Ras inhibitor antibody-drug conjugates and methods of use thereof

Abstract

The present application is related to antibody-drug conjugates that comprise a RAS inhibitor drug moiety. The disclosure further relates to methods and compositions for treating cancers by administering the antibody-drug conjugates.

Description

RAS INHIBITOR ANTIBODY-DRUG CONJUGATES AND METHODS OF USE THEREOFCROSS-REFERENCE TO RELATED APPLICATIONS

[0001] The present application claims priority from Application Nos.PCT / CN2024 / 122982, filed September 30, 2024, and PCT / CN2025 / 095139, filed May 15, 2025. The contents of the priority applications are incorporated by reference herein in their entirety.SEQUENCE LISTING

[0002] The instant application contains a Sequence Listing which has been submitted electronically in XML format and is hereby incorporated by reference herein in its entirety. The electronic copy of the Sequence Listing, created on September 30, 2025, is named 12771 l.W0008.xml and is 56,972 bytes in size.TECHNICAL FIELD

[0003] The present disclosure relates to antibody-drug conjugate (ADC) comprising a RAS inhibitor and an antibody or antigen-binding fragment thereof that binds an antigen target, which may be expressed on a tumor or cancer cell.

[0004] The disclosure further relates to methods and compositions useful in the treatment of a cancer that expresses a target antigen. In some embodiments, the cancer is treated by modulating RAS expression and activity. Also provided are methods of making those compositions.

[0005] Linker-drug conjugates comprising a RAS inhibitor drug moiety and methods of making the same are also disclosed.BACKGROUND

[0006] The RAS family (including KRAS4A, KRAS4B, HRAS, and NRAS) is a family of small, membrane-bound guanine nucleotide-binding proteins that act as molecular switches by cycling between an active GTP -bound state and an inactive GDP -bound state. When RAS binds to a GEF family protein such as S0S1, its conformation changes, and its affinity forGDP is reduced. This causes RAS to dissociate from GDP and bind to GTP, thus becoming active. In normal cells, activation of receptor tyrosine kinases such as epidermal growth factor receptor (EGFR) promotes the exchange of GDP and GTP in (and therefore activation of) RAS, which plays a key role in regulating cell survival, proliferation, and differentiation through multiple cascading reactions, including the PI3K-AKT-mT0R, RAF-MEK-ERK, and RALGDS-RAL pathways. Mutations in RAS are often driving forces for carcinogenesis and tumor development, as they disrupt the guanine exchange cycle and lock RAS in the activated state, continuously activating downstream signaling pathways and leading to the development of tumors.

[0007] RAS mutations occur in approximately 19% of all cancers and play an important role in tumor occurrence and progression. Among them, KRAS is the most commonly mutated subtype, followed by NRAS and HRAS. KRAS mutations commonly occur in pancreatic ductal adenocarcinoma, lung adenocarcinoma, and colorectal adenocarcinoma, while NRAS mutations have a relatively higher frequency in hematologic malignancies such as chronic myeloid leukemia and acute myeloid leukemia, as well as in malignant melanoma, thyroid cancer, and laryngeal cancer. HRAS mutations have a relatively higher mutation rate in head and neck squamous cell carcinoma, bladder cancer, salivary gland carcinoma, and oral cancer.

[0008] Given the key role of the RAS family of proteins in cancer occurrence and progression, there remains a need for the development of RAS inhibitors.SUMMARY OF THE INVENTION

[0009] The present disclosure provides, in part, a novel antibody-drug conjugate (ADC) compound. In some embodiments, the ADC compound has biological activity against cancer cells, may inhibit tumor growth in mammals, and / or may be useful for treating human cancer patients.

[0010] In some embodiments, the ADC compounds are capable of binding and killing cancer cells. In some embodiments, the ADC compounds disclosed herein comprise a conjugate linker that attaches a RAS inhibitor to a full-length antibody or an antigen-binding fragment thereof. In some embodiments, the ADC compounds are also capable of internalizing into a target cell after binding. In some embodiments, the Ras inhibitors are molecular glues.

[0011] In a first aspect, the ADC compound has a structure according to formula (IA):, wherein:Ab is an antibody or an antigen-binding fragment thereof that targets a cancer cell;D is a RAS inhibitor;L is a conjugate linker that covalently attaches Ab to D; and p is an integer from 1 to 16.

[0012] In some embodiments, the conjugate linker L comprises an attachment group, at least one bridging spacer group, a peptide group, and at least one cleavable group.

[0013] In a second aspect, the ADC compounds have a structure according to formula(IIA),, whereinAb is an antibody or an antigen-binding fragment thereof that targets a cancer cell;D is a RAS inhibitor;Li is an attachment group that is joined or covalently linked to Ab and L2;L2 is a bridging spacer group that is joined or covalently linked to Li and L3;L3 is a peptide group that is joined or covalently linked to L2 and L4;L4 is a cleavable group that is joined or covalently linked to L3 and D; and p is the number of linker-drug conjugates [L1-L2-L3-L4-D], selected from any inte- ger between 1 and 16.

[0014] Due to possible heterogeneity of “p” among molecules in an ADC composition, the average number of drugs conjugated to the antibodies or antigen-binding portions thereof in a composition (drug-to-antibody ratio or DAR) may be a number between consecutive integers.Li Attachment Group

[0015] In some embodiments, the attachment group Li is formed by the reaction of at least one reactive precursor group with an Ab moiety, optionally wherein the reactive precursor group is selected from a maleimide group, a thiol group, a cyclooctyne group, an azido group,or a pyrimidine group. In some embodiments, Li has the structure:. In some em- bodiments, Li has the structure. In some embodiments, Li has the structure:

[0016] In some embodiments, a reactive azide moiety on the Ab is reacted with a reactive precursor group. In such embodiments,Ab— L|-t- may comprise the structure, wherein the three conjguated nitrogen atoms are derived from the reactive azide moiety on the Ab.

[0017] In some embodiments, a reactive thiol (e.g., reactive cysteine) moiety on the Ab is reacted with a reactive precursor group. In such embodiments,Ab— L<|-|- may comprise the structure:wherein the sulfur atom is derived from the reactive thiol moiety on the Ab.

[0018] The term “joined” refers to covalently attached to or covalently linked.

[0019] In some embodiments, the attachment between Ab and Li is formed by a reaction comprising at least one reactive group. In some cases, the attachment between Ab and Li isformed by reacting a first reactive group that is attached to the linker-drug precusor with a second reactive group that is attached to Ab or is an amino acid residue of Ab.

[0020] In some embodiments, at least one of the reactive groups comprises a thiol, a malei- mide, a haloacetamide, an azide, an alkyne, a cyclcooctene, a triaryl phosphine, an oxanobor- nadiene, a cyclooctyne, a diaryl tetrazine, a monoaryl tetrazine, a norbornene, an aldehyde, a hydroxylamine, a hydrazine, NH2-NH-C(=O)-, a ketone, a vinyl sulfone, an aziridine, an aminowherein:R31is H or C1-6 alkyl;R41is 2-pyridyl or 4-pyridyl; each R51is independently H, C1-6 alkyl, F, Cl, or -OH; each R61is independently H, Ci-6alkyl, F, Cl, -NH2, -OCH3, -OCH2CH3, -N(CH3)2,-CN, -NO2, or -OH; each R71is independently H, C1-6 alkyl, fluoro, benzyloxy substituted with - C(=O)OH, benzyl substituted with -C(=O)OH, C1-4 alkoxy substituted with -C(=O)OH, or C1-4 alkyl substituted with -C(=O)OH.

[0021] In some embodiments, the first reactive group and second reactive group comprise, respectively: a thiol and a maleimide; a thiol and a haloacetamide; a thiol and a vinyl sulfone; a thiol and an aziridine; an azide and an alkyne; an azide and a cyclooctyne; an azide and a cyclooctene; an azide and a triaryl phosphine; an azide and an oxanobornadiene; a diaryl tetrazine and a cyclooctene; a monoaryl tetrazine and a nonbornene; an aldehyde and a hydroxylamine; an aldehyde and a hydrazine; an aldehyde and NH2-NH-C(=O)-; a ketone and a hydroxylamine; a ketone and a hydrazine; a ketone and NH2-NH-C(=O)-; a hydroxylamine and; or a CoA or CoA analogue and a serine residue.Ab— L^

[0022] In some embodiments, comprises the structure:wherein:R32is H, Ci-4 alkyl, phenyl, pyrimidine, or pyridine;R35is H, Ci-6 alkyl, phenyl, or C1-4 alkyl substituted with 1 to 3 -OH groups; each R72is independently H, Ci-6 alkyl, fluoro, benzyloxy substituted with -C(=O)OH, benzyl substituted with-C(=O)OH, Ci-4 alkoxy substituted with -C(=O)OH, or Ci-4 alkyl substituted with -C(=O)OH; each R37is independently H, phenyl, or pyridine;Q is 0, 1, 2, or 3;R81is H or methyl; andR91is H, -CH3or phenyl.

[0023] In some embodiments,comprises the structure:L2 Bridging Spacer Group

[0025] In some embodiments, the bridging spacer group L2 comprises a butanoyl, penta- noyl, hexanoyl, heptanoyl, octanoyl, a polyoxyethylene (PEG) group, -CO-CH2-CH2-PEG-, -NH-CH2-CH2-PEG-, -C(O)-N(CH3)-CH2-CH2-N(CH3)-C(O)-, -C(O)-CH2-CH2-PEG-NH-C(O)CH2-CH2-. In some embodiments, the PEG group is selected from PEG1, PEG2, PEG3,PEG4, PEG5, PEG6, PEG7, PEG8, PEG9, PEG10, PEGU, PEG12, PEG13, PEG14, andPEG15.

[0026] In some embodiments, L2 comprises a butanoyl, pentanoyl, hexanoyl, heptanoyl, octanoyl, or polyoxyethylene (PEG) group.

[0027] In some embodiments, L2is -CH2CH2-O-CH2CH2-CO- or -C(O)-N(CH3)-CH2- CH2-N(CH3)-C(O)-.

[0028] In some embodiments, L2has the structure, ,OH OH , or OH OH , wherein n2is an integer from 1 to 12.

[0029] In some embodiments, L2has the structure:*-C(=O)(CH2)MO(CH2)M-**;*-C(=O)((CH2)MO)T(CH2)N-**;*-C(=O)(CH2)M-**;*-C(=O)NH((CH2)MO)T(CH2)N-**;*-C(=O)O(CH2)MC(=O)NH(CH2)M-**;*-C(=O)(CH2)MNH(CH2)M-**;*-C(=O)(CH2)MNH(CH2)NC(=O)-* * ;*-C(=O)(CH2)MXL2(CH2)M-**;*-C(=O)((CH2)MO)T(CH2)NXL2(CH2)N-**;*-C(=O)(CH2)MNHC(=O)(CH2)N-* * ;*-C(=O)((CH2)MO)T(CH2)NNHC(=O)(CH2)N-**;*-C(=O)(CH2)MNHC(=O)(CH2)NXL2(CH2)N-* * ;*-C(=O)(CH2)MO)T(CH2)MNHC(=O)(CH2)NXL2(CH2)N-**;*-C(=O)((CH2)MO)T(CH2)NC(=O)NH(CH2)M-**;where * indicates the point of direct or indirect attachment to L3, and ** indicates the point of direct or indirect attachment to Li, and whereineach M is independently 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10; each N is independently 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10; and each T is independently 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19,20, 21, 22, 23, 24, 25, 26, 27, 28, 29, or 30.La, the peptide group

[0030] In some embodiments, the peptide group comprises 1 to 2, 1 to 3, 1 to 4, 1 to 6, 1 to 8, 1 to 10 or 1 to 12 amino acid residues. The amino acid residues may be selected from L-gly- cine (Gly), L-valine (Vai), L-citrulline(Cit), L-cysteic acid (sulfo-Ala), L-lysine (Lys), L-iso- leucine (lie), L-phenylalanine (Phe), L-methionine (Met), L-asparagine (Asn), L-proline(Pro), L-alanine (Ala), L-leucine (Leu), L-tryptophan (Trp), and L-tyrosine (Tyr). In some embodiments, the peptide group comprises Val-Cit, Vai-Ala, Val-Lys, sulfo-Ala-Val-Ala, or a combination thereof.

[0031] In some embodiments, the peptide group (L3) comprises the structure:

[0032] In some embodiments, L3 comprises 1 to 6 amino acid residues. In some embodiments, L3 comprises 1 to 4 amino acid residues. In some embodiments, L3 comprises 1 to 3 amino acid residues. In some embodiments, L3 comprises 1 to 2 amino acid residues.

[0033] In some embodiments, the amino acid residues are selected from L-glycine (Gly), L-valine (Vai), L-citrulline (Cit), L-cysteic acid (sulfo-Ala), L-lysine (Lys), L-isoleucine (lie), L-phenylalanine (Phe), L-methionine (Met), L-asparagine (Asn), L-proline(Pro), L-alanine (Ala), L-leucine(Leu), L-tryptophan (Trp), and L-tyrosine (Tyr). In some embodiments, the peptide group comprises Val-Cit, Phe-Lys, Vai-Ala, Val-Lys, Leu-Cit, sulfo- Ala-Vai, and / or sulfo-Ala-Val-Ala.

[0034] In some embodiments, L3 is selected from the group consisting of:L4, Cleavable Group

[0035] In some embodiments, L4 comprises

[0036] In some embodiments, L4 is -pyrophosphate-CH2-CH2-NH2-.

[0037] In some embodiments, L4 comprises para-aminobenzyl-carbamate, para-aminoben- zyl-ammonium, para-amino-(sulfo)benzyl-ammonium, para-amino- (sulfo)benzyl-carbamate, para-amino-(alkoxy-PEG-alkyl)benzyl-carbamate, para-amino-(polyhydroxycarboxytetrahy- dropyranyl)alkyl-benzyl-carbamate, or para-amino- (polyhydroxycarboxytetrahydropyranyl)al- ky 1 -b enzy 1 -ammonium .

[0038] In some embodiments, L4 comprises a self-immolative spacer.

[0039] In some embodiments, L4 has a structure arccording to formula (IVA):wherein Gi is attached to L3 and G3 is attached to D;Gi is a bond, -NH- or -NH-Ph-;G2 is a bond, methylene, neopentylene, or C2-3 alkenylene;G3 is a bond, -OC(=O)-,OC(=O)N(CH3)CH2CH2N(CH3)C(=O)-, or -OC(=O)N(CH3)C(Rga)2C(Rga)2N(CH3)C(=O)-, whereineach Rgais independently H, Ci-6 alkyl, or C3-8 cycloalkyl;G4 is a spacer moiety; andG5 is a hydrophilic moiety.

[0040] In some embodiments, G4 has the structure, wherein:X41 is connected to Gs and W41 is connected to Gi,W4iis -CH2-, -CH2O-, -CH2N(Rbb)C(=O)O-, -NHC(=O)C(Rbb)2NHC(=O)O-, - NHC(=O)C(Rbb)2NH-, -NHC(=O)C(Rbb)2NHC(=O)-, -CH2N(X4i-G5)C(=O)O-, -C(=O)N(X4I- G5)-, -CH2N(X4i-G5)C(=O)-, -C(=O)NRbb-, -C(=O)NH-, -CH2NRbbC(=O)-, - CH2NRbbC(=O)NH-, -CH2NRbbC(=O)NRbb-, -NHC(=O)-, -NHC(=O)O-, -NHC(=O)NH-, - OC(=O)NH-, -S(O)2NH-, -NHS(O)2-, -C(=O)-, -C(=O)O-, or -NH-, wherein each Rbbis independently H, C1-6 alkyl, or C3-8 cycloalkyl; andX4i is a bond, triazolyl, -CH2-triazolyl-, -CH2-triazolyl-Ci-4 alkylene- OC(O)NHS(O)2NH-, -C4-6cycloalkylene-OC(O)NHS(O)2NH-, -(CH2CH2O)nC(O)NHS(O)2NH-, -(CH2CH2O)n ’-C(O)NHS(O)2NH-(CH2CH2O)n -CH2-triazolyl-Ci-4al- kylene-OC(O)NHS(O)2NH-(CH2CH2O)nor -C4-6 cycloalkylene-OC(O)NHS(O)2NH- (CH2CH2O)nwherein each n’” independently is 1, 2, or 3.

[0041] In some embodiments, G5 is a hydrophilic moiety comprising polyethylene glycol, polyalkylene glycol, a polyol, a polysarcosine, a sugar, an oligosaccharide, a polypeptide, C2-6 o o|— O-P-OH | — P-OH alkyl substituted with 1 to 3 H or 6H groups, or C2-6 alkyl substituted with 1 to 2 substituents independently selected from -OC(=O)NHS(O)2NHCH2CH2OCH3, -NHC(=O)Ci-4alkylene-P(O)(OCH2CH3)2, and -COOH.

[0042] In some embodiments, G5 is

[0043] In some embodiments, Gs comprises a polyethylene glycol of formula:whereinRnis H, -CH3CH2CH2NHC(=O)ORga, -CH2CH2NHC(=O)Rga, or - CH2CH2C(=O)ORga,Rmis OH, -OCH3, -CH2CH2NHC(=O)ORga, -CH2CH2NHC(=O)Rga, or - OCH2CH2C(=O)ORga; each Rgais independently H, Ci-6 alkyl, or C3-8 cycloalkyl; and each of m’ and n’ is an integer between 2 and 25 (e.g., between 3 and 25).

[0044] In some embodiments, Gs comprises a polysarcosin. In some embodiments, Gs has the structurewherein n” is an integer between 3 and 25; andRgbis H, -CH3, or -CH2CH2C(=O)OH.

[0045] Based on the context, it should be understood that “L is a linker that covalently binds Ab and D” means that the linker L covalently binds to the S atom or other atom on Ab and also covalently binds to D. Similar expressions in the following text have a similar meaning.Linker-Drug Conjugate

[0046] In some embodiments, the linker-drug conjugate has the formula L1R-L2-L3-L4-D.In some embodiments, the linker-drug moiety has the structure:

[0047] In some embodiments, the linker-drug conjugate L1R-L2-L3-L4-D has the structure:whereinR77is independently H, -CH3, or -CH2CH2C(=O)OH;Xa or Xb is independently -CH2-, -OCH2-, -NHCH2-, or -NRCH2-; andD is a RAS inhibitor. o 0 0

[0048] In some embodiments, each G3 is a bond, OC(=O)-, OH , 6H 6H ,OC(=O)N(CH3)C(Rga)2C(Rga)2N(CH3)C(=O)-, and each Rgais independently selected from H,C1-6 alkyl, and C3-8 cycloalkyl.

[0049] In some embodiments, -[L-D] is formed from a compound selected from Table 1A or an enantiomer, a diastereoisomer, and / or a pharmaceutically acceptable salt thereof.

[0050] In some embodiments, the maleimide group o in the compound selected from Table 1A form a covalent bond with the antibody or antigen-binding fragment thereof(Ab) to form the ADC compound of formula (I A) comprising a o moiety, whereinCA represents Ab.

[0051] For compounds in Table 1A, Table IB, Table 1C, and Table ID, depending on their electronic charge, these compounds can contain one pharmaceutically acceptable monovalent anionic counterion Mf. In some embodiments, the monovalent anionic counterion Mf is bromide, chloride, iodide, acetate, trifluoroacetate, benzoate, mesylate, tosylate, tritiate, or formate. In some embodiments, the monovalent anionic counterion Mf is trifluoroacetate or formate.Table 1A. Exemplary Linker-Drug GroupsExemplary ADCs

[0052] In some embodiments,Ab~L Dhas the structure:wherein A, D, and R77are as defined herein.

[0053] In some embodiments, Ab-Li-L2-L3-L4-D comprises the structure:wherein the L1-L2-L3-L4-D group is bracketed.

[0054] In some embodiments of formula (IIA),(HA) ,p is an integer from 1 to 5, 1 to 6, 1 to 8, or2 to 4. In some embodiments, p is 1, 2, or 4.

[0055] In some embodiments, p is determined by liquid chromatography-mass spectrometry (LC-MS).

[0056] The ADCs depicted above can also be represented by the following formula:Ab— L— D p(IA) wherein Ab or represents an antibody or an antigen-binding fragment thereof cova- lently linked to the linker-payload [L-D] depicted above; p is an integer from 1 to 16. In some embodiments, p is an integer from 1 to 8. In some embodiments, p is an integer from 1 to 5. In some embodiments, p is an integer from 2 to 4. In some embodiments, p is 1. In some embodiments, p is 2. In some embodiments, p is 4.

[0057] In some embodiments, the antibody-drug conjugate has a formula according to any one of the structures shown in Table IB.Table IB. Exemplary ADC Structures

[0058] In some embodiments, D comprises a RAS inhibitor compound of formula (I) or formula (I’) covalently attached to the linker L:or a stereoisomer, pharmaceutically acceptable salt, metabolite, prodrug, or solvate thereof, or a solvate of the pharmaceutically acceptable salt thereof, wherein is a double bond or single bond; n is 0, 1, 2, or 3;A, in the context of a RAS inhibitor (D), is optionally substituted 5 to 6-membered heterocycloalkylene, optionally substituted 5 to 6-membered arylene, or optionally substituted5 to 6-membered heteroarylene;B, in the context of a RAS inhibitor (D), is optionally substituted 3 to 6-membered heterocycloalkylene, optionally substituted 3 to 6-membered heterocycloalkenylene, optionally substituted 4 to 11 -membered bicyclic cycloalkylene, or optionally substituted 4 to 11 -membered bicyclic heterocycloalkylene;G is optionally substituted Ci-6 alkylene;U and T, in the context of a RAS inhibitor (D), are each independently absent, a bond, O, S, -NR3, or optionally substituted Ci-6 alkylene;R8and R9are each independently hydrogen, deuterium, halogen, hydroxy, cyano, or optionally substituted C1-3 alkyl, or R8and R9combine with the atoms to which they are attached to form an optionally substituted C3-6 cycloalkyl or a carbonyl;R10and R11are each independently hydrogen, deuterium, halogen, hydroxy, cyano, or optionally substituted C1-3 alkyl; or R10and R11combine with the atoms to which they are attached to form an optionally substituted C3-6 cycloalkyl or a carbonyl;R12and R13are each independently hydrogen, deuterium, halogen, hydroxy, optionally substituted C1-3 alkyl, -©(optionally substituted C1-6 alkyl), -S(optionally substituted C1-6 alkyl), or -N(optionally substituted C1-6 alkyl)(optionally substituted C1-6 alkyl);RAis optionally substituted C3-6 cycloalkyl, optionally substituted C3-6 heterocycloalkyl (or 4 to 7-membered heterocycloalkyl), optionally substituted 5 to 8-membered aryl, optionally substituted 5 to 8-membered heteroaryl, optionally substituted 8 to 10-membered fused bicyclic aryl, or optionally substituted 8 to 10-membered fused bicyclic heteroaryl;RBis hydrogen, C1-6 alkyl, C1-6 alkoxyl, C1-6 haloalkyl, Ci-e haloalkoxyl, optionally substituted C3-6 cycloalkyl, or optionally substituted C3-6 heterocycloalkyl (or 4 to 7- membered heterocycloalkyl); or, when n exceeds 1, any two of RBmay combine with the atoms to which they are attached to form a 3 to 6-membered ring, wherein the ring may be optionally substituted with halogen, hydroxy, or C1-3 alkyl;X1is N or C;X2is N or -CRa-;X3is N or -CRb-;X4is N or -CRC-;X5is N or C;X6is S, O, N, or -CH-;Ra, Rb, and Rcare each independently hydrogen, halogen, cyano, C1-3 alkyl, C1-3 alkoxyl, C1-3 haloalkyl, C1-3 haloalkoxyl, C3-6 cycloalkyl, or C3-6 heterocycloalkyl (or 4 to 7- membered heterocycloalkyl);R3is absent, hydrogen, C1-6 alkyl, or C1-6 haloalkyl, provided that when X6is O or S, R3is absent;E is a bond, N, or -CRd-, wherein Rdis hydrogen, halogen, hydroxy, cyano, carboxyl, optionally substituted C1-6 alkyl, optionally substituted C1-6 alkoxyl, C1-6 aminoalkyl, Ci- 6 hydroxyalkyl, or -NReRf;Reand Rfare independently hydrogen or optionally substituted C1-6 alkyl;R4is hydrogen, optionally substituted C1-6 alkyl, optionally substituted C1-6 heteroalkyl, optionally substituted C3-10 cycloalkyl, optionally substituted C3-10 cycloalkenyl, optionallysubstituted C3-10 heterocycloalkyl (or 4 to 12-membered heterocycloalkyl), optionally substi-R6RlL / N tuted 6 to 10-membered aryl, optionally substituted 5 to 10-membered heteroaryl, or ' andR5is hydrogen, Ci-6 alkyl or C3-6 cycloalkyl, furthermore, the C1-6 alkyl or C3-6 cycloalkyl may be further optionally substituted; orR4and R5combine with the atoms to which they are attached to form a ring, wherein the ring is optionally substituted 3 to 10-membered cycloalkyl, optionally substituted 3 to 10-membered heterocycloalkyl, optionally substituted 3 to 6-membered cycloalkenyl, optionally substituted 4 to 11 -membered bicyclic cycloalkyl, or optionally substituted 4 to 11- membered bicyclic heterocycloalkyl;L, in the context of a RAS inhibitor (D), is absent, -CH2-, -C(O)-, -CHRg- or - C(Rg)2-, wherein Rgis optionally substituted C1-6 alkyl;R6is hydrogen or optionally substituted C1-6 alkyl;R7is optionally substituted C1-6 alkyl, optionally substituted C 1-6 heteroalkyl, optionally substituted C3-10 cycloalkyl, optionally substituted C3-10 heterocycloalkyl (or 3 to 10-mem- bered heterocycloalkyl), optionally substituted 6 to 10-membered aryl, or optionally substituted 5 to 10-membered heteroaryl; or L, R6, and R7combine with the atoms to which they are attached to form a ring, wherein the ring is optionally substituted 3 to 10-membered cycloalkyl, optionally substituted 3 to 10-membered heterocycloalkyl, optionally substituted 3 to 6-membered cycloalkenyl, optionally substituted 4 to 11 -membered bicyclic cycloalkyl, or optionally substituted 4 to 11- membered bicyclic heterocycloalkyl.

[0059] In some embodiments, the RAS inhibitor (D) comprises a compound of formula (I) or (I’):or stereoisomer, pharmaceutically acceptable salt, metabolite, prodrug, or solvate thereof, or the solvate of the pharmaceutically acceptable salt thereof, wherein the variables are as described herein.

[0060] In some embodiments, U and T are each independently absent, a bond, O, S, -NR3, or optionally substituted Ci-6 alkylene. In some embodiments, U is R3and T is absent.

[0061] In some embodiments, B is optionally substituted

[0062] In some embodiments, B isor deuteratedIn some embod-,

[0065] In some embodiments, R1is hydrogen, Ci-6 alkyl, Ci-6 alkoxyl, Ci-6 haloalkyl, Ci-6 haloalkoxyl, Ci-e hydroxyalkyl, Ci-6 aminoalkyl, optionally substituted C3-6 cycloalkyl, optionally substituted C3-6 heterocycloalkyl, optionally substituted 5 to 8-membered aryl, optionally substituted 5 to 8-membered heteroaryl, optionally substituted 8 to 10-membered fused bicyclic aryl, optionally substituted 8 to 10-membered fused bicyclic heteroaryl, optionally substituted -Ci-2alkylene-C3-6 cycloalkyl, optionally substituted -Ci-2alkylene-C3-6 heterocycloalkyl, optionally substituted -Ci-2alkylene-5 to 8-membered aryl, optionally substituted -Ci-2alkylene-5 to 8-membered heteroaryl, optionally substituted -Ci-2alkylene-8 to 10-membered fused bicyclic aryl, or optionally substituted -Ci-2alkylene-8 to 10-membered fused bicyclic heteroaryl. In some embodiments, R1is hydrogen, C1-6 alkyl, C1-6 alkoxyl, C1-6 haloalkyl, C 1-6 haloalkoxyl, Ci-6 hydroxyalkyl, C1-6 aminoalkyl, optionally substituted C3-6 cycloalkyl, optionally substituted C3-6 heterocycloalkyl, optionally substituted 5 to 8-membered aryl, optionally substituted 5 to 8-membered heteroaryl, optionally substituted 8 to 10-membered fused bicyclic aryl, or optionally substituted 8 to 10-membered fused bicyclic heteroaryl); furthermore, the C1-6 alkyl, C1-6 alkoxyl, C 1-6 haloalkyl, C 1-6 haloalkoxyl, and C1-6 hydroxyalkyl (optionally the C1-6 alkyl) may be further optionally substituted.

[0066] In some embodiments, in R1, when the C1-6 alkyl, C1-6 alkoxyl, C1-6 haloalkyl, C1-6 haloalkoxyl, or Ci-e hydroxyalkyl (optionally, the C1-6 alkyl) is further substituted, the substituent is selected from the group consisting of C1-6 alkyl, C1-6 alkoxyl, C1-6 haloalkyl, C1-6 haloalkoxyl, Ci-e hydroxyalkyl, C1-6 aminoalkyl, carbonyl, -(C=O)NR100R101, optionally substituted C3-6 cycloalkyl, optionally substituted C3-6 heterocycloalkyl, optionally substituted 5 to 8-mem- bered aryl, optionally substituted 5 to 8-membered heteroaryl, optionally substituted 8 to 10- membered fused bicyclic aryl, optionally substituted 8 to 10-membered fused bicyclic heteroaryl; optionally, the substituent is selected from the group consisting of optionally substituted C3-6 cycloalkyl, optionally substituted C3-6 heterocycloalkyl, optionally substituted 5 to 8- membered aryl, optionally substituted 5 to 8-membered heteroaryl, optionally substituted 8 to 10-membered fused bicyclic aryl, optionally substituted 8 to 10-membered fused bicyclic heteroaryl; further optionally, the substituent is optionally substituted C3-6 heterocycloalkyl. In some embodiments, R100and R101are each independently selected from hydrogen, deuterium, optionally substituted C1-6 alkyl, or R100and R101combine with the atoms to which they are attached to form an optionally substituted C3-6 heterocycloalkyl

[0067] In some embodiments, in R1, optionally substituted means unsubstituted or substituted with one or more (e.g., 1, 2, or 3) substituents selected from the group consisting of deuterium, halogen, Ci-6 alkyl, Ci-6 hydroxyalkyl, and Ci-6 deuteroalkyl.

[0068] In some embodiments, RMand RNare each independently hydrogen, halogen, hydroxy, cyano, carboxyl, Ci-6 alkyl, Ci-e alkoxyl, Ci-e haloalkyl, Ci-e haloalkoxyl, Ci-6 hydroxyalkyl, Ci -6 aminoalkyl, optionally substituted C3-6 cycloalkyl, or optionally substituted C3-6 heterocycloalkyl; furthermore, the C1-6 alkyl, Ci-e alkoxyl, Ci-e haloalkyl, Ci-e haloalkoxyl, C1-6 hydroxyalkyl may be further optionally substituted. In some embodiments, RMand RNare each independently hydrogen or C1-6 alkyl.

[0069] In some embodiments, Y is -CH- or N. In some embodiments, Y is N.

[0070] In some embodiments, R2is optionally substituted C1-6 alkoxy, or optionally substituted C1-6 alkyl. In some embodiments, R2is optionally substituted C1-6 alkyl.

[0071] In some embodiments, in R2, optionally substituted means unsubstituted or substituted with one or more (e.g., 1, 2 or 3) substituents selected from the group consisting of deuterium, C1-6 alkoxy, C1-6 deuteroalkoxy, and C1-6 haloalkoxy.

[0072] In some embodiments, B is, , U is R3, T is absent, and RAis optionally substituted phenyl or optionally substituted 6-membered heteroaryl. In some embodiments, the RAS inhibitor (D) of formula (I) or formula (I’) is a compound of formula (II):or a pharmaceutically acceptable salt, metabolite, prodrug, or a solvate thereof, or a solvate of the pharmaceutically acceptable salt thereof, whereinA is optionally substituted 5 to 6-membered heterocycloalkylene, optionally substituted 5 to 6-membered arylene, or optionally substituted 5 to 6-membered heteroarylene;G is optionally substituted Ci-6 alkylene;R8and R9are each independently hydrogen, deuterium, halogen, hydroxy, cyano, or optionally substituted C1-3 alkyl, or R8and R9combine with the atoms to which they are attached to form an optionally substituted C3-6 cycloalkyl or a carbonyl;R10and R11are each independently hydrogen, deuterium, halogen, hydroxy, cyano, or optionally substituted C1-3 alkyl, or R10and R11combine with the atoms to which they are attached to form an optionally substituted C3-6 cycloalkyl or a carbonyl;R12and R13are each independently hydrogen, deuterium, halogen, hydroxy, optionally substituted C1-3 alkyl, -O(Ci-6 alkyl), -S(Ci-6 alkyl), or -N(CI-6 alkyl)(Ci-6 alkyl); furthermore, the C1-6 alkyl may be further optionally substituted;Y is -CH- or N;X1is N or C;X2is N or -CRa-;X3is N or -CRb-;X4is N or -CRC-;X5is N or C;X6is S, O, N, or -CH-;Ra, Rb, and Rcare each independently hydrogen, halogen, cyano, C1-3 alkyl, C1-3 alkoxyl, C1-3 haloalkyl, C1-3 haloalkoxyl, C3-6 cycloalkyl, or C3-6 heterocycloalkyl (or 3 to 6- membered heterocycloalkyl);R1is hydrogen, C1-6 alkyl, C1-6 alkoxyl, C1-6 haloalkyl, C 1-6 haloalkoxyl, C1-6 hydroxyalkyl, Ci -6 aminoalkyl, optionally substituted C3-6 cycloalkyl, optionally substituted 3 to 6- membered heterocycloalkyl, optionally substituted 5 to 8-membered aryl, optionally substituted 5 to 8-membered heteroaryl, optionally substituted 8 to 10-membered fused bicyclic aryl, or optionally substituted 8 to 10-membered fused bicyclic heteroaryl; furthermore, the C1-6 alkyl, C1-6 alkoxyl, C1-6 haloalkyl, C1-6 haloalkoxyl, and C1-6 hydroxyalkyl may be further optionally substituted;R2is optionally substituted C1-6 alkoxy, or optionally substituted C1-6 alkyl;RMand RNare each independently hydrogen, halogen, hydroxy, cyano, carboxyl, Ci-6 alkyl, Ci-e alkoxyl, Ci-e haloalkyl, Ci-e haloalkoxyl, Ci-6 hydroxyalkyl, Ci-6 aminoalkyl, optionally substituted C3-6 cycloalkyl, or optionally substituted C3-6 heterocycloalkyl (or 4 to 7- membered heterocycloalkyl); furthermore, the C1-6 alkyl, Ci-e alkoxyl, Ci-e haloalkyl, C1-6 haloalkoxyl, and C1-6 hydroxyalkyl may be further optionally substituted;R3is absent, hydrogen, C1-6 alkyl, or C1-6 haloalkyl, provided that when X6is O or S, R3is absent;E is a bond, N, or -CRd-, wherein Rdis selected from hydrogen, halogen, hydroxy, cyano, carboxyl, optionally substituted C1-6 alkyl, optionally substituted C1-6 alkoxyl, C1-6 aminoalkyl, Ci-e hydroxyalkyl, or -NReRf;Reand Rfare each independently selected from hydrogen, or optionally substituted C1-6 alkyl;R4is hydrogen, optionally substituted C1-6 alkyl, optionally substituted C1-6 heteroalkyl, optionally substituted C3-10 cycloalkyl, optionally substituted C3-10 cycloalkenyl, optionally substituted C3-10 heterocycloalkyl (or 4 to 12-membered heterocycloalkyl), optionally substi-R6RlL / N tuted 6 to 10-membered aryl, optionally substituted 5 to 10-membered heteroaryl, or ' ;R5is hydrogen, C1-6 alkyl, or C3-6 cycloalkyl, furthermore, the C1-6 alkyl or C3-6 cycloalkyl may be further optionally substituted; or R4and R5combine with the atoms to which they are attached to form a ring, wherein the ring is optionally substituted 3 to 10-membered cycloalkyl, optionally substituted 3 to 10-membered heterocycloalkyl, optionally substituted 3 to 6-membered cycloalkenyl, optionally substituted 4 to 11 -membered bicyclic cycloalkyl, or optionally substituted 4 to 11- membered bicyclic heterocycloalkyl, whereinL is absent, -CH2-, -C(O)-, -CHRg- or -C(Rg)2-,Rgis optionally substituted C1-6 alkyl;R6is hydrogen or optionally substituted C1-6 alkyl;R7is optionally substituted C1-6 alkyl, optionally substituted C 1-6 heteroalkyl, optionally substituted C3-10 cycloalkyl, optionally substituted C3-10 heterocycloalkyl (or 4 to 12-mem- bered heterocycloalkyl), optionally substituted 6 to 10-membered aryl, or optionally substituted 5 to 10-membered heteroaryl; oror L, R6, and R7combine with the atoms to which they are attached to form a ring, wherein the ring is selected from optionally substituted 3 to 10-membered cycloalkyl, optionally substituted 3 to 10-membered heterocycloalkyl, optionally substituted 3 to 6-membered cycloalkenyl, optionally substituted 4 to 11 -membered bicyclic cycloalkyl, optionally substituted 4 to 11 -membered bicyclic heterocycloalkyl.

[0073] In some embodiments, X1is C, X2is -CRa- (e.g., -CH-), X3is -CRb- (e.g., -CH-), X4is -CRC- (e.g., -CH-), and / or X5is -C-.

[0074] In some embodiments, Ra, Rb, and Rcare each independently hydrogen, halogen, cyano, C1-3 alkyl, C1-3 alkoxyl, C1-3 haloalkyl, or C1-3 haloalkoxyl. In some embodiments, Ra, Rb, and Rcare each independently hydrogen or C1-3 alkyl.

[0075] In some embodiments , X1is C, X2, X3, X4, and X5are each -CH-, and RMand RNare hydrogen.

[0076] In some embodiments, R8, R9, R10, R11, R12and R13are each independently hydrogen, deuterium, halogen, hydroxy, cyano, or optionally substituted C1-3 alkyl. In some embodiments, R8, R9, R10, R11, R12, and R13are hydrogen.

[0077] In some embodiments, the RAS inhibitor (D) of formula (II) is a compound of for-or a pharmaceutically acceptable salt, metabolite, prodrug, or solvate thereof, or a solvate of the pharmaceutically acceptable salt thereof, whereinA is optionally substituted 5 to 6-membered heterocycloalkylene, optionally substituted 5 to 6-membered arylene, or optionally substituted 5 to 6-membered heteroarylene;G is optionally substituted C1-6 alkylene;Y is -CH- or N;X6is S, O, N, or -CH-;Raand Rbare hydrogen, halogen, cyano, C1-3 alkyl, C1-3 alkoxyl, C1-3 haloalkyl, C1-3 haloalkoxyl, C3-6 cycloalkyl, or C3-6 heterocycloalkyl (or 4 to 7-membered heterocycloalkyl);R1is hydrogen, C1-6 alkyl, C1-6 alkoxyl, C1-6 haloalkyl, C 1-6 haloalkoxyl, C1-6 hydroxyalkyl, Ci -6 aminoalkyl, optionally substituted C3-6 cycloalkyl, optionally substituted C3-6 heterocycloalkyl (or 4 to 7-membered heterocycloalkyl), optionally substituted 5 to 8-membered aryl, optionally substituted 5 to 8-membered heteroaryl, optionally substituted 8 to 10-mem- bered fused bicyclic aryl, or optionally substituted 8 to 10-membered fused bicyclic heteroaryl; furthermore, the C1-6 alkyl, C1-6 alkoxyl, C1-6 haloalkyl, C 1-6 haloalkoxyl, and Ci-e hydroxyalkyl may be further optionally substituted;R2is optionally substituted C1-6 alkoxy or optionally substituted C1-6 alkyl;R3is absent, hydrogen, C1-6 alkyl, or C1-6 haloalkyl, provided that when X6is O or S, R3is absent;E is a bond, N, or -CRd-,Rdis selected from hydrogen, halogen, hydroxy, cyano, carboxyl, optionally substituted C1-6 alkyl, optionally substituted C1-6 alkoxyl, C1-6 aminoalkyl, C1-6 hydroxyalkyl, or - NReRf;Reand Rfare independently selected from hydrogen, or optionally substituted C1-6 alkyl;R4is hydrogen, optionally substituted C1-6 alkyl, optionally substituted C1-6 heteroalkyl, optionally substituted C3-10 cycloalkyl, optionally substituted C3-10 cycloalkenyl, optionally substituted C3-10 heterocycloalkyl (or 4 to 12-membered heterocycloalkyl), optionally substi-R6RlL / N tuted 6 to 10-membered aryl, optionally substituted 5 to 10-membered heteroaryl, or ' ;R5is hydrogen, C1-6 alkyl or C3-6 cycloalkyl, furthermore, the C1-6 alkyl or C3-6 cycloalkyl may be further optionally substituted; or R4and R5combine with the atoms to which they are attached to form a ring, wherein the ring is selected from optionally substituted 3 to 10-membered cycloalkyl, optionally substituted 3 to 10-membered heterocycloalkyl, optionally substituted 3 to 6-membered cycloalkenyl, optionally substituted 4 to 11 -membered bicyclic cycloalkyl, optionally substituted 4 to 11 -membered bicyclic heterocycloalkyl;L is absent, -CH2-, -C(O)-, -CHRg-, or -C(Rg)2-,Rgis optionally substituted C1-6 alkyl;R6is hydrogen or optionally substituted C1-6 alkyl;R7is optionally substituted C1-6 alkyl, optionally substituted C 1-6 heteroalkyl, option- ally substituted C3-10 cycloalkyl, optionally substituted C3-10 heterocycloalkyl (or 3 to 10-mem- bered heterocycloalkyl), optionally substituted 6 to 10-membered aryl, optionally substituted 5 to 10-membered heteroaryl; or L, R6and R7combine with the atoms to which they are attached to form a ring, wherein the ring is selected from optionally substituted 3 to 10-membered cycloalkyl, optionally substituted 3 to 10-membered heterocycloalkyl, optionally substituted 3 to 6-membered cycloalkenyl, optionally substituted 4 to 11 -membered bicyclic cycloalkyl, optionally substituted 4 to 11 -membered bicyclic heterocycloalkyl.

[0078] Furthermore, in the 5 to 6-membered heterocycloalkylene, 5 to 6-membered heteroarylene, C3-5 heterocycloalkyl (or 4 to 6-membered heterocycloalkyl), C3-6 heterocycloalkyl (or 4 to 7- membered heterocycloalkyl), 5 to 6-membered heteroaryl, 8 to 10-membered fused bicyclic heteroaryl, C 1-6 heteroalkyl, C3-10 heterocycloalkyl, 5 to 10-membered heteroaryl, 3 to 10-membered heterocycloalkyl or 4 to 11 -membered bicyclic heterocycloalkyl, the heteroatom is independently selected from one or more of N, O and S, and the number of the heteroatom is independently 1 to 4.

[0079] In some embodiments , the compound of formula (III) is a compound of formula (IVa) or formula (IVb):or a pharmaceutically acceptable salt thereof, metabolite, prodrug, or a solvate thereof, or a solvate of the pharmaceutically acceptable salt thereof, whereinA is optionally substituted 5 to 6-membered heterocycloalkylene, optionally substituted 5 to 6-membered arylene, or optionally substituted 5 to 6-membered heteroarylene;G is optionally substituted C1-6 alkylene;Y is -CH- or N;X6is S, O, N, or -CH-;Raand Rbare each independently hydrogen, halogen, cyano, C1-3 alkyl, C1-3 alkoxyl, C1-3 haloalkyl, C1-3 haloalkoxyl, C3-6 cycloalkyl, or C3-6 heterocycloalkyl (or 4 to 7- membered heterocycloalkyl);R1is hydrogen, C1-6 alkyl, C1-6 alkoxyl, C1-6 haloalkyl, C 1-6 haloalkoxyl, C1-6 hydroxyalkyl, Ci -6 aminoalkyl, optionally substituted C3-6 cycloalkyl, optionally substituted C3-6 heterocycloalkyl (or 4 to 7-membered heterocycloalkyl), optionally substituted 5 to 8-membered aryl, optionally substituted 5 to 8-membered heteroaryl, optionally substituted 8 to 10-mem- bered fused bicyclic aryl, or optionally substituted 8 to 10-membered fused bicyclic heteroaryl; furthermore, the C1-6 alkyl, C1-6 alkoxyl, C1-6 haloalkyl, C 1-6 haloalkoxyl, C1-6 hydroxyalkyl may be further optionally substituted;R2is optionally substituted C1-6 alkoxy or optionally substituted C1-6 alkyl;R3is absent, hydrogen, C1-6 alkyl, or C1-6 haloalkyl, provided that when X6is O or S, R3is absent;E is a bond, or selected from N, or -CRd-,Rdis selected from hydrogen, halogen, hydroxy, cyano, carboxyl, optionally substituted C1-6 alkyl, optionally substituted C1-6 alkoxyl, C1-6 aminoalkyl, C1-6 hydroxyalkyl, or - NReRf;Reand Rfare independently selected from hydrogen, or optionally substituted C1-6 alkyl;R4is hydrogen, optionally substituted C1-6 alkyl, optionally substituted C1-6 heteroalkyl, optionally substituted C3-10 cycloalkyl, optionally substituted C3-10 cycloalkenyl, optionally substituted C3-10 heterocycloalkyl (or 4 to 12-membered heterocycloalkyl), optionally substi-R6RlL / N tuted 6 to 10-membered aryl, optionally substituted 5 to 10-membered heteroaryl, or 'R5is hydrogen, C1-6 alkyl, or C3-6 cycloalkyl, furthermore, the C1-6 alkyl or C3-6 cycloalkyl may be further optionally substituted; or R4and R5combine with the atoms to which they are attached to form a ring, wherein the ring is optionally substituted 3 to 10-membered cycloalkyl, optionally substituted 3to 10-membered heterocycloalkyl, optionally substituted 3 to 6-membered cycloalkenyl, optionally substituted 4 to 11 -membered bicyclic cycloalkyl, or optionally substituted 4 to 11- membered bicyclic heterocycloalkyl; whereinL is absent, or selected from -CH2-, -C(O)-, -CHRg- or -C(Rg)2-, wherein Rgis optionally substituted C1-6 alkyl;R6is hydrogen, or optionally substituted C1-6 alkyl;R7is optionally substituted C1-6 alkyl, optionally substituted C 1-6 heteroalkyl, optionally substituted C3-10 cycloalkyl, optionally substituted C3-10 heterocycloalkyl, optionally substituted 6 to 10-membered aryl, optionally substituted 5 to 10-membered heteroaryl; or L, R6and R7combine with the atoms to which they are attached to form a ring, wherein the ring is selected from optionally substituted 3 to 10-membered cycloalkyl, optionally substituted 3 to 10-membered heterocycloalkyl, optionally substituted 3 to 6-membered cycloalkenyl, optionally substituted 4 to 11 -membered bicyclic cycloalkyl, optionally substituted 4 to 11 -membered bicyclic heterocycloalkyl.

[0080] In some embodiments, in the 5 to 6-membered heterocycloalkylene, 5 to 6-mem- bered heteroarylene, C3-5 heterocycloalkyl, C3-6 heterocycloalkyl(or 3 to 6-membered heterocycloalkyl), 5 to 6-membered heteroaryl, 8 to 10-membered fused bicyclic heteroaryl, C1-6 heteroalkyl, C3-10 heterocycloalkyl (or 3 to 10-membered heterocycyoalkyl), 5 to 10-membered heteroaryl, 3 to 10-membered heterocycloalkyl, or 4 to 11 -membered bicyclic heteroalkyl, the heteroatom is independently selected from one or more of N, O, and S, and the number of het- eroatom(s) is independently 1 to 4.

[0081] In some embodiments, the 5 to 6-membered heterocycloalkylene contains one or two heteroatoms. In some embodiments, each heteroatom is independently N, O, or S.

[0082] In some embodiments, the RAS inhibitor D is attached to the conjugate linker represented by L at the A, R1, or R4(R7) position of D. In some embodiments, the RAS inhibitor D comprises a formula of the formula (IVaa)or a pharmaceutically acceptable salt, metabolite, prodrug, or solvate thereof, or a solvate of the pharmaceutically acceptable salt thereof, wherein the variables are as described above.

[0083] In some embodiments, A is optionally substituted 5 to 6-membered heterocycloalkylene, wherein the heterocycloalkylene comprises one or two N, O, or S atoms.

[0085] In some embodiments, A is optionally substituted 5 to 6-membered arylene;

[0087] In some embodiments, the 5 to 6-membered heteroarylene comprises one, two or three (e.g., one or two) heteroatoms. In some embodiments, each heteroatom is independentlyN, O, or S.

[0088] In some embodiments, A is optionally substituted 5 to 6-membered heteroarylene, wheren the heteroarylene comprises 1-3 heteroatoms, and wherein each heteroatom is independently selected from one or two of N, O, and S.

[0090] In some embodiments, B is optionally substituted 3 to 6-membered heterocycloalkylene, optionally substituted 3 to 6-membered heterocycloalkenylene, optionally substituted 4 to 11 -membered bicyclic alkylene, or optionally substituted 4 to 11 -membered bicyclic het- eroalkylene.

[0092] In some embodiments, G is optionally substituted Ci-6 alkylene. In some embodiments, G is optionally substituted -C(Ci-3alkyl)2-. In some embodiments, in G, optionally substituted means unsub stitued or substituted with one or more deuterium.

[0093] In some embodiments,

[0094] In some embodiments, Y is N.

[0095] In some embodiments, X6is N.

[0096] In some embodiments, R1is Ci-6 alkyl, Ci-e alkoxyl, Ci-e haloalkyl, C i -6 haloalkoxy 1, Ci-6 hydroxyalkyl, Ci-6 aminoalkyl, optionally substituted C3-6 cycloalkyl, or optionally substituted C3-6 heterocycloalkyl (or 3 to 6-membered heterocycloalkyl).

[0098] In some embodiments, R1is C1-6 alkyl that may be further substituted with optionally substituted C3-6 cycloalkyl, optionally substituted C3-6 heterocycloalkyl.

[0100] In some embodiments, R1is optionally substituted 4 to 5-membered heteroalkyl and4 to 5 -membered heteroaryl.

[0102] In some embodiments, R1is optionally substituted 5 to 8-membered aryl, optionally substituted 5 to 8-membered heteroaryl, optionally substituted 8 to 10-membered fused bicyclic aryl, or optionally substituted 8 to 10-membered fused bicyclic heteroaryl. The heteroaryl may comprise 1-4 heteroatoms, each of which may be independently selected from one or two of N, O and S.

[0104] In some embodiments, R2is optionally substituted C1-6 alkyl or optionally substi-tuted C1-6 alkoxy. In some embodiments, R2is0,0,D, or

[0105] In some embodiments, R3is Ci-6 alkyl. In some embodiments, R3is Ci-6 deuterated alkyl. In some embodiments, R3is

[0106] In some embodiments, R is Ci-6 haloalky. In some embodiments, R is, or c

[0107] In some embodiments, E is a bond, N, or -CRd-, wherein Rdis hydrogen, halogen, hydroxy, cyano, carboxyl, optionally substituted Ci-6 alkyl, optionally substituted Ci-e alkoxyl, Ci-6 aminoalkyl, Ci-6 hydroxyalkyl, or -NReRf; wherein Reand Rfare independently hydrogen or optionally substituted Ci-6 alkyl. In some embodiments, E is a bond, N, or -CRd-, wherein Rdis hydrogen, halogen, hydroxy, or Ci-6 alkyl.

[0108] In some embodiments, Rdis halogen. In some embodiments, Rdis -F, -Cl, -Br or -I; optionally, -F.

[0109] In some embodiments, Rdis Ci-6 alkyl. In some embodiments, Rdis

[0110] In some embodiments, Rdis Ci-e haloalkyl. In some embodiments, Rdis -CF3.

[0111] In some embodiments, Rdis C1-6 alkoxyl. In some embodiments, Rdis

[0112] In some embodiments of the present disclosure, Rdis C1-6 aminoalkyl. In some embodiments,10113] In some embodiments, Reor Rfis C1-6 alkyl. In some embodiments, one of Reor Rf

[0114] In some embodiments, L is -CH2-, -C(O)-, -CHRg-, or -C(Rg)2-, wherein Rgis optionally substituted C1-6 alkyl.

[0115] In some embodiments, R4is hydrogen, optionally substituted C1-6 alkyl, optionally substituted C 1-6 heteroalkyl, optionally substituted C3-10 cycloalkyl, optionally substituted C3-10 heterocycloalkyl (or 4 to 12-membered heterocycloalkyl), optionally substituted 6 to 10-mem-R6Rl^N bered aryl, optionally substituted 5 to 10-membered heteroaryl, or ' . In some embodi-R6RlL / Ny ments, R4is hydrogen, optionally substituted Ci-6 alkyl, or ' .

[0116] In some embodiments, R6is hydrogen or optionally substituted Ci-6 alkyl; optionally, hydrogen, or Ci-6 alkyl.

[0117] In some embodiments, R7is optionally substituted Ci-6 alkyl, optionally substituted C 1-6 heteroalkyl, optionally substituted C3-10 cycloalkyl, optionally substituted C3- 10 heterocycloalkyl, optionally substituted 6 to 10-membered aryl, or optionally substituted 5 to 10-mem- bered heteroaryl. In some embodiments, R7is C1-6 alkyl or optionally substituted C3-10 cycloalkyl.

[0118] In some embodiments, R4is hydrogen, optionally substituted C1-6 alkyl, optionally substituted C 1-6 heteroalkyl, optionally substituted C3-10 cycloalkyl, optionally substituted C3-10 heterocycloalkyl (or 4 to 12-membered heterocycloalkyl), optionally substituted 6 to 10-mem-R6RlL / Ny bered aryl, optionally substituted 5 to 10-membered heteroaryl, or ' whereinR6is hydrogen or optionally substituted C1-6 alkyl;R7is optionally substituted C1-6 alkyl, optionally substituted C 1-6 heteroalkyl, optionally substituted C3-10 cycloalkyl, optionally substituted C3-10 heterocycloalkyl, optionally substituted 6 to 10-membered aryl, or optionally substituted 5 to 10-membered heteroaryl.

[0119] In some embodiments, in R4, optionally substituted means unsubstituted or substituted by one or more substituents selected from the group consisting of hydroxyl, cyano, halo-gen, and C1-6 alkyl. In some embodiments, R4is hydrogen, C1-6 alkyl, 3 to 6-membered heterocycloalkyl, 3 to 6-membered cycloalkyl, 6 to 10-membered aryl, 5 to 10-membered heteroaryl,whereinR6is hydrogen or C1-6 alkyl;R7is C1-6 alkyl or 3- to 10-membered heterocycloalkyl; wherein the 3 to 10-mem- bered heterocycloalkyl is optionally substituted by Ci-6 alkyl, 6 to 10-membered aryl, -CO-O- C3-6 cycloalkyl or -CO-O-C1-6 alkyl; the 3 to 6-membered cycloalkyl is optionally substituted by hydroxyl, cyano, halogen, or C1-6 alkyl; in 3 to 10-membered heterocycloalkyl, the heteroatom is independently selected from one or more of N, O and S, and the number of the heteroatom is independently 1 to 3. In some embodiments, R4is hydrogen, C1-6 alkyl, orwherein R6is hydrogen or C1-6 alkyl; R7is C1-6 alkyl or 3 to 10-membered heterocycloalkyl.

[0120] In some embodiments, in R4, the C3-10 heterocycloalkyl (or 4 to 12-membered heterocycloalkyl) contains 1 or 2 heteroatoms selected from the group consisting of N, O, and S.

[0121] In some embodiments, R4is optionally substituted C1-6 alkyl, optionally substituted C 1-6 heteroalkyl, optionally substituted C3-10 cycloalkyl, optionally substituted C3- 10 heterocycloalkyl, the heteroatom is N, O or S, and the number of the heteroatom is independently 1 to

[0122] In some embodiments, R4is optionally substituted 6 to 10-membered aryl, option-

[0123] In some embodiments, R5is optionally substituted C1-6 alkyl. In some embodiments,R5is ~ I.

[0124] In some embodiments, R5is optionally substituted C3-6 cycloalkyl. In some embodi- ments, R5is

[0125] In some embodiments, in the ring formed by R4, R5and the atoms to which they are attached, the heterocycloalkyl or the bicyclic heterocycloalkyl contains 1, 2, or 3 heteroatoms selected from the group consisting of N, O, and S.

[0126] In some embodiments, R4and R5combine with the atoms to which they are attached to form a ring, and the ring is selected from optionally substituted 3 to 10-membered cycloalkyl, optionally substituted 3 to 10-membered heterocycloalkyl, optionally substituted 4 to 11 -membered bicyclic cycloalkyl, optionally substituted 4 to 11 -membered bicyclic heterocycloalkyl, the heteroatom is N, O or S, and the number of the heteroatom is independently 1 to3. In some embodiments, the ring is

[0127] In some embodiments, R4and R5combine with the atoms to which they are attached to form a ring, and the ring is optionally substituted 3 to 10-membered cycloalkyl. In some embodiments, the ring is optionally substituted 3 to 4-membered cycloalkyl; optionally, the ring is cy optionally substituted clopropyl; wherein optionally substituted means unsubstituted or substituted with one or more substituents selected from the group consisting of Ci-4 alkyl, C 1-4 deuteroalkyl, cyano, Ci-4hydroxyalkyl, and Ci-4haloalkyl.

[0128] In some embodiments, R6is optionally substituted Ci-6 alkyl. In some embodiments,

[0129] In some embodiments, R7is optionally substituted C3-10 cycloalkyl or optionally substituted C3-10 heterocycloalkyl.

[0130] In some embodiments, in R7, substituents for the C3-10 heterocycloalkyl are selected from the group consisting of C1-6 alkyl, 6 to 10-membered aryl, -CO-O-C3-6 cycloalkyl and - CO-O-C1-6 alkyl, and / or substituents for the C3-10 cycloalkyl are selected from the group consisting of hydroxyl, cyano, halogen, or C1-6 alkyl.

[0131] In some embodiments, in R7, the C3-10 heterocycloalkyl contains 1 to 3 heteroatoms selected from the group consisting of N, O and S.

[0132] In some embodiments, R7is optionally substituted C3-10 cycloalkyl, optionally substituted C3-10 heterocycloalkyl; optionally, the C3-10 heterocycloalkyl optionally substituted byC1-6 alkyl, Ce-io aryl , -CO-O-C3-6 cycloalkyl or -CO-O-C1-6 alkyl; the C3-10 cycloalkyl optionally substituted by hydroxyl, cyano, halogen, or C1-6 alkyl; in C3-10 heterocycloalkyl, the heteroatom is independently selected from one or more of N, O and S, and the number of the heteroatom is independently 1 to 3.

[0133] In some embodiments, R7is C1-6 alkyl. In some embodiments, R7is

[0134] In some embodiments, R7is optionally substituted 3 to 6-membered heterocycloalkyl. In some embodiments, in R7, the 3 to 6-membered heterocycloalkyl contains 1 or 2 het- eroatom selected from N, O or S. In some embodiments, R7, is,

[0135] In some embodiments, R7is 3 to 6-membered heterocycloalkyl. In some embodiments, the heteroatom is N, O or S, and the number of the heteroatoms is 1 to 2. In some em- bodiments,

[0136] In some embodiments, R7is optionally substituted C3-6 cycloalkyl. In some embodiments, in R7, the C3-6 cycloalkyl is

[0137] In some embodiments, R7is C3-6 cycloalkyl. In some embodiments, R7is

[0138] In some embodiments, R7is optionally substituted Ce-io aryl. In some embodiments, in R7, the Ce-io aryl

[0139] In some embodiments, R7is Ce-io aryl. In some embodiments, R7is \= /

[0140] In some embodiments, R7is optionally substituted C1-6 alkyl or optionally substituted 3 to 6-membered heterocycloalkyl. In some embodiments, in R7, substituents for the 3 to 6-membered heterocycloalkyl may be -C(O)R‘ or-NHC(O)R‘; wherein R‘ is C1-6 alkyl, -C2- ealkenyl, or C2-6 alkynyl; wherein the alkyl, alkenyl, or alkynyl is unsubtituted or is substituted (i.e., by replacing one H atom of the group) with one or more (such as 1, 2, 3 or 4) substituentsselected from the group consisting of D, halogen, -CN, -OH, C1-6 alkyl, C1-6 haloalkyl, C1-6 deuteroalkyl, C1-6 hydroxyalkyl, C 1-6 aminoalkyl, and alkylamino.

[0141] In some embodiments, in R7, substituents for the 3 to 6-membered heterocycloalkyl are selected from 6 to 10-membered aryl and -CO-O-Ci-6 alkyl. In some embodiments, in R7, the 3- to 6-membered heterocycloalkyl contains 1 or 2 heteroatoms selected from N and O.

[0142] In some embodiments, R7is C1-6 alkyl or 3 to 6-membered heterocycloalkyl. In some embodiments, the 3 to 6-membered heterocycloalkyl is optionally substituted by 6 to 10- membered aryl or -CO-O-Ci-6 alkyl. In some embodiments, in the 3 to 6-membered heterocycloalkyl, the number of heteroatoms is 1 or 2, and each heteroatom is independently selected from one or two of N and O.

[0144] In some embodiments, L, R6, and R7combine with the atoms to which they are attached to form a ring, wherein the ring is optionally substituted 3 to 10-membered cycloalkyl, optionally substituted 3 to 10-membered heterocycloalkyl, optionally substituted 3 to 6-mem- bered cycloalkenyl, optionally substituted 4 to 11 -membered bicyclic cycloalkyl, or optionally substituted 4 to 11 -membered bicyclic heterocycloalkyl.

[0145] In some embodiments, the ring formed by L, R6and R7combined with the atoms to which they are attached is substituted with -C(O)R‘, wherein R1is Ci-6 alkyl, -C2-ealkenyl, C2-6 alkynyl, C3-10 cycloalkyl, or 3 to 10-membered heterocycloalkyl; wherein the alkyl, alkenyl, alkynyl, cycloalkyl, or heterocycloalky is unsubtituted or is substituted (i.e., by replacing one H atom of the group) with one or more (such as 1, 2, 3 or 4) substituents selected from the group consisting of D, halogen, C1-6 alkyl, Ci-e haloalkyl, C1-6 deuteroalkyl, C1-6 hydroxyalkyl, Ci -6 aminoalkyl, alkylamino, and C3-6 cycloalkyl.

[0148] In some embodiments, “halogen” is F, Cl, Br, or I. In some embodiments, the halogen is F.

[0149] In some embodiments, the compound of formula (IVa) is a compound of formula(V):or a pharmaceutically acceptable salt, metabolite, prodrug, or solvate thereof, or a solvate of the pharmaceutically acceptable salt thereof, wherein the variables are as described herein.

[0150] The present application also contemplates the combination of values for X1, X2, X3, X4, X5, X6, A, B, E, G, L, Y, Ra, Rb, Rc, RA, RB, RM, RN, R1, R2, R3, R4, R5, R6, R7and n from one or more different compounds.

[0151] In another aspect, the present invention also provides, but is not limited to, the following compounds, and pharmaceutically acceptable salts, metabolites, prodrugs, or solvates thereof, or solvates of the pharmaceutically acceptable salt thereof:

[0152] In some embodiments, these compounds are modified (e.g., by conceptually replacing an atom (e.g., a hydrogen atom) with a connection point) so that they may be attached to an antibody or antigen-binding fragment thereof. In some embodiments, the compounds are attached to the antibody or fragment via a linker.

[0153] In some embodiments, the atoms in the compounds above may exhibit their natural isotopic abundances, or one or more of the atoms may be artificially enriched in a particular isotope having the same atomic number, but an atomic mass or mass number different from the atomic mass or mass number predominantly found in nature. The present disclosure as described and claimed herein is meant to include all suitable isotopic variations of the compounds of formulas above and embodiments thereof. For example, different isotopic forms of hydrogen^) include protium(lH) and deuterium (2H, also denoted herein as D). Protium is the predominant hydrogen isotope found in nature. Enriching for deuterium may afford certain therapeutic advantages, such as increasing in vivo half-life or reducing dosage requirements or may provide a compound useful as a standard for characterization of biological samples. Isotopi- cally-enriched compounds can be prepared without undue experimentation by conventional techniques well known to those skilled in the art or by processes analogous to those described in the Schemes and Examples herein using appropriate isotopically-enriched reagents and / or intermediates.

[0154] In some embodiments, the compound of formula (V) is a compound of formula(VI):or a pharmaceutically acceptable salt, metabolite, prodrug, or solvate thereof, or a solvate of the pharmaceutically acceptable salt thereof.

[0155] In some embodiments, R1of formula (VI) is

[0158] In some embodiments, the compound of formula (IVa) is a compound of formula (VIII):

[0160] In some embodiments, the compound of formula (I) is a RAS inhibitor D as defined below. In some embodiments, D represents a RAS inhibitor attached to the conjugate linker L by a covalent bond.

[0161] The present invention provides a RAS inhibitor D, or a pharmaceutically acceptable salt or solvate thereof, or a solvate of the pharmaceutically acceptable salt thereof, wherein the D is selected from any one of the compounds in Table 1C.Table 1C. Exemplary RAS Inhibitors (D)

[0162] In some embodiments, the RAS inhibitor D is selected from any one of the compounds in Table ID or a pharmaceutically acceptable salt thereof.Table ID. Exemplary Structures of RAS Inhibitors in the Context of an ADCwherein I represents a bond to the conjugate linker.Pharmaceutical Composition

[0163] The present application also provides a pharmaceutical composition comprising the compound or stereoisomer, pharmaceutically acceptable salt, metabolite, prodrug, or solvate thereof, or the solvate of the pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.

[0164] In another aspect, the present invention also provides a pharmaceutical composition comprising a compound, wherein a pharmaceutically acceptable salt thereof, a solvate thereofor a solvate of the pharmaceutically acceptable salt as defined above, and a pharmaceutically acceptable carrier, optionally, the compound is RAS inhibitor D as defined above.

[0165] Also provided herein, in some embodiments, are compositions comprising multiple copies of an antibody-drug conjugate (e.g., any of the exemplary antibody-drug conjugates described herein). In some embodiments, the average p of the antibody-drug conjugates in the composition is from about 2 to about 4.

[0166] Also provided herein, in some embodiments, are pharmaceutical compositions comprising an antibody-drug conjugate (e.g., any of the exemplary antibody-drug conjugates described herein) or a composition (e.g., any of the exemplary compositions described herein), and a pharmaceutically acceptable carrier.Methods of Use

[0167] The present applicatoin also provides a use of the the compound or stereoisomer, pharmaceutically acceptable salt, metabolite, prodrug, or solvate thereof, or the solvate of the pharmaceutically acceptable salt thereof, in the preparation of a medicament used for the treatment of cancer.

[0168] In some embodiments, the cancer is a Ras-driven cancer.

[0169] In some embodiments, the cancer comprises a Ras mutation. In some embodiments, wherein the Ras mutation is a position 12, 13 or 61. In some embodiments, the Ras mutation is at position 12.

[0170] In some embodiments, the Ras mutation is selected from the group consisting of G12C, G12D, G12V, G12A, G12R, G12S, G13C, G13D, Q61H, Q61R and Q61L, or a combination thereof.

[0171] In some embodiments, the Ras mutation is a position selected from the group consisting of G12D, G12V, and G12R, or a combination thereof.

[0172] In some embodiments, the cancer is pancreatic cancer, appendiceal cancer, small bowel cancer, colorectal cancer, ampullary cancer, non-small cell lung cancer, cervical cancer, lung cancer, endometrial cancer, acute myeloid leukemia, gastrointestinal neuroendocrine tumor, uterine endometrioid carcinoma, oesophagogastric cancer, bladder cancer, ovarian cancer, melanoma, multiple myeloma, thyroid gland adenocarcinoma, a myelodysplastic syndrome, or squamous cell lung carcinoma.

[0173] In some embodiments, the cancer is pancreatic cancer, lung cancer, or colorectal cancer.

[0174] In some embodiments, the Ras protein is KRAS.

[0175] Also provided herein are therapeutic uses for the described ADC compounds and compositions, e.g., for use in treating a cancer. In some embodiments, the present disclosure provides methods of treating a cancer (e.g., a cancer that expresses an antigen targeted by the antibody or antigen-binding fragment of the ADC, such as EphA2 or B7-H3(CD276)). In some embodiments, the present disclosure provides methods of reducing or slowing the expansion of a cancer cell population in a subject. In some embodiments, the present disclosure provides methods of determining whether a subject having or suspected of having a cancer will be responsive to treatment with an ADC compound or composition disclosed herein. In some embodiments, the subject is a human.

[0176] An exemplary embodiment is a method of treating a subject (e.g., a human) having or suspected of having a cancer, comprising administering to the subject a therapeutically effective amount of an antibody-drug conjugate, composition, or pharmaceutical composition (e.g., any of the exemplary antibody-drug conjugates, compositions, or pharmaceutical compositions disclosed herein). In some embodiments, the cancer expresses a target antigen. In some embodiments, the target antigen is BCMA, CD33, HER2, CD38, CD48, CD79b, PCAD, CD74, CD138, SLAMF7, CD123, CLL1, FLT3, CD7, CKIT, CD56, DLL3, DLK1, B7-H3, B7-H4, EGFR, CD71, EPCAM, FOLR1, ENPP3, MET, AXL, SLC34A2 (NaPi2b), Nectin4, TROP2, LIV1, CD46, MSLN, CD142 (F3), MUC1, MUC16, SLC39A6, TFRC, TACSTD2, GPNMB, EphA2, CD56, SEZ6, CD25, CCR8, CEACAM5, CEACAM6, 4-1BB, 5AC, 5T4, Alpha-fetoprotein, angiopoietin 2 ASLG659, TCLI, BMPRIB, Brevican BCAN, BEHAB, C242 antigen, C5, CA-125, CA-125 (imitation), CA-IX (Carbonic anhydrase 9), CCR4, CD140a, CD 152, CD 19, CD20, CD200, CD21 (C3DR)I), CD22(B-cell receptor CD22-B isoform), CD221, CD23 (gE receptor), CD28, CD30 (TNFRSF8), CD37, CD4, CD40, CD44 v6, CD51, CD52, CD70, CD72 (Lyb-2, B-cell differentiation antigen CD72), CD79a, CD80, CD 166 (AL- CAM), CDH17, CA9, CEA, CEA-related antigen, ch4D5, CLDN18.2, CRIPTO (CR, CRI, CRGF, TDGF1, CFC1B), CTLA-4, CXCR5, DLL4, DR5, El 6 (LATI, SLC7A5), EGFL7, EphB2R (DRT, ERK, Hek5, EPHT3, Tyro5), Episialin, ERBB3, ETBR (Endothelin type B receptor), FCRHI (Fc receptor-like protein 1), FcRH2 (IFGP4, IRTA4, SPAPI, SPAP IB, SPAP IC), Fibronectin extra domain-B, Frizzled receptor, GD2, GD3 ganglioside, GEDA, HER1,HER2 / neu, HER3, HGF, HLA-DOB, HLA-DR, Human scatter factor receptor kinase, IGF-I receptor, IL-13, IL20R (ZCYTOR7), IL-6, ILGF2, ILFRIR, integrin u, IRTA2 (Immunoglobulin superfamily receptor translocation associated 2), Lewis-Y antigen, LY64(RP105), LY6E, STEAP1, ADAM9, PTK7, MMP14, TM4SF1, ITGB6, FXYD5, MCP-I, MDP(DPEPI), MPF, MSLN, SMR, mesothelin, megakaryocyte, PD-I, PDCDI, PDGF-Ru, Prostate specific membrane antigen (PSMA), PSCA (Prostate stem cell antigen precursor), PRLR(Prolactin Receptor), PSCA hlg, RANKL, RON, SDCI, Serna Sb, STEAP I, STEAP2, PCANAP I, STAMP I, STEAP2, STMP, prostate cancer associated gene I, TAG-72, TEMI, Tenascin C, TENB2, (TMEFF2, tomoregulin, TPEF, HPPI, TR), TGF-IJ, TRAIL-E2, TRAIL-RI, TRAIL-R2, T17M4 (BR22450, FLJ20041, TRPM4, TRPM4B, transient receptor potential cation channel subfamily M, member 4), TWEAK-R, TYRPI (glycoprotein 75), VEGF, VEGF-A, EGFR- 1, VEGFR-2, or Vimentin.

[0177] In some embodiments, the cancer is a tumor or a hematological cancer. In some embodiments, the cancer is breast cancer (e.g., ER positive breast cancer), multiple myeloma, plasma cell myeloma, leukemia, lymphoma, sarcoma, gastric cancer, stomach cancer, acute myeloid leukemia, bladder cancer, brain cancer, bone marrow cancer, cervical cancer, chronic lymphocytic leukemia, colorectal cancer, pancreatic cancer, esophageal cancer, hepatocellular cancer, lymphoblastic leukemia (e.g., acute lymphoblastic leukemia), follicular lymphoma, Ilymphoid malignancies of T-cell or B-cell origin, metastatic castration resistant prostate cancer, bladder urothelial carcinoma, melanoma, myelogenous leukemia, myeloma, oral cancer, ovarian cancer, non-small cell lung cancer, prostate cancer, small cell lung cancer, spleen cancer, or head and neck cancer.

[0178] In some embodiments, administration of the antibody-drug conjugate, composition, or pharmaceutical composition reduces or inhibits the growth of the tumor by at least about 10%, at least about 20%, at least about 30%, at least about 40%, at least about 50%, at least about 60%, at least about 70%, at least about 80%, at least about 90%, at least about 95%, or at least about 99%.Ab Moiety

[0179] : Any antibody or antigen-binding fragment thereof described herein, e.g., anti- EphA2 antibody, anti-B7-H3 antibody, anti-EGFR antibody, anti-PD-Ll antibody, or antigen-binding fragments thereof.

[0180] “L-D” refers to the linker-payloads, linker-drugs, or linker-compounds disclosed herein and the term “L#-D#” is used to refer to a specific linker-drug disclosed herein, while the codes “D#” is used to refer to a specific compound unless otherwise specified, including an enantiomer, diastereoisomer, atropisomer, deuterated derivative, and / or pharmaceutically acceptable salt of any of the foregoing.

[0181] In some embodiments (e.g., for ADCs depicted in Table ID), Ab is an antibody or an antigen-binding fragment thereof described herein. In some embodiments, for ADCs depicted in Table ID, Ab is an anti-EphA2 antibody or antigen-binding fragment thereof. In some embodiments, Ab is an anti-B7-H3 antibody or antigen-binding fragment thereof.

[0182] In some embodiments (e.g., for ADCs depicted in Table ID), Ab is an antibody or an antigen-binding fragment thereof described herein. In some embodiments (e.g., for ADCs depicted in Table ID), Ab is an anti-EphA2 antibody or antigen-binding fragment thereof. In some embodiments, Ab is an anti-B7-H3 antibody or antigen-binding fragment thereof.

[0183] The antibody or antigen-binding fragment (Ab) of Formula (IA) is any antibody or antigen-binding fragment that specifically binds to a target antigen on a cell.

[0184] In some embodiments, the target antigen is BCMA, CD33, HER2, CD38, CD48, CD79b, PCAD, CD74, CD138, SLAMF7, CD123, CLL1, FLT3, CD7, CKIT, CD56, DLL3, DLK1, B7-H3, B7-H4, EGFR, CD71, EPCAM, FOLR1, ENPP3, MET, AXL, SLC34A2, Nec- tin4, TROP2, LIV1, CD46, MSLN, CD142 (F3), MUC1, MUC16, SLC39A6, TFRC, TAC- STD2, GPNMB, EphA2, CD56, SEZ6, CD25, CCR8, CEACAM5, CEACAM6, 4-1BB, 5AC, 5T4, ASLG659, TCLI, BMPRIB, BEHAB, C5, CA-125, CA-125, CA-IX, CCR4, CD140a, CD152, CD19, CD20 CD200, CD21, CD22, CD221, CD23, CD28, CD30 (TNFRSF8), CD37, CD4, CD40, CD44 v6, CD51, CD52, CD70, CD72, CD79a, CD80, CD 166 (ALCAM), CDH17, CA9, CEA, CLDN18.2, CRIPTO (CR, CRI, CRGF, TDGF1, CFC1B), CTLA-4, CXCR5, DLL4, DR5, E16 (LATI, SLC7A5), EGFL7, EphB2R (DRT, ERK, Hek5, EPHT3, Tyro5), Episialin, ERBB3, ETBR, FCRHI, FcRH2 (IFGP4, IRTA4, SPAPI, SPAP IB, SPAP IC), GD2, GD3 ganglioside, GEDA, HER1, HER2 / neu, HER3, HGF, HLA-DOB, HLA-DR, IL- 13, IL20R, IL-6, ILGF2, ILFRIR, IRTA2, LY64 (RP105), LY6E, STEAP1, ADAM9, PTK7, MMP14, TM4SF1, ITGB6, FXYD5, MCP-I, MDP (DPEPI), MPF, MSLN, SMR, PD- 1, PDCDI, PDGF-Ru, PSMA, PSCA, PRLR, PSCA hlg, RANKL, RON, SDCI, Serna Sb, STEAP I, STEAP2, PCANAP I, STAMP I, STEAP2, STMP, TAG-72, TEMI, TENB2, TGF-IJ, TRAIL-E2, TRAIL-RI, TRAIL-R2, T17M4, TWEAK-R, TYRP I, VEGF, VEGF -A, EGFR- I, or VEGFR-2.

[0185] In some embodiments, the target antigen is EphA2 or B7-H3.

[0186] In some embodiments, the antibody or antigen -binding fragment (Ab) of Formula(IA) is any antibody or antigen-binding fragment that specifically binds to a target antigen on a cancer cell.

[0187] Amino acid sequences of exemplary antibodies, in addition to exemplary antigen targets, are set forth in Tables 1E-1J.Table IE. Antibodies ExemplifiedTable IF. Exemplary Target Antigen Amino Acid SequencesTable 1G. Amino Acid and Nucleic Acid Sequences of Full-Length mAb Ig ChainsTable 1H. Amino Acid Sequences of mAb Variable RegionsTable 1J. Amino Acid Sequences of mAb CDRs (Combined)

[0188] In some embodiments, the antibody or antigen-binding fragment is an anti-EphA2 antibody or antigen-binding fragment. In some embodiments, the anti-EphA2 antibody or antigen-binding fragment comprises three heavy chain complementarity determining regions (HCDRs) and three light chain complementarity determining regions (LCDRs) selected from the group consisting of: heavy chain CDRl(HCDRl) sequence consisting of SEQ ID NO: 17, HCDR2 sequence consisting of SEQ ID NO: 18, heavy chain CDR3 (HCDR3) sequence consisting of SEQ ID NO: 19; light chain CDR1 (LCDR1) sequence consisting of SEQ ID NO:26, light chain CDR2 (LCDR2) sequence consisting of SEQ ID NO:27, and light chain CDR3 (LCDR3) sequence consisting of SEQ ID NO:28;HCDR1 sequence comprising SEQ ID NO: 17, HCDR2 sequence comprising SEQ ID NO: 18, HCDR3 sequence comprising SEQ ID NO:19; LCDR1 sequence comprising SEQ ID NO:26, LCDR2 sequence comprising SEQ ID NO:27, and LCDR3 sequence comprisingSEQ ID NO:28;HCDR1 sequence consisting of SEQ ID NO:20, HCDR2 sequence consisting of SEQ ID NO:21, HCDR3 sequence consisting of SEQ ID NO: 19; LCDR1 sequence consisting of SEQ ID NO:29, LCDR2 sequence consisting of SEQ ID NO:30, and LCDR3 sequence consisting of SEQ ID NO:31;HCDR1 sequence comprising SEQ ID NO:20, HCDR2 sequence comprising SEQ ID NO:21, HCDR3 sequence comprising SEQ ID NO: 19; LCDR1 sequence comprising SEQ ID NO:29, LCDR2 sequence comprising SEQ ID NO:30, and LCDR3 sequence comprising SEQ ID NO:31;HCDR1 sequence consisting of SEQ ID NO:22, HCDR2 sequence consisting of SEQ ID NO:23, HCDR3 sequence consisting of SEQ ID NO:24; LCDR1 sequence consisting of SEQ ID NO:32, LCDR2 consisting of SEQ ID NO:27, and LCDR3 sequence consisting of SEQ ID NO:31;HCDR1 sequence comprising SEQ ID NO:22, HCDR2 sequence comprising SEQ ID NO:23, HCDR3 sequence comprising SEQ ID NO:24; LCDR1 sequence comprising SEQ ID NO:32, LCDR2 comprising SEQ ID NO:27, and LCDR3 sequence comprising SEQ ID NO:31;HCDR1 sequence consisting of SEQ ID NO:25, HCDR2 sequence consisting of SEQ ID NO:21, HCDR3 sequence consisting of SEQ ID NO: 19; LCDR1 sequence consisting of SEQ ID NO:29, LCDR2 sequence consisting of SEQ ID NO:30, and LCDR3 sequence consisting of SEQ ID NO: 31 ; andHCDR1 sequence comprising SEQ ID NO:25, HCDR2 sequence comprising SEQ ID NO:21, HCDR3 sequence comprising SEQ ID NO: 19; LCDR1 sequence comprising SEQ ID NO:29, LCDR2 sequence comprising SEQ ID NO:30, and LCDR3 sequence comprising SEQ ID NO:31.

[0189] In some embodiments, the anti-EphA2 antibody or antigen-binding fragment comprises a heavy chain variable region comprising the amino acid sequence SEQ ID NO: 11, and a light chain variable region comprising the amino acid sequence SEQ ID NO: 12. In some embodiments, the anti-EphA2 antibody or antigen-binding fragment comprises an IgGl heavyIllchain constant domain or a modified IgGl heavy chain constant domain. In some embodiments, the IgGl heavy chain constant domain comprises cysteine residues (C) at positions 152 and position 375. In some embodiments, the antibody or antigen-binding fragment comprises an Ig kappa light chain constant domain.

[0190] In some embodiments, the anti-EphA2 antibody or antigen-binding fragment comprises a heavy chain variable region comprising the amino acid sequence SEQ ID NO: 11, and a light chain variable region comprising the amino acid sequence SEQ ID NO: 12. In some embodiments, the anti-EphA2 antibody or antigen-binding fragment comprises an IgGl heavy chain constant domain or a modified IgGl heavy chain constant domain. In some embodiments, the IgGl heavy chain constant domain comprises cysteine residues (C) at positions 152 and position 375. In some embodiments, the antibody or antigen-binding fragment comprises an Ig kappa light chain constant domain.

[0191] In some embodiments, the antibody or antigen-binding fragment is an anti-B7-H3 (CD276) antibody or antigen-binding fragment. In some embodiments, the anti-B7-H3 (CD276) antibody or antigen-binding fragment comprises three heavy chain complementarity determining regions (HCDRs) and three light chain complementarity determining regions (LCDRs) selected from the group consisting of:HCDR1 sequence consisting of SEQ ID NO:33, HCDR2 sequence consisting of SEQ ID NO:34, HCDR3 sequence consisting of SEQ ID NO:35; LCDR1 sequence consisting of SEQ ID NO:42, LCDR2 sequence consisting of SEQ ID NO:43, and LCDR3 sequence consisting of SEQ ID NO:44;HCDR1 sequence consisting of SEQ ID NO:36, HCDR2 sequence consisting of SEQ ID NO:37, HCDR3 sequence consisting of SEQ ID NO:35; LCDR1 sequence consisting of SEQ ID NO:45, LCDR2 sequence consisting of SEQ ID NO:46, and LCDR3 sequence consisting of SEQ ID NO:47;HCDR1 sequence consisting of SEQ ID NO:38, HCDR2 sequence consisting of SEQ ID NO:39, HCDR3 sequence consisting of SEQ ID NO:40; LCDR1 sequence consisting of SEQ ID NO:48, LCDR2 sequence consisting of SEQ ID NO:43, and LCDR3 sequence consisting of SEQ ID NO:47;HCDR1 sequence consisting of SEQ ID NO:41, HCDR2 sequence consisting of SEQ ID NO:37, HCDR3 sequence consisting of SEQ ID NO:35; LCDR1 sequence consistingof SEQ ID NO:45, LCDR2 sequence consisting of SEQ ID NO:46, and LCDR3 sequence consisting of SEQ ID NO:47;HCDR1 sequence consisting of SEQ ID NO:49, HCDR2 sequence consisting of SEQ ID NO:50, HCDR3 sequence consisting of SEQ ID NO:51; LCDR1 sequence consisting of SEQ ID NO:58, LCDR2 sequence consisting of SEQ ID NO:59, and LCDR3 sequence consisting of SEQ ID NO: 60;HCDR1 sequence consisting of SEQ ID NO:52, HCDR2 sequence consisting of SEQ ID NO:53, HCDR3 sequence consisting of SEQ ID NO:51; LCDR1 sequence consisting of SEQ ID NO:61, LCDR2 sequence consisting of SEQ ID NO:62, and LCDR3 sequence consisting of SEQ ID NO: 63;HCDR1 sequence consisting of SEQ ID NO:54, HCDR2 sequence consisting of SEQ ID NO:55, HCDR3 sequence consisting of SEQ ID NO:56; LCDR1 sequence consisting of SEQ ID NO:64, LCDR2 sequence consisting of SEQ ID NO:59, and LCDR3 sequence consisting of SEQ ID NO: 63;HCDR1 sequence consisting of SEQ ID NO:57, HCDR2 sequence consisting of SEQ ID NO:53, HCDR3 sequence consisting of SEQ ID NO:51; LCDR1 sequence consisting of SEQ ID NO:61, LCDR2 sequence consisting of SEQ ID NO:62, and LCDR3 sequence consisting of SEQ ID NO: 63;HCDR1 sequence comprising SEQ ID NO:33, HCDR2 sequence comprising SEQ ID NO:34, HCDR3 sequence comprising SEQ ID NO:35; LCDR1 sequence comprising SEQ ID NO:42, LCDR2 sequence comprising SEQ ID NO:43, and LCDR3 sequence comprising SEQ ID NO:44;HCDR1 sequence comprising SEQ ID NO:36, HCDR2 sequence comprising SEQ ID NO:37, HCDR3 sequence comprising SEQ ID NO:35; LCDR1 sequence comprising SEQ ID NO:45, LCDR2 sequence comprising SEQ ID NO:46, and LCDR3 sequence comprising SEQ ID NO:47;HCDR1 sequence comprising SEQ ID NO:38, HCDR2 sequence comprising SEQ ID NO:39, HCDR3 sequence comprising SEQ ID NO:40; LCDR1 sequence comprising SEQ ID NO:48, LCDR2 sequence comprising SEQ ID NO:43, and LCDR3 sequence comprising SEQ ID NO:47;HCDR1 sequence comprising SEQ ID NO:41, HCDR2 sequence comprising SEQ ID NO:37, HCDR3 sequence comprising SEQ ID NO:35; LCDR1 sequence comprising SEQID NO:45, LCDR2 sequence comprising SEQ ID NO:46, and LCDR3 sequence comprising SEQ ID NO:47;HCDR1 sequence comprising SEQ ID NO:49, HCDR2 sequence comprising SEQ ID NO:50, HCDR3 sequence comprising SEQ ID NO:51; LCDR1 sequence comprising SEQ ID NO:58, LCDR2 sequence comprising SEQ ID NO:59, and LCDR3 sequence comprising SEQ ID NO: 60;HCDR1 sequence comprising SEQ ID NO:52, HCDR2 sequence comprising SEQ ID NO:53, HCDR3 sequence comprising SEQ ID NO:51; LCDR1 sequence comprising SEQ ID NO:61, LCDR2 sequence comprising SEQ ID NO:62, and LCDR3 sequence comprising SEQ ID NO:63;HCDR1 sequence comprising SEQ ID NO:54, HCDR2 sequence comprising SEQ ID NO:55, HCDR3 sequence comprising SEQ ID NO:56; LCDR1 sequence comprising SEQ ID NO:64, LCDR2 sequence comprising SEQ ID NO:59, and LCDR3 sequence comprising SEQ ID NO: 63; andHCDR1 sequence comprising SEQ ID NO:57, HCDR2 sequence comprising SEQ ID NO:53, HCDR3 sequence comprising SEQ ID NO:51; LCDR1 sequence comprising SEQ ID NO:61, LCDR2 sequence comprising SEQ ID NO:62, and LCDR3 sequence comprising SEQ ID NO:63.

[0192] In some embodiments, the anti-B7-H3 (CD276) antibody or antigen-binding fragment comprises a heavy chain variable region comprising the amino acid sequence SEQ ID NO: 13, and a light chain variable region comprising the amino acid sequence SEQ ID NO: 14. In some embodiments, the antibody or antigen-binding fragment comprises an IgGl heavy chain constant domain or a modified IgGl heavy chain constant domain. In some embodiments, the IgGl heavy chain constant domain comprises cysteine residues (C) at position 152 and position 375. In some embodiments, the antibody or antigen-binding fragment comprises an Ig kappa light chain constant domain.

[0193] In some embodiments, the anti-B7-H3(CD276) antibody or antigen-binding fragment comprises a heavy chain variable region comprising the amino acid sequence SEQ ID NO: 15 and a light chain variable region comprising the amino acid sequence SEQ ID NO: 16. In some embodiments, the antibody or antigen-binding fragment comprises an IgGl heavy chain constant domain or a modified IgGl heavy chain constant domain. In some embodiments, the IgGl heavy chain constant domain comprises cysteine residues (C) at position 152and position 375. In some embodiments, the antibody or antigen-binding fragment comprises an Ig kappa light chain constant domain.

[0194] In some embodiments, the anti-B7-H3 (CD276) antibody or antigen-binding fragment comprises a heavy chain comprising the amino acid sequence SEQ ID NO:7, and a light chain comprising the amino acid sequence SEQ ID NO:8.

[0195] In some embodiments, the anti-B7-H3 (CD276) antibody or antigen-binding fragment comprises a heavy chain comprising the amino acid sequence SEQ ID NO:9, and a light chain comprising the amino acid sequence SEQ ID NO: 10.Methods of Synthesis

[0196] Methods of producing the described ADC compounds and compositions are also disclosed. An exemplary embodiment is a method of producing an antibody-drug conjugate by reacting an antibody or antigen-binding fragment with a cleavable conjugate linker joined or covalently attached to a RAS inhibitor under conditions that allow conjugation.

[0197] The present invention provides various methods of conjugating linker-drug groups of the invention to antibodies or antibody fragments to produce antibody drug conjugates. In some embodiments, the conjguates comprise a conjugate linker having one or more hydrophilic moieties.

[0198] A general reaction scheme for the formation of antibody drug conjugates is shown in Scheme 1 below:Scheme 1 L-ioo — Li — 1-2 — L3 — L4 — D p, whereinRG is a reactive group on the Ab which reacts with a compatible LIR group on the linker-drug group to form a corresponding L100 group. Li, L2, L3, L4, L100, Ab, p, and L100 are as defined herein.

[0199] Schemes 2 and 3 further illustrate this general approach for the formation of an antibody drug conjugate, wherein the antibody comprises reactive groups (e.g., -SH) which react with an LIR group (as defined herein) to covalently attach the linker-drug group to the antibody. For illustrative purposes only, Scheme 2 shows an antibody having four -SH groups.Scheme 2

[0200] In another aspect, the linker-drug groups are conjugated to antibodies via lysine res- idues in the antibodies. Scheme 3 illustrates this approach for the formation of an antibody drug conjugate wherein a free amine group (e.g., -NH2) from the lysine residues in the antibody reacts with an LIR group (where LIR is an NHS ester, a pentafluorophenyl or a tetrafluorophenyl) to covalently attach the linker-drug group to the antibody via an L100 group (where L100 is an amide). For illustrative purposes only, Scheme 3 shows an antibody having four amine groups.Scheme 3Synthesis of Compounds of Formula (II)

[0201] The general synthetic procedure for preparing compounds of formula (II) is shown in Scheme 4:Scheme 4Scheme 4 illustrates an exemplary preparation of compound of formula (II). The coupling of compounds of formula (1) may be obtained through standard Suzuki coupling conditions (using, for example, Pd(dppf)C12 and K2CO3) to provide compound of formula (2). The compound of formula (2) may be coupled with a compound of formula (3) under Suzuki coupling conditions (for example Pd(dppf)C12 and K2CO3) to give a compound of formula (4), which may be converted to a compound of formula (5) in the presence of iodization reagents, such as I2 or NIS. Deprotection (via hydrolysis of the ester with LiOH H2O, or via removal of a silicon protective group with TBAF) of a compound of formula (5) may then be performed to provide a compound of formula (6). A compound of formula (8) may be attained by routine amid coupling conditions between the compound of formula (6) and the amine of formula (7) with coupling reagents, such as HATU, EDCI / HOBt or PyBOP, in the presence of an organic base such as EtsN, DIPEA or pyridine. Compound of formula (8) may be hydrolyzed to provide the acid of formula (9) using a base such as LiOH H2O. The intramolecular coupling of compound of formula (9) with coupling reagents, such as EDCI / HOBt and HATU, may be used to give a compound of formula (10). The coupling of a compound of formula (10) may be obtained through standard Suzuki coupling conditions (for example Pd(dppf)C12 and K2CO3) to provide compound of formula (11). A compound of formula (11) may be coupled with a compound of formula (12) under Suzuki coupling conditions (for example Pd(dppf)C12 and K2CO3) to give a compound of formula (13). A compound of formula (13) may be converted to a compound of formula (14) with alkylate reagents, such iodomethane or iodoethane, in the presence of an inorganic base, such as CS2CO3. Deprotection of compound (14) in the presence of an acid, suchas TFA, may afford compound of formula (15). Compound of formula (II) can be obtained by a coupling reaction between acid of formula (16) and a compound of formula (15) with coupling reagents, such as HATU, EDCI / HOBy, PyBOP or COMU, in the presence of a base, such as TEA, DIPEA, pyridine or 2,6-lutidine.TERM DEFINITIONS

[0202] Various terms relating to aspects of the description are used throughout the specification and claims. Such terms are to be given their ordinary meaning in the art unless otherwise indicated. Other specifically defined terms are to be construed in a manner consistent with the definitions provided herein.

[0203] The singular forms “a,” “an,” and “the” include plural forms unless the context clearly dictates otherwise. The terms “comprising,” “having,” “being of,” “including,” and “containing” are to be construed as open terms (i.e., meaning “including, but not limited to”) unless otherwise noted. Additionally, whenever “comprising” or another open-ended term is used in an embodiment, it is to be understood that the same embodiment may be more narrowly claimed using the intermediate term “consisting essentially of’ or the closed term “consisting of.”

[0204] The term “about” or “approximately,” when used in the context of numerical values and ranges, refers to values or ranges that approximate or are close to the recited values or ranges such that the embodiment may perform as intended, as is apparent to the skilled person from the teachings contained herein. In some embodiments, “about” means plus or minus 20%, 15%, 10%, 5%, 1%, 0.5%, or 0.1% of a numerical amount (e.g., values which are 10%, 5%, or 1% more or less than the specified value).

[0205] The terms “antibody-drug conjugate,” “antibody conjugate,” “conjugate,” “immunoconjugate,” and “ADC” are used interchangeably, and refer to a conjugate having one or more therapeutic compounds (e.g., a RAS inhibitor) that is linked to one or more antibodies or antigen-binding fragments. In some embodiments, the ADC is defined by the generic formula: Ab-(L-D)p(formula I), wherein Ab is an antibody or antigen-binding fragment (e.g., an anti- EphA2 antibody or anti-B7-H3 antibody, or an antigen-binding fragment thereof) is L=a conjugate linker moiety, D is a drug moiety (e.g., a panRAS inhibitor drug moiety), and p is the number of linker-drug moi eties per antibody or antigen-binding fragment. In ADCs comprising aRAS inhibitor drug moiety, “p” refers to the number of RAS inhibitor compounds linked to the antibody or antigen-binding fragment.

[0206] The term “antibody” is used in the broadest sense to refer to an immunoglobulin molecule that recognizes and specifically binds to a target, such as a protein, polypeptide, carbohydrate, polynucleotide, or lipid, or a combination of the foregoing, through at least one antigen recognition site within the variable region of the immunoglobulin molecule. An antibody may be polyclonal or monoclonal, multiple or single chain, or an intact immunoglobulin, and may be derived from natural sources or from recombinant sources. An “intact” antibody is a glycoprotein that typically comprises at least two heavy(H)chains and two light (L)chains interconnected by disulfide bonds. Each heavy chain is comprised of a heavy chain variable region (abbreviated herein as VH)and a heavy chain constant region. The heavy chain constant region comprises three domains, CHI, CH2 and CH3. Each light chain is comprised of a light chain variable region (abbreviated herein as VL) and a light chain constant region. The light chain constant region is comprised of one domain, CL. The VH and VL regions may be further subdivided into regions of hypervariability, termed complementarity determining regions (CDR), interspersed with regions that are more conserved, termed framework regions (FR). Each VH and VL is composed of three CDRs and four FRs arranged from amino-terminus to carboxylterminus in the following order: FR1, CDR1, FR2, CDR2, FR3, CDR3, FR4. The variable regions of the heavy and light chains contain a binding domain that interacts with an antigen.

[0207] The constant regions of the antibodies may mediate the binding of the immunoglobulin to host tissues or factors, including various cells of the immune system (e.g., effector cells) and the first component (Clq) of the classical complement system. An antibody can be a monoclonal antibody, human antibody, humanized antibody, camelised antibody, or chimeric antibody. The antibody may be of any isotype (e.g., IgG, IgE, IgM, IgD, IgA and IgY), class (e.g., IgGl, IgG2, IgG3, IgG4, IgAl and IgA2), or subclass. An antibody can be an intact antibody or an antigen-binding fragment thereof. In some embodiments, the antibody is an IgGl antibody.

[0208] The term “antibody fragment,” “antigen-binding fragment,” or “functional antibody fragment” refers to at least one portion of an antibody that retains the ability to specifically interact with (e.g., by binding, steric hinderance, stabilizing / destabilizing, or spatial distribution) an epitope of an antigen (e.g., EphA2 or B7-H3(CD276)). Antigen-binding fragments may also retain the ability to internalize into an antigen-expressing cell. In some embodiments, antigen-binding fragments also retain immune effector activity. The terms antibody, antibody fragment, antigen-binding fragment, and the like are intended to embrace the use of binding domains from antibodies in the context of larger macromolecules such as ADCs. It has been shown that fragments of a full-length antibody can perform the antigen binding function of a full-length antibody. Examples of antibody fragments include, but are not limited to, Fab, Fab', F(ab')2, Fv fragments, scFv antibody fragments, disulfide-linked Fvs (sdFv), a Fd fragment consisting of the VH and CHI domains, linear antibodies, single domain antibodies such as sdAb (either VL or VH), camelid VHH domains, multi-specific antibodies formed from antibody fragments such as a bivalent fragment comprising two Fab fragments linked by a disulfide bridge at the hinge region, and an isolated CDR or other epitope binding fragments of an antibody. An antigen-binding fragment can also be incorporated into a single-domain antibody, maxibody, minibody, nanobody, intrabody, diabody, triabody, tetrabody, bispecific or multi-specific antibody construct, ADC, v-NAR, or bis-scFv. Antigen-binding fragments can also be grafted into scaffolds based on polypeptides such as a fibronectin type I (Fn3). The term“scFv” refers to a fusion protein comprising at least one antigen-binding fragment comprising a variable region of a light chain and at least one antigen-binding fragment comprising a variable region of a heavy chain, wherein the light and heavy chain variable regions are contiguously linked, e.g., via a synthetic linker, e.g., a short flexible polypeptide linker, and capable of being expressed as a single chain polypeptide. The scFv retains the specificity of the intact antibody from which it is derived. Unless specified, an scFv may have the VL and VH variable regions in either order, e.g., with respect to the N-terminal and C-terminal ends of the polypeptide, the sCFv may comprise VL-linker-VH or may comprise VH-linker-VL. Antigen-binding fragments are obtained using conventional techniques known to those of skill in the art, and the binding fragments are screened for utility (e.g., binding affinity, internalization) in the same manner as are intact antibodies. Antigen-binding fragments may be prepared, for example, by cleavage of the intact protein, e.g., by protease or chemical cleavage.

[0209] The term “anti-EphA2 antibody” or “antibody that binds to EphA2,” refers to any form of antibody or antigen-binding fragment thereof that binds, e.g., specifically binds, to EphA2. The term encompasses monoclonal antibodies (including full-length monoclonal antibodies), polyclonal antibodies, and biologically functional antigen-binding fragments so long as they bind, e.g., specifically bind, to EphA2. W02007 / 030642, which is incorporated herein by reference, provides exemplary EphA2 -binding sequences, including exemplary anti-EphA2antibody sequences. In some embodiments, the anti-EphA2 antibody used in the ADCs disclosed herein is an internalizing antibody or internalizing antigen-binding fragment.

[0210] The term “anti-B7-H3 antibody” or “antibody that binds to B7-H3” refers to any form of antibody or antigen-binding fragment thereof that binds, e.g., specifically binds, to B7- H3. B7-H3 may also be referred to as CD276. The term encompasses monoclonal antibodies (including full-length monoclonal antibodies), polyclonal antibodies, and biologically functional antigen-binding fragments so long as they bind, e.g., specifically bind, to B7- H3(CD276). WO2017214322 and WO2012147713, which are incorporated herein by reference, provide exemplary B7-H3-binding sequences, including exemplary anti-B7-H3(CD276) antibody sequences. ABBV-155 and DS-5573a are examples of exemplary anti-B7-H3 (CD276) antibodies.

[0211] As used herein, the terms “peptide,” “polypeptide,” and “protein” are used interchangeably to refer to a polymer of amino acid residues. The terms encompass amino acid polymers comprising two or more amino acids joined to each other by peptide bonds, amino acid polymers in which one or more amino acid residues is a synthetic chemical mimetic of a corresponding naturally-occurring amino acid, as well as naturally-occurring amino acid polymers, and non-naturally-occurring amino acid polymers. The terms include, for example, biologically active fragments, substantially homologous polypeptides, oligopeptides, homodimers, heterodimers, variants of polypeptides, modified polypeptides, derivatives, analogs, fusion proteins, among others. The terms also include natural peptides, recombinant peptides, synthetic peptides, or a combination thereof. Unless otherwise indicated, a particular polypeptide sequence also implicitly encompasses conservatively modified variants thereof.

[0212] The term “chemotherapeutic agent” or “anti-cancer agent” is used herein to refer to an agent that is effective in treating cancer (regardless of mechanism of action). Inhibition of metastasis or angiogenesis is frequently a property of a chemotherapeutic agent. Chemotherapeutic agents include antibodies, biological molecules, and small molecules, and encompass the RAS inhibitors and ADCs described herein. A chemotherapeutic agent may be a cytotoxic or cytostatic agent. The term “cytostatic agent” refers to an agent that inhibits or suppresses cell growth and / or multiplication of cells. The term “cytotoxic agent” refers to a substance that causes cell death primarily by interfering with a cell's expression activity and / or functioning.

[0213] The term “inhibit,” “inhibition,” or “inhibiting” means to reduce a biological activity or process by a measurable amount, and can include but does not require complete prevention or inhibition. In some embodiments, “inhibition” means to reduce the expression and / or activity of RAS and / or one or more upstream modulators or downstream targets thereof.

[0214] The term “RAS inhibitor” refers to an agent capable of reducing the expression and / or activity of RAS (e.g., K-Ras (including splice variants KRAS4A and KRAS4B), H-Ras and N-Ras) and / or one or more upstream modulators or downstream targets thereof.

[0215] “RAS inhibitor drug moiety,” “RAS inhibitor,” and the like refer to the component of an ADC or composition that is derived from the structure of a RAS inhibitor compound by modifying the compound for attachment to an ADC. The RAS inhibitor retains essentially the same, similar, or enhanced biological function or activity as compared to the original compound. In some embodiments, the panRAS inhibitor drug moiety is component (D) in an ADC of formula (I).

[0216] The antibody-drug conjugate (ADC) compounds include those with anti-cancer activity. In particular, the ADC compounds include an antibody or antigen-binding fragment conjugated (i.e., covalently attached by a conjugate linker) to a drug moiety (e.g., a RAS inhibitor). The drug moiety, when not conjugated to an antibody or antigen-binding fragment, has a cytotoxic or cytostatic effect. In some embodiments, the drug moiety when not conjugated to an antibody or antigen-binding fragment is capable of reducing the expression and / or activity of RAS and / or one or more upstream modulators or downstream targets thereof. Without being bound by theory, the ADCs disclosed herein are hypothesized to to be anti-cancer agents by targeting RAS expression and / or activity. Furthermore, it is hypothesized that by conjugating the drug moiety to an antibody that binds an antigen associated with expression in a tumor cell or cancer, the ADC may provide improved activity, better cytotoxic specificity, and / or reduced off-target killing as compared to the drug moiety when administered alone.

[0217] The term “pharmaceutically acceptable salt” refers to a salt that is non-toxic. When the compound of the present invention is acidic, its corresponding salt can be prepared from pharmaceutically acceptable (e.g. non-toxic) bases, including inorganic bases and organic bases. When the compound of the present invention is basic, its corresponding salt can be conveniently prepared from pharmaceutically acceptable (e.g. non-toxic) acids, including inorganic and organic acids.

[0218] The term “solvate” refers to a solvent addition form of a compound that contains either stoichiometric or non-stoichiometric amounts of solvent (e.g., water).

[0219] An excipient that is useful in preparing a pharmaceutical composition is generally safe, nontoxic, and neither biologically nor otherwise undesirable. The excipient (e.g., carrier) may be acceptable for veterinary use or human pharmaceutical use.

[0220] A “pharmaceutically acceptable carrier” includes one or more than one such carrier. The term “pharmaceutically acceptable carrier” also encompasses “pharmaceutically acceptable excipient” and “pharmaceutically acceptable diluent.” The particular carrier used in the pharmaceutical compositions will depend upon the means and purpose for which the conjugates are being applied.

[0221] Unless otherwise specified, the term “optionally substituted” refers to unsubtituted or substituted with one or more (such as 1, 2, 3 or 4) substituents. Suitable substituents for each group may be found herein. Unless otherwise specified, exemplary substituents may be selected from the group consisting of D, halogen, -CN, -NO2, R1, -Ci^alkylene-R1, -C2-4alkenylene-Ri, -C2-4alkynylene-Ri, -OR1, -OC(O)R\ - OjR-, -CO2R1-, -CONR^"-, - OC(O)NNR'R"-, -NR"C(O)R'-, -NRi-C(O)NRiiRiii-, -NR^QO^R1-, -NH-C(NH2)=NH-, NRiC(NH2)=NH-, -NH-C(NH2)=NRi-, -S(O)R-, -S(O)2R-, -S(O)2NRiRii-, and -NR^O^R"; wherein R1, R11and R111are each independently selected from the group consisting of H, C1-6 alkyl, -C2-6 alkenyl, C2-e alkynyl, C3-10 cycloalkyl, C3-10 cycloalkenyl, 3 to 10-membered heterocycloalkyl, 3 to 10-membered heterocycloalkenyl, Ce-io aryl, 5 to 10-membered heteroaryl, -Ci- 4 alkyl ene-Cs- 10 cycloalkyl, -Ci-4 alkylene-C3-io cycloalkenyl, -Ci-4 alkylene-3 to 10-membered heterocycloalkyl, -C1-4 alkylene-3 to 10-membered heterocycloalkenyl, -C1-4 alkylene-Ce-io aryl, and -C1-4 alkyl ene-5 to 10-membered heteroaryl; or R1and R11, R11and R111together with the atom to which they are attached to form C3-10 cycloalkenyl, 3 to 10-membered heterocycloalkyl, 3 to 10-membered heterocycloalkenyl, Ce-io aryl, 5 to 10-membered heteroaryl. The alkylene, alkenylene, alkynylene, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, heterocycloalkyl, heterocycloalkenyl, aryl or heteroaryl can be unsubtituted or may be substituted with one or more (such as 1, 2, 3 or 4) substituents selected from the group consisting of D, halogen, - CN, -OH, C1-6 alkyl, Ci-e haloalkyl, C1-6 deuteroalkyl, C1-6 hydroxyalkyl, C1-6 aminoalkyl, amino, alkylamino, -C(O)C 1-6 alkyl, -OC1-6 alkyl, -OC(O)Ci-6 alkyl, -S(O)Ci-6 alkyl, -S(O)2Ci-6 0 II N=S— alkyl, -COOC 1-6 alkyl, ' I , oxo (=0), C1-6 alkylidene, C1-6 haloalkylidene, C1-6 deuteroalkylidene, C1-6 hydroxyalkylidene, C1-6 aminoalkylidene, C3-6 cycloalkyl optionally substitutedwith one or more of D, halogen, -CN, -OH, Ci-6 alkyl, Ci-e haloalkyl, Ci-6 deuteroalkyl, Ci-6 hydroxyalkyl, and Ci-6 aminoalkyl, 3 to 6-membered heterocycloalkyl optionally substituted with one or more ofD, halogen, -CN, -OH, Ci-6 alkyl, Ci-e haloalkyl, Ci-6 deuteroalkyl, Ci-6 hydroxyalkyl, and Ci-6 aminoalkyl, 3 to 6-membered heterocycloalkenyl optionally substituted with one or more ofD, halogen, -CN, -OH, Ci-6 alkyl, Ci-e haloalkyl, Ci-6 deuteroalkyl, Ci-6 hydroxyalkyl, and Ci-6 aminoalkyl, phenyl, 5 to 6-membered heteroaryl optionally substituted with one or more ofD, halogen, -CN, -OH, Ci-6 alkyl, Ci-e haloalkyl, Ci-6 deuteroalkyl, Ci-6 hydroxyalkyl, and Ci-6 aminoalkyl. In some embodiments, “optionally substituted” means that the group is substituted by one or more substituents selected from the group consisting of deuterium, halogen, amino, nitro, cyano, hydroxyl, oxo (=0), thio (=S), C1-C4 alkyl, C1-C4 haloalkyl, C1-C4 hydroxyalkyl, C1-C4 alkoxy, C1-C4 haloalkoxy, C2-C4 alkenyl, C2-C4 alkyne, C3-C6 cycloalkyl, and 3 to 6-membered heterocycloalkyl.

[0222] The term “alkyl” refers to a saturated aliphatic hydrocarbon group including straight chain and branched chain groups having the number of carbon atoms designated. C1-20 means 1 to 20 carbon atoms. In some embodiments, an alkyl group is an alkyl having 1 to 12 carbon atoms (i.e., C1-12 alkyl); 1 to 6 carbon atoms (i.e., C1-6 alkyl); or 1 to 4 carbon atoms (i.e., C1-4 alkyl). Representative examples include, but are not limited to, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, sec-butyl, n-pentyl, 1,1 -dimethyl propyl, 1,2-dimethyl propyl,2.2-dimethyl propyl, 1 -ethylpropyl, 2-methylbutyl, 3 -methylbutyl, n-hexyl, l-ethyl-2- methylpropyl, 1,1,2-trimethylpropyl, 1,1 -dimethylbutyl, 1,2-dimethylbutyl, 2,2-dimethylbutyl,1.3-dimethylbutyl, 2-ethylbutyl, 2-methylpentyl, 3 -methylpentyl, 4-methylpentyl, 2,3-dime- thylbutyl, n-heptyl, 2-methylhexyl, 3 -methylhexyl, 4-methylhexyl, 5-methylhexyl, 2,3-dime- thylpentyl, 2,4-dimethylpentyl, 2,2-dimethylpentyl, 3, 3 -dimethylpentyl, 2-ethylpentyl, 3- ethylpentyl, n-octyl, 2,3 -dimethylhexyl, 2,4-dimethylhexyl, 2,5-dimethylhexyl, 2,2-dime- thylhexyl, 3,3 -dimethylhexyl, 4.4-dimethylhexyl, 2-ethylhexyl, 3-ethylhexyl, 4-ethylhexyl, 2- methyl-2-ethylpentyl, 2-methy 1-3 -ethylpentyl, n-nonyl, 2-methyl -2-ethylhexyl, 2-methyl-3- ethylhexyl, 2,2-diethylpentyl, n-decyl, 3, 3 -di ethyl hexyl, 2,2-diethylhexyl, and the isomers of branched chain thereof. Further optionally an alkyl group is a lower alkyl having 1 to 6 carbon atoms. Representative examples include, but are not limited to, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, sec-butyl, n-pentyl, 1,1 -dimethylpropyl, 1,2-dimethylpropyl, 2,2-dimethylpropyl, 1 -ethylpropyl, 2-methylbutyl, 3 -methylbutyl, n-hexyl, l-ethyl-2- methylpropyl, 1,1,2-trimethylpropyl, 1,1 -dimethylbutyl, 1.2-dimethylbutyl, 2,2-dimethylbutyl,1,3-dimethylbutyl, 2-ethylbutyl, 2-methylpentyl, 3 -methylpentyl, 4-methylpentyl, 2,3-dime- thylbutyl, etc. The alkyl group may be substituted or unsubstituted. When substituted, the substituent group(s) may be substituted at any available connection point. In some embodiments, the substituent group(s) are selected from the group consisting of alkyl, halogen, alkoxy, alkenyl, alkynyl, alkylsulfo, alkylamino, thiol, hydroxy, nitro, cyano, amino, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkoxyl, heterocylic, cycloalkylthio, heterocylic alkylthio and oxo.

[0223] The term “alkylene” refers to a divalent saturated linear or branched aliphatic hydrocarbon group that is conceptually formed by removing two hydrogen atoms from the same or different carbon atom(s) of the parent alkane. The straight or branched chain group may have 1 to 20 carbon atoms, optionally 1 to 12 carbon atoms, further optionally 1 to 6 carbon atoms. Non-limiting examples of alkylene groups include, but are not limited to, methylene (- CH2-), 1,1-ethylene (-CH(CH3)-), 1,2-ethylene (-CH2CH2)-, 1,1-propylene (-CH(CH2CH3)-), 1,2-propylene (-CH2CH(CH3)-), 1,3-propylene (-CH2CH2CH2-), and 1,4-butylidene (- CH2CH2CH2CH2-). The alkylene group may be substituted or unsubstituted. When substituted, the number of substituent group(s) may be one or more (e.g., one to five or one to three) group(s) independently selected from the group consisting of selected from alkyl, alkenyl, alkynyl, alkoxy, alkylsulfo, alkylamino, halogen, thiol, hydroxy, nitro, cyano, cycloalkyl, heterocyclic alkyl, aryl, heteroaryl, cycloalkoxyl, heterocylic alkoxyl, cycloalkylthio and heterocylic alkylthio.

[0224] The term “alkenyl” refers to an alkyl that has at least two carbon atoms and at least one carbon-carbon double bond, for example, a vinyl, 1 -propenyl, 2- propenyl, 1-2-, or 3-bu- tenyl group. In some embodiments, the alkenyl is a C2-20 alkenyl (e.g., C2-12 or C2-6 alkenyl). The alkenyl group may be substituted or unsubstituted. When substituted, the number of substituent group(s) may be one or more (e.g., one to five or one to three) group(s) independently selected from the group consisting of alkyl, halogen, alkoxy, alkenyl, alkynyl, alkylsulfo, alkylamino, thiol, hydroxy, nitro, cyano, amino, cycloalkyl, heterocyclic alkyl, aryl, heteroaryl, cycloalkoxyl, heterocylic, cycloalkylthio, heterocylic alkylthio and oxo group.

[0225] The term “alkenylene” refers to a di-radical (i.e., divalent) alkene group that is conceptually formed by removing two hydrogen atoms from the same or different carbon atom(s) of the parent alkene). Non-limiting examples of alkenylene groups include, but are not limited to, -CH=CH-, -CH=CHCH2, -CH=CHCH2CH2, and -CH2CH=CHCH2-. The alkenylene groupmay be substituted or unsubstituted. When substituted, the number of substituent group(s) may be one or more (e.g., one to five one to three) group(s) independently selected from the group consisting of selected from alkyl, alkenyl, alkynyl, alkoxy, alkylsulfo, alkylamino, halogen, thiol, hydroxy, nitro, cyano, cycloalkyl, heterocyclic alkyl, aryl, heteroaryl, cycloalkoxyl, het- erocylic alkoxyl, cycloalkylthio and heterocylic alkylthio.

[0226] The term “alkynyl” refers to an alkyl defined as above that has at least two carbon atoms and at least one carbon-carbon triple bond, for example, ethynyl, 1-propynyl, 2- propynyl, 1-2-, or 3-butynyl. The alknyl may be a C2-20 alkynyl, C2-12 alkynyl, or C2-6 alkynyl. The alkynyl group may be substituted or unsubstituted. When substituted, the number of substituent group(s) may be one or more (e.g., one to five orone to three) group(s) independently selected from the group consisting of alkyl, alkenyl, alkynyl, alkoxy, alkylsulfo, alkylamino, halogen, thiol, hydroxy, nitro, cyano, cycloalkyl, heterocyclic alkyl, aryl, heteroaryl, cycloalkoxyl, heterocylic alkoxyl, cycloalkylthio and heterocylic alkylthio.

[0227] The term “aryl” refers to a 6 to 14-membered (or Ce-u) all-carbon monocyclic ring or a polycyclic fused ring. A "fused" ring system is system having two or more rings, wherein each ring in the system shares an adjacent pair of carbon atoms with another ring in the system An aryl group has a completely conjugated pi-electron system. In some embodiments, the aryl is 6 to 10-membered (or Ce-io), for example phenyl or naphthyl. The aryl can be fused to a heteroaryl, heterocyclyl or cycloalkyl ring. Representative eExamples of structures comprising aryl groups include, but are not limited to, the following:

[0228] The aryl group may be substituted or unsubstituted. When substituted, the number of substituent group(s) is optionally one or more (e.g., one to five or one to three) substituent(s) independently selected from the group consisting of alkyl, alkenyl, alkynyl, alkoxy, alkylsulfo, alkylamino, halogen, thiol, hydroxy, nitro, cyano, cycloalkyl, heterocyclic alkyl, aryl, heteroaryl, cycloalkoxyl, heterocylicalkoxyl, cycloalkylthio and heterocylic alkylthio.

[0229] The term “arylene” refers to a di-radical (i.e., divalent) aryl group that is conceptually formed by removing two hydrogen atoms from the same or different carbon atom(s) of the parent aryl.

[0230] As used herein, the term “heteroaryl” refers to an aryl system having 1 to 4 heteroatoms selected from the group consisting of O, S, and N as ring atoms. The heteroaryl may have, e.g., 5 to 14 ring atoms. In some embodiments, the heteroaryl is 5 to 10-membered or 5 or 6-membered. In some embodiments, the heteroaryl is thiadiazolyl, pyrazolyl, oxazolyl, oxadiazolyl, imidazolyl, triazolyl, thiazolylfuryl, thienyl, pyridyl, pyrrolyl, N-alkyl pyrrolyl, pyrimidinyl, pyrazinyl, imidazolyl, tetrazolyl, and the like. The heteroaryl can be fused with the ring of an aryl, heterocyclyl or cycloalkyl, wherein the ring bound to parent structure is heteroaryl. Representative examples of structures comprising a heteroaryl group include, but are not limited to, the following:

[0231] The heteroaryl group may be substituted or unsubstituted. When substituted, the number of substituent group(s) may be one or more (e.g., one to five or one to three) substituents independently selected from the group consisting of alkyl, alkenyl, alkynyl, alkoxy, alkylsulfo, alkylamino, halogen, thiol, hydroxy, nitro, cyano, cycloalkyl, heterocyclic alkyl, aryl, heteroaryl, cycloalkoxyl, heterocylic alkoxyl, cycloalkylthio, heterocylic alkylthio and -NReRf.

[0232] The term “heteroarylene” refers to a di -radical (i.e., divalent) heteroaryl group that is conceptually formed by removing two hydrogen atoms from the same or different carbon atom(s) of the parent heteroaryl.

[0233] The term “bicyclic” includes spiro, fused-ring, or bridged-ring structures. “Spiro” refers to two rings that shares one ring atom (e.g., carbon). “Fused” refers to two rings that share two adjacent ring atoms with one another. “Bridged” refers to two rings that share three adjacent ring atoms with one another.

[0234] “Cycloalkyl” refers to a saturated and / or partially unsaturated monocyclic or polycyclic hydrocarbon group having 3 to 20 carbon atoms (refered as C3-20), optionally 3 to 12 carbon atoms (refered as C3-12), further optionally 3 to 10 carbon atoms (refered as C3-10), 3 to 8carbon atoms(refered as C3-8), or 3 to 6 carbon atoms (refered as C3-6). In some embodiments, cycloalkyl is monocyclic cycloalkyl. Representative examples of monocyclic cycloalkyls include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexenyl, cyclohexadienyl, cycloheptyl, cycloheptatrienyl, cyclooctyl, etc. In some embodiments, cycloalkyl is polycyclic cycloalkyl (such as bicyclic cycloalkyl). In some embodiments, cycloalkyl is a spiro cycloalkyl, a fused cycloalkyl or a bridged cycloalkyl. Polycyclic cycloalkyl includes a cycloalkyl having a spiro ring, fused ring or bridged ring. The cycloalkyl can be fused to the ring of an aryl, heteroaryl or heterocyclic alkyl. Representative examples of compounds comprising a cycloalkyl group include, but are not limited to indanylacetic, tetrahydronaphthalene, and benzocycloheptyl. The cycloalkyl is optionally substituted or unsubstituted. When substituted, the number of substituent group(s) is one or more (e.g., one to five or one to three) substituents independently selected from the group consisting of alkyl, halogen, alkoxy, alkenyl, alkynyl, alkylsulfo, alkylamino, thiol, hydroxy, nitro, cyano, amino, cycloalkyl, heterocyclic alkyl, aryl, heteroaryl, cycloalkoxyl, heterocylic, cyeloalkylthio, heterocylic alkylthio and oxo group.

[0235] The term “cycloalkylene” refers to a di-radical (i.e., divalent) cycloalkyl group that is conceptually formed by removing two hydrogen atoms from the same or different carbon atom(s) of the parent cycloalkyl.

[0236] “Spiro Cycloalkyl” refers to a 5 to 20-membered polycyclic group with rings that are connected through one common carbon atom (called a spiro atom). One or more of the rings can contain one or more double bonds. None of the rings may have a completely conjugated pi-electron system. In some embodiments, a spiro cycloalkyl is 6 to 14-membered (e.g., 7 to 10-membered). According to the number of common spiro atoms, a spiro cycloalkyl is divided into mono-spiro cycloalkyl, di-spiro cycloalkyl, or poly-spiro cycloalkyl. In some embodiments, the cycloalkyl is to a mono-spiro cycloalkyl or di-spiro cycloalkyl. In some embodiments, the spiro cycloalkyl is a 4-membered / 4-membered, 4-membered / 5-membered, 4-mem- bered / 6-membered, 5-membered / 5-membered, or 5-membered / 6-membered mono-spiro cycloalkyl. Representative examples of spiro cycloalkyl include, but are not limited to the following:

[0237] “Fused cycloalkyl” refers to a 5 to 20-membered polycyclic hydrocarbon system having two or more rings, wherein each ring in the system shares an adjacent pair of carbon atoms with another ring. The one or more rings may contain one or more double bonds, but none of the rings has a completely conjugated pi -electron system. A fused cycloalkyl group may be, e.g., 6 to 14-membered (e.g., 7 to 10-membered). According to the number of rings, fused cycloalkyl may be divided into bicyclic, tricyclic, tetracyclic or polycyclic fused cycloalkyl. In some embodiments, the fused cycloalkyl is a bicyclic or tricyclic fused cycloalkyl (e.g., a 5- membered / 5-membered, or 5-membered / 6-membered bicyclic fused cycloalkyl). Representative examples of fusedcycloalkyls include, but are not limited to, the following:

[0238] “Bridged cycloalkyl” refers to a 5 to 20-membered polycyclic hydrocarbon group, wherein every two rings in the system share two disconnected carbon atoms. The rings may have one or more double bonds, but do not have a completely conjugated pi -electron system. In some embodiments, a bridged cycloalkyl is 6 to 14-membered (e.g., 7 to 10-membered). According to the number of membered rings, bridged cycloalkyl may be divided into bicyclic, tricyclic, tetracyclic or polycyclic bridged cycloalkyl. Representative examples of bridged cycloalkyls include, but are not limited to, the following substituents:

[0239] The term “heterocyclyl” or “heterocycloalkyl” refers to a 3 to 20-membered saturated and / or partially unsaturated monocyclic or polycyclic hydrocarbon group having one or more (e.g., one to five or one to three) carbon ring atoms replaced with heteroatoms selected from the group consisting of N, O, and S(O)m(wherein m is 0, 1, or 2) as ring atoms, but excluding -O-O-,-O-S-, or -S-S- in the ring. The remaining ring atoms are C. In some embodiments, the heterocyclyl is a 3 to 12-membered ring having 1 to 4 heteroatoms; optoinally a 3 to 10-membered ring having 1 to 3 heteroatoms; further optionaly a 4 to 8-membered ring having 1 to 3 heteroatoms or a 5 to 6-membered ring having 1 to 2 heteroatoms. In some embodiments, heterocycloalkyl / heterocyclyl is monocyclic. Representative examples of monocyclic heterocy- clyls or heterocycloalkyl include, but are not limited to, oxetanyl, azabutyl, pyrrolidyl, piperidyl, piperazinyl, morpholinyl, sulfo-morpholinyl, homopiperazinyl, and so on. In some embodiments, heterocycloalkyl / heterocyclyl is polycyclic heterocycloalkyl / heterocyclyl (such as bicyclic heterocycloalkyl / heterocyclyl). In some embodiments, heterocycloalkyl / heterocyclyl is a spiro heterocycloalkyl / heterocyclyl, a fused heterocycloalkyl / heterocyclyl, or a bridged heterocycloalkyl / heterocyclyl. Polycyclic heterocyclyl or heterocycloalkyl includes a heterocyclyl having a spiro ring, fused ring or bridged ring. Examples of such heterocyclyl groups areWhen the heterocyclyl has substituents, the substituents may be attached to any atom in the ring, provided that a stable chemical structure results.

[0240] The term “heterocycloalkylene” refers to a di-radical (i.e., divalent) heterocycloalkylene group that is conceptually formed by removing two hydrogen atoms from the same or different carbon atom(s) of the parent heterocycloalkylene.

[0241] “Spiro heterocyclyl” refers to a 5 to 20-membered polycyclic heterocyclyl with rings connected through one common carbon atom (called a spiro atom), wherein said rings have one or more (e.g., one to five or one to three) heteroatoms selected from the group consisting of N, O, and S(O)m, (wherein m is 0,1 or 2) as ring atoms. The remaining ring atoms are C. One or more rings may contain one or more double bonds, but none of the rings may have a completely conjugated pi -electron system. In some embodiments, a spiro heterocyclyl is 6 to 14-membered, optionally 7 to 10-membered. According to the number of common spiroatoms, spiro heterocyclyl may be divided into mono-spiro heterocyclyl, di-spiro heterocyclyl, or polyspiro heterocyclyl (e.g., 4-membered / 4-membered, 4-membered / 5-membered, 4-membered / 6-membered, 5-membered / 5-membered, or 5-membered / 6-membered mono-spiro heterocyclyl).Representative examples of spiro heterocyclyl include, but are not limited to the following:

[0242] “Fused heterocyclyl" refers to a 5 to 20-membered polycyclic heterocyclyl group, wherein each ring in the system shares an adjacent pair of carbon atoms with an other ring. One or more rings may contain one or more double bonds, but none of the rings may have a completely conjugated pi-electron system. The rings may have one or more (e.g. one to five or one to three) heteroatoms selected from the group consisting of N, O, and S(O)P, (wherein p is 0,1, or 2) as ring atoms. The remaining ring atoms are C. In some embodiments, a fused heterocyclyl is 6 to 14-membered (e.g. 7 to 10-membered). According to the number of membered rings, fused heterocyclyl may be divided into bicyclic, tricyclic, tetracyclic or polycyclic fused heterocyclyl (e.g. 5-membered / 5-membered, or 5-membered / 6-membered bicyclic fused heterocyclyl). Representative examples of fused heterocyclyl include, but are not limited to, the following:

[0243] The ring of the heterocyclyl may be fused to the ring of an aryl, heteroaryl, or cycloalkyl. Representative examples include, but are not limited to the following:

[0244] The may be substituted or unsubstituted. When substituted, the number of substituent group(s) is one or more (e.g., one to five or one to three) group(s) independently selected from the group consisting of alkyl, alkenyl, alkynyl, alkoxy, alkylsulfo, alkylamino, halogenthiol, hydroxy, nitro, cyano, cycloalkyl, heterocyclic alkyl, aryl, heteroaryl, cycloalkoxyl, heterocylic alkoxyl, cycloalkylthio, and heterocylic alkylthio.

[0245] “Bridged heterocyclyl” refers to a 5 to 14-membered polycyclic heterocyclic alkyl group, wherein every rings in the system shares two disconnected atoms with another ring. The rings may have one or more double bonds, but may not have a completely conjugated pi-elec- tron system. The rings may have one or more heteroatoms selected from the group consisting of N, O, and S(O)m(wherein m is 0, 1, or 2) as ring atoms. The remaining ring atoms are C. In some embodiments, a bridged heterocyclyl is 6 to 14-membered (e.g., 7 to 10-membered). According to the number of membered rings, bridged heterocyclyl may be divided into bicyclic, tricyclic, tetracyclic or polycyclic bridged heterocyclyl. Representative examples of bridged heterocyclyl include, but are not limited to, the following substituents:

[0246] The term “Ci-6 haloalkoxyl” refers to an alkoxyl group in which one or more hydrogen atoms are replaced by a halogen, for example, -OCF3.

[0247] The term “haloalkyl” refers to an alkyl group in which one or more hydrogen atoms are replaced by a halogen, for example, -CF3.

[0248] The term “C1-6 alkoxyCi-6 alkyl” refers to a Ci- 6 alkyl group in which one or more hydrogen atoms are replaced by C1-6 alkoxy or a C1-6 alkoxy group in which one or more hydrogen atoms are replaced by C1-6 alkyl.

[0249] The term “alkoxy” refers to a straight or branched alkoxy group containing the specified number of carbon atoms. For example, Ci-6 alkoxy means a straight or branched alkoxy group containing at least 1, and at most 6, carbon atoms. Examples of “alkoxy” as used herein include, but not limited to, methoxy, ethoxy, prop- 1 -oxy, pro-2-oxy, pentoxy, hexyloxy, and the like.

[0250] The term “aminoalkyl” refers to an alkyl moiety substituted by one or more amino moieties, for example, -CEhCNEh).

[0251] The term “alkylamino” refers to an amino group substituted by one or more alkyl such as -NH(Ci-6alkyl) or -N(Ci-6alkyl)2. Examples of alkylamino include, but not limited to, - NH(CH3) and -N(CH3)2.

[0252] The term “halogen” or “halo” refers to fluorine (F), chlorine (Cl), bromine (Br) or iodine (I).

[0253] The term "oxo" means that =0, oxygen atoms replace two hydrogens on the same carbon atom, that is, a carbonyl group replaces a methylene group.

[0254] The term “bond” refers to a covalent bond using a sign of “ — ”. = represents a double bond or single bond.

[0255] It is to be understood that the foregoing description of embodiments is intended to be purely illustrative of the principles of the invention, rather than exhaustive thereof, and that changes and variations will be apparent to those skilled in the art, and that the present application is not intended to be limited other than expressly set forth in the following claims.

[0256] The following examples provide illstrative embodiments of the disclosure. One of ordinary skill in the art will recognize the numerous modifications and variations that may be performed without altering the spirit or scope of the disclosure. Such modifications and variations are encompassed within the scope of the disclosure. The examples provided do not in any way limit the disclosure.

[0257] The compounds of the present invention can be prepared by any conventional means. Suitable processes for synthesizing these compounds as well as their starting materials are provided in the schemes below and in the examples. All substituents are as defined above unless otherwise indicated. Furthermore, and unless explicitly otherwise stated, all reactions, reaction conditions, abbreviations and symbols have the meanings well known to a person of ordinary skill.

[0258] Unless otherwise defined, all technical and scientific terms in the present invention have the same meanings as generally understood by a person skilled in the art to which the invention belongs. In accordance with the general technical knowledge and customary means in the art, under the premise of not departing from the above-mentioned basic technical ideas of the present invention, other forms of modification, replacement or change can also be made.

[0259] Unless otherwise stated, the raw materials and reagents used in the following Examples are commercially available or may be prepared by known methods.

[0260] The present invention is described in detail below by embodiments, but does not imply any adverse restriction on the present invention. The compounds of the present invention can be prepared by a variety of synthesis methods well known to those skilled in the art, including the specific embodiments listed below, the embodiments formed by the combination of the invention with other chemical synthesis methods, and the equivalent substitution methods well known to those skilled in the art. embodiments include, but are not limited to, embodiments of the present invention. To those skilled in the art, various changes and improvements to the specific embodiments of the present invention without departing from the spirit and scope of the invention will be obvious and shall also be regarded as the scope of protection of the present invention.

[0261] All literature mentioned in the present application are incorporated herein by reference, as though each one is individually incorporated by reference. Additionally, it should be understood that after reading the above teachings, those skilled in the art can make various changes and modifications to the present invention. These equivalents also fall within the scope defined by the appended claims.EXAMPLESExample 1. Preparation of Intermediate A 3-(5-bromo-lH-indol-3-yl)-2.,2-dimethylDroDyl acetateStep 1. Preparation of (5-bromo-lH-indol-3-yl)methanol

[0262] To a solution of 5-bromo-lH-indole-3-carbaldehyde (100.0 g, 0.45 mol) in premixed solvents THF / MeOH (I L, V: V = 4:1) was stirred at 0°C for 5 mins, then NaBJL (20.0g, 0.53 mol) was added into the above solution at room temperature. The resulting mixture was stirred at 0°C for 2h. The reaction was monitored by LCMS. After completion, the reaction mixture was quenched with H2O (300 mL) dropwise and diluted with EtOAc (100 mL), then the resulting mixture was extracted with EtOAc (100 mL x 4). The organic layer was separated, dried over anhydrous Na2SO4 and concentrated to give the crude product (5-bromo-lH- indol-3-yl)methanol (107.5g, 98%) as a white solid. The crude product was proceeded to the next reaction without purification. LCMS (ESI) calcd. for CLfLBrNO [M-H]+m / z 224.07, found: 224.10.Step 2. Preparation of methyl 3-(5-bromo-lH-indol-3-yl)-2,2-dimethylpropanoate

[0263] To a solution of ((l-methoxy-2-methylprop-l-en-l-yl)oxy)trimethylsilane (157.3 g, 0.90 mol) in dry THF (150 mL) under N2 atmosphere, the reaction mixture was stirred at -40°C for 5 mins, then (5-bromo-lH-indol-3-yl)methanol (107.5 g, 0.48 mol) in dry THF (50 mL) was added under N2 atmosphere. After 10 mins, TMSOTf (90.0 g, 0.40 mol) in dry THF (50 mL) was added into the above solution by dropwise at nitrogen atmosphere. The reaction mixture was stirred at this temperature for 2h. The reaction was monitored by LCMS. After completion, the reaction mixture was warmed to room temperature and diluted with NaHCCh solution (100 mL), then the resulting mixture was extracted with EtOAc (100 mL x 4). The organic layer was separated, dried over anhydrous Na2SO4 and concentrated to give the crude product, which was further purified by silica gel chromatography eluting with petroleum ether / EtOAc (from 0% to 20%) to obtain methyl 3-(5-bromo-lH-indol-3-yl)-2,2-dimethylpropanoate (98g, 70%) as a yellow solid. LCMS (ESI) calcd. for CwHieBr TCL [M+H]+m / z 310.19, found: 310.20.Step 3. Preparation of 3-(5-bromo-lH-indol-3-yl)-2,2-dimethylpropan-l-ol

[0264] To a solution of methyl 3-(5-bromo-lH-indol-3-yl)-2,2-dimethylpropanoate (98g, 0.32 mol) and LiBH4 (40g, 1.82 mol) was added in dry THF (300 mL) at room temperature, the reaction mixture was stirred at 80°C for 12h. The reaction was monitored by LCMS. After completion, the reaction mixture was cooled to room temperature, quenched with NH4CI solution (150 mL) and diluted with EtOAc (100 mL), then the resulting mixture was extracted withEtOAc (100 mL x 4). The organic layer was separated, dried over anhydrous Na2SO4 and concentrated to give the crude product 3-(5-bromo-lH-indol-3-yl)-2,2-dimethylpropan-l-ol (91.3g, 99%) as a light-yellow solid. The crude product was taken to the next reaction without purification. LCMS (ESI) calcd. for Ci3Hi6BrNO [M+H]+m / z 282.18, found: 282.40.Step 4. Preparation of 3-(5-bromo-lH-indol-3-yl)-2,2-dimethylpropyl acetate

[0265] To a solution of 3-(5-bromo-lH-indol-3-yl)-2,2-dimethylpropan-l-ol (91.3g, 0.31 mol) in dry DCM (150 mL) at room temperature under N2 atmosphere, then DIPEA (62.7g, 0.49 mol), DMAP (4.0g, 0.03 mol) and AC2O (24.0 g, 0.31 mol) was added into the above solution under N2 atmosphere. The reaction mixture was stirred at room temperature for 3h. The reaction was monitored by LCMS. After completion, the reaction mixture was diluted with Na- HCO3 solution (100 mL), then the resulting mixture was extracted with DCM (100 mL x 4), the combined organic phase was washed with saturated NaCl (50 mL), then died over with Na2SO4, following with concentration under reduced pressure to obtain crude one, which was purified by silica gel column eluting with petroleum ether / EtOAc (from 0% to 20%) to afford 3-(5-bromo-lH-indol-3-yl)-2,2-dimethylpropyl acetate (82.0 g, 79%) as a white solid. LCMS (ESI) calcd. for Ci5Hi8BrNO2[M+H]+m / z 324.22, found: 324.60.Example 2. Synthesis of Intermediate B methyl (S)-3-(4-bromothiazol-2-yl)-2-((tert- butoxycarbonyl)amino)DroDanoateIntermediate BStep 1. Preparation of methyl (S)-3-(4-bromothiazol-2-yl)-2-((tert-butoxycarbonyl)amino)pro- panoate

[0266] To a solution of activated Zn dust (22 g, 334 mmol) and DMF (100 mL) was added to a 250 mL three-necked round-bottomed flask and purged with N2, then a solution of I2 (1.5 g, 6.08 mmol) in DMF (5 mL) was added to the above solution. The mixture was stirred for 10 min at rt, then a solution of methyl (R)-2-((tert-butoxycarbonyl)amino)-3-iodopropanoate (20 g, 60.79 mmol) in DMF (200 mL) was added dropwise over a period of 10 min. The mixture was heated at 35°C and stirred for 2 h, then the reaction was cooled to rt. Transfer the liquid to another 500 mL three-necked round-bottomed flask and purged with N2, and a solution ofPd(PPh3)Ch (2.1 g, 3.04 mmol) and 2,4-dibromothiazole 2 (17.7 g, 72.95 mmol) in DMF (100 mL) was added dropwise over a period of 10 min. The reaction was stirred at 50°C for 16 h under N2 atmosphere, the reaction was monitored by LCMS. After completion, the reaction mixture was diluted with brine and extracted with EtOAc (2 x 500 mL). The organic layers were combined, washed with saturated NaCl (2 x 500 mL), dried over anhydrous ISfeSCU and concentrated to give the crude product. The crude product was purified by silica gel column chromatography purified by silica gel column eluting with EtOAc / PE from 0% to 25% to afford methyl (S)-3-(4-bromothiazol-2-yl)-2-((tert-butoxycarbonyl)amino)propanoate (10 g, 45.2 %) as a yellow solid. LCMS (ESI) calcd. for CnHnBrlS CUS [M+H]+m / z 365.01, found: 367.3.Example 3. Synthesis of Intermediate C (S)-4-(methoxycarbonyl)-2,3-diazabicv- clo[3.1.1]heptan-2-ium 2,2,2-trifluoroacetateIntermediate CStep 1. Preparation of 3-oxocyclobutane-l -carbonyl chloride

[0267] To a stirred solution of 3-oxocyclobutane-l -carboxylic acid (50 g, 438.60 mmol) in DCM (500 mL) and DMF (321 mg, 4.39 mmol) was added (COC1)2 (83.51 g, 657.89 mmol), the resulting mixture was stirred at rt for 3 h. The reaction mixture was concentrated under reduced pressure to give the crude product. The crude product was used to next step without purification. LCMS (ESI) calcd. for C5H5CIO2 [M+H]+m / z 133.00, found: 133.4.Step 2. Preparation of 3-(2-diazoacetyl)cyclobutan-l-one

[0268] To a stirred solution of crude 3 -oxocyclobutane- 1 -carbonyl chloride in THF (250 mL) and CH3CN (250 mL) was added TMSCHN2 (2M in hexanes, 285 mL, 570.18 mmol) dropwisely at 0°C. The resulting mixture was stirred at rt for 18 h. After completion, the reaction solution was concentrated under reduced pressure to give the residual, the residual was purified by silica gel column (eluting with EtOAc / PE from 0% to 50%) to afford 3-(2-diazoace- tyl)cyclobutan-l-one (60.2 g, 99.5 %) as a yellow oil. LCMS (ESI) calcd. for CeH S CL [M+H]+m / z 139.04, found: 139.4.Step 3. Preparation of 2 -(3 -oxocyclobutyl) acetic acid

[0269] To a stirred solution of CF3COOAg (4.82 g, 21.81 mmol) in THF (300 mL), H2O (30 mL) and TEA (181.91 mL, 1.31 mol) was added a solution of 3-(2-diazoacetyl)cyclobutan- 1-one (60.20 g, 436.23 mmol) in THF (300 mL) and H2O (30 mL) at 0°C, the reaction mixture was stirred at rt for 18 h. After completion, the reaction solution was concentrated under reduced pressure to give the residual, the residual was diluted with H2O and acidified with HC1 (2N) to pH = 2. The resuliting mixture was extracted with EtOAc (5*300 mL). The organic layers were combined and dried over ISfeSCU, following with concentration under reduced pressure to afford crude 2-(3-oxocyclobutyl)acetic acid (55. 8g, 99.9 %) as a brown oil. LCMS (ESI) calcd. for C6H8O3[M+H]+m / z 129.13, found: 129.4.Step 4. Preparation of (S)-4-benzyl-3-(2-(3-oxocyclobutyl)acetyl)oxazolidin-2-one

[0270] To a stirred solution of 2-(3-oxocyclobutyl)acetic acid (52.0 g, 406.3 mmol), (5)-4- benzyloxazolidin-2-one (71.9 g, 406.3 mmol), 4-Dimethylaminopyridine (5.0 g, 40.6 mmol) and triethylamine (141.2 mL, 1015.6 mmol) in DCM (1 L) was added 2-Chloro-l -methylpyridinium iodide (135.0 g, 528.1 mmol) in portions at 0°C. The reaction mixture was stirred at R.T. for 4 h. After completion, the reaction solution was diluted with H2O and extracted with DCM, the combined organic phase was washed with H2O dried over Na2SO4, following with concentration under reduced pressure to obtain crude product which was purified by silica gel column (eluting with EA / PE from 0% to 20%) to give (5)-4-benzyl-3-(2-(3-oxocyclobutyl)ace- tyl)oxazolidin-2-one (68 g 58.3 %) as a yellow oil. LCMS (ESI) calcd. for C16H17NO4 [M+H]+m / z 288.1, found: 288.5Step 5. Preparation of (S)-4-benzyl-3-(2-(3-hydroxycyclobutyl)acetyl)oxazolidin-2-one

[0271] To a stirred solution of (S)-4-benzyl-3-(2-(3-oxocyclobutyl)acetyl)oxazolidin-2-one (45.0 g, 156.8 mmol) in THF (500 mL) was added AcOH (17.9 mL, 313.6 mmol) and NaBH4 (6.5 g, 172.5 mmol) in portions at 0°C. The reaction mixture was stirred at r.t. for 2 h. Aftercompletion, the reaction solution was diluted with H2O then concentrated under reduced pressure to remove THF. The residual was extracted with EtOAc, the combined organic phase was dried over Na2SO4, following with concentration under reduced pressure to obtain (5)-4-ben- zyl-3-(2-(3-hydroxycyclobutyl)acetyl)oxazolidin-2-one (45 g, 99.3 %) as a light yellow oil. LCMS (ESI) calcd. for C16H19NO4 [M+H]+m / z 290.1, found: 290.5.Step 6. Preparation of (S)-3-(2-(4-benzyl-2-oxooxazolidin-3-yl)-2-oxoethyl)cyclobutyl 4- methylbenzenesulfonate

[0272] To a stirred solution of (5)-4-benzyl-3-(2-(3 -hydroxy cy cl obutyl)acetyl)oxazolidin- 2-one (48.0 g, 156.8 mmol) and DIEA (43.3 g, 249.1 mmol) in DCM (500 mL) was added 4- dimethylaminopyridine (16.2 g, 132.9 mmol) and tosyl chloride (34.8 g, 182.7 mmol) at 0°C. The reaction mixture was stirred at r.t. for 14 h. After completion, the reaction solution was diluted with H2O and extracted with DCM, the combined organic phase was washed with H2O and dried over Na2SO4, and concentrated under reduced pressure to obtain crude product which was purified by silica gel column (eluting with EA / PE from 0% to 30%) to give (5)-3-(2-(4- benzyl-2-oxooxazolidin-3-yl)-2-oxoethyl)cyclobutyl 4-methylbenzenesulfonate (62.0 g, 84.3 %) as a yellow oil. LCMS (ESI) calcd. for C23H25NO6S [M+H]+m / z 444.1, found: 444.6. Step 7. Preparation of (S)-4-benzyl-3-(2-(3-bromocyclobutyl)acetyl)oxazolidin-2-one

[0273] To a stirred solution of (5)-3-(2-(4-benzyl-2-oxooxazolidin-3-yl)-2-oxoethyl)cyclo- butyl 4-methylbenzenesulfonate (62.0 g, 139.8 mmol) in N-Methyl-2-pyrrolidone (650 mL) was added Lithium bromide (24.3 g, 279.6 mmol), the resulting mixture was stirred at 65°C for 13 h. The reaction was monitored by LCMS. After completion, the reaction solution was diluted with H2O and extracted with EtOAc, the combined organic phase was washed with NaCl (aq.) dried over Na2SO4, following with concentration under reduced pressure to obtain crude product which was purified by silica gel column (eluting with EA / PE from 0% to 20%) to give (5)-4-benzyl-3-(2-(3-bromocyclobutyl)acetyl)oxazolidin-2-one (42 g, 85.3 %) as a light yellow oil. LCMS (ESI) calcd. for Ci6Hi8BrNO3[M+H]+m / z 352.0, found: 352.5.Step 8. Preparation of (S)-2,3-bis(tert-butoxycarbonyl)-2,3-diazabicyclo[3.1.1]heptane-4-car- boxylic acid

[0274] To a stirred solution of (5)-4-benzyl-3-(2-(3-bromocyclobutyl)acetyl)oxazolidin-2- one (30.0 g, 85.5 mmol) in THF (300 mL) was added LDA (2 M in THF, 111.0 mmol) was added dropwise over a period of 15 minutes at -78 oC under N2 condition. The reaction mixture was stirred at -78°C for 30 mins, then a solution of Di-tert-Butyl azodi carb oxy late (23.6 g,102.6 mmol) in DCM (50 mL) was added rapidly. The reaction mixture was stirred at -78°C for 30 mins, then l,3-Dimethyl-3,4,5,6-tetrahydro-2(lH)-pyrimidinone (310 mL, 2565.0 mmol) was added dropwise at -78°C. The reaction mixture was stirred at r.t. for 14 h. After completion, the reaction solution was quenched with water (200 mL), then LiOH LO (10.8 g, 256.5 mmol) was added and the reaction solution was stirred at r.t. for 2 h. After completion, the reaction solution was diluted with brine (200 mL) and washed with tert-Butyl methyl ether 2 times, the aqueous phase was acidified to pH = 3-4 with 2 N HC1. The resulting mixture was extracted with EtOAc, washed with water and brine, then dried over Na2SO4, following with concentration under reduced pressure to obtain crude product (5)-2,3-bis(tert-butoxycarbonyl)- 2,3-diazabicyclo[3.1.1]heptane-4-carboxylic acid, which was used directly for the next step. LCMS (ESI) calcd. for Ci6H26N2O6[M+H]+m / z 343.39, found: 343.5.Step 9. Preparation of 2,3 -di-tert-buty 14-methyl (S)-2,3-diazabicyclo[3.1.1]heptane-2,3,4-tri- carboxylate

[0275] To a stirred solution of crude product (5)-2,3-bis(tert-butoxycarbonyl)-2,3-diazabi- cyclo[3.1.1]heptane-4-carboxylic acid (27.0 g, 78.9 mmol) in DMF (300 mL) was added K2CO3 (27.3 g, 197.4 mmol) and lodomethane (10 mL, 157.8 mmol) at r.t. The reaction mixture was stirred at r.t. for 2 h. After completion, the reaction solution was concentration under reduced pressure to obtain crude product which was purified by silica gel column (eluting with EA / PE from 0% to 23%) to give 2,3-di-tert-butyl 4-methyl (5)-2,3-diazabicyclo[3.1.1]heptane- 2,3,4-tricarboxylate (5.6 g, 18.45 % in two-steps) as a light yellow oil. LCMS (ESI) calcd. for C17H28N2O6 [M-H]- m / z 357.2, found: 357.6.Step 10. Preparation of (S)-4-(methoxycarbonyl)-2,3-diazabicyclo[3.1.1]heptan-2-ium 2,2,2- trifluoroacetate

[0276] To a stirred solution of 2,3-di-tert-butyl 4-methyl (5)-2,3-diazabicyclo[3.1.1]hep- tane-2,3,4-tricarboxylate (7.3 g, 0.18 mmol) in DCM (100 mL) was added TFA (40 mL), the resulting mixture was stirred at rt for 2 h. The reaction mixture was concentrated to give the crude product (5)-4-(methoxycarbonyl)-2,3-diazabicyclo[3.1.1]heptan-2-ium 2,2,2-trifluoro- acetate (7.2 g) as a yellow solid. LCMS (ESI) calcd. for C15H23BO4 [M+H]+m / z 157.09, found: 157.4.Example 4. Synthesis of Intermediate D tert-butyl ((63S.,4S.,Z)-10,10-dimethyl-5.,7-dioxo- l2-(4.,4.,5.,5-tetramethyl-l.,3.,2-dioxaborolan-2-yl)-61.,62.,63.,64.,65.,66-hexahydro-l1H-8-oxa- 2(4,2)-thiazola-l(5.,3)-indola-6(l.,3)-DyridazinacvcloundecaDhane-4-yl)carbamateStep 1. Preparation of 2,2-dimethyl-3-(5-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)-lH-in- dol-3-yl)propyl acetate

[0277] To a stirred solution of 3-(5-bromo-lH-indol-3-yl)-2,2-dimethylpropyl acetate (20 g, 61.92 mmol) in 1,4-dioxane (400 mL) was added Pd(dppf)C12 (2.2 g, 3.10 mmol) and KOAc (18.4 g, 185.76 mmol). The reaction was stirred at 90°C for 16 h under N2 atmosphere, the reaction was monitored by LCMS. After completion, the reaction solution was concentrated under reduced pressure to remove 1,4-dioxane, the residual was diluted with H2O and extracted with EtOAc (500 mL x 3), the combined organic phase was washed with saturated NaCl (500 mL), then dried over Na2 SO4, following with concentration under reduced pressure to obtain crude product which was purified by silica gel column eluting with EtOAc / PE from 0% to 27% to afford 2,2-dimethyl-3-(5-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)-lH-indol-3-yl)propyl acetate (18.7 g, 81.4 %) as a light yellow solid. LCMS (ESI) calcd. for C21H30BNO4 [M+H]+m / z 372.23, found: 372.5.Step 2. Preparation of methyl (S)-3-(4-(3-(3-acetoxy-2,2-dimethylpropyl)-lH-indol-5-yl)thia- zol-2-yl)-2-( tert-butoxycarbonyl)amino)propanoate

[0278] To a stirred solution of 2,2-dimethyl-3-(5-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan- 2-yl)-lH-indol-3-yl)propyl acetate (18.7 g, 50.40 mmol), methyl (S)-3-(4-bromothiazol-2-yl)- 2-((tert-butoxycarbonyl)amino)propanoate (27.5 g, 75.61 mmol) and K3PO4 (26.7 g, 126.01 mmol) in toluene / l,4-dioxane / H2O (300 mL, V:V:V = 4: 1 : 1 ) was added Pd(dppf)C12 (1.6 g, 2.52 mmol) at rt. The reaction mixture was stirred at 70°C under N2 for 16 h. After completion,the reaction solution was concentrated under reduced pressure to remove 1,4-di oxane and toluene, the residual was diluted with H2O and extracted with EtOAc (500 mL x 3), the combined organic phase was washed with saturated NaCl (500 mL), then dried over ISfeSCU, following with concentration under reduced pressure to obtain crude product which was purified by silica gel column eluting with EtOAc / PE from 0% to 36% to afford methyl (S)-3-(4-(3 -(3 -acetoxy - 2,2-dimethylpropyl)-lH-indol-5-yl)thiazol-2-yl)-2-((tert-butoxycarbonyl)amino)propanoate (20.7 g, 77.6 %) as a light yellow solid. LCMS (ESI) calcd. for C27H35N3O6S [M+H]+m / z 530.22, found: 530.6.Step 3. Preparation of methyl (S)-3-(4-(3-(3-acetoxy-2,2-dimethylpropyl)-2-iodo-lH-indol-5- yl)thiazol-2-yl)-2-((tert-butoxycarbonyl)amino)propanoate

[0279] To a stirred solution of methyl (S)-3-(4-(3-(3-acetoxy-2,2-dimethylpropyl)-lH-in- dol-5-yl)thiazol-2-yl)-2-((tert-butoxycarbonyl)amino)propanoate (12.3 g, 23.25 mmol) and Na- HCO3 (2.3 g, 27.90 mmol) in THF (150 mL) under ice-water bath was added AgSCLCFs (7.2 g, 27.90 mmol) in THF (50 mL) and I2 (5.0 g, 19.76 mmol) in THF (50 mL) by dropwise to the reaction mixture. The reaction was stirred at -20°C for 1 h, the reaction was monitored by LCMS. After completion, The reaction was quenched with saturated Na2S20s (200 mL) and was extracted with EtOAc (500 mL x 2), the combined organic phase was washed with saturated NaCl (500 mL), then dried over Na2SO4, following with concentration under reduced pressure to obtain crude product which was purified by silica gel column eluting with EtOAc / PE from 0% to 40% to afford methyl (S)-3-(4-(3-(3-acetoxy-2,2-dimethylpropyl)-2- iodo-lH-indol-5-yl)thiazol-2-yl)-2-((tert-butoxycarbonyl)amino)propanoate (12.0 g, 78.8 %) as a light yellow solid. LCMS (ESI) calcd. for C27H34IN3O6S [M+H]+m / z 656.12, found: 656.5. Step 4. Preparation of (S)-2-((tert-butoxycarbonyl)amino)-3-(4-(3-(3-hydroxy-2,2-dimethylpro- pyl) -2-iodo-lH-indol-5-yl) thiazol-2-yl)propanoic acid

[0280] To a solution of methyl (S)-3-(4-(3-(3-acetoxy-2,2-dimethylpropyl)-2-iodo-lH-in- dol-5-yl)thiazol-2-yl)-2-((tert-butoxycarbonyl)amino)propanoate (25 g, 38.17 mmol) in THF (500 mL) and H2O (100 mL) was added LiOH H2O (4.6 g, 190.84 mmol) at 0-10°C, the resulting mixture was stirred at 0-10°C for 16 h. The reaction was monitored by LCMS. After completion, the reaction mixture was acidified to pH = 3-4 with 2 N HC1. The resulting mixture was extracted with EtOAc (300 mL x 2), the combined organic phase was washed with saturated NaCl (500 mL), then dried over Na2SO4 and concentrated to give the (S)-2-((tert- butoxycarbonyl)amino)-3-(4-(3-(3-hydroxy-2,2-dimethylpropyl)-2-iodo-lH-indol-5-yl)thiazol-2-yl)propanoic acid (22.8 g, 100 %) as a light yellow solid. LCMS (ESI) calcd. for C24H30IN3O5S [M+H]+m / z 599.10, found: 600.6.Step 5. Preparation of (S)-2-((S)-2-((tert-butoxycarbonyl)amino)-3-(4-(3-(3-hydroxy-2,2-dime- thylpropyl)-2-iodo-lH-indol-5-yl)thiazol-2-yl)propanoyl)-2, 3 -diazabicyclo [3.1.1 ]heptane-4- carboxylate

[0281] To a solution of (S)-2-((tert-butoxycarbonyl)amino)-3-(4-(3 -(3 -hydroxy-2, 2-dime- thylpropyl)-2-iodo-lH-indol-5-yl)thiazol-2-yl)propanoic acid (1.10 g, 1.84 mmol) in DMF (15 mL) were added HATU (1.04 g, 2.75 mmol) and DIEA (1.30 mL, 7.35 mmol) at 0-10°C. The resulting mixture was stirred at 0-10°C for 10 min. Then methyl (5)-2,3-diazabicy- clo[3.1.1]heptane-4-carboxylate (472 mg, 1.84 mmol) was added into the reaction mixture, the resulting mixture was stirred at rt for 2 h. The reaction was monitored by LCMS. After completion, the reaction mixture was diluted with brine and extracted with EtOAc (2 x 400 mL), the combined organic phase was washed with saturated NaCl (500 mL), then dried over Na2SC>4, following with concentration under reduced pressure to obtain crude product which was purified by silica gel column eluting with EtOAc / PE from 0% to 60% to afford methyl (S)-2-((S)-2-((tert-butoxycarbonyl)amino)-3-(4-(3-(3-hydroxy-2,2-dimethylpropyl)-2-iodo-lH- indol-5-yl)thiazol-2-yl)propanoyl)-2,3-diazabicyclo[3.1.1]heptane-4-carboxylate (1.23 g, 90.7 %) as a light yellow solid. LCMS (ESI) calcd. for C31H40IN5O6S [M+H]+m / z 738.2, found: 738.6.Step 6. Preparation of (S)-2-((S)-2-((tert-butoxycarbonyl)amino)-3-(4-(3-(3-hydroxy-2,2-dime- thylpropyl)-2-iodo-lH-indol-5-yl)thiazol-2-yl)propanoyl)-2, 3 -diazabicyclo [3.1.1 ]heptane-4- carboxylic acid

[0282] To a solution of methyl (S)-2-((S)-2-((tert-butoxycarbonyl)amino)-3-(4-(3 -(3 -hydroxy -2, 2-dimethylpropyl)-2-iodo-lH-indol-5-yl)thi azol -2 -yl)propanoyl)-2,3-diazabicy- clo[3.1.1]heptane-4-carboxylate (1.23 g, 24.53 mmol) in THF (1.23 g, 24.53 mmol) and H2O (6 mL) was added LiOH-EEO (210 mg, 5.01 mmol) at 0-10°C, the resulting mixture was stirred at 0-10°C for 2 h. The reaction was monitored by LCMS. After completion, the reaction mixture was acidified to pH = 3-4 with 2 N HC1. The resulting mixture was extracted with EtOAc (300 mL x 2), the combined organic phase was washed with saturated NaCl (500 mL), then dried over Na2SO4 and concentrated to give the (S)-2-((S)-2-((tert-butoxycarbonyl)amino)-3-(4-(3-(3-hydroxy-2,2-dimethylpropyl)-2-iodo-lH-indol-5-yl)thiazol-2-yl)propanoyl)-2,3-di- azabicyclo[3.1.1]heptane-4-carboxylic acid (1.03 g, 85.3 %) as a light yellow solid. LCMS (ESI) calcd. for C30H38IN5O6S [M+H]+m / z 724.1, found: 724.9.Step 7. Preparation of tert-butyl ((64S,4S,Z)-l2-iodo-10,10-dimethyl-5, 7-dioxo-lIH-8-oxa- 62, 63-diaza-2(4,2)-thiazola-l(5,3)-indola-6(2,4)-bicyclo[3.1.1 ]heptanacycloundecaphane-4- y I) carbamate

[0283] To a solution of TCFH (994 mg, 3.54 mmol) in ACN (80 mL) was added a solution of (S)-2-((S)-2-((tert-butoxycarbonyl)amino)-3-(4-(3-(3-hydroxy-2,2-dimethylpropyl)-2-iodo- lH-indol-5-yl)thiazol-2-yl)propanoyl)-2,3-diazabicyclo[3.1.1]heptane-4-carboxylic acid 22 (640 mg, 0.89 mmol) and NMI (582 mg, 7.08 mmol) in ACN (48 mL), the reaction was gradually improved temperature to room temperature and stirred for 2 h. The reaction was monitored by LCMS. After completion, the reaction was concentrated under reduced pressure to give crude product which was purified by silica gel column (eluting with EtOAc / PE from 0% to 65% to afford tert-butyl ((64S,4S,Z)-12-iodo-10,10-dimethyl-5,7-dioxo-l lH-8-oxa-62,63-di- aza-2(4,2)-thiazola-l(5,3)-indola-6(2,4)-bicyclo[3.1.1]heptanacycloundecaphane-4-yl)carba- mate 23 (199 mg, 31.7 %) as a light yellow solid. LCMS (ESI) calcd. for C30H36IN5O5S [M+H]+ m / z 706.2, found: 706.8.Step 8. Preparation of tert-butyl ((64S,4S,Z)-10,10-dimethyl-5, 7-dioxo-l2-(4,4,5,5-tetramethyl- 1, 3, 2-dioxaborolan-2-yl)-lIH-8-oxa-62, 63-diaza-2 (4,2) -thiazola-1 (5,3) -indola-6(2, 4)-bicy- clo[3.1.1 ]heptanacycloundecaphane-4-yl)carbamate

[0284] To a stirred solution of tert-butyl ((64S,4S,Z)-l2-iodo-10,10-dimethyl-5,7-dioxo-11H-8-oxa-62,63-diaza-2(4,2)-thiazola-l (5,3)-indola-6(2,4)-bicyclo[3.1.1 ]heptanacycloundeca- phane-4-yl)carbamate (790 mg, 1.12 mmol), Pd2(dba)s (154 mg, 0.17 mmol), SPhos (154 mg, 0.17 mmol) and AcOK (495 mg, 5.04 mmol) in toluene was added B2Pin2 (1.08 g, 8.40 mmol) at 0°C under N2 atmosphere. The reaction mixture was stirred at 60°C under N2 for 3h. After completion, the reaction mixture was concentrated under reduced pressure to give the crude product which was purified by silica gel column (eluting with EtOAc / PE from 0% to 60%) to give crude tert-butyl ((64S,4S,Z)-10,10-dimethyl-5,7-dioxo-l2-(4,4,5,5-tetramethyl-l,3,2-diox- aborolan-2-yl)-l1H-8-oxa-62,63-diaza-2(4,2)-thiazola-l(5,3)-indola-6(2,4)-bicy- clo[3.1.1]heptanacycloundecaphane-4-yl)carbamate (810 mg) as a pale yellow solid. LCMS (ESI) calcd. for C36H48BN5O7S [M+H]+m / z 706.3, found: 707.0.Example 5. Synthesis of Intermediate E (S)-3-bromo-5-iodo-2-(l-methoxyethyl)pyridinepyIntermediate EStep 1. Preparation of (S)-l-(3-bromopyridin-2-yl)ethan-l-ol

[0285] To a stirred solution of TEA (151.76 g, 1.50 mol) was added FA (13.81 g, 299.96 mmol) at 0°C. Then (S,S)-N-(p-Toluenesulfonyl)-l,2-diphenylethanediamine(chloro)(p-cy- mene)ruthenium(II) (800 mg, 1.25 mmol) was added into the reaction mixture, the resulting mixture was stirred at 40°C under N2 for 0.5 h. l-(3-bromopyridin-2-yl)ethan-l-one (25.00 g, 124.98 mmol) was added into the reaction mixture, the resulitng mixture was stirred at 40°C under N2 for 1 h. The reaction was monitored by LCMS. After completion, the reaction mixture was diluted with EtOAc (500 mL), washed with saturated NH4CI (300 x 3 mL), then dried over Na2SO4, following with concentration under reduced pressure to obtain crude product which was purified by silica gel column (eluting with EtOAc / PE from 0% to 25%) to give (S)- 1 -(3 -brom opyri din-2 -yl)ethan-l-ol (28.80 g, 95.0 %) as a yellow oil. LCMS (ESI) calcd. for C7H6BrNO [M+H]+m / z 200.98, found: 202.1.Step 2. Preparation of (S)-3-bromo-2-(l-methoxyethyl)pyridine

[0286] To a stirred solution of (S)-l -(3 -brom opyri din-2 -yl)ethan-l-ol (23.80 g, 117.82 mmol) in THF (240 mL) was added NaH (60% in oil, 7.07 g, 176.73 mmol) portion wisely at 0°C, the resulting mixture was stirred at 0°C for 1 h. CH3I (33.45 g, 235.64 mmol) was added into the reaction mixture at 0°C, the resulting mixture was stirred at rt for 15 h. The reaction mixture was quenched with H2O (50 mL) at 0°C and extracted with EtOAc (2*200 mL). The organic layers were combined, washed with brine, dried over Na2SO4 and concentrated to give the crude product which was purified by silica gel column (eluting with EtOAc / PE from 0% to 25%) to give (S)-3-bromo-2-(l-m ethoxy ethyl)pyri dine (23.39 g, 91.9 %) as a light yellow oil. LCMS (ESI) calcd. for CsHwBrNO [M+H]+m / z 214.99, found: 216.3.Step 3. Preparation of (S)-3-bromo-2-(l-methoxyethyl)-5-(4,4,5,5-tetramethyl-l,3,2-dioxabo- rolan-2-yl)pyridine

[0287] To a stirred solution of (S)-3-bromo-2-(l-m ethoxy ethyl)pyri dine (12.00 g, 55.56 mmol) B2Pin2 (15.53 g, 61.11 mmol) in THF (180 mL) was added [Ir(COD)(OMe)]2 (737 mg, 1.11 mmol) and dtbpy (895 mg, 3.33 mmol) at rt , the resulting mixture was stirred at 75°C under N2 for 23 h. The reaction was monitored by LCMS. After completion, the reaction mixture was concentrated to give the crude product which was purified by silica gel column (eluting with EtOAc / PE from 0% to 80%) to give crude (S)-3-bromo-2-(l-methoxyethyl)-5-(4, 4,5,5- tetramethyl-l,3,2-dioxaborolan-2-yl)pyridine (20.9 g) as an orange oil. LCMS (ESI) calcd. for Ci4H2iBBrNO3[M+H]+m / z 341.08, found: 342.4.Step 4. Preparation of (S)-(5-bromo-6-(l-methoxyethyl)pyridin-3-yl)boronic acid

[0288] To a stirred solution of crude (S)-3-bromo-2-(l-methoxyethyl)-5-(4,4,5,5-tetrame- thyl-l,3,2-dioxaborolan-2-yl)pyridine (16.20 g, 47.51 mmol) in THF (150 mL) and H2O (150 mL) were added NH4OAc (14.60 g, 190.03 mmol ) and NaIO4(40.60 g, 190.03 mmol) at 0°C, the resulting mixture was stirred at rt for 3h. The reaction was monitored by LCMS. After completion, the reaction mixture was extracted with EtOAc (2*300 mL). The organic layers were combined, washed with brine, dried over Na2SO4and concentrated to give the crude product which was purified by silica gel column (eluting with EtOAc / PE from 0% to 80%) to give (S)-(5-bromo-6-(l-methoxyethyl)pyridin-3-yl)boronic acid (10.98 g, 89.2%) as a yellow solid. LCMS (ESI) calcd. for C8HnBBrNO3[M+H]+m / z 259.00, found: 260.3.Step 5. Preparation of (S)-3-bromo-5-iodo-2-(l-methoxyethyl)pyridine

[0289] To a stirred solution of (S)-(5-bromo-6-(l-methoxyethyl)pyridin-3-yl)boronic acid (3.00 g, 11.58 mmol) in CH3CN (45 mL) was added NIS (3.13 g, 13.90 mmol) at rt, the resulting mixture was stirred at 75°C for 20h. The reaction was monitored by LCMS. After completion, the reaction mixture was quenched with sat. aq. Na2SO3and concentrated to give the residue. The residue was extracted with EtOAc (2*30 mL). The organic layers were combined and washed with brine, then dried over Na2SO4and concentrated to give the crude product which was purified by silica gel column (eluting with EtOAc / PE from 0% to 20%) to give (S)-3- bromo-5-iodo-2-(l-methoxyethyl)pyridine (2.65 g, 67.1%) as a brown solid. LCMS (ESI) calcd. for C8H9BrINO3[M+H]+m / z 340.89, found: 342.3.Example 6. Synthesis of Intermediate of Compound 3: (S)-4-(5-bromo-6-(l-methoxy- ethyl)pyridin-3-yl)-2-methylbut-3-yn-2-olStep 1. Preparation of (S)-4-(5-bromo-6-(l-methoxyethyl)pyridin-3-yl)-2-methylbut-3-yn-2-ol

[0290] A mixture of (S)-3-bromo-5-iodo-2-(l-methoxyethyl)pyridine (200 mg, 0.59 mmol), 2-methylbut-3-yn-2-ol (99 mg, 1.17 mmol), K2CO3 (243 mg, 1.76 mmol), Pd(PPh3)2Cl2(41 mg, 0.059 mmol) and Cui (11 mg, 0.059 mmol) in THF (4.5 mL) was stirred at 65°C under N2for 23 h. The reaction was monitored by LCMS. After completion, the reaction mixture was concentrated to give the crude product which was purified by silica gel column (eluting with EtOAc / PE from 0% to 40%) to give (S)-4-(5-bromo-6-(l -methoxy ethyl)pyr- idin-3-yl)-2-methylbut-3-yn-2-ol (160 mg, 91.3%) as a brown solid. LCMS (ESI) calcd. for Ci3Hi6BrNO2[M+H]+m / z 297.04, found: 298.4.Example 7. Synthesis of Intermediate of Compound 5: tert-butyl (S)-3-((5-bromo-6-((S)- l-methoxyethyl)pyridin-3-yl)ethynyl)pyrrolidine-l-carboxylateStep 1. Preparation of tert-butyl (S)-3-ethynylpyrrolidine-l-carboxylate

[0291] To a stirred solution of tert-butyl (R)-3-formylpyrrolidine-l -carboxylate (1 g, 5.0 mmol) and K2CO3 (1.4 g, 10.0 mmol) in MeOH (15 mL) was added dimethyl (l-diazo-2-ox- opropyl)phosphonate (1.2 g, 6.0 mmol) at RT. The reaction mixture was stirred at RT for 2 h. After completion, the reaction mixture was diluted with EtOAc (50 mL), washed with brine (30 mL), then dried over Na2SO4, following with concentration under reduced pressure to obtain crude product tert-butyl (S)-3-ethynylpyrrolidine-l -carboxylate (980 mg) as a yellow oil. LCMS (ESI) calcd. for C11H17NO2 [M+H-56]+m / z 140.1, found: 140.4.Step 2. Preparation of tert-butyl (S)-3-((5-bromo-6-((S)-l-methoxyethyl)pyridin-3- yl)ethynyl)pyrrolidine-l-carboxylate

[0292] A mixture of tert-butyl (S)-3-ethynylpyrrolidine-l -carboxylate (980 mg, 5.0 mmol),(S)-3-bromo-5-iodo-2-(l -methoxy ethyl)pyri dine (1.7 g, 5.0 mmol), Cui (96 mg, 0.5 mmol) TEA (1.0 g, 10.0 mmol) and Pd(PPh3)2Cl2(352 mg, 0.5 mmol) in THF (20 mL) was stirred at50°C under N2 for 2 h. After completion, the reaction mixture was concentrated to give the crude product which was purified by silica gel column (eluting with EA / PE from 0% to 25%) to give tert-butyl (S)-3-((5-bromo-6-((S)-l-methoxyethyl)pyridin-3-yl)ethynyl)pyrrolidine-l- carboxylate (1.8 g, 90 % in 2 steps) as a brown oil. LCMS (ESI) calcd. for CwEEsBrlS Ch [M+H]+m / z 409.1, found: 409.6.Example 8. Synthesis of Addditional Alkyne Intermediates

[0293] The following intermediates in Table 2 were prepared using the method described above in step for the preparation of (S)-4-(5-bromo-6-(l-methoxyethyl)pyridin-3-yl)-2-methyl- but-3-yn-2-ol or tert-butyl (S)-3-((5-bromo-6-((S)-l-methoxyethyl)pyridin-3-yl)ethynyl)pyrrol- idine-1 -carboxylate and utilizing the appropriate starting materials and modifications.Table 2. Certain Intermediates containing alkynyl group of the Present inventionExample 9. Synthesis of Intermediate of Compound 15 (S)-4-(3-(5-bromo-6-(l-methoxy- ethyl)pyridin-3-yl)prop-2-vn-l-yl)morpholineStep 1. Preparation of 3-bromo-2-((S)-l-methoxyethyl)-5-(3-((tetrahydro-2H-pyran-2- yl)oxy)prop-l-yn-l-yl)pyridine

[0294] A mixture of (5)-3-bromo-5-iodo-2-(l-methoxyethyl)pyridine (10.00 g, 29.24 mmol), 2-(prop-2-yn-l-yloxy)tetrahydro-2H-pyran (4.92 g, 35.09 mmol), Cui (0.45 g, 2.34 mmol), TEA (8.88 g, 8.73 mmol) and Pd(PPh3)2C12 (1.64 g, 2.34 mmol) in THF (120.00 mL) was stirred at 50°C for 4h under N2 atmosphere, the reaction was monitored by LCMS. After completion, the mixture was filtered and the filtrate was concentrated, the residue was purified by silica gel column chromatography (eluting with EtOAc / PE, from 0% to 3% in 20 min) to obtain 3 -brom o-2-((5)- 1 -methoxy ethyl)-5 -(3 -((tetrahy dro-2H-pyran-2-yl)oxy)prop- 1 -yn- 1 - yl)pyridine (10.10 g, yield: 97.5%) as a yellow oil. LCMS (ESI) calcd. for CieEEoBrNCE [M+H]+m / z 354.1, found 354.5.Step 2. Preparation of (S)-3-(5-bromo-6-(l-methoxyethyl)pyridin-3-yl)prop-2-yn-l-ol

[0295] To a solution of 3-bromo-2-(fS')- l -methoxyethyl)-5-(3-((tetrahydro-2H-pyran-2- yl)oxy)prop-l-yn-l-yl)pyridine (10.10 g, 28.51 mmol) in MeOH (100.00 mL) was added TsOH (19.64 g, 114.05 mmol) at 0°C, the mixture was stirred at room temperature for 5 h under N2 atmosphere, the reaction was monitored by LCMS. After completion, the mixture was diluted with DCM (50.00 mL) and H2O (150.00 mL) and extracted with DCM (50 mL x 3), the combined layers were washed with saturated NaCl (150.00 mL), dried over Na2SO4, concentrated to obtain (5)-3-(5-bromo-6-(l-methoxyethyl)pyridin-3-yl)prop-2-yn-l-ol (7.10 g, yield: 92.2%) as a yellow oil. LCMS (ESI) calcd. for CnHi2BrNO2[M+H]+m / z 270.0, found 270.3. Step 3. Preparation of (S)-3-(5-bromo-6-(l-methoxyethyl)pyridin-3-yl)prop-2-yn-l-yl 4- methylbenzenesulfonate

[0296] To a solution of (5)-3-(5-bromo-6-(l-methoxyethyl)pyridin-3-yl)prop-2-yn-l-ol (7.10 g, 26.28 mmol) in THF (100.00 mL) were added TsCl (10.02 g, 52.57 mmol) and KOH(2.95 g, 52.57 mmol) at 0°C, the mixture was stirred at 0°C for 2 h under N2 atmosphere, the reaction was monitored by LCMS. After completion, the mixture was diluted with EtOAc (50.00 mL) and water (100.00 mL), then extracted with EA (50.00 mL x 3). The combined organic phase was washed with brine (100.00 mL), dried over Na2SO4 and concentrated under reduced pressure. The residual was purified by silica gel column chromatography (eluting with EtOAc / PE, from 0% to 30% in 30 min) to obtain (,S')-3 -(5 -bromo-6-(l -meth oxy ethyl)pyri din-3 - yl)prop-2-yn-l-yl 4-methylbenzenesulfonate (10.50 g, yield: 94.2%) as a brown solid. LCMS (ESI) calcd. for Ci8Hi8BrNO4S [M+H]+m / z 424.0, found 424.8.Step 4. Preparation of (S)-4-(3-(5-bromo-6-(l-methoxyethyl)pyridin-3-yl)prop-2-yn-l-yl)mor- pholine

[0297] To a solution of morpholine (358 mg, 4.11 mmol) in DCM (10 mL) were added DIEA (1.21 g, 9.34 mmol) and a solution of (5)-3-(5-bromo-6-(l-methoxyethyl)pyridin-3- yl)prop-2-yn-l-yl 4-methylbenzenesulfonate (1.58 g, 3.74 mmol) in DCM (10 mL) at rt, the resulting mixture was stirred at rt for 16 h. The reaction was monitored by LCMS. After completion, the mixture was concentrated under reduced pressureto give the residual which was purified by silica gel column chromatography (eluting with EtOAc / PE from 0% to 40%) to obtain (S)-4-(3-(5-bromo-6-(l-methoxyethyl)pyridin-3-yl)prop-2-yn-l-yl)morpholine (980 mg, yield: 77.5%) as a brown oil. LCMS (ESI) calcd. for CisHigBrNCL [M+H]+m / z 339.1, found 339.6.Example 10. Synthesis of Addditional Alkyne Intermediates

[0298] The following intermediates in Table 3 were prepared using the method described above in step for the preparation of (S)-4-(3-(5-bromo-6-(l-methoxyethyl)pyridin-3-yl)prop-2- yn-l-yl)morpholine and utilizing the appropriate starting materials and modifications.Table 3. Certain Intermediates Containing Alkynyl Group of the Present inventionExample 10. Synthesis of Intermediate of Compound 29: N-(dimethylcarbamoyl)-N-me- thyl-L-valineStep 1. Preparation of benzyl N-(dimethylcarbamoyl)-N-methyl-L-valinate

[0299] A mixture of benzyl (2S)-3-methyl-2-(methylamino)butanoate (500 mg, 2.26 mmol) and dimethylcarbamyl chloride (1.215 g, 11.3 mmol) in THF (5 mL), was added TEA (2.286 g, 22.59 mmol and DMAP (276.02 mg, 2.26 mmol) in portions under nitrogen atmosphere. The reaction mixture was stirred at 65°C for 12 h under nitrogen atmosphere, then quenched with water (100 ml) and was extracted with EtOAc (50 mL x 3). The combined organic phase was dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by reverse phase chromatography to afford benzyl N-(dime- thylcarbamoyl)-N-methyl-L-valinate (400 mg, 58.3% yield) as a colorless oil. LCMS (ESI) calcd. for C16H25N2O3 [M+H]+m / z 293.2, found: 293.4.Step 2. Preparation of N-(dime thy Icarbamoy I) -N-me thyl-L-valine

[0300] A mixture of benzyl N-(dimethylcarbamoyl)-N-methyl-L-valinate (400 mg, 1.37 mmol) and palladium hydroxide on carbon (400 mg, 2.85 mmol) in MeOH (10 mL) was stirredfor 4 h under hydrogen atmosphere. The reaction mixture was filtered and the filter cake was washed with MeOH (100 mL x3). The filtrate was concentrated under reduced pressure to afford N-(dimethylcarbamoyl)-N-methyl-L-valine (200 mg, crude) as a colorless oil. LCMS (ESI) calcd. for C9H19N2O3 [M+H]+m / z 203.1, found: 203.1.Example 11. Synthesis of Additional Peptides

[0301] The following compounds in Table 4 were prepared according to the representative procedure described above for the synthesis of N-methyl-N-((2R,3R)-3-phenyltetrahydrofuran- 2-carbonyl)-L-valine and utilizing the appropriate starting materials and modifications.Table 4. Certain Peptides of the Present inventionSynthesis and Characterization of PanRAS Payloads

[0302] Exemplary payloads were synthesized using exemplary methods described in PCT Application No. PCT / CN2025 / 087799, PCT / CN2025 / 102466 or PCT / IB2025 / 058838, whereare hereby incorporated by reference in their entirety. All reagents obtained from commercial sources were used without further purification. Anhydrous solvents were obtained from commercial sources and used without further drying.Example 12. Synthesis and Characterization of Conjugate Linkers, Linker-Payloads., and Precursors thereof

[0303] Exemplary conjugate linkers and precursors thereof were synthesized using exemplary methods described in PCT Application No.PCT / US2021 / 060620, where is hereby incorporated by reference in their entirety.

[0304] Exemplary linkers, linker-payloads, and precursors thereof were synthesized using exemplary methods described in this example.Abbreviations:DCC: di cyclohexylcarbodiimideDCE: di chloroethaneDCM: dichloromethaneDIEA / DIPEA: N,N-DiisopropylethylamineDMTMM: 4-(4,6-dimethoxy-l,3,5-triazin-2-yl)-4-methyl-morpholiniumchlorideDMF: dimethylformamideDMSO:dimethylsulfoxydeEDCZEDC-HC1: l-Ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochlorideHATU: l-[Bis(dimethylamino)methylene]-lH-l,2,3-triazolo[4,5-b]pyridinium 3-oxide hexafluorophosphateHBTU : (2-(lH-benzotriazol-l -yl)- 1 , 1 ,3,3 -tetramethyluronium hexafluorophosphateHO At: 1 -Hydroxy-7-azabenzotriazoleMeCN: acetonitrileMeOH: methanolNMP: N-methylpyrrolidineRT : room temperatureTES: tri ethylsilaneTBAF: tetrabutyl ammonium fluorideTBA1: tetrabutyl ammonium iodideTBTU: [Bis(dimethylamino)methylene]-lH-benzotriazolium 3-Oxide Tetrafluoroborate pTsOH: para-toluene sulfonic acidPyBOP: benzotriazol-l-yloxytripyrrolidinophosphonium hexafluorophosphateTSTU : O-(N-Succinimidyl)-N,N,N',N-tetramethyluronium tetrafluoroborateTHF : tetrahydrofuranTFA: trifluoroacetic acidTFE: 2,2,2-TrifluoroethanolExample 13. Materials, Methods & General Procedures

[0305] All reagents obtained from commercial sources were used without further purification. Anhydrous solvents were obtained from commercial sources and used without further drying. Flash chromatography was performed on CombiFlash Rf (Teledyne ISCO) with prepacked silica-gel cartridges (Macherey -Nagel Chromabond Flash). Thin layer chromatography was conducted with 5* 10 cm plates coated with Merck Type 60 F254 silica-gel. Microwave heating was performed in CEM DiscoverR instrument.

[0306] NMR data were acquired at a temperature of 298K on a Bruker Avance NMR spectrometer equipped with a 5 mm BBFO CryoProbe with z-gradient operating at a frequency of 400.13 MHz for 'H, 376.50 MHz for19F, 100.61 MHz for13C. Chemical shifts for the 'H and13C spectra were referenced by setting internal tetramethylsilane (TMS) to 0 ppm.Example 14. Synthesis of Compound 1 (lr,2R,3S)-N-((64S,4S,Z)-l1-ethyl-l2-(2-((S)-l- methoxyethyl)-5-(3-(4-methylpiperazin-l-yl)prop-l-yn-l-yl)pyridin-3-yl)-10,10-dimethyl- 5,7-dioxo-l1H-8-oxa-62,63-diaza-2(4,2)-thiazola-l(5,3)-indola-6(2,4)-bicyclo[3.1.1]heptana- cvcloundecaphane-4-yl)-2,3-dimethylcvclopropane-l-carboxamide

[0307] Substituting (S)-4-(3 -(5 -bromo-6-(l -methoxy ethyl)pyri din-3 -yl)prop-2-yn-l- yl)morpholine with (S)- 1 -(3 -(5 -bromo-6-( 1 -methoxy ethyl)pyri din-3 -yl)prop-2-yn- 1 -yl)-4- methylpiperazine in the Step 1 of Compound 5, the title compound was prepared by the same procedures as described for Compound 5. LCMS (ESI): 875.5 [M+l]+. 'HNMR (400 MHz,DMSO) 5 8.78 (d, J = 1.9 Hz, 1H), 8.39 (d, J = 11.7 Hz, 2H), 7.97 (d, J = 2.0 Hz, 1H), 7.79 (s, 1H), 7.71 (d, J = 7.5 Hz, 1H), 7.52 (d, J = 8.6 Hz, 1H), 5.86 (d, J = 11.1 Hz, 1H), 5.29 (t, J = 7.9 Hz, 1H), 4.71 (d, J = 11.1 Hz, 1H), 4.47 (d, J = 5.1 Hz, 1H), 3.99 - 3.72 (m, 4H), 3.60 - 3.47 (m, 4H), 3.27 - 2.98 (m, 8H), 2.60 (dd, J = 27.9, 22.1 Hz, 5H), 2.41 - 2.22 (m, 6H), 2.17 - 2.09 (m, 4H), 1.59 (t, J = 9.2 Hz, 1H), 1.29 - 1.02 (m, 16H), 0.89 (s, 3H), 0.45 (s, 3H).Example 15. Synthesis of Compound 2 (lS,2S)-N-((63S.,4S.,Z)-l1-ethyl-l2-(5-(3-hydroxy-3- methylbut-l-vn-l-yl)-2-((S)-l-methoxyethyl)pyridin-3-yl)-10,10-dimethyl-5.,7-dioxo-61,62.,63.,64.,65.,66-hexahvdro-l1H-8-oxa-2(4.,2)-thiazola-l(5.,3)-indola-6(l.,3)-pyridazi- nacycloundecaphane-4-yl)-2-methylcyclopropane-l-carboxamidemethoxyethyl)pyridin-3-yl)-10,10-dimethyl-5, 7-dioxo-l1H-8-oxa-62,63-diaza-2(4,2)-thiazola- l(5,3)-indola-6(2, 4)-bicyclo[ 3.1.1 ]heptanacycloundecaphane-4-yl)carbamate

[0308] A mixture of (S)-4-(5-bromo-6-(l-methoxyethyl)pyridin-3-yl)-2-methylbut-3-yn-2- ol (106 mg, 0.37 mmol), tert-butyl ((64S,4S,Z)-10,10-dimethyl-5,7-dioxo-l2-(4,4,5,5-tetrame- thyl-l,3,2-dioxaborolan-2-yl)-l1H-8-oxa-62,63-diaza-2(4,2)-thiazola-l(5,3)-indola-6(2,4)-bicy- clo[3.1.1]heptanacycloundecaphane-4-yl)carbamate (307 mg, 0.44 mmol), K2COs (127 mg, 0.92 mmol) and Pd(dppf)C12 (27 mg, 0.037 mmol) in toluene (6 mL), dioxane (2 mL) and H2O (2 mL) was stirred at 75°C under N2 for 22 h. After completion, the reaction mixture was concentrated to give the crude product which was purified by silica gel column (eluting with MeOH / DCM from 0% to 100%) to give tert-butyl ((64S,4S,Z)-l2-(5-(3-hydroxy-3-methylbut-1 -yn- 1 -yl)-2-((S)- 1 -methoxy ethyl)pyri din-3 -yl)- 10,10-dimethyl-5,7-dioxo- 11H-8-oxa-62,63-di- aza-2(4,2)-thiazola-l(5,3)-indola-6(2,4)-bicyclo[3.1.1]heptanacycloundecaphane-4-yl)carba- mate (159 mg, 54.8 %) as a brown solid. LCMS (ESI) calcd. for C42H52N6O7S [M+H]+m / z 784.36, found: 776.5.Step 2: Preparation of tert-butyl ((64S,4S,Z)-lI-ethyl-l2-(5-(3-hydroxy-3-methylbut-l-yn-l-yl)-2-((S)-l-methoxyethyl)pyridin-3-yl)-10,10-dimethyl-5, 7-dioxo-l1H-8-oxa-62,63-diaza-2(4,2)- thiazola-l(5,3)-indola-6(2,4)-bicyclo[3.1.1]heptanacycloundecaphane-4-yl)carbamate

[0309] To a stirred solution of tert-butyl ((64S,4S,Z)-l2-(5-(3-hydroxy-3-methylbut-l-yn-l- yl)-2-((S)-l -methoxy ethyl)pyridin-3-yl)-10,10-dimethyl-5,7-di oxo- l1H-8-oxa-62,63-diaza- 2(4,2)-thiazola-l(5,3)-indola-6(2,4)-bicyclo[3.1.1]heptanacycloundecaphane-4-yl)carbamate (240 mg, 0.31 mmol) in DMF (3.5 mL) was added CS2CO3 (200 mg, 0.61 mmol) and lo- doethane (96 mg, 0.61 mmol) at 0°C, the resulting mixture was stirred at rt for 3 h. The reaction was monitored by LCMS. After completion, the reaction mixture was diluted with EtOAc (100 mL), washed with water (100 mL x 3) and saturated NaCl (100 x 2 mL), then dried over Na2SO4, following with concentration under reduced pressure to obtain crude product which was purified by silica gel column (eluting with MeOH / DCM from 0% to 5%) to give tert-butyl ((64S,4S,Z)-l1-ethyl-l2-(5-(3-hydroxy-3-methylbut-l-yn-l-yl)-2-((S)-l-methoxyethyl)pyridin-3-yl)-10,10-dimethyl-5,7-dioxo-l1H-8-oxa-62,63-diaza-2(4,2)-thiazola-l(5,3)-indola-6(2,4)-bi- cyclo[3.1.1]heptanacycloundecaphane-4-yl)carbamate as two atropisomers (190 mg, 75.5 %). Then the mixture was purified by prep-HPLC (Prep-HPLC method: column: Phenomenex Luna Cis75x30mmx3um; mobile phase: [water(FA)-ACN]; B%: l%-40%, 8min) to give the atropisomer 1 (84 mg, 34%) as a brown foam. LCMS (ESI) calcd. for C44H56N6O7S [M+H]+m / z 812.39, found: 814.5Step 3: Preparation of (64S,4S,Z)-4-amino-lI-ethyl-l2-(5-(3-hydroxy-3-methylbut-l-yn-l-yl)-2- ((S)-l-methoxyethyl)pyridin-3-yl)-10,10-dimethyl-lIH-8-oxa-62,63-diaza-2(4,2)-thiazola- l(5,3)-indola-6(2, 4)-bicyclo[ 3.1.1 ]heptanacycloundecaphane-5, 7-dione

[0310] To a stirred solution of tert-butyl ((64S,4S,Z)-l1-ethyl-l2-(5-(3-hydroxy-3-methyl- but- 1 -yn- 1 -yl)-2-((S)- 1 -methoxy ethyl)pyri din-3 -yl)- 10,10-dimethyl-5,7-dioxo- 1 'H-8-oxa- 62,63-diaza-2(4,2)-thiazola-l(5,3)-indola-6(2,4)-bicyclo[3.1.1]heptanacycloundecaphane-4- yl)carbamate (atropisomer 1) (84 mg, 0.10 mmol) in dichloromethane (4 mL) was added TFA (1 mL) dropwise at rt, the resulting mixture was stirred at rt for Ih. The reaction mixture was concentrated to give the residue. The residue was purified with reverse phase chromatography(eluting with ACN / H2O (0.5 % NH4HCO3) from 0% to 60%) to give (64S,4S,Z)-4-amino-l1- ethyl- 12-(5 -(3 -hydroxy-3 -methylbut- 1 -yn- 1 -yl)-2-((S)- 1 -methoxy ethyl)pyri din-3 -y 1 ) - 10 , 10 -dimethyl- 11H-8-oxa-62,63-diaza-2(4,2)-thiazola-l (5,3)-indola-6(2,4)-bicyclo[3.1.1 ]heptana- cy cl oundecaphane-5, 7-dione (62 mg, 93.6 %) as a yellow solid. LCMS (ESI) calcd. for C39H48N6O5S [M+H]+ m / z 712.34, found: 714.1Step 4: Preparation of (lr,2R,3S)-N-((64S,4S,Z)-l1-ethyl-l2-(5-(3-hydroxy-3-methylbut-l-yn-l- yl)-2-( (S)-l-methoxyethyl)pyridin-3-yl)-10,10-dimethyl-5, 7-dioxo-l1H-8-oxa-62, 63-diaza- 2(4,2) -thiazola-1 (5,3) -indola-6(2, 4 ) -bicyclo [ 3.1.1 ]heptanacycloundecaphane-4-yl) -2, 3 -dime - thylcyclopropane-1 -carboxamide

[0311] To a stirred solution of (63S,4S,Z)-4-amino-l1-ethyl-l2-(5-(3-hydroxy-3-methylbut- l-yn-l-yl)-2-((S)-l -methoxy ethyl)pyridin-3-yl)-10,10-dimethyl-61,62,63,64,65,66-hexahydro- l1H-8-oxa-2(4,2)-thiazola-l(5,3)-indola-6(l,3)-pyridazinacycloundecaphane-5, 7-dione (62 mg, 0.10 mmol) and (lr,2R,3S)-2,3-dimethylcyclopropane-l-carboxylic acid (11 mg, 0.11 mmol) and 2,6-lutidine (11 mg, 0.44 mmol) in ACN (8 mL) was added COMU (56 mg, 0.13 mmol) at rt, the resulting mixture was stirred at rt for 2h. The reaction mixture was concentrated to give the crude product. The crude product was purified by HPLC (ACN / H2O (0.5 % NH4HCO3) from 20% to 95% in 30min) to give (lr,2R,3S)-N-((64S,4S,Z)-l1-ethyl-l2-(5-(3-hydroxy-3- methylbut- 1 -yn- 1 -yl)-2-((S)- 1 -m ethoxy ethyl)pyri din-3 -yl)- 10,10-dimethyl-5,7-dioxo- 1JH-8- oxa-62,63-diaza-2(4,2)-thiazola-l(5,3)-indola-6(2,4)-bicyclo[3.1.1]heptanacycloundecaphane- 4-yl)-2,3 -dimethylcyclopropane- 1 -carboxamide (40 mg, 64.5 %) as a white solid. LCMS (ESI) calcd. for C44H54N6O6S [M+H]+m / z 794.38, found: 796.3. 'HNMR (400 MHz, DMSO ) 8 8.75 (d, J= 2.1 Hz, 1H), 8.55 - 8.48 (m, 2H), 7.81 (s, 1H), 7.78 - 7.73 (m, 2H), 7.58 (d, J= 8.7 Hz, 1H), 5.61 - 5.51 (m, 2H), 5.08 (d, J= 12.3 Hz, 1H), 4.37 - 4.14 (m, 4H), 4.07 (dd, J= 14.7, 7.3 Hz, 1H), 3.57 (s, 2H), 3.34 (s, 1H), 3.30 (s, 2H), 3.25 (s, 3H), 3.14 (dd, J= 14.5, 9.1 Hz, 1H), 2.98 (d, .7= 14.5 Hz, 1H), 2.81 - 2.70 (m, 1H), 2.36 (d, J= 14.1 Hz, 1H), 2.08 (d, J = 10.2 Hz, 1H), 1.79 (s, 2H), 1.49 (s, 7H), 1.35 (d, J= 6.0 Hz, 3H), 1.05 (d, J= 10.9 Hz, 4H), 0.88 (dd, J= 17.3, 10.4 Hz, 6H), 0.54 (d, J= 5.4 Hz, 1H), 0.33 (s, 3H).Example 16. Synthesis of Compound 5 (lr,2R,3S)-N-((64S,4S,Z)-l1-ethyl-l2-(2-((S)-l- methoxyethyl)-5-(((S)-l-methylpyrrolidin-3-yl)ethynyl)pyridin-3-yl)-10,10-dimethyl-5,7- dioxo-l1H-8-oxa-62,63-diaza-2(4,2)-thiazola-l(5,3)-indola-6(2,4)-bicyclo[3.1.1]heptana- cvcloundecaphane-4-yl)-2,3-dimethylcvclopropane-l-carboxamideaborolan-2-yl)-!1H-8-oxa-62, 63-diaza-2 (4,2) -thiazola-1 (5,3) -indola-6(2, 4 ) -bicy- clo[3.1.1 ]heptanacycloundecaphane-5, 7 -dione

[0312] To a stirred solution of tert-butyl ((64S,4S,Z)-10,10-dimethyl-5,7-dioxo-l2-(4,4,5,5- tetramethyl-l,3,2-dioxaborolan-2-yl)-l1H-8-oxa-62,63-diaza-2(4,2)-thiazola-l(5,3)-indola- 6(2,4)-bicyclo[3.1.1]heptanacycloundecaphane-4-yl)carbamate (1.5 g, 2.1 mmol) in dichloromethane (30 mL) was added TFA (3 mL) dropwise at rt, the resulting mixture was stirred at rt for 1 h. The reaction mixture was washed with sat. NaHCCL (30 mL), brine (30 mL), then dried over Na2SO4, following with concentration under reduced pressure to obtain crude product (64S,4S,Z)-4-amino-10,10-dimethyl-l2-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)-l1H- 8-oxa-62,63-diaza-2(4,2)-thiazola-l(5,3)-indola-6(2,4)-bicyclo[3.1.1]heptanacycloundeca- phane-5, 7-dione (1.3 g) as a yellow solid. LCMS (ESI) calcd. for C31H40BN5O5S [M+H]+ m / z 606.3, found: 607.4Step 2: Preparation of (lr,2R,3S)-N-((64S,4S,Z)-10,10-dimethyl-5, 7-dioxo-l2-(4,4,5,5-tetrame- thyl-l,3,2-dioxaborolan-2-yl)-lIH-8-oxa-62,63-diaza-2(4,2)-thiazola-l(5,3)-indola-6(2,4)-bicy- clo[ 3.1.1 ]heptanacycloundecaphane-4-yl)-2, 3-dimethylcyclopropane-l -carboxamide

[0313] To a stirred solution of (64S,4S,Z)-4-amino-10,10-dimethyl-l2-(4,4,5,5-tetramethyl- l,3,2-dioxaborolan-2-yl)-l1H-8-oxa-62,63-diaza-2(4,2)-thiazola-l(5,3)-indola-6(2,4)-bicy- clo[3.1.1]heptanacy cl oundecaphane-5, 7-dione (1.3 g, 2.1 mmol) and (lr,2R,3S)-2,3-dimethyl- cyclopropane-1 -carboxylic acid (242 mg, 2.1 mmol) and NMI (436 mg, 5.3 mmol) in ACN / DCM (15 mL / 15 mL) was added TCFH (896 mg, 3.2 mmol) at rt, the resulting mixture was stirred at rt for 30 min. The reaction mixture was concentrated to give the crude product. The crude product was purified by silica gel column (eluting with EtOAc / PE from 0% to 80%) to give (lr,2R,3S)-N-((64S,4S,Z)-10,10-dimethyl-5,7-dioxo-l2-(4,4,5,5-tetramethyl-l,3,2-diox- aborolan-2-yl)-l1H-8-oxa-62,63-diaza-2(4,2)-thiazola-l(5,3)-indola-6(2,4)-bicy- clo[3.1.1 ]heptanacy cl oundecaphane-4-yl)-2, 3 -dimethylcyclopropane- 1 -carboxamide (1.5 g, 99% in 2 steps) as a yellow solid. LCMS (ESI) cal cd. for C37H48BN5O6S [M+H]+ m / z 702.3, found: 703.5Step 3: Preparation of tert-butyl (3S)-3-((5-((64S,4S,Z)-4-((lr,2R,3S)-2,3-dimethylcyclopro- pane-l-carboxamido)-10,10-dimethyl-5, 7-dioxo-l1H-8-oxa-62, 63-diaza-2(4,2)-thiazola-l (5, 3)- indola-6(2, 4)-bicyclo[ 3.1.1 ]heptanacycloundecaphane-l2-yl)-6-( (S) - 1 -methoxy ethyl)pyridin- 3- yl)ethynyl)pyrrolidine-l-carboxylate

[0314] A mixture of (lr,2R,3S)-N-((64S,4S,Z)-10,10-dimethyl-5,7-dioxo-l2-(4,4,5,5-tetra- methyl-l,3,2-dioxaborolan-2-yl)-l1H-8-oxa-62,63-diaza-2(4,2)-thiazola-l(5,3)-indola-6(2,4)- bicyclo[3.1.1]heptanacy cl oundecaphane-4-yl)-2, 3 -dimethylcy cl opropane-1 -carboxamide (1 g, 1.4 mmol), tert-butyl (S)-3-((5-bromo-6-((S)-l-methoxyethyl)pyridin-3-yl)ethynyl)pyrrolidine- 1-carboxylate (583 mg, 1.4 mmol), K2CO3 (491 mg, 3.6 mmol) and Pd(dppf)C12 (209 mg, 0.3 mmol) in dioxane (40 mL) and H2O (8 mL) was stirred at 90°C under N2 for 19 h. After completion, the reaction mixture was concentrated to give the crude product which was purified by silica gel column (eluting with EA / PE from 0% to 100%) to give tert-butyl (3S)-3-((5- ((64S,4S,Z)-4-((lr,2R,3S)-2,3-dimethylcyclopropane-l-carboxamido)-10,10-dimethyl-5,7-di- oxo-l1H-8-oxa-62,63-diaza-2(4,2)-thiazola-l(5,3)-indola-6(2,4)-bicyclo[3.1.1]heptanacycloun- decaphane-l2-yl)-6-((S)-l-methoxyethyl)pyridin-3-yl)ethynyl)pyrrolidine-l-carboxylate (900 mg, 70 %) as a yellow solid. LCMS (ESI) calcd. for C50H61N7O7S [M+H]+m / z 904.4, found: 904.9Step 4: Preparation of tert-butyl (3S)-3-((5-((64S,4S,Z)-4-((lr,2P^3S)-2,3-dimethylcyclopro- pane-l-carboxamido)-!1-ethyl-10, 10-dimethyl-5, 7-dioxo-l1H-8-oxa-62,63-diaza-2(4,2)-thia- zola-l(5,3)-indola-6(2, 4)-bicyclo[3.1.1 ]heptanacycloundecaphane-l2-yl)-6-( (S)-l-methoxy- ethyl)pyridin-3-yl)ethynyl)pyrrolidine-l-carboxylate

[0315] To a stirred solution of (lr,2R,3S)-N-((64S,4S,Z)-l4-amino-10,10-dimethyl-5,7-di- oxo-8-oxa-62,63-diaza-2(4,2)-thiazola-6(2,4)-bicyclo[3.1.1]heptana-l(l,3)-benzenacyclododec- aphane-4-yl)-2,3 -dimethylcyclopropane- 1 -carboxamide (900 mg, 1.0 mmol) in DMF (9 mL) were added CS2CO3 (649 mg, 2.0 mmol) and lodoethane (311 mg, 2.0 mmol) at 0°C, the resulting mixture was stirred at rt for 3 h. The reaction was monitored by LCMS. After completion, the reaction mixture was diluted with EtOAc (100 mL), washed with water (50 mL x 3) and saturated NaCl (50 x 2 mL), then dried over Na2SO4, following with concentration under reduced pressure to obtain crude product which was purified by silica gel column (eluting with EA / PE from 0% to 100%) to give tert-butyl (3S)-3-((5-((64S,4S,Z)-4-((lr,2R,3S)-2,3-dimethyl- cyclopropane- 1 -carboxamido)- 11 -ethyl- 10, 10-dimethyl-5,7-dioxo- 11H-8-oxa-62,63-diaza- 2(4,2)-thiazola-l(5,3)-indola-6(2,4)-bicyclo[3.1.1]heptanacycloundecaphane-l2-yl)-6-((S)-l- methoxyethyl)pyridin-3-yl)ethynyl)pyrrolidine-l -carboxylate as two atropisomers (927 mg, 99%) . Then the mixture was purified by prep-HPLC (Prep-HPLC method: column: Phenom- enex Luna Cis75x30mmx3um; mobile phase: [water(FA)-ACN]; B%: l%-40%, 8min) to give the atropisomer 1 (412 mg, 44%) as yellow solids. LCMS (ESI) calcd. for C52H65N7O7S [M+H]+ m / z 932.5, found: 933.6Step 5: Preparation of (lr,2R,3S)-N-((64S,4S,Z)-l1-ethyl-l2-(2-((S)-l-methoxyethyl)-5-(((S)~ pyrrolidin-3-yl)ethynyl)pyridin-3-yl)-10,10-dimethyl-5, 7-dioxo-l1H-8-oxa-62,63-diaza-2(4, 2)- thiazola-l(5,3)-indola-6(2, 4)-bicyclo[3.1.1 ]heptanacycloundecaphane-4-yl)-2, 3-dimethylcy- clopropane-1 -carboxamide

[0316] To a stirred solution of tert-butyl (3S)-3-((5-((64S,4S,Z)-4-((lr,2R,3S)-2,3-dime- thylcyclopropane- 1 -carboxamido)- 11-ethyl- 10,10-dimethyl-5,7-dioxo- 11H-8-oxa-62,63-diaza- 2(4,2)-thiazola-l(5,3)-indola-6(2,4)-bicyclo[3.1.1]heptanacycloundecaphane-l2-yl)-6-((S)-l- methoxyethyl)pyridin-3-yl)ethynyl)pyrrolidine-l -carboxylate (atropisomer 1) (412 mg, 1.0 mmol) in dichloromethane (10 mL) was added TFA (2.5 mL) dropwise at rt, the resulting mixture was stirred at rt for 1 h. The reaction mixture was washed with sat. NaHCCL (30 mL), brine (30 mL), then dried over ISfeSCU, following with concentration under reduced pressure to obtain crude product (lr,2R,3S)-N-((64S,4S,Z)-l1-ethyl-l2-(2-((S)-l-methoxyethyl)-5-(((S)-pyrrolidin-3-yl)ethynyl)pyridin-3-yl)-10,10-dimethyl-5,7-dioxo-l1H-8-oxa-62,63-diaza-2(4,2)- thiazola-l(5,3)-indola-6(2,4)-bicyclo[3.1.1]heptanacycloundecaphane-4-yl)-2,3-dimethylcyclo- propane-1 -carboxamide (276 mg, 75%) as a yellow solid. LCMS (ESI) calcd. for C47H57N7O5S [M+H]+ m / z 832.4, found: 832.9Step 6: Preparation of (lr,2R,3S)-N-((64S,4S,Z)-l1-ethyl-l2-(2-((S)-l-methoxyethyl)-5-(((S)-l- methylpyrrolidin-3-yl)ethynyl)pyridin-3-yl)-10,10-dimethyl-5, 7-dioxo-l1H-8-oxa-62,63-diaza- 2(4,2) -thiazola-1 (5,3) -indola-6(2, 4 ) -bicyclo [ 3.1.1 ]heptanacycloundecaphane-4-yl) -2, 3 -dime - thylcyclopropane-1 -carboxamide

[0317] To a stirred solution of (lr,2R,3S)-N-((64S,4S,Z)-l1-ethyl-l2-(2-((S)-l-methoxy- ethyl)-5-(((S)-pyrrolidin-3-yl)ethynyl)pyridin-3-yl)-10,10-dimethyl-5,7-dioxo-l1H-8-oxa-62,63- diaza-2(4,2)-thiazola-l(5,3)-indola-6(2,4)-bicyclo[3.1.1]heptanacycloundecaphane-4-yl)-2,3- dimethylcyclopropane-1 -carboxamide (276 mg, 0.33 mmol) in MeOH (12 mL) were added formaldehyde (266 mg, 3.3 mmol, 37% in water) and NaBEECN (62 mg, 0.97 mmol) at 0°C, the resulting mixture was stirred at rt for 1 h. The reaction was monitored by LCMS. After completion, the reaction mixture was diluted with EtOAc (100 mL), washed with water (50 mL x 3) and saturated NaCl (50 x 2 mL), then dried over ISfeSCU, following with concentration under reduced pressure to obtain crude product which was purified by pre-HPLC (eluting with CH3CN / H2O(0.1% NH4HCO3) from 20% to 80%) to giveethyl- 12-(2-((S)- 1 -m ethoxy ethyl)-5-(((S)- 1 -methylpyrrolidin-3 -yl)ethynyl)pyri din-3 -yl)- 10,10-dime- thyl-5,7-dioxo-l1H-8-oxa-62,63-diaza-2(4,2)-thiazola-l(5,3)-indola-6(2,4)-bicy- clo[3.1.1]heptanacycloundecaphane-4-yl)-2,3-dimethylcyclopropane-l-carboxamide (156 mg, 25%) as a white solid. LCMS (ESI) calcd. for C48H59N7O5S [M+H]+m / z 846.4, found: 846.9. 'HNMR (400 MHz, DMSO-tL) 8 8.72 (s, 1H), 8.40-8.37 (m, 2H), 7.80 (s, 1H), 7.76-7.72 (m, 2H), 7.55 (d, J= 8.4 Hz, 1H), 5.90 (d, J= 11.2 Hz, 1H), 5.35 (m, 1H), 4.64 (d, J= 11.2 Hz, 1H), 4.47-4.46 (m, 1H), 4.30 - 4.22 (m, 2H), 4.07-4.03 (m, 1H), 3.57 - 3.50 (m, 2H), 3.22-3.20 (m, 5H), 3.14-3.09 (m, 1H), 2.93-2.89 (m, 1H), 2.81 (t, J= 8.4 Hz, 1H), 2.61-2.60 (m, 1H), 2.52 - 2.48 (m, 5H), 2.45-2.37 (m, 2H), 2.32-2.30 (m, 1H), 2.23-2.11 (m, 4H), 1.89-1.81 (m, 1H), 1.57 - 1.55 (m, 1H), 1.30 (d, J= 6.0 Hz, 1H), 1.21-1.14 (m, 1H), 1.08-1.04 (m, 5H), 0.86- 0.83 (m, 5H), 0.30 (s, 3H).Example 17. Synthesis of Compound 6 (lr,2R,3S)-N-((64S,4S,Z)-l2-(5-(3-(l,l-dioxidothio- morpholino)prop-l-yn-l-yl)-2-((S)-l-methoxyethyl)pyridin-3-yl)-l1-ethyl-10,10-dimethyl-5,7-dioxo-l1H-8-oxa-62.,63-diaza-2(4.,2)-thiazola-l(5.,3)-indola-6(2.,4)-bicvclo[3.1.1]heptana- cvcloundecaphane-4-yl)-2,3-dimethylcvclopropane-l-carboxamide

[0318] Substituting (S)-4-(3 -(5 -bromo-6-(l-m ethoxy ethyl)pyri din-3 -yl)prop-2-yn-l- yl)morpholine with (S)-4-(3-(5-bromo-6-(l -methoxy ethyl)pyri din-3 -yl)prop-2 -yn-l-yl)thio- morpholine 1,1 -di oxide in the Step 1 of Compound 5, the title compound was prepared by the same procedures as described for Compound 5. LCMS (ESI): 910.4 [M+l]+.1H NMR (400 MHz, DMSO) 5 8.80 (d, J = 1.9 Hz, 1H), 8.40 (d, J = 9.6 Hz, 2H), 7.99 (d, J = 1.9 Hz, 1H), 7.80 (s, 1H), 7.72 (d, J = 8.7 Hz, 1H), 7.52 (d, J = 8.7 Hz, 1H), 5.87 (d, J = 11.1 Hz, 1H), 5.29 (t, J = 8.3 Hz, 1H), 4.71 (d, J = 11.1 Hz, 1H), 4.48 (d, J = 4.8 Hz, 1H), 3.98 - 3.87 (m, 2H), 3.85 - 3.68 (m, 3H), 3.59 (d, J = 10.7 Hz, 1H), 3.50 (d, J = 10.8 Hz, 1H), 3.23 (d, J = 14.2 Hz, 1H), 3.13 (t, J = 9.9 Hz, 4H), 3.07 (s, 2H), 3.02 (dd, J = 6.2, 3.3 Hz, 4H), 2.64 (dd, J = 12.4, 6.5 Hz, 1H), 2.38 - 2.26 (m, 2H), 2.13 (t, J = 9.7 Hz, 1H), 1.60 (t, J = 9.3 Hz, 1H), 1.30 - 1.13 (m, 5H), 1.12 - 1.00 (m, 7H), 0.90 (s, 3H), 0.46 (s, 2H).Example 18. Synthesis of Compound 9 (2R,3R)-N-((2S)-l-(((64S,4S,Z)-l1-ethyl-l2-(2-((S)- l-methoxyethyl)-5-(3-morpholinoprop-l-vn-l-yl)pyridin-3-yl)-10,10-dimethyl-5,7-dioxo- l1H-8-oxa-62,63-diaza-2(4,2)-thiazola-l(5,3)-indola-6(2,4)-bicvclo[3.1.1]heptanacvcloun- decaphane-4-yl)amino)-3-methyl-l-oxobntan-2-yl)-N-methyl-3-phenyltetrahvdrofnran-2- carboxamide

[0319] Substituting (lr,2R,3S)-2,3-dimethylcyclopropane-l-carboxylic acid with N-me- thyl-N-((2R,3R)-3-phenyltetrahydrofuran-2-carbonyl)-L-valine in the Step 4 of Compound 5, the title compound was prepared by the same procedures as described for Compound 5.LCMS (ESI): 1053.5 [M+l]+. 'HNMR (500 MHz, CDC13) 8 8.39 (d, J = 2.0 Hz, 1H), 8.25 (d,J = 12.6 Hz, 1H), 8.00 (d, J = 2.0 Hz, 1H), 7.77 (d, J = 2.4 Hz, 1H), 7.69 (dd, J = 7.7, 2.4 Hz, 1H), 7.59 (s, 1H), 7.48 (d, J = 7.7 Hz, 1H), 7.33 - 7.22 (m, 5H), 5.24 (q, J = 5.4 Hz, 1H), 4.90 (d, J = 8.4 Hz, 1H), 4.79 (d, J = 8.1 Hz, 1H), 4.75 (d, J = 7.3 Hz, 1H), 4.65 (q, J = 12.4 Hz, 1H), 4.15 (q, J = 4.4 Hz, 2H), 4.08 - 3.99 (m, 2H), 3.99 - 3.94 (m, 2H), 3.94 - 3.89 (m, 1H), 3.89 - 3.84 (m, 1H), 3.79 - 3.70 (m, 3H), 3.66 (dd, J = 6.5, 3.8 Hz, 2H), 3.58 (d, J = 2.6 Hz, 2H), 3.33 (s, 3H), 3.31 - 3.18 (m, 2H), 3.06 (d, J = 2.6 Hz, 2H), 2.97 (s, 3H), 2.78 - 2.66 (m, 5H), 2.30 (ddd, J = 7.5, 5.5, 4.8 Hz, 1H), 2.26 - 2.15 (m, 2H), 2.13 - 1.97 (m, 4H), 1.67 (d, J = 5.3 Hz, 3H), 1.37 (t, J = 4.4 Hz, 3H), 1.15 (s, 3H), 1.10 (s, 3H), 0.79 (d, J = 5.1 Hz, 3H), 0.74 (d, J = 5.0 Hz, 3H).Example 19. Synthesis of Compound 10 (2S)-N-((64S,4S,Z)-l1-ethyl-l2-(2-((S)-l-methoxy- ethyl)-5-(3-morpholinoprop-l-vn-l-yl)pyridin-3-yl)-10,10-dimethyl-5,7-dioxo-l1H-8-oxa- 62,63-diaza-2(4,2)-thiazola-l(5,3)-indola-6(2,4)-bicvclo[3.1.1]heptanacvcloundecaphane-4- yl)-3-methyl-2-(l,3,3-trimethylureido)butanamide

[0320] Substituting (lr,2R,3S)-2,3-dimethylcyclopropane-l-carboxylic acid with N-(dime- thylcarbamoyl)-N-methyl-L-valine in the Step 4 of Compound 5, the title compound was prepared by the same procedures as described for Compound 5. LCMS (ESI): 950.5 [M+l]+. 'H NMR (500 MHz, CDC13) 8 8.39 (d, J = 2.0 Hz, 1H), 8.25 (d, J = 12.6 Hz, 1H), 8.00 (d, J = 2.0 Hz, 1H), 7.77 (d, J = 2.3 Hz, 1H), 7.69 (dd, J = 7.7, 2.4 Hz, 1H), 7.59 (s, 1H), 7.48 (d, J = 7.7Hz, 1H), 5.24 (q, J = 5.4 Hz, 1H), 4.89 (d, J = 8.6 Hz, 1H), 4.70 - 4.59 (m, 2H), 4.15 (q, J = 4.4Hz, 2H), 4.08 - 3.99 (m, 2H), 3.99 - 3.89 (m, 2H), 3.73 (dd, J = 6.5, 3.8 Hz, 2H), 3.66 (dd, J = 6.5, 3.8 Hz, 2H), 3.58 (d, J = 2.6 Hz, 2H), 3.33 (s, 3H), 3.32 - 3.18 (m, 2H), 3.06 (d, J = 2.6Hz, 2H), 2.93 (d, J = 1.6 Hz, 9H), 2.78 - 2.66 (m, 5H), 2.21 (dhept, J = 8.1, 5.1 Hz, 1H), 2.13 -1.97 (m, 4H), 1.67 (d, J = 5.3 Hz, 3H), 1.37 (t, J = 4.4 Hz, 3H), 1.15 (s, 3H), 1.10 (s, 3H), 0.79 (d, J = 5.1 Hz, 3H), 0.75 (d, J = 5.1 Hz, 3H).Example 20. Synthesis of Compound 12 l-(4-(dimethylamino)-4-methylpent-2-ynoyl)-N- ((2S)-l-(((22S,64S,4S)-l1-ethyl-l2-(5-ethynyl-2-((S)-l-methoxyethyl)pyridin-3-yl)-10,10-di-methyl-5.,7-dioxo-l1H-8-oxa-62.,63-diaza-2(4.,2)-morpholina-l(5.,3)-indola-6(2.,4)-bicv- clo[3.1.1]heptanacvcloundecaphane-4-yl)amino)-3-methyl-l-oxobutan-2-yl)-4-fluoro-N- methylDiDeridine-4-carboxamide

[0321] Substituting (S)-4-(3 -(5 -bromo-6-(l-m ethoxy ethyl)pyri din-3 -yl)prop-2-yn-l- yl)morpholine with (S)-3-bromo-5-ethynyl-2-(l-methoxyethyl)pyridine in the Step 1 of Compound 14 and Substituting (S)-2-cyclopentyl-2-((S)-7-((2R,3R)-3-cyclopropyl-l-methylaziri- dine-2-carbonyl)-2,7-diazaspiro[4.4]nonan-2-yl)acetic acid with N-(l-(4-(dimethylamino)-4- methylpent-2-ynoyl)-4-fluoropiperidine-4-carbonyl)-N-methyl-L-valine in the Step 4 of Compound 14, the title compound was prepared by the same procedures as described for Compound 14. LCMS (ESI): 1048.6 [M+l]+. 'HNMR (500 MHz, CDC13) 8 8.49 (d, J = 2.0 Hz, 1H), 8.24 (d, J = 12.1 Hz, 1H), 8.06 (d, J = 2.0 Hz, 1H), 7.36 (d, J = 7.9 Hz, 1H), 7.21 (d, J = 2.2 Hz, 1H), 7.01 (dd, J = 7.9, 2.2 Hz, 1H), 5.24 (q, J = 5.4 Hz, 1H), 4.90 (d, J = 8.6 Hz, 1H), 4.75 (d, J = 7.3 Hz, 1H), 4.47 (q, J = 11.9 Hz, 1H), 4.15 (q, J = 4.4 Hz, 2H), 4.12 - 4.06 (m, 1H), 4.06 - 3.99 (m, 2H), 3.99 - 3.89 (m, 2H), 3.86 (dd, J = 7.5, 4.8 Hz, 1H), 3.81 (dd, J = 7.5, 4.8 Hz, 1H), 3.74 - 3.65 (m, 3H), 3.65 - 3.58 (m, 3H), 3.55 (d, J = 8.6 Hz, 1H), 3.48 - 3.42 (m, 2H), 3.33 (s, 3H), 3.09 (s, 2H), 2.96 (s, 3H), 2.72 (h, J = 7.9 Hz, 1H), 2.47 (dt, J = 9.3, 6.5 Hz, 4H), 2.35 (s, 6H), 2.25 - 1.97 (m, 7H), 1.67 (d, J = 5.3 Hz, 3H), 1.43 - 1.35 (m, 9H), 1.15 (s, 3H), 1.10 (s, 3H), 0.79 (d, J = 5.1 Hz, 3H), 0.75 (d, J = 5.0 Hz, 3H).Example 21. Synthesis of Compound 14. (2S)-2-cvclopentyl-2-((S)-7-((2R.,3R)-3-cvclopro- pyl-l-methylaziridine-2-carbonyl)-2.,7-diazaspiro[4.4]nonan-2-yl)-N-((22S.,64S.,4S)-l2-(2- ((S)-l-methoxyethyl)-5-(3-morpholinoprop-l-vn-l-yl)pyridin-3-yl)-10,10-dimethyl-5,7-di- oxo-l1-(2,2,2-trifluoroethyl)-l1H-8-oxa-62,63-diaza-2(4,2)-morpholina-l(5,3)-indola-6(2,4)- bicvclo[3.1.1]heptanacvcloundecaphane-4-yl)acetamide

[0322] Substituting tert-butyl ((64S,4S,Z)-10,10-dimethyl-5,7-dioxo-l2-(4,4,5,5-tetrame- thyl-l,3,2-dioxaborolan-2-yl)-l1H-8-oxa-62,63-diaza-2(4,2)-thiazola-l(5,3)-indola-6(2,4)-bicy- clo[3.1.1]heptanacycloundecaphane-4-yl)carbamate with tert-butyl ((22S,64S,4S)-10,10-dime- thyl-5,7-dioxo-l2-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)-l1H-8-oxa-62,63-diaza-2(4,2)- morpholina-l(5,3)-indola-6(2,4)-bicyclo[3.1.1]heptanacycloundecaphane-4-yl)carbamate in the Step 1 of Compound 5, Substituting iodoethane with l,l,l-trifluoro-2-iodoethane in the Step 2 of Compound 5 and Substituting (lr,2R,3S)-2,3-dimethylcyclopropane-l-carboxylic acid with (S)-2-cyclopentyl-2-((S)-7-((2R,3R)-3-cyclopropyl-l-methylaziridine-2-carbonyl)-2,7-dia- zaspiro[4.4]nonan-2-yl)acetic acid in the Step 4 of Compound 5, the title compound was prepared by the same procedures as described for Compound 5. LCMS (ESI): 1179.7 [M+l]+. 'H NMR (500 MHz, CDC13) 8 8.54 (s, 1H), 8.38 (d, J = 1.3 Hz, 1H), 8.14 (s, 1H), 8.06 (d, J = 1.3 Hz, 1H), 7.56 (s, 1H), 7.33 (s, 1H), 7.13 (s, 1H), 4.76 (s, 1H), 4.57 - 4.51 (m, 2H), 4.46 (d, J = 12.5 Hz, 1H), 4.32 (s, 1H), 4.24 (s, 1H), 4.15 (s, 1H), 4.01 (d, J = 13.7 Hz, 2H), 3.89 (d, J = 12.8 Hz, 2H), 3.84 - 3.78 (m, 3H), 3.77 (s, 1H), 3.73 (d, J = 17.2 Hz, 3H), 3.68 (s, 2H), 3.63 (s, 2H), 3.50 (d, J = 16.8 Hz, 2H), 3.38 - 3.24 (m, 7H), 2.85 - 2.75 (m, 3H), 2.67 (s, 1H), 2.62 - 2.55 (m, 6H), 2.52 (s, 1H), 2.47 (d, J = 10.1 Hz, 4H), 2.25 (s, 1H), 2.20 (d, J = 10.3 Hz, 2H), 1.98 (s, 1H), 1.92 (d, J = 11.5 Hz, 2H), 1.88 (s, 1H), 1.85 - 1.77 (m, 4H), 1.75 (d, J = 12.3 Hz, 1H), 1.72 - 1.65 (m, 7H), 1.59 (d, J = 13.0 Hz, 2H), 1.44 (d, J = 13.0 Hz, 2H), 1.37 (d, J = 4.9 Hz, 2H), 1.23 (d, J = 4.9 Hz, 2H), 1.16 (s, 3H), 1.11 (s, 3H).Example 22. Synthesis of Compound 15 (lr.,2R.,3S)-N-((64S.,4S.,Z)-l2-(5-(3-(4-acetylpiper- azin-l-yl)prop-l-yn-l-yl)-2-((S)-l-methoxyethyl)pyridin-3-yl)-l1-ethyl-10,10-dimethyl- 5,7-dioxo-l1H-8-oxa-62,63-diaza-2(4,2)-thiazola-l(5,3)-indola-6(2,4)-bicyclo[3.1.1]heptana- cvcloundecaphane-4-yl)-2,3-dimethylcvclopropane-l-carboxamide

[0323] Substituting (S)-4-(3 -(5 -bromo-6-(l-m ethoxy ethyl)pyri din-3 -yl)prop-2-yn-l- yl)morpholine with (S)- 1 -(4-(3 -(5-bromo-6-(l -methoxy ethyl)pyri din-3 -yl)prop-2-yn- 1 -yl)pi- perazin-l-yl)ethan-l-one in the Step 1 of Compound 5, the title compound was prepared by the same procedures as described for Compound 5. LCMS (ESI): 903.5 [M+l]+. 'HNMR(500 MHz, CDCI3) 8 8.39 (d, J = 2.0 Hz, 1H), 8.20 (d, J = 13.0 Hz, 1H), 8.02 (d, J = 2.0 Hz, 1H), 7.77 (d, J = 2.3 Hz, 1H), 7.69 (dd, J = 7.7, 2.4 Hz, 1H), 7.59 (s, 1H), 7.48 (d, J = 7.7 Hz, 1H), 5.24 (q, J = 5.4 Hz, 1H), 4.89 (d, J = 8.6 Hz, 1H), 4.63 (dt, J = 13.0, 12.3 Hz, 1H), 4.15 (q, J = 4.4 Hz, 2H), 4.08 - 3.99 (m, 2H), 3.99 - 3.89 (m, 2H), 3.60 - 3.52 (m, 3H), 3.52 - 3.45 (m, 4H), 3.33 (s, 3H), 3.31 - 3.23 (m, 2H), 3.22 (d, J = 3.5 Hz, 1H), 3.06 (d, J = 2.6 Hz, 2H), 2.72 (h, J = 7.9 Hz, 1H), 2.55 - 2.50 (m, 4H), 2.50 - 2.43 (m, 2H), 2.13 - 1.97 (m, 7H), 1.74 (dq, J = 8.6, 5.2 Hz, 2H), 1.67 (d, J = 5.3 Hz, 3H), 1.37 (t, J = 4.4 Hz, 3H), 1.15 (s, 3H), 1.10 (s, 3H), 0.95 (d, J = 5.1 Hz, 6H).Example 23. Synthesis of Compound 16 (lr,2R,3S)-N-((64S,4S,Z)-l1-ethyl-l2-(2-((S)-l- methoxyethyl)-5-(3-morpholinoprop-l-yn-l-yl)pyridin-3-yl)-10,10-dimethyl-5,7-dioxo- l1H-8-oxa-62,63-diaza-2(4,2)-thiazola-l(5,3)-indola-6(2,4)-bicvclo[3.1.1]heptanacvcloun- decaphane-4-yl)-2,3-dimethylcyclopropane-l-carboxamideStep 1: Preparation of tert-butyl ((64S,4S,Z)-l2-(2-((S)-l-methoxyethyl)-5-(3-morpholinoprop- l-yn-l-yl)pyridin-3-yl)-10, 10-dimethyl-5, 7-dioxo-l1H-8-oxa-6:, 63-diaza-2(4, 2)-thiazola-l(5,3)~ indola-6(2, 4)-bicyclo[3.1.1 ]heptanacycloundecaphane-4-yl) carbamate

[0324] A mixture of (S)-4-(3-(5-bromo-6-(l-methoxyethyl)pyridin-3-yl)prop-2-yn-l- yl)morpholine (253 mg, 0.74 mmol), tert-butyl ((64S,4S,Z)-10,10-dimethyl-5,7-dioxo-l2- (4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)-l1H-8-oxa-62,63-diaza-2(4,2)-thiazola-l(5,3)-in- dola-6(2,4)-bicyclo[3.1.1]heptanacycloundecaphane-4-yl)carbamate (525 mg, 0.74 mmol), K2CO3 (309 mg, 2.24 mmol) and Pd(dppf)C12 (55 mg, 0.075 mmol) in dioxane (8 mL) and H2O (2 mL) was stirred at 85 °C under N2 for 19 h. After completion, the reaction mixture was concentrated to give the crude product which was purified by silica gel column (eluting withMeOH / DCM from 0% to 100%) to give tert-butyl ((64S,4S,Z)-l2-(2-((S)-l-methoxyethyl)-5- (3 -morpholinoprop- 1 -yn- 1 -yl)pyri din-3 -yl)- 10,10-dimethyl-5,7-dioxo- 11H-8-oxa-62,63-diaza- 2(4,2)-thiazola-l(5,3)-indola-6(2,4)-bicyclo[3.1.1]heptanacycloundecaphane-4-yl)carbamate (323 mg, 52.1 %) as a yellow solid. LCMS (ESI) calcd. for C45H55N7O7S [M+H]+m / z 838.4, found: 839.5Step 2: Preparation of tert-butyl ((64S,4S,Z)-lI-ethyl-l2-(2-((S)-l-methoxyethyl)-5-(3-morpho- linoprop-l-yn-l-yl)pyridin-3-yl)-10,10-dimethyl-5, 7-dioxo-l1H-8-oxa-62,63-diaza-2(4,2)-thia- zola-l(5,3)-indola-6(2,4)-bicyclo[3.1.1]heptanacycloundecaphane-4-yl)carbamate

[0325] To a stirred solution of tert-butyl ((64S,4S,Z)-l2-(2-((S)-l-methoxyethyl)-5-(3-mor- pholinoprop-l-yn-l-yl)pyridin-3-yl)-10,10-dimethyl-5,7-dioxo-l1H-8-oxa-62,63-diaza-2(4,2)- thiazola-l(5,3)-indola-6(2,4)-bicyclo[3.1.1]heptanacycloundecaphane-4-yl)carbamate (323 mg, 0.39 mmol) in DMF (4.5 mL) were added CS2CO3 (251 mg, 0.77 mmol) and lodoethane (120 mg, 0.77 mmol) at 0°C, the resulting mixture was stirred at rt for 3 h. The reaction was monitored by LCMS. After completion, the reaction mixture was diluted with EtOAc (100 mL), washed with water (50 mL x 3) and saturated NaCl (50 x 2 mL), then dried over Na2SO4, following with concentration under reduced pressure to obtain crude product which was purified by pre-HPLC (eluting with CFLCN / ILOIO.1% NH4HCO3) from 20% to 80%) to give tert-butyl ((64S,4S,Z)-l1-ethyl-l2-(2-((S)-l-methoxyethyl)-5-(3-morpholinoprop-l-yn-l-yl)pyridin-3-yl)- 10,10-dimethyl-5, 7-dioxo-l1H-8-oxa-62,63-diaza-2(4,2)-thiazola-l (5, 3)-indola-6(2,4)-bicy- clo[3.1.1]heptanacycloundecaphane-4-yl)carbamate as atropisomer 1 (100 mg) and atropisomer 2 (140 mg) as white solids. LCMS (ESI) calcd. for C47H59N7O7S [M+H]+m / z 866.4, found: 866.8Step 3: Preparation of (64S,4S,Z)-4-amino-lI-ethyl-l2-(2-((S)-l-methoxyethyl)-5-(3-morpho- linoprop-l-yn-l-yl)pyridin-3-yl)-10,10-dimethyl-lIH-8-oxa-62,63-diaza-2(4,2)-thiazola-l(5,3)- indola-6(2, 4)-bicyclo[3.1.1 ]heptanacycloundecaphane-5, 7 -dione

[0326] To a stirred solution of tert-butyl ((64S,4S,Z)-l1-ethyl-l2-(2-((S)-l-methoxyethyl)- 5-(3-morpholinoprop-l-yn-l-yl)pyridin-3-yl)-10,10-dimethyl-5,7-dioxo-l1H-8-oxa-62,63-di- aza-2(4,2)-thiazola-l(5,3)-indola-6(2,4)-bicyclo[3.1.1]heptanacycloundecaphane-4-yl)carba- mate as atropisomer 1 (100 mg, 0.12 mmol) in dichloromethane (4 mL) was added TFA (1 mL) dropwisely at rt, the resulting mixture was stirred at rt for 1 h. The reaction mixture was concentrated and lyophilized to give (64S,4S,Z)-4-amino-l1-ethyl-l2-(2-((S)-l-methoxyethyl)- 5-(3-morpholinoprop-l-yn-l-yl)pyridin-3-yl)-10,10-dimethyl-l1H-8-oxa-62,63-diaza-2(4,2)-thiazola-l(5,3)-indola-6(2,4)-bicyclo[3.1.1]heptanacycloundecaphane-5, 7-dione (110 mg) of its TFA salt as a yellow solid. LCMS (ESI) calcd. for C42H51N7O5S [M+H]+m / z 766.4, found: 766.9Step 4: Preparation of (lr,2R,3S)-N-((64S,4S,Z)-l1-ethyl-l2-(2-((S)-l-methoxyethyl)-5-(3-mor- pholinoprop-l-yn-l-yl)pyridin-3-yl)-10,10-dimethyl-5, 7-dioxo-l1H-8-oxa-62,63-diaza-2(4,2)~ thiazola-l(5,3)-indola-6(2, 4)-bicyclo[3.1.1 ]heptanacycloundecaphane-4-yl)-2, 3-dimethylcy- clopropane-1 -carboxamide

[0327] To a stirred solution of (64S,4S,Z)-4-amino-l1-ethyl-l2-(2-((S)-l-methoxyethyl)-5- (3 -morpholinoprop- 1 -yn- 1 -yl)pyri din-3 -yl)- 10,10-dimethyl- 11H-8-oxa-62,63-diaza-2(4,2)-thia- zola-1 (5, 3)-indola-6(2,4)-bicyclo[3.1.1]heptanacy cl oundecaphane-5, 7-dione (125 mg, 0.16 mmol) and (lr,2R,3S)-2,3-dimethylcyclopropane-l-carboxylic acid (19 mg, 0.16 mmol) and 2,6-lutidine (88 mg, 0.82 mmol) in ACN (5 mL) was added COMU (105 mg, 0.24 mmol) at rt, the resulting mixture was stirred at rt for 2 h. The reaction mixture was concentrated to give the crude product. The crude product was purified by pre-HPLC (ACN / H2O (0.5 % NH4HCO3) from 20% to 95% in 30 min) to give (lr,2R,3S)-N-((64S,4S,Z)-l1-ethyl-l2-(2-((S)-l-methoxy- ethyl)-5-(3 -morpholinoprop- 1 -yn- 1 -yl)pyri din-3 -yl)- 10,10-dimethyl-5,7-dioxo- 1 'H-8-oxa- 62,63-diaza-2(4,2)-thiazola-l(5,3)-indola-6(2,4)-bicyclo[3.1.1]heptanacycloundecaphane-4-yl)- 2,3-dimethylcyclopropane-l-carboxamide (85 mg, 61.7%) as a white solid. LCMS (ESI) calcd. for C48H59N7O6S [M+H]+m / z 862.4, found: 862.9'1H NMR (400 MHz, DMSO-t / e) 8 8.82 (s, 1H), 8.40 (d, J= 13.3 Hz, 2H), 7.90 (s, 1H), 7.81 (s, 1H), 7.74 (d, J= 8.8 Hz, 1H), 7.57 (d, J= 8.8 Hz, 1H), 5.92 (d, J= 10.8 Hz, 1H), 5.34 (d, J= 22.7 Hz, 2H), 4.64 (d, J= 11.2 Hz, 1H), 4.48 (d, J= 4.9 Hz, 1H), 4.37 - 4.21 (m, 2H), 4.06 (d, J= 7.6 Hz, 5H), 3.75 - 3.48 (m, 6H), 3.22 (s, 3H), 3.16 (s, 10H), 3.00 - 2.85 (m, 2H), 2.62 (d, J= 5.7 Hz, 3H), 2.41 (d, J= 15.0 Hz, 1H), 2.32 (s, 1H), 2.21 - 2.09 (m, 1H), 1.99 (d, J= 8.0 Hz, 1H), 1.55 (s, 1H), 1.35 (d, J= 6.1 Hz, 2H), 1.22 (s, 4H), 1.16 (s, 2H), 1.07 (dd, J= 10.3, 5.8 Hz, 4H), 0.87 (t, J= 9.6 Hz, 4H), 0.32 (s, 3H).

[0328] Each of the compounds set forth was prepared following one of the procedures set forth above.

[0329] The following embodiments was synthesized from different starting materials according to the method of Examples above to obtain Compounds 3, 4, 7, 8, 11 and 13.Example 24. Synthesis of Compound 17 (lS,2S)-N-((64S,4S,Z)-l1-ethyl-l2-(5-ethvnyl-2- ((S)-l-methoxyethyl)pyridin-3-yl)-10,10-dimethyl-5,7-dioxo-l1H-8-oxa-62,63-diaza-2(4,2)-thiazola-l(5.,3)-indola-6(2.,4)-bicvclo[3.1.1]heptanacvcloundecaphane-4-yl)-2-methylcvclo- propane-l-carboxamide

[0330] Substituting (S)-4-(5-bromo-6-(l-methoxyethyl)pyridin-3-yl)-2-methylbut-3-yn-2- ol with (S)-3-bromo-5-ethynyl-2-(l-methoxyethyl)pyridine in the Step 1 of Compound 2 and Substituting (lr,2R,3S)-2,3-dimethylcyclopropane-l-carboxylic acid with (lS,2S)-2-methylcy- clopropane-1 -carboxylic acid in the Step 4 of Compound 2, the title compound was prepared by the same procedures as described for Example 2. LCMS (ESI): 750.3 [M+l]+.JH NMR (500 MHz, CDC13) 8 8.48 (d, J = 2.0 Hz, 1H), 8.12 - 8.05 (m, 2H), 7.77 (d, J = 2.4 Hz, 1H), 7.69 (dd, J = 7.7, 2.4 Hz, 1H), 7.59 (s, 1H), 7.48 (d, J = 7.7 Hz, 1H), 5.24 (q, J = 5.4 Hz, 1H), 4.90 (d, J = 8.4 Hz, 1H), 4.64 (q, J = 12.4 Hz, 1H), 4.15 (q, J = 4.4 Hz, 2H), 4.08 (d, J = 11.4 Hz, 1H), 4.05 - 3.93 (m, 3H), 3.46 (s, 1H), 3.33 (s, 3H), 3.28 - 3.14 (m, 2H), 3.09 - 2.99 (m, 2H), 2.72 (h, J = 8.0 Hz, 1H), 2.13 - 1.97 (m, 4H), 1.92 (td, J = 10.2, 7.3 Hz, 1H), 1.69 - 1.60 (m, 4H), 1.53 (ddd, J = 9.9, 8.9, 5.0 Hz, 1H), 1.37 (t, J = 4.4 Hz, 3H), 1.12 (d, J = 25.1 Hz, 7H), 0.92 (d, J = 5.0 Hz, 3H).Example 25. Synthesis of Compound 18 (lS,2S)-N-((64S,4S,Z)-l1-ethyl-l2-(5-((l-fluorocy- dopropyl)ethvnyl)-2-((S)-l-methoxyethyl)pyridin-3-yl)-10,10-dimethyl-5,7-dioxo-l1H-8- oxa-62,63-diaza-2(4,2)-thiazola-l(5,3)-indola-6(2,4)-bicvclo[3.1.1]heptanacvcloundeca- phane-4-yl)-2-methylcyclopropane-l-carboxamide

[0331] Substituting (S)-4-(5-bromo-6-(l-methoxyethyl)pyridin-3-yl)-2-methylbut-3-yn-2- ol with (S)-3-bromo-5-((l-fluorocyclopropyl)ethynyl)-2-(l-methoxyethyl)pyridine in the Step 1 of Compound 2 and Substituting (lr,2R,3S)-2,3-dimethylcyclopropane-l-carboxylic acid with (lS,2S)-2-methylcyclopropane-l-carboxylic acid in the Step 4 of Compound 2, the titlecompound was prepared by the same procedures as described for Compound 2. LCMS (ESI):807.4 [M+l]+. 'HNMR (500 MHz, CDC13) 8 8.28 (d, J = 2.0 Hz, 2H), 8.08 (d, J = 12.6 Hz, 2H), 7.92 (d, J = 2.0 Hz, 2H), 7.77 (d, J = 2.4 Hz, 2H), 7.69 (dd, J = 7.7, 2.4 Hz, 2H), 7.59 (s, 2H), 7.48 (d, J = 7.7 Hz, 2H), 5.24 (q, J = 5.4 Hz, 2H), 4.90 (d, J = 8.4 Hz, 2H), 4.64 (q, J =12.4 Hz, 2H), 4.15 (q, J = 4.4 Hz, 4H), 4.08 - 3.99 (m, 4H), 3.99 - 3.89 (m, 4H), 3.33 (s, 6H), 3.31 - 3.23 (m, 3H), 3.22 (d, J = 3.5 Hz, 1H), 3.06 (d, J = 2.6 Hz, 4H), 2.72 (h, J = 7.9 Hz, 2H), 2.23 (q, J = 4.9 Hz, 8H), 2.13 - 1.97 (m, 8H), 1.94 (td, J = 10.2, 7.3 Hz, 2H), 1.69 - 1.60 (m, 8H), 1.55 (ddd, J = 9.9, 8.8, 4.9 Hz, 2H), 1.37 (t, J = 4.4 Hz, 6H), 1.16 - 1.04 (m, 14H), 0.90 (d, J = 5.0 Hz, 6H).Example 26. Synthesis of Compound 19 (lr,2R,3S)-N-((64S,4S,Z)-l1-ethyl-l2-(2-((S)-l- methoxyethyl)-5-(((S)-l-methylpyrrolidin-2-yl)ethynyl)pyridin-3-yl)-10,10-dimethyl-5,7- dioxo-l1H-8-oxa-62,63-diaza-2(4,2)-thiazola-l(5,3)-indola-6(2,4)-bicyclo[3.1.1]heptana- cvcloundecaphane-4-yl)-2,3-dimethylcvclopropane-l-carboxamide

[0332] Substituting 3 -bromo-2-((S)- 1 -methoxy ethyl)-5-(((S)- 1 -methylpyrrolidin-3 - yl)ethynyl)pyridine with 3 -bromo-2-((S)- 1 -methoxy ethyl)-5-(((S)- 1 -methylpyrrolidin-2- yl)ethynyl)pyridine in the Step 3 of Compound 5, the title compound was prepared by the same procedures as described for Compound 5. LCMS (ESI): 846.4 [M+l]+. 'HNMR (400 MHz, DMSO) 5 8.76 (d, J = 2.1 Hz, 1H), 8.42 - 8.34 (m, 2H), 7.83 - 7.77 (m, 1H), 7.73 (d, J =8.7 Hz, 1H), 7.56 (d, J = 8.5 Hz, 1H), 5.90 (d, J = 11.0 Hz, 1H), 5.36 (s, 1H), 4.64 (d, J = 10.7 Hz, 1H), 4.46 (d, J = 4.8 Hz, 1H), 4.33 - 4.20 (m, 2H), 4.04 (dd, J = 14.4, 7.3 Hz, 1H), 3.60 - 3.46 (m, 2H), 3.40 - 3.32 (m, 1H), 3.21 (s, 3H), 3.12 (dd, J = 14.9, 7.3 Hz, 1H), 2.91 (d, J =13.7 Hz, 1H), 2.82 - 2.72 (m, 1H), 2.61 (d, J = 5.8 Hz, 1H), 2.40 (d, J = 16.0 Hz, 2H), 2.37 - 2.27 (m, 4H), 2.19 - 2.07 (m, 2H), 1.84 (ddd, J = 46.4, 30.9, 20.3 Hz, 4H), 1.56 (d, J = 9.6 Hz, 1H), 1.33 (t, J = 6.6 Hz, 3H), 1.20 (d, J = 10.7 Hz, 4H), 1.15 (d, J = 3.2 Hz, 2H), 1.10 - 1.00 (m, 4H), 0.92 - 0.77 (m, 5H), 0.31 (s, 3H).Example 27. Synthesis of Compound 20 (lr,2R,3S)-N-((64S,4S,Z)-l1-ethyl-l2-(2-((S)-l- methoxyethyl)-5-((5-methyl-l,3,4-thiadiazol-2-yl)ethvnyl)pyridin-3-yl)-10,10-dimethyl-5,7-dioxo-l1H-8-oxa-62,63-diaza-2(4,2)-thiazola-l(5,3)-indola-6(2,4)-bicyclo[3.1.1]heptana- cvcloundecaphane-4-yl)-2,3-dimethylcvclopropane-l-carboxamide

[0333] Substituting 3 -bromo-2-((S)- 1 -methoxy ethyl)-5-(((S)- 1 -methylpyrrolidin-3 - yl)ethynyl)pyridine with (S)-2-((5-bromo-6-(l -methoxy ethyl)pyridin-3-yl)ethynyl)-5-methyl- 1,3,4-thiadiazole in the Step 3 of Compound 5, the title compound was prepared by the same procedures as described for Compound 5. LCMS (ESI): 846.4 [M+l]+. 'HNMR (400 MHz, DMSO) 5 8.72 (d, J = 2.1 Hz, 1H), 8.42 - 8.33 (m, 2H), 7.79 (s, 1H), 7.74 (dd, J = 11.5, 5.9 Hz, 2H), 7.55 (d, J = 8.7 Hz, 1H), 5.89 (d, J = 10.9 Hz, 1H), 5.36 (s, 1H), 4.64 (d, J = 10.6 Hz, 1H), 4.46 (s, 1H), 4.33 - 4.19 (m, 2H), 4.04 (d, J = 7.3 Hz, 1H), 3.54 (dd, J = 21.3, 10.8 Hz, 2H), 3.22 (d, J = 10.8 Hz, 5H), 3.16 - 3.08 (m, 1H), 2.91 (d, J = 13.2 Hz, 1H), 2.85 - 2.77 (m, 1H), 2.66 - 2.58 (m, 1H), 2.52 (s, 1H), 2.41 (d, J = 21.8 Hz, 5H), 2.31 (s, 1H), 2.26 - 2.09 (m, 5H), 1.85 (dd, J = 13.2, 6.9 Hz, 1H), 1.55 (s, 1H), 1.33 (d, J = 6.1 Hz, 3H), 1.18 (d, J = 25.4 Hz, 4H), 1.06 (dd, J = 10.4, 5.8 Hz, 4H), 0.87 (d, J = 7.0 Hz, 5H), 0.31 (s, 3H).Example 28. Synthesis of Compound 21 (lr,2R,3S)-N-((64S,4S,Z)-l1-ethyl-l2-(2-((S)-l- methoxyethyl)-5-((l-methyl-lH-pyrazol-4-yl)ethynyl)pyridin-3-yl)-10,10-dimethyl-5,7-di- oxo-l1H-8-oxa-62,63-diaza-2(4,2)-thiazola-l(5,3)-indola-6(2,4)-bicyclo[3.1.1]heptana- cvcloundecaphane-4-yl)-2,3-dimethylcvclopropane-l-carboxamide

[0334] Substituting (S)-4-(5-bromo-6-(l-methoxyethyl)pyridin-3-yl)-2-methylbut-3-yn-2- ol with (S)-3-bromo-2-(l-methoxyethyl)-5-((l-methyl-lH-pyrazol-4-yl)ethynyl)pyridine in the Step 1 of Compound 2 and Substituting (lr,2R,3S)-2,3-dimethylcyclopropane-l-carboxylic acid with (lS,2S)-2-methylcyclopropane-l-carboxylic acid in the Step 4 of Compound 2, the title compound was prepared by the same procedures as described for Compound 2. LCMS(ESI): 829.4 [M+l]+. 'HNMR (500 MHz, CDCh) 6 8.29 (d, J = 2.0 Hz, 1H), 8.11 (d, J = 12.5 Hz, 1H), 8.04 (d, J = 2.0 Hz, 1H), 7.77 (d, J = 2.3 Hz, 1H), 7.73 (d, J = 1.6 Hz, 1H), 7.71 - 7.66 (m, 2H), 7.59 (s, 1H), 7.48 (d, J = 7.7 Hz, 1H), 5.24 (q, J = 5.4 Hz, 1H), 4.89 (d, J = 8.6 Hz, 1H), 4.64 (q, J = 12.4 Hz, 1H), 4.15 (q, J = 4.4 Hz, 2H), 4.08 - 3.99 (m, 2H), 3.99 - 3.89 (m, 2H), 3.83 (s, 3H), 3.33 (s, 3H), 3.31 - 3.23 (m, 1H), 3.22 (d, J = 3.5 Hz, 1H), 3.06 (d, J = 2.6 Hz, 2H), 2.72 (h, J = 7.9 Hz, 1H), 2.13 - 2.03 (m, 3H), 2.03 - 1.97 (m, 1H), 1.94 (td, J = 10.2, 7.2 Hz, 1H), 1.67 (d, J = 5.3 Hz, 3H), 1.65 - 1.60 (m, 1H), 1.55 (ddd, J = 9.9, 8.8, 4.9 Hz, 1H), 1.37 (t, J = 4.4 Hz, 3H), 1.15 (s, 3H), 1.10 (s, 4H), 0.91 (d, J = 5.0 Hz, 3H).Example 29. Synthesis of Compound 22 (lS,2S)-N-((64S,4S,Z)-l1-ethyl-l2-(2-((S)-l-meth- oxyethyl)-5-(pyrimidin-5-ylethynyl)pyridin-3-yl)-10,10-dimethyl-5,7-dioxo-l1H-8-oxa- 62,63-diaza-2(4,2)-thiazola-l(5,3)-indola-6(2,4)-bicvclo[3.1.1]heptanacvcloundecaphane-4- yl)-2-methylcyclopropane-l-carboxamide

[0335] Substituting (S)-4-(5-bromo-6-(l-methoxyethyl)pyridin-3-yl)-2-methylbut-3-yn-2- ol with (S)-5-((5-bromo-6-(l-methoxyethyl)pyridin-3-yl)ethynyl)pyrimidine in the Step 1 of Compound 2 and Substituting (lr,2R,3S)-2,3-dimethylcyclopropane-l-carboxylic acid with (lS,2S)-2-methylcyclopropane-l-carboxylic acid in the Step 4 of Compound 2, the title compound was prepared by the same procedures as described for Compound 2. LCMS (ESI): 827.4 [M+l]+. 'HNMR (500 MHz, CDCh) 8 9.15 (t, J = 1.7 Hz, 2H), 8.79 (d, J = 1.8 Hz, 4H), 8.31 (d, J = 2.0 Hz, 2H), 8.08 (d, J = 12.6 Hz, 2H), 8.04 (d, J = 2.0 Hz, 2H), 7.77 (d, J = 2.4 Hz, 2H), 7.69 (dd, J = 7.7, 2.4 Hz, 2H), 7.59 (s, 2H), 7.48 (d, J = 7.7 Hz, 2H), 5.24 (q, J = 5.4 Hz, 2H), 4.90 (d, J = 8.4 Hz, 2H), 4.64 (q, J = 12.4 Hz, 2H), 4.15 (q, J = 4.4 Hz, 4H), 4.08 - 3.99 (m, 4H), 3.99 - 3.89 (m, 4H), 3.33 (s, 6H), 3.31 - 3.23 (m, 3H), 3.22 (d, J = 3.5 Hz, 1H), 3.06 (d, J = 2.6 Hz, 4H), 2.72 (h, J = 7.9 Hz, 2H), 2.13 - 2.03 (m, 6H), 2.03 - 1.97 (m, 2H), 1.94 (td, J = 10.2, 7.2 Hz, 2H), 1.67 (d, J = 5.3 Hz, 6H), 1.65 - 1.60 (m, 1H), 1.55 (ddd, J = 9.9, 8.8, 4.9 Hz, 2H), 1.37 (t, J = 4.4 Hz, 6H), 1.15 (s, 6H), 1.10 (s, 8H), 0.91 (d, J = 5.0 Hz, 6H).Example 30. Synthesis of Compound 23. -N-((64S.,4S.Z)-l2-(5-(benzo[d]thiazol-6-ylethvnyl)-2-((S)-l-methoxyethyl)pyridin-3-yl)-l1-ethyl-10,10-dimethyl-5.,7-dioxo-l1H-8-oxa-62.,63-diaza-2(4.,2)-thiazola-l(5.,3)-indola-6(2.,4)-bicvclo[3.1.1]heptanacvcloundeca- phane-4-yl)-2-methylcvclopropane-l-carboxamide

[0336] Substituting (S)-4-(5-bromo-6-(l-methoxyethyl)pyridin-3-yl)-2-methylbut-3-yn-2- ol with (S)-5-((5-bromo-6-(l-methoxyethyl)pyridin-3-yl)ethynyl)benzo[d]thiazole in the Step 1 of Compound 2 and Substituting (lr,2R,3S)-2,3-dimethylcyclopropane-l-carboxylic acid with (lS,2S)-2-methylcyclopropane-l-carboxylic acid in the Step 4 of Compound 2, the title compound was prepared by the same procedures as described for Compound 2. LCMS (ESI):882.3 [M+l]+. 'HNMR (500 MHz, CDC13) 8 9.01 (s, 2H), 8.39 (d, J = 2.0 Hz, 2H), 8.11 (d, J = 12.5 Hz, 2H), 7.97 (d, J = 2.0 Hz, 2H), 7.83 (d, J = 1.7 Hz, 2H), 7.77 (d, J = 2.2 Hz, 2H), 7.72 - 7.66 (m, 4H), 7.63 - 7.57 (m, 4H), 7.48 (d, J = 7.7 Hz, 2H), 5.24 (q, J = 5.4 Hz, 2H), 4.89 (d, J = 8.6 Hz, 2H), 4.64 (q, J = 12.4 Hz, 2H), 4.15 (q, J = 4.4 Hz, 4H), 4.08 - 3.99 (m, 4H), 3.99 - 3.89 (m, 4H), 3.33 (s, 6H), 3.31 - 3.23 (m, 3H), 3.22 (d, J = 3.5 Hz, 1H), 3.06 (d, J = 2.6 Hz, 4H), 2.72 (h, J = 7.9 Hz, 2H), 2.13 - 1.89 (m, 10H), 1.69 - 1.60 (m, 8H), 1.55 (ddd, J = 9.9, 8.8, 4.9 Hz, 2H), 1.37 (t, J = 4.4 Hz, 6H), 1.12 (d, J = 24.9 Hz, 14H), 0.91 (d, J = 5.0 Hz, 6H).Example 31. Synthesis of Compound 24. (lS,2S)-N-((64S,4S,Z)-l1-ethyl-l2-(5-(imid- azo[l,2-a]pyrimidin-3-ylethvnyl)-2-((S)-l-methoxyethyl)pyridin-3-yl)-10,10-dimethyl-5,7- dioxo-l1H-8-oxa-62,63-diaza-2(4,2)-thiazola-l(5,3)-indola-6(2,4)-bicyclo[3.1.1]heptana- cvcloundecaphane-4-yl)-2-methylcvclopropane-l-carboxamide

[0337] Substituting (S)-4-(5-bromo-6-(l-methoxyethyl)pyridin-3-yl)-2-methylbut-3-yn-2- ol with (S)-3-((5-bromo-6-(l-methoxyethyl)pyridin-3-yl)ethynyl)imidazo[l,2-a]pyrimidine inthe Step 1 of Compound 2 and Substituting (lr,2R,3S)-2,3-dimethylcyclopropane-l-carbox- ylic acid with (lS,2S)-2-methylcyclopropane-l-carboxylic acid in the Step 4 of Compound 2, the title compound was prepared by the same procedures as described for Compound 2. LCMS (ESI): 866.4 [M+l]+. 'H NMR (400 MHz, DMSO) 5 8.96 (d, J = 2.0 Hz, 1H), 8.73 - 8.66 (m, 1H), 8.51 (d, J = 8.9 Hz, 1H), 8.42 (s, 1H), 8.26 - 8.22 (m, 1H), 8.17 (d, J = 2.0 Hz, 1H), 7.80 (s, 1H), 7.73 (d, J = 8.6 Hz, 1H), 7.54 (d, J = 8.7 Hz, 1H), 7.38 (dd, J = 9.2, 4.5 Hz, 1H), 5.88 (d, J = 11.1 Hz, 1H), 5.31 (t, J = 8.0 Hz, 1H), 4.72 (d, J = 11.2 Hz, 1H), 4.48 (d, J = 5.0 Hz, 1H), 4.03 - 3.77 (m, 3H), 3.59 (d, J = 10.8 Hz, 1H), 3.51 (d, J = 10.9 Hz, 1H), 3.24 (d, J = 14.7 Hz, 1H), 3.19 - 2.98 (m, 4H), 2.70 - 2.61 (m, 1H), 2.34 (dd, J = 16.0, 10.2 Hz, 2H), 2.18 - 2.07 (m, 1H), 1.60 (t, J = 9.3 Hz, 1H), 1.49 (s, 1H), 1.21 (d, J = 6.2 Hz, 3H), 1.11 (t, J = 7.1 Hz, 2H), 1.06 (s, 3H), 0.91 (s, 3H), 0.58 - 0.44 (m, 3H).Example 32. Synthesis of Compound 25. (lr,2R,3S)-N-((64S,4S,Z)-l2-(5-(3-(dimethyla- mino)prop-l-vn-l-yl)-2-((S)-l-methoxyethyl)pyridin-3-yl)-l1-ethyl-10,10-dimethyl-5.,7-di- oxo-l1H-8-oxa-62,63-diaza-2(4,2)-thiazola-l(5,3)-indola-6(2,4)-bicyclo[3.1.1]heptana- cvcloundecaphane-4-yl)-2,3-dimethylcvclopropane-l-carboxamide

[0338] Substituting (S)-4-(3 -(5 -bromo-6-(l -methoxy ethyl)pyri din-3 -yl)prop-2-yn-l- yl)morpholine with (S)-3-(5-bromo-6-(l -methoxy ethyl)pyri din-3 -yl)-N, N-dimethylprop-2-yn- 1 -amine in the Step 1 of Compound 16, the title compound was prepared by the same procedures as described for Compound 16. LCMS (ESI): 820.4 [M+l]+.XH NMR (400 MHz,DMSO) 5 8.80 (d, J = 2.0 Hz, 1H), 8.39 (d, J = 10.0 Hz, 2H), 7.98 (d, J = 2.0 Hz, 1H), 7.80 (s, 1H), 7.72 (d, J = 8.7 Hz, 1H), 7.52 (d, J = 8.7 Hz, 1H), 5.86 (d, J = 11.1 Hz, 1H), 5.29 (t, J = 8.5 Hz, 1H), 4.71 (d, J = 11.2 Hz, 1H), 4.47 (d, J = 5.1 Hz, 1H), 4.01 - 3.85 (m, 2H), 3.79 (dd, J = 14.6, 7.4 Hz, 1H), 3.63 - 3.45 (m, 3H), 3.23 (d, J = 14.7 Hz, 2H), 3.16 - 2.96 (m, 4H), 2.71 - 2.57 (m, 1H), 2.37 - 2.20 (m, 6H), 2.19 - 2.07 (m, 1H), 1.60 (t, J = 9.3 Hz, 1H), 1.30 - 1.11 (m, 5H), 1.14 - 0.99 (m, 6H), 0.86 (d, J = 26.9 Hz, 2H), 0.46 (s, 2H).Example 33. Synthesis of Compound 26. (lr,2R.,3S)-N-((64S.,4S.,Z)-l1-ethyl-l2-(5-(3-((R)-3-fluoropyrrolidin-l-yl)prop-l-vn-l-yl)-2-((S)-l-methoxyethyl)pyridin-3-yl)-10,10-dime- thyl-5.,7-dioxo-l1H-8-oxa-62.,63-diaza-2(4.,2)-thiazola-l(5.,3)-indola-6(2.,4)-bicv- clo[3.1.1]heptanacvcloundecaphane-4-yl)-2.,3-dimethylcvclopropane-l-carboxamide

[0339] Substituting (S)-4-(3 -(5 -bromo-6-(l-m ethoxy ethyl)pyri din-3 -yl)prop-2-yn-l- yl)morpholine with 3 -bromo-5 -(3 -((R)-3 -fluoropyrrolidin- 1 -yl)prop- 1 -yn- 1 -yl)-2-((S)- 1 -meth- oxyethyl)pyridine in the Step 1 of Compound 16, the title compound was prepared by the same procedures as described for Compound 16. LCMS (ESI): 864.4 [M+l]+.JH NMR (500 MHz, CDC13) 8 8.39 (d, J = 2.0 Hz, 1H), 8.20 (d, J = 13.0 Hz, 1H), 8.02 (d, J = 2.0 Hz, 1H), 7.77 (d, J = 2.4 Hz, 1H), 7.69 (dd, J = 7.7, 2.4 Hz, 1H), 7.59 (s, 1H), 7.48 (d, J = 7.7 Hz, 1H), 5.24 (q, J = 5.4 Hz, 1H), 4.89 (d, J = 8.6 Hz, 1H), 4.87 - 4.80 (m, 1H), 4.63 (dt, J = 13.0, 12.3 Hz, 1H), 4.15 (q, J = 4.4 Hz, 2H), 4.08 - 3.99 (m, 2H), 3.99 - 3.89 (m, 2H), 3.63 - 3.57 (m, 1H), 3.55 (s, 1H), 3.52 - 3.45 (m, 1H), 3.33 (s, 3H), 3.31 - 3.18 (m, 3H), 3.06 (d, J = 2.6 Hz, 2H), 2.94 (t, J = 5.6 Hz, 2H), 2.72 (h, J = 7.9 Hz, 1H), 2.47 (t, J = 8.6 Hz, 1H), 2.29 (q, J = 5.6 Hz, 1H), 2.14 - 1.97 (m, 5H), 1.74 (dq, J = 8.6, 5.2 Hz, 2H), 1.67 (d, J = 5.3 Hz, 3H), 1.37 (t, J = 4.4 Hz, 3H), 1.15 (s, 3H), 1.10 (s, 3H), 0.95 (d, J = 5.1 Hz, 6H).Example 34. Synthesis of Compound 27. (lr,2R,3S)-N-((64S,4S,Z)-l1-ethyl-l2-(2-((S)-l- methoxyethyl)-5-(3-(piperidin-l-yl)prop-l-vn-l-yl)pyridin-3-yl)-10,10-dimethyl-5,7-di- oxo-l1H-8-oxa-62,63-diaza-2(4,2)-thiazola-l(5,3)-indola-6(2,4)-bicyclo[3.1.1]heptana- cvcloundecaphane-4-yl)-2,3-dimethylcvclopropane-l-carboxamide[°34°] Substituting (S)-4-(3 -(5 -bromo-6-(l -methoxy ethyl)pyri din-3 -yl)prop-2-yn-l- yl)morpholine with (S)-3-bromo-2-(l-methoxyethyl)-5-(3-(piperidin-l-yl)prop-l-yn-l-yl)pyri- dine in the Step 1 of Compound 16, the title compound was prepared by the same proceduresas described for Compound 16. LCMS (ESI): 860.5 [M+l]+. ‘HNMR (400 MHz, DMSO) 5 8.78 (d, J = 1.8 Hz, 1H), 8.40 (d, J = 8.8 Hz, 2H), 7.97 (d, J = 1.9 Hz, 1H), 7.80 (s, 1H), 7.72 (d, J = 8.4 Hz, 1H), 7.52 (d, J = 8.7 Hz, 1H), 5.87 (d, J = 10.9 Hz, 1H), 5.29 (t, J = 8.3 Hz, 1H), 4.71 (d, J = 11.1 Hz, 1H), 4.47 (d, J = 5.0 Hz, 1H), 3.99 - 3.86 (m, 2H), 3.79 (dd, J = 14.8, 7.4 Hz, 1H), 3.63 - 3.42 (m, 4H), 3.26 - 2.98 (m, 6H), 2.64 (d, J = 5.7 Hz, 1H), 2.36 - 2.27 (m, 2H), 2.13 (t, J = 9.8 Hz, 1H), 1.60 (t, J = 9.4 Hz, 1H), 1.54 - 1.47 (m, 3H), 1.35 (s, 2H), 1.29 - 1.00 (m, 14H), 0.90 (s, 3H), 0.46 (s, 3H).Example 35. Synthesis of Compound 28. (lr,2R,3S)-N-((64S,4S,Z)-l1-ethyl-l2-(2-((S)-l- methoxyethyl)-5-(3-(4-methylpiperazin-l-yl)prop-l-vn-l-yl)pyridin-3-yl)-10,10-dimethyl- 5,7-dioxo-l1H-8-oxa-62,63-diaza-2(4,2)-thiazola-l(5,3)-indola-6(2,4)-bicyclo[3.1.1]heptana- cvcloundecaphane-4-yl)-2,3-dimethylcvclopropane-l-carboxamide

[0341] Substituting (S)-4-(3 -(5 -bromo-6-(l-m ethoxy ethyl)pyri din-3 -yl)prop-2-yn-l- yl)morpholine with (S)- 1 -(3 -(5 -bromo-6-( 1 -methoxy ethyl)pyri din-3 -yl)prop-2-yn- 1 -yl)-4- methylpiperazine in the Step 1 of Compound 16, the title compound was prepared by the same procedures as described for Compound 16. LCMS (ESI): 875.5 [M+l]+. 'H NMR (400 MHz, DMSO) 5 8.78 (d, J = 1.9 Hz, 1H), 8.39 (d, J = 11.7 Hz, 2H), 7.97 (d, J = 2.0 Hz, 1H), 7.79 (s, 1H), 7.71 (d, J = 7.5 Hz, 1H), 7.52 (d, J = 8.6 Hz, 1H), 5.86 (d, J = 11.1 Hz, 1H), 5.29 (t, J = 7.9 Hz, 1H), 4.71 (d, J = 11.1 Hz, 1H), 4.47 (d, J = 5.1 Hz, 1H), 3.99 - 3.72 (m, 4H), 3.60 - 3.47 (m, 4H), 3.27 - 2.98 (m, 8H), 2.60 (dd, J = 27.9, 22.1 Hz, 5H), 2.41 - 2.22 (m, 6H), 2.17 - 2.09 (m, 4H), 1.59 (t, J = 9.2 Hz, 1H), 1.29 - 1.02 (m, 16H), 0.89 (s, 3H), 0.45 (s, 3H).Example 36. Synthesis of Compound 29. (lr,2R.,3S)-N-((64S.,4S.,Z)-l2-(5-(3-(4-acetylpiper- azin-l-yl)prop-l-yn-l-yl)-2-((S)-l-methoxyethyl)pyridin-3-yl)-l1-ethyl-10,10-dimethyl- 5,7-dioxo-l1H-8-oxa-62,63-diaza-2(4,2)-thiazola-l(5,3)-indola-6(2,4)-bicyclo[3.1.1]heptana- cvcloundecaphane-4-yl)-2,3-dimethylcvclopropane-l-carboxamide

[0342] Substituting (S)-4-(3 -(5 -bromo-6-(l-m ethoxy ethyl)pyri din-3 -yl)prop-2-yn-l- yl)morpholine with (S)- 1 -(4-(3 -(5-bromo-6-(l -methoxy ethyl)pyri din-3 -yl)prop-2-yn- 1 -yl)pi- perazin-l-yl)ethan-l-one in the Step 1 of Compound 16, the title compound was prepared by the same procedures as described for Compound 16. LCMS (ESI): 903.5 [M+l]+. 'H N R (500 MHz, CDC13) 8 8.39 (d, J = 2.0 Hz, 1H), 8.20 (d, J = 13.0 Hz, 1H), 8.02 (d, J = 2.0 Hz, 1H), 7.77 (d, J = 2.3 Hz, 1H), 7.69 (dd, J = 7.7, 2.4 Hz, 1H), 7.59 (s, 1H), 7.48 (d, J = 7.7 Hz, 1H), 5.24 (q, J = 5.4 Hz, 1H), 4.89 (d, J = 8.6 Hz, 1H), 4.63 (dt, J = 13.0, 12.3 Hz, 1H), 4.15 (q, J = 4.4 Hz, 2H), 4.08 - 3.99 (m, 2H), 3.99 - 3.89 (m, 2H), 3.60 - 3.52 (m, 3H), 3.52 - 3.45 (m, 4H), 3.33 (s, 3H), 3.31 - 3.23 (m, 2H), 3.22 (d, J = 3.5 Hz, 1H), 3.06 (d, J = 2.6 Hz, 2H), 2.72 (h, J = 7.9 Hz, 1H), 2.55 - 2.50 (m, 4H), 2.50 - 2.43 (m, 2H), 2.13 - 1.97 (m, 7H), 1.74 (dq, J = 8.6, 5.2 Hz, 2H), 1.67 (d, J = 5.3 Hz, 3H), 1.37 (t, J = 4.4 Hz, 3H), 1.15 (s, 3H), 1.10 (s, 3H), 0.95 (d, J = 5.1 Hz, 6H).Example 37. Synthesis of Compound 30. (lS.,2S)-N-((64S.,4S.,Z)-l1-ethyl-l2-(2-((S)-l-meth- oxyethyl)-5-(3-morpholinoprop-l-yn-l-yl)pyridin-3-yl)-10,10-dimethyl-5.,7-dioxo-l1H-8- oxa-62,63-diaza-2(4,2)-thiazola-l(5,3)-indola-6(2,4)-bicvclo[3.1.1]heptanacvcloundeca- phane-4-yl)-2-methylcyclopropane-l-carboxamide

[0343] Substituting (lr,2R,3S)-2,3-dimethylcyclopropane-l-carboxylic acid with (1S,2S)- 2-methylcyclopropane-l -carboxylic acid in the Step 4 of Compound 16, the title compound was prepared by the same procedures as described for Compound 16. LCMS (ESI): 848.4 [M+l]+. ‘HNMR (500 MHz, CDCI3) 6 8.39 (d, J = 2.0 Hz, 1H), 8.11 (d, J = 12.5 Hz, 1H), 8.00 (d, J = 2.0 Hz, 1H), 7.77 (d, J = 2.3 Hz, 1H), 7.69 (dd, J = 7.7, 2.4 Hz, 1H), 7.59 (s, 1H), 7.48 (d, J = 7.7 Hz, 1H), 5.24 (q, J = 5.4 Hz, 1H), 4.89 (d, J = 8.6 Hz, 1H), 4.64 (q, J = 12.4 Hz, 1H), 4.15 (q, J = 4.4 Hz, 2H), 4.08 - 3.99 (m, 2H), 3.99 - 3.89 (m, 2H), 3.73 (dd, J = 6.5, 3.8 Hz, 2H), 3.66 (dd, J = 6.5, 3.8 Hz, 2H), 3.58 (d, J = 2.6 Hz, 2H), 3.33 (s, 3H), 3.31 - 3.23 (m,2H), 3.22 (d, J = 3.5 Hz, 1H), 3.06 (d, J = 2.6 Hz, 2H), 2.78 - 2.66 (m, 5H), 2.13 - 2.03 (m, 3H), 2.03 - 1.97 (m, 1H), 1.94 (td, J = 10.2, 7.2 Hz, 1H), 1.67 (d, J = 5.3 Hz, 3H), 1.65 - 1.60 (m, 1H), 1.55 (ddd, J = 9.9, 8.8, 4.9 Hz, 1H), 1.37 (t, J = 4.4 Hz, 3H), 1.15 (s, 3H), 1.10 (s, 4H), 0.91 (d, J = 5.0 Hz, 3H).Example 38. Synthesis of Compound 31. (lS,2S)-N-((64S,4S,Z)-l2-(5-(3-(l,l-dioxidothio- morpholino)prop-l-vn-l-yl)-2-((S)-l-methoxyethyl)pyridin-3-yl)-l1-ethyl-10,10-dimethyl- 5,7-dioxo-l1H-8-oxa-62,63-diaza-2(4,2)-thiazola-l(5,3)-indola-6(2,4)-bicyclo[3.1.1]heptana- cvcloundecaphane-4-yl)-2-methylcvclopropane-l-carboxamide

[0344] Substituting (S)-4-(3 -(5 -bromo-6-(l-m ethoxy ethyl)pyri din-3 -yl)prop-2-yn-l- yl)morpholine with (S)-4-(3-(5-bromo-6-(l -methoxy ethyl)pyri din-3 -yl)prop-2 -yn-l-yl)thio- morpholine 1,1-dioxide in the Step 1 of Compound 16 and Substituting (lr,2R,3S)-2,3-dime- thylcyclopropane-1 -carboxylic acid with (lS,2S)-2-methylcyclopropane-l-carboxylic acid in the Step 4 of Compound 16, the title compound was prepared by the same procedures as described for Compound 16. LCMS (ESI): 896.4 [M+l]+. 1H NMR (400 MHz, dmso) 5 8.78 (d, J = 2.0 Hz, 1H), 8.49 (d, J = 8.8 Hz, 1H), 8.40 (s, 1H), 7.85 (d, J = 2.1 Hz, 1H), 7.79 (s, 1H), 7.73 (d, J = 7.4 Hz, 1H), 7.56 (d, J = 8.6 Hz, 1H), 5.91 (d, J = 11.1 Hz, 1H), 5.37 (s, 1H), 4.64 (d, J = 10.8 Hz, 1H), 4.47 (d, J = 5.1 Hz, 1H), 4.37 - 4.20 (m, 2H), 4.04 (dd, J = 15.2, 7.3 Hz, 1H), 3.73 (s, 2H), 3.54 (dd, J = 20.9, 11.1 Hz, 2H), 3.21 (s, 4H), 3.11 (t, J = 10.5 Hz, 4H), 3.03 (s, 3H), 2.91 (d, J = 14.3 Hz, 1H), 2.61 (d, J = 5.7 Hz, 1H), 2.40 (d, J = 14.1 Hz, 1H), 2.31 (s, 1H), 2.18 - 2.08 (m, 1H), 1.55 (s, 1H), 1.47 (s, 1H), 1.34 (d, J = 6.0 Hz, 2H), 1.21 (s, 1H), 1.05 (s, 3H), 0.86 (t, J = 6.9 Hz, 5H), 0.54 (d, J = 5.4 Hz, 1H), 0.31 (s, 3H).Example 39. Synthesis of Conjugation Linkers for KAD-003 and KAD-022: 4-((S)-2-((S)- 2-(3-(2-(2,5-dioxo-2,5-dihydro-lH-Dyrrol-l-yl)ethoxy)DroDanamido)-3-methyl- bntanamido)-5-nreidopentanamido)benzyl (4-nitrophenyl) carbonate & 4-((S)-2-((S)-2-(3- (2-(2,5-dioxo-2.,5-dihvdro-lH-pyrrol-l-yl)ethoxy)propanamido)-3-methylbutanamido)-5- ureidopentanamidolbenzyl methyl(2-(methylamino)ethyl)carbamateStep 1: Synthesis of tert-butyl 3-(2-(2,5-dioxo-2,5-dihydro-lH-pyrrol-l-yl)ethoxy)propanoate

[0345] A mixture of tert-butyl 3-(2-aminoethoxy)propanoate (4.50 g, 23.78 mmol), furan- 2, 5-dione (3.03 g, 30.91 mmol) and TEA (3.61 g, 35.67 mmol) in ACN (70.00 mL) was stirred at room temperature for 2h, then the mixture was concentrated and the residue was dissolved into AC2O (55.00 mL) and NaAcO(2.34 g, 20.53 mmol) was added to the mixture, the mixture was stirred at 75°C for 2h under N2 atmosphere. The reaction was monitored by LCMS. After completion, the mixture was quenched with water (100.00 mL) and adjusted to pH=7 with sat. NaHCCL solution, then extracted with EA (200.00 mL x 3), the combined organic phase was concentrated under reduced pressure. The residual was purified by FCC (eluting with EtOAc / PE, from 0% to 21% in 25 min) to obtain tert-butyl 3-(2-(2,5-dioxo-2,5-dihydro-lH- pyrrol-l-yl)ethoxy)propanoate (4.10 g, 15.22 mmol, yield: 64.0 %) as a colorless oil. LCMS (ESI) calcd. for C13H19NO5 [M+H]+m / z 270.1, found: 270.5.Step 2: Synthesis of 3-(2-(2,5-dioxo-2,5-dihydro-lH-pyrrol-l-yl)ethoxy)propanoic acid

[0346] A mixture of tert-butyl 3-(2-(2,5-dioxo-2,5-dihydro-lH-pyrrol-l-yl)ethoxy)pro- panoate (4.10 g, 15.22 mmol) in DCM (40.00 mL) and TFA (40.00 mL) was stirred at room temperature for 2h. The reaction was monitored by LCMS. After completion, the mixture was concentrated under reduced pressure and the residue was triturated with PEZEtOAc (40.00 mL / 4.00 mL) to obtain 3-(2-(2,5-dioxo-2,5-dihydro-lH-pyrrol-l-yl)ethoxy)propanoic acid (3.10 g, 14.54 mmol, yield: 95.5%) as a white solid. LCMS (ESI) calcd. for C9H11NO5 [M-H]’ m / z 212.1, found: 212.3.Step 3: Synthesis of 2,5-dioxopyrrolidin-l-yl 3-(2-(2,5-dioxo-2,5-dihydro-lH-pyrrol-l-yl)eth- oxy)propanoate

[0347] To the mixture of 3-(2-(2,5-dioxo-2,5-dihydro-lH-pyrrol-l-yl)ethoxy)propanoic acid (1.52 g, 7.13 mmol) and 1 -hydroxypyrrolidine-2, 5-dione (0.90 g, 7.84 mmol) in THF (15.00 mL) and EtOH (15.00 mL) was added N-(3-dimethylaminopropyl)-N'-ethylcar- bodiimide hydrochloride (1.50 g, 7.84 mmol) at room temperature, the mixture was stirred at room temperature for 2h. The reaction was monitored by LCMS. After completion, the mixture was adjusted to pH=8 with sat. NaHCOs solution and extracted with DCM (30.00 mL x 3), the combined organic phase was washed with brine (50.00 mL ), dried over Na2SO4 and concentrated to afford 2,5-dioxopyrrolidin-l-yl 3-(2-(2,5-dioxo-2,5-dihydro-lH-pyrrol-l-yl)eth- oxy)propanoate (2.10 g, 6.77 mmol, yield: 95.0%) as a light yellow oil. LCMS (ESI) calcd. for C13H14N2O7 [M+H]+m / z 311.1, found: 311.4.Step 4: Synthesis of (S)-2-((S)-2-((((9H-fluoren-9-yl)methoxy)carbonyl)amino)-3-methyl- butanamido)-5-ureidopentanoic acid

[0348] To a mixture of 2,5-dioxopyrrolidin-l-yl (((9H-fluoren-9-yl)methoxy)carbonyl)-L- valinate (10.00 g, 22.91 mmol) in DME (60.00 mL) and THF (30.00 mL) was added a solution of (S)-2-amino-5-ureidopentanoic acid (4.01 g, 22.91 mmol) in sat. NaHCCL solution (20.00 mL) at room temperature, the mixture was stirred at room temperature overnight under N2 atmosphere, the reaction was monitored by LCMS. After completion, the mixture was poured into 15% citric acid solution (110.00 mL) and filtered, the filter cake was concentrated under reduced pressure to obtain (S)-2-((S)-2-((((9H-fluoren-9-yl)methoxy)carbonyl)amino)-3- methylbutanamido)-5-ureidopentanoic acid (11.00 g, 22.15 mmol, yield: 96.7%) as a white solid. LCMS (ESI) calcd. for C26H32N4O6 [M+H]+m / z 497.2, found: 497.7.Step 5: Synthesis of (9H-fluoren-9-yl)methyl ((S)-l-(((S)-l-((4-(hydroxymethyl)phenyl)amino)- 1 -oxo-5 -ureidopentan-2-y I) amino) -3 -me thy I- l-oxobutan-2-y I) carbamate

[0349] A mixture of (S)-2-((S)-2-((((9H-fluoren-9-yl)methoxy)carbonyl)amino)-3-methyl- butanamido)-5-ureidopentanoic acid (3.00 g, 6.04 mmol), (4-aminophenyl)methanol (1.86 g, 15.10 mmol) and EEDQ (3.74 g, 15.10 mmol) in DCM (60.00 mL) and MeOH (30.00 mL) was stirred at room temperature for 48h, the reaction was monitored by LCMS. After completion, the mixture was concentrated and the residue was triturated with MTBE (50.00 mL x 3) to obtain (9H-fluoren-9-yl)methyl ((S)- 1 -(((S)- 1 -((4-(hydroxymethyl)phenyl)amino)- 1 -oxo-5-ureidopentan-2-yl)amino)-3 -methyl- l-oxobutan-2-yl)carbamate (5.40 g, 8.97 mmol, yield: 63.6%) as a yellow solid. LCMS (ESI) calcd. for C33H39N5O6 [M+H]+m / z 602.3, found: 602.7. Step 6: Synthesis of (S)-2-((S)-2-amino-3-methylbutanamido)-N-(4-(hydroxymethyl)phenyl)-5- ureidopentanamide

[0350] To a mixture of (9H-fluoren-9-yl)m ethyl ((S)-l-(((S)-l-((4-(hydroxymethyl)phe- nyl)amino)-l-oxo-5-ureidopentan-2-yl)amino)-3-methyl-l-oxobutan-2-yl)carbamate (2.80 g, 4.65 mmol) in DMF (40.00 mL) was added piperidine (2.00 mL). The mixture was stirred at room temperature for Ih under N2 atmosphere, the reaction was monitored by LCMS. After completion, the mixture was concentrated and the residue was purified by FCC (eluting with MeOH / DCM, from 0% to 27% in 25 min) to afford (S)-2-((S)-2-amino-3-methylbutanamido)- N-(4-(hydroxymethyl)phenyl)-5-ureidopentanamide (1.20 g, 3.16 mmol, yield: 68.0%) as a brown solid. LCMS (ESI) calcd. for C18H29N5O4 [M+H]+m / z 380.2, found: 380.6.Step 7: Synthesis of (S)-2-((S)-2-(3-(2-(2,5-dioxo-2,5-dihydro-lH-pyrrol-l-yl)ethoxy)pro- panamido)-3-methylbutanamido)-N-(4-(hydroxymethyl)phenyl)-5-ureidopentanamide

[0351] A mixture of (S)-2-((S)-2-amino-3-methylbutanamido)-N-(4-(hydroxymethyl)phe- nyl)-5-ureidopentanamide (1.20 g, 3.16 mmol) and 2,5-dioxopyrrolidin-l-yl 3-(2-(2,5-dioxo- 2,5-dihydro-lH-pyrrol-l-yl)ethoxy)propanoate (1.17 g, 3.79 mmol) in DMF (15.00 mL) was stirred at room temperature for 16h, the reaction was monitored by LCMS. After completion, the mixture was concentrated under reduced pressure and the residual was triturated with MTBE (30.00 mL x 3) to afford (S)-2-((S)-2-(3-(2-(2,5-dioxo-2,5-dihydro-lH-pyrrol-l-yl)eth- oxy)propanamido)-3-methylbutanamido)-N-(4-(hydroxymethyl)phenyl)-5-ureidopentanamide (1.50 g, 2.61 mmol, yield: 82.6 %) as a grey solid. LCMS (ESI) calcd. for C27H38N6O8 [M+H]+m / z 575.3, found: 575.8.Step 8: Synthesis of 4-((S)-2-((S)-2-(3-(2-(2,5-dioxo-2,5-dihydro-lH-pyrrol-l-yl)ethoxy)pro- panamido)-3-methylbutanamido)-5-ureidopentanamido)benzyl ( 4-nitrophenyl) carbonate

[0352] A mixture of (S)-2-((S)-2-(3-(2-(2,5-dioxo-2,5-dihydro-lH-pyrrol-l-yl)ethoxy)pro- panamido)-3-methylbutanamido)-N-(4-(hydroxymethyl)phenyl)-5-ureidopentanamide (1.50 g, 2.61 mmol), bis(4-nitrophenyl) carbonate (3.97 g, 13.05 mmol) and DIEA (1.01 g, 7.83 mmol) in DMF (52.00 mL) was stirred at room temperature for 16h under N2 atmosphere, the reaction was monitored by LCMS. After completion, the mixture was concentrated and the residue was purified by FCC (eluting with MeOH / DCM, from 0% to 7% in 15 min) to afford 4-((S)-2-((S)- 2-(3-(2-(2,5-dioxo-2,5-dihydro-lH-pyrrol-l-yl)ethoxy)propanamido)-3-methylbutanamido)-5-ureidopentanamido)benzyl (4-nitrophenyl) carbonate (1.15 g, 1.55 mmol, yield: 59.6%) as a yellow solid. LCMS (ESI) calcd. for C34H41N7O12 [M+H]+m / z 740.3, found: 740.7.Step 9: Synthesis of tert-butyl (4-((S)-2-((S)-2-(3-(2-(2,5-dioxo-2,5-dihydro-lH-pyrrol-l-yl)eth- oxy)propanamido)-3-methylbutanamido)-5-ureidopentanamido)benzyl) ethane-1,2- diylbis(methylcarbamate )

[0353] A mixture of 4-((S)-2-((S)-2-(3-(2-(2,5-dioxo-2,5-dihydro-lH-pyrrol-l-yl)eth- oxy)propanamido)-3-methylbutanamido)-5-ureidopentanamido)benzyl (4-nitrophenyl) carbonate (1.00 g, 1.35 mmol), tert-butyl methyl(2-(methylamino)ethyl)carbamate (0.25 g, 1.35 mmol) and DIEA (0.52 g, 4.06 mmol) in DMF (10.00 mL) was stirred at 0°C for 0.5h under N2 atmosphere, the reaction was monitored by LCMS. After completion, the mixture was purified by reverse phase column (eluting with EEO / MeCN, from 5% to 33% in 15 min) to afford tertbutyl (4-((S)-2-((S)-2-(3-(2-(2,5-dioxo-2,5-dihydro-lH-pyrrol-l-yl)ethoxy)propanamido)-3- methylbutanamido)-5-ureidopentanamido)benzyl) ethane- 1 ,2-diylbis(methylcarbamate) (800 mg, 1.01 mmol, yield: 74.8%) as a white solid. LCMS (ESI) calcd. for C37H56N8O11 [M+H]+m / z 789.4, found: 789.8.Step 10: Synthesis of 4-((S)-2-((S)-2-(3-(2-(2,5-dioxo-2,5-dihydro-lH-pyrrol-l-yl)ethoxy)pro- panamido)-3-methylbutanamido)-5-ureidopentanamido)benzyl me thy 1(2 -(methylamino) ethyl) carbamate

[0354] A mixture of tert-butyl (4-((S)-2-((S)-2-(3-(2-(2,5-dioxo-2,5-dihydro-lH-pyrrol-l- yl)ethoxy)propanamido)-3-methylbutanamido)-5-ureidopentanamido)benzyl) ethane-1,2- diylbis(methylcarbamate) (800 mg, 1.01 mmol) in TFA (5.00 mL) and DCM (10.00 mL) was stirred at room temperature for 10 minutes under N2 atmosphere, the reaction was monitored by LCMS. After completion, the mixture was concentrated and the residue was purified by reverse phase column (eluting with EEO / MeCN, from 2% to 11% in 15 min) to afford 4-((S)-2- ((S)-2-(3-(2-(2,5-dioxo-2,5-dihydro-lH-pyrrol-l-yl)ethoxy)propanamido)-3-methyl- butanamido)-5-ureidopentanamido)benzyl methyl(2-(methylamino)ethyl)carbamate (467 mg, 0.68 mmol, yield: 67.1%) as a white solid. LCMS (ESI) calcd. for C32H48N8O9 [M+H]+m / z 689.4, found: 689.9.Example 40. Synthesis of LD-003 and LD-022 4-((S)-2-((S)-2-(3-(2-(2,5-dioxo-2,5-dihydro- lH-pyrrol-l-yl)ethoxy)propanamido)-3-methylbutanamido)-5-ureidopentanamido)benzyl 4-(3-(5-((64S,4S,Z)-4-((lr,2R,3S)-2,3-dimethylcyclopropane-l-carboxamido)-l1-ethyl-10,10-dimethyl-5,7-dioxo-l1H-8-oxa-62,63-diaza-2(4,2)-thiazola-l(5,3)-indola-6(2,4)-bicy- clo[3.1.1]heptanacycloundecaphane-l2-yl)-6-((S)-l-methoxyethyl)pyridin-3-yl)prop-2-yn- l-yl)piperazine-l-carboxylatecarboxamido)-lI-ethyl-10,10-dimethyl-5, 7-dioxo-l1H-8-oxa-62, 63-diaza-2(4,2)-thiazola-l (5, 3)- indola-6(2, 4)-bicyclo[ 3.1.1 ]heptanacycloundecaphane-l2-yl)-6-( (S) - 1 -methoxy ethyl)pyridin- 3- yl)prop-2-yn-l-yl)piperazine-l-carboxylate

[0355] A mixture of 5-((64S,4S,Z)-4-((lr,2R,3S)-2,3-dimethylcyclopropane-l-carboxam- ido)-l1-ethyl-10,10-dimethyl-5, 7-dioxo-l1H-8-oxa-62,63-diaza-2(4,2)-thiazola-l(5,3)-indola- 6(2,4)-bicyclo[3.1.1]heptanacycloundecaphane-l2-yl)-6-((S)-l-methoxyethyl)pyridin-3-yl trifluoromethanesulfonate (250 mg, 0.28 mmol), tert-butyl 4-(prop-2-yn-l-yl)piperazine-l -carboxylate (33 mg, 0.42 mmol), Cui (11 mg, 0.056 mmol), TEA (86 mg, 0.85 mmol) and Pd(PPhs)4 (50 mg, 0.043 mmol) in DMF (3 mL) was stirred at 100°C for 2 h under N2 atmosphere, the reaction was monitored by LCMS. After completion, the mixture was diluted with EtOAc (20 mL) and H2O (30 mL). The organic layer was separated, washed with brine (30 mL), dried over anhydrous Na2SO4 and concentrated to give the crude product. The crude product was purified by silica gel column chromatography (eluting with MeOH / DCM from 0% to 10% ) to give tert-butyl 4-(3-(5-((64S,4S,Z)-4-((lr,2R,3S)-2,3-dimethylcyclopropane-l-car- boxamido)-l1-ethyl-10,10-dimethyl-5,7-dioxo-l1H-8-oxa-62,63-diaza-2(4,2)-thiazola-l(5,3)- indola-6(2,4)-bicyclo[3.1.1]heptanacy cl oundecaphane-l2-yl)-6-((S)-l -meth oxy ethyl)pyri din-3- yl)prop-2-yn-l-yl)piperazine-l -carboxylate (217 mg, 80.7%) as a brown foam. LCMS (ESI) calcd. for CssEfcsNsCLS [M+H]+m / z 961.5, found: 961.7Step 2: Synthesis of (lr,2R,3S)-N-((64S,4S,Z)-l l-ethyl-l2-(2-((S)-l-methoxyethyl)-5-(3-(piper- azin-l-yl)prop-l-yn-l-yl)pyridin-3-yl)-10,10-dimethyl-5, 7-dioxo-l1H-8-oxa-62,63-diaza-2(4, 2)-thiazola-l(5,3)-indola-6(2, 4)-bicyclo[3.1.1 ]heptanacycloundecaphane-4-yl)-2, 3-dimethylcy- clopropane-1 -carboxamide

[0356] To a stirred solution of tert-butyl 4-(3-(5-((64S,4S,Z)-4-((lr,2R,3S)-2,3-dimethylcy- clopropane- 1 -carboxamido)- 1 Eethyl- 10,10-dimethyl-5,7-dioxo- 11H-8-oxa-62,63-diaza-2(4,2)- thiazola- 1 (5,3)-indola-6(2,4)-bicyclo[3.1.1 ]heptanacycloundecaphane- 12-yl)-6-((S)- 1 -m ethoxy - ethyl)pyridin-3-yl)prop-2-yn-l-yl)piperazine-l -carboxylate (215 mg, 0.22 mmol) in dichloromethane (3 mL) was added TFA (1 mL) dropwisely at rt, the resulting mixture was stirred at rt for 2 h. The reaction mixture was diluted with DCM (20 mL) and basified to neutral with sat. aq. NaHCCh solution. The organic layer was separated, dried over anhydrous ISfeSCU and concentrated to give crude (lr,2R,3S)-N-((64S,4S,Z)-l l-ethyl-l2-(2-((S)-l-methoxyethyl)-5-(3-(pi- perazin-l-yl)prop-l-yn-l-yl)pyridin-3-yl)-10,10-dimethyl-5,7-di oxo-11H-8-oxa-62,63-diaza- 2(4,2)-thiazola-l(5,3)-indola-6(2,4)-bicyclo[3.1.1]heptanacycloundecaphane-4-yl)-2,3-dime- thylcyclopropane-1 -carboxamide (187 mg ,98.9%) as a yellow foam. LCMS (ESI) calcd. for C48H6ON805S [M+H]+m / z 861.4, found: 862.1Step 3: Synthesis of 4-((S)-2-((S)-2-(3-(2-(2,5-dioxo-2,5-dihydro-lH-pyrrol-l-yl)ethoxy)pro- panamido)-3-methylbutanamido)-5-ureidopentanamido)benzyl 4-(3-(5-((64S,4S,Z)-4- ((lr,2R,3S)-2, 3-dimethylcyclopropane-l-carboxamido)-lI-ethyl-10,10-dimethyl-5, 7-dioxo-l1H- 8-oxa-62, 63-diaza-2(4,2)-thiazola-l(5,3)-indola-6(2, 4)-bicyclo[3.1.1 ]heptanacycloundeca- phane-l2-yl)-6-((S)-l-methoxyethyl)pyridin-3-yl)prop-2-yn-l-yl)piperazine-l-carboxylate

[0357] To a stirred solution of crude (lr,2R,3S)-N-((64S,4S,Z)-l l-ethyl-l2-(2-((S)-l-meth- oxyethyl)-5-(3-(piperazin-l-yl)prop-l-yn-l-yl)pyridin-3-yl)-10,10-dimethyl-5,7-dioxo-l1H-8- oxa-62,63-diaza-2(4,2)-thiazola-l(5,3)-indola-6(2,4)-bicyclo[3.1.1]heptanacycloundecaphane- 4-yl)-2,3 -dimethylcyclopropane- 1 -carboxamide (95 mg, 0.13 mmol) in DMF (1.5 mL) were added DIEA (45 mg, 0.35 mmol) and a solution of 4-((S)-2-((S)-2-(3-(2-(2,5-dioxo-2,5-dihy- dro-lH-pyrrol-l-yl)ethoxy)propanamido)-3-methylbutanamido)-5-ureidopentanamido)benzyl (4-nitrophenyl) carbonate (100 mg, 0.12 mmol) in DMF (1.5 mL) at rt, the resulting mixture was stirred at rt for 18 h. The reaction mixture was concentrated to give the crude product. The crude product was purified by pre-HPLC (eluting with CH3CN / H2O(0.1% NH4HCO3) from 20% to 80%) to give 4-((S)-2-((S)-2-(3-(2-(2,5-dioxo-2,5-dihydro-lH-pyrrol-l-yl)ethoxy)pro- panamido)-3-methylbutanamido)-5-ureidopentanamido)benzyl 4-(3-(5-((64S,4S,Z)-4- ((lr, 2R, 3 S)-2,3-dimethylcy cl opropane-1 -carboxamido)-! Eethyl- 10,10-dimethyl-5,7-di oxo-11H-8-oxa-62,63-diaza-2(4,2)-thiazola-l (5,3)-indola-6(2,4)-bicyclo[3.1.1 ]heptanacycloundeca- phane-l2-yl)-6-((S)-l-m ethoxy ethyl)pyri din-3 -yl)prop-2-yn-l-yl)piperazine-l -carboxylate (62.2 mg, 35.5%) as a white solid. LCMS (ESI) calcd. for C76H96N14O14S [M+H]+m / z 1461.7, found: 1462.0. 'HNMR (400 MHz, DMSO-cf.) 8 9.94 (s, 1H), 8.78 (s, 1H), 8.44 - 8.31 (m, 2H), 8.05 (d, J= 7.4 Hz, 1H), 7.88 - 7.65 (m, 4H), 7.56 (d, J= 7.6 Hz, 2H), 7.26 (d, J=8.3 Hz, 2H), 6.97 (s, 2H), 5.92 (dd, J= 16.1, 8.2 Hz, 2H), 5.37 (s, 2H), 4.97 (s, 2H), 4.63 (d, J = 11.1 Hz, 1H), 4.46 (d, J = 4.2 Hz, 1H), 4.39 - 4.20 (m, 3H), 4.22 - 4.11 (m, 1H), 4.09 - 3.98 (m, 1H), 3.53 (dd, J= 18.6, 7.7 Hz, 6H), 3.47 - 3.34 (m, 5H), 3.29 - 3.25 (m, 2H), 3.18 (d, J=23.3 Hz, 3H), 3.12 (dd, J= 15.1, 7.0 Hz, 1H), 3.04 - 2.85 (m, 3H), 2.60 (d, J= 5.5 Hz, 1H), 2.42 (dd, J= 13.2, 6.7 Hz, 3H), 2.31 (dd, J= 12.8, 7.3 Hz, 2H), 2.18 - 2.06 (m, 1H), 1.94 (dd, J= 13.4, 6.6 Hz, 1H), 1.66 (s, 1H), 1.54 (d, J= 8.8 Hz, 2H), 1.34 (d, J= 5.9 Hz, 3H), 1.18 (d, J = 24.3 Hz, 3H), 1.06 (dd, J= 10.2, 5.6 Hz, 4H), 0.83 (dt, J= 12.9, 8.9 Hz, 8H), 0.31 (s, 3H). Example 41. Synthesis of LD-022. 2-(4-(5-((64S.,4S.,Z)-4-((lr.,2R.,3S)-2.,3-dimethylcvcloDro- Dane-l-carboxamido)-10,10-dimethyl-5,7-dioxo-l1-(2,2,2-trifluoroethyl)-l1H-8-oxa-62,63- diaza-2(4,2)-thiazola-l(5,3)-indola-6(2,4)-bicvdo[3.1.1]heDtanacvcloundecaphane-l2-yl)- 6-((S)-l-methoxyethyl)pyridin-3-yl)-N,2,2-trimethylbut-3-vnamido)ethyl (4-((S)-2-((S)-2- (3-(2-(2,5-dioxo-2,5-dihvdro-lH-Dyrrol-l-yl)ethoxy)proDanamido)-3-methylbutanamido)-5-ureidopentanamido)benzyl) ethane-l,2-diylbis(methylcarbamate)Step 1: Synthesis of 2-(4-(5-((64S,4S,Z)-4-((lr,2R,3S)-2,3-dimethylcyclopropane-l-carboxam- ido)-10,10-dimethyl-5, 7-dioxo-lI-(2,2,2-trifluoroethyl)-lIH-8-oxa-62,63-diaza-2(4,2)-thiazola- l(5,3)-indola-6(2, 4)-bicyclo[ 3.1.1 ]heptanacycloundecaphane-l2-yl)-6-((S)-l-methoxy- ethyl)pyridin-3-yl)-N, 2, 2-trimethylbut-3-ynamido)ethyl ( 4-nitrophenyl) carbonate

[0358] A mixture of (lr,2R,3S)-N-((64S,4S,Z)-l2-(5-(4-((2-hydroxyethyl)(methyl)amino)- 3 , 3 -dimethyl-4-oxobut- 1 -yn- 1 -yl)-2-((S)- 1 -methoxy ethyl)pyri din-3 -y 1 ) - 10 , 10-dimethyl-5 , 7 - dioxo-l1-(2,2,2-trifluoroethyl)-l1H-8-oxa-62,63-diaza-2(4,2)-thiazola-l(5,3)-indola-6(2,4)-bicy- clo[3.1.1]heptanacycloundecaphane-4-yl)-2,3-dimethylcyclopropane-l-carboxamide (100 mg, 0.1 mmol), bis(4-nitrophenyl) carbonate (158 mg, 0.5 mmol) and DIEA (40 mg, 0.3 mmol) in DMF (1 mL) was stirred at room temperature for 1 h under N2 atmosphere, the reaction was monitored by LCMS. After completion, the mixture was concentrated and the residue was purified by FCC (eluting with MeOH / DCM, from 0% to 7% in 15 min) to afford 2-(4-(5- ((64S,4S,Z)-4-((lr,2R,3S)-2,3-dimethylcyclopropane-l-carboxamido)-10,10-dimethyl-5,7-di- oxo-l1-(2,2,2-trifluoroethyl)-l1H-8-oxa-62,63-diaza-2(4,2)-thiazola-l(5,3)-indola-6(2,4)-bicy- clo[3.1.1 ]heptanacy cl oundecaphane-l2-yl)-6-((S)-l -methoxy ethyl)pyri din-3 -yl)-N, 2, 2-trime- thylbut-3-ynamido)ethyl (4-nitrophenyl) carbonate (100 mg, yield: 85%) as a yellow solid.LCMS (ESI) calcd. for C34H41N7O12 [M+H]+m / z 1125.4, found: 1126.6.Step 2: Synthesis of 2-(4-(5-((64S,4S,Z)-4-((lr,2R,3S)-2,3-dimethylcyclopropane-l-carboxam- ido)-10,10-dimethyl-5, 7-dioxo-l1-(2,2,2-trifluoroethyl)-!1H-8-oxa-62,63-diaza-2(4,2)-thiazola- l(5,3)-indola-6(2, 4)-bicyclo[ 3.1.1 ]heptanacycloundecaphane-l2-yl)-6-((S)-l-methoxy- ethyl)pyridin-3-yl)-N,2,2-trimethylbut-3-ynamido)ethyl (4-((S)-2-((S)-2-(3-(2-(2,5-dioxo-2,5- dihydro-lH-pyrrol-l-yl)ethoxy)propanamido)-3-methylbutanamido)-5-ureidopentan- amido)benzyl) ethane-1, 2-diylbis(methylcarbamate)

[0359] A mixture of 2-(4-(5-((64S,4S,Z)-4-((lr,2R,3S)-2,3-dimethylcyclopropane-l-car- boxamido)-10,10-dimethyl-5, 7-dioxo-lx-(2, 2, 2-trifluoroethyl)-l1H-8-oxa-62,63-diaza-2(4, 2)- thiazola- 1 (5,3)-indola-6(2,4)-bicyclo[3.1.1 ]heptanacycloundecaphane- 12-yl)-6-((S)- 1 -m ethoxy - ethyl)pyridin-3-yl)-N,2,2-trimethylbut-3-ynamido)ethyl (4-nitrophenyl) carbonate (100 mg, 0.09 mmol), 4-((S)-2-((S)-2-(3-(2-(2,5-dioxo-2,5-dihydro-lH-pyrrol-l-yl)ethoxy)pro- panamido)-3-methylbutanamido)-5-ureidopentanamido)benzyl methyl(2-(methyla- mino)ethyl)carbamate (61 mg, 0.09 mmol) and DIEA (34 mg, 0.26 mmol) in DMF (1 mL) was stirred at 0°C for 0.5h under N2 atmosphere, the reaction was monitored by LCMS. After completion, the mixture was purified by reverse phase column (eluting with EEO / MeCN, from 5%to 33% in 15 min) to afford 2-(4-(5-((64S,4S,Z)-4-((lr,2R,3S)-2,3-dimethylcyclopropane-l- carboxamido)-10,10-dimethyl-5,7-dioxo-l1-(2,2,2-trifluoroethyl)-l1H-8-oxa-62,63-diaza- 2(4,2)-thiazola-l(5,3)-indola-6(2,4)-bicyclo[3.1.1]heptanacycloundecaphane-l2-yl)-6-((S)-l- methoxyethyl)pyridin-3-yl)-N,2,2-trimethylbut-3-ynamido)ethyl (4-((S)-2-((S)-2-(3-(2-(2,5- dioxo-2,5-dihydro-lH-pyrrol-l-yl)ethoxy)propanamido)-3-methylbutanamido)-5-ureidopen- tanamido)benzyl) ethane-l,2-diylbis(methylcarbamate) (44.8 mg, yield: 30%) as a white solid. LCMS (ESI) calcd. for C83H106F3N15O17S [M+H]+m / z 1674.8, found: 1676.0. 'HNMR (400 MHz, DMSO-de) 8 9.93 (s, 1H), 8.77 (s, 1H), 8.41-8.38 (m, 2H), 8.05 (d, J = 7.2 Hz, 1H), 7.85-7.73 (m, 4H), 7.55 (d, J = 8.4 Hz, 2H), 7.24-7.22 (m, 2H), 6.97 (s, 1H), 5.95-5.86 (m, 2H), 5.60-5.49 (m, 2H), 5.37-5.28 (m, 3H), 4.95-4.74 (m, 4H), 4.67 (d, J = 10.8 Hz, 1H), 4.48- 4.45 (m, 1H), 4.38-4.32 (m, 1H), 4.23-4.02 (m, 4H), 3.97-3.88 (m, 1H), 3.60- 3.41(m, 7H), 3.39-3.35 (m, 4H), 3.29-3.09 (m, 10H), 3.04-2.87 (m, 4H), 2.83- 2.58 (m, 7H), 2.53-2.51 (m, 2H), 2.46 - 2.26 (m, 6H), 2.14-2.09 (m, 2H), 1.99-1.87 (m, 2H), 1.76-1.53 (m, 4H), 1.47 (s, 4H), 1.34 (d, J = 6.0 Hz, 3H), 1.25- 1.12 (m, 4H), 1.08-1.04 (m, 5H), 0.87 (s, 2H), 0.83-0.78 (m, 4H), 0.25 (s, 3H).Example 42. Conjugation and Characterization of ADCsIn vitro Cysmab ADC preparation

[0360] Antibody (typically 5-10 mg) was incubated with rProtein A Sepharose resin (GE) at a ratio of 10 mg Ab to 1 ml resin in PBS for 15 minutes with mixing in an appropriately sized disposable column. Cysteine HCI was added to a final concentration of 20 mM and incubated with agitation for 30 min at room temperature to allow the reactive cysteines to bedeblocked. The resin was rapidly washed with 50 column volumes PBS on a vacuum manifold in multiple additions. The resin was then resuspended in an equal volume PBS containing 250 nM CuCh. Reformation of antibody interchain disulfides was monitored by taking time points. At each time point, 25 pL of resin slurry was removed, 1 pL of 20 mM MC-valcit- MMAE was added, and the tube flicked several times. The resin was spun down, supernatant removed, and then eluted with 50 pL Antibody elution buffer (Thermo). The resin was pelleted and the supernatant analyzed by reverse phase chromatography using an Agilent PLRP-S 4000A 5um,4.6x50mm column (Buffer A is water, 0.1%TFA, Buffer B Acetonitrile, 0.1%TF A, column held at 80°C, Flowrate 1.5 ml / min; Gradient O minutes-30% B, 5 minutes- 45% B, 6.5 min-100% B, 8 minutes- 100%B, 10 minutes-30%).

[0361] Once determined that the antibody has reformed its interchain disulfide bonds, the resin was washed with 10 column volumes PBS and the resin was resuspended in an equal volume PBS and 12 equivalents of the appropriate linker-payload (20 mM)in DMSO was added and then incubated at room temperature for 2 hours. The resin was then washed with 50 column volumes PBS to remove excess linker-payload. The ADC was eluted from the protein A resin with antibody elution buffer. The ADC was then dialyzed into PBS. The material was then concentrated using a centrifugal concentrator using an Amicon Ultra-15, 50KDa, regenerated cellulose (Millipore, UFC0905024), to 4.5 mg / ml and filtered sterilely through 0.22pm sterile PVDF Filter, 25mm (Millapore, SLGV013SL) and stored at 4°C. The following analyses were performed-analytical SEC to determine percent monomer, reduced mass spectroscopy to determine DAR,LAL test to determine endotoxin load and protein concentration was determined by A280 utilizing extinction coefficient and molecular weight of antibody. All in vitro materials were >90%monomer.Percent aggregation's determined by comparison of the area of the high- molecular-weight peak absorbance at 210 and 280 nm with the area of the peak absorbance for monomeric ADC.HRMS data(protein method)indicated a dominant mass of the heavy chain+2 species, giving a DAR of ~4.0 was calculated by comparing MS intensities of peaks for DARI DAR2 and DAR3 species.General Methodology

[0362] Drug-to-antibody ratio (DAR) of exemplary ADCs was determined by liquid chromatography-mass spectrometry (LC / MS) according to the following method. For all LC methods, mobile phase A was purified MS grade water (Honeywell, LC015- 1), mobile phase B was MS grade 80% Isopropanol (Honeywell LC323-1): 20% acetonitrile (Honeywell, LC015-1), LC323-1), supplemented with 1% of formic acid (FA) (Thermo Scientific, 85178). The column temperature was set at 80°C. A general MS method was optimized for all ADCs synthesized. The column used for analysis was an Agilent PLRP-S 4000 A; 2.1x150 mm, 8 um (Agilent, PL1912-3803). Flowrate used was 0.3 ml / min. The gradient used was 0-0.75 minute 95%A, 0.76-1.9 minute 75%A, 1.91-11.0 minute 50% A, 11.01-11.50 minute 10% A, 11.51- 13.50 minute 95%A, 13.51-18 minute 95% A on an Acuity Bio H-Class Quaternary UPLC (Waters). MS system was Xevo G2-XS QToF ESI mass spectrometer (Waters)and data acquired from 1.5-11 minutes and masses were analyzed between 15000-80000 daltons. DAR was determined from the deconvoluted spectra or UV chromatogram by summing the integrated MS (total ion current) or UV (280 nm) peak area of unconjugated and conjugated givenspecies (mAb or associated fragment), weighted by multiplying each area by the number of drugs attached. The summed, weighted areas were divided by the sum of total area and the results produced a final average DAR value for the full ADC.Size exclusion chromatography (SEC)

[0363] SEC was performed to determine the quality of the ADCs and aggregation percentage (%) after purification. The analysis was performed on analytical column Superdex 200 Increase 5 / 150 GL (GE Healthcare, 28990945) in isocratic conditions 100%PBS pH 7.2 ((Hy- clone SH30028.03)), flow 0.45 ml / min for 8 minutes. The % aggregate fraction of the ADC sample was quantified based on the peak area absorbance at 280 nm. Calculation was based on the ratio between the high molecular weight eluent at 280 nm divided by the sum of peak area absorbance at the same wavelength of the high molecular weight and monomericeluents multiplied by 100%.Data was acquired on an Agilent Bio-Inert 1260 HPLC outfitted with a Wyatt miniDAWN light scattering and Treos refractive index detectors (Wyatt Technologies, Santa Barbara, CA).In vitro assessment of panRAS antibody drug conjugates in multiple cancer cell line

[0364] The RAS antibody drug conjugates were tested against the following cancer cell lines:LU65: JCRB No. JCRB0079 cultured in RPMI-1640+10%FBS;HP AC: ATCC No.CRL-2119 cultured in DMEM:HAM's F12+5%FBS; NC1-H727: ATCC No.CRL-5815 cultured in RPMI-1640+10%FBS; and / or SW1271 : ATCC No.CRL-2177 cultured in DMEM+10%FBS.Inhibition of cell proliferation and survival

[0365] The ability of the RAS antibody drug conjugates to inhibit cell proliferation and survival was assessed using the Promega CellTiter-Glo® proliferation assay.

[0366] Cell lines were cultured in media that is optimal for their growth at 5% CO2, 37°C in a tissue culture incubator. Prior to seeding for the proliferation assay, the cells were split at least 2 days before the assay to ensure optimal growth density. On the day of seeding, cell viability and cell density were determined using a cell counter (Vi-Cell XR Cell Viability Analyzer, Beckman Coulter). Cells with higher than 85%viability were seeded in white clear bottom 384-well TC treated plates (Corning cat.#3765). Cells were seeded at a density of 1,000 cells per well in 45pL of standard growth media.Plates were incubated at 5% CO2, 37°C overnight in a tissue culture incubator. The next day, indicated compounds and ADCs were preparedat 10X in standard growth media. The prepared compounds and ADCs were then added to the cells resulting in final concentrations of 0.005-100 nM and a final volume of 50 pL per well. Each drug concentration was tested in quadruplets. Plates were incubated at 5% CO2, 37°C for 5 days in a tissue culture incubator, after which cell viability was assessed through the addition of 25pL of CellTiter GloR (Promega,cat#G7573), a reagent which lyses cells and measures total adenosine triphosphate (ATP) content. Plates were incubated at room temperature for 10 minutes to stabilize luminescent signals prior to reading using a luminescence reader (EnVision Multilabel Plate Reader, PerkinEImer). To evaluate the effect of the drug treatments, luminescent counts from wells containing untreated cells (100% viability) were used to normalize treated samples. A variable slope model was applied to fit a nonlinear regression curve to the data in GraphPad PRISM version 7.02 software. IC50 values were extrapolated from the resultant curves.

[0367] The concentrations of treatment required to inhibit 50% of cell growth or survival (IC50) were calculated with representative IC50 values of the cell lines tested summarized in Table 5. The panRAS ADCs tested (in the table below the “RAS ADC”is KAD-022) on representative cell lines demonstrated in vitro efficacy relative to the isotype matched non- targeting control ADC.

[0368] These studies indicate that RAS ADCs were capable of inhibiting cell proliferation on various cancer cell lines expressing antigens of interest. No cytotoxic activity was observed by the isotype matched non-targeting controls on the cancer cell lines tested.Table 5. RAS ADC CytotoxicityExample 43. Biological Activity ResultsRas: RAFI HTRF Assay

[0369] This example is to verify the binding between RAS protein and its interacting protein (S0S1 or RAFI). When RAS exists with S0S1 or RAF, the two interact to make the energy donor and receptor bound to it close enough, and then when the donor is excited by an external light source, energy resonance transfer occurs, thereby exciting the receptor and emitting a specific wavelength of emitted light, the FRET signal is detected.

[0370] Specific experimental methods: 20 nM purified RAS protein (e.g. KRAS-G12C, G12D, G12V, G12S, WT) was incubated with the drug to be screened (the drug was diluted in a 3-fold gradient to a final concentration of 1000 nM) at room temperature for 1 h. Subsequently, 30 nM purified SOSl-Cat was added and incubated at room temperature for 0.5-1 h. After adding the detection antibody (PerkinElmer, Cisbio, HTRF antibody), the value was measured according to the manufacturer's instructions.Representative compound results

[0371] The representative RAS inhibitor D significantly inhibited the interaction of RAFI with active RASMutantprotein or RASWTprotein.

[0372] The inhibitory IC50 of the compounds of the present invention was shown in Table6Table 6. RAS-GTP & Raf Disruption / HTRF Assay*Cell viability assay

[0373] Selective screening using RAS-driven and RAS-non-driven cells: (1) RAS-driven cells, including cells with persistent RAS activation due to RAS mutations and upstream EGFR activation. Cells that are continuously activated due to RAS mutations, such as KRAS G12D (AsPC-1, HP AC, AGS, etc.) mutant cells, KRAS G12C (NCI-H358, MIAPaCa-2, etc.) KRAS G13D (LOVO, HCT15, etc.) mutant cells, etc. Cells with continuous activation of RAS due to EGFR mutations, such as EGFRExl9del (PC-9, etc.) mutant cells, EGFRT790M / L858R (NCI- H1975, etc.) mutant cells, etc.;

[0374] (2) Non-RAS driven cells, including BRAFV600E (A375, SK,) -MEL-3, etc.) mutant cells, RASWT (BxPC-3, etc.) cells, etc.

[0375] Specific experimental methods: The above cells were seeded in a 96-well plate at a density of 1000-10000 per well. Drugs were diluted in DMSO to make a 10 mM stock solution. Subsequently, the drug was diluted in a 3 -fold gradient to a final concentration of 1000nM. The cells were treated with the drug for 5 days. Cell viability was then detected by the MTS method.Representative Compound Results

[0376] The representative RAS inhibitors significantly inhibited the cell viability of KRAS mutant cells: MIA PACA-2(KRAS G12C), NCI-H358 (KRAS G12C), NCI-H2122 (KRAS G12C) HPAF II (KRAS G12D), AGS (KRAS G12D), ASPC-1(KRAS G12D), HP AC (KRAS G12D), LS174T (KRAS G12D), SW480 (KRAS G12V), SW620 (KRAS G12V), CAL-62 (KRAS G12R), LOVO (KRAS G13D) Calu6 (KRAS Q61K) and HCC827 (EGFR)..

[0377] The inhibitory IC50 of the compounds of the present invention was shown in Table 7.Table 7. Activity of Compounds in KRAS Cell Viability Assay*Anti-proliferation IC50 Values of each cell line

[0378] Methods: The purpose of this cellular assay was to determine the effects of test compounds on the proliferation of human cancer cell lines: AGS, AsPC-1, SW620, HCT-116, LOVO, M0LM13 and A375 cells over a 5-day treatment using Cell Counting Kit-8 (CCK8). Cells were seeded 1000 cells / well (AGS), 3000 cells / well (AsPC-l)1500, 2000 cells / well (SW620), 2000 cells / well (HCT166), 2000 cells / well (LOVO), 2000 cells / well (M0LM13), 2000 cells / well (A375) in 96-well assay plates and incubated overnight. On the day of the assay, diluted compounds were then added to a final concentration of 0.5% DMSO. After 5 days incubation, a tenth of the volume of cell counting kit 8 (Dnjindo-CK04) was added into each well. Read the signal (OD450) using Biotek synergy Hl plate reader after incubation. IC50 was determined by Graphpad 8.0.

[0379] The inhibitory IC50 of representative panRAS ADC of the present invention was shown in Table 8.Table 8. Cellular Potency of Representative panRAS ADC and AntibodyResults

[0380] Results from vitro cell proliferation assays showed that Atezolizumab-LD-003 and Atezolizumab-LD-022 exhibited more potent inhibitory effect on cell growth compared to Ate- zolizumab; Cetuximab-LD-003, Cetuximab-LD-022 exhibited more potent inhibitory effect on cell growth compared to Cetuximab.

Claims

CLAIMS1. An antibody-drug conjugate of formula (IA)((A) wherein,Ab is an antibody or an antigen-binding fragment thereof;L is a conjugate linker that covalently attaches Ab to D; optionally wherein L comprises: an attachment group; at least one bridging spacer group; and at least one cleavable group, further optionally at least one cleavable group comprising a pyrophosphate group and / or a self-immola- tive group.D is a RAS inhibitor; p is an integer from 1 to 16; optionally wherein p is from 1 to 6 or from 2 to 4, or p is 2 or 4; optionally wherein p is determined by liquid chromatography-mass spectrometry (LC-MS).

2. The antibody-drug conjugate of claim 1, wherein the RAS inhibitor D has a formula selected from:or a stereoisomer, a pharmaceutically acceptable salt, a metabolite, a prodrug, or a solvate thereof, or a solvate of the pharmaceutically acceptable salt thereof, whereinA is optionally substituted 5 to 6-membered heterocycloalkylene, optionally substituted 5 to 6-membered arylene, or optionally substituted 5 to 6-membered heteroarylene;B is optionally substituted 3 to 6-membered heterocycloalkylene, optionally substituted 3 to 6-membered heterocycloalkenylene, optionally substituted 4 to 11 -membered bicyclic cycloalkylene, or optionally substituted 4 to 11 -membered bicyclic heterocycloalkylene;G is optionally substituted Ci-6 alkylene;U and T are each independently absent, a bond, O, S, -NR3, or optionally substituted Ci-6 alkylene;R8and R9are each independently hydrogen, deuterium, halogen, hydroxy, cyano, or optionally substituted C1-3 alkyl; or R8and R9combine with the atoms to which they are attached to form an optionally substituted C3-6 cycloalkyl or a carbonyl;R10and R11are each independently hydrogen, deuterium, halogen, hydroxy, cyano, or optionally substituted C1-3 alkyl; or R10and R11combine with the atoms to which they are attached to form an optionally substituted C3-6 cycloalkyl or a carbonyl;R12and R13are each independently hydrogen, deuterium, halogen, hydroxy, optionally substituted C1-3 alkyl, -O(Ci-6 alkyl), -S(Ci-6 alkyl), or -N(CI-6 alkyl)(Ci-6 alkyl), wherein, the C1-6 alkyl may be further optionally substituted;RAis optionally substituted C3-6 cycloalkyl, optionally substituted C3-6 heterocycloalkyl, optionally substituted 5 to 8-membered aryl, optionally substituted 5 to 8-membered heteroaryl, optionally substituted 8 to 10-membered fused bicyclic aryl, or optionally substituted 8 to 10- membered fused bicyclic heteroaryl; each RBis independently hydrogen, C1-6 alkyl, C1-6 alkoxyl, C1-6 haloalkyl, C1-6 haloalkoxyl, optionally substituted C3-6 cycloalkyl, or optionally substituted C3-6 heterocycloalkyl; or, when n exceeds 1, any two RBcombine with the atoms to which they are attached to form a 3 to 6- membered ring, wherein the ring is optionally substituted with halogen, hydroxy, or C1-3 alkyl;X1is N or C;X2is N or -CRa-;X3is N or -CRb-;X4is N or -CRC-;X5is N or C;X6is S, O, N, or C;Ra, Rb, and Rcare each independently hydrogen, halogen, cyano, C1-3 alkyl, C1-3 alkoxyl, Ci- 3 haloalkyl, C1-3 haloalkoxyl, C3-6 cycloalkyl, or C3-6 heterocycloalkyl;R3is absent, hydrogen, C1-6 alkyl, or C1-6 haloalkyl, provided that when X6is O or S, R3is absent;E is a bond N, or -CRd-, wherein Rdis hydrogen, halogen, hydroxy, cyano, carboxyl, optionally substituted C1-6 alkyl, optionally substituted C1-6 alkoxyl, C 1-6 aminoalkyl, C1-6 hydroxyalkyl, or -NReRf; wherein Reand Rfare independently hydrogen or optionally substituted C1-6 alkyl;R4is hydrogen, optionally substituted C1-6 alkyl, optionally substituted C1-6 heteroalkyl, optionally substituted C3-10 cycloalkyl, optionally substituted C3-10 cycloalkenyl, optionally substituted C3-10 heterocycloalkyl, optionally substituted 6 to 10-membered aryl, optionally substituted5 to 10-membered heteroaryl,R5is hydrogen, C1-6 alkyl, or C3-6 cycloalkyl; furthermore, the C1-6 alkyl or C3-6 cycloalkyl may be further optionally substituted; or R4and R5combine with the atoms to which they are attached to form a ring, wherein the ring is optionally substituted 3 to 10-membered cycloalkyl, optionally substituted 3 to 10-mem- bered heterocycloalkyl, optionally substituted 3 to 6-membered cycloalkenyl, optionally substituted 4 to 11 -membered bicyclic cycloalkyl, or optionally substituted 4 to 11 -membered bicyclic heterocycloalkyl; whereinL, in the context of D, is absent, -CH2-, -C(O)-, -CHRg-, or -C(Rg)2-, wherein Rgis optionally substituted C1-6 alkyl;R6is hydrogen or optionally substituted C1-6 alkyl;R7is optionally substituted C1-6 alkyl, optionally substituted C1-6 heteroalkyl, optionally substituted C3-10 cycloalkyl, optionally substituted C3-10 heterocycloalkyl, optionally substituted 6 to 10-membered aryl, optionally substituted 5 to 10-membered heteroaryl; or L, R6and R7combine with the atoms to which they are attached to form a ring, wherein the ring is selected from optionally substituted 3 to 10-membered cycloalkyl, optionally substituted 3 to 10-membered heterocycloalkyl, optionally substituted 3 to 6-membered cycloalkenyl,optionally substituted 4 to 11 -membered bicyclic alkyl, or optionally substituted 4 to 11 -membered bicyclic heteroalkyl, optionally wherein D is attached to the conjugate linker L at the A, R1, R4, or R7) position ofD.

3. The antibody-drug conjugate of claim 1 or 2, wherein the RAS inhibitor D has a structure according to formula (II):or a stereoisomer, a pharmaceutically acceptable salt, a metabolite, a prodrug, or a solvate thereof, or a solvate of the pharmaceutically acceptable salt thereof, whereinA, G, X1, X2, X3, X4, X5, X6, R3, E, R8, R9, R10, R11, R12, and R13are defined as in claim 2;Y is CH or N;R1is hydrogen, Ci-6 alkyl, Ci-6 alkoxyl, Ci-6 haloalkyl, Ci-6 haloalkoxyl, Ci-6 hydroxyalkyl, Ci -6 aminoalkyl, optionally substituted C3-6 cycloalkyl, optionally substituted C3-6 heterocycloalkyl, optionally substituted 5 to 8-membered aryl, optionally substituted 5 to 8-membered heteroaryl, optionally substituted 8 to 10-membered fused bicyclic aryl, or optionally substituted 8 to 10-membered fused bicyclic heteroaryl; wherein the C1-6 alkyl, C1-6 alkoxyl, C1-6 haloalkyl, C 1-6 haloalkoxyl, or C1-6 hydroxyalkyl may be further optionally substituted; optionally wherein R1is hydrogen, C1-6 alkyl, C1-6 alkoxyl, C 1-6 haloalkyl, C 1-6 haloalkoxyl, C1-6 hydroxyalkyl, C1-6 aminoalkyl, optionally substituted C3-6 cycloalkyl, optionally substituted C3-6 heterocycloalkyl, optionally substituted 5 to 8-membered aryl, optionally substituted 5 to 8-membered heteroaryl, optionally substituted 8 to 10-membered fused bicyclic aryl, optionally substituted 8 to 10-membered fused bicyclic heteroaryl, optionally substituted -Ci-2alkylene-C3-6 cycloalkyl, optionally substituted -Ci-2alkylene-C3-6 heterocycloalkyl, optionally substituted -Ci-2alkylene-5 to 8-membered aryl, optionally substituted -Ci-2alkylene-5 to 8-membered heteroaryl, optionally substituted -Ci-2alkylene-8 to 10-mem- bered fused bicyclic aryl, and optionally substituted -Ci-2alkylene-8 to 10-membered fused bicyclic heteroaryl, further optionally wherein R1is hydrogen, Ci-6 alkyl, Ci-6 alkoxyl, Ci -6 haloalkyl, Ci-6 haloalkoxyl, Ci-6 hydroxyalkyl, Ci-6 aminoalkyl, optionally substituted C3-6 cycloalkyl, optionally substituted C3-6 heterocycloalkyl, optionally substituted 5 to 8-membered aryl, optionally substituted 5 to 8-membered heteroaryl, optionally substituted 8 to 10-membered fused bicyclic aryl, or optionally substituted 8 to 10-membered fused bicyclic heteroaryl); wherein, the C1-6 alkyl, C1-6 alkoxyl, C1-6 haloalkyl, C 1-6 haloalkoxyl, C1-6 hydroxyalkyl (optionally the C1-6 alkyl) is optionally substituted; further optionally wherein the C1-6 alkyl, C1-6 alkoxyl, C1-6 haloalkyl, C1-6 haloalkoxyl, or C1-6 hydroxyalkyl (optionally, the C1-6 alkyl) is further substituted, the substituent is C1-6 alkyl, C1-6 alkoxyl, C1-6 haloalkyl, C1-6 haloalkoxyl, C1-6 hydroxyalkyl, C 1-6 aminoalkyl, carbonyl, -(C=O)NR100R101, optionally substituted C3-6 cycloalkyl, optionally substituted C3-6 heterocycloalkyl, optionally substituted 5 to 8-membered aryl, optionally substituted 5 to 8- membered heteroaryl, optionally substituted 8 to 10-membered fused bicyclic aryl, or optionally substituted 8 to 10-membered fused bicyclic heteroaryl; optionally, the substituent is optionally substituted C3-6 cycloalkyl, optionally substituted C3-6 heterocycloalkyl, optionally substituted 5 to 8-membered aryl, optionally substituted 5 to 8-membered heteroaryl, optionally substituted 8 to 10-membered fused bicyclic aryl, or optionally substituted 8 to 10-membered fused bicyclic heteroaryl; further optionally, the substituent is optionally substituted C3-6 heterocycloalkylR100and R101are each independently hydrogen, deuterium, or optionally substituted Ci- 6 alkyl; or R100and R101combine with the atoms to which they are attached to form an optionally substituted C3-6 heterocycloalkyl;wherein optionally substituted means unsubstituted or substituted with one or more (e.g., 1, 2, or 3) substituents selected from the group consisting of deuterium, halogen, C1-6 alkyl, C1-6 hydroxyalkyl, and C1-6 deuteroalkyl;R2is optionally substituted C1-6 alkoxy or optionally substituted C1-6 alkyl;RMand RNare each independently hydrogen, halogen, hydroxy, cyano, carboxyl, C1-6 alkyl, C1-6 alkoxyl, C 1-6 haloalkyl, C1-6 haloalkoxyl, C1-6 hydroxyalkyl, C1-6 aminoalkyl, optionally substituted C3-6 cycloalkyl, or optionally substituted C3-6 heterocycloalkyl;whereinthe C1-6 alkyl, C1-6 alkoxyl, C1-6 haloalkyl, C1-6 haloalkoxyl, and C1-6 hydroxyalkyl is optionally substituted;R4and R5are as defined as in claim 2; optionally wherein R4and R5combine with the atoms to which they are attached to form a ring, wherein the ring is optionally substituted 3 to 10-membered cycloalkyl, optionally substituted 3 to 10-membered heterocycloalkyl, optionally substituted 3 to 6-membered cycloalkenyl, optionally substituted 4 to 11 -membered bicyclic cycloalkyl, or optionally substituted 4 to 11-membered bicyclic heterocycloalkyl.

4. The antibody-drug conjudate of any one of claims 1-3, wherein the RAS inhibitor D has a structure according to formula (III):or a stereoisomer, a pharmaceutically acceptable salt, a metabolite, a prodrug, or a solvate thereof, or a solvate of the pharmaceutically acceptable salt thereof, whereinA, G, X6, R3, and E are defined as in claim 2 or 3;Y, R1, R2, R4, and R5are defined as in claim 2 or 3;Raand Rbare each independently hydrogen, halogen, cyano, C1-3 alkyl, C1-3 alkoxyl, C1-3 haloalkyl, C1-3 haloalkoxyl, C3-6 cycloalkyl, or C3-6 heterocycloalkyl; wherein the number of heteroatoms in the 5 to 6-membered heterocycloalkylene, 5 to 6-membered heteroarylene, C3-5 heterocycloalkyl, C3-6 heterocycloalkyl, 5 to 6-membered heteroaryl, 8 to 10- membered fused bicyclic heteroaryl, C 1-6 heteroalkyl, C3-10 heterocycloalkyl, 5 to 10-membered heteroaryl, 3 to 10-membered heterocycloalkyl, or 4 to 11-membered bicyclic heteroalkyl is 1- 4, and wherein each heteroatom is independently selected from one or more of N, O and S.

5. The antibody-drug conjudate of any one of claims 1-4, wherein the RAS inhibitor D has a structure according to formula (IVa) or (IVb):or a stereoisomer, a pharmaceutically acceptable salt, a metabolite, a prodrug, or a solvate thereof, or a solvate of the pharmaceutically acceptable salt thereof, whereinA, G, X6, R3, and E are defined as in claim 2-4;Y, R1, R2, R4, and R5are defined as in any one of claims 2-4;Raand Rbare defined as in claim 2-4; optionally, in the 5 to 6-membered heterocycloalkylene, 5 to 6-membered heteroarylene, C3-5 heterocycloalkyl, C3-6 heterocycloalkyl, 5 to 6-membered heteroaryl, 8 to 10-membered fused bicyclic heteroaryl, C 1-6 heteroalkyl, C3-10 heterocycloalkyl, 5 to 10-membered heteroaryl, 3 to 10-membered heterocycloalkyl or 4 to 11 -membered bicyclic heteroalkyl, the heteroatom is independently selected from one or more of N, O, and S, and the number of the heteroatom is independently 1-4.

6. The antibody-drug conjugate of any one of claims 1-5, or a stereoisomer, a pharmaceutically acceptable salt, a metabolite, a prodrug, or a solvate thereof, or a solvate of the pharmaceutically acceptable salt thereof, wherein R4isR6RlL / NL, R6, and R7in the context of D are defined as in any one of claims 2-5; optionally, L, R6, and R7combine with the atoms to which they are attached to form a ring, wherein the ring is optionally substituted 3 to 10-membered cycloalkyl, optionally substituted 3 to 10-membered heterocycloalkyl, optionally substituted 3 to 6-membered cycloalkenyl, optionally substituted 4 to 11 -membered bicyclic cycloalkyl, or optionally substituted 4 to 11 -membered bicyclic heterocycloalkyl;further optionally, in the C1-6 heteroalkyl, C3-10 heterocycloalkyl, 5 to 10-membered heteroaryl, 3 to 10-membered heterocycloalkyl or 4 to 11 -membered bicyclic heteroalkyl, the heteroatom is independently N, O, or S, and the number of the heteroatom is independently 1 to 12.

7. The antibody-drug conjugate of any one of claims 1-6, wherein the RAS inihibitor D is selected from any one of the compounds in Table D, or a stereoisomer, a pharmaceutically acceptable salt, a metabolite, a prodrug, or a solvate thereof, or a solvate of the pharmaceutically acceptable salt thereof.

8. The antibody-drug conjugate of any one of claims 1-7, wherein the antibody-drug conjugate has the structure according to formula (IIA):, wherein:Li is an attachment group, that is joined or covalently linked to Ab and L2;L2 is a bridging spacer group, that is joined or covalently linked to Li and L3;L3 is a peptide group, that is joined or covalently linked to L2 and L4;L4 is a cleavable group, that is joined or covalently linked to L3 and D; p is the number of Ab couplings [L1-L2-L3-L4-D], selected from any integer between 1 and 16.

9. The antibody-drug conjugate of any one of claims 1-8, wherein LI, the attachment group, is formed from at least one reactive group selected from a maleimide group, thiol group, cyclooctyne group, and an azido group;the maleimide group may have the structure: o ; The cyclooctyne group may have thepreferably, the attachment group Li is formed by a reaction comprising at least one reactive group; the attachment group is formed by reacting: a first reactive group that is attached to the conjugate linker, and a second reactive group that is attached to the antibody or antigen-binding fragmentthereof or is an amino acid residue of the antibody or antigen-binding fragment thereof; optionally, at least one of the reactive groups comprises: a thiol, a maleimide, a haloacetamide, an azide, an alkyne, a cyclcooctene, a triaryl phosphine, an oxanob ornadiene, a cyclooctyne, a diaryl tetrazine, a monoaryl tetrazine, a norbornene, an aldehyde, a hydroxyl amine, a hydrazine,wherein: each R31is independently selected from H and Ci-6 alkyl; each R41is 2-pyridyl or 4-pyridyl; each R51is independently selected from H, Ci-6 alkyl, F, Cl, and -OH; each R61is independently selected from H, Ci-6 alkyl, F, Cl, -NH2, -OCH3, -OCH2CH3, -N(CH3)2, -CN, -NO2 and -OH; each R71is independently selected from H, C1-6 alkyl, fluoro, benzyloxy substituted with -C(=O)OH, benzyl substituted with -C(=O)OH, C1-4 alkoxy substituted with -C(=O)OH and C1-4 alkyl substituted with -C(=O)OH; the first reactive group and second reactive group comprise: optionally, a thiol and a maleimide; a thiol and a haloacetamide; a thiol and a vinyl sulfone; a thiol and an aziridine; an azide and an alkyne; an azide and a cyclooctyne; an azide and a cyclooctene; an azide and a triaryl phosphine; an azide and an oxanobomadiene; a diaryl tetrazine and a cyclooctene; a monoaryl tetrazine and a nonbornene; an aldehyde and a hydroxyl amine; an aldehyde and a hydrazine; an aldehyde and NH2-NH-C(=0)-; a ketone and a hydroxylamine; a ketone and a hydrazine; a ketone and NH2-NH-C(=0)-; a hydroxylamine andanaminea CoA or CoA analogue and a serine residue; optionally wherein, the attachment group comprises a group selected from:wherein:R32is H, Ci-4 alkyl, phenyl, pyrimidine or pyridine;R35is H,CI-6 alkyl, phenyl or C1-4 alkyl substituted with 1 to 3-OH groups;each R72is independently selected from H, C1-6 alkyl, fluoro, benzyloxy substituted with - C(=O)OH, benzyl substituted with-C(=O)OH, C1-4 alkoxy substituted with -C(=O)OH and Ci- 4 alkyl substituted with -C(=O)OH;R37is independently selected from H, phenyl and pyridine; Q is 0, 1, 2 or 3R81is H or methyl; and R91is H, -CH3or phenyl.

10. The antibody-drug conjugate of any one of claims 1-9, wherein L2 comprises a butanoyl, pentanoyl, hexanoyl, heptanoyl, octanoyl group, a polyoxyethylene (PEG) group or -CO-CH2- CH2-PEG-, -NH-CH2-CH2-PEG-, -C(O)-N(CH3)-CH2-CH2-N(CH3)-C(O)-, -C(O)-CH2-CH2- PEG-NH-C(O)CH2-CH2- ; optionally, the PEG group may be selected from PEG1, PEG2, PEG3, PEG4, PEG5, PEG6, PEG7, PEG8, PEG9, PEG10, PEGU, PEG12, PEG13, PEG14, and PEG15; optionally, the bridging spacer group is -CH2CH2-O-CH2CH2-CO-, -C(O)-N(CH3)-CH2-CH2-N(CH3)-C(O)-,wherein each n2 is an integer from 1 to 12; optionally, L2 is a bridging spacer comprising:*-C(=O)(CH2)MO(CH2)M-**;*-C(=O)((CH2)MO)T(CH2)N-**;*-C(=O)(CH2)M-**;*-C(=O)NH((CH2)MO)T(CH2)N-**;*-C(=O)O(CH2)MC(=O)NH(CH2)M-**;*-C(=O)(CH2)MNH(CH2)M-**;*-C(=O)(CH2)MNH(CH2)NC(=O)-* * ;*-C(=O)(CH2)MXL2(CH2)M-**;*-C(=O)((CH2)MO)T(CH2)NXL2(CH2)N-**;*-C(=O)(CH2)MNHC(=O)(CH2)N-* * ;*-C(=O)((CH2)MO)T(CH2)NNHC(=O)(CH2)N-**;*-C(=O)(CH2)MNHC(=O)(CH2)NXL2(CH2)N-* * ;*-C(=O)(CH2)MO)T(CH2)MNHC(=O)(CH2)NXL2(CH2)N-**;*-C(=O)((CH2)MO)T(CH2)NC(=O)NH(CH2)M-**;where the * of L2 indicates the point of direct or indirect attachment to L3, and the ** of L2 indicates the point of direct or indirect attachment to Li wherein XL2 isand each M is independently se- lected from 1, 2, 3, 4, 5, 6, 7, 8, 9 and 10; each N is independently selected from 1, 2, 3, 4, 5, 6, 7, 8, 9 and 10; and each T is independently selected from 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29 and 30.

11. The antibody-drug conjugate of any one of claims 1-10, wherein L3 comprises 1 to 2, 1 to 3, 1 to 4, 1 to 6, 1 to 8, 1 to 10 or 1 to 12 amino acid residues; optionally wherein the amino acid residues are selected from L-glycine (Gly), L-valine (Vai), L-citrulline(Cit), L-cysteic acid (sulfo-Ala), L-lysine (Lys), L-isoleucine (lie), L-phenylalanine (Phe), L-methionine (Met), L- asparagine (Asn), L-proline(Pro), L-alanine (Ala), L-leucine (Leu), L-tryptophan (Trp), and L- tyrosine (Tyr); for example, the peptide group may comprise Val-Cit, Vai-Ala, Val-Lys, and / or sulfo-Ala-Val-Ala; further optionally wherein L3 comprises a group:

12. The antibody-drug conjugate of any one of claims 1-11, , wherein L4comprises para-ami- nobenzyl-carbamate, para-aminobenzyl-ammonium,para-amino-(sulfo)benzyl-ammonium, para-amino-(sulfo)benzyl-carbamate, para-amino-(alkoxy-PEG-alkyl)benzyl-carbamate, para-amino-(polyhydroxycarboxytetrahydropyranyl)alkyl-benzyl-carbamate or para-amino- (polyhydroxy carboxytetrahydropyranyl)alkyl-benzyl-ammonium;13. The antibody-drug conjugate of any one of claims 1-12, wherein the cleavable group L4 has formula (IVA) :, wherein-G1-G2-G3- is a self-immolative spacer;Gi is a bond, -NH-, or -NH-Ph-;G2 is a bond, methylene, neopentylene, or a C2-3 alkenylene;G3 is a bond, -OC(=O)-,OC(=O)N(CH3)CH2CH2N(CH3)C(=O)-, or -OC(=O)N(CH3)C(Rga)2C(Rga)2N(CH3)C(=O)-, wherein each Rgais independently H, C1-6 alkyl, or C3-8 cycloalkyl; G4is a spacer moiety; and G5 is a hydrophilic moiety;G4is a spacer moiety having the structure:, , wherein:W4iis -CH2-, -CH2O-, -CH2N(Rbb)C(=O)O-, -NHC(=O)C(Rbb)2NHC(=O)O-, - NHC(=O)C(Rbb)2NH-, -NHC(=O)C(Rbb)2NHC(=O)-, -CH2N(X4i-G5)C(=O)O-, -C(=O)N(X4I- G5)-, -CH2N(X4i-G5)C(=O)-, -C(=O)NRbb-, -C(=O)NH-, -CH2NRbbC(=O)-,CH2NRbbC(=O)NH-, -CH2NRbbC(=O)NRbb-, -NHC(=O)-, -NHC(=O)O-, -NHC(=O)NH-, - OC(=O)NH-, -S(O)2NH-, -NHS(O)2-, -C(=O)-, -C(=O)O- or -NH-, wherein each Rbbis independently selected from H, C1-6 alkyl, and C3-8 cycloalkyl; andX41 is a bond, triazolyl or -CH2-triazolyl-, -CH2-triazolyl-Ci-4alkylene-OC(O)NHS(O)2NH-, -C4-6cycloalkylene-OC(O)NHS(O)2NH-, -(CH2CH2O)n’-C(O)NHS(O)2NH-, -(CH2CH2O)n’- C(O)NHS(O)2NH-(CH2CH2O)n’-, -CH2-triazolyl-Ci-4alkylene-OC(O)NHS(O)2NH- (CH2CH2O)n’-, or -C4-6 cycloalkylene-OC(O)NHS(O)2NH-(CH2CH2O)n’-, wherein each n’” independently is 1, 2, or 3;Gs comprises a polyethylene glycol of formula:wherein Rn’ is H, -CH3CH2CH2NHC(=O)ORga, -CH2CH2NHC(=O)Rga, or -CH2CH2C(=O)ORga, Rmis OH, -OCH3, -CH2CH2NHC(=O)ORga, -CH2CH2NHC(=O)Rga, or -OCH2CH2C(=O)ORga; Rgais independently selected from H, C1-6 alkyl, and C3-8 cycloalkyl; each of m’ and n’ is an integer between 2 and 25 (e.g., between 3 and 25); or a polysarcosin having the structurewherein n” is an integer between 3 and 25; and Rgbis H, -CH3 or -14. The antibody-drug conjugate of any one of claims 1-13, wherein the antibody-drug conjugate is formed from a compound selected from:, or a stereoisomer, a pharmaceutically acceptable salt, a metabolite, a prodrug, or a solvate thereof, or a solvate of the pharmaceutically acceptable salt thereof, wherein D is any one of the compounds selected from Table 1C or ID.

15. The antibody-drug conjugate of any one of claims 1-13, wherein the antibody-drug conjugate comprises the antibody or antigen-binding fragment thereof and the linker-drug group, Ab-[L1-L2-L3-L4-D], which comprises a formula selected from:

16. The antibody-drug conjugate of any one of claims 1-15, wherein the antibody or antigenbinding fragment thereof binds to a target antigen on a cancer cell, wherein the target antigen is EphA2 or B7-H3 (CD276), and wherein the antibody or antigen-binding fragment thereof is an anti-EphA2 antibody or antigen-binding fragment thereof, and the anti-EphA2 antibody or antigen- binding fragment thereof comprises three heavy chain CDRs and three light chain CDRs are selected from: heavy chain CDR1(HCDR1) sequence consisting of SEQ ID NO: 17, heavy chain CDR2 (HCDR2) sequence consisting of SEQ ID NO: 18, heavy chain CDR3 (HCDR3) sequence consisting of SEQ ID NO: 19; light chain CDR1 (LCDR1) sequence consisting of SEQ ID NO:26, light chain CDR2(LCDR2) sequence consisting of SEQ ID NO: 27, and light chain CDR3 (LCDR3) sequence consisting of SEQ ID NO:28; heavy chain CDR1 (HCDR1) sequence consisting of SEQ ID NO:20, heavy chain CDR2 (HCDR2) sequence consisting of SEQ ID NO:21, heavy chain CDR3 (HCDR3 consisting of SEQ ID NO: 19; light chain CDR1 (LCDR1) sequence consisting of SEQ ID NO:29, light chain CDR2 (LCDR2) sequence consisting of SEQ ID NO:30, and light chain CDR3 (LCDR3) sequence consisting of SEQ ID NO:31; heavy chain CDR1 (HCDR1) sequence consisting of SEQ ID NO:22, heavy chain CDR2 (HCDR2) sequence consisting of SEQ ID NO:23, heavy chain CDR3 (HCDR3) sequence consisting of SEQ ID NO:24; light chain CDR1 (LCDR1 consisting of SEQ ID NO:32, light chain CDR2 (LCDR2) sequence consisting of SEQ ID NO: 27, and light chain CDR3 (LCDR3) sequence consisting of SEQ ID NO:31; and heavy chain CDR1 (HCDR1) sequence consisting of SEQ ID NO:25, heavy chain CDR2 (HCDR2) sequence consisting of SEQ ID NO:21, heavy chain CDR3 (HCDR3) sequence consisting of SEQ ID NO: 19; light chain CDR1 (LCDR1) sequence consisting of SEQ ID NO:29, light chain CDR2 (LCDR2) sequence consisting of SEQ ID NO:30, and light chain CDR3 (LCDR3) sequence consisting of SEQ ID NO:31; optionally wherein the anti-EphA2 antibody or antigen-binding fragment thereof comprises:a heavy chain variable region comprising the amino acid sequence of SEQ ID NO: 11, and a light chain variable region comprising the amino acid sequence of SEQ ID NO: 12; further optionally wherein the anti-EphA2 antibody or antigen-binding fragment thereof comprises: a heavy chain comprising the amino acid sequence of SEQ ID NO:3, and a light chain comprising the amino acid sequence of SEQ ID NO:5.

17. The antibody-drug conjugate of any one of claims 1-15, wherein the antibody or anti -genbinding fragment thereof binds to a target antigen on a cancer cell, the antibody or antigen-binding fragment thereof is an anti-B7-H3 (CD276) antibody or antigen-binding fragment; and the anti-B7-H3 (CD276) antibody comprises three heavy chain CDRs and three light chain CDRs selected from the group consisting of: heavy chain CDR1 (HCDR1) sequence consisting of SEQ ID NO:33, heavy chain CDR2 (HCDR2) sequence consisting of SEQ ID NO:34, heavy chain CDR3 (HCDR3) sequence consisting of SEQ ID NO:35; light chain CDR1 (LCDR1) sequence consisting of SEQ ID NO:42, light chain CDR2 (LCDR2) sequence consisting of SEQ ID NO:43, and light chain CDR3 (LCDR3) sequence consisting of SEQ ID NO:44; heavy chain CDR1 (HCDR1) sequence consisting of SEQ ID NO:36, heavy chain CDR2 (HCDR2) sequence consisting of SEQ ID NO:37, heavy chain CDR3 (HCDR3) sequence consisting of SEQ ID NO:35; light chain CDR1 (LCDR1) sequence consisting of SEQ ID NO:45, light chain CDR2 (LCDR2) sequence consisting of SEQ ID NO:46, and light chain CDR3 (LCDR3) sequence consisting of SEQ ID NO: 47; heavy chain CDR1 (HCDR1) sequence consisting of SEQ ID NO:38, heavy chain CDR2 (HCDR2) sequence consisting of SEQ ID NO:39, heavy chain CDR3 (HCDR3) sequence consisting of SEQ ID NO:40; light chain CDR1 (LCDR1) sequence consisting of SEQ ID NO:48, light chain CDR2 (LCDR2) sequence consisting of SEQ ID NO:43, and light chain CDR3 (LCDR3) sequence consisting of SEQ ID NO: 47; and heavy chain CDR1 (HCDR1) sequence consisting of SEQ ID NO:41, heavy chain CDR2 (HCDR2) sequence consisting of SEQ ID NO:37, heavy chain CDR3 (HCDR3) sequence consisting of SEQ ID NO:35; light chain CDR1 (LCDR1) sequence consisting of SEQ ID NO:45, light chain CDR2 (LCDR2) sequence consisting of SEQ ID NO:46, and light chain CDR3 (LCDR3) sequence consisting of SEQ ID NO: 47;optionally wherein the anti-B7-H3 antibody comprises a heavy chain variable region comprising the amino acid sequence of SEQ ID NO: 13, and a light chain variable region comprising the amino acid sequence of SEQ ID NO: 14; further otpionaly wherein the anti-B7-H3 (CD276) antibody comprises: a heavy chain comprising the amino acid sequence of SEQ ID NO:7 and a light chain comprising the amino acid sequence of SEQ ID NO: 8.

18. The antibody-drug conjugate of any one of claims 1-15, wherein the antibody or anti-genbinding fragment thereof binds to a target antigen on a cancer cell, wherein the antibody or antigen-binding fragment thereof binds to a target antigen on a can-cer cell, the antibody or antigenbinding fragment thereof is an anti-B7-H3 (CD276) antibody or antigen-binding fragment; and the anti-B7-H3 (CD276) antibody comprises three heavy chain CDRs and three light chain CDRs selected from the group consisting of: heavy chain CDR1 (HCDR1) sequence consisting of SEQ ID NO:49, heavy chain CDR2 (HCDR2) sequence consisting of SEQ ID NO:50, heavy chain CDR3 (HCDR3) sequence consisting of SEQ ID NO:51; light chain CDR1 (LCDR1) sequence consisting of SEQ ID NO:58, light chain CDR2 (LCDR2) sequence consisting of SEQ ID NO:59, and light chain CDR3 (LCDR3) sequence consisting of SEQ ID NO:60; heavy chain CDR1(HCDR1) sequence consisting of SEQ ID NO:52, heavy chain CDR2 (HCDR2) sequence consisting of SEQ ID NO:53, heavy chain CDR3 (HCDR3) sequence consisting of SEQ ID NO:51; light chain CDR1 (LCDR1) sequence consisting of SEQ ID NO:61 light chain CDR2 (LCDR2) sequence consisting of SEQ ID NO:62, and light chain CDR3 (LCDR3) sequence consisting of SEQ ID NO: 63; heavy chain CDR1 (HCDR1) sequence consisting of SEQ ID NO:54, heavy chain CDR2 (HCDR2) sequence consisting of SEQ ID NO:55, heavy chain CDR3 (HCDR3) sequence consisting of SEQ ID NO:56; light chain CDR1 (LCDR1) sequence consisting of SEQ ID NO:64, light chain CDR2 (LCDR2) sequence consisting of SEQ ID NO:59, and light chain CDR3 (LCDR3) sequence consisting of SEQ ID NO: 63; and heavy chain CDR1 (HCDR1) sequence consisting of SEQ ID NO:57, heavy chain CDR2 (HCDR2) sequence consisting of SEQ ID NO:53, heavy chain CDR3 (HCDR3) sequence consisting of SEQ ID NO:51; light chain CDRl(LCDRl) sequence consisting of SEQ ID NO:61, light chain CDR2 (LCDR2) sequence consisting of SEQ ID NO:62, and light chain CDR3(LCDR3) sequence consisting of SEQ ID NO: 63; optionally wherein the anti-B7-H3 (CD276) antibody comprises: a heavy chain variable region comprising the amino acid sequence of SEQ ID NO: 15, and a light chain variable region comprising the amino acid sequence of SEQ ID NO: 16; further optionally wherein, the anti-B7-H3 (CD276) antibody comprises: a heavy chain comprising the amino acid sequence of SEQ ID NO:9, and the light chain comprising the amino acid sequence of SEQ ID NO: 10.

19. A composition comprising multiple copies of the antibody-drug conjugate of any one of claims 1 to 18, wherein the average p of the antibody-drug conjugates in the composition is from about 2 to about 16, e.g., about 2 to about 8, e.g., about 2 to about 4.

20. A pharmaceutical composition comprising the antibody-drug conjugate of any one of claims 1 to 18 and a pharmaceutically acceptable carrier.

21. A method of treating a cancer in a subject, comprising administering to the subject in need thereof a therapeutically effective amount of the antibody-drug conjugate of any one of claims 1 to 18 or the composition of claim 19 or 20.

22. The method of claim 21, wherein the cancer is a tumor or a hematological cancer, optionally, the cancer is a breast cancer including ER positive breast cancer, multiple myeloma, plasma cell myeloma, leukemia, lymphoma, sarcoma, gastric or stomach cancer, acute myeloid leukemia, bladder cancer, brain cancer, bone marrow cancer, cervical cancer, chronic lymphocytic leukemia, colorectal cancer, pancreatic cancer, esophageal cancer, hepatocellular cancer, lymphoblastic leukemia including acute lymphoblastic leukemia, follicular lymphoma, lymphoid malignancies of T-cell or B-cell origin, metastatic castration resistant prostate cancer, bladder urothelial carcinoma, melanoma, myelogenous leukemia, myeloma, oral cancer, ovarian cancer, non-small cell lung cancer, prostate cancer, small cell lung cancer, spleen cancer, or head and neck cancer.

23. A method of reducing or inhibiting the growth of a tumor in a subject, comprising administering to the subject a therapeutically effective amount of the antibody -drug conjugate of anyone of claims 1 to 18.

24. The method of claim 22 or 23, wherein the hematological cancer is chronic lymphocytic leukemia (CLL), follicular lymphoma, mantle cell lymphoma, diffuse large B-cell lymphoma, acute lymphoblastic leukemia(ALL), acute myeloid leukemia(AML), chronic lymphocytic leu- kemia(CLL), chronic myelogenous leukemia (CML), chronic myelomonocytic leukemia (CMML), acute monocytic leukemia (AMoL), Hodgkin's lymphoma, non -Hodgkin's lymphoma or myelodysplasia syndrome (MDS).

25. The method of any one of claims 21-24, wherein administration of the antibody-drug conjugate, composition, or pharmaceutical composition reduces or inhibits the growth of the tumor or hematological cancer by at least about 10%, at least about 20%, at least about 30%, at least about 40%, at least about 50%, at least about 60%, at least about 70%, at least about 80%, at least about 90%, at least about 95%, or at least about 99%.

26. The method of any one of claims 21-25, wherein the antibody-drug conjugate is administered as monotherapy.

27. The method of any one of claims 24-26, wherein the antibody-drug conjugate is administered adjunctive to another therapeutic agent or radiation therapy.

28. The method of claim 23, wherein the antibody-drug conjugate is administered in an amount effective to sensitize the tumor cells to one or more additional therapeutic agents and / or radiation therapy.

29. The method of any one of claims 21-28, further comprising administering to the subject in need thereof at least one additional therapeutic agent.

30. The method of any one of claims 21-29, wherein the cancer is a Ras-driven cancer and the cancer comprises a Ras mutation.

31. The method of claim 30, wherein the Ras mutation is at a position selected from the groupconsisting of G12C, G12D, G12V, G12A, G12R, G12S, G13C, G13D, Q61H, Q61R and Q61L, or a combination thereof.

32. The method of any one of claims 30-31, wherein the Ras protein is KRAS.

33. The method of any one of claims 21-32, wherein the method is provided of treating a Ras protein-related disorder in a subject in need thereof.

34. The method of any one of claims 21-33, wherein the method further comprises administering an additional anti-cancer therapy.

35. The method of claim 34, wherein the additional anti-cancer therapy is an EGFR inhibitor, a second Ras inhibitor, a SHP2 inhibitor, a S0S1 inhibitor, a Raf inhibitor, a MEK inhibitor, an ERK inhibitor, a P13K inhibitor, a PTEN inhibitor, an AKT inhibitor, an mTORCl inhibitor, a BRAF inhibitor, a PD-L1 inhibitor, a PD-1 inhibitor, a CDK4 / 6 inhibitor, a HER2 inhibitor, or a combination thereof.

36. Use of the antibody-drug conjugate of any one of claims 1-18, or the composition of claim 19 or 20, in the method of any one of claims 21-35.

37. Use of the antibody-drug conjugate of any one of claims 1-18, or the composition of claim 19 or 20, in the manufacture of a medicament for the use in the method of any one of claims 21- 35.

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