Targeted degrader molecules and ligand drug conjugates thereof

Abstract

Targeted degrader compounds are described, including Drug-Linker compounds, Ligand-Drug Conjugate compounds, methods of use, and preparations thereof.

Description

TARGETED DEGRADER MOLECULES AND LIGAND DRUG CONJUGATES THEREOF CROSS-REFERENCE TO RELATED APPLICATIONS

[0001] This application claims priority to and the benefit of U.S. Application No. 63 / 580,712, filed September 5, 2023, and U.S. Application No. 63 / 609,812, filed December 13, 2023, the disclosures of which are hereby incorporated by reference in their entirety for all purposes. BACKGROUND OF THE INVENTION

[0002] A variety of ligands have been investigated for the targeted delivery of cytotoxic agents to tumor cells, including oligopeptides, antibodies, and other proteins. While various drug classes have been evaluated for targeted delivery by these ligands, only a few drug classes have proved sufficiently active as Ligand-Drug Conjugates, while having a suitable toxicity profile and other pharmacological properties, to warrant clinical development. There is thus a need for additional molecules with improved toxicity profile and other pharmacological properties.

[0003] Proteolysis targeting chimeras (targeted degraders) are heterobifunctional molecules containing two active domains and a linker, which are capable of removing specific unwanted proteins. Targeting the bromodomain and extra-terminal domain (BET) family of proteins with targeted degraders has been reported to have potential anticancer activity. However, off-target effects can result in unwanted toxicities. Thus, there remains a need for targeted degraders, including BET-targeting degraders, with more effective targeting that reduces the off-target effects. BRIEF SUMMARY OF THE INVENTION

[0004] Provided herein is a compound of Formula (I):Formula (I), or a pharmaceutically acceptable salt thereof, wherein: X is CH, N, O, or S; Z1is H or absent; Z2is H; or Z1and Z2are taken together to form a single bond or a C1-C4alkylene group; provided that when X is O or S, Z1is absent; Y1and Y2are independently CH, CF, or N; Q is absent or C(O), NR11, S, SO2NR11, NR11SO2, O, C(O)O, or C(O)NR11; R1is H, halogen, OH, CN, N3, SH, COOR12, SO2R12, SO2NR11R12, or NR11R12; L2is absent or –CH2CH2(OCH2CH2)k–, -C1-C10alkylene-, 2- to 14-membered heteroalkylene-, -C3-C8carbocyclo-, -O(C1-C8 alkylene)-, -arylene-, -C1-C10 alkylene- arylene-, -arylene-C1-C10alkylene-, -C1-C10alkylene-(C3-C8carbocyclo)-, -(C3-C8carbocyclo)-C1-C10alkylene-, 3- to 12-membered heterocyclo-, -C1-C10alkylene-( 3- to 12- membered heterocyclo)-, -( 3- to 12-membered heterocyclo)-C1-C10 alkylene, -C2-C10alkenylene-, 3- to 14-membered heteroalkenylene-, -O(C2-C8alkenylene)-, -C2-C10alkenylene-arylene-, -arylene-C2-C10alkenylene-, -C2-C10alkenylene-(C3-C8carbocyclo)-, - (C3-C8 carbocyclo)-C2-C10alkenylene-, -C2-C10alkenylene-(3- to 12-membered heterocyclo)- , -(3- to 12-membered heterocyclo)-C2-C10alkenylene, -C2-C10alkynylene-, 3- to 14- membered heteroalkynylene-, -O(C2-C8alkynylene)-, -C2-C10alkynylene-arylene-, -arylene- C2-C10alkynylene-, -C2-C10alkynylene-(C3-C8carbocyclo)-, -(C3-C8carbocyclo)-C2-C10alkynylene-, -C2-C10alkynylene-(3- to 12-membered heterocyclo)-, or -(3- to 12-membered heterocyclo)-C2-C10alkynylene, each of which is optionally substituted; subscript k is an integer ranging from 1 to 36, provided that QL2R1is not H; and R2is optionally substituted C1-C6 alkyl; R3is C3-C8 cycloalkyl, -C1-C10 alkylene-(C3-C8 cycloalkyl), C3-C8 cycloalkenyl, -C1-C10 alkylene-(C3-C8cycloalkenyl), C6-C14aryl, -C1-C10alkylene-(C6-C14aryl), 5- to 10- membered heteroaryl, -C1-C10 alkylene-(5- to 10-membered heteroaryl), 3- to 12-membered heterocyclyl, or -C1-C10 alkylene (3- to 12-membered heterocyclyl), wherein the C3-C8 cycloalkyl, -C1-C10alkylene-(C3-C8cycloalkyl), C6-C14aryl, -C1-C10alkylene-(C6-C14aryl), 5- to 10-membered heteroaryl, -C1-C10alkylene-(5- to 10-membered heteroaryl), 3- to 12- membered heterocyclyl, or -C1-C10 alkylene (3- to 12-membered heterocyclyl) are optionally substituted by halo, OH, CN, C1-C6 alkyl, or C1-C6 haloalkyl; R4is -NHSO2R12or -CH2SO2R12; R5is H or halo; R6is H or optionally substituted C1-C6 alkyl; R7and R8are each H, or R7and R8, taken together with the carbon to which they are attached, form a carbonyl or 3- to 6-membered carbocycle; R9, R10a, and R10bare each independently H, halo, optionally substituted C1-C6alkyl, C3-C8cycloalkyl, or C1-C6haloalkyl; L1is a linking group having the structure:wherein W1is C2-C6alkenylene, C2-C6alkynylene, optionally substituted 5- to 10- membered heteroarylene, optionally substituted 3- to 12-membered heterocyclene, CO, CONR11, C(O)O, SO2NR11, or absent; W2is, independently at each occurrence, O, S, NR11, -COO-, -OCO-, -CONR11-, - NR11CO-, -SO2NR11-, -NR11SO2-, optionally substituted C3-C8cycloalkylene, optionally substituted C3-C8 cycloalkenylene, optionally substituted C6-C14 arylene, optionallysubstituted 5- to 10-membered heteroarylene, optionally substituted 3- to 12-membered heterocyclylene, or absent; W3is, independently at each occurrence, O, S, NR11, optionally substituted C1-C10 alkylene, optionally substituted C2-C10alkenylene, optionally substituted C2-C10alkynylene, optionally substituted 2- to 14-membered heteroalkylene, or absent; subscript n is an integer from 1 to 6; * indicates the point of attachment to * in Formula (I); ** indicates the point of attachment to ** in Formula (I); provided that at least one of W1, W2, and W3is not absent; and R11and R12are, independently of each other and independently at each occurrence, H, halo, C1-C6alkyl, C1-C6haloalkyl, C1-C6alkoxy, or C3-C8cycloalkyl.

[0005] In some embodiments of Formula (I), Y1and Y2are CH or CF. In some embodiments, Y1and Y2are CH.

[0006] In some embodiments of Formula (I), X is O or S, Z1is absent, and Z2is H. In some embodiments, X is CH or N, Z1is H, and Z2is H. In some embodiments, X is CH or N and Z1and Z2are taken together to form a single bond or a C1-C4 alkylene group.

[0007] In some embodiments of Formula (I), the compound is a compound of Formula (IIa):wherein X is CH or N.

[0008] In some embodiments of Formula (I), the compound is a compound of Formula (IIb):Formula (IIb), wherein Z1is H or absent.

[0009] In some embodiments of Formula (I), R9, R10a, and R10bare each independently H, halo, or optionally substituted C1-C6 alkyl. In some embodiments of Formula (I), R9, R10a, and R10bare each H.

[0010] In some embodiments of Formula (I), the compound is a compound of Formula (IIIa):Formula (IIIa), wherein X is CH or N.

[0011] In some embodiments of Formula (I), the compound is a compound of Formula (IIIa-R):Formula (IIIa-R), wherein X is CH or N.

[0012] In some embodiments of Formula (I), the compound is a compound of Formula (IIIa-S):wherein X is CH or N.

[0013] In some embodiments of Formula (I), the compound is a compound of Formula (IIIa-4):wherein X is CH or N.

[0014] In some embodiments of Formula (I), the compound is a compound of Formula (IIIa-5):wherein X is CH or N.

[0015] In some embodiments of Formula (I), X is N.

[0016] In some embodiments of Formula (I), the compound is a compound of Formula (IIIb):wherein Z1is absent or H.

[0017] In some embodiments of Formula (I), the compound is a compound of Formula (IIIb-R):wherein Z1is absent or H.

[0018] In some embodiments of Formula (I), the compound is a compound of Formula (IIIb-S):wherein Z1is absent or H.

[0019] In some embodiments of Formula (I), the compound is a compound of Formula (IIIb-4):wherein Z1is absent or H.

[0020] In some embodiments of Formula (I), the compound is a compound of Formula (IIIb-5):wherein Z1is absent or H.

[0021] In some embodiments of Formula (I), X is N or CH and Z1is H. In some embodiments, X is N and Z1is H. In some embodiments, X is O or S and Z1is absent. In some embodiments, X is O and Z1is absent.

[0022] In some embodiments of Formula (I), R2is methyl.

[0023] In some embodiments of Formula (I), R4is -NHSO2CH3or -CH2SO2CH3.

[0024] In some embodiments of Formula (I), R5is H.

[0025] In some embodiments of Formula (I), R6is H or methyl.

[0026] In some embodiments of Formula (I), R7and R8are each H. In some embodiments of Formula (I), R7and R8are taken together with the carbon to which they are attached to form a carbonyl.

[0027] In some embodiments of Formula (I), R3is C3-C8cycloalkyl, -C1-C10alkylene- (C3-C8cycloalkyl), C6-C14aryl, -C1-C10alkylene-(C6-C14aryl), 5- to 10-membered heteroaryl, or -C1-C10 alkylene-(5- to 10-membered heteroaryl). In some embodiments ofFormula (I), R3is C3-C8cycloalkyl, -C1-C10alkylene-(C3-C8cycloalkyl), or C6-C14aryl. R3is cyclohexyl, -CH2-(cyclopropyl), or phenyl.

[0028] In some embodiments of Formula (I), Q is absent, C(O), NR11, C(O)O, or C(O)NR11; L2is –CH2CH2(OCH2CH2)k–, -C1-C10alkylene-, -C3-C8carbocyclo-, -C1-C10alkylene-(C3-C8 carbocyclo)-, -(C3-C8 carbocyclo)-C1-C10 alkylene-, -C2-C10alkenylene-, - C2-C10alkenylene-(C3-C8 carbocyclo)-, -(C3-C8 carbocyclo)-C2-C10alkenylene-, -C2-C10alkynylene-, -C2-C10alkynylene-(C3-C8carbocyclo)-, or -(C3-C8carbocyclo)-C2-C10alkynylene-; and R1is OH, COOR12, or NR11R12.

[0029] In some embodiments of Formula (I), Q is C(O)NR11; L2is -C1-C10 alkylene-, -C1- C10alkylene-(C3-C8carbocyclo)-, -(C3-C8carbocyclo)-C1-C10alkylene-, -C2-C10alkenylene-, or -C2-C10alkynylene-; and R1is NR11R12.

[0030] In some embodiments of Formula (I), L2is -C1-C10 alkylene-.

[0031] In some embodiments of Formula (I), Q is CONH; L2is -CH2CH2-; and R1is NH2.

[0032] In some embodiments of Formula (I), L1is *-W3-W1-**, *-W3-W2-W3-W1-**, *- W3-W2-W2-W1-**, *-W3-W2-W1-**, *-W3-W2-W3-W2-W1-**, or *-W3-W2-W3-W2-W3-W2- W1-**. In some embodiments of Formula (I), L1is *-W3-W1-**, *-W3-W2-W3-W1-**, or *- W3-W2-W2-W1-**.

[0033] In some embodiments of Formula (I), W1is C2-C6 alkenylene, C2-C6 alkynylene, CO, CONR11, or absent; W2is, independently at each occurrence, O, NR11, -CONR11-, -NR11CO-, optionally substituted C3-C8 cycloalkylene, optionally substituted C3-C8 cycloalkenylene, optionally substituted 3- to 12-membered heterocyclylene, or absent; W3is, independently at each occurrence, O, NR11, optionally substituted C1-C10alkylene, optionally substituted C2-C10alkenylene, optionally substituted C2-C10alkynylene, optionally substituted 2- to 14-membered heteroalkylene, or absent; and subscript n is an integer from 1 to 3; provided that at least one of W1, W2, and W3is not absent.

[0034] In some embodiments of Formula (I), W1is CO or CONR11;W2is, independently at each occurrence, O, NR11, optionally substituted C3-C8cycloalkylene, optionally substituted 3- to 12-membered heterocyclylene, or absent; W3is, independently at each occurrence, O, NR11, optionally substituted C1-C10 alkylene, or absent; and subscript n is an integer from 1 to 3.

[0035] In some embodiments of Formula (I), L1is selected from the group consisting of: ,

[0036] In some embodiments of Formula (I), R2is methyl, R4is -CH2SO2CH3, R5is H, R6is H, R7and R8are H, R3is -C1-C10 alkylene-(C3-C8 cycloalkyl), Q is CONR11, L2is -C1- C10 alkylene-, R1is NR11R12, and L1is

[0037] In some embodiments of Formula (I), R2is methyl, R4is -NHSO2CH3, R5is H, R6is H, R7and R8are H, R3is C3-C8 cycloalkyl, Q is CONR11, L2is -C1-C10 alkylene-, R1is

[0038] In some embodiments of Formula (I), the compound is selected from the group consisting of: ,

[0039] In some embodiments, the compound is a compound of Table 1.

[0040] In another aspect, provided herein is a Drug-Linker compound of the following formula: Z'-A-D, or a pharmaceutically acceptable salt thereof, wherein Z' is a Stretcher Unit precursor; A is a bond or a Connector Unit; and D is a Drug Unit of Formula (I'):Formula (I'), wherein: X is CH, N, O, or S; Z1is H or absent; Z2is H; or Z1and Z2are taken together to form a single bond or a C1-C4 alkylene group; provided that when X is O or S, Z1is absent; Y1and Y2are independently CH, CF, or N; Q is absent or C(O), NR11, S, SO2NR11, NR11SO2, O, C(O)O, or C(O)NR11; R1is O, S, COO, SO2, SO2NR11, or NR11; L2is absent or –CH2CH2(OCH2CH2)k–, -C1-C10alkylene-, 2- to 14-membered heteroalkylene-, -C3-C8 carbocyclo-, -O(C1-C8 alkylene)-, -arylene-, -C1-C10 alkylene- arylene-, -arylene-C1-C10 alkylene-, -C1-C10 alkylene-(C3-C8 carbocyclo)-, -(C3-C8 carbocyclo)-C1-C10alkylene-, 3- to 12-membered heterocyclo-, -C1-C10alkylene-( 3- to 12-membered heterocyclo)-, -( 3- to 12-membered heterocyclo)-C1-C10alkylene, - C2-C10alkenylene-, 3- to 14-membered heteroalkenylene-, -O(C2-C8 alkenylene)-, - C2-C10alkenylene-arylene-, -arylene-C2-C10alkenylene-, -C2-C10alkenylene-(C3-C8carbocyclo)-, -(C3-C8carbocyclo)-C2-C10alkenylene-, -C2-C10alkenylene-(3- to 12-membered heterocyclo)-, -(3- to 12-membered heterocyclo)-C2-C10alkenylene, -C2- C10 alkynylene-, 3- to 14-membered heteroalkynylene-, -O(C2-C8 alkynylene)-, -C2- C10 alkynylene-arylene-, -arylene-C2-C10alkynylene-, -C2-C10alkynylene-(C3-C8 carbocyclo)-, -(C3-C8carbocyclo)-C2-C10alkynylene-, -C2-C10alkynylene-(3- to 12- membered heterocyclo)-, or -(3- to 12-membered heterocyclo)-C2-C10alkynylene, each of which is optionally substituted; subscript k is an integer ranging from 1 to 36, wherein # denotes the point of attachment to A; and R2is optionally substituted C1-C6 alkyl; R3is C3-C8cycloalkyl, -C1-C10alkylene-(C3-C8cycloalkyl), C3-C8cycloalkenyl, -C1- C10alkylene-(C3-C8cycloalkenyl), C6-C14aryl, -C1-C10alkylene-(C6-C14aryl), 5- to 10- membered heteroaryl, -C1-C10 alkylene-(5- to 10-membered heteroaryl), 3- to 12-membered heterocyclyl, or -C1-C10 alkylene (3- to 12-membered heterocyclyl), wherein the C3-C8 cycloalkyl, -C1-C10alkylene-(C3-C8cycloalkyl), C6-C14aryl, -C1-C10alkylene-(C6-C14aryl), 5- to 10-membered heteroaryl, -C1-C10 alkylene-(5- to 10-membered heteroaryl), 3- to 12- membered heterocyclyl, or -C1-C10 alkylene (3- to 12-membered heterocyclyl) are optionally substituted by halo, OH, CN, C1-C6alkyl, or C1-C6haloalkyl; R4is -NHSO2R12or -CH2SO2R12; R5is H or halo; R6is H or optionally substituted C1-C6alkyl; R7and R8are each H, or R7and R8, taken together with the carbon to which they are attached, form a carbonyl or 3- to 6-membered carbocycle; R9, R10a, and R10bare each independently H, halo, optionally substituted C1-C6alkyl, C3-C8 cycloalkyl, or C1-C6 haloalkyl; L1is a linking group having the structure:** ; wherein W1is C2-C6alkenylene, C2-C6alkynylene, optionally substituted 5- to 10- membered heteroarylene, optionally substituted 3- to 12-membered heterocyclene, CO, CONR11, C(O)O, SO2NR11, or absent; W2is, independently at each occurrence, O, S, NR11, -COO-, -OCO-, -CONR11-, - NR11CO-, -SO2NR11-, -NR11SO2-, optionally substituted C3-C8 cycloalkylene, optionally substituted C3-C8 cycloalkenylene, optionally substituted C6-C14 arylene, optionallysubstituted 5- to 10-membered heteroarylene, optionally substituted 3- to 12-membered heterocyclylene, or absent; W3is, independently at each occurrence, O, S, NR11, optionally substituted C1-C10 alkylene, optionally substituted C2-C10alkenylene, optionally substituted C2-C10alkynylene, optionally substituted 2- to 14-membered heteroalkylene, or absent; subscript n is an integer from 1 to 6; * indicates the point of attachment to * in Formula (I); ** indicates the point of attachment to ** in Formula (I); provided that at least one of W1, W2, and W3is not absent; and R11and R12are, independently of each other and independently at each occurrence, H, halo, C1-C6alkyl, C1-C6haloalkyl, C1-C6alkoxy, or C3-C8cycloalkyl.

[0041] In some embodiments, the Stretcher Unit Z' iswherein R17is –CH2CH2(OCH2CH2)k–, -C1-C10 alkylene-, C1-C10 heteroalkylene-, -C3-C8 carbocyclo-, -O-(C1-C8alkylene)-, -arylene-, -C1-C10alkylene-arylene-, -arylene-C1-C10alkylene-, -C1- C10alkylene-(C3-C8carbocyclo)-, -(C3-C8carbocyclo)-C1-C10alkylene-, -C3-C8heterocyclo-, -C1-C10 alkylene-(C3-C8 heterocyclo)-, -(C3-C8 heterocyclo)-C1-C10 alkylene-, -C1-C10 alkylene-C(=O)-, C1-C10heteroalkylene-C(=O)-, -C3-C8carbocyclo-C(=O)-, -O-(C1-C8alkylene)-C(=O)-, -arylene-C(=O)-, -C1-C10alkylene-arylene-C(=O)-, -arylene-C1-C10alkylene-C(=O)-, -C1-C10 alkylene-(C3-C8 carbocyclo)-C(=O)-,-(C3-C8 carbocyclo)-C1-C10 alkylene-C(=O)-, -C3-C8heterocyclo-C(=O)-, -C1-C10alkylene-(C3-C8heterocyclo)-C(=O)-, - (C3-C8heterocyclo)-C1-C10alkylene-C(=O)-, -C1-C10alkylene-NH-, C1-C10heteroalkylene- NH-, -C3-C8 carbocyclo-NH-, -O-(C1-C8 alkylene)-NH-, -arylene-NH-, -C1-C10 alkylene- arylene-NH-, -arylene-C1-C10 alkylene-NH-, -C1-C10 alkylene-(C3-C8 carbocyclo)-NH-, -(C3- C8carbocyclo)-C1-C10alkylene-NH-, -C3-C8heterocyclo-NH-, -C1-C10alkylene-(C3-C8heterocyclo)-NH-, -(C3-C8 heterocyclo)-C1-C10 alkylene-NH-, -C1-C10 alkylene-S-, C1-C10 heteroalkylene-S -, -C3-C8 carbocyclo-S -, -O-(C1-C8 alkylene)-S -, -arylene-S-, -C1-C10alkylene-arylene-S-, -arylene-C1-C10alkylene-S-, -C1-C10alkylene-(C3-C8carbocyclo)-S-, - (C3-C8 carbocyclo)-C1-C10 alkylene-S-, -C3-C8 heterocyclo-S-, -C1-C10 alkylene-(C3-C8 heterocyclo)-S-, or -(C3-C8 heterocyclo)-C1-C10 alkylene-S-; subscript k is an integer ranging from 1 to 36; R17is optionally substituted by a Basic Unit (BU) such as an aminoalkyl moiety, wherein x is an integer of from 1-4 and each Rais independently selected from the group consisting of C1-6 alkyl and C1-6haloalkyl, or two Ragroups are combined with the nitrogen to which they are attached to form an azetidinyl, pyrrolidinyl or piperidinyl group; and the wavy line indicates the point of covalent attachment to the rest of the Drug-Linker compound.

[0042] In some embodiments, the Stretcher Unit Z' is, wherein the wavy lines indicate the point of covalent attachment to the rest of the Drug- Linker compound.

[0043] In some embodiments, the Connector Unit A is, wherein each R100is independently hydrogen or -C1-C3 alkyl; R111is independently selected from the group consisting of hydrogen, p-hydroxybenzyl, methyl, isopropyl, isobutyl, sec-butyl, -CH2OH, -CH(OH)CH3, -CH2CH2SCH3, -CH2CONH2, -CH2COOH, -CH2CH2CONH2, -CH2CH2COOH, -(CH2)3NHC(=NH)NH2, -(CH2)3NH2, - (CH2)3NHCOCH3, -(CH2)3NHCHO, -(CH2)4NHC(=NH)NH2, -(CH2)4NH2, - (CH2)4NHCOCH3, -(CH2)4NHCHO, -(CH2)3NHCONH2, -(CH2)4NHCONH2, - CH2CH2CH(OH)CH2NH2, 2-pyridylmethyl-, 3-pyridylmethyl-, 4-pyridylmethyl-,each subscript c is an independently selected integer from 1 to 10; and the wavy lines indicate attachment of the Connector Unit to the rest of the Drug-Linker compound.

[0044] In some embodiments, the Connector Unit A isc is an integer ranging from 1 to 6; and the wavy lines indicate the site of attachment to the rest of the Drug-Linker compound or pharmaceutically acceptable salt thereof.

[0045] In some embodiments, A is a bond.

[0046] In some embodiments,R17is C1-C10alkylene; A is a bond; and the wavy lines indicate the site of attachment to the rest of the Drug-Linker compound or pharmaceutically acceptable salt thereof.

[0047] In some embodiments,.

[0048] In some embodiments, X is N or CH and Z1is H. In some embodiments, X is N and Z1is H. In some embodiments, X is O or S and Z1is absent, preferably wherein X is O and Z1is absent.

[0049] In some embodiments, R2is methyl, R4is -NHSO2CH3 or -CH2SO2CH3, R5is H, and R6is H or methyl.

[0050] In some embodiments, R7and R8are each H, or R7and R8are taken together with the carbon to which they are attached to form a carbonyl.

[0051] In some embodiments, R3is C3-C8cycloalkyl, -C1-C10alkylene-(C3-C8cycloalkyl), C6-C14 aryl, -C1-C10 alkylene-(C6-C14 aryl), 5- to 10-membered heteroaryl, or - C1-C10 alkylene-(5- to 10-membered heteroaryl). In some embodiments, R3is C3-C8 cycloalkyl, -C1-C10alkylene-(C3-C8cycloalkyl), or C6-C14aryl. In some embodiments, R3is cyclohexyl, -CH2-(cyclopropyl), or phenyl.

[0052] In some embodiments, Q is absent, C(O), NR11, C(O)O, or C(O)NR11; L2is –CH2CH2(OCH2CH2)k–, -C1-C10alkylene-, -C3-C8carbocyclo-, -C1-C10alkylene-(C3-C8carbocyclo)-, -(C3-C8 carbocyclo)-C1-C10 alkylene-, -C2-C10alkenylene-, -C2-C10alkenylene- (C3-C8 carbocyclo)-, -(C3-C8 carbocyclo)-C2-C10alkenylene-, -C2-C10alkynylene-, -C2-C10alkynylene-(C3-C8carbocyclo)-, or -(C3-C8carbocyclo)-C2-C10alkynylene-; and R1is OH, COOR12, or NR11.

[0053] In some embodiments, L1is *-W3-W1-**, *-W3-W2-W3-W1-**, *-W3-W2-W2-W1- **, *-W3-W2-W1-**, *-W3-W2-W3-W2-W1-**, or *-W3-W2-W3-W2-W3-W2-W1-**.

[0054] In some embodiments, W1is CO or CONR11; W2is, independently at each occurrence, O, NR11, optionally substituted C3-C8 cycloalkylene, optionally substituted 3- to 12-membered heterocyclylene, or absent; W3is, independently at each occurrence, O, NR11, optionally substituted C1-C10alkylene, or absent; and subscript n is an integer from 1 to 3.

[0055] In some embodiments, L1is selected from the group consisting of:, and .

[0056] In some embodiments, the compound isor a pharmaceutically acceptable salt thereof.

[0057] In some embodiments, the Drug-Linker compound is a compound of Table 2.

[0058] Also provided herein is a Ligand-Drug Conjugate compound, or a pharmaceutically acceptable salt thereof, comprising a Drug Unit of Formula (I'):Formula (I), wherein: X is CH, N, O, or S;Z1is H or absent; Z2is H; or Z1and Z2are taken together to form a single bond or a C1-C4 alkylene group; provided that when X is O or S, Z1is absent; Y1and Y2are independently CH, CF, or N; Q is absent or C(O), NR11, S, SO2NR11, NR11SO2, O, C(O)O, or C(O)NR11; R1is O, S, COO, SO2, SO2NR11, or NR11; L2is absent or –CH2CH2(OCH2CH2)k–, -C1-C10 alkylene-, 2- to 14-membered heteroalkylene-, -C3-C8 carbocyclo-, -O(C1-C8 alkylene)-, -arylene-, -C1-C10 alkylene- arylene-, -arylene-C1-C10alkylene-, -C1-C10alkylene-(C3-C8carbocyclo)-, -(C3-C8carbocyclo)-C1-C10alkylene-, 3- to 12-membered heterocyclo-, -C1-C10alkylene-( 3- to 12-membered heterocyclo)-, -( 3- to 12-membered heterocyclo)-C1-C10 alkylene, - C2-C10alkenylene-, 3- to 14-membered heteroalkenylene-, -O(C2-C8 alkenylene)-, - C2-C10alkenylene-arylene-, -arylene-C2-C10alkenylene-, -C2-C10alkenylene-(C3-C8carbocyclo)-, -(C3-C8 carbocyclo)-C2-C10alkenylene-, -C2-C10alkenylene-(3- to 12- membered heterocyclo)-, -(3- to 12-membered heterocyclo)-C2-C10alkenylene, -C2- C10alkynylene-, 3- to 14-membered heteroalkynylene-, -O(C2-C8alkynylene)-, -C2- C10 alkynylene-arylene-, -arylene-C2-C10alkynylene-, -C2-C10alkynylene-(C3-C8 carbocyclo)-, -(C3-C8 carbocyclo)-C2-C10alkynylene-, -C2-C10alkynylene-(3- to 12- membered heterocyclo)-, or -(3- to 12-membered heterocyclo)-C2-C10alkynylene, each of which is optionally substituted; subscript k is an integer ranging from 1 to 36, wherein # denotes the point of attachment to the reminder of the Ligand-Drug Conjugate compound; and R2is optionally substituted C1-C6 alkyl; R3is C3-C8 cycloalkyl, -C1-C10 alkylene-(C3-C8 cycloalkyl), C3-C8 cycloalkenyl, -C1- C10alkylene-(C3-C8cycloalkenyl), C6-C14aryl, -C1-C10alkylene-(C6-C14aryl), 5- to 10- membered heteroaryl, -C1-C10 alkylene-(5- to 10-membered heteroaryl), 3- to 12-membered heterocyclyl, or -C1-C10 alkylene (3- to 12-membered heterocyclyl), wherein the C3-C8 cycloalkyl, -C1-C10alkylene-(C3-C8cycloalkyl), C6-C14aryl, -C1-C10alkylene-(C6-C14aryl), 5- to 10-membered heteroaryl, -C1-C10alkylene-(5- to 10-membered heteroaryl), 3- to 12- membered heterocyclyl, or -C1-C10 alkylene (3- to 12-membered heterocyclyl) are optionally substituted by halo, OH, CN, C1-C6 alkyl, or C1-C6 haloalkyl; R4is -NHSO2R12or -CH2SO2R12;R5is H or halo; R6is H or optionally substituted C1-C6 alkyl; R7and R8are each H, or R7and R8, taken together with the carbon to which they are attached, form a carbonyl or 3- to 6-membered carbocycle; R9, R10a, and R10bare each independently H, halo, optionally substituted C1-C6 alkyl, C3-C8cycloalkyl, or C1-C6haloalkyl; L1is a linking group having the structure:** ; wherein W1is C2-C6 alkenylene, C2-C6 alkynylene, optionally substituted 5- to 10- membered heteroarylene, optionally substituted 3- to 12-membered heterocyclene, CO, CONR11, C(O)O, SO2NR11, or absent; W2is, independently at each occurrence, O, S, NR11, -COO-, -OCO-, -CONR11-, - NR11CO-, -SO2NR11-, -NR11SO2-, optionally substituted C3-C8cycloalkylene, optionally substituted C3-C8 cycloalkenylene, optionally substituted C6-C14 arylene, optionally substituted 5- to 10-membered heteroarylene, optionally substituted 3- to 12-membered heterocyclylene, or absent; W3is, independently at each occurrence, O, S, NR11, optionally substituted C1-C10alkylene, optionally substituted C2-C10alkenylene, optionally substituted C2-C10alkynylene, optionally substituted 2- to 14-membered heteroalkylene, or absent; subscript n is an integer from 1 to 6; * indicates the point of attachment to * in Formula (I); ** indicates the point of attachment to ** in Formula (I); provided that at least one of W1, W2, and W3is not absent; and R11and R12are, independently of each other and independently at each occurrence, H, halo, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy, or C3-C8 cycloalkyl.

[0059] In some embodiments, the Ligand-Drug Conjugate compound has the formula: L-(Z-A-D)por a pharmaceutically acceptable salt thereof, wherein L is a Ligand Unit; Z is a Stretcher Unit; A is a bond or a Connector Unit;D is the Drug Unit of Formula (I'); and subscript p is an integer ranging from 1 to 12.

[0060] In some embodiments, the Ligand Unit L and the Stretcher Unit Z together are, wherein R17is –CH2CH2(OCH2CH2)k–, -C1-C10alkylene-, C1-C10heteroalkylene-, -C3-C8carbocyclo-, -O-(C1-C8alkylene)-, -arylene-, -C1-C10alkylene-arylene-, -arylene-C1-C10alkylene-, -C1- C10 alkylene-(C3-C8 carbocyclo)-, -(C3-C8 carbocyclo)-C1-C10 alkylene-, -C3-C8 heterocyclo-, -C1-C10alkylene-(C3-C8heterocyclo)-, -(C3-C8heterocyclo)-C1-C10alkylene-, -C1-C10alkylene-C(=O)-, C1-C10heteroalkylene-C(=O)-, -C3-C8carbocyclo-C(=O)-, -O-(C1-C8alkylene)-C(=O)-, -arylene-C(=O)-, -C1-C10 alkylene-arylene-C(=O)-, -arylene-C1-C10 alkylene-C(=O)-, -C1-C10 alkylene-(C3-C8 carbocyclo)-C(=O)-,-(C3-C8 carbocyclo)-C1-C10 alkylene-C(=O)-, -C3-C8heterocyclo-C(=O)-, -C1-C10alkylene-(C3-C8heterocyclo)-C(=O)-, - (C3-C8 heterocyclo)-C1-C10 alkylene-C(=O)-, -C1-C10 alkylene-NH-, C1-C10 heteroalkylene- NH-, -C3-C8 carbocyclo-NH-, -O-(C1-C8 alkylene)-NH-, -arylene-NH-, -C1-C10 alkylene- arylene-NH-, -arylene-C1-C10alkylene-NH-, -C1-C10alkylene-(C3-C8carbocyclo)-NH-, -(C3- C8carbocyclo)-C1-C10alkylene-NH-, -C3-C8heterocyclo-NH-, -C1-C10alkylene-(C3-C8heterocyclo)-NH-, -(C3-C8 heterocyclo)-C1-C10 alkylene-NH-, -C1-C10 alkylene-S-, C1-C10 heteroalkylene-S -, -C3-C8carbocyclo-S -, -O-(C1-C8alkylene)-S -, -arylene-S-, -C1-C10alkylene-arylene-S-, -arylene-C1-C10alkylene-S-, -C1-C10alkylene-(C3-C8carbocyclo)-S-, -(C3-C8carbocyclo)-C1-C10alkylene-S-, -C3-C8heterocyclo-S-, -C1-C10alkylene-(C3-C8heterocyclo)-S-, or -(C3-C8 heterocyclo)-C1-C10 alkylene-S-; subscript k is an integer ranging from 1 to 36; R17is optionally substituted by a Basic Unit (BU) such as an aminoalkyl moiety, wherein x is an integer of from 1-4 and each Rais independently selected from the group consisting of C1-6 alkyl and C1-6 haloalkyl, or two Ragroups are combined with the nitrogen to which they are attached to form an azetidinyl, pyrrolidinyl or piperidinyl group; and the wavy line indicates the point of covalent attachment to the rest of the Ligand-Drug Conjugate compound.

[0061] In some embodiments, the Ligand Unit L and the Stretcher Unit Z together arewherein the wavy lines indicate the point of covalent attachment to the rest of the Ligand- Drug Conjugate compound.

[0062] In some embodiments, the Connector Unit A iswherein each R100is independently hydrogen or -C1-C3 alkyl; R111is independently selected from the group consisting of hydrogen, p-hydroxybenzyl, methyl, isopropyl, isobutyl, sec-butyl, -CH2OH, -CH(OH)CH3, -CH2CH2SCH3, -CH2CONH2, -CH2COOH, -CH2CH2CONH2, -CH2CH2COOH, -(CH2)3NHC(=NH)NH2, -(CH2)3NH2, -(CH2)3NHCOCH3, -(CH2)3NHCHO, -(CH2)4NHC(=NH)NH2, -(CH2)4NH2, - (CH2)4NHCOCH3, -(CH2)4NHCHO, -(CH2)3NHCONH2, -(CH2)4NHCONH2, - CH2CH2CH(OH)CH2NH2, 2-pyridylmethyl-, 3-pyridylmethyl-, 4-pyridylmethyl-,each subscript c is an independently selected integer from 1 to 10; and the wavy lines indicate attachment of the Connector Unit to the rest of the Ligand-Drug Conjugate compound or pharmaceutically acceptable salt thereof.

[0063] In some embodiments, the Connector Unit A isc is an integer ranging from 1 to 6; and the wavy lines indicate the site of attachment to the rest of the Ligand-Drug Conjugate compound or pharmaceutically acceptable salt thereof.

[0064] In some embodiments, A is a bond.

[0065] In some embodiments, R17is C1-C10 alkylene; and A is a bond.

[0066] In some embodiments, the Ligand Unit L and Z-A- together are.

[0067] In some embodiments, X is N or CH and Z1is H. In some embodiments, X is N and Z1is H. In some embodiments, X is O or S and Z1is absent, preferably wherein X is O and Z1is absent.

[0068] In some embodiments, R2is methyl, R4is -NHSO2CH3 or -CH2SO2CH3, R5is H, and R6is H or methyl.

[0069] In some embodiments, R7and R8are each H, or R7and R8are taken together with the carbon to which they are attached to form a carbonyl.

[0070] In some embodiments, R3is C3-C8cycloalkyl, -C1-C10alkylene-(C3-C8cycloalkyl), C6-C14aryl, -C1-C10alkylene-(C6-C14aryl), 5- to 10-membered heteroaryl, or - C1-C10 alkylene-(5- to 10-membered heteroaryl). R3is C3-C8 cycloalkyl, -C1-C10 alkylene- (C3-C8 cycloalkyl), or C6-C14 aryl. R3is cyclohexyl, -CH2-(cyclopropyl), or phenyl.

[0071] In some embodiments, Q is absent, C(O), NR11, C(O)O, or C(O)NR11; L2is –CH2CH2(OCH2CH2)k–, -C1-C10 alkylene-, -C3-C8 carbocyclo-, -C1-C10 alkylene-(C3-C8 carbocyclo)-, -(C3-C8 carbocyclo)-C1-C10 alkylene-, -C2-C10alkenylene-, -C2-C10alkenylene- (C3-C8carbocyclo)-, -(C3-C8carbocyclo)-C2-C10alkenylene-, -C2-C10alkynylene-, -C2-C10alkynylene-(C3-C8carbocyclo)-, or -(C3-C8carbocyclo)-C2-C10alkynylene-; and R1is OH, COOR12, or NR11.

[0072] In some embodiments, L1is *-W3-W1-**, *-W3-W2-W3-W1-**, *-W3-W2-W2-W1- **, *-W3-W2-W1-**, *-W3-W2-W3-W2-W1-**, or *-W3-W2-W3-W2-W3-W2-W1-**.

[0073] In some embodiments, W1is CO or CONR11; W2is, independently at each occurrence, O, NR11, optionally substituted C3-C8cycloalkylene, optionally substituted 3- to 12-membered heterocyclylene, or absent; W3is, independently at each occurrence, O, NR11, optionally substituted C1-C10 alkylene, or absent; and subscript n is an integer from 1 to 3.

[0074] In some embodiments, L1is selected from the group consisting of:

[0075] In some embodiments, the compound is,or a pharmaceutically acceptable salt thereof.

[0076] In some embodiments, p is an integer ranging from 2 to 8. In some embodiments, p is 4.

[0077] In some embodiments, the Ligand-Drug Conjugate compound is a compound of Table 4 and p is an integer ranging from 1 to 12.

[0078] In some embodiments, the ligand is an antibody. In some embodiments, the antibody is a monoclonal antibody.

[0079] Also provided herein is a Released Drug-Linker cysteine adduct compound, wherein the Released Drug-Linker cysteine adduct compound is a compound of Table 3.

[0080] Also provided herein is a pharmaceutical composition comprising the Ligand- Drug Conjugate compound as described herein and a pharmaceutically acceptable excipient. In some embodiments, the composition comprises a plurality of Ligand-Drug Conjugate compounds with an average value of p from 2 to 8. In some embodiments, the average value of p is about 4. In some embodimetns, the average value of p is from 3.5 to 4.5.

[0081] Also provided herein is a method of treating cancer comprising administering a therapeutically effective amount of the Ligand-Drug Conjugate compound as described herein, or a pharmaceutically acceptable salt thereof, to a subject in need thereof. BRIEF DESCRIPTION OF THE DRAWINGS

[0082] FIG. 1 shows mean tumor volume in a BxPC3-59 mouse model over time with administration of one dose of an ADC with a targeted degrader molecule and an Ag3 antibody. DETAILED DESCRIPTION OF THE INVENTION

[0083] Provided herein are targeted degrader molecules and ligand-drug conjugates thereof that can target the BET family of proteins and may be used in treatment of conditions such as cancer and autoimmune diseases. I. Definitions

[0084] Unless stated otherwise, the following terms and phrases as used herein are intended to have the following meanings. When trade names are used herein, the trade name includesthe product formulation, the generic drug, and the active pharmaceutical ingredient(s) of the trade name product, unless otherwise indicated by context.

[0085] The term “antibody” as used herein is used in the broadest sense and specifically covers intact monoclonal antibodies, polyclonal antibodies, monospecific antibodies, multispecific antibodies (e.g., bispecific antibodies), and antibody fragments that retain, at least in part, one or more of the the desired biological activities of the full-length antibody, for example, affinity for its cognate antigen. The native form of an antibody is a tetramer and consists of two identical pairs of immunoglobulin chains, each pair having one light chain and one heavy chain. In each pair, the light and heavy chain variable regions (VL and VH) are together primarily responsible for binding to an antigen. The light chain and heavy chain variable domains consist of a framework region interrupted by three hypervariable regions, also called “complementarity determining regions” or “CDRs.” In some embodiments, the constant regions are recognized by and interact with the immune system (see, e.g., Janeway et al., 2001, Immunol. Biology, 5th Ed., Garland Publishing, New York). The antibodies herein are of any type (e.g., IgG, IgE, IgM, IgD, and IgA), class (e.g., IgG1, IgG2, IgG3, IgG4, IgA1 and IgA2), or subclass thereof. In some embodiments, the antibody is derived from a suitable species. In some embodiments, the antibody is of human or murine origin. In some embodiments, the antibody is human, humanized, or chimeric.

[0086] The term “monoclonal antibody” as used herein refers to an antibody obtained from a population of substantially homogeneous antibodies, i.e., the individual antibodies comprising the population are identical except for possible naturally occurring mutations that are present, in some embodiments, in minor amounts. Monoclonal antibodies are highly specific, being directed against a single antigenic site. The modifier “monoclonal” indicates the character of the antibody as being obtained from a substantially homogeneous population of antibodies and is not to be construed as requiring production of the antibody by any particular method.

[0087] An “intact antibody” is one which comprises an antigen-binding variable region as well as a light chain constant domain (CL) and heavy chain constant domains, CH1, CH2, CH3 and CH4, as appropriate for the antibody class. In some embodiments, the constant domains are native sequence constant domains (e.g., human native sequence constant domains) and in other embodiments are amino acid sequence variants thereof.

[0088] An “antibody fragment” comprises a portion of an intact antibody, comprising the antigen-binding or variable region thereof. Examples of antibody fragments include Fab, Fab’, F(ab’)2, and Fv fragments, diabodies, triabodies, tetrabodies, linear antibodies, single-chain antibody molecules, scFv, scFv-Fc, multispecific antibody fragments formed from antibody fragment(s), a fragment(s) produced by a Fab expression library, or an epitope-binding fragments of any of the above which immunospecifically bind to a target antigen (e.g., a cancer cell antigen, a viral antigen or a microbial antigen).

[0089] An “antigen” is an entity to which an antibody specifically binds.

[0090] The terms “specific binding” and “specifically binds” mean that the antibody or antibody derivative will bind, in a highly selective manner, with its corresponding epitope of a target antigen and not with the multitude of other antigens. Typically, the antibody or antibody derivative binds with an affinity of at least about 1x10-7M, and preferably 10-8M to 10-9M, 10-10M, 10-11M, or 10-12M and binds to the predetermined antigen with an affinity that is at least two-fold greater than its affinity for binding to a non-specific antigen (e.g., BSA, casein) other than the predetermined antigen or a closely related antigen.

[0091] The term "inhibits" or "inhibition of" means to reduce by a measurable amount, or to prevent entirely.

[0092] The term “therapeutically effective amount” refers to an amount of a conjugate effective to treat a disease or disorder in a mammal. In the case of cancer, the therapeutically effective amount of the conjugate may reduce the number of cancer cells; reduce the tumor size; inhibit (i.e., slow to some extent and preferably stop) cancer cell infiltration into peripheral organs; inhibit (i.e., slow to some extent and preferably stop) tumor metastasis; inhibit, to some extent, tumor growth; and / or relieve to some extent one or more of the symptoms associated with the cancer. In some embodiments, the drug inhibits growth and / or kills existing cancer cell. In some embodiments, the drug is cytostatic and / or cytotoxic. For cancer therapy, efficacy is measured by commonly available tools. In some embodiments, efficacy is measured by assessing the time to disease progression (TTP) and / or determining the response rate (RR).

[0093] The term “substantial” or “substantially” refers to a majority, i.e. >50% of a population, of a mixture or a sample, preferably more than 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97 %, 98%, or 99% of a population.

[0094] The term “cytotoxic activity” refers to a cell-killing effect of a drug or Ligand-Drug Conjugate compound or an intracellular metabolite of a Ligand-Drug Conjugate compound.Cytotoxic activity can be expressed as the IC50value, which is the concentration (molar or mass) per unit volume at which half the cells survive.

[0095] The term “potency” or “activity” can also refer to ability of a drug or a Ligand-Drug Conjugate to induce a response (e.g. the ability to stimulate an IRF-Lucia luciferase reporter gene from THP1-DualTMcells). Potency or activity can be expressed as the EC50 value, which is the concentration (molar or mass) per unit volume that induces a response halfway between the baseline and maximal response.

[0096] The term “cytostatic activity” refers to an anti-proliferative effect of a drug or Ligand-Drug Conjugate compound or an intracellular metabolite of a Ligand-Drug Conjugate compound.

[0097] The term “cytotoxic agent” as used herein refers to a substance that has cytotoxic activity and causes destruction of cells. The term is intended to include chemotherapeutic agents, and toxins such as small molecule toxins or enzymatically active toxins of bacterial, fungal, plant or animal origin, including synthetic analogs and derivatives thereof.

[0098] The term “cytostatic agent” as used herein refers to a substance that inhibits a function of cells, including cell growth or multiplication. Cytostatic agents include inhibitors such as protein inhibitors, e.g., enzyme inhibitors. Cytostatic agents have cytostatic activity.

[0099] The terms “cancer” and “cancerous” refer to or describe the physiological condition or disorder in mammals that is typically characterized by unregulated cell growth. A “tumor” comprises one or more cancerous cells.

[0100] An “autoimmune disease” as used herein refers to a disease or disorder arising from and directed against an individual’s own tissues or proteins.

[0101] “Patient” as used herein refers to a subject to whom is administered a Ligand-Drug Conjugate compound of the present invention. Patient includes, but are not limited to, a human, rat, mouse, guinea pig, non-human primate, pig, goat, cow, horse, dog, cat, bird and fowl. Typically, the patient is a rat, mouse, dog, human or non-human primate, more typically a human.

[0102] The terms “treat” or “treatment,” unless otherwise indicated by context, refer to therapeutic treatment and prophylactic wherein the object is to inhibit or slow down (lessen) an undesired physiological change or disorder, such as the development or spread of cancer. For purposes of this invention, beneficial or desired clinical results include, but are not limitedto, alleviation of symptoms, diminishment of extent of disease, stabilized (i.e., not worsening) state of disease, delay or slowing of disease progression, amelioration or palliation of the disease state, and remission (whether partial or total), whether detectable or undetectable. “Treatment” can also mean prolonging survival as compared to expected survival if not receiving treatment. Those in need of treatment include those already with the condition or disorder as well as those prone to have the condition or disorder.

[0103] In the context of cancer, the term “treating” includes any or all of: killing tumor cells; inhibiting growth of tumor cells, cancer cells, or of a tumor; inhibiting replication of tumor cells or cancer cells, lessening of overall tumor burden or decreasing the number of cancerous cells, and ameliorating one or more symptoms associated with the disease.

[0104] In the context of an autoimmune disease, the term “treating” includes any or all of: inhibiting replication of cells associated with an autoimmune disease state including, but not limited to, cells that produce an autoimmune antibody, lessening the autoimmune-antibody burden and ameliorating one or more symptoms of an autoimmune disease.

[0105] “Compound” as the term is used herein, refers to and encompasses the chemical compound itself, either named or represented by structure, and salt form(s) thereof, whether explicitly stated or not, unless context makes clear that such salt forms are to be excluded. The term “compound” further encompasses solvate forms of the compound, in which solvent is noncovalently associated with the compound or is reversibly associated covalently with the compound, as when a carbonyl group of the compound is hydrated to form a gem-diol. Solvate forms include those of the compound itself and its salt form(s) and are inclusive of hemisolvates, monosolvates, disolvates, including hydrates; when a compound is associated with two or more solvent molecules, the two or more solvent molecules are the same or different.

[0106] In some instances, a compound of the invention will include an explicit reference to one or more of the above forms, e.g., salts and solvates, which does not imply any solid state form of the compound; however, this reference is for emphasis only, and is not to be construed as excluding any other of the forms as identified above. Furthermore, when explicit reference to a salt and / or solvate form of a compound or a Ligand Drug Conjugate composition is not made, that omission is not to be construed as excluding the salt and / or solvate form(s) of the compound or Conjugate unless context make clear that such salt and / or solvate forms are to be excluded.

[0107] The phrase “salt thereof” as the phrase is used herein, refers to a salt form of a compound (e.g., a Drug, a Drug-Linker compound or a Ligand-Drug Conjugate compound). A salt form of a compound is of one or more internal salt forms and / or involves the inclusion of another molecule such as an acetate ion, a succinate ion or other counterion. The counterion in a salt form of a compound is typically an organic or inorganic moiety that stabilizes the charge on the parent compound. A salt form of a compound has one or more than one charged atom in its structure. In instances where multiple charged atoms are part of the salt form, multiple counter ions and / or multiple charged counter ions are present. Hence, a salt form of a compound typically has one or more charged atoms corresponding to those of the non-salt form of the compound and one or more counterions. In some embodiments, the non-salt form of a compound contains at least one amino group or other basic moiety, and accordingly in the presence of an acid, an acid addition salt with the basic moiety is obtained. In other embodiments, the non-salt form of a compound contains at least one carboxylic acid group or other acidic moiety, and accordingly in the presence of a base, a carboxylate or other anionic moiety is obtained. Exemplary salts include, but are not limited to, sulfate, trifluoroacetate, citrate, acetate, oxalate, chloride, bromide, iodide, nitrate, bisulfate, phosphate, acid phosphate, isonicotinate, lactate, salicylate, acid citrate, tartrate, oleate, tannate, pantothenate, bitartrate, ascorbate, succinate, maleate, gentisinate, fumarate, gluconate, glucuronate, saccharate, formate, benzoate, glutamate, methanesulfonate, ethanesulfonate, benzenesulfonate, p-toluenesulfonate, and pamoate (i.e., 1,1’-methylene-bis-(2-hydroxy-3-naphthoate)) salts.

[0108] A pharmaceutically acceptable salt is a salt form of a compound that is suitable for administration to a subject as described herein and in some embodiments includes countercations or counteranions as described by P. H. Stahl and C. G. Wermuth, editors, Handbook of Pharmaceutical Salts: Properties, Selection and Use, Weinheim / Zürich:Wiley- VCH / VHCA, 2002.

[0109] A “Linker Unit” as used herein is a bifunctional moiety that connects or is capable of connecting a Drug Unit to a Ligand Unit in a Ligand-Drug Conjugate compound. The Linker Units provided herein may in some embodiments comprise two or more components selected from the group consisting of a Stretcher Unit, which in some embodiments will have a Basic Unit; and a Connector Unit.

[0110] “Halogen” / “halo” as the term is used herein by itself or in combination with another term, unless otherwise stated or implied by context, refers to fluorine, chlorine, bromine, or iodine and is typically -F or -Cl.

[0111] Unless otherwise indicated, the term "alkyl" by itself or as part of another term refers to a straight chain or branched, saturated hydrocarbon having the indicated number of carbon atoms (e.g., “-C1-C4 alkyl,” “-C1-C8 alkyl,” or “-C1-C10”alkyl refer to an alkyl group having from 1 to 4, 1 to 8, or 1 to 10 carbon atoms, respectively). When the number of carbon atoms is not indicated, the alkyl group has from 1 to 8 carbon atoms. Representative straight chain “-C1-C8 alkyl” groups include, but are not limited to, -methyl, -ethyl, -n-propyl, -n-butyl, -n-pentyl, -n-hexyl, -n-heptyl and -n-octyl; while branched –C3-C8alkyls include, but are not limited to, -isopropyl, -sec-butyl, -isobutyl, -tert-butyl, -isopentyl, and -2-methylbutyl.

[0112] Unless otherwise indicated, "alkylene," by itself of as part of another term, refers to a saturated branched, saturated straight chain, or saturated cyclic hydrocarbon radical of the stated number of carbon atoms, typically 1-4, 1-8, or 1-10 carbon atoms, and having two monovalent radical centers derived by the removal of two hydrogen atoms from the same or two different carbon atoms of a parent alkane. Typical alkylene radicals include but are not limited to: methylene (-CH2-), 1,2-ethylene (-CH2CH2-), 1,3-propylene (-CH2CH2CH2-), 1,4- butylene (-CH2CH2CH2CH2-), and the like. In some embodiments, an alkylene is a branched or straight chain hydrocarbon (i.e., it is not a cyclic hydrocarbon).

[0113] “Alkenyl,” as the term is used herein, by itself or as part of another term, unless otherwise stated or implied by context, refers to an organic moiety, substituent or group that comprises one or more double bond functional groups (e.g., a -CH=CH- moiety) or 1, 2, 3, 4, 5, or 6 or more, typically 1, 2, or 3 of such functional groups, more typically one such functional group, and in some embodiments may contain non-aromatic linked normal, secondary, tertiary or cyclic carbon atoms, i.e., linear, branched, cyclic or any combination thereof as part of the base moiety unless the alkenyl substituent, moiety or group is a vinyl moiety (e.g., a -CH=CH2 moiety). An alkenyl moiety, group or substituent having multiple double bonds may have the double bonds arranged contiguously (i.e., a 1,3-butadienyl moiety) or non-contiguously with one or more intervening saturated carbon atoms or a combination thereof, provided that a cyclic, contiguous arrangement of double bonds do not form a cyclic conjugated system of 4n + 2 electrons (i.e., is not aromatic).

[0114] An alkenyl moiety, group or substituent contains at least one sp2carbon atom in which that carbon atom is divalent and is doubly bonded to another organic moiety or Markush structure to which it is associated, or contains at least two sp2carbon atoms in conjugation to each other in which one of the sp2carbon atoms is monovalent and is singly bonded to another organic moiety or Markush structure to which it is associated. Typically, when alkenyl is usedas a Markush group (i.e., is a substituent) the alkenyl is singly bonded to a Markush formula or another organic moiety with which it is associated through a sp2carbon of an alkene functional group of the alkenyl moiety. In some embodiments, when an alkenyl moiety is specified, species encompasses those corresponding to any of the optionally substituted alkyl or carbocyclyl, groups moieties or substituents described herein that has one or more endo double bonds in which a sp2carbon atom thereof is monovalent and monovalent moieties derived from removal of a hydrogen atom from a sp2carbon of a parent alkene compound. Such monovalent moieties are exemplified without limitation by vinyl (-CH=CH2), allyl, 1- methylvinyl, butenyl, iso-butenyl, 3-methyl-2-butenyl, 1-pentenyl, cyclopentenyl, 1-methyl- cyclopentenyl, 1-hexenyl, 3-hexenyl, and cyclohexenyl. In some embodiments, the term alkenyl encompasses those and / or other linear, cyclic, and branched chained, all carbon- containing moieties containing at least one double bond functional group in which one of the sp2carbon atoms is monovalent.

[0115] The number of carbon atoms in an alkenyl moiety is defined by the number of sp2carbon atoms of the alkene functional group(s) that defines it as an alkenyl substituent and the total number of contiguous non-aromatic carbon atoms appended to each of these sp2carbons not including any carbon atom of the other moiety or Markush structure for which the alkenyl moiety is a variable group and carbon atoms from any optional substituent to the alkenyl moiety. That number ranges from 1 to 30, typically 1 to 20 or 1 to 12, more typically, 1 to 8, 1 to 6, or 1 to 4 carbon atoms when the double bond functional group is doubly bonded to a Markush structure (e.g. =CH2), or ranges from 2 to 50, typically 2 to 30, 2 to 20 or 2 to 12, more typically 2 to 8, 2 to 6 or 2 to 4 carbon atoms, when the double bond functional group is singly bonded to the Markush structure (e.g., -CH=CH2). For example, C2-C8 alkenyl or C2- C8 alkenyl means an alkenyl moiety containing 2, 3, 4, 5, 6, 7, or 8 carbon atoms in which at least two are sp2carbon atoms in conjugation with each other with one of these carbon atoms being monovalent, and C2-C6 alkenyl or C2-C6 alkenyl means an alkenyl moiety containing 2, 3, 4, 5, or 6 carbon atoms in which at least two are sp2carbons that are in conjugation with each other with one of these carbon atoms being monovalent. In some embodiments, an alkenyl substituent or group is a C2-C6 or C2-C4 alkenyl moiety having only two sp2carbons that are in conjugation with each other with one of these carbon atoms being monovalent. Typically, an alkenyl substituent is a C2-C6or C2-C4alkenyl moiety having only two sp2carbons that are in conjugation with each other. When the number of carbon atoms is not indicated, an alkenyl moiety has from 2 to 8 carbon atoms.

[0116] “Alkenylene” as the term is used herein, by itself of as part of another term, unless otherwise stated or implied by context, refers to an organic moiety, substituent or group that comprises one or more double bond moieties, as previously described for alkenyl, of the stated number of carbon atoms and has two radical centers derived by the removal of two hydrogen atoms from the same or two different sp2carbon atoms of an alkene functional group or removal of two hydrogen atoms from two separate alkene functional groups in a parent alkene. In some embodiments, an alkenylene moiety is that of an alkenyl radical as described herein in which a hydrogen atom has been removed from the same or different sp2carbon atom of a double bond functional group of the alkenyl radical, or from a sp2carbon from a different double bonded moiety to provide a diradical. Typically, alkenylene moieties encompass diradicals containing the structure of –C=C- or –C=C-X1-C=C- wherein X1is absent or is an alkylene as defined herein, which is typically a C1-C6 alkylene. The number of carbon atoms in an alkenylene moiety is defined by the number of sp2carbon atoms of its alkene functional group(s) that defines it as an alkenylene moiety and the total number of contiguous non- aromatic carbon atoms appended to each of its sp2carbons not including any carbon atoms of the other moiety or Markush structure in which the alkenyl moiety is a present as a variable group. That number, unless otherwise specified, ranges from 2 to 50 or 2 to 30, typically from 2 to 20 or 2 to 12, more typically from 2 to 8, 2 to 6, or 2 to 4 carbon atoms. For example, C2- C8 alkenylene or C2-C8 alkenylene means an alkenylene moiety containing 2, 3, 4, 5, 6, 7, or 8 carbon atoms, in which at least two are sp2carbons in which one is divalent or both are monovalent, that are in conjugation with each other and C2-C6alkenylene or C2-C6 alkenylene means an alkenyl moiety containing 2, 3, 4, 5, or 6 carbon atoms in which at least two are sp2carbons, in which at least two are sp2carbons in which one is divalent or both are monovalent, that are in conjugation with each other. In some embodiments, an alkenylene moiety is a C2- C6 or C2-C4 alkenylene having two sp2carbons that are in conjugation with each other in which both sp2carbon atoms are monovalent. When the number of carbon atoms is not indicated, an alkenylene moiety has from 2 to 8 carbon atoms.

[0117] “Alkynyl,” as the term is used herein, by itself or as part of another term, unless otherwise stated or implied by context, refers to an organic moiety, substituent or group that comprises one or more triple bond functional groups (e.g., a -C≡C- moiety) or 1, 2, 3, 4, 5, or 6 or more, typically 1, 2, or 3 of such functional groups, more typically one such functional group. An alkynyl moiety, group, or substituent having multiple triple bonds may have the triple bonds arranged contiguously or non-contiguously with one or more intervening saturatedor unsaturated carbon atoms or a combination thereof, provided that a cyclic, contiguous arrangement of triple bonds do not form a cyclic conjugated system of 4n + 2 electrons (i.e., is not aromatic).

[0118] An alkynyl moiety, group or substituent contains at least two sp carbon atom in which the carbon atoms are conjugation to each other and in which one of the sp carbon atoms is singly bonded, to another organic moiety or Markush structure to which it is associated. When alkynyl is used as a Markush group (i.e., is a substituent) the alkynyl is singly bonded to a Markush formula or another organic moiety with which it is associated through a triple- bonded carbon (i.e., a sp carbon) of a terminal alkyne functional group. In some embodiments, when an alkynyl moiety, group or substituent is specified, species encompasses are any of the alkyl or carbocyclyl, groups moieties or substituents described herein that has one or more endo triple bonds and monovalent moieties derived from removal of a hydrogen atom from a sp carbon of a parent alkyne compound. Such monovalent moieties are exemplified without limitation by -C≡CH, and -C≡C-CH3, and -C≡C-Ph.

[0119] The number of carbon atoms in an alkynyl substituent is defined by the number of sp carbon atoms of the alkene functional group that defines it as an alkynyl substituent and the total number of contiguous non-aromatic carbon atoms appended to each of these sp carbons not including any carbon atom of the other moiety or Markush structure for which the alkenyl moiety is a variable group. That number can vary ranging from 2 to 30, 2 to 20, or 2 to 12, typically 2 to 8, 2 to 6, or 2 to 4 carbon atoms, when the triple bond functional group is singly bonded to the Markush structure (e.g., -CH≡CH). For example, C2-C8alkynyl or C2-C8 alkynyl means an alkynyl moiety containing 2, 3, 4, 5, 6, 7, or 8 carbon atoms in which at least two are sp carbon atoms in conjugation with each other with one of these carbon atoms being monovalent, and C2-C6alkynyl or C2-C6 alkynyl means an alkynyl moiety containing 2, 3, 4, 5, or 6 carbon atoms in which at least two are sp carbons that are in conjugation with each other with one of these carbon atoms being monovalent. In some embodiments, an alkynyl substituent or group is a C2-C6or C2-C4alkynyl moiety having two sp carbons that are in conjugation with each other with one of these carbon atoms being monovalent. When the number of carbon atoms is not indicated, an alkynyl moiety, group or substituent has from 2 to 8 carbon atoms.

[0120] The term “Prodrug” as used herein refers to a less biologically active or inactive compound which is transformed within the body into a more biologically active compound via a chemical or biological process (i.e., a chemical reaction or an enzymatic biotransformation).Typically, a biologically active compound is rendered less biologically active (i.e., is converted to a prodrug) by chemically modifying the compound with a prodrug moiety. In some embodiments, the prodrug is a Type II prodrug, which are bioactivated outside cells, e.g., in digestive fluids, or in the body's circulation system, e.g., in blood. Exemplary prodrugs are esters and β-D-glucopyranosides.

[0121] Unless otherwise indicated, "aryl," by itself or as part of another term, means amonovalent carbocyclic aromatic hydrocarbon radical of the stated number of carbon atoms, typically 6-20 carbon atoms, derived by the removal of one hydrogen atom from a single carbon atom of a parent aromatic ring system. Some aryl groups are represented in the exemplary structures as “Ar.” Typical aryl groups include, but are not limited to, radicals derived from benzene, naphthalene, anthracene, biphenyl, and the like. An exemplary aryl group is a phenyl group.

[0122] Unless otherwise indicated, an “arylene,” by itself or as part of another term, is an aryl group as defined above which has two covalent bonds (i.e., it is divalent) and is in the ortho, meta, or para orientations as shown in the following structures, with phenylene as the exemplary group:

[0123] Unless otherwise indicated, a “heterocycle,” by itself or as part of another term, refers to a monovalent aromatic or non-aromatic monocyclic or bicyclic ring system having from 2 to 8 carbon atoms (also referred to as ring members) and one to four heteroatom ring members independently selected from N, O, P, or S, and derived by removal of one hydrogen atom from a ring atom of a parent ring system. In some embodiments, one or more N, C, or S atoms in the heterocycle is / are oxidized. In some embodiments, the ring that includes the heteroatom is aromatic or nonaromatic. Heterocycles in which all the ring atoms are involved in aromaticity are referred to as heteroaryls and otherwise are referred to heterocarbocycles.

[0124] Unless otherwise noted, the heterocycle is attached to its pendant group at any heteroatom or carbon atom that results in a stable structure. In some embodiments, a heteroaryl is bonded through an aromatic carbon of its aromatic ring system, referred to as a C-linkedheteroaryl. In other embodiments, a heteroaryl is bonded through a non-double-bonded N atom (i.e., not =N-) in its aromatic ring system, which is referred to as an N-linked heteroaryl. Thus, nitrogen-containing heterocycles are C-linked or N-linked and include pyrrole moieties, such as pyrrol-1-yl (N-linked) and pyrrol-3-yl (C-linked), and imidazole moieties such as imidazol- 1-yl and imidazol-3-yl (both N-linked), and imidazol-2-yl, imidazol-4-yl and imidazol-5-yl moieties (all of which are C-linked).

[0125] Unless otherwise indicated, a “heteroaryl,” is an aromatic heterocycle (e.g., a C3-C8heterocycle) in which the subscript denotes the total number of carbons of the cyclic ring system of the heterocycle or the total number of aromatic carbons of the aromatic ring system of the heteroaryl and does not implicate the size of the ring system or the presence or absence of ring fusion. Representative examples of a C3-C8heterocycle include, but are not limited to, pyrrolidinyl, azetidinyl, piperidinyl, morpholinyl, tetrahydrofuranyl, tetrahydropyranyl, benzofuranyl, benzothiophene, indolyl, benzopyrazolyl, pyrrolyl, thiophenyl (thiophene), furanyl, thiazolyl, imidazolyl, pyrazolyl, pyrimidinyl, pyridinyl, pyrazinyl, pyridazinyl, isothiazolyl, triazolyl, oxazolyl, and isoxazolyl.

[0126] When explicitly given, the size of the ring system of a heterocycle or heteroaryl is indicated by the total number of atoms in the ring. For example, designation as a 5- or 6- membered heteroaryl indicates the total number of aromatic atoms (i.e., 5 or 6) in the heteroaromatic ring system of the heteroaryl but does not imply the number of aromatic heteroatoms or the number of aromatic carbon atoms in that ring system. Fused heteroaryls are explicitly stated or implied by context as such and are typically indicated by the number of aromatic atoms in each aromatic ring that are fused together to make up the fused heteroaromatic ring system. For example, a 5,6-membered heteroaryl is an aromatic 5- membered ring fused to an aromatic 6-membered ring in which one or both rings have aromatic heteroatom(s) or where a heteroatom is shared between the two rings.

[0127] A heterocycle fused to an aryl or heteroaryl such that the heterocycle remains non- aromatic and is part of a larger structure through attachment with the non-aromatic portion of the fused ring system is an example of a heterocycle in which the heterocycle is substituted by ring fusion with the aryl or heteroaryl. Likewise, an aryl or heteroaryl fused to heterocycle or carbocycle that is part of a larger structure through attachment with the aromatic portion of the fused ring system is an example of an aryl or heterocycle in which the aryl or heterocycle is substituted by ring fusion with the heterocycle or carbocycle. Such structures can be referred to as fused heterocyclic rings.

[0128] Unless otherwise indicated, “heterocyclo,” by itself or as part of another term, refers to a heterocyclic (e.g., C3-C8 heterocyclic) defined above wherein one of the hydrogen atoms of the heterocycle is replaced with a bond (i.e., it is divalent). Unless otherwise indicated, a “heteroarylene,” by itself or as part of another term, refers to a heteroaryl group (e.g., a C3-C8heteroaryl group) defined above wherein one of the heteroaryl group’s hydrogen atoms is replaced with a bond (i.e., it is divalent). When explicitly given, the size of the ring system of a heteroarylene is indicated by the total number of atoms in the ring. For example, designation as a 5- or 6-membered heteroarylene indicates the total number of atoms (i.e., 5 or 6) in the heterocyclic ring system of the heterocycle but does not imply the number of heteroatoms or the number of carbon atoms in that ring system.

[0129] Unless otherwise indicated, a “carbocycle,” by itself or as part of another term, is a 3-, 4-, 5-, 6-, 7-, or 8-membered monovalent saturated or unsaturated non-aromatic monocyclic or bicyclic carbocyclic ring derived by the removal of one hydrogen atom from a ring atom of a parent ring system. Representative carbocycles (e.g., C3-C8carbocycles) include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclopentadienyl, cyclohexyl, cyclohexenyl, 1,3-cyclohexadienyl, 1,4-cyclohexadienyl, cycloheptyl, 1,3-cycloheptadienyl, 1,3,5- cycloheptatrienyl, cyclooctyl, and cyclooctadienyl.

[0130] Unless otherwise indicated, a “carbocyclo,” by itself or as part of another term, refers to a carbocycle group (e.g., C3-C8 carbocycle group) defined above wherein another one of the carbocycle group’s hydrogen atoms is replaced with a bond (i.e., it is divalent).

[0131] Unless otherwise indicated, the term "heteroalkyl," by itself or in combination with another term, means, unless otherwise stated, a stable straight or branched chain hydrocarbon, or combinations thereof, fully saturated or containing from 1 to 3 degrees of unsaturation, consisting of the stated number of carbon atoms and from one to ten, preferably one to three, heteroatoms selected from the group consisting of O, N, Si, and S, and wherein the nitrogen and sulfur atoms are optionally oxidized and the nitrogen heteroatom is optionally quaternized. The heteroatom(s) O, N, and S are placed at any interior position of the heteroalkyl group or at the position at which the alkyl group is attached to the remainder of the molecule. The heteroatom Si is placed at any position of the heteroalkyl group, including the position at which the alkyl group is attached to the remainder of the molecule. When explicitly given, the number of atoms in a heteroalkyl or heteroarylene is indicated by the total number of atoms in the group. For example, designation as a C1-C2 heteroalkyl indicates the total number of atoms (i.e., 1 or2) in the heteroalkyl group, but does not imply the number of heteroatoms or the number of carbon atoms in that group.

[0132] Examples of heteroalkyls include –CH2-CH2-O-CH3, -CH2-CH2-NH-CH3, -CH2- CH2-N(CH3)-CH3, -CH2-S-CH2-CH3, -CH2-CH2-S(O)-CH3, -NH-CH2-CH2-NH-C(O)-CH2- CH3, -CH2-CH2-S(O)2-CH3, -CH=CH-O-CH3, -Si(CH3)3, -CH2-CH=N-O-CH3, and –CH=CH- N(CH3)-CH3. In some aspects, two heteroatoms are consecutive, such as, for example, -CH2- NH-OCH3and –CH2-O-Si(CH3)3. Typically, a C1to C4heteroalkyl or heteroalkylene has 1 to 4 carbon atoms and 1 or 2 heteroatoms and a C1 to C3 heteroalkyl or heteroalkylene has 1 to 3 carbon atoms and 1 or 2 heteroatoms. In some embodiments, a heteroalkyl or heteroalkylene is saturated.

[0133] Unless otherwise indicated, the term "heteroalkylene" by itself or in combination with another term means a divalent group derived from heteroalkyl (as discussed above), as exemplified by –CH2-CH2-S-CH2-CH2- and –CH2-S-CH2-CH2-NH-CH2-. For heteroalkylene groups, heteroatoms can also occupy either or both of the chain termini. Still further, for alkylene and heteroalkylene linking groups, no orientation of the linking group is implied.

[0134] Unless otherwise indicated, “aminoalkyl” by itself or in combination with another term means a heteroalkyl wherein an alkyl moiety as defined herein is substituted with an amino, alkylamino, dialkylamino or cycloalkylamino group. Exemplary non-limiting aminoalkyls are –CH2NH2, -CH2CH2NH2, -CH2CH2NHCH3, and -CH2CH2N(CH3)2 and further includes branched species such as –CH(CH3)NH2and -C(CH3)CH2NH2in the (R)- or (S)- configuration. Alternatively, an aminoalkyl is an alkyl moiety, group, or substituent as defined herein wherein a sp3carbon other than the radical carbon atom of the alkyl moiety has been replaced with an amino or alkylamino moiety wherein its sp3nitrogen atom replaces the sp3carbon of the alkyl moiety provided that at least one sp3carbon atom of the alkyl moiety remains. When referring to an aminoalkyl moiety as a substituent to a larger structure or another moiety the aminoalkyl is covalently attached to the structure or moiety through the carbon radical of the alkyl moiety of the aminoalkyl.

[0135] “Hydroxyalkyl” as the term is used herein by itself or in combination with another term, unless otherwise stated or implied by context, refers to an alkyl moiety, group, or substituent having a hydroxyl radical in place of one or more hydrogen atoms of the alkyl moiety, group, or substituent. In some embodiments, one or two hydrogen atoms are each replaced with a hydroxyl substituent in a hydroxyalkyl group. A hydroxyalkyl is typicallydenoted by the number of contiguous carbon atoms of its alkyl or alkylene moiety. Thus, a C1hydroxyalkyl is exemplified without limitation by –CH2OH, and a C2 hydroxyalkyl is exemplified without limitation by –CH2CH2OH or –CH2(OH)CH3.

[0136] “Haloalkyl” as the term is used herein by itself or in combination with another term, unless otherwise stated or implied by context, referes to an alkyl moiety, group, or substituent having a halogen in place of one or more hydrogen atoms of the alkyl moiety, group, or substituent. In some embodiments, one or two hydrogen atoms are each replaced with a halogen in a haloalkyl group. A haloalkyl is typically denoted by the number of contiguous carbon atoms of its alkyl or alkylene moiety. Thus, a C1 haloalkyl is exemplified without limitation by –CH2F, –CH2Cl, –CH2Br, or –CH2I, and a C2haloalkyl is exemplified without limitation by –CH2CH2F, –CH2CH2Cl, –CH2CH2Br, –CH2CH2I, –CH2(F)CH3, –CH2(Cl)CH3, – CH2(Br)CH3, or –CH2(I)CH3. In some embodiments, the term “haloalkyl” refers to an alkyl moiety, group, or substituent having halogens in place of two or more hydrogen atoms. For example, a C1haloalkyl is also exemplified without limitation by –CHF2, –CHCl2, –CHBr2, or –CHI2, and a C2 haloalkyl is exemplified without limitation by –CH2CHF2, –CH2CHCl2, – CH2CHBr2, –CH2CHI2, –CF2CH3, –CCl2CH3, –CBr2CH3, or –CI2CH3. In some embodiments, the term “haloalkyl” refers to an alkyl moiety, group, or substituent having halogens in place of all hydrogen atoms. Thus, in some embodiments, the term “haloalkyl” encompasses fully halogenated alkyl moieties, groups, or substituents. For example, a C1 haloalkyl is also exemplified without limitation by –CF3, –CCl3, –CBr3, or –CI3.

[0137] Unless otherwise indicated, “alkylamino” and “cycloalkylamino” by itself or in combination with another term means an alkyl or cycloalkyl radical, as described herein, wherein the radical carbon atom of the alkyl or cycloalkyl radical has been replaced with a nitrogen radical, provided that at least one sp3carbon atom of the alkyl or cycloalkyl radical remains. In those instances where the alkylamino is substituted at its nitrogen with another alkyl moiety the resulting substituted radical is sometimes referred to as a dialkylamino moiety, group or substituent wherein the alkyl moieties substituting nitrogen are independently selected.

[0138] Exemplary and non-limiting amino, alkylamino, and dialkylamino substituents include those having the structure of –N(R’)2, wherein R’ are independently hydrogen or C1-6alkyl, typically hydrogen or methyl, whereas in cycloalkyl amines, which are included in heterocycloalkyls, both R’ together with the nitrogen to which they are attached form a heterocyclic ring. When both R’ are hydrogen or alkyl, the moiety is sometimes described asa primary amino group and a tertiary amine group, respectively. When one R’ is hydrogen and the other is alkyl, then the moiety is sometimes described as a secondary amino group. Primary and secondary alkylamino moieties are typically more reactive as nucleophiles towards carbonyl-containing electrophilic centers whereas tertiary amines are typically more basic.

[0139] The term “substituted” means that the specified group or moiety bears one or more substituents. Typical substituents include, but are not limited to -X, -R'', -OH, -OR'', -SR'', -N(R'')2, -N(R'')3, =NR'', -CX3, -CN, -NO2, -NR''C(=O)R'', - C(=O)R'', -C(=O)N(R'')2, -S(=O)2R'', -S(=O)2NR'', -S(=O)R'', -OP(=O)(OR'')2, -P(=O)(OR'')2, -PO3=, PO3H2, -C(=O)R'', -C(=S)R'', -CO2R'', -CO2-, -C(=S)OR'', -C(=O)SR'', -C(=S)SR'', - C(=O)N(R'')2, -C(=S)N(R'')2, and -C(=NR)N(R'')2, where each X is independently selected from the group consisting of a halogen: -F, -Cl, -Br, and -I; and wherein each R'' is independently selected from the group consisting of -H, -C1-C20 alkyl, -C3-C20 cycloalkyl, -C6- C20aryl, -C3-C14heterocycle, a protecting group, and a prodrug moiety.

[0140] More typically, substituents are selected from the group consisting of -X, -R'', -OH, -OR'', -SR'', -N(R'')2, -N(R'')3, =NR'', -NR''C(=O)R'', -C(=O)R'', - C(=O)N(R'')2, -S(=O)2R'', -S(=O)2NR'', -S(=O)R'', -C(=O)R'', -C(=S)R'', -C(=O)N(R'')2, - C(=S)N(R'')2, and -C(=NR)N(R'')2, wherein each X is independently selected from the group consisting of –F and -Cl, or are selected from the group consisting of -X, -R'', -OH, -OR'', - N(R'')2, -N(R'')3, -NR''C(=O)R'', -C(=O)N(R'')2, -S(=O)2R'', -S(=O)2NR'', -S(=O)R'', - C(=O)R'', -C(=O)N(R'')2, -C(=NR)N(R'')2, a protecting group, and a prodrug moiety, wherein each X is –F; and wherein each R’is independently selected from the group consisting of hydrogen, -C1-C20 alkyl, -C6-C20 aryl, -C3-C14 heterocycle, a protecting group, and a prodrug moiety.

[0141] In some embodiments, a substituent on an alkyl, alkenyl, or alkynyl is selected from the group consisting -N(R'')2, -N(R'')3 and -C(=NR)N(R'')2, wherein R'' is selected from the group consisting of hydrogen and -C1-C20alkyl. In some embodiments, alkylene, carbocycle, carbocyclo, arylene, heteroalkyl, heteroalkylene, heterocycle, heterocyclo, heteroaryl, and heteroarylene groups as described above are similarly substituted.

[0142] The term “unsubstituted” means that the specified group bears no substituents. Where the term “substituted” is used to describe a structural system, the substitution is meant to occur at any valency-allowed position on the system. When a group or moiety bears morethan one substituent, it is understood that the substituents may be the same or different from one another. In some embodiments, a substituted group or moiety bears from one to five substituents. In some embodiments, a substituted group or moiety bears one substituent. In some embodiments, a substituted group or moiety bears two substituents. In some embodiments, a substituted group or moiety bears three substituents. In some embodiments, a substituted group or moiety bears four substituents. In some embodiments, a substituted group or moiety bears five substituents.

[0143] By “optional” or “optionally” is meant that the subsequently described event or circumstance may or may not occur, and that the description includes instances where the event or circumstance occurs and instances in which it does not. For example, “optionally substituted alkyl” encompasses both “alkyl” and “substituted alkyl” as defined herein. It will be understood by those skilled in the art, with respect to any group containing one or more substituents, that such groups are not intended to introduce any substitution or substitution patterns that are sterically impractical, synthetically non-feasible, and / or inherently unstable. It will also be understood that where a group or moiety is optionally substituted, the disclosure includes both embodiments in which the group or moiety is substituted and embodiments in which the group or moiety is unsubstituted.

[0144] “Protecting group” or “protective group,” as used herein, means a moiety that prevents or reduces the ability of the atom or functional group to which it is linked from participating in unwanted reactions. Typical protecting groups for atoms or functional groups are given in Greene (2006), “PROTECTIVE GROUPS IN ORGANIC SYNTHESIS, 4THED.”, Wiley Interscience, which is incorporated by reference herein. Protecting groups for heteroatoms such as oxygen, sulfur and nitrogen are used in some instances to minimize or avoid unwanted their reactions with electrophilic compounds. In other instances, the protecting group is used to reduce or eliminate the nucleophilicity and / or basicity of the unprotected heteroatom. Non- limiting examples of protected oxygen are given by -ORPR, wherein RPRis a protecting group for hydroxyl, wherein hydroxyl is typically protected as an ester (e.g. acetate, propionate, or benzoate). Other protecting groups for hydroxyl avoid interfering with the nucleophilicity of organometallic reagents or other highly basic reagents, where hydroxyl is typically protected as an ether, including alkyl or heterocycloalkyl ethers, (e.g., methyl or tetrahydropyranyl ethers), alkoxymethyl ethers (e.g., methoxymethyl or ethoxymethyl ethers), optionally substituted aryl ethers, and silyl ethers (e.g., trimethylsilyl (TMS), triethylsilyl (TES), tert- butyldiphenylsilyl (TBDPS), tert-butyldimethylsilyl (TBS / TBDMS), triisopropylsilyl (TIPS),and [2-(trimethylsilyl)ethoxy]-methylsilyl (SEM)). Nitrogen protecting groups include those for primary or secondary amines as in -NHRPRor -N(RPR)2-, wherein least one of RPRis a nitrogen atom protecting group or both RPRtogether comprise a protecting group. Non-limiting examples of such nitrogen protecting groups include t-butyloxycaronyl (Boc), 9- fluorenylmethoxycarbonyl (Fmoc), trimethylsilyl (TMS), carboxybenzyl (CBz), acetyl (Ac), benzoyl (Bz), benzyl (Bn), trityl (Tr), dimethoxytrityl (DMT), phthaloyl, Carbamate, p- methoxybenzyl (PMB), 3,4-dimethoxybenzyl (DMPM), p-methoxyphenyl (PMP), and tosyl (Ts).

[0145] A protecting group is suitable when it is capable of preventing or avoiding unwanted side-reactions or premature loss of the protecting group under reaction conditions required to effect desired chemical transformation elsewhere in the molecule and during purification of the newly formed molecule when desired, and are removable under conditions that do not adversely affect the structure or stereochemical integrity of that newly formed molecule. By way of example and not limitation, a suitable protecting group includes those previously described for protecting otherwise reactive functional groups. A suitable protecting group is sometimes a protecting group used in peptide coupling reactions.

[0146] “Electron withdrawing group,” as used herein, means a functional group or electronegative atom that draws electron density away from an atom to which it is bonded either inductively and / or through resonance, whichever is more dominant (i.e., in some embodiments, a functional group or atom is electron withdrawing inductively but is overall electron donating through resonance) and tends to stabilize anions or electron-rich moieties. The electron withdrawing effect is typically transmitted inductively, albeit in attenuated form, to other atoms attached to the bonded atom that has been made electron deficient by the electron withdrawing group (EWG), thus affecting the electrophilicity of a more remote reactive center. Exemplary electron withdrawing groups include, but are not limited to -C(=O), -CN, -NO2, - CX3, -X, -C(=O)OR’, -C(=O)N(R’)2, -C(=O)R’, -C(=O)X, -S(=O)2R’, -S(=O)2OR’, - S(=O)2NHR’, -S(=O)2N(R’)2, -P(=O)(OR’)2, -P(=O)(CH3)NHR’, -NO, -N(R’)3+, wherein X is - F, -Br, -Cl, or -I, and R’in some embodiments is, at each occurrence, independently selected from the group consisting of hydrogen and C1-6 alkyl, and certain O-linked moieties as described herein such as acyloxy.

[0147] Exemplary EWGs can also include aryl groups (e.g., phenyl) depending on substitution of its aromatic ring and certain heteroaryl groups (e.g., pyridine). Thus, the term “electron withdrawing groups” also includes aryls or heteroaryls that are further substitutedwith electron withdrawing groups. Typically, electron withdrawing groups on aryls or heteroaryls are -C(=O), -CN, -NO2, -CX3, and –X, wherein X independently selected is halogen, typically –F or -Cl. Depending on their substituents, an alkyl moiety may also be an electron withdrawing group.

[0148] “Succinimide moiety” as used herein refers to an organic moiety comprising a succinimide ring system, which is present in one type of Stretcher Unit (Z) that typically further comprises an alkylene-containing moiety bonded to the imide nitrogen of that ring system. A succinimide moiety typically results from Michael addition of a sulfhydryl group of a Ligand Unit to the maleimide ring system of a Stretcher Unit precursor (Z') in a Drug Linker compound or maleimide-containing intermediate thereof. A succinimide moiety therefore comprises a thio-substituted succinimide ring system and when present in a Ligand-Drug Conjugate compound has its imide nitrogen substituted with the remainder of the Linker Unit of the Ligand-Drug Conjugate compound and is optionally substituted with substituent(s) that were present on the maleimide ring system of Z'.

[0149] “Succinic acid-amide moiety” as used herein refers to a succinic acid moiety wherein one of the two carboxylic acid groups is replaced with an amide substituent that results from the thio-substituted succinimide ring system of a succinimide moiety as defined herein having undergone breakage of one of its carbonyl-nitrogen bonds by hydrolysis. In some embodiments, the succinic acid-amide moiety has the structure:wherein the wavy line on the left indicates attachment to a Ligand Unit or hydrogen atom and the wavy line on the right indicates attachment to the remainder of a Ligand-Drug Conjugate compound, Drug-Linker compound, intermediate, or fragment thereof. Hydrolysis resulting in a succinic acid-amide moiety provides a Linker Unit less likely to suffer premature loss of the Ligand Unit to which it is bonded through elimination of the antibody-thio substituent. Hydrolysis of the succinimide ring system of the thio-substituted succinimide moiety is expected to provide regiochemical isomers of acid-amide moieties that are due to differences in reactivity of the two carbonyl carbons of the succinimide ring system attributable at least inpart to any substituent present in the maleimide ring system of the Stretcher Unit precursor and to the thio substituent introduced by the targeting ligand, which is a precursor to the Ligand Unit.

[0150] In many instances, the assembly of the conjugates, linkers and components described herein will refer to reactive groups. A “reactive group” or RG is a group that contains a reactive site (RS) capable of forming a bond with either the components of the Linker Unit or the Drug Unit D. RS is the reactive site within a Reactive Group (RG). Reactive groups include sulfhydryl groups to form disulfide bonds or thioether bonds, aldehyde, ketone, or hydrazine groups to form hydrazone bonds, carboxylic or amino groups to form peptide bonds, carboxylic or hydroxy groups to form ester bonds, sulfonic acids to form sulfonamide bonds, alcohols to form carbamate bonds, and amines to form sulfonamide bonds or carbamate bonds.

[0151] The following table is illustrative of Reactive Groups, Reactive Sites, and exemplary functional groups capable of forming after reaction of the reactive site. The table is not limiting. One of skill in the art will appreciate that the noted R*and R**portions in the table are effectively any organic moiety (e.g., an alkyl group, aryl group, heteroaryl group, or substituted alkyl, aryl, or heteroaryl, group) that is compatible with the bond formation provided in converting RG to one of the Exemplary Functional Groups. It will also be appreciated that, as applied to the various aspects of the present invention, R*represents one or more components of the self-stabilizing linker or optional secondary linker, and R**represents one or more components of the optional secondary linker, Drug Unit, stabilizing unit, or detection unit.II. Embodiments A. Targeted Degrader Molecule Compounds

[0152] In some embodiments herein, provided are targeted degrader molecule compounds. In some embodiments, provided herein are Drug-Linker compounds comprising a targeted degrader moiety, as described herein. In some embodiments, provided herein are Ligand-Drug Conjugate compounds comprising a targeted degrader moiety, as described herein. In some embodiments, provided herein are methods of treating cancer using the Ligand-Drug Conjugate compounds described herein. In some embodiments, provided are methods of making targeted degrader compounds, Drug-Linkers thereof and their intermediates, and Ligand-Drug Conjugate compounds thereof.

[0153] In some embodiments, provided is a compound of Formula (I):Formula (I), or a pharmaceutically acceptable salt thereof, wherein: X is CH, N, O, or S; Z1is H or absent; Z2is H; or Z1and Z2are taken together to form a single bond or a C1-C4 alkylene group; provided that when X is O or S, Z1is absent; Y1and Y2are independently CH, CF, or N; Q is absent or C(O), NR11, S, SO2NR11, NR11SO2, O, C(O)O, or C(O)NR11;R1is H, halogen, OH, CN, N3, SH, COOR12, SO2R12, SO2NR11R12, or NR11R12; L2is absent or –CH2CH2(OCH2CH2)k–, -C1-C10 alkylene-, 2- to 14-membered heteroalkylene-, -C3-C8 carbocyclo-, -O(C1-C8 alkylene)-, -arylene-, -C1-C10 alkylene- arylene-, -arylene-C1-C10alkylene-, -C1-C10alkylene-(C3-C8carbocyclo)-, -(C3-C8carbocyclo)-C1-C10 alkylene-, 3- to 12-membered heterocyclo-, -C1-C10 alkylene-( 3- to 12- membered heterocyclo)-, -( 3- to 12-membered heterocyclo)-C1-C10 alkylene, -C2-C10alkenylene-, 3- to 14-membered heteroalkenylene-, -O(C2-C8alkenylene)-, -C2-C10alkenylene-arylene-, -arylene-C2-C10alkenylene-, -C2-C10alkenylene-(C3-C8 carbocyclo)-, - (C3-C8 carbocyclo)-C2-C10alkenylene-, -C2-C10alkenylene-(3- to 12-membered heterocyclo)- , -(3- to 12-membered heterocyclo)-C2-C10alkenylene, -C2-C10alkynylene-, 3- to 14- membered heteroalkynylene-, -O(C2-C8alkynylene)-, -C2-C10alkynylene-arylene-, -arylene- C2-C10alkynylene-, -C2-C10alkynylene-(C3-C8 carbocyclo)-, -(C3-C8 carbocyclo)-C2-C10alkynylene-, -C2-C10alkynylene-(3- to 12-membered heterocyclo)-, or -(3- to 12-membered heterocyclo)-C2-C10alkynylene, each of which is optionally substituted; subscript k is an integer ranging from 1 to 36, provided that QL2R1is not H; and R2is optionally substituted C1-C6alkyl; R3is C3-C8 cycloalkyl, -C1-C10 alkylene-(C3-C8 cycloalkyl), C3-C8 cycloalkenyl, -C1- C10 alkylene-(C3-C8 cycloalkenyl), C6-C14 aryl, -C1-C10 alkylene-(C6-C14 aryl), 5- to 10- membered heteroaryl, -C1-C10alkylene-(5- to 10-membered heteroaryl), 3- to 12-membered heterocyclyl, or -C1-C10alkylene (3- to 12-membered heterocyclyl), wherein the C3-C8cycloalkyl, -C1-C10 alkylene-(C3-C8 cycloalkyl), C6-C14 aryl, -C1-C10 alkylene-(C6-C14 aryl), 5- to 10-membered heteroaryl, -C1-C10 alkylene-(5- to 10-membered heteroaryl), 3- to 12- membered heterocyclyl, or -C1-C10alkylene (3- to 12-membered heterocyclyl) are optionally substituted by halo, OH, CN, C1-C6 alkyl, or C1-C6 haloalkyl; R4is -NHSO2R12or -CH2SO2R12; R5is H or halo; R6is H or optionally substituted C1-C6 alkyl; R7and R8are each H, or R7and R8, taken together with the carbon to which they are attached, form a carbonyl or 3- to 6-membered carbocycle;R9, R10a, and R10bare each independently H, halo, optionally substituted C1-C6alkyl, C3-C8 cycloalkyl, or C1-C6 haloalkyl; L1is a linking group having the structure:** ; wherein W1is C2-C6 alkenylene, C2-C6 alkynylene, optionally substituted 5- to 10-membered heteroarylene, optionally substituted 3- to 12-membered heterocyclene, CO, CONR11, C(O)O, SO2NR11, or absent; W2is, independently at each occurrence, O, S, NR11, -COO-, -OCO-, - CONR11-, -NR11CO-, -SO2NR11-, -NR11SO2-, optionally substituted C3-C8 cycloalkylene, optionally substituted C3-C8 cycloalkenylene, optionally substituted C6-C14 arylene, optionally substituted 5- to 10-membered heteroarylene, optionally substituted 3- to 12- membered heterocyclylene, or absent; W3is, independently at each occurrence, O, S, NR11, optionally substituted C1- C10alkylene, optionally substituted C2-C10alkenylene, optionally substituted C2-C10alkynylene, optionally substituted 2- to 14-membered heteroalkylene, or absent; subscript n is an integer from 1 to 6; * indicates the point of attachment to * in Formula (I); ** indicates the point of attachment to ** in Formula (I); provided that at least one of W1, W2, and W3is not absent; and R11and R12are, independently of each other and independently at each occurrence, H, halo, C1-C6alkyl, C1-C6haloalkyl, C1-C6alkoxy, or C3-C8cycloalkyl.

[0154] In some embodiments, provided is compound of Formula (Ia):Formula (Ia), or a pharmaceutically acceptable salt thereof, wherein the variables are as defined for Formula (I).

[0155] In some embodiments, provided is compound of Formula (Ib):Formula (Ib), or a pharmaceutically acceptable salt thereof, wherein the variables are as defined for Formula (I).

[0156] In some embodiments, provided is compound of Formula (IIa):Formula (IIa), or a pharmaceutically acceptable salt thereof, wherein the variables are as defined for Formula (I).

[0157] In some embodiments, provided is compound of Formula (IIb):Formula (IIb), or a pharmaceutically acceptable salt thereof, wherein the variables are as defined for Formula (I).

[0158] In some embodiments, provided is compound of Formula (IIIa):Formula (IIIa), or a pharmaceutically acceptable salt thereof, wherein the variables are as defined for Formula (I).

[0159] In some embodiments, provided is compound of Formula (IIIa-R):Formula (IIIa-R), or a pharmaceutically acceptable salt thereof, wherein the variables are as defined for Formula (I).

[0160] In some embodiments, provided is compound of Formula (IIIa-S):Formula (IIIa-S), or a pharmaceutically acceptable salt thereof, wherein the variables are as defined for Formula (I).

[0161] In some embodiments, provided is compound of Formula (IIIa-4):Formula (IIIa-4), or a pharmaceutically acceptable salt thereof, wherein the variables are as defined for Formula (I).

[0162] In some embodiments, provided is compound of Formula (IIIa-5):Formula (IIIa-5),or a pharmaceutically acceptable salt thereof, wherein the variables are as defined for Formula (I).

[0163] In some embodiments, provided is compound of Formula (IIIb):Formula (IIIb), or a pharmaceutically acceptable salt thereof, wherein the variables are as defined for Formula (I).

[0164] In some embodiments, provided is compound of Formula (IIIb-R):Formula (IIIb-R), or a pharmaceutically acceptable salt thereof, wherein the variables are as defined for Formula (I).

[0165] In some embodiments, provided is compound of Formula (IIIb-S):Formula (IIIb-S),or a pharmaceutically acceptable salt thereof, wherein the variables are as defined for Formula (I).

[0166] In some embodiments, provided is compound of Formula (IIIb-4):Formula (IIIb-4), or a pharmaceutically acceptable salt thereof, wherein the variables are as defined for Formula (I).

[0167] In some embodiments, provided is compound of Formula (IIIb-5):Formula (IIIb-5), or a pharmaceutically acceptable salt thereof, wherein the variables are as defined for Formula (I).

[0168] In some embodiments of Formula (I), Z1is H or absent and Z2is H. In some such embodiments, Z1is H and Z2is H. In some such embodiments, Z1is absent and Z2is H.

[0169] In some embodiments of Formula (I), Z1and Z2are taken together to form a single bond or a C1-C4 alkylene group. In some such embodiments, Z1and Z2are taken together to form a single bond. In some such embodiments, Z1and Z2are taken together to form a C1-C4alkylene group. In some such embodiments, Z1and Z2are taken together to form methylene. In some such embodiments, Z1and Z2are taken together to form ethylene.

[0170] In some embodiments of Formula (Ib), (IIb), (IIIb), (IIIb-R), (IIIb-S), (IIIb-4), or (IIIb-5), Z1is H or absent. In some such embodiments, Z1is H. In some such embodiments, Z1is absent.

[0171] In some embodiments of Formula (I), (Ia), or (Ib), Y1is CH, CF, or N. In some such embodiments, Y1is CH. In some such embodiments, Y1is CF. In some such embodiments, Y1is N.

[0172] In some embodiments of Formula (I), (Ia), or (Ib), Y2is CH, CF, or N. In some such embodiments, Y2is CH. In some such embodiments, Y2is CF. In some such embodiments, Y2is N.

[0173] In some embodiments of Formula (I), Z1is H or absent; Z2is H; Y1is CH, CF, or N; and Y2is CH, CF, or N. In some such embodiments, Z1is H, Z2is H, Y1is CH, and Y2is CH. In some such embodiments, Z1is H, Z2is H, Y1is CF, and Y2is CH. In some such embodiments, Z1is H, Z2is H, Y1is CH, and Y2is CF. In some such embodiments, Z1is H, Z2is H, Y1is N, and Y2is CH. In some such embodiments, Z1is H, Z2is H, Y1is CH, and Y2is N. In some such embodiments, Z1is H, Z2is H, Y1is N, and Y2is N. In some such embodiments, Z1is absent, Z2is H, Y1is CH, and Y2is CH. In some such embodiments, Z1is absent, Z2is H, Y1is CF, and Y2is CH. In some such embodiments, Z1is absent, Z2is H, Y1is CH, and Y2is CF. In some such embodiments, Z1is absent, Z2is H, Y1is N, and Y2is CH. In some such embodiments, Z1is absent, Z2is H, Y1is CH, and Y2is N. In some such embodiments, Z1is absent, Z2is H, Y1is N, and Y2is N.

[0174] In some embodiments of Formula (I), Y1is CH, CF, or N; Y2is CH, CF, or N; and Z1and Z2are taken together to form a single bond or a C1-C4 alkylene group. In some such embodiments, Y1is CH, Y2is CH, and Z1and Z2are taken together to form a single bond. In some such embodiments, Y1is CF, Y2is CH, and Z1and Z2are taken together to form a single bond. In some such embodiments, Y1is CH, Y2is CF, and Z1and Z2are taken together to form a single bond. In some such embodiments, Y1is N, Y2is CH, and Z1and Z2are taken together to form a single bond. In some such embodiments, Y1is CH, Y2is N, and Z1and Z2are taken together to form a single bond. In some such embodiments, Y1is N, Y2is N, and Z1and Z2are taken together to form a single bond. In some such embodiments, Y1is CH, Y2is CH, and Z1and Z2are taken together to form a C1-C4alkylene group. In some such embodiments, Y1is CF, Y2is CH, and Z1and Z2are taken together to form a C1-C4alkylene group. In some such embodiments, Y1is CH, Y2is CF, and Z1and Z2are takentogether to form a C1-C4alkylene group. In some such embodiments, Y1is N, Y2is CH, and Z1and Z2are taken together to form a C1-C4 alkylene group. In some such embodiments, Y1is CH, Y2is N, and Z1and Z2are taken together to form a C1-C4 alkylene group. In some such embodiments, Y1is N, Y2is N, and Z1and Z2are taken together to form a C1-C4alkylene group. In some such embodiments, Y1is CH, Y2is CH, and Z1and Z2are taken together to form methylene. In some such embodiments, Y1is CH, Y2is CH, and Z1and Z2are taken together to form ethylene.

[0175] In some embodiments of Formula (Ia) or (Ib), Y1is CH, CF, or N and Y2is CH, CF, or N. In some such embodiments, Y1is CH and Y2is CH. In some such embodiments, Y1is CF and Y2is CH. In some such embodiments, Y1is CH and Y2is CF. In some such embodiments, Y1is N and Y2is CH. In some such embodiments, Y1is CH and Y2is N. In some such embodiments, Y1is N and Y2is N.

[0176] In some embodiments of Formula (I), (Ia), (Ib), (IIa), or (IIb), R9is H, halo, optionally substituted C1-C6alkyl, C3-C8cycloalkyl, or C1-C6haloalkyl. In some such embodiments, R9is H. In some such embodiments, R9is halo. In some such embodiments, R9is F, Cl, or Br. In some such embodiments, R9is F. In some such embodiments, R9is Cl. In some such embodiments, R9is Br. In some such embodiments, R9is optionally substituted C1-C6 alkyl. In some such embodiments, R9is methyl, ethyl, n-propyl, or isopropyl, each optionally substituted. In some such embodiments, R9is C1-C6 alkyl. In some such embodiments, R9is methyl, ethyl, n-propyl, or isopropyl. In some such embodiments, R9is methyl. In some such embodiments, R9is ethyl. In some such embodiments, R9is n-propyl. In some such embodiments, R9is isopropyl. In some such embodiments, R9is C3-C8 cycloalkyl. In some such embodiments, R9is cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl. In some such embodiments, R9is cyclopropyl. In some such embodiments, R9is cyclobutyl. In some such embodiments, R9is cyclopentyl. In some such embodiments, R9is cyclohexyl. In some such embodiments, R9is C1-C6 haloalkyl. In some such embodiments, R9is C1haloalkyl. In some such embodiments, R9is fluoromethyl. In some such embodiments, R9is trifluoromethyl. In some such embodiments, R9is C2 haloalkyl. In some such embodiments, R9is C3 haloalkyl.

[0177] In some embodiments of Formula (I), (Ia), (Ib), (IIa), or (IIb), R10is H, halo, optionally substituted C1-C6alkyl, C3-C8cycloalkyl, or C1-C6haloalkyl. In some such embodiments, R10is H. In some such embodiments, R10is halo. In some such embodiments, R10is F, Cl, or Br. In some such embodiments, R10is F. In some such embodiments, R10isCl. In some such embodiments, R10is Br. In some such embodiments, R10is optionally substituted C1-C6 alkyl. In some such embodiments, R10is methyl, ethyl, n-propyl, or isopropyl, each optionally substituted. In some such embodiments, R10is C1-C6 alkyl. In some such embodiments, R10is methyl, ethyl, n-propyl, or isopropyl. In some such embodiments, R10is methyl. In some such embodiments, R10is ethyl. In some such embodiments, R10is n-propyl. In some such embodiments, R10is isopropyl. In some such embodiments, R10is C3-C8cycloalkyl. In some such embodiments, R10is cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl. In some such embodiments, R10is cyclopropyl. In some such embodiments, R10is cyclobutyl. In some such embodiments, R10is cyclopentyl. In some such embodiments, R10is cyclohexyl. In some such embodiments, R10is C1-C6haloalkyl. In some such embodiments, R10is C1haloalkyl. In some such embodiments, R10is fluoromethyl. In some such embodiments, R10is trifluoromethyl. In some such embodiments, R10is C2 haloalkyl. In some such embodiments, R10is C3 haloalkyl.

[0178] In some embodiments of Formula (I), (Ia), (Ib), (IIa), or (IIb), R11is H, halo, optionally substituted C1-C6 alkyl, C3-C8 cycloalkyl, or C1-C6 haloalkyl. In some such embodiments, R11is H. In some such embodiments, R11is halo. In some such embodiments, R11is F, Cl, or Br. In some such embodiments, R11is F. In some such embodiments, R11is Cl. In some such embodiments, R11is Br. In some such embodiments, R11is optionally substituted C1-C6 alkyl. In some such embodiments, R11is methyl, ethyl, n-propyl, or isopropyl, each optionally substituted. In some such embodiments, R11is C1-C6alkyl. In some such embodiments, R11is methyl, ethyl, n-propyl, or isopropyl. In some such embodiments, R11is methyl. In some such embodiments, R11is ethyl. In some such embodiments, R11is n-propyl. In some such embodiments, R11is isopropyl. In some such embodiments, R11is C3-C8cycloalkyl. In some such embodiments, R11is cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl. In some such embodiments, R11is cyclopropyl. In some such embodiments, R11is cyclobutyl. In some such embodiments, R11is cyclopentyl. In some such embodiments, R11is cyclohexyl. In some such embodiments, R11is C1-C6haloalkyl. In some such embodiments, R11is C1 haloalkyl. In some such embodiments, R11is fluoromethyl. In some such embodiments, R11is trifluoromethyl. In some such embodiments, R11is C2haloalkyl. In some such embodiments, R11is C3haloalkyl.

[0179] In some embodiments of Formula (I), (Ia), (Ib), (IIa), or (IIb), R9, R10a, and R10bare each independently H, halo, optionally substituted C1-C6 alkyl, C3-C8 cycloalkyl, or C1-C6 haloalkyl. In some such embodiments, R9, R10a, and R10bare each independently H, halo, oroptionally substituted C1-C6alkyl. In some such embodiments, R9, R10a, and R10bare each independently H, F, Cl, Br, or optionally substituted C1-C6 alkyl. In some such embodiments, R9, R10a, and R10bare each independently H, F, Cl, Br, substituted methyl, substituted ethyl, substituted n-propyl, or substituted isopropyl. In some such embodiments, R9, R10a, and R10bare each independently H, F, Cl, Br, or C1-C6 alkyl. In some such embodiments, R9, R10a, and R10bare each independently H, F, Cl, Br, methyl, ethyl, n-propyl, or isopropyl. In some such embodiments, R9, R10a, and R10bare each H.

[0180] In some embodiments of Formula (I), (Ia), (Ib), (IIa), (IIb), (IIIa), (IIIa-R), (IIIa- S), (IIIa-4), (IIIa-5), (IIIb), (IIIb-R), (IIIb-S), (IIIb-4), or (IIIb-5), R2is optionally substituted C1-C6alkyl. In some such embodiments, R2is substituted methyl, substituted ethyl, substituted n-propyl, or substituted isopropyl. In some such embodiments, R2is substituted methyl. In some such embodiments, R2is substituted ethyl. In some such embodiments, R2is substituted n-propyl. In some such embodiments, R2is isopropyl. In some such embodiments, R2is C1-C6alkyl. In some such embodiments, R2is methyl, ethyl, n-propyl, or isopropyl. In some such embodiments, R2is methyl. In some such embodiments, R2is ethyl. In some such embodiments, R2is n-propyl. In some such embodiments, R2is isopropyl.

[0181] In some embodiments of Formula (I), (Ia), (Ib), (IIa), (IIb), (IIIa), (IIIa-R), (IIIa- S), (IIIa-4), (IIIa-5), (IIIb), (IIIb-R), (IIIb-S), (IIIb-4), or (IIIb-5), R4is -NHSO2R12or - CH2SO2R12. In some such embodiments, R4is -NHSO2R12. In some such embodiments, R4is -NHSO2R12and R12is H, halo, or C1-C6alkyl. In some such embodiments, R4is - NHSO2CH3. In some such embodiments, R4is -CH2SO2R12. In some such embodiments, R4is -CH2SO2R12and R12is H, halo, or C1-C6 alkyl. In some such embodiments, R4is - CH2SO2CH3.

[0182] In some embodiments of Formula (I), (Ia), (Ib), (IIa), (IIb), (IIIa), (IIIa-R), (IIIa- S), (IIIa-4), (IIIa-5), (IIIb), (IIIb-R), (IIIb-S), (IIIb-4), or (IIIb-5), R5is H or halo. In some such embodiments, R5is H, F, Cl, or Br. In some such embodiments, R5is H. In some such embodiments, R5is halo. In some such embodiments, R5is F. In some such embodiments, R5is Cl. In some such embodiments, R5is Br.

[0183] In some embodiments of Formula (I), (Ia), (Ib), (IIa), (IIb), (IIIa), (IIIa-R), (IIIa- S), (IIIa-4), (IIIa-5), (IIIb), (IIIb-R), (IIIb-S), (IIIb-4), or (IIIb-5), R2is optionally substituted C1-C6alkyl, R4is -NHSO2R12or -CH2SO2R12, and R5is H or halo. In some such embodiments, R2is C1-C6 alkyl, R4is -NHSO2R12, and R5is H. In some such embodiments,R2is methyl, R4is -NHSO2R12, and R5is H. In some such embodiments, R2is ethyl, R4is - NHSO2R12, and R5is H. In some such embodiments, R2is methyl, R4is -NHSO2CH3, and R5is H. In some such embodiments, R2is ethyl, R4is -NHSO2CH3, and R5is H. In some such embodiments, R2is C1-C6alkyl, R4is -CH2SO2R12, and R5is H. In some such embodiments, R2is methyl, R4is -CH2SO2R12, and R5is H. In some such embodiments, R2is ethyl, R4is -CH2SO2R12, and R5is H. In some such embodiments, R2is methyl, R4is - CH2SO2CH3, and R5is H. In some such embodiments, R2is ethyl, R4is -CH2SO2CH3, and R5is H.

[0184] In some embodiments of Formula (I), (Ia), (Ib), (IIa), (IIb), (IIIa), (IIIa-R), (IIIa- S), (IIIa-4), (IIIa-5), (IIIb), (IIIb-R), (IIIb-S), (IIIb-4), or (IIIb-5), R3is C3-C8cycloalkyl, -C1- C10alkylene-(C3-C8cycloalkyl), C3-C8cycloalkenyl, -C1-C10alkylene-(C3-C8cycloalkenyl), C6-C14 aryl, -C1-C10 alkylene-(C6-C14 aryl), 5- to 10-membered heteroaryl, -C1-C10 alkylene- (5- to 10-membered heteroaryl), 3- to 12-membered heterocyclyl, or -C1-C10 alkylene (3- to 12-membered heterocyclyl), wherein the C3-C8cycloalkyl, -C1-C10alkylene-(C3-C8cycloalkyl), C6-C14 aryl, -C1-C10 alkylene-(C6-C14 aryl), 5- to 10-membered heteroaryl, -C1- C10 alkylene-(5- to 10-membered heteroaryl), 3- to 12-membered heterocyclyl, or -C1-C10 alkylene (3- to 12-membered heterocyclyl) are optionally substituted by halo, OH, CN, C1-C6alkyl, or C1-C6 haloalkyl. In some such embodiments, R3is is C3-C8 cycloalkyl, -C1-C10 alkylene-(C3-C8 cycloalkyl), C3-C8 cycloalkenyl, -C1-C10 alkylene-(C3-C8 cycloalkenyl), C6- C14aryl, -C1-C10alkylene-(C6-C14aryl), 5- to 10-membered heteroaryl, -C1-C10alkylene-(5- to 10-membered heteroaryl), 3- to 12-membered heterocyclyl, or -C1-C10alkylene (3- to 12- membered heterocyclyl), wherein the C3-C8 cycloalkyl, -C1-C10 alkylene-(C3-C8 cycloalkyl), C6-C14 aryl, -C1-C10 alkylene-(C6-C14 aryl), 5- to 10-membered heteroaryl, -C1-C10 alkylene- (5- to 10-membered heteroaryl), 3- to 12-membered heterocyclyl, or -C1-C10alkylene (3- to 12-membered heterocyclyl) are optionally substituted by halo, OH, or C1-C6 alkyl. In some such embodiments, R3is is C3-C8 cycloalkyl, -C1-C10 alkylene-(C3-C8 cycloalkyl), C3-C8 cycloalkenyl, -C1-C10alkylene-(C3-C8cycloalkenyl), C6-C14aryl, -C1-C10alkylene-(C6-C14aryl), 5- to 10-membered heteroaryl, -C1-C10 alkylene-(5- to 10-membered heteroaryl), 3- to 12-membered heterocyclyl, or -C1-C10 alkylene (3- to 12-membered heterocyclyl). In some such embodiments, R3is C3-C8cycloalkyl, -C1-C10alkylene-(C3-C8cycloalkyl), C6-C14aryl, - C1-C10alkylene-(C6-C14aryl), 5- to 10-membered heteroaryl, or -C1-C10alkylene-(5- to 10- membered heteroaryl), wherein the C3-C8 cycloalkyl, -C1-C10 alkylene-(C3-C8 cycloalkyl), C6-C14 aryl, -C1-C10 alkylene-(C6-C14 aryl), 5- to 10-membered heteroaryl, or -C1-C10alkylene-(5- to 10-membered heteroaryl) are optionally substituted by halo, OH, CN, C1-C6alkyl, or C1-C6 haloalkyl. In some such embodiments, R3is C3-C8 cycloalkyl, -C1-C10 alkylene-(C3-C8 cycloalkyl), C6-C14 aryl, -C1-C10 alkylene-(C6-C14 aryl), 5- to 10-membered heteroaryl, or -C1-C10alkylene-(5- to 10-membered heteroaryl), wherein the C3-C8cycloalkyl, -C1-C10 alkylene-(C3-C8 cycloalkyl), C6-C14 aryl, -C1-C10 alkylene-(C6-C14 aryl), 5- to 10-membered heteroaryl, or -C1-C10 alkylene-(5- to 10-membered heteroaryl) are optionally substituted by halo, OH, or C1-C6alkyl. In some such embodiments, R3is C3-C8cycloalkyl, -C1-C10 alkylene-(C3-C8 cycloalkyl), C6-C14 aryl, -C1-C10 alkylene-(C6-C14 aryl), 5- to 10-membered heteroaryl, or -C1-C10 alkylene-(5- to 10-membered heteroaryl). In some such embodiments, R3is C3-C8cycloalkyl, -C1-C10alkylene-(C3-C8cycloalkyl), or C6-C14aryl, wherein the C3-C8cycloalkyl, -C1-C10alkylene-(C3-C8cycloalkyl), or C6-C14aryl are optionally substituted by halo, OH, CN, C1-C6 alkyl, or C1-C6 haloalkyl. In some such embodiments, R3is C3-C8 cycloalkyl, -C1-C10 alkylene-(C3-C8 cycloalkyl), or C6-C14 aryl, wherein the C3-C8cycloalkyl, -C1-C10alkylene-(C3-C8cycloalkyl), or C6-C14aryl are optionally substituted by halo, OH, or C1-C6 alkyl. In some such embodiments, R3is C3-C8 cycloalkyl, -C1-C10 alkylene-(C3-C8 cycloalkyl), or C6-C14 aryl. In some such embodiments, R3is -CH2-cyclopropyl, cyclohexyl, or phenyl, each optionally substituted by halo, OH, CN, C1-C6 alkyl, or C1-C6 haloalkyl. In some such embodiments, R3is -CH2-cyclopropyl, cyclohexyl, or phenyl, each optionally substituted by halo, OH, or C1-C6 alkyl. In some such embodiments, R3is -CH2-cyclopropyl, cyclohexyl, or phenyl.

[0185] In some embodiments of Formula (I), (Ia), (Ib), (IIa), (IIb), (IIIa), (IIIa-R), (IIIa- S), (IIIa-4), (IIIa-5), (IIIb), (IIIb-R), (IIIb-S), (IIIb-4), or (IIIb-5), R3is C3-C8 cycloalkyl optionally substituted by halo, OH, CN, C1-C6 alkyl, or C1-C6 haloalkyl. In some such embodiments, R3is C3-C8cycloalkyl optionally substituted by halo, OH, or C1-C6alkyl. In some such embodiments, R3is C3-C8 cycloalkyl. In some such embodiments, R3is cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl, each optionally substituted by halo, OH, CN, C1-C6alkyl, or C1-C6haloalkyl. In some such embodiments, R3is cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl, each optionally substituted by halo, OH, or C1-C6 alkyl. In some such embodiments, R3is cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl. In some such embodiments, R3is cyclopropyl substituted by halo, OH, CN, C1-C6alkyl, or C1-C6haloalkyl. In some such embodiments, R3is cyclopropyl. In some such embodiments, R3is cyclobutyl substituted by halo, OH, CN, C1-C6 alkyl, or C1-C6 haloalkyl. In some such embodiments, R3is cyclobutyl. In some such embodiments, R3is cyclopentyl substituted byhalo, OH, CN, C1-C6alkyl, or C1-C6haloalkyl. In some such embodiments, R3is cyclopentyl. In some such embodiments, R3is cyclohexyl substituted by halo, OH, CN, C1- C6 alkyl, or C1-C6 haloalkyl. In some such embodiments, R3is cyclohexyl.

[0186] In some embodiments of Formula (I), (Ia), (Ib), (IIa), (IIb), (IIIa), (IIIa-R), (IIIa- S), (IIIa-4), (IIIa-5), (IIIb), (IIIb-R), (IIIb-S), (IIIb-4), or (IIIb-5), R3is -C1-C10 alkylene-(C3- C8 cycloalkyl) optionally substituted by halo, OH, CN, C1-C6 alkyl, or C1-C6 haloalkyl. In some such embodiments, R3is -C1-C10alkylene-(C3-C8cycloalkyl) optionally substituted by halo, OH, or C1-C6 alkyl. In some such embodiments, R3is -C1-C10 alkylene-(C3-C8 cycloalkyl). In some such embodiments, R3is -C1 alkylene-(C3-C8 cycloalkyl) optionally substituted by halo, OH, CN, C1-C6alkyl, or C1-C6haloalkyl. In some such embodiments, R3is -C1alkylene-(C3-C8cycloalkyl). In some such embodiments, R3is -C2alkylene-(C3-C8cycloalkyl) optionally substituted by halo, OH, CN, C1-C6 alkyl, or C1-C6 haloalkyl. In some such embodiments, R3is -C2 alkylene-(C3-C8 cycloalkyl). In some such embodiments, R3is - C3alkylene-(C3-C8cycloalkyl) optionally substituted by halo, OH, CN, C1-C6alkyl, or C1-C6haloalkyl. In some such embodiments, R3is -C3 alkylene-(C3-C8 cycloalkyl). In some such embodiments, R3is -C1-C10 alkylene-cyclopropyl optionally substituted by halo, OH, CN, C1- C6alkyl, or C1-C6haloalkyl. In some such embodiments, R3is -C1-C10alkylene-cyclopropyl. In some such embodiments, R3is -C1-C10 alkylene-cyclobutyl optionally substituted by halo, OH, CN, C1-C6 alkyl, or C1-C6 haloalkyl. In some such embodiments, R3is -C1-C10 alkylene- cyclobutyl. In some such embodiments, R3is -C1-C10alkylene-cyclopentyl optionally substituted by halo, OH, CN, C1-C6alkyl, or C1-C6haloalkyl. In some such embodiments, R3is -C1-C10 alkylene-cyclopentyl. In some such embodiments, R3is -C1-C10 alkylene- cyclohexyl optionally substituted by halo, OH, CN, C1-C6 alkyl, or C1-C6 haloalkyl. In some such embodiments, R3is -C1-C10alkylene-cyclohexyl. In some such embodiments, R3is -C1- C4 alkylene-cyclohexyl optionally substituted by halo, OH, CN, C1-C6 alkyl, or C1-C6 haloalkyl. In some such embodiments, R3is -C1-C4 alkylene-cyclohexyl. In some such embodiments, R3is -CH2-cyclohexyl optionally substituted by halo, OH, CN, C1-C6alkyl, or C1-C6 haloalkyl. In some such embodiments, R3is -CH2-cyclohexyl.

[0187] In some embodiments of Formula (I), (Ia), (Ib), (IIa), (IIb), (IIIa), (IIIa-R), (IIIa- S), (IIIa-4), (IIIa-5), (IIIb), (IIIb-R), (IIIb-S), (IIIb-4), or (IIIb-5), R3is C6-C14aryl optionally substituted by halo, OH, CN, C1-C6alkyl, or C1-C6haloalkyl. In some such embodiments, R3is C6-C14 aryl optionally substituted by halo, OH, or C1-C6 alkyl. In some such embodiments, R3is C6-C14 aryl. In some such embodiments, R3is C6-C10 aryl optionally substituted byhalo, OH, CN, C1-C6alkyl, or C1-C6haloalkyl. In some such embodiments, R3is C6-C10aryl optionally substituted by halo, OH, or C1-C6 alkyl. In some such embodiments, R3is C6-C10 aryl. In some such embodiments, R3is phenyl or naphthyl, each optionally substituted by halo, OH, CN, C1-C6alkyl, or C1-C6haloalkyl. In some such embodiments, R3is phenyl or naphthyl, each optionally substituted by halo, OH, or C1-C6 alkyl. In some such embodiments, R3is phenyl or naphthyl. In some such embodiments, R3is phenyl substituted by halo, OH, CN, C1-C6alkyl, or C1-C6haloalkyl. In some such embodiments, R3is phenyl. In some such embodiments, R3is naphthyl substituted by halo, OH, CN, C1-C6 alkyl, or C1- C6 haloalkyl. In some such embodiments, R3is naphthyl.

[0188] In some embodiments of Formula (I), (Ia), (Ib), (IIa), (IIb), (IIIa), (IIIa-R), (IIIa- S), (IIIa-4), (IIIa-5), (IIIb), (IIIb-R), (IIIb-S), (IIIb-4), or (IIIb-5), R3is -C1-C10alkylene-(C6- C14 aryl) optionally substituted by halo, OH, CN, C1-C6 alkyl, or C1-C6 haloalkyl. In some embodiments, R3is -C1-C10 alkylene-(C6-C14 aryl) optionally substituted by halo, OH, or C1- C6alkyl. In some embodiments, R3is -C1-C10alkylene-(C6-C14aryl). In some embodiments, R3is -methylene-(C6-C14 aryl). In some embodiments, R3is -ethylene-(C6-C14 aryl). In some embodiments, R3is -methylene-phenyl. In some embodiments, R3is -ethylene-phenyl.

[0189] In some embodiments of Formula (I), (Ia), (Ib), (IIa), (IIb), (IIIa), (IIIa-R), (IIIa- S), (IIIa-4), (IIIa-5), (IIIb), (IIIb-R), (IIIb-S), (IIIb-4), or (IIIb-5), R3is 5- to 10-membered heteroaryl optionally substituted by halo, OH, CN, C1-C6 alkyl, or C1-C6 haloalkyl. In some such embodiments, R3is 5- to 10-membered heteroaryl optionally substituted by halo, OH, or C1-C6alkyl. In some such embodiments, R3is 5- to 10-membered heteroaryl. In some such embodiments, R3is pyridyl or quinolinyl optionally substituted by halo, OH, CN, C1-C6 alkyl, or C1-C6 haloalkyl. In some such embodiments, R3is pyridyl or quinolinyl optionally substituted by halo, OH, or C1-C6alkyl. In some such embodiments, R3is pyridyl or quinolinyl. In some such embodiments, R3is pyridyl. In some such embodiments, R3is quinolinyl.

[0190] In some embodiments of Formula (I), (Ia), (Ib), (IIa), (IIb), (IIIa), (IIIa-R), (IIIa- S), (IIIa-4), (IIIa-5), (IIIb), (IIIb-R), (IIIb-S), (IIIb-4), or (IIIb-5), R3is -C1-C10 alkylene-(5- to 10-membered heteroaryl) optionally substituted by halo, OH, CN, C1-C6 alkyl, or C1-C6 haloalkyl. In some such embodiments, R3is -C1-C10alkylene-(5- to 10-membered heteroaryl) optionally substituted by halo, OH, or C1-C6alkyl. In some such embodiments, R3is -C1-C10 alkylene-(5- to 10-membered heteroaryl). In some such embodiments, R3is -C1 alkylene-(5- to 10-membered heteroaryl) optionally substituted by halo, OH, CN, C1-C6alkyl, or C1-C6haloalkyl. In some such embodiments, R3is -C1alkylene-(5- to 10-membered heteroaryl) optionally substituted by halo, OH, or C1-C6 alkyl. In some such embodiments, R3is -C1 alkylene-(5- to 10-membered heteroaryl). In some such embodiments, R3is -C2 alkylene-(5- to 10-membered heteroaryl) optionally substituted by halo, OH, CN, C1-C6alkyl, or C1-C6 haloalkyl. In some such embodiments, R3is -C2 alkylene-(5- to 10-membered heteroaryl) optionally substituted by halo, OH, or C1-C6 alkyl. In some such embodiments, R3is -C2alkylene-(5- to 10-membered heteroaryl). In some such embodiments, R3is -C1-C10alkylene-pyridinyl optionally substituted by halo, OH, CN, C1-C6 alkyl, or C1-C6 haloalkyl. In some such embodiments, R3is -C1-C10 alkylene-pyridinyl optionally substituted by halo, OH, or C1-C6alkyl. In some such embodiments, R3is -C1-C10alkylene-pyridinyl. In some such embodiments, R3is -C1-C10alkylene-quinolinyl optionally substituted by halo, OH, CN, C1-C6 alkyl, or C1-C6 haloalkyl. In some such embodiments, R3is -C1-C10 alkylene- quinolinyl optionally substituted by halo, OH, or C1-C6 alkyl. In some such embodiments, R3is -C1-C10alkylene-quinolinyl.

[0191] In some embodiments of Formula (I), (Ia), (Ib), (IIa), (IIb), (IIIa), (IIIa-R), (IIIa- S), (IIIa-4), (IIIa-5), (IIIb), (IIIb-R), (IIIb-S), (IIIb-4), or (IIIb-5), R3is C3-C8 cycloalkenyl optionally substituted by halo, OH, CN, C1-C6alkyl, or C1-C6haloalkyl. In some embodiments, R3is C3-C8 cycloalkenyl optionally substituted by halo, OH, or C1-C6 alkyl. In some embodiments, R3is C3-C8 cycloalkenyl.

[0192] In some embodiments of Formula (I), (Ia), (Ib), (IIa), (IIb), (IIIa), (IIIa-R), (IIIa- S), (IIIa-4), (IIIa-5), (IIIb), (IIIb-R), (IIIb-S), (IIIb-4), or (IIIb-5), R3is -C1-C10alkylene-(C3- C8 cycloalkenyl) optionally substituted by halo, OH, CN, C1-C6 alkyl, or C1-C6 haloalkyl. In some embodiments, R3is -C1-C10 alkylene-(C3-C8 cycloalkenyl) optionally substituted by halo, OH, or C1-C6alkyl. In some embodiments, R3is -C1-C10alkylene-(C3-C8cycloalkenyl).

[0193] In some embodiments of Formula (I), (Ia), (Ib), (IIa), (IIb), (IIIa), (IIIa-R), (IIIa- S), (IIIa-4), (IIIa-5), (IIIb), (IIIb-R), (IIIb-S), (IIIb-4), or (IIIb-5), R3is 3- to 12-membered heterocyclyl optionally substituted by halo, OH, CN, C1-C6 alkyl, or C1-C6 haloalkyl. In some embodiments, R3is 3- to 12-membered heterocyclyl optionally substituted by halo, OH, or C1-C6alkyl. In some embodiments, R3is 3- to 12-membered heterocyclyl.

[0194] In some embodiments of Formula (I), (Ia), (Ib), (IIa), (IIb), (IIIa), (IIIa-R), (IIIa- S), (IIIa-4), (IIIa-5), (IIIb), (IIIb-R), (IIIb-S), (IIIb-4), or (IIIb-5), R3is -C1-C10 alkylene (3- to12-membered heterocyclyl) optionally substituted by halo, OH, CN, C1-C6alkyl, or C1-C6haloalkyl. In some embodiments, R3is -C1-C10 alkylene (3- to 12-membered heterocyclyl) optionally substituted by halo, OH, or C1-C6 alkyl. In some embodiments, R3is -C1-C10 alkylene (3- to 12-membered heterocyclyl).

[0195] In some embodiments of Formula (I), (Ia), (Ib), (IIa), (IIb), (IIIa), (IIIa-R), (IIIa- S), (IIIa-4), (IIIa-5), (IIIb), (IIIb-R), (IIIb-S), (IIIb-4), or (IIIb-5), R6is H or optionally substituted C1-C6alkyl. In some such embodiments, R6is H. In some such embodiments, R6is optionally substituted C1-C6 alkyl. In some such embodiments, R6is methyl, ethyl, n- propyl, or isopropyl, each optionally substituted. In some such embodiments, R6is optionally substituted methyl. In some such embodiments, R6is optionally substituted ethyl. In some such embodiments, R6is optionally substituted n-propyl. In some such embodiments, R6is optionally substituted isopropyl. In some such embodiments, R6is C1-C6 alkyl. In some such embodiments, R6is methyl, ethyl, n-propyl, or isopropyl. In some such embodiments, R6is methyl. In some such embodiments, R6is ethyl. In some such embodiments, R6is n- propyl. In some such embodiments, R6is isopropyl.

[0196] In some embodiments of Formula (I), (Ia), (Ib), (IIa), (IIb), (IIIa), (IIIa-R), (IIIa- S), (IIIa-4), (IIIa-5), (IIIb), (IIIb-R), (IIIb-S), (IIIb-4), or (IIIb-5), R7and R8are each H or R7and R8, taken together with the carbon to which they are attached, form a carbonyl or 3- to 6- membered carbocycle. In some such embodiments, R7and R8are each H. In some such embodiments, R7and R8, taken together with the carbon to which they are attached, form a carbonyl or a 3- to 6-membered carbocycle. In some such embodiments, R7and R8, taken together with the carbon to which they are attached, form a carbonyl. In some such embodiments, R7and R8, taken together with the carbon to which they are attached, form a 3- to 6-membered carbocycle. In some such embodiments, R7and R8, taken together with the carbon to which they are attached, form a 3-membered carbocycle. In some such embodiments, R7and R8, taken together with the carbon to which they are attached, form a 4- membered carbocycle. In some such embodiments, R7and R8, taken together with the carbon to which they are attached, form a 5-membered carbocycle. In some such embodiments, R7and R8, taken together with the carbon to which they are attached, form a 6-membered carbocycle.

[0197] In some embodiments of Formula (I), (Ia), (Ib), (IIa), (IIb), (IIIa), (IIIa-R), (IIIa- S), (IIIa-4), (IIIa-5), (IIIb), (IIIb-R), (IIIb-S), (IIIb-4), or (IIIb-5), R6is H or optionally substituted C1-C6 alkyl and R7and R8are each H or R7and R8, taken together with the carbonto which they are attached, form a carbonyl or 3- to 6-membered carbocycle. In some such embodiments, R6is H or optionally substituted C1-C6 alkyl and R7and R8are each H. In some such embodiments, R6is H or optionally substituted C1-C6 alkyl and R7and R8, taken together with the carbon to which they are attached, form a carbonyl or 3- to 6-membered carbocycle. In some such embodiments, R6is H and R7and R8are each H. In some such embodiments, R6is H and R7and R8, taken together with the carbon to which they are attached, form a carbonyl. In some such embodiments, R6is C1-C6alkyl and R7and R8are each H. In some such embodiments, R6is C1-C6 alkyl and R7and R8, taken together with the carbon to which they are attached, form a carbonyl. In some such embodiments, R6is methyl and R7and R8are each H. In some such embodiments, R6is methyl and R7and R8, taken together with the carbon to which they are attached, form a carbonyl.

[0198] In some embodiments of Formula (I), (Ia), (Ib), (IIa), (IIb), (IIIa), (IIIa-R), (IIIa- S), (IIIa-4), (IIIa-5), (IIIb), (IIIb-R), (IIIb-S), (IIIb-4), or (IIIb-5), Q is absent or C(O), NR11, S, SO2NR11, NR11SO2, O, C(O)O, or C(O)NR11. In some such embodiments, Q is absent or C(O), NR11, C(O)O, or C(O)NR11. In some such embodiments, Q is absent. In some such embodiments, Q is C(O). In some such embodiments, Q is NR11. In some such embodiments, Q is C(O)O. In some such embodiments, Q is C(O)NR11.

[0199] In some embodiments of Formula (I), (Ia), (Ib), (IIa), (IIb), (IIIa), (IIIa-R), (IIIa- S), (IIIa-4), (IIIa-5), (IIIb), (IIIb-R), (IIIb-S), (IIIb-4), or (IIIb-5), L2is absent or – CH2CH2(OCH2CH2)k–, -C1-C10alkylene-, 2- to 14-membered heteroalkylene-, -C3-C8carbocyclo-, -O(C1-C8alkylene)-, -arylene-, -C1-C10alkylene-arylene-, -arylene-C1-C10alkylene-, -C1-C10 alkylene-(C3-C8 carbocyclo)-, -(C3-C8 carbocyclo)-C1-C10 alkylene-, 3- to 12-membered heterocyclo-, -C1-C10 alkylene-( 3- to 12-membered heterocyclo)-, -( 3- to 12- membered heterocyclo)-C1-C10alkylene, -C2-C10alkenylene-, 3- to 14-membered heteroalkenylene-, -O(C2-C8 alkenylene)-, -C2-C10alkenylene-arylene-, -arylene-C2-C10alkenylene-, -C2-C10alkenylene-(C3-C8 carbocyclo)-, -(C3-C8 carbocyclo)-C2-C10alkenylene- , -C2-C10alkenylene-(3- to 12-membered heterocyclo)-, -(3- to 12-membered heterocyclo)- C2-C10alkenylene, -C2-C10alkynylene-, 3- to 14-membered heteroalkynylene-, -O(C2-C8 alkynylene)-, -C2-C10alkynylene-arylene-, -arylene-C2-C10alkynylene-, -C2-C10alkynylene- (C3-C8carbocyclo)-, -(C3-C8carbocyclo)-C2-C10alkynylene-, -C2-C10alkynylene-(3- to 12- membered heterocyclo)-, or -(3- to 12-membered heterocyclo)-C2-C10alkynylene, each of which is optionally substituted. In some such embodiments, L2is –CH2CH2(OCH2CH2)k–, - C1-C10 alkylene-, -C3-C8 carbocyclo-, -C1-C10 alkylene-(C3-C8 carbocyclo)-, -(C3-C8carbocyclo)-C1-C10alkylene-, -C2-C10alkenylene-, -C2-C10alkenylene-(C3-C8carbocyclo)-, - (C3-C8 carbocyclo)-C2-C10alkenylene-, -C2-C10alkynylene-, -C2-C10alkynylene-(C3-C8 carbocyclo)-, or -(C3-C8 carbocyclo)-C2-C10alkynylene-, each of which is optionally substituted. In some such embodiments, L2is –CH2CH2(OCH2CH2)k–, -C1-C10alkylene-, - C3-C8 carbocyclo-, -arylene-, -C1-C10 alkylene-arylene-, -arylene-C1-C10 alkylene-, -C1-C10 alkylene-(C3-C8 carbocyclo)-, -(C3-C8 carbocyclo)-C1-C10 alkylene-, -C2-C10alkenylene-, - C2-C10alkynylene-, each of which is optionally substituted. In some such embodiments, L2is -C1-C10 alkylene-, -C1-C10 alkylene-(C3-C8 carbocyclo)-, -(C3-C8 carbocyclo)-C1-C10 alkylene-, -C2-C10alkenylene-, or -C2-C10alkynylene-, each of which is optionally substituted. In some such embodiments, L2is optionally substituted -C1-C10alkylene-. In some such embodiments, L2is optionally substituted methylene. In some such embodiments, L2is optionally substituted ethylene. In some such embodiments, L2is optionally substituted propylene. In some such embodiments, L2is -C1-C10 alkylene-. In some such embodiments, L2is methylene. In some such embodiments, L2is ethylene. In some such embodiments, L2is propylene.

[0200] In some embodiments of Formula (I), (Ia), (Ib), (IIa), (IIb), (IIIa), (IIIa-R), (IIIa- S), (IIIa-4), (IIIa-5), (IIIb), (IIIb-R), (IIIb-S), (IIIb-4), or (IIIb-5), R1is H, halogen, OH, CN, N3, SH, COOR12, SO2R12, SO2NR11R12, or NR11R12. In some such embodiments, R1is H, OH, COOR12, SO2NR11, or NR11R12. In some such embodiments, R1is OH, COOR12, or NR11R12. In some such embodiments, R1is H. In some such embodiments, R1is halogen. In some such embodiments, R1is F, Cl, or Br. In some such embodiments, R1is F. In some such embodiments, R1is Cl. In some such embodiments, R1is Br. In some such embodiments, R1is OH. In some such embodiments, R1is CN. In some such embodiments, R1is N3. In some such embodiments, R1is SH. In some such embodiments, R1is COOR12. In some such embodiments, R1is COOH. In some such embodiments, R1is SO2R12. In some such embodiments, R1is SO2H. In some such embodiments, R1is SO2NR11R12. In some such embodiments, R1is SO2NH2. In some such embodiments, R1is NR11R12. In some such embodiments, R1is NH2.

[0201] In some embodiments of Formula (I), (Ia), (Ib), (IIa), (IIb), (IIIa), (IIIa-R), (IIIa- S), (IIIa-4), (IIIa-5), (IIIb), (IIIb-R), (IIIb-S), (IIIb-4), or (IIIb-5), L1is a linking group having the structure** . In some such embodiments, subscript n is an integerfrom 1 to 6. In some such embodiments, W1is CONR11, CO, C2-C6alkenylene, C2-C6alkynylene, or absent. In some such embodiments, W1is CONR11or CO. In some such embodiments, W1is C(O)NH. In some such embodiments, W2is, independently at each occurrence, O, NR11, -CONR11-, -NR11CO-, optionally substituted C3-C8cycloalkylene, optionally substituted C3-C8 cycloalkenylene, optionally substituted C6-C14 arylene, optionally substituted 5- to 10-membered heteroarylene, optionally substituted 3- to 12- membered heterocyclylene, or absent. In some such embodiments, W2is, independently at each occurrence, O, NR11, optionally substituted C3-C8 cycloalkylene, optionally substituted 3- to 12-membered heterocyclylene, or absent. In some such embodiments, W3is, independently at each occurrence, O, NR11, optionally substituted C1-C10alkylene, optionally substituted C2-C10alkenylene, optionally substituted C2-C10alkynylene, optionally substituted 2- to 14-membered heteroalkylene, or absent. In some such embodiments, W3is, independently at each occurrence, O, NR11, optionally substituted C1-C10 alkylene, optionally substituted 2- to 14-membered heteroalkylene, or absent. In some such embodiments, L1is *-W3-W1-**, *-W3-W2-W3-W1-**, *-W3-W2-W2-W1-**, *-W3-W2-W1-**, *-W3-W2-W3-W2- W1-**, or *-W3-W2-W3-W2-W3-W2-W1-**. In some such embodiments, L1is *-W3-W1-**, *-W3-W2-W3-W1-**, or *-W3-W2-W2-W1-**. In some such embodiments, L1is *-W3-W1- **. In some such embodiments, L1is *-W3-W2-W3-W1-**. In some such embodiments, L1is *-W3-W2-W2-W1-**. In some such embodiments, L1is,, , ,. In some such embodiments, L1isIn some such embodiments, L1is. In some such embodiments, L1is. In some such embodiments, L1isIn some such embodiments, L1is. In some such embodiments, L1is. In some such embodiments, L1is . 1In some such embodiments, L is . In some such embodiments, L1is. In some such embodiments, L1is1. In some such embodiments, L is .In some such embodiments, L1is . In some such embodiments, L1is.

[0202] In some embodiments, provided is a compound of Table 1, or a salt thereof (e.g., a pharmaceutically acceptable salt). Table 1. Targeted degrader compoundsDrug-Linker Compounds

[0203] In some embodiments, when preparing Ligand-Drug Conjugate compounds described herein, it will be desirable to synthesize the full Drug-Linker compound prior toconjugation to a targeting agent, wherein after the conjugation of the Drug Linker compound with the Drug Linker, the targeting agent becomes the Ligand Unit of the Ligand-Drug Conjugate compound. In such embodiments, Drug-Linker compounds as described herein, are intermediate compounds. In those embodiments, the Stretcher Unit in a Drug-Linker compound is not yet covalently attached to the Ligand Unit (i.e., is a Stretcher Unit precursor, Z'), and therefore has a functional group for conjugation to a targeting agent. In one embodiment, a Drug-Linker compound comprises a targeted degrader moiety (shown herein as Formula (I), or any subformula thereof) or, and a Linker Unit through which the Ligand Unit is connected to the Drug Unit.

[0204] In some embodiments, a Drug-Linker compound comprises a targeted degrader compound of Formula (I), or any subformula thereof, as a Drug Unit (D) and a Linker Unit. The Linker Unit comprises a Stretcher Unit precursor (Z') comprising a functional group for conjugation to a targeting agent that is the precursor to the Ligand Unit and thus is capable of (directly or indirectly) connecting the Drug Unit to the Ligand Unit. In some embodiments, the Linker Unit comprises a Connector Unit (A).

[0205] In one group of embodiments, a Drug-Linker compound comprises a targeted degrader compound of Formula (I), or any subformula thereof, and a Linker Unit, wherein the Linker Unit comprises a Stretcher Unit precursor (Z'), wherein Z' comprises a functional group capable of forming a covalent bond to a targeting agent.

[0206] In another group of embodiments, a Drug-Linker compound comprises a targeted degrader compound of Formula (I), (Ia), (Ib), (IIa), (IIb), (IIIa), (IIIa-R), (IIIa-S), (IIIa-4), (IIIa- 5), (IIIb), (IIIb-R), (IIIb-S), (IIIb-4), or (IIIb-5), or any subformula thereof. In such embodiments, the Drug-Linker compound comprises a targeted degrader compound according to any of the embodiments as described herein.

[0207] It will be understood that depictions of a tetravalent N atom in any of the formulas or embodiments herein represents a tetravalent N atom with a positive charge. It will be understood that depictions of trivalent N atoms in any of the formulas or embodiments herein also represent a protonated tetravalent N atom.

[0208] In some embodiments, the Drug Linker compound has following formula: Z'-A-D, or a pharmaceutically acceptable salt thereof, whereinZ' is a Stretcher Unit precursor; A is a bond or a Connector Unit; and D is a Drug Unit of Formula (I'):Formula (I'), wherein: X is CH, N, O, or S; Z1is H or absent; Z2is H; or Z1and Z2are taken together to form a single bond or a C1-C4 alkylene group; provided that when X is O or S, Z1is absent; Y1and Y2are independently CH, CF, or N; Q is absent or C(O), NR11, S, SO2NR11, NR11SO2, O, C(O)O, or C(O)NR11; R1is O, S, COO, SO2, SO2NR11, or NR11; L2is absent or –CH2CH2(OCH2CH2)k–, -C1-C10alkylene-, 2- to 14-membered heteroalkylene-, -C3-C8carbocyclo-, -O(C1-C8alkylene)-, -arylene-, -C1-C10alkylene- arylene-, -arylene-C1-C10 alkylene-, -C1-C10 alkylene-(C3-C8 carbocyclo)-, -(C3-C8 carbocyclo)-C1-C10alkylene-, 3- to 12-membered heterocyclo-, -C1-C10alkylene-( 3- to 12-membered heterocyclo)-, -( 3- to 12-membered heterocyclo)-C1-C10alkylene, - C2-C10alkenylene-, 3- to 14-membered heteroalkenylene-, -O(C2-C8 alkenylene)-, - C2-C10alkenylene-arylene-, -arylene-C2-C10alkenylene-, -C2-C10alkenylene-(C3-C8 carbocyclo)-, -(C3-C8carbocyclo)-C2-C10alkenylene-, -C2-C10alkenylene-(3- to 12- membered heterocyclo)-, -(3- to 12-membered heterocyclo)-C2-C10alkenylene, -C2- C10 alkynylene-, 3- to 14-membered heteroalkynylene-, -O(C2-C8 alkynylene)-, -C2- C10alkynylene-arylene-, -arylene-C2-C10alkynylene-, -C2-C10alkynylene-(C3-C8carbocyclo)-, -(C3-C8carbocyclo)-C2-C10alkynylene-, -C2-C10alkynylene-(3- to 12-membered heterocyclo)-, or -(3- to 12-membered heterocyclo)-C2-C10alkynylene, each of which is optionally substituted; subscript k is an integer ranging from 1 to 36, wherein # denotes the point of attachment to A; and R2is optionally substituted C1-C6 alkyl; R3is C3-C8 cycloalkyl, -C1-C10 alkylene-(C3-C8 cycloalkyl), C3-C8 cycloalkenyl, -C1- C10alkylene-(C3-C8cycloalkenyl), C6-C14aryl, -C1-C10alkylene-(C6-C14aryl), 5- to 10- membered heteroaryl, -C1-C10 alkylene-(5- to 10-membered heteroaryl), 3- to 12-membered heterocyclyl, or -C1-C10 alkylene (3- to 12-membered heterocyclyl), wherein the C3-C8 cycloalkyl, -C1-C10alkylene-(C3-C8cycloalkyl), C6-C14aryl, -C1-C10alkylene-(C6-C14aryl), 5- to 10-membered heteroaryl, -C1-C10alkylene-(5- to 10-membered heteroaryl), 3- to 12- membered heterocyclyl, or -C1-C10 alkylene (3- to 12-membered heterocyclyl) are optionally substituted by halo, OH, CN, C1-C6 alkyl, or C1-C6 haloalkyl; R4is -NHSO2R12or -CH2SO2R12; R5is H or halo; R6is H or optionally substituted C1-C6 alkyl; R7and R8are each H, or R7and R8, taken together with the carbon to which they are attached, form a carbonyl or 3- to 6-membered carbocycle; R9, R10a, and R10bare each independently H, halo, optionally substituted C1-C6alkyl, C3-C8cycloalkyl, or C1-C6haloalkyl; L1is a linking group having the structure:** ; wherein W1is C2-C6alkenylene, C2-C6alkynylene, optionally substituted 5- to 10- membered heteroarylene, optionally substituted 3- to 12-membered heterocyclene, CO, CONR11, C(O)O, SO2NR11, or absent; W2is, independently at each occurrence, O, S, NR11, -COO-, -OCO-, -CONR11-, - NR11CO-, -SO2NR11-, -NR11SO2-, optionally substituted C3-C8cycloalkylene, optionally substituted C3-C8 cycloalkenylene, optionally substituted C6-C14 arylene, optionally substituted 5- to 10-membered heteroarylene, optionally substituted 3- to 12-membered heterocyclylene, or absent;W3is, independently at each occurrence, O, S, NR11, optionally substituted C1-C10alkylene, optionally substituted C2-C10alkenylene, optionally substituted C2-C10alkynylene, optionally substituted 2- to 14-membered heteroalkylene, or absent; subscript n is an integer from 1 to 6; * indicates the point of attachment to * in Formula (I); ** indicates the point of attachment to ** in Formula (I); provided that at least one of W1, W2, and W3is not absent; and R11and R12are, independently of each other and independently at each occurrence, H, halo, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy, or C3-C8 cycloalkyl.

[0209] In the context of the Drug-Linker Compounds – the assembly is best described in terms of its component groups. While some procedures for the preparation of Drug-Linker compounds are described herein, the order of assembly and the general conditions to prepare the compounds will be well understood by one of skill in the art in view of the teachings of the application. C. Component groups 1. Drug Unit D

[0210] The Drug Units of the Drug-Linker compounds, or Ligand-Drug Conjugate thereof, provided herein are targeted degrader moieities of the compounds disclosed herein and are referred to herein as Drug Units.

[0211] In some embodiments, the Drug Unit D has Formula (I'), as described above. 2. Linker Unit

[0212] As noted above, in some embodiments, the Linker Unit has the formula Z'-A-, wherein Z' is a Stretcher Unit and A is a bond or a Connector Unit. 3. Stretcher Unit Precursor Z'

[0213] A Stretcher Unit (Z) is a component of a Ligand-Drug Conjugate that acts to connect the Ligand Unit to the remainder of the conjugate. A Stretcher Unit precursor (Z') is a component of a Drug-Linker compound or intermediate thereof has a functional group that can form a bond with a functional group of a targeting ligand to form a Stretcher Unit (Z).

[0214] In some embodiments, a Stretcher Unit precursor (Z') has an electrophilic group that is capable of interacting with a reactive nucleophilic group present on a Ligand Unit (e.g., an antibody) to provide a covalent bond between a Ligand Unit and the Stretcher Unit of a Linker Unit. Nucleophilic groups on an antibody having that capability include but are notlimited to, sulfhydryl, hydroxyl, and amino functional groups. In some embodiments, the heteroatom of the nucleophilic group of an antibody is reactive to an electrophilic group on a Stretcher Unit precursor and can provide a covalent bond between the Ligand Unit and Stretcher Unit of a Linker Unit or Drug-Linker moiety. Useful electrophilic groups for that purpose include, but are not limited to, maleimide, haloacetamide groups, and NHS esters. The electrophilic group provides a convenient site for antibody attachment to form a Ligand-Drug Conjugate compound or Ligand Unit-Linker intermediate compound.

[0215] In other embodiments, a Stretcher Unit precursor has a reactive site which has a nucleophilic group that is reactive to an electrophilic group present on a Ligand Unit (e.g., an antibody). Useful electrophilic groups on an antibody for that purpose include, but are not limited to, aldehyde and ketone carbonyl groups. The heteroatom of a nucleophilic group of a Stretcher Unit precursor can react with an electrophilic group on an antibody and form a covalent bond to the antibody. Useful nucleophilic groups on a Stretcher Unit precursor for that purpose include, but are not limited to, hydrazide, hydroxylamine, amino, hydrazine, thiosemicarbazone, hydrazine carboxylate, and arylhydrazide. The electrophilic group on an antibody provides a convenient site for antibody attachment to form a Ligand-Drug Conjugate compound or Ligand Unit-Linker intermediate compound.

[0216] In some embodiments, a sulfur atom of a Ligand Unit is bound to a succinimide ring system of a Stretcher Unit formed by reaction of a thiol functional group of a targeting ligand with a maleimide moiety of the corresponding Stretcher Unit precursor. In other embodiments, a thiol functional group of a Ligand Unit reacts with an alpha haloacetamide moiety to provide a sulfur-bonded Stretcher Unit by nucleophilic displacement of its halogen substituent.

[0217] Illustrative Stretcher Units prior to conjugation to the Ligand Unit (i.e., Stretcher Unit precursors) comprise a maleimide moiety and are represented by structures including that of formula Z'awherein the wavy line adjacent the carbonyl carbon atom indicates attachment to A in the formulae above, depending on the presence or absence of A, R17is –(CH2)1-5– or –CH2CH2(OCH2CH2)1-36–. In some embodiments, R17is -CH2-, -(CH2)2-, -(CH2)3-, -(CH2)4-, -(CH2)5-, –CH2CH2OCH2CH2-, –CH2CH2(OCH2CH2)2–, –CH2CH2(OCH2CH2)3–, –CH2CH2(OCH2CH2)4–, –CH2CH2(OCH2CH2)5–, –CH2CH2(OCH2CH2)6–, –CH2CH2(OCH2CH2)7–, –CH2CH2(OCH2CH2)8–, –CH2CH2(OCH2CH2)10–, –CH2CH2(OCH2CH2)12–, –CH2CH2(OCH2CH2)14–, –CH2CH2(OCH2CH2)16–, –CH2CH2(OCH2CH2)18–, –CH2CH2(OCH2CH2)20–, –CH2CH2(OCH2CH2)24–, –CH2CH2(OCH2CH2)28–, –CH2CH2(OCH2CH2)32–, or –CH2CH2(OCH2CH2)36–.

[0218] Other illustrative Stretcher Units prior to conjugation to the Ligand Unit (i.e., Stretcher Unit precursors) comprises a maleimide moiety and are represented by structures including that of formula Z'a-BUwherein the wavy line adjacent the carbonyl carbon atom indicates attachment to A in the formulae above, depending on the presence or absence of A, R17is –(CH2)1-5– or –CH2CH2(OCH2CH2)1-5–, substituted with a Basic Unit (BU), such as an optionally substituted aminoalkyl, e.g., –(CH2 )xNH2, –(CH2 )xNHRa, and –(CH2 )xN(Ra) 2, wherein subscript x is an integer of from 1-4, preferably R17is -CH2- or -CH2CH2- and subscript x is 1 or 2, and each Rais independently selected from the group consisting of C1-6alkyl and C1-6 haloalkyl, or two Ragroups are combined with the nitrogen to which they are attached to form an azetidinyl, pyrrolidinyl or piperidinyl group.

[0219] In some embodiments of formula Z'a, a Stretcher Unit precursor (Z') is represented by one of the following structures:wherein the wavy line adjacent to the carbonyl is as defined for Z'a or Z'a-BU.

[0220] In other embodiments the Stretcher unit precursor (Z') comprises a maleimide moiety and is represented by the structure of:, wherein the wavy line adjacent to the carbonyl is as defined for Z'a and the amino group is optional protonated or protected by an amino protecting group.

[0221] In Stretcher Units having a BU moiety, it will be understood that the amino functional group of that moiety is typically protected by an amino protecting group during synthesis, e.g., an acid labile protecting group (e.g., BOC).

[0222] Illustrative Stretcher Unit precursors covalently attached to a Connector Unit that comprise the structure of Z'a or Z'a-BU in which –R17- or –R17(BU)- is –CH2-, -CH2CH2- or –CH(CH2NH2)- have the following structures:,, wherein the wavy line adjacent to the carbonyl is as defined for Z'a or Z'a-BU.

[0223] In some embodiments, the Stretcher Unit has a mass of no more than about 1000 daltons, no more than about 500 daltons, no more than about 200 daltons, from about 30, 50 or 100 daltons to about 1000 daltons, from about 30, 50 or 100 daltons to about 500 daltons, or from about 30, 50 or 100 daltons to about 200 daltons. Connector Unit (A)

[0224] In some embodiments, a Connector Unit (A), is included in a Drug-Linker Compound in instances where it is desirable to add additional distance between the Stretcher Unit precursor (Z') and the Drug Unit. Accordingly, the Connector Unit (A), when present, extends the framework of the Linker Unit. In that regard, a Connector Unit (A) is covalently bonded with the Stretcher Unit (or its precursor) at one terminus and is covalently bonded to the Drug Unit at its other terminus.

[0225] The skilled artisan will appreciate that the Connector Unit is any group that serves to provide for attachment of the Releasable Linker to the remainder of the Linker Unit. The Connector Unit can, for example, comprise one or more (e.g., 1-10, preferably, 1, 2, 3, or 4) proteinogenic or non-proteinogenic amino acid, amino alcohol, amino aldehyde, diamino residues. In some embodiments, the Connector Unit is a single proteinogenic or non- proteinogenic amino acid, amino alcohol, amino aldehyde, or diamino residue. An exemplary amino acid capable of acting as Connector units is β-alanine.

[0226] In some of those embodiments, the Connector Unit has the formula denoted below:, wherein the wavy lines indicate attachment of the Connector Unit within the Drug-Linker Compound; and wherein R111is independently selected from the group consisting of hydrogen, p-hydroxybenzyl, methyl, isopropyl, isobutyl, sec-butyl, -CH2OH, -CH(OH)CH3, - CH2CH2SCH3, -CH2CONH2, -CH2COOH, -CH2CH2CONH2, -CH2CH2COOH, - (CH2)3NHC(=NH)NH2, -(CH2)3NH2, -(CH2)3NHCOCH3, -(CH2)3NHCHO, - (CH2)4NHC(=NH)NH2, -(CH2)4NH2, -(CH2)4NHCOCH3, -(CH2)4NHCHO, - (CH2)3NHCONH2, -(CH2)4NHCONH2, -CH2CH2CH(OH)CH2NH2, 2-pyridylmethyl-, 3- pyridylmethyl-, 4-pyridylmethyl-,, and each R100is independently selected from hydrogen or -C1-C3 alkyl, preferably hydrogen or CH3; and subscript c is an independently selected integer from 1 to 10, preferably 1 to 3.

[0227] In some embodiments, provided herein is a Drug-Linker compound of Table 2, or a salt thereof.Table 2. Exemplary Drug-Linker compoundsLigand-Drug Conjugate compounds

[0228] In another aspect, the disclosure provides Ligand-Drug Conjugate compounds (LDCs) comprising targeted degrader moieties of the disclosure. In context of Ligand-Drug Conjugate compounds, the assembly is described by the component groups as described for Drug-Linker compounds, with the exception of the Stretcher Unit Z and the Ligand Unit L. The Stretcher Unit Z is coordinated to the Ligand Unit L in Ligand-Drug Conjugate compounds, as described below. While some procedures for the preparation of Ligand-Drug Conjugate compounds are described herein, the order of assembly and the general conditions to prepare the compounds will be well understood by one of skill in the art.

[0229] In some embodiments, a Ligand-Drug Conjugate compound disclosed herein comprises a targeted degrader compound of Formula (I), or any subformula thereof, a Linker Unit comprising a Stretcher Unit (Z) connected to the Ligand Unit. In some embodiments, a Connector Unit (A) is present when it is desirable to add more distance between the Stretcher Unit and the Drug moiety.

[0230] In some embodiments, the Ligand-Drug Conjugate compound has the formula: L-(Z-A-D)p or a pharmaceutically acceptable salt thereof, wherein L is a Ligand Unit; Z is a Stretcher Unit; A is a bond or a Connector Unit;D is a Drug Unit of Formula (I'):Formula (I'), wherein: X is CH, N, O, or S; Z1is H or absent; Z2is H; or Z1and Z2are taken together to form a single bond or a C1-C4alkylene group; provided that when X is O or S, Z1is absent; Y1and Y2are independently CH, CF, or N; Q is absent or C(O), NR11, S, SO2NR11, NR11SO2, O, C(O)O, or C(O)NR11; R1is O, S, COO, SO2, SO2NR11, or NR11; L2is absent or –CH2CH2(OCH2CH2)k–, -C1-C10alkylene-, 2- to 14-membered heteroalkylene-, -C3-C8 carbocyclo-, -O(C1-C8 alkylene)-, -arylene-, -C1-C10 alkylene- arylene-, -arylene-C1-C10alkylene-, -C1-C10alkylene-(C3-C8carbocyclo)-, -(C3-C8carbocyclo)-C1-C10alkylene-, 3- to 12-membered heterocyclo-, -C1-C10alkylene-( 3- to 12- membered heterocyclo)-, -( 3- to 12-membered heterocyclo)-C1-C10 alkylene, -C2-C10alkenylene-, 3- to 14-membered heteroalkenylene-, -O(C2-C8alkenylene)-, -C2-C10alkenylene-arylene-, -arylene-C2-C10alkenylene-, -C2-C10alkenylene-(C3-C8carbocyclo)-, - (C3-C8 carbocyclo)-C2-C10alkenylene-, -C2-C10alkenylene-(3- to 12-membered heterocyclo)- , -(3- to 12-membered heterocyclo)-C2-C10alkenylene, -C2-C10alkynylene-, 3- to 14- membered heteroalkynylene-, -O(C2-C8alkynylene)-, -C2-C10alkynylene-arylene-, -arylene- C2-C10alkynylene-, -C2-C10alkynylene-(C3-C8carbocyclo)-, -(C3-C8carbocyclo)-C2-C10alkynylene-, -C2-C10alkynylene-(3- to 12-membered heterocyclo)-, or -(3- to 12-membered heterocyclo)-C2-C10alkynylene, each of which is optionally substituted; subscript k is an integer ranging from 1 to 36, wherein # denotes the point of attachment to the reminder of the Ligand-Drug Conjugate compound; and R2is optionally substituted C1-C6 alkyl; R3is C3-C8cycloalkyl, -C1-C10alkylene-(C3-C8cycloalkyl), C3-C8cycloalkenyl, -C1-C10alkylene-(C3-C8 cycloalkenyl), C6-C14 aryl, -C1-C10 alkylene-(C6-C14 aryl), 5- to 10- membered heteroaryl, -C1-C10 alkylene-(5- to 10-membered heteroaryl), 3- to 12-membered heterocyclyl, or -C1-C10alkylene (3- to 12-membered heterocyclyl), wherein the C3-C8cycloalkyl, -C1-C10alkylene-(C3-C8cycloalkyl), C6-C14aryl, -C1-C10alkylene-(C6-C14aryl), 5- to 10-membered heteroaryl, -C1-C10 alkylene-(5- to 10-membered heteroaryl), 3- to 12- membered heterocyclyl, or -C1-C10 alkylene (3- to 12-membered heterocyclyl) are optionally substituted by halo, OH, CN, C1-C6alkyl, or C1-C6haloalkyl; R4is -NHSO2R12or -CH2SO2R12; R5is H or halo; R6is H or optionally substituted C1-C6alkyl; R7and R8are each H, or R7and R8, taken together with the carbon to which they are attached, form a carbonyl or 3- to 6-membered carbocycle; R9, R10a, and R10bare each independently H, halo, optionally substituted C1-C6alkyl, C3-C8cycloalkyl, or C1-C6 haloalkyl; L1is a linking group having the structure:** ; wherein W1is C2-C6 alkenylene, C2-C6 alkynylene, optionally substituted 5- to 10- membered heteroarylene, optionally substituted 3- to 12-membered heterocyclene, CO, CONR11, C(O)O, SO2NR11, or absent; W2is, independently at each occurrence, O, S, NR11, -COO-, -OCO-, -CONR11-, - NR11CO-, -SO2NR11-, -NR11SO2-, optionally substituted C3-C8 cycloalkylene, optionallysubstituted C3-C8cycloalkenylene, optionally substituted C6-C14arylene, optionally substituted 5- to 10-membered heteroarylene, optionally substituted 3- to 12-membered heterocyclylene, or absent; W3is, independently at each occurrence, O, S, NR11, optionally substituted C1-C10alkylene, optionally substituted C2-C10alkenylene, optionally substituted C2-C10alkynylene, optionally substituted 2- to 14-membered heteroalkylene, or absent; subscript n is an integer from 1 to 6; * indicates the point of attachment to * in Formula (I); ** indicates the point of attachment to ** in Formula (I); provided that at least one of W1, W2, and W3is not absent; and R11and R12are, independently of each other and independently at each occurrence, H, halo, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy, or C3-C8 cycloalkyl; and subscript p is an integer ranging from 1 to 12.

[0231] In the context of the Ligand-Drug Conjugate compounds – the assembly is best described in terms of its component groups. While some procedures for the preparation of Ligand-Drug Conjugate compounds are described herein, the order of assembly and the general conditions to prepare the compounds will be well understood by one of skill in the art. The component groups of the Ligand-Drug Conjugate compounds described are in many cases identical to the component groups for Drug-Linker compounds as described above, including A and D. It is to be understood that embodiments are contemplated wherein the Drug Unit D of the Ligand-Drug Conjugates described herein is conforms to the description of Formula (I'), or any subformula thereof. Other component groups are described below. Stretcher Unit Z

[0232] Representative Stretcher Units of such embodiments include those having the structures of:wherein the wavy line adjacent to R17indicates attachment to the Connector Unit (A), the other wavy line indicates covalent attachment to a sulfur atom of a Ligand Unit, and R17is –CH2CH2(OCH2CH2)k–, -C1-C10 alkylene-, C1-C10 heteroalkylene-, -C3-C8 carbocyclo-, -O- (C1-C8alkylene)-, -arylene-, -C1-C10alkylene-arylene-, -arylene-C1-C10alkylene-, -C1-C10alkylene-(C3-C8carbocyclo)-, -(C3-C8carbocyclo)-C1-C10alkylene-, -C3-C8heterocyclo-, -C1- C10 alkylene-(C3-C8 heterocyclo)-, -(C3-C8 heterocyclo)-C1-C10 alkylene-, -C1-C10 alkylene- C(=O)-, C1-C10heteroalkylene-C(=O)-, -C3-C8carbocyclo-C(=O)-, -O-(C1-C8alkylene)- C(=O)-, -arylene-C(=O)-, -C1-C10alkylene-arylene-C(=O)-, -arylene-C1-C10alkylene-C(=O)-, -C1-C10 alkylene-(C3-C8 carbocyclo)-C(=O)-, -(C3-C8 carbocyclo)-C1-C10 alkylene-C(=O)-, - C3-C8 heterocyclo-C(=O)-, -C1-C10 alkylene-(C3-C8 heterocyclo)-C(=O)-, -(C3-C8 heterocyclo)-C1-C10alkylene-C(=O)-, -C1-C10alkylene-NH-, -C1-C10heteroalkylene-NH-, - C3-C8carbocyclo-NH-, -O-(C1-C8alkylene)-NH-, -arylene-NH-, -C1-C10alkylene-arylene- NH-, -arylene-C1-C10 alkylene-NH-, -C1-C10 alkylene-(C3-C8 carbocyclo)-NH-, -(C3-C8 carbocyclo)-C1-C10alkylene-NH-, -C3-C8heterocyclo-NH-, -C1-C10alkylene-(C3-C8heterocyclo)-NH-, -(C3-C8heterocyclo)-C1-C10alkylene-NH-, -C1-C10alkylene-S-, C1-C10heteroalkylene-S -, -C3-C8 carbocyclo-S -, -O-(C1-C8 alkylene)-S -, -arylene-S-, -C1-C10 alkylene-arylene-S-, -arylene-C1-C10alkylene-S-, -C1-C10alkylene-(C3-C8carbocyclo)-S-, - (C3-C8carbocyclo)-C1-C10alkylene-S-, -C3-C8heterocyclo-S-, -C1-C10alkylene-(C3-C8heterocyclo)-S-, or -(C3-C8 heterocyclo)-C1-C10 alkylene-S-, wherein subscript k is an integer ranging from 1 to 36.

[0233] In some embodiments, the R17group is optionally substituted by a Basic Unit (BU) such as an aminoalkyl moiety, e.g. –(CH2)xNH2, –(CH2)xNHRa, and –(CH2)xNRa2, wherein subscript x is an integer of from 1-4 and each Rais independently selected from the groupconsisting of C1-6alkyl and C1-6haloalkyl, or two Ragroups are combined with the nitrogen to which they are attached to form an azetidinyl, pyrrolidinyl or piperidinyl group.

[0234] An illustrative Stretcher Unit is that of Formula Za or Za-BU in which R17is –CH2CH2(OCH2CH2)k–, -C1-C10alkylene-C(=O)-, -C1-C10heteroalkylene-C(=O)-, -C3-C8carbocyclo-C(=O)-, -O-(C1-C8 alkylene)-C(=O)-, -arylene-C(=O)-, -C1-C10 alkylene-arylene- C(=O)-, -arylene-C1-C10 alkylene-C(=O)-, -C1-C10 alkylene-(C3-C8 carbocyclo)-C(=O)-,-(C3- C8carbocyclo)-C1-C10alkylene-C(=O)-, -C3-C8heterocyclo-C(=O)-, -C1-C10alkylene-(C3-C8heterocyclo)-C(=O)-, or -(C3-C8 heterocyclo)-C1-C10 alkylene-C(=O), wherein subscript k is an integer ranging from 1 to 36:, wherein the wavy line adjacent the carbonyl carbon atom indicates attachment to LP, B, A, or S*, in the formulae above, depending on the presence or absence of A and / or B, and the other wavy line indicates covalent bonding of the succinimide ring carbon atom to a sulfur atom of a Ligand Unit. In some embodiments, the basic amino functional group of the Basic Unit (BU) is protected by a protecting group during synthesis.

[0235] In some embodiments, Stretcher Units of formula Za and Za-BU are as follows:wherein the wavy line adjacent the carbonyl carbon atom indicates attachment to B, A, or S*, in the formulae above, depending on the presence or absence of A and / or B, and the otherwavy line indicates covalent bonding of the succinimide ring carbon atom to a sulfur atom of a Ligand Unit.

[0236] It will be understood that a Ligand Unit-substituted succinimide may exist in hydrolyzed form(s). Those forms are exemplified below for hydrolysis of Za or Za-BU, wherein the structures representing the regioisomers from that hydrolysis have formula Zb and Zc or Zb-BU and Zc-BU.

[0237] Accordingly, in some embodiments, a Stretcher unit (Z) comprises a succinic acid-amide moiety represented by the following:wherein the wavy line adjacent to the carbonyl carbon atom bonded to R17and the wavy line adjacent to the carbon atom of the succinic acid-amide moiety is as defined for Za or Za-BU, depending on the presence or absence of A and / or B; and R17is –C1-C5 alkylene-, wherein in Zb-BU and Zc-BU the alkylene is substituted by a Basic Unit (BU), wherein BU is –(CH2 )xNH2, –(CH2)xNHRa, or –(CH2 )xN(Ra)2, wherein subscript x is an integer of from 1-4 and each Rais independently selected from the group consisting of C1-6 alkyl and C1-6 haloalkyl, or both Ratogether with the nitrogen to which they are attached define an azetidinyl, pyrrolidinyl or piperidinyl group.

[0238] In some embodiments, -Z-A- comprises a moiety derived from a maleimido- alkanoic acid moiety or an mDPR moiety. See, for example, see WO 2013 / 173337. In one group of embodiments, Z-A- is derived from a maleimido-propionyl moiety.

[0239] In some embodiments, a Stretcher unit (Z) comprises an succinic acid-amide moiety represented by the structure of formula Zb', Zc', (R / S)-Zb'-BU, (S)-Zb'-BU, (R / S)-Zc'- BU or (S)-Zc'-BU as follows:wherein the wavy lines are as defined for Za or Za-BU.

[0240] In some embodiments, a Stretcher unit (Z) comprises a succinimide moiety represented by the structure of. , which may be generated from a maleimido-amino-propionyl (mDPR) analog (a 3-amino-2- (2,5-dioxo-2,5-dihydro-1H-pyrrol-1-yl)propanoic acid derivative), or comprises a succinic acid-amide moiety represented by the structure of:or .

[0241] Illustrative Stretcher Units bonded to a Connector Unit (A) which comprise Za’, Zb' or Zc', in which –R17- of Za, Zb or Zc is –CH2- or -CH2CH2-, or comprise Za'-BU, Zb'-BU or Zc'-BU in which –R17(BU)- of Za'-BU, Zb'-BU or Zc'-BU is –CH(CH2NH2)-, have the following structures:, ,, wherein the wavy lines are as defined for Za or Za-BU.

[0242] In another embodiment, the Stretcher Unit is attached to the Ligand Unit via a disulfide bond between a sulfur atom of the Ligand Unit and a sulfur atom of the Stretcher unit. A representative Stretcher Unit of this embodiment is depicted within the square brackets of Formula Zb:wherein the wavy line indicates attachment to the Connector Unit (A) and R17is –CH2CH2(OCH2CH2)k–, -C1-C10 alkylene-, C1-C10 heteroalkylene-, -C3-C8 carbocyclo-, -O- (C1-C8alkylene)-, -arylene-, -C1-C10alkylene-arylene-, -arylene-C1-C10alkylene-, -C1-C10alkylene-(C3-C8 carbocyclo)-, -(C3-C8 carbocyclo)-C1-C10 alkylene-, -C3-C8 heterocyclo-, -C1- C10 alkylene-(C3-C8 heterocyclo)-, -(C3-C8 heterocyclo)-C1-C10 alkylene-, -C1-C10 alkylene-C(=O)-, C1-C10heteroalkylene-C(=O)-, -C3-C8carbocyclo-C(=O)-, -O-(C1-C8alkylene)- C(=O)-, -arylene-C(=O)-, -C1-C10 alkylene-arylene-C(=O)-, -arylene-C1-C10 alkylene-C(=O)-, -C1-C10 alkylene-(C3-C8 carbocyclo)-C(=O)-,-(C3-C8 carbocyclo)-C1-C10 alkylene-C(=O)-, - C3-C8heterocyclo-C(=O)-, -C1-C10alkylene-(C3-C8heterocyclo)-C(=O)-, -(C3-C8heterocyclo)-C1-C10 alkylene-C(=O)-, -C1-C10 alkylene-NH-, C1-C10 heteroalkylene-NH-, -C3- C8 carbocyclo-NH-, -O-(C1-C8 alkylene)-NH-, -arylene-NH-, -C1-C10 alkylene-arylene-NH-, - arylene-C1-C10alkylene-NH-, -C1-C10alkylene-(C3-C8carbocyclo)-NH-, -(C3-C8carbocyclo)- C1-C10 alkylene-NH-, -C3-C8 heterocyclo-NH-, -C1-C10 alkylene-(C3-C8 heterocyclo)-NH-, - (C3-C8 heterocyclo)-C1-C10 alkylene-NH-, -C1-C10 alkylene-S-, C1-C10 heteroalkylene-S -, - C3-C8carbocyclo-S -, -O-(C1-C8alkylene)-S -, -arylene-S-, -C1-C10alkylene-arylene-S-, - arylene-C1-C10alkylene-S-, -C1-C10alkylene-(C3-C8carbocyclo)-S-, -(C3-C8carbocyclo)-C1- C10 alkylene-S-, -C3-C8 heterocyclo-S-, -C1-C10 alkylene-(C3-C8 heterocyclo)-S-, or -(C3-C8 heterocyclo)-C1-C10 alkylene-S-, wherein subscript k is an integer ranging from 1 to 36.

[0243] In yet another embodiment, the reactive group of a Stretcher Unit precursor contains a reactive site that can form a bond with a primary or secondary amino group of a Ligand Unit. Examples of these reactive sites include, but are not limited to, activated esters such as succinimide esters, 4-nitrophenyl esters, pentafluorophenyl esters, tetrafluorophenyl esters, anhydrides, acid chlorides, sulfonyl chlorides, isocyanates and isothiocyanates. Representative Stretcher Units of this embodiment are depicted within the square brackets of Formulas Zci, Zcii and Zciii:wherein the wavy line indicates attachment to the Connector Unit (A) and R17is –CH2CH2(OCH2CH2)k–, -C1-C10 alkylene-, C1-C10 heteroalkylene-, -C3-C8 carbocyclo-, -O- (C1-C8 alkylene)-, -arylene-, -C1-C10 alkylene-arylene-, -arylene-C1-C10 alkylene-, -C1-C10 alkylene-(C3-C8carbocyclo)-, -(C3-C8carbocyclo)-C1-C10alkylene-, -C3-C8heterocyclo-, -C1- C10 alkylene-(C3-C8 heterocyclo)-, -(C3-C8 heterocyclo)-C1-C10 alkylene-, -C1-C10 alkylene- C(=O)-, C1-C10 heteroalkylene-C(=O)-, -C3-C8 carbocyclo-C(=O)-, -O-(C1-C8 alkylene)- C(=O)-, -arylene-C(=O)-, -C1-C10alkylene-arylene-C(=O)-, -arylene-C1-C10alkylene-C(=O)-, -C1-C10 alkylene-(C3-C8 carbocyclo)-C(=O)-,-(C3-C8 carbocyclo)-C1-C10 alkylene-C(=O)-, - C3-C8 heterocyclo-C(=O)-, -C1-C10 alkylene-(C3-C8 heterocyclo)-C(=O)-, -(C3-C8 heterocyclo)-C1-C10alkylene-C(=O)-, -C1-C10alkylene-NH-, C1-C10heteroalkylene-NH-, -C3- C8carbocyclo-NH-, -O-(C1-C8alkylene)-NH-, -arylene-NH-, -C1-C10alkylene-arylene-NH-, - arylene-C1-C10 alkylene-NH-, -C1-C10 alkylene-(C3-C8 carbocyclo)-NH-, -(C3-C8 carbocyclo)- C1-C10 alkylene-NH-, -C3-C8 heterocyclo-NH-, -C1-C10 alkylene-(C3-C8 heterocyclo)-NH-, - (C3-C8heterocyclo)-C1-C10alkylene-NH-, -C1-C10alkylene-S-, C1-C10heteroalkylene-S -, -C3- C8 carbocyclo-S -, -O-(C1-C8 alkylene)-S -, -arylene-S-, -C1-C10 alkylene-arylene-S-, -arylene- C1-C10 alkylene-S-, -C1-C10 alkylene-(C3-C8 carbocyclo)-S-, -(C3-C8 carbocyclo)-C1-C10 alkylene-S-, -C3-C8heterocyclo-S-, -C1-C10alkylene-(C3-C8heterocyclo)-S-, or -(C3-C8heterocyclo)-C1-C10 alkylene-S-, wherein subscript k is an integer ranging from 1 to 36.

[0244] In still other embodiments, the reactive group of the Stretcher Unit precursor contains a reactive nucleophile that is capable of reacting with an electrophile present on, or introduced to, a Ligand Unit. For example, in some embodiments, a carbohydrate moiety on a targeting ligand is mildly oxidized using a reagent such as sodium periodate and the resulting electrophilic functional group (-CHO) of the oxidized carbohydrate is condensed with a Stretcher Unit precursor that contains a reactive nucleophile such as a hydrazide, an oxime, a primary or secondary amine, a hydrazine, a thiosemicarbazone, a hydrazine carboxylate, or an arylhydrazide such as those described by Kaneko, T. et al. (1991) Bioconjugate Chem. 2:133-41. Representative Stretcher Units of this embodiment are depicted within the square brackets of Formulas Zdi, Zdii, and Zdiii:diii),

[0245] wherein the wavy line indicates attachment to the Connector Unit (A), and R17is –CH2CH2(OCH2CH2)k–, -C1-C10alkylene-, C1-C10heteroalkylene-, -C3-C8carbocyclo-, -O- (C1-C8 alkylene)-, -arylene-, -C1-C10 alkylene-arylene-, -arylene-C1-C10 alkylene-, -C1-C10 alkylene-(C3-C8 carbocyclo)-, -(C3-C8 carbocyclo)-C1-C10 alkylene-, -C3-C8 heterocyclo-, -C1- C10alkylene-(C3-C8heterocyclo)-, -(C3-C8heterocyclo)-C1-C10alkylene-, -C1-C10alkylene- C(=O)-, C1-C10heteroalkylene-C(=O)-, -C3-C8carbocyclo-C(=O)-, -O-(C1-C8alkylene)- C(=O)-, -arylene-C(=O)-, -C1-C10 alkylene-arylene-C(=O)-, -arylene-C1-C10 alkylene-C(=O)-, -C1-C10alkylene-(C3-C8carbocyclo)-C(=O)-,-(C3-C8carbocyclo)-C1-C10alkylene-C(=O)-, - C3-C8heterocyclo-C(=O)-, -C1-C10alkylene-(C3-C8heterocyclo)-C(=O)-, -(C3-C8heterocyclo)-C1-C10 alkylene-C(=O)-, -C1-C10 alkylene-NH-, C1-C10 heteroalkylene-NH-, -C3- C8 carbocyclo-NH-, -O-(C1-C8 alkylene)-NH-, -arylene-NH-, -C1-C10 alkylene-arylene-NH-, - arylene-C1-C10alkylene-NH-, -C1-C10alkylene-(C3-C8carbocyclo)-NH-, -(C3-C8carbocyclo)- C1-C10 alkylene-NH-, -C3-C8 heterocyclo-NH-, -C1-C10 alkylene-(C3-C8 heterocyclo)-NH-, - (C3-C8 heterocyclo)-C1-C10 alkylene-NH-, -C1-C10 alkylene-S-, C1-C10 heteroalkylene-S -, - C3-C8carbocyclo-S -, -O-(C1-C8alkylene)-S -, -arylene-S-, -C1-C10alkylene-arylene-S-, - arylene-C1-C10alkylene-S-, -C1-C10alkylene-(C3-C8carbocyclo)-S-, -(C3-C8carbocyclo)-C1- C10 alkylene-S-, -C3-C8 heterocyclo-S-, -C1-C10 alkylene-(C3-C8 heterocyclo)-S-, or -(C3-C8 heterocyclo)-C1-C10alkylene-S-, wherein subscript k is an integer ranging from 1 to 36.

[0246] In some embodiments, the Q Linker Unit of the Ligand-Drug Conjugate compound constitutes a non-cleavable Linker Unit. In some such embodiments, wherein the the Drug moiety is attached via a non-cleavable Linker Unit to the thiol group of a cysteine of the Ligand Unit of the Ligand-Drug conjugate, the Ligand-Drug Conjugate releases the Drug moiety as a metabolized Drug-Linker cysteine adduct. In some such embodiments, the released Drug- Linker cysteine adduct compound is a compound of Table 3. Released Drug-Linker cysteineadduct compounds corresponding to the compounds of Table 3, but having a succinic acid- amide moiety in place of the succinimide moiety are contemplated. Table 3. Released Drug-Linker cysteine adduct compounds

[0247] In some embodiments, provided herein is a Ligand-Drug Conjguate compound of Table 4, or a pharmaceutically acceptable salt thereof. Ligand-Drug Conjugate compounds corresponding to the compounds of Table 4 but having a succinic acid-amide moiety in place of the succinimide moiety are contemplated.Table 4. Ligand-Drug Conjugate compoundsSubscript “p”

[0248] In one group of embodiments of the invention, subscript p represents the number of Drug Linker moieties on a Ligand Unit of an individual Ligand-Drug Conjugate compound and is an integer ranging from 1 to 16, 1 to 12, 1 to 10, or 1 to 8. In any of the embodiments herein, there are 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, or 16 Drug Linker moieties conjugated to a Ligand Unit of an individual Ligand-Drug Conjugate compound.

[0249] In some embodiments, any of the structures and descriptions as described herein represent a population of individual Ligand-Drug Conjugate compounds substantially identical except for the number of Drug-Linker moieties bound to each Ligand Unit (i.e., a Ligand-Drug Conjugate composition) so that subscript p represents the average number of Drug-Linkermoieties bound to the Ligand Units of the Ligand-Drug Conjugate composition. In that group of embodiments, subscript p is a number ranging from 1 to about 16, 1 to about 12, 1 to about 10, or 1 to about 8, from 2 to about 16, 2 to about 12, 2 to about 10, or 2 to about 8. In some embodiments, p is about 2. In some embodiments, p is about 4. In some embodiments, p is about 8. In some embodiments, p is about 16. In some embodiments, p is 2. In some embodiments, p is 4. In some embodiments, p is 8. In some embodiments, p is 16. In some embodiments, the value of subscript p refers to the average drug loading as well as the drug loading of the predominate Ligand-Drug Conjugate compound in the composition.

[0250] In some embodiments, conjugation will be via the reduced interchain disulfides and there will from 1 to about 8 Drug-Linker Compound molecules conjugated to a targeting agent that becomes a Ligand Unit. In some embodiments, conjugation will be via an introduced cysteine residue as well as reduced interchain disulfides and there will be from 1 to 10, or 1 to 12, or 1 to 14, or 1 to 16 Drug-Linker Compound moieties conjugated to a Ligand Unit. In some embodiments, conjugation will be via an introduced cysteine residue and there will be 2 or 4 Drug-Linker Compound molecules conjugated to a Ligand Unit. Ligand Unit L

[0251] In some embodiments, a Ligand Unit is present. The Ligand Unit (L-) is a targeting agent that specifically binds to a target moiety. In one group of embodiments, the Ligand Unit specifically and selectively binds to a cell component (a Cell Binding Agent) or to another target molecule of interest. The Ligand Unit acts to target and present the targeted degrader molecule (such as one of Formula (I), (Ia), (Ib), (IIa), (IIb), (IIIa), (IIIa-R), (IIIa-S), (IIIa-4), (IIIa-5), (IIIb), (IIIb-R), (IIIb-S), (IIIb-4), or (IIIb-5), or any subformula thereof) to the particular target cell population with which the Ligand Unit interacts due to the presence of its targeted component or molecule and allows for subsequent release of free drug within (i.e., intracellularly) or within the vicinity of the target cells (i.e., extracellularly). Ligand Units, L, include, but are not limited to, proteins, polypeptides, and peptides. Suitable Ligand Units include, for example, antibodies, e.g., full-length antibodies and antigen binding fragments thereof, interferons, lymphokines, hormones, growth factors, colony-stimulating factors, vitamins, nutrient-transport molecules (such as, but not limited to, transferrin), or any other cell binding molecule or substance. In some embodiments, the Ligand Unit (L) is from an antibody or a non-antibody protein targeting agent.

[0252] In one group of embodiments a Ligand Unit is bonded to a Linker Unit. As noted above, still other linking components can be present in the conjugates described herein to servethe purpose of providing additional space between the targeted degrader drug compound and the Ligand Unit (e.g., a Stretcher Unit and optionally a Connector Unit, A). In some of those embodiments, the Ligand Unit is bonded to Z of the Linker Unit via a heteroatom of the Ligand Unit. Heteroatoms that may be present on a Ligand Unit for that bonding include sulfur (in one embodiment, from a sulfhydryl group of a targeting ligand), oxygen (in one embodiment, from a carboxyl or hydroxyl group of a targeting ligand) and nitrogen, optionally substituted (in one embodiment, from a primary or secondary amine functional group of a targeting ligand or in another embodiment from an optionally substituted amide nitrogen). Those heteroatoms can be present on the targeting ligand in the ligand’s natural state, for example in a naturally occurring antibody, or can be introduced into the targeting ligand via chemical modification or biological engineering.

[0253] In one embodiment, a targeting agent that is a precursor to a Ligand Unit has a sulfhydryl functional group so that the Ligand Unit is bonded to the Linker Unit via the sulfur atom of the sulfhydryl functional group.

[0254] In another embodiment, a targeting agent that is a precursor to Ligand Unit has one or more lysine residues that are capable of reacting with activated esters (such esters include, but are not limited to, N-hydroxysuccimide, pentafluorophenyl, and p-nitrophenyl esters) of a Stretcher Unit precursor of a targeted degrader-Linker Compound intermediate and thus provides an amide bond consisting of the nitrogen atom of the Ligand Unit and the C=O group of the Linker Unit’s Stretcher Unit.

[0255] In some embodiments, a targeting agent that is a precursor to Ligand Unit has one or more lysine residues capable of chemical modification to introduce one or more sulfhydryl groups. In those embodiments, the Ligand Unit is covalently attached to the Linker Unit via the sulfhydryl functional group’s sulfur atom. The reagents that can be used to modify lysines in that manner include, but are not limited to, N-succinimidyl S-acetylthioacetate (SATA) and 2-Iminothiolane hydrochloride (Traut’s Reagent).

[0256] In another embodiment, a targeting agent that is a precursor to a Ligand Unit has one or more carbohydrate groups capable of modification to provide one or more sulfhydryl functional groups. The chemically modified Ligand Unit in a targeted degrader Conjugate is bonded to a Linker Unit component (e.g., a Stretcher Unit) via the sulfur atom of the sulfhydryl functional group.

[0257] In yet another embodiment, a targeting agent that is a precursor to a Ligand Unit has one or more carbohydrate groups that can be oxidized to provide an aldehyde (-CHO) functional group (see, e.g., Laguzza, et al., 1989, J. Med. Chem. 32(3):548-55). In these embodiments, the corresponding aldehyde interacts with a reactive site on a Stretcher Unit precursor to form a bond between the Stretcher Unit and the Ligand Unit. Reactive sites on a Stretcher Unit precursor that capable of interacting with a reactive carbonyl-containing functional group on a targeting Ligand Unit include, but are not limited to, hydrazine and hydroxylamine. Other protocols for the modification of proteins for the attachment of Linker Units or related species are described in Coligan et al., Current Protocols in Protein Science, vol. 2, John Wiley & Sons (2002) (incorporated herein by reference).

[0258] In some embodiments, a targeting agent that is a precursor to a Ligand Unit is capable of forming a bond by interacting with a reactive functional group on a Stretcher Unit precursor (Z') to form a covalent bond between the Stretcher Unit (Z) and the Ligand Unit, which corresponds in structure to the targeting agent. The functional group of Z' having that capability for interacting with a targeting agent will depend on the nature of the targeting agent that will correspond in structure to the Ligand Unit. In some embodiments, the reactive group is a maleimide that is present on a Stretcher Unit prior to its attachment to form a Ligand Unit (i.e., a maleimide moiety of a Stretcher Unit precursor). Covalent attachment of a Ligand Unit to a Stretcher Unit is accomplished through a sulfhydryl functional group of a targeting agent that is a precursor to a Ligand Unit interacting with the maleimide functional group of Z' to form a thio-substituted succinimide. The sulfhydryl functional group can be present on the targeting agent in the targeting agent’s natural state, for example, in a naturally occurring residue, or can be introduced into the targeting agent via chemical modification or by biological engineering.

[0259] In still another embodiment, the Ligand Unit is from an antibody and the sulfhydryl group is generated by reduction of an interchain disulfide of the antibody. Accordingly, in some embodiments, the Linker Unit is conjugated to a cysteine residue from reduced interchain disulfide(s).

[0260] In yet another embodiment, the Ligand Unit is from an antibody and the sulfhydryl functional group is chemically introduced into the antibody, for example, by introduction of a cysteine residue. Accordingly, in some embodiments, the Linker Unit (with or without an attached targeted degrader moiety) is conjugated to a Ligand Unit through an introduced cysteine residue of a Ligand Unit.

[0261] It has been observed for bioconjugates that the site of drug conjugation can affect a number of parameters including ease of conjugation, drug-linker stability, effects on biophysical properties of the resulting bioconjugates, and in vitro cytotoxicity. With respect to drug-linker stability, the site of conjugation of a drug-linker moiety to a Ligand Unit can affect the ability of the conjugated drug-linker moiety to undergo an elimination reaction, in some instances, to cause premature release of free drug. Sites for conjugation on a targeting agent include, for example, a reduced interchain disulfide as well as selected cysteine residues at engineered sites. In some embodiments conjugation methods to form targeted degrader Conjugates as described herein use thiol residues at genetically engineered sites that are less susceptible to the elimination reaction (e.g., positions 239 according to the EU index as set forth in Kabat) in comparison to conjugation methods that use thiol residues from a reduced disulfide bond. In other embodiments conjugation methods to form targeted degrader Conjugates as described herein use thiol residues resulting from interchain disulfide bond reduction.

[0262] In some embodiments, a targeted degrader Conjugate comprises a non- immunoreactive protein, polypeptide, or peptide as its Ligand Unit. Accordingly, in some embodiments, the Ligand Unit is from a non-immunoreactive protein, polypeptide, or peptide. Examples include, but are not limited to, transferrin, epidermal growth factors (“EGF”), bombesin, gastrin, gastrin-releasing peptide, platelet-derived growth factor, IL-2, IL-6, transforming growth factors (“TGF”), such as TGF-α and TGF-β, vaccinia growth factor (“VGF”), insulin and insulin-like growth factors I and II, somatostatin, lectins and apoprotein from low density lipoprotein.

[0263] Particularly preferred Ligand Units are from antibodies. Accordingly, in any one of the embodiments described herein, the Ligand Unit is from an antibody. Useful polyclonal antibodies are heterogeneous populations of antibody molecules derived from the sera of immunized animals. Useful monoclonal antibodies are homogeneous populations of antibodies to a particular antigenic determinant (e.g., a cancer cell antigen, a viral antigen, a microbial antigen, a protein, a peptide, a carbohydrate, a chemical, nucleic acid, or fragments thereof). A monoclonal antibody (mAb) to an antigen-of-interest in some embodiments is prepared by using any technique known in the art, which provides for production of antibody molecules by continuous cell lines in culture.

[0264] Useful monoclonal antibodies include, but are not limited to, human monoclonal antibodies, humanized monoclonal antibodies, or chimeric human-mouse (or other species)monoclonal antibodies. The antibodies include full-length antibodies and antigen binding fragments thereof. Human monoclonal antibodies can be made by any of numerous techniques known in the art (e.g., Teng et al., 1983, Proc. Natl. Acad. Sci. USA.80:7308-7312; Kozbor et al., 1983, Immunology Today 4:72-79; and Olsson et al., 1982, Meth. Enzymol. 92:3-16).

[0265] An antibody useful for inclusion into the Ligand-Drug conjugates of the disclosure is an intact antibody or a functionally active fragment, derivative, or analog of an antibody, wherein the antibody or fragment thereof is capable of immunospecific binding to target cells (e.g., cancer cell antigens, viral antigens, or microbial antigens) or other antibodies that are bound to tumor cells or matrix. In this regard, “functionally active” means that the fragment, derivative, or analog is able to immunospecifically bind to target cells. To determine which CDR sequences bind the antigen, synthetic peptides containing the CDR sequences in some embodiments are used in binding assays with the antigen by a binding assay method known in the art (e.g., the BiacoreTMassay) (See, e.g., Kabat et al., 1991, Sequences of Proteins of Immunological Interest, Fifth Edition, National Institute of Health, Bethesda, Md; Kabat E et al., 1980, J. Immunology 125(3):961-969).

[0266] Other useful Ligands include fragments of antibodies such as, but not limited to, F(ab’)2fragments, Fab fragments, Fvs, single chain antibodies, diabodies, triabodies, tetrabodies, scFv, scFv-FV, or any other molecule with the same specificity as the antibody.

[0267] Additionally, recombinant antibodies, such as chimeric and humanized monoclonal antibodies, comprising both human and non-human portions, which in some embodiments are made using standard recombinant DNA techniques, are useful antibodies. A chimeric antibody is a molecule in which different portions are derived from different animal species, such as for example, those having a variable region derived from a murine monoclonal and human immunoglobulin constant regions. (See, e.g., U.S. Patent No. 4,816,567; and U.S. Patent No. 4,816,397, which are incorporated herein by reference in their entirety.) Humanized antibodies are antibody molecules from non-human species having one or more complementarity determining regions (CDRs) from the non-human species and a framework region from a human immunoglobulin molecule. (See, e.g., U.S. Patent No.5,585,089, which is incorporated herein by reference in its entirety.) Such chimeric and humanized monoclonal antibodies in some embodiments are produced by recombinant DNA techniques known in the art, for example using methods described in International Publication No. WO 87 / 02671; European Patent Publication No.0184187; European Patent Publication No.0171496; European Patent Publication No. 0 173 494; International Publication No. WO 86 / 01533; U.S. Patent No.4,816,567; Berter et al., Science (1988) 240: 1041-1043; Liu et al., Proc. Nat'l. Acad. Sci. USA (1987) 84: 3439-3443; Liu et al., J. Immunol. (1987) 139: 3521-3526; Sun et al., Proc. Natl. Acad. Sci. USA (1987) 84: 214-218; Nishimura et al., Cancer. Res. (1987) 47: 999-1005; Wood et al., Nature (1985) 314: 446-449; Shaw et al., J. Natl. Cancer Inst. (1988) 80: 1553-1559; Morrison, Science (1985) 229: 1202-1207; Oi et al., BioTechniques (1986) 4: 214-221; U.S. Patent No. 5,225,539; Jones et al., Nature (1986) 321: 552-525; Verhoeyan et al., Science (1988) 239: 1534-1536; and Beidler et al., J. Immunol. (1988) 141: 4053-4060; each of which is incorporated herein by reference in its entirety.

[0268] Completely human antibodies in some instances (e.g., when immunogenicity to a non-human or chimeric antibody may occur) are more desirable and in some embodiments are produced using transgenic mice that are incapable of expressing endogenous immunoglobulin heavy and light chains genes, but which are capable of expressing human heavy and light chain genes.

[0269] Antibodies include analogs and derivatives that are either modified, i.e., by the covalent attachment of any type of molecule as long as such covalent attachment permits the antibody to retain its antigen binding immunospecificity. For example, but not by way of limitation, derivatives and analogs of the antibodies include those that have been further modified, e.g., by glycosylation, acetylation, PEGylation, phosphorylation, amidation, derivitization by known protecting / blocking groups, proteolytic cleavage, linkage to a cellular antibody unit or other protein, etc. In some embodiments one or more of those numerous chemical modifications are carried out by known techniques including, but not limited to, specific chemical cleavage, acetylation, formylation, metabolic synthesis in the presence of tunicamycin, etc. In other embodiments, an analog or derivative of an antibody contains one or more unnatural amino acids, which is sometimes in combination with one or more of the above-described chemical modifications.

[0270] In some embodiments the antibody has one or more modifications (e.g., substitutions, deletions or additions) in amino acid residues that interact with Fc receptors. Those include modifications in amino acid residues identified as involved in the interaction between the anti-Fc domain and the FcRn receptor (see, e.g., International Publication No. WO 97 / 34631, which is incorporated herein by reference in its entirety).

[0271] In some embodiments, antibodies immunospecific for a cancer cell antigen are obtained commercially or produced by a method known to one of skill in the art such as,recombinant expression techniques. The nucleotide sequence encoding antibodies immunospecific for a cancer cell antigen is sometimes obtained, e.g., from the GenBank database or a database like it, the literature publications, or by routine cloning and sequencing.

[0272] In a specific embodiment, a known antibody for the treatment of cancer is used.

[0273] In another specific embodiment, an antibody for the treatment of an autoimmune disease is used in accordance with the compositions and methods of the invention.

[0274] In certain embodiments, useful antibodies bind to a receptor or a receptor complex expressed on an activated lymphocyte. That receptor or receptor complex, in some embodiments, is an immunoglobulin gene superfamily member, a TNF receptor superfamily member, an integrin, a cytokine receptor, a chemokine receptor, a major histocompatibility protein, a lectin, or a complement control protein.

[0275] Throughout this application, unless the context indicates otherwise, references to a compound of Formula (I), (Ia), (Ib), (IIa), (IIb), (IIIa), (IIIa-R), (IIIa-S), (IIIa-4), (IIIa-5), (IIIb), (IIIb-R), (IIIb-S), (IIIb-4), (IIIb-5), or (I'), or any subformula thereof, includes all subgroups of Formula (I), (Ia), (Ib), (IIa), (IIb), (IIIa), (IIIa-R), (IIIa-S), (IIIa-4), (IIIa-5), (IIIb), (IIIb-R), (IIIb-S), (IIIb-4), (IIIb-5), or (I'), or any subformula thereof, defined herein, including all substructures, subgenera, preferences, embodiments, examples and particular compounds defined and / or described herein. References to a compound of Formula (I), (Ia), (Ib), (IIa), (IIb), (IIIa), (IIIa-R), (IIIa-S), (IIIa-4), (IIIa-5), (IIIb), (IIIb-R), (IIIb-S), (IIIb-4), (IIIb-5), or (I'), or any subformula thereof, include ionic forms, polymorphs, pseudopolymorphs, amorphous forms, solvates, co-crystals, chelates, isomers, tautomers, oxides (e.g., N-oxides, S-oxides), esters, prodrugs, isotopes and / or protected forms thereof. In some embodiments, references to a compound of Formula (I), (Ia), (Ib), (IIa), (IIb), (IIIa), (IIIa-R), (IIIa-S), (IIIa-4), (IIIa-5), (IIIb), (IIIb-R), (IIIb-S), (IIIb-4), (IIIb-5), or (I'), or any subformula thereof, include polymorphs, solvates, co-crystals, isomers, tautomers and / or oxides thereof. In some embodiments, references to a compound of Formula (I), (Ia), (Ib), (IIa), (IIb), (IIIa), (IIIa-R), (IIIa-S), (IIIa-4), (IIIa-5), (IIIb), (IIIb-R), (IIIb-S), (IIIb-4), (IIIb-5), or (I'), or any subformula thereof, include polymorphs, solvates, and / or co-crystals thereof. In some embodiments, references to a compound of Formula (I), (Ia), (Ib), (IIa), (IIb), (IIIa), (IIIa-R), (IIIa-S), (IIIa- 4), (IIIa-5), (IIIb), (IIIb-R), (IIIb-S), (IIIb-4), (IIIb-5), or (I'), or any subformula thereof, include isomers, tautomers and / or oxides thereof. In some embodiments, references to a compound of Formula (I), (Ia), (Ib), (IIa), (IIb), (IIIa), (IIIa-R), (IIIa-S), (IIIa-4), (IIIa-5), (IIIb), (IIIb-R),(IIIb-S), (IIIb-4), (IIIb-5), or (I'), or any subformula thereof, include solvates thereof. Similarly, the term “salts” includes solvates of salts of compounds.

[0276] Any formula given herein, such as Formula (I), (Ia), (Ib), (IIa), (IIb), (IIIa), (IIIa- R), (IIIa-S), (IIIa-4), (IIIa-5), (IIIb), (IIIb-R), (IIIb-S), (IIIb-4), (IIIb-5), or (I'), or any subformula thereof, is intended to represent compounds having structures depicted by the structural formula as well as certain variations or forms. In particular, compounds of any formula given herein may have asymmetric centers and therefore exist in different enantiomeric or diastereomeric forms. All optical isomers and stereoisomers of the compounds of the general formula, and mixtures thereof in any ratio, are considered within the scope of the formula. Thus, any formula given herein is intended to represent a racemate, one or more enantiomeric forms, one or more diastereomeric forms, one or more atropisomeric forms, and mixtures thereof in any ratio. Where a compound of one of Tables 1, 2, 3, or 4 is depicted with a particular stereochemical configuration, also provided herein is any alternative stereochemical configuration of the compound, as well as a mixture of stereoisomers of the compound in any ratio. For example, where a compound of Tables 1, 2, 3, or 4 has a stereocenter that is in an “S” stereochemical configuration, also provided herein is enantiomer of the compound wherein that stereocenter is in an “R” stereochemical configuration. Likewise, when a compound of Tables 1, 2, 3, or 4 has a stereocenter that is in an “R” configuration, also provided herein is enantiomer of the compound in an “S” stereochemical configuration. Also provided are mixtures of the compound with both the “S” and the “R” stereochemical configuration. Additionally, if a compound of Tables 1, 2, 3, or 4 has two or more stereocenters, also provided are any enantiomer or diastereomer of the compound. For example, if a compound of Tables 1, 2, 3, or 4 contains a first stereocenter and a second stereocenter with “R” and “R” stereochemical configurations, respectively, also provided are stereoisomers of the compound having first and second stereocenters with “S” and “S” stereochemical configurations, respectively, “S” and “R” stereochemical configurations, respectively, and “R” and “S” stereochemical configurations, respectively. If a compound of Tables 1, 2, 3, or 4 contains a first stereocenter and a second stereocenter with “S” and “S” stereochemical configurations, respectively, also provided are stereoisomers of the compound having first and second stereocenters with “R” and “R” stereochemical configurations, respectively, “S” and “R” stereochemical configurations, respectively, and “R” and “S” stereochemical configurations, respectively. If a compound of Tables 1, 2, 3, or 4 contains a first stereocenter and a second stereocenter with “S” and “R” stereochemical configurations, respectively, alsoprovided are stereoisomers of the compound having first and second stereocenters with “R” and “S” stereochemical configurations, respectively, “R” and “R” stereochemical configurations, respectively, and “S” and “S” stereochemical configurations, respectively. Similarly, if a compound of Tables 1, 2, 3, or 4 contains a first stereocenter and a second stereocenter with “R” and “S” stereochemical configurations, respectively, also provided are stereoisomers of the compound having first and second stereocenters with “S” and “R” stereochemical configurations, respectively, “R” and “R” stereochemical configurations, respectively, and “S” and “S” stereochemical configurations, respectively. Furthermore, certain structures may exist as geometric isomers (i.e., cis and trans isomers), as tautomers, or as atropisomers. Additionally, any formula given herein is intended to refer also to any one of hydrates, solvates, and amorphous and polymorphic forms of such compounds, and mixtures thereof, even if such forms are not listed explicitly. In some embodiments, the solvent is water and the solvates are hydrates.

[0277] The compounds depicted herein may be present as salts even if salts are not depicted, and it is understood that the compositions and methods provided herein embrace all salts and solvates of the compounds depicted here, as well as the non-salt and non-solvate form of the compound, as is well understood by the skilled artisan. In some embodiments, the salts of the compounds provided herein are pharmaceutically acceptable salts.

[0278] Embodiments are contemplated wherein any variation or embodiment of R1, R2, R3, R4, R5, R6, R7, R8, R9, R10a, R10b, X, Y1, Y2, Z1, Z2, Q, L1, L2, and / or subscript p provided herein is combined with every other variation or embodiment of R1, R2, R3, R4, R5, R6, R7, R8, R9, R10a, R10b, X, Y1, Y2, Z1, Z2, Q, L1, L2, and / or subscript p, as if each combination had been individually and specifically described.

[0279] In some embodiments, any of the compounds described herein, such as a compound of Formula (I), (Ia), (Ib), (IIa), (IIb), (IIIa), (IIIa-R), (IIIa-S), (IIIa-4), (IIIa-5), (IIIb), (IIIb-R), (IIIb-S), (IIIb-4), (IIIb-5), or (I'), or any subformula thereof, or a compound of any one of Tables 1, 2, 3, or 4, or a salt of any of the foregoing, may be deuterated (e.g., a hydrogen atom is replaced by a deuterium atom). In some of these variations, the compound is deuterated at a single site. In other variations, the compound is deuterated at multiple sites. Deuterated compounds are sometimes prepared from deuterated starting materials in a manner similar to the preparation of the corresponding non-deuterated compounds. In some embodiments, hydrogen atoms are be replaced with deuterium atoms using other methods known in the art.

[0280] Other embodiments will be apparent to those skilled in the art from the following detailed description.

[0281] As used herein, when any variable occurs more than one time in a chemical formula, its definition on each occurrence is independent of its definition at every other occurrence. Ligand-Drug Conjugate Mixtures and Compositions

[0282] The present disclosure provides Ligand-Drug Conjugate mixtures and pharmaceutical compositions comprising any of the Ligand-Drug Conjugates described herein. The mixtures and pharmaceutical compositions comprise a plurality of conjugates. In some embodiments, each of the conjugates in the mixture or composition is identical or substantially identical, however, the distribution of drug-linkers on the ligands in the mixture or compositions may vary as well as the drug loading. For example, the conjugation technology used to conjugate drug-linkers to antibodies as the targeting agent in some embodiments results in a composition or mixture that is heterogeneous with respect to the distribution of Drug- Linker compounds on the antibody (Ligand Unit) within the mixture and / or composition. In some of those embodiments, the loading of Drug-Linker compounds on each of the antibody molecules in a mixture or composition of such molecules is an integer that ranges from 1 to 16.

[0283] In those embodiments, when referring to the composition as a whole, the loading of drug-linkers is a number ranging from 1 to about 16. Within the composition or mixture, there sometimes is a small percentage of unconjugated antibodies. The average number of drug- linkers per Ligand Unit in the mixture or composition (i.e., average drug-load) is an important attribute as it determines the maximum amount of drug that is delivered to the target cell. Typically, the average drug load is 1, 2 or about 2, 3 or about 3, 4 or about 4, 5 or about 5, 6 or about 6, 7 or about 7, 8 or about 8, 9 or about 9, 10 or about 10, 11 or about 11, 12 or about 12, 13 or about 13, 14 or about 14, 15 or about 15, 16 or about 16. In some embodiments, the average drug loading is from about 1 to about 16, from about 2 to about 12, from about 3 to about 8, or about 4. In some embodiments, the average drug loading is from about 3 to about 5, from about 3.5 to about 4.5, from about 3.7 to about 4.3, from about 3.9 to about 4.3, or about 4. In some embodiments, the average drug loading is from about 1 to about 8, from about 2 to about 8, from about 3 to about 8, from about 4 to about 8, from about 5 to about 8, from about 6 to about 8, from about 7 to about 8, or about 8.

[0284] In some embodiments, the mixtures and pharmaceutical compositions comprise a plurality (i.e., population) of conjugates, however, the conjugates are identical or substantiallyidentical and are substantially homogenous with respect to the distribution of drug-linkers on the ligand molecules within the mixture and / or composition and with respect to loading of drug-linkers on the ligand molecules within the mixture and / or composition. In some such embodiments, the loading of drug-linkers on an antibody Ligand Unit is 2, 4, 6, or 8. Within the composition or mixture, there may also be a small percentage of unconjugated antibodies. The average drug load in such embodiments is about 2, about 4, about 6, or about 8. Typically, such compositions and mixtures result from the use of site-specific conjugation techniques and conjugation is due to an introduced cysteine residue.

[0285] The average number of Drug Units or Drug-Linker compounds per Ligand Unit in a preparation from a conjugation reaction may be characterized by conventional means such as mass spectrometry, ELISA assay, HPLC (e.g., HIC). In those instances, the quantitative distribution of Ligand-Drug Conjugates in terms of subscript p may also be determined. In other instances, separation, purification, and characterization of homogeneous Ligand-Drug Conjugates may be achieved by conventional means such as reverse phase HPLC or electrophoresis.

[0286] In some embodiments, the compositions are pharmaceutical compositions comprising the Ligand-Drug Conjugates described herein and a pharmaceutically acceptable carrier. In some of those embodiments, the pharmaceutical composition is in liquid form. In some embodiments, the pharmaceutical composition is a solid. In other of those embodiments, the pharmaceutical composition is a lyophilized powder.

[0287] The compositions, including pharmaceutical compositions, are provided in purified form. As used herein, “purified” means that when isolated, the isolate contains at least 95%, and in other embodiments at least 98%, of Conjugate by weight of the isolate. Methods of Use Treatment of Cancer

[0288] The Ligand-Drug Conjugates are useful for inhibiting the multiplication of a tumor cell or cancer cell, causing apoptosis in a tumor or cancer cell, or for treating a cancer in a patient. The Ligand-Drug Conjugates are used accordingly in a variety of settings for the treatment of cancers. The Ligand-Drug Conjugates are intended to deliver a drug to a tumor cell or cancer cell. Without being bound by theory, in one embodiment, the Ligand Unit of a Ligand-Drug Conjugate binds to or associates with a cancer-cell or a tumor-cell-associated antigen, and the Ligand-Drug Conjugate is taken up (internalized) inside the tumor cell orcancer cell through receptor-mediated endocytosis or other internalization mechanism. In some embodiments, the antigen is attached to a tumor cell or cancer cell or is an extracellular matrix protein associated with the tumor cell or cancer cell. Once inside the cell, via activation of the Activation Unit, the drug is released within the cell. In an alternative embodiment, the free drug is released from the Ligand-Drug Conjugate outside the tumor cell or cancer cell, and the free drug subsequently penetrates the cell.

[0289] In one embodiment, the Ligand Unit binds to the tumor cell or cancer cell.

[0290] In another embodiment, the Ligand Unit binds to a tumor cell or cancer cell antigen which is on the surface of the tumor cell or cancer cell.

[0291] In another embodiment, the Ligand Unit binds to an immune cell in a tumor microenvironment.

[0292] In another embodiment, the Ligand Unit binds to a stromal cell in a tumor microenvironment.

[0293] In another embodiment, the Ligand Unit binds to a tumor cell or cancer cell antigen that is an extracellular matrix protein associated with the tumor cell or cancer cell.

[0294] The specificity of the Ligand Unit for a particular tumor cell or cancer cell is an important consideration for determining the tumors or cancers that are most effectively treated. For example, Ligand-Drug Conjugates that target a cancer cell antigen present on hematopoietic cancers are useful treating hematologic malignancies. Ligand-Drug Conjugates that target a cancer cell antigen present on solid tumors in some embodiments are useful treating such solid tumors.

[0295] Cancers that are intended to be treated with a Drug-Linker Conjugate include, but are not limited to, hematopoietic cancers such as, for example, lymphomas (Hodgkin Lymphoma and Non-Hodgkin Lymphomas) and leukemias and solid tumors. Examples of hematopoietic cancers include, follicular lymphoma, anaplastic large cell lymphoma, mantle cell lymphoma, acute myeloblastic leukemia, chronic myelocytic leukemia, chronic lymphocytic leukemia, diffuse large B cell lymphoma, and multiple myeloma. Examples of solid tumors include fibrosarcoma, myxosarcoma, liposarcoma, chondrosarcoma, osteogenic sarcoma, chordoma, angiosarcoma, endotheliosarcoma, lymphangiosarcoma, lymphangioendotheliosarcoma, synovioma, mesothelioma, Ewing’s tumor, leiomyosarcoma, rhabdomyosarcoma, colon cancer, colorectal cancer, kidney cancer, pancreatic cancer, bone cancer, breast cancer, ovarian cancer, prostate cancer, esophageal cancer, stomach cancer, oralcancer, nasal cancer, throat cancer, squamous cell carcinoma, basal cell carcinoma, adenocarcinoma, sweat gland carcinoma, sebaceous gland carcinoma, papillary carcinoma, papillary adenocarcinomas, cystadenocarcinoma, medullary carcinoma, bronchogenic carcinoma, renal cell carcinoma, hepatoma, bile duct carcinoma, cholangiocarcinoma, choriocarcinoma, seminoma, embryonal carcinoma, Wilms’ tumor, cervical cancer, uterine cancer, testicular cancer, small cell lung carcinoma, bladder carcinoma, lung cancer, epithelial carcinoma, glioma, glioblastoma multiforme, astrocytoma, medulloblastoma, craniopharyngioma, ependymoma, pinealoma, hemangioblastoma, acoustic neuroma, oligodendroglioma, meningioma, neuroblastoma, and retinoblastoma.

[0296] In some embodiments, the treated cancer is any one of the above-listed lymphomas and leukemias. Multi-Modality Therapy for Cancer

[0297] Cancers, including, but not limited to, a tumor, metastasis, or other disease or disorder characterized by uncontrolled cell growth are intended to be treated or inhibited by administration of an effective amount of a Ligand-Drug Conjugate disclosed herein.

[0298] In one group of embodiments, methods for treating cancer are provided, including administering to a patient in need thereof an effective amount of a Ligand-Drug Conjugate and a chemotherapeutic agent. In one embodiment the chemotherapeutic agent is one in which treatment of the cancer has not been found to be refractory to that agent. In another embodiment, the chemotherapeutic agent is one in which the treatment of cancer has been found to be refractory to that agent.

[0299] In another group of embodiments, the Ligand-Drug Conjugates is administered to a patient that has also undergone surgery as treatment for the cancer. In such embodiments a chemotherapeutic agent is typically administered over a series of sessions, or one or a combination of the chemotherapeutic agents, such a standard of care chemotherapeutic agent(s), is administered.

[0300] In either group of embodiments, the patient also receives an additional treatment, such as radiation therapy. In a specific embodiment, the Ligand-Drug Conjugate is administered concurrently with the chemotherapeutic agent or with radiation therapy. In another specific embodiment, the chemotherapeutic agent or radiation therapy is administered prior or subsequent to administration of a Ligand-Drug Conjugate.

[0301] Additionally, methods of treatment of cancer with a Ligand-Drug Conjugate are provided as an alternative to chemotherapy or radiation therapy where the chemotherapy or the radiation therapy has proven or can prove too toxic, e.g., results in unacceptable or unbearable side effects, for the subject being treated. The patient being treated is optionally treated with another cancer treatment such as surgery, radiation therapy or chemotherapy, depending on which treatment is found to be acceptable or bearable. Treatment of Autoimmune Diseases

[0302] The Ligand-Drug Conjugates of the disclosure are intended to be useful for killing or inhibiting the unwanted replication of cells that produce an autoimmune disease or for treating an autoimmune disease.

[0303] The Ligand-Drug Conjugates are used accordingly in a variety of settings for the treatment of an autoimmune disease in a patient. The Ligand-Drug Conjugates are typically used to deliver a Drug Unit to a target cell. Without being bound by theory, in one embodiment, the Ligand-Drug Conjugate associates with an antigen on the surface of a pro-inflammatory or inappropriately stimulated immune cell, and the Ligand-Drug Conjugate is then taken up inside the targeted cell through receptor-mediated endocytosis. Once inside the cell, the Linker Unit is cleaved, resulting in release of the Drug Unit as free drug. The free drug is then able to migrate within the cytosol and induce a cytotoxic or cytostatic activity. In an alternative embodiment, the Drug Unit is cleaved from the Ligand-Drug Conjugate outside the target cell, and the free drug resulting from that release subsequently penetrates the cell.

[0304] In one embodiment, the Ligand Unit binds to an autoimmune antigen. In one such embodiment, the antigen is on the surface of a cell involved in an autoimmune condition.

[0305] In one embodiment, the Ligand Unit binds to activated lymphocytes that are associated with the autoimmune disease state.

[0306] In a further embodiment, the Ligand-Drug Conjugate kills or inhibits the multiplication of cells that produce an autoimmune antibody associated with a particular autoimmune disease.

[0307] Particular types of autoimmune diseases intended to be treated with the Ligand- Drug Conjugates include, but are not limited to, Th2 lymphocyte related disorders (e.g., atopic dermatitis, atopic asthma, rhinoconjunctivitis, allergic rhinitis, Omenn’s syndrome, systemic sclerosis, and graft versus host disease); Th1 lymphocyte-related disorders (e.g., rheumatoid arthritis, multiple sclerosis, psoriasis, Sjorgren’s syndrome, Hashimoto’s thyroiditis, Grave’sdisease, primary biliary cirrhosis, Wegener’s granulomatosis, and tuberculosis); and activated B lymphocyte-related disorders (e.g., systemic lupus erythematosus, Goodpasture’s syndrome, rheumatoid arthritis, and type I diabetes). Multi-Drug Therapy of Autoimmune Diseases

[0308] Methods for treating an autoimmune disease are also disclosed including administering to a patient in need thereof an effective amount of a Ligand-Drug Conjugate of the disclosure and another therapeutic agent known for the treatment of an autoimmune disease. For any of the methods of treatment described herein, the Ligand-Drug Conjugate compound may be administered to a subject who is unable to tolerate another Ligand-Drug Conjugate compound in therapeutically effective doses. In some embodiments, the patient has greater tolerance for a Ligand-Drug Conjugate compound provided herein as compared to another Ligand-Drug Conjugate compound. Tolerability may be determined using known methods or any of the methods decribed herein. Compositions and Methods of Administration

[0309] The present invention provides pharmaceutical compositions comprising the Ligand-Drug Conjugates described herein and at least one pharmaceutically acceptable carrier. The pharmaceutical composition is in any form that allows the compound to be administered to a patient for treatment of a disorder associated with expression of the antigen to which the Ligand unit binds. For example, the conjugates are in the form of a liquid or solid. The preferred route of administration is parenteral. Parenteral administration includes subcutaneous, intravenous, intramuscular, and intrasternal injection or infusion techniques. In one embodiment, the pharmaceutical compositions are administered parenterally. In one embodiment, the pharmaceutical compositions are administered intravenously. Administration is by any convenient route, for example by infusion or bolus injection.

[0310] Pharmaceutical compositions are formulated to allow a Ligand-Drug Conjugate to be bioavailable upon administration of the composition to a patient. Compositions sometimes take the form of one or more dosage units.

[0311] Materials used in preparing the pharmaceutical compositions are preferably non- toxic in the amounts used. It will be evident to those of ordinary skill in the art that the optimal dosage of the active ingredient(s) in the pharmaceutical composition will depend on a variety of factors. Relevant factors include, without limitation, the type of animal (e.g., human), the particular form of the compound, the manner of administration, and the composition employed.

[0312] The composition in some embodiments is in the form of a liquid. The liquid in some of those embodiments is useful for delivery by injection. In some embodiments a composition for administration by injection, in addition to the Ligand-Drug Conjugate, contains one or more excipients selected from the group consisting of a surfactant, preservative, wetting agent, dispersing agent, suspending agent, buffer, stabilizer and isotonic agent.

[0313] The liquid compositions, whether they are solutions, suspensions or other like form, in some embodiments include one or more of the following: sterile diluents such as water for injection, saline solution, preferably physiological saline, Ringer’s solution, isotonic sodium chloride, fixed oils such as synthetic mono or digylcerides which can serve as the solvent or suspending medium, polyethylene glycols, glycerin, cyclodextrin, propylene glycol or other solvents; antibacterial agents such as benzyl alcohol or methyl paraben; antioxidants such as ascorbic acid or sodium bisulfite; chelating agents such as ethylenediaminetetraacetic acid; buffers such as amino acids, acetates, citrates or phosphates; detergents, such as nonionic surfactants, polyols; and agents for the adjustment of tonicity such as sodium chloride or dextrose. A parenteral composition is sometimes enclosed in ampoule, a disposable syringe or a multiple-dose vial made of glass, plastic or other material. Physiological saline is an exemplary adjuvant. An injectable composition is preferably sterile.

[0314] The amount of the conjugate that is effective in the treatment of a particular disorder or condition will depend on the nature of the disorder or condition, which in some embodiments is determined by standard clinical techniques. In addition, in vitro or in vivo assays are optionally employed to help identify optimal dosage ranges. The precise dose to be employed in the compositions will also depend on the route of administration, and the seriousness of the disease or disorder, and should be decided according to the judgment of the practitioner and each patient’s circumstances.

[0315] The term “carrier” refers to a diluent, adjuvant or excipient, with which a compound is administered. Such pharmaceutical carriers in some embodiments is a liquid, such as water and oils, including those of petroleum, animal, vegetable or synthetic origin, such as peanut oil, soybean oil, mineral oil, or sesame oil. Other carriers include saline, gum acacia, gelatin, starch paste, talc, keratin, colloidal silica, or urea. In addition, auxiliary, stabilizing, thickening, lubricating, and coloring agents are sometimes used. In one embodiment, when administered to a patient, the Ligand-Drug Conjugate or compositions thereof and pharmaceutically acceptable carriers are sterile.

[0316] Water is an exemplary carrier when the compounds are administered intravenously. Saline solutions and aqueous dextrose and glycerol solutions are often employed as liquid carriers, particularly for injectable solutions. Suitable pharmaceutical carriers also include excipients such as starch, glucose, lactose, sucrose, gelatin, malt, rice, flour, chalk, silica gel, sodium stearate, glycerol monostearate, talc, sodium chloride, dried skim milk, glycerol, propylene, glycol, water, or ethanol. The present compositions, if desired, also contain minor amounts of wetting or emulsifying agents, or pH buffering agents.

[0317] In an embodiment, the conjugates are formulated in accordance with routine procedures as a pharmaceutical composition adapted for intravenous administration to animals, particularly human beings. Typically, the carriers or vehicles for intravenous administration are sterile isotonic aqueous buffer solutions. Where necessary, the compositions include a solubilizing agent. Compositions for intravenous administration optionally comprise a local anesthetic such as lignocaine to ease pain at the site of the injection. Generally, the ingredients are supplied either separately or mixed together in unit dosage form, for example, as a dry lyophilized powder or water free concentrate in a hermetically sealed container such as an ampoule or sachets indicating the quantity of active agent. Where a conjugate is to be administered by infusion, it is typically dispensed, for example, with an infusion bottle containing sterile pharmaceutical grade water or saline. In some embodiments, where the conjugate is administered by injection, an ampoule of sterile water for injection or saline is sometimes provided and the ingredients are mixed prior to administration.

[0318] The pharmaceutical compositions are generally formulated as sterile, substantially isotonic and in full compliance with all Good Manufacturing Practice (GMP) regulations of the U.S. Food and Drug Administration. Methods of Preparing Drug-Linker compounds and Ligand-Drug Conjugate Compounds

[0319] Provided herein are methods for preparing Drug-Linker compounds from the targeted degrader compounds provided herein. In addition to the methods recited below, method of preparing Drug-Linker compounds from targeted degrader compounds will be well known to a person of skill in the art.

[0320] Provided herein are methods for preparing Ligand-Drug Conjugate compounds from the targeted degrader compounds and Drug-Linker compounds provided herein. Methodsfor preparing the Ligand-Drug Conjugate compounds will be well known to a person of skill in the art. EXAMPLES Example 1. General Methods.

[0321] All commercially available anhydrous solvents were used without further purification. All commercially available reagents were used without further purification unless otherwise noted. Analytical thin layer chromatography (TLC) was performed on silica gel 60 F254 aluminum sheets (EMD Chemicals, Gibbstown, NJ). Flash column chromatography was performed on a Biotage Isolera One™ flash purification system 20 or Biotage Selekt™ flash purification system (Charlotte, NC). UPLC-MS analysis was performed on one of six systems.

[0322] UPLC-MS system 1 (C8): Waters Xevo G2 TOF mass spectrometer interfaced to a Waters Acquity H-class Ultra Performance LC equipped with a CORTECS C82.1 x 50 mm, 1.6 μm, 90 Å reversed-phase column with a Waters 2996 Photodiode Array Detector.

[0323] UPLC-MS system 2 (C18): Shimadzu LC-20 AD & MS 2020 interfaced with a diode array detector (DAD) and positive ESI mass spectrometer equipped with an Kinetx C182.1 x 50 mm, 5 µm particle size reversed-phase column maintained at 40oC, a Luna-C18 2.0 x 50 mm, 5 μm reversed-phase column maintained at 40 °C or an XBridge C182.1 x 50mm, 5 μm particle size reversed-phase column maintained at 40oC.

[0324] UPLC-MS system 3 (C18): Agilent 1200 series LC system interfaced with a diode array detector (DAD) and Agilent 6110 positive ESI quadrupole mass spectrometer equipped with a Luna-C182.0 x 50 mm, 5 μm reversed-phase column maintained at 40 °C.

[0325] UPLC-MS system 4 (C18): Agilent 1200 series LC system interfaced with a diode array detector (DAD) and Agilent 6110 positive ESI quadrupole mass spectrometer equipped with an XBridge C182.1 x 50mm, 5 μm particle size reversed-phase column maintained at 40oC.

[0326] UPLC-MS system 5 (C18): Waters single quad detector mass spectrometer interfaced to a Waters Acquity UPLC system equipped with a CORTECS C182.1x50 mm, 1.6 μm, 90 Å reversed-phase column.

[0327] UPLC-MS system 6 (C18): Agilent 1200 series LC system interfaced with an ELSD detector and Agilent 6120 single quadrupole mass spectrometer equipped with a Kinetx C182..1 x 50 mm, 5 µm particle size reversed-phase column maintained at 40oC.

[0328] Compounds were eluted using one of Methods A-Q, as described herein.

[0329] Method A – a linear gradient of 3-60% acetonitrile in water over 1.1 min, then 60- 97% acetonitrile to 1.5 min, followed by isocratic flow of 97% acetonitrile to 2.5 min followed by column equilibration back to 3% acetonitrile. The flow rate was 0.6 mL / min and the water and acetonitrile each contained 0.1% (v / v) formic acid. The column used was a CORTECS C82.1 x 50 mm, 1.6 μm, 90 Å reversed-phase column.

[0330] Method B – a linear gradient of 5-95% acetonitrile in water over 0.7 min, followed by isocratic flow of 95% acetonitrile to 1.16 min, and equilibration back to 5% acetonitrile to 1.5 min. The flow rate was 1.5 mL / min and the water contained 0.04% TFA (v / v) and the acetonitrile contained 0.02% TFA (v / v). The column used was an Kinetex-EVO C18, 2.1x30 mm, 5 μm particle size reversed-phase column.

[0331] Method C– isocratic flow of 5% acetonitrile in water for 0.4 min, followed by a linear gradient of 5-95% acetonitrile in water to 3.0 min, followed by isocratic flow of 95% acetonitrile to 4.0 min and column equilibration back to 5% acetonitrile to 4.5 min. The flow rate was 1.0 mL / min and the water contained 0.04% TFA (v / v) and the acetonitrile contained 0.02% TFA (v / v). The column used was a Phenomenex Luna-C182.0 x 50 mm, 5 μm reversed-phase column or Kinetex C182.1 x 50 mm, 5 µm reversed-phase column.

[0332] Method D – a linear gradient of 5-95% acetonitrile in water over 2.5 min, followed by isocratic flow of 95% acetonitrile to 3.0 min, and equilibration back to 5% acetonitrile to 3.5 min. The flow rate was 1.0 mL / min until equilibration (1.2 mL / min). The water contained 0.04% TFA (v / v), and the acetonitrile contained 0.02% (v / v) TFA. The column used was a Phenomenex Luna-C182.0 x 30mm, 3 μm reversed-phase column.

[0333] Method E – a linear gradient of 5-95% acetonitrile in water over 3.0 min, followed by isocratic flow of 95% acetonitrile to 3.5 min, and column equilibration back to 5% acetonitrile to 4 min, followed by isocratic flow of 5% acetonitrile to 4.3 min. The flow rate was 1.0 mL / min and the water contained 10 mM NH4HCO3. The column used was an Xbridge C182.1 x 50mm, 5 μm particle size reversed-phase column.

[0334] Method F – a linear gradient of 5-95% acetonitrile in water over 2.5 min, followed by isocratic flow of 95% acetonitrile to 3 min, and column equilibration back to 5%acetonitrile to 3.5 min. The flow rate was 1 mL / min and the water contained 10 mM NH4HCO3. The column used was an Xbridge C182.1 x 50mm, 5 μm particle size reversed- phase column.

[0335] Method G – a linear gradient of 5-95% acetonitrile in water over 3.4 min, followed by isocratic flow of 95% acetonitrile to 3.85 min, and equilibration back to 5% acetonitrile to 4.5 min. The flow rate was 0.8 mL / min and the water contained 10 mM NH-4HCO3. The column used was an Xbridge C182.1 x 50mm, 5 μm particle size reversed-phase column.

[0336] Method H – a linear gradient of 5-95% acetonitrile over 1.0 min, then 95-100% acetonitrile to 1.8 min, followed by column equilibration back to 5% acetonitrile. The flow rate was 1.0 mL / min and the water contained 10 mM NH4OH. The column used was a XBridge C182.1 x 50 mm, 5 μm particle size reversed-phase column.

[0337] Method I – a linear gradient of 5-95% acetonitrile in water over 2.5 min, followed by isocratic flow of 95% acetonitrile to 3.0 min. The flow rate was 1.0 mL / min and the water contained 0.04% (v / v) TFA and the acetonitrile contained 0.02% (v / v) TFA. The column used was an Xbridge C182.1 x 30 mm, 5 μm particle size reversed-phase column.

[0338] Method J - a linear gradient of 5-95% acetonitrile in water over 0.7 min, followed by isocratic flow of 95% acetonitrile to 1.16 min, and equilibration back to 5% acetonitrile to 1.5 min. The flow rate was 1.5 mL / min and the water contained 10 mM NH4HCO3. The column used was an Xbridge C182.1 x 50mm, 5 μm particle size reversed-phase column.

[0339] Method K – a linear gradient of 5 – 95% acetonitrile in water over 2.5 min, followed by isocratic flow of 95% acetonitrile to 3.0 min, followed by column equilibration back to 5% acetonitrile. The flow rate was 1 mL / min and the water contained 0.05% NH4OH.

[0340] Method L – a linear gradient of 5-95% acetonitrile in water over 0.7 min, followed by isocratic flow of 95% acetonitrile to 1.3 min. The flow rate was 1.5 mL / min and the water contained 0.04% (v / v) TFA and the acetonitrile contained 0.02% (v / v) TFA. The column used was an Halo-C183 x 30mm, 5 μm particle size reversed-phase column.

[0341] Method M – a linear gradient of 10-100% acetonitrile in water over 0.5 min, followed by isocratic flow of 100% acetonitrile to 0.9 min. The flow rate was 2.0 mL / min and and the water contained 0.04% (v / v) TFA and the acetonitrile contained 0.02% (v / v)TFA. The column used was an Xbridge C182.1 x 50mm, 5 μm particle size reversed-phase column.

[0342] Method N – isocratic flow of 5% acetonitrile to 0.4 min, followed by a linear gradient of 5-95% acetonitrile to 5.5 min, followed by isocratic flow of 100% acetonitrile to 7 min, followed by equilibration to 5% acetonitrile to 7.5 min. The flow rate was 0.8 mL / min and the water contained 0.04% (v / v) TFA and the acetonitrile contained 0.02% (v / v) TFA. The column used was a Luna C182.0 x 50 mm, 5 μm particle size reversed-phase column.

[0343] Method O – isocratic flow of 5% acetonitrile to 0.4 min, followed by a linear gradient of 5-95% acetonitrile to 3 min, followed by isocratic flow of 95% acetonitrile to 4 min, followed by equilibration to 5% acetonitrile. The flow rate was 1.0 mL / min and the water contained 0.04% (v / v) TFA and the acetonitrile contained 0.02% (v / v) TFA. The column used was a Kinetex C182.1 x 50 mm, 5 μm particle size reversed-phase column.

[0344] Method P – a linear gradient of 5-95% acetonitrile in water over 3.0 min, followed by isocratic flow of 95% acetonitrile to 3.5 min, and column equilibration back to 5% acetonitrile and isocratic flow of 5% acetonitrile to 4.3 min. The flow rate was 1.0 mL / min and the water contained 0.04% (v / v) TFA and the acetonitrile contained 0.02% (v / v) TFA. The column used was Kinetex-C18, 2.1 x 30 mm, 5 μm particle size reversed-phase column.

[0345] Method Q – a linear gradient of 5-95% acetonitrile in water over 0.5 min, followed by isocratic flow of 95% acetonitrile to 0.90 min, and equilibration back to 5% acetonitrile. The flow rate was 2.0 mL / min. The water contained 0.04% (v / v) TFA and the acetonitrile contained 0.02% (v / v) TFA.

[0346] Unless otherwise specified, preparatory HPLC (PrepHPLC) was performed on one of six instruments using the procedures listed herein:

[0347] Method 1 – a Waters 2545 binary gradient module with a 2998 detector and one of two columns (i) 10 x 250 mm Synergi C12, 4 µm, Max-RP 80 Å LC Column, or (ii) 21.2 x 250 mm Synergi C12, 4 µm, Max-RP 80 Å LC Column using acetonitrile / water containing 0.05% (v / v) TFA as the mobile phase.

[0348] Method 2 – a Shimadzu LC-8A preparative HPLC with one of two columns (i) a Phenomenex Luna C-18250 x 70 mm, 15 μm reversed-phase column or (ii) a Welch Xtimate C18250 x 70mm, 10 μm reversed-phase column using water containing 0.09% (v / v) TFA / acetonitrile or water containing 10 mM NH4HCO3 / acetonitrile as mobile phase.

[0349] Method 3 – a Gilson 281 semi-preparative HPLC system with one of two columns (i) Phenomenex Luna 80x30mm, 3 µm reversed-phase column or (ii) Phenomenex Luna 75x30mm, 3 µm reversed-phase column using water containing 0.075% (v / v) TFA / acetonitrile or 10mM NH4HCO3in H2O / acetonitrile as the mobile phase.

[0350] NMR spectra were recorded on a Bruker Avance III HD (400 MHz) instrument and referenced to the residual solvent peak. Example 2. Synthesis of 2-((2-((tert-butoxycarbonyl)amino)ethyl)carbamoyl)-4- (cyclopropylmethyl)-10-methyl-7-((methylsulfonyl)methyl)-11-oxo-3,4,10,11-tetrahydro- 1H-1,4,10-triazadibenzo[cd,f]azulene-6-carboxylic acid (Compound BBET13_1b)

[0351] To a solution of PP1_1 (3.6 g, 7.94 mmol) in dioxane (80 mL) was added a solution of NaOH (2 M, 15.88 mL) at 25°C. The reaction was stirred at 90°C for 2 h. LCMS showed the reactant was consumed completely and one main peak with desired mass was detected. The mixture was acidified by adding 2 N hydrochloric acid dropwise to pH = 3. The resulting mixture was partitioned between ethyl acetate (100 mL) and water (50 mL), and then the aqueous phase was further extracted with ethyl acetate (3 × 100 mL). Thecombined organic phase was washed with brine, dried over Na2SO4, filtered and concentrated under reduced pressure to give PP1_B (1.8 g, yield 83.62%) as a white solid. LCMS (System 2, method H): (ESI+): m / z 271.0, 273.0 (M+H, M+2)+, Rt: 0.737 min.

[0352] To a solution of PP1_B (1.3 g, 4.80 mmol) in DMF (13 mL) was added 1- Hydroxy-7-azabenzotriazole (HOAt, 1.70 g, 12.47 mmol), 3- (ethyliminomethylideneamino)propyl-dimethylazanium chloride (EDCI, 2.39 g, 12.47 mmol) and N,N-Diisopropyl-ethylamin (DIEA, 2.48 g, 19.18 mmol) at 25°C. The reaction was stirred at 25°C for 0.5 h. To the reaction was added tert-butyl N-(2-aminoethyl)carbamate (1.84 g, 11.51 mmol) at 25°C and then heated the mixture to 50°C and stirred for 4 h. The resulting mixture was partitioned between ethyl acetate (100 mL) and 1N HCl (100 mL), and then the aqueous phase was further extracted with ethyl acetate (6 × 50 mL). The organic phase was washed with brine, dried over Na2SO4, filtered and concentrated under reduced pressure to give a residue which was purified by prep-HPLC (Method 3, NH4HCO3) to give PP1_3 (1 g, yield 50.46%) as a white solid. LCMS (System 4, Method G): (ESI+): m / z 413.1, 415.1 (M+H, M+2)+, Rt: 2.543 min.1H NMR: (400MHz, DMSO-d6). δ = 8.54 - 8.40 (m, 1H), 7.56 (s, 1H), 6.97 - 6.88 (m, 1H), 6.83 (s, 1H), 3.49 (s, 3H), 3.26 - 3.22 (m, 2H), 3.10 (q, J = 5.6 Hz, 2H), 1.37 (s, 9H).

[0353] To a mixture of XPhos Pd G2 (30.46 mg, 38.72 umol), PP1_3 (200 mg, 483.95 umol), XPhos (18.46 mg, 38.72 umol), potassium acetate (KOAc, 142.49 mg, 1.45 mmol) and bis(pinacolato)diboron (BPD, 245.79 mg, 967.90 umol) was added the degassed anhydrous 2-methyl tetrahydrofuran (2-MeTHF, 4 mL) at 25°C. The reaction was stirred at 75°C for 24 h under N2. The mixture was cooled to ambient temperature and diluted with water and ethyl acetae, and the biphasic mixture was stirred for about 0.5 h with 20 mg of ammonium pyrrolidine dithiocarbamate. The resulting mixture was partitioned, and then theaqueous phase was further extracted with ethyl acetate (3 × 20 mL). The organic phase was washed with brine, dried over Na2SO4, filtered and concentrated under reduced pressure to give a residue, which was purified by prep-HPLC (Method 3, Welch Ultimate XB SiO2, heptane:ethanol) to give PP1_3_Bpin (51 mg, yield: 22.89%) as a white solid. LCMS (System 4, Method G): (ESI+): m / z 461.3 (M+H)+, Rt: 2.846 min.1H NMR: (400MHz, DMSO-d6). δ = 12.11 (br s, 1H), 8.42 (br t, J = 4.8 Hz, 1H), 7.56 (s, 1H), 7.05 (d, J = 1.2 Hz, 1H), 6.90 (br s, 1H), 3.55 (s, 3H), 3.30 - 3.25 (m, 2H), 3.15 - 3.06 (m, 2H), 1.37 (s, 9H), 1.31 (s, 12H).

[0354] To a solution of PP1_3_Bpin (2.06 g, 4.47 mmol) in 1,4-dioxane (40 mL) and water (20 mL) were added [1,1-bis(diphenylphosphino)ferrocene]dichloropalladium(II) (Pd(dppf)Cl2, 218.02 mg, 297.96 umol), Methylsulfonyl Benzoate (1.1 g, 2.98 mmol) and NaHCO3 (625.77 mg, 7.45 mmol) at 20oC under N2, then the resulting mixture was slowly warmed up to 90oC and stirred at 90oC for 1 h. Three vials were set up as described above. All four reaction mixtures were combined for work up and purification. The reaction mixture was concentrated under reduced pressure to remove 1, 4-dioxane, then diluted with water 50 mL and extracted with ethyl acetate 1500 mL (3 × 500 mL). The combined organic layers were washed with brine 900 mL (3 × 300 mL), dried over Na2SO4, filtered and concentrated under reduced pressure to give a residue. The residue was triturated with ethyl acetate at 20oC for 30 min then filtered to give BBET5_1 (5 g, yield 73.6%) as a white solid. LCMS (System 2, method K): (ESI+ ): m / z 1151.5 (2M+H)+, Rt: 1.455 min. 1H NMR: (400MHz, DMSO-d6).δ ppm 12.28 (br s, 1H), 8.36 (br t, J = 5.2 Hz, 1H), 7.33 (s, 1H), 7.27 (s, 1H), 7.22 (s, 1H), 6.93 - 6.82 (m, 1H), 6.68 (s, 1H), 5.34 (s, 2H), 4.77 (s, 2H), 3.82 (s, 3H), 3.57 (s, 3H), 3.26 (q, J = 6.0 Hz, 2H), 3.11 - 3.02 (m, 2H), 2.83 (s, 3H), 1.36 (s, 9H).

[0355] Cyclopropanecarbaldehyde (3.66g, 52.12 mmol, 3.9 mL) and acetic acid (HOAc, 40.00 mL) was added to a mixture of BBET5_1 (1 g, 17.38 umol) in dimethylformamide (DMF, 120 mL) at 20oC and stirred at 20oC for 30 min, then sodium triacetyl borohydride (NaBH(OAc)3, 920.46 mg, 4.34 mmol) was added. The resulting reaction mixture was slowly warmed up to 50oC and stirred at 50oC for 1 h. Four vials were set up as described above. All five reaction mixtures were combined for work up and purification. The resulting mixture was quenched by addition NaHCO31 L at 20oC, and then extracted with ethyl acetate 3 L (3 × 1 L). The combined organic layers were washed with brine 1.5 L (3 × 500 mL), dried over Na2SO4, filtered and concentrated under reduced pressure to give a residue of BBET5_1a (5.5 g, crude) as a white solid which was used for next step without further purification. LCMS (System 2, method F): (ESI+ ): m / z 530.0 (M-55)+, Rt: 1.460 min.1H NMR: (400MHz, CHLOROFORM-d). δ ppm 11.16 (br s, 1H), 7.50 (br s, 1H), 7.34 (s, 1H), 7.30 (s, 1H), 7.11 (s, 1H), 6.77 (br s, 1H), 5.31 (s, 1H), 5.16 (br s, 1H), 4.79 (br s, 2H), 3.95 (s, 3H), 3.73 (s, 3H), 3.57 (q, J = 4.8 Hz, 2H), 3.37 (br d, J = 2.8 Hz, 2H), 3.04 (br d, J = 6.4 Hz, 2H), 2.84 (s, 3H), 1.35 (s, 9H), 1.05 - 0.95 (m, 1H), 0.54 - 0.45 (m, 2H), 0.20 (br d, J = 4.4 Hz, 2H).

[0356] To a solution of BBET5_1a (0.5 g, 794.00 umol) in acetic acid (HOAc, 50 mL) was added paraformaldehyde (21.46 mg, 714.60 umol) at 25oC, then degassed and purged with N2for 3 times at 25oC. Then the resulting mixture was slowly warmed up to 75oC and stirred at 75oC for 1 h. The resulting mixture was quenched by addition NaHCO31 L at 20oC, and then extracted with ethyl acetate 3 L (3 × 1 L). The combined organic layers were washed with brine 1.5 L (3 × 500 mL), dried over Na2SO4, filtered and concentrated under reduced pressure to give a yellow residue. The residue was purified by prep-HPLC (Method 2, TFA) to give BBET13_1a (250 mg, yield 27% of 2 steps) as a yellow solid. LCMS (System 2, Method I) (ESI+ ): m / z 642.1 (M+H)+, Rt: 1.296 min.1H NMR: ET49026-376- P1 (400MHz, DMSO–d6). δ ppm 12.14 (br s, 1H), 8.30 (br t, J = 4.8 Hz, 1H), 7.83 (s, 1H), 7.71 (br d, J = 9.2 Hz, 2H), 6.92 (br t, J = 5.6 Hz, 1H), 4.92 (s, 2H), 4.70 - 4.52 (m, 2H), 3.89- 3.81 (m, 3H), 3.66 (s, 3H), 3.30 (br d, J = 6.4 Hz, 2H), 3.14 - 3.07 (m, 2H), 2.94 - 2.85 (m, 5H), 1.39 - 1.34 (m, 9H), 0.89 - 0.76 (m, 1H), 0.40 - 0.32 (m, 2H), 0.07 - 0.00 (m, 2H).

[0357] To a solution of BBET13_1a (0.1 g, 155.83 umol) in tetrahydrofuran (THF, 8 mL), methanol (MeOH, 2 mL) and water (2 mL) was added LiOH.H2O (52.31 mg, 1.25 mmol) at 25oC and stirred at 25oC for 14 h. Another vial was set up as described above. Both two reaction mixtures were combined for work up and purification. The resulting mixture was concentrated under reduced pressure to give a yellow residue. The residue was purified by prep-HPLC (Method 3, NH4HCO3) to give BBET13_1b (175 mg, yield: 70%) as a yellow solid. LCMS (System 3, method C): (ESI+ ): m / z 628.2 (M+H)+, Rt: 2.015 min.1H NMR: (400MHz, DMSO–d6). δ ppm 13.13 - 10.64 (m, 1H), 8.31 (br t, J = 4.8 Hz, 1H), 7.76 - 7.69 (m, 2H), 7.62 (s, 1H), 6.91 (br t, J = 5.6 Hz, 1H), 5.01 (br s, 2H), 4.58 (br d, J = 1.2 Hz, 2H), 3.64 (s, 3H), 3.28 - 3.27 (m, 2H), 3.13 - 3.08 (m, 2H), 2.88 (d, J = 6.4 Hz, 2H), 2.84 (s, 3H), 1.36 (s, 9H), 0.87 - 0.77 (m, 1H), 0.39 - 0.30 (m, 2H), 0.03 (q, J = 4.8 Hz, 2H). Alternative Procedure to Synthesize a Mixture of BBET13_1a&BBET5_1a

[0358] To a solution of BBET13_1a&BBET5_1a (1.2 g, 1.86 mmol) in tetrahydrofuran (THF, 64 mL), methanol (MeOH, 16 mL) and water (16 mL) was added LiOH.H2O (392.34 mg, 9.34 mmol) at 25oC and stirred at 25oC for 24 h. The resulting mixture was concentratedunder reduced pressure to give a yellow residue. The residue was partially purified by prep- HPLC (Method 2, NH4HCO3) to give BBET13_1b&BBET5_1b (1:1 mixture, 550 mg, yield: 30% of 2 steps) as a yellow solid, which was used in subsequent coupling reactions. LCMS (System 2, method D) (ESI+ ): m / z 628.1 (M+H)+, Rt: 1.133 min; m / z 516.1 (M- 100)+, Rt: 1.302 min. Example 3. General procedure for preparation of 4-(2-((2-((tert- butoxycarbonyl)amino)ethyl)carbamoyl)-6-methyl-7-oxo-6,7-dihydro-1H-pyrrolo[2,3- c]pyridin-4-yl)-5-(cyclohexyloxy)-2-(methylsulfonamido)benzoic acid (Compound BBET23_6)

[0359] To a solution of BBET23_1a (10 g, 99.84 mmol) in dichloromethane (DCM, 150 mL) were added triethylamine (TEA, 20.21 g, 199.68 mmol) and 4-dimethylaminopyridine (DMAP, 24.39 g, 199.68 mmol) at 20 °C. Then the reaction was cooled to 0 °C. Then the solution of 4-methylbenzenesulfonyl chloride (TsCl, 28.55 g, 149.76 mmol) in dichloromethane (DCM, 150 mL) was added dropwise to the reaction flask at 0 °C. The reaction was warmed to 20 °C and stirred at 20 °C for 3 h. The aqueous phase was extractedwith dichloromethane (3×150 mL). The combined organic phase was washed with brine (3 ×70 mL), dried with anhydrous Na2SO4, filtered and concentrated in vacuum. The residue was purified by column chromatography (silica gel, petroleum ether: ethyl acetate= 10: 1) to give BBET23_1b (23.88 g, yield 94.04%) as a colorless oil.1H NMR: (400MHz, CHLOROFORM-d). δ ppm 7.73 (s, 1H), 7.72 - 7.69 (m, 1H), 7.26 (s, 1H), 7.24 (s, 1H), 4.47 - 4.38 (m, 1H), 2.37 (s, 3H), 1.76 - 1.67 (m, 2H), 1.63 (br d, J = 6.0 Hz, 2H), 1.52 - 1.38 (m, 3H), 1.24 - 1.14 (m, 3H).

[0360] To a solution of BBET23_OH (1.8 g, 6.52 mmol) in dimethylformamide (DMF, 40 mL) were added K2CO3 (7.21 g, 52.17 mmol) and BBET23_1b (13.27 g, 52.17 mmol) at 20°C. The mixture was heated to 120 °C and stirred at 120 °C for 2 h. The mixture was poured into hydrochloric acid (HCl, 1 M, 70 mL). The aqueous phase was extracted with ethyl acetate (3×100 mL). The combined organic phase was washed with brine (2×100 mL), dried with anhydrous Na2SO4, filtered and concentrated in vacuum. The residue was purified by column chromatography (silica gel, petroleum ether: ethyl acetate= 10: 1) to give BBET23_2 (1.16 g, yield 51.79%) as a yellow solid.1H NMR: (400MHz, DMSO-d6) δ ppm 8.40 (s, 1H), 7.54 (s, 1H), 4.83 - 4.75 (m, 1H), 3.86 (s, 3H), 1.87 (dt, J = 3.2, 8.0 Hz, 2H), 1.76 - 1.66 (m, 2H), 1.62 - 1.49 (m, 3H), 1.48 - 1.37 (m, 3H).

[0361] To a solution of BBET23_2 (2.7 g, 7.54 mmol) in tetrahydrofuran (THF, 40 mL) was added Fe (2.10 g, 37.69 mmol) and NH4Cl (1.21 g, 22.61 mmol) in ethanol (EtOH, 40 mL) and H2O (20 mL) at 20℃. The resulting mixture was slowly warmed up to 100 °C and stirred at 100 ℃ for 3 h. The mixture was concentrated in vacuum and poured into water (100 mL). The aqueous phase was extracted with ethyl acetate (3×200 mL). The combined organic phase was washed with brine (3×100 mL), dried with anhydrous Na2SO4, filteredand concentrated in vacuum. The residue was purified by column chromatography (silica gel, petroleum ether: ethyl acetate= 10: 1) to give BBET23_3 (1.90 g, yield 76.80%) as a yellow solid. 1H NMR: (400MHz, DMSO-d6). δ ppm 7.31 (s, 1H), 7.09 (s, 1H), 6.49 - 6.36 (m, 2H), 4.14 - 4.05 (m, 1H), 3.79 (s, 3H), 1.89 - 1.78 (m, 2H), 1.77 - 1.64 (m, 2H), 1.55 - 1.41 (m, 3H), 1.38 - 1.23 (m, 3H).

[0362] To a solution of BBET23_3 (1.6 g, 4.88 mmol) in chloroform (40 mL) was added triethylamine (TEA, 986.61 mg, 9.75 mmol). Then the reaction was cooled to 0 °C and methylsulfonyl methanesulfonate (1.70 g, 9.75 mmol) was added dropwise at 0 °C. The mixture was slowly warmed up to 20 °C and stirred at 20 °C for 7 h. The reaction mixture was quenched by saturated sodium bicarbonate solution to pH=7. The mixture was poured into water (50 mL). The aqueous phase was extracted with ethyl acetate (3×100 mL). The combined organic phase was washed with brine (2×50 mL), dried with anhydrous Na2SO4, filtered and concentrated in vacuum to give BBET23_4& BBET23_4a (3.15 g) as a yellow oil. LCMS (System 2, method F): (ESI+): BBET23_4: m / z 423.1 (M+18)+, Rt: 2.389 min； BBET23_4a: m / z 503.0 (M+18)+, Rt: 2.288 min.

[0363] To a solution of BBET23_4& BBET23_4a (3.15 g, 6.50 mmol) in methanol (MeOH, 32 mL) was added K2CO3(898.8 mg, 6.50 mmol) at 20 °C. The mixture was heated to 30 °C and stirred at 30 °C for 4 h. LCMS analysis showed BBET23_4a was consumed completely. The mixture was filtered and concentrated in vacuum. Then the mixture was poured into water (100 mL). The aqueous phase was extracted with ethyl acetate (3×100 mL). The combined organic phase was washed with brine (2×50 mL), dried with anhydrous Na2SO4, filtered and concentrated in vacuum to give BBET23_4 (1.42 g, crude) as a yellow solid. LCMS(System 2, method F) (ESI+): m / z 423.1 (M+18)+, Rt: 2.389 min.

[0364] To a solution of BBET23_4 (100 mg, 246.15 umol) and PP1_3_Bpin (169.95 mg, 369.20 umol) in H2O (3 mL) and 1,4-dioxane (6 mL) was added Pd(dppf)Cl2(18.00 mg, 24.61 umol) and NaHCO3 (51.69 mg, 615.31 umol) at 20 °C under N2. Then the mixture was slowly warmed up to 70 °C and stirred at 70 °C for 1 h. LCMS analysis showed BBET23_4 was consumed completely. The mixture was concentrated in vacuum and poured into water (20 mL). The aqueous phase was extracted with ethyl acetate (3×30 mL). The combined organic phase was washed with brine (2×15 mL), dried with anhydrous Na2SO4, filtered and concentrated in vacuum to give BBET23_5 (250 mg, crude) as a brown oil. LCMS (System 2, method F) (ESI+): m / z 660.4 (M+H)+, Rt: 2.023 min.

[0365] To a solution of BBET23_5 (200 mg, 303.15 umol) in tetrahydrofuran (THF, 12 mL), methanol (MeOH, 4 mL) and H2O (4 mL) was added LiOH.H2O (152.65 mg, 3.64 mmol) at 20 °C. The mixture was stirred at 20 °C for 12 h. The mixture was filtered and filtrate was purified by reversed-phase HPLC (Method 3, 0.1% FA in water \ acetonitrile) to give BBET23_6 (79 mg, yield 40.36%) as a white solid. LCMS (System 3, method C): (ESI+): m / z 590.2 (M-55)+, Rt: 2.476 min.1H NMR: (400MHz, DMSO-d6). δ ppm 12.23 (br s, 1H), 8.35 (br t, J = 5.2 Hz, 1H), 7.63 (s, 1H), 7.50 (s, 1H), 7.38 (s, 1H), 6.86 (br t, J = 5.6 Hz, 1H), 6.78 (d, J = 2.0 Hz, 1H), 4.30 - 4.21 (m, 1H), 3.57 (s, 3H), 3.25 (br s, 2H), 3.07 (br d, J = 6.0 Hz, 3H), 3.03 (s, 2H), 1.83 - 1.70 (m, 2H), 1.49 (br d, J = 6.4 Hz, 2H), 1.42 (br s, 2H), 1.35 - 1.31 (m, 9H), 1.30 - 1.23 (m, 2H), 1.23 - 1.07 (m, 2H). Example 4. Synthesis of 4-(2-((2-((tert-butoxycarbonyl)amino)ethyl)carbamoyl)-6- methyl-7-oxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridin-4-yl)-2-(methylsulfonamido)-5- phenoxybenzoic acid (Compound BBET25_6)

[0366] To a solution of BBET25_1 (5 g, 18.0 mmol) in dimethylsulfoxide (DMSO, 60 mL) was added phenol (1.2 g, 12.75 mmol) and K2CO3 (497.09 mg, 3.60 mmol) at 20oC. The mixture was heated to 85oC stirred at 85oC for 2 h. The reaction mixture was diluted with H2O (100 mL) and extracted with ethyl acetate (3×150 mL). The combined organic phase was washed with brine (3×100 mL), dried over Na2SO4, filtered and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (SiO2, petroleum ether / ethyl acetate= 10:1) to give BBET25_2 (4.8 g, yield 75.8%) as a white solid.1H NMR: (400 MHz, DMSO-d6) δ ppm 8.52 (s, 1H), 7.52 - 7.46 (m, 2H), 7.33 - 7.28 (m, 1H), 7.22 - 7.18 (m, 2H), 7.13 (s, 1H), 3.77 (s, 3H).

[0367] To a solution of BBET25_2 (4.5 g, 12.78 mmol) in tetrahydrofuran (THF, 75 mL), ethanol (EtOH, 75 mL) and H2O (37.5 mL) was added Fe (3.57 g, 63.9 mmol) and NH4Cl (2.05 g, 38.4 mmol) at 20oC. The resulting mixture was slowly warmed up to 100oC and stirred at 100oC for 1 h. LCMS analysis showed BBET25_2 was consumed completely and 88.6% of desired compound was detected. The reaction mixture was filtered and concentrated in vacuum, then diluted with water 100 mL and extracted with ethyl acetate 300 mL (3×100 mL). The combined organic layers were washed with brine 150 mL (3×50 mL),dried over Na2SO4, filtered and concentrated under reduced pressure to give BBET25_3 (5.4 g, crude) as a yellow solid.

[0368] LCMS (System 2, method F) (ESI+): m / z 322.1 (M+1)+, Rt: 1.975 min.1H NMR: (400 MHz, DMSO-d6). δ ppm 7.41 (s, 1H), 7.34 - 7.30 (m, 2H), 7.21 (s, 1H), 7.06 - 7.03 (m, 1H), 6.86 – 6.84 (d, 2H), 6.75 (s, 2H) , 3.74 (s, 3H).

[0369] To solution of BBET25_3 (5.4 g, 16.8 mmol) in chloroform (80 mL) was added triethylamine (TEA, 3.39 g, 33.5 mmol) and then methylsulfonyl methanesulfonate (5.83 g, 33.5 mmol) was added dropwise at 0oC. The mixture was slowly warmed up to 20oC and stirred at 20oC for 7 h. The reaction mixture was quenched by saturated sodium bicarbonate solution to pH=7. The aqueous phase was extracted with ethyl acetate (3×200 mL). The combined organic phase was washed with brine (3×150 mL), dried with anhydrous Na2SO4, filtered and concentrated in vacuum to give BBET25_4& BBET25_4a (6 g, crude) as a brown solid. LCMS (System 2, method F): (ESI+): BBET25_4: m / z 427.3 (fragment), Rt: 2.190 min; BBET25_4a: m / z 495.0 (M+18)+, Rt: 2.116 min.

[0370] To a solution of BBET25_4 & BBET25_4a (1 g, 1.75 mmol, mixture) in tetrahydrofuran (THF, 40 mL) and H2O (10 mL) was added [2-(2-aminophenyl)phenyl]- chloro-palladium;dicyclohexyl-[3-(2,4,6-triisopropylphenyl)phenyl]phosphane (Xphos Pd G2, 196.58 mg, 174.89 μmol), PP1_3_Bpin (1.38 g, 2.10 mmol) and K3PO4 (1.06 g, 3.50 mmol) under N2 at 20oC. The mixture was heated to 80oC and stirred at 80oC for 2 h. The mixture was filtered, concentrated in vacuum and poured into water. The aqueous phase was extracted with ethyl acetate (3×50 mL). The combined organic phase was washed with brine (3×50 mL), dried with anhydrous Na2SO4, filtered and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (SiO2, Ethylacetate / Methanol = 3 / 1) to give BBET25_5 (877 mg, yield 76.71%) as a yellow solid. LCMS (System 2) (ESI+): m / z 598.4 (M-55)+, Rt: 1.835 min.1H NMR: (400 MHz, DMSO-d6). δ ppm 12.33 (br s, 1H), 9.91 (s, 1H), 8.38 (br t, J = 5.2 Hz, 1H), 7.68 (s, 1H), 7.50 (s, 1H), 7.47 (s, 1H), 7.30 (t, J = 8.0 Hz, 2H), 7.06 (t, J = 7.2 Hz, 1H), 6.91 (br d, J = 8.4 Hz, 4H), 3.84 (s, 3H), 3.53 (s, 3H), 3.27 (q, J = 6.0 Hz, 2H), 3.18 (s, 3H), 3.08 (q, J = 5.6 Hz, 2H), 1.38 - 1.34 (m, 9H).

[0371] To a solution of BBET25_5 (877 mg, 1.34 mmol) in tetrahydrofuran (THF, 80 mL), methanol (MeOH 20 mL) and H2O (20 mL) was added LiOH.H2O (449.88 mg, 10.71 mmol) at 20oC. The mixture was stirred at 20oC for 16 h. TLC (ethyl acetate: methanol = 3:1, Rf= 0.3) indicated BBET25_5 was consumed completely and one new spot was formed. The mixture was concentrated in vacuum to give a residue. The residue was purified by prep-HPLC (Biotage Isolera one, 330 g Agela C18 column, 20～ 35 um C18, Water (0.1% TFA); B: MeCN, Flow rate 60 mL / min, Gradient 35%-42% B over 80 min) to give BBET25_6 (825 mg, yield 96.24%) as a white solid. LCMS (System 4, method C): m / z 584.1 (M-55)+, Rt: 2.268 min.1H NMR: (400 MHz, DMSO-d6). δ ppm 12.32 (br s, 1H), 10.46 (s, 1H), 8.37 (br t, J = 5.2 Hz, 1H), 7.68 (s, 1H), 7.56 (s, 1H), 7.46 (s, 1H), 7.32 - 7.27 (m, 2H), 7.08 - 7.03 (m, 1H), 6.93 - 6.87 (m, 4H), 3.53 (s, 3H), 3.27 (br d, J = 6.0 Hz, 2H), 3.22 (s, 3H), 3.08 (br d, J = 6.0 Hz, 2H), 1.35 (s, 9H). Example 5. Synthesis of Alkyl Substituted Cereblon Recruiting Fragments: General Procedure

[0372] To a solution of B10 (280 mg, 866.49 umol) in dimethylformamide (DMF, 10 mL) were added di-μ-chlorodimethylbis(triphenylphosphine)dipalladium (Pd(PPh3)2Cl2,60.82 mg, 86.64 umol), CuI (23 mg, 113.13 umol), and tert-butyl N-prop-2-ynylcarbamate (336.18 mg, 2.16 mmol) at 25 °C under N2. Then triethylamine (TEA, 5 mL) was added at 25 °C under N2. The reaction mixture was heated to 70 °C and stirred at 70 °C for 8 h. An addition vial was set up using the procedure described above (totally 380 mg of was used) was combined for following the reaction completion. The combined mixture was concentrated to give a residue which was purified by flash silica gel chromatography (Ethylacetate / Petroleum etherg) to give B11 (400 mg, yield 86.04%) as a yellow solid. LCMS (System 2, method D): (ESI+ ): m / z 342.1 (M-55)+, Rt: 1.632 min1H NMR: (400MHz, DMSO–d6). δ ppm 11.02 (s, 1H), 7.74 (d, J = 7.6 Hz, 1H), 7.66 (d, 7.6 Hz, 1H), 7.58 - 7.52 (m, 1H), 7.39 (br s, 1H), 5.16 (dd, J = 5.2, 13.2 Hz, 1H), 4.50 - 4.26 (m, 2H), 4.02 (br d, J = 5.6 Hz, 2H), 2.99 - 2.90 (m, 1H), 2.65 - 2.56 (m, 1H), 2.39 - 2.36 (m, 1H), 2.07 - 1.98 (m, 1H), 1.40 (s, 9H)

[0373] To a solution of B11 (300 mg, 125.81 umol) in tetrahydrofuran (THF, 3 mL) were added Pd / C (133.89 mg, 125.81 umol, 10% purity) and Pd(OH)2 (2.65 mg, 3.77 umol, 20% purity) at 20 °C under H2 at 15 Psi and stirred for 3 h. The precipitate was filtered using a Buchner funnel. The filter cake was washed with tetrahydrofuran, and the filtrate was concentrated to give B12 (280 mg, yield 92.40%) as a yellow solid which was used into the next step without further purification.LCMS (System 2, method B) (ESI+ ): m / z 447.2 (M+2Na)+, Rt: 0.570 min.

[0374] To a solution of B12 (280 mg, 697.46 umol) in dichloromethane (DCM, 10 mL) was added trifluoroacetic acid (TFA, 1 mL) at 20°C and stirred for 2 h. LCMS analysis showed the reactant was consumed completely and one main peak with desired mass was detected. The resulting mixture was concentrated to give a residue which was purified by prep-HPLC (TFA) to give B13 (170 mg, yield 61.1%, TFA salt) as a white solid. LCMS (System 3, method C) (ESI+ ): m / z 302.1 (M+H)+, Rt: 1.230 min1H NMR: (400MHz, DMSO–d6). δ ppm 11.02 (s, 1H), 7.77 - 7.65 (m, 2H), 7.61 (dd, J = 1.6, 6.8 Hz, 1H), 7.54 - 7.46 (m, 2H), 5.17 (dd, J = 6.0, 13.6 Hz, 1H), 4.53 - 4.25 (m, 2H), 3.02 - 2.89 (m, 1H), 2.87 - 2.78 (m, 2H), 2.72 (br t, J = 7.6 Hz, 2H), 2.65 - 2.59 (m, 1H), 2.37 (br dd, J = 4.0, 13.2 Hz, 1H), 2.08 - 1.98 (m, 1H), 1.87 (quin, J = 7.6 Hz, 2H).

[0375] The general procedure was followed to synthesize B16. LCMS (System 2, method J) (ESI+ ): m / z 316.1 (M+H)+, Rt: 1.456 min.1H NMR (400MHz, DMSO-d6). δ ppm: 11.01 (s, 1H), 7.74 - 7.64 (m, 2H), 7.60 - 7.57 (m, 1H), 7.49 - 7.45 (m, 2H), 5.15 (dd, J = 5.2, 13.3 Hz, 1H), 4.55 - 4.23 (m, 2H), 3.01 - 2.88 (m, 1H), 2.87 - 2.77 (m, 2H), 2.66 (q, J = 7.2 Hz, 2H), 2.44 - 2.30 (m, 2H), 2.08 - 1.97 (m, 1H), 1.72 - 1.50 (m, 4H).

[0376] The general procedure was followed to synthesize B19. LCMS (System 3, method C) (ESI+): m / z 330.1 (M+H)+, Rt: 1.555 min.1H NMR: (400MHz, METHANOL- d4). δ ppm 7.70 - 7.63 (m, 1H), 7.51 - 7.46 (m, 2H), 5.19 (dd, J = 4.8, 13.2 Hz, 1H), 4.57 - 4.41 (m, 2H), 2.95 - 2.87 (m, 3H), 2.81 (br d, J = 2.0 Hz, 1H), 2.76 (t, J = 7.6 Hz, 2H), 2.59 - 2.44 (m, 1H), 2.23 - 2.14 (m, 1H), 1.82 - 1.62 (m, 4H), 1.53 - 1.40 (m, 2H).

[0377] The general procedure was followed to synthesize B22. LCMS (system 3, method C) (ESI+): m / z 344.1 (M+H)+, Rt: 1.652 min.1H NMR: (400MHz, METHANOL-d4). δ ppm 7.69 - 7.61 (m, 1H), 7.50 - 7.43 (m, 2H), 5.18 (dd, J = 5.2, 13.2 Hz, 1H), 4.58 - 4.38 (m, 2H), 2.95 - 2.86 (m, 3H), 2.84 - 2.79 (m, 1H), 2.74 (br t, J = 7.6 Hz, 2H), 2.52 (dq, J = 4.8, 13.2 Hz, 1H), 2.24 - 2.12 (m, 1H), 1.79 - 1.58 (m, 4H), 1.44 (br s, 4H).

[0378] The general procedure was followed to synthesize B27. LCMS (system 6, method C): m / z 358.1 (M-100+H)+, Rt: 1.652 min.1H NMR: (400MHz, METHANOL-d4). δ ppm 7.71 - 7.63 (m, 1H), 7.53 - 7.46 (m, 2H), 5.20 (dd, J = 5.2, 13.2 Hz, 1H), 4.60 - 4.49 (m, 2H), 2.96 - 2.88 (m, 3H), 2.83 (dd, J = 2.4, 4.8 Hz, 1H), 2.81 - 2.69 (m, 2H), 2.54 (dq, J = 4.4, 13.2 Hz, 1H), 2.25 - 2.15 (m, 1H), 1.78 - 1.69 (m, 2H), 1.68 - 1.60 (m, 2H), 1.43 (br s, 6H).

[0379] To a solution of BBET40_1 (400 mg, 1.24 mmol) and tert-butyl N-hex-5- ynylcarbamate (453.66 mg, 2.48 mmol) in dimethylformamide (DMF, 4 mL) were added copper iodide (CuI, 47.15 mg, 247.57 umol), di-μ- chlorodimethylbis(triphenylphosphine)dipalladium (Pd(PPh3)2Cl2, 86.88 mg, 123.78 umol) and triethylamine (TEA, 4 mL) at 25oC under N2. The resulting mixture was heated to 80oC and stirred at 80oC for 2 h. The residue was purified by flash silica gel chromatography (60- 100% Ethyl acetate / Petroleum ether) to give BBET42_1 (510 mg, yield 96%) as a brown solid. LCMS (System 2, method D): (ESI+ ): m / z 370.1 (M-55)+, Rt: 1.635 min.1H NMR:(400MHz, DMSO-d6). δ ppm 10.99 (s, 1H), 7.68 (br d, J = 7.6 Hz, 1H), 7.63 (s, 1H), 7.51 (br d, J = 8.0 Hz, 1H), 6.89 (br s, 1H), 5.11 (br dd, J = 4.8, 13.2 Hz, 1H), 4.48 - 4.27 (m, 2H), 3.06 (q, J = 6.4 Hz, 2H), 2.97 - 2.83 (m, 1H), 2.59 (br d, J = 17.2 Hz, 1H), 2.46 (br t, J = 7.2 Hz, 2H), 2.39 (br dd, J = 4.0, 13.2 Hz, 1H), 2.06 - 1.96 (m, 1H), 1.67 (quin, J = 6.8 Hz, 2H), 1.38 (s, 9H).

[0380] To a solution of BBET42_1 (500 mg, 1.18 mmol) in tetrahydrofuran (THF, 10 mL) were added palladium (2.50 g, 2.35 mmol, purity 10%) and Pd(OH)2 (49.5 mg, 70.5 umol, purity 20%) at 25oC. The suspension was degassed and purged with H2 for 3 times. The resulting mixture was stirred under H2(15 psi) at 25oC for 3 h. The reaction mixture was filtered and concentrated under reduced pressure to give BBET42_2 (450 mg, yield 97%) as a brown solid. LCMS (System 2, method D) (ESI+ ): m / z 452.1 (M+23)+, Rt: 1.692 min.1H NMR: (400MHz, DMSO-d6). δ ppm 10.97 (s, 1H), 7.62 (d, J = 8.0 Hz, 1H), 7.42 (s, 1H), 7.33 (d, J = 8.0 Hz, 1H), 6.75 (br t, J = 5.2 Hz, 1H), 5.10 (dd, J = 5.2, 13.2 Hz, 1H), 4.45 - 4.25 (m, 2H), 3.60 (t, J = 6.8 Hz, 1H), 2.96 - 2.85 (m, 2H), 2.68 (br t, J = 7.6 Hz, 2H), 2.60 (br d, J = 16.8 Hz, 1H), 2.39 (br dd, J = 4.4, 13.2 Hz, 1H), 2.08 - 1.93 (m, 1H), 1.76 (td, J = 3.2, 6.8 Hz, 1H), 1.65 - 1.51 (m, 2H), 1.44 - 1.32 (m, 10H), 1.31 - 1.20 (m, 2H).

[0381] To a solution of BBET42_2 (450 mg, 1.05 mmol) in dichloromethane (DCM, 20 mL) was added trifluoroacetic acid (TFA, 4 mL) at 25oC and stirred at 25 °C for 2 h The reaction mixture was filtered and concentrated under reduced pressure to give a residue. The residue was purified by prep-HPLC (Method 2, TFA) to give BBET42 (115 mg, yield 94%, TFA salt) as a white solid. LCMS (System 6, method C) (ESI+): m / z 330.1 (M+H)+, Rt: 1.550 min.1H NMR (400MHz, DMSO-d6). δ ppm 10.98 (s, 1H), 7.74 (br s, 2H), 7.64 (d, J = 8.0 Hz, 1H), 7.43 (s, 1H), 7.35 (d, J = 8.0 Hz, 1H), 5.09 (dd, J = 5.2, 13.2 Hz, 1H), 4.46 - 4.24 (m, 2H), 2.96 - 2.84 (m, 1H), 2.77 (br dd, J = 6.8, 13.6 Hz, 2H), 2.70 (br t, J = 7.2 Hz,2H), 2.60 (br d, J = 17.2 Hz, 1H), 2.46 - 2.31 (m, 1H), 2.04 - 1.94 (m, 1H), 1.70 - 1.49 (m, 4H), 1.38 - 1.27 (m, 2H). Example 6. Synthesis of Cereblon Ligand 3-(4-((1-(3-aminopropyl)piperidin-4- yl)methyl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione (Compound E3_d)

[0382] To a solution of tritert-butylphosphonium tetrafluoroborate (t-Bu3PHBF4, 185.03 mg, 637.75 umol) in dioxane (10 mL) was added N-cyclohexyl-N-methyl-cyclohexanamine (MeN(Cy)2, 417.20 mg, 2.14 mmol) and Pd2(dba)3(977.85 mg, 1.07 mmol) at 20°C under N2. The reaction was stirred at 20°C for 0.5 h. To the mixture was added E3_D1 (500 mg, 1.48 mmol) and E3_3 (643.68 mg, 3.26 mmol) at 20°C under N2. The reaction was heated to 55°C and stirred at 55°C for 1.5 h under N2. Two additional vials were set up as described above. All three reaction mixtures were combined. The resulting mixture was concentrated to give a residue which was purified by flash silica gel chromatography (0~100% ethylacetate: petroleum ether) to give a mixture of E3_D2 and E3_D2a (239 mg, yield 35.12%) as a white solid.

[0383] LCMS (System 2, method P) (ESI+): m / z 440.2(M+H)+, 340.1(M-100+H)+, 384.1(M-55)+, Rt: 1.552 min, 1.603 min.

[0384] To a solution of E3_D2 and E3_D2a (750 mg, 1.71 mmol) in tetrahydrofuran (THF, 30 mL) was added wet Pd / C (326.88 mg, 307.16 umol, 10% purity) at 20°C under nitrogen. The mixture was degassed under vacuum and purged with H2 for 3 times, then stirred at 20°C under H2(15 psi) for 16 h. The reaction mixture was filtered and concentrated under reduced pressure to give a crude product. The crude product was triturated with petroleum ether: ethyl acetate = 1: 1 (3 mL) at 20oC for 20 min and the precipitate was filtered to give E3_D3 (600 mg, yield: 79.63%) as a white solid. LCMS (system 2, method D) (ESI+): m / z 342.3(M-100+H)+, 386.3 (M-55)+, Rt: 0.733 min.

[0385] A mixture of E3_D3 (500 mg, 1.13 mmol) in dichloromethane (DCM, 20 mL) was added trifluoroacetic acid (TFA, 3.08 g, 27.01 mmol) and the mixture was stirred at 20°C for 1 h. The reaction mixture was concentrated under reduced pressure to give the E3_D4 (600 mg, crude) as a colorless oil. LCMS (System 2, method D) (ESI+): m / z 342.2 (M+H)+, Rt: 0.244 min.

[0386] To a solution of E3_D4 (100 mg, 292.91µmol, TFA salt) and N,N-Diisopropyl- ethylamine (DIEA, 64.38 mg, 498.14 umol) in dichloroethane (DCE, 10 mL) was added E3_2 (50.75 mg, 293.02 umol) at 20°C. The reaction mixture was stirred at 20°C for 2 min. To the mixture was added NaBH(OAc)3 (267.04 mg, 1.26 mmol) and the reaction mixture was stirred at 20°C for 2 h. Five additional vials were set up as described above. All six reaction mixtures were combined. The reaction mixture was quenched by adding acetic acid (2 mL) at 20°C, and concentrated under reduced pressure to give a residue that was purified by pre-HPLC (Method 3, TFA) to give E3_D5 (260 mg, yield: 32.21%) as a white solid. LCMS (System 2, method D) (ESI+): m / z 499.4 (M+H)+, Rt: 0.441 min.1H NMR: (DMSO-d6, 400MHz) δ = 11.02 (s, 1H), 8.94 (br s, 1H), 7.61 (d, J=7.2 Hz, 1H), 7.52 - 7.42 (m, 2H), 6.96 (br t, J=5.2 Hz, 1H), 5.16 (dd, J=4.8, 13.2 Hz, 1H), 4.51 - 4.41 (m, 1H), 4.35 -4.25 (m, 1H), 3.47 - 3.39 (m, 2H), 3.04 - 2.91 (m, 5H), 2.89 - 2.73 (m, 2H), 2.66 - 2.57 (m, 3H), 2.39 (br dd, J=4.4, 13.2 Hz, 1H), 2.08 - 1.94 (m, 1H), 2.08 - 1.94 (m, 1H), 2.08 - 1.94 (m, 1H), 1.82 - 1.68 (m, 5H), 1.60 (br d, J=12.8 Hz, 1H), 1.38 - 1.36 (m, 9H).

[0387] To a solution of E3_D5 (260 mg, 424.39 umol, TFA salt) in dichloromethane (DCM, 8 mL) was added trifluoroacetic acid (TFA, 1.25 g, 10.99 mmol) and the reaction was stirred at 20°C for 2 h. LCMS showed E3_D5 was consumed completely and one main peak with desired mass was detected. The reaction mixture was concentrated under reduced pressure to give a residue. The residue was purified by prep-HPLC (Method 2, TFA) to give the E3_D (197 mg, yield: 74.12%, 2TFA salt) as a white solid. LCMS(ESI+): m / z 399.3 (M+H)+ 1H NMR: ET38458-232-p1 (400MHz, DMSO-d6) δ = 11.03 (s, 1H), 9.47 (br s, 1H), 7.88 (br s, 3H), 7.62 (dd, J=1.2, 7.2 Hz, 1H), 7.52 - 7.41 (m, 2H), 5.16 (dd, J=5.2, 13.2 Hz, 1H), 4.51 - 4.43 (m, 1H), 4.30 (d, J=17.2 Hz, 1H), 3.41 (br s, 2H), 3.22 (br d, J=1.2 Hz, 1H), 3.07 (br s, 2H), 2.99 - 2.80 (m, 5H), 2.62 (br d, J=7.2 Hz, 2H), 2.39 (br dd, J=4.4, 13.1 Hz, 1H), 2.07 - 1.98 (m, 1H), 1.96 - 1.84 (m, 3H), 1.79 (br d, J=13.6 Hz, 2H), 1.53 - 1.37 (m, 2H). Example 7. Synthesis of 3-(4-((1-(3-aminopropyl)piperidin-4-yl)amino)-1-oxoisoindolin- 2-yl)piperidine-2,6-dione (Compound B28)

[0388] To a solution of B_8a (4 g, 15.43 mmol) in dichloromethane (DCE, 72 mL) and acetic acid (AcOH, 0.72 mL) were added B_8b (5.23 g, 26.23 mmol) and 4Å molecular sieve (200 mg) at 25oC, the mixture was stirred at 30oC for 16 h. Then sodium triacetoxyborohydride (9.81 g, 46.29 mmol) was added at 25oC and the mixture was stirred for 16 h. The reaction was quenched with aqueous Na2CO3solution, and the layers were separated. The dichloromethane phase was washed by water. The aqueous layer was extracted with ethyl acetate (100 mL) for 2 times. The ethyl acetate phase was washed by water and the organic phases were combined, dried over Na2SO4and concentrated to give residue. The residue was purified by flash silica gel chromatography (0 to 6% dichloromethane / methanol) to give a residue that was further purified by pre-HPLC (Method 2, TFA condition) to give B_8c (1 g, yield: 14.65%) as a white solid. LCMS (System 2, method B): (ESI+): m / z 387.2 (M-55)+, Rt: 0.613 min.1H NMR: (400MHz, DMSO-d6) δ ppm 11.01 (s, 1H), 7.28 (t, J = 7.6 Hz, 1H), 6.94 (d, J = 7.2 Hz, 1H), 6.86 (d, J = 8.0 Hz, 1H), 5.12 (dd, J = 5.2, 13.2 Hz, 1H), 4.22 - 4.12 (m, 3H), 3.91 (br d, J = 12.0 Hz, 1H), 3.63 - 3.48 (m, 1H), 3.00 - 2.84 (m, 3H), 2.65 - 2.58 (m, 1H), 2.29 (br dd, J = 4.4, 13.2 Hz, 1H), 2.09 - 1.98 (m, 1H), 1.90 (br t, J = 8.8 Hz, 2H), 1.40 (s, 9H), 1.30 (br d, J = 11.2 Hz, 2H).

[0389] To a solution of B_8c (1.3 g, 2.94 mmol) in dichloromethane (DCM, 13 mL) was added trifluoroacetic acid (TFA, 1.3 mL) at 20oC. The reaction mixture was concentrated to give a residue and the residual TFA was removed by lyophilization to give B_8 (1.6 g, crude, TFA salt) as a yellow solid. LCMS (System 2, method B) (ESI+): m / z 343.2 (M+H)+, Rt: 0.529 min.1H NMR: (400MHz, DMSO-d6) δ ppm 11.02 (s, 1H), 8.70 - 8.52 (m, 1H), 8.50 - 8.32 (m, 1H), 7.30 (t, J = 8.0 Hz, 1H), 6.97 (d, J = 7.2 Hz, 1H), 6.87 (d, J = 8.0 Hz, 1H), 5.13 (dd, J = 5.2, 13.2 Hz, 1H), 4.29 - 4.09 (m, 2H), 3.73 - 3.60 (m, 1H), 3.34 (br d, J = 12.8 Hz, 2H), 3.11 - 2.87 (m, 3H), 2.62 (br d, J = 16.8 Hz, 1H), 2.28 (dd, J = 4.4, 13.2 Hz, 1H), 2.14 - 1.96 (m, 3H), 1.68 - 1.51 (m, 2H).

[0390] To a solution of B28_a (1.44 g, 8.31 mmol) in dichloroethane (DCE, 190 mL) was added B_8 (4.53 g, 8.31 mmol) in N,N-Diisopropyl-ethylamine (DIEA, 3.22 g, 24.94 mmol, 4.34 mL). The mixture was cooled to 0°C, and then sodium triacetoxyborohydride (7.58 g, 35.74 mmol) was added at 0°C. The temperature was raised to 25°C and stirred at 25°C for 3 h. The mixture was filtered and concentrated under reduced pressure to give a residue that was purified by column chromatography (SiO2, ethyl acetate / ethanol=7 / 3 to 1 / 1) to give B28_b (4.65 g, crude) as a white solid which was used into next step without further purification.

[0391] LCMS-reaction (System 2, method B) (ESI+): m / z 500.4 (M+H)+, Rt: 0.528 min.

[0392] To a solution of B28_b (4.9 g, 9.81 mmol) in dichloromethane (DCM, 49 mL) was added trifluoroacetic acid (TFA, 25.08 g, 219.98 mmol, 16.34 mL). The mixture was stirred at 25°C for 2 h. The reaction mixture was concentrated to give a residue that was further purified by prep-HPLC (Method 2, TFA condition). The residual trifluoroacetic acid (TFA) is removed by lyophilization to give B28 (1.6 g, yield 24% of 3 steps) as a yellow solid. LCMS (System 2, method B) (ESI+): m / z 400.3 (M+H)+, Rt: 0.389 min.1H NMR: (400MHz, DMSO-d6) δ ppm 10.75 (br s, 1H), 8.41 - 7.76 (m, 2H), 7.31 (t, J = 7.8 Hz, 1H), 7.01 (d, J = 7.2 Hz, 1H), 6.88 (d, J = 8.0 Hz, 1H), 5.09 (dd, J = 5.2, 13.2 Hz, 1H), 4.34 - 4.17 (m, 2H), 3.76 - 3.62 (m, 1H), 3.53 - 3.30 (m, 3H), 3.21 - 3.02 (m, 4H), 2.98 - 2.85 (m, 3H), 2.70 - 2.59 (m, 1H), 2.32 (dq, J = 4.4, 13.2Hz, 1H), 2.21 - 1.95 (m, 5H), 1.88 - 1.70 (m, 2H). Example 8. General Procedure for Synthesis of N-alkyl intermediates from 3-(1-oxo-4- (piperidin-4-ylamino)isoindolin-2-yl)piperidine-2,6-dione (Compound B_8)

[0393] To a solution of B_8 (500 mg, 917.48 μmol, TFA) in dichloroethane (DCE, 25 mL) were added tert-butyl 4-oxopiperidine-1-carboxylate (182.80 mg, 917.48 μmol) and N,N-Diisopropyl-ethylamine (DIEA, 355.72 mg, 2.75 mmol, 479.41 μL). The mixture was cooled to 0°C and added sodium triacetoxyboranuide (836.14 mg, 3.95 mmol) at 0°C. The mixture was warmed to 20°C and stirred at 20°C for 12 h. The mixture was filtered and concentrated under reduced pressure to give a residue that was purified by column chromatography (SiO2, ethyl acetate: ethanol =1:1) to give B29_1 (625 mg, crude) as a green oil which was used into the next step without further purification. LCMS (System 2, method M) (ESI+): m / z 526.2 (M+H)+, Rt: 0.341 min.

[0394] To a solution of B29_1 (0.2 g, 380.49 μmol) in dichloromethane (DCM, 3.2 mL) was added trifluoroacetic acid (TFA, 1.23 g, 10.77 mmol, 0.8 mL) at 20oC. The mixture was stirred at 20oC for 4 h. LCMS analysis showed B29_1 was consumed completely and one main peak with desired m / z was detected. The reaction mixture was filtered and the filtrate was under reduced pressure to give a residue. The residue was purified by pre-HPLC (Method 2, TFA) give B29 (0.1 g, yield: 11.41%, 3TFA) as a yellow solid . LCMS (system 3, method C) (ESI+): m / z 426.2 (M+H)+, Rt: 1.594 min.1H NMR: (400 MHz, DMSO-d6) δ ppm 11.02 (s, 1H), 9.93 - 9.81 (m, 1H), 8.83 (br d, J = 9.2 Hz, 1H), 8.67 - 8.50 (m, 1H), 7.31 (br t, J = 7.6 Hz, 1H), 7.04 - 6.95 (m, 1H), 6.91 - 6.83 (m, 1H), 5.72 - 5.51 (m, 1H), 5.22 - 5.07 (m, 1H), 4.34 - 4.09 (m, 2H), 3.75 - 3.59 (m, 1H), 3.56 - 3.50 (m, 2H), 3.23 - 3.08 (m,2H), 3.02 - 2.86 (m, 3H), 2.69 - 2.58 (m, 1H), 2.34 - 2.12 (m, 5H), 2.10 - 1.95 (m, 2H), 1.90 - 1.61 (m, 4H), 1.30 - 1.20 (m, 2H).

[0395] This general procedure was followed to synthesize B30 from B_8. LCMS (system 3, method C) (ESI+): m / z 414.2 (M+H)+, Rt: 1.650 min.1H NMR: (400 MHz, DMSO-d6) δ ppm 10.75 (br s, 1H), 8.05 - 7.69 (m, 2H), 7.31 (t, J = 7.6 Hz, 1H), 7.01 (d, J = 7.2 Hz, 1H), 6.88 (d, J = 8.0 Hz, 1H), 5.09 (dd, J = 5.2, 13.2 Hz, 1H), 4.33 - 4.17 (m, 2H), 3.77 - 3.60 (m, 1H), 3.57 - 3.39 (m, 2H), 3.23 - 3.02 (m, 4H), 2.98 - 2.90 (m, 1H), 2.86 (br t,. Hz, 2H), 2.70 - 2.61 (m, 1H), 2.32 (dq, J = 4.4, 13.2 Hz, 1H), 2.21 - 2.03 (m, 3H), 1.76 (td, J = 7.6, 15.2 Hz, 4H), 1.69 - 1.59 (m, 2H)

[0396] This general procedure was followed to synthesize B31 from B_8. LCMS (system 3, method C) (ESI+): m / z 428.2 (M+H)+, Rt: 1.675 min.1H NMR: (400 MHz, DMSO-d6) δ ppm 10.75 ( s, 1H), 8.30 - 7.52 (m, 2H), 7.31 (t, J = 7.6 Hz, 1H), 7.00 (d, J = 7.2 Hz, 1H), 6.88 (d, J = 8.0 Hz, 1H), 5.08 (dd, J = 4.8, 13.2 Hz, 1H), 4.35 - 4.15 (m, 2H), 3.69 ( d, J = 6.6 Hz, 1H), 3.59 - 3.39 (m, 2H), 3.14 (br s, 1H), 3.09 - 3.02 (m, 2H), 2.99 - 2.87 (m, 1H), 2.83 ( t, J = 7.6 Hz, 2H), 2.65 ( d, J = 16.4 Hz, 1H), 2.32 (dq, J = 4.4, 13.2 Hz, 1H), 2.15 ( d, J = 10.4 Hz, 2H), 2.12 - 2.00 (m, 2H), 1.81 ( s, 2H), 1.71 (td, J = 7.6, 15.6 Hz, 2H), 1.62 (quin, J = 7.6 Hz, 2H), 1.46 - 1.33 (m, 2H)

[0397] This general procedure was followed to synthesize B32 from B_8. LCMS (system 3, method C) (ESI+): m / z 426.2 (M+H)+, Rt: 1.640 min.1H NMR: (400 MHz,DMSO-d6) δ ppm 10.84 - 10.62 (m, 1H), 7.34 - 7.27 (m, 1H), 7.00 (d, J = 7.2 Hz, 1H), 6.88 (br d, J = 8.0 Hz, 1H), 5.08 (dd, J = 5.2, 13.2 Hz, 1H), 4.33 - 4.17 (m, 2H), 3.77 - 3.65 (m, 1H), 3.64 - 3.48 (m, 2H), 3.37 (br d, J = 11.6 Hz, 2H), 3.10 - 2.85 (m, 3H), 2.85 - 2.70 (m, 1H), 2.70 - 2.57 (m, 3H), 2.57 - 2.52 (m, 3H), 2.45 (br s, 1H), 2.32 (dq, J = 4.2, 13.2 Hz, 1H), 2.19 - 2.03 (m, 3H), 1.86 - 1.70 (m, 2H).

[0398] This general procedure was followed to synthesize B33 from B_8. LCMS (system 3, method C) (ESI+): m / z 426.2 (M+H)+, Rt: 1.630 min.1H NMR: (400 MHz, DMSO-d6) δ ppm 10.75 (br s, 1H), 7.30 (t, J = 7.8 Hz, 1H), 7.00 (d, J = 7.4 Hz, 1H), 6.88 (d, J = 8.2 Hz, 1H), 5.08 (dd, J = 5.2, 13.2 Hz, 1H), 4.34 - 4.18 (m, 2H), 3.86 - 3.78 (m, 1H), 3.77 - 3.63 (m, 2H), 3.59 - 3.42 (m, 2H), 3.24 - 3.09 (m, 2H), 2.97 - 2.85 (m, 1H), 2.70 - 2.61 (m, 1H), 2.39 - 2.25 (m, 2H), 2.24 - 2.11 (m, 4H), 2.11 - 1.98 (m, 2H), 1.95 - 1.75 (m, 3H), 1.74 - 1.64 (m, 1H) Example 9. Synthesis of N-Methyl Glutarimide Compound 3-(4-(4-aminobutyl)-1- oxoisoindolin-2-yl)-1-methylpiperidine-2,6-dione (Compound B26)

[0399] To a solution of B10 (0.1 g, 309.46 umol) in dimethylformamide (DMF, 1 mL) was added K2CO3(42.77 mg, 309.46 umol), degassed and purged with N2for 3 times, theniodomethane (43.92 mg, 309.46 umol) was added dropwise at 20oC under N2atmosphere. The resulting reaction mixture was stirred at 20oC for 10 h. Another vial was set up as described above. Both two reaction mixtures were combined for work up and purification. The reaction mixture was quenched by addition water 30 mL at 20oC, and then extracted with ethyl acetate 150 mL (3 × 50 mL). The combined organic layers were washed with brine 90 mL (3 × 30 mL), dried over Na2SO4, filtered and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (silica gel, petroleum ether: ethyl acetate = 3: 1 to 2: 1) to give B23 (95 mg, yield: 45.5%) as a brown solid. LCMS (system 2, method E) (ESI+ ): m / z 337.1 (M+H)+, m / z 339.1 (M+H)+, Rt: 1.532 min.1H NMR: (400MHz, DMSO–d6). δ ppm 7.88 (br d, J = 8.0 Hz, 1H), 7.78 (br d, J = 7.6 Hz, 1H), 7.56 - 7.48 (m, 1H), 5.22 (br dd, J = 4.8, 13.2 Hz, 1H), 4.46 - 4.21 (m, 2H), 3.00 (s, 3H), 2.95 (br d, J = 5.2 Hz, 1H), 2.75 (br d, J = 17.6 Hz, 1H), 2.45 (br d, J = 4.4 Hz, 1H), 2.08 - 2.00 (m, 1H).

[0400] To a solution of B23 (95 mg, 252.10 umol) in dimethylformamide (DMF, 4 mL) were added di-μ-chlorodimethylbis(triphenylphosphine)dipalladium (Pd(PPh3)2Cl2, 17.69 mg, 25.21 umol), copper iodide (CuI, 9.60 mg, 50.42 umol) and tert-butyl N-but-3- ynylcarbamate (85.32 mg, 504.20 umol) under N2at 25oC, then added triethylamine (TEA, 2 mL) at 25oC. The resulting reaction mixture was slowly warmed up to 70oC and stirred at 70oC for 3 h. The resulting mixture was concentrated under reduced pressure to give a residue purified by column chromatography (silica gel, petroleum ether: ethyl acetate = 3: 1 to 2: 1) to give B24 (105 mg, yield: 88.9%) as a yellow solid.1H NMR: (400MHz, DMSO–d6). δ ppm 7.72 (d, J = 7.6 Hz, 1H), 7.67 - 7.61 (m, 1H), 7.56 - 7.47 (m, 1H), 7.07 (br t, J = 5.6 Hz, 1H), 5.22 (dd, J = 5.2, 13.6 Hz, 1H), 4.51 - 4.26 (m, 2H), 3.23 - 3.14 (m, 2H), 3.01 (s, 3H), 2.78 (br s, 1H), 2.72 - 2.66 (m, 1H), 2.57 (br t, J = 6.8 Hz, 2H), 2.44 (br dd, J = 4.0, 13.2 Hz, 1H), 2.07 - 2.00 (m, 1H), 1.36 (s, 9H).

[0401] To a solution of B24 (105 mg, 246.78 umol ) in tetrahydrofuran (THF, 10 mL) were added Pd / C (525.3 mg, 493.56 umol, 10% purity) and Pd(OH)2 (10.4 mg, 14.81 umol, 20% purity) at 25oC. The suspension was degassed and purged with H2for 3 times. The resulting mixture was stirred under H2(15 psi) at 25oC for 3 h. The reaction mixture was filtered and concentrated under reduced pressure to give B25 (95 mg, yield 89.9%) as a yellow solid. LCMS (system 2, method D) (ESI+ ): m / z 452.2 (M+23)+, Rt: 1.835 min.1H NMR: (400MHz, DMSO–d6). δ ppm 7.66 - 7.53 (m, 2H), 7.48 - 7.44 (m, 1H), 6.81 (br t, J = 5.6 Hz, 1H), 5.21 (dd, J = 5.2, 13.2 Hz, 1H), 4.51 - 4.24 (m, 2H), 3.01 (s, 3H), 2.98 - 2.91 (m, 2H), 2.82 - 2.71 (m, 1H), 2.68 - 2.59 (m, 2H), 2.43 (br dd, J = 4.4, 13.2 Hz, 1H), 2.07 - 1.97 (m, 1H), 1.80 - 1.69 (m, 1H), 1.62 - 1.52 (m, 2H), 1.48 - 1.39 (m, 2H), 1.36 (s, 9H).

[0402] To a solution of B25 (95 mg, 256.11 umol) in dichloromethane (DCM, 5 mL) was added trifluoroacetic acid (TFA, 1 mL) at 20oC and stirred at 20oC for 1 h. The reaction mixture was filtered and concentrated under reduced pressure to give a residue that was purified by prep-HPLC (Method 3, TFA) to give B26 (53 mg, yield 71%, TFA salt) as a white solid. LCMS (System 3, method C): (ESI+): m / z 330.1 (M+H)+, Rt: 1.541 min.1H NMR: (400MHz, DMSO–d6). δ ppm 7.63 - 7.57 (m, 3H), 7.48 (d, J = 4.0 Hz, 2H), 5.22 (dd, J = 4.8, 13.2 Hz, 1H), 4.51 - 4.27 (m, 2H), 3.07 - 2.95 (m, 4H), 2.85 - 2.79 (m, 2H), 2.76 (br s, 1H), 2.67 (br t,. Hz, 2H), 2.44 - 2.35 (m, 1H), 2.03 (ddd, J = 2.0, 5.2, 7.2 Hz, 1H), 1.71 - 1.62 (m, 2H), 1.61 - 1.51 (m, 2H). Example 10. General Procedure for Amide Coupling of each of 2-((2-((tert- butoxycarbonyl)amino)ethyl)carbamoyl)-4-(cyclopropylmethyl)-10-methyl-7- ((methylsulfonyl)methyl)-11-oxo-3,4,10,11-tetrahydro-1H-1,4,10- triazadibenzo[cd,f]azulene-6-carboxylic acid (Compound BBET13_1b) and 4-(2-((2-((tert-butoxycarbonyl)amino)ethyl)carbamoyl)-6-methyl-7-oxo-6,7-dihydro-1H- pyrrolo[2,3-c]pyridin-4-yl)-5-((cyclopropylmethyl)amino)-2- ((methylsulfonyl)methyl)benzoic acid (Compound BBET5_1b) with Cereblon Recruiting Fragments

[0403] To a solution of BBET13_1b&BBET5_1b (50.00 mg, 1: 1) in dimethylformamide (DMF, 1 mL) were added hexafluorophosphate (HATU, 19.99 mg, 52.57 umol) and N,N-diisopropyl-ethylamine (DIEA, 30.88 mg, 238.96 umol, 41.62 uL) at 20oC and stirred at 20oC for 10 min. Then the reaction mixture was added B13 (19.85 mg, 47.79 umol, TFA) at 20oC and stirred at 20oC for 1 h. The resulting reaction mixture was purified by prep-HPLC (Method 3, TFA) to give BBET13a (17 mg, yield 39.1%) as a white solid and BBET5a (14 mg, yield 32.6%) as a white solid. Compounds BBET13a and BBET5a can each be deprotected by methods known to one skilled in the art to remove the Boc group and produce compound 1.2 and compound 1.23, respectively. Analytical data of BBET13a:

[0404] LCMS (system 3, method C) (ESI+ ): m / z 911.3 (M+H)+, Rt: 2.158 min.1H NMR : (400MHz, DMSO–d6). δ ppm 12.30 - 12.10 (m, 1H), 10.99 (s, 1H), 8.60 - 8.52 (m, 1H), 8.34 (br s, 1H), 7.81 (br s, 1H), 7.66 (br s, 1H), 7.58 (d, J = 7.2 Hz, 1H), 7.55 - 7.45 (m, 2H), 7.42 (br s, 1H), 6.92 (br t, J = 6.0 Hz, 1H), 5.14 (dd, J = 5.2, 13.2 Hz, 1H), 4.83 (br s, 2H), 4.77 - 4.59 (m, 2H), 4.51 - 4.30 (m, 2H), 3.66 (s, 3H), 3.35 - 3.28 (m, 4H), 3.15 - 3.07 (m, 2H), 2.95 (br d, J = 5.2 Hz, 2H), 2.91 (s, 3H), 2.80 - 2.68 (m, 2H), 2.60 (br d, J = 17.2 Hz, 2H), 2.40 (br dd, J = 4.4, 13.2 Hz, 1H), 2.06 - 1.97 (m, 1H), 1.93 - 1.81 (m, 2H), 1.37 (s, 9H), 0.91 - 0.77 (m, 1H), 0.39 - 0.31 (m, 2H), 0.03 (q, J = 4.4 Hz, 2H).Analytical data of BBET5a:

[0405] LCMS (system 3, method C) (ESI+ ): m / z 899.3 (M+H)+, Rt: 2.305 min.1H NMR: (400MHz, DMSO–d6). δ ppm 12.33 (br s, 1H), 10.99 (s, 1H), 8.45 (br t, J = 5.2 Hz, 1H), 8.34 (br t, J = 5.2 Hz, 1H), 7.60 - 7.44 (m, 3H), 7.24 - 7.19 (m, 1H), 7.19 - 7.14 (m, 1H), 6.90 - 6.81 (m, 2H), 6.63 (d, J = 2.0 Hz, 1H), 5.14 (dd, J = 5.2, 13.2 Hz, 1H), 4.67 (s, 2H), 4.52 - 4.30 (m, 2H), 3.57 (s, 3H), 3.35 - 3.19 (m, 4H), 3.11 - 3.03 (m, 2H), 2.98 (br d, J = 6.4 Hz, 2H), 2.82 (s, 3H), 2.78 - 2.69 (m, 2H), 2.65 - 2.55 (m, 2H), 2.40 (br dd, J = 4.4, 13.2 Hz, 1H), 2.07 - 1.96 (m, 1H), 1.92 - 1.81 (m, 2H), 1.35 (s, 9H), 1.10 - 0.99 (m, 1H), 0.42 - 0.32 (m, 2H), 0.13 (br d, J = 3.6 Hz, 2H). Example 11. Synthesis of tert-butyl (2-(4-(cyclopropylmethyl)-6-((4-(2-(2,6- dioxopiperidin-3-yl)-1-oxoisoindolin-4-yl)butyl)carbamoyl)-10-methyl-7- ((methylsulfonyl)methyl)-11-oxo-3,4,10,11-tetrahydro-1H-1,4,10- triazadibenzo[cd,f]azulene-2-carboxamido)ethyl)carbamate (Compound BBET14a) and tert-butyl (2-(4-(2-((cyclopropylmethyl)amino)-4-((4-(2-(2,6-dioxopiperidin-3-yl)-1- oxoisoindolin-4-yl)butyl)carbamoyl)-5-((methylsulfonyl)methyl)phenyl)-6-methyl-7-oxo- 6,7-dihydro-1H-pyrrolo[2,3-c]pyridine-2-carboxamido)ethyl)carbamate (Compound BBET6a)

[0406] Following the general procedure of Example 10, a mixture of BBET13_1b&BBET5_1b (40.00 mg, 1: 1) was coupled to B16 (12.6 mg, 38.24 umol, TFA) to give BBET14a (13 mg, yield 36.21%) as a white solid and BBET6a (8 mg, yield 33.2%) as a white solid. Compounds BBET14a and BBET6a can each be deprotected by methods known to one skilled in the art to remove the Boc group and produce compound 1.1 and compound 1.22, respectively.Analytical data of BBET14a:

[0407] LCMS (system 1, method A) (ESI+): m / z 925.48 (M+H)+, Rt: 1.66 min.1H NMR: (400MHz, DMSO-d6). δ ppm 12.15 (br s, 1H), 10.98 (s, 1H), 8.51 (br t, J = 5.6 Hz, 1H), 8.32 (br s, 1H), 7.77 (br s, 1H), 7.63 (br s, 1H), 7.57 (dd, J = 1.4, 7.2 Hz, 1H), 7.52 - 7.42 (m, 2H), 7.36 (br s, 1H), 6.96 - 6.88 (m, 1H), 5.12 (dd, J = 5.2, 13.2 Hz, 1H), 4.84 - 4.74 (m, 2H), 4.73 - 4.56 (m, 2H), 4.51 - 4.42 (m, 1H), 4.38 - 4.28 (m, 1H), 3.65 (s, 3H), 3.34 - 3.26 (m, 4H), 3.14 - 3.08 (m, 2H), 2.92 (br d, J = 6.0 Hz, 2H), 2.87 (s, 3H), 2.73 - 2.65 (m, 3H), 2.37 - 2.31 (m, 2H), 2.02 - 1.95 (m, 1H), 1.73 - 1.56 (m, 4H), 1.37 (s, 9H), 0.88 - 0.76 (m, 1H), 0.38 - 0.30 (m, 2H), 0.01 (q, J = 4.8 Hz, 2H). Analytical data of BBET6a:

[0408] LCMS (system 1, method A) (ESI+): m / z 913.48 (M+H)+, Rt: 1.67 min. Example 12. Synthesis of tert-butyl (2-(4-(cyclopropylmethyl)-6-((5-(2-(2,6- dioxopiperidin-3-yl)-1-oxoisoindolin-4-yl)pentyl)carbamoyl)-10-methyl-7- ((methylsulfonyl)methyl)-11-oxo-3,4,10,11-tetrahydro-1H-1,4,10- triazadibenzo[cd,f]azulene-2-carboxamido)ethyl)carbamate (Compound BBET15a) and tert-butyl (2-(4-(2-((cyclopropylmethyl)amino)-4-((5-(2-(2,6-dioxopiperidin-3-yl)-1- oxoisoindolin-4-yl)pentyl)carbamoyl)-5-((methylsulfonyl)methyl)phenyl)-6-methyl-7- oxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridine-2-carboxamido)ethyl)carbamate (Compound BBET7a)

[0409] Following the general procedure of Example 10, a mixture of BBET13_1b&BBET5_1b (40.00 mg, 1: 1) was coupled to B13 (12.6 mg, 38.24 umol, TFA) to give BBET15a (13 mg, yield 36.21%) as a white solid and BBET7a (8 mg, yield 33.2%) as a white solid. Compounds BBET15a and BBET7a can each be deprotected by methods known to one skilled in the art to remove the Boc group and produce compound 1.5 and compound 1.24, respectively.Analytical data of BBET15a:

[0410] LCMS (system 3, method C) (ESI+): m / z 939.3 (M+H)+, Rt: 2.270 min.1H NMR: (400 MHz, DMSO-d6) δ ppm 12.30 - 12.09 (m, 1H), 11.02 - 10.94 (m, 1H), 8.52 - 8.45 (m, 1H), 8.39 - 8.28 (m, 1H), 7.80 (br s, 1H), 7.65 (br s, 1H), 7.59 - 7.54 (m, 1H), 7.50 - 7.44 (m, 2H), 7.39 (br s, 1H), 6.92 (br t, J = 5.2 Hz, 1H), 5.13 (dd, J = 5.2, 13.3 Hz, 1H), 4.85 - 4.76 (m, 2H), 4.75 - 4.54 (m, 2H), 4.50 - 4.26 (m, 2H), 3.66 (s, 3H), 3.35 - 3.18 (m, 4H), 3.16 - 3.06 (m, 2H), 2.94 (br d, J = 5.6 Hz, 2H), 2.89 (s, 3H), 2.70 - 2.63 (m, 2H), 2.62 - 2.55 (m, 1H), 2.48 - 2.31 (m, 2H), 2.05 - 1.95 (m, 1H), 1.71 - 1.53 (m, 4H), 1.46 - 1.29 (m, 11H), 0.89 - 0.82 (m, 1H), 0.39 - 0.32 (m, 2H), 0.03 (br d, J = 4.8 Hz, 2H). Analytical data of BBET7a:

[0411] LCMS (system 3, method C) (ESI+): m / z 927.5 (M+H)+, Rt: 2.420 min.1H NMR: (400 MHz, DMSO-d6) δ ppm 12.33 (br s, 1H), 10.99 (s, 1H), 8.41 - 8.32 (m, 2H), 7.57 (dd, J = 2.4, 6.0 Hz, 1H), 7.49 - 7.45 (m, 2H), 7.19 (d, J = 16.0 Hz, 2H), 6.87 (br t, J = 5.6 Hz, 1H), 6.80 (s, 1H), 6.63 (d, J = 1.6 Hz, 1H), 5.13 (dd, J = 5.2, 13.2 Hz, 1H), 4.63 (s, 2H), 4.52 - 4.42 (m, 1H), 4.36 - 4.27 (m, 1H), 3.57 (s, 3H), 3.30 - 3.19 (m, 4H), 3.10 - 3.01 (m, 2H), 2.97 (br d, J = 6.4 Hz, 2H), 2.82 (s, 3H), 2.66 (br t, J = 7.6 Hz, 2H), 2.59 (br d, J = 18.0 Hz, 2H), 2.41 (br d, J = 4.0 Hz, 1H), 2.05 - 1.97 (m, 1H), 1.70 - 1.53 (m, 4H), 1.45 - 1.39 (m, 2H), 1.35 (s, 9H), 1.09 - 0.99 (m, 1H), 0.40 - 0.32 (m, 2H), 0.13 (br d, J = 4.4 Hz, 2H). Example 13. Synthesis of tert-butyl (2-(4-(cyclopropylmethyl)-6-((6-(2-(2,6- dioxopiperidin-3-yl)-1-oxoisoindolin-4-yl)hexyl)carbamoyl)-10-methyl-7- ((methylsulfonyl)methyl)-11-oxo-3,4,10,11-tetrahydro-1H-1,4,10- triazadibenzo[cd,f]azulene-2-carboxamido)ethyl)carbamate (Compound BBET16a) and tert-butyl (2-(4-(2-((cyclopropylmethyl)amino)-4-((6-(2-(2,6-dioxopiperidin-3-yl)-1- oxoisoindolin-4-yl)hexyl)carbamoyl)-5-((methylsulfonyl)methyl)phenyl)-6-methyl-7-oxo- 6,7-dihydro-1H-pyrrolo[2,3-c]pyridine-2-carboxamido)ethyl)carbamate (Compound BBET8a)

[0412] Following the general procedure of Example 10, a mixture of BBET13_1b&BBET5_1b (40.00 mg, 1: 1) was coupled with B22 (12.6 mg, 38.24 umol, TFA) to give BBET16a (1.9 mg, yield 5.21%) as a white solid and BBET8a (3 mg, yield 8.34%) as a white solid. Compounds BBET16a and BBET8a can each be deprotected by methods known to one skilled in the art to remove the Boc group and produce compound 1.6 and compound 1.25, respectively. Analytical data of BBET16a:

[0413] LCMS (system 3, method C) (ESI+): m / z 953.3 (M+H)+, Rt: 2.334 min.1H NMR: (400 MHz, DMSO-d6) δ ppm 12.22 - 12.07 (m, 1H), 10.98 (s, 1H), 8.46 (br t, J = 5.2 Hz, 1H), 8.32 (br s, 1H), 7.77 (s, 1H), 7.62 (br s, 1H), 7.59 - 7.53 (m, 1H), 7.49 - 7.44 (m, 2H), 7.35 (br s, 1H), 6.92 (br t, J = 5.2 Hz, 1H), 5.13 (dd, J = 5.2, 13.2 Hz, 1H), 4.79 (br s, 2H), 4.72 - 4.53 (m, 2H), 4.50 - 4.42 (m, 1H), 4.37 - 4.25 (m, 1H), 3.65 (s, 3H), 3.32 - 3.28 (m, 2H), 3.25 - 3.18 (m, 2H), 3.11 (br d, J = 5.6 Hz, 2H), 2.92 (br d, J = 6.0 Hz, 2H), 2.88 (s, 3H), 2.66 (br t, J = 7.6 Hz, 2H), 2.63 - 2.54 (m, 2H), 2.46 - 2.36 (m, 1H), 2.06 - 1.94 (m, 1H), 1.68 - 1.47 (m, 4H), 1.37 (s, 13H), 0.91 - 0.78 (m, 1H), 0.34 (br d, J = 7.6 Hz, 2H), 0.02 (br d, J = 4.4 Hz, 2H). Analytical data of BBET8a:

[0414] LCMS (system 3, method C) (ESI+): m / z 941.4 (M+H)+, Rt: 2.478 min.1H NMR: (400 MHz, DMSO-d6) δ ppm 12.33 (br s, 1H), 10.98 (s, 1H), 8.40 - 8.31 (m, 2H), 7.58 - 7.54 (m, 1H), 7.48 - 7.43 (m, 2H), 7.21 (s, 1H), 7.17 (s, 1H), 6.87 (br t, J = 5.6 Hz, 1H), 6.81 (s, 1H), 6.63 (d, J = 1.6 Hz, 1H), 5.13 (dd, J = 5.2, 13.2 Hz, 1H), 4.62 (s, 2H), 4.51 - 4.42 (m, 1H), 4.37 - 4.26 (m, 1H), 3.57 (br s, 3H), 3.24 (br dd, J = 6.0, 9.2 Hz, 4H), 3.09 - 3.03 (m, 2H), 2.97 (br d, J = 6.4 Hz, 2H), 2.81 (s, 3H), 2.67 (br d, J = 7.2 Hz, 2H), 2.60 (br d, J = 17.6 Hz, 2H), 2.43 (br dd, J = 4.0, 13.0 Hz, 1H), 2.05 - 1.96 (m, 1H), 1.68 - 1.58 (m, 2H),1.53 (br d, J = 5.6 Hz, 2H), 1.38 (br s, 4H), 1.35 (s, 9H), 1.09 - 0.99 (m, 1H), 0.39 - 0.31 (m, 2H), 0.12 (br d, J = 4.4 Hz, 2H). Example 14. Synthesis of tert-butyl (2-(4-(cyclopropylmethyl)-10-methyl-6-((4-(2-(1- methyl-2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-4-yl)butyl)carbamoyl)-7- ((methylsulfonyl)methyl)-11-oxo-3,4,10,11-tetrahydro-1H-1,4,10- triazadibenzo[cd,f]azulene-2-carboxamido)ethyl)carbamate (Compound BBET38) and tert-butyl (2-(4-(2-((cyclopropylmethyl)amino)-4-((4-(2-(1-methyl-2,6-dioxopiperidin-3- yl)-1-oxoisoindolin-4-yl)butyl)carbamoyl)-5-((methylsulfonyl)methyl)phenyl)-6-methyl- 7-oxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridine-2-carboxamido)ethyl)carbamate (Compound BBET37)

[0415] Following the general procedure of Example 10, a mixture of BBET13_1b&BBET5_1b (80.00 mg, 1: 1) was coupled with B26 (56.51 mg, 127.45 umol, TFA) to give BBET37 (25 mg, yield 33.8%) as a white solid and BBET38 (30 mg, yield 40.1%) as a white solid. Compounds BBET38 and BBET37 can each be deprotected by methods known to one skilled in the art to remove the Boc group and produce compound 1.8 and compound 1.26, respectively. Analytical data of BBET38:

[0416] LCMS (system 3, method C) (ESI+ ): m / z 939.3 (M+H)+, Rt: 2.288 min.1H NMR: (400MHz, DMSO–d6).δ ppm 12.29 - 12.15 (m, 1H), 8.52 (br t, J = 5.2 Hz, 1H), 8.34 (br s, 1H), 7.81 (br s, 1H), 7.67 (br s, 1H), 7.58 (d, J = 6.4 Hz, 1H), 7.52 - 7.43 (m, 2H), 6.92 (br t, J = 5.6 Hz, 1H), 5.19 (dd, J = 5.2, 13.2 Hz, 1H), 4.81 (br s, 2H), 4.77 - 4.54 (m, 2H), 4.51 - 4.43 (m, 1H), 4.36 - 4.28 (m, 1H), 3.66 (s, 3H), 3.56 (s, 1H), 3.35 - 3.24 (m, 4H), 3.15 - 3.07 (m, 2H), 2.99 (s, 3H), 2.96 - 2.92 (m, 2H), 2.89 (s, 3H), 2.75 (br d, J = 2.4 Hz, 1H), 2.72 - 2.66 (m, 2H), 2.44 - 2.32 (m, 1H), 2.05 - 1.95 (m, 1H), 1.74 - 1.64 (m, 2H), 1.63 - 1.53(m, 2H), 1.38 - 1.34 (m, 9H), 0.88 - 0.76 (m, 1H), 0.39 - 0.30 (m, 2H), 0.01 (br d, J = 4.4 Hz, 2H). Analytical data of BBET37:

[0417] LCMS (system 3, method C) (ESI+ ): m / z 927.5 (M+H)+, Rt: 2.431 min.1H NMR: (400MHz, DMSO–d6).δ ppm 12.33 (br s, 1H), 8.41 (br t, J = 4.8 Hz, 1H), 8.36 - 8.30 (m, 1H), 7.66 - 7.55 (m, 2H), 7.54 - 7.43 (m, 2H), 7.21 (s, 1H), 7.17 (s, 1H), 6.90 - 6.84 (m, 1H), 6.80 (s, 1H), 6.62 (s, 1H), 5.20 (br dd, J = 5.2, 13.6 Hz, 1H), 4.63 (s, 2H), 4.52 - 4.45 (m, 1H), 4.36 - 4.29 (m, 1H), 3.57 (s, 3H), 3.26 (td, J = 6.4, 13.2 Hz, 4H), 3.06 (br d, J = 5.6 Hz, 2H), 3.00 (s, 3H), 2.96 (br d, J = 6.8 Hz, 2H), 2.80 (s, 3H), 2.77 (br s, 1H), 2.74 - 2.65 (m, 3H), 2.41 (br dd, J = 3.6, 13.2 Hz, 1H), 2.05 - 1.97 (m, 1H), 1.74 - 1.65 (m, 2H), 1.64 - 1.56 (m, 2H), 1.35 (s, 9H), 1.08 - 0.97 (m, 1H), 0.35 (br d, J = 7.6 Hz, 2H), 0.11 (br d, J = 4.4 Hz, 2H). Example 15. Synthesis of tert-butyl (2-(4-(2-((cyclopropylmethyl)amino)-4-((5-(2-(2,6- dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)pentyl)carbamoyl)-5- ((methylsulfonyl)methyl)phenyl)-6-methyl-7-oxo-6,7-dihydro-1H-pyrrolo[2,3- c]pyridine-2-carboxamido)ethyl)carbamate (Compound BBET45) and tert-butyl (2-(4- (cyclopropylmethyl)-6-((5-(2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5- yl)pentyl)carbamoyl)-10-methyl-7-((methylsulfonyl)methyl)-11-oxo-3,4,10,11- tetrahydro-1H-1,4,10-triazadibenzo[cd,f]azulene-2-carboxamido)ethyl)carbamate (Compound BBET46)

[0418] Following the general procedure of Example 10, a mixture of BBET13_1b&BBET5_1b (40.00 mg, 1: 1) were coupled with BBET42 (28.26 mg, 63.72 umol, TFA salt) give BBET45 (9 mg, yield 24.4%) as a white solid and BBET46 (12.5 mg,yield 33.4%) as a white solid. Compound BBET46 can be deprotected by methods known to one skilled in the art to remove the Boc group and produce compound 1.9. Analytical data of BBET45:

[0419] LCMS (system 3, method C) (ESI+): m / z 927.3 (M+H)+, Rt: 2.418 min.1H NMR: (400 MHz, DMSO-d6) δ ppm 12.32 (br s, 1H), 10.97 (s, 1H), 8.40 - 8.32 (m, 2H), 7.63 (d, J = 8.0 Hz, 1H), 7.44 (s, 1H), 7.36 (d, J = 8.0 Hz, 1H), 7.21 (s, 1H), 7.17 (s, 1H), 6.86 (br t, J = 5.6 Hz, 1H), 6.80 (s, 1H), 6.63 (d, J = 2.0 Hz, 1H), 5.09 (dd, J = 5.2, 13.2 Hz, 1H), 5.03 - 4.88 (m, 1H), 4.63 (s, 2H), 4.45 - 4.25 (m, 2H), 3.57 (s, 3H), 3.27 - 3.23 (m, 4H), 3.09 - 3.03 (m, 2H), 2.97 (br d, J = 6.4 Hz, 2H), 2.82 (s, 3H), 2.72 (br t, J = 7.6 Hz, 2H), 2.59 (br d, J = 18.8 Hz, 2H), 2.38 (br dd, J = 4.4, 13.2 Hz, 1H), 1.99 (br dd, J = 5.2, 10.8 Hz, 1H), 1.71 - 1.62 (m, 2H), 1.60 - 1.52 (m, 2H), 1.43 - 1.38 (m, 2H), 1.35 (s, 9H), 1.09 - 1.00 (m, 1H), 0.42 - 0.33 (m, 2H), 0.13 (br d, J = 4.4 Hz, 2H). Analytical data of BBET 46:

[0420] LCMS (system 3, method C) (ESI+): m / z 939.3 (M+H)+, Rt: 2.276 min.1H NMR: ET49026-477-p1 (400 MHz, DMSO-d6) δ ppm 12.13 (br s, 1H), 10.96 (s, 1H), 8.47 (br t, J = 5.6 Hz, 1H), 8.31 (br s, 1H), 7.77 (s, 1H), 7.65 - 7.59 (m, 2H), 7.44 (s, 1H), 7.36 (br d, J = 7.6 Hz, 2H), 6.91 (br t, J = 5.6 Hz, 1H), 5.09 (dd, J = 5.2, 13.2 Hz, 1H), 4.79 (br s, 2H), 4.72 - 4.56 (m, 2H), 4.44 - 4.24 (m, 2H), 3.65 (s, 3H), 3.27 - 3.19 (m, 4H), 3.14 - 3.09 (m, 2H), 2.92 (br d, J = 6.4 Hz, 2H), 2.89 (s, 3H), 2.72 (br t, J = 7.6 Hz, 2H), 2.58 (br d, J = 18.0 Hz, 2H), 2.43 - 2.34 (m, 1H), 2.03 - 1.93 (m, 1H), 1.71 - 1.62 (m, 2H), 1.60 - 1.51 (m, 2H), 1.37 (s, 11H), 0.90 - 0.79 (m, 1H), 0.39 - 0.32 (m, 2H), 0.06 - -0.01 (m, 2H). Example 16. Synthesis of tert-butyl (2-(4-(2-((cyclopropylmethyl)amino)-4-((7-(2-(2,6- dioxopiperidin-3-yl)-1-oxoisoindolin-4-yl)heptyl)carbamoyl)-5- ((methylsulfonyl)methyl)phenyl)-6-methyl-7-oxo-6,7-dihydro-1H-pyrrolo[2,3- c]pyridine-2-carboxamido)ethyl)carbamate (Compound BBET47) and tert-butyl (2-(4- (cyclopropylmethyl)-6-((7-(2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-4- yl)heptyl)carbamoyl)-10-methyl-7-((methylsulfonyl)methyl)-11-oxo-3,4,10,11- tetrahydro-1H-1,4,10-triazadibenzo[cd,f]azulene-2-carboxamido)ethyl)carbamate (Compound BBET48)

[0421] Following the general procedure of Example 10, a mixture of BBET5_1b (14.71 mg, 23.90 umol) and BBET13_1b (25 mg, 39.83 umol) was coupled with B27 (30.04 mg, 63.72 umol) to give BBET47 (8 mg, yield: 21.03%) as a white solid and BBET48 (10 mg, yield: 25.96%) as a white solid. Compound BBET48 can be deprotected by methods known to one skilled in the art to remove the Boc group and produce compound 1.11. Analytical data of BBET48:

[0422] LCMS (System 4, method G) (ESI+): m / z 967.5 (M+H)+, Rt: 2.709 min.1H NMR: (400MHz, DMSO-d6).δ ppm 12.26 - 12.14 (m, 1H), 10.98 (s, 1H), 8.46 (br t, J = 5.2 Hz, 1H), 8.37 - 8.30 (m, 1H), 7.78 (s, 1H), 7.64 (s, 1H), 7.59 - 7.52 (m, 1H), 7.48 - 7.42 (m, 2H), 7.37 (s, 1H), 6.92 (br t, J = 5.6 Hz, 1H), 5.20 - 5.07 (m, 1H), 4.79 (br s, 2H), 4.77 - 4.57 (m, 2H), 4.50 - 4.24 (m, 2H), 3.69 - 3.62 (m, 3H), 3.35 - 3.26 (m, 4H), 3.25 - 3.17 (m, 2H), 3.15 - 3.07 (m, 2H), 2.98 - 2.91 (m, 2H), 2.88 (s, 3H), 2.70-2.65 (m,2 H), sss2.47 - 2.39 (m, 1H), 2.01 (ddd, J = 2.4, 5.2, 10.0 Hz, 1H), 1.68 - 1.57 (m, 2H), 1.56 - 1.45 (m, 2H), 1.41 - 1.26 (m, 15H), 0.89 - 0.79 (m, 1H), 0.39 - 0.31 (m, 2H), 0.05 - -0.02 (m, 2H). Analytical data of BBET47:

[0423] LCMS (System 4, method G) (ESI+): m / z 955.5 (M+H)+, Rt: 2.707 min.1H NMR: (400MHz, DMSO-d6). δ ppm 12.14 (s, 1H), 10.80 (s, 1H), 8.16 (q, J = 5.6 Hz, 2H), 7.41 - 7.32 (m, 1H), 7.31 - 7.22 (m, 2H), 7.02-6.95 (m, 2H), 6.68 (br t, J = 5.6 Hz, 1H), 6.61 (s, 1H), 6.44 (d, J = 2.0 Hz, 1H), 4.94 (dd, J = 5.2, 13.3 Hz, 1H), 4.43 (s, 2H), 4.31 - 4.09 (m, 2H), 3.38 (s, 3H), 3.10 - 3.01 (m, 4H), 2.87 (q, J = 5.6 Hz, 2H), 2.78 (br d, J = 6.8 Hz, 2H), 2.75 - 2.67 (m, 1H), 2.62 (s, 3H), 2.50 - 2.41 (m, 3H), 2.28 - 2.18 (m, 1H), 1.87 - 1.76 (m, 1H), 1.42 (br d, J = 6.8 Hz, 2H), 1.38 - 1.28 (m, 2H), 1.16 (s, 16H), 0.90 - 0.78 (m, 1H), 0.22 - 0.13 (m, 2H), -0.07 (br d, J = 3.6 Hz, 2H)Example 17. General Procedure for amine coupling with purified 2-((2-((tert- butoxycarbonyl)amino)ethyl)carbamoyl)-4-(cyclopropylmethyl)-10-methyl-7- ((methylsulfonyl)methyl)-11-oxo-3,4,10,11-tetrahydro-1H-1,4,10- triazadibenzo[cd,f]azulene-6-carboxylic acid (Compound BBET13_1b)

[0424] To a solution of BBET13_1b (200 mg, 318.6 umol) in dimethylformamide (DMF, 2 mL) were added 2-(7-Azabenzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate (HATU, 266.55 mg, 700.95 umol) and N,N-diisopropyl-ethylamine (DIEA, 741.25 mg, 5.75 mmol, 998.95 uL) at 25oC. After stirred for 10 min, B28 (254.55 mg, 637.25 umol) was added and the mixture was stirred at 25oC for 1 h. The resulting mixture was purified by prep-HPLC (Method 2, 0.1% formic acid in water / acetonitrile) to give BBET50 (98 mg, yield: 30%) as a white solid. Compound BBET50 can be deprotected by methods known to one skilled in the art to remove the Boc group and produce compound 1.7.

[0425] LCMS (system 2, method C) (ESI+): m / z 1009.3 (M+H)+, Rt: 1.951 min.1H NMR: (400 MHz, DMSO-d6). δ ppm 12.10 (br s, 1H), 11.00 (s, 1H), 8.54 - 8.43 (m, 1H), 8.35 - 8.25 (m, 1H), 8.16 (s, 1H), 7.76 (s, 1H), 7.60 (s, 1H), 7.34 (s, 1H), 7.31 - 7.21 (m, 1H), 6.92 (br d, J = 7.2 Hz, 2H), 6.81 (d, J = 8.0 Hz, 1H), 5.31 (br d, J = 7.6 Hz, 1H), 5.11 (br dd, J = 5.6, 12.8 Hz, 1H), 4.80 (br s, 2H), 4.68 - 4.58 (m, 1H), 4.27 - 4.08 (m, 2H), 3.65 (s, 3H), 3.61 - 3.52 (m, 1H), 3.15 - 3.08 (m, 2H), 2.98 - 2.83 (m, 9H), 2.65 - 2.61 (m, 4H), 2.43 - 2.36 (m, 3H), 2.14 - 1.99 (m, 3H), 1.97 - 1.86 (m, 2H), 1.76 - 1.64 (m, 2H), 1.52 - 1.44 (m, 2H), 1.37 (s, 9H), 0.90 - 0.81 (m, 1H), 0.36 (br d, J = 8.0 Hz, 2H), 0.04 (br d, J = 4.8 Hz, 2H). Example 18. Synthesis of tert-butyl (2-(4-(cyclopropylmethyl)-6-((3-(4-((2-(2,6- dioxopiperidin-3-yl)-1-oxoisoindolin-4-yl)methyl)piperidin-1-yl)propyl)carbamoyl)-10- methyl-7-((methylsulfonyl)methyl)-11-oxo-3,4,10,11-tetrahydro-1H-1,4,10- triazadibenzo[cd,f]azulene-2-carboxamido)ethyl)carbamate (Compound 1.3-Boc)

[0426] Following the general procedure of Example 17, BBET13_1b was coupled with E3_d to provide compound 1.3-Boc. Compound 1.3-Boc can be deprotected by methods known to one skilled in the art to remove the Boc group and produce compound 1.3.

[0427] LCMS (system 1, method A) (ESI+): m / z 1008.5 (M+H)+, Rt: 1.33 min. Example 19. Synthesis of tert-butyl (2-(7-(cyclopropylmethyl)-9-((2-(3-(2-(2,6- dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)propoxy)ethyl)carbamoyl)-2-methyl-10- ((methylsulfonyl)methyl)-3-oxo-3,4,6,7-tetrahydro-2H-2,4,7-triazadibenzo[cd,f]azulene- 5-carboxamido)ethyl)carbamate (Compound 1.4-Boc)

[0428] Following the general procedure of Example 17, BBET13_1b was coupled with 4-(3-(2-aminoethoxy)propyl)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione to provide 1.4-Boc. Compound 1.4-Boc can be deprotected by methods known to one skilled in the art to remove the Boc group and produce compound 1.4.

[0429] LCMS (system 1, method A) (ESI+): m / z 955.48 (M+H)+, Rt: 1.49 min. Example 20. General Procedure for coupling of amines with 4-(2-((2-((tert- butoxycarbonyl)amino)ethyl)carbamoyl)-6-methyl-7-oxo-6,7-dihydro-1H-pyrrolo[2,3- c]pyridin-4-yl)-5-(cyclohexyloxy)-2-(methylsulfonamido)benzoic acid (Compound BBET23_6)

[0430] To a solution of BBET23_6 ( 20 mg, 30.97 umol ) in dimethylformamide (DMF, 0.5 mL) were added 2-(7-Azabenzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate (HATU, 25.91 mg, 68.14 umol) and N,N-diisopropyl-ethylamine (DIEA, 52.04 mg, 402.65 umol) at 20oC and stirred at 20oC for 10 min. Then the mixture was added 3-[4-(6-aminohexyl)-1-oxo-isoindolin-2-yl] piperidine-2, 6-dione (42.55 mg, 93.01 umol) at 20oC and stirred at 20oC for 12 h. The resulting mixture was purified by prep-HPLC (Method 3, TFA) to give BBET24 (5 mg, yield 16.35%) as a yellow solid. Compound BBET24 can be deprotected by methods known to one skilled in the art to remove the Boc group and produce compound 1.12.

[0431] LCMS (System 3, method N) (ESI+ ): m / z 436.4 [(M-100) / 2+H]+, Rt: 4.133 min. 1H NMR: (400MHz, DMSO–d6). δ ppm 12.27 (br s, 1H), 10.99 (s, 1H), 10.69 (s, 1H), 8.83 (br t, J = 5.6 Hz, 1H), 8.43 - 8.26 (m, 1H), 7.59 - 7.55 (m, 1H), 7.49 (s, 1H), 7.47 (s, 1H), 7.46 - 7.43 (m, 1H), 7.38 (s, 1H), 6.88 (br t, J = 5.2 Hz, 1H), 6.77 (d, J = 2.0 Hz, 1H), 5.14 (dd, J = 4.8, 13.2 Hz, 1H), 4.51 - 4.43 (m, 1H), 4.39 (td, J = 3.6, 7.2 Hz, 1H), 4.35 - 4.27 (m, 1H), 3.58 (s, 3H), 3.29 (br dd, J = 6.4, 13.2 Hz, 4H), 3.11 - 3.06 (m, 2H), 3.04 - 3.00 (m, 3H), 2.93 (ddd, J = 4.8, 13.2, 17.6 Hz, 2H), 2.70 - 2.66 (m, 2H), 2.63 (br d, J = 3.6 Hz, 1H), 2.44 (br dd, J = 4.4, 13.2 Hz, 1H), 2.05 - 1.96 (m, 1H), 1.79 - 1.70 (m, 2H), 1.68 - 1.56 (m, 4H), 1.52 - 1.44 (m, 3H), 1.40 (br s, 4H), 1.36 (s, 9H), 1.29 - 1.13 (m, 4H). Example 21. Synthesis of tert-butyl (2-(4-(2-(cyclohexyloxy)-4-((5-(2-(2,6- dioxopiperidin-3-yl)-1-oxoisoindolin-4-yl)pentyl)carbamoyl)-5- (methylsulfonamido)phenyl)-6-methyl-7-oxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridine-2- carboxamido)ethyl)carbamate (Compound BBET23)

[0432] Following the general procedure of Example 20, BBET23_6 ( 20 mg, 30.97 umol) was coupled with B19 (40.81 mg, 123.89 umol) to give BBET23 (7.5 mg, yield 25.30%) as a yellow solid. Compound BBET23 can be deprotected by methods known to one skilled in the art to remove the Boc group and produce compound 1.13.

[0433] LCMS (System 3, method N) (ESI+ ): m / z 429.5 [(M-100) / 2+H]+, Rt: 4.032 min. 1H NMR: (400MHz, DMSO–d6). δ ppm 12.26 (br s, 1H), 10.99 (s, 1H), 10.71 (s, 1H), 8.85 (t, J = 5.6 Hz, 1H), 8.35 (br t, J = 5.2 Hz, 1H), 7.56 (dd, J = 2.0, 6.4 Hz, 1H), 7.49 (s, 1H), 7.46 (s, 1H), 7.44 (s, 1H), 7.37 (s, 1H), 6.88 (br t, J = 5.6 Hz, 1H), 6.77 (d, J = 2.0 Hz, 1H), 5.13 (dd, J = 5.2, 13.2 Hz, 1H), 4.52 - 4.44 (m, 1H), 4.39 (td, J = 4.0, 7.2 Hz, 1H), 4.35 - 4.24 (m, 1H), 3.58 (br s, 3H), 3.35 - 3.25 (m, 4H), 3.07 (br d, J = 6.0 Hz, 2H), 3.03 - 2.99 (m, 3H), 2.99 - 2.83 (m, 2H), 2.67 (br t, J = 7.6 Hz, 2H), 2.60 (br d, J = 17.6 Hz, 1H), 2.45 - 2.31 (m, 1H), 2.08 - 1.93 (m, 1H), 1.80 - 1.70 (m, 2H), 1.70 - 1.59 (m, 4H), 1.53 - 1.44 (m, 3H), 1.42 - 1.38 (m, 2H), 1.35 (s, 9H), 1.29 - 1.13 (m, 4H). Example 22. Synthesis of tert-butyl (2-(4-(2-(cyclohexyloxy)-4-((3-(4-((2-(2,6- dioxopiperidin-3-yl)-1-oxoisoindolin-4-yl)amino)piperidin-1-yl)propyl)carbamoyl)-5- (methylsulfonamido)phenyl)-6-methyl-7-oxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridine-2- carboxamido)ethyl)carbamate (Compound BBET49)

[0434] Following the general procedure of Example 20, BBET23_6 (30 mg, 46.46 umol) was coupled with B28 (95.43 mg, 185.84 umol, TFA salt) to give BBET49 (6 mg, yield13%) as a white solid. Compound BBET49 can be deprotected by methods known to one skilled in the art to remove the Boc group and produce compound 1.14.

[0435] LCMS (System 6, method C) (ESI+): m / z 1027.3 (M+H)+, Rt: 2.154 min.1H NMR: (400 MHz, DMSO-d6). δ ppm 12.33 - 12.18 (m, 1H), 11.02 (s, 1H), 8.42 - 8.30 (m, 1H), 7.50 - 7.45 (m, 2H), 7.36 (s, 1H), 7.30 - 7.23 (m, 1H), 6.92 (d, J = 7.6 Hz, 1H), 6.90 - 6.86 (m, 1H), 6.81 (d, J = 8.0 Hz, 1H), 6.77 (s, 1H), 5.35 (br d, J = 8.0 Hz, 1H), 5.12 (dd, J = 5.2, 13.2 Hz, 1H), 4.40 - 4.28 (m, 1H), 4.26 - 4.07 (m, 2H), 3.57 (s, 3H), 3.28 - 3.23 (m, 4H), 3.11 - 3.04 (m, 2H), 3.02 - 2.85 (m, 6H), 2.69 - 2.57 (m, 2H), 2.47 - 2.38 (m, 2H), 2.34 - 2.26 (m, 1H), 2.18 - 1.99 (m, 3H), 1.98 - 1.87 (m, 2H), 1.80 - 1.69 (m, 4H), 1.54 - 1.43 (m, 4H), 1.35 (s, 12H), 1.28 - 1.13 (m, 3H). Example 23. General Procedure for coupling of amines with 4-(2-((2-((tert- butoxycarbonyl)amino)ethyl)carbamoyl)-6-methyl-7-oxo-6,7-dihydro-1H-pyrrolo[2,3- c]pyridin-4-yl)-2-(methylsulfonamido)-5-phenoxybenzoic acid (Compound BBET25_6)

[0436] To a solution of BBET25_6 (120 mg, 187.6 μmol) in dimethylformamide (DMF, 12 mL) were added B22 (117.92 mg, 206.36 μmol, TFA salt), N,N-diisopropyl-ethylamine (DIEA, 242.44 mg, 1.87 mmol, 0.32 mL) and benzotriazol-1-yloxy(tripyrrolidin-1- yl)phosphanium hexafluorophosphate (PyBop, 146.44 mg, 281.4 μmol) at 20oC and stirred at 20oC for 15 min. The reaction mixture was quenched by addition acetic acid to pH= 6. The resulting mixture was purified by prep-HPLC (Method 3, TFA) to give BBET25 (106 mg, yield 58.55%) as a white solid. Compound BBET25 can be deprotected by methods known to one skilled in the art to remove the Boc group and produce compound 1.15.

[0437] LCMS (system 4, method G) (ESI+): m / z 965.6 (M+H)+, Rt: 2.615 min.1H NMR: (400 MHz, DMSO-d6). δ ppm 12.30 (br s, 1H), 11.15 (s, 1H), 10.99 (s, 1H), 8.85 (br t, J = 5.6 Hz, 1H), 8.36 (br t, J = 4.8 Hz, 1H), 7.69 (s, 1H), 7.64 (s, 1H), 7.58 - 7.54 (m, 1H), 7.45 (d, J = 4.8 Hz, 2H), 7.37 (s, 1H), 7.23 - 7.17 (m, 2H), 6.96 - 6.88 (m, 2H), 6.85 (d, J =2.0 Hz, 1H), 6.76 (d, J = 8.0 Hz, 2H), 5.13 (dd, J = 5.2, 13.6 Hz, 1H), 4.47 (s, 2H), 3.49 (s, 3H), 3.29 - 3.22 (m, 4H), 3.14 (s, 3H), 3.11 - 3.05 (m, 2H), 2.98 - 2.86 (m, 1H), 2.69 - 2.60 (m, 3H), 2.46 - 2.37 (m, 1H), 2.05 - 1.97 (m, 1H), 1.65 - 1.49 (m, 4H), 1.35 (s, 13H). Example 24. Synthesis of tert-butyl (2-(4-(4-((3-(4-((2-(2,6-dioxopiperidin-3-yl)-1- oxoisoindolin-4-yl)amino)piperidin-1-yl)propyl)carbamoyl)-5-(methylsulfonamido)-2- phenoxyphenyl)-6-methyl-7-oxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridine-2- carboxamido)ethyl)carbamate (Compound BBET26)

[0438] Following the general procedure of Example 23, BBET25_6 (120 mg, 187.6 μmol) was coupled with B28 (129.48 mg, 206.36 μmol, TFA salt), to provide give BBET26 (120 mg, yield 62.64%) as a white solid. Compound BBET26 can be deprotected by methods known to one skilled in the art to remove the Boc group and produce compound 1.16.

[0439] LCMS (System 6, method C) (ESI+): m / z 1021.2 (M+H)+, Rt: 2.080 min.1H NMR: (400 MHz, DMSO-d6). δ ppm 12.33 (br s, 1H), 11.05 - 11.01 (m, 1H), 10.97 - 10.92 (m, 1H), 9.13 - 9.01 (m, 1H), 8.98 - 8.92 (m, 1H), 8.41 - 8.33 (m, 1H), 7.69 - 7.63 (m, 2H), 7.38 (s, 1H), 7.31 (t, J = 8.0 Hz, 1H), 7.26 - 7.18 (m, 2H), 7.03 - 6.94 (m, 2H), 6.91 (br t, J = 6.4 Hz, 1H), 6.88 - 6.82 (m, 2H), 6.77 (d, J = 8.0 Hz, 2H), 5.64 - 5.55 (m, 1H), 5.14 (dd, J = 5.2, 13.2 Hz, 1H), 4.29 - 4.10 (m, 2H), 3.50 (s, 3H), 3.39 - 3.32 (m, 3H), 3.31 - 3.23 (m, 3H), 3.19 - 3.17 (m, 3H), 3.16 - 3.05 (m, 5H), 3.01 - 2.88 (m, 1H), 2.66 - 2.58 (m, 1H), 2.30 - 2.23 (m, 1H), 2.21 - 2.10 (m, 2H), 2.09 - 2.01 (m, 1H), 1.99 - 1.88 (m, 3H), 1.70 - 1.57 (m, 2H), 1.36 (s, 9H). Example 25. Synthesis of tert-butyl (2-(4-(4-((4-(4-((2-(2,6-dioxopiperidin-3-yl)-1- oxoisoindolin-4-yl)amino)piperidin-1-yl)butyl)carbamoyl)-5-(methylsulfonamido)-2- phenoxyphenyl)-6-methyl-7-oxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridine-2- carboxamido)ethyl)carbamate (Compound BBET54)

[0440] Following the general procedure of Example 23, BBET25_6 (30 mg, 46.9 μmol) was coupled with B30 (38.98 mg, 51.59 μmol, TFA salt), to provide BBET54 (17.5 mg, yield 36.05%) as a white solid. Compound BBET54 can be deprotected by methods known to one skilled in the art to remove the Boc group and produce compound 1.17.

[0441] LCMS (System 6, method C) (ESI+): m / z 1035.3 (M+H)+, Rt: 2.099 min.1H NMR: (400 MHz, DMSO-d6). δ ppm 12.32 (br s, 1H), 11.06 (br d, J = 19.6 Hz, 2H), 9.18 - 9.07 (m, 1H), 8.96 - 8.87 (m, 1H), 8.38 (br d, J = 3.2 Hz, 1H), 7.73 - 7.60 (m, 2H), 7.37 (s, 1H), 7.31 (t, J = 7.6 Hz, 1H), 7.21 (t, J = 8.0 Hz, 2H), 7.02 - 6.95 (m, 2H), 6.94 - 6.90 (m, 1H), 6.89 - 6.82 (m, 2H), 6.76 (br d, J = 8.0 Hz, 2H), 5.66 - 5.54 (m, 1H), 5.14 (dd, J = 5.2, 13.2 Hz, 1H), 4.29 - 4.08 (m, 2H), 3.49 (s, 3H), 3.34 - 3.23 (m, 5H), 3.17 (s, 3H), 3.12 - 3.02 (m, 5H), 3.02 - 2.88 (m, 2H), 2.68 - 2.57 (m, 1H), 2.34 - 2.24 (m, 1H), 2.19 - 2.10 (m, 2H), 2.08 - 2.00 (m, 1H), 1.99 - 1.90 (m, 1H), 1.75 - 1.64 (m, 3H), 1.62 - 1.50 (m, 3H), 1.35 (s, 9H). Example 26. Synthesis of tert-butyl (2-(4-(4-(((1S)-3-(4-((2-(2,6-dioxopiperidin-3-yl)-1- oxoisoindolin-4-yl)amino)piperidin-1-yl)cyclopentyl)carbamoyl)-5- (methylsulfonamido)-2-phenoxyphenyl)-6-methyl-7-oxo-6,7-dihydro-1H-pyrrolo[2,3- c]pyridine-2-carboxamido)ethyl)carbamate (Compound BBET55)

[0442] Following the general procedure of Example 23, BBET25_6 (30 mg, 46.9 μmol) was coupled with B33 to provide BBET55 (19.8 mg, yield 40.32%) as a white solid. Compound BBET55 can be deprotected by methods known to one skilled in the art to remove the Boc group and produce compound 1.18.

[0443] LCMS (System 6, method C) (ESI+): m / z 1047.3 (M+H)+, Rt: 2.108 min.1H NMR: (400 MHz, DMSO-d6). δ ppm 12.33 (br s, 1H), 11.04 (s, 1H), 10.87 (d, J = 6.4 Hz, 1H), 9.46 - 9.23 (m, 1H), 8.93 - 8.74 (m, 1H), 8.37 (br t, J = 5.2 Hz, 1H), 7.74 - 7.68 (m, 1H), 7.66 - 7.62 (m, 1H), 7.37 (s, 1H), 7.31 (t, J = 7.2 Hz, 1H), 7.24 - 7.18 (m, 2H), 7.03 - 6.96 (m, 1H), 6.95 - 6.90 (m, 2H), 6.90 - 6.82 (m, 2H), 6.74 (d, J = 8.0 Hz, 2H), 5.68 - 5.57 (m, 1H), 5.21 - 5.08 (m, 1H), 4.43 - 4.31 (m, 1H), 4.30 - 4.10 (m, 3H), 3.49 (s, 3H), 3.32 - 3.23 (m, 3H), 3.17 (s, 3H), 3.13 - 3.02 (m, 4H), 3.01 - 2.88 (m, 1H), 2.69 - 2.58 (m, 1H), 2.34 - 2.25 (m, 1H), 2.24 - 2.10 (m, 4H), 2.09 - 1.94 (m, 4H), 1.84 - 1.58 (m, 4H), 1.36 (s, 9H). Example 27. Synthesis of tert-butyl (2-(4-(4-(4-((2-(2,6-dioxopiperidin-3-yl)-1- oxoisoindolin-4-yl)amino)-[1,4'-bipiperidine]-1'-carbonyl)-5-(methylsulfonamido)-2- phenoxyphenyl)-6-methyl-7-oxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridine-2- carboxamido)ethyl)carbamate (Compound BBET56)

[0444] Following the general procedure of Example 23, BBET25_6 (30 mg, 46.9 μmol) was coupled with B29 (39.6 mg, 51.59 μmol, TFA salt) to provide BBET56 (23 mg, yield 46.83%) as a white solid. Compound BBET56 can be deprotected by methods known to one skilled in the art to remove the Boc group and produce compound 1.19.

[0445] LCMS (System 6, method C) (ESI+): m / z 1047.3 (M+H)+, Rt: 2.038 min.1H NMR: (400 MHz, DMSO-d6). δ ppm 12.35 - 12.28 (m, 1H), 11.04 (s, 1H), 9.32 (s, 1H), 9.20 - 9.05 (m, 1H), 8.42 - 8.34 (m, 1H), 7.55 - 7.51 (m, 1H), 7.36 (s, 1H), 7.34 - 7.31 (m, 1H), 7.30 (s, 1H), 7.27 (s, 1H), 7.06 - 7.01 (m, 2H), 6.98 (d, J = 7.6 Hz, 1H), 6.90 (br d, J = 6.8 Hz, 5H), 5.63 - 5.57 (m, 1H), 5.19 - 5.10 (m, 1H), 4.67 - 4.58 (m, 1H), 4.29 - 4.10 (m, 2H), 3.72 - 3.62 (m, 2H), 3.52 (s, 3H), 3.27 (br d, J = 6.0 Hz, 2H), 3.18 - 3.04 (m, 8H), 3.00 - 2.87 (m, 2H), 2.80 - 2.71 (m, 1H), 2.65 - 2.58 (m, 1H), 2.30 - 2.25 (m, 1H), 2.23 - 2.13 (m, 2H), 2.10 - 1.91 (m, 4H), 1.74 - 1.56 (m, 4H), 1.36 (s, 9H). Example 28. Synthesis of tert-butyl (2-(4-(4-((3-(4-((2-(2,6-dioxopiperidin-3-yl)-1- oxoisoindolin-4-yl)amino)piperidin-1-yl)cyclobutyl)(methyl)carbamoyl)-5- (methylsulfonamido)-2-phenoxyphenyl)-6-methyl-7-oxo-6,7-dihydro-1H-pyrrolo[2,3- c]pyridine-2-carboxamido)ethyl)carbamate (Compound BBET57)

[0446] Following the general procedure of Example 23, BBET25_6 (30 mg, 46.9 μmol) was coupled with B32 (39.6 mg, 51.59 μmol, TFA salt) to provide BBET57 (21.5 mg, yield 43.78%) as a white solid. Compound BBET57 can be deprotected by methods known to one skilled in the art to remove the Boc group and produce compound 1.20.

[0447] LCMS (System 6, method C) (ESI+): m / z 1047.3 (M+H)+, Rt: 2.061 min.1H NMR: (400 MHz, DMSO-d6). δ ppm 12.39 - 12.25 (m, 1H), 11.04 (s, 1H), 9.43 - 9.27 (m, 2H), 8.43 - 8.33 (m, 1H), 7.57 - 7.47 (m, 1H), 7.40 - 7.27 (m, 4H), 7.15 - 7.06 (m, 1H), 7.00 (br dd, J = 7.6, 13.6 Hz, 2H), 6.94 - 6.87 (m, 4H), 6.71 (s, 1H), 5.66 - 5.57 (m, 1H), 5.18 -5.11 (m, 1H), 4.28 - 4.10 (m, 2H), 4.05 - 3.83 (m, 1H), 3.69 - 3.60 (m, 1H), 3.57 - 3.52 (m, 3H), 3.28 (br d, J = 5.6 Hz, 3H), 3.12 - 3.06 (m, 2H), 3.03 (s, 3H), 2.99 - 2.89 (m, 5H), 2.83 (br s, 1H), 2.62 (br d, J = 16.0 Hz, 1H), 2.57 - 2.53 (m, 1H), 2.46 - 2.38 (m, 2H), 2.31 - 2.13 (m, 4H), 2.09 - 1.94 (m, 2H), 1.65 - 1.51 (m, 2H), 1.36 (s, 9H). Example 29. Synthesis of tert-butyl (2-(4-(4-((5-(4-((2-(2,6-dioxopiperidin-3-yl)-1- oxoisoindolin-4-yl)amino)piperidin-1-yl)pentyl)carbamoyl)-5-(methylsulfonamido)-2- phenoxyphenyl)-6-methyl-7-oxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridine-2- carboxamido)ethyl)carbamate (Compound BBET58)

[0448] Following the general procedure of Example 23, BBET25_6 (30 mg, 46.9 μmol) was coupled with B31 (33.82 mg, 51.59 μmol, TFA salt) to provide BBET58 (25 mg, yield 50.81%) as a white solid. Compound BBET58 can be deprotected by methods known to one skilled in the art to remove the Boc group and produce compound 1.21.

[0449] LCMS (System 6, method C) (ESI+): m / z 1049.3 (M+H)+, Rt: 2.143 min.1H NMR: (400 MHz, DMSO-d6). δ ppm 12.31 (br s, 1H), 11.13 (s, 1H), 11.02 (s, 1H), 9.18 - 9.05 (m, 1H), 8.88 (br t, J = 5.6 Hz, 1H), 8.36 (br t, J = 4.8 Hz, 1H), 7.70 (s, 1H), 7.65 (s, 1H), 7.36 (s, 1H), 7.31 (t, J = 7.6 Hz, 1H), 7.24 - 7.18 (m, 2H), 7.03 - 6.93 (m, 2H), 6.92 - 6.87 (m, 1H), 6.87 - 6.83 (m, 1H), 6.76 (br d, J = 8.0 Hz, 2H), 5.68 - 5.33 (m, 1H), 5.14 (dd, J = 4.8, 13.2 Hz, 1H), 4.33 - 4.09 (m, 2H), 3.88 - 3.76 (m, 1H), 3.49 (s, 5H), 3.32 - 3.24 (m, 4H), 3.19 - 3.14 (m, 3H), 3.11 - 3.01 (m, 5H), 3.01 - 2.86 (m, 2H), 2.62 (br d, J = 16.8 Hz, 1H), 2.27 (br dd, J = 4.4, 13.2 Hz, 1H), 2.24 - 2.10 (m, 2H), 2.08 - 1.90 (m, 2H), 1.73 - 1.52 (m, 5H), 1.36 (s, 10H).Example 30. General Procedure for Drug Linker synthesis.

[0450] To a vial containing BBET13a (1.00 eq, 3.6 mg, 0.00351 mmol) was added DCM (0.25mL) and TFA (0.1 mL) and stirred at room temp for 30 min, leading to complete conversion to amine 1.2. The solution was concentrated under reduced pressure, then the residue was concentrated from 0.5 mL of toluene three times under reduced pressure at 35oC. The amine intermediate was used without further purification.

[0451] LCMS (System 1, method A) (ESI+): m / z 811.42 (M+H)+, Rt: 1.21 min.

[0452] A solution of (2,5-dioxopyrrolidin-1-yl) 3-(2,5-dioxopyrrol-1-yl)propanoate (1.20 eq, 1.1 mg, 0.00421 mmol), dissolved in DMF (0.1mL) was then added to the residue, followed by N,N-Diisopropylethylamine (5.00 eq, 3.1 uL, 0.0176 mmol). After 30 min the reaction was treated with AcOH (100 uL) then concentrated under reduced pressure and purified by prep HPLC (Method 1, TFA). The combined product fractions were freeze dried to obtain the TFA salt of compound 2.2 (3.2 mg).

[0453] LCMS (System 1, method A) (ESI+): m / z 962.44 (M+H)+, Rt: 1.32 min. Table 5. LCMS characterization of synthesized Drug Linker compoundsExample 31. In vitro cytotoxicity assay

[0454] The cytotoxicity of free drugs and drug conjugates was measured by a cell proliferation assay employing the protocol described in Promega Corp. Technical Bulletin TB288; and Mendoza et al., 2002, Cancer Res. 62:5485-5488), the methods of which are specifically incorporated by reference herein. Briefly, an aliquot of 40 μl of cell culture containing about 400 cells in medium was deposited in each well of a 384-well, opaque- walled plate. A 10 μL aliquot of free drug or drug conjugate was added to the experimental wells and incubated for 96 h and was then equilibrated to room temperature for approximately 30 minutes whereupon a volume of CellTiter-GloTM reagent equal to the volume of cell culture medium present in each well was added. The contents were mixed for 2 minutes on an orbital shaker to induce cell lysis and the plate was incubated at room temperature for 10 minutes to stabilize the luminescence signal for recordation. Cell types tested included DEL, Karpas299, L540cy, and MOLM13.

[0455] All of the BOC-protected compounds 1.1-1.15, with the exception of compound 1.8, were cytotoxic to MOLM13 cells with an IC50 value less than 1000 nM. The BOC- protected version of compound 1.8 was not cytotoxic to MOLM13 cells at the top concentration evaluated (1000 nM).

[0456] Free drug compounds were additionally tested in the following cell types: pancreatic cancer cells (BXPC3), lung cancer cells (CALU1), colorectal cancer cells (LS174T), breast cancer cells (MDAMB231), acute myeloid leukemia cells (MOLM13), and B-lymphocyte cancer cells (SUDHL4). Results are provided in Table 6. IC50 values are reported in nM at 96 h. Table 6. In vitro potency (IC50 values provided in nM)+ denotes > 1000 nM; ++ denotes 300-1000 nM; +++ denotes < 300 nM; ND denotes Not Determined

[0457] Antibody-drug conjugates were tested in the following cell types: pancreatic cancer cells (BXPC3), lung cancer cells (CALU1), colorectal cancer cells (LS174T), breast cancer cells (MDAMB231), acute myeloid leukemia cells (MOLM13), and B-lymphocyte cancer cells (SUDHL4). All conjugates were prepared with an antibody that selectively binds to an antigen (Ag1) that is commonly upregulated in various tumors, and having a drug- antibody ratio (DAR) of 4. Results are provided in Table 7. IC50 values are reported in ng / mL at 96 h. Table 7. In vitro potency (IC50 values provided in ng / mL)+ denotes > 1000 ng / mL; ++ denotes 300-1000 ng / ,mL; +++ denotes < 300 ng / mL; ND denotes Not Determined Example 32. In vitro protein degradation

[0458] Protein degradation was determined by either a SPRINTER assay or an ALPHALISA assay.BRD4 Sprinter assay:

[0459] BRD4 protein degradation was measured by a Sprinter assay from Eurofins discovery according to the Manufacturer’s instructions. The Sprinter assay for sensing protein internal turnover is based on enzyme fragment complementation where the enzyme donor (ED) fragment of beta galactosidase being in close proximity to the enzyme acceptor (EA) fragment of beta-galactosidase creates a functional beta-galactosidase enzyme that produces a chemiluminescent signal in the presence of the assay substrate.

[0460] The K562 BRD4 Sprinter cell line harbors CRISPR / Cas9 based knockin of small β-galactosidase (β-gal) enzyme donor (ED) fragment into the endogenous locus of BRD4 gene. The K562 BRD4 Sprinter cell line was acquired from the manufacturer and treated with different BRD4 degrading free dr...

Claims

WHAT IS CLAIMED IS:

1. A compound of Formula (I):Formula (I), or a pharmaceutically acceptable salt thereof, wherein: X is CH, N, O, or S; Z1is H or absent; Z2is H; or Z1and Z2are taken together to form a single bond or a C1-C4 alkylene group; provided that when X is O or S, Z1is absent; Y1and Y2are independently CH, CF, or N; Q is absent or C(O), NR11, S, SO2NR11, NR11SO2, O, C(O)O, or C(O)NR11; R1is H, halogen, OH, CN, N3, SH, COOR12, SO2R12, SO2NR11R12, or NR11R12; L2is absent or –CH2CH2(OCH2CH2)k–, -C1-C10alkylene-, 2- to 14-membered heteroalkylene-, -C3-C8 carbocyclo-, -O(C1-C8 alkylene)-, -arylene-, -C1-C10 alkylene- arylene-, -arylene-C1-C10alkylene-, -C1-C10alkylene-(C3-C8carbocyclo)-, -(C3-C8carbocyclo)-C1-C10alkylene-, 3- to 12-membered heterocyclo-, -C1-C10alkylene-( 3- to 12-membered heterocyclo)-, -( 3- to 12-membered heterocyclo)-C1-C10 alkylene, - C2-C10alkenylene-, 3- to 14-membered heteroalkenylene-, -O(C2-C8 alkenylene)-, - C2-C10alkenylene-arylene-, -arylene-C2-C10alkenylene-, -C2-C10alkenylene-(C3-C8carbocyclo)-, -(C3-C8carbocyclo)-C2-C10alkenylene-, -C2-C10alkenylene-(3- to 12- membered heterocyclo)-, -(3- to 12-membered heterocyclo)-C2-C10alkenylene, -C2- C10alkynylene-, 3- to 14-membered heteroalkynylene-, -O(C2-C8alkynylene)-, -C2- C10alkynylene-arylene-, -arylene-C2-C10alkynylene-, -C2-C10alkynylene-(C3-C8carbocyclo)-, -(C3-C8carbocyclo)-C2-C10alkynylene-, -C2-C10alkynylene-(3- to 12- membered heterocyclo)-, or -(3- to 12-membered heterocyclo)-C2-C10alkynylene, each of which is optionally substituted; subscript k is an integer ranging from 1 to 36, provided that QL2R1is not H; and R2is optionally substituted C1-C6 alkyl; R3is C3-C8cycloalkyl, -C1-C10alkylene-(C3-C8cycloalkyl), C3-C8cycloalkenyl, -C1- C10 alkylene-(C3-C8 cycloalkenyl), C6-C14 aryl, -C1-C10 alkylene-(C6-C14 aryl), 5- to 10- membered heteroaryl, -C1-C10 alkylene-(5- to 10-membered heteroaryl), 3- to 12-membered heterocyclyl, or -C1-C10alkylene (3- to 12-membered heterocyclyl), wherein the C3-C8cycloalkyl, -C1-C10alkylene-(C3-C8cycloalkyl), C6-C14aryl, -C1-C10alkylene-(C6-C14aryl), 5- to 10-membered heteroaryl, -C1-C10 alkylene-(5- to 10-membered heteroaryl), 3- to 12- membered heterocyclyl, or -C1-C10 alkylene (3- to 12-membered heterocyclyl) are optionally substituted by halo, OH, CN, C1-C6alkyl, or C1-C6haloalkyl; R4is -NHSO2R12or -CH2SO2R12; R5is H or halo; R6is H or optionally substituted C1-C6alkyl; R7and R8are each H, or R7and R8, taken together with the carbon to which they are attached, form a carbonyl or 3- to 6-membered carbocycle; R9, R10a, and R10bare each independently H, halo, optionally substituted C1-C6alkyl, C3-C8 cycloalkyl, or C1-C6 haloalkyl; L1is a linking group having the structure:** ; wherein W1is C2-C6 alkenylene, C2-C6 alkynylene, optionally substituted 5- to 10- membered heteroarylene, optionally substituted 3- to 12-membered heterocyclene, CO, CONR11, C(O)O, SO2NR11, or absent; W2is, independently at each occurrence, O, S, NR11, -COO-, -OCO-, -CONR11-, - NR11CO-, -SO2NR11-, -NR11SO2-, optionally substituted C3-C8 cycloalkylene, optionally substituted C3-C8cycloalkenylene, optionally substituted C6-C14arylene, optionally substituted 5- to 10-membered heteroarylene, optionally substituted 3- to 12-membered heterocyclylene, or absent;W3is, independently at each occurrence, O, S, NR11, optionally substituted C1-C10alkylene, optionally substituted C2-C10alkenylene, optionally substituted C2-C10alkynylene, optionally substituted 2- to 14-membered heteroalkylene, or absent; subscript n is an integer from 1 to 6; * indicates the point of attachment to * in Formula (I); ** indicates the point of attachment to ** in Formula (I); provided that at least one of W1, W2, and W3is not absent; and R11and R12are, independently of each other and independently at each occurrence, H, halo, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy, or C3-C8 cycloalkyl.

2. The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein Y1and Y2are CH or CF.

3. The compound of claim 1 or claim 2, or a pharmaceutically acceptable salt thereof, wherein Y1and Y2are CH.

4. The compound of any one of claims 1-3, or a pharmaceutically acceptable salt thereof, wherein X is O or S, Z1is absent, and Z2is H.

5. The compound of any one of claims 1-3, or a pharmaceutically acceptable salt thereof, wherein X is CH or N, Z1is H, and Z2is H.

6. The compound of any one of claims 1-3, or a pharmaceutically acceptable salt thereof, wherein X is CH or N and Z1and Z2are taken together to form a single bond or a C1-C4alkylene group.

7. The compound of any one of claims 1-3, or a pharmaceutically acceptable salt thereof, wherein the compound is a compound of Formula (IIa):Formula (IIa), wherein X is CH or N.

8. The compound of any one of claims 1-5, or a pharmaceutically acceptable salt thereof, wherein the compound is a compound of Formula (IIb):Formula (IIb), wherein Z1is H or absent.

9. The compound of any one of claims 1-8, or a pharmaceutically acceptable salt thereof, wherein R9, R10a, and R10bare each independently H, halo, or optionally substituted C1-C6 alkyl.

10. The compound of any one of claims 1-9, or a pharmaceutically acceptable salt thereof, wherein R9, R10a, and R10bare each H.

11. The compound of any one of claims 1-3, 6, 7, 9, or 10, or a pharmaceutically acceptable salt thereof, wherein the compound is a compound of Formula (IIIa):Formula (IIIa),wherein X is CH or N.

12. The compound of any one of claims 1-3, 6, 7, or 9-11, or a pharmaceutically acceptable salt thereof, wherein the compound is a compound of Formula (IIIa-R):Formula (IIIa-R), wherein X is CH or N.

13. The compound of any one of claims 1-3, 6, 7, or 9-11, or a pharmaceutically acceptable salt thereof, wherein the compound is a compound of Formula (IIIa-S):wherein X is CH or N.

14. The compound of any one of claims 1-3, 6, 7, or 9-13, or a pharmaceutically acceptable salt thereof, wherein the compound is a compound of Formula (IIIa-4):wherein X is CH or N.

15. The compound of any one of claims 1-3, 6, 7, or 9-13, or a pharmaceutically acceptable salt thereof, wherein the compound is a compound of Formula (IIIa-5):Formula (IIIa-5), wherein X is CH or N.

16. The compound of any one of claims 1-3, 6, 7, or 9-15, or a pharmaceutically acceptable salt thereof, wherein X is N.

17. The compound of any one of claims 1-5 or 7-10, or a pharmaceutically acceptable salt thereof, wherein the compound is a compound of Formula (IIIb):wherein Z1is absent or H.

18. The compound of any one of claims 1-5, 7-10, or 17, or a pharmaceutically acceptable salt thereof, wherein the compound is a compound of Formula (IIIb-R):wherein Z1is absent or H.

19. The compound of any one of claims 1-5, 7-10, or 17, or a pharmaceutically acceptable salt thereof, wherein the compound is a compound of Formula (IIIb-S):wherein Z1is absent or H.

20. The compound of any one of claims 1-5, 7-10, or 17-19, or a pharmaceutically acceptable salt thereof, wherein the compound is a compound of Formula (IIIb-4):wherein Z1is absent or H.

21. The compound of any one of claims 1-5, 7-10, or 17-19, or a pharmaceutically acceptable salt thereof, wherein the compound is a compound of Formula (IIIb-5):wherein Z1is absent or H.

22. The compound of any one of claims 1-5, 7-10, or 17-21, or a pharmaceutically acceptable salt thereof, wherein X is N or CH and Z1is H.

23. The compound of any one of claims 1-5, 7-10, or 17-22, or a pharmaceutically acceptable salt thereof, wherein X is N and Z1is H.

24. The compound of any one of claims 1-5, 7-10, or 17-21, or a pharmaceutically acceptable salt thereof, wherein X is O or S and Z1is absent.

25. The compound of any one of claims 1-5, 7-10, 17-21, or 24, or a pharmaceutically acceptable salt thereof, wherein X is O and Z1is absent.

26. The compound of any one of claims 1-25, or a pharmaceutically acceptable salt thereof, wherein R2is methyl.

27. The compound of any one of claims 1-26, or a pharmaceutically acceptable salt thereof, wherein R4is -NHSO2CH3or -CH2SO2CH3.

28. The compound of any one of claims 1-27, or a pharmaceutically acceptable salt thereof, wherein R5is H.

29. The compound of any one of claims 1-28, or a pharmaceutically acceptable salt thereof, wherein R6is H or methyl.

30. The compound of any one of claims 1-29, or a pharmaceutically acceptable salt thereof, wherein R7and R8are each H.

31. The compound of any one of claims 1-29, or a pharmaceutically acceptable salt thereof, wherein R7and R8are taken together with the carbon to which they are attached to form a carbonyl.

32. The compound of any one of claims 1-31, or a pharmaceutically acceptable salt thereof, wherein R3is C3-C8cycloalkyl, -C1-C10alkylene-(C3-C8cycloalkyl), C6-C14aryl, -C1-C10alkylene-(C6-C14aryl), 5- to 10-membered heteroaryl, or -C1-C10alkylene-(5- to 10- membered heteroaryl).

33. The compound of any one of claims 1-32, or a pharmaceutically acceptable salt thereof, wherein R3is C3-C8 cycloalkyl, -C1-C10 alkylene-(C3-C8 cycloalkyl), or C6-C14 aryl.

34. The compound of any one of claims 1-33, or a pharmaceutically acceptable salt thereof, wherein R3is cyclohexyl, -CH2-(cyclopropyl), or phenyl.

35. The compound of any one of claims 1-34, or a pharmaceutically acceptable salt thereof, wherein Q is absent, C(O), NR11, C(O)O, or C(O)NR11; L2is –CH2CH2(OCH2CH2)k–, -C1-C10 alkylene-, -C3-C8 carbocyclo-, -C1-C10 alkylene-(C3-C8 carbocyclo)-, -(C3-C8carbocyclo)-C1-C10alkylene-, -C2-C10alkenylene-, -C2-C10alkenylene- (C3-C8carbocyclo)-, -(C3-C8carbocyclo)-C2-C10alkenylene-, -C2-C10alkynylene-, -C2-C10alkynylene-(C3-C8 carbocyclo)-, or -(C3-C8 carbocyclo)-C2-C10alkynylene-; and R1is OH, COOR12, or NR11R12.

36. The compound of any one of claims 1-35, or a pharmaceutically acceptable salt thereof, wherein Q is C(O)NR11; L2is -C1-C10alkylene-, -C1-C10alkylene-(C3-C8carbocyclo)-, -(C3-C8carbocyclo)-C1-C10alkylene-, -C2-C10alkenylene-, or -C2-C10alkynylene-; and R1is NR11R12.

37. The compound of any one of claims 1-36, or a pharmaceutically acceptable salt thereof, wherein L2is -C1-C10 alkylene-.

38. The compound of any one of claims 1-37, or a pharmaceutically acceptable salt thereof, wherein Q is CONH; L2is -CH2CH2-; and R1is NH2.

39. The compound of any one of claims 1-38, or a pharmaceutically acceptable salt thereof, wherein L1is *-W3-W1-**, *-W3-W2-W3-W1-**, *-W3-W2-W2-W1-**, *-W3-W2-W1-**, *- W3-W2-W3-W2-W1-**, or *-W3-W2-W3-W2-W3-W2-W1-**.

40. The compound of any one of claims 1-39, or a pharmaceutically acceptable salt thereof, wherein L1is *-W3-W1-**, *-W3-W2-W3-W1-**, or *-W3-W2-W2-W1-**.

41. The compound of any one of claims 1-40, or a pharmaceutically acceptable salt thereof, wherein W1is C2-C6 alkenylene, C2-C6 alkynylene, CO, CONR11, or absent; W2is, independently at each occurrence, O, NR11, -CONR11-, -NR11CO-, optionally substituted C3-C8cycloalkylene, optionally substituted C3-C8cycloalkenylene, optionally substituted 3- to 12-membered heterocyclylene, or absent; W3is, independently at each occurrence, O, NR11, optionally substituted C1-C10 alkylene, optionally substituted C2-C10alkenylene, optionally substituted C2-C10alkynylene, optionally substituted 2- to 14-membered heteroalkylene, or absent; and subscript n is an integer from 1 to 3; provided that at least one of W1, W2, and W3is not absent.

42. The compound of any one of claims 1-41, or a pharmaceutically acceptable salt thereof, wherein W1is CO or CONR11; W2is, independently at each occurrence, O, NR11, optionally substituted C3-C8cycloalkylene, optionally substituted 3- to 12-membered heterocyclylene, or absent; W3is, independently at each occurrence, O, NR11, optionally substituted C1-C10 alkylene, or absent; and subscript n is an integer from 1 to 3.

43. The compound of any one of claims 1-42, or a pharmaceutically acceptable salt thereof, 1wherein L is selected from the group consisting of: ,.

44. The compound of claim 14, wherein R2is methyl, R4is -CH2SO2CH3, R5is H, R6is H, R7and R8are H, R3is -C1-C10 alkylene-(C3-C8 cycloalkyl), Q is CONR11, L2is -C1-C10 alkylene-45. The compound of claim 20, or a pharmaceutically acceptable salt thereof, wherein R2is methyl, R4is -NHSO2CH3, R5is H, R6is H, R7and R8are H, R3is C3-C8 cycloalkyl, Q is CONR11, L2is -C1-C10 alkylene-,46. The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein the compound is selected from the group consisting of:,.

47. A compound selected from the group consisting of the compounds listed in Table 1, or a pharmaceutically acceptable salt thereof.

48. A Drug Linker compound of the following formula: Z'-A-D, or a pharmaceutically acceptable salt thereof, wherein Z' is a Stretcher Unit precursor; A is a bond or a Connector Unit; and D is a Drug Unit of Formula (I'):Formula (I'), wherein: X is CH, N, O, or S; Z1is H or absent; Z2is H; or Z1and Z2are taken together to form a single bond or a C1-C4 alkylene group; provided that when X is O or S, Z1is absent; Y1and Y2are independently CH, CF, or N; Q is absent or C(O), NR11, S, SO2NR11, NR11SO2, O, C(O)O, or C(O)NR11; R1is O, S, COO, SO2, SO2NR11, or NR11; L2is absent or –CH2CH2(OCH2CH2)k–, -C1-C10alkylene-, 2- to 14-membered heteroalkylene-, -C3-C8carbocyclo-, -O(C1-C8alkylene)-, -arylene-, -C1-C10alkylene- arylene-, -arylene-C1-C10 alkylene-, -C1-C10 alkylene-(C3-C8 carbocyclo)-, -(C3-C8 carbocyclo)-C1-C10alkylene-, 3- to 12-membered heterocyclo-, -C1-C10alkylene-( 3- to 12-membered heterocyclo)-, -( 3- to 12-membered heterocyclo)-C1-C10alkylene, - C2-C10alkenylene-, 3- to 14-membered heteroalkenylene-, -O(C2-C8 alkenylene)-, - C2-C10alkenylene-arylene-, -arylene-C2-C10alkenylene-, -C2-C10alkenylene-(C3-C8carbocyclo)-, -(C3-C8carbocyclo)-C2-C10alkenylene-, -C2-C10alkenylene-(3- to 12- membered heterocyclo)-, -(3- to 12-membered heterocyclo)-C2-C10alkenylene, -C2- C10 alkynylene-, 3- to 14-membered heteroalkynylene-, -O(C2-C8 alkynylene)-, -C2- C10alkynylene-arylene-, -arylene-C2-C10alkynylene-, -C2-C10alkynylene-(C3-C8carbocyclo)-, -(C3-C8carbocyclo)-C2-C10alkynylene-, -C2-C10alkynylene-(3- to 12- membered heterocyclo)-, or -(3- to 12-membered heterocyclo)-C2-C10alkynylene, each of which is optionally substituted; subscript k is an integer ranging from 1 to 36, wherein # denotes the point of attachment to A; andR2is optionally substituted C1-C6alkyl; R3is C3-C8 cycloalkyl, -C1-C10 alkylene-(C3-C8 cycloalkyl), C3-C8 cycloalkenyl, -C1- C10 alkylene-(C3-C8 cycloalkenyl), C6-C14 aryl, -C1-C10 alkylene-(C6-C14 aryl), 5- to 10- membered heteroaryl, -C1-C10alkylene-(5- to 10-membered heteroaryl), 3- to 12-membered heterocyclyl, or -C1-C10 alkylene (3- to 12-membered heterocyclyl), wherein the C3-C8 cycloalkyl, -C1-C10 alkylene-(C3-C8 cycloalkyl), C6-C14 aryl, -C1-C10 alkylene-(C6-C14 aryl), 5- to 10-membered heteroaryl, -C1-C10alkylene-(5- to 10-membered heteroaryl), 3- to 12- membered heterocyclyl, or -C1-C10 alkylene (3- to 12-membered heterocyclyl) are optionally substituted by halo, OH, CN, C1-C6 alkyl, or C1-C6 haloalkyl; R4is -NHSO2R12or -CH2SO2R12; R5is H or halo; R6is H or optionally substituted C1-C6 alkyl; R7and R8are each H, or R7and R8, taken together with the carbon to which they are attached, form a carbonyl or 3- to 6-membered carbocycle; R9, R10a, and R10bare each independently H, halo, optionally substituted C1-C6 alkyl, C3-C8cycloalkyl, or C1-C6haloalkyl; L1is a linking group having the structure:** ; wherein W1is C2-C6 alkenylene, C2-C6 alkynylene, optionally substituted 5- to 10- membered heteroarylene, optionally substituted 3- to 12-membered heterocyclene, CO, CONR11, C(O)O, SO2NR11, or absent; W2is, independently at each occurrence, O, S, NR11, -COO-, -OCO-, -CONR11-, - NR11CO-, -SO2NR11-, -NR11SO2-, optionally substituted C3-C8cycloalkylene, optionally substituted C3-C8 cycloalkenylene, optionally substituted C6-C14 arylene, optionally substituted 5- to 10-membered heteroarylene, optionally substituted 3- to 12-membered heterocyclylene, or absent; W3is, independently at each occurrence, O, S, NR11, optionally substituted C1-C10alkylene, optionally substituted C2-C10alkenylene, optionally substituted C2-C10alkynylene, optionally substituted 2- to 14-membered heteroalkylene, or absent; subscript n is an integer from 1 to 6; * indicates the point of attachment to * in Formula (I); ** indicates the point of attachment to ** in Formula (I);provided that at least one of W1, W2, and W3is not absent; and R11and R12are, independently of each other and independently at each occurrence, H, halo, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy, or C3-C8 cycloalkyl.

49. The Drug-Linker compound of claim 48, or a pharmaceutically acceptable salt thereof, wherein the Stretcher Unit Z' iswherein R17is –CH2CH2(OCH2CH2)k–, -C1-C10alkylene-, C1-C10heteroalkylene-, -C3-C8carbocyclo-, -O-(C1-C8alkylene)-, -arylene-, -C1-C10alkylene-arylene-, -arylene-C1-C10alkylene-, -C1-C10 alkylene-(C3-C8 carbocyclo)-, -(C3-C8 carbocyclo)-C1-C10 alkylene-, -C3- C8heterocyclo-, -C1-C10alkylene-(C3-C8heterocyclo)-, -(C3-C8heterocyclo)-C1-C10alkylene- , -C1-C10alkylene-C(=O)-, C1-C10heteroalkylene-C(=O)-, -C3-C8carbocyclo-C(=O)-, -O- (C1-C8 alkylene)-C(=O)-, -arylene-C(=O)-, -C1-C10 alkylene-arylene-C(=O)-, -arylene-C1-C10 alkylene-C(=O)-, -C1-C10 alkylene-(C3-C8 carbocyclo)-C(=O)-,-(C3-C8 carbocyclo)-C1-C10 alkylene-C(=O)-, -C3-C8heterocyclo-C(=O)-, -C1-C10alkylene-(C3-C8heterocyclo)-C(=O)-, - (C3-C8heterocyclo)-C1-C10alkylene-C(=O)-, -C1-C10alkylene-NH-, C1-C10heteroalkylene- NH-, -C3-C8 carbocyclo-NH-, -O-(C1-C8 alkylene)-NH-, -arylene-NH-, -C1-C10 alkylene- arylene-NH-, -arylene-C1-C10alkylene-NH-, -C1-C10alkylene-(C3-C8carbocyclo)-NH-, -(C3- C8carbocyclo)-C1-C10alkylene-NH-, -C3-C8heterocyclo-NH-, -C1-C10alkylene-(C3-C8heterocyclo)-NH-, -(C3-C8 heterocyclo)-C1-C10 alkylene-NH-, -C1-C10 alkylene-S-, C1-C10 heteroalkylene-S -, -C3-C8carbocyclo-S -, -O-(C1-C8alkylene)-S -, -arylene-S-, -C1-C10alkylene-arylene-S-, -arylene-C1-C10alkylene-S-, -C1-C10alkylene-(C3-C8carbocyclo)-S-, - (C3-C8 carbocyclo)-C1-C10 alkylene-S-, -C3-C8 heterocyclo-S-, -C1-C10 alkylene-(C3-C8 heterocyclo)-S-, or -(C3-C8 heterocyclo)-C1-C10 alkylene-S-; subscript k is an integer ranging from 1 to 36; R17is optionally substituted by a Basic Unit (BU) such as an aminoalkyl moiety, wherein x is an integer of from 1-4 and each Rais independently selected from the groupconsisting of C1-6alkyl and C1-6haloalkyl, or two Ragroups are combined with the nitrogen to which they are attached to form an azetidinyl, pyrrolidinyl or piperidinyl group; and the wavy line indicates the point of covalent attachment to the rest of the Drug-Linker compound.

50. The Drug-Linker compound of claim 48 or claim 49, or a pharmaceutically acceptable salt thereof, wherein the Stretcher Unit Z' is, wherein the wavy lines indicate the point of covalent attachment to the rest of the Drug- Linker compound.

51. The Drug-Linker compound of any one of claims 48-50, or a pharmaceutically acceptable salt thereof, wherein the Connector Unit A is, wherein each R100is independently hydrogen or -C1-C3alkyl; R111is independently selected from the group consisting of hydrogen, p- hydroxybenzyl, methyl, isopropyl, isobutyl, sec-butyl, -CH2OH, -CH(OH)CH3, - CH2CH2SCH3, -CH2CONH2, -CH2COOH, -CH2CH2CONH2, -CH2CH2COOH, - (CH2)3NHC(=NH)NH2, -(CH2)3NH2, -(CH2)3NHCOCH3, -(CH2)3NHCHO, - (CH2)4NHC(=NH)NH2, -(CH2)4NH2, -(CH2)4NHCOCH3, -(CH2)4NHCHO, - (CH2)3NHCONH2, -(CH2)4NHCONH2, -CH2CH2CH(OH)CH2NH2, 2-pyridylmethyl-, 3- pyridylmethyl-, 4-pyridylmethyl-,each subscript c is an independently selected integer from 1 to 10; and the wavy lines indicate attachment of the Connector Unit to the rest of the Drug- Linker compound.

52. The Drug-Linker compound of any one of claims 48-51, or a pharmaceutically acceptable salt thereof, wherein the Connector Unit A isc is an integer ranging from 1 to 6; and the wavy lines indicate the site of attachment to the rest of the Drug-Linker compound or pharmaceutically acceptable salt thereof.

53. The Drug-Linker compound of any one of claims 48-50, or a pharmaceutically acceptable salt thereof, wherein A is a bond.

54. The Drug-Linker compound of any one of claims 48, 49, or 53, or a pharmaceutically acceptable salt thereof, whereinR17is C1-C10 alkylene; A is a bond; and the wavy lines indicate the site of attachment to the rest of the Drug-Linker compound or pharmaceutically acceptable salt thereof.

55. The Drug-Linker compound of any one of claims 48, 49, 53, or 54, wherein Z'-A- is.

56. The Drug-Linker compound of any one of claims 48-55, or a pharmaceutically acceptable salt thereof, wherein X is N or CH and Z1is H.

57. The Drug-Linker compound of any one of claims 48-55, or a pharmaceutically acceptable salt thereof, wherein X is N and Z1is H.

58. The Drug-Linker compound of any one of claims 48-55, or a pharmaceutically acceptable salt thereof, wherein X is O or S and Z1is absent, preferably wherein X is O and Z1is absent.

59. The Drug-Linker compound of any one of claims 48-58, or a pharmaceutically acceptable salt thereof, wherein R2is methyl, R4is -NHSO2CH3or -CH2SO2CH3, R5is H, and R6is H or methyl.

60. The Drug-Linker compound of any one of claims 48-59, or a pharmaceutically acceptable salt thereof, wherein R7and R8are each H, or R7and R8are taken together with the carbon to which they are attached to form a carbonyl.

61. The Drug-Linker compound of any one of claims 48-60, or a pharmaceutically acceptable salt thereof, wherein R3is C3-C8 cycloalkyl, -C1-C10 alkylene-(C3-C8 cycloalkyl), C6-C14 aryl, -C1-C10alkylene-(C6-C14aryl), 5- to 10-membered heteroaryl, or -C1-C10alkylene-(5- to 10- membered heteroaryl).

62. The Drug-Linker compound of any one of claims 48-61, or a pharmaceutically acceptable salt thereof, wherein R3is C3-C8cycloalkyl, -C1-C10alkylene-(C3-C8cycloalkyl), or C6-C14aryl.

63. The Drug-Linker compound of any one of claims 48-62, or a pharmaceutically acceptable salt thereof, wherein R3is cyclohexyl, -CH2-(cyclopropyl), or phenyl.

64. The Drug-Linker compound of any one of claims 48-63, or a pharmaceutically acceptable salt thereof, wherein Q is absent, C(O), NR11, C(O)O, or C(O)NR11; L2is –CH2CH2(OCH2CH2)k–, -C1-C10 alkylene-, -C3-C8 carbocyclo-, -C1-C10 alkylene-(C3-C8 carbocyclo)-, -(C3-C8carbocyclo)-C1-C10alkylene-, -C2-C10alkenylene-, -C2-C10alkenylene- (C3-C8carbocyclo)-, -(C3-C8carbocyclo)-C2-C10alkenylene-, -C2-C10alkynylene-, -C2-C10alkynylene-(C3-C8 carbocyclo)-, or -(C3-C8 carbocyclo)-C2-C10alkynylene-; and R1is OH, COOR12, or NR11.

65. The Drug-Linker compound of any one of claims 48-64, or a pharmaceutically acceptable salt thereof, wherein L1is *-W3-W1-**, *-W3-W2-W3-W1-**, *-W3-W2-W2-W1-**, *-W3- W2-W1-**, *-W3-W2-W3-W2-W1-**, or *-W3-W2-W3-W2-W3-W2-W1-**.

66. The Drug-Linker compound of any one of claims 48-65, or a pharmaceutically acceptable salt thereof, wherein W1is CO or CONR11; W2is, independently at each occurrence, O, NR11, optionally substituted C3-C8cycloalkylene, optionally substituted 3- to 12-membered heterocyclylene, or absent; W3is, independently at each occurrence, O, NR11, optionally substituted C1-C10 alkylene, or absent; andsubscript n is an integer from 1 to 3.

67. The Drug-Linker compound of any one of claims 48-66, or a pharmaceutically acceptable 1salt thereof, wherein L is selected from the group consisting of: ,.

68. The Drug-Linker compound of any one of claims 48, 49, or 53-67, wherein the compound isor a pharmaceutically acceptable salt thereof.

69. A Drug-Linker compound selected from the group consisting of the compounds listed in Table 2, or a pharmaceutically acceptable salt thereof.

70. A Ligand-Drug Conjugate compound, or a pharmaceutically acceptable salt thereof, comprising a Drug Unit of Formula (I'):o u a ( ), wherein: X is CH, N, O, or S; Z1is H or absent; Z2is H; or Z1and Z2are taken together to form a single bond or a C1-C4 alkylene group; provided that when X is O or S, Z1is absent; Y1and Y2are independently CH, CF, or N; Q is absent or C(O), NR11, S, SO2NR11, NR11SO2, O, C(O)O, or C(O)NR11; R1is O, S, COO, SO2, SO2NR11, or NR11; L2is absent or –CH2CH2(OCH2CH2)k–, -C1-C10alkylene-, 2- to 14-membered heteroalkylene-, -C3-C8carbocyclo-, -O(C1-C8alkylene)-, -arylene-, -C1-C10alkylene- arylene-, -arylene-C1-C10 alkylene-, -C1-C10 alkylene-(C3-C8 carbocyclo)-, -(C3-C8 carbocyclo)-C1-C10alkylene-, 3- to 12-membered heterocyclo-, -C1-C10alkylene-( 3- to 12-membered heterocyclo)-, -( 3- to 12-membered heterocyclo)-C1-C10alkylene, - C2-C10alkenylene-, 3- to 14-membered heteroalkenylene-, -O(C2-C8 alkenylene)-, - C2-C10alkenylene-arylene-, -arylene-C2-C10alkenylene-, -C2-C10alkenylene-(C3-C8carbocyclo)-, -(C3-C8carbocyclo)-C2-C10alkenylene-, -C2-C10alkenylene-(3- to 12- membered heterocyclo)-, -(3- to 12-membered heterocyclo)-C2-C10alkenylene, -C2- C10 alkynylene-, 3- to 14-membered heteroalkynylene-, -O(C2-C8 alkynylene)-, -C2- C10alkynylene-arylene-, -arylene-C2-C10alkynylene-, -C2-C10alkynylene-(C3-C8carbocyclo)-, -(C3-C8carbocyclo)-C2-C10alkynylene-, -C2-C10alkynylene-(3- to 12- membered heterocyclo)-, or -(3- to 12-membered heterocyclo)-C2-C10alkynylene, each of which is optionally substituted; subscript k is an integer ranging from 1 to 36,wherein # denotes the point of attachment to the reminder of the Ligand-Drug Conjugate compound; and R2is optionally substituted C1-C6 alkyl; R3is C3-C8cycloalkyl, -C1-C10alkylene-(C3-C8cycloalkyl), C3-C8cycloalkenyl, -C1- C10 alkylene-(C3-C8 cycloalkenyl), C6-C14 aryl, -C1-C10 alkylene-(C6-C14 aryl), 5- to 10- membered heteroaryl, -C1-C10 alkylene-(5- to 10-membered heteroaryl), 3- to 12-membered heterocyclyl, or -C1-C10alkylene (3- to 12-membered heterocyclyl), wherein the C3-C8cycloalkyl, -C1-C10 alkylene-(C3-C8 cycloalkyl), C6-C14 aryl, -C1-C10 alkylene-(C6-C14 aryl), 5- to 10-membered heteroaryl, -C1-C10 alkylene-(5- to 10-membered heteroaryl), 3- to 12- membered heterocyclyl, or -C1-C10alkylene (3- to 12-membered heterocyclyl) are optionally substituted by halo, OH, CN, C1-C6alkyl, or C1-C6haloalkyl; R4is -NHSO2R12or -CH2SO2R12; R5is H or halo; R6is H or optionally substituted C1-C6alkyl; R7and R8are each H, or R7and R8, taken together with the carbon to which they are attached, form a carbonyl or 3- to 6-membered carbocycle; R9, R10a, and R10bare each independently H, halo, optionally substituted C1-C6 alkyl, C3-C8 cycloalkyl, or C1-C6 haloalkyl; L1is a linking group having the structure:** ; wherein W1is C2-C6 alkenylene, C2-C6 alkynylene, optionally substituted 5- to 10- membered heteroarylene, optionally substituted 3- to 12-membered heterocyclene, CO, CONR11, C(O)O, SO2NR11, or absent; W2is, independently at each occurrence, O, S, NR11, -COO-, -OCO-, -CONR11-, - NR11CO-, -SO2NR11-, -NR11SO2-, optionally substituted C3-C8 cycloalkylene, optionally substituted C3-C8cycloalkenylene, optionally substituted C6-C14arylene, optionally substituted 5- to 10-membered heteroarylene, optionally substituted 3- to 12-membered heterocyclylene, or absent; W3is, independently at each occurrence, O, S, NR11, optionally substituted C1-C10alkylene, optionally substituted C2-C10alkenylene, optionally substituted C2-C10alkynylene, optionally substituted 2- to 14-membered heteroalkylene, or absent; subscript n is an integer from 1 to 6;* indicates the point of attachment to * in Formula (I); ** indicates the point of attachment to ** in Formula (I); provided that at least one of W1, W2, and W3is not absent; and R11and R12are, independently of each other and independently at each occurrence, H, halo, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy, or C3-C8 cycloalkyl.

71. The Ligand-Drug Conjugate compound of claim 70, having the formula: L-(Z-A-D)p or a pharmaceutically acceptable salt thereof, wherein L is a Ligand Unit; Z is a Stretcher Unit; A is a bond or a Connector Unit; D is the Drug Unit of Formula (I'); and subscript p is an integer ranging from 1 to 12.

72. The Ligand-Drug Conjugate compound of claim 70, or a pharmaceutically acceptable salt thereof, wherein the Ligand Unit L and the Stretcher Unit Z together are, wherein R17is –CH2CH2(OCH2CH2)k–, -C1-C10alkylene-, C1-C10heteroalkylene-, -C3-C8carbocyclo-, -O-(C1-C8 alkylene)-, -arylene-, -C1-C10 alkylene-arylene-, -arylene-C1-C10 alkylene-, -C1-C10 alkylene-(C3-C8 carbocyclo)-, -(C3-C8 carbocyclo)-C1-C10 alkylene-, -C3-C8heterocyclo-, -C1-C10alkylene-(C3-C8heterocyclo)-, -(C3-C8heterocyclo)-C1-C10alkylene- , -C1-C10 alkylene-C(=O)-, C1-C10 heteroalkylene-C(=O)-, -C3-C8 carbocyclo-C(=O)-, -O- (C1-C8 alkylene)-C(=O)-, -arylene-C(=O)-, -C1-C10 alkylene-arylene-C(=O)-, -arylene-C1-C10 alkylene-C(=O)-, -C1-C10alkylene-(C3-C8carbocyclo)-C(=O)-,-(C3-C8carbocyclo)-C1-C10alkylene-C(=O)-, -C3-C8 heterocyclo-C(=O)-, -C1-C10 alkylene-(C3-C8 heterocyclo)-C(=O)-, - (C3-C8 heterocyclo)-C1-C10 alkylene-C(=O)-, -C1-C10 alkylene-NH-, C1-C10 heteroalkylene- NH-, -C3-C8carbocyclo-NH-, -O-(C1-C8alkylene)-NH-, -arylene-NH-, -C1-C10alkylene- arylene-NH-, -arylene-C1-C10 alkylene-NH-, -C1-C10 alkylene-(C3-C8 carbocyclo)-NH-, -(C3- C8 carbocyclo)-C1-C10 alkylene-NH-, -C3-C8 heterocyclo-NH-, -C1-C10 alkylene-(C3-C8 heterocyclo)-NH-, -(C3-C8heterocyclo)-C1-C10alkylene-NH-, -C1-C10alkylene-S-, C1-C10heteroalkylene-S -, -C3-C8carbocyclo-S -, -O-(C1-C8alkylene)-S -, -arylene-S-, -C1-C10alkylene-arylene-S-, -arylene-C1-C10 alkylene-S-, -C1-C10 alkylene-(C3-C8 carbocyclo)-S-, - (C3-C8 carbocyclo)-C1-C10 alkylene-S-, -C3-C8 heterocyclo-S-, -C1-C10 alkylene-(C3-C8 heterocyclo)-S-, or -(C3-C8heterocyclo)-C1-C10alkylene-S-; subscript k is an integer ranging from 1 to 36; R17is optionally substituted by a Basic Unit (BU) such as an aminoalkyl moiety, wherein x is an integer of from 1-4 and each Rais independently selected from the group consisting of C1-6 alkyl and C1-6 haloalkyl, or two Ragroups are combined with the nitrogen to which they are attached to form an azetidinyl, pyrrolidinyl or piperidinyl group; and the wavy line indicates the point of covalent attachment to the rest of the Ligand-Drug Conjugate compound.

73. The Ligand-Drug Conjugate compound of claim 71 or claim 72, or a pharmaceutically acceptable salt thereof, wherein the Ligand Unit L and the Stretcher Unit Z together arewherein the wavy lines indicate the point of covalent attachment to the rest of the Ligand- Drug Conjugate compound.

74. The Ligand-Drug Conjugate compound of any one of claims 71-73, or a pharmaceutically acceptable salt thereof, wherein the Connector Unit A iswherein each R100is independently hydrogen or -C1-C3 alkyl; R111is independently selected from the group consisting of hydrogen, p- hydroxybenzyl, methyl, isopropyl, isobutyl, sec-butyl, -CH2OH, -CH(OH)CH3, - CH2CH2SCH3, -CH2CONH2, -CH2COOH, -CH2CH2CONH2, -CH2CH2COOH, -(CH2)3NHC(=NH)NH2, -(CH2)3NH2, -(CH2)3NHCOCH3, -(CH2)3NHCHO, -(CH2)4NHC(=NH)NH2, -(CH2)4NH2, - (CH2)4NHCOCH3, -(CH2)4NHCHO, -(CH2)3NHCONH2, -(CH2)4NHCONH2, - CH2CH2CH(OH)CH2NH2, 2-pyridylmethyl-, 3-pyridylmethyl-, 4-pyridylmethyl-,each subscript c is an independently selected integer from 1 to 10; and the wavy lines indicate attachment of the Connector Unit to the rest of the Ligand- Drug Conjugate compound or pharmaceutically acceptable salt thereof.

75. The Ligand-Drug Conjugate compound of any one of claims 71-74, or a pharmaceutically acceptable salt thereof, wherein the Connector Unit A isc is an integer ranging from 1 to 6; and the wavy lines indicate the site of attachment to the rest of the Ligand-Drug Conjugate compound or pharmaceutically acceptable salt thereof.

76. The Ligand-Drug Conjugate compound of any one of claims 71-73, or a pharmaceutically acceptable salt thereof, wherein A is a bond.

77. The Ligand-Drug Conjugate compound of claim 72 or claim 76, or a pharmaceutically acceptable salt thereof, wherein R17is C1-C10alkylene; and A is a bond.

78. The Ligand-Drug Conjugate compound of any one of claims 71-73, 76, or 77, or a pharmaceutically acceptable salt thereof, wherein the Ligand Unit L and Z-A- together are.

79. The Ligand-Drug Conjugate compound of any one of claims 71-78, or a pharmaceutically acceptable salt thereof, wherein X is N or CH and Z1is H.

80. The Ligand-Drug Conjugate compound of any one of claims 71-78, or a pharmaceutically acceptable salt thereof, wherein X is N and Z1is H.

81. The Ligand-Drug Conjugate compound of any one of claims 71-78, or a pharmaceutically acceptable salt thereof, wherein X is O or S and Z1is absent, preferably wherein X is O and Z1is absent.

82. The Ligand-Drug Conjugate compound of any one of claims 71-81, or a pharmaceutically acceptable salt thereof, wherein R2is methyl, R4is -NHSO2CH3 or -CH2SO2CH3, R5is H, and R6is H or methyl.

83. The Ligand-Drug Conjugate compound of any one of claims 71-82, or a pharmaceutically acceptable salt thereof, wherein R7and R8are each H, or R7and R8are taken together with the carbon to which they are attached to form a carbonyl.

84. The Ligand-Drug Conjugate compound of any one of claims 71-83, or a pharmaceutically acceptable salt thereof, wherein R3is C3-C8cycloalkyl, -C1-C10alkylene-(C3-C8cycloalkyl), C6-C14aryl, -C1-C10alkylene-(C6-C14aryl), 5- to 10-membered heteroaryl, or -C1-C10alkylene-(5- to 10-membered heteroaryl).

85. The Ligand-Drug Conjugate compound of any one of claims 71-84, or a pharmaceutically acceptable salt thereof, wherein R3is C3-C8 cycloalkyl, -C1-C10 alkylene-(C3-C8 cycloalkyl), or C6-C14 aryl.

86. The Ligand-Drug Conjugate compound of any one of claims 71-85, or a pharmaceutically acceptable salt thereof, wherein R3is cyclohexyl, -CH2-(cyclopropyl), or phenyl.

87. The Ligand-Drug Conjugate compound of any one of claims 71-86, or a pharmaceutically acceptable salt thereof, wherein Q is absent, C(O), NR11, C(O)O, or C(O)NR11; L2is –CH2CH2(OCH2CH2)k–, -C1-C10 alkylene-, -C3-C8 carbocyclo-, -C1-C10 alkylene-(C3-C8 carbocyclo)-, -(C3-C8carbocyclo)-C1-C10alkylene-, -C2-C10alkenylene-, -C2-C10alkenylene- (C3-C8 carbocyclo)-, -(C3-C8 carbocyclo)-C2-C10alkenylene-, -C2-C10alkynylene-, -C2-C10alkynylene-(C3-C8 carbocyclo)-, or -(C3-C8 carbocyclo)-C2-C10alkynylene-; and R1is OH, COOR12, or NR11.

88. The Ligand-Drug Conjugate compound of any one of claims 71-87, or a pharmaceutically acceptable salt thereof, wherein L1is *-W3-W1-**, *-W3-W2-W3-W1-**, *-W3-W2-W2-W1- **, *-W3-W2-W1-**, *-W3-W2-W3-W2-W1-**, or *-W3-W2-W3-W2-W3-W2-W1-**.

89. The Ligand-Drug Conjugate compound of any one of claims 71-88, or a pharmaceutically acceptable salt thereof, wherein W1is CO or CONR11;W2is, independently at each occurrence, O, NR11, optionally substituted C3-C8cycloalkylene, optionally substituted 3- to 12-membered heterocyclylene, or absent; W3is, independently at each occurrence, O, NR11, optionally substituted C1-C10 alkylene, or absent; and subscript n is an integer from 1 to 3.

90. The Drug-Linker compound of any one of claims 48-66, or a pharmaceutically acceptable 1salt thereof, wherein L is selected from the group consisting of: ,.

91. The Ligand-Drug Conjugate compound of any one of claims 71, 72, or 76-90, wherein the compound is,, or a pharmaceutically acceptable salt thereof.

92. The Ligand-Drug Conjugate compound of any one of claims 71-91, wherein p is an integer ranging from 2 to 8.

93. The Ligand-Drug Conjugate compound of any one of claims 71-92, wherein p is 4.

94. A Ligand-Drug Conjugate compound selected from the group consisting of the compounds listed in Table 4, or a pharmaceutically acceptable salt thereof, and p is an integer ranging from 1 to 12.

95. The Ligand-Drug Conjugate compound of any one of claims 70-94, wherein the ligand is an antibody.

96. The Ligand-Drug Conjugate compound of claim 95, wherein the antibody is a monoclonal antibody.

97. A Released Drug-Linker cysteine adduct, wherein the Released Drug-Linker cysteine adduct is selected from the group consisting of the compounds listed in Table 3, or a pharmaceutically acceptable salt thereof.

98. A pharmaceutical composition comprising the Ligand-Drug Conjugate compound of any one of claims 70-96 and a pharmaceutically acceptable excipient.

99. The pharmaceutical composition of claim 98, wherein the composition comprises a plurality of Ligand-Drug Conjugate compounds with an average value of p from 2 to 8.

100. The pharmaceutical composition of claim 99, wherein the average value of p is about 4.

101. The pharmaceutical composition claim 99, wherein the average value of p is from 3.5 to 4.

5.

102. A method of treating cancer comprising administering a therapeutically effective amount of the Ligand-Drug Conjugate compound of any one of claims 70-96, or a pharmaceutically acceptable salt thereof, to a subject in need thereof.

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