Oxoadenine TLR7 agonist compounds and conjugates

Abstract

The present disclosure is related to oxoadenine TLR7 agonists and conjugates, pharmaceutical compositions thereof, and the use of the agonists, conjugates, and pharmaceutical compositions to treat diseases and disorders, including inflammatory diseases and disorders, cell proliferation, and cancer.

Description

Attorney Docket No.108843.00582 SU-0514WO OXOADENINE TLR7 AGONIST COMPOUNDS AND CONJUGATES CROSS-REFERENCE TO RELATED APPLICATIONS

[0001] This application claims priority to Provisional Patent Application No.63 / 661,347 filed June 18, 2024, the entirety of which is incorporated by reference for all purposes. FIELD

[0002] The present disclosure is related to oxoadenine TLR7 agonists and conjugates, pharmaceutical compositions thereof, and the use of the agonists, conjugates, and pharmaceutical compositions to treat diseases and disorders, including inflammatory diseases and disorders, cell proliferation, and cancer. BACKGROUND

[0003] The innate immune system recognizes structurally conserved pathogen-associated molecular patterns via Toll-like receptors (TLRs), which are usually expressed on immune cells such as macrophages and dendritic cells. Activation of TLRs induces innate (rapid, non- specific) and / or adaptive (slower, more specific) immune responses such as induction of cytokines and / or co-stimulation of phagocytes and / or activation of the T-cell response. Among TLRs, TLR3, 7, 8 and 9 are expressed in the intracellular endosomes, while others (TLR1, 2, 4, 5, 6, 10, and 11) are localized on the plasmalemma. Each TLR elicits specific cellular responses to pathogens owing to differential usage of intracellular adapter proteins. TLR7 is an intracellular receptor expressed on endosomal membranes and is closely related to TLR8. TLR7 recognizes nucleosides and nucleotides from intracellular pathogens. Activation of TLR7 can induce Type 1 interferon and an inflammatory response. Saitoh, S-I et al., Nature Communications 2017, 8, Article number: 1592.

[0004] Malignant cells exploit the natural immunomodulatory functions of TLRs to foster their survival, invasion, and evasion of anti-tumor immune responses. Current research has demonstrated context-specific roles for TLR activation in different malignancies, promoting disease progression in certain instances while limiting cancer growth in others. Braunstein M. J. et al., Target Oncol.2018, 13(5), 583-598.

[0005] Some TLR agonists have been found to induce antitumor activity by indirectly activating the tolerant host immune system to destroy cancer cells. The use of TLR7 agonists, such as imiquimod, loxoribine, CL264 (a 9-benzyl-8 hydroxyadenine derivative containing a glycine on the benzyl group), ssRNA40, R848, and SM-276001, either alone or as vaccine 1 1104675906\1\AMERICASAttorney Docket No.108843.00582 SU-0514WO adjuvants, induces potent immunity leading to antitumor therapeutic efficacy in several murine models. Currently, three TLR agonists are FDA approved, including imiquimod for primary superficial basal cell carcinoma (sBCC). TLR7 agonist injection reduces tumor progression and modulates the systemic and intratumoral immune response in colon, renal, and mammary carcinomas. Antitumor effects associated with TLR7 stimulation have been demonstrated in human skin cancers and cervical intraepithelial neoplasia. Dajon, M. et al., Oncoimmunology.2015, 4(3), e991615.

[0006] TLR7 targeting may provide new treatment options for both anti-inflammatory, and / or anti-cancer therapy. There is a need in the field for new treatments for inflammatory and / or immunomodulatory diseases, particularly cancer. SUMMARY

[0007] In one aspect, provided herein is a compound of Formula (I):or a pharmaceutically acceptable salt, stereoisomer, or tautomer thereof; wherein: L1is C1-6 alkylene, C2-6 alkenylene, or C2-6 alkynylene, each of which is optionally substituted with one or more substituents independently selected from R5; L2is selected from -O-, -NR2-, C1-6alkylene, C2-6alkenylene, C2-6alkynylene, -O-(C1-6alkylene)-, and -NR2-(C1-6alkylene)- wherein the alkylene, either alone or part of another group, is optionally substituted with one or more one or more substituents independently selected from R5; R1is C1-10alkyl, C2-6alkenyl, or C2-6alkynyl, each of which is optionally substituted with one or more substituents independently selected from R5; R2is independently hydrogen or C1-6 alkyl; X1is bond, -O-, or -NR2-; Ring A is either (a) a bicyclic heterocycle optionally substituted with one or more R8; (b) a 3- to 5-membered heterocycle optionally substituted with one or more R4aand further optionally substituted with one or more R8; or (c) a 6- to 12-membered heterocycle substituted with R4band optionally substituted with one or more R8; 2 1104675906\1\AMERICASAttorney Docket No.108843.00582 SU-0514WO Ring B is arylene or heteroarylene, each of which is optionally substituted with one or more R8; R4ais a 3- to 12-membered heterocycle optionally substituted with one or more R8; R4bis a bicyclic heterocycle optionally substituted with one or more R8; R5is independently selected from halogen, -OR6, -SR6, -C(O)N(R6)(R7), -N(R6)C(O)R7, -N(R6)C(O)N(R6)(R7), -N(R6)(R7), -C(O)R6, -C(O)OR6, -OC(O)R6, -NO2, =O, =S, =N(R6), -CN, C3-12carbocycle, and 3- to 12-membered heterocycle; R6and R7are independently selected at each occurrence from hydrogen, C1-10 alkyl, C2-10 alkenyl, C2-10 alkynyl, C3-12 carbocycle, and 3- to 12-membered heterocycle each of which, except hydrogen, is optionally substituted with one or more R9; R8is independently selected from halogen, -OR6, -SR6, -C(O)N(R6)(R7), -N(R6)C(O)R7, -N(R6)C(O)N(R6)(R7), -N(R6)(R7), -C(O)R6, -C(O)OR6, -OC(O)R6, -NO2, =O, =S, =N(R6), -CN, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C3-12 carbocycle, and 3- to 12-membered heterocycle wherein the C1-6alkyl, C2-6alkenyl, C2-6alkynyl, C3-12carbocycle, and 3- to 12-membered heterocycle are optionally substituted with one or more R9; R9is independently selected at each occurrence from halogen, -CN, -NO2, -OH, -NR9aR9b, -C(O)NR9aR9b, =O, =S, C1-10alkyl, C2-10alkenyl, C2-10alkynyl, C3-12carbocycle, 3- to 12- membered heterocycle, and C1-10haloalkyl; and R9aand R9bare independently selected at each occurrence from hydrogen, C1-10 alkyl, C2-10alkenyl, C2-10alkynyl, C3-12carbocycle, and 3- to 12-membered heterocycle.

[0008] In one embodiment, the compound of Formula (I) is a compound of Formula (IA):or a pharmaceutically acceptable salt, stereoisomer, or tautomer thereof; wherein: X2and X3are independently selected from N and CR3; and R3is independently hydrogen, –OR6, -SR6, -C(O)N(R6)(R7), -N(R6)C(O)R7, -N(R6)C(O)N(R6)(R7), -N(R6)(R7), -C(O)R6, -C(O)OR6, -OC(O)R6, -NO2, or -CN.

[0009] Also provided herein are linker-payloads comprising compounds of Formula (I) or Formula (IA) wherein the compound of Formula (I) or Formula (IA) is linked to a reactive linker group (RG) optionally via a linker. 3 1104675906\1\AMERICASAttorney Docket No.108843.00582 SU-0514WO

[0010] In one embodiment, the linker-payload is of Formula (LP-I):or a pharmaceutically acceptable salt, stereoisomer, or tautomer thereof; wherein: L is a linker; RG is a reactive group; and L1, L2, R1, R2, X1, Ring A, Ring B, R4a, R4b, R5, R6, R7, R8, R9, R9a, and R9bare as defined herein.

[0011] In one embodiment, the linker-payload of Formula (LP-I) is a linker-payload of Formula (LP-II) wherein -L- is -W1-W2-SG-HP-:or a pharmaceutically acceptable salt, stereoisomer, or tautomer thereof; wherein: SG is absent or a divalent spacer group; W1is absent,wherein the -NH- is bound to W2and eachindicates a point of attachment to the rest of the formula; L3is independently a bond or C1-6 alkylene optionally substituted with one, two, or three substituents selected from halogen, C1-6 alkyl, haloC1-6 alkyl, hydroxyl, amino, C1-6 alkylamino, and C1-6alkoxy; R11is independently hydrogen or C1-6alkyl; R12is independently a residue of an amino acid sidechain; 4 1104675906\1\AMERICASAttorney Docket No.108843.00582 SU-0514WO w is an integer selected from 0, 1, and 2; W2is absent, an amino acid residue, or a peptide residue wherein the amino acid residue or peptide residue is optionally substituted with a HP1group; HP is absent or a divalent hydrophilic group; HP1, when present, is a monovalent hydrophilic group; each RAis independently, at each occurrence, C1-6 alkyl optionally substituted with one, two, or three substituents selected from halogen, haloC1-6alkyl, hydroxyl, amino, alkylC1-6amino, and C1-6 alkoxy; each O-Su is independently, at each occurrence, a release trigger group; RG is a reactive group; each y is an integer independently selected from 0, 1, and 2; each z is an integer independently selected from 0 and 1; and L1, L2, R1, R2, X1, Ring A, Ring B, R4a, R4b, R5, R6, R7, R8, R9, R9a, and R9bare as defined herein.

[0012] In one embodiment, the linker-payload of Formula (LP-II) is a linker-payload of Formula (LP-IIA):or a pharmaceutically acceptable salt, stereoisomer, or tautomer thereof; wherein X2, X3, and R3are as defined in Formula (I-A).

[0013] In another aspect, provided herein are conjugates comprising a compound of Formula (I) or Formula (IA) wherein the compound of Formula (I) or Formula (IA) is linked to a COMP optionally via a linker wherein COMP is a macromolecule. In one embodiment, the COMP is an antibody or antigen binding fragment thereof. In one embodiment, the COMP is an antibody chain.

[0014] In one embodiment, the conjugate is of Formula (CONJ-I):5 1104675906\1\AMERICASAttorney Docket No.108843.00582 SU-0514WO or a pharmaceutically acceptable salt, stereoisomer, tautomer, or catabolite thereof; wherein: COMP is a macromolecule; L is a linker; x is an integer selected from 1 to 30; and L1, L2, R1, R2, X1, Ring A, Ring B, R4a, R4b, R5, R6, R7, R8, R9, R9a, and R9bare as defined herein.

[0015] In one embodiment, the conjugate of Formula (CONJ-I) is a conjugate of Formula (CONJ-II) wherein -L- is -W1-W2-SG-HP-RL-:or a pharmaceutically acceptable salt, stereoisomer, tautomer, or catabolite thereof; wherein RL is a reactive linker residue; and L1, L2, L3, R1, R2, X1, Ring A, Ring B, R4a, R4b, R5, R6, R7, R8, R9, R9a, R9b, R11, R12, SG, W1, W2, HP, HP1, RA, O-Su, x, w, y, and z are as defined herein.

[0016] In one embodiment, the conjugate of Formula (CONJ-II) is a conjugate of Formula (CONJ-IIA):or a pharmaceutically acceptable salt, stereoisomer, tautomer, or catabolite thereof; wherein X2, X3, and R3are as defined in Formula (I-A).

[0017] In one embodiment, the conjugate is of Formula (CONJ-III):or a pharmaceutically acceptable salt, stereoisomer, tautomer, or catabolite thereof; 6 1104675906\1\AMERICASAttorney Docket No.108843.00582 SU-0514WO wherein: CY is a residue of cytotoxic agent; Lais a first linker; Lbis a second linker; xx is an integer selected from 1 to 30; and COMP, L1, L2, R1, R2, X1, Ring A, Ring B, R4a, R4b, R5, R6, R7, R8, R9, R9a, R9b, and x are as defined herein.

[0018] In one embodiment, the conjugate of Formula (CONJ-III) is a conjugate of Formula(CONJ-IV) or a pharmaceutically acceptable salt, stereoisomer, tautomer, or catabolite thereof; wherein RL01is a reactive linker residue; SG01is absent or a divalent spacer group; Y is –X1a-C1-6 alkylene-[X1a-C1-6 alkylene]a1-[X1a]b1–, –X1a-C2-6 alkenylene-[X1a-C2-6 alkenylene]a1-[X1a]b1–, or –X1a-C2-6alkynylene-[X1a-C2-6alkynylene]a1-[X1a]b1–, wherein at least one C1-6 alkylene, C2-6 alkenylene, or C2-6 alkynylene in Y is substituted with one or more substituents selected from R70; and -[X1a]b1- is attached to RL01; and wherein the C1-6alkylene, C2-6alkenylene, or C2-6alkynylene in Y is optionally substituted with one or more substituents selected from R71; R70is –C1-6 alkylene-X2a-[C1-6 alkylene]c1-HP2, –C2-6 alkenylene-X2a-[C2-6 alkenylene]c1-HP2, or –C2-6alkynylene-X2a-[C2-6alkynylene]c1-HP2, wherein each C1-6alkylene, C2-6alkenylene, or C2-6alkynylene of R70is optionally substituted with one or more 7 1104675906\1\AMERICASAttorney Docket No.108843.00582 SU-0514WO substituents selected from halogen, -CN, -NO2, -OH, -NR60R61, -C(O)NR60R61, -C(O)-, -C(S)-, -C(O)OCH2C6H5, -NHC(O)OCH2C6H5, C1-10 alkyl, C2-10 alkenyl, C2-10 alkynyl, C3-12 carbocycle, 3- to 12-membered heterocycle, and C1-10 haloalkyl; R71is independently selected from halogen, -CN, -NO2, -OH, -NR60R61, -C(O)NR60R61, -C(O)-, -C(S)-, -C(O)OCH2C6H5, -NHC(O)OCH2C6H5, C1-10 alkyl, C2-10 alkenyl, C2-10 alkynyl, C3-12 carbocycle, 3- to 12-membered heterocycle, and C1-10 haloalkyl; X1aand X2aare independently selected from –N(R60)–, –C(O)–, and –N(R60)C(O)–; HP2is a monovalent hydrophilic group; R60and R61are independently selected at each occurrence from hydrogen, C1-10 alkyl, C2-10alkenyl, C2-10alkynyl, C3-12carbocycle, 3- to 12-membered heterocycle, and C1-10haloalkyl; a1 is an integer selected from 0, 1, 2, and 3; b1 is an integer selected from 0 and 1; c1 is an integer selected from 0 and 1; and CY, L1, L2, L3, R1, R2, X1, Ring A, Ring B, R4a, R4b, R5, R6, R7, R8, R9, R9a, R9b, R11, R12, SG, W1, W2, HP, HP1, RA, RL, O-Su, x, xx, w, y, and z are as defined herein.

[0019] In one embodiment, the conjugate of Formula (CONJ-IV) is a conjugate of Formula (CONJ-IVA):(CONJ-IVA) or a pharmaceutically acceptable salt, stereoisomer, tautomer, or catabolite thereof; CY, L1, L2, L3, R1, R2, X1, X1a, X2a, HP2, Ring A, Ring B, R4a, R4b, R5, R6, R7, R8, R9, R9a, R9b, R11, R12, SG, W1, W2, HP, HP1, RA, RL, RL01, SG01, Y, O-Su, x, xx, w, y, and z are as defined herein. 8 1104675906\1\AMERICASAttorney Docket No.108843.00582 SU-0514WO

[0020] In one embodiment, the conjugate of Formula (CONJ-IV) is a conjugate of Formula (CONJ-IVB):(CONJ-IVB) or a pharmaceutically acceptable salt, stereoisomer, tautomer, or catabolite thereof; CY, L1, L2, L3, R1, R2, X1, X1a, X2a, HP2,Ring A, Ring B, R4a, R4b, R5, R6, R7, R8, R9, R9a, R9b, R11, R12, SG, W1, W2, HP, HP1, RA, RL, RL01, SG01, Y, O-Su, x, xx, w, y, and z are as defined herein.

[0021] Following administration of conjugates of Formula (CONJ-I)-(CONJ-IVA), in certain embodiments, the conjugates are cleaved by enzymatic and chemical processes to release payloads, for example a compound of Formula (I) and (IA), and catabolites. Therefore, in another aspect, provided herein are catabolites of conjugates of Formula (CONJ-I)-(CONJ- IVB), for example a catabolite of (CA-I), (CA-II), or (CA-IIA):9 1104675906\1\AMERICASAttorney Docket No.108843.00582 SU-0514WOwherein RL' is a residue resulting from the catabolism of -RL-COMP; and L1, L2, L3, R1, R2, X1, Ring A, Ring B, R4a, R4b, R5, R6, R7, R8, R9, R9a, R9b, R11, R12, SG, W1, W2, HP, HP1, RA, O-Su, w, y, and z are as defined herein.

[0022] In one embodiment

[0023] The present disclosure provides at least the following embodiments: a) A compound of Formula (I) or Formula (IA) or a pharmaceutically acceptable salt or tautomer thereof; b) A compound selected from the compounds of Table A or a pharmaceutically acceptable salt, stereoisomer, or tautomer thereof; c) A conjugate compound of Formula (CONJ-I), (CONJ-II), or (CONJ-IIA) or a pharmaceutically acceptable salt, stereoisomer, tautomer, or catabolite thereof; d) A conjugate compound of Formula (CONJ-III), (CONJ-IV), (CONJ-IVA), or (CONJ- IVB) or a pharmaceutically acceptable salt, stereoisomer, tautomer, or catabolite thereof; e) A conjugate compound selected from the conjugate compounds of Table C or Table C-1 or a pharmaceutically acceptable salt, stereoisomer, or tautomer thereof; f) A conjugate compound selected from the conjugate compounds of Table C-2 or a pharmaceutically acceptable salt, stereoisomer, or tautomer thereof; g) A pharmaceutical composition comprising a compound of any one of (a)-(f) and a pharmaceutically acceptable excipient, diluent, or carrier; h) A linker-payload compound of Formula (LP-I), (LP-II), (LP-IIA) or a pharmaceutically acceptable salt, stereoisomer, or tautomer thereof; i) A linker-payload selected from the compounds of Table B or Table B-1 or a pharmaceutically acceptable salt, stereoisomer, or tautomer thereof; 10 1104675906\1\AMERICASAttorney Docket No.108843.00582 SU-0514WO j) A method for promoting the activation of Toll-like receptor 7 in a subject in need thereof comprising administering a therapeutically effective amount of a compound of (a) or (b), a conjugate compound of any one of (c)-(f), or a pharmaceutical composition of (g); k) A method of treating or preventing a disease, disorder, or condition in a subject in need thereof comprising administering a therapeutically effective amount of a compound of (a) or (b), a conjugate compound any one of (c)-(f), or a pharmaceutical composition of (g); l) The method of (k) wherein the disease or disorder is a cellular proliferative disorder, including, but not limited to cancer; m) The method of (l) wherein the cancer is selected from acute myeloid leukemia, breast cancer, colorectal cancer, glioma, head and neck squamous cell carcinoma, lung cancer, including non-small cell lung cancer, head and neck cancer, lymphoma, including a malignant lymphoma, melanoma, nasopharyngeal carcinoma, ovary cancer, pancreatic cancer, prostate cancer, urothelial cancer, and tongue squamous cell carcinoma; n) The method of (k) wherein the disease or disorder is an inflammatory disease, disorder, or condition; o) A method of inducing or modulating the immune system in a subject in need thereof comprising administering a therapeutically effective amount of a compound of (a) or (b), a conjugate compound of any one of (c)-(f), or a pharmaceutical composition of (g); p) A method of treating abnormal cellular proliferation in a subject in need thereof comprising administering a therapeutically effective amount of a compound of (a) or (b), a conjugate compound of any one of (c)-(f), or a pharmaceutical composition of (g); q) The method of (p) wherein the abnormal cellular proliferation is cancer; r) The method of any one of (j)-(q), further comprising administering an additional therapeutic agent; s) The method of (r) wherein the additional therapeutic agent is a chemotherapeutic agent, hormonal agent, antitumor agent, immunostimulatory agent, immunomodulator, an immunotherapeutic agent, or combination thereof; t) The use of a therapeutically effective amount of a compound of (a) or (b), a conjugate compound of any one of (c)-(f), or a pharmaceutical composition of (g) for promoting the activation of Toll-like receptor 7 in a subject in need thereof; u) The use of a therapeutically effective amount of a compound of (a) or (b), a conjugate compound of any one of (c)-(f), or a pharmaceutical composition of (g) for treating or preventing a disease, disorder, or condition in a subject in need thereof; 11 1104675906\1\AMERICASAttorney Docket No.108843.00582 SU-0514WO v) The use of (u) wherein the disease or disorder is a cellular proliferative disorder, including, but not limited to cancer; w) The use of (v) wherein the cancer is selected from acute myeloid leukemia, breast cancer, colorectal cancer, glioma, head and neck squamous cell carcinoma, lung cancer, including non-small cell lung cancer, head and neck cancer, lymphoma, including a malignant lymphoma, melanoma, nasopharyngeal carcinoma, ovary cancer, pancreatic cancer, prostate cancer, urothelial cancer, and tongue squamous cell carcinoma; x) The use of (u) wherein the disease or disorder is an inflammatory disease, disorder, or condition; y) The use of a therapeutically effective amount of a compound of (a) or (b), a conjugate compound of any one of (c)-(f), or a pharmaceutical composition of (g) for inducing or modulating the immune system in a subject in need thereof; z) The use of a therapeutically effective amount of a compound of (a) or (b), a conjugate compound of any one of (c)-(f), or a pharmaceutical composition of (g) for treating abnormal cellular proliferation in a subject in need thereof; aa) The use of (z) wherein the abnormal cellular proliferation is cancer; bb) The use of any one of (t)-(aa), further comprising administering an additional therapeutic agent; cc) The use of (bb) wherein the additional therapeutic agent is a chemotherapeutic agent, hormonal agent, antitumor agent, immunostimulatory agent, immunomodulator, an immunotherapeutic agent, or combination thereof; dd) A kit comprising a therapeutically effective amount of a compound of (a) or (b), a conjugate compound of any one of (c)-(f), or a pharmaceutical composition of (g) and instructions for use of the compound; ee) A method of producing a conjugate compound of (c) or (e) comprising contacting a linker-payload of (h) or (i) with COMP under conditions suitable for conjugation; ff) A method of producing a conjugate compound of (d) or (f) comprising (1) contacting a linker-payload of (h) or (i) with COMP under conditions suitable for conjugation and (2) contacting a linker-payloadwherein RG, Y, SG01, Su, and CY 12 1104675906\1\AMERICASAttorney Docket No.108843.00582 SU-0514WO are as defined herein with the COMP conjugated to the linker-payload of (h) or (i) under conditions suitable for conjugation; gg) A catabolite of Formula (CA-I), (CA-II), or (CA-II); and hh) The catabolite of (dgg) wherein the catabolite is selected from Table D or Table D-1. BRIEF DESCRIPTION OF FIGURES

[0024] FIG.1A is the dose response curve of the effect of select compounds of Table 1 on the HEK293-human TLR7 cell line.

[0025] FIG.1B is the dose response curve of the effect of select compounds of Table 1 on the HEK293-human TLR8 cell line.

[0026] FIG.1C is the dose response curve of the effect of select compounds of Table 1 on the HEK293-mouse TLR7 cell line.

[0027] FIG.1D is the dose response curve of the effect of select compounds of Table 1 on HEK 293-Blue™ Null cells.

[0028] FIG.2A is a graph showing the effect of Compound 1 and Compound 2 on CAOV3 cells co-cultured with human PBMCs.

[0029] FIG.2B is a graph showing that Compound 1 and Compound 2 induce activation of monocytes.

[0030] FIG.2C is a graph showing that Compound 1 and Compound 2 induce activation of CD4+ cells.

[0031] FIG.2D is a graph showing that Compound 1 and Compound 2 induce activation of CD8+ T cells.

[0032] FIG.2E is a graph showing that Compound 1 and Compound 2 induce activation of B cells.

[0033] FIG.2F is a graph showing that Compound 1 and Compound 2 induce activation of NK cells.

[0034] FIG.3A is a graph showing that Conjugates 2-6 induce CAOV3 cell death.

[0035] FIG.3B is a graph showing that Conjugates 2-6 induce activation of monocytes.

[0036] FIG.3C is a graph showing that Conjugates 2-6 induce activation of DC.

[0037] FIG.3D is a graph showing that Conjugates 2-6 induce activation of B cells.

[0038] FIG.3E is a graph showing that Conjugates 2-6 induce activation of NK cells.

[0039] FIG.3F is a graph showing that Conjugates 2-6 induce activation of CD4+ cells.

[0040] FIG.3G is a graph showing that Conjugates 2-6 induce activation of CD8+ T cells. 13 1104675906\1\AMERICASAttorney Docket No.108843.00582 SU-0514WO DETAILED DESCRIPTION I. Definitions

[0041] When referring to the compounds provided herein, the following terms have the following meanings unless indicated otherwise. Unless defined otherwise, all technical and scientific terms used herein have the same meaning as is commonly understood by one of ordinary skill in the art. In the event that there is a plurality of definitions for a term herein, those in this section prevail unless stated otherwise.

[0042] As used herein, the singular forms “a,” “an,” and “the” include the plural referents unless the context clearly indicates otherwise.

[0043] The term “about” indicates and encompasses an indicated value and a range above and below that value. In certain embodiments, the term “about” indicates the designated value ± 10%, ± 5%, or ± 1%. In certain embodiments, the term “about” indicates the designated value ± one standard deviation of that value. In certain embodiments, for example, logarithmic scales (e.g., pH), the term “about” indicates the designated value ± 0.3, ±0.2, or ± 0.1.

[0044] When referring to the compounds provided herein, the following terms have the following meanings unless indicated otherwise. Unless defined otherwise, all technical and scientific terms used herein have the same meaning as is commonly understood by one of ordinary skill in the art. In the event that there is a plurality of definitions for a term herein, those in this section prevail unless stated otherwise.

[0045] “Alkoxy” and “alkoxyl,” refer to the group –OR′′ where R′′ is alkyl or cycloalkyl. Alkoxy groups include, in certain embodiments, methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, tert-butoxy, sec-butoxy, n-pentoxy, n-hexoxy, 1,2-dimethylbutoxy, and the like.

[0046] The term “alkoxyamine,” as used herein, refers to the group -alkylene-O-NH2, wherein alkylene is as defined herein. In some embodiments, alkoxyamine groups can react with aldehydes to form oxime residues. Examples of alkoxyamine groups include -CH2CH2-O-NH2, -CH2-O-NH2, and -O-NH2.

[0047] The term “alkyl,” as used herein, unless otherwise specified, refers to a saturated straight or branched hydrocarbon. In certain embodiments, the alkyl group is a primary, secondary, or tertiary hydrocarbon. In certain embodiments, the alkyl group includes one to ten carbon atoms (i.e., C1to C10alkyl). In certain embodiments, the alkyl is a lower alkyl, for example, C1-6alkyl, and the like. In certain embodiments, the alkyl group is selected from the group consisting of methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, t-butyl, pentyl, isopentyl, neopentyl, hexyl, isohexyl, 3-methylpentyl, 2,2-dimethylbutyl, and 2,3- 14 1104675906\1\AMERICASAttorney Docket No.108843.00582 SU-0514WO dimethylbutyl. In certain embodiments, “substituted alkyl” refers to an alkyl substituted with, for example, one, two, or three groups independently selected from a halogen (e.g., fluoro (F), chloro (Cl), bromo (Br), or iodo (I)), alkyl, -CN, -NO2, amido, -C(O)-, -C(S)-, ester, carbamate, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, dialkylamino, haloalkyl, hydroxyl, amino, alkylamino, and alkoxy. In some embodiments, alkyl is unsubstituted.

[0048] The term “alkylene,” as used herein, unless otherwise specified, refers to a divalent alkyl group, as defined herein. “Substituted alkylene” refers to an alkylene group substituted as described herein for alkyl. In some embodiments, alkylene is unsubstituted.

[0049] “Alkenyl” refers to an olefinically unsaturated hydrocarbon group, in certain embodiments, having up to about eleven carbon atoms or from two to six carbon atoms (e.g., “lower alkenyl”), which can be straight-chained or branched, and having at least one or from one to two sites of olefinic unsaturation. “Substituted alkenyl” refers to an alkenyl group substituted as described herein for alkyl.

[0050] “Alkenylene” refers to a divalent alkenyl as defined herein. Lower alkenylene is, for example, C2-C6-alkenylene.

[0051] “Alkynyl” refers to acetylenically unsaturated hydrocarbon groups, in certain embodiments, having up to about eleven carbon atoms or from two to six carbon atoms (e.g., “lower alkynyl”), which can be straight-chained or branched, and having at least one or from one to two sites of acetylenic unsaturation. Non-limiting examples of alkynyl groups include acetylene (-C≡CH), propargyl (-CH2C≡CH), and the like. “Substituted alkynyl” refers to an alkynyl group substituted as described herein for alkyl.

[0052] “Alkynylene” refers to a divalent alkynyl as defined herein. Lower alkynylene is, for example, C2-C6-alkynylene.

[0053] “Amino” refers to -NH2.

[0054] The term “aminoalkyl,” as used herein, and unless otherwise specified, refers to an alkyl group, as defined herein, which is substituted with one or more amino groups. In some embodiments, the aminoalkyl is an alkyl group substituted with one -NH2group (e.g., -R′(NH2) wherein R′ is alkyl as defined herein).

[0055] The term “alkylamino,” as used herein, and unless otherwise specified, refers to the group –NHR′′ where R′′ is, for example, C1-10alkyl, C2-10 alkenyl, C2-10 alkynyl, C3-12 carbocycle, 3- to 12-membered heterocycle, C1-10haloalkyl, and the like as defined herein. In certain embodiments, alkylamino is C1-6alkylamino.

[0056] The term “dialkylamino,” as used herein, and unless otherwise specified, refers to the group –NR′′R′′ where each R′′ is independently C1-10alkyl, as defined herein. In certain 15 1104675906\1\AMERICASAttorney Docket No.108843.00582 SU-0514WO embodiments, dialkylamino is, for example, di-C1-6alkylamino, C2-10alkenyl, C2-10alkynyl, C3-12 carbocycle, 3- to 12-membered heterocycle, C1-10 haloalkyl, and the like.

[0057] The term “aryl,” as used herein, and unless otherwise specified, refers to phenyl, biphenyl, or naphthyl. The term includes both substituted and unsubstituted moieties. An aryl group can be substituted with any described moiety including, but not limited to, one or more moieties (e.g., in some embodiments one, two, or three moieties) selected from the group consisting of halogen (e.g., fluoro (F), chloro (Cl), bromo (Br), or iodo (I)), alkyl, haloalkyl, hydroxyl, amino, alkylamino, arylamino, alkoxy, aryloxy, nitro, cyano, sulfonic acid, sulfate, phosphonic acid, phosphate, and phosphonate, wherein each moiety is independently either unprotected, or protected as necessary, as would be appreciated by those skilled in the art (see, e.g., Greene, et al., Protective Groups in Organic Synthesis, John Wiley and Sons, Second Edition, 1991); and wherein the aryl in the arylamino and aryloxy substituents are not further substituted.

[0058] The term “arylamino,” as used herein, and unless otherwise specified, refers to an - NR′R′′ group where R′ is hydrogen or C1-C6-alkyl; and R′′ is aryl, as defined herein.

[0059] The term “arylene,” as used herein, and unless otherwise specified, refers to a divalent aryl group, as defined herein.

[0060] The term “aryloxy,” as used herein, and unless otherwise specified, refers to an -OR group where R is aryl, as defined herein.

[0061] “Alkarylene” refers to an arylene group, as defined herein, wherein the aryl ring is substituted with one or two alkyl groups. “Substituted alkarylene” refers to an alkarylene, as defined herein, where the arylene group is further substituted, as defined herein for aryl.

[0062] “Aralkylene” refers to a -CH2-arylene-, -arylene-CH2-, or -CH2-arylene-CH2- group, where arylene is as defined herein. “Substituted aralkylene” refers to an aralkylene, as defined herein, where the aralkylene group is substituted, as defined herein for aryl.

[0063] “Carboxyl” or “carboxy” refers to -C(O)OH or -COOH.

[0064] The term “carbocycle” as used herein, unless otherwise specified, refers to a saturated, unsaturated, or aromatic ring in which all atoms of the ring are carbon. In certain embodiments, the “carbocycle” group may be saturated, and / or bridged, and / or non-bridged, and / or a fused bicyclic group, and / or a spirocyclic bicyclic group. In certain embodiments, the “carbocycle” group includes three to ten carbon atoms (i.e., C3to C10cycloalkyl). In some embodiments, the “carbocycle” has from three to fifteen carbons (C3-15), from three to ten carbons (C3-10), from three to seven carbons (C3-7), or from three to six carbons (C3-C6) (i.e., “lower cycloalkyl”). In certain embodiments, the “carbocycle” group is cyclopropyl, 16 1104675906\1\AMERICASAttorney Docket No.108843.00582 SU-0514WO cyclobutyl, cyclopentyl, cyclohexyl, cyclohexylmethyl, cycloheptyl, bicyclo[2.1.1]hexyl, bicyclo[2.2.1]heptyl, decalinyl, or adamantyl. Exemplary “carbocycles” include cyclopentyl, cyclohexyl, cyclohexenyl, adamantyl, phenyl, indanyl, and naphthyl. “Carbocycle” includes 3- to 10-membered monocyclic rings, 6- to 12-membered bicyclic rings, and 6- to 12- membered bridged rings. Each ring of a bicyclic carbocycle may be selected from saturated, unsaturated, and aromatic rings. A bicyclic carbocycle includes any combination of saturated, unsaturated and aromatic bicyclic rings, as valence permits. A bicyclic carbocycle includes any combination of ring sizes such as 4-5 fused ring systems, 5-5 fused ring systems, 5-6 fused ring systems, 6-6 fused ring systems, 5-7 fused ring systems, 6-7 fused ring systems, 5- 8 fused ring systems, and 6-8 fused ring systems. Non-limiting examples of bridged bicyclic carbocycle groups include, but are not limited to, bicyclo[1.1.1]pentyl, bicyclo[2.1.1]hexyl, bicyclo[2.1.1]hexyl, bicyclo[3.1.1]heptyl, bicyclo[2.2.1]heptyl, bicyclo[3.2.1]octyl, bicyclo[2.2.2]octyl, bicyclo[3.3.1]nonyl, bicyclo[3.3.2]decyl, and 2-oxabicyclo[2.2.2]octyl. Non-limiting examples of spirocyclic carbocycle groups include, but are not limited to, spiro[3.3]heptyl, spiro[3.4]octyl, spiro[3.5]nonyl, spiro[3.6]decyl, spiro[4.4]nonyl, spiro[4.5]decyl, spiro[5.5]undecyl, spiro[5.6]dodecyl, and spiro[5.7]tridecyl.

[0065] “Carbocyclene” refers to a divalent carbocycle as defined herein.

[0066] The term “bicyclic ring system” includes 6-12 (e.g., 8-12 or 9-, 10-, or 11-) membered structures that form two rings, wherein the two rings have at least one atom in common (e.g., two atoms in common). Bicyclic rings can be fused, bridged, or spirocyclic. Bicyclic ring systems include bicycloaliphatics (e.g., bicycloalkyl or bicycloalkenyl), bicycloheteroaliphatics, bicyclic aryls, and bicyclic heteroaryls.

[0067] The term “bridged bicyclic ring system” refers to a bicyclic heterocyclicalipahtic ring system or bicyclic cycloaliphatic ring system in which the rings are bridged. Examples of bridged bicyclic ring systems include, but are not limited to, adamantanyl, norbornanyl, bicyclo[1.1.1]pentyl, bicyclo[2.1.1]hexyl, bicyclo[2.1.1]hexyl, bicyclo[3.1.1]heptyl, bicyclo[2.2.1]heptyl, bicyclo[3.2.1]octyl, bicyclo[2.2.2]octyl, bicyclo[3.3.1]nonyl, bicyclo[3.3.2]decyl, 2-oxabicyclo[2.2.2]octyl, 6-azabicyclo[3.1.1]heptyl, 6- azabicyclo[3.1.1]heptyl, 1-azabicyclo[2.2.1]heptyl, 2-azabicyclo[2.2.1]heptyl, 7- azabicyclo[2.2.1]heptyl, 1-azabicyclo[2.2.2]octyl, 3-azabicyclo[3.2.1]octyl, and 2- oxabicyclo[3.1.1]heptyl, 2,6-dioxa-tricyclo[3.3.1.03,7]nonyl. A bridged bicyclic ring system can be optionally substituted with one or more substituents such as alkyl (including carboxyalkyl, hydroxyalkyl, and haloalkyl such as trifluoromethyl), alkenyl, alkynyl, cycloalkyl, (cycloalkyl)alkyl, heterocycloalkyl, (heterocycloalkyl)alkyl, aryl, heteroaryl, 17 1104675906\1\AMERICASAttorney Docket No.108843.00582 SU-0514WO alkoxy, cycloalkyloxy, heterocycloalkyloxy, aryloxy, heteroaryloxy, aralkyloxy, heteroaralkyloxy, aroyl, heteroaroyl, nitro, carboxy, alkoxycarbonyl, alkylcarbonyloxy, aminocarbonyl, alkylcarbonylamino, cycloalkylcarbonylamino, (cycloalkylalkyl)carbonylamino, arylcarbonylamino, aralkylcarbonylamino, (heterocycloalkyl)carbonylamino, (heterocycloalkylalkyl)carbonylamino, heteroarylcarbonylamino, heteroaralkylcarbonylamino, cyano, halo, hydroxy, acyl, mercapto, alkylsulfanyl, sulfoxy, urea, thiourea, sulfamoyl, sulfamide, oxo, or carbamoyl.

[0068] The term “spiro bicyclic ring system” refers to a bicyclic heterocyclicalipahtic ring system or bicyclic cycloaliphatic ring system in which 2 or 3 rings are linked together by one common atom. Spiro compounds depicted with overlapping rings indicate that the rings canbond at any vertex. For instance, in the spiro group, the two rings can bond at any of the three available vertex atoms in either ring. In some embodiments, a spiro bicyclic ring is a 3- to 12- membered spirocyclic bicyclic heterocycle comprising two nitrogen atoms and one oxygen atom. Non-limiting examples of a spirocyclic bicyclic heterocycle include a 10- membered spirocyclic bicyclic heterocycle, a 9- membered spirocyclic bicyclic heterocycle, and a 8- membered spirocyclic bicyclic heterocycle. The 3- to 12- membered spirocyclic bicyclic heterocycle include, but are not limited to, nitrogen (N), oxygen (O), and sulfur (S) atoms, for example two nitrogen atoms and one oxygen atom. For example, a 5-oxa-2,8- diazaspiro[3.5]nonane is a compound in which a 4 membered heterocyclic ring and a 6 membered heterocyclic ring are bonded through a single carbon atom wherein an oxygen atom is in the 6 membered heterocyclo ring.

[0069] The term “cycloalkylene,” as used herein refers to a divalent cycloalkyl group, as defined herein. In certain embodiments, the cycloalkylene group is cyclopropylene, cyclobutylene, cyclopentylene, cyclohexylene, cycloheptylene, and the like. Lower cycloalkylene refers to a C3-C6-cycloalkylene.

[0070] The term “cycloalkylalkyl,” as used herein, unless otherwise specified, refers to an alkyl group, as defined herein, substituted with one or two cycloalkyl, as defined herein. 18 1104675906\1\AMERICASAttorney Docket No.108843.00582 SU-0514WO

[0071] The term “ester,” as used herein, refers to -C(O)OR or -COOR where R is alkyl, as defined herein.

[0072] The term “fluorene” as used herein refers to, wherein any one or more carbons bearing one or more hydrogens can be substituted with a chemical functional group as described herein.

[0073] The term “haloalkyl” refers to an alkyl group, as defined herein, substituted with one or more halogen atoms (e.g., in some embodiments one, two, three, four, or five) which are independently selected.

[0074] The term “heteroalkyl” refers to an alkyl, as defined herein, in which one or more carbon atoms are replaced by heteroatoms. As used herein, “heteroalkenyl” refers to an alkenyl, as defined herein, in which one or more carbon atoms are replaced by heteroatoms. As used herein, “heteroalkynyl” refers to an alkynyl, as defined herein, in which one or more carbon atoms are replaced by heteroatoms. Suitable heteroatoms include, but are not limited to, nitrogen (N), oxygen (O), and sulfur (S) atoms. Heteroalkyl, heteroalkenyl, and heteroalkynyl are optionally substituted. Examples of heteroalkyl moieties include, but are not limited to, aminoalkyl, sulfonylalkyl, and sulfinylalkyl. Examples of heteroalkyl moieties also include, but are not limited to, methylamino, methylsulfonyl, and methylsulfinyl. “Substituted heteroalkyl” refers to heteroalkyl substituted with one, two, or three groups independently selected from halogen (e.g., fluoro (F), chloro (Cl), bromo (Br), or iodo (I)), alkyl, haloalkyl, hydroxyl, amino, alkylamino, and alkoxy. In some embodiments, a heteroalkyl group may comprise one, two, three, or four heteroatoms. Those of skill in the art will recognize that a 4-membered heteroalkyl may generally comprise one or two heteroatoms, a 5- or 6-membered heteroalkyl may generally comprise one, two, or three heteroatoms, and a 7- to 10-membered heteroalkyl may generally comprise one, two, three, or four heteroatoms.

[0075] The term “heteroalkylene,” as used herein, refers to a divalent heteroalkyl, as defined herein. “Substituted heteroalkylene” refers to a divalent heteroalkyl, as defined herein, substituted as described for heteroalkyl.

[0076] The term “heterocycle” refers to a saturated, unsaturated or aromatic ring comprising one or more heteroatoms. Exemplary heteroatoms include N, O, Si, P, B, and S atoms where the nitrogen or sulfur atoms may be optionally oxidized, and the nitrogen atoms may be optionally quaternized and the remaining ring atoms of the non-aromatic ring are carbon 19 1104675906\1\AMERICASAttorney Docket No.108843.00582 SU-0514WO atoms. A “heterocycle” includes 3- to 10-membered monocyclic rings, 6- to 12-membered bicyclic rings, and 6- to 12-membered bridged rings. In certain embodiments, “heterocycle” is a monovalent, monocyclic, or multicyclic fully-saturated ring system. In certain embodiments, the “heterocycle” group may be unsaturated, and / or bridged, and / or non- bridged, and / or a fused bicyclic group, and / or a spirocyclic bicyclic group. A bicyclic “heterocycle” includes any combination of ring sizes such as 4-5 fused ring systems, 5-5 fused ring systems, 5-6 fused ring systems, 6-6 fused ring systems, 5-7 fused ring systems, 6- 7 fused ring systems, 5-8 fused ring systems, and 6-8 fused ring systems. In certain embodiments, the “heterocycle” group has from three to twenty, from three to fifteen, from three to ten, from three to eight, from four to seven, from four to eleven, or from five to six ring atoms. The “heterocycle” may be attached to a core structure at any heteroatom or carbon atom which results in the creation of a stable compound. In certain embodiments, the “heterocycle” is a monocyclic, bicyclic, tricyclic, or tetracyclic ring system, which may include a fused or bridged or spirocyclic ring system and in which the nitrogen or sulfur atoms may be optionally oxidized, and / or the nitrogen atoms may be optionally quaternized. In some embodiments, “heterocycle” radicals include, but are not limited to, 2,5- diazabicyclo[2.2.2]octanyl, decahydroisoquinolinyl, dihydrobenzisoxazinyl, dihydrofuryl, dihydroisoindolyl, dihydropyranyl, dihydropyrazolyl, dihydropyrazinyl, dihydropyridinyl, dihydropyrimidinyl, dihydropyrrolyl, dioxolanyl, 1,4-dithianyl, furanonyl, imidazolidinyl, imidazolinyl, indolinyl, isothiazolidinyl, isoxazolidinyl, morpholinyl, octahydroindolyl, octahydroisoindolyl, oxazolidinonyl, oxazolidinyl, oxiranyl, piperazinyl, piperidinyl, 4- piperidonyl, pyrazolidinyl, pyrazolinyl, pyrrolidinyl, pyrrolinyl, quinuclidinyl, tetrahydrofuryl, tetrahydroisoquinolinyl, tetrahydropyranyl, tetrahydrothienyl, thiamorpholinyl, thiazolidinyl, tetrahydroquinolinyl, and 1,3,5-trithianyl. Non-limiting examples of bridged heterocycle groups include, but are not limited to, 6- azabicyclo[3.1.1]heptyl, 6-azabicyclo[3.1.1]heptyl, 1-azabicyclo[2.2.1]heptyl, 2- azabicyclo[2.2.1]heptyl, 7-azabicyclo[2.2.1]heptyl, 1-azabicyclo[2.2.2]octyl, 3- azabicyclo[3.2.1]octyl, and 2-oxabicyclo[3.1.1]heptyl, 2,6-dioxa-tricyclo[3.3.1.03,7]nonyl. Non-limiting examples of spirocyclic heterocycle groups include, but are not limited to, 2,8- diazaspiro[4.5]decyl; 2,7-diazaspiro[3.5]nonyl; 3,9-diazaspiro[5.5]undecyl; 3- azaspiro[5.5]undecyl; 2-oxa-6-azaspiro[3.4]octyl; 2-oxa-9-azaspiro[5.5]undecyl; 3-oxa-9- azaspiro[5.5]undecyl; 7-azaspiro[3.5]nonyl; 2-azaspiro[3.5]nonyl; 7-oxaspiro[3.5]nonyl; and 2-oxaspiro[3.5]nonyl. In certain embodiments, “heterocycle” may also be optionally substituted as described herein. In certain embodiments, “heterocycle” is substituted with 20 1104675906\1\AMERICASAttorney Docket No.108843.00582 SU-0514WO one, two, or three groups independently selected from halogen (e.g., fluoro (F), chloro (Cl), bromo (Br), or iodo (I)), alkyl, haloalkyl, hydroxyl, amino, alkylamino, and alkoxy. In some embodiments, a “heterocycle” group may comprise one, two, three, or four heteroatoms. Those of skill in the art will recognize that a 4-membered “heterocycle” may generally comprise one or two heteroatoms, a 5- or 6-membered “heterocycle” may generally comprise one, two, or three heteroatoms, and a 7- to 10-membered “heterocycle” may generally comprise one, two, three, or four heteroatoms.

[0077] “Heterocycloalkylene” refers to a divalent heterocycloalkyl as defined herein.

[0078] The term “heteroaryl” refers to a monovalent, monocyclic aromatic group and / or multicyclic aromatic group, wherein at least one aromatic ring contains one or more heteroatoms independently selected from oxygen, sulfur, and nitrogen within the ring. Each ring of a heteroaryl group can contain one or two oxygen atoms, one or two sulfur atoms, and / or one to four nitrogen atoms, provided that the total number of heteroatoms in each ring is four or less and each ring contains at least one carbon atom. In certain embodiments, the heteroaryl has from five to twenty, from five to fifteen, or from five to ten ring atoms. A heteroaryl may be attached to the rest of the molecule via a nitrogen or a carbon atom. In some embodiments, monocyclic heteroaryl groups include, but are not limited to, furanyl, imidazolyl, isothiazolyl, isoxazolyl, oxadiazolyl, oxazolyl, pyrazinyl, pyrazolyl, pyridazinyl, pyridyl, pyrimidinyl, pyrrolyl, triazolyl, thiadiazolyl, thiazolyl, thienyl, tetrazolyl, and triazinyl. Examples of bicyclic heteroaryl groups include, but are not limited to, benzofuranyl, benzimidazolyl, benzoisoxazolyl, benzopyranyl, benzothiadiazolyl, benzothiazolyl, benzothienyl, benzotriazolyl, benzoxazolyl, furopyridyl, imidazopyridinyl, imidazothiazolyl, indolizinyl, indolyl, indazolyl, isobenzofuranyl, isobenzothienyl, isoindolyl, isoquinolinyl, naphthyridinyl, oxazolopyridinyl, phthalazinyl, pteridinyl, purinyl, pyridopyridyl, pyrrolopyridyl, quinolinyl, quinoxalinyl, quinazolinyl, thiadiazolopyrimidyl, and thienopyridyl. Examples of tricyclic heteroaryl groups include, but are not limited to, acridinyl, benzindolyl, carbazolyl, dibenzofuranyl, perimidinyl, phenanthrolinyl, phenanthridinyl, phenarsazinyl, phenazinyl, phenothiazinyl, phenoxazinyl, and xanthenyl. In certain embodiments, heteroaryl may also be optionally substituted as described herein. “Substituted heteroaryl” is a heteroaryl substituted as defined for aryl.

[0079] The term “heteroarylene” refers to a divalent heteroaryl group, as defined herein. “Substituted heteroarylene” is a heteroarylene substituted as defined for aryl.

[0080] The term “protecting group,” as used herein, and unless otherwise specified, refers to a group that is added to an oxygen, nitrogen, or phosphorus atom to prevent further reaction 21 1104675906\1\AMERICASAttorney Docket No.108843.00582 SU-0514WO at the (protected) oxygen, nitrogen, or phosphorus, or for other purposes. A wide variety of oxygen and nitrogen protecting groups are known to those skilled in the art of organic synthesis (see, e.g., Greene, et al., Protective Groups in Organic Synthesis, John Wiley and Sons, Fourth Edition, 2006, which is incorporated herein by reference in its entirety).

[0081] “Pharmaceutically acceptable salt” refers to any salt of a compound provided herein which retains its biological properties and which is not toxic or otherwise undesirable for pharmaceutical use. Such salts may be derived from a variety of organic and inorganic counter-ions well known in the art. Such salts include, but are not limited to (1) acid addition salts formed with organic or inorganic acids such as hydrochloric, hydrobromic, sulfuric, nitric, phosphoric, sulfamic, acetic, trifluoroacetic, trichloroacetic, propionic, hexanoic, cyclopentylpropionic, glycolic, glutaric, pyruvic, lactic, malonic, succinic, sorbic, ascorbic, malic, maleic, fumaric, tartaric, citric, benzoic, 3-(4-hydroxybenzoyl)benzoic, picric, cinnamic, mandelic, phthalic, lauric, methanesulfonic, ethanesulfonic, 1,2-ethane-disulfonic, 2-hydroxyethanesulfonic, benzenesulfonic, 4-chlorobenzenesulfonic, 2-naphthalenesulfonic, 4-toluenesulfonic, camphoric, camphorsulfonic, 4-methylbicyclo[2.2.2]-oct-2-ene-1- carboxylic, glucoheptonic, 3-phenylpropionic, trimethylacetic, tert-butylacetic, lauryl sulfuric, gluconic, glutamic, hydroxynaphthoic, salicylic, stearic, cyclohexylsulfamic, quinic, and muconic acids, and the like; or (2) salts formed when an acidic proton present in the parent compound either (a) is replaced by a metal ion, for example, an alkali metal ion, an alkaline earth ion, or an aluminum ion, or alkali metal or alkaline earth metal hydroxides, such as sodium, potassium, calcium, magnesium, aluminum, lithium, zinc, and barium hydroxide, or ammonia; or (b) coordinates with an organic base, such as aliphatic, alicyclic, or aromatic organic amines, including, without limitation, ammonia, methylamine, dimethylamine, diethylamine, picoline, ethanolamine, diethanolamine, triethanolamine, ethylenediamine, lysine, arginine, ornithine, choline, N,N′-dibenzylethylene-diamine, chloroprocaine, procaine, N-benzylphenethylamine, N-methylglucamine piperazine, tris(hydroxymethyl)-aminomethane, tetramethylammonium hydroxide, and the like.

[0082] Pharmaceutically acceptable salts further include, by way of example and without limitation, sodium, potassium, calcium, magnesium, ammonium, and tetraalkylammonium salts, and the like, and when the compound contains a basic functionality, salts of non-toxic organic or inorganic acids, such as hydrohalides, for example, hydrochloride and hydrobromide, sulfate, phosphate, sulfamate, nitrate, acetate, trifluoroacetate, trichloroacetate, propionate, hexanoate, cyclopentylpropionate, glycolate, glutarate, pyruvate, lactate, malonate, succinate, sorbate, ascorbate, malate, maleate, fumarate, tartarate, citrate, 22 1104675906\1\AMERICASAttorney Docket No.108843.00582 SU-0514WO benzoate, 3-(4-hydroxybenzoyl)benzoate, picrate, cinnamate, mandelate, phthalate, laurate, methanesulfonate (mesylate), ethanesulfonate, 1,2-ethane-disulfonate, 2-hydroxyethanesulfonate, benzenesulfonate (besylate), 4-chlorobenzenesulfonate, 2-naphthalenesulfonate, 4-toluenesulfonate, camphorate, camphorsulfonate, 4-methylbicyclo[2.2.2]-oct-2-ene-1-carboxylate, glucoheptonate, 3-phenylpropionate, trimethylacetate, tert-butylacetate, lauryl sulfate, gluconate, glutamate, hydroxynaphthoate, salicylate, stearate, cyclohexylsulfamate, quinate, muconate, and the like.

[0083] The term “substantially free of” or “substantially in the absence of” with respect to a composition refers to a composition that includes at least 85% or 90% by weight, in certain embodiments 95%, 98%, 99%, or 100% by weight; or in certain embodiments, 95%, 98%, 99%, or 100% of the designated enantiomer or diastereomer of a compound. In certain embodiments, in the methods and compounds provided herein, the compounds are substantially free of one of two enantiomers. In certain embodiments, in the methods and compounds provided herein, the compounds are substantially free of one of two diastereomers. In certain embodiments, in the methods and compounds provided herein, the compounds are substantially free of enantiomers (i.e., the compounds are not a racemic or 50:50 mixture of compounds).

[0084] Similarly, the term “isolated” with respect to a composition refers to a composition that includes at least 85%, 90%, 95%, 98%, or 99% to 100% by weight, of the compound, the remainder comprising other chemical species, enantiomers, or diastereomers.

[0085] “Solvate” refers to a compound provided herein, or a salt thereof, that further includes a stoichiometric or non-stoichiometric amount of solvent bound by non-covalent intermolecular forces. Where the solvent is water, the solvate is a hydrate.

[0086] The term “substituted” refers to moieties having substituents replacing a hydrogen on one or more carbons or substitutable heteroatoms, e.g., an NH or NH2of a compound. It will be understood that “substitution” or “substituted with” includes the implicit proviso that such substitution is in accordance with permitted valence of the substituted atom and the substituent, and that the substitution results in a stable compound, i.e., a compound which does not spontaneously undergo transformation such as by rearrangement, cyclization, elimination, etc. In certain embodiments, substituted refers to moieties having substituents replacing two hydrogen atoms on the same carbon atom, such as substituting the two hydrogen atoms on a single carbon with an oxo, imino or thioxo group. As used herein, the term “substituted” is contemplated to include all permissible substituents of organic compounds. In a broad aspect, the permissible substituents include acyclic and cyclic, 23 1104675906\1\AMERICASAttorney Docket No.108843.00582 SU-0514WO branched and unbranched, carbocyclic and heterocyclic, aromatic and non-aromatic substituents of organic compounds. The permissible substituents can be one or more and the same or different for appropriate organic compounds.

[0087] In some embodiments, substituents may include any substituents described herein, for example: halogen, hydroxy, oxo (=O), thioxo (=S), cyano (-CN), nitro (-NO2), imino (=N-H), oximo (=N-OH), hydrazino (=N- NH2), -Rb1-ORa1, -Rb1-OC(O)-Ra1, -Rb1-OC(O)-ORa1, -Rb1- OC(O)-N(Ra1)2, -Rb1-N(Ra)2, -Rb1-C(O)Ra1, -Rb1-C( O)ORa1, -Rb1-C(O)N(Ra1)2, -Rb1-O-Rc1- C(O)N(Ra1)2, -Rb1-N(Ra1)C(O)ORa1, -Rb1-N(Ra)C(O)Ra1, -Rb1-N(Ra1)S( O)tRa1(where t is 1 or 2), -Rb1-S(O)tRa1(where t is 1 or 2), -Rb1-S(O)tORa1(where t is 1 or 2), and -Rb1- S(O)tN(Ra1)2(where t is 1 or 2); and alkyl, alkenyl, alkynyl, aryl, aralkyl, aralkenyl, aralkynyl, cycloalkyl, cycloalkylalkyl, heterocycloalkyl, heterocycloalkylalkyl, heteroaryl, and heteroarylalkyl any of which may be optionally substituted by alkyl, alkenyl, alkynyl, halogen, haloalkyl, haloalkenyl, haloalkynyl, oxo (=O), thioxo (=S), cyano (-CN), nitro (- NO2), imino (=N- H), oximo (=N-OH), hydrazine (=N- NH2), -Rb1-ORa1, -Rb1-OC(O)-Ra1, - Rb1-OC(O)-ORa1, -Rb1-OC(O)-N(Ra1)2, -Rb1-N(Ra)2, -Rb1-C(O)Ra1, -Rb1-C( O)ORa1, -Rb1- C(O)N(Ra1)2, -Rb1-O-Rc1-C(O)N(Ra1)2, -Rb1-N(Ra1)C(O)ORa1, -Rb1-N(Ra1)C(O)Ra1, -Rb1- N(Ra1)S(O)tRa1(where t is 1 or 2), -Rb1-S(O)tRa1(where t is 1 or 2), -Rb1-S(O)tORa1(where t is 1 or 2) and -Rb1-S(O)tN(Ra1)2(where t is 1 or 2); wherein each Ra1is independently selected from hydrogen, alkyl, cycloalkyl, cycloalkylalkyl, aryl, aralkyl, heterocycloalkyl, heterocycloalkylalkyl, heteroaryl, or heteroarylalkyl, wherein each Ra1, valence permitting, may be optionally substituted with alkyl, alkenyl, alkynyl, halogen, haloalkyl, haloalkenyl, haloalkynyl, oxo (=O), thioxo (=S), cyano (-CN), nitro (-NO2), imino (=N-H), oximo (=N- OH), hydrazine (=N- NH2), -Rb1-ORa1, -Rb1-OC(O)-Ra1, -Rb1-OC(O)-ORa1, -Rb1-OC(O)- N(Ra1)2, -Rb1-N(Ra1)2, -Rb1-C(O)Ra1, -Rb1-C( O)ORa1, -Rb1-C(O)N(Ra1)2, -Rb1-O-Rc1- C(O)N(Ra1)2, -Rb1-N(Ra1)C(O)ORa1, -Rb1-N(Ra1)C(O)Ra1, -Rb1-N(Ra)S( O)tRa1(where t is 1 or 2), -Rb1-S(O)tRa1(where t is 1 or 2), -Rb1-S(O)tORa1(where t is 1 or 2) and -Rb1- S(O)tN(Ra1)2 (where t is 1 or 2); and wherein each Rb1is independently selected from a direct bond or a straight or branched alkylene, alkenylene, or alkynylene chain, and each Rcis a straight or branched alkylene, alkenylene or alkynylene chain.

[0088] It will be understood by those skilled in the art that substituents can themselves be substituted, if appropriate.

[0089] “Isotopic composition” refers to the amount of each isotope present for a given atom, and “natural isotopic composition” refers to the naturally occurring isotopic composition or abundance for a given atom. Atoms containing their natural isotopic composition may also be 24 1104675906\1\AMERICASAttorney Docket No.108843.00582 SU-0514WO referred to herein as “non-enriched” atoms. Unless otherwise designated, the atoms of the compounds recited herein are meant to represent any stable isotope of that atom. For example, unless otherwise stated, when a position is designated specifically as hydrogen (H), the position is understood to have hydrogen at its natural isotopic composition.

[0090] “Isotopic enrichment” refers to the percentage of incorporation of an amount of a specific isotope at a given atom in a molecule in the place of that atom’s natural isotopic abundance. For example, deuterium (D) enrichment of 1% at a given position means that 1% of the molecules in a given sample contain deuterium at the specified position. Because the naturally occurring distribution of deuterium is about 0.0156%, deuterium enrichment at any position in a compound synthesized using non-enriched starting materials is about 0.0156%. The isotopic enrichment of the compounds provided herein can be determined using conventional analytical methods known to one of ordinary skill in the art, including mass spectrometry and nuclear magnetic resonance spectroscopy.

[0091] “Isotopically enriched” refers to an atom having an isotopic composition other than the natural isotopic composition of that atom. “Isotopically enriched” may also refer to a compound containing at least one atom having an isotopic composition other than the natural isotopic composition of that atom.

[0092] As used herein, “alkyl,” “alkylene,” “alkylamino,” “dialkylamino,” “cycloalkyl,” “aryl,” “arylene,” “alkoxy,” “amino,” “carboxyl,” “heterocycloalkyl,” “heteroaryl,” “heteroarylene,” “carboxyl,” and “amino acid” groups optionally comprise deuterium (D) at one or more positions where hydrogen (H) atoms are present, and wherein the deuterium composition of the atom or atoms is other than the natural isotopic composition.

[0093] Also as used herein, “alkyl,” “alkylene,” “alkylamino,” “dialkylamino,” “cycloalkyl,” “aryl,” “arylene,” “alkoxy,” “amino,” “carboxyl,” “heterocycloalkyl,” “heteroaryl,” “heteroarylene,” “carboxyl,” and “amino acid” groups optionally comprise carbon-13 (13C) at an amount other than the natural isotopic composition.

[0094] The term “macromolecule” or “macromolecular moiety” refers to a protein, peptide, antibody, nucleic acid, carbohydrate, or other large molecule composed of polymerized monomers. They include peptides of two or more residues, or ten or more residues. In certain embodiments, a macromolecule is at least 1000 Da in mass. In certain embodiments, a macromolecule has at least 1000 atoms. In certain embodiments, a macromolecule can be modified. For instance, a protein, peptide, or antibody can be modified with one or more carbohydrates and / or small molecule therapeutic compounds. 25 1104675906\1\AMERICASAttorney Docket No.108843.00582 SU-0514WO

[0095] The term “immunoglobulin” refers to a class of structurally related proteins generally comprising two pairs of polypeptide chains: one pair of light (L) chains, and one pair of heavy (H) chains. In an “intact immunoglobulin,” all four of these chains are interconnected by disulfide bonds. The structure of immunoglobulins has been well characterized. See, e.g., Paul, Fundamental Immunology 7th ed., Ch.5 (2013) Lippincott Williams & Wilkins, Philadelphia, PA. Briefly, each heavy chain typically comprises a heavy chain variable region (VHor VH) and a heavy chain constant region (CHor CH). The heavy chain constant region typically comprises three domains, abbreviated CH1 (or CH1), CH2 (or CH2), and CH3 (or CH3). Each light chain typically comprises a light chain variable region (VL or VL) and a light chain constant region. The light chain constant region typically comprises one domain, abbreviated CLor CL.

[0096] The term “antibody” is used herein in its broadest sense. An antibody includes intact antibodies (e.g., intact immunoglobulins), and antibody fragments (e.g., antigen binding fragments or antigen-binding fragments of antibodies). Antibodies comprise at least one antigen-binding domain. One example of an antigen-binding domain is an antigen binding domain formed by a VH-VL dimer.

[0097] An “antibody fragment” comprises a portion of an intact antibody, such as the antigen binding or variable region of an intact antibody. Antibody fragments include, for example, Fv fragments, Fab fragments, F(ab’)2 fragments, Fab’ fragments, scFv (sFv) fragments, and scFv-Fc fragments. “Fv” fragments comprise a non-covalently-linked dimer of one heavy chain variable domain and one light chain variable domain. “Fab” fragments comprise, in addition to the heavy and light chain variable domains, the constant domain of the light chain and the first constant domain (CH1) of the heavy chain. Fab fragments may be generated, for example, by recombinant methods or by papain digestion of a full-length antibody. “F(ab’)2” fragments contain two Fab’ fragments joined, near the hinge region, by disulfide bonds. F(ab’)2 fragments may be generated, for example, by recombinant methods or by pepsin digestion of an intact antibody. The F(ab’) fragments can be dissociated, for example, by treatment with β-mercaptoethanol. “Single-chain Fv” or “sFv” or “scFv” antibody fragments comprise a VH domain and a VL domain in a single polypeptide chain. The VH and VL are generally linked by a peptide linker. See Plückthun A. (1994). Antibodies from Escherichia coli. In Rosenberg M. & Moore G.P. (Eds.), The Pharmacology of Monoclonal Antibodies vol.113 (pp.269-315). Springer-Verlag, New York, are incorporated by reference in their entirety. “scFv-Fc” fragments comprise an scFv attached to an Fc domain. For example, an Fc domain may be attached to the C-terminus of the scFv. The Fc domain may follow the VH26 1104675906\1\AMERICASAttorney Docket No.108843.00582 SU-0514WO or VL, depending on the orientation of the variable domains in the scFv (i.e., VH-VLor VL- VH). Any suitable Fc domain known in the art or described herein may be used. In some cases, the Fc domain comprises an IgG1 Fc domain.

[0098] The term “amino acid” or “amino acid residue” refers to a D- or L-natural or non- naturally occurring amino acid. refers to the twenty common naturally occurring amino acids. Naturally occurring amino acids include alanine (Ala; A), arginine (Arg; R), asparagine (Asn; N), aspartic acid (Asp; D), cysteine (Cys; C); glutamic acid (Glu; E), glutamine (Gln; Q), Glycine (Gly; G); histidine (His; H), isoleucine (Ile; I), leucine (Leu; L), lysine (Lys; K), methionine (Met; M), phenylalanine (Phe; F), proline (Pro; P), serine (Ser; S), threonine (Thr; T), tryptophan (Trp; W), tyrosine (Tyr; Y), and valine (Val; V), and the less common cystine, pyrrolysine, and selenocysteine. Unnatural amino acids are not proteinogenic amino acids, or post-translationally modified variants thereof. In particular, the term unnatural amino acid refers to an amino acid that is not one of the twenty common amino acids, cystine, pyrrolysine, or selenocysteine, or post-translationally modified variants thereof. Non-limiting examples of unnatural amino acids include sulfoalanine, hydroxyproline (Hyp), beta-alanine, citrulline (Cit), ornithine (Orn), norleucine (Nle), 3-nitrotyrosine, nitroarginine, pyroglutamic acid (Pyr), naphtylalanine (Nal), 2,4-diaminobutyric acid (DAB), methionine sulfoxide, and methionine sulfone. Naturally encoded amino acids include post-translation modification (PTM) or post-translational variants of the twenty-two naturally occurring amino acids such as prenylated amino acids, isoprenylated amino acids, myrisoylated amino acids, palmitoylated amino acids, N-linked glycosylated amino acids, O-linked glycosylated amino acids, phosphorylated amino acids, and acylated amino acids.

[0099] The term “amino acid” also includes non-natural (or unnatural) or synthetic ^-, ^-, ^-, or ^-amino acids, and includes, but is not limited to, amino acids found in proteins, i.e., glycine, alanine, valine, leucine, isoleucine, methionine, phenylalanine, tryptophan, proline, serine, threonine, cysteine, tyrosine, asparagine, glutamine, aspartate, glutamate, lysine, arginine, and histidine. In certain embodiments, the amino acid is in the L-configuration. In certain embodiments, the amino acid is in the D-configuration. Alternatively, the amino acid can be a derivative of alanyl, valinyl, leucinyl, isoleucinyl, prolinyl, phenylalaninyl, tryptophanyl, methioninyl, glycinyl, serinyl, threoninyl, cysteinyl, tyrosinyl, asparaginyl, glutaminyl, aspartoyl, glutaroyl, lysinyl, argininyl, histidinyl, ^-alanyl, ^-valinyl, ^-leucinyl, ^-isoleucinyl, ^-prolinyl, ^-phenylalaninyl, ^-tryptophanyl, ^-methioninyl, ^-glycinyl, 27 1104675906\1\AMERICASAttorney Docket No.108843.00582 SU-0514WO ^-serinyl, ^-threoninyl, ^-cysteinyl, ^-tyrosinyl, ^-asparaginyl, ^-glutaminyl, ^-aspartoyl, ^-glutaroyl, ^-lysinyl, ^-argininyl, or ^-histidinyl.

[0100] The term “modified amino acid” is an amino acid or non-natural amino acid that comprises a reactive group capable of forming a covalent bond to a linker payload. The reactive group can be an amino, carboxy, acetyl, hydrazino, hydrazido, hydroxylamine, semicarbazido, sulfanyl, azido or alkynyl group. Non-limiting examples of non-natural amino acids include p-acetyl-L-phenylalanine, O-methyl-L-tyrosine, 3-methyl-phenylalanine, O-4- allyl-L-tyrosine, 4-propyl-L-tyrosine, fluorinated phenylalanine, isopropyl-L-phenylalanine, p-azido-L-phenylalanine, p-acyl-L-phenylalanine, p-benzoyl-L-phenylalanine, p-iodo- phenylalanine, p-bromophenylalanine, p-amino-L-phenylalanine, isopropyl-L-phenylalanine, p-propargyloxy-phenylalanine, and p-azidomethyl-L-phenyl alanine.

[0101] The term “conjugate” refers to a compound or drug moiety described herein linked to one or more macromolecular moieties. The macromolecular moiety is as defined herein or is any macromolecule deemed suitable to the person of skill in the art. For example, the macromolecular moiety can be an antibody or an antigen binding fragment. The compound or drug moiety can be any compound or drug moiety, such as cytotoxic agents and oxoadenine TLR7 agonists, described herein. The compound or drug moiety can be directly linked to the macromolecular moiety via a covalent bond, or the compound or drug moiety can be linked to the macromolecular moiety indirectly via a linker. Typically, the linker is covalently bonded to the macromolecular moiety and also covalently bonded to the compound or drug moiety. A “conjugate” can have one or more compounds or drug moieties described herein linked to one or more macromolecular moieties. The term “antibody drug conjugate” or “ADC” as used herein refers to antibody or antigen binding fragment thereof directly or indirectly, via a linker, covalently bound to at least one cytotoxic agent. The term “immunomodulatory antibody drug conjugate” or “iADC” as used herein refers to an antibody or antigen binding fragment thereof directly or indirectly, via a linker, covalently bound to at least one immunomodulatory agent, such as an oxoadenine TLR7 agonist, and at least one cytotoxic agent.

[0102] “pAMF,” “pAMF residue,” “pAzMeF,” or “pAMF mutation” refers to a variant phenylalanine residue (i.e., para-azidomethyl-L-phenylalanine) added or substituted into a polypeptide.

[0103] pAcF,” “pAcetylF,” “pAcF mutation” refers to a variant phenylalanine residue, i.e., para-acetyl-L-phenylalanine, added or substituted into a polypeptide. 28 1104675906\1\AMERICASAttorney Docket No.108843.00582 SU-0514WO

[0104] The term “linker” refers to a molecular moiety that is capable of forming at least two covalent bonds. Typically, a linker is capable of forming at least one covalent bond to a macromolecular moiety and at least another covalent bond to a compound. In certain embodiments, a linker can form more than one covalent bond to a macromolecular moiety. In certain embodiments, a linker can form more than one covalent bond to a compound or can form covalent bonds to more than one compound. After a linker forms a bond to a macromolecular moiety, or a compound or both, the remaining structure (i.e. the residue of the linker (“linker residue”) after one or more covalent bonds are formed) may still be referred to as a “linker” herein. The term “linker precursor” refers to a linker having one or more reactive groups capable of forming a covalent bond with a macromolecule, or compound, or both. A person of ordinary skill in the art, given the context of how the term linker is used, would understand whether “linker” means linker precursor with one reactive group, a linker precursor with more than one reactive groups, a linker residue which is covalently bonded to the macromolecule, a linker residue which is covalently bonded to a compound, and / or a linker residue which is covalently bonded to the macromolecule and is covalently bonded to a compound. In some embodiments, the linker is a cleavable linker. For example, a cleavable linker can be one that is released by a bio-labile or enzymatic function, which may or may not be engineered. In some embodiments, the linker is a non-cleavable linker. For example, a non-cleavable linker can be one that is released upon degradation of the macromolecular moiety.

[0105] As used herein, term “EC50” refers to a dosage, concentration, or amount of a particular test compound that elicits a dose-dependent response at 50% of maximal expression of a particular response that is induced, provoked, or potentiated by the particular test compound.

[0106] As used herein, and unless otherwise specified, the term “IC50” refers to an amount, concentration, or dosage of a particular test compound that achieves a 50% inhibition of a maximal response in an assay that measures such response.

[0107] As used herein, the terms “subject” and “patient” are used interchangeably. The terms “subject” and “subjects” refer to an animal, such as a mammal including a non-primate (e.g., a cow, pig, horse, cat, dog, rat, and mouse) and a primate (e.g., a monkey, such as a cynomolgus monkey, a chimpanzee, and a human), and in certain embodiments, a human. In certain embodiments, the subject is a farm animal (e.g., a horse, a cow, a pig, etc.) or a pet (e.g., a dog or a cat). In certain embodiments, the subject is a human. 29 1104675906\1\AMERICASAttorney Docket No.108843.00582 SU-0514WO

[0108] As used herein, the terms “therapeutic agent” and “therapeutic agents” refer to any agent(s) which can be used in the treatment or prevention of a disorder or one or more symptoms thereof. In certain embodiments, the term “therapeutic agent” includes a compound or conjugate provided herein. In certain embodiments, a therapeutic agent is an agent which is known to be useful for, or has been or is currently being used for the treatment or prevention of a disorder or one or more symptoms thereof.

[0109] “Therapeutically effective amount” refers to an amount of a compound, conjugate, or composition that, when administered to a subject for treating a condition, is sufficient to effect such treatment for the condition. A “therapeutically effective amount” can vary depending on, inter alia, the compound, the conjugate, the disease or disorder and its severity, and the age, weight, etc., of the subject to be treated.

[0110] “Treating” or “treatment” of any disease or disorder refers, in certain embodiments, to ameliorating a disease or disorder that exists in a subject. In another embodiment, “treating” or “treatment” includes ameliorating at least one physical parameter, which may be indiscernible by the subject. In yet another embodiment, “treating” or “treatment” includes modulating the disease or disorder, either physically (e.g., stabilization of a discernible symptom) or physiologically (e.g., stabilization of a physical parameter) or both. In yet another embodiment, “treating” or “treatment” includes delaying or preventing the onset of the disease or disorder, or delaying or preventing recurrence of the disease or disorder. In yet another embodiment, “treating” or “treatment” includes the reduction or elimination of either the disease or disorder, or retarding the progression of the disease or disorder or of one or more symptoms of the disease or disorder, or reducing the severity of the disease or disorder or of one or more symptoms of the disease or disorder.

[0111] As used herein, the term “inhibits growth” (e.g., referring to cells, such as tumor cells) is intended to include any measurable decrease in cell growth (e.g., tumor cell growth) when contacted with a compound, or conjugate herein, as compared to the growth of the same cells not in contact with the compound, or conjugate herein. In some embodiments, growth may be inhibited by at least about 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, 99%, or 100%. The decrease in cell growth can occur via a variety of mechanisms, including but not limited to, conjugate or compound, internalization, apoptosis, necrosis, and / or effector function- mediated activity.

[0112] As used herein, the terms “prophylactic agent” and “prophylactic agents” as used refer to any agent(s) which can be used in the prevention of a disorder or one or more symptoms thereof. In certain embodiments, the term “prophylactic agent” includes a 30 1104675906\1\AMERICASAttorney Docket No.108843.00582 SU-0514WO compound or conjugate provided herein. In certain other embodiments, the term “prophylactic agent” does not refer a compound or conjugate provided herein. For example, a prophylactic agent is an agent which is known to be useful for, or has been or is currently being used to prevent or impede the onset, development, progression, and / or severity of a disorder.

[0113] As used herein, the phrase “prophylactically effective amount” refers to the amount of a therapy (e.g., prophylactic agent) which is sufficient to result in the prevention or reduction of the development, recurrence, or onset of one or more symptoms associated with a disorder or to enhance or improve the prophylactic effect(s) of another therapy (e.g., another prophylactic agent).

[0114] In some chemical structures illustrated herein, certain substituents, chemical groups, and atoms are depicted with a curvy / wavy / wiggly line (e.g.,or ) that intersects a bond or bonds to indicate the atom through which the substituents, chemical groups, and atoms are bonded. For example, in some structures, such as but not limited to,, this curvy / wavy / wiggly line indicates the atoms in the backbone of a conjugate, compound, or drug moiety structure to which the illustrated chemical entity is bonded. In some structures, such as but not limited, this curvy / wavy / wiggly line indicates the atoms in the macromolecule as well as the atoms in the backbone of a conjugate, compound, or drug moiety structure to which the illustrated chemical entity is bonded.

[0115] As used herein, illustrations showing substituents bonded to a cyclic group (e.g., aromatic, heteroaromatic, fused ring, and saturated or unsaturated cycloalkyl or heterocycloalkyl) through a bond between ring atoms are meant to indicate, unless specified otherwise, that the cyclic group may be substituted with that substituent at any ring position in the cyclic group or on any ring in the fused ring group, according to techniques set forth 31 1104675906\1\AMERICASAttorney Docket No.108843.00582 SU-0514WO herein or which are known in the field to which the instant disclosure pertains. For example, the group,, wherein the positions of substituent O-Su and RAare described generically, i.e., not directly attached to any vertex of the bond line structure, i.e., specific ring carbon atom, includes the following, non-limiting examples of groups in which the substituent O-Su and RAare bonded to a specific ring carbon atom include, for example,

[0116] The term “site-specific” refers to a modification of a polypeptide at a predetermined sequence location in the polypeptide. The modification is at a single, predictable residue of the polypeptide with little or no variation. In particular embodiments, a modified amino acid is introduced at that sequence location, for instance recombinantly or synthetically. Similarly, a moiety can be “site-specifically” linked to a residue at a particular sequence location in the polypeptide. In certain embodiments, a polypeptide can comprise more than one site-specific modification.

[0117] The term "cancer" is used throughout the specification to refer to the pathological process that results in the formation and growth of a cancerous or malignant neoplasm, i.e., abnormal tissue (solid) or cells (non-solid) that grow by cellular proliferation, often more rapidly than normal and continues to grow after the stimuli that initiated the new growth cease. Malignant neoplasms show partial or complete lack of structural organization and functional coordination with the normal tissue and most invade surrounding tissues, can metastasize to several sites, are likely to recur after attempted removal and may cause the death of the patient unless adequately treated. As used herein, the term neoplasia is used to describe all cancerous disease states and embraces or encompasses the pathological process associated with malignant hematogenous, ascitic and solid tumors.

[0118] As used herein, the term “immune response” relates to any one or more of the following: specific immune response, non-specific immune response, both specific and non- specific response, innate response, primary immune response, adaptive immunity, secondary 32 1104675906\1\AMERICASAttorney Docket No.108843.00582 SU-0514WO immune response, memory immune response, immune cell activation, immune cell proliferation, immune cell differentiation, and cytokine expression. II. Compounds, Linker-Payloads, Conjugates, and Catabolites of Conjugates

[0119] Provided herein are compounds that bind TLR7. In certain embodiments, the compounds selectively bind TLR7. In certain embodiments, the compounds bind TLR8. In certain embodiments, the compounds bind TLR7 and TLR8. In certain embodiments, the compounds bind TLR7 selectively relative to binding TLR8. Antibody conjugates to TLR7 agonists could be used to deliver therapeutic or diagnostic payload moieties to target cells expressing tumor antigens for the treatment and / or diagnosis of such diseases. It is an object of the present disclosure to provide novel compounds and compositions thereof that can target TLR7 and / or provide treatment of diseases and disorders mediated by TLR7, such as inflammatory diseases and disorder, cell proliferation, and cancer.

[0120] Provided herein are compounds of Formula (I) and (IA):or a pharmaceutically acceptable salt, stereoisomer, or tautomer thereof; wherein L1, L2, R1, R2, X1, X2, X3, Ring A, Ring B, R4a, R4b, R5, R6, R7, R8, R9, R9a, and R9bare as defined herein. 33 1104675906\1\AMERICASAttorney Docket No.108843.00582 SU-0514WO

[0121] Also provided herein are linker-payloads of Formula (LP-I), (LP-II), and (LP-IIA):or a pharmaceutically acceptable salt, stereoisomer, or tautomer thereof; wherein L1, L2, L3, R1, R2, X1, X2, X3, Ring A, Ring B, R4a, R4b, R5, R6, R7, R8, R9, R9a, R9b, R11, R12, SG, W1, W2, HP, HP1, RA, O-Su, RL, w, y, and z are as defined herein.

[0122] Also provided herein are conjugates of the compounds. Antibody conjugates of TLR7 agonists could be used to deliver therapeutic or diagnostic payload moieties to target cells expressing tumor antigens for the treatment and / or diagnosis of such diseases. It is therefore an object of the present disclosure to provide conjugates and compositions thereof that can target TLR7 and / or provide treatment of diseases and disorders mediated by TLR7, such as inflammatory diseases and disorder, cell proliferation, and cancer.

[0123] Provided herein are conjugates of Formula (CONJ-I), (CONJ-II), and (CONJ-IIA):34 1104675906\1\AMERICASAttorney Docket No.108843.00582 SU-0514WOor a pharmaceutically acceptable salt, stereoisomer, tautomer, or catabolite thereof; wherein COMP, L, L1, L2, L3, R1, R2, X1, X2, X3, Ring A, Ring B, R4a, R4b, R5, R6, R7, R8, R9, R9a, R9b, R11, R12, SG, W1, W2, HP, HP1, RA, O-Su, RL, w, y, x, and z are as defined herein.

[0124] Also provided herein are conjugates of the compounds that comprise at least one TLR7 agonist and at least one additional cytotoxic payload. These conjugates could be used to deliver two therapeutic or diagnostic payload moieties to target cells expressing tumor antigens for the treatment and / or diagnosis of such diseases.

[0125] Provided herein are conjugates of Formula (CONJ-III), (CONJ-IV), (CONJ-IVA), and (CONJ-IVB):35 1104675906\1\AMERICASAttorney Docket No.108843.00582 SU-0514WO(CONJ-IVB) or a pharmaceutically acceptable salt, stereoisomer, tautomer, or catabolite thereof; wherein CY, L1, L2, L3, R1, R2, X1, Ring A, Ring B, R4a, R4b, R5, R6, R7, R8, R9, R9a, R9b, R11, R12, SG, W1, W2, HP, HP1, RA, RL, RL01, SG01, Y, O-Su, x, xx, w, y, and z are as defined herein. 36 1104675906\1\AMERICASAttorney Docket No.108843.00582 SU-0514WO

[0126] Also provided herein are catabolites of conjugates of Formula (CONJ-I)-(CONJ- IVB), for example a catabolite of (CA-I), (CA-II), or (CA-IIA):wherein RL' is a residue resulting from the catabolism of -RL-COMP; and L1, L2, L3, R1, R2, X1, Ring A, Ring B, R4a, R4b, R5, R6, R7, R8, R9, R9a, R9b, R11, R12, SG, W1, W2, HP, HP1, RA, O-Su, w, y, and z are as defined herein.

[0127] In certain embodiments of Formula (I), (IA), (LP-I), (LP-II), (LP-IIA), (CONJ-I), (CONJ-II), (CONJ-IIA), (CONJ-III), (CONJ-IV), (CONJ-IVA), (CONJ-IVB), (CA-I), (CA- II), or (CA-IIA), R1is C1-10alkyl optionally substituted with one or more substituents independently selected from R5. In certain embodiments of Formula (I), (IA), (LP-I), (LP-II), (LP-IIA), (CONJ-I), (CONJ-II), (CONJ-IIA), (CONJ-III), (CONJ-IV), (CONJ-IVA), (CONJ- IVB), (CA-I), (CA-II), or (CA-IIA), R1is unsubstituted C1-10alkyl. In certain embodiments of Formula (I), (IA), (LP-I), (LP-II), (LP-IIA), (CONJ-I), (CONJ-II), (CONJ-IIA), (CONJ-III), (CONJ-IV), (CONJ-IVA), (CONJ-IVB), (CA-I), (CA-II), or (CA-IIA), R1is C2-6 alkenylene or C2-6alkynylene, each of which is optionally substituted with one or more substituents independently selected from R5. In certain embodiments of Formula (I), (IA), (LP-I), (LP-II), (LP-IIA), (CONJ-I), (CONJ-II), (CONJ-IIA), (CONJ-III), (CONJ-IV), (CONJ-IVA), (CONJ- 37 1104675906\1\AMERICASAttorney Docket No.108843.00582 SU-0514WO IVB), (CA-I), (CA-II), or (CA-IIA), R1is unsubstituted C2-6alkenylene or unsubstituted C2-6 alkynylene.

[0128] In certain embodiments of Formula (I), (IA), (LP-I), (LP-II), (LP-IIA), (CONJ-I), (CONJ-II), (CONJ-IIA), (CONJ-III), (CONJ-IV), (CONJ-IVA), (CONJ-IVB), (CA-I), (CA- II), or (CA-IIA), R1is C1-6 alkyl optionally substituted with one or more substituents independently selected from R5. In certain embodiments of Formula (I), (IA), (LP-I), (LP-II), (LP-IIA), (CONJ-I), (CONJ-II), (CONJ-IIA), (CONJ-III), (CONJ-IV), (CONJ-IVA), (CONJ- IVB), (CA-I), (CA-II), or (CA-IIA), R1is unsubstituted C1-6 alkyl. In certain embodiments of Formula (I), (IA), (LP-I), (LP-II), (LP-IIA), (CONJ-I), (CONJ-II), (CONJ-IIA), (CONJ-III), (CONJ-IV), (CONJ-IVA), (CONJ-IVB), (CA-I), (CA-II), or (CA-IIA), R1is C1-4alkyl optionally substituted with one or more substituents independently selected from R5. In certain embodiments of Formula (I), (IA), (LP-I), (LP-II), (LP-IIA), (CONJ-I), (CONJ-II), (CONJ-IIA), (CONJ-III), (CONJ-IV), (CONJ-IVA), (CONJ-IVB), (CA-I), (CA-II), or (CA- IIA), R1is unsubstituted C1-4alkyl. In certain embodiments of Formula (I), (IA), (LP-I), (LP- II), (LP-IIA), (CONJ-I), (CONJ-II), (CONJ-IIA), (CONJ-III), (CONJ-IV), (CONJ-IVA), (CONJ-IVB), (CA-I), (CA-II), or (CA-IIA), R1is unsubstituted n-butyl.

[0129] In certain embodiments of Formula (I), (IA), (LP-I), (LP-II), (LP-IIA), (CONJ-I), (CONJ-II), (CONJ-IIA), (CONJ-III), (CONJ-IV), (CONJ-IVA), (CONJ-IVB), (CA-I), (CA- II), or (CA-IIA), X1is bond. In certain embodiments of Formula (I), (IA), (LP-I), (LP-II), (LP-IIA), (CONJ-I), (CONJ-II), (CONJ-IIA), (CONJ-III), (CONJ-IV), (CONJ-IVA), (CONJ- IVB), (CA-I), (CA-II), or (CA-IIA), X1is -O-. In certain embodiments of Formula (I), (IA), (LP-I), (LP-II), (LP-IIA), (CONJ-I), (CONJ-II), (CONJ-IIA), (CONJ-III), (CONJ-IV), (CONJ-IVA), (CONJ-IVB), (CA-I), (CA-II), or (CA-IIA), X1is -NR2-. In certain embodiments of Formula (I), (IA), (LP-I), (LP-II), (LP-IIA), (CONJ-I), (CONJ-II), (CONJ- IIA), (CONJ-III), (CONJ-IV), (CONJ-IVA), (CONJ-IVB), (CA-I), (CA-II), or (CA-IIA), X1is -NH-.

[0130] In certain embodiments of Formula (I), (IA), (LP-I), (LP-II), (LP-IIA), (CONJ-I), (CONJ-II), (CONJ-IIA), (CONJ-III), (CONJ-IV), (CONJ-IVA), (CONJ-IVB), (CA-I), (CA- II), or (CA-IIA), R1is C1-6 alkyl optionally substituted with one or more substituents independently selected from R5and X1is -O-. In certain embodiments of Formula (I), (IA), (LP-I), (LP-II), (LP-IIA), (CONJ-I), (CONJ-II), (CONJ-IIA), (CONJ-III), (CONJ-IV), (CONJ-IVA), (CONJ-IVB), (CA-I), (CA-II), or (CA-IIA), R1is C1-6 alkyl optionally substituted with one or more substituents independently selected from R5and X1is -NH-. In certain embodiments of Formula (I), (IA), (LP-I), (LP-II), (LP-IIA), (CONJ-I), (CONJ-II), 38 1104675906\1\AMERICASAttorney Docket No.108843.00582 SU-0514WO (CONJ-IIA), (CONJ-III), (CONJ-IV), (CONJ-IVA), (CONJ-IVB), (CA-I), (CA-II), or (CA- IIA), R1is unsubstituted C1-6 alkyl and X1is -O-. In certain embodiments of Formula (I), (IA), (LP-I), (LP-II), (LP-IIA), (CONJ-I), (CONJ-II), (CONJ-IIA), (CONJ-III), (CONJ-IV), (CONJ-IVA), (CONJ-IVB), (CA-I), (CA-II), or (CA-IIA), R1is unsubstituted C1-6alkyl and X1is -NH-. In certain embodiments of Formula (I), (IA), (LP-I), (LP-II), (LP-IIA), (CONJ-I), (CONJ-II), (CONJ-IIA), (CONJ-III), (CONJ-IV), (CONJ-IVA), (CONJ-IVB), (CA-I), (CA- II), or (CA-IIA), R1is unsubstituted n-butyl and X1is -O-. In certain embodiments of Formula (I), (IA), (LP-I), (LP-II), (LP-IIA), (CONJ-I), (CONJ-II), (CONJ-IIA), (CONJ-III), (CONJ-IV), (CONJ-IVA), (CONJ-IVB), (CA-I), (CA-II), or (CA-IIA), R1is unsubstituted n- butyl and X1is -NH-.

[0131] In certain embodiments of Formula (I), (IA), (LP-I), (LP-II), (LP-IIA), (CONJ-I), (CONJ-II), (CONJ-IIA), (CONJ-III), (CONJ-IV), (CONJ-IVA), (CONJ-IVB), (CA-I), (CA- II), or (CA-IIA), including any of the foregoing, L1is C1-6 alkyl optionally substituted with one or more substituents independently selected from R5. In certain embodiments of Formula (I), (IA), (LP-I), (LP-II), (LP-IIA), (CONJ-I), (CONJ-II), (CONJ-IIA), (CONJ-III), (CONJ- IV), (CONJ-IVA), (CONJ-IVB), (CA-I), (CA-II), or (CA-IIA), including any of the foregoing, L1is unsubstituted C1-6alkyl. In certain embodiments of Formula (I), (IA), (LP-I), (LP-II), (LP-IIA), (CONJ-I), (CONJ-II), (CONJ-IIA), (CONJ-III), (CONJ-IV), (CONJ-IVA), (CONJ-IVB), (CA-I), (CA-II), or (CA-IIA), including any of the foregoing, L1is C2- 6 alkenylene or C2-6alkynylene, each of which is optionally substituted with one or more substituents independently selected from R5. In certain embodiments of Formula (I), (IA), (LP-I), (LP-II), (LP-IIA), (CONJ-I), (CONJ-II), (CONJ-IIA), (CONJ-III), (CONJ-IV), (CONJ-IVA), (CONJ-IVB), (CA-I), (CA-II), or (CA-IIA), including any of the foregoing, L1is unsubstituted C2-6alkenylene or unsubstituted C2-6alkynylene. In certain embodiments of Formula (I), (IA), (LP-I), (LP-II), (LP-IIA), (CONJ-I), (CONJ-II), (CONJ-IIA), (CONJ-III), (CONJ-IV), (CONJ-IVA), (CONJ-IVB), (CA-I), (CA-II), or (CA-IIA), including any of the foregoing, L1is C1-4alkyl optionally substituted with one or more substituents independently selected from R5. In certain embodiments of Formula (I), (IA), (LP-I), (LP-II), (LP-IIA), (CONJ-I), (CONJ-II), (CONJ-IIA), (CONJ-III), (CONJ-IV), (CONJ-IVA), (CONJ-IVB), (CA-I), (CA-II), or (CA-IIA), including any of the foregoing, L1is unsubstituted C1-4 alkyl. In certain embodiments of Formula (I), (IA), (LP-I), (LP-II), (LP-IIA), (CONJ-I), (CONJ-II), 39 1104675906\1\AMERICASAttorney Docket No.108843.00582 SU-0514WO (CONJ-IIA), (CONJ-III), (CONJ-IV), (CONJ-IVA), (CONJ-IVB), (CA-I), (CA-II), or (CA- IIA), including any of the foregoing, L1is unsubstituted -CH2-.

[0132] In certain embodiments of Formula (I), (IA), (LP-I), (LP-II), (LP-IIA), (CONJ-I), (CONJ-II), (CONJ-IIA), (CONJ-III), (CONJ-IV), (CONJ-IVA), (CONJ-IVB), (CA-I), (CA- II), or (CA-IIA), including any of the foregoing, L2is -O-. In certain embodiments of Formula (I), (IA), (LP-I), (LP-II), (LP-IIA), (CONJ-I), (CONJ-II), (CONJ-IIA), (CONJ-III), (CONJ-IV), (CONJ-IVA), (CONJ-IVB), (CA-I), (CA- II), or (CA-IIA), including any of the foregoing, L2is -NR2-. In certain embodiments of Formula (I), (IA), (LP-I), (LP-II), (LP-IIA), (CONJ-I), (CONJ-II), (CONJ-IIA), (CONJ-III), (CONJ-IV), (CONJ-IVA), (CONJ-IVB), (CA-I), (CA-II), or (CA-IIA), including any of the foregoing, L2is -NH-.

[0133] In certain embodiments of Formula (I), (IA), (LP-I), (LP-II), (LP-IIA), (CONJ-I), (CONJ-II), (CONJ-IIA), (CONJ-III), (CONJ-IV), (CONJ-IVA), (CONJ-IVB), (CA-I), (CA- II), or (CA-IIA), including any of the foregoing, L2is C1-6alkylene optionally substituted with one or more one or more substituents independently selected from R5. In certain embodiments of Formula (I), (IA), (LP-I), (LP-II), (LP-IIA), (CONJ-I), (CONJ-II), (CONJ- IIA), (CONJ-III), (CONJ-IV), (CONJ-IVA), (CONJ-IVB), (CA-I), (CA-II), or (CA-IIA), including any of the foregoing, L2is unsubstituted C1-6alkylene. In certain embodiments of Formula (I), (IA), (LP-I), (LP-II), (LP-IIA), (CONJ-I), (CONJ-II), (CONJ-IIA), (CONJ-III), (CONJ-IV), (CONJ-IVA), (CONJ-IVB), (CA-I), (CA-II), or (CA-IIA), including any of the foregoing, L2is C1-4alkylene optionally substituted with one or more one or more substituents independently selected from R5. In certain embodiments of Formula (I), (IA), (LP-I), (LP-II), (LP-IIA), (CONJ-I), (CONJ-II), (CONJ-IIA), (CONJ-III), (CONJ-IV), (CONJ-IVA), (CONJ-IVB), (CA-I), (CA-II), or (CA-IIA), including any of the foregoing, L2is unsubstituted C1-4alkylene. In certain embodiments of Formula (I), (IA), (LP-I), (LP-II), (LP-IIA), (CONJ-I), (CONJ-II), (CONJ-IIA), (CONJ-III), (CONJ-IV), (CONJ-IVA), (CONJ- IVB), (CA-I), (CA-II), or (CA-IIA), including any of the foregoing, L2is -CH2-.

[0134] In certain embodiments of Formula (I), (IA), (LP-I), (LP-II), (LP-IIA), (CONJ-I), (CONJ-II), (CONJ-IIA), (CONJ-III), (CONJ-IV), (CONJ-IVA), (CONJ-IVB), (CA-I), (CA- II), or (CA-IIA), including any of the foregoing, L2is C2-6 alkenylene optionally substituted with one or more one or more substituents independently selected from R5. In certain embodiments of Formula (I), (IA), (LP-I), (LP-II), (LP-IIA), (CONJ-I), (CONJ-II), (CONJ- IIA), (CONJ-III), (CONJ-IV), (CONJ-IVA), (CONJ-IVB), (CA-I), (CA-II), or (CA-IIA), including any of the foregoing, L2is C2-6alkynylene optionally substituted with one or more 40 1104675906\1\AMERICASAttorney Docket No.108843.00582 SU-0514WO one or more substituents independently selected from R5. In certain embodiments of Formula (I), (IA), (LP-I), (LP-II), (LP-IIA), (CONJ-I), (CONJ-II), (CONJ-IIA), (CONJ-III), (CONJ- IV), (CONJ-IVA), (CONJ-IVB), (CA-I), (CA-II), or (CA-IIA), including any of the foregoing, L2is unsubstituted C2-6alkenylene or unsubstituted C2-6alkynylene. In certain embodiments of Formula (I), (IA), (LP-I), (LP-II), (LP-IIA), (CONJ-I), (CONJ-II), (CONJ- IIA), (CONJ-III), (CONJ-IV), (CONJ-IVA), (CONJ-IVB), (CA-I), (CA-II), or (CA-IIA), including any of the foregoing, L2is -O-(C1-6alkylene)- or -NR2-(C1-6alkylene)- wherein the alkylene is optionally substituted with one or more one or more substituents independently selected from R5. In certain embodiments of Formula (I), (IA), (LP-I), (LP-II), (LP-IIA), (CONJ-I), (CONJ-II), (CONJ-IIA), (CONJ-III), (CONJ-IV), (CONJ-IVA), (CONJ-IVB), (CA-I), (CA-II), or (CA-IIA), including any of the foregoing, L2is unsubstituted -O-(C1-6alkylene)- or unsubstituted -NR2-(C1-6 alkylene)-.

[0135] In certain embodiments of Formula (I), (LP-I), (LP-II), (CONJ-I), (CONJ-II), (CONJ- III), (CONJ-IV), (CONJ-IVA), (CONJ-IVB), (CA-I), or (CA-II), including any of the foregoing, Ring B is arylene optionally substituted with one or more R8. In certain embodiments of Formula (I), (LP-I), (LP-II), (CONJ-I), (CONJ-II), (CONJ-III), (CONJ-IV), (CONJ-IVA), (CONJ-IVB), (CA-I), or (CA-II), including any of the foregoing, Ring B is arylene substituted with one or more R8wherein R8is -OR6, -C(O)R6, -C(O)OR6, or -OC(O)R6. In certain embodiments of Formula (I), (LP-I), (LP-II), (CONJ-I), (CONJ-II), (CONJ-III), (CONJ-IV), (CONJ-IVA), (CONJ-IVB), (CA-I), or (CA-II), including any of the foregoing, Ring B is arylene substituted with one or more R8wherein R8is -OCH3, -C(O)CH3, -C(O)OH, -C(O)OCH3, or -OC(O)CH3. In certain embodiments of Formula (I), (LP-I), (LP-II), (CONJ-I), (CONJ-II), (CONJ-III), (CONJ-IV), (CONJ-IVA), (CONJ-IVB), (CA-I), or (CA-II), including any of the foregoing, Ring B is arylene substituted with one or more R8wherein R8is -OCH3, -C(O)OH, or -C(O)OCH3. In certain embodiments of Formula (I), (LP-I), (LP-II), (CONJ-I), (CONJ-II), (CONJ-III), (CONJ-IV), (CONJ-IVA), (CONJ- IVB), (CA-I), or (CA-II), including any of the foregoing, Ring B is unsubstituted arylene. In certain embodiments of Formula (CONJ-III), (CONJ-IV), (CONJ-IVA), or (CONJ-IVB), including any of the foregoing, Ring B iswherein X2and X3are independently selected from N and CR3.

[0136] In certain embodiments of Formula (I), (LP-I), (LP-II), (CONJ-I), (CONJ-II), (CONJ- III), (CONJ-IV), (CONJ-IVA), (CONJ-IVB), (CA-I), or (CA-II), including any of the 41 1104675906\1\AMERICASAttorney Docket No.108843.00582 SU-0514WO foregoing, Ring B is heteroarylene optionally substituted with one or more R8. In certain embodiments of Formula (I), (LP-I), (LP-II), (CONJ-I), (CONJ-II), (CONJ-III), (CONJ-IV), (CONJ-IVA), (CONJ-IVB), (CA-I), or (CA-II), including any of the foregoing, Ring B is a monocyclic heteroarylene optionally substituted with one or more R8. In certain embodiments of Formula (I), (LP-I), (LP-II), (CONJ-I), (CONJ-II), (CONJ-III), (CONJ-IV), (CONJ-IVA), (CONJ-IVB), (CA-I), or (CA-II), including any of the foregoing, Ring B is a monocyclic heteroarylene with 5 to 15 ring atoms optionally substituted with one or more R8. In certain embodiments of Formula (I), (LP-I), (LP-II), (CONJ-I), (CONJ-II), (CONJ-III), (CONJ-IV), (CONJ-IVA), (CONJ-IVB), (CA-I), or (CA-II), including any of the foregoing, Ring B is a monocyclic heteroarylene comprising at least one oxygen and / or one nitrogen optionally substituted with one or more R8. In certain embodiments of Formula (I), (LP-I), (LP-II), (CONJ-I), (CONJ-II), (CONJ-III), (CONJ-IV), (CONJ-IVA), (CONJ-IVB), (CA-I), or (CA- II), including any of the foregoing, Ring B is a monocyclic heteroarylene comprising at least one nitrogen atom optionally substituted with one or more R8.

[0137] In certain embodiments of Formula (I), (LP-I), (LP-II), (CONJ-I), (CONJ-II), (CONJ- III), (CONJ-IV), (CONJ-IVA), (CONJ-IVB), (CA-I), or (CA-II), including any of the foregoing, Ring B is unsubstituted heteroarylene. In certain embodiments of Formula (I), (LP-I), (LP-II), (CONJ-I), (CONJ-II), (CONJ-III), (CONJ-IV), (CONJ-IVA), (CONJ-IVB), (CA-I), or (CA-II), including any of the foregoing, Ring B is unsubstituted heteroarylene comprising at least one oxygen atom and / or one nitrogen atom. In certain embodiments of Formula (I), (LP-I), (LP-II), (CONJ-I), (CONJ-II), (CONJ-III), (CONJ-IV), (CONJ-IVA), (CONJ-IVB), (CA-I), or (CA-II), including any of the foregoing, Ring B is an unsubstituted monocyclic heteroarylene. In certain embodiments of Formula (I), (LP-I), (LP-II), (CONJ-I), (CONJ-II), (CONJ-III), (CONJ-IV), (CONJ-IVA), (CONJ-IVB), (CA-I), or (CA-II), including any of the foregoing, Ring B is an unsubstituted monocyclic heteroarylene with 5 to 15 ring atoms.

[0138] In certain embodiments of Formula (IA), (LP-IIA), (CONJ-IIA), (CONJ-III), (CONJ- IV), (CONJ-IVA), (CONJ-IVB), or (CA-I), including any of the foregoing, X2is CR3and X3is CR3. In certain embodiments of Formula (IA), (LP-IA), (CONJ-IIA), (CONJ-III), (CONJ- IV), (CONJ-IVA), (CONJ-IVB), or (CA-I), including any of the foregoing, X2is N and X3is CR3. In certain embodiments of Formula (IA), (LP-IIA), (CONJ-IIA), (CONJ-III), (CONJ- IV), (CONJ-IVA), (CONJ-IVB), or (CA-I), including any of the foregoing, X2is CR3and X3is N. In certain embodiments of Formula (IA), (LP-IIA), (CONJ-IIA), (CONJ-III), (CONJ- 42 1104675906\1\AMERICASAttorney Docket No.108843.00582 SU-0514WO IV), (CONJ-IVA), (CONJ-IVB), or (CA-I), including any of the foregoing, X2is N and X3is N.

[0139] In certain embodiments of Formula (IA), (LP-IIA), (CONJ-IIA), (CONJ-III), (CONJ- IV), (CONJ-IVA), (CONJ-IVB), or (CA-I), including any of the foregoing, X2is CH and X3is CR3. In certain embodiments of Formula (IA), (LP-IIA), (CONJ-IIA), (CONJ-III), (CONJ- IV), (CONJ-IVA), (CONJ-IVB), or (CA-I), including any of the foregoing, X2is CR3and X3is CH. In certain embodiments of Formula (IA), (LP-IIA), (CONJ-IIA), (CONJ-III), (CONJ- IV), (CONJ-IVA), (CONJ-IVB), or (CA-I), including any of the foregoing, X2is CH and X3is CH.

[0140] In certain embodiments of Formula (IA), (LP-IIA), (CONJ-IIA), (CONJ-III), (CONJ- IV), (CONJ-IVA), (CONJ-IVB), or (CA-I), including any of the foregoing, R3is hydrogen, - OR6, -C(O)R6, -C(O)OR6, or -OC(O)R6. In certain embodiments of Formula (IA), (LP-IIA), (CONJ-IIA), (CONJ-III), (CONJ-IV), (CONJ-IVA), (CONJ-IVB), or (CA-I), including any of the foregoing, R3is hydrogen, -OR6, or -C(O)OR6. In certain embodiments of Formula (IA), (LP-IIA), (CONJ-IIA), (CONJ-III), (CONJ-IV), (CONJ-IVA), (CONJ-IVB), or (CA-I), including any of the foregoing, R3is hydrogen. In certain embodiments of Formula (IA), (LP- IIA), (CONJ-IIA), or (CA-I), including any of the foregoing, R3is -OR6. In certain embodiments of Formula (IA), (LP-IIA), (CONJ-IIA), (CONJ-III), (CONJ-IV), (CONJ-IVA), (CONJ-IVB), or (CA-I), including any of the foregoing, R3is -OH. In certain embodiments of Formula (IA), (LP-IIA), (CONJ-IIA), (CONJ-III), (CONJ-IV), (CONJ-IVA), (CONJ- IVB), or (CA-I), including any of the foregoing, R3is -OCH3. In certain embodiments of Formula (IA), (LP-IIA), (CONJ-IIA), or (CA-I), including any of the foregoing, R3is -C(O)OR6. In certain embodiments of Formula (IA), (LP-IIA), (CONJ-IIA), (CONJ-III), (CONJ-IV), (CONJ-IVA), (CONJ-IVB), or (CA-I), including any of the foregoing, R3is -C(O)OH. In certain embodiments of Formula (IA), (LP-IIA), (CONJ-IIA), (CONJ-III), (CONJ-IV), (CONJ-IVA), (CONJ-IVB), or (CA-I), including any of the foregoing, R3is -C(O)OCH3.

[0141] In certain embodiments of Formula (IA), (LP-IIA), (CONJ-IIA), (CONJ-III), (CONJ- IV), (CONJ-IVA), (CONJ-IVB), or (CA-I), including any of the foregoing, R6is hydrogen or C1-10 alkyl. In certain embodiments of Formula (IA), (LP-IIA), (CONJ-IIA), (CONJ-III), (CONJ-IV), (CONJ-IVA), (CONJ-IVB), or (CA-I), including any of the foregoing, R6is hydrogen. In certain embodiments of Formula (IA), (LP-IIA), (CONJ-IIA), (CONJ-III), (CONJ-IV), (CONJ-IVA), (CONJ-IVB), or (CA-I), including any of the foregoing, R6is C1-10 alkyl. In certain embodiments of Formula (IA), (LP-IIA), (CONJ-IIA), (CONJ-III), (CONJ- 43 1104675906\1\AMERICASAttorney Docket No.108843.00582 SU-0514WO IV), (CONJ-IVA), (CONJ-IVB), or (CA-I), including any of the foregoing, R6is C1-4alkyl. In certain embodiments of Formula (IA), (LP-IIA), (CONJ-IIA), (CONJ-III), (CONJ-IV), (CONJ-IVA), (CONJ-IVB), or (CA-I), including any of the foregoing, R6is -CH3.

[0142] In certain embodiments of Formula (IA), (LP-IIA), (CONJ-IIA), (CONJ-III), (CONJ- IV), (CONJ-IVA), (CONJ-IVB), or (CA-I), including any of the foregoing, X2is CR3and X3is CH wherein R3is -C(O)OCH3. In certain embodiments of Formula (IA), (LP-IIA), (CONJ- IIA), (CONJ-III), (CONJ-IV), (CONJ-IVA), (CONJ-IVB), or (CA-I), including any of the foregoing, X2is CR3and X3is CH wherein R3is -C(O)OH. In certain embodiments of Formula (IA), (LP-IIA), (CONJ-IIA), (CONJ-III), (CONJ-IV), (CONJ-IVA), (CONJ-IVB), or (CA-I), including any of the foregoing, X2is CR3and X3is CH wherein R3is -OCH3.

[0143] In certain embodiments of Formula (I), (IA), (LP-I), (LP-II), (LP-IIA), (CONJ-I), (CONJ-II), (CONJ-IIA), (CONJ-III), (CONJ-IV), (CONJ-IVA), (CONJ-IVB), (CA-I), or (CA-II), including any of the foregoing, R1is C1-10 alkyl optionally substituted with one or more substituents independently selected from R5; X1is O or NH; L1is C1-4alkylene optionally substituted with one or more substituents independently selected from R5; and L2is -CH2- or -O-.

[0144] In certain embodiments of Formula (I), (IA), (LP-I), (LP-II), (LP-IIA), (CONJ-I), (CONJ-II), (CONJ-IIA), (CONJ-III), (CONJ-IV), (CONJ-IVA), (CONJ-IVB), (CA-I), or (CA-II), including any of the foregoing, R1is unsubstituted C1-6 alkyl; X1is O or NH; L1is unsubstituted C1-4alkylene; and L2is -CH2- or -O-.

[0145] In certain embodiments of Formula (I), (IA), (LP-I), (LP-II), (LP-IIA), (CONJ-I), (CONJ-II), (CONJ-IIA), (CONJ-III), (CONJ-IV), (CONJ-IVA), (CONJ-IVB), (CA-I), or (CA-II), including any of the foregoing, R1is n-butyl; X1is O or NH; L1is -CH2-; and L2is -CH2- or -O-.

[0146] In certain embodiments of Formula (IA), (LP-IIA), (CONJ-IIA), or (CA-IIA),, 44 1104675906\1\AMERICASAttorney Docket No.108843.00582 SU-0514WOrepresents the attachment to the remainder of the formula.

[0147] In certain embodiments of Formula (I), (LP-I), (LP-II), (CONJ-I), (CONJ-II), (CONJ- III), (CONJ-IV), (CONJ-IVA), (CONJ-IVB), (CA-I), or (CA-II),45 1104675906\1\AMERICASAttorney Docket No.108843.00582 SU-0514WO; wherein represents the attachment to the remainder of the formula. a. Compounds of Formula (I) and (IA)

[0148] In one embodiment of Formula (I) or (IA), including any of the foregoing, Ring A is a bicyclic heterocycle optionally substituted with one or more R8. In one embodiment of Formula (I) or (IA), including any of the foregoing, Ring A is a bridged, fused, or spirocyclic bicyclic heterocycle optionally substituted with one or more R8. In one embodiment of Formula (I) or (IA), including any of the foregoing, Ring A is a bridged, fused, or spirocyclic bicyclic heterocycle comprising at least one N atom and / or at least one O atom wherein the heterocycle is optionally substituted with one or more R8. In one embodiment of Formula (I) or (IA), including any of the foregoing, Ring A is a bridged, fused, or spirocyclic bicyclic heterocycle comprising two N atoms and one O atom wherein the heterocycle is optionally substituted with one or more R8. In one embodiment of Formula (I) or (IA), including any of the foregoing, Ring A is an optionally substituted 5- to 12- membered bridged, fused, or spirocyclic bicyclic heterocycle optionally substituted with one or more R8. In one embodiment of Formula (I) or (IA), including any of the foregoing, Ring A is an optionally substituted 8- to 12- membered bridged, fused, or spirocyclic bicyclic heterocycle optionally substituted with one or more R8.

[0149] In one embodiment of Formula (I) or (IA), including any of the foregoing, Ring A is a N-linked bridged, fused, or spirocyclic bicyclic heterocycle optionally substituted with one or more R8. In one embodiment of Formula (I) or (IA), including any of the foregoing, Ring A is a N-linked bridged or spirocyclic bicyclic heterocycle comprising at least one nitrogen atoms, including the nitrogen attached to L2wherein the heterocycle is optionally substituted with one or more R8. In one embodiment of Formula (I) or (IA), including any of the foregoing, 46 1104675906\1\AMERICASAttorney Docket No.108843.00582 SU-0514WO Ring A is a N-linked bridged or spirocyclic bicyclic heterocycle comprising at least two nitrogen atoms, including the nitrogen attached to L2wherein the heterocycle is optionally substituted with one or more R8. In one embodiment of Formula (I) or (IA), including any of the foregoing, Ring A is a N-linked bridged or spirocyclic bicyclic heterocycle comprising at least two nitrogen atoms, including the nitrogen attached to L2, and one oxygen atom wherein the heterocycle is optionally substituted with one or more R8.

[0150] In one embodiment of Formula (I) or (IA), including any of the foregoing, Ring A is selected froman integer selected from 1, 2, 3, 4, and 5; each of m, n, o, and p is an integer independently selected from 1, 2, and 3; andrepresents attachment to the rest of the compound.

[0151] In one embodiment of Formula (I) or (IA), including any of the foregoing, Ring A isw e e represents attachment to the rest of the compound. In one embodiment of Formula (I) or (IA), including any of the foregoing, Ring A is.

[0152] In one embodiment of Formula (I) or (IA), including any of the foregoing, Ring A isw eren represents attachment to the rest of the compound. In one embodiment of Formula (I) or (IA), including any of the foregoing, Ring,47 1104675906\1\AMERICASAttorney Docket No.108843.00582 SU-0514WO

[0153] In one embodiment of Formula (I) or (IA), including any of the foregoing, Ring A isw e e represents attachment to the rest of the compound. In one embodiment of Formula (I) or (IA), including any of the foregoing, Ring A is ,

[0154] In one embodiment of Formula (I) or (IA), including any of the foregoing, Ring A is,represents attachment to the rest of the compound.

[0155] In one embodiment of Formula (I) or (IA), including any of the foregoing, Ring A isattachment to the rest of the compound. In one embodiment of Formula (I) or (IA), including any of the foregoing, Ring A is.

[0156] In one embodiment of Formula (I) or (IA), including any of the foregoing, Ring A isw ere n represents attachment to the rest of the compound. In one embodiment of Formula (I) or (IA), including any of the foregoing, Ring A is. In one embodiment of Formula (I) or (IA), including any of the 48 1104675906\1\AMERICASAttorney Docket No.108843.00582 SU-0514WO foregoing, Ring A is . In one embodiment of Formula (I) or (IA), including any of the foregoing, Ring A is.

[0157] In one embodiment of Formula (I) or (IA), including any of the foregoing, Ring A is orwhereinrepresents attachment to the rest of the compound.

[0158] In one embodiment of Formula (I) or (IA), including any of the foregoing, Ring A isrepresents attachment to the rest of the compound.

[0159] In one embodiment of Formula (I) or (IA), including any of the foregoing, Ring A is a 3- to 5-membered heterocycle optionally substituted with one or more R4aand further optionally substituted with one or more R8. In one embodiment of Formula (I) or (IA), including any of the foregoing, Ring A is a 3- to 5-membered heterocycle comprising at least one nitrogen atom wherein the heterocycle is optionally substituted with one or more R4aand further optionally substituted with one or more R8. In one embodiment of Formula (I) or (IA), including any of the foregoing, Ring A is a N-linked 3- to 5-membered heterocycle optionally substituted with one or more R4aand further optionally substituted with one or more R8. In one embodiment of Formula (I) or (IA), including any of the foregoing, Ring A is a N-linked 3- to 5-membered heterocycle comprising at least one nitrogen atom, including the N attached to L2, wherein the heterocycle is optionally substituted with one or more R4aand further optionally substituted with one or more R8. In one embodiment of Formula (I) or (IA), including any of the foregoing, Ring A is an unsubstituted N-linked 3- to 5-membered heterocycle comprising at least one nitrogen atom, including the N attached to L2. In one embodiment of Formula (I) or (IA), including any of the foregoing, Ring A is, orwherein represents attachment to the rest of the compound.

[0160] In one embodiment of Formula (I) or (IA), including any of the foregoing, R4ais a 5- to 8-membered heterocycle optionally substituted with one or more R8. In one embodiment of Formula (I) or (IA), including any of the foregoing, R4ais a 5- to 8-membered heterocycle 49 1104675906\1\AMERICASAttorney Docket No.108843.00582 SU-0514WO comprising at least one nitrogen atom and the heterocycle is optionally substituted with one or more R8. In one embodiment of Formula (I) or (IA), including any of the foregoing, R4ais an unsubstituted 5- to 8-membered heterocycle comprising at least one nitrogen atom.

[0161] In one embodiment of Formula (I) or (IA), including any of the foregoing, R4aisrepresents attachment to the rest of the compound. In one embodiment of Formula (I) or (IA), including any of the foregoing, R4ais.

[0162] In one embodiment of Formula (I) or (IA), including any of the foregoing, Ring A is, , represents attachment to the rest of the compound. In one embodiment of Formula (I) or (IA), including any of the

[0163] In one embodiment of Formula (I) or (IA), including any of the foregoing, Ring A is a 6- to 12-membered heterocycle substituted with R4band optionally substituted with one or more R8. In one embodiment of Formula (I) or (IA), including any of the foregoing, Ring A is a 6- to 8-membered heterocycle substituted with R4band optionally substituted with one or more R8. In one embodiment of Formula (I) or (IA), including any of the foregoing, Ring A is a 6- to 8-membered heterocycle comprising at least one nitrogen wherein the heterocycle is substituted with R4band optionally substituted with one or more R8.

[0164] In one embodiment of Formula (I) or (IA), including any of the foregoing, Ring A isrest of the compound. 50 1104675906\1\AMERICASAttorney Docket No.108843.00582 SU-0514WO

[0165] In one embodiment of Formula (I) or (IA), including any of the foregoing, Ring A is

[0166] In one embodiment of Formula (I) or (IA), including any of the foregoing, Ring A is. In one embodiment of Formula (I) or (IA), including any of the foregoing, Ring A iswhereinrepresents attachment to the rest of the compound.

[0167] In one embodiment of Formula (I) or (IA), including any of the foregoing, R4bis an 8- to 12- membered bridged or fused bicyclic heterocycle optionally substituted with one or more R8. In one embodiment of Formula (I) or (IA), including any of the foregoing, R4bis an 8- to 12- membered bridged or fused bicyclic heterocycle comprising 1, 2, 3, or 4 heteroatoms selected from N, S, and O wherein at least one heteroatom is N and wherein the heterocycle is optionally substituted with one or more R8. In one embodiment of Formula (I) or (IA), including any of the foregoing, R4bis a 5-5 fused ring system, a 5-6 fused ring system, a 6-6 fused ring system, or a 5-7 fused ring system comprising 1, 2, 3, or 4 heteroatoms selected from N, S, and O wherein at least one heteroatom is N and wherein the heterocycle is optionally substituted with one or more R8. In one embodiment of Formula (I) or (IA), including any of the foregoing, R4bis a 5-6 fused ring system comprising 1, 2, 3, or 4 heteroatoms selected from N, S, and O wherein at least one heteroatom is N and wherein the heterocycle is optionally substituted with one or more R8. 51 1104675906\1\AMERICASAttorney Docket No.108843.00582 SU-0514WO

[0168] In one embodiment of Formula (I) or (IA), including any of the foregoing, R4bis ,wherein X5, X6, X9, X10are independently N or CR20; X7and X8are independently NH, O, or CHR20; R20is hydrogen or C1-6 alkyl; R5is as defined herein; and is the point of attachment to the rest of the compound; wherein if four of any one of X5-X10are present, at least one is CR20or CHR20.

[0169] In one embodiment of Formula (I) or (IA), including any of the foregoing, R4bis ,

[0170] In one embodiment of Formula (I) or (IA), including any of the foregoing, R4bis.

[0171] In one embodiment of Formula (I) or (IA), including any of the foregoing, Ring A is. 52 1104675906\1\AMERICASAttorney Docket No.108843.00582 SU-0514WO

[0172] In one embodiment of Formula (I) or (IA), the compound is selected from the compounds of Table A:53 1104675906\1\AMERICASAttorney Docket No.108843.00582 SU-0514WO54 1104675906\1\AMERICASAttorney Docket No.108843.00582 SU-0514WO55 1104675906\1\AMERICASAttorney Docket No.108843.00582 SU-0514WOor a pharmaceutically acceptable salt, stereoisomer, or tautomer thereof. b. Linker Payloads of Formula (LP-I), (LP-II), and (LP-IIA), Conjugates of Formula (CONJ-I), (CONJ-II), (CONJ-IIA), (CONJ-III), (CONJ-IV), (CONJ-IVA), and (CONJ- IVB) and Catabolites of Formula (CA-I), (CA-II), and (CA-IIA) 56 1104675906\1\AMERICASAttorney Docket No.108843.00582 SU-0514WO

[0173] Provided herein are linker-payload compounds comprising a compound of Formula (I) or (IA) wherein the compound of Formula (I) or (IA) is linked to RG optionally via a linker wherein RG is a reactive linker group. In one embodiment, the linker-payload is of Formula (LP-I). In one embodiment, the linker-payload is of Formula (LP-II). In one embodiment, the linker-payload is of Formula (LP-IIA).

[0174] Also provided herein are conjugates comprising a compound of Formula (I) or Formula (IA) wherein the compound of Formula (I) or Formula (IA) is linked to a COMP optionally via a linker wherein COMP is a macromolecule. In one embodiment, the COMP is an antibody or antigen binding fragment thereof. In one embodiment, the COMP is an antibody chain. In one embodiment, the conjugate is of Formula (CONJ-I). In one embodiment, the conjugate is of Formula (CONJ-II). In one embodiment, the conjugate is of Formula (CONJ-IIA).

[0175] Also provided herein are conjugates comprising (a) a compound of Formula (I) or Formula (IA) wherein the compound of Formula (I) or Formula (IA) is linked to a COMP optionally via a first linker and (b) an additional cytotoxic agent linked to COMP optionally via a second linker wherein COMP is a macromolecule. In one embodiment, the COMP is an antibody or antigen binding fragment thereof. In one embodiment, the COMP is an antibody chain. In one embodiment, the conjugate is of Formula (CONJ-III). In one embodiment, the conjugate is of Formula (CONJ-IV). In one embodiment, the conjugate is of Formula (CONJ- IVA). In one embodiment, the conjugate is of Formula (CONJ-IVB).

[0176] Also provided herein are catabolites of conjugates of Formula (CONJ-I), (CONJ-II), (CONJ-IIA), (CONJ-III), (CONJ-IV), (CONJ-IVA), and (CONJ-IVB). In one embodiment, the catabolite is of Formula (CA-I). In one embodiment, the catabolite is of Formula (CA-II). In one embodiment, the catabolite is of Formula (CA-IIA).

[0177] In one embodiment of Formula (LP-I), (LP-II), (LP-IIA), (CONJ-I), (CONJ-II), (CONJ-IIA), (CONJ-III), (CONJ-IV), (CONJ-IVA), (CONJ-IVB), (CA-I), (CA-II), or (CA- IIA), including any of the foregoing, Ring A is a bicyclic heterocycle optionally substituted with one or more R8wherein Ring A is attached to L. In one embodiment of Formula (LP-I), (LP-II), (LP-IIA), (CONJ-I), (CONJ-II), (CONJ-IIA), (CONJ-III), (CONJ-IV), (CONJ-IVA), (CONJ-IVB), (CA-I), (CA-II), or (CA-IIA), including any of the foregoing, Ring A is a bridged, fused, or spirocyclic bicyclic heterocycle optionally substituted with one or more R8wherein Ring A is attached to L. In one embodiment of Formula (LP-I), (LP-II), (LP-IIA), (CONJ-I), (CONJ-II), (CONJ-IIA), (CONJ-III), (CONJ-IV), (CONJ-IVA), (CONJ-IVB), (CA-I), (CA-II), or (CA-IIA), including any of the foregoing, Ring A is a bridged, fused, or 57 1104675906\1\AMERICASAttorney Docket No.108843.00582 SU-0514WO spirocyclic bicyclic heterocycle comprising at least one N atom and / or at least one O atom wherein the heterocycle is optionally substituted with one or more R8wherein Ring A is attached to L. In one embodiment of Formula (LP-I), (LP-II), (LP-IIA), (CONJ-I), (CONJ-II), (CONJ-IIA), (CONJ-III), (CONJ-IV), (CONJ-IVA), (CONJ-IVB), (CA-I), (CA-II), or (CA- IIA), including any of the foregoing, Ring A is a bridged, fused, or spirocyclic bicyclic heterocycle comprising two N atoms and one O atom wherein the heterocycle is optionally substituted with one or more R8wherein Ring A is attached to L. In one embodiment of Formula (LP-I), (LP-II), (LP-IIA), (CONJ-I), (CONJ-II), (CONJ-IIA), ((CONJ-III), (CONJ- IV), (CONJ-IVA), (CONJ-IVB), CA-I), (CA-II), or (CA-IIA), including any of the foregoing, Ring A is an optionally substituted 5- to 12- membered bridged, fused, or spirocyclic bicyclic heterocycle optionally substituted with one or more R8wherein Ring A is attached to L. In one embodiment of Formula (LP-I), (LP-II), (LP-IIA), (CONJ-I), (CONJ-II), (CONJ-IIA), (CONJ-III), (CONJ-IV), (CONJ-IVA), (CONJ-IVB), (CA-I), (CA-II), or (CA-IIA), including any of the foregoing, Ring A is an optionally substituted 8- to 12- membered bridged, fused, or spirocyclic bicyclic heterocycle optionally substituted with one or more R8wherein Ring A is attached to L.

[0178] In one embodiment of Formula (LP-I), (LP-II), (LP-IIA), (CONJ-I), (CONJ-II), (CONJ-IIA), (CONJ-III), (CONJ-IV), (CONJ-IVA), (CONJ-IVB), (CA-I), (CA-II), or (CA- IIA), including any of the foregoing, Ring A is a N-linked bridged, fused, or spirocyclic bicyclic heterocycle optionally substituted with one or more R8wherein Ring A is attached to L. In one embodiment of Formula (LP-I), (LP-II), (LP-IIA), (CONJ-I), (CONJ-II), (CONJ- IIA), (CONJ-III), (CONJ-IV), (CONJ-IVA), (CONJ-IVB), (CA-I), (CA-II), or (CA-IIA), including any of the foregoing, Ring A is a N-linked bridged or spirocyclic bicyclic heterocycle comprising at least one nitrogen atoms, including the nitrogen attached to L2wherein the heterocycle is optionally substituted with one or more R8wherein Ring A is attached to L. In one embodiment of Formula (LP-I), (LP-II), (LP-IIA), (CONJ-I), (CONJ-II), (CONJ-IIA), (CONJ-III), (CONJ-IV), (CONJ-IVA), (CONJ-IVB), (CA-I), (CA-II), or (CA- IIA), including any of the foregoing, Ring A is a N-linked bridged or spirocyclic bicyclic heterocycle comprising at least two nitrogen atoms, including the nitrogen attached to L2wherein the heterocycle is optionally substituted with one or more R8wherein Ring A is attached to L. In one embodiment of Formula (LP-I), (LP-II), (LP-IIA), (CONJ-I), (CONJ-II), (CONJ-IIA), (CONJ-III), (CONJ-IV), (CONJ-IVA), (CONJ-IVB), (CA-I), (CA-II), or (CA- IIA), including any of the foregoing, Ring A is a N-linked bridged or spirocyclic bicyclic heterocycle comprising at least two nitrogen atoms, including the nitrogen attached to L2, and 58 1104675906\1\AMERICASAttorney Docket No.108843.00582 SU-0514WO one oxygen atom wherein the heterocycle is optionally substituted with one or more R8wherein Ring A is attached to L.

[0179] In one embodiment of Formula (LP-I), (LP-II), (LP-IIA), (CONJ-I), (CONJ-II), (CONJ-IIA), (CONJ-III), (CONJ-IV), (CONJ-IVA), (CONJ-IVB), (CA-I), (CA-II), or (CA- IIA), including any of the foregoing, Ring A is selected from,wherein m is an integer selected from 1, 2, 3, 4, and 5; each of m, n, o, and p is an integer independently selected from 1, 2, and 3;the point of attachment to L; and is the point of attachment to the rest of the compound.

[0180] In one embodiment of Formula (LP-I), (LP-II), (LP-IIA), (CONJ-I), (CONJ-II), (CONJ-IIA), (CONJ-III), (CONJ-IV), (CONJ-IVA), (CONJ-IVB), (CA-I), (CA-II), or (CA- IIA), including any of the foregoing, Ring A iswhereinis the point of attachment to L andis the point of attachment to the rest of the compound. In one embodiment of Formula (LP-I), (LP-II), (LP-IIA), (CONJ-I), (CONJ-II), (CONJ-IIA), (CONJ-III), (CONJ-IV), (CONJ-IVA), (CONJ-IVB), (CA-I), (CA-II), or (CA-IIA), including any of the foregoing, Ring.

[0181] In one embodiment of Formula (LP-I), (LP-II), (LP-IIA), (CONJ-I), (CONJ-II), (CONJ-IIA), (CA-I), (CA-II), or (CA-IIA), including any of the foregoing, Ring A is wherein is the point of attachment to L; and is the point of attachment to the rest of the compound. In one embodiment of Formula (LP-I), (LP-II), (LP- IIA), (CONJ-I), (CONJ-II), (CONJ-IIA), (CONJ-III), (CONJ-IV), (CONJ-IVA), (CONJ- 59 1104675906\1\AMERICASAttorney Docket No.108843.00582 SU-0514WO IVB), (CA-I), (CA-II), or (CA-IIA), including any of the foregoing, Ring,

[0182] In one embodiment of Formula (LP-I), (LP-II), (LP-IIA), (CONJ-I), (CONJ-II), (CONJ-IIA), (CONJ-III), (CONJ-IV), (CONJ-IVA), (CONJ-IVB), (CA-I), (CA-II), or (CA-IIA), including any of the foregoing, Ring A is wherein is the point of attachment to L; andis the point of attachment to the rest of the compound. In one embodiment of Formula (LP-I), (LP-II), (LP-IIA), (CONJ-I), (CONJ-II), (CONJ-IIA), (CONJ-III), (CONJ-IV), (CONJ-IVA), (CONJ-IVB), (CA-I), (CA-II), or (CA-IIA), including any of the foregoing, Ring

[0183] In one embodiment of Formula (LP-I), (LP-II), (LP-IIA), (CONJ-I), (CONJ-II), (CONJ-IIA), (CONJ-III), (CONJ-IV), (CONJ-IVA), (CONJ-IVB), (CA-I), (CA-II), or (CA- IIA), including any of the foregoing, Ring A is selected from,wherein is the point of attachment to L andis the point of attachment to the rest of the compound.

[0184] In one embodiment of Formula (LP-I), (LP-II), (LP-IIA), (CONJ-I), (CONJ-II), (CONJ-IIA), (CONJ-III), (CONJ-IV), (CONJ-IVA), (CONJ-IVB), (CA-I), (CA-II), or (CA- 60 1104675906\1\AMERICASAttorney Docket No.108843.00582 SU-0514WO.

[0185] In one embodiment of Formula (LP-I), (LP-II), (LP-IIA), (CONJ-I), (CONJ-II), (CONJ-IIA), (CONJ-III), (CONJ-IV), (CONJ-IVA), (CONJ-IVB), (CA-I), (CA-II), or (CA- IIA), including any of the foregoing, Ring A is, ,point of attachment to L andis the point of attachment to the rest of the compound. In one embodiment of Formula (LP-I), (LP-II), (LP-IIA), (CONJ-I), (CONJ-II), (CONJ-IIA), (CONJ-III), (CONJ-IV), (CONJ-IVA), (CONJ-IVB), (CA-I), (CA-II), or (CA-IIA), including any of the foregoing, Ring A is. In one embodiment of Formula (LP-I), (LP-II), (LP-IIA), (CONJ-I), (CONJ-II), (CONJ-IIA), (CONJ-III), (CONJ-IV), (CONJ-IVA), (CONJ-IVB), (CA-I), (CA-II), or (CA-IIA), including any of the foregoing, Ring A is. In one embodiment of Formula (LP-I), (LP-II), (LP- IIA), (CONJ-I), (CONJ-II), (CONJ-IIA), (CONJ-III), (CONJ-IV), (CONJ-IVA), (CONJ- 61 1104675906\1\AMERICASAttorney Docket No.108843.00582 SU-0514WO IVB), (CA-I), (CA-II), or (CA-IIA), including any of the foregoing, Ring A is.

[0186] In one embodiment of Formula (LP-I), (LP-II), (LP-IIA), (CONJ-I), (CONJ-II), (CONJ-IIA), (CONJ-III), (CONJ-IV), (CONJ-IVA), (CONJ-IVB), (CA-I), (CA-II), or (CA- IIA), including any of the foregoing, Ring A isor wherein is the point of attachment to L and is the point of attachment to the rest of the compound.

[0187] In one embodiment of Formula (LP-I), (LP-II), (LP-IIA), (CONJ-I), (CONJ-II), (CONJ-IIA), (CONJ-III), (CONJ-IV), (CONJ-IVA), (CONJ-IVB), (CA-I), (CA-II), or (CA- IIA), including any of the foregoing, Ringwhereinis the point of attachment to L andis the point of attachment to the rest of the compound.

[0188] In one embodiment of Formula (LP-I), (LP-II), (LP-IIA), (CONJ-I), (CONJ-II), (CONJ-IIA), (CONJ-III), (CONJ-IV), (CONJ-IVA), (CONJ-IVB), (CA-I), (CA-II), or (CA- IIA), including any of the foregoing, Ring A is a 3- to 5-membered heterocycle optionally substituted with one or more R4aand further optionally substituted with one or more R8wherein R4ais attached to L. In one embodiment of Formula (LP-I), (LP-II), (LP-IIA), (CONJ-I), (CONJ-II), (CONJ-IIA), (CONJ-III), (CONJ-IV), (CONJ-IVA), (CONJ-IVB), (CA-I), (CA-II), or (CA-IIA), including any of the foregoing, Ring A is a 3- to 5-membered heterocycle comprising at least one nitrogen atom wherein the heterocycle is optionally substituted with one or more R4aand further optionally substituted with one or more R8wherein R4ais attached to L. In one embodiment of Formula (LP-I), (LP-II), (LP-IIA), (CONJ-I), (CONJ-II), (CONJ-IIA), (CONJ-III), (CONJ-IV), (CONJ-IVA), (CONJ-IVB), (CA-I), (CA-II), or (CA-IIA), including any of the foregoing, Ring A is a N-linked 3- to 5- membered heterocycle optionally substituted with one or more R4aand further optionally substituted with one or more R8wherein R4ais attached to L. In one embodiment of Formula (LP-I), (LP-II), (LP-IIA), (CONJ-I), (CONJ-II), (CONJ-IIA), (CONJ-III), (CONJ-IV), (CONJ-IVA), (CONJ-IVB), (CA-I), (CA-II), or (CA-IIA), including any of the foregoing, Ring A is a N-linked 3- to 5-membered heterocycle comprising at least one nitrogen atom, 62 1104675906\1\AMERICASAttorney Docket No.108843.00582 SU-0514WO including the N attached to L2, wherein the heterocycle is optionally substituted with one or more R4aand further optionally substituted with one or more R8wherein R4ais attached to L. In one embodiment of Formula (LP-I), (LP-II), (LP-IIA), (CONJ-I), (CONJ-II), (CONJ-IIA), (CONJ-III), (CONJ-IV), (CONJ-IVA), (CONJ-IVB), (CA-I), (CA-II), or (CA-IIA), including any of the foregoing, Ring A is an unsubstituted N-linked 3- to 5-membered heterocycle comprising at least one nitrogen atom, including the N attached to L2wherein R4ais attached to L. In one embodiment of Formula (LP-I), (LP-II), (LP-IIA), (CONJ-I), (CONJ-II), (CONJ- IIA), (CONJ-III), (CONJ-IV), (CONJ-IVA), (CONJ-IVB), (CA-I), (CA-II), or (CA-IIA), including any of the foregoing, Ring A iswherein R4ais attached .

[0189] In one embodiment of Formula (LP-I), (LP-II), (LP-IIA), (CONJ-I), (CONJ-II), (CONJ-IIA), (CONJ-III), (CONJ-IV), (CONJ-IVA), (CONJ-IVB), (CA-I), (CA-II), or (CA- IIA), including any of the foregoing, R4ais a 5- to 8-membered heterocycle optionally substituted with one or more R8wherein R4ais attached to L. In one embodiment of Formula (LP-I), (LP-II), (LP-IIA), (CONJ-I), (CONJ-II), (CONJ-IIA), (CONJ-III), (CONJ-IV), (CONJ-IVA), (CONJ-IVB), (CA-I), (CA-II), or (CA-IIA), including any of the foregoing, R4ais a 5- to 8-membered heterocycle comprising at least one nitrogen atom and the heterocycle is optionally substituted with one or more R8wherein R4ais attached to L. In one embodiment of Formula (LP-I), (LP-II), (LP-IIA), (CONJ-I), (CONJ-II), (CONJ-IIA), (CONJ-III), (CONJ-IV), (CONJ-IVA), (CONJ-IVB), (CA-I), (CA-II), or (CA-IIA), including any of the foregoing, R4ais an unsubstituted 5- to 8-membered heterocycle comprising at least one nitrogen atom wherein R4ais attached to L.

[0190] In one embodiment of Formula (LP-I), (LP-II), (LP-IIA), (CONJ-I), (CONJ-II), (CONJ-IIA), (CONJ-III), (CONJ-IV), (CONJ-IVA), (CONJ-IVB), (CA-I), (CA-II), or (CA-to Lis the point of attachment to the rest of the compound. In one embodiment of Formula (LP-I), (LP-II), (LP-IIA), (CONJ-I), (CONJ-II), (CONJ-IIA), (CONJ-III), (CONJ- 63 1104675906\1\AMERICASAttorney Docket No.108843.00582 SU-0514WO IV), (CONJ-IVA), (CONJ-IVB), (CA-I), (CA-II), or (CA-IIA), including any of the foregoing,.

[0191] In one embodiment of Formula (LP-I), (LP-II), (LP-IIA), (CONJ-I), (CONJ-II), (CONJ-IIA), (CONJ-III), (CONJ-IV), (CONJ-IVA), (CONJ-IVB), (CA-I), (CA-II), or (CA- IIA), including any of the foregoing, Ring A is, ,is the point of attachment to L andis the point of attachment to the rest of the compound. In one embodiment of Formula (LP-I), (LP-II), (LP- IIA), (CONJ-I), (CONJ-II), (CONJ-IIA), (CONJ-III), (CONJ-IV), (CONJ-IVA), (CONJ- IVB), (CA-I), (CA-II), or (CA-IIA), including any of the foregoing, Ring A is.

[0192] In one embodiment of Formula (LP-I), (LP-II), (LP-IIA), (CONJ-I), (CONJ-II), (CONJ-IIA), (CONJ-III), (CONJ-IV), (CONJ-IVA), (CONJ-IVB), (CA-I), (CA-II), or (CA- IIA), including any of the foregoing, Ring A is a 6- to 12-membered heterocycle substituted with R4band optionally substituted with one or more R8wherein R4bis attached to L. In one embodiment of Formula (LP-I), (LP-II), (LP-IIA), (CONJ-I), (CONJ-II), (CONJ-IIA), (CONJ-III), (CONJ-IV), (CONJ-IVA), (CONJ-IVB), (CA-I), (CA-II), or (CA-IIA), including any of the foregoing, Ring A is a 6- to 8-membered heterocycle substituted with R4band optionally substituted with one or more R8wherein R4bis attached to L. In one embodiment of Formula (LP-I), (LP-II), (LP-IIA), (CONJ-I), (CONJ-II), (CONJ-IIA), (CA-I), (CONJ-III), (CONJ-IV), (CONJ-IVA), (CONJ-IVB), (CA-II), or (CA-IIA), including any of the foregoing, Ring A is a 6- to 8-membered heterocycle comprising at least one nitrogen wherein the heterocycle is substituted with R4band optionally substituted with one or more R8wherein R4bis attached to L.

[0193] In one embodiment of Formula (LP-I), (LP-II), (LP-IIA), (CONJ-I), (CONJ-II), (CONJ-IIA), (CONJ-III), (CONJ-IV), (CONJ-IVA), (CONJ-IVB), (CA-I), (CA-II), or (CA- 64 1104675906\1\AMERICASAttorney Docket No.108843.00582 SU-0514WO IIA), including any of the foregoing, Ring.

[0194] In one embodiment of Formula (LP-I), (LP-II), (LP-IIA), (CONJ-I), (CONJ-II), (CONJ-IIA), (CONJ-III), (CONJ-IV), (CONJ-IVA), (CONJ-IVB), (CA-I), (CA-II), or (CA- IIA), including any of the foregoing, Ring A is selected from,is attached to L.

[0195] In one embodiment of Formula (LP-I), (LP-II), (LP-IIA), (CONJ-I), (CONJ-II), (CONJ-IIA), (CONJ-III), (CONJ-IV), (CONJ-IVA), (CONJ-IVB), (CA-I), (CA-II), or (CA- IIA), including any of the foregoing, Ring A is selected fromorwherein R4bis attached to L. In one embodiment of Formula (LP-I), (LP-II), (LP-IIA), (CONJ-I), (CONJ-II), (CONJ-IIA), (CONJ-III), (CONJ-IV), (CONJ-IVA), (CONJ- IVB), (CA-I), (CA-II), or (CA-IIA), including any of the foregoing, Ring A is.

[0196] In one embodiment of Formula (LP-I), (LP-II), (LP-IIA), (CONJ-I), (CONJ-II), (CONJ-IIA), (CONJ-III), (CONJ-IV), (CONJ-IVA), (CONJ-IVB), (CA-I), (CA-II), or (CA- IIA), including any of the foregoing, R4bis an 8- to 12- membered bridged or fused bicyclic heterocycle optionally substituted with one or more R8wherein R4bis attached to L. In one embodiment of Formula (LP-I), (LP-II), (LP-IIA), (CONJ-I), (CONJ-II), (CONJ-IIA), (CONJ-III), (CONJ-IV), (CONJ-IVA), (CONJ-IVB), (CA-I), (CA-II), or (CA-IIA), including 65 1104675906\1\AMERICASAttorney Docket No.108843.00582 SU-0514WO any of the foregoing, R4bis an 8- to 12- membered bridged or fused bicyclic heterocycle comprising 1, 2, 3, or 4 heteroatoms selected from N, S, and O wherein at least one heteroatom is N and wherein the heterocycle is optionally substituted with one or more R8wherein R4bis attached to L. In one embodiment of Formula (LP-I), (LP-II), (LP-IIA), (CONJ-I), (CONJ-II), (CONJ-IIA), (CONJ-III), (CONJ-IV), (CONJ-IVA), (CONJ-IVB), (CA-I), (CA-II), or (CA-IIA), including any of the foregoing, R4bis a 5-5 fused ring system, a 5-6 fused ring system, a 6-6 fused ring system, or a 5-7 fused ring system comprising 1, 2, 3, or 4 heteroatoms selected from N, S, and O wherein at least one heteroatom is N and wherein the heterocycle is optionally substituted with one or more R8. In one embodiment of Formula (LP-I), (LP-II), (LP-IIA), (CONJ-I), (CONJ-II), (CONJ-IIA), (CONJ-III), (CONJ-IV), (CONJ-IVA), (CONJ-IVB), (CA-I), (CA-II), or (CA-IIA), including any of the foregoing, R4bis a 5-6 fused ring system comprising 1, 2, 3, or 4 heteroatoms selected from N, S, and O wherein at least one heteroatom is N and wherein the heterocycle is optionally substituted with one or more R8wherein R4bis attached to L.

[0197] In one embodiment of Formula (LP-I), (LP-II), (LP-IIA), (CONJ-I), (CONJ-II), (CONJ-IIA), (CONJ-III), (CONJ-IV), (CONJ-IVA), (CONJ-IVB), (CA-I), (CA-II), or (CA- IIA), including any of the foregoing,,, 66 1104675906\1\AMERICASAttorney Docket No.108843.00582 SU-0514WOwherein X5, X6, X9, X10are independently N or CR20; X7and X8are independently NH, O, or CHR20; R20is hydrogen or C1-6 alkyl; R5is as defined herein; is the point of attachment to the rest of the compound; and is the point of attachment to L; wherein if four of any one of X5-X10are present, at least one is CR20or CHR20. In one embodiment of Formula (LP-I), (LP-II), (LP-IIA), (CONJ-I), (CONJ-II), (CONJ-IIA), (CONJ-III), (CONJ-IV), (CONJ-IVA), (CONJ-IVB), (CA-I), (CA-II), or (CA-IIA), including ,compound and is the point of attachment to L. In one embodiment of Formula (LP-I), (LP-II), (LP-IIA), (CONJ-I), (CONJ-II), (CONJ-IIA), (CONJ-III), (CONJ-IV), (CONJ-IVA), 67 1104675906\1\AMERICASAttorney Docket No.108843.00582 SU-0514WO (CONJ-IVB), (CA-I), (CA-II), or (CA-IIA), including any of the foregoing,.

[0198] In one embodiment of Formula (LP-I), (LP-II), (LP-IIA), (CONJ-I), (CONJ-II), (CONJ-IIA), (CONJ-III), (CONJ-IV), (CONJ-IVA), (CONJ-IVB), (CA-I), (CA-II), or (CA- IIA), including any of the foregoing, Ring A ispoint of attachment to the rest of the compound andis the point of attachment to L.

[0199] In certain embodiments of Formula (LP-IIA), (CONJ-IIA), or (CA-IIA), including any of the foregoing,selected from the group consisting of:68 1104675906\1\AMERICASAttorney Docket No.108843.00582 SU-0514WO69 1104675906\1\AMERICASAttorney Docket No.108843.00582 SU-0514WO70 1104675906\1\AMERICASAttorney Docket No.108843.00582 SU-0514WO71 1104675906\1\AMERICASAttorney Docket No.108843.00582 SU-0514WO72 1104675906\1\AMERICASAttorney Docket No.108843.00582 SU-0514WO

[0200] In certain embodiments of Formula (I), (LP-I), (LP-II), (CONJ-I), (CONJ-II), (CONJ- III), (CONJ-IV), (CONJ-IVA), (CONJ-IVB), (CA-I), or (CA-II), including any of the f73 1104675906\1\AMERICASAttorney Docket No.108843.00582 SU-0514WO74 1104675906\1\AMERICASAttorney Docket No.108843.00582 SU-0514WO75 1104675906\1\AMERICASAttorney Docket No.108843.00582 SU-0514WO76 1104675906\1\AMERICASAttorney Docket No.108843.00582 SU-0514WOi. Linkers

[0201] The linker (L) of the linker-payload, conjugate, or catabolite can be any linker capable of forming at least one bond to COMP and at least one bond to the compound of Formula (I) or Formula (IA). In some embodiments, including any of the foregoing, the linker comprises a protease cleavable linker, an enzyme cleavable linker, a pH-sensitive linker, or a non- cleavable linker.

[0202] In one embodiment, the linker-payload is of Formula (LP-II) or (LP-IIA) wherein -L- is -W1-W2-SG-HP-. In one embodiment, the conjugate is of Formula (CONJ-II) or (CONJ- IIA) wherein -L- is -W1-W2-SG-HP-RL-. In one embodiment, the conjugate is of Formula (CONJ-IV), (CONJ-IVA), or (CONJ-IVB) wherein -La- is -W1-W2-SG-HP-RL- and Lbis of 77 1104675906\1\AMERICASAttorney Docket No.108843.00582 SU-0514WO formula. In one embodiment, the catabolite is of Formula (CA-II) or (CA-IIA) wherein -L- is -W1-W2-SG-HP-.

[0203] In certain embodiments, SG and SG01are independently divalent spacer groups that facilitate incorporation of eliminator groups, release trigger groups, hydrophobic groups, attaching groups, and / or the conjugating group into a compound. Spacer groups that facilitate the spacing of the conjugating group from the other groups of the compounds can lead to more efficient conjugation of the compounds described herein to COMP as well as more efficient cleavage of the active catabolite. Spacer groups can also stabilize the conjugating group and lead to improved overall antibody-drug conjugate properties. Useful spacer groups are known to, and are apparent to, those of skill in the art. Examples of useful spacer groups are provided herein. In certain embodiments, a spacer group can comprise a divalent ketone, divalent ester, divalent ether, divalent amide, divalent amine, alkylene, arylene, sulfide, disulfide, carbonylene, or a combination thereof. In certain embodiments a spacer group can comprise –C(O)–, –C(O)-alkyl–, –O–, –C(O)NH–, –C(O)NH-alkyl–, –OC(O)NH–, – SC(O)NH–, –NH–, –NH-alkyl–, –C(O)N(CH3)–, –C(O)N(CH3)-alkyl–, –N(CH3)–, –N(CH3)- alkyl–, –N(CH3)CH2CH2N(CH3)–, –C(O)CH2CH2CH2C(O)–, –S–, –S-S–, –OCH2CH2O–, or the reverse (e.g. –NHC(O)–) thereof, or a combination thereof.

[0204] In certain embodiments of Formula (LP-II), (LP-IIA), (CONJ-II), (CONJ-IIA), (CONJ-IV), (CONJ-IVA), (CONJ-IVB), (CA-II), or (CA-IIA), including any of the foregoing, SG is absent or selected from -C1-10alkylene-, -C(O)-, -C(O)-C1-10alkylene- , -C(O)(C1-10 alkylene)-C(O)-NR15C1-10alkylene- wherein the -C(O)- is bound to W2, -C(O)- C1-10 alkylene-C(O)-, -C(O)(C1-10 alkylene)NR15C(O)-, -C(O)(C1-10 alkylene)OC(O)-, and -C(O)(C1-10alkylene)SC(O)-; wherein R15is hydrogen or optionally substituted C1-10alkyl; and the C1-10 alkylene of SG, alone or part of another group, is optionally substituted with one, two, or three substituents selected from halogen, haloC1-6alkyl, hydroxyl, amino, C1-6alkylamino, and C1-6alkoxy.

[0205] In certain embodiments of Formula (LP-II), (LP-IIA), (CONJ-II), (CONJ-IIA), (CONJ-IV), (CONJ-IVA), (CONJ-IVB), (CA-II), or (CA-IIA), including any of the foregoing, SG is -C(O)-C1-10 alkylene- wherein the -C(O)- is bound to W2and the C1-10 alkylene is optionally substituted with one, two, or three substituents selected from halogen, 78 1104675906\1\AMERICASAttorney Docket No.108843.00582 SU-0514WO haloC1-6alkyl, hydroxyl, amino, C1-6alkylamino, and C1-6alkoxy. In certain embodiments of Formula (LP-II), (LP-IIA), (CONJ-II), (CONJ-IIA), (CONJ-IV), (CONJ-IVA), (CONJ-IVB), (CA-II), or (CA-IIA), including any of the foregoing, SG is -C(O)-C1-10 alkylene- wherein the -C(O)- is bound to W2and the C1-10alkylene is unsubstituted.

[0206] In certain embodiments of Formula (LP-II), (LP-IIA), (CONJ-II), (CONJ-IIA), (CONJ-IV), (CONJ-IVA), (CONJ-IVB), (CA-II), or (CA-IIA), including any of the foregoing, SG is -C(O)-C1-6alkylene- or -C(O)-C1-3alkylene- wherein the -C(O)- is bound to W2and the C1-6 alkylene or -C(O)-C1-3 alkylene- is optionally substituted with one, two, or three substituents selected from halogen, haloC1-6alkyl, hydroxyl, amino, C1-6alkylamino, and C1-6alkoxy. In certain embodiments of Formula (LP-II), (LP-IIA), (CONJ-II), (CONJ-IIA), (CONJ-IV), (CONJ-IVA), (CONJ-IVB), (CA-II), or (CA-IIA), including any of the foregoing, SG is -C(O)-C1-6 alkylene- or -C(O)-C1-3 alkylene- wherein the -C(O)- is bound to W2and the C1-6 alkylene -C(O)-C1-3 alkylene- is unsubstituted.

[0207] In certain embodiments of Formula (LP-II), (LP-IIA), (CONJ-II), (CONJ-IIA), (CONJ-IV), (CONJ-IVA), (CONJ-IVB), (CA-II), or (CA-IIA), including any of the foregoing, SG is unsubstituted -C(O)-C1-5 alkylene-. In certain embodiments of Formula (LP- II), (LP-IIA), (CONJ-II), (CONJ-IIA), (CONJ-IV), (CONJ-IVA), (CONJ-IVB), (CA-II), or (CA-IIA), including any of the foregoing, SG is unsubstituted -C(O)-C1-2alkylene-.

[0208] In certain embodiments of Formula (CONJ-IV), (CONJ-IVA), or (CONJ-IVB), including any of the foregoing, SG01is absent. In certain embodiments of Formula (CONJ- IV), (CONJ-IVA), or (CONJ-IVB), including any of the foregoing, SG01is a divalent spacer group. In certain embodiments of Formula (CONJ-IV), (CONJ-IVA), or (CONJ-IVB), including any of the foregoing, SG01is -C1-6 alkylene- optionally substituted with one or more substituents selected from halogen, -CN, -NO2, -OH, -N(R10)2, -C(O)N(R10)2, -C(O)-, -C(S)-, -C(O)OCH2C6H5, -NHC(O)OCH2C6H5, C1-10alkyl, C2-10alkenyl, C2-10alkynyl, C3-12carbocycle, 3- to 12-membered heterocycle, and C1-10 haloalkyl wherein R10is independently selected at each occurrence from hydrogen, C1-10alkyl, C2-10alkenyl, C2-10alkynyl, C3-12carbocycle, 3- to 12-membered heterocycle, and C1-10haloalkyl. In certain embodiments of Formula (CONJ-IV), (CONJ-IVA), or (CONJ-IVB), including any of the foregoing, SG01is unsubstituted -C1-6 alkylene-. In certain embodiments of Formula (CONJ-IV), (CONJ-IVA), or (CONJ-IVB), including any of the foregoing, SG01is -C1-3alkylene-, optionally substituted with one or more substituents selected from halogen, -CN, -NO2, -OH, -N(R10)2, - C(O)N(R10)2, -C(O)-, -C(S)-, -C(O)OCH2C6H5, -NHC(O)OCH2C6H5, C1-10 alkyl, C2-10 alkenyl, C2-10alkynyl, C3-12carbocycle, 3- to 12-membered heterocycle, and C1-10haloalkyl.. 79 1104675906\1\AMERICASAttorney Docket No.108843.00582 SU-0514WO In certain embodiments of Formula (CONJ-IV), (CONJ-IVA), or (CONJ-IVB), including any of the foregoing, SG01is -CH2-. In some embodiments, SG01is -CH2CH2-. In certain embodiments of Formula (CONJ-IV), (CONJ-IVA), or (CONJ-IVB), including any of the foregoing, SG01is -CH2CH2CH2-.

[0209] In certain embodiments, W1-W2is an eliminator group. Eliminator groups facilitate the separation of a biologically active portion of a linker-payload or conjugate described herein from the remainder of the linker-payload or conjugate in vivo and / or in vitro. Non- limiting examples of Eliminator groups include cathepsin B-cleavable groups (for example, a linker comprising a dipeptide, such as valine-citrulline or cyclobutyl-citrulline, or a linker comprising a triglcyl peptide linker (CX)); acid-cleavable groups (for example, a linker comprising a pH-sensitive hydrazone, a carbonate, or a silyl ether); GSH-cleavable groups (for example, a linker comprising a disulfide or disulfide carbamate); glycosidase-cleavable groups (for example, a linker comprising a β-glucuronidase-cleavable group); enzyme- cleavable groups (for example, a linker comprising a β-galactosidase-cleavable group); and a self-immolative group (for example, p-aminobenzyloxycarbonyl (PABC)). Eliminator groups can also facilitate separation of a biologically active portion of a linker-payload or conjugate described herein in conjunction with a release trigger group. For example, the eliminator group and the release trigger group can react in a Releasing Reaction to release a biologically active portion of a compound or conjugate described herein from the compound or conjugate in vivo and / or in vitro. Upon initiation of the Releasing Reaction by the release trigger, the eliminator group cleaves the biologically active moiety, or a prodrug form of the biologically active moiety, and forms a stable, non-toxic entity that has no further effect on the activity of the biologically active moiety.

[0210] In certain embodiments of Formula (LP-II), (LP-IIA), (CONJ-II), (CONJ-IIA), (CONJ-IV), (CONJ-IVA), (CONJ-IVB), (CA-II), or (CA-IIA), including any of the foregoing, W1is absent. In certain embodiments of Formula (LP-II), (LP-IIA), (CONJ-II), (CONJ-IIA), (CONJ-IV), (CONJ-IVA), (CONJ-IVB), (CA-II), or (CA-IIA), including any of the foregoing, W1is absent,wherein the -NH- is bound to W2and each indicates a point of attachment to the rest of 80 1104675906\1\AMERICASAttorney Docket No.108843.00582 SU-0514WO the formula. In certain embodiments of Formula (LP-II), (LP-IIA), (CONJ-II), (CONJ-IIA), (CONJ-IV), (CONJ-IVA), (CONJ-IVB), (CA-II), or (CA-IIA), including any of the. ents of Formula (LP-II), (LP-IIA), (CONJ-II), (CONJ-IIA), (CONJ-IV), (CONJ-IVA), (CONJ- including any of the foregoing,.

[0211] When z is 1, the conjugate comprises a release trigger group, designated as OSu herein, which facilitates the separation of a biologically active portion of a compound or conjugate described herein from the remainder of the compound or conjugate in vivo and / or in vitro. Release trigger groups can also facilitate separation of a biologically active portion of a compound or conjugate described herein in conjunction with an eliminator group. For example, the eliminator group and the release trigger group can react in a Releasing Reaction 81 1104675906\1\AMERICASAttorney Docket No.108843.00582 SU-0514WO to release a biologically active portion of a compound or conjugate described herein from the compound or conjugate in vivo and / or in vitro. In certain embodiment, the release trigger can act through a biologically-driven reaction with high tumor:nontumor specificity, such as the proteolytic action of an enzyme overexpressed in a tumor environment.

[0212] In certain embodiments of Formula (LP-II), (LP-IIA), (CONJ-II), (CONJ-IIA), (CONJ-IV), (CONJ-IVA), (CONJ-IVB), (CA-II), or (CA-IIA), including any of the foregoing, Su is independently a sugar moiety. In certain embodiments of Formula (LP-II), (LP-IIA), (CONJ-II), (CONJ-IIA), (CONJ-IV), (CONJ-IVA), (CONJ-IVB), (CA-II), or (CA- IIA), including any of the foregoing, Su is independently a hexose form of a monosaccharide. In certain embodiments of Formula (LP-II), (LP-IIA), (CONJ-II), (CONJ-IIA), (CONJ-IV), (CONJ-IVA), (CONJ-IVB), (CA-II), or (CA-IIA), including any of the foregoing, Su is independently a glucuronic acid or mannose residue. In certain embodiments of Formula (LP- II), (LP-IIA), (CONJ-II), (CONJ-IIA), (CONJ-IV), (CONJ-IVA), (CONJ-IVB), (CA-II), or (CA-IIA), including any of the foregoing, OSu is independently a β-glucuronidase-cleavable β-glucuronide. In certain embodiments of Formula (LP-II), (LP-IIA), (CONJ-II), (CONJ- IIA), (CONJ-IV), (CONJ-IVA), (CONJ-IVB), (CA-II), or (CA-IIA), including any of the foregoing, OSu is independentlythe point of attachment to the rest of the formula. In certain embodiments of Formula (LP-II), (LP-IIA), (CONJ-II), (CONJ-IIA), (CONJ-IV), (CONJ-IVA), (CONJ-IVB), (CA-II), or (CA-IIA), including any of the foregoing, OSu is independently.

[0213] In certain embodiments of Formula (LP-II), (LP-IIA), (CONJ-II), (CONJ-IIA), (CONJ-IV), (CONJ-IVA), (CONJ-IVB), (CA-II), or (CA-IIA), including any of the foregoing,. certain embodiments of Formula (LP- 82 1104675906\1\AMERICASAttorney Docket No.108843.00582 SU-0514WO II), (LP-IIA), (CONJ-II), (CONJ-IIA), (CONJ-IV), (CONJ-IVA), (CONJ-IVB), (CA-II), or (CA-IIA), including any of the foregoing,.

[0214] Hydrophilic groups, designated HP, HP1, and HP2herein, facilitate increasing the hydrophilicity of the linker-payloads and conjugates described herein. It is believed that increased hydrophilicity allows for greater solubility in aqueous solutions, such as aqueous solutions found in biological systems. Hydrophilic groups can also function as spacer groups, which are described in further detail herein. Useful hydrophilic groups include those described herein.

[0215] In certain embodiments, Formula (LP-II), (LP-IIA), (CONJ-II), (CONJ-IIA), (CONJ- IV), (CONJ-IVA), (CONJ-IVB), (CA-II), or (CA-IIA), including any of the foregoing, HP is absent. In certain embodiments, Formula (LP-II), (LP-IIA), (CONJ-II), (CONJ-IIA), (CONJ- IV), (CONJ-IVA), (CONJ-IVB), (CA-II), or (CA-IIA), including any of the foregoing, HP is divalent poly(ethylene glycol). In certain embodiments of Formula (LP-II), (LP-IIA), (CONJ- II), (CONJ-IIA), (CONJ-IV), (CONJ-IVA), (CONJ-IVB), (CA-II), or (CA-IIA), including any of the foregoing, HP is absent orwherein R20is hydrogen or methyl and x1 is an integer between 1 and 50, inclusive; and eachis the point of attachment to the rest of the formula. In certain embodiments of Formula (LP-II), (LP-IIA), (CONJ-II), (CONJ- IIA), (CONJ-IV), (CONJ-IVA), (CONJ-IVB), (CA-II), or (CA-IIA), including any of the foregoing, HP is absent orwherein x1 is an integer between 1 and 20, inclusive. In certain embodiments of Formula (LP-II), (LP-IIA), (CONJ-II), (CONJ-IIA), (CONJ-IV), (CONJ-IVA), (CONJ-IVB), (CA-II), or (CA-IIA), including any of the foregoing, HP is. In certain embodiments of Formula (LP-II), (LP-IIA), 83 1104675906\1\AMERICASAttorney Docket No.108843.00582 SU-0514WO (CONJ-II), (CONJ-IIA), (CONJ-IV), (CONJ-IVA), (CONJ-IVB), (CA-II), or (CA-IIA), including any of the foregoing, HP is.

[0216] In certain embodiments, including any of the foregoing, x1 is an integer between 1 and 20, inclusive. In certain embodiments, including any of the foregoing, x1 is an integer between 1 and 15, inclusive. In certain embodiments, including any of the foregoing, x1 is 10, inclusive. In certain embodiments, including any of the foregoing, x1 is an integer between 1 and 5, inclusive. In certain embodiments, including any of the foregoing, x1 is 4.

[0217] In certain embodiments of Formula (LP-II), (LP-IIA), (CONJ-II), (CONJ-IIA), (CONJ-IV), (CONJ-IVA), (CONJ-IVB), (CA-II), or (CA-IIA), including any of the foregoing, HP isand x1 is an integer between 1 and 5, inclusive. In certain embodiments of Formula (LP-II), (LP-IIA), (CONJ-II), (CONJ-IIA), (CONJ-IV), (CONJ- IVA), (CONJ-IVB), (CA-II), or (CA-IIA), including any of the foregoing, HP is.

[0218] In certain embodiments of Formula (LP-II), (LP-IIA), (CONJ-II), (CONJ-IIA), (CONJ-IV), (CONJ-IVA), (CONJ-IVB), (CA-II), or (CA-IIA), including any of the foregoing, W2is absent, an amino acid residue, or a peptide residue wherein the amino acid residue or the peptide residue is optionally substituted with HP1. In certain embodiments of Formula (LP-II), (LP-IIA), (CONJ-II), (CONJ-IIA), (CONJ-IV), (CONJ-IVA), (CONJ-IVB), (CA-II), or (CA-IIA), including any of the foregoing, W2is absent. In certain embodiments of Formula (LP-II), (LP-IIA), (CONJ-II), (CONJ-IIA), (CONJ-IV), (CONJ-IVA), (CONJ-IVB), (CA-II), or (CA-IIA), including any of the foregoing, W2is an amino acid residue or a peptide residue wherein the amino acid residue or the peptide residue is optionally substituted with HP1. In certain embodiments, W2is a non-natural amino acid selected from 3- sulfoalanine, hydroxyproline (Hyp), citrulline (Cit), ornithine (Orn), norleucine (Nle), 3- nitrotyrosine, nitroarginine, pyroglutamic acid (Pyr), naphtylalanine (Nal), 2,4- diaminobutyric acid (DAB), methionine sulfoxide, methionine sulfone, 2,3- diaminopropionate, and beta-alanine. In certain embodiments, W2is citrulline (Cit).

[0219] In certain embodiments of Formula (LP-II), (LP-IIA), (CONJ-II), (CONJ-IIA), (CONJ-IV), (CONJ-IVA), (CONJ-IVB), (CA-II), or (CA-IIA), including any of the 84 1104675906\1\AMERICASAttorney Docket No.108843.00582 SU-0514WO foregoing, W2is an amino acid residue. In certain embodiments, the amino acid residue is a beta-amino acid.

[0220] In certain embodiments of Formula (LP-II), (LP-IIA), (CONJ-II), (CONJ-IIA), (CONJ-IV), (CONJ-IVA), (CONJ-IVB), (CA-II), or (CA-IIA), including any of the foregoing, W2is selected from -(C(O)CHR13NR11)a-, -(C(O)CH2CHR13NR11)b-, -(C(O)CHR13CH2NR11)a-, -(C(O)CH2CHR13NR11)b-(C(O)CHR13NR11)a-, -(C(O)CHR13CH2NR11)b-(C(O)CHR13NR11)a-, -(C(O)CHR13NR11)a-(C(O)CH2CHR13NR11)b-, and –(C(O)CHR13NR11)a-(C(O)CHR13CH2NR11)b-; wherein R13is independently an amino acid sidechain residue optionally substituted with HP1; R11is independently hydrogen or C1-6alkyl; each of a and b is an integer independently an integer between 1 and 10, inclusive; and the -C(O)- of W2is bound to W1.

[0221] In certain embodiments of Formula (LP-II), (LP-IIA), (CONJ-II), (CONJ-IIA), (CONJ-IV), (CONJ-IVA), (CONJ-IVB), (CA-II), or (CA-IIA), including any of the foregoing, W2is selected from -(C(O)CHR13NR11)a-, -(C(O)CH2CHR13NR11)b-, -(C(O)CHR13CH2NR11)b-, -(C(O)CH2CHR13NR11)b-(C(O)CHR13NR11)a-, and -(C(O)CHR13CH2NR11)b-(C(O)CHR13NR11)a-

[0222] In certain embodiments of Formula (LP-II), (LP-IIA), (CONJ-II), (CONJ-IIA), (CONJ-IV), (CONJ-IVA), (CONJ-IVB), (CA-II), or (CA-IIA), including any of the foregoing, W2is absent, -(C(O)CHR13NR11)a-, or (C(O)CH2CHR13NR11)b-.

[0223] In certain embodiments of Formula (LP-II), (LP-IIA), (CONJ-II), (CONJ-IIA), (CONJ-IV), (CONJ-IVA), (CONJ-IVB), (CA-II), or (CA-IIA), including any of the foregoing, W2is -(C(O)CHR13NR11)a-. In certain embodiments of Formula (LP-II), (LP-IIA), (CONJ-II), (CONJ-IIA), (CONJ-IV), (CONJ-IVA), (CONJ-IVB), (CA-II), or (CA-IIA), including any of the foregoing, W2is -(C(O)CH2CHR13NR11)b-. In certain embodiments of Formula (LP-II), (LP-IIA), (CONJ-II), (CONJ-IIA), (CONJ-IV), (CONJ-IVA), (CONJ-IVB), (CA-II), or (CA-IIA), including any of the foregoing, W2is -(C(O)CH2CHR13NR11)b- (C(O)CHR13NR11)a-.

[0224] In certain embodiments, including any of the foregoing, R13is an amino acid sidechain residue independently selected from valine, citrulline, alanine, glycine, asparagine, and lysine optionally substituted with HP1. In certain embodiments, including any of the foregoing, R11is hydrogen. In certain embodiments, including any of the foregoing, a is 85 1104675906\1\AMERICASAttorney Docket No.108843.00582 SU-0514WO independently an integer between 1 and 4, inclusive. In certain embodiments, including any of the foregoing, b is 1.

[0225] In certain embodiments of Formula (LP-II), (LP-IIA), (CONJ-II), (CONJ-IIA), (CONJ-IV), (CONJ-IVA), (CONJ-IVB), (CA-II), or (CA-IIA), including any of the foregoing, HP1is independently polyethylene glycol (PEG), methoxypolyethylene glycol (mPEG), poly(propylene glycol) (PPG), copolymers of ethylene glycol and propylene glycol, poly(oxyethylated polyol), poly(olefinic alcohol), poly(vinylpyrrolidone), poly(hydroxyalkylmethacrylamide), poly(hydroxyalkylmethacrylate), poly(saccharides), poly(α-hydroxy acid), poly(vinyl alcohol), polyphosphazene, polyoxazolines (POZ), poly(N- acryloylmorpholine), polysarcosine, or a combination thereof.

[0226] In certain embodiments of Formula (LP-II), (LP-IIA), (CONJ-II), (CONJ-IIA), (CONJ-IV), (CONJ-IVA), (CONJ-IVB), (CA-II), or (CA-IIA), including any of theis the point of attachment to the rest of the formula. In certain embodiments of Formula (LP-II), (LP-IIA), (CONJ-II), CONJ-IIA), (CONJ-IV), (CONJ-IVA), (CONJ-IVB), (CA-II), or (CA-IIA), including any of the foregoing, W2is86 1104675906\1\AMERICASAttorney Docket No.108843.00582 SU-0514WO.

[0227] In certain embodiments of Formula (LP-II), (LP-IIA), (CONJ-II), CONJ-IIA), (CONJ-IV), (CONJ-IVA), (CONJ-IVB), (CA-II), or (CA-IIA), -W1-W2- is87 1104675906\1\AMERICASAttorney Docket No.108843.00582 SU-0514WO

[0228] In certain embodiments of Formula (CONJ-IV), (CONJ-IVA), or (CONJ-IVB), including any of the foregoing, Y is –X1a-C1-6 alkylene-[X1a-C1-6 alkylene]a1-[X1a]b1–, wherein at least one alkylene in Y is substituted with one or more substituents selected from R70and wherein the alkylene in Y is optionally substituted with one or more substituents selected from R71. In certain embodiments of Formula (CONJ-IV), (CONJ-IVA), or (CONJ-IVB), including any of the foregoing, Y is –X1a-C1-6 alkylene-[X1a-C1-6 alkylene]a1-X1a–, wherein at least one alkylene in Y is substituted with one or more substituents selected from R70and wherein the alkylene in Y is optionally substituted with one or more substituents selected from R71. In certain embodiments of Formula (CONJ-IV), (CONJ-IVA), or (CONJ-IVB), including any of the foregoing, Y is –X1a-C2-6alkenylene-[X1a-C2-6alkenylene]a1-X1a– wherein at least one alkenylene in Y is substituted with one or more substituents selected from R70and wherein the alkylene in Y is optionally substituted with one or more substituents selected from R71. In certain embodiments of Formula (CONJ-IV), (CONJ-IVA), or (CONJ- IVB), including any of the foregoing, Y is –X1a-C2-6alkynylene-[X1a-C2-6alkynylene]a1-X1a– wherein at least one alkynylene in Y is substituted with one or more substituents selected from R70and wherein the alkylene in Y is optionally substituted with one or more substituents selected from R71.

[0229] In certain embodiments of Formula (CONJ-IV), (CONJ-IVA), or (CONJ-IVB), including any of the foregoing, Y is –X1a-C1-4 alkylene-[X1a-C1-4 alkylene]a1-X1a–, wherein at least one alkylene in Y is substituted with one or more substituents selected from R70and wherein the alkylene in Y is optionally substituted with one or more substituents selected from R71. In certain embodiments of Formula (CONJ-IV), (CONJ-IVA), or (CONJ-IVB), including any of the foregoing, Y is –X1a-C1-4 alkylene-X1a–, wherein at least one alkylene in Y is substituted with one or more substituents selected from R70and wherein the alkylene in Y is optionally substituted with one or more substituents selected from R71. In certain embodiments of Formula (CONJ-IV), (CONJ-IVA), or (CONJ-IVB), including any of the foregoing, Y is –X1a-C1-4alkylene-X1a-C1-4alkylene-X1a–, wherein at least one alkylene in Y is substituted with one or more substituents selected from R70and wherein the alkylene in Y is optionally substituted with one or more substituents selected from R71. In certain embodiments of Formula (CONJ-IV), (CONJ-IVA), or (CONJ-IVB), including any of the foregoing, Y is –X1a-C1-4alkylene-[X1a-C1-4alkylene]2-X1a–, wherein at least one alkylene in Y is substituted with one or more substituents selected from R70and wherein the alkylene in Y is optionally substituted with one or more substituents selected from R71. In certain embodiments of Formula (CONJ-IV), (CONJ-IVA), or (CONJ-IVB), including any of the 88 1104675906\1\AMERICASAttorney Docket No.108843.00582 SU-0514WO foregoing, Y is –X1a-C1-4alkylene-[X1a-C1-4alkylene]3-X1a–, wherein at least one alkylene in Y is substituted with one or more substituents selected from R70and wherein the alkylene in Y is optionally substituted with one or more substituents selected from R71. In certain embodiments of Formula (CONJ-IV), (CONJ-IVA), or (CONJ-IVB), including any of the foregoing, Y is –NHC(O)-C1-4 alkylene-[NHC(O)-C1-4 alkylene]a1-C(O)–, wherein at least one alkylene in Y is substituted with one or more substituents selected from R70and wherein the alkylene in Y is optionally substituted with one or more substituents selected from R71. In certain embodiments of Formula (CONJ-IV), (CONJ-IVA), or (CONJ-IVB), including any of the foregoing, Y is –NHC(O)-C1-4 alkylene-[NHC(O)-C1-4 alkylene]2-C(O)–, wherein at least one alkylene in Y is substituted with one or more substituents selected from R70and wherein the alkylene in Y is optionally substituted with one or more substituents selected from R71. In certain embodiments of Formula (CONJ-IV), (CONJ-IVA), or (CONJ-IVB), including any of the foregoing, Y is –NHC(O)-C1-4 alkylene-[NHC(O)-C1-4 alkylene]2-C(O)–, wherein at least one alkylene in Y is substituted with one or more substituents selected from R70.

[0230] In certain embodiments of Formula (CONJ-IV), (CONJ-IVA), or (CONJ-IVB), including any of the foregoing, Y is –X1a-C1-6 alkylene-[X1a-C1-6 alkylene]a1–, wherein at least one alkylene in Y is substituted with one or more substituents selected from R70, and wherein the alkylene in Y is optionally substituted with one or more substituents selected from R71. In certain embodiments of Formula (CONJ-IV), (CONJ-IVA), or (CONJ-IVB), including any of the foregoing, Y is –X1a-C2-6alkenylene-[X1a-C2-6alkenylene]a1–, wherein at least one alkenylene in Y is substituted with one or more substituents selected from R70, and wherein the alkenylene in Y is optionally substituted with one or more substituents selected from R71. In certain embodiments of Formula (CONJ-IV), (CONJ-IVA), or (CONJ-IVB), including any of the foregoing, Y is –X1a-C2-6alkynylene-[X1a-C2-6alkynylene]a1–, wherein at least one or alkynylene in Y is substituted with one or more substituents selected from R70, and wherein the alkynylene in Y is optionally substituted with one or more substituents selected from R71.

[0231] In certain embodiments of Formula (CONJ-IV), (CONJ-IVA), or (CONJ-IVB), including any of the foregoing, Y is –X1a-C1-4alkylene-[X1a-C1-4alkylene]a1-, wherein at least one alkylene in Y is substituted with one or more substituents selected from R70and wherein the alkylene in Y is optionally substituted with one or more substituents selected from R71. In certain embodiments of Formula (CONJ-IV), (CONJ-IVA), or (CONJ-IVB), including any of the foregoing, Y is –X1a-C1-4 alkylene-, wherein at least one alkylene in Y is substituted with one or more substituents selected from R70and wherein the alkylene in Y is optionally substituted with one or more substituents selected from R71. In certain embodiments of 89 1104675906\1\AMERICASAttorney Docket No.108843.00582 SU-0514WO Formula (CONJ-IV), (CONJ-IVA), or (CONJ-IVB), including any of the foregoing, Y is – X1a-C1-4 alkylene-X1a-C1-4 alkylene-, wherein at least one alkylene in Y is substituted with one or more substituents selected from R70and wherein the alkylene in Y is optionally substituted with one or more substituents selected from R71. In certain embodiments of Formula (CONJ- IV), (CONJ-IVA), or (CONJ-IVB), including any of the foregoing, Y is –X1a-C1-4 alkylene- [X1a-C1-4 alkylene]2-, wherein at least one alkylene in Y is substituted with one or more substituents selected from R70and wherein the alkylene in Y is optionally substituted with one or more substituents selected from R71. In certain embodiments of Formula (CONJ-IV), (CONJ-IVA), or (CONJ-IVB), including any of the foregoing, Y is –X1a-C1-4 alkylene-[X1a- C1-4alkylene]3-, wherein at least one alkylene in Y is substituted with one or more substituents selected from R70and wherein the alkylene in Y is optionally substituted with one or more substituents selected from R71.

[0232] In certain embodiments of Formula (CONJ-IV), (CONJ-IVA), or (CONJ-IVB), including any of the foregoing, b1 is zero. In certain embodiments of Formula (CONJ-IV), (CONJ-IVA), or (CONJ-IVB), including any of the foregoing, b1 is one. In certain embodiments of Formula (CONJ-IV), (CONJ-IVA), or (CONJ-IVB), including any of the foregoing, a1 is zero. In certain embodiments of Formula (CONJ-IV), (CONJ-IVA), or (CONJ-IVB), including any of the foregoing, a1 is one. In certain embodiments of Formula (CONJ-IV), (CONJ-IVA), or (CONJ-IVB), including any of the foregoing, a1 is two. In certain embodiments of Formula (CONJ-IV), (CONJ-IVA), or (CONJ-IVB), including any of the foregoing, a1 is three. In certain embodiments of Formula (CONJ-IV), (CONJ-IVA), or (CONJ-IVB), including any of the foregoing, b1 is one and a1 is two.

[0233] In certain embodiments of Formula (CONJ-IV), (CONJ-IVA), or (CONJ-IVB), including any of the foregoing, X1aand X2aare independently selected from –NH–, –C(O)–, and –NHC(O)–. In certain embodiments of Formula (CONJ-IV), (CONJ-IVA), or (CONJ- IVB), including any of the foregoing, X1aand X2aare independently selected from –C(O)– and –N(R60)C(O)–. In certain embodiments of Formula (CONJ-IV), (CONJ-IVA), or (CONJ- IVB), including any of the foregoing, X1aand X2aare independently selected from –C(O)– and –NHC(O)–.

[0234] In certain embodiments of Formula (CONJ-IV), (CONJ-IVA), or (CONJ-IVB), including any of the foregoing, R70is –C1-6alkylene-X2a-[C1-6alkylene]c1-HP2, wherein each alkylene of R70is optionally substituted with one or more substituents selected from halogen, -CN, -NO2, -OH, -NR60R61, -C(O)NR60R61, -C(O)-, -C(S)-, -C(O)OCH2C6H5, - NHC(O)OCH2C6H5, C1-10alkyl, C2-10alkenyl, C2-10alkynyl, C3-12carbocycle, 3- to 12- 90 1104675906\1\AMERICASAttorney Docket No.108843.00582 SU-0514WO membered heterocycle, and C1-10haloalkyl. In certain embodiments of Formula (CONJ-IV), (CONJ-IVA), or (CONJ-IVB), including any of the foregoing, R70is –C1-4 alkylene-X2a-[C1-4 alkylene]c1-HP2, wherein each alkylene of R70is optionally substituted with one or more substituents selected from halogen, -CN, -NO2, -OH, -NR60R61, -C(O)NR60R61, -C(O)-, - C(S)-, -C(O)OCH2C6H5, -NHC(O)OCH2C6H5, C1-10 alkyl, C2-10 alkenyl, C2-10 alkynyl, C3-12 carbocycle, 3- to 12-membered heterocycle, and C1-10 haloalkyl. In certain embodiments of Formula (CONJ-IV), (CONJ-IVA), or (CONJ-IVB), including any of the foregoing, each alkylene of R70is optionally substituted with one or more substituents selected from halogen, -OH, -NR60R61, -C(O)NR60R61, -C(O)-, C1-10 alkyl, C2-10 alkenyl, C2-10 alkynyl, C3-12 carbocycle, 3- to 12-membered heterocycle, and C1-10haloalkyl. In certain embodiments of Formula (CONJ-IV), (CONJ-IVA), or (CONJ-IVB), including any of the foregoing, R70is –C1-6 alkylene-X2a-C1-6 alkylene-HP2. In certain embodiments of Formula (CONJ-IV), (CONJ-IVA), or (CONJ-IVB), including any of the foregoing, R70is –C1-6 alkylene-NHC(O)- [C1-6alkylene]c1-HP2. In certain embodiments of Formula (CONJ-IV), (CONJ-IVA), or (CONJ-IVB), including any of the foregoing, R70is –C1-6 alkylene-NHC(O)-C1-6 alkylene- HP2.

[0235] In certain embodiments of Formula (CONJ-IV), (CONJ-IVA), or (CONJ-IVB), including any of the foregoing, R70is –C2-6alkenylene-X2a-[C2-6alkenylene]c1-HP2, wherein each alkenylene of R70is optionally substituted with one or more substituents selected from halogen, -CN, -NO2, -OH, -NR60R61, -C(O)NR60R61, -C(O)-, -C(S)-, -C(O)OCH2C6H5, - NHC(O)OCH2C6H5, C1-10alkyl, C2-10alkenyl, C2-10alkynyl, C3-12carbocycle, 3- to 12- membered heterocycle, and C1-10 haloalkyl. In certain embodiments of Formula (CONJ-IV), (CONJ-IVA), or (CONJ-IVB), including any of the foregoing, R70is –C2-6 alkynylene-X2a- [C2-6alkynylene]c1- HP2, wherein each alkynylene of R70is optionally substituted with one or more substituents selected from halogen, -CN, -NO2, -OH, -NR60R61, -C(O)NR60R61, -C(O)-, -C(S)-, -C(O)OCH2C6H5, -NHC(O)OCH2C6H5, C1-10 alkyl, C2-10 alkenyl, C2-10 alkynyl, C3-12 carbocycle, 3- to 12-membered heterocycle, and C1-10haloalkyl. -B), including any of the foregoing, c is one.

[0236] In certain embodiments of Formula (CONJ-IV), (CONJ-IVA), or (CONJ-IVB), including any of the foregoing, c1 is zero. In certain embodiments of Formula (Ib), (Ib-A), (Ib-B), (Ic), (Ic-A), (Ic-B), (Id), (Id-A), or (Id-B), including any of the foregoing, c1 is one.

[0237] In certain embodiments of Formula (CONJ-IV), (CONJ-IVA), or (CONJ-IVB), including any of the foregoing, R71is independently selected from halogen, -CN, -NO2, -OH, -NH2, -C(O)NH2, and -C(O)-. In certain embodiments of Formula (CONJ-IV), (CONJ-IVA), 91 1104675906\1\AMERICASAttorney Docket No.108843.00582 SU-0514WO or (CONJ-IVB), including any of the foregoing, R71is halogen. In certain embodiments of Formula (CONJ-IV), (CONJ-IVA), or (CONJ-IVB), including any of the foregoing, R71is - CN. In some embodiments, R51is -NO2. In certain embodiments of Formula (CONJ-IV), (CONJ-IVA), or (CONJ-IVB), including any of the foregoing, R71is -OH. In certain embodiments of Formula (CONJ-IV), (CONJ-IVA), or (CONJ-IVB), including any of the foregoing, R71is -NH2. In certain embodiments of Formula (CONJ-IV), (CONJ-IVA), or (CONJ-IVB), including any of the foregoing, R71is -C(O)NH2. In certain embodiments of Formula (CONJ-IV), (CONJ-IVA), or (CONJ-IVB), including any of the foregoing, including any of the foregoing, R71is -C(O)-.

[0238] In certain embodiments of Formula (CONJ-IV), (CONJ-IVA), or (CONJ-IVB), including any of the foregoing, -SG01-Y- is -C1-6alkylene-NHC(O)-C1-6alkylene-[NHC(O)- C1-6 alkylene]2-[C(O)]– wherein at least one alkylene in Y is substituted with one or more substituents selected from R70. In certain embodiments of Formula (CONJ-IV), (CONJ-IVA), or (CONJ-IVB), including any of the foregoing, -SG01-Y- is -CH2-NHC(O)-C2alkylene- NHC(O)-CH2-NHC(O)-C4alkylene-[C(O)]– wherein at least one alkylene in Y is substituted with one or more substituents selected from R70. In certain embodiments of Formula (CONJ- IV), (CONJ-IVA), or (CONJ-IVB), including any of the foregoing, -SG01-Y- is –CH2- NHC(O)-C2alkylene-NHC(O)-CH(R70)-NHC(O)-C4alkylene-[C(O)]– wherein R70is –C1-6alkylene-X2a-[C1-6 alkylene]c1-HP2. In certain embodiments of Formula (CONJ-IV), (CONJ- IVA), or (CONJ-IVB), including any of the foregoing, -SG01-Y- is –CH2-NHC(O)- C2alkylene-NHC(O)-CH(R70)-NHC(O)-C4alkylene-[C(O)]– wherein R70is –C1-6alkylene- X2a-HP2. In certain embodiments of Formula (CONJ-IV), (CONJ-IVA), or (CONJ-IVB), including any of the foregoing, -SG01-Y- is –CH2-NHC(O)-C2alkylene-NHC(O)-CH(R70)- NHC(O)-C4alkylene-[C(O)]– wherein R70is –CH2-NHC(O)-HP2.

[0239] In certain embodiments of Formula (CONJ-IV), (CONJ-IVA), or (CONJ-IVB), including any of the foregoing, -SG01-Y- is -C1-6 alkylene-NHC(O)-C1-6 alkylene-[NHC(O)- C1-6alkylene]2– wherein at least one alkylene in Y is substituted with one or more substituents selected from R70. In certain embodiments of Formula (CONJ-IV), (CONJ-IVA), or (CONJ-IVB), including any of the foregoing, -SG01-Y- is -CH2-NHC(O)-C2alkylene- NHC(O)-CH2-NHC(O)-C4alkylene- wherein at least one alkylene in Y is substituted with one or more substituents selected from R70. In certain embodiments of Formula (CONJ-IV), (CONJ-IVA), or (CONJ-IVB), including any of the foregoing, -SG01-Y- is –CH2-NHC(O)- C2alkylene-NHC(O)-CH(R70)-NHC(O)-C4alkylene- wherein R70is –C1-6 alkylene-X2a-[C1-6 alkylene]c1-HP2. In certain embodiments of Formula (CONJ-IV), (CONJ-IVA), or (CONJ- 92 1104675906\1\AMERICASAttorney Docket No.108843.00582 SU-0514WO IVB), including any of the foregoing, -SG01-Y- is –CH2-NHC(O)-C2alkylene-NHC(O)- CH(R70)-NHC(O)-C4alkylene- wherein R70is –C1-6 alkylene-X2a-HP2. In certain embodiments of Formula (CONJ-IV), (CONJ-IVA), or (CONJ-IVB), including any of the foregoing, - SG01-Y- is –CH2-NHC(O)-C2alkylene-NHC(O)-CH(R70)- NHC(O)-C4alkylene-[C(O)]– wherein R70is –CH2-NHC(O)-HP2.

[0240] In certain embodiments of Formula (CONJ-IV), (CONJ-IVA), or (CONJ-IVB), including any of the foregoing, HP2is polyethylene glycol (PEG), methoxypolyethylene glycol (mPEG), poly(propylene glycol) (PPG), copolymers of ethylene glycol and propylene glycol, poly(oxyethylated polyol), poly(olefinic alcohol), poly(vinylpyrrolidone), poly(hydroxyalkylmethacrylamide), poly(hydroxyalkylmethacrylate), poly(saccharides), poly(α-hydroxy acid), poly(vinyl alcohol), polyphosphazene, polyoxazolines (POZ), poly(N- acryloylmorpholine), polysarcosine, or a combination thereof. In certain embodiments of Formula (CONJ-IV), (CONJ-IVA), or (CONJ-IVB), including any of the foregoing, HP2is polyethylene glycol (PEG). In certain embodiments of Formula (CONJ-IV), (CONJ-IVA), or (CONJ-IVB), including any of the foregoing, HP2is methoxypolyethylene glycol (mPEG). In certain embodiments of Formula (CONJ-IV), (CONJ-IVA), or (CONJ-IVB), including any of the foregoing, HP2is poly(propylene glycol) (PPG). In certain embodiments of Formula (CONJ-IV), (CONJ-IVA), or (CONJ-IVB), including any of the foregoing, HP2is copolymers of ethylene glycol and propylene glycol. In certain embodiments of Formula (CONJ-IV), (CONJ-IVA), or (CONJ-IVB), including any of the foregoing, HP2is poly(oxyethylated polyol). In certain embodiments of Formula (CONJ-IV), (CONJ-IVA), or (CONJ-IVB), including any of the foregoing, HP2is poly(olefinic alcohol). In some embodiments, HP2is poly(vinylpyrrolidone). In certain embodiments of Formula (CONJ-IV), (CONJ-IVA), or (CONJ-IVB), including any of the foregoing, HP2is poly(hydroxyalkylmethacrylamide). In certain embodiments of Formula (CONJ-IV), (CONJ- IVA), or (CONJ-IVB), including any of the foregoing, HP2is poly(hydroxyalkylmethacrylate). In certain embodiments of Formula (CONJ-IV), (CONJ- IVA), or (CONJ-IVB), including any of the foregoing, HP2is poly(saccharides). In some embodiments, HP2is poly(α-hydroxy acid). In certain embodiments of Formula (CONJ-IV), (CONJ-IVA), or (CONJ-IVB), including any of the foregoing, HP2is poly(vinyl alcohol). In some embodiments, HP2is polyphosphazene. In certain embodiments of Formula (CONJ- IV), (CONJ-IVA), or (CONJ-IVB), including any of the foregoing, HP2is polyoxazolines (POZ). In certain embodiments of Formula (CONJ-IV), (CONJ-IVA), or (CONJ-IVB), including any of the foregoing, POLY is poly(N-acryloylmorpholine). In certain 93 1104675906\1\AMERICASAttorney Docket No.108843.00582 SU-0514WO embodiments of Formula (CONJ-IV), (CONJ-IVA), or (CONJ-IVB), including any of the foregoing, HP2is polysarcosine. In certain embodiments of Formula (CONJ-IV), (CONJ- IVA), or (CONJ-IVB), including any of the foregoing, HP2is a nonpeptidic, water-soluble polymer.

[0241] In certain embodiments of Formula (CONJ-IV), (CONJ-IVA), or (CONJ-IVB), including any of the foregoing, HP2is independently a monovalent poly(ethylene glycol). In certain embodiments of Formula (CONJ-IV), (CONJ-IVA), or (CONJ-IVB), including any of the foregoing, HP2iswherein R200is hydrogen or methyl and x20 is an integer between 1 and 50, inclusive; and eachis the point of attachment to the rest of the compound. In certain embodiments of Formula (CONJ-IV), (CONJ-IVA), or (CONJ-IVB), including any of the foregoing, R200is hydrogen. In certain embodiments of Formula (CONJ- IV), (CONJ-IVA), or (CONJ-IVB), including any of the foregoing, R200is methyl.

[0242] In certain embodiments of Formula (CONJ-IV), (CONJ-IVA), or (CONJ-IVB), including any of the foregoing, x20 is an integer between 1 and 20, inclusive. In certain embodiments of Formula (CONJ-IV), (CONJ-IVA), or (CONJ-IVB), including any of the foregoing, x20 is an integer between 10 and 20, inclusive. In certain embodiments of Formula (CONJ-IV), (CONJ-IVA), or (CONJ-IVB), including any of the foregoing, x20 is 12.

[0243] In certain embodiments of Formula (CONJ-IV), (CONJ-IVA), or (CONJ-IVB), including any of the foregoing, x20 is an integer between 1 and 20, inclusive, and R200is hydrogen. In certain embodiments of Formula (CONJ-IV), (CONJ-IVA), or (CONJ-IVB), including any of the foregoing, x20 is an integer between 10 and 20, inclusive, and R200is hydrogen. In certain embodiments of Formula (CONJ-IV), (CONJ-IVA), or (CONJ-IVB), including any of the foregoing, x20 is 12 and R200is hydrogen.

[0244] In certain embodiments of Formula (CONJ-IV), (CONJ-IVA), or (CONJ-IVB), including any of the foregoing, -SG01-Y- is –CH2-NHC(O)-C2alkylene-NHC(O)-CH(R70)- 47022P2NHC(O)-C alkylene-[C(O)]– wherein R is –CH -NHC(O)-HP and H is .

[0245] In some embodiments of Formula (CONJ-III), (CONJ-IV), (CONJ-IVA), or (CONJ- IVB), CY is a cytotoxic agent. Any cytotoxic agent with cytotoxic activity can be used. For example, in certain embodiments, CY is selected from the group consisting of irinotecan, SN- 38, topotecan, exatecan, etoposide, teniposide, tafluposide, hemiasterlins, 3-aminopheny 94 1104675906\1\AMERICASAttorney Docket No.108843.00582 SU-0514WO hemiasterlin, taltobulin (HTI-286) amanitin , deruxtecan (DXd), camptothecins, PNU- 159682, pyrrolobenzodiazepine (PBD), EDA PNU-159682 derivatives, MMAF, MMAE, daunorubicin, anthracycline, doxorubicin, epirubicin, idarubicin, mitoxantrone, valrubicinm, mitoxantrone, valrubicin, cyclophosphamide, mechlorethamine, chlorambucil, melphalan, vorinostat, romidepsin, bortezomib, erlotinib, gefitinib, imatinib, vemurafenib, vismodegib, vemurafenib, azacitidine, azathioprine, capecitabine, cyatarabine, doxifluridine, fluorouracil, gemcitabine, hydroxyurea, mercaptopurine, methotrexate, tioguanine (formerly thioguanine), doxifluridine, gemcitabine, methotrexate, carboplatin, cisplatin, and oxaliplatin.

[0246] In certain embodiments, CY is selected from the group consisting of an alkylating agent, a DNA-crosslinking agent, an anti-tumor antibiotic, an anti-metabolite, an anti-mitotic agent, a histone-deacetylase (HDAC) inhibitor, a telomerase inhibitor, an immunogenic cell death agent, a tubulin inhibitor, and a topoisomerase inhibitor. In certain embodiments, CY is selected from the group consisting of topoisomerase I inhibitor selected from the group consisting of camptothecin, irinotecan, SN-38, topotecan, and exatecan. In certain embodiments, CY is exatecan.

[0247] In some embodiments of Formula (CONJ-III), (CONJ-IV), (CONJ-IVA), or (CONJ-95 1104675906\1\AMERICASAttorney Docket No.108843.00582 SU-0514WO point of attachment to the rest of the formula. In some embodiments of Formula (CONJ-III), (CONJ-IV), (CONJ-IVA), or (CONJ-IVB), CY is independently selected from.

[0248] In some embodiments of Formula (CONJ-III), (CONJ-IV), (CONJ-IVA), or (CONJ- IVB), CY is independently selected from,a derivative thereof; and eachis a point of attachment to the rest of the formula. In some embodiments of Formula (CONJ-III), (CONJ-IV), (CONJ-IVA), or (CONJ-IVB), CY is 96 1104675906\1\AMERICASAttorney Docket No.108843.00582 SU-0514WOderivative thereof.

[0249] In one embodiment of Formula (LP-I), (LP-II), or (LP-IIA), including any of the foregoing, RG is a group comprising an alkyne, cyclooctyne, a strained alkene, a tetrazine, an amine, methylcyclopropene, a thiol, a para-acetyl-phenylalanine residue, an oxyamine, a maleimide, or an azide. In one embodiment of Formula (LP-I), (LP-II), or (LP-IIA), including any of the foregoing, RG is an oxyamine. In one embodiment of Formula (LP-I)-(LP-VA), including any of the foregoing, RG comprises is selected from the group consisting of, 97 1104675906\1\AMERICASAttorney Docket No.108843.00582 SU-0514WO, , , –N3, –NH2, methylcyclopropene, trans cyclooctyne derivatives, and –SH; wherein RTis C1-6alkyl; andrepresents attachment to the remainder of the compound. In one embodiment of Formula (LP-I), (LP-II), or (LP-IIA), including any of the foregoing, RG is .

[0250] In one embodiment of Formula (CONJ-I), (CONJ-II), (CONJ-IIA), (CONJ-IV), (CONJ-IVA), or (CONJ-IVB), RL is a group comprising a triazole, pyridazine, a thiol, or an oxime. In one embodiment of Formula (CONJ-I), (CONJ-II), (CONJ-IIA), (CONJ-IV), (CONJ-IVA), or (CONJ-IVB), RL is a group comprising an oxime.

[0251] In one embodiment of Formula (CONJ-I), (CONJ-II), (CONJ-IIA), (CONJ-IV), (CONJ-IVA), or (CONJ-IVB), RL is selected from the group consisting ofpoint of attachment to the rest of the compound. In one embodiment of Formula (CONJ-I),98 1104675906\1\AMERICASAttorney Docket No.108843.00582 SU-0514WO.

[0252] In one embodiment of Formula (CONJ-IV), (CONJ-IVA), or (CONJ-IVB), RL01is a group comprising a triazole, pyridazine, a thiol, or an oxime. In one embodiment of Formula (CONJ-IV), (CONJ-IVA), or (CONJ-IVB), RL01is a group comprising triazole. In one embodiment of Formula (CONJ-IV), (CONJ-IVA), or (CONJ-IVB), RL is a group comprising an oxime and RL01is a group comprising a triazole.

[0253] In one embodiment of Formula (CONJ-IV), (CONJ-IVA), or (CONJ-IVB), RL01is, 99 1104675906\1\AMERICASAttorney Docket No.108843.00582 SU-0514WOeach is a point of attachment to the rest of the compound. embodiment of Formula (CONJ-IV), (CONJ-IVA), or (CONJ-IVB), RL01is selected from the group consistingmixture thereof. In one embodiment of Formula (CONJ-IV), (CONJ-IVA), or (CONJ-IVB), including any of the foregoing, RL isand RL01is selected from the group consisting of.

[0254] In one embodiment,.

[0255] In one embodiment of Formula (LP-II), (LP-IIA), (CONJ-II), (CONJ-IIA), (CONJ- IV), (CONJ-IVA), (CONJ-IVB), (CA-II), or (CA-IIA), including any of the foregoing, W1- 100 1104675906\1\AMERICASAttorney Docket No.108843.00582 SU-0514WO; w e e represents attachment to the remainder of the compound.

[0256] In one embodiment of Formula (LP-II), (LP-IIA), (CONJ-II), (CONJ-IIA), (CONJ- IV), (CONJ-IVA), (CONJ-IVB), (CA-II), or (CA-IIA), including any of the foregoing, W1- W2-SG-HP- is selected from, 101 1104675906\1\AMERICASAttorney Docket No.108843.00582 SU-0514WO.

[0257] In one embodiment of Formula (CONJ-IV), (CONJ-IVA), or (CONJ-IVB), including any of the foregoing, W1-W2-SG-HP- is selected,, 102 1104675906\1\AMERICASAttorney Docket No.108843.00582 SU-0514WOremainder of the compound.

[0258] In one embodiment of Formula (CONJ-IV), (CONJ-IVA), or (CONJ-IVB), including any of the foregoing, W1-W2-SG-HP- is selected from, 103 1104675906\1\AMERICASAttorney Docket No.108843.00582 SU-0514WO. 104 1104675906\1\AMERICASAttorney Docket No.108843.00582 SU-0514WO

[0259] In one embodiment of Formula (LP-I), (LP-II) or (LP-IIA), the linker-payload is selected from the compounds of Table B:105 1104675906\1\AMERICASAttorney Docket No.108843.00582 SU-0514WO106 1104675906\1\AMERICASAttorney Docket No.108843.00582 SU-0514WO107 1104675906\1\AMERICASAttorney Docket No.108843.00582 SU-0514WO

[0260] In one embodiment of Formula (LP-I), (LP-II) or (LP-IIA), the linker-payload is selected from the compounds of Table B-1:108 1104675906\1\AMERICASAttorney Docket No.108843.00582 SU-0514WO109 1104675906\1\AMERICASAttorney Docket No.108843.00582 SU-0514WOor a pharmaceutically acceptable salt, stereoisomer, or tautomer thereof. 110 1104675906\1\AMERICASAttorney Docket No.108843.00582 SU-0514WO

[0261] In one embodiment of Formula (CONJ-I), (CONJ-II) or (CONJ-IIA), the conjugate is selected from the compounds of Table C:111 1104675906\1\AMERICASAttorney Docket No.108843.00582 SU-0514WO112 1104675906\1\AMERICASAttorney Docket No.108843.00582 SU-0514WO113 1104675906\1\AMERICASAttorney Docket No.108843.00582 SU-0514WOor a pharmaceutically acceptable salt, stereoisomer, or tautomer thereof.

[0262] In one embodiment of Formula (CONJ-I), (CONJ-II) or (CONJ-IIA), the conjugate is selected from the compounds of Table C-1:114 1104675906\1\AMERICASAttorney Docket No.108843.00582 SU-0514WO115 1104675906\1\AMERICASAttorney Docket No.108843.00582 SU-0514WO116 1104675906\1\AMERICASAttorney Docket No.108843.00582 SU-0514WOor a pharmaceutically acceptable salt, stereoisomer, or tautomer thereof.

[0263] In one embodiment of Formula (CONJ-IV),selected from the 117 1104675906\1\AMERICASAttorney Docket No.108843.00582 SU-0514WO

[0264] In one embodiment of Formula (CONJ-IV),selected from the 118 1104675906\1\AMERICASAttorney Docket No.108843.00582 SU-0514WO119 1104675906\1\AMERICASAttorney Docket No.108843.00582 SU-0514WO

[0265] In one embodiment of Formula (CONJ-IV), the conjugate is selected from the compounds of Table C-2:120 1104675906\1\AMERICASAttorney Docket No.108843.00582 SU-0514WO121 1104675906\1\AMERICASAttorney Docket No.108843.00582 SU-0514WO122 1104675906\1\AMERICASAttorney Docket No.108843.00582 SU-0514WO 123 1104675906\1\AMERICASAttorney Docket No.108843.00582 SU-0514WO124 1104675906\1\AMERICASAttorney Docket No.108843.00582 SU-0514WO

[0266] In one embodiment of Formula (CONJ-I)-(CONJ-IVB), including any of the foregoing, x is an integer selected from 1 to 25. In one embodiment of Formula (CONJ-I)- (CONJ-IVB), including any of the foregoing, x is an integer selected from 1 to 20. In one embodiment of Formula (CONJ-I)-(CONJ-IVB), including any of the foregoing, x is an integer selected from 1 to 15. In one embodiment of Formula (CONJ-I)-(CONJ-IVB), including any of the foregoing, x is an integer selected from 1 to 10. In one embodiment of Formula (CONJ-I)-(CONJ-IVB), including any of the foregoing, x is an integer selected from 1 to 8. In one embodiment of Formula (CONJ-I)-(CONJ-IVB), including any of the foregoing, x is an integer selected from 1 to 6. In one embodiment of Formula (CONJ-I)- (CONJ-IVB), including any of the foregoing, x an integer selected from 1 to 4.

[0267] In one embodiment of Formula (CONJ-III)-(CONJ-IVB), including any of the foregoing, xx is an integer selected from 1 to 25. In one embodiment of Formula (CONJ-III)- (CONJ-IVB), including any of the foregoing, xx is an integer selected from 1 to 20. In one embodiment of Formula (CONJ-III)-(CONJ-IVB), including any of the foregoing, xx is an integer selected from 1 to 15. In one embodiment of Formula (CONJ-III)-(CONJ-IVB), including any of the foregoing, xx is an integer selected from 1 to 10. In one embodiment of Formula (CONJ-III)-(CONJ-IVB), including any of the foregoing, xx is an integer selected from 1 to 8. In one embodiment of Formula (CONJ-III)-(CONJ-IVB), including any of the foregoing, xx is an integer selected from 1 to 6. In one embodiment of Formula (CONJ-I)- (CONJ-IVB), including any of the foregoing, x an integer selected from 1 to 4.

[0268] In one embodiment of Formula (CONJ-III)-(CONJ-IVB), including any of the foregoing, x is an integer selected from 1 to 10 and xx is an integer selected from 1 to 10. In one embodiment of Formula (CONJ-III)-(CONJ-IVB), including any of the foregoing, x is an integer selected from 1 to 8 and xx is an integer selected from 1 to 8. In one embodiment of Formula (CONJ-III)-(CONJ-IVB), including any of the foregoing, x is an integer selected from 1 to 6 and xx is an integer selected from 1 to 6. In one embodiment of Formula (CONJ- III)-(CONJ-IVB), including any of the foregoing, x is an integer selected from 1 to 4 and xx is an integer selected from 1 to 4. In one embodiment of Formula (CONJ-III)-(CONJ-IVB), including any of the foregoing, x is 2 and xx is 4. In one embodiment of Formula (CONJ-III)- (CONJ-IVB), including any of the foregoing, the molar ratio of x to xx is 1:2. In one embodiment of Formula (CONJ-III)-(CONJ-IVB), including any of the foregoing, the molar ratio of x to xx is 1:1. In one embodiment of Formula (CONJ-III)-(CONJ-IVB), including any of the foregoing, the molar ratio of x to xx is 2:1. 125 1104675906\1\AMERICASAttorney Docket No.108843.00582 SU-0514WO

[0269] In one embodiment of Formula (CA-I), (CA-II) or (CA-IIA), the catabolite is selected from the compounds of Table D:126 1104675906\1\AMERICASAttorney Docket No.108843.00582 SU-0514WO

[0270] In one embodiment of Formula (CA-I), (CA-II) or (CA-IIA), the catabolite is selected127 1104675906\1\AMERICASAttorney Docket No.108843.00582 SU-0514WOii. COMP

[0271] The COMP of Formula (CONJ-I), (CONJ-II), (CONJ-IIA), (CONJ-IV), (CONJ-IVA), or (CONJ-IVB), can be any macromolecule deemed suitable by the person of skill in the art. In certain embodiments, the macromolecule is a second compound. In certain embodiments, the macromolecule is a protein, peptide, antibody or antigen-binding fragment thereof, nucleic acid, carbohydrate, or other large molecule composed of polymerized monomers. In certain embodiments, the macromolecule is a peptide of two or more residues. In certain embodiments, the macromolecule is a peptide of ten or more residues. In certain embodiments, the macromolecule is at least 1000 Da in mass. In certain embodiments, the macromolecule comprises at least 1000 atoms. Useful macromolecules are described in the sections below.

[0272] In certain embodiments, the macromolecule is a protein, peptide, antibody or antigen binding fragment thereof, nucleic acid, carbohydrate, or other large molecule composed of polymerized monomers. In certain embodiments, the macromolecule is a protein. In certain embodiments, the macromolecule is an antibody, or an antigen binding fragment thereof. In 128 1104675906\1\AMERICASAttorney Docket No.108843.00582 SU-0514WO some embodiments, COMP is a polypeptide. In some embodiments, COMP is an antibody. In some embodiments, COMP is an antibody fragment.

[0273] In some embodiments, the macromolecule is a known antibody. Useful antibodies include, but are not limited to, rituximab (Rituxan®, IDEC / Genentech / Roche) (see, e.g., U.S. Pat. No.5,736,137), a chimeric anti-CD20 antibody approved to treat Non-Hodgkin’s lymphoma; HuMax-CD20, an anti-CD20 currently being developed by Genmab, an anti- CD20 antibody described in U.S. Pat. No.5,500,362, AME-133 (Applied Molecular Evolution), hA20 (Immunomedics, Inc.), HumaLYM (Intracel), and PRO70769 (PCT Application No. PCT / US2003 / 040426), trastuzumab (Herceptin®, Genentech) (see, e.g., U.S. Pat. No.5,677,171), a humanized anti-Her2 / neu antibody approved to treat breast cancer; pertuzumab (rhuMab-2C4, Omnitarg®), currently being developed by Genentech; an anti- Her2 antibody (U.S. Pat. No.4,753,894; cetuximab (Erbitux®, Imclone) (U.S. Pat. No. 4,943,533; PCT Publication No. WO 96 / 40210), a chimeric anti-EGFR antibody in clinical trials for a variety of cancers; ABX-EGF (U.S. Pat. No.6,235,883), currently being developed by Abgenix-Immunex-Amgen; HuMax-EGFr (U.S. Pat. No.7,247,301), currently being developed by Genmab; 425, EMD55900, EMD62000, and EMD72000 (Merck KGaA) (U.S. Pat. No.5,558,864; Murthy, et al. (1987) Arch. Biochem. Biophys.252(2): 549-60; Rodeck, et al. (1987) J. Cell. Biochem.35(4): 315-20; Kettleborough, et al. (1991) Protein Eng.4(7): 773-83); ICR62 (Institute of Cancer Research) (PCT Publication No. WO 95 / 20045; Modjtahedi, et al. (1993) J. Cell. Biophys.22(I-3): 129-46; Modjtahedi, et al. (1993) Br. J. Cancer 67(2): 247-53; Modjtahedi, et al. (1996) Br. J. Cancer 73(2): 228-35; Modjtahedi, et al. (2003) Int. J. Cancer 105(2): 273-80); TheraCIM hR3 (YM Biosciences, Canada and Centro de Immunologia Molecular, Cuba (U.S. Pat. No.5,891,996; U.S. Pat. No. 6,506,883; Mateo, et al. (1997) Immunotechnol.3(1): 71-81); mAb-806 (Ludwig Institute for Cancer Research, Memorial Sloan-Kettering) (Jungbluth, et al. (2003) Proc. Natl. Acad. Sci. USA.100(2): 639-44); KSB-102 (KS Biomedix); MR1-1 (IVAX, National Cancer Institute) (PCT Publication No. WO 01 / 62931A2); and SC100 (Scancell) (PCT Publication No. WO 01 / 88138); alemtuzumab (Campath®, Millenium), a humanized mAb currently approved for treatment of B-cell chronic lymphocytic leukemia; muromonab-CD3 (Orthoclone OKT3®), an anti-CD3 antibody developed by Ortho Biotech / Johnson & Johnson, ibritumomab tiuxetan (Zevalin®), an anti-CD20 antibody developed by IDEC / Schering AG, gemtuzumab ozogamicin (Mylotarg®), an anti-CD33 (p67 protein) antibody developed by Celltech / Wyeth, alefacept (Amevive®), an anti-LFA-3 Fc fusion developed by Biogen), abciximab (ReoPro®), developed by Centocor / Lilly, basiliximab (Simulect®), developed by 129 1104675906\1\AMERICASAttorney Docket No.108843.00582 SU-0514WO Novartis, palivizumab (Synagis®), developed by Medimmune, infliximab (Remicade®), an anti-TNFalpha antibody developed by Centocor, adalimumab (Humira®), an anti-TNFalpha antibody developed by Abbott, Humicade®, an anti-TNFalpha antibody developed by Celltech, golimumab (CNTO-148), a fully human TNF antibody developed by Centocor, etanercept (Enbrel®), an p75 TNF receptor Fc fusion developed by Immunex / Amgen, Ienercept, an p55TNF receptor Fc fusion previously developed by Roche, ABX-CBL, an anti-CD147 antibody being developed by Abgenix, ABX-IL8, an anti-IL8 antibody being developed by Abgenix, ABX-MA1, an anti-MUC18 antibody being developed by Abgenix, Pemtumomab (R1549, 90Y-muHMFG1), an anti-MUC1 in development by Antisoma, Therex (R1550), an anti-MUC1 antibody being developed by Antisoma, AngioMab (AS1405), being developed by Antisoma, HuBC-1, being developed by Antisoma, Thioplatin (AS1407) being developed by Antisoma, Antegren® (natalizumab), an anti-alpha-4-beta-1 (VLA-4) and alpha-4-beta-7 antibody being developed by Biogen, VLA-1 mAb, an anti- VLA-1 integrin antibody being developed by Biogen, LTBR mAb, an anti-lymphotoxin beta receptor (LTBR) antibody being developed by Biogen, CAT-152, an anti-TGF-β antibody being developed by Cambridge Antibody Technology, ABT 874 (J695), an anti-IL-12 p40 antibody being developed by Abbott, CAT-192, an anti-TGFβ1 antibody being developed by Cambridge Antibody Technology and Genzyme, CAT-213, an anti-Eotaxin1 antibody being developed by Cambridge Antibody Technology, LymphoStat-B® an anti-Blys antibody being developed by Cambridge Antibody Technology and Human Genome Sciences Inc., TRAIL-R1 mAb, an anti-TRAIL-R1 antibody being developed by Cambridge Antibody Technology and Human Genome Sciences, Inc., Avastin® bevacizumab, rhuMAb-VEGF), an anti-VEGF antibody being developed by Genentech, an anti-HER receptor family antibody being developed by Genentech, Anti-Tissue Factor (ATF), an anti-Tissue Factor antibody being developed by Genentech, Xolair® (Omalizumab), an anti-IgE antibody being developed by Genentech, Raptiva® (Efalizumab), an anti-CD11a antibody being developed by Genentech and Xoma, MLN-02 Antibody (formerly LDP-02), being developed by Genentech and Millenium Pharmaceuticals, HuMax CD4, an anti-CD4 antibody being developed by Genmab, HuMax-IL15, an anti-IL15 antibody being developed by Genmab and Amgen, HuMax-Inflam, being developed by Genmab and Medarex, HuMax-Cancer, an anti- Heparanase I antibody being developed by Genmab and Medarex and Oxford GlycoSciences, HuMax-Lymphoma, being developed by Genmab and Amgen, HuMax-TAC, being developed by Genmab, IDEC-131, and anti-CD40L antibody being developed by IDEC Pharmaceuticals, IDEC-151 (Clenoliximab), an anti-CD4 antibody being developed by IDEC 130 1104675906\1\AMERICASAttorney Docket No.108843.00582 SU-0514WO Pharmaceuticals, IDEC-114, an anti-CD80 antibody being developed by IDEC Pharmaceuticals, IDEC-152, an anti-CD 23 being developed by IDEC Pharmaceuticals, anti- macrophage migration factor (MIF) antibodies being developed by IDEC Pharmaceuticals, BEC2, an anti-idiotypic antibody being developed by Imclone, IMC-1C11, an anti-KDR antibody being developed by Imclone, DC101, an anti-flk-1 antibody being developed by Imclone, anti-VE cadherin antibodies being developed by Imclone, CEA-Cide® (Iabetuzumab), an anti-carcinoembryonic antigen (CEA) antibody being developed by Immunomedics, LymphoCide® (Epratuzumab), an anti-CD22 antibody being developed by Immunomedics, AFP-Cide, being developed by Immunomedics, MyelomaCide, being developed by Immunomedics, LkoCide, being developed by Immunomedics, ProstaCide, being developed by Immunomedics, MDX-010, an anti-CTLA4 antibody being developed by Medarex, MDX-060, an anti-CD30 antibody being developed by Medarex, MDX-070 being developed by Medarex, MDX-018 being developed by Medarex, Osidem® (IDM-1), and anti-Her2 antibody being developed by Medarex and Immuno-Designed Molecules, HuMax®-CD4, an anti-CD4 antibody being developed by Medarex and Genmab, HuMax- IL15, an anti-IL15 antibody being developed by Medarex and Genmab, CNTO 148, an anti- TNFα antibody being developed by Medarex and Centocor / J&J, CNTO 1275, an anti- cytokine antibody being developed by Centocor / J&J, MOR101 and MOR102, anti- intercellular adhesion molecule-1 (ICAM-1) (CD54) antibodies being developed by MorphoSys, MOR201, an anti-fibroblast growth factor receptor 3 (FGFR-3) antibody being developed by MorphoSys, Nuvion® (visilizumab), an anti-CD3 antibody being developed by Protein Design Labs, HuZAF®, an anti-gamma interferon antibody being developed by Protein Design Labs, Anti-α5β1 Integrin, being developed by Protein Design Labs, anti-IL- 12, being developed by Protein Design Labs, ING-1, an anti-Ep-CAM antibody being developed by Xoma, Xolair® (Omalizumab) a humanized anti-IgE antibody developed by Genentech and Novartis, and MLN01, an anti-Beta2 integrin antibody being developed by Xoma.

[0274] In another embodiment, the therapeutics include KRN330 (Kirin); huA33 antibody (A33, Ludwig Institute for Cancer Research); CNTO 95 (alpha V integrins, Centocor); MEDI-522 (alpha Vβ3integrin, Medimmune); volociximab (alpha Vβ1 integrin, Biogen / PDL); Human mAb 216 (B cell glycosolated epitope, NCl); BiTE MT103 (bispecific CD19×CD3, Medimmune); 4G7×H22 (Bispecific Bcell×FcgammaR1, Medarex / Merck Kga); rM28 (Bispecific CD28×MAPG, EP Patent No. EP1444268); MDX447 (EMD 82633) (Bispecific CD64×EGFR, Medarex); Catumaxomab (removab) (Bispecific EpCAM× anti- 131 1104675906\1\AMERICASAttorney Docket No.108843.00582 SU-0514WO CD3, Trion / Fres); Ertumaxomab (bispecific HER2 / CD3, Fresenius Biotech); oregovomab (OvaRex) (CA-125, ViRexx); Rencarex® (WX G250) (carbonic anhydrase IX, Wilex); CNTO 888 (CCL2, Centocor); TRC105 (CD105 (endoglin), Tracon); BMS-663513 (CD137 agonist, Bristol Myers Squibb); MDX-1342 (CD19, Medarex); Siplizumab (MEDI-507) (CD2, Medimmune); Ofatumumab (Humax-CD20) (CD20, Genmab); Rituximab (Rituxan) (CD20, Genentech); veltuzumab (hA20) (CD20, Immunomedics); Epratuzumab (CD22, Amgen); lumiliximab (IDEC 152) (CD23, Biogen); muromonab-CD3 (CD3, Ortho); HuM291 (CD3 fc receptor, PDL Biopharma); HeFi-1, CD30, NCl); MDX-060 (CD30, Medarex); MDX-1401 (CD30, Medarex); SGN-30 (CD30, Seattle Genentics); SGN-33 (Lintuzumab) (CD33, Seattle Genentics); Zanolimumab (HuMax-CD4) (CD4, Genmab); HCD122 (CD40, Novartis); SGN-40 (CD40, Seattle Genentics); MabCampath (Alemtuzumab) (CD52, Genzyme); MDX-1411 (CD70, Medarex); hLL1 (EPB-1) (CD74.38, Immunomedics); Galiximab (IDEC-144) (CD80, Biogen); MT293 (TRC093 / D93) (cleaved collagen, Tracon); HuLuc63 (CS1, PDL Pharma); ipilimumab (MDX-010) (CTLA4, Bristol Myers Squibb); Tremelimumab (Ticilimumab, CP-675,2) (CTLA4, Pfizer); HGS-ETR1 (Mapatumumab) (DR4TRAIL-R1 agonist, Human Genome Science / Glaxo Smith Kline); AMG-655 (DR5, Amgen); Apomab (DR5, Genentech); CS-1008 (DR5, Daiichi Sankyo); HGS-ETR2 (lexatumumab) (DR5TRAIL-R2 agonist, HGS); Cetuximab (Erbitux) (EGFR, Imclone); IMC-11F8, (EGFR, Imclone); Nimotuzumab (EGFR, YM Bio); Panitumumab (Vectabix) (EGFR, Amgen); Zalutumumab (HuMaxEGFr) (EGFR, Genmab); CDX-110 (EGFRvIII, AVANT Immunotherapeutics); adecatumumab (MT201) (Epcam, Merck); edrecolomab (Panorex, 17-1A) (Epcam, Glaxo / Centocor); MORAb-003 (folate receptor a, Morphotech); KW-2871 (ganglioside GD3, Kyowa); MORAb-009 (GP-9, Morphotech); CDX-1307 (MDX-1307) (hCGb, Celldex); Trastuzumab (Herceptin) (HER2, Celldex); Pertuzumab (rhuMAb 2C4) (HER2 (DI), Genentech); apolizumab (HLA-DR beta chain, PDL Pharma); AMG-479 (IGF-1R, Amgen); anti-IGF-1R R1507 (IGF1-R, Roche); CP 751871 (IGF1-R, Pfizer); IMC-A12 (IGF1-R, Imclone); BIIB022 (IGF-1R, Biogen); Mik-beta-1 (IL- 2Rb (CD122), Hoffman-La Roche); CNTO 328 (IL6, Centocor); Anti-KIR (1-7F9) (Killer cell Ig-like Receptor (KIR), Novo); Hu3S193 (Lewis (y), Wyeth, Ludwig Institute of Cancer Research); hCBE-11 (LTβR, Biogen); HuHMFG1 (MUC1, Antisoma / NCl); RAV12 (N- linked carbohydrate epitope, Raven); CAL (parathyroid hormone-related protein (PTH-rP), University of California); CT-011 (PD1, CureTech); MDX-1106 (ono-4538) (PD1, Medarex / Ono); Mab CT-011 (PD1, Curetech); IMC-3G3 (PDGFRa, Imclone); bavituximab (phosphatidylserine, Peregrine); huJ591 (PSMA, Cornell Research Foundation); muJ591 132 1104675906\1\AMERICASAttorney Docket No.108843.00582 SU-0514WO (PSMA, Cornell Research Foundation); GC1008 (TGFb (pan) inhibitor (IgG4), Genzyme); Infliximab (Remicade) (TNFa, Centocor); A27.15 (transferrin receptor, Salk Institute, INSERN WO 2005 / 111082); E2.3 (transferrin receptor, Salk Institute); Bevacizumab (Avastin) (VEGF, Genentech); HuMV833 (VEGF, Tsukuba Research Lab, PCT Publication No. WO / 2000 / 034337, University of Texas); IMC-18F1 (VEGFR1, Imclone); IMC-1121 (VEGFR2, Imclone).

[0275] In certain embodiments, the antibody is an anti-TROP2 antibody, including, but not limited to GS-0132, IMMU-132, Dato-DXd, DS-1062a, MK-2870, SKB264, SHR-A1921, 9MW2921, BAT8008, BIO-106, BL-M02D1, DB-1305, ESG-401, HS-20105, IBI130, LCB84, MHB036C, BAT8003, DXC1002, FDA018, FZ-AD004, JS108, PF-06664178 or STI-3258. In certain embodiments, the anti-TROP2 antibody is selected from Sacituzumab (hRS7) and Datopotamab.

[0276] Examples of useful bispecific antibodies include, but are not limited to, those with one antibody directed against a tumor cell antigen and the other antibody directed against a cytotoxic trigger molecule such as anti-FcγRI / anti-CD 15, anti-p185HER2 / FcγRIII (CD16), anti-CD3 / anti-malignant B-cell (1D10), anti-CD3 / anti-p185HER2, anti-CD3 / anti-p97, anti- CD3 / anti-renal cell carcinoma, anti-CD3 / anti-OVCAR-3, anti-CD3 / L-D1 (anti-colon carcinoma), anti-CD3 / anti-melanocyte stimulating hormone analog, anti-EGF receptor / anti- CD3, anti-CD3 / anti-CAMA1, anti-CD3 / anti-CD19, anti-CD3 / MoV18, anti-neural cell adhesion molecule (NCAM) / anti-CD3, anti-folate binding protein (FBP) / anti-CD3, anti-pan carcinoma associated antigen (AMOC-31) / anti-CD3; bispecific antibodies with one antibody which binds specifically to a tumor antigen and another antibody which binds to a toxin such as anti-saporin / anti-Id-1, anti-CD22 / anti-saporin, anti-CD7 / anti-saporin, anti-CD38 / anti- saporin, anti-CEA / anti-ricin A chain, anti-interferon-α (IFN-α) / anti-hybridoma idiotype, anti- CEA / anti-vinca alkaloid; bispecific antibodies for converting enzyme activated prodrugs such as anti-CD30 / anti-alkaline phosphatase (which catalyzes conversion of mitomycin phosphate prodrug to mitomycin alcohol); bispecific antibodies which can be used as fibrinolytic agents such as anti-fibrin / anti-tissue plasminogen activator (tPA), anti-fibrin / anti-urokinase-type plasminogen activator (uPA); bispecific antibodies for targeting immune complexes to cell surface receptors such as anti-low density lipoprotein (LDL) / anti-Fc receptor (e.g., FcγRI, FcγRII or FcγRIII); bispecific antibodies for use in therapy of infectious diseases such as anti-CD3 / anti-herpes simplex virus (HSV), anti-T-cell receptor:CD3 complex / anti-influenza, anti-FcγR / anti-HIV; bispecific antibodies for tumor detection in vitro or in vivo such as anti- CEA / anti-EOTUBE, anti-CEA / anti-DPTA, anti- anti-p185HER2 / anti-hapten; bispecific 133 1104675906\1\AMERICASAttorney Docket No.108843.00582 SU-0514WO antibodies as vaccine adjuvants (see Fanger, M W et al., Crit Rev Immunol.1992; 12(34):101-24, which is incorporated by reference herein); and bispecific antibodies as diagnostic tools such as anti-rabbit IgG / anti-ferritin, anti-horse radish peroxidase (HRP) / anti- hormone, anti-somatostatin / anti-substance P, anti-HRP / anti-FITC, anti-CEA / anti-β- galactosidase (see Nolan, O. and O'Kennedy, R., Biochim Biophys Acta.1990 Aug.1; 1040(1):1-11, which is incorporated by reference herein). Examples of trispecific antibodies include anti-CD3 / anti-CD4 / anti-CD37, anti-CD3 / anti-CD5 / anti-CD37 and anti-CD3 / anti- CD8 / anti-CD37. iii. Non-natural or Modified Amino Acids

[0277] When the antibody conjugate comprises a modified amino acid, the modified amino acid can be any modified amino acid deemed suitable by the practitioner. In particular embodiments, the modified amino acid comprises a reactive group useful for forming a covalent bond to a linker precursor or to a payload precursor. In certain embodiments, the modified amino acid is a non-natural amino acid. In certain embodiments, the reactive group is selected from the group consisting of amino, carboxy, acetyl, hydrazino, hydrazido, semicarbazido, sulfanyl, azido and alkynyl. Modified amino acids are also described in, for example, WO 2013 / 185115 and WO 2015 / 006555, each of which is incorporated herein by reference in its entirety. In certain embodiments, the non-natural or modified amino acid for use in the present conjugates are those described in WO 2013 / 185115 and WO 2015 / 006555, each of which is incorporated herein by reference in its entirety.

[0278] In particular embodiments of Formula (CONJ-I), (CONJ-II), and (CONJ-IIA), the antibody or the antigen-binding fragment thereof in the antibody conjugate comprises at least one modified amino acid residues suitable for conjugation that is covalently linked to L.

[0279] In particular embodiments of Formula (CONJ-IIII), (CONJ-IV), (CONJ-IVA), and (CONJ-IVB), the antibody or the antigen-binding fragment thereof in the antibody conjugate comprises at least two modified amino acid residues suitable for conjugation that are covalently linked to Laand / or Lb. In particular embodiments, the antibody or the antigen- binding fragment thereof in the antibody conjugate comprises at least three modified amino acid residues suitable for conjugation that are covalently linked to Laand / or Lb. In particular embodiments, the antibody or the antigen-binding fragment thereof in the antibody conjugate comprises (a) a modified amino acid residue suitable for conjugation that is covalently linked to Laand (b) a modified amino acid residue suitable for conjugation that is covalently linked to Lband different than the modified amino acid in (a). 134 1104675906\1\AMERICASAttorney Docket No.108843.00582 SU-0514WO

[0280] In particular embodiments, the modified amino acid residue is independently selected from the group consisting of ortho-substituted tyrosine, meta substituted tyrosine, para- substituted phenylalanine, ortho-substituted phenylalanine, and meta-substituted phenylalanine. In particular embodiments, the modified amino acid residue is selected from the group consisting of p-acetyl-L-phenylalanine, O-methyl-L-tyrosine, 3-methyl- phenylalanine, O-4-allyl-L-tyrosine, 4-propyl-L-tyrosine, fluorinated phenylalanine, isopropyl-L-phenylalanine, p-azido-L-phenylalanine, p-acyl-L-phenylalanine, p-A benzoyl- L-phenylalanine, p-iodo-phenylalanine, p-bromophenylalanine, p-amino-L-phenylalanine, isopropyl-L-phenylalanine, p-propargyloxy-phenylalanine, and p-azidomethyl-L-phenyl alanine. In particular embodiments, the modified amino acid residue is selected from the group consisting of p-azidomethyl-L-phenyl alanine and p-acetyl-L-phenylalanine.

[0281] In particular embodiments, provided herein are conjugates according to any of the conjugates described herein wherein Ab comprises a residue of the modified amino acid according to Formula (30), below. In particular embodiments, provided herein are conjugates according to any of the conjugates described herein wherein Ab comprises a residue of the modified amino acid according to Formula (30), below, at heavy chain position 404 according to the EU numbering system. In particular embodiments, provided herein are conjugates according to any of the conjugates described herein wherein Ab comprises a residue of the modified amino acid according to Formula (30), below, at heavy chain position 180 according to the EU numbering system. In particular embodiments, provided herein are conjugates according to any of the conjugates described herein wherein Ab comprises a residue of the modified amino acid according to Formula (30), below, at heavy chain position 241 according to the EU numbering system. In particular embodiments, provided herein are conjugates according to any of the conjugates described herein wherein Ab comprises a residue of the modified amino acid according to Formula (30), below, at heavy chain position 222 according to the EU numbering system. In particular embodiments, provided herein are conjugates according to any of the conjugates described herein wherein Ab comprises a residue of the modified amino acid according to Formula (30), below, at light chain position 7 according to the Kabat or Chothia numbering system. In particular embodiments, provided herein are conjugates according to any of the conjugates described herein wherein Ab comprises a residue of the modified amino acid according to Formula (30), below, at light chain position 42 according to the Kabat or Chothia numbering system. 135 1104675906\1\AMERICASAttorney Docket No.108843.00582 SU-0514WO

[0282] In particular embodiments, provided herein are conjugates according to any of the conjugates described herein wherein Ab comprises a residue of the modified amino acid according to Formula (65), below. In particular embodiments, provided herein are conjugates according to any of the conjugates described herein wherein Ab comprises a residue of the modified amino acid according to Formula (65), below, at heavy chain position 404 according to the EU numbering system. In particular embodiments, provided herein are conjugates according to any of the conjugates described herein wherein Ab comprises a residue of the modified amino acid according to Formula (65), below, at heavy chain position 180 according to the EU numbering system. In particular embodiments, provided herein are conjugates according to any of the conjugates described herein wherein Ab comprises a residue of the modified amino acid according to Formula (65), below, at heavy chain position 241 according to the EU numbering system. In particular embodiments, provided herein are conjugates according to any of the conjugates described herein wherein Ab comprises a residue of the modified amino acid according to Formula (65), below, at heavy chain position 222 according to the EU numbering system. In particular embodiments, provided herein are conjugates according to any of the conjugates described herein wherein Ab comprises a residue of the modified amino acid according to Formula (65), below, at light chain position 7 according to the Kabat or Chothia numbering system. In particular embodiments, provided herein are conjugates according to any of the conjugates described herein wherein Ab comprises a residue of the modified amino acid according to Formula (65), below, at light chain position 42 according to the Kabat or Chothia numbering system.

[0283] In particular embodiments, provided herein are conjugates according to any of the conjugates described herein wherein Ab comprises a modified amino acid residue of para- 136 1104675906\1\AMERICASAttorney Docket No.108843.00582 SU-0514WO azido-L-phenylalanine. In particular embodiments, provided herein are conjugates according to any of the conjugates described herein wherein Ab comprises the modified amino acid residue para-azido-phenylalanine at heavy chain position 404 according to the EU numbering system. In particular embodiments, provided herein are conjugates according to any of the conjugates described herein wherein Ab comprises a modified amino acid residue of para- azido-L-phenylalanine at heavy chain position 180 according to the EU numbering system. In particular embodiments, provided herein are conjugates according to any of the conjugates described herein wherein Ab comprises a modified amino acid residue para-azido-L- phenylalanine at heavy chain position 241 according to the EU numbering system. In particular embodiments, provided herein are conjugates according to any of the conjugates described herein wherein Ab comprises a modified amino acid residue para-acetyl- phenylalanine at light chain position 42 according to the Kabat or Chothia numbering system. In particular embodiments, the antibody of the antibody conjugate comprises modified amino acid residues at least two positions selected from the group consisting of heavy chain position 180 according to the EU numbering system (HC-Y180), heavy chain position 241 according to the EU numbering system (HC-F241), heavy chain position 404 according to the EU numbering system (HC-F404), and light chain position 42 according to the Kabat or Chothia numbering system (LC-K42). In particular embodiments, the antibody of the antibody conjugate comprises modified amino acid residues at HC-Y180, HC-F404 and LC-K42. In particular embodiments, the antibody of the antibody conjugate comprises modified amino acid residues at HC-F241, HC-F404 and LC-K42. In particular embodiments, the anti- TROP2 antibody of the antibody conjugate comprises p-azidomethyl-L-phenyl alanine residues at HC-Y180 and HC-F404 and p-acetyl-L-phenylalanine residue at LC-K42. In particular embodiments, the = antibody of the antibody conjugate comprises p-azidomethyl- L-phenyl alanine residues at HC-Y241 and HC-F404 and p-acetyl-L-phenylalanine residue at LC-K42.

[0284] In any of the foregoing embodiments, for instance wherein the antibody conjugate has a structure according to a formula described herein, for example, according to any one of the Formulas in Table C-2, the bracketed structures (structures bracketed by either x or xx) can be covalently bonded to one or more non-natural or modified amino acids of the antibody, wherein the one or more non-natural or modified amino acids are located at sites independently selected from the group consisting of: HC-F241, HC-F404, HC-Y180, and LC- K42, and combinations thereof, according to the Kabat or EU numbering scheme of Kabat. In some embodiments, a bracketed structure is covalently bonded to one or more non-natural or 137 1104675906\1\AMERICASAttorney Docket No.108843.00582 SU-0514WO modified amino acids at site HC-F404 of the antibody. In some embodiments, a bracketed structure is covalently bonded to one or more non-natural or modified amino acids at site HC-Y180 of the antibody. In some embodiments, a bracketed structure is covalently bonded to one or more non-natural or modified amino acids at site HC-F241 of the antibody. In some embodiments, a bracketed structure is covalently bonded to one or more non-natural or modified amino acids at site LC-K42 of the antibody. In some embodiments, a bracketed structure is covalently bonded to one or more non-natural or modified amino acids at sites HC-F404 and HC-Y180 of the antibody. In some embodiments, one bracketed structure is covalently bonded to one or more non-natural or modified amino acids at sites HC-F404 and HC-Y180 of the antibody, and the other bracketed structure is bonded to a non-natural or modified amino acids at site LC-K42 of the antibody. In some embodiments, a bracketed structure is covalently bonded to one or more non-natural or modified amino acids at sites HC-F404 and HC-F241 of the antibody. In some embodiments, a bracketed structure is covalently bonded to one or more non-natural or modified amino acids at sites HC-F404 and HC-F241 of the antibody, and the other bracketed structure is bonded to a non-natural or modified amino acids at site LC-K42 of the antibody. In some embodiments, a bracketed structure is covalently bonded to one or more non-natural or modified amino acids at sites HC-F241, HC-F404, and HC-Y180 of the antibody.

[0285] In some embodiments, a bracketed structure is covalently bonded to one or more non- natural or modified amino acids at sites HC-Y180 and LC-K42 of the antibody. In some embodiments, a bracketed structure is covalently bonded to one or more non-natural or modified amino acids at sites HC-F404 and LC-K42 of the antibody. In some embodiments, the bracketed structure is covalently bonded to one or more non-natural or modified amino acids at sites HC-F404, HC-Y180, and LC-K42 of the antibody. In some embodiments, one bracketed structure binds to L-para-acetyl-phenylalanine (pAcF) at one or more sites and the other bracketed structure binds to a residue according to L-para-azido-phenylalanine (pAMF) at one or more sites.

[0286] In particular embodiments, the antibody of the antibody conjugate comprises p- azidomethyl-L-phenyl alanine residues at HC-Y180 and HC-F404 and p-acetyl-L- phenylalanine residue at LC-K42, the structure bracketed by xx is bonded to the p- azidomethyl-L-phenyl alanine residues at HC-Y180 and HC-F404, and the structure bracked by xx is bonded to the p-acetyl-L-phenylalanine at LC-K42. 138 1104675906\1\AMERICASAttorney Docket No.108843.00582 SU-0514WO c. Optically Active Compounds

[0287] In certain embodiments, compounds, linker-payloads, and conjugates provided herein may have several chiral centers and may exist in and be isolated in optically active and racemic forms. In certain embodiments, some compounds, linker-payloads, or conjugates may exhibit polymorphism. A person of skill in the art will appreciate that compounds, linker-payloads, and conjugates provided herein can exist in any racemic, optically-active, diastereomeric, polymorphic, regioisomeric and / or stereoisomeric form, and / or mixtures thereof.

[0288] A person of skill in the art will also appreciate that such compounds, linker-payloads, and conjugates described herein that possess the useful properties also described herein are within the scope of this disclosure. A person of skill in the art will further appreciate how to prepare optically active forms of the compounds, linker-payloads, and conjugates described herein, for example, by resolution of racemic forms via recrystallization techniques, by synthesis from optically-active starting materials, by chiral synthesis, or by chromatographic separation using a chiral stationary phase. In addition, most amino acids are chiral (i.e., designated as L- or D-, wherein the L- enantiomer is the naturally occurring configuration) and can exist as separate enantiomers.

[0289] Examples of methods to obtain optically active materials are known in the art, and include at least the following: i) physical separation of crystals – a technique whereby macroscopic crystals of the individual enantiomers are manually separated. This technique can be used if crystals of the separate enantiomers exist (i.e., the material is a conglomerate, and the crystals are visually distinct); ii) simultaneous crystallization – a technique whereby the individual enantiomers are separately crystallized from a solution of the racemate, only if the latter is a conglomerate in the solid state; iii) enzymatic resolutions – a technique wherein partial or complete separation of a racemate is accomplished by virtue of different rates of reaction of the enantiomers in the presence of an enzyme; iv) enzymatic asymmetric synthesis – a synthetic technique wherein at least one step of the synthesis uses an enzymatic reaction to obtain an enantiomerically pure or enriched synthetic precursor of the desired enantiomer; 139 1104675906\1\AMERICASAttorney Docket No.108843.00582 SU-0514WO v) chemical asymmetric synthesis – a synthetic technique wherein the desired enantiomer is synthesized from an achiral precursor using chiral catalysts or chiral auxiliaries to produce asymmetry (i.e., chirality) in the product; vi) diastereomer separations – a technique wherein a racemic compound is treated with an enantiomerically pure reagent (a chiral auxiliary) that converts the individual enantiomers to diastereomers. The resulting diastereomers are then separated by chromatography or crystallization by virtue of their now more distinct diastereomeric differences, and then the chiral auxiliary is removed to obtain each enantiomer; vii) first- and second-order asymmetric transformations – a technique wherein diastereomers of the racemate equilibrate in solution to yield a preponderance of a diastereomer of the desired enantiomer, or where kinetic or thermodynamic crystallization of the diastereomer of the desired enantiomer perturbs the equilibrium such that eventually in principle all the material is converted to the crystalline diastereomer of the desired enantiomer. The desired enantiomer is then derived from the diastereomer; viii) kinetic resolutions – this technique refers to the achievement of partial or complete resolution of a racemate (or of a further resolution of a partially resolved compound) by virtue of unequal reaction rates of the enantiomers with a chiral or non-racemic reagent or catalyst under kinetic conditions; ix) enantiospecific synthesis from non-racemic precursors – a synthetic technique wherein the desired enantiomer is obtained from chiral starting materials and where the stereochemical integrity is not or is only minimally compromised over the course of the synthesis; x) chiral liquid chromatography – a technique wherein the enantiomers of a racemate are separated in a liquid mobile phase by virtue of their different interactions with a stationary phase. The stationary phase can be made of chiral material or the mobile phase can contain an additional chiral material to provoke the different interactions; xi) chiral gas chromatography – a technique wherein the racemate is volatilized and enantiomers are separated by virtue of their different interactions in the gaseous mobile phase with a column containing a fixed non-racemic adsorbent phase; 140 1104675906\1\AMERICASAttorney Docket No.108843.00582 SU-0514WO xii) extraction with chiral solvents – a technique wherein the enantiomers are separated by virtue of kinetic or thermodynamic dissolution of one enantiomer into a particular chiral solvent; a) transport across chiral membranes – a technique wherein a racemate is placed in contact with a thin membrane barrier. The barrier typically separates two miscible fluids, one containing the racemate, and a driving force such as a concentration or pressure differential causes preferential transport across the membrane barrier. Separation occurs as a result of the non-racemic nature of the membrane which allows only one enantiomer of the racemate to pass through.

[0290] In some embodiments, provided herein are compositions of the compounds, linker- payloads, or conjugates of the present disclosure that are substantially free of a designated stereoisomer of that compound, linker-payload, or conjugate, respectively. In certain embodiments, in the methods, compounds, linker-payloads, and conjugates of this disclosure, the compounds, linker-payloads, or conjugates are substantially free of other stereoisomers. In some embodiments, the composition includes a compound, linker-payload, or conjugate that is at least 85%, 90%, 95%, 98%, or 99% to 100% by weight of the compound, linker- payload or conjugate, respectively, the remainder comprising other chemical species or enantiomers. In some embodiments, provided herein are compositions of compounds of Formula (I)-(IA), linker-payloads of Formula (LP-I)-(LP-IIA), and conjugates of Formula (CONJ-I)-(CONJ-IVB) that are substantially free of a designated enantiomer of that compound, linker-payload, or conjugate, respectively. In certain embodiments, in the methods, compounds, linker-payloads, and conjugates of this disclosure, the compounds, linker-payloads, or conjugates are substantially free of other enantiomers. In some embodiments, the composition includes a compound, linker-payload, or conjugate that is at least 85%, 90%, 95%, 98%, or 99% to 100% by weight of the compound, linker-payload, or conjugate, respectively, the remainder comprising other chemical species or enantiomers. d. Isotopically Enriched Compounds

[0291] Also provided herein are isotopically enriched compounds, linker-payloads, and conjugates including, but not limited to, isotopically enriched compounds of Formula (I)- (IA), linker-payloads of Formula (LP-I)-(LP-IIA), and conjugates of Formula (CONJ-I)- (CONJ-IVB). 141 1104675906\1\AMERICASAttorney Docket No.108843.00582 SU-0514WO

[0292] Isotopic enrichment (for example, deuteration) of pharmaceuticals to improve pharmacokinetics (“PK”), pharmacodynamics (“PD”), and / or toxicity profiles, has been previously demonstrated within some classes of drugs. See, for example, Lijinsky et al., Food Cosmet. Toxicol., 20: 393 (1982); Lijinsky et al., J. Nat. Cancer Inst., 69: 1127 (1982); Mangold et al., Mutation Res.308: 33 (1994); Gordon et al., Drug Metab. Dispos., 15: 589 (1987); Zello et al., Metabolism, 43: 487 (1994); Gately et al., J. Nucl. Med., 27: 388 (1986); Wade D, Chem. Biol. Interact.117: 191 (1999).

[0293] Isotopic enrichment of a drug can be used, for example, to (1) reduce or eliminate unwanted metabolites; (2) increase the half-life of the parent drug; (3) decrease the number of doses needed to achieve a desired effect; (4) decrease the amount of a dose necessary to achieve a desired effect; (5) increase the formation of active metabolites, if any are formed; and / or (6) decrease the production of deleterious metabolites in specific tissues. Isotopic enrichment of a drug can also be used to create a more effective and / or safer drug for combination therapy, whether the combination therapy is intentional or not.

[0294] Replacement of an atom for one of its isotopes often will result in a change in the reaction rate of a chemical reaction. This phenomenon is known as the Kinetic Isotope Effect (“KIE”). For example, if a C–H bond is broken during a rate-determining step in a chemical reaction (i.e., the step with the highest transition state energy), substitution of a (heavier) isotope for that reactive hydrogen will cause a decrease in the reaction rate. The Deuterium Kinetic Isotope Effect (“DKIE”) is the most common form of KIE. (See, e.g., Foster et al., Adv. Drug Res., vol.14, pp.1-36 (1985); Kushner et al., Can. J. Physiol. Pharmacol., vol.77, pp.79-88 (1999)).

[0295] The magnitude of the DKIE can be expressed as the ratio between the rates of a given reaction in which a C–H bond is broken, and the same reaction where deuterium is substituted for hydrogen and the C–D bond is broken. The DKIE can range from about one (no isotope effect) to very large numbers, such as 50 or more, meaning that the reaction can be fifty, or more, times slower when deuterium has been substituted for hydrogen.

[0296] Substitution of tritium (“T”) for hydrogen results in yet a stronger bond than deuterium and gives numerically larger isotope effects. Similarly, substitution of isotopes for other elements including, but not limited to,13C or14C for carbon;33S,34S, or36S for sulfur; 15N for nitrogen; and17O or18O for oxygen may lead to a similar kinetic isotope effect.

[0297] The animal body expresses a variety of enzymes for the purpose of eliminating foreign substances, such as therapeutic agents, from its circulation system. Examples of such enzymes include the cytochrome P450 enzymes (“CYPs”), esterases, proteases, reductases, 142 1104675906\1\AMERICASAttorney Docket No.108843.00582 SU-0514WO dehydrogenases, and monoamine oxidases to react with and convert these foreign substances to more polar intermediates or metabolites for renal excretion. Some of the most common metabolic reactions of pharmaceutical compounds involve the oxidation of a carbon- hydrogen (C–H) bond to either a carbon-oxygen (C–O) or carbon-carbon (C=C) pi-bond. The resultant metabolites may be stable or unstable under physiological conditions, and can have substantially different PK / PD, and acute and long-term toxicity profiles relative to the parent compounds. For many drugs, such oxidations are rapid. Therefore, these drugs often require the administration of multiple or high daily doses.

[0298] Therefore, isotopic enrichment at certain positions of a compound provided herein will produce a detectable KIE that will affect the pharmacologic, PK, PD, and / or toxicological profiles of a compound provided herein in comparison with a similar compound having a natural isotopic composition. III. Conjugation

[0299] In certain embodiments, the conjugate can be formed from a macromolecule that comprises one or more reactive groups. In certain embodiments, the conjugate can be formed from a macromolecule comprising all naturally encoded amino acids. Those of skill in the art will recognize that several naturally encoded amino acids include reactive groups capable of conjugation to a compound of Formula (I)-(IA) or to a linker-payload of Formula (LP-I)-(LP- IIA). These reactive groups include cysteine side chains, lysine side chains, and amino- terminal groups. In these embodiments, the conjugate can comprise a compound of Formula (I)-(IA) or linker-payload of Formula (LP-I)-(LP-IIA) linked to the residue of an antibody reactive group. In these embodiments, the compound of Formula (I)-(IA) precursor or linker- payload of Formula (LP-I)-(LP-IIA) precursor comprises a reactive group capable of forming a bond with an antibody or antigen binding fragment thereof reactive group. Typical reactive groups include maleimide groups, activated carbonates (including, but not limited to, p- nitrophenyl ester), activated esters (including, but not limited to, N-hydroxysuccinimide, p- nitrophenyl ester, and aldehydes). Particularly useful reactive groups include maleimide and succinimide, for instance N-hydroxysuccinimide, for forming bonds to cysteine and lysine side chains. Further reactive groups are described in the sections and examples below.

[0300] Reactive Groups

[0301] As described herein, reactive groups facilitate conjugation of the compounds of Formula (I)-(IA) or linker-payloads (LP-I)-(LP-IIA) as described herein to a second compound, such as an macromolecule (i.e., COMP) described herein to form a conjugate of Formula (CONJ-I)-(CONJ-IVB) as described herein. In certain embodiments, the reactive 143 1104675906\1\AMERICASAttorney Docket No.108843.00582 SU-0514WO group is designated RG herein. Reactive groups can react via any suitable reaction mechanism known to those of skill in the art. In certain embodiments, a reactive group (RG) reacts through a [3+2] alkyne-azide cycloaddition reaction, inverse-electron demand Diels- Alder ligation reaction, thiol-electrophile reaction, or carbonyl-oxyamine reaction, as described in detail herein. In certain embodiments, the reactive group (RG) comprises an alkyne, strained alkyne, tetrazine, thiol, para-acetyl-phenylalanine residue, oxyamine, maleimide, or azide. In certain embodiments, the reactive group i,methylcyclopropene, and –SH; wherein RTis C1-6alkyl; andrepresents attachment to the remainder of the compound. In certain embodiments, RTis methyl, ethyl, or propyl. In some embodiments, RTis methyl. In some embodiments, RTis ethyl. In some embodiments, RTis propyl. Additional reactive groups are described in, for example, U.S. Patent Application Publication No.2014 / 0356385, U.S. Patent Application Publication No. 2013 / 0189287, U.S. Patent Application Publication No.2013 / 0251783, U.S. Patent No. 8,703,936, U.S. Patent No.9,145,361, U.S. Patent No.9,222,940, and U.S. Patent No. 8,431,558.

[0302] After conjugation, a divalent residue of the reactive group (referred to as RL herein) is formed and is bonded to the residue of a second compound (e.g., COMP). The structure of the divalent residue is determined by the type of conjugation reaction employed to form the conjugate. 144 1104675906\1\AMERICASAttorney Docket No.108843.00582 SU-0514WO

[0303] [3+2] Alkyne-Azide Cycloaddition Reaction

[0304] Advantageously, the compounds described herein comprising a conjugating alkyne group or an azide group facilitate selective and efficient reactions with a second compound comprising a complementary azide group or alkyne group. It is believed the azide and alkyne groups react in a 1,3-dipolar cycloaddition reaction to form a 1,2,3-triazolylene moiety which links the compounds described herein comprising an alkyne group or an azide group to the second compound. This reaction between an azide and alkyne to form a triazole is generally known to those in the art as a Huisgen cycloaddition reaction or a [3+2] alkyne-azide cycloaddition reaction.

[0305] The unique reactivity of azide and alkyne functional groups makes them useful for the selective modification of polypeptides and other biological molecules. Organic azides, particularly aliphatic azides, and alkynes are generally stable toward common reactive chemical conditions. In particular, both the azide and the alkyne functional groups are inert toward the side chains of the twenty common amino acids found in naturally-occurring polypeptides. It is believed that, when brought into close proximity, the "spring-loaded" nature of the azide and alkyne groups is revealed and azide and alkyne groups react selectively and efficiently via a [3+2] alkyne-azide cycloaddition reaction to generate the corresponding triazole. See, e.g., Chin J., et al., Science 301:964-7 (2003); Wang, Q., et al., J. Am. Chem. Soc.125, 3192-3193 (2003); Chin, J. W., et al., J. Am. Chem. Soc.124:9026-9027 (2002).

[0306] Because the [3+2] alkyne-azide cycloaddition reaction involves a selective cycloaddition reaction [see, e.g., Padwa, A., in COMPREHENSIVE ORGANIC SYNTHESIS, Vol.4, (ed. Trost, B. M., 1991), pp.1069-1109; Huisgen, R. in 1,3-DIPOLAR CYCLOADDITION CHEMISTRY, (ed. Padwa, A., 1984), pp.1-176] rather than a nucleophilic substitution, the incorporation of non-naturally encoded amino acids bearing azide and alkyne-containing side chains permits the resultant polypeptides to be modified selectively at the position of the non-naturally encoded amino acid. Cycloaddition reactions involving azide or alkyne-containing compounds can be carried out at room temperature under aqueous conditions by the addition of Cu(II) (including, but not limited to, catalytic 145 1104675906\1\AMERICASAttorney Docket No.108843.00582 SU-0514WO amounts of CuSO4) in the presence of a reducing agent for reducing Cu(II) to Cu(I), in situ, in catalytic amounts. See, e.g., Wang, Q., et al., J. Am. Chem. Soc.125, 3192-3193 (2003); Tornoe, C. W., et al., J. Org. Chem.67:3057-3064 (2002); Rostovtsev, et al., Angew. Chem. Int. Ed.41:2596-2599 (2002). Exemplary reducing agents include, but are not limited to, ascorbate, metallic copper, quinine, hydroquinone, vitamin K, glutathione, cysteine, Fe2+, Co2+, and an applied electric potential.

[0307] In certain embodiments when a conjugate is formed through a [3+2] alkyne-azide cycloaddition reaction, the divalent residue of the reactive group (e.g., RL) comprises a triazole ring or fused cyclic group comprising a triazole ring. In certain embodiments, when a conjugate is formed through a strain-promoted [3+2] alkyne-azide cycloaddition (SPAAC) reaction, the divalent residue of the reactive group.

[0308] If a conjugate of Formula (CONJ-I)-(CONJ-IVB) is formed by a [3+2] alkyne-azide cycloaddition, the conjugate encompasses both regioisomers. In certain embodiments, a conjugate of Formula (CONJ-I)-(CONJ-IVB) is a mixture of regioisomers formed from a [3+2] alkyne-azide cycloaddition.

[0309] Inverse Electron Demand Ligation Reaction

[0310] Advantageously, compounds comprising a terminal tetrazine or strained alkene group facilitate selective and efficient reactions with a second compound comprising a strained alkene or tetrazine group. It is believed that the tetrazine and strained alkene react in an inverse-demand Diels-Alder reaction followed by a retro-Diels-Alder reaction which links compounds comprising a terminal tetrazine or strained alkene group to the second compound. 146 1104675906\1\AMERICASAttorney Docket No.108843.00582 SU-0514WO The reaction is believed to be specific, with little to no cross-reactivity with functional groups within biomolecules. The reaction may be carried out under mild conditions, for example, at room temperature and without a catalyst. This reaction between a tetrazine and a strained alkene is generally known to those in the art as a tetrazine ligation reaction.

[0311] In certain embodiments, when a conjugate is formed through a tetrazine inverse electron demand Diels-Alder ligation reaction, the divalent residue of the reactive group (e.g., RL) comprises a fused bicyclic ring having at least two adjacent nitrogen atoms in the ring. In certain embodiments, when a conjugate is formed through a tetrazine inverse electron demand Diels-Alder ligation reaction, the divalent residue of the reactive group (e.g., RL) is.

[0312] If a conjugate of Formula (CONJ-I)-(CONJ-IVB) is formed by an inverse electron demand ligation reaction, the conjugate encompasses both regioisomers. In certain embodiments, a conjugate of Formula (CONJ-I)-(CONJ-IVB) is a mixture of regioisomers formed from an inverse electron demand ligation reaction.

[0313] Thiol Reactions

[0314] Advantageously, compounds comprising a terminal thiol group or suitable electrophilic or disulfide-forming group facilitate selective and efficient reactions with a second compound comprising a complementary electrophilic or disulfide-forming group or thiol group. These reactions are believed to be selective with little to no cross-reactivity with functional groups within biomolecules. In some embodiments, the thiol reaction does not include reaction of a maleimide group. 147 1104675906\1\AMERICASAttorney Docket No.108843.00582 SU-0514WO

[0315] In certain embodiments, when a conjugate is formed through a thiol-maleimide reaction, the divalent residue of the reactive group comprisessulfur linkage. In certain embodiments, when a conjugate is formed through a thiol-maleimide reaction,, the divalent residue of the reactive groupcertain embodiments, when a conjugate is formed through a thiol-maleimide reaction,, the divalent residue of the reactive group (e.g., RL) is .

[0316] In certain embodiments, a conjugate is formed through a thiol-N-hydroxysuccinimide reaction using the following group:. The reaction involved for formation of the conjugate comprises the following step:, and the resulting divalent residue of the reactive group

[0317] Carbonyl-Oxyamine Reaction

[0318] Advantageously, compounds comprising a terminal carbonyl or oxyamine group facilitate selective and efficient reactions with a second compound comprising an oxyamine or carbonyl group. It is believed that the carbonyl and oxyamine react to form an oxime 148 1104675906\1\AMERICASAttorney Docket No.108843.00582 SU-0514WO linkage. The reaction is believed to be specific, with little to no cross-reactivity with functional groups within biomolecules.

[0319] In certain embodiments when a conjugate is formed through an oxime conjugation reaction, the divalent residue of the reactive group comprises a divalent residue of a non- natural amino acid. In certain embodiments when a conjugate is formed through an oxime conjugation reaction, the divalent residue of the reactive group. certain embodiments when a conjugate is formed through an oxime conjugation reaction, the divalent residue of the reactive group comprises an oxime linkage. In certain embodiments when a conjugate is formed through an oxime conjugation reaction, the divalent residue of the reactive group

[0320] Other Reactions

[0321] Other suitable conjugation reactions are described in the literature. See, for example, Lang, K. and Chin, J.2014, Bioorthogonal Reactions for Labeling Proteins, ACS Chem Biol 9, 16-20; Paterson, D. M. et al.2014, Finding the Right (Bioorthogonal) Chemistry, ACS Chem Biol 9, 592-605; King, M. and Wagner, A.2014, Developments in the Field of Bioorthogonal Bond Forming Reactions – Past and Present Trends, Bioconjugate Chem., 2014, 25 (5), pp 825-839; and Ramil, C.P. and Lin, Q., 2013, Bioorthogonal chemistry: strategies and recent developments, Chem Commun 49, 11007-11022. IV. Releasing Reactions

[0322] Releasing Reactions are reactions that act to release a biologically active portion of a compound or conjugate described herein from the compound or conjugate in vivo and / or in vitro. In certain embodiments, the released biologically active portion is a compound described elsewhere herein (e.g., cytotoxic agents), or a pharmaceutically acceptable salt, 149 1104675906\1\AMERICASAttorney Docket No.108843.00582 SU-0514WO solvate, stereoisomer, or tautomer thereof. One example of a releasing reaction is an intramolecular reaction between an eliminator group and a release trigger group of a compound or conjugate described herein to release a biologically active portion of a compound or conjugate described herein. The eliminator group may itself devolve into two reactive components, as exemplified in these reactions where X is a drug having a heteroatom nitrogen or oxygen for linkage. Exemplary Releasing Reactions are depicted in the scheme below:V. Water soluble polymers

[0323] In certain embodiments, a compound or conjugate described herein comprises one or more water soluble polymers. A wide variety of macromolecular polymers and other molecules can be linked to the polypeptides described herein to modulate biological properties of the polypeptide, and / or provide new biological properties to the polypeptide. These macromolecular polymers can be linked to the polypeptide via a naturally encoded amino acid, via a non-naturally encoded amino acid, or any functional substituent of a natural or modified amino acid, or any substituent or functional group added to a natural or modified amino acid. The molecular weight of the polymer may include a wide range including, but not limited to, between about 100 Da and about 100,000 Da or more.

[0324] The polymer selected may be water soluble so that a protein to which it is attached does not precipitate in an aqueous environment, such as a physiological environment. The 150 1104675906\1\AMERICASAttorney Docket No.108843.00582 SU-0514WO polymer may be branched or unbranched. In certain embodiments, for therapeutic use of the end-product preparation, the polymer will be pharmaceutically acceptable.

[0325] In certain embodiments, the proportion of polyethylene glycol molecules to polypeptide molecules will vary, as will their concentrations in the reaction mixture. In general, the optimum ratio (in terms of efficiency of reaction in that there is minimal excess unreacted protein or polymer) may be determined by the molecular weight of the polyethylene glycol selected and on the number of available reactive groups available. Regarding molecular weight, typically the higher the molecular weight of the polymer, the fewer number of polymer molecules which may be attached to the protein. Similarly, branching of the polymer should be taken into account when optimizing these parameters. Generally, the higher the molecular weight (or the more branches) the higher the polymer:protein ratio.

[0326] The water soluble polymer may be any structural form including, but not limited to, linear, forked, or branched. Typically, the water soluble polymer is a poly(alkylene glycol), such as poly(ethylene glycol) (PEG), but other water soluble polymers can also be employed. By way of example, PEG is used to describe certain embodiments.

[0327] PEG is a well-known, water soluble polymer that is commercially available or can be prepared by ring-opening polymerization of ethylene oxide according to methods well known in the art (Sandler and Karo, Polymer Synthesis, Academic Press, New York, Vol.3, pages 138-161). The term “PEG” is used broadly to encompass any polyethylene glycol molecule, without regard to size or to modification at an end of a PEG, and can be represented as linked to a polypeptide by the formula: X′O–(CH2CH2O)n–CH2CH2–Y′ where n is an integer selected from 2 to 10,000, X′ is hydrogen or a terminal modification including, but not limited to, C1-4alkyl, and Y′ is the attachment point to the polypeptide.

[0328] In some cases, a PEG terminates on one end with hydroxy or methoxy, i.e., X′ is hydrogen or CH3 (aka “methoxy PEG”). Alternatively, the PEG can terminate with a PEG reactive group, thereby forming a bifunctional polymer. Typical PEG reactive groups can include those reactive groups that are commonly used to react with the functional groups found in the twenty common amino acids (including, but not limited to, maleimide groups, activated carbonates (including, but not limited to, p-nitrophenyl ester), activated esters (including, but not limited to, N-hydroxysuccinimide, p-nitrophenyl ester, and aldehydes) as well as functional groups that are inert to the twenty common amino acids, but that react specifically with complementary functional groups present in non-naturally encoded amino acids (including, but not limited to, azide groups and / or alkyne groups). It is noted that the 151 1104675906\1\AMERICASAttorney Docket No.108843.00582 SU-0514WO other end of the PEG, which is shown in the above formula by Y′, will attach either directly or indirectly to a polypeptide via a naturally-occurring or non-naturally encoded amino acid. For instance, Y′ may be an amide, carbamate, or urea linkage to an amine group (including, but not limited to, the epsilon amine of lysine or the N-terminus) of the polypeptide. Alternatively, Y′ may be a maleimide linkage to a thiol group (including, but not limited to, the thiol group of cysteine). Alternatively, Y′ may be a linkage to a residue not commonly accessible via the twenty common amino acids. For example, an azide group on the PEG can be reacted with an alkyne group on the polypeptide to form a Huisgen [3+2] cycloaddition product. Alternatively, an alkyne group on the PEG can be reacted with an azide group present in a non-naturally encoded amino acid, such as the modified amino acids described herein, to form a similar product. In some embodiments, a strong nucleophile (including, but not limited to, hydrazine, hydrazide, hydroxylamine, or semicarbazide) can be reacted with an aldehyde or ketone group present in a non-naturally encoded amino acid to form a hydrazone, oxime, or semicarbazone, as applicable, which in some cases can be further reduced by treatment with an appropriate reducing agent. Alternatively, the strong nucleophile can be incorporated into the polypeptide via a non-naturally encoded amino acid and used to react preferentially with a ketone or aldehyde group present in the water soluble polymer.

[0329] Any molecular mass for a PEG can be used as practically desired including, but not limited to, from about 100 Daltons (Da) to 100,000 Da or more as desired (including, but not limited to, in certain embodiments 0.1-50 kDa or 10-40 kDa). Branched chain PEGs including, but not limited to, PEG molecules with each chain having a molecular weight (MW) ranging from 1-100 kDa (including, but not limited to, 1-50 kDa or 5-20 kDa) can also be used. A wide range of PEG molecules are described in the Shearwater Polymers, Inc. catalog, and the Nektar Therapeutics catalog, each incorporated herein by reference.

[0330] Generally, at least one terminus of the PEG molecule is available for reaction with the remainder of the compound of Formula (I),(IA), or (IB). For example, PEG derivatives bearing alkyne and azide moieties for reaction with amino acid side chains can be used to attach PEG to non-naturally encoded amino acids as described herein. If the non-naturally encoded amino acid comprises an azide, then the PEG will typically contain either an alkyne moiety to effect formation of the [3+2] cycloaddition product or an activated PEG species (i.e., ester, carbonate) containing a phosphine group to effect formation of the amide linkage. Alternatively, if the non-naturally encoded amino acid comprises an alkyne, then the PEG will typically contain an azide moiety to effect formation of the [3+2] Huisgen cycloaddition 152 1104675906\1\AMERICASAttorney Docket No.108843.00582 SU-0514WO product. If the non-naturally encoded amino acid comprises a carbonyl group, the PEG will typically comprise a nucleophile (including, but not limited to, a hydrazide, hydrazine, hydroxylamine, or semicarbazide functionality) in order to effect formation of corresponding hydrazone, oxime, and semicarbazone linkages, respectively. In other alternatives, a reverse of the orientation of the reactive groups described herein can be used (i.e., an azide moiety in the non-naturally encoded amino acid can be reacted with a PEG derivative containing an alkyne).

[0331] In some embodiments, the polypeptide variant with a PEG derivative contains a chemical functionality that is reactive with the chemical functionality present on the side chain of the non-naturally encoded amino acid.

[0332] In certain embodiments, the water soluble polymer is an azide- or acetylene- containing polymer comprising a water soluble polymer backbone having an average molecular weight from about 800 Da to about 100,000 Da. The polymer backbone of the water-soluble polymer can be poly(ethylene glycol). However, it should be understood that a wide variety of water soluble polymers including, but not limited to, poly(ethylene)glycol and other related polymers, including poly(dextran) and poly(propylene glycol), are also suitable for use and that the use of the term “PEG” or “poly(ethylene glycol)” is intended to encompass and include all such molecules. The term “PEG” further includes, but is not limited to, poly(ethylene glycol) in any of its forms, including bifunctional PEG, multiarmed PEG, derivatized PEG, forked PEG, branched PEG, pendent PEG (i.e., PEG or related polymers having one or more functional groups pendent to the polymer backbone), or PEG with degradable linkages therein.

[0333] The polymer backbone can be linear or branched. Branched polymer backbones are generally known in the art. Typically, a branched polymer has a central branch core moiety and a plurality of linear polymer chains linked to the central branch core. PEG is commonly used in branched forms that can be prepared by addition of ethylene oxide to various polyols, such as glycerol, glycerol oligomers, pentaerythritol, and sorbitol. The central branch moiety can also be derived from several amino acids, such as lysine. The branched poly(ethylene glycol) can be represented in general form as R-(-PEG-OH)m in which R is derived from a core moiety, such as glycerol, glycerol oligomers, or pentaerythritol, and m represents the number of arms. Multi-armed PEG molecules, such as those described in U.S. Pat. Nos. 5,932,462; 5,643,575; 5,229,490; and 4,289,872; U.S. Pat. Appl. No.2003 / 0143596; and WO 96 / 21469 and WO 93 / 21259, each of which is incorporated by reference herein in its entirety, can also be used as the polymer backbone. 153 1104675906\1\AMERICASAttorney Docket No.108843.00582 SU-0514WO

[0334] Branched PEG can also be in the form of a forked PEG represented by PEG(-Y′′CHZ2)n, where Y′′ is a linking group and Z is an activated terminal group linked to CH by a chain of atoms of defined length. Yet another branched form, the pendant PEG, has PEG reactive groups, such as carboxyl, along the PEG backbone rather than at the end of PEG chains. In addition to these forms of PEG, the polymer can also be prepared with weak or degradable linkages in the backbone. For example, PEG can be prepared with ester linkages in the polymer backbone that are subject to hydrolysis. As shown herein, this hydrolysis results in cleavage of the polymer into fragments of lower molecular weight: -PEG-CO2-PEG-+H2O→PEG-CO2H+HO-PEG-. It is understood by those skilled in the art that the term “poly(ethylene glycol)” or “PEG” represents or includes all the forms known in the art including, but not limited to, those disclosed herein. Many other polymers are also suitable for use. In some embodiments, polymer backbones that are water-soluble, with from two to about three hundred termini, are particularly suitable. Examples of suitable polymers include, but are not limited to, other poly(alkylene glycols), such as poly(propylene glycol) (“PPG”), copolymers thereof (including, but not limited to, copolymers of ethylene glycol and propylene glycol), terpolymers thereof, mixtures thereof, and the like. Although the molecular weight of each chain of the polymer backbone can vary, it is typically in the range of from about 800 Da to about 100,000 Da, often from about 6,000 Da to about 80,000 Da. Those of ordinary skill in the art will recognize that the foregoing list for substantially water-soluble backbones is by no means exhaustive and is merely exemplary, and that all polymeric materials having the qualities described herein are contemplated as being suitable for use. In some embodiments the polymer derivatives are “multi-functional,” meaning that the polymer backbone has at least two termini, and possibly as many as about 300 termini, functionalized or activated with a functional group. Multifunctional polymer derivatives include, but are not limited to, linear polymers having two termini, each terminus being bonded to a functional group which may be the same or different. VI. Uses of the Compounds, Conjugates, and Compositions

[0335] In one aspect, an effective amount of a compound or conjugate described herein or a composition thereof is used to promote the activation of Toll-like receptor 7 (TLR7) in a subject in need thereof. In another aspect, an effective amount of a compound or conjugate described herein or a composition thereof is used to induce or modulate the immune system in a subject in need thereof. In another aspect, an effective amount of a compound or conjugate described herein or a composition thereof is used to treat abnormal cellular 154 1104675906\1\AMERICASAttorney Docket No.108843.00582 SU-0514WO proliferation in a subject in need thereof. In one embodiment, the abnormal cellular proliferation is cancer.

[0336] In certain embodiments, the term "cancer" includes, but is not limited to, the following cancers: epidermoid oral: buccal cavity, lip, tongue, mouth, pharynx, squamous cell carcinoma of the head and neck (HNSCC); cardiac: sarcoma (angiosarcoma, fibrosarcoma, rhabdomyosarcoma, liposarcoma), myxoma, rhabdomyoma, fibroma, lipoma, and teratoma; lung: bronchogenic carcinoma (squamous cell or epidermoid, undifferentiated small cell, undifferentiated large cell, adenocarcinoma), alveolar (bronchiolar) carcinoma, bronchial adenoma, sarcoma, lymphoma, chondromatous hamartoma, mesothelioma, non- small cell lung cancer (NSCLC); gastrointestinal: gastric cancer, esophagus (squamous cell carcinoma, larynx, adenocarcinoma, leiomyosarcoma, lymphoma), stomach (carcinoma, lymphoma, leiomyosarcoma), pancreas (ductal adenocarcinoma, insulinoma, glucagonoma, gastrinoma, vipoma), small bowel or small intestines (adenocarcinoma, lymphoma, Karposi's sarcoma, leiomyoma, hemangioma, lipoma, neurofibroma, fibroma), large bowel or large intestines (adenocarcinoma, tubular adenoma, villous adenoma, hamartoma, leiomyoma), colon, colon-rectum, colorectal, microsatellite stable colorectal cancer (MSS CRC), rectum; genitourinary tract: kidney (adenocarcinoma, Wilm's tumor (nephroblastoma), lymphoma, leukemia), bladder and urethra (squamous cell carcinoma, transitional cell carcinoma, adenocarcinoma), prostate (adenocarcinoma, sarcoma), testis (seminoma, teratoma, embryonal carcinoma, teratocarcinoma, sarcoma, interstitial cell carcinoma, fibroma, fibroadenoma, adenomatoid tumors, lipoma), metastatic castrate-resistant prostate cancer (mCRPC), muscle-invasive urothelial cancer; Liver: hepatoma (hepatocellular carcinoma), cholangiocarcinoma, hepatoblastoma, hepatocellular adenoma, hemangioma, biliary passages; bone: osteogenic sarcoma (osteosarcoma), fibrosarcoma, malignant fibrous histiocytoma, Ewing's sarcoma, malignant lymphoma (reticulum cell sarcoma), malignant giant cell tumor osteochronfroma (osteocartilaginous exostoses), benign chondroma, chondroblastoma, chondromyxofibroma, osteoid osteoma and giant cell tumors; nervous system: skull (osteoma, hemangioma, granuloma, xanthoma, osteitis deformans), meninges (meningioma, meningiosarcoma, gliomatosis), brain (astrocytoma, medulloblastoma, glioma, germinoma (pinealoma), glioblastoma multiform, oligodendroglioma, schwannoma, retinoblastoma, congenital tumors), spinal cord neurofibroma, meningioma, glioma, sarcoma); gynecological: uterus (endometrial carcinoma), cervix (cervical cancer, cervical carcinoma, pre-tumor cervical dysplasia), ovaries (ovarian carcinoma (serous cystadenocarcinoma, mucinous cystadenocarcinoma, unclassified carcinoma), granulosa- 155 1104675906\1\AMERICASAttorney Docket No.108843.00582 SU-0514WO thecal cell tumors, Sertoli-Leydig cell tumors, dysgerminoma, malignant teratoma), vulva (squamous cell carcinoma, intraepithelial carcinoma, adenocarcinoma, fibrosarcoma, melanoma), vagina (clear cell carcinoma, squamous cell carcinoma, botryoid sarcoma (embryonal rhabdomyosarcoma), fallopian tubes (carcinoma), breast, triple-negative breast cancer (TNBC), platinum-resistant epithelial ovarian cancer (EOC); hematologic: blood (myeloid leukemia (acute and chronic), acute lymphoblastic leukemia, chronic lymphocytic leukemia, myeloproliferative diseases, multiple myeloma (MM), myelodysplastic syndrome), Hodgkin's disease, non-Hodgkin's lymphoma (malignant lymphoma) hairy cell; lymphoid disorders (e.g., mantle cell lymphoma, Waldenström’s macroglobulinemia, Marginal zone lymphoma, and Follicular lymphoma); skin: malilymphgnant melanoma, basal cell carcinoma, squamous cell carcinoma, Karposi's sarcoma, keratoacanthoma, moles dysplastic nevi, lipoma, angioma, dermatofibroma, keloids, psoriasis; thyroid gland: papillary thyroid carcinoma, follicular thyroid carcinoma; medullary thyroid carcinoma, undifferentiated thyroid cancer, multiple endocrine neoplasia type 2A, multiple endocrine neoplasia type 2B, familial medullary thyroid cancer, pheochromocytoma, paraganglioma; Adrenal glands: neuroblastoma; and metatstaic melanoma.

[0337] In certain embodiments, the cancer is selected from acute myeloid leukemia, breast cancer, colorectal cancer, glioma, head and neck squamous cell carcinoma, lung cancer, including non-small cell lung cancer, head and neck cancer, lymphoma, including a malignant lymphoma, melanoma, nasopharyngeal carcinoma, ovary cancer, pancreatic cancer, prostate cancer, urothelial cancer, and tongue squamous cell carcinoma.

[0338] In certain embodiments, the cancer is a solid tumor. A solid tumor, as used herein, refers to an abnormal mass of tissue that usually does not contain cysts or liquid areas. Different types of solid tumors are named for the type of cells that form them. Examples of classes of solid tumors include, but are not limited to, sarcomas, carcinomas, and lymphomas. Additional examples of solid tumors include, but are not limited to, squamous cell carcinoma, colon cancer, breast cancer, prostate cancer, lung cancer, liver cancer, pancreatic cancer, and melanoma. In one embodiment, the solid tumor is an advanced solid tumor.

[0339] Non-limiting examples of cancers that can be treated using the compounds described herein include, but are not limited to, acoustic neuroma, an adenocarcinoma, adrenal gland cancer, anal cancer, an angiosarcoma (e.g., lymphangiosarcoma, lymphangioendotheliosarcoma, hemangiosarcoma), appendix cancer, benign monoclonal gammopathy, biliary cancer (e.g., cholangiocarcinoma), bladder cancer, breast cancer (e.g., adenocarcinoma of the breast, papillary carcinoma of the breast, mammary cancer, medullary 156 1104675906\1\AMERICASAttorney Docket No.108843.00582 SU-0514WO carcinoma of the breast), brain cancer (e.g., meningioma, glioma, astrocytoma, oligodendroglioma; medulloblastoma), bronchus cancer, carcinoid tumor, cervical cancer, choriocarcinoma, chordoma, craniopharyngioma, colorectal cancer (e.g., colon cancer, rectal cancer, colorectal adenocarcinoma), epithelial carcinoma, ependymoma, endotheliosarcoma (e.g., multiple idiopathic hemorrhagic sarcoma), endometrial cancer (e.g., uterine cancer, uterine sarcoma), esophageal cancer (e.g., adenocarcinoma of the esophagus, Barrett's adenocarcinoma), eye cancer (e.g., intraocular melanoma, retinoblastoma), familiar hypereosinophilia, gallbladder cancer, gastric cancer (e.g., stomach adenocarcinoma), gastrointestinal stromal tumor (GIST), head and neck cancer (e.g., head and neck squamous cell carcinoma), oral cancer (e.g., oral squamous cell carcinoma (OSCC)), throat cancer (e.g., laryngeal cancer, pharyngeal cancer, nasopharyngeal cancer, oropharyngeal cancer), a hematopoietic cancer, heavy chain disease (e.g., alpha chain disease, gamma chain disease, mu chain disease), hemangioblastoma, inflammatory myofibroblastic tumors, immunocytic amyloidosis, kidney cancer (e.g., nephroblastoma a.k.a. Wilms' tumor, renal cell carcinoma), liver cancer (e.g., hepatocellular cancer (HCC), malignant hepatoma), lung cancer (e.g., bronchogenic carcinoma, small cell lung cancer (SCLC), non-small cell lung cancer (NSCLC), adenocarcinoma of the lung), leiomyosarcoma (LMS), mastocytosis (e.g., systemic mastocytosis), myelodysplastic syndrome (MDS), mesothelioma, myeloproliferative disorder (MPD) (e.g., polycythemia Vera (PV), essential thrombocytosis (ET), agnogenic myeloid metaplasia (AMM) a.k.a. myelofibrosis (MF), chronic idiopathic myelofibrosis, chronic myelocytic leukemia (CML), chronic neutrophilic leukemia (CNL), hypereosinophilic syndrome (HES)), neuroblastoma, neurofibroma (e.g., neurofibromatosis (NF) type 1 or type 2, schwannomatosis), neuroendocrine cancer (e.g., gastroenteropancreatic neuroendoctrine tumor (GEP-NET), carcinoid tumor), osteosarcoma, ovarian cancer (e.g., cystadenocarcinoma, ovarian embryonal carcinoma, ovarian adenocarcinoma), papillary adenocarcinoma, pancreatic cancer (e.g., pancreatic andenocarcinoma, intraductal papillary mucinous neoplasm (IPMN), Islet cell tumors), penile cancer (e.g., Paget' s disease of the penis and scrotum), pinealoma, primitive neuroectodermal tumor (PNT), prostate cancer (e.g., prostate adenocarcinoma), rectal cancer, rhabdomyosarcoma, salivary gland cancer, skin cancer (e.g., squamous cell carcinoma (SCC), keratoacanthoma (KA), melanoma, basal cell carcinoma (BCC)), small bowel cancer (e.g., appendix cancer), soft tissue sarcoma (e.g., malignant fibrous histiocytoma (MFH), liposarcoma, malignant peripheral nerve sheath tumor (MPNST), chondrosarcoma, fibrosarcoma, myxosarcoma), sebaceous gland carcinoma, sweat gland carcinoma, synovioma, testicular cancer (e.g., seminoma, testicular 157 1104675906\1\AMERICASAttorney Docket No.108843.00582 SU-0514WO embryonal carcinoma), thyroid cancer (e.g., papillary carcinoma of the thyroid, papillary thyroid carcinoma (PTC), medullary thyroid cancer), Wilms' tumor, urethral cancer, vaginal cancer and vulvar cancer (e.g., Paget' s disease of the vulva).

[0340] In one embodiment, the cancer is a sarcoma, including, but not limited to, Ewing's sarcoma, Kaposi's sarcoma, liposarcoma, myosarcomas, peripheral neuroepithelioma, synovial sarcoma, gliomas, astrocytomas (including anaplastic astrocytoma, diffuse astrocytoma and low-grade astrocytoma), oligodendrogliomas, gliobastomas, neuroblastomas, ganglioneuromas, gangliogliomas, medulloblastomas, pineal cell tumors, meningiomas, meningeal sarcomas, neurofibromas, and Schwannomas.

[0341] In one embodiment, the cancer is a hematopoietic cancer, including, but not limited to, leukemia, such as acute lymphocytic leukemia (ALL), also known as acute lymphoblastic leukemia or acute lymphoid leukemia (e.g., B-cell ALL, T-cell ALL), acute myelocytic leukemia (AML) (e.g., B-cell AML, T-cell AML), acute granulocytic leukemia, chronic myelocytic leukemia (CML) (e.g., B-cell CML, T-cell CML), a chronic lymphocytic leukemia (CLL) (e.g., B-cell CLL, T-cell CLL), and hairy cell leukemia (HCL). In one embodiment, the hematopoietic cancer is a lymphoma, such as Hodgkin lymphoma (HL) (e.g., B-cell HL, T-cell HL), non-Hodgkin lymphoma (NHL) (e.g., B-cell NHL such as diffuse large cell lymphoma (DLCL) (e.g., diffuse large B-cell lymphoma (DLBCL)), follicular lymphoma, chronic lymphocytic leukemia / small lymphocytic lymphoma (CLL / SLL), mantle cell lymphoma (MCL), marginal zone B-cell lymphomas (e.g., mucosa- associated lymphoid tissue (MALT) lymphomas, nodal marginal zone B-cell lymphoma, splenic marginal zone B-cell lymphoma), primary mediastinal B-cell lymphoma, Burkitt lymphoma, lymphoplasmacytic lymphoma (i.e., "Waldenstrom's macroglobulinemia"), immunoblastic large cell lymphoma, precursor B-lymphoblastic lymphoma and primary central nervous system (CNS) lymphoma; and T-cell NHL such as precursor T-lymphoblastic lymphoma / leukemia, peripheral T-cell lymphoma (PTCL) (e.g., cutaneous T-cell lymphoma (CTCL) (e.g., mycosis fungiodes, Sezary syndrome), angioimmunoblastic T-cell lymphoma, extranodal natural killer T-cell lymphoma, enteropathy type T-cell lymphoma, subcutaneous panniculitis-like T-cell lymphoma, anaplastic large cell lymphoma), and a mixture of one or more leukemia / lymphoma as described above. Additional leukemias and lymphomas include T-cell lineage acute lymphoblastic leukemia (T-ALL), T-cell lineage lymphoblastic lymphoma (T- LL), peripheral T-cell lymphoma, Adult T-cell leukemia, Pre-B ALL, Pre-B lymphomas, large B-cell lymphoma, Philadelphia chromosome positive ALL, Philadelphia chromosome positive CML, juvenile myelomonocytic leukemia (JMML), acute 158 1104675906\1\AMERICASAttorney Docket No.108843.00582 SU-0514WO promyelocytic leukemia (a subtype of AML), large granular lymphocytic leukemia, Adult T- cell chronic leukemia, diffuse large B cell lymphoma, follicular lymphoma; Mucosa- Associated Lymphatic Tissue lymphoma (MALT), small cell lymphocytic lymphoma, mediastinal large B cell lymphoma, nodal marginal zone B cell lymphoma (NMZL); splenic marginal zone lymphoma (SMZL); intravascular large B-cell lymphoma; primary effusion lymphoma; or lymphomatoid granulomatosis; B-cell prolymphocytic leukemia; splenic lymphoma / leukemia, splenic diffuse red pulp small B-cell lymphoma; lymphoplasmacytic lymphoma;

[0342] In certain embodiments, the cancer that is treated using the disclosed compounds is selected from adenosarcoma, adrenal cancer, adrenocortical carcinoma, bile duct cancer, bone cancer, bone marrow cancer, brain stem glioma, breast cancer, (including, but not limited to triple (estrogen, progesterone and HER-2) negative breast cancer, double negative breast cancer (two of estrogen, progesterone and HER-2 are negative), single negative (one of estrogen, progesterone and HER-2 is negative), estrogen-receptor positive, HER2- negative breast cancer, estrogen receptor-negative breast cancer, estrogen receptor positive breast cancer, metastatic breast cancer, luminal A breast cancer, luminal B breast cancer, Her2- negative breast cancer, HER2-positive or negative breast cancer, progesterone receptor- negative breast cancer, progesterone receptor-positive breast cancer, recurrent breast cancer, or inflammatory breast cancer (IBC), mesothelioma metastatic breast cancer), colorectal cancer, cutaneous lymphoma, cutaneous melanoma, , ductal carcinoma in situ (DCIS), endometrial cancer, epithelioid sarcoma, esophageal cancer, extrahepatic eye cancer, fallopian tube cancer, fibrosarcoma, gastric cancer, gastrointestinal cancer, gastrointestinal carcinoid cancer, gastrointestinal stromal tumors (GIST), germ cell tumor glioblastoma multiforme (GBM), glioma, hairy cell leukemia, hemangioendothelioma, hypopharyngeal cancer, infiltrating ductal carcinoma (IDC), infiltrating lobular carcinoma (ILC), intestinal cancer, intrahepatic bile duct cancer, invasive / infiltrating breast cancer, Islet cell cancer, jaw cancer, kidney cancer, laryngeal cancer, leiomyosarcoma, leptomeningeal metastases, lip cancer, liposarcoma, liver cancer, lobular carcinoma in situ, lung cancer, lymph node cancer, lymphoma, male breast cancer, medullary carcinoma, medulloblastoma, melanoma, meningioma, Merkel cell carcinoma, mesenchymal chondrosarcoma, mesenchymous, metastatic melanoma metastatic squamous neck cancer, mixed gliomas, monodermal teratoma, mouth cancer mucinous carcinoma, mucosal melanoma, multiple myeloma, Mycosis Fungoides, myelodysplastic syndrome, nasal cavity cancer, nasopharyngeal cancer, neck cancer, neuroblastoma, neuroendocrine tumors (NETs), oat cell cancer, ocular cancer, 159 1104675906\1\AMERICASAttorney Docket No.108843.00582 SU-0514WO ocular melanoma, oligodendroglioma, oral cancer, oral cavity cancer, oropharyngeal cancer, osteogenic sarcoma, osteosarcoma, ovarian cancer, ovarian epithelial cancer ovarian germ cell tumor, ovarian primary peritoneal carcinoma, ovarian sex cord stromal tumor, Paget's disease, pancreatic cancer, papillary carcinoma, paranasal sinus cancer, parathyroid cancer, pelvic cancer, penile cancer, peripheral nerve cancer, peritoneal cancer, pharyngeal cancer, pheochromocytoma, pilocytic astrocytoma, pineal region tumor, pineoblastoma, pituitary gland cancer, primary central nervous system (CNS) lymphoma, rectal cancer, renal cell carcinoma, renal pelvis cancer, rhabdomyosarcoma, salivary gland cancer, soft tissue sarcoma, bone sarcoma, sarcoma, sinus cancer, skin cancer, small cell lung cancer (SCLC), small intestine cancer, spinal cancer, spinal column cancer, spinal cord cancer, squamous cell carcinoma, stomach cancer, synovial sarcoma, T-cell lymphoma, testicular cancer, throat cancer, thymoma / thymic carcinoma, thyroid cancer, tongue cancer, tonsil cancer, transitional cell cancer, tubal cancer, tubular carcinoma, undiagnosed cancer, ureteral cancer, urethral cancer, uterine adenocarcinoma, uterine cancer, uterine sarcoma, vaginal cancer, vulvar cancer, plasma cell myeloma, solitary plasmacytoma of bone, and extraosseous plasmacytoma.

[0343] In other embodiments, the cell-proliferation disorder is selected from benign papillomatosis, benign neoplastic diseases and gestational trophoblastic diseases. In certain embodiments, the benign neoplastic disease is selected from skin papilloma (warts) and genital papilloma. In certain embodiments, the gestational trophoblastic disease is selected from the group consisting of hydatidiform moles, and gestational trophoblastic neoplasia (e.g., invasive moles, choriocarcinomas, placental-site trophoblastic tumors, and epithelioid trophoblastic tumors).

[0344] The compound or conjugate described herein or a composition thereof can be administered at any dose deemed suitable by the practitioner of skill. In certain embodiments, the dose is 0.1-1000 mg / kg. In certain embodiments, the dose is 0.1-900 mg / kg. In certain embodiments, the dose is 0.1-800 mg / kg. In certain embodiments, the dose is 0.1-700 mg / kg. In certain embodiments, the dose is 0.1-600 mg / kg. In certain embodiments, the dose is 0.1- 500 mg / kg. In certain embodiments, the dose is 0.1-400 mg / kg. In certain embodiments, the dose is 0.1-300 mg / kg. In certain embodiments, the dose is 0.1-200 mg / kg. In certain embodiments, the dose is 0.1-100 mg / kg. In certain embodiments, the dose is selected from the group consisting of 100 mg / kg, 200 mg / kg, 300 mg / kg, 450 mg / kg, 600 mg / kg, 800 mg / kg, and 1000 mg / kg. In certain embodiments, the dose is about 25 mg / kg. In certain embodiments, the dose is about 50 mg / kg. In certain embodiments, the dose is about 75 160 1104675906\1\AMERICASAttorney Docket No.108843.00582 SU-0514WO mg / kg. In certain embodiments, the dose is about 100 mg / kg. In certain embodiments, the dose is about 150 mg / kg. In certain embodiments, the dose is about 200 mg / kg. In certain embodiments, the dose is about 250 mg / kg. In certain embodiments, the dose is about 300 mg / kg. In certain embodiments, the dose is about 400 mg / kg. In certain embodiments, the dose is about 450 mg / kg. In certain embodiments, the dose is about 500 mg / kg. In certain embodiments, the dose is about 600 mg / kg. In certain embodiments, the dose is about 700 mg / kg. In certain embodiments, the dose is about 750 mg / kg. In certain embodiments, the dose is about 800 mg / kg. In certain embodiments, the dose is about 900 mg / kg. In certain embodiments, the dose is about 1000 mg / kg.

[0345] The dose can be administered on a schedule deemed suitable by the person of skill in the art. In certain embodiments, the dose is administered once per day. In certain embodiments, the dose is administered twice per day. In certain embodiments, the dose is administered three times per day. In certain embodiments, the dose is administered four times per day. In certain embodiments, the dose is administered in divided doses. In certain embodiments, the dose is administered in two divided doses per day. In certain embodiments, the dose is administered in three divided doses per day. In certain embodiments, the dose is administered in four divided doses per day.

[0346] Dosing can continue for any length of time deemed suitable by the person of skill in the art. In certain embodiments, the dose is administered daily for fourteen days. In certain embodiments, the dose is administered daily for thirteen days. In certain embodiments, the dose is administered daily for twelve days. In certain embodiments, the dose is administered daily for eleven days. In certain embodiments, the dose is administered daily for ten days. In certain embodiments, the dose is administered daily for nine days. In certain embodiments, the dose is administered daily for eight days. In certain embodiments, the dose is administered daily for seven days. In certain embodiments, the dose is administered daily for six days. In certain embodiments, the dose is administered daily for five days. In certain embodiments, the dose is administered daily for four days. In certain embodiments, the dose is administered daily for three days. In certain embodiments, the dose is administered daily for two days. In certain embodiments, the dose is administered for one day.

[0347] In the dosing schedule, the doses can be administered on consecutive days or cyclically, according to the judgment of the practitioner of skill. In certain embodiments, the doses are administered on consecutive days. In certain embodiments, the doses are administered with an interval between doses. In certain embodiments, the interval is one day. In certain embodiments, the interval is two days. In certain embodiments, the interval is three 161 1104675906\1\AMERICASAttorney Docket No.108843.00582 SU-0514WO days. In certain embodiments, the interval is four days. In certain embodiments, the interval is five days. In certain embodiments, the interval is six days.

[0348] In certain embodiments, the dose is administered weekly. In certain embodiments, the dose is administered twice per week. In certain embodiments, the dose is administered three times per week.

[0349] In certain embodiments, the dose(s) are administered for a period of time with a first interval between dose(s), and then the dose(s) are re-administered for a period of time following the first interval between dose(s), wherein this dosing regimen can be repeated (i.e., cyclicly or cyclically, for example, after a second, third, etc. interval between subsequent administrations of dose(s)) according to the judgment of the practitioner of skill. For example, in one embodiment, a first dose is administered for one week, followed by a first interval of one week without the first dose administration; then, a second dose is re- administered for another week, followed by a second interval of one week without the first or second dose administration, and so on cyclically. Other perturbations for first, second, third, etc. dose(s) followed by perturbations for first, second, third, etc. interval(s), and combinations thereof, are contemplated herein as would be appreciated by the practitioner of skill and the need of the patient. For example, in one embodiment, a first dose is administered daily for one week, followed by a first interval of three weeks without the first daily dose administration; then, a second dose is re-administered biweekly for another week, followed by a second interval of four weeks without the first daily or second biweekly dose administration, and so on cyclically.

[0350] The effective amount of a compound or conjugate described herein or a composition thereof can be administered by any route of administration deemed suitable by the practitioner of skill. In certain embodiments, the dose is administered orally. Formulations and techniques for administration are described in detail below. VI. Pharmaceutical Compositions

[0351] The compounds or conjugates described herein can be formulated into pharmaceutical compositions that further comprise a pharmaceutically acceptable carrier, diluent, excipient, or vehicle. In one embodiment, this disclosure provides a pharmaceutical composition comprising a compound or conjugates described herein, and a pharmaceutically acceptable carrier, diluent, excipient, or vehicle. In one embodiment, provided herein are pharmaceutical compositions comprising an effective amount of a compound or conjugates described herein and one or more pharmaceutically acceptable carriers, diluents, excipients, or vehicles. 162 1104675906\1\AMERICASAttorney Docket No.108843.00582 SU-0514WO

[0352] According to another embodiment, the description provides a composition comprising a compound or conjugates described herein and a pharmaceutically acceptable carrier, or vehicle. Pharmaceutical compositions of this description comprise a therapeutically effective amount of a compound of Formula (I)-(IA) or a conjugate of Formula (CONJ-I)-(CONJ-IVB) or a pharmaceutically acceptable salt, stereoisomer, or salt thereof.

[0353] It also will be appreciated that certain compounds and conjugates of this disclosure can exist in free form for treatment, or where appropriate, as a pharmaceutically acceptable derivative (e.g., a salt) thereof. According to this disclosure, a pharmaceutically acceptable derivative includes, but is not limited to, pharmaceutically acceptable prodrugs, salts, esters, salts of such esters, or any other adduct / educt or derivative that upon administration to a patient in need is capable of providing, directly or indirectly, a compound as otherwise described herein, or a metabolite or residue thereof.

[0354] A pharmaceutically acceptable carrier may contain inert ingredients that do not unduly inhibit the biological activity of the compounds. The pharmaceutically acceptable carriers should be biocompatible, for example, non-toxic, non-inflammatory, non- immunogenic, or devoid of other undesired reactions or side-effects upon the administration to a subject. Standard pharmaceutical formulation techniques can be employed.

[0355] The pharmaceutically acceptable carrier, adjuvant, or vehicle, as used herein, includes any and all solvents, diluents, or other liquid vehicle, dispersion or suspension aids, surface active agents, isotonic agents, thickening or emulsifying agents, preservatives, solid binders, lubricants, and the like, as suited to the particular dosage form desired. Remington's Pharmaceutical Sciences, Sixteenth Edition, E. W. Martin (Mack Publishing Co., Easton, Pa., 1980) discloses various carriers used in formulating pharmaceutically acceptable compositions and known techniques for the preparation thereof. Except insofar as any conventional carrier medium is incompatible with the compounds described herein, such as by producing any undesirable biological effect or otherwise interacting in a deleterious manner with any other component(s) of the pharmaceutically acceptable composition, the use of such conventional carrier medium is contemplated to be within the scope of this description. As used herein, the phrase "side effects" encompasses unwanted and adverse effects of a therapy (e.g., a prophylactic or therapeutic agent). Side effects are always unwanted, but unwanted effects are not necessarily adverse. An adverse effect from a therapy (e.g., prophylactic or therapeutic agent) might be harmful, uncomfortable, or risky. Side effects include, but are not limited to, fever, chills, lethargy, gastrointestinal toxicities (including gastric and intestinal ulcerations and erosions), nausea, vomiting, neurotoxicities, 163 1104675906\1\AMERICASAttorney Docket No.108843.00582 SU-0514WO nephrotoxicities, renal toxicities (including such conditions as papillary necrosis and chronic interstitial nephritis), hepatic toxicities (including elevated serum liver enzyme levels), myelotoxicities (including leukopenia, myelosuppression, thrombocytopenia and anemia), dry mouth, metallic taste, prolongation of gestation, weakness, somnolence, pain (including muscle pain, bone pain, and headache), hair loss, asthenia, dizziness, extra-pyramidal symptoms, akathisia, cardiovascular disturbances, and sexual dysfunction.

[0356] Some examples of materials that can serve as pharmaceutically acceptable carriers include, but are not limited to, ion exchangers, alumina, aluminum stearate, lecithin, serum proteins (such as human serum albumin), buffer substances (such as tween 80, phosphates, glycine, sorbic acid, or potassium sorbate), partial glyceride mixtures of saturated vegetable fatty acids, water, salts or electrolytes (such as protamine sulfate, disodium hydrogen phosphate, potassium hydrogen phosphate, sodium chloride, or zinc salts), colloidal silica, magnesium trisilicate, polyvinyl pyrrolidone, polyacrylates, waxes, polyethylene- polyoxypropylene-block polymers, methylcellulose, hydroxypropyl methylcellulose, wool fat, sugars such as lactose, glucose, and sucrose; starches such as corn starch and potato starch; cellulose and its derivatives such as sodium carboxymethyl cellulose, ethyl cellulose, and cellulose acetate; powdered tragacanth; malt; gelatin; talc; excipients such as cocoa butter and suppository waxes; oils such as peanut oil, cottonseed oil, safflower oil, sesame oil, olive oil, corn oil, and soybean oil; glycols such a propylene glycol or polyethylene glycol; esters such as ethyl oleate and ethyl laurate; agar; buffering agents such as magnesium hydroxide and aluminum hydroxide; alginic acid; pyrogen-free water; isotonic saline; Ringer's solution; ethyl alcohol, and phosphate buffer solutions, as well as other non-toxic compatible lubricants such as sodium lauryl sulfate and magnesium stearate, as well as coloring agents, releasing agents, coating agents, sweetening, flavoring, and perfuming agents. Preservatives and antioxidants can also be present in the composition, according to the judgment of the formulator.

[0357] The compositions of the present invention may be administered orally, parenterally, by inhalation spray, topically, rectally, nasally, buccally, vaginally or via an implanted reservoir. As used herein, the term "parenteral" includes subcutaneous, intravenous, intramuscular, intra-articular, intra-synovial, intrasternal, intrathecal, intraocular, intrahepatic, intralesional and intracranial injection or infusion techniques. Preferably, the compositions are administered orally, intraperitoneally or intravenously. Sterile injectable forms of the compositions of this invention may be aqueous or oleaginous suspension. These suspensions may be formulated according to techniques known in the art using suitable dispersing or 164 1104675906\1\AMERICASAttorney Docket No.108843.00582 SU-0514WO wetting agents and suspending agents. The sterile injectable preparation also may be a sterile injectable solution or suspension in a non-toxic parenterally-acceptable diluent or solvent, for example as a solution in 1,3-butanediol. Among the acceptable vehicles and solvents that may be employed are water, Ringer's solution and isotonic sodium chloride solution. In addition, sterile, fixed oils are conventionally employed as a solvent or suspending medium.

[0358] For this purpose, any bland fixed oil may be employed including synthetic mono- or di-glycerides. Fatty acids, such as oleic acid and its glyceride derivatives, are useful in the preparation of injectables, as are natural pharmaceutically acceptable oils, such as olive oil or castor oil, especially in their polyoxyethylated versions. These oil solutions or suspensions also may contain a long-chain alcohol diluent or dispersant, such as carboxymethyl cellulose or similar dispersing agents that are commonly used in the formulation of pharmaceutically acceptable dosage forms including emulsions and suspensions. Other commonly used surfactants, such as Tweens, Spans and other emulsifying agents or bioavailability enhancers that are commonly used in the manufacture of pharmaceutically acceptable solid, liquid, or other dosage forms may also be used for the purposes of formulation.

[0359] The pharmaceutically acceptable compositions of this invention may be orally administered in any orally acceptable dosage form including, but not limited to, capsules, tablets, aqueous suspensions or solutions. In the case of tablets for oral use, carriers commonly used include lactose and corn starch. Lubricating agents, such as magnesium stearate, are also typically added. For oral administration in a capsule form, useful diluents include lactose and dried cornstarch. When aqueous suspensions are required for oral use, the active ingredient is combined with emulsifying and suspending agents. If desired, certain sweetening, flavoring or coloring agents also may be added.

[0360] Alternatively, the pharmaceutically acceptable compositions of this invention may be administered in the form of suppositories for rectal or vaginal administration. These can be prepared by mixing the agent with a suitable non-irritating excipient that is solid at room temperature but liquid at rectal temperature and therefore will melt in the rectum or vaginal cavity to release the drug. Such materials include cocoa butter, polyethylene glycol or a suppository wax that is solid at ambient temperature but liquid at body temperature and therefore melt in the rectum or vaginal cavity and release the active compound.

[0361] The pharmaceutically acceptable compositions of this invention also may be administered topically, especially when the target of treatment includes areas or organs readily accessible by topical application, including diseases of the eye, skin, or lower 165 1104675906\1\AMERICASAttorney Docket No.108843.00582 SU-0514WO intestinal tract. Suitable topical formulations are readily prepared for each of these areas or organs.

[0362] Topical application for the lower intestinal tract can be effected in a rectal suppository formulation (see above) or in a suitable enema formulation. Topically-transdermal patches also may be used.

[0363] For topical applications, the pharmaceutically acceptable compositions may be formulated in a suitable ointment containing the active component suspended or dissolved in one or more carriers. Carriers for topical administration of the compounds of this invention include, but are not limited to, mineral oil, liquid petrolatum, white petrolatum, propylene glycol, polyoxyethylene, polyoxypropylene compound, emulsifying wax and water. Alternatively, the pharmaceutically acceptable compositions can be formulated in a suitable lotion or cream containing the active components suspended or dissolved in one or more pharmaceutically acceptable carriers. Suitable carriers include, but are not limited to, mineral oil, sorbitan monostearate, polysorbate 60, cetyl esters wax, cetearyl alcohol, 2 octyldodecanol, benzyl alcohol and water.

[0364] For ophthalmic use, the pharmaceutically acceptable compositions may be formulated, e.g., as micronized suspensions in isotonic, pH adjusted sterile saline or other aqueous solution, or, preferably, as solutions in isotonic, pH adjusted sterile saline or other aqueous solution, either with or without a preservative such as benzylalkonium chloride. Alternatively, for ophthalmic uses, the pharmaceutically acceptable compositions may be formulated in an ointment such as petrolatum. The pharmaceutically acceptable compositions of this invention also may be administered by nasal aerosol or inhalation. Such compositions are prepared according to techniques well-known in the art of pharmaceutical formulation and may be prepared as solutions in saline, employing benzyl alcohol or other suitable preservatives, absorption promoters to enhance bioavailability, fluorocarbons, and / or other conventional solubilizing or dispersing agents.

[0365] In certain embodiments, the compositions of this disclosure are administered orally. The pharmaceutically acceptable compositions of this description may be orally administered in any orally acceptable dosage form including, but not limited to, capsules, tablets, aqueous suspensions, or solutions. In the case of tablets for oral use, carriers commonly used include lactose and corn starch. Lubricating agents, such as magnesium stearate, are also typically added. For oral administration in a capsule form, useful diluents include lactose and dried cornstarch. When aqueous suspensions are required for oral use, the active ingredient is 166 1104675906\1\AMERICASAttorney Docket No.108843.00582 SU-0514WO combined with emulsifying and suspending agents. If desired, certain sweetening, flavoring, or coloring agents also may be added.

[0366] Liquid dosage forms for oral administration include, but are not limited to, pharmaceutically acceptable emulsions, microemulsions, solutions, suspensions, syrups, and elixirs. In addition to the active compounds herein, the liquid dosage forms may contain inert diluents commonly used in the art such as, for example, water or other solvents, solubilizing agents and emulsifiers such as ethyl alcohol, isopropyl alcohol, ethyl carbonate, ethyl acetate, benzyl alcohol, benzyl benzoate, propylene glycol, 1,3-butylene glycol, dimethylformamide, oils (in particular, cottonseed, groundnut, corn, germ, olive, castor, and sesame oils), glycerol, tetrahydrofurfuryl alcohol, polyethylene glycols and fatty acid esters of sorbitan, and mixtures thereof. Besides inert diluents, the oral compositions also can include adjuvants such as wetting agents, emulsifying and suspending agents, sweetening, flavoring, and perfuming agents.

[0367] Solid dosage forms for oral administration include capsules, tablets, pills, powders, and granules. In such solid dosage forms, the active compound herein is mixed with at least one inert, pharmaceutically acceptable excipient or carrier such as sodium citrate or dicalcium phosphate and / or a) fillers or extenders such as starches, lactose, sucrose, glucose, mannitol, and silicic acid; b) binders such as carboxymethylcellulose, alginates, gelatin, polyvinylpyrrolidinone, sucrose, and acacia; c) humectants such as glycerol; d) disintegrating agents such as agar-agar, calcium carbonate, potato or tapioca starch, alginic acid, certain silicates, and sodium carbonate; e) solution retarding agents such as paraffin; f) absorption accelerators such as quaternary ammonium compounds; g) wetting agents such as, for example, cetyl alcohol and glycerol monostearate; h) absorbents such as kaolin and bentonite clay; and i) lubricants such as talc, calcium stearate, magnesium stearate, solid polyethylene glycols, sodium lauryl sulfate, and mixtures thereof. In the case of capsules, tablets, and pills, the dosage form also may comprise buffering agents.

[0368] Solid compositions of a similar type also may be employed as fillers in soft and hard- filled gelatin capsules using such excipients as lactose or milk sugar as well as high molecular weight polyethylene glycols and the like. The solid dosage forms of tablets, dragees, capsules, pills, and granules can be prepared with coatings and shells such as enteric coatings and other coatings well known in the pharmaceutical formulating art. Solid dosage forms optionally may contain opacifying agents. These solid dosage forms also can be of a composition such that they release the active ingredient(s) only, for example, in a certain part of the intestinal tract, optionally, in a delayed manner. Examples of embedding compositions 167 1104675906\1\AMERICASAttorney Docket No.108843.00582 SU-0514WO that can be used include polymeric substances and waxes. Solid compositions of a similar type also may be employed as fillers in soft and hard-filled gelatin capsules using such excipients as lactose or milk sugar as well as high molecular weight polethylene glycols and the like.

[0369] The compounds and conjugates described herein also can be in micro-encapsulated form with one or more excipients as noted above. The solid dosage forms of tablets, dragees, capsules, pills, and granules can be prepared with coatings and shells such as enteric coatings, release controlling coatings, and other coatings well known in the pharmaceutical formulating art. In such solid dosage forms the active compound may be admixed with at least one inert diluent such as sucrose, lactose, or starch. Such dosage forms also may comprise, as is normal practice, additional substances other than inert diluents, for example, tableting lubricants and other tableting aids such a magnesium stearate and microcrystalline cellulose. In the case of capsules, tablets and pills, the dosage forms also may comprise buffering agents. They may optionally contain opacifying agents and also can be of a composition such that they release the active ingredient(s) only, for example, in a certain part of the intestinal tract, optionally, in a delayed manner. Examples of embedding compositions that can be used include polymeric substances and waxes.

[0370] The compounds and conjugates of the description are formulated in dosage unit form for ease of administration and uniformity of dosage. As used herein, the phrase "dosage unit form" refers to a physically discrete unit of agent appropriate for the patient to be treated. It will be understood, however, that the total daily usage of the compounds and compositions of this disclosure will be decided by the attending physician within the scope of sound medical judgment. The specific effective dose level for any particular patient or organism will depend upon a variety of factors including the disorder being treated and the severity of the disorder; the activity of the specific compound employed; the specific composition employed; the age, body weight, general health, sex, and diet of the patient; the time of administration, route of administration, and rate of excretion of the specific compound employed; the duration of the treatment; drugs used in combination or coincidental with the specific compound employed, and like factors well known in the medical arts.

[0371] The amount of the compounds or conjugates of this disclosure that may be combined with the carrier materials to produce a composition in a single dosage form will vary depending upon the host treated, the particular mode of administration, and other factors. The compositions should be formulated so that a dosage of between 0.01 - 100 mg / kg body 168 1104675906\1\AMERICASAttorney Docket No.108843.00582 SU-0514WO weight / day of the compound or inhibitor can be administered to a patient receiving these compositions. VII. Combinations

[0372] In certain embodiments, provided are compositions, therapeutic formulations, and methods of treatment or uses comprising any of the compounds or conjugates provided herein in combination with one or more additional therapeutic agents wherein the additional therapeutic agent is a chemotherapeutic agent, hormonal agent, antitumor agent, immunostimulatory agent, immunomodulator, an immunotherapeutic agent, or combination thereof.

[0373] Examples of chemotherapeutic agents include, but are not limited to, Bendamustine (TREANDA®, Cephalon), Venetoclax (VENCLEXTA®, Abbvie, Genentech), Denosumab (XGEVA®, Amgen; PROLIA®, Amgen), Carfilzomib (KYPROLIS®, Amgen), Ixazomib (NINLARO®, Takeda), Erlotinib (TARCEVA®, Genentech / OSI Pharm.), Bortezomib (VELCADE®, Millennium Pharm.), Fulvestrant (FASLODEX®, AstraZeneca), Sutent (SU11248, Pfizer), Letrozole (FEMARA®, Novartis), Imatinib mesylate (GLEEVEC®, Novartis), PTK787 / ZK 222584 (Novartis), Oxaliplatin (Eloxatin®, Sanofi), 5-FU (5- fluorouracil), Leucovorin, Rapamycin (Sirolimus, RAPAMUNE®, Wyeth), Lapatinib (TYKERB®, GSK572016, Glaxo Smith Kline), Lonafarnib (SCH 66336), Sorafenib (BAY43-9006, Bayer Labs), and Gefitinib (IRESSA®, AstraZeneca), AG1478, AG1571 (SU 5271; Sugen), alkylating agents such as thiotepa and CYTOXAN® cyclosphosphamide; alkyl sulfonates such as busulfan, improsulfan and piposulfan; aziridines such as benzodopa, carboquone, meturedopa, and uredopa; ethylenimines and methylamelamines including altretamine, triethylenemelamine, triethylenephosphoramide, triethylenethiophosphoramide and trimethylomelamine; acetogenins (especially bullatacin and bullatacinone); a camptothecin (including the synthetic analog topotecan); bryostatin; callystatin; CC-1065 (including its adozelesin, carzelesin and bizelesin synthetic analogs); cryptophycins (particularly cryptophycin 1 and cryptophycin 8); dolastatin; duocarmycin (including the synthetic analogs, KW-2189 and CB1-TM1); eleutherobin; pancratistatin; a sarcodictyin; spongistatin; nitrogen mustards such as chlorambucil, chlomaphazine, chlorophosphamide, estramustine, ifosfamide, mechlorethamine, mechlorethamine oxide hydrochloride, melphalan, novembichin, phenesterine, prednimustine, trofosfamide, uracil mustard; nitrosureas such as carmustine, chlorozotocin, fotemustine, lomustine, nimustine, and ranimnustine; antibiotics such as the enediyne antibiotics (e.g., calicheamicin, especially uncialamycin, calicheamicin gammall, and calicheamicin omegall (Angew Chem. Intl. Ed. 169 1104675906\1\AMERICASAttorney Docket No.108843.00582 SU-0514WO Engl. (1994) 33:183-186); dynemicin, including dynemicin A; bisphosphonates, such as clodronate; an esperamicin; as well as neocarzinostatin chromophore and related chromoprotein enediyne antibiotic chromophores), aclacinomysins, actinomycin, authramycin, azaserine, bleomycins, cactinomycin, carabicin, caminomycin, carzinophilin, chromomycinis, dactinomycin, daunorubicin, detorubicin, 6-diazo-5-oxo-L-norleucine, ADRIAMYCIN® (doxorubicin), morpholino-doxorubicin, cyanomorpholino-doxorubicin, 2- pyrrolino-doxorubicin and deoxydoxorubicin), epirubicin, esorubicin, idarubicin, marcellomycin, mitomycins such as mitomycin C, mycophenolic acid, nogalamycin, olivomycins, peplomycin, porfiromycin, puromycin, quelamycin, rodorubicin, streptonigrin, streptozocin, tubercidin, ubenimex, zinostatin, zorubicin; anti-metabolites such as methotrexate and 5-fluorouracil (5-FU); folic acid analogs such as denopterin, methotrexate, pladienolide B, pteropterin, trimetrexate; purine analogs such as fludarabine, 6-mercaptopurine, thiamniprine, thioguanine; pyrimidine analogs such as ancitabine, azacitidine, 6-azauridine, carmofur, cytarabine, dideoxyuridine, doxifluridine, enocitabine, floxuridine; androgens such as calusterone, dromostanolone propionate, epitiostanol, mepitiostane, testolactone; anti-adrenals such as aminoglutethimide, mitotane, trilostane; folic acid replenisher such as frolinic acid; aceglatone; aldophosphamide glycoside; aminolevulinic acid; eniluracil; amsacrine; bestrabucil; bisantrene; edatraxate; defofamine; demecolcine; diaziquone; elformithine; elliptinium acetate; an epothilone; etoglucid; gallium nitrate; hydroxyurea; lentinan; lonidainine; maytansinoids such as maytansine and ansamitocins; mitoguazone; mitoxantrone; mopidanmol; nitraerine; pentostatin; phenamet; pirarubicin; losoxantrone; podophyllinic acid; 2-ethylhydrazide; procarbazine; PSK® polysaccharide complex (JHS Natural Products, Eugene, Oreg.); razoxane; rhizoxin; sizofuran; spirogermanium; tenuazonic acid; triaziquone; 2,2',2''-trichlorotriethylamine; trichothecenes (especially T-2 toxin, verracurin A, roridin A and anguidine); urethan; vindesine; dacarbazine; mannomustine; mitobronitol; mitolactol; pipobroman; gacytosine; arabinoside (“Ara-C”); cyclophosphamide; thiotepa; taxoids, e.g., TAXOL® (paclitaxel; Bristol-Myers Squibb Oncology, Princeton, N.J.), ABRAXANE® (Cremophor-free), albumin-engineered nanoparticle formulations of paclitaxel (American Pharmaceutical Partners, Schaumberg, Ill.), and TAXOTERE® (doxetaxel; Rhone-Poulenc Rorer, Antony, France); chloranmbucil; GEMZAR® (gemcitabine); 6-thioguanine; mercaptopurine; methotrexate; platinum analogs such as cisplatin and carboplatin; vinblastine; etoposide (VP- 16); ifosfamide; mitoxantrone; vincristine; NAVELBINE® (vinorelbine); novantrone; teniposide; edatrexate; daunomycin; aminopterin; capecitabine (XELODA®); ibandronate; 170 1104675906\1\AMERICASAttorney Docket No.108843.00582 SU-0514WO CPT-11; topoisomerase inhibitor RFS 2000; difluoromethylornithine (DMFO); retinoids such as retinoic acid; and pharmaceutically acceptable salts, acids and derivatives of any of the above.

[0374] The agents administered in combination with the compounds or conjugates disclosed herein can be administered just prior to, concurrent with, or shortly after the administration of the compounds or conjugates. In certain embodiments, the compounds or conjugates provided herein are administered on a first dosing schedule, and the one or more second agents are administered on their own dosing schedules. For purposes of the present disclosure, such administration regimens are considered the administration of an compound or conjugate “in combination with” an additional therapeutically active component. Embodiments include pharmaceutical compositions in which a compound or conjugate disclosed herein is co-formulated with one or more of the chemotherapeutic agents or immunomodulatory agents disclosed herein.

[0375] In certain embodiments, provided are compositions, therapeutic formulations, and methods of treatment or uses comprising any of the compounds or conjugates provided herein in combination with one or more LAG3 inhibitors, and methods of treatment comprising administering such combinations to subjects in need thereof. In some embodiments, the one or more LAG3 inhibitors comprise a small molecule blocker of the LAG3 pathway. In some embodiments, the one or more LAG3 inhibitors comprise an antibody that inhibits LAG3 activity. In some embodiments, the one or more LAG3 inhibitors are independently selected from the group consisting of: IMP321 (Eftilagimod alpha, Immutep), relatilimab (Bristol- Myers Squibb), LAG525 (Novartis), MK4280 (Merck), BI 754111 (Boehringer Ingelheim), REGN3767 (Regeneron / Sanofi), Sym022 (Symphogen) and TSR-033 (Tesaro / GSK).

[0376] In certain embodiments, provided are compositions, therapeutic formulations, and methods of treatment or uses comprising any of the compounds or conjugates provided herein in combination with one or more TIM3 inhibitors, and methods of treatment comprising administering such combinations to subjects in need thereof. In some embodiments, the one or more TIM3 inhibitors comprise a small molecule blocker of the TIM3 pathway. In some embodiments, the one or more TIM3 inhibitors comprise an antibody that inhibits TIM3 activity. In some embodiments, the one or more TIM3 inhibitors are independently selected from the group consisting of: TSR-022 (Tesaro), LY3321367 (Eli Lilly), Sym023 (Symphogen) and MBG453 (Novartis).

[0377] In certain embodiments, provided are compositions, therapeutic formulations, and methods of treatment or uses comprising any of the compounds or conjugates provided herein 171 1104675906\1\AMERICASAttorney Docket No.108843.00582 SU-0514WO in combination with one or more TIGIT inhibitors, and methods of treatment comprising administering such combinations to subjects in need thereof. In some embodiments, the one or more TIGIT inhibitors comprise a small molecule blocker of the TIGIT pathway. In some embodiments, the one or more TIGIT inhibitors comprise an antibody that inhibits TIGIT activity. In some embodiments, the one or more TIGIT inhibitors are independently selected from the group consisting of: BMS-986207 (BMS), tiragolumab (RG6058, Genentech), ASP- 8374 (Potenza Therapeutics), etigilimab (Oncomed / Mereo BioPharma, AB-154 (Arcus).

[0378] In certain embodiments, provided are compositions, therapeutic formulations, and methods of treatment or uses comprising any of the compounds or conjugates provided herein in combination with one or more inhibitors of V-domain Ig suppressor of T cell activation (VISTA), and methods of treatment comprising administering such combinations to subjects in need thereof. In some embodiments, the one or more VISTA inhibitors comprise a small molecule blocker of the VISTA pathway. In some embodiments, the one or more VISTA inhibitors comprise an antibody that inhibits VISTA activity. In some embodiments, the one or more VISTA inhibitors are independently selected from the group consisting of: PMC-309 (PharmaAbcine Inc), HMBD-002 (Hummingbird Bioscience Pte Ltd), JNJ-61610588 (Janssen), CA-170 (Aurigene Discovery Technologies Ltd).

[0379] In certain embodiments, provided are compositions, therapeutic formulations, and methods of treatment or uses comprising any of the antibody conjugates provided herein in combination with one or more CSF1R inhibitors, and methods of treatment comprising administering such combinations to subjects in need thereof. In some embodiments, the one or more CSF1R inhibitors comprise a small molecule blocker of the CSF1R pathway. In some embodiments, the one or more CSF1R inhibitors comprise an antibo...

Claims

1. Attorney Docket No.108843.00582 SU-0514WO Claims What is claimed is:

1. A compound of Formula (I): or a pharmaceutically acceptable salt, stereoisomer, or tautomer thereof; wherein: L1is C1-6 alkylene, C2-6 alkenylene, or C2-6 alkynylene, each of which is optionally substituted with one or more substituents independently selected from R5; L2is selected from -O-, -NR2-, C1-6 alkylene, C2-6 alkenylene, C2-6 alkynylene, -O-(C1-6 alkylene)-, and -NR2-(C1-6 alkylene)- wherein each alkylene, each alkenylene, or each alkynylene, each either alone or part of another group, is optionally substituted with one or more one or more substituents independently selected from R5; R1is C1-10 alkyl, C2-6 alkenyl, or C2-6 alkynyl, each of which is optionally substituted with one or more substituents independently selected from R5; R2is independently hydrogen or C1-6 alkyl; X1is bond, -O-, or -NR2-; Ring A is either (a) a bicyclic heterocycle optionally substituted with one or more R8; (b) a 3- to 5-membered heterocycle optionally substituted with one or more R4aand further optionally substituted with one or more R8; or (c) a 6- to 12-membered heterocycle substituted with R4band optionally substituted with one or more R8; Ring B is arylene or heteroarylene, each of which is optionally substituted with one or more R8; R4ais a 3- to 12-membered heterocycle optionally substituted with one or more R8; R4bis a bicyclic heterocycle optionally substituted with one or more R8; 238 1104675906\1\AMERICAS Attorney Docket No.108843.00582 SU-0514WO R5is independently selected from halogen, -OR6, -SR6, -C(O)N(R6)(R7), -N(R6)C(O)R7, -N(R6)C(O)N(R6)(R7), -N(R6)(R7), -C(O)R6, -C(O)OR6, -OC(O)R6, - NO2, =O, =S, =N(R6), -CN, C3-12 carbocycle, and 3- to 12-membered heterocycle; R6and R7are independently selected at each occurrence from hydrogen, C1-10alkyl, C2-10 alkenyl, C2-10 alkynyl, C3-12 carbocycle, and 3- to 12-membered heterocycle each of which, except hydrogen, is optionally substituted with one or more R9; R8is independently selected from halogen, -OR6, -SR6, -C(O)N(R6)(R7), -N(R6)C(O)R7, -N(R6)C(O)N(R6)(R7), -N(R6)(R7), -C(O)R6, -C(O)OR6, -OC(O)R6, - NO2, =O, =S, =N(R6), -CN, C1-6alkyl, C2-6alkenyl, C2-6alkynyl, C3-12carbocycle, and 3- to 12-membered heterocycle wherein the C1-6alkyl, C2-6alkenyl, C2-6alkynyl, C3-12 carbocycle, and 3- to 12-membered heterocycle are optionally substituted with one or more R9; R9is independently selected at each occurrence from halogen, -CN, -NO2, - OH, -NR9aR9b, -C(O)NR9aR9b, =O, =S, C1-10 alkyl, C2-10 alkenyl, C2-10 alkynyl, C3-12 carbocycle, 3- to 12- membered heterocycle, and C1-10 haloalkyl; and R9aand R9bare independently selected at each occurrence from hydrogen, C1-10alkyl, C2-10alkenyl, C2-10alkynyl, C3-12carbocycle, and 3- to 12-membered heterocycle.

2. The compound of claim 1, of Formula IA: wherein: X2and X3are independently selected from N and CR3; and R3is independently hydrogen, –OR6, -SR6, -C(O)N(R6)(R7), -N(R6)C(O)R7, -N(R6)C(O)N(R6)(R7), -N(R6)(R7), -C(O)R6, -C(O)OR6, -OC(O)R6, -NO2, or -CN.

3. The compound of claim 1 or 2, wherein: R1is C1-10alkyl optionally substituted with one or more substituents independently selected from R5; X1is O or NH; 239 1104675906\1\AMERICAS Attorney Docket No.108843.00582 SU-0514WO L1is C1-4alkylene optionally substituted with one or more substituents independently selected from R5; and L2is -CH2- or -O-.

4. The compound of any one of claims 1-3, wherein R1is unsubstituted C1-6alkyl.

5. The compound of any one of claims 1-4, wherein R1is n-butyl.

6. The compound of any one of claims 1-5, wherein L1is unsubstituted C1-4 alkyl.

7. The compound of any one of claims 1-6, wherein L1is -CH2-.

8. The compound of any one of claims 2-7, wherein X2is CR3and X3is CR3.

9. The compound of any one of claims 2-7, wherein X2is N and X3is CR3.

10. The compound of any one of claims 2-7, wherein X2is CR3and X3is N.

11. The compound of any one of claims 2-10, wherein R3is hydrogen, –OR6, -C(O)R6, -C(O)OR6, or -OC(O)R6.

12. The compound of any one of claims 2-11, wherein R3is hydrogen.

13. The compound of any one of claims 2-11, wherein R3is –OR6or -C(O)OR6.

14. The compound of any one of claims 2-13, wherein R6is hydrogen or C1-10 alkyl.

15. The compound of any one of claims 1-14, wherein Ring A is a bicyclic heterocycle optionally substituted with one or more R8.

16. The compound of any one of claims 1-15, wherein Ring A is a bridged, fused, or spirocyclic bicyclic heterocycle optionally substituted with one or more R8.

17. The compound of any one of claims 1-16, wherein Ring A is a 5- to 12- membered fused, spirocyclic or bridged bicyclic heterocycle optionally substituted with one or more R8.

18. The compound of any one of claims 1-17, wherein Ring A is a 8- to 12- membered fused, spirocyclic or bridged bicyclic heterocycle optionally substituted with one or more R8.

19. The compound of claims 16-18, wherein the fused, spirocyclic, or bridged bicyclic heterocycle comprises at least one nitrogen atom and / or at least one oxygen atom optionally substituted with one or more R8.

20. The compound of claim 19, wherein the fused, spirocyclic, or bridged bicyclic heterocycle comprises two nitrogen atoms and one oxygen atom optionally substituted with one or more R8.

21. The compound of any one of claims 16-20, wherein Ring A is a N-linked bridged, fused, or spirocyclic bicyclic heterocycle optionally substituted with one or more R8. 240 1104675906\1\AMERICAS Attorney Docket No.108843.00582 SU-0514WO 22. The compound of claim 21, wherein Ring A is a N-linked spirocyclic or bridged bicyclic heterocycle comprising at least two nitrogen atoms, including the nitrogen attached to L2, wherein the heterocycle is optionally substituted with one or more R8.

23. The compound of claim 19, wherein Ring A is selected from wherein m is an integer selected from 1, 2, 3, 4, and 5; and each of m, n, o, and p is an integer independently selected from 1, 2, and 3.

24. The compound of claim 23, wherein Ring A is and is selected from .

25. The compound of claim 24, wherein Ring A is .

26. The compound of claim 23, wherein Ring A is and is selected from 27. The compound of claim 26, wherein Ring A is .

28. The compound of claim 23, wherein Ring A is and is selected from 29. The compound of claim 28, wherein Ring A is . 241 1104675906\1\AMERICAS Attorney Docket No.108843.00582 SU-0514WO 30. The compound of claim 16, wherein Ring .

31. The compound of any one of claims 1-14, wherein Ring A is a 3- to 5-membered heterocycle substituted with one or more R4aand optionally substituted with one or more R8.

32. The compound of any one of claims 1-14 and 31, wherein Ring A is a 3- to 5- membered heterocycle comprising one nitrogen atom wherein the heterocycle is substituted with one or more R4aand optionally substituted with one or more R8.

33. The compound of claim 32, wherein Ring A is .

34. The compound of any one of claims 1-14 and 31-33, wherein R4ais a 5- to 8- membered heterocycle optionally substituted with one or more R8.

35. The compound of any one of claims 1-14 and 31-34, wherein R4ais a 5- to 8- membered heterocycle comprising at least one nitrogen atom and the heterocycle is optionally substituted with one or more R8.

36. The compound of any one of claims 1-14 and 31-35, wherein R4ais 37. The compound of any one of claims 1-14 and 31-36, wherein Ring A is 38. The compound of any one of claims 1-14, wherein Ring A is a 6- to 12-membered heterocycle substituted with R4band optionally substituted with one or more R8.

39. The compound of any one of claims 1-14 and 38, wherein Ring A is a 6- to 8- membered heterocycle substituted with R4band optionally substituted with one or more R8.

40. The compound of any one of claims 1-14 and 38-39, wherein Ring A is 242 1104675906\1\AMERICAS Attorney Docket No.108843.00582 SU-0514WO 41. The compound of any one of claims 1-14 and 38-40, wherein R4bis a 5-5 fused ring system, a 5-6 fused ring system, a 6-6 fused ring system, or a 5-7 fused ring system comprising 1, 2, 3, or 4 heteroatoms selected from N, S, and O, and wherein the fused ring system is optionally substituted with one or more R8.

42. The compound of any one of claims 1-14 and 38-41, wherein R4bis a 5-6 fused ring system optionally substituted with one or more R8.

43. The compound of any one of claims 1-14 and 38-42, wherein , 44. The compound of any one of claim 1-14 and 38-43, wherein Ring A is .

45. The compound of claim 1, selected from the group consisting of: 243 1104675906\1\AMERICAS Attorney Docket No.108843.00582 SU-0514WO 244 1104675906\1\AMERICAS Attorney Docket No.108843.00582 SU-0514WO 245 1104675906\1\AMERICAS Attorney Docket No.108843.00582 SU-0514WO 246 1104675906\1\AMERICAS Attorney Docket No.108843.00582 SU-0514WO or a pharmaceutically acceptable salt, stereoisomer, or tautomer thereof.

46. The compound of claim 45, selected from the group consisting of: 247 1104675906\1\AMERICAS Attorney Docket No.108843.00582 SU-0514WO 248 1104675906\1\AMERICAS Attorney Docket No.108843.00582 SU-0514WO or a pharmaceutically acceptable salt, stereoisomer, or tautomer thereof.

47. The compound of claim 46, of the structure:

48. The compound of claim 46, of the structure: or a pharmaceutically acceptable salt, stereoisomer, or tautomer thereof. 249 1104675906\1\AMERICAS Attorney Docket No.108843.00582 SU-0514WO 49. A linker-payload compound of Formula (LP-I): or a pharmaceutically acceptable salt, stereoisomer, or tautomer thereof; wherein: L is a linker; RG is a reactive group; L1is C1-6 alkylene, C2-6 alkenylene, or C2-6 alkynylene, each of which is optionally substituted with one or more substituents independently selected from R5; L2is selected from -O-, -NR2-, C1-6 alkylene, -O-(C1-6 alkylene)-, and -NR2-(C1-6 alkylene)- wherein the alkylene, either alone or part of another group, is optionally substituted with one or more one or more substituents independently selected from R5; R1is C1-10 alkyl, C2-6 alkenyl, or C2-6 alkynyl, each of which is optionally substituted with one or more substituents independently selected from R5; R2is independently hydrogen or C1-6alkyl; X1is bond, -O-, or -NR2-; Ring A is either (a) a bicyclic heterocycle optionally substituted with one or more R8; (b) a 3- to 5-membered heterocycle optionally substituted with one or more R4aand further optionally substituted with one or more R8; or (c) a 6- to 12-membered heterocycle substituted with R4band optionally substituted with one or more R8; Ring B is arylene or heteroarylene, each of which is optionally substituted with one or more R8; R4ais a 3- to 12-membered heterocycle optionally substituted with one or more R8; R4bis a bicyclic heterocycle optionally substituted with one or more R8; R5is independently selected from halogen, -OR6, -SR6, -C(O)N(R6)(R7), -N(R6)C(O)R7, -N(R6)C(O)N(R6)(R7), -N(R6)(R7), -C(O)R6, -C(O)OR6, -OC(O)R6, - NO2, =O, =S, =N(R6), -CN, C3-12carbocycle, and 3- to 12-membered heterocycle; R6and R7are independently selected at each occurrence from hydrogen, C1-10alkyl, C2-10 alkenyl, C2-10 alkynyl, C3-12 carbocycle, and 3- to 12-membered 250 1104675906\1\AMERICAS Attorney Docket No.108843.00582 SU-0514WO heterocycle each of which, except hydrogen, is optionally substituted with one or more R9; R8is independently selected from halogen, -OR6, -SR6, -C(O)N(R6)(R7), -N(R6)C(O)R7, -N(R6)C(O)N(R6)(R7), -N(R6)(R7), -C(O)R6, -C(O)OR6, -OC(O)R6, - NO2, =O, =S, =N(R6), -CN, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C3-12 carbocycle, and 3- to 12-membered heterocycle wherein the C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C3- 12carbocycle, and 3- to 12-membered heterocycle are optionally substituted with one or more R9; R9is independently selected at each occurrence from halogen, -CN, -NO2, -OH, -NR9aR9b, -C(O)NR9aR9b, =O, =S, C1-10alkyl, C2-10alkenyl, C2-10alkynyl, C3-12carbocycle, 3- to 12- membered heterocycle, and C1-10haloalkyl; and R9aand R9bare independently selected at each occurrence from hydrogen, C1- 10 alkyl, C2-10 alkenyl, C2-10 alkynyl, C3-12 carbocycle, and 3- to 12-membered heterocycle.

50. The linker-payload compound of claim 49, of Formula (LP-II): or a pharmaceutically acceptable salt, stereoisomer, or tautomer thereof; wherein: SG is absent or a divalent spacer group; W1is absent, wherein the -NH- is bound to W2and each indicates a point of attachment to the rest of the formula; 251 1104675906\1\AMERICAS Attorney Docket No.108843.00582 SU-0514WO L3is independently a bond or C1-6alkylene optionally substituted with one, two, or three substituents selected from halogen, C1-6 alkyl, haloC1-6 alkyl, hydroxyl, amino, C1-6 alkylamino, and C1-6 alkoxy; R11is independently hydrogen or C1-6alkyl; R12is independently a residue of an amino acid sidechain; w is an integer selected from 0, 1, and 2; W2is absent, an amino acid residue, or a peptide residue wherein the amino acid residue or peptide residue is optionally substituted with a HP1group; HP is absent or a divalent hydrophilic group; HP1, when present, is a monovalent hydrophilic group; each RAis independently, at each occurrence, C1-6alkyl optionally substituted with one, two, or three substituents selected from halogen, haloC1-6 alkyl, hydroxyl, amino, alkylC1-6 amino, and C1-6 alkoxy; each O-Su is independently, at each occurrence, a release trigger group; each y is an integer independently selected from 0, 1, and 2; and each z is an integer independently selected from 0 and 1.

51. The linker-payload compound of claim 50, of Formula (LP-IIA): or a pharmaceutically acceptable salt, stereoisomer, or tautomer thereof; wherein: X2and X3are independently selected from N and CR3; and R3is independently hydrogen, –OR6, -SR6, -C(O)N(R6)(R7), -N(R6)C(O)R7, -N(R6)C(O)N(R6)(R7), -N(R6)(R7), -C(O)R6, -C(O)OR6, -OC(O)R6, -NO2, or -CN.

52. The linker-payload of any one of claims 49-51, wherein: R1is C1-10alkyl optionally substituted with one or more substituents independently selected from R5; X1is O or NH; L1is C1-4alkylene optionally substituted with one or more substituents independently selected from R5; and L2is -CH2- or -O-. 252 1104675906\1\AMERICAS Attorney Docket No.108843.00582 SU-0514WO 53. The linker-payload compound of any one of claims 49-52, wherein W1is absent, .

54. The linker-payload compound of any one of claims 49-53, wherein W1is .

55. The linker-payload compound of any one of claims 49-54, wherein Su is , wherein represents attachment to the remainder of the compound.

56. The linker-payload compound of any one of claims 49-55, wherein Su is , wherein represents attachment to the remainder of the compound.

57. The linker-payload compound of any one of claims 49-56, wherein W2is absent, an amino acid residue, or a peptide residue wherein the amino acid residue or the peptide residue is optionally substituted with HP1.

58. The linker-payload compound of any one of claims 49-57, wherein W2is absent, - (C(O)CHR13NR11)a-, or (C(O)CH2CHR13NR11)b-; wherein R13is independently a residue of an amino acid sidechain optionally substituted with HP1; R11is independently hydrogen or C1-6 alkyl; each of a and b is independently an integer between 1 and 10, inclusive; and the -C(O)- of W2is bound to W1.

59. The linker-payload compound of claim 58, wherein R13is a residue of an amino acid sidechain selected from valine, citrulline, alanine, glycine, and asparagine. 253 1104675906\1\AMERICAS Attorney Docket No.108843.00582 SU-0514WO 60. The linker-payload compound of any one of claims 49-59, wherein W2is .

61. The linker-payload compound of any one of claims 49-60, wherein SG is -C1-10 alkylene-C(O)- wherein the -C(O)- is bound to W2and the C1-10 alkylene is optionally substituted with one, two, or three substituents selected from halogen, haloC1-6alkyl, hydroxyl, amino, C1-6alkylamino, and C1-6alkoxy.

62. The linker-payload compound of any one of claims 49-61, wherein HP is absent or wherein R20is hydrogen or methyl and x1 is an integer between 1 and 20, inclusive; and each is the point of attachment to the rest of the formula.

63. The linker-payload compound of any one of claims 49-62, wherein HP is and x1 is an integer between 1 and 5, inclusive.

64. The linker-payload compound of any one of claims 49-63, wherein RG is selected from 254 1104675906\1\AMERICAS Attorney Docket No.108843.00582 SU-0514WO cyclooctyne derivatives and –SH; wherein RTis C1-6alkyl; and represents attachment to the remainder of the compound.

65. The linker-payload compound of any one of claims 49-64, wherein RG is .

66. The linker-payload compound of any one of claims 49-65, wherein is 67. The compound of claim 49, selected from the group consisting of: 255 1104675906\1\AMERICAS Attorney Docket No.108843.00582 SU-0514WO 256 1104675906\1\AMERICAS Attorney Docket No.108843.00582 SU-0514WO 257 1104675906\1\AMERICAS Attorney Docket No.108843.00582 SU-0514WO 258 1104675906\1\AMERICAS Attorney Docket No.108843.00582 SU-0514WO or a pharmaceutically acceptable salt, stereoisomer, or tautomer thereof.

68. A conjugate comprising the compound of any one of claims 1-48 linked to COMP optionally via a linker, wherein COMP is a macromolecule.

69. The conjugate of claim 68, wherein the compound is linked to COMP via a linker.

70. The conjugate of claim 68 or 69, wherein the linker comprises a protease cleavable linker, a pH sensitive linker, or a non-cleavable linker.

71. A conjugate of Formula (CONJ-I): or a pharmaceutically acceptable salt, stereoisomer, or tautomer thereof; wherein: COMP is a macromolecule; L is a linker; x is an integer selected from 1 to 30; L1is C1-6alkylene, C2-6alkenylene, or C2-6alkynylene, each of which is optionally substituted with one or more substituents independently selected from R5; L2is selected from -O-, -NR2-, C1-6 alkylene, -O-(C1-6 alkylene)-, and -NR2-(C1-6 alkylene)- wherein the alkylene, either alone or part of another group, is optionally substituted with one or more one or more substituents independently selected from R5; R1is C1-10 alkyl, C2-6 alkenyl, or C2-6 alkynyl, each of which is optionally substituted with one or more substituents independently selected from R5; R2is independently hydrogen or C1-6 alkyl; X1is bond, -O-, or -NR2-; 259 1104675906\1\AMERICAS Attorney Docket No.108843.00582 SU-0514WO Ring A is either (a) a bicyclic heterocycle optionally substituted with one or more R8; (b) a 3- to 5-membered heterocycle optionally substituted with one or more R4aand further optionally substituted with one or more R8; or (c) a 6- to 12-membered heterocycle substituted with R4band optionally substituted with one or more R8; Ring B is arylene or heteroarylene, each of which is optionally substituted with one or more R8; R4ais a 3- to 12-membered heterocycle optionally substituted with one or more R8; R4bis a bicyclic heterocycle optionally substituted with one or more R8; R5is independently selected from halogen, -OR6, -SR6, -C(O)N(R6)(R7), -N(R6)C(O)R7, -N(R6)C(O)N(R6)(R7), -N(R6)(R7), -C(O)R6, -C(O)OR6, -OC(O)R6, - NO2, =O, =S, =N(R6), -CN, C3-12 carbocycle, and 3- to 12-membered heterocycle; R6and R7are independently selected at each occurrence from hydrogen, C1-10 alkyl, C2-10alkenyl, C2-10alkynyl, C3-12carbocycle, and 3- to 12-membered heterocycle each of which, except hydrogen, is optionally substituted with one or more R9; R8is independently selected from halogen, -OR6, -SR6, -C(O)N(R6)(R7), -N(R6)C(O)R7, -N(R6)C(O)N(R6)(R7), -N(R6)(R7), -C(O)R6, -C(O)OR6, -OC(O)R6, - NO2, =O, =S, =N(R6), -CN, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C3-12 carbocycle, and 3- to 12-membered heterocycle wherein the C1-6alkyl, C2-6alkenyl, C2-6alkynyl, C3-12carbocycle, and 3- to 12-membered heterocycle are optionally substituted with one or more R9; R9is independently selected at each occurrence from halogen, -CN, -NO2, - OH, -NR9aR9b, -C(O)NR9aR9b, =O, =S, C1-10alkyl, C2-10alkenyl, C2-10alkynyl, C3-12carbocycle, 3- to 12- membered heterocycle, and C1-10 haloalkyl; and R9aand R9bare independently selected at each occurrence from hydrogen, C1- 10alkyl, C2-10alkenyl, C2-10alkynyl, C3-12carbocycle, and 3- to 12-membered heterocycle.

72. The conjugate of claim 71, of Formula (CONJ-II): 260 1104675906\1\AMERICAS Attorney Docket No.108843.00582 SU-0514WO or a pharmaceutically acceptable salt, stereoisomer, or tautomer thereof; wherein: SG is absent or a divalent spacer group; W1is absent, wherein the -NH- is bound to W2and each indicates a point of attachment to the rest of the formula; L3is independently a bond or a C1-6alkylene optionally substituted with one, two, or three substituents selected from halogen, C1-6alkyl, haloC1-6alkyl, hydroxyl, amino, C1-6 alkylamino, and C1-6 alkoxy; R11is independently hydrogen or C1-6 alkyl; R12is independently a residue of an amino acid sidechain; w is an integer selected from 0, 1, and 2; W2is absent, an amino acid residue, or a peptide residue wherein the amino acid residue or peptide residue is optionally substituted with a HP1group; HP is absent or a divalent hydrophilic group; HP1, when present, is a monovalent hydrophilic group; each RAis independently, at each occurrence, C1-6 alkyl optionally substituted with one, two, or three substituents selected from halogen, haloC1-6alkyl, hydroxyl, amino, alkylC1-6 amino, and C1-6 alkoxy; each O-Su is independently, at each occurrence, a release trigger group; RL is a reactive linker; each y is an integer independently selected from 0, 1, and 2; and each z is an integer independently selected from 0 and 1.

73. The conjugate of claim 72, of Formula (CONJ-IIA): (CONJ-IIA) 261 1104675906\1\AMERICAS Attorney Docket No.108843.00582 SU-0514WO or a pharmaceutically acceptable salt, stereoisomer, or tautomer thereof; wherein: X2and X3are independently selected from N and CR3; and R3is independently hydrogen, –OR6, -SR6, -C(O)N(R6)(R7), -N(R6)C(O)R7, -N(R6)C(O)N(R6)(R7), -N(R6)(R7), -C(O)R6, -C(O)OR6, -OC(O)R6, -NO2, or -CN.

74. A conjugate of Formula (CONJ-III): or a pharmaceutically acceptable salt, stereoisomer, or tautomer thereof; wherein: CY is a residue of cytotoxic agent; Lais a first linker; Lbis a second linker; L is a linker; x is an integer selected from 1 to 30; xx is an integer selected from 1 to 30; L1is C1-6 alkylene, C2-6 alkenylene, or C2-6 alkynylene, each of which is optionally substituted with one or more substituents independently selected from R5; L2is selected from -O-, -NR2-, C1-6alkylene, -O-(C1-6alkylene)-, and -NR2-(C1-6alkylene)- wherein the alkylene, either alone or part of another group, is optionally substituted with one or more one or more substituents independently selected from R5; R1is C1-10alkyl, C2-6alkenyl, or C2-6alkynyl, each of which is optionally substituted with one or more substituents independently selected from R5; R2is independently hydrogen or C1-6 alkyl; X1is bond, -O-, or -NR2-; Ring A is either (a) a bicyclic heterocycle optionally substituted with one or more R8; (b) a 3- to 5-membered heterocycle optionally substituted with one or more R4aand further optionally substituted with one or more R8; or (c) a 6- to 12-membered heterocycle substituted with R4band optionally substituted with one or more R8; 262 1104675906\1\AMERICAS Attorney Docket No.108843.00582 SU-0514WO Ring B is arylene or heteroarylene, each of which is optionally substituted with one or more R8; R4ais a 3- to 12-membered heterocycle optionally substituted with one or more R8; R4bis a bicyclic heterocycle optionally substituted with one or more R8; R5is independently selected from halogen, -OR6, -SR6, -C(O)N(R6)(R7), -N(R6)C(O)R7, -N(R6)C(O)N(R6)(R7), -N(R6)(R7), -C(O)R6, -C(O)OR6, -OC(O)R6, -NO2, =O, =S, =N(R6), -CN, C3-12 carbocycle, and 3- to 12-membered heterocycle; R6and R7are independently selected at each occurrence from hydrogen, C1-10 alkyl, C2-10alkenyl, C2-10alkynyl, C3-12carbocycle, and 3- to 12-membered heterocycle each of which, except hydrogen, is optionally substituted with one or more R9; R8is independently selected from halogen, -OR6, -SR6, -C(O)N(R6)(R7), -N(R6)C(O)R7, -N(R6)C(O)N(R6)(R7), -N(R6)(R7), -C(O)R6, -C(O)OR6, -OC(O)R6, - NO2, =O, =S, =N(R6), -CN, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C3-12 carbocycle, and 3- to 12-membered heterocycle wherein the C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C3- 12carbocycle, and 3- to 12-membered heterocycle are optionally substituted with one or more R9; R9is independently selected at each occurrence from halogen, -CN, -NO2, - OH, -NR9aR9b, -C(O)NR9aR9b, =O, =S, C1-10alkyl, C2-10alkenyl, C2-10alkynyl, C3-12carbocycle, 3- to 12- membered heterocycle, and C1-10haloalkyl; and R9aand R9bare independently selected at each occurrence from hydrogen, C1- 10 alkyl, C2-10 alkenyl, C2-10 alkynyl, C3-12 carbocycle, and 3- to 12-membered heterocycle.

75. The conjugate of claim 74, of Formula (CONJ-IV): (CONJ-IV) 263 1104675906\1\AMERICAS Attorney Docket No.108843.00582 SU-0514WO or a pharmaceutically acceptable salt, stereoisomer, or tautomer thereof; wherein: RL01is a reactive linker residue; OSu is a release trigger group; SG01is absent or a divalent spacer group; Y is –X1a-C1-6 alkylene-[X1a-C1-6 alkylene]a1-[X1a]b1–, –X1a-C2-6 alkenylene- [X1a-C2-6alkenylene]a1-[X1a]b1–, or –X1a-C2-6alkynylene-[X1a-C2-6alkynylene]a1- [X1a]b1–, wherein at least one C1-6 alkylene, C2-6 alkenylene, or C2-6 alkynylene in Y is substituted with one or more substituents selected from R70; and -[X1a]b1- is attached to RL01; and wherein the C1-6alkylene, C2-6alkenylene, or C2-6alkynylene in Y is optionally substituted with one or more substituents selected from R71; R70is –C1-6 alkylene-X2a-[C1-6 alkylene]c1-HP2, –C2-6 alkenylene-X2a-[C2-6 alkenylene]c1-HP2, or –C2-6alkynylene-X2a-[C2-6alkynylene]c1-HP2, wherein each C1-6alkylene, C2-6 alkenylene, or C2-6 alkynylene of R70is optionally substituted with one or more substituents selected from halogen, -CN, -NO2, -OH, -NR60R61, - C(O)NR60R61, -C(O)-, -C(S)-, -C(O)OCH2C6H5, -NHC(O)OCH2C6H5, C1-10alkyl, C2-10alkenyl, C2-10alkynyl, C3-12carbocycle, 3- to 12-membered heterocycle, and C1-10haloalkyl; R71is independently selected from halogen, -CN, -NO2, -OH, -NR60R61, -C(O)NR60R61, -C(O)-, -C(S)-, -C(O)OCH2C6H5, -NHC(O)OCH2C6H5, C1-10alkyl, C2-10 alkenyl, C2-10 alkynyl, C3-12 carbocycle, 3- to 12-membered heterocycle, and C1-10 haloalkyl; X1aand X2aare independently selected from –N(R60)–, –C(O)–, and – N(R60)C(O)–; HP2is a monovalent hydrophilic group; R60and R61are independently selected at each occurrence from hydrogen, C1-10alkyl, C2-10 alkenyl, C2-10 alkynyl, C3-12 carbocycle, 3- to 12-membered heterocycle, and C1-10 haloalkyl; a1 is an integer selected from 0, 1, 2, and 3; b1 is an integer selected from 0 and 1; and c1 is an integer selected from 0 and 1. 264 1104675906\1\AMERICAS Attorney Docket No.108843.00582 SU-0514WO 76. The conjugate of claim 75, of Formula (CONJ-IVA): (CONJ-IVA) or a pharmaceutically acceptable salt, stereoisomer, or tautomer thereof.

77. The conjugate of claim 75, of Formula (CONJ-IVB): (CONJ-IVB) or a pharmaceutically acceptable salt, stereoisomer, or tautomer thereof.

78. The conjugate of any one of claims 69-77, wherein: R1is C1-10 alkyl optionally substituted with one or more substituents independently selected from R5; X1is O or NH; L1is C1-4 alkylene optionally substituted with one or more substituents independently selected from R5; and L2is -CH2- or -O-. 265 1104675906\1\AMERICAS Attorney Docket No.108843.00582 SU-0514WO 79. The conjugate of any one of claims 71-78, wherein W1is absent, .

80. The conjugate of any one of claims 71-78, wherein .

81. The conjugate of any one of claims 71-80, wherein represents attachment to the remainder of the compound.

82. The conjugate of any one of claims 71-81, wherein represents attachment to the remainder of the compound.

83. The conjugate of any one of claims 71-82, wherein W2is absent, -(C(O)CHR13NR11)a-, or (C(O)CH2CHR13NR11)b-; wherein R13is independently a residue of an amino acid sidechain optionally substituted with HP1; R11is independently hydrogen or C1-6 alkyl; each of a and b is independently an integer between 1 and 10, inclusive; and the -C(O)- of W2is bound to W1.

84. The conjugate of claim 83, wherein R13is a residue of an amino acid sidechain selected from valine, citrulline, alanine, glycine, and asparagine. 266 1104675906\1\AMERICAS Attorney Docket No.108843.00582 SU-0514WO 86. The conjugate of any one of claims 71-85, wherein SG is -C1-10 alkylene-C(O)- wherein the -C(O)- is bound to W2.

87. The conjugate of any one of claims 71-86, wherein HP is absent or wherein R20is hydrogen or methyl and x1 is an integer between 1 and 20, inclusive; and each is the point of attachment to the rest of the formula.

88. The conjugate of any one of claims 71-87, wherein HP is and x1 is an integer between 1 and 5, inclusive.

89. The conjugate of any one of claims 71-88, wherein RL is selected from 267 1104675906\1\AMERICAS Attorney Docket No.108843.00582 SU-0514WO is a point of attachment to the rest of the compound.

90. The conjugate of any one of claims 71-89, wherein RL is .

91. The conjugate of any one of claims 71-90, wherein is 92. The conjugate of any one of claims 74-91, wherein SG01is unsubstituted -C1-6 alkylene-.

93. The conjugate of any one of claims 74-92, wherein SG01is -CH2-, -CH2CH2-, or -CH2CH2CH2-.

94. The conjugate of any one of claims 74-93, wherein Y is –X1a-C1-6 alkylene-[X1a-C1-6 alkylene]a1-[X1a]b1–, wherein at least one alkylene in Y is substituted with one or more substituents selected from R70and wherein the alkylene in Y is optionally substituted with one or more substituents selected from R71.

95. The conjugate of any one of claims 74-94, wherein Y is –X1a-C1-4alkylene-[X1a-C1-4alkylene]a1-X1a–, wherein at least one alkylene in Y is substituted with one or more 268 1104675906\1\AMERICAS Attorney Docket No.108843.00582 SU-0514WO substituents selected from R70and wherein the alkylene in Y is optionally substituted with one or more substituents selected from R71.

96. The conjugate of any one of claims 74-95, wherein Y is –X1a-C1-4 alkylene-[X1a-C1-4 alkylene]2-X1a–, wherein at least one alkylene in Y is substituted with one or more substituents selected from R70and wherein the alkylene in Y is optionally substituted with one or more substituents selected from R71.

97. The conjugate of any one of claims 74-96, wherein Y is –NHC(O)-C1-4alkylene- [NHC(O)-C1-4 alkylene]2-C(O)–, wherein at least one alkylene in Y is substituted with one or more substituents selected from R70.

98. The conjugate of any one of claims 74-97, wherein R70is –C1-6alkylene-X2a-[C1-6alkylene]c1-HP2, wherein each alkylene of R70is optionally substituted with one or more substituents selected from halogen, -CN, -NO2, -OH, -NR60R61, -C(O)NR60R61, - C(O)-, -C(S)-, -C(O)OCH2C6H5, -NHC(O)OCH2C6H5, C1-10 alkyl, C2-10 alkenyl, C2-10 alkynyl, C3-12carbocycle, 3- to 12-membered heterocycle, and C1-10haloalkyl.

99. The conjugate of any one of claims 74-98, wherein R70is -C1-6 alkylene-X2a-C1-6 alkylene-HP2.

100. The conjugate of any one of claims 74-99, wherein R70is -C1-6alkylene-NHC(O)-C1-6alkylene-HP2.

101. The conjugate of any one of claims 74-100, wherein HP2is wherein R200is hydrogen or methyl and x20 is an integer between 1 and 50, inclusive; and each is the point of attachment to the rest of the compound.

102. The conjugate of any one of claims 74-101, wherein R200is hydrogen and x20 is an integer between 10 and 20, inclusive.

103. The conjugate of any one of claims 74-102, wherein CY is selected from the group consisting of an alkylating agent, a DNA-crosslinking agent, an anti-tumor antibiotic, an anti-metabolite, an anti-mitotic agent, a histone-deacetylase (HDAC) inhibitor, a telomerase inhibitor, an immunogenic cell death agent, a tubulin inhibitor, and a topoisomerase inhibitor. In certain embodiments, CY is selected from the group consisting of topoisomerase I inhibitor selected from the group consisting of camptothecin, irinotecan, SN-38, topotecan, and exatecan.

104. The conjugate of any one of claims 74-103, wherein CY is exatecan. 269 1104675906\1\AMERICAS Attorney Docket No.108843.00582 SU-0514WO 105. The conjugate of any one of claims 73-91, wherein selected from the group consisting of: 270 1104675906\1\AMERICAS Attorney Docket No.108843.00582 SU-0514WO 271 1104675906\1\AMERICAS Attorney Docket No.108843.00582 SU-0514WO 272 1104675906\1\AMERICAS Attorney Docket No.108843.00582 SU-0514WO 273 1104675906\1\AMERICAS Attorney Docket No.108843.00582 SU-0514WO 274 1104675906\1\AMERICAS Attorney Docket No.108843.00582 SU-0514WO 275 1104675906\1\AMERICAS Attorney Docket No.108843.00582 SU-0514WO 276 1104675906\1\AMERICAS Attorney Docket No.108843.00582 SU-0514WO 277 1104675906\1\AMERICAS Attorney Docket No.108843.00582 SU-0514WO 107. The conjugate of claim 75, wherein selected from the compounds of Table 278 1104675906\1\AMERICAS Attorney Docket No.108843.00582 SU-0514WO 108. The conjugate of claim 107, wherein selected from the compounds of Table mixture thereof. 279 1104675906\1\AMERICAS Attorney Docket No.108843.00582 SU-0514WO 109. The conjugate of claim 75, 107, or 108, of the structure: 280 1104675906\1\AMERICAS Attorney Docket No.108843.00582 SU-0514WO or a pharmaceutically acceptable salt, stereoisomer, or tautomer thereof.

110. The conjugate of any one of claims 71-109, wherein x is an integer selected from 1 to 10.

111. The conjugate of any one of claims 71-110, wherein x is an integer selected from 1 to 6.

112. The conjugate of any one of claims 74-111, wherein xx is an integer selected from 1 to 10.

113. The conjugate of any one of claims 74-112, wherein xx is an integer selected from 1 to 6.

114. The conjugate of any one of claims 71-113, wherein COMP is a polypeptide.

115. The conjugate of any one of claims 71-113, wherein COMP is an antibody or antigen-binding fragment thereof. 281 1104675906\1\AMERICAS Attorney Docket No.108843.00582 SU-0514WO 116. The conjugate of any one of claims 71-113, wherein COMP is an antibody chain.

117. A compound of Formula (CA-I): or a pharmaceutically acceptable salt, stereoisomer, or tautomer thereof; wherein: L is a linker; RL' is a residue resulting from the catabolism of -RL-COMP; L1is C1-6alkylene, C2-6alkenylene, or C2-6alkynylene, each of which is optionally substituted with one or more substituents independently selected from R5; L2is selected from -O-, -NR2-, C1-6 alkylene, -O-(C1-6 alkylene)-, and -NR2-(C1-6alkylene)- wherein the alkylene, either alone or part of another group, is optionally substituted with one or more one or more substituents independently selected from R5; R1is C1-10alkyl, C2-6alkenyl, or C2-6alkynyl, each of which is optionally substituted with one or more substituents independently selected from R5; R2is independently hydrogen or C1-6 alkyl; X1is bond, -O-, or -NR2-; Ring A is either (a) a bicyclic heterocycle optionally substituted with one or more R8; (b) a 3- to 5-membered heterocycle optionally substituted with one or more R4aand further optionally substituted with one or more R8; or (c) a 6- to 12-membered heterocycle substituted with R4band optionally substituted with one or more R8; Ring B is arylene or heteroarylene, each of which is optionally substituted with one or more R8; R4ais a 3- to 12-membered heterocycle optionally substituted with one or more R8; R4bis a bicyclic heterocycle optionally substituted with one or more R8; R5is independently selected from halogen, -OR6, -SR6, -C(O)N(R6)(R7), -N(R6)C(O)R7, -N(R6)C(O)N(R6)(R7), -N(R6)(R7), -C(O)R6, -C(O)OR6, -OC(O)R6, - NO2, =O, =S, =N(R6), -CN, C3-12 carbocycle, and 3- to 12-membered heterocycle; 282 1104675906\1\AMERICAS Attorney Docket No.108843.00582 SU-0514WO R6and R7are independently selected at each occurrence from hydrogen, C1-10alkyl, C2-10 alkenyl, C2-10 alkynyl, C3-12 carbocycle, and 3- to 12-membered heterocycle each of which, except hydrogen, is optionally substituted with one or more R9; R8is independently selected from halogen, -OR6, -SR6, -C(O)N(R6)(R7), -N(R6)C(O)R7, -N(R6)C(O)N(R6)(R7), -N(R6)(R7), -C(O)R6, -C(O)OR6, -OC(O)R6, - NO2, =O, =S, =N(R6), -CN, C1-6alkyl, C2-6alkenyl, C2-6alkynyl, C3-12carbocycle, and 3- to 12-membered heterocycle wherein the C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C3- 12 carbocycle, and 3- to 12-membered heterocycle are optionally substituted with one or more R9; R9is independently selected at each occurrence from halogen, -CN, -NO2, -OH, -NR9aR9b, -C(O)NR9aR9b, =O, =S, C1-10 alkyl, C2-10 alkenyl, C2-10 alkynyl, C3-12 carbocycle, 3- to 12- membered heterocycle, and C1-10 haloalkyl; and R9aand R9bare independently selected at each occurrence from hydrogen, C1-10 alkyl, C2-10 alkenyl, C2-10 alkynyl, C3-12 carbocycle, and 3- to 12-membered heterocycle.

118. The compound of claim 117, of Formula (CA-II): or a pharmaceutically acceptable salt, stereoisomer, or tautomer thereof; wherein: SG is absent or a divalent spacer group; W1is absent, wherein the -NH- is bound to W2and each indicates a point of attachment to the rest of the formula; 283 1104675906\1\AMERICAS Attorney Docket No.108843.00582 SU-0514WO L3is independently a bond or C1-6alkylene optionally substituted with one, two, or three substituents selected from halogen, C1-6 alkyl, haloC1-6 alkyl, hydroxyl, amino, C1-6 alkylamino, and C1-6 alkoxy; R11is independently hydrogen or C1-6alkyl; R12is independently a residue of an amino acid sidechain; w is an integer selected from 0, 1, and 2; W2is absent, an amino acid residue, or a peptide residue wherein the amino acid residue or peptide residue is optionally substituted with a HP1group; HP is absent or a divalent hydrophilic group; HP1, when present, is a monovalent hydrophilic group; each RAis independently, at each occurrence, C1-6alkyl optionally substituted with one, two, or three substituents selected from halogen, haloC1-6 alkyl, hydroxyl, amino, alkylC1-6 amino, and C1-6 alkoxy; each O-Su is independently, at each occurrence, a release trigger group; each y is an integer independently selected from 0, 1, and 2; and each z is an integer independently selected from 0 and 1.

119. The compound of claim 118, of Formula (CA-IIA): or a pharmaceutically acceptable salt, stereoisomer, or tautomer thereof; wherein: X2and X3are independently selected from N and CR3; and R3is independently hydrogen, –OR6, -SR6, -C(O)N(R6)(R7), -N(R6)C(O)R7, -N(R6)C(O)N(R6)(R7), -N(R6)(R7), -C(O)R6, -C(O)OR6, -OC(O)R6, -NO2, or -CN.

120. The compound of any one of claims 117-119, wherein RL' is .

121. The compound of claim 119, wherein the compound is selected from: 284 1104675906\1\AMERICAS Attorney Docket No.108843.00582 SU-0514WO 285 1104675906\1\AMERICAS Attorney Docket No.108843.00582 SU-0514WO 122. A pharmaceutical composition comprising a compound of any one of claims 1-48 or a conjugate of any one of claims 71-116 and pharmaceutically carrier.

123. A method of treating or preventing a disease, disorder, or condition in a subject in need thereof comprising administering a compound of any one of claims 1- 48, a conjugate of any one of claims 71-116, or a pharmaceutical composition of claim 122.

124. A method of diagnosing a disease, disorder, or condition in a subject in need thereof comprising administering a compound of any one of claims 1-48, a conjugate of any one of claims 71-116, or a pharmaceutical composition of claim 122.

125. The method of claim 123 or 124, wherein the disease, disorder, or condition is cancer.

126. The method of claim 123 or 124, wherein the disease, disorder, or condition is an inflammatory disease, disorder, or condition.

127. A method for promoting the activation of Toll-like receptor 7 in a subject in need thereof comprising administering a compound of any one of claims 1-48, a conjugate of any one of claims 71-116, or a pharmaceutical composition of claim 122.

128. A method of inducing or modulating the immune system in a subject in need thereof comprising administering a compound of any one of claims 1-48, a conjugate of any one of claims 71-116, or a pharmaceutical composition of claim 122.

129. A method of treating abnormal cellular proliferation in a subject in need thereof administering a compound of any one of claims 1-48, a conjugate of any one of claims 71-116, or a pharmaceutical composition of claim 122.

130. The method of claim 127, wherein the abnormal cellular proliferation is cancer.

131. The method of any one of claims 123-130, further comprising administering an additional therapeutic agent.

132. The method of claim 131, wherein the additional therapeutic agent is a chemotherapeutic agent, hormonal agent, antitumor agent, immunostimulatory agent, immunomodulator, an immunotherapeutic agent, or combination thereof.

133. Use of a compound of any one of claims 1-48, a conjugate of any one of claims 71-116, or a pharmaceutical composition of claim 122 for treating or preventing a disease, disorder, or condition in a subject in need thereof. 286 1104675906\1\AMERICAS Attorney Docket No.108843.00582 SU-0514WO 134. Use of a compound of any one of claims 1-48, a conjugate of any one of claims 71-116, or a pharmaceutical composition of claim 122 for diagnosing a disease, disorder, or condition in a subject in need thereof.

135. The use of claim 133 or 134, wherein the disease, disorder, or condition is cancer.

136. The use of claim 133 or 134, wherein the disease, disorder, or condition is an inflammatory disease, disorder, or condition.

137. Use of a compound of any one of claims 1-48, a conjugate of any one of claims 71-116, or a pharmaceutical composition of claim 122 for promoting the activation of Toll-like receptor 7 in a subject in need thereof.

138. Use of a compound of any one of claims 1-48, a conjugate of any one of claims 71-116, or a pharmaceutical composition of claim 122 for inducing or modulating the immune system in a subject in need thereof.

139. Use of a compound of any one of claims 1-48, a conjugate of any one of claims 71-116, or a pharmaceutical composition of claim 122 for treating abnormal cellular proliferation in a subject in need thereof.

140. The use of claim 139, wherein the abnormal cellular proliferation is cancer.

141. The use of any one of claims 133-141, further comprising administering an additional therapeutic agent.

142. The use of claim 141, wherein the additional therapeutic agent is a chemotherapeutic agent, hormonal agent, antitumor agent, immunostimulatory agent, immunomodulator, an immunotherapeutic agent, or combination thereof.

143. A method of producing a conjugate of any one of claims 71-116, comprising contacting a linker-payload of any of claims 49-66 with COMP under conditions suitable for conjugation.

144. A method of producing a conjugate of any one of claims 74-104 and 107-116, comprising (1) contacting a linker-payload of any of claims 49-66 with COMP under conditions suitable for conjugation to afford a conjugate and (2) contacting a linker- payload the COMP of the conjugate under conditions suitable for conjugation to afford a conjugate; 287 1104675906\1\AMERICAS Attorney Docket No.108843.00582 SU-0514WO wherein RG is a reactive group; CY is a residue of cytotoxic agent; OSu is a release trigger group; SG01is absent or a divalent spacer group; Y is –X1a-C1-6 alkylene-[X1a-C1-6 alkylene]a1-[X1a]b1–, –X1a-C2-6 alkenylene- [X1a-C2-6alkenylene]a1-[X1a]b1–, or –X1a-C2-6alkynylene-[X1a-C2-6alkynylene]a1- [X1a]b1–, wherein at least one C1-6 alkylene, C2-6 alkenylene, or C2-6 alkynylene in Y is substituted with one or more substituents selected from R70; and -[X1a]b1- is attached to RL01; and wherein the C1-6alkylene, C2-6alkenylene, or C2-6alkynylene in Y is optionally substituted with one or more substituents selected from R71; R70is –C1-6 alkylene-X2a-[C1-6 alkylene]c1-HP2, –C2-6 alkenylene-X2a-[C2-6 alkenylene]c1-HP2, or –C2-6alkynylene-X2a-[C2-6alkynylene]c1-HP2, wherein each C1-6alkylene, C2-6 alkenylene, or C2-6 alkynylene of R70is optionally substituted with one or more substituents selected from halogen, -CN, -NO2, -OH, -NR60R61, - C(O)NR60R61, -C(O)-, -C(S)-, -C(O)OCH2C6H5, -NHC(O)OCH2C6H5, C1-10alkyl, C2-10alkenyl, C2-10alkynyl, C3-12carbocycle, 3- to 12-membered heterocycle, and C1-10haloalkyl; R71is independently selected from halogen, -CN, -NO2, -OH, -NR60R61, -C(O)NR60R61, -C(O)-, -C(S)-, -C(O)OCH2C6H5, -NHC(O)OCH2C6H5, C1-10alkyl, C2-10 alkenyl, C2-10 alkynyl, C3-12 carbocycle, 3- to 12-membered heterocycle, and C1-10 haloalkyl; X1aand X2aare independently selected from –N(R60)–, –C(O)–, and – N(R60)C(O)–; HP2is a monovalent hydrophilic group; R60and R61are independently selected at each occurrence from hydrogen, C1-10alkyl, C2-10 alkenyl, C2-10 alkynyl, C3-12 carbocycle, 3- to 12-membered heterocycle, and C1-10 haloalkyl; a1 is an integer selected from 0, 1, 2, and 3; b1 is an integer selected from 0 and 1; and c1 is an integer selected from 0 and 1. 288 1104675906\1\AMERICAS

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