TW202506691A - Sting agonist compounds and conjugates thereof - Google Patents

Abstract

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

Description

STING agonist compounds and conjugates thereof

The present invention relates to STING agonist compounds, including drug-linker compounds, ligand-drug conjugate compounds, methods of use and formulations thereof.

A variety of ligands have been investigated for targeted delivery of cytotoxic agents to tumor cells, including oligopeptides, antibodies, and other proteins. Although a variety of drug classes have been evaluated for targeted delivery via these ligands, only a few have demonstrated sufficient activity as ligand-drug conjugates, while possessing an appropriate toxicity profile and other pharmacological properties, to warrant clinical development. Therefore, there is a need for additional molecules with improved toxicity profiles and other pharmacological properties.

The cGAS-STING pathway is an innate immune pathway that recognizes intracellular DNA and triggers type I interferon and inflammatory interferon responses that are important for both antiviral and anti-tumor immunity. After DNA binding, cGMP-AMP synthase (cGAS) produces cGAMP, which is the endogenous ligand of STING. See, e.g., Villaneuva, Nat. Rev. Drug Disc. 2019: 18; 15. At the molecular level, after activation by cGAMP, the transmembrane STING dimer translocates from the endoplasmic reticulum to the Golgi apparatus, ultimately recruiting TANK-binding kinase 1 (TBK1) and the transcription factor interferon regulatory factor 3 (IRF3), thereby inducing type I interferons (IFNs) and inflammatory responses. See Konno et al., Cell 2013: 155; 688-698. This innate immune pathway must be tightly regulated, as excessive cGAS-STING activity has led to a variety of autoimmune and inflammatory disorders. See Barber, Nat. Rev. Immunol. 2015: 15; 760-770; see also Liu et al., N. Engl. J. Med. 2014: 371; 507-518.

Exogenous STING agonists can help overcome the immunosuppressive tumor microenvironment by activating immune responses against tumors, leading to tumor regression. See Sun et al., Science 2013: 6121; 786-791; see also Corrales and Gajewski, Clinc. Cancer Res. 2015: 21; 4774-4779. Examples include nucleotide-based STING agonists, which are cyclic dinucleotides similar to endogenous ligands. These compounds are typically charged and hydrophilic, susceptible to enzymatic degradation, and have poor bioavailability and pharmacokinetics. Therefore, there is still a need for STING agonists with improved pharmacological properties and avoiding systemic interleukin induction.

Provided herein is a compound of formula (A): , Formula (A) or a pharmaceutically acceptable salt thereof, wherein L ¹ is or ; X ¹ is N or CR ^1X ; Y ¹ is N or CR ^1Y ; Z ¹ , Y ² and Z ² are each independently N, CH or CF; X ² is N or CR ^2X ; X ³ is N or CR ^3X ; T ⁴ is N, S, O or CH; X ⁴ is C or N; Y ⁴ is N, NR ^4Y or CR ^4Y ; Z ⁴ is N, S, O, CF or CH; R ¹ is C ₁ -C ₆ alkyl, C ₃ -C ₈ cycloalkyl or C ₁ -C ₆ halogenalkyl; wherein at least one of X ¹ , Y ¹ and X ³ is not N; R ^1X , R ^1Y and R ^3X are each independently H, -OH, halogen, optionally substituted C ₁ -C ₆ alkyl, -O(C ₁ -C ₆ alkyl) or , wherein no more than one of R ^1X , R ^1Y and R ^3X is ; wherein the wavy line indicates the point of attachment to the rest of the compound; ^Xa and ^Xb are independently H, ^OH , ^SH , _CO2R4 or ^NR4R5 , or ^Xa and ^Xb together with the carbon atom to which they are attached form wherein the asterisk (*) represents the carbon atom to which ^Xa and ^Xb are attached, ^Xc is H, a halogen group or an optionally substituted _C1 - _C6 alkyl group; q is an integer from 0 to 6; n is 0, 1 or 2; m is 1 or 2; ^R8 and ^R9 are each independently H, a halogen group, CN, SH, OH, _CO2H , ^NR4R5 or ^an optionally substituted _C1 - _C6 alkyl group with OH, a halogen group or _CO2H ; ^R10 is H or an optionally substituted C1-C6 alkyl group with OH, a halogen group, ^NR4R5 or _CO2R4 ^{; R2X} is H, a halogen group, a _C1 - _C6 alkyl group, a _C3 - _C6 cycloalkyl group or a _C1 - _C6 halogen group; ^R4Y is H, a halogen group, a _{C1-C6 alkyl group or a C3} ^- _{C6 cycloalkyl} group; C ₆ alkyl, C ₁ -C ₆ halogenalkyl or C ₃ -C ₆ cycloalkyl; T is C(O)NR ⁴ R ⁵ or S(O) ₂ NR ⁶ R ⁷ ; R ⁴ , R ⁵ , R ⁶ and R ⁷ are independently and independently H or optionally substituted C ₁ -C ₆ alkyl at each occurrence; the virtual bonds of formula (A) are each independently single or double bonds, so that the ring with the virtual bonds is an aromatic ring; and Ring A is , or , where the wavy line indicates the point of attachment to the rest of the compound; The restriction is that when L ¹ is , Ring A is , X ¹ is CR ^1X , Y ¹ is CH , Z ¹ is CH , Z ² is CH , and X ² is N , then T ⁴ , X ⁴ , Y ⁴ , Z ⁴ and R ¹ cannot be simultaneously selected such that T ⁴ is CH , X ⁴ is C , Y ⁴ is NR ^4Y , Z ⁴ is N , and R ¹ is an optionally substituted methyl group.

In some embodiments, the compound of formula (A) is a compound of formula (I): , Formula (I) or a pharmaceutically acceptable salt thereof, wherein X ¹ is N or CR ^1X ; Y ¹ is N or CR ^1Y ; Z ¹ , Y ² and Z ² are each independently N, CH or CF; X ² is N or CR ^2X ; X ³ is N or CR ^3X ; T ⁴ is N, S, O or CH; X ⁴ is C or N; Y ⁴ is N, NR ^4Y or CR ^4Y ; Z ⁴ is N, S, O, CF or CH; R ¹ is C ₁ -C ₆ alkyl, C ₃ -C ₈ cycloalkyl or C ₁ -C ₆ halogenalkyl; wherein at least one of X ¹ , Y ¹ and X ³ is not N; R ^1X , R ^1Y and R ^3X are each independently H, -OH, halogen, optionally substituted C ₁ -C ₆ alkyl, -O(C ₁ -C ₆ alkyl) or , wherein no more than one of R ^1X , R ^1Y and R ^3X is ; wherein the wavy line indicates the point of attachment to the rest of the compound; ^Xa and ^Xb are independently H, ^OH , ^SH , _CO2R4 or ^NR4R5 , or ^Xa and ^Xb together with the carbon atom to which they are attached form wherein the asterisk (*) represents the carbon atom to which ^Xa and ^Xb are attached, ^Xc is H, a halogen group or an optionally substituted _C1 - _C6 alkyl group; q is an integer from 0 to 6; n is 0, 1 or 2; m is 1 or 2; ^R8 and ^R9 are each independently H, a halogen group, CN, SH, OH, _-CO2H , ^NR4R5 or ^an optionally substituted _C1 - _C6 alkyl group by -OH, a halogen group or _-CO2H ; ^R10 is H or an optionally substituted C1-C6 alkyl group by OH, a halogen group, ^NR4R5 or _CO2R4 ^{; R2X} is H, a halogen group, a _C1 - _C6 alkyl group, a _C3 - _C6 cycloalkyl group or a _C1 - _C6 halogen group; ^R4Y is H, a halogen group, a _{C1-C6 alkyl group or a C3} ^- _{C6 cycloalkyl} group; C ₆ alkyl, C ₁ -C ₆ halogenalkyl or C ₃ -C ₆ cycloalkyl; T is C(O)NR ⁴ R ⁵ or S(O) ₂ NR ⁶ R ⁷ ; R ⁴ , R ⁵ , R ⁶ and R ⁷ are independently and independently H or optionally substituted C ₁ -C ₆ alkyl at each occurrence; the virtual bonds of formula (I) are each independently single or double bonds, so that the ring with the virtual bonds is an aromatic ring; and Ring A is , or , where the wavy line indicates the point of attachment to the rest of the compound; the restriction is that when Ring A is , X ¹ is CR ^1X , Y ¹ is CH , Z ¹ is CH , Z ² is CH , and X ² is N , then T ⁴ , X ⁴ , Y ⁴ , Z ⁴ and R ¹ cannot be simultaneously selected such that T ⁴ is CH , X ⁴ is C , Y ⁴ is NR ^4Y , Z ⁴ is N , and R ¹ is an optionally substituted methyl group.

In some embodiments of Formula (I), T is C(O)NR ⁴ R ⁵ . In some embodiments, T is C(O)NH ₂ .

In some embodiments of formula (I), X ³ is CR ^3X . In some embodiments, X ³ is N.

In some embodiments of formula (I), X ⁴ is C, T ⁴ is O, Z ⁴ is N, and Y ⁴ is CR ^4Y ; or X ⁴ is C, T ⁴ is S, Z ⁴ is N, and Y ⁴ is CR ^4Y ; or X ⁴ is C, T ⁴ is N, Z ⁴ is N, and Y ⁴ is NR ^4Y . In some embodiments, X ⁴ is C, T ⁴ is O, Z ⁴ is N, and Y ⁴ is CR ^4Y . In some embodiments, X ⁴ is C, T ⁴ is S, Z ⁴ is N, and Y ⁴ is CR ^4Y . In some embodiments, X ⁴ is C, T ⁴ is N, Z ⁴ is N, and Y ⁴ is NR ^4Y . In some embodiments, R ¹ is methyl and R ^4Y is ethyl. In some embodiments, Y ² is N. In some embodiments, ^X2 is N, ^Z1 is CH, and ^Z2 is CH.

In some embodiments of formula (I), ^X1 is ^CR1X and ^Y1 is ^CR1Y . In some embodiments, ^X1 is ^CR1X and ^Y1 is N. In some embodiments, ^X1 is N and ^Y1 is ^CR1Y . In some embodiments, ^X2 is ^CR2X , ^Z2 is N, ^X1 is ^CR1X , ^Y1 is ^CR1Y , and ^Z1 is CH.

In some embodiments of formula (I), exactly one of R ^1X , R ^1Y and R ^3X is -OH or and the remainder of R ^1X , R ^1Y and R ^3X , when present, are each independently H or -OC ₁ -C ₆ alkyl. In some embodiments, exactly one of R ^1X , R ^1Y and R ^3X is -OH and the remainder of R ^1X , R ^1Y and R ^3X , when present, are each independently H or -OC ₁ -C ₆ alkyl. In some embodiments, exactly one of R ^1X , R ^1Y and R ^3X is -OCH ₂ CH ₂ CH ₂ OH and the remainder of R ^1X , R ^1Y and R ^3X , when present, are each independently H or -OC ₁ -C ₆ alkyl. In some embodiments, exactly one of R ^1X , R ^1Y and R ^3X is and the remaining parts of R ^1X , R ^1Y and R ^3X , when present, are each independently H or -OC ₁ -C ₆ alkyl. In some embodiments, Ring A is In some embodiments, Ring A is In some embodiments, Ring A is .

In some embodiments of formula (I), the compound is , , , , , , or , or a pharmaceutically acceptable salt thereof.

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

In another embodiment, provided herein is a drug-linker compound of the formula: QD, or a pharmaceutically acceptable salt thereof, wherein Q is a linker unit selected from the group consisting of: (i) Z'-A-RL-, (ii) Z'-A-RL-Y-, (iii) Z'-AS ^* -RL-, (iv) Z'-AS ^* -RL-Y-, (v) Z'-AB(S ^* )-RL-, (vi) Z'-AB(S ^* )-RL-Y-, (vii) Z'-A-, (viii) Z'-AS *-W-, (ix) Z'-AB(S *)-W-, (x) Z'-AS *-W-RL-, and (xi) Z'-AB(S *)-W-RL-; Z' is a stretcher unit precursor; A is a bond or linker unit; B is a parallel linker unit; S* is a separator; RL is a releasable linker; W is an amino acid unit; Y is a second spacer unit; and D is a drug unit of formula (A'): , Formula (A') wherein L ¹ is or ; X ¹ is N or CR ^1X ; Y ¹ is N or CR ^1Y ; Z ¹ , Y ² and Z ² are each independently N, CH or CF; X ² is N or CR ^2X ; X ³ is N or CR ^3X ; T ⁴ is N, S, O or CH; X ⁴ is C or N; Y ⁴ is N, NR ^4Y or CR ^4Y ; Z ⁴ is N, S, O, CF or CH; R ¹ is C ₁ -C ₆ alkyl, C ₃ -C ₈ cycloalkyl or C ₁ -C ₆ halogenalkyl; wherein at least one of X ¹ , Y ¹ and X ³ is not N; R ^1X , R ^1Y and R ^3X are each independently H, -OH, halogen, optionally substituted C ₁ -C ₆ alkyl, -O(C ₁ -C ₆ alkyl) or -S ¹ -#, the restriction is that exactly one of R ^1X , R ^1Y and R ^3X is -S ¹ -#, -S ¹ -# is or , wherein the wavy line indicates the point of attachment to the remainder of D and # represents the point of attachment to Q; ^Xc is H, halogen, or optionally substituted _C1 - _C6 alkyl; q is an integer from 0 to 6; n is 0, 1 or 2; m is 1 or 2; ^R8 and ^R9 are each independently H, ^halogen , CN, SH, OH, _CO2H , ^NR4R5 , or _C1 - _C6 alkyl substituted with OH, halogen, or _CO2H ; ^R10 is C1- _C6 ^alkyl substituted with OH, ^halogen , ^NR4R5 , or _CO2R4 , or ^R10 is absent; ^R2X is H, halogen, _C1 - _{C6 alkyl} , _C3 - _C6 cycloalkyl, or _C1 - _C6 halogenalkyl; R ^4Y is H, halogen, C ₁ -C ₆ alkyl, C ₁ -C ₆ halogenalkyl or C ₃ -C ₆ cycloalkyl; T is -C(O)NR ⁴ R ⁵ or -S(O) ₂ NR ⁶ R ⁷ ; R ⁴ , R ⁵ , R ⁶ and R ⁷ are independently and independently H or optionally substituted C ₁ -C ₆ alkyl at each occurrence; the dummy bonds of formula (A') are each independently single or double bonds, such that the ring with the dummy bonds is an aromatic ring; and Ring A is , or , where the wavy line indicates the point of attachment to the rest of the compound; The restriction is that when L ¹ is , Ring A is , X ¹ is CR ^1X , Y ¹ is CH , Z ¹ is CH , Z ² is CH , and X ² is N , then T ⁴ , X ⁴ , Y ⁴ , Z ⁴ and R ¹ cannot be simultaneously selected such that T ⁴ is CH , X ⁴ is C , Y ⁴ is NR ^4Y , Z ⁴ is N , and R ¹ is an optionally substituted methyl group.

In another embodiment, provided herein is a drug-linker compound of the formula: QD, or a pharmaceutically acceptable salt thereof, wherein Q is a linker unit selected from the group consisting of: (i) Z'-A-RL-, (ii) Z'-A-RL-Y-, (iii) Z'-AS ^* -RL-, (iv) Z'-AS ^* -RL-Y-, (v) Z'-AB(S ^* )-RL-, (vi) Z'-AB(S ^* )-RL-Y-, (vii) Z'-A-, (viii) Z'-AS *-W-, (ix) Z'-AB(S *)-W-, (x) Z'-AS *-W-RL-, and (xi) Z'-AB(S *)-W-RL-; Z' is a stretcher unit precursor; A is a bond or linker unit; B is a parallel linker unit; S* is a separator; RL is a releasable linker; W is an amino acid unit; Y is a second spacer unit; and D is a drug unit of formula (I'): , Formula (I') wherein X ¹ is N or CR ^1X ; Y ¹ is N or CR ^1Y ; Z ¹ , Y ² and Z ² are each independently N, CH or CF; X ² is N or CR ^2X ; X ³ is N or CR ^3X ; T ⁴ is N, S, O or CH; X ⁴ is C or N; Y ⁴ is N, NR ^4Y or CR ^4Y ; Z ⁴ is N, S, O, CF or CH; R ¹ is C ₁ -C ₆ alkyl, C ₃ -C ₈ cycloalkyl or C ₁ -C ₆ halogenalkyl; wherein at least one of X ¹ , Y ¹ and X ³ is not N; R ^1X , R ^1Y and R ^3X are each independently H, -OH, halogen, optionally substituted C ₁ -C ₆ alkyl, -O(C ₁ -C ₆ alkyl) or -S ¹ -#, with the proviso that exactly one of R ^1X , R ^1Y and R ^3X is -S ¹ -#, -S ¹ -# is or , wherein the wavy line indicates the point of attachment to the remainder of D and # represents the point of attachment to Q; ^Xc is H, halogen, or optionally substituted _C1 - _C6 alkyl; q is an integer from 0 to 6; n is 0, 1 or 2; m is 1 or 2; ^R8 and ^R9 are each independently H, ^halogen , CN, SH, OH, _CO2H , ^NR4R5 , or _C1 - _C6 alkyl substituted with OH, halogen, or _CO2H ; ^R10 is C1- _C6 ^alkyl substituted with OH, ^halogen , ^NR4R5 , or _CO2R4 , or ^R10 is absent; ^R2X is H, halogen, _C1 - _{C6 alkyl} , _C3 - _C6 cycloalkyl, or _C1 - _C6 halogenalkyl; R ^4Y is H, halogen, C ₁ -C ₆ alkyl, C ₁ -C ₆ halogenalkyl or C ₃ -C ₆ cycloalkyl; T is -C(O)NR ⁴ R ⁵ or -S(O) ₂ NR ⁶ R ⁷ ; R ⁴ , R ⁵ , R ⁶ and R ⁷ are independently and independently H or optionally substituted C ₁ -C ₆ alkyl at each occurrence; the virtual bonds of formula (I') are each independently single or double bonds, so that the ring with the virtual bonds is an aromatic ring; and Ring A is , or , where the wavy line indicates the point of attachment to the rest of the compound; the restriction is that when Ring A is , X ¹ is CR ^1X , Y ¹ is CH , Z ¹ is CH , Z ² is CH , and X ² is N , then T ⁴ , X ⁴ , Y ⁴ , Z ⁴ and R ¹ cannot be simultaneously selected such that T ⁴ is CH , X ⁴ is C , Y ⁴ is NR ^4Y , Z ⁴ is N , and R ¹ is an optionally substituted methyl group.

In some embodiments, the linker unit Q has formula (i), (ii), (iii), (iv), (x) or (xi). In some embodiments, the linker unit Q has formula (v), (vi), (ix) or (xi). In some embodiments, the linker unit Q has formula (viii), (ix), (x) or (xi).

In some embodiments, the extension unit Z' is wherein R ¹⁷ is -CH ₂ CH ₂ (OCH ₂ CH ₂ ) _k -, -C ₁ -C ₁₀ alkylene-, C ₁ -C ₁₀ heteroalkylene-, -C ₃ -C ₈ carbocyclyl-, -O-(C 1 -C ₈ alkylene)-, -arylene-, -C ₁ -C ₁₀ alkylene-arylene-, -arylene-C ₁ -C ₁₀ alkylene-, -C ₁ -C ₁₀ alkylene-(C ₃ -C ₈ carbocyclyl)-, -(C ₃ -C ₈ carbocyclyl)-C ₁ -C ₁₀ alkylene-, -C _{3 -C 8} heterocyclyl-, -C ₁ -C ₁₀ alkylene-(C ₃ -C ₈ heterocyclyl)-, -(C ₃ -C 8 _{-C 1 -C 10} alkylene-, -C ₁ -C ₁₀ alkylene-C(=O)-, C ₁ -C ₁₀ heteroalkylene-C(=O)-, -C ₃ -C ₈ carbocyclyl-C(=O)-, -O-(C ₁ -C ₈ alkylene)-C(=O)-, -arylene-C(=O)-, -C ₁ -C ₁₀ alkylene-arylene-C(=O)-, -arylene-C ₁ -C ₁₀ alkylene-C(=O)-, -C ₁ -C ₁₀ alkylene-(C ₃ -C ₈ carbocyclyl)-C(=O)-, -(C ₃ -C ₈ carbocyclyl)-C ₁ -C ₁₀ alkylene-C(=O)-, -C ₃ -C 8 -C ₁ -C ₁₀ alkylene-(C ₃ -C _{8 heterocyclic} group)-C(=O)-, -(C ₃ -C ₈ heterocyclic group)-C 1 -C 10 alkylene-C(=O)-, -C ₁ -C ₁₀ alkylene-NH-, C ₁ -C ₁₀ heteroalkylene-NH-, -C ₃ -C ₈ carbocyclic group-NH-, -O-(C ₁ -C ₈ alkylene)-NH-, -arylene-NH-, -C 1 -C 10 alkylene-arylene-NH-, -arylene-C 1 -C 10 alkylene-NH-, -C ₁ -C ₁₀ alkylene-(C 3 -C ₈ carbocyclic group)-NH-, -O-(C ₁ -C 8 alkylene)-NH-, -arylene-NH-, -C ₁ -C ₁₀ alkylene-arylene-NH-, -arylene-C ₁ -C ₁₀ alkylene-NH-, -C ₁ -C 10 alkylene-(C ₃ -C ₈ carbocyclic group)-NH-, - -C ₈ carbocyclyl)-C ₁ -C ₁₀ alkylene-NH-, -C ₃ -C ₈ heterocyclyl-NH-, -C ₁ -C ₁₀ alkylene-(C ₃ -C ₈ heterocyclyl)-NH-, -(C ₃ -C ₈ heterocyclyl)-C ₁ -C ₁₀ alkylene-NH-, -C ₁ -C ₁₀ alkylene-S-, C ₁ -C ₁₀ heteroalkylene-S-, -C ₃ -C ₈ carbocyclyl-S-, -O-(C ₁ -C ₈ alkylene)-S-, -arylene-S-, -C ₁ -C ₁₀ alkylene-arylene-S-, -arylene-C ₁ -C ₁₀ alkylene-S-, -C ₁ -C ₁₀ alkylene-(C ₃ -C 8 heterocyclyl)- -(C ₃ -C ₈ carbocyclyl)-S-, -(C 3 -C ₈ carbocyclyl)-C ₁ -C ₁₀ alkylene-S-, -C ₃ -C ₈ heterocyclyl-S-, -C ₁ -C ₁₀ alkylene-(C ₃ -C ₈ heterocyclyl)-S- or -(C ₃ -C ₈ heterocyclyl)-C ₁ -C ₁₀ alkylene-S-; subscript k is an integer ranging from 1 to 36; R ¹⁷ is optionally substituted by a basic unit (BU), such as an aminoalkyl moiety, for example -(CH ₂ ) _x NH ₂ , -(CH ₂ ) _x NHR ^a and -(CH ₂ ) _x NR ^a ₂ , wherein x is an integer of 1-4 and each ^Ra is independently selected from the group consisting of C _1-6 alkyl and C The wavy line indicates the point of covalent attachment _to the remainder of the ^drug -linker compound.

In some embodiments, the extension unit Z' is , where the wavy line indicates the point of covalent attachment to the remainder of the drug-linker compound.

In some embodiments, the connector unit A is , wherein each R ¹⁰⁰ is independently hydrogen or -C ₁ -C ₃ alkyl; R ¹¹¹ is independently selected from the group consisting of hydrogen, p-hydroxybenzyl, methyl, isopropyl, isobutyl, dibutyl, -CH ₂ OH, -CH(OH)CH ₃ , -CH ₂ CH ₂ SCH ₃ , -CH ₂ CONH ₂ , -CH ₂ COOH, -CH ₂ CH ₂ CONH ₂ , -CH ₂ CH ₂ COOH, -(CH ₂ ) ₃ NHC(=NH)NH ₂ , -(CH ₂ ) ₃ NH ₂ , -(CH ₂ ) ₃ NHCOCH ₃ , -(CH ₂ ) ₃ NHCHO, -(CH ₂ ) ₄ NHC(=NH)NH ₂ , -(CH ₂ ) ₄ NH ₂ 、-(CH ₂ ) ₄ NHCOCH ₃ 、 -(CH ₂ ) ₄ NHCHO、-(CH ₂ ) ₃ NHCONH ₂ 、-(CH ₂ ) ₄ NHCONH ₂ 、 -CH ₂ CH ₂ CH(OH)CH ₂ NH ₂ 、2-pyridylmethyl-、3-pyridylmethyl-、4-pyridylmethyl-、 ; Each subscript c is an integer independently selected from 1 to 10; and the wavy line indicates that the linker unit is connected to the rest of the drug-linker compound.

In some embodiments, the connector unit A is ; c is an integer ranging from 1 to 6; and the wavy line indicates the site of attachment to the remainder of the drug-linker compound or a pharmaceutically acceptable salt thereof.

In some embodiments, A is a key.

In some embodiments, B is ; Each AA is independently a proteinogenic amino acid or a non-proteinogenic amino acid; and the wavy line indicates the point of attachment to the remainder of the drug-linker compound or a pharmaceutically acceptable salt thereof.

In some embodiments, B is an amino acid. In some embodiments, B is or ; The wavy line indicates the point of attachment to the spacer S*; and the asterisk indicates the point of attachment to the rest of the drug-linker structure.

In some embodiments, the spacer S* is a polyethylene glycol (PEG) unit, a cyclodextrin unit, a polyamide, a hydrophilic peptide, a polysaccharide, or a dendrimer. In some embodiments, the spacer S ^* is a PEG unit comprising 4 to 72 (CH ₂ CH ₂ O) subunits. In some embodiments, the PEG unit is ; b is selected from the group consisting of 4 to 36; and the wavy line indicates the site of attachment to the remainder of the drug-linker compound or a pharmaceutically acceptable salt thereof.

In some embodiments, the releasable linker RL is -(AA) _1-12 -; and each AA is independently a proteinogenic amino acid or a non-proteinogenic amino acid.

In some embodiments, the releasable connector RL is -AA ₁ -AA ₂ - or -AA ₁ -AA ₂ -AA ₃ -, wherein AA ₁ is connected to the extension unit Z' or the connector unit A. In some embodiments, the releasable connector RL is or ; and the wavy line adjacent to the -NH- group indicates connection to the stretcher unit Z' or the linker unit A and the wavy line adjacent to the -C(=O)- group indicates connection to the second spacer unit Y or the drug unit D.

In some embodiments, the releasable linker RL is a glycoside. In some embodiments, the releasable linker RL is wherein Su is a 6-carbon carbohydrate moiety; O' represents an oxygen atom of a glycosidic bond capable of being cleaved by a glycosidase; the wavy line marked with a single asterisk (*) indicates the site of covalent attachment to D; and the wavy line marked with a double asterisk (**) indicates the site of covalent attachment to the remainder of Q.

In some embodiments, the releasable link RL is ; The wavy line marked with a single asterisk (*) indicates the site of covalent attachment to D; and the wavy line marked with a double asterisk (**) indicates the site of covalent attachment to the remainder of Q.

In some embodiments, the second spacer unit Y is , , or Wherein EWG is an electron-withdrawing group; and the wavy line indicates the attachment site to the rest of the drug-linker compound or its salt.

In some embodiments, the second spacer unit Y is or ; and the wavy line indicates the site of attachment to the remainder of the drug-linker compound or its salt.

In some embodiments, Z' is ; R ¹⁷ is C ₁ -C ₁₀ alkylene; A is a bond; RL is -AA ₁ -AA ₂ -; AA ₁ and AA ₂ are each independently a protein amino acid; Y is or ; and the wavy line indicates the site of attachment to the remainder of the drug-linker compound or its pharmaceutically acceptable salt.

In some embodiments, the connector unit is .

In some embodiments, the drug-linker compound is or , or its pharmaceutically acceptable salts.

In some embodiments, the connector unit is .

In some embodiments, the drug-linker compound is , or , or its pharmaceutically acceptable salts.

In some embodiments, the connector unit is .

In some embodiments, the drug-linker compound is , or , or its pharmaceutically acceptable salts.

In some embodiments, the drug-linker compound is a compound of Table 2.

Also provided herein are ligand-drug conjugate compounds of the formula: L-(QD) _p or a pharmaceutically acceptable salt thereof, wherein L is a ligand unit; Q is a linker unit selected from the group consisting of: (i) ZA-RL-, (ii) ZA-RL-Y-, (iii) ZAS ^* -RL-, (iv) ZAS ^* -RL-Y-, (v) ZAB(S ^* )-RL-, (vi) ZAB(S ^* )-RL-Y-, (vii) ZA-, (viii) ZAS*-W-, (ix) ZAB(S*)-W-, (x) ZAS*-W-RL-, and (xi) ZAB(S*)-W-RL-; Z is a stretcher unit; A is a bond or linker unit; B is a parallel linker unit; S* is a spacer; RL is a releasable linker; W is an amino acid unit; Y is a second spacer unit; and D is a drug unit of formula (A'): , Formula (A') wherein L ¹ is or ; X ¹ is N or CR ^1X ; Y ¹ is N or CR ^1Y ; Z ¹ , Y ² and Z ² are each independently N, CH or CF; X ² is N or CR ^2X ; X ³ is N or CR ^3X ; T ⁴ is N, S, O or CH; X ⁴ is C or N; Y ⁴ is N, NR ^4Y or CR ^4Y ; Z ⁴ is N, S, O, CF or CH; R ¹ is C ₁ -C ₆ alkyl, C ₃ -C ₈ cycloalkyl or C ₁ -C ₆ halogenalkyl; wherein at least one of X ¹ , Y ¹ and X ³ is not N; R ^1X , R ^1Y and R ^3X are each independently H, -OH, halogen, optionally substituted C ₁ -C ₆ alkyl, -O(C ₁ -C ₆ alkyl) or -S ¹ -#, the restriction is that exactly one of R ^1X , R ^1Y and R ^3X is -S ¹ -#, -S ¹ -# is or , wherein the wavy line indicates the point of attachment to the remainder of D and # represents the point of attachment to Q; ^Xc is H, halogen, or optionally substituted _C1 - _C6 alkyl; q is an integer from 0 to 6; n is 0, 1 or 2; m is 1 or 2; ^R8 and ^R9 are each independently H, ^halogen , CN, SH, OH, _CO2H , ^NR4R5 , or _C1 - _C6 alkyl substituted with OH, halogen, or _CO2H ; ^R10 is C1- _C6 ^alkyl substituted with OH, ^halogen , ^NR4R5 , or _CO2R4 , or ^R10 is absent; ^R2X is H, halogen, _C1 - _{C6 alkyl} , _C3 - _C6 cycloalkyl, or _C1 - _C6 halogenalkyl; R ^4Y is H, halogen, C ₁ -C ₆ alkyl, C ₁ -C ₆ halogenalkyl or C ₃ -C ₆ cycloalkyl; T is -C(O)NR ⁴ R ⁵ or -S(O) ₂ NR ⁶ R ⁷ ; R ⁴ , R ⁵ , R ⁶ and R ⁷ are independently H or optionally substituted C ₁ -C ₆ alkyl at each occurrence; the virtual bonds of formula (A') are each independently single or double bonds, so that the ring with the virtual bonds is an aromatic ring; Ring A is , or , where the wavy line indicates the point of attachment to the rest of the compound; The restriction is that when L ¹ is , Ring A is , X ¹ is CR ^1X , Y ¹ is CH , Z ¹ is CH , Z ² is CH , and X ² is N , then T ⁴ , X ⁴ , Y ⁴ , Z ⁴ and R ¹ cannot be simultaneously selected such that T ⁴ is CH , X ⁴ is C , Y ⁴ is NR ^4Y , Z ⁴ is N , and R ¹ is an optionally substituted methyl group ; and p is an integer ranging from 1 to 12.

Also provided herein are ligand-drug conjugate compounds of the formula: L-(QD) _p or a pharmaceutically acceptable salt thereof, wherein L is a ligand unit; Q is a linker unit selected from the group consisting of: (i) ZA-RL-, (ii) ZA-RL-Y-, (iii) ZAS ^* -RL-, (iv) ZAS ^* -RL-Y-, (v) ZAB(S ^* )-RL-, (vi) ZAB(S ^* )-RL-Y-, (vii) ZA-, (viii) ZAS*-W-, (ix) ZAB(S*)-W-, (x) ZAS*-W-RL-, and (xi) ZAB(S*)-W-RL-; Z is a stretcher unit; A is a bond or linker unit; B is a parallel linker unit; S* is a spacer; RL is a releasable linker; W is an amino acid unit; Y is a second spacer unit; and D is a drug unit of formula (I'): , Formula (I') wherein X ¹ is N or CR ^1X ; Y ¹ is N or CR ^1Y ; Z ¹ , Y ² and Z ² are each independently N, CH or CF; X ² is N or CR ^2X ; X ³ is N or CR ^3X ; T ⁴ is N, S, O or CH; X ⁴ is C or N; Y ⁴ is N, NR ^4Y or CR ^4Y ; Z ⁴ is N, S, O, CF or CH; R ¹ is C ₁ -C ₆ alkyl, C ₃ -C ₈ cycloalkyl or C ₁ -C ₆ halogenalkyl; wherein at least one of X ¹ , Y ¹ and X ³ is not N; R ^1X , R ^1Y and R ^3X are each independently H, -OH, halogen, optionally substituted C ₁ -C ₆ alkyl, -O(C ₁ -C ₆ alkyl) or -S ¹ -#, with the proviso that exactly one of R ^1X , R ^1Y and R ^3X is -S ¹ -#, -S ¹ -# is or , wherein the wavy line indicates the point of attachment to the remainder of D and # represents the point of attachment to Q; ^Xc is H, halogen, or optionally substituted _C1 - _C6 alkyl; q is an integer from 0 to 6; n is 0, 1 or 2; m is 1 or 2; ^R8 and ^R9 are each independently H, ^halogen , CN, SH, OH, _CO2H , ^NR4R5 , or _C1 - _C6 alkyl substituted with OH, halogen, or _CO2H ; ^R10 is C1- _C6 ^alkyl substituted with OH, ^halogen , ^NR4R5 , or _CO2R4 , or ^R10 is absent; ^R2X is H, halogen, _C1 - _{C6 alkyl} , _C3 - _C6 cycloalkyl, or _C1 - _C6 halogenalkyl; R ^4Y is H, halogen, C ₁ -C ₆ alkyl, C ₁ -C ₆ halogenalkyl or C ₃ -C ₆ cycloalkyl; T is -C(O)NR ⁴ R ⁵ or -S(O) ₂ NR ⁶ R ⁷ ; R ⁴ , R ⁵ , R ⁶ and R ⁷ are independently and independently H or optionally substituted C ₁ -C ₆ alkyl at each occurrence; the virtual bonds of formula (I') are each independently single or double bonds, so that the ring with the virtual bonds is an aromatic ring; Ring A is , or , where the wavy line indicates the point of attachment to the rest of the compound; the restriction is that when Ring A is , X ¹ is CR ^1X , Y ¹ is CH , Z ¹ is CH , Z ² is CH , and X ² is N , then T ⁴ , X ⁴ , Y ⁴ , Z ⁴ and R ¹ cannot be simultaneously selected such that T ⁴ is CH , X ⁴ is C , Y ⁴ is NR ^4Y , Z ⁴ is N , and R ¹ is an optionally substituted methyl group ; and p is an integer ranging from 1 to 12.

In some embodiments, the linker unit Q has formula (i), (ii), (iii), (iv), (x) or (xi). In some embodiments, the linker unit Q has formula (v), (vi), (ix) or (xi). In some embodiments, the linker unit Q has formula (viii), (ix), (x) or (xi).

In some embodiments, the ligand unit L and the stretcher unit Z together are , or wherein R ¹⁷ is -CH ₂ CH ₂ (OCH ₂ CH ₂ ) _k -, -C ₁ -C ₁₀ alkylene-, C ₁ -C ₁₀ heteroalkylene-, -C ₃ -C ₈ carbocyclyl-, -O-(C ₁ -C ₈ alkylene)-, -arylene-, -C 1 -C ₁₀ alkylene-arylene-, -arylene-C ₁ -C ₁₀ alkylene-, -C ₁ -C ₁₀ alkylene-(C ₃ -C ₈ carbocyclyl)-, -(C ₃ -C ₈ carbocyclyl)-C ₁ -C ₁₀ alkylene-, -C _{3 -C 8} heterocyclyl-, -C ₁ -C ₁₀ alkylene-(C ₃ -C ₈ heterocyclyl)-, -(C ₃ -C 8 _{-C 1 -C 10} alkylene-, -C ₁ -C ₁₀ alkylene-C(=O)-, C ₁ -C ₁₀ heteroalkylene-C(=O)-, -C ₃ -C ₈ carbocyclyl-C(=O)-, -O-(C ₁ -C ₈ alkylene)-C(=O)-, -arylene-C(=O)-, -C ₁ -C ₁₀ alkylene-arylene-C(=O)-, -arylene-C ₁ -C ₁₀ alkylene-C(=O)-, -C ₁ -C ₁₀ alkylene-(C ₃ -C ₈ carbocyclyl)-C(=O)-, -(C ₃ -C ₈ carbocyclyl)-C ₁ -C ₁₀ alkylene-C(=O)-, -C ₃ -C 8 -C ₁ -C ₁₀ alkylene-(C ₃ -C _{8 heterocyclic} group)-C(=O)-, -(C ₃ -C ₈ heterocyclic group)-C 1 -C 10 alkylene-C(=O)-, -C ₁ -C ₁₀ alkylene-NH-, C ₁ -C ₁₀ heteroalkylene-NH-, -C ₃ -C ₈ carbocyclic group-NH-, -O-(C ₁ -C ₈ alkylene)-NH-, -arylene-NH-, -C 1 -C 10 alkylene-arylene-NH-, -arylene-C 1 -C 10 alkylene-NH-, -C ₁ -C ₁₀ alkylene-(C 3 -C ₈ carbocyclic group)-NH-, -O-(C ₁ -C 8 alkylene)-NH-, -arylene-NH-, -C ₁ -C ₁₀ alkylene-arylene-NH-, -arylene-C ₁ -C ₁₀ alkylene-NH-, -C ₁ -C 10 alkylene-(C ₃ -C ₈ carbocyclic group)-NH-, - -C ₈ carbocyclyl)-C ₁ -C ₁₀ alkylene-NH-, -C ₃ -C ₈ heterocyclyl-NH-, -C ₁ -C ₁₀ alkylene-(C ₃ -C ₈ heterocyclyl)-NH-, -(C ₃ -C ₈ heterocyclyl)-C ₁ -C ₁₀ alkylene-NH-, -C ₁ -C ₁₀ alkylene-S-, C ₁ -C ₁₀ heteroalkylene-S-, -C ₃ -C ₈ carbocyclyl-S-, -O-(C ₁ -C ₈ alkylene)-S-, -arylene-S-, -C ₁ -C ₁₀ alkylene-arylene-S-, -arylene-C ₁ -C ₁₀ alkylene-S-, -C ₁ -C ₁₀ alkylene-(C ₃ -C 8 heterocyclyl)- -(C ₃ -C ₈ carbocyclyl)-S-, -(C 3 -C ₈ carbocyclyl)-C ₁ -C ₁₀ alkylene-S-, -C ₃ -C ₈ heterocyclyl-S-, -C ₁ -C ₁₀ alkylene-(C ₃ -C ₈ heterocyclyl)-S- or -(C ₃ -C ₈ heterocyclyl)-C ₁ -C ₁₀ alkylene-S-; subscript k is an integer ranging from 1 to 36; R ¹⁷ is optionally substituted by a basic unit (BU), such as an aminoalkyl moiety, for example -(CH ₂ ) _x NH ₂ , -(CH ₂ ) _x NHR ^a and -(CH ₂ ) _x NR ^a ₂ , wherein x is an integer of 1-4 and each ^Ra is independently selected from the group consisting of C _1-6 alkyl and C The wavy line indicates the point of ^covalent attachment _to the remainder of the ligand-drug conjugate compound.

In some embodiments, the ligand unit L and the stretcher unit Z together are The wavy line indicates the point of covalent attachment to the remainder of the ligand-drug conjugate compound.

In some embodiments, the connector unit A is wherein each R ¹⁰⁰ is independently selected from hydrogen or -C ₁ -C ₃ alkyl; and R ¹¹¹ is independently selected from the group consisting of hydrogen, p-hydroxybenzyl, methyl, isopropyl, isobutyl, dibutyl, -CH ₂ OH, -CH(OH)CH ₃ , -CH ₂ CH ₂ SCH ₃ , -CH ₂ CONH ₂ , -CH ₂ COOH, -CH ₂ CH ₂ CONH ₂ , -CH ₂ CH ₂ COOH, -(CH ₂ ) ₃ NHC(=NH)NH ₂ , -(CH ₂ ) ₃ NH ₂ , -(CH ₂ ) ₃ NHCOCH ₃ , -(CH ₂ ) ₃ NHCHO, -(CH ₂ ) ₄ NHC(=NH)NH ₂ , -(CH ₂ ) ₄ NH ₂ 、-(CH ₂ ) ₄ NHCOCH ₃ 、 -(CH ₂ ) ₄ NHCHO、-(CH ₂ ) ₃ NHCONH ₂ 、-(CH ₂ ) ₄ NHCONH ₂ 、 -CH ₂ CH ₂ CH(OH)CH ₂ NH ₂ 、2-pyridylmethyl-、3-pyridylmethyl-、4-pyridylmethyl-、 ; Each subscript c is an integer independently selected from 1 to 10; and the wavy line indicates that the linker unit is connected to the remainder of the ligand-drug conjugate compound or a pharmaceutically acceptable salt thereof.

In some embodiments, the connector unit A is ; c is an integer ranging from 1 to 6; and the wavy line indicates the site of attachment to the remainder of the ligand-drug conjugate compound or a pharmaceutically acceptable salt thereof.

In some embodiments, A is a key.

In some embodiments, B is ; Each AA is independently a proteinogenic amino acid or a non-proteinogenic amino acid; and the wavy line indicates the point of attachment to the remainder of the ligand-drug conjugate compound or a pharmaceutically acceptable salt thereof.

In some embodiments, B is an amino acid. In some embodiments, B is or ; The wavy line indicates the point of attachment to the spacer S*; and the asterisk indicates the point of attachment to the remainder of the ligand-drug conjugate compound or a pharmaceutically acceptable salt thereof.

In some embodiments, the spacer S ^* is a polyethylene glycol (PEG) unit, a cyclodextrin unit, a polyamide, a hydrophilic peptide, a polysaccharide, or a dendrimer. In some embodiments, the spacer S ^* is a PEG unit comprising 4 to 72 (CH ₂ CH ₂ O) subunits. In some embodiments, the PEG unit is ; b is selected from the group consisting of 4 to 36; and the wavy line indicates the site of attachment to the remainder of the ligand-drug conjugate compound or a pharmaceutically acceptable salt thereof.

In some embodiments, the releasable linker RL is -(AA) _1-12 -; and each AA is independently a proteinogenic amino acid or a non-proteinogenic amino acid.

In some embodiments, the releasable link RL is -AA ₁ -AA ₂ - or -AA ₁ -AA ₂ -AA ₃ -, wherein AA ₁ is connected to the extension unit Z or the connector unit A.

In some embodiments, the releasable link RL is or ; and the wavy line adjacent to the -NH- group indicates connection to the stretcher unit Z or the linker unit A, and the wavy line adjacent to the -C(=O)- group indicates connection to the second spacer unit Y or the drug unit D.

In some embodiments, the releasable linker RL is a glycoside.

In some embodiments, the releasable link RL is wherein Su is a 6-carbon carbohydrate moiety; O' represents an oxygen atom of a glycosidic bond capable of being cleaved by a glycosidase; the wavy line marked with a single asterisk (*) indicates the site of covalent attachment to D; and the wavy line marked with a double asterisk (**) indicates the site of covalent attachment to the remainder of Q.

In some embodiments, the releasable link RL is ; The wavy line marked with a single asterisk (*) indicates the site of covalent attachment to D; and the wavy line marked with a double asterisk (**) indicates the site of covalent attachment to the remainder of Q.

In some embodiments, the second spacer unit Y is , , or Wherein EWG is an electron withdrawing group; and the wavy line indicates the site of attachment to the rest of the ligand-drug conjugate compound or its pharmaceutically acceptable salt.

In some embodiments, the second spacer unit Y is or ; and the wavy line indicates the site of attachment to the remainder of the ligand-drug conjugate compound or a pharmaceutically acceptable salt thereof.

In some embodiments, R ¹⁷ is C ₁ -C ₁₀ alkylene; A is a bond; RL is -AA ₁ -AA ₂ -; AA ₁ and AA ₂ are each independently a protein amino acid; Y is or ; and the wavy line indicates the site of attachment to the remainder of the ligand-drug conjugate compound or its pharmaceutically acceptable salt.

In some embodiments, the ligand unit L and the linker unit Q together are .

In some embodiments, the ligand-drug conjugate compound is , , , , , or , or its pharmaceutically acceptable salts.

In some embodiments, the ligand unit L and the linker unit Q together are , or .

In some embodiments, the ligand unit L and the linker unit Q together are , or .

In some embodiments, the ligand-drug conjugate compound is a compound of Table 4.

In some embodiments, p is an integer in the range of 2 to 8. In some embodiments, p is 4.

Also provided herein is a released drug-linker cysteine adduct compound, wherein the released drug-linker cysteine adduct compound is a compound of Table 3.

Also provided herein is a pharmaceutical composition comprising a ligand-drug conjugate compound as described herein and a pharmaceutically acceptable excipient. In some embodiments, the composition comprises a plurality of ligand-drug conjugate compounds, the average p of which is 2 to 8. In some embodiments, the average p is about 4. In some embodiments, the average p is 3.5 to 4.5.

Also provided herein is a method of treating cancer, comprising administering to a subject in need thereof a therapeutically effective amount of a ligand-drug conjugate compound as described herein or a pharmaceutically acceptable salt thereof. In some embodiments, the subject tolerates treatment with a therapeutically effective amount of the ligand-drug conjugate compound better than another ligand-drug conjugate compound.

Cross-references to related applications

This application claims the benefit of priority to U.S. Provisional Application No. 63/497,439 filed on April 20, 2023 and U.S. Provisional Application No. 63/599,999 filed on November 16, 2023, which are incorporated herein by reference in their entirety for all purposes. Citation of Electronic Sequence Listing

The contents of the electronic sequence listing (761683009801SEQLIST.xml; size: 976,261 bytes; and creation date: November 16, 2023) are incorporated herein by reference in their entirety. I. Definitions

Unless otherwise indicated, the following terms and phrases as used herein are intended to have the following meanings. Unless otherwise indicated herein, when a trademark name is used herein, the trademark name includes the product formulation, generic drug and active pharmaceutical ingredient of the trademarked product.

As used herein, the term "antibody" is used in the broadest sense and specifically encompasses intact monoclonal antibodies, polyclonal antibodies, monospecific antibodies, multispecific antibodies ( e.g. , bispecific antibodies), and antibody fragments that retain at least in part one or more desired biological activities of the full-length antibody, such as affinity for its cognate antigen. The native form of an antibody is a tetramer and consists of two identical pairs of immunoglobulin chains, each pair having one light chain and one heavy chain. In each pair, the light and heavy chain variable regions ( _VL and _VH ) are together primarily responsible for binding to the antigen. The light and heavy chain variable domains consist of framework regions interrupted by three hypervariable regions, also known as "complementary determining regions" or "CDRs." In some embodiments, the constant region is recognized by and interacts with the immune system ( see, e.g., Janeway et al. , 2001, Immunol. Biology, 5th edition , Garland Publishing, New York). The antibodies herein are of any type ( e.g. , IgG, IgE, IgM, IgD, and IgA), class ( e.g. , IgG ₁ , IgG ₂ , IgG ₃ , IgG ₄ , IgA ₁ , and IgA ₂ ), or subclass thereof. In some embodiments, the antibodies are derived from a suitable species. In some embodiments, the antibodies are of human or murine origin. In some embodiments, the antibodies are human, humanized, or chimeric.

As used herein, the term "monoclonal antibody" refers to an antibody obtained from a population of substantially homogeneous antibodies, i.e. , the individual antibodies comprising the population are identical except for possible naturally occurring mutations that may be present in trace amounts in some embodiments. Monoclonal antibodies are highly specific for a single antigenic site. The modifier "monoclonal" indicates the character of the antibody as being obtained from a substantially homogeneous population of antibodies, and should not be construed as requiring the antibody to be produced by any particular method.

An "intact antibody" is an antibody comprising an antigen-binding variable region and a light chain constant domain ( _CL ) and heavy chain constant domains _CH1 , _CH2 , _CH3 and _CH4 , as appropriate to the antibody class. In some embodiments, the constant domains are native sequence constant domains ( e.g. , human native sequence constant domains) and in other embodiments are amino acid sequence variants thereof.

"Antibody fragments" include a portion of an intact antibody that includes its antigen binding region or variable region. Examples of antibody fragments include Fab, Fab', F(ab') ₂ and Fv fragments, bifunctional antibodies, trifunctional antibodies, tetrafunctional antibodies, linear antibodies, single-chain antibody molecules, scFv, scFv-Fc, multispecific antibody fragments formed from antibody fragments, fragments generated from Fab expression libraries, or antigenic determinant binding fragments of any of the above that immunospecifically bind to a target antigen ( e.g. , a cancer cell antigen, a viral antigen, or a microbial antigen).

"Antigen" is the entity to which antibodies specifically bind.

The terms "specific binding" and "specifically bind" mean that the antibody or antibody derivative will bind to the corresponding antigenic determinant of its target antigen in a highly selective manner, while not binding to a variety of other antigens. Typically, the antibody or antibody derivative binds with an affinity of at least about 1× ^10-7 M and preferably ^10-8 M to ^10-9 M, ^10-10 M, ^10-11 M or ^10-12 M, and the affinity of binding to the predetermined antigen is at least two times greater than its affinity for binding to non-specific antigens other than the predetermined antigen or closely related antigens ( e.g. , BSA, casein).

The terms "inhibits" or "inhibition of" mean either a measurable reduction in the amount of an infection or its complete prevention.

The term "therapeutically effective amount" refers to an amount of the conjugate that is effective to treat a disease or condition in a mammal. In the case of cancer, a therapeutically effective amount of the conjugate can reduce the number of cancer cells; reduce tumor size; inhibit ( i.e. , slow to some extent and preferably stop) cancer cell infiltration into peripheral organs; inhibit ( i.e. , slow to some extent and preferably stop) tumor metastasis; inhibit to some extent tumor growth; and/or alleviate to some extent one or more symptoms associated with the cancer. In some embodiments, the drug inhibits growth and/or kills existing cancer cells. In some embodiments, the drug is cytostatic and/or cytotoxic. With respect to cancer therapy, efficacy is measured by common tools. In some embodiments, efficacy is measured by assessing time to disease progression (TTP) and/or determining response rate (RR).

The terms "substantial" or "substantially" refer to a majority of a population, mixture or sample, i.e., >50%, preferably more than 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% of the population.

The term "cytotoxic activity" refers to the cytotoxic effect of a drug or ligand-drug conjugate compound or an intracellular metabolite of a ligand-drug conjugate compound. Cytotoxic activity can be expressed as an _IC50 value, which is the concentration per unit volume (molar or mass) at which half of the cells survive.

The term "potency" or "activity" may also refer to the ability of a drug or ligand-drug conjugate to induce a response (e.g., the ability to stimulate an IRF-Lucia luciferase reporter gene from THP1-Dual ^TM cells). Potency or activity may be expressed as an _EC50 value, which is the concentration per unit volume (molar or mass) that induces a response midway between baseline and maximal response.

The term "cytostatic activity" refers to the antiproliferative effects of a drug or ligand-drug conjugate compound or intracellular metabolites of a ligand-drug conjugate compound.

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

As used herein, the term "cytostatic agent" refers to a substance that inhibits cell function, including cell growth or multiplication. Cytostatic agents include inhibitors, such as protein inhibitors, such as enzyme inhibitors. Cytostatic agents have cytostatic activity.

The terms "cancer" and "cancerous" refer to or describe the physiological disease or condition in mammals that is typically characterized by unregulated cell growth. A "tumor" comprises one or more cancer cells.

As used herein, "autoimmune disease" refers to a disease or disorder that is caused by and directed against an individual's own tissues or proteins.

As used herein, "patient" refers to an individual to whom the ligand-drug conjugate compounds of the present invention are administered. Patients include, but are not limited to, humans, rats, mice, guinea pigs, non-human primates, pigs, goats, cattle, horses, dogs, cats, birds, and poultry. Typically, the patient is a rat, mouse, dog, human, or non-human primate, more typically a human.

Unless the context indicates otherwise, the terms "treat" and "treatment" refer to both therapeutic treatment and preventive, in which the goal is to inhibit or slow (lessen) an undesirable physiological change or condition, such as the development or spread of cancer. For purposes of the present invention, beneficial or desirable clinical results include, but are not limited to, relief of symptoms; diminishment of disease severity; stabilization ( i.e. , not worsening) of the disease state; delay or slowing of disease progression; amelioration or palliation of the disease state; and remission (whether partial or complete), whether detectable or undetectable. "Treatment" may also mean prolonging survival as compared to expected survival if not receiving treatment. Those in need of treatment include those already with the disease or condition as well as those prone to having the disease or condition.

In the context of cancer, the term "treating" includes any or all of the following: killing tumor cells; inhibiting the growth of tumor cells, cancer cells, or tumors; inhibiting the replication of tumor cells or cancer cells, reducing the overall tumor burden or reducing the number of cancer cells, and ameliorating one or more disease-related symptoms.

In the context of autoimmune disease, the term "treating" includes any or all of the following: inhibiting the replication of cells associated with the autoimmune disease state (including but not limited to cells that produce autoimmune antibodies), reducing the autoimmune-antibody burden, and ameliorating one or more symptoms of the autoimmune disease.

"Compound" as the term is used herein refers to and encompasses the compound itself (named or represented by structure), and salt forms thereof (whether or not expressly specified, unless the context clearly indicates that such salt forms are intended to be excluded). The term "compound" further encompasses solvate forms of the compound, wherein a solvent is non-covalently associated with the compound or reversibly covalently associated with the compound, such as when the carbonyl group of the compound is hydrated to form a geminal diol. Solvate forms include those of the compound itself and its salt forms, and include semisolvates, monosolvates, disolvates, including hydrates; when a compound is associated with two or more solvent molecules, the two or more solvent molecules are the same or different.

In some cases, the compounds of the present invention will include one or more of the above forms, such as salts and solvents, which are explicitly mentioned, and this does not imply any solid form of the compound; however, this mention is only for emphasis and should not be considered to exclude any other forms identified above. In addition, when the salt and/or solvent form of a compound or ligand drug conjugate composition is not explicitly mentioned, the omission should not be considered to exclude the salt and/or solvent form of the compound or conjugate, unless the context clearly indicates that such salt and/or solvent form is intended to be excluded.

The phrase "salt thereof" as the phrase is used herein refers to a salt form of a compound (e.g., a drug, a drug-linker compound, or a ligand-drug conjugate compound). A salt form of a compound is one or more internal salt forms and/or involves the inclusion of another molecule, such as an acetate ion, a succinate ion, or other counter ion. The counter ion in a salt form of a compound is typically an organic or inorganic moiety that stabilizes the charge on the parent compound. A salt form of a compound has one or more than one charged atom in its structure. In cases where multiple charged atoms are part of the salt form, there are multiple counter ions and/or multiple charged counter ions. Thus, a salt form of a compound typically has one or more charged atoms corresponding to those charged atoms of the non-salt form of the compound, and one or more counter ions. In some embodiments, a non-salt form of a compound contains at least one amine group or other basic moiety, and thus, in the presence of an acid, obtains an acid addition salt having the basic moiety. In other embodiments, a non-salt form of a compound contains at least one carboxylic acid group or other acidic moiety, and thus, in the presence of a base, obtains a carboxylate or other anionic moiety. Exemplary salts include, but are not limited to, sulfates, trifluoroacetates, citrates, acetates, oxalates, chlorides, bromides, iodides, nitrates, bisulfates, phosphates, acid phosphates, isonicotinates, lactates, salicylates, acid citrates, tartrates, oleates, tannates, pantothenates, bitartarates, ascorbic acid, and the like. salts, succinates, maleates, gentians, fumarates, gluconates, glucuronates, sucroseates, formates, benzoates, glutamines, methanesulfonates, ethanesulfonates, benzenesulfonates, p-toluenesulfonates, and bis(hydroxynaphthoate) salts ( i.e. , 1,1'-methylene-bis-(2-hydroxy-3-naphthoate)).

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

As used herein, a "linker unit" is a bifunctional portion of a ligand-drug conjugate compound that connects or is capable of connecting a drug unit to a ligand unit. In some embodiments, the linker units provided herein may include two or more components selected from the group consisting of: a stretcher unit, which in some embodiments will have a basic unit; a linker unit; a parallel linker unit; a releasable linker; and a second spacer unit.

As used herein, "PEG", "PEG unit" or "polyethylene glycol" is an organic moiety comprising repeating ethylene-oxy subunits and is polydisperse, monodisperse or discrete (i.e., having a discrete number of ethylene-oxy subunits). Polydisperse PEG is a heterogeneous mixture of size and molecular weight, while monodisperse PEG is typically purified from a heterogeneous mixture and thus provides a single chain length and molecular weight. A preferred PEG unit is discrete PEG, a compound synthesized in a stepwise manner rather than via a polymerization process. Discrete PEG provides a single molecule with a defined and specific chain length.

The PEG units provided herein comprise one or more polyethylene glycol chains, each polyethylene glycol chain comprising one or more ethyleneoxy subunits covalently linked to each other. The polyethylene glycol chains are linked together in any pattern ( e.g. , in a linear, branched chain, or star configuration). Typically, prior to incorporation into a ligand-drug conjugate compound, at least one polyethylene glycol chain is derivatized at one end with an alkyl moiety substituted with an electrophilic group to covalently link to the carbamate nitrogen of a methylene carbamate unit (i.e., representing an example of R). Typically, the terminal ethyleneoxy subunits of each polyethylene glycol chain that are not involved in covalent attachment to the remainder of the linker unit are modified with a PEG capping unit (typically H or _an optionally substituted alkyl group such as _-CH3 , _-CH2CH3 , or _-CH2CH2CO2H ). Preferred PEG units have a single _{polyethylene glycol chain having 4 to 24 -CH2CH2O- subunits covalently} linked in series and terminated at one end with a _PEG capping unit.

Unless otherwise stated or implicit from the context, "halogen"/"halogen" as used herein by itself or in combination with another term refers to fluoro, chloro, bromo or iodo and is typically -F or -Cl.

Unless otherwise indicated, the term "alkyl" by itself or as part of another term refers to a straight or branched chain, saturated hydrocarbon having the indicated number of carbon atoms ( e.g. , "-C ₁ -C ₄ alkyl", "-C ₁ -C ₈ alkyl", or "-C ₁ -C ₁₀ ^" alkyl refers to an alkyl having 1 to 4, 1 to 8, or 1 to 10 carbon atoms, respectively). When the number of carbon atoms is not indicated, the alkyl has 1 to 8 carbon atoms. Representative straight chain "-C ₁ -C ₈ alkyl" include, but are not limited to, -methyl, -ethyl, -n-propyl, -n-butyl, -n-pentyl, -n-hexyl, -n-heptyl, and -n-octyl; while branched chain -C ₃ -C ₈ alkyl includes, but is not limited to, -isopropyl, -dibutyl, -isobutyl, -tertiary butyl, -isopentyl, and -2-methylbutyl.

Unless otherwise indicated, "alkylene" by itself or as part of another term refers to a saturated branched chain, saturated straight chain, or saturated cyclic hydrocarbon radical of the specified number of carbon atoms (typically 1-4, 1-8, or 1-10 carbon atoms) and having two monovalent radical centers derived by removing two hydrogen atoms from the same carbon atom or from two _different carbon atoms of the parent alkane. Typical alkylene radicals include, but are not limited to, methylene ( _-CH2- ), _1,2 -ethylene ( _-CH2CH2- ), 1,3-propylene ( _{-CH2CH2CH2- )} , 1,4-butylene _{(-CH2CH2CH2CH2- )} , and _{the like} . In some embodiments, the alkylene radical is a branched chain or straight chain hydrocarbon (i.e., it is not a cyclic hydrocarbon).

Unless otherwise stated or implicit from the context, "alkenyl" as used herein by itself or as part of another term refers to an organic moiety, substituent or group that includes one or more bibond functional groups (e.g., a -CH=CH- moiety) or 1, 2, 3, 4, 5 or 6 or more, typically 1, 2 or 3 such functional groups, more typically 1 such functional group, and in some embodiments may contain non-aromatic linked positive carbon, secondary carbon, tertiary carbon or cyclic carbon atoms (i.e., straight chain, branched chain, cyclic or any combination thereof) as part of the base moiety, unless the alkenyl substituent, moiety or group is a vinyl moiety (e.g., a -CH=CH2 _moiety ). An alkenyl moiety, group or substituent having multiple double bonds may have the double bonds to one or more intervening saturated carbon atoms or combinations thereof in a continuous (i.e., 1,3-butadienyl moiety) or non-continuous arrangement, provided that the cyclic, continuous arrangement of the double bonds does not form a 4n + 2 electron cyclic conjugated system (i.e., is not aromatic).

An alkenyl moiety, group or substituent contains at least one ^sp2 carbon atom, wherein the carbon atom is divalent and is doubly bonded to another organic moiety or Markush structure to which it is bonded, or contains at least two sp2 ^carbon atoms that are conjugated to each other, wherein one ^sp2 carbon atom is monovalent and is single-bonded to another organic moiety or Markush structure to which it is bonded. Typically, when an alkenyl is used as a Markush group (i.e., as a substituent), the alkenyl is single-bonded to another organic moiety to which it is bonded, either in the Markush form or via an ^sp2 carbon of an olefinic functional group of the alkenyl moiety. In some embodiments, when an alkenyl moiety is specified, the species encompasses those corresponding to any optionally substituted alkyl or carbocyclic group, radical moiety or substituent described herein, which has one or more internal double bonds in which its ^sp2 carbon atom is monovalent and monovalent moieties derived by removing a hydrogen atom from an ^sp2 carbon of the parent olefin compound. Such monovalent moieties are exemplified, but not limited to, vinyl (-CH= _CH2 ), allyl, 1-methylvinyl, butenyl, isobutenyl, 3-methyl-2-butenyl, 1-pentenyl, cyclopentenyl, 1-methyl-cyclopentenyl, 1-hexenyl, 3-hexenyl, and cyclohexenyl. In some embodiments, the term alkenyl encompasses those and/or other straight chain, cyclic and branched chain, all-carbon containing moieties containing at least one dibond functional group, wherein one ^sp2 carbon atom is monovalent.

The number of carbon atoms in the alkenyl portion is defined by the number of ^sp2 carbon atoms in the olefinic functionality which are defined as alkenyl substituents and the total number of consecutive non-aromatic carbon atoms attached to each of these ^sp2 carbons, excluding any carbon atoms in which the alkenyl portion is other part of a variable group or Markush structure and carbon atoms from any optional substituents of the alkenyl portion. The number ranges from 1 to 30, typically 1 to 20 or 1 to 12, more typically 1 to 8, 1 to 6 or 1 to 4 carbon atoms when the dibond functional group is dibond to a Markush structure (e.g., =CH _{2 )} , or from 2 to 50, typically 2 to 30, 2 to 20 or 2 to 12, more typically 2 to 8, 2 to 6 or 2 to 4 carbon atoms when the dibond functional group is monobond to a Markush structure (e.g., -CH=CH 2 ). For example, C2- _C8 alkenyl or C2-C8 alkenyl means an alkenyl moiety containing 2, 3, 4 _, 5, 6, 7, or 8 carbon atoms, at least two of which are ^sp2 carbon atoms conjugated to each _{other, wherein one of these carbon atoms is monovalent, and C2-C6 alkenyl} or C2-C6 alkenyl means an alkenyl moiety containing 2, 3, 4, 5, or 6 carbon atoms, at least two of which are ^sp2 carbons conjugated to each other, wherein one of these carbon atoms is monovalent. In some embodiments, the alkenyl substituent or group is a _C2 - _C6 or C2- _{C4 alkenyl} moiety having only two ^sp2 carbons conjugated to each other, wherein one of these carbon atoms is monovalent. Typically, an alkenyl substituent is a _C2 - _C6 or _C2 - _C4 alkenyl moiety having only two ^sp2 carbons conjugated to each other. When the number of carbon atoms is not specified, the alkenyl moiety has 2 to 8 carbon atoms.

Unless otherwise stated or implied by the context, "alkenylene," as used herein by itself or in combination with another term, refers to an organic moiety, substituent, or radical that comprises one or more dibonding moieties as previously described for alkenyl of the specified number of carbon atoms and has two radical centers derived by removing two hydrogen atoms from the same or two different ^sp2 carbon atoms of an olefinic functional group or from two different olefinic functional groups in the parent olefin. In some embodiments, the alkenylene moiety is a moiety of an alkenyl group as described herein, wherein hydrogen atoms have been removed from the same or different ^sp2 carbon atoms of a dibonding functional group of an alkenyl group or from ^sp2 carbons of different dibonding moieties to provide a diradical. Typically, alkenyl moieties encompass diradicals containing the structure -C=C- or -C= ^CX -C=C-, wherein ^X1 is absent or is an alkylene group as defined herein, which is typically a _C1 - _C6 alkylene group. The number of carbon atoms in the alkenyl moiety is defined by the number of ^sp2 carbon atoms in its olefinic functionality that define it as an alkenyl moiety and the total number of consecutive non-aromatic carbon atoms attached to each of its ^sp2 carbons, excluding any carbon atoms of other moieties or Markush structures in which the alkenyl moiety is present as a variable group. Unless otherwise specified, the number ranges from 2 to 50 or 2 to 30, typically 2 to 20 or 2 to 12, more typically 2 to 8, 2 to 6 or 2 to 4 carbon atoms. For example, _C2 - _C8 alkenylene or C2-C8 alkenylene means an alkenylene moiety containing 2, 3, 4, 5, 6, 7, or 8 carbon atoms, at least two of which are ^sp2 carbons conjugated to each other, one of which is divalent or both are monovalent, and _C2 - _C6 alkenylene or C2-C6 alkenylene means an alkenyl moiety containing 2, 3, 4, 5, or 6 carbon atoms, at least two of which are ^sp2 carbons, at least two of which are ^sp2 carbons conjugated to each other, one of which is divalent or both are monovalent. In some embodiments, the alkenylene moiety is _C2 - _C6 or _C2 - _C4 alkenylene having two ^sp2 carbons conjugated to each other, wherein both ^sp2 carbon atoms are monovalent. When the number of carbon atoms is not specified, the alkenylene moiety has 2 to 8 carbon atoms.

Unless otherwise stated or implicit from the context, "alkynyl" as used herein by itself or as part of another term refers to an organic moiety, substituent or group that contains one or more linker functional groups (e.g., a -C≡C- moiety) or 1, 2, 3, 4, 5 or 6 or more, typically 1, 2 or 3 such functional groups, more typically 1 such functional group. Alkynyl moieties, groups or substituents having multiple linkers may have the linkers arranged serially or non-continuously with one or more intervening saturated or unsaturated carbon atoms or combinations thereof, provided that the cyclic, continuous arrangement of the linkers does not form a cyclic conjugated system of 4n + 2 electrons (i.e., is not aromatic).

Alkynyl moieties, radicals or substituents contain at least two sp carbon atoms, wherein the carbon atoms are conjugated to each other and one of the sp carbon atoms is single-bonded to another organic moiety or Markush structure to which it is attached. When the alkynyl group is used as a Markush group (i.e., as a substituent), the alkynyl group is single-bonded to another organic moiety to which it is attached in a Markush form or via a reference bond carbon (i.e., sp carbon) of a terminal alkynyl functional group. In some embodiments, when an alkynyl moiety, radical or substituent is specified, the species encompasses any alkyl or carbocyclic group, radical moiety or substituent described herein, which has one or more internal reference bonds and a monovalent moiety derived by removing a hydrogen atom from an sp carbon of the parent alkynyl compound. Such unit price parts are exemplified but not limited to -C≡CH, -C≡C- _CH3 and -C≡C-Ph.

The number of carbon atoms in an alkynyl substituent is defined by the number of sp carbon atoms in the alkene functional group that defines it as an alkynyl substituent and the total number of consecutive non-aromatic carbon atoms attached to each of these sp carbons, not including any carbon atoms where the alkene moiety is other part of a variable group or Markush structure. When the key functional group is single-bonded to a Markush structure (e.g., -CH≡CH), the number can vary from 2 to 30, 2 to 20, or 2 to 12, typically 2 to 8, 2 to 6, or 2 to 4 carbon atoms. For example, _C2 - _C8 alkynyl or C2-C8 alkynyl means an alkynyl moiety containing 2, 3, 4, 5, 6, 7, or 8 carbon atoms, at least two of which are sp carbon atoms conjugated to each other, wherein one of these carbon atoms is monovalent, and _C2 - _C6 alkynyl or C2-C6 alkynyl means an alkynyl moiety containing 2, 3, 4, ₅ , or 6 carbon atoms, at least two of which are sp carbons conjugated to each other, wherein one of these carbon atoms is monovalent. In some embodiments, the alkynyl substituent or group is a _C2 -C6 or C2 _{- C4} alkynyl moiety having two sp carbons conjugated to each other, wherein one of these carbon atoms is monovalent. When the number of carbon atoms is not specified, the alkynyl moiety, group, or substituent has 2 to 8 carbon atoms.

As used herein, the term "prodrug" refers to a compound with less biological activity or no activity that is converted to a more biologically active compound in vivo through a chemical or biological process (i.e., a chemical reaction or enzymatic bioconversion). Typically, the biologically active compound is rendered less biologically active (i.e., converted to a prodrug) by chemically modifying the compound with a prodrug moiety. In some embodiments, the prodrug is a Type II prodrug, which is bioactivated outside the cell (e.g., in digestive juices) or in the body's circulatory system (e.g., in the blood). Exemplary prodrugs are esters and β-D-pyranoglucoside.

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

Unless otherwise indicated, "arylene" by itself or as part of another term is an aryl group as defined above having two covalent bonds (i.e., it is divalent) and in an ortho-, meta-, or para-orientation, as shown in the following structure, in which phenylene is an exemplary group: , and .

Unless otherwise indicated, "heterocycle" by itself or as part of another term refers to a monovalent aromatic or nonaromatic monocyclic or bicyclic ring system having 2 to 8 carbon atoms (also referred to as ring members) and 1 to 4 heteroatom ring members independently selected from N, O, P or S, and derived by removing one hydrogen atom from a ring atom of the parent ring system. In some embodiments, one or more N, C or S atoms in the heterocycle are oxidized. In some embodiments, the ring including the heteroatom is aromatic or nonaromatic. A heterocycle in which all ring atoms participate in aromaticity is referred to as a heteroaryl, otherwise it is referred to as a heterocarbocycle.

Unless otherwise specified, a heterocyclic ring is attached to its side group at any heteroatom or carbon atom that creates a stable structure. In some embodiments, the heteroaryl is bonded through an aromatic carbon of its aromatic ring system, referred to as a C-attached heteroaryl. In other embodiments, the heteroaryl is bonded through a non-dibonded N atom (i.e., not =N-) in its aromatic ring system, referred to as an N-attached heteroaryl. Thus, the nitrogen-containing heterocyclic ring is C-attached or N-attached and includes pyrrole moieties such as pyrrol-1-yl (N-attached) and pyrrol-3-yl (C-attached), and imidazole moieties such as imidazol-1-yl and imidazol-3-yl (both N-attached) as well as imidazol-2-yl, imidazol-4-yl and imidazol-5-yl moieties (all C-attached).

Unless otherwise indicated, "heteroaryl" is an aromatic heterocycle (e.g., _C3 - _C8 heterocycle) wherein the subscript represents the total number of carbons in the ring system of the heterocycle or the total number of aromatic carbons in the aromatic ring system of the heteroaryl and does not refer to the size of the ring system or the presence or absence of ring fusion. Representative examples of _C3 - _C8 heterocycles include, but are not limited to, pyrrolidinyl, azetidinyl, piperidinyl, oxolinyl, tetrahydrofuranyl, tetrahydropyranyl, benzofuranyl, benzothiophene, indolyl, benzopyrazolyl, pyrrolyl, thienyl (thiophene), furanyl, thiazolyl, imidazolyl, pyrazolyl, pyrimidinyl, pyridinyl, pyrazinyl, oxazinyl, isothiazolyl, triazolyl, oxazolyl, and isoxazolyl.

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

A heterocycle fused to an aryl or heteroaryl group such that the heterocycle remains non-aromatic and becomes part of a larger structure by being attached to the non-aromatic portion of the fused ring system is an example of a heterocycle where the heterocycle is substituted by the ring to which the aryl or heteroaryl group is fused. Similarly, an aryl or heteroaryl group fused to a heterocycle or carbocycle becomes part of a larger structure by being attached to the aromatic portion of the fused ring system is an example of an aryl or heterocycle where the aryl or heterocycle is substituted by the ring to which the heterocycle or carbocycle is fused. Such structures may be referred to as fused heterocycles.

Unless otherwise indicated, "heterocyclyl" by itself or as part of another term refers to a heterocycle as defined above (e.g., a C ₃ -C ₈ heterocycle) in which one of the hydrogen atoms of the heterocycle is replaced by a bond (i.e., it is divalent). Unless otherwise indicated, "heteroaryl" by itself or as part of another term refers to a heteroaryl as defined above (e.g., a C ₃ -C ₈ heteroaryl) in which one of the hydrogen atoms of the heteroaryl is replaced by a bond (i.e., it is divalent). When explicitly stated, the ring system size of a heteroaryl is indicated by the total number of atoms in the ring. For example, designation as a 5- or 6-membered heteroaryl indicates the total number of atoms in the heterocyclic ring system (ie, 5 or 6), but does not imply the number of heteroatoms or carbon atoms in that ring system.

Unless otherwise indicated, "carbocycle" by itself or as part of another term is a 3-, 4-, 5-, 6-, 7-, or 8-membered monovalent saturated or unsaturated nonaromatic monocyclic or bicyclic carbocycle derived by removing one hydrogen atom from a ring atom of a parent ring system. Representative carbocycles (e.g., _C3 - _C8 carbocycles) include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclopentadienyl, cyclohexyl, cyclohexenyl, 1,3-cyclohexadienyl, 1,4-cyclohexadienyl, cycloheptyl, 1,3-cycloheptadienyl, 1,3,5-cycloheptatrienyl, cyclooctyl, and cyclooctadienyl.

Unless otherwise indicated, "carbocyclyl" by itself or as part of another term refers to a carbocyclyl as defined above (eg, C ₃ -C ₈ carbocyclyl) wherein another hydrogen atom of the carbocyclyl is replaced by a bond (ie, it is divalent).

Unless otherwise indicated, the term "heteroalkyl" by itself or in combination with another term means (unless otherwise indicated) a stable straight or branched chain hydrocarbon or combination thereof, fully saturated or containing 1 to 3 degrees of unsaturation, consisting of the specified number of carbon atoms and 1 to 10, preferably 1 to 3 heteroatoms selected from the group consisting of O, N, Si and S, and wherein the nitrogen and sulfur atoms are optionally oxidized and the nitrogen heteroatom is optionally quaternary ammonium. The heteroatoms O, N and S are located at any interior position of the heteroalkyl group, or at the position where the alkyl group is attached to the rest of the molecule. The heteroatom Si is located at any position of the heteroalkyl group, including the position where the alkyl group is attached to the rest of the molecule. When explicitly stated, the number of atoms in a heteroalkyl or heteroaryl group is indicated by the total number of atoms in the group. For example, a designation of _C1 - _{C2heteroalkyl} indicates the total number of atoms in the heteroalkyl group (ie, 1 or 2), but does not imply the number of heteroatoms or carbon atoms in that group.

Examples of heteroalkyl groups include -CH2- _CH2 - _O - _CH3 , -CH2 _-CH2 - _NH - _CH3 , -CH2- _{CH2 -N} ( _CH3 ) _-CH3 , -CH2 _- S- _CH2 - _CH3 , -CH2 _-CH2 - _S (O) _-CH3 , -NH- _CH2 - _CH2 -NH-C(O) _-CH2 -CH ₃ , -CH ₂ -CH ₂ -S(O) ₂ -CH ₃ , -CH=CH-O-CH ₃ , -Si(CH ₃ ) ₃ , -CH ₂ -CH=NO-CH ₃ and -CH=CH-N(CH ₃ )-CH ₃ . In some aspects, the two heteroatoms are consecutive, such as -CH2 _- NH- _OCH3 and _-CH2 -O-Si( _CH3 ) ₃ . Typically, the _C1 - _C4 heteroalkyl or heteroalkylene group has 1 to 4 carbon atoms and 1 or 2 heteroatoms, and the _C1 - _C3 heteroalkyl or heteroalkylene group has 1 to 3 carbon atoms and 1 or 2 heteroatoms. In some embodiments, the heteroalkyl or heteroalkylene group is saturated.

Unless otherwise indicated, the term "heteroalkylene" by itself or in combination with another term means a divalent radical derived from a heteroalkylene (as discussed above), as exemplified by -CH2- _CH2 - _S -CH2- _{CH2- and} -CH2-S- _{CH2 - CH2} -NH- _CH2- . For heteroalkylene, heteroatoms may also occupy one or both chain ends. Further, for alkylene and heteroalkylene linking groups, no orientation of the linking group is implied.

Unless otherwise indicated, "aminoalkyl" by itself or in combination with another term means a heteroalkyl group in which _the alkyl portion as defined herein is substituted with an amino, alkylamino, dialkylamino, or cycloalkylamino group. Exemplary non-limiting aminoalkyl groups _{are -CH2NH2} , _-CH2CH2NH2 , _-CH2CH2NHCH3 , and _-CH2CH2N ( _CH3 ) _{2 and} further include branched chain species such as _-CH ( _CH3 ) _NH2 and _-C (CH3) _CH2NH2 in either the (R)- or ( _S ) _{- configuration} . Alternatively, an aminoalkyl is an alkyl moiety, radical or substituent as defined herein, wherein an ^sp3 carbon other than the radical carbon atom of the alkyl moiety has been replaced by an amine or alkylamino moiety wherein its ^sp3 nitrogen atom replaces an ^sp3 carbon of the alkyl moiety, with the proviso that at least one ^sp3 carbon atom of the alkyl moiety remains. When referring to an aminoalkyl moiety as a substituent of a larger structure or another moiety, the aminoalkyl is covalently attached to the structure or moiety via the carbon radical of the alkyl moiety of the aminoalkyl.

Unless otherwise specified or implied by the context, "hydroxyalkyl" as used herein by itself or in combination with another term refers to an alkyl portion, group or substituent having a hydroxyl group replacing one or more hydrogen atoms of the alkyl portion, group or substituent. In some embodiments, in the hydroxyalkyl group, one or two hydrogen atoms are each replaced by a hydroxyl substituent. Hydroxylalkyl groups are typically represented by the number of consecutive carbon atoms of their alkyl or alkylene portion. Thus, C ₁ hydroxyalkyl groups are exemplified, but not limited to, -CH ₂ OH, and C ₂ hydroxyalkyl groups are exemplified, but not limited to, -CH ₂ CH ₂ OH or -CH ₂ (OH) CH ₃ .

Unless otherwise specified or implied by the context, "haloalkyl" as used herein by itself or in combination with another term refers to an alkyl portion, group or substituent having a halogen replacing one or more hydrogen atoms of the alkyl portion, group or substituent. In some embodiments, in the haloalkyl group, one or two hydrogen atoms are each replaced by a halogen. A haloalkyl group is typically represented by the number of consecutive carbon atoms of its alkyl or alkylene portion. Therefore, _C1 haloalkyl groups include, but are not limited to, _-CH2F , _-CH2Cl , _-CH2Br , or _-CH2I , and _C2 haloalkyl groups include, but are not limited to, _-CH2CH2F , _-CH2CH2Cl , _-CH2CH2Br , _-CH2CH2I , _-CH2 (F _{) CH3} , _-CH2 (Cl) _CH3 , _-CH2 (Br _{) CH3 ,} or _-CH2 ( _I ) _CH3 . In some embodiments, the term "haloalkyl" refers to an alkyl moiety, group, or substituent having halogens replacing two or more hydrogen atoms. For example, _C1 haloalkyl is also exemplified but not limited to _-CHF2 , _-CHCl2 , _-CHBr2 , or _{-CHI2 ,} and _C2 haloalkyl is exemplified but not limited to _-CH2CHF2 , _-CH2CHCl2 , _-CH2CHBr2 , _-CH2CHI2 , _-CF2CH3 , _{-CCl2CH3 , -CBr2CH3} , or _-CI2CH3 . In some embodiments _, the term "haloalkyl" refers to an alkyl moiety, group, or _{substituent having} halogens that replace _all hydrogen _atoms . Therefore, in some embodiments, _the term "haloalkyl" encompasses fully halogenated alkyl moieties, groups, or substituents. For example, the C ₁ halogen alkyl group is also exemplified by, but not limited to, -CF ₃ , -CCl ₃ , -CBr ₃ or -CI ₃ .

Unless otherwise indicated, "alkylamino" and "cycloalkylamino" by themselves or in combination with another term mean an alkyl or cycloalkyl group as described herein, wherein a radical carbon atom of the alkyl or cycloalkyl group has been replaced with a nitrogen radical, provided that at least one ^sp3 carbon atom of the alkyl or cycloalkyl group remains. In those cases where an alkylamino group is substituted on its nitrogen with another alkyl moiety, the resulting substituted radical is sometimes referred to as a dialkylamino moiety, group or substituent, wherein the alkyl moiety replacing the nitrogen is independently selected.

Exemplary and non-limiting amine, alkylamine and dialkylamine substituents include those with -N(R') ₂ structures, wherein R' is independently hydrogen or _C1-6 alkyl, typically hydrogen or methyl, and in cycloalkylamines included in heterocycloalkyls, two R's form a heterocycle together with the nitrogen to which they are attached. When both R's are hydrogen or alkyl, the moieties are sometimes described as primary amine and tertiary amine, respectively. When one R' is hydrogen and the other is alkyl, the moieties are sometimes described as secondary amine. Primary and secondary alkylamine moieties are typically more reactive as nucleophiles to electrophilic centers containing carbonyls, while tertiary amines are typically more basic.

The term "substituted" means that the specified group or moiety carries one or more substituents. Typical substituents include, but are not limited to, -X, -R", -OH, -OR", -SR", -N(R") ₂ , -N(R") ₃ , =NR", -CX ₃ , -CN, -NO ₂ , -NR"C(=O)R", -C(=O)R", -C(=O)N(R") ₂ , -S(=O) ₂ R", -S(=O) ₂ NR", -S(=O)R", -OP(=O)(OR") ₂ , -P(=O)(OR") ₂ , -PO ₃ ^＝ , PO ₃ H ₂ , -C(=O)R", -C(=S)R", -CO ₂ R", -CO ₂ ^- , -C(=S)OR", -C(=O)SR", -C(=S)SR", -C(=O)N(R") ₂ , -C(=S)N(R") ₂ and -C(=NR)N(R") ₂ , wherein each X is independently selected from the group consisting of halogen: -F, -Cl, -Br and -I; and wherein each R" is independently selected from the group consisting of: -H, -C ₁ -C ₂₀ alkyl, -C ₃ -C ₂₀ cycloalkyl, -C ₆ -C ₂₀ aryl, -C ₃ -C ₁₄ heterocycle, protecting group and prodrug moiety.

More typically, the substituent is selected from the group consisting of -X, -R", -OH, -OR", -SR", -N(R") ₂ , -N(R") ₃ , =NR", -NR"C(=O)R", -C(=O)R", -C(=O)N(R") ₂ , -S(=O) ₂ R", -S(=O) ₂ NR", -S(=O)R", -C(=O)R", -C(=S)R", -C(=O)N(R") ₂ , -C(=S)N(R") ₂ , and -C(=NR)N(R") ₂ , wherein each X is independently selected from the group consisting of -F and -Cl, or from the group consisting of -X, -R", -OH, -OR", -N(R") ₂ , -N(R") ₃ , -NR"C(=O)R", -C(=O)N(R") ₂ , -S(=O) ₂ R", -S(=O) ₂ NR", -S(=O)R", -C(=O)R", -C(=O)N(R") ₂ , -C(=NR)N(R") ₂ , a protecting group and a prodrug moiety, wherein each X is -F; and wherein each R' is independently selected from the group consisting of hydrogen, -C ₁ -C ₂₀ alkyl, -C ₆ -C ₂₀ aryl, -C ₃ -C ₁₄ heterocycle, a protecting group and a prodrug moiety.

In some embodiments, the substituents on the alkyl, alkenyl or alkynyl are selected from the group consisting of -N(R") ₂ , -N(R") ₃ and -C(=NR)N(R") ₂ , wherein R" is selected from the group consisting of hydrogen and -C ₁ -C ₂₀ alkyl. In other embodiments, the alkyl, alkenyl or alkynyl is substituted with a series of ethyleneoxy moieties to define a PEG unit as described herein. In some embodiments, the alkylene, carbocycle, carbocyclyl, arylene, heteroalkylene, heteroalkylene, heterocyclo, heterocycloyl, heteroaryl and heteroarylene groups as described above are similarly substituted.

The term "unsubstituted" means that the specified group carries no substituents. Where the term "substituted" is used to describe a structural system, substitution is intended to occur at any valence-permitted position on the system. When a group or moiety carries more than one substituent, it is understood that the substituents may be the same or different from one another. In some embodiments, the substituted group or moiety carries one to five substituents. In some embodiments, the substituted group or moiety carries one substituent. In some embodiments, the substituted group or moiety carries two substituents. In some embodiments, the substituted group or moiety carries three substituents. In some embodiments, the substituted group or moiety carries four substituents. In some embodiments, the substituted group or moiety carries five substituents.

"Optional" or "optionally" means that the subsequently described event or circumstance may or may not occur, and that the description includes instances where the event or circumstance occurs and instances where the event or circumstance does not occur. For example, "optionally substituted alkyl" encompasses both "alkyl" and "substituted alkyl" as defined herein. It will be understood by those skilled in the art that with respect to any group containing one or more substituents, such group is not intended to introduce any substitution or substitution pattern that is sterically impractical, synthetically unfeasible, and/or inherently unstable. It will also be understood that where a group or moiety is optionally substituted, the present disclosure includes both embodiments in which the group or moiety is substituted and embodiments in which the group or moiety is not substituted.

As used herein, "protecting group" means a moiety that prevents or reduces the ability of an atom or functional group to which it is attached to participate in an undesired reaction. Typical protecting groups for atoms or functional groups are given in Greene (2006), "PROTECTIVE GROUPS IN ORGANIC SYNTHESIS, 4th Edition", Wiley Interscience (which is incorporated herein by reference). In some cases, protecting groups for heteroatoms such as oxygen, sulfur, and nitrogen are used to minimize or avoid their undesired reactions with electrophilic compounds. In other cases, protecting groups are used to reduce or eliminate the nucleophilicity and/or basicity of unprotected heteroatoms. A non-limiting example of a protected oxygen is given by -OR ^PR , wherein R ^PR is a protecting group for a hydroxy group, wherein the hydroxy group is typically protected as an ester (eg, acetate, propionate, or benzoate). Other protecting groups for hydroxyl groups avoid interference with the nucleophilicity of organometallic reagents or other strongly basic reagents, wherein hydroxyl groups are typically protected as ethers, including alkyl or heterocycloalkyl ethers (e.g., methyl or tetrahydropyranyl ether), alkoxymethyl ethers (e.g., methoxymethyl or ethoxymethyl ether), optionally substituted aryl ethers, and silyl ethers (e.g., trimethylsilyl (TMS), triethylsilyl (TES), tert-butyldiphenylsilyl (TBDPS), tert-butyldimethylsilyl (TBS/TBDMS), triisopropylsilyl (TIPS), and [2-(trimethylsilyl)ethoxy]-methylsilyl (SEM)). Nitrogen protecting groups include those used for primary amines or secondary amines (such as -NHR ^PR or -N(R ^PR ) ₂ -), wherein at least one R ^PR is a nitrogen atom protecting group or two R ^PR together constitute a protecting group. Non-limiting examples of such nitrogen protecting groups include tert-butyloxycarbonyl (Boc), 9-fluorenylmethoxycarbonyl (Fmoc), trimethylsilyl (TMS), carboxybenzyl (CBz), acetyl (Ac), benzyl (Bz), benzyl (Bn), trityl (Tr), dimethoxytrityl (DMT), o-phthaloyl, carbamate, p-methoxybenzyl (PMB), 3,4-dimethoxybenzyl (DMPM), p-methoxyphenyl (PMP) and tosyl (Ts).

The protecting group is suitable when it is capable of preventing or avoiding undesirable side reactions or premature loss of the protecting group under the reaction conditions required to achieve the desired chemical transformation elsewhere in the molecule and, if necessary, during purification of the newly formed molecule, and can be removed under conditions that do not adversely affect the structural or stereochemical integrity of the newly formed molecule. For example and not limitation, suitable protecting groups include those previously described for protecting other reactive functional groups. Suitable protecting groups are sometimes protecting groups used in peptide coupling reactions.

As used herein, "electron withdrawing group" means a functional group or electronegative atom that withdraws electron density from the atom to which it is bonded inductively and/or via resonance (whichever is more dominant) (i.e., in some embodiments, the functional group or atom inductively withdraws electrons, but generally donates electrons via resonance) and tends to stabilize anions or electron-rich moieties. The electron-withdrawing effect is typically transmitted inductively (albeit in a weakened form) to other atoms that are already bonded to the electron-deficient bonding atom due to the electron-withdrawing group (EWG), thus affecting the electrophilicity of more distant reaction centers. Exemplary electron withdrawing groups include, but are not limited to, -C(=O), -CN, _-NO2 , _-CX3 , -X, -C(=O)OR', -C(=O)N(R') ₂ , -C(=O)R', -C(=O)X, -S(=O) _2R ', -S(=O) _2OR ', -S(=O) _2NHR ', -S(=O) _{2N(R')2 ,} -P(=O)(OR') ₂ ^, -P(=O)( _CH3 )NHR', -NO, -N(R') ₃₊ , wherein X is -F, -Br, -Cl or -I, and in some embodiments, R' at each occurrence is independently selected from the group consisting of hydrogen and _C1-6 alkyl, as well as certain O-linking moieties as described herein (such as acyloxy).

Exemplary EWGs may also include aryl groups (e.g., phenyl), depending on the substitution of the aromatic ring; and certain heteroaryl groups (e.g., pyridine). Therefore, the term "electron-withdrawing group" also includes aryl or heteroaryl groups further substituted with electron-withdrawing groups. Typically, the electron-withdrawing groups on the aryl or heteroaryl groups are -C(=O), -CN, -NO ₂ , -CX ₃ , and -X, wherein independently selected X is a halogen, typically -F or -Cl. Depending on its substituents, the alkyl portion may also be an electron-withdrawing group.

As used herein, "succinimide moiety" refers to an organic moiety comprising a succinimide ring system that is present in a type of Stretcher unit (Z) that typically further comprises an alkylene-containing moiety bonded to the imide nitrogen of that ring system. The succinimide moiety is typically generated by Michael addition of the alkyl group of the Ligand unit to the maleimide ring system of the Stretcher unit precursor (Z') in the Drug Linker compound or its maleimide-containing intermediate. Thus, the succinimide moiety comprises a thio-substituted succinimide ring system and, when present in a ligand-drug conjugate compound, its imide nitrogen is substituted with the remainder of the Linker unit of the ligand-drug conjugate compound and the succinimide moiety is optionally substituted with a substituent present on the maleimide ring system of Z'.

As used herein, "succinic acid-amide moiety" refers to a succinic acid moiety in which one of the two carboxylic acid groups is replaced by an amide substituent resulting from the succinimide ring system of the sulfide-substituted succinimide moiety as defined herein undergoing cleavage of one of its carbonyl-nitrogen bonds by hydrolysis. In some embodiments, the succinic acid-amide moiety has the following structure: or Where the left wavy line indicates linkage to a ligand unit or hydrogen atom, and the right wavy line indicates linkage to the remainder of the ligand-drug conjugate compound, drug-linker compound, intermediate, or fragment thereof. Hydrolysis to produce the succinic acid-amide moiety provides a linker unit that is less likely to prematurely lose the ligand unit to which it is bonded by eliminating the antibody-sulfhydryl substituent. Hydrolysis of the succinimide ring system of the thio-substituted succinimide moiety is expected to provide regiochemical isomers of the acid-amide moiety resulting from differences in the reactivity of the two carbonyl carbons of the succinimide ring system, which differences are attributable at least in part to any substituents present in the maleimide ring system of the Stretcher unit prodriver and the thio substituent introduced by the Targeting Ligand, which is the Ligand unit prodriver.

In many cases, the conjugates, linkers, and components described herein as a whole will be referred to as a reactive group. A "reactive group" or RG is a group containing a reactive site (RS) that is capable of forming a bond with a component of a linker unit Q or a drug unit D. RS is a reactive site within the reactive group (RG). Reactive groups include hydryl groups that form disulfide or thioether bonds, aldehyde groups, ketone groups, or hydrazines that form hydrazone bonds, carboxyl groups or amine groups that form peptide bonds, carboxyl groups or hydroxyl groups that form ester bonds, sulfonic acids that form sulfonamide bonds, alcohols that form carbamate bonds, and amines that form sulfonamide or carbamate bonds.

The following table illustrates reactive groups, reactive sites, and exemplary functional groups that can be formed after reaction at the reactive sites. The table is not limiting. One skilled in the art will appreciate that the R ^* and R ^** moieties referenced in the table are effectively any organic moiety (e.g., an alkyl, aryl, heteroaryl, or substituted alkyl, aryl, or heteroaryl) that is compatible with the bond formation provided when converting RG to an exemplary functional group. It will also be appreciated that when applied to the various aspects of the present invention, R ^* represents one or more components of a self-stabilizing linker or, optionally, a second linker, and R ^** represents one or more components of an optionally selected second linker, a drug unit, a stabilizing unit, or a detection unit. II. Example A. STING agonist compounds

In some embodiments herein, STING agonist compounds are provided. In some embodiments, provided herein are drug-linker compounds comprising a STING agonist moiety as described herein. In some embodiments, provided herein are ligand-drug conjugate compounds comprising a STING agonist moiety as described herein. In some embodiments, provided herein are methods of treating cancer using the ligand-drug conjugate compounds described herein. In some embodiments, provided herein are methods of preparing STING agonist compounds, drug-linkers thereof, and intermediates thereof, and ligand-drug conjugate compounds thereof.

In some embodiments, a compound of formula (A) is provided: , Formula (A) or a pharmaceutically acceptable salt thereof, wherein L ¹ is or ; X ¹ is N or CR ^1X ; Y ¹ is N or CR ^1Y ; Z ¹ , Y ² and Z ² are each independently N, CH or CF; X ² is N or CR ^2X ; X ³ is N or CR ^3X ; T ⁴ is N, S, O or CH; X ⁴ is C or N; Y ⁴ is N, NR ^4Y or CR ^4Y ; Z ⁴ is N, S, O, CF or CH; R ¹ is C ₁ -C ₆ alkyl, C ₃ -C ₈ cycloalkyl or C ₁ -C ₆ halogenalkyl; wherein at least one of X ¹ , Y ¹ and X ³ is not N; R ^1X , R ^1Y and R ^3X are each independently H, -OH, halogen, optionally substituted C ₁ -C ₆ alkyl, -O(C ₁ -C ₆ alkyl) or , wherein no more than one of R ^1X , R ^1Y and R ^3X is ; wherein the wavy line indicates the point of attachment to the rest of the compound; ^Xa and ^Xb are independently H, ^OH , ^SH , _CO2R4 or ^NR4R5 , or ^Xa and ^Xb together with the carbon atom to which they are attached form wherein the asterisk (*) represents the carbon atom to which ^Xa and ^Xb are attached, ^Xc is H, a halogen group or an optionally substituted _C1 - _C6 alkyl group; q is an integer from 0 to 6; n is 0, 1 or 2; m is 1 or 2; ^R8 and ^R9 are each independently H, a halogen group, CN, SH, OH, _-CO2H , ^NR4R5 or ^an optionally substituted _C1 - _C6 alkyl group by -OH, a halogen group or _-CO2H ; ^R10 is H or an optionally substituted C1-C6 alkyl group by OH, a halogen group, ^NR4R5 or _CO2R4 ^{; R2X} is H, a halogen group, a _C1 - _C6 alkyl group, a _C3 - _C6 cycloalkyl group or a _C1 - _C6 halogen group; ^R4Y is H, a halogen group, a _{C1-C6 alkyl group or a C3} ^- _{C6 cycloalkyl} group; C ₆ alkyl, C ₁ -C ₆ halogenalkyl or C ₃ -C ₆ cycloalkyl; T is C(O)NR ⁴ R ⁵ or S(O) ₂ NR ⁶ R ⁷ ; R ⁴ , R ⁵ , R ⁶ and R ⁷ are independently and independently H or optionally substituted C ₁ -C ₆ alkyl at each occurrence; the virtual bonds of formula (A) are each independently single or double bonds, so that the ring with the virtual bonds is an aromatic ring; and Ring A is , or , where the wavy line indicates the point of attachment to the rest of the compound; The restriction is that when L ¹ is , Ring A is , X ¹ is CR ^1X , Y ¹ is CH , Z ¹ is CH , Z ² is CH , and X ² is N , then T ⁴ , X ⁴ , Y ⁴ , Z ⁴ and R ¹ cannot be simultaneously selected such that T ⁴ is CH , X ⁴ is C , Y ⁴ is NR ^4Y , Z ⁴ is N , and R ¹ is an optionally substituted methyl group.

In some embodiments, a compound of formula (I) is provided: , Formula (I) or a pharmaceutically acceptable salt thereof, wherein X ¹ is N or CR ^1X ; Y ¹ is N or CR ^1Y ; Z ¹ , Y ² and Z ² are each independently N, CH or CF; X ² is N or CR ^2X ; X ³ is N or CR ^3X ; T ⁴ is N, S, O or CH; X ⁴ is C or N; Y ⁴ is N, NR ^4Y or CR ^4Y ; Z ⁴ is N, S, O, CF or CH; R ¹ is C ₁ -C ₆ alkyl, C ₃ -C ₈ cycloalkyl or C ₁ -C ₆ halogenalkyl; wherein at least one of X ¹ , Y ¹ and X ³ is not N; R ^1X , R ^1Y and R ^3X are each independently H, -OH, halogen, optionally substituted C ₁ -C ₆ alkyl, -O(C ₁ -C ₆ alkyl) or , wherein no more than one of R ^1X , R ^1Y and R ^3X is ; wherein the wavy line indicates the point of attachment to the rest of the compound; ^Xa and ^Xb are independently H, ^OH , ^SH , _CO2R4 or ^NR4R5 , or ^Xa and ^Xb together with the carbon atom to which they are attached form wherein the asterisk (*) represents the carbon atom to which ^Xa and ^Xb are attached, ^Xc is H, a halogen group or an optionally substituted _C1 - _C6 alkyl group; q is an integer from 0 to 6; n is 0, 1 or 2; m is 1 or 2; ^R8 and ^R9 are each independently H, a halogen group, CN, SH, OH, _-CO2H , ^NR4R5 or ^an optionally substituted _C1 - _C6 alkyl group with OH, a halogen group or _CO2H ; ^R10 is H or ^an optionally substituted C1-C6 alkyl group with -OH, a halogen group, ^NR4R5 or ^-CO2R4 ; _R2X is H, a halogen group, a _C1 - _C6 alkyl group, a _C3 - _C6 cycloalkyl group or a _C1 - _C6 halogen group; ^R4Y is H, a halogen group, a _{C1-C6 alkyl group or a C3} ^- _{C6 cycloalkyl} group; C ₁ -C ₆ alkyl, C 1 -C ₆ halogenalkyl or C ₃ -C ₆ cycloalkyl; T is -C(O)NR ⁴ R ⁵ or -S(O) ₂ NR ⁶ R ⁷ ; R ⁴ , R ⁵ , R ⁶ and R ⁷ are independently H or optionally substituted C ₁ -C ₆ alkyl at each occurrence; the virtual bonds of formula (I) are each independently single or double bonds, so that the ring with the virtual bonds is an aromatic ring; and Ring A is , or , where the wavy line indicates the point of attachment to the rest of the compound; the restriction is that when Ring A is , X ¹ is CR ^1X , Y ¹ is CH , Z ¹ is CH , Z ² is CH , and X ² is N , then T ⁴ , X ⁴ , Y ⁴ , Z ⁴ and R ¹ cannot be simultaneously selected such that T ⁴ is CH , X ⁴ is C , Y ⁴ is NR ^4Y , Z ⁴ is N , and R ¹ is an optionally substituted methyl group.

In some embodiments, a compound of formula (IIa) is provided: , Formula (IIa) or a pharmaceutically acceptable salt thereof, wherein the variables are as defined for Formula (I); wherein at least one of X ¹ , Y ¹ and X ³ is not N; and the virtual bonds of Formula (IIa) are each independently a single bond or a double bond, such that the rings with the virtual bonds are aromatic rings.

In some embodiments, a compound of formula (IIIa) is provided: , formula (IIIa) or a pharmaceutically acceptable salt thereof, wherein the variables are as defined for formula (I); wherein at least one of X ¹ , Y ¹ and X ³ is not N; and the virtual bonds of formula (IIIa) are each independently single bonds or double bonds, such that the rings with the virtual bonds are aromatic rings; with the restriction that when X ¹ is CR ^1X , Y ¹ is CH , Z ¹ is CH , Z ² is CH , and X ² is N , then T ⁴ , X ⁴ , Y ⁴ , Z ⁴ and R ¹ cannot be simultaneously selected such that T ⁴ is CH , X ⁴ is C , Y ⁴ is NR ^4Y , Z ⁴ is N , and R ¹ is an optionally substituted methyl group.

In some embodiments, a compound of formula (IVa) is provided: , Formula (IVa) or a pharmaceutically acceptable salt thereof, wherein the variables are as defined for Formula (I); wherein at least one of X ¹ , Y ¹ and X ³ is not N; and the virtual bonds of Formula (IVa) are each independently a single bond or a double bond, such that the rings with the virtual bonds are aromatic rings.

In some embodiments, a compound of formula (IIb) is provided: , Formula (IIb) or a pharmaceutically acceptable salt thereof, wherein Y ¹ is N or CR ^1Y ; X ³ is N or CR ^3X ; R ^1Y and R ^3X are each independently H, -OH, a halogen group, an optionally substituted C ₁ -C ₆ alkyl group, or -O(C ₁ -C ₆ alkyl group); R ^1X is H, -OH, a halogen group, an optionally substituted C ₁ -C ₆ alkyl group, -O(C ₁ -C ₆ alkyl group), or ; wherein the wavy line represents the point of attachment to the rest of the compound; wherein the remaining variables are as defined for formula (I); and the virtual bonds of formula (IIb) are each independently a single bond or a double bond such that the ring bearing the virtual bonds is an aromatic ring.

In some embodiments, a compound of formula (IIIb) is provided: , Formula (IIIb) or a pharmaceutically acceptable salt thereof, wherein Y ¹ is N or CR ^1Y ; X ³ is N or CR ^3X ; R ^1Y and R ^3X are each independently H, -OH, a halogen group, an optionally substituted C ₁ -C ₆ alkyl group, or -O(C ₁ -C ₆ alkyl group); R ^1X is H, -OH, a halogen group, an optionally substituted C ₁ -C ₆ alkyl group, -O(C ₁ -C ₆ alkyl group), or ; wherein the wavy line represents the point of connection to the rest of the compound; wherein the remaining variables are as defined for formula (I); and the virtual bonds of formula (IIIb) are each independently single or double bonds such that the rings bearing the virtual bonds are aromatic; with the restriction that when Y ¹ is CH, Z ¹ is CH, Z ² is CH, and X ² is N, then T ⁴ , X ⁴ , Y ⁴ , Z ⁴ and R ¹ cannot be simultaneously selected such that T ⁴ is CH, X ⁴ is C, Y ⁴ is NR ^4Y , Z ⁴ is N, and R ¹ is an optionally substituted methyl group.

In some embodiments, a compound of formula (IVb) is provided: , Formula (IVb) or a pharmaceutically acceptable salt thereof, wherein Y ¹ is N or CR ^1Y ; X ³ is N or CR ^3X ; R ^1Y and R ^3X are each independently H, -OH, a halogen group, an optionally substituted C ₁ -C ₆ alkyl group, or -O(C ₁ -C ₆ alkyl group); R ^1X is H, -OH, a halogen group, an optionally substituted C ₁ -C ₆ alkyl group, -O(C ₁ -C ₆ alkyl group), or ; wherein the wavy line represents the point of attachment to the rest of the compound; wherein the remaining variables are as defined for formula (I); and the virtual bonds of formula (IVb) are each independently a single bond or a double bond such that the ring bearing the virtual bonds is an aromatic ring.

In some embodiments, a compound of formula (IIc) is provided: , Formula (IIc) or a pharmaceutically acceptable salt thereof, wherein X ¹ is N or CR ^1X ; Y ¹ is N or CR ^1Y ; R ^1X and R ^1Y are each independently H, -OH, a halogen group, an optionally substituted C ₁ -C ₆ alkyl group, or -O(C ₁ -C ₆ alkyl group); R ^3X is H, -OH, a halogen group, an optionally substituted C ₁ -C ₆ alkyl group, -O(C ₁ -C ₆ alkyl group), or ; wherein the wavy line represents the point of attachment to the rest of the compound; wherein the remaining variables are as defined for formula (I); and the virtual bonds of formula (IIc) are each independently a single bond or a double bond such that the ring bearing the virtual bonds is an aromatic ring.

In some embodiments, a compound of formula (IIIc) is provided: , Formula (IIIc) or a pharmaceutically acceptable salt thereof, wherein X ¹ is N or CR ^1X ; Y ¹ is N or CR ^1Y ; R ^1X and R ^1Y are each independently H, -OH, a halogen group, an optionally substituted C ₁ -C ₆ alkyl group, or -O(C ₁ -C ₆ alkyl group); R ^3X is H, -OH, a halogen group, an optionally substituted C ₁ -C ₆ alkyl group, -O(C ₁ -C ₆ alkyl group), or ; wherein the wavy line represents the point of attachment to the rest of the compound; wherein the remaining variables are as defined for formula (I); and the virtual bonds of formula (IIIc) are each independently a single bond or a double bond such that the ring bearing the virtual bonds is an aromatic ring.

In some embodiments, a compound of formula (IVc) is provided: , Formula (IVc) or a pharmaceutically acceptable salt thereof, wherein X ¹ is N or CR ^1X ; Y ¹ is N or CR ^1Y ; R ^1X and R ^1Y are each independently H, -OH, a halogen group, an optionally substituted C ₁ -C ₆ alkyl group, or -O(C ₁ -C ₆ alkyl group); R ^3X is H, -OH, a halogen group, an optionally substituted C ₁ -C ₆ alkyl group, -O(C ₁ -C ₆ alkyl group), or ; wherein the wavy line represents the point of attachment to the rest of the compound; wherein the remaining variables are as defined for formula (I); and the virtual bonds of formula (IVc) are each independently a single bond or a double bond such that the ring bearing the virtual bonds is an aromatic ring.

In some embodiments of formula (A), L ¹ is In some embodiments of formula (A), L ¹ is .

In some embodiments of formula (I), T is -C(O)NR ⁴ R ⁵ or -S(O) ₂ NR ⁶ R ^7. In some embodiments, T is -C(O)NR ⁴ R ^5. In some embodiments, T is -C(O)NR ⁴ R ⁵ , R ⁴ is alkyl, and R ⁵ is halogen alkyl or hydroxy alkyl. In some embodiments, T is -C(O)NH(R ⁴ ). In some embodiments, T is -C(O)N(CH ₃ )(R ⁴ ). In some embodiments, T is -C(O)N(CH ₂ CH ₃ )(R ⁴ ). In some embodiments, T is -C(O)NH _2. In some embodiments, T is -C(O)N(CH ₃ ) ₂ . In some embodiments, T is -C(O)NH(CH ₃ ). In some embodiments, T is -C(O)N(CH ₃ )(CH ₂ CH ₃ ). In some embodiments, T is -S(O) ₂ NR ⁶ R ⁷ . In some embodiments, T is -S(O) ₂ NR ⁶ R ^{7 ,} R ⁶ is alkyl, and R ⁷ is halogen alkyl or hydroxy alkyl. In some embodiments, T is -S(O) ₂ NH(R ⁶ ). In some embodiments, T is -S(O) ₂ N(CH ₃ )(R ⁶ ). In some embodiments, T is -S(O) ₂ N(CH ₂ CH ₃ )(R ⁶ ). In some embodiments, T is -S(O) ₂ NH ₂ . In some embodiments, T is -S(O) ₂ N(CH ₃ ) ₂ . In some embodiments, T is -S(O) ₂ NH(CH ₃ ). In some embodiments, T is -S(O) ₂ N(CH ₃ )(CH ₂ CH ₃ ).

In some embodiments of Formula (I), Ring A is , or In some embodiments, Ring A is In some embodiments, Ring A is In some embodiments, Ring A is .

In some embodiments of Formula (I), T is -C(O)NR ⁴ R ⁵ or -S(O) ₂ NR ⁶ R ⁷ and Ring A is . In some such embodiments, T is -C(O)NR ⁴ R ⁵ . In some such embodiments, T is -C(O)NR ⁴ R ⁵ , R ⁴ is alkyl, and R ⁵ is haloalkyl or hydroxyalkyl. In some such embodiments, T is -C(O)NH(R ⁴ ). In some such embodiments, T is -C(O)N(CH ₃ )(R ⁴ ). In some such embodiments, T is -C(O)N(CH ₂ CH ₃ )(R ⁴ ). In some such embodiments, T is -C(O)NH ₂ . In some such embodiments, T is -C(O)N(CH ₃ ) ₂ . In some such embodiments, T is -C(O)NH(CH ₃ ). In some such embodiments, T is -C(O)N(CH ₃ )(CH ₂ CH ₃ ). In some such embodiments, T is -S(O) ₂ NR ⁶ R ⁷ . In some such embodiments, T is -S(O) ₂ NR ⁶ R ⁷ , R ⁶ is alkyl, and R ⁷ is haloalkyl or hydroxyalkyl. In some such embodiments, T is -S(O) ₂ NH(R ⁶ ). In some such embodiments, T is -S(O) ₂ N(CH ₃ )(R ⁶ ). In some such embodiments, T is -S(O) ₂ N(CH ₂ CH ₃ )(R ⁶ ). In some such embodiments, T is -S(O) ₂ NH ₂ . In some such embodiments, T is -S(O) _2N ( _CH3 ) ₂ . In some _such embodiments, T is -S(O) _2NH (CH3). In some such embodiments, T is -S(O) _2N ( _CH3 )( _{CH2CH3 )} .

In some embodiments of Formula (I), T is -C(O)NR ⁴ R ⁵ or -S(O) ₂ NR ⁶ R ⁷ and Ring A is . In some such embodiments, T is -C(O)NR ⁴ R ⁵ . In some such embodiments, T is -C(O)NR ⁴ R ⁵ , R ⁴ is alkyl, and R ⁵ is haloalkyl or hydroxyalkyl. In some such embodiments, T is -C(O)NH(R ⁴ ). In some such embodiments, T is -C(O)N(CH ₃ )(R ⁴ ). In some such embodiments, T is -C(O)N(CH ₂ CH ₃ )(R ⁴ ). In some such embodiments, T is -C(O)NH ₂ . In some such embodiments, T is -C(O)N(CH ₃ ) ₂ . In some such embodiments, T is -C(O)NH(CH ₃ ). In some such embodiments, T is -C(O)N(CH ₃ )(CH ₂ CH ₃ ). In some such embodiments, T is -S(O) ₂ NR ⁶ R ⁷ . In some such embodiments, T is -S(O) ₂ NR ⁶ R ⁷ R ⁶ is alkyl, and R ⁷ is haloalkyl or hydroxyalkyl. In some such embodiments, T is -S(O) ₂ NH(R ⁶ ). In some such embodiments, T is -S(O) ₂ N(CH ₃ )(R ⁶ ). In some such embodiments, T is -S(O) ₂ N(CH ₂ CH ₃ )(R ⁶ ). In some such embodiments, T is -S(O) ₂ NH ₂ . In some such embodiments, T is -S(O) _2N ( _CH3 ) ₂ . In some _such embodiments, T is -S(O) _2NH (CH3). In some such embodiments, T is -S(O) _2N ( _CH3 )( _{CH2CH3 )} .

In some embodiments of Formula (I), T is -C(O)NR ⁴ R ⁵ or -S(O) ₂ NR ⁶ R ⁷ and Ring A is . In some such embodiments, T is -C(O)NR ⁴ R ⁵ . In some such embodiments, T is -C(O)NR ⁴ R ⁵ , R ⁴ is alkyl, and R ⁵ is haloalkyl or hydroxyalkyl. In some such embodiments, T is -C(O)NH(R ⁴ ). In some such embodiments, T is -C(O)N(CH ₃ )(R ⁴ ). In some such embodiments, T is -C(O)N(CH ₂ CH ₃ )(R ⁴ ). In some such embodiments, T is -C(O)NH ₂ . In some such embodiments, T is -C(O)N(CH ₃ ) ₂ . In some such embodiments, T is -C(O)NH(CH ₃ ). In some such embodiments, T is -C(O)N(CH ₃ )(CH ₂ CH ₃ ). In some such embodiments, T is -S(O) ₂ NR ⁶ R ⁷ . In some such embodiments, T is -S(O) ₂ NR ⁶ R ^{7 ,} R ⁶ is alkyl, and R ⁷ is haloalkyl or hydroxyalkyl. In some such embodiments, T is -S(O) ₂ NH(R ⁶ ). In some such embodiments, T is -S(O) ₂ N(CH ₃ )(R ⁶ ). In some such embodiments, T is -S(O) ₂ N(CH ₂ CH ₃ )(R ⁶ ). In some such embodiments, T is -S(O) ₂ NH ₂ . In some such embodiments, T is -S(O) _2N ( _CH3 ) ₂ . In some _such embodiments, T is -S(O) _2NH (CH3). In some such embodiments, T is -S(O) _2N ( _CH3 )( _{CH2CH3 )} .

In some embodiments of Formula (A), (I), (IIa), (IIIa) or (IVa), X ¹ is N. In some embodiments of Formula (A), (I), (IIa), (IIIa) or (IVa), X ³ is N. In some embodiments of Formula (A), (I), (IIa), (IIIa) or (IVa), Y ¹ is N.

In some embodiments of Formula (A), (I), (IIa), (IIIa) or (IVa), X ¹ is CR ^1X and R ^1X is H, -OH, halo, optionally substituted C ₁ -C ₆ alkyl, or -O(C ₁ -C ₆ alkyl). In some such embodiments, R ^1X is H. In some such embodiments, R ^1X is halo. In some such embodiments, R ^1X is F, Cl or Br. In some such embodiments, R ^1X is F. In some such embodiments, R ^1X is Cl. In some such embodiments, R ^1X is Br. In some such embodiments, R ^1X is optionally substituted C ₁ -C ₆ alkyl. In some such embodiments, R ^1X is C ₁ -C ₆ alkyl. In some such embodiments, R ^1X is methyl, ethyl or isopropyl. In some such embodiments, R ^1X is methyl. In some such embodiments, R ^1X is ethyl. In some such embodiments, R 1X is isopropyl. In some such embodiments, R ^1X is substituted C ₁ -C ₆ alkyl ^{. In some such embodiments, R 1X is} C ₁ -C ₆ alkyl substituted with one or more of halogen, -OH, -NR ⁴ R ⁵ or C ₃ -C ₈ cycloalkyl, wherein R ⁴ and R ⁵ are as defined for formula (I). In some such embodiments, R ^1X is C ₁ -C ₆ alkyl substituted with one or more halogens. In some such embodiments, R ^1X is C ₁ -C ₆ alkyl substituted with one or more F, Cl or Br. In some such embodiments, R ^1X is C ₁ -C ₆ alkyl substituted with one or more F. In some such embodiments, R ^1X is C ₁ -C ₆ alkyl substituted with one or more Cl. In some such embodiments, R ^1X is C ₁ -C ₆ alkyl substituted with one or more Br. In some such embodiments, R ^1X is C ₁ -C ₆ alkyl substituted with one or more -OH. In some such embodiments, R ^1X is C ₁ -C ₆ alkyl substituted with one or more -NR ⁴ R ^5. In some such embodiments, R ^1X is C ₁ -C ₆ alkyl substituted with one or more NHR ⁴ . In some such embodiments, R ^1X is C ₁ -C ₆ alkyl substituted with one or more NCH ₃ (R ⁴ ). In some such embodiments, R ^1X is C ₁ -C ₆ alkyl substituted with one or more NH _2. In some such embodiments, R ^1X is C ₁ -C ₆ alkyl substituted with one or more N(CH ₃ ) _2. In some such embodiments, R ^1X is C 1 -C 6 alkyl substituted with one or more NH(CH ₃ ). In some such embodiments, R ^1X is C ₁ -C ₆ alkyl substituted with one or more NH(CH ₂ CH ₃ ). In some such embodiments, R ^1X is _{C 1} -C ₆ alkyl substituted with one or more C _{3 -C 8} cycloalkyl. In some such embodiments, R ^1X is C 1 _{-C 6} alkyl substituted with one or more C ₃ cycloalkyl, C ₄ cycloalkyl, C ₅ cycloalkyl, C ₆ cycloalkyl, C ₇ cycloalkyl, or C ₈ cycloalkyl. In some such embodiments, R ^1X is C ₁ -C ₆ alkyl substituted with one or more C ₃ cycloalkyl. In some such embodiments, R ^1X is C ₁ -C ₆ alkyl substituted with one or more C ₄ cycloalkyl. In some such embodiments, R ^1X is C ₁ -C 6 alkyl substituted with one or more C ₅ cycloalkyl. In some such embodiments, R ^1X is _{C 1 -C 6} alkyl substituted with one or more C ₆ cycloalkyl. In some such embodiments, R ^1X is C ₁ -C ₆ alkyl substituted with one or more C ₇ cycloalkyl groups. In some such embodiments, R ^1X is C ₁ -C ₆ alkyl substituted with one or more C ₈ cycloalkyl groups. In some such embodiments, R ^1X is C ₁ -C ₆ alkyl substituted with one or more cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl groups. In some such embodiments, R ^1X is C 1 -C 6 alkyl substituted with one or more cyclopropyl. In some such embodiments, R ^1X is C ₁ -C ₆ alkyl substituted with one or more cyclobutyl. In some such embodiments, R ^1X is _{C 1 -C 6} alkyl substituted with one or more cyclopentyl groups. In some such embodiments, R ^1X is C ₁ -C ₆ alkyl substituted with one or more cyclohexyl groups. In some such embodiments, R ^1X is -O(C ₁ -C ₆ alkyl). In some such embodiments, R ^1X is -O(C ₁ alkyl). In some such embodiments, R ^1X is -O(C ₂ alkyl). In some such embodiments, R ^1X is -O(C ₃ alkyl). In some such embodiments, R ^1X is -O(C ₄ alkyl). In some such embodiments, R ^1X is -O(C ₅ alkyl). In some such embodiments, R ^1X is -O(C ₆ alkyl).

In some embodiments of Formula (A), (I), (IIa), (IIIa) or (IVa), X ¹ is CR ^1X and R ^1X is . In some such embodiments, q is 0 to 6. In some such embodiments, q is 0. In some such embodiments, q is 1. In some such embodiments, q is 2. In some such embodiments, q is 3. In some such embodiments, q is 4. In some such embodiments, q is 5. In some such embodiments, q is 6. In some such embodiments, R ⁸ is H, halogen, CN, SH, OH, -CO ₂ H, NR ⁴ R ⁵ , or C ₁ -C ₆ alkyl optionally substituted with OH, halogen, or CO ₂ H. In some such embodiments, R ⁸ is H. In some such embodiments, R ⁸ is halogen. In some such embodiments, R ⁸ is F, Cl, or Br. In some such embodiments, R ⁸ is F. In some such embodiments, R ⁸ is Cl. In some such embodiments, R ⁸ is Br. In some such embodiments, R ⁸ is CN. In some such embodiments, R ⁸ is SH. In some such embodiments, R ⁸ is OH. In some such embodiments, R ⁸ is -CO ₂ H. In some such embodiments, R ⁸ is NR ⁴ R ^5. In some such embodiments, R ⁸ is NHR ^4. In some such embodiments, R ⁸ is NCH ₃ (R ⁴ ). In some such embodiments, R ⁸ is NH ₂ . In some such embodiments, R ⁸ is N(CH ₃ ) ₂ . In some such embodiments, R ⁸ is NH(CH ₃ ). In some such embodiments, R ⁸ is NH(CH ₂ CH ₃ ). In some such embodiments, R ⁸ is C ₁ -C ₆ alkyl substituted with -OH, halogen or -CO ₂ H, as appropriate. In some such embodiments, R ⁸ is C ₁ -C ₆ alkyl. In some such embodiments, R ⁸ is methyl, ethyl or isopropyl. In some such embodiments, R ⁸ is methyl. In some such embodiments, R ⁸ is ethyl. In some such embodiments, R ⁸ is isopropyl. In some such embodiments, R ⁸ is C ₁ -C ₆ alkyl substituted with -OH, halogen or -CO ₂ H. In some such embodiments, R ⁸ is C ₁ -C ₆ alkyl substituted with -OH. In some such embodiments, R ⁸ is C ₁ -C ₆ alkyl substituted with halogen. In some such embodiments, ^R is C ₁ -C ₆ alkyl substituted with -CO ₂ H. In some such embodiments, ^R is methyl substituted with -OH. In some such embodiments, ^R is ethyl substituted with -OH. In some such embodiments, ^R is isopropyl substituted with -OH. In some such embodiments, ^R is methyl substituted with halogen. In some such embodiments, ^R is ethyl substituted with halogen. In some such embodiments, R is isopropyl substituted with halogen. In some such embodiments, ^R is methyl substituted with -CO ² H. In some such embodiments, ^R is ethyl substituted with _{-CO 2 H.} In some such embodiments, R is ^isopropyl substituted with -CO ₂ H. In some such embodiments, R ⁹ is H, halogen, CN, SH, OH, -CO ₂ H, NR ⁴ R ⁵ , or C ₁ -C ₆ alkyl optionally substituted with -OH or -CO ₂ H. In some such embodiments, R ⁹ is H. In some such embodiments, R ⁹ is halogen. In some such embodiments, R ⁹ is F, Cl, or Br. In some such embodiments, R ⁹ is F. In some such embodiments, R ⁹ is Cl. In some such embodiments, R ⁹ is Br. In some such embodiments, R ⁹ is CN. In some such embodiments, R ⁹ is SH. In some such embodiments, R ⁹ is OH. In some such embodiments, R ⁹ is -CO ₂ H. In some such embodiments, R ⁹ is NR ⁴ R ⁵ . In some such embodiments, R ⁹ is NHR ⁴ . In some such embodiments, R ⁹ is NCH ₃ (R ⁴ ). In some such embodiments, R ⁹ is NH ₂ . In some such embodiments, R ⁹ is N(CH ₃ ) ₂ . In some such embodiments, R ⁹ is NH(CH ₃ ). In some such embodiments, R ⁹ is NH(CH ₂ CH ₃ ). In some such embodiments, R ⁹ is C ₁ -C ₆ alkyl, optionally substituted with -OH, halogen, or -CO ₂ H. In some such embodiments, R ⁹ is C ₁ -C ₆ alkyl. In some such embodiments, R ⁹ is methyl, ethyl, or isopropyl. In some such embodiments, R ⁹ is methyl. In some such embodiments, R ⁹ is ethyl. In some such embodiments, R ⁹ is isopropyl. In some such embodiments, R ⁹ is C ₁ -C ₆ alkyl substituted with -OH, halogen or -CO ₂ H. In some such embodiments, R ⁹ is C ₁ -C ₆ alkyl substituted with -OH. In some such embodiments, R ⁹ is C ₁ -C ₆ alkyl substituted with halogen. In some such embodiments, R ⁹ is C ₁ -C ₆ alkyl substituted with -CO ₂ H. In some such embodiments, R ⁹ is methyl substituted with -OH. In some such embodiments, R ⁹ is ethyl substituted with -OH. In some such embodiments, R ⁹ is isopropyl substituted with -OH. In some such embodiments, R ⁹ is methyl substituted with halogen. In some such embodiments, R ⁹ is ethyl substituted with -halo. In some such embodiments, R ⁹ is isopropyl substituted with halo. In some such embodiments, R ⁹ is methyl substituted with -CO ₂ H. In some such embodiments, R 9 is ethyl substituted with ^-CO ₂ H. In some such embodiments, R ⁹ is isopropyl substituted with -CO ₂ H.

In some embodiments of Formula (A), (I), (IIa), (IIIa) or (IVa), X ¹ is CR ^1X and R ^1X is . In some such embodiments, ^Xa is H, OH, SH, _CO2H , _CO2R4 ^{, or NR4R5 .} In some ^such embodiments, ^Xa is H. In some such embodiments, ^Xa is OH. In some such embodiments, ^Xa is SH. In some such embodiments, ^Xa is _CO2H . In some such embodiments, ^Xa is _CO2R4 . In some such embodiments, ^Xa is _CO2R4 and ^R4 is optionally substituted C1-C6 alkyl. In some such embodiments, ^Xa is ^CO2R4 and ^R4 is _{C1 - C6} alkyl. In some such embodiments _, ^{Xa is} _CO2R4 ^{and R4} is ^methyl , ethyl _, or isopropyl. In some such embodiments, ^Xa is _CO2R4 and ^R4 is methyl. In some such embodiments, ^Xa is ^{CO2R4 and} R4 is ethyl. In some such embodiments, ^Xa is _CO2R4 ^{and R4} is isopropyl. In some such embodiments, ^Xa is _CO2R4 ^{and R4 is} substituted _C1 - _C6 alkyl. In some such embodiments, ^Xa is _CO2R4 ^{and R4} is substituted ^methyl . In some such embodiments, ^Xa is _{CO2R4 and} ^R4 is substituted ethyl. ^In some such embodiments, ^{Xa is} _CO2R4 ^{and R4} is substituted isopropyl. In some such embodiments, ^Xa is ^NR4R5 . In some such embodiments, ^Xa is ^NHR4 . In some such embodiments, ^Xa is _NCH3 ( ^R4 ). In some such embodiments, ^Xa is _NH2 . In some such embodiments, ^Xa is N( _CH3 ) ₂ . In some such embodiments, ^Xa is NH(CH3). In some such embodiments, ^Xa is _NH ( _CH2CH3 ). In some such embodiments, ^Xb is H, OH, _SH , _CO2H , _CO2R4 ^, or ^NR4R5 . In some ^such embodiments, ^Xb is H. In some such embodiments, ^Xb is OH. In some such embodiments, ^Xb is SH. In some such embodiments, ^Xb is _CO2H . In some ^such embodiments, ^Xb is _CO2R4 . In some such embodiments, X ^b is CO ₂ R ⁴ and R ⁴ is optionally substituted C ₁ -C ₆ alkyl. In some such embodiments, X ^b is CO ₂ R ⁴ and R ⁴ is C ₁ -C ₆ alkyl. In some such embodiments, X ^b is CO ₂ R ⁴ and R ⁴ is methyl, ethyl or isopropyl. In some such embodiments, X ^b is CO ₂ R ⁴ and R ⁴ is methyl. In some such embodiments, X ^b is CO ₂ R ⁴ and R ⁴ is ethyl. In some such embodiments, X ^b is CO ₂ R ⁴ and R ⁴ is isopropyl. In some such embodiments, X ^b is CO ₂ R ⁴ and R ⁴ is substituted C ₁ -C ₆ alkyl. In some such embodiments, X ^b is CO ₂ R ⁴ and R ⁴ is substituted methyl. In some such embodiments, X ^b is CO ₂ R ⁴ and R ⁴ is substituted ethyl. In some such embodiments, X ^b is CO ₂ R ⁴ and R ⁴ is substituted isopropyl. In some such embodiments, X ^b is NR ⁴ R ⁵ . In some such embodiments, X ^b is NHR ⁴ . In some such embodiments, X ^b is NCH ₃ (R ⁴ ). In some such embodiments, X ^b is NH ₂ . In some such embodiments, X ^b is N(CH ₃ ) ₂ . In some such embodiments, X ^b is NH(CH ₃ ). In some such embodiments, X ^b is NH(CH ₂ CH ₃ ). In some such embodiments, ^Xc is H, halogen, or optionally substituted _C1 - _C6 alkyl. In some such embodiments, ^Xc is H. In some such embodiments, ^Xc is halogen. In some such embodiments, ^Xc is F, Cl, or Br. In some such embodiments, ^Xc is F. In some such embodiments, ^Xc is Cl. In some such embodiments, ^Xc is Br. In some such embodiments, ^Xc is optionally substituted _C1 - _C6 alkyl. In some such embodiments, ^Xc is _C1 - _C6 alkyl. In some such embodiments, ^Xc is methyl, ethyl, or isopropyl. In some such embodiments, ^Xc is methyl. In some such embodiments, ^Xc is ethyl. In some such embodiments, ^Xc is isopropyl. In some such embodiments, ^Xc is substituted _C1 - _C6 alkyl. In some such embodiments, ^Xc is substituted methyl. In some such embodiments, ^Xc is substituted ethyl. In some such embodiments, ^Xc is substituted isopropyl.

In some embodiments of Formula (A), (I), (IIa), (IIIa) or (IVa), X ¹ is CR ^1X and R ^1X is , and ^Xa and ^Xb together with the carbon atom to which they are attached form , wherein the asterisk (*) indicates the carbon atom to which ^Xa and ^Xb are attached. In some such embodiments, n is 0, 1 or 2. In some such embodiments, n is 0 or 1. In some such embodiments, n is 1 or 2. In some such embodiments, n is 0. In some such embodiments, n is 1. In some such embodiments, n is 2. In some such embodiments, m is 1 or 2. In some such embodiments, m is 1. In some such embodiments, m is 2. In some such embodiments, R ¹⁰ is H or C ₁ -C ₆ alkyl optionally substituted with OH, halogen, NR ⁴ R ⁵ , CO 2 R ⁴ or CO ₂ H. In some such embodiments, R ¹⁰ is H. In some such embodiments, R ¹⁰ is C ₁ -C ₆ alkyl, optionally substituted with OH, halogen, NR ⁴ R ⁵ , CO 2 R ⁴ or CO ₂ H. In some such embodiments, R ¹⁰ is C ₁ -C ₆ alkyl. In some such embodiments, R ¹⁰ is methyl, ethyl or isopropyl. In some such embodiments, R ¹⁰ is methyl. In some such embodiments, R ¹⁰ is ethyl. In some such embodiments, R ¹⁰ is isopropyl. In some such embodiments, R ¹⁰ is C ₁ -C ₆ alkyl, optionally substituted with OH, halogen, NR ⁴ R ⁵ , CO 2 R ⁴ or CO ₂ H. In some such embodiments, R ¹⁰ is methyl substituted by OH, halo, NR ⁴ R ⁵ , CO2R ⁴ or CO ₂ H. In some such embodiments, R ¹⁰ is ethyl substituted by OH, halo, NR ⁴ R ⁵ , CO2R ⁴ or CO ₂ H. In some such embodiments, R ¹⁰ is isopropyl substituted by OH, halo, NR ⁴ R ⁵ , CO2R ⁴ or CO ₂ H. In some such embodiments, X ^c is H, halo or optionally substituted C ₁ -C ₆ alkyl. In some such embodiments, X ^c is H. In some such embodiments, X ^c is halo. In some such embodiments, X ^c is F, Cl or Br. In some such embodiments, X ^c is F. In some such embodiments, ^Xc is Cl. In some such embodiments, ^Xc is Br. In some such embodiments, Xc is optionally substituted C1-C6 alkyl. In some such embodiments, ^Xc is _{C1 - C6} alkyl. In some such embodiments, ^Xc is methyl _, ethyl or isopropyl. In some such embodiments, ^Xc is methyl. In some such embodiments, ^Xc is ^ethyl . In some such embodiments, ^Xc is isopropyl. In some such embodiments, ^Xc is substituted _C1 - _C6 alkyl. In some such embodiments, ^Xc is substituted methyl. In some such embodiments, ^Xc is substituted ethyl. In some such embodiments, ^Xc is substituted isopropyl.

In some embodiments of formula (A), (I), (IIa), (IIIa) or (IVa), X ³ is CR ^3X and R ^3X is H, -OH, halo, optionally substituted C ₁ -C ₆ alkyl or -O(C ₁ -C ₆ alkyl). In some such embodiments, R ^3X is H. In some such embodiments, R ^3X is halo. In some such embodiments, R ^3X is F, Cl or Br. In some such embodiments, R ^3X is F. In some such embodiments, R ^3X is Cl. In some such embodiments, R ^3X is Br. In some such embodiments, R ^3X is optionally substituted C ₁ -C ₆ alkyl. In some such embodiments, R ^3X is C ₁ -C ₆ alkyl. In some such embodiments, R ^3X is methyl, ethyl or isopropyl. In some such embodiments, R ^3X is methyl. In some such embodiments, R ^3X is ethyl. In some such embodiments, R 3X is isopropyl. In some such embodiments, R ^3X is substituted C ₁ -C ₆ alkyl ^{. In some such embodiments, R 3X is} C ₁ -C ₆ alkyl substituted with one or more of halogen, OH, NR ⁴ R ⁵ or C ₃ -C ₈ cycloalkyl, wherein R ⁴ and R ⁵ are as defined for formula (I). In some such embodiments, R ^3X is C ₁ -C ₆ alkyl substituted with one or more halogens. In some such embodiments, R ^3X is C ₁ -C ₆ alkyl substituted with one or more F, Cl or Br. In some such embodiments, R ^3X is C ₁ -C ₆ alkyl substituted with one or more F. In some such embodiments, R ^3X is C ₁ -C ₆ alkyl substituted with one or more Cl. In some such embodiments, R ^3X is C ₁ -C ₆ alkyl substituted with one or more Br. In some such embodiments, R ^3X is C ₁ -C ₆ alkyl substituted with one or more -OH. In some such embodiments, R ^3X is C ₁ -C ₆ alkyl substituted with one or more -NR ⁴ R ^5. In some such embodiments, R ^3X is C ₁ -C ₆ alkyl substituted with one or more NHR ⁴ . In some such embodiments, R ^3X is C ₁ -C ₆ alkyl substituted with one or more NCH ₃ (R ⁴ ). In some such embodiments, R ^3X is C ₁ -C ₆ alkyl substituted with one or more NH _2. In some such embodiments, R ^3X is C ₁ -C ₆ alkyl substituted with one or more N(CH ₃ ) _2. In some such embodiments, R ^3X is C 1 -C 6 alkyl substituted with one or more NH(CH ₃ ). In some such embodiments, R ^3X is C ₁ -C ₆ alkyl substituted with one or more NH(CH ₂ CH ₃ ). In some such embodiments, R ^3X is _{C 1} -C ₆ alkyl substituted with one or more C _{3 -C 8} cycloalkyl. In some such embodiments, R ^3X is C 1 _{-C 6} alkyl substituted with one or more C ₃ cycloalkyl, C ₄ cycloalkyl, C ₅ cycloalkyl, C ₆ cycloalkyl, C ₇ cycloalkyl or C ₈ cycloalkyl. In some such embodiments, R ^3X is C ₁ -C ₆ alkyl substituted with one or more C ₃ cycloalkyl. In some such embodiments, R ^3X is C ₁ -C ₆ alkyl substituted with one or more C ₄ cycloalkyl. In some such embodiments, R ^3X is C ₁ -C 6 alkyl substituted with one or more C ₅ cycloalkyl. In some such embodiments, R ^3X is _{C 1 -C 6} alkyl substituted with one or more C ₆ cycloalkyl. In some such embodiments, R ^3X is C ₁ -C ₆ alkyl substituted with one or more C ₇ cycloalkyl groups. In some such embodiments, R ^3X is C ₁ -C ₆ alkyl substituted with one or more C ₈ cycloalkyl groups. In some such embodiments, R ^3X is C ₁ -C ₆ alkyl substituted with one or more cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl groups. In some such embodiments, R ^3X is C 1 -C 6 alkyl substituted with one or more cyclopropyl. In some such embodiments, R ^3X is C ₁ -C ₆ alkyl substituted with one or more cyclobutyl. In some such embodiments, R ^3X is _{C 1 -C 6} alkyl substituted with one or more cyclopentyl groups. In some such embodiments, R ^3X is C ₁ -C ₆ alkyl substituted with one or more cyclohexyl groups. In some such embodiments, R ^3X is O(C ₁ -C ₆ alkyl). In some such embodiments, R ^3X is O(C ₁ alkyl). In some such embodiments, R ^3X is O(C ₂ alkyl). In some such embodiments, R ^3X is -O(C ₃ alkyl). In some such embodiments, R ^3X is O(C ₄ alkyl). In some such embodiments, R ^3X is O(C ₅ alkyl). In some such embodiments, R ^3X is O(C ₆ alkyl).

In some embodiments of Formula (A), (I), (IIa), (IIIa) or (IVa), X ³ is CR ^3X and R ^3X is . In some such embodiments, q is 0 to 6. In some such embodiments, q is 0. In some such embodiments, q is 1. In some such embodiments, q is 2. In some such embodiments, q is 3. In some such embodiments, q is 4. In some such embodiments, q is 5. In some such embodiments, q is 6. In some such embodiments, R ⁸ is H, halogen, CN, SH, OH, -CO ₂ H, NR ⁴ R ⁵ , or C ₁ -C ₆ alkyl optionally substituted with OH, halogen, or CO ₂ H. In some such embodiments, R ⁸ is H. In some such embodiments, R ⁸ is halogen. In some such embodiments, R ⁸ is F, Cl, or Br. In some such embodiments, R ⁸ is F. In some such embodiments, R ⁸ is Cl. In some such embodiments, R ⁸ is Br. In some such embodiments, R ⁸ is CN. In some such embodiments, R ⁸ is SH. In some such embodiments, R ⁸ is OH. In some such embodiments, R ⁸ is CO ₂ H. In some such embodiments, R ⁸ is NR ⁴ R ^5. In some such embodiments, R ⁸ is NHR ^4. In some such embodiments, R ⁸ is NCH ₃ (R ⁴ ). In some such embodiments, R ⁸ is NH ₂ . In some such embodiments, R ⁸ is N(CH ₃ ) ₂ . In some such embodiments, R ⁸ is NH(CH ₃ ). In some such embodiments, R ⁸ is NH(CH ₂ CH ₃ ). In some such embodiments, R ⁸ is C ₁ -C ₆ alkyl, optionally substituted with OH, halogen, or CO ₂ H. In some such embodiments, R ⁸ is C ₁ -C ₆ alkyl. In some such embodiments, R ⁸ is methyl, ethyl, or isopropyl. In some such embodiments, R 8 is methyl. In some such embodiments, R ⁸ is ethyl. In some such embodiments, R ⁸ is isopropyl. In some such embodiments, R ⁸ is C 1 -C 6 alkyl, optionally substituted with OH, halogen, or CO ₂ H. In some such embodiments, R ⁸ is C ₁ -C ₆ alkyl, optionally substituted with OH, halogen, or CO 2 H. In some such embodiments, R ⁸ is C ₁ -C ₆ alkyl, optionally substituted with OH. In some such embodiments, R ⁸ is C ₁ -C ₆ alkyl, optionally substituted with halogen. In some such embodiments, ^R is C ₁ -C ₆ alkyl substituted with CO ₂ H. In some such embodiments, ^R is methyl substituted with -OH. In some such embodiments, ^R is ethyl substituted with -OH. In some such embodiments, ^R is isopropyl substituted with -OH. In some such embodiments, ^R is methyl substituted with halogen. In some such embodiments, ^R is ethyl substituted with halogen. In some such embodiments, R is isopropyl substituted with halogen. In some such embodiments, ^R is methyl substituted with -CO ² H. In some such embodiments, ^R is ethyl substituted with _{-CO 2 H.} In some such embodiments, R is ^isopropyl substituted with -CO ₂ H. In some such embodiments, R ⁹ is H, halogen, CN, SH, OH, CO ₂ H, NR ⁴ R ⁵ , or C ₁ -C ₆ alkyl optionally substituted with OH, halogen, or CO ₂ H. In some such embodiments, R ⁹ is H. In some such embodiments, R ⁹ is halogen. In some such embodiments, R ⁹ is F, Cl, or Br. In some such embodiments, R ⁹ is F. In some such embodiments, R ⁹ is Cl. In some such embodiments, R ⁹ is Br. In some such embodiments, R ⁹ is CN. In some such embodiments, R ⁹ is SH. In some such embodiments, R ⁹ is OH. In some such embodiments, R ⁹ is -CO ₂ H. In some such embodiments, R ⁹ is NR ⁴ R ⁵ . In some such embodiments, R ⁹ is NHR ⁴ . In some such embodiments, R ⁹ is NCH ₃ (R ⁴ ). In some such embodiments, R ⁹ is NH ₂ . In some such embodiments, R ⁹ is N(CH ₃ ) ₂ . In some such embodiments, R ⁹ is NH(CH ₃ ). In some such embodiments, R ⁹ is NH(CH ₂ CH ₃ ). In some such embodiments, R ⁹ is C ₁ -C ₆ alkyl optionally substituted with OH, halogen or CO ₂ H. In some such embodiments, R ⁹ is C ₁ -C ₆ alkyl. In some such embodiments, R ⁹ is methyl, ethyl or isopropyl. In some such embodiments, R ⁹ is methyl. In some such embodiments, R ⁹ is ethyl. In some such embodiments, R ⁹ is isopropyl. In some such embodiments, R ⁹ is C ₁ -C ₆ alkyl substituted with OH, halogen or CO ₂ H. In some such embodiments, R ⁹ is C ₁ -C ₆ alkyl substituted with OH. In some such embodiments, R ⁹ is C ₁ -C ₆ alkyl substituted with halogen. In some such embodiments, R ⁹ is C ₁ -C ₆ alkyl substituted with CO ₂ H. In some such embodiments, R ⁹ is methyl substituted with OH. In some such embodiments, R ⁹ is ethyl substituted with -OH. In some such embodiments, R ⁹ is isopropyl substituted with -OH. In some such embodiments, R ⁹ is methyl substituted by halogen. In some such embodiments, R ⁹ is ethyl substituted by -halogen. In some such embodiments, R ⁹ is isopropyl substituted by halogen. In some such embodiments, R ⁹ is methyl substituted by CO ₂ H. In some such embodiments, R ⁹ is ethyl substituted by CO ₂ H. In some such embodiments, R ⁹ is isopropyl substituted by CO ₂ H.

In some embodiments of Formula (A), (I), (IIa), (IIIa) or (IVa), X ³ is CR ^3X and R ^3X is . In some such embodiments, ^Xa is H, OH, SH, _CO2H , _CO2R4 ^{, or NR4R5 .} In some ^such embodiments, ^Xa is H. In some such embodiments, ^Xa is OH. In some such embodiments, ^Xa is SH. In some such embodiments, ^Xa is _CO2H . In some such embodiments, ^Xa is _CO2R4 . In some such embodiments, ^Xa is _CO2R4 and ^R4 is optionally substituted C1-C6 alkyl. In some such embodiments, ^Xa is ^CO2R4 and ^R4 is _{C1 - C6} alkyl. In some such embodiments _, ^{Xa is} _CO2R4 ^{and R4} is ^methyl , ethyl _, or isopropyl. In some such embodiments, ^Xa is _CO2R4 and ^R4 is methyl. In some such embodiments, ^Xa is ^{CO2R4 and} R4 is ethyl. In some such embodiments, ^Xa is _CO2R4 ^{and R4} is isopropyl. In some such embodiments, ^Xa is _CO2R4 ^{and R4 is} substituted _C1 - _C6 alkyl. In some such embodiments, ^Xa is _CO2R4 ^{and R4} is substituted ^methyl . In some such embodiments, ^Xa is _{CO2R4 and} ^R4 is substituted ethyl. ^In some such embodiments, ^{Xa is} _CO2R4 ^{and R4} is substituted isopropyl. In some such embodiments, ^Xa is ^NR4R5 . In some such embodiments, ^Xa is ^NHR4 . In some such embodiments, ^Xa is _NCH3 ( ^R4 ). In some such embodiments, ^Xa is _NH2 . In some such embodiments, ^Xa is N( _CH3 ) ₂ . In some such embodiments, ^Xa is NH(CH3). In some such embodiments, ^Xa is _NH ( _CH2CH3 ). In some such embodiments, ^Xb is H, OH, _SH , _CO2H , _CO2R4 ^, or ^NR4R5 . In some ^such embodiments, ^Xb is H. In some such embodiments, ^Xb is OH. In some such embodiments, ^Xb is SH. In some such embodiments, ^Xb is _CO2H . In some ^such embodiments, ^Xb is _CO2R4 . In some such embodiments, X ^b is CO ₂ R ⁴ and R ⁴ is optionally substituted C ₁ -C ₆ alkyl. In some such embodiments, X ^b is CO ₂ R ⁴ and R ⁴ is C ₁ -C ₆ alkyl. In some such embodiments, X ^b is CO ₂ R ⁴ and R ⁴ is methyl, ethyl or isopropyl. In some such embodiments, X ^b is CO ₂ R ⁴ and R ⁴ is methyl. In some such embodiments, X ^b is CO ₂ R ⁴ and R ⁴ is ethyl. In some such embodiments, X ^b is CO ₂ R ⁴ and R ⁴ is isopropyl. In some such embodiments, X ^b is CO ₂ R ⁴ and R ⁴ is substituted C ₁ -C ₆ alkyl. In some such embodiments, X ^b is CO ₂ R ⁴ and R ⁴ is substituted methyl. In some such embodiments, X ^b is CO ₂ R ⁴ and R ⁴ is substituted ethyl. In some such embodiments, X ^b is CO ₂ R ⁴ and R ⁴ is substituted isopropyl. In some such embodiments, X ^b is NR ⁴ R ⁵ . In some such embodiments, X ^b is NHR ⁴ . In some such embodiments, X ^b is NCH ₃ (R ⁴ ). In some such embodiments, X ^b is NH ₂ . In some such embodiments, X ^b is N(CH ₃ ) ₂ . In some such embodiments, X ^b is NH(CH ₃ ). In some such embodiments, X ^b is NH(CH ₂ CH ₃ ). In some such embodiments, ^Xc is H, halogen, or optionally substituted _C1 - _C6 alkyl. In some such embodiments, ^Xc is H. In some such embodiments, ^Xc is OH. In some such embodiments, ^Xc is F, Cl, or Br. In some such embodiments, ^Xc is F. In some such embodiments, ^Xc is Cl. In some such embodiments, ^Xc is Br. In some such embodiments, ^Xc is optionally substituted _C1 - _C6 alkyl. In some such embodiments, ^Xc is _C1 - _C6 alkyl. In some such embodiments, ^Xc is methyl, ethyl, or isopropyl. In some such embodiments, ^Xc is methyl. In some such embodiments, ^Xc is ethyl. In some such embodiments, ^Xc is isopropyl. In some such embodiments, ^Xc is substituted _C1 - _C6 alkyl. In some such embodiments, ^Xc is substituted methyl. In some such embodiments, ^Xc is substituted ethyl. In some such embodiments, ^Xc is substituted isopropyl.

In some embodiments of Formula (A), (I), (IIa), (IIIa) or (IVa), X ³ is CR ^3X and R ^3X is , and ^Xa and ^Xb together with the carbon atom to which they are attached form , wherein the asterisk (*) indicates the carbon atom to which ^Xa and ^Xb are attached. In some such embodiments, n is 0, 1 or 2. In some such embodiments, n is 0 or 1. In some such embodiments, n is 1 or 2. In some such embodiments, n is 0. In some such embodiments, n is 1. In some such embodiments, n is 2. In some such embodiments, m is 1 or 2. In some such embodiments, m is 1. In some such embodiments, m is 2. In some such embodiments, R ¹⁰ is H or C ₁ -C ₆ alkyl optionally substituted with OH, halogen, NR ⁴ R ⁵ , CO 2 R ⁴ or CO ₂ H. In some such embodiments, R ¹⁰ is H. In some such embodiments, R ¹⁰ is C ₁ -C ₆ alkyl, optionally substituted with OH, halogen, NR ⁴ R ⁵ , CO 2 R ⁴ or CO ₂ H. In some such embodiments, R ¹⁰ is C ₁ -C ₆ alkyl. In some such embodiments, R ¹⁰ is methyl, ethyl or isopropyl. In some such embodiments, R ¹⁰ is methyl. In some such embodiments, R ¹⁰ is ethyl. In some such embodiments, R ¹⁰ is isopropyl. In some such embodiments, R ¹⁰ is C ₁ -C ₆ alkyl, optionally substituted with OH, halogen, NR ⁴ R ⁵ , CO 2 R ⁴ or CO ₂ H. In some such embodiments, R ¹⁰ is methyl substituted by OH, halo, NR ⁴ R ⁵ , CO2R ⁴ or CO ₂ H. In some such embodiments, R ¹⁰ is ethyl substituted by OH, halo, NR ⁴ R ⁵ , CO2R ⁴ or CO ₂ H. In some such embodiments, R ¹⁰ is isopropyl substituted by OH, halo, NR ⁴ R ⁵ , CO2R ⁴ or CO ₂ H. In some such embodiments, X ^c is H, halo or optionally substituted C ₁ -C ₆ alkyl. In some such embodiments, X ^c is H. In some such embodiments, X ^c is OH. In some such embodiments, X ^c is F, Cl or Br. In some such embodiments, X ^c is F. In some such embodiments, X ^c is Cl. In some such embodiments, ^Xc is Br. In some such embodiments, ^Xc is optionally substituted _C1 - _C6 alkyl. In some such embodiments, ^Xc is _C1 - _C6 alkyl. In some such embodiments, ^Xc is methyl, ethyl or isopropyl. In some such embodiments, ^Xc is methyl. In some such embodiments, ^Xc is ethyl. In some such embodiments, ^Xc is isopropyl. In some such embodiments, ^Xc is substituted _C1 - _C6 alkyl. In some such embodiments, ^Xc is substituted methyl. In some such embodiments, ^Xc is substituted ethyl. In some such embodiments, ^Xc is substituted isopropyl.

In some embodiments of Formula (A), (I), (IIa), (IIIa) or (IVa), Y ¹ is CR ^1Y and R ^1Y is H, -OH, halo, optionally substituted C ₁ -C ₆ alkyl, or -O(C ₁ -C ₆ alkyl). In some such embodiments, R ^1Y is H. In some such embodiments, R ^1Y is halo. In some such embodiments, R ^1Y is F, Cl or Br. In some such embodiments, R ^1Y is F. In some such embodiments, R ^1Y is Cl. In some such embodiments, R ^1Y is Br. In some such embodiments, R ^1Y is optionally substituted C ₁ -C ₆ alkyl. In some such embodiments, R ^1Y is C ₁ -C ₆ alkyl. In some such embodiments, R ^1Y is methyl, ethyl or isopropyl. In some such embodiments, R ^1Y is methyl. In some such embodiments, R ^1Y is ethyl. In some such embodiments, R 1Y is isopropyl. In some such embodiments, R ^1Y is substituted C ₁ -C ₆ alkyl ^{. In some such embodiments, R 1Y is} C ₁ -C ₆ alkyl substituted with one or more of halo, -OH, -NR ⁴ R ⁵ or C ₃ -C ₈ cycloalkyl, wherein R ⁴ and R ⁵ are as defined for formula (I). In some such embodiments, R ^1Y is C ₁ -C ₆ alkyl substituted with one or more halo. In some such embodiments, R ^1Y is C ₁ -C ₆ alkyl substituted with one or more F, Cl or Br. In some such embodiments, R ^1Y is C ₁ -C ₆ alkyl substituted with one or more F. In some such embodiments, R ^1Y is C ₁ -C ₆ alkyl substituted with one or more Cl. In some such embodiments, R ^1Y is C ₁ -C ₆ alkyl substituted with one or more Br. In some such embodiments, R ^1Y is C ₁ -C ₆ alkyl substituted with one or more OH. In some such embodiments, R ^1Y is C ₁ -C ₆ alkyl substituted with one or more NR ⁴ R ^5. In some such embodiments, R ^1Y is C ₁ -C ₆ alkyl substituted with one or more NHR ⁴ . In some such embodiments, R ^1Y is C ₁ -C ₆ alkyl substituted with one or more NCH ₃ (R ⁴ ). In some such embodiments, R ^1Y is C ₁ -C ₆ alkyl substituted with one or more NH _2. In some such embodiments, R ^1Y is C ₁ -C ₆ alkyl substituted with one or more N(CH ₃ ) _2. In some such embodiments, R ^1Y is C 1 -C 6 alkyl substituted with one or more NH(CH ₃ ). In some such embodiments, R ^1Y is C ₁ -C ₆ alkyl substituted with one or more NH(CH ₂ CH ₃ ). In some such embodiments, R ^1Y is _{C 1} -C ₆ alkyl substituted with one or more C _{3 -C 8} cycloalkyl. In some such embodiments, R ^1Y is C 1 _{-C 6} alkyl substituted with one or more C ₃ cycloalkyl, C ₄ cycloalkyl, C ₅ cycloalkyl, C ₆ cycloalkyl, C ₇ cycloalkyl, or C ₈ cycloalkyl. In some such embodiments, R ^1Y is C ₁ -C ₆ alkyl substituted with one or more C ₃ cycloalkyl. In some such embodiments, R ^1Y is C ₁ -C ₆ alkyl substituted with one or more C ₄ cycloalkyl. In some such embodiments, R ^1Y is C ₁ -C ₆ alkyl substituted with one or more C ₅ cycloalkyl. In some such embodiments, R ^1Y is C _{1 -C 6} alkyl substituted with one or more C ₆ cycloalkyl. In some such embodiments, R ^1Y is C ₁ -C ₆ alkyl substituted with one or more C ₇ cycloalkyl groups. In some such embodiments, R ^1Y is C ₁ -C ₆ alkyl substituted with one or more C ₈ cycloalkyl groups. In some such embodiments, R ^1Y is C ₁ -C ₆ alkyl substituted with one or more cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl groups. In some such embodiments, R ^1Y is C 1 -C 6 alkyl substituted with one or more cyclopropyl. In some such embodiments, R ^1Y is C ₁ -C ₆ alkyl substituted with one or more cyclobutyl. In some such embodiments, R ^1Y is _{C 1 -C 6} alkyl substituted with one or more cyclopentyl groups. In some such embodiments, R ^1Y is C ₁ -C ₆ alkyl substituted with one or more cyclohexyl groups. In some such embodiments, R ^1Y is -O(C ₁ -C ₆ alkyl). In some such embodiments, R ^1Y is -O(C ₁ alkyl). In some such embodiments, R ^1Y is -O(C ₂ alkyl). In some such embodiments, R ^1Y is -O(C ₃ alkyl). In some such embodiments, R ^1Y is -O(C ₄ alkyl). In some such embodiments, R ^1Y is -O(C ₅ alkyl). In some such embodiments, R ^1Y is -O(C ₆ alkyl).

In some embodiments of Formula (A), (I), (IIa), (IIIa) or (IVa), Y ¹ is CR ^1Y and R ^1Y is . In some such embodiments, q is 0 to 6. In some such embodiments, q is 0. In some such embodiments, q is 1. In some such embodiments, q is 2. In some such embodiments, q is 3. In some such embodiments, q is 4. In some such embodiments, q is 5. In some such embodiments, q is 6. In some such embodiments, R ⁸ is H, halogen, CN, SH, OH, -CO ₂ H, NR ⁴ R ⁵ , or C ₁ -C ₆ alkyl optionally substituted with -OH, halogen, or -CO ₂ H. In some such embodiments, R ⁸ is H. In some such embodiments, R ⁸ is halogen. In some such embodiments, R ⁸ is F, Cl, or Br. In some such embodiments, R ⁸ is F. In some such embodiments, R ⁸ is Cl. In some such embodiments, R ⁸ is Br. In some such embodiments, R ⁸ is CN. In some such embodiments, R ⁸ is SH. In some such embodiments, R ⁸ is OH. In some such embodiments, R ⁸ is -CO ₂ H. In some such embodiments, R ⁸ is NR ⁴ R ^5. In some such embodiments, R ⁸ is NHR ^4. In some such embodiments, R ⁸ is NCH ₃ (R ⁴ ). In some such embodiments, R ⁸ is NH ₂ . In some such embodiments, R ⁸ is N(CH ₃ ) ₂ . In some such embodiments, R ⁸ is NH(CH ₃ ). In some such embodiments, R ⁸ is NH(CH ₂ CH ₃ ). In some such embodiments, R ⁸ is C ₁ -C ₆ alkyl substituted with -OH, halogen or -CO ₂ H, as appropriate. In some such embodiments, R ⁸ is C ₁ -C ₆ alkyl. In some such embodiments, R ⁸ is methyl, ethyl or isopropyl. In some such embodiments, R ⁸ is methyl. In some such embodiments, R ⁸ is ethyl. In some such embodiments, R ⁸ is isopropyl. In some such embodiments, R ⁸ is C ₁ -C ₆ alkyl substituted with OH, halogen or CO ₂ H. In some such embodiments, R ⁸ is C ₁ -C ₆ alkyl substituted with OH. In some such embodiments, R ⁸ is C ₁ -C ₆ alkyl substituted with halogen. In some such embodiments, ^R is C ₁ -C ₆ alkyl substituted with CO ₂ H. In some such embodiments, ^R is methyl substituted with OH. In some such embodiments, ^R is ethyl substituted with -OH. In some such embodiments, ^R is isopropyl substituted with -OH. In some such embodiments, ^R is methyl substituted with halogen. In some such embodiments, ^R is ethyl substituted with halogen. In some such embodiments, R is isopropyl substituted with halogen. In some such embodiments, ^R is methyl substituted with CO ² H. In some such embodiments, ^R is ethyl substituted with CO _{2 H.} In some such embodiments, R is ^isopropyl substituted with CO ₂ H. In some such embodiments, R ⁹ is H, halogen, CN, SH, OH, -CO ₂ H, NR ⁴ R ⁵ , or C ₁ -C ₆ alkyl optionally substituted with OH, halogen, or CO ₂ H. In some such embodiments, R ⁹ is H. In some such embodiments, R ⁹ is halogen. In some such embodiments, R ⁹ is F, Cl, or Br. In some such embodiments, R ⁹ is F. In some such embodiments, R ⁹ is Cl. In some such embodiments, R ⁹ is Br. In some such embodiments, R ⁹ is CN. In some such embodiments, R ⁹ is SH. In some such embodiments, R ⁹ is OH. In some such embodiments, R ⁹ is CO ₂ H. In some such embodiments, R ⁹ is NR ⁴ R ⁵ . In some such embodiments, R ⁹ is NHR ⁴ . In some such embodiments, R ⁹ is NCH ₃ (R ⁴ ). In some such embodiments, R ⁹ is NH ₂ . In some such embodiments, R ⁹ is N(CH ₃ ) ₂ . In some such embodiments, R ⁹ is NH(CH ₃ ). In some such embodiments, R ⁹ is NH(CH ₂ CH ₃ ). In some such embodiments, R ⁹ is C ₁ -C ₆ alkyl optionally substituted with OH, halogen or CO ₂ H. In some such embodiments, R ⁹ is C ₁ -C ₆ alkyl. In some such embodiments, R ⁹ is methyl, ethyl or isopropyl. In some such embodiments, R ⁹ is methyl. In some such embodiments, R ⁹ is ethyl. In some such embodiments, R ⁹ is isopropyl. In some such embodiments, R ⁹ is C ₁ -C ₆ alkyl substituted with OH, halogen or CO ₂ H. In some such embodiments, R ⁹ is C ₁ -C ₆ alkyl substituted with OH. In some such embodiments, R ⁹ is C ₁ -C ₆ alkyl substituted with halogen. In some such embodiments, R ⁹ is C ₁ -C ₆ alkyl substituted with CO ₂ H. In some such embodiments, R ⁹ is methyl substituted with -OH. In some such embodiments, R ⁹ is ethyl substituted with -OH. In some such embodiments, R ⁹ is isopropyl substituted with -OH. In some such embodiments, R ⁹ is methyl substituted by halogen. In some such embodiments, R ⁹ is ethyl substituted by halogen. In some such embodiments, R ⁹ is isopropyl substituted by halogen. In some such embodiments, R ⁹ is methyl substituted by CO ₂ H. In some such embodiments, R ⁹ is ethyl substituted by CO ₂ H. In some such embodiments, R ⁹ is isopropyl substituted by CO ₂ H.

In some embodiments of Formula (A), (I), (IIa), (IIIa) or (IVa), Y ¹ is CR ^1Y and R ^1Y is . In some such embodiments, ^Xa is H, OH, SH, _CO2H , _CO2R4 ^{, or NR4R5 .} In some ^such embodiments, ^Xa is H. In some such embodiments, ^Xa is OH. In some such embodiments, ^Xa is SH. In some such embodiments, ^Xa is _CO2H . In some such embodiments, ^Xa is _CO2R4 . In some such embodiments, ^Xa is _CO2R4 and ^R4 is optionally substituted C1-C6 alkyl. In some such embodiments, ^Xa is ^CO2R4 and ^R4 is _{C1 - C6} alkyl. In some such embodiments _, ^{Xa is} _CO2R4 ^{and R4} is ^methyl , ethyl _, or isopropyl. In some such embodiments, ^Xa is _CO2R4 and ^R4 is methyl. In some such embodiments, ^Xa is ^{CO2R4 and} R4 is ethyl. In some such embodiments, ^Xa is _CO2R4 ^{and R4} is isopropyl. In some such embodiments, ^Xa is _CO2R4 ^{and R4 is} substituted _C1 - _C6 alkyl. In some such embodiments, ^Xa is _CO2R4 ^{and R4} is substituted ^methyl . In some such embodiments, ^Xa is _{CO2R4 and} ^R4 is substituted ethyl. ^In some such embodiments, ^{Xa is} _CO2R4 ^{and R4} is substituted isopropyl. In some such embodiments, ^Xa is ^NR4R5 . In some such embodiments, ^Xa is ^NHR4 . In some such embodiments, ^Xa is _NCH3 ( ^R4 ). In some such embodiments, ^Xa is _NH2 . In some such embodiments, ^Xa is N( _CH3 ) ₂ . In some such embodiments, ^Xa is NH(CH3). In some such embodiments, ^Xa is _NH ( _CH2CH3 ). In some such embodiments, ^Xb is H, OH, _SH , _CO2H , _CO2R4 ^, or ^NR4R5 . In some ^such embodiments, ^Xb is H. In some such embodiments, ^Xb is OH. In some such embodiments, ^Xb is SH. In some such embodiments, ^Xb is _CO2H . In some ^such embodiments, ^Xb is _CO2R4 . In some such embodiments, X ^b is CO ₂ R ⁴ and R ⁴ is optionally substituted C ₁ -C ₆ alkyl. In some such embodiments, X ^b is CO ₂ R ⁴ and R ⁴ is C ₁ -C ₆ alkyl. In some such embodiments, X ^b is CO ₂ R ⁴ and R ⁴ is methyl, ethyl or isopropyl. In some such embodiments, X ^b is CO ₂ R ⁴ and R ⁴ is methyl. In some such embodiments, X ^b is CO ₂ R ⁴ and R ⁴ is ethyl. In some such embodiments, X ^b is CO ₂ R ⁴ and R ⁴ is isopropyl. In some such embodiments, X ^b is CO ₂ R ⁴ and R ⁴ is substituted C ₁ -C ₆ alkyl. In some such embodiments, X ^b is CO ₂ R ⁴ and R ⁴ is substituted methyl. In some such embodiments, X ^b is CO ₂ R ⁴ and R ⁴ is substituted ethyl. In some such embodiments, X ^b is CO ₂ R ⁴ and R ⁴ is substituted isopropyl. In some such embodiments, X ^b is NR ⁴ R ⁵ . In some such embodiments, X ^b is NHR ⁴ . In some such embodiments, X ^b is NCH ₃ (R ⁴ ). In some such embodiments, X ^b is NH ₂ . In some such embodiments, X ^b is N(CH ₃ ) ₂ . In some such embodiments, X ^b is NH(CH ₃ ). In some such embodiments, X ^b is NH(CH ₂ CH ₃ ). In some such embodiments, ^Xc is H, halogen, or optionally substituted _C1 - _C6 alkyl. In some such embodiments, ^Xc is H. In some such embodiments, ^Xc is OH. In some such embodiments, ^Xc is F, Cl, or Br. In some such embodiments, ^Xc is F. In some such embodiments, ^Xc is Cl. In some such embodiments, ^Xc is Br. In some such embodiments, ^Xc is optionally substituted _C1 - _C6 alkyl. In some such embodiments, ^Xc is _C1 - _C6 alkyl. In some such embodiments, ^Xc is methyl, ethyl, or isopropyl. In some such embodiments, ^Xc is methyl. In some such embodiments, ^Xc is ethyl. In some such embodiments, ^Xc is isopropyl. In some such embodiments, ^Xc is substituted _C1 - _C6 alkyl. In some such embodiments, ^Xc is substituted methyl. In some such embodiments, ^Xc is substituted ethyl. In some such embodiments, ^Xc is substituted isopropyl.

In some embodiments of Formula (A), (I), (IIa), (IIIa) or (IVa), Y ¹ is CR ^1Y and R ^1Y is , and ^Xa and ^Xb together with the carbon atom to which they are attached form , wherein the asterisk (*) indicates the carbon atom to which ^Xa and ^Xb are attached. In some such embodiments, n is 0, 1 or 2. In some such embodiments, n is 0 or 1. In some such embodiments, n is 1 or 2. In some such embodiments, n is 0. In some such embodiments, n is 1. In some such embodiments, n is 2. In some such embodiments, m is 1 or 2. In some such embodiments, m is 1. In some such embodiments, m is 2. In some such embodiments, R ¹⁰ is H or C ₁ -C ₆ alkyl optionally substituted with OH, halogen, NR ⁴ R ⁵ , CO 2 R ⁴ or CO ₂ H. In some such embodiments, R ¹⁰ is H. In some such embodiments, R ¹⁰ is C ₁ -C ₆ alkyl, optionally substituted with OH, halogen, NR ⁴ R ⁵ , CO 2 R ⁴ or CO ₂ H. In some such embodiments, R ¹⁰ is C ₁ -C ₆ alkyl. In some such embodiments, R ¹⁰ is methyl, ethyl or isopropyl. In some such embodiments, R ¹⁰ is methyl. In some such embodiments, R ¹⁰ is ethyl. In some such embodiments, R ¹⁰ is isopropyl. In some such embodiments, R ¹⁰ is C ₁ -C ₆ alkyl, optionally substituted with OH, halogen, NR ⁴ R ⁵ , CO 2 R ⁴ or CO ₂ H. In some such embodiments, R ¹⁰ is methyl substituted by OH, halo, NR ⁴ R ⁵ , CO2R ⁴ or CO ₂ H. In some such embodiments, R ¹⁰ is ethyl substituted by OH, halo, NR ⁴ R ⁵ , CO2R ⁴ or CO ₂ H. In some such embodiments, R ¹⁰ is isopropyl substituted by OH, halo, NR ⁴ R ⁵ , CO2R ⁴ or CO ₂ H. In some such embodiments, X ^c is H, halo or optionally substituted C ₁ -C ₆ alkyl. In some such embodiments, X ^c is H. In some such embodiments, X ^c is OH. In some such embodiments, X ^c is F, Cl or Br. In some such embodiments, X ^c is F. In some such embodiments, X ^c is Cl. In some such embodiments, ^Xc is Br. In some such embodiments, ^Xc is optionally substituted _C1 - _C6 alkyl. In some such embodiments, ^Xc is _C1 - _C6 alkyl. In some such embodiments, ^Xc is methyl, ethyl or isopropyl. In some such embodiments, ^Xc is methyl. In some such embodiments, ^Xc is ethyl. In some such embodiments, ^Xc is isopropyl. In some such embodiments, ^Xc is substituted _C1 - _C6 alkyl. In some such embodiments, ^Xc is substituted methyl. In some such embodiments, ^Xc is substituted ethyl. In some such embodiments, ^Xc is substituted isopropyl.

In some embodiments of formula (A), (I), (IIa), (IIIa) or (IVa), X ¹ is CR ^1X and R ^1X is H. In some embodiments, X ¹ is CR ^1X and R ^1X is OH. In some embodiments, X ¹ is CR ^1X and R ^1X is OCH ₃ . In some embodiments, X ¹ is CR ^1X ; R ^1X is ; q is 1 or 2; R ⁸ is H, halogen or OH; R ⁹ is H, halogen or OH; X ^c is H, halogen or optionally substituted C ₁ -C ₆ alkyl; X ^a is H, OH, NR ⁴ R ⁵ ; X ^b is H, OH, NR ⁴ R ⁵ ; or X ^a and X ^b together with the carbon atom to which they are attached form , wherein the asterisk (*) indicates the carbon atom to which ^Xa and ^Xb are attached; ^R10 is H or _C1 - _C6 alkyl optionally substituted with OH, ^halogen , ^NR4R5 , _CO2R4 or ^CO2H ; n is 0, 1 or ₂ ; and m is 1 or 2. In some embodiments, ^X1 is ^CR1X ; ^R1X is ; q is 1 or 2; R ⁸ is H, halogen or OH; R ⁹ is H, halogen or OH; X ^c is H, halogen or optionally substituted C ₁ -C ₆ alkyl; X ^a is H, OH, NR ⁴ R ⁵ ; and X ^b is H, OH, NR ⁴ R ⁵ . In some embodiments, X ¹ is CR ^1X ; R ^1X is ; q is 2; R ⁸ is H or OH; R ⁹ is H or OH; X ^c is H; X ^a is OH or NR ⁴ R ⁵ ; and X ^b is H. In some embodiments, X ¹ is CR ^1X ; R ^1X is ; q is 2; R ⁸ is H; R ⁹ is H; X ^c is H; X ^a is OH or NR ⁴ R ⁵ ; and X ^b is H. In some embodiments, X ¹ is CR ^1X ; R ^1X is In some embodiments, X ¹ is CR ^1X ; R ^1X is In some embodiments, X ¹ is CR ^1X ; R ^1X is q is 1 or 2; R ⁸ is H, halogen or OH; R ⁹ is H, halogen or OH; X ^c is H, halogen or optionally substituted C ₁ -C ₆ alkyl; X ^a and X ^b together with the carbon atom to which they are attached form , wherein the asterisk (*) indicates the carbon atom to which ^Xa and ^Xb are attached; ^R10 is H or _C1 - _C6 alkyl optionally substituted with OH, ^halogen , ^NR4R5 , _CO2R4 or ^CO2H ; n is 0, 1 or ₂ ; and m is 1 or 2. In some embodiments, ^X1 is ^CR1X ; ^R1X is ; q is 2; R ⁸ is H or OH; R ⁹ is H or OH; X ^c is H, halogen or optionally substituted C ₁ -C ₆ alkyl; X ^a and X ^b together with the carbon atom to which they are attached form , wherein the asterisk (*) indicates the carbon atom to which ^Xa and ^Xb are attached; ^R10 is H or _C1 - _C6 alkyl optionally substituted with OH, ^halogen , ^NR4R5 , _{CO2R4 or} ^CO2H ; n is 0; and m is 1. In some embodiments, ^X1 is ^CR1X and ^R1X is In some embodiments, X ¹ is CR ^1X and R ^1X is .

In some embodiments of formula (A), (I), (IIa), (IIIa) or (IVa), X ³ is CR ^3X and R ^3X is H. In some embodiments, X ³ is CR ^3X and R ^3X is OH. In some embodiments, X ³ is CR ^3X and R ^3X is OCH ₃ . In some embodiments, X ³ is CR ^3X ; R ^3X is ; q is 1 or 2; R ⁸ is H, halogen or OH; R ⁹ is H, halogen or OH; X ^c is H, halogen or optionally substituted C ₁ -C ₆ alkyl; X ^a is H, OH, NR ⁴ R ⁵ ; X ^b is H, OH, NR ⁴ R ⁵ ; or X ^a and X ^b together with the carbon atom to which they are attached form , wherein the asterisk (*) indicates the carbon atom to which ^Xa and ^Xb are attached; ^R10 is H or _C1 - _C6 alkyl optionally substituted with OH, ^halogen , ^NR4R5 , _CO2R4 or ^CO2H ; n is 0, 1 or ₂ ; and m is 1 or 2. In some embodiments, ^X3 is ^CR3X ; ^R3X is ; q is 1 or 2; R ⁸ is H, halogen or OH; R ⁹ is H, halogen or OH; X ^c is H, halogen or optionally substituted C ₁ -C ₆ alkyl; X ^a is H, OH, NR ⁴ R ⁵ ; and X ^b is H, OH, NR ⁴ R ⁵ . In some embodiments, X ³ is CR ^3X ; R ^3X is ; q is 2; R ⁸ is H or OH; R ⁹ is H or OH; X ^c is H; X ^a is OH or NR ⁴ R ⁵ ; and X ^b is H. In some embodiments, X ³ is CR ^3X ; R ^3X is ; q is 2; R ⁸ is H; R ⁹ is H; X ^c is H; X ^a is OH or NR ⁴ R ⁵ ; and X ^b is H. In some embodiments, X ³ is CR ^3X ; R ^3X is In some embodiments, X ³ is CR ^3X ; R ^3X is In some embodiments, X ³ is CR ^3X ; R ^3X is q is 1 or 2; R ⁸ is H, halogen or OH; R ⁹ is H, halogen or OH; X ^c is H, halogen or optionally substituted C ₁ -C ₆ alkyl; X ^a and X ^b together with the carbon atom to which they are attached form , wherein the asterisk (*) indicates the carbon atom to which ^Xa and ^Xb are attached; ^R10 is H or _C1 - _C6 alkyl optionally substituted with OH, ^halogen , ^NR4R5 , _CO2R4 or ^CO2H ; n is 0, 1 or ₂ ; and m is 1 or 2. In some embodiments, ^X3 is ^CR3X ; ^R3X is ; q is 2; R ⁸ is H or OH; R ⁹ is H or OH; X ^c is H, halogen or optionally substituted C ₁ -C ₆ alkyl; X ^a and X ^b together with the carbon atom to which they are attached form , wherein the asterisk (*) indicates the carbon atom to which ^Xa and ^Xb are attached; ^R10 is H or _C1 - _C6 alkyl optionally substituted with OH, ^halogen , ^NR4R5 , _CO2R4 or ^CO2H ; n is 0; and m is 1. In some embodiments, _X3 ^{is CR3X} and ^R3X is In some embodiments, X ³ is CR ^3X and R ^3X is .

In some embodiments of formula (A), (I), (IIa), (IIIa) or (IVa), Y ¹ is CR ^1Y and R ^1Y is H. In some embodiments, Y ¹ is CR ^1Y and R ^1Y is OH. In some embodiments, Y ¹ is CR ^1Y and R ^1Y is OCH ₃ . In some embodiments, Y ¹ is CR ^1Y ; R ^1Y is ; q is 1 or 2; R ⁸ is H, halogen or OH; R ⁹ is H, halogen or OH; X ^c is H, halogen or optionally substituted C ₁ -C ₆ alkyl; X ^a is H, OH, NR ⁴ R ⁵ ; X ^b is H, OH, NR ⁴ R ⁵ ; or X ^a and X ^b together with the carbon atom to which they are attached form , wherein the asterisk (*) indicates the carbon atom to which ^Xa and ^Xb are attached; ^R10 is H or _C1 - _C6 alkyl optionally substituted with OH, ^halogen , ^NR4R5 , _CO2R4 or ^CO2H ; n is 0, 1 or ₂ ; and m is 1 or 2. In some embodiments, ^Y1 is ^CR1Y ; ^R1Y is ; q is 1 or 2; R ⁸ is H, halogen or OH; R ⁹ is H, halogen or OH; X ^c is H, halogen or optionally substituted C ₁ -C ₆ alkyl; X ^a is H, OH, NR ⁴ R ⁵ ; and X ^b is H, OH, NR ⁴ R ⁵ . In some embodiments, Y ¹ is CR ^1Y ; R ^1Y is ; q is 2; R ⁸ is H or OH; R ⁹ is H or OH; X ^c is H; X ^a is OH or NR ⁴ R ⁵ ; and X ^b is H. In some embodiments, Y ¹ is CR ^1Y ; R ^1Y is ; q is 2; R ⁸ is H; R ⁹ is H; X ^c is H; X ^a is OH or NR ⁴ R ⁵ ; and X ^b is H. In some embodiments, Y ¹ is CR ^1Y ; R ^1Y is In some embodiments, Y ¹ is CR ^1Y ; R ^1Y is In some embodiments, Y ¹ is CR ^1Y ; R ^1Y is q is 1 or 2; R ⁸ is H, halogen or OH; R ⁹ is H, halogen or OH; X ^c is H, halogen or optionally substituted C ₁ -C ₆ alkyl; X ^a and X ^b together with the carbon atom to which they are attached form , wherein the asterisk (*) indicates the carbon atom to which ^Xa and ^Xb are attached; ^R10 is H or _C1 - _C6 alkyl optionally substituted with OH, ^halogen , ^NR4R5 , _CO2R4 or ^CO2H ; n is 0, 1 or ₂ ; and m is 1 or 2. In some embodiments, ^Y1 is ^CR1Y ; ^R1Y is ; q is 2; R ⁸ is H or OH; R ⁹ is H or OH; X ^c is H, halogen or optionally substituted C ₁ -C ₆ alkyl; X ^a and X ^b together with the carbon atom to which they are attached form , wherein the asterisk (*) indicates the carbon atom to which ^Xa and ^Xb are attached; ^R10 is H or _C1 - _C6 alkyl optionally substituted with OH, ^halogen , ^NR4R5 , _{CO2R4 or} ^CO2H ; n is 0; and m is 1. In some embodiments, ^Y1 is ^CR1Y and ^R1Y is In some embodiments, Y ¹ is CR ^1Y and R ^1Y is .

In some embodiments of formula (A), (I), (IIa), (IIIa) or (IVa), Y ¹ is CH, N, C-OH or C-OCH ₃ ; X ³ is CH, N, C-OH or C-OCH ₃ ; X ¹ is CR ^1X ; and R ^1X is OH. In some embodiments, Y ¹ is CH, N, C-OH or C-OCH ₃ ; X ³ is CH, N, C-OH or C-OCH ₃ ; X ¹ is CR ^1X ; and R ^1X is ; q is 1 or 2; R ⁸ is H, halogen or OH; R ⁹ is H, halogen or OH; X ^c is H, halogen or optionally substituted C ₁ -C ₆ alkyl; X ^a is H, OH, NR ⁴ R ⁵ ; X ^b is H, OH, NR ⁴ R ⁵ ; or X ^a and X ^b together with the carbon atom to which they are attached form , wherein the asterisk (*) indicates the carbon atom to which ^Xa and ^Xb are attached; ^R10 is H or _C1 - _C6 alkyl optionally substituted with OH, ^halogen , ^NR4R5 , _CO2R4 or ^CO2H ; n is 0, 1 or ₂ ; and m is 1 or 2. In some embodiments, ^Y1 is CH, N, C-OH or C- _OCH3 ; ^X3 is CH, N, C-OH or C- _OCH3 ; ^X1 is ^CR1X ; ^R1X is ; q is 1 or 2; R ⁸ is H, halogen or OH; R ⁹ is H, halogen or OH; X ^c is H, halogen or optionally substituted C ₁ -C ₆ alkyl; X ^a is H, OH, NR ⁴ R ⁵ ; and X ^b is H, OH, NR ⁴ R ⁵ . In some embodiments, Y ¹ is CH, N, C-OH or C-OCH ₃ ; X ³ is CH, N, C-OH or C-OCH ₃ ; X ¹ is CR ^1X ; R ^1X is ; q is 2; R ⁸ is H or OH; R ⁹ is H or OH; X ^c is H; X ^a is OH or NR ⁴ R ⁵ ; and X ^b is H. In some embodiments, Y ¹ is CH, N, C-OH, or C-OCH ₃ ; X ³ is CH, N, C-OH, or C-OCH ₃ ; X ¹ is CR ^1X ; R ^1X is ; q is 2; R ⁸ is H; R ⁹ is H; X ^c is H; X ^a is OH or NR ⁴ R ⁵ ; and X ^b is H. In some embodiments, Y ¹ is CH, N, C-OH, or C-OCH ₃ ; X ³ is CH, N, C-OH, or C-OCH ₃ ; X ¹ is CR ^1X ; and R ^1X is In some embodiments, Y ¹ is CH, N, C-OH or C-OCH ₃ ; X ³ is CH, N, C-OH or C-OCH ₃ ; X ¹ is CR ^1X ; and R ^1X is In some embodiments, Y ¹ is CH, N, C-OH or C-OCH ₃ ; X ³ is CH, N, C-OH or C-OCH ₃ ; X ¹ is CR ^1X ; R ^1X is q is 1 or 2; R ⁸ is H, halogen or OH; R ⁹ is H, halogen or OH; X ^c is H, halogen or optionally substituted C ₁ -C ₆ alkyl; X ^a and X ^b together with the carbon atom to which they are attached form , wherein the asterisk (*) indicates the carbon atom to which ^Xa and ^Xb are attached; ^R10 is H or _C1 - _C6 alkyl optionally substituted with OH, ^halogen , ^NR4R5 , _CO2R4 or ^CO2H ; n is 0, 1 or ₂ ; and m is 1 or 2. In some embodiments, ^Y1 is CH, N, C-OH or C- _OCH3 ; ^X3 is CH, N, C-OH or C- _OCH3 ; ^X1 is ^CR1X ; ^R1X is ; q is 2; R ⁸ is H or OH; R ⁹ is H or OH; X ^c is H, halogen or optionally substituted C ₁ -C ₆ alkyl; X ^a and X ^b together with the carbon atom to which they are attached form , wherein the asterisk (*) indicates the carbon atom to which ^Xa and ^Xb are attached; ^R10 is H or _C1 - _C6 alkyl optionally substituted with OH, ^halogen , ^NR4R5 , _CO2R4 or ^CO2H ; n is 0; and m is 1. In some embodiments, ^Y1 is CH, N, C-OH or C- _{OCH3 ;} ^X3 is CH, N, C-OH or C- _OCH3 ; ^X1 is ^CR1X ; and ^R1X is In some embodiments, Y ¹ is CH, N, C-OH or C-OCH ₃ ; X ³ is CH, N, C-OH or C-OCH ₃ ; X ¹ is CR ^1X ; and R ^1X is .

In some embodiments of formula (A), (I), (IIa), (IIIa) or (IVa), Y ¹ is CH, N, C-OH or C-OCH ₃ ; X ¹ is CH, N, C-OH or C-OCH ₃ ; X ³ is CR ^3X ; and R ^3X is OH. In some embodiments, Y ¹ is CH, N, C-OH or C-OCH ₃ ; X ¹ is CH, N, C-OH or C-OCH ₃ ; X ³ is CR ^3X ; and R ^3X is ; q is 1 or 2; R ⁸ is H, halogen or OH; R ⁹ is H, halogen or OH; X ^c is H, halogen or optionally substituted C ₁ -C ₆ alkyl; X ^a is H, OH, NR ⁴ R ⁵ ; X ^b is H, OH, NR ⁴ R ⁵ ; or X ^a and X ^b together with the carbon atom to which they are attached form , wherein the asterisk (*) indicates the carbon atom ^to which ^Xa and ^Xb are attached; ^R10 is H or _C1 - _C6 alkyl substituted with OH, halogen, ^NR4R5 , _CO2R4 or ^CO2H as appropriate; n is 0, 1 or ₂ ; and m is 1 or 2. In some embodiments, ^Y1 is CH, N, C-OH or C- _OCH3 ; ^X1 is CH, N, C-OH or C- _OCH3 ; ^X3 is ^CR3X ; ^R3X is ; q is 1 or 2; R ⁸ is H, halogen or OH; R ⁹ is H, halogen or OH; X ^c is H, halogen or optionally substituted C ₁ -C ₆ alkyl; X ^a is H, OH, NR ⁴ R ⁵ ; and X ^b is H, OH, NR ⁴ R ⁵ . In some embodiments, Y ¹ is CH, N, C-OH or C-OCH ₃ ; X ¹ is CH, N, C-OH or C-OCH ₃ ; X ³ is CR ^3X ; R ^3X is ; q is 2; R ⁸ is H or OH; R ⁹ is H or OH; X ^c is H; X ^a is OH or NR ⁴ R ⁵ ; and X ^b is H. In some embodiments, Y ¹ is CH, N, C-OH, or C-OCH ₃ ; X ¹ is CH, N, C-OH, or C-OCH ₃ ; X ³ is CR ^3X ; R ^3X is ; q is 2; R ⁸ is H; R ⁹ is H; X ^c is H; X ^a is OH or NR ⁴ R ⁵ ; and X ^b is H. In some embodiments, Y ¹ is CH, N, C-OH, or C-OCH ₃ ; X ¹ is CH, N, C-OH, or C-OCH ₃ ; X ³ is CR ^3X ; and R ^3X is In some embodiments, Y ¹ is CH, N, C-OH or C-OCH ₃ ; X ¹ is CH, N, C-OH or C-OCH ₃ ; X ³ is CR ^3X ; and R ^3X is In some embodiments, Y ¹ is CH, N, C-OH or C-OCH ₃ ; X ¹ is CH, N, C-OH or C-OCH ₃ ; X ³ is CR ^3X ; R ^3X is q is 1 or 2; R ⁸ is H, halogen or OH; R ⁹ is H, halogen or OH; X ^c is H, halogen or optionally substituted C ₁ -C ₆ alkyl; X ^a and X ^b together with the carbon atom to which they are attached form , wherein the asterisk (*) indicates the carbon atom ^to which ^Xa and ^Xb are attached; ^R10 is H or _C1 - _C6 alkyl substituted with OH, halogen, ^NR4R5 , _CO2R4 or ^CO2H as appropriate; n is 0, 1 or ₂ ; and m is 1 or 2. In some embodiments, ^Y1 is CH, N, C-OH or C- _OCH3 ; ^X1 is CH, N, C-OH or C- _OCH3 ; ^X3 is ^CR3X ; ^R3X is ; q is 2; R ⁸ is H or OH; R ⁹ is H or OH; X ^c is H, halogen or optionally substituted C ₁ -C ₆ alkyl; X ^a and X ^b together with the carbon atom to which they are attached form , wherein the asterisk (*) indicates the carbon atom to which ^Xa and ^Xb are attached; ^R10 is H or _C1 - _C6 alkyl optionally substituted with OH, ^halogen , ^NR4R5 , _CO2R4 or ^CO2H ; n is 0; and m is 1. In some embodiments, ^Y1 is CH, N, C-OH or C- _{OCH3 ;} ^X1 is CH, N, C-OH or C- _OCH3 ; ^X3 is ^CR3X ; and ^R3X is In some embodiments, Y ¹ is CH, N, C-OH or C-OCH ₃ ; X ¹ is CH, N, C-OH or C-OCH ₃ ; X ³ is CR ^3X ; and R ^3X is .

In some embodiments of Formula (A), (I), (IIa), (IIIa) or (IVa), ^X1 is CH, N, C-OH or C- _OCH3 ; ^X3 is CH, N, C-OH or C- _OCH3 ; ^Y1 is ^CR1Y ; and ^R1Y is OH. In some embodiments, ^X1 is CH, N, C-OH or C- _OCH3 ; ^X3 is CH, N, C-OH or C- _OCH3 ; ^Y1 is ^CR1Y ; and ^R1Y is ; q is 1 or 2; R ⁸ is H, halogen or OH; R ⁹ is H, halogen or OH; X ^c is H, halogen or optionally substituted C ₁ -C ₆ alkyl; X ^a is H, OH, NR ⁴ R ⁵ ; X ^b is H, OH, NR ⁴ R ⁵ ; or X ^a and X ^b together with the carbon atom to which they are attached form , wherein the asterisk (*) indicates the carbon atom to which ^Xa and ^Xb are attached; ^R10 is H or _C1 - _C6 alkyl optionally substituted with OH, ^halogen , ^NR4R5 , _CO2R4 or ^CO2H ; n is 0, 1 or ₂ ; and m is 1 or 2. In some embodiments, ^X1 is CH, N, C-OH or C- _OCH3 ; ^X3 is CH, N, C-OH or C- _OCH3 ; ^Y1 is ^CR1Y ; ^R1Y is ; q is 1 or 2; R ⁸ is H, halogen or OH; R ⁹ is H, halogen or OH; X ^c is H, halogen or optionally substituted C ₁ -C ₆ alkyl; X ^a is H, OH, NR ⁴ R ⁵ ; and X ^b is H, OH, NR ⁴ R ⁵ . In some embodiments, X ¹ is CH, N, C-OH or C-OCH ₃ ; X ³ is CH, N, C-OH or C-OCH ₃ ; Y ¹ is CR ^1Y ; R ^1Y is ; q is 2; R ⁸ is H or OH; R ⁹ is H or OH; X ^c is H; X ^a is OH or NR ⁴ R ⁵ ; and X ^b is H. In some embodiments, X ¹ is CH, N, C-OH, or C-OCH ₃ ; X ³ is CH, N, C-OH, or C-OCH ₃ ; Y ¹ is CR ^1Y ; R ^1Y is ; q is 2; R ⁸ is H; R ⁹ is H; X ^c is H; X ^a is OH or NR ⁴ R ⁵ ; and X ^b is H. In some embodiments, X ¹ is CH, N, C-OH, or C-OCH ₃ ; X ³ is CH, N, C-OH, or C-OCH ₃ ; Y ¹ is CR ^1Y ; and R ^1Y is In some embodiments, X ¹ is CH, N, C-OH or C-OCH ₃ ; X ³ is CH, N, C-OH or C-OCH ₃ ; Y ¹ is CR ^1Y ; and R ^1Y is In some embodiments, X ¹ is CH, N, C-OH or C-OCH ₃ ; X ³ is CH, N, C-OH or C-OCH ₃ ; Y ¹ is CR ^1Y ; R ^1Y is q is 1 or 2; R ⁸ is H, halogen or OH; R ⁹ is H, halogen or OH; X ^c is H, halogen or optionally substituted C ₁ -C ₆ alkyl; X ^a and X ^b together with the carbon atom to which they are attached form , wherein the asterisk (*) indicates the carbon atom to which ^Xa and ^Xb are attached; ^R10 is H or _C1 - _C6 alkyl optionally substituted with OH, ^halogen , ^NR4R5 , _CO2R4 or ^CO2H ; n is 0, 1 or ₂ ; and m is 1 or 2. In some embodiments, ^X1 is CH, N, C-OH or C- _OCH3 ; ^X3 is CH, N, C-OH or C- _OCH3 ; ^Y1 is ^CR1Y ; ^R1Y is ; q is 2; R ⁸ is H or OH; R ⁹ is H or OH; X ^c is H, halogen or optionally substituted C ₁ -C ₆ alkyl; X ^a and X ^b together with the carbon atom to which they are attached form , wherein the asterisk (*) indicates the carbon atom to which ^Xa and ^Xb are attached; ^R10 is H or _C1 - _C6 alkyl optionally substituted with OH, ^halogen , ^NR4R5 , _CO2R4 or ^CO2H ; n is 0; and m is 1. In some embodiments, ^X1 is CH, N, C-OH or C- _{OCH3 ;} ^X3 is CH, N, C-OH or C- _OCH3 ; ^Y1 is ^CR1Y ; and ^R1Y is In some embodiments, X ¹ is CH, N, C-OH or C-OCH ₃ ; X ³ is CH, N, C-OH or C-OCH ₃ ; Y ¹ is CR ^1Y ; and R ^1Y is .

In some embodiments of formula (IIb), (IIIb) or (IVb), R ^1X is H, OH, halogen, optionally substituted C ₁ -C ₆ alkyl or O(C ₁ -C ₆ alkyl). In some embodiments, R ^1X is H. In some embodiments, R ^1X is halogen. In some embodiments, R ^1X is F, Cl or Br. In some embodiments, R ^1X is F. In some embodiments, R ^1X is Cl. In some embodiments, R ^1X is Br. In some embodiments, R ^1X is optionally substituted C ₁ -C ₆ alkyl. In some embodiments, R ^1X is C ₁ -C ₆ alkyl. In some embodiments, R ^1X is methyl, ethyl or isopropyl. In some embodiments, R ^1X is methyl. In some embodiments, R ^1X is ethyl. In some embodiments, R ^1X is isopropyl. In some embodiments, R ^1X is substituted C ₁ -C ₆ alkyl. In some embodiments, R ^1X is C 1 -C 6 alkyl substituted by one or more of halogen, -OH, -NR ⁴ R ⁵ or C ₃ -C ₈ cycloalkyl, wherein R ⁴ and R ⁵ are as defined for formula (I). In some embodiments, R ^1X is C ₁ -C ₆ alkyl substituted by one or more halogen. In some embodiments, R ^1X is C ₁ -C ₆ alkyl substituted by one or more F, Cl or Br. In some embodiments, R ^1X is _{C 1 -C 6 alkyl substituted by} one or more F. In some embodiments, R ^1X is C ₁ -C ₆ alkyl substituted with one or more Cl. In some embodiments, R ^1X is C 1 -C 6 alkyl substituted with one or more Br. In some embodiments, R ^1X is C ₁ -C ₆ alkyl substituted with one or more OH. In some embodiments, R ^1X is C ₁ -C ₆ alkyl substituted with one or more -NR ⁴ R ^5. In some embodiments, R ^1X is C _{1 -C 6} alkyl substituted with one or more NHR ^4. In some embodiments, R ^1X is C _{1 -C 6} alkyl substituted with one or more _{NCH 3} (R ⁴ ). In some embodiments, R ^1X is C ₁ -C ₆ alkyl substituted with one or more NH ₂ . In some embodiments, R ^1X is C ₁ -C ₆ alkyl substituted with one or more N(CH ₃ ) _2. In some embodiments, R ^1X is C ₁ -C ₆ alkyl substituted with one or more NH(CH ₃ ). In some embodiments, R ^1X is C ₁ -C ₆ alkyl substituted with one or more NH(CH ₂ CH ₃ ). In some embodiments, R ^1X is C 1 -C 6 alkyl substituted with one or more C ₃ -C ₈ cycloalkyl. In some embodiments, R ^1X is C ₁ -C ₆ alkyl substituted with one or _more C ₃ cycloalkyl, C ₄ cycloalkyl, C ₅ cycloalkyl, C ₆ cycloalkyl, C ₇ cycloalkyl, or _{C 8} cycloalkyl. In some embodiments, R ^1X is C ₁ -C ₆ alkyl substituted with one or more C ₃ cycloalkyl groups. In some embodiments, R ^1X is C ₁ -C ₆ alkyl substituted with one or more C ₄ cycloalkyl groups. In some embodiments, R ^1X is C ₁ -C ₆ alkyl substituted with one or more C ₅ cycloalkyl groups. In some embodiments, R ^1X is C ₁ -C ₆ alkyl substituted with one or more C ₆ cycloalkyl groups. In some embodiments, R ^1X is C ₁ -C ₆ alkyl substituted with one or more C ₇ cycloalkyl groups. In some embodiments, R ^1X is C ₁ -C ₆ alkyl substituted with one or more C ₈ cycloalkyl groups. In some embodiments, R ^1X is C ₁ -C ₆ alkyl substituted by one or more cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl. In some embodiments, R ^1X is C 1 -C 6 alkyl substituted by one or more cyclopropyl. In some embodiments, R ^1X is C ₁ -C ₆ alkyl substituted by one or more cyclobutyl. In some embodiments, R ^1X is C _{1 -C 6} alkyl substituted by one or more cyclopentyl. In some embodiments, R ^1X is C ₁ -C ₆ alkyl substituted by one or more cyclohexyl. In some embodiments, R ^1X is O( _{C 1} -C ₆ alkyl). In some embodiments, R ^1X is O(C ₁ alkyl). In some embodiments, R ^1X is O(C ₂ alkyl). In some embodiments, R ^1X is O(C ₃ alkyl). In some embodiments, R ^1X is O(C ₄ alkyl). In some embodiments, R ^1X is O(C ₅ alkyl). In some embodiments, R ^1X is O(C ₆ alkyl).

In some embodiments of Formula (IIb), (IIIb) or (IVb), R ^1X is . In some such embodiments, ^Xa is H, OH, SH, _CO2H , _CO2R4 ^{, or NR4R5 .} In some ^such embodiments, ^Xa is H. In some such embodiments, ^Xa is OH. In some such embodiments, ^Xa is SH. In some such embodiments, ^Xa is _CO2H . In some such embodiments, ^Xa is _CO2R4 . In some such embodiments, ^Xa is _CO2R4 and ^R4 is optionally substituted C1-C6 alkyl. In some such embodiments, ^Xa is ^CO2R4 and ^R4 is _{C1 - C6} alkyl. In some such embodiments _, ^{Xa is} _CO2R4 ^{and R4} is ^methyl , ethyl _, or isopropyl. In some such embodiments, ^Xa is _CO2R4 and ^R4 is methyl. In some such embodiments, ^Xa is ^{CO2R4 and} R4 is ethyl. In some such embodiments, ^Xa is _CO2R4 ^{and R4} is isopropyl. In some such embodiments, ^Xa is _CO2R4 ^{and R4 is} substituted _C1 - _C6 alkyl. In some such embodiments, ^Xa is _CO2R4 ^{and R4} is substituted ^methyl . In some such embodiments, ^Xa is _{CO2R4 and} ^R4 is substituted ethyl. ^In some such embodiments, ^{Xa is} _CO2R4 ^{and R4} is substituted isopropyl. In some such embodiments, ^Xa is ^NR4R5 . In some such embodiments, ^Xa is ^NHR4 . In some such embodiments, ^Xa is _NCH3 ( ^R4 ). In some such embodiments, ^Xa is _NH2 . In some such embodiments, ^Xa is N( _CH3 ) ₂ . In some such embodiments, ^Xa is NH(CH3). In some such embodiments, ^Xa is _NH ( _CH2CH3 ). In some such embodiments, ^Xb is H, OH, _SH , _CO2H , _CO2R4 ^, or ^NR4R5 . In some ^such embodiments, ^Xb is H. In some such embodiments, ^Xb is OH. In some such embodiments, ^Xb is SH. In some such embodiments, ^Xb is _CO2H . In some ^such embodiments, ^Xb is _CO2R4 . In some such embodiments, X ^b is CO ₂ R ⁴ and R ⁴ is optionally substituted C ₁ -C ₆ alkyl. In some such embodiments, X ^b is CO ₂ R ⁴ and R ⁴ is C ₁ -C ₆ alkyl. In some such embodiments, X ^b is CO ₂ R ⁴ and R ⁴ is methyl, ethyl or isopropyl. In some such embodiments, X ^b is CO ₂ R ⁴ and R ⁴ is methyl. In some such embodiments, X ^b is CO ₂ R ⁴ and R ⁴ is ethyl. In some such embodiments, X ^b is CO ₂ R ⁴ and R ⁴ is isopropyl. In some such embodiments, X ^b is CO ₂ R ⁴ and R ⁴ is substituted C ₁ -C ₆ alkyl. In some such embodiments, X ^b is CO ₂ R ⁴ and R ⁴ is substituted methyl. In some such embodiments, X ^b is CO ₂ R ⁴ and R ⁴ is substituted ethyl. In some such embodiments, X ^b is CO ₂ R ⁴ and R ⁴ is substituted isopropyl. In some such embodiments, X ^b is NR ⁴ R ⁵ . In some such embodiments, X ^b is NHR ⁴ . In some such embodiments, X ^b is NCH ₃ (R ⁴ ). In some such embodiments, X ^b is NH ₂ . In some such embodiments, X ^b is N(CH ₃ ) ₂ . In some such embodiments, X ^b is NH(CH ₃ ). In some such embodiments, X ^b is NH(CH ₂ CH ₃ ). In some such embodiments, ^Xc is H, halogen, or optionally substituted _C1 - _C6 alkyl. In some such embodiments, ^Xc is H. In some such embodiments, ^Xc is OH. In some such embodiments, ^Xc is F, Cl, or Br. In some such embodiments, ^Xc is F. In some such embodiments, ^Xc is Cl. In some such embodiments, ^Xc is Br. In some such embodiments, ^Xc is optionally substituted _C1 - _C6 alkyl. In some such embodiments, ^Xc is _C1 - _C6 alkyl. In some such embodiments, ^Xc is methyl, ethyl, or isopropyl. In some such embodiments, ^Xc is methyl. In some such embodiments, ^Xc is ethyl. In some such embodiments, ^Xc is isopropyl. In some such embodiments, ^Xc is substituted _C1 - _C6 alkyl. In some such embodiments, ^Xc is substituted methyl. In some such embodiments, ^Xc is substituted ethyl. In some such embodiments, ^Xc is substituted isopropyl.

In some embodiments of Formula (IIb), (IIIb) or (IVb), R ^1X is and ^Xa and ^Xb together with the carbon atom to which they are attached form , wherein the asterisk (*) indicates the carbon atom to which ^Xa and ^Xb are attached. In some such embodiments, n is 0, 1 or 2. In some such embodiments, n is 0 or 1. In some such embodiments, n is 1 or 2. In some such embodiments, n is 0. In some such embodiments, n is 1. In some such embodiments, n is 2. In some such embodiments, m is 1 or 2. In some such embodiments, m is 1. In some such embodiments, m is 2. In some such embodiments, R ¹⁰ is H or C ₁ -C ₆ alkyl optionally substituted with OH, halogen, NR ⁴ R ⁵ , CO 2 R ⁴ or CO ₂ H. In some such embodiments, R ¹⁰ is H. In some such embodiments, R ¹⁰ is C ₁ -C ₆ alkyl, optionally substituted with OH, halogen, NR ⁴ R ⁵ , CO 2 R ⁴ or CO ₂ H. In some such embodiments, R ¹⁰ is C ₁ -C ₆ alkyl. In some such embodiments, R ¹⁰ is methyl, ethyl or isopropyl. In some such embodiments, R ¹⁰ is methyl. In some such embodiments, R ¹⁰ is ethyl. In some such embodiments, R ¹⁰ is isopropyl. In some such embodiments, R ¹⁰ is C ₁ -C ₆ alkyl, optionally substituted with OH, halogen, NR ⁴ R ⁵ , CO 2 R ⁴ or CO ₂ H. In some such embodiments, R ¹⁰ is methyl substituted by OH, halo, NR ⁴ R ⁵ , CO2R ⁴ or CO ₂ H. In some such embodiments, R ¹⁰ is ethyl substituted by OH, halo, NR ⁴ R ⁵ , CO2R ⁴ or CO ₂ H. In some such embodiments, R ¹⁰ is isopropyl substituted by OH, halo, NR ⁴ R ⁵ , CO2R ⁴ or CO ₂ H. In some such embodiments, X ^c is H, halo or optionally substituted C ₁ -C ₆ alkyl. In some such embodiments, X ^c is H. In some such embodiments, X ^c is OH. In some such embodiments, X ^c is F, Cl or Br. In some such embodiments, X ^c is F. In some such embodiments, X ^c is Cl. In some such embodiments, ^Xc is Br. In some such embodiments, ^Xc is optionally substituted _C1 - _C6 alkyl. In some such embodiments, ^Xc is _C1 - _C6 alkyl. In some such embodiments, ^Xc is methyl, ethyl or isopropyl. In some such embodiments, ^Xc is methyl. In some such embodiments, ^Xc is ethyl. In some such embodiments, ^Xc is isopropyl. In some such embodiments, ^Xc is substituted _C1 - _C6 alkyl. In some such embodiments, ^Xc is substituted methyl. In some such embodiments, ^Xc is substituted ethyl. In some such embodiments, ^Xc is substituted isopropyl.

In some embodiments of Formula (IIb), (IIIb) or (IVb), ^X3 is N. In some embodiments of Formula (IIb), (IIIb) or (IVb), ^Y1 is N.

In some embodiments of formula (IIb), (IIIb) or (IVb), X ³ is CR ^3X and R ^3X is H, OH, halo, optionally substituted C ₁ -C ₆ alkyl or O(C ₁ -C ₆ alkyl). In some such embodiments, R ^3X is H. In some such embodiments, R ^3X is halo. In some such embodiments, R ^3X is F, Cl or Br. In some such embodiments, R ^3X is F. In some such embodiments, R ^3X is Cl. In some such embodiments, R ^3X is Br. In some such embodiments, R ^3X is optionally substituted C ₁ -C ₆ alkyl. In some such embodiments, R ^3X is C ₁ -C ₆ alkyl. In some such embodiments, R ^3X is methyl, ethyl or isopropyl. In some such embodiments, R ^3X is methyl. In some such embodiments, R ^3X is ethyl. In some such embodiments, R 3X is isopropyl. In some such embodiments, R ^3X is substituted C ₁ -C ₆ alkyl ^{. In some such embodiments, R 3X is} C ₁ -C ₆ alkyl substituted with one or more of halogen, OH, NR ⁴ R ⁵ or C ₃ -C ₈ cycloalkyl, wherein R ⁴ and R ⁵ are as defined for formula (I). In some such embodiments, R ^3X is C ₁ -C ₆ alkyl substituted with one or more halogens. In some such embodiments, R ^3X is C ₁ -C ₆ alkyl substituted with one or more F, Cl or Br. In some such embodiments, R ^3X is C ₁ -C ₆ alkyl substituted with one or more F. In some such embodiments, R ^3X is C ₁ -C ₆ alkyl substituted with one or more Cl. In some such embodiments, R ^3X is C ₁ -C ₆ alkyl substituted with one or more Br. In some such embodiments, R ^3X is C ₁ -C ₆ alkyl substituted with one or more OH. In some such embodiments, R ^3X is C ₁ -C ₆ alkyl substituted with one or more NR ⁴ R ^5. In some such embodiments, R ^3X is C ₁ -C ₆ alkyl substituted with one or more NHR ⁴ . In some such embodiments, R ^3X is C ₁ -C ₆ alkyl substituted with one or more NCH ₃ (R ⁴ ). In some such embodiments, R ^3X is C ₁ -C ₆ alkyl substituted with one or more NH _2. In some such embodiments, R ^3X is C ₁ -C ₆ alkyl substituted with one or more N(CH ₃ ) _2. In some such embodiments, R ^3X is C 1 -C 6 alkyl substituted with one or more NH(CH ₃ ). In some such embodiments, R ^3X is C ₁ -C ₆ alkyl substituted with one or more NH(CH ₂ CH ₃ ). In some such embodiments, R ^3X is _{C 1} -C ₆ alkyl substituted with one or more C _{3 -C 8} cycloalkyl. In some such embodiments, R ^3X is C 1 _{-C 6} alkyl substituted with one or more C ₃ cycloalkyl, C ₄ cycloalkyl, C ₅ cycloalkyl, C ₆ cycloalkyl, C ₇ cycloalkyl or C ₈ cycloalkyl. In some such embodiments, R ^3X is C ₁ -C ₆ alkyl substituted with one or more C ₃ cycloalkyl. In some such embodiments, R ^3X is C ₁ -C ₆ alkyl substituted with one or more C ₄ cycloalkyl. In some such embodiments, R ^3X is C ₁ -C 6 alkyl substituted with one or more C ₅ cycloalkyl. In some such embodiments, R ^3X is _{C 1 -C 6} alkyl substituted with one or more C ₆ cycloalkyl. In some such embodiments, R ^3X is C ₁ -C ₆ alkyl substituted with one or more C ₇ cycloalkyl groups. In some such embodiments, R ^3X is C ₁ -C ₆ alkyl substituted with one or more C ₈ cycloalkyl groups. In some such embodiments, R ^3X is C ₁ -C ₆ alkyl substituted with one or more cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl groups. In some such embodiments, R ^3X is C 1 -C 6 alkyl substituted with one or more cyclopropyl. In some such embodiments, R ^3X is C ₁ -C ₆ alkyl substituted with one or more cyclobutyl. In some such embodiments, R ^3X is _{C 1 -C 6} alkyl substituted with one or more cyclopentyl groups. In some such embodiments, R ^3X is C ₁ -C ₆ alkyl substituted with one or more cyclohexyl groups. In some such embodiments, R ^3X is O(C ₁ -C ₆ alkyl). In some such embodiments, R ^3X is O(C ₁ alkyl). In some such embodiments, R ^3X is O(C ₂ alkyl). In some such embodiments, R ^3X is O(C ₃ alkyl). In some such embodiments, R ^3X is O(C ₄ alkyl). In some such embodiments, R ^3X is O(C ₅ alkyl). In some such embodiments, R ^3X is O(C ₆ alkyl).

In some embodiments of formula (IIb), (IIIb) or (IVb), Y ¹ is CR ^1Y and R ^1Y is H, OH, halo, optionally substituted C ₁ -C ₆ alkyl or O(C ₁ -C ₆ alkyl). In some such embodiments, R ^1Y is H. In some such embodiments, R ^1Y is halo. In some such embodiments, R ^1Y is F, Cl or Br. In some such embodiments, R ^1Y is F. In some such embodiments, R ^1Y is Cl. In some such embodiments, R ^1Y is Br. In some such embodiments, R ^1Y is optionally substituted C ₁ -C ₆ alkyl. In some such embodiments, R ^1Y is C ₁ -C ₆ alkyl. In some such embodiments, R ^1Y is methyl, ethyl or isopropyl. In some such embodiments, R ^1Y is methyl. In some such embodiments, R ^1Y is ethyl. In some such embodiments, R 1Y is isopropyl. In some such embodiments, R ^1Y is substituted C ₁ -C ₆ alkyl ^{. In some such embodiments, R 1Y is} C ₁ -C ₆ alkyl substituted with one or more of halogen, OH, -NR ⁴ R ⁵ or C ₃ -C ₈ cycloalkyl, wherein R ⁴ and R ⁵ are as defined for formula (I). In some such embodiments, R ^1Y is C ₁ -C ₆ alkyl substituted with one or more halogens. In some such embodiments, R ^1Y is C ₁ -C ₆ alkyl substituted with one or more F, Cl or Br. In some such embodiments, R ^1Y is C ₁ -C ₆ alkyl substituted with one or more F. In some such embodiments, R ^1Y is C ₁ -C ₆ alkyl substituted with one or more Cl. In some such embodiments, R ^1Y is C ₁ -C ₆ alkyl substituted with one or more Br. In some such embodiments, R ^1Y is C ₁ -C ₆ alkyl substituted with one or more OH. In some such embodiments, R ^1Y is C ₁ -C ₆ alkyl substituted with one or more -NR ⁴ R ^5. In some such embodiments, R ^1Y is C ₁ -C ₆ alkyl substituted with one or more NHR ⁴ . In some such embodiments, R ^1Y is C ₁ -C ₆ alkyl substituted with one or more NCH ₃ (R ⁴ ). In some such embodiments, R ^1Y is C ₁ -C ₆ alkyl substituted with one or more NH _2. In some such embodiments, R ^1Y is C ₁ -C ₆ alkyl substituted with one or more N(CH ₃ ) _2. In some such embodiments, R ^1Y is C 1 -C 6 alkyl substituted with one or more NH(CH ₃ ). In some such embodiments, R ^1Y is C ₁ -C ₆ alkyl substituted with one or more NH(CH ₂ CH ₃ ). In some such embodiments, R ^1Y is _{C 1} -C ₆ alkyl substituted with one or more C _{3 -C 8} cycloalkyl. In some such embodiments, R ^1Y is C 1 _{-C 6} alkyl substituted with one or more C ₃ cycloalkyl, C ₄ cycloalkyl, C ₅ cycloalkyl, C ₆ cycloalkyl, C ₇ cycloalkyl, or C ₈ cycloalkyl. In some such embodiments, R ^1Y is C ₁ -C ₆ alkyl substituted with one or more C ₃ cycloalkyl. In some such embodiments, R ^1Y is C ₁ -C ₆ alkyl substituted with one or more C ₄ cycloalkyl. In some such embodiments, R ^1Y is C ₁ -C ₆ alkyl substituted with one or more C ₅ cycloalkyl. In some such embodiments, R ^1Y is C _{1 -C 6} alkyl substituted with one or more C ₆ cycloalkyl. In some such embodiments, R ^1Y is C ₁ -C ₆ alkyl substituted with one or more C ₇ cycloalkyl groups. In some such embodiments, R ^1Y is C ₁ -C ₆ alkyl substituted with one or more C ₈ cycloalkyl groups. In some such embodiments, R ^1Y is C ₁ -C ₆ alkyl substituted with one or more cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl groups. In some such embodiments, R ^1Y is C 1 -C 6 alkyl substituted with one or more cyclopropyl. In some such embodiments, R ^1Y is C ₁ -C ₆ alkyl substituted with one or more cyclobutyl. In some such embodiments, R ^1Y is _{C 1 -C 6} alkyl substituted with one or more cyclopentyl groups. In some such embodiments, R ^1Y is C ₁ -C ₆ alkyl substituted with one or more cyclohexyl groups. In some such embodiments, R ^1Y is O(C ₁ -C ₆ alkyl). In some such embodiments, R ^1Y is O(C ₁ alkyl). In some such embodiments, R ^1Y is -O(C ₂ alkyl). In some such embodiments, R ^1Y is O(C ₃ alkyl). In some such embodiments, R ^1Y is O(C ₄ alkyl). In some such embodiments, R ^1Y is O(C ₅ alkyl). In some such embodiments, R ^1Y is O(C ₆ alkyl).

In some embodiments of formula (IIb), (IIIb) or (IVb), R ^1X is H. In some embodiments, R ^1X is OH. In some embodiments, R ^1X is OCH ₃ . In some embodiments, R ^1X is ; q is 1 or 2; R ⁸ is H, halogen or OH; R ⁹ is H, halogen or OH; X ^c is H, halogen or optionally substituted C ₁ -C ₆ alkyl; X ^a is H, OH, NR ⁴ R ⁵ ; X ^b is H, OH, NR ⁴ R ⁵ ; or X ^a and X ^b together with the carbon atom to which they are attached form , wherein the asterisk (*) indicates the carbon atom to which ^Xa and ^Xb are attached; ^R10 is H or _C1 - _C6 alkyl optionally substituted with OH, ^halogen , ^NR4R5 , _CO2R4 or ^CO2H ; n is 0, 1 or ₂ ; and m is 1 or 2. In some embodiments, ^R1X is ; q is 1 or 2; R ⁸ is H, halogen or OH; R ⁹ is H, halogen or OH; X ^c is H, halogen or optionally substituted C ₁ -C ₆ alkyl; X ^a is H, OH, NR ⁴ R ⁵ ; and X ^b is H, OH, NR ⁴ R ⁵ . In some embodiments, R ^1X is ; q is 2; R ⁸ is H or OH; R ⁹ is H or OH; X ^c is H; X ^a is OH or NR ⁴ R ⁵ ; and X ^b is H. In some embodiments, R ^1X is ; q is 2; R ⁸ is H; R ⁹ is H; X ^c is H; X ^a is OH or NR ⁴ R ⁵ ; and X ^b is H. In some embodiments, R ^1X is In some embodiments, R ^1X is In some embodiments, R ^1X is q is 1 or 2; R ⁸ is H, halogen or OH; R ⁹ is H, halogen or OH; X ^c is H, halogen or optionally substituted C ₁ -C ₆ alkyl; X ^a and X ^b together with the carbon atom to which they are attached form , wherein the asterisk (*) indicates the carbon atom to which ^Xa and ^Xb are attached; ^R10 is H or _C1 - _C6 alkyl optionally substituted with OH, ^halogen , ^NR4R5 , _CO2R4 or ^CO2H ; n is 0, 1 or ₂ ; and m is 1 or 2. In some embodiments, ^R1X is ; q is 2; R ⁸ is H or OH; R ⁹ is H or OH; X ^c is H, halogen or optionally substituted C ₁ -C ₆ alkyl; X ^a and X ^b together with the carbon atom to which they are attached form , wherein the asterisk (*) indicates the carbon atom to which ^Xa and ^Xb are attached; ^R10 is H or _C1 - _C6 alkyl optionally substituted with OH, ^halogen , ^NR4R5 , _{CO2R4 or} ^CO2H ; n is 0; and m is 1. In some embodiments, ^R1X is In some embodiments, R ^1X is .

In some embodiments of formula (IIb), (IIIb) or (IVb), Y ¹ is CH, N, C-OH or C-OCH ₃ ; X ³ is CH, N, C-OH or C-OCH ₃ ; and R ^1X is OH. In some embodiments, Y ¹ is CH, N, C-OH or C-OCH ₃ ; X ³ is CH, N, C-OH or C-OCH ₃ ; and R ^1X is OH. ; q is 1 or 2; R ⁸ is H, halogen or OH; R ⁹ is H, halogen or OH; X ^c is H, halogen or optionally substituted C ₁ -C ₆ alkyl; X ^a is H, OH, NR ⁴ R ⁵ ; X ^b is H, OH, NR ⁴ R ⁵ ; or X ^a and X ^b together with the carbon atom to which they are attached form , wherein the asterisk (*) indicates the carbon atom ^to which ^Xa and ^Xb are attached; ^R10 is H or _C1 - _C6 alkyl substituted with OH, halogen, ^NR4R5 , _CO2R4 or ^CO2H as appropriate; n is 0, 1 or ₂ ; and m is 1 or 2. In some embodiments, ^Y1 is CH, N, C-OH or C- _OCH3 ; ^X3 is CH, N, C-OH or C- _OCH3 ; ^R1X is ; q is 1 or 2; R ⁸ is H, halogen or OH; R ⁹ is H, halogen or OH; X ^c is H, halogen or optionally substituted C ₁ -C ₆ alkyl; X ^a is H, OH, NR ⁴ R ⁵ ; and X ^b is H, OH, NR ⁴ R ⁵ . In some embodiments, Y ¹ is CH, N, C-OH or C-OCH ₃ ; X ³ is CH, N, C-OH or C-OCH ₃ ; R ^1X is ; q is 2; R ⁸ is H or OH; R ⁹ is H or OH; X ^c is H; X ^a is OH or NR ⁴ R ⁵ ; and X ^b is H. In some embodiments, Y ¹ is CH, N, C-OH, or C-OCH ₃ ; X ³ is CH, N, C-OH, or C-OCH ₃ ; R ^1X is ; q is 2; R ⁸ is H; R ⁹ is H; X ^c is H; X ^a is OH or NR ⁴ R ⁵ ; and X ^b is H. In some embodiments, Y ¹ is CH, N, C-OH, or C-OCH ₃ ; X ³ is CH, N, C-OH, or C-OCH ₃ ; and R ^1X is In some embodiments, Y ¹ is CH, N, C-OH or C-OCH ₃ ; X ³ is CH, N, C-OH or C-OCH ₃ ; and R ^1X is In some embodiments, Y ¹ is CH, N, C-OH or C-OCH ₃ ; X ³ is CH, N, C-OH or C-OCH ₃ ; R ^1X is q is 1 or 2; R ⁸ is H, halogen or OH; R ⁹ is H, halogen or OH; X ^c is H, halogen or optionally substituted C ₁ -C ₆ alkyl; X ^a and X ^b together with the carbon atom to which they are attached form , wherein the asterisk (*) indicates the carbon atom ^to which ^Xa and ^Xb are attached; ^R10 is H or _C1 - _C6 alkyl substituted with OH, halogen, ^NR4R5 , _CO2R4 or ^CO2H as appropriate; n is 0, 1 or ₂ ; and m is 1 or 2. In some embodiments, ^Y1 is CH, N, C-OH or C- _OCH3 ; ^X3 is CH, N, C-OH or C- _OCH3 ; ^R1X is ; q is 2; R ⁸ is H or OH; R ⁹ is H or OH; X ^c is H, halogen or optionally substituted C ₁ -C ₆ alkyl; X ^a and X ^b together with the carbon atom to which they are attached form , wherein the asterisk (*) indicates the carbon atom ^to which ^Xa and ^Xb are attached; ^R10 is H or _C1 - _C6 alkyl optionally substituted with OH, halogen, ^NR4R5 , _CO2R4 or ^CO2H ; n is 0; and m is 1. In some embodiments, ^Y1 is CH, N, C-OH or C- _{OCH3 ;} ^X3 is CH, N, C-OH or C- _OCH3 ; and ^R1X is In some embodiments, Y ¹ is CH, N, C-OH or C-OCH ₃ ; X ³ is CH, N, C-OH or C-OCH ₃ ; and R ^1X is .

In some embodiments of formula (IIc), (IIIc) or (IVc), R ^3X is H, -OH, halogen, optionally substituted C ₁ -C ₆ alkyl or -O(C ₁ -C ₆ alkyl). In some embodiments, R ^3X is H. In some embodiments, R ^3X is halogen. In some embodiments, R ^3X is F, Cl or Br. In some embodiments, R ^3X is F. In some embodiments, R ^3X is Cl. In some embodiments, R ^3X is Br. In some embodiments, R ^3X is optionally substituted C ₁ -C ₆ alkyl. In some embodiments, R ^3X is C ₁ -C ₆ alkyl. In some embodiments, R ^3X is methyl, ethyl or isopropyl. In some embodiments, R ^3X is methyl. In some embodiments, R ^3X is ethyl. In some embodiments, R ^3X is isopropyl. In some embodiments, R ^3X is substituted C ₁ -C ₆ alkyl. In some embodiments, R ^3X is C 1 -C 6 alkyl substituted by one or more of halogen, OH, -NR ⁴ R ⁵ or C ₃ -C ₈ cycloalkyl, wherein R ⁴ and R ⁵ are as defined for formula (I). In some embodiments, R ^3X is C ₁ -C ₆ alkyl substituted by one or more halogen. In some embodiments, R ^3X is C ₁ -C ₆ alkyl substituted by one or more F, Cl or Br. In some embodiments, R ^3X is _{C 1 -C 6 alkyl substituted by} one or more F. In some embodiments, R ^3X is C ₁ -C ₆ alkyl substituted with one or more Cl. In some embodiments, R ^3X is C 1 -C 6 alkyl substituted with one or more Br. In some embodiments, R ^3X is C ₁ -C ₆ alkyl substituted with one or more OH. In some embodiments, R ^3X is C _{1 -C 6} alkyl substituted with one or more NR ⁴ R ^5. In some embodiments, R ^3X is C ₁ -C ₆ alkyl substituted with one or more NHR ^4. In some embodiments, R ^3X is C _{1 -C 6} alkyl substituted with one or more NCH ₃ (R ⁴ ). In some embodiments, R ^3X is C ₁ -C ₆ alkyl substituted _with one or more NH ₂ . In some embodiments, R ^3X is a C ₁ -C ₆ alkyl substituted with one or more N(CH ₃ ) _2. In some embodiments, R ^3X is a C ₁ -C ₆ alkyl substituted with one or more NH(CH ₃ ). In some embodiments, R ^3X is a C ₁ -C ₆ alkyl substituted with one or more NH(CH ₂ CH ₃ ). In some embodiments, R ^3X is a C 1 -C 6 alkyl substituted with one or more C ₃ -C ₈ cycloalkyl. In some embodiments, R ^3X is a C ₁ -C ₆ alkyl substituted with one or more C ₃ cycloalkyl, C ₄ cycloalkyl, C ₅ cycloalkyl, C ₆ cycloalkyl, C ₇ cycloalkyl _, or _{C 8} cycloalkyl. In some embodiments, R ^3X is C ₁ -C ₆ alkyl substituted with one or more C ₃ cycloalkyl groups. In some embodiments, R ^3X is C ₁ -C ₆ alkyl substituted with one or more C ₄ cycloalkyl groups. In some embodiments, R ^3X is C ₁ -C ₆ alkyl substituted with one or more C ₅ cycloalkyl groups. In some embodiments, R ^3X is C ₁ -C ₆ alkyl substituted with one or more C ₆ cycloalkyl groups. In some embodiments, R ^3X is C ₁ -C ₆ alkyl substituted with one or more C ₇ cycloalkyl groups. In some embodiments, R ^3X is C ₁ -C ₆ alkyl substituted with one or more C ₈ cycloalkyl groups. In some embodiments, R ^3X is C ₁ -C ₆ alkyl substituted by one or more cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl. In some embodiments, R ^3X is C 1 -C 6 alkyl substituted by one or more cyclopropyl. In some embodiments, R ^3X is C ₁ -C ₆ alkyl substituted by one or more cyclobutyl. In some embodiments, R ^3X is C _{1 -C 6} alkyl substituted by one or more cyclopentyl. In some embodiments, R ^3X is C ₁ -C ₆ alkyl substituted by one or more cyclohexyl. In some embodiments, R ^3X is O( _{C 1} -C ₆ alkyl). In some embodiments, R ^3X is O(C ₁ alkyl). In some embodiments, R ^3X is O(C ₂ alkyl). In some embodiments, R ^3X is O(C ₃ alkyl). In some embodiments, R ^3X is O(C ₄ alkyl). In some embodiments, R ^3X is O(C ₅ alkyl). In some embodiments, R ^3X is O(C ₆ alkyl).

In some embodiments of Formula (IIc), (IIIc) or (IVc), R ^3X is . In some such embodiments, q is 0 to 6. In some such embodiments, q is 0. In some such embodiments, q is 1. In some such embodiments, q is 2. In some such embodiments, q is 3. In some such embodiments, q is 4. In some such embodiments, q is 5. In some such embodiments, q is 6. In some such embodiments, R ⁸ is H, halogen, CN, SH, OH, -CO ₂ H, NR ⁴ R ⁵ , or C ₁ -C ₆ alkyl optionally substituted with OH, halogen, or CO ₂ H. In some such embodiments, R ⁸ is H. In some such embodiments, R ⁸ is halogen. In some such embodiments, R ⁸ is F, Cl, or Br. In some such embodiments, R ⁸ is F. In some such embodiments, R ⁸ is Cl. In some such embodiments, R ⁸ is Br. In some such embodiments, R ⁸ is CN. In some such embodiments, R ⁸ is SH. In some such embodiments, R ⁸ is OH. In some such embodiments, R ⁸ is CO ₂ H. In some such embodiments, R ⁸ is NR ⁴ R ^5. In some such embodiments, R ⁸ is NHR ^4. In some such embodiments, R ⁸ is NCH ₃ (R ⁴ ). In some such embodiments, R ⁸ is NH ₂ . In some such embodiments, R ⁸ is N(CH ₃ ) ₂ . In some such embodiments, R ⁸ is NH(CH ₃ ). In some such embodiments, R ⁸ is NH(CH ₂ CH ₃ ). In some such embodiments, R ⁸ is C ₁ -C ₆ alkyl, optionally substituted with OH, halogen, or CO ₂ H. In some such embodiments, R ⁸ is C ₁ -C ₆ alkyl. In some such embodiments, R ⁸ is methyl, ethyl, or isopropyl. In some such embodiments, R 8 is methyl. In some such embodiments, R ⁸ is ethyl. In some such embodiments, R ⁸ is isopropyl. In some such embodiments, R ⁸ is C 1 -C 6 alkyl, optionally substituted with OH, halogen, or CO ₂ H. In some such embodiments, R ⁸ is C ₁ -C ₆ alkyl, optionally substituted with OH, halogen, or CO 2 H. In some such embodiments, R ⁸ is C ₁ -C ₆ alkyl, optionally substituted with OH. In some such embodiments, R ⁸ is C ₁ -C ₆ alkyl, optionally substituted with halogen. In some such embodiments, ^R is C ₁ -C ₆ alkyl substituted with CO ₂ H. In some such embodiments, ^R is methyl substituted with -OH. In some such embodiments, ^R is ethyl substituted with OH. In some such embodiments, ^R is isopropyl substituted with OH. In some such embodiments, ^R is methyl substituted with halogen. In some such embodiments, ^R is ethyl substituted with halogen. In some such embodiments, R is isopropyl substituted with halogen. In some such embodiments, ^R is methyl substituted with CO ² H. In some such embodiments, ^R is ethyl substituted with CO _{2 H.} In some such embodiments, R is ^isopropyl substituted with CO ₂ H. In some such embodiments, R ⁹ is H, halogen, CN, SH, OH, CO ₂ H, NR ⁴ R ⁵ , or C ₁ -C ₆ alkyl optionally substituted with OH, halogen, or CO ₂ H. In some such embodiments, R ⁹ is H. In some such embodiments, R ⁹ is halogen. In some such embodiments, R ⁹ is F, Cl, or Br. In some such embodiments, R ⁹ is F. In some such embodiments, R ⁹ is Cl. In some such embodiments, R ⁹ is Br. In some such embodiments, R ⁹ is CN. In some such embodiments, R ⁹ is SH. In some such embodiments, R ⁹ is OH. In some such embodiments, R ⁹ is -CO ₂ H. In some such embodiments, R ⁹ is NR ⁴ R ⁵ . In some such embodiments, R ⁹ is NHR ⁴ . In some such embodiments, R ⁹ is NCH ₃ (R ⁴ ). In some such embodiments, R ⁹ is NH ₂ . In some such embodiments, R ⁹ is N(CH ₃ ) ₂ . In some such embodiments, R ⁹ is NH(CH ₃ ). In some such embodiments, R ⁹ is NH(CH ₂ CH ₃ ). In some such embodiments, R ⁹ is C ₁ -C ₆ alkyl optionally substituted with OH, halogen or CO ₂ H. In some such embodiments, R ⁹ is C ₁ -C ₆ alkyl. In some such embodiments, R ⁹ is methyl, ethyl or isopropyl. In some such embodiments, R ⁹ is methyl. In some such embodiments, R ⁹ is ethyl. In some such embodiments, R ⁹ is isopropyl. In some such embodiments, R ⁹ is C ₁ -C ₆ alkyl substituted with OH, halogen or CO ₂ H. In some such embodiments, R ⁹ is C ₁ -C ₆ alkyl substituted with OH. In some such embodiments, R ⁹ is C ₁ -C ₆ alkyl substituted with halogen. In some such embodiments, R ⁹ is C ₁ -C ₆ alkyl substituted with CO ₂ H. In some such embodiments, R ⁹ is methyl substituted with OH. In some such embodiments, R ⁹ is ethyl substituted with -OH. In some such embodiments, R ⁹ is isopropyl substituted with OH. In some such embodiments, R ⁹ is methyl substituted by halogen. In some such embodiments, R ⁹ is ethyl substituted by halogen. In some such embodiments, R ⁹ is isopropyl substituted by halogen. In some such embodiments, R ⁹ is methyl substituted by CO ₂ H. In some such embodiments, R ⁹ is ethyl substituted by CO ₂ H. In some such embodiments, R ⁹ is isopropyl substituted by CO ₂ H.

In some embodiments of Formula (IIc), (IIIc) or (IVc), R ^3X is . In some such embodiments, ^Xa is H, OH, SH, _CO2H , _CO2R4 ^{, or NR4R5 .} In some ^such embodiments, ^Xa is H. In some such embodiments, ^Xa is OH. In some such embodiments, ^Xa is SH. In some such embodiments, ^Xa is _CO2H . In some such embodiments, ^Xa is _CO2R4 . In some such embodiments, ^Xa is _CO2R4 and ^R4 is optionally substituted C1-C6 alkyl. In some such embodiments, ^Xa is ^CO2R4 and ^R4 is _{C1 - C6} alkyl. In some such embodiments _, ^{Xa is} _CO2R4 ^{and R4} is ^methyl , ethyl _, or isopropyl. In some such embodiments, ^Xa is _CO2R4 and ^R4 is methyl. In some such embodiments, ^Xa is ^{CO2R4 and} R4 is ethyl. In some such embodiments, ^Xa is _CO2R4 ^{and R4} is isopropyl. In some such embodiments, ^Xa is _CO2R4 ^{and R4 is} substituted _C1 - _C6 alkyl. In some such embodiments, ^Xa is _CO2R4 ^{and R4} is substituted ^methyl . In some such embodiments, ^Xa is _{CO2R4 and} ^R4 is substituted ethyl. ^In some such embodiments, ^{Xa is} _CO2R4 ^{and R4} is substituted isopropyl. In some such embodiments, ^Xa is ^NR4R5 . In some such embodiments, ^Xa is ^NHR4 . In some such embodiments, ^Xa is _NCH3 ( ^R4 ). In some such embodiments, ^Xa is _NH2 . In some such embodiments, ^Xa is N( _CH3 ) ₂ . In some such embodiments, ^Xa is NH(CH3). In some such embodiments, ^Xa is _NH ( _CH2CH3 ). In some such embodiments, ^Xb is H, OH, _SH , _CO2H , _CO2R4 ^, or ^NR4R5 . In some ^such embodiments, ^Xb is H. In some such embodiments, ^Xb is OH. In some such embodiments, ^Xb is SH. In some such embodiments, ^Xb is _CO2H . In some ^such embodiments, ^Xb is _CO2R4 . In some such embodiments, X ^b is CO ₂ R ⁴ and R ⁴ is optionally substituted C ₁ -C ₆ alkyl. In some such embodiments, X ^b is CO ₂ R ⁴ and R ⁴ is C ₁ -C ₆ alkyl. In some such embodiments, X ^b is CO ₂ R ⁴ and R ⁴ is methyl, ethyl or isopropyl. In some such embodiments, X ^b is CO ₂ R ⁴ and R ⁴ is methyl. In some such embodiments, X ^b is CO ₂ R ⁴ and R ⁴ is ethyl. In some such embodiments, X ^b is CO ₂ R ⁴ and R ⁴ is isopropyl. In some such embodiments, X ^b is CO ₂ R ⁴ and R ⁴ is substituted C ₁ -C ₆ alkyl. In some such embodiments, X ^b is CO ₂ R ⁴ and R ⁴ is substituted methyl. In some such embodiments, X ^b is CO ₂ R ⁴ and R ⁴ is substituted ethyl. In some such embodiments, X ^b is CO ₂ R ⁴ and R ⁴ is substituted isopropyl. In some such embodiments, X ^b is NR ⁴ R ⁵ . In some such embodiments, X ^b is NHR ⁴ . In some such embodiments, X ^b is NCH ₃ (R ⁴ ). In some such embodiments, X ^b is NH ₂ . In some such embodiments, X ^b is N(CH ₃ ) ₂ . In some such embodiments, X ^b is NH(CH ₃ ). In some such embodiments, X ^b is NH(CH ₂ CH ₃ ). In some such embodiments, ^Xc is H, halogen, or optionally substituted _C1 - _C6 alkyl. In some such embodiments, ^Xc is H. In some such embodiments, ^Xc is OH. In some such embodiments, ^Xc is F, Cl, or Br. In some such embodiments, ^Xc is F. In some such embodiments, ^Xc is Cl. In some such embodiments, ^Xc is Br. In some such embodiments, ^Xc is optionally substituted _C1 - _C6 alkyl. In some such embodiments, ^Xc is _C1 - _C6 alkyl. In some such embodiments, ^Xc is methyl, ethyl, or isopropyl. In some such embodiments, ^Xc is methyl. In some such embodiments, ^Xc is ethyl. In some such embodiments, ^Xc is isopropyl. In some such embodiments, ^Xc is substituted _C1 - _C6 alkyl. In some such embodiments, ^Xc is substituted methyl. In some such embodiments, ^Xc is substituted ethyl. In some such embodiments, ^Xc is substituted isopropyl.

In some embodiments of Formula (IIc), (IIIc) or (IVc), R ^3X is and ^Xa and ^Xb together with the carbon atom to which they are attached form , wherein the asterisk (*) indicates the carbon atom to which ^Xa and ^Xb are attached. In some such embodiments, n is 0, 1 or 2. In some such embodiments, n is 0 or 1. In some such embodiments, n is 1 or 2. In some such embodiments, n is 0. In some such embodiments, n is 1. In some such embodiments, n is 2. In some such embodiments, m is 1 or 2. In some such embodiments, m is 1. In some such embodiments, m is 2. In some such embodiments, R ¹⁰ is H or C ₁ -C ₆ alkyl optionally substituted with OH, halogen, NR ⁴ R ⁵ , CO 2 R ⁴ or CO ₂ H. In some such embodiments, R ¹⁰ is H. In some such embodiments, R ¹⁰ is C ₁ -C ₆ alkyl, optionally substituted with OH, halogen, NR ⁴ R ⁵ , CO 2 R ⁴ or CO ₂ H. In some such embodiments, R ¹⁰ is C ₁ -C ₆ alkyl. In some such embodiments, R ¹⁰ is methyl, ethyl or isopropyl. In some such embodiments, R ¹⁰ is methyl. In some such embodiments, R ¹⁰ is ethyl. In some such embodiments, R ¹⁰ is isopropyl. In some such embodiments, R ¹⁰ is C ₁ -C ₆ alkyl, optionally substituted with OH, halogen, NR ⁴ R ⁵ , CO 2 R ⁴ or CO ₂ H. In some such embodiments, R ¹⁰ is methyl substituted by OH, halo, NR ⁴ R ⁵ , CO2R ⁴ or CO ₂ H. In some such embodiments, R ¹⁰ is ethyl substituted by OH, halo, NR ⁴ R ⁵ , CO2R ⁴ or CO ₂ H. In some such embodiments, R ¹⁰ is isopropyl substituted by OH, halo, NR ⁴ R ⁵ , CO2R ⁴ or CO ₂ H. In some such embodiments, X ^c is H, halo or optionally substituted C ₁ -C ₆ alkyl. In some such embodiments, X ^c is H. In some such embodiments, X ^c is OH. In some such embodiments, X ^c is F, Cl or Br. In some such embodiments, X ^c is F. In some such embodiments, X ^c is Cl. In some such embodiments, ^Xc is Br. In some such embodiments, ^Xc is optionally substituted _C1 - _C6 alkyl. In some such embodiments, ^Xc is _C1 - _C6 alkyl. In some such embodiments, ^Xc is methyl, ethyl or isopropyl. In some such embodiments, ^Xc is methyl. In some such embodiments, ^Xc is ethyl. In some such embodiments, ^Xc is isopropyl. In some such embodiments, ^Xc is substituted _C1 - _C6 alkyl. In some such embodiments, ^Xc is substituted methyl. In some such embodiments, ^Xc is substituted ethyl. In some such embodiments, ^Xc is substituted isopropyl.

In some embodiments of Formula (IIc), (IIIc) or (IVc), X ¹ is N. In some embodiments of Formula (IIc), (IIIc) or (IVc), Y ¹ is N.

In some embodiments of formula (IIc), (IIIc) or (IVc), X ¹ is CR ^1X and R ^1X is H, OH, halo, optionally substituted C ₁ -C ₆ alkyl or O(C ₁ -C ₆ alkyl). In some such embodiments, R ^1X is H. In some such embodiments, R ^1X is halo. In some such embodiments, R ^1X is F, Cl or Br. In some such embodiments, R ^1X is F. In some such embodiments, R ^1X is Cl. In some such embodiments, R ^1X is Br. In some such embodiments, R ^1X is optionally substituted C ₁ -C ₆ alkyl. In some such embodiments, R ^1X is C ₁ -C ₆ alkyl. In some such embodiments, R ^1X is methyl, ethyl or isopropyl. In some such embodiments, R ^1X is methyl. In some such embodiments, R ^1X is ethyl. In some such embodiments, R 1X is isopropyl. In some such embodiments, R ^1X is substituted C ₁ -C ₆ alkyl ^{. In some such embodiments, R 1X is} C ₁ -C ₆ alkyl substituted with one or more of halogen, OH, NR ⁴ R ⁵ or C ₃ -C ₈ cycloalkyl, wherein R ⁴ and R ⁵ are as defined for formula (I). In some such embodiments, R ^1X is C ₁ -C ₆ alkyl substituted with one or more halogens. In some such embodiments, R ^1X is C ₁ -C ₆ alkyl substituted with one or more F, Cl or Br. In some such embodiments, R ^1X is C ₁ -C ₆ alkyl substituted with one or more F. In some such embodiments, R ^1X is C ₁ -C ₆ alkyl substituted with one or more Cl. In some such embodiments, R ^1X is C ₁ -C ₆ alkyl substituted with one or more Br. In some such embodiments, R ^1X is C ₁ -C ₆ alkyl substituted with one or more OH. In some such embodiments, R ^1X is C ₁ -C ₆ alkyl substituted with one or more NR ⁴ R ^5. In some such embodiments, R ^1X is C ₁ -C ₆ alkyl substituted with one or more NHR ⁴ . In some such embodiments, R ^1X is C ₁ -C ₆ alkyl substituted with one or more NCH ₃ (R ⁴ ). In some such embodiments, R ^1X is C ₁ -C ₆ alkyl substituted with one or more NH _2. In some such embodiments, R ^1X is C ₁ -C ₆ alkyl substituted with one or more N(CH ₃ ) _2. In some such embodiments, R ^1X is C 1 -C 6 alkyl substituted with one or more NH(CH ₃ ). In some such embodiments, R ^1X is C ₁ -C ₆ alkyl substituted with one or more NH(CH ₂ CH ₃ ). In some such embodiments, R ^1X is _{C 1} -C ₆ alkyl substituted with one or more C _{3 -C 8} cycloalkyl. In some such embodiments, R ^1X is C 1 _{-C 6} alkyl substituted with one or more C ₃ cycloalkyl, C ₄ cycloalkyl, C ₅ cycloalkyl, C ₆ cycloalkyl, C ₇ cycloalkyl, or C ₈ cycloalkyl. In some such embodiments, R ^1X is C ₁ -C ₆ alkyl substituted with one or more C ₃ cycloalkyl. In some such embodiments, R ^1X is C ₁ -C ₆ alkyl substituted with one or more C ₄ cycloalkyl. In some such embodiments, R ^1X is C ₁ -C 6 alkyl substituted with one or more C ₅ cycloalkyl. In some such embodiments, R ^1X is _{C 1 -C 6} alkyl substituted with one or more C ₆ cycloalkyl. In some such embodiments, R ^1X is C ₁ -C ₆ alkyl substituted with one or more C ₇ cycloalkyl groups. In some such embodiments, R ^1X is C ₁ -C ₆ alkyl substituted with one or more C ₈ cycloalkyl groups. In some such embodiments, R ^1X is C ₁ -C ₆ alkyl substituted with one or more cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl groups. In some such embodiments, R ^1X is C 1 -C 6 alkyl substituted with one or more cyclopropyl. In some such embodiments, R ^1X is C ₁ -C ₆ alkyl substituted with one or more cyclobutyl. In some such embodiments, R ^1X is _{C 1 -C 6} alkyl substituted with one or more cyclopentyl groups. In some such embodiments, R ^1X is C ₁ -C ₆ alkyl substituted with one or more cyclohexyl groups. In some such embodiments, R ^1X is O(C ₁ -C ₆ alkyl). In some such embodiments, R ^1X is O(C ₁ alkyl). In some such embodiments, R ^1X is O(C ₂ alkyl). In some such embodiments, R ^1X is O(C ₃ alkyl). In some such embodiments, R ^1X is O(C ₄ alkyl). In some such embodiments, R ^1X is O(C ₅ alkyl). In some such embodiments, R ^1X is O(C ₆ alkyl).

In some embodiments of formula (IIc), (IIIc) or (IVc), Y ¹ is CR ^1Y and R ^1Y is H, OH, halo, optionally substituted C ₁ -C ₆ alkyl or O(C ₁ -C ₆ alkyl). In some such embodiments, R ^1Y is H. In some such embodiments, R ^1Y is halo. In some such embodiments, R ^1Y is F, Cl or Br. In some such embodiments, R ^1Y is F. In some such embodiments, R ^1Y is Cl. In some such embodiments, R ^1Y is Br. In some such embodiments, R ^1Y is optionally substituted C ₁ -C ₆ alkyl. In some such embodiments, R ^1Y is C ₁ -C ₆ alkyl. In some such embodiments, R ^1Y is methyl, ethyl or isopropyl. In some such embodiments, R ^1Y is methyl. In some such embodiments, R ^1Y is ethyl. In some such embodiments, R 1Y is isopropyl. In some such embodiments, R ^1Y is substituted C ₁ -C ₆ alkyl ^{. In some such embodiments, R 1Y is} C ₁ -C ₆ alkyl substituted with one or more of halogen, OH, NR ⁴ R ⁵ or C ₃ -C ₈ cycloalkyl, wherein R ⁴ and R ⁵ are as defined for formula (I). In some such embodiments, R ^1Y is C ₁ -C ₆ alkyl substituted with one or more halogens. In some such embodiments, R ^1Y is C ₁ -C ₆ alkyl substituted with one or more F, Cl or Br. In some such embodiments, R ^1Y is C ₁ -C ₆ alkyl substituted with one or more F. In some such embodiments, R ^1Y is C ₁ -C ₆ alkyl substituted with one or more Cl. In some such embodiments, R ^1Y is C ₁ -C ₆ alkyl substituted with one or more Br. In some such embodiments, R ^1Y is C ₁ -C ₆ alkyl substituted with one or more OH. In some such embodiments, R ^1Y is C ₁ -C ₆ alkyl substituted with one or more NR ⁴ R ^5. In some such embodiments, R ^1Y is C ₁ -C ₆ alkyl substituted with one or more NHR ⁴ . In some such embodiments, R ^1Y is C ₁ -C ₆ alkyl substituted with one or more NCH ₃ (R ⁴ ). In some such embodiments, R ^1Y is C ₁ -C ₆ alkyl substituted with one or more NH _2. In some such embodiments, R ^1Y is C ₁ -C ₆ alkyl substituted with one or more N(CH ₃ ) _2. In some such embodiments, R ^1Y is C 1 -C 6 alkyl substituted with one or more NH(CH ₃ ). In some such embodiments, R ^1Y is C ₁ -C ₆ alkyl substituted with one or more NH(CH ₂ CH ₃ ). In some such embodiments, R ^1Y is _{C 1} -C ₆ alkyl substituted with one or more C _{3 -C 8} cycloalkyl. In some such embodiments, R ^1Y is C 1 _{-C 6} alkyl substituted with one or more C ₃ cycloalkyl, C ₄ cycloalkyl, C ₅ cycloalkyl, C ₆ cycloalkyl, C ₇ cycloalkyl, or C ₈ cycloalkyl. In some such embodiments, R ^1Y is C ₁ -C ₆ alkyl substituted with one or more C ₃ cycloalkyl. In some such embodiments, R ^1Y is C ₁ -C ₆ alkyl substituted with one or more C ₄ cycloalkyl. In some such embodiments, R ^1Y is C ₁ -C ₆ alkyl substituted with one or more C ₅ cycloalkyl. In some such embodiments, R ^1Y is C _{1 -C 6} alkyl substituted with one or more C ₆ cycloalkyl. In some such embodiments, R ^1Y is C ₁ -C ₆ alkyl substituted with one or more C ₇ cycloalkyl groups. In some such embodiments, R ^1Y is C ₁ -C ₆ alkyl substituted with one or more C ₈ cycloalkyl groups. In some such embodiments, R ^1Y is C ₁ -C ₆ alkyl substituted with one or more cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl groups. In some such embodiments, R ^1Y is C 1 -C 6 alkyl substituted with one or more cyclopropyl. In some such embodiments, R ^1Y is C ₁ -C ₆ alkyl substituted with one or more cyclobutyl. In some such embodiments, R ^1Y is _{C 1 -C 6} alkyl substituted with one or more cyclopentyl groups. In some such embodiments, R ^1Y is C ₁ -C ₆ alkyl substituted with one or more cyclohexyl groups. In some such embodiments, R ^1Y is O(C ₁ -C ₆ alkyl). In some such embodiments, R ^1Y is O(C ₁ alkyl). In some such embodiments, R ^1Y is O(C ₂ alkyl). In some such embodiments, R ^1Y is O(C ₃ alkyl). In some such embodiments, R ^1Y is O(C ₄ alkyl). In some such embodiments, R ^1Y is O(C ₅ alkyl). In some such embodiments, R ^1Y is O(C ₆ alkyl).

In some embodiments of formula (IIc), (IIIc) or (IVc), R ^3X is H. In some embodiments, R ^3X is OH. In some embodiments, R ^3X is OCH ₃ . In some embodiments, R ^3X is ; q is 1 or 2; R ⁸ is H, halogen or OH; R ⁹ is H, halogen or OH; X ^c is H, halogen or optionally substituted C ₁ -C ₆ alkyl; X ^a is H, OH, NR ⁴ R ⁵ ; X ^b is H, OH, NR ⁴ R ⁵ ; or X ^a and X ^b together with the carbon atom to which they are attached form , wherein the asterisk (*) indicates the carbon atom to which ^Xa and ^Xb are attached; ^R10 is H or _C1 - _C6 alkyl optionally substituted with OH, ^halogen , ^NR4R5 , _CO2R4 or ^CO2H ; n is 0, 1 or ₂ ; and m is 1 or 2. In some embodiments, ^R3X is ; q is 1 or 2; R ⁸ is H, halogen or OH; R ⁹ is H, halogen or OH; X ^c is H, halogen or optionally substituted C ₁ -C ₆ alkyl; X ^a is H, OH, NR ⁴ R ⁵ ; and X ^b is H, OH, NR ⁴ R ⁵ . In some embodiments, R ^3X is ; q is 2; R ⁸ is H or OH; R ⁹ is H or OH; X ^c is H; X ^a is OH or NR ⁴ R ⁵ ; and X ^b is H. In some embodiments, R ^3X is ; q is 2; R ⁸ is H; R ⁹ is H; X ^c is H; X ^a is OH or NR ⁴ R ⁵ ; and X ^b is H. In some embodiments, R ^3X is In some embodiments, R ^3X is In some embodiments, R ^3X is q is 1 or 2; R ⁸ is H, halogen or OH; R ⁹ is H, halogen or OH; X ^c is H, halogen or optionally substituted C ₁ -C ₆ alkyl; X ^a and X ^b together with the carbon atom to which they are attached form , wherein the asterisk (*) indicates the carbon atom to which ^Xa and ^Xb are attached; ^R10 is H or _C1 - _C6 alkyl optionally substituted with OH, ^halogen , ^NR4R5 , _CO2R4 or ^CO2H ; n is 0, 1 or ₂ ; and m is 1 or 2. In some embodiments, ^R3X is ; q is 2; R ⁸ is H or OH; R ⁹ is H or OH; X ^c is H, halogen or optionally substituted C ₁ -C ₆ alkyl; X ^a and X ^b together with the carbon atom to which they are attached form , wherein the asterisk (*) indicates the carbon atom to which ^Xa and ^Xb are attached; ^R10 is H or _C1 - _C6 alkyl optionally substituted with OH, ^halogen , ^NR4R5 , _{CO2R4 or} ^CO2H ; n is 0; and m is 1. In some embodiments, ^R3X is In some embodiments, R ^3X is .

In some embodiments of formula (IIc), (IIIc) or (IVc), Y ¹ is CH, N, C-OH or C-OCH ₃ ; X ³ is CH, N, C-OH or C-OCH ₃ ; and R ^3X is OH. In some embodiments, Y ¹ is CH, N, C-OH or C-OCH ₃ ; X ¹ is CH, N, C-OH or C-OCH ₃ ; and R ^3X is ; q is 1 or 2; R ⁸ is H, halogen or OH; R ⁹ is H, halogen or OH; X ^c is H, halogen or optionally substituted C ₁ -C ₆ alkyl; X ^a is H, OH, NR ⁴ R ⁵ ; X ^b is H, OH, NR ⁴ R ⁵ ; or X ^a and X ^b together with the carbon atom to which they are attached form , wherein the asterisk (*) indicates the carbon atom to which ^Xa and ^Xb are attached; ^R10 is H or _C1 - _C6 alkyl optionally substituted with OH, ^halogen , ^NR4R5 , _CO2R4 or ^CO2H ; n is 0, 1 or ₂ ; and m is 1 or 2. In some embodiments, ^Y1 is CH, N, C-OH or C- _OCH3 ; ^X1 is CH, N, C-OH or C- _OCH3 ; ^R3X is ; q is 1 or 2; R ⁸ is H, halogen or OH; R ⁹ is H, halogen or OH; X ^c is H, halogen or optionally substituted C ₁ -C ₆ alkyl; X ^a is H, OH, NR ⁴ R ⁵ ; and X ^b is H, OH, NR ⁴ R ⁵ . In some embodiments, Y ¹ is CH, N, C-OH or C-OCH ₃ ; X ¹ is CH, N, C-OH or C-OCH ₃ ; R ^3X is ; q is 2; R ⁸ is H or OH; R ⁹ is H or OH; X ^c is H; X ^a is OH or NR ⁴ R ⁵ ; and X ^b is H. In some embodiments, Y ¹ is CH, N, C-OH or C-OCH ₃ ; X ¹ is CH, N, C-OH or C-OCH ₃ ; R ^3X is ; q is 2; R ⁸ is H; R ⁹ is H; X ^c is H; X ^a is OH or NR ⁴ R ⁵ ; and X ^b is H. In some embodiments, Y ¹ is CH, N, C-OH, or C-OCH ₃ ; X ¹ is CH, N, C-OH, or C-OCH ₃ ; and R ^3X is In some embodiments, Y ¹ is CH, N, C-OH or C-OCH ₃ ; X ¹ is CH, N, C-OH or C-OCH ₃ ; and R ^3X is In some embodiments, Y ¹ is CH, N, C-OH or C-OCH ₃ ; X ¹ is CH, N, C-OH or C-OCH ₃ ; R ^3X is q is 1 or 2; R ⁸ is H, halogen or OH; R ⁹ is H, halogen or OH; X ^c is H, halogen or optionally substituted C ₁ -C ₆ alkyl; X ^a and X ^b together with the carbon atom to which they are attached form , wherein the asterisk (*) indicates the carbon atom to which ^Xa and ^Xb are attached; ^R10 is H or _C1 - _C6 alkyl optionally substituted with OH, ^halogen , ^NR4R5 , _CO2R4 or ^CO2H ; n is 0, 1 or ₂ ; and m is 1 or 2. In some embodiments, ^Y1 is CH, N, C-OH or C- _OCH3 ; ^X1 is CH, N, C-OH or C- _OCH3 ; ^R3X is ; q is 2; R ⁸ is H or OH; R ⁹ is H or OH; X ^c is H, halogen or optionally substituted C ₁ -C ₆ alkyl; X ^a and X ^b together with the carbon atom to which they are attached form , wherein the asterisk (*) indicates the carbon atom to which ^Xa and ^Xb are attached; ^R10 is H or _C1 - _C6 alkyl optionally substituted with OH, ^halogen , ^NR4R5 , _CO2R4 or ^CO2H ; n is 0; and m is 1. In some embodiments, ^Y1 is CH, N, C-OH or _C - _OCH3 ; ^X1 is CH, N, C-OH or C- _OCH3 ; and ^R3X is In some embodiments, Y ¹ is CH, N, C-OH or C-OCH ₃ ; X ¹ is CH, N, C-OH or C-OCH ₃ ; and R ^3X is .

In some embodiments of Formula (A), (I), (IIa), (IIIa), (IVa), (IIb), (IIIb), (IVb), (IIc), (IIIc), or (IVc), Z ¹ is N, CH, or CF. In some embodiments, Z ¹ is N. In some embodiments, Z ¹ is CH. In some embodiments, Z ¹ is CF.

In some embodiments of Formula (A), (I), (IIa), (IIIa), (IVa), (IIb), (IIIb), (IVb), (IIc), (IIIc) or (IVc), X ² is N or CR ^2X . In some embodiments, X ² is N. In some embodiments, X ² is CR ^2X . In some such embodiments, R ^2X is H, halo, C ₁ -C ₆ alkyl, C ₃ -C ₆ cycloalkyl or C ₁ -C ₆ haloalkyl. In some such embodiments, R ^2X is H. In some such embodiments, R ^2X is halo. In some such embodiments, R ^2X is F, Cl or Br. In some such embodiments, R ^2X is F. In some such embodiments, R ^2X is Cl. In some such embodiments, R ^2X is Br. In some such embodiments, R ^2X is C ₁ -C ₆ alkyl. In some such embodiments, R ^2X is methyl, ethyl or isopropyl. In some such embodiments, R ^2X is methyl. In some such embodiments, R ^2X is ethyl. In some such embodiments, R ^2X is isopropyl. In some such embodiments, R ^2X is C ₃ -C ₆ cycloalkyl. In some such embodiments, R ^2X is C ₃ cycloalkyl. In some such embodiments, R ^2X is C ₄ cycloalkyl. In some such embodiments, R ^2X is C ₅ cycloalkyl. In some such embodiments, R ^2X is C ₆ cycloalkyl. In some such embodiments, R ^2X is C ₁ -C ₆ haloalkyl. In some such embodiments, R ^2X is C ₁ haloalkyl. In some such embodiments, R ^2X is C ₂ haloalkyl. In some such embodiments, R ^2X is C ₃ haloalkyl. In some such embodiments, R ^2X is C ₄ haloalkyl. In some such embodiments, R ^2X is C ₅ haloalkyl. In some such embodiments, R ^2X is C ₆ haloalkyl.

In some embodiments of Formula (A), (I), (IIa), (IIIa), (IVa), (IIb), (IIIb), (IVb), (IIc), (IIIc), or (IVc), Y ^is N, CH, or CF. In some embodiments, Y ^is N. In some embodiments, Y is ^CH . In some embodiments, Y ^is CF.

In some embodiments of Formula (A), (I), (IIa), (IIIa), (IVa), (IIb), (IIIb), (IVb), (IIc), (IIIc), or (IVc), ^Z is N, CH, or CF. In some embodiments, ^Z is N. In some embodiments, ^Z is CH. In some embodiments, ^Z is CF.

In some embodiments of Formula (A), (I), (IIa), (IIIa), (IVa), (IIb), (IIIb), (IVb), (IIc), (IIIc) or (IVc), X ² is N or CR ^2X , Y ² is N, CH or CF, and Z ² is N, CH or CF. In some embodiments, X ² is N, Y ² is N, CH or CF, and Z ² is N, CH or CF. In some embodiments, X ² is CR ^2X , Y ² is N, CH or CF, and Z ² is N, CH or CF. In some embodiments, X ² is CR ^2X , R ^2X is H, halo, C ₁ -C ₆ alkyl, C ₃ -C ₆ cycloalkyl or C ₁ -C ₆ haloalkyl, Y ² is N, CH or CF, and Z ² is N, CH or CF. In some embodiments, ^X2 is ^CR2X , ^R2X is H, ^Y2 is N, CH or CF, and ^Z2 is N, CH or CF. In some embodiments, ^X2 is ^CR2X , ^R2X is halogen, ^Y2 is N, CH or CF, and ^Z2 is N, CH or CF. In some embodiments, ^X2 is ^CR2X , ^R2X is F, Cl or Br, Y2 is N, CH or CF, and ^Z2 is N, CH or CF. In some embodiments, ^X2 is ^CR2X , ^R2X is F, Y2 is N, CH or CF, and ^Z2 is N, CH or CF. In some embodiments, ^X2 is ^CR2X , R2X is F, ^Y2 is N, CH or CF, and ^Z2 is N, CH or CF. In some embodiments, X2 is CR2X, ^R2X is Cl, ^Y2 is N, CH or CF, and ^Z2 is N, CH or CF. In some embodiments, X ² is CR ^2X , R ^2X is Br, Y ² is N, CH or CF, and Z ² is N, CH or CF. In some embodiments, X ² is CR ^{2X , R 2X is C 1 -C 6 alkyl, Y 2 is N, CH or CF, and Z 2 is N, CH or CF. In some embodiments, X 2 is CR 2X , R 2X} _{is methyl} ^{, ethyl or isopropyl} , Y 2 is N, CH or CF, and Z ² is N, CH or CF. In some embodiments, X ² is CR 2X , R ^{2X is methyl, Y 2} is N, CH or CF, and Z 2 is N, CH or CF. In some embodiments, X ² is CR ^2X , R ^2X is methyl, Y ² is N, CH or CF, and Z ² is N, CH or CF. In some embodiments, X ² is CR ^2X , R ^2X is ethyl, Y ² is N, CH or CF, and Z ² is N, CH or CF. In some embodiments, X ² is CR ^2X , R ^2X is isopropyl, Y ² is N, CH or CF, and Z ² is N, CH or CF. In some embodiments, X ² is CR ^2X , R ^2X is C ₃ -C ₆ cycloalkyl, Y ² is N, CH or CF, and Z ² is N, CH or CF. In some embodiments, X ² is CR ^2X , R ^2X is C ₃ cycloalkyl, Y ² is N, CH or CF, and Z ² is N, CH or CF. In some embodiments, X ² is CR ^2X , R ^2X is C ₄ cycloalkyl, Y ² is N, CH or CF, and Z ² is N, CH or CF. In some embodiments, X ² is CR ^2X , R ^2X is C ₅ cycloalkyl, Y ² is N, CH or CF, and Z ² is N, CH or CF. In some embodiments, X ² is CR ^2X , R ^2X is C ₆ cycloalkyl, Y ² is N, CH or CF, and Z ² is N, CH or CF. In some embodiments, X ² is CR ^2X , R ^2X is C ₁ -C ₆ haloalkyl, Y ² is N, CH or CF, and Z ² is N, CH or CF. In some embodiments, X ² is CR ^2X , R ^2X is C ₁ haloalkyl, Y ² is N, CH or CF, and Z ² is N, CH or CF. In some embodiments, ^X2 is ^CR2X , ^R2X is _C2 haloalkyl, ^Y2 is N, CH or CF, and ^Z2 is N, CH or CF. In some embodiments, ^X2 is ^CR2X , ^R2X is _C3 haloalkyl, ^Y2 is N, CH or CF, and ^Z2 is N, CH or CF. In some embodiments, ^X2 is ^CR2X , ^R2X is _C4 haloalkyl, ^Y2 is N, CH or CF, and ^Z2 is N, CH or CF. In some embodiments, ^X2 is ^CR2X , ^R2X is _C5 haloalkyl, ^Y2 is N, CH or CF, and ^Z2 is N, CH or CF. In some embodiments, ^X2 is ^CR2X , ^R2X is _C6 haloalkyl, ^Y2 is N, CH or CF, and ^Z2 is N, CH or CF. In some embodiments, ^X2 is N or CH, ^Y2 is N, and ^Z2 is N, CH or CF. In some embodiments, ^X2 is N, ^Y2 is N, and ^Z2 is CH. In some embodiments, ^X2 is CH, ^Y2 is N, and ^Z2 is N. In some embodiments, ^X2 is ^CR2X , ^R2X is H, halo, _C1 - _C6 alkyl, _C3 - _C6 cycloalkyl or _C1 - _C6 haloalkyl, ^Y2 is N, and ^Z2 is CH. In some embodiments, ^X2 is CH, ^Y2 is N, and ^Z2 is CH.

In some embodiments of Formula (A), (I), (IIa), (IIIa), (IVa), (IIb), (IIIb), (IVb), (IIc), (IIIc), or ( ^IVc ), X is C or N. In some embodiments, X is ^C. In some embodiments, X is ^N.

In some embodiments of Formula (A), (I), (IIa), (IIIa), (IVa), (IIb), (IIIb), (IVb), (IIc), (IIIc) or (IVc), Y ⁴ is N, NR ^4Y or CR ^4Y . In some embodiments, Y ⁴ is N. In some embodiments, Y ⁴ is NR ^4Y . In some embodiments, Y ⁴ is CR ^4Y . In some such embodiments, R ^4Y is H, halogen, C ₁ -C ₆ alkyl, C ₁ -C ₆ halogenalkyl or C ₃ -C ₆ cycloalkyl. In some such embodiments, R ^4Y is H. In some such embodiments, R ^4Y is halogen. In some such embodiments, R ^4Y is F, Cl or Br. In some such embodiments, R ^4Y is F. In some such embodiments, R ^4Y is Cl. In some such embodiments, R ^4Y is Br. In some such embodiments, R ^4Y is C ₁ -C ₆ alkyl. In some such embodiments, R ^4Y is methyl, ethyl or isopropyl. In some such embodiments, R ^4Y is methyl. In some such embodiments, R ^4Y is ethyl. In some such embodiments, R ^4Y is isopropyl. In some such embodiments, R ^4Y is C ₁ -C ₆ haloalkyl. In some such embodiments, R ^4Y is C ₁ haloalkyl. In some such embodiments, R ^4Y is C ₂ haloalkyl. In some such embodiments, R ^4Y is C ₃ haloalkyl. In some such embodiments, R ^4Y is C ₄ haloalkyl. In some such embodiments, R ^4Y is C ₅ haloalkyl. In some such embodiments, R ^4Y is C ₆ haloalkyl. In some such embodiments, R ^4Y is C ₃ -C ₆ cycloalkyl. In some such embodiments, R ^4Y is C ₃ cycloalkyl. In some such embodiments, R ^4Y is C ₄ cycloalkyl. In some such embodiments, R ^4Y is C ₅ cycloalkyl. In some such embodiments, R ^4Y is C ₆ cycloalkyl.

In some embodiments of Formula (A), (I), (IIa), (IIIa), (IVa), (IIb), (IIIb), (IVb), (IIc), (IIIc), or (IVc), Z ⁴ is N, S, O, CF, or CH. In some embodiments, Z ⁴ is N. In some embodiments, Z ⁴ is S. In some embodiments, Z ⁴ is O. In some embodiments, Z ⁴ is CF. In some embodiments, Z ⁴ is CH.

In some embodiments of Formula (A), (I), (IIa), (IIIa), (IVa), (IIb), (IIIb), (IVb), (IIc), (IIIc), or (IVc), ^T is N, S, O, or CH. In some embodiments, T is ^N. In some embodiments, ^T is S. In some embodiments, T ^is O. In some embodiments, T is ^CH .

In some embodiments of Formula (A), (I), (IIa), (IIIa), (IVa), (IIb), (IIIb), (IVb), (IIc), (IIIc) or (IVc), R ¹ is C ₁ -C ₆ alkyl, C ₃ -C ₈ cycloalkyl or C ₁ -C ₆ halogenalkyl. In some embodiments, R ¹ is C ₁ -C ₆ alkyl. In some embodiments, R ¹ is methyl, ethyl or isopropyl. In some embodiments, R ¹ is methyl. In some embodiments, R ¹ is ethyl. In some embodiments, R ¹ is isopropyl. In some embodiments, R ¹ is C ₃ -C ₈ cycloalkyl. In some embodiments, R ¹ is C ₃ cycloalkyl. In some embodiments, R ¹ is C ₄ cycloalkyl. In some embodiments, R ¹ is C ₅ cycloalkyl. In some embodiments, R ¹ is C ₆ cycloalkyl. In some embodiments, R ¹ is C ₇ cycloalkyl. In some embodiments, R ¹ is C ₈ cycloalkyl. In some embodiments, R ¹ is C ₁ -C ₆ haloalkyl. In some embodiments, R ¹ is C ₁ haloalkyl. In some embodiments, R ¹ is C ₂ haloalkyl. In some embodiments, R ¹ is C ₃ haloalkyl. In some embodiments, R ¹ is C ₄ haloalkyl. In some embodiments, R ¹ is C ₅ haloalkyl. In some embodiments, R ¹ is C ₆ haloalkyl.

In some embodiments of Formula (A), (I), (IIa), (IIIa), (IVa), (IIb), (IIIb), (IVb), (IIc), (IIIc) or (IVc), X ⁴ is C or N; Y ⁴ is N, NR ^4Y or CR ^4Y ; Z ⁴ is N, S, O, CF or CH; T ⁴ is N, S, O or CH; and R ¹ is C ₁ -C ₆ alkyl, C ₃ -C ₈ alkyl or C ₁ -C ₆ halogenalkyl. In some embodiments, X ⁴ is C; Y ⁴ is N, NR ^4Y or CR ^4Y ; Z ⁴ is N, S, O, CF or CH; T ⁴ is N, S, O or CH; and R ¹ is C ₁ -C ₆ alkyl, C ₃ -C ₈ alkyl or C ₁ -C ₆ halogenalkyl. In some embodiments, ^X4 is C; ^Y4 is N, ^NR4Y or ^CR4Y ; ^Z4 is N; ^T4 is N, S, O or CH; and ^R1 is C1- _C6 alkyl, C3 _{-C8 alkyl} or _C1 - _C6 halogen. In some embodiments, ^X4 is C; ^Y4 is ^NR4Y or ^CR4Y ; ^Z4 is N; ^T4 is N, S, O or CH; and ^R1 is _C1 - _C6 alkyl, _C3 - _{C8 alkyl} or _C1 - _C6 halogen. In some embodiments, X ⁴ is C; Y ⁴ is NR ^4Y or CR ^4Y ; R ^4Y is H or C ₁ -C ₆ alkyl; Z ⁴ is N; T ⁴ is N, S, O or CH; and R ¹ is C ₁ -C ₆ alkyl, C ₃ -C ₈ alkyl or C ₁ -C ₆ halogen. In some embodiments, X ⁴ is C; Y ⁴ is NR ^4Y or CR ^4Y ; R ^4Y is C ₁ -C ₆ alkyl; Z ⁴ is N; T ⁴ is N, S, O or CH; and R ¹ is C ₁ -C ₆ alkyl. In some embodiments, X ⁴ is C; Y ⁴ is NR ^4Y or CR ^4Y ; R ^4Y is -CH ₃ or -CH ₂ CH ₃ ; Z ⁴ is N; T ⁴ is N, S, O, or CH; and R ¹ is C ₁ -C ₆ alkyl. In some embodiments, X ⁴ is C; Y ⁴ is NR ^4Y or CR ^4Y ; R ^4Y is -CH ₃ or -CH ₂ CH ₃ ; Z ⁴ is N; T ⁴ is N, S, O, or CH; and R ¹ is -CH ₃ or -CH ₂ CH _3. In some embodiments, X ⁴ is C; Y ⁴ is NCH ₂ CH ₃ , CCH ₂ CH ₃ , or CCH ₃ ; Z ⁴ is N; T ⁴ is N, S, O, or CH; and R ¹ is CH ₃ . In some embodiments, X ⁴ is C; Y ⁴ is NCH ₂ CH ₃ ; Z ⁴ is N; T ⁴ is N; and R ¹ is CH ₃ . In some embodiments, X ⁴ is C; Y ⁴ is NCH ₂ CH ₃ ; Z ⁴ is N; T ⁴ is S; and R ¹ is CH ₃ . In some embodiments, X ⁴ is C; Y ⁴ is NCH ₂ CH ₃ ; Z ⁴ is N; T ⁴ is O; and R ¹ is CH ₃ . In some embodiments, X ⁴ is C; Y ⁴ is NCH ₂ CH ₃ ; Z ⁴ is N; T ⁴ is CH; and R ¹ is CH ₃ . In some embodiments, X ⁴ is C; Y ⁴ is CCH ₂ CH ₃ ; Z ⁴ is N; T ⁴ is N; and R ¹ is CH ₃ . In some embodiments, X ⁴ is C; Y ⁴ is CCH ₂ CH ₃ ; Z ⁴ is N; T ⁴ is S; and R ¹ is CH ₃ . In some embodiments, X ⁴ is C; Y ⁴ is CCH ₂ CH ₃ ; Z ⁴ is N; T ⁴ is O; and R ¹ is CH ₃ . In some embodiments, X ⁴ is C; Y ⁴ is CCH ₂ CH ₃ ; Z ⁴ is N; T ⁴ is CH; and R ¹ is CH ₃ . In some embodiments, X ⁴ is C; Y ⁴ is CCH ₃ ; Z ⁴ is N; T ⁴ is N; and R ¹ is CH ₃ . In some embodiments, X ⁴ is C; Y ⁴ is CCH ₃ ; Z ⁴ is N; T ⁴ is S; and R ¹ is CH ₃ . In some embodiments, ^X4 is C; ^Y4 is _CCH3 ; ^Z4 is N; ^T4 is O; and ^R1 is _CH3 . In some embodiments, ^X4 is C; ^Y4 is _CCH3 ; ^Z4 is N; ^T4 is CH; and ^R1 is _CH3 .

In some embodiments of Formula (A), (I), (IIa), (IIIa), (IVa), (IIb), (IIIb), (IVb), (IIc), (IIIc) or (IVc), Z ¹ is N, CH or CF; X ² is N or CR ^2X ; Y ² is N, CH or CF; Z ² is N, CH or CF; X ⁴ is C or N; Y ⁴ is N, NR ^4Y or CR ^4Y ; Z ⁴ is N, S, O, CF or CH; T ⁴ is N, S, O or CH; and R ¹ is C ₁ -C ₆ alkyl, C ₃ -C ₈ alkyl or C ₁ -C ₆ halogenalkyl. In some embodiments, Z ¹ is N, CH or CF; X ² is N or CH; Y ² is N, CH or CF; Z ² is N, CH or CF; X ⁴ is C or N; Y ⁴ is NCH ₂ CH ₃ , CCH ₂ CH ₃ or CCH ₃ ; Z ⁴ is N; T ⁴ is N, S, O or CH; and R ¹ is C ₁ -C ₆ alkyl. In some embodiments, Z ¹ is CH, X ² is N, Y ² is N, Z ² is CH, X ⁴ is C, Y ⁴ is NCH ₂ CH ₃ , Z ⁴ is N, T ⁴ is CH, and R ¹ is methyl. In some embodiments, ^Z1 is N, ^X2 is N, ^Y2 is N, ^Z2 is CH, ^X4 is C, ^Y4 is _NCH2CH3 , ^Z4 is _N , ^T4 is CH, and ^R1 is _CH3 . In some embodiments, ^Z1 is N, ^X2 is N, Y2 is N, ^Z2 is CH, ^X4 is C, ^Y4 is ^NCH2CH3 , ^Z4 is N ^, _T4 is _CH , and ^R1 is _CH3 . In some embodiments, ^Z1 is CH, ^X2 is N, Y2 is ^N , ^Z2 is CH, ^X4 is C, ^Y4 is _NCH2CH3 , ^Z4 is N, ^T4 is CH, and ^R1 is _{CH3 .} In some embodiments, ^Z1 is CH, ^X2 is N, ^Y2 is N, ^Z2 is CH, ^X4 is C, ^Y4 is _CCH2CH3 , ^Z4 is _N , ^T4 is O, and ^R1 is _CH3 . In some embodiments, ^Z1 is CH, ^X2 is N, Y2 is N, ^Z2 is CH, ^X4 is C, ^Y4 is ^CCH2CH3 , ^Z4 is _N ^, _T4 is S, and ^R1 is _S3 . In some embodiments, ^Z1 is CH, ^X2 is CH, ^Y2 is N, ^Z2 is N, ^X4 is C, ^Y4 is _NCH2CH3 , ^Z4 is N, ^T4 is CH, and ^R1 is _{CH3 .} In some embodiments, ^Z1 is CH, ^X2 is CH, ^Y2 is N, ^Z2 is CH _, ^X4 is C, ^Y4 is _NCH2CH3 , Z4 is N, T4 is CH, and ^R1 is _CH31 . In some embodiments, ^Z1 is CH, ^X2 is N, ^Y2 is N, ^Z2 is CH, ^X4 is C, ^Y4 is _CCH3 , ^Z4 is N, ^T4 is O, and ^R1 is _CH3 .

In some embodiments of formula (I), T is -C(O)NH ₂ or -S(O) ₂ NH ₂ ; Ring A is , or ; Y ¹ is CH, N, C-OH or C-OCH ₃ ; X ³ is CH, N, C-OH or C-OCH ₃ ; X ¹ is CR ^1X ; R ^1X is -OH, , , or ; Z ¹ is N, CH or CF; X ² is N or CH; Y ² is N, CH or CF; Z ² is N, CH or CF; X ⁴ is C or N; Y ⁴ is NCH ₂ CH ₃ , CCH ₂ CH ₃ or CCH ₃ ; Z ⁴ is N; T ⁴ is N, S, O or CH; and R ¹ is C ₁ -C ₆ alkyl. In some embodiments, T is -C(O)NH ₂ ; Ring A is , or ; Y ¹ is CH or N; X ³ is N or C-OCH ₃ ; X ¹ is CR ^1X ; R ^1X is -OH, , or ; Z ¹ is CH; X ² is N; Y ² is N; Z ² is CH; X ⁴ is C; Y ⁴ is NCH ₂ CH ₃ ; Z ⁴ is N; T ⁴ is CH; and R ¹ is methyl. In some embodiments, T is C(O)NH ₂ or S(O) ₂ NH ₂ ; Ring A is , or ; Y ¹ is CH, N, C-OH or C-OCH ₃ ; X ¹ is CH, N, C-OH or C-OCH ₃ ; X ³ is CR ^3X ; R ^3X is -OH, , , or ; Z ¹ is N, CH or CF; X ² is N or CH; Y ² is N, CH or CF; Z ² is N, CH or CF; X ⁴ is C or N; Y ⁴ is NCH ₂ CH ₃ , CCH ₂ CH ₃ or CCH ₃ ; Z ⁴ is N; T ⁴ is N, S, O or CH; and R ¹ is C ₁ -C ₆ alkyl. In some embodiments, T is C(O)NH ₂ ; Ring A is , or ; Y ¹ is CH or N; X ¹ is N, CH, CCH ₃ or C-OCH ₃ ; X ³ is CR ^3X ; R ^3X is -OH, , or ; Z ¹ is N, CH or CF; X ² is N or CH; Y ² is N; Z ² is N, CH or CF; X ⁴ is C; Y ⁴ is CCH ₃ , CCH ₂ CH ₃ or NCH ₂ CH ₃ ; Z ⁴ is N; T ⁴ is N, S, O or CH; and R ¹ is CH ₃ . In some embodiments, T is -C(O)NH ₂ or -S(O) ₂ NH ₂ ; Ring A is , or ; X ¹ is CH, N, C-OH or C-OCH ₃ ; X ³ is CH, N, C-OH or C-OCH ₃ ; Y ¹ is CR ^1Y ; R ^1Y is -OH, , , or ; Z ¹ is N, CH or CF; X ² is N or CH; Y ² is N, CH or CF; Z ² is N, CH or CF; X ⁴ is C or N; Y ⁴ is NCH ₂ CH ₃ , CCH ₂ CH ₃ or CCH ₃ ; Z ⁴ is N; T ⁴ is N, S, O or CH; and R ¹ is C ₁ -C ₆ alkyl.

In some embodiments of formula (IIa), (IIIa) or (IVa), Y ¹ is CH, N, C-OH or C-OCH ₃ ; X ³ is CH, N, C-OH or C-OCH ₃ ; X ¹ is CR ^1X ; R ^1X is -OH, , , or ; Z ¹ is N, CH or CF; X ² is N or CH; Y ² is N, CH or CF; Z ² is N, CH or CF; X ⁴ is C or N; Y ⁴ is NCH ₂ CH ₃ , CCH ₂ CH ₃ or CCH ₃ ; Z ⁴ is N; T ⁴ is N, S, O or CH; and R ¹ is C ₁ -C ₆ alkyl. In some embodiments, Y ¹ is CH or N; X ³ is N or C-OCH ₃ ; X ¹ is CR ^1X ; R ^1X is -OH, , or ; Z ¹ is CH; X ² is N; Y ² is N; Z ² is CH; X ⁴ is C; Y ⁴ is NCH ₂ CH ₃ ; Z ⁴ is N; T ⁴ is CH; and R ¹ is methyl. In some embodiments, Y ¹ is CH, N, C-OH, or C-OCH ₃ ; X ¹ is CH, N, C-OH, or C-OCH ₃ ; X ³ is CR ^3X ; R ^3X is -OH, , , or ; Z ¹ is N, CH or CF; X ² is N or CH; Y ² is N, CH or CF; Z ² is N, CH or CF; X ⁴ is C or N; Y ⁴ is NCH ₂ CH ₃ , CCH ₂ CH ₃ or CCH ₃ ; Z ⁴ is N; T ⁴ is N, S, O or CH; and R ¹ is C ₁ -C ₆ alkyl. In some embodiments, Y ¹ is CH or N; X ¹ is N, CH, CCH ₃ or C-OCH ₃ ; X ³ is CR ^3X ; R ^3X is -OH, , or ; Z ¹ is N, CH or CF; X ² is N or CH; Y ² is N; Z ² is N, CH or CF; X ⁴ is C; Y ⁴ is CCH ₃ , CCH ₂ CH ₃ or NCH ₂ CH ₃ ; Z ⁴ is N; T ⁴ is N, S, O or CH; and R ¹ is methyl. In some embodiments, X ¹ is CH, N, C-OH or C-OCH ₃ ; X ³ is CH, N, C-OH or C-OCH ₃ ; Y ¹ is CR ^1Y ; R ^1Y is -OH, , , or ; Z ¹ is N, CH or CF; X ² is N or CH; Y ² is N, CH or CF; Z ² is N, CH or CF; X ⁴ is C or N; Y ⁴ is NCH ₂ CH ₃ , CCH ₂ CH ₃ or CCH ₃ ; Z ⁴ is N; T ⁴ is N, S, O or CH; and R ¹ is C ₁ -C ₆ alkyl.

In some embodiments of formula (IIb), (IIIb) or (IVb), Y ¹ is CH, N, C-OH or C-OCH ₃ ; X ³ is CH, N, C-OH or C-OCH ₃ ; R ^1X is -OH, , , or ; Z ¹ is N, CH or CF; X ² is N or CH; Y ² is N, CH or CF; Z ² is N, CH or CF; X ⁴ is C or N; Y ⁴ is NCH ₂ CH ₃ , CCH ₂ CH ₃ or CCH ₃ ; Z ⁴ is N; T ⁴ is N, S, O or CH; and R ¹ is C ₁ -C ₆ alkyl. In some embodiments, Y ¹ is CH or N; X ³ is N or C-OCH ₃ ; R ^1X is -OH, , or ; Z ¹ is CH; X ² is N; Y ² is N; Z ² is CH; X ⁴ is C; Y ⁴ is NCH ₂ CH ₃ ; Z ⁴ is N; T ⁴ is CH; and R ¹ is CH ₃ . In some embodiments, Y ¹ is CH; X ³ is N, and R ^1X is , Z ¹ is CH, X ² is N, Y ² is N, Z ² is CH, X ⁴ is C, Y ⁴ is NCH ₂ CH ₃ , Z ⁴ is N, T ⁴ is CH, and R ¹ is CH ₃ . In some embodiments, Y ¹ is CH, X ³ is C-OCH ₃ , R ^1X is , Z ¹ is CH, X ² is N, Y ² is N, Z ² is CH, X ⁴ is C, Y ⁴ is NCH ₂ CH ₃ , Z ⁴ is N, T ⁴ is CH, and R ¹ is CH ₃ . In some embodiments, Y ¹ is CH, X ³ is N, R ^1X is , Z ¹ is CH, X ² is N, Y ² is N, Z ² is CH, X ⁴ is C, Y ⁴ is NCH ₂ CH ₃ , Z ⁴ is N, T ⁴ is CH, and R ¹ is CH ₃ . In some embodiments, Y ¹ is CH, X ³ is C-OCH ₃ , R ^1X is , Z ¹ is CH, X ² is N, Y ² is N, Z ² is CH, X ⁴ is C, Y ⁴ is NCH ₂ CH ₃ , Z ⁴ is N, T ⁴ is CH, and R ¹ is CH ₃ . In some embodiments, Y ¹ is CH, X ³ is N, R ^1X is , Z ¹ is CH, X ² is N, Y ² is N, Z ² is CH, X ⁴ is C, Y ⁴ is NCH ₂ CH ₃ , Z ⁴ is N, T ⁴ is CH, and R ¹ is CH _3. In some embodiments, Y ¹ is CH, X ³ is C-OCH ₃ , R ^1X is -OH, Z ¹ is CH, X ² is N, Y ² is N, Z ² is CH, X ⁴ is C, Y ⁴ is NCH ₂ CH ₃ , Z ⁴ is N, T ⁴ is CH, and R ¹ is CH ₃ . In some embodiments, ^Y1 is CH, ^X3 is N, ^R1X is -OH, ^Z1 is CH, ^X2 is N, Y2 is ^N , ^Z2 is CH _, ^X4 is C, ^Y4 is _NCH2CH3 , ^Z4 is N, ^T4 is CH, and ^R1 is _CH3 .

In some embodiments of formula (IIc), (IIIc) or (IVc), Y ¹ is CH, N, C-OH or C-OCH ₃ ; X ¹ is CH, N, C-OH or C-OCH ₃ ; R ^3X is -OH, , , or ; Z ¹ is N, CH or CF; X ² is N or CH; Y ² is N, CH or CF; Z ² is N, CH or CF; X ⁴ is C or N; Y ⁴ is NCH ₂ CH ₃ , CCH ₂ CH ₃ or CCH ₃ ; Z ⁴ is N; T ⁴ is N, S, O or CH; and R ¹ is C ₁ -C ₆ alkyl. In some embodiments, Y ¹ is CH or N; X ¹ is N, CH, CCH ₃ or C-OCH ₃ ; R ^3X is -OH, , or ; Z ¹ is N, CH or CF; X ² is N or CH; Y ² is N; Z ² is N, CH or CF; X ⁴ is C; Y ⁴ is CCH ₃ , CCH ₂ CH ₃ or NCH ₂ CH ₃ ; Z ⁴ is N; T ⁴ is N, S, O or CH; and R ¹ is CH ₃ . In some embodiments, Y ¹ is CH, X ¹ is CH, R ^3X is , Z ¹ is N, X ² is N, Y ² is N, Z ² is CH, X ⁴ is C, Y ⁴ is NCH ₂ CH ₃ , Z ⁴ is N, T ⁴ is CH, and R ¹ is CH ₃ . In some embodiments, Y ¹ is N, X ¹ is CCH ₃ , R ^3X is , Z ¹ is CH, X ² is N, Y ² is N, Z ² is CH, X ⁴ is C, Y ⁴ is NCH ₂ CH ₃ , Z ⁴ is N, T ⁴ is CH, and R ¹ is CH ₃ . In some embodiments, Y ¹ is CH, X ¹ is C-OCH ₃ , R ^3X is , Z ¹ is CH, X ² is CH, Y ² is N, Z ² is CH, X ⁴ is C, Y ⁴ is NCH ₂ CH ₃ , Z ⁴ is N, T ⁴ is CH, and R ¹ is CH ₃ . In some embodiments, Y ¹ is CH, X ¹ is C-OCH ₃ , R ^3X is , Z ¹ is CH, X ² is CH, Y ² is N, Z ² is N, X ⁴ is C, Y ⁴ is NCH ₂ CH ₃ , Z ⁴ is N, T ⁴ is CH, and R ¹ is CH ₃ . In some embodiments, Y ¹ is CH, X ¹ is C-OCH ₃ , R ^3X is , Z ¹ is CH, X ² is N, Y ² is N, Z ² is CH, X ⁴ is C, Y ⁴ is NCH ₂ CH ₃ , Z ⁴ is N, T ⁴ is N, and R ¹ is CH ₃ . In some embodiments, Y ¹ is CH, X ¹ is C-OCH ₃ , R ^3X is , Z ¹ is CH, X ² is N, Y ² is N, Z ² is CH, X ⁴ is C, Y ⁴ is CCH ₂ CH ₃ , Z ⁴ is N, T ⁴ is O, and R ¹ is CH ₃ . In some embodiments, Y ¹ is CH, X ¹ is C-OCH ₃ , R ^3X is , Z ¹ is CH, X ² is N, Y ² is N, Z ² is CH, X ⁴ is C, Y ⁴ is CCH ₂ CH ₃ , Z ⁴ is N, T ⁴ is S, and R ¹ is CH ₃ . In some embodiments, Y ¹ is CH, X ¹ is C-OCH ₃ , R ^3X is , Z ¹ is CH, X ² is N, Y ² is N, Z ² is CH, X ⁴ is C, Y ⁴ is NCH ₂ CH ₃ , Z ⁴ is N, T ⁴ is CH, and R ¹ is CH ₃ . In some embodiments, Y ¹ is CH, X ¹ is C-OCH ₃ , R ^3X is , Z ¹ is CH, X ² is N, Y ² is N, Z ² is N, X ⁴ is C, Y ⁴ is CCH ₃ , Z ⁴ is N, T ⁴ is O, and R ¹ is CH ₃ . In some embodiments, Y ¹ is CH, X ¹ is C-OCH ₃ , R ^3X is , Z ¹ is CH, X ² is N, Y ² is N, Z ² is CH, X ⁴ is C, Y ⁴ is NCH ₂ CH ₃ , Z ⁴ is N, T ⁴ is CH, and R ¹ is CH _3. In some embodiments, Y ¹ is CH, X ¹ is C-OCH ₃ , R ^3X is -OH, Z 1 is CH, X 2 is N, Y 2 is N, Z ² is CH, X ⁴ is C, Y ⁴ is NCH 2 CH 3, Z ⁴ is N, T ⁴ is CH, and R 1 is CH _3. In some embodiments, Y 1 is CH, X ¹ is C-OCH ₃ , R ^3X is -OH, Z ¹ is CH, X 2 is N, Y ² is N, Z ² is CH, X 4 is C, Y ^{4 is NCH 2 CH 3, Z 4} is N, T ₄ is CH, and R ^{1 is CH 3} _. , Z ¹ is N, X ² is N, Y ² is N, Z ² is CH, X ⁴ is C, Y ⁴ is NCH ₂ CH ₃ , Z ⁴ is N, T ⁴ is CH, and R ¹ is CH ₃ . In some embodiments, Y ¹ is N, X ¹ is C-OCH ₃ , R ^3X is , Z ¹ is N, X ² is N, Y ² is N, Z ² is CH, X ⁴ is C, Y ⁴ is NCH ₂ CH ₃ , Z ⁴ is N, T ⁴ is CH, and R ¹ is CH ₃ . In some embodiments, Y ¹ is CH, X ¹ is N, R ^3X is , Z ¹ is CH, X ² is N, Y ² is N, Z ² is CH, X ⁴ is C, Y ⁴ is NCH ₂ CH ₃ , Z ⁴ is N, T ⁴ is CH, and R ¹ is CH ₃ .

In some embodiments, when ^L1 is , Ring A is , X ¹ is CR ^1X , Y ¹ is CH, Z ¹ is CH, Z ² is CH, and X ² is N, then T ⁴ , X ⁴ , Y ⁴ , Z ⁴ and R ¹ cannot be simultaneously selected such that T ⁴ is CH, X ⁴ is C, Y ⁴ is NR ^4Y , Z ⁴ is N, and R ¹ is an optionally substituted methyl group. In some embodiments, when L ¹ is When T ⁴ is CH, X ⁴ is C, Y ⁴ is NR ^4Y , Z ⁴ is N, and R ¹ is an optionally substituted methyl group.

In some embodiments, a compound or a salt thereof (e.g., a pharmaceutically acceptable salt) of Table 1 is provided. Table 1. STING agonist compounds Drug-Linker Compounds

In some embodiments, when preparing the ligand-drug conjugate compounds described herein, it will be necessary to synthesize a complete drug-linker compound, which is then conjugated to a targeting agent, wherein after the drug-linker compound is conjugated to the drug linker, the targeting agent becomes the ligand unit of the ligand-drug conjugate compound. In such embodiments, the drug-linker compounds as described herein are intermediate compounds. In those embodiments, the Stretcher unit in the drug-linker compound has not yet been covalently linked to the Ligand unit ( i.e. , is a Stretcher unit precursor Z'), and therefore has a functional group for conjugation to a targeting agent. In one embodiment, the drug-linker compound comprises a STING agonist moiety (shown herein as formula (I) or any subformula thereof) and a linker unit (Q), wherein the ligand unit is linked to the drug unit via the linker unit.

In some embodiments, the drug-linker compound comprises a STING agonist compound of formula (I) or any subformula thereof as a drug unit and a linker unit (Q) comprising a releasable linker (RL) other than a glycoside (e.g., glucuronide) unit, through which the ligand unit is linked to the bound STING agonist compound. In addition to the RL, the linker unit also comprises a stretcher unit prodriver (Z') comprising a functional group for binding to a targeting agent, which is a prodriver of the ligand unit, and thus the linker unit is capable of (directly or indirectly) linking the RL to the ligand unit. In some of those embodiments, when it is desired to add a spacer (S ^* ) as a side chain appendage, a parallel linker unit (B) is present. In any of those embodiments, when more distance needs to be added between the extension unit and the RL, a connector unit (A) is present.

In one set of embodiments, the drug-linker compound comprises a STING agonist compound of Formula (I) or any subformula thereof and a Linker unit (Q), wherein Q comprises a releasable Linker (RL) that is a glycoside (e.g., a glucuronide) unit, which is directly linked to a Stretcher unit prodriver (Z') or indirectly linked to Z' via an intervening component (i.e., A, S ^* and/or B(S ^* )) linked to the Linker unit of the drug-linker compound, wherein Z' comprises a functional group capable of forming a covalent bond with a targeting agent.

In another set of embodiments, the drug-linker compound comprises a STING agonist of Formula (I) or any subformula thereof and a Linker unit (Q), wherein Q comprises a releasable Linker (RL) other than a glycoside (e.g., glucuronide) unit (RL), which is directly linked to a Stretcher unit prodriver (Z') or indirectly linked to Z' via an intervening component (i.e., A, S ^* and/or B(S ^* )) linked to a Linker unit of the drug-linker compound, wherein Z' comprises a functional group capable of forming a covalent bond with a targeting agent.

In another set of embodiments, the drug-linker compound comprises a STING agonist of Formula (A), (I), (IIa), (IIIa), (IVa), (IIb), (IIIb), (IVb), (IIc), (IIIc), (IVc) or any subformula thereof. In such embodiments, the drug-linker compound comprises a STING agonist according to any embodiment as described herein.

It is to be understood that the depiction of a tetravalent N atom in any of the formulas or examples herein represents a tetravalent N atom having a positive charge.

In some embodiments, the drug linker compound has the formula: QD, or a pharmaceutically acceptable salt thereof, wherein Q is a linker unit selected from the group consisting of: (i) Z'-A-RL-, (ii) Z'-A-RL-Y-, (iii) Z'-AS ^* -RL-, (iv) Z'-AS ^* -RL-Y-, (v) Z'-AB(S ^* )-RL-, (vi) Z'-AB(S ^* )-RL-Y-, (vii) Z'-A-, (viii) Z'-AS *-W-, (ix) Z'-AB(S *)-W-, (x) Z'-AS *-W-RL-, and (xi) Z'-AB(S *)-W-RL-; Z' is a stretcher unit precursor; A is a bond or linker unit; B is a parallel linker unit; S* is a separator; RL is a releasable linker; W is an amino acid unit; Y is a second spacer unit; and D is a drug unit of formula (A'): , Formula (A') wherein L ¹ is or ; X ¹ is N or CR ^1X ; Y ¹ is N or CR ^1Y ; Z ¹ , Y ² and Z ² are each independently N, CH or CF; X ² is N or CR ^2X ; X ³ is N or CR ^3X ; T ⁴ is N, S, O or CH; X ⁴ is C or N; Y ⁴ is N, NR ^4Y or CR ^4Y ; Z ⁴ is N, S, O, CF or CH; R ¹ is C ₁ -C ₆ alkyl, C ₃ -C ₈ cycloalkyl or C ₁ -C ₆ halogenalkyl; wherein at least one of X ¹ , Y ¹ and X ³ is not N; R ^1X , R ^1Y and R ^3X are each independently H, -OH, halogen, optionally substituted C ₁ -C ₆ alkyl, -O(C ₁ -C ₆ alkyl) or -S ¹ -#, the restriction is that exactly one of R ^1X , R ^1Y and R ^3X is -S ¹ -#, -S ¹ -# is , , or , wherein the wavy line indicates the point of attachment to the remainder of D and # represents the point of attachment to Q; ^Xc is H, halogen, or optionally substituted _C1 - _C6 alkyl; q is an integer from 0 to 6; n is 0, 1 or 2; m is 1 or 2; ^R8 and ^R9 are each independently H, ^halogen , CN, SH, OH, _CO2H , ^NR4R5 , or _C1 - _C6 alkyl substituted with OH, halogen, or _CO2H ; ^R10 is C1- _C6 ^alkyl substituted with OH, ^halogen , ^NR4R5 , or _CO2R4 , or ^R10 is absent; ^R2X is H, halogen, _C1 - _{C6 alkyl} , _C3 - _C6 cycloalkyl, or _C1 - _C6 halogenalkyl; R ^4Y is H, halogen, C ₁ -C ₆ alkyl, C ₁ -C ₆ halogenalkyl or C ₃ -C ₆ cycloalkyl; T is C(O)NR ⁴ R ⁵ or S(O) ₂ NR ⁶ R ⁷ ; R ⁴ , R ⁵ , R ⁶ and R ⁷ are independently and independently H or optionally substituted C ₁ -C ₆ alkyl at each occurrence; the virtual bonds of formula (A') are each independently single or double bonds, so that the ring with the virtual bonds is an aromatic ring; and Ring A is , or , where the wavy line indicates the point of attachment to the rest of the compound; The restriction is that when L ¹ is , Ring A is , X ¹ is CR ^1X , Y ¹ is CH , Z ¹ is CH , Z ² is CH , and X ² is N , then T ⁴ , X ⁴ , Y ⁴ , Z ⁴ and R ¹ cannot be simultaneously selected such that T ⁴ is CH , X ⁴ is C , Y ⁴ is NR ^4Y , Z ⁴ is N , and R ¹ is an optionally substituted methyl group.

In some embodiments, the drug linker compound has the formula: QD, or a pharmaceutically acceptable salt thereof, wherein Q is a linker unit selected from the group consisting of: (i) Z'-A-RL-, (ii) Z'-A-RL-Y-, (iii) Z'-AS ^* -RL-, (iv) Z'-AS ^* -RL-Y-, (v) Z'-AB(S ^* )-RL-, (vi) Z'-AB(S ^* )-RL-Y-, (vii) Z'-A-, (viii) Z'-AS *-W-, (ix) Z'-AB(S *)-W-, (x) Z'-AS *-W-RL-, and (xi) Z'-AB(S *)-W-RL-; Z' is a stretcher unit precursor; A is a bond or linker unit; B is a parallel linker unit; S* is a separator; RL is a releasable linker; W is an amino acid unit; Y is a second spacer unit; and D is a drug unit of formula (I'): , Formula (I') wherein X ¹ is N or CR ^1X ; Y ¹ is N or CR ^1Y ; Z ¹ , Y ² and Z ² are each independently N, CH or CF; X ² is N or CR ^2X ; X ³ is N or CR ^3X ; T ⁴ is N, S, O or CH; X ⁴ is C or N; Y ⁴ is N, NR ^4Y or CR ^4Y ; Z ⁴ is N, S, O, CF or CH; R ¹ is C ₁ -C ₆ alkyl, C ₃ -C ₈ cycloalkyl or C ₁ -C ₆ halogenalkyl; wherein at least one of X ¹ , Y ¹ and X ³ is not N; R ^1X , R ^1Y and R ^3X are each independently H, -OH, halogen, optionally substituted C ₁ -C ₆ alkyl, -O(C ₁ -C ₆ alkyl) or -S ¹ -#, with the proviso that exactly one of R ^1X , R ^1Y and R ^3X is -S ¹ -#, -S ¹ -# is , , or , wherein the wavy line indicates the point of attachment to the remainder of D and # represents the point of attachment to Q; ^Xc is H, halogen, or optionally substituted _C1 - _C6 alkyl; q is an integer from 0 to 6; n is 0, 1 or 2; m is 1 or 2; ^R8 and ^R9 are each independently H, ^halogen , CN, SH, OH, _CO2H , ^NR4R5 , or _C1 - _C6 alkyl substituted with OH, halogen, or _CO2H ; ^R10 is C1- _C6 ^alkyl substituted with OH, ^halogen , ^NR4R5 , or _CO2R4 , or ^R10 is absent; ^R2X is H, halogen, _C1 - _{C6 alkyl} , _C3 - _C6 cycloalkyl, or _C1 - _C6 halogenalkyl; R ^4Y is H, halogen, C ₁ -C ₆ alkyl, C ₁ -C ₆ halogenalkyl or C ₃ -C ₆ cycloalkyl; T is C(O)NR ⁴ R ⁵ or S(O) ₂ NR ⁶ R ⁷ ; R ⁴ , R ⁵ , R ⁶ and R ⁷ are independently and independently H or optionally substituted C ₁ -C ₆ alkyl at each occurrence; the virtual bonds of formula (I') are each independently single or double bonds, so that the ring with the virtual bonds is an aromatic ring; and Ring A is , or , where the wavy line indicates the point of attachment to the rest of the compound; the restriction is that when Ring A is , X ¹ is CR ^1X , Y ¹ is CH , Z ¹ is CH , Z ² is CH , and X ² is N , then T ⁴ , X ⁴ , Y ⁴ , Z ⁴ and R ¹ cannot be simultaneously selected such that T ⁴ is CH , X ⁴ is C , Y ⁴ is NR ^4Y , Z ⁴ is N , and R ¹ is an optionally substituted methyl group.

In the context of drug-linker compounds, the assembly is best described according to its component groups. Although some procedures for preparing drug-linker compounds are described herein, the order of assembly and general conditions for preparing such compounds should be fully understood by those skilled in the art in view of the teachings of this application. C. Component Groups 1. Drug Unit D

The drug unit of the drug-linker compounds or ligand-drug conjugates thereof provided herein is the STING agonist portion of the compounds disclosed herein and is referred to herein as the drug unit.

In some embodiments, drug unit D has formula (I') as described above.

In some embodiments, drug unit D has formula (IIa'): , Formula (IIa') wherein the variables are as defined for Formula (I'); wherein at least one of X ¹ , Y ¹ and X ³ is not N; and the virtual bonds of Formula (IIa') are each independently single or double bonds, such that the rings with the virtual bonds are aromatic rings.

In some embodiments, drug unit D has formula (IIIa'): , Formula (IIIa') wherein the variables are as defined for Formula (I'); wherein at least one of X ¹ , Y ¹ and X ³ is not N; and the virtual bonds of Formula (IIIa') are each independently single bonds or double bonds, such that the rings with the virtual bonds are aromatic rings; with the restriction that when X ¹ is CR ^1X , Y ¹ is CH, Z ¹ is CH, Z ² is CH, and X ² is N, then T ⁴ , X ⁴ , Y ⁴ , Z ⁴ and R ¹ cannot be simultaneously selected such that T ⁴ is CH, X ⁴ is C, Y ⁴ is NR ^4Y , Z ⁴ is N, and R ¹ is an optionally substituted methyl group.

In some embodiments, drug unit D has formula (IVa'): , Formula (IVa') wherein the variables are as defined for Formula (I'); wherein at least one of X ¹ , Y ¹ and X ³ is not N; and the virtual bonds of Formula (IVa') are each independently single or double bonds, such that the rings with the virtual bonds are aromatic rings.

In some embodiments, drug unit D has formula (IIb'): , Formula (IIb') wherein Y ¹ is N or CR ^1Y ; X ³ is N or CR ^3X ; R ^1Y and R ^3X are each independently H, OH, halogen, optionally substituted C ₁ -C ₆ alkyl or O(C ₁ -C ₆ alkyl); R ^1X is -S ¹ -#, -S ¹ -# is , , or , wherein the wavy line indicates the point of attachment to the remainder of D and # indicates the point of attachment to Q; wherein the remaining variables are as defined for formula (I'); and the virtual bonds of formula (IIb') are each independently a single bond or a double bond, such that the ring with the virtual bonds is an aromatic ring.

In some embodiments, drug unit D has formula (IIIb'): , Formula (IIIb') wherein Y ¹ is N or CR ^1Y ; X ³ is N or CR ^3X ; R ^1Y and R ^3X are each independently H, OH, halogen, optionally substituted C ₁ -C ₆ alkyl or O(C ₁ -C ₆ alkyl); R ^1X is -S ¹ -#, -S ¹ -# is , , or , wherein the wavy line indicates the point of connection with the rest of D and # represents the point of connection with Q; wherein the remaining variables are as defined for formula (I'); and the virtual bonds of formula (IIIb') are each independently single bonds or double bonds, such that the ring with the virtual bonds is an aromatic ring; with the restriction that when Y ¹ is CH, Z ¹ is CH, Z ² is CH, and X ² is N, then T ⁴ , X ⁴ , Y ⁴ , Z ⁴ and R ¹ cannot be simultaneously selected such that T ⁴ is CH, X ⁴ is C, Y ⁴ is NR ^4Y , Z ⁴ is N, and R ¹ is an optionally substituted methyl group.

In some embodiments, drug unit D has formula (IVb'): , Formula (IVb') wherein Y ¹ is N or CR ^1Y ; X ³ is N or CR ^3X ; R ^1Y and R ^3X are each independently H, OH, halogen, optionally substituted C ₁ -C ₆ alkyl or O(C ₁ -C ₆ alkyl); R ^1X is -S ¹ -#, -S ¹ -# is , , or , wherein the wavy line indicates the point of attachment to the remainder of D and # indicates the point of attachment to Q; wherein the remaining variables are as defined for formula (I'); and the virtual bonds of formula (IVb') are each independently a single bond or a double bond, such that the ring bearing the virtual bonds is an aromatic ring.

In some embodiments, drug unit D has formula (IIc'): , Formula (IIc') wherein X ¹ is N or CR ^1X ; Y ¹ is N or CR ^1Y ; R ^1X and R ^1Y are each independently H, OH, halogen, optionally substituted C ₁ -C ₆ alkyl or O(C ₁ -C ₆ alkyl); R ^3X is -S ¹ -#, -S ¹ -# is , , or , wherein the wavy line indicates the point of attachment to the remainder of D and # indicates the point of attachment to Q; wherein the remaining variables are as defined for formula (I'); and the virtual bonds of formula (IIc') are each independently a single bond or a double bond, such that the ring with the virtual bonds is an aromatic ring.

In some embodiments, drug unit D has formula (IIIc'): , Formula (IIIc') wherein X ¹ is N or CR ^1X ; Y ¹ is N or CR ^1Y ; R ^1X and R ^1Y are each independently H, OH, halogen, optionally substituted C ₁ -C ₆ alkyl or O(C ₁ -C ₆ alkyl); R ^3X is -S ¹ -#, -S ¹ -# is , , or , wherein the wavy line indicates the point of attachment to the remainder of D and # indicates the point of attachment to Q; wherein the remaining variables are as defined for formula (I'); and the virtual bonds of formula (IIIc') are each independently a single bond or a double bond, such that the ring with the virtual bonds is an aromatic ring.

In some embodiments, drug unit D has formula (IVc'): , Formula (IVc') wherein X ¹ is N or CR ^1X ; Y ¹ is N or CR ^1Y ; R ^1X and R ^1Y are each independently H, OH, halogen, optionally substituted C ₁ -C ₆ alkyl or O(C ₁ -C ₆ alkyl); R ^3X is -S ¹ -#, -S ¹ -# is , , or , wherein the wavy line indicates the point of attachment to the remainder of D and # indicates the point of attachment to Q; wherein the remaining variables are as defined for formula (I'); and the virtual bonds of formula (IVc') are each independently a single bond or a double bond, such that the ring bearing the virtual bonds is an aromatic ring.

In some embodiments of Formula (A'), (I'), (IIa'), (IIIa') or (IVa'), X ¹ is CR ^1X and R ^1X is -S ¹ -#. In some such embodiments, -S ¹ -# is , , or . In some such embodiments, q is 0 to 6. In some such embodiments, q is 0. In some such embodiments, q is 1. In some such embodiments, q is 2. In some such embodiments, q is 3. In some such embodiments, q is 4. In some such embodiments, q is 5. In some such embodiments, q is 6. In some such embodiments, R ⁸ is H, halogen, CN, SH, OH, CO ₂ H, NR ⁴ R ⁵ , or C ₁ -C ₆ alkyl optionally substituted with OH, halogen, or CO ₂ H. In some such embodiments, R ⁸ is H. In some such embodiments, R ⁸ is halogen. In some such embodiments, R ⁸ is F, Cl, or Br. In some such embodiments, R ⁸ is F. In some such embodiments, R ⁸ is Cl. In some such embodiments, R ⁸ is Br. In some such embodiments, R ⁸ is CN. In some such embodiments, R ⁸ is SH. In some such embodiments, R ⁸ is OH. In some such embodiments, R ⁸ is -CO ₂ H. In some such embodiments, R ⁸ is NR ⁴ R ^5. In some such embodiments, R ⁸ is NHR ^4. In some such embodiments, R ⁸ is NCH ₃ (R ⁴ ). In some such embodiments, R ⁸ is NH ₂ . In some such embodiments, R ⁸ is N(CH ₃ ) ₂ . In some such embodiments, R ⁸ is NH(CH ₃ ). In some such embodiments, R ⁸ is NH(CH ₂ CH ₃ ). In some such embodiments, R ⁸ is C ₁ -C ₆ alkyl, optionally substituted with OH, halogen, or CO ₂ H. In some such embodiments, R ⁸ is C ₁ -C ₆ alkyl. In some such embodiments, R ⁸ is methyl, ethyl, or isopropyl. In some such embodiments, R 8 is methyl. In some such embodiments, R ⁸ is ethyl. In some such embodiments, R ⁸ is isopropyl. In some such embodiments, R ⁸ is C 1 -C 6 alkyl, optionally substituted with OH, halogen, or CO ₂ H. In some such embodiments, R ⁸ is C ₁ -C ₆ alkyl, optionally substituted with OH, halogen, or CO 2 H. In some such embodiments, R ⁸ is C ₁ -C ₆ alkyl, optionally substituted with OH. In some such embodiments, R ⁸ is C ₁ -C ₆ alkyl, optionally substituted with halogen. In some such embodiments, ^R is C ₁ -C ₆ alkyl substituted with CO ₂ H. In some such embodiments, ^R is methyl substituted with -OH. In some such embodiments, ^R is ethyl substituted with OH. In some such embodiments, ^R is isopropyl substituted with OH. In some such embodiments, ^R is methyl substituted with halogen. In some such embodiments, ^R is ethyl substituted with halogen. In some such embodiments, R is isopropyl substituted with halogen. In some such embodiments, ^R is methyl substituted with CO ² H. In some such embodiments, ^R is ethyl substituted with CO _{2 H.} In some such embodiments, ^R is isopropyl substituted with CO ₂ H. In some such embodiments, R ⁹ is H, halogen, CN, SH, OH, CO ₂ H, NR ⁴ R ⁵ , or C ₁ -C ₆ alkyl optionally substituted with OH, halogen, or CO ₂ H. In some such embodiments, R ⁹ is H. In some such embodiments, R ⁹ is halogen. In some such embodiments, R ⁹ is F, Cl, or Br. In some such embodiments, R ⁹ is F. In some such embodiments, R ⁹ is Cl. In some such embodiments, R ⁹ is Br. In some such embodiments, R ⁹ is CN. In some such embodiments, R ⁹ is SH. In some such embodiments, R ⁹ is OH. In some such embodiments, R ⁹ is CO ₂ H. In some such embodiments, R ⁹ is NR ⁴ R ⁵ . In some such embodiments, R ⁹ is NHR ⁴ . In some such embodiments, R ⁹ is NCH ₃ (R ⁴ ). In some such embodiments, R ⁹ is NH ₂ . In some such embodiments, R ⁹ is N(CH ₃ ) ₂ . In some such embodiments, R ⁹ is NH(CH ₃ ). In some such embodiments, R ⁹ is NH(CH ₂ CH ₃ ). In some such embodiments, R ⁹ is C ₁ -C ₆ alkyl optionally substituted with OH, halogen or CO ₂ H. In some such embodiments, R ⁹ is C ₁ -C ₆ alkyl. In some such embodiments, R ⁹ is methyl, ethyl or isopropyl. In some such embodiments, R ⁹ is methyl. In some such embodiments, R ⁹ is ethyl. In some such embodiments, R ⁹ is isopropyl. In some such embodiments, R ⁹ is C ₁ -C ₆ alkyl substituted with OH, halogen or CO ₂ H. In some such embodiments, R ⁹ is C ₁ -C ₆ alkyl substituted with OH. In some such embodiments, R ⁹ is C ₁ -C ₆ alkyl substituted with halogen. In some such embodiments, R ⁹ is C ₁ -C ₆ alkyl substituted with CO ₂ H. In some such embodiments, R ⁹ is methyl substituted with OH. In some such embodiments, R ⁹ is ethyl substituted with OH. In some such embodiments, R ⁹ is isopropyl substituted with OH. In some such embodiments, R ⁹ is methyl substituted by halogen. In some such embodiments, R ⁹ is ethyl substituted by halogen. In some such embodiments, R ⁹ is isopropyl substituted by halogen. In some such embodiments, R ⁹ is methyl substituted by CO ₂ H. In some such embodiments, R ⁹ is ethyl substituted by CO ₂ H. In some such embodiments, R ⁹ is isopropyl substituted by CO ₂ H. In some such embodiments, n is 0, 1 or 2. In some such embodiments, n is 0 or 1. In some such embodiments, n is 1 or 2. In some such embodiments, n is 0. In some such embodiments, n is 1. In some such embodiments, n is 2. In some such embodiments, m is 1 or 2. In some such embodiments, m is 1. In some such embodiments, m is 2. In some such embodiments, R ¹⁰ is C ₁ -C ₆ alkyl, optionally substituted with OH, halogen, NR ⁴ R ⁵ , CO2R ⁴ or CO ₂ H, or R ¹⁰ is absent. In some such embodiments, R ¹⁰ is C ₁ -C ₆ alkyl, optionally substituted with OH, halogen, NR ⁴ R ⁵ , CO2R ⁴ or CO ₂ H. In some such embodiments, R ¹⁰ is C ₁ -C ₆ alkyl. In some such embodiments, R ¹⁰ is methyl, ethyl or isopropyl. In some such embodiments, R ¹⁰ is methyl. In some such embodiments, R ¹⁰ is ethyl. In some such embodiments, R ¹⁰ is isopropyl. In some such embodiments, R ¹⁰ is C ₁ -C ₆ alkyl substituted with OH, halo, NR ⁴ R ⁵ , CO2R ⁴ or CO ₂ H. In some such embodiments, R ¹⁰ is methyl substituted with OH, halo, NR ⁴ R ⁵ , CO2R ⁴ or CO ₂ H. In some such embodiments, R ¹⁰ is ethyl substituted with OH, halo, NR ⁴ R ⁵ , CO2R ⁴ or CO ₂ H. In some such embodiments, R ¹⁰ is isopropyl substituted with OH, halo, NR ⁴ R ⁵ , CO2R ⁴ or CO ₂ H. In some such embodiments, R ¹⁰ is absent. In some such embodiments, X ^c is H, halo or optionally substituted C ₁ -C ₆ alkyl. In some such embodiments, ^Xc is H. In some such embodiments, ^Xc is OH. In some such embodiments, ^Xc is F, Cl or Br. In some such embodiments, ^Xc is F. In some such embodiments, ^Xc is Cl. In some such embodiments, ^Xc is Br. In some such embodiments, ^Xc is optionally substituted C1-C6 alkyl. In some such embodiments, ^Xc is _{C1 - C6} alkyl. In some such embodiments, ^Xc is methyl _, ethyl or isopropyl. In some such embodiments, ^Xc is methyl. In some such embodiments, ^Xc is ethyl. In some such embodiments, ^Xc is isopropyl. In some such embodiments, ^Xc is substituted _C1 - _C6 alkyl. In some such embodiments, ^Xc is substituted methyl. In some such embodiments, ^Xc is substituted ethyl. In some such embodiments, ^Xc is substituted isopropyl.

In some embodiments of Formula (A'), (I'), (IIa'), (IIIa') or (IVa'), X ³ is CR ^3X and R ^3X is -S ¹ -#. In some such embodiments, -S ¹ -# is , , or . In some such embodiments, q is 0 to 6. In some such embodiments, q is 0. In some such embodiments, q is 1. In some such embodiments, q is 2. In some such embodiments, q is 3. In some such embodiments, q is 4. In some such embodiments, q is 5. In some such embodiments, q is 6. In some such embodiments, R ⁸ is H, halogen, CN, SH, OH, CO ₂ H, NR ⁴ R ⁵ , or C ₁ -C ₆ alkyl optionally substituted with -OH, halogen, or -CO ₂ H. In some such embodiments, R ⁸ is H. In some such embodiments, R ⁸ is halogen. In some such embodiments, R ⁸ is F, Cl, or Br. In some such embodiments, R ⁸ is F. In some such embodiments, R ⁸ is Cl. In some such embodiments, R ⁸ is Br. In some such embodiments, R ⁸ is CN. In some such embodiments, R ⁸ is SH. In some such embodiments, R ⁸ is OH. In some such embodiments, R ⁸ is CO ₂ H. In some such embodiments, R ⁸ is NR ⁴ R ^5. In some such embodiments, R ⁸ is NHR ^4. In some such embodiments, R ⁸ is NCH ₃ (R ⁴ ). In some such embodiments, R ⁸ is NH ₂ . In some such embodiments, R ⁸ is N(CH ₃ ) ₂ . In some such embodiments, R ⁸ is NH(CH ₃ ). In some such embodiments, R ⁸ is NH(CH ₂ CH ₃ ). In some such embodiments, R ⁸ is C ₁ -C ₆ alkyl, optionally substituted with OH, halogen, or CO ₂ H. In some such embodiments, R ⁸ is C ₁ -C ₆ alkyl. In some such embodiments, R ⁸ is methyl, ethyl, or isopropyl. In some such embodiments, R 8 is methyl. In some such embodiments, R ⁸ is ethyl. In some such embodiments, R ⁸ is isopropyl. In some such embodiments, R ⁸ is C 1 -C 6 alkyl, optionally substituted with OH, halogen, or CO ₂ H. In some such embodiments, R ⁸ is C ₁ -C ₆ alkyl, optionally substituted with OH, halogen, or CO 2 H. In some such embodiments, R ⁸ is C ₁ -C ₆ alkyl, optionally substituted with OH. In some such embodiments, R ⁸ is C ₁ -C ₆ alkyl, optionally substituted with halogen. In some such embodiments, ^R is C ₁ -C ₆ alkyl substituted with CO ₂ H. In some such embodiments, ^R is methyl substituted with OH. In some such embodiments, ^R is ethyl substituted with OH. In some such embodiments, ^R is isopropyl substituted with OH. In some such embodiments, ^R is methyl substituted with halogen. In some such embodiments, ^R is ethyl substituted with halogen. In some such embodiments, R is isopropyl substituted with halogen. In some such embodiments, ^R is methyl substituted with CO ² H. In some such embodiments, ^R is ethyl substituted with CO _{2 H.} In some such embodiments, ^R is isopropyl substituted with CO ₂ H. In some such embodiments, R ⁹ is H, halogen, CN, SH, OH, CO ₂ H, NR ⁴ R ⁵ , or C ₁ -C ₆ alkyl optionally substituted with OH, halogen, or CO ₂ H. In some such embodiments, R ⁹ is H. In some such embodiments, R ⁹ is halogen. In some such embodiments, R ⁹ is F, Cl, or Br. In some such embodiments, R ⁹ is F. In some such embodiments, R ⁹ is Cl. In some such embodiments, R ⁹ is Br. In some such embodiments, R ⁹ is CN. In some such embodiments, R ⁹ is SH. In some such embodiments, R ⁹ is OH. In some such embodiments, R ⁹ is CO ₂ H. In some such embodiments, R ⁹ is NR ⁴ R ⁵ . In some such embodiments, R ⁹ is NHR ⁴ . In some such embodiments, R ⁹ is NCH ₃ (R ⁴ ). In some such embodiments, R ⁹ is NH ₂ . In some such embodiments, R ⁹ is N(CH ₃ ) ₂ . In some such embodiments, R ⁹ is NH(CH ₃ ). In some such embodiments, R ⁹ is NH(CH ₂ CH ₃ ). In some such embodiments, R ⁹ is C ₁ -C ₆ alkyl optionally substituted with OH, halogen or CO ₂ H. In some such embodiments, R ⁹ is C ₁ -C ₆ alkyl. In some such embodiments, R ⁹ is methyl, ethyl or isopropyl. In some such embodiments, R ⁹ is methyl. In some such embodiments, R ⁹ is ethyl. In some such embodiments, R ⁹ is isopropyl. In some such embodiments, R ⁹ is C ₁ -C ₆ alkyl substituted with OH, halogen or CO ₂ H. In some such embodiments, R ⁹ is C ₁ -C ₆ alkyl substituted with OH. In some such embodiments, R ⁹ is C ₁ -C ₆ alkyl substituted with halogen. In some such embodiments, R ⁹ is C ₁ -C ₆ alkyl substituted with CO ₂ H. In some such embodiments, R ⁹ is methyl substituted with -OH. In some such embodiments, R ⁹ is ethyl substituted with -OH. In some such embodiments, R ⁹ is isopropyl substituted with OH. In some such embodiments, R ⁹ is methyl substituted by halogen. In some such embodiments, R ⁹ is ethyl substituted by -halogen. In some such embodiments, R ⁹ is isopropyl substituted by halogen. In some such embodiments, R ⁹ is methyl substituted by CO ₂ H. In some such embodiments, R ⁹ is ethyl substituted by CO ₂ H. In some such embodiments, R ⁹ is isopropyl substituted by CO ₂ H. In some such embodiments, n is 0, 1 or 2. In some such embodiments, n is 0 or 1. In some such embodiments, n is 1 or 2. In some such embodiments, n is 0. In some such embodiments, n is 1. In some such embodiments, n is 2. In some such embodiments, m is 1 or 2. In some such embodiments, m is 1. In some such embodiments, m is 2. In some such embodiments, R ¹⁰ is C ₁ -C ₆ alkyl, optionally substituted with OH, halogen, NR ⁴ R ⁵ , CO2R ⁴ or CO ₂ H, or R ¹⁰ is absent. In some such embodiments, R ¹⁰ is C ₁ -C ₆ alkyl, optionally substituted with OH, halogen, NR ⁴ R ⁵ , CO2R ⁴ or CO ₂ H. In some such embodiments, R ¹⁰ is C ₁ -C ₆ alkyl. In some such embodiments, R ¹⁰ is methyl, ethyl or isopropyl. In some such embodiments, R ¹⁰ is methyl. In some such embodiments, R ¹⁰ is ethyl. In some such embodiments, R ¹⁰ is isopropyl. In some such embodiments, R ¹⁰ is C ₁ -C ₆ alkyl substituted with OH, halo, NR ⁴ R ⁵ , CO2R ⁴ or CO ₂ H. In some such embodiments, R ¹⁰ is methyl substituted with OH, halo, NR ⁴ R ⁵ , CO2R ⁴ or CO ₂ H. In some such embodiments, R ¹⁰ is ethyl substituted with OH, halo, NR ⁴ R ⁵ , CO2R ⁴ or CO ₂ H. In some such embodiments, R ¹⁰ is isopropyl substituted with OH, halo, NR ⁴ R ⁵ , CO2R ⁴ or CO ₂ H. In some such embodiments, R ¹⁰ is absent. In some such embodiments, X ^c is H, halo or optionally substituted C ₁ -C ₆ alkyl. In some such embodiments, ^Xc is H. In some such embodiments, ^Xc is OH. In some such embodiments, ^Xc is F, Cl or Br. In some such embodiments, ^Xc is F. In some such embodiments, ^Xc is Cl. In some such embodiments, ^Xc is Br. In some such embodiments, ^Xc is optionally substituted C1-C6 alkyl. In some such embodiments, ^Xc is _{C1 - C6} alkyl. In some such embodiments, ^Xc is methyl _, ethyl or isopropyl. In some such embodiments, ^Xc is methyl. In some such embodiments, ^Xc is ethyl. In some such embodiments, ^Xc is isopropyl. In some such embodiments, ^Xc is substituted _C1 - _C6 alkyl. In some such embodiments, ^Xc is substituted methyl. In some such embodiments, ^Xc is substituted ethyl. In some such embodiments, ^Xc is substituted isopropyl.

In some embodiments of Formula (A'), (I'), (IIa'), (IIIa'), or (IVa'), Y ¹ is CR ^1Y and R ^1Y is -S ¹ -#. In some such embodiments, -S ¹ -# is , , or . In some such embodiments, q is 0 to 6. In some such embodiments, q is 0. In some such embodiments, q is 1. In some such embodiments, q is 2. In some such embodiments, q is 3. In some such embodiments, q is 4. In some such embodiments, q is 5. In some such embodiments, q is 6. In some such embodiments, R ⁸ is H, halogen, CN, SH, OH, CO ₂ H, NR ⁴ R ⁵ , or C ₁ -C ₆ alkyl optionally substituted with -OH, halogen, or -CO ₂ H. In some such embodiments, R ⁸ is H. In some such embodiments, R ⁸ is halogen. In some such embodiments, R ⁸ is F, Cl, or Br. In some such embodiments, R ⁸ is F. In some such embodiments, R ⁸ is Cl. In some such embodiments, R ⁸ is Br. In some such embodiments, R ⁸ is CN. In some such embodiments, R ⁸ is SH. In some such embodiments, R ⁸ is OH. In some such embodiments, R ⁸ is CO ₂ H. In some such embodiments, R ⁸ is NR ⁴ R ^5. In some such embodiments, R ⁸ is NHR ^4. In some such embodiments, R ⁸ is NCH ₃ (R ⁴ ). In some such embodiments, R ⁸ is NH ₂ . In some such embodiments, R ⁸ is N(CH ₃ ) ₂ . In some such embodiments, R ⁸ is NH(CH ₃ ). In some such embodiments, R ⁸ is NH(CH ₂ CH ₃ ). In some such embodiments, R ⁸ is C ₁ -C ₆ alkyl, optionally substituted with OH, halogen, or CO ₂ H. In some such embodiments, R ⁸ is C ₁ -C ₆ alkyl. In some such embodiments, R ⁸ is methyl, ethyl, or isopropyl. In some such embodiments, R 8 is methyl. In some such embodiments, R ⁸ is ethyl. In some such embodiments, R ⁸ is isopropyl. In some such embodiments, R ⁸ is C 1 -C 6 alkyl, optionally substituted with OH, halogen, or CO ₂ H. In some such embodiments, R ⁸ is C ₁ -C ₆ alkyl, optionally substituted with OH, halogen, or CO 2 H. In some such embodiments, R ⁸ is C ₁ -C ₆ alkyl, optionally substituted with OH. In some such embodiments, R ⁸ is C ₁ -C ₆ alkyl, optionally substituted with halogen. In some such embodiments, ^R is C ₁ -C ₆ alkyl substituted with CO ₂ H. In some such embodiments, ^R is methyl substituted with OH. In some such embodiments, ^R is ethyl substituted with OH. In some such embodiments, ^R is isopropyl substituted with OH. In some such embodiments, ^R is methyl substituted with halogen. In some such embodiments, ^R is ethyl substituted with halogen. In some such embodiments, R is isopropyl substituted with halogen. In some such embodiments, ^R is methyl substituted with CO ² H. In some such embodiments, ^R is ethyl substituted with CO _{2 H.} In some such embodiments, ^R is isopropyl substituted with CO ₂ H. In some such embodiments, R ⁹ is H, halogen, CN, SH, OH, CO ₂ H, NR ⁴ R ⁵ , or C ₁ -C ₆ alkyl optionally substituted with OH, halogen, or CO ₂ H. In some such embodiments, R ⁹ is H. In some such embodiments, R ⁹ is halogen. In some such embodiments, R ⁹ is F, Cl, or Br. In some such embodiments, R ⁹ is F. In some such embodiments, R ⁹ is Cl. In some such embodiments, R ⁹ is Br. In some such embodiments, R ⁹ is CN. In some such embodiments, R ⁹ is SH. In some such embodiments, R ⁹ is OH. In some such embodiments, R ⁹ is CO ₂ H. In some such embodiments, R ⁹ is NR ⁴ R ⁵ . In some such embodiments, R ⁹ is NHR ⁴ . In some such embodiments, R ⁹ is NCH ₃ (R ⁴ ). In some such embodiments, R ⁹ is NH ₂ . In some such embodiments, R ⁹ is N(CH ₃ ) ₂ . In some such embodiments, R ⁹ is NH(CH ₃ ). In some such embodiments, R ⁹ is NH(CH ₂ CH ₃ ). In some such embodiments, R ⁹ is C ₁ -C ₆ alkyl optionally substituted with OH, halogen or CO ₂ H. In some such embodiments, R ⁹ is C ₁ -C ₆ alkyl. In some such embodiments, R ⁹ is methyl, ethyl or isopropyl. In some such embodiments, R ⁹ is methyl. In some such embodiments, R ⁹ is ethyl. In some such embodiments, R ⁹ is isopropyl. In some such embodiments, R ⁹ is C ₁ -C ₆ alkyl substituted with OH, halogen or CO ₂ H. In some such embodiments, R ⁹ is C ₁ -C ₆ alkyl substituted with -OH. In some such embodiments, R ⁹ is C ₁ -C ₆ alkyl substituted with halogen. In some such embodiments, R ⁹ is C ₁ -C ₆ alkyl substituted with CO ₂ H. In some such embodiments, R ⁹ is methyl substituted with OH. In some such embodiments, R ⁹ is ethyl substituted with OH. In some such embodiments, R ⁹ is isopropyl substituted with OH. In some such embodiments, R ⁹ is methyl substituted by halogen. In some such embodiments, R ⁹ is ethyl substituted by halogen. In some such embodiments, R ⁹ is isopropyl substituted by halogen. In some such embodiments, R ⁹ is methyl substituted by CO ₂ H. In some such embodiments, R ⁹ is ethyl substituted by CO ₂ H. In some such embodiments, R ⁹ is isopropyl substituted by CO ₂ H. In some such embodiments, n is 0, 1 or 2. In some such embodiments, n is 0 or 1. In some such embodiments, n is 1 or 2. In some such embodiments, n is 0. In some such embodiments, n is 1. In some such embodiments, n is 2. In some such embodiments, m is 1 or 2. In some such embodiments, m is 1. In some such embodiments, m is 2. In some such embodiments, R ¹⁰ is C ₁ -C ₆ alkyl, optionally substituted with OH, halogen, NR ⁴ R ⁵ , CO2R ⁴ or CO ₂ H, or R ¹⁰ is absent. In some such embodiments, R ¹⁰ is C ₁ -C ₆ alkyl, optionally substituted with OH, halogen, NR ⁴ R ⁵ , CO2R ⁴ or CO ₂ H. In some such embodiments, R ¹⁰ is C ₁ -C ₆ alkyl. In some such embodiments, R ¹⁰ is methyl, ethyl or isopropyl. In some such embodiments, R ¹⁰ is methyl. In some such embodiments, R ¹⁰ is ethyl. In some such embodiments, R ¹⁰ is isopropyl. In some such embodiments, R ¹⁰ is C ₁ -C ₆ alkyl substituted with OH, halo, NR ⁴ R ⁵ , CO2R ⁴ or CO ₂ H. In some such embodiments, R ¹⁰ is methyl substituted with OH, halo, NR ⁴ R ⁵ , CO2R ⁴ or CO ₂ H. In some such embodiments, R ¹⁰ is ethyl substituted with OH, halo, NR ⁴ R ⁵ , CO2R ⁴ or CO ₂ H. In some such embodiments, R ¹⁰ is isopropyl substituted with OH, halo, NR ⁴ R ⁵ , CO2R ⁴ or CO ₂ H. In some such embodiments, R ¹⁰ is absent. In some such embodiments, X ^c is H, halo or optionally substituted C ₁ -C ₆ alkyl. In some such embodiments, ^Xc is H. In some such embodiments, ^Xc is OH. In some such embodiments, ^Xc is F, Cl or Br. In some such embodiments, ^Xc is F. In some such embodiments, ^Xc is Cl. In some such embodiments, ^Xc is Br. In some such embodiments, ^Xc is optionally substituted C1-C6 alkyl. In some such embodiments, ^Xc is _{C1 - C6} alkyl. In some such embodiments, ^Xc is methyl _, ethyl or isopropyl. In some such embodiments, ^Xc is methyl. In some such embodiments, ^Xc is ethyl. In some such embodiments, ^Xc is isopropyl. In some such embodiments, ^Xc is substituted _C1 - _C6 alkyl. In some such embodiments, ^Xc is substituted methyl. In some such embodiments, ^Xc is substituted ethyl. In some such embodiments, ^Xc is substituted isopropyl.

In some embodiments of Formula (A'), (I'), (IIa'), (IIIa') or (IVa'), X ¹ is CR ^1X and R ^1X is H. In some embodiments, X ¹ is CR ^1X and R ^1X is OH. In some embodiments, X ¹ is CR ^1X and R ^1X is OCH ₃ . In some embodiments, X ¹ is CR ^1X ; R ^1X is , , or ; q is 1 or 2; R ⁸ is H, halogen or OH; R ⁹ is H, halogen or OH; X ^c is H, halogen or optionally substituted C ₁ -C ₆ alkyl; R ¹⁰ is C ₁ -C ₆ alkyl optionally substituted with OH, halogen, NR ⁴ R ⁵ , CO ₂ R ⁴ or CO ₂ H, or R ¹⁰ is absent; n is 0, 1 or 2; and m is 1 or 2. In some embodiments, X ¹ is CR ^1X ; R ^1X is or ; q is 1 or 2; R ⁸ is H, halogen or OH; R ⁹ is H, halogen or OH; X ^c is H, halogen or optionally substituted C ₁ -C ₆ alkyl; X ^a is H, OH, NR ⁴ R ⁵ ; and X ^b is H, OH, NR ⁴ R ⁵ . In some embodiments, X ¹ is CR ^1X ; R ^1X is or ; q is 2; R ⁸ is H or OH; R ⁹ is H or OH; X ^c is H; X ^a is OH or NR ⁴ R ⁵ ; and X ^b is H. In some embodiments, X ¹ is CR ^1X ; R ^1X is or ; q is 2; R ⁸ is H; R ⁹ is H; X ^c is H; X ^a is OH or NR ⁴ R ⁵ ; and X ^b is H. In some embodiments, X ¹ is CR ^1X ; R ^1X is In some embodiments, X ¹ is CR ^1X ; R ^1X is In some embodiments, X ¹ is CR ^1X ; R ^1X is ; q is 1 or 2; R ⁸ is H, halogen or OH; R ⁹ is H, halogen or OH; X ^c is H, halogen or optionally substituted C ₁ -C ₆ alkyl; R ¹⁰ is C ₁ -C ₆ alkyl optionally substituted with OH, halogen, NR ⁴ R ⁵ , CO ₂ R ⁴ or CO ₂ H, or R ¹⁰ is absent; n is 0, 1 or 2; and m is 1 or 2. In some embodiments, X ¹ is CR ^1X ; R ^1X is ; q is 2; R ⁸ is H or OH; R ⁹ is H or OH; X ^c is H, halogen or optionally substituted C ₁ -C ₆ alkyl; R ¹⁰ is C ₁ -C ₆ alkyl optionally substituted with OH, halogen, NR ⁴ R ⁵ , CO ₂ R ⁴ or CO ₂ H, or R ¹⁰ is absent; n is 0; and m is 1. In some embodiments, X ¹ is CR ^1X and R ^1X is In some embodiments, X ¹ is CR ^1X and R ^1X is .

In some embodiments of Formula (A'), (I'), (IIa'), (IIIa') or (IVa'), X ³ is CR ^3X and R ^3X is H. In some embodiments, X ³ is CR ^3X and R ^3X is OH. In some embodiments, X ³ is CR ^3X and R ^3X is OCH ₃ . In some embodiments, X ³ is CR ^3X ; R ^3X is , , or ; q is 1 or 2; R ⁸ is H, halogen or OH; R ⁹ is H, halogen or OH; X ^c is H, halogen or optionally substituted C ₁ -C ₆ alkyl; R ¹⁰ is C ₁ -C ₆ alkyl optionally substituted with OH, halogen, NR ⁴ R ⁵ , CO ₂ R ⁴ or CO ₂ H, or R ¹⁰ is absent; n is 0, 1 or 2; and m is 1 or 2. In some embodiments, X ³ is CR ^3X ; R ^3X is or ; q is 1 or 2; R ⁸ is H, halogen or OH; R ⁹ is H, halogen or OH; X ^c is H, halogen or optionally substituted C ₁ -C ₆ alkyl; X ^a is H, OH, NR ⁴ R ⁵ ; and X ^b is H, OH, NR ⁴ R ⁵ . In some embodiments, X ³ is CR ^3X ; R ^3X is or ; q is 2; R ⁸ is H or OH; R ⁹ is H or OH; X ^c is H; X ^a is OH or NR ⁴ R ⁵ ; and X ^b is H. In some embodiments, X ³ is CR ^3X ; R ^3X is or ; q is 2; R ⁸ is H; R ⁹ is H; X ^c is H; X ^a is OH or NR ⁴ R ⁵ ; and X ^b is H. In some embodiments, X ³ is CR ^3X and R ^3X is In some embodiments, X ³ is CR ^3X and R ^3X is In some embodiments, X ³ is CR ^3X ; R ^3X is ; q is 1 or 2; R ⁸ is H, halogen or OH; R ⁹ is H, halogen or OH; X ^c is H, halogen or optionally substituted C ₁ -C ₆ alkyl; R ¹⁰ is C ₁ -C ₆ alkyl optionally substituted with OH, halogen, NR ⁴ R ⁵ , CO ₂ R ⁴ or CO ₂ H, or R ¹⁰ is absent; n is 0, 1 or 2; and m is 1 or 2. In some embodiments, X ³ is CR ^3X ; R ^3X is ; q is 2; R ⁸ is H or OH; R ⁹ is H or OH; X ^c is H, halogen or optionally substituted C ₁ -C ₆ alkyl; R ¹⁰ is C ₁ -C ₆ alkyl optionally substituted with OH, halogen, NR ⁴ R ⁵ , CO ₂ R ⁴ or CO ₂ H, or R ¹⁰ is absent; n is 0; and m is 1. In some embodiments, X ³ is CR ^3X and R ^3X is In some embodiments, X ³ is CR ^3X and R ^3X is .

In some embodiments of Formula (A'), (I'), (IIa'), (IIIa') or (IVa'), Y ¹ is CR ^1Y and R ^1Y is H. In some embodiments, Y ¹ is CR ^1Y and R ^1Y is OH. In some embodiments, Y ¹ is CR ^1Y and R ^1Y is OCH ₃ . In some embodiments, Y ¹ is CR ^1Y ; R ^1Y is , , or ; q is 1 or 2; R ⁸ is H, halogen or OH; R ⁹ is H, halogen or OH; X ^c is H, halogen or optionally substituted C ₁ -C ₆ alkyl; R ¹⁰ is C ₁ -C ₆ alkyl optionally substituted with OH, halogen, NR ⁴ R ⁵ , CO ₂ R ⁴ or CO ₂ H, or R ¹⁰ is absent; n is 0, 1 or 2; and m is 1 or 2. In some embodiments, Y ¹ is CR ^1Y ; R ^1Y is or ; q is 1 or 2; R ⁸ is H, halogen or OH; R ⁹ is H, halogen or OH; X ^c is H, halogen or optionally substituted C ₁ -C ₆ alkyl; X ^a is H, OH, NR ⁴ R ⁵ ; and X ^b is H, OH, NR ⁴ R ⁵ . In some embodiments, Y ¹ is CR ^1Y ; R ^1Y is or ; q is 2; R ⁸ is H or OH; R ⁹ is H or OH; X ^c is H; X ^a is OH or NR ⁴ R ⁵ ; and X ^b is H. In some embodiments, Y ¹ is CR ^1Y ; R ^1Y is or ; q is 2; R ⁸ is H; R ⁹ is H; X ^c is H; X ^a is OH or NR ⁴ R ⁵ ; and X ^b is H. In some embodiments, Y ¹ is CR ^1Y and R ^1Y is In some embodiments, Y ¹ is CR ^1Y and R ^1Y is In some embodiments, Y ¹ is CR ^1Y ; R ^1Y is ; q is 1 or 2; R ⁸ is H, halogen or OH; R ⁹ is H, halogen or OH; X ^c is H, halogen or optionally substituted C ₁ -C ₆ alkyl; R ¹⁰ is C ₁ -C ₆ alkyl optionally substituted with OH, halogen, NR ⁴ R ⁵ , CO ₂ R ⁴ or CO ₂ H, or R ¹⁰ is absent; n is 0, 1 or 2; and m is 1 or 2. In some embodiments, Y ¹ is CR ^1Y ; R ^1Y is ; q is 2; R ⁸ is H or OH; R ⁹ is H or OH; X ^c is H, halogen or optionally substituted C ₁ -C ₆ alkyl; R ¹⁰ is C ₁ -C ₆ alkyl optionally substituted with OH, halogen, NR ⁴ R ⁵ , CO ₂ R ⁴ or CO ₂ H, or R ¹⁰ is absent; n is 0; and m is 1. In some embodiments, Y ¹ is CR ^1Y and R ^1Y is In some embodiments, Y ¹ is CR ^1Y and R ^1Y is .

In some embodiments of Formula (A'), (I'), (IIa'), (IIIa') or (IVa'), Y ¹ is CH, N, C-OH or C-OCH ₃ ; X ³ is CH, N, C-OH or C-OCH ₃ ; X ¹ is CR ^1X ; R ^1X is , , or ; q is 1 or 2; R ⁸ is H, halogen or OH; R ⁹ is H, halogen or OH; X ^c is H, halogen or optionally substituted C ₁ -C ₆ alkyl; R ¹⁰ is C 1 -C ₆ alkyl optionally substituted with OH, halogen, NR ⁴ R ⁵ , CO ₂ R ⁴ or CO ₂ H, or R ₁₀ is absent; n is 0, 1 or 2; and m is 1 or 2. In some embodiments, Y ¹ is CH, N, C ^- OH or C-OCH ₃ ; X ³ is CH, N, C-OH or C-OCH ₃ ; X ¹ is CR ^1X ; R ^1X is or ; q is 1 or 2; R ⁸ is H, halogen or OH; R ⁹ is H, halogen or OH; X ^c is H, halogen or optionally substituted C ₁ -C ₆ alkyl; X ^a is H, OH, NR ⁴ R ⁵ ; and X ^b is H, OH, NR ⁴ R ⁵ . In some embodiments, Y ¹ is CH, N, C-OH or C-OCH ₃ ; X ³ is CH, N, C-OH or C-OCH ₃ ; X ¹ is CR ^1X ; R ^1X is or ; q is 2; R ⁸ is H or OH; R ⁹ is H or OH; X ^c is H; X ^a is OH or NR ⁴ R ⁵ ; and X ^b is H. In some embodiments, Y ¹ is CH, N, C-OH, or C-OCH ₃ ; X ³ is CH, N, C-OH, or C-OCH ₃ ; X ¹ is CR ^1X ; R ^1X is or ; q is 2; R ⁸ is H; R ⁹ is H; X ^c is H; X ^a is OH or NR ⁴ R ⁵ ; and X ^b is H. In some embodiments, Y ¹ is CH, N, C-OH, or C-OCH ₃ ; X ³ is CH, N, C-OH, or C-OCH ₃ ; X ¹ is CR ^1X ; and R ^1X is In some embodiments, Y ¹ is CH, N, C-OH or C-OCH ₃ ; X ³ is CH, N, C-OH or C-OCH ₃ ; X ¹ is CR ^1X ; and R ^1X is In some embodiments, Y ¹ is CH, N, C-OH or C-OCH ₃ ; X ³ is CH, N, C-OH or C-OCH ₃ ; X ¹ is CR ^1X ; R ^1X is ; q is 1 or 2; R ⁸ is H, halogen or OH; R ⁹ is H, halogen or OH; X ^c is H, halogen or optionally substituted C ₁ -C ₆ alkyl; R ¹⁰ is C 1 -C ₆ alkyl optionally substituted with OH, halogen, NR ⁴ R ⁵ , CO ₂ R ⁴ or CO ₂ H, or R ₁₀ is absent; n is 0, 1 or 2; and m is 1 or 2. In some embodiments, Y ¹ is CH, N, C ^- OH or C-OCH ₃ ; X ³ is CH, N, C-OH or C-OCH ₃ ; X ¹ is CR ^1X ; R ^1X is ; q is 2; R ⁸ is H or OH; R ⁹ is H or OH; X ^c is H, halogen, or optionally substituted C ₁ -C ₆ alkyl; R ¹⁰ is C ₁ -C ₆ alkyl optionally substituted with OH, halogen, NR ⁴ R ⁵ , CO ₂ R ⁴ or CO ₂ H, or R ¹⁰ is absent; n is 0; and m is 1. In some embodiments, Y ¹ is CH, N, C-OH, or C-OCH ₃ ; X ³ is CH, N, C-OH, or C-OCH ₃ ; X ¹ is CR ^1X ; and R ^1X is In some embodiments, Y ¹ is CH, N, C-OH or C-OCH ₃ ; X ³ is CH, N, C-OH or C-OCH ₃ ; X ¹ is CR ^1X ; and R ^1X is .

In some embodiments of Formula (A'), (I'), (IIa'), (IIIa') or (IVa'), Y ¹ is CH, N, C-OH or C-OCH ₃ ; X ¹ is CH, N, C-OH or C-OCH ₃ ; X ³ is CR ^3X ; R ^3X is , , or ; q is 1 or 2; R ⁸ is H, halogen or OH; R ⁹ is H, halogen or OH; X ^c is H, halogen or optionally substituted C ₁ -C ₆ alkyl; R ¹⁰ is C 1 -C ₆ alkyl optionally substituted with OH, halogen, NR ⁴ R ⁵ , CO ₂ R ⁴ or CO ₂ H, or R ₁₀ is absent; n is 0, 1 or 2; and m is 1 or 2. In some embodiments, Y ¹ is CH, N, C ^- OH or C-OCH ₃ ; X ¹ is CH, N, C-OH or C-OCH ₃ ; X ³ is CR ^3X ; R ^3X is or ; q is 1 or 2; R ⁸ is H, halogen or OH; R ⁹ is H, halogen or OH; X ^c is H, halogen or optionally substituted C ₁ -C ₆ alkyl; X ^a is H, OH, NR ⁴ R ⁵ ; and X ^b is H, OH, NR ⁴ R ⁵ . In some embodiments, Y ¹ is CH, N, C-OH or C-OCH ₃ ; X ¹ is CH, N, C-OH or C-OCH ₃ ; X ³ is CR ^3X ; R ^3X is or ; q is 2; R ⁸ is H or OH; R ⁹ is H or OH; X ^c is H; X ^a is OH or NR ⁴ R ⁵ ; and X ^b is H. In some embodiments, Y ¹ is CH, N, C-OH, or C-OCH ₃ ; X ¹ is CH, N, C-OH, or C-OCH ₃ ; X ³ is CR ^3X ; R ^3X is or ; q is 2; R ⁸ is H; R ⁹ is H; X ^c is H; X ^a is OH or NR ⁴ R ⁵ ; and X ^b is H. In some embodiments, Y ¹ is CH, N, C-OH, or C-OCH ₃ ; X ¹ is CH, N, C-OH, or C-OCH ₃ ; X ³ is CR ^3X ; and R ^3X is In some embodiments, Y ¹ is CH, N, C-OH or C-OCH ₃ ; X ¹ is CH, N, C-OH or C-OCH ₃ ; X ³ is CR ^3X ; and R ^3X is In some embodiments, Y ¹ is CH, N, C-OH or C-OCH ₃ ; X ¹ is CH, N, C-OH or C-OCH ₃ ; X ³ is CR ^3X ; R ^3X is ; q is 1 or 2; R ⁸ is H, halogen or OH; R ⁹ is H, halogen or OH; X ^c is H, halogen or optionally substituted C ₁ -C ₆ alkyl; R ¹⁰ is C 1 -C ₆ alkyl optionally substituted with OH, halogen, NR ⁴ R ⁵ , CO ₂ R ⁴ or CO ₂ H, or R ₁₀ is absent; n is 0, 1 or 2; and m is 1 or 2. In some embodiments, Y ¹ is CH, N, C ^- OH or C-OCH ₃ ; X ¹ is CH, N, C-OH or C-OCH ₃ ; X ³ is CR ^3X ; R ^3X is ; q is 2; R ⁸ is H or OH; R ⁹ is H or OH; X ^c is H, halogen or optionally substituted C ₁ -C ₆ alkyl; R ¹⁰ is C ₁ -C ₆ alkyl optionally substituted with OH, halogen, NR ⁴ R ⁵ , CO ₂ R ⁴ or CO ₂ H, or R ¹⁰ is absent; n is 0; and m is 1. In some embodiments, Y ¹ is CH, N, C-OH or C-OCH ₃ ; X ¹ is CH, N, C-OH or C-OCH ₃ ; X ³ is CR ^3X ; and R ^3X is In some embodiments, Y ¹ is CH, N, C-OH or C-OCH ₃ ; X ¹ is CH, N, C-OH or C-OCH ₃ ; X ³ is CR ^3X ; and R ^3X is .

In some embodiments of Formula (A'), (I'), (IIa'), (IIIa') or (IVa'), ^X1 is CH, N, C-OH or C- _OCH3 ; ^X3 is CH, N, C-OH or C- _OCH3 ; ^Y1 is ^CR1Y ; ^R1Y is , , or ; q is 1 or 2; R ⁸ is H, halogen or OH; R ⁹ is H, halogen or OH; X ^c is H, halogen or optionally substituted C ₁ -C ₆ alkyl; R ¹⁰ is C 1 -C ₆ alkyl optionally substituted with OH, halogen, NR ⁴ R ⁵ , CO ₂ R ⁴ or CO ₂ H, or R ₁₀ is absent; n is 0, 1 or 2; and m is 1 or 2. In some embodiments, X ¹ is CH, N, C ^- OH or C-OCH ₃ ; X ³ is CH, N, C-OH or C-OCH ₃ ; Y ¹ is CR ^1Y ; R ^1Y is or ; q is 1 or 2; R ⁸ is H, halogen or OH; R ⁹ is H, halogen or OH; X ^c is H, halogen or optionally substituted C ₁ -C ₆ alkyl; X ^a is H, OH, NR ⁴ R ⁵ ; and X ^b is H, OH, NR ⁴ R ⁵ . In some embodiments, X ¹ is CH, N, C-OH or C-OCH ₃ ; X ³ is CH, N, C-OH or C-OCH ₃ ; Y ¹ is CR ^1Y ; R ^1Y is or ; q is 2; R ⁸ is H or OH; R ⁹ is H or OH; X ^c is H; X ^a is OH or NR ⁴ R ⁵ ; and X ^b is H. In some embodiments, X ¹ is CH, N, C-OH, or C-OCH ₃ ; X ³ is CH, N, C-OH, or C-OCH ₃ ; Y ¹ is CR ^1Y ; R ^1Y is or ; q is 2; R ⁸ is H; R ⁹ is H; X ^c is H; X ^a is OH or NR ⁴ R ⁵ ; and X ^b is H. In some embodiments, X ¹ is CH, N, C-OH, or C-OCH ₃ ; X ³ is CH, N, C-OH, or C-OCH ₃ ; Y ¹ is CR ^1Y ; and R ^1Y is In some embodiments, X ¹ is CH, N, C-OH or C-OCH ₃ ; X ³ is CH, N, C-OH or C-OCH ₃ ; Y ¹ is CR ^1Y ; and R ^1Y is In some embodiments, X ¹ is CH, N, C-OH or C-OCH ₃ ; X ³ is CH, N, C-OH or C-OCH ₃ ; Y ¹ is CR ^1Y ; R ^1Y is ; q is 1 or 2; R ⁸ is H, halogen or OH; R ⁹ is H, halogen or OH; X ^c is H, halogen or optionally substituted C ₁ -C ₆ alkyl; R ¹⁰ is C 1 -C ₆ alkyl optionally substituted with OH, halogen, NR ⁴ R ⁵ , CO ₂ R ⁴ or CO ₂ H, or R ₁₀ is absent; n is 0, 1 or 2; and m is 1 or 2. In some embodiments, X ¹ is CH, N, C ^- OH or C-OCH ₃ ; X ³ is CH, N, C-OH or C-OCH ₃ ; Y ¹ is CR ^1Y ; R ^1Y is ; q is 2; R ⁸ is H or OH; R ⁹ is H or OH; X ^c is H, halogen, or optionally substituted C ₁ -C ₆ alkyl; R ¹⁰ is C ₁ -C ₆ alkyl optionally substituted with OH, halogen, NR ⁴ R ⁵ , CO ₂ R ⁴ or CO ₂ H, or R ¹⁰ is absent; n is 0; and m is 1. In some embodiments, X ¹ is CH, N, C-OH, or C-OCH ₃ ; X ³ is CH, N, C-OH, or C-OCH ₃ ; Y ¹ is CR ^1Y ; and R ^1Y is In some embodiments, X ¹ is CH, N, C-OH or C-OCH ₃ ; X ³ is CH, N, C-OH or C-OCH ₃ ; Y ¹ is CR ^1Y ; and R ^1Y is .

In some embodiments of Formula (IIb'), (IIIb') or (IVb'), -S ¹ -# is , , or . In some such embodiments, q is 0 to 6. In some such embodiments, q is 0. In some such embodiments, q is 1. In some such embodiments, q is 2. In some such embodiments, q is 3. In some such embodiments, q is 4. In some such embodiments, q is 5. In some such embodiments, q is 6. In some such embodiments, R ⁸ is H, halogen, CN, SH, OH, CO ₂ H, NR ⁴ R ⁵ , or C ₁ -C ₆ alkyl optionally substituted with OH, halogen, or CO ₂ H. In some such embodiments, R ⁸ is H. In some such embodiments, R ⁸ is halogen. In some such embodiments, R ⁸ is F, Cl, or Br. In some such embodiments, R ⁸ is F. In some such embodiments, R ⁸ is Cl. In some such embodiments, R ⁸ is Br. In some such embodiments, R ⁸ is CN. In some such embodiments, R ⁸ is SH. In some such embodiments, R ⁸ is OH. In some such embodiments, R ⁸ is CO ₂ H. In some such embodiments, R ⁸ is NR ⁴ R ^5. In some such embodiments, R ⁸ is NHR ^4. In some such embodiments, R ⁸ is NCH ₃ (R ⁴ ). In some such embodiments, R ⁸ is NH ₂ . In some such embodiments, R ⁸ is N(CH ₃ ) ₂ . In some such embodiments, R ⁸ is NH(CH ₃ ). In some such embodiments, R ⁸ is NH(CH ₂ CH ₃ ). In some such embodiments, R ⁸ is C ₁ -C ₆ alkyl substituted with -OH, halogen or -CO ₂ H, as appropriate. In some such embodiments, R ⁸ is C ₁ -C ₆ alkyl. In some such embodiments, R ⁸ is methyl, ethyl or isopropyl. In some such embodiments, R ⁸ is methyl. In some such embodiments, R ⁸ is ethyl. In some such embodiments, R ⁸ is isopropyl. In some such embodiments, R ⁸ is C ₁ -C ₆ alkyl substituted with OH, halogen or CO ₂ H. In some such embodiments, R ⁸ is C ₁ -C ₆ alkyl substituted with -OH. In some such embodiments, R ⁸ is C ₁ -C ₆ alkyl substituted with halogen. In some such embodiments, ^R is C ₁ -C ₆ alkyl substituted with -CO ₂ H. In some such embodiments, ^R is methyl substituted with -OH. In some such embodiments, ^R is ethyl substituted with -OH. In some such embodiments, ^R is isopropyl substituted with OH. In some such embodiments, ^R is methyl substituted with halogen. In some such embodiments, ^R is ethyl substituted with halogen. In some such embodiments, R is isopropyl substituted with halogen. In some such embodiments, ^R is methyl substituted with -CO ² H. In some such embodiments, ^R is ethyl substituted with CO _{2 H.} In some such embodiments, R is ^isopropyl substituted with CO ₂ H. In some such embodiments, R ⁹ is H, halogen, CN, SH, OH, -CO ₂ H, NR ⁴ R ⁵ , or C ₁ -C ₆ alkyl optionally substituted with -OH, halogen, or -CO ₂ H. In some such embodiments, R ⁹ is H. In some such embodiments, R ⁹ is halogen. In some such embodiments, R ⁹ is F, Cl, or Br. In some such embodiments, R ⁹ is F. In some such embodiments, R ⁹ is Cl. In some such embodiments, R ⁹ is Br. In some such embodiments, R ⁹ is CN. In some such embodiments, R ⁹ is SH. In some such embodiments, R ⁹ is OH. In some such embodiments, R ⁹ is CO ₂ H. In some such embodiments, R ⁹ is NR ⁴ R ⁵ . In some such embodiments, R ⁹ is NHR ⁴ . In some such embodiments, R ⁹ is NCH ₃ (R ⁴ ). In some such embodiments, R ⁹ is NH ₂ . In some such embodiments, R ⁹ is N(CH ₃ ) ₂ . In some such embodiments, R ⁹ is NH(CH ₃ ). In some such embodiments, R ⁹ is NH(CH ₂ CH ₃ ). In some such embodiments, R ⁹ is C ₁ -C ₆ alkyl optionally substituted with OH, halogen or CO ₂ H. In some such embodiments, R ⁹ is C ₁ -C ₆ alkyl. In some such embodiments, R ⁹ is methyl, ethyl or isopropyl. In some such embodiments, R ⁹ is methyl. In some such embodiments, R ⁹ is ethyl. In some such embodiments, R ⁹ is isopropyl. In some such embodiments, R ⁹ is C ₁ -C ₆ alkyl substituted with -OH, halogen, or -CO ₂ H. In some such embodiments, R ⁹ is C ₁ -C ₆ alkyl substituted with OH. In some such embodiments, R ⁹ is C ₁ -C ₆ alkyl substituted with halogen. In some such embodiments, R ⁹ is C ₁ -C ₆ alkyl substituted with CO ₂ H. In some such embodiments, R ⁹ is methyl substituted with OH. In some such embodiments, R ⁹ is ethyl substituted with OH. In some such embodiments, R ⁹ is isopropyl substituted with OH. In some such embodiments, R ⁹ is methyl substituted by halogen. In some such embodiments, R ⁹ is ethyl substituted by halogen. In some such embodiments, R ⁹ is isopropyl substituted by halogen. In some such embodiments, R ⁹ is methyl substituted by CO ₂ H. In some such embodiments, R ⁹ is ethyl substituted by CO ₂ H. In some such embodiments, R ⁹ is isopropyl substituted by CO ₂ H. In some such embodiments, n is 0, 1 or 2. In some such embodiments, n is 0 or 1. In some such embodiments, n is 1 or 2. In some such embodiments, n is 0. In some such embodiments, n is 1. In some such embodiments, n is 2. In some such embodiments, m is 1 or 2. In some such embodiments, m is 1. In some such embodiments, m is 2. In some such embodiments, R ¹⁰ is C ₁ -C ₆ alkyl, optionally substituted with OH, halogen, NR ⁴ R ⁵ , CO2R ⁴ or CO ₂ H, or R ¹⁰ is absent. In some such embodiments, R ¹⁰ is C ₁ -C ₆ alkyl, optionally substituted with OH, halogen, NR ⁴ R ⁵ , CO2R ⁴ or CO ₂ H. In some such embodiments, R ¹⁰ is C ₁ -C ₆ alkyl. In some such embodiments, R ¹⁰ is methyl, ethyl or isopropyl. In some such embodiments, R ¹⁰ is methyl. In some such embodiments, R ¹⁰ is ethyl. In some such embodiments, R ¹⁰ is isopropyl. In some such embodiments, R ¹⁰ is C ₁ -C ₆ alkyl substituted with OH, halo, NR ⁴ R ⁵ , CO2R ⁴ or CO ₂ H. In some such embodiments, R ¹⁰ is methyl substituted with OH, halo, NR ⁴ R ⁵ , CO2R ⁴ or CO ₂ H. In some such embodiments, R ¹⁰ is ethyl substituted with OH, halo, NR ⁴ R ⁵ , CO2R ⁴ or CO ₂ H. In some such embodiments, R ¹⁰ is isopropyl substituted with OH, halo, NR ⁴ R ⁵ , CO2R ⁴ or CO ₂ H. In some such embodiments, R ¹⁰ is absent. In some such embodiments, X ^c is H, halo or optionally substituted C ₁ -C ₆ alkyl. In some such embodiments, ^Xc is H. In some such embodiments, ^Xc is OH. In some such embodiments, ^Xc is F, Cl or Br. In some such embodiments, ^Xc is F. In some such embodiments, ^Xc is Cl. In some such embodiments, ^Xc is Br. In some such embodiments, ^Xc is optionally substituted C1-C6 alkyl. In some such embodiments, ^Xc is _{C1 - C6} alkyl. In some such embodiments, ^Xc is methyl _, ethyl or isopropyl. In some such embodiments, ^Xc is methyl. In some such embodiments, ^Xc is ethyl. In some such embodiments, ^Xc is isopropyl. In some such embodiments, ^Xc is substituted _C1 - _C6 alkyl. In some such embodiments, ^Xc is substituted methyl. In some such embodiments, ^Xc is substituted ethyl. In some such embodiments, ^Xc is substituted isopropyl.

In some embodiments of Formula (IIb'), (IIIb') or (IVb'), R ^1X is , , or ; q is 1 or 2; R ⁸ is H, halogen or OH; R ⁹ is H, halogen or OH; X ^c is H, halogen or optionally substituted C ₁ -C ₆ alkyl; R ¹⁰ is C ₁ -C ₆ alkyl optionally substituted with OH, halogen, NR ⁴ R ⁵ , CO ₂ R ⁴ or CO ₂ H, or R ¹⁰ is absent; n is 0, 1 or 2; and m is 1 or 2. In some embodiments, R ^1X is or ; q is 1 or 2; R ⁸ is H, halogen or OH; R ⁹ is H, halogen or OH; X ^c is H, halogen or optionally substituted C ₁ -C ₆ alkyl; X ^a is H, OH, NR ⁴ R ⁵ ; and X ^b is H, OH, NR ⁴ R ⁵ . In some embodiments, R ^1X is or ; q is 2; R ⁸ is H or OH; R ⁹ is H or OH; X ^c is H; X ^a is OH or NR ⁴ R ⁵ ; and X ^b is H. In some embodiments, R ^1X is or ; q is 2; R ⁸ is H; R ⁹ is H; X ^c is H; X ^a is OH or NR ⁴ R ⁵ ; and X ^b is H. In some embodiments, R ^1X is In some embodiments, R ^1X is In some embodiments, R ^1X is ; q is 1 or 2; R ⁸ is H, halogen or OH; R ⁹ is H, halogen or OH; X ^c is H, halogen or optionally substituted C ₁ -C ₆ alkyl; R ¹⁰ is C ₁ -C ₆ alkyl optionally substituted with OH, halogen, NR ⁴ R ⁵ , CO ₂ R ⁴ or CO ₂ H, or R ¹⁰ is absent; n is 0, 1 or 2; and m is 1 or 2. In some embodiments, R ^1X is ; q is 2; R ⁸ is H or OH; R ⁹ is H or OH; X ^c is H, halogen or optionally substituted C ₁ -C ₆ alkyl; R ¹⁰ is C ₁ -C ₆ alkyl optionally substituted with OH, halogen, NR ⁴ R ⁵ , CO ₂ R ⁴ or CO ₂ H, or R ¹⁰ is absent; n is 0; and m is 1. In some embodiments, R ^1X is In some embodiments, R ^1X is .

In some embodiments of formula (IIb'), (IIIb') or (IVb'), Y ¹ is CH, N, C-OH or C-OCH ₃ ; X ³ is CH, N, C-OH or C-OCH ₃ ; R ^1X is , , or ; q is 1 or 2; R ⁸ is H, halogen or OH; R ⁹ is H, halogen or OH; X ^c is H, halogen or optionally substituted C ₁ -C ₆ alkyl; R ¹⁰ is C 1 -C ₆ alkyl optionally substituted with OH, halogen, NR ⁴ R ⁵ , CO ₂ R ⁴ or CO ₂ H, or R ₁₀ is absent; n is 0, 1 or 2; and m is 1 or 2. In some embodiments, Y ¹ is CH, N, C ^- OH or C-OCH ₃ ; X ³ is CH, N, C-OH or C-OCH ₃ ; R ^1X is or ; q is 1 or 2; R ⁸ is H, halogen or OH; R ⁹ is H, halogen or OH; X ^c is H, halogen or optionally substituted C ₁ -C ₆ alkyl; X ^a is H, OH, NR ⁴ R ⁵ ; and X ^b is H, OH, NR ⁴ R ⁵ . In some embodiments, Y ¹ is CH, N, C-OH or C-OCH ₃ ; X ³ is CH, N, C-OH or C-OCH ₃ ; R ^1X is or q is 2; R ⁸ is H or OH; R ⁹ is H or OH; X ^c is H; X ^a is OH or NR ⁴ R ⁵ ; and X ^b is H. In some embodiments, Y ¹ is CH, N, C-OH or C-OCH ₃ ; X ³ is CH, N, C-OH or C-OCH ₃ ; R ^1X is or ; q is 2; R ⁸ is H; R ⁹ is H; X ^c is H; X ^a is OH or NR ⁴ R ⁵ ; and X ^b is H. In some embodiments, Y ¹ is CH, N, C-OH, or C-OCH ₃ ; X ³ is CH, N, C-OH, or C-OCH ₃ ; and R ^1X is In some embodiments, Y ¹ is CH, N, C-OH or C-OCH ₃ ; X ³ is CH, N, C-OH or C-OCH ₃ ; and R ^1X is In some embodiments, Y ¹ is CH, N, C-OH or C-OCH ₃ ; X ³ is CH, N, C-OH or C-OCH ₃ ; R ^1X is ; q is 1 or 2; R ⁸ is H, halogen or OH; R ⁹ is H, halogen or OH; X ^c is H, halogen or optionally substituted C ₁ -C ₆ alkyl; R ¹⁰ is C 1 -C ₆ alkyl optionally substituted with OH, halogen, NR ⁴ R ⁵ , CO ₂ R ⁴ or CO ₂ H, or R ₁₀ is absent; n is 0, 1 or 2; and m is 1 or 2. In some embodiments, Y ¹ is CH, N, C ^- OH or C-OCH ₃ ; X ³ is CH, N, C-OH or C-OCH ₃ ; R ^1X is ; q is 2; R ⁸ is H or OH; R ⁹ is H or OH; X ^c is H, halogen or optionally substituted C ₁ -C ₆ alkyl; R ¹⁰ is C ₁ -C ₆ alkyl optionally substituted with OH, halogen, NR ⁴ R ⁵ , CO ₂ R ⁴ or CO ₂ H, or R ¹⁰ is absent; n is 0; and m is 1. In some embodiments, Y ¹ is CH, N, C-OH or C-OCH ₃ ; X ³ is CH, N, C-OH or C-OCH ₃ ; and R ^1X is In some embodiments, Y ¹ is CH, N, C-OH or C-OCH ₃ ; X ³ is CH, N, C-OH or C-OCH ₃ ; and R ^1X is .

In some embodiments of formula (IIc'), (IIIc') or (IVc'), R ^3X is -S ¹ -#. In some such embodiments, -S ¹ -# is , , or . In some such embodiments, q is 0 to 6. In some such embodiments, q is 0. In some such embodiments, q is 1. In some such embodiments, q is 2. In some such embodiments, q is 3. In some such embodiments, q is 4. In some such embodiments, q is 5. In some such embodiments, q is 6. In some such embodiments, R ⁸ is H, halogen, CN, SH, OH, CO ₂ H, NR ⁴ R ⁵ , or C ₁ -C ₆ alkyl optionally substituted with OH, halogen, or CO ₂ H. In some such embodiments, R ⁸ is H. In some such embodiments, R ⁸ is halogen. In some such embodiments, R ⁸ is F, Cl, or Br. In some such embodiments, R ⁸ is F. In some such embodiments, R ⁸ is Cl. In some such embodiments, R ⁸ is Br. In some such embodiments, R ⁸ is CN. In some such embodiments, R ⁸ is SH. In some such embodiments, R ⁸ is OH. In some such embodiments, R ⁸ is CO ₂ H. In some such embodiments, R ⁸ is NR ⁴ R ^5. In some such embodiments, R ⁸ is NHR ^4. In some such embodiments, R ⁸ is NCH ₃ (R ⁴ ). In some such embodiments, R ⁸ is NH ₂ . In some such embodiments, R ⁸ is N(CH ₃ ) ₂ . In some such embodiments, R ⁸ is NH(CH ₃ ). In some such embodiments, R ⁸ is NH(CH ₂ CH ₃ ). In some such embodiments, R ⁸ is C ₁ -C ₆ alkyl, optionally substituted with OH, halogen, or CO ₂ H. In some such embodiments, R ⁸ is C ₁ -C ₆ alkyl. In some such embodiments, R ⁸ is methyl, ethyl, or isopropyl. In some such embodiments, R 8 is methyl. In some such embodiments, R ⁸ is ethyl. In some such embodiments, R ⁸ is isopropyl. In some such embodiments, R ⁸ is C 1 -C 6 alkyl, optionally substituted with OH, halogen, or CO ₂ H. In some such embodiments, R ⁸ is C ₁ -C ₆ alkyl, optionally substituted with OH, halogen, or CO 2 H. In some such embodiments, R ⁸ is C ₁ -C ₆ alkyl, optionally substituted with OH. In some such embodiments, R ⁸ is C ₁ -C ₆ alkyl, optionally substituted with halogen. In some such embodiments, ^R is C ₁ -C ₆ alkyl substituted with CO ₂ H. In some such embodiments, ^R is methyl substituted with OH. In some such embodiments, ^R is ethyl substituted with OH. In some such embodiments, ^R is isopropyl substituted with OH. In some such embodiments, ^R is methyl substituted with halogen. In some such embodiments, ^R is ethyl substituted with halogen. In some such embodiments, R is isopropyl substituted with halogen. In some such embodiments, ^R is methyl substituted with CO ² H. In some such embodiments, ^R is ethyl substituted with CO _{2 H.} In some such embodiments, R is ^isopropyl substituted with CO ₂ H. In some such embodiments, R ⁹ is H, halogen, CN, SH, OH, CO ₂ H, NR ⁴ R ⁵ , or C ₁ -C ₆ alkyl optionally substituted with OH, halogen, or CO ₂ H. In some such embodiments, R ⁹ is H. In some such embodiments, R ⁹ is halogen. In some such embodiments, R ⁹ is F, Cl, or Br. In some such embodiments, R ⁹ is F. In some such embodiments, R ⁹ is Cl. In some such embodiments, R ⁹ is Br. In some such embodiments, R ⁹ is CN. In some such embodiments, R ⁹ is SH. In some such embodiments, R ⁹ is OH. In some such embodiments, R ⁹ is CO ₂ H. In some such embodiments, R ⁹ is NR ⁴ R ⁵ . In some such embodiments, R ⁹ is NHR ⁴ . In some such embodiments, R ⁹ is NCH ₃ (R ⁴ ). In some such embodiments, R ⁹ is NH ₂ . In some such embodiments, R ⁹ is N(CH ₃ ) ₂ . In some such embodiments, R ⁹ is NH(CH ₃ ). In some such embodiments, R ⁹ is NH(CH ₂ CH ₃ ). In some such embodiments, R ⁹ is C ₁ -C ₆ alkyl, optionally substituted with -OH, halogen, or -CO ₂ H. In some such embodiments, R ⁹ is C ₁ -C ₆ alkyl. In some such embodiments, R ⁹ is methyl, ethyl, or isopropyl. In some such embodiments, R ⁹ is methyl. In some such embodiments, R ⁹ is ethyl. In some such embodiments, R ⁹ is isopropyl. In some such embodiments, R ⁹ is C ₁ -C ₆ alkyl substituted with OH, halogen or CO ₂ H. In some such embodiments, R ⁹ is C ₁ -C ₆ alkyl substituted with OH. In some such embodiments, R ⁹ is C ₁ -C ₆ alkyl substituted with halogen. In some such embodiments, R ⁹ is C ₁ -C ₆ alkyl substituted with -CO ₂ H. In some such embodiments, R ⁹ is methyl substituted with -OH. In some such embodiments, R ⁹ is ethyl substituted with OH. In some such embodiments, R ⁹ is isopropyl substituted with OH. In some such embodiments, R ⁹ is methyl substituted by halogen. In some such embodiments, R ⁹ is ethyl substituted by halogen. In some such embodiments, R ⁹ is isopropyl substituted by halogen. In some such embodiments, R ⁹ is methyl substituted by CO ₂ H. In some such embodiments, R ⁹ is ethyl substituted by CO ₂ H. In some such embodiments, R ⁹ is isopropyl substituted by CO ₂ H. In some such embodiments, n is 0, 1 or 2. In some such embodiments, n is 0 or 1. In some such embodiments, n is 1 or 2. In some such embodiments, n is 0. In some such embodiments, n is 1. In some such embodiments, n is 2. In some such embodiments, m is 1 or 2. In some such embodiments, m is 1. In some such embodiments, m is 2. In some such embodiments, R ¹⁰ is C ₁ -C ₆ alkyl, optionally substituted with OH, halogen, NR ⁴ R ⁵ , CO2R ⁴ or CO ₂ H, or R ¹⁰ is absent. In some such embodiments, R ¹⁰ is C ₁ -C ₆ alkyl, optionally substituted with OH, halogen, NR ⁴ R ⁵ , CO2R ⁴ or CO ₂ H. In some such embodiments, R ¹⁰ is C ₁ -C ₆ alkyl. In some such embodiments, R ¹⁰ is methyl, ethyl or isopropyl. In some such embodiments, R ¹⁰ is methyl. In some such embodiments, R ¹⁰ is ethyl. In some such embodiments, R ¹⁰ is isopropyl. In some such embodiments, R ¹⁰ is C ₁ -C ₆ alkyl substituted with OH, halo, NR ⁴ R ⁵ , CO2R ⁴ or CO ₂ H. In some such embodiments, R ¹⁰ is methyl substituted with OH, halo, NR ⁴ R ⁵ , CO2R ⁴ or CO ₂ H. In some such embodiments, R ¹⁰ is ethyl substituted with OH, halo, NR ⁴ R ⁵ , CO2R ⁴ or CO ₂ H. In some such embodiments, R ¹⁰ is isopropyl substituted with OH, halo, NR ⁴ R ⁵ , CO2R ⁴ or CO ₂ H. In some such embodiments, R ¹⁰ is absent. In some such embodiments, X ^c is H, halo or optionally substituted C ₁ -C ₆ alkyl. In some such embodiments, ^Xc is H. In some such embodiments, ^Xc is OH. In some such embodiments, ^Xc is F, Cl or Br. In some such embodiments, ^Xc is F. In some such embodiments, ^Xc is Cl. In some such embodiments, ^Xc is Br. In some such embodiments, ^Xc is optionally substituted C1-C6 alkyl. In some such embodiments, ^Xc is _{C1 - C6} alkyl. In some such embodiments, ^Xc is methyl _, ethyl or isopropyl. In some such embodiments, ^Xc is methyl. In some such embodiments, ^Xc is ethyl. In some such embodiments, ^Xc is isopropyl. In some such embodiments, ^Xc is substituted _C1 - _C6 alkyl. In some such embodiments, ^Xc is substituted methyl. In some such embodiments, ^Xc is substituted ethyl. In some such embodiments, ^Xc is substituted isopropyl.

In some embodiments of Formula (IIc'), (IIIc') or (IVc'), R ^3X is , , or ; q is 1 or 2; R ⁸ is H, halogen or OH; R ⁹ is H, halogen or OH; X ^c is H, halogen or optionally substituted C ₁ -C ₆ alkyl; R ¹⁰ is C ₁ -C ₆ alkyl optionally substituted with OH, halogen, NR ⁴ R ⁵ , CO ₂ R ⁴ or CO ₂ H, or R ¹⁰ is absent; n is 0, 1 or 2; and m is 1 or 2. In some embodiments, R ^3X is or ; q is 1 or 2; R ⁸ is H, halogen or OH; R ⁹ is H, halogen or OH; X ^c is H, halogen or optionally substituted C ₁ -C ₆ alkyl; X ^a is H, OH, NR ⁴ R ⁵ ; and X ^b is H, OH, NR ⁴ R ⁵ . In some embodiments, R ^3X is or ; q is 2; R ⁸ is H or OH; R ⁹ is H or OH; X ^c is H; X ^a is OH or NR ⁴ R ⁵ ; and X ^b is H. In some embodiments, R ^3X is or ; q is 2; R ⁸ is H; R ⁹ is H; X ^c is H; X ^a is OH or NR ⁴ R ⁵ ; and X ^b is H. In some embodiments, R ^3X is In some embodiments, R ^3X is In some embodiments, R ^3X is ; q is 1 or 2; R ⁸ is H, halogen or OH; R ⁹ is H, halogen or OH; X ^c is H, halogen or optionally substituted C ₁ -C ₆ alkyl; R ¹⁰ is C ₁ -C ₆ alkyl optionally substituted with OH, halogen, NR ⁴ R ⁵ , CO ₂ R ⁴ or CO ₂ H, or R ¹⁰ is absent; n is 0, 1 or 2; and m is 1 or 2. In some embodiments, R ^3X is ; q is 2; R ⁸ is H or OH; R ⁹ is H or OH; X ^c is H, halogen or optionally substituted C ₁ -C ₆ alkyl; R ¹⁰ is C ₁ -C ₆ alkyl optionally substituted with OH, halogen, NR ⁴ R ⁵ , CO ₂ R ⁴ or CO ₂ H, or R ¹⁰ is absent; n is 0; and m is 1. In some embodiments, R ^3X is In some embodiments, R ^3X is .

In some embodiments of Formula (IIc'), (IIIc') or (IVc'), Y ¹ is CH, N, C-OH or C-OCH ₃ ; X ¹ is CH, N, C-OH or C-OCH ₃ ; R ^3X is , , or ; q is 1 or 2; R ⁸ is H, halogen or OH; R ⁹ is H, halogen or OH; X ^c is H, halogen or optionally substituted C ₁ -C ₆ alkyl; R ¹⁰ is C 1 -C ₆ alkyl optionally substituted with OH, halogen, NR ⁴ R ⁵ , CO ₂ R ⁴ or CO ₂ H, or R ₁₀ is absent; n is 0, 1 or 2; and m is 1 or 2. In some embodiments, Y ¹ is CH, N, C ^- OH or C-OCH ₃ ; X ¹ is CH, N, C-OH or C-OCH ₃ ; R ^3X is or ; q is 1 or 2; R ⁸ is H, halogen or OH; R ⁹ is H, halogen or OH; X ^c is H, halogen or optionally substituted C ₁ -C ₆ alkyl; X ^a is H, OH, NR ⁴ R ⁵ ; and X ^b is H, OH, NR ⁴ R ⁵ . In some embodiments, Y ¹ is CH, N, C-OH or C-OCH ₃ ; X ¹ is CH, N, C-OH or C-OCH ₃ ; R ^3X is or ; q is 2; R ⁸ is H or OH; R ⁹ is H or OH; X ^c is H; X ^a is OH or NR ⁴ R ⁵ ; and X ^b is H. In some embodiments, Y ¹ is CH, N, C-OH or C-OCH ₃ ; X ¹ is CH, N, C-OH or C-OCH ₃ ; R ^3X is or ; q is 2; R ⁸ is H; R ⁹ is H; X ^c is H; X ^a is OH or NR ⁴ R ⁵ ; and X ^b is H. In some embodiments, Y ¹ is CH, N, C-OH, or C-OCH ₃ ; X ¹ is CH, N, C-OH, or C-OCH ₃ ; and R ^3X is In some embodiments, Y ¹ is CH, N, C-OH or C-OCH ₃ ; X ¹ is CH, N, C-OH or C-OCH ₃ ; and R ^3X is In some embodiments, Y ¹ is CH, N, C-OH or C-OCH ₃ ; X ¹ is CH, N, C-OH or C-OCH ₃ ; R ^3X is ; q is 1 or 2; R ⁸ is H, halogen or OH; R ⁹ is H, halogen or OH; X ^c is H, halogen or optionally substituted C ₁ -C ₆ alkyl; R ¹⁰ is C 1 -C ₆ alkyl optionally substituted with OH, halogen, NR ⁴ R ⁵ , CO ₂ R ⁴ or CO ₂ H, or R ₁₀ is absent; n is 0, 1 or 2; and m is 1 or 2. In some embodiments, Y ¹ is CH, N, C ^- OH or C-OCH ₃ ; X ¹ is CH, N, C-OH or C-OCH ₃ ; R ^3X is ; q is 2; R ⁸ is H or OH; R ⁹ is H or OH; X ^c is H, halogen or optionally substituted C ₁ -C ₆ alkyl; R ¹⁰ is C ₁ -C ₆ alkyl optionally substituted with OH, halogen, NR ⁴ R ⁵ , CO ₂ R ⁴ or CO ₂ H, or R ¹⁰ is absent; n is 0; and m is 1. In some embodiments, Y ¹ is CH, N, C-OH or C-OCH ₃ ; X ¹ is CH, N, C-OH or C-OCH ₃ ; and R ^3X is In some embodiments, Y ¹ is CH, N, C-OH or C-OCH ₃ ; X ¹ is CH, N, C-OH or C-OCH ₃ ; and R ^3X is .

In some embodiments of Formula (I'), T is -C(O _{) NH2} or -S(O) _2NH2 ; Ring A is , or ; Y ¹ is CH, N, C-OH or C-OCH ₃ ; X ³ is CH, N, C-OH or C-OCH ₃ ; X ¹ is CR ^1X ; R ^1X is , , , or ; Z ¹ is N, CH or CF; X ² is N or CH; Y ² is N, CH or CF; Z ² is N, CH or CF; X ⁴ is C or N; Y ⁴ is NCH ₂ CH ₃ , CCH ₂ CH ₃ or CCH ₃ ; Z ⁴ is N; T ⁴ is N, S, O or CH; and R ¹ is C ₁ -C ₆ alkyl. In some embodiments, T is C(O)NH ₂ ; Ring A is , or ; Y ¹ is CH or N; X ³ is N or C-OCH ₃ ; X ¹ is CR ^1X ; R ^1X is , , or ; Z ¹ is CH; X ² is N; Y ² is N; Z ² is CH; X ⁴ is C; Y ⁴ is NCH ₂ CH ₃ ; Z ⁴ is N; T ⁴ is CH; and R ¹ is methyl. In some embodiments, T is C(O)NH ₂ or S(O) ₂ NH ₂ ; Ring A is , or ; Y ¹ is CH, N, C-OH or C-OCH ₃ ; X ¹ is CH, N, C-OH or C-OCH ₃ ; X ³ is CR ^3X ; R ^3X is , , , or ; Z ¹ is N, CH or CF; X ² is N or CH; Y ² is N, CH or CF; Z ² is N, CH or CF; X ⁴ is C or N; Y ⁴ is NCH ₂ CH ₃ , CCH ₂ CH ₃ or CCH ₃ ; Z ⁴ is N; T ⁴ is N, S, O or CH; and R ¹ is C ₁ -C ₆ alkyl. In some embodiments, T is -C(O)NH ₂ ; Ring A is , or ; Y ¹ is CH or N; X ¹ is N, CH, CCH ₃ or C-OCH ₃ ; X ³ is CR ^3X ; R ^3X is , , or ; Z ¹ is N, CH or CF; X ² is N or CH; Y ² is N; Z ² is N, CH or CF; X ⁴ is C; Y ⁴ is CCH ₃ , CCH ₂ CH ₃ or NCH ₂ CH ₃ ; Z ⁴ is N; T ⁴ is N, S, O or CH; and R ¹ is methyl. In some embodiments, T is -C(O)NH ₂ or -S(O) ₂ NH ₂ ; Ring A is , or ; X ¹ is CH, N, C-OH or C-OCH ₃ ; X ³ is CH, N, C-OH or C-OCH ₃ ; Y ¹ is CR ^1Y ; R ^1Y is , or ; Z ¹ is N, CH or CF; X ² is N or CH; Y ² is N, CH or CF; Z ² is N, CH or CF; X ⁴ is C or N; Y ⁴ is NCH ₂ CH ₃ , CCH ₂ CH ₃ or CCH ₃ ; Z ⁴ is N; T ⁴ is N, S, O or CH; and R ¹ is C ₁ -C ₆ alkyl.

In some embodiments of formula (IIa'), (IIIa') or (IVa'), Y ¹ is CH, N, C-OH or C-OCH ₃ ; X ³ is CH, N, C-OH or C-OCH ₃ ; X ¹ is CR ^1X ; R ^1X is , , , or ; Z ¹ is N, CH or CF; X ² is N or CH; Y ² is N, CH or CF; Z ² is N, CH or CF; X ⁴ is C or N; Y ⁴ is NCH ₂ CH ₃ , CCH ₂ CH ₃ or CCH ₃ ; Z ⁴ is N; T ⁴ is N, S, O or CH; and R ¹ is C ₁ -C ₆ alkyl. In some embodiments, Y ¹ is CH or N; X ³ is N or C-OCH ₃ ; X ¹ is CR ^1X ; R ^1X is , , or ; Z ¹ is CH; X ² is N; Y ² is N; Z ² is CH; X ⁴ is C; Y ⁴ is NCH ₂ CH ₃ ; Z ⁴ is N; T ⁴ is CH; and R ¹ is CH ₃ . In some embodiments, Y ¹ is CH, N, C-OH, or C-OCH ₃ ; X ¹ is CH, N, C-OH, or C-OCH ₃ ; X ³ is CR ^3X ; R ^3X is or ; Z ¹ is N, CH or CF; X ² is N or CH; Y ² is N, CH or CF; Z ² is N, CH or CF; X ⁴ is C or N; Y ⁴ is NCH ₂ CH ₃ , CCH ₂ CH ₃ or CCH ₃ ; Z ⁴ is N; T ⁴ is N, S, O or CH; and R ¹ is C ₁ -C ₆ alkyl. In some embodiments, Y ¹ is CH or N; X ¹ is N, CH, CCH ₃ or C-OCH ₃ ; X ³ is CR ^3X ; R ^3X is , , or ; Z ¹ is N, CH or CF; X ² is N or CH; Y ² is N; Z ² is N, CH or CF; X ⁴ is C; Y ⁴ is CCH ₃ , CCH ₂ CH ₃ or NCH ₂ CH ₃ ; Z ⁴ is N; T ⁴ is N, S, O or CH; and R ¹ is CH ₃ . In some embodiments, X ¹ is CH, N, C-OH or C-OCH ₃ ; X ³ is CH, N, C-OH or C-OCH ₃ ; Y ¹ is CR ^1Y ; R ^1Y is or ; Z ¹ is N, CH or CF; X ² is N or CH; Y ² is N, CH or CF; Z ² is N, CH or CF; X ⁴ is C or N; Y ⁴ is NCH ₂ CH ₃ , CCH ₂ CH ₃ or CCH ₃ ; Z ⁴ is N; T ⁴ is N, S, O or CH; and R ¹ is C ₁ -C ₆ alkyl.

In some embodiments of formula (IIb'), (IIIb') or (IVb'), Y ¹ is CH, N, C-OH or C-OCH ₃ ; X ³ is CH, N, C-OH or C-OCH ₃ ; R ^1X is , or ; Z ¹ is N, CH or CF; X ² is N or CH; Y ² is N, CH or CF; Z ² is N, CH or CF; X ⁴ is C or N; Y ⁴ is NCH ₂ CH ₃ , CCH ₂ CH ₃ or CCH ₃ ; Z ⁴ is N; T ⁴ is N, S, O or CH; and R ¹ is C ₁ -C ₆ alkyl. In some embodiments, Y ¹ is CH or N; X ³ is N or C-OCH ₃ ; R ^1X is or ; Z ¹ is CH; X ² is N; Y ² is N; Z ² is CH; X ⁴ is C; Y ⁴ is NCH ₂ CH ₃ ; Z ⁴ is N; T ⁴ is CH; and R ¹ is methyl. In some embodiments, Y ¹ is CH; X ³ is N, R ^1X is , Z ¹ is CH, X ² is N, Y ² is N, Z ² is CH, X ⁴ is C, Y ⁴ is NCH ₂ CH ₃ , Z ⁴ is N, T ⁴ is CH, and R ¹ is CH ₃ . In some embodiments, Y ¹ is CH, X ³ is C-OCH ₃ , R ^1X is , Z ¹ is CH, X ² is N, Y ² is N, Z ² is CH, X ⁴ is C, Y ⁴ is NCH ₂ CH ₃ , Z ⁴ is N, T ⁴ is CH, and R ¹ is CH ₃ . In some embodiments, Y ¹ is CH, X ³ is N, R ^1X is , Z ¹ is CH, X ² is N, Y ² is N, Z ² is CH, X ⁴ is C, Y ⁴ is NCH ₂ CH ₃ , Z ⁴ is N, T ⁴ is CH, and R ¹ is CH ₃ . In some embodiments, Y ¹ is CH, X ³ is C-OCH ₃ , R ^1X is , Z ¹ is CH, X ² is N, Y ² is N, Z ² is CH, X ⁴ is C, Y ⁴ is NCH ₂ CH ₃ , Z ⁴ is N, T ⁴ is CH, and R ¹ is CH ₃ . In some embodiments, Y ¹ is CH, X ³ is N, R ^1X is , Z ¹ is CH, X ² is N, Y ² is N, Z ² is CH, X ⁴ is C, Y ⁴ is NCH ₂ CH ₃ , Z ⁴ is N, T ⁴ is CH, and R ¹ is CH ₃ . In some embodiments, Y ¹ is CH, X ³ is C-OCH ₃ , R ^1X is , Z ¹ is CH, X ² is N, Y ² is N, Z ² is CH, X ⁴ is C, Y ⁴ is NCH ₂ CH ₃ , Z ⁴ is N, T ⁴ is CH, and R ¹ is CH ₃ . In some embodiments, Y ¹ is CH, X ³ is N, R ^1X is , Z ¹ is CH, X ² is N, Y ² is N, Z ² is CH, X ⁴ is C, Y ⁴ is NCH ₂ CH ₃ , Z ⁴ is N, T ⁴ is CH, and R ¹ is CH ₃ .

In some embodiments of Formula (IIc'), (IIIc') or (IVc'), Y ¹ is CH, N, C-OH or C-OCH ₃ ; X ¹ is CH, N, C-OH or C-OCH ₃ ; R ^3X is , or ; Z ¹ is N, CH or CF; X ² is N or CH; Y ² is N, CH or CF; Z ² is N, CH or CF; X ⁴ is C or N; Y ⁴ is NCH ₂ CH ₃ , CCH ₂ CH ₃ or CCH ₃ ; Z ⁴ is N; T ⁴ is N, S, O or CH; and R ¹ is C ₁ -C ₆ alkyl. In some embodiments, Y ¹ is CH or N; X ¹ is N, CH, CCH ₃ or C-OCH ₃ ; R ^3X is or ; Z ¹ is N, CH or CF; X ² is N or CH; Y ² is N; Z ² is N, CH or CF; X ⁴ is C; Y ⁴ is CCH ₃ , CCH ₂ CH ₃ or NCH ₂ CH ₃ ; Z ⁴ is N; T ⁴ is N, S, O or CH; and R ¹ is CH ₃ . In some embodiments, Y ¹ is CH, X ¹ is CH, R ^3X is , Z ¹ is N, X ² is N, Y ² is N, Z ² is CH, X ⁴ is C, Y ⁴ is NCH ₂ CH ₃ , Z ⁴ is N, T ⁴ is CH, and R ¹ is CH ₃ . In some embodiments, Y ¹ is N, X ¹ is CCH ₃ , R ^3X is , Z ¹ is CH, X ² is N, Y ² is N, Z ² is CH, X ⁴ is C, Y ⁴ is NCH ₂ CH ₃ , Z ⁴ is N, T ⁴ is CH, and R ¹ is CH ₃ . In some embodiments, Y ¹ is CH, X ¹ is C-OCH ₃ , R ^3X is , Z ¹ is CH, X ² is CH, Y ² is N, Z ² is CH, X ⁴ is C, Y ⁴ is NCH ₂ CH ₃ , Z ⁴ is N, T ⁴ is CH, and R ¹ is CH ₃ . In some embodiments, Y ¹ is CH, X ¹ is C-OCH ₃ , R ^3X is , Z ¹ is CH, X ² is CH, Y ² is N, Z ² is N, X ⁴ is C, Y ⁴ is NCH ₂ CH ₃ , Z ⁴ is N, T ⁴ is CH, and R ¹ is CH ₃ . In some embodiments, Y ¹ is CH, X ¹ is C-OCH ₃ , R ^3X is , Z ¹ is CH, X ² is N, Y ² is N, Z ² is CH, X ⁴ is C, Y ⁴ is NCH ₂ CH ₃ , Z ⁴ is N, T ⁴ is N, and R ¹ is CH ₃ . In some embodiments, Y ¹ is CH, X ¹ is C-OCH ₃ , R ^3X is , Z ¹ is CH, X ² is N, Y ² is N, Z ² is CH, X ⁴ is C, Y ⁴ is CCH ₂ CH ₃ , Z ⁴ is N, T ⁴ is O, and R ¹ is CH ₃ . In some embodiments, Y ¹ is CH, X ¹ is C-OCH ₃ , R ^3X is , Z ¹ is CH, X ² is N, Y ² is N, Z ² is CH, X ⁴ is C, Y ⁴ is CCH ₂ CH ₃ , Z ⁴ is N, T ⁴ is S, and R ¹ is CH ₃ . In some embodiments, Y ¹ is CH, X ¹ is C-OCH ₃ , R ^3X is , Z ¹ is CH, X ² is N, Y ² is N, Z ² is CH, X ⁴ is C, Y ⁴ is NCH ₂ CH ₃ , Z ⁴ is N, T ⁴ is CH, and R ¹ is CH ₃ . In some embodiments, Y ¹ is CH, X ¹ is C-OCH ₃ , R ^3X is , Z ¹ is CH, X ² is N, Y ² is N, Z ² is N, X ⁴ is C, Y ⁴ is CCH ₃ , Z ⁴ is N, T ⁴ is O, and R ¹ is CH ₃ . In some embodiments, Y ¹ is CH, X ¹ is C-OCH ₃ , R ^3X is , Z ¹ is CH, X ² is N, Y ² is N, Z ² is CH, X ⁴ is C, Y ⁴ is NCH ₂ CH ₃ , Z ⁴ is N, T ⁴ is CH, and R ¹ is CH ₃ . In some embodiments, Y ¹ is CH, X ¹ is C-OCH ₃ , R ^3X is , Z ¹ is CH, X ² is N, Y ² is N, Z ² is CH, X ⁴ is C, Y ⁴ is NCH ₂ CH ₃ , Z ⁴ is N, T ⁴ is CH, and R ¹ is CH ₃ . In some embodiments, Y ¹ is CH, X ¹ is C-OCH ₃ , R ^3X is , Z ¹ is N, X ² is N, Y ² is N, Z ² is CH, X ⁴ is C, Y ⁴ is NCH ₂ CH ₃ , Z ⁴ is N, T ⁴ is CH, and R ¹ is CH ₃ . In some embodiments, Y ¹ is N, X ¹ is C-OCH ₃ , R ^3X is , Z ¹ is N, X ² is N, Y ² is N, Z ² is CH, X ⁴ is C, Y ⁴ is NCH ₂ CH ₃ , Z ⁴ is N, T ⁴ is CH, and R ¹ is CH ₃ . In some embodiments, Y ¹ is CH, X ¹ is N, R ^3X is , Z ¹ is CH, X ² is N, Y ² is N, Z ² is CH, X ⁴ is C, Y ⁴ is NCH ₂ CH ₃ , Z ⁴ is N, T ⁴ is CH, and R ¹ is CH ₃ . 2. Linker unit Q

As mentioned above, in some embodiments, the connector unit Q has a formula selected from the group consisting of: (i) Z'-A-RL-, (ii) Z'-A-RL-Y-, (iii) Z'-AS ^* -RL-, (iv) Z'-AS ^* -RL-Y-, (v) Z'-AB(S ^* )-RL-, (vi) Z'-AB(S ^* )-RL-Y-, (vii) Z'-A-, (viii) Z'-AS*-W-, (ix) Z'-AB(S*)-W-, (x) Z'-AS*-W-RL-, and (xi) Z'-AB(S*)-W-RL-; wherein Z' is an extension unit; A is a key or connector unit; B is a parallel connector unit; S ^* is a separator; RL is a releasable linker; W is an amino acid unit; and Y is a second spacer unit.

In other embodiments, the linker unit Q has a formula selected from the group consisting of: (i) Z'-A-RL-, (ii) Z'-A-RL-Y-, (iii) Z'-AS ^* -RL-, (iv) Z'-AS ^* -RL-Y-, (x) Z'-AS*-W-RL-, and (xi) Z'-AB(S*)-W-RL-.

In some embodiments, the linker unit Q has a formula selected from the group consisting of: (v) Z'-AB(S ^* )-RL-, (vi) Z'-AB(S ^* )-RL-Y-, (ix) Z'-AB(S*)-W-, and (xi) Z'-AB(S*)-W-RL-.

In some embodiments, the linker unit Q has a formula selected from the group consisting of: (iii) Z'-AS ^* -RL-, (iv) Z'-AS ^* -RL-Y-, (v) Z'-AB(S ^* )-RL-, (vi) Z'-AB(S ^* )-RL-Y-, (viii) Z'-AS*-W-, (ix) Z'-AB(S*)-W-, (x) Z'-AS*-W-RL-, and (xi) Z'-AB(S*)-W-RL-.

In some embodiments, the linker unit Q has a formula selected from the group consisting of: (viii) Z'-A-S*-W-, (ix) Z'-A-B(S*)-W-, (x) Z'-A-S*-W-RL-, and (xi) Z'-A-B(S*)-W-RL-. 3. Extension unit Z'

Stretcher unit (Z) is a component of the ligand-drug conjugate that is used to link the ligand unit to the rest of the conjugate. Stretcher unit prodriver (Z') is a component of the drug-linker compound or an intermediate thereof that has a functional group that can form a bond with a functional group of the targeting ligand to form the Stretcher unit (Z).

In some embodiments, the Stretcher unit prodriver (Z') has an electrophilic group that is capable of interacting with a reactive nucleophilic group present on a Ligand unit (e.g., an antibody) to provide a covalent bond between the Ligand unit and the Stretcher unit of the Linker unit. Nucleophilic groups on antibodies that have this capability include, but are not limited to, hydroxyl, and amine functional groups. In some embodiments, a heteroatom of the nucleophilic group of the antibody can react with an electrophilic group on the Stretcher unit prodriver and can provide a covalent bond between the Ligand unit and the Linker unit or the Stretcher unit of the Drug-Linker portion. Electrophilic groups that can be used for this purpose include, but are not limited to, maleimide, haloacetamide groups, and NHS esters. The electrophilic group provides a convenient site for antibody attachment to form a ligand-drug conjugate compound or a ligand unit-linker intermediate compound.

In other embodiments, the Stretcher unit prodriver has a reactive site having a nucleophilic group that can react with an electrophilic group present on a Ligand unit (e.g., an antibody). Electrophilic groups on antibodies that can be used for this purpose include, but are not limited to, aldehyde and ketone carbonyl groups. The heteroatom of the nucleophilic group of the Stretcher unit prodriver can react with the electrophilic group on the antibody and form a covalent bond with the antibody. Nucleophilic groups on the Stretcher unit prodriver that can be used for this purpose include, but are not limited to, hydrazides, hydroxylamines, amines, hydrazines, thiosemicarbazides, carboxylates, and arylhydrazides. The electrophilic groups on the antibody provide convenient sites for antibody attachment to form ligand-drug conjugate compounds or Ligand unit-linker intermediates.

In some embodiments, the sulfur atom of the Ligand unit is bound to the succinimide ring system of the Stretcher unit formed by reaction of the thiol functional group of the Targeting Ligand with the maleimide moiety of the corresponding Stretcher unit prodriver. In other embodiments, the thiol functional group of the Ligand unit reacts with an alpha halogen acetamide moiety to provide a sulfur-bonded Stretcher unit by nucleophilic displacement of its halogen substituent.

Illustrative Stretcher units prior to binding to a Ligand unit (i.e., Stretcher unit prodrivers) include a maleimide moiety and are represented by structures including those of Formula Z'a (Z'a), wherein the wavy line adjacent to the carbonyl carbon atom indicates connection to B, A or S ^* , in the above formulae, depending on the presence or absence of A and/or B, R ¹⁷ is -(CH ₂ ) _1-5 - or -CH ₂ CH ₂ (OCH ₂ CH ₂ ) _1-36 -. In some embodiments, R ¹⁷ is -CH ₂ -, -(CH ₂ ) ₂ -, -(CH ₂ ) ₃ -, -(CH ₂ ) ₄ -, -(CH ₂ ) ₅ -, -CH ₂ CH ₂ OCH ₂ CH ₂ -, -CH ₂ CH ₂ (OCH ₂ CH ₂ ) ₂ -, -CH ₂ CH ₂ (OCH ₂ CH ₂ ) ₃ -, -CH ₂ CH ₂ (OCH ₂ CH ₂ ) ₄ -, -CH ₂ CH ₂ (OCH ₂ CH ₂ ) ₅ -, -CH ₂ CH ₂ (OCH ₂ CH ₂ ) ₆ -, -CH ₂ CH ₂ (OCH ₂ CH ₂ ) ₇ -, -CH ₂ CH ₂ (OCH ₂ CH ₂ ) ₈ -, -CH ₂ CH ₂ (OCH ₂ CH ₂ ) ₁₀ -, -CH ₂ CH ₂ (OCH ₂ CH ₂ ) ₁₂ -, -CH ₂ CH ₂ (OCH ₂ CH ₂ ) ₁₄ -, -CH ₂ CH ₂ (OCH ₂ CH ₂ ) ₁₆ -, -CH ₂ CH ₂ (OCH ₂ CH ₂ ) ₁₈ -, -CH ₂ CH ₂ (OCH ₂ CH ₂ ) ₂₀ -, -CH ₂ CH ₂ (OCH ₂ CH ₂ ) ₂₄ -, -CH ₂ CH ₂ (OCH ₂ CH ₂ ) ₂₈ -, -CH ₂ CH ₂ (OCH ₂ CH ₂ ) ₃₂ - or -CH ₂ CH ₂ (OCH ₂ CH ₂ ) ₃₆ -.

Other illustrative Stretcher units prior to binding to a Ligand unit (i.e., Stretcher unit precursors) include a maleimide moiety and are represented by structures including those of Formula Z'a-BU (Z'a-BU), wherein the wavy line adjacent to the carbonyl carbon atom indicates connection to B, A or S ^* , in each of the above formulae, depending on the presence or absence of A and/or B, R ¹⁷ is R ¹⁷ is -(CH ₂ ) _1-5 - or -CH ₂ CH ₂ (OCH ₂ CH ₂ ) _1-5 -, substituted by a basic unit (BU), such as an optionally substituted aminoalkyl, for example -(CH ₂ ) _x NH ₂ , -(CH ₂ ) _x NHR ^a and -(CH ₂ ) _x N(R ^a ) ₂ , wherein the subscript x is an integer of 1-4, preferably R ¹⁷ is -CH ₂ - or -CH ₂ CH ₂ - and the subscript x is 1 or 2, and each R ^a is independently selected from C _1-6 alkyl and C 1-6 alkyl. or two ^Ra groups are combined with _the nitrogen to which they are attached to form an azacyclobutane, pyrrolidinyl or piperidinyl group.

In some embodiments of formula Z'a, the extension unit precursor (Z') is represented by one of the following structures: , , , or , where the wavy line adjacent to the carbonyl group is as defined for Z'a or Z'a-BU.

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

In stretcher units having a BU moiety, it will be appreciated that the amine functionality of that moiety is typically protected during synthesis by an amine protecting group such as an acid-labile protecting group such as BOC.

Illustrative Stretcher Unit Promotors covalently linked to the Linker Unit include the structure of Z'a or Z'a-BU, wherein -R ¹⁷ - or -R ¹⁷ (BU)- is -CH ₂ -, -CH ₂ CH ₂ -, or -CH(CH ₂ NH ₂ )-, having the following structure: , , , where the wavy line adjacent to the carbonyl group is as defined for Z'a or Z'a-BU.

The other extension unit front drive body bonded to the connector unit (A) has the above structure, wherein A in any of the above Z'-A- and Z'(BU)-A- structures is replaced by a parallel connector unit and a separator (-B(S ^* )-), the separator having the structure , wherein the subscript m ranges from 1 to 6; n ranges from 8 to 24; R ^PEG is a PEG end-capping unit, preferably H, -CH ₃ or -CH ₂ CH ₂ CO ₂ H, the asterisk (*) indicates covalent attachment to a stretcher unit prodriver corresponding in structure to Formula Z'a and the wavy line indicates covalent attachment to RL. In cases such as those shown here, the PEG groups shown are intended to exemplify a variety of spacers, including PEG groups of varying lengths and other spacers that are directly attached or modified to attach to parallel linker units.

In some embodiments, the extension unit has a mass of no more than about 1000 Daltons, no more than about 500 Daltons, no more than about 200 Daltons, about 30, 50, or 100 Daltons to about 1000 Daltons, about 30, 50, or 100 Daltons to about 500 Daltons, or about 30, 50, or 100 Daltons to about 200 Daltons. Connector Unit (A)

In some embodiments, where it is desired to add additional distance between the Stretcher unit prodriver (Z') and the releasable Linker, a Linker unit (A) is included in the Drug-Linker compound. In some embodiments, the additional distance will facilitate activation within the RL. Thus, the Linker unit (A) when present expands the framework of the Linker unit. In this regard, the Linker unit (A) is covalently bonded to the Stretcher unit (or its prodriver) at one end and to an optionally selected parallel Linker unit or Spacer (S ^* ) at its other end.

The skilled artisan will appreciate that a linker unit is any group that provides a connection between a releasable linker and the rest of the linker unit (Q). A linker unit may, for example, comprise one or more (e.g., 1-10, preferably 1, 2, 3, or 4) proteinaceous or non-proteinaceous amino acids, amino alcohols, amino aldehydes, diamine residues. In some embodiments, a linker unit is a single proteinaceous or non-proteinaceous amino acid, amino alcohol, amino aldehyde, or diamine residue. An exemplary amino acid that can serve as a linker unit is β-alanine.

In some of those embodiments, the connector unit has the following expression: , wherein the wavy line indicates that the linker unit is connected to the drug-linker compound; and wherein R ¹¹¹ is independently selected from the group consisting of hydrogen, p-hydroxybenzyl, methyl, isopropyl, isobutyl, dibutyl, -CH ₂ OH, -CH(OH)CH ₃ , -CH ₂ CH ₂ SCH ₃ , -CH ₂ CONH ₂ , -CH ₂ COOH, -CH ₂ CH ₂ CONH ₂ , -CH ₂ CH ₂ COOH, -(CH ₂ ) ₃ NHC(=NH)NH ₂ , -(CH ₂ ) ₃ NH ₂ , -(CH ₂ ) ₃ NHCOCH ₃ , -(CH ₂ ) ₃ NHCHO, -(CH ₂ ) ₄ NHC(=NH)NH ₂ , -(CH ₂ ) ₄ NH ₂ , -(CH ₂ ) ₄ NHCOCH ₃ , -(CH ₂ ) ₄ NHCHO, -(CH ₂ ) ₃ NHCONH ₂ , -(CH ₂ ) ₄ NHCONH ₂ , -CH ₂ CH ₂ CH(OH)CH ₂ NH ₂ , 2-pyridylmethyl-, 3-pyridylmethyl-, 4-pyridylmethyl-, , and each R ¹⁰⁰ is independently selected from hydrogen or -C ₁ -C ₃ alkyl, preferably hydrogen or CH ₃ ; and the subscript c is independently selected from an integer of 1 to 10, preferably 1 to 3.

Representative linker units having a carbonyl group for attachment to a separator (S ^* ) or -B(S ^* )- are as follows: wherein in each case R ¹³ is independently selected from the group consisting of -CH ₂ CH ₂ (OCH ₂ CH ₂ ) _k -, -C ₁ -C ₆ alkylene-, -C ₃ -C ₈ carbocyclyl-, -arylene-, -C ₁ -C _{10 heteroalkylene-, -C 3 -C 8} heterocyclyl-, -C ₁ -C ₁₀ alkylene-arylene-, -arylene-C ₁ -C ₁₀ alkylene-, -C ₁ -C ₁₀ alkylene-(C 3 -C 8 carbocyclyl)-, -(C ₃ -C ₈ carbocyclyl)-C ₁ -C ₁₀ alkylene-, -C ₁ -C ₁₀ alkylene-(C ₃ -C ₈ heterocyclyl)-, and -(C ₃ -C ₈ carbocyclyl)-C _{1 -C 10} alkylene- In some embodiments _, R ¹³ is -C ₁ -C ₆ alkylene and c _{is 1} .

Another representative linker unit having a carbonyl group for attachment to a spacer (S ^* ) or -B(S ^* )- is as follows: wherein R ¹³ is -CH ₂ CH ₂ (OCH ₂ CH ₂ ) _k -, -C ₁ -C ₆ alkylene-, -C ₃ -C ₈ carbocyclyl-, -arylene-, -C _{1 -C 10 heteroalkylene-, -C 3 -C 8 heterocyclyl-, -C 1 -C 10 alkylene - arylene- ,} -arylene-C ₁ -C ₁₀ alkylene-, -C ₁ -C ₁₀ alkylene-(C 3 -C 8 carbocyclyl)-, -(C ₃ -C ₈ carbocyclyl)-C ₁ -C ₁₀ alkylene- _{, -C 1 -C 10 alkylene-(C 3 -C 8 heterocyclyl ) - , or} -(C ₃ -C ₈ heterocyclyl)-C ₁ -C In some embodiments, R ¹³ is _{-C 1} -C ₆ alkylene.

Representative linker units having an NH moiety attached to a separator (S ^* ) or -B(S ^* )- are as follows: wherein in each case R ¹³ is independently selected from the group consisting of -CH ₂ CH ₂ (OCH ₂ CH ₂ ) _k -, -C ₁ -C ₆ alkylene-, -C ₃ -C ₈ carbocyclyl-, -arylene-, -C ₁ -C _{10 heteroalkylene-, -C 3 -C 8} heterocyclyl-, -C ₁ -C ₁₀ alkylene-arylene-, -arylene-C ₁ -C ₁₀ alkylene-, -C ₁ -C ₁₀ alkylene-(C 3 -C 8 carbocyclyl)-, -(C ₃ -C ₈ carbocyclyl)-C ₁ -C ₁₀ alkylene-, -C ₁ -C ₁₀ alkylene-(C ₃ -C ₈ heterocyclyl)-, and -(C ₃ -C ₈ carbocyclyl)-C _{1 -C 10} alkylene- In some embodiments _, R ¹³ is -C ₁ -C ₆ alkylene and subscript c _{is 1} .

Another representative linker unit having an NH moiety attached to a separator (S ^* ) or -B(S ^* )- is as follows: wherein R ¹³ is -CH ₂ CH ₂ (OCH ₂ CH ₂ ) _k -, -C ₁ -C ₆ alkylene-, -C ₃ -C ₈ carbocyclyl-, -arylene-, -C _{1 -C 10 heteroalkylene-, -C 3 -C 8 heterocyclyl-, -C 1 -C 10 alkylene - arylene- ,} -arylene-C ₁ -C ₁₀ alkylene-, -C ₁ -C ₁₀ alkylene-(C 3 -C 8 carbocyclyl)-, -(C ₃ -C ₈ carbocyclyl)-C ₁ -C ₁₀ alkylene- _{, -C 1 -C 10 alkylene-(C 3 -C 8 heterocyclyl ) - , -} (C ₃ -C ₈ heterocyclyl)-C ₁ -C _10Alkylene- , -C(=O)C ₁ -C ₆ alkylene-, or -C ₁ -C ₆ alkylene-C(=O)-C ₁ -C ₆ alkylene, wherein the subscript k is an integer ranging from 1 to 36.

Selected embodiments of the connector unit include those having the following structures: or , wherein the wavy line adjacent to the nitrogen indicates covalent attachment to the stretcher unit (Z) (or its prodromal Z'), and the wavy line adjacent to the carbonyl group indicates covalent attachment to the spacer (S ^* ) or -B(S ^* )-; and m is an integer ranging from 1 to 6, preferably from 2 to 6, more preferably from 2 to 4. Releasable Linker (RL)

The releasable linker (RL) can be linked to a second spacer unit (Y) or a drug unit (D). The RL comprises a cleavable bond (i.e., a reactive site) that releases the free drug under the action of an enzyme present in hyperproliferative cells or overactivated immune cells or unique to the immediate environment of such abnormal or unwanted cells, or under non-enzymatic action caused by conditions that hyperproliferative cells are more likely to experience compared to normal cells. Alternatively, the RL comprises a cleavable bond that is more likely to act intracellularly in hyperproliferative cells or overactivated immune cells because of preferential entry into such cells compared to normal cells. Peptide releasable linkers

In some embodiments, the releasable linker is a peptide releasable linker. In some embodiments, a peptide releasable linker (RL) will comprise one or more continuous or non-continuous amino acid sequences (e.g., such that the RL has 1 to no more than 12 amino acids). The peptide releasable linker may comprise or consist of, for example, amino acid, dipeptide, tripeptide, tetrapeptide, pentapeptide, hexapeptide, heptapeptide, octapeptide, nonapeptide, decapeptide, undecapeptide, or dodecapeptide units. In some embodiments, in the presence of an enzyme (e.g., a tumor-associated protease), the amide bond between the amino acids is cleaved, which ultimately results in the release of the free drug.

Each amino acid is proteinaceous or non-proteinaceous and/or a D- or L-isomer, with the proviso that the RL comprises a cleavable bond that, when cleaved, initiates release of the drug unit. In some embodiments, the peptide releasable linker will comprise only proteinaceous amino acids. In some embodiments, the peptide releasable linker will have 1 to no more than 12 amino acids in a contiguous sequence.

In some embodiments, each amino acid is independently selected from the group consisting of alanine, arginine, aspartic acid, asparagine, histidine, glycine, glutamine, glutamine, phenylalanine, lysine, leucine, serine, tyrosine, threonine, isoleucine, proline, tryptophan, valine, cysteine, methionine, selenocysteine, ornithine, penicillamine, β-alanine, aminoalkanoic acid, aminoacetic acid, aminoalkanoic acid, aminobenzoic acid, amino-heterocyclic-alkanoic acid, heterocyclic-carboxylic acid, citrulline, statins, diaminoalkanoic acid and derivatives thereof. In some embodiments, each amino acid is independently selected from the group consisting of alanine, arginine, aspartic acid, asparagine, histidine, glycine, glutamine, glutamine, phenylalanine, lysine, leucine, serine, tyrosine, threonine, isoleucine, proline, tryptophan, valine, cysteine, methionine, and selenocysteine. In some embodiments, each amino acid is independently selected from the group consisting of alanine, arginine, aspartic acid, asparagine, histidine, glycine, glutamine, glutamine, phenylalanine, lysine, leucine, serine, tyrosine, threonine, isoleucine, proline, tryptophan and valine. In some embodiments, each amino acid is selected from protein or non-protein amino acids.

In another embodiment, each amino acid is independently selected from the group consisting of the following L-(protein) amino acids: alanine, arginine, aspartic acid, asparagine, histidine, glycine, glutamine, glutamine, phenylalanine, lysine, leucine, serine, tyrosine, threonine, isoleucine, tryptophan and valine.

In another embodiment, each amino acid is independently selected from the group consisting of the following D-isomers of these protein amino acids: alanine, arginine, aspartic acid, asparagine, histidine, glycine, glutamine, glutamine, phenylalanine, lysine, leucine, serine, tyrosine, threonine, isoleucine, tryptophan and valine.

In certain embodiments, the peptide releasable linker comprises only protein amino acids. In other embodiments, the peptide releasable linker comprises only non-protein amino acids. In some embodiments, the peptide releasable linker comprises a protein amino acid linked to a non-protein amino acid. In some embodiments, the peptide releasable linker comprises a protein amino acid linked to a D-isomer of a protein amino acid.

In another embodiment, each amino acid is independently selected from the group consisting of β-alanine, N-methylglycine, glycine, lysine, valine, and phenylalanine.

Exemplary peptide releasable linkers include dipeptides or tripeptides having -Val-Lys-Gly-, -Val-Cit-, -Phe-Lys-, or -Val-Ala-.

Useful peptide releasable linkers are designed and optimized for selectivity for enzymatic cleavage by specific enzymes (e.g., tumor-associated proteases). In some embodiments, cleavage of the bond is catalyzed by cathepsin B, C or D or cytosolic proteases.

In some embodiments, the peptide releasable linker (RL) will be represented by -(-AA-) _1-12 - or (-AA-AA-) _1-6 , wherein AA is independently selected from protein or non-protein amino acids at each occurrence. In one embodiment, AA is independently selected from protein amino acids at each occurrence. In another embodiment, RL is a tripeptide having the formula: AA ₁ -AA ₂ -AA ₃ , wherein AA ₁ , AA ₂ and AA ₃ are each independently amino acids and wherein AA ₁ is linked to -NH- and AA ₃ is linked to S*. In yet another embodiment, AA ₃ is gly or β-ala.

In some embodiments, the peptide releasable linker has the formula represented below in square brackets, with the subscript w being an integer ranging from 1 to 12; or w is 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, or 12; or w is 2, 3, or 4; or w is 3; or w is 4: wherein R ¹⁹ is in each case independently selected from the group consisting of hydrogen, methyl, isopropyl, isobutyl, dibutyl, benzyl, p-hydroxybenzyl, -CH ₂ OH, -CH(OH)CH ₃ , -CH 2 CH ₂ SCH ₃ , -CH ₂ CONH ₂ , -CH ₂ COOH, -CH ₂ CH ₂ CONH ₂ , -CH ₂ CH ₂ COOH, -( _{CH 2} ) ₃ NHC(=NH)NH ₂ , -(CH ₂ ) ₃ NH ₂ , -(CH ₂ ) ₃ NHCOCH ₃ , -(CH ₂ ) ₃ NHCHO, -(CH ₂ ) ₄ NHC(=NH)NH ₂ , -(CH ₂ ) ₄ NH ₂ , -(CH ₂ ) ₄ NHCOCH ₃ , -(CH ₂ ) ₄ NHCHO, -(CH ₂ ) ₃ NHCONH ₂ , -(CH ₂ ) ₄ NHCONH ₂ , -CH ₂ CH ₂ CH(OH)CH ₂ NH ₂ , 2-pyridylmethyl-, 3-pyridylmethyl-, 4-pyridylmethyl-, phenyl, cyclohexyl, . In some embodiments, subscript w is not 3.

In some embodiments, each R ¹⁹ is independently hydrogen, methyl, isopropyl, isobutyl, dibutyl, -(CH ₂ ) ₃ NH ₂ , or -(CH ₂ ) ₄ NH _2. In some embodiments, each R ¹⁹ is independently hydrogen, isopropyl, or -(CH ₂ ) ₄ NH ₂ .

Illustrative peptide releasable linkers are represented by formulas (Pa), (Pb), and (Pc): (Pa), wherein R ²⁰ and R ²¹ are as follows: R ²⁰ R ²¹ Benzyl (CH ₂ ) ₄ NH ₂ ; methyl (CH ₂ ) ₄ NH ₂ ; Isopropyl (CH ₂ ) ₄ NH ₂ ; Isopropyl (CH ₂ ) ₃ NHCONH ₂ ; Benzyl (CH ₂ ) ₃ NHCONH ₂ ; Isobutyl (CH ₂ ) ₃ NHCONH ₂ ; Secondary butyl (CH ₂ ) ₃ NHCONH ₂ ; (CH ₂ ) ₃ NHCONH ₂ ; Benzyl methyl; and Benzyl (CH ₂ ) ₃ NHC(=NH)NH ₂ ; (Pb), wherein R ²⁰ , R ²¹ and R ²² are as follows: R ²⁰ R ²¹ R ²² Benzyl Benzyl -(CH ₂ ) ₄ NH ₂ Isopropyl Benzyl -(CH ₂ ) ₄ NH ₂ H Isopropyl Benzyl-(CH ₂ ) ₄ NH ₂ -(CH ₂ ) ₄ NH ₂ -H (Pc), wherein R ²⁰ , R ²¹ , R ²² and R ²³ are as follows: R ²⁰ R ²¹ R ²² R ²³ H Benzyl Isobutyl H; and methyl Isobutyl methyl isobutyl.

In some embodiments, the RL comprises a peptide selected from the group consisting of gly-gly, gly-gly-gly, gly-gly-gly-gly (SEQ ID NO: 1043), val-gly-gly, val-cit-gly, val-gln-gly, val-glu-gly, phe-lys-gly, leu-lys-gly, gly-val-lys-gly (SEQ ID NO: 1044), val-lys-gly-gly (SEQ ID NO: 1045), val-lys-gly, val-lys-ala, val-lys-leu, leu-leu-gly, gly-gly-phe-gly (SEQ ID NO: 1046), gly-gly-phe-gly-gly (SEQ ID NO: 1047), val-gly and val-lys-β-ala.

In other embodiments, the RL comprises a peptide selected from the group consisting of gly-gly-gly, gly-gly-gly-gly (SEQ ID NO: 1043), val-gly-gly, val-cit-gly, val-gln-gly, val-glu-gly, phe-lys-gly, leu-lys-gly, gly-val-lys-gly (SEQ ID NO: 1044), val-lys-gly-gly (SEQ ID NO: 1045), val-lys-gly, val-lys-ala, val-lys-leu, leu-leu-gly, gly-gly-phe-gly (SEQ ID NO: 1046) and val-lys-β-ala.

In other embodiments, the RL comprises a peptide selected from the group consisting of gly-gly-gly, val-gly-gly, val-cit-gly, val-gln-gly, val-glu-gly, phe-lys-gly, leu-lys-gly, val-lys-gly, val-lys-ala, val-lys-leu, leu-leu-gly and val-lys-β-ala.

In other embodiments, the RL comprises a peptide selected from the group consisting of gly-gly-gly-gly (SEQ ID NO: 1043), gly-val-lys-gly (SEQ ID NO: 1044), val-lys-gly-gly (SEQ ID NO: 1045), and gly-gly-phe-gly (SEQ ID NO: 1046).

In other embodiments, RL is a peptide selected from the group consisting of val-gln-gly, val-glu-gly, phe-lys-gly, leu-lys-gly, val-lys-gly, val-lys-ala, val-lys-leu, leu-leu-gly and val-lys-β-ala.

In other embodiments, RL is val-lys-gly.

In other embodiments, RL is val-lys-β-ala.

In some embodiments, the releasable link RL is or The wavy line adjacent to the -NH- group indicates that it is connected to the stretcher unit Z' or the linker unit A, and the wavy line adjacent to the -C(=O)- group indicates that it is connected to the second spacer unit Y or the drug unit D. Glycoside unit releasable linker

In some embodiments, the releasable linker is a glycosidic (e.g., glucuronide) unit. In such embodiments, the self-destructive cascade is activated by operating a glycosidase on the carbohydrate portion of the glycosidic (e.g., glucuronide) unit. Many sugars can be used in the embodiments described herein. Specific carbohydrate moieties include galactose, glucose, mannose, xylose, arabinose, mannose-6-phosphate, fucose, rhamnose, gulose, allose, 6-deoxy-glucose, lactose, maltose, cellulosic disaccharide, gentian disaccharide, maltotriose, GlcNAc, GalNAc, and those portions of maltohexaose.

A glycoside (e.g., glucuronide) unit typically comprises a sugar moiety (Su) linked to a self-immolative spacer via an oxygen glycosidic bond. Cleavage of the oxygen glycosidic bond initiates a self-immolative reaction sequence, thereby releasing the free drug. In some embodiments, a self-immolative sequence is activated by cleavage of a glycoside (e.g., glucuronide) unit, which is an exemplary glycoside unit. A glycoside (e.g., glucuronide) unit comprises an activation unit and a self-immolative second spacer unit. A glycoside (e.g., glucuronide) unit comprises a sugar moiety (Su) linked to a self-immolative second spacer unit via an oxygen glycosidic bond.

In some embodiments, the glycoside (eg, glucuronide) unit comprises a sugar moiety (Su) linked via an oxygen glycosidic bond (-O'-) to a self-immolative unit (SP) of the formula: , wherein the wavy lines indicate that the drug unit of formula (A'), (I'), (IIa'), (IIIa'), (IVa ^{'), (IIb'} ), (IIIb'), (IVb'), (IIc'), (IIIc'), (IVc') or any subformula thereof is covalently linked to a drug unit (STING agonist compound of the present disclosure) directly or indirectly via a linker unit (A) or a parallel linker unit (B), a spacer (S*), or a combination of a linker unit and a parallel linker unit, or is covalently linked to a second spacer unit linked to the drug unit (STING agonist compound of the present disclosure), and is covalently linked to a stretcher unit (Z) or a prodriver thereof (Z').

The oxygen glycosidic bond (-O'-) is typically a β-glucuronidase cleavage site (i.e., Su is from a glucuronide), such as a glycosidic bond cleavable by human lysosomal β-glucuronidase.

In some embodiments, Su is a monosaccharide. In some embodiments, Su is a 6-carbon carbohydrate moiety. In some embodiments, Su is a hexose. In some embodiments, Su is galactose, glucose, mannose, xylose, arabinose, mannose-6-phosphate, fucose, rhamnose, gulose, allose, 6-deoxy-glucose, lactose, maltose, cellulosic disaccharide, gentian disaccharide, maltotriose, GlcNAc, GalNAc or maltohexaose. In some embodiments, Su is galactose, glucose, mannose, mannose-6-phosphate, fucose, rhamnose, gulose, allose, 6-deoxy-glucose, GlcNAc or GalNAc.

In some embodiments, the glycoside (eg, glucuronide) unit can be represented by the formula Ga, Gb, or Gc: (Ga) (Gb) or (Gc); wherein Su is a sugar moiety, -O'- represents an oxygen glycosidic bond; R ^1S , R ^2S and R ^3S are independently hydrogen, halogen, -CN, -NO ₂ or other electron withdrawing or electron pushing groups; ^RBZ is selected from the group consisting of: C ₁ -C ₆ alkyl, C ₁ -C ₆ halogen alkyl, PEG unit, cyclodextrin unit, polyamide, hydrophilic peptide, polysaccharide and dendrimer; and wherein the wavy line indicates direct or indirect (via a linker unit or a linker unit in parallel or a linker unit and a linker unit in parallel) connection to the stretcher unit (Z) (or its prodriver (Z')); and # indicates connection to the STING agonist moiety (drug unit) or the second spacer (directly or indirectly via an intervening functional group or other moiety).

In some embodiments, the glycoside (e.g., glucuronide) unit can be represented by the formula Ga*, Gb*, or Gc*: (Ga*), (Gb*) or (Gc*); wherein Su is a sugar moiety, -O'- represents an oxygen glycosidic bond; R ^1S , R ^2S and R ^3S are independently hydrogen, a halogen, CN, NO ₂ or other electron-withdrawing groups, or electron-pushing groups; and wherein the wavy line indicates direct or indirect connection to the stretcher unit (Z) (or its prodriver (Z') via a linker unit or a parallel linker unit or a linker unit and a parallel linker unit); and # indicates connection to the STING agonist moiety or the second spacer (directly or indirectly via an intervening functional group or other moiety).

In some embodiments, the glycoside (eg, glucuronide) unit can be represented by the formula Ga**, Gb**, or Gc**: (Ga**), (Gb**) or (Gc**); wherein Su is a sugar moiety, -O'- represents an oxygen glycosidic bond; R ^1S , R ^2S and R ^3S are independently hydrogen, halogen, -CN, -NO ₂ or other electron-withdrawing groups, or electron-pushing groups; and wherein the wavy line indicates direct or indirect (via a linker unit or a parallel linker unit or a linker unit and a parallel linker unit) connection to the stretcher unit (Z) (or its prodromal (Z'));# indicates connection to the STING agonist moiety, optionally via a second spacer unit; and G* is an intervening moiety, the intervening moiety comprising a functional group capable of connecting to the second spacer unit or the STING agonist moiety. In some embodiments, the intervening moiety is -OC(O)-.

In some embodiments, the glycoside (eg, glucuronide) unit can be represented by the formula Ga***, Gb***, or Gc***: (Ga***), (Gb***) or (Gc***); wherein Su is a sugar moiety, -O'- represents an oxygen glycosidic bond; R ^1S , R ^2S and R ^3S are independently hydrogen, a halogen, -CN, -NO ₂ or other electron-pulling groups, or electron-pushing groups; and wherein the wavy line indicates direct or indirect connection to the stretcher unit (Z) (or its prodriver (Z') via a linker unit or a parallel linker unit or a linker unit and a parallel linker unit); and # indicates connection to the STING agonist moiety, optionally via a second spacer unit.

In some embodiments, R ^1S , R ^2S and R ^3S are independently selected from hydrogen, halogen, -CN or -NO _2. In some embodiments, R ^1S , R ^2S and R ^3S are each hydrogen. In some embodiments, R ^2S is an electron withdrawing group, preferably NO ₂ , and R ^1S and R ^3S are each hydrogen.

In some embodiments, the activatable self-immolative group capable of being cleaved by a glycosidase to initiate a self-immolative reaction sequence is represented by the formula Gd: (Gd), wherein R ^4S is CH ₂ OH or -CO ₂ H, the wavy line indicates covalent linkage to the stretcher unit (Z) (or its precursor Z') directly or indirectly via a linker unit or a parallel linker unit or a linker unit and a parallel linker unit, and the hash mark (#) indicates covalent linkage to a methylene carbamate unit.

In some embodiments, the activatable self-immolative group capable of being cleaved by a glycosidase to initiate a self-immolative reaction sequence is represented by the formula Gd*: (Gd*), wherein R ^4S is CH ₂ OH or -CO ₂ H, the wavy line indicates covalent attachment to the stretcher unit (Z) (or its prodromal Z') directly or indirectly via a linker unit or a parallel linker unit or a linker unit and a parallel linker unit, and the hash mark (#) indicates covalent attachment to an -OC(O)- unit, which is attached to a second spacer unit or a STING agonist moiety. In some embodiments, the -OC(O)- unit is attached to a nitrogen atom of the second spacer unit or the STING agonist moiety to form a methylene carbamate moiety. In some embodiments, the -OC(O)- unit is attached to an oxygen atom of the second spacer unit or the STING agonist moiety to form a methylene carbonate moiety.

In some embodiments, the activatable self-immolative group capable of being cleaved by a glycosidase to initiate a self-immolative reaction sequence is represented by the formula Gd**: (Gd**), wherein R ^4S is CH ₂ OH or -CO ₂ H, the wavy line indicates covalent attachment to the stretcher unit (Z) (or its prodromal Z') directly or indirectly via a linker unit or a parallel linker unit or a linker unit and a parallel linker unit, and the hash mark (#) indicates covalent attachment to the second spacer unit or the STING agonist moiety. In some embodiments, the -OC(O)- unit is attached to the nitrogen atom of the second spacer unit or the STING agonist moiety to form a methylene carbamate moiety. In some embodiments, the -OC(O)- unit is attached to the oxygen atom of the second spacer unit or the STING agonist moiety to form a methylene carbonate moiety.

In some embodiments where the activatable self-immolative moiety comprises a glycoside (e.g., a glucuronide) unit, the moiety is represented by the following formula Ge: (Ge), wherein the wavy line indicates covalent attachment to the stretcher unit (Z) (or its prodromal Z') directly or indirectly via a linker unit or a parallel linker unit or a linker unit and a parallel linker unit, and the hash mark (#) indicates covalent attachment to the benzyl carbon of a second spacer or functional group of the STING agonist portion. In some embodiments, the functional group is -OC(O)-. In some embodiments, the structure of formula Ge is attached to the drug unit via a quaternary ammonium tertiary amine (N ⁺ ), wherein the nitrogen atom is from the tertiary amine functional group on the unbound drug unit.

In some embodiments where the activatable self-immolative moiety comprises a glycoside (e.g., a glucuronide) unit, the moiety is represented by the following formula Ge: (Ge*), wherein the wavy line indicates covalent attachment to the stretcher unit (Z) (or its prodromal Z') directly or indirectly via a linker unit or a parallel linker unit or a linker unit and a parallel linker unit, and the hash mark and # indicate attachment to the STING agonist moiety or a second spacer unit (directly or indirectly via an intervening functional group or other moiety). In some embodiments, the intervening functional group is -OC(O)-. In some embodiments, the structure of formula Ge is attached to the drug unit via a quaternary ammonium tertiary amine (N ⁺ ), wherein the nitrogen atom is from the tertiary amine functional group on the unbound drug unit.

In some embodiments, the releasable connector has the following structure: , or .

In some embodiments, the releasable connector has the following structure: .

In some embodiments, the releasable connector has the following structure: .

In some embodiments, the releasable connector has the following structure: .

In some embodiments, the releasable connector has the following structure: .

In some embodiments, the releasable connector has the following structure: .

In some embodiments, the releasable connector has the following structure: .

In some embodiments, the releasable connector has the following structure: .

In some embodiments, the releasable connector has the following structure: .

Another type of releasable linker that provides a mechanism for separating the STING agonist moiety from the ligand unit and other components of the linker unit via activation of a self-immolative cascade within the linker unit comprises a p-aminobenzyloxycarbonyl (PAB) moiety whose phenylene component is substituted with _Jm , wherein the subscript m indicates the number of substituents as an integer ranging from 0-4, and each J is independently _-C1 - _C8 alkyl, -O-( _C1 - _C8 alkyl), -halogen, -nitro, or -cyano.

In some embodiments, RL is a self-immolative group capable of releasing -D without a separate hydrolysis step or subsequent self-immolative event. In some embodiments, -RL- is a PAB moiety that is linked to the carbonyl group of -W- via the amine nitrogen atom of the PAB group and is directly linked to -D via a carbonate group. In related embodiments, -RL- comprises a PAB moiety that is linked to the carbonyl group of -A-, -S ^* -, or -B- via the amine nitrogen atom of the PAB group and is directly linked to -D via a carbonate group. Without being bound by any particular theory or mechanism, possible mechanisms for drug release from RL include a PAB moiety where RL is directly linked to -D via a carbonate group as shown in Toki et al. (2002) J Org. Chem. 67:1866-1872, the disclosure of which is incorporated herein by reference.

In some embodiments, the RL unit containing the PAB moiety is represented by the following formula: , wherein the subscript m is an integer in the range of 0-4, and each J is independently -C ₁ -C ₈ alkyl, -O-(C ₁ -C ₈ alkyl), -halogen, -nitro or -cyano.

Other examples of self-immolative groups include, but are not limited to, aromatic compounds that are electronically similar to the PAB moiety, such as 2-aminoimidazole-5-methanol derivatives (Hay et al. (1999) Bioorg. Med. Chem. Lett. 9:2237) and o- or p-aminobenzyl acetals. Other RLs undergo cyclization after amide bond hydrolysis, such as substituted and unsubstituted 4-aminobutyric acid amides (Rodrigues et al ., Chemistry Biology, 1995, 2, 223), appropriately substituted bicyclo[2.2.1] and bicyclo[2.2.2] ring systems (Storm et al. , J. Amer. Chem. Soc., 1972, 94, 5815), and 2-aminophenylpropionic acid amide (Amsberry et al. , J. Org. Chem., 1990, 55, 5867).

In one embodiment, RL is a branched-chain bis(hydroxymethyl)styrene (BHMS) unit.

In some embodiments, RL has the formula: The wavy lines marked with ** indicate the connection sites with D; and the wavy lines marked with * indicate the connection sites with the additional linker components of Q. In some embodiments, RL comprises the following formula: The wavy line marked with ** indicates the site of connection with D; and the wavy line marked with * indicates the site of connection with other parts of RL (such as the peptide releasable linker or glycoside unit releasable linker described herein).

In some embodiments, RL comprises a heterocyclic "self-immolative moiety" of Formula I-RL , II-RL or III-RL conjugated to a drug and incorporates an amide group that, upon hydrolysis by an intracellular protease, initiates a reaction that ultimately cleaves the self-immolative moiety from the drug, allowing the drug to be released from the conjugate in an active form. The linker moiety further comprises a peptide sequence adjacent to the self-immolative moiety, the peptide sequence being a substrate for an intracellular enzyme (e.g., an intracellular protease, such as a cathepsin (e.g., cathepsin B)), which cleaves the peptide at the amide bond shared with the self-immolative moiety.

In some embodiments, the heterocyclic self-immolative group (RL) is selected from the group consisting of Formula I-RL , II-RL and III-RL : I-RL , II-RL , III-RL , wherein the wavy line indicates the site of covalent attachment to the cell-specific ligand and the D'drug moiety, and wherein U ^RL is O, S or NR ^6RL ; Q ^RL is CR ^4RL or N; V ^1RL , V ^2RL and V ^3RL are independently CR ^4RL or N, with the proviso that for Formula II-RL and III-RL , at least one of Q, V ^1RL and V ^2RL is N; T ^RL is a hydroxyl or thiol or primary or secondary or N-heterocyclic or N-amide or N-carbamate heteroatom of a drug unit of Formula (A'), (I'), (IIa'), (IIIa'), (IVa'), (IIb'), (IIIb'), (IVb'), (IIc'), (IIIc'), (IVc'), wherein T ^RL and D' together form a drug unit of Formula (A'), (I'), (IIa'), (IIIa'), (IVa'), (IIb'), (IIIb'), (IVb'), (IIc'), (IIIc'), (IVc') or any subformula thereof, or any compound of Table 1; ^R1RL , ^R2RL , ^R3RL and ^R4RL are independently selected from the group consisting of H, F, Cl, Br, I, OH, -N ( ^R5RL ) ₂ ^, -N ( ^R5RL ) ₃₊ , _C1 - _C8 alkyl halide, carboxylate, sulfate, sulfamate, sulfonate, _-SO2R5RL , -S(=O) ^{R5RL , -SR5RL} , _-SO2N ( ^R5RL ) ₂ , -C(=O) ^{R5RL ,} _-CO2R5RL , -C(=O)N(R ^5RL ) ₂ , -CN, -N ₃ , -NO ₂ , C ₁ -C ₈ alkoxy, C ₁ -C 8 halogen-substituted alkyl, polyethyleneoxy, phosphonate, phosphate, C ₁ -C ₈ alkyl, C ₁ -C ₈ substituted alkyl, C ₂ -C ₈ alkenyl, C _{2 -C 8 substituted} alkenyl, C ₂ -C ₈ alkynyl, C ₂ -C ₈ substituted alkynyl, C ₆ -C ₂₀ aryl, C ₆ -C ₂₀ substituted aryl, C ₁ -C ₂₀ heterocycle, and C ₁ -C ₂₀ substituted heterocycle; or when taken together, R ^2RL and R ^3RL form a carbonyl (=O), or a spirocarbocycle of 3 to 7 carbon atoms; and R ^5RL and R ^{R 5RL ) 2} is independently selected from H, C ₁ -C ₈ alkyl, C ₁ -C ₈ substituted alkyl, C ₂ -C ₈ alkenyl, C ₂ -C ₈ substituted alkenyl, C ₂ -C ₈ alkynyl, C ₂ -C ₈ substituted alkynyl, C ₆ -C ₂₀ aryl, C ₆ -C ₂₀ substituted aryl, C ₁ -C ₂₀ heterocyclic ring and C ₁ -C ₂₀ substituted heterocyclic ring; wherein C ₁ -C ₈ substituted alkyl, C ₂ -C ₈ substituted alkenyl, C ₂ -C ₈ substituted alkynyl, C ₆ -C ₂₀ substituted aryl and C ₂ -C ₂₀ substituted heterocyclic ring are independently substituted with one or more substituents selected from the group consisting of F, Cl, Br, I, OH, -N(R ^5RL ) ₂ , -N(R ^5RL ) ₃ ⁺ , C ₁ -C ₈ alkyl halide, carboxylate, sulfate, sulfamate, sulfonate, C ₁ -C ₈ alkylsulfonate, C ₁ -C ₈ alkylamino, 4-dialkylaminopyridinium, C ₁ -C ₈ alkylhydroxyl, C ₁ -C ₈ alkylthiol, -SO ₂ R ^{5RL , -S(═O)R 5RL} , -SR ^5RL , -SO ₂ N(R ^5RL ) ₂ , -C(═O)R ^5RL , -CO ₂ R ^5RL , -C( ^═O )N(R ^5RL ) ₂ , -CN, -N ₃ , -NO ₂ , C ₁ -C ₈ alkoxy, C ₁ -C ₈ trifluoroalkyl, C ₁ -C ₈ alkyl, C ₃ -C _12- carbon ring, C ₆ -C ₂₀ aryl group, C ₂ -C ₂₀ heterocyclic group, polyethyleneoxy group, phosphonate group and phosphate group.

The conjugates disclosed herein may be stable outside of cells or in the absence of an enzyme capable of cleaving the amide bond of the self-immolative moiety. However, upon entry into cells or exposure to an appropriate enzyme, the amide bond may be cleaved, thereby initiating a spontaneous self-immolative reaction, resulting in cleavage of the bond covalently linking the self-immolative moiety to the drug, thereby releasing the drug in an underivatized or pharmacologically active form.

The self-immolative moieties in the conjugates of the present disclosure may incorporate one or more heteroatoms and thereby provide improved solubility, improved cleavage rate, and/or reduced tendency of the conjugate to aggregate. In some cases, these improvements of the heterocyclic self-immolative linker constructs of the present invention relative to non-heterocyclic, PAB-type linkers may result in surprising and unexpected biological properties, such as increased efficacy, reduced toxicity, and/or improvements in one or more desirable pharmacokinetic and/or pharmacodynamic properties.

Without wishing to be bound by theory or any particular mechanism, the presence of electron withdrawing groups on the heterocyclic ring of the linker of Formula I-RL , II-RL or III-RL may moderate the rate of fragmentation.

In one embodiment, the self-immolative moiety is a group of formula I-RL , wherein Q ^RL is N and U ^RL is O or S. Such groups have nonlinear structural characteristics that can improve the solubility of the conjugate. In this case, R can be H, methyl, nitro or CF _3. In one embodiment, Q ^RL is N and U ^RL is O, thereby forming an oxazole ring and R is H. In another embodiment, Q ^RL is N and U ^RL is S, thereby forming a thiazole ring substituted with a Me or CF ₃ group at R, as appropriate.

In another exemplary embodiment, the self-immolative moiety is a group of formula II-RL , wherein ^QRL is N and ^V1RL and ^V2RL are independently N or CH. In another embodiment, ^QRL , ^V1RL and ^V2RL are each N. In another embodiment, ^QRL and ^V1RL are N, and ^V2RL is CH. In another embodiment, ^QRL and ^V2RL are N, and ^V1RL is CH. In another embodiment, ^QRL and ^V1RL are both CH and ^V2RL is N. In another embodiment, ^QRL is N, and ^V1RL and ^V2RL are both CH.

In another embodiment, the self-immolative moiety is a group of formula III-RL , wherein Q ^RL , V ^1RL , V ^2RL and V ^3RL are each independently N or CH. In another embodiment, Q ^RL is N, and V ^1RL , V ^2RL and V ^3RL are each N. In another embodiment, Q ^RL , V ^1RL and V ^2RL are each CH, and V ^3RL is N. In another embodiment, Q ^RL , V ^2RL and V ^3RL are each CH, and V ^1RL is N. In another embodiment, Q ^RL , V ^1RL and V ^3RL are each CH, and V ^2RL is N. In another embodiment, Q ^RL and V ^2RL are both N, and V ^1RL and V ^3RL are both CH. In another embodiment, ^QRL and ^V2RL are both CH, and ^V1RL and ^V3RL are both N. In another embodiment, ^QRL and ^V3RL are both N, and ^V1RL and ^V2RL are both CH.

Without being bound by theory, Scheme 1a depicts the mechanism of releasing a free drug from a STING agonist drug unit (e.g., a compound of the present disclosure) that is linked to a releasable linker that is a glycoside (e.g., a glucuronide) unit via the nitrogen atom of the amine substituent in the free drug. Scheme 1a : Separator S*

The ligand-drug conjugates described herein may also include a spacer (S ^* ). For example, the function of the spacer is to mask the hydrophobicity of a particular drug unit or linker unit component.

Representative spacers include polyethylene glycol (PEG) units, cyclodextrin units, polyamides, hydrophilic peptides, polysaccharides, and dendrimers.

When polyethylene glycol (PEG) units, cyclodextrin units, polyamides, hydrophilic peptides, polysaccharides or dendrimers are included in Q, these groups may be present as "in-line" components or as side-chain or branched components. For those embodiments in which branched forms are present, the linker unit may include a lysine residue (or a parallel linker unit, B) that provides, for example, simple functional binding of the PEG unit to the rest of the linker unit .

When present, polydisperse PEG, monodisperse PEG and discrete PEG are used as part of the spacer in the compounds of the invention. Polydisperse PEG is a heterogeneous mixture of size and molecular weight, while monodisperse PEG is typically purified from a heterogeneous mixture and thus provides a single chain length and molecular weight. The preferred PEG unit is discrete PEG, a compound synthesized in a stepwise manner rather than through a polymerization process. Discrete PEG provides a single molecule with a defined and specified chain length.

The PEG units provided herein may comprise one or more polyethylene glycol chains. The polyethylene glycol chains are composed of at least two ethylene oxide (CH ₂ CH ₂ O) subunits. In some embodiments, the polyethylene glycol chains are linked together, for example, in a linear, branched, or star configuration. Typically, at least one PEG chain is derivatized at one end to covalently link to an appropriate site on a component of a linker unit (e.g., B), or used as an internal in-line (e.g., bifunctional) linking group to covalently join two linker unit components (e.g., ZAS ^* -RL-, ZAS ^* -RL-Y-). Exemplary linkages within a linker unit are by means of a non-conditionally cleavable bond or via a conditionally cleavable bond. Exemplary linkages are via amide, ether, ester, hydrazone, oxime, disulfide, peptide, or triazole bonds. In some embodiments, linkage within a linker unit is via a non-conditionally cleavable bond. In some embodiments, linkage within a linker unit is not via an ester, hydrazone, oxime, or disulfide bond. In some embodiments, linkage within a linker unit is not via a hydrazone bond.

Conditionally cleavable linkages are linkages that are substantially insensitive to cleavage when circulating in plasma, but are sensitive to cleavage in an intracellular or intratumoral environment. Non-conditionally cleavable linkages are linkages that are substantially insensitive to cleavage in any biological environment. Chemical hydrolysis of hydrazones, reduction of disulfides, and enzymatic cleavage of peptide or glycosidic linkages are examples of conditionally cleavable linkages.

In some embodiments, the PEG unit is directly linked to the parallel connector unit B, wherein the other end (or ends) of the PEG unit is free and untethered and may take the form of a methoxy group, a carboxylic acid, an alcohol, or other suitable functional group. The methoxy group, carboxylic acid, an alcohol, or other suitable functional group serves as a cap for the terminal PEG subunit of the PEG unit. Untethered means that the PEG unit will not be connected to a drug unit, an antibody, or another linking component at the untethered site. A skilled artisan will appreciate that a PEG unit may contain non-PEG materials (e.g., to facilitate coupling of multiple PEG chains to each other) in addition to repeating ethylene glycol subunits. Non-PEG materials refer to atoms in the PEG unit that are not part of the repeating -CH ₂ CH ₂ O- subunit. In some embodiments provided herein, the PEG unit comprises two monomeric PEG chains connected to each other via non-PEG elements. In other embodiments provided herein, the PEG unit comprises two linear PEG chains connected to a central core or parallel connector unit (i.e., the PEG unit itself is a branched chain).

Many PEG conjugation methods are available to those skilled in the art, [see, for example, Goodson et al. (1990) Bio/Technology 8 :343 (PEGylation of interleukin-2 at its glycosylation site following site-directed mutagenesis); EP 0 401 384 (coupling PEG to G-CSF); Malik et al. (1992) Exp. Hematol . 20 :1028-1035 (PEGylation of GM-CSF using trifluoroethanesulfonyl chloride); PCT Publication No. WO 1994061. No. 90/12874 (PEGylation of erythropoietin containing a recombinantly introduced cysteine residue using cysteine-specific mPEG derivatives); U.S. Patent No. 5,757,078 (PEGylation of EPO peptides); U.S. Patent No. 5,672,662 (Poly(ethylene glycol)s and related polymers monosubstituted with propionic acid or butyric acid and functional derivatives thereof for biotechnological applications); U.S. Patent No. 6,077,939 (PEGylation of the N-terminal α-carbon of peptides); Veronese et al., (1985) Appl. Biochem. Biotechnol 11 :141-142 (PEGylation of the N-terminal α-carbon of peptides using PEG-nitrophenyl carbonate ("PEG-NPC") or PEG-trichlorophenyl carbonate); and Veronese (2001) Biomaterials 22 :405-417 (a review article on peptide and protein PEGylation)]. The disclosure of the above references is incorporated herein by reference.

For example, PEG can be covalently bound to an amino acid residue via a reactive group. Reactive groups are those (e.g., free amine or carboxyl groups) that can bind to an activated PEG molecule. For example, the N-terminal amino acid residue and the lysine (K) residue have free amine groups; and the C-terminal amino acid residue has a free carboxyl group. Thiol groups (e.g., as found on cysteine residues) can also be used as reactive groups for attaching PEG. In addition, enzyme-assisted methods have been described for the specific introduction of activated groups (e.g., hydrazides, aldehydes, and aromatic amines) at the C-terminus of polypeptides (see Schwarz et al. (1990) Methods Enzymol. 184 :160; Rose et al. (1991) Bioconjugate Chem . 2 :154; and Gaertner et al. (1994) J. Biol. Chem . 269 :7224].

In some embodiments, methoxylated PEG ("mPEG") with various reactive moieties can be used to link PEG molecules to amine groups. Non-limiting examples of such reactive moieties include succinimidyl succinate (SS), succinimidyl carbonate (SC), mPEG-imidate, p-nitrophenyl carbonate (NPC), succinimidyl propionate (SPA), and cyanuric chloride. Non-limiting examples of such mPEGs include mPEG-succinimidyl succinate (mPEG-SS), mPEG ₂ -succinimidyl succinate (mPEG ₂ -SS); mPEG-succinimidyl carbonate (mPEG-SC), mPEG ₂ -succinimidyl carbonate (mPEG ₂ -SC); mPEG-imidate, mPEG-p-nitrophenyl carbonate (mPEG-NPC), mPEG-imidate; mPEG ₂ -p-nitrophenyl carbonate (mPEG ₂ -NPC); mPEG-succinimidyl propionate (mPEG-SPA); mPEG ₂ -succinimidyl propionate (mPEG ₂ -SPA); mPEG-N-hydroxy-succinimide (mPEG-NHS); mPEG ₂ -N-hydroxy-succinimide (mPEG ₂ -NHS); mPEG-cyanuric chloride; mPEG ₂ -cyanuric chloride; mPEG ₂ -lysine-NPC and mPEG ₂ -Lys-NHS.

Generally, at least one PEG chain comprising a PEG unit is functionalized so that it can be covalently linked to other linker unit components.

Functionalization includes, for example, via an amine, thiol, NHS ester, maleimide, alkyne, azide, carbonyl, or another functional group. In some embodiments, the PEG unit further comprises a non-PEG material (i.e., a material that does not _{comprise -CH2CH2O-} ) that provides coupling to other Linker unit components or facilitates coupling of two or more PEG chains.

The presence of a PEG unit (or other spacer) in a linker unit can have two potential effects on the pharmacokinetics of the resulting ligand-drug conjugate. The desired effect is a decrease in clearance (and subsequent increase in exposure) resulting from a reduction in nonspecific interactions induced by either the exposed hydrophobic elements of the ligand-drug conjugate or the drug unit itself. The second effect is undesirable and is a decrease in size and distribution rate, which is sometimes caused by an increase in the molecular weight of the ligand-drug conjugate.

Increasing the number of PEG subunits increases the hydrodynamic radius of the conjugate, typically resulting in a decrease in diffusion rate. In turn, decreased diffusivity typically decreases the ability of the ligand-drug conjugate to penetrate the tumor (Schmidt and Wittrup, Mol Cancer Ther 2009;8:2861-2871). Because of these two competing pharmacokinetic effects, it may be necessary to use a PEG that is large enough to reduce the clearance of the ligand-drug conjugate, thereby increasing plasma exposure, but not so large as to greatly reduce its diffusivity to the point where it interferes with the ability of the ligand-drug conjugate to reach the intended target cell population. For methods for selecting the optimal PEG size for a particular drug-linker, see the examples of US2016/0310612 (e.g., Examples 1, 18, and 21), which are incorporated herein by reference.

In one set of embodiments, the PEG unit comprises one or more linear PEG chains, each linear PEG chain having at least 2 subunits, at least 3 subunits, at least 4 subunits, at least 5 subunits, at least 6 subunits, at least 7 subunits, at least 8 subunits, at least 9 subunits, at least 10 subunits, at least 11 subunits, at least 12 subunits, at least 13 subunits, at least 14 subunits, at least 15 subunits, at least 16 subunits, at least 17 subunits, at least 18 subunits, at least 19 subunits, at least 20 subunits, at least 21 subunits, at least 22 subunits, at least 23 subunits, or at least 24 subunits. In some embodiments, the PEG unit comprises a combined total of at least 4 subunits, at least 6 subunits, at least 8 subunits, at least 10 subunits, or at least 12 subunits. In some such embodiments, the PEG unit comprises no more than about 72 subunits in total, preferably no more than about 36 subunits in total.

In one set of embodiments, the PEG unit comprises one or more linear PEG chains, each linear PEG chain having 2 subunits, 3 subunits, 4 subunits, 5 subunits, 6 subunits, 7 subunits, 8 subunits, 9 subunits, 10 subunits, 11 subunits, 12 subunits, 13 subunits, 14 subunits, 15 subunits, 16 subunits, 17 subunits, 18 subunits, 19 subunits, 20 subunits, 21 subunits, 22 subunits, 23 subunits, or 24 subunits. In some embodiments, the PEG unit comprises a combined total of 4 subunits, 6 subunits, 8 subunits, 10 subunits, or 12 subunits. In some such embodiments, the PEG unit contains no more than about 72 combined total subunits, preferably no more than about 36 combined total subunits.

In another set of embodiments, the PEG unit comprises a combined total of 4 to 72, 4 to 60, 4 to 48, 4 to 36, or 4 to 24 subunits, 5 to 72, 5 to 60, 5 to 48, 5 to 36, or 5 to 24 subunits, 6 to 72, 6 to 60, 6 to 48, 6 to 36, or 6 to 24 subunits, 7 to 72, 7 to 60, 7 to 48, 7 to 36, or 7 to 24 subunits, 8 to 72, 8 to 60, 8 to 48, 8 to 36, or 8 to 24 subunits, 9 to 72, 9 to 60, 9 to 48, 9 to 36 or 9 to 24 subunits, 10 to 72, 10 to 60, 10 to 48, 10 to 36 or 10 to 24 subunits, 11 to 72, 11 to 60, 11 to 48, 11 to 36 or 11 to 24 subunits, 12 to 72, 12 to 60, 12 to 48, 12 to 36 or 12 to 24 subunits, 13 to 72, 13 to 60, 13 to 48, 13 to 36 or 13 to 24 subunits, 14 to 72, 14 to 60, 14 to 48, 14 18-72, 18-60, 18-48, 18-36 or 18-24 subunits; 19-72, 19-60, 19-48, 19-36 or 19-24 subunits; 20-24-36, ... 9 to 24 subunits, 20 to 72, 20 to 60, 20 to 48, 20 to 36 or 20 to 24 subunits, 21 to 72, 21 to 60, 21 to 48, 21 to 36 or 21 to 24 subunits, 22 to 72, 22 to 60, 22 to 48, 22 to 36 or 22 to 24 subunits, 23 to 72, 23 to 60, 23 to 48, 23 to 36 or 23 to 24 subunits or 24 to 72, 24 to 60, 24 to 48, 24 to 36 or 24 subunits.

In some embodiments, the spacer S* is a linear PEG unit comprising 2 to 20 or 2 to 12 or 4 to 12 or 4, 8 or _{12 -CH2CH2O-} subunits. In some embodiments, the linear PEG unit is linked to a RL unit at one end of the PEG unit and to a stretcher/linker unit (ZA-) at the other end of the PEG unit. In some embodiments, the PEG unit is linked to the RL unit via a _-CH2CH2C (O)- group, which forms an amide bond with the RL unit (e.g., -( _CH2CH2O ) _{n - CH2CH2C} (O) _{-RL )} , and is linked to the Stretcher unit/Linker unit (ZA-) via a -NH- group, which forms an amide bond with the ZA- portion (e.g., _ZA -NH-( _CH2CH2O ) _n- ).

An illustrative embodiment of a PEG unit connected to a RL and an extension/connector unit (ZA-) is shown below: , and in a specific embodiment, the PEG unit is: , wherein the wavy line on the left indicates the attachment site to ZA-, the wavy line on the right indicates the attachment site to RL, and each b is independently selected from 2 to 72, 4 to 72, 6 to 72, 8 to 72, 10 to 72, 12 to 72, 2 to 24, 4 to 24, 6 to 24 or 8 to 24, 2 to 12, 4 to 12, 6 to 12, and 8 to 12. In some embodiments, subscript b is 2, 4, 8, 12, or 24. In some embodiments, subscript b is 2. In some embodiments, subscript b is 4. In some embodiments, subscript b is 8. In some embodiments, subscript b is 12.

In some embodiments, a linear PEG unit is linked to a parallel linker unit at one end and comprises a terminal cap at the other end. In some embodiments, a PEG unit is linked to a parallel linker unit via a carbonyl group that forms an amide bond with a parallel linker unit lysine residue amine group (e.g. _{, -CH2CH2} ( _{OCH2CH2 ) k} -C(O)-B-, wherein k is an integer from 1 to 36), and comprises a PEG unit terminal capping group selected from the group consisting of _C1-4 alkyl and _C1-4 alkyl- _CO2H . In some embodiments, a spacer S* is a linear PEG unit comprising 4, 8, or 12 _-CH2CH2O- subunits and a terminal _methyl cap.

Illustrative linear PEG units for use in any of the examples provided herein are as follows: And in a specific embodiment, the PEG unit is: , wherein the wavy lines indicate connection sites with the parallel connector unit (B), and each n is independently selected from 4 to 72, 6 to 72, 8 to 72, 10 to 72, 12 to 72, 6 to 24, or 8 to 24. In some embodiments, the subscript b is about 4, about 8, about 12, or about 24.

As used herein, the terms "PEG2", "PEG4", "PEG8", and "PEG12" refer to specific embodiments of PEG units that include the number of PEG subunits (i.e., the number of subscript "b"). For example, "PEG2" refers to an embodiment of a PEG unit that includes 2 PEG subunits, "PEG4" refers to an embodiment of a PEG unit that includes 4 PEG subunits, "PEG8" refers to an embodiment of a PEG unit that includes 8 PEG subunits, and "PEG12" refers to an embodiment of a PEG unit that includes 12 PEG subunits.

As described herein, the PEG unit is selected so that it improves the clearance rate of the resulting ligand-drug conjugate, but does not significantly affect the ability of the conjugate to penetrate the tumor. In embodiments, the PEG unit to be selected for use will preferably have 2 subunits to about 24 subunits, 4 subunits to about 24 subunits, and more preferably about 4 subunits to about 12 subunits.

In some embodiments of the present disclosure, the PEG unit is about 300 daltons to about 5 kilodaltons; about 300 daltons to about 4 kilodaltons; about 300 daltons to about 3 kilodaltons; about 300 daltons to about 2 kilodaltons; or about 300 daltons to about 1 kilodaltons. In some such embodiments, the PEG unit has at least 6 subunits or at least 8, 10, or 12 subunits. In some such aspects, the PEG unit has at least 6 subunits or at least 8, 10, or 12 subunits, but no more than 72 subunits, preferably no more than 36 subunits.

It should be understood that when referring to PEG subunits, and depending on the context, the number of subunits may represent an average number, for example, when referring to a population of ligand-drug conjugates or drug-linker compounds, and/or when polydisperse PEG is used. Parallel Linker Units (B)

In some embodiments, the ligand-drug conjugate and drug-linker compounds will include a parallel linker unit to provide a point of attachment to a spacer (shown as -B(S ^* )- in the linker unit). In some embodiments, a PEG unit is linked to a parallel linker unit (such as lysine), as shown below, where the wavy line and asterisk indicate a covalent bond within the linker unit of the ligand-drug conjugate or drug-linker compound: .

In some embodiments, the parallel connector unit (B) and separator (S*) (together, -B(S ^* )-) have the following structure: wherein m ranges from 0 to 6; n ranges from 2 to 24; R ^PEG is a PEG end-capping unit, preferably H, -CH ₃ or -CH ₂ CH ₂ CO ₂ H, the asterisk (*) indicates a covalent connection to the corresponding linker unit A in formula Za, Za', Zb' or Zc' and the wavy line indicates a covalent connection to a releasable linker (RL). In some embodiments, the structure is connected to the linker unit A in formula Za or Za'. In some embodiments, n is 2, 4, 8 or 12. In cases such as those shown here, the PEG groups shown are intended to exemplify a variety of spacers, including PEG groups of different lengths and other spacers directly connected or modified to connect to parallel linker units. Second Spacer Unit (Y)

In some embodiments, the ligand-drug conjugates provided herein will have a second spacer (Y) between the releasable linker (RL) and the drug unit. The second spacer unit is a functional group that facilitates the attachment of the RL to the drug unit, or provides an additional structural component to further facilitate the release of the drug unit from the rest of the conjugate (e.g., a methylene carbamate unit or a self-immolative p-aminobenzyl (PAB) component).

In those embodiments that further promote the release of the drug unit as a free drug, the second spacer unit Y is represented by one of the following formulas: , , or wherein EWG represents an electron withdrawing group and the wavy line indicates the site of attachment to the rest of the drug-linker compound or its salt. In some embodiments, EWG is selected from the group consisting of CN, NO ₂ , CX ₃ , X, C(=O)OR', C(=O)N(R') ₂ , C(=O)R', C(=O)X, S(=O) ₂ R', S(=O) ₂ OR', S(=O) ₂ NHR', S(=O) ₂ N(R') ₂ , P(=O)(OR') ₂ , P(=O)(CH ₃ )NHR', NO, N(R') ₃ ⁺ , wherein X is F, Br, Cl or I, and R' is independently selected from the group consisting of hydrogen and C ₁ -C ₆ alkyl.

In some embodiments, the second Spacer unit-Drug unit group (-YT*-D) is represented by one of the following formulas: , wherein the adjacent wavy lines are the points of covalent attachment to RL, T* is as defined above, and D' represents the remainder of the drug unit, wherein T* and D' together form a drug unit of Formula (Ia) or any subformula thereof.

In some embodiments, the second spacer unit is represented by the formula: Wherein the wavy line adjacent to the nitrogen atom is the covalent attachment point to RL, as defined above, and the wavy line adjacent to the benzyl carbon atom is attached to the drug unit. In some embodiments, the drug unit is attached to the benzyl carbon atom via the quaternary ammonium tertiary amine (N+) of D.

In other embodiments, the second spacer unit is represented by the formula: , wherein the wavy line adjacent to the nitrogen atom is the point of covalent attachment to RL, as defined above, and the wavy line adjacent to the -OC(O)- group is attached to the drug unit. In some embodiments, the drug unit is attached via a primary amine or a secondary amine.

In some embodiments, provided herein are the drug-linker compounds or salts thereof of Table 2. Table 2. Exemplary drug-linker compounds Ligand-drug conjugate compounds

In another aspect, the present disclosure provides ligand-drug conjugate compounds (LDCs) comprising a portion of the STING agonists of the present disclosure. In the context of ligand-drug conjugate compounds, the assembly is described by the component groups as described for drug-linker compounds, with the exception of Stretcher unit Z and Ligand unit L. Stretcher unit Z is coordinated with Ligand unit L in the ligand-drug conjugate compound, as described below. Although some procedures for preparing ligand-drug conjugate compounds are described herein, the assembly order and general conditions for preparing such compounds should be fully understood by those skilled in the art.

In some embodiments, the ligand-drug conjugate compounds disclosed herein comprise a STING agonist compound of formula (I) or any subformula thereof, a linker unit (Q) comprising a releasable linker (RL) other than a glycoside (e.g., glucuronide) unit, and a ligand unit (L) through which the ligand unit is linked to the bound STING agonist compound. In addition to the RL, the linker unit also comprises a stretcher unit (Z) linked to the ligand unit and capable of linking (directly or indirectly) the RL to the ligand unit. In some embodiments, when it is desired to add a spacer (S ^* ) as a side chain appendage, a parallel linker unit (B) is present. In any of those embodiments, when more distance needs to be added between the extension unit and the RL, a connector unit (A) is present.

In some embodiments, the ligand-drug conjugate compound comprises a STING agonist compound of Formula (I) or any subformula thereof and a Linker unit (Q), wherein Q comprises a releasable Linker (RL) that is a glycoside (e.g., glucuronide) unit, which is directly linked to a Stretcher unit (Z) or indirectly linked to Z via an intervening component (i.e., A, S ^* and/or B(S ^* )) that is linked to the Linker unit of the ligand-drug conjugate compound, wherein Z forms a covalent bond with the targeting agent ( e.g. , Ligand unit).

In another set of embodiments, the ligand-drug conjugate compound comprises a STING agonist of Formula (I) or any subformula thereof, a Linker unit (Q), wherein Q comprises a releasable Linker (RL) other than a glycoside (e.g., glucuronide) unit (RL), the releasable Linker being directly linked to a Stretcher unit (Z) or indirectly linked to Z via an intervening component (i.e., A, S ^* and/or B(S ^* )) linked to the Linker unit of the ligand-drug conjugate compound, wherein Z forms a covalent bond with a targeting agent ( e.g. , a Ligand unit).

In some embodiments, the ligand-drug conjugate compound has the formula: L-(QD) _p or a pharmaceutically acceptable salt thereof, wherein L is a ligand unit; Q is a linker unit selected from the group consisting of: (i) ZA-RL-, (ii) ZA-RL-Y-, (iii) ZAS ^* -RL-, (iv) ZAS ^* -RL-Y-, (v) ZAB(S ^* )-RL-, (vi) ZAB(S ^* )-RL-Y-, (vii) ZA-, (viii) ZAS*-W-, (ix) ZAB(S*)-W-, (x) ZAS*-W-RL-, and (xi) ZAB(S*)-W-RL-; Z is a stretcher unit; A is a bond or linker unit; B is a parallel linker unit; S* is a spacer; RL is a releasable linker; W is an amino acid unit; Y is a second spacer unit; and D is a drug unit of formula (A'): , Formula (A') wherein X ¹ is N or CR ^1X ; Y ¹ is N or CR ^1Y ; Z ¹ , Y ² and Z ² are each independently N, CH or CF; X ² is N or CR ^2X ; X ³ is N or CR ^3X ; T ⁴ is N, S, O or CH; X ⁴ is C or N; Y ⁴ is N, NR ^4Y or CR ^4Y ; Z ⁴ is N, S, O, CF or CH; R ¹ is C ₁ -C ₆ alkyl, C ₃ -C ₈ cycloalkyl or C ₁ -C ₆ halogenalkyl; wherein at least one of X ¹ , Y ¹ and X ³ is not N; R ^1X , R ^1Y and R ^3X are each independently H, -OH, halogen, optionally substituted C ₁ -C ₆ alkyl, -O(C ₁ -C ₆ alkyl) or -S ¹ -#, with the proviso that exactly one of R ^1X , R ^1Y and R ^3X is -S ¹ -#, -S ¹ -# is , , or , wherein the wavy line indicates the point of attachment to the remainder of D and # represents the point of attachment to Q; ^Xc is H, halogen, or optionally substituted _C1 - _C6 alkyl; q is an integer from 0 to 6; n is 0, 1 or 2; m is 1 or 2; ^R8 and ^R9 are each independently H, ^halogen , CN, SH, OH, _-CO2H , ^NR4R5 , or _C1 - _C6 alkyl optionally substituted with -OH, halogen, or ^-CO2H ; ^R10 is ^C1 _{-C6 alkyl} optionally substituted with OH, halogen, ^NR4R5 , or _CO2R4 , or ^R10 is absent; ^R2X is H, halogen, _C1 - _C6 alkyl, _{C3 -C6 cycloalkyl} , or _C1 - _C6 halogenalkyl; R ^4Y is H, halogen, C ₁ -C ₆ alkyl, C ₁ -C ₆ halogenalkyl or C ₃ -C ₆ cycloalkyl; T is -C(O)NR ⁴ R ⁵ or -S(O) ₂ NR ⁶ R ⁷ ; R ⁴ , R ⁵ , R ⁶ and R ⁷ are independently H or optionally substituted C ₁ -C ₆ alkyl at each occurrence; the virtual bonds of formula (A') are each independently single or double bonds, so that the ring with the virtual bonds is an aromatic ring; Ring A is , or , where the wavy line indicates the point of attachment to the rest of the compound; The restriction is that when L ¹ is , Ring A is , X ¹ is CR ^1X , Y ¹ is CH , Z ¹ is CH , Z ² is CH , and X ² is N , then T ⁴ , X ⁴ , Y ⁴ , Z ⁴ and R ¹ cannot be simultaneously selected such that T ⁴ is CH , X ⁴ is C , Y ⁴ is NR ^4Y , Z ⁴ is N , and R ¹ is an optionally substituted methyl group ; and p is an integer ranging from 1 to 12.

In some embodiments, the ligand-drug conjugate compound has the formula: L-(QD) _p or a pharmaceutically acceptable salt thereof, wherein L is a ligand unit; Q is a linker unit selected from the group consisting of: (i) ZA-RL-, (ii) ZA-RL-Y-, (iii) ZAS ^* -RL-, (iv) ZAS ^* -RL-Y-, (v) ZAB(S ^* )-RL-, (vi) ZAB(S ^* )-RL-Y-, (vii) ZA-, (viii) ZAS*-W-, (ix) ZAB(S*)-W-, (x) ZAS*-W-RL-, and (xi) ZAB(S*)-W-RL-; Z is a stretcher unit; A is a bond or linker unit; B is a parallel linker unit; S* is a spacer; RL is a releasable linker; W is an amino acid unit; Y is a second spacer unit; and D is a drug unit of formula (I'): , Formula (I') wherein X ¹ is N or CR ^1X ; Y ¹ is N or CR ^1Y ; Z ¹ , Y ² and Z ² are each independently N, CH or CF; X ² is N or CR ^2X ; X ³ is N or CR ^3X ; T ⁴ is N, S, O or CH; X ⁴ is C or N; Y ⁴ is N, NR ^4Y or CR ^4Y ; Z ⁴ is N, S, O, CF or CH; R ¹ is C ₁ -C ₆ alkyl, C ₃ -C ₈ cycloalkyl or C ₁ -C ₆ halogenalkyl; wherein at least one of X ¹ , Y ¹ and X ³ is not N; R ^1X , R ^1Y and R ^3X are each independently H, -OH, halogen, optionally substituted C ₁ -C ₆ alkyl, -O(C ₁ -C ₆ alkyl) or -S ¹ -#, with the proviso that exactly one of R ^1X , R ^1Y and R ^3X is -S ¹ -#, -S ¹ -# is , , or , wherein the wavy line indicates the point of attachment to the remainder of D and # represents the point of attachment to Q; ^Xc is H, halogen, or optionally substituted _C1 - _C6 alkyl; q is an integer from 0 to 6; n is 0, 1 or 2; m is 1 or 2; ^R8 and ^R9 are each independently H, ^halogen , CN, SH, OH, _-CO2H , ^NR4R5 , or _C1 - _C6 alkyl optionally substituted with -OH, halogen, or ^-CO2H ; ^R10 is ^C1 _{-C6 alkyl} optionally substituted with OH, halogen, ^NR4R5 , or _CO2R4 , or ^R10 is absent; ^R2X is H, halogen, _C1 - _C6 alkyl, _{C3 -C6 cycloalkyl} , or _C1 - _C6 halogenalkyl; R ^4Y is H, halogen, C ₁ -C ₆ alkyl, C ₁ -C ₆ halogenalkyl or C ₃ -C ₆ cycloalkyl; T is -C(O)NR ⁴ R ⁵ or -S(O) ₂ NR ⁶ R ⁷ ; R ⁴ , R ⁵ , R ⁶ and R ⁷ are independently and independently H or optionally substituted C ₁ -C ₆ alkyl at each occurrence; the virtual bonds of formula (I') are each independently single or double bonds, so that the ring with the virtual bonds is an aromatic ring; Ring A is , or , where the wavy line indicates the point of attachment to the rest of the compound; the restriction is that when Ring A is , X ¹ is CR ^1X , Y ¹ is CH , Z ¹ is CH , Z ² is CH , and X ² is N , then T ⁴ , X ⁴ , Y ⁴ , Z ⁴ and R ¹ cannot be simultaneously selected such that T ⁴ is CH , X ⁴ is C , Y ⁴ is NR ^4Y , Z ⁴ is N , and R ¹ is an optionally substituted methyl group ; and p is an integer ranging from 1 to 12.

In some embodiments, provided herein are ligand-drug conjugate compounds of formula L-(QD) _p , wherein the drug unit D has formula (IIa*): , Formula (IIa*) wherein the variables are as defined for Formula (I'); wherein at least one of ^X1 , ^Y1 and ^X3 is not N; and the virtual bonds of Formula (IIa*) are each independently single or double bonds, such that the rings with the virtual bonds are aromatic rings.

In some embodiments, provided herein are ligand-drug conjugate compounds of formula L-(QD) _p , wherein the drug unit D has formula (IIIa*): , Formula (IIIa*) wherein the variables are as defined for Formula (I'); wherein at least one of X ¹ , Y ¹ and X ³ is not N; and the virtual bonds of Formula (IIIa*) are each independently single bonds or double bonds, such that the rings with the virtual bonds are aromatic rings; with the restriction that when X ¹ is CR ^1X , Y ¹ is CH, Z ¹ is CH, Z ² is CH, and X ² is N, then T ⁴ , X ⁴ , Y ⁴ , Z ⁴ and R ¹ cannot be simultaneously selected such that T ⁴ is CH, X ⁴ is C, Y ⁴ is NR ^4Y , Z ⁴ is N, and R ¹ is an optionally substituted methyl group.

In some embodiments, provided herein are ligand-drug conjugate compounds of formula L-(QD) _p , wherein the drug unit D has the formula (IVa*): , Formula (IVa*) wherein the variables are as defined for Formula (I'); wherein at least one of ^X1 , ^Y1 and ^X3 is not N; and the virtual bonds of Formula (IVa*) are each independently single or double bonds, such that the rings bearing the virtual bonds are aromatic rings.

In some embodiments, provided herein are ligand-drug conjugate compounds of formula L-(QD) _p , wherein the drug unit D has formula (IIb*): , Formula (IIb*) wherein Y ¹ is N or CR ^1Y ; X ³ is N or CR ^3X ; R ^1Y and R ^3X are each independently H, -OH, halogen, optionally substituted C ₁ -C ₆ alkyl or -O(C ₁ -C ₆ alkyl); R ^1X is -S ¹ -#, -S ¹ -# is , , or , wherein the wavy line indicates the point of attachment to the remainder of D and # indicates the point of attachment to Q; wherein the remaining variables are as defined for formula (I'); and the virtual bonds of formula (IIb*) are each independently a single bond or a double bond, such that the rings bearing the virtual bonds are aromatic rings.

In some embodiments, provided herein are ligand-drug conjugate compounds of formula L-(QD) _p , wherein the drug unit D has formula (IIIb*): , Formula (IIIb*) wherein Y ¹ is N or CR ^1Y ; X ³ is N or CR ^3X ; R ^1Y and R ^3X are each independently H, -OH, halogen, optionally substituted C ₁ -C ₆ alkyl or -O(C ₁ -C ₆ alkyl); R ^1X is -S ¹ -#, -S ¹ -# is , , or , wherein the wavy line indicates the point of connection with the rest of D and # represents the point of connection with Q; wherein the remaining variables are as defined for formula (I'); and the virtual bonds of formula (IIIb*) are each independently single bonds or double bonds, such that the rings with the virtual bonds are aromatic rings; with the restriction that when Y ¹ is CH, Z ¹ is CH, Z ² is CH, and X ² is N, then T ⁴ , X ⁴ , Y ⁴ , Z ⁴ and R ¹ cannot be simultaneously selected such that T ⁴ is CH, X ⁴ is C, Y ⁴ is NR ^4Y , Z ⁴ is N, and R ¹ is an optionally substituted methyl group.

In some embodiments, provided herein are ligand-drug conjugate compounds of formula L-(QD) _p , wherein the drug unit D has the formula (IVb*): , Formula (IVb*) wherein Y ¹ is N or CR ^1Y ; X ³ is N or CR ^3X ; R ^1Y and R ^3X are each independently H, -OH, halogen, optionally substituted C ₁ -C ₆ alkyl or -O(C ₁ -C ₆ alkyl); R ^1X is -S ¹ -#, -S ¹ -# is , , or , wherein the wavy line indicates the point of attachment to the remainder of D and # indicates the point of attachment to Q; wherein the remaining variables are as defined for formula (I'); and the virtual bonds of formula (IVb*) are each independently a single bond or a double bond, such that the ring bearing the virtual bonds is an aromatic ring.

In some embodiments, provided herein are ligand-drug conjugate compounds of formula L-(QD) _p , wherein the drug unit D has the formula (IIc*): , Formula (IIc*) wherein X ¹ is N or CR ^1X ; Y ¹ is N or CR ^1Y ; R ^1X and R ^1Y are each independently H, -OH, halogen, optionally substituted C ₁ -C ₆ alkyl or -O(C ₁ -C ₆ alkyl); R ^3X is -S ¹ -#, -S ¹ -# is , , or , wherein the wavy line indicates the point of attachment to the remainder of D and # indicates the point of attachment to Q; wherein the remaining variables are as defined for formula (I'); and the virtual bonds of formula (IIc*) are each independently a single bond or a double bond, such that the ring bearing the virtual bonds is an aromatic ring.

In some embodiments, provided herein are ligand-drug conjugate compounds of formula L-(QD) _p , wherein the drug unit D has the formula (IIIc*): , Formula (IIIc*) wherein X ¹ is N or CR ^1X ; Y ¹ is N or CR ^1Y ; R ^1X and R ^1Y are each independently H, -OH, halogen, optionally substituted C ₁ -C ₆ alkyl or -O(C ₁ -C ₆ alkyl); R ^3X is -S ¹ -#, -S ¹ -# is , , or , wherein the wavy line indicates the point of attachment to the remainder of D and # indicates the point of attachment to Q; wherein the remaining variables are as defined for formula (I'); and the virtual bonds of formula (IIIc*) are each independently a single bond or a double bond, such that the rings bearing the virtual bonds are aromatic rings.

In some embodiments, provided herein are ligand-drug conjugate compounds of formula L-(QD) _p , wherein the drug unit D has the formula (IVc*): , Formula (IVc*) wherein X ¹ is N or CR ^1X ; Y ¹ is N or CR ^1Y ; R ^1X and R ^1Y are each independently H, -OH, halogen, optionally substituted C ₁ -C ₆ alkyl or -O(C ₁ -C ₆ alkyl); R ^3X is -S ¹ -#, -S ¹ -# is , , or , wherein the wavy line indicates the point of attachment to the remainder of D and # indicates the point of attachment to Q; wherein the remaining variables are as defined for formula (I'); and the virtual bonds of formula (IVc*) are each independently a single bond or a double bond, such that the ring bearing the virtual bonds is an aromatic ring.

In the context of ligand-drug conjugate compounds - the assembly is best described in terms of its component groups. Although some procedures for preparing ligand-drug conjugate compounds are described herein, those skilled in the art should fully understand the assembly order and general conditions for preparing such compounds. The component groups of the ligand-drug conjugate compounds are in many cases the same as the component groups of the drug-linker compounds described above, including A, B, S*, RL, W, Y and D. It should be understood that the following embodiments are contemplated, in which the drug unit D of the ligand-drug conjugate described herein conforms to the description of formula (I') or any subformula thereof. Other component groups are described below. Stretcher unit Z

Representative extension units of such embodiments include those having the following structures: and , wherein the wavy line adjacent to R ¹⁷ indicates connection to the parallel connector unit (B) or the connector unit (A) (if B is absent), or the separator (S ^* ) (if B is absent), another wavy line indicates covalent connection to the sulfur atom of the ligand unit, and R ¹⁷ is -CH ₂ CH ₂ (OCH ₂ CH ₂ ) _k -, -C ₁ -C ₁₀ alkylene-, C ₁ -C ₁₀ heteroalkylene-, -C ₃ -C ₈ carbocyclyl-, -O-(C ₁ -C ₈ alkylene)-, -arylene-, -C ₁ -C ₁₀ alkylene-arylene-, -arylene-C ₁ -C ₁₀ alkylene-, -C ₁ -C ₁₀ alkylene-(C ₃ -C ₈ carbocyclyl)-, -(C ₃ -C 8 -C ₈ carbocyclyl)-C ₁ -C ₁₀ alkylene-, -C ₃ -C ₈ heterocyclyl-, -C ₁ -C ₁₀ alkylene-(C ₃ -C ₈ heterocyclyl)-, -(C ₃ -C ₈ heterocyclyl)-C 1 -C 10 alkylene-, -C ₁ -C ₁₀ alkylene-C(=O)-, C ₁ -C ₁₀ heteroalkylene-C(=O)-, _{-C 3} -C ₈ carbocyclyl-C(=O)-, -O-(C ₁ -C ₈ alkylene)-C(=O)-, -arylene-C(=O)-, -C ₁ -C ₁₀ alkylene-arylene- _C (=O)-, -arylene-C ₁ -C ₁₀ alkylene-C(=O)-, -C ₁ -C 10 -C ₁₀ alkylene-(C ₃ -C ₈ carbocyclyl)-C(=O)-, -(C ₃ -C ₈ carbocyclyl)-C ₁ -C ₁₀ alkylene-C(=O)-, -C ₃ -C ₈ heterocyclyl-C(=O)-, -C ₁ -C ₁₀ alkylene-(C ₃ -C ₈ heterocyclyl)-C(=O)-, -(C ₃ -C ₈ heterocyclyl)-C ₁ -C ₁₀ alkylene-C(=O)-, -C ₁ -C ₁₀ alkylene-NH-, C ₁ -C ₁₀ heteroalkylene-NH-, -C ₃ -C ₈ carbocyclyl-NH-, -O-(C ₁ -C ₈ alkylene)-NH-, -arylene-NH-, -C ₁ -C 10 -C 1 -C ₁₀ alkylene-arylene-NH-, -arylene-C ₁ -C ₁₀ alkylene-NH-, -C ₁ -C ₁₀ alkylene-(C ₃ -C ₈ carbocyclyl)-NH-, -(C ₃ -C ₈ carbocyclyl)-C ₁ -C ₁₀ alkylene-NH-, -C ₃ -C ₈ heterocyclyl-NH-, -C ₁ -C ₁₀ alkylene-(C ₃ -C ₈ heterocyclyl)-NH-, -(C ₃ -C ₈ heterocyclyl)-C ₁ -C ₁₀ alkylene-NH-, -C ₁ -C ₁₀ alkylene-S-, C ₁ -C ₁₀ heteroalkylene-S-, -C ₃ -C ₈ carbocyclyl-S-, -O-(C ₁ -C 10 -C ₈ alkylene)-S-, -arylene-S-, -C ₁ -C ₁₀ alkylene-arylene-S-, -arylene-C ₁ -C ₁₀ alkylene-S-, -C ₁ -C ₁₀ alkylene-(C ₃ -C ₈ carbocyclyl)-S-, -(C 3 -C ₈ carbocyclyl)-C ₁ -C ₁₀ alkylene-S-, -C ₃ -C ₈ heterocyclyl-S-, -C 1 -C ₁₀ alkylene-(C _{3 -C 8} heterocyclyl)-S-, or -(C _{3 -C 8} heterocyclyl)-C ₁ -C ₁₀ alkylene-S-, wherein the subscript k is an integer ranging from 1 to 36.

In some embodiments, the ^R17 group is optionally substituted with a basic unit (BU), such as an aminoalkyl moiety, for example _- ( _CH2 ) _xNH2 , -( _CH2 ) _xNHRa ^, _and -( _CH2 ) _xNRa2 , wherein the subscript x is an integer from 1 to 4 and each ^Ra is independently selected from the group consisting of _C1-6 alkyl and _C1-6 haloalkyl, or two ^Ra groups are combined with the nitrogen to which they are attached to ^form an azacyclobutane, pyrrolidinyl, or piperidinyl.

Illustrative stretch units are stretch units of formula Za or Za-BU, wherein R ¹⁷ is -CH ₂ CH ₂ (OCH ₂ CH ₂ ) _k -, -C ₁ -C ₁₀ alkylene-C(=O)-, -C ₁ -C ₁₀ heteroalkylene-C(=O)-, -C ₃ -C ₈ carbocyclyl-C(=O)-, -O-(C ₁ -C ₈ alkylene)-C(=O)-, -arylene-C(=O)-, -C ₁ -C ₁₀ alkylene-arylene-C(=O)-, -arylene-C ₁ -C ₁₀ alkylene-C(=O)-, -C ₁ -C ₁₀ alkylene-(C ₃ -C ₈ carbocyclyl)-C(=O)-, -(C ₃ -C ₈ carbocyclyl)-C ₁ -C -C 1 -C ₁₀ alkylene-C(=O)-, -C ₃ -C ₈ heterocycloyl-C(=O)-, -C ₁ -C ₁₀ alkylene-(C ₃ -C ₈ heterocycloyl)-C(=O)-, or -(C ₃ -C ₈ heterocycloyl)-C ₁ -C ₁₀ alkylene-C(=O), wherein the subscript k is an integer ranging from 1 to 36: (Za), (Za-BU), wherein the wavy line adjacent to the carbonyl carbon atom indicates the connection to ^LP , B, A or S ^* in the above formulas, depending on the presence or absence of A and/or B, and another wavy line indicates the covalent bond between the succinimide ring carbon atom and the sulfur atom of the ligand unit. In some embodiments, the basic amine functional group of the basic unit (BU) is protected by a protecting group during synthesis.

In some embodiments, the extended body unit of formula Za and Za-BU is as follows: The wavy line adjacent to the carbonyl carbon atom indicates linkage to B, A or S ^* in the above formulae, depending on the presence or absence of A and/or B, and the other wavy line indicates the covalent bond between the succinimide ring carbon atom and the sulfur atom of the ligand unit.

It is understood that the succinimide substituted with a Ligand unit may exist in a hydrolyzed form. Such forms are exemplified below for the hydrolysis of Za or Za-BU, wherein the structures representing the regioisomers from the hydrolysis have the formula Zb and Zc or Zb-BU and Zc-BU.

Thus, in some embodiments, the Stretcher unit (Z) comprises a succinic acid-amide moiety represented by : (Zb), (Zc), (Zb-BU), (Zc-BU), wherein the wavy line adjacent to the carbon atom of the carbonyl group bonded to R ¹⁷ and the wavy line adjacent to the carbon atom of the succinic acid-amide moiety are as defined for Za or Za-BU, depending on the presence or absence of A and/or B; and R ¹⁷ is -C ₁ -C ₅ alkylene-, wherein in Zb-BU and Zc-BU, the alkylene is substituted with a basic unit (BU), wherein BU is -(CH ₂ ) _x NH ₂ , -(CH ₂ ) _x NHR ^a or -(CH ₂ ) _x N( ^Ra ) ₂ , wherein the subscript x is an integer from 1 to 4 and each ^Ra is independently selected from the group consisting of C _1-6 alkyl and C _1-6 haloalkyl, or two R ^a together with the nitrogen to which it is attached defines an azacyclobutane, pyrrolidinyl or piperidinyl radical.

In some embodiments, -Z-A- comprises a moiety derived from a maleimido-alkanoic acid moiety or an mDPR moiety. See, e.g., WO 2013/173337. In one set of embodiments, Z-A- is derived from a maleimido-propionyl moiety.

In some embodiments, the Stretcher unit (Z) comprises a succinic acid-amide moiety represented by the structure of formula Zb', Zc', (R/S)-Zb'-BU, (S)-Zb'-BU, (R/S)-Zc'-BU or (S)-Zc'-BU, as follows: The waveform is as defined for Za or Za-BU.

In some embodiments, the Stretcher unit (Z) comprises a succinimide moiety represented by the following structure: The succinimide moiety may be derived from a maleimido-amino-propionyl (mDPR) analog (3-amino-2-(2,5-dioxo-2,5-dihydro-1H-pyrrol-1-yl) propionic acid derivative) or comprise a succinimide moiety represented by the following structure: or .

Illustrative stretch units bonded to the linker unit (A) include Za', Zb' or Zc', wherein -R ¹⁷ - of Za, Zb or Zc is -CH ₂ - or -CH ₂ CH ₂ -, or include Za'-BU, Zb'-BU or Zc'-BU, wherein -R ¹⁷ (BU)- of Za'-BU, Zb'-BU or Zc'-BU is -CH(CH ₂ NH ₂ )-, and these stretch units have the following structures: , , , , , , , , where the waveform is as defined for Za or Za-BU.

The other stretcher units bonded to the ligand unit (L) and the connector unit (A) have the above structure, wherein A in any of the above -Za'-A-, -Za'(BU)-A-, -Za'-A-, -Za'(BU)-A-, -Zb'-A-, -Zb'(BU)-A-, -Zb'-A-, -Zb'(BU)-, -Zc'-A-, and Zc'(BU)-A- structures is replaced by a parallel connector unit having the following structure: , wherein subscript m ranges from 1 to 6; n ranges from 8 to 24; R ^PEG is a PEG end-capping unit, preferably H, -CH ₃ or -CH ₂ CH ₂ CO ₂ H, an asterisk (*) indicates covalent attachment to a stretcher unit having a structure corresponding to formula Za, Za', Zb' or Zc' and a wavy line indicates covalent attachment to a releasable linker (RL).

In another embodiment, the Stretcher unit is linked to the Ligand unit via a disulfide bond between the sulfur atom of the Ligand unit and the sulfur atom of the Stretcher unit. A representative Stretcher unit of this embodiment is depicted within the square brackets of Formula Zb: (Zb ) wherein the wavy line indicates connection to a parallel connector unit (B) or a connector unit (A) (if B is absent), or a separator (S ^* ) (if A and B are absent), and R ¹⁷ is -CH ₂ CH ₂ (OCH ₂ CH ₂ ) _k -, -C ₁ -C ₁₀ alkylene-, C ₁ -C ₁₀ heteroalkylene-, -C ₃ -C ₈ carbocyclyl-, -O-(C ₁ -C ₈ alkylene)-, -arylene-, -C ₁ -C ₁₀ alkylene-arylene-, -arylene-C ₁ -C ₁₀ alkylene-, -C ₁ -C ₁₀ alkylene-(C ₃ -C ₈ carbocyclyl)-, -(C ₃ -C ₈ carbocyclyl)-C ₁ -C ₁₀ alkylene-, -C ₃ -C 8 _{-C 1 -C 10} alkylene-(C ₃ -C ₈ heterocyclic group)-, -(C ₃ -C ₈ heterocyclic group)-C ₁ -C ₁₀ alkylene-, -C 1 -C _{10 alkylene-C(=O)-, C 1 -C 10 heteroalkylene -} C(=O)-, -C _{3 -C 8} carbocyclic group-C(=O)-, -O-(C ₁ -C ₈ alkylene)-C(=O)-, -arylene-C(=O)-, -C ₁ -C ₁₀ alkylene-arylene-C(=O)-, -arylene-C ₁ -C ₁₀ alkylene-C(=O)-, -C ₁ -C ₁₀ alkylene-(C ₃ -C 8 heterocyclic group)- -C ₈ carbocyclyl)-C ₁ -C ₁₀ alkylene-C(=O)-, -C ₃ -C ₈ heterocyclyl-C(=O)-, -C ₁ -C ₁₀ alkylene-(C ₃ -C ₈ heterocyclyl)-C(=O)-, -(C _{3 -C 8} heterocyclyl)-C ₁ -C ₁₀ alkylene-C(=O)-, -C ₁ -C ₁₀ alkylene-NH-, C ₁ -C ₁₀ heteroalkylene-NH-, -C ₃ -C ₈ carbocyclyl-NH-, -O-(C ₁ -C ₈ alkylene)-NH-, -arylene-NH- _, -C ₁ -C ₁₀ alkylene-arylene-NH-, -arylene-C _{-C 1} -C ₁₀ alkylene-NH-, -C ₁ -C ₁₀ alkylene-(C ₃ -C ₈ carbocyclyl)-NH-, -(C ₃ -C ₈ carbocyclyl)-C ₁ -C ₁₀ alkylene-NH-, -C ₃ -C ₈ heterocyclyl-NH-, -C ₁ -C ₁₀ alkylene-(C ₃ -C ₈ heterocyclyl)-NH-, -(C ₃ -C ₈ heterocyclyl)-C ₁ -C ₁₀ alkylene-NH-, -C ₁ -C ₁₀ alkylene-S-, C ₁ -C ₁₀ heteroalkylene-S-, -C ₃ -C ₈ carbocyclyl-S-, -O-(C ₁ -C ₈ alkylene)-S-, -arylene-S-, -C ₁ -C 10 -C 1 -C ₁₀ alkylene-arylene-S-, -arylene-C ₁ -C ₁₀ alkylene-S-, -C ₁ -C ₁₀ alkylene-(C ₃ -C ₈ carbocyclyl)-S-, -(C ₃ -C ₈ carbocyclyl)-C ₁ -C ₁₀ alkylene-S-, -C ₃ -C ₈ heterocyclyl-S-, -C ₁ -C ₁₀ alkylene-(C ₃ -C ₈ heterocyclyl)-S-, or -(C ₃ -C ₈ heterocyclyl)-C ₁ -C ₁₀ alkylene-S-, wherein the subscript k is an integer ranging from 1 to 36.

In another embodiment, the reactive group of the Stretcher unit precursor contains a reactive site that can form a bond with a primary or secondary amine group of the Ligand unit. Examples of such reactive sites include, but are not limited to, activated esters, such as succinimidyl esters, 4-nitrophenyl esters, pentafluorophenyl esters, tetrafluorophenyl esters, anhydrides, acid chlorides, sulfonyl chlorides, isocyanates, and isothiocyanates. Representative Stretcher units of this embodiment are depicted in square brackets of Formula Zci, Formula Zcii, and Formula Zciii: ( Zci ) ( Zcii ) (Zciii ) , wherein the wavy line indicates connection to a parallel connector unit (B) or a connector unit (A) (if B is absent), or a separator (S ^* ) (if A and B are absent), and R ¹⁷ is -CH ₂ CH ₂ (OCH ₂ CH ₂ ) _k -, -C ₁ -C ₁₀ alkylene-, C ₁ -C ₁₀ heteroalkylene-, -C ₃ -C ₈ carbocyclyl-, -O-(C ₁ -C ₈ alkylene)-, -arylene-, -C ₁ -C ₁₀ alkylene-arylene-, -arylene-C ₁ -C ₁₀ alkylene-, -C ₁ -C ₁₀ alkylene-(C ₃ -C ₈ carbocyclyl)-, -(C ₃ -C ₈ carbocyclyl)-C ₁ -C ₁₀ alkylene-, -C ₃ -C 8 _{-C 1 -C 10} alkylene-(C ₃ -C ₈ heterocyclic group)-, -(C ₃ -C ₈ heterocyclic group)-C ₁ -C ₁₀ alkylene-, -C 1 -C _{10 alkylene-C(=O)-, C 1 -C 10 heteroalkylene -} C(=O)-, -C _{3 -C 8} carbocyclic group-C(=O)-, -O-(C ₁ -C ₈ alkylene)-C(=O)-, -arylene-C(=O)-, -C ₁ -C ₁₀ alkylene-arylene-C(=O)-, -arylene-C ₁ -C ₁₀ alkylene-C(=O)-, -C ₁ -C ₁₀ alkylene-(C ₃ -C 8 heterocyclic group)- -C ₈ carbocyclyl)-C ₁ -C ₁₀ alkylene-C(=O)-, -C ₃ -C ₈ heterocyclyl-C(=O)-, -C ₁ -C ₁₀ alkylene-(C ₃ -C ₈ heterocyclyl)-C(=O)-, -(C _{3 -C 8} heterocyclyl)-C ₁ -C ₁₀ alkylene-C(=O)-, -C ₁ -C ₁₀ alkylene-NH-, C ₁ -C ₁₀ heteroalkylene-NH-, -C ₃ -C ₈ carbocyclyl-NH-, -O-(C ₁ -C ₈ alkylene)-NH-, -arylene-NH- _, -C ₁ -C ₁₀ alkylene-arylene-NH-, -arylene-C _{-C 1} -C ₁₀ alkylene-NH-, -C ₁ -C ₁₀ alkylene-(C ₃ -C ₈ carbocyclyl)-NH-, -(C ₃ -C ₈ carbocyclyl)-C ₁ -C ₁₀ alkylene-NH-, -C ₃ -C ₈ heterocyclyl-NH-, -C ₁ -C ₁₀ alkylene-(C ₃ -C ₈ heterocyclyl)-NH-, -(C ₃ -C ₈ heterocyclyl)-C ₁ -C ₁₀ alkylene-NH-, -C ₁ -C ₁₀ alkylene-S-, C ₁ -C ₁₀ heteroalkylene-S-, -C ₃ -C ₈ carbocyclyl-S-, -O-(C ₁ -C ₈ alkylene)-S-, -arylene-S-, -C ₁ -C 10 -C 1 -C ₁₀ alkylene-arylene-S-, -arylene-C ₁ -C ₁₀ alkylene-S-, -C ₁ -C ₁₀ alkylene-(C ₃ -C ₈ carbocyclyl)-S-, -(C ₃ -C ₈ carbocyclyl)-C ₁ -C ₁₀ alkylene-S-, -C ₃ -C ₈ heterocyclyl-S-, -C ₁ -C ₁₀ alkylene-(C ₃ -C ₈ heterocyclyl)-S-, or -(C ₃ -C ₈ heterocyclyl)-C ₁ -C ₁₀ alkylene-S-, wherein the subscript k is an integer ranging from 1 to 36.

In other embodiments, the reactive group of the Stretcher unit prodriver contains a reactive nucleophilic reagent that is capable of reacting with an electrophilic reagent present on or introduced into the Ligand unit. For example, in some embodiments, a reagent such as sodium periodate is used to moderately oxidize the carbohydrate moiety on the targeting ligand, and the resulting electrophilic functional group (-CHO) of the oxidized carbohydrate is condensed with the Stretcher unit prodriver, which contains a reactive nucleophilic reagent such as a hydrazine, an oxime, a primary or secondary amine, a hydrazine, a thiosemicarbazide, a carboxylic acid hydrazine, or an aryl hydrazine, such as those described by Kaneko, T. et al. (1991) Bioconjugate Chem. 2:133-41. Representative extension units of this embodiment are depicted within the square brackets of Formulas Zdi, Zdii, and Zdiii: ( Zdi ) ( Zdii ) (Zdiii ) , wherein the wavy line indicates connection to a parallel connector unit (B) or a connector unit (A), or a separator (S ^* ) (if A and B are not present), and R ¹⁷ is -CH ₂ CH ₂ (OCH ₂ CH ₂ ) _k -, -C ₁ -C ₁₀ alkylene-, C ₁ -C ₁₀ heteroalkylene-, -C ₃ -C ₈ carbocyclyl-, -O-(C ₁ -C ₈ alkylene)-, -arylene-, -C ₁ -C ₁₀ alkylene-arylene-, -arylene-C ₁ -C ₁₀ alkylene-, -C ₁ -C ₁₀ alkylene-(C ₃ -C ₈ carbocyclyl)-, -(C ₃ -C ₈ carbocyclyl)-C ₁ -C ₁₀ alkylene-, -C ₃ -C 8 _{-C 1 -C 10} alkylene-(C ₃ -C ₈ heterocyclic group)-, -(C ₃ -C ₈ heterocyclic group)-C ₁ -C ₁₀ alkylene-, -C 1 -C _{10 alkylene-C(=O)-, C 1 -C 10 heteroalkylene -} C(=O)-, -C _{3 -C 8} carbocyclic group-C(=O)-, -O-(C ₁ -C ₈ alkylene)-C(=O)-, -arylene-C(=O)-, -C ₁ -C ₁₀ alkylene-arylene-C(=O)-, -arylene-C ₁ -C ₁₀ alkylene-C(=O)-, -C ₁ -C ₁₀ alkylene-(C ₃ -C 8 heterocyclic group)- -C ₈ carbocyclyl)-C ₁ -C ₁₀ alkylene-C(=O)-, -C ₃ -C ₈ heterocyclyl-C(=O)-, -C ₁ -C ₁₀ alkylene-(C ₃ -C ₈ heterocyclyl)-C(=O)-, -(C _{3 -C 8} heterocyclyl)-C ₁ -C ₁₀ alkylene-C(=O)-, -C ₁ -C ₁₀ alkylene-NH-, C ₁ -C ₁₀ heteroalkylene-NH-, -C ₃ -C ₈ carbocyclyl-NH-, -O-(C ₁ -C ₈ alkylene)-NH-, -arylene-NH- _, -C ₁ -C ₁₀ alkylene-arylene-NH-, -arylene-C _{-C 1} -C ₁₀ alkylene-NH-, -C ₁ -C ₁₀ alkylene-(C ₃ -C ₈ carbocyclyl)-NH-, -(C ₃ -C ₈ carbocyclyl)-C ₁ -C ₁₀ alkylene-NH-, -C ₃ -C ₈ heterocyclyl-NH-, -C ₁ -C ₁₀ alkylene-(C ₃ -C ₈ heterocyclyl)-NH-, -(C ₃ -C ₈ heterocyclyl)-C ₁ -C ₁₀ alkylene-NH-, -C ₁ -C ₁₀ alkylene-S-, C ₁ -C ₁₀ heteroalkylene-S-, -C ₃ -C ₈ carbocyclyl-S-, -O-(C ₁ -C ₈ alkylene)-S-, -arylene-S-, -C ₁ -C 10 -C 1 -C ₁₀ alkylene-arylene-S-, -arylene-C ₁ -C ₁₀ alkylene-S-, -C ₁ -C ₁₀ alkylene-(C ₃ -C ₈ carbocyclyl)-S-, -(C ₃ -C ₈ carbocyclyl)-C ₁ -C ₁₀ alkylene-S-, -C ₃ -C ₈ heterocyclyl-S-, -C ₁ -C ₁₀ alkylene-(C ₃ -C ₈ heterocyclyl)-S-, or -(C ₃ -C ₈ heterocyclyl)-C ₁ -C ₁₀ alkylene-S-, wherein the subscript k is an integer ranging from 1 to 36.

In some embodiments, the Q linker unit of the ligand-drug conjugate compound constitutes a non-cleavable linker unit. In some such embodiments in which the drug moiety is linked to the thiol group of the cysteine of the ligand unit of the ligand-drug conjugate via the non-cleavable linker unit, the ligand-drug conjugate releases the drug moiety in the form of a metabolic drug-linker cysteine adduct. In some such embodiments, the released drug-linker cysteine adduct compound is a compound of Table 3. Contemplated released drug-linker cysteine adduct compounds correspond to compounds of Table 3, but have a succinate-amide moiety in place of the succinimide moiety. Table 3. Released drug - linker cysteine adduct compounds

In some embodiments, provided herein are ligand-drug conjugate compounds of Table 4 or pharmaceutically acceptable salts thereof. Contemplated ligand-drug conjugate compounds correspond to compounds of Table 4, but have a succinic acid-amide moiety in place of the succinimide moiety. Table 4. Ligand-drug conjugate compounds Subscript " p "

In one set of embodiments of the invention, the subscript p represents the number of drug linker moieties on the Ligand unit of an individual ligand-drug conjugate compound and is an integer ranging from 1 to 16, 1 to 12, 1 to 10, or 1 to 8. In any of the embodiments herein, there are 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, or 16 drug linker moieties bound to the Ligand unit of an individual ligand-drug conjugate compound.

In some embodiments, any of the structures and descriptions as described herein represent a population of individual ligand-drug conjugate compounds that are substantially identical except for the number of drug-linker moieties (i.e., ligand-drug conjugate compositions) bound to each ligand unit, such that the subscript p represents the average number of drug-linker moieties bound to the ligand units of the ligand-drug conjugate compositions. In such sets of embodiments, the subscript p is a number ranging from 1 to about 16, 1 to about 12, 1 to about 10, or 1 to about 8, 2 to about 16, 2 to about 12, 2 to about 10, or 2 to about 8. In some embodiments, p is about 2. In some embodiments, p is about 4. In some embodiments, p is about 8. In some embodiments, p is about 16. In some embodiments, p is 2. In some embodiments, p is 4. In some embodiments, p is 8. In some embodiments, p is 16. In some embodiments, the value of the subscript p refers to the average drug loading, as well as the drug loading of the primary ligand-drug conjugate compound in the composition.

In some embodiments, binding will be via reduced interchain disulfides and there will be 1 to about 8 molecules of the Drug-Linker compound bound to the targeting agent that becomes the Ligand unit. In some embodiments, binding will be via introduced cysteine residues and reduced interchain disulfides and there will be 1 to 10 or 1 to 12 or 1 to 14 or 1 to 16 Drug-Linker compound moieties bound to the Ligand unit. In some embodiments, binding will be via introduced cysteine residues and there will be 2 or 4 molecules of the Drug-Linker compound bound to the Ligand unit. Ligand unit L

In some embodiments, a ligand unit is present. The ligand unit (L-) is a targeting agent that specifically binds to a target moiety. In one set of embodiments, the ligand unit specifically and selectively binds to a cell component (cell binding agent) or another related target molecule. The ligand unit is used to target and present a STING agonist (such as Formula (A), (I), (IIa), (IIIa), (IVa), (IIb), (IIIb), (IVb), (IIc), (IIIc), (IVc) or any subformula thereof) to a specific target cell population, and the ligand unit interacts with the specific target cell population due to the presence of its targeting component or molecule and allows the subsequent release of free drugs within the target cell (i.e., intracellular) or near the target cell (i.e., extracellular). The ligand unit L includes but is not limited to proteins, polypeptides and peptides. Suitable ligand units include, for example, antibodies (e.g., full-length antibodies and antigen-binding fragments thereof), interferons, lymphocyte mediators, hormones, growth factors, colony stimulating factors, vitamins, nutrient transporters (such as but not limited to transferrin), or any other cell-binding molecule or substance. In some embodiments, the ligand unit (L) is derived from an antibody or non-antibody protein targeting agent.

In one set of embodiments, the Ligand unit is bonded to Q (Linker unit) comprising a glucuronide-releasable Linker. As mentioned above, other linking components may be present in the conjugates described herein to provide additional space between the STING agonist drug compound and the Ligand unit (e.g., Stretcher unit and optionally Linker unit A), or to provide solubility-enhancing properties to the composition (e.g., Spacer S ^* ). In some of those embodiments, the Ligand unit is bonded to Z of the Linker unit via a heteroatom of the Ligand unit. Heteroatoms that may be present on the ligand unit for the bonding include sulfur (in one embodiment, from the hydroxyl group of the targeting ligand), oxygen (in one embodiment, from the carboxyl or hydroxyl group of the targeting ligand), and optionally substituted nitrogen (in one embodiment, from the primary or secondary amine functional group of the targeting ligand, or in another embodiment, from the optionally substituted amide nitrogen). Such heteroatoms may be present on the targeting ligand in the natural state of the ligand, for example, in a naturally occurring antibody, or may be introduced into the targeting ligand by chemical modification or bioengineering.

In one embodiment, the targeting agent as a precursor of the ligand unit has a hydroxyl functional group, so that the ligand unit is bonded to the linker unit via the sulfur atom of the hydroxyl functional group.

In another embodiment, the targeting agent as a ligand unit prodriver has one or more lysine residues that are capable of reacting with an activated ester (such esters include but are not limited to N -hydroxysuccinimide, pentafluorophenyl ester and p-nitrophenyl ester) of the Stretcher unit prodriver of the STING agonist-linker compound intermediate, and thereby provide an amide bond composed of the nitrogen atom of the ligand unit and the C=O group of the Stretcher unit of the Linker unit.

In some embodiments, the targeting agent as a precursor to the ligand unit has one or more lysine residues that can be chemically modified to introduce one or more hydroxyl groups. In those embodiments, the ligand unit is covalently linked to the linker unit via the sulfur atom of the hydroxyl functional group. Reagents that can be used to modify lysine in this manner include, but are not limited to, S-acetylthioacetic acid N-succinimidyl ester (SATA) and 2-imidothiocyclopentane hydrochloride (Traut's Reagent).

In another embodiment, the targeting agent as a precursor of the ligand unit has one or more carbohydrate groups that can be modified to provide one or more alkyl functional groups. The chemically modified ligand unit in the STING agonist conjugate is bonded to the linker unit component (e.g., stretcher unit) via the sulfur atom of the alkyl functional group.

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

In some embodiments, the targeting agent as a ligand unit prodriver is capable of forming a bond by interacting with a reactive functional group on a stretcher unit prodriver (Z') to form a covalent bond between the stretcher unit (Z) and the ligand unit, which corresponds structurally to the targeting agent. The functional group of Z' that has the ability to interact with the targeting agent will depend on the nature of the targeting agent that structurally corresponds to the ligand unit. In some embodiments, the reactive group is a maleimide present on the stretcher unit (i.e., the maleimide portion of the stretcher unit prodriver) prior to being linked to form the ligand unit. The covalent attachment of the ligand unit to the stretcher unit is achieved via the hydroxyl functional group of the targeting agent as a precursor of the ligand unit, which interacts with the maleimide functional group of Z' to form a sulfhydryl-substituted succinimide. The hydroxyl functional group may be present on the targeting agent in its natural state, for example, in a naturally occurring residue, or may be introduced into the targeting agent by chemical modification or by bioengineering.

In yet another embodiment, the Ligand unit is derived from an antibody and the alkyl group is generated by reducing the interchain disulfides of the antibody. Thus, in some embodiments, the Linker unit binds to the cysteine residue from the reduced interchain disulfide.

In yet another embodiment, the Ligand unit is derived from an antibody and the hydroxyl functionality is chemically introduced into the antibody, e.g., by the introduction of a cysteine residue. Thus, in some embodiments, the Linker unit (with or without an attached STING agonist moiety) is bound to the Ligand unit via the introduced cysteine residue of the Ligand unit.

It has been observed for bioconjugates that the drug binding site can affect many parameters, including ease of binding, drug-linker stability, effects on the biophysical properties of the resulting bioconjugate, and in vitro cytotoxicity. With respect to drug-linker stability, the binding site of the drug-linker moiety to the ligand unit can affect the ability of the bound drug-linker moiety to undergo elimination reactions, in some cases leading to premature release of free drug. Binding sites on targeting agents include, for example, reduced interchain disulfides and selected cysteine residues at engineered sites. In some embodiments, the conjugation methods for forming the STING agonist conjugates as described herein use a thiol residue at a genetically engineered site (e.g., position 239 according to the EU index as described in Kabat) that is less susceptible to elimination reactions than conjugation methods that use a thiol residue from a reduced disulfide bond. In other embodiments, the conjugation methods for forming the STING agonist conjugates as described herein use a thiol residue resulting from the reduction of an interchain disulfide bond.

In some embodiments, the STING agonist conjugate comprises a non-immunoreactive protein, polypeptide or peptide as its ligand unit. Thus, in some embodiments, the ligand unit is derived from a non-immunoreactive protein, polypeptide or peptide. Examples include, but are not limited to, transferrin, epidermal growth factor ("EGF"), leptin, gastrin, gastrin-releasing peptide, platelet-derived growth factor, IL-2, IL-6, transforming growth factor ("TGF", such as TGF-α and TGF-β), vaccinia growth factor ("VGF"), insulin and insulin-like growth factors I and II, somatostatin, lectin, and apolipoproteins from low-density lipoprotein.

Particularly preferred ligand units are derived from antibodies. Thus, in any of the embodiments described herein, the ligand units are derived from antibodies. Polyclonal antibodies may be heterogeneous populations of antibody molecules derived from the serum of immunized animals. Monoclonal antibodies may be homogeneous populations of antibodies directed against specific antigenic determinants ( e.g. , cancer cell antigens, viral antigens, microbial antigens, proteins, peptides, carbohydrates, chemicals, nucleic acids or fragments thereof). In some embodiments, monoclonal antibodies (mAbs) directed against the relevant antigen are prepared using any technique known in the art for preparing antibody molecules produced by continuous cell lines in culture.

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

Antibodies useful for incorporation into the ligand-drug conjugates of the present disclosure are intact antibodies or functionally active fragments, derivatives, or analogs of antibodies, wherein the antibody or fragment thereof is capable of immunospecifically binding to a target cell ( e.g. , a cancer cell antigen, a viral antigen, or a microbial antigen) or other antibodies that bind to tumor cells or stroma. In this context, "functionally active" means that the fragment, derivative, or analog is capable of immunospecifically binding to a target cell. To determine which CDR sequences bind to the antigen, in some embodiments, synthetic peptides containing the CDR sequences are used in a binding assay with the antigen by binding assay methods known in the art ( e.g. , Biacore ^™ analysis) ( see, e.g., Kabat et al. , 1991, Sequences of Proteins of Immunological Interest , 5th Edition, National Institute of Health, Bethesda, Md; Kabat E et al. , 1980, J. Immunology 125(3):961-969).

Other useful ligands include antibody fragments such as, but not limited to, F(ab') ₂ fragments, Fab fragments, Fv, single chain antibodies, bifunctional antibodies, trifunctional antibodies, tetrafunctional antibodies, scFv, scFv-FV or any other molecule having the same specificity as the antibody.

In addition, recombinant antibodies comprising both human and non-human parts (such as chimeric and humanized monoclonal antibodies) made using standard recombinant DNA technology are useful antibodies in some embodiments. Chimeric antibodies are molecules in which different parts are derived from different animal species, such as those having variable regions derived from a murine monoclonal and constant regions of human immunoglobulins. ( See, e.g., U.S. Patent No. 4,816,567; and U.S. Patent No. 4,816,397, which are incorporated herein by reference in their entirety.) Humanized antibodies are antibody molecules from non-human species that have one or more complementary determining regions (CDRs) from non-human species and framework regions from human immunoglobulin molecules. ( See, e.g., U.S. Patent No. 5,585,089, which is incorporated herein by reference in its entirety.) In some embodiments, such chimeric and humanized monoclonal antibodies are produced by recombinant DNA technology known in the art, such as using the methods described in International Publication No. WO 87/02671; European Patent Publication No. 0 184 187; European Patent Publication No. 0 171 496; European Patent Publication No. 0 173 494; International Publication No. WO 86/01533; U.S. Patent No. 4,816,567; Berter et al. , Science (1988) 240: 1041-1043; Liu et al. , Proc. Nat'l. Acad. Sci. USA (1987) 84: 3439-3443; Liu et al. , J. Immunol . (1987) 139: 3521-3526; Sun et al. , Proc. Natl. Acad. Sci. USA (1987) 84: 214-218; Nishimura et al. , Cancer. Res. (1987) 47: 999-1005; Wood et al. , Nature (1985) 314: 446-449; Shaw et al. , J. Natl. Cancer Inst . (1988) 80: 1553-1559; Morrison, Science (1985) 229: 1202-1207; Oi et al. , BioTechniques (1986) 4: 214-221; U.S. Patent No. 5,225,539; Jones et al. , Nature (1986) 321: 552-525; Verhoeyan et al. , Science (1988) 239: 1534-1536; and Beidler et al. , J. Immunol. (1988) 141: 4053-4060; each of which is incorporated herein by reference in its entirety.

In some cases (e.g., when immunogenicity to non-human or chimeric antibodies might arise), fully human antibodies are more desirable and in some embodiments are produced using transgenic mice that are unable to express endogenous immunoglobulin heavy and light chain genes but are able to express human heavy and light chain genes.

Antibodies include analogs and derivatives that have been modified ( i.e. , by covalent attachment of any type of molecule) so long as such covalent attachment allows the antibody to retain its antigen-binding immunospecificity. For example, but not limitation, derivatives and analogs of antibodies include those that have been further modified, for example, by glycosylation, acetylation, PEGylation, phosphorylation, amidation, derivatization by known protecting/blocking groups, proteolytic cleavage, attachment to cellular antibody units or other proteins, etc. In some embodiments, one or more of these numerous chemical modifications are performed by known techniques, including but not limited to specific chemical cleavage, acetylation, formylation, metabolic synthesis in the presence of chlamydine, etc. In other embodiments, analogs or derivatives of the antibodies contain one or more unnatural amino acids, sometimes in combination with one or more of the above-described chemical modifications.

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

In some embodiments, antibodies immunospecific to cancer cell antigens can be obtained commercially or produced by methods known to those skilled in the art (e.g., recombinant expression techniques). Nucleotide sequences encoding antibodies immunospecific to cancer cell antigens are sometimes obtained , for example, from the GenBank database or a similar database, literature publications, or by routine cloning and sequencing.

In a specific embodiment, known antibodies used to treat cancer are used.

In another specific embodiment, the compositions and methods according to the invention are used for the treatment of autoimmune diseases.

In certain embodiments, the antibody can be used to bind to a receptor or receptor complex expressed on activated lymphocytes. In some embodiments, the receptor or receptor complex is a member of the immunoglobulin gene superfamily, a member of the TNF receptor superfamily, an integrin, an interleukin receptor, a chemokine receptor, a major histocompatibility protein, a lectin, or a complement control protein.

In some embodiments, the antibody incorporated into the STING agonist conjugate will specifically bind B7-H4, CD19, CD30, CD33, CD70, CD228, ITGB6 (integrin β6), Nectin-4, TF (tissue factor), Her2, STn, ALPP, or LIV-1.

Exemplary antigens are provided below. Exemplary antibodies that bind to the indicated antigens are shown in parentheses.

In some embodiments, the antigen is a tumor-associated antigen. In some embodiments, the tumor-associated antigen is a transmembrane protein. For example, the following antigens are transmembrane proteins: ANTXR1, BAFF-R, CA9 (exemplary antibodies include gemtuximab), CD147 (exemplary antibodies include gavilimumab and metuzumab), CD19, CD20 (exemplary antibodies include rituximab, divozimab and ibritumomab tiuxetan), CD274 (also known as PD-L1, exemplary antibodies include adebelimumab, atezolizumab, galivumab, durvalumab and avelumab), CD30 (exemplary antibodies include itumumab and brentuximab), CD33 (exemplary antibodies include lintuzumab), CD352, CD45 (exemplary antibodies include etuzumab), CD47 (exemplary antibodies include leterlimumab and mololimab), CLPTM1L, DLL3, DPP4, EGFR, ERVMER34-1, FASL, FSHR, FZD5, FZD8, GUCY2C (exemplary antibodies include indolimab), IFNAR1 (exemplary antibodies include aniluomab), IFNAR2, LMP2, MLANA, SIT1, TLR2/4/1 (exemplary antibodies include toralimumab), TM4SF5, TMEM132A, TMEM40, UPK1B, VEGF, and VEFGR2 (exemplary antibodies include quintuximab).

In some embodiments, the tumor-associated antigen is a transmembrane transporter. For example, the following antigens are transmembrane transporters: ASCT2 (exemplary antibodies include idarucizumab), MFSD13A, Mincle, NaPi2b, NOX1, SLC10A2, SLC12A2, SLC17A2, SLC38A1, SLC39A5, SLC39A6 (also known as LIV1, exemplary antibodies include latuzumab), SLC44A4, SLC6A15, SLC6A6, SLC7A11 and SLC7A5.

In some embodiments, the tumor-associated antigen is a transmembrane or membrane-associated glycoprotein. For example, the following antigens are transmembrane or membrane-associated glycoproteins: CA-125, CA19-9, CAMPATH-1/CD52 (exemplary antibodies include alemtuzumab), carcinoembryonic antigen/CEA (exemplary antibodies include acitumomab), CEACAM5 (exemplary antibodies include certutumab and labetuzumab), CD112, CD155, CD24, CD247, CD37 (exemplary antibodies include rilotuzumab), CD38 (exemplary antibodies include fibrezumab), CD3D, CD3E (exemplary antibodies include forasomumab and teliguzumab), CD3G, CD96, CDCP1, CDH17, CDH3, CDH6, CEACAM1, CEACAM6, CLDN1, CLDN16, CLDN18.1, CLDN18.2 (exemplary antibodies include zobetulumab), CLDN19, CLDN2, CLEC12A (exemplary antibodies include teputizumab), DPEP1, DPEP3, DSG2, endosialin (exemplary antibodies include ontuximab), ENPP1, EPCAM (exemplary antibodies include adelimumab), FN, FN1, Gp100, GPA33, gpNMB (exemplary antibodies include gebatumumab), ICAM1, L1CAM, LAMP1, MELTF (also known as CD228), NCAM1, Nectin-4 (exemplary antibodies include enrofloxacin), PDPN, PMSA, PROM1, PSCA, PSMA, Siglecs 1-16, SIRPa, SIRPg, TACSTD2, TAG-72, tenascin, tissue factor (also known as TF, exemplary antibodies include tesozumab) and ULBP1/2/3/4/5/6.

In some embodiments, the tumor-associated antigen is a transmembrane or membrane-associated receptor kinase. For example, the following antigens are transmembrane or membrane-associated receptor kinases: ALK, Axl (exemplary antibodies include teviruzumab), BMPR2, DCLK1, DDR1, EPHA receptor, EPHA2, ERBB2 (also known as HER2, exemplary antibodies include trastuzumab, pertuzumab, decitumomab/RC48 and magetuximab), ERBB3, FLT3, PDGFR-B (exemplary antibodies include linusumab), PTK7 (exemplary antibodies include colefeucin), RET, ROR1 (exemplary antibodies include cisutuzumab), ROR2, ROS1 and Tie3.

In some embodiments, the tumor-associated antigen is a membrane-associated or membrane-localized protein. For example, the following antigens are membrane-associated or membrane-localized proteins: ALPP, ALPPL2, ANXA1, FOLR1 (exemplary antibodies include facilizumab), IL13Ra2, IL1RAP (exemplary antibodies include nidalizumab), NT5E, OX40, Ras mutants, RGS5, RhoC, SLAMF7 (exemplary antibodies include elotuzumab) and VSIR.

In some embodiments, the tumor-associated antigen is a transmembrane G protein-coupled receptor (GPCR). For example, the following antigens are GPCRs: CALCR, CD97, GPR87, and KISS1R.

In some embodiments, the tumor-associated antigen is a cell surface associated antigen or a cell surface receptor. For example, the following antigens are cell surface associated and/or cell surface receptors: B7-DC, BCMA, CD137, CD 244, CD3 (exemplary antibodies include ocilizumab and visilizumab), CD48, CD5 (exemplary antibodies include zofranomab), CD70 (exemplary antibodies include cusatuzumab and wortuzumab), CD74 (exemplary antibodies include milatuzumab), CD79A, CD262/DR5 (exemplary antibodies include tegtuzumab), DR4 (exemplary antibodies include mapatumumab), FAS, FGFR1, FGFR2 (exemplary antibodies include aprazumab), FGFR3 (exemplary antibodies include wortuzumab), FGFR4, GITR (exemplary antibodies include ragevulimumab), HAVCR2, HLA-E, HLA-F, HLA-G, LAG-3 (exemplary antibodies include ansarizumab), LY6G6D, LY9, MICA, MICB, MSLN, MUC1, MUC5AC, NY-ESO-1, OY-TES1, PVRIG, Sialyl-Thomsen-Nouveau antigen, sperm protein 17, TNFRSF12, and uPAR.

In some embodiments, the tumor-associated antigen is an interleukin receptor or an interleukin receptor. For example, the following antigens are interleukin receptors or interleukin receptors: CD115 (exemplary antibodies include asatiglimumab, cabilizumab, and imatinib), CD123, CXCR4 (exemplary antibodies include uropromab), IL-21R, and IL-5R (exemplary antibodies include benralizumab).

In some embodiments, the tumor-associated antigen is a co-stimulatory or co-inhibitory, surface-expressed protein. For example, the following antigens are co-stimulatory or co-inhibitory, surface-expressed proteins: B7-H3 (exemplary antibodies include enoxizumab and omraquinone), B7-H4, B7-H6, and B7-H7.

In some embodiments, the tumor-associated antigen is a transcription factor or a DNA binding protein. For example, the following antigens are transcription factors: ETV6-AML, MYCN, PAX3, PAX5, and WT1. The following protein is a DNA binding protein: BORIS.

In some embodiments, the tumor-associated antigen is an integral membrane protein. For example, the following antigens are integral membrane proteins: SLITRK6 (exemplary antibodies include cetrozumab), UPK2, and UPK3B.

In some embodiments, the tumor-associated antigen is an integrin. For example, the following antigens are integrin antigens: integrin αvβ6, ITGAV (exemplary antibodies include abituzumab), ITGB6 and ITGB8.

In some embodiments, the tumor-associated antigen is a glycolipid. For example, the following are glycolipid antigens: FucGM1, GD2 (exemplary antibodies include dinutuximab), GD3 (exemplary antibodies include mitumomab), GloboH, GM2 and GM3 (exemplary antibodies include ranitumomab).

In some embodiments, the tumor-associated antigen is a cell surface hormone receptor. For example, the following antigens are cell surface hormone receptors: AMHR2 and androgen receptor.

In some embodiments, the tumor-associated antigen is a transmembrane or membrane-associated protease. For example, the following antigens are transmembrane or membrane-associated proteases: ADAM12, ADAM9, TMPRSS11D, and metalloproteinases.

In some embodiments, the tumor-associated antigen is aberrantly expressed in an individual with cancer. For example, the following antigens may be abnormally expressed in individuals with cancer: AFP, AGR2, AKAP-4, ARTN, BCR-ABL, C5 complement, CCNB1, CSPG4, CYP1B1, De2-7 EGFR, EGF, Fas-related antigen 1, FBP, G250, GAGE, HAS3, HPV E6, HPV E7, hTERT, IDO1, LCK, podocyte protein, LYPD1, MAD-CT-1, MAD-CT-2, MAGEA3, MAGEA4, MAGEC2, MerTk, ML-IAP, NA17, NY-BR-1, p53, p53 mutants, PAP, PLAV I, polysialic acid, PR1, PSA, sarcoma translocation breakpoints, SART3, sLe, SSX2, survivin, Tn, TRAIL, TRAIL1, TRP-2, and XAGE1.

In some embodiments, the antigen is an immune cell-associated antigen. In some embodiments, the immune cell-associated antigen is a transmembrane protein. For example, the following antigens are transmembrane proteins: BAFF-R, CD163, CD19, CD20 (exemplary antibodies include rituximab, omecilizumab, divozimab; ibritumomab tiuxetan), CD25 (exemplary antibodies include basiliximab), CD274 (also known as PD-L1, exemplary antibodies include adelimumab, atezolizumab, galivumab, durvalumab and avelumab), CD30 (exemplary antibodies include itumumab and brentuximab), CD33 (exemplary antibodies include lintuzumab), CD352, CD45 (exemplary antibodies include etuximab), CD47 (exemplary antibodies include leterumab and mololimab), CTLA4 (exemplary antibodies include ipilimumab), FASL, IFNAR1, IFNAR2, LAYN, LILRB2, LILRB4, PD-1 (exemplary antibodies include nivolumab, pembrolizumab, batilizumab, brigatinib, jelolimab, toripalimab, and pidilizumab), SIT1, and TLR2/4/1 (exemplary antibodies include toralimumab).

In some embodiments, the immune cell-associated antigen is a transmembrane transporter. For example, Mincle is a transmembrane transporter.

In some embodiments, the immune cell-associated antigen is a transmembrane or membrane-associated glycoprotein. For example, the following antigens are transmembrane or membrane-associated glycoproteins: CD112, CD155, CD24, CD247, CD28, CD30L, CD37 (exemplary antibodies include rilotomab), CD38 (exemplary antibodies include filostatumab), CD3D, CD3E (exemplary antibodies include forasumab and teligumab), CD3G, CD44, CLEC12A (exemplary antibodies include teputizumab), DCIR, DCSIGN, Dectin 1, Dectin 2, ICAM1, LAMP1, Siglecs 1-16, SIRPa, SIRPg, and ULBP1/2/3/4/5/6.

In some embodiments, the immune cell-associated antigen is a transmembrane or membrane-associated receptor kinase. For example, the following antigens are transmembrane or membrane-associated receptor kinases: Axl (exemplary antibodies include tevetumumab) and FLT3.

In some embodiments, the immune cell-associated antigen is a membrane-associated or membrane-localized protein. For example, the following antigens are membrane-associated or membrane-localized proteins: CD83, IL1RAP (exemplary antibodies include nidalizumab), OX40, SLAMF7 (exemplary antibodies include elotuzumab) and VSIR.

In some embodiments, the immune cell-associated antigen is a transmembrane G protein-coupled receptor (GPCR). For example, the following antigens are GPCRs: CCR4 (exemplary antibodies include moglizumab-kpkc), CCR8, and CD97.

In some embodiments, the immune cell-associated antigen is a cell surface-associated antigen or a cell surface receptor. For example, the following antigens are cell surface associated and/or cell surface receptors: B7-DC, BCMA, CD137, CD2 (exemplary antibodies include sipizumab), CD244, CD27 (exemplary antibodies include varilumab), CD278 (exemplary antibodies include fiadilimab and vopelimab), CD3 (exemplary antibodies include ocilizumab and visilizumab), CD40 (exemplary antibodies include daclizumab and rukatumomab), CD48, CD5 (exemplary antibodies include zofranomab), CD70 (exemplary antibodies include cusatuzumab and wortuzumab), CD74 (exemplary antibodies include milatuzumab), CD79A, CD262/CD5 (exemplary antibodies include tegtuzumab), DR4 (exemplary antibodies include mapatumumab), GITR (exemplary antibodies include ragavulimab), HAVCR2, HLA-DR, HLA-E, HLA-F, HLA-G, LAG-3 (exemplary antibodies include ansarizumab), MICA, MICB, MRC1, PVRIG, Sialyl-Thomsen-Nouveau antigen, TIGIT (exemplary antibodies include etilizumab), Trem2, and uPAR.

In some embodiments, the immune cell-associated antigen is an interleukin receptor or an interleukin receptor. For example, the following antigens are interleukin receptors or interleukin receptors: CD115 (exemplary antibodies include asatiglimumab, cabilizumab, and imatinib), CD123, CXCR4 (exemplary antibodies include uropromab), IL-21R, and IL-5R (exemplary antibodies include benralizumab).

In some embodiments, the immune cell-associated antigen is a co-stimulatory or co-inhibitory, surface-expressed protein. For example, the following antigens are co-stimulatory or co-inhibitory, surface-expressed proteins: B7-H3 (exemplary antibodies include enoxizumab and omraquinone), B7-H4, B7-H6, and B7-H7.

In some embodiments, the immune cell-associated antigen is a peripheral membrane protein. For example, the following antigens are peripheral membrane proteins: B7-1 (exemplary antibodies include galiximab) and B7-2.

In some embodiments, the immune cell-associated antigen is abnormally expressed in individuals with cancer. For example, the following antigens may be abnormally expressed in individuals with cancer: C5 complement, IDO1, LCK, MerTk, and Tyrol.

In some embodiments, the antigen is a stromal cell-associated antigen. In some embodiments, the stromal cell-associated antigen is a transmembrane or membrane-associated protein. For example, the following antigens are transmembrane or membrane-associated proteins: FAP (exemplary antibodies include sirolimus), IFNAR1, and IFNAR2.

In some embodiments, the antigen is CD30. In some embodiments, the antibody is an antibody or antigen binding fragment that binds to CD30, as described in International Patent Publication No. WO 02/43661. In some embodiments, the anti-CD30 antibody is cAC10, which is described in International Patent Publication No. WO 02/43661. cAC10 is also known as brentuximab. In some embodiments, the anti-CD30 antibody comprises the CDRs of cAC10. In some embodiments, the CDRs are defined as the Kabat numbering scheme. In some embodiments, the CDRs are defined as the Chothia numbering scheme. In some embodiments, the CDRs are defined as the IMGT numbering scheme. In some embodiments, the CDRs are defined as the AbM numbering scheme. In some embodiments, the anti-CD30 antibody comprises CDR-H1, CDR-H2, CDR-H3, CDR-L1, CDR-L2 and CDR-L3, which respectively comprise the amino acid sequences of SEQ ID NOs: 1, 2, 3, 4, 5 and 6. In some embodiments, the anti-CD30 antibody comprises a heavy chain variable region comprising an amino acid sequence that is at least 80%, at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99% or 100% identical to the amino acid sequence of SEQ ID NO: 7; and a light chain variable region comprising an amino acid sequence that is at least 80%, at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99% or 100% identical to the amino acid sequence of SEQ ID NO: 8. In some embodiments, the anti-CD30 antibody comprises a heavy chain comprising an amino acid sequence that is at least 80%, at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical to the amino acid sequence of SEQ ID NO: 9 or SEQ ID NO: 10; and a light chain comprising an amino acid sequence that is at least 80%, at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical to the amino acid sequence of SEQ ID NO: 11.

In some embodiments, the antigen is CD70. In some embodiments, the antibody is an antibody or antigen-binding fragment that binds to CD70, as described in International Patent Publication No. WO 2006/113909. In some embodiments, the antibody is h1F6 anti-CD70 antibody, which is described in International Patent Publication No. WO 2006/113909. h1F6 is also known as worthuzumab. In some embodiments, the anti-CD70 antibody comprises a heavy chain variable region comprising three CDRs of SEQ ID NOs: 279, 280, and 281; and a light chain variable region comprising three CDRs of SEQ ID NOs: 282, 283, and 284. In some embodiments, the CDRs are defined as the Kabat numbering scheme. In some embodiments, the CDRs are defined as the Chothia numbering scheme. In some embodiments, the CDRs are defined as the IMGT numbering scheme. In some embodiments, the CDRs are defined as the AbM numbering scheme. In some embodiments, the anti-CD70 antibody comprises a heavy chain variable region comprising an amino acid sequence that is at least 80%, at least 85%, at least 90%, at least 95% at least 96%, at least 97%, at least 98%, at least 99% or 100% identical to the amino acid sequence of SEQ ID NO: 285; and a light chain variable region comprising an amino acid sequence that is at least 80%, at least 85%, at least 90%, at least 95% at least 96%, at least 97%, at least 98%, at least 99% or 100% identical to the amino acid sequence of SEQ ID NO: 286. In some embodiments, the anti-CD70 antibody comprises a heavy chain comprising an amino acid sequence that is at least 80%, at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99% or 100% identical to the amino acid sequence of SEQ ID NO: 287; and a light chain comprising an amino acid sequence that is at least 80%, at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99% or 100% identical to the amino acid sequence of SEQ ID NO: 288.

In some embodiments, the antigen is interleukin-1 receptor accessory protein (IL1RAP). IL1RAP is a co-receptor of IL1 receptor (IL1R1) and is required for interleukin-1 (IL1) signaling. IL1 has been implicated in resistance to certain chemotherapy regimens. IL1RAP is overexpressed in a variety of solid tumors, both on cancer cells and in the tumor microenvironment, but has low expression on normal cells. IL1RAP is also overexpressed in hematopoietic stem and progenitor cells, making it a candidate for targeting chronic myeloid leukemia (CML). IL1RAP has also been shown to be overexpressed in acute myeloid leukemia (AML). Antibody binding to IL1RAP may block IL-1 and IL-33 signaling into cells and allow NK cells to recognize tumor cells and subsequently kill them via antibody-dependent cytotoxicity (ADCC).

In some embodiments, the antigen is ASCT2. ASCT2 is also known as SLC1A5. ASCT2 is a ubiquitously expressed, broad-spectrum specific, sodium-dependent natural amino acid exchanger. ASCT2 is involved in glutamine transport. ASCT2 is overexpressed in different cancers and is closely associated with poor prognosis. Downregulation of ASCT2 has been shown to inhibit intracellular glutamine levels and downstream glutamine metabolism, including glutathione production. Due to its high expression in multiple cancers, ASCT2 is a potential therapeutic target. These effects reduce growth and proliferation, increase apoptosis and autophagy, and increase oxidative stress and mTORC1 pathway inhibition in head and neck squamous cell carcinoma (HNSCC). Additionally, silencing ASCT2 improves response to cetuximab in HNSCC.

In some embodiments, the antibody-drug conjugate (ADC) provided herein binds to TROP2. In some embodiments, the antibody of the antibody-drug conjugate comprises CDR-H1, CDR-H2, CDR-H3, CDR-L1, CDR-L2 and CDR-L3, which respectively comprise the amino acid sequences of SEQ ID NO: 289, 290, 291, 292, 293 and 294. In some embodiments, the antibody of the antibody-drug conjugate comprises a heavy chain variable region comprising an amino acid sequence that is at least 80%, at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical to the amino acid sequence of SEQ ID NO: 295; and a light chain variable region comprising an amino acid sequence that is at least 80%, at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical to the amino acid sequence of SEQ ID NO: 296. In some embodiments, the antibody of the antibody-drug conjugate is taciturnumab. In some embodiments, the antibody of the antibody-drug conjugate comprises CDR-H1, CDR-H2, CDR-H3, CDR-L1, CDR-L2 and CDR-L3, which respectively comprise an amino acid sequence that is at least 95%, at least 96%, at least 97%, at least 98%, at least 99% or 100% identical to the amino acid sequence of SEQ ID NO: 297, 298, 299, 300, 301 and 302. In some embodiments, the antibody of the antibody-drug conjugate comprises a heavy chain variable region comprising an amino acid sequence that is at least 80%, at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical to the amino acid sequence of SEQ ID NO: 303; and a light chain variable region comprising an amino acid sequence that is at least 80%, at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical to the amino acid sequence of SEQ ID NO: 304. In some embodiments, the antibody of the antibody-drug conjugate is datopotamab.

In some embodiments, the antibody-drug conjugates provided herein bind to MICA. In some embodiments, the antibody of the antibody-drug conjugate comprises CDR-H1, CDR-H2, CDR-H3, CDR-L1, CDR-L2 and CDR-L3, which respectively comprise the amino acid sequences of SEQ ID NO: 305, 306, 307, 308, 309 and 310. In some embodiments, the antibody of the antibody-drug conjugate comprises a heavy chain variable region comprising an amino acid sequence that is at least 80%, at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical to the amino acid sequence of SEQ ID NO: 311; and a light chain variable region comprising an amino acid sequence that is at least 80%, at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical to the amino acid sequence of SEQ ID NO: 312. In some embodiments, the antibody of the antibody-drug conjugate is h1D5v11 hIgG1K. In some embodiments, the antibody of the antibody-drug conjugate comprises CDR-H1, CDR-H2, CDR-H3, CDR-L1, CDR-L2 and CDR-L3, which comprise the amino acid sequences of SEQ ID NOs: 313, 314, 315, 316, 317 and 318, respectively. In some embodiments, the antibody of the antibody-drug conjugate comprises a heavy chain variable region comprising an amino acid sequence that is at least 80%, at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical to the amino acid sequence of SEQ ID NO: 319; and a light chain variable region comprising an amino acid sequence that is at least 80%, at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical to the amino acid sequence of SEQ ID NO: 320. In some embodiments, the antibody of the antibody-drug conjugate is MICA.36 hIgG1K G236A. In some embodiments, the antibody of the antibody-drug conjugate comprises CDR-H1, CDR-H2, CDR-H3, CDR-L1, CDR-L2 and CDR-L3, which comprise the amino acid sequences of SEQ ID NOs: 321, 322, 323, 324, 325 and 326, respectively. In some embodiments, the antibody of the antibody-drug conjugate comprises a heavy chain variable region comprising an amino acid sequence that is at least 80%, at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical to the amino acid sequence of SEQ ID NO: 327; and a light chain variable region comprising an amino acid sequence that is at least 80%, at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical to the amino acid sequence of SEQ ID NO: 328. In some embodiments, the antibody of the antibody-drug conjugate is h3F9 H1L3 hIgG1K. In some embodiments, the antibody of the antibody-drug conjugate comprises CDR-H1, CDR-H2, CDR-H3, CDR-L1, CDR-L2 and CDR-L3, which comprise the amino acid sequences of SEQ ID NOs: 329, 330, 331, 332, 333 and 334, respectively. In some embodiments, the antibody of the antibody-drug conjugate comprises a heavy chain variable region comprising an amino acid sequence that is at least 80%, at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical to the amino acid sequence of SEQ ID NO: 335; and a light chain variable region comprising an amino acid sequence that is at least 80%, at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical to the amino acid sequence of SEQ ID NO: 336. In some embodiments, the antibody of the antibody-drug conjugate is CM33322 Ab28 hIgG1K.

In some embodiments, the antibody-drug conjugates provided herein bind to CD24. In some embodiments, the antibody of the antibody-drug conjugate comprises CDR-H1, CDR-H2, CDR-H3, CDR-L1, CDR-L2 and CDR-L3, which respectively comprise the amino acid sequences of SEQ ID NO: 1035, 1036, 1037, 1038, 1039 and 1040. In some embodiments, the antibody of the antibody-drug conjugate comprises a heavy chain variable region comprising an amino acid sequence that is at least 80%, at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical to the amino acid sequence of SEQ ID NO: 1041; and a light chain variable region comprising an amino acid sequence that is at least 80%, at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical to the amino acid sequence of SEQ ID NO: 1042. In some embodiments, the antibody of the antibody-drug conjugate is SWA11.

In some embodiments, the antibody-drug conjugates provided herein bind to ITGav (also known as CD51). In some embodiments, the antibody of the antibody-drug conjugate comprises CDR-H1, CDR-H2, CDR-H3, CDR-L1, CDR-L2 and CDR-L3, which respectively comprise the amino acid sequences of SEQ ID NOs: 337, 338, 339, 340, 341 and 342. In some embodiments, the antibody of the antibody-drug conjugate comprises a heavy chain variable region comprising an amino acid sequence that is at least 80%, at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical to the amino acid sequence of SEQ ID NO: 343; and a light chain variable region comprising an amino acid sequence that is at least 80%, at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical to the amino acid sequence of SEQ ID NO: 344. In some embodiments, the antibody of the antibody-drug conjugate is intumumab. In some embodiments, the antibody of the antibody-drug conjugate comprises CDR-H1, CDR-H2, CDR-H3, CDR-L1, CDR-L2 and CDR-L3, which comprise the amino acid sequences of SEQ ID NOs: 345, 346, 347, 348, 349 and 350, respectively. In some embodiments, the antibody of the antibody-drug conjugate comprises a heavy chain variable region comprising an amino acid sequence that is at least 80%, at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical to the amino acid sequence of SEQ ID NO: 351; and a light chain variable region comprising an amino acid sequence that is at least 80%, at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical to the amino acid sequence of SEQ ID NO: 352. In some embodiments, the antibody of the antibody-drug conjugate is abituzumab.

In some embodiments, the antibody-drug conjugates provided herein bind to gpA33. In some embodiments, the antibody of the antibody-drug conjugate comprises CDR-H1, CDR-H2, CDR-H3, CDR-L1, CDR-L2 and CDR-L3, which respectively comprise the amino acid sequences of SEQ ID NO: 353, 354, 355, 356, 357 and 358. In some embodiments, the antibody of the antibody-drug conjugate comprises a heavy chain variable region comprising an amino acid sequence that is at least 80%, at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical to the amino acid sequence of SEQ ID NO: 359; and a light chain variable region comprising an amino acid sequence that is at least 80%, at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical to the amino acid sequence of SEQ ID NO: 360.

In some embodiments, the antibody-drug conjugates provided herein bind to IL1Rap. In some embodiments, the antibody of the antibody-drug conjugate comprises CDR-H1, CDR-H2, CDR-H3, CDR-L1, CDR-L2 and CDR-L3, which respectively comprise the amino acid sequences of SEQ ID NO: 361, 362, 363, 364, 365 and 366. In some embodiments, the antibody of the antibody-drug conjugate comprises a heavy chain variable region comprising an amino acid sequence that is at least 80%, at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical to the amino acid sequence of SEQ ID NO: 367; and a light chain variable region comprising an amino acid sequence that is at least 80%, at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical to the amino acid sequence of SEQ ID NO: 368. In some embodiments, the antibody of the antibody-drug conjugate is nidalimab.

In some embodiments, the antibody-drug conjugates provided herein bind to EpCAM. In some embodiments, the antibody of the antibody-drug conjugate comprises CDR-H1, CDR-H2, CDR-H3, CDR-L1, CDR-L2 and CDR-L3, which respectively comprise the amino acid sequences of SEQ ID NO: 369, 370, 371, 372, 373 and 374. In some embodiments, the antibody of the antibody-drug conjugate comprises a heavy chain variable region comprising an amino acid sequence that is at least 80%, at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical to the amino acid sequence of SEQ ID NO: 375; and a light chain variable region comprising an amino acid sequence that is at least 80%, at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical to the amino acid sequence of SEQ ID NO: 376. In some embodiments, the antibody of the antibody-drug conjugate is adetumumab. In some embodiments, the antibody of the antibody-drug conjugate comprises CDR-H1, CDR-H2, CDR-H3, CDR-L1, CDR-L2 and CDR-L3, which comprise the amino acid sequences of SEQ ID NOs: 377, 378, 379, 380, 381 and 382, respectively. In some embodiments, the antibody of the antibody-drug conjugate comprises a heavy chain variable region comprising an amino acid sequence that is at least 80%, at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99% or 100% identical to the amino acid sequence of SEQ ID NO: 383; and a light chain variable region comprising an amino acid sequence that is at least 80%, at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99% or 100% identical to the amino acid sequence of SEQ ID NO: 384. In some embodiments, the antibody of the antibody-drug conjugate is Ep157305. In some embodiments, the antibody of the antibody-drug conjugate comprises CDR-H1, CDR-H2, CDR-H3, CDR-L1, CDR-L2 and CDR-L3, which comprise the amino acid sequences of SEQ ID NOs: 385, 386, 387, 388, 389 and 390, respectively. In some embodiments, the antibody of the antibody-drug conjugate comprises a heavy chain variable region comprising an amino acid sequence that is at least 80%, at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99% or 100% identical to the amino acid sequence of SEQ ID NO: 391; and a light chain variable region comprising an amino acid sequence that is at least 80%, at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99% or 100% identical to the amino acid sequence of SEQ ID NO: 392. In some embodiments, the antibody of the antibody-drug conjugate is Ep3-171. In some embodiments, the antibody of the antibody-drug conjugate comprises CDR-H1, CDR-H2, CDR-H3, CDR-L1, CDR-L2 and CDR-L3, which comprise the amino acid sequences of SEQ ID NOs: 393, 394, 395, 396, 397 and 398, respectively. In some embodiments, the antibody of the antibody-drug conjugate comprises a heavy chain variable region comprising an amino acid sequence that is at least 80%, at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical to the amino acid sequence of SEQ ID NO: 399; and a light chain variable region comprising an amino acid sequence that is at least 80%, at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical to the amino acid sequence of SEQ ID NO: 400. In some embodiments, the antibody of the antibody-drug conjugate is Ep3622w94. In some embodiments, the antibody of the antibody-drug conjugate comprises CDR-H1, CDR-H2, CDR-H3, CDR-L1, CDR-L2 and CDR-L3, which comprise the amino acid sequences of SEQ ID NOs: 401, 402, 403, 404, 405 and 406, respectively. In some embodiments, the antibody of the antibody-drug conjugate comprises a heavy chain variable region comprising an amino acid sequence that is at least 80%, at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical to the amino acid sequence of SEQ ID NO: 407; and a light chain variable region comprising an amino acid sequence that is at least 80%, at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical to the amino acid sequence of SEQ ID NO: 408. In some embodiments, the antibody of the antibody-drug conjugate is EpING1. In some embodiments, the antibody of the antibody-drug conjugate comprises CDR-H1, CDR-H2, CDR-H3, CDR-L1, CDR-L2 and CDR-L3, which comprise the amino acid sequences of SEQ ID NOs: 409, 410, 411, 412, 413 and 414, respectively. In some embodiments, the antibody of the antibody-drug conjugate comprises a heavy chain variable region comprising an amino acid sequence that is at least 80%, at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical to the amino acid sequence of SEQ ID NO: 415; and a light chain variable region comprising an amino acid sequence that is at least 80%, at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical to the amino acid sequence of SEQ ID NO: 416. In some embodiments, the antibody of the antibody-drug conjugate is EpAb2-6.

In some embodiments, the antibody-drug conjugates provided herein bind to CD352. In some embodiments, the antibody of the antibody-drug conjugate comprises CDR-H1, CDR-H2, CDR-H3, CDR-L1, CDR-L2 and CDR-L3, which respectively comprise the amino acid sequences of SEQ ID NOs: 417, 418, 419, 420, 421 and 422. In some embodiments, the antibody of the antibody-drug conjugate comprises a heavy chain variable region comprising an amino acid sequence that is at least 80%, at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical to the amino acid sequence of SEQ ID NO: 423; and a light chain variable region comprising an amino acid sequence that is at least 80%, at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical to the amino acid sequence of SEQ ID NO: 424. In some embodiments, the antibody of the antibody-drug conjugate is h20F3.

In some embodiments, the antibody-drug conjugates provided herein bind to CS1 (also known as SLAMF7). In some embodiments, the antibody of the antibody-drug conjugate comprises CDR-H1, CDR-H2, CDR-H3, CDR-L1, CDR-L2, and CDR-L3, which comprise the amino acid sequences of SEQ ID NOs: 425, 426, 427, 428, 429, and 430, respectively. In some embodiments, the antibody of the antibody-drug conjugate comprises a heavy chain variable region comprising an amino acid sequence that is at least 80%, at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical to the amino acid sequence of SEQ ID NO: 431; and a light chain variable region comprising an amino acid sequence that is at least 80%, at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical to the amino acid sequence of SEQ ID NO: 432. In some embodiments, the antibody of the antibody-drug conjugate is elotuzumab.

In some embodiments, the antibody-drug conjugates provided herein bind to CD38. In some embodiments, the antibody of the antibody-drug conjugate comprises CDR-H1, CDR-H2, CDR-H3, CDR-L1, CDR-L2 and CDR-L3, which respectively comprise the amino acid sequences of SEQ ID NOs: 433, 434, 435, 436, 437 and 438. In some embodiments, the antibody of the antibody-drug conjugate comprises a heavy chain variable region comprising an amino acid sequence that is at least 80%, at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical to the amino acid sequence of SEQ ID NO: 439; and a light chain variable region comprising an amino acid sequence that is at least 80%, at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical to the amino acid sequence of SEQ ID NO: 440. In some embodiments, the antibody of the antibody-drug conjugate is daratumumab.

In some embodiments, the antibody-drug conjugates provided herein bind to CD25. In some embodiments, the antibody of the antibody-drug conjugate comprises CDR-H1, CDR-H2, CDR-H3, CDR-L1, CDR-L2 and CDR-L3, which respectively comprise the amino acid sequences of SEQ ID NO: 441, 442, 443, 444, 445 and 446. In some embodiments, the antibody of the antibody-drug conjugate comprises a heavy chain variable region comprising an amino acid sequence that is at least 80%, at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical to the amino acid sequence of SEQ ID NO: 447; and a light chain variable region comprising an amino acid sequence that is at least 80%, at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical to the amino acid sequence of SEQ ID NO: 448. In some embodiments, the antibody of the antibody-drug conjugate is daclizumab.

In some embodiments, the antibody-drug conjugate provided herein binds to ADAM9. In some embodiments, the antibody of the antibody-drug conjugate comprises CDR-H1, CDR-H2, CDR-H3, CDR-L1, CDR-L2 and CDR-L3, which respectively comprise the amino acid sequences of SEQ ID NO: 449, 450, 451, 452, 453 and 454. In some embodiments, the antibody of the antibody-drug conjugate comprises a heavy chain variable region comprising an amino acid sequence that is at least 80%, at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical to the amino acid sequence of SEQ ID NO: 455; and a light chain variable region comprising an amino acid sequence that is at least 80%, at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical to the amino acid sequence of SEQ ID NO: 456. In some embodiments, the antibody of the antibody-drug conjugate is chMAbA9-A. In some embodiments, the antibody of the antibody-drug conjugate comprises CDR-H1, CDR-H2, CDR-H3, CDR-L1, CDR-L2 and CDR-L3, which comprise the amino acid sequences of SEQ ID NOs: 457, 458, 459, 460, 461 and 462, respectively. In some embodiments, the antibody of the antibody-drug conjugate comprises a heavy chain variable region comprising an amino acid sequence that is at least 80%, at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99% or 100% identical to the amino acid sequence of SEQ ID NO: 463; and a light chain variable region comprising an amino acid sequence that is at least 80%, at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99% or 100% identical to the amino acid sequence of SEQ ID NO: 464. In some embodiments, the antibody of the antibody-drug conjugate is hMAbA9-A. In some embodiments, the antibody of the antibody-drug conjugate comprises CDR-H1 comprising the amino acid sequence of SEQ ID NO: 449. In some embodiments, the antibody of the antibody-drug conjugate comprises a CDR-H1 comprising the amino acid sequence of SEQ ID NO: 457. In some embodiments, the antibody of the antibody-drug conjugate comprises a CDR-L1 comprising the amino acid sequence of SEQ ID NO: 460.

In some embodiments, the antibody-drug conjugates provided herein bind to CD59. In some embodiments, the antibody of the antibody-drug conjugate comprises CDR-H1, CDR-H2, CDR-H3, CDR-L1, CDR-L2 and CDR-L3, which respectively comprise the amino acid sequences of SEQ ID NO: 465, 466, 467, 468, 469 and 470. In some embodiments, the antibody of the antibody-drug conjugate comprises a heavy chain variable region comprising an amino acid sequence that is at least 80%, at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical to the amino acid sequence of SEQ ID NO: 471; and a light chain variable region comprising an amino acid sequence that is at least 80%, at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical to the amino acid sequence of SEQ ID NO: 472. In some embodiments, the antibody of the antibody-drug conjugate comprises a CDR-H1 comprising an amino acid sequence of SEQ ID NO: 465. In some embodiments, the antibody of the antibody-drug conjugate comprises a CDR-H2 comprising an amino acid sequence of SEQ ID NO: 466.

In some embodiments, the antibody-drug conjugate provided herein binds to CD25. In some embodiments, the antibody of the antibody-drug conjugate is Clone123.

In some embodiments, the antibody-drug conjugate provided herein binds to CD229. In some embodiments, the antibody of the antibody-drug conjugate is h8A10.

In some embodiments, the antibody-drug conjugates provided herein bind to CD 19. In some embodiments, the antibody of the antibody-drug conjugate comprises CDR-H1, CDR-H2, CDR-H3, CDR-L1, CDR-L2, and CDR-L3, which comprise the amino acid sequences of SEQ ID NOs: 473, 474, 475, 476, 477, and 478, respectively. In some embodiments, the antibody of the antibody-drug conjugate comprises a heavy chain variable region comprising an amino acid sequence that is at least 80%, at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical to the amino acid sequence of SEQ ID NO: 479; and a light chain variable region comprising an amino acid sequence that is at least 80%, at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical to the amino acid sequence of SEQ ID NO: 480. In some embodiments, the anti-CD19 antibody comprises a heavy chain comprising an amino acid sequence that is at least 80%, at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99% or 100% identical to the amino acid sequence of SEQ ID NO: 481; and a light chain comprising an amino acid sequence that is at least 80%, at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99% or 100% identical to the amino acid sequence of SEQ ID NO: 482. In some embodiments, the antibody of the antibody-drug conjugate is denidozumab, also known as hBU12. See WO2009052431.

In some embodiments, the antibody-drug conjugates provided herein bind to CD70. In some embodiments, the antibody of the antibody-drug conjugate comprises CDR-H1, CDR-H2, CDR-H3, CDR-L1, CDR-L2, and CDR-L3, which comprise the amino acid sequences of SEQ ID NOs: 279, 280, 281, 282, 283, and 284, respectively. In some embodiments, the antibody of the antibody-drug conjugate comprises a heavy chain variable region comprising an amino acid sequence that is at least 80%, at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical to the amino acid sequence of SEQ ID NO: 285; and a light chain variable region comprising an amino acid sequence that is at least 80%, at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical to the amino acid sequence of SEQ ID NO: 286. In some embodiments, the antibody of the antibody-drug conjugate is worse. In some instances, the antibodies provided herein bind to CD70. In some such cases, the antibody comprises CDR-H1, CDR-H2, CDR-H3, CDR-L1, CDR-L2, and CDR-L3 sequences that comprise at least 80% sequence identity, at least 85% sequence identity, at least 90% sequence identity, or at least 95% sequence identity to the amino acid sequences of SEQ ID NOs: 279, 280, 281, 282, 283, and 284, respectively. In some cases, the antibody comprises CDR-H1, CDR-H2, CDR-H3, CDR-L1, CDR-L2, and CDR-L3 sequences that each comprise at most one mutation relative to the amino acid sequences of SEQ ID NOs: 279, 280, 281, 282, 283, and 284, respectively.

In some embodiments, the antibody-drug conjugates provided herein bind to B7-H3. In some embodiments, the antibody of the antibody-drug conjugate comprises CDR-H1, CDR-H2, CDR-H3, CDR-L1, CDR-L2 and CDR-L3, which respectively comprise the amino acid sequences of SEQ ID NO: 675, 676, 677, 678, 679 and 680. In some embodiments, the antibody of the antibody-drug conjugate comprises a heavy chain variable region comprising an amino acid sequence that is at least 80%, at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical to the amino acid sequence of SEQ ID NO: 681; and a light chain variable region comprising an amino acid sequence that is at least 80%, at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical to the amino acid sequence of SEQ ID NO: 682. In some embodiments, the antibody of the antibody-drug conjugate is mizotocin.

In some cases, an antibody provided herein binds to B7-H4. In some cases, the antibody comprises a set of CDR sequences (CDR-H1, CDR-H2, CDR-H3, CDR-L1, CDR-L2 and CDR-L3, respectively), wherein each sequence comprises at least 80% sequence identity, at least 85% sequence identity, at least 90% sequence identity, at least 95% or 100% sequence identity with an amino acid sequence in the set of amino acid sequences selected from the group consisting of: SEQ ID No: 57-62, SEQ ID No: 71-76, SEQ ID No: 79-84, SEQ ID No: 87-92, SEQ ID No: 95-100, SEQ ID No: 103-108, SEQ ID No: 111-116, SEQ ID No: 119-124, SEQ ID No: 127-132, SEQ ID No: 135-140, SEQ ID No: 143-148, SEQ ID No: 151-156, SEQ ID No: 159-164, SEQ ID No: 167-172, SEQ ID No: 175-180, SEQ ID No: 183-188, SEQ ID No: 191-196, SEQ ID No: 199-204, SEQ ID No: 207-212, SEQ ID No: 215-220 and SEQ ID No: 223-228. In some cases, the antibody comprises a set of CDR sequences (CDR-H1, CDR-H2, CDR-H3, CDR-L1, CDR-L2 and CDR-L3, respectively), each sequence comprising at most one mutation relative to an amino acid sequence in the set of amino acid sequences selected from the group consisting of: SEQ ID No: 57-62, SEQ ID No: 71-76, SEQ ID No: 79-84, SEQ ID No: 87-92, SEQ ID No: 95-100, SEQ ID No: 103-108, SEQ ID No: 111-116, SEQ ID No: 119-124, SEQ ID No: 127-132, SEQ ID No: 135-140, SEQ ID No: 143-148, SEQ ID No: 151-156, SEQ ID No: 159-164, SEQ ID No: 167-172, SEQ ID No: 175-180, SEQ ID No: 183-188, SEQ ID No: 191-196, SEQ ID No: 199-204, SEQ ID No: 207-212, SEQ ID No: 215-220 and SEQ ID NO: 223-228. In some cases, the anti-B7-H4 antibody comprises a heavy chain and a light chain comprising an amino acid sequence that is at least 80%, at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical to the following amino acid sequence: SEQ ID NOs: 65 and 67, SEQ ID NOs: 66 and 67, SEQ ID NOs: 68 and 67, SEQ ID NOs: 69 and 67, SEQ ID NOs: 68 and 70, SEQ ID NOs: 69 and 70, SEQ ID NOs: 231 and 232, SEQ ID NOs: 233 and 234, SEQ ID NOs: 235 and 236, SEQ ID NOs: 237 and 238, SEQ ID NOs: 239 and 240, SEQ ID NOs: 241 and 242, SEQ ID NOs: 243 and 244, SEQ ID NOs: 245 and 246, SEQ ID NO: 247 and 248, SEQ ID NO: 249 and 250, SEQ ID NO: 251 and 252, SEQ ID NO: 253 and 254, SEQ ID NO: 255 and 256, SEQ ID NO: 257 and 258, SEQ ID NO: 259 and 260, SEQ ID NO: 261 and 262, SEQ ID NO: 263 and 264, SEQ ID NO: 265 and 266, SEQ ID NO: 267 and 268 or SEQ ID NO: 269 and 270. In some embodiments, the anti-B7-H4 antibody comprises a heavy chain variable region and a light chain variable region, which respectively comprise an amino acid sequence that is at least 80%, at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical to the following amino acid sequence: SEQ ID NOs: 63 and 64, SEQ ID NOs: 77 and 78, SEQ ID NOs: 85 and 86, SEQ ID NOs: 93 and 94, SEQ ID NOs: 101 and 102, SEQ ID NOs: 109 and 110, SEQ ID NOs: 117 and 118, SEQ ID NOs: 125 and 126, SEQ ID NOs: 133 and 134, SEQ ID NOs: 141 and 142, SEQ ID NOs: 149 and 150, SEQ ID NOs: 157 and 158, SEQ ID NOs: 165 and 166, SEQ ID NO: 173 and 174, SEQ ID NO: 181 and 182, SEQ ID NO: 189 and 190, SEQ ID NO: 197 and 198, SEQ ID NO: 205 and 206, SEQ ID NO: 213 and 214, SEQ ID NO: 221 and 222 or SEQ ID NO: 229 and 230.

In some embodiments, the antibody-drug conjugates provided herein bind to CD 138. In some embodiments, the antibody of the antibody-drug conjugate comprises CDR-H1, CDR-H2, CDR-H3, CDR-L1, CDR-L2 and CDR-L3, which respectively comprise the amino acid sequences of SEQ ID NOs: 483, 484, 485, 486, 487 and 488. In some embodiments, the antibody of the antibody-drug conjugate comprises a heavy chain variable region comprising an amino acid sequence that is at least 80%, at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical to the amino acid sequence of SEQ ID NO: 489; and a light chain variable region comprising an amino acid sequence that is at least 80%, at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical to the amino acid sequence of SEQ ID NO: 490. In some embodiments, the antibody of the antibody-drug conjugate is indatuximab.

In some embodiments, the antibody-drug conjugate provided herein binds to CD 166. In some embodiments, the antibody of the antibody-drug conjugate comprises CDR-H1, CDR-H2, CDR-H3, CDR-L1, CDR-L2 and CDR-L3, which respectively comprise the amino acid sequences of SEQ ID NO: 491, 492, 493, 494, 495 and 496. In some embodiments, the antibody of the antibody-drug conjugate comprises a heavy chain variable region comprising an amino acid sequence that is at least 80%, at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical to the amino acid sequence of SEQ ID NO: 497; and a light chain variable region comprising an amino acid sequence that is at least 80%, at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical to the amino acid sequence of SEQ ID NO: 498. In some embodiments, the antibody of the antibody-drug conjugate is protuzumab.

In some embodiments, the antibody-drug conjugates provided herein bind to CD56. In some embodiments, the antibody of the antibody-drug conjugate comprises CDR-H1, CDR-H2, CDR-H3, CDR-L1, CDR-L2 and CDR-L3, which respectively comprise the amino acid sequences of SEQ ID NO: 499, 500, 501, 502, 503 and 504. In some embodiments, the antibody of the antibody-drug conjugate comprises a heavy chain variable region comprising an amino acid sequence that is at least 80%, at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical to the amino acid sequence of SEQ ID NO: 505; and a light chain variable region comprising an amino acid sequence that is at least 80%, at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical to the amino acid sequence of SEQ ID NO: 506. In some embodiments, the antibody of the antibody-drug conjugate is lovotouzumab.

In some embodiments, the antibody-drug conjugates provided herein bind to CD74. In some embodiments, the antibody of the antibody-drug conjugate comprises CDR-H1, CDR-H2, CDR-H3, CDR-L1, CDR-L2, and CDR-L3, which comprise the amino acid sequences of SEQ ID NOs: 507, 508, 509, 510, 511, and 512, respectively. In some embodiments, the antibody of the antibody-drug conjugate comprises a heavy chain variable region comprising an amino acid sequence that is at least 80%, at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical to the amino acid sequence of SEQ ID NO: 513; and a light chain variable region comprising an amino acid sequence that is at least 80%, at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical to the amino acid sequence of SEQ ID NO: 514. In some embodiments, the antibody of the antibody-drug conjugate is milatuzumab.

In some embodiments, the antibody-drug conjugates provided herein bind to CEACAM5. In some embodiments, the antibody of the antibody-drug conjugate comprises CDR-H1, CDR-H2, CDR-H3, CDR-L1, CDR-L2 and CDR-L3, which comprise the amino acid sequences of SEQ ID NO: 515, 516, 517, 518, 519 and 520, respectively. In some embodiments, the antibody of the antibody-drug conjugate comprises a heavy chain variable region comprising an amino acid sequence that is at least 80%, at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical to the amino acid sequence of SEQ ID NO: 521; and a light chain variable region comprising an amino acid sequence that is at least 80%, at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical to the amino acid sequence of SEQ ID NO: 522. In some embodiments, the antibody of the antibody-drug conjugate is labetuzumab.

In some embodiments, the antibody-drug conjugates provided herein bind to CanAg. In some embodiments, the antibody of the antibody-drug conjugate comprises CDR-H1, CDR-H2, CDR-H3, CDR-L1, CDR-L2 and CDR-L3, which respectively comprise the amino acid sequences of SEQ ID NO: 523, 524, 525, 526, 527 and 528. In some embodiments, the antibody of the antibody-drug conjugate comprises a heavy chain variable region comprising an amino acid sequence that is at least 80%, at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical to the amino acid sequence of SEQ ID NO: 529; and a light chain variable region comprising an amino acid sequence that is at least 80%, at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical to the amino acid sequence of SEQ ID NO: 530. In some embodiments, the antibody of the antibody-drug conjugate is cantuzumab.

In some embodiments, the antibody-drug conjugates provided herein bind to DLL-3. In some embodiments, the antibody of the antibody-drug conjugate comprises CDR-H1, CDR-H2, CDR-H3, CDR-L1, CDR-L2 and CDR-L3, which comprise the amino acid sequences of SEQ ID NOs: 531, 532, 533, 534, 535 and 536, respectively. In some embodiments, the antibody of the antibody-drug conjugate comprises a heavy chain variable region comprising an amino acid sequence that is at least 80%, at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical to the amino acid sequence of SEQ ID NO: 537; and a light chain variable region comprising an amino acid sequence that is at least 80%, at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical to the amino acid sequence of SEQ ID NO: 538. In some embodiments, the antibody of the antibody-drug conjugate is lovatuzumab.

In some embodiments, the antibody-drug conjugates provided herein bind to DPEP-3. In some embodiments, the antibody of the antibody-drug conjugate comprises CDR-H1, CDR-H2, CDR-H3, CDR-L1, CDR-L2 and CDR-L3, which respectively comprise the amino acid sequences of SEQ ID NO: 539, 540, 541, 542, 543 and 544. In some embodiments, the antibody of the antibody-drug conjugate comprises a heavy chain variable region comprising an amino acid sequence that is at least 80%, at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical to the amino acid sequence of SEQ ID NO: 545; and a light chain variable region comprising an amino acid sequence that is at least 80%, at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical to the amino acid sequence of SEQ ID NO: 546. In some embodiments, the antibody of the antibody-drug conjugate is talinomab.

In some embodiments, the antibody-drug conjugate provided herein binds to EGFR. In some embodiments, the antibody of the antibody-drug conjugate comprises CDR-H1, CDR-H2, CDR-H3, CDR-L1, CDR-L2 and CDR-L3, which respectively comprise the amino acid sequences of SEQ ID NO: 547, 548, 549, 550, 551 and 552. In some embodiments, the antibody of the antibody-drug conjugate comprises a heavy chain variable region comprising an amino acid sequence that is at least 80%, at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical to the amino acid sequence of SEQ ID NO: 553; and a light chain variable region comprising an amino acid sequence that is at least 80%, at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical to the amino acid sequence of SEQ ID NO: 554. In some embodiments, the antibody of the antibody-drug conjugate is latuximab. In some embodiments, the antibody of the antibody-drug conjugate comprises CDR-H1, CDR-H2, CDR-H3, CDR-L1, CDR-L2 and CDR-L3, which comprise the amino acid sequences of SEQ ID NOs: 555, 556, 557, 558, 559 and 560, respectively. In some embodiments, the antibody of the antibody-drug conjugate comprises a heavy chain variable region comprising an amino acid sequence that is at least 80%, at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99% or 100% identical to the amino acid sequence of SEQ ID NO: 561; and a light chain variable region comprising an amino acid sequence that is at least 80%, at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99% or 100% identical to the amino acid sequence of SEQ ID NO: 562. In some embodiments, the antibody of the antibody-drug conjugate is rotuximab. In some embodiments, the antibody of the antibody-drug conjugate is sinostatin. In some embodiments, the antibody of the antibody-drug conjugate comprises CDR-H1, CDR-H2, CDR-H3, CDR-L1, CDR-L2 and CDR-L3, which comprise the amino acid sequences of SEQ ID NOs: 563, 564, 565, 566, 567 and 568, respectively. In some embodiments, the antibody of the antibody-drug conjugate comprises a heavy chain variable region comprising an amino acid sequence that is at least 80%, at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical to the amino acid sequence of SEQ ID NO: 569; and a light chain variable region comprising an amino acid sequence that is at least 80%, at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical to the amino acid sequence of SEQ ID NO: 570. In some embodiments, the antibody of the antibody-drug conjugate is cetuximab.

In some embodiments, the antibody-drug conjugates provided herein bind to FRα. In some embodiments, the antibody of the antibody-drug conjugate comprises CDR-H1, CDR-H2, CDR-H3, CDR-L1, CDR-L2 and CDR-L3, which respectively comprise the amino acid sequences of SEQ ID NOs: 571, 572, 573, 574, 575 and 576. In some embodiments, the antibody of the antibody-drug conjugate comprises a heavy chain variable region comprising an amino acid sequence that is at least 80%, at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical to the amino acid sequence of SEQ ID NO: 577; and a light chain variable region comprising an amino acid sequence that is at least 80%, at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical to the amino acid sequence of SEQ ID NO: 578. In some embodiments, the antibody of the antibody-drug conjugate is miviltuximab. In some embodiments, the antibody of the antibody-drug conjugate comprises CDR-H1, CDR-H2, CDR-H3, CDR-L1, CDR-L2 and CDR-L3, which comprise the amino acid sequences of SEQ ID NOs: 579, 580, 581, 582, 583 and 584, respectively. In some embodiments, the antibody of the antibody-drug conjugate comprises a heavy chain variable region comprising an amino acid sequence that is at least 80%, at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical to the amino acid sequence of SEQ ID NO: 585; and a light chain variable region comprising an amino acid sequence that is at least 80%, at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical to the amino acid sequence of SEQ ID NO: 586. In some embodiments, the antibody of the antibody-drug conjugate is fatuzumab.

In some embodiments, the antibody-drug conjugates provided herein bind to MUC-1. In some embodiments, the antibody of the antibody-drug conjugate comprises CDR-H1, CDR-H2, CDR-H3, CDR-L1, CDR-L2 and CDR-L3, which comprise the amino acid sequences of SEQ ID NOs: 587, 588, 589, 590, 591 and 592, respectively. In some embodiments, the antibody of the antibody-drug conjugate comprises a heavy chain variable region comprising an amino acid sequence that is at least 80%, at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical to the amino acid sequence of SEQ ID NO: 593; and a light chain variable region comprising an amino acid sequence that is at least 80%, at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical to the amino acid sequence of SEQ ID NO: 594. In some embodiments, the antibody of the antibody-drug conjugate is galotuzumab.

In some embodiments, the antibody-drug conjugates provided herein bind to mesothelin. In some embodiments, the antibody of the antibody-drug conjugate comprises CDR-H1, CDR-H2, CDR-H3, CDR-L1, CDR-L2 and CDR-L3, which respectively comprise the amino acid sequences of SEQ ID NO: 595, 596, 597, 598, 599 and 600. In some embodiments, the antibody of the antibody-drug conjugate comprises a heavy chain variable region comprising an amino acid sequence that is at least 80%, at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical to the amino acid sequence of SEQ ID NO: 601; and a light chain variable region comprising an amino acid sequence that is at least 80%, at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical to the amino acid sequence of SEQ ID NO: 602. In some embodiments, the antibody of the antibody-drug conjugate is anetomab.

In some embodiments, the antibody-drug conjugates provided herein bind to ROR-1. In some embodiments, the antibody of the antibody-drug conjugate comprises CDR-H1, CDR-H2, CDR-H3, CDR-L1, CDR-L2 and CDR-L3, which respectively comprise the amino acid sequences of SEQ ID NOs: 603, 604, 605, 606, 607 and 608. In some embodiments, the antibody of the antibody-drug conjugate comprises a heavy chain variable region comprising an amino acid sequence that is at least 80%, at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical to the amino acid sequence of SEQ ID NO: 609; and a light chain variable region comprising an amino acid sequence that is at least 80%, at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical to the amino acid sequence of SEQ ID NO: 610. In some embodiments, the antibody of the antibody-drug conjugate is zilovertamab.

In some embodiments, the antibody-drug conjugates provided herein bind to B7-H4. In some embodiments, the antibody of the antibody-drug conjugate comprises CDR-H1, CDR-H2, CDR-H3, CDR-L1, CDR-L2 and CDR-L3, which comprise the amino acid sequences of SEQ ID NO: 95, 96, 97, 98, 99 and 100, respectively. In some embodiments, the antibody of the antibody-drug conjugate comprises a heavy chain variable region comprising an amino acid sequence that is at least 80%, at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99% or 100% identical to the amino acid sequence of SEQ ID NO: 101; and a light chain variable region comprising an amino acid sequence that is at least 80%, at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99% or 100% identical to the amino acid sequence of SEQ ID NO: 102. In some embodiments, the antibody of the antibody-drug conjugate is 20502. See WO2019040780.

In some embodiments, the antibody-drug conjugates provided herein bind to B7-H3. In some embodiments, the antibody of the antibody-drug conjugate comprises CDR-H1, CDR-H2, CDR-H3, CDR-L1, CDR-L2 and CDR-L3, which respectively comprise the amino acid sequences of SEQ ID NO: 611, 612, 613, 614, 615 and 616. In some embodiments, the antibody of the antibody-drug conjugate comprises a heavy chain variable region comprising an amino acid sequence that is at least 80%, at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99% or 100% identical to the amino acid sequence of SEQ ID NO: 617; and a light chain variable region comprising an amino acid sequence that is at least 80%, at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99% or 100% identical to the amino acid sequence of SEQ ID NO: 618. In some embodiments, the antibody of the antibody-drug conjugate is chAb-A (BRCA84D). In some embodiments, the antibody of the antibody-drug conjugate is hAb-B. In some embodiments, the antibody of the antibody-drug conjugate comprises CDR-H1, CDR-H2, CDR-H3, CDR-L1, CDR-L2 and CDR-L3, which comprise the amino acid sequences of SEQ ID NOs: 619, 620, 621, 622, 623 and 624, respectively. In some embodiments, the antibody of the antibody-drug conjugate comprises a heavy chain variable region comprising an amino acid sequence that is at least 80%, at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical to the amino acid sequence of SEQ ID NO: 625; and a light chain variable region comprising an amino acid sequence that is at least 80%, at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical to the amino acid sequence of SEQ ID NO: 626. In some embodiments, the antibody of the antibody-drug conjugate is hAb-C. In some embodiments, the antibody of the antibody-drug conjugate comprises CDR-H1, CDR-H2, CDR-H3, CDR-L1, CDR-L2 and CDR-L3, which comprise the amino acid sequences of SEQ ID NOs: 627, 628, 629, 630, 631 and 632, respectively. In some embodiments, the antibody of the antibody-drug conjugate comprises a heavy chain variable region comprising an amino acid sequence that is at least 80%, at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical to the amino acid sequence of SEQ ID NO: 633; and a light chain variable region comprising an amino acid sequence that is at least 80%, at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical to the amino acid sequence of SEQ ID NO: 634. In some embodiments, the antibody of the antibody-drug conjugate is hAb-D. In some embodiments, the antibody of the antibody-drug conjugate comprises CDR-H1, CDR-H2, CDR-H3, CDR-L1, CDR-L2 and CDR-L3, which comprise the amino acid sequences of SEQ ID NOs: 635, 636, 637, 638, 639 and 640, respectively. In some embodiments, the antibody of the antibody-drug conjugate comprises a heavy chain variable region comprising an amino acid sequence that is at least 80%, at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical to the amino acid sequence of SEQ ID NO: 641; and a light chain variable region comprising an amino acid sequence that is at least 80%, at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical to the amino acid sequence of SEQ ID NO: 642. In some embodiments, the antibody of the antibody-drug conjugate is chM30. In some embodiments, the antibody of the antibody-drug conjugate comprises CDR-H1, CDR-H2, CDR-H3, CDR-L1, CDR-L2 and CDR-L3, which comprise the amino acid sequences of SEQ ID NOs: 643, 644, 645, 646, 647 and 648, respectively. In some embodiments, the antibody of the antibody-drug conjugate comprises a heavy chain variable region comprising an amino acid sequence that is at least 80%, at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical to the amino acid sequence of SEQ ID NO: 649; and a light chain variable region comprising an amino acid sequence that is at least 80%, at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical to the amino acid sequence of SEQ ID NO: 650. In some embodiments, the antibody of the antibody-drug conjugate is hM30-H1-L4. In some embodiments, the antibody of the antibody-drug conjugate comprises CDR-H1, CDR-H2, CDR-H3, CDR-L1, CDR-L2 and CDR-L3, which comprise the amino acid sequences of SEQ ID NOs: 651, 652, 653, 654, 655 and 656, respectively. In some embodiments, the antibody of the antibody-drug conjugate comprises a heavy chain variable region comprising an amino acid sequence that is at least 80%, at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical to the amino acid sequence of SEQ ID NO: 657; and a light chain variable region comprising an amino acid sequence that is at least 80%, at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical to the amino acid sequence of SEQ ID NO: 658. In some embodiments, the antibody of the antibody-drug conjugate is AbV_huAb18-v4. In some embodiments, the antibody of the antibody-drug conjugate comprises CDR-H1, CDR-H2, CDR-H3, CDR-L1, CDR-L2 and CDR-L3, which comprise the amino acid sequences of SEQ ID NOs: 659, 660, 661, 662, 663 and 664, respectively. In some embodiments, the antibody of the antibody-drug conjugate comprises a heavy chain variable region comprising an amino acid sequence that is at least 80%, at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical to the amino acid sequence of SEQ ID NO: 665; and a light chain variable region comprising an amino acid sequence that is at least 80%, at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical to the amino acid sequence of SEQ ID NO: 666. In some embodiments, the antibody of the antibody-drug conjugate is AbV_huAb3-v6. In some embodiments, the antibody of the antibody-drug conjugate comprises CDR-H1, CDR-H2, CDR-H3, CDR-L1, CDR-L2 and CDR-L3, which comprise the amino acid sequences of SEQ ID NOs: 667, 668, 669, 670, 671 and 672, respectively. In some embodiments, the antibody of the antibody-drug conjugate comprises a heavy chain variable region comprising an amino acid sequence that is at least 80%, at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical to the amino acid sequence of SEQ ID NO: 673; and a light chain variable region comprising an amino acid sequence that is at least 80%, at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical to the amino acid sequence of SEQ ID NO: 674. In some embodiments, the antibody of the antibody-drug conjugate is AbV_huAb3-v2.6. In some embodiments, the antibody of the antibody-drug conjugate comprises CDR-H1, CDR-H2, CDR-H3, CDR-L1, CDR-L2 and CDR-L3, which comprise the amino acid sequences of SEQ ID NOs: 675, 676, 677, 678, 679 and 680, respectively. In some embodiments, the antibody of the antibody-drug conjugate comprises a heavy chain variable region comprising an amino acid sequence that is at least 80%, at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99% or 100% identical to the amino acid sequence of SEQ ID NO: 681; and a light chain variable region comprising an amino acid sequence that is at least 80%, at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99% or 100% identical to the amino acid sequence of SEQ ID NO: 682. In some embodiments, the antibody of the antibody-drug conjugate is AbV_huAb13-v1-CR. In some embodiments, the antibody of the antibody-drug conjugate comprises CDR-H1, CDR-H2, CDR-H3, CDR-L1, CDR-L2 and CDR-L3, which comprise the amino acid sequences of SEQ ID NOs: 683, 684, 685, 686, 687 and 688, respectively. In some embodiments, the antibody of the antibody-drug conjugate comprises a heavy chain variable region comprising an amino acid sequence that is at least 80%, at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical to the amino acid sequence of SEQ ID NO: 689; and a light chain variable region comprising an amino acid sequence that is at least 80%, at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical to the amino acid sequence of SEQ ID NO: 690. In some embodiments, the antibody of the antibody-drug conjugate is 8H9-6m. In some embodiments, the antibody of the antibody-drug conjugate comprises a heavy chain variable region comprising an amino acid sequence that is at least 80%, at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical to the amino acid sequence of SEQ ID NO: 691; and a light chain variable region comprising an amino acid sequence that is at least 80%, at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical to the amino acid sequence of SEQ ID NO: 692. In some embodiments, the antibody of the antibody-drug conjugate is m8517. In some embodiments, the antibody of the antibody-drug conjugate comprises CDR-H1, CDR-H2, CDR-H3, CDR-L1, CDR-L2 and CDR-L3, which comprise the amino acid sequences of SEQ ID NOs: 693, 694, 695, 696, 697 and 698, respectively. In some embodiments, the antibody of the antibody-drug conjugate comprises a heavy chain variable region comprising an amino acid sequence that is at least 80%, at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical to the amino acid sequence of SEQ ID NO: 699; and a light chain variable region comprising an amino acid sequence that is at least 80%, at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical to the amino acid sequence of SEQ ID NO: 700. In some embodiments, the antibody of the antibody-drug conjugate is TPP-5706. In some embodiments, the antibody of the antibody-drug conjugate comprises a heavy chain variable region comprising an amino acid sequence that is at least 80%, at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical to the amino acid sequence of SEQ ID NO: 701; and a light chain variable region comprising an amino acid sequence that is at least 80%, at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical to the amino acid sequence of SEQ ID NO: 702. In some embodiments, the antibody of the antibody-drug conjugate is TPP-6642. In some embodiments, the antibody of the antibody-drug conjugate comprises a heavy chain variable region comprising an amino acid sequence that is at least 80%, at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical to the amino acid sequence of SEQ ID NO: 703; and a light chain variable region comprising an amino acid sequence that is at least 80%, at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical to the amino acid sequence of SEQ ID NO: 704. In some embodiments, the antibody of the antibody-drug conjugate is TPP-6850. In some embodiments, the antibody of the antibody-drug conjugate comprises a CDR-H2 comprising the amino acid sequence of SEQ ID NO: 612. In some embodiments, the antibody of the antibody-drug conjugate comprises a CDR-H3 comprising an amino acid sequence of SEQ ID NO: 613. In some embodiments, the antibody of the antibody-drug conjugate comprises a CDR-L1 comprising an amino acid sequence of SEQ ID NO: 614. In some embodiments, the antibody of the antibody-drug conjugate comprises a CDR-L2 comprising an amino acid sequence of SEQ ID NO: 615. In some embodiments, the antibody of the antibody-drug conjugate comprises a CDR-L3 comprising an amino acid sequence of SEQ ID NO: 616. In some embodiments, the antibody of the antibody-drug conjugate is chAb-A (BRCA84D). In some embodiments, the antibody of the antibody-drug conjugate comprises a CDR-H1 comprising an amino acid sequence of SEQ ID NO: 619. In some embodiments, the antibody of the antibody-drug conjugate comprises a CDR-H2 comprising an amino acid sequence of SEQ ID NO: 620. In some embodiments, the antibody of the antibody-drug conjugate comprises a CDR-H3 comprising an amino acid sequence of SEQ ID NO: 621. In some embodiments, the antibody of the antibody-drug conjugate comprises a CDR-L1 comprising an amino acid sequence of SEQ ID NO: 622. In some embodiments, the antibody of the antibody-drug conjugate is hAb-B. In some embodiments, the antibody of the antibody-drug conjugate comprises a CDR-L3 comprising an amino acid sequence of SEQ ID NO: 624. In some embodiments, the antibody of the antibody-drug conjugate comprises a CDR-H1 comprising an amino acid sequence of SEQ ID NO: 627. In some embodiments, the antibody of the antibody-drug conjugate comprises a CDR-H2 comprising an amino acid sequence of SEQ ID NO: 628. In some embodiments, the antibody of the antibody-drug conjugate comprises a CDR-H3 comprising an amino acid sequence of SEQ ID NO: 629. In some embodiments, the antibody of the antibody-drug conjugate comprises a CDR-L1 comprising an amino acid sequence of SEQ ID NO: 630. In some embodiments, the antibody of the antibody-drug conjugate comprises a CDR-L2 comprising an amino acid sequence of SEQ ID NO: 631. In some embodiments, the antibody of the antibody-drug conjugate comprises a CDR-L3 comprising an amino acid sequence of SEQ ID NO: 632. In some embodiments, the antibody of the antibody-drug conjugate comprises a CDR-H1 comprising an amino acid sequence of SEQ ID NO: 651. In some embodiments, the antibody of the antibody-drug conjugate comprises a CDR-H1 comprising an amino acid sequence of SEQ ID NO: 659. In some embodiments, the antibody of the antibody-drug conjugate comprises a CDR-H3 comprising an amino acid sequence of SEQ ID NO: 661. In some embodiments, the antibody of the antibody-drug conjugate comprises a CDR-H1 comprising an amino acid sequence of SEQ ID NO: 667. In some embodiments, the antibody of the antibody-drug conjugate comprises a CDR-H1 comprising an amino acid sequence of SEQ ID NO: 675. In some embodiments, the antibody of the antibody-drug conjugate comprises a CDR-H2 comprising an amino acid sequence of SEQ ID NO: 684. In some embodiments, the antibody of the antibody-drug conjugate comprises a CDR-L3 comprising an amino acid sequence of SEQ ID NO: 688.

In some embodiments, the antibody-drug conjugate provided herein binds to CDCP1. In some embodiments, the antibody of the antibody-drug conjugate is 10D7.

In some embodiments, the antibody-drug conjugates provided herein bind to HER3. In some embodiments, the antibody of the antibody-drug conjugate comprises a heavy chain comprising an amino acid sequence that is at least 80%, at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical to the amino acid sequence of SEQ ID NO: 705; and a light chain comprising an amino acid sequence that is at least 80%, at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical to the amino acid sequence of SEQ ID NO: 706. In some embodiments, the antibody of the antibody-drug conjugate is Pertuzumab. In some embodiments, the antibody of the antibody-drug conjugate comprises a heavy chain comprising an amino acid sequence that is at least 80%, at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical to the amino acid sequence of SEQ ID NO: 707; and a light chain comprising an amino acid sequence that is at least 80%, at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical to the amino acid sequence of SEQ ID NO: 708. In some embodiments, the antibody of the antibody-drug conjugate is cerituzumab. In some embodiments, the antibody of the antibody-drug conjugate comprises a heavy chain comprising an amino acid sequence that is at least 80%, at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical to the amino acid sequence of SEQ ID NO: 709; and a light chain comprising an amino acid sequence that is at least 80%, at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical to the amino acid sequence of SEQ ID NO: 710. In some embodiments, the antibody of the antibody-drug conjugate is efrucizumab. In some embodiments, the antibody of the antibody-drug conjugate comprises a heavy chain, an amino acid sequence that is at least 80%, at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical to the amino acid sequence of SEQ ID NO: 711; and a light chain, which comprises an amino acid sequence that is at least 80%, at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical to the amino acid sequence of SEQ ID NO: 712. In some embodiments, the antibody of the antibody-drug conjugate is rutuzumab.

In some embodiments, the antibody-drug conjugates provided herein bind to RON. In some embodiments, the antibody of the antibody-drug conjugate is Zt/g4.

In some embodiments, the antibody-drug conjugates provided herein bind to claudin-2.

In some embodiments, the antibody-drug conjugates provided herein bind to HLA-G.

In some embodiments, the antibody-drug conjugates provided herein bind to PTK7. In some embodiments, the antibody of the antibody-drug conjugate comprises CDR-H1, CDR-H2, CDR-H3, CDR-L1, CDR-L2 and CDR-L3, which respectively comprise the amino acid sequences of SEQ ID NO: 713, 714, 715, 716, 717 and 718. In some embodiments, the antibody of the antibody-drug conjugate comprises a heavy chain variable region comprising an amino acid sequence that is at least 80%, at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical to the amino acid sequence of SEQ ID NO: 719; and a light chain variable region comprising an amino acid sequence that is at least 80%, at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical to the amino acid sequence of SEQ ID NO: 720. In some embodiments, the antibody of the antibody-drug conjugate is PTK7 mab 1. In some embodiments, the antibody of the antibody-drug conjugate comprises CDR-H1, CDR-H2, CDR-H3, CDR-L1, CDR-L2 and CDR-L3, which comprise the amino acid sequences of SEQ ID NOs: 721, 722, 723, 724, 725 and 726, respectively. In some embodiments, the antibody of the antibody-drug conjugate comprises a heavy chain variable region comprising an amino acid sequence that is at least 80%, at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical to the amino acid sequence of SEQ ID NO: 727; and a light chain variable region comprising an amino acid sequence that is at least 80%, at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical to the amino acid sequence of SEQ ID NO: 728. In some embodiments, the antibody of the antibody-drug conjugate is PTK7 mab 2. In some embodiments, the antibody of the antibody-drug conjugate comprises CDR-H1, CDR-H2, CDR-H3, CDR-L1, CDR-L2 and CDR-L3, which comprise the amino acid sequences of SEQ ID NOs: 729, 730, 731, 732, 733 and 734, respectively. In some embodiments, the antibody of the antibody-drug conjugate comprises a heavy chain variable region comprising an amino acid sequence that is at least 80%, at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical to the amino acid sequence of SEQ ID NO: 735; and a light chain variable region comprising an amino acid sequence that is at least 80%, at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical to the amino acid sequence of SEQ ID NO: 736. In some embodiments, the antibody of the antibody-drug conjugate is PTK7 mab 3.

In some embodiments, the antibody-drug conjugates provided herein bind to LIV1. In some embodiments, the antibody of the antibody-drug conjugate comprises CDR-H1, CDR-H2, CDR-H3, CDR-L1, CDR-L2 and CDR-L3, which respectively comprise the amino acid sequences of SEQ ID NOs: 737, 738, 739, 740, 741 and 742. In some embodiments, the antibody of the antibody-drug conjugate comprises a heavy chain variable region comprising an amino acid sequence that is at least 80%, at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical to the amino acid sequence of SEQ ID NO: 743; and a light chain variable region comprising an amino acid sequence that is at least 80%, at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical to the amino acid sequence of SEQ ID NO: 744. In some embodiments, the antibody of the antibody-drug conjugate comprises a heavy chain comprising an amino acid sequence that is at least 80%, at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99% or 100% identical to the amino acid sequence of SEQ ID NO: 745; and a light chain comprising an amino acid sequence that is at least 80%, at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99% or 100% identical to the amino acid sequence of SEQ ID NO: 746. In some embodiments, the antibody of the antibody-drug conjugate is latuzumab, which is also known as hLIV22 and hglg. See WO2012078668.

In some embodiments, the antibody-drug conjugates provided herein bind to integrin avb6 (or integrin β6/ITGB6). In some embodiments, the antibody of the antibody-drug conjugate comprises CDR-H1, CDR-H2, CDR-H3, CDR-L1, CDR-L2 and CDR-L3, which respectively comprise the amino acid sequences of SEQ ID NOs: 43, 44, 45, 46, 47 and 48. In some embodiments, the antibody of the antibody-drug conjugate comprises a heavy chain variable region comprising an amino acid sequence that is at least 80%, at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical to the amino acid sequence of SEQ ID NO: 49; and a light chain variable region comprising an amino acid sequence that is at least 80%, at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical to the amino acid sequence of SEQ ID NO: 50. In some embodiments, the antibody of the antibody-drug conjugate comprises a heavy chain comprising an amino acid sequence that is at least 80%, at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical to the amino acid sequence of SEQ ID NO: 51 or SEQ ID NO: 52; and a light chain comprising an amino acid sequence that is at least 80%, at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical to the amino acid sequence of SEQ ID NO: 53. In some embodiments, the antibody of the antibody-drug conjugate comprises a heavy chain comprising an amino acid sequence that is at least 80%, at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99% or 100% identical to the amino acid sequence of SEQ ID NO: 54 or SEQ ID NO: 55; and a light chain comprising an amino acid sequence that is at least 80%, at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99% or 100% identical to the amino acid sequence of SEQ ID NO: 56. In some embodiments, the antibody of the antibody-drug conjugate is h2A2. See PCT/US20/63390. In some embodiments, the antibody of the antibody-drug conjugate comprises CDR-H1, CDR-H2, CDR-H3, CDR-L1, CDR-L2 and CDR-L3, which comprise the amino acid sequences of SEQ ID NOs: 747, 748, 749, 750, 751 and 752, respectively. In some embodiments, the antibody of the antibody-drug conjugate comprises a heavy chain variable region comprising an amino acid sequence that is at least 80%, at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99% or 100% identical to the amino acid sequence of SEQ ID NO: 753; and a light chain variable region comprising an amino acid sequence that is at least 80%, at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99% or 100% identical to the amino acid sequence of SEQ ID NO: 754. In some embodiments, the antibody of the antibody-drug conjugate is h15H3. See WO 2013/123152.

In some cases, the antibodies provided herein bind to integrin avB6 (or integrin β6/ITGB6). In some such cases, the antibody comprises CDR-H1, CDR-H2, CDR-H3, CDR-L1, CDR-L2, and CDR-L3 sequences, which contain at least 80% sequence identity, at least 85% sequence identity, at least 90% sequence identity, or at least 95% sequence identity with the amino acid sequences of SEQ ID NOs: 43, 44, 45, 46, 47, and 48, respectively. In some cases, the antibody comprises CDR-H1, CDR-H2, CDR-H3, CDR-L1, CDR-L2, and CDR-L3 sequences, each of which contains at most one mutation relative to the amino acid sequences of SEQ ID NOs: 43, 44, 45, 46, 47, and 48, respectively. In some embodiments, the antibody comprises a heavy chain variable region comprising an amino acid sequence that is at least 80%, at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical to the amino acid sequence of SEQ ID NO: 49; and a light chain variable region comprising an amino acid sequence that is at least 80%, at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical to the amino acid sequence of SEQ ID NO: 50. In some embodiments, the antibody comprises a heavy chain comprising an amino acid sequence that is at least 80%, at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99% or 100% identical to the amino acid sequence of SEQ ID NO: 51 or 52; and a light chain comprising an amino acid sequence that is at least 80%, at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99% or 100% identical to the amino acid sequence of SEQ ID NO: 53. In some embodiments, the antibody comprises a heavy chain comprising an amino acid sequence that is at least 80%, at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99% or 100% identical to the amino acid sequence of SEQ ID NO: 54 or 55; and a light chain comprising an amino acid sequence that is at least 80%, at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99% or 100% identical to the amino acid sequence of SEQ ID NO: 56.

In some embodiments, the antibody-drug conjugates provided herein bind to CD48. In some embodiments, the antibody of the antibody-drug conjugate comprises CDR-H1, CDR-H2, CDR-H3, CDR-L1, CDR-L2 and CDR-L3, which respectively comprise the amino acid sequences of SEQ ID NO: 755, 756, 757, 758, 759 and 760. In some embodiments, the antibody of the antibody-drug conjugate comprises a heavy chain variable region comprising an amino acid sequence that is at least 80%, at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99% or 100% identical to the amino acid sequence of SEQ ID NO: 761; and a light chain variable region comprising an amino acid sequence that is at least 80%, at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99% or 100% identical to the amino acid sequence of SEQ ID NO: 762. In some embodiments, the antibody of the antibody-drug conjugate is hMEM102. See WO2016149535.

In some embodiments, the antibody-drug conjugates provided herein bind to PD-L1. In some embodiments, the antibody of the antibody-drug conjugate comprises CDR-H1, CDR-H2, CDR-H3, CDR-L1, CDR-L2 and CDR-L3, which respectively comprise the amino acid sequences of SEQ ID NO: 271, 272, 273, 274, 275 and 276. In some embodiments, the antibody of the antibody-drug conjugate comprises a heavy chain variable region comprising an amino acid sequence that is at least 80%, at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99% or 100% identical to the amino acid sequence of SEQ ID NO: 277; and a light chain variable region comprising an amino acid sequence that is at least 80%, at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99% or 100% identical to the amino acid sequence of SEQ ID NO: 278. In some embodiments, the antibody of the antibody-drug conjugate is SG-559-01 mAb or SG-559-01 LALA mAb. See PCT/US2020/054037.

In some cases, the anti-PDL1 antibody comprises CDR-H1, CDR-H2, CDR-H3, CDR-L1, CDR-L2 and CDR-L3, which respectively comprise at least 80% sequence identity, at least 85% sequence identity, at least 90% sequence identity, at least 95% sequence identity, at least 98% sequence identity or at least 99% sequence identity with the amino acid sequence of SEQ ID NOs: 271, 272, 273, 274, 275 and 276. In some cases, the antibody comprises CDR-H1, CDR-H2, CDR-H3, CDR-L1, CDR-L2 and CDR-L3, each of which comprises at most one mutation relative to the amino acid sequence of SEQ ID NOs: 271, 272, 273, 274, 275 and 276, respectively.

In some embodiments, the antibody comprises a heavy chain variable region comprising an amino acid sequence that is at least 80%, at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical to the amino acid sequence of SEQ ID NO: 277; and a light chain variable region comprising an amino acid sequence that is at least 80%, at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical to the amino acid sequence of SEQ ID NO: 278.

In some embodiments, the antibodies provided herein bind to EphA2. In some embodiments, the antibodies comprise CDR-H1, CDR-H2, CDR-H3, CDR-L1, CDR-L2, and CDR-L3, which comprise an amino acid sequence that is at least 80%, at least 85%, at least 90%, at least 95%, at least 98%, or at least 99% identical to the amino acid sequence of SEQ ID NOs: 12, 13, 14, 15, 16, and 17, respectively.

In some embodiments, the anti-EphA2 antibody comprises a heavy chain variable region comprising an amino acid sequence that is at least 80%, at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical to the amino acid sequence of SEQ ID NO: 18; and a light chain variable region comprising an amino acid sequence that is at least 80%, at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical to the amino acid sequence of SEQ ID NO: 19. In some embodiments, the anti-EphA2 antibody comprises a heavy chain comprising an amino acid sequence that is at least 80%, at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99% or 100% identical to the amino acid sequence of SEQ ID NO: 20 or SEQ ID NO: 21; and a light chain comprising an amino acid sequence that is at least 80%, at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99% or 100% identical to the amino acid sequence of SEQ ID NO: 22. In some embodiments, the anti-EphA2 antibody comprises a heavy chain comprising an amino acid sequence that is at least 80%, at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99% or 100% identical to the amino acid sequence of SEQ ID NO: 23 or SEQ ID NO: 24; and a light chain comprising an amino acid sequence that is at least 80%, at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99% or 100% identical to the amino acid sequence of SEQ ID NO: 25. In some embodiments, the anti-EphA2 antibody comprises a heavy chain that is at least 80%, at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical to the amino acid sequence of SEQ ID NO: 26 or SEQ ID NO: 27, and a light chain that comprises an amino acid sequence that is at least 80%, at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical to the amino acid sequence of SEQ ID NO: 28. In some embodiments, the antibody is h1C1 or 1C1.

In some embodiments, the anti-EphA2 antibody comprises a heavy chain variable region comprising an amino acid sequence that is at least 80%, at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical to the amino acid sequence of SEQ ID NO: 18; and a light chain variable region comprising an amino acid sequence that is at least 80%, at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical to the amino acid sequence of SEQ ID NO: 19.

In some embodiments, the antibody-drug conjugates provided herein bind to IGF-1R. In some embodiments, the antibody of the antibody-drug conjugate comprises CDR-H1, CDR-H2, CDR-H3, CDR-L1, CDR-L2 and CDR-L3, which respectively comprise the amino acid sequences of SEQ ID NO: 763, 764, 765, 766, 767 and 768. In some embodiments, the antibody of the antibody-drug conjugate comprises a heavy chain variable region comprising an amino acid sequence that is at least 80%, at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical to the amino acid sequence of SEQ ID NO: 769; and a light chain variable region comprising an amino acid sequence that is at least 80%, at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical to the amino acid sequence of SEQ ID NO: 770. In some embodiments, the antibody of the antibody-drug conjugate is cixitumumab.

In some embodiments, the antibody-drug conjugates provided herein bind to claudin-18.2. In some embodiments, the antibody of the antibody-drug conjugate comprises CDR-H1, CDR-H2, CDR-H3, CDR-L1, CDR-L2, and CDR-L3, which respectively comprise the amino acid sequences of SEQ ID NOs: 771, 772, 773, 774, 775, and 776. In some embodiments, the antibody of the antibody-drug conjugate comprises a heavy chain variable region comprising an amino acid sequence that is at least 80%, at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical to the amino acid sequence of SEQ ID NO: 777; and a light chain variable region comprising an amino acid sequence that is at least 80%, at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical to the amino acid sequence of SEQ ID NO: 778. In some embodiments, the antibody of the antibody-drug conjugate is levobetumab (175D10). In some embodiments, the antibody of the antibody-drug conjugate comprises CDR-H1, CDR-H2, CDR-H3, CDR-L1, CDR-L2 and CDR-L3, which comprise the amino acid sequences of SEQ ID NOs: 779, 780, 781, 782, 783 and 784, respectively. In some embodiments, the antibody of the antibody-drug conjugate comprises a heavy chain variable region comprising an amino acid sequence that is at least 80%, at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical to the amino acid sequence of SEQ ID NO: 785; and a light chain variable region comprising an amino acid sequence that is at least 80%, at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical to the amino acid sequence of SEQ ID NO: 786. In some embodiments, the antibody of the antibody-drug conjugate is 163E12.

In some embodiments, the antibody-drug conjugates provided herein bind to nectin-4. In some embodiments, the antibody of the antibody-drug conjugate comprises CDR-H1, CDR-H2, CDR-H3, CDR-L1, CDR-L2 and CDR-L3, which respectively comprise the amino acid sequences of SEQ ID NOs: 787, 788, 789, 790, 791 and 792. In some embodiments, the antibody of the antibody-drug conjugate comprises a heavy chain variable region comprising an amino acid sequence that is at least 80%, at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99% or 100% identical to the amino acid sequence of SEQ ID NO: 793; and a light chain variable region comprising an amino acid sequence that is at least 80%, at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99% or 100% identical to the amino acid sequence of SEQ ID NO: 794. In some embodiments, the antibody of the antibody-drug conjugate is enroku. See WO 2012047724.

In some embodiments, the antibody-drug conjugates provided herein bind to SLTRK6. In some embodiments, the antibody of the antibody-drug conjugate comprises CDR-H1, CDR-H2, CDR-H3, CDR-L1, CDR-L2 and CDR-L3, which respectively comprise the amino acid sequences of SEQ ID NO: 795, 796, 797, 798, 799 and 800. In some embodiments, the antibody of the antibody-drug conjugate comprises a heavy chain variable region comprising an amino acid sequence that is at least 80%, at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical to the amino acid sequence of SEQ ID NO: 801; and a light chain variable region comprising an amino acid sequence that is at least 80%, at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical to the amino acid sequence of SEQ ID NO: 802. In some embodiments, the antibody of the antibody-drug conjugate is cetrozumab.

In some embodiments, the antibody-drug conjugates provided herein bind to CD228. In some embodiments, the antibody of the antibody-drug conjugate comprises CDR-H1, CDR-H2, CDR-H3, CDR-L1, CDR-L2 and CDR-L3, which respectively comprise the amino acid sequences of SEQ ID NOs: 29, 30, 31, 32, 33 and 34. In some embodiments, the antibody of the antibody-drug conjugate comprises a heavy chain variable region comprising an amino acid sequence that is at least 80%, at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99% or 100% identical to the amino acid sequence of SEQ ID NO: 35; and a light chain variable region comprising an amino acid sequence that is at least 80%, at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99% or 100% identical to the amino acid sequence of SEQ ID NO: 36. In some embodiments, the antibody of the antibody-drug conjugate is hL49. See WO 2020/163225.

In some cases, the antibodies provided herein bind to CD228. In some such cases, the antibody comprises CDR-H1, CDR-H2, CDR-H3, CDR-L1, CDR-L2 and CDR-L3 sequences, which contain at least 80% sequence identity, at least 85% sequence identity, at least 90% sequence identity or at least 95% sequence identity with the amino acid sequences of SEQ ID NOs: 29, 30, 31, 32, 33 and 34, respectively. In some cases, the antibody comprises CDR-H1, CDR-H2, CDR-H3, CDR-L1, CDR-L2 and CDR-L3 sequences, each of which contains at most one mutation relative to the amino acid sequences of SEQ ID NOs: 29, 30, 31, 32, 33 and 34, respectively. In some embodiments, the anti-CD228 antibody comprises a heavy chain variable region comprising an amino acid sequence that is at least 80%, at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical to the amino acid sequence of SEQ ID NO: 35; and a light chain variable region comprising an amino acid sequence that is at least 80%, at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical to the amino acid sequence of SEQ ID NO: 36. In some embodiments, the anti-CD228 antibody comprises a heavy chain comprising an amino acid sequence that is at least 80%, at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical to the amino acid sequence of any one of SEQ ID NO: 37 or 38; and a light chain comprising an amino acid sequence that is at least 80%, at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical to the amino acid sequence of SEQ ID NO: 39. In some embodiments, the anti-CD228 antibody comprises a heavy chain comprising an amino acid sequence that is at least 80%, at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical to the amino acid sequence of any one of SEQ ID NO: 40 or 41; and a light chain comprising an amino acid sequence that is at least 80%, at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical to the amino acid sequence of SEQ ID NO: 42.

In some embodiments, the antibody-drug conjugates provided herein bind to CD142 (tissue factor; TF). In some embodiments, the antibody of the antibody-drug conjugate comprises CDR-H1, CDR-H2, CDR-H3, CDR-L1, CDR-L2 and CDR-L3, which respectively comprise the amino acid sequences of SEQ ID NOs: 803, 804, 805, 806, 807 and 808. In some embodiments, the antibody of the antibody-drug conjugate comprises a heavy chain variable region comprising an amino acid sequence that is at least 80%, at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99% or 100% identical to the amino acid sequence of SEQ ID NO: 809; and a light chain variable region comprising an amino acid sequence that is at least 80%, at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99% or 100% identical to the amino acid sequence of SEQ ID NO: 810. In some embodiments, the antibody of the antibody-drug conjugate is tisomonab. See WO 2010/066803.

In some embodiments, the antibody-drug conjugate provided herein is bound to STn. In some embodiments, the antibody of the antibody-drug conjugate comprises CDR-H1, CDR-H2, CDR-H3, CDR-L1, CDR-L2 and CDR-L3, which respectively comprise the amino acid sequences of SEQ ID NO: 811, 812, 813, 814, 815 and 816. In some embodiments, the antibody of the antibody-drug conjugate comprises a heavy chain variable region comprising an amino acid sequence that is at least 80%, at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical to the amino acid sequence of SEQ ID NO: 817; and a light chain variable region comprising an amino acid sequence that is at least 80%, at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical to the amino acid sequence of SEQ ID NO: 818. In some embodiments, the antibody of the antibody-drug conjugate is h2G12.

In some embodiments, the antibody-drug conjugates provided herein bind to CD20. In some embodiments, the antibody of the antibody-drug conjugate comprises CDR-H1, CDR-H2, CDR-H3, CDR-L1, CDR-L2 and CDR-L3, which comprise the amino acid sequences of SEQ ID NOs: 819, 820, 821, 822, 823 and 824, respectively. In some embodiments, the antibody of the antibody-drug conjugate comprises a heavy chain variable region comprising an amino acid sequence that is at least 80%, at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical to the amino acid sequence of SEQ ID NO: 825; and a light chain variable region comprising an amino acid sequence that is at least 80%, at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical to the amino acid sequence of SEQ ID NO: 826. In some embodiments, the antibody of the antibody-drug conjugate is rituximab.

In some embodiments, the antibody-drug conjugates provided herein bind to HER2. In some embodiments, the antibody of the antibody-drug conjugate comprises CDR-H1, CDR-H2, CDR-H3, CDR-L1, CDR-L2 and CDR-L3, which respectively comprise the amino acid sequences of SEQ ID NOs: 827, 828, 829, 830, 831 and 832. In some embodiments, the antibody of the antibody-drug conjugate comprises a heavy chain variable region comprising an amino acid sequence that is at least 80%, at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical to the amino acid sequence of SEQ ID NO: 833; and a light chain variable region comprising an amino acid sequence that is at least 80%, at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical to the amino acid sequence of SEQ ID NO: 834. In some embodiments, the antibody of the antibody-drug conjugate is trastuzumab. In some embodiments, the antibody of the antibody-drug conjugate comprises CDR-H1, CDR-H2, CDR-H3, CDR-L1, CDR-L2 and CDR-L3, which comprise the amino acid sequences of SEQ ID NOs: 1048, 1049, 1050, 1051, 1052 and 1053, respectively. In some embodiments, the antibody of the antibody-drug conjugate comprises a heavy chain variable region comprising an amino acid sequence that is at least 80%, at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical to the amino acid sequence of SEQ ID NO: 1054; and a light chain variable region comprising an amino acid sequence that is at least 80%, at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical to the amino acid sequence of SEQ ID NO: 1055. In some embodiments, the antibody of the antibody-drug conjugate is desizumab/RC48.

In some embodiments, the antibody-drug conjugates provided herein bind to FLT3.

In some embodiments, the antibody-drug conjugates provided herein bind to CD46.

In some embodiments, the antibody-drug conjugates provided herein are conjugated to GloboH.

In some embodiments, the antibody-drug conjugates provided herein bind to AG7.

In some embodiments, the antibody-drug conjugates provided herein bind to mesothelin.

In some embodiments, the antibody-drug conjugates provided herein bind to FCRH5.

In some embodiments, the antibody-drug conjugates provided herein bind to ETBR.

In some embodiments, the antibody-drug conjugates provided herein bind to Tim-1.

In some embodiments, the antibody-drug conjugates provided herein bind to SLC44A4.

In some embodiments, the antibody-drug conjugates provided herein bind to ENPP3.

In some embodiments, the antibody-drug conjugates provided herein bind to CD37.

In some embodiments, the antibody-drug conjugates provided herein bind to CA9.

In some embodiments, the antibody-drug conjugates provided herein bind to Notch3.

In some embodiments, the antibody-drug conjugates provided herein bind to EphA2.

In some embodiments, the antibody-drug conjugates provided herein are conjugated to TRFC.

In some embodiments, the antibody-drug conjugates provided herein bind to PSMA.

In some embodiments, the antibody-drug conjugates provided herein bind to LRRC15.

In some embodiments, the antibody-drug conjugates provided herein bind to 5T4.

In some embodiments, the antibody-drug conjugates provided herein bind to CD79b. In some embodiments, the antibody of the antibody-drug conjugate comprises CDR-H1, CDR-H2, CDR-H3, CDR-L1, CDR-L2 and CDR-L3, which respectively comprise the amino acid sequences of SEQ ID NO: 835, 836, 837, 838, 839 and 840. In some embodiments, the antibody of the antibody-drug conjugate comprises a heavy chain variable region comprising an amino acid sequence that is at least 80%, at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical to the amino acid sequence of SEQ ID NO: 841; and a light chain variable region comprising an amino acid sequence that is at least 80%, at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical to the amino acid sequence of SEQ ID NO: 842. In some embodiments, the antibody of the antibody-drug conjugate is polotuzumab.

In some embodiments, the antibody-drug conjugates provided herein bind to NaPi2B. In some embodiments, the antibody of the antibody-drug conjugate comprises CDR-H1, CDR-H2, CDR-H3, CDR-L1, CDR-L2 and CDR-L3, which respectively comprise the amino acid sequences of SEQ ID NO: 843, 844, 845, 846, 847 and 848. In some embodiments, the antibody of the antibody-drug conjugate comprises a heavy chain variable region comprising an amino acid sequence that is at least 80%, at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical to the amino acid sequence of SEQ ID NO: 849; and a light chain variable region comprising an amino acid sequence that is at least 80%, at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical to the amino acid sequence of SEQ ID NO: 850. In some embodiments, the antibody of the antibody-drug conjugate is rifatuzumab.

In some embodiments, the antibody-drug conjugates provided herein bind to Muc 16. In some embodiments, the antibody of the antibody-drug conjugate comprises CDR-H1, CDR-H2, CDR-H3, CDR-L1, CDR-L2 and CDR-L3, which respectively comprise the amino acid sequences of SEQ ID NOs: 851, 852, 853, 854, 855 and 856. In some embodiments, the antibody of the antibody-drug conjugate comprises a heavy chain variable region comprising an amino acid sequence that is at least 80%, at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical to the amino acid sequence of SEQ ID NO: 857; and a light chain variable region comprising an amino acid sequence that is at least 80%, at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical to the amino acid sequence of SEQ ID NO: 858. In some embodiments, the antibody of the antibody-drug conjugate is sofetozumab.

In some embodiments, the antibody-drug conjugates provided herein bind to STEAP1. In some embodiments, the antibody of the antibody-drug conjugate comprises CDR-H1, CDR-H2, CDR-H3, CDR-L1, CDR-L2 and CDR-L3, which comprise the amino acid sequences of SEQ ID NOs: 859, 860, 861, 862, 863 and 864, respectively. In some embodiments, the antibody of the antibody-drug conjugate comprises a heavy chain variable region comprising an amino acid sequence that is at least 80%, at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical to the amino acid sequence of SEQ ID NO: 865; and a light chain variable region comprising an amino acid sequence that is at least 80%, at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical to the amino acid sequence of SEQ ID NO: 866. In some embodiments, the antibody of the antibody-drug conjugate is vendotumab.

In some embodiments, the antibody-drug conjugates provided herein bind to BCMA. In some embodiments, the antibody of the antibody-drug conjugate comprises CDR-H1, CDR-H2, CDR-H3, CDR-L1, CDR-L2 and CDR-L3, which respectively comprise the amino acid sequences of SEQ ID NOs: 867, 868, 869, 870, 871 and 872. In some embodiments, the antibody of the antibody-drug conjugate comprises a heavy chain variable region comprising an amino acid sequence that is at least 80%, at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical to the amino acid sequence of SEQ ID NO: 873; and a light chain variable region comprising an amino acid sequence that is at least 80%, at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical to the amino acid sequence of SEQ ID NO: 874. In some embodiments, the antibody of the antibody-drug conjugate is berantuzumab.

In some embodiments, the antibody-drug conjugates provided herein bind to c-Met. In some embodiments, the antibody of the antibody-drug conjugate comprises CDR-H1, CDR-H2, CDR-H3, CDR-L1, CDR-L2 and CDR-L3, which respectively comprise the amino acid sequences of SEQ ID NO: 875, 876, 877, 878, 879 and 880. In some embodiments, the antibody of the antibody-drug conjugate comprises a heavy chain variable region comprising an amino acid sequence that is at least 80%, at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99% or 100% identical to the amino acid sequence of SEQ ID NO: 881; and a light chain variable region comprising an amino acid sequence that is at least 80%, at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99% or 100% identical to the amino acid sequence of SEQ ID NO: 882. In some embodiments, the antibody of the antibody-drug conjugate is terituzumab.

In some embodiments, the antibody-drug conjugate provided herein binds to EGFR. In some embodiments, the antibody of the antibody-drug conjugate comprises CDR-H1, CDR-H2, CDR-H3, CDR-L1, CDR-L2 and CDR-L3, which respectively comprise the amino acid sequences of SEQ ID NO: 883, 884, 885, 886, 887 and 888. In some embodiments, the antibody of the antibody-drug conjugate comprises a heavy chain variable region comprising an amino acid sequence that is at least 80%, at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical to the amino acid sequence of SEQ ID NO: 889; and a light chain variable region comprising an amino acid sequence that is at least 80%, at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical to the amino acid sequence of SEQ ID NO: 890. In some embodiments, the antibody of the antibody-drug conjugate is detuximab.

In some embodiments, the antibody-drug conjugates provided herein bind to SLAMF7. In some embodiments, the antibody of the antibody-drug conjugate comprises CDR-H1, CDR-H2, CDR-H3, CDR-L1, CDR-L2 and CDR-L3, which respectively comprise the amino acid sequences of SEQ ID NO: 891, 892, 893, 894, 895 and 896. In some embodiments, the antibody of the antibody-drug conjugate comprises a heavy chain variable region comprising an amino acid sequence that is at least 80%, at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical to the amino acid sequence of SEQ ID NO: 897; and a light chain variable region comprising an amino acid sequence that is at least 80%, at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical to the amino acid sequence of SEQ ID NO: 898. In some embodiments, the antibody of the antibody-drug conjugate is atuximab.

In some embodiments, the antibody-drug conjugates provided herein bind to C4.4a (also known as LYPD3). In some embodiments, the antibody of the antibody-drug conjugate comprises CDR-H1, CDR-H2, CDR-H3, CDR-L1, CDR-L2 and CDR-L3, which comprise the amino acid sequences of SEQ ID NOs: 899, 900, 901, 902, 903 and 904, respectively. In some embodiments, the antibody of the antibody-drug conjugate comprises a heavy chain variable region comprising an amino acid sequence that is at least 80%, at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical to the amino acid sequence of SEQ ID NO: 905; and a light chain variable region comprising an amino acid sequence that is at least 80%, at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical to the amino acid sequence of SEQ ID NO: 906. In some embodiments, the antibody of the antibody-drug conjugate is rupaturomab.

In some embodiments, the antibody-drug conjugates provided herein bind to GCC. In some embodiments, the antibody of the antibody-drug conjugate comprises CDR-H1, CDR-H2, CDR-H3, CDR-L1, CDR-L2 and CDR-L3, which respectively comprise the amino acid sequences of SEQ ID NO: 907, 908, 909, 910, 911 and 912. In some embodiments, the antibody of the antibody-drug conjugate comprises a heavy chain variable region comprising an amino acid sequence that is at least 80%, at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical to the amino acid sequence of SEQ ID NO: 913; and a light chain variable region comprising an amino acid sequence that is at least 80%, at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical to the amino acid sequence of SEQ ID NO: 914. In some embodiments, the antibody of the antibody-drug conjugate is indolimab.

In some embodiments, the antibody-drug conjugates provided herein bind to Axl. In some embodiments, the antibody of the antibody-drug conjugate comprises CDR-H1, CDR-H2, CDR-H3, CDR-L1, CDR-L2 and CDR-L3, which respectively comprise the amino acid sequences of SEQ ID NO: 915, 916, 917, 918, 919 and 920. In some embodiments, the antibody of the antibody-drug conjugate comprises a heavy chain variable region comprising an amino acid sequence that is at least 80%, at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical to the amino acid sequence of SEQ ID NO: 921; and a light chain variable region comprising an amino acid sequence that is at least 80%, at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical to the amino acid sequence of SEQ ID NO: 922. In some embodiments, the antibody of the antibody-drug conjugate is vincelotuzumab.

In some embodiments, the antibody-drug conjugates provided herein bind to gpNMB. In some embodiments, the antibody of the antibody-drug conjugate comprises CDR-H1, CDR-H2, CDR-H3, CDR-L1, CDR-L2 and CDR-L3, which respectively comprise the amino acid sequences of SEQ ID NO: 923, 924, 925, 926, 927 and 928. In some embodiments, the antibody of the antibody-drug conjugate comprises a heavy chain variable region comprising an amino acid sequence that is at least 80%, at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical to the amino acid sequence of SEQ ID NO: 929; and a light chain variable region comprising an amino acid sequence that is at least 80%, at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical to the amino acid sequence of SEQ ID NO: 930. In some embodiments, the anti-gpNMB antibody comprises a heavy chain comprising an amino acid sequence that is at least 80%, at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical to the amino acid sequence of SEQ ID NO: 931; and a light chain comprising an amino acid sequence that is at least 80%, at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical to the amino acid sequence of SEQ ID NO: 932. In some embodiments, the antibody of the antibody-drug conjugate is gebatumumab.

In some embodiments, the antibody-drug conjugate provided herein is bound to prolactin receptor (PRLR). In some embodiments, the antibody of the antibody-drug conjugate comprises CDR-H1, CDR-H2, CDR-H3, CDR-L1, CDR-L2 and CDR-L3, which respectively comprise the amino acid sequence of SEQ ID NO: 933, 934, 935, 936, 937 and 938. In some embodiments, the antibody of the antibody-drug conjugate comprises a heavy chain variable region comprising an amino acid sequence that is at least 80%, at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical to the amino acid sequence of SEQ ID NO: 939; and a light chain variable region comprising an amino acid sequence that is at least 80%, at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical to the amino acid sequence of SEQ ID NO: 940. In some embodiments, the antibody of the antibody-drug conjugate is lorinomab.

In some embodiments, the antibody-drug conjugates provided herein bind to FGFR2. In some embodiments, the antibody of the antibody-drug conjugate comprises CDR-H1, CDR-H2, CDR-H3, CDR-L1, CDR-L2 and CDR-L3, which respectively comprise the amino acid sequences of SEQ ID NO: 941, 942, 943, 944, 945 and 946. In some embodiments, the antibody of the antibody-drug conjugate comprises a heavy chain variable region comprising an amino acid sequence that is at least 80%, at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical to the amino acid sequence of SEQ ID NO: 947; and a light chain variable region comprising an amino acid sequence that is at least 80%, at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical to the amino acid sequence of SEQ ID NO: 948. In some embodiments, the antibody of the antibody-drug conjugate is aprazumab.

In some embodiments, the antibody-drug conjugate provided herein binds to CDCP1. In some embodiments, the antibody of the antibody-drug conjugate comprises CDR-H1, CDR-H2, CDR-H3, CDR-L1, CDR-L2 and CDR-L3, which respectively comprise the amino acid sequences of SEQ ID NOs: 949, 950, 951, 952, 953 and 954. In some embodiments, the antibody of the antibody-drug conjugate comprises a heavy chain variable region comprising an amino acid sequence that is at least 80%, at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical to the amino acid sequence of SEQ ID NO: 955; and a light chain variable region comprising an amino acid sequence that is at least 80%, at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical to the amino acid sequence of SEQ ID NO: 956. In some embodiments, the antibody of the antibody-drug conjugate is humanized CUB4 #135 HC4-H. In some embodiments, the antibody of the antibody-drug conjugate comprises CDR-H1, CDR-H2, CDR-H3, CDR-L1, CDR-L2 and CDR-L3, which comprise the amino acid sequences of SEQ ID NOs: 957, 958, 959, 960, 961 and 962, respectively. In some embodiments, the antibody of the antibody-drug conjugate comprises a heavy chain variable region comprising an amino acid sequence that is at least 80%, at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical to the amino acid sequence of SEQ ID NO: 963; and a light chain variable region comprising an amino acid sequence that is at least 80%, at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical to the amino acid sequence of SEQ ID NO: 964. In some embodiments, the antibody of the antibody-drug conjugate is CUB4. In some embodiments, the antibody of the antibody-drug conjugate comprises CDR-H1, CDR-H2, CDR-H3, CDR-L1, CDR-L2 and CDR-L3, which comprise the amino acid sequences of SEQ ID NOs: 965, 966, 967, 968, 969, 970, respectively. In some embodiments, the antibody of the antibody-drug conjugate comprises a heavy chain variable region comprising an amino acid sequence that is at least 80%, at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical to the amino acid sequence of SEQ ID NO: 971; and a light chain variable region comprising an amino acid sequence that is at least 80%, at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical to the amino acid sequence of SEQ ID NO: 972. In some embodiments, the antibody of the antibody-drug conjugate is CP13E10-WT. In some embodiments, the antibody of the antibody-drug conjugate comprises CDR-H1, CDR-H2, CDR-H3, CDR-L1, CDR-L2 and CDR-L3, which comprise the amino acid sequences of SEQ ID NOs: 973, 974, 975, 976, 977 and 978, respectively. In some embodiments, the antibody of the antibody-drug conjugate comprises a heavy chain variable region comprising an amino acid sequence that is at least 80%, at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99% or 100% identical to the amino acid sequence of SEQ ID NO: 979; and a light chain variable region comprising an amino acid sequence that is at least 80%, at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99% or 100% identical to the amino acid sequence of SEQ ID NO: 980. In some embodiments, the antibody of the antibody-drug conjugate is CP13E10-54HCv13-89LCv1. In some embodiments, the antibody-drug conjugates provided herein bind to CDCP1. In some embodiments, the antibody of the antibody-drug conjugate comprises a heavy chain variable region comprising an amino acid sequence that is at least 80%, at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical to the amino acid sequence of SEQ ID NO: 955; and a light chain variable region comprising an amino acid sequence that is at least 80%, at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical to the amino acid sequence of SEQ ID NO: 956. In some embodiments, the antibody of the antibody-drug conjugate is humanized CUB4 #135 HC4-H. In some embodiments, the antibody of the antibody-drug conjugate comprises a heavy chain variable region comprising an amino acid sequence that is at least 80%, at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical to the amino acid sequence of SEQ ID NO: 963; and a light chain variable region comprising an amino acid sequence that is at least 80%, at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical to the amino acid sequence of SEQ ID NO: 964. In some embodiments, the antibody of the antibody-drug conjugate is CUB4. In some embodiments, the antibody of the antibody-drug conjugate comprises CDR-H1, CDR-H2, CDR-H3, CDR-L1, CDR-L2 and CDR-L3, which comprise the amino acid sequences of SEQ ID NOs: 965, 966, 967, 968, 969, 970, respectively.

In some embodiments, the antibody-drug conjugates provided herein bind to ASCT2. In some embodiments, the antibody of the antibody-drug conjugate comprises a heavy chain variable region comprising an amino acid sequence that is at least 80%, at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical to the amino acid sequence of SEQ ID NO: 981; and a light chain variable region comprising an amino acid sequence that is at least 80%, at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical to the amino acid sequence of SEQ ID NO: 982. In some embodiments, the antibody of the antibody-drug conjugate is KM8094a. In some embodiments, the antibody of the antibody-drug conjugate comprises a heavy chain variable region comprising an amino acid sequence that is at least 80%, at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical to the amino acid sequence of SEQ ID NO: 983; and a light chain variable region comprising an amino acid sequence that is at least 80%, at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical to the amino acid sequence of SEQ ID NO: 984. In some embodiments, the antibody of the antibody-drug conjugate is KM8094b. In some embodiments, the antibody of the antibody-drug conjugate comprises CDR-H1, CDR-H2, CDR-H3, CDR-L1, CDR-L2 and CDR-L3, which comprise the amino acid sequences of SEQ ID NOs: 985, 986, 987, 988, 989 and 990, respectively. In some embodiments, the antibody of the antibody-drug conjugate comprises a heavy chain variable region comprising an amino acid sequence that is at least 80%, at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical to the amino acid sequence of SEQ ID NO: 991; and a light chain variable region comprising an amino acid sequence that is at least 80%, at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical to the amino acid sequence of SEQ ID NO: 992. In some embodiments, the antibody of the antibody-drug conjugate is KM4018.

In some embodiments, the antibody-drug conjugate provided herein binds to CD 123. In some embodiments, the antibody of the antibody-drug conjugate comprises CDR-H1, CDR-H2, CDR-H3, CDR-L1, CDR-L2 and CDR-L3, which respectively comprise the amino acid sequences of SEQ ID NO: 993, 994, 995, 996, 997 and 998. In some embodiments, the antibody of the antibody-drug conjugate comprises a heavy chain variable region comprising an amino acid sequence that is at least 80%, at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99% or 100% identical to the amino acid sequence of SEQ ID NO: 999; and a light chain variable region comprising an amino acid sequence that is at least 80%, at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99% or 100% identical to the amino acid sequence of SEQ ID NO: 1000. In some embodiments, the antibody of the antibody-drug conjugate is h7G3. See WO 2016201065.

In some embodiments, the antibody-drug conjugates provided herein bind to GPC3. In some embodiments, the antibody of the antibody-drug conjugate comprises CDR-H1, CDR-H2, CDR-H3, CDR-L1, CDR-L2 and CDR-L3, which respectively comprise the amino acid sequences of SEQ ID NOs: 1001, 1002, 1003, 1004, 1005 and 1006. In some embodiments, the antibody of the antibody-drug conjugate comprises a heavy chain variable region comprising an amino acid sequence that is at least 80%, at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99% or 100% identical to the amino acid sequence of SEQ ID NO: 1007; and a light chain variable region comprising an amino acid sequence that is at least 80%, at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99% or 100% identical to the amino acid sequence of SEQ ID NO: 1008. In some embodiments, the antibody of the antibody-drug conjugate is hGPC3-1. See WO 2019161174. In some embodiments, the antibody of the antibody-drug conjugate comprises a CDR-H2 comprising an amino acid sequence of SEQ ID NO: 1002. In some embodiments, the antibody of the antibody-drug conjugate comprises a CDR-L1 comprising the amino acid sequence of SEQ ID NO: 1004.

In some embodiments, the antibody-drug conjugates provided herein bind to TIGIT. In some embodiments, the antibody of the antibody-drug conjugate comprises CDR-H1, CDR-H2, CDR-H3, CDR-L1, CDR-L2 and CDR-L3, which respectively comprise the amino acid sequences of SEQ ID NO: 1009, 1010, 1011, 1012, 1013 and 1014. In some embodiments, the antibody of the antibody-drug conjugate comprises a heavy chain variable region comprising an amino acid sequence that is at least 80%, at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99% or 100% identical to the amino acid sequence of SEQ ID NO: 1015; and a light chain variable region comprising an amino acid sequence that is at least 80%, at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99% or 100% identical to the amino acid sequence of SEQ ID NO: 1016. In some embodiments, the antibody of the antibody-drug conjugate is Clone 13 (also known as ADI-23674 or mAb13). See WO 2020041541. In some embodiments, the antibody-drug conjugate provided herein binds to TIGIT. In some embodiments, the antibody of the antibody-drug conjugate comprises CDR-H1, CDR-H2, CDR-H3, CDR-L1, CDR-L2, and CDR-L3, which respectively comprise the amino acid sequences of SEQ ID NOs: 1009, 1010, 1011, 1012, 1013, and 1014. In some embodiments, the antibody of the antibody-drug conjugate comprises CDR-H3, which comprises the amino acid sequence of SEQ ID NO: 1011.

In some embodiments, the antibody-drug conjugate provided herein binds to STN. In some embodiments, the antibody of the antibody-drug conjugate comprises CDR-H1, CDR-H2, CDR-H3, CDR-L1, CDR-L2 and CDR-L3, which respectively comprise the amino acid sequences of SEQ ID NO: 811, 812, 813, 814, 815 and 816. In some embodiments, the antibody of the antibody-drug conjugate comprises a heavy chain variable region comprising an amino acid sequence that is at least 80%, at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99% or 100% identical to the amino acid sequence of SEQ ID NO: 817; and a light chain variable region comprising an amino acid sequence that is at least 80%, at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99% or 100% identical to the amino acid sequence of SEQ ID NO: 818. In some embodiments, the antibody of the antibody-drug conjugate is 2G12-2B2. See WO 2017083582.

In some embodiments, the antibody-drug conjugates provided herein bind to CD33. In some embodiments, the antibody of the antibody-drug conjugate comprises CDR-H1, CDR-H2, CDR-H3, CDR-L1, CDR-L2 and CDR-L3, which respectively comprise the amino acid sequences of SEQ ID NOs: 1017, 1018, 1019, 1020, 1021 and 1022. In some embodiments, the antibody of the antibody-drug conjugate comprises a heavy chain variable region comprising an amino acid sequence that is at least 80%, at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99% or 100% identical to the amino acid sequence of SEQ ID NO: 1023; and a light chain variable region comprising an amino acid sequence that is at least 80%, at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99% or 100% identical to the amino acid sequence of SEQ ID NO: 1024. In some embodiments, the antibody of the antibody-drug conjugate is h2H12. See WO2013173496.

In some embodiments, the antibody-drug conjugates provided herein bind to NTBA (also known as CD352). In some embodiments, the antibody of the antibody-drug conjugate comprises CDR-H1, CDR-H2, CDR-H3, CDR-L1, CDR-L2, and CDR-L3, which comprise the amino acid sequences of SEQ ID NOs: 417, 418, 419, 420, 421, and 422, respectively. In some embodiments, the antibody of the antibody-drug conjugate comprises a heavy chain variable region comprising an amino acid sequence that is at least 80%, at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99% or 100% identical to the amino acid sequence of SEQ ID NO: 423; and a light chain variable region comprising an amino acid sequence that is at least 80%, at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99% or 100% identical to the amino acid sequence of SEQ ID NO: 424. In some embodiments, the antibody of the antibody-drug conjugate is h20F3 HDLD. See WO 2017004330.

In some embodiments, the antibody-drug conjugates provided herein bind to BCMA. In some embodiments, the antibody of the antibody-drug conjugate comprises CDR-H1, CDR-H2, CDR-H3, CDR-L1, CDR-L2 and CDR-L3, which respectively comprise the amino acid sequences of SEQ ID NO: 1025, 1026, 1027, 1028, 1029 and 1030. In some embodiments, the antibody of the antibody-drug conjugate comprises a heavy chain variable region comprising an amino acid sequence that is at least 80%, at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99% or 100% identical to the amino acid sequence of SEQ ID NO: 1031; and a light chain variable region comprising an amino acid sequence that is at least 80%, at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99% or 100% identical to the amino acid sequence of SEQ ID NO: 1032. In some embodiments, the antibody of the antibody-drug conjugate is SEA-BCMA (also known as hSG16.17). See WO 2017/143069.

In some embodiments, the antibody-drug conjugates provided herein bind to tissue factor (also referred to as TF). In some embodiments, the antibody of the antibody-drug conjugate comprises CDR-H1, CDR-H2, CDR-H3, CDR-L1, CDR-L2 and CDR-L3, which respectively comprise the amino acid sequences of SEQ ID NOs: 803, 804, 805, 806, 807 and 808. In some embodiments, the antibody of the antibody-drug conjugate comprises a heavy chain variable region comprising an amino acid sequence that is at least 80%, at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99% or 100% identical to the amino acid sequence of SEQ ID NO: 809; and a light chain variable region comprising an amino acid sequence that is at least 80%, at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99% or 100% identical to the amino acid sequence of SEQ ID NO: 810. In some embodiments, the antibody of the antibody-drug conjugate is tisomonab. See WO 2010/066803 and US 9,150,658.

Throughout this application, unless the context indicates otherwise, references to Formula (A), (I), (IIa), (IIIa), (IVa), (IIb), (IIIb), (IVb), (IIc), (IIIc), (IVc), (A'), (I'), (IIa'), (IIIa'), (IVa'), (IIb'), (IIIb'), (IVb'), (IIc'), (IIIc'), (IVc') are referred to as References to compounds of Formula (A), (I), (IIa), (IIIa), (IVa), (IIb), (IIIb), (IVb), (IIc), (IIIc), (IVc), (A'), (I'), (IIa'), (IIIa'), (IVa'), (IIb'), (IIIb'), (IVb'), (IIc'), (IIIc'), (IVc') (IIa*), (IIIa*), (IVa*), (IIb*), (IIIb*), (IVb*), (IIc*), (IIIc*), (IVc*) or any subformula thereof as defined herein include all subgroups of Formula (A), (I), (IIa), (IIIa), (IVa), (IIb), (IIIb), (IVb), (IIc), (IIIc), (IVc), (A'), (I'), (IIa'), (IIIa'), (IVa'), (IIb'), (IIIb'), (IVb'), (IIc'), (IIIc'), (IVc') or any subformula thereof as defined herein, including all substructures, subgenera, preferences, embodiments, examples and specific compounds defined and/or described herein. Reference to a compound of Formula (A), (I), (IIa), (IIIa), (IVa), (IIb), (IIIb), (IVb), (IIc), (IIIc), (IVc), (A'), (I'), (IIa'), (IIIa'), (IVa'), (IIb'), (IIIb'), (IVb'), (IIc'), (IIIc'), (IVc') (IIa*), (IIIa*), (IVa*), (IIb*), (IIIb*), (IVb*), (IIc*), (IIIc*), (IVc*) or any subformula thereof includes ionic forms, polymorphs, pseudopolymorphs, amorphous forms, solvates, cocrystals, chelates, isomers, tautomers, oxides (e.g., N-oxides, S-oxides), esters, prodrugs, isotopes and/or protected forms thereof. In some embodiments, reference to a compound of Formula (A), (I), (IIa), (IIIa), (IVa), (IIb), (IIIb), (IVb), (IIc), (IIIc), (IVc), (A'), (I'), (IIa'), (IIIa'), (IVa'), (IIb'), (IIIb'), (IVb'), (IIc'), (IIIc'), (IVc') (IIa*), (IIIa*), (IVa*), (IIb*), (IIIb*), (IVb*), (IIc*), (IIIc*), (IVc*) or any subformula thereof includes polymorphs, solvates, cocrystals, isomers, tautomers, and/or oxides thereof. In some embodiments, reference to a compound of Formula (A), (I), (IIa), (IIIa), (IVa), (IIb), (IIIb), (IVb), (IIc), (IIIc), (IVc), (A'), (I'), (IIa'), (IIIa'), (IVa'), (IIb'), (IIIb'), (IVb'), (IIc'), (IIIc'), (IVc') (IIa*), (IIIa*), (IVa*), (IIb*), (IIIb*), (IVb*), (IIc*), (IIIc*), (IVc*) or any subformula thereof includes polymorphs, solvates and/or co-crystals thereof. In some embodiments, reference to a compound of Formula (A), (I), (IIa), (IIIa), (IVa), (IIb), (IIIb), (IVb), (IIc), (IIIc), (IVc), (A'), (I'), (IIa'), (IIIa'), (IVa'), (IIb'), (IIIb'), (IVb'), (IIc'), (IIIc'), (IVc') (IIa*), (IIIa*), (IVa*), (IIb*), (IIIb*), (IVb*), (IIc*), (IIIc*), (IVc*) or any subformula thereof includes isomers, tautomers, and/or oxides thereof. In some embodiments, reference to a compound of Formula (A), (I), (IIa), (IIIa), (IVa), (IIb), (IIIb), (IVb), (IIc), (IIIc), (IVc), (A'), (I'), (IIa'), (IIIa'), (IVa'), (IIb'), (IIIb'), (IVb'), (IIc'), (IIIc'), (IVc') (IIa*), (IIIa*), (IVa*), (IIb*), (IIIb*), (IVb*), (IIc*), (IIIc*), (IVc*), or any subformula thereof includes solvent complexes thereof. Similarly, the term "salt" includes solvent complexes of salts of the compound.

Any formula given herein (e.g., Formula (A), (I), (IIa), (IIIa), (IVa), (IIb), (IIIb), (IVb), (IIc), (IIIc), (IVc), (A'), (I'), (IIa'), (IIIa'), (IVa'), (IIb'), (IIIb'), (IVb'), (IIc'), (IIIc'), (IVc') (IIa*), (IIIa*), (IVa*), (IIb*), (IIIb*), (IVb*), (IIc*), (IIIc*), (IVc*) or any subformula thereof) is intended to represent compounds having the structure depicted by the formula as well as certain variations or forms. In particular, compounds of any formula given herein may have asymmetric centers and therefore exist in different enantiomeric or diastereomeric forms. All optical isomers and stereoisomers of the compounds of the general formula, and mixtures thereof in any ratio, are considered to be within the scope of the formula. Thus, any formula given herein is intended to represent a racemate, one or more enantiomeric forms, one or more diastereomeric forms, one or more atropisomeric forms, and mixtures thereof in any ratio. Where a compound of one of Tables 1, 2, 3, or 4 is depicted in a specific stereochemical configuration, any alternative stereochemical configuration of the compound, as well as mixtures of stereoisomers of the compound in any ratio, are also provided herein. For example, where a compound of Tables 1, 2, 3, or 4 has a stereocenter in the "S" stereochemical configuration, enantiomers of the compound are also provided herein, wherein the stereocenter is in the "R" stereochemical configuration. Likewise, when a compound of Table 1, 2, 3, or 4 has a stereocenter in the "R" configuration, enantiomers of the compound in the "S" stereochemical configuration are also provided herein. Mixtures of compounds having both "S" and "R" stereochemical configurations are also provided. In addition, if a compound of Table 1, 2, 3, or 4 has two or more stereocenters, any enantiomer or diastereomer of the compound is also provided. For example, if a compound of Table 1, 2, 3, or 4 contains a first stereocenter and a second stereocenter having "R" and "R" stereochemical configurations, respectively, stereoisomers of the compound having first and second stereocenters having "S" and "S" stereochemical configurations, respectively, having "S" and "R" stereochemical configurations, respectively, and having "R" and "S" stereochemical configurations, respectively, are also provided. If the compound of Table 1, 2, 3 or 4 contains a first stereocenter and a second stereocenter having the "S" and "S" stereochemical configurations, respectively, stereoisomers of the compound having first and second stereocenters having "R" and "R" stereochemical configurations, respectively, having "S" and "R" stereochemical configurations, respectively, and having "R" and "S" stereochemical configurations, respectively, are also provided. If the compound of Table 1, 2, 3 or 4 contains a first stereocenter and a second stereocenter having the "S" and "R" stereochemical configurations, respectively, stereoisomers of the compound having first and second stereocenters having "R" and "S" stereochemical configurations, respectively, having "R" and "R" stereochemical configurations, respectively, and having "S" and "S" stereochemical configurations, respectively, are also provided. Likewise, if a compound of Table 1, 2, 3, or 4 contains a first stereocenter and a second stereocenter having "R" and "S" stereochemical configurations, respectively, stereoisomers of the compound having first and second stereocenters having "S" and "R" stereochemical configurations, respectively, "R" and "R" stereochemical configurations, respectively, and "S" and "S" stereochemical configurations, respectively, are also provided. In addition, certain structures may exist as geometric isomers (i.e., cis and trans isomers), tautomers, or atropisomers. In addition, any formula given herein is intended to also refer to any of the hydrates, solvates, and amorphous and polymorphic forms of such compounds, as well as mixtures thereof, even if such forms are not explicitly listed. In some embodiments, the solvent is water and the solvate is a hydrate.

The compounds depicted herein may exist in salt form, even if a salt is not depicted, and it is understood that the compositions and methods provided herein encompass all salts and solvent complexes of the compounds depicted herein, as well as non-salt and non-solvent complex forms of the compounds, as is well understood by the skilled artisan. In some embodiments, the salts of the compounds provided herein are pharmaceutically acceptable salts.

Consider the following embodiments in which any variation or embodiment of Q, D, Z or Z', A, B, S*, RL, Y, W, L, ^X1 , ^Y1 , ^Z1 , X2, ^Y2 , Z2, ^X3 , ^X4 , Y4, ^Z4 , ^T4 , T, Ring A, R1, R4, ^R5 , ^R6 , ^R7 , ^R1X , ^R1Y , R2X, R3X, R4Y, ^S1 , ^Xc , q, n, m, R8, R9, ^{R10, and/or the subscript p provided herein are combined with Q, D, Z or Z '} , A, ^B , S ^* , RL, ^Y , W, L, ^X1 , ^Y1 , Z1, ^X2 , Y2, ^Z2 , X3, ^X4 , Y4, Z4, T4, T, Ring A, R1, R4, R5, R6, R7, R1X, R1Y, R2X, R3X, ^R4Y , S1, Xc, q, n, m, ^R8 , ^R9 , ^R10 , and/or the subscript p ^{and / or each additional} variation ^{or combination of embodiments of the subscript p , as if each} combination ^{had been} individually and ^{specifically described .}

In some embodiments, any of the compounds described herein (e.g., compounds of Formula (A), (I), (IIa), (IIIa), (IVa), (IIb), (IIIb), (IVb), (IIc), (IIIc), (IVc), (A'), (I'), (IIa'), (IIIa'), (IVa'), (IIb'), (IIIb'), (IVb'), (IIc'), (IIIc'), (IVc') (IIa*), (IIIa*), (IVa*), (IIb*), (IIIb*), (IVb*), (IIc*), (IIIc*), (IVc*), or any subformula thereof, or a compound of any of Tables 1, 2, 3, or 4, or a salt of any of the foregoing) can be deuterated (e.g., a hydrogen atom is replaced by a deuterium atom). In some of these variations, the compound is deuterated at a single site. In other variations, the compound is deuterated at multiple sites. Deuterated compounds are sometimes prepared from deuterated starting materials in a manner similar to the preparation of corresponding non-deuterated compounds. In some embodiments, deuterium atoms are substituted for hydrogen atoms using other methods known in the art.

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

As used herein, when any variable occurs more than one time in a chemical formula, its definition on each occurrence is independent of its definition at every other occurrence.

The present disclosure provides ligand-drug conjugate mixtures and pharmaceutical compositions comprising any of the ligand-drug conjugates described herein. Such mixtures and pharmaceutical compositions contain a plurality of conjugates. In some embodiments, each conjugate in the mixture or composition is identical or substantially identical, however, the drug-linker distribution on the ligands in the mixture or composition and the drug loading may vary. For example, in some embodiments, the conjugation technology used to conjugate the drug-linker to an antibody as a targeting agent produces a composition or mixture that is heterogeneous with respect to the distribution of the drug-linker compound on the antibody (ligand unit) within the mixture and/or composition. In some of those embodiments, the drug-linker compound loading on each antibody molecule in such a mixture or composition of molecules is an integer ranging from 1-16.

In those embodiments, the drug-linker loading is a number ranging from 1 to about 16 when referring to the composition as a whole. Sometimes there is a small amount of unbound antibody in the composition or mixture. The average number of drug-linkers per ligand unit in the mixture or composition (i.e., the average drug loading) is an important property because it determines the maximum amount of drug delivered to the target cells. Typically, the average drug loading is 1, 2 or about 2, 3 or about 3, 4 or about 4, 5 or about 5, 6 or about 6, 7 or about 7, 8 or about 8, 9 or about 9, 10 or about 10, 11 or about 11, 12 or about 12, 13 or about 13, 14 or about 14, 15 or about 15, 16 or about 16. In some embodiments, the average drug loading is about 1 to about 16, about 2 to about 12, about 3 to about 8, or about 4. In some embodiments, the average drug loading is about 3 to about 5, about 3.5 to about 4.5, about 3.7 to about 4.3, about 3.9 to about 4.3, or about 4.

In some embodiments, the mixtures and pharmaceutical compositions contain a plurality of conjugates (i.e., populations), however, the conjugates are identical or substantially identical and substantially homogeneous with respect to the distribution of the drug-linker on the ligand molecules within the mixture and/or composition and with respect to the drug-linker loading on the ligand molecules within the mixture and/or composition. In some such embodiments, the drug-linker loading on the antibody ligand unit is 2 or 4. There may also be a small fraction of unbound antibody within the composition or mixture. The average drug loading in such embodiments is about 2 or about 4. Typically, such compositions and mixtures are produced by using site-specific binding techniques, and binding is due to an introduced cysteine residue.

The average number of drug units or drug-linker compounds per ligand unit in the preparation from the binding reaction can be characterized by conventional means, such as mass spectrometry, ELISA analysis, HPLC (e.g., HIC). In those cases, the quantitative distribution of the ligand-drug conjugate, represented by the subscript p, can also be determined. In other cases, separation, purification and characterization of homogeneous ligand-drug conjugates can be achieved by conventional means, such as reverse phase HPLC or electrophoresis.

In some embodiments, the compositions are pharmaceutical compositions comprising the ligand-drug conjugates described herein and a pharmaceutically acceptable carrier. In some of these embodiments, the pharmaceutical composition is in liquid form. In some embodiments, the pharmaceutical composition is a solid. In other embodiments of these embodiments, the pharmaceutical composition is a lyophilized powder.

Compositions, including pharmaceutical compositions, are provided in purified form. As used herein, "purified" means that when isolated, the isolate contains at least 95%, and in other embodiments at least 98%, of the conjugate by weight of the isolate. Methods of Use Cancer Treatment

The ligand-drug conjugates can be used to inhibit the proliferation of tumor cells or cancer cells, thereby causing apoptosis of tumor cells or cancer cells, or can be used to treat cancer in patients. The ligand-drug conjugates are accordingly used to treat cancer in a variety of settings. The ligand-drug conjugates are intended to deliver drugs to tumor cells or cancer cells. Without being bound by theory, in one embodiment, the ligand unit of the ligand-drug conjugate binds or associates with a cancer cell or tumor cell-associated antigen, and the ligand-drug conjugate is taken up (internalized) into the tumor cell or cancer cell by receptor-mediated endocytosis or other internalization mechanisms. In some embodiments, the antigen is linked to a tumor cell or cancer cell, or is an extracellular matrix protein associated with a tumor cell or cancer cell. Once inside the cell, the drug is released inside the cell upon activation by the activation unit. In an alternative embodiment, the free drug is released from the ligand-drug conjugate outside the tumor cell or cancer cell, and the free drug then permeates the cell.

In one embodiment, the Ligand unit binds to a tumor cell or cancer cell.

In another embodiment, the Ligand unit binds to a tumor cell or cancer cell antigen on the surface of a tumor cell or cancer cell.

In another embodiment, the ligand unit binds to immune cells in the tumor microenvironment.

In another embodiment, the ligand unit binds to stromal cells in the tumor microenvironment.

In another embodiment, the ligand unit binds to a tumor cell or cancer cell antigen, which is an extracellular matrix protein associated with the tumor cell or cancer cell.

The specificity of the ligand unit for a particular tumor cell or cancer cell is an important consideration for determining the most effective tumor or cancer to treat. For example, a ligand-drug conjugate targeting a cancer cell antigen present on a hematopoietic cancer can be used to treat a blood malignancy (e.g., anti-CD30, anti-CD70, anti-CD19, anti-CD33 binding ligand unit (e.g., antibody) can be used to treat a blood malignancy). In some embodiments, a ligand-drug conjugate targeting a cancer cell antigen present on a solid tumor can be used to treat such a solid tumor.

Cancers that are intended to be treated with drug-linker conjugates include, but are not limited to, hematopoietic cancers such as lymphomas (Hodgkin's lymphoma and non-Hodgkin's lymphoma) as well as leukemias and solid tumors. Examples of hematopoietic cancers include follicular lymphoma, anaplastic large cell lymphoma, mantle cell lymphoma, acute myeloblastic leukemia, chronic myeloid leukemia, chronic lymphocytic leukemia, diffuse large B-cell lymphoma, and multiple myeloma. Examples of solid tumors include fibrosarcoma, myxosarcoma, liposarcoma, chondrosarcoma, osteogenic sarcoma, chordoma, angiosarcoma, endotheliosarcoma, lymphangiosarcoma, lymphangioendotheliosarcoma, synovial tumor, mesothelioma, Ewing's tumor, leiomyosarcoma, rhabdomyosarcoma, colon cancer, colorectal cancer, kidney cancer, pancreatic cancer, bone cancer, breast cancer, ovarian cancer, prostate cancer, esophageal cancer, gastric cancer, oral cancer, nasal cancer, laryngeal cancer, squamous cell carcinoma, basal cell carcinoma, adenocarcinoma, sweat gland carcinoma, sebaceous gland carcinoma, papillary carcinoma, papillary adenocarcinoma, cystadenocarcinoma, medullary carcinoma, bronchial carcinoma, renal cell carcinoma, hepatoma, bile duct cancer, carcinoma/cholangiocarcinoma), choriocarcinoma, seminoma, embryonal carcinoma, Wilms tumor, cervical cancer, uterine cancer, testicular cancer, small cell lung cancer, bladder cancer, lung cancer, epithelial carcinoma, neuroglioma, multiform neuroglioma, astrocytoma, medulloblastoma, craniopharyngioma, ependymoma, pinealoma, hemangioblastoma, acoustic neuroma, oligodendroglioma, meningioma, neuroblastoma, and retinoblastoma.

In some embodiments, the cancer treated is any of the lymphomas and leukemias listed above. Multimodal therapy for cancer

It is contemplated that cancer, including but not limited to tumors, metastases, or other diseases or conditions characterized by uncontrolled cell growth, may be treated or inhibited by administering an effective amount of a ligand-drug conjugate disclosed herein.

In one set of embodiments, methods for treating cancer are provided, comprising administering to a patient in need thereof an effective amount of a ligand-drug conjugate and a chemotherapeutic agent. In one embodiment, the chemotherapeutic agent is a chemotherapeutic agent for a treatment of a cancer that has not been found to be refractory to the agent. In another embodiment, the chemotherapeutic agent is a chemotherapeutic agent for a treatment of a cancer that has been found to be refractory to the agent.

In another set of embodiments, the ligand-drug conjugates are administered to patients who have also undergone surgery as a cancer treatment. In such embodiments, the chemotherapy is typically administered over a series of courses, or one or a combination of chemotherapy agents is administered, such as standard of care chemotherapy.

In any set of embodiments, the patient also receives an additional treatment, such as radiation therapy. In a specific embodiment, the ligand-drug conjugate is administered simultaneously with the chemotherapy or radiation therapy. In another specific embodiment, the chemotherapy or radiation therapy is administered before or after the ligand-drug conjugate is administered.

Additionally, methods of treating cancer with ligand-drug conjugates are provided as an alternative to chemotherapy or radiation therapy, where the chemotherapy or radiation therapy has proven or may prove to be too toxic, e.g., causes side effects that are unacceptable or intolerable to the individual being treated. The patient being treated is then treated with another cancer treatment, such as surgery, radiation therapy, or chemotherapy, depending on which treatment is found to be acceptable or tolerable. Treatment of autoimmune diseases

The ligand-drug conjugates of the present disclosure are intended to be used to kill or inhibit the unwanted replication of cells that cause autoimmune diseases or to treat autoimmune diseases.

The ligand-drug conjugates are accordingly used in a variety of settings to treat autoimmune diseases in patients. The ligand-drug conjugates are typically used to deliver drug units to target cells. Without being bound by theory, in one embodiment, the ligand-drug conjugate binds to an antigen on the surface of a pro-inflammatory or inappropriately stimulated immune cell, and the ligand-drug conjugate is then taken up into the interior of the targeted cell by receptor-mediated endocytosis. Once inside the cell, the linker unit is cleaved, resulting in the release of the drug unit in the form of free drug. The free drug is then able to migrate within the cytosol and induce cytotoxic or cytostatic activity. In an alternative embodiment, the drug unit is cleaved from the ligand-drug conjugate outside the target cell, and the free drug resulting from the release subsequently permeates the cell.

In one embodiment, the ligand unit binds to an autoimmune antigen. In one such embodiment, the antigen is on the surface of a cell involved in an autoimmune disease.

In one embodiment, the ligand unit binds to activated lymphocytes associated with an autoimmune disease state.

In another embodiment, the ligand-drug conjugate kills or inhibits the proliferation of cells that produce autoimmune antibodies associated with a particular autoimmune disease.

Specific types of autoimmune diseases that are intended to be treated with ligand-drug conjugates include, but are not limited to, Th2 lymphocyte-associated disorders ( e.g. , atopic dermatitis, atopic asthma, rhinoconjunctivitis, allergic rhinitis, Omenn's syndrome, systemic sclerosis, and graft-versus-host disease); Th1 lymphocyte-associated disorders ( e.g. , rheumatoid arthritis, multiple sclerosis, psoriasis, Sjögren's syndrome, Hashimoto's thyroiditis, Graves' disease, primary biliary cirrhosis, Wegener's granulomatosis, and tuberculosis); and activated B lymphocyte-associated disorders ( e.g. , systemic lupus erythematosus, Goodpasture's syndrome, rheumatoid arthritis, and type I diabetes). Multidrug therapy for autoimmune diseases

Also disclosed are methods for treating autoimmune diseases, comprising administering to a patient in need thereof an effective amount of a ligand-drug conjugate of the present disclosure and another therapeutic agent known to treat an autoimmune disease. For any of the treatment methods described herein, a ligand-drug conjugate compound may be administered in a therapeutically effective amount to an individual who cannot tolerate another ligand-drug conjugate compound. In some embodiments, a patient has greater tolerance to a ligand-drug conjugate compound provided herein, such as compared to another ligand-drug conjugate compound. Tolerance may be determined using known methods or any of the methods described herein. Compositions and Methods of Administration

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

The pharmaceutical composition is formulated so that the ligand-drug conjugate is bioavailable after the composition is administered to a patient. The composition sometimes takes the form of one or more dosage units.

The materials used to prepare the pharmaceutical compositions are preferably non-toxic at the dosages used. It should be apparent to one of ordinary skill that the optimal dosage of the active ingredient in the pharmaceutical composition will depend on a variety of factors. Relevant factors include, but are not limited to, the type of animal ( e.g. , human), the specific form of the compound, the mode of administration, and the composition employed.

In some embodiments, the composition is in liquid form. In some of those embodiments, the liquid can be used for delivery by injection. In some embodiments, in addition to the ligand-drug conjugate, the composition for injection also contains one or more excipients selected from the group consisting of: surfactants, preservatives, wetting agents, dispersants, suspending agents, buffers, stabilizers and isotonic agents.

In some embodiments, the liquid compositions (which are solutions, suspensions or other similar forms) include one or more of the following: sterile diluents, such as water for injection, physiological saline solution (preferably physiological saline), Ringer's solution, isotonic sodium chloride, non-volatile oils that can serve as solvents or suspending media (such as synthetic monoglycerides or diglycerides), polyethylene glycol, glycerol, Cyclodextrin, propylene glycol or other solvents; antibacterial agents such as benzyl alcohol or methyl paraben; antioxidants such as ascorbic acid or sodium bisulfite; chelating agents such as ethylenediaminetetraacetic acid; buffers such as amino acids, acetates, citrates or phosphates; detergents such as nonionic surfactants, polyols; and agents for regulating tonicity such as sodium chloride or dextrose. Parenteral compositions are sometimes packaged in ampoules, disposable syringes or multidose vials made of glass, plastic or other materials. Physiological saline is an exemplary adjuvant. Injectable compositions are preferably sterile.

The amount of the conjugate effective to treat a particular condition or disorder will depend on the nature of the condition or disorder, which in some embodiments is determined by standard clinical techniques. In addition, in vitro or in vivo assays are employed as appropriate to help identify optimal dosage ranges. The precise dose to be used in the compositions will also depend on the route of administration, and the severity of the disease or disorder, and should be determined according to the judgment of the practitioner and each patient's circumstances.

The compositions contain an effective amount of the ligand-drug conjugate such that a suitable dosage will be obtained. Typically, the amount is at least about 0.01% of the compound by weight of the composition.

For intravenous administration, the pharmaceutical composition typically comprises about 0.01 to about 100 mg of ligand-drug conjugate per kg of animal weight. In one embodiment, the composition may include about 1 to about 100 mg of ligand-drug conjugate per kg of animal weight. In another aspect, the amount administered will be in the range of about 0.1 to about 25 mg/kg of body weight of the compound. In some embodiments, depending on the drug used, the dosage is even lower, such as 1.0 μg/kg to 5.0 mg/kg, 4.0 mg/kg, 3.0 mg/kg, 2.0 mg/kg or 1.0 mg/kg or 1.0 μg/kg to 500.0 μg/kg of individual weight.

In general, the dose of the conjugate administered to a patient is typically about 0.01 mg/kg to about 100 mg/kg of the individual's body weight or 1.0 μg/kg to 5.0 mg/kg of the individual's body weight. In some embodiments, the dose administered to a patient is between about 0.01 mg/kg to about 15 mg/kg of the individual's body weight. In some embodiments, the dose administered to a patient is between about 0.1 mg/kg and about 15 mg/kg of the individual's body weight. In some embodiments, the dose administered to a patient is between about 0.1 mg/kg and about 20 mg/kg of the individual's body weight. In some embodiments, the dose administered is between about 0.1 mg/kg to about 5 mg/kg or about 0.1 mg/kg to about 10 mg/kg of the individual's body weight. In some embodiments, the dose administered is between about 1 mg/kg and about 15 mg/kg of the subject's body weight. In some embodiments, the dose administered is between about 1 mg/kg and about 10 mg/kg of the subject's body weight. In some embodiments, the dose administered is between about 0.1 to 4 mg/kg, even more preferably 0.1 to 3.2 mg/kg, or even more preferably 0.1 to 2.7 mg/kg of the subject's body weight in one treatment cycle.

The term "carrier" refers to a diluent, adjuvant or excipient with which the compound is administered. In some embodiments, such pharmaceutical carriers are liquids, such as water and oils, including those of petroleum, animal, plant or synthetic origin, such as peanut oil, soybean oil, mineral oil or sesame oil. Other carriers include physiological saline, gum arabic, gelatin, starch paste, talc, keratin, colloidal silica or urea. In addition, adjuvants, stabilizers, thickeners, lubricants and colorants are sometimes used. In one embodiment, the ligand-drug conjugate or combination thereof and the pharmaceutically acceptable carrier are sterile when administered to a patient.

When the compounds are administered intravenously, water is an exemplary carrier. Physiological saline solutions and aqueous dextrose and glycerol solutions are commonly used as liquid carriers, especially for injectable solutions. Suitable pharmaceutical carriers also include excipients such as starch, glucose, lactose, sucrose, gelatin, malt, rice, flour, chalk, silica gel, sodium stearate, glycerol monostearate, talc, sodium chloride, skimmed milk powder, glycerol, propylene glycol, water or ethanol. The compositions of the present invention may also contain trace amounts of wetting agents or emulsifiers, or pH buffers, if necessary.

In one embodiment, the conjugates are formulated as pharmaceutical compositions adapted for intravenous administration to animals, especially humans, according to conventional procedures. Typically, the carrier or vehicle for intravenous administration is a sterile isotonic buffered aqueous solution. Where necessary, the compositions include a solubilizing agent. Compositions for intravenous administration optionally contain a local anesthetic, such as lidocaine, to relieve pain at the injection site. Generally, the components are supplied separately or mixed together in unit dosage forms, such as a lyophilized powder or anhydrous concentrate in an airtight container (such as an ampoule or sachet) indicating the amount of active agent. In the case where the conjugate is to be administered by infusion, it is typically dispensed, for example, with an infusion bottle containing sterile pharmaceutical grade water or saline. In some embodiments, in the case where the conjugate is administered by injection, an ampoule of sterile water for injection or saline is sometimes provided and the ingredients are mixed before administration.

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

Provided herein are methods for preparing drug-linker compounds from the STING agonist compounds provided herein. In addition to the methods described below, methods for preparing drug-linker compounds from STING agonist compounds will also be familiar to those skilled in the art.

Provided herein are methods for preparing ligand-drug conjugate compounds from the STING agonist compounds and drug-linker compounds provided herein. Methods for preparing ligand-drug conjugate compounds will be familiar to those skilled in the art. EXAMPLES Example 1. General Methods .

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

UPLC-MS System 1 (C8): Waters Xevo G2 TOF mass spectrometer connected to a Waters Acquity H-class Ultra Performance LC equipped with a CORTECS C8 2.1×50 mm, 1.6 μm, 90Å reversed-phase column and a Waters 2996 photodiode array detector.

UPLC-MS System 2 (C18): Shimadzu LC-20 AD & MS 2020 with diode array detector (DAD) and positive ESI mass spectrometer equipped with an Agilent Poroshell SB-C18 3.0 × 30 mm, 3 μm particle size reversed phase column maintained at 40 °C or an XBridge C18 2.1 × 50 mm, 5 μm particle size reversed phase column maintained at 40 °C.

UPLC-MS System 3 (C18): Agilent 1200 Series LC system connected to a diode array detector (DAD) and an Agilent 6110 positive ESI quadrupole mass spectrometer equipped with a Luna-C18 2.0 × 50 mm, 5 μm reverse phase column maintained at 40 °C.

UPLC-MS System 4 (C18): Agilent 1200 Series LC system connected to a diode array detector (DAD) and an Agilent 6110 positive ESI quadrupole mass spectrometer equipped with an XBridge C18 2.1 × 50 mm, 5 μm particle size reversed phase column maintained at 40 °C.

UPLC-MS System 5 (C18): Waters single quadrupole detector mass spectrometer connected to a Waters Acquity UPLC system equipped with a CORTECS C18 2.1×50 mm, 1.6 μm, 90Å reversed phase column.

UPLC-MS System 6 (C18): Agilent 1200 Series LC system connected to an ELSD detector and an Agilent 6120 single quadrupole mass spectrometer equipped with a Kinetx C8 2.1 × 50 mm, 5 μm particle size reversed phase column maintained at 40 °C.

The compound was eluted using one of Methods A-R as described herein.

Method A - Linear gradient of 3-60% acetonitrile/water in 1.1 min, followed by 60-97% acetonitrile in 1.5 min, followed by isocratic flow of 97% acetonitrile for 2.5 min, after which the column was equilibrated back to 3% acetonitrile. The flow rate was 0.6 mL/min, and the water and acetonitrile each contained 0.1% (v/v) formic acid. The column used was a CORTECS C8 2.1×50 mm, 1.6 μm, 90Å reversed phase column.

Method B - Linear gradient of 10-100% acetonitrile/water in 0.7 min followed by isocratic flow of 100% acetonitrile to 1.3 min. The flow rate was 1.5 mL/min with water containing 0.04% (v/v) TFA and acetonitrile containing 0.02% (v/v) TFA. The column used was an Agilent Poroshell SB-C18 3.0 × 30 mm, 3 μm reverse phase column.

Method C - 5% acetonitrile/water isocratic flow for 0.4 min, followed by a linear gradient of 5-95% acetonitrile/water to 3.0 min, followed by isocratic flow of 95% acetonitrile to 4.0 min and column equilibration back to 5% acetonitrile to 4.5 min. The flow rate was 1.0 mL/min, and the water contained 0.04% TFA (v/v) and the acetonitrile contained 0.02% TFA (v/v). The columns used were Phenomenex Luna-C18 2.0×50 mm, 5 μm reverse phase columns or Kinetex C18 2.1×50 mm, 5 μm reverse phase columns.

Method D - Linear gradient of 5-95% acetonitrile/water in 2.5 min, followed by isocratic flow of 95% acetonitrile to 3.0 min and equilibration back to 5% acetonitrile to 3.5 min. Flow rate was 1.0 mL/min until equilibrium (1.2 mL/min). Water contained 0.04% TFA (v/v) and acetonitrile contained 0.02% (v/v) TFA. The column used was a Phenomenex Luna-C18 2.0 × 30 mm, 3 μm reverse phase column.

Method E - Linear gradient of 5-95% acetonitrile/water in 3.0 min, followed by isocratic flow of 95% acetonitrile to 3.5 min, and column equilibration back to 5% acetonitrile to 4 min, followed by isocratic flow of 5% acetonitrile to 4.3 min. The flow rate was 1.0 mL/min and the water contained 10 mM NH ₄ HCO ₃ . The column used was an Xbridge C18 2.1×50 mm, 5 μm particle size reverse phase column.

Method F - Linear gradient of 5-95% acetonitrile/water in 2.5 min, followed by isocratic flow of 95% acetonitrile for 3 min, and column equilibration back to 5% acetonitrile for 3.5 min. The flow rate was 1 mL/min and the water contained 10 mM NH ₄ HCO ₃ . The column used was an Xbridge C18 2.1×50 mm, 5 μm particle size reversed phase column.

Method G - Linear gradient of 5-95% acetonitrile/water in 3.4 min, followed by isocratic flow of 95% acetonitrile to 3.85 min and equilibration back to 5% acetonitrile to 4.5 min. The flow rate was 0.8 mL/min and the water contained 10 mM NH ₄ HCO ₃ . The column used was an Xbridge C18 2.1×50 mm, 5 μm particle size reverse phase column.

Method H - Linear gradient of 3-60% acetonitrile/water in 1.7 min, followed by 60-95% acetonitrile to 2.0 min, followed by isocratic flow of 95% acetonitrile to 2.5 min, after which the column was equilibrated back to 3% acetonitrile. The flow rate was 0.6 mL/min and the water contained 0.1% (v/v) formic acid and the acetonitrile contained 0.05% (v/v) formic acid. The column used was a CORTECS C18 2.1×50 mm, 1.6 90Å reversed phase column.

Method I - Linear gradient of 5-100% acetonitrile/water in 0.8 min followed by isocratic flow of 100% acetonitrile to 1.3 min. The flow rate was 1.5 mL/min with water containing 0.04% (v/v) TFA and acetonitrile containing 0.02% (v/v) TFA. The column used was an Xbridge C18 2.1×50 mm, 5 μm particle size reversed phase column.

Method J - Linear gradient of 5-95% acetonitrile/water in 0.7 min, followed by isocratic flow to 95% acetonitrile at 1.16 min and equilibration back to 5% acetonitrile at 1.5 min. The flow rate was 1.5 mL/min and the water contained 10 mM NH ₄ HCO ₃ . The column used was an Xbridge C18 2.1×50 mm, 5 μm particle size reverse phase column.

Method K - Linear gradient from 5 to 95% acetonitrile/water in 2.50 min, followed by isocratic flow of 95% acetonitrile until 3.0 min, after which the column was equilibrated back to 5% acetonitrile. The flow rate was 1 mL/min and the water contained 0.05% NH4OH.

Method L - Linear gradient of 10-100% acetonitrile/water in 0.5 min followed by isocratic flow of 100% acetonitrile to 0.9 min. The flow rate was 2.0 mL/min with water containing 0.04% (v/v) TFA and acetonitrile containing 0.02% (v/v) TFA. The column used was an Xbridge C18 2.1×50 mm, 5 μm particle size reversed phase column.

Method M - Linear gradient of 10-100% acetonitrile/water in 0.5 min followed by isocratic flow of 100% acetonitrile to 0.9 min. The flow rate was 2.0 mL/min and the water contained 10 mM NH ₄ HCO ₃ . The column used was an Xbridge C18 2.1×50 mm, 5 μm particle size reverse phase column.

Method N - Linear gradient of 10-100% acetonitrile/water in 0.5 min followed by isocratic flow of 100% acetonitrile to 0.9 min. The flow rate was 1.5 mL/min and the water contained 10 mM NH ₄ HCO ₃ . The columns used were Agilent Poroshell SB-C18 3.0×30 mm, 3 μm particle size reversed phase column or XBridge C18 2.1×50 mm, 5 μm particle size reversed phase column.

Method O - 5% acetonitrile isocratic flow to 0.4 min, followed by a linear gradient of 5-95% acetonitrile to 3 min, followed by an isocratic flow of 95% acetonitrile to 4 min, followed by equilibration to 5% acetonitrile. The flow rate was 1.0 mL/min, and the water contained 0.04% (v/v) TFA and the acetonitrile contained 0.02% (v/v) TFA. The column used was a Kinetex C18 2.1×50 mm, 5 μm particle size reverse phase column.

Method P - Linear gradient of 5-95% acetonitrile/water in 2.5 min, followed by isocratic flow of 95% acetonitrile to 3.0 min and equilibrium back to 5% acetonitrile to 3.5 min. Flow rate was 1.0 mL/min until equilibrium (1.2 mL/min). Water contained 10 mM NH ₄ HCO ₃ . The column used was a Phenomenex Luna-C18 2.0×30 mm, 3 μm reverse phase column.

Method Q - Linear gradient from 5-95% acetonitrile/water in 0.5 min, followed by isocratic flow to 95% acetonitrile until 0.90 min and equilibration back to 5% acetonitrile. The flow rate was 2.0 mL/min. The water contained 0.04% (v/v) TFA and the acetonitrile contained 0.02% (v/v) TFA.

Method R - Linear gradient 5-95% MeCN/water in 1.5 min, followed by isocratic flow at 95% MeCN to 2.0 min and equilibration back to 5% MeCN to 2.5 min. Flow rate was 1.2 mL/min. Water contained 10 mM NH ₄ HCO ₃ .

Unless otherwise specified, preparative HPLC (PrepHPLC) was performed using the procedures listed in this article on one of six instruments:

Method 1 - Teledyne ISCO ACCQPrep HP150 equipped with one of three Phenomenex preparative HPLC columns: (i) a 10 × 250 mm Synergi C12, 4 μm, Max-RP 80Å LC column, (ii) a 21.2 × 250 mm Synergi C12, 4 μm, Max-RP 80Å LC column, or (iii) a 30 × 250 mm Synergi C12, 4 μm, Max-RP 80Å LC column, using acetonitrile/water with 0.05% (v/v) TFA as the mobile phase.

Method 2 - Shimadzu LC-8A preparative HPLC with one of two columns: (i) Phenomenex Luna C-18 250×70 mm, 15 μm reverse phase column or (ii) Welch Xtimate C18 250×70 mm, 10 μm reverse phase column, using either 0.09% (v/v) TFA/acetonitrile in water or 10 mM NH ₄ HCO ₃ /acetonitrile in water as the mobile phase.

Method 3 - Gilson 281 semi-preparative HPLC system with one of two columns: (i) Phenomenex Luna 80 × 30 mm, 3 μm reversed phase column or (ii) Phenomenex Luna 75 × 30 mm, 3 μm reversed phase column, using 0.075% (v/v) TFA in acetonitrile in water as the mobile phase.

Method 4 - Auno-600 preparative HPLC system equipped with a Phenomenex Luna C-18 250×70 mm, 15 μm reverse phase column using 0.1% (v/v) water/acetonitrile as the mobile phase.

Method 5 - An Auno-300 preparative HPLC system equipped with a Welch Ultimate C18 250×70 mm, 10 μm reverse phase column was used with water containing 0.1% (v/v) TFA/acetonitrile as the mobile phase.

Method 6 - Auno-300 preparative HPLC system equipped with an Agela DuraShell C18 250 x 70 mm, 10 μm reverse phase column using water containing 10 mM NH ₄ HCO ₃ /acetonitrile as the mobile phase.

Method 7 - A Shimadzu LC-20AP preparative HPLC system equipped with a Phenomenex Luna C18 250×70 mm, 15 μm reverse phase column was used with water containing 0.2% FA/MeCN as the mobile phase.

Method 8 - An Auno-600 preparative HPLC system equipped with a Welch Xtimate C18 250 x 10 mm, 10 μm reverse phase column was used with water containing 10 mM NH ₄ HCO ₃ /MeCN as the mobile phase.

Method 9 - Agela-1000 preparative HPLC system equipped with a Phenomenex Luna C18 250×150, 15 μm reverse phase column using water containing 0.01% TFA/MeCN as the mobile phase.

Method 10 - Gilson 281 semi-preparative HPLC system equipped with a Phenomenex Gemini-NX 150 x 30 mm, 5 μm reverse phase column using water containing 10 mM NH ₄ HCO ₃ /MeCN as the mobile phase.

Method 11 - An Auno-300 preparative HPLC system equipped with a Welch Xtimate C18 250×70 mm, 10 μm reverse phase column was used with water containing 0.2% FA/MeCN as the mobile phase.

Method 12 - An Agela-600 preparative HPLC system equipped with a Phenomenex Luna C18 250×100×15 μm reverse phase column was used with water containing 0.2% FA/MeCN as the mobile phase.

General Method 1 - The tricyclic dimer (1 equiv.) and MP-OSu (2 equiv.) were dissolved in DMA (0.1 M in dimer). DIPEA (5 equiv.) was added and the reaction was stirred at 30 °C for 1 h. After complete conversion, the product was purified directly by prepHPLC (Method 1). The pure fractions were collected, frozen, and lyophilized to give the product.

General Method 2 - The maleimide-containing dimer (1 equiv.) was dissolved in DMSO (0.01 M). L-cysteine (2 equiv.) was added as a 0.1 M solution in PBS. The reaction was stirred at 30 °C for 1 h and purified directly by prepHPLC (Method 1). The fractions were collected, frozen, and lyophilized to give the product.

General Method 3 - The tricyclic dimer (1 equiv.) and MP-Val-Ala-PAB-Opfp (1.5 equiv.) were dissolved in DMSO (0.2 M in dimer). DIPEA (6 equiv.) was added and the reaction was stirred at 30 °C for 1 h. Upon completion, the product was purified directly by prepHPLC (Method 1). The fractions were collected, frozen, and lyophilized to give the product.

General Method 4 - The tricyclic dimer (1 equiv.) and compound 23 (1.5 equiv.) were dissolved in DMSO (0.1 M). DIPEA (5 equiv.) was added and the reaction was stirred at 30 °C for 16 h. After completion, the reaction was purified by prepHPLC (Method 1). The pure fractions were collected, frozen and lyophilized to give the product.

General Method 5 - The protected glucuronide (1 equiv.) was dissolved in anhydrous THF/MeOH (0.1 M, 1:1) in a well-purged vial. The solution was cooled to 0°C in an ice bath, and 0.5 M NaOMe in MeOH (1 equiv.) was added. After 1 h, or when complete acetate deprotection was observed, aqueous LiOH (1 M, 3 equiv.) was added. The reaction was stirred at 30°C for 1 h. The solvent was removed under reduced pressure and the crude mixture was purified by prepHPLC (Method 1). The pure fractions were collected, frozen, and lyophilized to give the product.

General Method 6 - To a solution of the deprotected glucuronide (1 equiv.) and MP-OSu (2 equiv.) in DMA (0.05 M in glucuronide) was added DIPEA (4 equiv.). The reaction was stirred for 1-2 h and purified directly by prepHPLC (Method 1). The pure fractions were collected, frozen, and lyophilized to give the product.

NMR spectra were recorded on a Bruker Avance III HD (400 MHz) instrument. Example 2. Synthesis of (E)-N-(6- aminoformyl- 3-(4- chlorobut -2- en -1- yl )-3H- imidazo [4,5-b] pyridin -2- yl )-4- ethyl -2- methyloxazole -5- carboxamide ( Compound 1) Synthesis of compound 1c

Compound 1a (5.00 g, 24.7 mmol) and 1b (6.60 g, 29.6 mmol) were dissolved in 1-butanol (82 mL) and DIPEA (17.2 mL, 98.7 mmol) was added. The reactants were heated to 90 °C via an oil bath and stirred for 18 h. The reaction was monitored by LCMS. After complete conversion, 1M HCl was added and extracted 3 times with EtOAc to give compound 1c (7.57 g, 21.5 mmol, 87% yield). The product was used without further purification. UPLC-MS: (Method A, ESI+): m/z [M + H] ⁺ = 353.1 (theoretical value), 353.3 (observed value). HPLC retention time: 1.57 min. Synthesis of compound 1d

Compound 1c (7.57 g, 21.5 mmol), NH ₄ Cl (4.60 g, 85.4 mmol) and HATU (17.2 g, 45.1 mmol) were dissolved in DMF (43 mL) and DIPEA (18.7 mL, 107 mmol) was added. The reaction was stirred at 30 °C for 4 h and monitored by LCMS. After complete conversion, 1 M HCl was added and extracted 3 times with EtOAc. The organics were combined and washed 3 times with brine. The organics were collected, dried over MgSO ₄ , filtered and concentrated onto celite. The product was purified by flash chromatography (SiO ₂ column, eluted with 0-20% MeOH/DCM) to give compound 1d (3.72 g. 10.6 mmol, 49% yield). UPLC-MS (Method A, ESI+): m/z [M + H] ⁺ = 352.2 (theoretical value), 352.2 (observed value). HPLC retention time: 1.49 min. Synthesis of compound 1e

Compound 1d (3.22 g, 9.16 mmol) and _B2 (OH) ₄ (4.11 g, 45.8 mmol) were dissolved in DMA (25 mL). A solution of 4-(4-pyridyl)pyridine (71.6 mg, 0.46 mmol) in DMA (6 mL) was added dropwise at 0 °C. The reaction was warmed to room temperature and stirred for 5 minutes. The reaction was monitored by LCMS. After complete conversion, cold MeCN was added and filtered to precipitate. The resulting solid was redissolved in MeOH and concentrated onto celite. The product was purified by flash chromatography (SiO ₂ column, eluted with 0-20% 10:1 NH ₄ OH:MeOH/DCM) to give compound 1e (1.58 g, 4.90 mmol, 54% yield). UPLC-MS (Method A, ESI+): m/z [M + H] ⁺ = 322.2 (theoretical value), 322.3 (observed value). HPLC retention time: 1.09 min. Synthesis of compound 1f

Compound 1e (1.30 g, 4.04 mmol) was dissolved in MeOH (20 mL) and 3M CNBr in DCM (10.8 mL) was added. The reaction was stirred at 50 °C for 18 h and monitored by LCMS. The reaction was concentrated to leave a mixture of starting material and product 1f , which was used without further purification. UPLC-MS (Method A, ESI+): m/z [M + H] ⁺ = 347.2 (theoretical value), 347.2 (observed value). HPLC retention time: 1.09 min. Synthesis of compound 1h

Compound 1g (371 mg, 2.39 mmol) and HATU (1.21 g, 3.19 mmol) were dissolved in DMA (8 mL), to which DIPEA (1.11 mL, 6.37 mmol) was added. The mixture was stirred for 20 min and then added to compound 1f (681 mg, 1.59 mmol). The reaction was heated at 75 °C for 1 h via a microwave reactor. After complete conversion, the product was directly purified by prepHPLC (Method 1). The pure fractions were frozen and lyophilized to give compound 1h (292 mg, 0.603 mmol, 38% yield). UPLC-MS (Method A, ESI+): m/z [M + H] ⁺ = 484.2 (theoretical value), 484.3 (observed value). HPLC retention time: 1.40 min. Synthesis of compound 1i

Compound 1h (46.1 mg, 0.0954 mmol) was dissolved in MeCN containing 30% TFA. The reaction was stirred at 30 °C for 1 h and monitored by LCMS. After complete conversion, the product was concentrated to give compound 1i (53.3 mg, 0.0872 mmol, 91% yield), which was used without purification. UPLC-MS (Method A, ESI+): m/z [M + H] ⁺ = 384.2 (theoretical value), 384.2 (observed value). HPLC retention time: 1.01 min. Synthesis of compound 1j

To a solution of compound 1i (1.2 g, 2.86 mmol) in THF (15 mL) and H ₂ O (15 mL) were added KBr (510 mg, 4.29 mmol) and NaNO ₂ (296 mg, 4.29 mmol) at rt. The mixture was stirred at rt for 1 h and then at 60 °C for 3 h. The reaction was monitored by LCMS. Upon completion, the reaction mixture was filtered and concentrated under reduced pressure to give a residue, which was purified by prepHPLC (Method 2, TFA) to give compound 1j (415 mg, 1.08 mmol, 38% yield). UPLC-MS (Method B, ESI+): m/z [M + H] ⁺ = 385.2 (theoretical value), 385.1 (observed value). HPLC retention time: 0.462 min. ¹ H NMR (400MHz, DMSO- d ₆ ) δ ppm 12.88 - 12.71 (m, 1H), 8.74 (d, J = 1.6 Hz, 1H), 8.14 (d, J = 1.6 Hz, 2H), 7.53 (br s, 1H), 5.88 - 5.78 (m, 1H), 5.77 - 5.68 (m, 1H), 4.79 (br d, J = 5.2 Hz, 2H), 3.93 - 3.85 (m, 2H), 3.01 (q, J = 7.6 Hz, 2H), 2.46 (s, 3H), 1.21 (t, J = 7.2 Hz, 3H). Synthesis of compound 1

To a solution of compound 1j (100 mg, 0.260 mmol) in DCM (3 mL) was added TEA (109 μL, 0.780 mmol), DMAP (3.18 mg, 0.0260 mmol), NaCl (45.6 mg, 0.780 mmol) and MsCl (89.4 mg, 0.780 mmol). The reaction was stirred at 20 °C for 16 h and then at 40 °C for 16 h. Upon completion, the reaction mixture was filtered to give a residue which was purified by prepHPLC (Method 3) to give compound 1 (36 mg, 0.0814 mmol, 34% yield). UPLC-MS (Method C, ESI+): m/z [M + H] ⁺ = 403.1 (theoretical value), 403.0 (observed value). HPLC retention time: 2.13 min. ¹ H NMR (400 MHz, methanol- d ₄ ) δ ppm 8.78 (d, J = 2.0 Hz, 1H), 8.21 (d, J = 1.6 Hz, 1H), 6.07 (td, J = 5.6, 15.2 Hz, 1H), 5.87 (td, J = 6.8, 15.2 Hz, 1H), 4.94 (d, J = 5.6 Hz, 2H), 4.08 (d, J = 6.8 Hz, 2H), 3.15 - 3.05 (m, 2H), 2.51 (s, 3H), 1.29 (t, J = 7.6 Hz, 3H). Example 3. Synthesis of (E)-3-(4- chlorobut - 2 -en -1 - yl )-2-(1- ethyl -3- methyl -1H -pyrazole -5 -carboxamido )-3H- imidazo [4,5-b] pyridine -6- carboxamide ( Compound 2) Synthesis of compound 2b

To a solution of compound 2a (1.34 g, 8.66 mmol) in DMF (30 mL) was added HBTU (3.72 g, 9.82 mmol) and DIPEA (3.52 mL, 20.2 mmol) at 25 °C. The reaction was heated to 60 °C for 30 min. Compound 1f (2.0 g, 5.8 mmol) was added at 25 °C and the mixture was stirred at 60 °C for 12 h. The reaction mixture was then slowly poured into 1M HCl (15 mL) at 20 °C and stirred for 10 min. The precipitate was filtered and the filter cake was washed with H ₂ O. The crude product was triturated with H ₂ O to give compound 2b (2.6 g, 5.4 mmol, 93% yield). UPLC-MS (Method B, ESI+): m/z [M + H] ⁺ = 483.2 (theoretical value), 483.3 (observed value). HPLC retention time: 0.62 min. ¹ H NMR (400MHz, DMSO- d ₆ ) δ ppm 12.89 (br s, 1H), 8.75 (s, 1H), 8.14 (br d, J = 6.8 Hz, 2H), 7.53 (br s, 1H), 6.92 (br s, 1H), 6.69 (s, 1H), 5.80 - 5.60 (m, 2H), 4.79 (br s, 2H), 4.60 (br d, J = 7.2 Hz, 2H), 3.50 (br s, 2H), 2.18 (s, 3H), 1.45 - 1.11 (m, 12H). Synthesis of compound 2c

Compound 2b (2.6 g, 5.4 mmol) was dissolved in HCl/EtOAc (4 M, 26 mL) and stirred at 20 °C for 1 h. After completion, the reaction mixture was filtered and concentrated under reduced pressure to give 2c (2.42 g, 5.78 mmol) as HCl salt. The product was used without further purification. ¹ H NMR (400MHz, DMSO- d ₆ ) δ ppm 8.78 (d, J = 1.6 Hz, 1H), 8.23 (br s, 1H), 8.16 (d, J = 1.6 Hz, 1H), 8.05 (br s, 3H), 7.55 (br s, 1H), 6.73 (s, 1H), 6.06 (td, J = 5.6, 15.6 Hz, 1H), 5.77 - 5.59 (m, 1H), 4.85 (br d, J = 5.2 Hz, 2H), 4.60 (q, J = 7.2 Hz, 2H), 3.41 (br t, J = 5.6 Hz, 2H), 2.19 (s, 3H), 1.36 (t, J = 7.2 Hz, 3H). Synthesis of compound 2d

To a solution of compound 2c (2.0 g, 4.0 mmol HCl salt) in H ₂ O (40 mL) and THF (40 mL) at 20°C were added KBr (1.20 g, 10.1 mmol) and NaNO ₂ (695 mg, 10.1 mmol). The reaction mixture was stirred at 20°C for 3 h and then heated to 40°C for 12 h. The reaction mixture was filtered and concentrated under reduced pressure to give a residue which was purified by prepHPLC (Method 2, TFA) to give compound 2d (60 mg, 0.16 mmol, 19% yield). UPLC-MS (Method D, ESI+): m/z [M + H] ⁺ = 384.2 (theoretical), 384.1 (observed). HPLC retention time: 1.32 min. ¹ H NMR: (400MHz, DMSO- d ₆ ) δ ppm 13.09 - 12.72 (m, 1H), 8.75 (d, J = 1.6 Hz, 1H), 8.21 - 8.11 (m, 2H), 7.54 (br s, 1H), 6.71 (s, 1H), 5.88 - 5.79 (m, 1H), 5.78 - 5.71 (m, 1H), 4.81 (br d, J = 4.8 Hz, 2H), 4.60 (q, J = 6.8 Hz, 2H), 3.90 (d, J = 4.0 Hz, 2H), 2.18 (s, 3H), 1.35 (t, J = 7.2 Hz, 3H). Synthesis of compound 2

To a solution of compound 2d (200 mg, 0.522 mmol) in DCM (2.5 mL) was added TEA (363 μL, 2.60 mmol), MsCl (299 mg, 202 μL, 2.60 mmol), DMAP (6.4 mg, 0.052 mmol) and NaCl (152 mg, 2.60 mmol) at 20 °C. The reaction mixture was heated to 40 °C for 15 h. The reaction mixture was filtered to give a residue which was purified by prepHPLC (Method 3) to give compound 2 (80 mg, 0.20 mmol, 44% yield). UPLC-MS (Method C, ESI+): m/z [M + H] ⁺ = 402.1 (theoretical), 402.1 (observed). HPLC retention time: 2.21 min. ¹ H NMR (400MHz, methanol- d ₄ ) δ ppm 8.78 (d, J = 2.0 Hz, 1H), 8.20 (d, J = 2.0 Hz, 1H), 6.78 (s, 1H), 6.11 - 6.02 (m, 1H), 5.90 (td, J = 6.8, 15.2 Hz, 1H), 4.95 (d, J = 5.6 Hz, 2H), 4.70 (q, J = 7.2 Hz, 2H), 4.09 (dd, J = 0.8, 6.4 Hz, 2H), 2.27 (s, 3H), 1.43 (t, J = 7.2 Hz, 3H). Example 4. Synthesis of tert-butyl 3-(2-((6 -aminomethyl- 2-(1- ethyl -3- methyl -1H -pyrazol -5- yl )-9H- pyrimido [4,5-b] indol- 8- yl ) oxy ) ethyl ) azinecyclobutane -1 -carboxylate ( Compound 3) Synthesis of compound 3b

A solution of compound 3a (10 g, 36 mmol) was stirred in NH ₄ OH (150 mL) at 20°C for 16 h. The reaction was filtered and the filter cake was washed with ice water to produce compound 3b (8 g, 30 mmol, 85% yield). ¹ H NMR (DMSO- d 6, 400MHz) δ ppm 8.30 (s, 1H), 8.18 (br s, 1H), 8.06 (d, J = 0.8 Hz, 1H), 7.91 (s, 1H). Synthesis of compound 3d

Sodium hydride (608 mg, 15.1 mmol, 60%) was added to anhydrous THF (60 mL). Compound 3c (1.5 g, 7.62 mmol) was slowly added to the mixture at rt, and the mixture was stirred for 10 min. Compound 3b (2 g, 1.52 mmol) was then added. The reaction mixture was heated to 60 °C for 1 h. TLC showed the reaction was complete. A second reaction was prepared as described above, and the mixtures were combined for work-up and purification. The reaction was quenched by slow addition of saturated NH ₄ Cl (80 mL), extracted with EtOAc (3×100 mL), and concentrated under reduced pressure to give a residue, which was then purified by flash chromatography to give compound 3d (4.8 g, 10.8 mmol, 71% yield). ¹ H NMR (400 MHz, DMSO- d ₆ ) d ppm 8.23 (br s, 1H), 7.84 (d, J = 1.6 Hz, 1H), 7.78 (br s, 1H), 7.74 (d, J = 1.2 Hz, 1H) 4.22 (t, J = 6.0 Hz, 2H) 3.89 (br s, 2H), 3.52 (br s, 2H), 2.63 - 2.56 (m, 1H) 2.02 - 1.96 (m, 2H), 1.37 (s, 9H). Synthesis of compound 3f

To a solution of compound 3d (1.0 g, 2.2 mmol) in dioxane (20 mL) and H ₂ O (4 mL) at rt under N ₂ atmosphere were added compound 3e (514 mg, 1.69 mmol), PdCl ₂ (dppf) (182 mg, 0.225 mmol) and (358 mg, 3.38 mmol). The mixture was degassed with N ₂ , then heated to 110 °C and stirred for 4 h. The second reaction was prepared as described above. Upon completion, the reactions were combined, the product filtered and purified by prepHPLC (Method 2, NH ₄ HCO ₃ ) to give a mixture containing compound 3f (410 mg). UPLC-MS (Method E, ESI+): m/z [M - 100 + H] ⁺ = 378.1 (theoretical value), 378.1 (observed value). HPLC retention time: 2.21 min. ¹ H NMR (400 MHz, DMSO- d ₆ ) d ppm 8.87 (s, 2H), 8.26 - 8.21 (m, 2H), 7.85 (br d, J = 10 Hz, 3H), 7.78 (br s, 2H), 7.72 (br d, J = 13.2 Hz, 3H), 4.25 (td, J = 6.0, 19.2 Hz, 6H), 3.90 (br d, J = 7.2 Hz, 6H), 3.53 (br s, 6H), 2.62 (br d, J = 7.2 Hz, 3H), 2.06 - 1.96 (m, 6H), 1.36 (s, 27H). Synthesize compound 3h

To a solution of compound 3f (0.45 g, 0.94 mmol) in dioxane (45 mL) and H ₂ O (9 mL) were added compound 3g (1.13 g, 4.68 mmol), PdCl _{2 (} dppf) (77 mg, 0.094 mmol) and sodium carbonate (301 mg, 2.83 mmol) at 20 °C under N 2 atmosphere. The mixture was degassed with N ₂ for several times and then heated to 90 °C for 2 h. The reaction was monitored by LCMS. After complete conversion, the solution was filtered and the filtrate was purified by prepHPLC (Method 2, NH ₄ HCO ₃ ) to give compound 3h (205 mg, 0.372 mmol, 16% yield over 2 steps). UPLC-MS (Method F, ESI+): m/z [M + H] ⁺ = 552.3 (theoretical value), 552.3 (observed value). HPLC retention time: 2.05 min. ¹ H NMR (400 MHz, DMSO- d ₆ ) δ ppm 8.95 (s, 2H), 8.23 (s, 1H), 7.85 (s, 1H), 7.80 - 7.73 (m, 2H), 6.87 (s, 1H), 4.68 (q, J = 7.2 Hz, 2H), 4.28 (t, J = 6.0 Hz, 2H), 3.91 (s, 2H), 3.55 (s, 2H), 2.68 - 2.56 (m, 1H), 2.22 (s, 3H), 2.06 - 1.99 (m, 2H), 1.36 (s, 9H), 1.36 - 1.32 (m, 3H). Synthesis of compound 3

To a solution of compound 3h (40 mg, 0.073 mmol) and PPh ₃ (47.5 mg, 0.181 mmol) in dioxane (2 mL) was added 1,2,3,5-tetrakis(carbazol-9-yl)-4,6-dicyanobenzene (4CzIPN, 2.86 mg, 3.63 μmol) in a glove box under an inert atmosphere. The mixture was stirred at 55 °C under 35 W blue (450 nm) LED irradiation for 48 h. LCMS analysis showed 70% conversion with 30% starting material remaining. Seven additional vials were prepared as described above. Eight mixtures were combined for work-up and purification. The reaction was concentrated in vacuo to give a residue, which was purified by preparative TLC (DME:MeOH 20:1, R _f = 0.25) to give compound 3 (90 mg, 0.173 mmol, 30% yield). UPLC-MS (Method G, ESI+): m/z [M + H] ⁺ = 520.3 (theoretical value), 520.3 (observed value). HPLC retention time: 2.76 min. ¹ H NMR (400 MHz, DMSO- d ₆ ) δ ppm 12.70 (br s, 1H), 9.49 (s, 1H), 8.41 (s, 1H), 8.01 (s, 1H), 7.61 (s, 1H), 7.32 (s, 1H), 6.80 (s, 1H), 4.81 (q, J = 7.2 Hz, 2H), 4.25 (t, J = 6.0 Hz, 2H), 3.98 (t, J = 6.8 Hz, 2H), 3.65 (t, J = 6.8 Hz, 2H), 2.98 - 2.84 (m, 1H), 2.23 (s, 3H), 2.13 (q, J = 6.0 Hz, 2H), 1.42 - 1.38 (m, 3H), 1.37 (s, 9H). Example 5. Synthesis of (E)-N-(3-(4-(8-(2-( Azocyclobutane- 3- yl ) ethoxy )-6- aminoformyl- 2-(1- ethyl -3- methyl -1H -pyrazol -5- yl )-9H- pyrimido [4,5-b] indol- 9- yl ) but- 2-en-1-yl ) -6 - aminoformyl - 3H - imidazo [4,5-b] pyridin -2- yl )-4- ethyl -2- methyloxazole -5- carboxamide ( Compound 1.1) Synthesis of compound 4a

Compound 1 (31.0 mg, 0.077 mmol) and compound 3 (20.0 mg, 0.0385 mmol) were added to an oven-dried vial containing Cs ₂ CO ₃ (37.6 mg, 0.116 mmol) in anhydrous DMF (0.5 mL). The reaction was stirred at 55 °C for 16 h. Upon completion, the reaction was filtered and directly purified by prepHPLC (Method 1). The fractions containing the pure product were collected, frozen, and lyophilized to produce compound 4a (21.3 mg, 0.024 mmol, 62% yield). UPLC-MS (Method A, ESI+): m/z [M + H] ⁺ = 886.4 (theoretical value), 886.5 (observed value). HPLC retention time: 1.50 min. Synthesis of compound 1.1

Compound 4a (21.3 mg, 0.024 mmol) was dissolved in MeOH (0.48 mL). HCl in dioxane (4M, 60.1 μL, 0.240 mmol) was added and the mixture was stirred at 35 °C for 1 h. Upon completion, the mixture was concentrated and purified by prepHPLC (Method 1). The fractions containing the pure product were collected, frozen, and lyophilized to yield compound 1.1 (5.5 mg, 4.8 μmol, 20% yield). UPLC-MS (Method A, ESI+): m/z [M + H] ⁺ = 786.4 (theoretical value), 786.4 (observed value). HPLC retention time: 1.28 min. Example 6. Synthesis of (E)-8-(2-( Azocyclobutane -3- yl ) ethoxy )-9-(4-(6- aminoformyl- 2-(1- ethyl -3- methyl -1H -pyrazol -5 -carboxamido )-3H- imidazo [4,5-b] pyridin -3- yl ) but -2- en-1-yl ) -2- (1- ethyl -3- methyl -1H -pyrazol -5- yl )-9H- pyrimido [4,5-b] indole -6- carboxamide ( Compound 1.2) Synthesis of compound 5a

Compound 5a was prepared by following the same procedure as compound 4a using compounds 2 (61.8 mg, 0.154 mmol) and 3 (40 mg, 0.077 mmol) as starting materials. After prepHPLC (method 1), the pure fractions were collected, frozen and lyophilized to yield compound 5a (47.2 mg, 0.053 mmol, 69% yield). UPLC-MS (method A, ESI+): m/z [M + H] ⁺ = 885.4 (theoretical value), 885.5 (observed value). HPLC retention time: 1.50 min. Synthesis of compound 1.2

Compound 1.2 was prepared following the same procedure as compound 1.1 using compound 5a (19.7 mg, 0.0222 mmol) as starting material. After prepHPLC (Method 1), the pure fractions were collected, frozen, and lyophilized to yield compound 1.2 (7.83 mg, 6.9 μmol, 31% yield). UPLC-MS (Method A, ESI+): m/z [M + H] ⁺ = 785.4 (theoretical value), 785.5 (observed value). HPLC retention time: 1.21 min. Example 7. Synthesis of (E)-(3-((5- aminoformyl - 1-(4- chlorobut - 2- en - 1- yl )-2-(4- ethyl -2- methyloxazole -5 -carboxamido )-1H- benzo [d] imidazol -7- yl ) oxy ) propyl )( methyl ) carbamic acid tert-butyl ester ( Compound 6) Synthesis of compound 6b

A solution of (E)-but-2-ene-1,4-diol ( 6a , 3.4 mL, 41.2 mmol) and solid supported triphenylphosphine (1.6 mmol/gram, 2 equiv., 25 g, 40.0 mmol) in THF (200 mL) was stirred for 15 min. The solution was cooled to 0 °C and o-phthalimide (3.00 g, 20.4 mmol) was added. The ice bath was removed and the solution was stirred for 60 min, at which time complete conversion was observed by LC-MS (Method A). The crude solution was filtered, the beads were washed with THF (50 mL), the filtrate was combined, and the solvent was removed in vacuo . The crude product was purified by column chromatography (SiO2, hexane/MTBE) to afford 6b (2.85 g, 13.1 mmol, 64% yield) as a white solid. UPLC-MS (Method A, ESI+): m/z [M- _H2O ] ⁺ = 200.07 (theoretical value), 200.14 (observed value). HPLC retention time: 1.30 min. Synthesis of compound 6c

To a solution of compound 6b (2.85 g, 13.1 mmol) and imidazole (2.68 g, 39.4 mmol) in DMF (55 mL) was added TBDPSCl (10.25 mL, 39.4 mmol). The mixture was stirred at 80 °C for 18 h. The reaction was poured into 1M HCl (250 mL) and the aqueous layer was extracted with ether (3×150 mL). The organics were combined, washed with brine (2×150 mL), dried over MgSO ₄ , filtered and the solvent removed in vacuo to yield a yellow oil. The crude material was purified by column chromatography (SiO ₂ , hexanes/MTBE) to give compound 6c (2.91 g, 6.4 mmol, 49% yield). UPLC-MS (method A, ESI+): m/z [M + Na] ⁺ = 478.18 (theoretical value), 478.28 (observed value). HPLC retention time: 2.25 min. Synthesis of compound 6d

To a solution of compound 6c (2.91 g, 6.4 mmol) in DCM (40 mL) and MeOH (40 mL) was added hydrazine hydrate (4.7 mL, 97 mmol). The mixture was heated to 40 °C for 2 h. The mixture was poured into saturated NaHCO ₃ and extracted 3 times with 3:1 CHCl ₃ :EtOH. The organic layers were combined, dried over MgSO ₄ , filtered and the solvent was removed in vacuo to give a white solid. The crude material was purified by column chromatography (SiO ₂ , DCM/10:1 MeOH:NH ₄ OH) to give 6d (1.93 g, 5.95 mmol, 93% yield). UPLC-MS (Method A, ESI+): m/z [M + H] ⁺ = 326.19 (theoretical value), 326.28 (observed value). HPLC retention time: 1.52 min. Synthesis of compound 6f

Compound 6e (15 g, 22 mmol) was stirred in NH ₄ OH (500 mL) at 50 °C for 16 h. Precipitation by filtration and azeotropy with toluene three times gave compound 6f (10 g, 43 mmol, 71% yield). This material was used without further purification. UPLC-MS (Method D, ESI+): m/z [M + H] ⁺ = 231.0 (theoretical), 230.6 (observed). HPLC retention time: 1.49 min. ¹ H NMR : (400 MHz, DMSO-d ₆ ) δ ppm 8.30 (br s, 1H), 8.05 (d, J = 1.6 Hz, 1H), 7.88 (d, J = 2 Hz, 1H), 7.79 (br s, 1H), 4.03 (s, 3H). Synthesis of compound 6g

To a solution of compound 6f (13 g, 56 mmol) in DCE (260 mL) was added BBr ₃ (1 M, 124 mL) at 0 °C. The mixture was stirred at 40 °C for 16 h. Two additional vials were set up as described. The three reaction mixtures were combined for purification. The mixture was cooled to 0 °C and water (10 V) was added at 0 °C. The mixture was stirred at 0 °C for 1.5 h, then filtered and concentrated under reduced pressure to give compound 6g (26 g, 120 mmol, 71% yield). UPLC-MS (Method D, ESI+): m/z [M + H] ⁺ = 217.0 (theoretical), 216.6 (observed). HPLC retention time: 1.26 min. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ ppm 11.51 (br s, 1H), 8.17 (br s, 1H), 7.92 (d, J = 2 Hz, 1H), 7.71 (d, J = 2 Hz, 1H), 7.65 (br s, 1H). Synthesis of compound 6i

To a stirred solution of compound 6g (1.0 g, 4.6 mmol) and Cs ₂ CO ₃ (2.26 g, 6.93 mmol) in DMF (20 mL) at 25 °C were added compound 6h (1.75 g, 6.93 mmol), TBAI (85.3 mg, 231 mmol) successively. The reaction mixture was stirred at 40 °C for 18 h. Four more vials were set up as described. All five reaction vials were combined for purification. The reaction mixture was filtered to remove impurities. The filtrate was purified by flash chromatography (SiO ₂ , hexane/EtOAc) to give compound 6i (6 g, 15 mmol, 67% yield). UPLC-MS (Method D, ESI+): m/z [M + Na] ⁺ = 410.1 (theoretical value), 410.1 (observed value). HPLC retention time: 2.00 min. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ ppm 8.27 (br s, 1H), 8.04 (br s, 1H), 7.86 (br s, 1H), 7.77 (br s, 1H), 4.22 (br s, 2H), 3.37 (br s, 2H), 2.79 (br s, 3H), 1.99 (br s, 2H), 1.28 (br s, 9H). Synthesis of compound 6j

To a sealed tube was added a solution of compound 6d (3.78 g, 11.6 mmol) in 1-butanol (30 mL). DIPEA (5.4 mL, 31 mmol) and Na ₂ CO ₃ (1.64 g, 15.5 mmol). The mixture was stirred at 20 °C for 10 min, then compound 6i (3 g, 7.7 mmol) was added and the mixture was stirred at 115 °C for 48 h. An additional vial was set up as described. The two reactions were combined for purification. The mixture was cooled to 25 °C and EtOAc (10 V) was added. The liquid was filtered and concentrated to yield compound 6j (24 g, 35 mmol, crude). UPLC-MS (method D, ESI+): m/z [M + H] ⁺ = 677.3 (theoretical value), 677.3 (observed value). HPLC retention time: 2.84 min. Synthetic compound 6k

To a stirred solution of compound 6j (15 g, 61 mmol) in MeOH (500 mL) at 0 °C was added Na ₂ S ₂ O ₄ (38.6 g, 222 mmol) dissolved in H ₂ O (150 mL) followed immediately by the addition of NH ₄ OH (75 mL). The mixture was warmed to 25 °C and stirred for 16 h. The solution was diluted with H ₂ O and the organics were extracted with EtOAc (3×100 mL). The organic phases were combined and washed with H ₂ O (3×100 mL). The organic phases were dried over Na ₂ SO ₄ and concentrated to give compound 6k (9.5 g, 15 mmol, crude). UPLC-MS (Method D, ESI+): m/z [M + H] ⁺ = 647.4 (theoretical), 647.4 (observed). HPLC retention time: 2.30 min. Synthesis of compound 6l

To a solution of compound 6k (9.5 g, 15 mmol) in MeOH (380 mL) was added CNBr (43.2 mL, 587 mmol) at 25 °C. The mixture was stirred at 25 °C for 16 h. The mixture was concentrated to give a residue. The crude product was dissolved in MeOH (20 mL) and then triturated with MTBE (500 mL) at 25 °C. The filtrate was concentrated under reduced pressure to give compound 6l (5 g, 7.4 mmol, 34% yield over two steps). UPLC-MS (Method D, ESI+): m/z [M + H] ⁺ = 672.4 (theoretical value), 672.4 (observed value). HPLC retention time: 2.44 min. Synthesis of compound 6m

To a solution of compound 1g (693 mg, 4.48 mmol) in DMF (30 mL) was added HBTU (1.96 g, 5.08 mmol) and DIPEA (3.64 mL, 20.8 mmol) at 25 °C. The mixture was heated to 60 °C and stirred for 30 min. Then, compound 61 (2.0 g, 3.0 mmol) was added at 25 °C. The mixture was stirred at 60 °C for 16 h. The reaction was diluted with 1 M HCl (200 mL), and the organic phase was extracted with EtOAc (3×60 mL). The organic phases were combined and washed with H ₂ O (3×80 mL). The organic phase was dried over Na ₂ SO ₄ and concentrated to give a residue, which was purified by flash chromatography (SiO ₂ , hexane/EtOAc) to give compound 6m (1.37 g, 1.69 mmol, 57% yield). UPLC-MS (Method D, ESI+): m/z [M + H] ⁺ = 809.4 (theoretical value), 809.4 (observed value). HPLC retention time: 2.70 min. Synthesis of compound 6n

To a solution of compound 6m (1.2 g, 1.5 mmol) in THF (12 mL) was slowly added TBAF (1 M, 2.22 mL) at 0°C. The reaction was warmed to 25°C and stirred for 4 h. The solvent was concentrated under reduced pressure and the residue was purified by flash chromatography (SiO ₂ , DCM/MeOH) to give compound 6n (624 mg, 1.09 mmol, 74% yield). UPLC-MS (Method D, ESI+): m/z [M + H] ⁺ = 571.3 (theoretical value), 571.3 (observed value). HPLC retention time: 1.75 min. Synthesis of compound 6

To a solution of compound 6n (580 mg, 1.02 mmol) in DCM (9 mL) was added TEA (0.71 mL, 5.1 mmol), MsCl (0.39 mL, 5.1 mmol), DMAP (12.4 mg, 102 μmol) and NaCl (297 mg, 5.1 mmol) at 25 °C. The reaction was stirred at 25 °C for 16 h. The reaction mixture was concentrated under reduced pressure and the residue was purified by prepHPLC (Method 3) to give compound 6 (255 mg, 0.433 mmol, 43% yield). UPLC-MS (Method D, ESI+): m/z [M + H] ⁺ = 589.3 (theoretical value), 589.2 (observed value). HPLC retention time: 2.03 min. Example 8. Synthesis of (E)-(3-((5- aminoformyl - 1-(4- chlorobut - 2- en - 1- yl )-2-(4- ethyl -2- methyloxazole -5 -carboxamido )-1H- benzo [d] imidazol -7- yl ) oxy ) propyl )( methyl ) carbamic acid tert-butyl ester ( Compound 7) Synthesis of compound 7a

Compound 7a was prepared by following the same procedure as compound 6m using compound 2a (344 mg, 2.23 mmol) and compound 6l (1.0 g, 1.5 mmol) as starting materials. The product was purified by flash chromatography (SiO ₂ , hexane/EtOAc) to give compound 7a (0.9 g, 1.11 mmol, 75% yield). UPLC-MS (Method D, ESI+): m/z [M + H] ⁺ = 809.4 (theoretical value), 808.4 (observed value). HPLC retention time: 2.75 min. Synthesis of compound 7b

Compound 7b was prepared by following the same procedure as compound 6n using compound 7a (900 mg, 1.11 mmol) as the starting material. The product was purified by flash chromatography (SiO ₂ , DCM/MeOH) to give compound 7b (500 mg, 0.876 mmol, 79% yield). UPLC-MS (Method D, ESI+): m/z [M + H] ⁺ = 571.3 (theoretical value), 570.2 (observed value). Synthesis of compound 7

Compound 7 was prepared by following the same procedure as compound 6 using compound 7b (800 mg, 1.40 mmol) as the starting material. The product was purified by prepHPLC (Method 3) to give compound 7 (254 mg, 0.432 mmol, 31% yield). UPLC-MS (Method D, ESI+): m/z [M + H] ⁺ = 588.3 (theoretical value), 588.1 (observed value). HPLC retention time: 1.89 min. ¹ H NMR: (CHLOROFORM- d , 400MHz) δ ppm 7.47 (s, 2H), 6.77 (s, 1H), 6.07 - 5.98 (m, 1H), 5.85 - 5.73 (m, 1H), 5.16 - 5.07 (m, 2H), 4.81 - 4.72 (m, 2H), 4.24 (t, J = 6.0 Hz, 2H), 4.03 (d, J = 6.4 Hz, 2H), 3.45 (t, J = 6.0 Hz, 2H), 2.91 (s, 3H), 2.37 (s, 3H), 2.16 - 2.10 (m, 3H), 1.49 (t, J = 7.2 Hz, 3H), 1.44 (s, 9H), 1.30 - 1.23 (m, 1H) Example 9. Synthesis of 2-(1- ethyl -3- methyl -1H -pyrazol -5- yl )-8- methoxy -9H- pyrimido [4,5-b] indole -6- carboxamide ( Compound 8) Synthesis of compound 8a

To a solution of compound 3b (0.50 g, 1.9 mmol) in MeOH (5 mL) was added NaOMe (308 mg, 5.70 mmol). The reaction mixture was stirred at 60 °C for 2 h. The solvent was evaporated under reduced pressure, and the residue was dissolved in EtOAc. The precipitate was filtered and the filtrate was concentrated to give compound 8a (450 mg, 1.64 mmol, crude material) UPLC-MS (Method E, ESI+): m/z [M + H] ⁺ = 275.0 (theoretical value), 275.0 (observed value). HPLC retention time: 1.62 min. ¹ H NMR (DMSO- d 6, 400MHz) δ ppm 8.25 (s, 1H), 7.84 (s, 1H), 7.78 (s, 1H), 7.76 (s, 1H), 3.96 (s, 3H). Synthesis of compound 8b

Compound 8b was prepared following the same procedure as compound 3f using compound 8a (0.85 g, 3.1 mmol) as the starting material. Upon completion, the reaction mixture was poured into water (20 mL) and the aqueous phase was extracted with EtOAc (2×20 mL). The combined organic phases were dried over anhydrous Na ₂ SO ₄ , filtered, and concentrated under vacuum. The residue was purified by prepHPLC (Method 2, TFA) to give compound 8b (0.5 g, 1.6 mmol, 52% yield). UPLC-MS (Method F, ESI+): m/z [M - H] ⁺ = 307.0 (theoretical value), 307.0 (observed value). ¹ H NMR: (DMSO- d 6, 400MHz) δ ppm 8.88 (s, 2H), 7.89 (d, J = 1.3 Hz, 1H), 7.72 (m, 3H), 7.71 (d, J = 1.5 Hz, 1H), 4.02 (s, 3H). Synthesis of compound 8c

Compound 8c was prepared following the same procedure as compound 3h using compound 8b (1.03 g, 3.34 mmol) as the starting material. Upon completion, the reaction mixture was poured into water (20 mL) and the aqueous phase was extracted with EtOAc (2×20 mL). The combined organic phases were dried over anhydrous Na ₂ SO ₄ , filtered and concentrated under vacuum. The residue was purified by prepHPLC (Method 2, NH ₄ HCO ₃ ) to give compound 8c (0.20 g, 0.52 mmol, 16% yield). UPLC-MS (Method F, ESI+): m/z [M + H] ⁺ = 383.1 (theoretical value), 383.2 (observed value). HPLC retention time: 1.71 min. ¹ H NMR (DMSO- d 6, 400MHz) δ ppm 8.95 (s, 2H), 8.26 (s, 1H), 7.88 (d, J = 1.3 Hz, 1H), 7.81 - 7.74 (m, 2H), 6.87 (s, 1H), 4.68 (q, J = 7.1 Hz, 2H), 4.02 (s, 3H), 2.22 (s, 3H), 1.35 (t, J = 7.1 Hz, 3H). Synthesis of compound 8

Compound 8 was prepared following the same procedure as compound 3 using compound 8c (40 mg, 0.105 mmol) as starting material. Three additional reaction vials were prepared as described. The four mixtures were combined for purification. The solvent was removed under reduced pressure and the crude product was purified by flash chromatography (SiO ₂ , DCM/MeOH) to yield compound 3 (35 mg, 0.10 mmol, 24% yield). UPLC-MS (Method G, ESI+): m/z [M + H] ⁺ = 351.2 (theoretical value), 351.2 (observed value). HPLC retention time: 2.24 min. ¹ H NMR (DMSO- d 6, 400MHz) δ ppm 12.77 (s, 1H), 9.52 (s, 1H), 8.43 (s, 1H), 8.06 (br s, 1H), 7.70 - 7.61 (m, 1H), 7.37 (br s, 1H), 6.80 (s, 1H), 4.78 (q, J = 7.2 Hz, 2H), 4.05 (s, 3H), 2.23 (s, 3H), 1.39 (t, J = 7.2 Hz, 3H). Example 10. Synthesis of (E)-N-(5- aminoformyl- 1-(4-(6- aminoformyl- 2-(1- ethyl -3- methyl -1H -pyrazol -5- yl )-8- methoxy -9H- pyrimido [4,5-b] indol -9- yl ) but -2- en - 1 - yl )-7-(3-( methylamino ) propoxy )-1H- benzo [d] imidazol -2- yl )-4- ethyl -2- methyloxazole -5- carboxamide ( Compound 1.3) Synthesis of compound 9a

Compound 9a was prepared following the same procedure as compound 4a using compound 6 (20.4 mg, 0.029 mmol) and compound 8 (6.77 mg, 0.0193 mmol) as starting materials. After completion, the product was directly purified by prepHPLC (method 1). The pure fractions were frozen, dried, and lyophilized to give compound 9a (16.4 mg, 0.0145 mmol, 75% yield). UPLC-MS (method A, ESI+): m/z [M + H] ⁺ = 903.4 (theoretical value), 903.4 (observed value). HPLC retention time: 1.60 min. Synthesis of compound 1.3

Compound 9a (90 mg, 0.08 mmol) was dissolved in DCM (0.8 mL) containing 40% TFA (v/v%). The reaction was stirred at 30 °C for 1 h. The solvent was removed under vacuum and the product was purified by prepHPLC (Method 1). The pure fractions were collected, frozen, and lyophilized to give compound 1.3 (53.2 mg, 0.0464 mmol, 58% yield). UPLC-MS (Method A, ESI+): m/z [M + H] ⁺ = 803.4 (theoretical value), 803.5 (observed value). HPLC retention time: 1.26 min. Example 11. Synthesis of (E)-9-(4-(5- aminoformyl- 2-(1- ethyl -3- methyl -1H -pyrazole -5 -carboxamido )-7-(3-( methylamino ) propoxy )-1H- benzo [d] imidazol -1- yl ) but -2- en - 1 - yl )-2-(1- ethyl -3- methyl -1H - pyrazole -5- yl )-8- methoxy -9H- pyrimido [4,5-b] indole -6- carboxamide ( Compound 1.4) Synthesis of Compound 10a The same procedure as Compound 4a was followed, using Compound 7 (30.0 mg, 0.0428 mmol) and Compound 8 (10 mg, 0.029 mmol) as starting materials to prepare Compound 10a . Upon completion, the product was directly purified by prepHPLC (Method 1). The pure fractions were frozen, dried, and lyophilized to give Compound 10a (12.8 mg, 0.0113 mmol, 40% yield). UPLC-MS (Method A, ESI+): m/z [M + H] ⁺ = 902.4 (theoretical value), 902.5 (observed value). HPLC retention time: 1.62 min. Synthesis of Compound 1.4

Compound 1.4 was prepared following the same procedure as compound 1.3 using compound 10a (12.8 mg, 0.0113 mmol) as starting material. After completion, the product was purified by prepHPLC (Method 1). The pure fractions were collected, frozen, and lyophilized to give compound 1.4 (7.98 mg, 0.007 mmol, 62% yield). UPLC-MS (Method A, ESI+): m/z [M + H] ⁺ = 802.4 (theoretical value), 802.5 (observed value). HPLC retention time: 1.27 min. Example 12. Synthesis of (E)-N-(6- aminoformyl- 3-(4-(6- aminoformyl- 8-(2-(1-(3-(2,5- dioxo -2,5- dihydro -1H -pyrrol -1- yl ) propionyl ) azinecyclobutane -3 - yl ) ethoxy )-2-(1- ethyl -3- methyl -1H -pyrazol -5 -yl )-9H - pyrimido [4,5-b] indol- 9- yl ) but - 2 - en - 1- yl )-3H- imidazo [4,5-b] pyridin -2- yl )-4- ethyl -2- methyloxazole -5- carboxamide ( Compound 2.1)

Compound 2.1 (4.11 mg, 0.044 mmol, 34% yield) was prepared following General Procedure 1 using compound 1.1 (10 mg, 0.013 mmol) as starting material. UPLC-MS (Method A, ESI+): m/z [M + H] ⁺ = 937.4 (theoretical value), 937.5 (observed value). HPLC retention time: 1.33 min. Example 13. Synthesis of (E)-9-(4-(6- aminoformyl- 2-(1- ethyl - 3- methyl -1H -pyrazol -5 -carboxamido )-3H- imidazo [4,5-b] pyridin -3- yl ) but-2- en - 1 -yl ) -8-(2-(1-(3-(2,5- dioxo -2,5- dihydro -1H - pyrrol -1 - yl ) propanoyl ) azinecyclobutane -3- yl ) ethoxy )-2-(1- ethyl -3- methyl -1H -pyrazol -5- yl )-9H- pyrimido [4,5-b] indole -6- carboxamide ( Compound 2.2)

Compound 2.2 (5.01 mg, 0.0043 mmol, 62% yield) was prepared following General Procedure 1 using compound 1.2 (7.83 mg, 0.0069 mmol) as starting material. UPLC-MS (Method A, ESI+): m/z [M + H] ⁺ = 936.4 (theoretical value), 936.5 (observed value). HPLC retention time: 1.33 min. Example 14. Synthesis of (E)-N-(5- aminoformyl- 1-(4-(6- aminoformyl- 2-(1- ethyl -3- methyl -1H -pyrazol -5- yl )-8- methoxy -9H- pyrimido [4,5-b] indol -9- yl ) but- 2 - en -1 - yl )-7-(3-(3-(2,5- dihydroxy -2,5- dihydro -1H -pyrrol -1- yl )-N -methylpropionamido ) propoxy )-1H - benzo [d] imidazol -2- yl )-4- ethyl -2- methyloxazole -5- carboxamide ( Compound 2.3)

Compound 2.3 (5.87 mg, 0.005 mmol, 57% yield) was prepared following General Method 1 using compound 1.3 (10 mg, 0.0087 mmol) as starting material. UPLC-MS (Method A, ESI+): m/z [M + H] ⁺ = 954.4 (theoretical value), 954.5 (observed value). HPLC retention time: 1.41 min. Example 15. Synthesis of (E)-9-(4-(5- aminoformyl- 7-(3-(3-(2,5- dioxo -2,5- dihydro -1H -pyrrol -1- yl )-N -methylpropionamido ) propoxy )-2-(1- ethyl - 3- methyl - 1H -pyrazole -5 -carboxamido )-1H - benzo [d] imidazol - 1 - yl ) but-2- en -1- yl ) -2-(1- ethyl -3- methyl -1H -pyrazol - 5 - yl )-8- methoxy- 9H- pyrimido [4,5-b] indole -6- carboxamide ( Compound 2.4)

Compound 2.4 (6.35 mg, 0.0054 mmol, 31% yield) was prepared following General Procedure 1 using compound 1.4 (20 mg, 0.0175 mmol) as starting material. UPLC-MS (Method A, ESI+): m/z [M + H] ⁺ = 953.4 (theoretical value), 953.5 (observed value). HPLC retention time: 1.47 min. Example 16. Synthesis of S-(1-(3-(3-(2-((6- aminoformyl- 9-((E)-4-(6- aminoformyl- 2-(4- ethyl -2 -methyloxazole -5 -carboxamido )-3H- imidazo [4,5-b] pyridin -3- yl ) but - 2- en -1- yl )-2-(1- ethyl -3- methyl -1H -pyrazol -5- yl )-9H- pyrimido [4,5-b] indol- 8- yl ) oxy ) ethyl ) azinecyclobutane -1- yl )-3 -oxopropyl )-2,5 -dioxopyrrolidin -3- yl )-L- cysteine ( Compound 3.1)

Compound 3.1 (2.58 mg, 0.0018 mmol, 70% yield) was prepared following General Method 2 using compound 2.1 (3.1 mg, 0.0026 mmol) as starting material. UPLC-MS (Method A, ESI+): m/z [M + H] ⁺ = 1058.4 (theoretical value), 1058.4 (observed value). HPLC retention time: 1.07 min. Example 17. Synthesis of S-(1-(3-(3-(2-((6- aminoformyl- 9-(4-(6- aminoformyl -2-(1- ethyl -3- methyl -1H -pyrazol -5 -carboxamido )-3H- imidazo [4,5-b] pyridin -3- yl ) butyl )-2-(1- ethyl -3- methyl -1H -pyrazol -5- yl )-9H- pyrimido [4,5-b] indol- 8- yl ) oxy ) ethyl ) azinecyclobutane -1- yl )-3 -oxopropyl )-2,5 -dioxopyrrolidin- 3- yl )-L- cysteine ( Compound 3.2)

Compound 3.2 (4.74 mg, 0.0034 mmol, 79% yield) was prepared following General Method 2 using compound 2.2 (5.0 mg, 0.0043 mmol) as starting material. UPLC-MS (Method A, ESI+): m/z [M + H] ⁺ = 1057.4 (theoretical value), 1057.5 (observed value). HPLC retention time: 1.30 min. Example 18. Synthesis of S-(1-(3-((3-((5 -aminoformyl -1-((E)-4-(6- aminoformyl -2-(1- ethyl -3- methyl -1H -pyrazol -5- yl )-8- methoxy- 9H- pyrimido [4,5-b] indol- 9- yl ) but - 2- en - 1 - yl )-2-(4- ethyl -2- methyloxazole -5 -carboxamido )-1H- benzo [d] imidazol - 7- yl ) oxy ) propyl )( methyl ) amino )-3 - oxopropyl )-2,5 -dioxopyrrolidin -3- yl )-L- cysteine ( Compound 3.3)

Compound 3.3 (4.7 mg, 0.0033 mmol, 76% yield) was prepared following General Method 2 using compound 2.3 (5.15 mg, 0.0044 mmol) as starting material. UPLC-MS (Method A, ESI+): m/z [M + H] ⁺ = 1075.4 (theoretical value), 1075.5 (observed value). HPLC retention time: 1.12 min. Example 19. Synthesis of S-(1-(3-((3-((5 -aminoformyl -1-((E)-4-(6- aminoformyl -2-(1- ethyl -3- methyl -1H -pyrazol -5- yl )-8- methoxy- 9H- pyrimido [4,5-b] indol- 9- yl ) but- 2- en - 1 - yl )-2-(1- ethyl -3- methyl -1H -pyrazol -5 -carboxamido )-1H - benzo [d] imidazol - 7 -yl)oxy)propyl)(methyl)amino ) -3 - oxopropyl ) -2,5 - dioxopyrrolidin - 3 - yl ) -L- cysteine ( Compound 3.4)

Compound 3.4 (5.45 mg, 0.0038 mmol, 81% yield) was prepared following General Method 2 using compound 2.4 (5.63 mg, 0.0048 mmol) as starting material. UPLC-MS (Method A, ESI+): m/z [M + H] ⁺ = 1074.4 (theoretical value), 1074.5 (observed value). HPLC retention time: 1.16 min. Example 20. Synthesis of 4 -(( R)-2-((R)-2-(3-(2,5- dioxo-2,5-dihydro-1H-pyrrol-1-yl)propionamido)-3-methylbutanamido)propionamido)benzyl 3-(2-((6 - aminoformyl - 9 - ( ( E ) -4- ( 6 - aminoformyl - 2- ( 4 - ethyl - 2 - methyloxazol -5- carboxamido )-3H- imidazo [ 4,5-b] pyridin - 3- yl ) but -2 - en -1-yl ) -2- (1- ethyl -3 - methyl -1H -pyrazol- 5- yl ) -9H -pyrimido[4,5-b]indol -8-yl ) oxy ) ethyl ) azinecyclobutane-1- carboxylate ( Compound 2.5)

Compound 2.5 (11.4 mg, 0.0077 mmol, 22% yield) was prepared following General Method 3 using compound 1.1 (38.5 mg, 0.0341 mmol) as starting material. UPLC-MS (Method A, ESI+): m/z [M + H] ⁺ = 1256.5 (theoretical value), 1256.6 (observed value). HPLC retention time: 1.49 min. Example 21. Synthesis of 4 -( (R)-2-((R)-2-(3-(2,5- dioxo -2,5- dihydro -1H -pyrrol -1 - yl )propionamido )-3-methylbutanamido) propionamido ) benzyl 3- ( 2 -((6 -aminoformyl -9-(( E ) -4-(6- aminoformyl - 2-( 1-ethyl - 3- methyl -1H -pyrazole -5- carboxamido )-3H- imidazo [4,5-b] pyridin - 3- yl ) but - 2- en- 1- yl ) -2-(1- ethyl -3- methyl - 1H- pyrazol -5- yl ) -9H -pyrimido [4,5- b ] indol- 8-yl ) oxy)ethyl ) azinecyclobutane-1 - carboxylate ( Compound 2.6)

Compound 2.6 (10.0 mg, 0.0068 mmol, 21% yield) was prepared following General Method 3 using compound 1.2 (36.6 mg, 0.0325 mmol) as starting material. UPLC-MS (Method A, ESI+): m/z [M + H] ⁺ = 1255.5 (theoretical value), 1255.6 (observed value). HPLC retention time: 1.49 min. Example 22. Synthesis of (3-((5- aminoformyl- 1-((E)-4-(6- aminoformyl- 2-(1- ethyl -3- methyl -1H -pyrazol -5 - yl )-8- methoxy -9H- pyrimido [4,5-b] indol- 9- yl ) but -2- en - 1 - yl )-2-(4- ethyl -2- methyloxazole -5 -carboxamido )-1H- benzo [d] imidazol -7- yl ) oxy ) propyl )( methyl ) carbamate 4-((S)-2-((S)-2-(3-(2,5- dihydroxy - 2,5- dihydro -1H -pyrrol -1- yl ) propionamido )-3 -methylbutanamido ) propionamido ) benzyl ester ( Compound 2.7)

Compound 2.7 (6.17 mg, 0.0041 mmol, 47% yield) was prepared following General Method 3 using compound 1.3 (10 mg, 0.0087 mmol) as starting material. UPLC-MS (Method A, ESI+): m/z [M + H] ⁺ = 1273.6 (theoretical value), 1273.8 (observed value). HPLC retention time: 1.33 min. Example 23. Synthesis of (3-((5- aminoformyl- 1-((E)-4-(6- aminoformyl- 2-(1- ethyl -3- methyl -1H -pyrazol -5 - yl )-8- methoxy -9H- pyrimido [4,5-b] indol- 9- yl ) but- 2 - en - 1 - yl )-2-(1- ethyl -3- methyl - 1H -pyrazol -5 -carboxamido )-1H - benzo [d] imidazol -7- yl ) oxy ) propyl )( methyl ) carbamate 4-((S)-2-((S)-2-(3-(2,5- dihydroxy - 2,5 - dihydro -1H -pyrrol -1- yl ) propionamido )-3 -methylbutanamido ) propionamido ) benzyl ester ( Compound 2.8)

Compound 2.8 (3.48 mg, 0.0023 mmol, 27% yield) was prepared following General Method 3 using compound 1.4 (10 mg, 0.0087 mmol) as starting material. UPLC-MS (Method A, ESI+): m/z [M + H] ⁺ = 1272.6 (theoretical), 1272.6 (observed). HPLC retention time: 1.53 min. Example 24. Synthesis of (2S,3R,4S,5S,6S)-2-(2-(3-((((9H- fluoren -9- yl ) methoxy ) carbonyl ) amino ) propionamido )-4-(((( perfluorophenoxy ) carbonyl ) oxy ) methyl ) phenoxy )-6-( methoxycarbonyl ) tetrahydro -2H- pyran -3,4,5- triyl triacetate ( Compound 23)

To a solution of compound 23a (3.83 g, 5.12 mmol) and PFP carbonate (4.03 g, 10.2 mmol) in anhydrous DCM (25 mL) was added DIPEA (2.7 mL, 15.4 mmol). The reaction was stirred at rt for 1 h. The solvent was removed and the product was purified by flash chromatography (SiO ₂ , hexane/EtOAc) to give compound 23 (4.55 g, 4.75 mmol, 93% yield). UPLC-MS (Method H, ESI+): m/z [M + H] ⁺ = 959.2 (theoretical value), 959.4 (observed value). HPLC retention time: 2.27 min. Example 25. Synthesis of (2S,3S,4S,5R,6S)-6-(4-(((3-(2-((6- aminoformyl- 9-((E)-4-(6- aminoformyl -2-(4- ethyl - 2- methyloxazole -5 -carboxamido )-3H- imidazo [4,5-b] pyridin -3- yl ) but - 2- en - 1- yl )-2-(1- ethyl -3- methyl - 1H -pyrazol - 5- yl )-9H -pyrimido [4,5-b] indol- 8- yl ) oxy ) ethyl ) azidocyclobutane -1- carbonyl ) oxy ) methyl )-2-(3-(3-(2,5- dihydroxy -2,5 - dihydro -1H - pyrrol -1- yl ) propionamido ) propionamido ) phenoxy )-3,4,5- trihydroxytetrahydro -2H- pyran -2-carboxylic acid ( Compound 2.9) Synthesis of compound 24a

Compound 24a (20.4 mg, 0.0114 mmol, 32% yield) was prepared following General Method 4 using compound 1.1 (27.9 mg, 0.0355 mmol) as starting material. UPLC-MS (Method A, ESI+): m/z [M + H] ⁺ = 1560.6 (theoretical value), 1560.8 (observed value). HPLC retention time: 1.94 min. Synthesis of compound 24b

Following General Method 5, compound 24a (20.38 mg, 0.0114 mmol) was used as the starting material to prepare compound 24b (6.62 mg, 0.0043 mmol, 38% yield). UPLC-MS (Method A, ESI+): m/z [M + H] ⁺ = 1198.5 (theoretical value), 1198.6 (observed value). HPLC retention time: 1.31 min. Synthesis of compound 2.9

Compound 2.9 (3.82 mg, 0.0028 mmol, 66% yield) was prepared following General Method 6 using compound 24b (6.62 mg, 0.0043 mmol) as starting material. UPLC-MS (Method A, ESI+): m/z [M + H] ⁺ = 1349.5 (theoretical value), 1349.7 (observed value). HPLC retention time: 1.33 min. Example 26. Synthesis of (2S,3S,4S,5R,6S)-6-(4-(((3-(2-((6- aminoformyl- 9-((E)-4-(6- aminoformyl- 2-(1- ethyl -3- methyl - 1H -pyrazole -5- carboxamido )-3H- imidazo [4,5-b] pyridin -3- yl ) but-2- en -1 - yl )-2-(1- ethyl - 3- methyl -1 H -pyrazol -5- yl )-9H- pyrimido [4,5-b] indol- 8- yl ) oxy ) ethyl ) azacyclobutane -1 -carbonyl ) oxy ) methyl )-2-(3-(3-(2,5- dioxo - 2,5 -dihydro -1H -pyrrol -1- yl ) propionamido ) propionamido ) phenoxy )-3,4,5- trihydroxytetrahydro -2H- pyran -2- carboxylic acid ( Compound 2.10) Synthesis of compound 25a

Compound 25a (17.7 mg, 0.0099 mmol, 31% yield) was prepared following General Method 4 using compound 1.2 (36.6 mg, 0.0325 mmol) as starting material. UPLC-MS (Method A, ESI+): m/z [M + H] ⁺ = 1559.6 (theoretical value), 1559.7 (observed value). HPLC retention time: 1.67 min. Synthesis of compound 25b

Following General Method 5, compound 25a (17.7 mg, 0.0099 mmol) was used as the starting material to prepare compound 25b (7.9 mg, 0.0055 mmol, 56% yield). UPLC-MS (Method A, ESI+): m/z [M + H] ⁺ = 1197.5 (theoretical value), 1197.6 (observed value). HPLC retention time: 1.15 min. Synthesis of compound 2.10

Compound 2.10 (3.39 mg, 0.0022 mmol, 39% yield) was prepared following General Method 6 using compound 25b (8.53 mg, 0.0055 mmol) as starting material. UPLC-MS (Method A, ESI+): m/z [M + H] ⁺ = 1348.5 (theoretical value), 1348.6 (observed value). HPLC retention time: 1.30 min. Example 27. Synthesis of (2S,3S,4S,5R,6S)-6-(4-((((3-((5- aminoformyl -1-((E)-4-(6- aminoformyl- 2-(1- ethyl - 3 -methyl -1H -pyrazol -5- yl )-8- methoxy -9H- pyrimido [4,5-b] indol -9 - yl ) but- 2-en-1-yl ) -2- ( 4 - ethyl -2 -methyloxazole - 5 -carboxamido )-1H- benzo [d] imidazol -7- yl ) oxy ) propyl )( methyl ) aminocarboxamido ) oxy ) methyl )-2-(3-(3-(2,5- dihydroxy -2,5- dihydro -1H -pyrrol -1- yl ) propionamido ) propionamido ) phenoxy )-3,4,5- trihydroxytetrahydro -2H- pyran -2-carboxylic acid ( Compound 2.11) Synthesis of compound 26a

Compound 26a (35.8 mg, 0.0198 mmol, 68% yield) was prepared following General Method 4 using compound 1.3 (33.2 mg, 0.029 mmol) as starting material. UPLC-MS (Method A, ESI+): m/z [M + H] ⁺ = 1577.6 (theoretical value), 1577.7 (observed value). HPLC retention time: 1.87 min. Synthesis of compound 26b

Following General Method 5, compound 26a (35.8 mg, 0.0198 mmol) was used as the starting material to prepare compound 26b (15.7 mg, 0.0101 mmol, 51% yield). UPLC-MS (Method A, ESI+): m/z [M + H] ⁺ = 1215.5 (theoretical value), 1215.5 (observed value). HPLC retention time: 1.17 min. Synthesis of compound 2.11

Compound 2.11 (8.65 mg, 0.0054 mmol, 54% yield) was prepared following General Method 6 using compound 26b (15.7 mg, 0.0101 mmol) as starting material. UPLC-MS (Method A, ESI+): m/z [M + H] ⁺ = 1366.5 (theoretical value), 1366.4 (observed value). HPLC retention time: 1.22 min. Example 28. Synthesis of (2S,3S,4S,5R,6S)-6-(4-((((3-((5- aminoformyl -1-((E)-4-(6- aminoformyl- 2-(1- ethyl - 3-methyl -1H -pyrazol -5- yl )-8- methoxy -9H- pyrimido [4,5-b] indol- 9 - yl ) but -2- en - 1- yl )-2-(1- ethyl -3- methyl ( 2- ( 3- ( 2,5 - dihydroxy - 2,5 - dihydro - 1H - pyrrol - 1 - yl ) propionamido ) propionamido ) phenoxy ) -3,4,5 - trihydroxytetrahydro - 2H - pyran - 2 - carboxylic acid ( Compound 2.12 ) ​ ​ ​ Synthesis of compound 27a

Compound 27a (15.9 mg, 0.0088 mmol, 31% yield) was prepared following General Method 4 using compound 1.4 (33 mg, 0.029 mmol) as starting material. UPLC-MS (Method A, ESI+): m/z [M + H] ⁺ = 1576.6 (theoretical value), 1576.7 (observed value). HPLC retention time: 1.82 min. Synthesis of compound 27b

Following General Method 5, compound 27a (15.9 mg, 0.0088 mmol) was used as the starting material to prepare compound 27b (7.6 mg, 0.0053 mmol, 60% yield). UPLC-MS (Method A, ESI+): m/z [M + H] ⁺ = 1214.5 (theoretical value), 1214.6 (observed value). HPLC retention time: 1.31 min. Synthesis of compound 2.12

Compound 2.12 (5.64 mg, 0.0035 mmol, 72% yield) was prepared following General Method 6 using compound 27b (7.6 mg, 0.0053 mmol) as starting material. UPLC-MS (Method A, ESI+): m/z [M + H] ⁺ = 1365.5 (theoretical), 1365.6 (observed). HPLC retention time: 1.38 min. Example 29. Synthesis of 2-(1- ethyl -3- methyl -1H -pyrazol -5- yl )-9H -pyrido [2',3':4,5] pyrrolo [2,3-d] pyrimidine -6- carboxamide ( Compound 28) . Synthesis of compound 28b

To a solution of 28a (40 g, 263 mmol) in acetonitrile (1000 mL) was added NaBr (27.05 g, 263 mmol) in water (240 mL), followed by Oxone (162 g, 263 mmol) in water (300 mL). The mixture was stirred at 20 °C for 2 h. The reaction mixture was cooled to 0 °C and quenched by the addition of saturated Na ₂ SO ₃ (1000 mL). The mixture was then extracted with dichloromethane (2×1000 mL), the organic layers were combined, washed with brine (2×1000 mL), dried over Na ₂ SO ₄ , filtered and concentrated in vacuo to give a brown solid. The crude product 28b (50 g, 82%) was used in the next step without further purification. UPLC-MS (Method I, ESI+): m/z [M + H] ⁺ = 231.0 (theoretical value), 231.0 (observed value). HPLC retention time: 0.477 min. ¹ H NMR : (400 MHz, methanol- d ₄ ) δ ppm 7.84 (d, J = 8.4 Hz, 1H), 7.11 (d, J = 8.4 Hz, 1H), 3.88 (s, 3H). Synthesis of compound 28c

To a solution _{of H2O2 (} 98.6 g, 1.45 mol, 83.6 mL, 50% purity) in dichloromethane (700 mL) was added trifluoroacetic anhydride (354.5 g, 1.69 mol, 235 mL) at 0°C. The solution was warmed to 25°C and dichloromethane (300 mL) containing 28b (50 g, 216.4 mmol) was added. The reaction mixture was heated to 40°C and stirred at 40°C for 1 h, after which the mixture was cooled to 0°C and the reaction was _quenched by the slow addition of saturated _Na2SO3 . The reaction mixture was extracted with dichloromethane (DCM) 600 mL (2×300 mL), and the organic layers were combined, washed with brine, dried over Na ₂ SO ₄ , filtered, and concentrated in vacuo . The residue was purified by column chromatography (SiO ₂ , petroleum ether/ethyl acetate = 20:1 to 5:1) to give 28c as a white solid (36.2 g, 64% yield). UPLC-MS (Method I, ESI+): m/z [M + H] ⁺ = 231.0 (theoretical value), 261.0 (observed value). HPLC retention time: 0.630 min. ¹ H NMR (400 MHz, methanol- d ₄ ) δ ppm 8.45 (d, J = 8.0 Hz, 1H), 8.28 (d, J = 8.0 Hz, 1H), 4.01 (s, 3H). Synthesis of Compound 28d

A solution of 28c (10 g, 38.3 mmol) in NH ₃ .H ₂ O (150 mL, 28% w/w) was stirred at 20 °C for 1.5 h. LCMS analysis (Method J) showed complete consumption of the reactants and a major peak of the desired mass was detected. The reaction mixture was filtered and concentrated in vacuo to give the crude product 28d (7 g, 28.45 mmol, 74% yield) as a brown solid, which was used in the next step without further purification. UPLC-MS (Method J, ESI+): m/z [M + H] ⁺ = 246.0 (theoretical), 246.0 (observed). HPLC retention time: 0.571 min. ¹ H NMR (400 MHz, methanol- d ₄ ) δ ppm 8.46 (d, J = 8.0 Hz, 1H), 8.28 (d, J = 8.0 Hz, 1H). Synthesis of Compound 28e

A mixture of 28d (7 g, 28.5 mmol) and 3e (6.76 g, 42.7 mmol) in dioxane (80 mL) was degassed and purged with _N2 three times. Pd(dppf) _Cl2 (2.08 g, 2.85 mmol), _Na2CO3 (6.03 g, 56.91 mmol) and _H2O (10 mL) were then _added , and the mixture was heated to 110 °C under _N2 atmosphere for 3 h. The reaction mixture was concentrated in vacuo to give the crude product. The crude material was purified by column chromatography ( _SiO2 , petroleum ether:ethyl acetate ) to give 28e (3 g, 38% yield) as a yellow solid. UPLC-MS (method K, ESI-): m/z [M - H] ^- = 278.0 (theoretical value), 277.9 (observed value). HPLC retention time: 1.095 min. ¹ H NMR (400 MHz, methanol- d ₄ ) δ ppm 9.00 (s, 1H), 8.76 (d, J = 8.4 Hz, 1H), 8.40 (d, J = 8.8 Hz, 1H). Synthesis of compound 28f

A solution of 28e (3 g, 10.7 mmol) and 3g (5.83 g, 24.7 mmol) in dioxane (60 mL) was degassed and purged with _N2 for 3 times, and then Pd(dppf) _Cl2 (785 mg, 1.07 mmol), _Na2CO3 (2.27 g, 21.5 mmol) and water (12 ml) were added. The mixture was heated to 110 °C and stirred at 110 °C for ₃ h under _N2 atmosphere. The reaction mixture was concentrated in vacuo and the crude residue was purified by column chromatography ( _SiO2 , petroleum ether:ethyl acetate ) to give 28f (1.88 g, 50% yield) as a yellow solid. UPLC-MS (Method J, ESI+): m/z [M + H] ⁺ = 354.1 (theoretical value), 354.1 (observed value). HPLC retention time: 0.654 min. ¹ H NMR (400 MHz, methanol- d ₄ ) δ ppm 9.13 (s, 2H), 8.72 (d, J = 8.4 Hz, 1H), 8.38 (d, J = 8.4 Hz, 1H), 6.96 (s, 1H), 4.80 (q, J = 7.2 Hz, 2H), 2.31 (s, 3H), 1.44 (t, J = 7.2 Hz, 3H). Synthesis of compound 28

Compound 28 was prepared by following the same procedure as compound 3 using compound 28f (1000 mg, 2.83 mmol) as the starting material. The crude product was purified by column chromatography (SiO ₂ , dichloromethane:methanol = 15:1 to 10:1) to give 28 (200 mg, 0.622 mmol, 22%) as an off-white solid. UPLC-MS (Method G, ESI+): m/z [M + H] ⁺ = 322.1 (theoretical value), 322.1 (observed value). HPLC retention time: 2.006 min ¹ H NMR (400 MHz, DMSO- d ₆ ) δ ppm 9.58 (s, 1H), 8.27 - 8.17 (m, 2H), 8.09 (d, J = 8.4 Hz, 1H), 7.69 (br s, 1H), 6.88 (s, 1H), 4.80 (q, J = 7.2 Hz, 2H), 2.24 (s, 3H), 1.41 (t, J = 7.2 Hz, 3H). Example 30. Synthesis of 2-(1- ethyl -3- methyl -1H -pyrazol -5- yl )-8- methyl -9H -pyrido [4′,3′:4,5] pyrrolo [2,3-d] pyrimidine -6- carboxamide ( Compound 29) . Synthesis of compound 29b

To a solution of 29a (23 g, 212 mmol) in methanol (450 mL) at 25 °C under _N2 was added triethylamine (46.1 mmol, 6.41 mL) and Pd(dppf) _Cl2 (3.88 g, 5.30 mmol). The suspension was degassed under vacuum and purged with CO several times. The mixture was stirred at 70 °C under carbon monoxide atmosphere (CO, 50 psi) for 16 h. LCMS analysis showed complete consumption of the starting material. Another vial was set up as described above. The two reaction mixtures were combined for work-up and purification. The reaction mixture was filtered, concentrated and purified by column chromatography ( _SiO2 , petroleum ether:ethyl acetate) to give 29b (13 g, 31% yield) as a yellow solid. UPLC-MS (method I, ESI+): m/z [M + H] ⁺ = 197.1 (theoretical value), 197.1 (observed value). HPLC retention time: 0.466 min ¹ H NMR (400MHz, DMSO- d ₆ ) δ ppm 8.57 (d, J = 8.4 Hz, 1H), 8.11 (d, J = 8.4 Hz, 1H), 3.92 (s, 3H), 2.77 (s, 3H) Synthesis of compound 29c

A solution of 29b (1.5 g, 7.65 mmol) in NH ₃ ^.H ₂ O (15 mL) was stirred at 20°C for 16 h. The reaction mixture was filtered and concentrated in vacuo to yield a yellow solid 29c (1.4 g, crude), which was used in the next step without further purification. UPLC-MS (Method I, ESI+): m/z [M + H] ⁺ = 182.1 (theoretical value), 182.1 (observed value). HPLC retention time: 0.470 min Synthesis of compound 29d

A solution of 29c (500 mg, 2.76 mmol) and Pd/C (500 mg, 10% Pd) in dioxane (10 mL) was degassed and purged with _H2 three times. The mixture was stirred at 25 °C under 1 atmosphere of _H2 for 25 h. The reaction mixture was filtered and concentrated in vacuo to yield 29d (400 mg, crude) as a white solid. The crude product was used in the next step without further purification. UPLC-MS (Method I, ESI+): m/z [M + H] ⁺ = 152.1 (theoretical), 152.2 (observed). HPLC retention time: 0.138 min Synthesis of compound 29e

To a solution of 29d (6 g, 39.7 mmol) in acetonitrile (120 mL) was added N-bromosuccinimide (NBS, 9.18 g, 51.6 mmol) at 0 °C. The mixture was stirred at 25 °C for 2 h. The reaction mixture was filtered and the solvent was removed in vacuo . The residue was quenched by the addition of saturated NaHCO ₃ and saturated Na ₂ SO ₃ at 20 °C and extracted with ethyl acetate (3×200 mL). The organics were combined, dried over Na ₂ S ₂ O ₄ , filtered and the solvent was removed in vacuo to give the crude product. The residue was purified by column chromatography (SiO ₂ , petroleum ether/ethyl acetate = 3:2 to 1:4) to afford 29e as a yellow solid (3.87 g, 42% yield). UPLC-MS (Method L, ESI+): m/z [M + H] ⁺ = 230.0 (theoretical value), 230.1 (observed value). HPLC retention time: 0.245 min ¹ H NMR (400 MHz, DMSO-d ₆ ) δ ppm 7.83 (s, 1H), 7.68 (br dd, J = 1.2, 3.2 Hz, 1H), 7.37 - 7.27 (m, 1H), 5.86 (s, 2H), 2.41 (s, 3H). Synthesis of compound 29f

To a solution of hydrogen peroxide (6.42 g, 56.6 mmol, 30% purity) in dichloromethane (30 mL) was added trifluoroacetic anhydride (14.24 g, 67.8 mmol) at 0 °C. The solution was warmed to 25 °C and 29e (2 g, 8.69 mmol) was added. The mixture was stirred at 40 °C for 36 h. The mixture was cooled to 0 °C and saturated Na ₂ SO ₃ was added slowly to quench the reaction. The mixture was extracted with DCM (3×100 mL), the organic layers were combined, washed with brine (100 mL), dried over Na ₂ SO ₄ , filtered, and concentrated in vacuo to give a residue. The residue was purified by column chromatography (SiO ₂ , petroleum ether:ethyl acetate) to give compound 29f (190 mg, 8.4% yield) as a white solid. (Method I, ESI+): m/z [M + H] ⁺ = 260.0 (theoretical value), 260.0 (observed value). HPLC retention time: 0.587 min ¹ H NMR (400MHz, DMSO- d ₆ ) δ ppm 8.27 (s, 1H), 8.25 (br s, 1H), 7.98 (br s, 1H), 2.59 (s, 3H). Synthesis of compound 29g

To a mixture of 3g (2 g, 8.47 mmol) and 5-bromo-2-iodopyrimidine (2.41 g, 8.47 mmol) in dioxane (40 mL) was added Pd(dppf)Cl ₂ (310 mg, 424 μmol), Na ₂ CO ₃ (1.80 g, 16.9 mmol) and H ₂ O (8 mL). The mixture was degassed and purged with N ₂ 3 times, and then stirred at 75 °C under N ₂ atmosphere for 2 h. The reaction mixture was filtered, concentrated and purified by column chromatography (SiO ₂ , petroleum ether:ethyl acetate) to give 29g (810 mg, 36% yield) as a white solid. (Method K, ESI+): m/z [M + H] ⁺ = 267.0 (theoretical value), 266.9 (observed value). HPLC retention time: 1.669 min. ¹ H NMR (400MHz, DMSO- d ₆ ) δ ppm 9.08 (s, 2H), 6.80 (s, 1H), 4.63 (q, J = 7.2 Hz, 2H), 2.22 (s, 3H), 1.33 (t, J = 7.2 Hz, 3H). Synthesis of compound 29h

A mixture of 29g (2.6 g, 9.73 mmol), bis(pinacolato)diboron (3.21 g, 12.65 mmol), potassium acetate (1.91 g, 19.5 mmol) and Pd(dppf) _Cl2 (712 mg, 973 μmol) in dioxane (60 mL) was degassed and purged with _N2 three times, and then the mixture was stirred at 80 °C under _N2 atmosphere for 16 h. The reaction mixture was filtered, concentrated and purified by column chromatography ( _SiO2 , petroleum ether:ethyl acetate) to give 29h (610 mg, 87% yield) as a yellow oil. (Method L, ESI+): m/z [M+H] ⁺ = 233.1 (theoretical), 232.9 (observed). HPLC retention time: 0.315 min. ¹ H NMR (400MHz, chloroform- d ) δ ppm 8.96 (s, 2H), 6.81 (s, 1H), 4.69 (q, J = 7.2 Hz, 2H), 2.24 (s, 3H), 1.33 (t, J = 7.2 Hz, 3H). Synthesis of compound 29i

To a mixture of 29h ₍ 1.16 g, 5.00 mmol) and 29f (1 g, 3.85 mmol) in dioxane (20 mL) were added Pd(dppf) _Cl (140.69 mg, 192.27 μmol), potassium carbonate (1.06 g, 7.69 mmol), and _H2O (4 mL) under N2. The mixture was degassed and purged with _N2 three times, and then the mixture was stirred at 75 °C under nitrogen for 1 h. The reaction mixture was filtered, concentrated, and the residue was purified by column chromatography ( _SiO2 , petroleum ether:ethyl acetate) to give 29i (760 mg, 2.07 mmol, 54% yield) as a yellow solid. (Method L, ESI+): m/z [M + H] ⁺ = 368.1 (theoretical value), 368.2 (observed value). HPLC retention time: 0.455 min. ¹ H NMR (400 MHz, DMSO- d ₆ ) δ ppm 8.97 (s, 2H), 8.30 (s, 1H), 8.19 (s, 1H), 7.97 (s, 1H), 6.85 (s, 1H), 4.65 (q, J = 6.8 Hz, 2H), 2.65 (s, 3H), 2.19 (s, 3H), 1.32 (t, J = 7.2 Hz, 3H). Synthesis of compound 29

Compound 29 was prepared by following the same procedure as compound 3 using compound 29i (230 mg, 0.626 mmol) as the starting material. The crude product was purified by prepHPLC (Method 3) to give compound 29 (50 mg, 12% yield). UPLC-MS (Method C, ESI+): m/z [M + H] ⁺ = 336.2 (theoretical value), 336.1 (observed value). HPLC retention time: 1.906 min. ¹ H NMR (400 MHz, DMSO- d ₆ ) δ ppm 13.01 (s, 1H), 9.80 (s, 1H), 8.82 (s, 1H), 8.05 (br s, 1H), 7.59 - 7.53 (m, 1H), 6.87 (s, 1H), 4.82 (q, J = 7.2 Hz, 2H), 2.87 (s, 3H), 2.25 (s, 3H), 1.42 (t, J = 7.2 Hz, 3H). Example 31. Synthesis of methanesulfonic acid (E)-4-(7-(3-(( tert-butyloxycarbonyl )( methyl ) amino ) propoxy )-5- aminocarbonyl -2-(4- ethyl -2- methyloxazole -5- carboxamido )-1H- benzo [d] imidazol -1- yl ) but -2- en -1- yl ester ( Compound 30) . Synthesis of compound 30

A mixture of 6n (1.00 eq, 500 mg, 0.876 mmol), methanesulfonic anhydride (1.20 eq, 183 mg, 1.05 mmol) and 2,6-lutidine (3.00 eq, 0.3 mL, 2.63 mmol) in DCM (9 mL) was stirred at room temperature for 30 min. The solvent was reduced by half and the crude material was purified by column chromatography (SiO2, DCM/MeOH) to give 30 (441 mg, 0.680 mmol, 78% yield) as an off-white solid. UPLC-MS (Method A, ESI+): m/z [M + H] ⁺ = 649.3 (theoretical), 649.3 (observed). HPLC retention time: 1.56 min. Example 32. Synthesis of (E)-N-(5- aminoformyl- 1-(4-(6- aminoformyl- 2-(1- ethyl -3- methyl -1H -pyrazol -5- yl )-9H - pyrido [2′,3′:4,5] pyrrolo [2,3-d] pyrimidin -9 - yl ) but - 2- en-1-yl ) -7-(3-( methylamino ) propoxy )-1H- benzo [d] imidazol -2- yl )-4- ethyl -2- methyloxazole -5- carboxamide ( Compound 1.5) . Synthesis of compound 31a

A mixture of compound 30 (52 mg, 0.0802 mmol), compound 28 (13 mg, 0.0405 mmol) and cesium carbonate (40 mg, 0.121 mmol) in DMF (1 mL) was heated to 55 °C and stirred for 24 hours. After completion, the solution was filtered and the product was purified by prepHPLC (Method 1). The pure fractions were frozen, dried, and lyophilized to give compound 31a (34.2 mg, 0.0391 mmol, 97% yield). UPLC-MS (Method A, ESI+): m/z [M + H] ⁺ = 874.4 (theoretical value), 874.6 (observed value). HPLC retention time: 1.56 min. Synthesis of compound 1.5

Compound 31a (34.2 mg, 0.0391 mmol) was dissolved in 20% TFA in DCM (2 mL) and the solution was stirred for 30 min. The solvent was removed in vacuo and the crude product was purified by prepHPLC (Method 1). The pure fractions were collected, frozen, and lyophilized to give compound 1.5 (20.5 mg, 0.0231 mmol, 59% yield). UPLC-MS (Method A, ESI+): m/z [M + H] ⁺ = 774.4 (theoretical value), 774.5 (observed value). HPLC retention time: 1.05 min. Example 33. Synthesis of (E)-N-(5 -aminoformyl- 1-(4-(6- aminoformyl- 2-(1- ethyl -3- methyl -1H -pyrazol -5- yl )-8- methyl -9H - pyrido [4′,3′:4,5] pyrrolo [2,3-d] pyrimidin -9- yl ) but - 2- en -1 - yl )-7-(3-( methylamino ) propoxy )-1H- benzo [d] imidazol -2- yl )-4 - ethyl -2- methyloxazole -5- carboxamide ( Compound 1.6) . Synthesis of compound 32a

A mixture of compound 30 (176 mg, 0.298 mmol), compound 29 (50 mg, 0.149 mmol) and cesium carbonate (146 mg, 0.447 mmol) in DMF (3 mL) was heated to 60 °C and stirred for 24 hours. After completion, the solution was filtered and the product was purified by prepHPLC (Method 1). The pure fractions were frozen, dried, and lyophilized to give compound 32a (68.6 mg, 0.0773 mmol, 52% yield). UPLC-MS (Method A, ESI+): m/z [M + H] ⁺ = 888.43 (theoretical value), 888.39 (observed value). HPLC retention time: 1.55 min. Synthesis of compound 1.6

Compound 32a (68.6 mg, 0.0773 mmol) was dissolved in 20% TFA in DCM (4 mL) and the solution was stirred for 30 min. The solvent was removed in vacuo and the crude product was used without further purification to yield 1.6 (74 mg, 0.0655 mmol, 85% yield) as a 3x TFA salt. UPLC-MS (Method A, ESI+): m/z [M + H] ⁺ = 788.37 (theoretical), 788.45 (observed). HPLC retention time: 1.09 min. Example 34. Synthesis of (3-((5- aminoformyl- 1-((E)-4-(6- aminoformyl- 2-(1- ethyl -3- methyl -1H -pyrazol -5- yl )-9H -pyrido [2',3':4,5] pyrrolo [2,3-d] pyrimidin -9- yl ) but -2-en - 1 - yl )-2-(4- ethyl -2- methyloxazole -5 -carboxamido )-1H- benzo [d] imidazol -7 -yl ) oxy ) propyl )( methyl ) carbamate 4-((S)-2-((S)-2-(3-(2,5- dioxo -2,5- dihydro -1H -pyrrol -1- yl ) propionamido )-3 -methylbutanamido ) propionamido ) benzyl ester ( Compound 2.13) .

Compound 2.13 (5.60 mg, 0.0045 mmol, 66% yield) was prepared following General Method 3 using compound 1.5 (5.29 mg, 0.0068 mmol) as starting material and DMA as solvent. UPLC-MS (Method A, ESI+): m/z [M + H] ⁺ = 1244.5 (theoretical value), 1244.5 (observed value). HPLC retention time: 1.45 Example 35. Synthesis of (2S,3S,4S,5R,6S)-6-(4-((((3-((5- aminoformyl -1-((E)-4-(6- aminoformyl- 2-(1- ethyl -3- methyl - 1H -pyrazol -5- yl )-9H -pyrido [2',3':4,5] pyrrolo [2,3-d] pyrimidin -9- yl ) but -2- en -1- yl )-2-(4 -ethyl - 2 -methyloxazole -5 -carboxamido )-1H- benzo [d] imidazol -7 -yl ) oxy ) propyl )( methyl ) aminocarboxamido ) oxy ) methyl )-2-(3-(3-(2,5- dihydroxy - 2,5 - dihydro -1H -pyrrol -1- yl ) propionamido ) propionamido ) phenoxy )-3,4,5- trihydroxytetrahydro -2H- pyran -2-carboxylic acid ( Compound 2.14) . Synthesis of compound 34a

Following General Method 4, compound 1.5 (14.7 mg, 0.019 mmol) was used as the starting material to prepare compound 34a (12.9 mg, 0.0083 mmol, 44% yield). UPLC-MS (Method A, ESI+): m/z [M + H] ⁺ = 1548.6 (theoretical value), 1548.5 (observed value). HPLC retention time: 1.76 min. Synthesis of compound 34b

Following General Method 5, compound 34a (12.9 mg, 0.0083 mmol) was used as the starting material to prepare compound 34b (6.95 mg, 0.0059 mmol, 70% yield). UPLC-MS (Method A, ESI+): m/z [M + H] ⁺ = 1186.5 (theoretical value), 1186.5 (observed value). HPLC retention time: 1.28 min. Synthesis of compound 2.14

Compound 2.14 (3.01 mg, 0.0023 mmol, 38% yield) was prepared following General Method 6 using compound 34b (6.95 mg, 0.0059 mmol) as starting material. UPLC-MS (Method A, ESI+): m/z [M + H] ⁺ = 1337.5 (theoretical value), 1337.4 (observed value). HPLC retention time: 1.33 min. Example 36. Synthesis of (E)-N-(5- aminoformyl- 1-(4-(6- aminoformyl- 2-(1- ethyl -3- methyl -1H -pyrazol -5- yl )-9H -pyrido [2',3':4,5] pyrrolo [2,3-d] pyrimidin -9- yl ) but - 2- en-1-yl ) -7-(3-(3-(2,5- dioxo -2,5- dihydro -1H -pyrrol -1- yl )-N- methylpropionamido ) propoxy ) -1H- benzo [d] imidazol -2- yl )-4- ethyl -2- methyloxazole -5- carboxamide ( Compound 2.15) . Synthesis of compound 2.15

Compound 2.15 (1.6 mg, 0.0018 mmol, 35% yield) was prepared following General Procedure 1 using compound 1.5 (4.4 mg, 0.005 mmol) as starting material. UPLC-MS (Method A, ESI+): m/z [M + H] ⁺ = 925.4 (theoretical value), 925.5 (observed value). HPLC retention time: 1.37 min. Example 37. Synthesis of (E)-N-(5 -aminoformyl- 1-(4-(6- aminoformyl- 2-(1- ethyl -3- methyl -1H -pyrazol -5- yl )-8- methyl -9H - pyrido [4′,3′:4,5] pyrrolo [2,3-d] pyrimidin -9 - yl ) but - 2- en -1- yl )-7-(3-(3-(2,5- dioxo -2,5- dihydro -1H - pyrrol -1- yl )-N -methylpropionamido ) propoxy )-1H- benzo [d] imidazol -2- yl )-4- ethyl -2- methyloxazole -5- carboxamide ( Compound 2.16) . Synthesis of compound 2.16

Compound 2.16 (2.3 mg, 0.0024 mmol, 49% yield) was prepared following General Procedure 1 using compound 1.6 (4.5 mg, 0.005 mmol) as starting material. UPLC-MS (Method A, ESI+): m/z [M + H] ⁺ = 939.4 (theoretical value), 939.5 (observed value). HPLC retention time: 1.38 min. Example 38. Synthesis of (3-((5- aminoformyl- 1-((E)-4-(6- aminoformyl- 2-(1- ethyl -3- methyl -1H -pyrazol -5 - yl )-8- methyl -9H -pyrido [4′,3′:4,5] pyrrolo [2,3-d] pyrimidin -9 - yl ) but-2- en -1- yl ) -2-(4- ethyl - 2- methyloxazole -5 -carboxamido )-1H- benzo [d] imidazol -7- yl ) oxy ) propyl )( methyl ) carbamate 4-((S)-2-((S)-2-(3-(2,5- dihydroxy -2,5 -dihydro -1H -pyrrol -1- yl ) propionamido )-3 -methylbutanamido ) propionamido ) benzyl ester ( Compound 2.17) . Synthesis of compound 2.17

Compound 2.17 (16.7 mg, 0.012 mmol, 92% yield) was prepared following General Method 3 using compound 1.6 (15 mg, 0.013 mmol) as starting material and DMA as solvent. UPLC-MS (Method A, ESI+): m/z [M + H] ⁺ = 1258.55 (theoretical value), 1258.51 (observed value). HPLC retention time: 1.46 Example 39. Synthesis of (2S,3S,4S,5R,6S)-6-(4-((((3-((5- aminoformyl -1-((E)-4-(6- aminoformyl- 2-(1- ethyl -3- methyl - 1H -pyrazol -5- yl )-8- methyl -9H -pyrido [4',3':4,5] pyrrolo [2,3-d] pyrimidin -9- yl ) but -2- en -1- yl )-2 -(4- ethyl -2- methyloxazole -5 -carboxamido )-1H- benzo [d] imidazol -7- yl ) oxy ) propyl )( methyl ) aminocarboxamido ) oxy ) methyl )-2-(3-(3-(2,5- dihydroxy - 2,5- dihydro -1H -pyrrol -1- yl ) propionamido ) propionamido ) phenoxy )-3,4,5- trihydroxytetrahydro -2H- pyran -2-carboxylic acid ( Compound 2.18) . Synthesis of compound 38a

Compound 38a was prepared following General Method 4 using compound 1.6 (59 mg, 0.052 mmol) as starting material. UPLC-MS (Method A, ESI+): m/z [M + H] ⁺ = 1562.6 (theoretical value), 1562.5 (observed value). HPLC retention time: 1.80 min. Synthesis of Compound 38b

To a solution of compound 38a (30 mg, 0.192 mmol) in THF (1 mL) and MeOH (0.5 mL) was added LiOH (1 M in water, 0.18 mL, 0.18 mmol), and the reaction was stirred at room temperature for 30 min. The solvent was removed in vacuo and the crude product was purified by prepHPLC (Method 1) to give 38b (7.1 mg, 0.0059 mmol, 31% yield) as a white solid. UPLC-MS (Method A, ESI+): m/z [M + H] ⁺ = 1200.5 (theoretical), 1200.4 (observed). HPLC retention time: 1.34 min. Synthesis of compound 2.18

Compound 2.18 (5.83 mg, 0.0043 mmol, 73% yield) was prepared following General Method 6 using compound 34b (7.1 mg, 0.0059 mmol) as starting material. UPLC-MS (Method A, ESI+): m/z [M + H] ⁺ = 1351.51 (theoretical value), 1351.54 (observed value). HPLC retention time: 1.34 min. Example 40. Synthesis of (E)-N-(5 -aminoformyl- 1-(4-(6- aminoformyl- 2-(2,4 -dimethyloxazol -5 - yl )-8- methoxy -9H- pyrimido [4,5-b] indol- 9- yl ) but- 2-en-1-yl ) -7- ( 3- ( methylamino ) propoxy )-1H- benzo [d] imidazol -2- yl )-4- ethyl -2- methyloxazole -5- carboxamide ( Compound 1.7) . Synthesis of compound 39a

A 1.5 M solution of K ₃ PO ₄ in water (1.3 mL, 1.94 mmol) was purged in a 20 mL vial for 5 min. Then a separate 40 mL vial was charged with SPhos Pd G2 (152 mg, 0.210 mmol), compound 8b (300 mg, 0.972 mmol) and 2,4-dimethyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)oxazole (434 mg, 1.94 mmol) and the headspace was purged under Ar for 3 min. The reactants were dissolved in THF (18.141 mL) and purged for 45 min. Under _{N2 , K3PO4} (1.3 mL, 1.94 mmol) in water was transferred to a 40 mL vial containing the solution; the vial was then removed from Ar and stirred at 60 °C for 1 h. After 1 h, the crude product was extracted with ethyl acetate, washed with _NaHCO3 and brine, dried over _MgSO4 , and concentrated. It was then purified by prepHPLC (Method 1) to yield 39a (71.3 mg, 0.193 mmol, 19% yield). UPLC-MS (Method A, ESI+): m/z [M + H] ⁺ = 370.34 (theoretical value), 370.07 (observed value). HPLC retention time: 1.41 min. Synthesis of compound 39b

To an oven-dried 8 mL vial was charged 39a (18 mg, 0.0477 mmol), 4CzIPN (0.75 mg, 0.000953 mmol) and triphenylphosphine (31 mg, 0.119 mmol). The headspace of the vial was purged with Ar for 5 min. The reactants were dissolved in 1,4-dioxane (0.529 mL) and the solution was purged with Ar for another 30 min. The reaction was carried out under Ar for 24 h and irradiated with a blue LED (365 nm). The crude reactant was poured into water and extracted with ethyl acetate followed by washing with aqueous NaHCO ₃ and brine. It was then purified by flash chromatography (SiO2, 0-30% MeOH/DCM) to yield 39b (5.8 mg, 0.0172 mmol, 36% yield). UPLC-MS (Method A, ESI+): m/z [M + H] ⁺ = 338.34 (theoretical value), 338.08 (observed value). HPLC retention time: 1.17 min. Synthesis of compound 39c

To an oven-dried 4 mL vial was charged 39b (5.8 mg, 0.0172 mmol), compound 30 (15 mg, 0.0258 mmol) and Cs ₂ CO ₃ (17 mg, 0.0516 mmol). The reaction was dissolved in DMF (0.17 mL) and stirred at 55 °C overnight. The reaction was then purified by prepHPLC (Method 1) to afford 39c (2 mg, 0.0022 mmol, 13% yield). UPLC-MS (Method A, ESI+): m/z [M + H] ⁺ = 890.97 (theoretical value), 890.30 (observed value). HPLC retention time: 1.54 min. Synthesis of compound 1.7

Compound 39c (2.0 mg, 0.00225 mmol) was dissolved in 20% TFA in DCM (0.045 mL) and stirred at 23 °C for 2 h to yield compound 1.7 (1.6 mg, 0.002 mmol, 90% yield), which was tested without further purification. UPLC-MS (Method A, ESI+): m/z [M + H] ⁺ = 790.85 (theoretical value), 790.31 (observed value). HPLC retention time: 1.29 min. Example 41. (E)-N-(5- aminoformyl- 1-(4-(6- aminoformyl- 2-(1- ethyl - 3- methyl - 1H-1,2,4- triazol -5- yl )-8- methoxy -9H- pyrimido [4,5-b] indol- 9- yl ) but -2-en-1 - yl ) -7-(3-( methylamino ) propoxy )-1H- benzo [d] imidazol -2- yl )-4- ethyl -2- methyloxazole -5- carboxamide ( Compound 1.8) . Synthesis of compound 40a

To a solution of 5-bromopyrimidine-2-carboxylic acid (5 g, 24.6 mmol) in DCM (65 mL) was added oxalyl chloride (19 mL, 37 mmol), followed by dropwise addition of DMF (1 mL) and the solution was stirred at room temperature for 2.5 h. The solvent was removed in vacuo to yield compound 40a (5,145 mg, 23.2 mmol, 94% yield) as a brown solid. Note: The product was quenched in ethanol and the ethyl ester of the product was characterized. UPLC-MS (Method A, ESI+): m/z [M + H] ⁺ = 230.98 (theoretical), 230.97 (observed). HPLC retention time: 1.68 min. Synthesis of compound 40b

To a solution of 40a (3.30 g, 14.9 mmol) and ethyl acetimidate hydrochloride (2.762 g, 22.4 mmol) in chloroform (100 mL) was added triethylamine (6.5 mL, 46.6 mmol) and the solution was stirred at room temperature for 1.5 h. To the flask was added ethylhydrazine hydrochloride (4,317 mg, 44.7 mmol), the reaction was stirred for 2 h, additional triethylamine (6.5 mL, 46.6 mmol, 3.1 equiv.) was added and the solution was stirred at room temperature overnight. The crude reaction was poured into brine (200 mL) and extracted with EtOAc (3×200 mL), the organics were combined, dried over MgSO 4 , filtered and the solvent removed in vacuo to yield the crude product. This material was dissolved in DMSO and purified by prepHPLC (Method 1) to yield compound 40b (1.328 g, 4.95 mmol, 33% yield) as a light brown solid. UPLC-MS (Method A, ESI+): m/z [M + H] ⁺ = 268.0 (theoretical), 268.1 (observed). HPLC retention time: 1.31 min Synthesis of compound 40c

To a 5 mL oven-dried microwave vial was charged compound 40b (50 mg, 0.186 mmol), 4,4,5,5-tetramethyl-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1,3,2-dioxaborolan (95 mg, 0.373 mmol), potassium acetate (55 mg, 0.559 mmol) and _PdCl2 (dppf) (14 mg, 0.019 mmol). The vial was purged with Ar for 5 min and then 1,4-dioxane (3.7 mL) was added and the solution was purged with Ar for 15 min. The reaction was heated at 100 °C for 12 h by microwave, cooled to rt and the conversion to the arylboronic acid was confirmed by UPLC-MS (Method A, ESI+); m/z [M + H] ⁺ = 234.11 (theoretical value), 234.13 (observed value). HPLC retention time: 1.04 min

To the boronic acid solution was added 3-bromo-5-methoxy-4-nitro-benzamide (Compound 8a , 150 mg, 0.545 mmol), _PdCl2 (dppf) (14 mg, 0.019 mmol) and an argon-purged potassium carbonate solution (0.75 mL, 0.563 mmol). The reaction was further purged with Ar for 10 min and then heated in a microwave at 100 °C for 2 h. The solvent was removed in vacuo and the residual palladium was removed by flash column chromatography (SiO2, DCM/MeOH). The crude material was then dissolved in DMSO and purified by prepHPLC to yield Compound 40c (40 mg, 0.0804 mmol, 43% yield) as a white solid and 1x TFA salt. UPLC-MS (method A, ESI+): m/z [M + H] ⁺ = 384.14 (theoretical value), 384.13 (observed value). HPLC retention time: 1.56 min. Synthesis of compound 40d

A solution of 40c (40 mg, 0.0804 mmol), triphenylphosphine (53 mg, 0.201 mmol) and 4CzIPN (13 mg, 0.0161 mmol) in THF (4 mL) was purged with Ar for 10 min, sealed and stirred while irradiating with a blue LED (420 nm) for 22 h under a cooling fan. Complete conversion was observed by UPLC-MS (Method A). The solvent was then removed in vacuo , the crude material was dissolved in DMSO and the product was purified by prepHPLC (Method 1) to yield 40d (11 mg, 0.0305 mmol, 38% yield). UPLC-MS (Method A, ESI+): m/z [M + H] ⁺ = 352.15 (theoretical), 352.13 (observed). HPLC retention time: 1.18 min. Synthesis of compound 40e

A mixture of 40d (11 mg, 0.0305 mmol), compound 6 (36 mg, 0.0609 mmol) and cesium carbonate (30 mg, 0.0914 mmol) in DMF (1.5 mL) was stirred at 55 °C for 24 h. The crude reaction was filtered and purified by prepHPLC (Method 1) to 40e (11 mg, 0.0116 mmol, 38.18% yield). UPLC-MS (Method A, ESI+): m/z [M + H] ⁺ = 904.42 (theoretical value), 940.39 (observed value). HPLC retention time: 1.49 min. Synthesis of compound 1.8

Compound 40e (10.5 mg, 0.0116 mmol) was dissolved in 30% TFA in MeCN (1 mL). The solution was stirred at 30 °C for 1 h and monitored by LCMS. After complete conversion, the solvent was removed in vacuo and the crude product was redissolved in DMSO for prepHPLC purification (Method 1). The pure fractions were frozen and lyophilized to give compound 1.8 (5.85 mg, 0.0073 mmol, 63% yield). UPLC-MS (Method A, ESI+): m/z [M + H] ⁺ = 804.4 (theoretical), 804.4 (observed). HPLC retention time: 1.35 min. Example 42. (E)-N-(5- aminoformyl- 1-(4-(6- aminoformyl- 2-(1- ethyl - 3- methyl - 1H-1,2,4- triazol -5- yl )-8- methoxy -9H- pyrimido [4,5-b] indol- 9- yl ) but- 2- en-1-yl ) -7- ( 3-(3-(2,5- dioxo -2,5- dihydro -1H -pyrrol -1- yl )-N -methylpropionamido ) propoxy )-1H - benzo [d] imidazol -2- yl )-4- ethyl -2- methyloxazole -5- carboxamide ( Compound 2.19) . Synthesis of compound 2.19

Compound 2.19 (2.1 mg, 0.0022 mmol, 60% yield) was prepared following General Method 1 using compound 1.8 (2.93 mg, 0.0036 mmol) as starting material. UPLC-MS (Method A, ESI+): m/z [M + H] ⁺ = 955.4 (theoretical value), 955.5 (observed value). HPLC retention time: 1.42 min. Example 43. 4-(( S )-2-((S)-2-(3- ( 2,5- dioxo -2,5- dihydro -1H-pyrrol - 1- yl ) propionamido )-3 - methylbutanamido ) propionamido ) benzyl (3-( (5- aminoformyl- 1-( ( E )-4-(6- aminoformyl - 2- ( 1-ethyl - 3- methyl -1H -1,2,4- triazol - 5 -yl ) -8- methoxy-9H-pyrimido[4,5-b]indol-9-yl)but-2-en - 1 - yl ) -2- ( 4 - ethyl-2- methyloxazole - 5- carboxamido ) -1H - benzo [d ] imidazol - 7-yl ) oxy ) propyl) (methyl ) carbamate ( Compound 2.20) . Synthesis of compound 2.20

Compound 2.20 (2.92 mg, 0.0023 mmol, 63% yield) was prepared following General Method 3 using compound 1.8 (2.93 mg, 0.0036 mmol) as starting material. UPLC-MS (Method A, ESI+): m/z [M + H] ⁺ = 1274.6 (theoretical value), 1274.6 (observed value). HPLC retention time: 1.45 min. Example 44. S-(1-(3-((3-((5- aminoformyl -1-((E)-4-(6- aminoformyl -2-(1- ethyl -3- methyl -1H-1,2,4- triazol -5- yl )-8- methoxy -9H- pyrimido [4,5-b] indol- 9- yl ) but-2- en - 1 - yl )-2-(4- ethyl -2- methyloxazole -5 -carboxamido )-1H- benzo [d] imidazol - 7- yl ) oxy ) propyl )( methyl ) amino )-3 - oxopropyl )-2,5 -dioxopyrrolidin -3- yl )-L- cysteine ( Compound 3.8) . Synthesis of compound 3.8

Compound 3.8 (0.80 mg, 0.0007 mmol, 34% yield) was prepared following General Method 2 using compound 2.19 (2.1 mg, 0.0022 mmol) as starting material. UPLC-MS (Method A, ESI+): m/z [M + H] ⁺ = 1076.4 (theoretical value), 1076.4 (observed value). HPLC retention time: 1.26 min. Example 45. (E)-N-(5- aminoformyl- 1-(4-(6- aminoformyl -2-(1- ethyl - 3- methyl -1H -pyrazol -5- yl )-9H -pyrido [3',2':4,5] pyrrolo [2,3-d] pyrimidin -9- yl ) but - 2- en -1 - yl )-7-(3-( methylamino ) propoxy )-1H- benzo [d] imidazol -2- yl )-4- ethyl -2- methyloxazole - 5-carboxamide ( Compound 1.13) Synthesis of compound 41a

To a solution of 5-bromo-2,4-dichloropyrimidine (5 g, 21.94 mmol) in EtOAc (30 mL) was added DIPEA (7.64 mL, 43.88 mmol) and PMB-NH ₂ (3.31 g, 24.14 mmol). The mixture was stirred at 40 °C for 4 h. LCMS analysis showed that the starting material was completely consumed and one major peak with the desired mass was detected. A second vial was prepared as described and the reaction mixtures were combined for purification. The mixture was poured into water (300 mL) and extracted with EtOAc (200 mL×2). The residue was purified by column chromatography (SiO ₂ , hexane:EtOAc) to give compound 41a (20 g, 60.87 mmol, 92% yield) as a colorless oil. UPLC-MS (method D, ESI+): m/z [M + H] ⁺ = 328.0 (theoretical value), 328.2 (observed value). HPLC retention time: 1.854 min. ¹ H NMR (400MHz, DMSO- d ₆ ) δ ppm 8.26 (br s, 1H), 8.25 (s, 1H), 7.25 (d, J = 8.4 Hz, 2H), 6.90 - 6.86 (m, 2H), 4.49 (br d, J = 5.6 Hz, 2H), 3.72 (s, 3H). Synthesis of compound 41b

A mixture of methyl 6-fluoronicotinate (25 g, 161.16 mmol), BPD (40.92 g, 161.16 mmol), [Ir(OMe)(COD)] ₂ (3.20 g, 4.83 mmol) and dtbpy (2.60 g, 9.67 mmol) in MTBE (500 mL) was degassed and purged with _N2 . The mixture was stirred at 20 °C under _N2 atmosphere for 3 h. LCMS analysis showed that the starting material had been consumed and one major peak with the desired mass was detected. A second reaction was prepared as described and the reactants were combined for purification. The solvent was removed under reduced pressure and the residue was purified by column chromatography (SiO ₂ , DCM/MeOH) to give compound 41b (89 g, 316.62 mmol, 98% yield) as an orange oil. UPLC-MS (Method M, ESI+): m/z [M + H] ⁺ = 282.1 (theoretical value), 282.3 (observed value). HPLC retention time: 0.347 min. Synthesis of compound 41c

Compound 41a (15 g, 53.36 mmol), compound 41b (15.788 g, 48.03 mmol) and K ₂ CO ₃ (14.75 g, 106.73 mmol) were dissolved in dioxane (750 mL) and water (75 mL) under N ₂ atmosphere. Pd(PPh ₃ ) ₄ (6.17 g, 5.34 mmol) was added to the solution while N ₂ was passed through the solution. The reaction was degassed and stirred at 100 °C under N ₂ for 5 h. LCMS analysis showed that the starting material had been consumed and one major peak with the desired mass was detected. Four identical reactions were prepared as described and combined for purification. The mixture was filtered and the filtrate was collected. The solvent was removed under reduced pressure. Water (500 mL) was added to the mixture and then extracted with EtOAc (500 mL×2). The organics were collected, dried over anhydrous Na ₂ SO ₄ , filtered and concentrated. The residue was purified by column chromatography (SiO ₂ hexane/EtOAc) to give compound 41c (9.8 g, 24.33 mmol, 36% yield) as a white solid. UPLC-MS (Method L, ESI+): m/z [M + H] ⁺ = 403.1 (theoretical value), 403.0 (observed value). HPLC retention time: 0.520 min. ¹ H NMR (400MHz, DMSO- d ₆ ) δ ppm 8.87 (d, J = 2.0 Hz, 1H), 8.44 (dd, J = 2.3, 9.0 Hz, 1H), 8.01 - 7.97 (m, 1H), 7.21 (d, J = 8.6 Hz, 2H), 6.88 (d, J = 8.6 Hz, 2H), 4.45 (br d, J = 5.8 Hz, 2H), 3.94 (s, 3H), 3.93 - 3.90 (m, 3H), 3.72 (s, 3H). Synthesis of compound 41d

Compound 41c (6 g, 14.90 mmol) was dissolved in THF (600 mL). DBU (13.37 mL, 89.37 mmol) was added to the solution at 25 °C. The mixture was allowed to reach 40 °C and stirred for 72 h. LCMS analysis showed the desired product was detected. Four additional vials were prepared as described and combined for purification. The solvent was removed under reduced pressure and the residue was purified by column chromatography (SiO ₂ , hexanes/EtOAc) to give compound 41d (9.8 g, 25.60 mmol, 32% yield) as a white solid. UPLC-MS (Method L, ESI+): m/z [M + H] ⁺ = 383.1 (theoretical value), 382.9 (observed value). HPLC retention time: 0.569 min. ¹ H NMR (400MHz, DMSO- d ₆ ) δ ppm 9.62 (s, 1H), 9.33 (d, J = 1.9 Hz, 1H), 9.18 (d, J = 1.8 Hz, 1H), 7.31 (br d, J = 8.5 Hz, 2H), 6.86 (br d, J = 8.6 Hz, 2H), 5.61 (s, 2H), 3.95 (s, 3H), 3.68 (s, 3H). Synthesis of compound 41e

A solution of compound 41d (500 mg, 1.31 mmol), compound 3g (323.83 mg, 1.37 mmol) and _Na2CO3 (276.88 mg, 2.61 mmol) in _dioxane (10 mL) and water (2 mL) was degassed and placed under _N2 . Pd(dppf) _Cl2.CH2Cl2 (64.00 mg, 78.37 μmol) was added to the solution under _N2 . The reaction was brought to 100 °C and stirred for 5 _h . LCMS analysis showed consumption of starting material and one major peak _with the desired m/z was detected. Two additional vials were prepared as described and combined for purification. The mixture was filtered and the filtrate was concentrated under reduced pressure. The residue was purified by column chromatography (SiO ₂ hexane: EtOAc) to give compound 41e (780 mg, 1.71 mmol, 65% yield) as a brown solid. UPLC-MS (Method L, ESI+): m/z [M + H] ⁺ = 457.2 (theoretical value), 457.1 (observed value). HPLC retention time: 0.594 min. ¹ H NMR (400MHz, DMSO- d ₆ ) δ ppm 9.74 (s, 1H), 9.29 (d, J = 1.9 Hz, 1H), 9.17 (d, J = 1.9 Hz, 1H), 7.35 (br d, J = 8.1 Hz, 2H), 6.93 (s, 1H), 6.85 (br d, J = 8.6 Hz, 2H), 5.68 (s, 2H), 4.79 - 4.71 (m, 2H), 3.95 (s, 3H), 3.67 (s, 3H), 2.23 (s, 3H), 1.35 (s, 3H). Synthesis of compound 41f

To a solution of compound 41e (780 mg, 1.71 mmol) in THF (16 mL) at 20 °C was added a solution of NaOH (2 g, 50 mmol) in water (8 mL). The reaction was allowed to reach 50 °C and stirred for 16 h. LCMS analysis showed consumption of starting material and the desired m/z was detected. Another vial was prepared as described and the reactants were combined for purification. Saturated citric acid solution was added dropwise to the reaction mixture to adjust the pH to 5. The mixture was filtered and the filter cake was dried under reduced pressure to give compound 41f (1.23 g, 2.78 mmol, crude) as a brown solid. UPLC-MS (Method L, ESI+): m/z [M + H] ⁺ = 443.2 (theoretical), 443.1 (observed). HPLC retention time: 0.500 min. Synthetic compound 41g

To a solution of compound 41f (400 mg, 0.90 mmol) in DMF (6 mL) was added EDCI (346.60 mg, 1.81 mmol), HOBt (244.31 mg, 1.81 mmol) NH ₄ Cl (241.79 mg, 4.52 mmol) and DIPEA (787.32 μL, 4.52 mmol). The reaction was stirred at 20 °C for 16 h. LCMS analysis showed consumption of starting material, and the desired m/z. Two additional vials were prepared as described and combined for purification. The solution was frozen and lyophilized, then triturated with MeOH (50 mL). The solution was filtered and the filter cake was washed with MeOH (20 mL) and hexane (20 mL) to yield compound 41g (1 g, 2.27 mmol, crude) as a brown solid. UPLC-MS (Method N, ESI+): m/z [M + H] ⁺ = 442.2 (theoretical value), 442.3 (observed value). HPLC retention time: 0.432 min. Synthesis of compound 41h

Compound 41g (350 mg, 0.79 mmol) was dissolved in HCl (12 M, 8 mL) at 20 °C. The reaction was brought to 100 °C and stirred for 3 h. LCMS analysis showed consumption of starting material, and the desired m/z. A second vial was prepared as described and the reactions were combined. The mixture was frozen and lyophilized to give compound 41h· HCl (392 mg, 1.22 mmol, crude) as a brown solid. UPLC-MS (Method L, ESI+): m/z [M + H] ⁺ = 323.1 (theoretical), 323.0 (observed). HPLC retention time: 0.347 min. Synthesis of compound 41i

To a solution of compound 41h ·HCl (100 mg, 0.14 mmol) in DMA (16 mL) was added EDCI (60.13 mg, 313.67 μmol), HOBt (36.86 mg, 272.76 μmol) and NH ₄ Cl (72.95 mg, 1.36 mmol) at 20 °C. The reaction was allowed to reach 35 °C and stirred for 48 h. LCMS analysis showed consumption of starting material and desired m/z. A second reaction was prepared as described and combined for purification. The solution was frozen and lyophilized and triturated with MeOH (20 mL) and hexanes (20 mL) to give compound 41i (334.1 mg, 1.0 mmol, 48% yield) as a brown solid. UPLC-MS (method O, ESI+): m/z [M + H] ⁺ = 322.1 (theoretical value), 322.1 (observed value). HPLC retention time: 1.793 min. ¹ H NMR (400MHz, DMSO- d ₆ ) δ ppm 13.37 - 12.95 (m, 1H), 9.60 (s, 1H), 9.20 - 8.96 (m, 2H), 8.19 (br s, 1H), 7.54 (br s, 1H), 6.83 (s, 1H), 4.78 (br d, J = 6.8 Hz, 2H), 2.23 (s, 3H), 1.39 (br t, J = 6.7 Hz, 3H). Synthesis of compound 41j

To a solution of compound 41i (25 mg, 77.8 μmol) in DMF (0.778 mL) was added compound 6 (68.7 mg, 117 μmol) and Cs ₂ CO ₃ (76 mg, 233 μmol). The reaction was brought to 55 °C and stirred for 16 h. LCMS analysis showed consumption of starting material and desired m/z. The reaction was filtered and the filtrate was purified by prepHPLC (Method 1). The fractions were collected, frozen, and lyophilized to give compound 41j (46.67 mg, 53.4 μmol, 69% yield) as a white solid. UPLC-MS (Method A, ESI+): m/z [M + H] ⁺ = 874.4 (theoretical), 874.4 (observed). HPLC retention time: 1.48 min. Synthesis of compound 1.13

Compound 41j (23.14 mg, 26.5 μmol) was dissolved in 30% TFA in MeCN (2.6 ml). The reaction was stirred at 30 °C for 1 h. LCMS analysis showed consumption of starting material and desired m/z. The solvent was removed under reduced pressure, and the residue was redissolved in DMSO for purification by prepHPLC (Method 1). The pure fractions were collected, frozen, and lyophilized to give compound 1.13 x1 TFA (9.62 mg, 12.4 μmol, 47% yield) as a white solid. UPLC-MS (Method A, ESI+): m/z [M + H] ⁺ = 774.4 (theoretical value), 774.4 (observed value). HPLC retention time: 1.24 min. Example 46. (E)-N-(5- aminoformyl- 1-(4-(6- aminoformyl -2-(1- ethyl - 3- methyl -1H -pyrazol -5- yl )-9H -pyrido [3',2':4,5] pyrrolo [2,3-d] pyrimidin -9- yl ) but - 2- en -1- yl )-7-(3-(3-(2,5- dihydroxy -2,5 -dihydro -1H -pyrrol -1- yl )-N- methylpropionamido ) propoxy )-1H - benzo [d] imidazol -2- yl )-4- ethyl -2- methyloxazole -5- carboxamide ( Compound 2.37)

Compound 2.37 (4.08 mg, 4.4 μmol, 71% yield) was prepared following General Procedure 1 using compound 1.13 (4.81 mg, 6.2 μmol) as starting material. UPLC-MS (Method A, ESI+): m/z [M + H] ⁺ = 925.4 (theoretical value), 925.4 (observed value). HPLC retention time: 1.35 min. Example 47. S-(1-(3-((3-((5- aminoformyl -1-((E)-4-(6- aminoformyl -2-(1- ethyl -3- methyl -1H -pyrazol- 5- yl )-9H -pyrido [3',2':4,5] pyrrolo [2,3-d] pyrimidin -9- yl ) but -2- en-1-yl ) -2- ( 4- ethyl -2- methyloxazole -5 -carboxamido )-1H- benzo [d] imidazol -7- yl ) oxy ) propyl )( methyl ) amino )-3 - oxopropyl )-2,5 -dioxopyrrolidin -3- yl )-L- cysteine ( Compound 3.13)

Compound 3.13 (3.1 mg, 3.0 μmol, 67% yield) was prepared following General Method 2 using compound 2.37 (4.08 mg, 4.4 μmol) as starting material. UPLC-MS (Method A, ESI+): m/z [M + H] ⁺ = 1046.4 (theoretical value), 1046.4 (observed value). HPLC retention time: 1.25 min. Example 48. (3-((5- aminoformyl- 1-((E)-4-(6- aminoformyl- 2-(1- ethyl -3- methyl -1H -pyrazol -5- yl )-9H -pyrido [3',2':4,5] pyrrolo [2,3-d] pyrimidin -9- yl ) but - 2- en -1- yl )-2-(4- ethyl -2- methyloxazole -5 -carboxamido )-1H- benzo [d] imidazol -7- yl ) oxy ) propyl )( methyl ) carbamate 4-((S)-2-((S) -2- (3-(2,5- dihydroxy -2,5- dihydro -1H -pyrrol -1- yl ) propionamido )-3 -methylbutanamido ) propionamido ) benzyl ester ( Compound 2.38)

Compound 2.38 (3.71 mg, 3 μmol, 48% yield) was prepared following General Method 3 using compound 1.13 (4.81 mg, 6.2 μmol) as starting material. UPLC-MS (Method A, ESI+): m/z [M + H] ⁺ = 1244.5 (theoretical value), 1244.5 (observed value). HPLC retention time: 1.54 min. Example 49. (2S,3S,4S,5R,6S)-6-(4-((((3-((5- aminoformyl -1-((E)-4-(6- aminoformyl- 2-(1- ethyl -3- methyl -1H -pyrazol -5- yl )-9H -pyrido [3',2':4,5] pyrrolo [2,3-d] pyrimidin -9 - yl ) but -2- en -1- yl )-2-(4- ethyl -2 -methyloxazole - 5 -carboxamido )-1H- benzo [d] imidazol -7- yl ) oxy ) propyl )( methyl ) aminocarboxamido ) oxy ) methyl )-2-(3-(3-(2,5- dihydroxy -2,5- dihydro -1H -pyrrol -1- yl ) propionamido ) propionamido ) phenoxy )-3,4,5- trihydroxytetrahydro -2H- pyran -2-carboxylic acid ( Compound 2.39) Synthesis of compound 42a

Following General Method 4, compound 1.13 (52.46 mg, 67.8 μmol) was used as the starting material to prepare compound 42a (45.5 mg, 29.4 μmol, 43% yield). UPLC-MS (Method A, ESI+): m/z [M + H] ⁺ = 1548.6 (theoretical value), 1548.6 (observed value). HPLC retention time: 1.72 min. Synthesis of compound 42b General Method 7 :

To a solution of the tricyclic dimer (1 equiv.) in 1:1 THF:MeOH (0.1 M in dimer) was added aqueous LiOH.H ₂ O (1 M, 5 equiv.). The mixture was allowed to reach 30 °C and stirred for 16 h. LCMS analysis showed consumption of starting material and the desired m/z. The reaction was quenched with AcOH (5 equiv.) and the solvent was removed under reduced pressure. The crude product was purified by prepHPLC (Method 1). The pure fractions were collected, frozen, and lyophilized to give the product.

Following General Method 7, compound 42b (19.93 mg, 15.3 μmol, 52% yield) was prepared using compound 42a (45.5 mg, 29.4 μmol) as starting material. UPLC-MS (Method A, ESI+): m/z [M + H] ⁺ = 1186.5 (theoretical value), 1186.5 (observed value). HPLC retention time: 1.29 min. Synthesis of compound 2.39

Compound 2.39 (15.5 mg, 11.6 μmol, 76% yield) was prepared following General Method 6 using compound 42b (19.93 mg, 15.3 μmol) as starting material. UPLC-MS (Method A, ESI+): m/z [M + H] ⁺ = 1337.5 (theoretical value), 1337.5 (observed value). HPLC retention time: 1.32 min. Example 50. (E)-N-(5- aminoformyl- 1-(4-(6- aminoformyl- 2-(1- ethyl - 3- methyl -1H -pyrazol -5- yl )-8- methoxy -9H -pyrido [2',3':4,5] pyrrolo [2,3-d] pyrimidin -9- yl ) but -2 - en - 1- yl )-7-(3-( methylamino ) propoxy )-1H- benzo [d] imidazol -2- yl )-4- ethyl -2- methyloxazole - 5-carboxamide ( Compound 1.14) Synthesis of compound 43a

To a solution of methyl 5-aminopicolinate (20 g, 131.45 mmol) in MeCN (500 mL) was added a solution of sodium bromide (13.53 g, 131.45 mmol) in H ₂ O (120 mL) followed by a solution of Oxone (80.81 g, 131.45 mmol) in H ₂ O (140 mL). The mixture was stirred at 20 °C for 2 h. LCMS analysis showed consumption of starting material and the desired m/z. A second reaction was prepared as described and combined for purification. The mixture was quenched with saturated Na ₂ SO ₃ (800 mL) at 0 °C and then extracted with DCM (2×800 mL). The combined organic layers were washed with brine (2×800 mL), dried over Na ₂ SO ₄ , filtered, and concentrated under reduced pressure to give compound 43a (31 g, 134.17 mol, crude) as a yellow solid. UPLC-MS (Method L, ESI+): m/z [M + H] ⁺ = 231.0 (theoretical value), 231.0 (observed value). HPLC retention time: 0.304 min. ¹ H NMR (400MHz, DMSO- d ₆ ) δ ppm 7.84 (d, J = 8.3 Hz, 1H), 7.11 (d, J = 8.4 Hz, 1H), 3.88 (s, 3H). Synthesis of compound 43b

To a solution of compound 43a (10 g, 43.27 mmol) in MeCN (150 mL) was added NCS (8.67 g, 64.92 mmol). The reaction was allowed to reach 85 °C for 2 h. LCMS analysis showed consumption of starting material and desired m/z. A second reaction was prepared as described and combined for purification. The reaction was filtered to remove impurities. The residue was concentrated and purified by prepHPLC (Method 2). The pure fractions were collected, frozen, and lyophilized to give compound 43b (8.7 g, 32.77 mmol, 38% yield) as a yellow solid. UPLC-MS (Method K, ESI+): m/z [M + H] ⁺ = 264.9 (theoretical value), 264.7 (observed value). HPLC retention time: 1.294 min. ¹ H NMR (400MHz, DMSO- d ₆ ) δ ppm 8.08 - 7.86 (m, 1H), 6.68 - 6.60 (m, 2H), 3.81 (s, 3H). Synthesis of Compound 43c

A solution of compound 43b (4.35 g, 16.38 mmol) in H ₂ SO ₄ (90 mL) was added to a mixture of H ₂ O ₂ (29.66 mL, 30%) and H ₂ SO ₄ (59.32 mL) at 0°C. The reaction was allowed to reach 20°C and stirred for 2 h. LCMS analysis showed consumption of starting material and desired m/z. A second reaction was prepared as described and combined for purification. The mixture was poured into cold saturated NaHCO ₃ (2 L) and extracted with EtOAc (300 mL×3). The combined organics were washed with brine, dried over Na ₂ SO ₄ , filtered, and concentrated to give compound 43c (8.4 g, 28.43 mmol, crude) as a white solid. UPLC-MS (method D, ESI+): m/z [M + H] ⁺ = 294.9 (theoretical value), 295.0 (observed value). HPLC retention time: 1.722 min. ¹ H NMR (400MHz, DMSO- d ₆ ) δ ppm 8.65 - 8.42 (m, 1H), 4.02 - 3.85 (m, 3H). Synthesis of compound 43d

To a solution of compound 43c (4.2 g, 14.21 mmol) in THF (110 mL) and dioxane (55 mL) was added NaOMe (3.38 g, 15.64 mmol, 25% w/w in MeOH) at 0°C. The reaction was stirred at 0°C for 1 h. LCMS analysis showed consumption of starting material and desired m/z. A second reaction was prepared as described and combined for purification. The reaction was poured into cold saturated _NH4Cl (60 mL) and extracted with EtOAc (100 mL), _dried over _Na2SO4 , filtered, and concentrated. The residue was purified by column chromatography (SiO ₂ hexane/EtOAc) to give compound 43d (5.2 g, 17.87 mmol, 63% yield) as a white solid. UPLC-MS (Method D, ESI+): m/z [M + H] ⁺ = 291.0 (theoretical value), 291.1 (observed value). HPLC retention time: 1.585 min. ¹ H NMR (400MHz, DMSO- d ₆ ) δ ppm 8.02 - 7.96 (m, 1H), 4.15 - 4.05 (m, 3H), 4.01 - 3.91 (m, 3H). Synthesis of compound 43e

To a mixture of compound 43d ( _2.6 g, 8.94 mmol) and compound 29h (3.36 g, 10.72 mmol) in dioxane (50 mL) was added Pd(dppf) _Cl (653.64 mg, 893.3 μmol), _KCO (2.46 g, 17.86 mmol) and _H0 (10 mL) under _N2 . The mixture was degassed and purged, then brought to 75 °C under _N2 atmosphere for 4 h. LCMS analysis showed consumption of starting material and desired m/z. A second reaction was prepared as described and combined for purification. The resulting mixture was diluted with _H0 (200 mL) and extracted with EtOAc (200 mL x 3). The organic phase was concentrated under reduced pressure to obtain compound 43e (5 g, 12.55 mmol, crude material) as a yellow solid. UPLC-MS (method M, ESI+): m/z [M + H] ⁺ = 399.1 (theoretical value), 299.3 (observed value). HPLC retention time: 0.567 min. Synthesis of compound 43f

Compound 43 (5 g, 12.55 mmol) was dissolved in NH ₄ OH (150 mL). The mixture was stirred at 20 °C for 16 h. LCMS analysis showed consumption of starting material and desired m/z. The reaction mixture was concentrated under reduced pressure. The residue was purified by column chromatography (SiO ₂ hexane/EtOAc) to give compound 43f (3.8 g, 9.91 mmol, 79% yield) as a white solid. UPLC-MS (Method M, ESI+): m/z [M + H] ⁺ = 384.1 (theoretical), 384.3 (observed). HPLC retention time: 0.523 min. ¹ H NMR (400MHz, DMSO- d ₆ ) δ ppm 9.21 (s, 2H), 8.51 (s, 1H), 8.03 - 7.95 (m, 2H), 6.90 (s, 1H), 4.70 (q, J = 7.2 Hz, 2H), 4.16 (s, 3H), 2.23 (s, 3H), 1.37 (t, J = 7.2 Hz, 3H). Synthetic compound 43g

To a solution of compound 43f (200 mg, 521.7 μmol) in dioxane (3 mL) was added _PPh (342.09 mg, 1.30 mmol) and 4CzIPN (41.16 mg, 52.17 μmol) at 25 °C under _N2 . The resulting mixture was stirred at 55 °C for 48 h under a 35 W blue LED. LCMS analysis showed consumption of starting material and the desired m/z. Four additional reactions were prepared as described and combined for purification. The reaction was filtered to remove impurities. The residue was purified by prepHPLC (Method 2). The pure fractions were collected, frozen, and lyophilized to give compound 43g (202.7 mg, 576.90 μmol, 22% yield) as a yellow solid. UPLC-MS (method O, ESI+): m/z [M + H] ⁺ = 352.2 (theoretical), 352.1 (observed). HPLC retention time: 1.962 min. ¹ H NMR (400 MHz, DMSO- d ₆ ) δ ppm 13.08 (br s, 1H), 9.55 (s, 1H), 8.19 (br s, 1H), 7.84 (s, 1H), 7.70 (br d, J = 0.8 Hz, 1H), 6.85 (s, 1H), 4.80 (q, J = 6.8 Hz, 2H), 4.15 (s, 3H), 2.24 (s, 3H), 1.40 (t, J = 7.2 Hz, 3H). Synthesis of compound 43h

To a solution of compound 43g (30 mg, 85.4 μmol) and compound 6 (75.45 mg, 128.1 μmol) in DMF (2 mL) was added Cs ₂ CO ₃ (83.46 mg, 256 μmol). The reaction was brought to 55 °C and stirred for 24 h. LCMS analysis showed consumption of starting material and desired m/z. The mixture was filtered and the filtrate was purified by prepHPLC (Method 1). The fractions were collected, frozen, and lyophilized to give compound 43h (60.5 mg, 66.9 μmol, 78% yield) as a white solid. UPLC-MS (Method A, ESI+): m/z [M + H] ⁺ = 904.4 (theoretical value), 904.4 (observed value). HPLC retention time: 1.58 min. Synthesis of compound 1.14

Compound 43h (60.5 mg, 66.9 μmol) was dissolved in 20% TFA in DCM. The reaction was stirred at room temperature until complete conversion at the desired m/z was observed by LCMS. The solvent was removed under reduced pressure and the residue was purified by prepHPLC (Method 1) to give compound 1.14 x1 TFA (52 mg, 65.1 μmol, 97% yield). UPLC-MS (Method A, ESI+): m/z [M + H] ⁺ = 804.4 (theoretical), 804.3 (observed). HPLC retention time: 1.29 min. Example 51. (E)-N-(5- aminoformyl- 1-(4-(6- aminoformyl- 2-(1- ethyl - 3- methyl - 1H -pyrazol -5- yl )-8- methoxy -9H -pyrido [2',3':4,5] pyrrolo [2,3-d] pyrimidin -9 - yl ) but - 2- en - 1- yl )-7-(3-(3-(2,5- dihydroxy - 2,5 -dihydro -1H -pyrrol -1- yl )-N -methylpropionamido ) propoxy )-1H- benzo [d] imidazol -2- yl )-4- ethyl -2- methyloxazole -5 - carboxamide ( Compound 2.40)

Compound 2.40 (7.9 mg, 8.3 μmol, 83% yield) was prepared following General Method 1 using compound 1.14 x 1 TFA (9.18 mg, 10 μmol) as starting material. UPLC-MS (Method A, ESI+): m/z [M + H] ⁺ = 955.4 (theoretical value), 955.4 (observed value). HPLC retention time: 1.41 min. Example 52. S-(1-(3-((3-((5- aminoformyl -1-((E)-4-(6- aminoformyl- 2-(1- ethyl -3- methyl -1H -pyrazol- 5- yl )-8- methoxy -9H -pyrido [2',3':4,5] pyrrolo [2,3-d] pyrimidin -9- yl ) but-2-en-1-yl ) -2- ( 4 - ethyl -2- methyloxazole -5 -carboxamido )-1H- benzo [d] imidazol -7- yl ) oxy ) propyl )( methyl ) amino ) -3 -oxopropyl )-2,5- dioxopyrrolidin- 3- yl )-L- cysteine ( Compound 3.14)

Compound 3.14 (2.09 mg, 1.9 μmol, 78% yield) was prepared following General Method 2 using compound 2.40 (2.39 mg, 2.5 μmol) as starting material. UPLC-MS (Method A, ESI+): m/z [M + H] ⁺ = 1076.4 (theoretical value), 1076.4 (observed value). HPLC retention time: 1.31 min. Example 53. (3-((5- aminoformyl- 1-((E)-4-(6- aminoformyl- 2-(1- ethyl -3- methyl -1H -pyrazol- 5- yl )-8- methoxy -9H -pyrido [2',3':4,5] pyrrolo [2,3-d] pyrimidin -9- yl ) but-2-en-1-yl ) -2- ( 4 - ethyl -2- methyloxazole -5 -carboxamido )-1H- benzo [d] imidazol -7- yl ) oxy ) propyl )( methyl ) carbamate 4-((S)-2-((S)-2-(3-(2,5- dihydroxy -2,5 -dihydro -1H -pyrrol -1- yl ) propionamido )-3 -methylbutanamido ) propionamido ) benzyl ester ( Compound 2.41)

Compound 2.41 (11.06 mg, 8.7 μmol, 87% yield) was prepared following General Method 3 using compound 1.14 x 1 TFA (9.18 mg, 10 μmol) as starting material. UPLC-MS (Method A, ESI+): m/z [M + H] ⁺ = 1274.5 (theoretical value), 1274.5 (observed value). HPLC retention time: 1.49 min. Example 54. (2S,3S,4S,5R,6S)-6-(4-((((3-((5- aminoformyl -1-((E)-4-(6- aminoformyl- 2-(1- ethyl -3- methyl -1H -pyrazol -5- yl )-8- methoxy -9H -pyrido [2',3':4,5] pyrrolo [2,3-d] pyrimidin -9- yl ) but -2- en -1 - yl )-2-(4- ethyl ( 2 -((2 - ((((((((((((((((((((((( ( ( (( ( ( ( ( ( ( ( ((( (((((((((((((((((((((((((((((((((((((((((((((((((((((((((((((((((((((((((((((((((((((((((((((((((((((((((((((( ( ( ( ( ( ( ( ((((((((( ( ( ( ( ( ( ( ( ( ((((((((((((((((( ( ( ((((( (( ((((((((((((((((((( ( ((((((((((( ( ( ( ( (( ( (((( Synthesis of compound 44a

Compound 44a (16.30 mg, 10.3 μmol, 52% yield) was prepared following General Method 4 using compound 1.14 x1 TFA (18.36 mg, 20 μmol) as starting material. UPLC-MS (Method A, ESI+): m/z [M + H] ⁺ = 1578.6 (theoretical value), 1578.5 (observed value). HPLC retention time: 1.77 min. Synthesis of compound 44b

Compound 44b x1 TFA (2.35 mg, 1.8 μmol, 17% yield) was prepared following General Method 7 using compound 44a (16.0 mg, 10.1 μmol) as starting material. UPLC-MS (Method A, ESI+): m/z [M + H] ⁺ = 1216.4 (theoretical value), 1216.5 (observed value). HPLC retention time: 1.32 min. Synthesis of compound 2.42

Compound 2.42 (1.83 mg, 1.3 μmol, 76% yield) was prepared following General Method 6 using compound 44b x 1 TFA (2.35 mg, 1.8 μmol) as starting material. UPLC-MS (Method A, ESI+): m/z [M + H] ⁺ = 1367.5 (theoretical value), 1367.5 (observed value). HPLC retention time: 1.33 min. Example 55. (E)-N-(5- aminoformyl- 1-(4-(8- aminoformyl- 3-(1- ethyl - 3- methyl - 1H -pyrazol -5- yl )-6- methoxy -5H -pyrido [4,3-b] indol- 5- yl ) but -2- en - 1 - yl )-7-(3-( methylamino ) propoxy )-1H- benzo [d] imidazol -2- yl )-4- ethyl -2- methyloxazole -5- carboxamide ( Compound 1.10) Synthesis of compound 45a

To a solution of 3-fluoro-4-nitrobenzamide (45 g, 244.4 mmol) in MeOH (900 mL) was added NaOMe (79.2 g, 366.6 mmol, 25% w/w in MeOH) at 20 °C. The resulting mixture was heated to 60 °C and stirred for 1 h. LCMS analysis showed consumption of starting material and desired m/z. The resulting mixture was filtered and the filtrate was concentrated under reduced pressure to give a residue. The crude product was triturated with MeOH at 20 °C for 10 min to give compound 45a (33 g, 168.32 mmol, 69% yield) as a yellow solid. UPLC-MS (Method P, ESI+): m/z [M + H] ⁺ = 197.1 (theoretical), 197.0 (observed). HPLC retention time: 1.005 min. Synthesis of compound 45b

To a solution of compound 45a (15 g, 76.47 mmol) in MeOH (150 mL), H ₂ O (150 mL) and THF (150 mL) were added NH ₄ Cl (40.90 g, 764.68 mmol) and Zn (50 g, 74.68 mmol) at 20° C. The resulting mixture was stirred at 20° C. for 1 h. LCMS analysis showed consumption of starting material and desired m/z. The mixture was filtered and the filtrate was concentrated under reduced pressure to give a residue. The crude product was triturated with H ₂ O (150 mL) at 20° C. for 10 min to give compound 45b (10.6 g, 54 mmol, 83% yield) as a pink solid. UPLC-MS (method Q, ESI+): m/z [M + H] ⁺ = 167.1 (theoretical value), 167.0 (observed value). HPLC retention time: 0.105 min. ¹ H NMR (400MHz, DMSO- d ₆ ) δ ppm 7.62 (br s, 1H), 7.39 - 7.25 (m, 2H), 6.88 (br s, 1H), 6.60 (d, J = 8.1 Hz, 1H), 5.23 (s, 2H), 3.79 (s, 3H) Synthesis of compound 45c

To a solution of 4-fluoropyridin-2-amine (20 g, 178.40 mmol) in MeCN (200 mL) was added NBS (33.34 g, 187.32 mmol) at 20 °C. The mixture was stirred at 20 °C for 2 h. TLC (hexanes/EtOAc 1:1, _Rf = 0.5) indicated the reaction was complete. Four additional vials were prepared as described and combined for purification. The reaction was poured into saturated brine and extracted with EtOAc (3 x 1000 mL). The organic phases were combined and washed with saturated _{Na2SO3 x} 3 and saturated brine. The organic phase was dried over Na ₂ SO ₄ and concentrated to afford compound 45c (140 g, crude) as an off-white solid, which was used without further purification. ¹ H NMR (400 MHz, DMSO- d ₆ ) δ ppm 8.13 (d, J = 9.6 Hz, 1H), 6.27 (d, J = 10.0 Hz, 1H), 4.65 (br s, 2H). Synthesis of compound 45d

To a solution of compound 45c (35 g, 183.25 mmol) in DCM (350 mL) was added tributyl nitrite (188.96 g, 1.83 mol) and KI (152.10 g, 916.23 mmol) at 20 °C. The mixture was stirred at 20 °C for 16 h. TLC (hexanes/EtOAc 20:1, _Rf = 0.4) indicated the reaction was complete. A second reaction was prepared as described and the mixtures were combined for work-up and purification. The mixture was diluted with DCM (1 L ₎ and the organics were washed _with saturated _{Na2CO3 , Na2SO3} , and brine. The organics were dried over _Na2SO4 , filtered, and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (SiO ₂ , hexane/EtOAc) to give compound 45d (20 g, crude) as a colorless oil. Synthesis of compound 45e

To a solution of compound 45d (6 g, 13.91 mmol) and compound 3g (3.29 g, 13.91 mmol) in dioxane (60 mL) and H ₂ O (12 mL) at 20 °C under N ₂ was added Pd(dppf)Cl ₂ (1.02 g, 1.39 mmol) and K ₂ CO ₃ (3.85 g, 27.83 mmol). The resulting mixture was heated to 50 °C and stirred for 16 h. LCMS analysis showed consumption of starting material and the desired m/z. A second reaction was prepared as described and the mixtures were combined for work-up and purification. The resulting mixture was diluted with H ₂ O (200 mL) and extracted with EtOAc (3×150 mL). The combined organic layers were washed with brine (200 mL), dried over Na ₂ SO ₄ , filtered, and concentrated under reduced pressure to yield a residue. The residue was purified by column chromatography (SiO ₂ , hexane/EtOAc) to afford compound 45e (3.34 g, 11.76 mmol, 42% yield) as a yellow oil. UPLC-MS (Method Q, ESI+): m/z [M + H] ⁺ = 284.0 (theoretical), 284.1 (observed). HPLC retention time: 0.535 min. ¹ H NMR (400MHz, DMSO- d ₆ ) δ ppm 8.73 (d, J = 9.6 Hz, 1H), 7.32 (d, J = 9.6 Hz, 1H), 6.36 (s, 1H), 4.59 (q, J = 7.2 Hz, 2H), 2.32 (s, 3H), 1.41 (t, J = 7.2 Hz, 3H). Synthesis of compound 45f

To a solution of compound 45e (1.05 g, 6.34 mmol) in THF (18 mL) at 0 °C under _N2 was added LiHMDS (1 M, 25.35 mL, 35.34 mmol) and stirred for 0.5 h. Then, compound 45b (1.8 g, 6.34 mmol) was added and the mixture was allowed to reach 20 °C for 8 h. LCMS analysis showed consumption of starting material and desired m/z. The mixture was quenched by addition of _NH4Cl (200 mL) at 20 °C, then diluted with _H2O (100 mL) and extracted with EtOAc (3 x 150 mL). The organic layers were combined and washed with brine (200 mL), dried over Na ₂ SO ₄ , filtered, and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (SiO ₂ , hexane/EtOAc) to give compound 45f (1 g, 2.32 mmol, 37% yield) as a white solid. UPLC-MS (Method N, ESI+): m/z [M + H] ⁺ = 430.1 (theoretical value), 430.2 (observed value). HPLC retention time: 0.441 min. ¹ H NMR (400MHz, DMSO- d ₆ ) δ ppm 8.61 (s, 1H), 7.60 (d, J = 1.6 Hz, 1H), 7.46 - 7.39 (m, 2H), 7.38 - 7.33 (m, 1H), 7.09 - 7.03 (m, 1H), 6.24 (s, 1H), 4.55 (q, J = 7.2 Hz, 2H), 4.01 (s, 3H), 2.33 - 2.25 (m, 3H), 1.40 (t, J = 7.2 Hz, 3H). Synthesis of compound 45g

To a solution of compound 45f (500 mg, 1.16 mmol) in DMF (18 mL) at 20 °C under _N2 was added Pd( _PPh3 ) _2Cl2 (81.56 mg, 116.20 μmol) and NaOAc (400.35 mg, 4.88 mmol). _The resulting mixture was heated to 120 °C and stirred for 16 h. LCMS analysis showed consumption of starting material and the desired m/z. A second reaction was prepared as described and the reactions were combined for work-up and purification. The mixture was filtered to give a residue. The residue was purified by prepHPLC (Method 3). The pure fractions were collected, frozen, and lyophilized to give compound 45g (333 mg, 953 μmol, 41% yield) as a white solid. UPLC-MS (Method O, ESI+): m/z [M + H] ⁺ = 350.2 (theoretical value), 350.1 (observed value). HPLC retention time: 1.658 min. ¹ H NMR (400MHz, DMSO- d ₆ ) δ ppm 12.94 - 12.66 (m, 1H), 9.59 (s, 1H), 8.56 (s, 1H), 8.07 (br s, 1H), 7.78 (s, 1H), 7.70 (s, 1H), 7.41 (br s, 1H), 6.54 (s, 1H), 4.39 (q, J = 6.8 Hz, 2H), 4.08 (s, 3H), 2.25 (s, 3H), 1.32 (t, J = 7.2 Hz, 3H). Synthesis of compound 45h

A solution of compound 45g (50 mg, 143.1 μmol), compound 6 (126.45 mg, 214.7 μmol) and Cs ₂ CO ₃ (233.13 mg, 715.5 μmol) in DMF (716 μL) was brought to 55 °C and stirred for 16 h. LCMS analysis showed consumption of starting material and desired m/z. The solution was filtered and purified directly by prepHPLC (Method 1). The fractions were collected, frozen, and lyophilized to give compound 45h (69.54 mg, 77.1 μmol, 54% yield) as a white solid. UPLC-MS (Method A, ESI+): m/z [M + H] ⁺ = 902.4 (theoretical), 902.4 (observed). HPLC retention time: 1.54 min. Synthesis of compound 1.10

A solution of compound 45h (69.54 mg, 77.1 μmol) in 30% TFA in MeCN (771 μL) was brought to 30 °C and stirred for 1 h. LCMS analysis showed consumption of starting material and desired m/z. The solvent was removed under reduced pressure and the residue was purified by prepHPLC (Method 1). The fractions were collected, frozen, and lyophilized to give compound 1.10 x1 TFA (42.01 mg, 45.9 μmol, 60% yield) as a white solid. UPLC-MS (Method A, ESI+): m/z [M + H] ⁺ = 802.4 (theoretical), 802.4 (observed). HPLC retention time: 1.24 min. Example 56. (E)-N-(5- aminoformyl- 1-(4-(8- aminoformyl- 3-(1- ethyl - 3- methyl - 1H -pyrazol -5- yl )-6- methoxy -5H -pyrido [4,3-b] indol- 5- yl ) but- 2- en - 1 - yl )-7-(3-(3-(2,5- dihydroxy - 2,5- dihydro -1H -pyrrol -1- yl )-N -methylpropionamido ) propoxy )-1H- benzo [d] imidazol -2- yl )-4- ethyl -2- methyloxazole -5- carboxamide ( Compound 2.28)

Compound 2.28 (6.84 mg, 7.2 μmol, 66% yield) was prepared following General Method 1 using compound 1.10 x1 TFA (10 mg, 10.9 μmol) as starting material. UPLC-MS (Method A, ESI+): m/z [M + H] ⁺ = 953.4 (theoretical value), 953.4 (observed value). HPLC retention time: 1.36 min. Example 57. S-(1-(3-((3-((5- aminoformyl -1-((E)-4-(8- aminoformyl- 3-(1- ethyl -3- methyl -1H -pyrazol- 5- yl )-6- methoxy -5H -pyrido [4,3-b] indol- 5- yl ) but- 2- en - 1 - yl )-2-(4- ethyl -2- methyloxazole -5 -carboxamido )-1H- benzo [d] imidazol -7 - yl ) oxy ) propyl )( methyl ) amino )-3 - oxopropyl )-2,5 -dioxopyrrolidin -3- yl )-L- cysteine ( Compound 3.10)

Compound 3.10 (2.65 mg, 2.2 μmol, 71% yield) was prepared following General Method 2 using compound 2.28 (3 mg, 3.1 μmol) as starting material. UPLC-MS (Method A, ESI+): m/z [M + H] ⁺ = 1074.4 (theoretical value), 1074.4 (observed value). HPLC retention time: 1.26 min. Example 58. (3-((5- aminoformyl- 1-((E)-4-(8- aminoformyl- 3-(1- ethyl -3- methyl -1H -pyrazol -5- yl )-6- methoxy -5H -pyrido [4,3-b] indol -5- yl ) but - 2- en - 1 - yl )-2-(4- ethyl -2- methyloxazole -5 -carboxamido )-1H- benzo [d] imidazol -7- yl ) oxy ) propyl )( methyl ) carbamate 4-((S)-2-((S)-2-(3-(2,5- dihydroxy - 2,5 - dihydro -1H -pyrrol -1- yl ) propionamido )-3 -methylbutanamido ) propionamido ) benzyl ester ( Compound 2.29)

Compound 2.29 (4.75 mg, 3.7 μmol, 60% yield) was prepared following General Method 3 using compound 1.10 x1 TFA (5 mg, 6.2 μmol) as starting material. UPLC-MS (Method A, ESI+): m/z [M + H] ⁺ = 1272.5 (theoretical value), 1272.5 (observed value). HPLC retention time: 1.44 min. Example 59. (2S,3S,4S,5R,6S)-6-(4-((((3-((5- aminoformyl -1-((E)-4-(8- aminoformyl- 3-(1- ethyl -3- methyl -1H -pyrazol -5- yl )-6- methoxy -5H -pyrido [4,3-b] indol- 5- yl ) but-2-en-1 - yl) -2-(4- ethyl - 2 - methyloxadiazol - 5 - yl)-1 ... ( 2- ( 3- ( 2,5 - dihydroxy - 2,5 - dihydro - 1H - pyrrol - 1 - yl ) propionamido ) propionamido ) phenoxy ) -3,4,5 - trihydroxytetrahydro - 2H - pyran - 2 - carboxylic acid ( Compound 2.30 ) ​ Synthesis of compound 46a

Compound 46a (36.36 mg, 23.1 μmol, 78% yield) was prepared following General Method 4 using compound 1.10 x1 TFA (27.03 mg, 29.5 μmol) as starting material. UPLC-MS (Method A, ESI+): m/z [M + H] ⁺ = 1577.6 (theoretical value), 1577.6 (observed value). HPLC retention time: 1.79 min. Synthesis of compound 46b

Following General Method 7, compound 46b x1 TFA (25.31 mg, 19.1 μmol, 83% yield) was prepared using compound 46a (36.36 mg, 23.1 μmol) as starting material. UPLC-MS (Method A, ESI+): m/z [M + H] ⁺ = 1215.5 (theoretical value), 1215.5 (observed value). HPLC retention time: 1.28 min. Synthesis of compound 2.30

Compound 2.30 (14.37 mg, 10.5 μmol, 55% yield) was prepared following General Method 6 using 46b x 1 TFA (25.31 mg, 19.1 μmol) as starting material. UPLC-MS (Method A, ESI+): m/z [M + H] ⁺ = 1366.5 (theoretical), 1366.5 (observed). HPLC retention time: 1.30 min. Example 60. (E)-N-(5- aminoformyl- 1-(4-(6- aminoformyl- 2-(1- ethyl - 3- methyl -1H -pyrazol -5- yl )-8- methoxy -9H -pyrido [2,3-b] indol- 9- yl ) but -2- en - 1 - yl )-7-(3-( methylamino ) propoxy )-1H- benzo [d] imidazol -2- yl )-4- ethyl -2- methyloxazole -5- carboxamide ( Compound 1.12) Synthesis of compound 47a

To a solution of 2,5-dibromopyridine (18 g, 75.96 mmol) in MeCN (300 mL) was added _AgF2 (55.44 g, 379.89 mmol). The mixture was allowed to reach 50 °C and stirred under _N2 in the dark for 16 h. HPLC analysis showed 33% starting material and 57% product. The reaction mixture was concentrated and the residue was dissolved in EtOAc. The precipitate was removed by filtration and the filtrate was concentrated to give compound 47a (11 g, crude) as an oily solid, which was used without further purification. Synthesis of compound 47b

To a solution of compound 45b (488.98 mg, 2.94 mmol) in THF (50 mL) was added LiHMDS (1 M, 24.54 mL) at 0 °C under _N2 and stirred for 30 min. Then, compound 47a (1.5 g, 5.89 mmol) was added. The mixture was allowed to reach 20 °C and stirred for 3.5 h. LCMS analysis showed consumption of the starting material and the desired m/z. The reaction mixture was quenched with _NH4Cl (50 mL) and extracted with EtOAc (50 mL x 2). The combined organic layers were washed with brine (50 mL), dried _{over Na2SO4} , filtered, and concentrated under reduced pressure to give a residue. The residue was triturated with MTBE (100 mL) at 20°C for 10 min and filtered to yield compound 47b (2.5 g, crude) as a yellow solid. UPLC-MS (Method D, ESI+): m/z [M + H] ⁺ = 399.9 (theoretical value), 400.0 (observed value). HPLC retention time: 1.867 min. Synthesis of compound 47c

To a solution of compound 47b (2.5, 6.24 mmol) in THF (30 mL) and H ₂ O (6 mL) were added compound 3g (1.47 g, 6.24 mmol), Pd(PPh ₃ ) ₄ (720.32 mg, 623.36 μmol), and K ₂ CO ₃ (1723 g, 12.46 mmol). The mixture was brought to 50 °C and stirred for 2 h. LCMS analysis showed consumption of starting material and the desired m/z. The mixture was concentrated under reduced pressure and the residue was purified by prepHPLC (Method 4). The pure fractions were collected, frozen, and lyophilized to give compound 47c (1.2 g, 2.79 mmol, 24% over two steps) as a yellow solid. UPLC-MS (Method D, ESI+): m/z [M + H] ⁺ = 430.1 (theoretical value), 430.1 (observed value). HPLC retention time: 1.804 min. ¹ H NMR (400MHz, DMSO- d ₆ ) δ ppm 8.14 (d, J = 8.4 Hz, 1H), 8.05 (d, J = 8.0 Hz, 1H), 8.01 (s, 1H), 7.95 (br s, 1H), 7.59 (d, J = 1.2 Hz, 1H), 7.57 - 7.52 (m, 1H), 7.28 (br s, 1H), 7.09 (d, J = 8.0 Hz, 1H), 6.48 (s, 1H), 4.33 (q, J = 7.2 Hz, 2H), 3.93 (s, 3H), 2.17 (s, 3H), 1.15 (t, J = 7.2 Hz, 3H). Synthesis of compound 47d

To a solution of compound 47c (1.2 g, 2.78 mmol) in DMF (20 mL) was added Pd(PPh ₃ )Cl ₂ (195.74 mg, 278.88 μmol) and NaOAc (960.84 mg, 11.72 mmol). The mixture was brought to 120 °C and stirred under N ₂ for 16 h. LCMS analysis showed consumption of starting material and desired m/z. The mixture was filtered and purified by prepHPLC (Method 5). The pure fractions were collected, frozen, and lyophilized to give compound 47d (240 mg, 686.9 μmol, 43% yield) as a yellow solid. UPLC-MS (Method C, ESI+): m/z [M + H] ⁺ = 350.2 (theoretical value), 350.1 (observed value). HPLC retention time: 2.049 min. ¹ H NMR (400MHz, DMSO- d ₆ ) δ ppm 12.27 (s, 1H), 8.54 (d, J = 8.1 Hz, 1H), 8.39 (s, 1H), 7.99 (br s, 1H), 7.61 - 7.56 (m, 2H), 7.29 (br s, 1H), 6.59 (s, 1H), 4.66 (q, J = 7.1 Hz, 2H), 4.05 (s, 3H), 2.22 (s, 3H), 1.40 - 1.33 (m, 3H). Synthesis of compound 47e

A solution of compound 47d (50 mg, 143.1 μmol), compound 6 (126.45 mg, 214.7 μmol) and Cs ₂ CO ₃ (233.13 mg, 715.5 μmol) was brought to 55 °C and stirred for 16 h. LCMS analysis showed consumption of starting material and desired m/z. The mixture was filtered and the filtrate was purified by prepHPLC (Method 1). The fractions were collected, frozen, and lyophilized to give compound 47e (110.4 mg, 122.4 μmol, 86% yield) as a white solid. UPLC-MS (Method A, ESI+): m/z [M + H] ⁺ = 902.4 (theoretical value), 902.5 (observed value). HPLC retention time: 1.63 min. Synthesis of compound 1.12

Compound 47e (110.4 mg, 122.4 μmol) was dissolved in 30% TFA in MeCN (1.22 mL). The solution was allowed to reach 30 °C and stirred for 1 h. LCMS analysis showed consumption of starting material and desired m/z. The solvent was removed under reduced pressure to yield a residue. The residue was purified by prepHPLC (Method 1). The fractions were collected, frozen, and lyophilized to afford compound 1.12 x1 TFA (66.34 mg, 72.4 μmol, 59% yield) as a white solid. UPLC-MS (Method A, ESI+): m/z [M + H] ⁺ = 802.4 (theoretical), 802.4 (observed). HPLC retention time: 1.42 min. Example 61. (E)-N-(5- aminoformyl- 1-(4-(6- aminoformyl- 2-(1- ethyl - 3- methyl - 1H -pyrazol -5- yl )-8- methoxy -9H -pyrido [2,3-b] indol- 9- yl ) but- 2- en -1-yl ) -7- (3-(3-(2,5- dihydroxy - 2,5- dihydro -1H -pyrrol -1- yl )-N -methylpropionamido ) propoxy )-1H- benzo [d] imidazol -2- yl )-4- ethyl -2- methyloxazole -5- carboxamide ( Compound 2.34)

Compound 2.34 (6.66 mg, 7 μmol, 64% yield) was prepared following General Method 1 using compound 1.12 x 1 TFA (10 mg, 10.9 μmol) as starting material. UPLC-MS (Method A, ESI+): m/z [M + H] ⁺ = 953.4 (theoretical value), 953.4 (observed value). HPLC retention time: 1.48 min. Example 62. (E)-S-(1-(3-((3-((5- aminoformyl -1-(4-(6- aminoformyl -2-(1- ethyl -3- methyl -1H -pyrazol- 5- yl )-8- methoxy -9H - pyrido [2,3-b] indol- 9- yl ) but - 2- en - 1- yl )-2-(4- ethyl -2- methyloxazole -5 -carboxamido )-1H- benzo [d] imidazol -7- yl ) oxy ) propyl )( methyl ) amino )-3 - oxopropyl )-2,5 -dioxopyrrolidin -3- yl ) cysteine ( Compound 3.12)

Compound 3.12 x1 TFA (1.93 mg, 1.8 μmol, 57% yield) was prepared following General Method 2 using compound 2.34 (3 mg, 3.1 μmol) as starting material. UPLC-MS (Method A, ESI+): m/z [M + H] ⁺ = 1074.4 (theoretical value), 1074.5 (observed value). HPLC retention time: 1.37 min. Example 63. 4-(( S)-2-((S)-2-(3-(2,5 - dihydroxy - 2,5 - dihydro - 1H -pyrrol- 1- yl ) propionamido )-3- methylbutanamido )propionamido ) benzyl (3-( (5-aminoformyl-1-((E)-4-(6-aminoformyl-2-(1-ethyl-3-methyl-1H-pyrazol-5-yl)-8-methoxy-9H-pyrido[2,3-b] indol - 9 - yl ) but - 2 - en - 1 - yl ) -2- ( 4 - ethyl - 2 - methyloxazole - 5- carboxamido ) -1H - benzo [d ] imidazol - 7 - yl ) oxy ) propyl) (methyl ) carbamate ( Compound 2.35)

Compound 2.35 (4.07 mg, 3.2 μmol, 59% yield) was prepared following General Method 3 using compound 1.12 (5 mg, 5.5 μmol) as starting material. UPLC-MS (Method A, ESI+): m/z [M + H] ⁺ = 1273.5 (theoretical value), 1273.6 (observed value). HPLC retention time: 1.56 min. Example 64. (2S,3S,4S,5R,6S)-6-(4-((((3-((5- aminoformyl -1-((E)-4-(6- aminoformyl- 2-(1- ethyl -3- methyl -1H - pyrazol -5- yl )-8- methoxy -9H -pyrido [2,3-b] indol- 9- yl ) but -2- en-1-yl ) -2- ( 4- ethyl -2- methyloxadiazol- ( 2- ( 3- ( 2,5 - dihydroxy - 2,5 - dihydro - 1H - pyrrol - 1 - yl ) propionamido ) propionamido ) phenoxy ) -3,4,5 - trihydroxytetrahydro - 2H - pyran - 2 - carboxylic acid ( Compound 2.36 ) ​ Synthesis of compound 48a

Compound 48a (28.4 mg, 18 μmol, 30% yield) was prepared following General Method 4 using compound 1.12 x1 TFA (54.6 mg, 59.6 μmol) as starting material. UPLC-MS (Method A, ESI+): m/z [M + H] ⁺ = 1577.6 (theoretical value), 1577.6 (observed value). HPLC retention time: 1.84 min. Synthesis of compound 48b

Following General Method 7, compound 48b x1 TFA (5.13 mg, 4.2 μmol, 23% yield) was prepared using compound 48a (28.4 mg, 18 μmol) as starting material. UPLC-MS (Method A, ESI+): m/z [M + H] ⁺ = 1215.5 (theoretical value), 1215.5 (observed value). HPLC retention time: 1.41 min. Synthesis of compound 2.36

Compound 2.36 (2.3 mg, 1.7 μmol, 44% yield) was prepared following General Method 6 using 48b x 1 TFA (5.13 mg, 4.2 μmol) as starting material. UPLC-MS (Method A, ESI+): m/z [M + H] ⁺ = 1366.5 (theoretical value), 1366.5 (observed value). HPLC retention time: 1.48 min. Example 65. (E)-N-(5- aminoformyl- 1-(4-(8- aminoformyl- 3-(1- ethyl - 3- methyl - 1H -pyrazol -5- yl )-6- methoxy -5H -pyrido [3,2-b] indol- 5- yl ) but -2- en - 1 - yl )-7-(3-( methylamino ) propoxy )-1H- benzo [d] imidazol -2- yl )-4- ethyl -2- methyloxazole -5- carboxamide ( Compound 1.11) Synthesis of compound 49a

To a solution of methyl 4-bromo-3-methoxybenzoate (25 g, 102.02 mmol) in THF (500 mL) at 20 °C was added aqueous NaOH (20%, 500 mL). The mixture was allowed to reach 50 °C and stirred for 3 h. LCMS analysis showed consumption of starting material and the desired m/z. The mixture was adjusted to pH = 6 with citric acid and concentrated under reduced pressure followed by filtration to yield compound 49a (24 g, crude), which was used without further purification. UPLC-MS (Method D, ESI+): m/z [M + H] ⁺ = 231.0 (theoretical), 232.2 (observed). HPLC retention time: 1.179 min. Synthesis of compound 49b

To a solution of compound 49a (12 g, 51.94 mmol) in DMF (180 mL) was added EDCI (19.92 g, 103.88 mmol), HOBt (14.04 g, 103.88 mmol), NH ₄ Cl (5.56 g, 103.88 mmol) and DIPEA (18 mL, 103.88 mmol) at 20° C. The mixture was stirred at 20° C. for 12 h. TLC (hexane/EtOAc, R _f = 0.4) showed consumption of the starting material and a new spot had formed. The mixture was diluted with water (400 mL) and extracted with EtOAc (3×300 mL). The combined organic layers were washed with water (3 x 300 mL), dried over _{Na2SO4 ,} filtered, and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography ( _SiO2 , hexanes/EtOAc) to give compound 49b (11 g, 47.81 mmol, 46% yield) as a yellow solid. ¹ H NMR (400MHz, DMSO- d ₆ ) δ ppm 8.07 (br s, 1H), 7.65 (d, J = 8.4 Hz, 1H), 7.55 (d, J = 1.6 Hz, 1H), 7.48 (br s, 1H), 7.40 (dd, J = 2.0, 8.0 Hz, 1H), 3.90 (s, 3H). Synthesis of compound 49c

To a solution of 2-chloro-5-iodopyridin-3-amine (10 g, 39.30 mmol) in THF (150 mL) was added NaHMDS (1 M, 162.7 mL) and (Boc) ₂ O (17.33 mL, 75.46 mmol) at 0 °C. The resulting mixture was stirred at 0 °C for 2 h. LCMS analysis showed consumption of starting material and the desired m/z. The reaction mixture was quenched with NH ₄ Cl (200 mL) at 0 °C and extracted with EtOAc (3×200 mL). The combined organic layers were washed with brine (3×150 mL), dried over Na ₂ SO ₄ , filtered, and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (SiO ₂ , hexane/EtOAc) to give compound 49c (8.5 g, 23.97 mmol, 61% yield) as a white solid. UPLC-MS (Method P, ESI+): m/z [M + H] ⁺ = 355.0 (theoretical value), 355.0 (observed value). HPLC retention time: 2.281 min. ¹ H NMR (400 MHz, DMSO- d ₆ ) δ ppm 8.99 (s, 1H), 8.40 (d, J = 2.0 Hz, 1H), 8.37 (d, J = 2.0 Hz, 1H), 1.47 (s, 9H). Synthesis of compound 49d

To a solution of compound 49c (8 g, 22.56 mmol) and compound 3g (7.99 g, 33.84 mmol) in dioxane (80 mL) and water (20 mL) at 20 °C was added Pd(dppf) _Cl2 (825.45 mg, 1.13 mmol) and _K2CO3 (6.24 g, 45.12 mmol). This mixture was brought to 80 °C and stirred for 2 h _. LCMS analysis showed consumption of starting material and desired m/z. The mixture was diluted with EtOAc (100 mL) and extracted with EtOAc (3 x 100 mL). The combined organic layers were washed with brine (3 x 100 mL), dried _{over Na2SO4} , filtered, and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (SiO ₂ , hexane/EtOAc) to give compound 49d (4.8 g, 14.26 mmol, 63% yield) as a yellow solid. UPLC-MS (Method D, ESI+): m/z [M + H] ⁺ = 337.1 (theoretical value), 337.3 (observed value). HPLC retention time: 1.925 min. Synthesis of compound 49e

A mixture of compound 49d (4.8 g, 14.26 mmol) in HCl/EtOAc (4 M, 100 mL) was stirred at 20 °C for 2 h. LCMS analysis showed consumption of starting material and desired m/z. The reaction mixture was filtered to yield compound 49e x1 HCl (4 g, crude) as a pink solid. The crude product was used without further purification. UPLC-MS (Method L, ESI+): m/z [M + H] ⁺ = 237.1 (theoretical), 237.2 (observed). HPLC retention time: 0.374 min. Synthesis of compound 49f

_To a solution of compound 49e (6 g, 21.96 mmol) and compound 49b (6.06 g, 26.36 mmol) in 2-methylbutan-2-ol (120 mL) at 20 °C under _N2 atmosphere was added _Cs2CO3 (35.78 g, 109.82 mmol) and rac-BINAP-Pd-G3 (4.36 g, 2.20 mmol). The mixture was brought to 110 °C and stirred for 12 h. LCMS analysis showed consumption of starting material and desired m/z. The mixture was diluted with EtOAc and extracted (3 x 100 mL). The combined organic layers were washed with water (3 x 100 mL), _dried over _Na2SO4 , and filtered. The filter cake was washed with THF (100 mL) and the filtrate was concentrated under reduced pressure to yield a residue. The residue was purified by prepHPLC (Method 4). The fractions were collected, frozen, and lyophilized to afford compound 49f (2.4 g, 6.22 mmol, 28% yield) as a brown solid. UPLC-MS (Method D, ESI+): m/z [M + H] ⁺ = 386.1 (theoretical value), 386.2 (observed value). HPLC retention time: 1.482 min. ¹ H NMR (400MHz, DMSO- d ₆ ) δ ppm 7.99 (d, J = 2.0 Hz, 1H), 7.92 (br s, 1H), 7.63 (s, 1H), 7.57 (d, J = 1.6 Hz, 1H), 7.49 (dd, J = 1.6, 8.0 Hz, 1H), 7.28 (br s, 1H), 7.23 - 7.16 (m, 2H), 6.20 (s, 1H), 4.01 (q, J = 7.2 Hz, 2H), 3.86 (s, 3H), 2.16 (s, 3H), 1.23 (t, J = 7.2 Hz, 3H). Synthesis of compound 49g

To a solution of compound 49f (500 mg, 1.30 mmol) in DMF (5 mL) was added Pd(PPh ₃ ) ₂ Cl ₂ (90.96 mg, 129.59 μmol) and NaOAc (446.48 mg, 5.44 mmol) under N ₂ atmosphere. The mixture was brought to 120 °C and stirred for 12 h. LCMS analysis showed consumption of starting material and desired m/z. The reaction mixture was filtered and the filtrate was concentrated. The residue was purified by prepHPLC (Method 3) to give compound 49g x 1 TFA (225 mg, 643.97 μmol, 37% yield) as a yellow solid. UPLC-MS (Method O, ESI+): m/z [M + H] ⁺ = 350.2 (theoretical value), 350.1 (observed value). HPLC retention time: 1.809 min. ¹ H NMR (400MHz, DMSO- d ₆ ) δ ppm 12.04 (s, 1H), 8.60 (d, J = 2.0 Hz, 1H), 8.48 (s, 1H), 8.13 (br s, 1H), 7.91 (d, J = 1.6 Hz, 1H), 7.67 (d, J = 1.2 Hz, 1H), 7.32 (br s, 1H), 6.31 (s, 1H), 4.11 (s, 2H), 4.07 (s, 3H), 2.23 (s, 3H), 1.33 (t, J = 7.2 Hz, 3H). Synthesis of compound 49h

A solution of compound 49g x 1 TFA (50 mg, 107.9 μmol), compound 6 (95.34 mg, 161.8 μmol) and Cs ₂ CO ₃ (105.46 mg, 323.7 μmol) in DMF (1 mL) was brought to 55 °C and stirred for 16 h. LCMS analysis showed consumption of starting material and desired m/z. The reaction was filtered and the filtrate was purified by prepHPLC (Method 1). The fractions were collected, frozen, and lyophilized to give compound 49h (55.65 mg, 61.7 μmol, 57% yield) as a white solid. UPLC-MS (Method A, ESI+): m/z [M + H] ⁺ = 902.4 (theoretical), 902.4 (observed). HPLC retention time: 1.52 min. Synthesis of compound 1.11

A solution of compound 49h (55.65 mg, 61.7 μmol) in 20% (v/v) TFA in MeCN (1 mL) was stirred at 30 °C for 1 h. LCMS analysis showed consumption of starting material and desired m/z. The solvent was removed under reduced pressure and the residue was purified by prepHPLC (Method 1). The fractions were collected, frozen, and lyophilized to give compound 1.11 x 1 TFA (42.70 mg, 46.6 μmol, 76% yield) as a white solid. UPLC-MS (Method A, ESI+): m/z [M + H] ⁺ = 802.4 (theoretical), 802.4 (observed). HPLC retention time: 1.30 min. Example 66. (E)-N-(5- aminoformyl- 1-(4-(8- aminoformyl- 3-(1- ethyl - 3- methyl - 1H -pyrazol -5- yl )-6- methoxy -5H -pyrido [3,2-b] indol- 5- yl ) but- 2- en - 1 - yl )-7-(3-(3-(2,5- dihydroxy - 2,5- dihydro -1H -pyrrol -1- yl )-N -methylpropionamido ) propoxy )-1H- benzo [d] imidazol -2- yl )-4- ethyl -2- methyloxazole -5- carboxamide ( Compound 2.31)

Compound 2.31 (4.64 mg, 4.87 μmol, 87% yield) was prepared following General Method 1 using compound 1.11 x 1 TFA (5.0 mg, 5.5 μmol) as starting material. UPLC-MS (Method A, ESI+): m/z [M + H] ⁺ = 953.4 (theoretical value), 953.4 (observed value). HPLC retention time: 1.39 min. Example 67. S-(1-(3-((3-((5- aminoformyl -1-((E)-4-(8- aminoformyl- 3-(1- ethyl -3- methyl -1H -pyrazol- 5- yl )-6- methoxy -5H -pyrido [3,2-b] indol- 5- yl ) but- 2- en - 1 - yl )-2-(4- ethyl -2- methyloxazole -5 -carboxamido )-1H- benzo [d] imidazol -7 - yl ) oxy ) propyl )( methyl ) amino )-3 - oxopropyl )-2,5 -dioxopyrrolidin -3- yl )-L- cysteine ( Compound 3.11)

Compound 3.11 x1 TFA (1.66 mg, 1.4 μmol, 44% yield) was prepared following General Method 2 using compound 2.31 (3 mg, 3.1 μmol) as starting material. UPLC-MS (Method A, ESI+): m/z [M + H] ⁺ = 953.4 (theoretical value), 1074.4 (observed value). HPLC retention time: 1.46 min. Example 68. 4-(( S)-2-((S)-2-(3-(2,5- dihydroxy-2,5-dihydro-1H-pyrrol-1-yl)propionamido)-3-methylbutanamido)propionamido)benzyl (3 - ( ( 5 - aminoformyl - 1 - ( ( E ) -4- (8-aminoformyl-3-(1-ethyl-3-methyl-1H-pyrazol-5-yl)-6-methoxy-5H-pyrido[3,2-b] indol - 5 - yl ) but - 2 - en - 1 - yl ) -2- ( 4 - ethyl - 2 - methyloxazole - 5 - carboxamido ) -1H - benzo [ d ] imidazol -7 - yl ) oxy ) propyl) (methyl ) carbamate ( Compound 2.32)

Compound 2.32 (6.3 mg, 5.0 μmol, 91% yield) was prepared following General Method 3 using compound 1.11 x 1 TFA (5.0 mg, 5.5 μmol) as starting material. UPLC-MS (Method A, ESI+): m/z [M + H] ⁺ = 1272.6 (theoretical value), 1272.6 (observed value). HPLC retention time: 1.46 min. Example 69. (2S,3S,4S,5R,6S)-6-(4-((((3-((5- aminoformyl -1-((E)-4-(8- aminoformyl- 3-(1- ethyl -3- methyl -1H - pyrazol -5- yl )-6- methoxy -5H -pyrido [3,2-b] indol- 5- yl ) but- 2- en-1-yl ) -2- ( 4- ethyl -2- methyloxadiazol- ( 2- ( 3- ( 2,5 - dihydroxy - 2,5 - dihydro - 1H - pyrrol - 1 - yl ) propionamido ) propionamido ) phenoxy ) -3,4,5 - trihydroxytetrahydro - 2H - pyran - 2 - carboxylic acid ( Compound 2.33 ) ​ Synthesis of compound 50a

Compound 50a (51.69 mg, 32.8 μmol, 92% yield) was prepared following General Method 4 using compound 1.11 x 1 TFA (32.70 mg, 35.7 μmol) as starting material. UPLC-MS (Method A, ESI+): m/z [M + H] ⁺ = 1572.6 (theoretical value), 1576.6 (observed value). HPLC retention time: 1.76 min. Synthesis of Compound 50b

Following General Method 7, Compound 50b x 1 TFA (37.92 mg, 28.5 μmol, 87% yield) was prepared using Compound 50a (51.69 mg, 32.8 μmol) as starting material. UPLC-MS (Method A, ESI+): m/z [M + H] ⁺ = 1214.5 (theoretical value), 1214.5 (observed value). HPLC retention time: 1.41 min. Synthesis of Compound 2.33

Compound 2.33 (17.99 mg, 13.2 μmol, 46% yield) was prepared following General Method 6 using compound 50b (37.92 mg, 29.5 μmol) as starting material. UPLC-MS (Method A, ESI+): m/z [M + H] ⁺ = 1365.5 (theoretical value), 1365.5 (observed value). HPLC retention time: 1.35 min. Example 70. (E)-N-(5- aminoformyl- 1-(4-(6- aminoformyl- 2-(4- ethyl - 2- methylthiazol -5 -yl )-8- methoxy -9H- pyrimido [4,5-b] indol -9- yl ) but-2- en - 1 - yl )-7-(3-( methylamino ) propoxy )-1H- benzo [d] imidazol -2- yl )-4- ethyl -2- methyloxazole -5- carboxamide ( Compound 1.20) Synthesis of compound 51a

A solution of 5-bromo-4-ethyl-2methyl-thiazole (1.24 g, 5.99 mmol) in THF (30 mL) in a 100 mL 2-neck RBF equipped with a stir bar and internal temperature monitoring was placed in a dry ice/acetone bath at -75 °C under Ar atmosphere. 1.6 M n -BuLi (3.75 mL, 5.99 mmol) was added dropwise to the solution to maintain the internal temperature below -65 °C. The solution was stirred at -75 °C for 30 min. Triethyl borate (3.0 mL, 17.63 mmol) was then added dropwise to maintain the internal temperature below -65 °C. The dry ice/acetone bath was replaced with an ice-water bath, allowing the temperature to quickly warm to 0 °C. The reaction was stirred between 0-2 °C for 1 h. Simultaneously, MIDA (2.64 g, 18.0 mmol) and DMSO (20 mL) were added to a separate 3-neck 100 mL oven-dried RBF. The RBF was equipped with a short-path distillation head and an internal temperature probe. This solution was heated to 120-125°C in an oil bath. The boronated thiazole solution was cannulated at a rate such that the internal temperature remained between 110-120°C while THF was rapidly distilled. Once the THF solution was fully cannulated and most of the DMSO was distilled off, the RBF was cooled to rt. The distillate was discarded and the RBF containing the product was placed under vacuum and heated to 70°C via an oil bath to remove excess DMSO, leaving a brown viscous residue. The residue was dissolved in acetone and filtered. The filter cake was discarded and the filtrate was concentrated to give the crude product. The residue was dissolved in acetone/DCM and purified by flash chromatography (SiO ₂ , MTBE/MeCN). The purified fractions contained a large amount of by-products. The fractions were concentrated and the resulting residue was redissolved in 1:1 acetone/DCM and purified a second time by flash chromatography (SiO ₂ , MTBE/MeCN) to give compound 51a (815 mg, 2.89 mmol, 48% yield) as a bright white solid. UPLC-MS (Method H, ESI+): m/z [M+H] ⁺ = 283.1 (theoretical value), 283.2 (observed value). HPLC retention time: 0.81 min. Synthesis of compound 51b

A 40 mL vial was charged with Pd(PPh ₃ ) ₄ (15 mg, 13 μmol), compound 51a (219 mg, 778 μmol) and compound 8b (80 mg, 259 μmol). The headspace was purged under Ar for 3 min, after which THF (5.2 mL) was added and the solution was purged for 15 min. The purged aqueous Na ₂ CO ₃ solution (2.3 M, 0.85 mL, 1.94 mmol) was transferred to the reaction vial under N _2. The reaction was sealed, brought to 100 °C and stirred for 1 h. LCMS analysis showed consumption of starting material and desired m/z. The crude product was diluted with water and extracted with EtOAc (×3). The combined organic layers were washed with saturated NaHCO ₃ and brine, dried over MgSO ₄ , and concentrated. The crude product was then purified by prepHPLC (Method 1). The pure fractions were collected, frozen, and lyophilized to give compound 51b (42.6 mg, 107 μmol, 41% yield). UPLC-MS (Method A, ESI+): m/z [M+H] ⁺ = 400.1 (theoretical value), 400.1 (observed value). HPLC retention time: 1.63 min. Synthesis of compound 51c

Compound 51b (13.3 mg, 33 μmol), 4CzIPN (0.02 M, 0.034 mL), and PPh ₃ (44 mg, 170 μmol) were fed to an oven-dried vial. The headspace of the vial was purged with Ar for 5 min. The solid was then dissolved in THF (3.4 mL). The solution was purged with Ar for 30 min. The vial was sealed and placed in a photoreactor equipped with a blue LED (365 nm) for 24 h. The crude mixture was poured into water and extracted with EtOAc. The combined organics were washed with saturated NaHCO ₃ and brine, dried over MgSO ₄ , filtered, and concentrated. The residue was then purified by flash chromatography (SiO ₂ , DCM/MeOH) to give compound 51c (3.4 mg, 9.3 μmol, 28% yield). UPLC-MS (Method A, ESI+): m/z [M+H] ⁺ = 368.1 (theoretical value), 368.1 (observed value). HPLC retention time: 1.38 min. Synthesis of compound 51d

A solution of compound 51c (5.9 mg, 16.1 μmol), compound 30 (14.1 mg, 24.1 μmol) and Cs ₂ CO ₃ (15.7 mg, 48.2 μmol) in DMF (320 μL) was brought to 55 °C and stirred for 16 h. LCMS analysis showed consumption of starting material and desired m/z. The reaction was filtered and purified by prepHPLC (Method 1). The fractions were collected, frozen, and lyophilized to give compound 51d (3.5 mg, 3.8 μmol, 24% yield) as a white solid. UPLC-MS (Method A, ESI+): m/z [M+H] ⁺ = 920.4 (theoretical value), 920.4 (observed value). HPLC retention time: 1.66 min. Synthesis of compound 1.20

A solution of compound 51d (3.5 mg, 3.8 μmol) in DCM (76 μL) containing 20% TFA (v/v) was stirred at 23 °C for 2 h. LCMS analysis showed consumption of starting material and desired m/z. The solvent was removed under reduced pressure and the residue was purified by prepHPLC (Method 1). The pure fractions were collected, frozen, and lyophilized to give compound 1.20 x 1 TFA (2.5 mg, 3.0 μmol, 80% yield) as a white solid. UPLC-MS (Method A, ESI+): m/z [M+H] ⁺ = 820.3 (theoretical value), 820.3 (observed value). HPLC retention time: 1.43 min. Example 71. (E)-N-(5- aminoformyl- 1-(4-(6- aminoformyl- 2-(4- ethyl - 2- methylthiazol -5 -yl )-8- methoxy -9H- pyrimido [4,5-b] indol- 9- yl ) but- 2-en-1- yl ) -7- ( 3-(3-(2,5- dioxo -2,5- dihydro -1H -pyrrol -1- yl )-N -methylpropionamido ) propoxy )-1H- benzo [d] imidazol -2 - yl )-4- ethyl -2- methyloxazole -5- carboxamide ( Compound 2.58)

Compound 2.58 (2.5 mg, 2.6 μmol, 38% yield) was prepared following General Procedure 1 using compound 1.20 x 1 TFA (2.5 mg, 3.0 μmol) as starting material. UPLC-MS (Method A, ESI+): m/z [M+H] ⁺ = 971.4 (theoretical value), 971.4 (observed value). HPLC retention time: 1.46 min. Example 72. 4-(( S)-2-((S)-2-(3-(2,5 - dihydroxy - 2,5- dihydro -1H- pyrrol -1- yl )propionamido)-3- methylbutanamido ) propionamido)benzyl ( 3-( (5- aminoformyl - 1 - ( (E ) -4-(6-aminoformyl-2-(4- ethyl - 2 - methylthiazol - 5-yl )-8- methoxy- 9H - pyrimido [ 4,5 - b ] indol -9-yl ) but -2-en-1-yl) -2- (4- ethyl - 2- methyloxazol- 5 - carboxamido ) -1H -benzo [ d ]imidazol - 7-yl)oxy ) propyl) (methyl ) carbamate ( Compound 2.59)

Compound 2.59 (1.84 mg, 1.4 μmol, 58% yield) was prepared following General Method 3 using compound 1.20 x 1 TFA (2.0 mg, 2.4 μmol) as starting material. UPLC-MS (Method A, ESI+): m/z [M+H] ⁺ = 1290.5 (theoretical value), 1290.5 (observed value). HPLC retention time: 1.56 min. Example 73. (2S,3S,4S,5R,6S)-6-(4-((((3-((5- aminoformyl -1-((E)-4-(6- aminoformyl -2-(4- ethyl -2- methylthiazol -5 - yl )-8- methoxy -9H- pyrimido [4,5-b] indol- 9- yl ) but -2- en -1- yl )-2-( 4- ethyl - 2- methylthiazol -5 -yl ) ( 5- ( 2- (3-( 2,5 - dihydroxy - 2,5 - dihydro - 1H - pyrrol - 1 - yl ) propionamido ) propionamido ) phenoxy ) -3,4,5 - trihydroxytetrahydro - 2H - pyran - 2 - carboxylic acid ( Compound 2.60 ) Synthesis of compound 52a

To a solution of compound 1.20 x 1 TFA (7.0 mg, 7.5 μmol) and compound 23 (10.8 mg, 11.0 μmol) in DMA (140 μL) was added DIPEA (7.8 μL, 45 μmol). The reaction was allowed to reach 30 °C and stirred for 16 h. LCMS analysis showed consumption of starting material and desired m/z. The crude mixture was purified by prepHPLC (Method 1). The pure fractions were collected, frozen, and lyophilized to give compound 52a (9.69 mg, 6.1 μmol, 81% yield) as a white solid. UPLC-MS (Method A, ESI+): m/z [M+H] ⁺ = 1594.6 (theoretical), 1594.6 (observed). HPLC retention time: 1.86 min. Synthesis of compound 52b

To a solution of compound 52a (9.69 mg, 6.1 μmol) in 1:1 THF:MeOH (610 μL) was added aqueous LiOH (0.2 M, 395 μL) at 0°C. The reaction was allowed to reach rt and stirred for 2 h. The reaction was quenched with AcOH and the solvent was removed under reduced pressure. The residue was purified by prepHPLC (Method 1). The pure fractions were collected, frozen, and lyophilized to give compound 52b x 1 TFA (1.6 mg, 1.3 μmol, 21% yield) as a white solid. UPLC-MS (Method A, ESI+): m/z [M+H] ⁺ = 1232.4 (theoretical value), 1232.5 (observed value). HPLC retention time: 1.46 min. Synthesis of compound 2.60

Compound 2.60 (0.9 mg, 7.0 μmol, 50% yield) was prepared following General Method 6 using compound 52b as starting material and 6.0 equiv. DIPEA. UPLC-MS (Method A, ESI+): m/z [M+H] ⁺ = 1383.5 (theoretical value), 1383.5 (observed value). HPLC retention time: 1.61 min. Example 74. (E)-N-(5- aminoformyl- 1-(4-(6- aminoformyl- 2-(4 -cyclopropyl - 2- methylthiazol -5- yl )-8- methoxy -9H- pyrimido [4,5-b] indol- 9- yl ) but-2- en - 1 - yl )-7-(3-( methylamino ) propoxy )-1H- benzo [d] imidazol -2- yl )-4- ethyl -2- methyloxazole -5- carboxamide ( Compound 1.21) Synthesis of compound 53a

A solution of 5-bromo-4-cyclopropyl-2-methyl-thiazole (2.76 g, 12.65 mmol) in THF (25 mL) was cooled to -75 °C under Ar atmosphere in an oven-dried 40 mL vial equipped with a stir bar and internal temperature monitoring. A 1.6 M solution of n -BuLi (8.3 mL, 13.29 mmol) was added dropwise to the solution, keeping the temperature between -60 and -75 °C. After the n -BuLi addition was complete, the solution was stirred for an additional 20 minutes. Triethyl borate (4.3 mL, 25.31 mmol) was then added dropwise, maintaining the temperature below -70 °C. The solution was stirred for an additional 30 minutes at below -70 °C. The dry ice/acetone bath was then replaced with an ice-water bath and the temperature was allowed to rise to 0 °C. The solution was stirred between 0 and 4 °C for another hour. Meanwhile, a 2-neck 100 mL RBF was prepared in an oil bath and equipped with a short-path water-cooled distillation head with a thermometer and a 50 mL RBF to collect the distillate. This apparatus was open to the atmosphere. MIDA (5.05 g, 37.96 mmol) and DMSO (25 mL) were added to the 2-neck flask. The internal temperature was measured and the solution was heated to 120 °C. The previous reactants were added dropwise to the hot solution of MIDA and DMSO via a syringe, maintaining the internal temperature of the solution between 110-120 °C while THF was rapidly distilled at 60-70 °C. Once the addition to the MIDA/DMSO solution was complete, the solution was cooled to 70 °C. The contents of the collection flask were discarded, and the product remaining in the RBF was placed under vacuum to remove residual DMSO. The crude yellow solid was cooled to rt and the vacuum was removed. The crude solid was dissolved in acetone (25 mL), filtered, and the solvent was removed under reduced pressure. The crude product was dissolved in acetone (5 mL) and purified by flash chromatography (SiO ₂ , Et ₂ O/MeCN) to give compound 53a (915 mg, 3.11 mmol, 25% yield) as a white solid. UPLC-MS (Method H, ESI+): m/z [M+H] ⁺ = 295.1 (theoretical value), 295.0 (observed value). HPLC retention time: 0.77 min. Synthesis of compound 53b

A 40 mL vial was charged with Pd(PPh ₃ ) ₄ (24 mg, 21.1 μmol), compound 53a (372 mg, 1.26 mmol) and compound 8b (130 mg, 421 μmol). The headspace was purged under Ar for 3 min, after which THF (5.2 mL) was added and the solution was purged for 15 min. The purged aqueous Na ₂ CO ₃ solution (2.3 M, 0.85 mL, 1.94 mmol) was transferred to the reaction vial under N _2. The reaction was sealed, brought to 100 °C and stirred for 1 h. LCMS analysis showed consumption of starting material and desired m/z. Water was added and the crude product was extracted with EtOAc (×3). The combined organic layers were washed with saturated NaHCO ₃ and brine, dried over MgSO ₄ , and concentrated. The crude product was then purified by prepHPLC (Method 1). The pure fractions were collected, frozen, and lyophilized to give compound 53b (35.2 mg, 85.6 μmol, 20% yield). UPLC-MS (Method A, ESI+): m/z [M+H] ⁺ = 412.1 (theoretical value), 412.1 (observed value). HPLC retention time: 1.76 min. Synthesis of compound 53c

Compound 53b (28 mg, 68.1 μmol), 4CzIPN (0.02 M, 0.034 mL), and PPh ₃ (44 mg, 170 μmol) were fed to an oven-dried vial. The headspace of the vial was purged with Ar for 5 min. The solid was then dissolved in THF (3.4 mL). The solution was purged with Ar for 30 min. The vial was sealed and placed in a photoreactor equipped with a blue LED (365 nm) for 24 h. The crude mixture was poured into water and extracted with EtOAc. The combined organics were washed with saturated NaHCO ₃ and brine, dried over MgSO ₄ , filtered, and concentrated. The residue was then purified by flash chromatography (SiO ₂ , DCM/MeOH) to give compound 53c (11.7 mg, 30.8 μmol, 45% yield). UPLC-MS (Method A, ESI+): m/z [M+H] ⁺ = 380.1 (theoretical value), 380.1 (observed value). HPLC retention time: 1.49 min. Synthesis of compound 53d

A solution of compound 53c (5.98 mg, 15.8 μmol), compound 30 (13.9 mg, 23.7 μmol) and Cs ₂ CO ₃ (15.4 mg, 47.4 μmol) in DMF (320 μL) was brought to 55 °C and stirred for 16 h. LCMS analysis showed consumption of starting material and desired m/z. The reaction was filtered and purified by prepHPLC (Method 1). The fractions were collected, frozen, and lyophilized to give compound 53d (7.7 mg, 8.3 μmol, 52% yield) as a white solid. UPLC-MS (Method A, ESI+): m/z [M+H] ⁺ = 932.4 (theoretical value), 932.4 (observed value). HPLC retention time: 1.71 min. Synthesis of compound 1.21

A solution of compound 53d (7.7 mg, 8.3 μmol) in DCM (165 μL) containing 20% TFA (v/v) was stirred at 23 °C for 2 h. LCMS analysis showed consumption of starting material and desired m/z. The solvent was removed under reduced pressure and the crude product was purified by prepHPLC (Method 1). The fractions were collected, frozen, and lyophilized to give compound 1.21 x 1 TFA (5.5 mg, 6.6 μmol, 80% yield) as a white solid. UPLC-MS (Method A, ESI+): m/z [M+H] ⁺ = 832.3 (theoretical value), 832.3 (observed value). HPLC retention time: 1.45 min. Example 75. (E)-N-(5- aminoformyl- 1-(4-(6- aminoformyl- 2-(4 -cyclopropyl -2- methylthiazol -5- yl )-8- methoxy -9H- pyrimido [4,5-b] indol- 9- yl ) but- 2 -en-1- yl ) -7- (3-(3-(2,5- dioxo -2,5- dihydro -1H -pyrrol -1- yl )-N -methylpropionamido ) propoxy )-1H- benzo [d] imidazol -2 - yl )-4- ethyl -2- methyloxazole -5- carboxamide ( Compound 2.61)

To a solution of compound 1.21 x 1 TFA (3.44 mg, 3.64 μmol) and MP-OSu (1.92 mg, 7.2 μmol) in DMA (180 μL) was added DIPEA (3.8 μL, 22 μmol). The solution was allowed to reach 25 °C and stirred for 1 h. LCMS analysis showed consumption of starting material and desired m/z. The crude mixture was purified by prepHPLC (Method 1). The pure fractions were collected, frozen, and lyophilized to give compound 2.61 (1.55 mg, 1.6 μmol, 44% yield) as a white solid. UPLC-MS (Method A, ESI+): m/z [M+H] ⁺ = 983.4 (theoretical), 983.4 (observed). HPLC retention time: 1.53 min. Example 76. (3-((5- aminoformyl- 1-((E)-4-(6- aminoformyl- 2-(4- cyclopropyl -2- methylthiazol -5- yl )-8- methoxy -9H- pyrimido [4,5-b] indol -9- yl ) but- 2- en - 1 - yl )-2-(4- ethyl - 2- methyloxazole -5 -carboxamido )-1H- benzo [d] imidazol -7- yl ) oxy ) propyl )( methyl ) carbamate 4-((S)-2-((S)-2-(3-(2,5- dihydroxy - 2,5 -dihydro -1H - pyrrol- 1- yl ) propionamido )-3 -methylbutanamido ) propionamido ) benzyl ester ( Compound 2.62)

To a solution of compound 1.21 x 1 TFA (3.0 mg, 3.6 μmol) and MP-Val-Ala-PAB-Opfp (4.7 mg, 7.2 μmol) in DMF (360 μL) was added DIPEA (5.4 μL, 31 μmol). The reaction was allowed to reach 25 °C and stirred for 1 h. LCMS analysis showed consumption of starting material and the desired m/z. The crude product was directly purified by prepHPLC (Method 1). The fractions were collected, frozen, and lyophilized to give compound 2.62 (2.25 mg, 1.7 μmol, 48% yield) as a white solid. UPLC-MS (Method A, ESI+): m/z [M+H] ⁺ = 1302.5 (theoretical), 1302.5 (observed). HPLC retention time: 1.77 min. Example 77. (2S,3S,4S,5R,6S)-6-(4-((((3-((5- aminoformyl- 1-((E)-4-(6- aminoformyl- 2-(4 -cyclopropyl -2- methylthiazol - 5- yl )-8- methoxy -9H- pyrimido [4,5-b] indol- 9- yl ) but-2- en - 1 - yl )-2-(4- ethyl -2- methyloxazol -5- carboxamido )-1H- benzo [d] imidazol -7- yl ) oxy ) propyl )( methyl ) aminocarboxamido ) oxy ) methyl )-2-(3-(3-(2,5- dihydroxy -2,5- dihydro -1H -pyrrol -1- yl ) propionamido ) propionamido ) phenoxy )-3,4,5- trihydroxytetrahydro -2H- pyran -2-carboxylic acid ( Compound 2.63) Synthesis of compound 54a

To a solution of compound 1.21 x 1 TFA (6.69 mg, 7.1 μmol) and compound 23 (6.7 mg, 7.1 μmol) in DMA (142 μL) was added DIPEA (7.4 μL, 43 μmol). The solution was allowed to reach 30 °C and stirred for 16 h. LCMS analysis showed consumption of starting material and the desired m/z. The crude mixture was directly purified by prepHPLC (Method 1). The pure fractions were collected, frozen, and lyophilized to give compound 54a (4.62 mg, 2.9 μmol, 41% yield) as a white solid. UPLC-Ms (Method A, ESI+): m/z [M+H] ⁺ = 1606.6 (theoretical value), 1606.5 (observed value). HPLC retention time: 1.88 min. Synthesis of compound 54b

A solution of compound 54a (4.62 mg, 2.9 μmol) in 1:1 THF:MeOH (150 μL) was placed in an ice bath at 0 °C and aqueous LiOH (0.2 M, 143 μL) was added. The reaction was allowed to warm to rt and stirred for 3 h. LCMS analysis showed consumption of starting material and the desired m/z. The solvent was removed under reduced pressure and the crude product was purified by prepHPLC (Method 1). The pure fractions were collected, frozen, and lyophilized to give compound 54b x 1 TFA (2.9 mg, 2.1 μmol, 74% yield) as a white solid. UPLC-MS (Method A, ESI+): m/z [M+H] ⁺ = 1244.4 (theoretical), 1244.4 (observed). HPLC retention time: 1.43 min. Synthesis of compound 2.63

To a solution of compound 54b x 1 TFA (2.9 mg, 2.1 μmol) and MP-OSu (1.1 mg, 4.3 μmol) was added DIPEA (2.2 μL, 12.8 μmol). The reaction was stirred at rt for 1 h. LCMS analysis showed consumption of starting material and desired m/z. The crude mixture was purified by prepHPLC (Method 1). The pure fractions were collected, frozen, and lyophilized to give compound 2.63 (1.4 mg, 1 μmol, 47% yield) as a white solid. UPLC-MS (Method A, ESI+): m/z [M+H] ⁺ = 1395.5 (theoretical), 1395.5 (observed). HPLC retention time: 1.45 min. Example 78. (E)-8-(2-( Azocyclobutane -3- yl ) ethoxy )-9-(4-(5- aminoformyl- 2-(1- ethyl -3- methyl -1H -pyrazole - 5-carboxamido )-7- methoxy -1H- benzo [d] imidazol -1- yl ) but - 2- en -1- yl )-2-(1- ethyl -3- methyl -1H -pyrazole -5- yl )-9H- pyrimido [4,5-b] indole -6- carboxamide ( Compound 1.18) Synthesis of compound 55a

To a solution of 6d (35 g, 107.52 mmol) in 1-butanol (160 mL) was added DIPEA (50 mL, 286.72 mmol), _Na2CO3 (15.19 g, 143.36 mmol) and compound 6f (16.53 g, 71.68 mol) at 20 °C. The mixture was brought to 115 °C and stirred for 48 _h . LCMS analysis showed consumption of starting material and desired m/z. Another reaction was prepared as described and combined for purification. The mixture was cooled to 25 °C and MeCN was added. The mixture was filtered and concentrated to give a residue. The crude product was triturated with hexanes/EtOAc (2:1) for 10 min. Compound 55a (60 g, 115.46 mmol, 81% yield) was obtained as a red solid. UPLC-MS (method L, ESI+): m/z [M+H] ⁺ = 520.2 (theoretical value), 520.3 (observed value). HPLC retention time: 0.657 min. Synthesis of Compound 55b

To a solution of compound 55a (7 g, 13.47 mmol) in MeOH (245 mL) was added a solution of Na ₂ S ₂ O ₄ (23.45 g, 134.70 mmol) in H ₂ O (70 mL) at 0° C., followed immediately by the addition of NH ₄ OH (35 mL). The mixture was warmed to 25° C. and stirred for _{16 h. LCMS analysis showed consumption of starting material and desired m/z. The reaction was diluted with water and extracted with EtOAc (3×300 mL). The combined organic phases were washed with brine (3×300 mL), dried over Na 2} SO ₄ , and concentrated to give a red solid residue, compound 55b (6 g, crude), which was used in the next step without further purification. UPLC-MS (method L, ESI+): m/z [M+H] ⁺ = 490.3 (theoretical value), 490.3 (observed value). HPLC retention time: 0.490 min. Synthesis of compound 55c

To a solution of compound 55b (31 g, 37.98 mmol) in DCM (230 mL) and MeOH (230 mL) was added CNBr (12.44 g, 117.45 mmol) at 25 °C and stirred for 16 h. LCMS analysis showed consumption of starting material and desired m/z. The mixture was concentrated to give a residue. The residue was triturated with MeOH (80 mL) and poured into MTBE (500 mL). The solution was filtered and the filter cake was washed with MTBE (30 mL) to give compound 55c (23.56 g, crude) as an orange solid. UPLC-MS (Method L, ESI+): m/z [M+H] ⁺ = 515.2 (theoretical), 515.3 (observed). HPLC retention time: 0.487 min. Synthesis of compound 55d

To a solution of compound 2a (3.37 g, 21.86 mmol) in DMF (120 mL) at 25 °C was added HBTU (9.39 g, 24.77 mmol) and DIPEA (18 mL, 102 mmol). The mixture was heated to 60 °C and stirred for 30 min. The mixture was cooled to 25 °C and then compound 55c (7.5 g, 14.57 mmol) was added. The reaction was returned to 60 °C and stirred for 16 h. LCMS analysis showed consumption of starting material and the desired m/z. The reaction was diluted with 1 M HCl (200 mL) and the organic phase was extracted with EtOAc (3×80 mL). The organic phases were combined and washed with water (3×80 mL), dried over Na ₂ SO ₄ , and concentrated to give a residue. The residue was purified by column chromatography (SiO ₂ , Hex:EtOAc) to give compound 55d (8 g, 12.29 mmol, 42% yield) as a yellow solid. UPLC-MS (Method L, ESI+): m/z [M+H] ⁺ = 651.3 (theoretical value), 651.4 (observed value). HPLC retention time: 0.624 min. Synthesis of compound 55e

To a solution of compound 55d (3 g, 4.61 mmol) in MeOH (306 mL), DCM (36 mL) and H ₂ O (18 mL) was added LiOH.H ₂ O (6.77 g, 161.33 mmol) at 25 °C. The mixture was allowed to reach 40 °C and stirred for 48 h. LCMS analysis showed consumption of starting material and desired m/z. The organic solvent was removed under reduced pressure and the residue was filtered. The filter cake was washed with hexane:EtOAc (5:1, 50 mL) and MeCN (50 mL) to give compound 55e (3 g, crude) as a white solid. UPLC-MS (Method D, ESI+): m/z [M+H] ⁺ = 413.2 (theoretical), 413.2 (observed). HPLC retention time: 1.267 min. Synthesis of compound 55f

To a solution of compound 55e (2.2 g, 5.34 mmol) in DCM (220 mL) at 0 °C were added NCS (2.14 g, 16.00 mmol) and PPh ₃ (4.10 g, 16.00 mmol). The mixture was allowed to reach 20 °C and stirred for 1 h. LCMS analysis showed consumption of starting material and desired m/z. The solution was concentrated under reduced pressure and the residue was purified by flash chromatography (SiO ₂ , DCM/MeOH) to give compound 55f (2.14 g, 4.97 mmol, 53% yield) as a brown solid. UPLC-MS (Method C, ESI+): m/z [M + H] ⁺ = 431.2 (theoretical), 431.1 (observed). HPLC retention time: 1.809 min. ¹ H NMR (400MHz, DMSO- d ₆ ) δ ppm 8.03 (br s, 1H), 7.67 (d, J = 0.6 Hz, 1H), 7.41 (s, 1H), 7.36 (br s, 1H), 6.67 (s, 1H), 6.03 (td, J = 5.6, 15.2 Hz, 1H), 5.81 - 5.62 (m, 1H), 4.98 (br d, J = 5.2 Hz, 2H), 4.60 (q, J = 7.2 Hz, 2H), 4.19 (br d, J = 6.8 Hz, 2H), 3.97 (s, 3H), 2.17 (s, 3H), 1.34 (t, J = 7.2 Hz, 3H) Synthesized compound 55g

A solution of compound 3 (50 mg, 96.2 μmol), compound 55f (62.19 mg, 144.3 μmol) and Cs ₂ CO ₃ (156.76 mg, 481.1 μmol) in DMF (962 μL) was brought to 55 °C and stirred for 16 h. LCMS analysis showed consumption of starting material and desired m/z. The mixture was filtered and the filtrate was concentrated by prepHPLC (Method 1). The fractions were collected, frozen, and lyophilized to give compound 55g (62.01 mg, 678 μmol, 71% yield) as a white solid. UPLC-MS (Method A, ESI+): m/z [M+H] ⁺ = 914.4 (theoretical), 914.5 (observed). HPLC retention time: 1.73 min. Synthesis of compound 1.18

A solution of compound 55g (2.01 mg, 67.8 μmol) in MeCN (678 μL) containing 30% TFA (v/v) was brought to 30 °C and stirred for 1 h. LCMS analysis showed consumption of starting material and desired m/z. The solvent was removed under reduced pressure and the residue was purified by prepHPLC (Method 1). The pure fractions were collected, frozen, and lyophilized to give compound 1.18 x 1 TFA (42.48 mg, 52.2 μmol, 77% yield). UPLC-MS (Method A, ESI+): m/z [M+H] ⁺ = 814.4 (theoretical value), 814.4 (observed value). HPLC retention time: 1.41 min. Example 79. (E)-9-(4-(5- aminoformyl- 2-(1- ethyl -3- methyl -1H -pyrazol -5 -carboxamido )-7- methoxy -1H- benzo [d] imidazol -1 - yl ) but - 2- en - 1- yl )-8-(2-(1-(3-(2,5- dioxo -2,5- dihydro -1H - pyrrol - 1 -yl ) propanoyl ) azinecyclobutane -3- yl ) ethoxy )-2-(1- ethyl -3- methyl -1H -pyrazol -5- yl )-9H -pyrimido [4,5-b] indole -6- carboxamide ( Compound 2.52)

Compound 2.52 (12.48 mg, 12.9 μmol, 80% yield) was prepared following General Method 1 using compound 1.18 x 1 TFA (15 mg, 16.2 μmol) as starting material. UPLC-MS (Method A, ESI+): m/z [M+H] ⁺ = 965.4 (theoretical value), 966.0 (observed value). HPLC retention time: 1.60 min. Example 80. S-(1-(3-(3-(2-((6- aminoformyl -9-((E)-4-(5- aminoformyl- 2-(1- ethyl -3- methyl -1H -pyrazol- 5 -carboxamido )-7- methoxy - 1H- benzo [d] imidazol -1- yl ) but - 2- en -1- yl )-2-(1- ethyl -3- methyl -1H -pyrazol -5- yl )-9H- pyrimido [4,5-b] indol- 8- yl ) oxy ) ethyl ) azinecyclobutane -1- yl )-3 - oxopropyl )-2,5 -dioxopyrrolidin -3- yl )-L- cysteine ( Compound 3.18)

Compound 3.18 x 1 TFA (4.94 mg, 4.12 μmol, 88% yield) was prepared following General Method 2 using compound 2.52 (5 mg, 5.2 μmol) as starting material. UPLC-MS (Method A, ESI+): m/z [M+H] ⁺ = 1086.4 (theoretical), 1086.5 (observed). HPLC retention time: 1.38 min Example 81. 3-(2-((6- aminoformyl- 9-((E)-4-(5- aminoformyl -2-(1- ethyl -3- methyl -1H -pyrazol -5 -carboxamido )-7- methoxy -1H- benzo [d] imidazol -1- yl ) but - 2- en - 1- yl )-2-(1- ethyl -3- methyl -1H -pyrazol -5- yl )-9H- pyrimido [4,5-b] indol- 8- yl ) oxy ) ethyl ) azinecyclobutane -1- carboxylic acid 4-((S)-2-((S)-2-(3-(2,5- dioxo -2,5- dihydro - 1H -pyrrol -1- yl ) propionamido )-3 -methylbutanamido ) propionamido ) benzyl ester ( Compound 2.53)

Compound 2.53 (4.99 mg, 3.9 μmol, 72% yield) was prepared following General Method 3 using compound 1.18 x 1 TFA (5 mg, 5.4 μmol) as starting material. UPLC-MS (Method A, ESI+): m/z [M+H] ⁺ = 1284.6 (theoretical), 1285.2 (observed). HPLC retention time: 1.72 min. Example 82. 3-(2-((6- aminoformyl- 9-((E)-4-(5- aminoformyl -2-(1- ethyl -3- methyl -1H -pyrazol -5 -carboxamido )-7- methoxy -1H- benzo [d] imidazol -1- yl ) but -2- en - 1 - yl )-2-(1- ethyl -3- methyl - 1H -pyrazol -5- yl )-9H- pyrimido [4,5-b] indol- 8- yl ) oxy 4-(((2S,3R,4S,5S,6S)-6-((15- oxoalkylene ) methyl ) -3,4,5 - trihydroxytetrahydro - 2H - pyran - 2- yl ) oxy )-3-(3-(3-(2,5- dihydroxy - 2,5 - dihydro -1H -pyrrol -1- yl ) propionamido ) propionamido ) benzyl ester ( Compound 2.54) Synthesis of compound 56a

Compound 56a (40.75 mg, crude) was prepared following General Method 4 using compound 1.18 x 1 TFA (22.48 mg, 24.2 μmol) as starting material. UPLC-MS (Method A, ESI+): m/z [M+H] ⁺ = 1588.6 (theoretical), 1588.7 (observed). HPLC retention time: 1.85 min. Synthesis of Compound 56b

Following General Method 7, Compound 56b x 1 TFA (11.16 mg, 8.3 μmol, 32% yield) was prepared using Compound 56a (40.75 mg, crude) as starting material. UPLC-MS (Method A, ESI+): m/z [M+H] ⁺ = 1226.5 (theoretical value), 1226.6 (observed value). HPLC retention time: 1.39 min. Synthesis of Compound 2.54

Compound 2.54 (7.79 mg, 5.7 μmol, 68% yield) was prepared following General Method 6 using compound 56b x 1 TFA (11.16 mg, 8.3 μmol) as starting material. UPLC-MS (Method A, ESI+): m/z [M+H] ⁺ = 1377.5 (theoretical value), 1377.6 (observed value). HPLC retention time: 1.40 min. Example 83. (E)-8-(2-( Azocyclobutane -3- yl ) ethoxy )-9-(4-(5- aminoformyl- 2-(1- ethyl -3- methyl -1H -pyrazol - 5-carboxamido )-7- methoxy -1H- benzo [d] imidazol -1- yl ) but - 2- en -1- yl )-2-(1- ethyl -3- methyl -1H -pyrazol -5- yl )-9H- pyrimido [4,5-b] indole -6- carboxamide ( Compound 1.16) Synthesis of compound 57a

To a solution of compound 1g (2.5 g, 16.12 mmol) in THF (50 mL) was added oxalyl chloride (2.1 mL, 24.18 mmol) and a catalytic amount of DMF (23.8 μL, 309.3 μmol) at 0°C under _N2 atmosphere. The mixture was slowly warmed to 25°C and stirred for 1 h. TLC (hexane/EtOAc, _Rf = 0.8) showed that the reaction was complete. The solvent was removed under reduced pressure, and the crude yellow oil was dissolved in anhydrous acetone (40 mL). The mixture was cooled to 0°C, and acetone (40 mL) containing KSCN (3.00 g, 30.93 mmol) was added dropwise at 0°C. The mixture was slowly warmed to 25°C and stirred for 3 h. TLC (hexane/EtOAc, R _f = 0.4) showed the reaction was complete. The mixture was concentrated under reduced pressure and the residue was purified by column chromatography (SiO ₂ , hexane/EtOAc) to give compound 57a (1.5 g, 7.65 mmol, 50% yield) as a yellow oil. Synthesis of compound 57b

To a solution of compound 55b (6.00 g, 7.35 mmol) in DMF (60 mL) at 0°C were added compound 57a (1.5 g, 7.65 mmol), DIPEA (2.67 mL, 15.5 mmol) and HATU (3.21 g, 8.4 mmol). The reaction mixture was warmed to 25°C and stirred for 16 h. LCMS analysis showed consumption of starting material and the desired m/z. The mixture was quenched by adding to ice water (500 mL) and filtered to give a residue. The residue was triturated with MeOH at 25°C for 30 min to give compound 57b (6.7 g, crude) as a red solid. UPLC-MS (method N, ESI+): m/z [M+H] ⁺ = 652.3 (theoretical value), 652.2 (observed value). HPLC retention time: 0.668 min. Synthesis of compound 57c

To a solution of compound 57b (6.6 g, 10.14 mmol) in MeOH (300 mL), DCM (36 mL) and H ₂ O (18 mL) was added LiOH.H ₂ O (14.88 g, 354.39 mmol) at 25°C. The mixture was allowed to reach 40°C and stirred for 48 h. LCMS analysis showed consumption of starting material and desired m/z. The mixture was quenched by addition of NH ₄ Cl to pH = 8 at 25°C. The mixture was filtered to give a residue, which was washed with water and then triturated with EtOAc at 25°C for 30 min to give compound 57c (2.4 g, 5.8 mmol, crude) as a yellow solid. UPLC-MS (method L, ESI+): m/z [M+H] ⁺ = 414.2 (theoretical value), 414.2 (observed value). HPLC retention time: 0.333 min. Synthesis of compound 57d

To a solution of compound 57c (2.4 g, 5.8 mmol) in DCM (240 mL) was added NCS (2.26 g, 17.4 mmol) and PPh ₃ (4.46 g, 16.98 mmol) at 0 °C under N ₂ atmosphere. The mixture was slowly warmed to 25 °C and stirred for 16 h. LCMS analysis showed consumption of starting material and desired m/z. The mixture was filtered to give a residue. The residue was triturated with EtOAc at 25 °C for 30 min to give compound 57d (1.2 g, 2.78 mmol, 50% yield) as a white solid. UPLC-MS (Method C, ESI+): m/z [M+H] ⁺ = 432.1 (theoretical value), 432.1 (observed value). HPLC retention time: 2.276 min. ¹ H NMR (400MHz, DMSO- d ₆ ) δ ppm 12.77 (br s, 1H), 7.99 (br s, 1H), 7.66 (s, 1H), 7.39 (s, 1H), 7.35 (br s, 1H), 6.12 - 5.95 (m, 1H), 5.76 - 5.61 (m, 1H), 4.96 (br d, J = 5.2 Hz, 2H), 4.19 (br d, J = 6.8 Hz, 2H), 3.96 (s, 3H), 2.98 (q, J = 7.6 Hz, 2H), 2.44 (s, 3H), 1.19 (t, J = 7.6 Hz, 3H). Synthesis of compound 57e

A solution of compound 3 (50 mg, 96.2 μmol), compound 57d (62.33 mg, 144.3 μmol) and Cs ₂ CO ₃ (156.76 mg, 481.1 μmol) in DMF (1 mL) was brought to 55 °C and stirred for 16 h. LCMS analysis showed consumption of starting material and desired m/z. The mixture was filtered and the filtrate was purified by prepHPLC (Method 1). The fractions were collected, frozen, and lyophilized to give compound 57e (57.8 mg, 63.2 μmol, 66% yield) as a white solid. UPLC-MS (Method A, ESI+): m/z [M+H] ⁺ = 915.4 (theoretical value), 915.5 (observed value). HPLC retention time: 1.66 min. Synthesis of compound 1.16

A solution of compound 57e (57.8 mg, 63.2 μmol) in MeCN (632 μL) containing 20% TFA (v/v) was brought to 30 °C and stirred for 1 h. LCMS analysis showed consumption of starting material and desired m/z. The solvent was removed under reduced pressure and the residue was purified by prepHPLC (Method 1). The pure fractions were collected, frozen, and lyophilized to give compound 1.16 x 1 TFA (42.19 mg, 51.8 μmol, 82% yield) as a white solid. UPLC-MS (Method A, ESI+): m/z [M+H] ⁺ = 815.4 (theoretical), 815.4 (observed). HPLC retention time: 1.41 min. Example 84. (E)-N-(5- aminoformyl- 1-(4-(6- aminoformyl- 8-(2-(1-(3-(2,5-dioxo - 2,5- dihydro -1H -pyrrol -1- yl ) propanoyl ) azinecyclobutane -3- yl ) ethoxy )-2-(1- ethyl -3- methyl -1H -pyrazol -5 -yl )-9H- pyrimido [4,5-b] indol- 9- yl ) but - 2- en-1-yl ) -7- methoxy -1H- benzo [d] imidazol - 2- yl )-4- ethyl -2- methyloxazole -5- carboxamide ( Compound 2.46)

Compound 2.46 (11.74 mg, 12.2 μmol, 75% yield) was prepared following General Method 1 using compound 1.16 x 1 TFA (15 mg, 16.1 μmol) as starting material. UPLC-MS (Method A, ESI+): m/z [M+H] ⁺ = 966.4 (theoretical value), 966.9 (observed value). HPLC retention time: 1.53 min. Example 85. S-(1-(3-(3-(2-((6- aminoformyl -9-((E)-4-(5- aminoformyl -2-(4- ethyl -2- methyloxazole -5 -carboxamido )-7- methoxy -1H- benzo [d] imidazol -1- yl ) but - 2- en -1- yl )-2-(1- ethyl -3- methyl -1H -pyrazol -5- yl )-9H- pyrimido [4,5-b] indol- 8- yl ) oxy ) ethyl ) azinecyclobutane -1- yl )-3- oxopropyl )-2,5 -dioxopyrrolidin -3- yl )-L- cysteine ( Compound 3.16)

Compound 3.16 x 1 TFA (5.00 mg, 4.6 μmol, 89% yield) was prepared following General Method 2 using compound 2.46 (5 mg, 5.2 μmol) as starting material. UPLC-MS (Method A, ESI+): m/z [M+H] ⁺ = 1087.4 (theoretical value), 1087.5 (observed value). HPLC retention time: 1.36 min. Example 86. 3-(2-((6- aminoformyl- 9-((E)-4-(5- aminoformyl -2-(4- ethyl -2- methyloxazole -5 -carboxamido )-7- methoxy -1H- benzo [d] imidazol - 1- yl ) but - 2- en-1-yl ) -2-(1- ethyl -3- methyl -1H -pyrazol -5- yl )-9H- pyrimido [4,5-b] indol- 8- yl ) oxy ) ethyl ) azinecyclobutane -1- carboxylic acid 4-((S)-2-((S)-2-(3-(2,5- dioxo -2,5- dihydro -1H -pyrrol -1- yl ) propionamido )-3 -methylbutanamido ) propionamido ) benzyl ester ( Compound 2.47)

Compound 2.47 (5.06 mg, 3.9 μmol, 73% yield) was prepared following General Method 3 using compound 1.16 x 1 TFA (5 mg, 5.4 μmol) as starting material. UPLC-MS (Method A, ESI+): m/z [M+H] ⁺ = 1285.5 (theoretical), 1086.2 (observed). HPLC retention time: 1.65 min. Example 87. (2S,3S,4S,5R,6S)-6-(4-(((3-(2-((6- aminoformyl- 9-((E)-4-(5- aminoformyl -2-(4- ethyl -2 -methyloxazol - 5 -carboxamido )-7- methoxy -1H- benzo [d] imidazol -1- yl ) but -2- en -1 - yl )-2-(1- ethyl -3- methyl -1H - pyrazole- (5- yl )-9H- pyrimido [4,5-b] indol- 8- yl ) oxy ) ethyl ) azacyclobutane -1- carbonyl ) oxy ) methyl )-2-(3-(3-(2,5- dioxo -2,5 - dihydro -1H - pyrrol- 1- yl ) propionamido ) propionamido ) phenoxy )-3,4,5- trihydroxytetrahydro -2H- pyran -2-carboxylic acid ( Compound 2.48) Synthesis of compound 58a

Compound 58a (50.55 mg, crude) was prepared following General Method 4 using compound 1.16 x 1 TFA (179 mg, 19.3 μmol) as starting material. UPLC-MS (Method A, ESI+): m/z [M+H] ⁺ = 1589.7 (theoretical value), 1589.7 (observed value). HPLC retention time: 1.81 min. Synthesis of Compound 58b

Following General Method 7, Compound 58b x 1 TFA (8.06 mg, 6.0 μmol, 19% yield) was prepared using Compound 58a (50.55 mg, crude) as starting material. UPLC-MS (Method A, ESI+): m/z [M+H] ⁺ = 1227.5 (theoretical value), 1227.5 (observed value). HPLC retention time: 1.36 min. Synthesis of Compound 2.48

Compound 2.48 (4.01 mg, 2.9 μmol, 48% yield) was prepared following General Method 6 using compound 58b x 1 TFA (8.06 mg, 6.0 μmol) as starting material. UPLC-MS (Method A, ESI+): m/z [M+H] ⁺ = 1378.5 (theoretical value), 1378.6 (observed value). HPLC retention time: 1.39 min. Example 88. (E)-N-(1-(4-(8-(2-( Azocyclobutane -3- yl ) ethoxy )-6 -aminoformyl- 2-(1- ethyl -3- methyl -1H -pyrazol -5 - yl )-9H- pyrimido [4,5-b] indol- 9- yl ) but- 2 - en-1-yl ) -5 - aminoformyl -7- methoxy -1H- benzo [d] imidazol -2- yl )-4- ethyl -2- methylthiazole -5- carboxamide ( Compound 1.17) Synthesis of compound 59a

To a solution of 4-ethyl-2-methylthiazole-5-carboxamide (3.70 g, 21.63 mmol) in DMF (230 mL) at 25 °C was added HBTU (9.30 g, 24.52 mmol) and DIPEA (17.6 mL, 100.95 mmol). The mixture was heated to 60 °C and stirred for 30 min. Compound 55c (7.42 g, 14.42 mmol) was then added to the reaction at 25 °C. The reaction was allowed to reach 60 °C and stirred for 16 h. LCMS analysis showed consumption of starting material and desired m/z. A second reaction was prepared as described and combined for work-up and purification. The solution was diluted with aqueous HCl (1 M, 200 mL) and extracted with EtOAc (3 x 60 mL). The combined organics were washed with water (3×200 mL), dried over Na ₂ SO ₄ , and concentrated to yield a residue. The residue was purified by column chromatography (SiO ₂ , hexane/EtOAc) to afford compound 59a (15.13 g, 22.65 mmol, 79% yield) as a yellow solid. UPLC-MS (Method L, ESI+): m/z [M+H] ⁺ = 668.3 (theoretical value), 668.4 (observed value). HPLC retention time: 0.608 min. ¹ H NMR (400MHz, DMSO- d ₆ ) δ ppm 12.82 (s, 1H), 7.95 (s, 2H), 7.67 (d, J = 1.1 Hz, 1H), 7.55 - 7.49 (m, 4H), 7.40 - 7.34 (m, 4H), 7.32 - 7.25 (m, 4H), 6.00 - 5.90 (m, 1H), 5.82 - 5.72 (m, 1H), 4.91 (br d, J = 5.8 Hz, 2H), 4.17 (br d, J = 2.8 Hz, 2H), 3.94 (s, 3H), 3.19 (d, J = 7.6 Hz, 2H), 2.56 (s, 3H), 1.21 (t, J = 7.5 Hz, 3H), 0.91 (s, 9H). Synthesis of compound 59b

To a solution of compound 59a (10.62 g, 15.9 mmol) in MeOH (500 mL), DCM (30 mL) and H ₂ O (15 mL) was added LiOH.H ₂ O (23.35 g, 556.53 mmol) at 20°C. The mixture was allowed to reach 40°C and stirred for 48 h. LCMS analysis showed consumption of starting material and desired m/z. The organic solvent was removed under reduced pressure and the residue was filtered. The filter cake was washed with hexane/EtOAc (4:1, 50 mL) and MeCN (50 mL) to give compound 59b (8.5 g, crude) as a white solid. UPLC-MS (Method L, ESI+): m/z [M+H] ⁺ = 430.2 (theoretical), 430.2 (observed). HPLC retention time: 0.342 min. ¹ H NMR (400MHz, DMSO- d ₆ ) δ ppm 8.01 - 7.69 (m, 1H), 7.47 (br s, 1H), 7.17 (br s, 1H), 7.08 (br s, 1H), 5.86 - 5.72 (m, 1H), 5.70 - 5.56 (m, 1H), 4.93 (br d, J = 4.1 Hz, 2H), 4.66 (br s, 1H), 3.92 (s, 3H), 3.87 (br s, 2H), 3.26 - 3.14 (m, 3H), 2.55 (s, 3H), 1.21 (br t, J = 7.1 Hz, 3H). Synthesis of compound 59c

To a solution of compound 59b (3.00 g, 6.98 mmol) in DCM (300 mL) at 0°C under _N2 atmosphere was added NCS (2.80 g, 20.95 mmol) and _PPh3 (5.50 g, 20.95 mmol). The reaction was stirred at 0°C for 30 min, then slowly warmed to 25°C and stirred for another 30 min. LCMS analysis showed consumption of starting material and desired m/z. The mixture was concentrated under reduced pressure and the crude product was purified by column chromatography ( _SiO2 , hexanes/EtOAc) to give compound 59c (1.88 g, 4.20 mmol, 60% yield) as a brown solid. UPLC-MS (Method C, ESI+): m/z [M+H] ⁺ = 448.1 (theoretical value), 448.1 (observed value). HPLC retention time: 2.212 min. ¹ H NMR (400MHz, DMSO- d ₆ ) δ ppm 12.82 (br s, 1H), 8.05 (br s, 1H), 7.65 (s, 1H), 7.41 (s, 1H), 7.35 (br s, 1H), 6.02 (td, J = 5.8, 15.1 Hz, 1H), 5.81 - 5.69 (m, 1H), 4.92 (br d, J = 5.4 Hz, 2H), 4.19 (d, J = 6.9 Hz, 2H), 3.97 (s, 3H), 3.23 - 3.17 (m, 2H), 2.60 (s, 3H), 1.22 (t, J = 7.4 Hz, 3H). Synthesis of compound 59d

A solution of compound 3 (50 mg, 96.2 μmol), compound 59c (64.66 mg, 1443 μmol) and Cs ₂ CO ₃ (156.76 mg, 481.1 μmol) in DMF (1 mL) was brought to 55 °C and stirred for 16 h. LCMS analysis showed consumption of starting material and desired m/z. The mixture was filtered and the filtrate was purified by prepHPLC (Method 1). The fractions were collected, frozen, and lyophilized to give compound 59d (58.04 mg, 62.3 μmol, 65% yield) as a white solid. UPLC-MS (Method A, ESI+): m/z [M+H] ⁺ = 931.4 (theoretical value), 931.4 (observed value). HPLC retention time: 1.73 min. Synthesis of compound 1.17

A solution of compound 59d (58.04 mg, 62.3 μmol) in MeCN (623 μL) containing 20% TFA (v/v) was brought to 30 °C and stirred for 1 h. LCMS analysis showed consumption of starting material and desired m/z. The solvent was removed under reduced pressure and the residue was purified by prepHPLC (Method 1). The pure fractions were collected, frozen, and lyophilized to give compound 1.17 x 1 TFA (39.09 mg, 47 μmol, 75% yield) as a white solid. UPLC-MS (Method A, ESI+): m/z [M+H] ⁺ = 831.3 (theoretical), 831.4 (observed). HPLC retention time: 1.46 min. Example 89. (E)-N-(5- aminoformyl- 1-(4-(6- aminoformyl- 8-(2-(1-(3-(2,5-dioxo - 2,5- dihydro -1H -pyrrol -1- yl ) propanoyl ) azinecyclobutane -3- yl ) ethoxy )-2-(1- ethyl -3- methyl -1H -pyrazol -5 -yl )-9H- pyrimido [4,5-b] indol- 9- yl ) but - 2- en-1-yl ) -7 - methoxy -1H- benzo [d] imidazol - 2- yl )-4- ethyl -2- methylthiazole -5- carboxamide ( Compound 2.49)

Compound 2.49 (13.05 mg, 13.3 μmol, 84% yield) was prepared following General Method 1 using compound 1.17 x 1 TFA (15 mg, 15.9 μmol) as starting material. UPLC-MS (Method A, ESI+): m/z [M+H] ⁺ = 982.4 (theoretical value), 983.8 (observed value). HPLC retention time: 1.60 min. Example 90. S-(1-(3-(3-(2-((6- aminoformyl- 9-((E)-4-(5- aminoformyl- 2-(4- ethyl -2- methylthiazole -5 -carboxamido )-7- methoxy -1H- benzo [d] imidazol -1- yl ) but - 2- en -1- yl )-2-(1- ethyl -3- methyl -1H -pyrazol -5- yl )-9H- pyrimido [4,5-b] indol- 8- yl ) oxy ) ethyl ) azinecyclobutane -1- yl )-3 -oxopropyl )-2,5 -dioxopyrrolidin -3- yl )-L- cysteine ( Compound 3.17)

Compound 3.17 x 1 TFA (4.71 mg, 4.3 μmol, 84% yield) was prepared following General Method 2 using compound 2.49 (5 mg, 5.1 μmol) as starting material. UPLC-MS (Method A, ESI+): m/z [M+H] ⁺ = 1103.4 (theoretical value), 1103.4 (observed value). HPLC retention time: 1.39 min. Example 91. 3-(2-((6- aminoformyl- 9-((E)-4-(5- aminoformyl -2-(4- ethyl -2- methylthiazole -5 -carboxamido )-7- methoxy -1H- benzo [d] imidazol -1- yl ) but - 2- en -1- yl )-2-(1- ethyl -3- methyl -1H -pyrazol -5- yl )-9H- pyrimido [4,5-b] indol- 8- yl ) oxy ) ethyl ) azinecyclobutane -1- carboxylic acid 4-((S)-2-((S)-2-(3-(2,5- dioxo -2,5- dihydro -1H -pyrrol -1- yl ) propionamido )-3 -methylbutanamido ) propionamido ) benzyl ester ( Compound 2.50)

Compound 2.50 (3.98 mg, 3.1 μmol, 58% yield) was prepared following General Method 3 using compound 1.17 x 1 TFA (5 mg, 5.3 μmol) as starting material. UPLC-MS (Method A, ESI+): m/z [M+H] ⁺ = 1301.5 (theoretical), 1302.3 (observed). HPLC retention time: 1.72 min. Example 92. (2S,3S,4S,5R,6S)-6-(4-(((3-(2-((6- aminoformyl- 9-((E)-4-(5- aminoformyl- 2-(4- ethyl -2- methylthiazole- 5 -carboxamido )-7- methoxy -1H- benzo [d] imidazol -1- yl ) but -2- en - 1- yl )-2-(1- ethyl -3- methyl -1H - pyrazole- (5- yl )-9H- pyrimido [4,5-b] indol- 8- yl ) oxy ) ethyl ) azacyclobutane -1- carbonyl ) oxy ) methyl )-2-(3-(3-(2,5- dioxo -2,5 - dihydro -1H - pyrrol- 1- yl ) propionamido ) propionamido ) phenoxy )-3,4,5- trihydroxytetrahydro -2H- pyran -2-carboxylic acid ( Compound 2.51) Synthesis of compound 60a

Compound 60a (20.94 mg, 13.0 μmol, 65% yield) was prepared following General Method 4 using compound 1.17 x 1 TFA (19.09 mg, 20.2 μmol) as starting material. UPLC-MS (Method A, ESI+): m/z [M+H] ⁺ = 1605.6 (theoretical value), 1605.6 (observed value). HPLC retention time: 1.87 min. Synthesis of Compound 60b

Following General Method 7, compound 60b x 1 TFA (7.3 mg, 5.4 μmol, 41% yield) was prepared using compound 60a (20.94 mg, 13.0 μmol) as starting material. UPLC-MS (Method A, ESI+): m/z [M+H] ⁺ = 1243.5 (theoretical value), 1243.5 (observed value). HPLC retention time: 1.41 min. Synthesis of compound 2.51

Compound 2.51 (4.24 mg, 3.0 μmol, 67% yield) was prepared following General Method 6 using compound 60b x 1 TFA (7.3 mg, 5.4 μmol) as starting material. UPLC-MS (Method A, ESI+): m/z [M+H] ⁺ = 1394.5 (theoretical value), 1394.5 (observed value). HPLC retention time: 1.42 min. Example 93. (E)-N-(6- aminoformyl- 3-(4-(6- aminoformyl- 2-(1- ethyl - 3- methyl - 1H -pyrazol -5- yl )-8-(3- hydroxypropoxy )-9H- pyrimido [4,5-b] indol- 9- yl ) but -2- en -1 - yl )-3H- imidazo [4,5-b] pyridin -2- yl )-4- ethyl -2- methyloxazole -5- carboxamide ( Compound 1.23) Synthesis of compound 61a

To a solution of compound 3b (7.83 g, 39.9 mmol) in THF (300 mL) at 0 °C under _N2 was added NaH (5.58 g, 139.7 mmol, 60% purity). The mixture was allowed to reach 20 °C and stirred for 30 min. Then, 3-((4-methoxybenzyl)oxy)propan-1-ol (10.5 g, 39.9 mmol) was added and the mixture was stirred at 20 °C for 16 h. LCMS analysis showed consumption of starting material and desired m/z. The reaction mixture was quenched by addition into _NH4Cl (600 mL) at 0 °C and then extracted with DCM (3 x 300 mL). The combined organic layers were dried over _Na2SO4 , filtered, and concentrated under reduced pressure to yield compound 61a (17.8 g, crude) as _a yellow solid. UPLC-MS (Method L, ESI+): m/z [M+H] ⁺ = 439.1 (theoretical value), 438.9 (observed value). HPLC retention time: 0.518 min. ¹ H NMR (400MHz, DMSO- d ₆ ) δ ppm 8.27 (s, 1H), 7.84 (d, J = 1.2 Hz, 1H), 7.79 (s, 1H), 7.76 (d, J = 0.8 Hz, 1H), 7.21 (d, J = 8.4 Hz, 2H), 6.85 (d, J = 8.8 Hz, 2H), 4.36 (s, 2H), 4.28 (t, J = 6.0 Hz, 2H), 3.75 - 3.68 (m, 3H), 3.46 (t, J = 6.0 Hz, 2H), 1.94 (q, J = 6.0 Hz, 2H). Synthesis of compound 61b

To a mixture of compound 29h (5.5 g, 1751 mmol) and compound 61a (6.41 g, 14.59 mmol) in dioxane (110 mL) and H ₂ O (22 mL) at 20 °C was added Pd(dppf)Cl ₂ (1.07 g, 1.46 mmol) and K ₂ CO ₃ (4.03 g, 29.18 mmol). The mixture was purged with N ₂ and degassed, then brought to 75 °C under N ₂ atmosphere for 2 h. LCMS analysis showed consumption of starting material and the desired m/z. A second reaction was prepared as described and combined for work-up and purification. The resulting mixture was diluted with H ₂ O (500 mL) and extracted with EtOAc (3×300 mL). The combined organic layers were washed with brine (400 mL), dried over _{Na2SO4 ,} filtered, and concentrated under reduced pressure to yield a residue. The residue was purified by prepHPLC (Method 6). The pure fractions were collected, frozen, and lyophilized to afford compound 61b (7.04 g, 12.88 mmol, 37% yield) as a brown solid. UPLC-MS (Method F, ESI+): m/z [M+H] ⁺ = 547.2 (theoretical value), 547.3 (observed value). HPLC retention time: 1.968 min. ¹ H NMR (400MHz, DMSO- d ₆ ) δ ppm 8.94 (s, 2H), 8.27 (br s, 1H), 7.87 (s, 1H), 7.82 - 7.73 (m, 2H), 7.23 (br d, J = 8.4 Hz, 2H), 6.87 (s, 2H), 6.85 (s, 1H), 4.68 (q, J = 7.2 Hz, 2H), 4.38 (s, 2H), 4.34 (br t, J = 6.0 Hz, 2H), 3.72 (s, 3H), 3.51 (br t, J = 6.0 Hz, 2H), 2.22 (s, 3H), 1.98 (br t, J = 6.0 Hz, 2H), 1.35 (t, J = 7.2 Hz, 3H). Synthesis of compound 61c

To a solution of compound 61b (200 g, 3.66 mmol) in dioxane (10 mL) was added _PPh (2.40 g, 9.15 mmol) and 4CzIPN (288.67 mg, 365.92 μmol) at 25 °C under _N2 . The resulting mixture was stirred at 55 °C for 72 h under 35 W blue LED. LCMS analysis showed consumption of starting material and desired m/z. The resulting mixture was concentrated under reduced pressure to give a residue. The residue was purified by column chromatography ( _SiO2 , hexanes/EtOAc) to give compound 61c (1.1 g, 2.14 mmol, 58% yield) as a white solid. UPLC-MS (Method G, ESI+): m/z [M+H] ⁺ = 515.2 (theoretical value), 515.2 (observed value). HPLC retention time: 2.726 min. ¹ H NMR (400MHz, DMSO- d ₆ ) δ ppm 12.68 (s, 1H), 9.51 (s, 1H), 8.42 (s, 1H), 8.05 (br s, 1H), 7.63 (s, 1H), 7.35 (br s, 1H), 7.22 (d, J = 8.4 Hz, 2H), 6.83 - 6.78 (m, 3H), 4.80 (br d, J = 6.8 Hz, 2H), 4.43 (s, 2H), 4.32 (t, J = 6.0 Hz, 2H), 3.72 (t, J = 6.4 Hz, 2H), 3.68 - 3.63 (m, 3H), 2.23 (s, 3H), 2.17 - 2.05 (m, 2H), 1.39 (t, J = 7.2 Hz, 3H). Synthesis of compound 61d

A solution of compound 61c (100 mg, 194.3 μmol), compound 1 (117.43 mg, 291.5 μmol) and Cs ₂ CO ₃ (189.95 mg, 583 μmol) was brought to 55 °C and stirred for 16 h. LCMS analysis showed consumption of starting material and desired m/z. The mixture was filtered and the filtrate was purified by prepHPLC (Method 1). The fractions were collected, frozen, and lyophilized to give compound 61d (112.84 mg, 128.1 μmol, 66% yield) as a white solid. UPLC-MS (Method A, ESI+): m/z [M+H] ⁺ = 881.4 (theoretical value), 881.4 (observed value). HPLC retention time: 1.55 min. Synthesis of compound 1.23

A solution of compound 61d (112.84 mg, 128.1 μmol) in MeCN (v/v, 3.0 mL) containing 30% HCl was brought to 30 °C and stirred for 1 h. LCMS analysis showed consumption of starting material and desired m/z. The solvent was removed under reduced pressure and the residue was purified by prepHPLC (Method 1). The pure fractions were collected, frozen, and lyophilized to give compound 1.23 (69.93 mg, 91.9 μmol, 60% yield) as a white solid. UPLC-MS (Method A, ESI+): m/z [M+H] ⁺ = 761.3 (theoretical), 761.3 (observed). HPLC retention time: 1.31 min. Example 94. N-(6- aminoformyl- 3-((E)-4-(6- aminoformyl- 8-(((8S,11S)-15-(2,5- dioxo -2,5- dihydro -1H -pyrrol -1- yl )-11 - isopropyl -8- methyl -7,10,13- trioxo - 4- oxa -6,9,12- triazapentadecyl ) oxy )-2-(1- ethyl - 3- methyl -1H -pyrazol -5- yl )-9H- pyrimido [4,5-b] indol- 9- yl ) but- 2- en-1-yl ) -3H - imidazo [ 4,5-b] pyridin -2 - yl )-4- ethyl -2- methyloxazole -5- carboxamide ( Compound 2.71) Synthesis of compound 62a

To a solution of Fmoc-Val-Ala-Gly (378 mg, 808.9 μmol) and Cu(OAc) ₂ (51.43 mg, 283.1 μmol) in DMF (8 mL) was added AcOH (104.1 μL, 1.82 mmol) followed by Pb(OAc) ₄ (900.74 mg, 2.02 mmol). The mixture was brought to 55 °C and stirred for 30 min. LCMS analysis showed consumption of starting material and the desired m/z. The mixture was diluted with EtOAc and washed with water (3x) and brine (3x). The organic layer was dried over _MgSO4 , filtered, and concentrated to give a residue. The residue was purified by prepHPLC (Method 1). The pure fractions were collected, frozen, and lyophilized to obtain compound 62a (189.5 mg, 393.5 μmol, 49% yield) as a white solid. UPLC-MS (Method A, ESI+): m/z [M+Na] ⁺ = 504.2 (theoretical value), 504.2 (observed value). HPLC retention time: 1.73 min. Synthesis of compound 62b

A solution of anhydrous compound 62a (85.76 mg, 183.8 μmol) in anhydrous DCM (4.6 mL) and TFA (41 μL, 552 μmol) was stirred at 20 °C for 1 h under Ar atmosphere. The solution was then transferred to a vial containing compound 1.23 (69.93 mg, 91.9 μmol) under Ar. The mixture was stirred at 20 °C for 16 h. LCMS analysis showed consumption of starting material and the desired m/z. The solvent was removed under reduced pressure to give a residue. The residue was purified by prepHPLC (Method 1). The pure fractions were collected, frozen, and lyophilized to give compound 62b (19.4 mg, 16.4 μmol, 18% yield) as a white solid. UPLC-MS (Method A, ESI+): m/z [M+H] ⁺ = 1182.5 (theoretical value), 1182.5 (observed value). HPLC retention time: 1.67 min. Synthesis of compound 62c

A solution of compound 62b (19.4 mg, 16.4 μmol) in 20% DBU in DMF (v/v) was brought to 30 °C and allowed to stir for 30 min. LCMS analysis showed consumption of starting material and desired m/z. The crude mixture was purified by prepHPLC (Method 1). The fractions were collected, frozen, and lyophilized to give compound 62c x 1 TFA (15.52 mg, 14.4 μmol, 88% yield) as a white solid. UPLC-MS (Method A, ESI+): m/z [M+H] ⁺ = 960.5 (theoretical), 960.5 (observed). HPLC retention time: 1.35 min. Synthesis of compound 2.71

To a solution of compound 62c (15.52 mg, 16.2 μmol), MP-OSu (6.4 mg, 24.4 μmol) in DMA (0.5 mL) was added DIPEA (11.3 μL, 64.7 μmol). The mixture was allowed to reach 30 °C and allowed to stir for 1 h. LCMS analysis showed consumption of starting material and the desired m/z. The crude mixture was purified by prepHPLC (Method 1). The pure fractions were collected, frozen, and lyophilized to give compound 2.71 (7.12 mg, 6.4 μmol, 40% yield) as a white solid. UPLC-MS (Method A, ESI+): m/z [M+H] ⁺ = 1111.5 (theoretical), 1111.5 (observed). HPLC retention time: 1.41 min. Example 95. (E)-N-(6- aminoformyl- 3-(4-(6- aminoformyl- 2-(1- ethyl - 3- methyl - 1H -pyrazol -5- yl )-8-(3- hydroxypropoxy )-9H- pyrimido [4,5-b] indol- 9- yl ) but -2- en -1 - yl )-3H- imidazo [4,5-b] pyridin -2- yl )-4- ethyl -2- methyloxazole -5- carboxamide ( Compound 1.26) Synthesis of compound 63a

A solution of compound 61c (50 mg, 97.2 μmol), compound 55 (62.80 mg, 145.7 μmol) and Cs ₂ CO ₃ (158.29 mg, 485.8 μmol) was brought to 55 °C and stirred for 16 h. LCMS analysis showed consumption of starting material and desired m/z. The mixture was filtered and the filtrate was purified by prepHPLC (Method 1). The fractions were collected, frozen, and lyophilized to give compound 63a (85.8 mg, 94.4 μmol, 97% yield) as a white solid. UPLC-MS (Method A, ESI+): m/z [M+H] ⁺ = 909.4 (theoretical value), 909.4 (observed value). HPLC retention time: 1.69 min. Synthesis of compound 1.26

A solution of compound 63a (85.8 mg, 94.4 μmol) in MeCN (v/v, 944 μL) containing 30% HCl was brought to 30 °C and stirred for 1 h. LCMS analysis showed consumption of starting material and desired m/z. The solvent was removed under reduced pressure and the residue was purified by prepHPLC (Method 1). The pure fractions were collected, frozen, and lyophilized to give compound 1.26 (60.29 mg, 76.4 μmol, 81% yield) as a white solid. UPLC-MS (Method A, ESI+): m/z [M+H] ⁺ = 789.4 (theoretical value), 789.4 (observed value). HPLC retention time: 1.44 min. Example 96. (2S,3S,4S,5R,6S)-6-(4-((((3-((5- aminoformyl -1-((E)-4-(6- aminoformyl -2-(1- ethyl -3- methyl -1H-1,2,4- triazol -5- yl )-8- methoxy -9H- pyrimido [4,5-b] indol -9- yl ) but -2- en - 1- yl )-2-(4- ethyl -2- 2 - ( ( 3- ( 2,5 - dihydroxy - 2,5 - dihydro - 1H - pyrrol - 1 - yl ) propionamido ) propionamido ) phenoxy ) -3,4,5 - trihydroxytetrahydro - 2H - pyran - 2 - carboxylic acid ( Compound 2.21 ) Synthesis of compound 64a

Compound 64a (15.91 mg, 10.1 μmol, 62% yield) was prepared following General Method 4 using compound 1.8 x 1 TFA (13.12 mg, 16.3 μmol) as starting material. UPLC-MS (Method A, ESI+): m/z [M+H] ⁺ = 1578.6 (theoretical value), 1578.6 (observed value). HPLC retention time: 1.75 min. Synthesis of Compound 64b

Following General Method 7, compound 64a (15.91 mg, 10.1 μmol) was used as the starting material to prepare compound 64b (9.02 mg, 7.4 μmol, 74% yield). UPLC-MS (Method A, ESI+): m/z [M+H] ⁺ = 1216.5 (theoretical value), 1216.5 (observed value). HPLC retention time: 1.34 min. Synthesis of compound 2.21

Compound 2.21 (6.11 mg, 4.5 μmol, 60% yield) was prepared following General Method 6 using compound 64b (9.02 mg, 7.4 μmol) as starting material. UPLC-MS (Method A, ESI+): m/z [M+H] ⁺ = 1367.5 (theoretical value), 1367.5 (observed value). HPLC retention time: 1.35 min. Example 97. (E)-N-(5- aminoformyl- 1-(4-(8- aminoformyl- 3-(1- ethyl - 3- methyl -1H -pyrazol -5- yl )-6- methoxy -5H -oxazin [4,3-b] indol - 5- yl ) but -2- en - 1 - yl )-7-(3-( methylamino ) propoxy )-1H- benzo [d] imidazol -2- yl )-4- ethyl -2- methyloxazole -5- carboxamide ( Compound 1.9) Synthesis of compound 65a

To a solution of 3,4,6-trichlorooxazine (6.62 g, 36.1 mmol) and compound 45b (3 g, 18.1 mmol) in 2-pentanol (40 mL) was added DIPEA (15.7 mL, 90.3 mmol) at 25 °C. The mixture was brought to 120 °C and stirred for 72 h. LCMS analysis showed consumption of starting material and the desired m/z. Two other reactions were prepared as described using 3 g and 4 g of compound 45b . The reactions were combined for work-up and purification. The mixture was diluted with petroleum ether (200 mL) and filtered under reduced pressure to give a residue. The residue was purified by prepHPLC (Method 8) to give compound 65a (4.8 g, 15.3 mmol, 42% yield). UPLC-MS (Method L, ESI+): m/z [M+H] ⁺ = 313.0 (theoretical value), 313.1 (observed value). HPLC retention time: 0.344 min. ¹ H NMR (400MHz, DMSO- d ₆ ) δ ppm 8.91 (s, 1H), 8.07 (br s, 1H), 7.66 (d, J = 1.6 Hz, 1H), 7.58 - 7.55 (m, 1H), 7.47 (br s, 1H), 7.39 (d, J = 8.0 Hz, 1H), 6.44 (s, 1H), 3.86 (s, 3H). Synthesis of Compound 65b

A mixture of compound 65a (450 mg, 1.44 mmol), NaOAc (472 mg, 5.75 mmol) and Pd(PPh ₃ )Cl ₂ (252 mg, 359 μmol) in DMF (9 mL) was degassed and purged with N _2. The mixture was brought to 120 °C and stirred under N ₂ atmosphere for 16 h. LCMS analysis showed consumption of starting material and desired m/z. The crude product was used in the next step without further purification. UPLC-MS (Method D, ESI+): m/z [M+H] ⁺ = 277.0 (theoretical), 276.9 (observed). HPLC retention time: 1.263 min. ¹ H NMR (400MHz, DMSO- d ₆ ) δ ppm 12.55 (s, 1H), 8.60 (s, 1H), 8.22 (br d, J = 0.8 Hz, 1H), 7.80 (d, J = 0.8 Hz, 1H), 7.74 (s, 1H), 7.48 - 7.39 (m, 1H), 4.08 (s, 3H). Synthesis of compound 65c

A mixture of compound 65b (6 g, crude), compound 3g (2.82 g, 10.2 mmol), Pd(dppf)Cl ₂ (681 mg, 931 μmol), K ₂ CO ₃ (3.86 g, 27.9 mmol) in dioxane (100 mL) and H ₂ O (20 mL) was degassed and purged with N _2. The mixture was brought to 75 °C and stirred under N ₂ atmosphere for 2 h. LCMS analysis showed consumption of starting material and desired m/z. The reaction mixture was filtered and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (SiO ₂ , DCM/MeOH). The crude compound was obtained and further purified by prepHPLC (Method 5) to give compound 65c (260 mg, 742 μmol, 10% yield over 2 steps). UPLC-MS (Method C, ESI+): m/z [M+H] ⁺ = 351.2 (theoretical value), 351.1 (observed value). HPLC retention time: 1.778 min. ¹ H NMR (400MHz, DMSO- d ₆ ) δ ppm 12.54 (s, 1H), 8.63 (s, 1H), 8.21 (br s, 1H), 7.82 (s, 1H), 7.80 (d, J = 1.2 Hz, 1H), 7.44 (br s, 1H), 6.66 (s, 1H), 4.55 (q, J = 7.2 Hz, 2H), 4.10 (s, 3H), 2.26 (s, 3H), 1.37 (t, J = 7.2 Hz, 3H). Synthesis of compound 65d

A solution of compound 65c (50 mg, 143 μmol), compound 6 (126 mg, 214 μmol) and Cs ₂ CO ₃ (232 mg, 712 μmol) in DMF (1.43 mL) was brought to 55 °C and stirred for 16 h. LCMS analysis showed consumption of starting material and desired m/z. The solution was filtered and the filtrate was purified by prepHPLC (Method 1). The fractions were collected, frozen, and lyophilized to give compound 65d (66.8 mg, 74 μmol, 52% yield). UPLC-MS (Method A, ESI+): m/z [M+H] ⁺ = 903.4 (theoretical value), 903.4 (observed value). HPLC retention time: 1.51 min. Synthesis of compound 1.9

A solution of compound 65d (66.8 mg, 74 μmol) in 20% TFA in MeCN (740 μL) was brought to 30 °C and stirred for 2 h. LCMS analysis showed consumption of starting material and desired m/z. The solvent was removed under reduced pressure and the residue was purified by prepHPLC (Method 1). The pure fractions were collected, frozen, and lyophilized to give compound 1.9 x1TFA (64.3 mg, 70.2 μmol, 95% yield). UPLC-MS (Method A, ESI+): m/z [M+H] ⁺ = 803.4 (theoretical), 803.3 (observed). HPLC retention time: 1.28 min. Example 98. (E)-N-(5- aminoformyl- 1-(4-(8- aminoformyl- 3-(1- ethyl - 3- methyl -1H -pyrazol -5- yl )-6- methoxy -5H- oxazino [4,3-b] indol - 5- yl ) but -2- en - 1 - yl )-7-(3-(3-(2,5- dihydroxy - 2,5- dihydro -1H -pyrrol -1- yl )-N -methylpropionamido ) propoxy )-1H- benzo [d] imidazol -2- yl )-4- ethyl -2- methyloxazole -5- carboxamide ( Compound 2.25)

Compound 2.25 (7.3 mg, 7.7 μmol, 47% yield) was prepared following General Procedure 1 using compound 1.9 x1 TFA (15 mg, 16.4 μmol) as starting material. UPLC-MS (Method A, ESI+): m/z [M+H]+ = 954.4 (theoretical value), 954.4 (observed value). HPLC retention time: 1.38 min. Example 99. S-(1-(3-((3-((5- aminoformyl -1-((E)-4-(8- aminoformyl- 3-(1- ethyl -3- methyl -1H -pyrazol- 5- yl )-6- methoxy -5H- oxazino [4,3-b] indol- 5- yl ) but- 2- en - 1 - yl )-2-(4- ethyl -2- methyloxazole -5 -carboxamido )-1H- benzo [d] imidazol -7 - yl ) oxy ) propyl )( methyl ) amino )-3 -oxopropyl )-2,5 -dioxopyrrolidin -3- yl )-L- cysteine ( Compound 3.9)

Compound 3.9 (1.63 mg, 1.5 μmol, 48% yield) was prepared following General Method 2 using compound 2.25 (3.00 mg, 3.1 μmol) as starting material. UPLC-MS (Method A, ESI+): m/z [M+H] ⁺ = 1075.4 (theoretical value), 1075.4 (observed value). HPLC retention time: 1.31 min. Example 100. 4-(( S)-2-((S)-2-(3-(2,5- dihydroxy - 2,5- dihydro -1H - pyrrol -1- yl ) propionamido )-3- methylbutanamido)propionamido) benzyl ( 3- ((5-aminoformyl-1-((E)-4-(8-aminoformyl-3-(1-ethyl-3-methyl-1H-pyrazol-5-yl)-6-methoxy-5H-oxazino[ 4,3 - b ] indol - 5 - yl ) but - 2 - en - 1 - yl ) -2- ( 4 - ethyl - 2 - methyloxazole - 5 - carboxamido ) -1H - benzo [ d ]imidazol- 7-yl)oxy ) propyl) (methyl ) carbamate ( Compound 2.26)

Compound 2.26 (4.24 mg, 3.3 μmol, 61% yield) was prepared following General Method 3 using compound 1.9 x 1 TFA (5.00 mg, 5.5 μmol) as starting material. UPLC-MS (Method A, ESI+): m/z [M+H] ⁺ = 1273.5 (theoretical), 1273.5 (observed). HPLC retention time: 1.42 min. Example 101. (2S,3S,4S,5R,6S)-6-(4-((((3-((5- aminoformyl -1-((E)-4-(8- aminoformyl- 3-(1- ethyl -3- methyl -1H -pyrazol -5- yl )-6- methoxy -5H -oxazino [4,3-b] indol- 5- yl ) but-2-en-1-yl) -2-(4- ethyl -2 - methyloxadiazol- 5 - yl ) -1 ... ( 2- ( 3- ( 2,5 - dihydroxy - 2,5 - dihydro - 1H - pyrrol - 1 - yl ) propionamido ) propionamido ) phenoxy ) -3,4,5 - trihydroxytetrahydro - 2H - pyran - 2 - carboxylic acid ( Compound 2.27 ) ​ Synthesis of compound 66a

Compound 66a (34.5 mg, 21.9 μmol, 45% yield) was prepared following General Method 4 using compound 1.9 x1 TFA (44.3 mg, 48.3 μmol) as starting material. UPLC-MS (Method A, ESI+): m/z [M+H] ⁺ = 1577.6 (theoretical value), 1577.5 (observed value). HPLC retention time: 1.73 min. Synthesis of compound 66b

Compound 66b x1 TFA (17.1 mg, 14.0 μmol, 64% yield) was prepared following General Method 7 using compound 66a (34.5 mg, 21.9 μmol) as starting material. UPLC-MS (Method A, ESI+): m/z [M+H] ⁺ = 1215.5 (theoretical value), 1215.4 (observed value). HPLC retention time: 1.30 min. Synthesis of compound 2.27

Compound 2.27 (9.75 mg, 7.1 μmol, 56% yield) was prepared following General Method 6 using 66b x 1 TFA (17.1 mg, 14.0 μmol) as starting material. UPLC-MS (Method A, ESI+): m/z [M+H] ⁺ = 1366.5 (theoretical value), 1366.4 (observed value). HPLC retention time: 1.36 min. Example 102. (E)-9-(4-(5- aminoformyl- 2-(1- ethyl -3- methyl -1H -pyrazol -5 -carboxamido )-7-(3-( methylamino ) propoxy )-1H- benzo [d] imidazol - 1- yl ) but-2-en - 1 - yl )-2-(1- ethyl -3- methyl -1H -pyrazol - 5- yl )-8- methoxy -9H -pyrido [2,3-b] indole -6- carboxamide ( Compound 1.27) Synthesis of compound 67a

A solution of compound 47d (50 mg, 143 μmol), compound 7 (126 mg, 215 μmol) and Cs ₂ CO ₃ (233 mg, 716 μmol) in DMF (1.43 mL) was brought to 55 °C and stirred for 16 h. LCMS analysis showed consumption of starting material and desired m/z. The solution was filtered and the filtrate was purified by prepHPLC (Method 1). The fractions were collected, frozen, and lyophilized to give compound 67a (69.8 mg, 77.5 μmol, 54% yield). UPLC-MS (Method A, ESI+): m/z [M+H] ⁺ = 901.4 (theoretical value), 901.4 (observed value). HPLC retention time: 1.66 min. Synthesis of compound 1.27

A solution of compound 67a (69.8 mg, 77.5 μmol) in 20% TFA in MeCN (775 μL) was brought to 35 °C and stirred for 2 h. LCMS analysis showed consumption of starting material and desired m/z. The solvent was removed under reduced pressure and the residue was purified by prepHPLC (Method 1). The pure fractions were collected, frozen, and lyophilized to give compound 1.27 xl TFA (58.6 mg, 61.4 μmol, 83% yield). UPLC-MS (Method A, ESI+): m/z [M+H] ⁺ = 801.4 (theoretical), 801.4 (observed). HPLC retention time: 1.44 min. Example 103. (E)-9-(4-(5- aminoformyl- 7-(3-(3-(2,5- dioxo -2,5- dihydro -1H -pyrrol -1- yl )-N -methylpropionamido ) propoxy )-2-(1- ethyl -3- methyl - 1H - pyrazole -5- carboxamido )-1H - benzo [d] imidazol - 1 - yl )but- 2 - en - 1- yl ) -2-(1- ethyl -3- methyl -1H -pyrazol -5 - yl )-8- methoxy -9H -pyrido [2,3-b] indole -6- carboxamide ( Compound 2.83)

Compound 2.83 (7.88 mg, 8.3 μmol, 50% yield) was prepared following General Method 1 using compound 1.27 x1 TFA (15 mg, 16.4 μmol) as starting material. UPLC-MS (Method A, ESI+): m/z [M+H] ⁺ = 952.4 (theoretical value), 952.4 (observed value). HPLC retention time: 1.51 min. Example 104. (E)-9-(4-(5- aminoformyl- 7-(3-(3-(2,5- dioxo -2,5- dihydro -1H -pyrrol -1- yl )-N -methylpropionamido ) propoxy )-2-(1- ethyl -3- methyl - 1H -pyrazole -5- carboxamido )-1H - benzo [d] imidazol - 1 - yl )but- 2 - en - 1 - yl ) -2-(1- ethyl -3- methyl -1H -pyrazol -5 - yl )-8- methoxy -9H -pyrido [2,3-b] indole -6- carboxamide ( Compound 3.26)

Compound 3.26 (3.8 mg, 3.5 μmol, 67% yield) was prepared following General Method 2 using compound 2.83 (5 mg, 5.3 μmol) as starting material. UPLC-MS (Method A, ESI+): m/z [M+H] ⁺ = 1073.4 (theoretical value), 1073.4 (observed value). HPLC retention time: 1.39 min. Example 105. 4-(( S)-2-((S)-2-(3-(2,5 - dihydroxy - 2,5 - dihydro - 1H -pyrrol- 1- yl ) propionamido )-3- methylbutanamido )propionamido ) benzyl (3-( (5- aminoformyl- 1-( ( E )-4-(6-aminoformyl-2-(1- ethyl - 3 - methyl - 1H -pyrazol -5 -yl )-8- methoxy -9H -pyrido [ 2,3-b ] indol - 9 - yl ) but - 2 -en-1- yl ) -2-(1- ethyl-3 - methyl -1H -pyrazol -5- carboxamido ) -1H -benzo [d]imidazol- 7-yl ) oxy ) propyl)(methyl ) carbamate ( Compound 2.84)

Compound 2.84 (4.54 mg, 3.6 μmol, 65% yield) was prepared following General Method 3 using compound 1.27 x1 TFA (5 mg, 5.5 μmol) as starting material. UPLC-MS (Method A, ESI+): m/z [M+H] ⁺ = 1271.6 (theoretical), 1271.5 (observed). HPLC retention time: 1.55 min. Example 106. (2S,3S,4S,5R,6S)-6-(4-((((3-((5- aminoformyl -1-((E)-4-(6- aminoformyl- 2-(1- ethyl -3- methyl -1H - pyrazol -5- yl )-8- methoxy -9H -pyrido [2,3-b] indol- 9- yl ) but-2- en-1-yl ) -2- ( 1- ethyl -3- methyl - 1H -pyrazole - 5 -carboxamido )-1H - benzo [d] imidazol -7- yl ) oxy ) propyl )( methyl ) aminocarboxamido ) oxy ) methyl )-2-(3-(3-(2,5- dihydroxy -2,5 - dihydro -1H -pyrrol -1- yl ) propionamido ) propionamido ) phenoxy )-3,4,5- trihydroxytetrahydro -2H- pyran -2-carboxylic acid ( Compound 2.85) Synthesis of compound 68a

Compound 68a (37.8 mg, 24 μmol, 57% yield) was prepared following General Method 4 using compound 1.27 x1 TFA (38.6 mg, 42.2 μmol) as starting material. UPLC-MS (Method A, ESI+): m/z [M+H] ⁺ = 1575.6 (theoretical value), 1575.5 (observed value). HPLC retention time: 1.87 min. Synthesis of compound 68b

Following General Method 7, compound 68b x1 TFA (18.1 mg, 13.7 μmol, 62% yield) was prepared using compound 68a (34.8 mg, 22.1 μmol) as starting material. UPLC-MS (Method A, ESI+): m/z [M+H] ⁺ = 1213.5 (theoretical value), 1213.5 (observed value). HPLC retention time: 1.35 min. Synthesis of compound 2.85

Compound 2.85 (12 mg, 8.8 μmol, 64% yield) was prepared following General Method 6 using 68b x 1 TFA (18.1 mg, 13.7 μmol) as starting material. UPLC-MS (Method A, ESI+): m/z [M+H] ⁺ = 1364.5 (theoretical), 1364.5 (observed). HPLC retention time: 1.45 min. Example 107. (E)-9-(4-(5- aminoformyl- 2-(1- ethyl -3- methyl -1H -pyrazole -5 -carboxamido )-7-(3-( methylamino ) propoxy )-1H- benzo [d] imidazol - 1- yl ) but-2-en - 1- yl ) -2-(1- ethyl -3- methyl -1H - pyrazol - 5- yl )-9H -pyrido [3',2':4,5] pyrrolo [2,3-d] pyrimidine -6- carboxamide ( Compound 1.28) Synthesis of compound 69a

A solution of compound 41i (50 mg, 156 μmol), compound 7 (137 mg, 233 μmol) and Cs ₂ CO ₃ (253 mg, 778 μmol) in DMF (1.56 mL) was brought to 55 °C and stirred for 16 h. LCMS analysis showed consumption of starting material and desired m/z. The solution was filtered and the filtrate was purified by prepHPLC (Method 1). The fractions were collected, frozen, and lyophilized to give compound 69a (41.3 mg, 47.3 μmol, 30% yield). UPLC-MS (Method A, ESI+): m/z [M+H] ⁺ = 873.4 (theoretical value), 873.4 (observed value). HPLC retention time: 1.52 min. Synthesis of compound 1.28

A solution of compound 69a (41.3 mg, 47.3 μmol) in 20% TFA in MeCN (473 μL) was brought to 35 °C and stirred for 2 h. LCMS analysis showed consumption of starting material and desired m/z. The solvent was removed under reduced pressure and the residue was purified by prepHPLC (Method 1). The pure fractions were collected, frozen, and lyophilized to give compound 1.28 xl TFA (28.8 mg, 37.3 μmol, 79% yield). UPLC-MS (Method A, ESI+): m/z [M+H] ⁺ = 773.4 (theoretical), 773.3 (observed). HPLC retention time: 1.33 min. Example 108. (E)-9-(4-(5- aminoformyl- 7-(3-(3-(2,5- dioxo -2,5- dihydro -1H -pyrrol -1- yl )-N -methylpropionamido ) propoxy )-2-(1- ethyl -3- methyl - 1H -pyrazole -5- carboxamido )-1H - benzo [d] imidazol - 1 - yl ) but- 2 - en - 1- yl )-2-(1- ethyl -3- methyl -1H -pyrazol -5- yl )-9H -pyrido [3',2':4,5] pyrrolo [2,3-d] pyrimidine -6- carboxamide ( Compound 2.86)

Compound 2.86 (6.14 mg, 6.6 μmol, 59% yield) was prepared following General Procedure 1 using compound 1.28 x1 TFA (10 mg, 11.3 μmol) as starting material. UPLC-MS (Method A, ESI+): m/z [M+H] ⁺ = 924.4 (theoretical), 924.4 (observed). HPLC retention time: 1.38 min. Example 109. S-(1-(3-((3-((5- aminoformyl -1-((E)-4-(6- aminoformyl- 2-(1- ethyl -3- methyl -1H -pyrazol -5- yl )-9H -pyrido [3',2':4,5] pyrrolo [2,3-d] pyrimidin -9- yl ) but -2- en - 1- yl )-2-(1- ethyl -3- methyl -1H -pyrazol -5 -carboxamido )-1H- benzo [d] imidazol -7 -yl ) oxy ) propyl )( methyl ) amino )-3-oxopropyl)-2,5 - dioxopyrrolidin - 3- yl )-L- cysteine ( Compound 3.27)

Compound 3.27 (3.7 mg, 3.5 μmol, 65% yield) was prepared following General Method 2 using compound 2.86 (5 mg, 5.4 μmol) as starting material. UPLC-MS (Method A, ESI+): m/z [M+H] ⁺ = 1045.4 (theoretical), 1045.4 (observed). HPLC retention time: 1.29 min. Example 110. (3-((5- aminoformyl- 1-((E)-4-(6- aminoformyl- 2-(1- ethyl -3- methyl -1H -pyrazol -5- yl )-9H -pyrido [3',2':4,5] pyrrolo [2,3-d] pyrimidin -9- yl ) but - 2- en - 1- yl )-2-(1- ethyl -3- methyl -1H -pyrazol -5 -carboxamido )-1H- benzo [d] imidazol -7- yl ) oxy ) propyl )( methyl ) carbamate 4-((S)-2-((S)-2-(3-(2,5- dihydroxy -2,5 -dihydro -1H -pyrrol -1- yl ) propionamido )-3 -methylbutanamido ) propionamido ) benzyl ester ( Compound 2.87)

Compound 2.87 (4.38 mg, 3.5 μmol, 62% yield) was prepared following General Method 3 using compound 1.28 x1 TFA (5 mg, 5.6 μmol) as starting material. UPLC-MS (Method A, ESI+): m/z [M+H] ⁺ = 1243.5 (theoretical), 1243.5 (observed). HPLC retention time: 1.44 min. Example 111. (2S,3S,4S,5R,6S)-6-(4-((((3-((5- aminoformyl -1-((E)-4-(6- aminoformyl- 2-(1- ethyl -3- methyl -1H -pyrazol -5- yl )-9H -pyrido [3',2':4,5] pyrrolo [2,3-d] pyrimidin -9 - yl ) but -2- en -1 - yl )-2-(1- ethyl -3- methyl ( 2- ( 3- ( 2,5 - dihydroxy - 2,5 - dihydro - 1H - pyrrol - 1 - yl ) propionamido ) propionamido ) phenoxy ) -3,4,5 - trihydroxytetrahydro - 2H - pyran - 2 - carboxylic acid ( Compound 2.88 ) ​ ​ ​ Synthesis of compound 70a

Compound 70a (8.5 mg, 5.5 μmol, 35% yield) was prepared following General Method 4 using compound 1.28 x1 TFA (12.8 mg, 15.6 μmol) as starting material. UPLC-MS (Method A, ESI+): m/z [M+H] ⁺ = 1547.6 (theoretical value), 1547.5 (observed value). HPLC retention time: 1.76 min. Synthesis of Compound 70b

Following General Method 7, compound 70a (8.5 mg, 5.5 μmol) was used as the starting material to prepare compound 70b (4.45 mg, 3.4 μmol, 62% yield). UPLC-MS (Method A, ESI+): m/z [M+H] ⁺ = 1185.5 (theoretical value), 1185.4 (observed value). HPLC retention time: 1.30 min. Synthesis of compound 2.88

Compound 2.88 (2.49 mg, 1.9 μmol, 54% yield) was prepared following General Method 6 using compound 70b (4.45 mg, 3.4 μmol) as starting material. UPLC-MS (Method A, ESI+): m/z [M+H] ⁺ = 1336.5 (theoretical value), 1336.5 (observed value). HPLC retention time: 1.34 min. Example 112. (E)-9-(4-(5- aminoformyl- 2-(1- ethyl -3 - methyl -1H -pyrazole -5 -carboxamido )-7- methoxy -1H- benzo [d] imidazol -1 - yl ) but -2- en -1- yl ) -2-(1- ethyl -3- methyl -1H -pyrazole -5- yl )-8-(3-( methylamino ) propoxy )-9H- pyrimido [4,5-b] indole -6- carboxamide ( Compound 1.29) Synthesis of compound 71a

To anhydrous THF (500 mL) was added NaH (10.85 g, 217.55 mmol, 60% purity) and the solution was cooled to 0 °C. Tributyl (3-hydroxypropyl)(methyl)carbamate (25.7 g, 135.78 mmol) was added slowly at 0 °C and the mixture was stirred for 10 min. 3-Fluoro-4-nitrobenzamide was added dropwise to the solution. The solution was allowed to reach 20 °C and stirred for 1 h. LCMS analysis showed consumption of starting material and desired m/z. The reaction was quenched by slow addition of NH ₄ Cl (500 mL). The product was extracted with EtOAc (3×300 mL). The organics were combined, dried over Na ₂ SO ₄ , and concentrated to give a residue. The residue was purified by column chromatography (SiO ₂ , hexane/EtOAc) to give compound 71a (25 g, 70.8 mmol, 52% yield) as a yellow solid. UPLC-MS (Method M, ESI+): m/z [M-99] ⁺ = 254.4 (theoretical value), 254.3 (observed value). HPLC retention time: 0.515 min. ¹ H NMR (400MHz, DMSO- d ₆ ) δ ppm 8.22 (br s, 1H), 7.94 (d, J = 8.4 Hz, 1H), 7.71 (br d, J = 18.8 Hz, 2H), 7.56 (dd, J = 1.2, 8.4 Hz, 1H), 4.20 (t, J = 5.6 Hz, 2H), 3.34 (br s, 1H), 3.31 - 3.29 (m, 1H), 2.77 (s, 3H), 1.93 (quintet, J = 6.4 Hz, 2H), 1.29 (br s, 9H). Synthesis of Compound 71b

To a solution of compound 71a (25 g, 70.8 mmol) in THF (250 mL), MeOH (250 mL) and H ₂ O (250 mL) were added NH ₄ Cl (37.84 g, 707.47 mmol) and Zn (46.26 g, 707.47 mmol). The reaction was stirred at 20 °C for 3 h. LCMS analysis showed consumption of starting material and desired m/z. The mixture was filtered to remove Zn and concentrated under reduced pressure to remove the solvent to give compound 71b (23 g, crude) as a pink solid which was used without further purification. UPLC-MS (Method L, ESI+): m/z [M+H] ⁺ = 324.2 (theoretical), 324.3 (observed). HPLC retention time: 0.364 min. ¹ H NMR (400MHz, DMSO- d ₆ ) δ ppm 7.59 (br s, 1H), 7.35 - 7.26 (m, 2H), 7.05 (br d, J = 2.0 Hz, 1H), 6.59 (d, J = 8.0 Hz, 1H), 5.21 (br s, 2H), 3.95 (t, J = 6.0 Hz, 2H), 3.39 - 3.35 (m, 2H), 2.78 (br s, 3H), 1.93 (td, J = 5.6, 12.0 Hz, 2H), 1.35 (br d, J = 14.8 Hz, 9H). Synthesis of compound 71c

To a solution of compound 71b (17.0 g, 52.55 mmol) and 2,4-dichloro-5-iodopyrimidine (28.9 g, 105.15 mmol) in pentan-2-ol (34 mL) was added DIPEA (27.5 mL, 157.7 mmol). The reaction mixture was brought to 130 °C and stirred for 48 h. LCMS analysis showed consumption of starting material and desired m/z. The mixture was filtered to remove impurities, and the solution was concentrated under reduced pressure to give a residue that was purified by column chromatography (SiO ₂ , hexanes/EtOAc) to give compound 71c (7 g, 12.5 mmol, 24% yield) as a grey solid. UPLC-MS (Method L, ESI+): m/z [M+H] ⁺ = 562.1 (theoretical value), 562.1 (observed value). HPLC retention time: 0.517 min. ¹ H NMR (400MHz, DMSO- d ₆ ) δ ppm 8.65 (s, 1H), 8.51 (br s, 1H), 8.16 (br d, J = 6.0 Hz, 1H), 7.99 (br s, 1H), 7.58 (br d, J = 8.4 Hz, 2H), 7.37 (br s, 1H), 4.13 (br t, J = 5.6 Hz, 2H), 3.41 (br t, J = 6.4 Hz, 2H), 2.79 (br s, 3H), 1.99 (br t, J = 5.6 Hz, 2H), 1.35 - 1.21 (m, 9H). Synthetic compound 71d

To a solution of compound 71c (2 g, 3.56 mmol) in DMF (10 mL) was added Pd(PPh ₃ )Cl ₂ (250 mg, 350 μmol) and NaOAc (1.23 g, 15.0 mmol). The reaction mixture was brought to 120 °C and stirred for 16 h. LCMS analysis showed consumption of starting material and the desired m/z. The mixture was filtered to remove impurities and the filtrate was purified by prepHPLC (Method 7) to give compound 71d (530 mg, 1.22 mmol, 34% yield). UPLC-MS (Method D, ESI+): m/z [M+H] ⁺ = 434.2 (theoretical), 434.2 (observed). HPLC retention time: 1.646 min. ¹ H NMR (400MHz, DMSO- d ₆ ) δ ppm 12.96 (s, 1H), 9.38 (s, 1H), 8.42 (s, 1H), 8.04 (br s, 1H), 7.60 (s, 1H), 7.41 - 7.33 (m, 1H), 4.24 (br t, J = 5.9 Hz, 2H), 3.51 - 3.43 (m, 2H), 2.82 (br s, 3H), 2.07 - 1.99 (m, 2H), 1.38 - 1.22 (m, 9H). Synthesis of compound 71e

To _a solution of compound 71d (880 mg, 2.03 mmol) and compound 3g (575 mg, 2.43 mmol) in dioxane (25 mL) was added Pd(dppf) _Cl (148 mg, 203 μmol), _NaCO (430 mg, 4.06 mmol) and _H0 (5 mL) under N2 _atmosphere . The mixture was degassed and purged with _N2 , then the mixture was brought to 90 °C and stirred for 4 h. A second reaction vial was prepared as described and the mixtures were combined for workup and purification. The reaction mixture was concentrated to give a residue. The residue was triturated with MeOH (200 mL). The resulting solid was collected by filtration, washed with EtOH, and dried under high vacuum to yield compound 71e (1.09 g, 2.15 mmol, 53% yield) as a yellow solid. UPLC-MS (Method C, ESI+): m/z [M+H] ⁺ = 508.3 (theoretical value), 508.2 (observed value). HPLC retention time: 2.372 min. ¹ H NMR (400MHz, DMSO- d ₆ ) δ ppm 12.70 (s, 1H), 9.52 (s, 1H), 8.42 (s, 1H), 8.04 (br s, 1H), 7.64 (s, 1H), 7.35 (br s, 1H), 6.80 (s, 1H), 4.80 (q, J = 7.2 Hz, 2H), 4.24 (br t, J = 5.6 Hz, 2H), 3.50 (br t, J = 6.0 Hz, 2H), 2.83 (br s, 3H), 2.23 (s, 3H), 2.09 - 2.01 (m, 2H), 1.41 - 1.22 (m, 12H). Synthesis of compound 71f

A solution of compound 71e (50 mg, 98.5 μmol), compound 55f (63.7 mg, 148 μmol) and Cs ₂ CO ₃ (160 mg, 493 μmol) in DMF (1 mL) was brought to 55 °C and stirred for 16 h. LCMS analysis showed consumption of starting material and desired m/z. The solution was filtered and the filtrate was purified by prepHPLC (Method 1). The fractions were collected, frozen, and lyophilized to give compound 71f (63.5 mg, 70.4 μmol, 71% yield). UPLC-MS (Method A, ESI+): m/z [M+H] ⁺ = 902.4 (theoretical value), 902.4 (observed value). HPLC retention time: 1.60 min. Synthesis of compound 1.29

A solution of compound 71f (63.5 mg, 70.4 μmol) in 20% TFA in MeCN (704 μL) was brought to 30 °C and stirred for 2 h. LCMS analysis showed consumption of starting material and desired m/z. The solvent was removed under reduced pressure to give a residue, which was purified by prepHPLC (Method 1). The pure fractions were collected, frozen, and lyophilized to give compound 1.29 x 1 TFA (46.3 mg, 50.6 μmol, 72% yield). UPLC-MS (Method A, ESI+): m/z [M+H] ⁺ = 802.4 (theoretical), 802.4 (observed). HPLC retention time: 1.36 min. Example 113. (E)-9-(4-(5- aminoformyl -2-(1- ethyl -3- methyl -1H -pyrazol -5 -carboxamido )-7- methoxy -1H- benzo [d] imidazol - 1- yl ) but -2- en - 1- yl )-8-(3-(3-(2,5- dihydroxy -2,5 -dihydro -1H -pyrrol -1 - yl )-N -methylpropionamido ) propoxy )-2-(1- ethyl -3- methyl -1H -pyrazol - 5- yl )-9H- pyrimido [4,5-b] indole -6- carboxamide ( Compound 2.89)

Compound 2.89 (9.25 mg, 9.7 μmol, 59% yield) was prepared following General Method 1 using compound 1.29 x 1 TFA (15 mg, 16.4 μmol) as starting material. UPLC-MS (Method A, ESI+): m/z [M+H] ⁺ = 953.4 (theoretical value), 953.4 (observed value). HPLC retention time: 1.49 min. Example 114. S-(1-(3-((3-((6- aminoformyl -9-((E)-4-(5- aminoformyl- 2-(1- ethyl -3- methyl -1H -pyrazol- 5 -carboxamido )-7- methoxy -1H- benzo [d] imidazol -1- yl ) but - 2- en -1- yl )-2-(1- ethyl -3- methyl -1H -pyrazol -5- yl )-9H- pyrimido [4,5-b] indol- 8- yl ) oxy ) propyl )( methyl ) amino )-3 - oxopropyl )-2,5 -dioxopyrrolidin -3- yl )-L- cysteine ( Compound 3.28)

Compound 3.28 (4.05 mg, 3.8 μmol, 72% yield) was prepared following General Method 2 using compound 2.89 (5.0 mg, 5.2 μmol) as starting material. UPLC-MS (Method A, ESI+): m/z [M+H] ⁺ = 1074.4 (theoretical value), 1074.4 (observed value). HPLC retention time: 1.48 min. Example 115. 4-( (S)-2-((S)-2-(3-(2,5 - dihydroxy - 2,5 - dihydro -1H -pyrrol - 1 - yl ) propionamido )-3 - methylbutanamido ) propionamido ) benzyl (3-((6- aminoformyl -9-((E)-4-(5-aminoformyl-2-(1-ethyl-3-methyl-1H-pyrazole-5-carboxamido)-7-methoxy-1H-benzo[d]imidazol- 1 - yl ) but - 2 - en - 1 - yl ) -2- ( 1 - ethyl - 3 - methyl - 1H - pyrazol -5-yl)-9H-pyrimido[4,5 - b ] indol - 8 - yl ) oxy ) propyl ) ( methyl ) carbamate ( Compound 2.90)

Compound 2.90 (4.16 mg, 3.3 μmol, 60% yield) was prepared following General Method 3 using compound 1.29 x 1 TFA (5.0 mg, 5.5 μmol) as starting material. UPLC-MS (Method A, ESI+): m/z [M+H] ⁺ = 1272.6 (theoretical), 1272.5 (observed). HPLC retention time: 1.47 min. Example 116. (2S,3S,4S,5R,6S)-6-(4-((((3-((6- aminoformyl -9-((E)-4-(5- aminoformyl- 2-(1- ethyl -3- methyl -1H - pyrazole -5 -carboxamido )-7- methoxy -1H- benzo [d] imidazol -1- yl ) but - 2- en - 1- yl )-2-(1- ethyl -3- methyl -1H -pyrazole oxazol -5- yl )-9H- pyrimido [4,5-b] indol- 8- yl ) oxy ) propyl )( methyl ) aminoformyl ) oxy ) methyl )-2-(3-(3-(2,5- dioxo -2,5 - dihydro -1H - pyrrol -1- yl ) propionamido ) propionamido ) phenoxy )-3,4,5- trihydroxytetrahydro -2H- pyran -2-carboxylic acid ( Compound 2.91) Synthesis of compound 72a

Compound 72a (17.5 mg, 11.1 μmol, 39% yield) was prepared following General Method 4 using compound 1.29 x 1 TFA (26.3 mg, 28.8 μmol) as starting material. UPLC-MS (Method A, ESI+): m/z [M+H] ⁺ = 1576.6 (theoretical value), 1576.5 (observed value). HPLC retention time: 1.82 min. Synthesis of compound 72b

Following General Method 7, compound 72b x1 TFA (10.5 mg, 7.9 μmol, 71% yield) was prepared using compound 72a (17.5 mg, 11.1 μmol) as starting material. UPLC-MS (Method A, ESI+): m/z [M+H] ⁺ = 1214.5 (theoretical value), 1214.5 (observed value). HPLC retention time: 1.38 min. Synthesis of compound 2.91

Compound 2.91 (5.57 mg, 4.1 μmol, 52% yield) was prepared following General Method 6 using 72b x1 TFA (10.5 mg, 7.9 μmol) as starting material. UPLC-MS (Method A, ESI+): m/z [M+H] ⁺ = 1365.5 (theoretical), 1365.5 (observed). HPLC retention time: 1.39 min. Example 117. (E)-9-(4-(5- aminoformyl- 2-(1- ethyl -3 - methyl -1H -pyrazole -5 -carboxamido )-7- methoxy -1H- benzo [d] imidazol -1 - yl ) but -2- en -1- yl ) -2-(1- ethyl -3- methyl -1H -pyrazole -5- yl )-8-(3-( methylamino ) propoxy )-9H- pyrimido [4,5-b] indole -6- carboxamide ( Compound 1.30) Synthesis of compound 73a

A mixture of compound 40b (7.0 g, 26.1 mmol), BPD (13.2 g, 52.2 mmol), KOAc (7.68 g, 78.4 mmol) in dioxane (140 mL) was degassed and purged with _N2 . Then, Pd(dppf) _Cl2 (1.91 g, 2.61 mmol) was added and the mixture was degassed a second time before it was brought to 100 °C and stirred under _N2 atmosphere for 5 h. LCMS analysis showed consumption of starting material and the desired m/z. The crude product was used in the next step without further purification. UPLC-MS (Method L, ESI+): m/z [M+H] ⁺ = 234.1 (theoretical), 234.1 (observed). HPLC retention time: 0.263 min. Synthesis of compound 73b

A mixture of compound 73a (5.91 g, 25.3 mmol), compound 3d (15 g, 30.4 mmol), K ₂ CO ₃ (10.5 g, 76 mmol) in dioxane (140 mL) and H ₂ O (35 mL) was degassed and purged with N _2. Then, Pd(dppf)Cl ₂ (1.85 g, 2.53 mmol) was added. The mixture was brought to 100 °C and stirred under N ₂ atmosphere for 2 h. TLC (EtOAc/MeOH 5:1, R _f = 0.6) showed consumption of starting material. The residue was purified by column chromatography (SiO ₂ , EtOAc/MeOH). The pure fractions were collected and concentrated to give a residue. The residue was triturated with 1:1 EtOAc/petroleum ether at 20°C for 10 min. Compound 73b (6.6 g, 12.6 mmol, 47% yield) was obtained as a yellow solid. UPLC-MS (Method N, ESI+): m/z [M+H] ⁺ = 553.2 (theoretical value), 553.3 (observed value). HPLC retention time: 0.440 min. ¹ H NMR (400MHz, DMSO- d ₆ ) δ ppm 9.07 (s, 2H), 8.26 (s, 1H), 7.87 (d, J = 0.8 Hz, 1H), 7.79 (br s, 1H), 7.77 (d, J = 0.8 Hz, 1H), 4.69 - 4.59 (m, 2H), 4.29 (t, J = 6.0 Hz, 2H), 3.91 (br s, 2H), 3.55 (br s, 2H), 2.69 - 2.57 (m, 1H), 2.34 (s, 3H), 2.07 - 1.99 (m, 2H), 1.41 (t, J = 7.2 Hz, 3H), 1.36 (s, 9H). Synthesis of compound 73c

To a solution of compound 73b (500 mg, 905 μmol) in dioxane (10 mL) was added PPh ₃ (831 mg, 3.17 mmol) and 4CzIPN (71.4 mg, 90.5 μmol). The mixture was stirred at 55 °C for 96 h under a 100 W blue LED. LCMS analysis showed consumption of starting material and the desired m/z. Twelve additional vials were prepared as described. Thirteen reaction mixtures were combined for work-up and purification. The mixture was concentrated to give a residue. The residue was purified by column chromatography (SiO ₂ , EtOAc/MeOH). The crude product was further purified by prepHPLC (Method 10) to give compound 73c (510 mg, 980 μmol, 9% yield). UPLC-MS (Method M, ESI+): m/z [M+H] ⁺ = 521.3 (theoretical value), 521.3 (observed value). HPLC retention time: 0.484 min. ¹ H NMR (400MHz, DMSO- d ₆ ) δ ppm 9.52 (s, 1H), 8.41 (d, J = 1.6 Hz, 1H), 7.67 (d, J = 1.2 Hz, 1H), 4.91 - 4.87 (m, 2H), 4.33 (t, J = 6.0 Hz, 2H), 4.11 (br t, J = 8.4 Hz, 2H), 3.82 - 3.66 (m, 2H), 3.01 - 2.91 (m, 1H), 2.45 (s, 3H), 2.30 - 2.22 (m, 2H), 1.54 (t, J = 7.2 Hz, 3H), 1.43 (s, 9H). Synthesis of compound 73d

A solution of compound 73c (50 mg, 96 μmol), compound 55f (62.1 mg, 144 μmol) and Cs ₂ CO ₃ (156 mg, 480 μmol) in DMF (0.5 mL) was brought to 55 °C and stirred for 16 h. LCMS analysis showed consumption of starting material and desired m/z. Cold water (5 mL) was added to precipitate the product. The solution was filtered and the filter cake was washed with cold water. The solid was collected and dried under high vacuum to give compound 73d (80.9 mg, crude), which was used without further purification. UPLC-MS (Method A, ESI+): m/z [M+H] ⁺ = 915.4 (theoretical value), 915.4 (observed value). HPLC retention time: 1.57 min. Synthesis of compound 1.30

A solution of compound 73d (91.2 mg, 99.7 μmol) in 20% TFA in MeCN (309 μL) was brought to 30 °C and stirred for 2 h. LCMS analysis showed consumption of starting material and desired m/z. The solvent was removed under reduced pressure to give a residue, which was purified by prepHPLC (Method 1). The pure fractions were collected, frozen, and lyophilized to give compound 1.30 x 1 TFA (58.3 mg, 62.8 μmol, 63% yield). UPLC-MS (Method A, ESI+): m/z [M+H] ⁺ = 815.4 (theoretical), 815.4 (observed). HPLC retention time: 1.31 min. Example 118. (E)-9-(4-(5- aminoformyl -2-(1- ethyl -3- methyl -1H -pyrazole -5 -carboxamido )-7- methoxy -1H- benzo [d] imidazol -1 - yl ) but -2- en - 1 - yl )-8-(2-(1-(3-(2,5- dioxo -2,5- dihydro -1H - pyrrol- 1 - yl ) propanoyl ) azinecyclobutane -3- yl ) ethoxy )-2-(1- ethyl -3- methyl -1H-1,2,4- triazol -5- yl )-9H- pyrimido [4,5-b] indole -6- carboxamide ( Compound 2.92)

Compound 2.92 (11.4 mg, 11.8 μmol, 55% yield) was prepared following General Procedure 1 using compound 1.30 x 1 TFA (20 mg, 21.5 μmol) as starting material. UPLC-MS (Method A, ESI+): m/z [M+H] ⁺ = 966.4 (theoretical), 966.4 (observed). HPLC retention time: 1.38 min. Example 119. S-(1-(3-(3-(2-((6- aminoformyl- 9-((E)-4-(5- aminoformyl- 2-(1- ethyl -3- methyl -1H -pyrazole -5 -carboxamido )-7- methoxy -1H- benzo [d] imidazol -1- yl ) but - 2- en -1- yl )-2-(1- ethyl -3- methyl -1H-1,2,4- triazol -5- yl )-9H- pyrimido [4,5-b] indol- 8- yl ) oxy ) ethyl ) azinecyclobutane -1- yl )-3 - oxopropyl )-2,5 -dioxopyrrolidin- 3- yl )-L- cysteine ( Compound 3.29)

Compound 3.29 (3.34 mg, 2.8 μmol, 54 % yield) was prepared following General Method 2 using compound 2.92 (5 mg, 5.2 μmol) as starting material. UPLC-MS (Method A, ESI+): m/z [M+H] ⁺ = 1087.4 (theoretical), 1087.4 (observed). HPLC retention time: 1.31 min. Example 120. 3-(2-((6- aminoformyl- 9-((E)-4-(5- aminoformyl -2-(1- ethyl -3- methyl -1H -pyrazole -5 -carboxamido )-7- methoxy -1H - benzo [d] imidazol -1- yl ) but - 2- en -1- yl )-2-(1- ethyl -3- methyl -1H-1,2,4- triazol -5- yl )-9H- pyrimido [4,5-b] indol- 8- yl ) oxy ) ethyl ) azinecyclobutane -1- carboxylic acid 4-((S)-2-((S)-2-(3-(2,5- dioxo - 2,5- dihydro -1H -pyrrol -1- yl ) propionamido )-3 -methylbutanamido ) propionamido ) benzyl ester ( Compound 2.93)

Compound 2.93 (4.32 mg, 3.4 μmol, 62% yield) was prepared following General Method 3 using compound 1.30 x 1 TFA (5 mg, 5.4 μmol) as starting material. UPLC-MS (Method A, ESI+): m/z [M+H] ⁺ = 1285.5 (theoretical), 1285.5 (observed). HPLC retention time: 1.48 min. Example 121. (2S,3S,4S,5R,6S)-6-(4-(((3-(2-((6- aminoformyl- 9-((E)-4-(5- aminoformyl- 2-(1- ethyl -3- methyl -1H - pyrazole -5 -carboxamido )-7- methoxy -1H- benzo [d] imidazol -1- yl ) but -2- en - 1- yl )-2-(1- ethyl -3- methyl -1H-1,2, (4- triazol -5- yl )-9H- pyrimido [4,5-b] indol- 8- yl ) oxy ) ethyl ) azacyclobutane -1- carbonyl ) oxy ) methyl )-2-(3-(3-(2,5- dioxo - 2,5 -dihydro -1H -pyrrol -1- yl ) propionamido ) propionamido ) phenoxy )-3,4,5- trihydroxytetrahydro -2H- pyran -2-carboxylic acid ( Compound 2.94) Synthesis of compound 74a

Compound 74a (34.5 mg, 21.7 μmol, 61% yield) was prepared following General Method 4 using compound 1.30 x 1 TFA (33.3 mg, 35.9 μmol) as starting material. UPLC-MS (Method A, ESI+): m/z [M+H] ⁺ = 1589.6 (theoretical value), 1589.6 (observed value). HPLC retention time: 1.73 min. Synthesis of compound 74b

Following General Method 7, compound 74b x1 TFA (18.5 mg, 13.8 μmol, 63% yield) was prepared using compound 74a (34.5 mg, 21.7 μmol) as starting material. UPLC-MS (Method A, ESI+): m/z [M+H] ⁺ = 1227.5 (theoretical value), 1227.5 (observed value). HPLC retention time: 1.30 min. Synthesis of compound 2.94

Compound 2.94 (11.0 mg, 8.0 μmol, 58% yield) was prepared following General Method 6 using 74b x 1 TFA (18.5 mg, 13.8 μmol) as starting material. UPLC-MS (Method A, ESI+): m/z [M+H] ⁺ = 1378.5 (theoretical), 1378.5 (observed). HPLC retention time: 1.33 min. Example 122. (E)-N-(1-(4-(8-(2-( Azocyclobutane- 3- yl ) ethoxy )-6 -aminoformyl- 2-(1- ethyl -3- methyl -1H-1,2,4- triazol -5 - yl )-9H- pyrimido [4,5-b] indol- 9- yl ) but - 2- en - 1 - yl )-5 - aminoformyl - 7- methoxy -1H- benzo [d] imidazol -2- yl )-4- ethyl -2- methyloxazole -5- carboxamide ( Compound 1.31) Synthesis of compound 75a

A solution of compound 73c (50 mg, 96 μmol), compound 57d (62.2 mg, 144 μmol) and Cs ₂ CO ₃ (156 mg, 480 μmol) in DMF (0.5 mL) was brought to 55 °C and stirred for 16 h. LCMS analysis showed consumption of starting material and desired m/z. Cold water (5 mL) was added to the solution to precipitate the product. The solution was filtered and the filter cake was washed with more cold water. The solid was dried under high vacuum to give compound 75a (52.4 mg, crude). UPLC-MS (Method A, ESI+): m/z [M+H] ⁺ = 916.4 (theoretical value), 916.4 (observed value). HPLC retention time: 1.53 min. Synthesis of compound 1.31

A solution of compound 75a (70.3 mg, 76.7 μmol) in 20% TFA in MeCN (257 μL) was brought to 30 °C and stirred for 2 h. LCMS analysis showed consumption of starting material and desired m/z. The solvent was removed under reduced pressure to give a residue, which was purified by prepHPLC (Method 1). The fractions were collected, frozen, and lyophilized to give compound 1.31 x 1 TFA (51.0 mg, 54.9 μmol, 72% yield). UPLC-MS (Method A, ESI+): m/z [M+H] ⁺ = 816.4 (theoretical), 816.4 (observed). HPLC retention time: 1.31 min. Example 123. (E)-N-(5- aminoformyl- 1-(4-(6- aminoformyl- 8-(2-(1-(3-(2,5-dioxo - 2,5- dihydro -1H -pyrrol- 1- yl ) propanoyl ) azinecyclobutan -3- yl ) ethoxy )-2-(1- ethyl -3- methyl- 1H-1,2,4- triazol -5- yl )-9H - pyrimido [4,5-b] indol- 9- yl ) but - 2- en - 1-yl ) -7- methoxy - 1H- benzo [d] imidazol -2- yl )-4- ethyl -2- methyloxazole -5- carboxamide ( Compound 2.95)

Compound 2.95 (9.45 mg, 9.8 μmol, 45% yield) was prepared following General Method 1 using compound 1.31 x 1 TFA (20 mg, 21.5 μmol) as starting material. UPLC-MS (Method A, ESI+): m/z [M+H] ⁺ = 967.4 (theoretical value), 967.4 (observed value). HPLC retention time: 1.40 min. Example 124. S-(1-(3-(3-(2-((6- aminoformyl- 9-((E)-4-(5- aminoformyl -2-(4- ethyl -2- methyloxazole -5 -carboxamido )-7- methoxy -1H- benzo [d] imidazol -1- yl ) but - 2- en -1- yl )-2-(1- ethyl -3- methyl -1H-1,2,4- triazol -5- yl )-9H- pyrimido [4,5-b] indol- 8- yl ) oxy ) ethyl ) azinecyclobutane -1- yl )-3 - oxopropyl )-2,5 -dioxopyrrolidin -3- yl )-L- cysteine ( Compound 3.30)

Compound 3.30 (5.45 mg, 4.5 μmol, 88% yield) was prepared following General Method 2 using compound 2.95 (5 mg, 5.2 μmol) as starting material. UPLC-MS (Method A, ESI+): m/z [M+H] ⁺ = 1088.4 (theoretical), 1088.4 (observed). HPLC retention time: 1.24 min. Example 125. 3-(2-((6- aminoformyl- 9-((E)-4-(5- aminoformyl -2-(4- ethyl -2- methyloxazol -5 -carboxamido )-7- methoxy -1H- benzo [d] imidazol - 1- yl ) but - 2- en -1- yl )-2-(1- ethyl -3- methyl -1H-1,2,4- triazol -5- yl )-9H- pyrimido [4,5-b] indol- 8- yl ) oxy ) ethyl ) azinecyclobutane -1- carboxylic acid 4-((S)-2-((S)-2-(3-(2,5- dioxo - 2,5 - dihydro -1H -pyrrol -1- yl ) propionamido )-3 -methylbutanamido ) propionamido ) benzyl ester ( Compound 2.96)

Compound 2.96 (5.42 mg, 4.2 μmol, 78 % yield) was prepared following General Method 3 using compound 1.31 x 1 TFA (5 mg, 5.4 μmol) as starting material. UPLC-MS (Method A, ESI+): m/z [M+H] ⁺ = 1286.5 (theoretical), 1286.5 (observed). HPLC retention time: 1.42 min. Example 126. (2S,3S,4S,5R,6S)-6-(4-(((3-(2-((6- aminoformyl- 9-((E)-4-(5- aminoformyl -2-(4- ethyl -2 -methyloxazol - 5- carboxamido )-7- methoxy -1H- benzo [d] imidazol -1- yl ) but - 2 - en - 1- yl )-2-(1- ethyl - 3- methyl- 1H-1,2,4- ( 2- ( 3- ( 2,5 - dihydroxy - 2,5 - dihydro - 1H - pyrrol - 1 - yl ) propionamido ) propionamido ) phenoxy ) -3,4,5 - trihydroxytetrahydro - 2H - pyran - 2 - carboxylic acid ( Compound 2.97 ) ​ Synthesis of compound 76a

Compound 76a (21.8 mg, 13.7 μmol, 49% yield) was prepared following General Method 4 using compound 1.31 x 1 TFA (26.0 mg, 28.0 μmol) as starting material. UPLC-MS (Method A, ESI+): m/z [M+H] ⁺ = 1590.6 (theoretical value), 1590.6 (observed value). HPLC retention time: 1.72 min. Synthesis of Compound 76b

Following General Method 7, compound 76b x1 TFA (10.1 mg, 7.5 μmol, 55% yield) was prepared using compound 76a (21.8 mg, 13.7 μmol) as starting material. UPLC-MS (Method A, ESI+): m/z [M+H] ⁺ = 1228.5 (theoretical value), 1228.5 (observed value). HPLC retention time: 1.28 min. Synthesis of compound 2.97

Compound 2.97 (3.58 mg, 2.6 μmol, 35% yield) was prepared following General Method 6 using 76b x 1 TFA (10.1 mg, 7.5 μmol) as starting material. UPLC-MS (Method A, ESI+): m/z [M+H] ⁺ = 1379.5 (theoretical), 1379.5 (observed). HPLC retention time: 1.29 min. Example 127. (E)-N-(1-(4-(8-(2-( Azocyclobutane- 3- yl ) ethoxy )-6 -aminoformyl- 2-(1- ethyl -3- methyl -1H-1,2,4- triazol -5 - yl )-9H- pyrimido [4,5-b] indol- 9- yl ) but -2- en - 1 - yl )-5- aminoformyl - 7- methoxy -1H- benzo [d] imidazol -2- yl )-4- ethyl -2- methylthiazole -5- carboxamide ( Compound 1.32) Synthesis of compound 77a

A solution of compound 73c (50 mg, 96 μmol), compound 59c (64.5 mg, 144 μmol) and Cs ₂ CO ₃ (156 mg, 480 μmol) in DMF (0.5 mL) was brought to 55 °C and stirred for 16 h. LCMS analysis showed consumption of starting material and desired m/z. Cold water (5 mL) was added to the solution to precipitate the product. The solution was filtered and the solid was dried under high vacuum to give compound 77a (37.7 mg, crude). UPLC-MS (Method A, ESI+): m/z [M+H] ⁺ = 932.4 (theoretical), 932.4 (observed). HPLC retention time: 1.58 min. Synthesis of compound 1.32

A solution of compound 77a (41.2 mg, 44.2 μmol) in 20% TFA in MeCN (791 μL) was brought to 30 °C and stirred for 2 h. LCMS analysis showed consumption of starting material and desired m/z. The solvent was removed under reduced pressure to give a residue, which was purified by prepHPLC (Method 1). The fractions were collected, frozen, and lyophilized to give compound 1.32 x 1 TFA (31.8 mg, 33.6 μmol, 76% yield). UPLC-MS (Method A, ESI+): m/z [M+H] ⁺ = 832.3 (theoretical), 832.4 (observed). HPLC retention time: 1.35 min. Example 128. (E)-N-(5- aminoformyl- 1-(4-(6- aminoformyl- 8-(2-(1-(3-(2,5-dioxo - 2,5- dihydro -1H -pyrrol -1- yl ) propionyl ) azinecyclobutan -3- yl ) ethoxy )-2-(1- ethyl -3- methyl- 1H-1,2,4- triazol -5- yl )-9H - pyrimido [4,5-b] indol- 9- yl ) but- 2- en - 1 - yl )-7- methoxy - 1H- benzo [d] imidazol -2- yl )-4- ethyl -2- methylthiazole -5- carboxamide ( Compound 2.98)

Compound 2.98 (8.27 mg, 8.4 μmol, 53% yield) was prepared following General Method 1 using compound 1.32 x 1 TFA (15 mg, 15.9 μmol) as starting material. UPLC-MS (Method A, ESI+): m/z [M+H] ⁺ = 983.4 (theoretical value), 983.4 (observed value). HPLC retention time: 1.37 min. Example 129. S-(1-(3-(3-(2-((6- aminoformyl- 9-((E)-4-(5- aminoformyl -2-(4- ethyl -2- methylthiazole -5 -carboxamido )-7- methoxy -1H- benzo [d] imidazol -1- yl ) but - 2- en -1- yl )-2-(1- ethyl -3- methyl- 1H-1,2,4- triazol -5- yl )-9H- pyrimido [4,5-b] indol- 8- yl ) oxy ) ethyl ) azinecyclobutane -1- yl )-3 - oxopropyl )-2,5 -dioxopyrrolidin -3- yl )-L- cysteine ( Compound 3.31)

Compound 3.31 (5.33 mg, 4.4 μmol, 86% yield) was prepared following General Method 2 using compound 2.98 (5 mg, 5.1 μmol) as starting material. UPLC-MS (Method A, ESI+): m/z [M+H] ⁺ = 1104.4 (theoretical), 1104.4 (observed). HPLC retention time: 1.29 min. Example 130. 3-(2-((6- aminoformyl- 9-((E)-4-(5- aminoformyl -2-(4- ethyl -2- methylthiazole -5 -carboxamido )-7- methoxy -1H- benzo [d] imidazol -1 - yl ) but - 2- en - 1 - yl )-2-(1- ethyl -3- methyl -1H-1,2,4- triazol -5- yl )-9H- pyrimido [4,5-b] indol- 8- yl ) oxy ) ethyl ) azinecyclobutane -1- carboxylic acid 4-((S)-2-((S)-2-(3-(2,5- dioxo -2,5- dihydro -1H -pyrrol -1- yl ) propionamido )-3 -methylbutanamido ) propionamido ) benzyl ester ( Compound 2.99)

Compound 2.99 (2.86 mg, 2.2 μmol, 42% yield) was prepared following General Method 3 using compound 1.32 x 1 TFA (5 mg, 5.3 μmol) as starting material. UPLC-MS (Method A, ESI+): m/z [M+H] ⁺ = 1302.5 (theoretical), 1302.5 (observed). HPLC retention time: 1.46 min. Example 131. (2S,3S,4S,5R,6S)-6-(4-(((3-(2-((6- aminoformyl- 9-((E)-4-(5- aminoformyl- 2-(4- ethyl -2- methylthiazole - 5 -carboxamido )-7- methoxy - 1H- benzo [d] imidazol -1- yl ) but - 2 - en - 1- yl )-2-(1- ethyl -3- methyl -1H-1,2,4- ( 2- ( 3- ( 2,5 - dihydroxy - 2,5 - dihydro - 1H - pyrrol - 1 - yl ) propionamido ) propionamido ) phenoxy ) -3,4,5 - trihydroxytetrahydro - 2H - pyran - 2 - carboxylic acid ( Compound 2.100 ) ​ Synthesis of compound 78a

Compound 78a (6.14 mg, 3.8 μmol, 31% yield) was prepared following General Method 4 using compound 1.32 x 1 TFA (11.8 mg, 12.4 μmol) as starting material. UPLC-MS (Method A, ESI+): m/z [M+H] ⁺ = 1606.6 (theoretical value), 1606.6 (observed value). HPLC retention time: 1.76 min. Synthesis of Compound 78b

Following General Method 7, compound 78a (6.14 mg, 3.8 μmol) was used as the starting material to prepare compound 78b x1 TFA (3.92 mg, 2.9 μmol, 76% yield). UPLC-MS (Method A, ESI+): m/z [M+H] ⁺ = 1244.5 (theoretical value), 1244.5 (observed value). HPLC retention time: 1.29 min. Synthetic compound 2.100

Compound 2.100 (2.73 mg, 2.0 μmol, % yield) was prepared following General Method 6 using 78b x 1 TFA (3.92 mg, 2.9 μmol) as starting material. UPLC-MS (Method A, ESI+): m/z [M+H] ⁺ = 1395.5 (theoretical value), 1395.5 (observed value). HPLC retention time: 1.27 min. Example 132. (E)-9-(4-(5- aminoformyl- 2-(1- ethyl -3- methyl -1H -pyrazole -5 -carboxamido )-7-(3-( methylamino ) propoxy )-1H- benzo [d] imidazol - 1- yl )but-2-en - 1- yl ) -2-(1- ethyl -3- methyl -1H - pyrazol - 5- yl )-9H -pyrido [2',3':4,5] pyrrolo [2,3-d] pyrimidine -6- carboxamide ( Compound 1.33) Synthesis of compound 79a

A solution of compound 28 (50 mg, 156 μmol), compound 7 (137 mg, 233 μmol) and Cs ₂ CO ₃ (253 mg, 778 μmol) in DMF (0.5 mL) was brought to 55 °C and stirred for 16 h. LCMS analysis showed consumption of starting material and desired m/z. The solution was filtered and the filtrate was purified by prepHPLC (Method 1). The fractions were collected, frozen, and lyophilized to give compound 79a (78.0 mg, 89.3 μmol, 57% yield). UPLC-MS (Method A, ESI+): m/z [M+H] ⁺ = 873.4 (theoretical value), 873.4 (observed value). HPLC retention time: 1.58 min. Synthesis of compound 1.33

A solution of compound 79a (78.0 mg, 89.3 μmol) in 20% TFA in MeCN (893 μL) was brought to 30 °C and stirred for 2 h. LCMS analysis showed consumption of starting material and desired m/z. The solvent was removed under reduced pressure to give a residue, which was purified by prepHPLC (Method 1). The fractions were collected, frozen, and lyophilized to give compound 1.33 x 1 TFA (64.7 mg, 73.0 μmol, 82% yield). UPLC-MS (Method A, ESI+): m/z [M+H] ⁺ = 773.4 (theoretical), 773.4 (observed). HPLC retention time: 1.40 min. Example 133. (E)-9-(4-(5- aminoformyl- 7-(3-(3-(2,5- dioxo -2,5- dihydro -1H -pyrrol -1- yl )-N -methylpropionamido ) propoxy )-2-(1- ethyl -3- methyl - 1H -pyrazole -5- carboxamido )-1H - benzo [d] imidazol - 1 - yl ) but- 2 - en - 1- yl )-2-(1- ethyl -3- methyl -1H -pyrazol -5- yl )-9H -pyrido [2',3':4,5] pyrrolo [2,3-d] pyrimidine -6- carboxamide ( Compound 2.101)

Compound 2.101 (9.71 mg, 10.5 μmol, 62% yield) was prepared following General Method 1 using compound 1.33 x 1 TFA (15 mg, 16.9 μmol) as starting material. UPLC-MS (Method A, ESI+): m/z [M+H] ⁺ = 924.4 (theoretical value), 924.4 (observed value). HPLC retention time: 1.43 min. Example 134. S-(1-(3-((3-((5- aminoformyl -1-((E)-4-(6- aminoformyl- 2-(1- ethyl -3- methyl -1H -pyrazol -5- yl )-9H -pyrido [2',3':4,5] pyrrolo [2,3-d] pyrimidin -9- yl ) but -2- en - 1- yl )-2-(1- ethyl -3- methyl -1H -pyrazol -5 -carboxamido )-1H- benzo [d] imidazol -7- yl ) oxy ) propyl )( methyl ) amino ) -3 - oxopropyl )-2,5 -dioxopyrrolidin- 3- yl )-L- cysteine ( Compound 3.32)

Compound 3.32 (3.86 mg, 3.3 μmol, 62 % yield) was prepared following General Method 2 using compound 2.101 (5 mg, 5.4 μmol) as starting material. UPLC-MS (Method A, ESI+): m/z [M+H] ⁺ = 1045.4 (theoretical), 1045.5 (observed). HPLC retention time: 1.34 min. Example 135. 4-(( S)-2-((S)-2-(3-(2,5- dihydroxy-2,5-dihydro-1H-pyrrol-1- yl ) propionamido ) -3 - methylbutanamido ) propionamido ) benzyl (3-((5- aminoformyl -1 - ( ( E)-4-(6-aminoformyl - 2- (1-ethyl-3-methyl-1H-pyrazol-5-yl)-9H-pyrido[2',3':4,5]pyrrolo[2,3-d]pyrimidin-9-yl)but-2-en-1- yl ) -2- ( 1 - ethyl - 3 - methyl - 1H - pyrazol - 5 - carboxamido ) -1H - benzo [ d ] imidazol - 7 - yl ) oxy ) propyl ) ( methyl ) carbamate ( Compound 2.102 )

Compound 2.102 (6.38 mg, 5.1 μmol, 91% yield) was prepared following General Method 3 using compound 1.33 x1 TFA (5 mg, 5.6 μmol) as starting material. UPLC-MS (Method A, ESI+): m/z [M+H] ⁺ = 1243.5 (theoretical), 1243.5 (observed). HPLC retention time: 1.53 min. Example 136. (2S,3S,4S,5R,6S)-6-(2-(3- aminopropionamido )-4-((((3-((5- aminoformyl- 1-((E)-4-(6- aminoformyl- 2-(1- ethyl -3- methyl -1H -pyrazol -5- yl )-9H -pyrido [2',3':4,5] pyrrolo [2,3-d] pyrimidin -9- yl ) but - 2-en-1- yl ) -2-(1- ethyl - 3- methyl - 1H -pyrazol -5- carboxamido )-1H- benzo [d] imidazol -7- yl ) oxy ) propyl )( methyl ) aminoformyl ) oxy ) methyl ) phenoxy )-3,4,5- trihydroxytetrahydro -2H- pyran- 2-carboxylic acid ( Compound 2.103 ) Synthesis of compound 80a

Compound 80a (42.4 mg, 27.4 μmol, 54% yield) was prepared following General Method 4 using compound 1.33 x1 TFA (44.7 mg, 50.4 μmol) as starting material. UPLC-MS (Method A, ESI+): m/z [M+H] ⁺ = 1547.6 (theoretical value), 1547.6 (observed value). HPLC retention time: 1.83 min. Synthesis of Compound 80b

Following General Method 7, Compound 80b (20.8 mg, 16 μmol, 58% yield) was prepared using Compound 80a (42.4 mg, 27.4 μmol) as starting material. UPLC-MS (Method A, ESI+): m/z [M+H] ⁺ = 1185.5 (theoretical value), 1185.5 (observed value). HPLC retention time: 1.41 min. Synthesis of Compound 2.103

Compound 2.103 (14.9 mg, 11.2 μmol, 70% yield) was prepared following General Method 7 using compound 80b (20.8 mg, 16 μmol) as starting material. UPLC-MS (Method A, ESI+): m/z [M+H] ⁺ = 1336.5 (theoretical value), 1336.5 (observed value). HPLC retention time: 1.37 min. Example 137. (E)-9-(4-(5- aminoformyl- 2-(1- ethyl -3- methyl -1H -pyrazole -5 -carboxamido )-7-(3-( methylamino ) propoxy )-1H- benzo [d] imidazol -1 - yl ) but-2-en - 1 - yl )-2-(1- ethyl -3- methyl -1H-1,2,4- triazol -5- yl )-8- methoxy -9H- pyrimido [4,5-b] indole -6- carboxamide ( Compound 1.34) Synthesis of compound 81a

A solution of compound 40d (50 mg, 142 μmol), compound 7 (126 mg, 214 μmol) and Cs ₂ CO ₃ (232 mg, 712 μmol) in DMF (0.5 mL) was brought to 55 °C and stirred for 16 h. LCMS analysis showed consumption of starting material and desired m/z. The reaction was filtered and the filtrate was purified by prepHPLC (Method 1). The fractions were collected, frozen, and lyophilized to give compound 81a (30.9 mg, 34.3 μmol, 24% yield). UPLC-MS (Method A, ESI+): m/z [M+H] ⁺ = 903.4 (theoretical value), 903.4 (observed value). HPLC retention time: 1.55 min. Synthesis of compound 1.34

A solution of compound 81a (30.9 mg, 34.3 μmol) in 20% TFA in MeCN (342 μL) was brought to 35 °C and stirred for 2 h. LCMS analysis showed consumption of starting material and desired m/z. The solution was concentrated to give a residue. The residue was purified by prepHPLC (Method 1). The fractions were collected, frozen, and lyophilized to give compound 1.34 x 1 TFA (22.3 mg, 24.3 μmol, 71% yield). UPLC-MS (Method A, ESI+): m/z [M+H] ⁺ = 803.4 (theoretical), 803.4 (observed). HPLC retention time: 1.31 min. Example 138. (E)-9-(4-(5- aminoformyl- 7-(3-(3-(2,5- dioxo -2,5- dihydro -1H -pyrrol -1- yl )-N -methylpropionamido ) propoxy )-2-(1- ethyl -3- methyl - 1H -pyrazole -5- carboxamido )-1H - benzo [d] imidazol - 1 - yl ) but -2- en - 1 - yl ) -2-(1- ethyl -3- methyl -1H-1,2,4- triazol -5 - yl )-8- methoxy- 9H- pyrimido [4,5-b] indole -6- carboxamide ( Compound 2.104)

Compound 2.104 (8.29 mg, 8.7 μmol, 80% yield) was prepared following General Method 1 using compound 1.34 x 1 TFA (10 mg, 10.9 μmol) as starting material. UPLC-MS (Method A, ESI+): m/z [M+H] ⁺ = 954.4 (theoretical value), 954.4 (observed value). HPLC retention time: 1.44 min.

Example 139. S-(1-(3-((3-((5- aminoformyl -1-((E)-4-(6- aminoformyl -2-(1- ethyl -3- methyl -1H-1,2,4- triazol -5- yl )-8- methoxy -9H- pyrimido [4,5-b] indol- 9- yl ) but-2- en - 1 - yl )-2-(1- ethyl -3- methyl -1H -pyrazole -5 -carboxamido )-1H - benzo [d] imidazol - 7 -yl)oxy)propyl)(methyl)amino ) -3 - oxopropyl ) -2,5 - dioxopyrrolidin - 3 - yl ) -L- cysteine ( Compound 3.33)

Compound 3.33 (3.97 mg, 3.3 μmol, 64% yield) was prepared following General Method 2 using compound 2.104 (5 mg, 5.2 μmol) as starting material. UPLC-MS (Method A, ESI+): m/z [M+H] ⁺ = 1075.4 (theoretical), 1075.5 (observed). HPLC retention time: 1.29 min. Example 140. 4-((S)-2-((S)-2-(3-(2,5-dihydroxy-2,5-dihydro-1H-pyrrol-1-yl)propionamido)-3-methylbutanamido)propionamido)benzyl (3-( ( 5 - aminoformyl - 1 - ( ( E ) -4- ( 6 - aminoformyl-2-(1-ethyl-3-methyl-1H-1,2,4-triazol-5-yl)-8-methoxy-9H-pyrimido[4,5-b] indol - 9 - yl ) but - 2 - en - 1 - yl) -2- ( 1 - ethyl - 3 - methyl - 1H - pyrazole - 5 - carboxamido ) -1H - benzo [ d] imidazol - 7 - yl )oxy ) propyl)( methyl ) carbamate ( Compound 2.105)

Compound 2.105 (3.08 mg, 2.4 μmol, 74% yield) was prepared following General Method 3 using compound 1.34 x 1 TFA (3 mg, 3.3 μmol) as starting material. UPLC-MS (Method A, ESI+): m/z [M+H] ⁺ = 1273.6 (theoretical), 1273.6 (observed). HPLC retention time: 1.46 min. Example 141. (2S,3S,4S,5R,6S)-6-(4-((((3-((5- aminoformyl -1-((E)-4-(6- aminoformyl -2-(1- ethyl -3- methyl -1H-1,2,4- triazol -5- yl )-8- methoxy -9H- pyrimido [4,5-b] indol- 9- yl ) but -2- en - 1 - yl )-2-(1- ethyl -3- methyl -1H -pyrazole -5 -carboxamido )-1H - benzo [d] imidazol -7- yl ) oxy ) propyl )( methyl ) aminocarboxamido ) oxy ) methyl )-2-(3-(3-(2,5- dihydroxy -2,5 - dihydro -1H - pyrrol -1- yl ) propionamido ) propionamido ) phenoxy )-3,4,5- trihydroxytetrahydro -2H- pyran -2-carboxylic acid ( Compound 2.106) Synthesis of compound 82a

Compound 82a (9.07 mg, 5.7 μmol, 57% yield) was prepared following General Method 4 using compound 1.34 x1 TFA (9.26 mg, 10.1 μmol) as starting material. UPLC-MS (Method A, ESI+): m/z [M+H] ⁺ = 1577.6 (theoretical value), 1577.6 (observed value). HPLC retention time: 1.77 min. Synthesis of Compound 82b

Following General Method 7, compound 82a (9.07 mg, 5.7 μmol) was used as the starting material to prepare compound 82b x1 TFA (4.08 mg, 3.1 μmol, 53% yield). UPLC-MS (Method A, ESI+): m/z [M+H] ⁺ = 1215.5 (theoretical value), 1215.5 (observed value). HPLC retention time: 1.31 min. Synthesis of compound 2.106

Compound 2.106 (2.75 mg, 2.0 μmol, 66% yield) was prepared following General Method 6 using 82b x1 TFA (4.08 mg, 3.1 μmol) as starting material. UPLC-MS (Method A, ESI+): m/z [M+H] ⁺ = 1366.5 (theoretical), 1366.5 (observed). HPLC retention time: 1.33 min. Example 142 (E)-N-(5- aminoformyl- 1-(4-(6- aminoformyl- 2-(1- ethyl - 3- methyl - 1H -pyrazol -5- yl )-8-(3- hydroxypropoxy )-9H- pyrimido [4,5-b] indol -9- yl ) but -2- en-1-yl ) -7 - methoxy - 1H- benzo [d] imidazol -2- yl )-4- ethyl -2- methyloxazole -5- carboxamide ( Compound 1.22) Synthesis of compound 83a

A solution of compound 61c (50 mg, 97.2 μmol), compound 57d (62.9 mg, 146 μmol) and Cs ₂ CO ₃ (158 mg, 486 μmol) in DMF (972 μL) was brought to 55° C. and stirred for 16 h. LCMS analysis showed consumption of starting material and desired m/z. The solution was filtered and the filtrate was purified by prepHPLC (Method 1). The fractions were collected, frozen, and lyophilized to give compound 83a (51.1 mg, 56.2 μmol, 58% yield). UPLC-MS (Method A, ESI+): m/z [M+H] ⁺ = 910.4 (theoretical value), 910.4 (observed value). HPLC retention time: 1.59 min. Synthesis of compound 1.22

A solution of compound 83a (51.1 mg, 56.2 μmol) in 20% HCl in DCM (561 μL) was brought to 30 °C and stirred for 30 min. LCMS analysis showed consumption of starting material and desired m/z. Cold water (50 mL) was added and the solution was filtered. The filter cake was washed with cold water again and the product was collected and dried under reduced pressure for 16 h to give compound 1.22 (22.8 mg, 28.8 μmol, 51% yield). UPLC-MS (Method A, ESI+): m/z [M+H] ⁺ = 790.3 (theoretical value), 790.3 (observed value). HPLC retention time: 1.38 min. Example 143. (E)-9-(4-(5- aminoformyl- 2-(1- ethyl -3- methyl -1H -pyrazole -5 -carboxamido )-7-(3-( methylamino ) propoxy )-1H- benzo [d] imidazol -1 - yl )but-2- en - 1- yl ) -2-(1- ethyl - 3- methyl -1H -pyrazol - 5- yl )-8- methyl -9H -pyrido [4',3':4,5] pyrrolo [2,3-d] pyrimidine -6- carboxamide ( Compound 1.35) Synthesis of compound 84a

A solution of compound 29 (50 mg, 149 μmol), compound 7 (132 mg, 224 μmol) and Cs ₂ CO ₃ (243 mg, 745 μmol) in DMF (1.5 mL) was brought to 55 °C and stirred for 16 h. LCMS analysis showed consumption of starting material and desired m/z. Cold water (10 mL) was added to the solution to precipitate the product. The resulting mixture was filtered and the filter cake was washed with cold water again. The solid was collected and dried under high vacuum for 16 h to give compound 84a (133 mg, crude). UPLC-MS (Method A, ESI+): m/z [M+H] ⁺ = 887.4 (theoretical value), 887.5 (observed value). HPLC retention time: 1.56 min. Synthesis of compound 1.35

A solution of compound 84a (133 mg mg, 151 μmol, crude) in 20% TFA in MeCN (1.5 mL) was brought to 35 °C and stirred for 2 h. LCMS analysis showed consumption of starting material and desired m/z. The solution was concentrated to give a residue. The residue was purified by prepHPLC (Method 1). The fractions were collected, frozen, and lyophilized to give compound 1.35 x 1 TFA (62.8 mg, 69.7 μmol, 46% yield). UPLC-MS (Method A, ESI+): m/z [M+H] ⁺ = 787.4 (theoretical), 787.4 (observed). HPLC retention time: 1.28 min. Example 144. (E)-9-(4-(5- aminoformyl- 7-(3-(3-(2,5- dioxo -2,5- dihydro -1H -pyrrol -1- yl )-N -methylpropionamido ) propoxy )-2-(1- ethyl -3- methyl - 1H -pyrazole -5- carboxamido )-1H - benzo [d] imidazol - 1 - yl ) but -2- en - 1 - yl )-2-(1- ethyl -3- methyl -1H -pyrazol -5 - yl )-8- methyl -9H -pyrido [4',3':4,5] pyrrolo [2,3-d] pyrimidine -6- carboxamide ( Compound 2.107)

Compound 2.107 (15.0 mg, 16.0 μmol, 52% yield) was prepared following General Method 1 using compound 1.35 x 1 TFA (27.8 mg, 30.8 μmol) as starting material. UPLC-MS (Method A, ESI+): m/z [M+H] ⁺ = 938.4 (theoretical value), 938.4 (observed value). HPLC retention time: 1.43 min. Example 145. S-(1-(3-((3-((5- aminoformyl -1-((E)-4-(6- aminoformyl- 2-(1- ethyl -3- methyl -1H -pyrazol- 5- yl )-8- methyl -9H -pyrido [4',3':4,5] pyrrolo [2,3-d] pyrimidin -9 - yl ) but-2-en - 1 - yl )-2-(1- ethyl -3- methyl -1H -pyrazol - 5 -carboxamido )-1H- benzo [d] imidazol -7- yl ) oxy ) propyl )( methyl ) amino ) -3 -oxopropyl )-2,5 -dioxopyrrolidin -3- yl )-L- cysteine ( Compound 3.34)

Compound 3.34 (4.64 mg, 4.4 μmol, 55% yield) was prepared following General Method 2 using compound 2.107 (7.5 mg, 8.0 μmol) as starting material. UPLC-MS (Method A, ESI+): m/z [M+H] ⁺ = 1059.4 (theoretical), 1059.5 (observed). HPLC retention time: 1.31 min. Example 146. (3-((5- aminoformyl -1-((E)-4-(6- aminoformyl -2-(1- ethyl-3 - methyl -1H - pyrazol -5- yl )-8- methyl -9H -pyrido [4',3':4,5] pyrrolo [2,3-d] pyrimidin -9- yl ) but - 2- en - 1- yl )-2-(1- ethyl -3- methyl -1H -pyrazol -5 -carboxamido )-1H- benzo [d] imidazol -7- yl ) oxy ) propyl )( methyl ) carbamate 4-((S)-2-((S)-2-(3-(2,5- dihydroxy -2,5 -dihydro -1H -pyrrol -1- yl ) propionamido )-3 -methylbutanamido ) propionamido ) benzyl ester ( Compound 2.108)

Compound 2.108 (3.4 mg, 2.7 μmol, 49% yield) was prepared following General Method 3 using compound 1.35 x 1 TFA (5.0 mg, 5.5 μmol) as starting material. UPLC-MS (Method A, ESI+): m/z [M+H] ⁺ = 1057.5 (theoretical), 1257.57 (observed). HPLC retention time: 1.45 min. Example 147. (2S,3S,4S,5R,6S)-6-(4-((((3-((5- aminoformyl -1-((E)-4-(6- aminoformyl- 2-(1- ethyl -3- methyl -1H - pyrazol -5- yl )-8- methyl -9H - pyrido [4',3':4,5] pyrrolo [2,3-d] pyrimidin -9- yl ) but -2- en -1 - yl )-2-(1- ethyl -3 -methyl - 1H -pyrazole -5 -carboxamido )-1H- benzo [d] imidazol -7- yl ) oxy ) propyl )( methyl ) aminocarboxamido ) oxy ) methyl )-2-(3-(3-(2,5- dihydroxy -2,5 -dihydro -1H -pyrrol -1- yl ) propionamido ) propionamido ) phenoxy )-3,4,5- trihydroxytetrahydro -2H- pyran -2-carboxylic acid ( Compound 2.109) Synthesis of compound 85a

Compound 85a (30.8 mg, 19.7 μmol, 59% yield) was prepared following General Method 4 using compound 1.35 x 1 TFA (30 mg, 33.3 μmol) as starting material. UPLC-MS (Method A, ESI+): m/z [M+H] ⁺ = 1561.6 (theoretical value), 1561.6 (observed value). HPLC retention time: 1.75 min. Synthesis of Compound 85b

Following General Method 7, Compound 85b x 1 TFA (7.48 mg, 5.7 μmol, 29% yield) was prepared using Compound 85a (30.8 mg, 19.7 μmol) as starting material. UPLC-MS (Method A, ESI+): m/z [M+H] ⁺ = 1199.5 (theoretical value), 1199.5 (observed value). HPLC retention time: 1.32 min. Synthesis of Compound 2.109

Compound 2.109 (5.37 mg, 4.0 μmol, 70% yield) was prepared following General Method 6 using compound 85b x 1 TFA (7.48 mg, 5.7 μmol) as starting material. UPLC-MS (Method A, ESI+): m/z [M+H] ⁺ = 1350.5 (theoretical value), 1350.5 (observed value). HPLC retention time: 1.33 min. Example 148. (E)-9-(4-(5- aminoformyl- 2-(1- ethyl -3- methyl -1H -pyrazole -5 -carboxamido )-7-(3-( methylamino ) propoxy )-1H- benzo [d] imidazol -1 - yl ) but-2- en - 1- yl )-2-(1- ethyl - 3- methyl -1H -pyrazol - 5- yl )-8- methoxy -9H -pyrido [2',3':4,5] pyrrolo [2,3-d] pyrimidine -6- carboxamide ( Compound 1.36) Synthesis of compound 86a

A solution of compound 43g (50 mg, 142 μmol), compound 7 (126 mg, 214 μmol) and Cs ₂ CO ₃ (232 mg, 712 μmol) in DMF (1.4 mL) was brought to 55 °C and stirred for 16 h. LCMS analysis showed consumption of starting material and desired m/z. Cold water (10 mL) was added to the solution to precipitate the product. The resulting mixture was filtered and the filter cake was washed with cold water again. The solid was collected and dried under high vacuum for 16 h to give compound 86a (147 mg, crude). UPLC-MS (Method A, ESI+): m/z [M+H] ⁺ = 903.4 (theoretical value), 903.5 (observed value). HPLC retention time: 1.59 min. Synthesis of compound 1.36

A solution of compound 86a (147 mg, 163 μmol, crude) in 20% TFA in MeCN (1.4 mL) was brought to 35 °C and stirred for 2 h. LCMS analysis showed consumption of starting material and desired m/z. The solution was concentrated to give a residue. The residue was purified by prepHPLC (Method 1). The fractions were collected, frozen, and lyophilized to give compound 1.36 x 1 TFA (94.3 mg, 103 μmol, 63% yield). UPLC-MS (Method A, ESI+): m/z [M+H] ⁺ = 803.4 (theoretical), 803.4 (observed). HPLC retention time: 1.31 min. Example 149. (E)-9-(4-(5- aminoformyl- 7-(3-(3-(2,5- dioxo -2,5- dihydro -1H -pyrrol -1- yl )-N -methylpropionamido ) propoxy )-2-(1- ethyl -3- methyl - 1H -pyrazole -5- carboxamido )-1H - benzo [d] imidazol - 1 - yl )but- 2 - en -1- yl ) -2-(1- ethyl -3- methyl -1H -pyrazol -5- yl )-8- methoxy -9H -pyrido [2',3':4,5] pyrrolo [2,3-d] pyrimidine -6- carboxamide ( Compound 2.110)

Compound 2.110 (33.7 mg, 35.3 μmol, 65% yield) was prepared following General Method 1 using compound 1.36 x 1 TFA (50 mg, 54.5 μmol) as starting material. UPLC-MS (Method A, ESI+): m/z [M+H] ⁺ = 954.4 (theoretical value), 954.4 (observed value). HPLC retention time: 1.43 min. Example 150. S-(1-(3-((3-((5- aminoformyl -1-((E)-4-(6- aminoformyl -2-(1- ethyl -3- methyl -1H -pyrazol- 5- yl )-8- methoxy -9H -pyrido [2',3':4,5] pyrrolo [2,3-d] pyrimidin -9 - yl ) but-2-en-1-yl ) -2- ( 1 - ethyl -3- methyl -1H -pyrazol - 5 -carboxamido )-1H- benzo [d] imidazol -7- yl ) oxy ) propyl )( methyl ) amino )-3 -oxopropyl )-2,5 -dioxopyrrolidin- 3- yl )-L- cysteine ( Compound 3.35)

Compound 3.35 (9.73 mg, 9.0 μmol, 58% yield) was prepared following General Method 2 using compound 2.110 (15 mg, 15.7 μmol) as starting material. UPLC-MS (Method A, ESI+): m/z [M+H] ⁺ = 1075.4 (theoretical), 1075.5 (observed). HPLC retention time: 1.34 min. Example 151. (3-((5- aminoformyl -1-((E)-4-(6- aminoformyl- 2-(1- ethyl -3- methyl -1H -pyrazol -5- yl )-8- methoxy -9H -pyrido [2',3':4,5] pyrrolo [2,3-d] pyrimidin -9- yl ) but - 2- en - 1- yl )-2-(1- ethyl -3- methyl -1H -pyrazol -5 -carboxamido )-1H- benzo [d] imidazol -7- yl ) oxy ) propyl )( methyl ) carbamate 4-((S)-2-((S)-2-(3-(2,5- dihydroxy -2,5 -dihydro -1H -pyrrol -1- yl ) propionamido )-3 -methylbutanamido ) propionamido ) benzyl ester ( Compound 2.111)

Compound 2.111 (4.05 mg, 3.2 μmol, 58% yield) was prepared following General Method 3 using compound 1.36 x 1 TFA (5.0 mg, 5.5 μmol) as starting material. UPLC-MS (Method A, ESI+): m/z [M+H] ⁺ = 1273.6 (theoretical), 1273.6 (observed). HPLC retention time: 1.50 min. Example 152. (2S,3S,4S,5R,6S)-6-(4-((((3-((5- aminoformyl -1-((E)-4-(6- aminoformyl- 2-(1- ethyl -3- methyl -1H -pyrazol -5- yl )-8- methoxy -9H -pyrido [2',3':4,5] pyrrolo [2,3-d] pyrimidin -9- yl ) but -2- en -1 - yl )-2-(1 - ethyl- (3- methyl -1H -pyrazole -5 -carboxamido )-1H- benzo [d] imidazol -7- yl ) oxy ) propyl )( methyl ) aminocarboxamido ) oxy ) methyl )-2-(3-(3-(2,5- dihydroxy - 2,5 - dihydro -1H -pyrrol -1- yl ) propionamido ) propionamido ) phenoxy )-3,4,5- trihydroxytetrahydro -2H- pyran -2-carboxylic acid ( Compound 2.112) Synthesis of compound 87a

Compound 87a (45.1 mg, 28.6 μmol, 67% yield) was prepared following General Method 4 using compound 1.36 x 1 TFA (39.3 mg, 42.9 μmol) as starting material. UPLC-MS (Method A, ESI+): m/z [M+H] ⁺ = 1577.6 (theoretical value), 1577.6 (observed value). HPLC retention time: 1.77 min. Synthesis of Compound 87b

Compound 87b x 1 TFA (22.2 mg, 16.7 μmol, 58% yield) was prepared following General Method 7 using compound 87a (45.1 mg, 28.6 μmol) as starting material. UPLC-MS (Method A, ESI+): m/z [M+H] ⁺ = 1215.5 (theoretical value), 1215.5 (observed value). HPLC retention time: 1.42 min. Synthesis of compound 2.112

Compound 2.112 (14.4 mg, 10.5 μmol, 63% yield) was prepared following General Method 6 using compound 87b x 1 TFA (22.2 mg, 16.7 μmol) as starting material. UPLC-MS (Method A, ESI+): m/z [M+H] ⁺ = 1366.5 (theoretical value), 1366.5 (observed value). HPLC retention time: 1.38 min. Example 153. (E)-N-(5- aminoformyl- 1-(4-(6- aminoformyl- 2-(1- ethyl -3 - methyl - 1H -pyrazol -5- yl )-8-(3-( methylamino ) propoxy )-9H- pyrimido [4,5-b] indol- 9- yl ) but -2- en -1 - yl )-7- methoxy -1H- benzo[d]imidazol - 2 - yl ) -4- ethyl -2- methyloxazole -5- carboxamide ( Compound 1.15) Synthesis of compound 88a

A solution of compound 71e (50 mg, 98.5 μmol), compound 57d (63.8 mg, 148 μmol) and Cs ₂ CO ₃ (160 mg, 493 μmol) in DMF (1 mL) was brought to 55 °C and stirred for 16 h. LCMS analysis showed consumption of starting material and desired m/z. Cold water (10 mL) was added to the solution to precipitate the product. The resulting mixture was filtered and the filter cake was washed with cold water again. The solid was collected and dried under high vacuum for 16 h to give compound 88a (70.9 mg, crude). UPLC-MS (Method A, ESI+): m/z [M+H] ⁺ = 903.4 (theoretical value), 903.4 (observed value). HPLC retention time: 1.54 min. Synthesis of compound 1.15

A solution of compound 88a (70.9 mg, 78.6 μmol, crude) in 20% TFA in MeCN (786 μL) was brought to 35 °C and stirred for 2 h. LCMS analysis showed consumption of starting material and desired m/z. The solution was concentrated to give a residue. The residue was purified by prepHPLC (Method 1). The fractions were collected, frozen, and lyophilized to give compound 1.15 x 1 TFA (44.7 mg, 48.7 μmol, 62% yield). UPLC-MS (Method A, ESI+): m/z [M+H] ⁺ = 803.4 (theoretical), 803.4 (observed). HPLC retention time: 1.33 min. Example 154. (E)-N-(5- aminoformyl -1-(4-(6- aminoformyl- 8-(3-(3-(2,5- dioxo -2,5 - dihydro -1H -pyrrol -1- yl )-N- methylpropionamido ) propoxy )-2-(1- ethyl- 3- methyl -1H -pyrazol -5- yl )-9H- pyrimido [4,5-b] indol -9 - yl ) but- 2-en-1-yl ) -7 - methoxy - 1H - benzo [d] imidazol -2- yl )-4- ethyl -2- methyloxazole -5- carboxamide ( Compound 2.43)

Compound 2.43 (4.68 mg, 4.9 μmol, 30% yield) was prepared following General Method 1 using compound 1.15 x 1 TFA (15 mg, 16.4 μmol) as starting material. UPLC-MS (Method A, ESI+): m/z [M+H] ⁺ = 954.4 (theoretical value), 954.4 (observed value). HPLC retention time: 1.41 min. Example 155. S-(1-(3-((3-((6- aminoformyl- 9-((E)-4-(5- aminoformyl- 2-(4- ethyl -2- methyloxazole -5 -carboxamido )-7- methoxy -1H- benzo [d] imidazol -1- yl ) but - 2- en -1- yl )-2-(1- ethyl -3- methyl -1H -pyrazol -5- yl )-9H- pyrimido [4,5-b] indol- 8 - yl ) oxy ) propyl )( methyl ) amino )-3 -oxopropyl )-2,5 -dioxopyrrolidin -3- yl )-L- cysteine ( Compound 3.15)

Compound 3.15 (0.56 mg, 5.0 μmol, 21% yield) was prepared following General Method 2 using compound 2.43 (2.34 mg, 2.5 μmol) as starting material. UPLC-MS (Method A, ESI+): m/z [M+H] ⁺ = 1075.4 (theoretical value), 1075.4 (observed value). HPLC retention time: 1.33 min. Example 156. 4-( (S)-2-((S)-2- ( 3-(2,5 - dihydroxy - 2,5 - dihydro- 1H-pyrrol- 1 - yl ) propionamido)-3-methylbutanamido ) propionamido ) benzyl (3-((6- aminoformyl - 9 -( ( E )-4-(5-aminoformyl-2-(4- ethyl - 2 - methyloxazol - 5 - carboxamido )-7 -methoxy-1H-benzo[d] imidazol -1- yl ) but -2-en-1-yl ) -2- ( 1 - ethyl -3-methyl-1H-pyrazol-5-yl)-9H-pyrimido[4,5 - b ] indol - 8 - yl ) oxy ) propyl ) (methyl ) carbamate ( Compound 2.44)

Compound 2.44 (3.67 mg, 2.9 μmol, 53% yield) was prepared following General Method 3 using compound 1.15 x 1 TFA (5.0 mg, 5.5 μmol) as starting material. UPLC-MS (Method A, ESI+): m/z [M+H] ⁺ = 1273.6 (theoretical), 1273.6 (observed). HPLC retention time: 1.48 min. Example 157. (2S,3S,4S,5R,6S)-6-(4-((((3-((6- aminoformyl -9-((E)-4-(5- aminoformyl- 2-(4- ethyl -2 -methyloxazol - 5-carboxamido )-7- methoxy -1H- benzo [d] imidazol -1- yl ) but-2-en -1-yl ) -2- ( 1- ethyl -3- methyl -1H - pyrazole- (5- yl )-9H- pyrimido [4,5-b] indol- 8- yl ) oxy ) propyl )( methyl ) aminoformyl ) oxy ) methyl )-2-(3-(3-(2,5- dihydroxy - 2,5 - dihydro -1H -pyrrol - 1- yl ) propionamido ) propionamido ) phenoxy )-3,4,5- trihydroxytetrahydro -2H- pyran -2-carboxylic acid ( Compound 2.45) Synthesis of compound 89a

Compound 89a (23.3 mg, 14.8 μmol, 55% yield) was prepared following General Method 4 using compound 1.15 x 1 TFA (24.7 mg, 26.9 μmol) as starting material. UPLC-MS (Method A, ESI+): m/z [M+H] ⁺ = 1577.6 (theoretical value), 1577.6 (observed value). HPLC retention time: 1.75 min. Synthesis of Compound 89b

Compound 89b x 1 TFA (7.75 mg, 5.8 μmol, 40% yield) was prepared following General Method 7 using compound 89a (23.3 mg, 14.8 μmol) as starting material. UPLC-MS (Method A, ESI+): m/z [M+H] ⁺ = 1215.5 (theoretical value), 1215.5 (observed value). HPLC retention time: 1.31 min. Synthesis of compound 2.45

Compound 2.45 (5.08 mg, 3.7 μmol, 64% yield) was prepared following General Method 6 using compound 89b x 1 TFA (7.75 mg, 5.8 μmol) as starting material. UPLC-MS (Method A, ESI+): m/z [M+H] ⁺ = 1366.5 (theoretical value), 1366.5 (observed value). HPLC retention time: 1.34 min. Example 158. (E)-5-(4-(5- aminoformyl- 2-(1- ethyl -3- methyl -1H -pyrazole -5- carboxamido )-7-(3-( methylamino ) propoxy )-1H- benzo [d] imidazol - 1- yl ) but-2- en - 1- yl )-3-(1- ethyl - 3- methyl -1H -pyrazole -5- yl )-6- methoxy -5H -oxazin [4,3-b] indole -8- carboxamide ( Compound 1.37) Synthesis of compound 90a

A solution of compound 65c (50 mg, 143 μmol), compound 7 (126 mg, 214 μmol) and Cs ₂ CO ₃ (232 mg, 712 μmol) in DMF (1.4 mL) was brought to 55 °C and stirred for 16 h. LCMS analysis showed consumption of starting material and desired m/z. Cold water (10 mL) was added to the solution to precipitate the product. The resulting mixture was filtered and the filter cake was washed with cold water again. The solid was collected and dried under high vacuum for 16 h to give compound 90a (133 mg, crude). UPLC-MS (Method A, ESI+): m/z [M+H] ⁺ = 902.4 (theoretical value), 902.4 (observed value). HPLC retention time: 1.52 min. Synthesis of compound 1.37

A solution of compound 90a (133 mg, 147 μmol, crude) in 20% TFA in MeCN (1.5 mL) was brought to 35 °C and stirred for 2 h. LCMS analysis showed consumption of starting material and desired m/z. The solution was concentrated to give a residue. The residue was purified by prepHPLC (Method 1). The fractions were collected, frozen, and lyophilized to give compound 1.37 x 1 TFA (75.2 mg, 82.0 μmol, 56% yield). UPLC-MS (Method A, ESI+): m/z [M+H] ⁺ = 802.4 (theoretical), 802.4 (observed). HPLC retention time: 1.29 min. Example 159. (E)-5-(4-(5- aminoformyl- 7-(3-(3-(2,5- dioxo -2,5- dihydro -1H -pyrrol -1- yl )-N -methylpropionamido ) propoxy )-2-(1- ethyl -3- methyl - 1H - pyrazole -5- carboxamido )-1H - benzo [d] imidazol - 1- yl ) but -2- en -1- yl ) -3-(1- ethyl -3- methyl -1H -pyrazol -5 - yl )-6- methoxy -5H- oxazino [4,3-b] indole -8- carboxamide ( Compound 2.113)

Compound 2.113 (3.39 mg, 3.6 μmol, 16% yield) was prepared following General Method 1 using compound 1.37 x 1 TFA (20 mg, 21.8 μmol) as starting material. UPLC-MS (Method A, ESI+): m/z [M+H] ⁺ = 953.4 (theoretical), 953.4 (observed). HPLC retention time: 1.42 min. Example 160. S-(1-(3-((3-((5- aminoformyl -1-((E)-4-(8- aminoformyl- 3-(1- ethyl -3- methyl -1H -pyrazol -5- yl )-6- methoxy - 5H- oxazino [4,3-b] indol -5- yl ) but- 2- en - 1 - yl )-2-(1- ethyl -3- methyl -1H -pyrazol -5 -carboxamido )-1H - benzo [d] imidazol -7- yl ) oxy ) propyl )( methyl ) amino )-3 - oxopropyl )-2,5 -dioxopyrrolidin -3- yl )-L- cysteine ( Compound 3.36)

Compound 3.36 (0.24 mg, 2 μmol, 13% yield) was prepared following General Method 2 using compound 2.113 (1.70 mg, 1.8 μmol) as starting material. UPLC-MS (Method A, ESI+): m/z [M+H] ⁺ = 1074.4 (theoretical), 1074.4 (observed). HPLC retention time: 1.39 min. Example 161. 4-(( S)-2-((S)-2-(3-(2,5- dihydroxy - 2,5- dihydro -1H -pyrrol - 1-yl)propionamido)-3-methylbutanamido)propionamido)benzyl (3- ( ( 5 - aminoformyl - 1 - ((E)-4-(8-aminoformyl-3-(1-ethyl-3-methyl-1H-pyrazol-5-yl)-6-methoxy-5H-oxazino[4,3-b] indol - 5 - yl ) but - 2 - en - 1 - yl ) -2- ( 1 - ethyl - 3 - methyl - 1H - pyrazol - 5 - carboxamido ) -1H - benzo [ d]imidazol - 7-yl ) oxy ) propyl)(methyl ) carbamate ( Compound 2.114)

Compound 2.114 (3.59 mg, 2.8 μmol, 52% yield) was prepared following General Method 3 using compound 1.37 x 1 TFA (5.0 mg, 5.5 μmol) as starting material. UPLC-MS (Method A, ESI+): m/z [M+H] ⁺ = 1272.6 (theoretical), 1272.6 (observed). HPLC retention time: 1.46 min. Example 162. (2S,3S,4S,5R,6S)-6-(4-((((3-((5- aminoformyl -1-((E)-4-(8- aminoformyl- 3-(1- ethyl -3- methyl -1H - pyrazol -5- yl )-6- methoxy -5H -oxazino [4,3-b] indol- 5- yl ) but-2- en -1 - yl )-2-(1- ethyl -3- methyl - 1H -pyrazole - 5 -carboxamido )-1H - benzo [d] imidazol -7- yl ) oxy ) propyl )( methyl ) aminocarboxamido ) oxy ) methyl )-2-(3-(3-(2,5- dihydroxy -2,5 - dihydro -1H -pyrrol -1- yl ) propionamido ) propionamido ) phenoxy )-3,4,5- trihydroxytetrahydro -2H- pyran -2-carboxylic acid ( Compound 2.115) Synthesis of compound 91a

Compound 91a (61.5 mg, 39.0 μmol, 71% yield) was prepared following General Method 4 using compound 1.37 x 1 TFA (50.2 mg, 54.8 μmol) as starting material. UPLC-MS (Method A, ESI+): m/z [M+H] ⁺ = 1576.6 (theoretical value), 1576.6 (observed value). HPLC retention time: 1.71 min. Synthesis of Compound 91b

Compound 91b x 1 TFA (32.3 mg, 24.3 μmol, 62% yield) was prepared following General Method 7 using compound 91a (61.5 mg, 39.0 μmol) as starting material. UPLC-MS (Method A, ESI+): m/z [M+H] ⁺ = 1214.5 (theoretical value), 1214.5 (observed value). HPLC retention time: 1.30 min. Synthesis of compound 2.115

Compound 2.115 (18.4 mg, 13.4 μmol, 55% yield) was prepared following General Method 6 using compound 91b x 1 TFA (32.3 mg, 24.3 μmol) as starting material. UPLC-MS (Method A, ESI+): m/z [M+H] ⁺ = 1365.5 (theoretical value), 1365.5 (observed value). HPLC retention time: 1.33 min. Example 163. (E)-9-(4-(5- aminoformyl- 2-(1- ethyl -3- methyl -1H -pyrazole -5- carboxamido )-7-(3-( methylamino ) propoxy )-1H- benzo [d] imidazol - 1- yl )but-2- en - 1- yl ) -7-(1- ethyl - 3- methyl -1H -pyrazol - 5- yl )-9H -pyrrolo [2,3-b:5,4-b'] bipyridine -3- carboxamide ( Compound 1.38) Synthesis of compound 92a

A solution of compound 41b (20 g, 71.2 mmol) in NH ₄ OH (250 mL) was stirred at 25 °C for 16 h. LCMS analysis showed consumption of starting material and desired m/z. The reaction mixture was concentrated under reduced pressure to give compound 92a (20 g, crude) as a white solid. UPLC-MS (Method P, ESI+): m/z [M+H] ⁺ = 267.1 (theoretical value), 267.1 (observed value). HPLC retention time: 0.688 min. Synthesis of compound 92b

To a solution of 3-bromo-6-chloropyridin-2-amine (1 g, 4.82 mmol) and compound 92a (2.57 g, 9.64 mmol) in dioxane (25 mL) and H ₂ O (5 mL) were added (A-taPhos) ₂ PdCl ₂ (650 mg, 918 μmol) and K ₂ CO ₃ (1.33 g. 9.64 mmol). The mixture was brought to 80 °C and stirred for 2 h. LCMS analysis showed consumption of starting material and the desired m/z. The reaction mixture was filtered and concentrated under reduced pressure to give a residue. The residue was purified by prepHPLC (Method 2) to give compound 92b (750 mg, 2.81 mmol,) as an off-white solid. UPLC-MS (method P, ESI+): m/z [M+H] ⁺ = 267.0 (theoretical value), 267.0 (observed value). HPLC retention time: 0.870 min. Synthesis of compound 92c

A mixture of compound 92b (617 mg, 2.31 mmol), compound 3g (1.09 g, 4.63 mmol), Pd(dppf) _Cl2 (254 mg, 347 μmol), _K2CO3 (640 mg, 4.63 mmol) in _dioxane (40 mL) and _H2O (8 mL) was degassed and purged with _N2 . The mixture was brought to 90 °C and stirred for 16 h. LCMS analysis showed consumption of starting material and the desired m/z. The reaction mixture was diluted with _H2O (30 mL) and extracted with EtOAc (2 x 50 mL). The combined organic layers were washed with aqueous NaCl (30 mL), dried _{over Na2SO4} , filtered, and concentrated under reduced pressure to give a residue. The residue was purified by prepHPLC (Method 11) to give compound 92c (466 mg, 1.37 mmol, 59% yield) as a white solid. UPLC-MS (Method D, ESI+): m/z [M+H] ⁺ = 341.1 (theoretical value), 341.3 (observed value). HPLC retention time: 1.072 min. Synthesis of compound 92d

A solution of compound 92c (250 mg, 735 μmol) and Cs ₂ CO ₃ (957 mg, 2.94 mmol) in DMA (10 mL) was placed in a microwave vial. The tube was sealed and heated to 165 °C for 30 min via microwave. LCMS analysis showed consumption of starting material and desired m/z. Three additional reactions were prepared as described and combined for work-up and purification. The reaction was diluted with H ₂ O (200 mL) and filtered. The filter cake was washed with MeOH (10 mL) and DCM (15 mL). The filter cake was dried to give compound 92d (145 mg, 453 μmol, 15% yield) as a grey solid. UPLC-MS (Method G, ESI+): m/z [M+H] ⁺ = 321.1 (theoretical value), 321.0 (observed value). HPLC retention time: 1.158 min. ¹ H NMR (400MHz, DMSO- d ₆ ) δ ppm 12.86 - 12.55 (m, 1H), 9.02 (br d, J = 15.3 Hz, 2H), 8.79 - 8.57 (m, 1H), 8.24 - 7.96 (m, 1H), 7.76 - 7.59 (m, 1H), 7.55 - 7.40 (m, 1H), 6.63 (br s, 1H), 4.84 - 4.44 (m, 2H), 2.22 (br s, 3H), 1.37 (br s, 3H). Synthesis of compound 92e

A solution of compound 92d (35 mg, 109 μmol), compound 7 (96.3 mg, 164 μmol) and Cs ₂ CO ₃ (178 mg, 546 μmol) in DMF (1.5 mL) was brought to 55 °C and stirred for 16 h. LCMS analysis showed consumption of starting material and desired m/z. Cold water (10 mL) was added to the mixture and the solid was filtered. The filter cake was washed with water (10 mL). The solid was dried under reduced pressure to give compound 92e (53.2 mg, 61 μmol, 56% yield), which was used without further purification. UPLC-MS (Method A, ESI+): m/z [M+H] ⁺ = 872.4 (theoretical), 872.4 (observed). HPLC retention time: 1.58 min. Synthesis of compound 1.38

A solution of compound 92e (53.2 mg, 61 μmol) in 20% TFA in MeCN (610 μL) was brought to 35 °C and stirred for 2 h. LCMS analysis showed consumption of starting material and desired m/z. The mixture was concentrated to give a residue that was purified by prepHPLC (Method 1). The fractions were collected, frozen, and lyophilized to give compound 1.38 x 1 TFA (28.5 mg, 32.2 μmol, 53% yield). UPLC-MS (Method A, ESI+): m/z [M+H] ⁺ = 772.4 (theoretical), 772.4 (observed). HPLC retention time: 1.32 min. Example 164. (E)-9-(4-(5- aminoformyl- 7-(3-(3-(2,5- dioxo -2,5- dihydro -1H -pyrrol- 1- yl )-N -methylpropionamido ) propoxy )-2-(1- ethyl -3- methyl - 1H -pyrazole -5- carboxamido )-1H - benzo [d] imidazol - 1 - yl ) but- 2 - en - 1- yl )-7-(1- ethyl -3- methyl -1H -pyrazol -5 - yl )-9H -pyrrolo [2,3-b:5,4-b'] bipyridine -3- carboxamide ( Compound 2.116)

Compound 2.116 (6.72 mg, 7.3 μmol, 64% yield) was prepared following General Method 1 using compound 1.38 x 1 TFA (10 mg, 11.3 μmol) as starting material. UPLC-MS (Method A, ESI+): m/z [M+H] ⁺ = 923.4 (theoretical), 923.4 (observed). HPLC retention time: 1.42 min. Example 165. S-(1-(3-((3-((5- aminoformyl -1-((E)-4-(6- aminoformyl- 2-(1- ethyl -3- methyl -1H -pyrazol- 5- yl )-9H -pyrrolo [2,3-b:5,4-b'] bipyridin - 9- yl ) but -2- en-1-yl ) -2- (1- ethyl -3- methyl -1H -pyrazol -5 -carboxamido )-1H- benzo [d] imidazol -7 -yl ) oxy ) propyl )( methyl ) amino )-3 - oxopropyl )-2,5 -dioxopyrrolidin -3- yl )-L- cysteine ( Compound 3.37)

Compound 3.37 (2.72 mg, 2.3 μmol, 72% yield) was prepared following General Method 2 using compound 2.116 (3.0 mg, 3.3 μmol) as starting material. UPLC-MS (Method A, ESI+): m/z [M+H] ⁺ = 1044.4 (theoretical), 1044.5 (observed). HPLC retention time: 1.29 min.

Example 166. 4-(( S)-2-((S)-2-(3-(2,5- dihydroxy- 2,5 - dihydro - 1H -pyrrol- 1- yl )propionamido )-3- methylbutanamido ) propionamido ) benzyl (3-((5- aminoformyl -1 - ((E )-4- ( 6- aminoformyl - 2-(1- ethyl - 3- methyl - 1H -pyrazol -5 - yl )-9H- pyrrolo [ 2,3- b :5,4-b'] bipyridin - 9 - yl ) but -2-en-1- yl ) -2-(1-ethyl-3- methyl - 1H -pyrazol - 5- carboxamido ) -1H - benzo [d ] imidazol-7-yl ) oxy ) propyl) (methyl ) carbamate ( Compound 2.117)

Compound 2.117 (1.76 mg, 1.4 μmol, 42% yield) was prepared following General Method 3 using compound 1.38 x 1 TFA (3.0 mg, 3.4 μmol) as starting material. UPLC-MS (Method A, ESI+): m/z [M+H] ⁺ = 1242.6 (theoretical), 1242.6 (observed). HPLC retention time: 1.49 min. Example 167. (2S,3S,4S,5R,6S)-6-(4-((((3-((5- aminoformyl -1-((E)-4-(6- aminoformyl- 2-(1- ethyl -3- methyl -1H - pyrazol -5- yl )-9H -pyrrolo [2,3-b:5,4-b'] bipyridin -9- yl ) but - 2- en -1 - yl )-2-(1- ethyl -3- methyl -1 H- pyrazole -5 -carboxamido )-1H - benzo [d] imidazol -7- yl ) oxy ) propyl )( methyl ) aminocarboxamido ) oxy ) methyl )-2-(3-(3-(2,5- dihydroxy - 2,5 - dihydro -1H -pyrrol -1- yl ) propionamido ) propionamido ) phenoxy )-3,4,5- trihydroxytetrahydro -2H- pyran -2-carboxylic acid ( Compound 2.118) Synthesis of compound 93a

Compound 93a (20.2 mg, 13.1 μmol, 74% yield) was prepared following General Method 4 using compound 1.38 x 1 TFA (15.5 mg, 17.5 μmol) as starting material. UPLC-MS (Method A, ESI+): m/z [M+H] ⁺ = 1546.6 (theoretical value), 1546.6 (observed value). HPLC retention time: 1.79 min. Synthesis of Compound 93b

Compound 93b x 1 TFA (11.4 mg, 8.8 μmol, 67% yield) was prepared following General Method 7 using compound 93a (20.2 mg, 13.1 μmol) as starting material. UPLC-MS (Method A, ESI+): m/z [M+H] ⁺ = 1184.5 (theoretical value), 1184.5 (observed value). HPLC retention time: 1.36 min. Synthesis of compound 2.118

Compound 2.118 (7.23 mg, 5.4 μmol, 62% yield) was prepared following General Method 6 using compound 93b x 1 TFA (11.4 mg, 8.8 μmol) as starting material. UPLC-MS (Method A, ESI+): m/z [M+H] ⁺ = 1335.5 (theoretical value), 1335.6 (observed value). HPLC retention time: 1.35 min. Example 168. (E)-N-(5- aminoformyl- 1-(4-(6- aminoformyl- 2-(1- ethyl - 3- methyl - 1H -pyrazol -5- yl )-9H -pyrrolo [2,3-b:5,4-b'] bipyridin -9- yl ) but -2- en -1 - yl )-7-(3-( methylamino ) propoxy )-1H- benzo [d] imidazol -2- yl )-4- ethyl -2- methyloxazole -5- carboxamide ( Compound 1.39) Synthesis of compound 94a

A solution of compound 92d (30 mg, 93.6 μmol), compound 6 (82.7 mg, 141 μmol) and Cs ₂ CO ₃ (153 mg, 468 μmol) in DMF (936 μL) was brought to 55 °C and stirred for 16 h. LCMS analysis showed consumption of starting material and desired m/z. Cold water (10 mL) was added to the mixture and the solid was filtered. The filter cake was washed with more cold water (10 mL) and the solid was dried under reduced pressure to give compound 94a (59.7 mg, 68.3 μmol, 73% yield), which was used without further purification. UPLC-MS (Method A, ESI+): m/z [M+H] ⁺ = 873.4 (theoretical value), 873.4 (observed value). HPLC retention time: 1.54 min. Synthetic compound 1.39

A solution of compound 94a (59.7 mg, 68.3 μmol) in 20% TFA in MeCN (683 μL) was brought to 35 °C and stirred for 2 h. LCMS analysis showed consumption of starting material and desired m/z. The solution was concentrated under reduced pressure to give a residue. The residue was purified by prepHPLC (Method 1). The fractions were collected, frozen, and lyophilized to give compound 1.39 x 1 TFA (34 mg, 38.3 μmol, 56% yield). UPLC-MS (Method A, ESI+): m/z [M+H] ⁺ = 773.4 (theoretical), 773.4 (observed). HPLC retention time: 1.27 min. Example 169. (E)-N-(5- aminoformyl- 1-(4-(6- aminoformyl- 2-(1- ethyl - 3- methyl - 1H -pyrazol -5- yl )-9H -pyrrolo [2,3-b:5,4-b'] bipyridin -9- yl ) but - 2- en -1 - yl )-7-(3-(3-(2,5- dihydroxy -2,5- dihydro -1H -pyrrol -1- yl )-N -methylpropionamido ) propoxy )-1H- benzo [d] imidazol -2- yl )-4- ethyl -2- methyloxazole -5- carboxamide ( Compound 2.119)

Compound 2.119 (4.65 mg, 5.0 μmol, 39% yield) was prepared following General Method 1 using compound 1.39 x 1 TFA (10 mg, 12.9 μmol) as starting material. UPLC-MS (Method A, ESI+): m/z [M+H] ⁺ = 924.4 (theoretical value), 924.4 (observed value). HPLC retention time: 1.37 min. Example 170. S-(1-(3-((3-((5- aminoformyl -1-((E)-4-(6- aminoformyl- 2-(1- ethyl -3- methyl -1H -pyrazol- 5- yl )-9H -pyrrolo [2,3-b:5,4-b'] bipyridin - 9- yl ) but -2- en-1-yl ) -2- (4- ethyl -2- methyloxazole -5 -carboxamido )-1H- benzo [d] imidazol -7 -yl ) oxy ) propyl )( methyl ) amino )-3 -oxopropyl )-2,5 -dioxopyrrolidin -3- yl )-L- cysteine ( Compound 3.38)

Compound 3.38 (0.17 mg, 0.2 μmol, 6% yield) was prepared following General Method 2 using compound 2.119 (2.33 mg, 2.5 μmol) as starting material. UPLC-MS (Method A, ESI+): m/z [M+H] ⁺ = 1045.4 (theoretical), 1045.5 (observed). HPLC retention time: 1.27 min. Example 171. 4-(( S)-2-((S)-2-(3-(2,5- dihydroxy- 2,5 - dihydro - 1H -pyrrol -1- yl ) propionamido )-3- methylbutanamido ) propionamido ) benzyl (3-( (5 - aminoformyl- 1 -((E )-4-(6- aminoformyl - 2- ( 1-ethyl - 3- methyl - 1H- pyrazol -5- yl )-9H- pyrrolo [ 2,3 - b: 5,4 - b '] bipyridin - 9-yl ) but-2- en -1-yl ) -2- (4- ethyl - 2- methyloxazole - 5- carboxamido ) -1H - benzo[d ]imidazol-7 -yl)oxy ) propyl)(methyl ) carbamate ( Compound 2.120)

Compound 2.120 (0.89 mg, 0.7 μmol, 18% yield) was prepared following General Method 3 using compound 1.39 x 1 TFA (3.0 mg, 3.9 μmol) as starting material. UPLC-MS (Method A, ESI+): m/z [M+H] ⁺ = 1243.5 (theoretical), 1243.6 (observed). HPLC retention time: 1.46 min. Example 172. (2S,3S,4S,5R,6S)-6-(4-((((3-((5- aminoformyl -1-((E)-4-(6- aminoformyl- 2-(1- ethyl -3- methyl -1H - pyrazol -5- yl )-9H -pyrrolo [2,3-b:5,4-b'] bipyridin -9 - yl ) but -2- en -1 - yl )-2-(4- ethyl -2- methyl ( 2- ( 3- ( 2,5 - dihydroxy - 2,5 - dihydro - 1H - pyrrol - 1 - yl ) propionamido ) propionamido ) phenoxy ) -3,4,5 - trihydroxytetrahydro - 2H - pyran - 2 - carboxylic acid ( Compound 2.121 ) ​ Synthesis of compound 95a

Compound 95a (23.2 mg, 15 μmol, 55% yield) was prepared following General Method 4 using compound 1.39 x 1 TFA (21.0 mg, 27.1 μmol) as starting material. UPLC-MS (Method A, ESI+): m/z [M+H] ⁺ = 1547.6 (theoretical value), 1547.6 (observed value). HPLC retention time: 1.75 min. Synthesis of Compound 95b

Following General Method 7, compound 95a (23.2 mg, 15 μmol) was used as the starting material to prepare compound 95b x 1 TFA (15.8 mg, 12.1 μmol, 81% yield). UPLC-MS (Method A, ESI+): m/z [M+H] ⁺ = 1185.5 (theoretical value), 1185.5 (observed value). HPLC retention time: 1.30 min. Synthesis of compound 2.121

Compound 2.121 (1.16 mg, 0.9 μmol, 7% yield) was prepared following General Method 6 using compound 95b x 1 TFA (15.8 mg, 12.1 μmol) as starting material. UPLC-MS (Method A, ESI+): m/z [M+H] ⁺ = 1336.5 (theoretical), 1336.5 (observed). HPLC retention time: 1.32 min. Example 173. (E)-9-(4-(5- aminoformyl- 2-(1- ethyl -3- methyl -1H -pyrazole -5- carboxamido )-7-(3-( methylamino ) propoxy )-1H- benzo [d] imidazol - 1- yl ) but- 2 - en - 1- yl )-7-(1- ethyl -3- methyl -1H-1,2,4 - triazol -5- yl )-9H -pyrrolo [2,3-b:5,4-b'] bipyridine -3- carboxamide ( Compound 1.40) Synthesis of compound 96a

To a solution of methyl 6-amino-5-bromopicolinate (10 g, 43.3 mmol) in THF (300 mL) was added TMSOK (11.1 g, 86.6 mmol). The mixture was brought to 65 °C and stirred for 3 h. LCMS analysis showed consumption of starting material and desired m/z. The mixture was concentrated under reduced pressure to give compound 96a (9.3 g, crude) as a white solid. The crude product was used without further purification. UPLC-MS (Method L, ESI+): m/z [M+H] ⁺ = 217.0 (theoretical), 216.9 (observed). HPLC retention time: 0.128 min. Synthesis of compound 96b

To a solution of compound 96a (7.9 g, 36.4 mmol) in DMF (100 mL) were added HATU (16.6 g, 43.7 mmol), DIPEA (12.7 mL, 72.8 mmol) and ethyl acetimidate hydrochloride (4.5 g, 36.4 mmol). The mixture was stirred at 20 °C for 5 h. LCMS analysis showed consumption of starting material and desired m/z. Ethylhydrazine hydrochloride (3.5 g, 36.4 mmol) and TEA (15.2 mL, 109.2 mmol) were then added to the mixture. The reaction was stirred at 20 °C for 16 h. LCMS analysis showed consumption of starting material and desired m/z. The mixture was poured into H ₂ O (300 mL) and extracted with EtOAc (3×200 mL). The combined organic layers were dried over _Na2SO4 , _filtered and concentrated under reduced pressure to yield a residue. A second reaction using 10.4 g of 96a was prepared as described and combined for purification. The residue was purified by column chromatography ( _SiO2 , petroleum ether/EtOAc) to afford compound 96b (10 g, 35.4 mmol, 42% yield) as a white solid. UPLC-MS (Method L, ESI+): m/z [M+H] ⁺ = 282.0 (theoretical), 282.2 (observed). HPLC retention time: 0.373 min. ¹ H NMR (400MHz, DMSO- d ₆ ) δ ppm 7.86 (d, J = 8.0 Hz, 1H), 7.17 (d, J = 8.0 Hz, 1H), 6.51 (s, 2H), 4.75 - 4.62 (m, 2H), 2.26 (s, 3H), 1.33 (t, J = 7.2 Hz, 3H). Synthesis of Compound 96c

A mixture of compound 96b (4 g, 14.2 mmol), compound 92a (7.5 g, 28.4 mmol) and K ₂ CO ₃ (3.9 g, 28.4 mmol) in dioxane (60 mL) was degassed and purged with N _2. Then, Pd(A-taPhos) ₂ Cl ₂ (2.0 g, 2.8 mmol) and H ₂ O (12 mL) were added to the mixture. The reaction was brought to 80 °C and stirred under N ₂ atmosphere for 2 h. LCMS analysis showed consumption of starting material and desired m/z. The mixture was diluted with H ₂ O (80 mL) and extracted with EtOAc (3×60 mL). The combined organic layers were washed with brine (100 mL), dried over _{Na2SO4 ,} filtered, and concentrated under reduced pressure to yield a residue. The crude product was purified by prepHPLC (Method 2). The fractions were collected, frozen, and lyophilized to afford compound 96c (2.5 g, 7.3 mmol, 52% yield) as a white solid. UPLC-MS (Method L, ESI+): m/z [M+H] ⁺ = 342.1 (theoretical), 342.2 (observed). HPLC retention time: 0.312 min. ¹ H NMR (400MHz, DMSO- d ₆ ) δ ppm 8.73 (d, J=2.0 Hz, 1H), 8.41 (dd, J=2.0, 8.8 Hz, 1H), 8.18 (s, 1H), 7.66 (s, 1H), 7.56 (d, J=7.6 Hz, 1H), 7.36 (d, J=8.0 Hz, 1H), 6.25 (s, 2H), 4.83 - 4.68 (m, 2H), 2.28 (s, 3H), 1.38 (t, J=7.2 Hz, 3H). Synthesis of compound 96d

To a solution of compound 96c (150 mg, 439 μmol) in NMP (15 mL) was added Cs ₂ CO ₃ (286.4 mg, 879 μmol). The mixture was brought to 150 °C via a microwave reactor for 45 min. LCMS analysis showed consumption of starting material and desired m/z. Five additional vials were prepared as described. The six reaction mixtures were combined for work-up and purification. The mixture was diluted with H ₂ O (900 mL) and the product was allowed to precipitate for 16 h. The crude product was triturated with DCM and petroleum ether at 20 °C for 3 min to afford compound 96d (183.5 mg, 571.1 μmol, 22% yield) as a grey solid. UPLC-MS (method G, ESI+): m/z [M+H] ⁺ = 322.1 (theoretical value), 322.2 (observed value). HPLC retention time: 0.312 min. ¹ H NMR (400MHz, DMSO- d ₆ ) δ ppm 9.08 (s, 1H), 9.04 (s, 1H), 8.74 (d, J=8.0 Hz, 1H), 8.14 (br s, 1H), 8.06 (d, J=8.0 Hz, 1H), 7.49 (br s, 1H), 4.90 - 4.76 (m, 2H), 2.33 (s, 3H), 1.46 (br t, J=7.2 Hz, 3H). Synthesis of compound 96e

A solution of compound 96d (25 mg, 77.8 μmol), compound 7 (68.6 mg, 117 μmol) and Cs ₂ CO ₃ (127 mg, 389 μmol) in DMF (778 μL) was brought to 55 °C and stirred for 16 h. LCMS analysis showed consumption of starting material and desired m/z. Cold water (10 mL) was added to the mixture and the solid was filtered. The filter cake was washed with more cold water (10 mL) and the solid was dried under reduced pressure to give compound 96e (60.8 mg, 69.7 μmol, 90% yield), which was used without further purification. UPLC-MS (Method A, ESI+): m/z [M+H] ⁺ = 873.4 (theoretical value), 873.4 (observed value). HPLC retention time: 1.50 min. Synthetic compound 1.40

A solution of compound 96e (60.8 mg, 69.7 μmol) in 20% TFA in MeCN (697 μL) was brought to 35 °C and stirred for 2 h. LCMS analysis showed consumption of starting material and desired m/z. The solution was concentrated under reduced pressure to give a residue. The residue was purified by prepHPLC (Method 1). The fractions were collected, frozen, and lyophilized to give compound 1.40 x 1 TFA (27.9 mg, 31.4 μmol, 45% yield). UPLC-MS (Method A, ESI+): m/z [M+H] ⁺ = 773.4 (theoretical), 773.4 (observed). HPLC retention time: 1.23 min. Example 174. (E)-9-(4-(5- aminoformyl- 7-(3-(3-(2,5- dioxo -2,5- dihydro -1H -pyrrol -1- yl )-N -methylpropionamido ) propoxy )-2-(1- ethyl -3- methyl - 1H - pyrazole -5- carboxamido )-1H - benzo [d] imidazol - 1 - yl ) but -2- en - 1- yl )-7-(1- ethyl -3- methyl -1H-1,2,4- triazol -5- yl )-9H -pyrrolo [2,3-b:5,4-b'] bipyridine -3- carboxamide ( Compound 2.122)

Compound 2.122 (2.94 mg, 3.2 μmol, 25% yield) was prepared following General Method 1 using compound 1.40 x 1 TFA (10 mg, 12.9 μmol) as starting material. UPLC-MS (Method A, ESI+): m/z [M+H] ⁺ = 924.4 (theoretical value), 924.4 (observed value). HPLC retention time: 1.36 min. Example 175. S-(1-(3-((3-((5- aminoformyl -1-((E)-4-(6- aminoformyl -2-(1- ethyl -3- methyl -1H-1,2,4- triazol -5- yl )-9H -pyrrolo [2,3-b:5,4-b'] bipyridin - 9- yl ) but-2-en-1-yl ) -2- ( 1 - ethyl -3- methyl -1H -pyrazol -5 -carboxamido )-1H- benzo [d] imidazol -7- yl ) oxy ) propyl )( methyl ) amino ) -3 - oxopropyl )-2,5 -dioxopyrrolidin- 3- yl )-L- cysteine ( Compound 3.39)

Compound 3.39 (0.34 mg, 0.3 μmol, 20% yield) was prepared following General Method 2 using compound 2.122 (1.47 mg, 1.6 μmol) as starting material. UPLC-MS (Method A, ESI+): m/z [M+H] ⁺ = 1045.4 (theoretical), 1045.5 (observed). HPLC retention time: 1.25 min. Example 176. 4-(( S)-2-((S)-2-(3-(2,5 - dihydroxy - 2,5-dihydro-1H- pyrrol - 1 - yl )propionamido)-3 - methylbutanamido ) propionamido ) benzyl (3-((5- aminoformyl- 1- ((E)-4-(6-aminoformyl - 2- ( 1 - ethyl - 3- methyl -1H - 1,2,4 -triazol -5 - yl )-9H- pyrrolo [ 2,3 -b:5,4-b'] bipyridin - 9 - yl ) but - 2 - en-1-yl)-2-(1-ethyl-3- methyl - 1H - pyrazole-5- carboxamido ) -1H -benzo [d ] imidazol - 7-yl ) oxy ) propyl) (methyl ) carbamate ( Compound 2.123)

Compound 2.123 (0.53 mg, 0.4 μmol, 11% yield) was prepared following General Method 3 using compound 1.40 x 1 TFA (3.0 mg, 3.9 μmol) as starting material. UPLC-MS (Method A, ESI+): m/z [M+H] ⁺ = 1243.5 (theoretical), 1243.6 (observed). HPLC retention time: 1.42 min. Example 177. (2S,3S,4S,5R,6S)-6-(4-((((3-((5- aminoformyl -1-((E)-4-(6- aminoformyl -2-(1- ethyl -3- methyl -1H-1,2,4- triazol -5- yl )-9H- pyrrolo [2,3-b:5,4-b'] bipyridin -9 - yl ) but -2- en -1 - yl )-2-(1- ethyl -3- methyl ( 2- ( 3- ( 2,5 - dihydroxy - 2,5 - dihydro - 1H - pyrrol - 1 - yl ) propionamido ) propionamido ) phenoxy ) -3,4,5 - trihydroxytetrahydro - 2H - pyran - 2 - carboxylic acid ( Compound 2.124 ) ​ ​ ​ Synthesis of compound 97a

Compound 97a (8.42 mg, 5.4 μmol, 28% yield) was prepared following General Method 4 using compound 1.40 x 1 TFA (14.9 mg, 19.2 μmol) as starting material. UPLC-MS (Method A, ESI+): m/z [M+H] ⁺ = 1547.6 (theoretical value), 1547.6 (observed value). HPLC retention time: 1.74 min. Synthesis of Compound 97b

Compound 97b x 1 TFA (3.53 mg, 2.7 μmol, 50% yield) was prepared following General Method 7 using compound 97a (8.42 mg, 5.4 μmol) as starting material. UPLC-MS (Method A, ESI+): m/z [M+H] ⁺ = 1185.5 (theoretical value), 1185.5 (observed value). HPLC retention time: 1.26 min. Synthesis of compound 2.124

Compound 2.124 (1.77 mg, 1.3 μmol, 49% yield) was prepared following General Method 6 using compound 97b x 1 TFA (3.53 mg, 2.7 μmol) as starting material. UPLC-MS (Method A, ESI+): m/z [M+H] ⁺ = 1336.5 (theoretical), 1336.6 (observed). HPLC retention time: 1.28 min. Example 178. (E)-N-(5- aminoformyl- 1-(4-(6- aminoformyl- 2-(1- ethyl - 3- methyl - 1H-1,2,4- triazol -5- yl )-9H -pyrrolo [2,3-b:5,4-b'] bipyridin -9- yl ) but -2- en -1 - yl )-7-(3-( methylamino ) propoxy )-1H- benzo [d] imidazol -2- yl )-4- ethyl -2- methyloxazole -5- carboxamide ( Compound 1.41) Synthesis of compound 98a

A solution of compound 96d (50 mg, 156 μmol), compound 6 (137 mg, 233 μmol) and Cs ₂ CO ₃ (253 mg, 778 μmol) in DMF (1.5 mL) was brought to 55 °C and stirred for 16 h. LCMS analysis showed consumption of starting material and desired m/z. Cold water (10 mL) was added to the mixture and the solid was filtered. The filter cake was washed with more cold water (10 mL) and the solid was dried under reduced pressure to give compound 98a (76.1 mg, 87.1 μmol, 56% yield), which was used without further purification. UPLC-MS (Method A, ESI+): m/z [M+H] ⁺ = 874.4 (theoretical), 874.4 (observed). HPLC retention time: 1.49 min. Synthesis of compound 1.40

A solution of compound 98a (76.1 mg, 87.1 μmol) in 20% TFA in MeCN (871 μL) was brought to 35 °C and stirred for 2 h. LCMS analysis showed consumption of starting material and desired m/z. The solution was concentrated under reduced pressure to give a residue. The residue was purified by prepHPLC (Method 1). The fractions were collected, frozen, and lyophilized to give compound 1.41 x 1 TFA (41.4 mg, 46.7 μmol, 54% yield). UPLC-MS (Method A, ESI+): m/z [M+H] ⁺ = 774.4 (theoretical), 773.3 (observed). HPLC retention time: 1.21 min. Example 179. (E)-N-(5- aminoformyl- 1-(4-(6- aminoformyl- 2-(1- ethyl - 3- methyl - 1H-1,2,4- triazol -5- yl )-9H -pyrrolo [2,3-b:5,4-b'] bipyridin -9- yl ) but -2- en -1 - yl )-7-(3-(3-(2,5- dihydroxy -2,5- dihydro -1H -pyrrol -1- yl )-N -methylpropionamido ) propoxy )-1H- benzo [d] imidazol -2- yl )-4- ethyl -2- methyloxazole -5- carboxamide ( Compound 2.125)

Compound 2.125 (3.2 mg, 3.5 μmol, 31% yield) was prepared following General Method 1 using compound 1.41 x 1 TFA (10 mg, 11.3 μmol) as starting material. UPLC-MS (Method A, ESI+): m/z [M+H] ⁺ = 925.4 (theoretical value), 925.4 (observed value). HPLC retention time: 1.38 min. Example 180. S-(1-(3-((3-((5- aminoformyl -1-((E)-4-(6- aminoformyl -2-(1- ethyl -3- methyl -1H-1,2,4- triazol -5- yl )-9H- pyrrolo [2,3-b:5,4-b'] bipyridin -9 - yl ) but-2-en - 1 - yl )-2-(4- ethyl -2- methyloxazole -5 -carboxamido )-1H- benzo [d] imidazol -7- yl ) oxy ) propyl )( methyl ) amino )-3 - oxopropyl )-2,5 -dioxopyrrolidin -3- yl )-L- cysteine ( Compound 3.40)

Compound 3.40 (3.2 mg, 2.8 μmol, 85% yield) was prepared following General Method 2 using compound 2.125 (3.0 mg, 3.3 μmol) as starting material. UPLC-MS (Method A, ESI+): m/z [M+H] ⁺ = 1046.4 (theoretical), 1046.4 (observed). HPLC retention time: 1.28 min. Example 181. 4-(( S)-2-((S)-2-(3-(2,5 - dihydroxy -2,5- dihydro -1H- pyrrol - 1- yl ) propionamido )-3 - methylbutanamido ) propionamido ) benzyl (3-( (5 - aminoformyl- 1-(( E )-4-(6- aminoformyl - 2- ( 1-ethyl - 3- methyl -1H -1,2,4- triazol - 5 -yl ) -9H - pyrrolo [ 2,3 -b:5,4-b'] bipyridin - 9 -yl)but - 2-en- 1-yl ) -2- (4- ethyl -2- methyloxazole - 5 - carboxamido ) -1H -benzo[ d ] imidazol-7-yl )oxy ) propyl)(methyl ) carbamate ( Compound 2.126)

Compound 2.126 (1.2 mg, 0.9 μmol, 16% yield) was prepared following General Method 3 using compound 1.41 x 1 TFA (5 mg, 5.6 μmol) as starting material. UPLC-MS (Method A, ESI+): m/z [M+H] ⁺ = 1244.5 (theoretical), 1244.6 (observed). HPLC retention time: 1.46 min. Example 182. (2S,3S,4S,5R,6S)-6-(4-((((3-((5- aminoformyl -1-((E)-4-(6- aminoformyl -2-(1- ethyl -3- methyl -1H-1,2,4- triazol -5- yl )-9H -pyrrolo [2,3-b:5,4-b'] bipyridin -9 - yl ) but -2- en -1- yl )-2-(4- ethyl -2 -methyloxazole - 5 -carboxamido )-1H- benzo [d] imidazol -7- yl ) oxy ) propyl )( methyl ) aminocarboxamido ) oxy ) methyl )-2-(3-(3-(2,5- dihydroxy -2,5- dihydro -1H -pyrrol -1- yl ) propionamido ) propionamido ) phenoxy )-3,4,5- trihydroxytetrahydro -2H- pyran -2-carboxylic acid ( Compound 2.127) Synthesis of compound 99a

Compound 99a (20.1 mg, 13 μmol, 44% yield) was prepared following General Method 4 using compound 1.41 x 1 TFA (26.4 mg, 29.8 μmol) as starting material. UPLC-MS (Method A, ESI+): m/z [M+H] ⁺ = 1548.6 (theoretical value), 1548.6 (observed value). HPLC retention time: 1.75 min. Synthesis of Compound 99b

Following General Method 7, Compound 99b x 1 TFA (7.8 mg, 6.0 μmol, % yield) was prepared using Compound 99a (20.1 mg, 13 μmol) as starting material. UPLC-MS (Method A, ESI+): m/z [M+H] ⁺ = 1186.5 (theoretical value), 1186.5 (observed value). HPLC retention time: 1.29 min. Synthesis of Compound 2.127

Compound 2.127 (4.0 mg, 3.0 μmol, 50% yield) was prepared following General Method 6 using compound 99b x 1 TFA (7.8 mg, 6.0 μmol) as starting material. UPLC-MS (Method A, ESI+): m/z [M+H] ⁺ = 1337.5 (theoretical value), 1337.5 (observed value). HPLC retention time: 1.31 min. Example 183. (E)-5-(4-(5- aminoformyl- 2-(1- ethyl -3- methyl -1H -pyrazole -5- carboxamido )-7-(3-( methylamino ) propoxy )-1H- benzo [d] imidazol - 1- yl ) but-2- en - 1- yl )-7-(1- ethyl - 3- methyl -1H -pyrazol - 5- yl )-4- methoxy -5H- pyrrolo [2,3-b:4,5-b'] bipyridine -2- carboxamide ( Compound 1.42) Synthesis of compound 100a

To a solution of 2-chloro-4-methoxy-5-nitropyridine (12.5 g, 66.3 mmol) in MeOH (188 mL) at 25 °C under CO atmosphere was added TEA (18.5 mL, 133 mmol) and Pd(dppf)Cl ₂ (14.6 g, 19.9 mmol). The suspension was degassed under vacuum and purged with CO. The mixture was brought to 70 °C and stirred under CO atmosphere for 24 h. LCMS analysis showed consumption of starting material and desired m/z. A second vial was prepared as described and the reactions were combined for work-up and purification. The reaction mixture was filtered and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (SiO ₂ , petroleum ether/EtOAC) to give compound 100a (9 g, 37.5 mmol, 28% yield) as a brown solid. UPLC-MS (Method N, ESI+): m/z [M+H] ⁺ = 241.1 (theoretical value), 241.1 (observed value). HPLC retention time: 0.427 min. ¹ H NMR (400MHz, DMSO- d ₆ ) δ ppm 9.13 (s, 1H), 8.88 (s, 1H), 7.65 (s, 1H), 3.94 (s, 3H), 3.86 (s, 3H), 3.69 (s, 3H). Synthesis of 100b

To a solution of compound 100a (2.5 g, 10.4 mmol) in THF (50 mL) was added TEA (4.4 mL, 31.2 mmol), DMAP (1.27 g, 10.4 mmol) and _Boc2O (4.54 g, 20.8 mmol). The solution was allowed to reach 25 °C and stirred for 16 h. LCMS analysis showed consumption of starting material and desired m/z. A second reaction was prepared as described and combined for work-up. The mixture was filtered and concentrated to give compound 100b (6 g, crude) as a brown solid which was used without further purification. UPLC-MS (Method N, ESI+): m/z [M+H] ⁺ = 341.1 (theoretical), 341.2 (observed). HPLC retention time: 0.475 min. Synthesis of compound 100c

To a solution of compound 100b (4 g, 11.8 mmol) in MeOH (30 mL) was added NH ₄ OH (80 mL) at 25 °C. The mixture was allowed to reach 45 °C and stirred for 16 h. LCMS analysis showed consumption of starting material and desired m/z. Two additional reactions were prepared as described and combined for work-up and purification. The reaction mixture was diluted with water (1 L) and extracted with EtOAc (3×100 mL). The organic phases were combined and washed with brine (200 mL), dried over Na ₂ SO ₄ , filtered, and concentrated to give compound 100c (11.5 g, crude) as a red solid. UPLC-MS (method N, ESI+): m/z [M+H] ⁺ = 268.1 (theoretical value), 268.2 (observed value). HPLC retention time: 0.460 min. Synthesis of compound 100d

A solution of compound 100c (4 g, 15 mmol) in EtOAc (80 mL) containing 4 M HCl was stirred at 25 °C for 16 h. LCMS analysis showed consumption of starting material and desired m/z. Two additional reactions were prepared as described and combined for work-up and purification. The reaction mixture was filtered to give compound 100d (7.3 g, crude HCl salt) as a brown solid. The crude product was used in the next step without further purification. UPLC-MS (Method N, ESI+): m/z [M+H] ⁺ = 168.1 (theoretical), 168.1 (observed). HPLC retention time: 0.485 min. ¹ H NMR (400MHz, DMSO- d ₆ ) δ ppm 9.20 (br s, 1H), 8.43 (s, 1H), 8.26 (br s, 2H), 8.06 (s, 2H), 4.13 (s, 3H). Synthesis of Compound 100e

A mixture of compound 100d (5.54 g, 33.2 mmol), 3-bromo-2-fluoro-6-iodopyridine (10 g, 33.2 mmol), Cs ₂ CO ₃ (21.6 g, 66.3 mmol) in DMA (50 mL) was degassed and purged with N _2. The mixture was brought to 80 °C and stirred under N ₂ atmosphere for 16 h. LCMS analysis showed consumption of starting material and the desired m/z. The mixture was filtered and concentrated under reduced pressure to give a residue. The residue was purified by prepHPLC (Method 12). The pure fractions were collected, frozen, and lyophilized to give compound 100e (2 g, 4.45 mmol, 13% yield) as a brown solid. UPLC-MS (method R, ESI+): m/z [M+H] ⁺ = 448.9 (theoretical value), 448.8 (observed value). HPLC retention time: 1.352 min. Synthesis of compound 100f

A mixture of compound 100e (1.5 g, 3.33 mmol), compound 3g (1.03 g, 4.35 mmol), Pd(dppf) _Cl2 (245 mg, 334 μmol), _K2CO3 (923 mg, 6.69 mmol) in _dioxane (20 mL) and _H2O (4 mL) was degassed and purged with _N2 . The mixture was brought to 70 °C and stirred under _N2 atmosphere for 2 h. LCMS analysis showed consumption of starting material and the desired m/z. Water (50 mL) was added and the mixture was extracted with EtOAc (100 mL). The organic phase was washed with water (2×40 _mL ), dried over _Na2SO4 , filtered, and concentrated under reduced pressure to give a residue. The residue was purified by prepHPLC (Method 2). The pure fractions were collected, frozen, and lyophilized to give compound 100f (700 mg, 1.62 mmol, 49% yield) as a white solid. UPLC-MS (Method N, ESI+): m/z [M+H] ⁺ = 431.1 (theoretical value), 431.2 (observed value). HPLC retention time: 0.546 min. Synthesis of compound 100g

A mixture of compound 100f (600 mg, 1.39 mmol), N-cyclohexyl-N-methyl-cyclohexylamine (815 mg, 696 μmol), P(tBu) ₃ Pd G4 (81.6 mg, 23.2 μmol) in DMF (18 mL) was degassed and purged with N _2. The mixture was brought to 140 °C via a microwave reactor and stirred for 45 min. LCMS analysis showed consumption of starting material and the desired m/z. The reaction mixture was filtered and concentrated to give a residue. The residue was purified by prepHPLC (Method 10). The pure fractions were collected, frozen, and lyophilized to give compound 100g (146 mg, 417 μmol, 30% yield) as a white solid. UPLC-MS (Method G, ESI+): m/z [M+H] ⁺ = 351.1 (theoretical value), 351.1 (observed value). HPLC retention time: 2.618 min. ¹ H NMR (400MHz, DMSO- d ₆ ) δ ppm 12.60 (s, 1H), 8.61 (d, J = 8.4 Hz, 1H), 8.19 (br s, 1H), 7.79 (s, 1H), 7.70 (d, J = 8.4 Hz, 1H), 7.64 (br d, J = 2.4 Hz, 1H), 6.66 (s, 1H), 4.68 (q, J = 7.2 Hz, 2H), 4.14 (s, 3H), 2.22 (s, 3H), 1.38 (t, J = 7.2 Hz, 3H). Synthesis of compound 100h

A solution of compound 100g (50 mg, 143 μmol), compound 7 (126 mg, 214 μmol) and Cs ₂ CO ₃ (232 mg, 714 μmol) in DMF (1.4 mL) was brought to 55 °C and stirred for 16 h. LCMS analysis showed consumption of starting material and desired m/z. Cold water (10 mL) was added to the mixture and the solid was filtered. The filter cake was washed with more cold water (10 mL) and the solid was dried under reduced pressure to give compound 100h (130 mg, crude), which was used without further purification. UPLC-MS (Method A, ESI+): m/z [M+H] ⁺ = 902.4 (theoretical value), 902.4 (observed value). HPLC retention time: 1.70 min. Synthesis of compound 1.42

A solution of compound 100h (130 mg, crude) in 20% TFA in MeCN (1.4 mL) was brought to 35 °C and stirred for 2 h. LCMS analysis showed consumption of starting material and desired m/z. The solution was concentrated under reduced pressure to give a residue. The residue was purified by prepHPLC (Method 1). The pure fractions were collected, frozen, and lyophilized to give compound 1.42 x 1 TFA (91.1 mg, 99.4 μmol, 69% yield). UPLC-MS (Method A, ESI+): m/z [M+H] ⁺ = 802.4 (theoretical), 802.4 (observed). HPLC retention time: 1.51 min. Example 184. (E)-5-(4-(5- aminoformyl- 7-(3-(3-(2,5- dioxo -2,5- dihydro -1H -pyrrol -1- yl )-N -methylpropionamido ) propoxy )-2-(1- ethyl -3- methyl - 1H - pyrazole -5- carboxamido )-1H - benzo [d] imidazol - 1- yl )but- 2 - en - 1- yl ) -7-(1- ethyl -3- methyl -1H -pyrazol -5- yl )-4- methoxy- 5H -pyrrolo [2,3-b:4,5-b'] bipyridine -2- carboxamide ( Compound 2.128)

Compound 2.128 (11.6 mg, 12.2 μmol, 56% yield) was prepared following General Method 1 using compound 1.42 x 1 TFA (20 mg, 21.8 μmol) as starting material. UPLC-MS (Method A, ESI+): m/z [M+H] ⁺ = 953.4 (theoretical value), 953.4 (observed value). HPLC retention time: 1.54 min. Example 185. S-(1-(3-((3-((5- aminoformyl -1-((E)-4-(2- aminoformyl- 7-(1- ethyl -3- methyl -1H -pyrazol- 5- yl )-4- methoxy -5H- pyrrolo [2,3-b:4,5-b'] bipyridin -5- yl ) but-2-en-1-yl ) -2- ( 1 - ethyl -3- methyl -1H -pyrazol -5 -carboxamido )-1H- benzo [d] imidazol -7- yl ) oxy ) propyl )( methyl ) amino ) -3 - oxopropyl )-2,5 -dioxopyrrolidin- 3- yl )-L- cysteine ( Compound 3.41)

Compound 3.41 (7.5 mg, 6.3 μmol, 52% yield) was prepared following General Method 2 using compound 2.128 (11.4 mg, 12.0 μmol) as starting material. UPLC-MS (Method A, ESI+): m/z [M+H] ⁺ = 1074.4 (theoretical value), 1074.4 (observed value). HPLC retention time: 1.41 min. Example 186. 4-(( S)-2-((S)-2-(3-(2,5- dihydroxy - 2,5- dihydro -1H -pyrrol- 1- yl )propionamido) -3- methylbutanamido ) propionamido ) benzyl (3-((5- aminoformyl -1 -(( E )-4-(2-aminoformyl-7-(1- ethyl - 3 - methyl - 1H - pyrazol -5-yl )-4- methoxy-5H - pyrrolo [ 2,3-b:4,5-b'] bipyridin -5-yl )but-2 - en - 1 - yl ) -2- (1-ethyl- 3 - methyl - 1H- pyrazol- 5- carboxamido ) -1H -benzo [d ] imidazol - 7-yl ) oxy ) propyl) (methyl ) carbamate ( Compound 2.129)

Compound 2.129 (2.5 mg, 2.0 μmol, 37% yield) was prepared following General Method 3 using compound 1.42 x 1 TFA (5 mg, 5.5 μmol) as starting material. UPLC-MS (Method A, ESI+): m/z [M+H] ⁺ = 1272.6 (theoretical), 1272.6 (observed). HPLC retention time: 1.61 min. Example 187. (2S,3S,4S,5R,6S)-6-(4-((((3-((5- aminoformyl -1-((E)-4-(2- aminoformyl- 7-(1- ethyl -3- methyl -1H - pyrazol -5- yl )-4- methoxy -5H- pyrrolo [2,3-b:4,5-b'] bipyridin - 5 - yl ) but -2- en -1 - yl )-2-(1- ethyl -3- methyl ( 2- ( 3- ( 2,5 - dihydroxy - 2,5 - dihydro - 1H - pyrrol - 1 - yl ) propionamido ) propionamido ) phenoxy ) -3,4,5 - trihydroxytetrahydro - 2H - pyran - 2 - carboxylic acid ( Compound 2.130 ) ​ ​ ​ Synthesis of compound 101a

Compound 101a (78.8 mg, 50 μmol, 69% yield) was prepared following General Method 4 using compound 1.42 x 1 TFA (66.1 mg, 72.1 μmol) as starting material. UPLC-MS (Method A, ESI+): m/z [M+H] ⁺ = 1576.6 (theoretical value), 1576.6 (observed value). HPLC retention time: 1.88 min. Synthesis of Compound 101b

Compound 101b x 1 TFA (38.2 mg, 28.7 μmol, 58% yield) was prepared following General Method 7 using compound 101a (78.8 mg, 50 μmol) as starting material. UPLC-MS (Method A, ESI+): m/z [M+H] ⁺ = 1214.5 (theoretical value), 1214.5 (observed value). HPLC retention time: 1.43 min. Synthesis of compound 2.130

Compound 2.130 (23.1 mg, 16.9 μmol, 59% yield) was prepared following General Method 6 using compound 101b x 1 TFA (38.2 mg, 28.7 μmol) as starting material. UPLC-MS (Method A, ESI+): m/z [M+H] ⁺ = 1365.5 (theoretical value), 1365.5 (observed value). HPLC retention time: 1.46 min. Example 188. (E)-N-(5- aminoformyl- 1-(4-(2- aminoformyl- 7-(1- ethyl - 3- methyl - 1H -pyrazol -5- yl )-4- methoxy -5H- pyrrolo [2,3-b:4,5-b'] bipyridin -5- yl ) but - 2- en-1-yl ) -7-(3-( methylamino ) propoxy )-1H- benzo [d] imidazol -2- yl )-4- ethyl -2- methyloxazole -5 -carboxamide ( Compound 1.43) Synthesis of compound 102a

A solution of compound 100g (50 mg, 143 μmol), compound 6 (151 mg, 214 μmol) and Cs ₂ CO ₃ (232 mg, 714 μmol) in DMF (1.4 mL) was brought to 55 °C and stirred for 16 h. LCMS analysis showed consumption of starting material and desired m/z. Cold water (10 mL) was added to the mixture and the solid was filtered. The filter cake was washed with more cold water (10 mL) and the solid was dried under reduced pressure to give compound 102a (134 mg, crude), which was used without further purification. UPLC-MS (Method A, ESI+): m/z [M+H] ⁺ = 903.4 (theoretical value), 903.4 (observed value). HPLC retention time: 1.68 min. Synthesis of compound 1.43

A solution of compound 102a (134 mg, crude) in 20% TFA in MeCN (1.5 mL) was brought to 35 °C and stirred for 2 h. LCMS analysis showed consumption of starting material and desired m/z. The solution was concentrated under reduced pressure to give a residue. The residue was purified by prepHPLC (Method 1). The fractions were collected, frozen, and lyophilized to give compound 1.43 x 1 TFA (117 mg, 127 μmol, 86% yield). UPLC-MS (Method A, ESI+): m/z [M+H] ⁺ = 803.4 (theoretical), 803.4 (observed). HPLC retention time: 1.39 min. Example 189. (E)-N-(5- aminoformyl- 1-(4-(2- aminoformyl- 7-(1- ethyl - 3- methyl - 1H -pyrazol -5- yl )-4- methoxy -5H- pyrrolo [2,3-b:4,5-b'] bipyridin -5 - yl ) but - 2- en - 1 - yl )-7-(3-(3-(2,5- dihydroxy -2,5 -dihydro -1H -pyrrol -1- yl )-N -methylpropionamido ) propoxy )-1H- benzo [d] imidazol -2- yl )-4- ethyl -2- methyloxazole -5- carboxamide ( Compound 2.131)

Compound 2.131 (18.6 mg, 19.5 μmol, 60% yield) was prepared following General Method 1 using compound 1.43 x 1 TFA (30 mg, 32.7 μmol) as starting material. UPLC-MS (Method A, ESI+): m/z [M+H] ⁺ = 954.4 (theoretical value), 954.4 (observed value). HPLC retention time: 1.50 min. Example 190. S-(1-(3-((3-((5- aminoformyl -1-((E)-4-(2- aminoformyl- 7-(1- ethyl -3- methyl -1H -pyrazol- 5- yl )-4- methoxy -5H -pyrrolo [2,3-b:4,5-b'] bipyridin - 5 - yl ) but-2-en-1-yl ) -2- ( 4 - ethyl -2- methyloxazole -5 -carboxamido )-1H- benzo [d] imidazol -7- yl ) oxy ) propyl )( methyl ) amino )-3 - oxopropyl )-2,5 -dioxopyrrolidin -3- yl )-L- cysteine ( Compound 3.42)

Compound 3.42 (11.9 mg, 10.0 μmol, 69% yield) was prepared following General Method 2 using compound 2.131 (13.9 mg, 14.5 μmol) as starting material. UPLC-MS (Method A, ESI+): m/z [M+H] ⁺ = 1075.4 (theoretical), 1075.4 (observed). HPLC retention time: 1.37 min. Example 191. (3-((5- aminoformyl- 1-((E)-4-(2- aminoformyl- 7-(1- ethyl -3- methyl -1H -pyrazol -5- yl )-4- methoxy -5H- pyrrolo [2,3-b:4,5-b'] bipyridin -5 - yl ) but - 2- en -1- yl )-2-(1- ethyl -3- methyl -1H -pyrazol -5 -carboxamido )-1H - benzo [d] imidazol - 7- yl ) oxy ) propyl )( methyl ) carbamate 4-((S)-2-((S)-2-(3-(2,5- dihydroxy -2,5 -dihydro -1H -pyrrol -1- yl ) propionamido )-3 -methylbutanamido ) propionamido ) benzyl ester ( Compound 2.132)

Compound 2.132 (2.71 mg, 2.1 μmol, 39% yield) was prepared following General Method 3 using compound 1.43 x 1 TFA (5.0 mg, 5.5 μmol) as starting material. UPLC-MS (Method A, ESI+): m/z [M+H] ⁺ = 1273.6 (theoretical), 1273.6 (observed). HPLC retention time: 1.58 min. Example 192. (2S,3S,4S,5R,6S)-6-(4-((((3-((5- aminoformyl -1-((E)-4-(2- aminoformyl- 7-(1- ethyl -3- methyl -1H - pyrazol -5- yl )-4- methoxy -5H- pyrrolo [2,3-b:4,5-b'] bipyridin - 5 - yl ) but -2- en -1 - yl )-2-(4- ethyl -2 -methyloxazole - 5 -carboxamido )-1H- benzo [d] imidazol -7- yl ) oxy ) propyl )( methyl ) aminocarboxamido ) oxy ) methyl )-2-(3-(3-(2,5- dihydroxy -2,5- dihydro -1H -pyrrol -1- yl ) propionamido ) propionamido ) phenoxy )-3,4,5- trihydroxytetrahydro -2H- pyran -2-carboxylic acid ( Compound 2.133) Synthesis of compound 103a

Compound 103a (50.9 mg, 32.3 μmol, 36% yield) was prepared following General Method 4 using compound 1.43 x 1 TFA (81.7 mg, 89.1 μmol) as starting material. UPLC-MS (Method A, ESI+): m/z [M+H] ⁺ = 1577.6 (theoretical value), 1577.6 (observed value). HPLC retention time: 1.84 min. Synthesis of Compound 103b

Compound 103b x 1 TFA (24.4 mg, 18.4 μmol, 57% yield) was prepared following General Method 7 using compound 103a (50.9 mg, 32.3 μmol) as starting material. UPLC-MS (Method A, ESI+): m/z [M+H] ⁺ = 1215.5 (theoretical value), 1215.5 (observed value). HPLC retention time: 1.39 min. Synthesis of compound 2.133

Compound 2.133 (18.4 mg, 13.5 μmol, 73% yield) was prepared following General Method 6 using compound 103b x 1 TFA (24.4 mg, 18.4 μmol) as starting material. UPLC-MS (Method A, ESI+): m/z [M+H] ⁺ = 1366.5 (theoretical value), 1366.5 (observed value). HPLC retention time: 1.51 min. Example 193. 9-(((1R,2R)-2-((5- aminomethyl- 2-(1- ethyl - 3- methyl -1H -pyrazole -5 -carboxamido )-7-(3-( methylamino ) propoxy )-1H- benzo [d] imidazol -1- yl ) methyl ) cyclopropyl ) methyl )-2-(1- ethyl -3- methyl -1H - pyrazol -5- yl )-8- methoxy -9H -pyrido [2,3-b] indole -6- carboxamide ( Compound 1.44) Synthesis of compound 104a

A 250 mL round bottom flask containing _LiAlH4 (2.5 M, 34.4 mL) in MTBE (100 mL) was brought to 0 °C. While stirring at 0 °C, (1R,2R)-cyclopropane-1,2-dicarboxylic acid diethyl ester (5 g, 26.9 mmol) in MTBE (30 mL) was slowly added. After addition, the ice-water bath was removed and the slurry was stirred at 25 °C for 3 h. TLC indicated complete consumption of the starting material and the formation of two new spots. Four additional vials were prepared as described and combined for work-up and purification. The reaction was quenched by the addition _{of Na2SO4} · _10H2O (164 g) in portions. After stirring at rt for 1 h, the mixture was filtered through celite and washed with DCM. The filtrate was concentrated under reduced pressure to yield a residue. The residue was purified by column chromatography (SiO ₂ , MeOH/EtOAc) to yield compound 104a (10 g, 97.9 mmol, 73% yield) as a colorless oil. ¹ H NMR (400 MHz, DMSO- d ₆ ) δ ppm 4.16 (br s, 2H), 3.81 (dd, J = 4.6, 11.2 Hz, 2H), 3.00 (dd, J = 8.8, 11.6 Hz, 2H), 1.06 - 0.90 (m, 2H), 0.48 - 0.30 (m, 2H). Synthesis of compound 104b

To a solution of compound 104a (1 g, 9.79 mmol) in DMF (30 mL) was added imidazole (833.2 mg, 12.2 mmol) and TBDPSCl (2.69 g, 9.79 mmol) at 0°C. The mixture was stirred, allowed to reach 20°C and stirred for 16 h. TLC indicated consumption of the starting material and formation of a new spot. The mixture was concentrated under reduced pressure to give a residue. The residue was purified by column chromatography ( _SiO2 , petroleum ether/EtOAc) to give compound 104b (1.3 g, 3.82 mmol, 39% yield) as a colorless oil. ¹ H NMR (400MHz, DMSO- d ₆ ) δ ppm 7.68 (d, J = 6.8 Hz, 4H), 7.52 - 7.33 (m, 6H), 3.70 (dd, J = 5.2, 10.6 Hz, 1H), 3.55 - 3.35 (m, 3H), 1.06 (s, 9H), 1.01 - 0.89 (m, 2H), 0.44 (tdd, J = 5.2, 8.0, 17.2 Hz, 2H). Synthesis of Compound 104c

To a solution of compound 104b (200 mg, 587 μmol) in toluene (2 mL) was added cyanomethylenetributylphosphane (212.6 mg, 881 μmol) and isoindoline-1,3-dione (104 mg, 705 μmol). The mixture was brought to 80 °C and stirred for 12 h. TLC (petroleum ether/EtOAc = 5:1, R _f = 0.4) indicated that the starting material was completely consumed and a new spot was formed. The reaction mixture was concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (SiO ₂ , petroleum ether/EtOAc) to give compound 104c (200 mg, 426 μmol, 73% yield) as a white solid. ¹ H NMR (400MHz, DMSO- d ₆ ) δ ppm 7.91 - 7.81 (m, 2H), 7.76 - 7.67 (m, 2H), 7.65 - 7.53 (m, 4H), 7.43 - 7.30 (m, 6H), 3.74 - 3.63 (m, 2H), 3.49 (dd, J = 7.9, 14.0 Hz, 1H), 3.28 (dd, J = 7.2, 10.6 Hz, 1H), 1.24 - 1.11 (m, 2H), 0.90 (s, 9H), 0.62 - 0.53 (m, 1H), 0.48 - 0.32 (m, 1H). Synthesis of compound 104d

To a solution of compound 104c (2.75 g, 5.86 mmol) in MeOH (120 mL) and DCM (120 mL) was added NH ₂ NH ₂ ·H ₂ O (3.20 mL, 52.7 mmol, 80% purity). The mixture was allowed to reach 40 °C and stirred for 2 h. TLC showed complete consumption of the starting material. The mixture was poured into water (300 mL) and extracted with DCM (3×200 mL). The combined organic phases were washed with saturated aqueous NaHCO ₃ solution (3×200 mL), dried over Na ₂ SO ₄ , filtered, and concentrated under vacuum. The crude product was used in the next step without further purification. Synthesis of compound 104e

A mixture of compound 104d (1.49 g, 4.39 mmol), compound 6i (1.3 g, 3.35 mmol), DIPEA (2.33 mL, 13.4 mmol) and _{Na2CO3 (} 1.07 g, 101 mmol) in n -BuOH (100 mL) was degassed and purged with _N2 . The mixture was brought to 115 °C and stirred under _N2 atmosphere for 16 h. LCMS analysis showed consumption of starting material and the desired m/z. Four additional vials were prepared as described and combined for work-up and purification. The mixture was filtered and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (SiO ₂ , petroleum ether/EtOAc) to give compound 104e (9.5 g, 13.7 mmol, 88% yield) as a red oil. UPLC-MS (method N, ESI+): m/z [M+H] ⁺ = 691.3 (theoretical value), 691.3 (observed value). HPLC retention time: 0.833 min. Synthesis of compound 104f

A mixture _of compound 104e (1.9 g, 2.75 mmol), _Na2S2O4 (4.79 g, 27.5 mmol) in MeOH (300 mL), _H2O (80 mL) and _NH4OH (45 mL) was degassed and purged _{with N2} . The mixture was allowed to reach 25 °C and stirred under _N2 atmosphere for 16 h. LCMS analysis showed consumption of starting material and desired m/z. The reaction mixture was filtered and concentrated under reduced pressure to remove MeOH, then diluted with _H2O (100 mL) and extracted with EtOAc (2 x 150 mL). The combined organic phases were dried _{over Na2SO4} , filtered, and concentrated to yield compound 104f (1.82 g, crude), which was used in the next step without further purification. UPLC-MS (Method N, ESI+): m/z [M+H] ⁺ = 661.4 (theoretical), 661.3 (observed). HPLC retention time: 0.771 min. Synthesis of compound 104g

To a solution of compound 104f (3.03 g, 4.58 mmol) in MeOH (70 mL) and DCM (70 mL) was added CNBr (1.46 g, 13.8 mmol). The mixture was stirred at 25 °C for 16 h. LCMS analysis showed consumption of starting material and the desired m/z. The resulting mixture was concentrated to give compound 104g (2.77 g, crude), which was used without further purification. UPLC-MS (Method N, ESI+): m/z [M+H] ⁺ = 686.4 (theoretical), 686.3 (observed). HPLC retention time: 0.695 min. Synthesis of compound 104h

A mixture of compound 104g (4.15 g, 6.05 mmol), compound 2a (1.40 g, 9.08 mmol), HBTU (3.90 g, 10.3 mmol), DIPEA (7.37 mL, 42.4 mmol) in DMF (100 mL) was degassed and purged with _N2 . The mixture was brought to 60 °C and stirred under _N2 atmosphere for 16 h. LCMS analysis showed consumption of starting material and desired m/z. A second vial was prepared as described and combined for work-up and purification. The mixture was diluted with _H2O (400 mL) and extracted with EtOAc (3 x 200 mL). The combined organic layers were washed with brine (2×300 mL), dried over Na ₂ SO ₄ , filtered, and concentrated under reduced pressure to yield a residue. The residue was purified by column chromatography (SiO ₂ , petroleum ether/EtOAc) to afford compound 104h (8 g, 9.73 mmol, 80% yield) as a yellow oil. UPLC-MS (Method N, ESI+): m/z [M+H] ⁺ = 822.4 (theoretical value), 822.4 (observed value). HPLC retention time: 0.839 min. Synthesis of compound 104i

A mixture of compound 104h (500 mg, 608 μmol), LiOH.H ₂ O (893 mg, 21.3 mmol) in MeOH (75 mL), H ₂ O (4.5 mL) and DCM (9 mL) was degassed and purged with N _2. The mixture was allowed to reach 40 °C and stirred under N ₂ atmosphere for 48 h. LCMS analysis showed consumption of starting material and desired m/z. Two additional vials were prepared as described and combined for work-up and purification. The reaction mixture was concentrated under reduced pressure to remove solvent. The residue was diluted with H ₂ O (50 mL) and extracted with EtOAc (2×30 mL). The combined organic layers were dried over Na ₂ SO ₄ , filtered, and concentrated under reduced pressure. The residue was purified by column chromatography (SiO ₂ , petroleum ether/EtOAc) to afford compound 104i (400 mg, 685 μmol, 38% yield) as a yellow solid. UPLC-MS (Method F, ESI+): m/z [M+H] ⁺ = 584.3 (theoretical value), 584.3 (observed value). HPLC retention time: 1.649 min. Synthesis of compound 104j

To a solution of compound 104i (400 mg, 685 μmol) in DCM (5 mL) was added NCS (274.5 mg, 2.06 mmol) and PPh ₃ (539 mg, 2.06 mmol). The mixture was allowed to reach 25 °C and stirred for 30 min. The pH of the solution was adjusted to pH = 7 using TEA. LCMS analysis showed consumption of starting material and the desired m/z. The mixture was concentrated under reduced pressure to give a residue. The residue was purified by prepHPLC (Method 6). The pure fractions were collected, frozen, and lyophilized to give compound 104j (206 mg, 342 μmol, 50% yield) as a white solid. UPLC-MS (method G, ESI+): m/z [M+H] ⁺ = 602.3 (theoretical value), 602.3 (observed value). HPLC retention time: 3.006 min. Synthetic compound 104k

A mixture of compound 47d (50 mg, 143 μmol), compound 104j (129 mg, 215 μmol) and Cs ₂ CO ₃ (233 mg, 716 μmol) in DMF (1.4 mL) was brought to 55 °C and stirred for 16 h. LCMS analysis showed consumption of starting material and desired m/z. Cold water (10 mL) was added to the mixture and the solid was filtered. The filter cake was washed with more cold water (10 mL) and the solid was dried under reduced pressure to give compound 104k (146 mg, crude), which was used without further purification. UPLC-MS (Method A, ESI+): m/z [M+H] ⁺ = 915.5 (theoretical value), 915.5 (observed value). HPLC retention time: 1.77 min. Synthesis of compound 1.44

A solution of compound 104k (159 mg, crude) in 20% TFA in MeCN (1.7 mL) was brought to 35 °C and stirred for 2 h. LCMS analysis showed consumption of starting material and desired m/z. The solution was concentrated under reduced pressure to give a residue. The residue was purified by prepHPLC (Method 1). The fractions were collected, frozen, and lyophilized to give compound 1.44 x 1 TFA (124 mg, 134 μmol, 77% yield). UPLC-MS (Method A, ESI+): m/z [M+H] ⁺ = 815.4 (theoretical), 815.4 (observed). HPLC retention time: 1.38 min. Example 194. 9-(((1R,2R)-2-((5- aminoformyl- 7-(3-(3-(2,5- dioxo -2,5- dihydro -1H -pyrrol -1- yl )-N -methylpropionamido ) propoxy )-2-(1- ethyl -3- methyl -1H -pyrazol -5 -carboxamido )-1H- benzo [d] imidazol -1 - yl ) methyl ) cyclopropyl ) methyl )-2-(1- ethyl -3- methyl -1H -pyrazol -5- yl )-8- methoxy -9H -pyrido [2,3-b] indole -6- carboxamide ( Compound 2.134)

Compound 2.134 (36.6 mg, 37.9 μmol, 70% yield) was prepared following General Method 1 using compound 1.44 x 1 TFA (50 mg, 53.8 μmol) as starting material. UPLC-MS (Method A, ESI+): m/z [M+H] ⁺ = 966.4 (theoretical value), 966.4 (observed value). HPLC retention time: 1.57 min. Example 195. S-(1-(3-((3-((5- aminoformyl- 1-(((1R,2R)-2-((6- aminoformyl- 2-(1- ethyl -3- methyl -1H -pyrazol -5- yl )-8- methoxy- 9H -pyrido [2,3-b] indol- 9- yl ) methyl ) cyclopropyl ) methyl )-2-(1- ethyl -3- methyl - 1H -pyrazol -5- carboxamido )-1H - benzo [d] imidazol -7- yl ) oxy ) propyl )( methyl ) amino )-3 - oxopropyl )-2,5 -dioxopyrrolidin -3- yl )-L -cysteine ( Compound 3.43)

Compound 3.43 (16.6 mg, 13.8 μmol, 73% yield) was prepared following General Method 2 using compound 2.134 (18.3 mg, 19 μmol) as starting material. UPLC-MS (Method A, ESI+): m/z [M+H] ⁺ = 1087.5 (theoretical value), 1087.5 (observed value). HPLC retention time: 1.49 min. Example 196. 4-(( S) -2-((S)-2-(3-(2,5- dihydroxy-2,5-dihydro-1H-pyrrol-1-yl)propionamido)-3-methylbutanamido)propionamido)benzyl (3-((5-aminoformyl - 1 - ( ( ( 1R , 2R ) -2 - ( ( 6 - aminoformyl - 2-(1- ethyl -3- methyl-1H - pyrazol-5-yl)-8-methoxy - 9H - pyrido [ 2,3 - b ] indol -9- yl ) methyl ) cyclopropyl ) methyl ) -2-(1-ethyl-3- methyl -1H - pyrazol - 5 - carboxamido ) -1H -benzo [d ] imidazol-7-yl ) oxy ) propyl) (methyl ) carbamate ( Compound 2.135)

Compound 2.135 (4.78 mg, 3.7 μmol, 35% yield) was prepared following General Method 3 using compound 1.44 x 1 TFA (10.0 mg, 10.8 μmol) as starting material. UPLC-MS (Method A, ESI+): m/z [M+H] ⁺ = 1285.6 (theoretical), 1285.6 (observed). HPLC retention time: 1.66 min. Example 197. (2S,3S,4S,5R,6S)-6-(4-((((3-((5- aminoformyl- 1-(((1R,2R)-2-((6- aminoformyl- 2-(1- ethyl -3- methyl - 1H -pyrazol -5- yl )-8- methoxy -9H -pyrido [2,3-b] indol - 9- yl ) methyl ) cyclopropyl ) methyl )-2-(1- ethyl -3- methyl -1H -pyrazole -5 -carboxamido )-1H - benzo [d] imidazol -7- yl ) oxy ) propyl )( methyl ) aminocarboxamido ) oxy ) methyl )-2-(3-(3-(2,5- dihydroxy -2,5 - dihydro -1H - pyrrol -1- yl ) propionamido ) propionamido ) phenoxy )-3,4,5- trihydroxytetrahydro -2H- pyran -2-carboxylic acid ( Compound 2.136) Synthesis of compound 105a

Compound 105a (66.0 mg, 41.5 μmol, 60% yield) was prepared following General Method 4 using compound 1.44 x 1 TFA (64.2 mg, 69.1 μmol) as starting material. UPLC-MS (Method A, ESI+): m/z [M+H] ⁺ = 1589.6 (theoretical value), 1589.7 (observed value). HPLC retention time: 1.91 min. Synthesis of Compound 105b

Compound 105b x 1 TFA (30.7 mg, 22.9 μmol, 55% yield) was prepared following General Method 7 using compound 105a (66.0 mg, 41.5 μmol) as starting material. UPLC-MS (Method A, ESI+): m/z [M+H] ⁺ = 1227.5 (theoretical value), 1227.5 (observed value). HPLC retention time: 1.47 min. Synthesis of compound 2.136

Following General Method 6, Compound 2.136 (21.5 mg, 15.6 μmol, 68% yield) was prepared using Compound 105b x 1 TFA (30.7 mg, 22.9 μmol) as starting material. UPLC-MS (Method A, ESI+): m/z [M+H] ⁺ = 1378.5 (theoretical value), 1378.6 (observed value). HPLC retention time: 1.49 min. Example 198 General procedure for characterization of antibody drug conjugates (ADCs) : ADCs were characterized using the following method:

Method M: Size exclusion chromatography (SEC) was performed using a Waters ACQUITY UPLC system and an Acquity UPLC Protein BEH SEC column (200Å, 1.7 μm, 4.6×150 mm, PN: 186005225). The mobile phase used was 7.5% isopropanol/92.5% water (25 mM sodium phosphate, 350 mM NaCl, pH 6.8), v/v. Elution was performed isocratically at ambient temperature with a flow rate of 0.4 mL/min.

Method N: Reverse phase chromatography (RP-HPLC) was performed on a Waters 2695 HPLC system and an Agilent PLRP-S column (1000Å, 8 μm 50×2.1 mm, PN: PL1912-1802). Prior to analysis, the ADC was treated with 10 mM DTT to reduce disulfide bonds. Sample elution was performed at 80°C using mobile phase A (0.05% (v/v) TFA/water) and mobile phase B (0.01% (v/v) TFA/MeCN) with a gradient of 25-44% B in 12.5 min. Drug:antibody ratio (DAR) was calculated based on the integrated peak area measured at UV 280 nm. Molar ratio calculation

The average drug loading per antibody light chain (MR _DLC ) or antibody heavy chain (MR _DHC ) was calculated using the following equation: Where MR _DLC = average drug:light chain ratio; LC area _n % = area of the nth loaded light chain species; (based on the area of the light chain peak only); MR _n = drug:antibody ratio of the nth loaded species; and Where MR _DHC = average drug:heavy chain ratio; HC area _n % = area of heavy chain species loaded in the nth load; (based on the area of heavy chain peak only); MR _n = drug:antibody ratio of the nth load.

The mean drug loading (MR _D ) for each antibody was calculated using the following equation: MR _D = 2 x (MR _DLC + MR _DHC ) where MR _D = mean drug:antibody ratio; MR _DLC = mean drug:light chain ratio; MR _DHC = mean drug:heavy chain ratio.

Method O: Residual unbound drug-conjugate was measured using an ACQUITY UPLC BEH C18 column (130Å, 1.7 µm, 2.1 mm×50 mm, PN: 186002350) on a Waters ACQUITY UPLC system. ADC samples were treated with 2x volumes of ice-cold MeOH to induce precipitation and pelleted by centrifugation. The supernatant containing any residual unbound drug-conjugate was injected onto the system. Samples were eluted at 50°C using mobile phase A (0.05% (v/v) TFA/water) and mobile phase B (0.01% TFA (v/v)/MeCN) with a gradient of 1-95% B in 2 minutes. Detection was performed at 215 nm and quantification of residual drug-linker compounds was achieved using external standards of the corresponding linker. Example B1 : In vitro potency assessment of STING agonists and corresponding ADCs THP1-Dual™ cell reporter gene assay

The potency of compounds and ADCs was evaluated using THP1-Dual™ cells (InvivoGen PN: thpd-nfis [also known as THP1 dual reporter cells]), which contain an IRF-Lucia luciferase reporter gene. Cells were cultured in RPMI-1640 (Gibco) containing 10% heat-killed live fetal bovine serum, Pen-Strep (100 U/mL-100 μg/mL, Gibco), HEPES (10 mM, Gibco), sodium pyruvate (1 mM, Gibco), MEM non-essential amino acids (1x, Gibco), GlutaMAX (1x, Gibco), and β-hydroxyethanol (55 μM, Gibco). Cells were seeded at approximately 100,000 cells/well in 200 μL with indicated concentrations of compound or ADC in 96-well flat-bottom tissue culture treated clear polystyrene plates (Corning Costar #3596). Supernatants were harvested 24 hours (compounds) or 48 hours (ADC) post-seeding for reporter gene analysis, or as indicated. To measure Lucia reporter signal, 10 μL of supernatant was combined with 40 μL of QUANTI-Luc™ Luminescence Assay Reagent (Invivogen PN: rep-qlc1) in 96-well clear flat-bottom tissue culture treated black polystyrene plates (Corning Costar #3603) and read on a Perkin Elmer Envision plate reader. The potency of the compounds and ADCs is summarized in Tables 5 and 6 . Table 5: Activity of STING agonist compounds on THP1-Dual ^TM reporter cells Table 6 : Activity of STING- targeted agonist ADCs on THP1-Dual ^TM reporter gene cells Example B2 : In vitro cytotoxicity of STING agonists and corresponding ADCs in a panel of cancer cell lines

Cancer cells were counted and plated in 40 µL of complete growth medium in 384-well white-walled tissue culture treated plates (Corning). The plates were incubated at 37°C and 5% CO₂Incubate overnight at 37°C to allow cells to equilibrate. Serially dilute the stock solution containing ADC or free drug in RPMI-1640 + 20% fetal bovine serum (FBS). Then, add 10 µL of each concentration to each cell plate in duplicate. Then, incubate the cells at 37°C and 5% CO₂The plates were incubated at 4 °C for 96 h, after which they were removed from the incubator and allowed to cool to room temperature for 30 min prior to analysis. CellTiter-Glo® luminescence assay reagent was prepared according to Promega's protocol (Promega Corporation, Madison, WI). 10 µL of CellTiter-Glo® was added to the assay plates using a Formulatrix Tempest liquid handler (Formulatrix), and the plates were incubated at room temperature for 30 min in the dark. Luminescence of the samples was measured using an EnVision Multimode plate reader (Perkin Elmer, Waltham, MA). Raw data were analyzed in Graphpad Prism (San Diego, CA) using a nonlinear 4-parameter curve fitting model [Y = bottom + (top - bottom) / (1 + 10^((LogEC50-X)*Hill slope))]. Results are reported as X50 values, which are defined as the concentration of ADC or free drug required to reduce cell viability by 50%. The cytotoxic activity of compounds and ADCs on cancer cell lines is summarized in surface 7Aand surface 7BADC corresponds to the conjugate of the drug-linker compound and either the antibody "targeting mAb A" or "targeting mAb B". surface 7A : STING Agonist ADC Cytotoxicity on a panel of cancer cell lines Target A performance + + + + + + + Target B performance - - - - + + + 786-O A2058 BxPc Calu1 DEL DELBVR Karpas299 Compound X50 (nM) Compound 1.1 ＞1K ＞1K ＞1K ＞1K 53 965 ＞1K Compound 1.2 ＞1K ＞1K ＞1K ＞1K 54 990 ＞1K Compound 1.3 ＞1K ＞1K ＞1K ＞1K 1 26 27 Compound 1.4 ＞1K ＞1K ＞1K ＞1K 1 38 189 Compound 1.5 ＞1K ＞1K ＞1K ＞1K 68 ＞1K ＞1K Compound 1.6 ＞1K ＞1K ＞1K ＞1K 63 ＞1K ＞1K Compound 1.7 ＞1K ＞1K ＞1K ＞1K ＞1K ＞1K ＞1K Compound 1.8 ＞1K ＞1K ＞1K ＞1K 9 253 ＞1K Compound 1.10 ＞1K ＞1K ＞1K ＞1K 207 ＞1K ＞1K Compound 1.11 ＞1K ＞1K ＞1K ＞1K 80 ＞1K ＞1K Compound 1.12 ＞1K ＞1K ＞1K ＞1K 1 twenty three 16 Compound 1.13 ＞1K ＞1K ＞1K ＞1K 15 639 ＞1K Compound 1.14 ＞1K ＞1K ＞1K ＞1K 12 279 ＞1K Compound 1.15 ＞1K ＞1K ＞1K ＞1K 0.5 31 10 Compound 1.16 ＞1K ＞1K ＞1K ＞1K 7 401 ＞1K Compound 1.17 ＞1K ＞1K ＞1K ＞1K 46 ＞1K ＞1K Compound 1.18 ＞1K ＞1K ＞1K ＞1K 8 345 ＞1K Compound 1.20 ＞1K ＞1K ＞1K ＞1K 7 N/A ＞1K Compound 1.21 ＞1K ＞1K ＞1K ＞1K ＞1K ＞1K ＞1K Compound 1.22 ＞1K ＞1K ＞1K ＞1K 0.3 3 ＞1K Compound 1.23 ＞1K ＞1K ＞1K ＞1K 4 54 ＞1K Compound 1.26 ＞1K ＞1K ＞1K ＞1K 1 15 ＞1K Compound 1.27 ＞1K ＞1K ＞1K ＞1K 0.6 20 43 Compound 1.28 ＞1K ＞1K ＞1K ＞1K 4 10 ＞1K Compound 1.29 ＞1K ＞1K ＞1K ＞1K 1 twenty three ＞1K Compound 1.30 ＞1K ＞1K ＞1K ＞1K 14 84 ＞1K Compound 1.31 ＞1K ＞1K ＞1K ＞1K 25 86 ＞1K Compound 1.32 ＞1K ＞1K ＞1K ＞1K 26 82 ＞1K Compound 1.33 ＞1K ＞1K ＞1K N/A 149 ＞1000 ＞1K Compound 1.34 ＞1K ＞1K ＞1K N/A 3 133 ＞1K Compound 1.35 ＞1K ＞1K ＞1K ＞1K 5 179 238 Compound 1.36 ＞1K ＞1K ＞1K ＞1K 2 33 17 Compound 1.37 ＞1K ＞1K ＞1K ＞1K 316 ＞1K ＞1K Compound 1.38 ＞1K ＞1K ＞1K ＞1K 2 116 ＞1K Compound 1.39 ＞1K ＞1K ＞1K ＞1K 4 208 383 Compound 1.40 ＞1K ＞1K ＞1K ＞1K 15 326 ＞1K Compound 1.41 ＞1K ＞1K ＞1K N/A 16 291 ＞1K Compound 1.42 ＞1K ＞1K ＞1K N/A 4 twenty two 114 Compound 1.43 ＞1K ＞1K ＞1K N/A 1 twenty four 146 Compound 1.44 ＞1K ＞1K ＞1K ＞1K ＞1K ＞1K ＞1K Compound 3.1 ＞1K ＞1K ＞1K ＞1K 62 149 ＞1K Compound 3.2 ＞1K ＞1K ＞1K ＞1K 83 203 ＞1K Compound 3.3 ＞1K ＞1K ＞1K ＞1K 4 7 ＞1K Compound 3.4 ＞1K ＞1K ＞1K ＞1K 5 9 ＞1K Compound 3.5 ＞1K ＞1K ＞1K ＞1K 7 9 766 Compound 3.6 ＞1K ＞1K ＞1K ＞1K 31 45 995 Compound 3.8 ＞1K ＞1K ＞1K ＞1K 3 3 ＞1K Compound 3.9 ＞1K ＞1K ＞1K ＞1K 34 99 ＞1K Compound 3.10 ＞1K ＞1K ＞1K ＞1K 135 126 ＞1K Compound 3.11 ＞1K ＞1K ＞1K ＞1K 4 5 ＞1K Compound 3.12 ＞1K ＞1K ＞1K ＞1K 1 1 19 Compound 3.13 ＞1K ＞1K ＞1K ＞1K 9 15 691 Compound 3.14 ＞1K ＞1K ＞1K ＞1K 4 7 ＞1K Compound 3.15 ＞1K ＞1K ＞1K ＞1K 1 2 ＞1K Compound 3.16 ＞1K ＞1K ＞1K ＞1K 14 59 ＞1K Compound 3.17 ＞1K ＞1K ＞1K ＞1K 96 952 ＞1K Compound 3.18 ＞1K ＞1K ＞1K ＞1K 14 60 ＞1K Compound 3.26 ＞1K ＞1K ＞1K N/A 0.3 0.9 ＞1K Compound 3.27 ＞1K ＞1K ＞1K N/A 3 2 ＞1K Compound 3.28 ＞1K ＞1K ＞1K N/A 1 3 ＞1K Compound 3.29 ＞1K ＞1K ＞1K ＞1K 47 128 ＞1K Compound 3.30 ＞1K ＞1K ＞1K ＞1K 257 947 ＞1K Compound 3.31 ＞1K ＞1K ＞1K ＞1K ＞1K ＞1K ＞1K Compound 3.32 ＞1K ＞1K N/A ＞1K 35 16 ＞1K Compound 3.33 ＞1K ＞1K N/A ＞1K 0.6 0.3 ＞1K Compound 3.34 ＞1K ＞1K ＞1K ＞1K 2 5 171 Compound 3.35 ＞1K ＞1K ＞1K ＞1K 0.9 1 twenty three Compound 3.36 ＞1K ＞1K ＞1K ＞1K ＞1K ＞1K ＞1K Compound 3.37 ＞1K ＞1K ＞1K ＞1K 2 3.9 76 Compound 3.38 ＞1K ＞1K ＞1K ＞1K 0.4 0.9 14 Compound 3.39 ＞1K ＞1K ＞1K ＞1K 2 3 80 Compound 3.40 ＞1K ＞1K ＞1K ＞1K 7 14 ＞1K Compound 3.41 ＞1K ＞1K ＞1K ＞1K 0.6 1 ＞1K Compound 3.42 ＞1K ＞1K ＞1K ＞1K 0.9 2 ＞1K Compound 3.43 ＞1K ＞1K ＞1K ＞1K ＞1K ＞1K ＞1K ADC X50 (ng/mL) Targeting mAb A 2.1 (8 loading) ＞1K ＞1K N/A ＞1K 0.02 0.3 15 Targeting mAb A 2.1 (4 loading) ＞1K ＞1K N/A ＞1K 0.04 0.5 44 Targeting mAb B 2.1 (8 loading) ＞1K ＞1K N/A ＞1K 0.04 0.2 7 Targeting mAb B 2.1 (4 loading) ＞1K ＞1K N/A ＞1K 0.1 0.2 80 Targeting mAb A 2.2 (8 loading) ＞1K ＞1K N/A ＞1K 0.5 0.5 50 Targeting mAb A 2.2 (4 loading) ＞1K ＞1K N/A ＞1K 0.1 1 ＞1K Targeting mAb B 2.2 (8 loading) ＞1K ＞1K N/A ＞1K 0.1 0.3 10 Targeting mAb B 2.2 (4 loading) ＞1K ＞1K N/A ＞1K 0.1 0.4 twenty one Targeting mAb A 2.3 (8 loading) ＞1K ＞1K ＞1K ＞1K 0.03 0.02 6 Targeting mAb A 2.3 (4 loading) ＞1K ＞1K ＞1K ＞1K 0.1 0.08 4 Targeting mAb B 2.3 (8 loading) ＞1K ＞1K ＞1K ＞1K 0.005 0.006 3 Targeting mAb B 2.3 (4 loading) ＞1K ＞1K ＞1K ＞1K 0.03 0.04 10 Targeting mAb A 2.4 (8 loading) ＞1K ＞1K ＞1K ＞1K 0.1 0.1 20 Targeting mAb A 2.4 (4 loading) ＞1K ＞1K ＞1K ＞1K 0.5 0.3 187 Targeting mAb B 2.4 (8 loading) ＞1K ＞1K ＞1K ＞1K 0.02 0.02 4 Targeting mAb B 2.4 (4 loading) ＞1K ＞1K ＞1K ＞1K 0.05 0.1 17 Targeting mAb A 2.5 (8 loading) ＞1K ＞1K N/A ＞1K 0.02 4 72 Targeting mAb A 2.5 (4 loading) ＞1K ＞1K N/A ＞1K 0.3 18 839 Targeting mAb B 2.5 (8 loading) ＞1K ＞1K N/A ＞1K 0.02 74 6 Targeting mAb B 2.5 (4 loading) ＞1K ＞1K N/A ＞1K 0.1 707 ＞1K Targeting mAb A 2.6 (8 loading) ＞1K ＞1K N/A ＞1K 0.3 16 551 Targeting mAb A 2.6 (4 loading) ＞1K ＞1K N/A ＞1K 0.6 60 ＞1K Targeting mAb B 2.6 (8 loading) ＞1K ＞1K N/A ＞1K 0.1 ＞1K ＞1K Targeting mAb B 2.6 (4 loading) ＞1K ＞1K N/A ＞1K 0.3 ＞1K ＞1K Targeting mAb A 2.7 (8 loading) ＞1K ＞1K 899 ＞1K 0.3 4 95 Targeting mAb A 2.7 (4 loading) ＞1K ＞1K ＞1K ＞1K 1 15 342 Targeting mAb B 2.7 (8 loading) ＞1K ＞1K ＞1K ＞1K 0.01 0.5 2 Targeting mAb B 2.7 (4 loading) ＞1K ＞1K ＞1K ＞1K 0.1 4 twenty one Targeting mAb A 2.8 (8 loading) ＞1K ＞1K ＞1K ＞1K 0.1 1 159 Targeting mAb A 2.8 (4 loading) ＞1K ＞1K ＞1K ＞1K 1 15 ＞1K Targeting mAb B 2.8 (8 loading) ＞1K ＞1K ＞1K ＞1K 0.02 2 9 Targeting mAb B 2.8 (4 loading) ＞1K ＞1K ＞1K ＞1K 0.1 12 114 Targeting mAb A 2.9 (8 loading) ＞1K ＞1K N/A ＞1K 0.1 5 120 Targeting mAb A 2.9 (4 loading) ＞1K ＞1K N/A ＞1K 0.7 31 ＞1K Targeting mAb B 2.9 (8 loading) ＞1K ＞1K N/A ＞1K 0.03 ＞1K ＞1K Targeting mAb B 2.9 (4 loading) ＞1K ＞1K N/A ＞1K 0.2 ＞1K ＞1K Targeting mAb A 2.10 (8 loading) ＞1K ＞1K N/A ＞1K 0.1 9 ＞1K Targeting mAb A 2.10 (4 loading) ＞1K ＞1K N/A ＞1K 0.1 55 ＞1K Targeting mAb B 2.10 (8 loading) ＞1K ＞1K N/A ＞1K 0.3 ＞1K ＞1K Targeting mAb B 2.10 (4 loading) ＞1K ＞1K N/A ＞1K 0.7 ＞1K ＞1K Targeting mAb A 2.11 (8 loading) ＞1K ＞1K ＞1K ＞1K 0.1 0.7 twenty two Targeting mAb A 2.11 (4 loading) ＞1K ＞1K ＞1K ＞1K 0.7 5 196 Targeting mAb B 2.11 (8 loading) ＞1K ＞1K ＞1K ＞1K 0.01 0.2 4 Targeting mAb B 2.11 (4 loading) ＞1K ＞1K ＞1K ＞1K 0.1 1 11 Targeting mAb A 2.12 (8 loading) ＞1K ＞1K ＞1K ＞1K 0.1 0.9 ＞1K Targeting mAb A 2.12 (4 loading) ＞1K ＞1K ＞1K ＞1K 1 10 ＞1K Targeting mAb B 2.12 (8 loading) ＞1K ＞1K ＞1K ＞1K 0.01 0.3 32 Targeting mAb B 2.12 (4 loading) ＞1K ＞1K ＞1K ＞1K 0.1 2 54 Targeting mAb A 2.13 (8 loading) ＞1K ＞1K ＞1K ＞1K 6 69 ＞1K Targeting mAb A 2.13 (4 loading) ＞1K ＞1K ＞1K ＞1K 15 ＞1K ＞1K Targeting mAb B 2.13 (8 loading) ＞1K ＞1K ＞1K ＞1K 0.9 ＞1K ＞1K Targeting mAb B 2.13 (4 loading) ＞1K ＞1K ＞1K ＞1K 4 ＞1K ＞1K Targeting mAb A 2.14 (8 loading) ＞1K ＞1K ＞1K ＞1K 4 ＞1K ＞1K Targeting mAb A 2.14 (4 loading) ＞1K ＞1K ＞1K ＞1K 14 ＞1K ＞1K Targeting mAb B 2.14 (8 loading) ＞1K ＞1K ＞1K ＞1K 0.7 ＞1K ＞1K Targeting mAb B 2.14 (4 loading) ＞1K ＞1K ＞1K ＞1K 4 ＞1K ＞1K Targeting mAb A 2.15 (8 loading) ＞1K ＞1K ＞1K ＞1K 0.5 <0.004 ＞1K Targeting mAb A 2.15 (4 loading) ＞1K ＞1K ＞1K ＞1K 0.8 0.3 ＞1K Targeting mAb B 2.15 (8 loading) ＞1K ＞1K ＞1K ＞1K 0.2 0.2 ＞1K Targeting mAb B 2.15 (4 loading) ＞1K ＞1K ＞1K ＞1K 0.3 0.3 ＞1K Targeting mAb A 2.16 (8 loading) ＞1K ＞1K ＞1K ＞1K 0.1 0.04 ＞1K Targeting mAb A 2.16 (4 loading) ＞1K ＞1K ＞1K ＞1K 4 2 ＞1K Targeting mAb B 2.16 (8 loading) ＞1K ＞1K ＞1K ＞1K 0.1 0.3 ＞1K Targeting mAb B 2.16 (4 loading) ＞1K ＞1K ＞1K ＞1K 1 1 ＞1K Targeting mAb A 2.17 (8 loading) ＞1K ＞1K ＞1K ＞1K 3 170 ＞1K Targeting mAb A 2.17 (4 loading) ＞1K ＞1K ＞1K ＞1K 9 ＞1K ＞1K Targeting mAb B 2.17 (8 loading) ＞1K ＞1K ＞1K ＞1K 1 ＞1K ＞1K Targeting mAb B 2.17 (4 loading) ＞1K ＞1K ＞1K ＞1K 3 ＞1K ＞1K Targeting mAb A 2.18 (8 loading) ＞1K ＞1K ＞1K ＞1K 4 ＞1K ＞1K Targeting mAb A 2.18 (4 loading) ＞1K ＞1K ＞1K ＞1K 7 ＞1K ＞1K Targeting mAb B 2.18 (8 loading) ＞1K ＞1K ＞1K ＞1K 1 ＞1K 968 Targeting mAb B 2.18 (4 loading) ＞1K ＞1K ＞1K ＞1K 3 ＞1K ＞1K Targeting mAb A 2.19 (8 loading) ＞1K ＞1K ＞1K ＞1K 0.1 0.1 77 Targeting mAb A 2.19 (4 loading) ＞1K ＞1K ＞1K ＞1K 1 1 ＞1K Targeting mAb B 2.19 (8 loading) ＞1K ＞1K ＞1K ＞1K 0.1 0.2 ＞1K Targeting mAb B 2.19 (4 loading) ＞1K ＞1K ＞1K ＞1K 0.4 0.4 ＞1K Targeting mAb A 2.20 (8 loading) ＞1K ＞1K ＞1K ＞1K 0.2 4 ＞1K Targeting mAb A 2.20 (4 loading) ＞1K ＞1K ＞1K ＞1K 1 twenty one 894 Targeting mAb B 2.20 (8 loading) ＞1K ＞1K ＞1K ＞1K 0.1 6 ＞1K Targeting mAb B 2.20 (4 loading) ＞1K ＞1K ＞1K ＞1K 0.3 ＞1K ＞1K Targeting mAb A 2.21 (8 loading) ＞1K ＞1K ＞1K ＞1K 0.2 4 ＞1K Targeting mAb A 2.21 (4 loading) ＞1K ＞1K ＞1K ＞1K 0.9 17 ＞1K Targeting mAb B 2.21 (8 loading) ＞1K ＞1K ＞1K ＞1K 0.04 4 ＞1K Targeting mAb B 2.21 (4 loading) ＞1K ＞1K ＞1K ＞1K 0.1 ＞1K ＞1K Targeting mAb A 2.25 (8 loading) ＞1K ＞1K ＞1K ＞1K ＞1K ＞1K ＞1K Targeting mAb A 2.25 (4 loading) ＞1K ＞1K ＞1K ＞1K ＞1K ＞1K ＞1K Targeting mAb B 2.25 (8 loading) ＞1K ＞1K ＞1K ＞1K ＞1K ＞1K ＞1K Targeting mAb B 2.25 (4 loading) ＞1K ＞1K ＞1K ＞1K ＞1K ＞1K ＞1K Targeting mAb A 2.26 (8 loading) ＞1K ＞1K ＞1K ＞1K ＞1K ＞1K ＞1K Targeting mAb A 2.26 (4 loading) ＞1K ＞1K ＞1K ＞1K ＞1K ＞1K ＞1K Targeting mAb B 2.26 (8 loading) ＞1K ＞1K ＞1K ＞1K ＞1K ＞1K ＞1K Targeting mAb B 2.26 (4 loading) ＞1K ＞1K ＞1K ＞1K ＞1K ＞1K ＞1K Targeting mAb A 2.27 (8 loading) ＞1K ＞1K ＞1K N/A ＞1K ＞1K ＞1K Targeting mAb A 2.27 (4 loading) ＞1K ＞1K ＞1K N/A ＞1K ＞1K ＞1K Targeting mAb B 2.27 (8 loading) ＞1K ＞1K ＞1K N/A ＞1K ＞1K ＞1K Targeting mAb B 2.27 (4 loading) ＞1K ＞1K ＞1K N/A ＞1K ＞1K ＞1K Targeting mAb A 2.28 (8 loading) ＞1K ＞1K ＞1K ＞1K 71 28 ＞1K Targeting mAb A 2.28 (4 loading) ＞1K ＞1K ＞1K ＞1K ＞1K ＞1K ＞1K Targeting mAb B 2.28 (8 loading) ＞1K ＞1K ＞1K ＞1K 26 ＞1K ＞1K Targeting mAb B 2.28 (4 loading) ＞1K ＞1K ＞1K ＞1K ＞1K ＞1K ＞1K Targeting mAb A 2.29 (8 loading) ＞1K ＞1K ＞1K ＞1K 47 102 ＞1K Targeting mAb A 2.29 (4 loading) ＞1K ＞1K ＞1K ＞1K ＞1K ＞1K ＞1K Targeting mAb B 2.29 (8 loading) ＞1K ＞1K ＞1K ＞1K 26 ＞1K ＞1K Targeting mAb B 2.29 (4 loading) ＞1K ＞1K ＞1K ＞1K 350 ＞1K ＞1K Targeting mAb A 2.30 (8 loading) ＞1K ＞1K ＞1K ＞1K ＞1K ＞1K ＞1K Targeting mAb A 2.30 (4 loading) ＞1K ＞1K ＞1K ＞1K ＞1K ＞1K ＞1K Targeting mAb B 2.30 (8 loading) ＞1K ＞1K ＞1K ＞1K ＞1K ＞1K ＞1K Targeting mAb B 2.30 (4 loading) ＞1K ＞1K ＞1K ＞1K ＞1K ＞1K ＞1K Targeting mAb A 2.31 (8 loading) ＞1K ＞1K ＞1K ＞1K 7 3 ＞1K Targeting mAb A 2.31 (4 loading) ＞1K ＞1K ＞1K ＞1K 35 15 ＞1K Targeting mAb B 2.31 (8 loading) ＞1K ＞1K ＞1K ＞1K 2 28 ＞1K Targeting mAb B 2.31 (4 loading) ＞1K ＞1K ＞1K ＞1K 9 474 ＞1K Targeting mAb A 2.32 (8 loading) ＞1K ＞1K ＞1K ＞1K 12 166 ＞1K Targeting mAb A 2.32 (4 loading) ＞1K ＞1K ＞1K ＞1K 63 ＞1K ＞1K Targeting mAb B 2.32 (8 loading) ＞1K ＞1K ＞1K ＞1K 3 ＞1K ＞1K Targeting mAb B 2.32 (4 loading) ＞1K ＞1K ＞1K ＞1K 20 ＞1K ＞1K Targeting mAb A 2.33 (8 loading) ＞1K ＞1K ＞1K ＞1K 15 ＞1K ＞1K Targeting mAb A 2.33 (4 loading) ＞1K ＞1K ＞1K ＞1K 58 ＞1K ＞1K Targeting mAb B 2.33 (8 loading) ＞1K ＞1K ＞1K ＞1K 4 ＞1K ＞1K Targeting mAb B 2.33 (4 loading) ＞1K ＞1K ＞1K ＞1K 15 ＞1K ＞1K Targeting mAb A 2.34 (8 loading) ＞1K ＞1K ＞1K ＞1K ＜ 0.004 ＜ 0.004 9 Targeting mAb A 2.34 (4 loading) ＞1K ＞1K ＞1K ＞1K 0.03 0.01 20 Targeting mAb B 2.34 (8 loading) ＞1K ＞1K ＞1K ＞1K ＜ 0.004 ＜ 0.004 1 Targeting mAb B 2.34 (4 loading) ＞1K ＞1K ＞1K ＞1K 0.01 0.01 7 Targeting mAb A 2.35 (8 loading) ＞1K ＞1K ＞1K ＞1K 0.02 0.6 15 Targeting mAb A 2.35 (4 loading) ＞1K ＞1K ＞1K ＞1K 0.2 3 52 Targeting mAb B 2.35 (8 loading) ＞1K ＞1K ＞1K ＞1K 0.01 1 2 Targeting mAb B 2.35 (4 loading) ＞1K ＞1K ＞1K ＞1K 0.03 10 10 Targeting mAb A 2.36 (8 loading) ＞1K ＞1K ＞1K ＞1K 0.1 0.4 32 Targeting mAb A 2.36 (4 loading) ＞1K ＞1K ＞1K ＞1K 0.2 1 269 Targeting mAb B 2.36 (8 loading) ＞1K ＞1K ＞1K ＞1K 0.01 0.2 0.9 Targeting mAb B 2.36 (4 loading) ＞1K ＞1K ＞1K ＞1K 0.05 0.4 1 Targeting mAb A 2.37 (8 loading) ＞1K ＞1K ＞1K ＞1K 0.2 0.2 17 Targeting mAb A 2.37 (4 loading) ＞1K ＞1K ＞1K ＞1K 0.2 0.1 44 Targeting mAb B 2.37 (8 loading) ＞1K ＞1K ＞1K ＞1K 0.005 0.006 0.5 Targeting mAb B 2.37 (4 loading) ＞1K ＞1K ＞1K ＞1K 0.01 0.02 0.9 Targeting mAb A 2.38 (8 loading) ＞1K ＞1K ＞1K ＞1K 0.2 2 103 Targeting mAb A 2.38 (4 loading) ＞1K ＞1K ＞1K ＞1K 0.3 4 ＞1K Targeting mAb B 2.38 (8 loading) ＞1K ＞1K ＞1K ＞1K 0.04 4 25 Targeting mAb B 2.38 (4 loading) ＞1K ＞1K ＞1K ＞1K 0.1 18 ＞1K Targeting mAb A 2.39 (8 loading) ＞1K ＞1K ＞1K ＞1K 0.1 0.4 49 Targeting mAb A 2.39 (4 loading) ＞1K ＞1K ＞1K ＞1K 0.3 1 ＞1K Targeting mAb B 2.39 (8 loading) ＞1K ＞1K ＞1K ＞1K 0.02 0.3 16 Targeting mAb B 2.39 (4 loading) ＞1K ＞1K ＞1K ＞1K 0.03 0.6 ＞1K Targeting mAb A 2.40 (8 loading) ＞1K ＞1K ＞1K ＞1K 0.2 0.2 ＞1K Targeting mAb A 2.40 (4 loading) ＞1K ＞1K ＞1K ＞1K 1 0.8 ＞1K Targeting mAb B 2.40 (8 loading) ＞1K ＞1K ＞1K ＞1K 0.1 0.1 237 Targeting mAb B 2.40 (4 loading) ＞1K ＞1K ＞1K ＞1K 0.4 0.4 ＞1K Targeting mAb A 2.41 (8 loading) ＞1K ＞1K ＞1K ＞1K 1 15 ＞1K Targeting mAb A 2.41 (4 loading) ＞1K ＞1K ＞1K ＞1K 2 340 ＞1K Targeting mAb B 2.41 (8 loading) ＞1K ＞1K ＞1K ＞1K 0.2 ＞1K ＞1K Targeting mAb B 2.41 (4 loading) ＞1K ＞1K ＞1K ＞1K 1 ＞1K ＞1K Targeting mAb A 2.42 (8 loading) ＞1K ＞1K ＞1K ＞1K 0.2 1 65 Targeting mAb A 2.42 (4 loading) ＞1K ＞1K ＞1K ＞1K 0.5 3 ＞1K Targeting mAb B 2.42 (8 loading) ＞1K ＞1K ＞1K ＞1K 0.1 1 11 Targeting mAb B 2.42 (4 loading) ＞1K ＞1K ＞1K ＞1K 0.2 16 44 Targeting mAb A 2.43 (8 loading) ＞1K ＞1K ＞1K ＞1K 0.05 <0.004 31 Targeting mAb A 2.43 (4 loading) ＞1K ＞1K ＞1K ＞1K 0.02 <0.004 ＞1K Targeting mAb B 2.43 (8 loading) ＞1K ＞1K ＞1K ＞1K <0.004 <0.004 9 Targeting mAb B 2.43 (4 loading) ＞1K ＞1K ＞1K ＞1K <0.004 <0.004 14 Targeting mAb A 2.44 (8 loading) ＞1K ＞1K ＞1K ＞1K <0.004 0.5 46 Targeting mAb A 2.44 (4 loading) ＞1K ＞1K ＞1K ＞1K <0.004 1 344 Targeting mAb B 2.44 (8 loading) ＞1K ＞1K ＞1K ＞1K <0.004 0.6 7 Targeting mAb B 2.44 (4 loading) ＞1K ＞1K ＞1K ＞1K <0.004 76 34 Targeting mAb A 2.45 (8 loading) ＞1K ＞1K ＞1K ＞1K <0.004 0.1 99 Targeting mAb A 2.45 (4 loading) ＞1K ＞1K ＞1K ＞1K 0.01 0.2 ＞1K Targeting mAb B 2.45 (8 loading) ＞1K ＞1K ＞1K ＞1K <0.004 <0.004 10 Targeting mAb B 2.45 (4 loading) ＞1K ＞1K ＞1K ＞1K <0.004 0.4 58 Targeting mAb A 2.46 (8 loading) ＞1K ＞1K N/A ＞1K 0.01 0.01 ＞1K Targeting mAb A 2.46 (4 loading) ＞1K ＞1K N/A ＞1K 0.02 0.05 ＞1K Targeting mAb B 2.46 (8 loading) ＞1K ＞1K N/A ＞1K 0.005 0.03 ＞1K Targeting mAb B 2.46 (4 loading) ＞1K ＞1K N/A ＞1K 0.02 0.1 ＞1K Targeting mAb A 2.47 (8 loading) 341 ＞1K N/A ＞1K <0.004 1 31 Targeting mAb A 2.47 (4 loading) ＞1K ＞1K N/A ＞1K <0.004 3 ＞1K Targeting mAb B 2.47 (8 loading) ＞1K ＞1K N/A ＞1K <0.004 49 8 Targeting mAb B 2.47 (4 loading) ＞1K ＞1K N/A ＞1K 0.01 ＞1K 20 Targeting mAb A 2.48 (8 loading) ＞1K ＞1K N/A ＞1K 0.01 2 ＞1K Targeting mAb A 2.48 (4 loading) ＞1K ＞1K N/A ＞1K 0.1 7 ＞1K Targeting mAb B 2.48 (8 loading) ＞1K ＞1K N/A ＞1K <0.004 9 325 Targeting mAb B 2.48 (4 loading) ＞1K ＞1K N/A ＞1K 0.03 32 ＞1K Targeting mAb A 2.49 (8 loading) ＞1K ＞1K N/A ＞1K 15 40 ＞1K Targeting mAb A 2.49 (4 loading) ＞1K ＞1K N/A ＞1K 13 36 ＞1K Targeting mAb B 2.49 (8 loading) ＞1K ＞1K N/A ＞1K 3 164 ＞1K Targeting mAb B 2.49 (4 loading) ＞1K ＞1K N/A ＞1K 4 twenty two ＞1K Targeting mAb A 2.50 (8 loading) 114 ＞1K N/A ＞1K 0.01 4 196 Targeting mAb A 2.50 (4 loadings) ＞1K ＞1K N/A ＞1K 0.9 38 ＞1K Targeting mAb B 2.50 (8 loading) ＞1K ＞1K N/A ＞1K 0.2 ＞1K 56 Targeting mAb B 2.50 (4 loadings) ＞1K ＞1K N/A ＞1K 0.8 ＞1K ＞1K Targeting mAb A 2.51 (8 loading) ＞1K ＞1K N/A ＞1K 0.7 13 ＞1K Targeting mAb A 2.51 (4 loading) ＞1K ＞1K N/A ＞1K 1 92 ＞1K Targeting mAb B 2.51 (8 loading) ＞1K ＞1K N/A ＞1K 0.4 10 ＞1K Targeting mAb B 2.51 (4 loading) ＞1K ＞1K N/A ＞1K 0.7 <0.004 ＞1K Targeting mAb A 2.52 (8 loading) ＞1K ＞1K N/A ＞1K 4 5 ＞1K Targeting mAb A 2.52 (4 loading) ＞1K ＞1K N/A ＞1K 1 0.9 ＞1K Targeting mAb B 2.52 (8 loading) ＞1K ＞1K N/A ＞1K 0.8 2 ＞1K Targeting mAb B 2.52 (4 loading) ＞1K ＞1K N/A ＞1K 2 6 ＞1K Targeting mAb A 2.53 (8 loading) ＞1K ＞1K N/A ＞1K <0.004 0.9 59 Targeting mAb A 2.53 (4 loading) ＞1K ＞1K N/A ＞1K <0.004 6 610 Targeting mAb B 2.53 (8 loading) ＞1K ＞1K N/A ＞1K <0.004 312 7 Targeting mAb B 2.53 (4 loading) ＞1K ＞1K N/A ＞1K 0.01 ＞1K 45 Targeting mAb A 2.54 (8 loading) ＞1K ＞1K N/A ＞1K 0.03 4 ＞1K Targeting mAb A 2.54 (4 loading) ＞1K ＞1K N/A ＞1K 0.1 10 ＞1K Targeting mAb B 2.54 (8 loading) ＞1K ＞1K N/A ＞1K 0.004 13 ＞1K Targeting mAb B 2.54 (4 loading) ＞1K ＞1K N/A ＞1K 0.1 ＞1K ＞1K Targeting mAb A 2.58 (8 loading) ＞1K ＞1K ＞1K ＞1K 0.1 N/A 26 Targeting mAb A 2.58 (4 loading) ＞1K ＞1K ＞1K ＞1K 0.2 N/A 458 Targeting mAb B 2.58 (8 loading) ＞1K ＞1K ＞1K ＞1K ＜ 0.004 N/A 2 Targeting mAb B 2.58 (4 loading) ＞1K ＞1K ＞1K ＞1K 0.04 N/A 6 Targeting mAb A 2.59 (8 loading) ＞1K ＞1K ＞1K ＞1K 0.1 2 141 Targeting mAb A 2.59 (4 loadings) ＞1K ＞1K ＞1K ＞1K 0.7 6 ＞1K Targeting mAb B 2.59 (8 loading) ＞1K ＞1K ＞1K ＞1K 0.03 4 15 Targeting mAb B 2.59 (4 loading) N/A N/A N/A N/A N/A N/A N/A Targeting mAb A 2.60 (8 loading) ＞1K ＞1K ＞1K N/A 3 9 ＞1K Targeting mAb A 2.60 (4 loadings) ＞1K ＞1K ＞1K N/A 8 30 ＞1K Targeting mAb B 2.60 (8 loading) ＞1K ＞1K ＞1K N/A 2 43 290 Targeting mAb B 2.60 (4 loading) ＞1K ＞1K ＞1K N/A 4 ＞1K ＞1K Targeting mAb A 2.61 (8 loading) ＞1K ＞1K ＞1K ＞1K ＞1K ＞1K ＞1K Targeting mAb A 2.61 (4 loading) ＞1K ＞1K ＞1K ＞1K ＞1K ＞1K ＞1K Targeting mAb B 2.61 (8 loading) ＞1K ＞1K ＞1K ＞1K ＞1K ＞1K ＞1K Targeting mAb B 2.61 (4 loading) ＞1K ＞1K ＞1K ＞1K ＞1K ＞1K ＞1K Targeting mAb A 2.62 (8 loading) ＞1K ＞1K ＞1K ＞1K ＞1K ＞1K ＞1K Targeting mAb A 2.62 (4 loading) ＞1K ＞1K ＞1K ＞1K ＞1K ＞1K ＞1K Targeting mAb B 2.62 (8 loading) ＞1K ＞1K ＞1K ＞1K ＞1K ＞1K ＞1K Targeting mAb B 2.62 (4 loading) ＞1K ＞1K ＞1K ＞1K ＞1K ＞1K ＞1K Targeting mAb A 2.63 (8 loading) N/A N/A N/A N/A N/A N/A N/A Targeting mAb A 2.63 (4 loading) ＞1K ＞1K ＞1K ＞1K ＞1K ＞1K ＞1K Targeting mAb B 2.63 (8 loading) ＞1K ＞1K ＞1K ＞1K ＞1K ＞1K ＞1K Targeting mAb B 2.63 (4 loading) ＞1K ＞1K ＞1K ＞1K ＞1K ＞1K ＞1K Targeting mAb A 2.71 (8 loading) ＞1K ＞1K N/A ＞1K 0.6 4 ＞1K Targeting mAb A 2.71 (4 loading) ＞1K ＞1K N/A ＞1K 0.6 3 ＞1K Targeting mAb B 2.71 (8 loading) ＞1K ＞1K N/A ＞1K 0.1 5 ＞1K Targeting mAb B 2.71 (4 loading) ＞1K ＞1K N/A ＞1K 0.2 14 ＞1K Targeting mAb A 2.83 (8 loading) ＞1K ＞1K ＞1K N/A 0.01 0.03 4 Targeting mAb A 2.83 (4 loading) ＞1K ＞1K ＞1K N/A 0.01 0.02 ＞1K Targeting mAb B 2.83 (8 loading) ＞1K ＞1K ＞1K N/A <0.004 <0.004 2 Targeting mAb B 2.83 (4 loading) ＞1K ＞1K ＞1K N/A <0.004 0.01 7 Targeting mAb A 2.84 (8 loading) ＞1K ＞1K ＞1K N/A <0.004 0.8 13 Targeting mAb A 2.84 (4 loading) ＞1K ＞1K ＞1K N/A <0.004 4 30 Targeting mAb B 2.84 (8 loading) ＞1K ＞1K ＞1K N/A <0.004 1 2 Targeting mAb B 2.84 (4 loading) ＞1K ＞1K ＞1K N/A 0.01 7 15 Targeting mAb A 2.85 (8 loading) ＞1K ＞1K ＞1K N/A <0.004 0.2 26 Targeting mAb A 2.85 (4 loading) ＞1K ＞1K ＞1K N/A 0.02 0.7 ＞1K Targeting mAb B 2.85 (8 loading) ＞1K ＞1K ＞1K N/A <0.004 0.1 10 Targeting mAb B 2.85 (4 loading) ＞1K ＞1K ＞1K N/A <0.004 0.4 43 Targeting mAb A 2.86 (8 loading) ＞1K ＞1K ＞1K N/A 0.03 0.04 33 Targeting mAb A 2.86 (4 loading) ＞1K ＞1K ＞1K N/A <0.004 0.01 124 Targeting mAb B 2.86 (8 loading) ＞1K ＞1K ＞1K N/A <0.004 <0.004 9 Targeting mAb B 2.86 (4 loading) ＞1K ＞1K ＞1K N/A <0.004 <0.004 14 Targeting mAb A 2.87 (8 loading) ＞1K ＞1K ＞1K N/A 0.02 1 400 Targeting mAb A 2.87 (4 loading) ＞1K ＞1K ＞1K N/A 0.1 4 ＞1K Targeting mAb B 2.87 (8 loading) ＞1K ＞1K ＞1K N/A 0.01 0.8 29 Targeting mAb B 2.87 (4 loading) ＞1K ＞1K ＞1K N/A 0.02 10 ＞1K Targeting mAb A 2.88 (8 loading) ＞1K ＞1K ＞1K N/A 0.02 1 ＞1K Targeting mAb A 2.88 (4 loading) ＞1K ＞1K ＞1K N/A 0.1 0.9 ＞1K Targeting mAb B 2.88 (8 loading) ＞1K ＞1K ＞1K N/A <0.004 0.3 ＞1K Targeting mAb B 2.88 (4 loading) ＞1K ＞1K ＞1K N/A 0.01 1 ＞1K Targeting mAb A 2.89 (8 loading) ＞1K ＞1K ＞1K N/A 0.04 0.08 199 Targeting mAb A 2.89 (4 loadings) ＞1K ＞1K ＞1K N/A 0.08 0.1 ＞1K Targeting mAb B 2.89 (8 loading) ＞1K ＞1K ＞1K N/A 0.01 0.03 66 Targeting mAb B 2.89 (4 loading) ＞1K ＞1K ＞1K N/A <0.004 0.02 ＞1K Targeting mAb A 2.90 (8 loading) ＞1K ＞1K ＞1K N/A 0.01 3 133 Targeting mAb A 2.90 (4 loadings) ＞1K ＞1K ＞1K N/A 0.04 8 ＞1K Targeting mAb B 2.90 (8 loading) ＞1K ＞1K ＞1K N/A <0.004 16 18 Targeting mAb B 2.90 (4 loading) ＞1K ＞1K ＞1K N/A 0.01 398 ＞1K Targeting mAb A 2.91 (8 loading) ＞1K ＞1K ＞1K N/A 0.01 1 ＞1K Targeting mAb A 2.91 (4 loading) ＞1K ＞1K ＞1K N/A 0.1 2 ＞1K Targeting mAb B 2.91 (8 loading) ＞1K ＞1K ＞1K N/A <0.004 0.7 26 Targeting mAb B 2.91 (4 loading) ＞1K ＞1K ＞1K N/A 0.01 3 ＞1K Targeting mAb A 2.92 (8 loading) ＞1K ＞1K ＞1K ＞1K 2 1 ＞1K Targeting mAb A 2.92 (4 loading) ＞1K ＞1K ＞1K ＞1K 4 4 ＞1K Targeting mAb B 2.92 (8 loading) ＞1K ＞1K ＞1K ＞1K 0.4 0.2 125 Targeting mAb B 2.92 (4 loading) ＞1K ＞1K ＞1K ＞1K 2 1 ＞1K Targeting mAb A 2.93 (8 loading) ＞1K ＞1K ＞1K ＞1K 2 twenty three 209 Targeting mAb A 2.93 (4 loading) ＞1K ＞1K ＞1K ＞1K 4 273 ＞1K Targeting mAb B 2.93 (8 loading) ＞1K ＞1K ＞1K ＞1K 922 ＞1000 25 Targeting mAb B 2.93 (4 loading) ＞1K ＞1K ＞1K ＞1K 836 ＞1000 ＞1K Targeting mAb A 2.94 (8 loading) ＞1K ＞1K ＞1K ＞1K 3 35 ＞1K Targeting mAb A 2.94 (4 loading) ＞1K ＞1K ＞1K ＞1K 8 ＞1000 ＞1K Targeting mAb B 2.94 (8 loading) ＞1K ＞1K ＞1K ＞1K 1 ＞1000 ＞1K Targeting mAb B 2.94 (4 loading) ＞1K ＞1K ＞1K ＞1K 5 ＞1000 ＞1K Targeting mAb A 2.95 (8 loading) ＞1K ＞1K ＞1K ＞1K 0.3 0.8 ＞1K Targeting mAb A 2.95 (4 loading) ＞1K ＞1K ＞1K ＞1K 0.9 2 ＞1K Targeting mAb B 2.95 (8 loading) ＞1K ＞1K ＞1K ＞1K 0.03 0.3 ＞1K Targeting mAb B 2.95 (4 loading) ＞1K ＞1K ＞1K ＞1K 0.2 0.9 ＞1K Targeting mAb A 2.96 (8 loading) ＞1K ＞1K ＞1K ＞1K 0.02 3 17 Targeting mAb A 2.96 (4 loading) ＞1K ＞1K ＞1K ＞1K 0.5 70 ＞1K Targeting mAb B 2.96 (8 loading) ＞1K ＞1K ＞1K ＞1K ＞1K ＞1K ＞1K Targeting mAb B 2.96 (4 loading) ＞1K ＞1K ＞1K ＞1K 0.06 ＞1K ＞1K Targeting mAb A 2.97 (8 loading) ＞1K ＞1K ＞1K ＞1K 0.4 ＞1000 ＞1K Targeting mAb A 2.97 (4 loading) ＞1K ＞1K ＞1K ＞1K 1 ＞1000 ＞1K Targeting mAb B 2.97 (8 loading) ＞1K ＞1K ＞1K ＞1K 0.2 ＞1000 ＞1K Targeting mAb B 2.97 (4 loading) ＞1K ＞1K ＞1K ＞1K 0.4 ＞1000 ＞1K Targeting mAb A 2.98 (8 loading) ＞1K ＞1K ＞1K ＞1K 0.9 2 ＞1K Targeting mAb A 2.98 (4 loading) ＞1K ＞1K ＞1K ＞1K 1 4 ＞1K Targeting mAb B 2.98 (8 loading) ＞1K ＞1K ＞1K ＞1K 0.1 1 ＞1K Targeting mAb B 2.98 (4 loading) ＞1K ＞1K ＞1K ＞1K 0.4 5 ＞1K Targeting mAb A 2.99 (8 loading) ＞1K ＞1K ＞1K ＞1K 16 108 ＞1K Targeting mAb A 2.99 (4 loadings) ＞1K ＞1K ＞1K ＞1K ＞1K ＞1K ＞1K Targeting mAb B 2.99 (8 loading) ＞1K ＞1K ＞1K ＞1K 13 ＞1K ＞1K Targeting mAb B 2.99 (4 loadings) ＞1K ＞1K ＞1K ＞1K ＞1K ＞1K ＞1K Targeting mAb A 2.100 (8 loading) ＞1K ＞1K ＞1K ＞1K 0.8 121 ＞1K Targeting mAb A 2.100 (4 loadings) ＞1K ＞1K ＞1K ＞1K 3 ＞1K ＞1K Targeting mAb B 2.100 (8 loading) ＞1K ＞1K ＞1K ＞1K 0.09 ＞1K ＞1K Targeting mAb B 2.100 (4 loadings) ＞1K ＞1K ＞1K ＞1K 0.5 ＞1K ＞1K Targeting mAb A 2.101 (8 loadings) ＞1K ＞1K ＞1K N/A 26 8 ＞1K Targeting mAb A 2.101 (4 loadings) ＞1K ＞1K ＞1K N/A 34 8 ＞1K Targeting mAb B 2.101 (8 loading) ＞1K ＞1K ＞1K N/A twenty three 8 ＞1K Targeting mAb B 2.101 (4 loading) ＞1K ＞1K ＞1K N/A 30 10 ＞1K Targeting mAb A 2.102 (8 loading) ＞1K ＞1K ＞1K N/A twenty one 225 ＞1K Targeting mAb A 2.102 (4 loading) ＞1K ＞1K ＞1K N/A 143 ＞1000 ＞1K Targeting mAb B 2.102 (8 loading) ＞1K ＞1K ＞1K N/A 55 ＞1000 ＞1K Targeting mAb B 2.102 (4 loading) ＞1K ＞1K ＞1K N/A 419 ＞1000 ＞1K Targeting mAb A 2.103 (8 loading) ＞1K ＞1K N/A ＞1K 0.8 3 ＞1K Targeting mAb A 2.103 (4 loading) ＞1K ＞1K N/A ＞1K 5 ＞1K ＞1K Targeting mAb B 2.103 (8 loading) ＞1K ＞1K N/A ＞1K 0.2 ＞1K ＞1K Targeting mAb B 2.103 (4 loading) ＞1K ＞1K N/A ＞1K 1 ＞1K ＞1K Targeting mAb A 2.104 (8 loading) ＞1K ＞1K ＞1K N/A 0.4 0.2 959 Targeting mAb A 2.104 (4 loading) ＞1K ＞1K ＞1K N/A 1 0.9 999 Targeting mAb B 2.104 (8 loading) ＞1K ＞1K ＞1K N/A 1 0.9 172 Targeting mAb B 2.104 (4 loading) ＞1K ＞1K ＞1K N/A 2 0.9 ＞1K Targeting mAb A 2.105 (8 loading) ＞1K ＞1K ＞1K N/A 0.3 4 ＞1K Targeting mAb A 2.105 (4 loading) ＞1K ＞1K ＞1K N/A 1 12 ＞1K Targeting mAb B 2.105 (8 loading) ＞1K ＞1K ＞1K N/A 0.7 15 79 Targeting mAb B 2.105 (4 loading) ＞1K ＞1K ＞1K N/A 2 45 198 Targeting mAb A 2.106 (8 loading) ＞1K ＞1K N/A ＞1K <0.004 0.1 332 Targeting mAb A 2.106 (4 loading) ＞1K ＞1K N/A ＞1K 0.03 0.4 955 Targeting mAb B 2.106 (8 loading) ＞1K ＞1K N/A ＞1K <0.004 0.02 101 Targeting mAb B 2.106 (4 loading) ＞1K ＞1K N/A ＞1K <0.004 0.1 ＞1K Targeting mAb A 2.107 (8 loading) ＞1K ＞1K ＞1K ＞1K <0.004 0.04 13 Targeting mAb A 2.107 (4 loading) ＞1K ＞1K ＞1K ＞1K <0.004 <0.004 ＞1K Targeting mAb B 2.107 (8 loading) ＞1K ＞1K ＞1K ＞1K <0.004 <0.004 0.7 Targeting mAb B 2.107 (4 loading) ＞1K ＞1K ＞1K ＞1K <0.004 <0.004 2 Targeting mAb A 2.108 (8 loading) ＞1K ＞1K ＞1K ＞1K 0.03 1 28 Targeting mAb A 2.108 (4 loading) ＞1K ＞1K ＞1K ＞1K 0.01 14 ＞1K Targeting mAb B 2.108 (8 loading) ＞1K ＞1K ＞1K ＞1K <0.004 ＞1K 1 Targeting mAb B 2.108 (4 loading) ＞1K ＞1K ＞1K ＞1K 0.02 ＞1K 722 Targeting mAb A 2.109 (8 loading) ＞1K ＞1K ＞1K ＞1K <0.004 2 506 Targeting mAb A 2.109 (4 loadings) ＞1K ＞1K ＞1K ＞1K 0.04 25 ＞1K Targeting mAb B 2.109 (8 loading) ＞1K ＞1K ＞1K ＞1K <0.004 ＞1K 8 Targeting mAb B 2.109 (4 loading) ＞1K ＞1K ＞1K ＞1K 0.01 ＞1K 132 Targeting mAb A 2.110 (8 loading) ＞1K ＞1K ＞1K ＞1K <0.004 <0.004 11 Targeting mAb A 2.110 (4 loading) ＞1K ＞1K ＞1K ＞1K <0.004 <0.004 5 Targeting mAb B 2.110 (8 loading) ＞1K ＞1K ＞1K ＞1K <0.004 <0.004 0.6 Targeting mAb B 2.110 (4 loading) ＞1K ＞1K ＞1K ＞1K <0.004 <0.004 0.8 Targeting mAb A 2.111 (8 loading) ＞1K ＞1K ＞1K ＞1K <0.004 0.2 13 Targeting mAb A 2.111 (4 loading) ＞1K ＞1K ＞1K ＞1K <0.004 1 twenty three Targeting mAb B 2.111 (8 loading) ＞1K ＞1K ＞1K ＞1K <0.004 11 0.2 Targeting mAb B 2.111 (4 loading) ＞1K ＞1K ＞1K ＞1K <0.004 858 1 Targeting mAb A 2.112 (8 loading) ＞1K ＞1K ＞1K ＞1K <0.004 0.1 9 Targeting mAb A 2.112 (4 loading) ＞1K ＞1K ＞1K ＞1K <0.004 0.1 14 Targeting mAb B 2.112 (8 loading) ＞1K ＞1K ＞1K ＞1K <0.004 0.2 0.8 Targeting mAb B 2.112 (4 loading) ＞1K ＞1K ＞1K ＞1K <0.004 3 2 Targeting mAb A 2.113 (8 loading) ＞1K ＞1K ＞1K ＞1K ＞1K ＞1K ＞1K Targeting mAb A 2.113 (4 loading) ＞1K ＞1K ＞1K ＞1K ＞1K ＞1K ＞1K Targeting mAb B 2.113 (8 loading) ＞1K ＞1K ＞1K ＞1K ＞1K ＞1K ＞1K Targeting mAb B 2.113 (4 loading) ＞1K ＞1K ＞1K ＞1K ＞1K ＞1K ＞1K Targeting mAb A 2.114 (8 loading) ＞1K ＞1K ＞1K ＞1K ＞1K ＞1K ＞1K Targeting mAb A 2.114 (4 loading) ＞1K ＞1K ＞1K ＞1K ＞1K ＞1K ＞1K Targeting mAb B 2.114 (8 loading) ＞1K ＞1K ＞1K ＞1K 249 ＞1K ＞1K Targeting mAb B 2.114 (4 loading) ＞1K ＞1K ＞1K ＞1K ＞1K ＞1K ＞1K Targeting mAb A 2.115 (8 loading) ＞1K ＞1K ＞1K ＞1K ＞1K ＞1K ＞1K Targeting mAb A 2.115 (4 loading) ＞1K ＞1K ＞1K ＞1K ＞1K ＞1K ＞1K Targeting mAb B 2.115 (8 loading) ＞1K ＞1K ＞1K ＞1K ＞1K ＞1K ＞1K Targeting mAb B 2.115 (4 loading) ＞1K ＞1K ＞1K ＞1K ＞1K ＞1K ＞1K Targeting mAb A 2.116 (8 loading) ＞1K ＞1K 18 ＞1K <0.004 <0.004 2 Targeting mAb A 2.116 (4 loading) ＞1K ＞1K ＞1K ＞1K <0.004 <0.004 78 Targeting mAb B 2.116 (8 loading) ＞1K ＞1K ＞1K ＞1K <0.004 <0.004 0.7 Targeting mAb B 2.116 (4 loading) ＞1K ＞1K ＞1K ＞1K <0.004 <0.004 2 Targeting mAb A 2.117 (8 loading) ＞1K ＞1K 117 ＞1K <0.004 <0.004 80 Targeting mAb A 2.117 (4 loading) ＞1K ＞1K ＞1K ＞1K <0.004 0.02 ＞1K Targeting mAb B 2.117 (8 loading) ＞1K ＞1K ＞1K ＞1K <0.004 0.03 1 Targeting mAb B 2.117 (4 loading) ＞1K ＞1K ＞1K ＞1K <0.004 5 ＞1K Targeting mAb A 2.118 (8 loading) ＞1K ＞1K ＞1K ＞1K 0.007 0.6 ＞1K Targeting mAb A 2.118 (4 loading) ＞1K ＞1K ＞1K ＞1K 0.2 3 ＞1K Targeting mAb B 2.118 (8 loading) ＞1K ＞1K ＞1K ＞1K <0.004 0.3 360 Targeting mAb B 2.118 (4 loading) ＞1K ＞1K ＞1K ＞1K 0.009 2 805 Targeting mAb A 2.119 (8 loading) ＞1K ＞1K ＞1K ＞1K <0.004 0.005 2 Targeting mAb A 2.119 (4 loading) ＞1K ＞1K ＞1K ＞1K 0.007 0.02 12 Targeting mAb B 2.119 (8 loading) ＞1K ＞1K ＞1K ＞1K <0.004 <0.004 0.8 Targeting mAb B 2.119 (4 loading) ＞1K ＞1K ＞1K ＞1K <0.004 <0.004 3 Targeting mAb A 2.120 (8 loading) ＞1K ＞1K ＞1K ＞1K 0.01 1 15 Targeting mAb A 2.120 (4 loadings) ＞1K ＞1K ＞1K ＞1K 0.05 3 ＞1K Targeting mAb B 2.120 (8 loading) ＞1K ＞1K ＞1K ＞1K 0.005 1 4 Targeting mAb B 2.120 (4 loading) ＞1K ＞1K ＞1K ＞1K <0.004 5 217 Targeting mAb A 2.121 (8 loadings) ＞1K ＞1K ＞1K ＞1K 0.02 1 347 Targeting mAb A 2.121 (4 loading) ＞1K ＞1K ＞1K ＞1K 0.08 3 ＞1K Targeting mAb B 2.121 (8 loading) ＞1K ＞1K ＞1K ＞1K <0.004 0.5 283 Targeting mAb B 2.121 (4 loading) ＞1K ＞1K ＞1K ＞1K 0.01 4 ＞1K Targeting mAb A 2.122 (8 loading) ＞1K ＞1K ＞1K ＞1K 0.009 0.01 5 Targeting mAb A 2.122 (4 loading) ＞1K ＞1K ＞1K ＞1K 0.03 0.04 25 Targeting mAb B 2.122 (8 loading) ＞1K ＞1K ＞1K ＞1K <0.004 <0.004 3 Targeting mAb B 2.122 (4 loading) ＞1K ＞1K ＞1K ＞1K <0.004 0.01 17 Targeting mAb A 2.123 (8 loading) ＞1K ＞1K ＞1K ＞1K 0.02 2 278 Targeting mAb A 2.123 (4 loading) ＞1K ＞1K ＞1K ＞1K 0.08 7 ＞1K Targeting mAb B 2.123 (8 loading) ＞1K ＞1K ＞1K ＞1K <0.004 2 ＞1K Targeting mAb B 2.123 (4 loading) ＞1K ＞1K ＞1K ＞1K <0.004 45 ＞1K Targeting mAb A 2.124 (8 loadings) ＞1K ＞1K ＞1K ＞1K 0.03 3 ＞1K Targeting mAb A 2.124 (4 loading) ＞1K ＞1K ＞1K ＞1K 0.2 10 ＞1K Targeting mAb B 2.124 (8 loadings) ＞1K ＞1K ＞1K ＞1K <0.004 3 583 Targeting mAb B 2.124 (4 loading) ＞1K ＞1K ＞1K ＞1K 0.01 19 572 Targeting mAb A 2.125 (8 loading) ＞1K ＞1K ＞1K N/A 0.07 0.06 12 Targeting mAb A 2.125 (4 loadings) ＞1K ＞1K ＞1K N/A 0.1 0.06 45 Targeting mAb B 2.125 (8 loading) ＞1K ＞1K ＞1K N/A 0.01 0.009 3 Targeting mAb B 2.125 (4 loading) ＞1K ＞1K ＞1K N/A 0.02 0.02 7 Targeting mAb A 2.126 (8 loadings) ＞1K ＞1K ＞1K N/A 0.3 1 49 Targeting mAb A 2.126 (4 loading) ＞1K ＞1K ＞1K N/A 0.4 4 ＞1K Targeting mAb B 2.126 (8 loading) ＞1K ＞1K ＞1K N/A 0.03 0.8 11 Targeting mAb B 2.126 (4 loading) ＞1K ＞1K ＞1K N/A 0.05 71 18 Targeting mAb A 2.127 (8 loading) ＞1K ＞1K ＞1K ＞1K 0.04 0.5 7 Targeting mAb A 2.127 (4 loading) ＞1K ＞1K ＞1K ＞1K 0.2 0.9 37 Targeting mAb B 2.127 (8 loading) ＞1K ＞1K ＞1K ＞1K <0.004 0.4 6 Targeting mAb B 2.127 (4 loading) ＞1K ＞1K ＞1K ＞1K 0.05 0.6 29 Targeting mAb A 2.128 (8 loading) ＞1K ＞1K ＞1K N/A 0.07 0.06 12 Targeting mAb A 2.128 (4 loading) ＞1K ＞1K ＞1K N/A 0.1 0.06 58 Targeting mAb B 2.128 (8 loading) ＞1K ＞1K ＞1K N/A 0.01 0.02 4 Targeting mAb B 2.128 (4 loading) ＞1K ＞1K ＞1K N/A 0.03 0.04 11 Targeting mAb A 2.129 (8 loadings) ＞1K ＞1K ＞1K N/A 0.06 0.9 34 Targeting mAb A 2.129 (4 loadings) ＞1K ＞1K ＞1K N/A 0.2 2 170 Targeting mAb B 2.129 (8 loading) ＞1K ＞1K ＞1K N/A 0.01 0.7 1 Targeting mAb B 2.129 (4 loadings) ＞1K ＞1K ＞1K N/A 0.03 29 6 Targeting mAb A 2.130 (8 loading) ＞1K ＞1K ＞1K ＞1K 0.1 0.5 39 Targeting mAb A 2.130 (4 loadings) ＞1K ＞1K ＞1K ＞1K 0.3 1 227 Targeting mAb B 2.130 (8 loading) ＞1K ＞1K ＞1K ＞1K <0.004 <0.004 9 Targeting mAb B 2.130 (4 loading) ＞1K ＞1K ＞1K ＞1K 0.03 0.8 72 Targeting mAb A 2.131 (8 loadings) ＞1K ＞1K ＞1K N/A 0.04 0.03 5 Targeting mAb A 2.131 (4 loadings) ＞1K ＞1K ＞1K N/A 0.1 0.08 16 Targeting mAb B 2.131 (8 loading) ＞1K ＞1K ＞1K N/A 0.01 0.02 2 Targeting mAb B 2.131 (4 loadings) ＞1K ＞1K ＞1K N/A 0.03 0.03 6 Targeting mAb A 2.132 (8 loading) ＞1K ＞1K ＞1K N/A 0.007 0.3 6 Targeting mAb A 2.132 (4 loading) ＞1K ＞1K ＞1K N/A 0.1 2 18 Targeting mAb B 2.132 (8 loading) ＞1K ＞1K ＞1K N/A 0.02 0.5 0.4 Targeting mAb B 2.132 (4 loading) ＞1K ＞1K ＞1K N/A 0.04 15 5 Targeting mAb A 2.133 (8 loading) ＞1K ＞1K ＞1K ＞1K <0.004 1 55 Targeting mAb A 2.133 (4 loading) ＞1K ＞1K ＞1K ＞1K 0.4 10 ＞1K Targeting mAb B 2.133 (8 loading) ＞1K ＞1K ＞1K ＞1K <0.004 5 61 Targeting mAb B 2.133 (4 loading) ＞1K ＞1K ＞1K ＞1K 0.08 ＞1K ＞1K Targeting mAb A 2.134 (8 loadings) ＞1K 45 ＞1K ＞1K 0.8 1 29 Targeting mAb A 2.134 (4 loading) ＞1K 318 ＞1K ＞1K 2 4 ＞1K Targeting mAb B 2.134 (8 loadings) ＞1K ＞1K ＞1K ＞1K 0.2 1 16 Targeting mAb B 2.134 (4 loading) ＞1K ＞1K ＞1K ＞1K 3 ＞1K ＞1K Targeting mAb A 2.135 (8 loading) ＞1K 16 229 ＞1K 0.6 1.0 44 Targeting mAb A 2.135 (4 loadings) ＞1K 273 ＞1K ＞1K 5 6 ＞1K Targeting mAb B 2.135 (8 loading) ＞1K ＞1K ＞1K ＞1K 0.4 1 41 Targeting mAb B 2.135 (4 loading) ＞1K ＞1K ＞1K ＞1K 1 15 ＞1K Targeting mAb A 2.136 (8 loading) ＞1K ＞1K ＞1K ＞1K 0.02 0.03 16 Targeting mAb A 2.136 (4 loading) ＞1K ＞1K ＞1K ＞1K 0.1 0.2 ＞1K Targeting mAb B 2.136 (8 loading) ＞1K ＞1K ＞1K ＞1K ＜ 0.004 0.005 6 Targeting mAb B 2.136 (4 loading) ＞1K ＞1K ＞1K ＞1K 0.01 0.02 36 Table 7B: Cytotoxicity of STING agonist ADC on a panel of cancer cell lines Target A performance + + + + + + Target B performance + - - - - - L540cy Ls174T MDAMB231 MIAPACA2CHOP MOLM-13 SU-DHL-4 Compound X50 (nM) Compound 1.1 ＞1K N/A ＞1K ＞1K 252 ＞1K Compound 1.2 ＞1K N/A ＞1K ＞1K 356 ＞1K Compound 1.3 47 N/A ＞1K ＞1K 36 ＞1K Compound 1.4 77 N/A ＞1K ＞1K 58 ＞1K Compound 1.5 ＞1K ＞1K ＞1K N/A 354 ＞1K Compound 1.6 ＞1K ＞1K ＞1K N/A 912 ＞1K Compound 1.7 ＞1K ＞1K ＞1K ＞1K ＞1K ＞1K Compound 1.8 544 ＞1K ＞1K ＞1K 42 ＞1K Compound 1.10 ＞1K ＞1K ＞1K ＞1K 943 ＞1K Compound 1.11 ＞1K ＞1K ＞1K ＞1K 124 ＞1K Compound 1.12 62 ＞1K ＞1K ＞1K 20 ＞1K Compound 1.13 356 ＞1K ＞1K ＞1K 229 ＞1K Compound 1.14 366 ＞1K ＞1K ＞1K 110 ＞1K Compound 1.15 148 ＞1K ＞1K ＞1K 32 ＞1K Compound 1.16 ＞1K ＞1K ＞1K ＞1K 202 ＞1K Compound 1.17 ＞1K ＞1K ＞1K ＞1K 885 ＞1K Compound 1.18 ＞1K ＞1K ＞1K ＞1K 920 ＞1K Compound 1.20 ＞1K ＞1K ＞1K ＞1K 251 ＞1K Compound 1.21 ＞1K ＞1K ＞1K ＞1K ＞1K ＞1K Compound 1.22 64 ＞1K ＞1K ＞1K 15 ＞1K Compound 1.23 53 ＞1K ＞1K ＞1K 8 ＞1K Compound 1.26 66 ＞1K ＞1K ＞1K 66 ＞1K Compound 1.27 67 ＞1K ＞1K ＞1K twenty three ＞1K Compound 1.28 334 ＞1K ＞1K ＞1K 65 ＞1K Compound 1.29 103 ＞1K ＞1K ＞1K 68 ＞1K Compound 1.30 860 ＞1K ＞1K ＞1K 97 ＞1K Compound 1.31 ＞1K ＞1K ＞1K ＞1K 233 ＞1K Compound 1.32 ＞1K ＞1K ＞1K ＞1K 147 ＞1K Compound 1.33 ＞1K ＞1K ＞1K ＞1K 290 ＞1K Compound 1.34 629 ＞1K ＞1K ＞1K 33 ＞1K Compound 1.35 453 ＞1K ＞1K ＞1K 357 ＞1K Compound 1.36 242 ＞1K ＞1K ＞1K 67 ＞1K Compound 1.37 ＞1K ＞1K ＞1K ＞1K ＞1K ＞1K Compound 1.38 313 ＞1K ＞1K ＞1K 30 ＞1K Compound 1.39 ＞1K ＞1K ＞1K N/A 46 ＞1K Compound 1.40 ＞1K ＞1K ＞1K N/A 93 ＞1K Compound 1.41 ＞1K N/A ＞1K ＞1K 60 ＞1K Compound 1.42 68 N/A ＞1K ＞1K 6 ＞1K Compound 1.43 92 N/A ＞1K ＞1K 6 ＞1K Compound 1.44 ＞1K N/A ＞1K ＞1K ＞1K ＞1K Compound 3.1 ＞1K ＞1K ＞1K ＞1K 116 ＞1K Compound 3.2 ＞1K ＞1K ＞1K ＞1K 256 ＞1K Compound 3.3 42 ＞1K ＞1K ＞1K 34 ＞1K Compound 3.4 60 ＞1K ＞1K ＞1K 43 ＞1K Compound 3.5 147 ＞1K ＞1K ＞1K twenty one ＞1K Compound 3.6 653 ＞1K ＞1K ＞1K 117 ＞1K Compound 3.8 35 ＞1K ＞1K ＞1K 4 ＞1K Compound 3.9 ＞1K ＞1K ＞1K ＞1K 138 ＞1K Compound 3.10 ＞1K ＞1K ＞1K ＞1K 62 ＞1K Compound 3.11 ＞1K ＞1K ＞1K ＞1K 4 ＞1K Compound 3.12 17 ＞1K ＞1K ＞1K 14 ＞1K Compound 3.13 52 ＞1K ＞1K ＞1K 58 ＞1K Compound 3.14 46 ＞1K ＞1K ＞1K 20 ＞1K Compound 3.15 17 ＞1K ＞1K ＞1K 13 ＞1K Compound 3.16 ＞1K ＞1K ＞1K ＞1K 71 ＞1K Compound 3.17 ＞1K ＞1K ＞1K ＞1K 554 ＞1K Compound 3.18 ＞1K ＞1K ＞1K ＞1K 165 ＞1K Compound 3.26 16 ＞1K ＞1K 5 ＞1K ＞1K Compound 3.27 49 ＞1K ＞1K 26 ＞1K ＞1K Compound 3.28 102 ＞1K ＞1K 58 ＞1K ＞1K Compound 3.29 ＞1K N/A ＞1K ＞1K 67 ＞1K Compound 3.30 ＞1K N/A ＞1K ＞1K 152 ＞1K Compound 3.31 ＞1K N/A ＞1K ＞1K 389 ＞1K Compound 3.32 ＞1K ＞1K ＞1K ＞1K 30 ＞1K Compound 3.33 14 ＞1K ＞1K ＞1K 1 ＞1K Compound 3.34 279 ＞1K ＞1K ＞1K twenty three ＞1K Compound 3.35 39 ＞1K ＞1K ＞1K 10 ＞1K Compound 3.36 ＞1K ＞1K ＞1K ＞1K 273 ＞1K Compound 3.37 76 ＞1K ＞1K N/A twenty four ＞1K Compound 3.38 13 ＞1K ＞1K N/A 3 ＞1K Compound 3.39 85 ＞1K ＞1K N/A 5 ＞1K Compound 3.40 150 N/A ＞1K ＞1K twenty one ＞1K Compound 3.41 twenty one N/A ＞1K ＞1K 5 ＞1K Compound 3.42 18 N/A ＞1K ＞1K 7 ＞1K Compound 3.43 ＞1K N/A ＞1K ＞1K ＞1K ＞1K ADC X50 (ng/mL) Targeting mAb A 2.1 (8 loading) 13 ＞1K ＞1K N/A 2 ＞1K Targeting mAb A 2.1 (4 loading) 50 ＞1K ＞1K N/A 8 ＞1K Targeting mAb B 2.1 (8 loading) 10 ＞1K ＞1K N/A 54 ＞1K Targeting mAb B 2.1 (4 loading) 41 ＞1K ＞1K N/A 849 ＞1K Targeting mAb A 2.2 (8 loading) 33 ＞1K ＞1K N/A 4 ＞1K Targeting mAb A 2.2 (4 loading) ＞1K ＞1K ＞1K N/A 36 ＞1K Targeting mAb B 2.2 (8 loading) 20 ＞1K ＞1K N/A 101 ＞1K Targeting mAb B 2.2 (4 loading) 39 ＞1K ＞1K N/A ＞1K ＞1K Targeting mAb A 2.3 (8 loading) 5 N/A ＞1K ＞1K 0.5 ＞1K Targeting mAb A 2.3 (4 loading) twenty one N/A ＞1K 20 8 ＞1K Targeting mAb B 2.3 (8 loading) 16 N/A ＞1K 33 9 ＞1K Targeting mAb B 2.3 (4 loading) 44 N/A ＞1K ＞1K 42 ＞1K Targeting mAb A 2.4 (8 loading) 6 N/A ＞1K 3 ＞1K ＞1K Targeting mAb A 2.4 (4 loading) 34 N/A ＞1K 9 ＞1K ＞1K Targeting mAb B 2.4 (8 loading) 3 N/A ＞1K 43 ＞1K ＞1K Targeting mAb B 2.4 (4 loading) 13 N/A ＞1K 317 ＞1K ＞1K Targeting mAb A 2.5 (8 loading) 47 ＞1K ＞1K N/A 2 ＞1K Targeting mAb A 2.5 (4 loading) 389 ＞1K ＞1K N/A 8 ＞1K Targeting mAb B 2.5 (8 loading) 27 ＞1K ＞1K N/A 36 ＞1K Targeting mAb B 2.5 (4 loading) 229 ＞1K ＞1K N/A 198 ＞1K Targeting mAb A 2.6 (8 loading) 523 ＞1K ＞1K N/A 5 ＞1K Targeting mAb A 2.6 (4 loading) ＞1K ＞1K ＞1K N/A 16 ＞1K Targeting mAb B 2.6 (8 loading) 75 ＞1K ＞1K N/A 239 ＞1K Targeting mAb B 2.6 (4 loading) 643 ＞1K ＞1K N/A ＞1K ＞1K Targeting mAb A 2.7 (8 loading) twenty three N/A ＞1K ＞1K 3 ＞1K Targeting mAb A 2.7 (4 loading) 54 N/A ＞1K ＞1K 6 ＞1K Targeting mAb B 2.7 (8 loading) 1 N/A ＞1K ＞1K 28 ＞1K Targeting mAb B 2.7 (4 loading) 18 N/A ＞1K ＞1K 291 ＞1K Targeting mAb A 2.8 (8 loading) twenty three N/A ＞1K ＞1K 2 ＞1K Targeting mAb A 2.8 (4 loading) 83 N/A ＞1K ＞1K 4 ＞1K Targeting mAb B 2.8 (8 loading) 16 N/A ＞1K ＞1K 87 ＞1K Targeting mAb B 2.8 (4 loading) 90 N/A ＞1K ＞1K 771 ＞1K Targeting mAb A 2.9 (8 loading) 98 ＞1K ＞1K N/A 3 ＞1K Targeting mAb A 2.9 (4 loading) ＞1K ＞1K ＞1K N/A twenty one ＞1K Targeting mAb B 2.9 (8 loading) 84 ＞1K ＞1K N/A 155 ＞1K Targeting mAb B 2.9 (4 loading) 543 ＞1K ＞1K N/A ＞1K ＞1K Targeting mAb A 2.10 (8 loading) ＞1K ＞1K ＞1K N/A 3 ＞1K Targeting mAb A 2.10 (4 loading) ＞1K ＞1K ＞1K N/A twenty one ＞1K Targeting mAb B 2.10 (8 loading) 539 ＞1K ＞1K N/A ＞1K ＞1K Targeting mAb B 2.10 (4 loading) ＞1K ＞1K ＞1K N/A ＞1K ＞1K Targeting mAb A 2.11 (8 loading) 9 N/A ＞1K ＞1K 0.9 ＞1K Targeting mAb A 2.11 (4 loading) 31 N/A ＞1K ＞1K 3 ＞1K Targeting mAb B 2.11 (8 loading) 4 N/A ＞1K ＞1K 30 ＞1K Targeting mAb B 2.11 (4 loading) 14 N/A ＞1K ＞1K 194 ＞1K Targeting mAb A 2.12 (8 loading) 7 N/A ＞1K ＞1K 1 ＞1K Targeting mAb A 2.12 (4 loading) 125 N/A ＞1K ＞1K 6 ＞1K Targeting mAb B 2.12 (8 loading) 7 N/A ＞1K ＞1K 111 ＞1K Targeting mAb B 2.12 (4 loading) 34 N/A ＞1K ＞1K ＞1K ＞1K Targeting mAb A 2.13 (8 loading) ＞1K ＞1K ＞1K N/A 16 ＞1K Targeting mAb A 2.13 (4 loading) ＞1K ＞1K ＞1K N/A 44 ＞1K Targeting mAb B 2.13 (8 loading) 315 ＞1K ＞1K N/A ＞1K ＞1K Targeting mAb B 2.13 (4 loading) ＞1K ＞1K ＞1K N/A ＞1K ＞1K Targeting mAb A 2.14 (8 loading) ＞1K ＞1K ＞1K N/A 17 ＞1K Targeting mAb A 2.14 (4 loading) ＞1K ＞1K ＞1K N/A 61 ＞1K Targeting mAb B 2.14 (8 loading) ＞1K ＞1K ＞1K N/A ＞1K ＞1K Targeting mAb B 2.14 (4 loading) ＞1K ＞1K ＞1K N/A ＞1K ＞1K Targeting mAb A 2.15 (8 loading) 74 ＞1K ＞1K N/A 4 ＞1K Targeting mAb A 2.15 (4 loading) ＞1K ＞1K ＞1K N/A twenty four ＞1K Targeting mAb B 2.15 (8 loading) 53 ＞1K ＞1K N/A 81 ＞1K Targeting mAb B 2.15 (4 loading) ＞1K ＞1K ＞1K N/A 511 ＞1K Targeting mAb A 2.16 (8 loading) 741 ＞1K ＞1K N/A 12 ＞1K Targeting mAb A 2.16 (4 loading) ＞1K ＞1K ＞1K N/A 35 ＞1K Targeting mAb B 2.16 (8 loading) 210 ＞1K ＞1K N/A 141 ＞1K Targeting mAb B 2.16 (4 loading) ＞1K ＞1K ＞1K N/A ＞1K ＞1K Targeting mAb A 2.17 (8 loading) ＞1K ＞1K ＞1K N/A 38 ＞1K Targeting mAb A 2.17 (4 loading) ＞1K ＞1K ＞1K N/A 67 ＞1K Targeting mAb B 2.17 (8 loading) ＞1K ＞1K ＞1K N/A ＞1K ＞1K Targeting mAb B 2.17 (4 loading) ＞1K ＞1K ＞1K N/A ＞1K ＞1K Targeting mAb A 2.18 (8 loading) ＞1K ＞1K ＞1K N/A 30 ＞1K Targeting mAb A 2.18 (4 loading) ＞1K ＞1K ＞1K N/A 69 ＞1K Targeting mAb B 2.18 (8 loading) ＞1K ＞1K ＞1K N/A ＞1K ＞1K Targeting mAb B 2.18 (4 loading) ＞1K ＞1K ＞1K N/A ＞1K ＞1K Targeting mAb A 2.19 (8 loading) 2 ＞1K ＞1K ＞1K 1 ＞1K Targeting mAb A 2.19 (4 loading) 147 ＞1K ＞1K ＞1K 18 ＞1K Targeting mAb B 2.19 (8 loading) 6 ＞1K ＞1K ＞1K 84 ＞1K Targeting mAb B 2.19 (4 loading) 55 ＞1K ＞1K ＞1K 342 ＞1K Targeting mAb A 2.20 (8 loading) 20 ＞1K ＞1K ＞1K 0.9 ＞1K Targeting mAb A 2.20 (4 loading) 65 ＞1K ＞1K ＞1K 6 ＞1K Targeting mAb B 2.20 (8 loading) 9 ＞1K ＞1K ＞1K 27 ＞1K Targeting mAb B 2.20 (4 loading) 239 ＞1K ＞1K ＞1K 714 ＞1K Targeting mAb A 2.21 (8 loading) 48 ＞1K ＞1K ＞1K 2 ＞1K Targeting mAb A 2.21 (4 loading) 253 ＞1K ＞1K ＞1K 15 ＞1K Targeting mAb B 2.21 (8 loading) twenty two ＞1K ＞1K ＞1K ＞1K ＞1K Targeting mAb B 2.21 (4 loading) 67 ＞1K ＞1K ＞1K ＞1K ＞1K Targeting mAb A 2.25 (8 loading) ＞1K ＞1K ＞1K ＞1K ＞1K ＞1K Targeting mAb A 2.25 (4 loading) ＞1K ＞1K ＞1K ＞1K ＞1K ＞1K Targeting mAb B 2.25 (8 loading) ＞1K ＞1K ＞1K ＞1K ＞1K ＞1K Targeting mAb B 2.25 (4 loading) ＞1K ＞1K ＞1K ＞1K ＞1K ＞1K Targeting mAb A 2.26 (8 loading) ＞1K ＞1K ＞1K ＞1K ＞1K ＞1K Targeting mAb A 2.26 (4 loading) ＞1K ＞1K ＞1K ＞1K ＞1K ＞1K Targeting mAb B 2.26 (8 loading) ＞1K ＞1K ＞1K ＞1K ＞1K ＞1K Targeting mAb B 2.26 (4 loading) ＞1K ＞1K ＞1K ＞1K ＞1K ＞1K Targeting mAb A 2.27 (8 loading) ＞1K ＞1K ＞1K ＞1K ＞1K ＞1K Targeting mAb A 2.27 (4 loading) ＞1K ＞1K ＞1K ＞1K ＞1K ＞1K Targeting mAb B 2.27 (8 loading) ＞1K ＞1K ＞1K ＞1K ＞1K ＞1K Targeting mAb B 2.27 (4 loading) ＞1K ＞1K ＞1K ＞1K ＞1K ＞1K Targeting mAb A 2.28 (8 loading) ＞1K ＞1K ＞1K ＞1K 92 ＞1K Targeting mAb A 2.28 (4 loading) ＞1K ＞1K ＞1K ＞1K 209 ＞1K Targeting mAb B 2.28 (8 loading) ＞1K ＞1K ＞1K ＞1K 998 ＞1K Targeting mAb B 2.28 (4 loading) ＞1K ＞1K ＞1K ＞1K ＞1K ＞1K Targeting mAb A 2.29 (8 loading) ＞1K ＞1K ＞1K ＞1K 73 ＞1K Targeting mAb A 2.29 (4 loading) ＞1K ＞1K ＞1K ＞1K 151 ＞1K Targeting mAb B 2.29 (8 loading) ＞1K ＞1K ＞1K ＞1K ＞1K ＞1K Targeting mAb B 2.29 (4 loading) ＞1K ＞1K ＞1K ＞1K ＞1K ＞1K Targeting mAb A 2.30 (8 loading) ＞1K ＞1K ＞1K ＞1K 89 ＞1K Targeting mAb A 2.30 (4 loading) ＞1K ＞1K ＞1K ＞1K 236 ＞1K Targeting mAb B 2.30 (8 loading) ＞1K ＞1K ＞1K ＞1K ＞1K ＞1K Targeting mAb B 2.30 (4 loading) ＞1K ＞1K ＞1K ＞1K ＞1K ＞1K Targeting mAb A 2.31 (8 loading) ＞1K ＞1K ＞1K ＞1K 30 ＞1K Targeting mAb A 2.31 (4 loading) ＞1K ＞1K ＞1K ＞1K 86 ＞1K Targeting mAb B 2.31 (8 loading) ＞1K ＞1K ＞1K ＞1K 309 ＞1K Targeting mAb B 2.31 (4 loading) ＞1K ＞1K ＞1K ＞1K 775 ＞1K Targeting mAb A 2.32 (8 loading) ＞1K ＞1K ＞1K ＞1K 80 ＞1K Targeting mAb A 2.32 (4 loading) ＞1K ＞1K ＞1K ＞1K 68 ＞1K Targeting mAb B 2.32 (8 loading) ＞1K ＞1K ＞1K ＞1K ＞1K ＞1K Targeting mAb B 2.32 (4 loading) ＞1K ＞1K ＞1K ＞1K ＞1K ＞1K Targeting mAb A 2.33 (8 loading) ＞1K ＞1K ＞1K ＞1K 66 ＞1K Targeting mAb A 2.33 (4 loading) ＞1K ＞1K ＞1K ＞1K 111 ＞1K Targeting mAb B 2.33 (8 loading) ＞1K ＞1K ＞1K ＞1K ＞1K ＞1K Targeting mAb B 2.33 (4 loading) ＞1K ＞1K ＞1K ＞1K ＞1K ＞1K Targeting mAb A 2.34 (8 loading) 5 ＞1K ＞1K ＞1K 1 ＞1K Targeting mAb A 2.34 (4 loading) 20 ＞1K ＞1K ＞1K 10 ＞1K Targeting mAb B 2.34 (8 loading) 2 ＞1K ＞1K ＞1K 1 ＞1K Targeting mAb B 2.34 (4 loading) 11 ＞1K ＞1K ＞1K 54 ＞1K Targeting mAb A 2.35 (8 loading) 18 ＞1K ＞1K ＞1K 2 ＞1K Targeting mAb A 2.35 (4 loading) 77 ＞1K ＞1K ＞1K 3 ＞1K Targeting mAb B 2.35 (8 loading) 32 ＞1K ＞1K ＞1K 26 ＞1K Targeting mAb B 2.35 (4 loading) 73 ＞1K ＞1K ＞1K 35 ＞1K Targeting mAb A 2.36 (8 loading) 16 ＞1K ＞1K ＞1K 2 ＞1K Targeting mAb A 2.36 (4 loading) 446 ＞1K ＞1K ＞1K 10 ＞1K Targeting mAb B 2.36 (8 loading) 38 ＞1K ＞1K ＞1K 11 ＞1K Targeting mAb B 2.36 (4 loading) 118 ＞1K ＞1K ＞1K 382 ＞1K Targeting mAb A 2.37 (8 loading) 3 ＞1K ＞1K ＞1K 3 ＞1K Targeting mAb A 2.37 (4 loading) 12 ＞1K ＞1K ＞1K 15 ＞1K Targeting mAb B 2.37 (8 loading) 0.6 ＞1K ＞1K ＞1K 40 ＞1K Targeting mAb B 2.37 (4 loading) 2 ＞1K ＞1K ＞1K 265 ＞1K Targeting mAb A 2.38 (8 loading) 11 ＞1K ＞1K ＞1K 2 ＞1K Targeting mAb A 2.38 (4 loading) 34 ＞1K ＞1K ＞1K 4 ＞1K Targeting mAb B 2.38 (8 loading) 13 ＞1K ＞1K ＞1K 94 ＞1K Targeting mAb B 2.38 (4 loading) 34 ＞1K ＞1K ＞1K 118 ＞1K Targeting mAb A 2.39 (8 loading) 29 ＞1K ＞1K ＞1K 2 ＞1K Targeting mAb A 2.39 (4 loading) 166 ＞1K ＞1K ＞1K 6 ＞1K Targeting mAb B 2.33 (8 loading) twenty four ＞1K ＞1K ＞1K 2 ＞1K Targeting mAb B 2.39 (4 loading) 67 ＞1K ＞1K ＞1K 30 ＞1K Targeting mAb A 2.40 (8 loading) 6 ＞1K ＞1K ＞1K 2 ＞1K Targeting mAb A 2.40 (4 loading) ＞1K ＞1K ＞1K ＞1K 28 ＞1K Targeting mAb B 2.40 (8 loading) 7 ＞1K ＞1K ＞1K 300 ＞1K Targeting mAb B 2.40 (4 loading) 123 ＞1K ＞1K ＞1K ＞1K ＞1K Targeting mAb A 2.41 (8 loading) 222 ＞1K ＞1K ＞1K 5 ＞1K Targeting mAb A 2.41 (4 loading) ＞1K ＞1K ＞1K ＞1K 10 ＞1K Targeting mAb B 2.41 (8 loading) 272 ＞1K ＞1K ＞1K ＞1K ＞1K Targeting mAb B 2.41 (4 loading) ＞1K ＞1K ＞1K ＞1K ＞1K ＞1K Targeting mAb A 2.42 (8 loading) 401 N/A ＞1K ＞1K 2 ＞1K Targeting mAb A 2.42 (4 loading) ＞1K N/A ＞1K ＞1K 6 ＞1K Targeting mAb B 2.42 (8 loading) 58 N/A ＞1K ＞1K 55 ＞1K Targeting mAb B 2.42 (4 loading) ＞1K N/A ＞1K ＞1K ＞1K ＞1K Targeting mAb A 2.43 (8 loading) 10 ＞1K ＞1K ＞1K 2 ＞1K Targeting mAb A 2.43 (4 loading) 29 ＞1K ＞1K ＞1K 8 ＞1K Targeting mAb B 2.43 (8 loading) 1 995 ＞1K ＞1K 9 ＞1K Targeting mAb B 2.43 (4 loading) 7 ＞1K ＞1K ＞1K 6 ＞1K Targeting mAb A 2.44 (8 loading) 17 ＞1K ＞1K ＞1K 0.2 ＞1K Targeting mAb A 2.44 (4 loading) 63 ＞1K ＞1K ＞1K 2 ＞1K Targeting mAb B 2.44 (8 loading) 13 ＞1K ＞1K ＞1K 6 ＞1K Targeting mAb B 2.44 (4 loading) ＞1K ＞1K ＞1K ＞1K 17 ＞1K Targeting mAb A 2.45 (8 loading) 74 ＞1K ＞1K ＞1K 2 ＞1K Targeting mAb A 2.45 (4 loading) 122 ＞1K ＞1K ＞1K 4 ＞1K Targeting mAb B 2.45 (8 loading) 18 ＞1K ＞1K ＞1K 3 ＞1K Targeting mAb B 2.45 (4 loading) 95 ＞1K ＞1K ＞1K 77 ＞1K Targeting mAb A 2.46 (8 loading) 191 N/A ＞1K ＞1K 0.3 ＞1K Targeting mAb A 2.46 (4 loading) ＞1K N/A ＞1K ＞1K 3 ＞1K Targeting mAb B 2.46 (8 loading) 62 N/A ＞1K ＞1K 8 ＞1K Targeting mAb B 2.46 (4 loading) ＞1K N/A ＞1K ＞1K 40 ＞1K Targeting mAb A 2.47 (8 loading) 158 N/A ＞1K ＞1K 0.2 ＞1K Targeting mAb A 2.47 (4 loading) 75 N/A ＞1K ＞1K 0.3 ＞1K Targeting mAb B 2.47 (8 loading) 12 N/A ＞1K ＞1K 5 ＞1K Targeting mAb B 2.47 (4 loading) 169 N/A ＞1K ＞1K 58 ＞1K Targeting mAb A 2.48 (8 loading) ＞1K N/A ＞1K ＞1K 0.6 ＞1K Targeting mAb A 2.48 (4 loading) ＞1K N/A ＞1K ＞1K 1 ＞1K Targeting mAb B 2.48 (8 loading) 761 N/A ＞1K ＞1K 28 ＞1K Targeting mAb B 2.48 (4 loading) ＞1K N/A ＞1K ＞1K 565 ＞1K Targeting mAb A 2.49 (8 loading) ＞1K N/A ＞1K ＞1K 30 ＞1K Targeting mAb A 2.49 (4 loading) ＞1K N/A ＞1K ＞1K 58 ＞1K Targeting mAb B 2.49 (8 loading) ＞1K N/A ＞1K ＞1K ＞1K ＞1K Targeting mAb B 2.49 (4 loading) ＞1K N/A ＞1K ＞1K ＞1K ＞1K Targeting mAb A 2.50 (8 loading) ＞1K N/A ＞1K ＞1K 1 ＞1K Targeting mAb A 2.50 (4 loading) ＞1K N/A ＞1K ＞1K 8 ＞1K Targeting mAb B 2.50 (8 loading) 394 N/A ＞1K ＞1K ＞1K ＞1K Targeting mAb B 2.50 (4 loadings) 307 N/A ＞1K ＞1K ＞1K ＞1K Targeting mAb A 2.51 (8 loading) ＞1K N/A ＞1K ＞1K 7 ＞1K Targeting mAb A 2.51 (4 loading) ＞1K N/A ＞1K ＞1K 20 ＞1K Targeting mAb B 2.51 (8 loading) ＞1K N/A ＞1K ＞1K ＞1K ＞1K Targeting mAb B 2.51 (4 loading) ＞1K N/A ＞1K ＞1K ＞1K ＞1K Targeting mAb A 2.52 (8 loading) ＞1K N/A ＞1K ＞1K 29 ＞1K Targeting mAb A 2.52 (4 loading) ＞1K N/A ＞1K ＞1K twenty one ＞1K Targeting mAb B 2.52 (8 loading) ＞1K N/A ＞1K ＞1K ＞1K ＞1K Targeting mAb B 2.52 (4 loading) ＞1K N/A ＞1K ＞1K ＞1K ＞1K Targeting mAb A 2.53 (8 loading) 36 N/A ＞1K ＞1K 0.03 ＞1K Targeting mAb A 2.53 (4 loading) 139 N/A ＞1K ＞1K 0.2 ＞1K Targeting mAb B 2.53 (8 loading) 19 N/A ＞1K ＞1K 3 ＞1K Targeting mAb B 2.53 (4 loading) ＞1K N/A ＞1K ＞1K 37 ＞1K Targeting mAb A 2.54 (8 loading) 806 N/A ＞1K ＞1K 1 ＞1K Targeting mAb A 2.54 (4 loading) ＞1K N/A ＞1K ＞1K 2 ＞1K Targeting mAb B 2.54 (8 loading) ＞1K N/A ＞1K ＞1K 46 ＞1K Targeting mAb B 2.54 (4 loading) ＞1K N/A ＞1K ＞1K ＞1K ＞1K Targeting mAb A 2.58 (8 loading) 27 ＞1K ＞1K ＞1K 3 ＞1K Targeting mAb A 2.58 (4 loading) ＞1K ＞1K ＞1K ＞1K 20 ＞1K Targeting mAb B 2.58 (8 loading) 11 ＞1K ＞1K ＞1K 16 ＞1K Targeting mAb B 2.58 (4 loading) 117 ＞1K ＞1K ＞1K 346 ＞1K Targeting mAb A 2.59 (8 loading) 233 ＞1K ＞1K ＞1K 2 ＞1K Targeting mAb A 2.59 (4 loading) ＞1K ＞1K ＞1K ＞1K 3 ＞1K Targeting mAb B 2.59 (8 loading) 69 ＞1K ＞1K ＞1K 8 ＞1K Targeting mAb B 2.59 (4 loading) N/A N/A N/A N/A N/A N/A Targeting mAb A 2.60 (8 loading) 272 ＞1K ＞1K N/A 5 ＞1K Targeting mAb A 2.60 (4 loadings) ＞1K ＞1K ＞1K N/A 16 ＞1K Targeting mAb B 2.60 (8 loading) 188 ＞1K ＞1K N/A ＞1K ＞1K Targeting mAb B 2.60 (4 loading) ＞1K ＞1K ＞1K N/A ＞1K ＞1K Targeting mAb A 2.61 (8 loading) ＞1K ＞1K ＞1K ＞1K ＞1K ＞1K Targeting mAb A 2.61 (4 loading) ＞1K ＞1K ＞1K ＞1K ＞1K ＞1K Targeting mAb B 2.61 (8 loading) ＞1K ＞1K ＞1K ＞1K ＞1K ＞1K Targeting mAb B 2.61 (4 loading) ＞1K ＞1K ＞1K ＞1K ＞1K ＞1K Targeting mAb A 2.62 (8 loading) ＞1K ＞1K ＞1K ＞1K ＞1K ＞1K Targeting mAb A 2.62 (4 loading) ＞1K ＞1K ＞1K ＞1K ＞1K ＞1K Targeting mAb B 2.62 (8 loading) ＞1K ＞1K ＞1K ＞1K ＞1K ＞1K Targeting mAb B 2.62 (4 loading) ＞1K ＞1K ＞1K ＞1K ＞1K ＞1K Targeting mAb A 2.63 (8 loading) N/A N/A N/A N/A N/A N/A Targeting mAb A 2.63 (4 loading) ＞1K ＞1K ＞1K ＞1K ＞1K ＞1K Targeting mAb B 2.63 (8 loading) ＞1K ＞1K ＞1K ＞1K ＞1K ＞1K Targeting mAb B 2.63 (4 loading) ＞1K ＞1K ＞1K ＞1K ＞1K ＞1K Targeting mAb A 2.71 (8 loading) ＞1K N/A ＞1K ＞1K 6 ＞1K Targeting mAb A 2.71 (4 loading) ＞1K N/A ＞1K ＞1K 3 ＞1K Targeting mAb B 2.71 (8 loading) 79 N/A ＞1K ＞1K 981 ＞1K Targeting mAb B 2.71 (4 loading) 74 N/A ＞1K ＞1K ＞1K ＞1K Targeting mAb A 2.83 (8 loading) 1 ＞1K ＞1K ＞1K 2 ＞1K Targeting mAb A 2.83 (4 loading) 4 ＞1K ＞1K ＞1K 11 ＞1K Targeting mAb B 2.83 (8 loading) 2 ＞1K ＞1K ＞1K 5 ＞1K Targeting mAb B 2.83 (4 loading) 3 ＞1K ＞1K ＞1K 33 ＞1K Targeting mAb A 2.84 (8 loading) 27 ＞1K ＞1K ＞1K 0.8 ＞1K Targeting mAb A 2.84 (4 loading) 61 ＞1K ＞1K ＞1K 1 ＞1K Targeting mAb B 2.84 (8 loading) 12 ＞1K ＞1K ＞1K 5 ＞1K Targeting mAb B 2.84 (4 loading) 112 ＞1K ＞1K ＞1K 17 ＞1K Targeting mAb A 2.85 (8 loading) 52 ＞1K ＞1K ＞1K 1 ＞1K Targeting mAb A 2.85 (4 loading) ＞1K ＞1K ＞1K ＞1K 5 ＞1K Targeting mAb B 2.85 (8 loading) 4 ＞1K ＞1K ＞1K twenty four ＞1K Targeting mAb B 2.85 (4 loading) 40 ＞1K ＞1K ＞1K 265 ＞1K Targeting mAb A 2.86 (8 loading) 3 ＞1K ＞1K ＞1K 2 ＞1K Targeting mAb A 2.86 (4 loading) 14 ＞1K ＞1K ＞1K 5 ＞1K Targeting mAb B 2.86 (8 loading) 2 ＞1K ＞1K ＞1K 2 ＞1K Targeting mAb B 2.86 (4 loading) 6 ＞1K ＞1K ＞1K 27 ＞1K Targeting mAb A 2.87 (8 loading) 28 ＞1K ＞1K ＞1K 0.6 ＞1K Targeting mAb A 2.87 (4 loading) 70 ＞1K ＞1K ＞1K 4 ＞1K Targeting mAb B 2.87 (8 loading) 20 ＞1K ＞1K ＞1K 8 ＞1K Targeting mAb B 2.87 (4 loading) 56 ＞1K ＞1K ＞1K 38 ＞1K Targeting mAb A 2.88 (8 loading) 5 ＞1K ＞1K ＞1K 4 ＞1K Targeting mAb A 2.88 (4 loading) ＞1K ＞1K ＞1K ＞1K 3 ＞1K Targeting mAb B 2.88 (8 loading) 0.3 ＞1K ＞1K ＞1K 14 ＞1K Targeting mAb B 2.88 (4 loading) ＞1K ＞1K ＞1K ＞1K 49 ＞1K Targeting mAb A 2.89 (8 loading) 12 ＞1K ＞1K ＞1K 1 ＞1K Targeting mAb A 2.89 (4 loadings) 207 ＞1K ＞1K ＞1K 9 ＞1K Targeting mAb B 2.89 (8 loading) 4 ＞1K ＞1K ＞1K 4 ＞1K Targeting mAb B 2.89 (4 loading) 8 ＞1K ＞1K ＞1K 257 ＞1K Targeting mAb A 2.90 (8 loading) 41 ＞1K ＞1K ＞1K 2 ＞1K Targeting mAb A 2.90 (4 loading) ＞1K ＞1K ＞1K ＞1K 0.4 ＞1K Targeting mAb B 2.90 (8 loading) 15 ＞1K ＞1K ＞1K 0.3 ＞1K Targeting mAb B 2.90 (4 loading) 81 ＞1K ＞1K ＞1K 89 ＞1K Targeting mAb A 2.91 (8 loading) 20 ＞1K ＞1K ＞1K 4 ＞1K Targeting mAb A 2.91 (4 loading) ＞1K ＞1K ＞1K ＞1K 5 ＞1K Targeting mAb B 2.91 (8 loading) twenty one ＞1K ＞1K ＞1K 4 ＞1K Targeting mAb B 2.91 (4 loading) ＞1K ＞1K ＞1K ＞1K 745 ＞1K Targeting mAb A 2.92 (8 loading) 62 N/A ＞1K ＞1K 2 ＞1K Targeting mAb A 2.92 (4 loading) ＞1K N/A ＞1K ＞1K 16 ＞1K Targeting mAb B 2.92 (8 loading) 87 N/A ＞1K ＞1K 45 ＞1K Targeting mAb B 2.92 (4 loading) 756 N/A ＞1K ＞1K 545 ＞1K Targeting mAb A 2.93 (8 loading) 143 N/A ＞1K ＞1K 2 ＞1K Targeting mAb A 2.93 (4 loading) ＞1K N/A ＞1K ＞1K 4 ＞1K Targeting mAb B 2.93 (8 loading) 20 N/A ＞1K ＞1K 268 ＞1K Targeting mAb B 2.93 (4 loading) 118 N/A ＞1K ＞1K ＞1K ＞1K Targeting mAb A 2.94 (8 loading) ＞1K N/A ＞1K ＞1K 2 ＞1K Targeting mAb A 2.94 (4 loading) ＞1K N/A ＞1K ＞1K 8 ＞1K Targeting mAb B 2.94 (8 loading) ＞1K N/A ＞1K ＞1K ＞1K ＞1K Targeting mAb B 2.94 (4 loading) ＞1K N/A ＞1K ＞1K ＞1K ＞1K Targeting mAb A 2.95 (8 loading) 408 N/A ＞1K ＞1K 5 ＞1K Targeting mAb A 2.95 (4 loading) ＞1K N/A ＞1K ＞1K 59 ＞1K Targeting mAb B 2.95 (8 loading) ＞1K N/A ＞1K ＞1K 474 ＞1K Targeting mAb B 2.95 (4 loading) ＞1K N/A ＞1K ＞1K ＞1K ＞1K Targeting mAb A 2.96 (8 loading) 49 N/A ＞1K ＞1K 1 ＞1K Targeting mAb A 2.96 (4 loading) ＞1K N/A ＞1K ＞1K 19 ＞1K Targeting mAb B 2.96 (8 loading) ＞1K N/A ＞1K ＞1K ＞1K ＞1K Targeting mAb B 2.96 (4 loading) ＞1K N/A ＞1K ＞1K ＞1K ＞1K Targeting mAb A 2.97 (8 loading) ＞1K N/A ＞1K ＞1K 7 ＞1K Targeting mAb A 2.97 (4 loading) ＞1K N/A ＞1K ＞1K twenty three ＞1K Targeting mAb B 2.97 (8 loading) ＞1K N/A ＞1K ＞1K ＞1K ＞1K Targeting mAb B 2.97 (4 loading) ＞1K N/A ＞1K ＞1K ＞1K ＞1K Targeting mAb A 2.98 (8 loading) 460 N/A ＞1K ＞1K 14 ＞1K Targeting mAb A 2.98 (4 loading) ＞1K N/A ＞1K ＞1K 46 ＞1K Targeting mAb B 2.98 (8 loading) ＞1K N/A ＞1K ＞1K ＞1K ＞1K Targeting mAb B 2.98 (4 loading) ＞1K N/A ＞1K ＞1K ＞1K ＞1K Targeting mAb A 2.99 (8 loading) ＞1K N/A ＞1K ＞1K 15 ＞1K Targeting mAb A 2.99 (4 loadings) ＞1K N/A ＞1K ＞1K 18 ＞1K Targeting mAb B 2.99 (8 loading) ＞1K N/A ＞1K ＞1K ＞1K ＞1K Targeting mAb B 2.99 (4 loadings) ＞1K N/A ＞1K ＞1K ＞1K ＞1K Targeting mAb A 2.100 (8 loading) ＞1K N/A ＞1K ＞1K 11 ＞1K Targeting mAb A 2.100 (4 loadings) ＞1K N/A ＞1K ＞1K 38 ＞1K Targeting mAb B 2.100 (8 loading) ＞1K N/A ＞1K ＞1K ＞1K ＞1K Targeting mAb B 2.100 (4 loadings) ＞1K N/A ＞1K ＞1K ＞1K ＞1K Targeting mAb A 2.101 (8 loading) ＞1K ＞1K ＞1K ＞1K 8 ＞1K Targeting mAb A 2.101 (4 loadings) ＞1K ＞1K ＞1K ＞1K twenty two ＞1K Targeting mAb B 2.101 (8 loading) 359 ＞1K ＞1K ＞1K ＞1K ＞1K Targeting mAb B 2.101 (4 loading) ＞1K ＞1K ＞1K ＞1K ＞1K ＞1K Targeting mAb A 2.102 (8 loading) ＞1K ＞1K ＞1K ＞1K 8 ＞1K Targeting mAb A 2.102 (4 loading) ＞1K ＞1K ＞1K ＞1K 16 ＞1K Targeting mAb B 2.102 (8 loading) ＞1K ＞1K ＞1K ＞1K ＞1K ＞1K Targeting mAb B 2.102 (4 loading) ＞1K ＞1K ＞1K ＞1K ＞1K ＞1K Targeting mAb A 2.103 (8 loading) ＞1K ＞1K ＞1K ＞1K 8 ＞1K Targeting mAb A 2.103 (4 loading) ＞1K ＞1K ＞1K ＞1K 17 ＞1K Targeting mAb B 2.103 (8 loading) ＞1K ＞1K ＞1K ＞1K ＞1K ＞1K Targeting mAb B 2.103 (4 loading) ＞1K ＞1K ＞1K ＞1K ＞1K ＞1K Targeting mAb A 2.104 (8 loading) 9 ＞1K ＞1K ＞1K 0.6 ＞1K Targeting mAb A 2.104 (4 loading) 131 ＞1K ＞1K ＞1K 5 ＞1K Targeting mAb B 2.104 (8 loading) 52 ＞1K ＞1K ＞1K 64 ＞1K Targeting mAb B 2.104 (4 loading) 172 ＞1K ＞1K ＞1K 232 ＞1K Targeting mAb A 2.105 (8 loading) 61 ＞1K ＞1K ＞1K 0.7 ＞1K Targeting mAb A 2.105 (4 loading) 179 ＞1K ＞1K ＞1K 3 ＞1K Targeting mAb B 2.105 (8 loading) 88 ＞1K ＞1K ＞1K 30 ＞1K Targeting mAb B 2.105 (4 loading) 146 ＞1K ＞1K ＞1K ＞1K ＞1K Targeting mAb A 2.106 (8 loading) 13 ＞1K ＞1K ＞1K 0.6 ＞1K Targeting mAb A 2.106 (4 loading) 40 ＞1K ＞1K ＞1K 3 ＞1K Targeting mAb B 2.106 (8 loading) 11 ＞1K ＞1K ＞1K 2 ＞1K Targeting mAb B 2.106 (4 loading) 11 ＞1K ＞1K ＞1K 14 ＞1K Targeting mAb A 2.107 (8 loading) 20 ＞1K ＞1K ＞1K 4 ＞1K Targeting mAb A 2.107 (4 loading) ＞1K ＞1K ＞1K ＞1K 18 ＞1K Targeting mAb B 2.107 (8 loading) 5 ＞1K ＞1K ＞1K 13 ＞1K Targeting mAb B 2.107 (4 loading) ＞1K ＞1K ＞1K ＞1K 369 ＞1K Targeting mAb A 2.108 (8 loading) 171 ＞1K ＞1K ＞1K 7 ＞1K Targeting mAb A 2.108 (4 loading) ＞1K ＞1K ＞1K ＞1K 10 ＞1K Targeting mAb B 2.108 (8 loading) 979 ＞1K ＞1K ＞1K ＞1K ＞1K Targeting mAb B 2.108 (4 loading) ＞1K ＞1K ＞1K ＞1K ＞1K ＞1K Targeting mAb A 2.109 (8 loading) ＞1K ＞1K ＞1K ＞1K 6 ＞1K Targeting mAb A 2.109 (4 loadings) ＞1K ＞1K ＞1K ＞1K 14 ＞1K Targeting mAb B 2.109 (8 loading) ＞1K ＞1K ＞1K ＞1K ＞1K ＞1K Targeting mAb B 2.109 (4 loading) ＞1K ＞1K ＞1K ＞1K ＞1K ＞1K Targeting mAb A 2.110 (8 loading) 13 ＞1K ＞1K ＞1K 4 ＞1K Targeting mAb A 2.110 (4 loading) 20 ＞1K ＞1K ＞1K 5 ＞1K Targeting mAb B 2.110 (8 loading) 2 ＞1K ＞1K ＞1K 2 ＞1K Targeting mAb B 2.110 (4 loading) 10 ＞1K ＞1K ＞1K 59 ＞1K Targeting mAb A 2.111 (8 loading) 15 ＞1K ＞1K ＞1K 1 ＞1K Targeting mAb A 2.111 (4 loading) 48 ＞1K ＞1K ＞1K 4 ＞1K Targeting mAb B 2.111 (8 loading) 107 ＞1K ＞1K ＞1K 13 ＞1K Targeting mAb B 2.111 (4 loading) ＞1K ＞1K ＞1K ＞1K 272 ＞1K Targeting mAb A 2.112 (8 loading) twenty three ＞1K ＞1K ＞1K 1 ＞1K Targeting mAb A 2.112 (4 loading) 38 ＞1K ＞1K ＞1K 7 ＞1K Targeting mAb B 2.112 (8 loading) 32 ＞1K ＞1K ＞1K 102 ＞1K Targeting mAb B 2.112 (4 loading) 125 ＞1K ＞1K ＞1K 246 ＞1K Targeting mAb A 2.113 (8 loading) ＞1K ＞1K ＞1K ＞1K 260 ＞1K Targeting mAb A 2.113 (4 loading) ＞1K ＞1K ＞1K ＞1K ＞1K ＞1K Targeting mAb B 2.113 (8 loading) ＞1K ＞1K ＞1K ＞1K ＞1K ＞1K Targeting mAb B 2.113 (4 loading) ＞1K ＞1K ＞1K ＞1K ＞1K ＞1K Targeting mAb A 2.114 (8 loading) ＞1K ＞1K ＞1K ＞1K ＞1K ＞1K Targeting mAb A 2.114 (4 loading) ＞1K ＞1K ＞1K ＞1K ＞1K ＞1K Targeting mAb B 2.114 (8 loading) ＞1K ＞1K ＞1K ＞1K ＞1K ＞1K Targeting mAb B 2.114 (4 loading) ＞1K ＞1K ＞1K ＞1K ＞1K ＞1K Targeting mAb A 2.115 (8 loading) ＞1K ＞1K ＞1K ＞1K ＞1K ＞1K Targeting mAb A 2.115 (4 loading) ＞1K ＞1K ＞1K ＞1K ＞1K ＞1K Targeting mAb B 2.115 (8 loading) ＞1K ＞1K ＞1K ＞1K ＞1K ＞1K Targeting mAb B 2.115 (4 loading) ＞1K ＞1K ＞1K ＞1K ＞1K ＞1K Targeting mAb A 2.116 (8 loading) 0.2 ＞1K ＞1K ＞1K 0.2 ＞1K Targeting mAb A 2.116 (4 loading) 2 ＞1K ＞1K ＞1K 5 ＞1K Targeting mAb B 2.116 (8 loading) 0.2 ＞1K ＞1K ＞1K 2 ＞1K Targeting mAb B 2.116 (4 loading) 1 ＞1K ＞1K ＞1K 11 ＞1K Targeting mAb A 2.117 (8 loading) 3 142 ＞1K ＞1K <0.004 ＞1K Targeting mAb A 2.117 (4 loading) 13 ＞1K ＞1K ＞1K 0.4 ＞1K Targeting mAb B 2.117 (8 loading) 10 ＞1K ＞1K ＞1K 3 ＞1K Targeting mAb B 2.117 (4 loading) 94 ＞1K ＞1K ＞1K 3 ＞1K Targeting mAb A 2.118 (8 loading) 61 N/A ＞1K ＞1K 0.6 ＞1K Targeting mAb A 2.118 (4 loading) ＞1K N/A ＞1K ＞1K 6 ＞1K Targeting mAb B 2.118 (8 loading) 40 N/A ＞1K ＞1K 3 ＞1K Targeting mAb B 2.118 (4 loading) 566 N/A ＞1K ＞1K 112 ＞1K Targeting mAb A 2.119 (8 loading) 0.6 N/A ＞1K ＞1K 0.2 ＞1K Targeting mAb A 2.119 (4 loading) 9 N/A ＞1K ＞1K 4 ＞1K Targeting mAb B 2.119 (8 loading) 0.4 N/A ＞1K ＞1K 0.9 ＞1K Targeting mAb B 2.119 (4 loading) 3 N/A ＞1K ＞1K 4 ＞1K Targeting mAb A 2.120 (8 loading) 15 N/A ＞1K ＞1K 0.3 ＞1K Targeting mAb A 2.120 (4 loadings) 30 N/A ＞1K ＞1K 1 ＞1K Targeting mAb B 2.120 (8 loading) 10 N/A ＞1K ＞1K 4 ＞1K Targeting mAb B 2.120 (4 loading) 70 N/A ＞1K ＞1K 8 ＞1K Targeting mAb A 2.121 (8 loadings) 44 N/A ＞1K ＞1K 0.4 ＞1K Targeting mAb A 2.121 (4 loading) 387 N/A ＞1K ＞1K 5 ＞1K Targeting mAb B 2.121 (8 loading) 49 N/A ＞1K ＞1K 0.6 ＞1K Targeting mAb B 2.121 (4 loading) ＞1K N/A ＞1K ＞1K 142 ＞1K Targeting mAb A 2.122 (8 loading) 1 N/A ＞1K ＞1K 0.2 ＞1K Targeting mAb A 2.122 (4 loading) 8 N/A ＞1K ＞1K 4 ＞1K Targeting mAb B 2.122 (8 loading) 0.5 N/A ＞1K ＞1K 0.5 ＞1K Targeting mAb B 2.122 (4 loading) 2 N/A ＞1K ＞1K 3 ＞1K Targeting mAb A 2.123 (8 loading) 26 N/A ＞1K ＞1K 0.3 ＞1K Targeting mAb A 2.123 (4 loading) 465 N/A ＞1K ＞1K 3 ＞1K Targeting mAb B 2.123 (8 loading) twenty four N/A ＞1K ＞1K 8 ＞1K Targeting mAb B 2.123 (4 loading) ＞1K N/A ＞1K ＞1K 58 ＞1K Targeting mAb A 2.124 (8 loadings) 49 N/A ＞1K ＞1K 0.6 ＞1K Targeting mAb A 2.124 (4 loading) 244 N/A ＞1K ＞1K 9 ＞1K Targeting mAb B 2.124 (8 loadings) 46 N/A ＞1K ＞1K 9 ＞1K Targeting mAb B 2.124 (4 loading) 144 N/A ＞1K ＞1K twenty two ＞1K Targeting mAb A 2.125 (8 loading) 7 N/A ＞1K ＞1K 1 ＞1K Targeting mAb A 2.125 (4 loadings) 20 N/A ＞1K ＞1K 7 ＞1K Targeting mAb B 2.125 (8 loading) 3 N/A ＞1K ＞1K 1 ＞1K Targeting mAb B 2.125 (4 loading) 11 N/A ＞1K ＞1K 7 ＞1K Targeting mAb A 2.126 (8 loading) 32 N/A ＞1K ＞1K 0.8 ＞1K Targeting mAb A 2.126 (4 loading) ＞1K N/A ＞1K ＞1K 5 ＞1K Targeting mAb B 2.126 (8 loading) 16 N/A ＞1K ＞1K 2 ＞1K Targeting mAb B 2.126 (4 loading) ＞1K N/A ＞1K ＞1K 18 ＞1K Targeting mAb A 2.127 (8 loading) ＞1K N/A ＞1K ＞1K 1 ＞1K Targeting mAb A 2.127 (4 loading) ＞1K N/A ＞1K ＞1K 5 ＞1K Targeting mAb B 2.127 (8 loading) ＞1K N/A ＞1K ＞1K 7 ＞1K Targeting mAb B 2.127 (4 loading) ＞1K N/A ＞1K ＞1K twenty four ＞1K Targeting mAb A 2.128 (8 loading) 9 N/A ＞1K ＞1K 0.7 ＞1K Targeting mAb A 2.128 (4 loading) 76 N/A ＞1K ＞1K 11 ＞1K Targeting mAb B 2.128 (8 loading) 10 N/A ＞1K ＞1K 1 ＞1K Targeting mAb B 2.128 (4 loading) 19 N/A ＞1K ＞1K 13 ＞1K Targeting mAb A 2.129 (8 loadings) 64 N/A ＞1K ＞1K 0.8 ＞1K Targeting mAb A 2.129 (4 loadings) 267 N/A ＞1K ＞1K 2 ＞1K Targeting mAb B 2.129 (8 loading) 95 N/A ＞1K ＞1K 1 ＞1K Targeting mAb B 2.129 (4 loading) 626 N/A ＞1K ＞1K 8 ＞1K Targeting mAb A 2.130 (8 loading) ＞1K N/A ＞1K ＞1K 1 ＞1K Targeting mAb A 2.130 (4 loadings) ＞1K N/A ＞1K ＞1K 7 ＞1K Targeting mAb B 2.130 (8 loading) ＞1K N/A ＞1K ＞1K 5 ＞1K Targeting mAb B 2.130 (4 loading) ＞1K N/A ＞1K ＞1K 59 ＞1K Targeting mAb A 2.131 (8 loadings) 5 N/A ＞1K ＞1K 0.9 ＞1K Targeting mAb A 2.131 (4 loading) twenty four N/A ＞1K ＞1K 9 ＞1K Targeting mAb B 2.131 (8 loading) 5 N/A ＞1K ＞1K 2 ＞1K Targeting mAb B 2.131 (4 loadings) 17 N/A ＞1K ＞1K 10 ＞1K Targeting mAb A 2.132 (8 loading) 26 N/A ＞1K ＞1K 3 ＞1K Targeting mAb A 2.132 (4 loadings) 72 N/A ＞1K ＞1K 4 ＞1K Targeting mAb B 2.132 (8 loading) 35 N/A ＞1K ＞1K 0.3 ＞1K Targeting mAb B 2.132 (4 loading) 383 N/A ＞1K ＞1K 4 ＞1K Targeting mAb A 2.133 (8 loading) ＞1K N/A ＞1K ＞1K 0.5 ＞1K Targeting mAb A 2.133 (4 loading) ＞1K N/A ＞1K ＞1K 8 ＞1K Targeting mAb B 2.133 (8 loading) ＞1K N/A ＞1K ＞1K 6 ＞1K Targeting mAb B 2.133 (4 loading) ＞1K N/A ＞1K ＞1K ＞1K ＞1K Targeting mAb A 2.134 (8 loadings) 16 N/A ＞1K 121 62 6 Targeting mAb A 2.134 (4 loading) 37 N/A ＞1K ＞1K 89 30 Targeting mAb B 2.134 (8 loadings) 15 N/A ＞1K ＞1K ＞1K ＞1K Targeting mAb B 2.134 (4 loading) 38 N/A ＞1K ＞1K ＞1K ＞1K Targeting mAb A 2.135 (8 loading) 16 N/A ＞1K 32 60 4 Targeting mAb A 2.135 (4 loadings) 118 N/A ＞1K ＞1K 190 30 Targeting mAb B 2.135 (8 loading) 15 N/A ＞1K ＞1K ＞1K ＞1K Targeting mAb B 2.135 (4 loading) 34 N/A ＞1K ＞1K ＞1K ＞1K Targeting mAb A 2.136 (8 loading) 3 N/A ＞1K ＞1K 0.5 ＞1K Targeting mAb A 2.136 (4 loadings) twenty two N/A ＞1K ＞1K 16 ＞1K Targeting mAb B 2.136 (8 loading) 0.9 N/A ＞1K ＞1K 1 ＞1K Targeting mAb B 2.136 (4 loading) 7 N/A ＞1K ＞1K 15 ＞1K Examples B3 : STING Agonist ADC In vivo antitumor activity Renca Tumor Model

Renca carcinoma cells (ATCC) were cultured in RPMI-1640 (ATCC) containing 10% heat-killed live fetal bovine serum, MEM non-essential amino acids (1x), sodium pyruvate (1 mM), and L-glutamine (2 mM). Renca carcinoma cells were implanted subcutaneously (2*10 ⁶ cells in 200 µL 25% Matrigel) in Balb/c female mice. When tumor volume reached 100 mm ³ , mice were dosed with ADC by intravenous injection for the indicated dosing schedules, and tumor volume was monitored twice a week.

Interleukins were measured in mouse plasma harvested at the indicated time points after treatment with compound or ADC using the Milliplex MAP Mouse Interleukin/Protein Magnetic Bead Panel Assay Kit (MCYTOMAG-70k-PX32) and analyzed using the Luminex™ MAGPIX™ Instrument System. Values outside the standard curve range (e.g., <3.2 or >10,000 pg/mL) were converted to 3.2 or 10,000 pg/mL to calculate the mean value.

The Renca syngeneic system was used to evaluate the ability of STING agonist ADCs to induce an immune response in vivo and drive an anti-tumor immune response. The Renca system is a subcutaneous mouse renal cancer model. On day 0, 2×10 ⁶ Renca cells were implanted subcutaneously in the flank of female Balb/c mice. When an average tumor size of 100 mm ³ (measured using the formula volume (mm ³ ) = 0.5 * length * width ² , where length is the longer dimension) was reached, mice were randomly divided into treatment groups of ≥ 5 mice per group. Animals were then treated intravenously with the indicated treatment every 7 days for a total of 3 doses (or as indicated). Tumor length and width and animal weight were measured throughout the study, and tumor volume was calculated using the above formula. Animals were followed until tumor volume reached approximately 1000 mm ³ ; animals were then euthanized.

The anti-tumor activity of non-cleavable linkers 2.4 , 2.1 and 2.3 and cleavable linkers 2.12 , 2.9 and 2.11 conjugated to mIgG2a mAb targeting EphA2 was evaluated; note that all mAb conjugates targeting EphA2 described herein consist of h1C1 mIgG2a mAb ( SEQ ID 24-25 ) conjugated to various drug linker compounds. Treatment with non-cleavable linker ( 2.4 , 2.1 and 2.3 ) conjugates resulted in robust anti-tumor activity. On the other hand, treatment with two cleavable linker ( 2.12 and 2.9 ) conjugates resulted in minimal tumor growth delay, while treatment with cleavable linker 2.11 conjugate resulted in robust anti-tumor activity ( Figure 1 ). The differences in the in vivo antitumor activities of these conjugates were surprising and could not be predicted based solely on in vitro potency ( Table 6 ) or in vitro cytotoxicity ( Table 7 ).

To explore the systemic immune activation elicited by the various conjugates, plasma interleukin concentrations were also assessed 6 and 24 hours after each dose ( Table 8 ). Plasma interleukin responses to the conjugates varied in vivo and did not correlate with in vitro potency ( Table 6 ) or antitumor activity ( Figure 1 ). For example, the mAb -2.4 conjugate targeting EphA2 elicited robust antitumor activity and minimal systemic interleukins compared to the other conjugates. On the other hand, the mAb- 2.12 conjugate targeting EphA2 elicited robust systemic interleukins but minimal antitumor activity. Overall, this suggests that antitumor activity elicited by the conjugates cannot be predicted simply by in vitro potency and, importantly, robust antitumor activity can be achieved independently of systemic interleukin induction. Table 8 : Interleukin production in peripheral blood ( plasma ) of Renca tumor-bearing mice following treatment with various conjugates comprising mIgG2a mAb targeting EphA2 conjugated to the indicated compounds . Plasma concentration (pg/mL)* Untreated mAb- 2.12 targeting EphA mAb- 2.4 targeting EphA2 mAb- 2.1 targeting EphA2 mAb- 2.9 targeting EphA2 mAb- 2.3 targeting EphA mAb- 2.11 targeting EphA2 G-CSF Dosage 1 6 h 1047 2752 1045 7766 327 3906 4560 Dosage 1 24 h 3435 3393 28175 794 66822 23607 Dosage 2 6 h 1058 955 1023 3289 2096 1390 1798 Dosage 2 24 h 1661 1928 1616 928 1410 2635 Dosage 3 6 h 2063 4734 1511 1585 1317 1585 1192 Dosage 3 24 h 1340 1450 4041 1101 1756 1177 Eosin Dosage 1 6 h 27793 30326 27307 33038 18326 31418 31886 Dosage 1 24 h 25769 27049 27626 27166 27690 27077 Dosage 2 6 h 28281 30488 22040 33868 30131 32246 36769 Dosage 2 24 h 16835 17620 28036 28817 32845 27120 Dosage 3 6 h 30591 37065 37942 39438 25552 36673 42601 Dosage 3 24 h 32545 32672 32138 28722 40768 35551 GM-CSF Dosage 1 6 h 383 858 383 934 468 773 967 Dosage 1 24 h 454 608 995 608 962 773 Dosage 2 6 h 493 995 493 799 694 522 815 Dosage 2 24 h 581 958 755 625 493 726 Dosage 3 6 h 918 1060 1532 1236 1174 753 1010 Dosage 3 24 h 1071 1306 1291 1118 1200 1137 IFNg Dosage 1 6 h 15 128 15 1004 7 639 796 Dosage 1 24 h 35 55 74 20 93 52 Dosage 2 6 h 18 124 27 317 34 191 336 Dosage 2 24 h 25 42 35 twenty two 153 36 Dosage 3 6 h 15 65 31 110 39 28 129 Dosage 3 24 h 28 29 43 37 36 34 IL-1a Dosage 1 6 h 2422 2426 2175 2208 1976 2139 2156 Dosage 1 24 h 2490 2505 2300 2202 2258 2435 Dosage 2 6 h 1329 4431 3140 2764 2283 2697 5048 Dosage 2 24 h 2270 4989 1656 5174 5635 3357 Dosage 3 6 h 2414 2994 2810 2906 3017 3394 2823 Dosage 3 24 h 2564 5425 3415 5185 2810 3158 IL-1b Dosage 1 6 h 90 301 84 312 6 187 187 Dosage 1 24 h 107 107 428 107 310 187 Dosage 2 6 h 4 170 53 180 78 110 181 Dosage 2 24 h 144 146 78 99 76 181 Dosage 3 6 h 117 221 168 186 222 134 178 Dosage 3 24 h 151 169 340 257 239 294 IL-2 Dosage 1 6 h 100 104 79 122 44 95 151 Dosage 1 24 h 131 107 141 91 122 95 Dosage 2 6 h 43 94 62 84 69 82 105 Dosage 2 24 h 74 106 94 88 82 88 Dosage 3 6 h 91 147 164 158 171 158 121 Dosage 3 24 h 185 205 311 256 206 258 IL-4 Dosage 1 6 h 5 18 5 41 2 twenty two 37 Dosage 1 24 h 8 10 14 7 9 11 Dosage 2 6 h 3 twenty one 4 28 7 9 36 Dosage 2 24 h 6 7 5 5 5 8 Dosage 3 6 h 18 15 10 17 18 10 12 Dosage 3 24 h 15 10 19 twenty three 14 15 IL-3 Dosage 1 6 h 9 16 7 17 6 11 15 Dosage 1 24 h 7 15 30 9 12 10 Dosage 2 6 h 5 7 3 7 3 3 5 Dosage 2 24 h 7 5 3 5 3 2 Dosage 3 6 h 15 15 11 13 11 10 6 Dosage 3 24 h 9 17 27 20 15 19 IL-5 Dosage 1 6 h 45 156 82 190 82 156 156 Dosage 1 24 h 97 120 180 74 182 147 Dosage 2 6 h 105 141 156 259 101 239 208 Dosage 2 24 h 115 191 129 112 278 170 Dosage 3 6 h 171 308 851 319 294 413 333 Dosage 3 24 h 243 241 317 308 270 320 IL-6 Dosage 1 6 h 14 379 36 8271 25 5171 5851 Dosage 1 24 h 194 308 779 96 1043 689 Dosage 2 6 h 27 1069 30 1958 103 761 2805 Dosage 2 24 h 147 592 280 136 240 335 Dosage 3 6 h 106 789 79 1099 1168 297 645 Dosage 3 24 h 190 118 368 173 164 188 IL-7 Dosage 1 6 h 205 176 138 238 52 923 255 Dosage 1 24 h 165 164 270 1084 220 177 Dosage 2 6 h 82 189 405 519 97 121 160 Dosage 2 24 h 117 274 571 116 160 131 Dosage 3 6 h 76 166 126 146 185 146 136 Dosage 3 24 h 116 115 210 181 136 161 IL-10 Dosage 1 6 h 34 185 62 171 twenty four 164 193 Dosage 1 24 h 117 117 208 53 206 131 Dosage 2 6 h 40 210 65 224 135 96 208 Dosage 2 24 h 88 107 118 90 64 90 Dosage 3 6 h 153 243 151 189 253 154 195 Dosage 3 24 h 179 133 293 236 209 215 IL-12p40 Dosage 1 6 h 144 255 111 302 88 164 249 Dosage 1 24 h 174 160 399 108 270 249 Dosage 2 6 h 74 187 73 172 124 103 176 Dosage 2 24 h 102 178 146 193 136 149 Dosage 3 6 h 159 201 201 212 170 138 175 Dosage 3 24 h 143 128 244 159 180 180 IL-12p70 Dosage 1 6 h 110 393 205 666 82 471 503 Dosage 1 24 h 286 361 551 177 411 326 Dosage 2 6 h 45 181 58 156 108 107 206 Dosage 2 24 h 107 157 132 156 132 157 Dosage 3 6 h 252 398 223 350 395 258 273 Dosage 3 24 h 319 251 503 503 336 382 LIF Dosage 1 6 h 87 86 45 91 25 91 138 Dosage 1 24 h 66 62 95 76 84 112 Dosage 2 6 h 55 88 253 258 55 88 94 Dosage 2 24 h 55 193 272 65 78 83 Dosage 3 6 h 61 87 69 72 84 69 71 Dosage 3 24 h 72 68 99 84 68 76 IL-13 Dosage 1 6 h 1295 2438 1295 3888 1411 2972 3944 Dosage 1 24 h 1813 1469 2266 1469 1984 2098 Dosage 2 6 h 1308 2475 1306 3217 1571 2188 3445 Dosage 2 24 h 1426 1456 2072 1809 2128 2129 Dosage 3 6 h 1674 2527 1910 2657 2291 2054 2750 Dosage 3 24 h 2292 1899 2382 2409 2271 2482 IL-15 Dosage 1 6 h 1782 1667 1208 1835 686 1719 1895 Dosage 1 24 h 1559 1428 1790 1527 1770 1500 Dosage 2 6 h 744 1366 2956 3430 999 1381 1535 Dosage 2 24 h 894 2276 3075 958 1180 1044 Dosage 3 6 h 1882 1968 1929 1946 1969 1930 1931 Dosage 3 24 h 1905 1917 2026 1997 1979 1949 IL-17 Dosage 1 6 h 12 35 12 73 6 68 65 Dosage 1 24 h 28 20 34 14 40 28 Dosage 2 6 h 10 31 14 69 twenty one 33 49 Dosage 2 24 h 14 29 20 20 10 27 Dosage 3 6 h 29 45 twenty one 48 43 32 59 Dosage 3 24 h 40 39 51 54 39 40 IP-10 Dosage 1 6 h 898 24459 4135 29327 2690 29937 29442 Dosage 1 24 h 5930 9535 17186 2656 21045 14167 Dosage 2 6 h 1096 21713 3768 26487 9125 23360 29125 Dosage 2 24 h 5436 4375 7275 2893 10230 8046 Dosage 3 6 h 695 30134 1471 31962 25017 12731 36120 Dosage 3 24 h 7742 3418 9576 4499 11843 8792 KC Dosage 1 6 h 1227 3874 836 2741 1253 9418 5506 Dosage 1 24 h 2898 2292 6339 1953 18200 8997 Dosage 2 6 h 1992 2717 1412 3252 2543 5211 2555 Dosage 2 24 h 516 1282 2049 1370 3503 1407 Dosage 3 6 h 2753 7633 1295 1757 9732 2014 2163 Dosage 3 24 h 2054 661 1131 3483 1749 1187 MCP-1 (MFI) Dosage 1 6 h 17 222 19 4935 17 2313 2905 Dosage 1 24 h 39 47 1247 20 2742 512 Dosage 2 6 h 18 553 19 812 78 129 844 Dosage 2 24 h twenty three twenty two 50 20 66 225 Dosage 3 6 h 19 745 19 1204 340 40 1005 Dosage 3 24 h 67 twenty one 185 31 100 38 MIP-1a Dosage 1 6 h 233 714 370 2452 265 2402 2150 Dosage 1 24 h 439 667 827 503 948 704 Dosage 2 6 h 1547 1812 1619 1940 1667 1858 1910 Dosage 2 24 h 1626 1718 1705 1652 1735 1720 Dosage 3 6 h 1679 1829 1716 1927 1846 1776 1930 Dosage 3 24 h 1742 1696 1853 1800 1798 1825 MIP-1b Dosage 1 6 h 439 5284 991 24633 586 23208 22262 Dosage 1 24 h 944 1464 5003 615 8429 3616 Dosage 2 6 h 301 6807 896 12804 2102 13343 8954 Dosage 2 24 h 789 845 1416 640 2115 1772 Dosage 3 6 h 602 8574 802 12771 3395 3778 12500 Dosage 3 24 h 1122 844 2270 896 1979 1383 M-CSF Dosage 1 6 h 124 286 89 270 twenty three 286 254 Dosage 1 24 h 107 206 318 91 398 294 Dosage 2 6 h 55 248 116 238 115 98 265 Dosage 2 24 h 133 152 187 98 134 187 Dosage 3 6 h 271 377 234 350 372 273 292 Dosage 3 24 h 350 292 412 349 367 368 MIP-2 Dosage 1 6 h 1984 2207 1367 2441 587 2209 2462 Dosage 1 24 h 2146 2051 2407 1443 2341 2235 Dosage 2 6 h 2093 2424 2210 2450 2297 2248 2458 Dosage 2 24 h 2288 2421 2322 2243 2365 2365 Dosage 3 6 h 4368 4983 4055 4235 5150 3675 4055 Dosage 3 24 h 4414 3855 4566 4386 3998 4235 MIG Dosage 1 6 h 2470 33034 3989 95180 2354 49912 87855 Dosage 1 24 h 23905 13181 50132 5744 47317 67804 Dosage 2 6 h 2846 27303 4095 55989 7395 21955 51363 Dosage 2 24 h 16827 5963 33521 11199 25910 36557 Dosage 3 6 h 2853 25093 2736 48323 13714 8371 53121 Dosage 3 24 h 30796 4452 31567 22037 20494 41819 RANTES Dosage 1 6 h 103 916 145 6609 226 3464 5126 Dosage 1 24 h 831 454 4362 314 6087 3296 Dosage 2 6 h 68 592 167 2828 180 555 2161 Dosage 2 24 h 215 262 923 213 1150 1095 Dosage 3 6 h 101 600 175 1264 296 386 1275 Dosage 3 24 h 670 307 1471 439 1329 1230 VEGF Dosage 1 6 h 9 17 12 twenty two 8 14 20 Dosage 1 24 h 12 12 18 8 15 13 Dosage 2 6 h 4 12 10 11 6 11 15 Dosage 2 24 h 6 7 7 7 7 7 Dosage 3 6 h 15 40 13 33 29 33 29 Dosage 3 24 h 13 15 20 15 13 17 TNFa Dosage 1 6 h 48 141 64 291 twenty two 250 265 Dosage 1 24 h 79 93 180 51 199 114 Dosage 2 6 h 51 177 75 255 83 164 239 Dosage 2 24 h 104 123 113 70 121 137 Dosage 3 6 h 109 209 118 226 171 148 193 Dosage 3 24 h 159 114 175 162 169 156 *pg/mL, unless otherwise indicated (MCP-1 values are mean fluorescence intensity [MFI] values of beads) Example B4 : In vivo anti-tumor activity of STING agonist ADC in MC38 tumor model

MC38 cancer cells (Kerafast) were cultured in DMEM (ATCC) containing 10% heat-killed live fetal bovine serum, MEM non-essential amino acids (1x), sodium pyruvate (1 mM), L-glutamine (2 mM), and gentamicin (50 µg/mL). MC38 cancer cells were implanted subcutaneously (1*10 ⁶ cells in 100 µL 25% Matrigel) into C57BL/6 female mice. When the tumor volume reached 100 mm ³ , the mice were dosed with ADC by intravenous injection at the indicated dosing schedule, and the tumor volume was monitored twice a week.

Interleukins were measured in mouse plasma harvested at the indicated time points after treatment with compound or ADC using the Milliplex MAP Mouse Interleukin/Protein Magnetic Bead Panel Assay Kit (MCYTOMAG-70k-PX32) and analyzed using the Luminex™ MAGPIX™ Instrument System. Values outside the standard curve range (e.g., <3.2 or >10,000 pg/mL) were converted to 3.2 or 10,000 pg/mL to calculate the mean value.

The MC38 syngeneic system was also used to evaluate the ability of STING agonist ADCs to induce an immune response in vivo and drive an anti-tumor immune response. The MC38 system is a subcutaneous mouse colorectal adenocarcinoma model. On day 0, 1×10 ⁶ MC38 cells were implanted subcutaneously in the flank of female C57BL/6 mice. When an average tumor size of 100 mm ³ (measured using the formula volume (mm ³ ) = 0.5 * length * width ² , where length is the longer dimension) was reached, the mice were randomly divided into treatment groups of ≥ 5 mice per group. Animals were then treated intravenously with the indicated treatments as indicated. Tumor length and width and animal weight were measured throughout the study, and tumor volume was calculated using the above formula. Animals were followed until tumor volume reached approximately 1000 mm ³ ; animals were then euthanized.

The antitumor activity of the non-cleavable linkers 2.4 , 2.1 , and 2.3 and the cleavable linker 2.11 conjugated to the mIgG2a mAb targeting EphA2 was evaluated; note that all mAb conjugates targeting EphA2 described herein consisted of the h1C1 mIgG2a mAb conjugated to various drug linker compounds. Treatment with all four conjugates elicited robust antitumor activity ( FIG. 2A ), similar to that observed in the Renca tumor model ( FIG. 1 ). However, in the MC38 tumor model, the conjugate 2.11 was more active than the conjugates 2.1 and 2.4 (and in the Renca tumor model, the conjugate 2.1 was more active than the conjugates 2.11 and 2.4 ).

To explore the systemic immune activation elicited by various conjugates, interleukin concentrations in plasma were also assessed 6 and 24 hours after each dose ( Table 9 ). Similar to the observations in the Renca tumor model ( Table 8 ), the mAb- 2.4 conjugate targeting EphA2 elicited robust antitumor activity and minimal systemic interleukins compared to the other conjugates. Thus, robust antitumor activity can be achieved independently of the induction of high levels of systemic interleukins. Table 9: Interleukin production in peripheral blood (plasma) of MC38 tumor-bearing mice after treatment with various conjugates comprising mIgG2a mAb targeting EphA2 conjugated to the indicated compounds*. Plasma concentration (pg/mL)* Untreated mAb targeting EphA2-2.1 mAb targeting EphA2-2.4 mAb targeting EphA2-2.3 mAb targeting EphA2-2.11 G-CSF 6 h 690 4064 729 1544 4342 24h 574 11294 1382 36536 5475 Eosin 6 h 10507 27842 19243 27915 26362 24h 13645 20851 14668 21620 19274 GM-CSF 6 h 201 382 274 261 382 24h 153 88 88 694 257 IFNg 6 h 15 212 17 213 156 24h 17 11 15 129 15 IL-1a 6 h 166 1091 1131 470 748 24h 225 166 134 183 61 IL-1b 6 h 89 174 130 434 166 24h 91 88 74 820 102 IL-2 6 h twenty one 32 40 59 37 24h 26 twenty one 32 37 15 IL-4 6 h 5 16 3 177 16 24h 6 2 4 6 4 IL-3 6 h 9 15 13 10 17 24h 15 1 6 34 2 IL-5 6 h 72 127 87 1331 115 24h 29 105 67 185 121 IL-6 6 h 20 9412 81 7445 6094 24h 89 261 95 577 211 IL-7 6 h 83 108 119 225 205 24h 65 83 twenty one 87 127 IL-9 6 h 98 229 192 254 241 24h 122 192 144 193 168 IL-10 6 h 27 203 111 776 211 24h 55 47 48 309 19 IL-12p40 6 h 13 55 13 13 twenty four 24h 13 13 13 465 13 IL-12p70 6 h 199 117 39 1309 109 24h 143 25 25 129 9 LIF 6 h 13 127 68 82 211 24h twenty two 47 27 93 135 IL-13 6 h 51 74 51 63 51 24h 51 51 51 82 51 LIX 6 h 23738 83396 80810 56394 56484 24h 42504 30287 35160 35733 20720 IL-15 6 h 324 1305 774 1162 1648 24h 324 820 473 969 1096 IL-17 6 h 11 48 15 63 35 24h 9 5 5 19 5 IP-10 6 h 1972 36483 9805 39627 38738 24h 1642 9150 4313 16424 8334 KC 6 h 191 2727 669 2427 2306 24h 238 1610 926 2314 922 MCP-1 6 h 366 125377 1700 67828 149596 24h 442 15128 1838 22037 13806 MIP-1a 6 h 548 2230 617 2446 2130 24h 668 870 890 1317 885 MIP-1b 6 h 203 21680 966 6312 18287 24h 180 2795 1072 5052 2452 M-CSF 6 h 36 131 88 119 126 24h 55 97 60 198 78 MIP-2 6 h 375 1306 707 803 1646 24h 378 754 852 1219 902 MIG 6 h 1568 43581 2941 35588 53822 24h 952 22371 3830 17983 28267 RANTES 6 h 10 1150 15 148 1222 24h 16 881 36 683 600 VEGF 6 h 5 10 8 10 10 24h 6 7 6 12 6 TNFa 6 h 34 241 67 163 213 24h 33 67 60 249 40 * Interleukin levels are reported as mean concentrations (pg/mL); values <LLOQ (lower limit of quantitation) were converted to LLOQ values to calculate mean concentrations. Example B5: In vivo antitumor activity of STING agonist compounds

Renca carcinoma cells (ATCC) were cultured in RPMI-1640 (ATCC) containing 10% heat-killed live fetal bovine serum, MEM non-essential amino acids (1x), sodium pyruvate (1 mM), and L-glutamine (2 mM). Renca carcinoma cells were implanted subcutaneously (2*10 ⁶ cells in 200 µL 25% Matrigel) in Balb/c female mice. When tumor volume reached 100 mm ³ , mice were dosed with compounds by intravenous injection for the indicated dosing schedules, and tumor volume was monitored twice a week. Compounds were formulated in saline (0.9% NaCl) containing 40% PEG400.

Interleukins were measured in mouse plasma harvested at the indicated time points after compound treatment using the Milliplex MAP Mouse Interleukin/Protein Magnetic Bead Panel Assay Kit (MCYTOMAG-70k-PX32) and analyzed using the Luminex™ MAGPIX™ Instrument System. Values outside the standard curve range (e.g., <3.2 or >10,000 pg/mL) were converted to 3.2 or 10,000 pg/mL to calculate the mean value.

The Renca syngeneic system was used to evaluate the ability of STING agonist compounds to induce an immune response in vivo and drive an anti-tumor immune response. The Renca system is a subcutaneous mouse renal cancer model. On day 0, 2×10 ⁶ Renca cells were implanted subcutaneously in the flank of female Balb/c mice. When an average tumor size of 100 mm ³ (measured using the formula volume (mm ³ ) = 0.5 * length * width ² , where length is the longer dimension) was reached, mice were randomized into treatment groups of ≥ 5 mice per group. Animals were then treated intravenously with the indicated treatment every 7 days for a total of 3 doses (or as indicated). Tumor length and width and animal weight were measured throughout the study, and tumor volume was calculated using the above formula. Animals were followed until tumor volume reached approximately 1000 mm ³ ; animals were then euthanized.

The antitumor activity of compounds 3.4 (drug released from mAb-2.4 conjugate) and 3.3 (drug released from mAb-2.3 conjugate) was also evaluated in the Renca tumor model compared to intravenously administered tris(2,2,2-trifluoroacetic acid)(E)-1-(4-(5-aminoformyl-2-(1-ethyl-3-methyl-1H-pyrazole-5-carboxamido)-7-(3-morpholinopropoxy)-1H-benzo[d]imidazol-1- yl )but- 2-en-1-yl)-2- (1-ethyl- 3- methyl-1H-pyrazole-5-carboxamido)-7-methoxy-1H-benzo[d]imidazol -5- carboxamide (Compound A , reference compound).

Treatment with reference compound A resulted in dose-dependent antitumor activity; delayed tumor growth was observed at the 0.5 mg/kg dose level, while tumor regression was observed in 4/5 mice at the 1.5 mg/kg dose level ( Figure 3A ). Treatment with 0.6 or 1.86 mg/kg compound 3.3 elicited robust antitumor activity similar to that observed at the 1.5 mg/kg dose level of compound A ( Figure 3A ). In addition, this antitumor activity was observed in the absence of significant weight loss 2 days after the first dose, compared to approximately 4% weight loss observed after treatment with reference compound A ( Figure 3B ). Treatment with the same dose of compound 3.4 induced a moderate dose-dependent antitumor activity that was significantly reduced compared to compound 3.3 . The differential activity of compounds 3.3 and 3.4 was surprising, given that compounds 3.3 and 3.4 induced comparable potency in vitro ( Table 5 ).

To explore the systemic immune activation elicited by various compounds, plasma interleukin concentrations were also assessed 3, 6, and 24 hours after the first dose ( Table 10 ). The plasma interleukin responses to these compounds in vivo varied and did not correlate with in vitro potency ( Table 5 ). For example, compounds 3.4 and 3.3 elicited similar potency in vitro ( Table 5 ), but compound 3.4 elicited minimal systemic interleukin induction in vivo compared to compound 3.3 . Furthermore, the plasma interleukin responses to these compounds in vivo did not directly correlate with in vivo activity. For example, compound 3.4 induced minimal systemic interleukin induction in vivo, but induced a moderate dose-dependent delay in tumor growth ( Table 10 ). Compared with compound A , compound 3.3 induced systemic interleukins with different kinetics. For example, IL-6, IP10, MCP1, MIP1a, MIP1b, and MIP-2 concentrations were reduced at 3 hours after administration with compound 3.3 compared with compound A , but were higher at 6 hours after administration with compound 3.3 compared with compound A ( Table 10 ). Overall, this suggests that compounds that induce longer-lasting interleukin responses can drive more robust anti-tumor activity in vivo. Table 10: Interleukin production in peripheral blood (plasma) of Renca tumor-bearing mice after treatment with various small molecules*. Medium 1.5 mg/kg of Compound A 0.5 mg/kg of compound A 1.86 mg/kg of compound 3.4 0.6 mg/kg of compound 3.4 1.86 mg/kg of compound 3.3 0.6 mg/kg of compound 3.3 G-CSF 3 h 152 1243 195 140 200 212 178 6 h 226 11809 762 270 338 3430 1392 24h 126 713 297 184 156 2688 512 Eosin 3 h 5189 6494 5032 5100 5506 5829 5228 6 h 4858 8166 5672 4556 4777 6167 6184 24h 3676 5339 4962 4587 3865 5807 4866 GM-CSF 3 h 3 196 138 59 87 101 120 6 h 64 133 93 66 78 192 74 24h 125 83 3 32 93 53 76 IFNg 3 h 5 33 9 6 7 12 8 6 h 4 110 19 7 3 64 27 24h 13 7 3 4 5 twenty three 6 IL-1a 3 h 340 442 704 497 358 315 402 6 h 253 431 248 365 407 598 401 24h 472 369 209 567 412 431 470 IL-1b 3 h 12 47 43 17 36 28 29 6 h 53 72 50 32 60 107 56 24h 47 29 4 13 34 13 27 IL-2 3 h 27 30 31 19 26 28 37 6 h 17 twenty four 19 19 twenty three 42 twenty two 24h 36 25 17 twenty three 33 25 35 IL-4 3 h 2 4 4 3 3 3 3 6 h 2 2 3 3 2 3 3 24h 2 2 2 2 2 1 1 IL-3 3 h 2 5 5 3 5 3 4 6 h 3 3 3 3 3 5 3 24h 4 3 3 3 4 3 3 IL-5 3 h 47 56 57 36 46 45 40 6 h 98 105 67 32 51 120 58 24h 57 43 3 twenty one 40 43 30 IL-6 3 h 161 6005 629 235 123 1263 389 6 h 32 1444 407 121 96 1534 904 24h twenty two 53 14 11 twenty one 60 33 IL-7 3 h twenty two 93 29 18 26 29 twenty three 6 h 20 54 twenty four twenty one 26 53 20 24h twenty two 54 6 16 twenty two 16 17 IL-9 3 h 118 222 543 277 163 133 224 6 h 112 195 151 111 222 373 146 24h 248 155 44 204 338 183 246 IL-10 3 h twenty three 77 64 25 27 49 44 6 h twenty four 56 28 25 29 77 30 24h 45 33 12 26 34 26 32 IL-12p40 3 h 14 25 29 10 14 12 17 6 h 8 twenty two 30 13 12 33 12 24h 18 7 4 8 15 9 10 IL-12p70 3 h 10 40 34 16 31 25 twenty four 6 h twenty two 36 30 twenty two twenty three 88 10 24h 56 38 4 143 46 13 twenty one LIF 3 h 16 64 20 16 19 twenty three 17 6 h 15 46 19 18 20 36 20 24h 16 38 7 12 15 17 15 IL-13 3 h 15 56 twenty three 13 twenty two twenty one twenty one 6 h 19 115 68 13 13 141 60 24h 19 26 13 11 17 19 19 LIX 3 h 25650 13246 21101 19390 16402 18486 17492 6 h 12784 11386 15498 18256 14871 23010 16622 24h 22057 7164 13162 11839 11916 16565 17489 IL-15 3 h 134 510 211 123 152 173 153 6 h 132 335 164 101 153 253 149 24h 169 388 59 97 167 153 126 IL-17 3 h 6 37 11 5 6 19 8 6 h 3 8 5 4 5 18 8 24h 5 5 4 3 6 7 5 IP-10 3 h 207 6628 1667 225 154 4032 1646 6 h 169 10436 8475 812 162 11060 12123 24h 172 1244 570 402 245 2085 1197 KC 3 h 507 4536 1957 997 757 2237 1184 6 h 574 2263 1663 576 529 2791 2837 24h 151 567 421 181 86 1139 446 MCP-1 3 h 259 7674 806 237 263 2301 654 6 h 148 14373 5164 205 206 18417 12457 24h 287 619 235 179 240 3069 757 MIP-1a 3 h 75 988 211 98 120 490 216 6 h 77 165 93 64 107 287 189 24h 188 125 3 66 133 113 93 MIP-1b 3 h 3 13187 1015 31 57 5656 1436 6 h 45 1631 731 51 36 3801 2545 24h 77 119 37 46 62 266 160 M-CSF 3 h 13 45 36 18 26 twenty three twenty four 6 h 19 56 48 twenty two 33 71 40 24h 29 twenty four 11 17 26 twenty four twenty one MIP-2 3 h 609 1718 1301 1256 678 650 980 6 h 166 418 277 177 237 562 309 24h 264 196 34 125 218 86 128 MIG 3 h 387 2319 367 272 273 574 325 6 h 277 17013 6890 261 205 12299 8620 24h 308 6173 2333 391 197 6871 5008 RANTES 3 h 11 286 18 9 11 56 15 6 h 10 1305 129 13 9 578 170 24h 7 111 25 11 7 443 85 VEGF 3 h 3 5 4 3 3 3 3 6 h 2 4 3 2 3 5 4 24h 2 3 1 2 2 3 2 TNFa 3 h 16 130 31 18 19 80 42 6 h 13 51 28 15 15 78 50 24h 19 14 5 8 15 10 14 * Interleukin levels are reported as mean concentrations (pg/mL); values <LLOQ (lower limit of quantitation) were converted to LLOQ values to calculate mean concentrations. Example B6: In vivo antitumor activity of STING agonist ADC

SKOV3 cancer cells were implanted subcutaneously (1*10 ⁷ cells in 200 µL 50% Matrigel) into CB.17 SCID mice. When tumor volume reached 100-150 mm ³ , mice were treated with a single intravenous dose of ADC on the first day of the study, and tumor volume was monitored twice a week.

The SKOV3 xenograft system was also used to evaluate the ability of STING agonist ADCs to induce an immune response in vivo and drive an anti-tumor immune response. The SKOV3 xenograft tumor model is a subcutaneous human ovarian cancer model. 1×10 ⁷ human SKOV3 tumor cells were implanted subcutaneously in the flank of CB.17 SCID mice. When an average tumor size of 100-150 mm ³ (measured by using the formula volume (mm ³ ) = 0.5 * length * width ² , where length is the longer dimension) was reached, mice were randomized into treatment groups of 6 mice per group. Animals were then treated intravenously with the indicated treatments as indicated. Tumor length and width and animal weight were measured throughout the study, and tumor volume was calculated using the above formula. Animals were followed until tumor volume reached approximately 1000 mm ³ ; animals were then euthanized.

The antitumor activity of the non-cleavable linkers 2.4 , 2.1 , and 2.3 and the cleavable linker 2.11 conjugated to a hIgG1 mAb targeting Her2 was evaluated. Treatment with all four conjugates elicited antitumor activity ( Figures 4A and 4B ). Consistent with the Renca ( Figure 1 ) and MC38 ( Figures 2A and 2B ) tumor models, the 2.3 conjugate elicited the most robust antitumor activity. In addition, in the SKOV3 tumor model, the 2.1 conjugate was more active than the 2.11 and 2.4 conjugates, consistent with the observations in the Renca tumor model ( Figure 1 ). This was different from the MC38 tumor model, where the 2.11 conjugate was more active than the 2.1 and 2.4 conjugates ( Figures 2A and 2B ).

Compared to vehicle-treated animals, treatment with 2.1 , 2.3 , and 2.11 Her2-targeted conjugates resulted in approximately 7% weight loss 1 day after dosing, while no significant weight loss was observed after treatment with 2.4 . Within 3 days of treatment with 2.1 , the weight returned to baseline, while those treated with 2.3 and 2.11 maintained approximately 3-4% weight loss 4 days after treatment ( Figure 4B ). Given that the 2.11 conjugate was less active than the 2.1 conjugate, this suggests that weight loss is not associated with anti-tumor activity.

To explore the systemic immune activation induced by various conjugates, plasma interleukin concentrations were also assessed 6 hours after treatment ( Table 11 ). The mAb -2.4 conjugate targeting Her2 induced antitumor activity and minimal interleukin induction compared to the other conjugates. The mAb- 2.1 , 2.3 , and 2.11 conjugates targeting Her2 induced robust systemic interleukin responses and different antitumor activities. For example, the 2.11 and 2.3 conjugates induced similar systemic interleukin responses, however, the 2.3 conjugate induced more antitumor activity. Consistent with the Renca and MC38 tumor models ( Tables 8 and 9 ), these data suggest that antitumor activity can be achieved independently of systemic interleukin induction. Table 11 : Interleukin production in peripheral blood ( plasma ) of SKOV3 tumor-bearing mice after treatment with various conjugates comprising a hIgG1 mAb targeting Her2 conjugated to the indicated compounds * . Plasma concentration (pg/mL) Medium 2 mg/kg of mAb-2.1 targeting Her2 2 mg/kg of mAb-2.4 targeting Her2 2 mg/kg of mAb-2.3 targeting Her2 2 mg/kg of mAb-2.11 targeting Her2 G-CSF 2658 30394 3004 5853 6973 Eosin 3087 5032 2148 4073 2751 GM-CSF 30 77 4 36 38 IFNg 39 383 18 263 274 IL-1a 309 709 433 544 585 IL-1b 3 13 7 9 9 IL-2 14 13 14 12 16 IL-4 1 2 1 1 1 IL-3 3 3 3 3 3 IL-5 53 38 65 twenty three 41 IL-6 303 6679 310 3430 4094 IL-7 3 3 3 3 3 IL-9 3 326 238 191 569 IL-10 3 3 3 3 3 IL-12p40 3 3 3 3 3 IL-12p70 10 56 3 25 twenty one LIF 3 7 3 3 3 IL-13 13 13 13 13 13 LIX 18031 17925 21755 19250 21153 IL-15 42 86 12 38 twenty four IL-17 10 twenty four 15 9 26 IP-10 697 14648 714 10420 9830 KC 607 3889 715 4134 3178 MCP-1 209 15088 241 8214 7998 MIP-1a 3 728 3 367 263 MIP-1b 59 5461 69 2946 3137 M-CSF 4 35 8 18 twenty one MIP-2 77 419 137 232 221 MIG 1072 11897 1052 4549 3857 RANTES 8 272 10 65 57 VEGF 4 5 2 3 3 TNFa 6 88 7 35 43 *Interleukin levels are reported as mean concentrations (pg/mL); values <LLOQ (lower limit of quantification) were converted to LLOQ values to calculate mean concentrations. Example B7 : Tumor /PBMC co-culture analysis

HT1080 (ATCC) tumor cells were cultured in DMEM (Gibco) containing 10% heat-killed live fetal bovine serum (Gibco), Pen-Strep (100 U/mL-100 mg/mL, Gibco), HEPES (10 mM, Gibco), sodium pyruvate (1 mM, Gibco), MEM non-essential amino acids (1x, Gibco), GlutaMAX (1x, Gibco), and β-hydroxyethanol (55 µM, Gibco) and transfected with Incucyte® Cytolight Red Lentivirus (Sartorius #4481) according to the manufacturer's instructions. Live cell killing assays were performed by seeding 2,500 RFP+ HT1080 tumor cells in 96-well flat-bottom plates (Corning #3603). The next day, 100,000 peripheral blood mononuclear cells (PBMCs) isolated from healthy donors were added to each well (40:1 PBMC:tumor cell ratio), and the cultures were treated with the indicated concentrations of small molecules or ADCs. Automated cell imaging was performed using the IncuCyte S3 Live Cell Analysis System (Sartorius) at 10× magnification and analyzed using the IncuCyte® Analysis Software. Tumor cell killing was quantified by calculating the confluence of RFP+ tumor cells at 90 hours relative to t = 0. Molar concentrations of small molecules, ADCs, or unconjugated mAbs (adjusted to equivalent payload concentrations) were plotted.

The ability of various CD228-targeting conjugates to induce tumor cell killing in vitro was also evaluated. Conjugates targeting CD228 with a WT Fc backbone induced more effective cell killing than non-binding conjugates or conjugates targeting CD228 with an ineffective LALAKA ( see, e.g., Schlothauer et al. , Protein Engineering, Design and Selection, 2016, 29(10):457-466; and Hezareh et al. , Journal of Virology, 2001, 75(24):12161-12168, each of which is incorporated herein by reference in its entirety) backbone ( FIG. 5 ). Although the potency of the conjugates varied from 3 to 50 ng/mL in the THP1 duplex assay ( Table 6 ), the conjugates targeting CD228 elicited comparable immune-mediated tumor cell killing in vitro ( Figure 5 ). Example B8 : In vivo antitumor activity of STING agonist ADCs MC38 tumor model

MC38 cancer cells (Kerafast) were cultured in DMEM (ATCC) containing 10% heat-killed live fetal bovine serum, MEM non-essential amino acids (1x), sodium pyruvate (1 mM), L-glutamine (2 mM), and gentamicin (50 µg/mL). MC38 cancer cells were implanted subcutaneously (1*10 ⁶ cells in 100 µL 25% Matrigel) into C57BL/6 female mice. When the tumor volume reached 100 mm ³ , the mice were dosed with ADC by intravenous injection at the indicated dosing schedule, and the tumor volume was monitored twice a week.

Interleukins were measured in mouse plasma harvested at the indicated time points after treatment with compound or ADC using the Milliplex MAP Mouse Interleukin/Protein Magnetic Bead Panel Assay Kit (MCYTOMAG-70k-PX32) and analyzed using the Luminex™ MAGPIX™ Instrument System. Values outside the standard curve range (e.g., <3.2 or >10,000 pg/mL) were converted to 3.2 or 10,000 pg/mL to calculate the mean value.

The MC38 syngeneic system was also used to evaluate the ability of STING agonist ADCs to induce an immune response in vivo and drive an anti-tumor immune response. The MC38 system is a subcutaneous mouse colorectal adenocarcinoma model. On day 0, 1×10 ⁶ MC38 cells were implanted subcutaneously in the flank of female C57BL/6 mice. When an average tumor size of 100 mm ³ (measured by using the formula volume (mm ³ ) = 0.5 * length * width ² , where length is the longer dimension) was reached, mice were randomly divided into treatment groups of ≥ 5 mice per group. Animals were then treated intravenously with the indicated treatments as indicated. Tumor length and width and animal weight were measured throughout the study, and tumor volume was calculated using the above formula. Animals were followed until tumor volume reached approximately 1000 mm ³ ; animals were then euthanized.

The anti-tumor activity of the non-cleavable linkers 2.4 , 2.1 and 2.2 and the cleavable linker 2.10 conjugated to the mIgG2a mAb targeting EphA2 was evaluated. Treatment with all three non-cleavable conjugates elicited anti-tumor activity ( Figure 6A ), while the cleavable conjugate of 2.10 was inactive. This was unexpected because the conjugates of 2.2 and 2.10 showed comparable in vitro potency ( Table 6 ), indicating that the in vivo activity of STING agonist conjugates cannot be predicted based solely on in vitro potency.

To explore the systemic immune activation elicited by the various conjugates, plasma interleukin concentrations were also assessed 6 and 24 hours after each dose ( Table 12 ). Compared to the EphA2-targeting mAb- 2.1 conjugate, the EphA2-targeting mAb- 2.2 and 2.4 conjugates elicited antitumor activity and very few systemic interleukins. The EphA2-targeting mAb- 2.10 conjugate elicited neither antitumor activity nor systemic interleukins, which was surprising given that the in vitro potency of the 2.2 and 2.10 conjugates was comparable ( Table 6 ). Table 12 : Interleukin production in peripheral blood ( plasma ) of MC38 tumor-bearing mice after treatment with various conjugates comprising mIgG2a mAb targeting EphA2 conjugated to the indicated compounds * . Plasma interleukin (pg/mL) Untreated mAb-2.4 targeting EphA2 (0.75 mg/kg) mAb-2.4 targeting EphA2 (3 mg/kg) mAb-2.1 targeting EphA2 (0.75 mg/kg) mAb-2.2 targeting EphA2 (0.75 mg/kg) mAb-2.10 targeting EphA2 (0.75 mg/kg) G-CSF 6 h 168 156 178 640 261 134 24h 161 307 525 1082 312 162 Eosin 6 h 3057 3873 4975 6615 4185 3494 24h 2754 3110 3612 3586 2179 2638 GM-CSF 6 h twenty two 51 40 112 69 121 24h twenty two 51 66 51 32 51 IFNg 6 h 3 5 twenty three 60 8 4 24h 2 3 5 2 2 2 IL-1a 6 h 127 436 210 441 588 550 24h 595 317 143 496 857 725 IL-1b 6 h 12 11 17 28 11 38 24h 5 15 twenty three 15 11 20 IL-2 6 h twenty one 16 twenty one 46 twenty one 29 24h 19 16 twenty four 18 twenty four 25 IL-4 6 h 1 1 1 6 1 2 24h 1 1 1 1 1 2 IL-3 6 h 2 3 3 2 3 4 24h 3 3 3 2 2 2 IL-5 6 h 26 19 18 47 13 45 24h 13 18 39 27 16 36 IL-6 6 h 8 54 410 1686 46 12 24h 7 25 50 33 17 17 IL-7 6 h 4 9 7 17 7 17 24h 5 7 10 6 9 8 IL-9 6 h 110 143 105 306 151 232 24h 141 157 141 108 151 125 IL-10 6 h 10 twenty one twenty three 54 36 32 24h 3 26 29 15 18 20 IL-12p40 6 h 6 3 4 11 3 11 24h 4 9 8 6 6 3 IL-12p70 6 h 7 2 2 27 2 41 24h 3 13 16 10 3 12 LIF 6 h 8 7 20 16 8 13 24h 5 7 twenty three 8 7 7 IL-13 6 h 13 13 15 61 13 12 24h 13 9 13 13 13 13 LIX 6 h 13420 12788 11616 13481 18778 20614 24h 22757 11674 12186 21164 20516 14559 IL-15 6 h 76 99 95 224 77 145 24h 60 81 133 161 110 122 IL-17 6 h 3 3 4 20 4 4 24h 2 3 3 4 2 3 IP-10 6 h 326 7059 8918 11065 3955 184 24h 312 1061 1415 1897 486 167 KC 6 h 87 231 200 923 414 109 24h 92 168 213 486 236 94 MCP-1 6 h 115 1482 6368 15759 1687 287 24h 175 724 4343 3203 576 256 MIP-1a 6 h 94 130 186 545 136 161 24h 49 60 134 123 89 114 MIP-1b 6 h 3 617 1836 7434 769 32 24h 8 115 438 447 71 8 M-CSF 6 h 13 13 17 30 9 twenty three 24h 6 17 17 16 15 13 MIP-2 6 h 144 242 294 518 242 398 24h 211 165 318 210 210 281 MIG 6 h 207 952 2240 8893 793 212 24h 232 1159 2211 3773 784 178 RANTES 6 h 3 15 33 466 31 7 24h 4 18 108 324 41 8 VEGF 6 h 2 3 1 4 2 2 24h 3 3 2 1 2 2 TNFa 6 h 5 4 11 50 11 twenty one 24h 3 10 19 13 14 11 * Interleukin levels are reported as mean concentrations (pg/mL); values <LLOQ (lower limit of quantitation) were converted to LLOQ values to calculate mean concentrations. Example B9 : In vivo antitumor activity of STING agonist ADCs MC38 tumor model

The antitumor activity of drug conjugate 2.4 conjugated to mIgG2a mAb targeting EphA2 or non-binding mIgG2a mAb was evaluated in wild-type (C57BL/6J; WT) or STING-deficient (C57BL/6J -Sting1 ^gt ) mice bearing MC38 tumors. Treatment with the mAb -2.4 conjugate targeting EphA2 showed robust antitumor activity in WT but not STING-deficient animals. In addition, treatment with non-binding mAb- 2.4 failed to elicit an antitumor response in WT animals. These results indicate that in the MC38 tumor model, non-tumor cells require STING signaling to elicit anti-tumor responses and, importantly, that the 2.4 conjugate requires targeted delivery to the tumor microenvironment to elicit anti-tumor responses ( Figure 7A and Figure 7B ).

Although the above written description of the compounds, uses and methods described herein enables one of ordinary skill to prepare and use the compounds, uses and methods described herein, one of ordinary skill will understand and recognize that there are variations, combinations and equivalents to the specific embodiments, methods and examples herein. Therefore, the compounds, uses and methods provided herein should not be limited to the above embodiments, methods or examples, but encompass all embodiments and methods within the scope and spirit of the compounds, uses and methods provided herein.

All references disclosed herein are incorporated by reference in their entirety.

Unless otherwise indicated, all sequences and SEQ IDs cited in this application correspond to the appropriate numbered sequences in the table below.

The following sequence listing provides exemplary antibody sequences consistent with the present disclosure. In this table, all targets correspond to human orthologs unless otherwise specified. surface 13 : Sequence Listing SEQ ID NO describe sequence 1 cAC10 CDR-H1 DYYIT 2 cAC10 CDR-H2 WIYPGSGNTKYNEKFKG 3 cAC10 CDR-H3 YGNYWFAY 4 cAC10 CDR-L1 KASQSVDFDGDSYMN 5 cAC10 CDR-L2 AASNLES 6 cAC10 CDR-L3 QQQSNEDPWT 7 AC10 VH QIQLQQSGPEVVKPGASVKISCKASGYTFTDYYITWVKQKPGQGLEWIGWIYPGSGNTKYNEKFKGKATLTVDTSSSTAFMQLSSLTSEDTAVYFCANYGNYWFAYWGQGTQVTVSA 8 AC10 VL DIVLTQSPASLAVSLGQRATISCKASQSVDFDGDSYMNWYQQKPGQPPKVLIYAASNLESGIPARFSGSGSGTDFTLNIHPVEEEDAATYYCQQSNEDPWTFGGGTKLEIK 9 cAC10 HC QIQLQQSGPEVVKPGASVKISCKASGYTFTDYYITWVKQKPGQGLEWIGWIYPGSGNTKYNEKFKGKATLTVDTSSSTAFMQLSSLTSEDTAVYFCANYGNYWFAYWGQGTQVTVSAAST KGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSS GLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKKVEPKSCDKTHTCPPCPAPELLGG PSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYN STYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSRDE LTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRW QQGNVFSCSVMHEALHNHYTQKSLSLSPGK 10 cAC10 HC v2 QIQLQQSGPEVVKPGASVKISCKASGYTFTDYYITWVKQKPGQGLEWIGWIYPGSGNTKYNEKFKGKATLTVDTSSSTAFMQLSSLTSEDTAVYFCANYGNYWFAYWGQGTQVTVSAAST KGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSS GLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKKVEPKSCDKTHTCPPCPAPELLGG PSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYN STYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSRDE LTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRW QQGNVFSCSVMHEALHNHYTQKSLSLSPG 11 cAC10 LC DIVLTQSPASLAVSLGQRATISCKASQSVDFDGDSYMNWYQQKPGQPPKVLIYAASNLESGIPARFSGSGSGTDFTLNIHPVEEEDAATYYCQQSNEDPWTFGGGTKLEIKR TVAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC 12 h1C1 CDR-H1 HYMMA 13 h1C1 CDR-H2 RIGPSGGPTHYADSVKG 14 h1C1 CDR-H3 YDSGYDYVAVAGPAEYFQH 15 h1C1 CDR-L1 RASQSISTWLA 16 h1C1 CDR-L2 KASNLHT 17 h1C1 CDR-L3 QQYNSYSRT 18 h1C1 VH EVQLLESGGGLVQPGGSLRLSCAASGFTFSHYMMAWVRQAPGKGLEWVSRIGPSGGPTHYADSVKGRFTISRDNSKNTLYLQMNSLRAEDTAVYYCAGYDSGYDYVAVAGPAEYFQHWGQGTLVTVSS 19 h1C1 DIQMTQSPSSSLSASVGDRVTITCRASQSISTWLAWYQQKPGKAPKLLIYKASNLHTGVPSRFSGSGSGTEFSLTISGLQPDDFATYYCQQYNSYSRTFGQGTKVEIK 20 h1C1 HC EVQLLESGGGLVQPGGSLRLSCAASGFTFSHYMMAWVRQAPGKGLEWVSRIGPSGGPTHYADSVKGRFTISRDNSKNTLYLQMNSLRAEDTAVYYCAGYDSGYDYVAVAGPAEYFQHWGQGTLVTVSSASTKGPSVFPLAPSSKSTSGGTAALG CLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKKVEPKSCDKTHTCPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYN STYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSRDE LTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRW QQGNVFSCSVMHEALHNHYTQKSLSLSPGK twenty one h1C1 HC v2 EVQLLESGGGLVQPGGSLRLSCAASGFTFSHYMMAWVRQAPGKGLEWVSRIGPSGGPTHYADSVKGRFTISRDNSKNTLYLQMNSLRAEDTAVYYCAGYDSGYDYVAVAGPAEYFQHWGQGTLVTVSSASTKGPSVFPLAPSSKSTSGGTAALG CLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKKVEPKSCDKTHTCPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYN STYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSRDE LTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRW QQGNVFSCSVMHEALHNHYTQKSLSLSPG twenty two h1C1 LC DIQMTQSPSSSLSASVGDRVTITCRASQSISTWLAWYQQKPGKAPKLLIYKASNLHTGVPSRFSGSGSGTEFSLTISGLQPDDFATYYCQQYNSYSRTFGQGTKVEIKRTVAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDS KDSTYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC twenty three h1C1 mIgG2a HC EVQLLESGGGLVQPGGSLRLSCAASGFTFSHYMMAWVRQAPGKGLEWVSRIGPSGGPTHYADSVKGRFTISRDNSKNTLYLQMNSLRAEDTAVYYCAGYDSGYDYVAVAGPAEY FQHWGQGTLVTVSSAKTTAPSVYPLAPVCGDTTGSSVTLGCLVKGYFPEPVTLTWNSGLSSGVHTFPAVLQSDLYTLSSSVTVTSSTWPSQSITCNVAHPASSTKVDKKIEPRG PTIKPCPPCKCPAPNLLGGPSVFIFPPPKIKDVLMISLSPIVTCVVVDVSEDDPDVQISWFVNNVEVHTAQTQTHREDYNSTLRVVSALPIQHQDWMSGKEFKCKVNNKDLPAPI ERTISKPKGSVRAPQVYVLPPPEEEMTKKQVTLTCMVTDFMPEDIYVEWTNNGKTELNYKNTEPVLDSDGSYFMYSKLRVEKKNWVERNSYSCSVVHEGLHNHHTTKSFSRTPGK twenty four h1C1 mIgG2a HC v2 EVQLLESGGGLVQPGGSLRLSCAASGFTFSHYMMAWVRQAPGKGLEWVSRIGPSGGPTHYADSVKGRFTISRDNSKNTLYLQMNSLRAEDTAVYYCAGYDSGYDYVAVAGPAEY FQHWGQGTLVTVSSAKTTAPSVYPLAPVCGDTTGSSVTLGCLVKGYFPEPVTLTWNSGLSSGVHTFPAVLQSDLYTLSSSVTSSTWPSQSITCNVAHPASSTKVDKKIEPR GPTIKPCPPCKCPAPNLLGGPSVFIFPPPKIKDVLMISLSPIVTCVVVDVSEDDPDVQISWFVNNVEVHTAQTQTHREDYNSTLRVVSALPIQHQDWMSGKEFKCKVNNKDLPAP IERTISKPKGSVRAPQVYVLPPPEEEMTKKQVTLTCMVTDFMPEDIYVEWTNNGKTELNYKNTEPVLDSDGSYFMYSKLRVEKKNWVERNSYSCSVVHEGLHNHHTTKSFSRTPG 25 h1C1 mκ LC DIQMTQSPSSSLSASVGDRVTITCRASQSISTWLAWYQQKPGKAPKLLIYKASNLHTGVPSRFSGSGSGTEFSLTISGLQPDDFATYYCQQYNSYSRTFGQGTKVEIK RADAAPTVSIFPPSSEQLTSGGASVVCFLNNFYPKDINVKWKIDGSERQNGVLNSWTDQDSKDSTYSMSSSTLTLTKDEYERHNSYTCEATHKTSTSPIVKSFNRNEC 26 h1C1 mIgG2a LALAPG HC EVQLLESGGGLVQPGGSLRLSCAASGFTFSHYMMAWVRQAPGKGLEWVSRIGPSGGPTHYADSVKGRFTISRDNSKNTLYLQMNSLRAEDTAVYYCAGYDSGYDYVAVAGPAEY FQHWGQGTLVTVSSAKTTAPSVYPLAPVCGDTTGSSVTLGCLVKGYFPEPVTLTWNSGLSSGVHTFPAVLQSDLYTLSSSVTVTSSTWPSQSITCNVAHPASSTKVDKKIEPRG PTIKPCPPCKCPAPNAAGGPSVFIFPPKIKDVLMISLSPIVTCVVVDVSEDDPDVQISWFVNNVEVHTAQTQTHREDYNSTLRVVSALPIQHQDWMSGKEFKCKVNNKDLGAPI ERTISKPKGSVRAPQVYVLPPPEEEMTKKQVTLTCMVTDFMPEDIYVEWTNNGKTELNYKNTEPVLDSDGSYFMYSKLRVEKKNWVERNSYSCSVVHEGLHNHHTTKSFSRTPGK 27 h1C1 mIgG2a LALAPG HC v2 EVQLLESGGGLVQPGGSLRLSCAASGFTFSHYMMAWVRQAPGKGLEWVSRIGPSGGPTHYADSVKGRFTISRDNSKNTLYLQMNSLRAEDTAVYYCAGYDSGYDYVAVAGPAEY FQHWGQGTLVTVSSAKTTAPSVYPLAPVCGDTTGSSVTLGCLVKGYFPEPVTLTWNSGLSSGVHTFPAVLQSDLYTLSSSVTSSTWPSQSITCNVAHPASSTKVDKKIEPR GPTIKPCPPCKCPAPNAAGGPSVFIFPPKIKDVLMISLSPIVTCVVVDVSEDDPDVQISWFVNNVEVHTAQTQTHREDYNSTLRVVSALPIQHQDWMSGKEFKCKVNNKDLGAP IERTISKPKGSVRAPQVYVLPPPEEEMTKKQVTLTCMVTDFMPEDIYVEWTNNGKTELNYKNTEPVLDSDGSYFMYSKLRVEKKNWVERNSYSCSVVHEGLHNHHTTKSFSRTPG 28 h1C1 LALAPG mκ LC DIQMTQSPSSSLSASVGDRVTITCRASQSISTWLAWYQQKPGKAPKLLIYKASNLHTGVPSRFSGSGSGTEFSLTISGLQPDDFATYYCQQYNSYSRTFGQGTKVEIK RADAAPTVSIFPPSSEQLTSGGASVVCFLNNFYPKDINVKWKIDGSERQNGVLNSWTDQDSKDSTYSMSSSTLTLTKDEYERHNSYTCEATHKTSTSPIVKSFNRNEC 29 hL49 HA CDR-H1 SGWY 30 hL49 HA CDR-H2 YISDSGITYYNPSLKS 31 hL49 HA CDR-H3 RTLATYYAMDY 32 hL49 LC CDR-L1 RASQSLVHSDGNTYLH 33 hL49 LC CDR-L2 RVSNRFS 34 hL49 LC CDR-L3 SQSTHVPPT 35 hL49 HA VH QVQLQESGPGLVKPSETLSLTCTVSGDSITSGYWNWIRQPPGKGLEYIGYISDSGITYYN PSLKSRVTISRDTSKNQYSLKLSSVTAADTAVYYCARRTLATYYAMDYWGQGTLVTVSS 36 hL49 LC VL DFVMTQSPLSLPVTLGQPASISCRASQSLVHSDGNTYLHWYQQRPGQSPRLLIYRVSNRFSGVPDRFSGSGSGTDFTLKISRVEAEDVGVYYCSQSTHVPPTFGQGTKLEIK 37 hL49 HA HC QVQLQESGPGLVKPSETLSLTCTVSGDSITSGYWNWIRQPPGKGLEYIGYISDSGITYYNPSLKSRVTISRDTSKNQYSLKLSSVTAADTAVYYCARRTLATYYAMDYWGQG TLVTVSSASTKGPSVFPLAPSSKSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKKVEPKSCDK THTCPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEK TISKAKGQPREPQVYTLPPSRDELTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGK 38 hL49 HA HC v2 QVQLQESGPGLVKPSETLSLTCTVSGDSITSGYWNWIRQPPGKGLEYIGYISDSGITYYNPSLKSRVTISRDTSKNQYSLKLSSVTAADTAVYYCARRTLATYYAMDYWGQG TLVTVSSASTKGPSVFPLAPSSKSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKKVEPKSCDK THTCPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEK TISKAKGQPREPQVYTLPPSRDELTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPG 39 hL49 LC LC DFVMTQSPLSLPVTLGQPASISCRASQSLVHSDGNTYLHWYQQRPGQSPRLLIYRVSNRFSGVPDRFSGSGSGTDFTLKISRVEAEDVGVYYCSQSTHVPPTFGQGTKL EIKRTVAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC 40 hL49 HA LALAKA HC QVQLQESGPGLVKPSETLSLTCTVSGDSITSGYWNWIRQPPGKGLEYIGYISDSGITYYNPSLKSRVTISRDTSKNQYSLKLSSVTAADTAVYYCARRTLATYYAMDYWGQG TLVTVSSASTKGPSVFPLAPSSKSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKKVEPKSCDK THTCPPCPAPEAAGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCAVSNKALPAPIEK TISKAKGQPREPQVYTLPPSRDELTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGK 41 hL49 HA LALAKA HC v2 QVQLQESGPGLVKPSETLSLTCTVSGDSITSGYWNWIRQPPGKGLEYIGYISDSGITYYNPSLKSRVTISRDTSKNQYSLKLSSVTAADTAVYYCARRTLATYYAMDYWGQG TLVTVSSASTKGPSVFPLAPSSKSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKKVEPKSCDK THTCPPCPAPEAAGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCAVSNKALPAPIEK TISKAKGQPREPQVYTLPPSRDELTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPG 42 hL49 LC LALAKA LC DFVMTQSPLSLPVTLGQPASISCRASQSLVHSDGNTYLHWYQQRPGQSPRLLIYRVSNRFSGVPDRFSGSGSGTDFTLKISRVEAEDVGVYYCSQSTHVPPTFGQGTKL EIKRTVAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC 43 H2A2 HC CDR-H1 DYNV 44 H2A2 HC CDR-H2 VINPKYGTTRYNQKFKG 45 H2A2 HC CDR-H3 GLNAWDY 46 H2A2 LG CDR-L1 GASENIYGALN 47 H2A2 LG CDR-L2 GATNLED 48 H2A2 LG CDR-L3 QNVLTTPYT 49 h2A2 HC VH QFQLVQSGAEVKKPGASVKVSCKASGYSFTDYNVNWVRQAPGQGLEWIGVINPKYGTTRYNQKFKGRATLTVDKSTSTAYMELSSLRSEDTAVYYCTRGLNAWDYWGQGTLVTVSS 50 h2A2 LG VL DIQMTQSPSSSLSASVGDRVTITTCGASENIYGALNWYQQKPGKAPKLLIYGATNLEDGVPSRFSGSGSGRDYTFTISSLQPEDIATYYCQNVLTTPYTFGQGTKLEIK 51 h2A2 HC HC QFQLVQSGAEVKKPGASVKVSCKASGYSFTDYNVNWVRQAPGQGLEWIGVINPKYGTTRYNQKFKGRATLTVDKSTSTAYMELSSLRSEDTAVYYCTRGLNAWDYWGQGTL VTVSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKKVEPKSCDKTH TCPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKT ISKAKGQPREPQVYTLPPSRDELTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGK 52 h2A2 HC HC v2 QFQLVQSGAEVKKPGASVKVSCKASGYSFTDYNVNWVRQAPGQGLEWIGVINPKYGTTRYNQKFKGRATLTVDKSTSTAYMELSSLRSEDTAVYYCTRGLNAWDYWGQGTL VTVSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKKVEPKSCDKT HTCPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEK TISKAKGQPREPQVYTLPPSRDELTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPG 53 h2A2 LG LC DIQMTQSPSSSLSASVGDRVTITTCGASENIYGALNWYQQKPGKAPKLLIYGATNLEDGVPSRFSGSGSGRDYTFTISSLQPEDIATYYCQNVLTTPYTFGQGTKLEIK RTVAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC 54 h2A2 HC LALAKA HC QFQLVQSGAEVKKPGASVKVSCKASGYSFTDYNVNWVRQAPGQGLEWIGVINPKYGTTRYNQKFKGRATLTVDKSTSTAYMELSSLRSEDTAVYYCTRGLNAWDYWGQGTL VTVSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKKVEPKSCDKTH TCPPCPAPEAAGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCAVSNKALPAPIEKT ISKAKGQPREPQVYTLPPSRDELTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGK 55 h2A2 HC LALAKA HC v2 QFQLVQSGAEVKKPGASVKVSCKASGYSFTDYNVNWVRQAPGQGLEWIGVINPKYGTTRYNQKFKGRATLTVDKSTSTAYMELSSLRSEDTAVYYCTRGLNAWDYWGQGTL VTVSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKKVEPKSCDKT HTCPPCPAPEAAGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCAVSNKALPAPIEK TISKAKGQPREPQVYTLPPSRDELTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPG 56 h2A2 LG LALAKA LC DIQMTQSPSSSLSASVGDRVTITTCGASENIYGALNWYQQKPGKAPKLLIYGATNLEDGVPSRFSGSGSGRDYTFTISSLQPEDIATYYCQNVLTTPYTFGQGTKLEIK RTVAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC 57 B7H41001 CDR-H1 SGSYYWG 58 B7H41001 CDR-H2 NIYYSGSTYYNPSLRS 59 B7H41001 CDR-H3 EGSYPNQFDP 60 B7H41001 CDR-L1 RASQSVSSNLA 61 B7H41001 CDR-L2 GASTRAT 62 B7H41001 CDR-L3 QQYHSFPFT 63 B7H41001 VH QLQLQESGPGLVKPSETLSLTCTVSGGSIKSGSYYWGWIRQPPGKGLEWIGNIYYSGSTYYNPSLRSRVTISVDTSKNQFSLKLSSVTAADTAVYYCAREGSYPNQFDPWGQGTLVTVSS 64 B7H41001 VL EIVMTQSPATLSVSPGERATLSCRASQSVSSNLAWYQQKPGQAPRLLIYGASTRATGIPARFSGSGSGTEFTLTISSLQSEDFAVYYCQQYHSFPFTFGGGTKVEIK 65 B7H41001 HC QLQLQESGPGLVKPSETLSLTCTVSGGSIKSGSYYWGWIRQPPGKGLEWIGNIYYSGSTYYNPSLRSRVTISSVDTSKNQFSLKLSSVTAADTAVYYCAREGSYPNQFDPWGQ GTLVTVSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKKVEPKSCDK THTCPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEK TISKAKGQPREPQVYTLPPSRDELTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGK 66 B7H41001 HC v2 QLQLQESGPGLVKPSETLSLTCTVSGGSIKSGSYYWGWIRQPPGKGLEWIGNIYYSGSTYYNPSLRSRVTISSVDTSKNQFSLKLSSVTAADTAVYYCAREGSYPNQFDPWGQ GTLVTVSSASTKGPSVFPLAPSSKSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKKVEPKSCD KTHTCPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIE KTISKAKGQPREPQVYTLPPSRDELTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPG 67 B7H41001 LC EIVMTQSPATLSVSPGERATLSCRASQSVSSNLAWYQQKPGQAPRLLIYGASTRATGIPARFSGSGSGTEFTLTISSLQSEDFAVYYCQQYHSFPFTFGGGTKVEIK RTVAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC 68 B7H41001 LALAKA HC QLQLQESGPGLVKPSETLSLTCTVSGGSIKSGSYYWGWIRQPPGKGLEWIGNIYYSGSTYYNPSLRSRVTISSVDTSKNQFSLKLSSVTAADTAVYYCAREGSYPNQFDPWGQ GTLVTVSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKKVEPKSCDK THTCPPCPAPEAAGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCAVSNKALPAPIEK TISKAKGQPREPQVYTLPPSRDELTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGK 69 B7H41001 LALAKA HC v2 QLQLQESGPGLVKPSETLSLTCTVSGGSIKSGSYYWGWIRQPPGKGLEWIGNIYYSGSTYYNPSLRSRVTISSVDTSKNQFSLKLSSVTAADTAVYYCAREGSYPNQFDPWGQ GTLVTVSSASTKGPSVFPLAPSSKSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKKVEPKSCD KTHTCPPCPAPEAAGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCAVSNKALPAPIE KTISKAKGQPREPQVYTLPPSRDELTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPG 70 B7H41001 LALAKA LC EIVMTQSPATLSVSPGERATLSCRASQSVSSNLAWYQQKPGQAPRLLIYGASTRATGIPARFSGSGSGTEFTLTISSLQSEDFAVYYCQQYHSFPFTFGGGTKVEIK RTVAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC 71 B7H4-15461 CDR-H1 GSISSSSYYWG 72 B7H4-15461 CDR-H2 NIYYSGSTYYNPSLKS 73 B7H4-15461 CDR-H3 AREGSYPNWFDP 74 B7H4-15461 CDR-L1 RASQSVSSNLA 75 B7H4-15461 CDR-L2 GASTRAT 76 B7H4-15461 CDR-L3 QQYHSFPFT 77 B7H4-15461 VH QLQLQESGPGLVKPSETLSLTCTVSGGSISSSSYYWGWIRQPPGKGLEWIGNIYYSGSTYYNPSLKSRVTISSVDTSKNQFSLKLSSVTAADTAVYYCAREGSYPNWFDPWGQGTLVTVSS 78 B7H4-15461 VL EIVMTQSPATLSVSPGERATLSCRASQSVSSNLAWYQQKPGQAPRLLIYGASTRATGIPARFSGSGSGTEFTLTISSLQSEDFAVYYCQQYHSFPFTFGGGTKVEIK 79 B7H4-20500 CDR-H1 GSIKSGSHYWG 80 B7H4-20500 CDR-H2 NIYYSGSTYYNPSLRS 81 B7H4-20500 CDR-H3 AREGSYPNWFDP 82 B7H4-20500 CDR-L1 RASQSVSSNLA 83 B7H4-20500 CDR-L2 GASTRAT 84 B7H4-20500 CDR-L3 QQYHSFPFT 85 B7H4-20500 VH QLQLQESGPGLVKPSETLSLTCTVSGGSIKSGSHYWGWIRQPPGKGLEWIGNIYYSGSTYYNPSLRSRVTISVDTSKNQFSLKLSSVTAADTAVYYCAREGSYPNWFDPWGQGTLVTVSS 86 B7H4-20500 VL EIVMTQSPATLSVSPGERATLSCRASQSVSSNLAWYQQKPGQAPRLLIYGASTRATGIPARFSGSGSGTEFTLTISSLQSEDFAVYYCQQYHSFPFTFGGGTKVEIK 87 B7H4-20501 CDR-H1 GSIKSGSHYWG 88 B7H4-20501 CDR-H2 NIYYSGSTYYNPSLKS 89 B7H4-20501 CDR-H3 AREGSYPNWLDP 90 B7H4-20501 CDR-L1 RASQSVSSNLA 91 B7H4-20501 CDR-L2 GASTRAT 92 B7H4-20501 CDR-L3 QQYHSFPFT 93 B7H4-20501 VH QLQLQESGPGLVKPSETLSLTCTVSGGSIKSGSHYWGWIRQPPGKGLEWIGNIYYSGSTYYNPSLKSRVTISSVDTSKNQFSLKLSSVTAADTAVYYCAREGSYPNWLDPWGQGTLVTVSS 94 B7H4-20501 VL EIVMTQSPATLSVSPGERATLSCRASQSVSSNLAWYQQKPGQAPRLLIYGASTRATGIPARFSGSGSGTEFTLTISSLQSEDFAVYYCQQYHSFPFTFGGGTKVEIK 95 B7H4-20502.1 CDR-H1 GSIKSGSYYWG 96 B7H4-20502.1 CDR-H2 NIYYSGSTYYNPSLKS 97 B7H4-20502.1 CDR-H3 AREGSYPNQFDP 98 B7H4-20502.1 CDR-L1 RASQSVSSNLA 99 B7H4-20502.1 CDR-L2 GASTRAT 100 B7H4-20502.1 CDR-L3 QQYHSFPFT 101 B7H4-20502.1 VH QLQLQESGPGLVKPSETLSLTCTVSGGSIKSGSYYWGWIRQPPGKGLEWIGNIYYSGSTYYNPSLKSRVTISSVDTSKNQFSLKLSSVTAADTAVYYCAREGSYPNQFDPWGQGILVTVSS 102 B7H4-20502.1 VL EIVMTQSPATLSVSPGERATLSCRASQSVSSNLAWYQQKPGQAPRLLIYGASTRATGIPARFSGSGSGTEFTLTISSLQSEDFAVYYCQQYHSFPFTFGGGTKVEIK 103 B7H4-22208 CDR-H1 GSIKSGSHYWG 104 B7H4-22208 CDR-H2 NIYYSGSTYYNPSLKS 105 B7H4-22208 CDR-H3 AREGSYPNWFDP 106 B7H4-22208 CDR-L1 RASQSVSTNLA 107 B7H4-22208 CDR-L2 DASARVT 108 B7H4-22208 CDR-L3 QQYHSFPFT 109 B7H4-22208 VH QLQLQESGPGLVKPSETLSLTCTVSGGSIKSGSHYWGWIRQPPGKGLEWIGNIYYSGSTYYNPSLKSRVTMSVDTSKNQFSLKLSSVTAADTAVYYCAREGSYPNWFDPWGQGTLVTVSS 110 B7H4-22208 VL EIVMTQSPATLSVSPGERATLSCRASQSVSTNLAWYQQKPGQAPRLLIYDASARVTGIPARFSGSGSGTEFTLTISSLQSEDFAVYYCQQYHSFPFTFGGGTKVEIK 111 B7H4-15462 CDR-H1 GSISSSSYYWG 112 B7H4-15462 CDR-H2 NIYYSGSTYYNPSLKS 113 B7H4-15462 CDR-H3 AREGSYTTVLNV 114 B7H4-15462 CDR-L1 RASQSVSSSYLA 115 B7H4-15462 CDR-L2 GASSRAT 116 B7H4-15462 CDR-L3 QQAASYPLT 117 B7H4-15462 VH QLQLQESGPGLVKPSETLSLTCTVSGGSISSSSYYWGWIRQPPGKGLEWIGNIYYSGSTYYNPSLKSRVTISSVDTSKNQFSLKLSSVTAADTAVYYCAREGSYTTVLNVWGQGTMVTVSS 118 B7H4-15462 VL EIVLTQSPGTLSLSPGERATLSCRASQSVSSSYLAWYQQKPGQAPRLLIYGASSRATGIPDRFSGSGSGTDFTLTISRLEPEDFAVYYCQQAASYPLTFGGGTKVEIK 119 B7H4-22213 CDR-H1 GSIGRGSYYWG 120 B7H4-22213 CDR-H2 NIYYSGSTYYNPSLKS 121 B7H4-22213 CDR-H3 AREGSYTTVLNV 122 B7H4-22213 CDR-L1 RASQSVASSHLA 123 B7H4-22213 CDR-L2 DAVSRAT 124 B7H4-22213 CDR-L3 QQAASYPLT 125 B7H4-22213 VH QLQLQESGPGLVKPSETLSLTCTVSGGSIGRGSYYWGWIRQPPGKGLEWIGNIYYSGSTYYNPSLKSRVTISSVDTSKNQFSLKLSSVTAADTAVYYCAREGSYTTVLNVWGQGTMVTVSS 126 B7H4-22213 VL EIVLTQSPGTLSLSPGERATLSCRASQSVASSHLAWYQQKPGQAPRLLIYDAVSRATGIPDRFSGSGSGTDFTLTISRLEPEDFAVYYCQQAASYPLTFGGGTKVEIK 127 B7H4-15465 CDR-H1 GSISSGGYYWS 128 B7H4-15465 CDR-H2 NIYYSGSTYYNPSLKS 129 B7H4-15465 CDR-H3 ARESSTISADFDL 130 B7H4-15465 CDR-L1 RASQGISRWLA 131 B7H4-15465 CDR-L2 AASSLQS 132 B7H4-15465 CDR-L3 QQAHTFPYT 133 B7H4-15465 VH QVQLQESGPGLVKPSQTLSLTCTVSGGSISSGGYYWSWIRQHPGKGLEWIGNIYYSGSTYYNPSLKSRVTISSVDTSKNQFSLKLSSVTAADTAVYYCARESSTISADFDLWGRGTLVTVSS 134 B7H4-15465 VL DIQMTQSPSSVSASVGDRVTITCRASQGISRWLAWYQQKPGKAPKLLIYAASSLQSGVPSRFSGSGSGTDFTLTISSLQPEDFATYYCQQAHTFPYTFGGGTKVEIK 135 B7H4-20506 CDR-H1 GSISHGGYYWS 136 B7H4-20506 CDR-H2 NIYYSGSTYYNPSLKS 137 B7H4-20506 CDR-H3 ARESSTISADFDL 138 B7H4-20506 CDR-L1 RASQGISRWLA 139 B7H4-20506 CDR-L2 AASSLQS 140 B7H4-20506 CDR-L3 QQAHTFPYT 141 B7H4-20506 VH QLQLQESGPGLVKPSETLSLTCTASGGSISHGGYYWSWIRQHPGKGLEWIGNIYYSGSTYYNPSLKSRVTMSVDTSKNQFSLKLSSVTAADTAVYYCARESSTISADFDLWGRGTLVTVSS 142 B7H4-20506 VL DIQMTQSPSSVSASVGDRVTITCRASQGISRWLAWYQQKPGKAPKLLIYAASSLQSGVPSRFSGSGSGTDFTLTISSLQPEDFATYYCQQAHTFPYTFGGGTKVEIK 143 B7H4-15483 CDR-H1 GSISSGGYYWS 144 B7H4-15483 CDR-H2 NIYYSGSTYYNPSLKS 145 B7H4-15483 CDR-H3 ARGLSTIDEAFDP 146 B7H4-15483 CDR-L1 RASQSISSWLA 147 B7H4-15483 CDR-L2 KASSLES 148 B7H4-15483 CDR-L3 QQDNSYPYT 149 B7H4-15483 VH QVQLQESGPGLVKPSQTLSLTCTVSGGSISSGGYYWSWIRQHPGKGLEWIGNIYYSGSTYYNPSLKSRVTISSVDTSKNQFSLKLSSVTAADTAVYYCARGLSTIDEAFDPWGQGTLVTVSS 150 B7H4-15483 VL DIQMTQSPSTLSASSVGDRVTITCRASQSISSWLAWYQQKPGKAPKLLIYKASSLESGVPSRFSGSGSGTEFTLTISSLQPDDFATYYCQQDNSYPYTFGGGTKVEIK 151 B7H4-20513 CDR-H1 GSISDGSYYWS 152 B7H4-20513 CDR-H2 NIYYSGSTYYNPSLRS 153 B7H4-20513 CDR-H3 ARGLSTIDEAFDP 154 B7H4-20513 CDR-L1 RASQSISSWLA 155 B7H4-20513 CDR-L2 KASSLES 156 B7H4-20513 CDR-L3 QQDNSYPYT 157 B7H4-20513 VH QLQLQESGPGLVKPSETLSLTCTVSGGSISDGSYYWSWIRQHPGKGLEWIGNIYYSGSTYYNPSLRSRVTMSVDTSKNQFSLKLSSVTAADTAVYYCARGLSTIDEAFDPWGQGTLVTVSS 158 B7H4-20513 VL DIQMTQSPSTLSASSVGDRVTITCRASQSISSWLAWYQQKPGKAPKLLIYKASSLESGVPSRFSGSGSGTEFTLTISSLQPDDFATYYCQQDNSYPYTFGGGTKVEIK 159 B7H4-22216 CDR-H1 GSISDGSYYWS 160 B7H4-22216 CDR-H2 NIYYSGSTYYNPSLRS 161 B7H4-22216 CDR-H3 ARGLSTIDEAFDP 162 B7H4-22216 CDR-L1 RASKSISSWLA 163 B7H4-22216 CDR-L2 EASSLHS 164 B7H4-22216 CDR-L3 QQDNSYPYT 165 B7H4-22216 VH QVQLQESGPGLVKPSQTLSLTCTVSGGSISDGSYYWSWIRQHPGKGLEWIGNIYYSGSTYYNPSLRSRVTMSVDTSKNQFSLKLSSVTAADTAVYYCARGLSTIDEAFDPWGQGTLVTVSS 166 B7H4-22216 VL DIQMTQSPSTLSASSVGDRVTITCRASKSISSWLAWYQQKPGKAPKLLIYEASSLHSGVPSRFSGSGSGTEFTLTISSLQPDDFATYYCQQDNSYPYTFGGGTKVEIK 167 B7H4-15489 CDR-H1 GSISSYYWS 168 B7H4-15489 CDR-H2 YIYSSGSTNYNPSLKS 169 B7H4-15489 CDR-H3 ARGSGQYAAPDYGMD 170 B7H4-15489 CDR-L1 RASQSISSWLA 171 B7H4-15489 CDR-L2 KASSLES 172 B7H4-15489 CDR-L3 QQDNSFPFT 173 B7H4-15489 VH QVQLQESGPGLVKPSETLSLTCTVSGGSISSYYWSWIRQPPGKGLEWIGYIYSSGSTNYNPSLKSRVTISSVDTSKNQFSLKLSSVTAADTAVYYCARGSGQYAAPDYGMDVWGQGTTVTVSS 174 B7H4-15489 VL DIQMTQSPSTLSASSVGDRVTITCRASQSISSWLAWYQQKPGKAPKLLIYKASSLESGVPSRFSGSGSGTEFTLTISSLQPDDFATYYCQQDNSFPFTFGGGTKVEIK 175 B7H4-20516 CDR-H1 GSIISYYWG 176 B7H4-20516 CDR-H2 YIYSSGSTSYNPSLKS 177 B7H4-20516 CDR-H3 ARGSGLYAAPDYGLDV 178 B7H4-20516 CDR-L1 RASQSISSWLA 179 B7H4-20516 CDR-L2 KASSLES 180 B7H4-20516 CDR-L3 QQDNSFPFT 181 B7H4-20516 VH QVQLQESGPGLVKPSETLSLTCTVSGGSIISYYWGWIRQPPGKGLEWIGYIYSSGSTSYNPSLKSRVTISSVDTSKNQFSLKLSSVTAADTAVYYCARGSGLYAAPDYGLDVWGQGTTVTVSS 182 B7H4-20516 VL DIQMTQSPSTLSASSVGDRVTITCRASQSISSWLAWYQQKPGKAPKLLIYKASSLESGVPSRFSGSGSGTEFTLTISSLQPDDFATYYCQQDNSFPFTFGGGTKVEIK 183 B7H4-15472 CDR-H1 FTFSSYAMS 184 B7H4-15472 CDR-H2 TISGSGGSTYYADSVKG 185 B7H4-15472 CDR-H3 ARGAGHYDLVGRY 186 B7H4-15472 CDR-L1 RASQSISSYLN 187 B7H4-15472 CDR-L2 AASSLQS 188 B7H4-15472 CDR-L3 QQLYSLPPT 189 B7H4-15472 VH EVQLLESGGGLVQPGGSLRLSCAASGFTFSSYAMSWVRQAPGKGLEWVSTISGSGGSTYYADSVKGRFTISRDNSKNTLYLQMNSLRAEDTAVYYCARGAGHYDLVGRYWGQGTLVTVSS 190 B7H4-15472 VL DIQMTQSPSSSLSASVGDRVTITCRASQSISSYLNWYQQKPGKAPKLLIYAASSLQSGVPSRFSGSGSGTDFTLTISSLQPEDFATYYCQQLYSLPPTFGGGTKVEIK 191 B7H4-15503 CDR-H1 FTFSSYAMS 192 B7H4-15503 CDR-H2 AISGSGGSTYYADSVKG 193 B7H4-15503 CDR-H3 ARVGFRALNY 194 B7H4-15503 CDR-L1 RASQDISSWLA 195 B7H4-15503 CDR-L2 AASSLQS 196 B7H4-15503 CDR-L3 QQATSYPPWT 197 B7H4-15503 VH EVQLLESGGGLVQPGGSLRLSCAASGFTFSSYAMSWVRQAPGKGLEWVSAISGSGGSTYYADSVKGRFTISRDNSKNTLYLQMNSLRAEDTAVYYCARVGFRALNYWGQGTTVTVSS 198 B7H4-15503 VL DIQLTQSPSSVSASVGDRVTITCRASQDISSWLAWYQQKPGKAPKLLIYAASSLQSGVPSRFSGSGSGTDFTLTISSLQPEDFATYYCQQATSYPPWTFGGGTKVEIK 199 B7H4-15495 CDR-H1 GTFSSYAIS 200 B7H4-15495 CDR-H2 GIIPIFGTASYAQKFQG 201 B7H4-15495 CDR-H3 ARQQYDGRRYFGL 202 B7H4-15495 CDR-L1 RASQSVSSNLA 203 B7H4-15495 CDR-L2 SASTRAT 204 B7H4-15495 CDR-L3 QQVNVWPPT 205 B7H4-15495 VH QVQLVQSGAEVKKPGSSVKVSCKASGGTFSSYAISWVRQAPGQGLEWMGGIIPIFGTASYAQKFQGRVTITADESTSTAYMELSSLRSEDTAVYYCARQQYDGRRYFGLWGRGTLVTVSS 206 B7H4-15495 VL EIVMTQSPATLSVSPGERATLSCRASQSVSSNLAWYQQKPGQAPRLLIYSASTRATGIPARFSGSGSGTEFTLTISSLQSEDFAVYYCQQVNVWPPTFGGGTKVEIK 207 B7H4-15478 CDR-H1 GTFSSYAIS 208 B7H4-15478 CDR-H2 GIIPIFGTANYAQKFQG 209 B7H4-15478 CDR-H3 ARGGPWFDP 210 B7H4-15478 CDR-L1 RASQSISSWLA 211 B7H4-15478 CDR-L2 KASSLES 212 B7H4-15478 CDR-L3 QQYNSYPPFT 213 B7H4-15478 VH QVQLVQSGAEVKKPGSSVKVSCKASGGTFSSYAISWVRQAPGQGLEWMGGIIPIFGTANYAQKFQGRVTITADESTSTAYMELSSLRSEDTAVYYCARGGPWFDPWGQGTLVTVSS 214 B7H4-15478 VL DIQMTQSPSTLSASSVGDRVTITCRASQSISSWLAWYQQKPGKAPKLLIYKASSLESGVPSRFSGSGSGTEFTLTISSLQPDDFATYYCQQYNSYPPFTFGGGTKVEIK 215 B7H4-15441 CDR-H1 FTFSSYAMS 216 B7H4-15441 CDR-H2 AISGSGGSTSYADSVKG 217 B7H4-15441 CDR-H3 AKPSLATMLAFDI 218 B7H4-15441 CDR-L1 RASQSISSWLA 219 B7H4-15441 CDR-L2 DASSLES 220 B7H4-15441 CDR-L3 QQSKSYPRT 221 B7H4-15441 VH EVQLLESGGGLVQPGGSLRLSCAASGFTFSSYAMSWVRQAPGKGLEWVSAISGSGGSTSYADSVKGRFTISRDNSKNTLYLQMNSLRAEDTAVYYCAKPSLATMLAFDIWGQGTMVTVSS 222 B7H4-15441 VL DIQMTQSPSTLSASSVGDRVTITCRASQSISSWLAWYQQKPGKAPKLLIYDASSLESGVPSRFSGSGSGTEFTLTISSLQPDDFATYYCQQSKSYPRTFGGGTKVEIK 223 B7H4-20496 CDR-H1 GSISSSVYYWS 224 B7H4-20496 CDR-H2 SILVSGSTYYNPSLKS 225 B7H4-20496 CDR-H3 ARAVSFLDV 226 B7H4-20496 CDR-L1 RASQSISSYLN 227 B7H4-20496 CDR-L2 GASSLQS 228 B7H4-20496 CDR-L3 QQQSYDPPWT 229 B7H4-20496 VH QLQLQESGPGLVKPSETLSLTCTVSGGSISSSVYYWSWIRQPPGKGLEWIGSILVSGSTYYNPSLKSRVTISSVDTSKNQFSLKLSSVTAADTAVYYCARAVSFLDVWGQGTMVIVSS 230 B7H4-20496 VL DIQMTQSPSSSLSASVGDRVTITCRASQSISSYLNWYQQKPGKAPKLLIYGASSLQSGVPSRFSGSGSGTDFTLTISSLQPEDFATYYCQQSYDPPWTFGGGTKVEIK 231 B7H4-15461 HC QLQLQESGPGLVKPSETLSLTCTVSGGSISSSSYYWGWIRQPPGKGLEWIGNIYYSGSTYYNPSLKSRVTISSVDTSKNQFSLKLSSVTAADTAVYYCAREGSYPNWFDPWGQ GTLVTVSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKKVEPKSCDK THTCPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEK TISKAKGQPREPQVYTLPPSRDELTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGK 232 B7H4-15461 LC EIVMTQSPATLSVSPGERATLSCRASQSVSSNLAWYQQKPGQAPRLLIYGASTRATGIPARFSGSGSGTEFTLTISSLQSEDFAVYYCQQYHSFPFTFGGGTKVEIK RTVAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC 233 B7H4-20500 HC QLQLQESGPGLVKPSETLSLTCTVSGGSIKSGSHYWGWIRQPPGKGLEWIGNIYYSGSTYYNPSLRSRVTISVDTSKNQFSLKLSSVTAADTAVYYCAREGSYPNWFDPWGQ GTLVTVSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKKVEPKSCDK THTCPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEK TISKAKGQPREPQVYTLPPSRDELTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGK 234 B7H4-20500 LC EIVMTQSPATLSVSPGERATLSCRASQSVSSNLAWYQQKPGQAPRLLIYGASTRATGIPARFSGSGSGTEFTLTISSLQSEDFAVYYCQQYHSFPFTFGGGTKVEIK RTVAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC 235 B7H4-20501 HC QLQLQESGPGLVKPSETLSLTCTVSGGSIKSGSHYWGWIRQPPGKGLEWIGNIYYSGSTYYNPSLKSRVTISSVDTSKNQFSLKLSSVTAADTAVYYCAREGSYPNWLDPWGQ GTLVTVSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKKVEPKSCDK THTCPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEK TISKAKGQPREPQVYTLPPSRDELTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGK 236 B7H4-20501 LC EIVMTQSPATLSVSPGERATLSCRASQSVSSNLAWYQQKPGQAPRLLIYGASTRATGIPARFSGSGSGTEFTLTISSLQSEDFAVYYCQQYHSFPFTFGGGTKVEIK RTVAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC 237 B7H4-20502.1 HC QLQLQESGPGLVKPSETLSLTCTVSGGSIKSGSYYWGWIRQPPGKGLEWIGNIYYSGSTYYNPSLKSRVTISSVDTSKNQFSLKLSSVTAADTAVYYCAREGSYPNQFDPWGQ GILVTVSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKKVEPKSCDK THTCPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEK TISKAKGQPREPQVYTLPPSRDELTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGK 238 B7H4-20502.1 LC EIVMTQSPATLSVSPGERATLSCRASQSVSSNLAWYQQKPGQAPRLLIYGASTRATGIPARFSGSGSGTEFTLTISSLQSEDFAVYYCQQYHSFPFTFGGGTKVEIK RTVAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC 239 B7H4-22208 HC QLQLQESGPGLVKPSETLSLTCTVSGGSIKSGSHYWGWIRQPPGKGLEWIGNIYYSGSTYYNPSLKSRVTMSVDTSKNQFSLKLSSVTAADTAVYYCAREGSYPNWFDPWGQ GTLVTVSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKKVEPKSCDK THTCPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEK TISKAKGQPREPQVYTLPPSRDELTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGK 240 B7H4-22208 LC EIVMTQSPATLSVSPGERATLSCRASQSVSTNLAWYQQKPGQAPRLLIYDASARVTGIPARFSGSGSGTEFTLTISSLQSEDFAVYYCQQYHSFPFTFGGGTKVEIK RTVAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC 241 B7H4-15462 HC QLQLQESGPGLVKPSETLSLTCTVSGGSISSSSYYWGWIRQPPGKGLEWIGNIYYSGSTYYNPSLKSRVTISSVDTSKNQFSLKLSSVTAADTAVYYCAREGSYTTVLNVWGQ GTMVTVSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKKVEPKSCDK THTCPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEK TISKAKGQPREPQVYTLPPSRDELTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGK 242 B7H4-15462 LC EIVLTQSPGTLSLSPGERATLSCRASQSVSSSYLAWYQQKPGQAPRLLIYGASSRATGIPDRFSGSGSGTDFTLTISRLEPEDFAVYYCQQAASYPLTFGGGTKVEI KRTVAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC 243 B7H4-22213 HC QLQLQESGPGLVKPSETLSLTCTVSGGSIGRGSYYWGWIRQPPGKGLEWIGNIYYSGSTYYNPSLKSRVTISSVDTSKNQFSLKLSSVTAADTAVYYCAREGSYTTVLNVWGQ GTMVTVSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKKVEPKSCDK THTCPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEK TISKAKGQPREPQVYTLPPSRDELTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGK 244 B7H4-22213 LC EIVLTQSPGTLSLSPGERATLSCRASQSVASSHLAWYQQKPGQAPRLLIYDAVSRATGIPDRFSGSGSGTDFTLTISRLEPEDFAVYYCQQAASYPLTFGGGTKVEI KRTVAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC 245 B7H4-15465 HC QVQLQESGPGLVKPSQTLSLTCTVSGGSISSGGYYWSWIRQHPGKGLEWIGNIYYSGSTYYNPSLKSRVTISSVDTSKNQFSLKLSSVTAADTAVYYCARESSTISADFDLWG RGTLVTVSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKKVEPKSCD KTHTCPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEK TISKAKGQPREPQVYTLPPSRDELTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGK 246 B7H4-15465 LC DIQMTQSPSSVSASVGDRVTITCRASQGISRWLAWYQQKPGKAPKLLIYAASSLQSGVPSRFSGSGSGTDFTLTISSLQPEDFATYYCQQAHTFPYTFGGGTKVEIK RTVAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC 247 B7H4-20506 HC QLQLQESGPGLVKPSETLSLTCTASGGSISHGGYYWSWIRQHPGKGLEWIGNIYYSGSTYYNPSLKSRVTMSVDTSKNQFSLKLSSVTAADTAVYYCARESSTISADFDLWG RGTLVTVSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKKVEPKSCD KTHTCPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEK TISKAKGQPREPQVYTLPPSRDELTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGK 248 B7H4-20506 LC DIQMTQSPSSVSASVGDRVTITCRASQGISRWLAWYQQKPGKAPKLLIYAASSLQSGVPSRFSGSGSGTDFTLTISSLQPEDFATYYCQQAHTFPYTFGGGTKVEIK RTVAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC 249 B7H4-15483 HC QVQLQESGPGLVKPSQTLSLTCTVSGGSISSGGYYWSWIRQHPGKGLEWIGNIYYSGSTYYNPSLKSRVTISSVDTSKNQFSLKLSSVTAADTAVYYCARGLSTIDEAFDPWG QGTLVTVSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKKVEPKSCD KTHTCPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEK TISKAKGQPREPQVYTLPPSRDELTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGK 250 B7H4-15483 LC DIQMTQSPSTLSASSVGDRVTITCRASQSISSWLAWYQQKPGKAPKLLIYKASSLESGVPSRFSGSGSGTEFTLTISSLQPDDFATYYCQQDNSYPYTFGGGTKVEIK RTVAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC 251 B7H4-20513 HC QLQLQESGPGLVKPSETLSLTCTVSGGSISDGSYYWSWIRQHPGKGLEWIGNIYYSGSTYYNPSLRSRVTMSVDTSKNQFSLKLSSVTAADTAVYYCARGLSTIDEAFDPWG QGTLVTVSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKKVEPKSCD KTHTCPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEK TISKAKGQPREPQVYTLPPSRDELTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGK 252 B7H4-20513 LC DIQMTQSPSTLSASSVGDRVTITCRASQSISSWLAWYQQKPGKAPKLLIYKASSLESGVPSRFSGSGSGTEFTLTISSLQPDDFATYYCQQDNSYPYTFGGGTKVEIK RTVAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC 253 B7H4-22216 HC QVQLQESGPGLVKPSQTLSLTCTVSGGSISDGSYYWSWIRQHPGKGLEWIGNIYYSGSTYYNPSLRSRVTMSVDTSKNQFSLKLSSVTAADTAVYYCARGLSTIDEAFDPWG QGTLVTVSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKKVEPKSCD KTHTCPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEK TISKAKGQPREPQVYTLPPSRDELTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGK 254 B7H4-22216 LC DIQMTQSPSTLSASSVGDRVTITCRASKSISSWLAWYQQKPGKAPKLLIYEASSLHSGVPSRFSGSGSGTEFTLTISSLQPDDFATYYCQQDNSYPYTFGGGTKVEIK RTVAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC 255 B7H4-15489 HC QVQLQESGPGLVKPSETLSLTCTVSGGSISSYYWSWIRQPPGKGLEWIGYIYSSGSTNYNPSLKSRVTISSVDTSKNQFSLKLSSVTAADTAVYYCARGSGQYAAPDYGMDVWG QGTTVTVSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKKVEPKSCD KTHTCPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEK TISKAKGQPREPQVYTLPPSRDELTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGK 256 B7H4-15489 LC DIQMTQSPSTLSASSVGDRVTITCRASQSISSWLAWYQQKPGKAPKLLIYKASSLESGVPSRFSGSGSGTEFTLTISSLQPDDFATYYCQQDNSFPFTFGGGTKVEIK RTVAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC 257 B7H4-20516 HC QVQLQESGPGLVKPSETLSLTCTVSGGSIISYYWGWIRQPPGKGLEWIGYIYSSGSTSYNPSLKSRVTISSVDTSKNQFSLKLSSVTAADTAVYYCARGSGLYAAPDYGLDVWG QGTTVTVSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKKVEPKSCD KTHTCPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEK TISKAKGQPREPQVYTLPPSRDELTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGK 258 B7H4-20516 LC DIQMTQSPSTLSASSVGDRVTITCRASQSISSWLAWYQQKPGKAPKLLIYKASSLESGVPSRFSGSGSGTEFTLTISSLQPDDFATYYCQQDNSFPFTFGGGTKVEIK RTVAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC 259 B7H4-15472 HC EVQLLESGGGLVQPGGSLRLSCAASGFTFSSYAMSWVRQAPGKGLEWVSTISGSGGSTYYADSVKGRFTISRDNSKNTLYLQMNSLRAEDTAVYYCARGAGHYDLVGRYWGQ GTLVTVSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKKVEPKSCDK THTCPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEK TISKAKGQPREPQVYTLPPSRDELTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGK 260 B7H4-15472 LC DIQMTQSPSSSLSASVGDRVTITCRASQSISSYLNWYQQKPGKAPKLLIYAASSLQSGVPSRFSGSGSGTDFTLTISSLQPEDFATYYCQQLYSLPPTFGGGTKVEIK RTVAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC 261 B7H4-15503 HC EVQLLESGGGLVQPGGSLRLSCAASGFTFSSYAMSWVRQAPGKGLEWVSAISGSGGSTYYADSVKGRFTISRDNSKNTLYLQMNSLRAEDTAVYYCARVGFRALNYWGQGT TVTVSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKKVEPKSCDKT HTCPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKT ISKAKGQPREPQVYTLPPSRDELTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGK 262 B7H4-15503 LC DIQLTQSPSSVSASVGDRVTITCRASQDISSWLAWYQQKPGKAPKLLIYAASSLQSGVPSRFSGSGSGTDFTLTISSLQPEDFATYYCQQATSYPPWTFGGGTKVEI KRTVAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC 263 B7H4-15495 HC QVQLVQSGAEVKKPGSSVKVSCKASGGTFSSYAISWVRQAPGQGLEWMGGIIPIFGTASYAQKFQGRVTITADESTSTAYMELSSLRSEDTAVYYCARQQYDGRRYFGLWGR GTLVTVSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKKVEPKSCDK THTCPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEK TISKAKGQPREPQVYTLPPSRDELTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGK 264 B7H4-15495 LC EIVMTQSPATLSVSPGERATLSCRASQSVSSNLAWYQQKPGQAPRLLIYSASTRATGIPARFSGSGSGTEFTLTISSLQSEDFAVYYCQQVNVWPPTFGGGTKVEIK RTVAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC 265 B7H4-15478 HC QVQLVQSGAEVKKPGSSVKVSCKASGGTFSSYAISWVRQAPGQGLEWMGGIIPIFGTANYAQKFQGRVTITADESTSTAYMELSSLRSEDTAVYYCARGGPWFDPWGQGTL VTVSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKKVEPKSCDKTH TCPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKT ISKAKGQPREPQVYTLPPSRDELTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGK 266 B7H4-15478 LC DIQMTQSPSTLSASSVGDRVTITCRASQSISSWLAWYQQKPGKAPKLLIYKASSLESGVPSRFSGSGSGTEFTLTISSLQPDDFATYYCQQYNSYPPFTFGGGTKVEI KRTVAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC 267 B7H4-15441 HC EVQLLESGGGLVQPGGSLRLSCAASGFTFSSYAMSWVRQAPGKGLEWVSAISGSGGSTSYADSVKGRFTISRDNSKNTLYLQMNSLRAEDTAVYYCAKPSLATMLAFDIWGQ GTMVTVSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKKVEPKSCDK THTCPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEK TISKAKGQPREPQVYTLPPSRDELTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGK 268 B7H4-15441 LC DIQMTQSPSTLSASSVGDRVTITCRASQSISSWLAWYQQKPGKAPKLLIYDASSLESGVPSRFSGSGSGTEFTLTISSLQPDDFATYYCQQSKSYPRTFGGGTKVEIK RTVAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC 269 B7H4-20496 HC QLQLQESGPGLVKPSETLSLTCTVSGGSISSSVYYWSWIRQPPGKGLEWIGSILVSGSTYYNPSLKSRVTISSVDTSKNQFSLKLSSVTAADTAVYYCARAVSFLDVWGQGT MVIVSSASTKGPSVFPLAPSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKKVEPKSCDKT HTCPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKT ISKAKGQPREPQVYTLPPSRDELTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGK 270 B7H4-20496 LC DIQMTQSPSSSLSASVGDRVTITCRASQSISSYLNWYQQKPGKAPKLLIYGASSLQSGVPSRFSGSGSGTDFTLTISSLQPEDFATYYCQQSYDPPWTFGGGTKVEIK RTVAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC 271 SG-559-01/PD-L1 CDR-H1 TAAIS 272 SG-559-01/PD-L1 CDR-H2 GIIPIFGKAHYAQKFQG 273 SG-559-01/PD-L1 CDR-H3 KFHFVSGSPFGMDV 274 SG-559-01/PD-L1 CDR-L1 RASQSVSSYLA 275 SG-559-01/PD-L1 CDR-L2 DASNRAT 276 SG-559-01/PD-L1 CDR-L3 QQRSNWPT 277 SG-559-01/PD-L1 VH QVQLVQSGAEVKKPGSSVKVSCKTSGDTFSTAAISWVRQAPGQGLEWMGGIIPIFGKAHYAQKFQGRVTITADESTSTAYMELSSLRSEDTAVYFCARKFHFVSGSPFGMDVWGQGTTVTVSS 278 SG-559-01/PD-L1 VL EIVLTQSPATLSLSPGERATLSCRASQSVSSYLAWYQQKPGQAPRLLIYDASNRATGIPARFSGSGSGTDFTLTISSLEPEDFAVYYCQQRSNWPTFGQGTKVEIK 279 h1F6 CDR-H1 NYGMN 280 h1F6 CDR-H2 WINTYTGEPTYADAFKG 281 h1F6 CDR-H3 DYGDYGMDY 282 h1F6 CDR-L1 RASKSVSTSGYSFMH 283 h1F6 CDR-L2 LASNLES 284 h1F6 CDR-L3 QHSREVPWT 285 h1F6 QVQLVQSGAEVKKPGASVKVSCKASGYTFTNYGMNWVRQAPGQGLKWMGWINTYTGEPTYADAFKGRVTMTRDTSISTAYMELSRLRSDDTAVYYCARDYGDYGMDYWGQGTTVTVSS 286 6V DIVMTQSPDSLAVSLGERATINCRASKSVSTSGYSFMHWYQQKPGQPPKLLIYLASNLESGVPDRFSGSGSGTDFTLTISSLQAEDVAVYYCQHSREVPWTFGQGTKVEIK 287 h1F6 QVQLVQSGAEVKKPGASVKVSCKASGYTFTNYGMNWVRQAPGQGLKWMGWINTYTGEPTYADAFKGRVTMTRDTSISTAYMELSRLRSDDTAVYYCARDYGDYGMDYWGQGT TVTVSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKKVEPKSCDKT HTCPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKT ISKAKGQPREPQVYTLPPSRDELTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGK 288 h1F6 LC DIVMTQSPDSLAVSLGERATINCRASKSVSTSGYSFMHWYQQKPGQPPKLLIYLASNLESGVPDRFSGSGSGTDFTLTISSLQAEDVAVYYCQHSREVPWTFGQGTKVE IKRTVAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC 289 TROP2 CDR-H1 NYGMN 290 TROP2 CDR-H2 WINTYTGEPTYTDDFKG 291 TROP2 CDR-H3 GGFGSSYWYFDV 292 TROP2 CDR-L1 KASQDVSIAVA 293 TROP2 CDR-L2 SASYRYT 294 TROP2 CDR-L3 QQHYITPLT 295 TROP2 VH QVQLQQSGSELKKPGASVKVSCKASGYTFTNYGMNWVKQAPGQGLKWMGWINTYTGEPTYTDDFKGRFAFSLDTSVSTAYLQISSLKADDTAVYFCARGGFGSSYWYFDVWGQGSLVTVSS 296 TROP2 VL DIQLTQSPSSSLSASVGDRVSITCKASQDVSIAVAWYQQKPGKAPKLLIYSASYRYTGVPDRFSGSGSGTDFTLTISSLQPEDFAVYYCQQHYITPLTFGAGTKVEIK 297 TROP2 CDR-H1 TAGMQ 298 TROP2 CDR-H2 WINTHSGVPKYAEDFKG 299 TROP2 CDR-H3 SGFGSSYWYFDV 300 TROP2 CDR-L1 KASQDVSTAVA 301 TROP2 CDR-L2 SASYRYT 302 TROP2 CDR-L3 QQHYITPLT 303 TROP2 VH QVQLVQSGAEVKKPGASVKVSCKASGYTFTTAGMQWVRQAPGQGLEWMGWINTHSGVPKYAEDFKGRVTISADTSTSTAYLQLSSLKSEDTAVYYCARSGFGSSYWYFDVWGQGTLVTVSS 304 TROP2 VL DIQMTQSPSSSLSASVGDRVTITCKASQDVSTAVAWYQQKPGKAPKLLIYSASYRYTGVPSRFSGSGSGTDFTLTISSLQPEDFAVYYCQQHYITPLTFGQGTKLEIK 305 MICA CDR-H1 QUR 306 MICA CDR-H2 YIEPYNVVPMYNPKFKG 307 MICA CDR-H3 SGSSNFDY 308 MICA CDR-L1 SASSSISSHYLH 309 MICA CDR-L2 RTSNLAS 310 MICA CDR-L3 QQGSSLPLT 311 MICA VH EIQLVQSGAEVKKPGASVKVSCKASGYAFTSQNIYWVRQAPGQGLEWIGYIEPYNVVPMYNPKFKGRATLTVDKSTSTAYLELSSLRSEDTAVYYCARSGSSNFDYWGQGTLVTVSS 312 MICA VL DIQLTQSPSSSLSASVGDRVTITCSASSSISSHYLHWYQQKPGKSPKLLIYRTSNLASGVPSRFSGSGSGTDYTLTISSLQPEDFATYYCQQGSSLPLTFGQGTKVEIK 313 MICA CDR-H1 NYAMH 314 MICA CDR-H2 LIWYDGSNKFYGDSVKG 315 MICA CDR-H3 EGSGHY 316 MICA CDR-L1 RASQGISSALA 317 MICA CDR-L2 DASSLES 318 MICA CDR-L3 QQFNSYPIT 319 MICA VH QVQLVESGGGVVQPGRSLRLSCAASGFTFSNYAMHWVRQAPGEGLEWVALIWYDGSNKFYGDSVKGRFTISRDNSKNTLYLQMNSLSAEDTAVYYCAREGSGHYWGQGTLVTVSS 320 MICA VL AIQLTQSPSSSLSASVGDRVTITCRASQGISSALAWYQQKPGKVPKSLIYDASSLESGVPSRFSGSGSGTDFTLTISSLQPEDFATYYCQQFNSYPITFGQGTRLEIK 321 MICA CDR-H1 NYAMS 322 MICA CDR-H2 YISPGGDYIYYADSVKG 323 MICA CDR-H3 DRRHYGSYAMDY 324 MICA CDR-L1 RSSKSLLHSNLNTYLY 325 MICA CDR-L2 RMSNLAS 326 MICA CDR-L3 MQHLEYPFT 327 MICA VH QVQLVESGGGLVKPGGSLRLSCAASGFTFSNYAMSWIRQAPGKGLEWVSYISPGGDYIYYADSVKGRFTISRDNAKNSLYLQMNSLRAEDTAVYYCTTDRRHYGSYAMDYWGQGTLVTVSS 328 MICA VL DIVMTQSPLSLPVTPGEPASISCRSSKSLLHSNLNTYLYWFLQKPGQSPQILIYRMSNLASGVPDRFSGSGSGTAFTLKISRVEAEDVGVYYCMQHLEYPFTFGPGTKLEIK 329 MICA CDR-H1 TYAFH 330 MICA CDR-H2 GIVPIFGTLKYAQKFQD 331 MICA CDR-H3 AIQLEGRPFDH 332 MICA CDR-L1 RASQGITSYLA 333 MICA CDR-L2 AASALQS 334 MICA CDR-L3 QQVNRGAAIT 335 MICA VH QVQLVQSGAEVKKPGSSVRVSCRASGGSSTTYAFHWVRQAPGQGLEWMGGIVPIFGTLKYAQKFQDRVTLTADKSTGTAYMELNSLRLDDTAVYYCARAIQLEGRPFDHWGQGTQVTVSA 336 MICA VL DIQLTQSPSFLSASVGDRVTITCRASQGITSYLAWYQQKPGKAPKLLIYAASALQSGVPSRFSGRGSGTEFTLTISSLQPEDFATYYCQQVNRGAAITFGHGTRLDIK 337 ITGav/CD51 CDR-H1 RYTMH 338 ITGav/CD51 CDR-H2 VISFDGSNKYYVDSVKG 339 ITGav/CD51 CDR-H3 EARGSYAFDI 340 ITGav/CD51 CDR-L1 RASQSVSSYLA 341 ITGav/CD51 CDR-L2 DASNRAT 342 ITGav/CD51 CDR-L3 QQRSNWPPFT 343 ITGav/CD51 VH QVQLVESGGGVVQPGRSRRLSCAASGFTFSRYTMHWVRQAPGKGLEWVAVISFDGSNKYYVDSVKGRFTISRDNSENTLYLQVNILRAEDTAVYYCAREARGSYAFDIWGQGTMVTVSS 344 ITGav/CD51 VL EIVLTQSPATLSLSPGERATLSCRASQSVSSYLAWYQQKPGQAPRLLIYDASNRATGIPARFSGSGSGTDFTLTISSLEPEDFAVYYCQQRSNWPPFTFGPGTKVDIK 345 ITGav/CD51 CDR-H1 SFWMH 346 ITGav/CD51 CDR-H2 YINPRSGYTEYNEIFRD 347 ITGav/CD51 CDR-H3 FLGRGAMDY 348 ITGav/CD51 CDR-L1 RASQDISNYLA 349 ITGav/CD51 CDR-L2 YTSKIHS 350 ITGav/CD51 CDR-L3 QQGNTFPYT 351 ITGav/CD51 VH QVQLQQSGGELAKPGASVKVSCKASGYTFSSFWMHWVRQAPGQGLEWIGYINPRSGYTEYNEIFRDKATMTTDTSTSTAYMELSSLRSEDTAVYYCASFLGRGAMDYWGQGTTVTVSS 352 ITGav/CD51 VL DIQMTQSPSSSLSASVGDRVTITCRASQDISNYLAWYQQKPGKAPKLLIYYTSKIHSGVPSRFSGSGSGTDYTFTISSLQPEDIATYYCQQGNTFPYTFGQGTKVEIK 353 gpA33 CDR-H1 TSSYYWG 354 gpA33 CDR-H2 TIYYNGSTYYSPSLKS 355 gpA33 CDR-H3 QGYDIKINIDV 356 gpA33 CDR-L1 RASQSVSSYLA 357 gpA33 CDR-L2 VASNRAT 358 gpA33 CDR-L3 QQRSNWPLT 359 gpA33 VH QLQLQESGPGLVKPSETLSLTCTVSGGSISTSSYYWGWIRQPPGKGLEWIGTIYYNGSTYYSPSLKSRVSISVDTSKNQFSLKLSSVTAADTSVYYCARQGYDIKINIDVWGQGTTVTVSS 360 gpA33 VL EIVLTQSPATLSLSPGERATLSCRASQSVSSYLAWYQQKPGQAPRLLIYVASNRATGIPARFSGSGSGTDFTLTISSLEPEDFAVYYCQQRSNWPLTFGGGTKVEIK 361 IL1Rap CDR-H1 SSWMN 362 IL1Rap CDR-H2 RIYPGDGNTHYAQKFQG 363 IL1Rap CDR-H3 GYLDPMDY 364 IL1Rap CDR-L1 QASQGINNYLN 365 IL1Rap CDR-L2 YTSGLHA 366 IL1Rap CDR-L3 QQYSILPWT 367 IL1Rap VH QVQLVQSGAEVKKPGSSVKVSCKASGYAFTSSWMNWVRQAPGQGLEWMGRIYPGDGNTHYAQKFQGRVTLTADKSTSTAYMELSSLRSEDTAVYYCGEGYLDPMDYWGQGTLVTVSS 368 IL1Rap VL DIQMTQSPSSSLSASVGDRVTITCQASQGINNYLNWYQQKPGKAPKLLIHYTSGLHAGVPSRFSGSGSGTDYTLTISSLEPEDVATYYCQQYSILPWTFGGGTKVEIK 369 EpCAM CDR-H1 SYGMH 370 EpCAM CDR-H2 VISYDGSNKYYADSVKG 371 EpCAM CDR-H3 DMGWGSGWRPYYYYGMDV 372 EpCAM CDR-L1 RTSQSISSYLN 373 EpCAM CDR-L2 WASTRES 374 EpCAM CDR-L3 QQSYDIPYT 375 EpCAM VH EVQLLESGGGVVQPGRSLRLSCAASGFTFSSYGMHWVRQAPGKGLEWVAVISYDGSNKYYADSVKGRFTISRDNSKNTLYLQMNSLRAEDTAVYYCAKDMGWGSGWRPYYYYGMDVWGQGTTVTVSS 376 EpCAM VL ELQMTQSPSSSLSASVGDRVTITCRTSQSISSYLNWYQQKPGQPPKLLIYWASTRESGVPDRFSGSGSGTDFTLTISSLQPEDSATYYCQQSYDIPYTFGQGTKLEIK 377 EpCAM CDR-H1 NYWMS 378 EpCAM CDR-H2 NIKQDGSEKFYADSVKG 379 EpCAM CDR-H3 VGPSWEQDY 380 EpCAM CDR-L1 TGSSSNIGSYYGVH 381 EpCAM CDR-L2 SDTNRPS 382 EpCAM CDR-L3 QSYDKGFGHRV 383 EpCAM VH EVQLVESGGGLVQPGGSLRLSCAASGFTFSNYWMSWVRQAPGKGLEWVANIKQDGSEKFYADSVKGRFTISRDNAKNSLYLQMNSLRAEDTAVYYCARVGPSWEQDYWGQGTLVTVSA 384 EpCAM VL QSVLTQPPSVSGAPGQRVTISCTGSSSNIGSYYGVHWYQQLPGTAPKLLIYSDTNRPSGVPDRFSGSKSGTSASLAITGLQAEDEADYYCQSYDKGFGHRVFGGGTKLTVL 385 EpCAM CDR-H1 SYAIS 386 EpCAM CDR-H2 GIIPIFGTANYAQKFQG 387 EpCAM CDR-H3 GLLW 388 EpCAM CDR-L1 RASQSVSSNLA 389 EpCAM CDR-L2 GASTTAS 390 EpCAM CDR-L3 QQYNNWPPAYT 391 EpCAM VH QVQLVQSGAEVKKPGSSVKVSCKASGGTFSSYAISWVRQAPGQGLEWMGGIIPIFGTANYAQKFQGRVTITADESTSTAYMELSSLRSEDTAVYYCARGLLWNYWGQGTLVTVSS 392 EpCAM VL EIVMTQSPATLSVSPGERATLSCRASQSVSSNLAWYQQKPGQAPRLIIYGASTTASGIPARFSASGSGTDFTLTISSLQSEDFAVYYCQQYNNWPPAYTFGQGTKLEIK 393 EpCAM CDR-H1 NYGMN 394 EpCAM CDR-H2 WINTYTGEPTYGEDFKG 395 EpCAM CDR-H3 FYVDY 396 EpCAM CDR-L1 RSSKNLLHSNGITYLY 397 EpCAM CDR-L2 QMSNLAS 398 EpCAM CDR-L3 AQNLEIPRT 399 EpCAM VH QVQLVQSGPEVKKPGASVKVSCKASGYTFTNYGMNWVRQAPGQGLEWMGWINTYTGEPTYGEDFKGRFAFSLDTSASTAYMELSSLRSEDTAVYFCARFGNYVDYWGQGSLVTVSS 400 EpCAM VL DIVMTQSPLSLPVTPGEPASISCRSSKNLLHSNGITYLYWYLQKPGQSPQLLIYQMSNLASGVPDRFSSSGSGTDFTLKISRVEAEDVGVYYCAQNLEIPRTFGQGTKVEIK 401 EpCAM CDR-H1 KYGMN 402 EpCAM CDR-H2 WINTYTEEPTYGDDFKG 403 EpCAM CDR-H3 FGSAVDY 404 EpCAM CDR-L1 RSSKSLLHSNGITYLY 405 EpCAM CDR-L2 QMSNRAS 406 EpCAM CDR-L3 AQNLELPRT 407 EpCAM VH QIQLVQSGPEVKKPGESVKISCKASGYTFTKYGMNWVKQAPGQGLKWMGWINTYTEEPTYGDDFKGRFTFTLDTSSTAYLEISSLRSEDTATYFCARFGSAVDYWGQGTLVTVSS 408 EpCAM VL DIVMTQSALSNPVTLGESGSISCRSSKSLLHSNGITYLYWYLQKPGQSPQLLIYQMSNRASGVPDRFSSSGSGTDFTLKISRVEAEDVGVYYCAQNLELPRTFGQGTKLEMKR 409 EpCAM CDR-H1 DYSMH 410 EpCAM CDR-H2 WINTETGEPTYADDFKG 411 EpCAM CDR-H3 TAVY 412 EpCAM CDR-L1 RASQEISVSLS 413 EpCAM CDR-L2 ATSTLDS 414 EpCAM CDR-L3 LQYASYPWT 415 EpCAM VH QVKLQESGPELKKPGETVKISCKASGYTFTDYSMHWVKQAPGKGLKWMGWINTETGEPTYADDFKGRFAFSLETSASTAYLQINNLKNEDTATYFCARTAVYWGQGTTVTVSS 416 EpCAM VL DIQMTQSPSSLSASLGERVSLTCRASQEISVSLSWLQQEPDGTIKRLIYATSTLDSGVPKRFSGSRSGSDYSLTISSLESEDFVDYYCLQYASYPWTFGGGTKLEIKR 417 CD352 CDR-H1 NYGMN 418 CD352 CDR-H2 WINTYSGEPRYADDFKG 419 CD352 CDR-H3 DYNAMIC 420 CD352 CDR-L1 RASSSVSHMH 421 CD352 CDR-L2 ATSNLAS 422 CD352 CDR-L3 QQWSSTPRT 423 CD352 VH QIQLVQSGSELKKPGASVKVSCKASGYTFTNYGMNWVRQAPGQDLKWMGWINTYSGEPRYADDFKGRFVFSLDKSVNTAYLQISSLKAEDTAVYYCARDYGRWYFDVWGQGTTVTVSS 424 CD352 VL QIVLSQSPATLSLSPGERATMSCRASSSVSHMHWYQQKPGQAPRPWIYATSNLASGVPARFSGSGSGTDYTLTISSLEPEDFAVYYCQQWSSTPRTFGGGTKVEIKR 425 CS1/SLAMF7 CDR-H1 RYWMS 426 CS1/SLAMF7 CDR-H2 EINPDSSTINYAPSLKD 427 CS1/SLAMF7 CDR-H3 PDGNYWYFDV 428 CS1/SLAMF7 CDR-L1 KASQDVGIAVA 429 CS1/SLAMF7 CDR-L2 WASTRHT 430 CS1/SLAMF7 CDR-L3 QQYSSYPYT 431 CS1/SLAMF7 VH EVQLVESGGGLVQPGGSLRLSCAASGFDFSRYWMSWVRQAPGKGLEWIGEINPDSSTINYAPSLKDKFIISRDNAKNSLYLQMNSLRAEDTAVYYCARPDGNYWYFDVWGQGTLVTVSS 432 CS1/SLAMF7 VL DIQMTQSPSSSLSASVGDRVTITCKASQDVGIAVAWYQQKPGKVPKLLIYWASTRHTGVPDRFSGSGSGTDFTLTISSLQPEDVATYYCQQYSSYPYTFGQGTKVEIKR 433 CD38 CDR-H1 SFAMS 434 CD38 CDR-H2 AISGSGGGTYYADSVKG 435 CD38 CDR-H3 DKILWFGEPVFDY 436 CD38 CDR-L1 RASQSVSSYLA 437 CD38 CDR-L2 DASNRAT 438 CD38 CDR-L3 QQRSNWPPT 439 CD38 VH EVQLLESGGGLVQPGGSLRLSCAVSGFTFNSFAMSWVRQAPGKGLEWVSAISGSGGGTYYADSVKGRFTISRDNSKNTLYLQMNSLRAEDTAVYFCAKDKILWFGEPVFDYWGQGTLVTVSS 440 CD38 VL EIVLTQSPATLSLSPGERATLSCRASQSVSSYLAWYQQKPGQAPRLLIYDASNRATGIPARFSGSGSGTDFTLTISSLEPEDFAVYYCQQRSNWPPTFGQGTKVEIKR 441 CD25 CDR-H1 SYRMH 442 CD25 CDR-H2 YINPSTGYTEYNQKFKD 443 CD25 CDR-H3 GGGVFDY 444 CD25 CDR-L1 SASSSISYMH 445 CD25 CDR-L2 TTSNLAS 446 CD25 CDR-L3 HQRSTYPLT 447 CD25 VH QVQLVQSGAEVKKPGSSVKVSCKASGYTFTSYRMHWVRQAPGQGLEWIGYINPSTGYTEYNQKFKDKATITADESTNTAYMELSSLRSEDTAVYYCARGGGVFDYWGQGTLVTVSS 448 CD25 VL DIQMTQSPSTLSSASVGDRVTITCSASSSISYMHWYQQKPGKAPKLLIYTTSNLASGVPARFSGSGSGTEFTLTISSLQPDDFATYYCHQRSTYPLTFGQGTKVEVK 449 ADAM9 CDR-H1 SYW 450 ADAM9 CDR-H2 EIIPINGHTNYNEKFKS 451 ADAM9 CDR-H3 GGYYYYGSRDYFDY 452 ADAM9 CDR-L1 KASQSVDYDGDSYMN 453 ADAM9 CDR-L2 AASDLES 454 ADAM9 CDR-L3 QQSHEDPFT 455 ADAM9 VH QVQLQQPGAELVKPGASVKLSCKASGYTFTSYWMHWVKQRPGQGLEWIGEIIPINGHTNYNEKFKSKATLTLDKSSSTAYMQLSSLASEDSAVYYCARGGYYYYGSRDYFDYWGQGTTLTVSS 456 ADAM9 VL DIVLTQSPASLAVSLGQRATISCKASQSVDYDGDSYMNWYQQIPGQPPKLLIYAASDLESGIPARFSGSGSGTDFTLNIHPVEEEDAATYYCQQSHEDPFTFGGGTKLEIK 457 ADAM9 CDR-H1 SYW 458 ADAM9 CDR-H2 EIIPIFGHTNYNEKFKS 459 ADAM9 CDR-H3 GGYYYYPRQGFLDY 460 ADAM9 CDR-L1 KASQSVDYSGDSYMN 461 ADAM9 CDR-L2 AASDLES 462 ADAM9 CDR-L3 QQSHEDPFT 463 ADAM9 VH EVQLVESGGGLVKPGGSLRLSCAASGFTFSSYWMHWVRQAPGKGLEWVGEIIPIFGHTNYNEKFKSRFTISLDNSKNTLYLQMGSLRAEDTAVYYCARGGYYYYPRQGFLDYWGQGTTVTVSS 464 ADAM9 VL DIVMTQSPDSLAVSLGERATISCKASQSVDYSGDSYMNWYQQKPGQPPKLLIYAASDLESGIPARFSGSGSGTDFTLTISSLEPEDFATYYCQQSHEDPFTFGQGTKLEIK 465 CD59 CDR-H1 SYGMN 466 CD59 CDR-H2 YISSSSSTIYYADSVKG 467 CD59 CDR-H3 GPGMDV 468 CD59 CDR-L1 KSSQSVLYSSNNKNYLA 469 CD59 CDR-L2 WASTRES 470 CD59 CDR-L3 QQYYSTPQLT 471 CD59 VH QVQLQQSGGGVVQPGRSLGLSCAASGFTFSSYGMNWVRQAPGKGLEWVSYISSSSSTIYYADSVKGRFTISRDNSKNTLYLQMNSLRAEDTAVYYCARGPGMDVWGQGTTVTVS 472 CD59 VL DIVLTQSPDSLAVSLGERATINCKSSQSVLYSSNNKNYLAWYQQKPGQPPKLLIYWASTRESGVPDRFSGSGSGTDFTPAISSLQAEDVAVYYCQQYYSTPQLTFGGGTKVDIK 473 CD19 (hBU12) CDR-H1 TSGMGVG 474 CD19 (hBU12) CDR-H2 HIWWDDKRYNPALKS 475 CD19 (hBU12) CDR-H3 MELWSYYFDY 476 CD19 (hBU12) CDR-L1 SASSSVSYMH 477 CD19 (hBU12) CDR-L2 DTSKLAS 478 CD19 (hBU12) CDR-L3 FQGVYP 479 CD19 (hBU12) VH QVQLQESGPGLVKPSQTLSLTCTVSGGSISTSGMGVGWIRQHPGKGLEWIGHIWWDDDKRYNPALKSRVTISVDTSKNQFSLKLSSVTAADTAVYYCARMELWSYYFDYWGQGTLVTVSS 480 CD19 (hBU12) VL EIVLTQSPATLSLSPGERATLSCSASSSVSYMHWYQQKPGQAPRLLIYDTSKLASGIPARFSGSGSGTDFTLTISSLEPEDVAVYYCFQGSVYPFTFGQGTKLEIKR 481 CD19 (hBU12) HC QVQLQESGPGLVKPSQTLSLTCTVSGGSISTSGMGVGWIRQHPGKGLEWIGHIWWDDDKRYNPALKSRVTISVDTSKNQFSLKLSSVTAADTAVYYCARMELWSYYFDYWGQ GTLVTVSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKKVEPKSCDK THTCPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEK TISKAKGQPREPQVYTLPPSRDELTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGK 482 CD19 (hBU12) LC EIVLTQSPATLSLSPGERATLSCSASSSVSYMHWYQQKPGQAPRLLIYDTSKLASGIPARFSGSGSGTDFTLTISSLEPEDVAVYYCFQGSVYPFTFGQGTKLEIK RTVAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC 483 CD138 CDR-H1 NYWIE 484 CD138 CDR-H2 EILPGTGRTIYNEKFKG 485 CD138 CDR-H3 RDYYGNFYYAMDY 486 CD138 CDR-L1 SASQGINNYLN 487 CD138 CDR-L2 YTSTLQS 488 CD138 CDR-L3 QQYSKLPRT 489 CD138 VH QVQLQQSGSELMMPGASVKISCKATGYTFSNYWIEWVKQRPGHGLEWIGEILPGTGRTIYNEKFKGKATFTADISSNTVQMQLSSLTSEDSAVYYCARRDYYGNFYYAMDYWGQGTSVTVSS 490 CD138 VL DIQMTQSTSSLSASLGDRVTISCSASQGINNYLNWYQQKPDGTVELLIYYTSTLQSGVPSRFSGSGSGTDYSLTISNLEPEDIGTYYCQQYSKLPRTFGGGTKLEIK 491 CD166 CDR-H1 TYGMGVG 492 CD166 CDR-H2 NIWWSEDKHYSPSLKS 493 CD166 CDR-H3 IDYGNDYAFTY 494 CD166 CDR-L1 RSSKSLLHSNGITYLY 495 CD166 CDR-L2 QMSNLAS 496 CD166 CDR-L3 AQNLELPYT 497 CD166 VH QITLKESGPTLVKPTQTLTLTCTFSGFSLSTYGMGVGWIRQPPGKALEWLANIWWSEDKHYSPSLKSRLTITKDTSKNQVVLTITNVDPVDTATYYCVQIDYGNDYAFTYWGQGTLVTVSS 498 CD166 VL DIVMTQSPLSLPVTPGEPASISCRSSKSLLHSNGITYLYWYLQKPGQSPQLLIYQMSNLASGVPDRFSGSGSGTDFTLKISRVEAEDVGVYYCAQNLELPYTFGQGTKLEIK 499 CD56 CDR-H1 SFGMH 500 CD56 CDR-H2 YISSGSFTIYYADSVKG 501 CD56 CDR-H3 MRKGYAMDY 502 CD56 CDR-L1 RSSQIIIHSDGNTYLE 503 CD56 CDR-L2 KVSNRFS 504 CD56 CDR-L3 FQSHPHT 505 CD56 VH QVQLVESGGGVVQPGRSLRLSCAASGFTFSSFGMHWVRQAPGKGLEWVAYISSGSFTIYYADSVKGRFTISRDNSKNTLYLQMNSLRAEDTAVYYCARMRKGYAMDYWGQGTLVTVSS 506 CD56 VL DVVMTQSPLSLPVTLGQPASISCRSSQIIIHSDGNTYLEWFQQRPGQSPRRLIYKVSNRFSGVPDRFSGSGSGTDFTLKISRVEAEDVGVYYCFQGSHVPHTFGQGTKVEIK 507 CD74 CDR-H1 NYGVN 508 CD74 CDR-H2 WINPNTGEPTFDDDFKG 509 CD74 CDR-H3 SRGKNEAWFAY 510 CD74 CDR-L1 RSSQSLVHRNGNTYLH 511 CD74 CDR-L2 TVSNRFS 512 CD74 CDR-L3 SQSSHVPPT 513 CD74 VH QVQLQQSGSELKKPGASVKVSCKASGYTFTNYGVNWIKQAPGQGLQWMGWINPNTGEPTFDDDFKGRFAFSLDTSVSTAYLQISSLKADDTAVYFCSRSRGKNEAWFAYWGQGTLVTVSS 514 CD74 VL DIQLTQSPLSLPVTLGQPASISCRSSQSLVHRNGNTYLHWFQQRPGQSPRLLIYTVSNRFSGVPDRFSGSGSGTDFTLKISRVEAEDVGVYFCSQSSHVPPTFGAGTRLEIK 515 CEACAM5 CDR-H1 TYWMS 516 CEACAM5 CDR-H2 EIHPDSSTINYAPSLKD 517 CEACAM5 CDR-H3 LYFGFPWFAY 518 CEACAM5 CDR-L1 KASQDVGTSVA 519 CEACAM5 CDR-L2 WTSTRHT 520 CEACAM5 CDR-L3 QQYSLYRS 521 CEACAM5 VH EVQLVESGGGVVQPGRSLRLSCSASGFDFTTYWMSWVRQAPGKGLEWIGEIHPDSSTINYAPSLKDRFTISRDNAKNTLFLQMDSLRPEDTGVYFCASLYFGFPWFAYWGQGTPVTVSS 522 CEACAM5 VL DIQLTQSPSSSLSASVGDRVTITCKASQDVGTSVAWYQQKPGKAPKLLIYWTSTRHTGVPSRFSGSGSGTDFTFTISSLQPEDIATYYCQQYSLYRSFGQGTKVEIK 523 CanAg CDR-H1 YYGM 524 CanAg CDR-H2 WIDTTTGEPTYAQKFQG 525 CanAg CDR-H3 R 526 CanAg CDR-L1 RSSKSLLHSNGNTYLY 527 CanAg CDR-L2 RMSNLVS 528 CanAg CDR-L3 LQHLEYPFT 529 CanA QVQLVQSGAEVKKPGETVKISCKASDYTFTYYGMNWVKQAPGQGLKWMGWIDTTTGEPTYAQKFQGRIAFSLETSASTAYLQIKSLKSEDTATYFCARRGPYNWYFDVWGQGTTVTVSS 530 V L DIVMTQSPLSVPVTPGEPVSISCRSSKSLLHSNGNTYLYWFLQRPGQSPQLLIYRMSNLVSGVPDRFSGSGSGTAFTLRISRVEAEDVGVYYCLQHLEYPFTFGPGTKLELK 531 DLL-3 CDR-H1 NYGMN 532 DLL-3 CDR-H2 WINTYTGEPTYADDFKG 533 DLL-3 CDR-H3 IGDSSPSDY 534 DLL-3 CDR-L1 KASQSVSNDVV 535 DLL-3 CDR-L2 YASNRYT 536 DLL-3 CDR-L3 QQDYTSPWT 537 DLL-3 VH QVQLVQSGAEVKKPGASVKVSCKASGYTFTNYGMNWVRQAPGQGLEWMGWINTYTGEPTYADDFKGRVTMTTDTSTAYMELRSLRSDDTAVYYCARIGDSSPSDYWGQGTLVTVSS 538 DLL-3 VL EIVMTQSPATLSVSPGERATLSCKASQSVSNDVVWYQQKPGQAPRLLIYYASNRYTGIPARFSGSGSGTEFTLTISSLQSEDFAVYYCQQDYTSPWTFGQGTKLEIK 539 DPEP-3 CDR-H1 SYWIE 540 DPEP-3 CDR-H2 EILPGSGNTYYNERFKD 541 DPEP-3 CDR-H3 RAAAYYSNPEWFAY 542 DPEP-3 CDR-L1 TASSSVNSFYLH 543 DPEP-3 CDR-L2 STSNLAS 544 DPEP-3 CDR-L3 HQYHRSPYT 545 DPEP-3 VH QVQLVQSGAEVKKPGSSVKVSCKASGGTFSSYWIEWVRQAPGQGLEWMGEILPGSGNTYYNERFKDRVTITADESTSTAYMELSSLRSEDTAVYYCARRAAAYYSNPEWFAYWGQGTLVTVSS 546 DPEP-3 VL EIVLTQSPATLSLSPGERATLSCTASSSVNSFYLHWYQQKPGLAPRLLIYSTSNLASGIPDRFSGSGSGTDFTLTISRLEPEDFAVYYCHQYHRSPYTFGQGTKLEIK 547 EGFR CDR-H1 SYWMQ 548 EGFR CDR-H2 TIYPGDGDTTYTQKFQG 549 EGFR CDR-H3 YDAP YAMDY 550 EGFR CDR-L1 RASQDINNYLA 551 EGFR CDR-L2 YTST 552 EGFR CDR-L3 LQYDNLLYT 553 EGFR VH QVQLVQSGAEVAKPGASVKLSCKASGYTFTSYWMQWVKQRPGQGLECIGTIYPGDGDTTYTQKFQGKATLTADKSSSTAYMQLSSLRSEDSAVYYCARYDAPGYAMDYWGQGTLVTVSS 554 EGFR VL DIQMTQSPSSSLSASVGDRVTITCRASQDINNYLAWYQHKPGKGPKLLIHYTSTLHPGIPSRFSGSGSGRDYSFSISSLEPEDIATYYCLQYDNLLYTFGQGTKLEIK 555 EGFR CDR-H1 RDFAWN 556 EGFR CDR-H2 YISYNGNTRYQPSLKS 557 EGFR CDR-H3 ASRGFPY 558 EGFR CDR-L1 HSSQDINSNIG 559 EGFR CDR-L2 HGTNLDD 560 EGFR CDR-L3 VQYAQFPWT 561 EGFR VH EVQLQESGPGLVKPSQTLSLTCTVSGYSISRDFAWNWIRQPPGKGLEWMGYISYNGNTRYQPSLKSRITISRDTSKNQFFLKLNSVTAADTATYYCVTASRGFPYWGQGTLVTVSS 562 EGFR VL DIQMTQSPSSSMSVSVGDRVTITCHSSQDINSNIGWLQQKPGKSFKGLIYHGTNLDDGVPSRFSGSGSGTDYTLTISSLQPEDFATYYCVQYAQFPWTFGGGTKLEIK 563 EGFR CDR-H1 NYGVH 564 EGFR CDR-H2 VIWSGGNTDYNTPFTS 565 EGFR CDR-H3 ALTYYDYEFAY 566 EGFR CDR-L1 RASQSIGTNIH 567 EGFR CDR-L2 YASESIS 568 EGFR CDR-L3 QQNNNWPTT 569 EGFR VH QVQLKQSGPGLVQPSQSLSITCTVSGFSLTNYGVHWVRQSPGKGLEWLGVIWSGGNTDYNTPFTSRLSINKDNSKSQVFFKMNSLQSNDTAIYYCARALTYYDYEFAYWGQGTLVTVSA 570 EGFR VL DILLTQSPVILSVSPGERVSFSCRASQSIGTNIHWYQQRTNGSPRLLIKYASESISGIPSRFSGSGSGTDFTLSINSVESEDIADYYCQQNNNWPTTFGAGTKLELK 571 FRa CDR-H1 GYFMN 572 FRa CDR-H2 RIHPYDGDTFYNQKFQG 573 FRa CDR-H3 YDGSRAMDY 574 FRa CDR-L1 KASQSVSFAGTSLMH 575 FRa CDR-L2 RASNLEA 576 FRa CDR-L3 QQSREYPYT 577 F V QVQLVQSGAEVVKPGASVKISCKASGYTFTGYFMNWVKQSPGQSLEWIGRIHPYDGDTFYNQKFQGKATLTVDKSSNTAHMELLSLTSEDFAVYYCTRYDGSRAMDYWGQGTTVTVSS 578 F V DIVLTQSPLSLAVSLGQPAIISCKASQSVSFAGTSLMHWYHQKPGQQPRLLIYRASNLEAGVPDRFSGSGSKTDFTLTISPVEAEDAATYYCQQSREYPYTFGGGTKLEIK 579 FRa CDR-H1 GYGLS 580 FRa CDR-H2 MISSGGSYTYYADSVKG 581 FRa CDR-H3 HGDDPAWFAY 582 FRa CDR-L1 SVSSSISSNNLH 583 FRa CDR-L2 GTSNLAS 584 FRa CDR-L3 QQWSSYPYMYT 585 F V EVQLVESGGGVVQPGRSLRLSCSASGFTFSGYGLSWVRQAPGKGLEWVAMISSGGSYTYYADSVKGRFAISRDNAKNTLFLQMDSLRPEDTGVYFCARHGDDPAWFAYWGQGTPVTVSS 586 F V DIQLTQSPSSSLSASVGDRVTITCSVSSSISSNNLHWYQQKPGKAPKPWIYGTSNLASGVPSRFSGSGSGTDYTFTISSLQPEDIATYYCQQWSSYPYMYTFGQGTKVEIK 587 MUC-1 CDR-H1 NYWMN 588 MUC-1 CDR-H2 EIRLKSNNYTTHYAESVKG 589 MUC-1 CDR-H3 HYYFDY 590 MUC-1 CDR-L1 RSSKSLLHSNGITYFF 591 MUC-1 CDR-L2 QMSNLAS 592 MUC-1 CDR-L3 AQNLELPPT 593 MUC-1 VH EVQLVESGGGLVQPGGSMRLSCVASGFPFSNYWMNWVRQAPGKGLEWVGEIRLKSNNYTTHYAESVKGRFTISRDDSKNSLYLQMNSLKTEDTAVYYCTRHYYFDYWGQGTLVTVSS 594 MUC-1 VL DIVMTQSPLSNPVTPGEPASISCRSSKSLLHSNGITYFFWYLQKPGQSPQLLIYQMSNLASGVPDRFSGSGSGTDFTLRISRVEAEDVGVYYCAQNLELPPTFGQGTKVEIK 595 Mesothelin CDR-H1 SYWIG 596 Mesothelin CDR-H2 IIDPGDSRTRYSPSFQG 597 Mesothelin CDR-H3 GQLYGGTYMDG 598 Mesothelin CDR-L1 TGTSSDIGGYNSVS 599 Mesothelin CDR-L2 GVNNRPS 600 Mesothelin CDR-L3 SSYDIESATPV 601 Mesothelin VH QVELVQSGAEVKKPGESLKISCKGSGYSFTSYWIGWVRQAPGKGLEWMGIIDPGDSRTRYSPSFQGQVTISADKSISTAYLQWSSLKASDTAMYYCARGQLYGGTYMDGWGQGTLVTVSS 602 Mesothelin VL DIALTQPASVSGSPGQSITISCTGTSSDIGGYNSVSWYQQHPGKAPKLMIYGVNNRPSGVSNRFSGSKSGNTASLTISGLQAEDEADYYCSSYDIESATPVFGGGTKLTVL 603 ROR-1 CDR-H1 AYNIH 604 ROR-1 CDR-H2 SFDPYDGGSSYNQKFKD 605 ROR-1 CDR-H3 GWYYFDY 606 ROR-1 CDR-L1 RASKSISKYLA 607 ROR-1 CDR-L2 SGTQ 608 ROR-1 CDR-L3 QQHDESPYT 609 ROR-1 VH QVQLQESGPGLVKPSQTLSLTCTVSGYAFTAYNIHWVRQAPGQGLEWMGSFDPYDGGSSYNQKFKDRLTISKDTSKNQVVLTMTNMDPVDTATYYCARGWYYFDYWGHGTLVTVSS 610 ROR-1 VL DIVMTQTPLSLPVTPGEPASISCRASKSISKYLAWYQQKPGQAPRLLIYSGSTLQSGIPPRFSGSGYGTDFTLTINNIESEDAAYYFCQQHDESPYTFGEGTKVEIK 611 B7-H3 CDR-H1 SFGMH 612 B7-H3 CDR-H2 YISSDSSAIYYADTVKG 613 B7-H3 CDR-H3 GRENIYYGSRLDY 614 B7-H3 CDR-L1 KASQNVDTNVA 615 B7-H3 CDR-L2 SASYRYS 616 B7-H3 CDR-L3 QQYNNYPFT 617 B7-H3 VH DVQLVESGGGLVQPGGSRKLSCAASGFTFSSFGMHWVRQAPEKGLEWVAYISSDSSAIYYADTVKGRFTISRDNPKNTLFLQMTSLRSEDTAMYYCGRGRENIYYGSRLDYWGQGTTLTVSS 618 B7-H3 VL DIAMTQSQKFMSTSVGDRVSVTCKASQNVDTNVAWYQQKPGQSPKALIYSASYRYSGVPDRFTGSGSGTDFTLTINNVQSEDLAEYFCQQYNNYPFTFGSGTKLEIK 619 B7-H3 CDR-H1 SYGMS 620 B7-H3 CDR-H2 TINSGGSNTYYPDSLKG 621 B7-H3 CDR-H3 HDGGAMDY 622 B7-H3 CDR-L1 RASESIYSYLA 623 B7-H3 CDR-L2 NTKTLPE 624 B7-H3 CDR-L3 QHHYGTPPWT 625 B7-H3 VH EVQLVESGGGLVKPGGSLRLSCAASGFTFSSYGMSWVRQAPGKGLEWVATINSGGSNTYYPDSLKGRFTISRDNAKNSLYLQMNSLRAEDTAVYYCARHDGGAMDYWGQGTTVTVSS 626 B7-H3 VL DIQMTQSPSSSLSASVGDRVTITCRASESIYSYLAWYQQKPGKAPKLLVYNTKTLPEGVPSRFSGSGSGTDFTLTISSLQPEDFATYYCQHHYGTPPWTFGQGTRLEIK 627 B7-H3 CDR-H1 SFGMH 628 B7-H3 CDR-H2 YISSGSGTIYYADTVKG 629 B7-H3 CDR-H3 HGYRYEGFDY 630 B7-H3 CDR-L1 KASQNVDTNVA 631 B7-H3 CDR-L2 SASYRYS 632 B7-H3 CDR-L3 QQYNNYPFT 633 B7-H3 VH EVQLVESGGGLVQPGGSLRLSCAASGFTFSSFGMHWVRQAPGKGLEWVAYISSGSGTIYYADTVKGRFTISRDNAKNSLYLQMNSLRAEDTAVYYCARHGYRYEGFDYWGQGTTVTVSS 634 B7-H3 VL DIQMTQSPSFLSASVGDRVTITCKASQNVDTNVAWYQQKPGKAPKALIYSASYRYSGVPSRFSGSGSGTDFTLTISSLQPEDFAEYFCQQYNNYPFTFGQGTKLEIK 635 B7-H3 CDR-H1 NYVMH 636 B7-H3 CDR-H2 YINPYNDDVKYNEKFKG 637 B7-H3 CDR-H3 WGYYGSPLYYFDY 638 B7-H3 CDR-L1 RASSRLIYMH 639 B7-H3 CDR-L2 ATSNLAS 640 B7-H3 CDR-L3 QQWNSNPPT 641 B7-H3 VH EVQLQQSGPELVKPGASVKMSCKASGYTFTNYVMHWVKQKPGQGLEWIGYINPYNDDVKYNEKFKGKATQTSDKSSSTAYMELSSLTSEDSAVYYCARWGYYGSPLYYFDYWGQGTTLTVSS 642 B7-H3 VL QIVLSQSPTILSASPGEKVTMTCRASSRLIYMHWYQQKPGSSPKPWIYATSNLASGVPARFSGSGSGTSYSLTISRVEAEDAATYYCQQWNSNPPTFGTGTKLELK 643 B7-H3 CDR-H1 NYVMH 644 B7-H3 CDR-H2 YINPYNDDVKYNEKFKG 645 B7-H3 CDR-H3 WGYYGSPLYYFDY 646 B7-H3 CDR-L1 RASSRLIYMH 647 B7-H3 CDR-L2 ATSNLAS 648 B7-H3 CDR-L3 QQWNSNPPT 649 B7-H3 VH QVQLVQSGAEVKKPGSSVKVSCKASGYTFTNYVMHWVRQAPGQGLEWMGYINPYNDDVKYNEKFKGRVTITADESTSTAYMELSSLRSEDTAVYYCARWGYYGSPLYYFDYWGQGTLVTVSS 650 B7-H3 VL EIVLTQSPATLSLSPGERATLSCRASSRLIYMHWYQQKPGQAPRPLIYATSNLASGIPARFSGSGSGTDFTLTISSLEPEDFAVYYCQQWNSNPPTFGQGTKVEIK 651 B7-H3 CDR-H1 SYTIH 652 B7-H3 CDR-H2 YINPNSRNTDYAQKFQG 653 B7-H3 CDR-H3 YSGSTPYWYFDV 654 B7-H3 CDR-L1 RASSSVSYMN 655 B7-H3 CDR-L2 ATSNLAS 656 B7-H3 CDR-L3 QQWSSNPLT 657 B7-H3 VH EVQLVQSGAEVKKPGSSVKVSCKASGYSFTSYTIHWVRQAPGQGLEWMGYINPNSRNTDYAQKFQGRVTLTADKSTSTAYMELSSLRSEDTAVYYCARYSGSTPYWYFDVWGQGTTVTVSS 658 B7-H3 VL DIQLTQSPSFLSAVGDRVTITCRASSSVSYMNWYQQKPGKSPKPWIYATSNLASGVPSRFSVSVSGTEHTLTISSLQPEDFATYYCQQWSSNPLTFGQGTKLEIK 659 B7-H3 CDR-H1 SYW 660 B7-H3 CDR-H2 LIHPDSGSTNYNEMFKN 661 B7-H3 CDR-H3 GGRLYFDY 662 B7-H3 CDR-L1 RSSQSLVHSNGDTYLR 663 B7-H3 CDR-L2 KVSNRFS 664 B7-H3 CDR-L3 SQSTHVPYT 665 B7-H3 VH EVQLVQSGAEVKKPGSSVKVSCKASGYTFSSYWMHWVRQAPGQGLEWIGLIHPDSGSTNYNEMFKNRATLTVDRSTSTAYVELSSLRSEDTAVYFCAGGGRLYFDYWGQGTTVTVSS 666 B7-H3 VL DVVMTQSPLSLPVTPGEPASISCRSSQSLVHSNGDTYLRWYLQKPGQSPQLLIYKVSNRFSGVPDRFSGSGSGTDFTLKISRVEAEDVGVYYCSQSTHVPYTFGGGTKVEIK 667 B7-H3 CDR-H1 SYW 668 B7-H3 CDR-H2 LIHPESGSTNYNEMFKN 669 B7-H3 CDR-H3 GGRLYFDY 670 B7-H3 CDR-L1 RSSQSLVHSNQDTYLR 671 B7-H3 CDR-L2 KVSNRFS 672 B7-H3 CDR-L3 SQSTHVPYT 673 B7-H3 VH EVQLVQSGAEVKKPGSSVKVSCKASGYTFSSYWMHWVRQAPGQGLEWIGLIHPESGSTNYNEMFKNRATLTVDRSTSTAYMELSSLRSEDTAVYYCAGGGRLYFDYWGQGTTVTVSS 674 B7-H3 VL DIVMTQSPLSLPVTPGEPASISCRSSQSLVHSNQDTYLRWYLQKPGQSPQLLIYKVSNRFSGVPDRFSGSGSGTDFTLKISRVEAEDVGVYYCSQSTHVPYTFGGGTKVEIK 675 B7-H3 CDR-H1 SGYSW 676 B7-H3 CDR-H2 YIHSSGSTNYNPSLKS 677 B7-H3 CDR-H3 YDDYFEY 678 B7-H3 CDR-L1 KASQNVGFNVAW 679 B7-H3 CDR-L2 SASYRYS 680 B7-H3 CDR-L3 QQYNWYPFT 681 B7-H3 VH EVQLQESGPGLVKPSETLSLTCAVTGYSITSGYSWHWIRQFPGNGLEWMGYIHSSGSTNYNPSLKSRISISRDTSKNQFFLKLSSVTAADTAVYYCAGYDDYFEYWGQGTTVTVSS 682 B7-H3 VL DIQMTQSPSSSLSASVGDRVTITCKASQNVGFNVAWYQQKPGKSPKALIYSASYRYSGVPSRFSGSGSGTDFTLTISSLQPEDFAEYFCQQYNWYPFTFGQGTKLEIK 683 B7-H3 CDR-H1 NYDIN 684 B7-H3 CDR-H2 WIFPGDDSTQYNEKFKG 685 B7-H3 CDR-H3 QTTGTWFAY 686 B7-H3 CDR-L1 RASQSISDYLY 687 B7-H3 CDR-L2 YASQSIS 688 B7-H3 CDR-L3 QNGHSFPLT 689 B7-H3 VH QVQLVQSGAEVVKPGASVKLSCKTSGYTFTNYDINWVRQRPGQGLEWIGWIFPGDDSTQYNEKFKGKATLTTDTSTSTAYMELSSLRSEDTAVYFCARQTTGTWFAYWGQGTLVTVSS 690 B7-H3 VL EIVMTQSPATLSVSPGERVTLSCRASQSISDYLYWYQQKSHESPRLLIKYASQSISGIPARFSGSGSGSEFTLTINSVEPEDVGVYYCQNGHSFPLTFGQGTKLELK 691 B7-H3 VH QVQLQQSGAEVKKPGSSVKVSCKASGGTFSSYAISWVRQAPGQGLEWMGGIIPILGIANYAQKFQGRVTITADESTSTAYMELSSLRSEDTAVYYCARGGSGSYHMDVWGKGTTVTVSS 692 B7-H3 VL EIVLTQSPATLSLSPGERATLSCRASQSVSSYLAWYQQKPGQAPRLLIYDASNRATGIPARFSGSGSGTDFTLTISSLEPEDFAVYYCQQRSNWPPRITFGQGTRLEIK 693 B7-H3 CDR-H1 YVH 694 B7-H3 CDR-H2 TIFPGNGDTSYNQKFKD 695 B7-H3 CDR-H3 WDDGNVGFAH 696 B7-H3 CDR-L1 RASENINNYLT 697 B7-H3 CDR-L2 HAKTLAE 698 B7-H3 CDR-L3 QHHYGTPPT 699 B7-H3 VH QVQLQQPGAELVKPGASVKMSCKASGYTFTIYNVHWIKQTPGQGLEWMGTIFPGNGDTSYNQKFKDKATLTTDKSSKTAYMQLNSLTSEDSAVYYCARWDDGNVGFAHWGQGTLVTVSA 700 B7-H3 VL DIQMTQSPASSLSASVGETVTITCRASENINNYLTWFQQKQGKSPQLLVYHAKTLAEGVPSRFSGSGSGTQFSLKINSLQPEDFGSYYCQHHYGTPPTFGGGTKLEIK 701 B7-H3 VH EVQLVQSGAEVKKPGASVKVSCKASGYTFTIYNVHWVRQAPGQGLEWMGTIFPGNGDTSYNQKFKDKVTMTTDTSSTAYMELSSLRSEDTAVYYCARWDDGNVGFAHWGQGTLVTVSS 702 B7-H3 VL DIQMTQSPSSSLSASVGDRVTITCRASENINNYLTWFQQKQGKSPQLLIYHAKTLAEGVPSRFSGSGSGTDFTLTISSLQPEDFATYYCQHHYGTPPTFGGGTKVEIK 703 B7-H3 VH EVQLVQSGAEVKKPGASVKVSCKASGYTFTIYNVHWIRQAPGQGLEWMGTIFPGNGDTSYNQKFKDRATLTTDKSTKTAYMELRSLRSDDTAVYYCARWDDGNVGFAHWGQGTLVTVSS 704 B7-H3 VL DIQMTQSPSSSLSASVGDRVTITCRASENINNYLTWFQQKPGKAPKLLVYHAKTLAEGVPSRFSGSGSGTQFTLTISSLQPEDFATYYCQHHYGTPPTFGQGTKLEIK 705 HER3H QVQLQQWGAGLLKPSETLSLTCAVYGGSFSGYYWSWIRQPPGKGLEWIGEINHSGSTNYNPSLKSRVTISVETSKNQFSLKLSSVTAADTAVYYCARDKWTWYFDLWGRGT LVTVSSASTKGPSVFPLAPSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKRVEPKSCDKT HTCPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKT ISKAKGQPREPQVYTLPPSREEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGK 706 HER3L DIEMTQSPDSLAVSLGERATINCRSSQSVLYSSSNRNYLAWYQQNPGQPPKLLIYWASTRESGVPDRFSGSGSGTDFTLTISSLQAEDVAVYYCQQYYSTPRTFGQGTKV EIKRTVAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC 707 HER3H EVQLLESGGGLVQPGGSLRLSCAASGFTFSHYVMAWVRQAPGKGLEWVSSISSSGGWTLYADSVKGRFTISRDNSKNTLYLQMNSLRAEDTAVYYCTRGLKMATIFDYWGQ GTLVTVSSASTKGPSVFPLAPCSRSTSESTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSNFGTQTYTCNVDHKPSNTKVDKTVERKCC VECPPCPAPPVAGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVQFNWYVDGVEVHNAKTKPREEQFNSTFRVVSVLTVVHQDWLNGKEYKCKVSNKGLPAPIEKT ISKTKGQPREPQVYTLPPSREEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPMLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGK 708 HER3L QSALTQPASVSGSPGQSITISCTGTSSDVGSYNVVSWYQQHPGKAPKLIIYEVSQRPSGVSNRFSGSKSGNTASLTISGLQTEDEADYYCCSYAGSSIFVIFGGGTKV TVLGQPKAAPSVTLFPPSSEELQANKATLVCLVSDFYPGAVTVAWKADGSPVKVGVETTKPSKQSNNKYAASSYLSLTPEQWKSHRSYSCRVTHEGSTVEKTVAPAECS 709 HER3H EVQLLESGGGLVQPGGSLRLSCAASGFTFSSYAMSWVRQAPGKGLEWVSAINSQGKSTYYADSVKGRFTISRDNSKNTLYLQMNSLRAEDTAVYYCARWGDEGFDIWGQGT LVTVSSASTKGPSVFPLAPSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKRVEPKSCDKT HTCPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKT ISKAKGQPREPQVYTLPPSREEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGK 710 HER3L DIQMTQSPSSSLSASVGDRVTITCRASQGISNWLAWYQQKPGKAPKLLIYGASSLQSGVPSRFSGSGSGTDFTLTISSLQPEDFATYYCQQYSSFPTTFGQGTKVEIK RTVAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC 711 HER3H QVQLVQSGAEVKKPGASVKVSCKASGYTFRSSYISWVRQAPGQGLEWMGWIYAGTGSPSYNQKLQGRVTMTTDTSTAYMELRSLRSDDTAVYYCARHRDYYSNSLTYWGQ GTLVTVSSASTKGPSVFPLAPSSKSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKKVEPKSCD KTHTCPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIE KTISKAKGQPREPQVYTLPPSRDELTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPG 712 HER3L DIVMTQSPDSLAVSLGERATINCKSSQSVLNSGNQKNYLTWYQQKPGQPPKLLIYWASTRESGVPDRFSGSGSGTDFTLTISSLQAEDVAVYYCQSDYSYPYTFGQGTKL EIKRTVAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC 713 PTK7 CDR-H1 TSNMGVG 714 PTK7 CDR-H2 HIWWDDDKYYSPSLKS 715 PTK7 CDR-H3 SNYGYAWFAY 716 PTK7 CDR-L1 KASQDIYPYLN 717 PTK7 CDR-L2 RTNRLLD 718 PTK7 CDR-L3 LQYDEFPLT 719 PTK7 VH QITLKESGPTLVKPTQTLTLTCTFSGFSLSTSNMGVGWIRQPPGKALEWLAHIWWDDDKYYSPSLKSRLTITKDTSKNQVVLTMTNMDPVDTATYYCVRSNYGYAWFAYWGQGTLVTVSS 720 PTK7 VL DIQMTQSPSSSLSASVGDRVTITCKASQDIYPYLNWFQQKPGKAPKTLIYRTNRLLDGVPSRFSGSGSGTDFTFTISSLQPEDIATYYCLQYDEFPLTFGAGTKLEIK 721 PTK7 CDR-H1 DYAV 722 PTK7 CDR-H2 VISTYNDYTYNNQDFKG 723 PTK7 CDR-H3 GNSYFYALDY 724 PTK7 CDR-L1 RASESVDSYGKSFMH 725 PTK7 CDR-L2 RASNLES 726 PTK7 CDR-L3 QQQSNEDPWT 727 PTK7 VH QVQLVQSGPEVKKPGASVKVSCKASGYTFTDYAVHWVRQAPGKRLEWIGVISTYNDYTYNNQDFKGRVTMTRDTSASTAYMELSRLRSEDTAVYYCARGNSYFYALDYWGQGTSVTVSS 728 PTK7 VL EIVLTQSPATLSLSPGERATLSCRASESVDSYGKSFMHWYQQKPGQAPRLLIYRASNLESGIPARFSGSGSGTDFTLTISSLEPEDFAVYYCQQSNEDPWTFGGGTKLEIK 729 PTK7 CDR-H1 RYWMS 730 PTK7 CDR-H2 DLNPDSSAINYVDSVKG 731 PTK7 CDR-H3 ITTLVPYTMDF 732 PTK7 CDR-L1 ITNTDIDDDMN 733 PTK7 CDR-L2 EGNGLRP 734 PTK7 CDR-L3 LQSDNLPLT 735 PTK7 VH EVQLVESGGGLVQPGGSLRLSCAASGFDFSRYWMSWVRQAPGKGLEWIGDLNPDSSAINYVDSVKGRFTISRDNAKNSLYLQMNSLRAEDTAVYYCTLITTLVPYTMDFWGQGTSVTVSS 736 PTK7 VL ETTLTQSPAFMSATPGDKVNISCITNTDIDDDMNWYQQKPGEAAILLISEGGNGLRPGIPPRFSGSGYGTDFTLTINNIESEDAAYYFCLQSDNLPLTFGSGTKLEIK 737 hLIV22/LIV1 CDR-H1 D Y 738 hLIV22/LIV1 CDR-H2 WIDPENGDTEYGPKFQG 739 hLIV22/LIV1 CDR-H3 HNAHYGTWFAY 740 hLIV22/LIV1 CDR-L1 RSSQSLLHSSGNTYLE 741 hLIV22/LIV1 CDR-L2 KISTRFS 742 hLIV22/LIV1 CDR-L3 FQSHPY 743 hLIV22/LIV1 VH QVQLVQSGAEVKKPGASVKVSCKASGLTIEDYYMHWVRQAPGQGLEWMGWIDPENGDTEYGPKFQGRVTMTRDTSINTAYMELSRLRSDDTAVYYCAVHNAHYGTWFAYWGQGTLVTVSS 744 hLIV22/LIV1 VL DVVMTQSPLSLPVTLGQPASISCRSSQSLLHSSGNTYLEWYQQRPGQSPRPLIYKISTRFSGVPDRFSGSGSGTDFTLKISRVEAEDVGVYYCFQGSHVPYTFGGGTKVEIK 745 hLIV22/LIV1 HC QVQLVQSGAEVKKPGASVKVSCKASGLTIEDYYMHWVRQAPGQGLEWMGWIDPENGDTEYGPKFQGRVTMTRDTSINTAYMELSRLRSDDTAVYYCAVHNAHYGTWFAYWGQ GTLVTVSSASTKGPSVFPLAPSSKSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKKVEPKSCD KTHTCPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIE KTISKAKGQPREPQVYTLPPSRDELTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPG 746 hLIV22/LIV1 LC DVVMTQSPLSLPVTLGQPASISCRSSQSLLHSSGNTYLEWYQQRPGQSPRPLIYKISTRFSGVPDRFSGSGSGTDFTLKISRVEAEDVGVYYCFQGSHVPYTFGGGTKV EIKRTVAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC 747 h15H3/avb6 CDR-H1 GYFMN 748 h15H3/avb6 CDR-H2 LINPYNGDSFYNQKFKG 749 h15H3/avb6 CDR-H3 GLRRDFDY 750 h15H3/avb6 CDR-L1 KSSQSLLDSDGKTYLN 751 h15H3/avb6 CDR-L2 LVSELDS 752 h15H3/avb6 CDR-L3 WQH 753 h15H3/avb6 VH QVQLVQSGAEVKKPGASVKVSCKASGYSFSGYFMNWVRQAPGQGLEWMGLINPYNGDSFYNQKFKGRVTMTRQTSTSTVYMELSSLRSEDTAVYYCVRGLRRDFDYWGQGTLVTVSS 754 h15H3/avb6 VL DVVMTQSPLSLPVTLGQPASISCKSSQSLLDSDGKTYLNWLFQRPGQSPRRLIYLVSELDSGVPDRFSGSGSGTDFTLKISRVEAEDVGVYYCWQGTHFPRTFGGGTKLEIK 755 CD48 CDR-H1 DFGMN 756 CD48 CDR-H2 WINTFTGEPSYGNVFKG 757 CD48 CDR-H3 RHGNGNVFDS 758 CD48 CDR-L1 RASQSIGSNIH 759 CD48 CDR-L2 YTSESIS 760 CD48 CDR-L3 QQSNSWPLT 761 CD48 VH QVQLVQSGSELKKPGASVKVSCKASGYTFTDFGMNWVRQAPGQGLEWMGWINTFTGEPSYGNVFKGRFVFSLDTSVSTAYLQISSLKAEDTAVYYCARRHGNGNVFDSWGQGTLVTVSS 762 CD48 VL EIVLTQSPDFQSVTPKEKVTITCRASQSIGSNIHWYQQKPDQSPKLLIKYTSESISGVPSRFSGSGSGTDFTLTINSLEAEDAATYYCQQSNSWPLTFGGGTKVEIKR 763 IGF-1R CDR-H1 SYAIS 764 IGF-1R CDR-H2 GIIPIFGTANYAQKFQG 765 IGF-1R CDR-H3 APLRFLEWSTQDHYYYYYMDV 766 IGF-1R CDR-L1 QGDSLRSYYAT 767 IGF-1R CDR-L2 GENKRPS 768 IGF-1R CDR-L3 KSRDGSGQHLV 769 IGF-1R VH EVQLVQSGAEVKKPGSSVKVSCKASGGTFSSYAISWVRQAPGQGLEWMGGIIPIFGTANYAQKFQGRVTITADKSTSTAYMELSSLRSEDTAVYYCARAPLRFLEWSTQDHYYYYYMDVWGKGTTVTVSS 770 IGF-1R VL SSELTQDPAVSVALGQTVRITCQGDSLRSYYATWYQQKPGQAPILVIYGENKRPSGIPDRFSGSSSSGNTASLTITGAQAEDEADYYCKSRDGSGQHLVFGGGTKLTVL 771 Claudin-18.2 CDR-H1 SYWIN 772 Claudin-18.2 CDR-H2 NIYPSDSYTNYNQKFKD 773 Claudin-18.2 CDR-H3 SWRGNSFDY 774 Claudin-18.2 CDR-L1 KSSQSLLNSGNQKNYLT 775 Claudin-18.2 CDR-L2 WASTRES 776 Claudin-18.2 CDR-L3 QNDYSYPFT 777 Claudin-18.2 VH QVQLQQPGAELVRPGASVKLSCKASGYTFTSYWINWVKQRPGQGLEWIGNIYPSDSYTNYNQKFKDKATLTVDKSSSTAYMQLSSPTSEDSAVYYCTRSWRGNSFDYWGQGTTLTVSS 778 Claudin-18.2 VL DIVMTQSPSSLTVTAGEKVTMSCKSSQSLLNSGNQKNYLTWYQQKPGQPPKLLIYWASTRESGVPDRFTGSGSGTDFTLTISSVQAEDLAVYYCQNDYSYPFTFGSGTKLEIK 779 Claudin-18.2 CDR-H1 NYGMN 780 Claudin-18.2 CDR-H2 WINTNTGEPTYAEEFKG 781 Claudin-18.2 CDR-H3 LGFGNAMDY 782 Claudin-18.2 CDR-L1 KSSQSLLNSGNQKNYLT 783 Claudin-18.2 CDR-L2 WASTRES 784 Claudin-18.2 CDR-L3 QNDYSYPLT 785 Claudin-18.2 VH QIQLVQSGPELKKPGETVKISCKASGYTFTNYGMNWVKQAPGKGLKWMGWINTNTGEPTYAEEFKGRFAFSLETSASTAYLQINNLKNEDTATYFCARLGFGNAMDYWGQGTSVTVSS 786 Claudin-18.2 VL DIVMTQSPSSLTVTAGEKVTMSCKSSQSLLNSGNQKNYLTWYQQKPGQPPKLLIYWASTRESGVPDRFTGSGSGTDFTLTISSVQAEDLAVYYCQNDYSYPLTFGAGTKLELK 787 Nectin-4 CDR-H1 SYNMN 788 Nectin-4 CDR-H2 YISSSSSTIYYADSVKG 789 Nectin-4 CDR-H3 YYYGMDV 790 Nectin-4 CDR-L1 RASQGISGWLA 791 Nectin-4 CDR-L2 AASTLQS 792 Nectin-4 CDR-L3 QQANSFPPT 793 Nectin-4 VH EVQLVESGGGLVQPGGSLRLSCAASGFTFSSYNMNWVRQAPGKGLEWVSYISSSSSTIYYADSVKGRFTISRDNAKNSSLLQMNSLRDEDTAVYYCARAYYYGMDVWGQGTTVTVSS 794 Nectin-4 VL DIQMTQSPSSVSASVGDRVTITCRASQGISGWLAWYQQKPGKAPKFLIYAASTLQSGVPSRFSGSGSGTDFTLTISSLQPEDFATYYCQQANSFPPTFGGGTKVEIK 795 SLTRK6 CDR-H1 SYGMH 796 SLTRK6 CDR-H2 VIWYDGSNQYYADSVKG 797 SLTRK6 CDR-H3 GLTSGRYGMDV 798 SLTRK6 CDR-L1 RSSQSLLLSHGFNYLD 799 SLTRK6 CDR-L2 LGSSRAS 800 SLTRK6 CDR-L3 MQPLQIPWT 801 SLTRK6 VH QVQLVESGGGVVQPGRSLRLSCAASGFTFSSYGMHWVRQAPGKGLEWVAVIWYDGSNQYYADSVKGRFTISRDNSKNTLFLQMHSLRAEDTAVYYCARGLTSGRYGMDVWGQGTTVTVSS 802 SLTRK6 VL DIVMTQSPLSLPVTPGEPASISCRSSQSLLLSHGFNYLDWYLQKPGQSPQLLIYLGSSRASGVPDRFSGSGSGTDFTLKISRVEAEDVGLYYCMQPLQIPWTFGQGTKVEIK 803 CD142 (TF) CDR-H1 NYAMS 804 CD142 (TF) CDR-H2 SISGSGDYTYYTDSVKG 805 CD142 (TF) CDR-H3 SPWGYYLDS 806 CD142 (TF) CDR-L1 RASQGISSRLA 807 CD142 (TF) CDR-L2 AASSLQS 808 CD142 (TF) CDR-L3 QQYNSYPYT 809 CD142 (TF) VH EVQLLESGGGLVQPGGSLRLSCAASGFTFSNYAMSWVRQAPGKGLEWVSSISGSGDYTYYTDSVKGRFTISRDNSKNTLYLQMNSLRAEDTAVYYCARSPWGYYLDSWGQGTLVTVSS 810 CD142 (TF) VL DIQMTQSPPSLSASAGDRVTITCRASQGISSRLAWYQQKPEKAPKSLIYAASSLQSGVPSRFSGSGSGTDFTLTISSLQPEDFATYYCQQYNSYPYTFGQGTKLEIK 811 h2G12/STn CDR-H1 DHAIH 812 h2G12/STn CDR-H2 YFSPGNDDIKYNEKFRG 813 h2G12/STn CDR-H3 SLSTPY 814 h2G12/STn CDR-L1 KSSQSLLNRGNHKNYLT 815 h2G12/STn CDR-L2 WASTRES 816 h2G12/STn CDR-L3 QNDYTYPYT 817 h2G12/STn VH EVQLVQSGAEVKKPGASVKVSCKASGYTFTDHAIHWVRQAPGQGLEWMGYFSPGNDDIKYNEKFRGRVTMTADKSSSTAYMELRSLRSDDTAVYFCKRSLSTPYWGQGTLVTVSS 818 h2G12/STn VL DIVMTQSPDSLAVSLGERATINCKSSQSLLNRGNHKNYLTWYQQKPGQPPKLLIYWASTRESGVPDRFSGSGSGTDFTLTISSLQAEDVAVYYCQNDYTYPYTFGQGTKVEIK 819 CD20 CDR-H1 SYNMH 820 CD20 CDR-H2 AIYPGNGDTSYNQKFKG 821 CD20 CDR-H3 STYYGGDWYFNV 822 CD20 CDR-L1 RASSSVSYIH 823 CD20 CDR-L2 ATSNLAS 824 CD20 CDR-L3 QQWTSNPPT 825 CD20 VH QVQLQQPGAELVKPGASVKMSCKASGYTFTSYNMHWVKQTPGRGLEWIGAIYPGNGDTSYNQKFKGKATLTADKSSSTAYMQLSSSLTSEDSAVYYCARSTYYGGDWYFNVWGAGTTVTVSA 826 CD20 VL QIVLSQSPAILSASPGEKVTMTCRASSSVSYIHWFQQKPGSSPKPWIYATSNLASGVPVRFSGSGSGTSYSLTISRVEAEDAATYYCQQWTSNPPTFGGGTKLEIK 827 HER2 CDR-H1 D T 828 HER2 CDR-H2 RIYPTNGYTRYADSVKG 829 HER2 CDR-H3 WGGDGFYAMDY 830 HER2 CDR-L1 RASQDVNTAVA 831 HER2 CDR-L2 SASFLYS 832 HER2 CDR-L3 QQHYTTPPT 833 HER2 VH EVQLVESGGGLVQPGGSLRLSCAASGFNIKDTYIHWVRQAPGKGLEWVARIYPTNGYTRYADSVKGRFTISADTSKNTAYLQMNSLRAEDTAVYYCSRWGGDGFYAMDYWGQGTLVTVSS 834 HER2 VL DIQMTQSPSSSLSASVGDRVTITCRASQDVNTAVAWYQQKPGKAPKLLIYSASFLYSGVPSRFSGSRSGTDFTLTISSLQPEDFATYYCQQHYTTPPTFGQGTKVEIK 835 CD79b CDR-H1 SYWIE 836 CD79b CDR-H2 EILPGGGDTNYNEIFKG 837 CD79b CDR-H3 RVPIRLDY 838 CD79b CDR-L1 KASQSVDYEGDSFLN 839 CD79b CDR-L2 AASNLES 840 CD79b CDR-L3 QQSNEDPLT 841 CD79b VH EVQLVESGGGLVQPGGSLRLSCAASGYTFSSYWIEWVRQAPGKGLEWIGEILPGGGDTNYNEIFKGRATFSADTSKNTAYLQMNSLRAEDTAVYYCTRRVPIRLDYWGQGTLVTVSS 842 CD79b VL DIQLTQSPSSSLSASVGDRVTITCKASQSVDYEGDSFLNWYQQKPGKAPKLLIYAASNLESGVPSRFSGSGSGTDFTLTISSLQPEDFATYYCQQSNEDPLTFGQGTKVEIK 843 NaPi2B CDR-H1 DFAMS 844 NaPi2B CDR-H2 TIGRVAFHTYYPDSMKG 845 NaPi2B CDR-H3 HRGFDVGHFDF 846 NaPi2B CDR-L1 RSSETLVHSSGNTYLE 847 NaPi2B CDR-L2 RVSNRFS 848 NaPi2B CDR-L3 FQGSFNPLT 849 NaPi2B VH EVQLVESGGGLVQPGGSLRLSCAASGFSFSDFAMSWVRQAPGKGLEWVATIGRVAFHTYYPDSMKGRFTISRDNSKNTLYLQMNSLRAEDTAVYYCARHRGFDVGHFDFWGQGTLVTVSS 850 NaPi2B VL DIQMTQSPSSSLSASVGDRVTITCRSSETLVHSSGNTYLEWYQQKPGKAPKLLIYRVSNRFSGVPSRFSGSGSGTDFTLTISSLQPEDFATYYCFQGSFNPLTFGQGTKVEIK 851 Muc16 CDR-H1 NDYAWN 852 Muc16 CDR-H2 YISYSGYTTYNPSLKS 853 Muc16 CDR-H3 WTSGLDY 854 Muc16 CDR-L1 KASDLIHNWLA 855 Muc16 CDR-L2 GATSLET 856 Muc16 CDR-L3 QQYWTTPFT 857 Muc16 VH EVQLVESGGGLVQPGGSLRLSCAASGYSITNDYAWNWVRQAPGKGLEWVGYISYSGYTTYNPSLKSRFTISRDTSKNTLYLQMNSLRAEDTAVYYCARWTSGLDYWGQGTLVTVSS 858 Muc16 VL DIQMTQSPSSSLSASVGDRVTITCKASDLIHNWLAWYQQKPGKAPKLLIYGATSLETGVPSRFSGSGSGTDFTLTISSLQPEDFATYYCQQYWTTPFTFGQGTKVEIK 859 STEAP1 CDR-H1 SDYAWN 860 STEAP1 CDR-H2 YISNSGSTSYNPSLKS 861 STEAP1 CDR-H3 ERNYDYDDYYYAMDY 862 STEAP1 CDR-L1 KSSQSLLYRSNQKNYLA 863 STEAP1 CDR-L2 WASTRES 864 STEAP1 CDR-L3 QQYYNYPRT 865 STEAP1 VH EVQLVESGGGLVQPGGSLRLSCAVSGYSITSDYAWNWVRQAPGKGLEWVGYISNSGSTSYNPSLKSRFTISRDTSKNTLYLQMNSLRAEDTAVYYCARERNYDYDDYYYAMDYWGQGTLVTVSS 866 STEAP1 VL DIQMTQSPSSSLSASVGDRVTITCKSSQSLLYRSNQKNYLAWYQQKPGKAPKLLIYWASTRESGVPSRFSGSGSGTDFTLTISSLQPEDFATYYCQQYYNYPRTFGQGTKVEIK 867 BCMA CDR-H1 NYWMH 868 BCMA CDR-H2 ATYRGHSDTYYNQKFKG 869 BCMA CDR-H3 GAIYDGYDVLDN 870 BCMA CDR-L1 SASQDISNYLN 871 BCMA CDR-L2 YTSNLHS 872 BCMA CDR-L3 QQYRKLPWT 873 BCMA VH QVQLVQSGAEVKKPGSSVKVSCKASGGTFSNYWMHWVRQAPGQGLEWMGATYRGHSDTYYNQKFKGRVTITADKSTSTAYMELSSLRSEDTAVYYCARGAIYDGYDVLDNWGQGTLVTVSS 874 BCMA VL DIQMTQSPSSSLSASVGDRVTITCSASQDISNYLNWYQQKPGKAPKLLIYYTSNLHSGVPSRFSGSGSGTDFTLTISSLQPEDFATYYCQQYRKLPWTFGQGTKLEIK 875 c-Met CDR-H1 YT M 876 c-Met CDR-H2 WIKPNNGLANYAQKFQG 877 c-Met CDR-H3 SEITTEFDY 878 c-Met CDR-L1 KSSESVDSYANSFLH 879 c-Met CDR-L2 RASTRES 880 c-Met CDR-L3 QQSKEDPLT 881 c-Met VH QVQLVQSGAEVKKPGASVKVSCKASGYIFTAYTMHWVRQAPGQGLEWMGWIKPNNGLANYAQKFQGRVTMTRDTSISTAYMELSRLRSDDTAVYYCARSEITTEFDYWGQGTLVTVSS 882 c-Met VL DIVMTQSPDSLAVSLGERATINCKSSESVDSYANSFLHWYQQKPGQPPKLLIYRASTRESGVPDRFSGSGSGTDFTLTISSLQAEDVAVYYCQQSKEDPLTFGGGTKVEIK 883 EGFR CDR-H1 SDFAWN 884 EGFR CDR-H2 YISYSGNTRYQPSLKS 885 EGFR CDR-H3 AGRGFPY 886 EGFR CDR-L1 HSSQDINSNIG 887 EGFR CDR-L2 HGTNLDD 888 EGFR CDR-L3 VQYAQFPWT 889 EGFR VH QVQLQESGPGLVKPSQTLSLTCTVSGYSISSDFAWNWIRQPPGKGLEWMGYISYSGNTRYQPSLKSRITISRDTSKNQFFLKLNSVTAADTATYYCVTAGRGFPYWGQGTLVTVSS 890 EGFR VL DIQMTQSPSSSMSVSVGDRVTITCHSSQDINSNIGWLQQKPGKSFKGLIYHGTNLDDGVPSRFSGSGSGTDYTLTISSLQPEDFATYYCVQYAQFPWTFGGGTKLEIK 891 SLAMF7 CDR-H1 DYYMA 892 SLAMF7 CDR-H2 SINYDGSSTYYVDSVKG 893 SLAMF7 CDR-H3 DRGYYFDY 894 SLAMF7 CDR-L1 RSSQSLVHSNGNTYLH 895 SLAMF7 CDR-L2 KVSNRFS 896 SLAMF7 CDR-L3 SQSTHVPPFT 897 SLAMF7 VH EVQLVESGGGLVQPGGSLRLSCAASGFTFSDYYMAWVRQAPGKGLEWVASINYDGSSTYYVDSVKGRFTISRDNAKNSLYLQMNSLRAEDTAVYYCARDRGYYFDYWGQGTTVTVSS 898 SLAMF7 VL DVVMTQTPLSLSVTPGQPASISCRSSQSLVHSNGNTYLHWYLQKPGQSPQLLIYKVSNRFSGVPDRFSGSGSGTDFTLKISRVEAEDVGVYFCSQSTHVPPFTFGGGTKVEIK 899 C4.4a CDR-H1 NAWMS 900 C4.4a CDR-H2 YISSSGSTIYYADSVKG 901 C4.4a CDR-H3 EGLWAFDY 902 C4.4a CDR-L1 TGSSSNIGAGYVVH 903 C4.4a CDR-L2 DNNKRPS 904 C4.4a CDR-L3 AAWDDRLNGPV 905 C4.4a VH EVQLLESGGGLVQPGGSLRLSCAASGFTFSNAWMSWVRQAPGKGLEWVSYISSSGSTIYYADSVKGRFTISRDNSKNTLYLQMNSLRAEDTAVYYCAREGLWAFDYWGQGTLVTVSS 906 C4.4a VL ESVLTQPPSVSGAPGQRVTISCTGSSSNIGAGYVVHWYQQLPGTAPKLLIYDNNKRPSGVPDRFSGSKTSASLAISGLRSEDEADYYCAAWDDRLNGPVFGGGTKLTVL 907 GCC CDR-H1 GYW 908 GCC CDR-H2 EINHRGNTNDNPSLKS 909 GCC CDR-H3 ERGYTYGNFDH 910 GCC CDR-L1 RASQSVSRNLA 911 GCC CDR-L2 GASTRAT 912 GCC CDR-L3 QQYKTWPRT 913 GCC VH QVQLQQWGAGLLKPSETLSLTCAVFGGSFSGYYWSWIRQPPGKGLEWIGEINHRGNTNDNPSLKSRVTISSVDTSKNQFALKLSSVTAADTAVYYCARERGYTYGNFDHWGQGTLVTVSS 914 GCC VL EIVMTQSPATLSVSPGERATLSCRASQSVSRNLAWYQQKPGQAPRLLIYGASTRATGIPARFSGSGSGTEFTLTIGSLQSEDFAVYYCQQYKTWPRTFGQGTNVEIK 915 Axl CDR-H1 SYAMN 916 Axl CDR-H2 TTSGSGASTYYADSVKG 917 Axl CDR-H3 IWIAFDI 918 Axl CDR-L1 RASQSVSSSYLA 919 Axl CDR-L2 GASSRAT 920 Axl CDR-L3 QQYGSSPYT 921 Axl VH EVQLLESGGGLVQPGGSLRLSCAASGFTFSSYAMNWVRQAPGKGLEWVSTTSGSGASTYYADSVKGRFTISRDNSKNTLYLQMNSLRAEDTAVYYCAKIWIAFDIWGQGTMVTVSS 922 Axl VL EIVLTQSPGTLSLSPGERATLSCRASQSVSSSYLAWYQQKPGQAPRLLIYGASSRATGIPDRFSGSGSGTDFTLTISRLEPEDFAVYYCQQYGSSPYTFGQGTKLEIK 923 CR011/gpNMB CDR-H1 SFNYYWS 924 CR011/gpNMB CDR-H2 YIYYSGSTYSNPSLKS 925 CR011/gpNMB CDR-H3 GYNWNYFDY 926 CR011/gpNMB CDR-L1 RASQSVDNNLV 927 CR011/gpNMB CDR-L2 GASTRAT 928 CR011/gpNMB CDR-L3 QQYNNWPPWT 929 CR011/gpNMB VH QVQLQESGPGLVKPSQTLSLTCTVSGGSISSFNYYWSWIRHHPGKGLEWIGYIYYSGSTYSNPSLKSRVTISSVDTSKNQFSLTLSSVTAADTAVYYCARGYNWNYFDYWGQGTLVTVSS 930 CR011/gpNMB VL EIVMTQSPATLSVSPGERATLSCRASQSVDNNLVWYQQKPGQAPRLLIYGASTRATGIPARFSGSGSGTEFTLTISSLQSEDFAVYYCQQYNNWPPWTFGQGTKVEIK 931 CR011/gpNMB HC QVQLQESGPGLVKPSQTLSLTCTVSGGSISSFNYYWSWIRHHPGKGLEWIGYIYYSGSTYSNPSLKSRVTISSVDTSKNQFSLTLSSVTAADTAVYYCARGYNWNYFDYWGQG TLVTVSSASTKGPSVFPLAPSSKSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKKVEPKSCDK THTCPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEK TISKAKGQPREPQVYTLPPSRDELTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGK 932 CR011/gpNMB LC EIVMTQSPATLSVSPGERATLSCRASQSVDNNLVWYQQKPGQAPRLLIYGASTRATGIPARFSGSGSGTEFTLTISSLQSEDFAVYYCQQYNNWPPWTFGQGTKVEI KRTVAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC 933 Prolactin receptor CDR-H1 TYW 934 Prolactin receptor CDR-H2 EIDPSDSYSNYNQKFKD 935 Prolactin receptor CDR-H3 NGGLGPAWFSY 936 Prolactin receptor CDR-L1 KASQYVGTAVA 937 Prolactin receptor CDR-L2 SASNRYT 938 Prolactin receptor CDR-L3 QQYSSYPWT 939 Prolactin receptor VH EVQLVQSGAEVKKPGSSVKVSCKASGYTFTTYWMHWVRQAPGQGLEWIGEIDPSDSYSNYNQKFKDRATLTVDKSTSTAYMELSSLRSEDTAVYYCARNGGLGPAWFSYWGQGTLVTVSS 940 Prolactin receptor VL DIQMTQSPSSVSASVGDRVTITCKASQYVGTAVAWYQQKPGKSPKLLIYSASNRYTGVPSRFSDSGSGTDFTLTISSLQPEDFATYFCQQYSSYPWTFGGGTKVEIK 941 FGFR2 CDR-H1 SYAMS 942 FGFR2 CDR-H2 AISGSGTSTYYADSVKG 943 FGFR2 CDR-H3 VRYNWNHGDWFDP 944 FGFR2 CDR-L1 SGSSSNIGNNYVS 945 FGFR2 CDR-L2 ENYNRPA 946 FGFR2 CDR-L3 SSWDDSLNYWV 947 FGFR2 VH EVQLLESGGGLVQPGGSLRLSCAASGFTFSSYAMSWVRQAPGKGLEWVSAISGSGTSTYYADSVKGRFTISRDNSKNTLYLQMNSLRAEDTAVYYCARVRYNWNHGDWFDPWGQGTLVTVSS 948 FGFR2 VL QSVLTQPPSASGTPGQRVTISCSGSSSNIGNNYVSWYQQLPGTAPKLLIYENYNRPAGVPDRFSGSKSGTSASLAISGLRSEDEADYYCSSWDDSLNYWVFGGGTKLTVL 949 CDCP1 CDR-H1 SYGMS 950 CDCP1 CDR-H2 TISSGGSYKYYVDSVKG 951 CDCP1 CDR-H3 HPDYDGVWFAY 952 CDCP1 CDR-L1 SVSSSVFYVH 953 CDCP1 CDR-L2 DTSKLAS 954 CDCP1 CDR-L3 QQWNSNPPT 955 CDCP1 VH EVQLVESGGGLVQPGGSLRLSCAASGFTFNSYGMSWVRQAPGKGLEWVATISSGGSYKYYVDSVKGRFTISRDNAKNSLYLQMNSLRAEDTAVYYCARHPDYDGVWFAYWGQGTLVTVSS 956 CDCP1 VL DIQMTQSPSSSLSASVGDRVTITCSVSSSVFYVHWYQQKPGKAPKLLIYDTSKLASGVPSRFSGSGSGTDFTFTISSLQPEDIATYYCQQWNSNPPTFGGGTKVEIK 957 CDCP1 CDR-H1 SYGMS 958 CDCP1 CDR-H2 TISSGGSYTYYPDSVKG 959 CDCP1 CDR-H3 HPDYDGVWFAY 960 CDCP1 CDR-L1 SVSSSVFYVH 961 CDCP1 CDR-L2 DTSKLAS 962 CDCP1 CDR-L3 QQWNSNPPT 963 CDCP1 VH EVQLVESGGDLVKPGGSLKLSCAASGFTFNSYGMSWVRQTPDKRLEWVATISSGGSYTYYPDSVKGRFTISRDNAKNTLYLQMSSLKSEDTAMYYCARHPDYDGVWFAYWGQGTLVTVSA 964 CDCP1 VL QIVLTQSPAIMSASPGEKVTMTCSVSSSVFYVHWYQQKSGTSPKRWIYDTSKLASGVPARFSGSGSGTSYSLTISSMEAEDAATYYCQQWNSNPPTFGGGTKLEIK 965 CDCP1 CDR-H1 YY 966 CDCP1 CDR-H2 IINPSGGSTSYAQKFQG 967 CDCP1 CDR-H3 DGVLRYFDWLLDYYYYMDV 968 CDCP1 CDR-L1 RASQSVGSYLA 969 CDCP1 CDR-L2 DASNRAT 970 CDCP1 CDR-L3 QQRANVFT 971 CDCP1 VH EVQLVQSGAEVKKPGASVKVSCKASGYTFTSYYMHWVRQAPGQGLEWMGIINPSGGSTSYAQKFQGRVTMTRDTSTSTVYMELSSLRSEDTAVYYCARDGVLRYFDWLLDYYYYMDVWGKGTTVTVSS 972 CDCP1 VL EIVLTQSPATLSLSPGERATLSCRASQSVGSYLAWYQQRPGQAPRLLIYDASNRATGIPARFSGSGSGTDFTLTISSLEPEDFAVYYCQQRANVFTFGQGTKVEIK 973 CDCP1 CDR-H1 YY 974 CDCP1 CDR-H2 IINPSGGSTSYAQKFQG 975 CDCP1 CDR-H3 DAELRHFDHLLDYHYYMDV 976 CDCP1 CDR-L1 RASQSVGSYLA 977 CDCP1 CDR-L2 DASNRAT 978 CDCP1 CDR-L3 QQRAQEFT 979 CDCP1 VH EVQLVQSGAEVKKPGASVKVSCKASGYTFTSYYMHWVRQAPGQGLEWMGIINPSGGSTSYAQKFQGRVTMTRDTSTSTVYMELSSLRSEDTAVYYCARDAELRHFDHLLDYHYYMDVWGQGTTVTVSS 980 CDCP1 VL EIVMTQSPATLSLSPGERATLSCRASQSVGSYLAWYQQKPGQAPRLLIYDASNRATGIPARFSGSGSGTDFTLTISSLQPEDFAVYYCQQRAQEFTFGQGTKVEIK 981 ASCT2 VH QVQLVQSGSELKKPGAPVKVSCKASGYTFSTFGMSWVRQAPGQGLKWMGWIHTYAGVPIYGDDFKGRFVFSLDTSVSTAYLQISSLKAEDTAVYFCARRSDNYRYFFDYWGQGTTVTVSS 982 ASCT2 VL DIQMTQSPSSLSASLGDRVTITCRASQDIRNYLNWYQQKPGKAPKLLIYYTSRLHSGVPSRFSGSGSGTDYTLTISSLQPEDFATYFCQQGHTLPPTFGQGTKLEIK 983 ASCT2 VH QIQLVQSGPELKKPGAPVKISCKASGYTFTTFGMSWVKQAPGQGLKWMGWIHTYAGVPIYGDDFKGRFVFSLDTSVSTAYLQISSVKAEDTATYFCARRSDNYRYFFDYWGQGTTLTVSS 984 ASCT2 VL DIQMTQSPSSLSASLGDRVTITCRASQDIRNYLNWYQQKPGKAPKLLIYYTSRLHSGVPSRFSGSGSGTDYTLTISSLQPEDFATYFCQQGHTLPPTFGQGTKLEIK 985 ASCT2 CDR-H1 NYYMA 986 ASCT2 CDR-H2 SITKGGGNTYYRDSVKG 987 ASCT2 CDR-H3 QVTIAAVSTSYFDS 988 ASCT2 CDR-L1 KTNQKVDYYGNSYVY 989 ASCT2 CDR-L2 LASNLAS 990 ASCT2 CDR-L3 QQSRNLPYT 991 ASCT2 VH EVQLVESGGGLVQSGRSIRLSCAASGFSFSNYYMAWVRQAPSKGLEWVASITKGGGNTYYRDSVKGRFTFSRDNAKSTLYLQMDSLRSEDTATYYCARQVTIAAVSTSYFDSWGQGVMVTVSS 992 ASCT2 VL DIVLTQSPALAVSLGQRATISCKTNQKVDYYGNSYVYWYQQKPGQQPKLLIYLASNLASGIPARFSGRGSGTDFTLTIDPVEADDTATYYCQQSRNLPYTFGAGTKLELK 993 CD123 CDR-H1 DYYMK 994 CD123 CDR-H2 DIIPSNGATFYNQKFKG 995 CD123 CDR-H3 SHLLRASWFAY 996 CD123 CDR-L1 KSSQSLLNSGNQKNYLT 997 CD123 CDR-L2 WASTRES 998 CD123 CDR-L3 QNDYSYPYT 999 CD123 VH QVQLVQSGAEVKKPGASVKMSCKASGYTFTDYYMKWVKQAPGQGLEWIGDIIPSNGATFYNQKFKGKATLTVDRSISTAYMHLNRLRSDDTAVYYCTRSHLLRASWFAYWGQGTLVTVSS 1000 CD123 VL DFVMTQSPDSLAVSLGERATINCKSSQSLLNSGNQKNYLTWYLQKPGQPPKLLIYWASTRESGVPDRFSGSGSGTDFTLTISSLQAEDVAVYYCQNDYSYPYTFGQGTKLEIK 1001 GPC3 CDR-H1 DYEM 1002 GPC3 CDR-H2 GIDPETGGTAYNQKFKG 1003 GPC3 CDR-H3 YYSFAY 1004 GPC3 CDR-L1 RSSQSIVHSNANTYLQ 1005 GPC3 CDR-L2 KVSNRFS 1006 GPC3 CDR-L3 FQVSHVPYT 1007 GPC3 VH EVQLVQSGAEVKKPGATVKISCKVSGYTFTDYEMHWVQQAPGKGLEWMGGIDPETGGTAYNQKFKGRVTLTADKSTDTAYMELSSLRSEDTAVYYCGRYYSFAYWGQGTLVTVSS 1008 GPC3 VL DVVMTQSPLSLPVTLGQPASISCRSSQSIVHSNANTYLQWFQQRPGQSPRLLIYKVSNRFSGVPDRFSGSGSGTDFTLKISRVEAEDVGVYYCFQVSHVPYTFGQGTKLEIK 1009 TIGIT CDR-H1 SYAIS 1010 TIGIT CDR-H2 SIIPIFGTANYAQKFQG 1011 TIGIT CDR-H3 GPSEVGAILGYVWFDP 1012 TIGIT CDR-L1 RSSQSLLHSNGYNYLD 1013 TIGIT CDR-L2 LGSNRAS 1014 TIGIT CDR-L3 MQARRIPIT 1015 TIGIT VH QVQLVQSGAEVKKPGSSVKVSCKASGGTFSSYAISWVRQAPGQGLEWMGSIIPIFGTANYAQKFQGRVTITADESTSTAYMELSSLRSEDTAVYYCARGPSEVGAILGYVWFDPWGQGTLVTVSS 1016 TIGIT VL DIVMTQSPLSLPVTPGEPASISCRSSQSLLHSNGYNYLDWYLQKPGQSPQLLIYLGSNRASGVPDRFSGSGSGTDFTLKISRVEAEDVGVYYCMQARRIPITFGGGTKVEIK 1017 CD33 CDR-H1 NYDIN 1018 CD33 CDR-H2 WIYPGDGSTKYNEKFKA 1019 CD33 CDR-H3 GYEDAMDY 1020 CD33 CDR-L1 KASQDINSYLS 1021 CD33 CDR-L2 RANRLVD 1022 CD33 CDR-L3 LQYDEFPLT 1023 CD33 VH QVQLVQSGAE VKKPGASVKV SCKASGYTFT NYDINWVRQA PGQGLEWIGW IYPGDGSTKY NEKFKAKATL TADTSTSTAY MELRSLRSDD TAVYYCASGY EDAMDYWGQG TTVTVSS 1024 CD33 VL DIQMTQSPS SLSASVGDRVT INCKASQDINSYLSWFQQKPGKAPKTL IYRANRLVDGVPS RFSGSGSGQDYTLT ISSLQPEDFATYYCLQYDEFPLTFGGGTKVEIK 1025 BCMA CDR-H1 DYYI 1026 BCMA CDR-H2 YINPNSGYTNYAQKFQG 1027 BCMA CDR-H3 YMWERVTGFFDF 1028 BCMA CDR-L1 LASEDISDDLA 1029 BCMA CDR-L2 TTSSLQS 1030 BCMA CDR-L3 QQTYKFPPT 1031 BCMA VH QVQLVQSGAEVKKPGASVKLSCKASGYTFTDYYIHWVRQAPGQGLEWIGYINPNSGYTNYAQKFQGRATMTADKSINTAYVELSRLRSDDTAVYFCTRYMWERVTGFFDFWGQGTMVTVSS 1032 BCMA VL DIQMTQSPSSVSASVGDRVTITTCLASEDISDDLAWYQQKPGKAPKVLVYTTSSLQSGVPSRFSGSGSGTDFTLTISSLQPEDFATYFCQQTYKFPPTFGGGTKVEIK 1033 ＜Q13433；Protein MARKLSVILI LTFALSVTNP LHELKAAAFP QTTEKISPNW ESGINVDLAI STRQYHLQQL FYRYGENNSL SVEGFRKLLQ NIGIDKIKRI HIHHDHDHHS DHEHHSDHER HSDHEHHSEH EHHSDHDHHS HHNHAASGKN KRKALCPDHD SDSSGKDPRN SQGKGAHRPE HASGRRNVKD SVSASEVTST VYNTVSEGTH FLETIETPRP GKLFPKDVSS STPPSVTSKS RVSRLAGRKT NESVSEPRKG FMYSRNTNEN PQECFNASKL LTSHGMGIQV PLNATEFNYL CPAIINQIDA RSCLIHTSEK KAEIPPKTYS LQIAWVGGFI AISIISFLSL LGVILVPLMN RVFFKFLLSF LVALAVGTLS GDAFLHLLPH SHASHHHSHS HEEPAMEMKR GPLFSHLSSQ NIEESAYFDS TWKGLTALGG LYFMFLVEHV LTLIKQFKDK KKKNQKKPEN DDDVEIKKQL SKYESQLSTN EEKVDTDDRT EGYLRADSQE PSHFDSQQPA VLEEEEVMIA HAHPQEVYNE YVPRGCKNKC HSHFHDTLGQ SDDLIHHHHD YHHILHHHHH QNHHPHSHSQ RYSREELKDA GVATLAWMVI MGDGLHNFSD GLAIGAAFTE GLSSGLSTSV AVFCHELPHE LGDFAVLLKA GMTVKQAVLY NALSAMLAYL GMATGIFIGH YAENVSMWIF ALTAGLFMYV ALVDMVPEML HNDASDHGCS RWGYFFLQNA GMLLGFGIML LISIFEHKIV FRINF 1034 hLIV22 antigenic determinant KGAHRPEH 1035 CD24 CDR-H1 TYAFH 1036 CD24 CDR-H2 GIVPIFGTLKYAQKFQD 1037 CD24 CDR-H3 AIQLEGRPFDH 1038 CD24 CDR-L1 RASQGITSYLA 1039 CD24 CDR-L2 AASALQS 1040 CD24 CDR-L3 QQVNRGAAIT 1041 CD24 VH QVQLVQSGAEVKKPGSSVRVSCRASGGSSTTYAFHWVRQAPGQGLEWMGGIVPIFGTLKYAQKFQDRVTLTADKSTGTAYMELNSLRLDDTAVYYCARAIQLEGRPFDHWGQGTQVTVSA 1042 CD24 VL DIQLTQSPSFLSASVGDRVTITCRASQGITSYLAWYQQKPGKAPKLLIYAASALQSGVPS RFSGRGSGTEFTLTISSLQPEDFATYYCQQVNRGAAITFGHGTRLDIK 1043 RL peptide GGGG 1044 RL peptide G JZ 1045 RL peptide VKG 1046 RL peptide GGFG 1047 RL peptide GGFGG 1048 RC48 CDR-H1 DYYI 1049 RC48 CDR-H2 RVNPDHGDSYYNQKFKD 1050 RC48 CDR-H3 NYLFDH 1051 RC48 CDR-L1 KASQDVGTAVA 1052 RC48 CDR-L2 WASIRHT 1053 RC48 CDR-L3 HQFATYT 1054 RC48 VH EVQLVQSGAEVKKPGATVKISCKVSGYTFTDYYIHWVQQAPGKGLEWMGRVNPDHGDSYYNQKFKDKATITADKSTDTAYMELSSLRSEDTAVYFCARNYLFDHWGQGTLVTVSS 1055 RC48 VL DIQMTQSPSSVSASVGDRVTITCKASQDVGTAVAWYQQKPGKAPKLLIYWASIRHTGVPSRFSGSGSGTDFTLTISSLQPEDFATYYCHQFATYTFGGGTKVEIK 1056 RC48 HC EVQLVQSGAEVKKPGATVKISCKVSGYTFTDYYIHWVQQAPGKGLEWMGRVNPDHGDSYYNQKFKDKATITADKSTDTAYMELSSLRSEDTAVYFCARNYLFDHWGQGTLV TVSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKKVEPKSCDKTH TCPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKT ISKAKGQPREPQVYTLPPSREEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGK 1057 RC48 HC v2 EVQLVQSGAEVKKPGATVKISCKVSGYTFTDYYIHWVQQAPGKGLEWMGRVNPDHGDSYYNQKFKDKATITADKSTDTAYMELSSLRSEDTAVYFCARNYLFDHWGQGTLV TVSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKKVEPKSCDKTH TCPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKT ISKAKGQPREPQVYTLPPSREEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPG 1058 RC48 LC DIQMTQSPSSVSASVGDRVTITCKASQDVGTAVAWYQQKPGKAPKLLIYWASIRHTGVPSRFSGSGSGTDFTLTISSLQPEDFATYYCHQFATYTFGGGTKVEIKR TVAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC

[ Figure 1 ] . Illustrate in vivo mean tumor volume data and weight change data for various ADCs comprising an EphA2-targeting mAb with a mIgG2a WT backbone conjugated to the indicated compounds (dosing schedule = Q1Wx3, or 3 weekly intravenous doses) in the Renca tumor mouse model. [ Figure 2A ] . Illustrate in vivo mean tumor volume data for various ADCs comprising an EphA2-targeting mAb with a mouse IgG2a (mIgG2a) WT backbone conjugated to the indicated compounds (dosing schedule = single intravenous dose) in the MC38 tumor mouse model. [ FIG. 2B ] . Illustrates in vivo weight change data for various ADCs comprising an EphA2-targeting mAb with a mIgG2a WT backbone conjugated to the indicated compounds in the MC38 tumor mouse model (dosing schedule = single intravenous dose). [ FIG. 3A ] . Illustrates in vivo mean tumor volume data for compounds dosed Q1Wx3 intravenously (3 weekly doses) in the Renca tumor mouse model. [ FIG. 3B ] . Illustrates in vivo weight change data for compounds dosed Q1Wx3 intravenously (3 weekly doses) in the Renca tumor mouse model. [ FIG. 4A ] . Illustrates in vivo mean tumor volume data of various ADCs comprising a mAb targeting Her2 with a human IgG1 (hIgG1) WT backbone conjugated to the indicated compounds (dosing schedule = single iv dose) in the SKOV3 tumor mouse model after a single iv dose. [ FIG. 4B ] . In vivo weight change data of ADCs comprising a mAb targeting Her2 with a hIgG1 WT backbone conjugated to the indicated compounds (dosing schedule = single iv dose) in the SKOV3 tumor mouse model after a single iv dose. [ Figure 5 ] illustrates RFP+ HT1080 tumor cell killing in response to treatment of tumor cells and co-cultures of peripheral blood mononuclear cells (PBMCs) with various ADCs comprising non-conjugated hIgG1 mAb (WT Fc), hIgG1 mAb targeting CD228 (WT Fc), or hIgG1 mAb targeting CD228 (LALAKA Fc) conjugated to the indicated compounds. RFP+ tumor cell confluence at 90 hours (relative to time t=0 hours) is plotted. [ FIG. 6A ] illustrates in vivo mean tumor volume data for various ADCs comprising an EphA2-targeting mAb with a mIgG2a WT backbone conjugated to the indicated compounds (dosing schedule = single intravenous dose) in the MC38 tumor mouse model. [ FIG. 6B ] illustrates in vivo weight change data for various ADCs comprising an EphA2-targeting mAb with a mIgG2a WT backbone conjugated to the indicated compounds (dosing schedule = single intravenous dose) in the MC38 tumor mouse model. [ FIG. 7A ] illustrates the in vivo mean tumor volume data of ADCs containing EphA2-targeting or non-conjugated mAbs with a mIgG2a WT backbone conjugated to Compound 2.4 in the MC38 tumor mouse model (WT C57BL/6 tumor-bearing mice; dosing schedule = single intravenous dose). [ FIG. 7B ] illustrates the in vivo mean tumor volume data of ADCs containing EphA2-targeting mAbs with a mIgG2a WT backbone conjugated to Compound 2.4 in the MC38 tumor-bearing STING-deficient mouse model (STING-deficient C57BL/6J- Sting1 ^gt /J tumor-bearing mice; dosing schedule = single intravenous dose).

TW202506691A_113114797_SEQL.xml

Claims (101)

A compound of formula (A): , Formula (A) or a pharmaceutically acceptable salt thereof, wherein L ¹ is or ; X ¹ is N or CR ^1X ; Y ¹ is N or CR ^1Y ; Z ¹ , Y ² and Z ² are each independently N, CH or CF; X ² is N or CR ^2X ; X ³ is N or CR ^3X ; T ⁴ is N, S, O or CH; X ⁴ is C or N; Y ⁴ is N, NR ^4Y or CR ^4Y ; Z ⁴ is N, S, O, CF or CH; R ¹ is C ₁ -C ₆ alkyl, C ₃ -C ₈ cycloalkyl or C ₁ -C ₆ halogenalkyl; wherein at least one of X ¹ , Y ¹ and X ³ is not N; R ^1X , R ^1Y and R ^3X are each independently H, -OH, halogen, optionally substituted C ₁ -C ₆ alkyl, -O(C ₁ -C ₆ alkyl) or , wherein no more than one of R ^1X , R ^1Y and R ^3X is ; wherein the wavy line indicates the point of attachment to the rest of the compound; ^Xa and ^Xb are independently H, ^OH , ^SH , _CO2R4 or ^NR4R5 , or ^Xa and ^Xb together with the carbon atom to which they are attached form wherein the asterisk (*) represents the carbon atom to which ^Xa and ^Xb are attached, ^Xc is H, a halogen group or an optionally substituted _C1 - _C6 alkyl group; q is an integer from 0 to 6; n is 0, 1 or 2; m is 1 or 2; ^R8 and ^R9 are each independently H, a halogen group, CN, SH, OH, _-CO2H , ^NR4R5 or ^an optionally substituted _C1 - _C6 alkyl group by -OH, a halogen group or _-CO2H ; ^R10 is H or an optionally substituted C1-C6 alkyl group by OH, a halogen group, ^NR4R5 or _CO2R4 ^{; R2X} is H, a halogen group, a _C1 - _C6 alkyl group, a _C3 - _C6 cycloalkyl group or a _C1 - _C6 halogen group; ^R4Y is H, a halogen group, a _{C1-C6 alkyl group or a C3} ^- _{C6 cycloalkyl} group; C ₆ alkyl, C ₁ -C ₆ halogenalkyl or C ₃ -C ₆ cycloalkyl; T is C(O)NR ⁴ R ⁵ or S(O) ₂ NR ⁶ R ⁷ ; R ⁴ , R ⁵ , R ⁶ and R ⁷ are independently and independently H or optionally substituted C ₁ -C ₆ alkyl at each occurrence; the virtual bonds of formula (A) are each independently single or double bonds, so that the ring with the virtual bonds is an aromatic ring; and Ring A is , or , where the wavy line indicates the point of attachment to the rest of the compound; The restriction is that when L ¹ is , Ring A is , X ¹ is CR ^1X , Y ¹ is CH , Z ¹ is CH , Z ² is CH , and X ² is N , then T ⁴ , X ⁴ , Y ⁴ , Z ⁴ and R ¹ cannot be simultaneously selected such that T ⁴ is CH , X ⁴ is C , Y ⁴ is NR ^4Y , Z ⁴ is N , and R ¹ is an optionally substituted methyl group. The compound of claim 1, wherein the compound has formula (I): , Formula (I) or a pharmaceutically acceptable salt thereof, wherein X ¹ is N or CR ^1X ; Y ¹ is N or CR ^1Y ; Z ¹ , Y ² and Z ² are each independently N, CH or CF; X ² is N or CR ^2X ; X ³ is N or CR ^3X ; T ⁴ is N, S, O or CH; X ⁴ is C or N; Y ⁴ is N, NR ^4Y or CR ^4Y ; Z ⁴ is N, S, O, CF or CH; R ¹ is C ₁ -C ₆ alkyl, C ₃ -C ₈ cycloalkyl or C ₁ -C ₆ halogenalkyl; wherein at least one of X ¹ , Y ¹ and X ³ is not N; R ^1X , R ^1Y and R ^3X are each independently H, -OH, halogen, optionally substituted C ₁ -C ₆ alkyl, -O(C ₁ -C ₆ alkyl) or , wherein no more than one of R ^1X , R ^1Y and R ^3X is ; wherein the wavy line indicates the point of attachment to the rest of the compound; ^Xa and ^Xb are independently H, ^OH , ^SH , _CO2R4 or ^NR4R5 , or ^Xa and ^Xb together with the carbon atom to which they are attached form wherein the asterisk (*) represents the carbon atom to which ^Xa and ^Xb are attached, ^Xc is H, a halogen group or an optionally substituted _C1 - _C6 alkyl group; q is an integer from 0 to 6; n is 0, 1 or 2; m is 1 or 2; ^R8 and ^R9 are each independently H, a halogen group, CN, SH, OH, _-CO2H , ^NR4R5 or ^an optionally substituted _C1 - _C6 alkyl group by -OH, a halogen group or _-CO2H ; ^R10 is H or an optionally substituted C1-C6 alkyl group by OH, a halogen group, ^NR4R5 or _CO2R4 ^{; R2X} is H, a halogen group, a _C1 - _C6 alkyl group, a _C3 - _C6 cycloalkyl group or a _C1 - _C6 halogen group; ^R4Y is H, a halogen group, a _{C1-C6 alkyl group or a C3} ^- _{C6 cycloalkyl} group; C ₆ alkyl, C ₁ -C ₆ halogenalkyl or C ₃ -C ₆ cycloalkyl; T is C(O)NR ⁴ R ⁵ or S(O) ₂ NR ⁶ R ⁷ ; R ⁴ , R ⁵ , R ⁶ and R ⁷ are independently and independently H or optionally substituted C ₁ -C ₆ alkyl at each occurrence; the virtual bonds of formula (I) are each independently single or double bonds, so that the ring with the virtual bonds is an aromatic ring; and Ring A is , or , where the wavy line indicates the point of attachment to the rest of the compound; the restriction is that when Ring A is , X ¹ is CR ^1X , Y ¹ is CH , Z ¹ is CH , Z ² is CH , and X ² is N , then T ⁴ , X ⁴ , Y ⁴ , Z ⁴ and R ¹ cannot be simultaneously selected such that T ⁴ is CH , X ⁴ is C , Y ⁴ is NR ^4Y , Z ⁴ is N , and R ¹ is an optionally substituted methyl group. The compound of claim 1 or 2 or a pharmaceutically acceptable salt thereof, wherein T is C(O)NR ⁴ R ⁵ , preferably T is C(O)NH ₂ . The compound or pharmaceutically acceptable salt thereof of any one of claims 1 to 3, wherein X ³ is CR ^3X . The compound of any one of claims 1 to 3 or a pharmaceutically acceptable salt thereof, wherein X ³ is N. The compound or pharmaceutically acceptable salt thereof of any one of claims 1 to 5, wherein X ⁴ is C, T ⁴ is O, Z ⁴ is N, and Y ⁴ is CR ^4Y ; or X ⁴ is C, T ⁴ is S, Z ⁴ is N, and Y ⁴ is CR ^4Y ; or X ⁴ is C, T ⁴ is N, Z ⁴ is N, and Y ⁴ is NR ^4Y . The compound or pharmaceutically acceptable salt thereof of any one of claims 1 to 6, wherein X ⁴ is C, T ⁴ is O, Z ⁴ is N, and Y ⁴ is CR ^4Y . The compound or pharmaceutically acceptable salt thereof of any one of claims 1 to 6, wherein X ⁴ is C, T ⁴ is S, Z ⁴ is N, and Y ⁴ is CR ^4Y . The compound or pharmaceutically acceptable salt thereof of any one of claims 1 to 6, wherein X ⁴ is C, T ⁴ is N, Z ⁴ is N, and Y ⁴ is NR ^4Y . The compound or pharmaceutically acceptable salt thereof of any one of claims 7 to 9, wherein R ¹ is methyl and R ^4Y is ethyl. The compound of any one of claims 1 to 10 or a pharmaceutically acceptable salt thereof, wherein Y ² is N. The compound or pharmaceutically acceptable salt thereof of any one of claims 1 to 11, wherein ^X2 is N, ^Z1 is CH, and ^Z2 is CH. The compound or pharmaceutically acceptable salt thereof of any one of claims 1 to 12, wherein X ¹ is CR ^1X and Y ¹ is CR ^1Y . The compound of any one of claims 1 to 12 or a pharmaceutically acceptable salt thereof, wherein X ¹ is CR ^1X and Y ¹ is N. The compound or pharmaceutically acceptable salt thereof of any one of claims 1 to 12, wherein X ¹ is N and Y ¹ is CR ^1Y . The compound or pharmaceutically acceptable salt thereof of any one of claims 1 to 11 and 13, wherein X ² is CR ^2X , Z ² is N, X ¹ is CR ^1X , Y ¹ is CR ^1Y , and Z ¹ is CH. The compound of any one of claims 1 to 16 or a pharmaceutically acceptable salt thereof, wherein exactly one of R ^1X , R ^1Y and R ^3X is OH or The remaining parts of R ^1X , R ^1Y and R ^3X , when present, are each independently H or O(C ₁ -C ₆ alkyl). The compound of any one of claims 1 to 17 or a pharmaceutically acceptable salt thereof, wherein exactly one of R ^1X , R ^1Y and R ^3X is -OH and the remaining R ^1X , R ^1Y and R ^3X , when present, are each independently H or O(C ₁ -C ₆ alkyl). The compound of any one of claims 1 to 17 or a pharmaceutically acceptable salt thereof, wherein exactly one of R ^1X , R ^1Y and R ^3X is -OCH ₂ CH ₂ CH ₂ OH and the remaining R ^1X , R ^1Y and R ^3X , when present, are each independently H or -OC ₁ -C ₆ alkyl. The compound of any one of claims 1 to 17 or a pharmaceutically acceptable salt thereof, wherein exactly one of R ^1X , R ^1Y and R ^3X is The remaining parts of R ^1X , R ^1Y and R ^3X , when present, are each independently H or -OC ₁ -C ₆ alkyl. The compound of any one of claims 1 to 20 or a pharmaceutically acceptable salt thereof, wherein Ring A is . The compound of any one of claims 1 to 3, 5, 10 to 13, 17 and 21, wherein the compound is , or its pharmaceutically acceptable salts. The compound of any one of claims 1 to 3, 5, 10 to 13 and 17, wherein the compound is , or its pharmaceutically acceptable salts. The compound of any one of claims 1 to 4, 10 to 13, 17 and 21, wherein the compound is , or its pharmaceutically acceptable salts. The compound of any one of claims 1 to 4, 10 to 13 and 17, wherein the compound is , or its pharmaceutically acceptable salts. The compound of any one of claims 1 to 4, 10, 11, 13, 17 and 21, wherein the compound is , or its pharmaceutically acceptable salts. The compound of any one of claims 1 to 4, 10 to 12, 14 and 21, wherein the compound is , or its pharmaceutically acceptable salts. The compound of any one of claims 1 to 4, 6, 7, 10 to 13, 17 and 21, wherein the compound is , or its pharmaceutically acceptable salts. The compound of any one of claims 1 to 4, 6, 9, 11 to 13, 17 and 21, wherein the compound is , or its pharmaceutically acceptable salts. A drug linker compound of the formula: QD, or a pharmaceutically acceptable salt thereof, wherein Q is a linker unit selected from the group consisting of: (i) Z'-A-RL-, (ii) Z'-A-RL-Y-, (iii) Z'-AS ^* -RL-, (iv) Z'-AS ^* -RL-Y-, (v) Z'-AB(S ^* )-RL-, (vi) Z'-AB(S ^* )-RL-Y-, (vii) Z'-A-, (viii) Z'-AS*-W-, (ix) Z'-AB(S*)-W-, (x) Z'-AS*-W-RL-, and (xi) Z'-AB(S*)-W-RL-;Z' is a stretcher unit precursor; A is a bond or linker unit; B is a parallel linker unit; S* is a spacer; RL is a releasable linker; W is an amino acid unit; Y is a second spacer unit; and D is a drug unit of formula (A'): , Formula (A') wherein L ¹ is or ; X ¹ is N or CR ^1X ; Y ¹ is N or CR ^1Y ; Z ¹ , Y ² and Z ² are each independently N, CH or CF; X ² is N or CR ^2X ; X ³ is N or CR ^3X ; T ⁴ is N, S, O or CH; X ⁴ is C or N; Y ⁴ is N, NR ^4Y or CR ^4Y ; Z ⁴ is N, S, O, CF or CH; R ¹ is C ₁ -C ₆ alkyl, C ₃ -C ₈ cycloalkyl or C ₁ -C ₆ halogenalkyl; wherein at least one of X ¹ , Y ¹ and X ³ is not N; R ^1X , R ^1Y and R ^3X are each independently H, -OH, halogen, optionally substituted C ₁ -C ₆ alkyl, -O(C ₁ -C ₆ alkyl) or -S ¹ -#, the restriction is that exactly one of R ^1X , R ^1Y and R ^3X is -S ¹ -#, -S ¹ -# is , , or , wherein the wavy line indicates the point of attachment to the remainder of D and # represents the point of attachment to Q; ^Xc is H, halogen, or optionally substituted _C1 - _C6 alkyl; q is an integer from 0 to 6; n is 0, 1 or 2; m is 1 or 2; ^R8 and ^R9 are each independently H, ^halogen , CN, SH, OH, _CO2H , ^NR4R5 , or _C1 - _C6 alkyl substituted with OH, halogen, or _CO2H ; ^R10 is C1- _C6 ^alkyl substituted with OH, ^halogen , ^NR4R5 , or _CO2R4 , or ^R10 is absent; ^R2X is H, halogen, _C1 - _{C6 alkyl} , _C3 - _C6 cycloalkyl, or _C1 - _C6 halogenalkyl; R ^4Y is H, halogen, C ₁ -C ₆ alkyl, C ₁ -C ₆ halogenalkyl or C ₃ -C ₆ cycloalkyl; T is C(O)NR ⁴ R ⁵ or S(O) ₂ NR ⁶ R ⁷ ; R ⁴ , R ⁵ , R ⁶ and R ⁷ are independently and independently H or optionally substituted C ₁ -C ₆ alkyl at each occurrence; the virtual bonds of formula (A') are each independently single or double bonds, so that the ring with the virtual bonds is an aromatic ring; and Ring A is , or , where the wavy line indicates the point of attachment to the rest of the compound; The restriction is that when L ¹ is , Ring A is , X ¹ is CR ^1X , Y ¹ is CH , Z ¹ is CH , Z ² is CH , and X ² is N , then T ⁴ , X ⁴ , Y ⁴ , Z ⁴ and R ¹ cannot be simultaneously selected such that T ⁴ is CH , X ⁴ is C , Y ⁴ is NR ^4Y , Z ⁴ is N , and R ¹ is an optionally substituted methyl group. The drug linker compound of claim 30, wherein the drug linker has the following formula: QD, or a pharmaceutically acceptable salt thereof, wherein Q is a linker unit selected from the group consisting of: (i) Z'-A-RL-, (ii) Z'-A-RL-Y-, (iii) Z'-AS ^* -RL-, (iv) Z'-AS ^* -RL-Y-, (v) Z'-AB(S ^* )-RL-, (vi) Z'-AB(S ^* )-RL-Y-, (vii) Z'-A-, (viii) Z'-AS*-W-, (ix) Z'-AB(S*)-W-, (x) Z'-AS*-W-RL-, and (xi) Z'-AB(S*)-W-RL-;Z' is a stretcher unit precursor; A is a bond or a linker unit; B is a parallel linker unit; S* is a separator; RL is a releasable linker; W is an amino acid unit; Y is a second spacer unit; and D is a drug unit of formula (I'): , Formula (I') wherein X ¹ is N or CR ^1X ; Y ¹ is N or CR ^1Y ; Z ¹ , Y ² and Z ² are each independently N, CH or CF; X ² is N or CR ^2X ; X ³ is N or CR ^3X ; T ⁴ is N, S, O or CH; X ⁴ is C or N; Y ⁴ is N, NR ^4Y or CR ^4Y ; Z ⁴ is N, S, O, CF or CH; R ¹ is C ₁ -C ₆ alkyl, C ₃ -C ₈ cycloalkyl or C ₁ -C ₆ halogenalkyl; wherein at least one of X ¹ , Y ¹ and X ³ is not N; R ^1X , R ^1Y and R ^3X are each independently H, -OH, halogen, optionally substituted C ₁ -C ₆ alkyl, -O(C ₁ -C ₆ alkyl) or -S ¹ -#, with the proviso that exactly one of R ^1X , R ^1Y and R ^3X is -S ¹ -#, and -S ¹ -# is , , or , wherein the wavy line indicates the point of attachment to the remainder of D and # represents the point of attachment to Q; ^Xc is H, halogen, or optionally substituted _C1 - _C6 alkyl; q is an integer from 0 to 6; n is 0, 1 or 2; m is 1 or 2; ^R8 and ^R9 are each independently H, ^halogen , CN, SH, OH, _CO2H , ^NR4R5 , or _C1 - _C6 alkyl substituted with OH, halogen, or _CO2H ; ^R10 is C1- _C6 ^alkyl substituted with OH, ^halogen , ^NR4R5 , or _CO2R4 , or ^R10 is absent; ^R2X is H, halogen, _C1 - _{C6 alkyl} , _C3 - _C6 cycloalkyl, or _C1 - _C6 halogenalkyl; R ^4Y is H, halogen, C ₁ -C ₆ alkyl, C ₁ -C ₆ halogenalkyl or C ₃ -C ₆ cycloalkyl; T is C(O)NR ⁴ R ⁵ or S(O) ₂ NR ⁶ R ⁷ ; R ⁴ , R ⁵ , R ⁶ and R ⁷ are independently and independently H or optionally substituted C ₁ -C ₆ alkyl at each occurrence; the virtual bonds of formula (I') are each independently single or double bonds, so that the ring with the virtual bonds is an aromatic ring; and Ring A is , or , where the wavy line indicates the point of attachment to the rest of the compound; the restriction is that when Ring A is , X ¹ is CR ^1X , Y ¹ is CH , Z ¹ is CH , Z ² is CH , and X ² is N , then T ⁴ , X ⁴ , Y ⁴ , Z ⁴ and R ¹ cannot be simultaneously selected such that T ⁴ is CH , X ⁴ is C , Y ⁴ is NR ^4Y , Z ⁴ is N , and R ¹ is an optionally substituted methyl group. The drug-linker compound or a pharmaceutically acceptable salt thereof of claim 30 or 31, wherein the linker unit Q has formula (i), (ii), (iii), (iv), (x) or (xi). The drug-linker compound or a pharmaceutically acceptable salt thereof of claim 30 or 31, wherein the linker unit Q has formula (v), (vi), (ix) or (xi). The drug-linker compound or a pharmaceutically acceptable salt thereof of claim 30 or 31, wherein the linker unit Q has formula (viii), (ix), (x) or (xi). The drug-linker compound of any one of claims 30 to 34 or a pharmaceutically acceptable salt thereof, wherein the stretcher unit Z' is wherein R ¹⁷ is -CH ₂ CH ₂ (OCH ₂ CH ₂ ) _k -, -C ₁ -C ₁₀ alkylene-, C ₁ -C ₁₀ heteroalkylene-, -C ₃ -C ₈ carbocyclyl-, -O-(C 1 -C ₈ alkylene)-, -arylene-, -C ₁ -C ₁₀ alkylene-arylene-, -arylene-C ₁ -C ₁₀ alkylene-, -C ₁ -C ₁₀ alkylene-(C 3 -C ₈ carbocyclyl)-, -(C ₃ -C ₈ carbocyclyl)-C ₁ -C ₁₀ alkylene-, _{-C 3 -C 8} heterocyclyl-, -C ₁ -C ₁₀ alkylene-(C ₃ -C ₈ heterocyclyl)- _, -(C ₃ -C ₈ heterocyclyl)-C _{-C 1} -C ₁₀ alkylene-, -C ₁ -C ₁₀ alkylene-C(=O)-, C ₁ -C ₁₀ heteroalkylene-C(=O)-, -C ₃ -C ₈ carbocyclyl-C(=O)-, -O-(C ₁ -C ₈ alkylene)-C(=O)-, -arylene-C(=O)-, -C ₁ -C ₁₀ alkylene-arylene-C(=O)-, -arylene-C ₁ -C ₁₀ alkylene-C(=O)-, -C ₁ -C ₁₀ alkylene-(C ₃ -C ₈ carbocyclyl)-C(=O)-, -(C ₃ -C ₈ carbocyclyl)-C ₁ -C ₁₀ alkylene-C(=O)-, -C ₃ -C ₈ heterocyclyl-C(=O)-, -C _{-C 1} -C ₁₀ alkylene-(C ₃ -C ₈ heterocyclic group)-C(═O)-, -(C ₃ -C ₈ heterocyclic group)-C ₁ -C ₁₀ alkylene-C(═O)-, -C ₁ -C ₁₀ alkylene-NH-, C ₁ -C ₁₀ heteroalkylene-NH-, -C ₃ -C ₈ carbocyclic group-NH-, -O-(C ₁ -C ₈ alkylene)-NH-, -arylene-NH-, -C ₁ -C ₁₀ alkylene-arylene-NH-, -arylene-C 1 -C ₁₀ alkylene-NH-, -C ₁ -C ₁₀ alkylene-(C _{3 -C 8 carbocyclic group)-NH-, -(C 3 -C 8} carbocyclic group)-C 1 -C 10 alkylene-NH-, -C ₁ -C ₁₀ alkylene-(C ₃ -C ₈ carbocyclic group)-NH-, -C _{-C 3} -C ₈ heterocyclic group-NH-, -C ₁ -C ₁₀ alkylene-(C ₃ -C ₈ heterocyclic group)-NH-, -(C ₃ -C ₈ heterocyclic group)-C ₁ -C ₁₀ alkylene-NH-, -C ₁ -C ₁₀ alkylene-S-, C ₁ -C ₁₀ heteroalkylene-S-, -C ₃ -C ₈ carbocyclic group-S-, -O-(C ₁ -C ₈ alkylene)-S-, -arylene-S-, -C ₁ -C ₁₀ alkylene-arylene-S-, -arylene-C ₁ -C ₁₀ alkylene-S-, -C 1 -C ₁₀ alkylene-(C ₃ -C ₈ carbocyclic group)-S-, -(C ₃ -C ₈ carbocyclic group)-C _{1 -C} The invention relates to a group consisting of: -C _1-6 alkyl and -C _1-6 halogen, -C _1-6 alkylene-S-, -C ₃ -C ₈ heterocycloyl-S-, -C ₁ -C ₁₀ alkylene-(C ₃ -C ₈ heterocycloyl)-S- or -(C ₃ -C ₈ heterocycloyl)-C 1 -C 10 alkylene-S-; the subscript k is an integer ranging from 1 to 36; R ¹⁷ is optionally substituted by a basic unit (BU), such as an aminoalkyl moiety, wherein x is an integer of 1-4 and each ^Ra is independently selected from the group consisting of C _1-6 alkyl and C _1-6 halogen, or two ^Ra groups are combined with the nitrogen to which they are attached to form an azacyclobutane, pyrrolidinyl or piperidinyl; and the wavy line indicates the point of covalent attachment to the rest of the drug-linker compound. The drug-linker compound of any one of claims 30 to 35 or a pharmaceutically acceptable salt thereof, wherein the stretcher unit Z' is , where the wavy line indicates the point of covalent attachment to the remainder of the drug-linker compound. The drug-linker compound or a pharmaceutically acceptable salt thereof of any one of claims 30 to 36, wherein the linker unit A is wherein each R ¹⁰⁰ is independently hydrogen or -C ₁ -C ₃ alkyl; and R ¹¹¹ is independently selected from the group consisting of hydrogen, p-hydroxybenzyl, methyl, isopropyl, isobutyl, dibutyl, -CH ₂ OH, -CH(OH)CH ₃ , -CH ₂ CH ₂ SCH ₃ , -CH ₂ CONH ₂ , -CH ₂ COOH, -CH ₂ CH ₂ CONH ₂ , -CH ₂ CH ₂ COOH, -(CH ₂ ) ₃ NHC(=NH)NH ₂ , -(CH ₂ ) ₃ NH ₂ , -(CH ₂ ) ₃ NHCOCH ₃ , -(CH ₂ ) ₃ NHCHO, -(CH ₂ ) ₄ NHC(=NH)NH ₂ , -(CH ₂ ) ₄ NH ₂ , -(CH ₂ ) ₄ NHCOCH ₃ , -(CH ₂ ) ₄ NHCHO, -(CH ₂ ) ₃ NHCONH ₂ , -(CH ₂ ) ₄ NHCONH ₂ , -CH ₂ CH ₂ CH(OH)CH ₂ NH ₂ , 2-pyridylmethyl-, 3-pyridylmethyl-, 4-pyridylmethyl-, Each subscript c is an integer independently selected from 1 to 10; and the wavy line indicates that the linker unit is connected to the rest of the drug-linker compound. The drug-linker compound or a pharmaceutically acceptable salt thereof of any one of claims 30 to 37, wherein the linker unit A is ; c is an integer ranging from 1 to 6; and the wavy line indicates the site of attachment to the remainder of the drug-linker compound or a pharmaceutically acceptable salt thereof. The drug-linker compound or a pharmaceutically acceptable salt thereof of any one of claims 30 to 36, wherein A is a bond. The drug-linker compound of any one of claims 30 to 39 or a pharmaceutically acceptable salt thereof, wherein B is ; each AA is independently a proteinogenic amino acid or a non-proteinogenic amino acid; and the wavy line indicates the point of attachment to the remainder of the drug-linker compound or a pharmaceutically acceptable salt thereof. The drug-linker compound or a pharmaceutically acceptable salt thereof of any one of claims 30 to 40, wherein B is an amino acid. The drug-linker compound of any one of claims 30 to 41 or a pharmaceutically acceptable salt thereof, wherein B is or ; The wavy line indicates the point of attachment to the spacer S*; and the asterisk indicates the point of attachment to the rest of the drug-linker structure. The drug-linker compound of any one of claims 30 to 42, or a pharmaceutically acceptable salt thereof, wherein the spacer S* is a polyethylene glycol (PEG) unit, a cyclodextrin unit, a polyamide, a hydrophilic peptide, a polysaccharide or a dendrimer. The drug-linker compound of any one of claims 30 to 43, or a pharmaceutically acceptable salt thereof, wherein the spacer S ^* is a PEG unit comprising 4 to 72 (CH ₂ CH ₂ O) subunits. The drug conjugate of any one of claims 30 to 44 or a pharmaceutically acceptable salt thereof, wherein the PEG unit is b is selected from the group consisting of 4 to 36; and the wavy line indicates the site of attachment to the remainder of the drug-linker compound or a pharmaceutically acceptable salt thereof. The drug-linker compound or pharmaceutically acceptable salt thereof of any one of claims 30 to 45, wherein the releasable linker RL is -(AA) _1-12 -; and each AA is independently a proteinogenic amino acid or a non-proteinogenic amino acid. The drug-linker compound or pharmaceutically acceptable salt thereof of any one of claims 30 to 46, wherein the releasable linker RL is -AA ₁ -AA ₂ - or -AA ₁ -AA ₂ -AA ₃ -, wherein AA ₁ is connected to the stretcher unit Z' or the linker unit A. The drug-linker compound of any one of claims 30 to 47 or a pharmaceutically acceptable salt thereof, wherein the releasable linker RL is or ; and the wavy line adjacent to the -NH- group indicates connection to the stretcher unit Z' or the linker unit A and the wavy line adjacent to the -C(=O)- group indicates connection to the second spacer unit Y or the drug unit D. The drug-linker compound of any one of claims 30 to 48, or a pharmaceutically acceptable salt thereof, wherein the releasable linker RL is a glycoside. The drug-linker compound of any one of claims 30 to 49 or a pharmaceutically acceptable salt thereof, wherein the releasable linker RL is wherein Su is a 6-carbon carbohydrate moiety; O' represents an oxygen atom of a glycosidic bond that can be cleaved by a glycosidase; the wavy line marked with a single asterisk (*) indicates the site of covalent attachment to D; and the wavy line marked with a double asterisk (**) indicates the site of covalent attachment to the remainder of Q. The drug-linker compound of any one of claims 30 to 50 or a pharmaceutically acceptable salt thereof, wherein the releasable linker RL is ; The wavy line marked with a single asterisk (*) indicates the site of covalent attachment to D; and the wavy line marked with a double asterisk (**) indicates the site of covalent attachment to the remainder of Q. The drug-linker compound or a pharmaceutically acceptable salt thereof of any one of claims 30 to 33 and 35 to 51, wherein the second spacer unit Y is , or Wherein EWG is an electron withdrawing group; and the wavy line indicates the attachment site to the rest of the drug-linker compound or its pharmaceutically acceptable salt. The drug-linker compound or a pharmaceutically acceptable salt thereof of any one of claims 30 to 33 and 35 to 52, wherein the second spacer unit Y is or ; and the wavy line indicates the site of attachment to the remainder of the drug-linker compound or a pharmaceutically acceptable salt thereof. The drug-linker compound of any one of claims 30, 31, 35, 36, 39, 42, 46, 48, 52 and 53, or a pharmaceutically acceptable salt thereof, wherein Z' is ; R ¹⁷ is C ₁ -C ₁₀ alkylene; A is a bond; RL is -AA ₁ -AA ₂ -; AA ₁ and AA ₂ are each independently a protein amino acid; Y is or ; and the wavy line indicates the site of attachment to the remainder of the drug-linker compound or a pharmaceutically acceptable salt thereof. The drug-linker compound of any one of claims 30, 31, 35, 36 and 39, wherein the linker unit is . The drug-linker compound of any one of claims 30, 31, 35, 36, 39 and 55, wherein the compound is or a pharmaceutically acceptable salt thereof. The drug-linker compound of any one of claims 30 to 32, 35, 36, 39, 46, 47 and 52 to 54, wherein the linker unit is . The drug-linker compound of any one of claims 30 to 32, 35, 36, 39, 46, 47, 52 to 54 and 57, wherein the compound is or a pharmaceutically acceptable salt thereof. The drug-linker compound of any one of claims 30 to 32, 35, 38 and 49, wherein the linker unit is . The drug-linker compound of any one of claims 30 to 32, 35, 38, 49, 51 and 59, wherein the compound is or a pharmaceutically acceptable salt thereof. A ligand-drug conjugate compound of the formula, L-(QD) _p or a pharmaceutically acceptable salt thereof, wherein L is a ligand unit; Q is a linker unit selected from the group consisting of: (i) ZA-RL-, (ii) ZA-RL-Y-, (iii) ZAS ^* -RL-, (iv) ZAS ^* -RL-Y-, (v) ZAB(S ^* )-RL-, (vi) ZAB(S ^* )-RL-Y-, (vii) ZA-, (viii) ZAS*-W-, (ix) ZAB(S*)-W-, (x) ZAS*-W-RL-, and (xi) ZAB(S*)-W-RL-; Z is a stretcher unit; A is a bond or linker unit; B is a parallel linker unit; S* is a spacer; RL is a releasable linker; W is an amino acid unit; Y is a second spacer unit; and D is a drug unit of formula (A'): , Formula (A') wherein L ¹ is or ; X ¹ is N or CR ^1X ; Y ¹ is N or CR ^1Y ; Z ¹ , Y ² and Z ² are each independently N, CH or CF; X ² is N or CR ^2X ; X ³ is N or CR ^3X ; T ⁴ is N, S, O or CH; X ⁴ is C or N; Y ⁴ is N, NR ^4Y or CR ^4Y ; Z ⁴ is N, S, O, CF or CH; R ¹ is C ₁ -C ₆ alkyl, C ₃ -C ₈ cycloalkyl or C ₁ -C ₆ halogenalkyl; wherein at least one of X ¹ , Y ¹ and X ³ is not N; R ^1X , R ^1Y and R ^3X are each independently H, -OH, halogen, optionally substituted C ₁ -C ₆ alkyl, -O(C ₁ -C ₆ alkyl) or -S ¹ -#, the restriction is that exactly one of R ^1X , R ^1Y and R ^3X is -S ¹ -#, -S ¹ -# is , , or , wherein the wavy line indicates the point of attachment to the remainder of D and # represents the point of attachment to Q; ^Xc is H, halogen, or optionally substituted _C1 - _C6 alkyl; q is an integer from 0 to 6; n is 0, 1 or 2; m is 1 or 2; ^R8 and ^R9 are each independently H, ^halogen , CN, SH, OH, _CO2H , ^NR4R5 , or _C1 - _C6 alkyl substituted with OH, halogen, or _CO2H ; ^R10 is C1- _C6 ^alkyl substituted with OH, ^halogen , ^NR4R5 , or _CO2R4 , or ^R10 is absent; ^R2X is H, halogen, _C1 - _{C6 alkyl} , _C3 - _C6 cycloalkyl, or _C1 - _C6 halogenalkyl; R ^4Y is H, halogen, C ₁ -C ₆ alkyl, C ₁ -C ₆ halogenalkyl or C ₃ -C ₆ cycloalkyl; T is -C(O)NR ⁴ R ⁵ or -S(O) ₂ NR ⁶ R ⁷ ; R ⁴ , R ⁵ , R ⁶ and R ⁷ are independently H or optionally substituted C ₁ -C ₆ alkyl at each occurrence; the virtual bonds of formula (A') are each independently single or double bonds, so that the ring with the virtual bonds is an aromatic ring; Ring A is , or , where the wavy line indicates the point of attachment to the rest of the compound; The restriction is that when L ¹ is , Ring A is , X ¹ is CR ^1X , Y ¹ is CH , Z ¹ is CH , Z ² is CH , and X ² is N , then T ⁴ , X ⁴ , Y ⁴ , Z ⁴ and R ¹ cannot be simultaneously selected such that T ⁴ is CH , X ⁴ is C , Y ⁴ is NR ^4Y , Z ⁴ is N , and R ¹ is an optionally substituted methyl group ; and p is an integer ranging from 1 to 12. The ligand-drug conjugate compound of claim 61, wherein the ligand-drug conjugate compound has the formula: L-(QD) _p or a pharmaceutically acceptable salt thereof, wherein L is a ligand unit; Q is a linker unit selected from the group consisting of: (i) ZA-RL-, (ii) ZA-RL-Y-, (iii) ZAS ^* -RL-, (iv) ZAS ^* -RL-Y-, (v) ZAB(S ^* )-RL-, (vi) ZAB(S ^* )-RL-Y-, (vii) ZA-, (viii) ZAS*-W-, (ix) ZAB(S*)-W-, (x) ZAS*-W-RL-, and (xi) ZAB(S*)-W-RL-; Z is a stretcher unit; A is a bond or linker unit; B is a parallel linker unit; S* is a spacer; RL is a releasable linker; W is an amino acid unit; Y is a second spacer unit; and D is a drug unit of formula (I'): , Formula (I') wherein X ¹ is N or CR ^1X ; Y ¹ is N or CR ^1Y ; Z ¹ , Y ² and Z ² are each independently N, CH or CF; X ² is N or CR ^2X ; X ³ is N or CR ^3X ; T ⁴ is N, S, O or CH; X ⁴ is C or N; Y ⁴ is N, NR ^4Y or CR ^4Y ; Z ⁴ is N, S, O, CF or CH; R ¹ is C ₁ -C ₆ alkyl, C ₃ -C ₈ cycloalkyl or C ₁ -C ₆ halogenalkyl; wherein at least one of X ¹ , Y ¹ and X ³ is not N; R ^1X , R ^1Y and R ^3X are each independently H, -OH, halogen, optionally substituted C ₁ -C ₆ alkyl, -O(C ₁ -C ₆ alkyl) or -S ¹ -#, with the proviso that exactly one of R ^1X , R ^1Y and R ^3X is -S ¹ -#, and -S ¹ -# is , , or , wherein the wavy line indicates the point of attachment to the remainder of D and # represents the point of attachment to Q; ^Xc is H, halogen, or optionally substituted _C1 - _C6 alkyl; q is an integer from 0 to 6; n is 0, 1 or 2; m is 1 or 2; ^R8 and ^R9 are each independently H, ^halogen , CN, SH, OH, _CO2H , ^NR4R5 , or _C1 - _C6 alkyl substituted with OH, halogen, or _CO2H ; ^R10 is C1- _C6 ^alkyl substituted with OH, ^halogen , ^NR4R5 , or _CO2R4 , or ^R10 is absent; ^R2X is H, halogen, _C1 - _{C6 alkyl} , _C3 - _C6 cycloalkyl, or _C1 - _C6 halogenalkyl; R ^4Y is H, halogen, C ₁ -C ₆ alkyl, C ₁ -C ₆ halogenalkyl or C ₃ -C ₆ cycloalkyl; T is -C(O)NR ⁴ R ⁵ or -S(O) ₂ NR ⁶ R ⁷ ; R ⁴ , R ⁵ , R ⁶ and R ⁷ are independently and independently H or optionally substituted C ₁ -C ₆ alkyl at each occurrence; the virtual bonds of formula (I') are each independently single or double bonds, so that the ring with the virtual bonds is an aromatic ring; Ring A is , or , where the wavy line indicates the point of attachment to the rest of the compound; the restriction is that when Ring A is , X ¹ is CR ^1X , Y ¹ is CH , Z ¹ is CH , Z ² is CH , and X ² is N , then T ⁴ , X ⁴ , Y ⁴ , Z ⁴ and R ¹ cannot be simultaneously selected such that T ⁴ is CH , X ⁴ is C , Y ⁴ is NR ^4Y , Z ⁴ is N , and R ¹ is an optionally substituted methyl group ; and p is an integer ranging from 1 to 12. The ligand-drug conjugate compound or a pharmaceutically acceptable salt thereof of claim 61 or 62, wherein the linker unit Q has formula (i), (ii), (iii), (iv), (x) or (xi). The ligand-drug conjugate compound or a pharmaceutically acceptable salt thereof of claim 61 or 62, wherein the linker unit Q has formula (v), (vi), (ix) or (xi). The ligand-drug conjugate compound or a pharmaceutically acceptable salt thereof of claim 61 or 62, wherein the linker unit Q has formula (viii), (ix), (x) or (xi). The ligand-drug conjugate compound of any one of claims 61 to 65 or a pharmaceutically acceptable salt thereof, wherein the ligand unit L and the stretcher unit Z together are , or wherein R ¹⁷ is -CH ₂ CH ₂ (OCH ₂ CH ₂ ) _k -, -C ₁ -C ₁₀ alkylene-, C ₁ -C ₁₀ heteroalkylene-, -C ₃ -C ₈ carbocyclyl-, -O-(C ₁ -C ₈ alkylene)-, -arylene-, -C 1 -C ₁₀ alkylene-arylene-, -arylene-C ₁ -C ₁₀ alkylene-, -C ₁ -C ₁₀ alkylene-(C ₃ -C ₈ carbocyclyl)-, -(C ₃ -C ₈ carbocyclyl)-C ₁ -C ₁₀ alkylene-, -C _{3 -C 8} heterocyclyl-, -C ₁ -C ₁₀ alkylene-(C ₃ -C ₈ heterocyclyl)-, -(C ₃ -C 8 _{-C 1 -C 10} alkylene-, -C ₁ -C ₁₀ alkylene-C(=O)-, C ₁ -C ₁₀ heteroalkylene-C(=O)-, -C ₃ -C ₈ carbocyclyl-C(=O)-, -O-(C ₁ -C ₈ alkylene)-C(=O)-, -arylene-C(=O)-, -C ₁ -C ₁₀ alkylene-arylene-C(=O)-, -arylene-C ₁ -C ₁₀ alkylene-C(=O)-, -C ₁ -C ₁₀ alkylene-(C ₃ -C ₈ carbocyclyl)-C(=O)-, -(C ₃ -C ₈ carbocyclyl)-C ₁ -C ₁₀ alkylene-C(=O)-, -C ₃ -C 8 -C ₁ -C ₁₀ alkylene-(C ₃ -C _{8 heterocyclic} group)-C(=O)-, -(C ₃ -C ₈ heterocyclic group)-C 1 -C 10 alkylene-C(=O)-, -C ₁ -C ₁₀ alkylene-NH-, C ₁ -C ₁₀ heteroalkylene-NH-, -C ₃ -C ₈ carbocyclic group-NH-, -O-(C ₁ -C ₈ alkylene)-NH-, -arylene-NH-, -C 1 -C 10 alkylene-arylene-NH-, -arylene-C 1 -C 10 alkylene-NH-, -C ₁ -C ₁₀ alkylene-(C 3 -C ₈ carbocyclic group)-NH-, -O-(C ₁ -C 8 alkylene)-NH-, -arylene-NH-, -C ₁ -C ₁₀ alkylene-arylene-NH-, -arylene-C ₁ -C ₁₀ alkylene-NH-, -C ₁ -C 10 alkylene-(C ₃ -C ₈ carbocyclic group)-NH-, - -C ₈ carbocyclyl)-C ₁ -C ₁₀ alkylene-NH-, -C ₃ -C ₈ heterocyclyl-NH-, -C ₁ -C ₁₀ alkylene-(C ₃ -C ₈ heterocyclyl)-NH-, -(C ₃ -C ₈ heterocyclyl)-C ₁ -C ₁₀ alkylene-NH-, -C ₁ -C ₁₀ alkylene-S-, C ₁ -C ₁₀ heteroalkylene-S-, -C ₃ -C ₈ carbocyclyl-S-, -O-(C ₁ -C ₈ alkylene)-S-, -arylene-S-, -C ₁ -C ₁₀ alkylene-arylene-S-, -arylene-C ₁ -C ₁₀ alkylene-S-, -C ₁ -C ₁₀ alkylene-(C ₃ -C 8 heterocyclyl)- -(C ₃ -C ₈ carbocyclyl)-S-, -(C 3 -C ₈ carbocyclyl)-C ₁ -C ₁₀ alkylene-S-, -C ₃ -C ₈ heterocyclyl-S-, -C ₁ -C ₁₀ alkylene-(C ₃ -C ₈ heterocyclyl)-S- or -(C ₃ -C ₈ heterocyclyl)-C ₁ -C ₁₀ alkylene-S-; subscript k is an integer ranging from 1 to 36; R ¹⁷ is optionally substituted by a basic unit (BU), such as an aminoalkyl moiety, wherein x is an integer of 1 to 4 and each ^Ra is independently selected from the group consisting of C _1-6 alkyl and C _1-6 halogenalkyl, or two R ^{The a} group combines with the nitrogen to which it is attached to form an azacyclobutane, pyrrolidinyl, or piperidinyl group; and the wavy line indicates the point of covalent attachment to the remainder of the ligand-drug conjugate compound. The ligand-drug conjugate compound of any one of claims 61 to 66 or a pharmaceutically acceptable salt thereof, wherein the ligand unit L and the stretcher unit Z together are The wavy line indicates the point of covalent attachment to the remainder of the ligand-drug conjugate compound. The ligand-drug conjugate compound of any one of claims 61 to 67 or a pharmaceutically acceptable salt thereof, wherein the linker unit A is wherein each R ¹⁰⁰ is independently hydrogen or -C ₁ -C ₃ alkyl; and R ¹¹¹ is independently selected from the group consisting of hydrogen, p-hydroxybenzyl, methyl, isopropyl, isobutyl, dibutyl, -CH ₂ OH, -CH(OH)CH ₃ , -CH ₂ CH ₂ SCH ₃ , -CH ₂ CONH ₂ , -CH ₂ COOH, -CH ₂ CH ₂ CONH ₂ , -CH ₂ CH ₂ COOH, -(CH ₂ ) ₃ NHC(=NH)NH ₂ , -(CH ₂ ) ₃ NH ₂ , -(CH ₂ ) ₃ NHCOCH ₃ , -(CH ₂ ) ₃ NHCHO, -(CH ₂ ) ₄ NHC(=NH)NH ₂ , -(CH ₂ ) ₄ NH ₂ , -(CH ₂ ) ₄ NHCOCH ₃ , -(CH ₂ ) ₄ NHCHO, -(CH ₂ ) ₃ NHCONH ₂ , -(CH ₂ ) ₄ NHCONH ₂ , -CH ₂ CH ₂ CH(OH)CH ₂ NH ₂ , 2-pyridylmethyl-, 3-pyridylmethyl-, 4-pyridylmethyl-, Each subscript c is an integer independently selected from 1 to 10; and the wavy line indicates that the linker unit is linked to the remainder of the ligand-drug conjugate compound or a pharmaceutically acceptable salt thereof. The ligand-drug conjugate compound of any one of claims 61 to 68 or a pharmaceutically acceptable salt thereof, wherein the linker unit A is ; c is an integer ranging from 1 to 6; and the wavy line indicates the site of attachment to the remainder of the ligand-drug conjugate compound or a pharmaceutically acceptable salt thereof. The ligand-drug conjugate compound of any one of claims 61 to 67, or a pharmaceutically acceptable salt thereof, wherein A is a bond. The ligand-drug conjugate compound of any one of claims 61 to 70 or a pharmaceutically acceptable salt thereof, wherein B is ; each AA is independently a proteinogenic amino acid or a non-proteinogenic amino acid; and the wavy line indicates the point of attachment to the remainder of the ligand-drug conjugate compound or a pharmaceutically acceptable salt thereof. The ligand-drug conjugate compound of any one of claims 61 to 71 or a pharmaceutically acceptable salt thereof, wherein B is an amino acid. The ligand-drug conjugate compound of any one of claims 61 to 72 or a pharmaceutically acceptable salt thereof, wherein B is or ; The wavy line indicates the point of attachment to the spacer S*; and the asterisk indicates the point of attachment to the remainder of the ligand-drug conjugate compound or a pharmaceutically acceptable salt thereof. The ligand-drug conjugate compound of any one of claims 61 to 73 or a pharmaceutically acceptable salt thereof, wherein the spacer S ^* is a polyethylene glycol (PEG) unit, a cyclodextrin unit, a polyamide, a hydrophilic peptide, a polysaccharide or a dendrimer. The ligand-drug conjugate compound of any one of claims 61 to 74, or a pharmaceutically acceptable salt thereof, wherein the spacer S ^* is a PEG unit containing 4 to 72 (CH ₂ CH ₂ O) subunits. The ligand-drug conjugate compound of any one of claims 61 to 75 or a pharmaceutically acceptable salt thereof, wherein the PEG unit is b is selected from the group consisting of 4 to 36; and the wavy line indicates the site of attachment to the remainder of the ligand-drug conjugate compound or a pharmaceutically acceptable salt thereof. The ligand-drug conjugate compound of any one of claims 61 to 76, or a pharmaceutically acceptable salt thereof, wherein the releasable linker RL is -(AA) _1-12 -; and each AA is independently a proteinogenic amino acid or a non-proteinogenic amino acid. The ligand-drug conjugate compound of any one of claims 61 to 77, or a pharmaceutically acceptable salt thereof, wherein the releasable linker RL is -AA ₁ -AA ₂ - or -AA ₁ -AA ₂ -AA ₃ -, wherein AA ₁ is connected to the stretcher unit Z or the linker unit A. The ligand-drug conjugate compound of any one of claims 61 to 78 or a pharmaceutically acceptable salt thereof, wherein the releasable linker RL is or ; and the wavy line adjacent to the -NH- group indicates connection to the stretcher unit Z or the linker unit A and the wavy line adjacent to the -C(=O)- group indicates connection to the second spacer unit Y or the drug unit D. The ligand-drug conjugate compound of any one of claims 61 to 79, or a pharmaceutically acceptable salt thereof, wherein the releasable linker RL is a glycoside. The ligand-drug conjugate compound of any one of claims 61 to 80 or a pharmaceutically acceptable salt thereof, wherein the releasable linker RL is wherein Su is a 6-carbon carbohydrate moiety; O' represents an oxygen atom of a glycosidic bond that can be cleaved by a glycosidase; the wavy line marked with a single asterisk (*) indicates the site of covalent attachment to D; and the wavy line marked with a double asterisk (**) indicates the site of covalent attachment to the remainder of Q. The ligand-drug conjugate compound of any one of claims 61 to 81 or a pharmaceutically acceptable salt thereof, wherein the releasable linker RL is ; The wavy line marked with a single asterisk (*) indicates the site of covalent attachment to D; and the wavy line marked with a double asterisk (**) indicates the site of covalent attachment to the remainder of Q. The ligand-drug conjugate compound of any one of claims 61 to 64 or 66 to 82 or a pharmaceutically acceptable salt thereof, wherein the second spacer unit Y is , or Wherein EWG is an electron withdrawing group; and the wavy line indicates the attachment site to the rest of the ligand-drug conjugate compound or its pharmaceutically acceptable salt. The ligand-drug conjugate compound or a pharmaceutically acceptable salt thereof of any one of claims 61 to 64 and 66 to 83, wherein the second spacer unit Y is or ; and the wavy line indicates the site of attachment to the remainder of the ligand-drug conjugate compound or a pharmaceutically acceptable salt thereof. The ligand-drug conjugate compound of any one of claims 61 to 63, 66, 67, 70, 77, 79, 83 and 84, or a pharmaceutically acceptable salt thereof, wherein R ¹⁷ is C ₁ -C ₁₀ alkylene; A is a bond; RL is -AA ₁ -AA ₂ -; AA ₁ and AA ₂ are each independently a protein amino acid; Y is or ; and the wavy line indicates the site of attachment to the remainder of the ligand-drug conjugate compound or a pharmaceutically acceptable salt thereof. The ligand-drug conjugate compound of any one of claims 61, 62, 66, 67 and 70 or a pharmaceutically acceptable salt thereof, wherein the ligand unit L and the linker unit Q together are . The ligand-drug conjugate compound of any one of claims 61, 62, 66, 67, 70 and 86, wherein the compound is or a pharmaceutically acceptable salt thereof. The ligand-drug conjugate compound of any one of claims 61 to 63, 66, 67, 70, 77, 78 and 83 to 85 or a pharmaceutically acceptable salt thereof, wherein the ligand unit L and the linker unit Q together are , or . The ligand-drug conjugate compound of any one of claims 61 to 63, 66, 69 and 80 to 82 or a pharmaceutically acceptable salt thereof, wherein the ligand unit L and the linker unit Q together are , or . A ligand-drug conjugate compound as claimed in any one of claims 61 to 89, wherein p is an integer in the range of 2 to 8. A ligand-drug conjugate compound as claimed in any one of claims 61 to 90, wherein p is 4. A pharmaceutical composition comprising the ligand-drug conjugate compound of any one of claims 61 to 89 and a pharmaceutically acceptable excipient. A pharmaceutical composition as claimed in claim 92, wherein the composition comprises a plurality of ligand-drug conjugate compounds, the average value p of which is 2 to 8. The pharmaceutical composition of claim 93, wherein the average value p is about 4. The pharmaceutical composition of claim 93, wherein the average value p is 3.5 to 4.5. A method for treating cancer, comprising administering to a subject in need thereof a therapeutically effective amount of a ligand-drug conjugate compound of any one of claims 62 to 91 or a pharmaceutically acceptable salt thereof. The method of claim 96, wherein the subject tolerates treatment with a therapeutically effective amount of the ligand-drug conjugate compound better than with another ligand-drug conjugate compound. A compound, wherein the compound is selected from the group consisting of the compounds listed in Table 1 or pharmaceutically acceptable salts thereof. A drug-linker compound, wherein the drug-linker compound is selected from the group consisting of compounds listed in Table 2 or pharmaceutically acceptable salts thereof. A released drug-linker cysteine adduct, wherein the released drug-linker cysteine adduct is selected from the group consisting of compounds listed in Table 3 or pharmaceutically acceptable salts thereof. A ligand-drug conjugate compound, wherein the ligand-drug conjugate compound is selected from the group consisting of compounds listed in Table 4 or pharmaceutically acceptable salts thereof, and p is an integer ranging from 1 to 12.

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