77 (dd, J = 8.7, 4.6 Hz, 2H), 6.55 (d, J = 9.3 Hz, 1H), 5.23 (d, J = 12.7 Hz, 1H), 4.42 (d, J = 15.7 Hz, 1H), 4.29 (d, J = 15.8 Hz, 1H), 3.88 (s, 1H), 3.84 – 3.66 (m, 4H), 3.50 – 3.28 (m, 8H), 3.23 (s, 4H), 3.10 (dd, J = 13.8, 5.0 Hz, 1H), 3.02 (dd, J = 13.8, 7.1 Hz, 1H), 2.96 – 2.83 (m, 8H), 2.81 – 2.51 (m, 9H), 2.51 – 2.24 (m, 12H), 2.25 – 2.05 (m, 5H), 1.95 – 1.84 (m, 4H), 1.76 – 1.69 (m, 1H), 1.69 – 1.62 (m, 1H), 1.62 – 1.55 (m, 1H), 1.51 – 1.43 (m, 1H), 0.98 (s, 3H). LC/MS (ESI) m/z 1468.5; [M+H] + calcd for C73H90ClF3N11O10S3 + : 1468.57. N-((4-(((R)-4-(1,4-oxazepan-4-yl)-1-(phenylthio)butan-2-yl)a mino)-3- ((trifluoromethyl)sulfonyl)phenyl)sulfonyl)-4-(4-(((4R)-4'-c hloro-4-((4-(6-(4-(2-(2,6- dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)piperazin-1-yl)hex anoyl)piperazin-1-yl)methyl)-4- methyl-3,4,5,6-tetrahydro-[1,1'-biphenyl]-2-yl)methyl)pipera zin-1-yl)benzamide (compound #3) (1.13 mg, 6% yield). 1 H NMR (600 MHz, Chloroform-d) δ 8.38 (s, 1H), 8.07 (d, J = 9.2 Hz, 1H), 7.79 (d, J = 8.7 Hz, 2H), 7.75 (d, J = 8.6 Hz, 1H), 7.42 – 7.36 (m, 2H), 7.34 – 7.23 (m, 6H), 7.10 (d, J = 8.4 Hz, 1H), 7.01 (d, 3H), 6.94 (d, J = 5.2 Hz, 1H), 6.79 (d, J = 8.7 Hz, 2H), 6.58 (d, J = 9.3 Hz, 1H), 5.24 (dd, J = 13.7, 4.1 Hz, 1H), 4.43 (d, J = 15.7 Hz, 1H), 4.29 (d, J = 15.8 Hz, 1H), 3.90 (s, 1H), 3.77 (t, J = 6.1 Hz, 2H), 3.75 – 3.64 (m, 4H), 3.48 (s, 4H), 3.43 – 3.32 (m, 2H), 3.23 (s, 4H), 3.10 (dd, J = 13.8, 5.1 Hz, 1H), 3.03 (dd, J = 14.0, 7.1 Hz, 1H), 2.96 – 2.76 (m, 8H), 2.76 – 2.53 (m, 8H), 2.53 – 2.17 (m, 17H), 2.12 – 2.05 (m, 1H), 1.91 – 1.84 (m, 4H), 1.79 – 1.56 (m, 7H), 1.51 – 1.45 (m, 1H), 0.99 (s, 3H). LC/MS (ESI) m/z 1496.7; [M+H] + calcd for C75H94ClF3N11O10S3 + : 1496.60. Example 3: Preparation of compound #4 Compound #4 was prepared by following General Procedure A: tert-butyl 2-(4-(3-(2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)pr op-2-yn-1- yl)piperazin-1-yl)acetate (4-1) (11 mg, 21% yield). 1 H NMR (600 MHz, Chloroform-d) δ 8.24 (s, 1H), 7.83 (d, J = 7.8 Hz, 1H), 7.56 (dd, J = 7.9, 1.3 Hz, 1H), 7.54 (s, 1H), 5.23 (dd, J = 13.4, 5.1 Hz, 1H), 4.49 (d, J = 16.0 Hz, 1H), 4.33 (d, J = 16.0 Hz, 1H), 3.58 (s, 2H), 3.15 (s, 2H), 2.95 (ddd, J = 17.8, 4.8, 2.5 Hz, 1H), 2.85 (ddd, J = 17.9, 13.4, 5.4 Hz, 1H), 2.76 (s, 4H), 2.69 (s, 4H), 2.38 (qd, J = 13.3, 4.7 Hz, 1H), 2.29 – 2.20 (m, 1H), 1.49 (s, 9H). LC/MS (ESI) m/z 481.1; [M+H] + calcd for C 26 H 33 N 4 O 5 + : 481.24. 2-(4-(3-(2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)pr op-2-yn-1-yl)piperazin-1- yl)acetic acid (4-2) (10 mg, quantitative yield). LC/MS (ESI) m/z 424.2; [M+H] + calcd for C 22 H 24 N 4 O 5 + : 424.17. N-((4-(((R)-4-(1,4-oxazepan-4-yl)-1-(phenylthio)butan-2-yl)a mino)-3- ((trifluoromethyl)sulfonyl)phenyl)sulfonyl)-4-(4-(((4R)-4'-c hloro-4-((4-(2-(4-(3-(2-(2,6- dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)prop-2-yn-1-yl)pip erazin-1-yl)acetyl)piperazin-1- yl)methyl)-4-methyl-3,4,5,6-tetrahydro-[1,1'-biphenyl]-2-yl) methyl)piperazin-1- yl)benzamide (compound #4) (8.27 mg, 41% yield). 1 H NMR (600 MHz, Chloroform-d) δ 8.32 (s, 1H), 8.07 (d, J = 9.1 Hz, 1H), 7.81 – 7.76 (m, 3H), 7.56 – 7.51 (m, 2H), 7.38 (d, J = 7.4 Hz, 2H), 7.33 – 7.22 (m, 6H), 7.09 – 7.06 (m, 1H), 7.04 – 6.98 (m, 2H), 6.77 (d, J = 8.6 Hz, 2H), 6.59 (d, J = 9.3 Hz, 1H), 5.25 (dd, J = 13.4, 4.6 Hz, 1H), 4.46 (d, J = 16.1 Hz, 1H), 4.33 (d, J = 16.2 Hz, 1H), 3.90 (s, 1H), 3.77 (t, J = 6.1 Hz, 2H), 3.75 – 3.68 (m, 2H), 3.67 – 3.52 (m, 6H), 3.25 (s, 4H), 3.21 (s, 2H), 3.11 (dd, J = 13.9, 5.0 Hz, 1H), 3.04 (dd, J = 13.9, 6.9 Hz, 1H), 2.95 – 2.83 (m, 4H), 2.83 – 2.48 (m, 16H), 2.47 – 2.27 (m, 6H), 2.27 – 2.04 (m, 8H), 2.01 – 1.86 (m, 3H), 1.82 – 1.69 (m, 1H), 1.67 – 1.56 (m, 1H), 1.52 – 1.42 (m, 1H), 0.97 (s, 3H). LC/MS (ESI) m/z 1478.4; [M+H] + calcd for C74H88ClF3N11O10S3 + : 1478.55. Compound #5 was prepared by following General Procedure A: tert-butyl 2-(4-((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)ethy nyl)piperidin-1- yl)acetate (5-1) (32 mg, 62% yield). 1 H NMR (600 MHz, Chloroform-d) δ 8.36 (s, 1H), 7.81 (d, J = 7.9 Hz, 1H), 7.52 (dd, J = 7.8, 1.3 Hz, 1H), 7.50 (s, 1H), 5.23 (dd, J = 13.3, 5.1 Hz, 1H), 4.48 (d, J = 15.9 Hz, 1H), 4.32 (d, J = 15.9 Hz, 1H), 3.15 (s, 2H), 2.97 – 2.90 (m, 1H), 2.89 – 2.80 (m, 3H), 2.71 – 2.65 (m, 1H), 2.45 (t, J = 10.1 Hz, 2H), 2.37 (qd, J = 13.2, 4.7 Hz, 1H), 2.28 – 2.20 (m, 1H), 2.03 – 1.94 (m, 2H), 1.90 – 1.79 (m, 2H), 1.48 (s, 9H). LC/MS (ESI) m/z 466.2; [M+H] + calcd for C 26 H 32 N 3 O 5 + : 466.23. 2-(4-((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)ethy nyl)piperidin-1-yl)acetic acid (5- 2) (11 mg, quantitative yield). LC/MS (ESI) m/z 410.1; [M+H] + calcd for C 22 H 24 N 3 O 5 + : 410.17. N-((4-(((R)-4-(1,4-oxazepan-4-yl)-1-(phenylthio)butan-2-yl)a mino)-3- ((trifluoromethyl)sulfonyl)phenyl)sulfonyl)-4-(4-(((4R)-4'-c hloro-4-((4-(2-(4-((2-(2,6- dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)ethynyl)piperidin- 1-yl)acetyl)piperazin-1- yl)methyl)-4-methyl-3,4,5,6-tetrahydro-[1,1'-biphenyl]-2-yl) methyl)piperazin-1- yl)benzamide (compound #5) (7.07 mg, 36% yield). 1 H NMR (600 MHz, Chloroform-d) δ 8.51 (s, 1H), 8.33 (t, J = 2.2 Hz, 1H), 8.07 (dt, J = 9.4, 2.7 Hz, 1H), 7.84 – 7.74 (m, 3H), 7.54 – 7.47 (m, 2H), 7.41 – 7.35 (m, 2H), 7.33 – 7.27 (m, 4H), 7.27 – 7.22 (m, 1H), 7.07 (d, J = 8.5 Hz, 1H), 7.03 – 6.98 (m, 2H), 6.76 (d, J = 8.7 Hz, 2H), 6.59 (d, J = 9.3 Hz, 1H), 5.29 (ddd, J = 16.0, 13.3, 5.1 Hz, 1H), 4.47 (d, J = 16.1 Hz, 1H), 4.33 (d, J = 16.1 Hz, 1H), 3.90 (d, J = 7.9 Hz, 1H), 3.80 – 3.75 (m, 2H), 3.75 – 3.68 (m, 2H), 3.60 (s, 4H), 3.35 – 3.17 (m, 6H), 3.11 (dd, J = 13.9, 5.0 Hz, 1H), 3.04 (dd, J = 13.9, 6.8 Hz, 1H), 2.96 – 2.75 (m, 10H), 2.75 – 2.49 (m, 8H), 2.45 – 2.21 (m, 12H), 2.17 (d, J = 17.4 Hz, 1H), 2.13 – 2.05 (m, 1H), 2.04 – 1.98 (m, 2H), 1.97 – 1.87 (m, 3H), 1.85 – 1.71 (m, 2H), 1.70 – 1.57 (m, 1H), 1.53 – 1.44 (m, 1H), 0.98 (s, 3H). LC/MS (ESI) m/z 1463.4; [M+H] + calcd for C74H87ClF3N10O10S3 + : 1463.54. Example 5: Preparation of compound #6 Compound #6 was prepared by following General Procedure D: 2-(4-(3-(2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)pr opyl)piperazin-1-yl)acetic acid (6-1) (17 mg, 89% yield). LC/MS (ESI) m/z 429.2; [M+H] + calcd for C22H29N4O5 + : 429.21. N-((4-(((R)-4-(1,4-oxazepan-4-yl)-1-(phenylthio)butan-2-yl)a mino)-3- ((trifluoromethyl)sulfonyl)phenyl)sulfonyl)-4-(4-(((4R)-4'-c hloro-4-((4-(2-(4-(3-(2-(2,6- dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)propyl)piperazin-1 -yl)acetyl)piperazin-1- yl)methyl)-4-methyl-3,4,5,6-tetrahydro-[1,1'-biphenyl]-2-yl) methyl)piperazin-1- yl)benzamide (compound #6) (5.28 mg, 26% yield). 1 H NMR (600 MHz, Chloroform-d) δ 8.38 (s, 1H), 8.04 (dd, J = 9.2, 2.2 Hz, 1H), 7.89 (d, 2H), 7.77 (dd, J = 7.8, 2.8 Hz, 1H), 7.41 – 7.37 (m, 2H), 7.35 – 7.22 (m, 7H), 7.05 – 6.95 (m, 3H), 6.79 (d, J = 8.6 Hz, 2H), 6.56 (d, J = 9.6, 1.7 Hz, 1H), 5.21 (ddd, J = 13.3, 5.2, 1.6 Hz, 1H), 4.46 – 4.24 (m, 2H), 3.87 (s, 1H), 3.77 (t, J = 6.1 Hz, 2H), 3.74 – 3.66 (m, 2H), 3.48 – 3.28 (m, 3H), 3.20 (s, 4H), 3.10 (dd, J = 14.0, 4.3 Hz, 1H), 3.06 – 2.96 (m, 3H), 2.96 – 2.87 (m, 3H), 2.87 – 2.53 (m, 16H), 2.50 – 2.13 (m, 18H), 2.12 – 1.99 (m, 3H), 1.91 – 1.82 (m, 3H), 1.77 – 1.68 (m, 1H), 1.67 – 1.55 (m, 2H), 1.49 – 1.42 (m, 1H), 0.97 (s, 3H). LC/MS (ESI) m/z 1482.6; [M+H] + calcd for C74H92ClF3N11O10S3 + : 1482.58. Example 6: Preparation of compound #7 Compound #7 was prepared by following General Procedure D: 2-(4-(2-(2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)et hyl)piperidin-1-yl)acetic acid (7- 1) (18 mg, 85% yield). LC/MS (ESI) m/z 414.2; [M+H] + calcd for C22H28N3O5 + : 414.20. N-((4-(((R)-4-(1,4-oxazepan-4-yl)-1-(phenylthio)butan-2-yl)a mino)-3- ((trifluoromethyl)sulfonyl)phenyl)sulfonyl)-4-(4-(((4R)-4'-c hloro-4-((4-(2-(4-(2-(2-(2,6- dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)ethyl)piperidin-1- yl)acetyl)piperazin-1-yl)methyl)- 4-methyl-3,4,5,6-tetrahydro-[1,1'-biphenyl]-2-yl)methyl)pipe razin-1-yl)benzamide (compound #7) (7.24 mg, 36% yield). 1 H NMR (600 MHz, Chloroform-d) δ 8.54 (s, 1H), 8.34 (t, J = 2.1 Hz, 1H), 8.05 (d, J = 9.1 Hz, 1H), 7.82 (dd, J = 8.9, 3.4 Hz, 2H), 7.80 – 7.75 (m, 1H), 7.40 – 7.35 (m, 2H), 7.34 – 7.21 (m, 7H), 7.05 – 6.98 (m, 3H), 6.77 (d, J = 8.6 Hz, 2H), 6.56 (d, J = 9.4 Hz, 1H), 5.30 – 5.23 (m, 1H), 4.46 (dd, J = 16.2, 2.5 Hz, 1H), 4.33 (d, J = 16.0 Hz, 1H), 3.88 (d, J = 10.5 Hz, 1H), 3.77 (t, J = 6.1 Hz, 2H), 3.75 – 3.71 (m, 2H), 3.63 – 3.47 (m, 4H), 3.37 (s, 2H), 3.26 (t, J = 5.3 Hz, 4H), 3.10 (dd, J = 13.9, 5.0 Hz, 1H), 3.07 – 2.99 (m, 3H), 2.95 – 2.84 (m, 4H), 2.83 – 2.61 (m, 9H), 2.54 (d, J = 17.6 Hz, 4H), 2.45 – 2.32 (m, 6H), 2.31 – 2.15 (m, 6H), 2.14 – 2.06 (m, 1H), 1.98 – 1.87 (m, 4H), 1.82 – 1.70 (m, 3H), 1.69 – 1.53 (m, 4H), 1.50 – 1.43 (m, 0H), 1.43 – 1.33 (m, 2H), 0.96 (s, 3H). LC/MS (ESI) m/z 1467.7; [M+H] + calcd for C 74 H 91 ClF 3 N 10 O 10 S 3 + : 1467.57. Example 7: Preparation of compounds #8-9 Compounds #8-9 were prepared by following General Procedure A: tert-butyl 2-(4-((4-(2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)p iperazin-1- yl)methyl)piperidin-1-yl)acetate (8-1) (21 mg, 29% yield). 1 H NMR (600 MHz, Chloroform-d) δ 8.12 (s, 1H), 7.75 (d, J = 8.6 Hz, 1H), 7.00 (dd, J = 8.7, 2.3 Hz, 1H), 6.89 (d, J = 2.2 Hz, 1H), 5.21 (dd, J = 13.4, 5.0 Hz, 1H), 4.42 (d, J = 15.5 Hz, 1H), 4.27 (d, J = 15.5 Hz, 1H), 3.33 (t, J = 4.9 Hz, 4H), 3.14 (s, 2H), 3.02 – 2.95 (m, 2H), 2.95 – 2.77 (m, 2H), 2.57 (t, J = 5.0 Hz, 4H), 2.39 – 2.29 (m, 1H), 2.26 (d, J = 7.1 Hz, 2H), 2.24 – 2.15 (m, 3H), 1.82 – 1.74 (m, 2H), 1.58 – 1.50 (m, 1H), 1.49 (s, 9H), 1.41 – 1.31 (m, 2H). LC/MS (ESI) m/z 540.3; [M+H] + calcd for C29H42N5O5 + : 540.32. tert-butyl 4-(4-((4-(2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)p iperazin-1- yl)methyl)piperidin-1-yl)butanoate (9-1) (12 mg, 35% yield). 1 H NMR (600 MHz, Chloroform-d) δ 8.63 (s, 1H), 7.74 (dd, J = 8.5, 1.7 Hz, 1H), 7.00 (d, J = 8.3 Hz, 1H), 6.89 (d, J = 2.3 Hz, 1H), 5.20 (dd, J = 13.0, 5.2 Hz, 1H), 4.41 (d, J = 15.4 Hz, 1H), 4.26 (d, J = 15.5 Hz, 1H), 3.34 (t, J = 5.0 Hz, 4H), 3.11 (s, 2H), 2.95 (d, J = 10.7 Hz, 2H), 2.92 – 2.77 (m, 2H), 2.61 (t, J = 5.0 Hz, 4H), 2.47 – 2.42 (m, 2H), 2.39 – 2.24 (m, 1H), 2.19 – 2.12 (m, 3H), 1.73 – 1.65 (m, 2H), 1.53 – 1.45 (m, 10H), 1.44 – 1.35 (m, 3H), 1.35 – 1.23 (m, 3H). LC/MS (ESI) m/z 568.4; [M+H] + calcd for C31H46N5O5 + : 568.35. 2-(4-((4-(2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)p iperazin-1-yl)methyl)piperidin-1- yl)acetic acid (8-2) (12 mg, quantitative yield). LC/MS (ESI) m/z 484.2; [M+H] + calcd for C25H34N5O5 + : 484.26. 4-(4-((4-(2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)p iperazin-1-yl)methyl)piperidin-1- yl)butanoic acid (9-2) (7 mg, quantitative yield). LC/MS (ESI) m/z 512.3; [M+H] + calcd for C27H38N5O5 + : 512.29. N-((4-(((R)-4-(1,4-oxazepan-4-yl)-1-(phenylthio)butan-2-yl)a mino)-3- ((trifluoromethyl)sulfonyl)phenyl)sulfonyl)-4-(4-(((4R)-4'-c hloro-4-((4-(2-(4-((4-(2-(2,6- dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)piperazin-1-yl)met hyl)piperidin-1- yl)acetyl)piperazin-1-yl)methyl)-4-methyl-3,4,5,6-tetrahydro -[1,1'-biphenyl]-2- yl)methyl)piperazin-1-yl)benzamide (compound #8) (5.38 mg, 34% yield 1 H NMR (600 MHz, Chloroform-d) δ 8.31 (t, J = 2.4 Hz, 1H), 8.04 (d, J = 9.0 Hz, 1H), 7.78 (dd, J = 8.9, 2.1 Hz, 2H), 7.72 (dd, J = 9.5, 2.6 Hz, 1H), 7.38 – 7.33 (m, 2H), 7.32 – 7.20 (m, 6H), 6.98 (dq, J = 8.9, 2.2 Hz, 3H), 6.88 (s, 1H), 6.80 – 6.75 (m, 2H), 6.56 (d, J = 9.3 Hz, 1H), 5.15 (dd, J = 13.5, 5.1 Hz, 1H), 4.40 (d, J = 15.8 Hz, 1H), 4.26 (d, J = 15.8 Hz, 1H), 3.86 (s, 1H), 3.75 (t, J = 6.1 Hz, 2H), 3.73 – 3.64 (m, 2H), 3.60 – 3.44 (m, 4H), 3.45 – 3.29 (m, 6H), 3.25 (t, J = 5.1 Hz, 4H), 3.09 (dd, J = 14.0, 4.9 Hz, 1H), 3.06 – 2.98 (m, 3H), 2.92 – 2.81 (m, 4H), 2.79 – 2.47 (m, 14H), 2.44 – 2.14 (m, 14H), 2.12 – 2.02 (m, 1H), 1.93 – 1.85 (m, 3H), 1.82 (d, J = 13.0 Hz, 2H), 1.76 – 1.66 (m, 1H), 1.66 – 1.54 (m, 3H), 1.48 – 1.39 (m, 1H), 1.38 – 1.28 (m, 2H), 0.94 (s, 3H). LC/MS (ESI) m/z 1537.5; [M+H] + calcd for C 77 H 97 ClF 3 N 12 O 10 S 3 + : 1537.62. N-((4-(((R)-4-(1,4-oxazepan-4-yl)-1-(phenylthio)butan-2-yl)a mino)-3- ((trifluoromethyl)sulfonyl)phenyl)sulfonyl)-4-(4-(((4R)-4'-c hloro-4-((4-(4-(4-((4-(2-(2,6- dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)piperazin-1-yl)met hyl)piperidin-1- yl)butanoyl)piperazin-1-yl)methyl)-4-methyl-3,4,5,6-tetrahyd ro-[1,1'-biphenyl]-2- yl)methyl)piperazin-1-yl)benzamide (compound #9) (0.95 mg, 7% yield). 1 H NMR (600 MHz, Chloroform-d) δ 8.38 – 8.35 (m, 1H), 8.00 (d, J = 8.4 Hz, 2H), 7.95 (d, J = 8.4 Hz, 1H), 7.72 (d, J = 8.5 Hz, 1H), 7.39 – 7.34 (m, 2H), 7.32 – 7.25 (m, 5H), 7.25 – 7.20 (m, 1H), 7.02 – 6.96 (m, 3H), 6.88 (s, 1H), 6.76 (d, J = 8.7 Hz, 2H), 6.50 (d, J = 9.2 Hz, 1H), 5.16 (dd, J = 13.4, 5.1 Hz, 1H), 4.40 (d, J = 15.8 Hz, 1H), 4.26 (d, J = 15.8 Hz, 1H), 3.81 (s, 1H), 3.77 – 3.72 (m, 2H), 3.71 – 3.62 (m, 4H), 3.43 – 3.39 (m, 4H), 3.30 (t, J = 5.1 Hz, 4H), 3.17 (s, 2H), 3.12 – 3.01 (m, 4H), 2.96 (dd, J = 13.8, 7.6 Hz, 1H), 2.90 – 2.78 (m, 3H), 2.71 – 2.49 (m, 10H), 2.45 (d, J = 13.8 Hz, 1H), 2.42 – 2.26 (m, 10H), 2.24 – 2.05 (m, 12H), 1.97 (d, J = 13.9 Hz, 1H), 1.90 – 1.73 (m, 5H), 1.72 – 1.53 (m, 5H), 1.50 – 1.44 (m, 1H), 1.36 – 1.29 (m, 2H), 0.97 (s, 3H). LC/MS (ESI) m/z 1565.8; [M+H] + calcd for C 79 H 101 ClF 3 N 12 O 10 S 3 + : 1565.66. Example 8: Preparation of compound #10 Compound #10 was prepared by following General Procedure A: tert-butyl 2-(4-(2-(4-(2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl )piperazin-1- yl)ethyl)piperidin-1-yl)acetate (10-1) (22 mg, 40% yield). 1 H NMR (600 MHz, Chloroform-d) δ 8.63 (s, 1H), 7.74 (dd, J = 9.0, 3.6 Hz, 1H), 7.00 (d, J = 8.4 Hz, 1H), 6.89 (s, 1H), 5.20 (dd, J = 13.4, 5.1 Hz, 1H), 4.42 (dd, J = 15.3, 4.3 Hz, 1H), 4.26 (dd, J = 15.7, 4.0 Hz, 1H), 3.34 (t, J = 5.0 Hz, 4H), 3.11 (s, 2H), 2.95 (d, J = 11.0 Hz, 2H), 2.92 – 2.77 (m, 2H), 2.61 (t, J = 5.0 Hz, 4H), 2.47 – 2.42 (m, 2H), 2.38 – 2.25 (m, 1H), 2.19 – 2.12 (m, 3H), 1.69 (d, 2H), 1.53 – 1.45 (m, 10H), 1.43 – 1.35 (m, 2H), 1.35 – 1.24 (m, 2H). LC/MS (ESI) m/z 554.4; [M+H] + calcd for C 30 H 44 N 5 O 5 + : 554.33. 2-(4-(2-(4-(2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl )piperazin-1-yl)ethyl)piperidin-1- yl)acetic acid (10-2) (12 mg, quantitative yield). LC/MS (ESI) m/z 498.3; [M+H] + calcd for C26H36N5O5 + : 498.27. N-((4-(((R)-4-(1,4-oxazepan-4-yl)-1-(phenylthio)butan-2-yl)a mino)-3- ((trifluoromethyl)sulfonyl)phenyl)sulfonyl)-4-(4-(((4R)-4'-c hloro-4-((4-(2-(4-(2-(4-(2-(2,6- dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)piperazin-1-yl)eth yl)piperidin-1- yl)acetyl)piperazin-1-yl)methyl)-4-methyl-3,4,5,6-tetrahydro -[1,1'-biphenyl]-2- yl)methyl)piperazin-1-yl)benzamide (compound #10) (1.18 mg, 6% yield). 1 H NMR (600 MHz, Chloroform-d) δ 8.32 (d, J = 2.2 Hz, 1H), 8.04 (dd, J = 9.2, 2.2 Hz, 1H), 7.79 (d, J = 8.8 Hz, 2H), 7.74 (d, J = 8.6 Hz, 1H), 7.39 – 7.34 (m, 2H), 7.32 – 7.20 (m, 6H), 7.03 – 6.97 (m, 3H), 6.92 (s, 1H), 6.79 (d, J = 8.9 Hz, 2H), 6.57 (d, J = 9.3 Hz, 1H), 5.17 (dd, J = 13.4, 5.0 Hz, 1H), 4.41 (d, J = 15.8 Hz, 1H), 4.28 (d, J = 15.9 Hz, 1H), 3.86 (s, 1H), 3.75 (t, J = 6.1 Hz, 2H), 3.71 – 3.56 (m, 3H), 3.54 – 3.39 (m, 10H), 3.30 – 3.16 (m, 4H), 3.11 – 3.05 (m, 1H), 3.02 (dd, J = 13.9, 7.2 Hz, 1H), 2.96 – 2.74 (m, 10H), 2.74 – 2.45 (m, 12H), 2.45 – 2.15 (m, 10H), 2.09 – 1.74 (m, 5H), 1.69 (d, J = 11.5 Hz, 1H), 1.66 – 1.56 (m, 6H), 1.54 – 1.46 (m, 1H), 1.46 – 1.39 (m, 1H), 1.38 – 1.21 (m, 2H), 0.95 (s, 3H). LC/MS (ESI) m/z 1551.7; [M+H] + calcd for C78H99ClF3N12O10S3 + : 1551.64. Example 9: Preparation of compound #12 Compound #12 was prepared by following General Procedure C: tert-butyl 4-((4-((4-(2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl) piperazin-1- yl)methyl)piperidin-1-yl)methyl)piperidine-1-carboxylate (12-1) (17 mg, 29% yield). 1 NMR (600 MHz, Chloroform-d) δ 8.06 (s, 1H), 7.75 (d, J = 8.5 Hz, 1H), 7.01 (dd, J = 8.6, 2.1 Hz, 1H), 6.89 (d, J = 2.1 Hz, 1H), 5.22 (dd, J = 13.3, 5.1 Hz, 1H), 4.43 (d, J = 15.5 Hz, 1H), 4.27 (d, J = 15.6 Hz, 1H), 4.21 – 3.95 (m, 3H), 3.33 (t, J = 5.0 Hz, 4H), 3.00 – 2.80 (m, 4H), 2.78 – 2.64 (m, 2H), 2.58 (t, J = 5.1 Hz, 4H), 2.40 – 2.30 (m, 1H), 2.29 – 2.13 (m, 3H), 2.03 – 1.62 (m, 9H), 1.61 – 1.51 (m, 1H), 1.47 (s, 9H), 1.19 – 1.03 (m, 3H). LC/MS (ESI) m/z 623.5; [M+H] + calcd for C34H51N6O5 + : 623.39. 3-(1-oxo-5-(4-((1-(piperidin-4-ylmethyl)piperidin-4-yl)methy l)piperazin-1-yl)isoindolin-2- yl)piperidine-2,6-dione hydrochloride (12-2) (9 mg, quantitative yield). LC/MS (ESI) m/z 523.3; [M+H] + calcd for C29H43N6O3 + : 523.34. N-((4-(((R)-4-(1,4-oxazepan-4-yl)-1-(phenylthio)butan-2-yl)a mino)-3- ((trifluoromethyl)sulfonyl)phenyl)sulfonyl)-4-(4-(((4R)-4'-c hloro-4-((4-((4-((4-(2-(2,6- dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)piperazin-1-yl)met hyl)piperidin-1- yl)methyl)piperidin-1-yl)methyl)-4-methyl-3,4,5,6-tetrahydro -[1,1'-biphenyl]-2- yl)methyl)piperazin-1-yl)benzamide (compound #12) (0.73 mg, 3% yield). 1 H NMR (600 MHz, Chloroform-d) δ 8.32 (s, 1H), 8.02 (d, J = 9.2 Hz, 1H), 7.83 (d, J = 8.5 Hz, 2H), 7.72 (dd, J = 8.4, 1.7 Hz, 2H), 7.37 (d, J = 7.6 Hz, 2H), 7.32 – 7.19 (m, 5H), 7.02 – 6.95 (m, 3H), 6.87 (s, 1H), 6.77 (d, J = 8.7 Hz, 2H), 6.54 (d, J = 9.2 Hz, 1H), 5.20 – 5.10 (m, 1H), 4.40 (d, J = 15.7 Hz, 1H), 4.26 (d, J = 15.8 Hz, 1H), 3.88 – 3.77 (m, 3H), 3.75 (dt, J = 6.9, 3.5 Hz, 2H), 3.69 – 3.62 (m, 3H), 3.40 (t, J = 1.7 Hz, 4H), 3.31 (s, 4H), 3.29 – 3.15 (m, 3H), 3.12 – 2.96 (m, 3H), 2.96 – 2.73 (m, 9H), 2.71 – 2.44 (m, 15H), 2.40 – 2.03 (m, 10H), 1.91 – 1.80 (m, 3H), 1.80 – 1.72 (m, 3H), 1.71 – 1.46 (m, 7H), 0.90 (s, 3H). LC/MS (ESI) m/z 1508.7; [M+H] + calcd for C 77 H 98 ClF 3 N 11 O 9 S 3 + : 1508.63. Example 10: Preparation of compound #13 Compound #13 was prepared by following General Procedure C: tert-butyl 4-((4-(3-(2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)p rop-2-yn-1- yl)piperazin-1-yl)methyl)piperidine-1-carboxylate (13-1) (65 mg, 72% yield). (600 MHz, Chloroform-d) δ 8.20 (s, 1H), 7.84 (d, 1H), 7.57 (dd, J = 7.9, 1.3 Hz, 1H), 7.55 (s, 1H), 523 (dd J = 134 51 Hz 1H) 450 (d J = 160 Hz 1H) 434 (d J = 160 Hz 1H) 421 – 398 (m, 3H), 3.56 (s, 2H), 2.95 (ddd, J = 17.8, 4.8, 2.5 Hz, 1H), 2.86 (ddd, J = 18.1, 13.4, 5.4 Hz, 1H), 2.79 – 2.61 (m, 5H), 2.59 – 2.45 (m, 3H), 2.38 (qd, J = 13.2, 4.7 Hz, 1H), 2.29 – 2.20 (m, 3H), 1.86 – 1.71 (m, 3H), 1.70 – 1.61 (m, 1H), 1.47 (s, 9H), 1.09 (qd, J = 12.3, 4.2 Hz, 2H). LC/MS (ESI) m/z 564.3; [M+H] + calcd for C 31 H 42 N 5 O 5 + : 564.32. 3-(1-oxo-5-(3-(4-(piperidin-4-ylmethyl)piperazin-1-yl)prop-1 -yn-1-yl)isoindolin-2- yl)piperidine-2,6-dione hydrochloride (13-2) (32 mg, quantitative yield). LC/MS (ESI) m/z 464.3; [M+H] + calcd for C26H34N5O3 + : 464.27. N-((4-(((R)-4-(1,4-oxazepan-4-yl)-1-(phenylthio)butan-2-yl)a mino)-3- ((trifluoromethyl)sulfonyl)phenyl)sulfonyl)-4-(4-(((4R)-4'-c hloro-4-((4-((4-(3-(2-(2,6- dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)prop-2-yn-1-yl)pip erazin-1-yl)methyl)piperidin-1- yl)methyl)-4-methyl-3,4,5,6-tetrahydro-[1,1'-biphenyl]-2-yl) methyl)piperazin-1- yl)benzamide (compound #13) (4.34 mg, 20% yield). 1 H NMR (600 MHz, Chloroform-d) δ 8.30 (dd, J = 5.8, 2.2 Hz, 1H), 8.02 – 7.97 (m, 1H), 7.84 (dd, J = 8.9, 3.3 Hz, 2H), 7.77 (dd, J = 16.7, 8.0 Hz, 1H), 7.55 – 7.47 (m, 2H), 7.40 – 7.35 (m, 2H), 7.33 – 7.19 (m, 6H), 6.98 (dd, J = 8.3, 1.6 Hz, 2H), 6.75 (dd, J = 11.7, 8.7 Hz, 2H), 6.48 (d, J = 9.3 Hz, 1H), 5.19 (dd, J = 13.4, 5.1 Hz, 1H), 4.43 (d, J = 16.3 Hz, 1H), 4.29 (d, J = 16.3 Hz, 1H), 3.81 (s, 1H), 3.77 (td, J = 6.1, 1.3 Hz, 2H), 3.74 – 3.67 (m, 2H), 3.58 (d, J = 6.9 Hz, 2H), 3.26 – 3.14 (m, 4H), 3.11 (dd, J = 13.8, 4.2 Hz, 1H), 3.06 – 2.95 (m, 3H), 2.92 – 2.46 (m, 16H), 2.44 – 2.15 (m, 16H), 2.13 – 2.04 (m, 1H), 2.04 – 1.84 (m, 3H), 1.81 – 1.49 (m, 8H), 1.48 – 1.35 (m, 1H), 0.98 (d, J = 9.1 Hz, 3H). LC/MS (ESI) m/z 1449.5; [M+H] + calcd for C74H89ClF3N10O9S3 + : 1449.56. Example 11: Preparation of compounds #14-15 Compounds #14-15 were prepared by following General Procedure F: 5-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)ami no)pentanoic acid (14-1) (175 mg, 65% yield). 1 H NMR (599 MHz, DMSO-d6) δ 11.08 (s, 1H), 7.58 (dd, J = 8.5, 7.1 Hz, 1H), 7.10 (d, J = 8.6 Hz, 1H), 7.02 (d, J = 7.0 Hz, 1H), 6.57 (t, J = 6.0 Hz, 1H), 5.04 (dd, J = 12.9, 5.5 Hz, 1H), 3.44 – 3.21 (m, 2H), 2.94 – 2.81 (m, 1H), 2.64 – 2.46 (m, 2H), 2.29 – 2.24 (m, 2H), 2.06 – 1.99 (m, 1H), 1.61 – 1.53 (m, 4H). LC/MS (ESI) m/z 374.1; [M+H] + calcd for C 18 H 20 N 3 O 6 + : 374.13. 2-(2-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl) amino)ethoxy)acetic acid (15-1) (143 mg, 53% yield). 1 H NMR (599 MHz, DMSO-d 6 ) δ 11.09 (s, 1H), 7.58 (dd, J = 8.6, 7.1 Hz, 1H), 7.15 (d, J = 8.6 Hz, 1H), 7.04 (d, J = 7.0 Hz, 1H), 6.68 (s, 1H), 5.05 (dd, J = 12.9, 5.4 Hz, 1H), 4.03 (s, 2H), 3.68 (q, J = 5.5 Hz, 2H), 3.53 – 3.46 (m, 2H), 2.94 – 2.82 (m, 1H), 2.65 – 2.45 (m, 2H), 2.07 – 1.97 (m, 1H). LC/MS (ESI) m/z 376.2; [M+H] + calcd for C17H18N3O7 + : 376.11. 4-(4-((4'-chloro-4-((4-(2-(4-(5-((2-(2,6-dioxopiperidin-3-yl )-1,3-dioxoisoindolin-4- yl)amino)pentanoyl)piperazin-1-yl)acetyl)piperazin-1-yl)meth yl)-4-methyl-3,4,5,6- tetrahydro-[1,1'-biphenyl]-2-yl)methyl)piperazin-1-yl)-N-((4 -(((R)-4-morpholino-1- (phenylthio)butan-2-yl)amino)-3-((trifluoromethyl)sulfonyl)p henyl)sulfonyl)benzamide (compound #14) (2.99 mg, 25% yield). 1 H NMR (600 MHz, Chloroform-d) δ 9.18 (s, 1H), 8.31 (d, J = 2.2 Hz, 1H), 8.06 (d, J = 9.1 Hz, 1H), 7.71 (d, J = 8.4 Hz, 2H), 7.48 (dd, J = 8.5, 7.1 Hz, 1H), 7.36 (d, J = 7.2 Hz, 2H), 7.32 – 7.20 (m, 6H), 7.07 (d, J = 7.1 Hz, 1H), 7.02 – 6.94 (m, 3H), 6.88 (d, J = 8.6 Hz, 1H), 6.72 (s, 2H), 6.59 (s, 1H), 6.23 (s, 1H), 4.88 (dd, J = 12.0, 5.5 Hz, 1H), 3.87 (s, 1H), 3.69 – 3.45 (m, 8H), 3.45 – 3.35 (m, 1H), 3.34 – 3.12 (m, 10H), 3.09 (dd, J = 13.9, 5.0 Hz, 1H), 3.01 (dd, J = 13.8, 7.1 Hz, 1H), 2.92 – 2.79 (m, 2H), 2.79 – 2.65 (m, 3H), 2.63 – 2.14 (m, 22H), 2.13 – 2.06 (m, 3H), 1.98 – 1.85 (m, 1H), 1.81 – 1.50 (m, 8H), 1.49 – 1.40 (m, 1H), 0.95 (s, 3H). LC/MS (ESI) m/z 1539.7; [M+H] + calcd for C75H91ClF3N12O12S3 + : 1539.57. 4-(4-((4'-chloro-4-((4-(2-(4-(2-(2-((2-(2,6-dioxopiperidin-3 -yl)-1,3-dioxoisoindolin-4- yl)amino)ethoxy)acetyl)piperazin-1-yl)acetyl)piperazin-1-yl) methyl)-4-methyl-3,4,5,6- tetrahydro-[1,1'-biphenyl]-2-yl)methyl)piperazin-1-yl)-N-((4 -(((R)-4-morpholino-1- (phenylthio)butan-2-yl)amino)-3-((trifluoromethyl)sulfonyl)p henyl)sulfonyl)benzamide (compound #15) (2.1 mg, 18% yield). 1 H NMR (600 MHz, Chloroform-d) δ 9.52 (s, 1H), 8.32 (s, 1H), 8.12 – 8.03 (m, 1H), 7.71 (d, J = 8.4 Hz, 2H), 7.49 (t, J = 7.8 Hz, 1H), 7.37 (d, J = 7.6 Hz, 2H), 7.34 – 7.20 (m, 6H), 7.10 (d, J = 7.1 Hz, 1H), 6.99 (d, J = 7.9 Hz, 3H), 6.89 (d, J = 8.6 Hz, 1H), 6.72 (s, 2H), 6.59 (s, 1H), 6.52 (s, 1H), 4.94 – 4.82 (m, 1H), 4.26 – 4.07 (m, 2H), 3.94 – 3.81 (m, 1H), 3.80 – 3.33 (m, 16H), 3.30 – 3.06 (m, 7H), 3.06 – 2.76 (m, 3H), 2.76 – 2.63 (m, 2H), 2.63 – 2.15 (m, 22H), 2.16 – 2.06 (m, 2H), 1.97 – 1.85 (m, 1H), 1.75 – 1.48 (m, 4H), 1.48 – 1.37 (m, 1H), 0.94 (s, 3H). LC/MS (ESI) m/z 1541.7; [M+H] + calcd for C74H89ClF3N12O13S3 + : 1541.55. Compound #16 was prepared by following General Procedure G: tert-butyl (2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)glycin ate (16-1) (405 mg, 58% yield). 1 H NMR (600 MHz, Chloroform-d) δ 7.99 (s, 1H), 7.51 (dd, J = 8.4, 7.2 Hz, 1H), 7.16 (d, J = 7.2 Hz, 1H), 6.76 (d, J = 8.4 Hz, 1H), 6.71 (t, J = 5.5 Hz, 1H), 4.93 (dd, J = 12.5, 5.4 Hz, 1H), 3.95 (d, J = 5.5 Hz, 2H), 2.92 – 2.87 (m, 1H), 2.88 – 2.68 (m, 2H), 2.16 – 2.09 (m, 1H), 1.50 (s, 9H). LC/MS (ESI) m/z 388.2; [M+H] + calcd for C 19 H 22 N 3 O 6 + : 388.15. (2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)glycin e (16-2) (4.2 mg, quantitative yield). LC/MS (ESI) m/z 332.1; [M+H] + calcd for C 15 H 14 N 3 O 6 + : 332.09. 4-(4-((4'-chloro-4-((4-(2-(4-((2-(2,6-dioxopiperidin-3-yl)-1 ,3-dioxoisoindolin-4- yl)glycyl)piperazin-1-yl)acetyl)piperazin-1-yl)methyl)-4-met hyl-3,4,5,6-tetrahydro-[1,1'- biphenyl]-2-yl)methyl)piperazin-1-yl)-N-((4-(((R)-4-morpholi no-1-(phenylthio)butan-2- yl)amino)-3-((trifluoromethyl)sulfonyl)phenyl)sulfonyl)benza mide (compound #16) (3.56 mg, 32% yield). 1 H NMR (600 MHz, Chloroform-d) δ 8.30 (d, 1H), 8.04 (d, 1H), 7.71 (d, J = 8.4 Hz, 2H), 7.45 (t, J = 24.5 Hz, 1H), 7.36 (d, J = 7.6 Hz, 2H), 7.32 – 7.21 (m, 6H), 7.11 (d, J = 7.2 Hz, 1H), 7.04 – 6.90 (m, 2H), 6.81 – 6.64 (m, 3H), 6.60 (s, 1H), 4.89 (dd, 1H), 4.06 – 3.81 (m, 3H) 377 335 (m 13H) 332 313 (m 6H) 309 (dd J = 139 50 Hz 1H) 301 (dd J = 13.9, 7.1 Hz, 1H), 2.95 – 2.64 (m, 5H), 2.64 – 2.15 (m, 20H), 2.13 – 2.02 (m, 2H), 2.02 – 1.86 (m, 1H), 1.77 – 1.38 (m, 5H), 0.96 (s, 3H). LC/MS (ESI) m/z 1497.4; [M+H] + calcd for C72H85ClF3N12O12S3 + : 1497.52. Example 13: Preparation of compound #17 Compound #17 was prepared by following General Procedure G: tert-butyl (2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)glycin ate (17-1) (510 mg, 73% yield). 1 H NMR (600 MHz, Chloroform-d) δ 8.11 (t, J = 29.3 Hz, 1H), 7.64 (dt, J = 8.3, 2.6 Hz, 1H), 6.95 (t, J = 1.6 Hz, 1H), 6.77 (ddd, J = 8.3, 2.2, 1.2 Hz, 1H), 4.93 (dd, J = 12.5, 5.4 Hz, 1H), 3.89 (dd, J = 4.9, 1.2 Hz, 2H), 2.92 – 2.68 (m, 3H), 2.16 – 2.08 (m, 1H), 1.51 (d, J = 1.0 Hz, 9H). LC/MS (ESI) m/z 388.1; [M+H] + calcd for C 19 H 22 N 3 O 6 + : 388.15. (2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-5-yl)glycin e (17-2) (3.8 mg, quantitative yield). LC/MS (ESI) m/z 332.1; [M+H] + calcd for C 15 H 14 N 3 O 6 + : 332.09. 4-(4-((4'-chloro-4-((4-(2-(4-((2-(2,6-dioxopiperidin-3-yl)-1 ,3-dioxoisoindolin-5- yl)glycyl)piperazin-1-yl)acetyl)piperazin-1-yl)methyl)-4-met hyl-3,4,5,6-tetrahydro-[1,1'- biphenyl]-2-yl)methyl)piperazin-1-yl)-N-((4-(((R)-4-morpholi no-1-(phenylthio)butan-2- yl)amino)-3-((trifluoromethyl)sulfonyl)phenyl)sulfonyl)benza mide (compound #17) (4.12 mg, 37% yield). 1 H NMR (600 MHz, Chloroform-d) δ 8.31 (d, J = 2.3 Hz, 1H), 8.09 (dd, J = 9.3, 2.3 Hz, 1H), 7.67 (d, J = 8.6 Hz, 2H), 7.61 (d, J = 8.3 Hz, 1H), 7.39 – 7.32 (m, 2H), 7.32 – 7.21 (m, 6H), 7.00 – 6.96 (m, 2H), 6.93 (d, J = 2.1 Hz, 1H), 6.85 (d, J = 8.4 Hz, 1H), 6.74 (d, J = 8.6 Hz, 2H), 6.64 – 6.56 (m, 1H), 4.92 (dd, J = 12.4, 5.4 Hz, 1H), 3.94 (s, 2H), 3.92 – 3.84 (m, 1H), 3.70 – 3.48 (m, 11H), 3.47 – 3.38 (m, 2H), 3.28 – 3.16 (m, 6H), 3.09 (dd, J = 13.9, 5.1 Hz, 1H), 3.02 (dd, J = 13.9, 7.1 Hz, 1H), 2.93 – 2.67 (m, 5H), 2.64 – 2.16 (m, 20H), 2.15 – 2.05 (m, 2H), 1.92 (d, J = 17.1 Hz, 1H), 1.74 – 1.49 (m, 4H), 1.47 – 1.37 (m, 1H), 0.95 (s, 3H). LC/MS (ESI) m/z 1497.4; [M+H] + calcd for C72H85ClF3N12O12S3 + : 1497.52. Compound #18 was prepared by following General Procedure G: tert-butyl 2-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)oxy )acetate (18-1) (190 mg, 67% yield). 1 H NMR (600 MHz, Chloroform-d) δ 8.01 (s, 1H), 7.66 (ddd, J = 8.5, 7.3, 1.6 Hz, 1H), 7.50 (d, J = 7.2 Hz, 1H), 7.10 (d, J = 8.5 Hz, 1H), 4.97 (dd, J = 12.3, 5.4 Hz, 1H), 4.78 (s, 2H), 2.92 – 2.70 (m, 3H), 2.16 – 2.07 (m, 1H), 1.47 (s, 9H). LC/MS (ESI) m/z 389.2; [M+H] + calcd for C19H21N2O7 + : 389.13. 2-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)oxy )acetic acid (18-2) (4.3 mg, quantitative yield). LC/MS (ESI) m/z 333.1; [M+H] + calcd for C15H13N2O7 + : 333.07. 4-(4-((4'-chloro-4-((4-(2-(4-(2-((2-(2,6-dioxopiperidin-3-yl )-1,3-dioxoisoindolin-4- yl)oxy)acetyl)piperazin-1-yl)acetyl)piperazin-1-yl)methyl)-4 -methyl-3,4,5,6-tetrahydro- [1,1'-biphenyl]-2-yl)methyl)piperazin-1-yl)-N-((4-(((R)-4-mo rpholino-1-(phenylthio)butan- 2-yl)amino)-3-((trifluoromethyl)sulfonyl)phenyl)sulfonyl)ben zamide (compound #18) (1.81 mg, 16% yield). 1 H NMR (600 MHz, Chloroform-d) δ 8.33 (d, J = 6.3, 2.2 Hz, 1H), 8.07 (t, J = 7.3 Hz, 1H), 7.73 (t, J = 7.7 Hz, 2H), 7.64 – 7.57 (m, 1H), 7.49 – 7.42 (m, 1H), 7.37 (d, J = 7.6 Hz, 2H), 7.34 – 7.21 (m, 6H), 7.06 (dd, J = 8.4, 4.1 Hz, 1H), 7.03 – 6.94 (m, 3H), 6.75 (s, 2H), 6.61 (d, J = 9.3 Hz, 1H), 4.94 (s, 1H), 4.77 (d, J = 5.1 Hz, 2H), 3.89 (s, 1H), 3.73 – 3.45 (m, 10H), 3.45 – 3.05 (m, 10H), 3.05 – 2.79 (m, 4H), 2.78 – 2.69 (m, 1H), 2.69 – 2.16 (m, 20H), 2.15 – 2.07 (m, 2H), 1.94 – 1.80 (m, 1H), 1.73 – 1.53 (m, 4H), 1.51 – 1.39 (m, 1H), 0.96 (s, 3H). LC/MS (ESI) m/z 1498.1; [M+H] + calcd for C72H84ClF3N11O13S3 + : 1498.05. Example 15: Preparation of compounds #19-21 Compound #19-21 were prepared by following General Procedure G: tert-butyl (2-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)am ino)ethyl)carbamate (19-1) (521 mg, 69% yield). 1 H NMR (600 MHz, Chloroform-d) δ 8.03 (s, 1H), 7.50 (dd, J = 8.5, 7.1 Hz, 1H), 7.12 (d, J = 7.1 Hz, 1H), 6.99 (d, J = 8.5 Hz, 1H), 6.39 (t, J = 6.0 Hz, 1H), 4.92 (dd, J = 12.4, 5.3 Hz, 1H), 4.82 (s, 1H), 3.45 (q, J = 6.1 Hz, 2H), 3.36 (q, J = 6.2 Hz, 2H), 2.93 – 2.86 (m, 1H), 2.85 – 2.69 (m, 2H), 2.17 – 2.08 (m, 1H), 1.45 (s, 9H). LC/MS (ESI) m/z 417.3; [M+H] + calcd for C20H25N4O6 + : 417.18. tert-butyl (4-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)am ino)butyl)carbamate (20-1) (443 mg, 55% yield). 1 H NMR (600 MHz, Chloroform-d) δ 8.23 (s, 1H), 7.48 (ddd, J = 8.6, 7.1, 1.8 Hz, 1H), 7.09 (dd, J = 7.1, 1.9 Hz, 1H), 6.88 (d, J = 8.6 Hz, 1H), 6.23 (t, J = 5.7 Hz, 1H), 4.91 (dd, J = 12.4, 5.3 Hz, 1H), 4.59 (s, 1H), 3.29 (q, J = 6.6 Hz, 2H), 3.17 (q, J = 6.8 Hz, 2H), 2.93 – 2.84 (m, 1H), 2.84 – 2.66 (m, 2H), 2.17 – 2.07 (m, 1H), 1.74 – 1.56 (m, 4H), 1.44 (s, 9H). LC/MS (ESI) m/z 445.2; [M+H] + calcd for C22H29N4O6 + : 445.21. tert-butyl (6-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)am ino)hexyl)carbamate (211) (617 mg 72% yield) 1 H NMR (600 MHz Chloroform d) δ 807 (s 1H) 749 (dd J = 85 7.1 Hz, 1H), 7.09 (d, J = 7.1 Hz, 1H), 6.87 (d, J = 8.5 Hz, 1H), 6.22 (t, J = 5.7 Hz, 1H), 4.91 (dd, J = 12.3, 5.4 Hz, 1H), 4.52 (s, 1H), 3.26 (q, J = 7.0, 5.6 Hz, 2H), 3.12 (q, J = 6.8 Hz, 2H), 2.93 – 2.85 (m, 1H), 2.85 – 2.67 (m, 2H), 2.17 – 2.09 (m, 1H), 1.66 (p, J = 7.2 Hz, 2H), 1.49 (q, J = 7.4 Hz, 2H), 1.47 – 1.40 (m, 11H), 1.40 – 1.34 (m, 2H). LC/MS [M+H] + calcd for C24H33N4O6 + : 473.21. 4-((2-aminoethyl)amino)-2-(2,6-dioxopiperidin-3-yl)isoindoli ne-1,3-dione hydrochloride (19-2) (5.1 mg, quantitative yield). LC/MS (ESI) m/z 317.2; [M+H] + calcd for C15H17N4O4 + : 317.12. 4-((4-aminobutyl)amino)-2-(2,6-dioxopiperidin-3-yl)isoindoli ne-1,3-dione hydrochloride (20-2) (6.5 mg, quantitative yield).. LC/MS (ESI) m/z 345.2; [M+H] + calcd for C17H21N4O4 + : 345.16. 4-((6-aminohexyl)amino)-2-(2,6-dioxopiperidin-3-yl)isoindoli ne-1,3-dione hydrochloride (21-2) (6.5 mg, quantitative yield). LC/MS (ESI) m/z 373.3; [M+H] + calcd for C19H25N4O4 + : 373.19. The preparation of 19-3-acid was performed according to patent WO 2023107606 A1. 2-(4-((4'-chloro-4-methyl-6-((4-(4-(((4-(((R)-4-morpholino-1 -(phenylthio)butan-2-yl)amino)- 3-((trifluoromethyl)sulfonyl)phenyl)sulfonyl)carbamoyl)pheny l)piperazin-1-yl)methyl)- 2,3,4,5-tetrahydro-[1,1'-biphenyl]-4-yl)methyl)piperazin-1-y l)-N-(2-((2-(2,6-dioxopiperidin- 3-yl)-1,3-dioxoisoindolin-4-yl)amino)ethyl)pyrimidine-5-carb oxamide (compound #19) (2.89 mg, 17% yield). 1 H NMR (600 MHz, Chloroform-d) δ 8.79 (s, 1H), 8.65 (s, 2H), 8.33 (d, J = 2.3 Hz, 1H), 8.08 (d, J = 9.1 Hz, 1H), 7.68 (d, J = 8.5 Hz, 2H), 7.43 (dd, J = 8.7, 7.0 Hz, 1H), 7.38 – 7.32 (m, 2H), 7.32 – 7.19 (m, 5H), 7.00 (ddd, J = 31.3, 13.1, 7.9 Hz, 4H), 6.89 (s, 1H), 6.73 (d, J = 8.6 Hz, 2H), 6.60 (d, J = 9.4 Hz, 1H), 6.42 (d, J = 6.8 Hz, 1H), 4.95 – 4.84 (m, 1H), 3.96 – 3.76 (m, 5H), 3.72 – 3.57 (m, 7H), 3.53 (s, 2H), 3.25 (s, 4H), 3.09 (dd, J = 13.8, 5.0 Hz, 1H), 3.01 (dd, J = 13.9, 7.1 Hz, 1H), 2.92 (s, 2H), 2.84 (d, J = 14.0 Hz, 1H), 2.80 – 2.65 (m, 2H), 2.60 (s, 4H), 2.53 – 2.17 (m, 15H), 2.15 – 2.03 (m, 2H), 2.01 – 1.86 (m, 1H), 1.73 – 1.57 (m, 3H), 1.50 – 1.38 (m, 1H), 0.97 (s, 3H). LC/MS (ESI) m/z 1478.7; [M+H] + calcd for C 71 H 80 ClF 3 N 13 O 11 S 3 + : 1478.49. 2-(4-((4'-chloro-4-methyl-6-((4-(4-(((4-(((R)-4-morpholino-1 -(phenylthio)butan-2-yl)amino)- 3-((trifluoromethyl)sulfonyl)phenyl)sulfonyl)carbamoyl)pheny l)piperazin-1-yl)methyl)- 2,3,4,5-tetrahydro-[1,1'-biphenyl]-4-yl)methyl)piperazin-1-y l)-N-(4-((2-(2,6-dioxopiperidin- 3-yl)-1,3-dioxoisoindolin-4-yl)amino)butyl)pyrimidine-5-carb oxamide (compound #20) (3.71 mg, 21% yield). 1 H NMR (600 MHz, Chloroform-d) δ 8.66 (s, 2H), 8.34 (d, J = 2.3 Hz, 1H), 8.09 (dd, J = 9.3, 2.3 Hz, 1H), 7.67 (d, J = 8.4 Hz, 2H), 7.45 (q, J = 8.1 Hz, 1H), 7.36 (d, J = 7.2 Hz, 2H), 7.32 – 7.21 (m, 5H), 7.06 (d, J = 7.1 Hz, 1H), 7.03 (d, J = 8.4 Hz, 1H), 6.99 (d, J = 8.3 Hz, 2H), 6.86 (d, J = 8.6 Hz, 1H), 6.73 (d, J = 8.6 Hz, 2H), 6.60 (d, J = 9.3 Hz, 1H), 6.27 (s, 1H), 6.23 (t, J = 5.8 Hz, 1H), 4.95 – 4.85 (m, 1H), 3.94 – 3.77 (m, 5H), 3.72 – 3.58 (m, 4H), 3.53 – 3.39 (m, 2H), 3.30 (d, J = 5.8 Hz, 2H), 3.28 – 3.17 (m, 4H), 3.10 (dd, J = 13.9, 5.0 Hz, 1H), 3.01 (dd, J = 13.9, 7.1 Hz, 1H), 2.94 – 2.80 (m, 3H), 2.80 – 2.66 (m, 2H), 2.60 (p, J = 6.0 Hz, 4H), 2.52 – 2.18 (m, 16H), 2.18 – 2.03 (m, 2H), 1.93 (d, J = 17.2 Hz, 1H), 1.77 – 1.59 (m, 7H), 1.52 – 1.40 (m, 1H), 0.97 (s, 3H). LC/MS (ESI) m/z 1506.6; [M+H] + calcd for C 73 H 84 ClF 3 N 13 O 11 S 3 + : 1506.52. 2-(4-((4'-chloro-4-methyl-6-((4-(4-(((4-(((R)-4-morpholino-1 -(phenylthio)butan-2-yl)amino)- 3-((trifluoromethyl)sulfonyl)phenyl)sulfonyl)carbamoyl)pheny l)piperazin-1-yl)methyl)- 2,3,4,5-tetrahydro-[1,1'-biphenyl]-4-yl)methyl)piperazin-1-y l)-N-(6-((2-(2,6-dioxopiperidin- 3-yl)-1,3-dioxoisoindolin-4-yl)amino)hexyl)pyrimidine-5-carb oxamide (compound #21) (3.25 mg, 18% yield). 1 H NMR (600 MHz, Chloroform-d) δ 8.90 (s, 1H), 8.67 (s, 2H), 8.31 (d, J = 2.2 Hz, 1H), 8.07 (d, J = 8.5 Hz, 1H), 7.70 (d, J = 8.5 Hz, 2H), 7.46 (dd, J = 8.5, 7.1 Hz, 1H), 7.35 (d, J = 7.5 Hz, 2H), 7.32 – 7.18 (m, 5H), 7.05 (d, J = 7.1 Hz, 1H), 6.99 (d, J = 8.0 Hz, 2H), 6.86 (d, J = 8.6 Hz, 1H), 6.71 (d, J = 8.6 Hz, 2H), 6.59 (d, J = 9.4 Hz, 1H), 6.47 (s, 1H), 6.21 (t, J = 5.6 Hz, 1H), 4.88 (ddd, J = 12.4, 5.4, 2.3 Hz, 1H), 4.03 – 3.75 (m, 4H), 3.74 – 3.58 (m, 4H), 3.46 – 3.28 (m, 6H), 3.28 – 3.20 (m, 2H), 3.09 (dd, J = 13.9, 5.0 Hz, 1H), 3.01 (dd, J = 13.9, 7.0 Hz, 1H), 2.88 – 2.80 (m, 1H), 2.80 – 2.60 (m, 6H), 2.60 – 2.18 (m, 16H), 2.18 – 2.01 (m, 2H), 1.92 – 1.51 (m, 10H), 1.51 – 1.34 (m, 6H), 0.99 (s, 3H). LC/MS (ESI) m/z 1534.6; [M+H] + calcd for C75H88ClF3N13O11S3 + : 1534.55. Example 16: Preparation of compound #22
Step 1: Synthesis of tert-butyl 4-(5-((5-hydroxypentyl)oxy)pyridin-2-yl)piperazine-1- carboxylate (22-2). A mixture of 22-1 (410 mg, 1.47 mmol), N-Boc-piperazine (491 mg, 2.94 mmol) and K2CO3 (608 mg, 4.41 mmol) in DMF (9.0 mL) was stirred at 80 °C overnight. The reaction mixture was diluted with EtOAc and washed with water and sat. aq. NH4Cl. The organic layers were dried over Na 2 SO 4 , filtered and concentrated. The residue was purified by flash column chromatography (0% to 60% of EtOAc in hexane) to afford 22-2 (160 mg, 30% yield). 1 H NMR (600 MHz, Chloroform-d) δ 7.92 (d, J = 3.0 Hz, 1H), 7.14 (dd, J = 9.0, 3.0 Hz, 1H), 6.63 (d, J = 9.1 Hz, 1H), 3.94 (t, J = 6.4 Hz, 2H), 3.67 (t, J = 6.5 Hz, 2H), 3.54 (t, J = 5.2 Hz, 4H), 3.39 – 3.36 (m, 4H), 1.82 – 1.76 (m, 2H), 1.66 – 1.60 (m, 2H), 1.57 – 1.50 (m, 2H), 1.48 (s, 9H). LC/MS (ESI) m/z 366.3; [M+H] + calcd for C19H32N3O4 + : 366.24. Step 2: Synthesis of tert-butyl 4-(5-((5-oxopentyl)oxy)pyridin-2-yl)piperazine-1-carboxylate (22-3). A mixture of 22-2 (30 mg, 0.082 mmol) and Dess-Martin periodinane (45 mg, 0.11 mmol) in EtOAc (1 mL) was stirred at room temperature for 1 h. The resulting mixture was filtered and concentrated to afford crude 22-3 (35 mg, quantitative yield), which was directly used in the next step. LC/MS (ESI) m/z 364.2; [M+H] + calcd for C19H30N3O4 + : 364.22. Step 3: Synthesis of tert-butyl 4-(5-((5-(4-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin -4- yl)piperazin 1 yl)pentyl)oxy)pyridin 2 yl)piperazine 1 carboxylate (224) 223 (35 mg crude) and NaBH(OAc) 3 (50 mg, 0.24 mmol) were added to a solution of Intermediate K (30 mg, 0.079 mmol) and TEA (55 µL, 0.4 mmol) in DCM (2 mL), then stirred at room temperature overnight. The resulting mixture was washed with sat. aq. NH4Cl. The organic layers were dried over Na 2 SO 4 , filtered and concentrated. The residue was purified by flash column chromatography (0% to 5% of MeOH in DCM) to afford 22-4 (21 mg, 37% yield in two steps). 1 H NMR (600 MHz, Chloroform-d) δ 8.40 (s, 1H), 7.91 (d, J = 3.1 Hz, 1H), 7.62 (dd, J = 8.4, 7.2 Hz, 1H), 7.47 – 7.43 (m, 1H), 7.19 (d, J = 8.1 Hz, 1H), 7.14 (dd, J = 9.1, 3.1 Hz, 1H), 6.62 (d, J = 9.1 Hz, 1H), 4.95 (dd, J = 12.4, 5.4 Hz, 1H), 3.93 (t, J = 6.2 Hz, 2H), 3.61 (t, J = 5.1 Hz, 4H), 3.54 (t, J = 5.3 Hz, 4H), 3.39 – 3.35 (m, 4H), 3.15 (s, 4H), 2.91 – 2.67 (m, 5H), 2.18 – 2.08 (m, 1H), 1.89 – 1.75 (m, 4H), 1.59 – 1.50 (m, 2H), 1.47 (s, 9H). LC/MS (ESI) m/z 690.4; [M+H] + calcd for C 36 H 48 N 7 O 7 + : 690.36. Step 4: Synthesis of 2-(2,6-dioxopiperidin-3-yl)-4-(4-(5-((6-(piperazin-1-yl)pyri din-3- yl)oxy)pentyl)piperazin-1-yl)isoindoline-1,3-dione hydrochloride (22-5). HCl (1 mL, 4 N HCl in dioxane) was added to a stirring solution of 22-4 (20 mg, 0.029 mmol) in DCM (1 mL) and stirred at room temperature for 2 hours. The reaction mixture was concentrated to afford 22-5 (19 mg, quantitative yield). LC/MS (ESI) m/z 590.4; [M+H] + calcd for C 31 H 40 N 7 O 5 + : 590.31. Step 5: Synthesis of 4-(4-((4'-chloro-4-((4-(5-((5-(4-(2-(2,6-dioxopiperidin-3-yl )-1,3- dioxoisoindolin-4-yl)piperazin-1-yl)pentyl)oxy)pyridin-2-yl) piperazin-1-yl)methyl)-4- methyl-3,4,5,6-tetrahydro-[1,1'-biphenyl]-2-yl)methyl)pipera zin-1-yl)-N-((4-(((R)-4- morpholino-1-(phenylthio)butan-2-yl)amino)-3- ((trifluoromethyl)sulfonyl)phenyl)sulfonyl)benzamide (compound #22). Intermediate B (19 mg, 0.019 mmol) and NaBH(OAc) 3 (5 mg, 0.023 mmol) were added to a solution of 22-5 (19 mg, 0.03 mmol) and TEA (16 µL, 0.12 mmol) in DCM (1 mL), then stirred at room temperature overnight. The resulting mixture was washed with sat. aq. NH4Cl and dried over Na2SO4, filtered and concentrated. The residue was purified by preparative TLC (DCM/MeOH) to afford compound #22 (2.24 mg, 7% yield). 1 H NMR (600 MHz, Chloroform-d) δ 8.34 (d, J = 2.2 Hz, 1H), 8.27 (s, 1H), 8.04 (dd, J = 9.3, 2.2 Hz, 1H), 7.88 (d, J = 3.0 Hz, 1H), 7.76 (d, J = 8.7 Hz, 2H), 7.61 (t, J = 8.4, 7.2 Hz, 1H), 7.44 (d, J = 7.2 Hz, 1H), 7.40 – 7.34 (m, 2H), 7.33 – 7.21 (m, 5H), 7.19 (d, J = 8.4 Hz, 1H), 7.08 (dd, J = 9.1, 3.1 Hz, 1H), 7.02 – 6.96 (m, 2H), 6.94 (d, J = 8.6 Hz, 1H), 6.75 (d, J = 8.7 Hz, 2H), 6.55 (d, J = 9.3 Hz, 1H), 6.53 (d, J = 9.1 Hz, 1H), 4.95 (dd, J = 12.4, 5.4 Hz, 1H), 3.92 (t, J = 6.3 Hz, 2H), 3.90 – 3.82 (m, 1H), 3.71 – 3.61 (m, 4H), 3.57 (s, 4H), 3.36 (s, 4H), 3.24 – 3.19 (m, 4H), 3.16 – 3.03 (m, 4H), 2.98 (dd, J = 13.8, 7.4 Hz, 1H), 2.93 – 2.63 (m, 11H), 2.50 – 2.19 (m, 15H), 2.18 – 2.07 (m, 2H), 1.88 (d, J = 17.4 Hz, 1H), 1.82 – 1.70 (m, 4H), 1.70 – 1.56 (m, 2H), 1.55 – 1.46 (m, 2H), 1.46 – 1.39 (m, 1H), 0.97 (s, 3H). LC/MS (ESI) m/z 1561.7; [M+H] + calcd for C78H93ClF3N12O11S3 + : 1561.59. Step 1: Synthesis of tert-butyl 4-(5-(5-hydroxypent-1-yn-1-yl)pyridin-2-yl)piperazine-1- carboxylate (23-2). Under an argon atmosphere, a mixture of 23-1 (100 mg, 0.29 mmol), pent-4- yn-1-ol (123 mg, 1.46 mmol), PdCl2(PPh3)2 (10.3 mg, 0.015 mmol), CuI (5.6 mg, 0.029 mmol) and TEA (0.5 mL) in DMSO (3 mL) was stirred at 80 °C overnight. After cooling to room temperature, the reaction mixture was diluted with EtOAc, then washed with water and sat. aq. NH 4 Cl. The organic layers were dried over Na 2 SO 4 , filtered and concentrated. The residue was purified by flash column chromatography (0% to 60% of EtOAc in hexanes) to afford 23-2 (60 mg, 59% yield). 1 H NMR (600 MHz, Chloroform-d) δ 8.20 (d, J = 2.3, 0.7 Hz, 1H), 7.46 (dd, J = 8.8, 2.3 Hz, 1H), 6.52 (d, J = 8.8, 0.8 Hz, 1H), 3.79 (t, J = 6.2 Hz, 2H), 3.55 – 3.49 (m, 8H), 2.52 (t, J = 6.9 Hz, 2H), 1.84 (p, 2H), 1.47 (s, 9H). LC/MS (ESI) m/z 346.3; [M+H] + calcd for C19H28N3O3 + : 346.21. Step 2: Synthesis of tert-butyl 4-(5-(5-oxopent-1-yn-1-yl)pyridin-2-yl)piperazine-1- carboxylate (23-3). A mixture of 23-2 (33 mg, 0.096 mmol) and Dess-Martin periodinane (49 mg, 0.11 mmol) in EtOAc (1 mL) was stirred at room temperature for 1 h. The resulting mixture was filtered and concentrated to afford crude 23-3 (41 mg, quantitative yield), which was directly used in the next step. LC/MS (ESI) m/z 344.2; [M+H] + calcd for C19H26N3O3 + : 344.20. Step 3: Synthesis of tert-butyl 4-(5-(5-(4-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin- 4- yl)piperazin-1-yl)pent-1-yn-1-yl)pyridin-2-yl)piperazine-1-c arboxylate (23-4).23-3 (41 mg, crude) and NaBH(OAc)3 (75 mg, 0.24 mmol) were added to a solution of Intermediate K (30 mg, 0.079 mmol) and TEA (55 µL, 0.4 mmol) in DCM (2 mL), then stirred at room temperature overnight. The resulting mixture was washed with sat. aq. NH4Cl. The organic layers were dried over Na2SO4, filtered and concentrated. The residue was purified by flash column chromatography (0% to 5% of MeOH in DCM) to afford 23-4 (25 mg, 39% yield in two steps). 1 H NMR (600 MHz, Chloroform-d) δ 8.44 (s, 1H), 8.21 (dd, J = 2.3, 0.7 Hz, 1H), 7.58 (dd, J = 8.4, 7.2 Hz, 1H), 7.46 (dd, J = 8.8, 2.3 Hz, 1H), 7.39 (dd, J = 7.2, 0.7 Hz, 1H), 7.18 – 7.14 (m, 1H), 6.54 (dd, J = 8.8, 0.9 Hz, 1H), 4.95 (dd, J = 12.5, 5.4 Hz, 1H), 3.59 – 3.46 (m, 8H), 3.44 – 3.28 (m, 4H), 2.91 – 2.76 (m, 2H), 2.76 – 2.64 (m, 5H), 2.57 (t, J = 7.4 Hz, 2H), 2.46 (t, J = 7.0 Hz, 2H), 2.13 – 2.06 (m, 1H), 1.82 (p, J = 7.2 Hz, 2H), 1.47 (s, 9H). LC/MS (ESI) m/z 670.2; [M+H] + calcd for C36H44N7O6 + : 670.33. Step 4: Synthesis of 2-(2,6-dioxopiperidin-3-yl)-4-(4-(5-(6-(piperazin-1-yl)pyrid in-3-yl)pent-4- yn-1-yl)piperazin-1-yl)isoindoline-1,3-dione hydrochloride (23-5). HCl (1 mL, 4 N HCl in dioxane) was added to a stirring solution of 23-4 (20 mg, 0.03 mmol) in DCM (1 mL) at room temperature. Then the resulting mixture was stirred at room temperature for 2 hours, then concentrated to afford 23-5 (23 mg, quantitative yield). LC/MS (ESI) m/z 570.3; [M+H] + calcd for C31H36N7O4 + : 570.28. Step 5: Synthesis of 4-(4-((4'-chloro-4-((4-(5-(5-(4-(2-(2,6-dioxopiperidin-3-yl) -1,3- dioxoisoindolin-4-yl)piperazin-1-yl)pent-1-yn-1-yl)pyridin-2 -yl)piperazin-1-yl)methyl)-4- methyl-3,4,5,6-tetrahydro-[1,1'-biphenyl]-2-yl)methyl)pipera zin-1-yl)-N-((4-(((R)-4- morpholino-1-(phenylthio)butan-2-yl)amino)-3- ((trifluoromethyl)sulfonyl)phenyl)sulfonyl)benzamide (compound #23). Intermediate B (23 mg, 0.023 mmol) and NaBH(OAc) 3 (6 mg, 0.028 mmol) were added to a solution of 23-5 (23 mg, 0.038 mmol) and TEA (16 µL, 0.12 mmol) in DCM (1 mL), then stirred at room temperature overnight. The resulting mixture was washed with sat. aq. NH4Cl. The organic layers were dried over Na2SO4, filtered and concentrated. The residue was purified by preparative TLC (DCM/MeOH) to afford compound #23 (3.89 mg, 11% yield). 1 H NMR (600 MHz, Chloroform- d) δ 8.37 (t, J = 1.7 Hz, 1H), 8.33 (s, 1H), 8.22 (d, J = 2.2 Hz, 1H), 8.09 (dd, J = 9.2, 2.2 Hz, 1H), 7.74 (d, J = 8.6 Hz, 2H), 7.62 (dd, J = 8.4, 7.2 Hz, 1H), 7.48 – 7.42 (m, 2H), 7.42 – 7.37 (m, 2H), 7.35 – 7.24 (m, 5H), 7.20 (d, J = 8.5 Hz, 1H), 7.05 – 6.97 (m, 3H), 6.77 (d, J = 9.0 Hz, 2H), 6.59 (d, J = 9.5 Hz, 1H), 6.52 (d, J = 8.8 Hz, 1H), 4.98 (dd, J = 12.5, 5.4 Hz, 1H), 3.94 – 3.85 (m, 1H), 3.73 – 3.62 (m, 4H), 3.59 – 3.43 (m, 8H), 3.26 (t, J = 5.2 Hz, 4H), 3.11 (dd, J = 13.9, 5.0 Hz, 1H), 3.02 (dd, J = 13.9, 7.4 Hz, 1H), 2.99 – 2.90 (m, 4H), 2.90 – 2.79 (m, 5H), 2.79 – 2.62 (m, 5H), 2.51 (t, J = 6.9 Hz, 2H), 2.49 – 2.22 (m, 13H), 2.19 – 2.08 (m, 2H), 1.99 – 1.87 (m, 3H), 1.73 – 1.61 (m, 3H), 1.52 – 1.44 (m, 1H), 0.99 (s, 3H). LC/MS (ESI) m/z 1541.6; [M+H] + calcd for C78H89ClF3N12O10S3 + : 1541.56. Example 18: Preparation of compound #24 Compound #24 was prepared by following General Procedure C: tert-butyl 3-((4-(2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)pipe razin-1- yl)methyl)azetidine-1-carboxylate (24-1) (67 mg, 20% yield). 1 H NMR (600 MHz, Chloroform-d) δ 8.06 (s, 1H), 7.75 (d, J = 8.5 Hz, 1H), 7.00 (dd, J = 8.6, 2.2 Hz, 1H), 6.89 (d, J = 2.1 Hz, 1H), 5.21 (dd, J = 13.3, 5.1 Hz, 1H), 4.43 (d, J = 15.5 Hz, 1H), 4.27 (d, J = 15.6 Hz, 1H), 4.06 (t, J = 8.4 Hz, 2H), 3.64 (dd, J = 8.6, 5.4 Hz, 2H), 3.32 (t, 4H), 2.92 (ddd, J = 17.8, 4.8, 2.5 Hz, 1H), 2.84 (ddd, J = 17.9, 13.3, 5.4 Hz, 1H), 2.81 – 2.74 (m, 1H), 2.66 (d, J = 7.4 Hz, 2H), 2.60 (t, J = 5.1 Hz, 4H), 2.34 (qd, J = 13.2, 4.8 Hz, 1H), 2.25 – 2.17 (m, 1H), 1.46 (s, 9H). LC/MS (ESI) m/z 498.2; [M+H] + calcd for C26H36N5O5 + : 498.27. 3-(5-(4-(azetidin-3-ylmethyl)piperazin-1-yl)-1-oxoisoindolin -2-yl)piperidine-2,6-dione hydrochloride (24-2) (20 mg, quantitative yield). LC/MS (ESI) m/z 398.2; [M+H] + calcd for C21H28N5O3 + : 398.22. N-((4-(((R)-4-(1,4-oxazepan-4-yl)-1-(phenylthio)butan-2-yl)a mino)-3- ((trifluoromethyl)sulfonyl)phenyl)sulfonyl)-4-(4-(((4R)-4'-c hloro-4-((3-((4-(2-(2,6- dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)piperazin-1-yl)met hyl)azetidin-1-yl)methyl)-4- methyl-3,4,5,6-tetrahydro-[1,1'-biphenyl]-2-yl)methyl)pipera zin-1-yl)benzamide (compound #24) (4.23 mg, 12% yield). 1 H NMR (600 MHz, Chloroform-d) δ 8.32 (s, 1H), 7.98 (d, J = 9.0 Hz, 1H), 7.91 (d, J = 8.2 Hz, 2H), 7.66 (d, J = 8.4 Hz, 1H), 7.38 – 7.30 (m, 2H), 7.28 – 7.22 (m, 4H), 7.19 (t, J = 7.3 Hz, 1H), 6.96 (d, J = 8.0 Hz, 2H), 6.89 – 6.79 (m, 2H), 6.79 – 6.72 (m, 1H), 6.66 (d, J = 8.3 Hz, 2H), 6.45 (d, J = 9.2 Hz, 1H), 5.10 (dd, J = 13.1 Hz, 1H), 4.41 – 4.00 (m, 3H), 3.85 – 3.60 (m, 6H), 3.25 – 2.92 (m, 12H), 2.92 – 2.36 (m, 17H), 2.36 – 1.95 (m, 13H), 1.93 – 1.75 (m, 2H), 1.74 – 1.52 (m, 2H), 1.52 – 1.37 (m, 1H), 1.05 (s, 3H). LC/MS (ESI) m/z 1383.7; [M+H] + calcd for C 69 H 83 ClF 3 N 10 O 9 S 3 + : 1383.51. Example 19: Preparation of compound #26 Step 1: Synthesis of tert-butyl 4-(prop-2-yn-1-yl)piperazine-1-carboxylate (26-1): A solution of N-Boc-piperazine (5 g, 26.88 mmol), 3-bromoprop-1-yne (6.4 g, 53.76 mmol) and DIPEA (18.7 mL, 107.53 mmol) in DCM (100 mL) was stirred at room temperature for 3 days. The reaction mixture was washed with water and sat. aq. NH4Cl. The organic layers were dried over Na 2 SO 4 , filtered and concentrated. The residue was purified by flash column chromatography (20% to 100% of EtOAc in hexanes) to afford 26-1 (3.2 g, 53% yield) as light-yellow oil. 1 H NMR (600 MHz, Chloroform-d) δ 3.49 (t, J = 5.1 Hz, 4H), 3.34 (d, J = 2.5 Hz, 2H), 2.53 (t, J = 5.1 Hz, 4H), 2.28 (t, J = 2.4 Hz, 1H), 1.48 (s, 9H). LC/MS (ESI) m/z 225.2; [M+H] + calcd for C 12 H 21 N 2 O 2 + : 225.16. Steps 2-4 were performed according to General Procedure B: tert-butyl 4-(3-(2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)prop- 2-yn-1-yl)piperazine- 1 carboxylate (262) (257 mg 45% yield) 1 H NMR (600 MHz Chloroform d) δ 807 (s 1H) 7.85 (d, J = 7.8 Hz, 1H), 7.57 (dd, J = 7.8, 1.3 Hz, 1H), 7.54 (s, 1H), 5.24 (dd, J = 13.3, 5.1 Hz, 1H), 4.50 (d, J = 16.0 Hz, 1H), 4.35 (d, J = 15.9 Hz, 1H), 3.59 (s, 2H), 3.53 (t, J = 5.0 Hz, 4H), 3.00 – 2.91 (m, 1H), 2.86 (ddd, J = 18.0, 13.4, 5.4 Hz, 1H), 2.61 (t, J = 5.0 Hz, 4H), 2.38 (qd, J = 13.3, 4.7 Hz, 1H), 2.31 – 2.19 (m, 1H), 1.49 (s, 9H). LC/MS (ESI) m/z 467.3; [M+H] + calcd for C25H31N4O5 + : 467.23. 3-(1-oxo-5-(3-(piperazin-1-yl)prop-1-yn-1-yl)isoindolin-2-yl )piperidine-2,6-dione hydrochloride (26-3) (63 mg, quantitative yield). LC/MS (ESI) m/z 367.1; [M+H] + calcd for C20H23N4O3 + : 367.18. N-((4-(((R)-4-(1,4-oxazepan-4-yl)-1-(phenylthio)butan-2-yl)a mino)-3- ((trifluoromethyl)sulfonyl)phenyl)sulfonyl)-4-(4-(((4R)-4'-c hloro-4-((4-(3-(2-(2,6- dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)prop-2-yn-1-yl)pip erazin-1-yl)methyl)-4-methyl- 3,4,5,6-tetrahydro-[1,1'-biphenyl]-2-yl)methyl)piperazin-1-y l)benzamide (compound #26) (5.69 mg, 21% yield). 1 H NMR (600 MHz, Chloroform-d) δ 8.32 (t, J = 2.2 Hz, 1H), 8.14 – 8.07 (m, 1H), 7.76 – 7.70 (m, 2H), 7.53 – 7.47 (m, 2H), 7.41 – 7.36 (m, 2H), 7.34 – 7.22 (m, 6H), 7.14 (t, J = 8.7 Hz, 1H), 7.02 (t, J = 8.2 Hz, 2H), 6.68 (d, J = 8.7 Hz, 1H), 6.64 – 6.56 (m, 2H), 5.42 (dt, J = 13.6, 4.5 Hz, 1H), 4.47 (t, J = 15.8 Hz, 1H), 4.36 (dd, J = 16.3, 9.3 Hz, 1H), 3.92 (s, 1H), 3.77 (td, J = 6.1, 1.1 Hz, 2H), 3.75 – 3.61 (m, 4H), 3.22 (dt, J = 18.7, 4.3 Hz, 4H), 3.11 (dd, J = 13.9, 5.1 Hz, 1H), 3.05 (dd, J = 13.9, 6.9 Hz, 1H), 2.99 – 2.89 (m, 2H), 2.84 (s, 2H), 2.79 – 2.54 (m, 14H), 2.46 – 2.20 (m, 12H), 2.14 – 2.04 (m, 1H), 2.02 – 1.84 (m, 3H), 1.78 – 1.58 (m, 2H), 0.96 (d, J = 13.3 Hz, 3H). LC/MS (ESI) m/z 1352.4; [M+H] + calcd for C68H78ClF3N9O9S3 + : 1352.47. Example 20: Preparation of compound #29 Compound #29 was prepared by following General Procedure B: tert-butyl 4-(3-(2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)prop- 2-yn-1-yl)piperidine- 1-carboxylate (29-1) (487 mg, 68% yield). 1 H NMR (600 MHz, Chloroform-d) δ 8.02 (s, 1H), 7.82 (d, J = 7.8 Hz, 1H), 7.52 (dd, J = 7.8, 1.3 Hz, 1H), 7.50 (s, 1H), 5.23 (dd, J = 13.4, 5.1 Hz, 1H), 4.49 (d, J = 15.9 Hz, 1H), 4.33 (d, J = 16.0 Hz, 1H), 4.17 (s, 2H), 2.99 – 2.91 (m, 1H), 2.86 (ddd, J = 18.1, 13.4, 5.4 Hz, 1H), 2.75 (s, 2H), 2.43 (d, J = 6.6 Hz, 2H), 2.41 – 2.32 (m, 1H), 2.29 – 2.21 (m, 1H), 1.84 (d, J = 13.0 Hz, 2H), 1.80 – 1.71 (m, 1H), 1.48 (s, 9H), 1.30 (qd, J = 12.3, 4.3 Hz, 2H). LC/MS (ESI) m/z 488.2 (M+23), 410.1 (M-56), 366.2 (M-Boc); [M+H] + calcd for C26H32N3O5 + : 466.23. 3-(1-oxo-5-(3-(piperidin-4-yl)prop-1-yn-1-yl)isoindolin-2-yl )piperidine-2,6-dione hydrochloride (29-2) (210 mg, quantitative yield). LC/MS (ESI) m/z 366.3; [M+H] + calcd for C21H24N3O3 + : 366.44. N-((4-(((R)-4-(1,4-oxazepan-4-yl)-1-(phenylthio)butan-2-yl)a mino)-3- ((trifluoromethyl)sulfonyl)phenyl)sulfonyl)-4-(4-(((4R)-4'-c hloro-4-((4-(3-(2-(2,6- dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)prop-2-yn-1-yl)pip eridin-1-yl)methyl)-4-methyl- 3,4,5,6-tetrahydro-[1,1'-biphenyl]-2-yl)methyl)piperazin-1-y l)benzamide (compound #29) (6.02 mg, 22% yield). 1 H NMR (600 MHz, Chloroform-d) δ 8.34 (d, J = 2.2 Hz, 1H), 8.11 – 8.01 (m, 1H), 7.77 (t, J = 8.3 Hz, 2H), 7.66 (dd, J = 34.5, 7.8 Hz, 1H), 7.45 (d, J = 9.6 Hz, 2H), 7.41 – 7.35 (m, 2H), 7.35 – 7.21 (m, 6H), 7.08 – 6.96 (m, 3H), 6.67 (s, 1H), 6.61 (d, J = 8.5 Hz, 1H), 6.53 (d, J = 9.2 Hz, 1H), 5.34 – 5.23 (m, 1H), 4.41 (t, J = 17.1 Hz, 1H), 4.29 (d, J = 16.0 Hz, 1H), 3.87 (s, 1H), 3.81 – 3.77 (m, 2H), 3.75 – 3.68 (m, 2H), 3.20 (s, 4H), 3.11 (dd, J = 13.9, 4.9 Hz, 1H), 3.04 (dd, J = 13.9, 6.9 Hz, 1H), 2.98 – 2.57 (m, 12H), 2.52 – 2.15 (m, 16H), 2.16 – 2.06 (m, 1H), 2.07 – 1.85 (m, 3H), 1.83 – 1.55 (m, 6H), 1.49 – 1.38 (m, 1H), 1.00 (d, J = 15.0 Hz, 3H). LC/MS (ESI) m/z 1351.6; [M+H] + calcd for C69H79ClF3N8O9S3 + : 1351.48. Example 21: Preparation of compounds #37-38
Compounds #37-38 were prepared by following General Procedure B: tert-butyl (3-(2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)prop-2- yn-1-yl)carbamate (37-1) (364 mg, 59% yield). 1 H NMR (600 MHz, Chloroform-d) δ 8.05 (s, 1H), 7.84 (d, J = 7.9 Hz, 1H), 7.55 (dd, J = 8.0, 1.3 Hz, 1H), 7.53 (s, 1H), 5.24 (dd, J = 13.4, 5.1 Hz, 1H), 4.83 (s, 1H), 4.50 (d, J = 16.0 Hz, 1H), 4.34 (d, J = 16.0 Hz, 1H), 4.21 (s, 2H), 3.00 – 2.91 (m, 1H), 2.86 (ddd, J = 18.1, 13.4, 5.4 Hz, 1H), 2.38 (qd, J = 13.3, 4.7 Hz, 1H), 2.29 – 2.20 (m, 1H), 1.50 (s, 9H). LC/MS (ESI) m/z 398.1; [M+H] + calcd for C 21 H 24 N 3 O 5 + : 398.17. 3-(5-(3-aminoprop-1-yn-1-yl)-1-oxoisoindolin-2-yl)piperidine -2,6-dione hydrochloride (37- 2) (106 mg, quantitative yield). LC/MS (ESI) m/z 298.1; [M+H] + calcd for C 16 H 16 N 3 O 3 + : 298.12. N-((4-(((R)-4-(1,4-oxazepan-4-yl)-1-(phenylthio)butan-2-yl)a mino)-3- ((trifluoromethyl)sulfonyl)phenyl)sulfonyl)-4-(4-(((4R)-4'-c hloro-4-(((3-(2-(2,6- dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)prop-2-yn-1-yl)ami no)methyl)-4-methyl-3,4,5,6- tetrahydro-[1,1'-biphenyl]-2-yl)methyl)piperazin-1-yl)benzam ide (37-3) (50 mg, 78% yield). LC/MS (ESI) m/z 1283.5; [M+H] + calcd for C 64 H 71 ClF 3 N 8 O 9 S 3 + : 1283.41. N-((4-(((R)-4-(1,4-oxazepan-4-yl)-1-(phenylthio)butan-2-yl)a mino)-3- ((trifluoromethyl)sulfonyl)phenyl)sulfonyl)-4-(4-(((4R)-4'-c hloro-4-(((3-(2-(2,6- dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)prop-2-yn-1-yl)(me thyl)amino)methyl)-4-methyl- 3,4,5,6-tetrahydro-[1,1'-biphenyl]-2-yl)methyl)piperazin-1-y l)benzamide (compound #37) (7.39 mg, 49% yield). 1 H NMR (600 MHz, Chloroform-d) δ 8.33 (d, J = 2.2 Hz, 1H), 8.16 – 8.07 (m, 1H), 7.78 – 7.60 (m, 3H), 7.56 – 7.49 (m, 2H), 7.38 (d, J = 7.2 Hz, 2H), 7.34 – 7.21 (m, 6H), 7.12 (t, J = 10.2 Hz, 1H), 7.07 – 7.02 (m, 1H), 7.02 – 6.99 (m, 1H), 6.62 (d, J = 9.2 Hz, 1H), 6.48 (d, J = 8.6 Hz, 1H), 6.44 (d, J = 8.7 Hz, 1H), 5.35 (d, J = 13.1 Hz, 1H), 4.60 – 4.24 (m, 2H), 3.92 (s, 1H), 3.77 (td, J = 6.1, 1.4 Hz, 2H), 3.74 – 3.66 (m, 2H), 3.64 (t, J = 5.9 Hz, 2H), 3.16 – 2.97 (m, 6H), 2.96 – 2.87 (m, 2H), 2.87 – 2.54 (m, 9H), 2.52 (d, J = 3.2 Hz, 3H), 2.47 – 2.20 (m, 10H), 2.12 – 2.03 (m, 1H), 1.99 – 1.85 (m, 3H), 1.85 – 1.77 (m, 1H), 1.76 – 1.69 (m, 1H), 1.54 – 1.42 (m, 1H), 1.06 (s, 3H). LC/MS (ESI) m/z 1297.5; [M+H] + calcd for C 65 H 73 ClF 3 N 8 O 9 S 3 + : 1297.43. N-((4-(((R)-4-(1,4-oxazepan-4-yl)-1-(phenylthio)butan-2-yl)a mino)-3- ((trifluoromethyl)sulfonyl)phenyl)sulfonyl)-4-(4-(((4R)-4'-c hloro-4-(((3-(2-(2,6- dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)prop-2-yn-1-yl)(is opropyl)amino)methyl)-4- methyl-3,4,5,6-tetrahydro-[1,1'-biphenyl]-2-yl)methyl)pipera zin-1-yl)benzamide (compound #38) (2.8 mg, 18% yield). 1 H NMR (600 MHz, Chloroform-d) δ 8.33 (dd, J = 8.7, 2.3 Hz, 1H), 8.11 (dd, J = 15.0, 9.2 Hz, 1H), 7.70 (td, J = 27.6, 8.2 Hz, 2H), 7.60 – 7.43 (m, 2H), 7.39 (d, J = 7.6 Hz, 2H), 7.35 – 7.23 (m, 6H), 7.21 – 7.12 (m, 1H), 7.09 – 7.04 (m, 1H), 7.04 – 6.99 (m, 1H), 6.62 (d, J = 9.3 Hz, 1H), 6.49 (d, J = 8.6 Hz, 1H), 6.38 (d, J = 8.6 Hz, 1H), 5.33 (dd, J = 52.2, 13.5 Hz, 1H), 4.57 – 4.24 (m, 2H), 3.92 (s, 1H), 3.82 – 3.73 (m, 2H), 3.74 – 3.63 (m, 4H), 3.18 – 3.00 (m, 6H), 2.99 – 2.89 (m, 2H), 2.89 – 2.77 (m, 1H), 2.76 – 2.51 (m, 8H), 2.51 – 2.17 (m, 11H), 2.13 – 2.03 (m, 1H), 2.01 – 1.93 (m, 1H), 1.90 – 1.62 (m, 4H), 1.46 – 1.38 (m, 1H), 1.15 (dd, J = 6.6, 2.0 Hz, 6H), 1.01 (d, J = 11.6 Hz, 3H). LC/MS (ESI) m/z 1325.6; [M+H] + calcd for C67H77ClF3N8O9S3 + : 1325.46. Example 22: Preparation of compound #40
Compound #40 was prepared by following General Procedure B: tert-butyl 4-(4-(2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)but-3 -yn-1-yl)piperazine-1- carboxylate (40-1) (280 mg, 38% yield). 1 H NMR (600 MHz, Chloroform-d) δ 8.08 (s, 1H), 7.82 (d, J = 7.8 Hz, 1H), 7.52 (dd, J = 8.0, 1.3 Hz, 1H), 7.49 (s, 1H), 5.23 (dd, J = 13.3, 5.1 Hz, 1H), 4.49 (d, J = 16.0 Hz, 1H), 4.33 (d, J = 16.0 Hz, 1H), 3.48 (t, J = 5.1 Hz, 4H), 2.95 (ddd, J = 17.8, 4.7, 2.5 Hz, 1H), 2.85 (ddd, J = 18.1, 13.4, 5.4 Hz, 1H), 2.76 – 2.70 (m, 2H), 2.68 – 2.62 (m, 2H), 2.51 (t, J = 5.1 Hz, 4H), 2.37 (qd, J = 13.3, 4.7 Hz, 1H), 2.28 – 2.20 (m, 1H), 1.49 (s, 9H). LC/MS (ESI) m/z 481.2; [M+H] + calcd for C 26 H 33 N 4 O 5 + : 481.24. 3-(1-oxo-5-(4-(piperazin-1-yl)but-1-yn-1-yl)isoindolin-2-yl) piperidine-2,6-dione hydrochloride (40-2) (121 mg, quantitative yield). LC/MS (ESI) m/z 381.1; [M+H] + calcd for C21H25N4O3 + : 381.19. N-((4-(((R)-4-(1,4-oxazepan-4-yl)-1-(phenylthio)butan-2-yl)a mino)-3- ((trifluoromethyl)sulfonyl)phenyl)sulfonyl)-4-(4-(((4R)-4'-c hloro-4-((4-(4-(2-(2,6- dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)but-3-yn-1-yl)pipe razin-1-yl)methyl)-4-methyl- 3,4,5,6-tetrahydro-[1,1'-biphenyl]-2-yl)methyl)piperazin-1-y l)benzamide (compound #40) (4.93 mg, 24% yield). 1 H NMR (600 MHz, Chloroform-d) δ 8.34 (t, J = 2.7 Hz, 1H), 8.06 (dt, J = 9.4, 2.9 Hz, 1H), 7.78 (dd, J = 9.1, 2.9 Hz, 2H), 7.70 (dd, J = 23.5, 8.1 Hz, 1H), 7.48 – 7.42 (m, 2H), 7.41 – 7.35 (m, 2H), 7.34 – 7.22 (m, 5H), 7.07 (d, J = 8.5 Hz, 1H), 7.03 – 6.98 (m, 2H), 6.74 (dd, J = 13.7, 8.8 Hz, 2H), 6.57 (d, J = 9.4 Hz, 1H), 5.32 – 5.24 (m, 1H), 4.45 (dd, J = 16.2, 6.4 Hz, 1H), 4.32 (d, J = 16.2 Hz, 1H), 3.90 (s, 1H), 3.78 (t, J = 6.1 Hz, 2H), 3.75 – 3.69 (m, 1H), 3.23 (s, 4H), 3.11 (dd, J = 14.0, 5.0 Hz, 1H), 3.04 (dd, J = 13.9, 7.0 Hz, 1H), 2.97 – 2.54 (m, 23H), 2.50 – 2.19 (m, 10H), 2.15 – 2.05 (m, 1H), 1.97 – 1.87 (m, 3H), 1.80 – 1.70 (m, 1H), 1.69 – 1.56 (m, 2H), 1.48 – 1.39 (m, 1H), 0.97 (d, J = 3.2 Hz, 3H). LC/MS (ESI) m/z 1366.6; [M+H] + calcd for C69H80ClF3N9O9S3 + : 1366.49. Compound #44 was prepared by following General Procedure C: tert-butyl 4-((4-(2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)-1,4 -diazepan-1- yl)methyl)piperidine-1-carboxylate (44-1) (58 mg, 79% yield). 1 H NMR (600 MHz, Chloroform-d) δ 7.90 (s, 1H), 7.68 (d, J = 8.6 Hz, 1H), 6.75 (dd, J = 8.7, 2.3 Hz, 1H), 6.64 (d, J = 2.2 Hz, 1H), 5.20 (dd, J = 13.3, 5.1 Hz, 1H), 4.38 (d, J = 15.4 Hz, 1H), 4.23 (d, J = 15.4 Hz, 1H), 4.07 (s, 2H), 3.61 – 3.52 (m, 4H), 2.93 – 2.87 (m, 1H), 2.82 (ddd, J = 18.0, 13.3, 5.4 Hz, 1H), 2.77 (t, J = 4.9 Hz, 2H), 2.72 – 2.62 (m, 2H), 2.61 – 2.54 (m, 2H), 2.35 – 2.26 (m, 3H), 2.24 – 2.15 (m, 1H), 1.94 (p, J = 5.9 Hz, 2H), 1.77 – 1.51 (m, 3H), 1.45 (s, 9H), 1.04 (q, J = 12.1 Hz, 2H). LC/MS (ESI) m/z 540.2; [M+H] + calcd for C29H42N5O5 + : 540.32. 3-(1-oxo-5-(4-(piperidin-4-ylmethyl)-1,4-diazepan-1-yl)isoin dolin-2-yl)piperidine-2,6-dione TFA salt (44-2) (31 mg, quantitative yield). LC/MS (ESI) m/z 440.2; [M+H] + calcd for C 24 H 34 N 5 O 3 + : 440.27. N-((4-(((R)-4-(1,4-oxazepan-4-yl)-1-(phenylthio)butan-2-yl)a mino)-3- ((trifluoromethyl)sulfonyl)phenyl)sulfonyl)-4-(4-(((4R)-4'-c hloro-4-((4-((4-(2-(2,6- dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)-1,4-diazepan-1-yl )methyl)piperidin-1-yl)methyl)- 4-methyl-3,4,5,6-tetrahydro-[1,1'-biphenyl]-2-yl)methyl)pipe razin-1-yl)benzamide (compound #44) (9.3 mg, 26% yield). 1 H NMR (600 MHz, Chloroform-d) δ 8.31 (s, 1H), 7.99 (d, J = 8.9 Hz, 1H), 7.87 (d, J = 8.3 Hz, 2H), 7.63 (d, J = 8.5 Hz, 1H), 7.34 (d, J = 7.6 Hz, 2H), 731 – 714 (m 5H) 696 (d J = 80 Hz 2H) 689 (d J = 83 Hz 1H) 677 – 665 (m 3H) 662 (s, 1H), 6.44 (d, J = 9.1 Hz, 1H), 5.13 (d, J = 13.0 Hz, 1H), 4.33 (d, J = 15.8 Hz, 1H), 4.20 (d, J = 15.7 Hz, 1H), 3.87 – 3.61 (m, 5H), 3.61 – 3.42 (m, 4H), 3.24 – 2.93 (m, 7H), 2.89 – 2.51 (m, 16H), 2.51 – 2.16 (m, 16H), 2.15 – 1.97 (m, 2H), 1.95 – 1.78 (m, 5H), 1.77 – 1.54 (m, 4H), 1.50 – 1.39 (m, 1H), 0.99 (s, 3H). LC/MS (ESI) m/z 1425.7; [M+H] + calcd for C 72 H 89 ClF 3 N 10 O 9 S 3 + : 1425.56. Compound #45 was prepared by following General Procedure C: tert-butyl 3-((4-(2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)-1,4 -diazepan-1- yl)methyl)azetidine-1-carboxylate (45-1) (47 mg, 68% yield). 1 H NMR (600 MHz, Chloroform-d) δ 7.95 (s, 1H), 7.68 (d, J = 8.6 Hz, 1H), 6.75 (dd, J = 8.7, 2.3 Hz, 1H), 6.63 (d, J = 2.2 Hz, 1H), 5.19 (dd, J = 13.4, 5.1 Hz, 1H), 4.38 (d, J = 15.4 Hz, 1H), 4.24 (d, J = 15.4 Hz, 1H), 3.97 (td, J = 8.2, 1.6 Hz, 2H), 3.61 – 3.51 (m, 6H), 2.90 (ddd, J = 17.5, 5.7, 2.9 Hz, 1H), 2.82 (ddd, J = 17.9, 13.3, 5.4 Hz, 1H), 2.76 (t, J = 4.9 Hz, 2H), 2.72 – 2.62 (m, 3H), 2.61 – 2.55 (m, 2H), 2.31 (qd, J = 13.3, 4.8 Hz, 1H), 2.22 – 2.15 (m, 1H), 1.95 (p, J = 6.1 Hz, 2H), 1.43 (s, 9H). LC/MS (ESI) m/z 512.4; [M+H] + calcd for C 27 H 38 N 5 O 5 + : 512.29. 3-(5-(4-(azetidin-3-ylmethyl)-1,4-diazepan-1-yl)-1-oxoisoind olin-2-yl)piperidine-2,6-dione TFA salt (45-2) (28 mg, quantitative yield). LC/MS (ESI) m/z 412.3; [M+H] + calcd for C22H30N5O3 + : 412.23. N-((4-(((R)-4-(1,4-oxazepan-4-yl)-1-(phenylthio)butan-2-yl)a mino)-3- ((trifluoromethyl)sulfonyl)phenyl)sulfonyl)-4-(4-(((4R)-4'-c hloro-4-((3-((4-(2-(2,6- dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)-1,4-diazepan-1-yl )methyl)azetidin-1-yl)methyl)-4- methyl-3,4,5,6-tetrahydro-[1,1'-biphenyl]-2-yl)methyl)pipera zin-1-yl)benzamide (compound #45) (6.3 mg, 18% yield). 1 H NMR (600 MHz, Chloroform-d) δ 8.32 (s, 1H), 7.98 (d, J = 9.0 Hz, 1H), 7.92 (d, J = 8.3 Hz, 2H), 7.63 (d, J = 8.5 Hz, 1H), 7.35 (d, J = 7.6 Hz, 2H), 7.30 – 7.16 (m, 5H), 6.95 (d, J = 8.0 Hz, 2H), 6.87 (d, J = 8.3 Hz, 1H), 6.73 – 6.62 (m, 3H), 6.59 (s, 1H), 6.46 (d, J = 9.2 Hz, 1H), 5.10 (s, 1H), 4.32 (d, J = 15.9 Hz, 1H), 4.19 (d, J = 15.6 Hz, 1H), 3.81 (s, 1H), 3.73 (t, J = 6.1 Hz, 2H), 3.71 – 3.60 (m, 2H), 3.57 – 3.35 (m, 5H), 3.15 – 2.87 (m, 8H), 2.86 – 2.45 (m, 20H), 2.35 – 2.13 (m, 8H), 2.13 – 1.95 (m, 3H), 1.93 – 1.75 (m, 5H), 1.74 – 1.48 (m, 2H), 1.48 – 1.37 (m, 1H), 1.01 (s, 3H). LC/MS (ESI) m/z 1397.6; [M+H] + calcd for C70H85ClF3N10O9S3 + : 1397.53. Compound #46 was prepared by following General Procedure E: tert-butyl 4-(2-(2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)ethyl )piperidine-1- carboxylate (46-1) (170 mg, 56% yield). 1 H NMR (600 MHz, Chloroform-d) δ 8.02 (s, 1H), 7.82 (d, J = 7.8 Hz, 1H), 7.32 (dd, J = 7.9, 1.4 Hz, 1H), 7.29 (s, 1H), 5.25 (dd, J = 13.3, 5.1 Hz, 1H), 4.49 (d, J = 15.8 Hz, 1H), 4.33 (d, J = 15.8 Hz, 1H), 4.20 – 4.01 (m, 2H), 2.94 (ddd, J = 17.8, 4.7, 2.5 Hz, 1H), 2.86 (ddd, J = 18.0, 13.4, 5.4 Hz, 1H), 2.80 – 2.73 (m, 2H), 2.73 – 2.63 (m, 2H), 2.38 (qd, J = 13.2, 4.8 Hz, 1H), 2.29 – 2.19 (m, 1H), 1.73 (d, J = 13.0 Hz, 2H), 1.66 – 1.57 (m, 2H), 1.50 – 1.40 (m, 10H), 1.17 (qd, J = 12.5, 4.4 Hz, 2H). LC/MS (ESI) m/z 478.3 (M+23), 400.2 (M-56), 356.2 (M-Boc); [M+H] + calcd for C 25 H 34 N 3 O 5 + : 456.25. 3-(1-oxo-5-(2-(piperidin-4-yl)ethyl)isoindolin-2-yl)piperidi ne-2,6-dione hydrochloride (46-2) (22 mg, quantitative yield). LC/MS (ESI) m/z 356.2; [M+H] + calcd for C 20 H 26 N 3 O 3 + : 356.20. N-((4-(((R)-4-(1,4-oxazepan-4-yl)-1-(phenylthio)butan-2-yl)a mino)-3- ((trifluoromethyl)sulfonyl)phenyl)sulfonyl)-4-(4-(((4R)-4'-c hloro-4-((4-(2-(2-(2,6- dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)ethyl)piperidin-1- yl)methyl)-4-methyl-3,4,5,6- tetrahydro-[1,1'-biphenyl]-2-yl)methyl)piperazin-1-yl)benzam ide (compound #46) (7.14 mg, 27% yield). 1 H NMR (600 MHz, Chloroform-d) δ 8.56 (s, 1H), 8.35 (d, J = 2.2 Hz, 1H), 8.05 – 8.00 (m, 1H), 7.86 (dd, J = 8.8, 2.7 Hz, 2H), 7.75 (t, J = 7.6 Hz, 1H), 7.40 – 7.36 (m, 2H), 7.33 – 7.27 (m, 6H), 7.26 – 7.20 (m, 1H), 6.99 (dd, J = 8.4, 2.2 Hz, 2H), 6.93 (d, J = 8.5 Hz, 1H), 6.72 (d, J = 8.1 Hz, 2H), 6.47 (d, J = 9.3 Hz, 1H), 5.23 (dt, J = 13.3, 4.6 Hz, 1H), 4.44 (dd, J = 16.1, 3.1 Hz, 1H), 4.31 (d, J = 16.0 Hz, 1H), 3.82 (s, 1H), 3.78 (t, J = 6.2 Hz, 2H), 3.75 – 3.71 (m, 2H), 3.35 – 3.14 (m, 8H), 3.11 (dd, J = 13.8, 4.8 Hz, 1H), 3.03 (dd, J = 13.9, 6.9 Hz, 1H), 2.96 – 2.74 (m, 9H), 2.74 – 2.48 (m, 8H), 2.47 – 2.25 (m, 6H), 2.25 – 2.17 (m, 1H), 2.16 – 2.07 (m, 1H), 1.93 (s, 2H), 1.81 – 1.68 (m, 4H), 1.68 – 1.52 (m, 5H), 1.51 – 1.44 (m, 1H), 1.06 (s, 3H). LC/MS (ESI) m/z 1341.5; [M+H] + calcd for C68H81ClF3N8O9S3 + : 1341.49. Compound #50 was prepared by following General Procedure C: tert-butyl 4-((4-(2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)-2,6 -dimethylpiperazin-1- yl)methyl)piperidine-1-carboxylate (50-1) (17 mg, 70% yield). 1 H NMR (600 MHz, Chloroform-d) δ 8.37 (s, 1H), 7.74 (d, J = 8.6 Hz, 1H), 6.97 (dd, J = 8.6, 2.2 Hz, 1H), 6.85 (d, J = 2.0 Hz, 1H), 5.24 (dd, J = 13.3, 5.1 Hz, 1H), 4.42 (d, J = 15.7 Hz, 1H), 4.27 (d, J = 15.7 Hz, 1H), 2.95 – 2.81 (m, 4H), 2.81 – 2.62 (m, 6H), 2.53 – 2.40 (m, 4H), 2.39 – 2.28 (m, 1H), 2.25 – 2.17 (m, 1H), 1.85 – 1.77 (m, 2H), 1.70 – 1.59 (m, 1H), 1.48 (s, 9H), 1.18 (d, J = 4.8 Hz, 6H), 1.13 – 1.03 (m, 2H). LC/MS (ESI) m/z 554.4; [M+H] + calcd for C 30 H 44 N 5 O 5 + : 554.33. 3-(5-(3,5-dimethyl-4-(piperidin-4-ylmethyl)piperazin-1-yl)-1 -oxoisoindolin-2-yl)piperidine- 2,6-dione hydrochloride (50-2) (11 mg, quantitative yield). LC/MS (ESI) m/z 454.4; [M+H] + calcd for C25H36N5O3 + : 454.28. N-((4-(((R)-4-(1,4-oxazepan-4-yl)-1-(phenylthio)butan-2-yl)a mino)-3- ((trifluoromethyl)sulfonyl)phenyl)sulfonyl)-4-(4-(((4R)-4'-c hloro-4-((4-((4-(2-(2,6- dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)-2,6-dimethylpiper azin-1-yl)methyl)piperidin-1- yl)methyl)-4-methyl-3,4,5,6-tetrahydro-[1,1'-biphenyl]-2-yl) methyl)piperazin-1- yl)benzamide (compound #50) (4.64 mg, 27% yield). 1 H NMR (600 MHz, Chloroform-d) δ 8.34 (d, J = 2.2 Hz, 1H), 8.16 (s, 1H), 8.03 (d, 1H), 7.78 (d, J = 8.4 Hz, 2H), 7.70 (d, J = 8.6 Hz, 1H), 7.36 (d, J = 7.3 Hz, 2H), 7.32 – 7.19 (m, 5H), 6.98 (d, J = 8.0 Hz, 3H), 6.92 (d, 1H), 6.81 (s, 1H), 6.72 (d, J = 8.5 Hz, 2H), 6.48 (d, J = 9.2 Hz, 1H), 5.18 (dd, J = 13.3, 5.1 Hz, 1H), 4.39 (d, J = 15.2 Hz, 1H), 4.24 (d, J = 15.7 Hz, 1H), 3.83 (s, 1H), 3.76 (t, J = 6.1 Hz, 2H), 3.73 – 3.62 (m, 2H), 3.54 – 3.44 (m, 2H), 3.20 (s, 4H), 3.09 (dd, J = 13.8, 4.9 Hz, 1H), 3.01 (dd, J = 13.9, 6.9 Hz, 1H), 2.94 – 2.54 (m, 14H), 2.51 – 2.23 (m, 12H), 2.22 – 2.15 (m, 1H), 2.14 – 2.05 (m, 2H), 2.03 – 1.97 (m, 1H), 1.96 – 1.84 (m, 2H), 1.84 – 1.67 (m, 3H), 1.67 – 1.58 (m, 3H), 1.53 – 1.39 (m, 3H), 1.37 – 1.28 (m, 2H), 1.10 (s, 6H), 1.03 (s, 3H). LC/MS (ESI) m/z 1439.7; [M+H] + calcd for C73H91ClF3N10O9S3 + : 1439.58. Example 27: Preparation of compound #65 Compound #65 was prepared by following General Procedure C: tert-butyl 4-(2-(4-(2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)pi perazin-1- yl)ethyl)piperidine-1-carboxylate (65-1) (148 mg, 52% yield). 1 H NMR (600 MHz, Chl f d) δ 802 ( 1H) 775 (d J 85 H 1H) 702 (dd J 87 22 H 1H) 690 (d J 2.2 Hz, 1H), 5.22 (dd, J = 13.4, 5.1 Hz, 1H), 4.43 (d, J = 15.6 Hz, 1H), 4.28 (d, J = 15.6 Hz, 1H), 4.10 (s, 2H), 3.35 (t, J = 5.2 Hz, 4H), 2.93 (ddd, J = 17.8, 4.8, 2.6 Hz, 1H), 2.89 – 2.80 (m, 1H), 2.71 (s, 2H), 2.62 (t, J = 5.0 Hz, 4H), 2.50 – 2.41 (m, 2H), 2.39 – 2.30 (m, 1H), 2.25 – 2.15 (m, 1H), 1.69 (d, J = 13.0 Hz, 2H), 1.55 – 1.43 (m, 12H), 1.22 – 1.09 (m, 2H). LC/MS (ESI) m/z 540.3; [M+H] + calcd for C29H42N5O5 + : 540.32. 3-(1-oxo-5-(4-(2-(piperidin-4-yl)ethyl)piperazin-1-yl)isoind olin-2-yl)piperidine-2,6-dione hydrochloride (65-2) (47 mg, quantitative yield). LC/MS (ESI) m/z 440.2; [M+H] + calcd for C24H34N5O3 + : 440.27. N-((4-(((R)-4-(1,4-oxazepan-4-yl)-1-(phenylthio)butan-2-yl)a mino)-3- ((trifluoromethyl)sulfonyl)phenyl)sulfonyl)-4-(4-(((4R)-4'-c hloro-4-((4-(2-(4-(2-(2,6- dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)piperazin-1-yl)eth yl)piperidin-1-yl)methyl)-4- methyl-3,4,5,6-tetrahydro-[1,1'-biphenyl]-2-yl)methyl)pipera zin-1-yl)benzamide (compound #65) (8.52 mg, 30% yield). 1 H NMR (600 MHz, Chloroform-d) δ 8.50 (s, 1H), 8.35 (d, J = 2.2 Hz, 1H), 8.04 – 7.97 (m, 1H), 7.88 (d, J = 8.7 Hz, 2H), 7.72 (d, J = 8.6 Hz, 1H), 7.40 – 7.35 (m, 2H), 7.32 – 7.26 (m, 5H), 7.26 – 7.19 (m, 1H), 7.02 – 6.96 (m, 3H), 6.95 – 6.86 (m, 1H), 6.75 – 6.70 (m, 2H), 6.45 (d, J = 9.1 Hz, 1H), 5.19 (dd, J = 13.3, 5.1 Hz, 1H), 4.40 (d, J = 15.7 Hz, 1H), 4.27 (d, J = 15.8 Hz, 1H), 3.85 – 3.69 (m, 5H), 3.42 – 3.32 (m, 5H), 3.30 – 3.06 (m, 8H), 3.02 (dd, J = 13.9, 6.9 Hz, 1H), 2.96 – 2.74 (m, 6H), 2.74 – 2.56 (m, 7H), 2.56 – 2.23 (m, 12H), 2.23 – 2.17 (m, 1H), 2.12 (d, J = 10.0 Hz, 2H), 2.00 – 1.85 (m, 3H), 1.79 – 1.59 (m, 5H), 1.56 – 1.43 (m, 4H), 1.43 – 1.33 (m, 1H), 1.04 (s, 3H). LC/MS (ESI) m/z 1425.7; [M+H] + calcd for C72H89ClF3N10O9S3 + : 1425.56. Example 28: Preparation of compound #127 N-((4-(((R)-4-(1,4-oxazepan-4-yl)-1-(phenylthio)butan-2-yl)a mino)-3- ((trifluoromethyl)sulfonyl)phenyl)sulfonyl)-4-(4-(((4R)-4'-c hloro-4-((4-(2-(2,6- dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)piperazin-1-yl)met hyl)-4-methyl-3,4,5,6- tetrahydro-[1,1'-biphenyl]-2-yl)methyl)piperazin-1-yl)benzam ide (compound #127) (4.52 mg, 23% yield). The preparation of compound #127 was performed according to General Procedure H. 1 H NMR (600 MHz, Chloroform-d) δ 8.51 (s, 1H), 8.32 (t, J = 1.8 Hz, 1H), 8.08 – 8.00 (m, 1H), 7.78 – 7.70 (m, 2H), 7.66 (dd, J = 18.1, 8.6 Hz, 1H), 7.38 – 7.33 (m, 2H), 7.28 (dt, J = 7.8, 3.2 Hz, 4H), 7.25 – 7.20 (m, 1H), 7.05 (d, J = 8.4 Hz, 1H), 7.01 – 6.97 (m, 2H), 6.93 (ddd, J = 10.6, 8.7, 2.1 Hz, 1H), 6.83 (t, J = 2.7 Hz, 1H), 6.75 – 6.66 (m, 2H), 6.57 (d, J = 9.1 Hz, 1H), 5.20 (dd, J = 12.5, 5.9 Hz, 1H), 4.38 (dd, J = 15.8, 10.3 Hz, 1H), 4.23 (dd, J = 16.0, 3.0 Hz, 1H), 3.88 (s, 1H), 3.81 – 3.67 (m, 4H), 3.33 – 3.16 (m, 8H), 3.08 (dd, J = 13.9, 5.0 Hz, 1H), 3.02 (dd, J = 13.9, 6.8 Hz, 1H), 2.96 – 2.57 (m, 12H), 2.53 – 2.37 (m, 4H), 2.37 – 2.21 (m, 8H), 2.21 – 2.13 (m, 1H), 2.13 – 2.04 (m, 1H), 1.95 – 1.86 (m, 3H), 1.79 – 1.70 (m, 1H), 1.68 – 1.58 (m, 1H), 1.49 – 1.40 (m, 1H), 1.01 – 0.94 (m, 3H). LC/MS (ESI) m/z 1314.6; [M+H] + calcd for C65H76ClF3N9O9S3 + : 1314.46. Example 29: Preparation of compound #128 Step 1: Synthesis of tert-butyl 4-(2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)-3,6- dihydropyridine-1(2H)-carboxylate (128-1). Under an argon atmosphere, a mixture of Intermediate E (600 mg, 1.86 mmol), tert-butyl 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)- 3,6-dihydropyridine-1(2H)-carboxylate (631 mg, 2.04 mmol), Pd(tert-Bu3P)2 (95 mg, 0.186 mmol) and TEA (1.3 Ml, 9.29 mmol) in DMSO (20 mL) was stirred at 80 °C overnight. After cooling to room temperature, the reaction mixture was diluted with EtOAc and washed with water and sat. aq. NH4Cl. The organic layers were dried over Na2SO4, filtered and concentrated. The residue was purified by flash column chromatography (30% to 90% of EtOAc in hexanes) to afford 128-1 (203 mg, 26% yield). 1 H NMR (600 MHz, Chloroform-d) δ 8.04 (s, 1H), 7.86 (d, J = 8.1 Hz, 1H), 7.54 – 7.48 (m, 2H), 7.46 (s, 1H), 5.26 (dd, J = 13.3, 2.7 Hz, 1H), 4.51 (d, J = 9.8 Hz, 1H), 4.38 (d, J = 9.3 Hz, 1H), 4.18 – 4.10 (m, 2H), 2.97 – 2.92 (m, 2H), 2.90 – 2.82 (m, 2H), 2.44 – 2.33 (m, 2H), 2.29 – 2.21 (m, 2H), 1.52 (s, 9H). LC/MS (ESI) m/z 426.2; [M+H] + calcd for C23H28N3O5 + : 426.20. Step 2: Synthesis of tert-butyl 4-(2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5- yl)piperidine-1-carboxylate (128-2). A stirring mixture of 128-1 (203 mg, 0.48 mmol), and 10% palladium on carbon (40 mg) in EtOAc/MeOH (5 mL/5 mL) was hydrogenated overnight with a hydrogen balloon. The resulting mixture was filtered through celite and the filtration was concentrated. The residue was purified by flash column chromatography (30% to 90% of EtOAc in hexanes) to afford 128-2 (141 mg, 69% yield). 1 H NMR (600 MHz, Chloroform-d) δ 8.06 (s, 1H), 7.85 (d, J = 7.8 Hz, 1H), 7.36 (dd, J = 7.9, 1.5 Hz, 1H), 7.32 (s, 1H), 5.25 (dd, J = 13.4, 5.1 Hz, 1H), 4.49 (d, J = 15.8 Hz, 1H), 4.36 – 4.20 (m, 3H), 3.02 – 2.70 (m, 4H), 2.38 (qd, J = 13.3, 4.8 Hz, 1H), 2.26 – 2.20 (m, 1H), 1.86 (d, J = 13.0 Hz, 2H), 1.73 – 1.58 (m, 3H), 1.51 (s, 9H). LC/MS (ESI) m/z 428.3; [M+H] + calcd for C 23 H 30 N 3 O 5 + : 428.22. Step 3: Synthesis of 3-(1-oxo-5-(piperidin-4-yl)isoindolin-2-yl)piperidine-2,6-di one TFA salt (128-3).4 N HCl in dioxane (0.5 mL) was added to a stirring solution of 128-2 (15 mg, 0.037 mmol) in DCM (0.5 mL), then stirred at room temperature for 2 hours. The reaction mixture was concentrated to afford 128-3 (23 mg, quantitative yield) as TFA salt, which was directly used in the next step. LC/MS (ESI) m/z 328.1; [M+H] + calcd for C 18 H 22 N 3 O 3 + : 328.17. Step 4: Synthesis of N-((4-(((R)-4-(1,4-oxazepan-4-yl)-1-(phenylthio)butan-2-yl)a mino)-3- ((trifluoromethyl)sulfonyl)phenyl)sulfonyl)-4-(4-(((4R)-4'-c hloro-4-((4-(2-(2,6- dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)piperidin-1-yl)met hyl)-4-methyl-3,4,5,6- tetrahydro-[1,1'-biphenyl]-2-yl)methyl)piperazin-1-yl)benzam ide (compound #128). Intermediate B (20 mg, 0.02 mmol) and NaBH(OAc)3 (5.5 mg, 0.026 mmol) were added to a solution of 128-3 (23 mg) and TEA (16.6 µL, 0.12 mmol) in DCM (1 mL), then stirred at room temperature overnight. The resulting mixture was washed with sat. aq. NH4Cl and dried over Na2SO4, filtered and concentrated. The residue was purified by preparative TLC (DCM/MeOH) to afford compound #128 (1.73 mg, 7% yield). 1 H NMR (599 MHz, Chloroform-d) δ 8.36 (d, J = 2.3 Hz, 1H), 8.09 (d, J = 9.2 Hz, 1H), 7.81 – 7.68 (m, 3H), 7.43 – 7.23 (m, 8H), 7.17 – 7.09 (m, 1H), 7.03 (d, J = 8.1 Hz, 2H), 6.74 (t, J = 6.8 Hz, 2H), 6.58 (d, J = 9.4 Hz, 1H), 5.36 – 5.21 (m, 1H), 4.45 (t, J = 15.7 Hz, 1H), 4.31 (d, J = 15.8 Hz, 1H), 3.90 (s, 1H), 3.83 – 3.62 (m, 4H), 3.30 – 3.18 (m, 4H), 3.11 (dd, J = 13.9, 5.0 Hz, 1H), 3.07 – 2.97 (m, 3H), 2.97 – 2.82 (m, 4H), 2.81 – 2.54 (m, 7H), 2.53 – 2.15 (m, 13H), 2.15 – 2.00 (m, 1H), 1.99 – 1.49 (m, 9H), 1.46 – 1.38 (m, 1H), 0.98 (d, J = 4.2 Hz, 3H). LC/MS (ESI) m/z 1313.7; [M+H] + calcd for C 66 H 77 ClF 3 N 8 O 9 S 3 + : 1313.46. Compound #129 was prepared by following General Procedure C: tert-butyl 3-((4-(2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)-2,6 -dimethylpiperazin-1- yl)methyl)azetidine-1-carboxylate (129-1) (18.5 mg, 80% yield). 1 H NMR (600 MHz, Chloroform-d) δ 8.36 (s, 1H), 7.71 (d, J = 8.5 Hz, 1H), 6.93 (dd, J = 8.6, 2.2 Hz, 1H), 6.82 (d, J = 2.1 Hz, 1H), 5.18 (dd, J = 13.3, 5.1 Hz, 1H), 4.39 (d, J = 15.6 Hz, 1H), 4.23 (d, J = 15.7 Hz, 1H), 3.99 (t, J = 8.4 Hz, 2H), 3.64 – 3.58 (m, 2H), 3.53 (d, J = 10.7 Hz, 2H), 2.92 (d, J = 7.1 Hz, 2H), 2.87 (ddd, J = 17.8, 4.9, 2.6 Hz, 1H), 2.84 – 2.76 (m, 2H), 2.75 – 2.65 (m, 4H), 2.36 – 2.25 (m, 1H), 2.20 – 2.14 (m, 1H), 1.43 (s, 9H), 1.16 (d, J = 5.8 Hz, 6H). LC/MS (ESI) m/z 526.3; [M+H] + calcd for C 28 H 40 N 5 O 5 + : 526.30. 3-(5-(4-(azetidin-3-ylmethyl)-3,5-dimethylpiperazin-1-yl)-1- oxoisoindolin-2-yl)piperidine- 2,6-dione hydrochloride (129-2) (10 mg, quantitative yield). LC/MS (ESI) m/z 426.3; [M+H] + calcd for C23H32N5O3 + : 426.25. N-((4-(((R)-4-(1,4-oxazepan-4-yl)-1-(phenylthio)butan-2-yl)a mino)-3- ((trifluoromethyl)sulfonyl)phenyl)sulfonyl)-4-(4-(((4R)-4'-c hloro-4-((3-((4-(2-(2,6- dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)-2,6-dimethylpiper azin-1-yl)methyl)azetidin-1- yl)methyl)-4-methyl-3,4,5,6-tetrahydro-[1,1'-biphenyl]-2-yl) methyl)piperazin-1- yl)benzamide (compound #129) (3.75 mg, 20% yield). 1 H NMR (600 MHz, Chloroform-d) δ 8.35 (d, J = 2.2 Hz, 1H), 7.99 – 7.95 (m, 1H), 7.90 (d, J = 8.6 Hz, 2H), 7.67 (d, J = 8.5 Hz, 1H), 7.36 (dt, J = 8.0, 1.3 Hz, 2H), 7.32 – 7.18 (m, 5H), 6.97 (d, J = 8.0 Hz, 2H), 6.90 – 6.82 (m, 2H), 6.78 (s, 1H), 6.65 (s, 2H), 6.40 (d, J = 8.8 Hz, 1H), 5.15 (dd, J = 12.8, 5.3 Hz, 1H), 4.37 (d, J = 15.7 Hz, 1H), 4.23 (d, J = 15.7 Hz, 1H), 3.86 – 3.63 (m, 5H), 3.54 – 3.38 (m, 2H), 3.20 – 3.05 (m, 2H), 3.05 – 2.91 (m, 8H), 2.91 – 2.70 (m, 8H), 2.70 – 2.50 (m, 10H), 2.39 – 2.13 (m, 11H), 2.13 – 2.06 (m, 1H), 1.97 – 1.81 (m, 3H), 1.75 – 1.66 (m, 1H), 1.66 – 1.57 (m, 1H), 1.53 – 1.43 (m, 1H), 1.11 (d, J = 5.7 Hz, 6H), 1.07 (s, 3H). LC/MS (ESI) m/z 1411.6; [M+H] + calcd for C71H87ClF3N10O9S3 + : 1411.55. Compound #130 was prepared by following General Procedure C: tert-butyl 4-((5-(2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)-2,5 - diazabicyclo[2.2.1]heptan-2-yl)methyl)piperidine-1-carboxyla te (130-1) (31 mg, 85% yield). 1 H NMR (600 MHz, Chloroform-d) δ 8.29 (s, 1H), 7.68 (dd, J = 8.4, 1.0 Hz, 1H), 6.60 (dd, J = 8.5, 2.1 Hz, 1H), 6.49 (d, J = 1.9 Hz, 1H), 5.19 (ddd, J = 13.3, 5.1, 2.4 Hz, 1H), 4.37 (dd, J = 15.5, 4.9 Hz, 1H), 4.31 – 4.26 (m, 1H), 4.23 (dd, J = 15.6, 3.4 Hz, 1H), 4.03 (s, 2H), 3.63 (t, J = 1.9 Hz, 1H), 3.42 (dt, J = 9.3, 2.4 Hz, 1H), 3.37 (d, J = 9.2 Hz, 1H), 3.11 – 3.03 (m, 1H), 2.88 (ddd, J = 17.8, 4.9, 2.6 Hz, 1H), 2.85 – 2.77 (m, 1H), 2.64 (s, 2H), 2.59 – 2.53 (m, 1H), 2.39 (dd, J = 7.0, 2.9 Hz, 2H), 2.30 (qd, J = 13.1, 5.0 Hz, 1H), 2.23 – 2.14 (m, 1H), 2.01 (d, J = 9.5 Hz, 1H), 1.91 (d, J = 9.6 Hz, 1H), 1.77 – 1.57 (m, 3H), 1.43 (s, 9H), 1.09 – 0.98 (m, 2H). LC/MS (ESI) m/z 538.4; [M+H] + calcd for C29H40N5O5 + : 538.30. 3-(1-oxo-5-(5-(piperidin-4-ylmethyl)-2,5-diazabicyclo[2.2.1] heptan-2-yl)isoindolin-2- yl)piperidine-2,6-dione TFA salt (130-2) (16 mg, quantitative yield). LC/MS (ESI) m/z 438.2; [M+H] + calcd for C24H32N5O3 + : 438.25. N-((4-(((R)-4-(1,4-oxazepan-4-yl)-1-(phenylthio)butan-2-yl)a mino)-3- ((trifluoromethyl)sulfonyl)phenyl)sulfonyl)-4-(4-(((4R)-4'-c hloro-4-((4-((5-(2-(2,6- dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)-2,5-diazabicyclo[ 2.2.1]heptan-2- yl)methyl)piperidin-1-yl)methyl)-4-methyl-3,4,5,6-tetrahydro -[1,1'-biphenyl]-2- yl)methyl)piperazin-1-yl)benzamide (compound #130) (6.86 mg, 30% yield). 1 H NMR (600 MHz, Chloroform-d) δ 8.34 (d, J = 8.2 Hz, 1H), 8.06 (d, J = 9.0 Hz, 1H), 7.74 (d, J = 8.3 Hz, 2H), 7.63 (d, J = 8.3 Hz, 1H), 7.40 – 7.34 (m, 2H), 7.32 – 7.21 (m, 5H), 7.07 – 6.95 (m, 3H), 6.71 (s, 2H), 6.55 (s, 2H), 6.49 (s, 1H), 5.19 (s, 1H), 4.36 (d, J = 15.5 Hz, 1H), 4.28 (s, 1H), 4.23 (d, J = 15.3 Hz, 1H), 3.87 (s, 1H), 3.80 – 3.62 (m, 6H), 3.45 – 3.32 (m, 2H), 3.20 (s, 4H), 3.10 (d, J = 13.9 Hz, 1H), 3.04 (d, J = 6.8 Hz, 1H), 2.92 – 2.81 (m, 2H), 2.79 – 2.54 (m, 6H), 2.53 – 2.20 (m, 16H), 2.20 – 1.51 (m, 17H), 1.46 – 1.39 (m, 1H), 0.99 (s, 3H). LC/MS (ESI) m/z 1423.6; [M+H] + calcd for C72H87ClF3N10O9S3 + : 1423.55. Compound #131 was prepared by following General Procedure C: tert-butyl 3-((5-(2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)-2,5 - diazabicyclo[2.2.1]heptan-2-yl)methyl)azetidine-1-carboxylat e (131-1) (25 mg, 72% yield). 1 H NMR (600 MHz, Chloroform-d) δ 8.42 (d, J = 10.9 Hz, 1H), 7.67 (d, J = 8.5 Hz, 1H), 6.59 (dt, J = 8.5, 1.8 Hz, 1H), 6.49 (t, J = 2.5 Hz, 1H), 5.17 (dd, J = 13.4, 4.9 Hz, 1H), 4.36 (dd, J = 15.5, 11.9 Hz, 1H), 4.27 (s, 1H), 4.22 (dd, J = 15.7, 2.6 Hz, 1H), 3.93 (dt, J = 16.8, 8.4 Hz, 2H), 3.59 – 3.50 (m, 3H), 3.41 (dt, J = 9.1, 1.8 Hz, 1H), 3.37 – 3.29 (m, 1H), 2.99 (dd, J = 9.3, 2.0 Hz, 1H), 2.90 – 2.84 (m, 1H), 2.84 – 2.75 (m, 1H), 2.68 (dd, J = 7.6, 2.2 Hz, 2H), 2.59 – 2.45 (m, 2H), 2.35 – 2.23 (m, 1H), 2.21 – 2.11 (m, 1H), 1.99 – 1.94 (m, 1H), 1.92 – 1.87 (m, 1H), 1.41 (s, 9H). LC/MS (ESI) m/z 510.4; [M+H] + calcd for C27H36N5O5 + : 510.27. 3-(5-(5-(azetidin-3-ylmethyl)-2,5-diazabicyclo[2.2.1]heptan- 2-yl)-1-oxoisoindolin-2- yl)piperidine-2,6-dione TFA salt (131-2) (17 mg, quantitative yield). LC/MS (ESI) m/z 410.2; [M+H] + calcd for C22H28N5O3 + : 410.22. N-((4-(((R)-4-(1,4-oxazepan-4-yl)-1-(phenylthio)butan-2-yl)a mino)-3- ((trifluoromethyl)sulfonyl)phenyl)sulfonyl)-4-(4-(((4R)-4'-c hloro-4-((3-((5-(2-(2,6- dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)-2,5-diazabicyclo[ 2.2.1]heptan-2- yl)methyl)azetidin-1-yl)methyl)-4-methyl-3,4,5,6-tetrahydro- [1,1'-biphenyl]-2- yl)methyl)piperazin-1-yl)benzamide (compound #131) (4.26 mg, 17% yield). 1 H NMR (600 MHz, Chloroform-d) δ 8.36 – 8.28 (m, 1H), 7.98 (d, J = 9.0 Hz, 1H), 7.91 (d, J = 8.3 Hz, 2H), 7.61 (d, J = 8.4 Hz, 1H), 7.35 (d, J = 7.6 Hz, 2H), 7.29 – 7.17 (m, 5H), 6.95 (d, J = 8.0 Hz, 2H), 6.86 (d, J = 8.3 Hz, 1H), 6.66 (d, J = 8.4 Hz, 2H), 6.53 – 6.40 (m, 3H), 5.10 (d, 1H), 4.37 – 3.97 (m, 4H), 3.81 (s, 1H), 3.74 (t, J = 5.9 Hz, 2H), 3.71 – 3.61 (m, 2H), 3.52 (s, 1H), 3.37 – 3.27 (m, 1H), 3.27 – 3.16 (m, 1H), 3.08 (dd, J = 13.6, 4.7 Hz, 1H), 3.04 – 2.89 (m, 6H), 2.88 – 2.47 (m, 12H), 2.23 (s, 12H), 2.06 (d, J = 23.8 Hz, 4H), 1.91 (d, J = 8.9 Hz, 1H), 1.88 – 1.77 (m, 4H), 1.72 – 1.63 (m, 1H), 1.63 – 1.50 (m, 2H), 1.50 – 1.39 (m, 1H), 1.04 (s, 3H). LC/MS (ESI) m/z 1395.7; [M+H] + calcd for C 70 H 83 ClF 3 N 10 O 9 S 3 + : 1395.51. Compound #132 was prepared by following General Procedure B: tert-butyl 4-((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)ethynyl )piperidine-1- carboxylate (132-1) (422 mg, 70% yield). 1 H NMR (600 MHz, Chloroform-d) δ 8.00 (s, 0H), 7.83 (d, J = 7.8 Hz, 1H), 7.53 (dd, J = 7.9, 1.3 Hz, 1H), 7.51 (s, 1H), 5.24 (dd, J = 13.4, 5.1 Hz, 1H) 450 (d J = 159 Hz 1H) 434 (d J = 159 Hz 1H) 377 (d J = 105 Hz 2H) 327 (ddd J = 13.5, 8.5, 3.4 Hz, 2H), 3.00 – 2.91 (m, 1H), 2.91 – 2.80 (m, 2H), 2.38 (qd, J = 13.3, 4.7 Hz, 1H), 2.29 – 2.20 (m, 1H), 1.96 – 1.84 (m, 2H), 1.76 – 1.66 (m, 2H), 1.49 (s, 9H). LC/MS (ESI) m/z 452.3; [M+H] + calcd for C25H30N3O5 + : 452.22. 3-(1-oxo-5-(piperidin-4-ylethynyl)isoindolin-2-yl)piperidine -2,6-dione hydrochloride (132-2) (22 mg, quantitative yield). LC/MS (ESI) m/z 352.2; [M+H] + calcd for C20H22N3O3 + : 352.17. N-((4-(((R)-4-(1,4-oxazepan-4-yl)-1-(phenylthio)butan-2-yl)a mino)-3- ((trifluoromethyl)sulfonyl)phenyl)sulfonyl)-4-(4-(((4R)-4'-c hloro-4-((4-((2-(2,6- dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)ethynyl)piperidin- 1-yl)methyl)-4-methyl-3,4,5,6- tetrahydro-[1,1'-biphenyl]-2-yl)methyl)piperazin-1-yl)benzam ide (compound #132) (5.1 mg, % yield). 1 H NMR (600 MHz, Chloroform-d) δ 8.36 (dd, J = 5.5, 2.3 Hz, 1H), 8.06 (d, J = 9.2 Hz, 1H), 7.82 – 7.71 (m, 3H), 7.53 – 7.44 (m, 2H), 7.41 – 7.35 (m, 2H), 7.34 – 7.21 (m, 6H), 7.09 – 6.96 (m, 3H), 6.75 (d, J = 8.7 Hz, 2H), 6.55 (d, J = 9.3 Hz, 1H), 5.29 – 5.20 (m, 1H), 4.47 (dd, J = 16.2, 4.4 Hz, 1H), 4.33 (d, J = 16.2 Hz, 1H), 3.88 (s, 1H), 3.82 – 3.71 (m, 4H), 3.25 (s, 4H), 3.11 (dd, J = 13.9, 5.0 Hz, 1H), 3.05 (dd, J = 14.0, 6.8 Hz, 1H), 2.99 – 2.84 (m, 6H), 2.84 – 2.74 (m, 4H), 2.75 – 2.52 (m, 5H), 2.48 – 2.19 (m, 11H), 2.16 – 2.06 (m, 1H), 2.05 – 1.89 (m, 4H), 1.88 – 1.62 (m, 5H), 1.50 – 1.41 (m, 1H), 0.99 (s, 3H). LC/MS (ESI) m/z 1337.6; [M+H] + calcd for C68H77ClF3N8O9S3 + : 1337.46. N-((4-(((R)-4-(1,4-oxazepan-4-yl)-1-(phenylthio)butan-2-yl)a mino)-3- ((trifluoromethyl)sulfonyl)phenyl)sulfonyl)-4-(4-(((4R)-4'-c hloro-4-((4-(2-(2,6- dioxopiperidin-3-yl)-3-oxoisoindolin-5-yl)piperazin-1-yl)met hyl)-4-methyl-3,4,5,6- tetrahydro-[1,1'-biphenyl]-2-yl)methyl)piperazin-1-yl)benzam ide (compound #132) (7.34 mg, 28% yield). The preparation of compound #132 was performed according to General Procedure H. 1 H NMR (600 MHz, Chloroform-d) δ 8.27 (t, J = 1.9 Hz, 1H), 8.10 – 8.03 (m, 1H), 7.90 – 7.81 (m, 2H), 7.38 – 7.30 (m, 3H), 7.31 – 7.15 (m, 7H), 7.02 – 6.95 (m, 2H), 6.83 – 677 (m 2H) 658 (dd J = 94 54 Hz 1H) 565 – 546 (m 1H) 437 (dd J = 157 32 Hz 1H) 4.29 (dd, J = 15.8, 4.4 Hz, 1H), 3.94 – 3.80 (m, 1H), 3.78 – 3.70 (m, 2H), 3.70 – 3.58 (m, 2H), 3.19 (t, J = 5.1 Hz, 8H), 3.07 (ddd, J = 13.8, 5.2, 2.6 Hz, 1H), 3.04 – 2.99 (m, 1H), 2.98 – 2.90 (m, 1H), 2.90 – 2.77 (m, 3H), 2.78 – 2.70 (m, 4H), 2.69 – 2.63 (m, 2H), 2.63 – 2.43 (m, 5H), 2.41 – 2.15 (m, 10H), 2.07 – 1.97 (m, 1H), 1.85 – 1.79 (m, 2H), 1.79 – 1.36 (m, 4H), 0.94 (d, J = 15.5 Hz, 3H). LC/MS (ESI) m/z 1314.5; [M+H] + calcd for C65H76ClF3N9O9S3 + : 1314.46. N-((4-(((R)-4-(1,4-oxazepan-4-yl)-1-(phenylthio)butan-2-yl)a mino)-3- ((trifluoromethyl)sulfonyl)phenyl)sulfonyl)-4-(4-(((4R)-4'-c hloro-4-((4-(2-(2,6- dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)-1,4-diazepan-1-yl )methyl)-4-methyl-3,4,5,6- tetrahydro-[1,1'-biphenyl]-2-yl)methyl)piperazin-1-yl)benzam ide (compound #135) (8.63 mg, 28% yield). The preparation of compound #135 was performed according to General Procedure H. 1 H NMR (600 MHz, Chloroform-d) δ 8.31 (t, J = 2.5 Hz, 1H), 8.06 (dd, J = 9.3, 2.2 Hz, 1H), 7.72 (dd, J = 8.8, 4.0 Hz, 2H), 7.47 (t, J = 8.2 Hz, 1H), 7.37 – 7.31 (m, 2H), 7.30 – 7.23 (m, 4H), 7.23 – 7.19 (m, 1H), 6.96 (d, J = 8.3 Hz, 2H), 6.73 – 6.64 (m, 3H), 6.62 (t, J = 2.9 Hz, 1H), 6.59 – 6.52 (m, 1H), 5.23 – 5.11 (m, 1H), 4.32 (dd, J = 15.7, 7.7 Hz, 1H), 4.17 (d, J = 15.7 Hz, 1H), 3.89 – 3.82 (m, 1H), 3.74 (t, J = 6.1 Hz, 2H), 3.72 – 3.64 (m, 2H), 3.59 – 3.47 (m, 4H), 3.15 (t, J = 5.2 Hz, 4H), 3.07 (dd, J = 13.9, 5.0 Hz, 1H), 3.01 (dd, J = 13.9, 7.0 Hz, 1H), 2.98 – 2.89 (m, 2H), 2.87 – 2.76 (m, 4H), 2.76 – 2.50 (m, 8H), 2.43 (dd, J = 14.1, 2.6 Hz, 1H), 2.40 – 2.15 (m, 8H), 2.15 – 2.09 (m, 1H), 2.09 – 2.02 (m, 1H), 1.96 – 1.83 (m, 4H), 1.75 – 1.50 (m, 4H), 1.39 – 1.33 (m, 1H), 0.90 (s, 3H). LC/MS (ESI) m/z 1328.6; [M+H] + calcd for C 66 H 78 ClF 3 N 9 O 9 S 3 + : 1328.47. Example 36: Preparation of compound #136
Compound #136 was prepared by following General Procedure C: tert-butyl 4-((4-(2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)-1,4 -diazepan-1-yl)methyl)- 4-methylpiperidine-1-carboxylate (136-1) (24 mg, 38% yield). 1 H NMR (600 MHz, Chloroform-d) δ 8.09 (s, 1H), 7.67 (d, J = 8.7 Hz, 1H), 6.74 (dd, J = 8.7, 2.2 Hz, 1H), 6.63 (d, J = 2.2 Hz, 1H), 5.19 (dd, J = 13.3, 5.1 Hz, 1H), 4.38 (d, J = 15.4 Hz, 1H), 4.23 (d, J = 15.5 Hz, 1H), 3.74 – 3.63 (m, 2H), 3.58 (t, J = 6.3 Hz, 2H), 3.55 (t, J = 5.0 Hz, 2H), 3.05 (t, J = 12.1 Hz, 2H), 2.92 – 2.86 (m, 3H), 2.82 (ddd, J = 18.0, 13.2, 5.3 Hz, 1H), 2.67 (t, J = 6.8, 4.6 Hz, 2H), 2.35 – 2.25 (m, 3H), 2.22 – 2.14 (m, 1H), 1.91 (p, J = 6.1 Hz, 2H), 1.45 (s, 9H), 1.43 – 1.35 (m, 2H), 1.27 – 1.17 (m, 2H), 0.91 (s, 3H). LC/MS (ESI) m/z 554.4; [M+H] + calcd for C 30 H 44 N 5 O 5 + : 554.33. 3-(5-(4-((4-methylpiperidin-4-yl)methyl)-1,4-diazepan-1-yl)- 1-oxoisoindolin-2-yl)piperidine- 2,6-dione TFA salt (136-2) (14 mg, quantitative yield). LC/MS (ESI) m/z 454.2; [M+H] + calcd for C25H36N5O3 + : 454.28. N-((4-(((R)-4-(1,4-oxazepan-4-yl)-1-(phenylthio)butan-2-yl)a mino)-3- ((trifluoromethyl)sulfonyl)phenyl)sulfonyl)-4-(4-(((4R)-4'-c hloro-4-((4-((4-(2-(2,6- dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)-1,4-diazepan-1-yl )methyl)-4-methylpiperidin-1- yl)methyl)-4-methyl-3,4,5,6-tetrahydro-[1,1'-biphenyl]-2-yl) methyl)piperazin-1- yl)benzamide (compound #136) (6.89 mg, 32% yield). 1 H NMR (600 MHz, Chloroform-d) δ 8.31 (d, J = 2.3 Hz, 1H), 8.00 (dd, J = 9.1, 2.2 Hz, 1H), 7.82 (d, J = 8.4 Hz, 2H), 7.61 (dd, J = 8.7, 3.4 Hz, 1H), 7.38 – 7.32 (m, 2H), 7.31 – 7.23 (m, 5H), 7.23 – 7.18 (m, 1H), 6.97 (d, J = 8.0 Hz, 2H), 6.67 (d, J = 8.1 Hz, 3H), 6.59 (s, 1H), 6.46 (d, J = 9.2 Hz, 1H), 5.12 (dt, J = 13.3, 6.8 Hz, 1H), 4.33 (d, J = 15.6 Hz, 1H), 4.21 (d, J = 15.7 Hz, 1H), 3.79 (s, 1H), 3.75 (t, J = 6.1 Hz, 2H) 371 – 365 (m 2H) 355 – 343 (m 4H) 323 – 304 (m 6H) 300 (dd J = 138 70 Hz 1H), 2.91 – 2.50 (m, 17H), 2.47 – 2.20 (m, 10H), 2.19 – 2.10 (m, 1H), 2.10 – 2.01 (m, 1H), 1.93 – 1.76 (m, 4H), 1.78 – 1.41 (m, 9H), 1.05 (s, 3H), 0.87 (t, J = 1.6 Hz, 3H). LC/MS (ESI) m/z 1439.7; [M+H] + calcd for C73H91ClF3N10O9S3 + : 1439.58. Example 37: Preparation of compound #137 Step 1: Synthesis of tert-butyl 4-(3-fluoro-4-(methoxycarbonyl)phenyl)piperazine-1- carboxylate (137-1). Under an argon atmosphere, a mixture of methyl 4-bromo-2-fluorobenzoate (1 g, 4.29 mmol), 4-Boc-piperazine (1.12 g, 6.01 mmol), Pd(OAc)2 (48 mg, 0.21 mmol), BINAP (267 mg, 0.43 mmol) and Cs 2 CO 3 (1.54g, 4.72 mmol) in toluene (20 mL) was stirred at 60 °C overnight. After cooling to room temperature, the reaction mixture was washed with water and sat. aq. NH4Cl. The organic layers were dried over Na2SO4, filtered and concentrated. The residue was purified by flash column chromatography (10% to 40% of EtOAc in hexanes) to afford 137-1 (410 mg, 37% yield). 1 H NMR (600 MHz, Chloroform-d) δ 7.83 (t, J = 8.8 Hz, 1H), 6.61 (dd, J = 9.0, 2.5 Hz, 1H), 6.50 (dd, J = 14.5, 2.5 Hz, 1H), 3.87 (s, 3H), 3.57 (t, J = 6.5, 4.1 Hz, 4H), 3.30 (t, J = 5.3 Hz, 4H), 1.48 (s, 9H). LC/MS (ESI) m/z 339.2; [M+H] + calcd for C 17 H 24 FN 2 O 4 + : 339.17. Step 2: Synthesis of methyl 2-fluoro-4-(piperazin-1-yl)benzoate hydrochloride (137-2).4 N HCl in dioxane (5 mL) was added to a stirring solution of 137-1 (200 mg, 0.59 mmol) in DCM (5 mL) at room temperature. The resulting mixture was stirred at room temperature for 2 hours, then concentrated to afford 137-2 (195 mg, quantitative yield), which was directly used in the next step. LC/MS (ESI) m/z 239.2; [M+H] + calcd for C12H16FN2O2 + : 239.12. Step 3: Synthesis of tert-butyl 4-((4-(3-fluoro-4-(methoxycarbonyl)phenyl)piperazin-1- yl)methyl)piperidine-1-carboxylate (137-3). tert-Butyl 4-formylpiperidine-1-carboxylate (189 mg, 0.89 mmol) and NaBH(OAc)3 (188 mg, 0.89 mmol) were added to a solution of 137-2 (195 mg, 0.71 mmol) and TEA (789 µL, 5.67 mmol) in DCM (10 mL), then stirred at room temperature overnight. The resulting mixture was washed with water and sat. aq. NH4Cl. The organic layers were dried over Na2SO4, filtered and concentrated. The residue was purified by flash column chromatography (10% to 40% of EtOAc in hexanes) to afford 137-3 (218 mg, 85% yield in two steps). 1 H NMR (600 MHz, Chloroform-d) δ 7.84 (t, J = 8.8 Hz, 1H), 6.64 (dd, J = 8.9, 2.5 Hz, 1H), 6.52 (dd, J = 14.7, 2.4 Hz, 1H), 4.12 (s, 2H), 3.90 (s, 3H), 3.33 (t, 4H), 2.72 (s, 2H), 2.55 (t, 4H), 2.24 (d, J = 7.2 Hz, 2H), 1.77 (d, J = 11.8 Hz, 2H), 1.73 – 1.63 (m, 1H), 1.48 (s, 9H), 1.11 (qd, J = 12.4, 4.3 Hz, 2H). LC/MS (ESI) m/z 436.3; [M+H] + calcd for C23H35FN3O4 + : 436.26. Step 4: Synthesis of 4-(4-((1-(tert-butoxycarbonyl)piperidin-4-yl)methyl)piperazi n-1-yl)-2- fluorobenzoic acid (137-4). To a solution of 137-3 (210 mg, 0.48 mmol) in MeOH/THF (5 mL/5mL) was added a solution of LiOH·H2O (61 mg, 0.14 mmol) in water (1 mL), then stirred at room temperature overnight. The reaction mixture was concentrated to remove the organic solvents, then adjusted to pH = 6 with 10% aq. citric acid and extracted with EtOAc. The combined organic layers were washed with brine and dried over Na2SO4, filtered and concentrated. The residue was purified by flash column chromatography (10% to 40% of EtOAc in hexanes) to afford 137-4 (179 mg, 88% yield). 1 H NMR (600 MHz, Chloroform-d) δ 7.89 (t, J = 8.9 Hz, 1H), 6.65 (dd, J = 9.1, 2.4 Hz, 1H), 6.53 (dd, J = 14.8, 2.4 Hz, 1H), 4.12 (s, 2H), 3.37 (t, J = 5.1 Hz, 4H), 2.73 (s, 2H), 2.58 (t, J = 5.1 Hz, 4H), 2.28 (d, J = 7.0 Hz, 2H), 1.77 (d, J = 11.7 Hz, 2H), 1.74 – 1.63 (m, 1H), 1.48 (s, 9H), 1.13 (qd, J = 12.5, 4.3 Hz, 2H). LC/MS (ESI) m/z 422.2; [M+H] + calcd for C22H33FN3O4 + : 422.24. Step 5: Synthesis of tert-butyl (S)-4-((4-(4-((2,6-dioxopiperidin-3-yl)carbamoyl)-3- fluorophenyl)piperazin-1-yl)methyl)piperidine-1-carboxylate (137-5). To a solution of 137-4 (18 mg, 0.043 mmol) and HATU (21 mg, 0.055 mmol) in (1 mL) was added a solution of (S)-3- aminopiperidine-2,6-dione hydrochloride (8 mg, 0.048 mmol) and DIPEA (30 µL, 0.17 mmol) in DCM (0.5 mL). The resulting mixture was stirred at room temperature for 2 hours, then washed with water and sat. aq. NH4Cl. The organic layers were dried over Na2SO4, filtered and concentrated. The residue was purified by preparative TLC (DCM/MeOH = 10/1) to afford 137-5 (14 mg, 62% yield). 1 H NMR (600 MHz, Chloroform-d) δ 8.31 (s, 1H), 7.94 (t, J = 9.2 Hz, 1H), 7.41 (dd, J = 14.1, 5.7 Hz, 1H), 6.70 (dd, J = 9.0, 2.4 Hz, 1H), 6.50 (dd, J = 16.3, 2.4 Hz, 1H), 4.84 – 4.70 (m, 1H), 4.09 (s, 2H), 3.30 (t, J = 5.1 Hz, 4H), 2.87 – 2.72 (m, 2H), 2.73 – 2.63 (m, 3H), 2.53 (t, J = 5.1 Hz, 4H), 2.22 (d, J = 7.1 Hz, 2H), 1.94 (qd, J = 12.9, 5.2 Hz, 1H), 1.79 – 1.70 (m, 2H), 1.70 – 1.59 (m, 1H), 1.45 (s, 9H), 1.09 (qd, J = 12.5, 4.3 Hz, 2H). LC/MS (ESI) m/z 532.4; [M+H] + calcd for C 27 H 39 FN 5 O 5 + : 532.29. Step 6: Synthesis of (S)-N-(2,6-dioxopiperidin-3-yl)-2-fluoro-4-(4-(piperidin-4- ylmethyl)piperazin-1-yl)benzamide hydrochloride (137-6). To a stirring solution of 137-5 (14 mg, 0.026 mmol) in DCM (0.5 mL) was added 4 N HCl in dioxane (0.5 mL) and stirred at room temperature for 2 hours. The reaction mixture was concentrated to afford 137-6 (13 mg, quantitative yield), which was directly used in the next step. LC/MS (ESI) m/z 432.3; [M+H] + calcd for C 22 H 31 FN 5 O 3 + : 432.24. Step 7: Synthesis of 4-(4-((1-(((R)-6-((4-(4-(((4-(((R)-4-(1,4-oxazepan-4-yl)-1- (phenylthio)butan-2-yl)amino)-3- ((trifluoromethyl)sulfonyl)phenyl)sulfonyl)carbamoyl)phenyl) piperazin-1-yl)methyl)-4'- chloro-4-methyl-2,3,4,5-tetrahydro-[1,1'-biphenyl]-4-yl)meth yl)piperidin-4- yl)methyl)piperazin-1-yl)-N-((S)-2,6-dioxopiperidin-3-yl)-2- fluorobenzamide (compound 137). Intermediate B (17 mg, 0.017 mmol) and NaBH(OAc) 3 (4.3 mg, 0.02 mmol) were added to a solution of 137-6 (13 mg, 0.027 mmol) and TEA (19 µL, 0.14 mmol) in DCM (1 mL), then stirred at room temperature overnight. The resulting mixture was washed with sat. aq. NH4Cl and dried over Na 2 SO 4 , filtered and concentrated. The residue was purified by preparative TLC (DCM/MeOH) to afford compound #137 (4.78 mg, 20% yield in two steps). 1 H NMR (600 MHz, Chloroform-d) δ 8.34 (d, J = 2.2 Hz, 1H), 8.07 (s, 1H), 8.02 (d, J = 9.1 Hz, 1H), 7.93 (t, J = 9.2 Hz, 1H), 7.77 (d, J = 8.5 Hz, 2H), 7.45 – 7.34 (m, 3H), 7.28 (s, 5H), 6.98 (d, J = 8.2 Hz, 3H), 6.72 (d, J = 8.1 Hz, 2H), 6.68 (dd, J = 9.0, 2.3 Hz, 1H), 6.53 – 6.44 (m, 2H), 4.82 – 4.72 (m, 1H), 3.83 (s, 1H), 3.80 – 3.66 (m, 4H), 3.24 (d, J = 31.7 Hz, 9H), 3.09 (dd, J = 13.9, 5.0 Hz, 1H), 3.02 (dd, J = 13.9, 7.0 Hz, 1H), 2.90 – 2.64 (m, 6H), 2.63 – 2.56 (m, 1H), 2.51 (s, 4H), 2.47 – 2.18 (m, 12H), 2.14 – 1.83 (m, 12H), 1.80 – 1.67 (m, 2H), 1.67 – 1.53 (m, 3H), 1.52 – 1.41 (m, 1H), 1.03 (s, 3H). ). LC/MS (ESI) m/z 1417.6; [M+H] + calcd for C70H86ClF4N10O9S3 + : 1417.54. Example 38: Preparation of compound #138
Step 1: Synthesis of tert-butyl (R)-4-((4-(4-((2,6-dioxopiperidin-3-yl)carbamoyl)-3- fluorophenyl)piperazin-1-yl)methyl)piperidine-1-carboxylate (138-1). To a solution of 137-4 (15 mg, 0.036 mmol) and HATU (17.6 mg, 0.046 mmol) in (1 mL) was added a solution of (R)- 3-aminopiperidine-2,6-dione hydrochloride (7 mg, 0.042 mmol) and DIPEA (25 µL, 0.14 mmol) in DCM (0.5 mL). The resulting mixture was stirred at room temperature for 2 hours, then washed with water and sat. aq. NH 4 Cl. The organic layers were dried over Na 2 SO 4 , filtered and concentrated. The residue was purified by preparative TLC (DCM/MeOH = 10/1) to afford 138-1 (13 mg, 69% yield). 1 H NMR (600 MHz, Chloroform-d) δ 8.03 (s, 1H), 7.95 (t, J = 9.2 Hz, 1H), 7.40 (dd, J = 14.2, 5.7 Hz, 1H), 6.70 (dd, J = 9.0, 2.4 Hz, 1H), 6.50 (dd, J = 16.3, 2.4 Hz, 1H), 4.85 – 4.71 (m, 1H), 4.10 (s, 2H), 3.31 (t, 4H), 2.88 – 2.73 (m, 2H), 2.73 – 2.63 (m, 3H), 2.53 (t, J = 5.1 Hz, 4H), 2.23 (d, J = 7.2 Hz, 2H), 1.94 (qd, J = 13.0, 5.1 Hz, 1H), 1.78 – 1.71 (m, 2H), 1.71 – 1.57 (m, 1H), 1.46 (s, 9H), 1.09 (qd, J = 12.5, 4.3 Hz, 2H). LC/MS (ESI) m/z 532.4; [M+H] + calcd for C 27 H 39 FN 5 O 5 + : 532.29. Step 2: Synthesis of (R)-N-(2,6-dioxopiperidin-3-yl)-2-fluoro-4-(4-(piperidin-4- ylmethyl)piperazin-1-yl)benzamide hydrochloride (138-2). To a stirring solution of 138-1 (13 mg, 0.026 mmol) in DCM (0.5 mL) was added 4 N HCl in dioxane (0.5 mL) and stirred at room temperature for 2 hours. The reaction mixture was concentrated to afford 138-2 (13 mg, quantitative yield), which was directly used in the next step. LC/MS (ESI) m/z 432.3; [M+H] + calcd for C 22 H 31 FN 5 O 3 + : 432.24. Step 3: Synthesis of 4-(4-((1-(((R)-6-((4-(4-(((4-(((R)-4-(1,4-oxazepan-4-yl)-1- (phenylthio)butan-2-yl)amino)-3- ((trifluoromethyl)sulfonyl)phenyl)sulfonyl)carbamoyl)phenyl) piperazin-1-yl)methyl)-4'- chloro-4-methyl-2,3,4,5-tetrahydro-[1,1'-biphenyl]-4-yl)meth yl)piperidin-4- yl)methyl)piperazin-1-yl)-N-((R)-2,6-dioxopiperidin-3-yl)-2- fluorobenzamide (compound 138). Intermediate B (17 mg, 0.017 mmol) and NaBH(OAc)3 (4.3 mg, 0.02 mmol) were added to a solution of 138-2 (13 mg, 0.027 mmol) and TEA (19 µL, 0.14 mmol) in DCM (1 mL), then stirred at room temperature overnight. The resulting mixture was washed with sat. aq. NH4Cl and dried over Na2SO4, filtered and concentrated. The residue was purified by preparative TLC (DCM/MeOH) to afford compound #138 (6.21 mg, 26% yield). 1 H NMR (600 MHz, Chloroform-d) δ 8.34 (d, J = 2.2 Hz, 1H), 8.07 (s, 1H), 8.05 – 7.99 (m, 1H), 7.93 (t, J = 9.2 Hz, 1H), 7.77 (d, J = 8.5 Hz, 2H), 7.40 (dd, J = 14.2, 5.8 Hz, 1H), 7.38 – 7.34 (m, 2H), 7.32 – 7.20 (m, 6H), 7.04 – 6.94 (m, 3H), 6.77 – 6.64 (m, 3H), 6.53 – 6.43 (m, 2H), 4.78 (dtd, J = 12.7, 5.5, 1.8 Hz, 1H), 3.83 (s, 1H), 3.76 (t, J = 6.1 Hz, 2H), 3.74 – 3.68 (m, 2H), 3.24 (d, J = 29.7 Hz, 9H), 3.09 (dd, J = 13.9, 5.0 Hz, 1H), 3.02 (dd, J = 13.9, 7.0 Hz, 1H), 2.92 – 2.64 (m, 6H), 2.64 – 2.55 (m, 1H), 2.51 (t, J = 5.2 Hz, 4H), 2.45 – 2.19 (m, 12H), 2.18 – 1.83 (m, 12H), 1.82 – 1.69 (m, 2H), 1.68 – 1.54 (m, 3H), 1.53 – 1.44 (m, 1H), 1.04 (s, 3H). ). LC/MS (ESI) m/z 1417.7; [M+H] + calcd for C70H86ClF4N10O9S3 + : 1417.54. Example 39: Preparation of compound #139 Step 1: Synthesis of tert-butyl (S)-4-(4-((2,6-dioxopiperidin-3- yl)carbamoyl)phenyl)piperazine-1-carboxylate (139-1). To a solution of 4-(4-(tert- butoxycarbonyl)piperazin-1-yl)benzoic acid (25 mg, 0.082 mmol) and HATU (40 mg, 0.11 mmol) in (1.0 mL) was added a solution of (S)-3-aminopiperidine-2,6-dione hydrochloride (15 mg, 0.091 mmol) and DIPEA (57 µL, 0.33 mmol) in DCM (1.0 mL). The resulting mixture was stirred at room temperature for 2 hours, then washed with water and sat. aq. NH4Cl. The organic layers were dried over Na 2 SO 4 , filtered and concentrated. The residue was purified by preparative TLC (DCM/MeOH = 10/1) to afford 140-1 (26 mg, 76% yield). 1 H NMR (600 MHz, Chloroform-d) δ 7.95 (s, 1H), 7.80 – 7.76 (m, 2H), 6.96 – 6.89 (m, 2H), 6.86 (d, J = 5.1 Hz, 1H), 4.76 (dt, J = 12.5, 5.0 Hz, 1H), 3.61 (t, J = 5.2 Hz, 4H), 3.31 (t, J = 5.2 Hz, 4H), 2.92 – 2.75 (m, 3H), 1.97 – 1.86 (m, 1H), 1.51 (s, 9H). LC/MS (ESI) m/z 417.1; [M+H] + calcd for C21H29N4O5 + : 417.21. Step 2: Synthesis of (S)-N-(2,6-dioxopiperidin-3-yl)-4-(piperazin-1-yl)benzamide hydrochloride (139-2). To a stirring solution of 139-1 (25 mg, 0.06 mmol) in DCM (0.5 mL) was added 4 N HCl in dioxane (0.5 mL) and stirred at room temperature for 2 hours. The reaction mixture was concentrated to afford 139-2 (23 mg, quantitative yield), which was directly used in the next step. LC/MS (ESI) m/z 317.2; [M+H] + calcd for C 16 H 21 N 4 O 3 + : 317.16. Step 3: Synthesis of tert-butyl (S)-4-((4-(4-((2,6-dioxopiperidin-3- yl)carbamoyl)phenyl)piperazin-1-yl)methyl)piperidine-1-carbo xylate (139-3). tert-butyl 4- formylpiperidine-1-carboxylate (16 mg, 0.075 mmol) and NaBH(OAc) 3 (28 mg, 0.13 mmol) were added to a solution of 139-2 (23 mg, 0.063 mmol) and TEA (45 µL, 0.33 mmol) in DCM (1 mL), then stirred at room temperature overnight. The resulting mixture was washed with water and sat. aq. NH 4 Cl. The organic layers were dried over Na 2 SO 4 , filtered and concentrated. The residue was purified by preparative TLC (DCM/MeOH = 10/1) to afford 139-3 (12 mg, 39% yield in two steps). 1 H NMR (600 MHz, Chloroform-d) δ 8.54 (s, 1H), 7.73 (dd, J = 9.0, 2.1 Hz, 2H), 6.93 (d, J = 5.5 Hz, 1H), 6.87 (d, J = 8.9 Hz, 1H), 4.79 – 4.70 (m, 1H), 4.08 (s, 2H), 3.30 (t, J = 4.8 Hz, 4H), 2.92 – 2.73 (m, 2H), 2.73 – 2.64 (m, 3H), 2.58 (t, J = 5.0 Hz, 4H), 2.25 (d, J = 7.0 Hz, 2H), 1.95 – 1.82 (m, 1H), 1.78 – 1.65 (m, 3H), 1.45 (s, 9H), 1.10 (qd, J = 12.4, 4.3 Hz, 2H). LC/MS (ESI) m/z 514.2; [M+H] + calcd for C27H40N5O5 + : 514.3. Step 4: Synthesis of (S)-N-(2,6-dioxopiperidin-3-yl)-4-(4-(piperidin-4-ylmethyl)p iperazin-1- yl)benzamide hydrochloride (139-4). To a stirring solution of 139-3 (12 mg, 0.023 mmol) in DCM (0.5 mL) was added 4 N HCl in dioxane (0.5 mL) and stirred at room temperature for 2 hours. The reaction mixture was concentrated to afford 139-4 (10 mg, quantitative yield), which was directly used in the next step. LC/MS (ESI) m/z 414.2; [M+H] + calcd for C22H32N5O3 + : 414.25. Step 5: Synthesis of N-((4-(((R)-4-(1,4-oxazepan-4-yl)-1-(phenylthio)butan-2-yl)a mino)-3- ((trifluoromethyl)sulfonyl)phenyl)sulfonyl)-4-(4-(((R)-4'-ch loro-4-((4-((4-(4-(((S)-2,6- dioxopiperidin-3-yl)carbamoyl)phenyl)piperazin-1-yl)methyl)p iperidin-1-yl)methyl)-4- methyl-3,4,5,6-tetrahydro-[1,1'-biphenyl]-2-yl)methyl)pipera zin-1-yl)benzamide (compound #139). Intermediate B (15 mg, 0.015 mmol) and NaBH(OAc) 3 (4.0 mg, 0.019 mmol) were added to a solution of 139-4 (10 mg, 0.022 mmol) and TEA (17 µL, 0.12 mmol) in DCM (1 mL), then stirred at room temperature overnight. The resulting mixture was washed with sat. aq. NH 4 Cl and dried over Na 2 SO 4 , filtered and concentrated. The residue was purified by preparative TLC (DCM/MeOH) to afford compound #139 (5.89 mg, 28% yield in two steps). 1 H NMR (600 MHz, Chloroform-d) δ 8.33 (d, J = 2.2 Hz, 1H), 8.02 (d, 1H), 7.79 (d, J = 8.4 Hz, 2H), 7.75 (d, 2H), 7.39 – 7.34 (m, 2H), 7.32 – 7.20 (m, 5H), 7.05 – 6.92 (m, 4H), 6.85 (d, J = 8.5 Hz, 2H), 6.73 (d, J = 8.6 Hz, 2H), 6.47 (d, J = 9.2 Hz, 1H), 4.81 – 4.68 (m, 1H), 3.82 (s, 1H), 3.76 (t, J = 6.1 Hz, 2H), 3.73 – 3.67 (m, 2H), 3.22 (d, J = 23.4 Hz, 9H), 3.09 (dd, J = 13.8, 4.9 Hz, 1H), 3.01 (dd, J = 13.9, 6.9 Hz, 1H), 2.90 – 2.70 (m, 5H), 2.71 – 2.65 (m, 1H), 2.60 (m, 1H), 2.53 (s, 4H), 2.49 – 2.19 (m, 12H), 2.20 – 1.83 (m, 12H), 1.80 – 1.68 (m, 2H), 1.66 – 1.53 (m, 3H), 1.52 – 1.40 (m, 2H), 1.02 (s, 3H). ). LC/MS (ESI) m/z 1399.7; [M+H] + calcd for C70H87ClF3N10O9S3 + : 1399.55. Example 40: Preparation of compound #140 Step 1: Synthesis of tert-butyl 4-(4-((2,6-dioxopiperidin-3-yl)amino)-2- fluorophenyl)piperazine-1-carboxylate (140-1). A mixture of tert-butyl 4-(4-amino-2- fluorophenyl)piperazine-1-carboxylate (295 mg, 1.0 mmol), 3-bromopiperidine-2,6-dione (288 mg, 1.5 mmol) and DIPEA (695 µL, 4.0 mmol) in DMSO (6 mL) was stirred at 70 °C overnight. The resulting mixture was cooled to room temperature and diluted with EtOAc, then washed with water and sat. aq. NH4Cl. The organic layers were dried over Na2SO4, filtered and concentrated. The residue was purified by flash column chromatography (20% to 80% of EtOAc in hexanes) to afford 140-1 (290 mg, 71% yield) as a light-green solid. 1 H NMR (600 MHz, Chloroform-d) δ 8.00 (s, 1H), 6.87 (t, J = 8.9 Hz, 1H), 6.49 – 6.39 (m, 2H), 4.64 (d, J = 3.8 Hz, 1H), 4.03 (dt, J = 12.5, 4.4 Hz, 1H), 3.60 (t, J = 5.0 Hz, 4H), 3.00 – 2.86 (m, 5H), 2.77 (ddd, J = 18.2, 13.5, 5.2 Hz, 1H), 2.58 – 2.51 (m, 1H), 1.99 – 1.87 (m, 1H), 1.50 (s, 9H). LC/MS (ESI) m/z 407.1; [M+H] + calcd for C 20 H 28 N 4 O 4 + : 407.21. Step 2: Synthesis of 3-((3-fluoro-4-(piperazin-1-yl)phenyl)amino)piperidine-2,6-d ione hydrochloride (140-2). To a solution of 137-1 (100 mg, 0.246 mmol) in DCM (4 mL) was added a solution of 4 N HCl in dioxane (4 mL) and stirred at room temperature for 2 hours. The resulting mixture was concentrated to afford 140-2 (112 mg, quantitative yield), which was directly used in the next step. LC/MS (ESI) m/z 307.2; [M+H] + calcd for C 15 H 20 N 4 O 2 + : 307.16. Step 3: Synthesis of N-((4-(((R)-4-(1,4-oxazepan-4-yl)-1-(phenylthio)butan-2-yl)a mino)-3- ((trifluoromethyl)sulfonyl)phenyl)sulfonyl)-4-(4-(((4R)-4'-c hloro-4-((4-(4-((2,6- dioxopiperidin-3-yl)amino)-2-fluorophenyl)piperazin-1-yl)met hyl)-4-methyl-3,4,5,6- tetrahydro-[1,1'-biphenyl]-2-yl)methyl)piperazin-1-yl)benzam ide (compound #140). Intermediate B (15 mg, 0.015 mmol) and NaBH(OAc)3 (3 mg, 0.023 mmol) were added to a solution of 140-2 (10.3 mg, 0.03 mmol) and TEA (13 µL, 0.09 mmol) in DCM (1 mL), then stirred at room temperature overnight. The resulting mixture was washed with sat. aq. NH4Cl. The organic layers were dried over Na2SO4, filtered and concentrated. The residue was purified by preparative TLC (DCM/MeOH) to afford compound #140 (4.91 mg, 19% yield) as an off- white solid. 1 H NMR (599 MHz, Chloroform-d) δ 8.41 – 8.27 (m, 2H), 8.07 (dt, J = 9.2, 2.4 Hz, 1H), 7.78 – 7.70 (m, 2H), 7.41 – 7.35 (m, 2H), 7.34 – 7.21 (m, 6H), 7.09 (d, J = 8.6 Hz, 1H), 7.04 – 6.99 (m, 2H), 6.86 (td, J = 9.1, 2.4 Hz, 1H), 6.77 (dd, J = 9.1, 3.2 Hz, 2H), 6.58 (d, J = 9.3 Hz, 1H), 6.47 – 6.39 (m, 2H), 4.57 (s, 1H), 4.02 (dt, J = 12.4, 4.3 Hz, 1H), 3.95 – 3.85 (m, 1H), 3.82 – 3.69 (m, 4H), 3.26 (t, J = 5.6 Hz, 4H), 3.11 (dd, J = 13.9, 5.0 Hz, 1H), 3.07 – 2.95 (m, 5H), 2.92 – 2.58 (m, 12H), 2.57 – 2.21 (m, 11H), 2.16 – 2.06 (m, 1H), 2.01 – 1.87 (m, 4H), 1.83 – 1.72 (m, 1H), 1.71 – 1.60 (m, 1H), 1.51 – 1.42 (m, 1H), 0.99 (d, J = 2.0 Hz, 3H). LC/MS (ESI) m/z 1292.6; [M+H] + calcd for C63H75ClF4N9O8S3 + : 1292.45. Example 41: Preparation of compound #141
Compound #141 was prepared by following General Procedure C: tert-butyl 4-((4-(4-((2,6-dioxopiperidin-3-yl)amino)-2-fluorophenyl)pip erazin-1- yl)methyl)piperidine-1-carboxylate (141-1) (115 mg, 70% yield). 1 H NMR (600 MHz, Chloroform-d) δ 7.97 (s, 1H), 6.89 (t, J = 8.9 Hz, 1H), 6.49 – 6.39 (m, 2H), 4.61 (d, J = 3.7 Hz, 1H), 4.21 – 4.05 (m, 2H), 4.02 (dt, J = 12.5, 4.4 Hz, 1H), 3.02 (t, J = 5.3 Hz, 4H), 2.89 (ddd, J = 18.0, 4.5, 2.7 Hz, 1H), 2.81 – 2.66 (m, 2H), 2.64 – 2.51 (m, 5H), 2.26 (d, J = 7.2 Hz, 2H), 1.92 (qd, J = 13.5, 4.5 Hz, 1H), 1.77 (d, J = 13.2 Hz, 2H), 1.72 – 1.65 (m, 1H), 1.48 (s, 9H), 1.11 (qd, J = 12.4, 4.3 Hz, 2H). LC/MS (ESI) m/z 504.3; [M+H] + calcd for C 26 H 39 N 5 O 4 + : 504.30. 3-((3-fluoro-4-(4-(piperidin-4-ylmethyl)piperazin-1-yl)pheny l)amino)piperidine-2,6-dione hydrochloride (141-2) (20 mg, quantitative yield). LC/MS (ESI) m/z 404.2; [M+H] + calcd for C21H31N5O2 + : 404.25. N-((4-(((R)-4-(1,4-oxazepan-4-yl)-1-(phenylthio)butan-2-yl)a mino)-3- ((trifluoromethyl)sulfonyl)phenyl)sulfonyl)-4-(4-(((4R)-4'-c hloro-4-((4-((4-(4-((2,6- dioxopiperidin-3-yl)amino)-2-fluorophenyl)piperazin-1-yl)met hyl)piperidin-1-yl)methyl)-4- methyl-3,4,5,6-tetrahydro-[1,1'-biphenyl]-2-yl)methyl)pipera zin-1-yl)benzamide (compound #141) (3.89 mg, 14% yield). 1 H NMR (600 MHz, Chloroform-d) δ 8.36 (d, J = 1.8 Hz, 1H), 8.12 (s, 1H), 8.05 – 7.99 (m, 1H), 7.84 (d, J = 8.4 Hz, 2H), 7.41 – 7.36 (m, 2H), 7.34 – 7.22 (m, 6H), 7.00 (d, J = 8.3 Hz, 2H), 6.96 (d, J = 8.5 Hz, 1H), 6.86 (t, J = 9.0 Hz, 1H), 6.76 (d, J = 8.6 Hz, 2H), 6.49 – 6.39 (m, 3H), 4.62 (s, 1H), 4.02 (dd, J = 12.5, 4.7 Hz, 1H), 3.88 – 3.69 (m, 5H), 3.29 – 3.16 (m, 4H), 3.16 – 3.07 (m, 2H), 3.07 – 2.96 (m, 6H), 2.92 – 2.72 (m, 8H), 2.73 – 2.57 (m, 7H), 2.55 – 2.42 (m, 4H), 2.41 – 2.18 (m, 12H), 2.18 – 2.01 (m, 1H), 2.00 – 1.85 (m, 3H), 1.83 – 1.56 (m, 4H), 1.55 – 1.41 (m, 1H), 1.03 (s, 3H). LC/MS (ESI) m/z 1389.6; [M+H] + calcd for C69H86ClF4N10O8S3 + : 1389.54. Example 42. Cell Viability Assay Acute lymphoblastic leukemia cells (MOLT-4 and RS4;11) were incubated with increasing concentrations of Bcl-xL/Bcl-2 degraders for 48 h. Cell viability was measured by tetrazolium-based MTS assay. The IC 50 values of individual agents were calculated with GraphPad Prism and presented in Table 1. Table 1. Anti-cancer activity of compounds of Formula (I)
a +++++: < 1 nM; ++++: 1-10 nM; +++: 10-100 nM; ++: 100-10 µM; +: > 10 µM; ND: Not determined. Example 43: Cell viability assay of senescent cells To induce senescence in WI-38 and HUVEC, cells were subjected to x-ray irradiation at 20 Gray using X-RAD 320 biological irradiator. Following between 10 to 15 days after irradiation, senescence was induced in cells, and irradiation-induced senescent cells (IR-SC) were then used for cell viability and Western blotting tests. WI-38 and HUVEC cells were incubated with increasing concentrations of degraders for 72 h. Cell viability was measured using PrestoBlue HS cell viability reagent. The IC50 values of individual compounds were calculated with GraphPad Prism and presented in Table 1. Example 44: Protein degradation assays in Jurkat, Hela and WI-38 cells Jurkat and Hela cells were incubated with increasing concentrations of test compounds for 16 h. The cells were harvested and lysed in RIPA lysis buffer supplemented with protease and phosphatase inhibitor cocktails. An equal amount of protein (20 pg/lane) was resolved on a pre- cast 4-20% SDS-PAGE gel. Proteins were subsequently transferred to NOVEX PVDF membranes by electrophoresis. The membranes were blocked in blocking buffer (5% non-fat dry milk in TBS-T), and incubated with primary antibodies (at optimized concentrations) overnight at 4 °C. After three washings in TBS-T, the membranes were incubated with an appropriate FIRP-conjugated secondary antibody for 1 h at room temperature. After extensive washing for three times, the proteins of interest were detected with ECL western blotting detection reagents and recorded with autoradiography (Pierce Biotech, Rockford, IL, USA). The primary antibodies for Bcl-xL (Cat #2762), Bcl-2 (Cat #2872), Bcl-w (Cat #2724) and β-actin (Cat #4970) were purchased from Cell Signaling Technology. The relative band intensity was measured using ImageJ software and normalized to β-actin. Representative data are presented in FIGs.1A, 1B, 1C, and 2. 753B or 753b is a compound of the formula: . INCORPORATION BY REFERENCE The contents of all references (including literature references, issued patents, published patent applications, and co-pending patent applications) cited throughout this application are hereby expressly incorporated herein in their entireties by reference. EQUIVALENTS AND SCOPE In the claims and throughout, articles such as “a,” “an,” and “the” may mean one or more than one unless indicated to the contrary or otherwise evident from the context. Embodiments or descriptions that include “or” between one or more members of a group are considered satisfied if one, more than one, or all of the group members are present in, employed in, or otherwise relevant to a given product or process unless indicated to the contrary or otherwise evident from the context. The disclosure includes embodiments in which exactly one member of the group is present in, employed in, or otherwise relevant to a given product or process. The disclosure includes embodiments in which more than one, or all of the group members are present in, employed in, or otherwise relevant to a given product or process. Furthermore, the disclosure encompasses all variations, combinations, and permutations in which one or more limitations, elements, clauses, and descriptive terms from one or more of the listed claims is introduced into another claim. For example, any claim that is dependent on another claim can be modified to include one or more limitations found in any other claims that is dependent on the same base claim. Where elements are presented as lists, e.g., in Markush group format, each subgroup of the elements is also disclosed, and any element(s) can be removed from the group. It should it be understood that, in general, where the disclosure, or aspects of the disclosure, is/are referred to as comprising particular elements and/or features, certain embodiments of the disclosure or aspects of the disclosure consist, or consist essentially of, such elements and/or features. For purposes of simplicity, those embodiments have not been specifically set forth in haec verba herein. It is also noted that the terms “comprising,” “including,” and “containing,” and all other tenses thereof, are intended to be open and permits the inclusion of additional possibilities (e.g., elements or steps). Where ranges are given, endpoints are included. Furthermore, unless otherwise indicated or otherwise evident from the context and understanding of one of ordinary skill in the art, values that are expressed as ranges can assume any specific value or sub–range within the stated ranges in different embodiments of the disclosure, to the tenth of the unit of the lower limit of the range, unless the context clearly dictates otherwise. This application refers to various issued patents, published patent applications, journal articles, and other publications, all of which are incorporated herein by reference. If there is a conflict between any of the incorporated references and the instant specification, the specification shall control. In addition, any particular embodiment of the present disclosure that falls within the prior art may be explicitly excluded from any one or more of the embodiments. Because such embodiments are deemed to be known to one of ordinary skill in the art, they may be excluded even if the exclusion is not set forth explicitly herein. Any particular embodiment of the disclosure can be excluded from any embodiment, for any reason, whether or not related to the existence of prior art. Those skilled in the art will recognize or be able to ascertain using no more than routine experimentation many equivalents to the specific embodiments described herein. The scope of the present embodiments described herein is not intended to be limited to the above Description, but rather is as set forth in the appended embodiments. Those of ordinary skill in the art will appreciate that various changes and modifications to this description may be made without departing from the spirit or scope of the present disclosure, as defined in the following claims.
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